Design and synthesis of aryloxypropanolamine as β3-adrenergic receptor antagonist in cancer and lipolysis

Article abstract of DOI:10.1016/j.ejmech.2018.03.032

β-adrenergic receptors (β-ARs) are broadly distributed in various tissues and regulate a panel of important physiological functions and disease states including cancer. Above all, β₃-adrenergic receptor (β₃-AR) plays a significant ro

Full text of DOI:10.1016/j.ejmech.2018.03.032

Accepted Manuscript
Design and synthesis of aryloxypropanolamine as β -adrenergic receptor antagonist
3
in cancer and lipolysis
Jiyu Jin, Chunxiao Miao, Zhilong Wang, Wanli Zhang, Xiongwen Zhang, Xin Xie, Wei
Lu
PII:
S0223-5234(18)30275-7
10.1016/j.ejmech.2018.03.032
EJMECH 10297
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 15 November 2017
Revised Date: 5 March 2018
Accepted Date: 9 March 2018
Please cite this article as: J. Jin, C. Miao, Z. Wang, W. Zhang, X. Zhang, X. Xie, W. Lu, Design and
synthesis of aryloxypropanolamine as β -adrenergic receptor antagonist in cancer and lipolysis,
3
European Journal of Medicinal Chemistry (2018), doi: 10.1016/j.ejmech.2018.03.032.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Design and Synthesis of aryloxypropanolamine as β3-adrenergic
receptor antagonist in cancer and lipolysis
Jiyu Jin a, 1, Chunxiao Miao b, 1, Zhilong Wang c, Wanli Zhang b, Xiongwen Zhang b, *, Xin Xie c, d, * and
Wei Lu a, *
aSchool of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan
Road, Shanghai, China
bShanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School
of Chemistry and Molecular Engineering, East ChinaNormal University, Shanghai, China
cCAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of
Materia Medica, Chinese Academy of Sciences, Shanghai, China
dState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of
Sciences, Shanghai, China
* Corresponding authors:
E-mail: wlu@chem.ecnu.edu.cn; Tel.: +86-21-62602475 (W. Lu);
E-mail: xxie@simm.ac.cn; Tel.: +86-21-50801313-156 (X. Xie);
E-mail: xwzhang@sat.ecnu.edu.cn; Tel.: +86-21-62221232 (XW. Zhang).
1These authors contributed equally.
Abstract
β-adrenergic receptors (β-ARs) are broadly distributed in various tissues and regulate a
panel of important physiological functions and disease states including cancer. Above all,
β3-adrenergic receptor (β3-AR) plays a significant role in regulating lipolysis and
thermogenesis in adipose tissue. In this study, we designed and synthesized a series of novel
L-748,337 derivatives as selective human β3-AR antagonists. Among all the tested L-748,337
analogs, compound 23d was found to display 23-fold more potent β3-AR antagonist activity
(EC50 = 0.5117 nM) than L-748,337 (EC50 = 11.91 nM). In vivo, compound 23d could
alleviate weight loss and inhibit tumor growth in C26 tumor cachexia animal model.
Keywords: β-adrenergic receptor, antagonist, cancer, lipolysis and cachexia
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1. Introduction
β-Adrenergic receptors (β-ARs) belong to the superfamily of membrane proteins termed G
protein-coupled receptors. β-ARs are distributed in the effector cells of most of the
sympathetic nerve fibers, and the receptors are of three types, the β1 receptor, the β2 receptor
and the β3 receptor.
[1, 2]
In mouse models of breast and prostate carcinomas,
as well as malignant melanoma
and leukemia, [3, 4] β-ARs antagonists have been found to block stress-induced enhancement
of tumor progression and/or metastasis without influencing primary tumor growth in vivo or
tumor cell proliferation in vitro. β-ARs antagonists alone or in combination with nonsteroidal
anti-inflammatory agents (NSAID) have also been found to inhibit surgery-induced
[3, 5, 6]
metastasis in animal model.
Preclinical laboratory models and human
pharmaco-epidemiologic studies both indicate that β-antagonists are likely to be the most
effective drugs in inhibiting the micrometastatic spread of early-stage tumors. [7]
It has been found that β3-AR plays a significant role in regulating lipolysis and
thermogenesis in both rodent and human adipose tissue. In rodent white adipose tissue,
[8]
β3-AR accounts for 90% of the β-ARs on the cell surface.
Data show that chronic
inflammation together with β-adrenergic activation functionally cooperate in the pathogenesis
[9]
of increased adipose tissue thermogenesis in cachexia.
β-adrenergic blockers can reduce
white blood cell adipose tissue (WAT) browning, decrease the severity of cachexia. β3-AR
blockade may protect against cachexia by means of decreased lipolysis. [10]
A few antagonists of β3-AR have been identified. At present, there are two typical β3-AR
[11]
inhibitors: aryloxy propanolamine tetrahydrate β3-AR inhibitor (SR59230A)
and
aryloxypropanolamine β3-AR inhibitor (L-748,337), and their structures are shown in Figure
1. SR59230A displays high affinity at human cloned β1-AR and β2-AR. Therefore,
[12]
SR59230A is a potent and nonselective β-AR antagonist.
In contrast, L-748,337 displays
more than 90-fold selectivity for human β3-AR over β1-AR, 45-fold selectivity for human
[12]
β3-AR over β2-AR, respectively.
In this study, we clarified the process of exploring and
developing potent and selective β3-AR antagonists. Meanwhile, we discussed the
structure-relationship (SAR) data that deviated from that of the aryloxypropanolamine
chemotype.
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Our design concept is outlined in Figure 2. We planned to introduce 2-ethylphenyl group
or 1H-indole group into the left-wing (part A) and to introduce urea group into the right-wing
(part B) to attempt to improve β3-AR antagonist activity. We design compounds I based on
an aryloxypropanolamine scaffold to facilitate rapid synthesis and SAR evaluation. This
paper describes these efforts and the discovery of a novel, potent and selective human β3-AR
antagonist. These compounds would maintain favorable activities in vitro and in vivo with
decreasing the severity of cancer cachexia and inhibiting the growth of cancer cells.
Figure 1. Chemical structure of early β3-AR antagonist.
part A
part A
O
OH
H
N
OH
OH
O
O
HO
O
S
O
N
O
O
OH
N
NH
O
H
N
HN
H
(S)-Pindolol
L-748,337
SR59230A
part A
part A
OH
H
N
part B
R2
O
R1
N
H
Figure 2. Design of compound based on (S)-pindolol, L-748,337 and SR59230A.
2. Results and discussion
2.1. Chemistry
SR59230A derivatives 8a-d were prepared as illustrated in Scheme 1. A commercially
available p-nitrophenylethylamine hydrochloride salt (1) reacted with paraformaldehyde to
form the Schiffs base. Without purification, the Schiffs base was reduced with NaBH4
directly to produce intermediate 2. 2-ethylphenol (3) was treated with sodium hydroxide in
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water and dioxane, and the resultant sodium salt was alkylated with commercially available
(R)-(-)-epichlorohydrin to provide epoxide 4. Aniline intermediate 6 was synthesized by the
reduction of the nitro group in the intermediate 5, which in turn was made from the coupling
of intermediate 2 and compound 4. The coupling of 6 with the appropriate arylacetic acid
derivatives, followed by deprotection of the benzyl group by hydrogenolysis afforded the
desired products 8a-d.
L-748,337 derivatives 17a-d were prepared from compound 13 in the same manner as the
synthesis of 8a-d as illustrated in Scheme 2. Compound 13 was synthesized by 4 reactions
from the starting material 3-hydroxybenzonitrile (9) via reduction, acylation, hydrolyzation
and alkylation.
Scheme 3 shows the synthesis of Indole derivatives 23a-m by the starting material
1H-indol-4-ol (18) in the same synthesis route of 8a-d. 1H-indol-4-ol (18) was alkylated with
(R)-(-)-epichlorohydrin using sodium hydroxide as a base to produce epoxide 19. After the
coupling of epoxide 19 and intermediate 2, following by reduction of the nitro group with
Tin(II) chloride, the desired product compound 21 was given. The coupling of compound 21
with the appropriate arylacetic acid derivatives, followed by de-protection of the benzyl
group by hydrogenolysis afforded the desired products 23a-m.
Compounds 27a-f were prepared from aniline intermediate 21 as illustrated in Scheme 4.
The coupling of aniline intermediate 21 with the appropriate arylacetic acid derivatives,
followed by reduction of the nitro group with Fe(OH)3 and hydrazine hydrate afforded the
desired products 25a-c. The acylation of 25a-c with the appropriate arylacetic acid
derivatives, followed by deprotection of the benzyl group by hydrogenolysis afforded the
desired products 27a-f.
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Scheme 1. Synthesis of SR59230A derivatives 8a-d. Reagent and conditions: (a) Paraformaldehyde EtOH
reflux, then NaBH4, EtOH, rt; (b) (R)-(-)-Epichlorohydrin, NaOH, warer/Dioxane, rt; (c) NaOH, IPA,
relfux; (d) SnCl2, EtOH, reflux; (e) R1Cl, Pyridine, DCM, rt; (f) Raney-Ni, H2, MeOH, rt.
Scheme 2. Synthesis of L-748,337 derivatives 17a-d. Reagent and conditions: (a) Raney-Ni, H2, MeOH, rt;
(b) Acetyl chloride, Pyridine, DCM, rt; (c) 15% NaOH(aq), MeOH, rt; (d) (R)-(-)-Epichlorohydrin, NaOH,
warer/Dioxane, rt; (e) NaOH, IPA, relfux; (f) SnCl2, EtOH, reflux; (g) R2Cl, Pyridine, DCM, rt; (h)
Raney-Ni, H2, MeOH, rt.
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Scheme 3. Synthesis of Indole derivatives 23a-m. Reagent and conditions: (a) (R)-(-)-Epichlorohydrin,
NaOH, warer/Dioxane, rt; (b) NaOH, IPA, relfux; (c) SnCl2, EtOH, reflux; (d) R3Cl, Pyridine, DCM, rt; (e)
Raney-Ni, H2, MeOH, rt.
Scheme 4. Synthesis of Indole derivatives 27a-f. Reagent and conditions: (a) ArCNO, Pyridine, DCM, rt;
(b) Fe(OH)3, N2H4H2O, EtOH, reflux; (c) Pyridine, DCM, rt; (d) Raney-Ni, H2, MeOH, rt.
2.2. β3-AR antagonist activity in vitro
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All compounds listed in Table1, 2 and 3 were evaluated in vitro for their antagonist
activities by using calcium mobilization assay with HEK293 cells expressing human β3-, β2-
or β1-ARs. The results of reference compounds (L-748,337) are also shown for comparison in
Table 1.
The L-748,337 of our lead compound was found to be a modestly potent β3-AR
antagonist (EC50 = 11.91 nM) with a lower potency for the β2-AR (EC50 = 23490 nM) and
β1-AR (EC50 = 889.0 nM). In order to improve β3-AR antagonist activity and selectivity over
β2- and β1-ARs, modification of the sulfonamido moiety in L-748,337 with the other
functional moieties was investigated Table 1.
Replacement of the sulfonamido moiety of L-748,337 with the formamide moiety (17a)
and the acetamide moiety (17b) resulted in slightly increased potency at the β3-AR (EC50 =
7.805 nM and 4.584 nM, respectively). Next, replacement of the sulfonamido moiety in
L-748,337 with the ureido moiety (17c) and the thiourea moiety (17d) resulted in a 3-fold
increase in potency at the β3-AR with antagonist activity (EC50 = 4.699 nM and 3.412 nM,
respectively) relative to L-748,337. The thiourea moiety is well-known to produce toxic
effects and unsuitable for drug designing, so we chose urea group for the next study. These
results indicated that the urea group played an important role in β3-AR antagonist activity
(EC50 = 4.699 nM) and selectivity over β2-AR (EC50 = 9842 nM) and β1-AR (EC50 = 12700
nM). Then, using 2-ethylphenyl and 1H-indole as representatives, the phenoxymethyl
compound 23d displayed high potent β3-AR antagonist activity (EC50 = 0.5117 nM) as
compared to L-748,337 (EC50 = 11.91 nM) and high selectivity over β2-AR (100-fold) and
β1-AR (6-fold).
In order to improve β3-AR antagonist activity, modification of the substituent on the
thiourea moiety in 23d was examined as shown in Table 2. For β3-AR activity, while a bulky
group such as cyclohexyl group and the alkyl substituted derivatives, 23e, 23f and 23g, were
less potent than compound 23d. These results revealed that replacement of the phenyl ring
with a cyclohexyl ring and isopropyl group and the insertion of an ethylene group between
the phenyl ring and ureido moiety in 23d may not have been efficacious for improving
antagonist activity at the β3-AR.
We then examined the effects of the substituents on the phenyl ring in 23d in Table 2.
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The introduction of the fluorine group as an electron-withdrawing group on the phenyl ring of
the phenylthiourea moiety (23h-j) resulted in slightly decreased antagonist activity at the
β3-AR relative to 23d, and the rank of order of potency seemed to be para-fluorine (EC50=
2.491 nM) > meta-fluorine (EC50= 2.927 nM) > ortho-fluorine (EC50= 3.575 nM). The
methoxy and methyl carbamate group as an electron-donating group was also introduced on
the phenyl ring of the phenylthiourea moiety (23k-m, 27a-c), which yielded results better
than those of the fluorinephenyl derivatives. The pentanamide group as a huge group was
also introduced on the phenyl ring of the phenylthiourea moiety (27d-f) resulted decreased
antagonist activity at the β3-AR relative to 23d, especially para- pentanamide. These results
revealed that the introduction of a substituent on the phenyl ring of the phenylthiourea moiety
in 23d allowed the potency of β3-AR to be maintained, but no one can be stronger than that of
23d.
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Table 1. β3-AR antagonist activity of aryloxypropanolamine derivatives.
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Table 2. β3-AR antagonist activity of urea derivatives.
2.3. Inhibitory effect of β3-AR antagonists on lipolysis in vitro
In order to identify the ability of some β3-AR antagonists to inhibit lipolysis, we used
ISO to induce lipolysis of mature 3T3-L1 adipocytes in vitro (Figure 3). Results showed that
the β3-AR antagonists of urea derivatives inhibited lipolysis to different degrees compared
with the inhibitory activity of SR59230A and L-748,337 in vitro (Figure 3). In detail, the
compounds 23d, 23e and 23g displayed a similar inhibitory activity compared with that of
L-748,337. The para-substituent on the phenylthiourea moiety (23j, 23m and 27c) and 23f
exhibited a more potent inhibitory activity on lipolysis than L-748,337 did.
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Figure 3. Antagonist of β3-adrenergic receptor inhibits lipolysis of 3T3-L1 mature adipocyte in vitro. The
lipolysis of 3T3-L1 adipocyte in cancer cachexia model in vitro was induced 1 µM ISO for 2 hr. Data
presented are the mean ± SE of three independent experiments. * versus control group. # versus ISO group.
#p < 0.05, ###p < 0.001. *p < 0.05, **p < 0.01.
2.4. Inhibitory effect of β3-AR antagonist 23d on C26 tumor-bearing mice
Finally, we tested the potent capacity of β3-AR antagonist (23d) attenuating lipolysis
with the C26 tumor bearing mice in vivo. At the end of the treatment (day 13), to avoid the
influence of tumor weight on body weight, we analyzed the tumor-free body weight. The
tumor-free body weight of mice treated with 23d (2.5 mg/kg) was higher than that of C26
model group. The changes of tumor-free body weight increased by 18.5% in healthy mice,
decreased by 8.3% and 4.6% in C26 model group and in 23d treatment group(2.5 mg/kg)
respectively (Figure. 4A). Interesting, compound 23d also influenced C26 tumor growth in
mice. C26 tumor volume of 23d (2.5 mg/kg) treated mice was significantly less than that of
C26 model mice (Figure. 4B). What’s more, 23d PDTC also effectively inhibited the lipolysis
of body fat. The glycerol content in mice serum further confirmed the protection of 23d on
lipolysis (Figure. 4C). It demonstrated that β3-adrenergic receptor antagonists (23d) have a
certain inhibitory effect on lipolysis in C26 tumor bearing mice.
The experimental results show that β3-adrenergic receptor antagonists (23d) can reduce
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the weight loss of cancer cachexia and also reduce tumor volume in animal models of tumor
cachexia.
Figure 4. 23d attenuates C26 tumor-induced body weight loss in vivo. Compound 23d (2.5 mg/kg) was
injected in tail vein daily (n=7). A) Tumor-free body weight of mice. B) C26 tumor volume of mice. C)
Content of glycerol in serum. Data presented are the mean ± SE of three independent experiments. * versus
health group mice. # versus C26 tumor bearing group mice. ###p<0.001. **p<0.01, ***p<0.001.
3. Conclusion
In summary, a series of novel L-748,337 derivatives as selective human β3-AR antagonists
were designed and synthesized to explore their biological activity and SAR with the lead
compound, L-748,337. SAR analysis indicated that 1H-indole moiety derivatives showed
higher β3-AR antagonist activity than that of 3-(acetamidomethyl)phenyl and 2-ethylphenyl
moiety in part A, and the rank of order of potency seemed to be 1H-indole >
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3-(acetamidomethyl)phenyl > 2-ethylphenyl. In the part B position, the connection moiety
was crucial for the β3-AR antagonist activity, and the preferred group was ureido moiety. For
the 1H-indole moiety antagonists of the human β3-AR described herein demonstrates in this
receptor of binding interaction that can accommodate small (23d) to larger and bulkier
substituents.
Among all the compounds, the novel L-748,337 derivative (23d) showed the potent human
β3-AR antagonist activity and high lipolysis inhibitory activity in vitro. The compound 23d
displayed 23-fold more potent β3-AR antagonist activity (EC50 = 0.5117 nM) than that of
L-748,337 (EC50 = 11.91 nM) and high selectivity over β2-AR (100-fold) and β1-AR (6-fold).
In vivo, compound 23d could alleviate weight loss and inhibit tumor growth in C26 tumor
cachexia animal model.
In conclusion, in this study, we investigated potent and selective human β3-AR antagonist
and demonstrated 23d as a useful in vitro and in vivo pharmacological tool for decreasing the
severity of cancer cachexia and inhibiting the growth of cancer cells.
4. Experimental sections
4.1. Materials and methods
All reagents are commercially available and were used without further purification. The
solvents used were of analytical grade. Melting points were taken on a FishereJohns melting
1
point apparatus, uncorrected and reported in degrees Centigrade. H NMR and 13C NMR
spectra were scanned on a Bruker DRX-400 (400 MHz) using tetramethylsilane (TMS) as
internal standard and using one or two of the following solvents, DMSO-d6 and CDCl3.
Chemical shifts are given in δ, ppm. Splitting patterns were designated as follows: s: singlet;
d: doublet; t: triplet; q: quartet; m: multiplet. The mass spectra (MS) were recorded on a
Finnigan MAT-95 mass spectrometer. The purity of all tested compounds was established by
HPLC to be >95.0%. HPLC analysis was performed at room temperature using an Agilent
Eclipse XDBC18 (250 mm × 4.6 mm) and as a mobile phase gradient from 5% MeCN/H2O
(1‰ TFA) for 1 min, 5% MeCN/H2O (1‰ TFA) to 95% MeCN/H2O (1‰ TFA) for 9 min
and 95% MeCN/H2O (1‰ TFA) for 5 min more, a flow rate of 1.0 mL/min and plotted at 254
nm.
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4.2. General synthesis
4.2.1. N-benzyl-2-(4-nitrophenyl)ethan-1-amine hydrochloride (2)
In a 250 mL round-bottomed flask was added 2-(4-nitrophenyl)ethan-1-amine hydrochloride
(1) (14.3 g, 70.6 mmol, 1.0 eq) in water (45 mL) and EA (75 mL) to give a colorless solution.
NaOH (3.10 g, 78 mmol, 1.1 eq) was added. The reaction mixture was held at rt with stirring
on for 30 min. The aqueous layer was backextracted with EA. The organic was dried Na2SO4,
filt and conc to give residue 11.7 g. In a 250 mL round-bottomed flask was added residue and
benzaldehyde (8.20 ml, 81 mmol, 1.15 eq) in EtOH (100 mL) to give a yellow suspension.
The reaction vessel was purged with nitrogen. The reaction was heated to 80°C with stirring
on for 16 hr to give a yellow solution. The reaction mixture was cooled to rt with stirring on
to give yellow suspension. NaBH4 (2.94 g, 78 mmol, 1.1 eq) was added slowly. The reaction
mixture was held at rt with stirring on for 1.5 hr. 1M HCl (75 mL) was added to adjust pH to
4. The reaction mixture was filtered through sintered glass funnel and washed with EtOH and
E2O to give N-benzyl-2-(4-nitrophenyl)ethan-1-amine hydrochloride (2) (20.5 g, 99 % yield)
as white solid. m.p. 255–257 °C; 1H NMR (400 MHz, DMSO) δ: 9.74 (s, 2H), 8.20 (d, J = 8.7
Hz, 2H), 7.58 (dd, J = 17.9, 7.1 Hz, 4H), 7.42 (d, J = 6.0 Hz, 3H), 4.17 (s, 2H), 3.20 (s, 4H).
13C NMR (101 MHz, DMSO) δ 146.38, 145.66, 132.04, 130.13, 130.01, 128.74, 128.51,
123.66, 49.77, 46.65, 31.01.
4.2.2. General procedure for the synthesis of 4, 13 and 19
In a 100 mL round-bottomed flask was added 2-ethylphenol (5 g, 40.9 mmol, 1.1 eq) and
sodium hydroxide (1.964 g, 49.1 mmol, 1.2 eq) in water (5 mL) and dioxane (20 mL) to give
a colorless solution. The reaction mixture was held at rt with stirring on for 5 hr.
(R)-2-(chloromethyl)oxirane (4.81 ml, 61.4 mmol, 1.5 eq) was added. The reaction mixture
was held at rt with stirring on for 5 days. The mixture was concentrated by rotovap. Water
(10 mL) was added. The aqueous layer was backextracted with EA. Combined the organic
layers and wash with water. The organic was dried Na2SO4, filt and conc. The crude product
was purified by column chromatography to give 4, 13 and 19.
4.2.2.1. (S)-2-((2-ethylphenoxy)methyl)oxirane (4)
Clear oil (5.58 g, 76% yield). 1H-NMR (400 MHz, CDCl3) δ: 7.15 (t, J = 8.0 Hz, 2H), 6.91 (t,
J = 7.4 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.23 (dd, J = 11.0, 2.6 Hz, 1H), 3.98 (dd, J = 11.0,
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5.4 Hz, 1H), 3.37 (s, 1H), 2.90 (t, J = 4.5 Hz, 1H), 2.81-2.75 (m, 1H), 2.67 (q, J = 7.5 Hz, 2H),
1.21 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 156.34, 133.02, 129.20, 126.86,
121.16, 111.50, 68.69, 50.39, 44.57, 23.38, 14.28.
4.2.2.2. (S)-N-(3-(oxiran-2-ylmethoxy)benzyl)acetamide (13)
Light-yellow solid (3.3 g, 50% yield). m.p. 73-75 °C; 1H NMR (400 MHz, CDCl3) δ 7.24 (t, J
= 7.8 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 6.83 (d, J = 11.2 Hz, 2H), 5.95 (s, 1H), 4.38 (d, J =
5.8 Hz, 2H), 4.23 (dd, J = 11.1, 2.9 Hz, 1H), 3.92 (dd, J = 11.0, 5.8 Hz, 1H), 3.34 (td, J = 6.2,
3.1 Hz, 1H), 2.90 (t, J = 4.5 Hz, 1H), 2.75 (dd, J = 4.9, 2.6 Hz, 1H), 2.01 (s, 3H).
4.2.2.3. (S)-4-(oxiran-2-ylmethoxy)-1H-indole (19)
1
White solid (3.6 g, 42% yield). m.p. 72-74 °C; H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H),
7.12 – 7.05 (m, 2H), 7.01 (d, J = 8.2 Hz, 1H), 6.67 (t, J = 2.3 Hz, 1H), 6.51 (d, J = 7.7 Hz,
1H), 4.34 (dd, J = 11.2, 3.3 Hz, 1H), 4.12 (dd, J = 11.1, 5.5 Hz, 1H), 3.44 (dt, J = 5.9, 3.2 Hz,
1H), 2.95 – 2.87 (m, 1H), 2.80 (dd, J = 5.0, 2.7 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ
152.22, 137.47, 123.13, 122.62, 118.82, 105.24, 100.91, 99.73, 68.87, 50.52, 44.89.
4.2.3. General procedure for the synthesis of 5, 14 and 20
In a 250 mL round-bottomed flask was added N-benzyl-2-(4-nitrophenyl)ethan-1-amine
hydrochloride (2) (1.15 eq) in water (3 mL) and EA (5 mL) to give a white suspension.
NaOH (1.15 eq) was added. The reaction mixture was held at RT with stirring on for 1 hr.
The aqueous layer was backextracted with EA. The organic was dried Na2SO4, filt and conc
to give residue. In a 100 mL round-bottomed flask was added residue and 4, 13 or 19 (1.0 eq)
in 2-Propanol (50 ml) to give a yellow solution. The reaction vessel was purged with nitrogen.
The reaction was heated to 85 °C with stirring on for 16 hr. The mixture was concentrated by
rotovap. The crude product was purified by column chromatography to give 5, 14 and 20.
4.2.3.1. (S)-1-(benzyl(4-nitrophenethyl)amino)-3-(2-ethylphenoxy)propan-2-ol (5)
Light-yellow oil (2.6 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.7 Hz, 2H),
7.28 (t, J = 6.3 Hz, 3H), 7.22 (dd, J = 10.3, 6.4 Hz, 4H), 7.18 – 7.10 (m, 2H), 6.91 (t, J = 7.4
Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 4.07 – 3.99 (m, 1H), 3.97 – 3.88 (m, 2H), 3.85 (d, J = 13.4
Hz, 1H), 3.59 (d, J = 13.4 Hz, 1H), 3.02 (s, 1H), 2.93 – 2.83 (m, 3H), 2.83 – 2.72 (m, 3H),
13
2.60 (q, J = 7.5 Hz, 2H), 1.18 (t, J = 7.5 Hz, 3H). C NMR (101 MHz, CDCl3) δ 156.24,
147.94, 146.50, 138.11, 132.57, 129.52, 129.02, 128.97, 128.53, 127.50, 126.85, 123.65,
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120.89, 111.04, 69.76, 66.66, 58.96, 56.79, 55.05, 33.47, 23.29, 14.20.
4.2.3.2.
(S)-N-(3-(3-(benzyl(4-nitrophenethyl)amino)-2-hydroxypropoxy)benzyl)acetamide
(14)
Yellow oil (8.5 g, 98 % yield). 1H NMR (400 MHz, DMSO) δ 8.30 (t, J = 5.7 Hz, 1H), 8.06
(d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 7.30 - 7.20 (m, 5H), 7.18 (t, J = 7.8 Hz, 1H),
6.80 (d, J = 7.5 Hz, 1H), 6.71 (s, 1H), 6.65 (dd, J = 8.2, 2.0 Hz, 1H), 4.83 (d, J = 4.9 Hz, 1H),
4.21 (d, J = 5.9 Hz, 2H), 3.87 (dd, J = 9.3, 5.0 Hz, 1H), 3.82 - 3.73 (m, 2H), 3.71 - 3.55 (m,
2H), 2.89 (t, J = 7.0 Hz, 2H), 2.83 - 2.69 (m, 2H), 2.65 (dd, J = 13.2, 6.7 Hz, 1H), 2.54 (d, J =
13
5.8 Hz, 1H), 1.87 (s, 3H). C NMR (101 MHz, DMSO) δ 169.06, 158.66, 149.30, 145.69,
141.12, 139.19, 129.91, 129.16, 128.71, 128.02, 126.75, 123.12, 119.28, 113.46, 112.24,
70.49, 67.22, 58.41, 56.28, 55.10, 41.99, 32.38, 22.53.
4.2.3.3. (S)-1-((1H-indol-4-yl)oxy)-3-(benzyl(4-nitrophenethyl)amino)propan-2-ol (20)
Yellow oil (4.9 g, 99% yield). 1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.02 (d, J = 8.5
Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.28 – 7.15 (m, 6H), 7.01 – 6.89 (m, 2H), 6.39 (s, 1H), 6.33
(d, J = 7.2 Hz, 1H), 4.86 (d, J = 4.8 Hz, 1H), 3.97 (ddd, J = 19.0, 9.8, 4.4 Hz, 2H), 3.84 (dd, J
= 9.6, 5.8 Hz, 1H), 3.77 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.7 Hz, 1H), 2.88 (t, J = 7.0 Hz,
2H), 2.77 (hept, J = 6.2 Hz, 3H), 2.60 (dd, J = 13.2, 5.7 Hz, 1H). 13C NMR (101 MHz,
DMSO) δ 152.03, 149.24, 145.67, 139.23, 137.27, 129.87, 128.68, 128.00, 126.72, 123.30,
123.06, 121.60, 118.32, 104.70, 99.67, 98.42, 70.37, 67.46, 58.48, 56.44, 55.03, 54.87, 32.38.
4.2.4. General procedure for the synthesis of 6, 15 and 21
In a 50 mL round-bottomed flask was added 5, 14 and 20 (1.0 eq) and Tin(II) chloride
dihydrate (3.0 eq) in EtOH (200 ml) to give a white suspension. The reaction was heated to
85°C with stirring on for 2 hr. 3M NaOH was added to adjust pH to 9. The reaction mixture
was filtered through sintered glass funnel with EtOH. The mixture was concentrated by
rotovap. Water (5 mL) was added. The aqueou layer was backextracted with EA. The organic
was dried Na2SO4, filt and conc to give 6, 15 and 21. The crude product was used to next step
without further purification.
4.2.4.1. (S)-1-((4-aminophenethyl)(benzyl)amino)-3-(2-ethylphenoxy)propan-2-ol (6)
Yellow oil (1.7 g, 73 % yield). 1H NMR (400 MHz, DMSO) δ 7.33 – 7.18 (m, 5H), 7.14 (ddd,
J = 9.9, 8.5, 3.8 Hz, 2H), 6.89 – 6.82 (m, 2H), 6.78 (d, J = 8.4 Hz, 2H), 6.48 (d, J = 8.3 Hz,
16

ACCEPTED MANUSCRIPT
2H), 4.80 (s, 2H), 4.74 (d, J = 4.3 Hz, 1H), 4.00 – 3.89 (m, 2H), 3.84 (dd, J = 9.5, 5.0 Hz,
1H), 3.74 (d, J = 13.8 Hz, 1H), 3.66 (d, J = 13.8 Hz, 1H), 2.75 (dd, J = 13.1, 6.0 Hz, 1H),
2.68 – 2.55 (m, 5H), 2.55 – 2.50 (m, 2H), 1.10 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz,
DMSO) δ 156.31, 146.41, 139.58, 131.78, 128.89, 128.57, 127.97, 127.24, 126.84, 126.62,
120.12, 113.96, 111.20, 70.33, 67.46, 58.67, 56.58, 56.47, 31.87, 22.70, 14.18.
4.2.4.2. (S)-N-(3-(3-((4-aminophenethyl)(benzyl)amino)-2-hydroxypropoxy)benzyl)acetamide
(15)
light-yellow oil (5.4 g, 96 % yield). 1H NMR (400 MHz, DMSO) δ 8.31 (t, J = 5.7 Hz, 1H),
7.28 (d, J = 4.5 Hz, 4H), 7.21 (dd, J = 10.4, 5.3 Hz, 2H), 6.86 – 6.68 (m, 5H), 6.44 (d, J = 8.2
Hz, 2H), 4.85 – 4.69 (m, 3H), 4.21 (d, J = 6.0 Hz, 2H), 3.95 – 3.84 (m, 2H), 3.73 (dd, J = 11.3,
13
6.7 Hz, 2H), 3.61 (d, J = 13.8 Hz, 1H), 2.69 – 2.51 (m, 6H), 1.87 (s, 3H). C NMR (101
MHz, DMSO) δ 169.06, 158.77, 146.41, 141.10, 139.53, 129.24, 128.89, 128.62, 128.00,
127.17, 126.66, 119.25, 113.89, 113.49, 112.46, 70.61, 67.26, 58.58, 56.49, 42.01, 40.12,
39.92, 39.70, 39.50, 39.29, 39.08, 38.87, 31.84, 22.53.
4.2.4.3. (S)-1-((1H-indol-4-yl)oxy)-3-((4-aminophenethyl)(benzyl)amino)propan-2-ol (21)
Yellow oil (11.3 g, 100% yield). 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.35 – 7.18 (m,
5H), 7.03 (t, J = 7.9 Hz, 1H), 7.00 – 6.95 (m, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 8.2
Hz, 2H), 6.56 (s, 1H), 6.53 (d, J = 8.3 Hz, 2H), 6.43 (d, J = 7.7 Hz, 1H), 4.12 – 3.98 (m, 3H),
3.82 (d, J = 13.6 Hz, 1H), 3.56 (d, J = 13.6 Hz, 1H), 3.33 (d, J = 48.6 Hz, 3H), 2.89 – 2.57 (m,
6H). 13C NMR (101 MHz, CDCl3) δ 152.49, 144.58, 138.74, 137.44, 129.98, 129.58, 129.12,
128.48, 127.27, 122.93, 122.61, 118.81, 115.47, 104.90, 100.74, 99.72, 70.41, 66.60, 58.80,
56.71, 56.10, 32.69.
4.2.5. General procedure for the synthesis of 7a-d, 16a-d, 22a-m and 24a-c
In a 250 mL round-bottomed flask was added 6, 15 and 21 (1.0 eq), benzoyl chloride (1.2 eq),
and pyridine (1.5 eq) in DCM (100 ml) to give a yellow solution. The reaction mixture was
held at rt with stirring on for 1 hr. The mixture was concentrated by rotovap. The crude
product was purified by column chromatography to give 7a-d, 16a-d, 22a-m and 24a-c.
4.2.5.1.
(S)-N-(4-(2-(benzyl(3-(2-ethylphenoxy)-2-hydroxypropyl)amino)ethyl)phenyl)benzenesulfona
mide (7a)
17

ACCEPTED MANUSCRIPT
1
White solid (200 mg, 74% yield). m.p. 86-88 °C; H NMR (400 MHz, DMSO) δ 10.74 (d, J
= 57.8 Hz, 1H), 10.37 (s, 1H), 7.78 (d, J = 7.0 Hz, 2H), 7.69 (s, 2H), 7.62 – 7.57 (m, 1H),
7.57 – 7.51 (m, 2H), 7.44 (s, 3H), 7.09 (d, J = 7.8 Hz, 6H), 6.88 (d, J = 6.9 Hz, 2H), 6.05 (d, J
= 9.1 Hz, 1H), 4.49 (t, J = 38.2 Hz, 3H), 3.94 (s, 1H), 3.86 (s, 1H), 3.37 (s, 3H), 3.07 (s, 2H),
2.42 (d, J = 6.1 Hz, 2H), 1.04 (dd, J = 12.4, 5.6 Hz, 3H).
4.2.5.2.
(S)-N-(4-(2-(benzyl(3-(2-ethylphenoxy)-2-hydroxypropyl)amino)ethyl)phenyl)benzamide (7b)
1
White solid (160 mg, 64% yield). m.p. 57-59 °C; H NMR (400 MHz, DMSO) δ 10.33 (s,
1H), 7.99 (d, J = 7.5 Hz, 2H), 7.81 – 7.70 (m, 4H), 7.51 (dd, J = 19.7, 10.5 Hz, 6H), 7.29 –
7.21 (m, 2H), 7.17 – 7.09 (m, 2H), 6.89 (dd, J = 12.1, 7.4 Hz, 2H), 6.10 (s, 1H), 4.72 – 4.36
(m, 3H), 4.05 – 3.85 (m, 2H), 3.35 (dd, J = 40.0, 12.4 Hz, 4H), 3.23 – 3.06 (m, 2H), 2.49 –
2.41 (m, 2H), 1.06 (dd, J = 17.9, 7.5 Hz, 3H).
4.2.5.3.
(S)-N-(4-(2-(benzyl(3-(2-ethylphenoxy)-2-hydroxypropyl)amino)ethyl)phenyl)-2-phenylaceta
mide (7c)
1
White solid (200 mg, 77% yield). m.p. 76-78 °C; H NMR (400 MHz, DMSO) δ 10.66 (d, J
= 46.7 Hz, 1H), 10.41 (s, 1H), 7.71 (s, 1H), 7.59 (d, J = 5.4 Hz, 2H), 7.45 (s, 2H), 7.33 (d, J =
12.5 Hz, 3H), 7.14 (d, J = 8.9 Hz, 4H), 6.88 (d, J = 6.7 Hz, 2H), 6.06 (s, 1H), 4.52 (t, J = 41.0
Hz, 3H), 4.03 – 3.79 (m, 2H), 3.66 (s, 2H), 3.38 (s, 4H), 3.11 (s, 2H), 2.44 (s, 2H), 1.06 (s,
3H).
4.2.5.4.
(S)-1-(4-(2-(benzyl(3-(2-ethylphenoxy)-2-hydroxypropyl)amino)ethyl)phenyl)-3-phenylurea
(7d)
1
White solid (190 mg, 73% yield). m.p. 94-96 °C; H NMR (400 MHz, DMSO) δ 10.40 (d, J
= 35.4 Hz, 1H), 9.31 (s, 2H), 7.70 (s, 2H), 7.46 (t, J = 10.1 Hz, 7H), 7.26 (t, J = 7.7 Hz, 2H),
7.22 – 7.09 (m, 4H), 6.95 (t, J = 7.3 Hz, 1H), 6.88 (t, J = 8.4 Hz, 2H), 6.06 (d, J = 13.7 Hz,
1H), 4.55 (dd, J = 71.7, 36.2 Hz, 3H), 4.07 – 3.83 (m, 2H), 3.39 (s, 4H), 3.10 (s, 2H), 2.47 (d,
J = 7.6 Hz, 2H), 1.13 – 0.97 (m, 3H).
4.2.5.5.
(S)-N-(4-(2-((3-(3-(acetamidomethyl)phenoxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)
18

ACCEPTED MANUSCRIPT
benzamide (16a)
1
White solid (195 mg, 90% yield). m.p. 97-99 °C; H NMR (400 MHz, DMSO) δ 10.17 (s,
1H), 8.32 (t, J = 5.6 Hz, 1H), 7.95 (d, J = 7.1 Hz, 2H), 7.75 – 7.44 (m, 6H), 7.44 – 7.01 (m,
8H), 6.84 – 6.66 (m, 3H), 4.21 (d, J = 5.9 Hz, 2H), 4.04 – 3.47 (m, 5H), 3.33 (s, 1H), 2.73 (s,
5H), 1.87 (s, 3H).
4.2.5.6.
(S)-N-(4-(2-((3-(3-(acetamidomethyl)phenoxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)
-2-phenylacetamide (16b)
White solid (2.3 g, 91% yield). m.p. 65-67 °C; 1H NMR (400 MHz, DMSO) δ 10.25 (s, 1H),
8.35 (s, 1H), 7.72 – 7.43 (m, 6H), 7.37 – 7.00 (m, 9H), 6.92 – 6.66 (m, 3H), 6.04 (s, 1H), 4.45
(t, J = 42.0 Hz, 4H), 4.21 (d, J = 5.7 Hz, 2H), 3.90 (s, 2H), 3.63 (s, 2H), 3.39 (s, 3H), 3.17 (s,
1H), 1.87 (s, 3H).
4.2.5.7.
(S)-N-(3-(3-(benzyl(4-(3-phenylureido)phenethyl)amino)-2-hydroxypropoxy)benzyl)acetamid
e (16c)
1
White solid (1.9 g, 75% yield). m.p. 70-72 °C; H NMR (400 MHz, DMSO) δ 8.58 (s, 1H),
8.52 (s, 1H), 8.30 (t, J = 5.8 Hz, 1H), 7.44 (d, J = 7.5 Hz, 2H), 7.33 – 7.17 (m, 10H), 7.03 (d,
J = 8.4 Hz, 2H), 6.95 (t, J = 7.3 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 6.76 (s, 1H), 6.72 (dd, J =
8.2, 2.2 Hz, 1H), 4.78 (d, J = 4.5 Hz, 1H), 4.22 (d, J = 5.9 Hz, 2H), 3.90 (d, J = 8.3 Hz, 2H),
3.79 – 3.69 (m, 2H), 3.63 (d, J = 13.8 Hz, 1H), 2.68 (dd, J = 13.0, 9.4 Hz, 5H), 2.54 (dd, J =
13.1, 5.6 Hz, 1H), 1.87 (s, 3H).
4.2.5.8.
(S)-N-(3-(3-(benzyl(4-(3-phenylthioureido)phenethyl)amino)-2-hydroxypropoxy)benzyl)aceta
mide (16d)
White solid (120 mg, 46% yield). m.p. 61-63 °C; 1H NMR (400 MHz, DMSO) δ 9.69 (s, 2H),
8.34 (t, J = 5.6 Hz, 1H), 7.48 (d, J = 7.8 Hz, 2H), 7.37 – 7.26 (m, 8H), 7.22 (dd, J = 10.4, 5.3
Hz, 2H), 7.11 (dd, J = 15.4, 7.8 Hz, 3H), 6.84 – 6.70 (m, 3H), 4.85 (d, J = 3.9 Hz, 1H), 4.23
(d, J = 5.9 Hz, 2H), 3.93 (d, J = 7.3 Hz, 2H), 3.83 – 3.73 (m, 2H), 3.65 (d, J = 13.7 Hz, 1H),
2.80 – 2.63 (m, 5H), 2.57 (dd, J = 13.1, 5.4 Hz, 1H), 1.88 (s, 3H).
4.2.5.9.
19

ACCEPTED MANUSCRIPT
(S)-N-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)benzenesul
fonamide (22a)
White solid (120 mg, 45% yield). m.p. 104-106 °C; 1H NMR (400 MHz, DMSO) δ 11.13 (s,
1H), 10.56 (d, J = 41.4 Hz, 1H), 10.35 (s, 1H), 7.76 (d, J = 7.4 Hz, 2H), 7.65 (d, J = 29.2 Hz,
2H), 7.59 (d, J = 7.2 Hz, 1H), 7.53 (t, J = 7.3 Hz, 2H), 7.45 (s, 3H), 7.20 (s, 1H), 7.10 – 6.93
(m, 6H), 6.44 (d, J = 7.2 Hz, 1H), 6.33 (s, 1H), 6.07 (d, J = 10.3 Hz, 1H), 4.50 (t, J = 23.4 Hz,
3H), 4.00 (d, J = 30.2 Hz, 2H), 3.30 (s, 4H), 3.05 (s, 2H).
4.2.5.10.
(S)-N-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)benzamide
(22b)
1
White solid (180 mg, 72% yield). m.p. 57-59 °C; H NMR (400 MHz, DMSO) δ 11.03 (s,
1H), 10.16 (s, 1H), 7.95 (d, J = 6.9 Hz, 2H), 7.65 (d, J = 7.5 Hz, 2H), 7.55 (dd, J = 16.4, 6.7
Hz, 3H), 7.41 – 7.16 (m, 7H), 7.08 (d, J = 7.4 Hz, 2H), 6.98 (s, 2H), 6.43 (s, 2H), 4.83 (s, 1H),
4.04 (s, 2H), 3.92 (s, 1H), 3.78 (d, J = 13.6 Hz, 1H), 3.69 (d, J = 13.9 Hz, 1H), 2.85 – 2.59 (m,
6H).
4.2.5.11.
(S)-N-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)-2-phenyla
cetamide (22c)
1
White solid (165 mg, 64% yield). m.p. 58-60 °C; H NMR (400 MHz, DMSO) δ 11.04 (s,
1H), 10.08 (s, 1H), 7.49 (d, J = 7.5 Hz, 2H), 7.41 – 7.14 (m, 12H), 7.08 – 6.94 (m, 4H), 6.53
– 6.35 (m, 2H), 4.83 (s, 1H), 4.04 (s, 2H), 3.92 (s, 1H), 3.77 (d, J = 13.7 Hz, 1H), 3.68 (d, J =
14.8 Hz, 1H), 3.64 (s, 2H), 2.86 – 2.59 (m, 6H).
4.2.5.12.
(S)-1-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)-3-phenylu
rea (22d)
White solid (2.0 g, 78% yield). m.p. 74-76 °C; 1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H),
8.59 (s, 1H), 8.53 (s, 1H), 7.44 (d, J = 7.9 Hz, 2H), 7.24 (ddd, J = 20.5, 14.1, 4.6 Hz, 10H),
7.05 – 6.90 (m, 5H), 6.42 (s, 2H), 4.81 (d, J = 2.8 Hz, 1H), 4.04 (d, J = 7.5 Hz, 2H), 3.91 (s,
1H), 3.77 (d, J = 13.7 Hz, 1H), 3.68 (d, J = 13.8 Hz, 1H), 2.82 – 2.58 (m, 6H).
4.2.5.13.
20

ACCEPTED MANUSCRIPT
(S)-1-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)-3-cyclohe
xylurea (22e)
1
White solid (188 mg, 72% yield). m.p. 75-77 °C; H NMR (400 MHz, DMSO) δ 11.01 (s,
1H), 8.14 (s, 1H), 7.28 (t, J = 6.8 Hz, 4H), 7.25 – 7.19 (m, 3H), 7.19 – 7.15 (m, 1H), 7.00 –
6.95 (m, 2H), 6.93 (d, J = 8.5 Hz, 4H), 6.40 (t, J = 4.1 Hz, 2H), 5.98 (d, J = 7.9 Hz, 1H), 4.78
(d, J = 4.6 Hz, 1H), 4.03 (dd, J = 12.9, 5.5 Hz, 2H), 3.94 – 3.85 (m, 1H), 3.71 (dd, J = 36.9,
13.8 Hz, 2H), 3.49 – 3.39 (m, 1H), 2.77 (dd, J = 13.1, 6.0 Hz, 1H), 2.69 – 2.57 (m, 5H), 1.79
(dd, J = 12.1, 3.2 Hz, 2H), 1.65 (dd, J = 8.8, 3.8 Hz, 2H), 1.53 (dd, J = 8.0, 4.3 Hz, 1H), 1.30
(dd, J = 23.3, 12.1 Hz, 2H), 1.22 – 1.09 (m, 3H).
4.2.5.14.
(S)-1-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)-3-isoprop
ylurea (22f)
1
White solid (170 mg, 70% yield). m.p. 68-70 °C; H NMR (400 MHz, DMSO) δ 11.01 (s,
1H), 8.13 (s, 1H), 7.28 (q, J = 7.5 Hz, 4H), 7.21 (d, J = 8.5 Hz, 3H), 7.19 – 7.16 (m, 1H),
7.00 – 6.95 (m, 2H), 6.93 (d, J = 8.4 Hz, 2H), 6.40 (t, J = 3.5 Hz, 2H), 5.90 (d, J = 7.5 Hz,
1H), 4.79 (d, J = 4.6 Hz, 1H), 4.03 (dd, J = 13.2, 5.6 Hz, 2H), 3.94 – 3.84 (m, 1H), 3.79 –
3.62 (m, 3H), 2.77 (dd, J = 13.1, 6.0 Hz, 1H), 2.69 – 2.56 (m, 5H), 1.07 (s, 6H).
4.2.5.15.
(S)-1-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)-3-pheneth
ylurea (22g)
1
White solid (227 mg, 84% yield). m.p. 63-65 °C; H NMR (400 MHz, DMSO) δ 11.01 (s,
1H), 8.33 (s, 1H), 7.33 – 7.20 (m, 12H), 7.19 – 7.16 (m, 1H), 6.96 (dt, J = 15.2, 6.7 Hz, 4H),
6.40 (dd, J = 5.1, 2.9 Hz, 2H), 6.03 (t, J = 5.6 Hz, 1H), 4.79 (d, J = 4.6 Hz, 1H), 4.03 (dd, J =
13.4, 5.8 Hz, 2H), 3.94 – 3.84 (m, 1H), 3.71 (dd, J = 36.6, 13.9 Hz, 2H), 3.32 (s, 2H), 2.80 –
2.71 (m, 3H), 2.70 – 2.56 (m, 5H).
4.2.5.16.
(S)-1-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)-3-(2-fluor
ophenyl)urea (22h)
1
White solid (243 mg, 91% yield). m.p. 76-78 °C; H NMR (400 MHz, DMSO) δ 11.01 (s,
1H), 8.95 (s, 1H), 8.48 (d, J = 2.6 Hz, 1H), 8.15 (td, J = 8.2, 1.6 Hz, 1H), 7.33 – 7.19 (m, 8H),
21

ACCEPTED MANUSCRIPT
7.19 – 7.17 (m, 1H), 7.13 (t, J = 7.8 Hz, 1H), 7.04 – 6.95 (m, 5H), 6.45 – 6.37 (m, 2H), 4.80
(d, J = 4.3 Hz, 1H), 4.06 – 3.98 (m, 2H), 3.95 – 3.85 (m, 1H), 3.72 (dd, J = 36.8, 13.8 Hz,
2H), 2.79 (dd, J = 13.1, 6.0 Hz, 1H), 2.74 – 2.56 (m, 5H).
4.2.5.17.
(S)-1-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)-3-(3-fluor
ophenyl)urea (22i)
1
White solid (245 mg, 91% yield). m.p. 75-77 °C; H NMR (400 MHz, DMSO) δ 11.00 (s,
1H), 8.82 (s, 1H), 8.58 (s, 1H), 7.48 (d, J = 11.9 Hz, 1H), 7.35 – 7.04 (m, 10H), 7.01 (d, J =
8.4 Hz, 2H), 6.99 – 6.94 (m, 2H), 6.76 (td, J = 8.6, 2.4 Hz, 1H), 6.42 (dd, J = 8.8, 4.0 Hz, 2H),
4.80 (d, J = 4.1 Hz, 1H), 4.04 (d, J = 8.3 Hz, 2H), 3.96 – 3.85 (m, 1H), 3.72 (dd, J = 36.5,
13.9 Hz, 2H), 2.79 (dd, J = 13.1, 5.9 Hz, 1H), 2.74 – 2.56 (m, 5H).
4.2.5.18.
(S)-1-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)-3-(4-fluor
ophenyl)urea (22j)
1
White solid (213 mg, 80% yield). m.p. 78-80 °C; H NMR (400 MHz, DMSO) δ 11.02 (s,
1H), 8.63 (s, 1H), 8.52 (s, 1H), 7.49 – 7.42 (m, 2H), 7.25 (dt, J = 17.6, 9.3 Hz, 8H), 7.11 (t, J
= 8.5 Hz, 2H), 7.03 – 6.95 (m, 4H), 6.42 (s, 2H), 4.81 (s, 1H), 4.04 (s, 2H), 3.91 (s, 1H), 3.77
(d, J = 13.8 Hz, 1H), 3.68 (d, J = 13.7 Hz, 1H), 2.86 – 2.60 (m, 6H).
4.2.5.19.
(S)-1-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)-3-(2-meth
oxyphenyl)urea (22k)
1
White solid (245 mg, 90% yield). m.p. 79-81 °C; H NMR (400 MHz, DMSO) δ 11.01 (s,
1H), 9.18 (s, 1H), 8.16 (s, 1H), 8.12 (dd, J = 7.8, 1.6 Hz, 1H), 7.29 (t, J = 7.2 Hz, 6H), 7.22 (d,
J = 6.5 Hz, 1H), 7.18 (t, J = 2.6 Hz, 1H), 7.03 – 6.85 (m, 7H), 6.41 (t, J = 4.2 Hz, 2H), 4.80 (s,
1H), 4.03 (dd, J = 7.3, 4.0 Hz, 2H), 3.91 (d, J = 9.7 Hz, 1H), 3.87 (s, 3H), 3.77 (d, J = 13.7
Hz, 1H), 3.68 (d, J = 13.9 Hz, 1H), 2.79 (dd, J = 13.2, 5.8 Hz, 1H), 2.72 – 2.59 (m, 6H).
4.2.5.20.
(S)-1-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)-3-(3-meth
oxyphenyl)urea (22l)
1
White solid (250 mg, 92% yield). m.p. 75-77 °C; H NMR (400 MHz, DMSO) δ 11.02 (s,
22

ACCEPTED MANUSCRIPT
1H), 8.61 (s, 1H), 8.52 (s, 1H), 7.29 (dd, J = 15.2, 7.9 Hz, 6H), 7.23 – 7.13 (m, 4H), 6.99 (dd,
J = 11.3, 6.0 Hz, 4H), 6.92 (d, J = 7.8 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.42 (s, 2H), 4.82 (s,
1H), 4.05 (d, J = 7.6 Hz, 2H), 3.92 (d, J = 5.4 Hz, 1H), 3.79 – 3.65 (m, 5H), 2.82 – 2.60 (m,
6H).
4.2.5.21.
(S)-1-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)-3-(4-meth
oxyphenyl)urea (22m)
1
White solid (220 mg, 81% yield). m.p. 81-83 °C; H NMR (400 MHz, DMSO) δ 11.02 (s,
1H), 8.44 (s, 1H), 8.40 (s, 1H), 7.36 – 7.17 (m, 11H), 6.99 (d, J = 8.4 Hz, 4H), 6.86 (d, J =
8.5 Hz, 1H), 6.42 (s, 2H), 4.81 (s, 1H), 4.05 (d, J = 7.7 Hz, 2H), 3.91 (d, J = 3.1 Hz, 1H),
3.77 (d, J = 13.8 Hz, 1H), 3.71 (s, 3H), 3.64 (d, J = 10.8 Hz, 1H), 2.81 – 2.60 (m, 6H).
4.2.5.22.
(S)-1-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)-3-(2-nitro
phenyl)urea (24a)
White solid (1.03 g, 74% yield). m.p. 71-73 °C; 1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H),
9.74 (s, 1H), 9.56 (s, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.69 (t, J = 7.8
Hz, 1H), 7.37 – 7.16 (m, 9H), 7.04 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 4.0 Hz, 2H), 6.42 (d, J =
8.2 Hz, 2H), 4.82 (d, J = 3.9 Hz, 1H), 4.04 (d, J = 7.3 Hz, 2H), 3.98 – 3.87 (m, 1H), 3.77 (d, J
= 13.8 Hz, 1H), 3.68 (d, J = 13.8 Hz, 1H), 2.86 – 2.58 (m, 6H).
4.2.5.23.
(S)-1-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)-3-(3-nitro
phenyl)urea (24b)
1
White solid (540 mg, 77% yield). m.p. 84-86 °C; H NMR (400 MHz, DMSO) δ 11.02 (s,
1H), 9.15 (s, 1H), 8.70 (s, 1H), 8.57 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H),
7.56 (t, J = 8.2 Hz, 1H), 7.27 (ddd, J = 29.2, 19.5, 10.2 Hz, 8H), 7.03 (d, J = 8.2 Hz, 2H),
6.98 (d, J = 4.0 Hz, 2H), 6.42 (s, 2H), 4.81 (d, J = 4.0 Hz, 1H), 4.04 (t, J = 6.9 Hz, 2H), 3.97
– 3.87 (m, 1H), 3.78 (d, J = 13.7 Hz, 1H), 3.68 (d, J = 13.8 Hz, 1H), 2.86 – 2.59 (m, 6H).
4.2.5.24.
(S)-1-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)(benzyl)amino)ethyl)phenyl)-3-(4-nitro
phenyl)urea (24c)
23

ACCEPTED MANUSCRIPT
1
White solid (500 mg, 72% yield). m.p. 91-93 °C; H NMR (400 MHz, DMSO) δ 11.01 (s,
1H), 9.37 (s, 1H), 8.79 (s, 1H), 8.19 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 9.2 Hz, 2H), 7.36 – 7.24
(m, 6H), 7.24 – 7.13 (m, 2H), 7.04 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 3.8 Hz, 2H), 6.42 (s, 2H),
4.81 (d, J = 4.1 Hz, 1H), 4.08 – 4.00 (m, 2H), 3.94 – 3.88 (m, 1H), 3.77 (d, J = 13.8 Hz, 1H),
3.68 (d, J = 13.8 Hz, 1H), 2.79 (dd, J = 13.0, 5.6 Hz, 1H), 2.75 – 2.57 (m, 5H).
4.2.6. General procedure for the synthesis of 8a-d, 17a-d, 23a-m and 27a-f
In a 50 mL round-bottomed flask was added 7a-d, 16a-d, 22a-m and 24a-c (1.0 eq) and
Raney-Ni (0.1 eq) in MeOH (10 mL) to give a colorless solution. The reaction vessel was
purged with nitrogen. The reaction vessel was purged with hydrogen (100 eq). The reaction
mixture was held at rt with stirring on for 2 hr. The reaction mixture was filtered through
celite with MeOH (5 mL). The mixture was concentrated by rotovap. The crude product was
purified by column chromatography to give 8a-d, 17a-d, 23a-m and 27a-f.
4.2.6.1.
(S)-N-(4-(2-((3-(2-ethylphenoxy)-2-hydroxypropyl)amino)ethyl)phenyl)benzenesulfonamide
(8a)
1
White solid (50 mg, 45% yield). m.p. 101-103 °C; H NMR (400 MHz, DMSO) δ 10.37 (s,
1H), 9.34 (s, 1H), 9.03 (s, 1H), 7.77 (d, J = 7.2 Hz, 2H), 7.59 (d, J = 7.3 Hz, 1H), 7.54 (t, J =
7.3 Hz, 2H), 7.20 – 7.09 (m, 4H), 7.06 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.0 Hz, 1H), 6.88 (t, J
= 7.3 Hz, 1H), 5.89 (d, J = 4.9 Hz, 1H), 4.26 (s, 1H), 3.96 (qd, J = 10.0, 5.2 Hz, 2H), 3.21 –
13
2.99 (m, 4H), 2.97 – 2.85 (m, 2H), 2.58 (q, J = 7.5 Hz, 2H), 1.12 (t, J = 7.5 Hz, 3H). C
NMR (101 MHz, DMSO) δ 155.87, 139.55, 136.27, 133.04, 132.77, 131.77, 129.16, 128.67,
126.88, 126.63, 120.56, 120.49, 111.44, 69.69, 64.94, 49.70, 47.99, 30.49, 22.59, 14.23.
HPLC: room temperature; tR=7.075 min, UV254=97.9%; HRMS(ESI)m/z calcd for
C25H30N2O4S [M+H]+: 455.1999, Found: 455.1997.
4.2.6.2.
(S)-N-(4-(2-((3-(2-ethylphenoxy)-2-hydroxypropyl)amino)ethyl)phenyl)benzamide
(8b)
1
White solid (60 mg, 34% yield). m.p. 166-168 °C; H NMR (400 MHz, DMSO) δ 10.29 (s,
1H), 9.16 (s, 1H), 8.93 (s, 1H), 7.97 (d, J = 7.0 Hz, 2H), 7.76 (d, J = 8.5 Hz, 2H), 7.59 (t, J =
7.3 Hz, 1H), 7.53 (t, J = 7.3 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 7.4 Hz, 2H), 6.94
(d, J = 7.9 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 5.90 (s, 1H), 4.28 (d, J = 5.1 Hz, 1H), 3.99 (qd, J
24

ACCEPTED MANUSCRIPT
= 10.0, 5.2 Hz, 2H), 3.21 (dt, J = 14.6, 8.6 Hz, 3H), 3.13 – 3.05 (m, 1H), 2.99 (ddd, J = 13.2,
13
7.8, 4.2 Hz, 2H), 2.61 (q, J = 7.5 Hz, 2H), 1.15 (t, J = 7.5 Hz, 3H). C NMR (101 MHz,
DMSO) δ 165.41, 155.89, 137.88, 134.83, 132.41, 131.80, 131.50, 128.70, 128.30, 127.67,
126.90, 120.60, 111.44, 69.70, 65.00, 49.72, 48.24, 30.84, 22.62, 14.25. HPLC: room
temperature; tR=8.314 min, UV254=97.9%; HRMS(ESI)m/z calcd for C26H30N2O3 [M+H]+:
419.2329, Found: 419.2330.
4.2.6.3.
(S)-N-(4-(2-((3-(2-ethylphenoxy)-2-hydroxypropyl)amino)ethyl)phenyl)-2-phenylacetamide
(8c)
1
White solid (68 mg, 54% yield). m.p. 173-175 °C; H NMR (400 MHz, DMSO) δ 10.30 (s,
1H), 9.05 (s, 1H), 8.86 (s, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.39 – 7.27 (m, 4H), 7.27 – 7.21 (m,
1H), 7.18 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 7.5 Hz, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.89 (t, J =
7.4 Hz, 1H), 5.88 (s, 1H), 4.25 (d, J = 5.4 Hz, 1H), 3.97 (ddd, J = 21.0, 10.0, 5.2 Hz, 2H),
3.64 (s, 2H), 3.25 – 3.13 (m, 3H), 3.06 (dd, J = 19.2, 10.3 Hz, 1H), 3.00 – 2.86 (m, 2H), 2.59
(q, J = 7.3 Hz, 2H), 1.13 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 169.07, 155.87,
138.02, 136.13, 131.80, 129.09, 128.77, 128.70, 128.20, 126.90, 126.42, 120.62, 119.31,
111.42, 69.68, 64.98, 49.67, 48.23, 43.21, 30.79, 22.61, 14.24. HPLC: room temperature;
tR=8.976 min, UV254=96.7%; HRMS(ESI)m/z calcd for C27H32N2O3 [M+H]+: 433.2486,
Found: 433.2484.
4.2.6.4. (S)-1-(4-(2-((3-(2-ethylphenoxy)-2-hydroxypropyl)amino)ethyl)phenyl)-3-phenylurea
(8d)
1
White solid (77 mg, 60% yield). m.p. 290-292 °C; H NMR (400 MHz, DMSO) δ 9.70 (s,
2H), 9.44 (s, 1H), 9.14 (s, 1H), 7.44 (dd, J = 13.0, 8.1 Hz, 4H), 7.26 (t, J = 7.8 Hz, 2H), 7.15
(dd, J = 7.7, 5.8 Hz, 4H), 6.93 (t, J = 7.4 Hz, 2H), 6.88 (t, J = 7.4 Hz, 1H), 5.93 (d, J = 4.9 Hz,
1H), 4.36 – 4.24 (m, 1H), 4.04 – 3.93 (m, 2H), 3.24 – 3.12 (m, 3H), 3.10 – 2.93 (m, 3H), 2.60
(dd, J = 15.0, 7.5 Hz, 2H), 1.14 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 155.89,
152.86, 140.02, 138.62, 131.75, 130.18, 128.80, 128.68, 126.88, 121.36, 120.53, 117.78,
117.55, 111.47, 69.73, 64.99, 49.76, 48.33, 30.60, 22.60, 14.25. HPLC: room temperature;
tR=9.023 min, UV254=99.4%; HRMS(ESI)m/z calcd for C26H31N3O3 [M+H]+: 434.2438,
Found: 434.2433.
25

ACCEPTED MANUSCRIPT
4.2.6.5.
(S)-N-(4-(2-((3-(3-(acetamidomethyl)phenoxy)-2-hydroxypropyl)amino)ethyl)phenyl)benzami
de (17a)
White solid (150 mg, 89% yield). m.p. 223-225 °C; 1H NMR (400 MHz, DMSO) δ 10.33 (s,
1H), 9.39 (s, 1H), 9.07 (s, 1H), 8.45 (t, J = 5.8 Hz, 1H), 7.99 (d, J = 7.0 Hz, 2H), 7.78 (d, J =
8.5 Hz, 2H), 7.59 (t, J = 7.3 Hz, 1H), 7.53 (t, J = 7.3 Hz, 2H), 7.24 (t, J = 9.0 Hz, 3H), 6.90 –
6.81 (m, 3H), 6.67 (s, 2H), 4.34 – 4.25 (m, 1H), 4.23 (d, J = 5.8 Hz, 2H), 4.05 – 3.92 (m, 2H),
3.18 (dd, J = 12.8, 5.6 Hz, 3H), 3.12 – 2.91 (m, 3H), 1.89 (s, 3H). 13C NMR (101 MHz,
DMSO) δ 169.14, 165.41, 158.29, 141.30, 137.85, 134.84, 132.42, 131.50, 129.31, 128.70,
128.31, 127.65, 120.60, 119.72, 113.60, 112.60, 69.66, 64.87, 49.60, 48.22, 41.95, 30.81,
22.54. HPLC: room temperature; tR=6.813 min, UV254=96.4%; HRMS(ESI)m/z calcd for
C27H31N3O4 [M+H]+: 462.2388, Found: 462.2386.
4.2.6.6.
(S)-N-(4-(2-((3-(3-(acetamidomethyl)phenoxy)-2-hydroxypropyl)amino)ethyl)phenyl)-2-phen
ylacetamide (17b)
1
White solid (95 mg, 80% yield). m.p. 221-223 °C; H NMR (400 MHz, DMSO) δ 10.44 (s,
1H), 9.28 (s, 1H), 8.99 (s, 1H), 8.43 (t, J = 5.8 Hz, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.35 (d, J =
6.9 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.23 (t, J = 8.0 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 6.88 –
6.79 (m, 3H), 4.27 (dd, J = 8.5, 5.3 Hz, 1H), 4.22 (d, J = 5.9 Hz, 2H), 4.05 – 3.89 (m, 2H),
13
3.66 (s, 2H), 3.25 – 3.10 (m, 3H), 3.08 – 2.88 (m, 3H), 1.88 (s, 3H). C NMR (101 MHz,
DMSO) δ 169.14, 169.06, 158.27, 141.30, 137.98, 136.11, 131.85, 129.31, 129.08, 128.77,
128.21, 126.43, 119.72, 119.32, 113.57, 112.58, 69.64, 64.85, 49.55, 48.21, 43.20, 41.95,
30.76, 22.54. HPLC: room temperature; tR=7.323 min, UV254=98.2%; HRMS(ESI)m/z calcd
for C28H33N3O4 [M+H]+: 476.2544, Found: 476.2540.
4.2.6.7.
(S)-N-(3-(2-hydroxy-3-((4-(3-phenylureido)phenethyl)amino)propoxy)benzyl)acetamide (17c)
White solid (100 mg, 66 % yield). m.p. 203-205 °C; 1H NMR (400 MHz, DMSO) δ 9.45 (d, J
= 3.6 Hz, 2H), 9.18 (s, 1H), 8.94 (s, 1H), 8.43 (s, 1H), 7.45 (dd, J = 11.4, 8.4 Hz, 4H), 7.25
(dd, J = 16.9, 8.2 Hz, 4H), 7.16 (d, J = 8.0 Hz, 2H), 6.94 (t, J = 7.2 Hz, 1H), 6.89 – 6.78 (m,
3H), 4.22 (d, J = 5.4 Hz, 3H), 3.97 (s, 2H), 3.28 – 3.11 (m, 3H), 3.09 – 2.87 (m, 3H), 1.88 (s,
26

ACCEPTED MANUSCRIPT
3H). 13C NMR (101 MHz, DMSO) δ 169.16, 158.27, 152.75, 141.28, 139.94, 138.62, 130.13,
129.32, 128.89, 128.69, 121.49, 119.73, 118.07, 117.80, 113.57, 112.59, 69.64, 64.86, 49.55,
48.33, 41.96, 30.72, 22.53. HPLC: room temperature; tR=7.394 min, UV254=98.9%;
HRMS(ESI)m/z calcd for C27H32N4O4 [M+H]+: 477.2497, Found: 477.2495.
4.2.6.8.
(S)-N-(3-(2-hydroxy-3-((4-(3-phenylthioureido)phenethyl)amino)propoxy)benzyl)acetamide
(17d)
White solid (123 mg, 81% yield). m.p. 145-147 °C; 1H NMR (400 MHz, DMSO) δ 9.31 (d, J
= 5.3 Hz, 2H), 9.06 (s, 1H), 8.85 (s, 1H), 8.41 (t, J = 5.9 Hz, 1H), 7.44 (dd, J = 10.5, 8.2 Hz,
4H), 7.25 (dd, J = 16.4, 8.8 Hz, 3H), 7.16 (d, J = 8.4 Hz, 2H), 6.94 (t, J = 7.3 Hz, 1H), 6.90 –
6.79 (m, 3H), 4.22 (d, J = 5.9 Hz, 3H), 4.04 – 3.89 (m, 2H), 3.23 – 3.11 (m, 3H), 3.09 – 2.89
(m, 3H), 1.88 (s, 3H). 13C NMR (101 MHz, DMSO) δ 169.27, 158.27, 141.22, 130.13,
129.89, 129.44, 129.30, 129.20, 126.10, 125.89, 125.51, 122.90, 122.30, 119.71, 113.59,
112.58, 69.64, 64.87, 49.53, 48.11, 41.95, 30.67, 22.51. HPLC: room temperature; tR=8.164
min, UV254=96.1%; HRMS(ESI)m/z calcd for C27H32N4O3S [M+H]+: 493.2268, Found:
493.2266.
4.2.6.9.
(S)-N-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)amino)ethyl)phenyl)benzenesulfonami
de (23a)
1
White solid (145 mg, 91% yield). m.p. 76-78 °C; H NMR (400 MHz, DMSO) δ 11.03 (s,
1H), 7.73 (d, J = 7.4 Hz, 2H), 7.60 – 7.49 (m, 3H), 7.19 (t, J = 2.6 Hz, 1H), 7.05 (d, J = 8.3
Hz, 2H), 7.02 – 6.92 (m, 4H), 6.48 – 6.38 (m, 2H), 4.95 (s, 1H), 4.07 – 3.82 (m, 3H), 3.32 (s,
2H), 2.79 – 2.65 (m, 3H), 2.65 – 2.55 (m, 3H). 13C NMR (101 MHz, DMSO) δ 152.03,
139.82, 137.30, 136.06, 135.71, 132.63, 129.21, 129.12, 126.58, 123.38, 121.72, 120.45,
118.37, 104.79, 99.87, 98.44, 70.49, 68.08, 52.33, 50.91, 35.02. HPLC: room temperature;
tR=7.995 min, UV254=97.0%; HRMS(ESI)m/z calcd for C25H27N3O4S [M+H]+: 466.1795,
Found: 466.1790.
4.2.6.10.
(S)-N-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)amino)ethyl)phenyl)benzamide (23b)
White solid (150 mg, 80% yield). m.p. 155-157 °C; 1H NMR (400 MHz, DMSO) δ 11.04 (s,
27

ACCEPTED MANUSCRIPT
1H), 10.18 (s, 1H), 7.94 (d, J = 7.0 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.56 (dt, J = 24.5, 7.1
Hz, 3H), 7.19 (dd, J = 5.7, 2.6 Hz, 3H), 7.06 – 6.91 (m, 2H), 6.56 – 6.41 (m, 2H), 4.98 (d, J =
3.3 Hz, 1H), 4.00 (dt, J = 13.8, 6.6 Hz, 3H), 2.79 (dd, J = 7.1, 5.1 Hz, 3H), 2.73 – 2.63 (m,
3H). 13C NMR (101 MHz, DMSO) δ 165.33, 152.05, 137.29, 137.02, 135.72, 135.03, 131.41,
128.66, 128.30, 127.57, 123.36, 121.70, 120.34, 118.36, 104.75, 99.86, 98.44, 70.55, 68.22,
52.49, 51.22, 35.42. HPLC: room temperature; tR=7.946 min, UV254=98.1%; HRMS(ESI)m/z
calcd for C26H27N3O3 [M+H]+: 430.2125, Found: 430.2121.
4.2.6.11.
(S)-N-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)amino)ethyl)phenyl)-2-phenylacetamid
e (23c)
White solid (64 mg, 77% yield). m.p. 70-72 °C; 1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H),
10.07 (s, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.36 – 7.27 (m, 4H), 7.27 – 7.21 (m, 1H), 7.20 – 7.16
(m, 1H), 7.13 (d, J = 8.2 Hz, 2H), 7.01 – 6.90 (m, 2H), 6.51 – 6.35 (m, 2H), 4.95 (s, 1H), 4.08
– 3.84 (m, 3H), 3.61 (s, 2H), 2.76 (dd, J = 13.9, 5.1 Hz, 3H), 2.69 – 2.60 (m, 3H), 1.87 (s,
1H). 13C NMR (101 MHz, DMSO) δ 168.86, 152.04, 137.31, 137.12, 136.08, 135.10, 129.05,
128.77, 128.25, 126.46, 123.37, 121.71, 119.13, 118.38, 104.78, 99.87, 98.44, 70.50, 68.07,
52.37, 51.07, 43.28, 35.15. HPLC: room temperature; tR=8.164 min, UV254=96.1%;
HRMS(ESI)m/z calcd for C27H29N3O3 [M+H]+: 444.2282, Found: 444.2278.
4.2.6.12.
(S)-1-(4-(2-((3-((1H-indol-4-yl)oxy)-2-hydroxypropyl)amino)ethyl)phenyl)-3-phenylurea
(23d)
1
White solid (1.3 g, 87% yield). m.p. 159-161 °C; H NMR (400 MHz, DMSO) δ 11.02 (s,
1H), 8.61 (s, 1H), 8.55 (s, 1H), 7.44 (d, J = 7.7 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.27 (t, J =
7.9 Hz, 2H), 7.21 – 7.17 (m, 1H), 7.12 (d, J = 8.4 Hz, 2H), 7.02 – 6.89 (m, 3H), 6.46 (dd, J =
6.1, 2.3 Hz, 1H), 6.45 – 6.40 (m, 1H), 4.94 (s, 1H), 3.99 (dd, J = 13.4, 7.9 Hz, 3H), 2.77 (dd,
J = 14.2, 5.3 Hz, 3H), 2.70 – 2.62 (m, 3H), 1.75 (s, 1H). 13C NMR (101 MHz, DMSO) δ
152.58, 152.00, 139.71, 137.45, 137.24, 133.74, 128.80, 128.75, 123.31, 121.67, 118.40,
118.22, 118.11, 104.73, 99.82, 98.41, 70.50, 68.17, 52.45, 51.32, 35.25. HPLC: room
temperature; tR=8.189 min, UV254=97.7%; HRMS(ESI)m/z calcd for C26H28N4O3 [M+H]+:
445.2234, Found: 445.2228.
28