Development of second generation EP2 antagonists with high selectivity

Article abstract of DOI:10.1016/j.ejmech.2014.05.076

EP2 receptor has emerged as an important biological target for therapeutic intervention. In particular, it has been shown to exacerbate disease progression of a variety of CNS and peripheral diseases. Deletion of the EP2 receptor in mouse models recapitulates several features of the COX-2 inhibition, thus presenting a new avenue for anti-inflammatory therapy which could bypass some of the adverse side effects observed by the COX-2 inhibition therapy. We have recently reported a cinnamic amide class of EP2 antagonists with high potency, but these compounds exhibited a moderate selectivity against prostanoid receptor DP1. Moreover they possess acrylamide moiety in the structure, which may result in liver toxicity over longer period of use in a chronic disease model. Thus, we now developed a second generation compounds that devoid of the acrylamide functionality and possess high potency and improved (>1000-fold) selectivity to EP2 over other prostanoid receptors.

Full text of DOI:10.1016/j.ejmech.2014.05.076

Accepted Manuscript
Development of second generation EP2 antagonists with high selectivity
Thota Ganesh , Jianxiong Jiang , Ray Dingledine
PII:
S0223-5234(14)00508-X
10.1016/j.ejmech.2014.05.076
EJMECH 7034
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 17 February 2014
Revised Date: 29 May 2014
Accepted Date: 31 May 2014
Please cite this article as: T. Ganesh, J. Jiang, R. Dingledine, Development of second generation
EP2 antagonists with high selectivity, European Journal of Medicinal Chemistry (2014), doi: 10.1016/
j.ejmech.2014.05.076.
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*Highlights (for review)
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Highlights:




EP2 receptor plays a pro-inflammatory role in CNS and peripheral diseases
EP2 deletion is beneficial in models of ALS, Alzheimer’s and Parkinson’s disease
Selective EP2 antagonists are limited so far to use in proof-of-concept studies
We developed selective EP2 antagonists and characterized the mechanism of antagonism

*Revised Manuscript
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ACCEPTED MANUSCRIPT
Development of second generation EP2 antagonists with high selectivity
†
,
†
†
Thota Ganesh , Jianxiong Jiang and Ray Dingledine
†
Department of Pharmacology, School of Medicine, Emory University, 1510 Clifton Rd, Atlanta, GA
0322, USA
3

Corresponding author. Tel.: +1-404-727-7393; Fax: +1-404-727-0365; Email: tganesh@emory.edu
Abstract:
EP2 receptor has emerged as an important biological target for therapeutic intervention. In particular, it has
been shown to exacerbate disease progression of a variety of CNS and peripheral diseases. Deletion of the
EP2 receptor in mouse models recapitulates several features of the COX-2 inhibition, thus presenting a new
avenue for anti-inflammatory therapy which could bypass some of the adverse side effects observed by the
COX-2 inhibition therapy. We have recently reported a cinnamic amide class of EP2 antagonists with high
potency, but these compounds exhibited a moderate selectivity against prostanoid receptor DP1. Moreover
they possess acrylamide moiety in the structure, which may result in liver toxicity over longer period of use
in a chronic disease model. Thus, we now developed a second generation compounds that devoid of the
acrylamide functionality and possess high potency and improved (>1000-fold) selectivity to EP2 over other
prostanoid receptors.
Keywords:
G protein-coupled receptor, Indole-amides, cyclic AMP, TR-FRET assay & Anti-inflammatory
—
——

1
. Introduction
ACCEPTED MANUSCRIPT
Prostanoid receptor subtype EP2 has emerged as an important biological target, playing a protective as well
as deleterious role in a variety of diseases [1, 2]. EP2 activation has been shown to be beneficial in
ischemic stroke and glaucoma models [3, 4]. So far several agonists have been developed. A compound
known as taprenepag isopropyl (PF-04217329) is undergoing phase-2 clinical evaluation for treating open-
angle glaucoma and ocular hypertension [5, 6]. A significant body of evidence suggests that EP2 plays a
pro-inflammatory role in central nervous system (CNS) disorders including Alzheimer’s disease (AD) [7],
Parkinson’s disease (PD) [8], amyotrophic lateral sclerosis (ALS)[9] and status epilepticus (SE) [10];
peripheral diseases such as rheumatoid arthritis (RA) [11], inflammatory bowel disease [12] and cancer
[
13-15]. Thus a highly selective antagonist for this receptor could be useful to develop treatments for these
diseases. So far, a majority of the conclusions about the deleterious roles of EP2 are drawn from studies of
EP2 knockout models, which also displayed salt-sensitive hypertension and infertility [16, 17]. However,
the data from pharmacological inhibition of this receptor are limited due to lack of selective EP2
antagonists until recently [18]. We recently reported a cinnamic amide class of EP2 antagonists which
displayed high EP2 potency, but modest selectivity against a structurally close prostanoid receptor DP1 [19,
2
0]. We now report several second generation EP2 antagonists with high potency and selectivity.
EP2, a Gs-coupled receptor, is activated by the endogenous ligand PGE , produced by the
2
cyclooxygenase enzymes (COX-1, COX-2). Upon activation, EP2 stimulates adenylate cyclase resulting in
elevation of cAMP, which initiates downstream signaling by protein kinase A (PKA) or exchange protein
activated by cAMP (Epac) [1, 2, 21, 22].
2
2
. Results and Discussion
.1. First generation EP2 antagonists show low selectivity, solubility and ADME properties. We
recently reported a high-throughput screening campaign that indentified cinnamic amide 1 (a.k.a. TG4-155)
as an initial hit (Figure 1). We initially synthesized about 27 analogs for structure activity relationship
study, which resulted in several compounds that displayed a high EP2 potency [20]. However, they showed
modest (~10-fold) selectivity against a close member of prostanoid receptor DP1. Moreover, several
compounds displayed low aqueous solubility and metabolic stability in microsomal fractions of mouse and
human liver. Despite the low stability in liver microsomes, a trifluoroindole derivative of cinnamic amide
(2, a.k.a. TG6-10-1) displayed a plasma half-life of 1.7 h, and brain-to plasma ratio of 1.7, and is currently
used as a lead compound for proof of concept studies [23]. Since then we synthesized 45 additional
cinnamic amide derivatives to optimize the selectivity properties. From this, one compound TG8-21
displayed 181-fold selectivity to EP2 over DP1, but others showed < 80-fold selectivity [19].
A majority of the first generation derivatives possess an acrylamide unit (Figure 1), a structural moiety
that mimics a Michael acceptor functionality, which is known to be reactive towards biologically active

nucleophiles, potentially leading to o Af f C- t aCr gE e Pt Te fEf eDc t sM. TA oNt eU s tS tCh Ri sI hP yTp othesis, we first treated 2 (Figure 1)
with reduced glutathione (GSH) (3eq) in acetonitrile and water as a solvent system. However, this
compound did not form any adduct with glutathione up until 72 hrs at ambient temperature. Furthermore, it
was also not reacted by N-acetyl ethanethiol and a reactive morpholine, suggesting that the acrylamide in
this class does not act like a Michael acceptor. In contrast, when we subjected the compound 2 to a reactive
metabolite trapping test in human liver microsomes in the presence of NADPH and glutathione, it indicated
the appearance of significant amount of glutathione adduct (+GSH-2H), in addition to other expected
adducts (e.g. GSH+O-2H, GSH+O). This result suggests that this class of compounds might form reactive
metabolites by liver metabolism [24]. However, when we tested the compound 2 for off-target activity
against 47 ancillary targets that include several receptors, kinases and CYP450 enzymes, it displayed weak
activity only against serotonin 5HT2A receptor with IC = 7.5 μM [23]. We did not explore any further to
5
0
determine whether the GSH adducts are stemming solely from acrylamide moiety, but we speculate that
this moiety might be a primary cause for the formation of reactive metabolites by this chemical class. Thus,
we designed a second generation of analogs in this class that is devoid of the acrylamide moiety for further
SAR study and selectivity characterization.
Figure 1:
2
.2. Synthesis of second generation amide EP2 antagonists. Earlier structure activity relationship (SAR)
study on 1 indicated that the acrylamide moiety is optimal, but not essential for EP2 bioactivity [19, 20].
The derivatives that are devoid of the acrylamide moiety, for example 3 (Figure 1) displayed EP2 Schild
potency of 214 nM, a 90-fold smaller potency than 1 [19, 20]. Thus, we envisioned synthesizing a variety
of a second generation analogs by shrinking the acrylamide to an ‘amide’ linker for further SAR study. We
first synthesized amide derivatives 6a and 6b as shown in Scheme 1, starting from 2-(2-methyl-1H-indol-1-
yl)ethan-1-amine (4a) and 3,4,5-trimethoxybenzoic acid (5a) and 3,4-dimethoxybenzoic acid (5b). The
other substituted derivatives on the phenyl ring (6c-z, 7a-z, & 8a-u), isomeric 3-inodole derivatives ((8x-z,

&
9a-g), and imidazole derivatives ( (A8 vC - Cw E) wP Te rEe Ds y Mn t hAe sNi zUe dS Ca nRa lI oP g To us to 6a and 6b as illustrated by the
general Scheme 1 (Table 1 for individual structures).
2
.3. Second generation analogs show low nanomolar EP2 potency and high selectivity index. More
than 92 amide derivatives have been synthesized and evaluated for inhibitory potency on PGE -mediated
2
EP2 activation by measuring the Schild K (Table 1). Interestingly, the 3,4,5-trimethoxyamide derivative
B
6
a showed no EP2 activity, where as the 4,5-dimethoxyamide derivative 6b displayed strong EP2 potency
(
Schild K = 22 nM). Thus, we used 6b as a lead for the synthesis of other second generation amide
B
derivatives. As shown in Table 1, we first focused on derivatising the phenyl group with a variety of
electron donating or withdrawing groups at various positions (ortho, meta and para). We describe the
potency of these analogs in rank order in comparison to the 3,4-dimethoxyderivative 6b. For example, a
compound with a single methoxy group at the para-position (6c) showed 3.4-fold less potency than
dimethoxyderivative (6b), and a compound with para-ethylamino group (6d) displayed nearly same
activity as 6b. Interestingly, a para-dimethylaminoamide (6e), or para-diethylaminoamide (6f) exhibited
about 2-fold or 8-fold improved EP2 potency respectively in comparison to 6b. Then we examined amides
with lengthy alkyl groups such as two propyls (6g) and two butyls (6h), but they indicated that ethyl group
is optimal for activity, because increasing the length of alkyls gradually decreases the potency (Table 1).
Nonetheless, the dipropylamino derivative displayed 2-fold higher potency than 6b. The unsubstituted
amine derivative (6i) showed reduced potency by 9-fold, and the derivatives with hydroxyl group (6j) and
guanidine group (6k) displayed loss of potency, suggesting this region may have been exposed into a
hydrophobic region on the EP2 receptor. We then explored several electron withdrawing groups at the same
para-position of the phenyl ring. For example, an acetoxyderivative (6m) showed 6.7-fold less potency, an
N-acetyl-derivative (8n) showed a 4-fold less and an N-benzoyl derivative (8o) showed 2-fold less in
comparison to 6b. Moreover, an acetamide derivative (6p) showed about 6.7-fold less, and a
dimethylacetamide (6q), diethylacetamide (6r) showed 58-fold and 35-fold less potency than 6b,
respectively. Likewise, a cyano derivative (6s), and a tert-butylcarbaoxylate (6t) showed decreased
potency by 6.2 and 4.4 –fold, respectively. A carboxylic acid group (6u) also reduced EP2 potency (245
nM), suggesting electron donating groups enhance the EP2 potency whereas the withdrawing groups, at
para-position of the phenyl ring, decrease potency (Table 1).
We also synthesized and tested analogs with additional groups such as fluorine, trifluoromethyl, and
methoxyl at the other positions (ortho (o), meta (m) and para (p)) of the phenyl to see any additional
advantages to the potency, but mostly these groups either reduced the potency or brought no changes in
comparison to the compounds without these groups. For example, a fluorine at m-position, next to
alkylamino group, reduced the potency about 2-fold (cf. 7a vs. 6e; 7d vs. 6f), but a fluorine at the same
position had no effect on p-cyano derivative (7h vs. 6s) and a p-methoxy derivative (7c vs. 6c), but moving

the fluorine from m-position to o-pos Ai ti Co nC rEe dP uTc Ee dD t hMe EA PN2 Up oS t Ce nRc Iy P( T7 i vs. 7h). Likewise, a trifluoromethyl
group next to p-ethylamino group had no impact on the EP2 potency (7f vs. 6d), but this group resulted in
1
13-fold reduced potency on p-diethylamino derivative (7e vs. 6f). Moreover, a methoxyl group at m-
position also reduced the potency by 22-fold (cf. 7g vs. 6f), suggesting single substitution only at p-position
of the phenyl is optimal for EP2 activity, and additional groups at other positions decrease the EP2 potency.
We also tested compound with a sulfonamide at p-position on the phenyl ring, this group also reduced the
potency by 21-fold, (6v vs. 6b), and the same group at m-position resulted in loss of potency (6w vs. 6b),
reinforcing the above assertion that substitution at p-position is optimal, but at m-position, it is detrimental
to the EP2 potency (Table 1).
We then explored derivatives in which the nitrogen heteroatom is connected to the phenyl ring with
extra methylene group to determine whether p-amino (to the amide group) is essential for EP2 potency. For
example, a p-methylamine derivative (6y) showed about 3-fold less potency than p-amino derivative (6i)
and a compound with two methylene groups between phenyl and amine (6z) displayed 6-fold less potency
than the p-amine derivative (6i), suggesting alkyl amino groups directly attached to phenyl ring provide
optimal EP2 potency than the ones that are away from the phenyl ring. Interestingly however, a tert-
butylcarboxylate protected p-methylamino derivative (6x) showed 2.4-fold higher potency than the free p-
amino derivative (6i) (Table 1).
We then synthesized and examined a variety of nitrogen heterocyclic rings at the p-position of the
phenyl ring. Pyrrolidine (7j) and homopiperidine (7o) derivatives showed approximately equal potency to
6
b. However, a piperidine derivative (7k) and a morpholine derivative (7p) both displayed about 2.3-fold
higher EP2 potency than 6b, (Table 1). Furthermore, we also synthesized and tested analogs with a methyl
group (7l) and an ethylester (7m) and carboxylic acid (7n), hydroxyl group (7w) on the piperidine ring.
Interestingly, while the ethyl ester piperidine derivative (7m) showed 20-fold less, a carboxylic acid
displayed 4-fold less activity to 6b, and a hydroxylpiperidine derivatives displayed nearly equal EP2
potency as 6b (Table 1), indicating hydrophilic groups on the piperidine ring will help to maintain the EP2
potency. Likewise, a methylpiperazine (7q), or a methylhomopiperizine ring (7v) at p-position of the
phenyl ring also resulted in 2.8-fold or 6.6-fold loss of potency, in comparison to 6b. We then explored
SAR by moving these heterocyclic rings from p-position to m-position. But this strategy resulted in less
active compounds in comparison to p-substituted derivatives (cf. 7s vs. 7p; 7r vs. 7q). Likewise,
incorporation of fluorine atom at m-position on the phenyl ring (next to the heterocyclic rings) showed a
trend towards increasing the potency in one case (cf. 7u vs.7q), but decreased the potency by 2-fold in other
(cf. 7t vs. 7p), reinforcing the suggestion (vide infra) that a single group at p-position provides optimal
higher EP2 potency.

We further explored other hetero cAy cCl iCc sE aPt Tt hEe Dp - Mp o As i tNi o Un So Cf tRh eI Pp Th enyl ring (7x-z), and few benzofused
heterocylcics (8a, 8e and 8f) for SAR study. The 1-tetrazoles 7x and 7y displayed 1.5-2-fold less potency,
but the 5-tetrazole (7z) and the benzofused-imidazole (8a) displayed equal potency to 6b, whereas the
benzofused-triazole (8e) and benzofused-quinazoline (8f) both displayed 4-fold reduced potency in
comparison to 6b. Interestingly, a cyclohexane ring at p-position (8b) showed 5.5-fold less potency in
comparison to 6b, suggesting nitrogen in the ring helps maintain the potency at < 100 nM, but a heteroatom
is not absolutely essential for full bioactivity. Again a strategy to extend these heterocyclic rings with an
extra methylene group or oxygen atom resulted in loss of potency (see 8i-k), reinforcing the notion that
direct nitrogen attachment to the phenyl ring will improve potency (Table 1).
We also envisioned synthesizing compounds with a pyrimidine ring replacing the phenyl ring, then
exploring substitutions on this ring. As shown in Table 1, a 2-aminopyrimidine-amide (8l) displayed loss of
potency, in comparison to an equivalent 6i which displayed EP2 potency of 210 nM. However, a 2-
ethylamino derivative (8n) or, 2-morpholino derivative (8o) showed EP2 potency of 58 and 76.5 nM,
respectively. These potencies are 4 to 8-fold less than their equivalents 6d, 7p. In contrast, a 2-phenylamino
derivative exhibited a higher EP2 potency (Schild K = 1.6 nM). Moreover, we also examined compounds
B
in which the phenyl ring is replaced by a nicotinamide ring (8p), and a pirimidine substituted cyclohexane
ring (8q), but both these derivatives displayed about 20-fold less potency in comparison to 6b, suggesting
phenyl or pyrimidine rings are optimal for high EP2 potency. Furthermore, we synthesized and tested
additional heterocycles such as imidazole (9h), 4-hydroxyquinoline (9i), and pyrrolidine (9j), replacing the
phenyl ring. However, 2-imidazole derivative 9h, 2-quinoline compound 9i showed weak EP2 potency (KB
=128 nM, 174 nM respectively), and the pyrrolidine derivative (9j) displayed loss of potency. These results
suggest further modifications on this phenyl region may yield compounds with enhanced bioactivity.

ACCEPTED MANUSCRIPT
Scheme 1.
Having identified several compounds with EP2 potency < 50 nM with modifications on the right side
phenyl ring, we explored the left side indole ring to determine whether any enhancement to the potency is
possible. Blocking the ortho-, and para-positions to the indole ring nitrogen could potentially limit
metabolic oxidation of the scaffold. Thus we have synthesized two compounds (8r and 8s) with fluorine at
th
5
position of the indole ring (Table 1). Interestingly, these two compounds displayed similar potencies in
comparison to the unsubstituted derivatives (8r vs. 7p; 8s vs. 7u), but we have not yet explored the o-
position to the indole nitrogen due to lack of available starting materials for synthesis. From our earlier
SAR on the first generation analogs, we learned that only limited modifications (e.g. CF ) are allowable at
3
nd
2
position of the indole ring with about 10-fold loss of potency (cf. 1 vs. 2) [20]. Thus, we only
nd
synthesized a few analogs with a trifluoromethyl group at 2 position. As shown by two examples, 8t and
nd
8
u (Table 1), the trifluoromethyl group at 2 position resulted in 12 to 54-fold less EP2 potency in
comparison to a methyl group at the same position (8t vs. 6f; 8u vs. 7p). We also synthesized analogs with
imidazole ring in place of indole ring with premise that an extra nitrogen in the imidazole ring offers
rd
additional drug like features, including enhanced solubility and metabolic stability by blocking the 3
position, where this position seems to liable in the case of indoles [25]. However, an imidazole derivative
(8v) showed a 70-fold less potency than its indole equivalent compound (6f). One point is noteworthy here.

nd
In the earlier study, we observed tAh aCt Ca E mP Te t Eh yDl Mg r oAu Np Ua tS C2 RI pP o Ts ition of the indole ring accelerates
metabolism in liver fractions compared with a trifluormethyl group [20]. Thus, we synthesized analogs
nd
without a methyl group at 2 position of the indole (6l), and imidazole ring (8w). However, the indole
derivative without methyl group (6l) was found to be 23-fold less potent than its methyl equivalent (6f), and
the imidazole derivative without methyl group (8w) displayed complete loss of EP2 potency, reinforcing
the observation that methyl is very important for high EP2 bioactivity (Table 1).
Figure 2.
We then examined isomeric 3-indole derivatives (8x-8z, 9a-9g) for SAR study. As shown in Table 1,
the 3-indole isomeric derivatives showed nearly equal potency to their 1-indole equivalent compounds (cf.
8
x vs.6n; 8y vs. 6r; 8z vs. 6e; 9a vs. 6f; 9b vs.7k; 9c vs.7p; 9d vs. 7t; 9e vs.7q), suggesting both 1-indole
and 3-indole derivatives are, in general, are potent antagonist of EP2 receptor and useful for further
development of EP2 drugs.
Finally, we explored the linker region for SAR study. Extension of the chain from two carbons to three
carbons, as illustrated by the indolepropane amide (9k), constraining the linker as in derivatives 9l and 9m
(Figure 2) resulted in loss of potency in comparison to their shorter equivalents (6f and 7p). Moreover, we
also synthesized an ester analog (9n) to determine whether the amide bond is necessary for EP2 potency.
This analog resulted in loss of potency, indicating that the amide is crucial for the EP2 bioactivity.
Overall, the SAR study indicates a dialkylaminogroup or nitrogen heterocycles at p-position, a methyl
nd
group at 2 position of indole ring, and an ethylamine linker are optimal for high EP2 potency. The
compounds 6f, 7p, 7z, 8z, 9a and 7k, 7p display high EP2 potency, with Schild K approximately 10 nM.
B
However, several other compounds (Table 1) displayed EP2 potency below 100 nM, and a variety of
heterocycles retains a modest EP2 potency, suggesting these scaffolds could be further refined into highly
potent antagonists for the EP2 receptor.

a
Table 1: Structures and bioactivity o fA s eC c Co nE dP gTe En eDr a tMi o An EN PU2 Sa Cn t Ra gI oP nTi sts.
Entry
Compd.
ID
R
R1
EP2
K (nM)
B
Entry
Compd.
ID
R
R1
EP2
K (nM)
B
6
6
a
TG7-112-1
>1000
22.3
6v
TG7-161
486
b
TG7-112-2
6w
TG7-165
>1000
6
c
TG7-224
TG7-237
75.6
15.5
6x
6y
TG7-254
TG7-258
84
6
d
690
6
e
TG7-142
9.8
6z
TG7-272
1220
6
f
TG7-171
TG7-192
TG7-188
2.7
7a
7b
7c
TG7-164
TG7-158
TG7-225
18.1
530
6
6
g
11.9
68.8
h
86.8
6
i
TG7-143
TG7-223
210
7d
7e
TG7-206
TG7-213
4.6
6
j
>1000
310
6
k
TG7-179
TG7-205
>1000
62.9
7f
TG6-201
TG7-214
20.2
61.2
6
l
7g
6
m
TG7-233
150
7h
TG7-155-1
140
6
n
o
TG7-117
TG7-157
97
51
7i
7j
TG7-155-2
TG7-173
280
6
24.7
6
6
p
q
TG7-140
150
7k
TG7-152
9.4
TG7-227
TG7-226
>1000
800
7l
TG7-240
TG8-24
30.3
500
6
r
s
7m
6
TG7-147
TG7-172
140
100
7n
7o
TG8-29
89.7
22.6
6
t
TG7-185
6
u
TG7-176
245
7p
TG7-170
9.6

Table 1-contd.
ACCEPTED MANUSCRIPT
7
q
TG7-166
64
8n
TG7-229
57.8
76.5
7
r
s
TG7-255
770
8o
TG7-249
7
TG7-256
TG7-153
>1000
25.7
8p
8q
TG7-259
TG7-244
520
380
7
t
7
u
v
TG7-141
TG7-182
45
8r
8s
TG7-183
TG7-184
14.9
62.2
7
148
7
w
TG7-180
TG7-159
TG8-8
26.8
42.2
32.2
8t
8u
8v
TG7-194
TG7-195
TG7-199
150
120
190
7
x
y
7
7
8
z
TG8-15
22.3
8w
TG7-203
>1000
a
TG7-178
TG7-193
20.9
120
8x
8y
TG7-146
TG7-231
138
8
b
>1000
8
c
TG7-202-2
TG7-211
410
8z
9a
TG7-167
TG7-181
10.8
6.9
8
d
50.2
8
e
TG7-257
TG7-207
TG7-264
87.5
84.1
95
9b
9c
9d
TG7-168
TG7-174
TG7-175
19.8
28.6
66
8
f
8
8
g
h
TG7-268
TG7-234
TG8-5
>1000
>1000
970
9e
9f
TG7-169
TG7-232
TG8-9
135
155
280
130
175
8
i
8
j
9g
9h
9i
8
k
TG8-5
>1000
>1000
TG7-118
TG7-148
8
l
TG7-261
8
m
TG7-228
1.6
9j
TG7-120
>1000
a
Schild K values are calculated using the formula log (dr-1) = log X –log K , where dr (dose ratio) = fold shift in EC of
B
B
B
50
PGE by the test compound, X is antagonist concentration [1 μM]. K value indicates a concentration required to produce a 2-
2
B
B
fold rightward shift of PGE concentration response curve. K values are average of 2-3 measurements run in duplicate.
2
B

2
.4. Characterization of selectivity Aa gCa Ci n Es tP oT t Eh eDr Mp r Ao s Nt a Un oS i Cd Rr eI cP e Tp tors. The EP2 receptor is a member
of the prostanoid receptor family and shares 20-30% structural homology with EP1, EP3 and EP4, all
which are activated by a common agonist PGE . However, EP2 exhibits the highest amino acid homology
2
to DP1 (44%) and IP (40%) receptors, which are activated by PGD and PGI respectively [26-28].
2
2
Furthermore, studies indicate that DP1 has similar physiological functions as EP2 [27], whereas the
activation of the IP receptor is shown to be important for cardioprotection [29, 30]. EP2, EP4, DP1 and IP
are all Gαs-coupled transmembrane receptors [27]. Thus we examined the selectivity of the novel EP2
antagonists mainly over EP4, DP1 and IP. We selected and tested several highly potent second generation
amide EP2 antagonists that showed EP2 K ≤ 50 nM. Interestingly, these amide derivatives showed much
B
improved selectivity in comparison to the first generations derivatives. For example, 6f displayed > 1200-
fold selectivity against DP1 receptor (Table 2), compound 6e displayed 655-fold, and 7j and 7p showed
5
16-fold and 533-fold selectivity over DP1 respectively. Moreover, compounds 6g, 7k, and 10z displayed
over 275-fold selectivity against DP1.
We then examined several of these compounds against EP4 and IP receptors at single concentration of
1
0 μM. The extrapolated Schild K s for these receptors are shown Table 2. A vast majority of these
B
derivatives displayed > 1000-fold selectivity over EP4, but a few derivatives such as 7t, and 7z displayed
only ~600-fold selectivity, and one other compound 7u displayed a moderate (100-fold) selectivity. Several
of these compounds also displayed very good selectivity against the IP receptor. For example 6f and 9c
displayed ~3000-fold selectivity; 7z, and 8a exhibited > 1000-fold selectivity; 7j, 7k, and 7w exhibited
selectivity in the range of 300 to 600-fold. Furthermore, we tested these derivatives to determine whether
they reduced viability of the parent C6-glioma cells, but a majority of these derivatives showed an effect
only at high micromolar concentrations (> 300 μM) with in vitro therapeutic indexes >10000, except two
compounds 7w and 8a, both of which showed an effect on cell viability at > 100 uM. Nonetheless, in vitro
therapeutic indexes > 6000-fold indicating that the bioactivity by this class of amide compounds is not
driven by cell viability (Table 2).

a
Table 2: EP2 potency, selectivity andAc Cy t Co t Eo xP i Tc i Et yDo fMs eAl e Nc t Ue dS EC P R2 I aPn Tt agonists.
Entry
Compd.
ID)
KB
EP2
nM
KB
EP4
μM
Selective
Index
EP4/ EP2
KB
DP1
nM
Selective
Index
(DP1/EP2)
KB
IP
μM
Selective
Index
(IP/EP2)
CC50
(μM)
Therapeutic
Index
(
(CC /EP2 K )
5
0
B
6
e
9.8
2.7
51
5,230
11,590
1320
1,160
3,210
1,045
2,190
565
6430
3190
3550
>10000
2570
7720
5210
2200
980
655
1,220
298
> 516
273
342
533
85
4.7
8.0
480
2,960
95
310
320
332
337
315
327
289
>500
300
163
31,630
118,520
28,130
16,120
33,510
14,470
30,100
>19,450
6,660
(
(
(
(
(
(
(
(
(
(
TG7-
42)
1
6
f
31.3
15.5
28.7
30.2
23.6
21
TG7-
1
71)
6
g
11.8
24.7
9.4
1.12
14.2
3.4
TG7-
1
92)
7
j
570
360
375
206
217
1,420
675
TG7-
73)
1
7
k
TG7-
1
52)
7
o
22.6
9.6
8.5
TG7-
1
85)
7
p
1.98
5.6
TG7-
1
70)
7
t
25.7
45
14.5
4.76
70.3
TG7-
53)
1
7
u
106
22
64.0
18.1
TG7-
1
41)
7w
26.8
2,620
4620
172
6,082
TG7-
1
80)
7
z
22.3
20.9
>10000
36.1
584
660
29
>10000
25.2
1040
1200
>300
154
>13,450
7,370
(
TG8-15)
8
a
1730
6290
300
(
(
(
(
TG7-
1
78)
8
z
10.8
6.9
16.4
48
1,520
6,945
2,645
3610
9480
7790
334
1374
272
63.1
>10000
85.0
5,840
ND
320
>500
311
29,630
>72,460
10,870
TG7-
1
67)
9
a
TG7-
1
81)
9
c
28.6
75.6
2,970
TG7-
74)
EP2, EP4, DP1 and IP K S are average of 2-3 independent experiments run in duplicate. CC are average one measurement
1
a
B
50
run in triplicate. CC50 = critical concentration required to kill 50% cells.
2
.5. Second generation amide derivatives show competitive mechanism of inhibition. We have
previously demonstrated that first generation acrylamide analogs 1 and 2 exhibit a competitive EP2
antagonism of EP2 [20, 23]. To confirm whether the second generation amides derivatives also display
competitive antagonism of EP2, we selected 3 potent compounds 6f, 7p, 9a and subjected them to a
concentration-response test on EC of PGE on EP2 receptors overexpressed in C6-glioma cells. A linear
5
0
2
regression of log (dr-1) on log X with slope of unity characterizes a competitive antagonism. Schild KB
B
values are derived by the equation log (dr − 1) = log X – log K , where dr = dose ratio, i.e. the fold shift in
B
B

EC ; X is [antagonist], and K i As Ct h Ce Ee Pq uT i El i bD ri uMm A dN i sUs oS c Ci a Rt i oI Pn Tconstant for the antagonist–receptor
50
B
B
complex. K value indicates the antagonist concentration required for a twofold rightward shift in the PGE
B
2
dose-response curve. Thus, a lower K value indicates a higher inhibitory potency. All the selected
B
members of the second generation compounds induced a concentration-dependent, parallel, rightward shift
in the PGE concentration-response curve (Figure 3 A–C). The Schild regression analyses demonstrated
2
that these compounds have a competitive mechanism of antagonism of EP2 (Figure 3D). Moreover, a less
potent carboxylic acid derivative (7n), and a 5-tetrazole derivative (7z) also displayed competitive
antagonism of EP2 with Schild K 97 nM for 7n, and 16.4 nM for 7z (not shown). Thus, the mechanism is
B
competitive in general in this whole class of second generation EP2 antagonists presented in this study.
Figure 3:
2
.6. Determination of liver microsomal stability and pharmacokinetics of the second generation
amide antagonists. Fifteen potent and selective EP2 antagonists were subjected to a stability test in human
and mouse liver microsomal fractions. As shown in supporting Table 1, several compounds showed
moderate to good stability in human microsomes, but a few of them (6e, 7p, 8z and 9c) were metabolized

completely in mouse liver microsom eAs Ci nC 6E 0P mT iEn Du te Ms (A< N1 %U Sr eC mR a Ii Pn iTn g). However, compounds 7j, 7k, 7x,
8m displayed > 7% remaining at 60 minutes in mouse liver fractions, thus are potential candidates to
&
study further. The other noteworthy examples are a 5-tetrazole derivative 7z and a carboxypiperidine
derivative 7n, both of which displayed high stability in mouse and human liver microsomes with greater
than 50% remaining at 60 min. These two derivatives also displayed high aqueous solubility by
nephelometry [31], when measured in PBS buffer (pH 7.4) with 1% DMSO (supporting Table 1).
Although the selectivity of 7z is moderate against DP1 (30-fold), we selected it for in vivo
pharmacokinetic study on the basis of its high stability in both microsomal fractions and its aqueous
solubility. As shown in supporting Table 2, it displayed about 12-fold higher peak concentrations in plasma
by intraperitoneal (ip) route of administration, in comparison to an oral route (po). It displayed plasma half-
life (t ) about 0.3 hrs by ip route. We did not calculate t from the oral route due to insufficient data.
1
/2
1/2
Moreover, we have not observed any compound in the brain tissue (LLOQ = 10 ng/mL), indicating this
compound does not cross the blood brain barrier. Thus, further work is needed to determine whether any
other compounds display superior in vivo pharmacokinetics.
2
.5. Conclusions. We developed a novel compound series that are devoid of highly vulnerable acrylamide
functionality, but still possess high EP2 potency and high selectivity against DP1, EP4 and IP receptors.
Further studies to characterize drug-like properties of these selected EP2 antagonists are currently
undergoing, but compounds 6e, 6f, 7j, 7p, 8a, and 9a display a potent and selective antagonism of the EP2,
and may be useful as tools for in vitro studies.
3
3
. Experimental
.1. Chemistry
Proton NMR spectra was recorded on a Varian Inova-400 (400 MHz). Thin layer chromatography was
performed on pre-coated, aluminum-backed plates (silica gel 60 F , 0.25 mm thickness) from EM Science
2
54
and was visualized by UV lamp. Column chromatography was performed with silica gel cartridges on
Teledyne-ISCO machine. Agilent LC-MS was used to measure purity of the products. Elemental analyses
were performed by Atlantic Microlab Inc. (Norcross, GA).
3
.2.1. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-4-(piperidin-1-yl)benzamide
procedure): A solution of 2-(2-methyl-1H-indol-1-yl)ethanamine (4a) (65 mg, 0.373 mmol) and 4-
piperidin-1-yl)benzoic acid (5) (76 mg, 1 eq.), and dimethylaminopyridine (catalytic, ~5 mg) in
dichloromethane (6 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.hydrochloride
EDCI) (92 mg, 1.3 eq.) at room temperature. The resulting reaction mixture was stirred for 6 h. At the
(7k)
(TG7-152)
(Typical
(
(

conclusion of the reaction (TLC), wAa tCe rC (E1 P5 T mE LD ) Mw aAs Na dU d Se dC Rt oI Pq Tu ench the reaction. The product was
extracted with ethyl acetate (20 mL x 3). Organics were washed with dilute HCl (10 mL), saturated
NaHCO solution (10 ml), water (10 ml) and brine solution (10 ml) and dried over Na SO and
3
2
4
concentrated. The resulting crude product was subjected to silica gel chromatography eluting with 0-40%
1
ethyl acetate in hexane to furnish 7k (TG7-152) (100 mg, 74% yield). H NMR (CDCl ):  7.52 (d, J = 5.6
3
Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8 Hz, 1H), 7.07 (m, 2H), 6.80 (d, J = 8.2 Hz, 2H), 6.23 (s,
1
H), 5.98 (t, J = 5.4 Hz, 1H), 4.33 (t, J = 6 Hz, 2H), 3.76 (q, J = 6 Hz, 2H), 3.25 (t, J = 4.8 Hz, 4H), 2.37
+
(
s, 3H), 1.6 (m, 6H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 362 [M+H] . Anal. Calcd. for
C H N O: C, 76.42; H, 7.53; N, 11.62; found; C, 76.48; H, 7.55; N, 11.59.
23
27
3
3
.2.2. All other compounds were synthesized analogously by this typical procedure in a 70-80% yield, and
1
1
13
then characterized by H NMR and LCMS. Representative H and C NMR spectra for selected
compounds are provided in supporting information. Elemental analysis is recorded for selected compounds
(see below).
3
.2.3. 3,4,5-Trimethoxy-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (6a) (TG7-112-1)
1
H NMR (CDCl ):  7.51 (d, J = 7.2, Hz, 1H), 7.32 (d, J = 7.6, Hz, 1H), 7.07 (m, 2H), 6.74 (s, 2H), 5.98
3
(t, J = 5.6 Hz, 1H), 4.36 (t, J = 5.6 Hz, 2H), 3.86 (s, 3H), 3.8 (q, J = 5.6 Hz, 2H), 3.77 (s, 6H), 2.41 (s, 3H).
+
LCMS (ESI): > 97% purity at λ 254, MS; m/z, 369 [M+H] .
3
.2.4. 3,4-Dimethoxy-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (6b) (TG7-112-2)
1
H NMR (CDCl ):  7.51 (dd, J = 7.2, 1.6 Hz, 1H), 7.31 (d, J = 6.8 Hz, 1H), 7.23 (d, J = 2 Hz, 1H), 7.0
3
(m, 3H), 6.77 (d, J = 8.4 Hz, 1H), 6.03 (broad t, 1H), 4.34 (t, J = 6 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.77
+
(
q, J = 6 Hz, 2H), 2.39 (s, 3H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 339 [M+H] .
3
.2.5. 4-Methoxy-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (6c) (TG7-224)
1
H NMR (CDCl ):  7.56 (dd, J = 7.2, 1.2 Hz, 2H), 7.51 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H),
3
7
3
.08 (m, 2H), 6.84 (dd, J = 7.2, 1.2 Hz, 2H), 6.24 (S, 1H), 6.05 (bs, 1H), 4.30 (t, J = 6.4 Hz, 2H), 3.80 (s,
+
H), 3.75 (q, J = 6.4 Hz, 2H), 2.37 (s, 3H). LCMS (ESI): > 95% purity at λ 254, MS; m/z, 309 [M+H] .
3
.2.6. 4-(Ethylamino)-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (6d) (TG7-237)
1
H NMR (CDCl ):  7.51 (d, J = 6.8 Hz, 1H), 7.45 (dd, J = 7.2, 1.2 Hz, 2H), 7.31 (d, J = 8.4 Hz, 1H),
3
7
6
2
.08 (m, 2H), 6.48 (dd, J = 7.2, 1.2 Hz, 2H), 6.23 (S, 1H), 5.95 (t, 1H), 4.32 (t, J = 6.4 Hz, 2H), 3.75 (q, J =
Hz, 2H), 3.16 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.23 (t, J = 6.8 Hz, 3H), LCMS (ESI): > 97% purity at λ
+
54, MS; m/z, 322 [M+H] .

3
.2.7. 4-(Dimethylamino)-N-(2-(2-me At h yC l -C1 EH P- i Tn dE o Dl -1 M- y lA) e Nt h Uy l S) bCe nR z Ia Pm Ti de (6e) (TG7-142)
1
H NMR (CDCl ):  7.52 (m, 3H), 7.32 (d, J = 7.2, Hz, 1H), 7.08 (m, 2H), 6.63 (d, J = 8.8 Hz, 2H), 6.23
3
(s, 1H), 5.9 (NH, 1H), 4.33 (t, J = 5.6 Hz, 2H), 3.76 (q, J = 6 Hz, 2H), 2.99 (s, 6H), 2.37 (s, 3H). LCMS
+
(
ESI): > 97% purity at λ 254, MS; m/z, 395 [M+H] . Anal. Calcd. for C H N O; C, 74.74; H, 7.21; N,
20
23
3
1
3.07; Found; C, 74.37; H, 7.16; N, 12.83.
3
.2.8. 4-(Diethylamino)-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (6f) (TG7-171)
1
H NMR (CDCl ):  7.49 (m, 3H), 7.32 (d, J = 8 Hz, 1H), 7.08 (m, 2H), 6.56 (d, J = 9.2 Hz, 2H), 6.23 (s,
3
1
H), 5.95 (t, J = 6 Hz, 1H), 4.32 (t, J = 5.6 Hz, 2H), 3.76 (q, J = 6 Hz, 2H), 3.37 (q, J = 7.2 Hz, 4H), 2.37
+
(
s, 3H), 1.15 (t, J = 7.2 Hz, 6H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 350 [M+H] . Anal. Calcd.
for C H N O; C, 75.61; H, 7.79; N, 12.02; Found; C, 75.47; H, 7.74; N, 11.86.
2
0
23
3
3
.2.9. 4-(Dipropylamino)-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (6g) (TG7-192)
1
H NMR (CDCl ):  7.51 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 6.8 Hz, 2H), 7.32 (d, J = 7.2 Hz, 1H), 7.09 (m,
3
2
2
H), 6.52 (d, J = 8.8 Hz, 2H), 6.23 (s, 1H), 5.92 (t, J = 6 Hz, 1H), 4.32 (t, J = 6 Hz, 2H), 3.76 (t, J = 6 Hz,
H), 3.24 (t, J = 7.6 Hz, 4H), 2.37 (s, 3H), 1.60 (q, J = 7.6 Hz, 4H), 0.91 (t, J = 7.2 Hz, 6H). LCMS (ESI):
+
>
97% purity at λ 254, MS; m/z, 378 [M+H] . Anal. Calcd. for C H N O; C, 76.35; H, 8.28; N, 11.13;
2
4
31
3
found, C, 76.08; H, 8.12; N, 10.97.
3
.2.10. 4-(Dibutylamino)-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (6h) (TG7-188)
1
H NMR (CDCl ):  7.51 (d, J = 7.6 Hz, 1H), 7.47 (dd, J = 9.2 Hz, 2H), 7.32 (d, J = 8 Hz, 1H), 7.08 (m,
3
2
2
H), 6.52 (d, J = 8.8 Hz, 2H), 6.23 (s, 1H), 5.93 (t, J = 5.6 Hz, 1H), 4.32 (t, J = 6 Hz, 2H), 3.75 (t, J = 6 Hz,
H), 3.26 (t, J = 8 Hz, 4H), 2.37 (s, 3H), 1.54 (m, 4H), 1.32 (m, 4H), 0.93 (t, J = 7.2 Hz, 6H). LCMS (ESI):
+
>
97% purity at λ 254, MS; m/z, 406 [M+H] .
3
.2.11. 4-Amino-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (6i)(TG7-143)
1
H NMR (CDCl ):  7.46 (d, J = 7.2, Hz, 1H), 7.40 (dd, J = 6.8, 2 Hz, 2H), 7.26 (d, J = 8 Hz, 1H),7.03
3
(m, 2H), 6.58 (dd, J = 6.8, 2 Hz, 2H), 4.27 (t, J = 6 Hz, 2H), 3.66 (t, J = 5.6 Hz, 2H), 2.3 (s, 3H). LCMS
+
(
ESI): > 95% purity at λ 254, MS; m/z, 294 [M+H] .
3
.2.12. 4-Hydroxy-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (6j) (TG7-223)
1
H NMR (CDCl ):  7.50 (m, 3H), 7.29 (d, J = 8 Hz, 1H), 7.08 (m, 2H), 6.78 (m, 2H), 6.24 (s, 1H), 6.04
3
(t, J = 6 Hz, 1H), 4.33 (t, J = 6.2 Hz, 2H), 3.77 (q, J = 6.2 Hz, 2H), 2.37 (s, 3H). LCMS (ESI): > 95% purity
+
at λ 254, MS; m/z, 295 [M+H] .

3
.2.13. 4-Guanidino-N-(2-(2-methyl- 1AH C- i Cn dEo Pl - T1 -Ey Dl )e tMh y Al ) bN e Un z Sa Cm Ri d Ie P( T6 k) (TG7-179)
1
H NMR (CDCl ):  7.48 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 7.6 Hz, 2H), 6.99
3
(m, 2H), 6.88 (d, J = 8.4 Hz, 2H), 6.17 (s, NH), 4.25 (t, J = 6.4 Hz, 2H), 3.6 (q, J = 6 Hz, 2H), 2.32 (s, 3H).
+
LCMS (ESI): > 97% purity at λ 254, MS; m/z, 336 [M+H] .
3
.2.14. N-(2-(1H-Indol-1-yl)ethyl)-4-(diethylamino)benzamide (6l) (TG7-205)
1
H NMR (CDCl ):  7.63 (d, J = 8 Hz, 1H), 7.49 (dd, J = 7, 1.6 Hz, 2H), 7.40 (d, J = 8 Hz, 1H), 7.19 (t, J
3
=
7.8 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 3.2 Hz, 1H), 6.56 (d, J = 9.2 Hz, 2H), 6.4 (d, J = 2.8
Hz, 1H), 5.89 (t, J = 5.4 Hz, 1H), 4.35 (t, J = 5.6 Hz, 2H), 3.79 (q, J = 6 Hz, 2H), 3.71 (q, J = 7.2 Hz, 4H),
+
1
3
4
.15 (t, J = 6.8 Hz, 6H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 351 [M+H] .
.2.15. 4-((2-(2-methyl-1H-indol-1-yl)ethyl)carbamoyl)phenyl acetate (6m) (TG7-233)
1
H NMR (CDCl ):  7.60 (d, J = 7.2 Hz, 2H), 7.51 (d, J = 8 Hz, 1H), 7.30 (d, J = 8 Hz, 1H), 7.08 (m,
3
H), 6.25 (s, 1H), 6.08 (broad triplet, 1H), 4.34 (t, J = 6 Hz, 2H), 3.77 (q, J = 6 Hz, 2H), 2.38 (s, 3H), 2.28
+
(
s, 3H). LCMS (ESI): > 98% purity at λ 254, MS; m/z, 295 [M+H] .
3
.2.16. 4-Acetamido-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (6n) (TG7-117)
1
H NMR (DMSO-d ):  7.49 (m, 5H), 7.25 (dd, J = 7.2 Hz, 1H), 6.98 (m, 2H), 4.23 (t, J = 6.4 Hz, 2H),
6
3
.61 (t, J = 6.4 Hz, 2H), 2.29 (s, 3H), 2.0 (s, 3H). ). LCMS (ESI): > 95% purity at λ 254, MS; m/z, 336
+
[
M+H] .
3
.2.17. 3-Fluoro-4-(2-fluorobenzamido)-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (6o) (TG7-157)
1
H NMR (CDCl ):  8.90 (d, J = 16.8 Hz, 2H), 8.49 (t x d, J = 6.8, 3.2 Hz, 1H), 8.11 (t, J = 7.6 Hz, 1H),
3
7
.52 (m, 3H), 7.30 (m, 3H), 7.17 (m, 1H), 7.08 (m, 2H), 4.34 (t, J = 6.2 Hz, 2H), 3.72 (q, J = 6.2 Hz, 2H),
+
2
.35 (s, 3H). LCMS (ESI): > 98% purity at λ 254, MS; m/z, 434 [M+H] .
3
.2.18. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)terephthalamide (6p) (TG7-140)
1
H NMR (CDCl ):  7.75 (dd, J = 7.2, 1.8 Hz, 2H), 7.62 (dd, J = 7.6, 1.6 Hz, 2H), 7.45 (m, 1H), 7.25 (m,
3
1
H), 7.0 (m, 2H), 4.3 (m, 2H), 3.6 (m, 2H), 2.33 (s, 3H). LCMS (ESI): > 95% purity at λ 254, MS; m/z, 322
+
[
M+H] .
3
.2.19. N, N-Dimethyl-N4-(2-(2-methyl-1H-indol-1-yl)ethyl)terephthalamide (6q) (TG7-227)
1
H NMR (CDCl ):  7.58 (dd, J = 7.2, 2 Hz, 1H), 7.51 (d, J = 8 Hz, 1H), 7.34 (d, J = 7.2 Hz, 2H), 7.30 (d,
3
J = 8 Hz, 1H), 7.07 (m, 2H), 6.36 (broad triplet, 1H), 6.25 (s, 1H), 4.36 (t, J = 6 Hz, 2H), 3.78 (q, J = 6 Hz,
+
2
H), 3.05 (s, 3H), 2.89 (s, 3H), 2.38 (s, 3H). LCMS (ESI): > 95% purity at λ 254, MS; m/z, 350 [M+H] .

ACCEPTED MANUSCRIPT
3
.2.20.
N, N-Diethyl-N4-(2-(2-methyl-1H-indol-1-yl)ethyl)terephthalamide ( 6r) (TG7-226)
1
H NMR (CDCl ):  7.55 (d, J = 7.6 Hz, 2H), 7.49 (d, J = 8 Hz, 1H), 7.31 (d, J = 8 Hz, 1H), 7.20 (m,
3
2
H), 7.06 (m, 2H), 6.85 (broad singlet, 1H), 4.33 (t, J = 6 Hz, 2H), 3.73 (q, J = 5.6 Hz, 2H), 3.40 (broad
singlet, 2H), 3.13 (broad singlet, 2H), 2.39 (s, 3H), 1.19 (broad singlet, 3H), 1.03 (broad singlet, 3H). Note:
The N-ethyl groups did not show usual spitting pattern of quartet and triplet. LCMS (ESI): > 95% purity at
+
λ 254, MS; m/z, 377 [M+H] .
3
.2.21. 4-Cyano-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (6s) (TG7-147)
1
H NMR (CDCl ):  7.64 (m, 4H), 7.51 (m, 1H), 7.27 (m, 1H), 7.06 (m, 2H), 6.1 (t, J = 5 Hz, NH), 4.37
3
(t, J = 6 Hz, 2H), 3.81 (q, J = 6 Hz, 2H), 2.38 (s, 3H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 304
+
[
M+H] .
t
3
.2.22. Butyl 4-((2-(2-methyl-1H-indol-1-yl)ethyl)-carbamoyl)benzoate (6t) (TG7-172)
1
H NMR (CDCl ):  7.95 (dd, J = 6.8 Hz, 2H), 7.59 (dd, J = 6.8, 2 Hz, 2H), 7.51 (d, J = 7.8 Hz, 1H),
3
7
.30 (d, J = 7.2 Hz, 1H), 7.08 (m, 2H), 6.25 (s, 1H), 6.15 (t, J = 5.4 Hz, 1H), 4.36 (t, J = 5.6 Hz, 2H), 3.8
+
(
q, J = 6 Hz, 2H), 2.37 (s, 3H), 1.57 (s, 9H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 379 [M+H] .
3
.2.23. 4-((2-(2-Methyl-1H-indol-1-yl)ethyl)carbamoyl)benzoic acid (6u) (TG7-176)
1
H NMR (CDCl ):  8.0 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8 Hz, 2H), 7.48 (dd, J = 6.6, 1.6 Hz, 1H), 7.27
3
(d, J = 8 Hz, 1H), 7.0 (m, 2H), 6.88 (t, J = 6 Hz, 1H), 6.2 (s, 1H), 4.32 (t, J = 5.8 Hz, 2H), 3.74 (q, J = 5.6
+
Hz, 2H), 2.34 (s, 3H). LCMS (ESI): > 95% purity at λ 254, MS; m/z, 323 [M+H] .
3
.2.24. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-4-sulfamoylbenzamide (6v) (TG7-161)
1
H NMR (DMSO-d ):  8.84 (t, J = 5.6 Hz, 1H), 7.87 (q, J = 8.8 Hz, 4H), 7.44 (s, 2H), 7.38 (t, J = 8 Hz,
6
2
H), 7.0 (t, J = 7.6 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 6.16 (s, 1H), 4.26 (t, J = 6.4 Hz, 2H), 3.53 (q, J = 6.4
+
Hz, 2H), 2.35 (s, 3H). LCMS (ESI): > 95% purity at λ 254, MS; m/z, 358 [M+H] .
3
.2.25. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-3-sulfamoylbenzamide (6w) (TG7-165)
1
H NMR (DMSO-d ):  8.9 (t, J = 5.6 Hz, 1H), 8.27 (t, J = 2 Hz, 1H), 7.93 (dd, J = 8, 1.6 Hz, 2H), 7.63
6
(t, J = 7.6 Hz, 1H), 7.43 (s, 2H), 7.39 (t, J = 8.4 Hz, 2H), 7.01 (t x d, J = 7.4, 1.2 Hz, 1H), 6.92 (t, J = 7.2
Hz, 1H), 6.16 (s, 1H), 4.26 (t, J = 6.4 Hz, 2H), 3.53 (q, J = 6 Hz, 2H), 2.35 (s, 3H). LCMS (ESI): > 95%
+
purity at λ 254, MS; m/z, 358 [M+H] .
t
3
.2.26. Butyl (4-((2-(2-methyl-1H-indol-1-yl)ethyl)carbamoyl)benzyl)carbamate (6x) (TG7-254)

1
H NMR (CDCl ):  7.52 (d, J = 7A . 2C HC zE , P2 TH E) , D7 . 4M4 A( dN, JU =S C8 RH Iz P, T1 H), 7.25 (m, 4H), 7.02 (m, 2H), 4.28
3
(t, J = 6 Hz, 2H), 4.23 (s, 2H), 3.67 (t, J = 6 Hz, 2H), 2.31 (s, 3H), 1.37 (s, 9H). LCMS (ESI): > 97% purity
+
at λ 254, MS; m/z, 408 [M+H] .
3
.2.27. 4-(Aminomethyl)-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (6y) (TG7-258)
1
H NMR (CDCl ):  7.55 (d, J = 7.2 Hz, 2H), 7.50 (d, J = 8 Hz, 2H), 7.28 (m, 3H), 7.06 (m, 2H), 6.30
3
(broad triplet, 1H), 6.22 (s, 1H), 4.39 (s, 2H), 4.31 (t, J = 6 Hz, 2H), 3.73 (q, J = 6.2 Hz, 2H), 2.35 (s, 3H).
+
LCMS (ESI): > 90% purity at λ 254, MS; m/z, 308 [M+H] .
3
.2.28. 4-(2-Aminoethyl)-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (6z) (TG7-272)
1
H NMR (CDCl ):  7.51 (t, J = 7.6 Hz, 3H), 7.30 (d, J = 8 Hz, 1H), 7.15 (d, J = 8 Hz, 1H), 7.07 (m,
3
2
H), 6.40 (broad triplet, 1H), 6.23 (s, 1H), 4.32 (t, J = 6 Hz, 2H), 3.74 (q, J = 6 Hz, 2H), 2.89 (q, J = 6.8
+
Hz, 2H), 2.71 (q, J = 6.8 Hz, 2H), 2.36 (s, 3H). LCMS (ESI): > 95% purity at λ 254, MS; m/z, 322 [M+H] .
3
.2.29. 4-(Dimethylamino)-3-fluoro-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (7a)(TG7-164)
1
H NMR (CDCl ):  7.51 (d, J = 7.6, Hz, 1H), 7.32 (dd, J = 11, 2.4 Hz, 1H), 7.29 (s, 1H), 7.21 (dd, J =
3
8
2
.4, 2 Hz, 1H), 7.09 (m, 2H), 6.72 (t, J = 8.8 Hz, 1H), 6.24 (s, 1H), 5.96 (t, J = 6 Hz, 1H), 4.33 (t, J = 6 Hz,
H), 3.75 (q, J = 6 Hz, 2H), 2.91 (s, 6H), 2.37 (s, 3H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 340
+
[
M+H] .
3
.2.30. 4-Acetamido-3-fluoro-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (7b) (TG7-158)
1
H NMR (DMSO-d ):  9.98 (s, 1H), 8.85 (t, J = 5.6 Hz, 1H), 8.0 (t, J = 8 Hz, 1H), 7.58 (m, 2H), 7.38 (t,
6
J = 6.4 Hz, 2H), 7.0 (t, J = 7.6 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 6.20 (s, 1H), 4.23 (t, J = 6.8 Hz, 2H), 3.49
+
(
q, J = 6.8 Hz, 2H), 2.34 (s, 3H), 2.08 (s, 3H). LCMS (ESI): > 98% purity at λ 254, MS; m/z, 354 [M+H] .
3
.2.31. 3-Fluoro-4-methoxy-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (7c) (TG7-225)
1
H NMR (CDCl ):  7.52 (d, J = 6.8 Hz, 1H), 7.38 (dd, J = 11.6, 2 Hz, 1H), 7.28 (m, 2H), 7.08 (m, 2H),
3
6
.89 (t, J = 8.4 Hz, 1H), 6.25 (s, 1H), 5.98 (broad singlet, 1H), 4.34 (t, J = 6.2 Hz, 2H), 3.89 (s, 3H), 3.77
+
(
q, J = 6.2 Hz, 2H), 2.37 (s, 3H). LCMS (ESI): > 95% purity at λ 254, MS; m/z, 327 [M+H] .
3
.2.32. 4-(Diethylamino)-3-fluoro-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (7d) (TG7-206)
1
H NMR (CDCl ):  7.51 (d, J = 7.2 Hz, 2H), 7.32-7.27 (m, 2H), 7.19 (dd, J = 8.4, 2.4 Hz, 1H), 7.13-
3
7
.04 (m, 2H), 6.71 (t, J = 8.8 Hz, 1H), 6.21 (s, 1H), 5.98 (t, J = 5.4 Hz, 1H), 4.33 (t, J = 6 Hz, 2H), 3.75 (q,
J = 5.6 Hz, 2H), 3.3 (q, J = 6.8 Hz, 4H), 2.3 (s, 3H), 1.26 (t, J = 6.8 Hz, 6H). LCMS (ESI): > 97% purity at
+
λ 254, MS; m/z, 368 [M+H] .

ACCEPTED MANUSCRIPT
3
2
.2.33. 4-(Diethylamino)-N-(2-(2-methyl-1H-indol-1-yl)ethyl)-3-(trifluoromethyl)benzamide (7e) (TG7-
13)
1
H NMR (CDCl ):  7.86 (d, J = 2 Hz, 1H), 7.68 (dd, J = 8.4, 2 Hz, 1H), 7.52 (dd, J = 7, 1.6 Hz, 1H),
3
7
1
.30 (d, J = 8 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.08 (m, 2H), 6.26 (t, J = 1.2 Hz, 1H), 6.06 (d, J = 5.4 Hz,
H), 4.35 (t, J = 5.6 Hz, 2H), 3.79 (q, J = 6.4 Hz, 2H), 3.0 (q, J = 7.2 Hz, 4H), 2.4 (s, 3H), 0.98 (t, J = 7.2
+
Hz, 6H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 418 [M+H] .
3
.2.34. 4-(Ethylamino)-N-(2-(2-methyl-1H-indol-1-yl)ethyl)-3-(trifluoromethyl)benzamide (7f) (TG6-201)
1
H NMR (CDCl ):  7.45 (d, J = 2 Hz, 1H), 7.59 (dd, J = 8.6, 2.4 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.30
3
(d, J = 7.6 Hz, 1H), 7.07 (m, 2H), 6.63 (d, J = 8.8 Hz, 1H), 6.2 (s, 1H), 5.96 (t, J = 5.6 Hz, 1H), 4.55 (bs,
1
2
H), 4.33 (t, J = 6 Hz, 2H), 3.76 (q, J = 6 Hz, 2H), 3.2 (m, 2H), 2.3 (s, 3H). LCMS (ESI): > 97% purity at λ
+
54, MS; m/z, 390 [M+H] .
3
.2.35. 4-(Diethylamino)-3-methoxy-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (7g) (TG7-214)
1
H NMR (CDCl ):  7.51 (d, J = 7.6 Hz, 1H), 7.33 (dd, J = 8 Hz, 1H), 7.21 (d, J = 2 Hz, 1H), 7.09 (m,
3
2
5
6
H), 7.0 (dd, J = 8.4, 2 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.25 (s, 1H), 6.05 (t, J = 5.2 Hz, 1H), 4.34 (t, J =
.6 Hz, 2H), 3.82 (s, 3H), 3.78 (t, J = 6.4 Hz, 2H), 3.21 (q, J = 7.2 Hz, 2H), 2.40 (s, 3H), 1.03 (t, J = 6.8 Hz,
+
H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 380 [M+H] .
3
.2.36. 4-Cyano-3-fluoro-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (7h)(TG7-155-1)
1
H NMR (CDCl ):  7.60 (dd, J = 8, 6.4 Hz, 1H), 7.52 (dd, J = 6.2, 3.6 Hz, 1H), 7.40 (dd, J = 9.2, 1.6
3
Hz, 1H), 7.29 (dd, J = 8.2, 1.6 Hz, 1H), 7.25 (m, 2H), 7.07 (m, 2H), 6.07 (t, J = 5.4 Hz, 1H), 4.36 (t, J = 6
+
Hz, 2H), 3.8 (t, J = 6 Hz, 2H), 2.39 (s, 3H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 322 [M+H] .
3
.2.37. 4-Cyano-2-fluoro-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (7i)(TG7-155-2)
1
H NMR (CDCl ):  8.5 (t, J = 8 Hz, 1H), 7.55 (dd, J = 8.2,1.6 Hz, 1H), 7.5 (dd, J = 7.4, 1.6 Hz, 1H),
3
7
6
.38 (dd, J = 10, 1.6 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.06 (m, 1H), 6.67 (m, 1H), 6.24 (s, 1H), 4.36 (t, J =
+
Hz, 2H), 3.80 (q, J = 6 Hz, 2H), 2.4 (s, 3H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 322 [M+H] .
3
.2.38. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-4-(pyrrolidin-1-yl)benzamide (7j) (TG7-173)
1
H NMR (CDCl ):  7.50 (dd, J = 6.8, 2 Hz, 3H), 7.32 (d, J = 8.4 Hz, 1H), 7.0 (m, 2H), 6.45 (d, J = 8.4
3
Hz, 2H), 6.23 (s, 1H), 5.96 (t, J = 6 Hz, 1H), 4.33 (t, J = 6 Hz, 2H), 3.75 (q, J = 6 Hz, 2H), 3. 29 (t, J = 6.4
+
Hz, 4H), 2.37 (s, 3H), 2.0 (m, 4H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 348 [M+H] . Anal.
Calcd. for C H N O; C, 76.05; H, 7.25; N, 12.09; found; C, 75.98; H, 7.25; N, 11.95.
2
2
25
3

ACCEPTED MANUSCRIPT
7
k (TG7-152): Please see section 3.2.1.
3
.2.39. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-4-(4-methylpiperidin-1-yl)benzamide (7l) (TG7-240)
1
H NMR (CDCl ):  7.52 (d, J = 6.8 Hz, 3H), 7.32 (d, J = 6.8 Hz, 1H), 7.07 (m, 2H), 6.80 (d, J = 6 Hz,
3
2
2
H), 6.23 (s, 1H), 6.0 (t, J = 5 Hz, 1H), 4.32 (t, J = 6 Hz, 2H), 3.75 (q, J = 6.8 Hz, 2H), 2. 80 (t, J = 6.8 Hz,
H), 2.37 (s, 3H), 1.73 (broad doublet, J = 8.4 Hz, 2H), 1.60 (m, 1H), 1.45 (m, 3H), 1.20 (m, 2H), 0.99 (d, J
+
=
6.4 Hz, 3H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 376 [M+H] .
3
.2.40. Ethyl-1-(4-((2-(2-methyl-1H-indol-1-yl)ethyl)carbamoyl)phenyl)piperidine-4-carboxylate
(7m)
(TG8-24)
1
H NMR (CDCl ):  7.52 (m, 3H), 7.31 (d, J = 8 Hz, 1H), 7.08 (m, 2H), 6.81 (d, J = 6 Hz, 2H), 6.23 (s,
3
1
H), 5.97 (t, J = 4 Hz, 1H), 4.33 (t, J = 6 Hz, 2H), 4.1 (q, J = 7.2 Hz, 2H), 3.76 (q, J = 6 Hz, 2H), 3. 72 (q, J
=
3.6 Hz, 2H), 2.88 (m, 2H), 2.46 (m, 1H), 2.37 (s, 3H), 2.01 (m, 2H), 1.81 (m, 2H), 1.25 (t, J = 7.2 Hz,
+
3
H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 434 [M+H] .
3
2
.2.41. 1-(4-((2-(2-Methyl-1H-indol-1-yl)ethyl)carbamoyl)phenyl)piperidine-4-carboxylic acid (7n) (TG8-
9)
1
H NMR (CDCl ):  7.52 (m, 3H), 7.31 (d, J = 8 Hz, 1H), 7.08 (m, 2H), 6.81 (d, J = 6 Hz, 2H), 6.24 (s,
3
1
H), 5.98 (t, J = 5.6 Hz, 1H), 4.33 (t, J = 6 Hz, 2H), 3.77 (m, 4H), 2.98 (m, 2H), 2.5 (m, 1H), 2.37 (s, 3H),
+
2
.02 (m, 2H), 1.84 (m, 2H). LCMS (ESI): > 98% purity at λ 254, MS; m/z, 406 [M+H] .
3
.2.42. 4-(Azepan-1-yl)-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (7o) (TG7-185)
1
H NMR (CDCl ):  7.50 (m, 3H), 7.33 (d, J = 8 Hz, 1H), 7.08 (m, 2H), 6.58 (d, J = 6.8 Hz, 2H), 6.23 (s,
3
1
3
H), 5.95 (t, J = 6.4 Hz, 1H), 4.32 (t, J = 6 Hz, 2H), 3.75 (q, J = 6 Hz, 2H), 3. 45 (t, J = 6 Hz, 4H), 2.38 (s,
+
H), 1.76 (m, 4H), 1.51 (m, 4H). LCMS (ESI): > 95% purity at λ 254, MS; m/z, 376 [M+H] . Anal. Calcd.
for C H N O; C, 76.76; H, 7.78; N, 11.19; found; C, 75.84; H, 7.65; N, 10.91.
2
4
29
3
3
.2.43. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-4-morpholinobenzamide (7p) (TG7-170)
1
H NMR (CDCl ):  7.52 (m, 3H), 7.31 (d, J = 8 Hz, 1H), 7.09 (m, 2H), 6.81 (d, J = 8.8 Hz, 2H), 6.24 (s,
3
1
2
H), 5.99 (t, J = 6.4 Hz, 1H), 4.34 (t, J = 5.6 Hz, 2H), 3.83 (t, J = 4.8 Hz, 4H), 3.77 (q, J = 5.6 Hz, 2H), 3.
+
1 (t, J = 5.2 Hz, 4H), 2.37 (s, 3H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 364 [M+H] . Anal.
Calcd for C H N O ; C, 72.70; H, 6.93; N, 11.56; found, C, 72.49; H, 6.91; N, 11.39.
2
2
25
3
2
3
.2.44. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-4-(4-methylpiperazin-1-yl)benzamide (7q) (TG7-166)

1
H NMR (CDCl ):  7.50 (m, 2H), 7A . 2C 9C( Ed ,PJT =E 8D H Mz , A1 HN ) U, 7S . 0C 7R( ImP , T2 H), 6.78 (d, J = 8.8 Hz, 2H), 6.22 (s,
3
2
H), 4.29 (t, J = 5.6 Hz, 2H), 3.70 (q, J = 6 Hz, 2H), 3.25 (t, J = 4.8 Hz, 4H), 2.51 (t, J = 5.2 Hz, 4H) 2.35
+
(
s, 3H), 2.31 (s, 3H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 377 [M+H] .
3
.2.45. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-3-(4-methylpiperazin-1-yl)benzamide (7r)(TG7-255)
1
H NMR (CDCl ):  7.50 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.20-6.95 (m, 6H), 6.25 (s, 1H),
3
6
.10 (broad triplet, 1H), 4.34 (t, J = 6 Hz, 2H), 3.76 (q, J = 6 Hz, 2H), 3.23 (t, J = 5.2 Hz, 4H), 2.63 (broad
+
singlet, 4H), 2.40 (s, 3H), 2.39 (s, 3H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 377 [M+H] .
3
.2.46. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-3-morpholinobenzamide (7s) (TG7-256)
1
H NMR (CDCl ):  7.50 (d, J = 7 Hz, 1H), 7.31 (d, J = 7 Hz, 1H), 7.27 (m, 2H), 7.18 (m, 4H), 6.25 (s,
3
1
H), 6.18 (broad triplet), 4.35 (t, J = 6 Hz, 2H), 3.89 (t, J = 5.2 Hz, 4H), 3.78 (q, J = 6 Hz, 2H), 3. 16 (t, J =
+
4
.8 Hz, 4H), 2.40 (s, 3H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 364 [M+H] .
3
.2.47. 3-Fluoro-N-(2-(2-methyl-1H-indol-1-yl)ethyl)-4-morpholinobenzamide (7t) (TG7-153)
1
H NMR (CDCl ):  7.52 (d, J = 7.8 Hz, 1H), 7.34 (dd, J = 10.2, 2.4 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H),
3
7
.22 (m, 1H), 7.08 (m, 2H), 6.83 (t, J = 8.4 Hz, 1H), 6.25 (s, 1H), 6.0 (t, J = 5 Hz, 1H), 4.33 (t, J = 5.6 Hz,
H), 3.84 (t, J = 4.4 Hz, 4H), 3.76 (q, J = 6 Hz, 2H), 3. 13 (q, J = 4 Hz, 4H), 2.37 (s, 3H). LCMS (ESI): >
2
+
9
7% purity at λ 254, MS; m/z, 381 [M+H] . Anal. Calcd. for C H FN O ; C, 69.27; H, 6.34; N, 11.02;
22
24
3
2
found; C, 69.10; H, 6.48; N, 11.00
3
.2.48. 3-Fluoro-N-(2-(2-methyl-1H-indol-1-yl)ethyl)-4-(4-methylpiperazin-1-yl)benzamide (7u) (TG7-141)
1
H NMR (CDCl ):  7.49 (dd, J = 7.2, 1.2 Hz, 1H), 7.33 (m, 3H), 7.07 (m, 2H), 6.81 (t, J = 8.4 Hz, 1H),
3
6
2
.24 (m, 1H), 6.23 (s, 1H), 4.29 (t, J = 5.6 Hz, 2H), 3.70 (q, J = 6.4 Hz, 2H), 3.15 (broad t, J = 4.4 Hz, 4H),
+
.55 (t, J = 4.8 Hz, 4H) 2.35 (s, 3H). LCMS (ESI): > 95% purity at λ 254, MS; m/z, 395 [M+H] .
3
.2.49. 4-(4-Methyl-1,4-diazepan-1-yl)-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (7v) (TG7-182)
1
H NMR (CDCl ):  7.50 (m, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.31 (d, J = 7.6 Hz, 1H), 7.08 (m, 2H), 6.57
3
(d, J = 9.2 Hz, 2H), 6.22 (s, 1H), 6.13 (t, J = 6 Hz, 1H), 4.29 (t, J = 6.4 Hz, 2H), 3.71 (q, J = 6 Hz, 2H),
3
3
.55 (t, J = 4.8 Hz, 2H), 3.47 (t, J = 6.4 Hz, 2H), 2.65 (t, J = 4.8 Hz, 2H) 2.51 (t, J = 5.6 Hz, 2H), 2.36 (s,
+
H), 2.34 (s, 3H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 391 [M+H] .
3
.2.50. 4-(4-Hydroxypiperidin-1-yl)-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (7w) (TG7-180)
1
H NMR (CDCl ):  7.52 (m, 1H), 7.50 (dd, J = 7.2, 2 Hz, 2H), 7.31 (d, J = 8 Hz, 1H), 7.07 (m, 2H), 6.81
3
(dd, J = 8.2, 2.8 Hz, 2H), 6.23 (s, 1H), 6.04 (t, J = 6 Hz, 1H), 4.32 (t, J = 6 Hz, 2H), 3.85 (m, 1H), 3.73 (q, J

=
6 Hz, 2H), 3.64 (m, 2H), 3.01 (m A, 2CH C) ,E2 P. 3T6 E( Ds , 3MH A) , N1 .U9 2S (Cm R, I2PHT ), 1.59 (m, 2H). LCMS (ESI): > 97%
+
purity at λ 254, MS; m/z, 378 [M+H] .
3
.2.51. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-4-(1H-tetrazol-1-yl)benzamide (7x) (TG7-159)
1
H NMR (DMSO-d ):  10.1 (s, 1H), 8.8 (t, J = 5.6 Hz, 1H), 8.0 (s, 4H), 7.40 (dd, J = 9.6, 8 Hz, 2H), 7.0
6
(t, J = 7.4 Hz, 1H), 6.92 (t, J = 7.4 Hz, 1H), 6.1 (s, 1H), 4.28 (t, J = 6.8 Hz, 2H), 3.5 (q, J = 6.8 Hz, 2H),
+
2
.36 (s, 3H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 358 [M+H] .
3
.2.52. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-4-(5-thioxo-4,5-dihydro-1H-tetrazol-1-yl)benzamide
(7y)
(TG8-8)
1
H NMR (DMSO-d ):  8.74 (t, J = 5.4 Hz, 1H), 8.20 (dd, J = 7, 2 Hz, 2H), 7.84 (d, J = 7.2, 2 Hz, 2H),
6
7
.40 (dd, J = 15.4, 7.6 Hz, 1H), 7.02 (t, J = 8 Hz, 1H), 6.94 (t, J = 8 Hz, 1H), 6.16 (s, 1H), 4.26 (t, J = 6.4
+
Hz, 2H), 3.52 (q, J = 6.4 Hz, 2H), 2.37 (s, 3H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 379 [M+H] .
3
.2.53. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-4-(5-thioxo-4,5-dihydro-1H-tetrazol-1-yl)benzamide
(7z)
(TG8-15)
1
H NMR (DMSO-d ):  8.83 (t, J = 5.6 Hz, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.4 Hz, 2H), 7.39
6
(dd, J = 15.4, 7.6 Hz, 1H), 7.01 (t, J = 8 Hz, 1H), 6.94 (t, J = 8 Hz, 1H), 6.16 (s, 1H), 4.27 (t, J = 6.4 Hz,
+
2
H), 3.52 (q, J = 6.4 Hz, 2H), 2.36 (s, 3H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 347 [M+H] .
3
.2.54. 1,3-Dimethyl-N-(2-(2-methyl-1H-indol-1-yl)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-
carboxamide (8a) (TG7-178)
1
H NMR (CDCl ):  7.53 (dd, J = 6.4, 1.6 Hz, 1H), 7.32 (d, J = 8 Hz, 1H), 7.27 (s, 1H), 7.25 (m, 1H),
3
7
.0 (m, 2H), 6.88 (d, J = 8 Hz, 1H), 6.28 (s, 1H), 6.10 (t, J = 5.6 Hz, 1H), 4.37 (t, J = 6 Hz, 2H), 3.8 (q, J =
+
5
.6 Hz, 2H), 3.40 (s, 3H), 2.39 (s, 3H). LCMS (ESI): > 95% purity at λ 254, MS; m/z, 363 [M+H] . Anal.
Calcd. for C21H22N4O2; C, 69.59; H, 6.12; N, 15.46; found; C, 69.45; H, 6.14; N, 15.36.
3
.2.55. 4-Cyclohexyl-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (8b) (TG7-193)
1
H NMR (CDCl ):  7.50 (d, J = 7.6 Hz, 3H), 7.31 (d, J = 8 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.08 (m,
3
2
3
H), 6.25 (s, 1H), 6.07 (t, J = 6 Hz, 1H), 4.34 (t, J = 6 Hz, 2H), 3.78 (q, J = 6 Hz, 2H), 2.5 (m, 1H), 2.38 (s,
+
H), 1.83 (m, 4H), 1.73 (m, 2H), 1.37 (m, 4H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 361 [M+H] .
3
.2.56. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-4-(piperazin-1-yl)benzamide (8c) (TG7-202-2)
1
H NMR (CDCl ):  7.51 (d, J = 9.2 Hz, 2H), 7.31 (d, J = 8 Hz, 1H), 7.08 (m, 2H), 6.81 (d, J = 8.8 Hz,
3
1
H), 6.23 (s, 1H), 6.18 (t, J = 5.4 Hz, 1H), 4.33 (t, J = 6 Hz, 2H), 3.77 (q, J = 6 Hz, 2H), 3.21 (q, J = 4.8

Hz, 4H), 2.99 (t, J = 4.8 Hz, 4H), A2 C. 3 C7 E( s P, T3 HE D) . ML CA MN SU (SE CS RI ) :I P> T97% purity at λ 254, MS; m/z, 363
+
[
M+H] .
3
.2.57. 4-(4-Acetylpiperazin-1-yl)-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide (8d) (TG7-211).
1
H NMR (CDCl ):  7.52 (m, 3H), 7.31 (d, J = 8 Hz, 1H), 7.08 (m, 2H), 6.81 (d, J = 9.2 Hz, 2H), 6.24 (s,
3
1
H), 6.0 (t, J = 5.4 Hz, 1H), 4.34 (t, J = 5.6 Hz, 2H), 3.75 (m, 4H), 3.60 (t, J = 5.2 Hz, 2H), 3.25 (m, 4H),
+
2
.37 (s, 3H), 2.12 (s, 3H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 405 [M+H] .
3
.2.58. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-1H-benzo[d][1,2,3]triazole-5-carboxamide (8e) (TG7-257)
1
H NMR (CDCl +MeOH-d ):  8.0 (s, 1H), 7.67 (s, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.24 (t, J = 4.4 Hz,
3
4
1
H), 6.91 (m, 2H), 4.25 (t, J = 6.4 Hz, 2H), 3.62 (t, J = 6.4 Hz, 2H), 2.29 (s, 3H). LCMS (ESI): > 97%
+
purity at λ 254, MS; m/z, 320 [M+H] .
3
.2.59. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide
(8f) (TG7-207)
1
H NMR (DMSO-d ):  8.90 (t, J = 5.6 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 7.53 (d, J = 8.4
6
Hz, 1H), 7.38 (t, J = 6.8 Hz, 2H), 7.01 (t, J = 7.2 Hz, 1H), 6.9 (t, J = 7.2 Hz, 1H), 6.16 (s, 1H), 4.25 (t, J =
6
.8 Hz, 2H), 3.52 (q, J = 6 Hz, 2H), 2.36 (s, 3H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 379
+
[
M+H] .
t
3
.2.60. Butyl 3-(4-((2-(2-methyl-1H-indol-1-yl)-ethyl)carbamoyl)phenyl)piperidine-1-carboxylate (8g)
(TG7-264)
1
H NMR (CDCl ):  7.53 (d, J = 7.6 Hz, 2H),), 7.51 (d, J = 4.8 Hz, 1H), 7.31 (d, J = 8 Hz, 1H), 7.22 (d,
3
J = 7.6 Hz, 2H), 7.08 (m, 2H), 6.06 (t, J = 6 Hz, 1H), 4.35 (t, J = 6 Hz, 2H), 4.13 (m, 2H), 3.78 (q, J = 6
Hz, 2H), 2.72 (m, 4H), 2.38 (s, 3H), 1.97 (m, 1H), 1.72 (m, 1H), 1.58 (m, 3H), 1.44 (s, 9H). LCMS (ESI):
+
>
97% purity at λ 254, MS; m/z, 462 [M+H] .
3
.2.61. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-4-(piperidin-3-yl)benzamide (8h) (TG7-268)
1
H NMR (CDCl ):  7.47 (m, 3H),), 7.25 (dd, J = 7.6, 1.6 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.0 (m, 3H),
3
6
.16 (d, J = 6 Hz, 1H), 4.33 (q, J = 6.2 Hz, 2H), 3.77 (q, J = 6.2 Hz, 2H), 3.30 (m, 1H), 3.11 (m, 1H), 2.72
+
(
m, 1H), 2.32 (s, 3H), 1.80-1.60 (m, 6H). LCMS (ESI): > 94% purity at λ 254, MS; m/z, 362 [M+H] .
3
.2.62. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-4-(piperidin-4-yloxy)benzamide (8i) (TG7-234)
1
H NMR (CDCl ):  7.53 (m, 2H),), 7.35 (m, 1H), 7.30 (d, J = 8 Hz, 1H), 7.10 (m, 1H), 6.85 (m, 3H),
3
6
.24 (s, 1H), 6.06 (t, J = 5.6 Hz, 1H), 4.6 (broad singlet, 1H), 4.33 (q, J = 6.2 Hz, 2H), 3.77 (q, J = 6.2 Hz,

2
H), 3.11 (m, 2H), 2.69 (m, 2H), 2.3 A7 C( s C, 3E HP )T, E1 .D9 8 M( mA , N1 HU ) S, C1 . R9 2I P( mT , 1H), 1.6 (m, 2H). LCMS (ESI): >
+
9
7% purity at λ 254, MS; m/z, 378 [M+H] .
3
.2.63. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-4-(morpholinomethyl)benzamide (8j) (TG8-5)
1
H NMR (CDCl ):  7.53 (t x d, J = 6.4, 1.6 Hz, 3H),), 7.34 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8 Hz, 1H),
3
7
.08 (m, 2H), 6.25 (s, 1H), 4.35 (t, J = 6 Hz, 2H), 3.77 (q, J = 6 Hz, 2H), 3.69 (t, J = 4.4 Hz, 4H), 3.50 (s,
+
2
H), 2.41 (broad singlet, 4H), 2.38 (s, 3H). LCMS (ESI): > 95% purity at λ 254, MS; m/z, 375 [M+H] .
3
.2.64. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide (8k) (TG8-6)
1
H NMR (CDCl ):  7.52 (t x d, J = 6.4, 1.6 Hz, 3H),), 7.32 (m, 3H), 7.07 (m, 2H), 6.25 (s, 1H), 4.35 (t,
3
J = 6 Hz, 2H), 3.77 (q, J = 6 Hz, 2H), 3.50 (s, 2H), 2.45 (broad singlet, 8H), 2.38 (s, 3H), 2.28 (s, 3H).
+
LCMS (ESI): > 97% purity at λ 254, MS; m/z, 391 [M+H] .
3
.2.65. 2-Amino-N-(2-(2-methyl-1H-indol-1-yl)ethyl)pyrimidine-5-carboxamide (8l) (TG7-261)
1
H NMR (DMSO-d ):  8.55 (s, 2H), 8.47 (t, J = 6 Hz, 1H), 7.37 (d, J = 8.8 Hz, 2H), 7.18 (s, 2H), 6.99 (t,
6
J = 6.8 Hz, 1H), 6.93 (t, J = 6.8 Hz, 1H), 6.16 (s, 1H), 4.23 (t, J = 6.8 Hz, 2H), 3.46 (q, J = 6.4 Hz, 2H),
+
2
.34 (s, 3H). LCMS (ESI): > 98% purity at λ 254, MS; m/z, 295 [M+H] .
3
.2.66. N-(2-(2-methyl-1H-indol-1-yl)ethyl)-2-(phenylamino)pyrimidine-5-carboxamide (8m) (TG7-228).
1
H NMR (CDCl +MeOH-d ):  8.60 (s, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.28 (m,
3
4
2
H), 7.04 (m, 3H), 6.19 (s, 1H), 4.27 (t, J = 6 Hz, 2H), 3.65 (t, J = 6 Hz, 2H), 2.33 (s, 3H). LCMS (ESI): >
+
9
7% purity at λ 254, MS; m/z, 372 [M+H] .
3
.2.67. 2-(Ethylamino)-N-(2-(2-methyl-1H-indol-1-yl)ethyl)pyrimidine-5-carboxamide (8n)(TG7-229)
1
H NMR (CDCl +MeOH-d ):  8.47 (s, 1H), 7.47 (d, J = 7.6 Hz, 2H), 7.25 (d, J = 7.6 Hz, 1H), 7.04 (m,
3
4
2
H), 6.21 (s, 1H), 4.29 (t, J = 6 Hz, 2H), 3.68 (q, J = 6 Hz, 2H), 3.41 (q, J = 7.2 Hz, 2H), 2.34 (s, 3H), 1.19
+
(
t, J = 7.2 Hz, 3H). LCMS (ESI): > 98% purity at λ 254, MS; m/z, 324 [M+H] .
3
.2.68. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-2-morpholinopyrimidine-5-carboxamide (8o) (TG7-249)
1
H NMR (CDCl ):  8.59 (s, 2H), 7.50 (d, J = 7.6 Hz, 2H), 7.30 (d, J = 8 Hz, 1H), 7.09 (m, 2H), 6.24 (s,
3
1
H), 6.05 (t, J = 4Hz, 1H), 4.33 (t, J = 6 Hz, 2H), 3.89 (t, J = 4.8 Hz, 4H), 3.75 (q, J = 4.8 Hz, 4H), 2.38 (s,
+
3
H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 366 [M+H] .
3
.2.69. 2-Amino-N-(2-(2-methyl-1H-indol-1-yl)ethyl)nicotinamide (8p) (TG7-259)

1
H NMR (CDCl ):  8.0 (d, J = 5 .A2 CH Cz ,E1 PH T) ,E D7 . 1M5 A( d N, JU =S C7 RH IzP, T1 H), 7.28 (d, J = 8 Hz, 1H), 7.08 (m,
3
2
1
9
H), 6.69 (broad singlet, 2H), 6.47 (dd, J = 7.8, 4.8 Hz, 1H), 6.26 (s, 1H), 6.15 (broad triplet, J = 7 Hz,
H), 4.33 (t, J = 6 Hz, 2H), 3.74 (t, J = 6 Hz, 4H), 3.74 (q, J = 6 Hz, 2H), 2.39 (s, 3H). LCMS (ESI): >
+
7% purity at λ 254, MS; m/z, 295 [M+H] .
3
.2.70. N-(2-(2-Methyl-1H-indol-1-yl)ethyl)-1-(pyrimidin-2-yl)piperidine-4-carboxamide (8q) (TG7-244)
1
H NMR (CDCl ):  8.29 (d, J = 4.8 Hz, 2H), 7.49 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.05
3
(m, 2H), 6.48 ( (t, J = 5.6 Hz, 1H), 6.24 (s, 1H), 5.50 (broad triplet, J = 7 Hz, 1H), 4.74 (d, J = 16 Hz, 2H),
4
.23 (t, J = 6 Hz, 2H), 3.58 (q, J = 6 Hz, 2H), 2.87 (t, J = 6 Hz, 2H), 2.39 (s, 3H), 2.21 (m, 1H), 1.79 (m,
+
2
H), 1.59 (m, 2H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 364 [M+H] .
3
.2.71. N-(2-(5-Fluoro-2-methyl-1H-indol-1-yl)ethyl)-4-morpholinobenzamide (8r) (TG7-183)
1
H NMR (CDCl ):  7.53 (dd, J = 7, 2 Hz, 2H), 7.21 (dd, J = 8.8, 4.4 Hz, 1H), 7.14 (dd, J = 9.6, 2.4 Hz,
3
1
H), 6.82 (m, 1H), 6.81 (d, J = 8.8 Hz, 2H), 6.19 (s, 1H), 6.06 (t, J = 6 Hz, 1H), 4.3 (t, J = 6 Hz, 2H), 3.8
(t, J = 4.8 Hz, 4H), 3.73 (t, J = 6 Hz, 2H), 3.22 (t, J = 4. 8 Hz, 4H), 2.36 (s, 3H). LCMS (ESI): > 97%
+
purity at λ 254, MS; m/z, 382 [M+H] .
3
.2.72. 3-Fluoro-N-(2-(5-fluoro-2-methyl-1H-indol-1-yl)ethyl)-4-(4-methylpiperazin-1-yl)benzamide (8s)
(TG7-184)
1
H NMR (CDCl ):  7.33 (dd, J = 13.6, 2 Hz, 1H), 7.25 (dd, J = 8.2, 2 Hz, 1H), 7.19 (dd, J = 8.8, 4.4 Hz,
3
1
2
H), 7.13 (dd, J = 9.6, 2.4 Hz, 1H), 6.83 (m, 2H), 6.19 (s, 1H), 6.12 (t, J = 5.4 Hz, 2H), 4.29 (t, J = 6 Hz,
H), 3.71 (q, J = 6 Hz, 2H), 3.16 (t, J = 4.8 Hz, 4H), 2.55 (t, J = 4.8 Hz, 4H), 2.35 (s, 3H), 2.32 (s, 3H).
+
LCMS (ESI): > 95% purity at λ 254, MS; m/z, 413 [M+H] .
3
.2.73. 4-(Diethylamino)-N-(2-(2-(trifluoromethyl)-1H-indol-1-yl)ethyl)benzamide (8t)(TG4-194)
1
H NMR (CDCl ):  7.64 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 7.2 Hz, 2H), 7.30 (t, J = 8.4 Hz, 1H), 7.15 (t, J
3
=
7.6 Hz, 1H), 6.95 (s, 1H), 6.57 (d, J = 8.8 Hz, 2H), 6.07 (t, J = 5.6 Hz, 1H), 4.4 (t, J = 6.8 Hz, 2H), 3.78
(q, J = 6 Hz, 2H), 3.37 (q, J = 7.2 Hz, 4H), 1.63 (t, J = 6.8 Hz, 6H). LCMS (ESI): > 97% purity at λ 254,
+
MS; m/z, 404 [M+H] .
3
.2.74. 4-Morpholino-N-(2-(2-(trifluoromethyl)-1H-indol-1-yl)ethyl)benzamide (8u) (TG7-195)
1
H NMR (CDCl ):  7.65 (d, J = 8 Hz, 1H), 7.6 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 7.2 Hz, 2H), 7.29 (t x d,
3
J = 7.2, 1.2 Hz, 1H), 7.15 (t x d, J = 7.2, 1.2 Hz, 1H), 6.96 (s, NH), 6.82 (dd, J = 6.8, 1.2 Hz, 2H), 6.13 (t, J
=
5.6 Hz, 1H), 4.49 (t, J = 6.4 Hz, 2H), 3.83 (q, J = 5.2 Hz, 4H), 3.81 (q, J = 6.4 Hz, 2H). LCMS (ESI): >
+
9
7% purity at λ 254, MS; m/z, 418 [M+H] .

ACCEPTED MANUSCRIPT
3
.2.75. 4-(Diethylamino)-N-(2-(2-methyl-1H-benzo[d]imidazol-1-yl)ethyl)benzamide (8v) (TG7-199)
1
H NMR (CDCl ):  7.64 (m, 1H), 7.53 (dd, J = 7.2, 2 Hz, 2H), 7.32 (m, 1H), 7.19 (m, 2H), 6.54 (d, J =
3
8
4
.8 Hz, 2H), 6.4 (t, J = 6 Hz, 1H), 4.35 (t, J = 5.6 Hz, 2H), 3.75 (q, J = 5.6 Hz, 2H), 3.35 (q, J = 7.2 Hz,
+
H), 2.43 (s, 3H), 1.14 (t, J = 7.2 Hz, 6H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 351 [M+H] .
3
.2.76. N-(2-(1H-Benzo[d]imidazol-1-yl)ethyl)-4-(diethylamino)benzamide (8w) (TG7-203)
1
H NMR (CDCl ):  7.69 (d, J = 4 Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 6.4 Hz, 1H), 7.23 (m,
3
2
7
H), 6.66 (bs, 1H), 6.53 (d, J = 8.8 Hz, 2H), 4.38 (t, J = 5.2 Hz, 2H), 3.75 (q, J = 5.6 Hz, 2H), 3.54 (q, J =
+
.2 Hz, 4H), 1.13 (t, J = 7.2 Hz, 6H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 337 [M+H] .
3
6
3
.2.77. 4-Acetamido-N-(2-(2-methyl-1H-indol-3-yl)ethyl)benzamide (8x) (TG7-146)
1
H NMR (CDCl ):  7.4 (m, 4H), 7.22 (d, J = 9 Hz, 2H), 7.0 (m, 2H), 3.6 (t, J = 6.4 Hz, 2H), 2.95 (t, J =
3
+
.4 Hz, 2H), 2.26 (s, 3H), 2.08(s, 3H). LCMS (ESI): > 95% purity at λ 254, MS; m/z, 336 [M+H] .
.2.78. N, N-Diethyl-N4-(2-(2-methyl-1H-indol-3-yl)-ethyl)terephthalamide (8y) (TG7-231)
1
H NMR (CDCl ):  7.61 (d, J = 8 Hz, 2H), 7.50 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8 Hz, 2H), 7.25 (d, J =
3
8
2
Hz, 1H), 7.06 (m, 2H), 6.25 (bs, 1H), 3.68 (q, J = 6 Hz, 2H), 3.51 (q, J = 6.8 Hz, 2H), 3.16 (q, J = 6.4 Hz,
H), 3.01 (t, J = 6.8 Hz, 2H), 2.30 (s, 3H), 1.23 (broad triplet, J = 6.4 Hz, 3H), 1.05(broad triplet, J = 6.4
+
Hz, 3H). LCMS (ESI): > 97% purity at λ 254, MS; m/z, 378 [M+H] .
3
.2.79. 4-(Dimethylamino)-N-(2-(2-methyl-1H-indol-3-yl)ethyl)benzamide (8z) (TG7-167)
1
H NMR (CDCl ):  8.2 (s, 1H), 7.54 (m, 3H), 7.25 (dd, J = 7.2, 2.4 Hz, 1H), 7.08 (m, 2H), 6.57 (dd, J =
3
7
, 1.6 Hz, 2H), 6.14 (t, J = 5.6 Hz, 2H), 3.65 (q, J = 6.8 Hz, 2H), 2.98 (m, 2H), 2.95 (s, 3H), 2.31 (s, 3H).
+
LCMS (ESI): > 95% purity at λ 254, MS; m/z, 322 [M+H] .
3
.2.80. 4-(Diethylamino)-N-(2-(2-methyl-1H-indol-3-yl)ethyl)benzamide (9a) (TG7-181)
1
H NMR (CDCl ):  8.05 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 7.4 Hz,
3
1
6
2
7
H), 7.10 (m, 2H), 6.55 (d, J = 9.2 Hz, 2H), 6.0 (t, J = 5.4 Hz, 1H), 3.67 (q, J = 6.4 Hz, 2H), 3.36 (q, J =
.8 Hz, 2H), 2.99 (t, J = 6.4 Hz, 2H), 2.35 (s, 3H), 1.14 (t, J = 7.2 Hz, 6H). LCMS (ESI): > 97% purity at λ
+
54, MS; m/z, 350 [M+H] . Anal. Calcd. for C H N O; C, 75.61; H, 7.79; N, 12.02; Found; C, 75.58; H,
2
0
23
3
.72; N, 12.07.
3
.2.81. N-(2-(2-Methyl-1H-indol-3-yl)ethyl)-4-(piperidin-1-yl)benzamide (9b) (TG7-168)