Design, synthesis, and structure-activity relationship of a novel series of GluN2C-selective potentiators

Article abstract of DOI:10.1021/jm401695d

NMDA receptors are tetrameric complexes composed of GluN1 and GluN2A-D subunits that mediate a slow Ca²⁺-permeable component of excitatory synaptic transmission. NMDA receptors have been implicated in a wide range of neurological diseases and thus represent an important therapeutic target. We herein describe a novel series of pyrrolidinones that selectively potentiate only NMDA receptors that contain the GluN2C subunit. The most active analogues tested were over 100-fold selective for recombinant GluN2C-containing receptors over GluN2A/B/D-containing NMDA receptors as well as AMPA and kainate receptors. This series represents the first class of allosteric potentiators that are selective for diheteromeric GluN2C-containing NMDA receptors.

Full text of DOI:10.1021/jm401695d

Article
pubs.acs.org/jmc
Open Access on 02/10/2015
Design, Synthesis, and Structure−Activity Relationship of a Novel
Series of GluN2C-Selective Potentiators
Sommer S. Zimmerman,† Alpa Khatri,‡ Ethel C. Garnier-Amblard,†,‡ Praseeda Mullasseril,‡
Natalie L. Kurtkaya,‡ Stefka Gyoneva,‡ Kasper B. Hansen,‡ Stephen F. Traynelis,*,‡
and Dennis C. Liotta*,†
†Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
‡Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, 1510 Clifton Road, Atlanta,
Georgia 30322, United States
S
* Supporting Information
ABSTRACT: NMDA receptors are tetrameric complexes composed of GluN1 and GluN2A−D
subunits that mediate a slow Ca2+-permeable component of excitatory synaptic transmission. NMDA
receptors have been implicated in a wide range of neurological diseases and thus represent an
important therapeutic target. We herein describe a novel series of pyrrolidinones that selectively
potentiate only NMDA receptors that contain the GluN2C subunit. The most active analogues tested
were over 100-fold selective for recombinant GluN2C-containing receptors over GluN2A/B/D-
containing NMDA receptors as well as AMPA and kainate receptors. This series represents the first
class of allosteric potentiators that are selective for diheteromeric GluN2C-containing NMDA
receptors.
(CIQ), 4-[6-methoxy-2-[(1E)-2-(3-nitrophen yl)ethenyl]-4-oxo-
3(4H)quinazolinyl]benzoic acid (QNZ46), 5-(4-bromophenyl)-3-
(1,2-dihydro-6- methyl-2-oxo-4-phenyl-3-quinolinyl)-4,5-dihydro-
g-oxo-1H-pyrazole-1-butanoic acid (DQP1105), and (2R,3S)-1-
(phenanthrenyl-3-carbonyl)piperazine-2,3-dicarboxylic acid
(UBP141).11 Here, we describe the development of the first
class of positive allosteric modulators that are selective for GluN2C-
containing NMDA receptors over GluN2A-, GluN2B-, and
GluN2D-containing receptors.
To identify this class of ligands, a GluN1/GluN2C cell line
and multiwell fluorescence-based assay were developed to enable
screening of compound libraries for NMDA receptor modu-
lators. We screened two commercial diversity libraries to identify
several compounds that modulate GluN2C-containing NMDA
receptors. One of these screening hits established a novel class of
subunit-selective potentiators for recombinant GluN1/GluN2C
NMDA receptors, exemplified by compound 1 (Figure 1).
Optimization of the initial lead pyrrolidinone scaffold involved
the development of a structure−activity relationship, which led
to the identification of a novel series of compounds with potency
in the low micromolar range and high selectivity for recombinant
GluN2C-containing receptors over GluN2A/B/D-containing
NMDA receptors. In addition, no detectable potentiation was
observed at recombinant AMPA, kainate, GABA, glycine,
serotonin, nicotinic, or purinergic receptors (data not shown).
INTRODUCTION
■
N-Methyl-D-aspartate (NMDA) receptors are members of the
family of ionotropic glutamate receptors that mediate excitatory
neurotransmission. NMDA receptors are tetrameric assemblies
of two GluN1 subunits, which bind the coagonist glycine,
and two GluN2 subunits, which bind glutamate.1 Both GluN1
and GluN2 subunits share a similar architecture, comprised of
an extracellular amino-terminal domain (ATD), an extracellular
ligand-binding domain (LBD), a transmembrane domain (TMD),
and an intracellular carboxyl-terminal domain (CTD).2 The GluN2
subunit is encoded by four distinct gene products (GluN2A-D),
which have temporally and spatially distinct expression patterns in
the brain.3 The GluN2 subunit controls pharmacological character-
istics such as agonist sensitivity, deactivation time course, mean
open time, and open probability.2,3b,4
The distinct anatomical locations of the GluN2 subunits could
allow subunit-selective modulators (either potentiators or inhib-
itors) to target specific brain regions for therapeutic gain. NMDA
receptors are thought to play a role in neuronal development,
learning, and memory formation,5 as well as being implicated in
ischemia,6 dementia,7 schizophrenia,8 treatment resistant depres-
sion,9 and Parkinson’s disease.10 Recently discovered modulators
have demonstrated selectivity for GluN2A, 3-chloro-4-fluoro-
N-[4-[[2-(phenylcarbonyl)hydrazino]carbonyl]benzyl]-
benzenesulfonamide (TCN201); GluN2A/GluN2B, 9-cyclopro-
pylphenanthrene-3-carboxylic acid (UBP710); and GluN2C/
GluN2D, (3-chlorophenyl) [3,4-dihydro-6,7-dimethoxy-1-[(4-
methoxyphenoxy)methyl]-2(1H)-isoquinolinyl]methanone
Received: November 5, 2013
Published: February 10, 2014
© 2014 American Chemical Society
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a
Scheme 2. Route for the Synthesis of Pyruvate Derivatives
Figure 1. Structure of screening hit. Chemical structure of methyl
4-(1-(2-(1H-indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-2,5-dihydro-
1H-pyrrol-2-yl)benzoate (compound 1) that was identified as a positive
modulator using a fluorescence-based screen of compound libraries in a
cell line expressing diheteromeric GluN1/GluN2C NMDA receptors.
a
These analogues represent a novel class of NMDA receptor
modulators that are highly selective for diheteromeric GluN1/
GluN2C receptor subtypes and provide a useful tool with which
to evaluate the physiological role of GluN2C in normal and
neuropathological conditions.
Reaction conditions: (a) diethyl oxalate, NaOEt, EtOH, 0 °C to rt,
4 h, 15% to >99% (procedure II); (b) TIPSCl, imidazole, rt, 6 h,
>99%; (c) diethyl oxalate, NaOEt, EtOH, 0 °C to rt, 4 h, 28%
(procedure II); (d) TBAF, 0 °C to rt, 1 h, 43%.
triisopropyl chloride (TIPSCl) before the addition of diethyl
oxalate. Standard deprotection afforded the target pyruvate (21).
Analogues containing disubstituted A-rings were synthesized
using several procedures based on the commercially available
precursors (Scheme 3). Benzaldehydes 32−41 were prepared
from methyl esters 145−154. Dibromination and hydrolysis
afforded analogues 32 and 33.12 Suzuki coupling between
dibutyl vinylboronate and the appropriately substituted methyl
4-iodobenzoate, followed by ozonolysis, gave phenols 34
and 35. Alternatively, addition of a Grignard reagent and N,N-
dimethylformamide (DMF) led to isolation of benzaldehyde
36. A palladium-catalyzed formylation was used to access
benzaldehydes 37−40.13 Finally, anisole 41 was prepared via a
dialkylation of both the hydroxyl and carboxylic acid functional
groups.
RESULTS
■
Chemistry. We used bioinformatic searches and medicinal
chemistry to obtain analogues for our initial screening hit,
compound 1 (see below). Both commercially available analogues
and compounds synthesized via a mi-component Biginelli-like
reaction (Scheme 1) were assessed at 30 μM. We determined
the EC50 and maximal potentiation from concentration−
effect curves for compounds that showed potentiation of more
than 120% of control at 30 μM. No compounds in this class
potentiated GluN2A-, GluN2B-, or GluN2D-containing recep-
tors, suggesting remarkable selectivity for this class (see below).
Modifications were made at either R1, the A-ring, or the B-ring
using alternative methodologies to access the appropriate
precursor.
Addition of diethyl oxalate and sodium ethoxide to a methyl
ketone generated a series of pyruvate analogues (3−20)
containing modifications at R1 (Scheme 2). Only when R1 was
a phenol was it necessary to first protect the hydroxyl group with
Benzaldehydes containing a para-amide (42−44) or para-
ester (45−47) substituent were synthesized as illustrated in
Scheme 4. Primary amide 42 was synthesized from carboxylic
acid 155 by generating the acid chloride in situ. Standard amide
a
Scheme 1. Synthesis of 1H-Pyrrol-2(5H)-ones
a
Reaction conditions: PPTS, rt, 1−24 h, 2% to >99% (procedure I). Final compounds 161−180, in which either the A or B ring is replaced, were
also prepared using these conditions.
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a
Scheme 3. Synthetic Routes to Access Substituted Benzaldehydes 32−41
a
Reaction conditions: (a) 2.0 equiv NBS, (PhCOO)2, reflux, 4 h, then AgNO3, rt, 3 h, 38−63%; (b) dibutyl vinylboronate, 5 mol % (PPh3)2PdCl2,
NaCO3, reflux, 2 h, 68−80%; (c) O3; then (CH3)2S, −78 °C to rt, 12 h, 60−87%; (d) i-PrMgCl, DMF, −15 °C to rt, 3 h, 70%; (e) CO(g)
(PPh3)2PdCl2, NaCO3, 110 °C, 8−24% (procedure IV); (f) CH3I, K2CO3, rt, 3 h, 58%.
,
Scheme 4. Routes for the Synthesis of Amides 42−44 and
160 were synthesized from enol 106 using the appropriate acyl
chloride and triethylamine.
a
Esters 45−47
Pyrrolidinones Selectively Potentiate GluN2C-Con-
taining Receptors. A fluorescence-based screen of 57504
compounds obtained from Asinex and ChemDiv libraries was
performed in BHK cells with inducible expression of GluN1/
GluN2C receptors. Hits were defined as compounds that
produced changes that were 2.5 standard deviations away
from the average response to maximally effective agonist (i.e.,
glutamate and glycine) application. In this primary screen, 1% of
the compounds met these criteria. Compounds that showed
potentiation were further evaluated for their ability to produce
responses in cells with no NMDA receptor expression (in
uninduced cells) in order to identify false positive hits. False
positive results can occur when the compounds directly release
Ca2+ from intracellular stores, enhance Ca2+ channel function,
possess fluorescent properties in the excitation/emission range
of Fluo-4, or otherwise produce an increase in intracellular Ca2+
signal independent of NMDA receptor activation. Compounds
that showed potentiation of glutamate responses in induced
cells and did not produce responses in uninduced cells were
subsequently studied by two-electrode voltage-clamp recording
of NMDA receptor responses.
a
Reaction conditions: (a) Vilsmeier reagent, aq NH3, 0 °C, 16 h, 30%;
(b) R2aR2bN where R2a = H and R2b = Me or where R2a = R2b = Me,
DMAP, EDCI, 0 °C to rt, 24 h, 14−51%; (c) R2I where R2 = Et or
R2 = i-Pr, K2CO3, rt, 4 h, 24−87%; (d) (CH3)2NCH(Ot-Bu)2, reflux,
11/2 h, 81%.
coupling conditions were employed for the preparation of
amides 43 and 44. Alkylation of carboxylic acid 155 with the
appropriate alkyl iodide afforded esters 45 and 46, while t-butyl
ester 47 was prepared using a method previously described.14
An alternative strategy was used to synthesize analogues
containing a modification at R11 starting from pyrrolidinones 1
and 106 (Scheme 5). Protection of analogue 1 with trimethylsilyl
diazomethane afforded methoxy 156. Amine 157 was generated
by reaction with ammonium formate. Esterification of 1 with
acetic anhydride gave acetate 158. Alternatively, esters 159 and
A single compound was found to selectively potentiate
the GluN1/GluN2C receptors and did not show any activity
at GluN2A/B/D-containing NMDA receptors expressed in
Xenopus laevis oocytes (Figure 2A). Compound 1, which contains
a pyrrolidinone core motif, potentiated GluN1/GluN2C
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a
Scheme 5. Route to Modifications at R11
a
Reaction conditions: (a) TMSCH2N2, rt, 5 h, 46%; (b) NH4HCO2, reflux, 3 h, 14%; (c) Ac2O, pyridine, rt, 61/2 h, 7%; (d) R11C(O)Cl where
R11 = CH2CH2CH3 or R11 = CHCH2, TEA, −30 °C, 2 h, 20−35%.
responses to 238 8.2% of control at 100 μM with an EC50 of
24 2.4 μM (n = 12) (Figure 2B). Compound 1 had no agonist
activity on its own in that it did not induce current responses in
oocytes expressing GluN1/GluN2C in the absence of glutamate
and glycine (n = 4). In addition, 30 μM of compound 1 did not
potentiate homomeric recombinant GluA1 AMPA receptor
responses (97 1.1% control, n = 16). In addition, 120 μM of
compound 1 did not potentiate homomeric GluK2 recombinant
kainate receptors (95 2.3% of control, n = 5).
Compound 1 (68 μM) did not detectably alter the EC50 of
glycine or glutamate (n = 4−6; Figure 2C). Additionally, the
reversal potential of glutamate and glycine induced current
responses was unchanged in the presence (−5.0 + 1.2 mV, n = 6)
or absence (−5.1 + 0.8 mV, n = 6) of compound 1. Potentiation
was not significantly different at −40 mV (202 11%) compared
to +30 mV (180 12%; p = 0.2679; paired t test), indicating that
potentiation of GluN2C-containing receptors by compound 1 at
20 μM was voltage-independent (n = 6; Figure 2D).
group, displayed a considerably higher potency at GluN2C-
containing receptors (7.0 0.9 μM) but caused significant
inhibition of GluN2A-, GluN2B-, and GluN2D-containing
receptors at 100 μM (responses were 76 2.0%, 42 1.6%,
and 48 2.4% of control, respectively, normalized to agonist
activated current). Such mixed-action modulators that potentiate
one subunit while inhibiting another are intriguing but of little
utility as pharmacological probes. Two compounds containing a
pyridine ring at R1 potentiated responses up to ∼200% with EC50
values of 12 1.9 μM (72) and 8.9 1.3 μM (73). Interestingly,
71, which contains a 2-substituted pyridine ring, was inactive at
all receptor subunits. These initial experiments confirmed the
ability of derivatives within this class to selectively potentiate
GluN2C-containing receptors compared to other NMDA
receptor subtypes.
Effect of A-Ring Modifications. Next, we evaluated the
effects of various A-ring substituents (Table 2) utilizing R1
substitutions shown to offer the desired activity. Positional
isomer analogues 81 and 82 were inactive at GluN1/GluN2C.
One compound, 84, which contains an ethyl ester at ring position
R2, displayed comparable potency compared to screening hit 1.
Analogues containing bulkier ester substituents (e.g., 85 with an
iso-propyl ester and 86 with a tert-butyl ester) led to inactivity.
A series of compounds containing ester isosteres including a
nitrile (87), nitro (88), amide (89−91), and sulfonamide (92
and 93) were also evaluated for their ability to potentiate
GluN2C-containing NMDA receptors. Unfortunately, none of
these analogues exhibited any activity.
Effect of Modifications to R1 on Potency at GluN2C-
Containing Receptors. We subsequently evaluated the
response to 30 μM of all pyrrolidinone analogues at GluN1/
GluN2A, GluN1/GluN2B, GluN1/GluN2C, and GluN1/
GluN2D and proceeded to determine the concentration−effect
curve when potentiation exceeded 120% of control. Exploration
of the effects of keto-linked R1 (Scheme 1; see Chemistry
section) substitutions on potentiation of GluN2C-containing
receptors in oocytes revealed that additional steric bulk was
tolerated, with only minimal improvements in potency (Table 1,
62−65). For example, replacement of R1 with a phenyl group, as
in 65, produced a small increase in potency (EC50 = 17 2.3)
accompanied by a modest decrease in maximal potentiation
compared to compound 1 (Table 1). Analogues containing
m-substituted phenyl rings (66−70) offered variable potentia-
tion, while analogues with o- and p-substituted phenyl rings were
inactive (data not shown). Notably, 66, with a meta-hydroxyl
A variety of substituents at A-ring positions R3 and R4 were
systematically tested while holding the para-methyl ester
constant at R2 (Table 3). Substitution at the meta position
(R3) revealed either a reduction in potency (95) or complete
inactivity (96−99). Evaluation of a series of ortho (R4) ring
substituents demonstrated a preference for electron donating
groups. For example, analogues containing an ortho-hydroxyl
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Figure 2. Compound 1 selectively potentiates the GluN1/GluN2C response. (A) Current traces for 1 at the GluN1/GluN2A, GluN1/GluN2B,
GluN1/GluN2C, and the GluN1/GluN2D receptors. (B) Compound 1 selectively potentiates the GluN1/GluN2C receptor to a fitted maximum of
275 10% with an EC50 of 24 2.4, n = 12. (C) The EC50 for glycine in the absence and presence of 1 is 0.20 0.01 μM (n = 6) and 0.16 0.02 μM
(n = 4), respectively. The EC50 for glutamate in the absence and presence of 1 is 0.8 0.07 μM (n = 8) and 1.2 0.04 μM (n = 6), respectively. The
presence of 1 did not shift the glycine or glutamate EC50 values significantly. (D) The reversal potential is −5.1 0.8 mV when activated by coagonists
(100 μM glutamate and 30 μM glycine) and is −5.0 1.2 mV (n = 6) when the GluN1/GluN2C receptor is potentiated by 1. The reversal potential was
not significantly shifted in the presence of 1, suggesting that potentiation is independent of membrane potential.
(100) exhibited potentiation with a modest increase in potency,
whereas ortho-chloro (103) or -fluoro (104) substituents were
slightly less active.
It is unclear whether the increase in potency observed for 111
can be ascribed to a steric effect or, alternatively, to a mildly
electropositive effect. Consistent with a steric effect, analogues
which contain larger R9 substituents such as R9 = OMe (112)
revealed a loss of potency compared to 111. Analogues
containing strongly electron withdrawing R9 substituents such
as R9 = F (109) also decreased the observed activity.
Effect of Combinatorial Modifications on Potency at
GluN2C-Containing Receptors. We subsequently evaluated
the effect of combining modifications at R1, the A-ring and the
B-ring that had previously demonstrated an improvement in
potency (Table 6). Substitution with either a meta- or para-
substituted pyridine ring at R1 and a para-ethyl ester at R2
revealed potentiation of GluN1/GluN2C responses with EC50
Effect of B-Ring Modifications. Replacement of the B-ring
with an assortment of acyclic, cyclic, and heterocyclic systems
generated a series of compounds that were evaluated for potency
and subunit selectivity while retaining optimal R1 and A-ring
substitutions (Table 4). Interestingly, substitution with a napthyl
derivative, as in 162, led to strong inhibition at all four subunits.
Replacement of the indole NH with an oxygen atom led only to
weak activity (163), suggesting the presence of a hydrogen bond
in the binding pocket. In all other instances, removal of the indole
led to complete inactivity (i.e., 164 and 165). These data suggest
that the indole functionality is preferred for activity.
This led us to examine B-ring substituents as an alternative
strategy to access increased potency. The data describing these
compounds is summarized in Table 5. Methylation of the
indole nitrogen led to inactivity (105), further suggesting the
importance of a hydrogen atom at this position in the binding
pocket. The best potency was obtained for analogues with
substitutions at B-ring position R9. Compound 111 demon-
strated an ability to selectively potentiate GluN2C-containing
NMDA receptors up to 218% with an EC50 value of 4.3 0.3 μM.
values of 8.2
0.9 μM (116) and 9.7
0.6 μM (117),
respectively. Modification of the B-ring and either R1 (R1 =
m-pyridine) or R2 (R2 = p-CO2Et) exhibited a similar increase in
on-target potency. For example, substitution with a methyl group
at R6 and a para-ethyl ester at R2, as in analogue 119, resulted in a
2-fold potency enhancement.
Effect of Linker Modifications on Potency of 1616-
Series. The original screening hit, 1, contains a two carbon
region linking the B-ring with the core pyrrolidinone. The linker
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Table 1. Optimization of Potency through Evaluation of Keto-Linked Substituents
a
Fitted EC50 values are shown for GluN1/GluN2C to two significant figures when potentiation at 30 μM of the test compound exceeded 120% of
control; values in parentheses are the fitted maximum response as a percentage of the initial glutamate (100 μM) and glycine (30 μM) response. Hill
slopes varied between 1.2 and 2.0. Data for active compounds at GluN1/GluN2C are from between 6 and 12 oocytes from 2−3 frogs for each
compound. When no effect was found (n = 3−15 oocytes), the lack of effect was confirmed by testing at 100 μM (data not shown, n ≥ 3 oocytes all
compounds). For all tables, GluN2 subunits were coexpressed with GluN1 in Xenopus oocytes and evaluated using two-electrode voltage-clamp
b
recordings. The response to 100 μM of test compound was greater than 140% of control.
modifications explored are illustrated in Table 7. Both shortening
(121) and extending (122) the linker eliminated all activity,
suggesting that the potency of pyrrolidinone analogues is highly
dependent on the length of the carbon linkage.
alcohol led to less potent analogues. For example, a 2-fold
decrease in potency was observed for acetate 158. In contrast,
propyl ester 159 maintained activity comparable to lead analogue
1, with an EC50 of 17 1.8 μM. These data suggest that enhance-
ments in potency cannot be gained though modifications of
the enol.
Effect of Absolute Configuration on Potency at GluN2C-
Containing Receptors. To enable evaluation of potential
stereoselectivity for pyrrolidinone analogues at GluN1/GluN2C,
we separated the enantiomers of 106 using a semipreparatory
Effect of Modifications to R11 on Potency at GluN2C-
Containing Receptors. Several modifications were made at R11
to determine the significance of the enol in controlling potency
and selectivity (Table 8). Replacement with an amine, as in 157,
led to a complete loss of potentiation at concentrations up to
100 μM. In most instances, compounds containing a protected
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Table 2. Optimization of A-Ring Substituents
a
Fitted EC50 values are shown for GluN1/GluN2C to two significant figures when potentiation at 30 μM of the test compound exceeded 120% of
control; values in parentheses are the fitted maximum response as a percentage of the initial glutamate (100 μM) and glycine (30 μM) response. Hill
slopes varied between 1.3 and 1.7. Data for active compounds at GluN1/GluN2C are from between 8 and 12 oocytes from 2−3 frogs for each
compound. When no effect was found (n = 3−11 oocytes), the lack of effect was confirmed by testing at 100 μM (data not shown, n ≥ 3 oocytes all
compounds).
OD-RH chiral HPLC column (see Chemistry Experimentals).
Each enantiomer was subjected to two-electrode voltage clamp
analysis in Xenopus laevis oocytes. The results, illustrated in
Figure 3, indicate that only one enantiomer (106a) is active and
may account for the activity of 106. Compound 106a potentiated
GluN2C response by 259 7.8% with an estimated EC50 value
of 18 0.6 μM (n = 6). In contrast, no activity was observed
for the other enantiomer (106b) (n = 6). The active analogue
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Table 3. Evaluation of Combinations of A-Ring Substituents
a
I30 μM/Icontrol (mean SEM %)
EC50 (max) μM (%)
#
R3
R4
GluN2A
GluN2B
GluN2C
GluN2D
GluN2C
95
OH
OMe
Me
Cl
H
81 1.7
98 3.3
108 3.4
88 4.3
99 4.1
107 3.9
102 6.1
101 1.8
103 3.9
93 2.5
79 1.2
80 1.8
91 2.5
95 5.1
83 2.2
86 3.8
83 0.3
95 4.2
87 1.7
96 2.0
123 2.5
92 2.4
90 3.0
86 1.4
86 0.4
83 1.5
93 5.3
88 1.9
100 3.1
85 1.9
90 0.6
91 1.1
29 2.8 (151)
96
H
97
H
88 2.1
98
H
113 4.2
114 3.3
173 3.0
132 3.3
129 3.6
139 2.8
123 3.4
99
F
H
100
101
102
103
104
H
OH
OMe
Me
Cl
15 0.6 (202)
46 19 (183)
35 1.4 (165)
36 3.0 (191)
37 2.6 (155)
H
H
H
H
F
a
Fitted EC50 values are shown for GluN1/GluN2C to two significant digits when potentiation at 30 μM of the test compound exceeded 120% of
control; values in parentheses are the fitted maximum response as a percentage of the initial glutamate (100 μM) and glycine (30 μM) response; Hill
slopes ranged between 1.3 and 1.8. Data for active compounds at GluN1/GluN2C are from between 3 and 12 oocytes from 2−3 frogs for each
compound. When no effect was found (n = 3−15 oocytes), the lack of effect was confirmed by testing at 100 μM (data not shown, n ≥ 5 oocytes for
all compounds).
Table 4. Effect of Replacing the B-Ring
a
Fitted EC50 values are shown for GluN1/GluN2C to two significant digits when potentiation at 30 μM of the test compound exceeded 120% of
control; values in parentheses are the fitted maximum response as a percentage of the initial glutamate (100 μM) and glycine (30 μM) response. All
data are from 3−14 oocytes from 2−3 frogs. When no effect was found, the lack of effect was confirmed by testing at 100 μM (data not shown, n ≥ 3
b
oocytes for all compounds). Inhibited at GluN1/GluN2A with an IC50 of 18 μM, at GluN1/GluN2B with an IC50 of 7.2 μM, at GluN1/GluN2C
with an IC50 of 11 μM, and GluN1/GluN2D with an IC50 of 5.7 μM.
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Table 5. Optimization of B-Ring Substituents
a
Fitted EC50 values are shown for GluN1/GluN2C to two significant digits when potentiation at 30 μM of the test compound exceeded 120% of
control; values in parentheses are the fitted maximum response as a percentage of the initial glutamate (100 μM) and glycine (30 μM) response. Hill
slopes were between 1.3 and 1.9. Data for active compounds at GluN1/GluN2C are from between 6 and 27 oocytes from 2−3 frogs for each
compound. When no effect was found (n = 4−11 oocytes), the lack of effect was confirmed by testing at 100 μM (data not shown, n ≥ 4 oocytes for
all compounds).
demonstrated weak inhibition at GluN2D-containing receptors
and had no effect at GluN2A- or GluN2B-containing receptors.
Compound 106b was inactive at all other subunits. These data
suggest that the activity of pyrrolidinone analogues may rely on
a single enantiomer and that the binding pocket can distinguish
between the enantiomers.
CONCLUSION
■
The incorporation of a methyl group at the C-7 position of the
indole of initial screening hit 1 afforded 111, which selectively
potentiates GluN2C-containing NMDA receptors with a
potency of 4.3 0.3 μM. In addition, the activity of this series
appears to originate from one enantiomer. These compounds
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Table 6. Optimization of Potency though Additional Modifications
a
Fitted EC50 values are shown for GluN1/GluN2C to two significant digits when potentiation at 30 μM of the test compound exceeded 120% of
control; values in parentheses are the fitted maximum response as a percentage of the initial glutamate (100 μM) and glycine (30 μM) response.
Data for active compounds at GluN1/GluN2C are from between 8 and 14 oocytes from 2 frogs for each compound; the Hill slope varied between
1.2 and 1.5. When no effect was found at 30 μM (n = 3−6 oocytes), the lack of effect was confirmed by testing at 100 μM (data not shown, n ≥ 7
oocytes for all compounds).
described;15 some experiments were performed with oocytes obtained
represent the first class of allosteric potentiators selective for
from Ecocyte (Austin, TX). Voltage-clamp recordings from oocytes
were made during perfusion with recording solution containing 90 mM
NaCl, 1.0 mM KCl, 0.5 mM BaCl2, 0.005 mM EDTA, and 10 mM
HEPES at pH 7.4 (23 °C). Glass microelectrodes had resistances
of 0.3−1.0 MΩ and were filled with 0.3−3.0 M KCl; the membrane
potential was held at −40 mV for all recordings. Compounds were
made as 20 mM stock solutions in DMSO and diluted to the final
concentration in recording solution; final DMSO content was 0.05−
0.5% (v/v). Oocytes expressing GluK2 receptors were pretreated with
10 μM concanavalin A for 10 min. NMDA receptors were activated by
100 μM glutamate plus 30 μM glycine; GluA1 and GluK2 receptors
were activated by 100 μM glutamate. To prevent a gradual increase in
current response over the course of the experiment of GluN1/GluN2A
receptor responses in oocytes, some oocytes expressing GluN1/
GluN2A were injected with 20−50 nL of 2 mM K-BAPTA (potassium
1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid). When the
response to agonist in the presence of 30 μM of a test compound
exceeded 120% of control, the response to glutamate and glycine in the
absence and presence of 5−7 concentrations of active analogues were
recorded in multiple oocytes obtained from two or more different frogs
for all experiments. The EC50 (half-maximally effective concentration of
potentiator) was determined by fitting the equation
diheteromeric GluN1/GluN2C receptors over receptors con-
taining GluN2A-, GluN2B-, and GluN2D subunits. Future
studies will address the activity of this series of modulators on
triheteromeric GluN2C-containing NMDA receptors containing
two different GluN2 subunits (e.g., GluN1/GluN2A/GluN2C).
This series of molecules may serve as a pharmacological tool
to evaluate the role of the GluN2C subunit in normal and
neuropathological function.
EXPERIMENTAL METHODS
■
Biology Experimentals. All protocols involving Xenopus laevis were
approved by the Emory University Institutional Animal Care and Use
Committee. Two-electrode voltage-clamp recordings were made from
Xenopus laevis oocytes expressing recombinant GluN1/GluN2A,
GluN1/GluN2B, GluN1/GluN2C, GluN1/GluN2D, GluA1, or
GluK2 receptors following injection of cRNA. cDNAs for rat GluN1−
1a (GenBank accession numbers U11418 and U08261; hereafter
GluN1), GluN2A (D13211), GluN2B (U11419), GluN2C (M91563),
GluN2D (L31611), GluA1 (X17184), and GluK2 (Z11548) were
provided by Drs. S. Heinemann (Salk Institute), S. Nakanishi (Kyoto
University), and P. Seeburg (University of Heidelberg). Oocyte
isolation, cRNA synthesis, and cRNA injection have been previously
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Table 7. Optimization of Potency though Linker Modifications
a
Fitted EC50 values are shown for GluN1/GluN2C to two significant digits when potentiation at 30 μM of the test compound exceeded 120%;
values in parentheses are the fitted maximum response as a percentage of the initial glutamate (100 μM) and glycine (30 μM) response. Data for
active compounds at GluN1/GluN2C are from between 7 and 8 oocytes from 2 frogs for each compound tested; the Hill slope varied between
1.3 and 1.4. When no effect was found at 30 μM (n = 3−11 oocytes), the lack of effect was confirmed by testing at 100 μM (data not shown, n ≥ 4
oocytes for all compounds).
response = (100 − maximum)/(1 + ([concentration]/EC50)N )
(1)
+ maximum
to the concentration−response data normalized to the current in the
Madison, WI). The ratio of GluN1 and GluN2C DNA used for
transfection was 10:1. The NMDA receptor antagonists DL-2-amino-5-
phosphonopentanoate (AP5) (200 μM; Abcam, Cambridge, MA) and
7-chloro-kynurenate (7-CKA) (200 μM; Abcam, Cambridge, MA) were
added to the culture medium to prevent NMDA receptor-mediated cell
death. The following day, the cells were diluted 1:1000 and 1:10,000 and
seeded in 144 mm dishes. The next day (e.g., two days after transfection),
10 μg/mL blasticidin S (Invivogen, San Diego, CA) was added to the
culture medium to select for transfected cells. Unless otherwise stated, the
culture medium for the cell lines always contained 1 mg/mL G418 and
10 μg/mL blasticidin S for selection as well as 200 μM AP5 and 200 μM
DCKA to prevent NMDA receptor-mediated cell death. The media was
changed every 2−3 days, and blasticidin S-resistant clones were isolated
10−20 days after transfection and evaluated for their response properties.
Fluorescence-based assays were conducted as previously described,17 and
test compounds were screened at 10 μM.
absence of potentiator (100%) for each oocyte, and the mean ( SEM)
presented. N is the Hill slope, which ranged between 1 and 2 and is not
reported; maximum is the fitted maximal response expressed as a percent
of control to a saturating concentration of potentiator. When responses
were inhibited by test compound at 30 μM to less than 60% of control,
the IC50 value was determined by fitting the equation
response = 100/(1 + ([concentration]/IC50)N )
(2)
to the concentration−response data normalized to the current. For
some compounds, visual detection of precipitation led to inclusion of
1−10 mM 2-hydroxypropyl-β-cyclodextrin in the recording solution to
enhance solubility and enable generation of the full concentration−
response data.
Chemistry Experimentals. Compounds for which synthesis is
not described were purchased from commercial vendors. Purity of
purchased compounds was greater than 90%, as determined by the
suppliers, via HPLC or NMR.
To generate a cell line with inducible NMDA receptor expression, we
used a previously described Tet-On (tetracycline-inducible promoter;
Clontech, Mountain View, CA) baby hamster kidney (BHK-21, ATCC
CCL-10) cell line.16 The BHK-21 Tet-On cell line was maintained at
37 °C, 5% CO2, and 95% relative humidity in culture medium com
posed of Dulbecco’s Modified Eagle Medium (DMEM) containing
GlutaMAX-I, 4500 mg/L glucose, and 110 mg/L sodium pyruvate
(Invitrogen, Carlsbad, CA) supplemented with penicillin (100 units/mL),
streptomycin (100 μg/mL), (Invitrogen, Carlsbad, CA), 10% dialyzed
fetal bovine serum (Invitrogen, Carlsbad, CA), and 1 mg/mL G418
(Invitrogen, Carlsbad, CA). The selection marker G418 was always
included to provide continuous selection of Tet-On-compatible BHK-21
cells. The cells were cotransfected with rat GluN1-1a (GenBank accession
no. U11418) in the inducible pTRE2 vector and rat GluN2C (GenBank
accession no. D13212) in the pCI-IRES-bla vector (see ref 16 for
details on this vector) using Fugene 6 transfection reagent (Promega,
All dry solvents were obtained from a Glass Contour System.
Reagents used were acquired from commercial suppliers and utilized
without additional purification. Precoated glass plates (silica gel
60 F254, 0.25 mm) were used to monitor the progress of reactions
by thin layer chromatography (TLC). Purification by flash column
chromatography was performed on a Teledyne ISCO Combiflash
Companion using prepackaged Teledyne RediSep disposable normal
phase silica columns. Melting temperatures were determined on a
1
Mel-Temp apparatus and are uncorrected. H and 13C NMR experi-
ments were each carried out on an INOVA-400 (400 MHz), VNMR
400 (400 MHz), INOVA-600 (600 MHz), Unity-600 (600 MHz), or
Mercury 300 Vx (300 MHz). All chemical shifts are reported in parts
per million and referenced to the residual solvent peak. All coupling
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Table 8. Optimization of Potency though Evaluation of Vinyl Substituents
a
Fitted EC50 values are shown for GluN1/GluN2C to two significant digits when potentiation at 30 μM of the test compound exceeded 120% of
control; values in parentheses are the fitted maximum response as a percentage of the initial glutamate (100 μM) and glycine (30 μM) response.
Data for active compounds at GluN1/GluN2C are from between 5 and 9 oocytes from 2−3 frogs for each compound. The Hill slope varied between
1.2 and 1.8 and was fixed to be 1.5 for less potent analogues (157, 159). When no effect was found (n = 3−9 oocytes), the lack of effect was
confirmed by testing at 100 μM (data not shown, n ≥ 4 oocytes for all compounds).
constants are reported in hertz (Hz). The IR spectra were acquired with
a Nicolet Avatar 370 DTGS. Mass spectra were performed by the Emory
University Mass Spectrometry Center on a VG 70-S Nier Johnson or
JEOL instrument. Purity of all final compounds was found to be ≥95%
by LC/MS analysis unless otherwise noted.
Upon the formation of a slurry, methyl acetopyruvate (1.0 equiv) was
added. The resulting mixture was allowed to stir at rt for up to 12 h.
In most instances, a precipitate was visible, which was collected via
filtration and washed with Et2O. The solid was dissolved in an
appropriate solvent and washed with saturated ammonium chloride and
brine before being dried over MgSO4, filtered, and concentrated in
vacuo. If a precipitate did not form, the mixture was concentrated in
vacuo before being subjected to the workup as described above.
Purification was achieved via flash column chromatography on SiO2
(MeOH/DCM) to afford the desired pyrrolidinone. Additional
purification was obtained by HPLC (85% ACN/15% water with 0.1%
formic acid) as needed.
General Preparation of Pyruvate Compounds (Procedure II: 3−20,
144). To a solution of sodium ethanolate (1.0 equiv) in EtOH (0.72 M)
at 0 °C was added a mixture of diethyl oxalate (1.0 equiv) and ethanone
(1.0 mmol) over 20 min. The mixture was allowed to stir at rt for 4 h.
In most instances, a precipitate had formed which was collected via
filtration and washed with absolute EtOH. If no precipitate was evident,
a minimal amount of water was added and the mixture was concentrated
in vacuo. The residue was dissolved in water, neutralized with acetic acid,
Separation of Enantiomers. The separation of the enantiomers of
106 was obtained using a ChiralPak OD-RH 30 mm × 250 mm, 5 μm
column with the following conditions: flow rate 10 mL/min, injection
volume 1−2 mL (5 mg/mL), 44% ACN/66% water with 0.1% formic
acid; 106a tR = 121.3 min; 106b tR = 129.3 min. Enantiomeric excess (ee)
of both enantiomers 106a and 106b was determined using a ChiralPak
OD-RH 4.6 mm × 150 mm, 5 μm column with the following conditions:
flow rate 0.5 mL/min, injection volume 10 μL, 44% ACN/66% water
with 0.1% formic acid; 106a [α]D20 −18(c = 0.10, methanol), tR = 26.1 min,
98% ee; 106b [α]2D0 + 9 (c = 0.10, methanol), tR = 29.1 min, 96% ee.
A Perkin-Elmer 314 instrument was used to obtain optical rotation data.
General Procedure for Synthesis of Pyrrolidinone Compounds
(Procedure I: 1, 62−82, 84−122, 161−180). To a stirred solution
of aldehyde (1.0 mmol) in dioxane (1.0 M) was added tryptamine
(1.0 equiv) and 10 mol % pyridinium 4-methylbenzenesulfonate.
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Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-3-isobutyryl-5-
oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (63). Compound 63 was
prepared via procedure I from methyl 4-formylbenzoate (0.088 g, 0.54
mmol), tryptamine (0.086 g, 0.54 mmol), and 4 (0.10 g, 0.54 mmol) to
1
yield a light-brown, amorphous solid (0.067 g, 28%). H NMR (600
MHz, DMSO-d6, 70 °C) δ 10.65 (s, 1H), 7.84 (d, J = 7.8 Hz, 2H), 7.32
(d, J = 7.8 Hz, 2H), 7.28 (d, J = 7.8 Hz, 2H), 7.06−7.03 (m, 2H), 6.92 (t,
J = 8.4 Hz, 1H), 5.18 (s, 1H), 3.83 (s, 3H), 3.79−3.75 (m, 1H), 3.40−
3.20 (m, 2H), 2.98−2.93 (m, 1H), 2.91−2.86 (m, 1H), 2.72−2.67 (m,
1H), 0.86 (d, J = 4.8 Hz, 6H). 13C NMR (150 MHz, DMSO-d6) δ 182.1,
166.0, 136.2, 129.2, 128.1, 128.0, 126.9, 125.5, 123.4, 122.8, 121.1, 121.0,
118.5, 118.2, 118.1, 111.6, 111.5, 110.9, 109.5, 60.0, 52.1, 40.9, 23.7,
23.2, 18.5, 17.7. HMS (APCI) calcd for C26H26N2O5 447.1915; found
447.1916 [M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-5-oxo-3-pivaloyl-
2,5-dihydro-1H-pyrrol-2-yl)benzoate (64). Compound 64 was pre-
pared via procedure I from methyl 4-formylbenzoate (0.082 g, 0.50 mmol),
tryptamine (0.080 g, 0.50 mmol), and 5 (0.10 g, 0.50 mmol) to yield an
orange oil (0.092 g, 40%). 1H NMR (600 MHz, CDCl3) δ 8.17 (br s, 1H),
7.93 (d, J = 7.8 Hz, 2H), 7.40−7.35 (m, 2H), 7.20 (t, J = 7.2 Hz, 1H), 7.09
(t, J = 7.2 Hz, 1H), 7.04 (dd, J = 1.2 Hz, J = 7.8 Hz, 2H), 6.96 (s, 1H), 5.04
(s, 1H), 4.02−3.99 (m, 1H), 3.91 (s, 3H), 3.09−3.00 (m, 2H), 2.95−2.91
(m, 1H), 1.06 (s, 9H). 13C NMR (150 MHz, CDCl3) δ 202.2, 181.2, 166.7,
141.2, 136.5, 130.6, 130.2, 128.0, 127.2, 122.5, 122.2, 119.8, 118.8, 118.7,
111.6, 111.4, 63.0, 52.4, 41.7, 27.7, 25.3, 24.5 (note: either carbon 1 or 2 is
absent). HMS (APCI) calcd for C27H28N2O5 461.2071; found 461.2077
[M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-benzoyl-4-hydroxy-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)benzoate (65). Compound 65 was pre-
pared via procedure I from 6 (0.15 g, 0.68 mmol), tryptamine (0.11 g,
0.68 mmol), and methyl 4-formylbenzoate (0.11 g, 0.68 mmol) to yield a
cream-colored solid (0.031 g, 9%). 1H NMR (400 MHz, DMSO-d6) δ
10.83 (s, 1H), 7.79 (d, J = 7.2 Hz, 2H), 7.59−7.48 (m, 2H), 7.40−7.28
(m, 3H), 7.24−7.21 (m, 3H), 7.11−7.04 (m, 2H), 6.92 (t, J = 7.6 Hz,
1H), 6.74 (s, 1H), 5.25 (s, 1H), 3.80−3.74 (m, 4H), 3.00−2.90 (m, 1H),
2.82−2.67 (m, 2H). 13C NMR (150 MHz, DMSO-d6) δ 190.1, 188.9,
165.9, 165.4, 142.1, 138.2, 136.4, 132.4, 129.6, 129.5, 128.7, 128.3, 128.1,
127.0, 123.0, 121.1, 118.9, 118.4, 118.2, 111.6, 110.9, 60.8, 52.1, 41.2,
23.8; mp 200−205 °C. HMS (APCI) calcd for C29H24N2O5 481.1771;
found 481.1765 [M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-3-(3-hydroxyben-
zoyl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (66). Compound
66 was prepared via procedure I from methyl 4-formylbenzoate (0.35 g,
2.1 mmol), tryptamine (0.34 g, 2.1 mmol), and 21 (0.50 g, 2.1 mmol) to
yield a cream-colored solid (1.0 g, 96%). 1H NMR (600 MHz, DMSO-d6)
δ 10.77 (s, 1H), 7.83 (d, J = 7.8 Hz, 2H), 7.37−7.29 (m, 6H), 7.13−7.12
(m, 1H), 7.07−7.03 (m, 3H), 6.91 (t, J = 7.8 Hz, 1H), 5.36 (s, 1H), 3.87−
3.81 (m, 4H), 3.00−2.93 (m, 2H), 2.78−2.73 (m, 1H). 13C NMR (150
MHz, DMSO-d6) δ 198.0, 166.0, 157.1, 136.40, 136.3, 129.4, 128.4, 128.2,
125.6, 123.4, 122.9, 121.2, 121.1, 119.5, 118.6, 118.4, 118.25, 118.19,
115.2, 111.7, 111.6, 110.9, 109.7, 66.5, 52.2, 41.2, 23.8; mp 78−80 °C.
HMS (APCI) calcd forC29H24N2O6 497.1707;found497.1707 [M+ H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-3-(3-methoxyben-
zoyl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (67). Compound
67 was prepared via procedure I from methyl 4-formylbenzoate
(0.066 g, 0.40 mmol), tryptamine (0.064 g, 0.40 mmol), and 7 (0.10 g,
0.40 mmol) to yield a pale-yellow, amorphous solid (0.046 g, 23%).
1H NMR (600 MHz, DMSO-d6, 80 °C) δ 10.64 (s, 1H), 7.89−7.82 (m,
3H), 7.35−7.22 (m, 6H), 7.07−7.05 (m, 2H), 6.98−6.91 (m, 2H), 5.34
(s, 1H), 4.26 (m, 1H), 3.82 (s, 3H), 3.74 (s, 3H), 3.01−2.90 (m, 2H),
2.78−2.75 (m, 1H). 13C NMR (150 MHz, DMSO-d6) δ 188.6, 165.9,
165.1, 158.9, 141.9, 139.3, 136.3, 129.6, 129.4, 129.3, 128.3, 128.1, 126.9,
125.5, 122.9, 121.2, 121.1, 119.0, 118.3, 118.1, 113.5, 111.5, 110.8, 60.7,
55.3, 52.2, 41.1, 23.8. HMS (APCI) calcd for C30H26N2O6 511.1877;
found 511.1871 [M + H]+.
Figure 3. Composite concentration−effect curves for 106 enantiomers.
Concentration−effect curves for the enantiomers of 106 demonstrate
that only one enantiomer, 106a, is active, potentiating the GluN1/
GluN2C receptor to a fitted maximum of 259 8% of control with an
EC50 of 18 0.6 μM (n = 6).
and extracted with Et2O (3×). The combined organic layers were dried
over MgSO4, filtered, and concentrated in vacuo. Purification was
achieved as needed via flash column chromatography on SiO2 (hexanes/
EtOAc: 4/1) to obtain the product.
General Preparation of Methyl Benzoate Compounds (Procedure
III: 184−186). To a solution of 4-bromobenzoic acid (1.0 mmol)
in THF:MeOH (4:1, 0.3 M) at 0 °C was added (diazomethyl)-
trimethylsilane (2.4 equiv). The reaction was allowed to warm to rt over
the period of 1 h. At this time, the mixture was concentrated in vacuo and
1.0 M HCl was added. The mixture was extracted with EtOAc (2×),
dried over MgSO4, filtered, and concentrated in vacuo to afford the
product.
General Preparation of Methyl 4-Formylbenzoate Compounds
(Procedure IV: 37−40). To a solution of methyl 4-bromobenzoate (1.0
mmol) in DMF (0.6 M) was added 17 mol % bis(triphenylphosphine)-
palladium(II) dichloride and sodium formate (1.5 equiv). The reaction
mixture was stirred at 110 °C under a steady stream of CO(g) for 2 h.
At this time, the mixture was cooled to rt, diluted with saturated
sodium carbonate, and extracted with EtOAc (2×). The combined
organic layers were washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo. Purification was achieved via flash column
chromatography on SiO2 (hexanes/EtOAc: 3/1) to yield the desired
product, which was taken on without further purification.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)benzoate (1). Compound 1 was prepared
via procedure I from methyl 4-formylbenzoate (3.0 g, 18 mmol),
tryptamine (2.9 g, 18 mmol), and methyl acetopyruvate (2.6 g, 18 mmol)
1
to yield a cream-colored solid (5.5 g, 72%). H NMR (400 MHz,
DMSO-d6) δ 10.83 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.33−7.24 (m, 4H),
7.12−7.03 (m, 2H), 6.91 (t, J = 7.6 Hz, 1H), 5.17 (s, 1H), 3.83 (s, 3H),
3.83−3.77 (m, 1H), 3.00−2.90 (m, 1H), 2.87−2.80 (m, 1H), 2.74−2.67
(m, 1H), 2.27 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 165.6, 165.1,
142.5, 136.3, 129.3, 128.1, 126.9, 125.5, 122.9, 121.2, 121.1, 118.4, 118.3,
118.1, 111.6, 111.5, 110.8, 66.4, 59.8, 52.2, 40.8, 23.6; mp 99−105 °C.
HMS (APCI) calcd for C24H22N2O5 419.1607; found 419.1606
[M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-5-oxo-3-propion-
yl-2,5-dihydro-1H-pyrrol-2-yl)benzoate (62). Compound 62 was
prepared via procedure I from methyl 4-formylbenzoate (0.095 g,
0.58 mmol), tryptamine (0.93 g, 0.58 mmol), and 3 (0.10 g, 0.58 mmol)
1
to yield a cream-colored solid (0.16 g, 64%). H NMR (400 MHz,
DMSO-d6) δ 10.84 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.33−7.23 (m, 4H),
7.09 (d, J = 2.4 Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H), 6.91 (t, J = 6.8 Hz, 1H),
5.17 (s, 1H), 3.83−3.76 (m, 4H), 2.96−2.89 (m, 1H), 2.86−2.79 (m,
1H), 2.75−2.57 (m, 3H), 0.85 (t, J = 7.6 Hz, 3H). 13C NMR (150 MHz,
DMSO-d6) δ 165.9, 165.1, 142.5, 136.2, 129.7, 129.3, 128.1, 126.9,
125.5, 122.9, 121.0, 118.2, 118.1, 111.5, 110.7, 59.8, 54.9, 52.2, 40.8,
40.0, 23.6 (note: carbons 1 and 2 are absent); mp 175−180 °C. HMS
(APCI) calcd C25H24N2O5 433.1758; found 433.1756 [M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-3-(3-methylben-
zoyl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (68). Compound
68 was prepared via procedure I from methyl 4-formylbenzoate (0.17 g,
1.0 mmol), tryptamine (0.17 g, 1.0 mmol), and 8 (0.24 g, 1.0 mmol) to
yield a pale-yellow, amorphous solid (0.029 g, 6%). 1H NMR (600 MHz,
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DMSO-d6, 80 °C) δ 10.67 (s, 1H), 7.72 (m, 2H), 7.36−7.33 (m, 2H),
7.28−7.21 (m, 2H), 7.11−7.04 (m, 6H), 6.93 (t, J = 7.2 Hz, 1H), 5.29 (s,
1H), 3.86−3.78 (m, 4H), 3.01−2.96 (m, 1H), 2.91−2.86 (m, 1H), 2.76−
2.72 (m, 1H), 2.23 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 190.2,
190.0, 182.1, 182.0, 166.0, 145.4, 144.7, 136.2, 128.8, 127.9, 126.9, 122.9,
122.8, 121.0, 118.3, 118.1, 111.5, 111.1, 109.2, 52.0, 48.6, 41.1, 23.6, 20.9
(note: carbons 1, 2, 3, and 4 are absent). HMS (APCI) calcd for
C30H26N2O5 493.1769; found 493.1768 [M − H]−.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-(3-chlorobenzoyl)-4-hy-
droxy-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (69). Compound
69 was prepared via procedure I from methyl 4-formylbenzoate (0.064 g,
0.39 mmol), tryptamine (0.063 g, 0.39 mmol), and 9 (0.10 g, 0.39 mmol)
to yield a pale-yellow, amorphous solid (0.045 g, 22%). 1H NMR
(600 MHz, DMSO-d6, 80 °C) δ 10.69 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H),
7.69 (s, 1H), 7.58 (d, J = 6.0 Hz, 1H), 7.35−7.32 (m, 3H), 7.29−7.26 (m,
3H), 7.07−7.05 (m, 2H), 6.93 (t, J = 7.2 Hz, 1H), 5.28 (s, 1H), 3.82−3.79
(m, 4H), 2.98−2.94 (m, 1H), 2.88−2.84 (m, 1H), 2.74−2.68 (m, 1H).
13C NMR (150 MHz, DMSO-d6) δ 182.1, 166.1, 145.4, 137.9, 136.4,
5.27 (s, 1H), 3.82−3.78 (m, 4H), 3.00−2.95 (m, 1H), 2.91−2.86 (m,
1H), 2.74−2.72 (m, 1H). 13C NMR (150 MHz, DMSO-d6) δ 191.3,
166.0, 149.5, 149.0, 146.6, 136.3, 128.9, 128.5, 128.0, 127.0, 122.8, 122.3,
121.1, 120.7, 118.3, 118.1, 111.5, 111.0, 52.0, 48.6, 41.1, 23.5 (note:
carbons 1 and 2 are absent); mp >250 °C. HMS (APCI) calcd for
C28H23N3O5 480.1570; found 480.1568 [M − H]−.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-3-(2-methoxyben-
zoyl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (74). Compound
74 was prepared via procedure I from methyl 4-formylbenzoate (0.13 g,
0.80 mmol), tryptamine (0.13 g, 0.80 mmol), and 11 (0.20 g, 0.80 mmol)
1
to yield a pink, amorphous solid (0.028 g, 7%). H NMR (600 MHz,
DMSO-d6) δ 10.83 (s, 1H), 7.89 (s, 1H), 7.50 (d, J = 6.0 Hz, 1H), 7.34−
7.18 (m, 5H), 7.09−7.04 (m, 3H), 6.96−6.88 (m, 3H), 5.27 (s, 1H),
3.83−3.74 (m, 6H), 2.99−2.87 (m, 2H), 2.73−2.65 (m, 2H). 13C NMR
(150 MHz, DMSO-d6) δ 190.1, 182.1, 166.2, 156.0, 146.1, 137.3,
132.7, 129.1, 128.8, 128.4, 128.1, 128.0, 127.7, 127.0, 125.6, 122.8, 121.0,
119.7, 118.2, 118.1, 111.5, 111.1, 111.0, 60.3, 56.1, 55.2, 52.1, 40.9, 23.6,
18.6. HMS (APCI) calcd for C30H26N2O6 509.1710; found 509.1711
[M − H]−.
136.3, 129.2, 128.2, 127.0, 126.8, 125.5, 123.44, 123.43, 122.8, 121.2,
121.0, 118.5, 118.3, 118.1, 111.6, 111.5, 111.0, 109.5, 60.5, 52.1, 23.2,
20.8. HMS (APCI) calcd for C29H23ClN2O5 513.1223; found 513.1219
[M − H]−.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-3-(2-methylben-
zoyl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (75). Compound
75 was prepared via procedure I from methyl 4-formylbenzoate (0.14 g,
0.85 mmol), tryptamine (0.14 g, 0.85 mmol), and 12 (0.20 g, 0.85 mmol)
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-(3-fluorobenzoyl)-4-hy-
droxy-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (70). Compound
70 was prepared via procedure I from methyl 4-formylbenzoate (0.069 g,
0.42 mmol), tryptamine(0.067 g, 0.42mmol), and10 (0.10 g, 0.42 mmol)
to yield a yellow, amorphous solid (0.028 g, 14%). 1H NMR (600 MHz,
DMSO-d6, 80°C) δ 10.66 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.53−7.45 (m,
2H), 7.34 (dd, J = 3.0 Hz, J = 8.4 Hz, 2H), 7.29−7.26 (m, 1H), 7.22 (d, J =
7.8 Hz, 2H), 7.13−7.10 (m, 1H), 7.07−7.04 (m, 2H), 6.93 (t, J = 7.8 Hz,
1H), 5.32 (s, 1H), 3.84−3.79 (m, 4H), 3.01−2.96 (m, 1H), 2.92−2.88 (m,
1H), 2.76−2.71 (m, 1H). 13C NMR (150 MHz, DMSO-d6) δ 191.7,
167.0, 161.5 (d, J = 241.7 Hz), 143.0, 137.6, 136.2, 129.3, 128.9, 128.6,
128.1, 127.9, 126.9, 125.5, 124.1, 122.8, 121.0, 118.3, 118.1, 116.6, 116.5,
111.5, 110.9, 61.0, 52.0, 41.2, 23.5 (note: carbon 3 is absent). HMS
(APCI) calcd for C29H23FN2O5 497.1510; found 497.1513 [M − H]−.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-5-oxo-3-picolino-
yl-2,5-dihydro-1H-pyrrol-2-yl)benzoate (71). Compound 71 was pre-
pared via procedure I from methyl 4-formylbenzoate (0.074 g, 0.45 mmol),
tryptamine (0.072 g, 0.45 mmol), and 18 (0.10 g, 0.45 mmol) to yield a
yellow, amorphous solid (0.037 g, 17%). 1H NMR (600 MHz, CDCl3) δ
8.66 (d, J = 4.2 Hz, 1H), 8.21 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.07 (dt, J =
1.2 Hz, J = 7.8 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.71 (dt, J = 0.6 Hz, J = 6.0
Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.21−7.17 (m,
3H), 7.07 (t, J = 8.4 Hz, 1H), 7.01 (d, J = 1.8 Hz, 1H), 5.14 (s, 1H), 4.15−
4.10 (m, 1H), 3.89 (s, 3H), 3.11−2.95 (m, 3H). 13C NMR (150 MHz,
CDCl3) δ 181.8, 173.2, 166.8, 165.7, 151.7, 145.3, 142.5, 140.6, 136.5,
130.3, 130.0, 128.3, 128.1, 127.3, 125.2, 122.3, 119.6, 118.7, 112.5, 111.5,
109.6, 61.6, 41.4, 29.9, 24.3 (note: carbon 3 is absent). HMS (APCI) calcd
for C28H23N3O5 482.1710; found 482.1708 [M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-3-nicotinoyl-5-
oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (72). Compound 72 was
prepared via procedure I from methyl 4-formylbenzoate (0.079 g,
0.48 mmol), tryptamine(0.077 g, 0.45mmol), and19 (0.10 g, 0.48 mmol)
to yield a yellow solid (0.11 g, 49%). 1H NMR (400 MHz, DMSO-d6) δ
10.89 (s, 1H), 8.80 (s, 1H), 8.69 (d, J = 4.4 Hz, 1H), 8.00 (d, J = 7.6 Hz,
1H), 7.88 (d, J = 7.2 Hz, 2H), 7.43−7.42 (m, 2H), 7.34−7.29 (m, 2H),
7.14 (d, J = 8.0 Hz, 2H), 7.06 (t, J = 6.8 Hz, 1H), 6.92 (t, J = 7.2 Hz, 1H),
5.42 (s, 1H), 3.87−3.82 (m, 4H), 3.02−2.89 (m, 2H), 2.79−2.74 (m, 1H).
13C NMR (150 MHz, DMSO-d6) δ 186.8, 165.9, 165.0, 152.1, 149.1,
142.1, 136.3, 133.9, 129.5, 129.4, 128.3, 128.1, 126.9, 125.5, 123.5, 122.9,
121.0, 118.3, 118.1, 111.5, 110.7, 109.5, 60.4, 52.2, 41.1, 23.7; mp 199−
205 °C. HMS (APCI) calcd for C28H23N3O5 482.1711; found 482.1707
[M + H]+.
1
to yield a pale-yellow, amorphous solid (0.040 g, 9%). H NMR (600
MHz, DMSO-d6, 70 °C) δ 10.71 (br s, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.37
(d, J = 9.0 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.13−6.99 (m, 4H), 6.94−
6.91 (m, 2H), 6.84−6.74 (m, 3H), 4.96 (s, 1H), 3.82−3.76 (m, 4H),
2.97−2.92 (m, 1H), 2.82−2.71 (m, 2H), 1.78 (s, 3H). 13C NMR (150
MHz, DMSO-d6) δ 190.1, 182.1, 182.03, 182.01, 165.9, 144.4, 139.4,
136.3, 134.2, 129.3, 128.8, 128.3, 127.9, 127.0, 124.7, 123.0, 122.7, 121.1,
118.3, 118.1, 111.6, 111.2, 108.9, 60.3, 52.0, 48.6, 41.1, 23.6. HMS (APCI)
calcd for C30H26N2O5 493.1761; found 493.1763 [M − H]−.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-(2-chlorobenzoyl)-4-hy-
droxy-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (76). Compound
76 was prepared via procedure I from methyl 4-formylbenzoate (0.13 g,
0.79 mmol), tryptamine (0.13 g, 0.79 mmol), and 13 (0.20 g, 0.79 mmol)
1
to yield a cream-colored solid (0.27 g, 66%). H NMR (600 MHz,
DMSO-d6, 80 °C) δ 10.64 (s,1H), 7.67 (m, 2H), 7.35 (d, J = 8.4 Hz, 1H),
7.30 (d, J = 7.8 Hz, 1H), 7.24−7.18 (m, 2H), 7.10−7.03 (m, 4H), 6.92 (t,
J = 7.2 Hz, 2H), 6.78 (m, 1H), 5.04 (s, 1H), 3.86−3.75 (m, 4H), 2.97−
2.92 (m, 1H), 2.85−2.83 (m, 1H), 2.73−2.68 (m, 1H). 13C NMR (150
MHz, DMSO-d6) δ 185.2, 165.9, 144.1, 136.3, 130.0, 129.5, 129.1, 128.8,
128.7, 128.6, 128.1, 128.0, 126.9, 126.5, 123.0, 121.0, 118.3, 118.1, 111.5,
111.0, 67.1, 52.1, 40.0, 25.2 (note: carbons 1, 2, and 3 are absent); mp
248−253 °C. HMS (APCI) calcd for C29H23ClN2O5 513.1214; found
513.1215 [M − H]−.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-(2-fluorobenzoyl)-4-hy-
droxy-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (77). Compound
77 was prepared via procedure I from methyl 4-formylbenzoate (0.19 g,
0.84 mmol), tryptamine (0.14 g, 0.84 mmol), and 14 (0.20 g, 0.84 mmol)
to yield a brown, amorphous solid (0.070 g, 17%). 1H NMR (600 MHz,
DMSO-d6, 70 °C) δ 10.68 (s, 1H), 7.80−7.54 (m, 2H), 7.35−7.30 (m,
4H), 7.11−6.78 (m, 7H), 5.07 (s, 1H), 3.81−3.74 (m, 4H), 2.97−2.92
(m, 1H), 2.87−2.82 (m, 1H), 2.72−2.67 (m, 1H). 13C NMR (150 MHz,
DMSO-d6) δ 172.6, 165.9, 161.2, 156.0, 155.1, 139.5, 136.3, 135.0, 130.0,
129.6, 128.6, 126.8, 126.7, 126.3, 125.3, 124.8, 123.1, 121.1, 119.3, 118.3,
118.0, 111.5, 110.6, 59.1, 52.3, 41.2, 23.8. HMS (APCI) calcd for
C29H23FN2O5 497.1510; found 497.1513 [M − H]−.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-(furan-2-carbonyl)-4-hy-
droxy-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (78). Compound
78 was prepared via procedure I from methyl 4-formylbenzoate (0.42 g,
2.6 mmol), tryptamine (0.41 g, 2.6 mmol), and 15 (0.50 g, 2.6 mmol) to
yield an orange solid (0.079 g, 7%). 1H NMR (600 MHz, CDCl3) δ 8.32
(s, 1H), 8.05 (s, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.43−7.41 (m, 2H), 7.32
(d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.16 (t, J = 7.2 Hz, 1H), 7.06
(t, J = 7.2 Hz, 1H), 6.94 (s, 1H), 6.39 (dd, J = 1.8 Hz, J = 3.6 Hz, 1H),
5.39 (s, 1H), 4.04−3.99 (m, 1H), 3.88 (s, 3H), 3.07−2.96 (m, 2H),
2.93−2.89 (m, 1H). 13C NMR (150 MHz, CDCl3) δ 173.9, 167.1, 153.1,
145.1, 136.5, 129.8, 129.7, 129.2, 128.4, 128.2, 127.4, 122.3, 122.2, 119.5,
118.9, 117.1, 114.2, 112.7, 111.7, 111.4, 111.3, 61.3, 52.2, 41.3, 24.3;
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-3-isonicotinoyl-5-
oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (73). Compound 73 was
prepared via procedure I from methyl 4-formylbenzoate (0.15 g,
0.9 mmol), tryptamine (0.15 g, 0.9 mmol), and 20 (0.20 g, 0.9 mmol)
to yield a yellow solid (0.13 g, 30%). 1H NMR (600 MHz, DMSO-d6,
80 °C) δ 10.63 (s, 1H), 8.47 (d, J = 2.8 Hz, 1H), 7.76−6.92 (m, 12H),
2347
dx.doi.org/10.1021/jm401695d | J. Med. Chem. 2014, 57, 2334−2356

Journal of Medicinal Chemistry
Article
mp 60−65 °C. HMS (APCI) calcd for C27H22N2O6 471.1551; found
471.1547 [M + H]+.
130.1 (×2), 128.5, 127.8 (×2), 127.4, 123.0, 119.1, 121.7, 119.8, 118.8,
113.0, 111.1, 54.7, 49.1, 26.6, 24.3; mp >250 °C. HMS (ESI+) calcd For
C23H20N2NaO5 427.1270; found 427.1263 [M + Na]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-5-oxo-3-(thio-
phene-2-carbonyl)-2,5-dihydro-1H-pyrrol-2-yl)benzoate (79). Com-
pound 79 was prepared via procedure I from methyl 4-formylbenzoate
(0.073 g, 0.44 mmol), tryptamine (0.071 g, 0.44 mmol), and 16 (0.10 g,
0.44 mmol) to yield a yellow, amorphous solid (0.043 g, 20%). 1H NMR
(400 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.55 (d,
J = 4.0 Hz, 1H), 7.34−7.29 (m, 4H), 7.06−7.02 (m, 3H), 6.92 (t, J = 7.2
Hz, 1H), 5.80−5.70 (m, 1H), 5.28 (s, 1H), 3.86−3.74 (m, 4H), 3.00−
2.89 (m, 1H), 2.85−2.78 (m, 1H), 2.73−2.67 (m, 1H). 13C NMR (150
MHz, DMSO-d6) δ 165.8, 144.7, 136.2, 129.0, 128.2, 126.9, 126.8,
123.4, 122.9, 121.2, 121.0, 118.5, 118.3, 118.1, 111.6, 111.5, 111.1, 109.5,
52.0, 48.6, 40.0, 23.5 (note: carbons 1, 2, and 4 are absent); mp 190−
195 °C. HMS (APCI) calcd for C27H22N2O5S 485.1177; found
485.1173 [M − H]−.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-5-oxo-3-(thio-
phene-3-carbonyl)-2,5-dihydro-1H-pyrrol-2-yl)benzoate (80). Com-
pound 80 was prepared via procedure I from methyl 4-formylbenzoate
(0.36 g, 2.2 mmol), tryptamine (0.35 g, 2.2 mmol), and 17 (0.50 g,
2.2 mmol) to yield a cream-colored solid (0.70 g, 65%). 1H NMR (400
MHz, DMSO-d6) δ 10.86 (s, 1H), 8.38 (d, J = 2.8 Hz, 1H), 7.85 (d, J =
7.6 Hz, 2H), 7.49 (t, J = 4.0 Hz, 1H), 7.37−7.31 (m, 4H), 7.13 (s, 1H),
7.07 (t, J = 7.6 Hz, 1H), 6.93 (t, J = 6.8 Hz, 1H), 5.76 (d, J = 1.2 Hz, 1H),
5.44 (s, 1H), 3.89−3.81 (m, 4H), 3.02−2.90 (m, 2H), 2.80−2.74 (m,
1H). 13C NMR (150 MHz, DMSO-d6) δ 181.8, 165.9, 142.1, 141.6,
136.3, 134.2, 129.5, 129.4, 128.3, 128.1, 127.3, 126.9, 126.3, 125.5,
122.9, 121.1, 118.3, 118.1, 111.5, 110.8, 60.7, 52.1, 41.1, 23.8; mp 189−
192 °C. HMS (APCI) calcd for C27H22N2O5S 487.1336; found
487.1335 [M + H]+.
Ethyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-2,5-
dihydro-1H-pyrrol-2-yl)benzoate (84). Compound 84 was prepared
via procedure I from 45 (0.20 g, 1.1 mmol), tryptamine (0.18 g, 1.1 mmol),
and methyl acetopyruvate (0.16 g, 1.1 mmol) to yield a pale-pink solid
(0.20 g, 42%). 1H NMR (400 MHz, DMSO-d6) δ 12.48 (br s, 1H), 10.82
(s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.33−7.24 (m, 4H), 7.09 (d, J = 2.4 Hz,
1H), 7.05 (t, J = 7.2 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 5.18 (s, 1H), 4.30 (q,
J = 7.2 Hz, 2H), 3.83−3.76 (m, 1H), 2.97−2.89 (m, 1H), 2.87−2.80 (m,
1H), 2.74−2.67 (m, 1H), 2.26 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H). 13C NMR
(150 MHz, DMSO-d6) δ 191.6, 165.4, 165.1, 142.4, 136.2, 129.6, 129.3,
128.1, 126.9, 122.9, 121.0, 118.3, 118.1, 111.5, 110.7, 60.7, 59.8, 40.8, 39.9,
23.6, 14.2 (note: carbon 3 and either carbon 1 or 2 are absent); mp 180−
183 °C. HMS (APCI) calcd for C25H24N2O5 433.1771; found 433.1765
[M + H]+.
Isopropyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)benzoate (85). Compound 85 was pre-
pared via procedure I from 46 (0.20 g, 1.0 mmol), tryptamine (0.17 g,
1.0 mmol), and methyl acetopyruvate (0.15 g, 1.0 mmol) to yield
an orange, amorphous solid (0.028 g, 6%). 1H NMR (400 MHz,
DMSO-d6) δ 10.70 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.33−7.23 (m, 3H),
7.11−7.00 (m, 3H), 6.91 (t, J = 7.6 Hz, 1H), 5.16−5.11 (m, 2H), 3.82−
3.77 (m, 1H), 3.02−2.85 (m, 2H), 2.76−2.71 (m, 1H), 2.26 (s, 3H),
1.32 (s, 3H), 1.31 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 190.0,
164.9, 136.2, 129.2, 128.1, 126.8, 125.5, 123.5, 122.8, 121.2, 121.0, 118.5,
118.3, 118.1, 111.5, 110.8, 68.1, 59.8, 40.9, 39.9, 23.6, 21.6 (note:
carbons 1 and 2 are absent). HMS (APCI) calcd for C26H26N2O5
447.1928; found 447.1922 [M + H]+.
Methyl 3-(1−2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)benzoate (81). Compound 81 was pre-
pared via procedure I from methyl 3-formylbenzoate (0.50 g, 3.1 mmol),
tryptamine (0.49 g, 3.1 mmol), and methyl acetopyruvate (0.44 g,
3.1 mmol) to yield a pale-pink solid (0.77 g, 60%). 1H NMR (400 MHz,
DMSO-d6) δ 10.82 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.73 (s, 1H), 7.45
(t, J = 7.2 Hz, 1H), 7.39−7.26 (m, 3H), 7.10 (d, J = 2.0 Hz, 1H), 7.05 (t,
J = 7.2 Hz, 1H), 6.89 (t, J = 8.0 Hz, 1H), 5.24 (s, 1H), 3.85−3.76 (m,
4H), 2.98−2.91 (m, 1H), 2.87−2.80 (m, 1H), 2.72−2.65 (m, 1H), 2.72
(s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 191.5, 166.0, 165.1, 154.8,
137.8, 136.3, 132.5, 129.9, 129.1, 129.0, 128.4, 126.9, 122.9, 121.1, 119.8,
118.3, 118.1, 111.5, 110.8, 59.8, 52.3, 40.8, 29.8, 23.7; mp 218−220 °C.
HMS (APCI) calcd for C24H22N2O5 419.1593; found 419.1596
[M + H]+.
tert-Butyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-
2, 5-dihydro-1H-pyrrol-2-yl) benzoate (86). Compound 86 was
prepared via procedure I from 47 (0.50 g, 2.4 mmol), tryptamine
(0.39 g, 2.4 mmol), and methyl acetopyruvate (0.35 g, 2.4 mmol) to
yield a pale-yellow solid (0.92 g, 83%). 1H NMR (400 MHz, DMSO-d6)
δ 10.83 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.33−7.22 (m, 4H), 7.10 (d, J =
2.0 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 5.17 (s,
1H), 3.83−3.76 (m, 1H), 2.96−2.89 (m, 1H), 2.86−2.81 (m, 1H),
2.79−2.67 (m, 1H), 2.26 (s, 3H), 1.53 (s, 9H). 13C NMR (150 MHz,
DMSO-d6) δ 191.5, 165.1, 164.6, 154.4, 142.0, 131.1, 129.1, 127.9,
126.9, 126.2, 122.8, 121.0, 119.8, 118.2, 118.1, 111.4, 110.7, 80.7, 59.8,
40.8, 29.7, 27.8, 23.6; mp 145−150 °C. HMS (APCI) calcd for
C27H28N2O5 461.2063; found 461.2065 [M + H]+.
4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-3-nicotinoyl-5-oxo-2,5-di-
hydro-1H-pyrrol-2-yl)benzonitrile (87). Compound 87 was pre-
pared via procedure I from 4-formylbenzonitrile (0.15 g, 1.1 mmol),
tryptamine (0.18 g, 1.1 mmol), and 19 (0.25 g, 1.1 mmol) to yield a
yellow solid (0.084 g, 17%). 1H NMR (600 MHz, DMSO-d6) δ 10.84 (s,
1H), 8.81 (s, 1H), 8.69 (d, J = 3.6 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.75
(d, J = 7.8 Hz, 2H), 7.50−7.47 (m, 3H), 7.33 (d, J = 8.4 Hz, 1H), 7.31 (d,
J = 7.8 Hz, 1H), 7.13 (s, 1H), 7.07 (t, J = 7.8 Hz, 1H), 6.94 (t, J = 7.2 Hz,
1H), 5.44 (s, 1H), 3.88−3.83 (m, 1H), 3.01−2.90 (m, 2H), 2.79−2.75
(m, 1H). 13C NMR (150 MHz, DMSO-d6) δ 189.3, 165.1, 152.1,
150.2, 149.2, 142.5, 136.3, 133.9, 132.4, 129.0, 126.9, 123.9, 123.4, 122.9,
121.1, 118.6, 118.3, 118.1, 117.7, 111.5, 111.0, 110.7, 60.3, 41.2, 23.7;
mp >250 °C. HMS (APCI) calcd for C27H20N4O3 449.1608; found
449.1607 [M + H]+.
1-(2-(1H-Indol-3-yl)ethyl)-4-acetyl-3-hydroxy-5-(4-nitrophenyl)-
1H-pyrrol-2(5H)-one (88). Compound 88 was prepared via procedure
I from 4-nitrobenzaldehyde (0.50 g, 3.3 mmol), tryptamine (0.53 g,
3.3 mmol), and methyl acetopyruvate (0.48 g, 3.3 mmol) to yield a pale-
yellow solid (1.0 g, 75%). 1H NMR (400 MHz, DMSO-d6) δ 12.62 (br s,
1H), 10.82 (s, 1H), 8.10 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H),
7.31 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 1.6 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H),
6.91 (t, J = 7.6 Hz, 1H), 5.26 (s, 1H), 3.85−3.78 (m, 1H), 2.97−2.84
(m, 2H), 2.80−2.77 (m, 1H), 2.27 (s, 3H). 13C NMR (150 MHz,
DMSO-d6) δ 191.6, 165.2, 154.7, 147.1, 144.9, 136.2, 129.0, 126.8,
123.5, 122.9, 121.0, 118.2, 118.0, 111.4, 110.7, 59.4, 41.0, 29.8, 23.5
(note: carbon 3 is absent); mp 142−150 °C. HMS (APCI) calcd for
C22H19N3O5 406.1398; found 406.1395 [M + H]+.
Methyl 2-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)benzoate (82). Compound 82 was pre-
pared via procedure I from methyl 2-formylbenzoate (0.10 g, 0.61 mmol),
tryptamine (0.098 g, 0.61 mmol), and methyl acetopyruvate (0.088 g,
1
0.61 mmol) to yield a white solid (0.18 g, 72%). H NMR (400 MHz,
DMSO-d6) δ 10.82 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.46 (t,
J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.32−7.25 (m, 2H), 7.10 (d, J =
1.6 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H), 5.24 (s, 1H),
3.86 (s, 3H), 3.82−3.75 (m, 1H), 2.97−2.90 (m, 1H), 2.86−2.79 (m, 1H),
2.71−2.66 (m, 1H), 2.27 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ
191.6, 166.0, 165.0, 154.5, 137.8, 136.2, 132.5, 129.8, 129.0, 128.9, 128.3,
126.8, 122.9, 121.0, 119.9, 118.2, 118.0, 111.4, 110.7, 59.7, 52.2, 40.8, 29.8,
23.6; mp 210−218 °C. HMS (APCI) calcd for C24H22N2O5 419.1602;
found 419.1599 [M + H]+.
4-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-2,5-dihy-
dro-1H-pyrrol-2-yl)benzoic Acid (83). To a suspension of 1 (0.10 g,
0.24 mmol) in EtOH (3.5 mL) was added a 2N aq sodium hydroxide
solution (0.8 mL). The reaction was heated at reflux for 2 h. The
solution was then cooled to 0 °C, and concentrated HCl was added
carefully. The precipitate was filtered off, rinsed with cold water, and
dried under vacuum for 12 h to afford a white powder (0.090 g, 93%).
1H NMR (400 MHz, DMSO-d6) δ 10.89 (br s, 1H), 10.79 (br s, 1H),
8.09 (d, J = 8.0 Hz, 2H), 7.30−7.28 (m, 2H), 7.23 (d, J = 8.0 Hz, 2H),
7.03−7.01 (m, 2H), 6.90 (app t, J = 8.0 Hz, 1H), 5.56 (s, 1H), 3.77−3.74
(m, 1H), 2.89−2.71 (m, 1H), 2.71−2.61 (m, 2H), 2.10 (s, 3H). 13C
NMR (150 MHz, DMSO-d6) δ 196.5, 179.9, 169.3, 164.3, 146.9, 136.5,
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4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-3-nicotinoyl-5-oxo-2,5-di-
hydro-1H-pyrrol-2-yl)benzamide (89). Compound 89 was prepared
via procedure I from 42 (0.29 g, 2.0 mmol), tryptamine (0.32 g,
2.0 mmol), and 19 (0.44 g, 2.0 mmol) to yield a yellow solid (0.70 g,
76%). 1H NMR (600 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.81 (s, 1H),
8.66 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.45−7.32
(m, 6H), 7.12−7.06 (m, 3H), 6.95 (t, J = 7.2 Hz, 1H), 5.39 (s, 1H),
3.91−3.86 (m, 1H), 3.04−2.98 (m, 2H), 2.83−2.79 (m, 1H). 13C NMR
(150 MHz, DMSO-d6) δ 186.1, 175.4, 167.3, 165.0, 148.7, 139.8, 136.1,
135.7, 135.3, 134.0, 133.9, 127.4, 127.2, 126.7, 122.8, 122.7, 122.4, 120.6,
117.7, 111.1, 110.7, 108.5, 60.2, 39.9, 13.7; mp 175−180 °C. HMS
(APCI) calcd for C27H22N4O4 467.17138; found 467.17160 [M + H]+.
4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-3-nicotinoyl-5-oxo-2,5-di-
hydro-1H-pyrrol-2-yl)-N-methylbenzamide (90). Compound 90 was
prepared via procedure I from 43 (0.15 g, 0.93 mmol), tryptamine
(0.15 g, 0.93 mmol), and 19 (0.21 g, 0.93 mmol) to yield a yellow solid
(0.33 g, 73%). 1H NMR (600 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.79 (s,
1H), 8.67 (d, J = 4.8 Hz, 1H), 8.24 (d, J = 3.6 Hz, 1H), 7.99 (d, J = 7.8
Hz, 1H), 7.75 (d, J = 7.8 Hz, 2H), 7.45 (t, J = 5.4 Hz, 1H), 7.39−7.34 (m,
4H), 7.11−7.05 (m, 2H), 6.94 (t, J = 7.2 Hz, 1H), 5.38 (s, 1H), 3.88−
3.84 (m, 1H), 3.11−3.09 (m, 1H), 3.02−2.94 (m, 2H), 2.76 (d, J = 4.8
Hz, 3H). 13C NMR (150 MHz, DMSO-d6) δ 166.3, 165.0, 152.3,
149.3, 136.3, 136.1, 134.5, 128.1, 127.9, 127.3, 125.5, 123.4, 122.4, 122.9,
121.0, 118.5, 118.3, 118.14, 118.1, 111.6, 110.8, 60.4, 41.0, 26.2, 23.7
(note: carbon 4 is absent); mp 240−245 °C. HMS (APCI) calcd for
C28H24N4O4 481.1876; found 481.1879 [M + H]+.
4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-3-nicotinoyl-5-oxo-2,5-di-
hydro-1H-pyrrol-2-yl)-N,N-dimethylbenzamide (91). Compound 91
was prepared via procedure I from 19 (0.38 g, 1.7 mmol), tryptamine
(0.27 g, 1.7 mmol), and 44 (0.30 g, 1.7 mmol) to yield a yellow solid
(0.33 g, 39%). 1H NMR (600 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.81 (s,
1H), 8.69 (d, J = 4.8 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.49−7.47 (m,
2H), 7.36−7.29 (m, 4H), 7.14−7.10 (m, 2H), 7.06 (t, J = 7.8 Hz, 1H),
6.92 (t, J = 7.2 Hz, 1H), 5.42 (s, 1H), 3.88−3.82 (m, 1H), 3.02−2.95 (m,
5H), 2.84 (s, 3H), 2.77−2.71 (m, 1H). 13C NMR (150 MHz, DMSO-
d6) δ 169.71, 164.9, 152.3, 149.3, 136.4, 136.3, 136.2, 128.1, 127.8,
127.2, 125.5, 123.4, 122.9, 121.2, 121.0, 118.5, 118.3, 118.1, 111.6, 111.5,
110.8, 60.5, 41.0, 40.0, 23.8, 23.2 (note: carbon 4 is absent); mp 210−
212 °C. HMS (APCI) calcd for C29H26N4O4 495.2040; found 495.2036
[M + H]+.
1-(2-(1H-Indol-3-yl)ethyl)-3-hydroxy-4-nicotinoyl-5-(4-
(trifluoromethyl)phenyl)-1H-pyrrol-2(5H)-one (94). Compound 94
was prepared via procedure I from 4-(trifluoromethyl)benzaldehyde
(0.17 g, 1.0 mmol), 19 (0.22 g, 1.0 mmol), and tryptamine (0.16 g, 1.0
1
mmol) to yield a yellow solid (0.24 g, 49%). H NMR (600 MHz,
DMSO-d6) δ 10.94 (s, 1H), 8.83 (d, J = 1.2 Hz, 1H), 8.70 (dd, J = 1.8 Hz,
J = 4.8 Hz, 1H), 8.20 (br s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.66 (d, J =
7.8 Hz, 2H), 7.54−7.48 (m, 3H), 7.34 (d, J = 8.4 Hz, 1H), 7.24 (d, J =
7.8 Hz, 1H), 7.13 (s, 1H), 7.05 (t, J = 7.8 Hz, 1H), 6.91 (t, J = 7.2 Hz,
1H), 5.46 (s, 1H), 3.88−3.83 (m, 1H), 3.02−2.92 (m, 2H), 2.78−2.73
(m, 1H). 13C NMR (150 MHz, DMSO-d6) δ 181.2, 165.3, 151.8, 149.0,
141.9, 136.6, 136.3, 134.2, 128.9, 128.2, 126.9, 125.5, 125.4, 123.5, 122.9,
121.2, 121.1, 118.2, 118.0, 111.5, 110.7, 60.3, 41.2, 23.7 (note: either
carbon 1 or 2 is absent); mp 235−240 °C. HMS (APCI) calcd for
C27H20F3N3O3 492.1535; found 492.1532 [M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)-2-hydroxybenzoate (95). Compound 95
was prepared via procedure I from 35 (0.15 g, 0.83 mmol), tryptamine
(0.13 g, 0.83 mmol), and methyl acetopyruvate (0.12 g, 0.83 mmol) to
1
yield a brown solid (0.10 g, 27%). H NMR (400 MHz, DMSO-d6) δ
10.82 (s, 1H), 10.49 (s, 1H), 7.68 (dd, J = 8.0 Hz, J = 2.4 Hz, 1H), 7.34−
7.30 (m, 2H), 7.10 (s, 1H), 7.05 (t, J = 6.8 Hz, 1H), 6.92 (t, J = 6.8 Hz,
1H), 6.84 (s, 1H), 6.64 (d, J = 8.0 Hz, 1H), 5.12 (s, 1H), 3.86 (s, 3H),
3.83−3.76 (m, 1H), 2.98−2.83 (m, 2H), 2.75−2.68 (m, 1H), 2.27 (s,
3H). 13C NMR (150 MHz, DMSO-d6) δ 191.7, 168.8, 165.0, 159.8,
154.4, 154.1, 136.0, 130.3, 126.9, 122.8, 121.0, 119.6, 118.3, 118.2,
118.1, 117.0, 112.8, 111.4, 110.7, 59.6, 52.4, 40.9, 29.8, 23.5; mp 188−
190 °C. HMS (APCI) calcd for C24H22N2O6 435.1551; found 435.1549
[M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)-2-methoxybenzoate (96). Compound
96 was prepared via procedure I from 33 (0.1 g, 0.52 mmol), tryptamine
(0.083 g, 0.52 mmol), and methyl acetopyruvate (0.074 g, 0.52 mmol)
1
to yield a cream-colored solid (0.17 g, 74%). H NMR (600 MHz,
DMSO-d6) δ 10.83 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.34−7.31 (m, 2H),
7.11 (s, 1H), 7.06 (t, J = 6.8 Hz, 1H), 6.94−6.91 (m, 2H), 6.70 (d, J =
8.0 Hz, 1H), 5.14 (s, 1H), 3.83−3.76 (m, 7H), 2.99−2.84 (m, 2H),
2.75−2.69 (m, 1H), 2.28 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ
165.9, 165.0, 158.1, 136.2, 130.9, 128.1, 126.9, 125.5, 125.0, 122.9, 121.0,
119.6, 118.6, 118.3, 118.1, 111.5, 110.8, 60.0, 55.9, 51.9, 40.9, 40.0, 23.6
(note: carbons 3 and 4 are absent); mp 130−135 °C. HMS (APCI)
calcd for C25H24N2O6 449.1707; found 449.1709 [M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)-2-methylbenzoate (97). Compound 97
was prepared via procedure I from 40 (0.10 g, 0.56 mmol), tryptamine
(0.090 g, 0.56 mmol), and methyl acetopyruvate (0.081 g, 0.56 mmol)
to yield a pale-orange solid (0.13 g, 53%). 1H NMR (400 MHz, CDCl3)
δ 8.14 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.40−7.36 (m, 2H), 7.23 (t, J =
7.6 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.00 (s, 1H), 6.83 (d, J = 7.6 Hz,
1H), 6.74 (s, 1H), 4.76 (s, 1H), 4.07−4.02 (m, 1H), 3.90 (s, 3H), 3.11−
2.93 (m, 3H), 2.51 (s, 3H), 1.98 (s, 3H). 13C NMR (150 MHz, CDCl3)
δ 194.6, 167.6, 164.6, 159.8, 141.4, 139.0, 136.5, 131.5, 131.3, 130.5,
127.2, 125.2, 122.6, 122.3, 119.8, 119.5, 118.7, 112.4, 111.6, 61.4,
52.2, 41.3, 28.2, 24.4, 21.9; mp 40−43 °C. HMS (APCI) calcd for
C25H24N2O5 433.1745; found 433.1745 [M + H]+.
4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-3-nicotinoyl-5-oxo-2,5,-
dihydro-1H-pyrrol-2-yl)benzenesulfonamide (92). Compound 92 was
prepared via procedure I from 4-formylbenzenesulfonamide (0.19 g,
1.0 mmol), 19 (0.22 g, 1.0 mmol), and tryptamine (0.16 g, 1.0 mmol) to
yield a pale-orange solid (0.024 g, 5%). 1H NMR (600 MHz, DMSO-d6)
δ 10.86 (s, 1H), 8.81 (s, 1H), 8.69 (d, J = 4.2 Hz, 1H), 8.01 (d, J = 7.8 Hz,
1H), 7.76 (d, J = 9.0 Hz, 2H), 7.50−7.47 (m, 3H), 7.34 (d, J = 7.8 Hz,
2H), 7.32 (s, 2H), 7.14 (d, J = 1.8 Hz, 1H), 7.07 (t, J = 8.4 Hz, 1H), 6.96
(t, J = 7.2 Hz, 1H), 5.41 (s, 1H), 3.91−3.86 (m, 1H), 3.03−2.98 (m,
1H), 2.92−2.88 (m, 1H), 2.81−2.76 (m, 1H). 13C NMR (150 MHz,
DMSO-d6) δ 181.3, 165.0, 149.3, 149.1, 143.9, 140.6, 136.3, 133.9,
131.8, 128.6, 126.9, 125.9, 123.4, 122.9, 121.1, 118.4, 118.2, 111.5, 110.8,
60.1, 41.0, 23.7 (note: two of either carbons 1, 2, or 3 are absent);
mp >250 °C. HMS (APCI) calcd for C26H22N4O5S 503.1384; found
503.1381 [M + H]+.
4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-3-nicotinoyl-5-oxo-2,5-di-
hydro-3-nicotinoyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)-N-methylben-
zenesulfonamide (93). Compound 93 was prepared via procedure
I from 4-formyl-N-methylbenzenesulfonamide (0.20 g, 1.0 mmol), 19
(0.22 g, 1.0 mmol), and tryptamine (0.16 g, 1.0 mmol) to yield an
orange-yellow solid (0.11 g, 21%). 1H NMR (600 MHz, DMSO-d6) δ
10.84 (s, 1H), 8.80 (s, 1H), 8.50 (d, J = 4.8 Hz, 1H), 8.02−8.00 (m, 2H),
7.71 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 4.8 Hz,
1H), 7.34−7.29 (m, 3H), 7.09−7.05 (m, 2H), 6.94 (t, J = 7.8 Hz, 1H),
3.84−3.79 (m, 1H), 3.01−2.95 (m, 1H), 2.89−2.85 (m, 1H), 2.70−2.65
(m, 1H), 2.39 (d, J = 4.8 Hz, 3H). 13C NMR (150 MHz, DMSO-d6) δ
169.7, 149.9, 149.6, 149.5, 146.1, 138.0, 136.4, 136.3, 135.9, 128.5, 128.1,
127.0, 126.5, 125.6, 123.4, 122.7, 122.5, 121.0, 118.5, 118.3, 118.1, 111.5,
111.1, 60.3, 41.1, 28.7, 23.6; mp >220 °C. HMS (APCI) calcd for
C27H24N4O5S 517.1540; found 517.1545 [M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)-2-chlorobenzoate (98). Compound 98
was prepared via procedure I from 39 (0.09 g, 0.45 mmol), tryptamine
(0.073 g, 0.45 mmol), and methyl acetopyruvate (0.065 g, 0.45 mmol)
to yield a pale-orange, amorphous solid (0.14 g, 68%). 1H NMR
(400 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.40−
7.23 (m, 4H), 7.14−7.03 (m, 2H), 6.93 (t, J = 7.6 Hz, 1H), 5.13 (s, 1H),
3.83−3.78 (m, 4H), 2.98−2.82 (m, 2H), 2.75−2.68 (m, 1H), 2.27 (s,
3H). 13C NMR (150 MHz, DMSO-d6) δ 190.8, 165.2, 142.8, 136.2,
131.8, 131.2, 130.5, 129.4, 128.0, 126.8, 126.0, 122.9, 121.0, 118.3, 118.0,
111.4, 110.7, 59.1, 52.5, 48.6, 40.8, 23.6 (note: carbons 1 and 2 are
absent). HMS (APCI) calcd for 453.1225; found 453.1219 [M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)-2-fluorobenzoate (99). Compound 99
was prepared via procedure I from 38 (0.08 g, 0.44 mmol), tryptamine
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(0.070 g, 0.44 mmol), and methyl acetopyruvate (0.063 g, 0.44 mmol)
to yield a pale-orange solid (0.096 g, 50%). 1H NMR (400 MHz, CDCl3)
δ 8.42 (s, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.40−7.27 (m, 2H), 7.20 (t, J =
7.2 Hz, 1H), 7.14−7.06 (m, 1H), 6.95 (d, J = 1.2 Hz, 1H), 6.78 (dd, J =
1.2 Hz, J = 7.6 Hz, 1H), 6.70 (dd, J = 1.2 Hz, J = 10.8 Hz, 1H), 4.80 (s,
1H), 4.09−4.03 (m, 1H), 3.92 (s, 3H), 3.10−2.96 (m, 3H), 2.19 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 198.1, 193.6, 165.5, 162.0 (d, J =
260.4 Hz), 142.8 (d, J = 7.4 Hz), 136.5, 132.8, 127.0, 123.5, 123.4 (d,
J = 26.0 Hz), 122.5, 122.3, 122.1, 120.1, 119.7, 118.7, 118.5, 111.9, 111.7,
61.2, 52.6, 41.6, 29.2, 24.4; mp 40−45 °C. HMS (APCI) calcd for
C24H21FN2O5 437.1512; found 437.1512 [M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl) ethyl)-3-acetyl-4-hydroxy-5-oxo-2,
5-dihydro-1H-pyrrol-2-yl)-3-hydroxybenzoate (100). Compound 100
was prepared via procedure I from 34 (0.1 g, 0.56 mmol), tryptamine
(0.089 g, 0.52 mmol), and methyl acetopyruvate (0.080 g, 0.56 mmol)
to yield an off-white solid (0.020 g, 8%). 1H NMR (400 MHz, DMSO-
d6) δ 10.68 (s, 1H), 10.07 (br s, 1H), 7.47 (s, 1H), 7.35−7.29 (m, 3H),
7.05−7.02 (m, 3H), 6.91 (t, J = 10.8 Hz, 1H), 5.58 (s, 1H), 3.83 (s, 3H),
3.80−3.74 (m, 1H), 3.02−2.88 (m, 2H), 2.76−2.68 (m, 1H), 2.27 (s,
3H). 13C NMR (150 MHz, DMSO-d6) δ 196.6, 190.2, 163.6, 151.5,
136.4, 136.2, 127.0, 126.9, 123.5, 123.0, 122.5, 121.0, 118.32, 118.25,
118.0, 111.4, 111.2, 110.4, 94.5, 52.7, 52.2, 44.8, 29.3, 26.7; mp 194−
197 °C. HMS (APCI) calcd for C24H22N2O6 435.1551; found 435.1552
[M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)-3-methoxybenzoate (101). Compound
101 was prepared via procedure I from 41 (0.20 g, 1.0 mmol),
tryptamine (0.17 g, 1.0 mmol), and methyl acetopyruvate (0.15 g, 1.0
mmol) to yield an off-white solid (0.16 g, 36%). 1H NMR (600 MHz,
DMSO-d6, 56 °C) δ 10.68 (s, 1H), 7.53 (s, 1H), 7.48 (dd, J = 1.6 Hz,
J = 8.0 Hz, 1H), 7.32−7.28 (m, 2H), 7.06−7.02 (m, 3H), 6.92 (td, J = 7.2
Hz, J = 0.8 Hz, 1H), 5.59 (s, 1H), 3.86 (s, 6H), 3.81−3.72 (m, 1H),
2.97−2.85 (m, 2H), 2.84−2.69 (m, 1H), 2.27 (s, 3H). 13C NMR (150
MHz, DMSO-d6) δ 191.5, 165.9, 165.2, 157.9, 154.8, 136.2, 130.6,
126.9, 126.6, 122.7, 121.9, 121.0, 118.3, 117.8, 111.7, 111.5, 110.7, 56.0,
52.3, 41.0, 40.1, 29.7, 23.4 (note: carbon 3 and either carbon 1 or 2 are
absent); mp 103−107 °C. HMS (APCI) calcd for C25H24N2O6
449.1707; found 449.1704 [M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)-3-methylbenzoate (102). Compound
102 was prepared via procedure I from 36 (0.10 g, 0.56 mmol),
tryptamine (0.090 g, 0.56 mmol), and methyl acetopyruvate (0.081 g,
0.56 mmol) to yield an orange solid (0.12 g, 50%). 1H NMR (600 MHz,
DMSO-d6) δ 10.83 (s, 1H), 7.75 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.31
(d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 1.8 Hz, 1H),
7.04 (t, J = 7.2 Hz, 1H), 6.90 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H),
5.27 (s, 1H), 3.81 (s, 3H), 3.75 (dt, J = 8.4 Hz, J = 13.8 Hz, 1H), 2.94−
2.89 (m, 1H), 2.76−2.69 (m, 2H), 2.31 (s, 3H), 2.25 (s, 3H). 13C NMR
(150 MHz, DMSO-d6) δ 166.0, 165.5, 140.6, 138.2, 136.3, 131.0, 128.8,
127.0, 126.8, 125.4, 122.9, 121.1, 118.3, 117.7, 111.5, 110.7, 55.6, 41.5,
40.1, 23.6, 18.5, 14.1 (note: carbons 3 and 4, and either carbons 1 or 2
are absent); mp 60−70 °C. HMS (APCI) calcd for C25H24N2O5
433.1763; found 433.1764 [M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)-3-chlorobenzoate (103). Compound
103 was prepared via procedure I from 32 (0.10 g, 0.50 mmol),
tryptamine (0.081 g, 0.50 mmol), and methyl acetopyruvate (0.073 g,
0.50 mmol) to yield a pale-yellow solid (0.080 g, 35%). 1H NMR (400
MHz, DMSO-d6) δ 12.50 (br s, 1H), 10.81 (s, 1H), 7.95 (d, J = 1.6 Hz,
1H), 7.76 (dd, J = 1.2 Hz, J = 8.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.09−
7.01 (m, 3H), 6.91 (t, J = 7.6 Hz, 1H), 5.68 (s, 1H), 3.85 (s, 3H), 3.80−
3.73 (m, 1H), 2.97−2.84 (m, 2H), 2.77−2.72 (m, 1H), 2.28 (s, 3H).
13C NMR (100 MHz, DMSO-d6) δ 192.5, 170.4, 165.5, 164.8, 139.8,
136.2, 134.7, 130.8, 129.8, 128.2, 127.8, 126.9, 122.8, 121.0, 118.3, 117.7,
111.5, 110.4, 59.8, 55.6, 52.6, 41.5, 23.5 (note: carbon 3 is absent); mp
55−60 °C. HMS (APCI) calcd for C24H21ClN2O5 453.1225; found
453.1222 [M + H]+.
tryptamine (0.11 g, 0.67 mmol), and methyl acetopyruvate (0.097 g,
0.67 mmol) to yield an orange, amorphous solid (0.033 g, 11%). H
1
NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.42
(d, J = 7.6 Hz, 1H), 7.31−7.27 (m, 2H), 7.11 (t, J = 7.2 Hz, 1H), 7.20 (t,
J = 7.6 Hz, 1H), 6.93 (s, 1H), 5.52 (s, 1H), 4.02−3.97 (m, 1H), 3.88 (s,
3H), 3.02−2.87 (m, 3H), 2.35 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
192.9, 191.4, 171.1, 167.1 (d, J = 186.7 Hz), 162.7, 136.4, 132.6, 130.9,
127.4, 125.4, 122.3, 121.9, 119.2, 118.7, 116.9 (d, J = 23.8), 114.0, 112.5,
111.3, 102.3, 52.4, 45.9, 41.3, 28.4, 24.1. HMS (APCI) calcd for
C24H21FN2O5 437.1507; found 437.1509 [M + H]+.
Methyl 4-(4-Hydroxy-1-(2-(1-methyl-1H-Indol-3-yl)ethyl)-3-nicoti-
noyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (105). Compound
105 was prepared via procedure I from methyl 4-formylbenzoate
(0.16 g, 1.0 mmol), 19 (0.22 g, 1.0 mmol), and 2-(1-methyl-1H-indol-3-
yl)ethanamine (0.17 g, 1.0 mmol) to yield cream-colored solid (0.21 g,
43%). 1H NMR (600 MHz, DMSO-d6) δ 8.81 (d, J = 1.8 Hz, 1H), 8.70
(dd, J = 1.8 Hz, J = 4.8, 1H), 8.01 (dt, J = 1.8 Hz, 8.4 Hz, 1H), 7.88 (d, J =
8.4 Hz, 2H), 7.50−7.46 (m, 3H), 7.36 (d, J = 9.0 Hz, 1H), 7.32 (d, J = 8.4
Hz, 1H), 7.14−7.10 (m, 2H), 6.96 (t, J = 7.8 Hz, 1H), 5.50 (s, 1H),
3.85−3.80 (m, 4H), 3.70 (s, 3H), 3.00−2.92 (m, 2H), 2.76−2.72 (m,
1H). 13C NMR (150 MHz, DMSO-d6) δ 181.2, 165.9, 165.0, 153.9,
152.2, 149.1, 142.0, 136.6, 136.3, 133.9, 129.5, 129.4, 128.4, 127.3, 127.2,
123.5, 121.2, 118.4, 118.3, 110.1, 109.7, 60.4, 52.2, 41.3, 32.2, 23.5 (note:
either carbon 1 or 2 is absent); mp 215−218 °C. HMS (APCI) calcd for
C29H25N3O5 496.1867; found 496.1872 [M + H]+.
Methyl 4-(3-Acetyl-4-hydroxy-1-(2-(2-methyl-1H-indol-3-yl)-
ethyl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (106). Compound
106 was prepared via procedure I from methyl 4-formylbenzoate
(0.094 g, 0.57 mmol), 2-(2-methyl-1H-indol-3-yl)ethanamine (0.10 g,
0.57 mmol), and methyl acetopyruvate (0.083 g, 0.57 mmol) to yield a
cream-colored solid (0.18 g, 73%). 1H NMR (600 MHz, DMSO-d6) δ
10.73 (s, 1H), 7.85 (d, J = 9.0 Hz, 2H), 7.21 (d, J = 7.8 Hz, 1H), 7.18−
7.15 (m, 3H), 6.97 (t, J = 7.8 Hz, 1H), 6.86 (t, J = 7.8 Hz, 1H), 5.03 (s,
1H), 3.83 (s, 3H), 3.64−3.59 (m, 1H), 2.92−2.87 (m, 1H), 2.77−2.72
(m, 1H), 2.60−2.56 (m, 1H), 2.26 (s, 3H), 2.17 (s, 3H). 13C NMR (150
MHz, DMSO-d6) δ 191.1, 165.9, 165.0, 142.4, 135.1, 132.2, 129.8,
129.7, 129.3, 128.1, 127.9, 125.6, 120.1, 118.2, 117.0, 110.5, 106.5, 60.1,
52.1, 40.9, 39.9, 24.5, 10.9; mp 182−187 °C. HMS (APCI) calcd for
C25H24N2O5 433.1758; found 433.1759 [M + H]+.
Methyl 4-(4-Hydroxy-1-(2-(4-methyl-1H-indol-3-yl)ethyl)-3-nicoti-
noyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (107). Compound
107 was prepared via procedure I from methyl 4-formylbenzoate
(0.16 g, 1.0 mmol), 19 (0.22 g, 1.0 mmol), and 2-(4-methyl-1H-indol-3-
yl)ethanamine (0.17 g, 1.0 mmol) to yield a pale-yellow solid (0.05 g,
11%). 1H NMR (600 MHz, DMSO-d6) δ 10.84 (d, J = 1.8 Hz, 1H), 8.82
(d, J = 1.8 Hz, 1H), 8.70 (dd, J = 1.8 Hz, J = 4.8 Hz, 1H), 8.01 (dt, J = 1.8
Hz, J = 8.4 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.49−7.44 (m, 3H), 7.15
(d, J = 8.4 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.92 (t, J = 6.6 Hz, 1H), 6.67
(d, J = 7.2 Hz, 1H), 5.48 (s, 1H), 3.89−3.81 (m, 4H), 3.14−3.09 (m,
1H), 2.98−2.87 (m, 2H), 2.44 (s, 3H). 13C NMR (150 MHz, DMSO-
d6) δ 186.9, 165.9, 165.1, 152.3, 149.3, 142.2, 136.7, 136.2, 133.9, 129.5,
129.4, 128.3, 125.4, 123.4, 123.1, 122.9, 121.1, 120.1, 119.9, 118.2, 111.5,
109.6, 66.4, 60.4, 52.2, 25.5, 19.7; mp 170−175 °C. HMS (APCI) calcd
for C29H25N3O5 496.1845; found 496.1850 [M + H]+.
Methyl 4-(4-Hydroxy-1-(2-(5-methoxy-1H-indol-3-yl)ethyl)-3-nic-
otinoyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (108). Com-
pound 108 was prepared via procedure I from methyl 4-formylbenzoate
(0.16 g, 1.0 mmol), 19 (0.22 g, 1.0 mmol), and 2-(5-methoxy-1H-indol-
3-yl)ethanamine (0.19 g, 1.0 mmol) to yield a yellow solid (0.35 g, 68%).
1H NMR (600 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.79 (d, J = 1.8 Hz,
1H), 8.68 (dd, J = 1.8 Hz, J = 4.8 Hz, 1H), 7.99 (dt, J = 1.8 Hz, J = 7.8 Hz,
1H), 7.88 (d, J = 8.4 Hz, 2H), 7.48−7.46 (m, 1H), 7.44 (d, J = 7.8 Hz,
2H), 7.22−7.21 (m, 2H), 7.09 (d, J = 2.4 Hz, 1H), 6.75 (d, J = 2.4 Hz,
1H), 6.70 (dd, J = 2.4 Hz, J = 9.0 Hz, 1H), 5.44 (s, H), 3.85−3.80 (m,
4H), 2.68 (s, 3H), 2.98−2.89 (m, 2H), 2.73−2.70 (m, 1H). 13C NMR
(150 MHz, DMSO-d6) δ 186.7, 181.1, 165.9, 165.2, 153.0, 152.0, 149.1,
142.4, 136.3, 134.1, 131.4, 129.5, 129.4, 128.3, 127.2, 123.6, 123.5, 117.9,
112.2, 111.3, 110.5, 99.7, 60.4, 55.2, 52.2, 41.1, 23.8; mp 222−225 °C.
HMS (APCI) calcd for C29H25N3O6 512.1816; found 512.1822
[M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)-3-fluorobenzoate (104). Compound
104 was prepared via procedure I from 37 (0.12 g, 0.67 mmol),
2350
dx.doi.org/10.1021/jm401695d | J. Med. Chem. 2014, 57, 2334−2356

Journal of Medicinal Chemistry
Article
Methyl 4-(1-(2-(6-Fluoro-1H-indol-3-yl)ethyl)-4-hydroxy-3-nicoti-
noyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (109). Compound
109 was prepared via procedure I from methyl 4-formylbenzoate
(0.16 g, 1.0 mmol), 19 (0.22 g, 1.0 mmol), and 3-(6-fluoro-1H-indol-3-
yl)ethanamine (0.18 g, 1.0 mmol) to yield a pale-orange solid (0.44 g,
1H NMR (600 MHz, DMSO-d6) δ 11.30 (s, 1H), 10.11 (s, 1H), 8.74 (m,
1H), 8.46 (m, 1H), 7.98−7.97 (m, 1H), 7.87−7.86 (m, 1H), 7.37−7.33
(m, 2H), 7.28 (m, 1H), 7.16−7.14 (m, 2H), 6.89−6.87 (m, 2H), 5.23 (s,
1H), 3.84−3.76 (m, 4H), 2.92 (m, 1H), 2.79 (m, 1H), 2.73−2.68 (m,
1H). 13C NMR (150 MHz, DMSO-d6) δ 193.0 (d, J = 13.4 Hz), 169.4,
166.2, 165.5, 150.0, 149.5, 148.4, 147.7, 139.1, 136.6, 134.3, 131.1, 129.7,
129.0, 128.7, 128.3, 127.7, 124.0, 118.6, 114.7, 112.4, 105.8, 60.0 (d, J =
45.5 Hz), 52.0 (d, J = 41.2 Hz), 40.1 (d, J = 21.8 Hz), 23.3; mp 65−69 °C.
HMS (APCI) calcd for C28H22FN3O5 500.1616; found 500.1616
[M + H]+.
Methyl 4-(1-(2-(7-Chloro-1H-indol-3-yl)ethyl)-4-hydroxy-3-nicoti-
noyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (114). To a slurry of
2-(7-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.15 g, 0.65 mmol)
in MeOH (0.072 mL) was added triethylamine (0.11 mL, 0.78 mmol).
Ether (3.62 mL) was added, and the mixture was stirred at −10 °C for 1 h.
The resulting triethylamine hydrochloride salt was filtered off, and the
filtrate was concentrated in vacuo to afford a white solid (0.074 g, 58%)
which was carried on immediately. Compound 114 was prepared via
procedure I from methyl 4-formylbenzoate (0.064 g, 0.39 mmol), 19
(0.086 g, 0.39 mmol), and 2-(7-chloro-1H-indol-3-yl)ethanamine hydro-
chloride (0.074 g, 0.39 mmol) to yield a yellow solid (0.009 g, 5%). 1H
NMR (600 MHz, DMSO-d6) δ 11.22 (s, 1H), 8.80 (s, 1H), 8.69 (d, J = 4.2
Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.49−7.44 (m,
3H), 7.31 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 1.8 Hz, 1H), 7.14 (d, J = 7.2 Hz,
1H), 6.94 (t, J = 7.2 Hz, 1H), 5.49 (s, 1H), 3.89−3.82 (m, 4H), 3.00−2.91
(m, 2H), 2.83−2.78 (m, 1H). 13C NMR (150 MHz, DMSO-d6) δ 181.3,
165.9, 165.0, 152.4, 149.3, 142.0, 136.2, 133.9, 133.0, 129.5, 129.4, 129.0,
128.3, 124.4, 123.5, 120.6, 119.4, 118.2, 117.3, 115.9, 112.3, 60.2, 52.2,
41.0, 23.6 (note: one of either carbon 1, 2, or 3 are absent); mp 246−
249 °C. HMS (APCI) calcd for C28H22ClN3O5 516.1321; found 516.1325
[M + H]+.
Methyl 4-(3-Acetyl-4-hydroxy-1-(2-(7-methyl-1H-indol-3-yl)-
ethyl)-5-oxo-2, 5-dihydro-1H-pyrrol-2-yl) benzoate (115). Com-
pound 115 was prepared via procedure I from methyl 4-formylbenzoate
(0.094 g, 0.57 mmol), 2-(7-methyl-1H-indol-3-yl) ethanamine (0.10 g,
0.57 mmol), and methyl acetopyruvate (0.083 g, 0.57 mmol) to yield a
white solid (0.16 g, 66%). 1H NMR (400 MHz, DMSO-d6) δ 12.50 (br s,
1H), 10.78 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H),
7.12−7.07 (m, 2H), 6.83−6.82 (m, 2H), 5.20 (s, 1H), 3.83−3.76 (m,
4H), 2.98−2.80 (m, 2H), 2.80−2.66 (m, 1H), 2.41 (s, 3H), 2.26 (s, 3H).
13C NMR (150 MHz, DMSO-d6) δ 165.9, 165.0, 142.4, 135.7, 129.3,
128.1, 126.5, 125.5, 122.5, 121.5, 120.5, 118.5, 115.7, 111.1, 109.7,
59.7, 52.1, 40.8, 40.0, 23.7, 16.7 (note: carbons 3 and 4 are absent); mp
220−227 °C. HMS (APCI) calcd from C25H24N2O5 433.1758; found
433.1758 [M + H]+.
1
87%). H NMR (600 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.82 (d, J =
0.6 Hz, 1H), 8.69 (d, J = 4.8 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.88 (d,
J = 8.4 Hz, 2H), 7.80 (br s, 1H), 7.49−7.47 (m, 1H), 7.43 (d, J = 7.8 Hz,
2H), 7.33−7.30 (m, 1H), 7.31−7.10 (m, 2H), 6.79 (td, J = 9.6 Hz, J = 1.8
Hz, 1H), 5.44 (s, 1H), 3.89−3.82 (m, 4H), 2.98−2.91 (m, 2H), 2.80−
2.76 (m, 1H). 13C NMR (150 MHz, DMSO-d6) δ 186.9, 181.1, 165.9,
165.1, 159.7, 158.1, 152.3, 142.2, 136.3, 136.1, 133.9, 129.5, 129.3,
128.3, 125.5, 123.8, 123.4, 119.1, 118.1, 111.1, 106.7, 106.6, 60.4 (d, J =
14.4 Hz), 52.1, 41.1, 23.1; mp 162−167 °C. HMS (APCI) calcd for
C28H22FN3O5 500.1595; found 500.1600 [M + H]+.
Methyl 4-(1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-hydroxy-3-nicoti-
noyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (110). Compound
110 was prepared via procedure I from methyl 4-formylbenzoate
(0.16 g, 1.0 mmol), 19 (0.22 g, 1.0 mmol), and 2-(6-chloro-1H-indol-3-
yl)ethanamine (0.20 g, 1.0 mmol) to yield a yellow solid (0.44 g, 85%).
1H NMR (600 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.80 (s, 1H), 8.68 (d,
J = 3.6 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.77
(br s, 1H), 7.48−7.41 (m, 3H), 7.37 (d, J = 1.2 Hz, 1H), 7.33 (d, J = 8.4
Hz, 1H), 7.17 (s, 1H), 6.94 (dd, J = 1.2 Hz, J = 8.4 Hz, 1H), 3.87−3.82
(m, 4H), 2.97−2.89 (m, 2H), 2.79−2.76 (m, 1H). 13C NMR (150 MHz,
DMSO-d6) δ 181.2, 165.9, 165.3, 149.2, 136.6, 136.2, 129.44, 129.36,
128.3, 128.1, 125.8, 125.7, 125.5, 124.7, 124.1, 123.3, 119.5, 118.8, 118.6,
111.2, 111.1, 109.8, 60.3, 52.1, 41.0, 23.4; mp 184−189 °C. HMS
(APCI) calcd for C28H22ClN3O5 516.1321; found 516.1324 [M + H]+.
Methyl 4-(4-Hydroxy-1-(2-(6-methyl-1H-indol-3-yl)ethyl)-3-nicoti-
noyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (111). Compound
111 was prepared via procedure I from methyl 4-formylbenzoate
(0.16 g, 1.0 mmol), 19 (0.22 g, 1.0 mmol), and 2-(6-methyl-1H-indol-3-
yl)ethanamine (0.17 g, 1.0 mmol) to yield a cream-colored solid (0.10 g,
20%). 1H NMR (600 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.79 (s, 1H),
8.68 (d, J = 3.6 Hz, 1H), 7.99 (d, J = 6.6 Hz, 1H), 7.87 (d, J = 7.8 Hz,
2H), 7.47 (t, J = 6.0 Hz, 1H), 7.42 (d, J = 7.8 Hz, 2H), 7.17 (d, J = 7.8 Hz,
1H), 7.11 (s, 1H), 7.02 (s, 1H), 6.75 (d, J = 7.8 Hz, 1H), 5.40 (s, 1H),
3.90−3.82 (m, 4H), 2.99−2.89 (m, 2H), 2.74−2.71 (m, 1H), 2.37 (s,
3H). 13C NMR (150 MHz, DMSO-d6) δ 186.7, 165.9, 165.1, 152.1,
149.1, 142.3, 136.7, 136.2, 134.0, 130.0, 129.5, 129.4, 128.4, 128.1, 125.5,
124.9, 123.4, 122.2, 120.0, 117.8, 111.3, 110.6, 60.4, 52.2, 41.1, 23.8,
21.4; mp 202−207 °C. HMS (APCI) calcd for C29H25N3O5 496.1867;
found 496.1868 [M + H]+.
Methyl 4-(4-Hydroxyl-1-(2-(6-methyoxy-1H-indol-3-yl)ethyl)-3-
nicotinoyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (112). Com-
pound 112 was prepared via procedure I from methyl 4-formylbenzoate
(0.16 g, 1.0 mmol), 19 (0.22 g, 1.0 mmol), and 2-(6-methoxy-1H-indol-
3-yl)ethanamine (0.19 g, 1.0 mmol) to yield a pale-orange solid (0.39 g,
76%). 1H NMR (600 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.78 (s, 1H),
8.67 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.55 (d,
J = 7.2 Hz, 1H), 7.41 (d, J = 7.8 Hz, 2H), 7.11 (d, J = 7.8 Hz, 1H), 6.96 (s,
1H), 6.83 (s, 1H), 6.58 (d, J = 7.8 Hz, 1H), 5.39 (s, 1H), 3.82 (s, 3H),
3.75−3.70 (m, 4H), 2.94−2.90 (m, 2H), 2.71−2.69 (m, 1H). 13C NMR
(150 MHz, DMSO-d6) δ 165.8, 155.6, 145.7, 137.6, 137.4, 137.0, 130.8,
130.4, 129.5, 129.4, 128.3, 128.11, 128.07, 125.5, 121.3, 118.7, 110.8,
108.5, 107.5, 94.5, 60.4, 55.2, 40.9, 23.8, 20.8 (note: two of either
carbon 1, 2, or 3 are absent); mp 195−200 °C. HMS (APCI) calcd for
C29H25N3O6 512.1816; found 512.1821 [M + H]+.
Ethyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-3-nicotinoyl-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)benzoate (116). Compound 116 was
prepared via procedure I from 19 (0.15 g, 0.68 mmol), tryptamine
(0.11 g, 0.68 mmol), and 35 (0.12 g, 0.68 mmol) to yield a yellow solid
(0.027 g, 8%). 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.75 (s,
1H), 8.48 (d, J = 3.2 Hz, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.83 (d, J = 8.0
Hz, 2H), 7.34−7.27 (m, 5H), 7.08−7.04 (m, 2H), 6.92 (t, J = 7.2 Hz,
1H), 5.33 (s, 1H), 4.28 (q, J = 7.6 Hz, 2H), 3.84−3.77 (m, 1H), 3.00−
2.93 (m, 1H), 2.87−2.80 (m, 1H), 2.73−2.66 (m, 1H), 1.28 (t, J = 6.8
Hz, 3H). 13C NMR (150 MHz, DMSO-d6) δ 186.8, 182.1, 162.9, 155.0,
148.3, 148.1, 136.4, 136.3, 127.0, 123.8, 123.4, 123.2, 123.1, 121.5, 121.3,
120.8, 118.5, 118.2, 117.8, 111.8, 111.2, 109.5, 60.6, 45.3, 23.6, 23.3,
14.0; mp >250 °C. HMS (APCI) calcd for C29H25N3O5 496.1867; found
496.1872 [M + H]+.
Methyl 4-(1-(2-(7-Fluoro-1H-indol-3-yl)ethyl)-4-hydroxy-3-nicoti-
noyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (113). To a slurry of
2-(7-fluoro-1H-indol-3-yl)ethanamine hydrochloride (0.05 g, 0.23 mmol)
in MeOH (0.026 mL) was added triethylamine (0.039 mL, 0.28 mmol).
Ether (1.3 mL) was added, and the mixture was stirred at −10 °C for 1 h.
The resulting triethylamine hydrochloride salt was filtered off, and the
filtrate was concentrated in vacuo to afford a white solid (0.040 g, >99%)
which was carried on immediately. Compound 113 was prepared via
procedure I from methyl 4-formylbenzoate (0.039 g, 0.24 mmol), 19
(0.052 g, 0.24 mmol), and 2-(7-fluoro-1H-indol-3-yl)ethanamine hydro-
chloride (0.040 g, 0.24 mmol) to yield a pale-yellow solid (0.11 g, 97%).
Ethyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-4-hydroxy-3-isonicotinoyl-5-
oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (117). Compound 117
was prepared via procedure I from 45 (0.40 g, 2.3 mmol), tryptamine
(0.36 g, 2.3 mmol), and 20 (0.50 g, 2.3 mmol) to yield a yellow solid
(0.019 g, 2%). 1H NMR (600 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.68 (d,
J = 5.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 5.4 Hz, 2H), 7.40
(d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H),
7.12 (d, J = 1.8 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.92 (t, J = 7.2 Hz, 1H),
5.40 (s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 3.88−3.82 (m, 1H), 3.00−2.90
(m, 2H), 2.78−2.73 (m, 1H), 1.29 (7.2 Hz, 3H). 13C NMR (150 MHz,
DMSO-d6) δ 189.0, 165.4, 165.0, 149.6, 145.8, 142.2, 136.2, 129.8,
2351
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Journal of Medicinal Chemistry
Article
129.7, 129.3, 128.3, 126.9, 122.9, 121.8, 121.1, 118.3, 118.1, 117.35,
111.5, 110.7, 60.7, 60.3, 41.1, 23.6, 14.2; mp 169−172 °C. HMS (APCI)
calcd for C29H25N3O5 496.1880; found 496.1877 [M + H]+.
120.8, 118.3, 118.0, 113.4, 111.4, 60.4, 52.3, 40.7, 28.0, 22.1 (note: either
carbon 1 or 2 and carbon 3 are absent); mp 221−226 °C. HMS (APCI)
calcd for C29H25N3O5 496.1845; found 496.1852 [M + H]+.
Methyl 4-(4-Hydroxy-1-(2-(2-methyl-1H-indol-3-yl)ethyl)-3-nicoti-
noyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (118). Compound
118 was prepared via procedure I from 19 (0.15 g, 0.68 mmol), 2-(2-
methyl-1H-indol-3-yl)ethanamine (0.12 g, 0.68 mmol), and methyl
4-formylbenzoate (0.11 g, 0.68 mmol) to yield an orange solid (0.046 g,
14%). 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.73 (s, 1H),
8.48 (d, J = 4.4 Hz, 1H), 7.93 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.30−7.17
(m, 5H), 6.97 (t, J = 6.4 Hz, 1H), 6.86 (t, J = 7.2 Hz, 1H), 5.23 (s, 1H),
3.81 (s, 3H), 3.63−3.56 (m, 1H), 2.96−2.88 (m, 1H), 2.76−2.69 (m,
1H), 2.57−2.50 (m, 1H), 2.18 (s, 3H). 13C NMR (150 MHz, DMSO-
d6) δ 182.6, 166.0, 150.4, 150.1, 149.2, 136.8, 136.1, 135.5, 135.2, 132.2,
129.0, 128.6, 128.0, 123.6, 122.6, 120.1, 118.2, 117.0, 110.6, 106.7, 61.2,
52.0, 41.3, 22.6, 11.0 (note: two of carbons 1, 2, 3, or 4 are absent);
mp >250 °C. HMS (APCI) calcd for C29H25N3O5 496.1867; found
496.1872 [M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-methoxy-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)benzoate (156). To a solution of 1 (0.50
g, 1.2 mmol) in DCM:MeOH (1:1, 0.13M) was added (diazomethyl)-
trimethylsilane (0.72 mL, 1.4 mmol). The reaction mixture continued to
stir at rt for 5 h before being concentrated in vacuo. The crude residue
was then purified using flash column chromatography on SiO2 (3%
1
MeOH/DCM) to yield a pale-yellow solid (0.24 g, 46%). H NMR
(400 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.88 (dd, J = 1.6 Hz, J = 8.0 Hz,
2H), 7.33−7.24 (m, 4H), 7.09−7.03 (m, 2H), 6.92 (t, J = 7.6 Hz, 1H),
5.20 (s, 1H), 4.36 (s, 3H), 3.84 (s, 3H), 3.80−3.71 (m, 1H), 2.96−2.89
(m, 1H), 2.84−2.77 (m, 1H), 2.72−2.63 (m, 1H), 2.25 (s, 3H). 13C
NMR (150 MHz, DMSO-d6) δ 191.9, 165.9, 164.2, 154.0, 141.7, 136.2,
129.5, 129.3, 128.2, 126.8, 126.2, 122.9, 121.0, 118.3, 118.0, 111.5, 110.7,
59.5, 59.1, 52.2, 40.9, 30.3, 23.6; mp 40−45 °C. HMS (APCI) calcd for
C25H24N2O5 433.1763; found 433.1761 [M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-amino-5-oxo-2,5-
dihydro-1H-pyrrol-2-yl)benzoate (157). To a solution of 1 (0.50 g,
1.2 mmol) in 2-methoxyethanol (8.36 mL, 0.14 M) was added
ammonium formate (0.11 mL, 2.2 mmol, 1.8 equiv). The reaction
mixture was refluxed for 3 h before being concentrated in vacuo, ground
with a mortar and pestle, and triturated with Et2O. Further purification
was achieved via flash column chromatography on SiO2 (10% MeOH/
DCM) to yield a pale-yellow solid (0.070 g, 14%). 1H NMR (400 MHz,
CDCl3, 56 °C) δ 10.02 (br s, 1H), 8.36 (br s, 1H), 7.92 (d, J = 8.0 Hz,
2H), 7.39−7.34 (m, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.08−7.02 (m, 3H),
6.97 (s, 1H), 6.44 (br s, 1H), 4.77 (s, 1H), 4.04−3.97 (m, 1H), 3.91 (s,
3H), 3.09−2.99 (m, 2H), 2.92−2.85 (m, 1H), 1.56 (s, 3H). 13C NMR
(150 MHz, DMSO-d6) δ 177.8, 165.9, 164.4, 163.2, 144.7, 136.2, 129.7,
129.5, 128.3, 126.9, 122.7, 121.0, 118.2, 118.0, 111.4, 110.8, 105.6,
58.0, 52.1, 48.6, 41.0, 23.2; mp 50−54 °C. HMS (APCI) calcd for
C24H23N3O4 418.1766; found 418.1766 [M + H]+.
Methyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-4-acetoxy-3-acetyl-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)benzoate (158). To a solution of 1 (0.50 g,
1.2 mmol) in DCM (11 mL, 0.11 M) was added acetic anhydride
(0.14 mL, 1.4 mmol, 1.2 equiv) and pyridine (0.14 mL, 1.8 mmol,
1.5 equiv). The reaction mixture was stirred at rt for 61/2 h before being
concentrated in vacuo. The crude material was then purified by flash
column chromatography on SiO2 (3% MeOH/DCM). Additional
purification was achieved using HPLC (75% ACN with 0.1% formic
acid) to give a yellow oil (0.038 g, 7%). 1H NMR (400 MHz, CDCl3) δ
8.06 (s, 1H), 7.94−7.92 (m, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.21 (t, J =
8.0 Hz, 1H), 7.10−7.05 (m, 3H), 6.98 (d, J = 2.0 Hz, 1H), 4.93 (s, 1H),
4.07−4.00 (m, 1H), 3.91 (s, 3H), 3.08−2.89 (m, 3H), 2.47 (s, 3H), 2.26
(s, 3H); 13C NMR (150 MHz, CDCl3) δ 191.5, 167.0, 166.6, 163.8,
147.7, 139.2, 137.0, 136.6, 131.0, 130.4, 128.1, 127.4, 122.6, 122.2, 119.9,
118.7, 112.6, 111.5, 62.3, 62.4, 41.5, 30.1, 24.4, 20.8. HMS (APCI) calcd
for C26H24N2O6 461.1721; found 461.1717 [M + H]+.
Methyl 4-(3-Acetyl-4-(butyryloxy)-1-(2-(2-methyl-1H-indol-3-yl)-
ethyl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (159). To a sol-
ution of 106 (0.30 g, 0.69 mmol) and triethylamine (0.19 mL, 1.4 mmol,
2.0 equiv) in THF (0.69 mL, 1.0 M) at −30 °C was added butyryl
chloride (0.072 mL, 0.69 mmol, 1.0 equiv) dropwise over 20 min. The
mixture was allowed to stir at −30 °C for 2 h before being concentrated
in vacuo. The crude material was dissolved in EtOAc, washed with
water and brine, dried over MgSO4, filtered, and concentrated in vacuo.
Purification was achieved via flash column chromatography on SiO2
(10% EtOAc:DCM) to afford a yellow, amorphous solid (0.12 g, 35%).
1H NMR (600 MHz, CDCl3) δ 7.96 (s, 1H), 7.88 (d, J = 7.8 Hz, 2H),
7.25 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H),
7.01 (t, J = 7.2 Hz, 1H), 6.94 (d, J = 7.8 Hz, 2H), 4.78 (s, 1H), 3.89 (s,
3H), 3.87−3.82 (m, 1H), 3.02 (dt, J = 13.8 Hz, J = 8.4 Hz, 1H), 2.91 (dt,
J = 13.8 Hz, J = 7.8 Hz, 1H), 2.82−2.78 (m, 1H), 2.70 (t, J = 7.8 Hz, 2H),
2.24 (s, 3H), 2.23 (s, 3H), 1.85 (sextet, 7.8 Hz, 2H), 1.09 (t, J = 7.2 Hz,
3H). 13C NMR (150 MHz, CDCl3) δ 191.6, 170.0, 166.6, 163.7, 147.9,
139.1, 136.9, 135.4, 132.1, 130.8, 130.2, 128.3, 128.0, 121.5, 119.7, 117.8,
110.6, 108.0, 62.5, 52.4, 41.4, 35.9, 30.2, 23.3, 18.4, 13.7, 11.5. HMS
(APCI) calcd for C29H30N2O6 503.2168; found 503.2172 [M + H]+.
Ethyl 4-(3-Acetyl-4-hydroxy-1-(2-(2-methyl-1H-indol-3-yl)ethyl)-
5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (119). Compound 119
was prepared via procedure I from 45 (0.15 g, 0.84 mmol), 2-(2-methyl-
1H-indol-3-yl)ethanamine (0.15 g, 0.84 mmol), and methyl acetopyr-
uvate (0.12 g, 0.84 mmol) to yield a cream-colored solid (0.078 g, 21%).
1H NMR (600 MHz, DMSO-d6, 80 °C) δ 10.5 (br s, 1H), 7.83 (d, J = 7.2
Hz, 2H), 7.23−7.18 (m, 4H), 6.95 (t, J = 7.2 Hz, 1H), 6.86 (t, J = 7.2 Hz,
1H), 5.09 (s, 1H), 4.30 (q, J = 7.2 Hz, 2H), 3.61−3.56 (m, 1H), 2.92−
2.87 (m, 1H), 2.80−2.75 (m, 1H), 2.57−2.53 (m, 1H), 2.19 (s, 3H),
2.05 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, DMSO-d6) δ
191.3, 189.3, 165.5, 135.1, 132.1, 129.1, 127.9, 120.1, 118.1, 117.0, 112.1,
110.5, 108.9, 106.6, 98.5, 90.2, 54.9, 48.7, 48.6, 40.0, 29.0, 14.2, 11.0
(note: one of either carbon 1, 2, or 4 is absent); mp 190−195 °C. HMS
(APCI) calcd for C26H26N2O5 447.1928; found 447.30 [M + H]+.
Ethyl 4-(1-(2-(1H-Indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-2,5-
dihydro-1H-pyrrol-2-yl)-3-hydroxybenzoate (120). Compound 120
was prepared via procedure I from 189 (0.15 g, 0.77 mmol), tryptamine
(0.12 g, 0.77 mmol), and methyl acetopyruvate (0.11 g, 0.77 mmol) to
yield a cream-colored solid (0.20 g, 57%). 1H NMR (400 MHz, DMSO-
d6) δ 10.81 (s, 1H), 10.42 (s, 1H), 7.59−7.46 (m, 1H), 7.34−7.23 (m,
3H), 7.12−7.02 (m, 2H), 6.97−6.89 (m, 2H), 5.76 (s, 1H), 4.28 (q, J =
7.2 Hz, 2H), 3.78−3.74 (m, 1H), 2.98−2.85 (m, 2H), 2.73−2.68 (m,
1H), 2.28 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz,
DMSO-d6) δ 191.7, 165.5, 165.1, 156.2, 154.8, 136.2, 130.5, 128.1,
127.0, 126.7, 125.5, 122.7, 121.0, 120.2, 118.3, 118.0, 116.1, 111.4, 110.8,
60.7, 41.0, 40.0, 29.7, 23.4, 14.2; mp 200−205 °C. HMS (APCI) calcd
for C25H24N2O6 449.1721; found 449.1723 [M + H]+.
Methyl 4-(1-((1H-Indol-3-yl)methyl)-4-hydroxy-3-isonicotinoyl-5-
oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (121). Compound 121
was prepared via procedure I from methyl 4-formylbenzoate (0.28 g,
1.7 mmol), (1H-indol-3-yl)methanamine (0.25 g, 1.7 mmol), and 20
(0.38 g, 1.7 mmol) to yield an orange solid (0.78 g, 98%). 1H NMR (400
MHz, DMSO-d6) δ 11.08 (s, 1H), 8.66 (d, J = 5.6 Hz, 2H), 7.92 (d, J =
8.0 Hz, 2H), 7.51−7.37 (m, 6H), 7.13−7.08 (m, 2H), 6.97 (t, J = 7.2 Hz,
1H), 5.11−5.07 (m, 2H), 3.84 (s, 3H), 3.80 (d, J = 14.8 Hz, 1H). 13C
NMR (150 MHz, DMSO-d6) δ 166.0, 165.1, 149.2, 129.45, 129.36,
128.2, 128.1, 126.2, 125.5, 125.1, 122.0, 121.7, 121.5, 119.0, 118.9, 118.6,
118.2, 111.7, 109.3, 59.2, 52.2, 35.5 (note: carbon 4 is absent); mp 240−
243 °C. HMS (APCI) calcd for C27H21N3O5 468.1567; found 468.1566
[M + H]+.
Methyl 4-(1-(3-(1H-Indol-3-yl)propyl)-4-hydroxy-3-nicotinoyl-5-
oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (122). Compound 122
was prepared via procedure I from methyl 4-formylbenzoate (0.16 g,
1.0 mmol), 19 (0.22 g, 1.0 mmol), and 3-(1H-indol-3-yl)propan-1-
amine (0.17 g, 1.0 mmol) to yield a yellow solid (0.35 g, 71%). 1H NMR
(600 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.82 (s, 1H), 8.69 (d, J = 4.8 Hz,
1H), 8.02 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.49−7.47 (m,
3H), 7.37 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.06−7.03 (m,
2H), 6.92 (t, J = 7.2 Hz, 1H), 5.54 (s, 1H), 3.62−3.55 (m, 4H), 2.83−
2.79 (m, 1H), 2.62−2.55 (m, 2H), 1.84−1.80 (m, 1H), 1.73−1.69 (m,
1H). 13C NMR (150 MHz, DMSO-d6) δ 186.9, 165.9, 165.2, 154.4,
152.1, 149.2, 142.4, 136.3, 134.0, 129.5, 128.3, 127.0, 123.5, 122.4, 122.3,
2352
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Journal of Medicinal Chemistry
Article
Methyl 4-(3-Acetyl-4-(acryloyloxy)-1-(2-(2-methyl-1H-indol-3-yl)-
ethyl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (160). To a sol-
ution of 106 (3.0 g, 6.9 mmol) and triethylamine (1.9 mL, 14 mmol,
2.0 equiv) in THF (6.9 mL, 1.0 M) at −30 °C was added acryloyl
chloride (0.72 mL, 6.9 mmol, 1.0 equiv) dropwise over 20 min. The
mixture was allowed to stir at −30 °C for 2 h before being concentrated
in vacuo. The crude material was dissolved in EtOAc, washed with
water and brine, dried over MgSO4, filtered, and concentrated in vacuo.
Purification was achieved via flash column chromatography on SiO2
(10% EtOAc:DCM) to afford a yellow, amorphous solid (0.68 g, 20%).
1H NMR (300 MHz, CDCl3) δ 8.00 (s, 1H), 7.89 (d, J = 8.7 Hz, 2H),
Methyl 4-(1-(2-(1H-Imidazol-4-yl)ethyl)-4-hydroxy-3-isonicotino-
yl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (165). Compound 165
was prepared via procedure I from methyl 4-formylbenzoate (0.37 g,
2.3 mmol), 2-(1H-imidazol-4-yl)ethanamine (0.25 g, 2.3 mmol), and
20 (0.50 g, 2.3 mmol) to yield an orange solid (0.031 g, 3%). 1H NMR
(400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.50 (d, J = 5.2 Hz, 2H), 7.88 (d,
J = 8.0 Hz, 2H), 7.51 (d, J = 5.2 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.26 (s,
1H), 7.11 (s, 1H), 5.27 (s, 1H), 3.90−3.82 (m, 4H), 2.83−2.76 (m, 3H).
13C NMR (150 MHz, DMSO-d6) δ 182.5, 169.1, 166.1, 148.8, 148.0,
134.0, 131.2, 129.0, 128.5, 128.1, 127.8, 127.6, 122.4, 116.4, 111.6, 66.3,
52.0, 40.0, 22.3; mp 64−70 °C. HMS (APCI) calcd for C23H20N4O5
433.1512; found 433.1513 [M + H]+.
7.27−7.20 (m, 2H), 7.11 (t, J = 7.2 Hz, 1H), 7.03−6.94 (m, 3H), 6.71
(d, J = 0.9 Hz, 1H), 6.43 (d, J = 10.2 Hz, 1H), 6.20 (d, J = 0.6 Hz, 1H),
4.81 (s, 1H), 3.89−3.81 (m, 4H), 3.08−2.76 (m, 3H), 2.24 (s, 6H). 13C
NMR (150 MHz, CDCl3) δ 196.1, 191.6, 186.7, 166.6, 163.6, 162.2,
147.6, 139.0, 137.3, 135.7, 135.4, 132.1, 130.8, 130.2, 128.3, 128.0, 126.0,
121.5, 119.6, 117.7, 110.7, 107.9, 62.6, 52.4, 41.5, 30.2, 23.3, 11.5. HMS
(APCI) calcd for C28H26N2O6 487.1837; found 487.1860 [M + H]+.
Methyl 4-(3-Acetyl-4-hydroxy-5-oxo-1-phenethyl-2,5-dihydro-1H-
pyrrol-2-yl)benzoate (161). Compound 161 was prepared via
procedure I from methyl 4-formylbenzoate (0.34 g, 2.1 mmol), ethyl
acetopyruvate (0.33 g, 2.1 mmol), and 2-phenylethanamine (0.25 g,
Methyl 4-(3-Acetyl-4-hydroxy-1-(3-methylphenethyl)-5-oxo-2,5-
dihydro-1H-pyrrol-2-yl)benzoate (166). Compound 166 was prepared
via procedure I from methyl 4-formylbenzoate (0.30 g, 1.8 mmol), ethyl
acetopyruvate (0.29 g, 1.8 mmol), and 2-(m-tolyl)ethanamine (0.25 g,
1
1.8 mmol) to yield a white solid (0.56 g, 76%). H NMR (400 MHz,
DMSO-d6) δ 7.90 (d, J = 7.6 Hz, 2H), 7.28 (d, J = 7.6 Hz, 2H), 7.12 (t,
J = 8.0 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.88−6.86 (m, 2H), 5.13 (s,
1H), 3.83 (s, 3H), 3.79−3.73 (m, 1H), 2.77−2.70 (m, 2H), 2.61−2.57
(m, 1H), 2.26 (s, 3H), 2.22 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ
191.5, 166.0, 165.1, 142.4, 138.4, 137.5, 129.4, 129.2, 128.4, 128.1, 127.1,
126.9, 125.62, 125.56, 119.7, 66.4, 59.7, 52.2, 41.6, 33.4, 21.0; mp 118−
123 °C. HMS (APCI) calcd for C23H23NO5 394.1649; found 394.1651
[M + H]+.
Methyl 4-(3-Acetyl-1-(3-chlorophenethyl)-4-hydroxy-5-oxo-2,5-
dihydro-1H-pyrrol-2-yl)benzoate (167). Compound 167 was prepared
via procedure I from methyl 4-formylbenzoate (0.26 g, 1.6 mmol), ethyl
acetopyruvate (0.25 g, 1.6 mmol), and 2-(3-chlorophenyl)ethanamine
(0.25 g, 1.6 mmol) to yield a pale-yellow solid (0.50 g, 76%). 1H NMR
(400 MHz, DMSO-d6) δ 7.90 (d, J = 8.4 Hz, 2H), 7.32−7.20 (m, 5H),
7.08 (d, J = 7.2 Hz, 1H), 5.22 (s, 1H), 3.83−3.79 (m, 4H), 2.79−2.69
(m, 3H), 2.26 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 165.9,
165.1, 142.3, 141.2, 133.0, 130.5, 130.2, 129.4, 128.5, 128.1, 127.6, 127.4,
126.4, 125.5, 59.5, 52.2, 41.1, 32.9, 29.7 (note: carbon 4 is absent); mp
118−122 °C. HMS (APCI) calcd for C22H20ClNO5 414.1108; found
414.1109 [M + H]+.
Methyl 4-(3-Acetyl-1-(3-fluorophenethyl)-4-hydroxy-5-oxo-2,5-di-
hydro-1H-pyrrol-2-yl)benzoate (168). Compound 168 was prepared
via procedure I from methyl 4-formylbenzoate (0.30 g, 1.8 mmol), ethyl
acetopyruvate (0.28 g, 1.8 mmol), and 2-(3-fluorophenyl)ethanamine
(0.25 g, 1.8 mmol) to yield an off-white solid (0.57 g, 79%). 1H NMR
(400 MHz, DMSO-d6) δ 7.90 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.0 Hz,
2H), 7.29−7.25 (m, 1H), 7.00−6.94 (m, 3H), 5.22 (s, 1H), 3.83−3.79
(m, 4H), 2.81−2.69 (m, 3H), 2.26 (s, 3H). 13C NMR (100 MHz,
DMSO-d6) δ 165.9, 165.1, 162.2 (d, J = 241.8 Hz), 142.3, 141.6, 141.5,
130.3 (d, J = 8.1 Hz), 129.44, 129.40, 128.1, 125.6, 124.8, 115.3 (d, J =
20.9 Hz), 113.2 (d, J = 20.9 Hz), 59.5, 52.2, 41.1, 33.0, 15.2 (note:
carbon 4 is absent); mp 114−119 °C. HMS (APCI) calcd for
C22H20FNO5 398.1403; found 398.1404 [M + H]+.
Methyl 4-(3-Acetyl-4-hydroxy-1-(3-methoxyphenethyl)-5-oxo-
2,5-dihydro-1H-pyrrol-2-yl)benzoate (169). Compound 169 was pre-
pared via procedure I from methyl 4-formylbenzoate (0.27 g, 1.7 mmol),
ethyl acetopyruvate (0.26 g, 1.7 mmol), and 2-(3-methoxyphenyl)-
ethanamine (0.25 g, 1.7 mmol) to yield an off-white solid (0.52 g, 76%).
1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 8.4 Hz, 2H), 7.30 (d, J =
1
2.1 mmol) to yield a white solid (0.73 g, 93%). H NMR (400 MHz,
DMSO-d6) δ 7.92 (d, J = 8.4 Hz, 2H), 7.31−7.24 (m, 4H), 7.19 (d, J =
7.2 Hz, 1H), 7.10 (d, J = 6.8 Hz, 2H), 5.15 (s, 1H), 3.83−3.76 (m, 4H),
2.82−2.60 (m, 3H), 2.26 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ
190.9, 165.9, 165.0, 142.4, 138.5, 129.4, 129.4, 128.6, 128.5, 128.1, 126.4,
125.6, 119.7, 66.4, 59.7, 52.2, 41.5, 33.5; mp 123−128 °C. HMS (APCI)
calcd for C22H21NO5 380.1493; found 380.1494 [M + H]+.
Methyl 4-(4-Hydroxy-3-isonicotinoyl-1-(2-(naphthalen-1-yl)-
ethyl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (162). Compound
162 was prepared via procedure I from methyl 4-formylbenzoate (0.40 g,
2.4 mmol), 188 (0.41 g, 2.4 mmol), and 20 (0.53 g, 2.4 mmol) to yield a
yellow solid (0.67 g, 56%). 1H NMR (600 MHz, DMSO-d6) δ 8.70 (d, J =
3.6 Hz, 2H), 7.93−7.84 (m, 4H), 7.81 (d, J = 7.8 Hz, 1H), 7.57−7.40 (m,
7H), 7.30 (d, J = 6.6 Hz, 1H), 5.40 (s, 1H), 3.84−3.80 (m, 4H), 3.37−
3.34 (m, 1H), 3.13−3.08 (m, 1H), 3.03−3.00 (m, 1H). 13C NMR (150
MHz, DMSO-d6) δ 196.1, 165.9, 162.1, 160.1, 136.4, 136.3, 130.7, 129.5,
128.2, 128.0, 125.5, 123.4, 122.8, 121.2, 120.8, 118.48, 118.45, 118.2,
118.1, 115.2, 111.6, 111.3, 61.5, 52.2, 48.6, 26.2; mp 221−224 °C. HMS
(APCI) calcd for C30H24N2O5 493.1758; found 493.1756 [M + H]+.
Methyl 4-(1-(2-(Benzofuran-3-yl)ethyl)-4-hydroxy-3-nicotinoyl-5-
oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (163). Compound 163
was prepared via procedure I from methyl 4-formylbenzoate (0.20 g,
1.2 mmol), 19 (0.27 g, 1.2 mmol), and 2-(benzofuran-3-yl)ethanamine
(0.20 g, 1.2 mmol) to yield a pale-yellow solid (0.028 g, 4.7%). 1H NMR
(600 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.57 (s, 1H), 7.99 (d, J = 7.2 Hz,
1H), 7.86 (d, J = 7.8 Hz, 2H), 7.77 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H),
7.47−7.42 (m, 3H), 7.37 (t, J = 5.4 Hz, 1H), 7.29 (t, J = 7.2 Hz, 1H), 7.20
(t, J = 7.2 Hz, 1H), 5.44 (s, 1H), 3.87−3.82 (m, 4H), 2.97−2.92 (m,
2H), 2.76−2.75 (m, 1H). 13C NMR (150 MHz, DMSO-d6) δ 189.3,
181.3, 166.0, 154.6, 150.6, 149.5, 142.4, 135.9, 129.1, 128.8, 128.1, 127.5,
124.4, 122.7, 122.4, 119.6, 117.0, 115.6, 111.3, 60.2, 52.1, 40.0, 21.7
(note: carbons 1, 2, and 3 are absent); mp 225−230 °C. HMS (APCI)
calcd for C28H22N2O6 481.1397; found 481.1396 [M − H]−.
Methyl 4-(1-(2-(1H-Benzo[d]imidazol-1-yl)ethyl)-4-hydroxy-3-iso-
nicotinoyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (164). Com-
pound 164 was prepared via procedure I from methyl 4-formylbenzoate
(0.19 g, 1.1 mmol), 2-(1H-benzo[d]imidazol-1-yl)ethanamine (0.18 g,
1.1 mmol), and 20 (0.25 g, 1.1 mmol) to yield a yellow solid (0.40 g,
73%). 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 1.3 Hz, 2H), 8.59
(s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.67 (t, J = 5.2 Hz, 1H), 7.61 (t, J = 5.2
Hz, 1H), 7.52 (d, J = 5.6 Hz, 2H), 7.33−7.29 (m, 4H), 5.37 (s, 1H),
4.61−4.54 (m, 1H), 4.48−4.44 (m, 1H), 4.03−3.98 (m, 1H), 3.82 (s,
3H), 3.08−3.04 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ 186.2,
166.4, 165.9, 149.2, 146.4, 143.4, 142.6, 139.6, 132.9, 129.4, 128.4,
128.14, 128.06, 125.5, 123.5, 123.1, 122.1, 118.2, 111.0, 60.08, 52.2,
43.1 (note: one sp3 carbon is under the DMSO peak); mp 135−140 °C.
HMS (APCI) calcd for C27H22N4O5 483.1676; found 483.1674
[M + H]+.
8.0 Hz, 2H), 7.16 (t, J = 8.0 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.68−6.66
(m, 2H), 5.15 (s, 1H), 3.83−3.76 (m, 4H), 3.69 (s, 3H), 2.77−2.70 (m,
2H), 2.65−2.60 (m, 1H), 2.26 (s, 3H). 13C NMR (100 MHz, DMSO-
d6) δ 166.0, 165.0, 159.3, 145.8, 142.4, 140.1, 129.5, 129.42, 129.38,
128.1, 125.5, 120.8, 114.1, 111.9, 59.6, 54.9, 52.2, 41.4, 33.4, 29.7
(note: carbon 4 is absent); mp 150−153 °C. HMS (APCI) calcd for
C23H23NO6 410.1603; found 410.1604 [M + H]+.
Methyl 4-(3-Acetyl-4-hydroxy-1-(3-hydroxyphenethyl)-5-oxo-2,5-
dihydro-1H-pyrrol-2-yl)benzoate (170). Compound 170 was prepared
via procedure I from methyl 4-formylbenzoate (0.55 g, 3.4 mmol), ethyl
acetopyruvate (0.53 g, 3.4 mmol), and 190 (0.46 g, 3.4 mmol) to yield
a cream-colored solid (1.0 g, 78%). 1H NMR (400 MHz, DMSO-d6) δ
9.34 (br s, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.08 (t,
J = 7.6 Hz, 1H), 6.61 (dt, J = 1.6 Hz, J = 6.8 Hz, 1H), 6.54−6.52 (m, 2H),
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5.16 (s, 1H), 3.87−3.83 (m, 4H), 2.74−2.69 (m, 2H), 2.56−2.52 (m,
1H), 2.30 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 193.0, 166.0,
165.0, 157.5, 142.4, 139.9, 129.9, 129.7, 129.5, 129.2, 128.1, 127.0, 119.2,
115.4, 113.5, 59.7, 52.2, 48.7, 41.6, 33.6; mp 98−104 °C. HMS (APCI)
calcd for C22H21NO6 396.1447; found 396.1446 [M + H]+.
Methyl 4-(4-Hydroxy-3-isonicotinoyl-5-oxo-1-(2-(pyridin-4-yl)-
ethyl)-2,5-dihydro-1H-pyrrol-2-yl)benzoate (171). Compound 171
was prepared via procedure I from methyl 4-formylbenzoate (0.19 g, 1.1
mmol), 2-(pyridin-4-yl)ethanamine (0.14 g, 1.1 mmol), and 20 (0.25 g,
1.1 mmol) to yield a yellow solid (0.47 g, 95%). 1H NMR (400 MHz,
DMSO-d6) δ 8.65 (d, J = 6.0 Hz, 2H), 8.49−8.48 (m, 2H), 7.92 (d, J =
8.0 Hz, 2H), 7.56−7.53 (m, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.29−7.26 (m,
2H), 5.47 (s, 1H), 3.91−3.83 (m, 4H), 2.88−2.78 (m, 3H). 13C NMR
(150 MHz, DMSO-d6) δ 190.1, 185.8, 182.0, 166.3, 166.0, 149.5, 149.2,
148.3, 146.6, 143.4, 129.4, 128.2, 124.6, 122.2, 115.6, 59.9, 52.2, 40.6,
32.7; mp 126−129 °C. HMS (APCI) calcd for C25H21N3O5 444.1567;
found 444.1566 [M + H]+.
Methyl 4-(4-Hydroxy-3-isonicotinoyl-5-oxo-1-(2-(pyridin-3-yl)-
ethyl)-2,5-dihydro-1H-pyrrol-2-yl)benzoate (172). Compound 172
was prepared via procedure I from methyl 4-formylbenzoate (0.19 g, 1.1
mmol), 2-(pyridin-3-yl)ethanamine (0.14 g, 1.1 mmol), and 20 (0.25 g,
1.1 mmol) to yield a yellow solid (0.47 g, 93%). 1H NMR (400 MHz,
DMSO-d6) δ 8.67 (d, J = 6.0 Hz, 2H), 8.44 (dd, J = 1.2 Hz, J = 4.8 Hz,
1H), 8.41 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.66 (d, J =
7.6 Hz, 1H), 7.55 (d, J = 6.0 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.35 (dd,
J = 4.8 Hz, J = 7.6 Hz, 1H), 5.51 (s, 1H), 3.91−3.83 (m, 4H), 2.91−2.77
(m, 3H). 13C NMR (100 MHz, DMSO-d6) δ 206.6, 186.6, 165.9, 165.6,
149.3, 148.9, 146.9, 146.1, 142.7, 137.3, 134.7, 129.5, 128.2, 128.1, 123.8,
122.0, 116.6, 59.9, 52.2, 41.3, 30.5; mp 160−163 °C. HMS (APCI) calcd
for C25H21N3O5 444.1567; found 444.1565 [M + H]+.
123.4, 122.9, 121.1, 118.3, 118.1, 111.5, 110.7, 58.4, 41.0, 23.7 (note:
carbons 1 and 2 are absent); mp 225−227 °C. HMS (APCI) calcd for
C25H20N4O3 425.1608; found 425.1610 [M + H]+.
1-(2-(1H-Indol-3-yl)ethyl)-3-hydroxy-4-nicotinoyl-5-(pyridine-2-
yl)-1H-pyrrol-2(5H)-one (176). Compound 176 was prepared via pro-
cedure I from picolinaldehyde (0.11 g, 1.0 mmol), 19 (0.22 g, 1.0 mmol),
and tryptamine (0.16 g, 1.0 mmol) to yield a yellow solid (0.30 g, 71%).
1H NMR (600 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.80 (d, J = 1.2 Hz,
1H), 8.69 (dd, J = 1.2 Hz, J = 4.8 Hz, 8.55 (d, J = 4.2 Hz, 1H), 8.00 (d, J =
7.2 Hz, 1H), 7.77 (td, J = 1.2 Hz, J = 7.2 Hz, 1H), 7.50−7.46 (m, 2H),
7.38−7.30 (m, 4H), 7.12 (d, J = 1.8 Hz, 1H), 7.05 (t, J = 7.8 Hz, 1H), 6.95
(t, J = 7.8 Hz, 1H), 5.54 (s, 1H), 3.87−3.82 (m, 1H), 3.01−2.91 (m, 2H),
2.72−2.67 (m, 1H). 13C NMR (150 MHz, DMSO-d6) δ 189.2, 165.4,
156.1, 151.9, 149.4, 149.0, 137.2, 136.3, 134.2, 128.2, 126.9, 125.5, 123.8,
123.4, 122.8, 121.0, 118.3, 118.1, 111.5, 110.8, 62.1, 41.4, 23.6 (note:
either carbon 1 or 2 and carbon 3 are absent); mp 218−223 °C. HMS
(APCI) calcd for C25H20N4O3 425.1613; found 425.1613 [M + H]+.
1-(2-(1H-Indol-3-yl)ethyl)-5-(furan-3-yl)-3-hydroxy-4-nicotinoyl-
1H-pyrrol-2(5H)-one (177). Compound 177 was prepared via pro-
cedure I from furan-3-carbaldehyde (0.10 g, 1.0 mmol), 19 (0.22 g,
1.0 mmol), and tryptamine (0.16 g, 1.0 mmol) to yield an orange solid
(0.12 g, 28%). 1H NMR (600 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.85 (d,
J = 1.8 Hz, 1H), 8.71 (dd, J = 1.2 Hz, J = 4.8 Hz, 1H), 8.05 (dt, J = 1.8 Hz,
J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.50−7.48 (m, 1H), 7.45 (d, J = 7.8 Hz,
1H), 7.34 (d, J = 7.8 Hz, 1H), 7.18 (s, 1H), 7.15 (d, J = 1.8 Hz, 1H), 7.10
(s, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.98 (t, J = 7.8 Hz, 1H), 6.48 (d, J = 1.2
Hz, 1H), 5.40 (s, 1H), 3.89−3.84 (m, 1H), 3.12−3.00 (m, 2H), 2.84−
2.80 (m, 1H). 13C NMR (150 MHz, DMSO-d6) δ 164.4, 152.4, 149.5,
144.1, 142.7, 136.3, 133.8, 127.0, 125.5, 123.4, 122.9, 121.1, 120.8, 118.3,
118.2, 117.5, 111.5, 110.9, 108.6, 52.4, 40.7, 23.7 (note: carbon 1 and 2
are absent); mp 211−217 °C. HMS (APCI) calcd for C24H19N3O4
414.1448; found 414.1449 [M + H]+.
1-(2-(1H-Indol-3-yl)ethyl)-5-(furan-2-yl)-3-hydroxy-4-nicotinoyl-
1H-pyrrol-2(5H)-one (178). Compound 178 was prepared via
procedure I from furfural (0.10 g, 1.0 mmol), 19 (0.22 g, 1.0 mmol),
and tryptamine (0.16 g, 1.0 mmol) to yield a mustard-colored solid
(0.06 g, 14%). 1H NMR (600 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.82 (d,
J = 1.2 Hz, 1H), 8.72 (dd, J = 1.8 Hz, J = 4.8 Hz, 1H), 8.03 (dt, J = 1.8 Hz,
J = 5.4 Hz, 1H), 7.62 (t, J = 0.6 Hz, 1H), 7.53−7.52 (m, 1H), 7.48 (d, J =
7.8 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.18 (s, 1H), 7.15 (d, J = 2.4 Hz,
1H), 7.10−7.06 (m, 2H), 6.99 (t, J = 6.6 Hz, 1H), 6.52 (d, J = 3.0 Hz,
1H), 6.433−6.425 (m, 1H), 3.82−3.77 (m, 1H), 3.19−3.14 (m, 1H),
3.00−2.95 (m, 1H), 2.66−2.61 (m, 1H). 13C NMR (150 MHz, DMSO-
d6) δ 186.9, 164.5, 152.3, 149.1, 148.9, 143.4, 143.2, 136.3, 134.0, 127.0,
123.5, 122.9, 122.8, 121.0, 118.4, 118.3, 118.1, 115.0, 111.5, 110.8, 110.2,
54.5, 41.4, 23.7; mp 211−216 °C. HMS (APCI) calcd for C24H19N3O4
414.1448; found 414.1452 [M + H]+.
1-(2-(1H-Indol-3-yl)ethyl)-3-hydroxy-4-nicotinoyl-5-(thiophen-2-
yl)-1H-pyrrol-2(5H)-one (179). Compound 179 was prepared via pro-
cedure I from thiophene-2-carbaldehyde (0.11 g, 1.0 mmol), 19 (0.22 g,
1.0 mmol), and tryptamine (0.16 g, 1.0 mmol) to yield an orange solid
(0.07 g, 16%). 1H NMR (600 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.81 (s,
1H), 8.72 (d, J = 4.8 Hz, 1H), 8.02 (dd, J = 1.8 Hz, J = 6.0 Hz, 1H), 7.53-
7.51 (m, 1H), 7.48−7.44 (m, 2H), 7.34 (d, J = 7.8, 1H), 7.20 (d, J = 3.0
Hz, 1H), 7.15 (d, J = 1.8 Hz, 1H), 7.07 (t, J = 7.8 Hz, 2H), 7.00−6.96 (m,
2H), 5.76 (s, 1H), 3.87−3.83 (m, 1H), 3.14−3.09 (m, 1H), 3.05−3.00
(m, 1H), 2.77−2.72 (m, 1H). 13C NMR (150 MHz, DMSO-d6) δ 164.2,
152.4, 149.2, 140.2, 136.3, 133.8, 130.3, 128.7, 127.02, 126.96, 126.5,
123.6, 122.9, 121.1, 118.3, 118.2, 111.5, 110.8, 56.1, 40.9, 23.6 (note:
carbons 1, 2, and 3 are absent); mp 150−155 °C. HMS (APCI) calcd for
C24H19N3O3S 430.1226; found 430.1223 [M + H]+.
1-(2-(1H-Indol-3-yl)ethyl)-3-hydroxy-4-nicotinoyl-5-(thiophen-3-
yl)-1H-pyrrol-2(5H)-one (180). Compound 180 was prepared via pro-
cedure I from thiophene-3-carbaldehyde (0.11 g, 1.0 mmol), 19 (0.22 g,
1.0 mmol), and tryptamine (0.16 g, 1.0 mmol) to yield a yellow solid
(0.11 g, 25%). 1H NMR (600 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.86 (s,
1H), 8.71 (d, J = 4.8 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 1.8
Hz, 1H), 7.50−7.47 (m, 2H), 7.40 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 7.8
Hz, 1H), 7.25 (s, 1H), 7.14 (s, 1H), 7.08−7.06 (m, 2H), 6.96 (t, J = 7.8
Hz, 1H), 5.55 (s, 1H), 3.86−3.80 (m, 1H), 3.06−2.98 (m, 2H),
Methyl 4-(4-Hydroxy-3-isonicotinoyl-5-oxo-1-(2-(pyridin-2-yl)-
ethyl)-2,5-dihydro-1H-pyrrol-2-yl)benzoate (173). Compound 173
was prepared via procedure I from methyl 4-formylbenzoate (0.19 g,
1.1 mmol), 2-(pyridin-2-yl)ethanamine (0.14 g, 1.1 mmol), and 20
1
(0.25 g, 1.1 mmol) to yield a yellow solid (0.50 g, >99%). H NMR
(400 MHz, DMSO-d6) δ 8.67 (d, J = 6.0 Hz, 2H), 8.48 (dd, J = 1.6 Hz,
J = 5.2 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.73 (td, J = 2.0 Hz, J = 7.6 Hz,
1H), 7.53 (dd, J = 1.2 Hz, J = 4.4 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.27
(s, 1H), 7.25 (t, J = 3.6 Hz, 1H), 5.44 (s, 1H), 4.00−3.93 (m, 1H), 3.82
(s, 3H), 3.07−2.97 (m, 2H), 2.92−2.84 (m, 1H). 13C NMR (100 MHz,
DMSO-d6) δ 206.6, 186.7, 165.9, 165.5, 158.1, 156.6, 149.4, 148.7,
146.1, 142.6, 137.3, 129.5, 128.2, 125.6, 123.6, 122.0, 116.9, 60.1, 52.2,
40.3, 35.4; mp 187−190 °C. HMS (APCI) calcd for C25H21N3O5
444.1567; found 444.1564 [M + H]+.
1-(2-(1H-Indol-3-yl(ethyl)-3-hydroxy-4-nicotinoyl-5-(pyridine-4-
yl)-1H-pyrrol-2(5H)-one (173). Compound 174 was prepared via pro-
cedure I from isonicotinaldehyde (0.11 g, 1.0 mmol), 19 (0.22 g, 1.0 mmol),
and tryptamine (0.16 g, 1.0 mmol) to yield a mustard-colored solid (0.32 g,
76%). 1H NMR (600 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.84 (d, J = 1.8 Hz,
1H), 8.67 (dd, J = 1.8 Hz, J = 4.8 Hz, 1H), 8.53 (d, J = 5.4 Hz, 2H), 8.05 (dt,
J = 2.4 Hz, J = 8.4 Hz, 1H), 7.49−7.47 (m, 2H), 7.42−7.34 (m, 3H), 7.30
(br s, 1H), 7.13 (d, J = 1.8 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.94 (t, J = 8.4
Hz, 1H), 5.34 (s, 1H), 3.92−3.87 (m, 1H), 3.02−2.91 (m, 2H), 2.82−2.77
(m, 1H). 13C NMR (150 MHz, DMSO-d6) δ 185.5, 166.1, 151.3, 148.9,
148.4, 136.7, 136.3, 134.5, 126.9, 125.5, 123.6, 123.4, 123.0, 121.1, 118.3,
118.1, 116.1, 111.6, 110.8, 59.7, 41.2, 23.7 (note: either carbon 1 or 2 is
absent); mp 225−230 °C. HMS (APCI) calcd for C25H20N4O3 425.1608;
found 425.1610 [M + H]+.
1-(2-(1H-Indol-3-yl)ethyl)-3-hydroxy-4-nicotinoyl-5-(pyridine-3-
yl)-1H-pyrrol-2(5H)-one (175). Compound 175 was prepared via
procedure I from nicotinaldehyde (0.11 g, 1.0 mmol), 19 (0.22 g,
1.0 mmol), and tryptamine (0.16 g, 1.0 mmol) to yield an orange solid
(0.29 g, 67%). 1H NMR (600 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.83 (d,
J = 2.4 Hz, 1H), 8.68 (dd, J = 1.8 Hz, J = 4.8 Hz, 1H), 8.57 (d, J = 1.8 Hz,
1H), 8.49 (dd, J = 2.4 Hz, J = 4.8 Hz, 1H), 8.04 (dt, J = 1.8 Hz, J = 7.8 Hz,
1H), 7.74 (d, J = 8.4 Hz, 1H), 7.49−7.47 (m, 1H), 7.36−7.32 (m, 3H),
7.24 (s, 1H), 7.13 (d, J = 1.8 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.94 (t, J =
8.4 Hz, 1H), 5.39 (s, 1H), 3.89−3.85 (m, 1H), 3.02−2.93 (m, 2H),
2.79−2.75 (m, 1H). 13C NMR (150 MHz, DMSO-d6) δ 165.3, 151.9,
149.3, 149.1, 148.9, 136.4, 136.3, 135.7, 134.1, 128.1, 126.9, 125.5, 124.0,
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Article
2.76−2.70 (m, 1H). 13C NMR (150 MHz, DMSO-d6) δ 187.4, 181.2,
164.5, 152.5, 137.2, 136.3, 133.8, 127.05, 126.98, 126.2, 126.0, 125.4,
123.5, 122.9, 122.8, 121.1, 118.4, 118.2, 118.0, 111.5, 110.9, 55.0, 41.2,
23.9; mp 238−242 °C. HMS (APCI) calcd for C24H19N3O3S 430.1198;
found 430.1201 [M + H]+.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental information and the generic formula for experi-
mental test compounds described in Tables 1−8. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*S.F.T. (for biology): phone, 404-727-0357; fax, 404 727 0365;
e-mail, strayne@emory.edu.
■
*D.C.L. (for chemistry): phone, 404-727-6602; fax, 404 412
8649; e-mail, dliotta@emory.edu.
Author Contributions
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Receptors by Tyrosine Phosphorylation-Dependent Subunit Traffick-
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Rationale for and use of NMDA receptor antagonists in Parkinson’s
disease. Pharmacol. Ther. 2004, 102, 155−174. (c) Hallett, P. J.; Dunah,
A. W.; Ravenscroft, P.; Zhou, S.; Bezard, E.; Crossman, A. R.; Brotchie, J.
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Pathogenesis, Clinical Symptoms and Levodopa-Induced Dyskinesia
Associated with Parkinson’s Disease. CNS Drugs 2012, 26, 1017−1032.
(e) Nakamura, T.; Lipton, S. A. Excitatory amino acids, S-nitrosylation,
and protein misfolding in neurodegenerative disease protection by
memantine and nitromemantine at NMDA-gated channels. Oxid. Stress
Dis. 2010, 26 (Micronutrients and Brain Health), 59−78.
The manuscript was written by all authors. All authors have given
approval to the final version of the manuscript.
Notes
The authors declare the following competing financial
interest(s): Some authors are coinventors on Emory owned IP
(S.S.Z., E.G.A., S.F.T., D.C.L.), have an equity position (S.F.T,
D.C.L.), are Board members (D.C.L.), or paid consultants
(S.F.T., K.B.H) for companies developing NMDA receptor
modulators.
ACKNOWLEDGMENTS
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We thank Kimberly Vellano, Phuong Le, and Jing Zhang for
excellent technical assistance. This work was supported by the
NIH (NS065371, S.F.T.; MH094525, S.F.T.; ES012870,
NS078873, A.K.) and a research grant from Lundbeck (S.F.T.).
(11) (a) Mullasseril, P.; Hansen, K.; Vance, K.; Ogden, K.; Yuan, H.;
Kurtkaya, N.; Santangelo, R.; Orr, A.; Le, P.; Vellano, K.; Liotta, D.;
Traynelis, S. A subunit-selective potentiator of NR2C- and NR2D-
containing NMDA receptors. Nature Commun. 2010, 1, 90. (b) Mosley,
C. A.; Acker, T. M.; Hansen, K. B.; Mullasseril, P.; Andersen, K. T.; Le,
ABBREVIATIONS USED
■
AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid;
NMDA, N-methyl D-aspartate; ATD, amino-terminal domain;
LBD, ligand-binding domain; TMD, transmembrane domain;
CTD, carboxyl-terminal domain; GABA, γ-aminobutyric acid;
DMF, dimethylformamide; SEM, standard error of the mean
P.; Vellano, K. M.; Brauner-Osborne, H.; Liotta, D. C.; Traynelis, S. F.
̈
Quinazolin-4-one Derivatives: A Novel Class of Noncompetitive
NR2C/D Subunit-Selective N-Methyl-D-aspartate Receptor Antago-
nists. J. Med. Chem. 2010, 53, 5476−5490. (c) Bettini, E.; Sava, A.;
Griffante, C.; Carignani, C.; Buson, A.; Capelli, A. M.; Negri, M.;
Andreeta, F.; Senar-Sancho, S. A.; Guiral, L.; Cardullo, F. Identification
and characterization of novel NMDA receptor antagonists selective for
NR2A- over NR2B-containing receptors. J. Pharmacol. Exp. Ther. 2010,
335, 636−644. (d) Costa, B. M.; Irvine, M. W.; Fang, G.; Eaves, R. J.;
Mayo-Martin, M. B.; Skifter, D. A.; Jane, D. E.; Monaghan, D. T. A
Novel Family of Negative and Positive Allosteric Modulators of NMDA
Receptors. J. Pharmacol. Exp. Ther. 2010, 335, 614−621. (e) Acker, T.
M.; Yuan, H.; Hansen, K. B.; Vance, K. M.; Ogden, K. K.; Jensen, H. S.;
Burger, P. B.; Mullasseril, P.; Snyder, J. P.; Liotta, D. C.; Traynelis, S. F.
Mechanism for Noncompetitive Inhibition by Novel GluN2C/D N-
Methyl-D-aspartate Receptor Subunit-Selective Modulators. Mol.
Pharmacol. 2011, 80, 782−795. (f) Santangelo Freel, R. M.; Ogden,
K. K.; Strong, K. L.; Khatri, A.; Chepiga, K. M.; Jensen, H. S.; Traynelis,
S. F.; Liotta, D. C. Synthesis and Structure−Activity Relationship of
Tetrahydroisoquinoline-Based Potentiators of GluN2C and GluN2D
Containing N-Methyl-D-aspartate Receptors. J. Med. Chem. 2013, 56,
5351−5381. (g) Acker, T. M.; Khatri, A.; Vance, K. M.; Slabber, C.;
Bacsa, J.; Snyder, J. P.; Traynelis, S. F.; Liotta, D. C. Structure−Activity
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Pyrazoline Containing Class of GluN2C/GluN2D Selective Antago-
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