Discovery of highly potent renin inhibitors potentially interacting with the S3' subsite of renin

Article abstract of DOI:10.1016/j.ejmech.2015.08.060

To exploit the S3′ subsite of renin active site for renin inhibitor design, 42 aliskiren derivatives with modified P2' portion were designed, synthesized and biologically evaluated. Some highly potent renin inhibitors (IC₅₀ < 3 nM) were identified, among which compounds 38 (IC₅₀ Combining double low line 0.9 nM) and 39 (IC₅₀ Combining double low line 0.7 nM) were over 2.5-fold more potent than aliskiren (IC₅₀ Combining double low line 2.3 nM). SAR analysis indicated that incorporation of polar hydrophilic moieties into the P2' portion of renin inhibitors generally enhanced the potency. Consistently with this, molecular modeling study revealed that the triazole part of 39 could provide additional interactions to the S3' subsite of renin active site. Moreover, in vivo evaluation in the double transgenic mouse hypertension model demonstrated that 39 produced greater reduction of the mean arterial blood pressure than ariskiren at the doses of 17.0 and 34.0 1/4mol/kg, respectively. Taken together, the S3' subsite of renin active site merits further consideration for renin inhibitor design.

Full text of DOI:10.1016/j.ejmech.2015.08.060

European Journal of Medicinal Chemistry 103 (2015) 269e288
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Research paper
Discovery of highly potent renin inhibitors potentially interacting with
the S30 subsite of renin
,
b
,
,
b
,
,
, b
Xiaowei Sun a 1, Xiaoan Wen a 1, Yan-yan Chen c, Chen Shi a b, Chengzhe Gao a
,
Yong Wu a b, Li-jun Wang c, Xiu-hong Yang c *, Hongbin Sun a
,
,
, b, **
a Center for Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China
b Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China
c Department of Physiology, School of Basic Medical Science, Hebei United University, 57 Jianshe South Road, Tangshan 063000, PR China
a r t i c l e i n f o
a b s t r a c t
To exploit the S30 subsite of renin active site for renin inhibitor design, 42 aliskiren derivatives with
modified P20 portion were designed, synthesized and biologically evaluated. Some highly potent renin
inhibitors (IC50 < 3 nM) were identified, among which compounds 38 (IC50 ¼ 0.9 nM) and 39
(IC50 ¼ 0.7 nM) were over 2.5-fold more potent than aliskiren (IC50 ¼ 2.3 nM). SAR analysis indicated that
incorporation of polar hydrophilic moieties into the P20 portion of renin inhibitors generally enhanced
the potency. Consistently with this, molecular modeling study revealed that the triazole part of 39 could
provide additional interactions to the S30 subsite of renin active site. Moreover, in vivo evaluation in the
double transgenic mouse hypertension model demonstrated that 39 produced greater reduction of the
Article history:
Received 17 November 2014
Received in revised form
28 August 2015
Accepted 30 August 2015
Available online 2 September 2015
Keywords:
Renin inhibitors
Structural modification
Aliskiren
mean arterial blood pressure than ariskiren at the doses of 17.0 and 34.0 mmol/kg, respectively. Taken
together, the S30 subsite of renin active site merits further consideration for renin inhibitor design.
© 2015 Elsevier Masson SAS. All rights reserved.
Antihypertension
1. Introduction
inhibitors, which can interrupt the interactions between renin and
angiotensinogen, are particularly attractive owing to renin's
The renin-angiotensin-aldosterone system (RAAS) plays major
roles in the regulation of blood pressure [1]. In the RAAS, angio-
tensinogen as the only known endogenous substrate of renin can be
cleaved under the catalysis of renin to release angiotensin I (Ang I),
which is in turn converted to angiotensin II (Ang II) by the angio-
tensin converting enzyme (ACE). Being a potent vaso-active pep-
tide, Ang II not only causes the blood vessel constriction by acting
on angiotensin receptor type 1 (AT1), but also stimulates the
aldosterone production from adrenal cortex and subsequently in-
duces the kidney tubules to increase the reabsorption of sodium
and water, thus resulting in increased plasma volume and blood
pressure. Blocking the cleavage of angiotensinogen has been pro-
posed as a promising approach to the treatment of hypertension
since it is a rate-limiting step at the upstream of RAAS [2]. Renin
extremely high specificity for angiotensinogen [3e5]. Tremendous
research efforts have been exerted to find orally active renin in-
hibitors [6e11] and some drug candidates have entered into clinical
trials (Fig. 1). However, to date, only aliskiren (1) was approved by
the U.S. FDA.
The catalytic site of renin was defined to comprise 4 parts: the
non-prime subsites S1eS4, the non-substrate cavity S3sp, the flap
b
-hairpin loop, and the prime subsites S10eS30 [12]. A large number
of renin inhibitors were designed to interact with the former 3
parts [13e18]. Nevertheless, increasing evidences emerged to imply
the importance of the prime subsites [6,7,9,19e24]. For example,
the crystallography study revealed that the prime subsite S20 had
key interactions with the P20 portion of aliskren. However, the
prime subsite S30 was neglected and thus remains to be explored. In
the previous study, we identified a highly potent aliskiren deriva-
tive (4) bearing a terminal 1H-1,2,3-triazole that might reach the
prime subsite S30 [25]. To investigate the compatibility of S30 sub-
site, we carried out further structural modifications based on 4.
Thus, various substituents were incorporated into the triazole ring
of 4 or used to replace the P20 portion of ariskiren, giving rise to
aliskiren derivatives 5-46 (Fig. 2). The in vitro and in vivo studies
* Corresponding author. Department of Physiology, School of Basic Medical Sci-
ence, Hebei United University, 57 Jianshe South Road, Tangshan 063000, PR China
** Corresponding author. Center for Drug Discovery, China Pharmaceutical Uni-
versity, 24 Tongjia Xiang, Nanjing 210009, PR China.
E-mail addresses: ljkyxhljn@163.com (X.-h. Yang), hbsun2000@yahoo.com
(H. Sun).
1
These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.ejmech.2015.08.060
0223-5234/© 2015 Elsevier Masson SAS. All rights reserved.

270
X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
Fig. 1. Chemical structures of representative renin inhibitors.
Fig. 2. Structural modification of the P20 segment of aliskiren.
showed that some compounds were highly potent renin inhibitors
that probably interacted with the renin S30 subsite. Herein, we
report the details of this work.
2.2. In vitro evaluation for renin inhibitory activity and SAR
analysis
Compounds 5-46 were evaluated for their inhibitory activity
against human renin, with using 1 and 4 as the positive controls. As
shown in Tables 1 and 2, all the designed compounds showed
considerable renin inhibitory activity (IC50 ꢀ 34 nM). In particular,
some highly potent renin inhibitors (IC50 < 3 nM) were identified,
among which compounds 38 (IC50 ¼ 0.9 nM) and 39 (IC50 ¼ 0.7 nM)
2. Result and discussion
2.1. Chemistry
Compounds 5-46 were synthesized according to the reaction
sequence depicted in Scheme 1 [26,27]. Lactone 47 [28] was ami-
dated with various amines 5b-46b (Supporting Information) in the
presence of 2-hydroxypyridine to afford the corresponding amides
5a-46a, which were treated with 4 N HCl/dioxane to give target
compounds 5-46 as hydrochloride salts.
exhibited the best potency. In comparison with triazole
4
(IC50 ¼ 2.0 nM), pyridines 5 (IC50 ¼ 2.2 nM), 6 (IC50 ¼ 1.5 nM) and 26
(IC50 ¼ 2.6 nM) maintained high inhibitory potency, while most of
the phenyl derivatives had decreased potency. For instance, com-
pound 7 (IC50 ¼ 34.0 nM) was 17-fold less potent than 4.
Reagents and conditions: a) Et3N, 2-hydroxypyridine, 100 °C; b) 4 N HCl/dioxane, 0 °C.
Scheme 1. Synthesis of compounds 5-46.

X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
271
Table 1
In vitro renin inhibitory activity of compounds 5-30.
Cpd
R1
IC50 (nM)
2.3
Cpd
R1
IC50 (nM)
1
17
15.5
4
2.0
18
1.8
5
6
7
8
2.2
1.5
19
20
21
22
8.5
12.1
11.5
27.7
34.0
9.2
9
9.8
23
24
7.2
4.4
10
16.1
11
12.4
25
11.0
12
13
9.8
26
27
2.6
12.3
30.0
14
15
16
10.2
13.4
11.2
28
29
30
15.2
33.7
20.9
Interestingly, removal of the geminal dimethyl groups (e.g. 20) or
incorporation of fluorine, chloride, oxygen and nitrogen-contained
functions (e.g. 8, 13 and 15) could recover the inhibitory potency to
some extent, indicating that the renin S30 subsite might tend to
accommodate hydrophilic polar moieties. This trend was reflected
particularly among triazoles 31-46 (Table 2). For example, com-
pounds 37-40 and 45-46 (IC50 ¼ 0.7e1.5 nM) all exhibited higher
potency than 4. In addition, substituent configuration (e.g. 28 vs 27,
30 vs 29) and size (e.g. 33 vs 34) had substantial effects on the renin
inhibitory potency.
2.3. Molecular dynamics modeling
Notably, triazoles 4 and 39 bear flexible long chains. Molecular
dynamics modeling [29] was performed to predict the possible
binding modes of 4 and 39 in human renin (Fig. 3A and B). For the

272
X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
Table 2
administration of 39 to dTGMs induced robust reduction of the mean
arterial blood pressure (MAP) in a dose-dependent manner. The
antihypertensive effect could be sustained over 14 h and the
maximum MAP reduction was reached up to 40e50 mmHg. At the
In vitro renin inhibitory activity of compounds 31-46.
dose of 8.5
mmol/kg, the antihypertensive effect of 39 was compa-
rable to that of 1 (Fig. 5B), while at the doses of 17.0 and 34.0
mmol/kg,
39 exhibited much better hypotensive effect than 1 (Fig. 5C and D).
3. Conclusion
Cpd
R2
H
IC50 (nM)
2.0
Cpd
R2
IC50 (nM)
0.9
Some highly potent renin inhibitors have been discovered by
structural modification of aliskiren derivative 4. Among them,
compounds 38-40 and 45-46 (IC50 ¼ 0.7e1.1 nM) were found to be
2e3 fold more potent than ariskiren (IC50 ¼ 2.3 nM). In the dTGM
hypertensive model, the selected compound 39 displayed compa-
rable or better in vivo antihypertensive effect than aliskiren. Mo-
lecular modeling study suggested that compounds 4 and 39 might
make additional interactions with the S30 subsite of renin active
site, thus highlighting its importance for further design of renin
inhibitors.
4
38
31
32
1.6
7.0
39
40
0.7
1.1
33
5.8
41
5.2
34
35
17.1
5.0
42
43
1.9
2.1
4. Experimental section
4.1. General
1H NMR and 13C NMR spectra were recorded at 300/500 and 75/
125 MHz respectively on an ACF * 300Q Bruker or ACF * 500Q
Bruker spectrometer with Me4Si as the internal reference. Low-
resolution and high-resolution mass spectra (LRMS and HRMS)
were given with electron impact mode. The mass analyzer type
used for the HRMS measurements was TOF. Reactions were moni-
tored by TLC on silica gel 60 F254 plates (Qingdao Ocean Chemical
Company, China). Column chromatography was carried out on silica
gel (200e300 mesh, Qingdao Ocean Chemical Company, China).
Optical rotation data were recorded on Jasco p-1020 Polarimeter.
The purity of final compounds was determined by HPLC in Agilent
1100 system or SHIMADZU LC-20AT with Diamonsil C18 column
36
37
13.1
1.5
44
2.7
45
46
1.0
1.1
convenience of comparison (Fig. 3C), the predicted binding
conformation of 39 was aligned to the crystal structure of 1 bound
to human renin (PDB code: 2V0Z). As illustrated in Fig. 3, the P1eP3
portions of 1, 4, and 39 were closely overlapped, which all made
hydrogen bonding interactions with Tyr14, Gly217, Asp32, Asp215
and Gly34. However, unlike 1, both 4 and 39 could extend toward
the S30 subsite, resulting in more interactions with renin. For
example, the triazole N3 atom of both 4 and 39 formed hydrogen
bond with the hydroxyl group of Thr295. Moreover, the hydrox-
yethyl group on the triazole ring of 39 made additional hydrogen
bonding interactions with the carboxylate of Pro293, indicating
why 39 was more potent than 4.
5
m
m 250 ꢁ 4.6 nm. Unless specially noted, 95% aqueous acetoni-
trile containing 0.1% trifluoroacetic acid was used as the HPLC
eluent. The flow rate, oven temperature and UV detection wave-
length were set to 0.5 mL/min, 25 ꢂC and 215 nm, respectively.
4.2. Synthesis of compounds 5a-46a
4.2.1. tert-Butyl (3S,5S,6S,8S)-8-(2,2-dimethyl-3-(naphthalen-2-yl)
propylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)
benzyl)-2,9-dimethyldecan-5-ylcarbamate (16a)
Compound 47 (92 mg, 0.17 mmol) was dissolved in Et3N (2 mL).
To the solution was added 2-hydroxypyridine (17 mg, 0.17 mmol)
and 16b (145 mg, 0.68 mmol). After stirred at 100 ꢂC for 18 h, the
mixture was concentrated in vacuo. The residue was dissolved in
ethyl acetate (5 mL) and acidified with 1 N HCl solution. The organic
layer was collected and the aqueous layer was extracted with ethyl
acetate (10 mL ꢁ 3). The organic layers were combined, washed
with brine (10 mL), dried over Na2SO4 and concentrated in vacuo.
The residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate ¼ 6/1) to afford 16a as a solid
2.4. Inhibitory selectivity for human renin over human cathepsins D
and E
Triazole 39 was selected to test its inhibitory selectivity for
human renin over other two aspartyl proteases, human cathepsins
D and E. As shown in Fig. 4, the inhibitory activity of 39 against both
cathepsins D and E was rather weak, indicating that 39 was highly
selective for human renin.
(79 mg, 62%). [
CDCl3) 0.80e0.83 (m, 6 H), 0.89e0.95 (m,12 H),1.17e1.25 (m, 2 H),
a
]25 D-25.0 (c 0.20, CH2Cl2). 1H NMR (500 MHz,
d
2.5. In vivo antihypertensive evaluation
1.43 (s, 9 H), 1.56e1.65 (m, 5 H), 1.80e1.87 (m, 1 H), 1.97e1.99 (m, 1
H), 2.04e2.10 (m, 2 H), 2.35e2.39 (m, 1 H), 2.58e2.62 (m, 1 H), 2.71
(s, 2 H), 3.11e3.14 (m, 1 H), 3.28e3.32 (m, 1 H), 3.34 (s, 3 H),
3.41e3.52 (m, 2 H), 3.56 (t, 2 H, J ¼ 5 Hz), 3.81 (s, 3 H), 4.10 (t, 2 H,
J ¼ 5 Hz), 4.63 (d, 1 H, J ¼ 10 Hz), 5.67 (s, 1 H), 6.67e6.76 (m, 3 H),
7.26e7.29 (m, 1 H), 7.41e7.47 (m, 2 H), 7.59 (s, 1 H), 7.75e7.82 (m, 3
Double transgenic hypertensive mice (dTGM) harboring both
human angiotensinogen and renin genes [30] were used for in vivo
antihypertensive evaluation of compound 39, with using aliskiren 1
as the positive control. As demonstrated in Fig. 5A, oral

X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
273
Fig. 3. Modelling predicted binding modes of 4 and 39 in the catalytic site of human renin. The inhibitors and the interacting amino acid residues are displayed in a stick model
(colored by atom: oxygen atom in red and nitrogen atom in blue). The amino acid residues forming hydrogen bonds (showed as dashed yellow lines) with the inhibitors are shown
in pink and those interacting with the inhibitors via hydrophobic contacts are shown in green. Graphs were generated using the PyMOL software. (For interpretation of the ref-
erences to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 4. Inhibitory activity of 39 against: A) human renin; B) Cathepsin D; C) Cathepsin E.
H). 13C NMR (125 MHz, CDCl3)
d
16.8, 20.3, 21.3, 25.1, 25.2, 28.1, 28.3,
2.74 mmol). Solid (128 mg, 66%). [
NMR (500 MHz, CDCl3) 0.78e0.84 (m, 6 H), 0.88e0.94 (m, 12 H),
a
]25 D-26.3 (c 0.30, CH2Cl2). 1H
29.7, 32.6, 34.5, 35.9, 37.4, 42.3, 46.7, 49.3, 51.6, 54.1, 56.0, 58.5, 66.0,
69.4, 71.3, 79.1, 111.7, 114.6, 121.3, 125.3, 125.9, 127.3, 128.7, 129.0,
132.0, 133.3, 134.3, 135.8, 147.6, 148.2, 156.7, 176.2. ESI-MS m/z 749.5
[MþH]þ. HRMS calcd for C45H69N2O7 [MþH]þ m/z 749.5105, found
749.5113.
d
1.16e1.25 (m, 2 H), 1.43 (s, 9 H), 1.55e1.64 (m, 5 H), 1.86e1.99 (m, 1
H), 2.06e2.08 (m, 3 H), 2.35e2.38 (m, 1 H), 2.54 (s, 2 H), 2.57e2.58
(m, 1 H), 3.02e3.06 (m, 1 H), 3.24e3.28 (m, 1 H), 3.34 (s, 3 H),
3.40e3.51 (m, 2 H), 3.56 (t, 2 H, J ¼ 6.0 Hz), 3.81 (s, 3 H), 4.09 (t, 2 H,
J ¼ 6.5 Hz), 4.67 (d, 1 H, J ¼ 8.5 Hz), 5.84 (s, 1 H), 6.67e6.75 (m, 3 H),
7.20e7.23 (m, 1 H), 7.49 (d, 1 H, J ¼ 7.5 Hz), 8.40 (s, 1 H), 8.46 (m, 1
4.2.2. tert-Butyl (3S,5S,6S,8S)-8-(2,2-dimethyl-3-(pyridin-3-yl)
propylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)
benzyl)-2,9-dimethyldecan-5-yl-carbamate (5a)
Following a similar procedure for the preparation of 16a, 5a was
prepared starting from 47 (150 mg, 0.28 mmol) and 5b (450 mg,
H). 13C NMR (125 MHz, CDCl3)
d 16.8, 20.3, 21.2, 24.6, 24.8, 28.2,
28.3, 29.6, 29.7, 32.4, 34.6, 35.5, 37.4, 42.3, 43.2, 49.1, 51.4, 54.1, 56.0,
58.6, 66.0, 69.4, 71.4, 79.2, 111.7, 114.5, 121.3, 123.0, 128.7, 133.7,
134.2, 137.8, 147.5, 147.6, 148.2, 151.1, 176.2. ESI-MS m/z 700.5

274
X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
Fig. 5. Effect of 1 and 39 on MAP in dTGMs.
[MþH]þ. HRMS calcd for C40H66N3O7 [MþH]þ m/z 700.4901, found
calcd for C41H67N2O7 [MþH]þ m/z 699.4948, found 699.4951.
700.4903.
4.2.5. tert-Butyl (3S,5S,6S,8S)-8-(3-(2-fluorophenyl)-2,2-
4.2.3. tert-Butyl (3S,5S,6S,8S)-8-(2,2-dimethyl-3-(pyridin-4-yl)
propylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)
benzyl)-2,9-dimethyldecan-5-ylcarbamate (6a)
dimethylpropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate (8a)
Following a similar procedure described for preparation of 16a,
8a was prepared starting from 47 (100 mg, 0.18 mmol) and 8b
Following a similar procedure for the preparation of 16a, 6a was
prepared starting from 47 (150 mg, 0.28 mmol) and 6b (450 mg,
(200 mg, 1.10 mmol). Solid (82 mg, 61%). [
a]25 D-19.3 (c 0.3,
2.74 mmol). Solid (108 mg, 55%). [
a
]25 D-12.0 (c 0.40, CH2Cl2). 1H
CH2Cl2). 1H NMR (500 MHz, CDCl3)
d
0.75e0.88 (m, 6 H), 0.92e1.00
NMR (500 MHz, CDCl3) 0.79e0.84 (m, 6 H), 0.88e0.97 (m, 12 H),
d
(m, 12 H), 1.20e1.32 (m, 2 H), 1.47 (s, 9 H), 1.55e1.65 (m, 2 H),
1.65e1.75 (m, 3 H), 1.90e2.00 (m, 1 H), 2.08e2.15 (m, 3 H),
2.37e2.45 (m, 1 H), 2.58e2.65 (m, 3 H), 3.08e3.15 (m, 1 H),
3.17e3.25 (m, 1 H), 3.37 (s, 3 H), 3.40e3.50 (m, 1 H), 3.55e3.63 (m, 3
H), 3.84 (s, 3 H), 4.13 (t, 2 H, J ¼ 6.3 Hz), 4.68 (d, 1 H, J ¼ 8.7 Hz),
5.85e6.00 (m, 1 H), 6.70e6.75 (m, 1 H), 6.75e6.82 (m, 2 H),
7.02e7.12 (m, 2 H), 7.15e7.25 (m, 2 H). 13C NMR (125 MHz, CDCl3)
1.18e1.26 (m, 2 H), 1.44 (s, 9 H), 1.55e1.73 (m, 5 H), 1.89e1.93 (m, 1
H), 2.07e2.09 (m, 3 H), 2.37e2.41 (m, 1 H), 2.53 (s, 2 H), 2.57e2.60
(m, 1 H), 3.04e3.08 (m, 1 H), 3.25e3.29 (m, 1 H), 3.35 (s, 3 H),
3.39e3.52 (m, 2 H), 3.57 (t, 2 H, J ¼ 6.5 Hz), 3.82 (s, 3 H), 4.10 (t, 2 H,
J ¼ 6.0 Hz), 4.64 (d, 1 H, J ¼ 9.0 Hz), 5.85 (s, 1 H), 6.67e6.76 (m, 3 H),
7.09 (d, 2 H, J ¼ 4.5 Hz), 8.50 (s, 2 H). 13C NMR (125 MHz, CDCl3)
d
16.8, 20.3, 21.2, 24.7, 24.8, 28.2, 28.3, 29.6, 29.8, 32.4, 34.7, 35.6,
d 16.8, 20.4, 21.3, 25.0, 25.1, 28.1, 28.4, 29.6, 32.6, 34.5, 36.1, 37.4,
37.4, 42.3, 45.5, 49.2, 51.4, 54.1, 56.0, 58.6, 66.0, 69.4, 71.4, 79.2,111.7,
114.5, 121.3, 125.8, 134.2, 147.4, 147.6, 148.2, 149.2, 156.8, 176.2. ESI-
MS m/z 700.5 [MþH]þ. HRMS calcd for C40H66N3O7 [MþH]þ m/z
700.4901, found 700.4900.
38.5, 42.4, 48.7, 51.7, 54.0, 56.0, 58.6, 66.0, 69.5, 71.2, 79.1, 111.8,
114.6, 115.1, 121.3, 123.7, 125.1, 128.1, 132.9, 134.3, 147.6, 148.3, 156.7,
160.5, 176.4. ESI-MS m/z 717.5 [MþH]þ. HRMS calcd for
C
41H66N2FO7 [MþH]þ m/z 717.4854, found 717.4856.
4.2.4. tert-Butyl (3S,5S,6S,8S)-8-(2,2-dimethyl-3-
4.2.6. tert-Butyl (3S,5S,6S,8S)-8-(3-(3-fluorophenyl)-2,2-
phenylpropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate (7a)
Following a similar procedure for the preparation of 16a, 7a was
prepared starting from 47 (120 mg, 0.22 mmol) and 7b (160 mg,
dimethylpropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate (9a)
Following a similar procedure for the preparation of 16a, 9a was
prepared starting from 47 (150 mg, 0.28 mmol) and 9b (203 mg,
0.88 mmol). Solid (103 mg, 67%). [
a
]25 D-14.1 (c 0.11, CH3OH). 1H
1.12 mmol). Solid (113 mg, 56%). [
NMR (500 MHz, CDCl3) 0.82e0.83 (m, 6 H), 0.89e0.98 (m, 12 H),
a
]25 D-13.5 (c 0.42, CH3OH). 1H
NMR (300 MHz, CDCl3) 0.80e0.83 (m, 6 H), 0.90e0.93 (m, 12 H),
d
d
1.18e1.26 (m, 2 H), 1.44 (s, 9 H), 1.57e1.64 (m, 4 H), 1.86e1.99 (m, 3
H), 2.04e2.12 (m, 2 H), 2.34e2.41 (m, 1 H), 2.55e2.62 (m, 3 H),
3.05e3.11 (m, 1 H), 3.21e3.28 (m, 1 H), 3.35 (s, 3 H), 3.42e3.50 (m, 2
H), 3.57 (t, 2 H, J ¼ 6 Hz), 3.82 (s, 3 H), 4.10 (t, 2 H, J ¼ 6 Hz), 4.65 (d, 1
1.18e1.27 (m, 1 H), 1.44 (s, 9 H), 1.56e1.71 (m, 5 H), 1.87e1.91 (m, 2
H), 2.04e2.10 (m, 3 H), 2.36e2.41 (m, 1 H), 2.54 (s, 2 H), 2.57e2.61
(m, 1 H), 3.05e3.09 (m, 1 H), 3.22e3.26 (m, 1 H), 3.35 (s, 3 H),
3.38e3.52 (m, 2 H), 3.57 (t, 2 H, J ¼ 5 Hz), 3.82 (s, 3 H), 4.10 (t, 2 H,
J ¼ 5 Hz), 4.63 (d, 1 H, J ¼ 10 Hz), 5.73 (s, 1 H), 6.68e6.92 (m, 6 H),
H, J ¼ 6 Hz), 5.68 (s, 1 H), 6.67e6.77 (m, 3 H), 7.13e7.30 (m, 5 H). 13
C
NMR (75 MHz, CDCl3)
d
16.7, 20.3, 21.3, 25.0, 25.1, 25.2, 28.0, 28.3,
7.21e7.24 (m,1 H). 13C NMR (125 MHz, CDCl3)
d 16.8, 20.3, 21.3, 24.9,
29.6, 32.5, 34.5, 35.6, 37.4, 42.2, 46.6, 49.2, 51.6, 54.0, 56.0, 58.5,
66.0, 69.4, 71.2, 79.1, 111.7, 114.5, 121.3, 126.2, 128.0, 130.3, 134.2,
138.2, 147.6, 148.2, 156.6, 176.2. ESI-MS m/z 699.1 [MþH]þ. HRMS
25.0, 28.2, 28.3, 29.6, 32.5, 34.6, 35.6, 37.4, 42.3, 46.1, 49.2, 51.6, 54.1,
56.0, 58.6, 66.0, 69.4, 71.3, 79.2, 111.8, 113.0, 114.6, 117.1, 121.3, 126.1,
126.1, 129.2, 129.3, 134.3, 140.7, 147.6, 148.3, 156.7, 161.6, 176.2. ESI-

X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
275
MS m/z 717.5 [MþH]þ. HRMS calcd for C41H66N2O7F [MþH]þ m/z
(640 mg, 3.31 mmol). Solid (148 mg, 73%). [
a
]25 D-13.0 (c 0.12,
717.4854, found 717.4862.
CH3OH). 1H NMR (500 MHz, CDCl3)
d 0.80e0.83 (m, 6 H), 0.89e0.95
(m, 12 H), 1.18e1.26 (m, 2 H), 1.44 (s, 9 H), 1.57e1.67 (m, 5 H),
1.86e2.09 (m, 4 H), 2.36e2.40 (m,1 H), 2.49 (s, 2 H), 2.59e2.61 (m,1
H), 3.05e3.09 (m, 1 H), 3.23e3.26 (m, 1 H), 3.35 (s, 3 H), 3.42e3.52
(m, 2 H), 3.57 (t, 2 H, J ¼ 5 Hz), 3.79 (s, 3 H), 3.82 (s, 3 H), 4.10 (t, 2 H,
J ¼ 5 Hz), 4.65 (d, 1 H, J ¼ 10 Hz), 5.62 (s, 1 H), 6.70e6.76 (m, 6 H),
4.2.7. tert-Butyl (3S,5S,6S,8S)-8-(3-(2,6-difluorophenyl)-2,2-
dimethylpropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate (10a)
Following a similar procedure for the preparation of 16a, 10a
was prepared starting from 47 (100 mg, 0.18 mmol) and 10b
7.18e7.21 (m, 1 H). 13C NMR (125 MHz, CDCl3)
d 16.7, 20.3, 21.2, 24.9,
(151 mg, 0.76 mmol). White solid (60 mg, 43%). [
a
]25 D-12.5 (c 0.47,
25.1, 25.2, 28.0, 28.3, 29.6, 32.5, 34.5, 35.6, 37.3, 42.2, 46.6, 49.1, 51.6,
54.0, 55.1, 56.0, 58.5, 65.9, 69.4, 71.2, 79.1, 111.1, 111.6, 114.5, 116.4,
121.3, 122.8, 128.9, 134.2, 139.9, 147.5, 148.2, 156.7, 159.2, 176.1. ESI-
MS m/z 729.5 [MþH]þ. HRMS calcd for C42H69N2O8 [MþH]þ m/z
729.5054, found 729.5056.
CH3OH). 1H NMR (300 MHz, CDCl3)
d
0.85e1.00 (m, 18 H), 1.20e1.30
(m, 2 H), 1.44 (s, 9 H), 1.55e1.70 (m, 4 H), 1.85e1.95 (m, 1 H),
2.00e2.20 (m, 4 H), 2.30e2.45 (m, 1 H), 2.55e2.65 (m, 3 H),
3.05e3.25 (m, 3 H), 3.34 (s, 3 H), 3.37e3.45 (m, 1 H), 3.57 (t, 2 H,
J ¼ 6.0 Hz), 3.82 (s, 3 H), 4.05e4.15 (m, 2 H), 4.66 (d, 1 H, J ¼ 8.1 Hz),
6.15e6.40 (m, 1 H), 6.65e6.90 (m, 5 H), 7.10e7.15 (m, 1 H). 13C NMR
4.2.11. tert-Butyl (3S,5S,6S,8S)-6-hydroxy-3-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-8-(3-(4-methoxyphenyl)-2,2-
(75 MHz, CDCl3)
d 16.7, 20.4, 21.2, 24.9, 28.1, 28.3, 29.6, 31.8, 32.5,
34.4, 36.8, 37.4, 42.3, 48.8, 51.4, 56.0, 58.5, 66.0, 69.5, 71.1, 80.2,
110.9, 111.2, 111.7, 114.6, 121.2, 127.9, 134.4, 147.5, 148.2, 160.2, 163.5,
174.8. ESI-MS m/z 757.5 [MþNa]þ. HRMS calcd for C41H64N2F2O7Na
[MþNa]þ m/z 757.4579, found 757.4581.
dimethylpropylcarbamoyl)-2,9-dimethyldecan-5-ylcarbamate (14a)
Following a similar procedure for the preparation of 16a, 14a
was prepared starting from 47 (150 mg, 0.28 mmol) and 14b
(320 mg, 1.66 mmol). Solid (133 mg, 65%). [
a]25 D-21.0 (c 0.2,
CH2Cl2). 1H NMR (500 MHz, CDCl3)
d
0.80e0.83 (m, 6 H), 0.89e0.95
4.2.8. tert-butyl (3S,5S,6S,8S)-8-(3-(2,5-difluorophenyl)-2,2-
dimethylpropylcarbamoyl)-6-hydroxy-3-(4- methoxy-3-(3-
methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate (11a)
Following a similar procedure for the preparation of 16a, 11a
was prepared starting from 47 (100 mg, 0.19 mmol) and 11b
(m, 12 H), 1.19e1.28 (m, 2 H), 1.45 (s, 9 H), 1.58e1.68 (m, 4 H),
1.85e1.89 (m, 2 H), 2.00e2.12 (m, 3 H), 2.37e2.41 (m, 1 H), 2.49 (s, 2
H), 2.60e2.63 (m, 1 H), 3.05e3.09 (m, 1 H), 3.22e3.26 (m, 1 H), 3.36
(s, 3 H), 3.43e3.53 (m, 2 H), 3.58 (t, 2 H, J ¼ 6.5 Hz), 3.80 (s, 3 H),
3.83 (s, 3 H), 4.11 (m, 2 H), 4.66 (d, 1 H, J ¼ 9.0 Hz), 5.67 (s, 1 H),
6.69e6.84 (m, 5 H), 7.05 (d, 2 H, J ¼ 8.5 Hz). 13C NMR (125 MHz,
(223 mg,1.12 mmol). White solid (117 mg, 85%). [
a]25 D-20.3 (c 0.11,
CH3OH). 1H NMR (500 MHz, CD3OD)
d
0.78e0.85 (m, 6 H), 0.89 (s, 6
CDCl3) d 16.8, 20.3, 21.2, 24.9, 25.0, 28.1, 28.3, 29.6, 32.5, 34.5, 35.4,
H), 0.93e1.00 (m, 6 H),1.15e1.25 (m,1 H), 1.46 (s, 9 H),1.47e1.52 (m,
1 H), 1.53e1.65 (m, 4 H), 1.68e1.75 (m, 1 H), 1.75e1.82 (m, 1 H),
1.98e2.03 (m, 2 H), 2.25e2.35 (m, 2 H), 2.58e2.63 (m, 2 H),
2.65e2.73 (m, 1 H), 3.10e3.15 (m, 2 H), 3.34 (s, 3 H), 3.38e3.45 (m, 1
H), 3.57 (t, 2 H, J ¼ 6.3 Hz), 3.79 (s, 3 H), 4.05 (t, 2 H, J ¼ 6.3 Hz), 5.98
(d, 2 H, J ¼ 9.8 Hz), 6.68e6.75 (m, 1 H), 6.75e6.85 (m, 2 H),
6.92e7.10 (m, 3 H), 7.70e7.78 (m, 1 H). 13C NMR (125 MHz, CD3OD)
37.3, 42.2, 45.7, 49.1, 51.6, 54.0, 55.1, 56.0, 58.5, 60.2, 66.0, 69.4, 71.1,
79.0, 111.7, 113.4, 114.5, 121.3, 130.2, 131.2, 134.2, 147.5, 148.2, 156.7,
158.1, 176.1. ESI-MS m/z 729.5 [MþH]þ. HRMS calcd for C42H69N2O8
[MþH]þ m/z 729.5054, found 729.5056.
4.2.12. tert-Butyl (3S,5S,6S,8S)-8-(2,2-dimethyl-3-(4-
(trifluoromethoxy)phenyl)propylcarbamoyl)-6-hydroxy-3 -(4-
methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-
ylcarbamate (15a)
Following a similar procedure for the preparation of 16a, 15a
was prepared starting from 47 (100 mg, 0.18 mmol) and 15b
(187 mg, 0.76 mmol). Solid (61 mg, 41%). 1H NMR (300 MHz, CDCl3)
d
17.0, 20.8, 21.0, 21.5, 25.1, 25.2, 28.9, 29.0, 29.0, 30.7, 32.0, 32.8,
35.2, 37.5, 38.2, 39.4, 43.7, 50.5, 51.8, 55.0, 56.7, 58.9, 67.3, 70.5, 73.3,
79.9, 113.5, 115.3, 116.2, 117.1, 119.9, 123.0, 128.9, 136.2, 149.1, 149.8,
158.6, 158.7, 160.6, 178.4. ESI-MS m/z 735.5 [MþH]þ. HRMS calcd for
C
41H65N2F2O7 [MþH]þ m/z 735.4760, found 735.4762.
d
0.80e1.00 (m, 18 H), 1.15e1.30 (m, 2 H), 1.43 (s, 9 H), 1.50e1.70 (m,
4.2.9. tert-Butyl (3S,5S,6S,8S)-8-(3-(3-chlorophenyl)-2,2-
4 H), 1.80e1.90 (m, 1 H), 2.00e2.10 (m, 3 H), 2.35e2.40 (m, 1 H),
2.50e2.60 (m, 4 H), 3.00e3.25 (m, 3 H), 3.34 (s, 3 H), 3.45e3.50 (m,
1 H), 3.56 (t, 2 H, J ¼ 6.3 Hz), 3.81 (s, 3 H), 4.09 (t, 2 H, J ¼ 6.3 Hz),
4.64 (d, 1 H, J ¼ 7.2 Hz), 5.80e6.10 (m, 1 H), 6.60e6.80 (m, 3 H),
dimethylpropylcarbamoyl)-6-hydroxy-3-(4-methoxy -3-(3-
methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate (12a)
Following a similar procedure for the preparation of 16a, 12a
was prepared starting from 47 (134 mg, 0.25 mmol) and 12b
7.05e7.20 (m, 4 H). 13C NMR (75 MHz, CDCl3)
d 16.8, 20.3, 21.2, 24.5,
(248 mg, 1.25 mmol). Solid (106 mg, 58%). [
a
]25 D-23.5 (c 0.2,
24.6, 24.8, 24.9, 28.3, 29.6, 32.4, 34.6, 35.5, 37.4, 42.3, 45.4, 45.5,
49.2, 51.4, 54.1, 56.0, 58.6, 66.0, 69.4, 71.3, 79.3, 111.6, 114.5, 120.4,
121.3, 131.4, 131.6, 134.1, 136.9, 147.5, 147.7, 148.3, 156.9, 176.4. ESI-
MS m/z 805.5 [MþNa]þ. HRMS calcd for C42H65N2O8F3Na
[MþNa]þ m/z 805.4591, found 805.4593.
CH2Cl2). 1H NMR (300 MHz, CDCl3)
d
0.80e0.83 (m, 6 H), 0.88e0.95
(m, 12 H), 1.18e1.26 (m, 2 H), 1.43 (s, 9 H), 1.60e1.68 (m, 5 H),
1.86e1.99 (m, 1 H), 2.03e2.12 (m, 3 H), 2.34e2.41 (m, 1 H),
2.51e2.62 (m, 3 H), 3.01e3.08 (m, 1 H), 3.21e3.27 (m, 1 H), 3.34 (s, 3
H), 3.42e3.50 (m, 2 H), 3.54 (t, 2 H, J ¼ 6.3 Hz), 3.81 (s, 3 H), 4.09 (t, 2
H, J ¼ 6.3 Hz), 4.63 (d, 1 H, J ¼ 9.3 Hz), 5.75 (s, 1 H), 6.66e6.76 (m, 3
4.2.13. tert-Butyl (3S,5S,6S,8S)-8-(3-cyclohexyl-2,2-
H), 7.02e7.21 (m, 4 H). 13C NMR (75 MHz, CDCl3)
d
16.3, 19.9, 20.8,
dimethylpropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3
-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate (17a)
Following a similar procedure for the preparation of 16a, 17a
was prepared starting from 47 (102 mg, 0.19 mmol) and 17b
24.3, 24.4, 27.7, 27.8, 31.9, 34.1, 35.1, 36.9, 41.8, 45.5, 48.6, 51.0, 53.6,
58.1, 65.5, 69.0, 70.8, 78.7, 111.2, 114.0, 120.8, 125.9, 128.1, 128.7,
129.8, 133.2, 133.7, 139.8, 147.1, 147.7, 156.3, 175.7. ESI-MS m/z 733.5
[MþH]þ. HRMS calcd for C41H66N2O7Cl [MþH]þ m/z 733.4559,
found 733.4562.
(600 mg, 3.55 mmol). Solid (98 mg, 74%). [
a]25 D-25.6 (c 0.30,
CH2Cl2). 1H NMR (300 MHz, CDCl3)
d
0.81e0.83 (m, 6 H), 0.85e0.95
(m, 12 H), 1.09e1.12 (m, 3 H), 1.13e1.35 (m, 6 H), 1.44 (s, 9 H),
1.55e1.70 (m, 11 H), 1.85e1.93 (m, 1 H), 2.04e2.12 (m, 2 H),
2.33e2.42 (m, 1 H), 2.55e2.65 (m, 1 H), 2.95e3.10 (m, 1 H),
3.10e3.25 (m,1 H), 3.34 (s, 3 H), 3.40e3.45 (m,1 H), 3.50e3.60 (m, 3
H), 3.82 (s, 3 H), 4.10 (t, 2 H, J ¼ 6.2 Hz), 4.64 (d, 1 H, J ¼ 8.5 Hz),
5.70e5.73 (m, 1 H), 6.67e6.76 (m, 3 H). 13C NMR (75 MHz, CDCl3)
4.2.10. tert-Butyl (3S,5S,6S,8S)-6-hydroxy-3-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-8-(3-(3-methoxyphenyl-2,2-
dimethylpropylcarbamoyl)-2,9-dimethyldecan-5-ylcarbamate (13a)
Following a similar procedure for the preparation of 16a, 13a
was prepared starting from 47 (150 mg, 0.28 mmol) and 13b

276
X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
d
16.7, 20.4, 21.3, 25.5, 25.6, 26.2, 26.5, 28.0, 28.4, 29.6, 29.7, 32.7,
4.2.17. tert-Butyl (3S,5S,6S,8S)-6-hydroxy-3-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-2,9-dimethyl-8- (phenethylcarbamoyl)
decan-5-ylcarbamate (21a)
33.6, 34.6, 34.8, 36.0, 37.5, 42.3, 47.7, 49.8, 51.8, 54.0, 56.1, 58.6, 66.0,
69.5, 71.2, 79.1, 111.7, 114.6, 121.3, 134.3, 147.5, 148.3, 156.7, 176.4.
ESI-MS m/z 727.5 [MþNa]þ. HRMS calcd for C41H72N2O7Na
[MþNa]þ m/z 727.5237, found 727.5239.
Following a similar procedure for the preparation of 16a, 21a
was prepared starting from 47 (80 mg, 0.15 mmol) and 21b (182 mg,
1.5 mmol). Solid (61 mg, 62%). [
(300 MHz, CDCl3) 0.82e0.89 (m, 12 H), 1.12e1.25 (m, 2 H), 1.44 (s,
a
]25 D-15.00 (c 0.2, CH2Cl2). 1H NMR
d
4.2.14. tert-Butyl (3S,5S,6S,8S)-8-(2,2-dimethyl-4-
9 H), 1.50e1.70 (m, 5 H), 1.82e1.93 (m, 2 H), 2.04e2.12 (m, 2 H),
2.34e2.42 (m,1 H), 2.59e2.65 (m,1 H), 2.74e2.92 (m, 2 H), 3.34 (s, 3
H), 3.35e3.45 (m, 2 H), 3.57 (m, 4 H), 3.82 (s, 3 H), 4.10 (t, 2 H,
J ¼ 6.4 Hz), 4.60 (d, 1 H, J ¼ 9 Hz), 5.70e5.73 (m, 1 H), 6.67e6.80 (m,
morpholinobutylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate (18a)
Following a similar procedure for the preparation of 16a, 18a
was prepared starting from 47 (100 mg, 0.18 mmol) and 18b
3 H), 7.20e7.33 (m, 5 H). 13C NMR (75 MHz, CDCl3)
d 16.8, 20.3, 20.4,
(190 mg, 1.10 mmol). Solid (73 mg, 55%). [
a]25 D-14.00 (c 0.2,
CH2Cl2). 1H NMR (500 MHz, CDCl3)
d
0.78e0.83 (m, 6 H), 0.90e1.00
21.2, 28.0, 28.4, 29.6, 29.7, 32.6, 34.4, 35.6, 37.4, 40.2, 42.2, 51.3, 53.9,
56.0, 58.6, 66.0, 69.5, 71.2, 79.1, 111.7, 114.6, 121.4, 126.5, 128.6, 128.7,
134.3, 138.9, 147.6, 148.3, 156.7, 176.1. ESI-MS m/z 657.4 [MþH]þ.
HRMS calcd for C38H61N2O7 [MþH]þ m/z 657.4479, found 657.4483.
(m, 12 H), 1.15e1.30 (m, 2 H), 1.44 (s, 9 H), 1.47e1.52 (m, 2 H),
1.55e1.69 (m, 4 H), 1.70e1.76 (m, 1 H), 1.90e1.95 (m, 1 H), 2.05e2.12
(m, 3 H), 2.33e2.40 (m,1 H), 2.43e2.53 (m, 2 H), 2.54e2.70 (m, 5 H),
3.07e3.13 (m, 2 H), 3.34 (s, 3 H), 3.42e3.50 (m,1 H), 3.57e3.60 (m, 3
H), 3.73e3.80 (m, 4 H), 3.82 (s, 3 H), 4.10 (t, 2 H, J ¼ 6.3 Hz), 4.60 (d,1
H, J ¼ 9.3 Hz), 6.65e6.73 (m, 1 H), 6.75e6.83 (m, 2 H), 6.95e7.05 (m,
4.2.18. tert-Butyl (3S,5S,6S,8S)-8-(2-chlorophenethylcarbamoyl)-6-
hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-
dimethyldecan-5-ylcarbamate (22a)
Following a similar procedure for the preparation of 16a, 22a
was prepared starting from 47 (80 mg, 0.15 mmol) and 22b
1 H). 13C NMR (125 MHz, CDCl3)
d 16.7, 20.4, 21.5, 25.8, 26.0, 28.0,
28.4, 29.5, 29.7, 32.7, 34.1, 34.4, 35.5, 37.4, 42.3, 48.0, 51.7, 53.5, 54.0,
54.4, 56.1, 58.6, 66.0, 66.3, 69.5, 70.9, 111.8, 114.7, 121.4, 134.5, 147.9,
148.3, 156.7, 176.3. ESI-MS m/z 722.5 [MþH]þ. HRMS calcd for
(234 mg, 1.5 mmol). Solid (52 mg, 51%). [
a]25 D-16.00 (c 0.3,
CH2Cl2). 1H NMR (300 MHz, CDCl3)
d
0.78e0.92 (m, 12 H), 1.10e1.25
C
40H72N3O8 [MþH]þ m/z 722.5319, found 722.5322.
(m, 2 H), 1.45 (s, 9 H), 1.50e1.55 (m, 1 H), 1.56e1.70 (m, 4 H),
1.80e2.00 (m, 2 H), 2.03e2.13 (m, 2 H), 2.30e2.45 (m, 1 H),
2.55e2.65 (m, 1 H), 2.90e3.05 (m, 2 H), 3.34 (s, 3 H), 3.38e3.50 (m,
2 H), 3.52e3.63 (m, 4 H), 3.82 (s, 3 H), 4.10 (t, 2 H, J ¼ 6.3 Hz), 4.64
(d,1 H, J ¼ 8.9 Hz), 5.70e5.90 (m,1 H), 6.65e6.80 (m, 3 H), 7.15e7.40
4.2.15. tert-Butyl (3S,5S,6S,8S)-8-(2,2-dimethyl-4-
phenoxybutylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate (19a)
Following a similar procedure for the preparation of 16a, 19a
was prepared starting from 47 (100 mg, 0.18 mmol) and 19b
(m, 4 H). 13C NMR (75 MHz, CDCl3)
d 16.8, 20.3, 20.4, 21.2, 28.1, 28.4,
29.6, 32.6, 33.3, 34.4, 37.4, 38.9, 42.3, 51.3, 53.9, 56.0, 58.6, 66.0,
69.5, 71.1, 79.1, 111.6, 114.5, 121.4, 127.0, 128.0, 129.6, 130.9, 134.1,
134.3, 136.4, 147.5, 148.2, 156.6, 176.2. ESI-MS m/z 713.4 [MþNa]þ.
HRMS calcd for C38H59N2O7ClNa [MþNa]þ m/z 713.3909, found
713.3911.
(217 mg, 1.12 mmol). Solid (107 mg, 78%). [
a]25 D-16.0 (c 0.1,
CH2Cl2). 1H NMR (500 MHz, CDCl3)
d
0.80e0.85 (m, 6 H), 0.92e0.98
(m, 6 H), 1.00e1.05 (m, 6 H), 1.10e1.40 (m, 2 H), 1.47 (s, 9 H),
1.53e1.70 (m, 4 H), 1.70e1.75 (m, 1 H), 1.76e1.80 (m, 2 H), 1.90e1.97
(m, 1 H), 2.03e2.07 (m, 1 H), 2.08e2.15 (m, 2 H), 2.37e2.43 (m, 1 H),
2.60e2.67 (m, 1 H), 3.15e3.22 (m, 1 H), 3.25e3.30 (m, 1 H), 3.38 (s, 3
H), 3.43e3.50 (m, 1 H), 3.54e3.57 (m, 1 H), 3.59 (t, 2 H, J ¼ 6.3 Hz),
3.85 (s, 3 H), 4.08 (t, 2 H, J ¼ 6.1 Hz), 4.13 (t, 2 H, J ¼ 6.3 Hz), 4.66 (d, 1
H, J ¼ 8.5 Hz), 6.10e6.17 (m, 1 H), 6.68e6.75 (m, 1 H), 6.75e6.83 (m,
4.2.19. tert-Butyl (3S,5S,6S,8S)-6-hydroxy-3-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-8-(3-methoxyphenethylcarbamoyl)-2,9-
dimethyldecan-5-ylcarbamate (23a)
Following a similar procedure for the preparation of 16a, 23a
was prepared starting from 47 (80 mg, 0.15 mmol) and 23b
2 H), 6.90e6.95 (m, 2 H), 6.96e7.02 (m, 1 H), 7.28e7.35 (m, 2 H). 13
C
NMR (125 MHz, CDCl3) d 16.8, 20.4, 21.4, 25.9, 26.0, 28.1, 28.4, 29.5,
(227 mg, 1.5 mmol). Solid (45 mg, 44%). [
a]25 D-21.1 (c 0.09,
CH3OH). 1H NMR (300 MHz, CDCl3)
d
0.75e0.90 (m, 12 H), 1.10e1.22
29.6, 32.7, 34.0, 34.5, 37.4, 38.6, 42.3, 48.5, 51.9, 54.1, 56.0, 58.6, 64.6,
66.0, 69.5, 71.1, 79.0, 111.7, 114.4, 114.6, 121.0, 121.3, 129.5, 134.4,
147.6, 148.2, 156.7, 158.4, 176.2. ESI-MS m/z 729.5 [MþH]þ. HRMS
calcd for C42H69N2O8 [MþH]þ m/z 729.5054, found 729.5057.
(m, 2 H), 1.44 (s, 9 H), 1.47e1.55 (m, 2 H), 1.55e1.70 (m, 3 H),
1.80e1.95 (m, 2 H), 2.03e2.11 (m, 2 H), 2.33e2.43 (m, 1 H),
2.55e2.65 (m, 1 H), 2.72e2.90 (m, 2 H), 3.34 (s, 3 H), 3.36e3.45 (m,
2 H), 3.50e3.65 (m, 4 H), 3.80 (s, 3 H), 3.82 (s, 3 H), 4.10 (t, 2 H,
J ¼ 6.2 Hz), 4.62 (d, 1 H, J ¼ 8.6 Hz), 5.65e5.75 (m, 1 H), 6.65e6.85
4.2.16. tert-Butyl (3S,5S,6S,8S)-6-hydroxy-3-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-2,9-dimethyl-8-(3-
(m, 6 H), 7.18e7.30 (m, 1 H). 13C NMR (75 MHz, CDCl3)
d 16.8, 20.4,
phenylpropylcarbamoyl)decan-5-ylcarbamate (20a)
Following a similar procedure for the preparation of 16a, 20a
was prepared starting from 47 (80 mg, 0.15 mmol) and 20b
20.5, 21.2, 28.1, 28.4, 29.7, 29.8, 32.6, 34.4, 35.7, 37.4, 40.2, 42.3, 51.2,
53.9, 55.2, 56.1, 58.6, 66.0, 69.5, 71.2, 79.1, 109.6, 111.7, 111.9, 114.6,
121.1, 121.4, 129.6, 134.3, 140.4, 147.4, 148.1, 156.6, 159.8, 175.9. ESI-
MS m/z 687.5 [MþH]þ. HRMS calcd for C39H63N2O8 [MþH]þ m/z
687.4584, found 687.4590.
(203 mg, 1.5 mmol). Solid was obtained (66 mg, 66%). [
a]25 D-10.00
(c 0.30, CH2Cl2). 1H NMR (300 MHz, CDCl3)
d
0.75e0.85 (m, 6 H),
0.85e1.00 (m, 6 H), 1.10e1.28 (m, 2 H), 1.44 (s, 9 H), 1.50e1.70 (m, 5
H), 1.80e1.90 (m, 3 H), 1.95e2.02 (m, 1 H), 2.05e2.15 (m, 2 H),
2.33e2.42 (m,1 H), 2.55e2.70 (m, 3 H), 3.15e3.28 (m,1 H), 3.35 (s, 3
H), 3.37e3.52 (m, 3 H), 3.57 (t, 2 H, J ¼ 6.2 Hz), 3.82 (s, 3 H), 4.10 (t, 2
H, J ¼ 6.2 Hz), 4.64 (d, 1 H, J ¼ 9 Hz), 5.70e5.85 (m, 1 H), 6.65e6.73
(m, 1 H), 6.74e6.85 (m, 2 H), 7.15e7.35 (m, 5 H). 13C NMR (75 MHz,
4.2.20. tert-Butyl (3S,5S,6S,8S)-8-(3,4-
dimethoxyphenethylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate (24a)
Following a similar procedure for the preparation of 16a, 24a
was prepared starting from 47 (80 mg, 0.15 mmol) and 24b
CDCl3)
d
16.8, 20.4, 20.5, 21.1, 28.2, 28.4, 29.6, 29.7, 31.2, 32.6, 33.4,
(272 mg, 1.5 mmol). Solid (83 mg, 77%). [
a]25 D-20.3 (c 0.11,
34.6, 37.4, 39.1, 42.2, 51.4, 54.0, 56.1, 58.6, 66.0, 69.5, 71.2, 79.2, 111.7,
114.6, 121.4, 126.0, 128.3, 128.5, 134.3, 141.4, 147.6, 148.3, 156.7, 176.1.
ESI-MS m/z 693.4 [MþNa]þ. HRMS calcd for C39H62N2O7Na
[MþNa]þ m/z 693.4455, found 693.4458.
CH3OH). 1H NMR (500 MHz, CDCl3)
d
0.78e0.90 (m, 12 H), 1.15e1.22
(m, 1 H), 1.44 (s, 9 H), 1.53e1.70 (m, 6 H), 1.80e1.90 (m, 1 H),
1.91e2.00 (m, 1 H), 2.04e2.11 (m, 2 H), 2.35e2.42 (m, 1 H),
2.57e2.65 (m, 1 H), 2.70e2.83 (m, 2 H), 3.34 (s, 3 H), 3.37e3.50 (m,

X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
277
4 H), 3.56 (t, 2 H, J ¼ 6.0 Hz), 3.81 (s, 3 H), 3.85 (s, 3 H), 3.86 (s, 3 H),
4.09 (t, 2 H, J ¼ 6.5 Hz), 4.63 (d, 1 H, J ¼ 8.5 Hz), 5.65e5.80 (m, 1 H),
6.67e6.85 (m, 6 H). 13C NMR (125 MHz, CDCl3)
16.8, 20.3, 21.2,
4.2.24. tert-Butyl (3S,5S,6S,8S)-8-((S)-1-(4-chlorophenyl)
ethylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)
benzyl)-2,9-dimethyldecan-5-ylcarbamate (28a)
d
28.2, 28.4, 29.7, 29.8, 32.6, 34.5, 35.4, 37.4, 40.5, 42.3, 51.3, 54.1, 55.9,
56.0, 56.1, 58.6, 60.3, 66.1, 69.5, 71.2, 79.1, 111.5, 111.8, 112.0, 114.7,
120.7, 121.3, 131.3, 134.3, 147.6, 147.9, 148.3, 149.2, 156.7, 175.9. ESI-
MS m/z 717.5 [MþH]þ. HRMS calcd for C40H65N2O9 [MþH]þ m/z
717.4690, found 717.4696.
Following a similar procedure for the preparation of 16a, 28a
was prepared starting from 47 (100 mg, 0.18 mmol) and 28b
(290 mg, 1.86 mmol). Solid (68 mg, 51%). [
a]25 D-45.50 (c 0.2,
CH2Cl2). 1H NMR (300 MHz, CDCl3)
d
0.79e0.90 (m, 12 H), 1.10e1.30
(m, 2 H), 1.45 (s, 9 H), 1.45e1.50 (m, 3 H), 1.53e1.70 (m, 5 H),
1.80e1.90 (m, 1 H), 2.04e2.11 (m, 3 H), 2.35e2.43 (m, 1 H),
2.55e2.62 (m, 1 H), 3.34 (s, 3H), 3.36e-3.50 (m, 2 H), 3.57 (t, 2 H,
J ¼ 6 Hz), 3.82 (s, 3 H), 4.10 (t, 2 H, J ¼ 6.3 Hz), 4.64 (d, 1 H,
J ¼ 8.4 Hz), 5.04e5.15 (m, 1 H), 6.00e6.15 (m, 1 H), 6.63e6.80 (m, 3
4.2.21. tert-Butyl (3S,5S,6S,8S)-8-(2-(benzo[d][1,3]dioxol-5-yl)
ethylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)
benzyl)-2,9-dimethyldecan-5-ylcarbamate (25a)
Following a similar procedure for the preparation of 16a, 25a
was prepared starting from 47 (80 mg, 0.15 mmol) and 25b
H), 7.20e7.35 (m, 5 H). 13C NMR (75 MHz, CDCl3)
d 16.9, 20.4, 21.1,
21.7, 28.2, 28.4, 29.6, 30.0, 32.5, 34.7, 37.4, 42.3, 48.1, 51.0, 54.1, 56.1,
58.6, 66.1, 69.5, 71.3, 79.3, 111.8, 114.6, 121.3, 127.6, 128.7, 133.0,
134.2, 141.9, 147.6, 148.3, 156.7, 175.3. ESI-MS m/z 713.4 [MþNa]þ.
HRMS calcd for C38H59N2O7ClNa [MþNa]þ m/z 713.3909, found
713.3910.
(248 mg, 1.5 mmol). Solid (83 mg, 79%). [
a]25 D-16.00 (c 0.2,
CH2Cl2) 1H NMR (300 MHz, CDCl3)
d
0.78e0.92 (m, 12 H), 1.10e1.27
(m, 2 H), 1.44 (s, 9 H), 1.53e1.58 (m, 2 H), 1.60e1.70 (m, 3 H),
1.80e2.00 (m, 2 H), 2.03e2.13 (m, 2 H), 2.30e2.45 (m, 1 H),
2.55e2.65 (m, 1 H), 2.66e2.80 (m, 2 H), 3.34 (s, 3 H), 3.38e3.50 (m,
4 H), 3.56 (t, 2 H, J ¼ 6.3 Hz), 3.82 (s, 3 H), 4.10 (t, 2 H, J ¼ 6.3 Hz),
4.64 (d, 1 H, J ¼ 8.7 Hz), 5.67e5.75 (m, 1 H), 5.92 (s, 2 H), 6.60e6.80
4.2.25. tert-Butyl (3S,5S,6S,8S)-8-((R)-1-(4-bromophenyl)
ethylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)
benzyl)-2,9-dimethyldecan-5-ylcarbamate (29a)
(m, 6 H). 13C NMR (75 MHz, CDCl3)
d 16.8, 20.3, 20.4, 21.2, 28.1, 28.4,
29.6, 29.7, 32.6, 34.5, 35.4, 37.4, 40.5, 42.3, 51.3, 54.0, 56.0, 58.6,
66.0, 69.5, 71.1, 79.1, 100.9, 108.3, 109.0, 111.7, 114.5, 121.3, 121.6,
132.5, 134.3, 146.2, 147.6, 147.8, 148.2, 156.7, 176.1. ESI-MS m/z 723.4
[MþNa]þ. HRMS calcd for C39H60N2O9Na [MþNa]þ m/z 723.4197,
found 723.4200.
Following a similar procedure described for the preparation of
16a, 29a was prepared starting from 47 (100 mg, 0.18 mmol) and
29b (373 mg, 1.86 mmol). Solid (82 mg, 58%). [
a
]25 Dþ6.50 (c 0.2,
CH2Cl2). 1H NMR (300 MHz, CDCl3)
d
0.75e0.95 (m, 12 H), 1.20e1.30
(m, 1 H), 1.43 (s, 9 H), 1.44e1.47 (m, 3 H), 1.50e1.70 (m, 5 H),
1.75e1.90 (m, 2 H), 2.00e2.12 (m, 3 H), 2.32e2.42 (m, 1 H),
2.46e2.60 (m,1 H), 3.15e3.25 (m, 1 H), 3.34 (s, 3 H), 3.36e3.45 (m, 1
H), 3.56 (t, 2 H, J ¼ 6.0 Hz), 3.82 (s, 3 H), 4.06 (t, 2 H, J ¼ 5.4 Hz), 4.52
(d,1 H, J ¼ 6.3 Hz), 5.05e5.15 (m,1 H), 6.00e6.15 (m,1 H), 6.60e6.75
(m, 3 H), 7.20e7.30 (m, 2 H), 7.40e7.50 (m, 2 H). 13C NMR (75 MHz,
4.2.22. tert-Butyl (3S,5S,6S,8S)-6-hydroxy-3-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-2,9-dimethyl-8-(2-(pyridin-2-yl)
ethylcarbamoyl)decan-5-ylcarbamate (26a)
Following a similar procedure for the preparation of 16a, 26a
was prepared starting from 47 (80 mg, 0.15 mmol) and 26b
CDCl3)
d 16.8, 20.3, 20.4, 21.1, 21.7, 28.4, 29.6, 29.9, 32.3, 35.0, 37.6,
(184 mg, 1.5 mmol). Solid (65 mg, 66%). [
a
]25 Dþ18.50 (c 0.2,
42.3, 48.1, 51.0, 54.2, 56.0, 58.6, 66.0, 69.5, 71.4, 79.3, 111.7, 114.5,
120.9, 121.2, 128.0, 131.6, 134.2, 142.7, 147.6, 148.2, 156.8, 175.1. ESI-
MS m/z 757.3 [MþNa]þ. HRMS calcd for C38H59N2O7BrNa [MþNa]þ
m/z 757.3403, found 757.3406.
CH2Cl2). 1H NMR (300 MHz, CDCl3)
d
0.72e0.92 (m, 12 H), 1.07e1.30
(m, 3 H), 1.45 (s, 9 H), 1.53e1.75 (m, 5 H), 1.82e1.92 (m, 1 H),
1.95e2.02 (m, 1 H), 2.03e2.13 (m, 2 H), 2.27e2.36 (m, 1 H),
2.63e2.68 (m, 1 H), 2.90e2.98 (m, 2 H), 3.35 (s, 3 H), 3.50e3.62 (m,
4 H), 3.81 (s, 3 H), 3.93e4.03 (m,1 H), 4.08 (t, 2 H, J ¼ 6 Hz), 4.77 (d,1
H, J ¼ 9.3 Hz), 6.37e6.47 (m, 1 H), 6.60e6.72 (m, 2 H), 6.73e6.80 (m,
1 H), 7.15e7.25 (m, 2 H), 7.62e7.72 (m, 1 H), 8.45 (d, 1 H, J ¼ 3.6 Hz).
4.2.26. tert-Butyl (3S,5S,6S,8S)-8-((S)-1-(4-bromophenyl)
ethylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)
benzyl)-2,9-dimethyldecan-5-ylcarbamate (30a)
Following a similar procedure for the preparation of 16a, 30a
was prepared starting from 47 (100 mg, 0.18 mmol) and 30b
13C NMR (75 MHz, CDCl3)
d
16.7, 20.2, 20.4, 21.3, 27.5, 28.4, 29.6,
29.8, 33.0, 34.6, 37.2, 37.6, 38.9, 42.1, 51.5, 53.2, 56.0, 58.6, 65.9, 69.5,
70.3, 78.7, 111.5, 114.5, 121.3, 121.8, 123.8, 134.5, 137.3, 147.4, 148.1,
148.7, 156.5, 159.7, 176.0. ESI-MS m/z 680.4 [MþNa]þ. HRMS calcd
for C37H59N3O7Na [MþNa]þ m/z 680.4251, found 680.4253.
(373 mg, 1.86 mmol). Solid (72 mg, 51%). [
a]25 D-43.00 (c 0.2,
CH2Cl2). 1H NMR (500 MHz, CDCl3)
d
0.80e0.90 (m, 12 H), 1.15e1.30
(m, 2 H), 1.44 (s, 9 H), 1.44e1.47 (m, 4 H), 1.55e1.70 (m, 5 H),
1.80e1.90 (m, 1 H), 2.00e2.10 (m, 3 H), 2.35e2.40 (m, 1 H),
2.52e2.60 (m, 1 H), 3.34 (s, 3 H), 3.35e3.50 (m, 2 H), 3.56 (t, 2 H,
J ¼ 6.0 Hz), 3.82 (s, 3 H), 4.10 (t, 2 H, J ¼ 6.0 Hz), 4.63 (d, 1 H,
J ¼ 8.0 Hz), 5.05e5.15 (m, 1 H), 5.95e6.10 (m, 1 H), 6.60e6.80 (m, 3
H), 7.15e7.25 (m, 2 H), 7.40e7.50 (m, 2 H). 13C NMR (125 MHz,
4.2.23. tert-Butyl (3S,5S,6S,8S)-8-((R)-1-(4-chlorophenyl)
ethylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)
benzyl)-2,9-dimethyldecan-5-ylcarbamate (27a)
Following a similar procedure for the preparation of 16a, 27a
was prepared starting from 47 (100 mg, 0.18 mmol) and 27b
CDCl3)
d 17.0, 20.3, 21.1, 21.6, 28.3, 28.4, 29.7, 30.1, 32.5, 34.7, 37.4,
(290 mg, 1.86 mmol). Solid (76 mg, 57%). [
a
]25 D-5.50 (c 0.2,
42.4, 48.2, 51.0, 54.1, 56.1, 58.6, 66.1, 69.5, 71.4, 79.3, 111.9, 114.7,
121.1, 121.4, 128.0, 131.7, 134.3, 142.5, 147.7, 148.3, 156.8, 175.2. ESI-
MS m/z 757.3 [MþNa]þ. HRMS calcd for C38H59N2O7BrNa
[MþNa]þ m/z 757.3403, found 757.3405.
CH2Cl2). 1H NMR (500 MHz, CDCl3)
d
0.77e0.83 (m, 6 H), 0.90e1.08
(m, 6 H), 1.00e1.10 (m, 1 H), 1.44 (s, 9 H), 1.44e1.47 (m, 3 H),
1.50e1.70 (m, 6 H), 1.82e1.90 (m, 1 H), 2.00e2.10 (m, 3 H),
2.32e2.40 (m,1 H), 2.50e2.60 (m, 1 H), 3.17e3.30 (m, 2 H), 3.34 (s, 3
H), 3.56 (t, 2 H, J ¼ 6.5 Hz), 3.82 (s, 3 H), 4.08 (t, 2 H, J ¼ 6.0 Hz), 4.52
(d, 1 H, J ¼ 9 Hz), 5.05e5.15 (m, 1 H), 6.00e6.10 (m, 1 H), 6.60e6.75
4.2.27. tert-Butyl (3S,5S,6S,8S)-8-(3-(4-cyclopropyl-1H-1,2,3-
triazol-1-yl)-2,2-dimethylpropylcarbamoyl)-6-hydroxy-3-(4-
methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-
ylcarbamate (31a)
Following a similar procedure for the preparation of 16a, 31a
was prepared starting from 47 (150 mg, 0.28 mmol) and 31b
(m, 3 H), 7.25e7.35 (m, 4 H). 13C NMR (125 MHz, CDCl3)
d 16.8, 20.3,
20.4, 21.1, 21.7, 28.4, 29.6, 29.9, 32.3, 35.0, 37.5, 42.3, 48.0, 51.0, 54.2,
56.1, 58.6, 66.1, 69.5, 71.4, 79.4, 111.9, 114.6, 121.4, 127.7, 128.7, 133.0,
134.2, 142.1, 147.7, 148.3, 156.8, 175.2. ESI-MS m/z 713.4 [MþNa]þ.
HRMS calcd for C38H59N2O7ClNa [MþNa]þ m/z 713.3909, found
713.3911.
(450 mg, 2.31 mmol). Solid (121 mg, 59%). [
a]25 D-11.00 (c 0.4,
CH2Cl2). 1H NMR (500 MHz, CDCl3)
d
0.81e0.87 (m, 6 H), 0.86e0.97

278
X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
(m, 16 H), 1.14e1.28 (m, 2 H), 1.45 (s, 9 H), 1.57e1.71 (m, 4 H),
1.92e1.97 (m, 3 H), 2.05e2.12 (m, 3 H), 2.34e2.38 (m, 1 H),
2.63e2.67 (m, 1 H), 2.95e2.99 (m, 1 H), 3.11e3.15 (m, 1 H), 3.35 (s, 3
H), 3.47e3.53 (m, 2 H), 3.58 (t, 2 H, J ¼ 6.5 Hz), 3.83 (s, 3 H),
4.06e4.14 (m, 4 H), 4.74 (d, 1 H, J ¼ 9.5 Hz), 6.48 (s, 1 H), 6.69e6.79
78.8, 104.4, 111.7, 114.6, 121.3, 122.3, 134.4, 147.5, 148.2, 156.6, 176.8.
ESI-MS m/z 774.6 [MþH]þ. HRMS calcd for C43H76N5O7 [MþH]þ m/z
774.5745, found 774.5751.
4.2.31. tert-Butyl (3S,5S,6S,8S)-8-(2,2-dimethyl-3-(4-phenyl-1H-
1,2,3-triazol-1-yl)propylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate (35a)
Following a similar procedure for the preparation of 16a, 35a
was prepared starting from 47 (150 mg, 0.28 mmol) and 35b
(m, 3 H), 7.34 (s, 1 H). 13C NMR (125 MHz, CDCl3)
d 6.5, 7.7, 7.8, 16.6,
20.3, 20.4, 21.3, 23.8, 24.1, 27.9, 28.4, 29.5, 29.6, 32.7, 34.3, 36.9, 37.3,
42.2, 46.1, 51.4, 53.8, 56.0, 57.5, 58.5, 66.0, 69.4, 71.0, 78.9, 111.7,
114.6, 121.3, 121.5, 134.4, 147.5, 148.2, 149.9, 156.6, 176.7. ESI-MS m/z
730.5 [MþH]þ. HRMS calcd for C40H68N5O7 [MþH]þ m/z 730.5119,
found 730.5121.
(193 mg, 0.84 mmol). Solid (98 mg, 46%). [
a]25 D-11.69 (c 0.32,
CH3OH). 1H NMR (300 MHz, CDCl3)
d
0.79e0.82 (m, 6 H), 0.95e1.01
(m, 12 H), 1.17e1.26 (m, 2 H), 1.44 (s, 9 H), 1.56e1.73 (m, 5 H),
1.93e1.94 (m, 1 H), 2.06e2.10 (m, 2 H), 2.17e2.19 (m, 1 H),
2.34e2.39 (m, 1 H), 2.60e2.64 (m, 1 H), 3.02e3.06 (m, 1 H),
3.17e3.21 (m, 1 H), 3.34 (s, 3 H), 3.48 (s, 2 H), 3.56 (t, 2 H, J ¼ 3.7 Hz),
3.81 (s, 3 H), 4.10 (t, 2 H, J ¼ 3.6 Hz), 4.18e4.22 (m, 2 H), 4.73 (d, 1 H,
J ¼ 5.6 Hz), 6.50 (s, 1 H), 6.68e6.78 (m, 3 H), 7.32e7.44 (m, 3 H),
4.2.28. tert-Butyl (3S,5S,6S,8S)-8-(3-(4-tert-butyl-1H-1,2,3-triazol-
1-yl)-2,2-dimethylpropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-
(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate
(32a)
Following a similar procedure for the preparation of 16a, 32a
was prepared starting from 47 (150 mg, 0.28 mmol) and 32b
7.83e7.85 (m, 2 H), 7.94 (s, 1 H). 13C NMR (75 MHz, CDCl3)
d 16.8,
(118 mg, 0.56 mmol). Solid (67 mg, 32%). [
a
]25 D-2.15 (c 0.27,
20.3, 21.3, 23.8, 28.0, 28.4, 29.6, 32.7, 34.4, 37.0, 37.4, 42.3, 46.2, 51.4,
53.9, 56.1, 57.7, 58.6, 66.1, 69.5, 71.2, 79.0, 111.8, 114.7, 121.3, 125.7,
128.3, 128.8, 130.1, 134.4, 147.5, 148.3, 156.7, 176.8. ESI-MS m/z 766.5
[MþH]þ. HRMS calcd for C43H68N5O7 [MþH]þ m/z 766.5119, found
766.5125.
CH3OH). 1H NMR (300 MHz, CDCl3)
d
0.79e0.83 (m, 6 H), 0.94e0.98
(m, 12 H), 1.16e1.26 (m,1H), 1.35 (s, 10 H), 1.44 (s, 9 H), 1.57e1.74 (m,
5 H), 1.93e1.95 (m, 1 H), 2.03e2.12 (m, 3 H), 2.33e2.37 (m, 1 H),
2.64e2.68 (m, 1 H), 2.95e2.99 (m, 1 H), 3.11e3.15 (m, 1 H), 3.35 (s, 3
H), 3.48e3.52 (m, 2 H), 3.57 (t, 2 H, J ¼ 3.8 Hz), 3.82 (s, 3 H),
4.08e4.15 (m, 4 H), 4.78 (d, 1 H, J ¼ 5.7 Hz), 6.54 (s, 1 H), 6.69e6.79
4.2.32. tert-Butyl (3S,5S,6S,8S)-8-(2,2-dimethyl-3-(4-p-tolyl-1H-
1,2,3-triazol-1-yl)propylcarbamoyl)-6- hydroxy-3-(4-methoxy-3-
(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate
(36a)
Following a similar procedure for the preparation of 16a, 36a
was prepared starting from 47 (150 mg, 0.28 mmol) and 36b
(m, 3 H), 7.29 (s, 1 H). 13C NMR (75 MHz, CDCl3)
d 16.6, 20.3, 20.5,
21.4, 23.8, 24.3, 27.9, 28.4, 29.5, 29.7, 30.4, 30.7, 32.8, 34.3, 36.9, 37.4,
42.2, 46.2, 51.6, 53.8, 56.1, 57.5, 58.6, 66.0, 69.5, 70.9, 78.9, 111.8,
114.7, 120.3, 121.4, 134.4, 147.6, 148.3, 156.6, 157.5, 176.8. ESI-MS m/z
746.5 [MþH]þ. HRMS calcd for C41H72N5O7 [MþH]þ m/z 746.5432,
found 746.5436.
(138 mg, 0.84 mmol). Solid (88 mg, 40%). [
a]25 D-7.00 (c 0.30,
CH3OH). 1H NMR (300 MHz, CDCl3)
d
0.79e0.82 (m, 6 H), 0.94e1.00
4.2.29. tert-Butyl (3S,5S,6S,8S)-8-(3-(4-butyl-1H-1,2,3-triazol-1-
yl)-2,2-dimethylpropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate (33a)
Following a similar procedure for the preparation of 16a, 33a
was prepared starting from 47 (150 mg, 0.28 mmol) and 33b
(m, 12 H), 1.18e1.25 (m, 2 H), 1.44 (s, 9 H), 1.56e1.72 (m, 5 H),
1.92e1.93 (m, 1 H), 2.02e2.09 (m, 2 H), 2.15e2.18 (m, 1 H), 2.37 (s, 4
H), 2.60e2.63 (m, 1 H), 3.00e3.04 (m, 1 H), 3.15e3.19 (m, 1 H), 3.33
(s, 3 H), 3.45e3.48 (m, 1 H), 3.53e3.57 (m, 3 H), 3.80 (s, 3 H),
4.08e4.10 (m, 2 H), 4.16e4.23 (m, 2 H), 4.71 (d, 1 H, J ¼ 5.4 Hz), 6.48
(s, 1 H), 6.67e6.77 (m, 3 H), 7.22e7.23 (m, 2 H), 7.70e7.72 (m, 2 H),
(610 mg, 2.9 mmol). Solid (110 mg, 53%). [
a]25 D-18.00 (c 0.2,
CH2Cl2). 1H NMR (300 MHz, CDCl3)
d
0.79e0.82 (m, 6 H), 0.91e0.96
7.83 (s, 1 H). 13C NMR (75 MHz, CDCl3)
d 16.7, 20.3, 21.2, 21.3, 23.8,
(m,15 H),1.14e1.22 (m, 2 H),1.34e1.44 (m,11 H),1.57e1.68 (m, 7 H),
1.92e2.12 (m, 4 H), 2.31e2.38 (m, 1 H), 2.64e2.74 (m, 3 H),
2.92e2.99 (m, 1 H), 3.10e3.15 (m, 1 H), 3.35 (s, 3 H), 3.50e3.59 (m, 4
H), 3.82 (s, 3 H), 4.08e4.12 (m, 4 H), 4.76 (d,1 H, J ¼ 9.3 Hz), 6.55 (s,1
24.1, 28.0, 28.4, 29.6, 32.6, 34.3, 37.0, 37.3, 42.2, 46.2, 51.5, 53.9, 56.0,
57.6, 58.5, 66.0, 69.4, 71.1, 79.0, 111.8, 114.7, 120.8, 121.3, 125.6, 127.4,
129.5, 124.4, 138.1, 147.6, 147.7, 148.2, 156.6, 176.7. ESI-MS m/z 780.5
[MþH]þ. HRMS calcd for C44H70N5O7 [MþH]þ m/z 780.5275, found
780.5283.
H), 6.68e6.79 (m, 3 H), 7.36 (s, 1 H). 13C NMR (75 MHz, CDCl3)
d 13.7,
16.6, 20.3, 20.4, 21.3, 22.2, 23.8, 24.1, 25.2, 27.9, 28.4, 29.6, 31.4, 32.7,
34.3, 36.9, 37.4, 42.2, 46.2, 51.5, 53.8, 56.1, 57.5, 58.6, 66.0, 69.5, 71.0,
78.9, 111.7, 114.6, 121.3, 122.3, 134.4, 147.5, 148.2, 148.3, 156.6, 176.8.
ESI-MS m/z 746.5 [MþH]þ. HRMS calcd for C41H72N5O7 [MþH]þ m/z
746.5432, found 746.5435.
4.2.33. tert-Butyl (3S,5S,6S,8S)-8-(2,2-dimethyl-3-(4-(pyridin-2-
yl)-1H-1,2,3-triazol-1-yl)propylcarbamoyl)-6-hydroxy-3-(4-
methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-
ylcarbamate (37a)
Following a similar procedure for the preparation of 16a, 38a was
prepared starting from 47 (150 mg, 0.28 mmol) and 37b (410 mg,
4.2.30. tert-Butyl (3S,5S,6S,8S)-8-(3-(4-hexyl-1H-1,2,3-triazol-1-
yl)-2,2-dimethylpropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate (34a)
Following a similar procedure for the preparation of 16a, 34a
was prepared starting from 47 (150 mg, 0.28 mmol) and 34b
1.78 mmol). Solid (162 mg, 76%). [
NMR (300 MHz, CDCl3) 0.79e0.83 (m, 6 H), 0.95e1.03 (m, 12 H),
a
]25 D-21.00 (c 0.1, CH2Cl2). 1H
d
1.23e1.28 (m, 2 H), 1.44 (s, 9 H), 1.56e1.74 (m, 4 H), 1.92e1.95 (m, 1
H), 2.04e2.10 (m, 3 H), 2.18e2.20 (m, 1 H), 2.32e2.39 (m, 1 H),
2.62e2.68 (m, 1 H), 3.01e3.08 (m, 1 H), 3.14e3.21 (m, 1 H), 3.34 (s, 3
H), 3.47e3.53 (m, 2 H), 3.57 (t, 2 H, J ¼ 6.3 Hz), 3.82 (s, 3 H), 4.10 (m,
2 H), 4.25 (s, 2 H), 4.80 (d, 1 H, J ¼ 9.6 Hz), 6.45e6.55 (m, 1 H),
6.68e6.78 (m, 3 H), 7.23e6.27 (m,1 H), 7.77e7.82 (m,1 H), 8.15e8.17
(m, 1 H), 8.24 (s, 1 H), 8.58 (d, 1 H, J ¼ 4.5 Hz). 13C NMR (75 MHz,
(267 mg, 1.12 mmol). Solid (117 mg, 54%). [
a
]25 D-15.0 (c 0.11,
CH3OH). 1H NMR (300 MHz, CDCl3)
d
0.81 (t, 6 H, J ¼ 6.0 Hz),
0.87e1.00 (m, 16 H), 1.11e1.21 (m, 2 H), 1.31e1.35 (m, 4 H), 1.44 (s, 9
H), 1.57e1.67 (m, 8 H), 1.91e1.94 (m, 1 H), 2.05e2.13 (m, 3 H),
2.30e2.37 (m, 1 H), 2.62e2.72 (m, 3 H), 2.92e2.99 (m, 1 H),
3.10e3.17 (m, 1 H), 3.34 (s, 3 H), 3.50e3.59 (m, 4 H), 3.82 (s, 3 H),
4.08e4.15 (m, 4 H), 4.76 (d, 1 H, J ¼ 9.2 Hz), 6.56 (s, 1 H), 6.67e6.78
CDCl3)
d 16.7, 20.3, 21.2, 23.7, 24.1, 27.9, 28.3, 29.6, 29.7, 32.6, 34.3,
37.0, 37.3, 42.2, 46.2, 51.4, 53.9, 56.0, 57.8, 58.5, 66.0, 69.4, 71.2, 79.0,
111.7, 114.6, 120.2, 121.3, 122.9, 123.6, 134.3, 134.6, 136.9, 147.5, 148.1,
148.2, 149.3, 156.6, 176.7. ESI-MS m/z 767.5 [MþH]þ. HRMS calcd for
(m, 3 H), 7.36 (s, 1 H). 13C NMR (75 MHz, CDCl3)
d 13.9, 16.6, 20.3,
20.4, 21.3, 22.3, 23.8, 24.1, 25.5, 27.8, 28.4, 28.8, 29.1, 29.6, 31.4, 32.7,
34.3, 36.9, 37.3, 42.2, 46.2, 51.4, 53.8, 56.0, 57.5, 58.6, 66.0, 69.5, 71.0,
C
42H67N6O7 [MþH]þ m/z 767.5071, found 767.5077.

X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
279
4.2.34. tert-Butyl (3S,5S,6S,8S)-6-hydroxy-8-(3-(4-
(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-2,2-
(266 mg, 1.12 mmol). Solid (131 mg, 64%). [
a
]23 D-11.50 (c 0.36,
CH3OH). 1H NMR (300 MHz, CDCl3)
d 0.80e0.81 (m, 6 H), 0.92e0.97
dimethylpropylcarbamoyl)-3-(4-methoxy-3-(3-methoxypropoxy)
benzyl)-2,9-dimethyldecan-5-ylcarbamate (38a)
Following a similar procedure for the preparation of 16a, 38a
was prepared starting from 47 (150 mg, 0.28 mmol) and 38b
(m, 12 H), 1.18e1.26 (m, 2 H), 1.43 (s, 9 H), 1.53e1.64 (m, 4 H),
1.82e1.92 (m, 3 H), 1.98e2.11 (m, 9 H), 2.31e2.39 (m, 2 H),
2.61e2.67 (m, 1 H), 3.04e3.18 (m, 2 H), 3.34 (s, 3 H), 3.48 (s, 2 H),
3.57 (t, 3 H, J ¼ 6.2 Hz), 3.82 (s, 3 H), 4.07e4.15 (m, 4 H), 4.79 (d, 1 H,
J ¼ 8.6 Hz), 6.36 (s, 1 H), 6.67e6.77 (m, 3 H), 7.55 (s, 1 H). 13C NMR
(205 mg, 0.84 mmol). Solid (88 mg, 40%). [
a]25 D-21.00 (c 0.30,
CH3OH). 1H NMR (300 MHz, CDCl3)
d
0.79 (s, 6 H), 0.91e0.95 (m, 12
(75 MHz, CDCl3) d 16.6, 20.3, 20.4, 21.2, 23.6, 23.9, 24.1, 27.8, 28.4,
H), 1.19e1.24 (m, 2 H), 1.42 (s, 9 H), 1.51e1.64 (m, 5 H), 1.83e1.87 (m,
1 H), 2.04e2.10 (m, 3 H), 2.33e2.37 (m, 1 H), 2.58e2.62 (m, 1 H),
2.89 (s, 1 H), 2.98e3.02 (m, 1 H), 3.12e3.16 (m, 1 H), 3.33 (s, 3 H),
3.39e3.44 (m, 2 H), 3.56 (t, 2 H, J ¼ 3.7 Hz), 3.80 (s, 3 H), 4.08e4.10
(m, 2 H), 4.17e4.20 (m, 2 H), 4.76 (s, 3 H), 6.41 (s, 1 H), 6.67e6.75 (m,
29.6, 32.4, 3414.3, 36.8, 37.3, 41.2, 41.3, 42.3, 46.3, 51.4, 53.8, 56.0,
57.9, 58.5, 65.9, 69.4, 71.2, 78.8, 111.7, 114.6, 121.3, 121.7, 134.3, 147.5,
148.2, 154.4, 156.6, 176.6. ESI-MS m/z 774.5 [MþH]þ. HRMS calcd for
C
42H72N5O8 [MþH]þ m/z 774.5381, found 774.5390.
3 H), 7.65 (s, 1 H). 13C NMR (75 MHz, CDCl3)
d
16.8, 20.3, 21.2, 23.9,
4.2.38. tert-Butyl (3S,5S,6S,8S)-8-(3-(4-((dimethylamino)methyl)-
1H-1,2,3-triazol-1-yl)-2,2-dimethylpropylcarbamoyl)-6-hydroxy-3-
(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-
ylcarbamate (42a)
Following a similar procedure for the preparation of 16a, 42a
was prepared starting from 47 (150 mg, 0.28 mmol) and 42b
28.0, 28.4, 29.6, 29.9, 32.1, 34.2, 36.8, 37.4, 42.3, 46.4, 51.2, 53.9, 56.1,
56.3, 58.0, 58.6, 66.1, 69.5, 71.3, 79.2, 111.8, 114.7, 121.3, 123.5, 134.4,
147.6, 147.9, 148.3, 156.7, 176.6. ESI-MS m/z 720.5 [MþH]þ. HRMS
calcd for C38H66N5O8 [MþH]þ m/z 720.4911, found 720.4917.
4.2.35. tert-Butyl (3S,5S,6S,8S)-6-hydroxy-8-(3-(4-(2-
hydroxyethyl)-1H-1,2,3-triazol-1-yl)-2,2-
(237 mg, 1.12 mmol). Solid (124 mg, 59%). [
a]25 D-11.11 (c 0.54,
CH3OH). 1H NMR (300 MHz, CDCl3)
d
0.84e0.86 (m, 6 H), 0.99e1.02
dimethylpropylcarbamoyl)-3-(4-methoxy-3-(3-methoxypropoxy)
benzyl)-2,9-dimethyldecan-5-ylcarbamate (39a)
Following a similar procedure for the preparation of 16a, 39a
was prepared starting from 47 (121 mg, 0.22 mmol) and 39b
(m, 12 H), 1.23e1.31 (m, 1 H), 1.49 (s, 9 H), 1.59e1.76 (m, 5 H),
1.93e2.20 (m, 4 H), 2.37 (s, 6 H), 2.67e2.73 (m,1 H), 2.90e3.06 (m,1
H), 3.16e3.23 (m,1 H), 3.40 (s, 3 H), 3.55e3.64 (m, 6 H), 3.72 (s, 2 H),
3.87 (s, 3 H), 4.15 (t, 2 H, J ¼ 6.0 Hz), 4.21e4.24 (m, 2 H), 4.87 (d, 1 H,
J ¼ 9.2 Hz), 6.61 (s, 1 H), 6.73e6.83 (m, 3 H), 7.73 (s, 1 H). 13C NMR
(179 mg, 0.90 mmol). Solid (128 mg, 62%). [
a]25 D-17.7 (c 0.18,
CH3OH). 1H NMR (300 MHz, CDCl3)
d
0.79e0.80 (m, 6 H), 0.92e0.95
(75 MHz, CDCl3) d 16.6, 20.3, 20.4, 21.2, 23.8, 24.0, 27.8, 28.4, 29.6,
(m, 12 H), 1.11e1.24 (m, 1 H), 1.43 (s, 9 H), 1.53e1.64 (m, 6 H),
1.87e1.92 (m, 1 H), 2.02e2.11 (m, 3 H), 2.31e2.38 (m, 1 H),
2.58e2.64 (m, 2 H), 2.90e2.98 (m, 2 H), 3.00e3.04 (m, 1 H),
3.11e3.18 (m, 1 H), 3.33 (s, 3 H), 3.47e3.53 (m, 2 H), 3.56 (t, 2 H,
J ¼ 6.3 Hz), 3.81 (s, 3 H), 3.92 (t, 2 H, J ¼ 5.7 Hz), 4.07e4.14 (m, 4 H),
4.73 (d,1 H, J ¼ 9.3 Hz), 6.43 (s,1 H), 6.66e6.76 (m, 3 H), 7.52 (s,1 H).
29.7, 32.5, 34.3, 36.9, 37.3, 42.2, 44.8, 46.1, 51.3, 53.3, 53.8, 54.0, 56.0,
57.6, 58.5, 65.9, 69.4, 71.1, 79.0, 111.7, 114.5, 121.3, 124.6, 134.3, 144.1,
147.5, 148.2, 156.6, 176.7. ESI-MS m/z 747.5 [MþH]þ. HRMS calcd for
C
40H71N6O7 [MþH]þ m/z 747.5384, found 747.5390.
4.2.39. tert-Butyl (3S,5S,6S,8S)-8-(3-(4-((diethylamino)methyl)-
1H-1,2,3-triazol-1-yl)-2,2- dimethylpropylcarbamoyl)-6-hydroxy-
3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-
ylcarbamate (43a)
Following a similar procedure for the preparation of 16a, 43a
was prepared starting from 47 (150 mg, 0.28 mmol) and 43b
(250 mg, 1.04 mmol). Solid (120 mg, 56%). 1H NMR (500 MHz,
13C NMR (75 MHz, CDCl3)
d 16.2, 19.8, 20.8, 23.3, 23.5, 27.4, 27.9,
28.1, 29.1, 29.2, 31.9, 33.8, 36.4, 36.8, 41.8, 45.8, 50.8, 53.3, 55.5, 57.2,
58.1, 60.9, 65.5, 68.9, 70.7, 78.5,111.2,114.1,120.8,123.0,133.8,144.9,
147.0, 147.7, 156.2, 176.2. ESI-MS m/z 734.5 [MþH]þ. HRMS calcd for
C
39H68N5O8 [MþH]þ m/z 734.5068, found 734.5074.
4.2.36. tert-Butyl (3S,5S,6S,8S)-6-hydroxy-8-(3-(4-(1-
hydroxyethyl)-1H-1,2,3-triazol-1-yl)-2,2-
dimethylpropylcarbamoyl)-3-(4-methoxy-3-(3-methoxypropoxy)
benzyl)-2,9-dimethyldecan-5-ylcarbamate (40a)
Following a similar procedure for the preparation of 16a, 40a
was prepared starting from 47 (150 mg, 0.28 mmol) and 40b
CDCl3) d 0.80e0.83 (m, 6 H), 0.94e0.97 (m,12 H),1.18e1.26 (m, 9 H),
1.44 (s, 9 H), 1.57e1.75 (m, 5 H), 1.90e1.94 (m, 1 H), 2.05e2.10 (m, 2
H), 2.10e2.14 (m, 1 H), 2.33e2.37 (m, 1 H), 2.64e2.73 (m, 4 H),
2.94e2.98 (m, 1 H), 3.11e3.15 (m, 1 H), 3.35 (s, 3 H), 3.50e3.56 (m, 2
H), 3.57 (t, 2 H, J ¼ 6.5 Hz), 3.82 (s, 3 H), 3.95 (s, 2 H), 4.10 (t, 2 H,
J ¼ 6.0 Hz), 4.17 (m, 2 H), 4.71 (d, 1 H, J ¼ 9.0 Hz), 6.47 (s, 1 H),
(222 mg, 0.84 mmol). Solid (91 mg, 44%). [
a
]25 D-8.00 (c 0.28,
6.68e6.78 (m, 3 H), 7.84 (s, 1 H). 13C NMR (125 MHz, CDCl3)
d 11.2,
CH3OH). 1H NMR (300 MHz, CDCl3)
d
0.81 (s, 6 H), 0.93e0.98 (m, 12
13.6, 16.6, 19.1, 20.4, 21.3, 23.8, 24.1, 27.9, 28.4, 29.6, 29.7, 30.5, 32.7,
34.3, 37.0, 37.3, 42.2, 46.1, 46.7, 47.4, 51.4, 53.8, 56.0, 57.6, 58.5, 65.5,
66.0, 69.5, 71.0, 78.9, 111.7, 114.7, 121.3, 125.0, 128.8, 130.8, 134.4,
147.7, 148.2, 156.7, 176.7. ESI-MS m/z 775.6 [MþH]þ. HRMS calcd for
H), 1.12e1.26 (m, 2 H), 1.44 (s, 9 H),1.55e1.66 (m, 9 H), 1.86e1.88 (m,
1 H), 2.05e2.12 (m, 3 H), 2.34e2.38 (m, 1 H), 2.60e2.64 (m, 1 H),
2.99e3.07 (m, 1 H), 3.11e3.20 (m, 1 H), 3.35 (s, 3 H), 3.40e3.48 (m, 2
H), 3.57 (t, 2 H, J ¼ 3.7 Hz), 3.82 (s, 3 H), 4.08e4.19 (m, 4 H),
4.74e4.79 (m, 1 H), 5.07 (t, 1 H, J ¼ 3.6 Hz), 6.39 (s, 1 H), 6.68e6.77
C
42H75N6O7 [MþH]þ m/z 775.5697, found 775.5702.
(m, 3 H), 7.58 (s, 1 H). 13C NMR (75 MHz, CDCl3)
d
16.7, 20.3, 21.2,
4.2.40. tert-Butyl (3S,5S,6S,8S)-8-(3-(4-((diisopropylamino)
methyl)-1H-1,2,3-triazol-1-yl)-2,2-dimethylpropylcarbamoyl)-6-
hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-
dimethyldecan-5-ylcarbamate (44a)
Following a similar procedure for the preparation of 16a, 44a
was prepared starting from 47 (150 mg, 0.28 mmol) and 44b
23.3, 23.8, 27.9, 28.4, 29.6, 29.9, 32.4, 34.4, 36.8, 37.3, 42.3, 46.3,
51.3, 53.9, 56.0, 57.9, 58.6, 62.9, 66.0, 69.4, 71.3, 79.1, 111.8, 114.7,
121.4, 121.9, 134.4, 147.6, 148.2, 152.4, 156.6, 176.5. ESI-MS m/z 734.5
[MþH]þ. HRMS calcd for C39H68N5O8 [MþH]þ m/z 734.5068, found
734.5071.
(300 mg, 1.12 mmol). Solid was obtained (121 mg, 54%). [
a]25 D-
4.2.37. tert-Butyl (3S,5S,6S,8S)-6-hydroxy-8-(3-(4-(1-
hydroxycyclopentyl)-1H-1,2,3-triazol-1-yl)-2,2-
dimethylpropylcarbamoyl)-3-(4-methoxy-3-(3-methoxypropoxy)
benzyl)-2,9-dimethyldecan-5-ylcarbamate (41a)
Following a similar procedure for the preparation of 16a, 41a
was prepared starting from 47 (150 mg, 0.28 mmol) and 41b
10.73 (c 0.41, CH3OH). 1H NMR (300 MHz, CDCl3)
d
0.84e0.86 (m, 6
H), 0.99e1.09 (m, 24 H), 1.16e1.31 (m, 2 H), 1.50 (s, 9 H), 1.62e1.74
(m, 5 H), 1.95e1.99 (m, 1 H), 2.09e2.24 (m, 3 H), 2.35e2.43 (m, 1 H),
2.69e2.75 (m, 1 H), 2.94e3.22 (m, 4 H), 3.40 (s, 3 H), 3.54e3.64 (m,
4 H), 3.81 (s, 2 H), 3.87 (s, 3 H), 4.13e4.19 (m, 5 H), 4.85 (d, 1 H,
J ¼ 9.3 Hz), 6.73e6.84 (m, 3 H), 7.50 (s, 1 H). 13C NMR (75 MHz,

280
X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
CDCl3)
d
16.5, 20.3, 20.4, 20.7, 21.3, 23.7, 24.1, 27.7, 28.4, 29.4, 29.6,
30.6, 32.1, 32.8, 35.0, 37.1, 38.1, 42.8, 47.4, 50.6, 51.2, 56.6, 56.8, 58.9,
67.3, 69.9, 70.4, 113.6, 116.1, 122.9, 126.3, 126.9, 128.2, 129.9, 130.3,
133.6, 134.7, 137.3, 149.4, 149.9, 177.7. ESI-MS m/z 649.5 [MþH]þ.
32.7, 34.3, 36.9, 37.3, 40.9, 42.2, 46.1, 51.4, 53.7, 56.0, 57.6, 58.5, 65.9,
69.4, 71.0, 78.8, 111.6, 114.6, 121.3, 123.8, 134.4, 147.5, 148.2, 150.7,
156.6, 176.7. ESI-MS m/z 803.6 [MþH]þ. HRMS calcd for C44H79N6O7
[MþH]þ m/z 803.6010, found 803.6016.
HRMS calcd for
649.4583.
C
40H61N2O5 [MþH]þ m/z 649.4580, found
4.2.41. tert-Butyl (3S,5S,6S,8S)-8-(2,2-dimethyl-3-(4-(piperidin-1-
ylmethyl)-1H-1,2,3-triazol-1-yl) propylcarbamoyl)-6-hydroxy-3-(4-
methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-
ylcarbamate (45a)
Following a similar procedure for the preparation of 16a, 45a
was prepared starting from 47 (150 mg, 0.28 mmol) and 45b
4.3.2. (2S,4S,5S,7S)-5-Amino-N-(2,2-dimethyl-3-(pyridin-3-yl)
propyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-8-methylnonanamide, hydrochloride salt
(5)
Following a similar procedure for the preparation of 16, 5 was
prepared starting from 5a (56 mg, 0.08 mmol). Solid (49 mg, 99%).
(400 mg, 1.6 mmol). Solid (113 mg, 52%). [
a]25 D-20.0 (c 0.1,
CH2Cl2). 1H NMR (500 MHz, CDCl3)
d
0.78e0.81 (m, 6 H), 0.93e0.96
[a d 0.91e1.00
]25 D-9.0 (c 0.20, CH2Cl2). 1H NMR (300 MHz, CD3OD)
(m, 12 H), 1.17e1.24 (m, 1 H), 1.43 (s, 9 H), 1.43e1.45 (m, 4 H),
1.60e1.62 (m, 8 H), 1.89e1.91 (m, 1 H), 2.05e2.07 (m, 2 H),
2.18e2.20 (m, 1 H), 2.31e2.35 (m, 1 H), 2.40e2.60 (m, 3 H),
2.64e2.66 (m, 1 H), 2.95e2.99 (m, 1 H), 3.13e3.17 (m, 1 H), 3.33 (s, 3
H), 3.50e3.57 (m, 3 H), 3.56 (t, 2 H, J ¼ 6.5 Hz), 3.70 (s, 2 H), 3.81 (s, 3
H), 4.09 (t, 2 H, J ¼ 6.0 Hz), 4.16 (m, 2 H), 4.72 (d,1 H, J ¼ 9.0 Hz), 5.52
(s, 1 H), 6.67e6.77 (m, 3 H), 7.70 (s, 1 H). 13C NMR (75 MHz, CDCl3)
(m, 18 H), 1.28e1.29 (m, 1 H), 1.45e1.65 (m, 3 H), 1.66e1.90 (m, 4 H),
2.01e2.03 (m, 2 H), 2.42e2.50 (m, 2 H), 2.59e2.63 (m, 1 H),
2.70e2.75 (m,1 H), 2.83 (s, 2 H), 3.06e3.09 (m,1 H), 3.20e3.23 (m,1
H), 3.35 (s, 3 H), 3.59 (t, 2 H, J ¼ 6 Hz), 3.80 (s, 3 H), 4.07 (t, 2 H,
J ¼ 6.3 Hz), 6.75e6.88 (m, 3 H), 7.95e8.10 (m, 1 H), 8.50e8.60 (m, 1
H), 8.74 (s, 1 H), 8.84 (s, 1 H). 13C NMR (75 MHz, CD3OD)
d 18.3, 19.3,
20.5, 21.4, 25.2, 30.7, 32.1, 32.8, 35.0, 37.7, 38.2, 42.8, 46.7, 50.3, 51.1,
56.7, 56.9, 58.8, 67.4, 68.1, 69.9, 70.4, 113.8, 116.3, 122.9, 127.9, 134.8,
140.8, 140.9, 143.6, 149.5, 149.9, 178.0, 178.1. ESI-MS m/z 600.4
[MþH]þ. HRMS calcd for C35H58N3O5 [MþH]þ m/z 600.4376, found
600.4380.
d
7.9, 16.6, 20.3, 20.4, 21.2, 23.8, 24.1, 25.4, 27.8, 28.4, 29.6, 29.7, 32.6,
34.5, 36.9, 37.3, 42.2, 46.2, 51.2, 52.9, 53.6, 53.7, 54.0, 56.0, 57.6, 58.5,
63.3, 66.0, 69.4, 70.5, 71.0, 78.8,111.7,114.6, 121.3, 124.8,134.4,147.5,
148.2, 156.0, 176.7. ESI-MS m/z 787.6 [MþH]þ. HRMS calcd for
C
43H75N6O7 [MþH]þ m/z 787.5697, found 787.5701.
4.2.42. tert-Butyl (3S,5S,6S,8S)-8-(2,2-dimethyl-3-(4-
(morpholinomethyl)-1H-1,2,3-triazol-1-yl) propylcarbamoyl)-6-
hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-
dimethyldecan-5-ylcarbamate (46a)
Following a similar procedure for the preparation of 16a, 46a
was prepared starting from 47 (150 mg, 0.28 mmol) and 46b
4.3.3. (2S,4S,5S,7S)-5-Amino-N-(2,2-dimethyl-3-(pyridin-4-yl)
propyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-8-methylnonanamide, hydrochloride salt
(6)
Following a similar procedure for the preparation of 16, 6 was
prepared starting from 6a (70 mg, 0.10 mmol). Solid (60 mg, 99%).
(284 mg, 1.12 mmol). Solid (80 mg, 36%). [
a]23 D-4.71 (c 0.42,
[
d
a
]25 D-20.0 (c 0.20, CH2Cl2). 1H NMR (300 MHz, CD3OD)
0.92e1.07 (m, 18 H), 1.41e1.45 (m, 1 H), 1.50e1.58 (m, 2 H),
CH3OH). 1H NMR (300 MHz, CDCl3)
d
0.80e0.82 (m, 6 H), 0.94e0.97
(m, 12 H), 1.18e1.26 (m, 2 H), 1.45 (s, 9 H), 1.56e1.68 (m, 5 H),
1.88e1.96 (m, 1 H), 2.04e2.12 (m, 3 H), 2.32e2.40 (m, 1 H), 2.51 (t, 4
H, J ¼ 4.0 Hz), 2.61e2.67 (m, 1 H), 2.90e3.01 (m, 1 H), 3.11e3.18 (m,
1 H), 3.34 (s, 3 H), 3.48e3.59 (m, 4 H), 3.68e3.72 (m, 6 H), 3.82 (s, 3
H), 4.10 (t, 2 H, J ¼ 6.3 Hz), 4.15 (s, 2 H), 4.73 (d, 1 H, J ¼ 9.3 Hz), 6.49
(s, 1 H), 6.67e6.77 (m, 3 H), 7.61 (s, 1 H). 13C NMR (75 MHz, CDCl3)
1.72e1.90 (m, 4 H), 2.01e2.03 (m, 2 H), 2.45e2.50 (m, 2 H),
2.58e2.63 (m, 1 H), 2.70e2.75 (m,1 H), 2.90 (s, 2 H), 3.09e3.12 (m,1
H), 3.23e3.26 (m,1 H), 3.34 (s, 3 H), 3.58 (t, 2 H, J ¼ 6.3 Hz), 3.80 (s, 3
H), 4.07 (t, 2 H, J ¼ 6.3 Hz), 6.76e6.88 (m, 3 H), 7.90e8.15 (m, 3 H),
8.73 (d, 2 H, J ¼ 5.1 Hz). 13C NMR (75 MHz, CD3OD)
d 18.2, 18.3, 19.4,
20.5, 21.4, 25.0, 25.1, 30.7, 32.1, 32.8, 35.0, 37.0, 38.2, 42.8, 43.2, 51.1,
56.7, 56.9, 58.9, 67.4, 69.9, 70.4, 113.8, 116.3, 122.9, 134.8, 140.8,
140.9, 143.6, 149.5, 149.9, 178.1. ESI-MS m/z 600.4 [MþH]þ. HRMS
calcd for C35H58N3O5 [MþH]þ m/z 600.4376, found 600.4378.
d
16.7, 20.3, 21.2, 23.8, 24.1, 27.9, 28.4, 29.6, 32.5, 34.3, 36.9, 37.3,
42.2, 46.1, 51.4, 53.3, 53.5, 53.8, 56.0, 57.5, 58.6, 65.9, 66.7, 69.4, 71.1,
79.0, 111.7, 114.5, 121.3, 124.3, 134.3, 143.8, 147.5, 148.2, 156.6, 176.7.
ESI-MS m/z 789.5 [MþH]þ. HRMS calcd for C42H73N6O8 [MþH]þ m/z
789.5490, found 789.5492.
4.3. Synthesis of compounds 5-46
4.3.4. (2S,4S,5S,7S)-5-Amino-N-(2,2-dimethyl-3-phenylpropyl)-4-
hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-
8-methylnonanamide, hydrochloride salt (7)
4.3.1. (2S,4S,5S,7S)-5-Amino-N-(2,2-dimethyl-3-(naphthalen-2-yl)
propyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-8-methylnonanamide, hydrochloride salt
(16)
Following a similar procedure for the preparation of 16, 7 was
prepared starting from 7a (30 mg, 0.043 mmol). Solid (26 mg, 98%).
Purity ¼ 95.2% (HPLC eluent: 90% aqueous acetonitrile containing
Compound 16a (35 mg, 0.047 mmol) was added to 4 N HCl/
dioxane (2.0 mL, 8.0 mmol) at ꢃ4 ꢂC under N2. After stirred for 2 h,
the solution was concentrated in vacuo to give 16 as a solid (30 mg,
98%). Purity ¼ 97.8% (HPLC eluent: 75% aqueous acetonitrile con-
0.1% trifluoroacetic acid). [
(500 MHz, CD3OD)
a
]25 D-10.0 (c 0.2, CH2Cl2). 1H NMR
0.82e0.89 (m, 12 H), 0.95e0.97 (d, 6 H,
d
J ¼ 10 Hz), 1.23e1.36 (m, 3 H), 1.42e1.49 (m, 1 H), 1.65e1.68 (m, 1 H),
1.75e1.81 (m, 3 H), 1.98e2.03 (m, 2 H), 2.26e2.29 (m, 1 H),
2.44e2.50 (m, 2 H), 2.55 (s, 2 H), 3.02e3.07 (m, 1 H), 3.15e3.17 (m, 1
H), 3.25e3.27 (m, 1 H), 3.33 (s, 3 H), 3.57 (t, 2 H, J ¼ 5 Hz), 3.78 (s, 3
taining 0.1% trifluoroacetic acid). [
NMR (300 MHz, CD3OD)
a
]25 D-15.0 (c 0.20, CH2Cl2). 1H
d
0.87e0.93 (m, 12 H), 0.96e1.00 (m, 6 H),
1.44e1.53 (m, 3 H), 1.71e1.79 (m, 4 H), 1.98e2.00 (m, 2 H),
2.36e2.39 (m, 2 H), 2.44e2.73 (m, 4 H), 3.05e3.10 (m, 1 H),
3.16e3.23 (m, 1 H), 3.28e3.30 (m, 1 H), 3.32 (s, 3 H), 3.56 (t, 2 H,
J ¼ 6 Hz), 3.77 (s, 3 H), 4.04 (t, 2 H, J ¼ 6 Hz), 6.71e6.84 (m, 3 H),
7.30e7.33 (m, 1 H), 7.40e7.45 (m, 2 H), 7.62 (s, 1 H), 7.73e7.81 (m, 3
H), 4.05 (t, 2 H, J ¼ 5 Hz), 6.72e6.83 (m, 3 H), 7.13e7.25 (m, 5 H). 13
C
NMR (125 MHz, CD3OD) d 16.5, 18.6, 19.3, 20.1, 23.9, 24.0, 29.0, 29.2,
30.6, 34.0, 35.3, 37.0, 41.8, 45.8, 49.2, 50.4, 54.1, 55.3, 57.4, 65.9, 69.0,
72.2, 112.2, 114.8, 121.4, 125.7, 127.2, 130.2, 134.3, 138.3, 147.8, 148.3,
176.7. ESI-MS m/z 599.3 [MþH]þ. HRMS calcd for C36H59N2O5
[MþH]þ m/z 599.4424, found 599.4426.
H). 13C NMR (125 MHz, CD3OD)
d 18.4, 19.2, 20.5, 21.4, 25.5, 25.6,

X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
281
4.3.5. (2S,4S,5S,7S)-5-Amino-N-(3-(2-fluorophenyl)-2,2-
95%). Purity ¼ 98.5%. [
a
]25 D-7.4 (c 0.46, CH3OH). 1H NMR
dimethylpropyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-8-methylnonanamide, hydrochloride salt
(8)
(300 MHz, CD3OD) d 0.78e1.00 (m, 18 H), 1.40e1.50 (m, 2 H),
1.50e1.60 (m, 2 H), 1.65e1.85 (m, 4 H), 1.95e2.05 (m, 2 H),
2.35e2.40 (m, 1 H), 2.40e2.50 (m, 1 H), 2.55e2.65 (m, 3 H),
2.65e2.75 (m, 1 H), 2.98e3.08 (m,1 H), 3.18e3.30 (m, 1 H), 3.34 (s, 3
H), 3.58 (t, 2 H, J ¼ 5.9 Hz), 3.79 (s, 3 H), 4.06 (t, 2 H, J ¼ 5.5 Hz),
6.65e6.90 (m, 3 H), 6.93e7.10 (m, 3 H). 13C NMR (75 MHz, CD3OD)
Following a similar procedure for the preparation of 16, 8 was
prepared starting from 8a (60 mg, 0.084 mmol). Solid (51 mg, 98%).
Purity ¼ 97.5%. [
a
]25 D-12.0 (c 0.23, CH3OH). 1H NMR (500 MHz,
CD3OD) 0.85e1.00 (m, 18 H), 1.40e1.46 (m, 1 H), 1.48e1.55 (m, 1
d
d 18.3, 19.1, 20.4, 20.6, 21.3, 25.1, 28.7, 28.8, 30.5, 30.6, 32.0, 32.8,
H), 1.55e1.60 (m, 1 H), 1.70e1.80 (m, 3 H), 1.80e1.85 (m, 1 H),
1.98e2.05 (m, 2 H), 2.30e2.37 (m, 1 H), 2.40e2.50 (m, 1 H),
2.58e2.65 (m, 3 H), 2.67e2.75 (m, 1 H), 3.00e3.05 (m, 1 H),
3.20e3.28 (m, 1 H), 3.29e3.32 (m, 1 H), 3.34 (s, 3 H), 3.58 (t, 2 H,
J ¼ 6.2 Hz), 3.80 (s, 3 H), 4.07 (t, 2 H, J ¼ 6.4 Hz), 6.73e6.78 (m, 1 H),
6.78e6.83 (m, 1 H), 6.83e6.87 (m, 1 H), 7.00e7.10 (m, 2 H),
34.9, 37.3, 38.0, 39.4, 42.7, 50.3, 51.1, 56.6, 56.7, 58.8, 67.2, 69.9, 70.3,
73.1, 113.5, 115.3, 116.0, 117.0, 119.8, 122.8, 128.3, 134.7, 149.3, 149.8,
157.1, 161.2, 177.7. ESI-MS m/z 635.4 [MþH]þ. HRMS calcd for
C
36H57N2F2O5 [MþH]þ m/z 635.4236, found 635.4241.
4.3.9. (2S,4S,5S,7S)-5-Amino-N-(3-(3-chlorophenyl)-2,2-
dimethylpropyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-8-methylnonanamide, hydrochloride salt
(12)
7.18e7.25 (m, 2 H). 13C NMR (125 MHz, CD3OD)
d 18.5, 19.2, 20.5,
21.4, 25.2, 30.7, 30.8, 32.2, 32.9, 35.0, 37.5, 38.1, 39.6, 42.9, 50.6, 51.3,
56.7, 56.9, 58.9, 67.4, 70.0, 70.4, 113.7, 116.0, 116.2, 122.9, 124.8,
126.5,129.3,134.2,134.9,149.5,150.0,162.0,163.9,177.7. ESI-MS m/z
617.5 [MþH]þ. HRMS calcd for C36H58N2FO5 [MþH]þ m/z 617.4330,
found 617.4332.
Following a similar procedure for the preparation of 16, 12 was
prepared starting from 12a (47 mg, 0.064 mmol). Solid (32 mg,
98%). Purity ¼ 98.0%. [
a
]25 D-14.0 (c 0.20, CH2Cl2). 1H NMR
(300 MHz, CD3OD) 0.85e0.99 (m, 18 H), 1.39e1.54 (m, 3 H),
d
4.3.6. (2S,4S,5S,7S)-5-Amino-N-(3-(3-fluorophenyl)-2,2-
dimethylpropyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-8-methylnonanamide, hydrochloride salt
(9)
1.72e1.86 (m, 4 H), 2.00e2.04 (m, 2 H), 2.36e2.48 (m, 2 H),
2.56e2.71 (m, 4 H), 2.99e3.04 (m, 1 H), 3.17e3.22 (m, 1 H),
3.30e3.33 (m, 1 H), 3.34 (s, 3 H), 3.58 (t, 2 H, J ¼ 6 Hz), 3.79 (s, 3 H),
4.06 (t, 2 H, J ¼ 6 Hz), 6.73e6.87 (m, 3 H), 7.09e7.27 (m, 4 H). 13
C
Following a similar procedure for the preparation of 16, 9 was
prepared starting from 9a (35 mg, 0.049 mmol). Solid (30.4 mg,
NMR (75 MHz, CD3OD) d 18.4, 19.2, 20.5, 21.4, 25.3, 25.3, 30.6, 32.1,
32.8, 34.9, 36.7, 38.1, 42.8, 46.7, 50.5, 51.1, 56.6, 56.8, 58.9, 67.3, 69.9,
70.3, 113.6, 116.0, 122.8, 127.2, 130.1, 130.3, 131.4, 134.6, 134.7, 142.0,
149.4, 149.9, 177.7. ESI-MS m/z 633.5 [MþH]þ. HRMS calcd for
95%). Purity ¼ 98.9%. [
a
]25 D-16.0 (c 0.2, CH2Cl2). 1H NMR
(300 MHz, CD3OD) 0.88e0.92 (m, 12 H), 0.98e1.00 (m, 6 H),
d
1.39e1.46 (m, 3 H), 1.54e1.82 (m, 4 H), 1.99e2.06 (m, 2 H),
2.36e2.48 (m, 2 H), 2.58e2.70 (m, 4 H), 3.00e3.04 (m, 1 H),
3.18e3.23 (m, 1 H), 3.30e3.31 (m, 1 H), 3.34 (s, 3 H), 3.58 (t, 2 H,
J ¼ 6 Hz), 3.80 (s, 3 H), 4.07 (t, 2 H, J ¼ 6 Hz), 6.74e6.99 (m, 6 H),
C
36H58N2O5Cl [MþH]þ m/z 633.4034, found 633.4035.
4.3.10. (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-(4-
methoxy-3-(3-methoxypropoxy)benzyl)-N-(3-(3-methoxyphenyl)-
2,2-dimethylpropyl)-8-methylnonanamide, hydrochloride salt (13)
Following a similar procedure for the preparation of 16, 13 was
prepared starting from 13a (53 mg, 0.073 mmol). Solid (46 mg,
7.23e7.31 (m,1 H). 13C NMR (75 MHz, CD3OD)
d 18.3,19.2, 20.5, 21.4,
25.3, 25.4, 30.6, 30.7, 32.1, 32.8, 34.9, 36.7, 38.1, 42.8, 46.8, 50.5, 51.2,
56.6, 56.8, 58.8, 67.3, 70.0, 70.3,113.7,114.0,116.0,118.0,122.8,127.5,
130.3, 134.8, 142.5, 149.4, 149.9, 162.3, 177.7. ESI-MS m/z 617.4
[MþH]þ. HRMS calcd for C36H58N2O5F [MþH]þ m/z 617.4330, found
617.4332.
98%). Purity ¼ 93.5%. [
a
]25 D-13.8 (c 0.4, CH2Cl2). 1H NMR
(500 MHz, CD3OD) 0.83e0.99 (m, 18 H), 1.25e1.50 (m, 5 H),
d
1.65e1.83 (m, 4 H), 2.01e2.03 (m, 2 H), 2.32e2.36 (m, 1 H),
2.42e2.46 (m, 1 H), 2.53e2.62 (m, 3 H), 2.70e2.71 (m, 1 H),
3.00e3.02 (m, 1 H), 3.34 (s, 3 H), 3.58 (t, 2 H, J ¼ 5 Hz), 3.77 (s, 3 H),
3.80 (s, 3 H), 4.06 (t, 2 H, J ¼ 5 Hz), 6.72e6.87 (m, 6 H), 7.15e7.18 (m,
4.3.7. (2S,4S,5S,7S)-5-Amino-N-(3-(2,6-difluorophenyl)-2,2-
dimethylpropyl)-4-hydroxy-2-isopropyl-7-(4- methoxy-3-(3-
methoxypropoxy)benzyl)-8-methylnonanamide, hydrochloride salt
(10)
1 H). 13C NMR (125 MHz, CD3OD)
d 18.0, 19.8, 20.7, 21.5, 25.5, 25.6,
30.4, 30.6, 32.0, 34.5, 35.2, 36.7, 38.3, 43.1, 47.3, 50.6, 51.6, 55.5, 55.9,
56.6, 58.8, 67.2, 70.4, 72.5, 112.2, 113.5, 116.1, 117.6, 122.8, 124.1,
129.7, 135.3, 141.2, 149.2, 149.8, 160.7, 178.0. ESI-MS m/z 629.5
[MþH]þ. HRMS calcd for C37H61N2O6 [MþH]þ m/z 629.4530, found
629.4532.
Following a similar procedure for the preparation of 16, 10 was
prepared starting from 10a (20 mg, 27.2 mmol). Solid (16.6 mg,
96%). Purity ¼ 95.6% (HPLC eluent: 90% aqueous acetonitrile con-
taining 0.1% trifluoroacetic acid). [
NMR (300 MHz, CD3OD)
a
]25 D-8.4 (c 0.53, CH3OH). 1H
0.85e1.00 (m, 18 H), 1.35e1.45 (m, 1 H),
d
1.50e1.60 (m, 2 H), 1.70e1.85 (m, 4 H), 1.95e2.05 (m, 2 H),
2.30e2.50 (m, 2 H), 2.60e2.70 (m, 4 H), 2.95e3.15 (m, 2 H),
3.25e3.30 (m, 1 H), 3.31 (s, 3 H), 3.58 (t, 2 H, J ¼ 6 Hz), 3.80 (s, 3 H),
4.3.11. (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-(4-
methoxy-3-(3-methoxypropoxy)benzyl)-N-(3-(4-methoxyphenyl)-
2,2-dimethylpropyl)-8-methylnonanamide, hydrochloride salt (14)
Following a similar procedure for the preparation of 16, 14 was
prepared starting from 14a (46 mg, 0.063 mmol). Solid (40 mg,
4.07 (t, 2 H, J ¼ 6.3 Hz), 6.73e6.90 (m, 5 H), 7.18e7.35 (m, 1 H). 13
C
NMR (75 MHz, CD3OD)
d 18.5, 19.2, 20.5, 21.4, 24.8, 25.2, 30.7, 32.1,
32.8, 33.2, 35.0, 38.0, 38.1, 42.8, 50.7, 51.3, 56.7, 56.8, 58.9, 67.4, 69.9,
70.4, 111.9, 113.7, 116.2, 122.9, 129.5, 134.8, 149.5, 149.9, 161.5, 164.8,
177.7. ESI-MS m/z 635.4 [MþH]þ. HRMS calcd for C36H57N2O5F2
[MþH]þ m/z 635.4236, found 635.4241.
99%). Purity ¼ 96.2%. [
a
]25 D-21.0 (c 0.2, CH2Cl2). 1H NMR
(500 MHz, CD3OD) 0.83e0.99 (m, 18H), 1.43e1.49 (m, 1 H),
d
1.54e1.57 (m, 2 H),1.72e1.75 (m, 3 H),1.80e1.83 (m,1 H), 2.01e2.03
(m, 2 H), 2.32e2.36 (m,1 H), 2.43e2.50 (m, 3 H), 2.58e2.62 (m,1 H),
2.70e2.71 (m, 1 H), 2.98e3.02 (m, 1 H), 3.17e3.21 (m, 1 H),
3.28e3.31 (m,1 H), 3.34 (s, 3 H), 3.58 (t, 2 H, J ¼ 6.0 Hz), 3.76 (s, 3 H),
3.79 (s, 3 H), 4.06 (t, 2 H, J ¼ 6.5 Hz), 6.74e6.87 (m, 5 H), 7.06e7.07
4.3.8. (2S,4S,5S,7S)-5-Amino-N-(3-(2,5-difluorophenyl)-2,2-
dimethylpropyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-8-methylnonanamide, hydrochloride salt
(11)
Following a similar procedure for the preparation of 16, 11 was
prepared starting from 11a (21 mg, 28.6 mmol). Solid (16.5 mg,
(m, 2 H). 13C NMR (125 MHz, CD3OD)
d 18.4, 19.2, 20.5, 21.4, 25.3,
25.4, 30.6, 32.1, 32.8, 35.0, 36.7, 38.1, 42.8, 46.4, 50.5, 50.6, 51.2, 51.3,
55.6, 56.7, 56.8, 58.9, 67.3, 69.9, 70.4, 113.7, 114.3, 116.1, 122.9, 131.6,
132.5, 134.8, 149.4, 149.9, 159.6, 177.7. ESI-MS m/z 629.5 [MþH]þ.

282
X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
HRMS calcd for C37H61N2O6 [MþH]þ m/z 629.4530, found 629.4533.
CD3OD) d 0.90e1.11 (m, 18 H), 1.38e1.45 (m, 2 H), 1.50e1.58 (m, 2
H), 1.70e1.77 (m, 5 H), 1.78e1.85 (m, 1 H), 1.98e2.05 (m, 2 H),
2.27e2.35 (m, 1 H), 2.40e2.47 (m, 1 H), 2.58e2.65 (m, 1 H),
2.65e2.73 (m, 1 H), 3.01e3.07 (m, 1 H), 3.23e3.27 (m, 1 H), 3.34 (s, 3
H), 3.58 (t, 2 H, J ¼ 6.2 Hz), 3.79 (s, 3 H), 4.03e4.10 (m, 4 H),
6.74e6.80 (m, 1 H), 6.81e6.83 (m, 1 H), 6.84e6.88 (m, 1 H),
6.89e6.93 (m, 3 H), 7.20e7.27 (m, 2 H). 13C NMR (125 MHz, CD3OD)
4.3.12. (2S,4S,5S,7S)-5-Amino-N-(2,2-dimethyl-3-(4-
(trifluoromethoxy)phenyl)propyl)-4-hydroxy-2-isopropyl -7-(4-
methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnonanamide,
hydrochloride salt (15)
Following a similar procedure for the preparation of 16, 15 was
prepared starting from 15a (20 mg, 25.5 mmol). Solid (16.3 mg,
93%). Purity ¼ 95.6% (HPLC eluent: 60% aqueous acetonitrile con-
d
18.5, 19.3, 20.5, 21.4, 26.1, 26.2, 28.8, 30.7, 30.8, 32.2, 32.9, 34.9,
35.2, 38.1, 39.8, 42.9, 50.3, 50.4, 51.3, 51.4, 56.7, 56.9, 58.9, 65.8, 67.4,
70.0, 70.4, 113.7, 115.6, 116.2, 121.7, 123.0, 130.5, 134.9, 149.5, 150.0,
160.3, 177.6. ESI-MS m/z 629.5 [MþH]þ. HRMS calcd for C37H61N2O6
[MþH]þ m/z 629.4530, found 629.4537.
taining 0.1% trifluoroacetic acid). [a
]25 D-4.0 (c 0.68, CH3OH). 1H
NMR (300 MHz, CD3OD)
d 0.80e1.00 (m, 18 H), 1.43e1.55 (m, 3 H),
1.65e1.85 (m, 4 H), 1.95e2.05 (m, 2 H), 2.30e2.50 (m, 2 H),
2.55e2.70 (m, 4 H), 2.95e3.25 (m, 3 H), 3.33 (s, 3 H), 3.58 (t, 2 H,
J ¼ 6.0 Hz), 3.79 (s, 3 H), 4.06 (t, 2 H, J ¼ 5.7 Hz), 6.70e6.90 (m, 3 H),
4.3.16. (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-(4-
methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl-N-(3-
phenylpropyl)nonanamide, hydrochloride salt (20)
7.10e7.30 (m, 4 H). 13C NMR (75 MHz, CD3OD)
d 18.3,19.3, 20.5, 21.4,
25.0, 25.3, 25.4, 30.7, 32.1, 32.8, 35.0, 36.7, 38.1, 42.8, 46.4, 50.6, 51.2,
56.7, 56.8, 58.9, 67.3, 70.0, 70.4,113.6, 116.1, 121.4, 122.9, 133.1, 133.2,
134.8, 139.0, 148.9, 149.4, 149.9, 177.8. ESI-MS m/z 683.4 [MþH]þ.
Following a similar procedure for the preparation of 16, 20 was
prepared starting from 20a (60 mg, 0.09 mmol). Solid (50 mg, 94%).
HRMS calcd for
683.4252.
C
37H58N2O6F3 [MþH]þ m/z 683.4247, found
Purity ¼ 94.4%. [
a
]25 D-7.1 (c 0.42, CH3OH). 1H NMR (500 MHz,
CD3OD) 0.88e0.92 (m, 6 H), 0.94e0.97 (m, 6 H),1.41e1.44 (m,1 H),
d
1.52e1.58 (m, 2 H), 1.70e1.85 (m, 6 H), 1.97e2.02 (m, 2 H),
2.18e2.26 (m, 1 H), 2.42e2.46 (m, 1 H), 2.57e2.74 (m, 4 H),
3.13e3.18 (m, 1 H), 3.24e3.32 (m, 2 H), 3.33 (s, 3 H), 3.57 (t, 2 H,
J ¼ 6.1 Hz), 3.79 (s, 3 H), 4.06 (t, 2 H, J ¼ 6.2 Hz), 6.74e6.76 (m, 1 H),
6.78e6.90 (m, 2 H), 7.13e7.26 (m, 5 H). 13C NMR (125 MHz, CD3OD)
4.3.13. (2S,4S,5S,7S)-5-Amino-N-(3-cyclohexyl-2,2-
dimethylpropyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-8-methylnonanamide, hydrochloride salt
(17)
Following a similar procedure for the preparation of 16, 17 was
prepared starting from 17a (21 mg, 29.8 mmol). Solid (17.2 mg,
d 18.5, 19.2, 20.6, 21.3, 30.7, 32.0, 32.5, 32.8, 34.3, 35.1, 38.1, 40.1,
42.9, 51.4, 56.7, 56.8, 58.9, 67.4, 69.9, 70.4, 113.8, 116.2, 122.9, 126.9,
129.4, 134.8, 142.9, 149.5, 149.9, 177.3. ESI-MS m/z 571.4 [MþH]þ.
HRMS calcd for C34H55N2O5 [MþH]þ m/z 571.4111, found 571.4116.
96%). Purity ¼ 99.0%. [
a
]25 D-7.1 (c 0.43, CH3OH). 1H NMR
(500 MHz, CD3OD) 0.87e1.05 (m, 18 H), 1.14e1.17 (m, 2 H),
d
1.25e1.47 (m, 6 H), 1.50e1.85 (m, 12 H), 2.00e2.05 (m, 2 H),
2.27e2.33 (m, 1 H), 2.44e2.48 (m, 1 H), 2.58e2.65 (m, 1 H),
2.67e2.75 (m, 1 H), 2.85e2.90 (m, 1 H), 3.17e3.22 (m, 1 H),
3.25e3.31 (m,1 H), 3.35 (s, 3 H), 3.59 (t, 2 H, J ¼ 6.2 Hz), 3.80 (s, 3 H),
4.07 (t, 2 H, J ¼ 6.3 Hz), 6.74e6.88 (m, 3 H). 13C NMR (125 MHz,
4.3.17. (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-(4-
methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl-N-
phenethylnonanamide, hydrochloride salt (21)
Following a similar procedure for the preparation of 16, 21 was
prepared starting from 21a (23 mg, 35.0 mmol). Solid (16.0 mg,
CD3OD) d 18.4, 19.2, 20.5, 21.4, 25.9, 26.0, 27.3, 27.6, 30.7, 32.1, 32.9,
34.9, 35.0, 36.3, 37.1, 38.1, 42.9, 51.1, 51.2, 51.3, 56.7, 56.8, 58.9, 67.4,
70.0, 70.4, 113.8, 116.2, 122.9, 134.8, 149.5, 150.0, 177.6. ESI-MS m/z
605.5 [MþH]þ. HRMS calcd for C36H65N2O5 [MþH]þ m/z 605.4893,
found 605.4898.
94%). Purity ¼ 97.6%. [
a
]25 D-8.1 (c 0.33, CH3OH). 1H NMR
(500 MHz, CD3OD) 0.85e0.97 (m, 12H), 1.27e1.30 (m, 1H),
d
1.35e1.44 (m, 1H), 1.50e1.60 (m, 2H), 1.70e1.80 (m, 3H), 2.00e2.03
(m, 2H), 2.17e2.21 (m, 1H), 2.42e2.48 (m, 1H), 2.61e2.65 (m, 1H),
2.70e2.75 (m, 1H), 2.79e2.82 (m, 2H), 3.28e3.32 (m, 2H), 3.33 (s,
3H), 3.50e3.55 (m, 1H), 3.57 (t, 2H, J ¼ 6.2 Hz), 3.78 (s, 3H), 4.05 (t,
2H, J ¼ 6.3 Hz), 6.74e6.78 (m, 1H), 6.82e6.86 (m, 2H), 7.17e7.29 (m,
4.3.14. (2S,4S,5S,7S)-5-Amino-N-(2,2-dimethyl-4-
morpholinobutyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3
-methoxypropoxy)benzyl)-8-methylnonanamide, hydrochloride salt
(18)
5H). 13C NMR (125 MHz, CD3OD)
d 18.5, 19.2, 20.6, 21.2, 28.8, 30.7,
32.0, 32.8, 35.0, 36.8, 38.1, 42.0, 42.3, 51.3, 56.7, 56.8, 58.9, 67.4, 69.8,
70.4, 113.7, 116.3, 123.0, 127.4, 129.5, 129.8, 134.9, 140.4, 149.5, 150.0,
177.2. ESI-MS m/z 557.4 [MþH]þ. HRMS calcd for C33H53N2O5
[MþH]þ m/z 557.3954, found 557.3961.
Following a similar procedure for the preparation of 16, 18 was
prepared starting from 18a (20 mg, 27.7 mmol). Solid (16.5 mg,
96%). Purity ¼ 95.3%. [
a
]25 D-3.1 (c 0.29, CH3OH). 1H NMR
(300 MHz, CD3OD) 0.80e1.10 (m, 18 H), 1.20e1.50 (m, 3 H),
d
1.50e1.65 (m, 2 H), 1.65e1.90 (m, 6 H), 1.95e2.05 (m, 2 H),
2.29e2.55 (m, 2 H), 2.56e2.75 (m, 2 H), 3.00e3.08 (m, 1 H),
3.10e3.20 (m, 3 H), 3.20e3.30 (m, 2 H), 3.35 (s, 4 H), 3.43e3.55 (m,
2 H), 3.59 (t, 2 H, J ¼ 6.2 Hz), 3.81 (s, 3 H), 3.83e3.90 (m, 1 H),
4.3.18. (2S,4S,5S,7S)-5-Amino-N-(2-chlorophenethyl)-4-hydroxy-
2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-
methylnonanamide, hydrochloride salt (22)
Following a similar procedure for the preparation of 16, 22 was
prepared starting from 22a (19 mg, 24.0 mmol). Solid (15.3 mg,
4.00e4.05 (m, 1 H), 4.08 (t, 2 H, J ¼ 6.3 Hz), 6.75e6.90 (m, 3 H). 13
C
NMR (75 MHz, CD3OD)
d
18.4, 19.4, 20.6, 21.5, 25.4, 25.5, 30.7, 30.9,
94%). Purity ¼ 99.4%. [
a
]25 D-9.5 (c 0.40, CH3OH). 1H NMR
(500 MHz, CD3OD) 0.80e0.95 (m, 12 H), 1.25e1.35 (m, 1 H),
32.1, 32.9, 33.8, 35.1, 35.4, 38.2, 42.9, 51.2, 53.2, 53.3, 54.9, 56.7, 57.0,
58.9, 65.1, 67.4, 69.9, 70.4, 113.7, 116.2, 123.0, 134.9, 149.5, 150.0,
178.1. ESI-MS m/z 622.5 [MþH]þ. HRMS calcd for C35H64N3O6
[MþH]þ m/z 622.4795, found 622.4801.
d
1.45e1.50 (m,1 H), 1.50e1.60 (m, 2 H), 1.70e1.80 (m, 4 H), 1.95e2.05
(m, 2 H), 2.15e2.25 (m, 1 H), 2.40e2.50 (m, 1 H), 2.60e2.67 (m, 1 H),
2.68e2.75 (m, 1 H), 2.96 (t, 2 H, J ¼ 7.5 Hz), 3.32e3.38 (m, 4 H),
3.53e3.60 (m, 3 H), 3.78 (s, 3 H), 4.05 (t, 2 H, J ¼ 6.2 Hz), 6.74e6.78
(m, 1 H), 6.80e6.87 (m, 2 H), 7.15e7.25 (m, 2 H), 7.28e7.38 (m, 2 H).
4.3.15. (2S,4S,5S,7S)-5-Amino-N-(2,2-dimethyl-4-phenoxybutyl)-4-
hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-
8-methylnonanamide, hydrochloride salt (19)
13C NMR (125 MHz, CD3OD)
d 18.5, 19.2, 20.5, 21.3, 28.7, 28.9, 30.7,
30.8, 32.0, 32.8, 34.5, 34.9, 38.1, 40.2, 42.9, 51.2, 56.7, 56.9, 58.9, 67.5,
69.8, 70.4, 113.7, 116.2, 122.9, 128.2, 129.3, 130.5, 132.1, 134.8, 135.1,
137.9, 149.5, 150.0, 177.4. ESI-MS m/z 591.4 [MþH]þ. HRMS calcd for
Following a similar procedure for the preparation of 16, 19 was
prepared starting from 19a (30 mg, 0.041 mmol). Solid (26.2 mg,
96%). Purity ¼ 94.2%. [
a
]25 D-8.6 (c 0.1, CH3OH). 1H NMR (500 MHz,
C
33H52N2O5Cl [MþH]þ m/z 591.3565, found 591.3569.

X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
283
4.3.19. (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-(4-
methoxy-3-(3-methoxypropoxy)benzyl)-N-(3-methoxyphenethyl)-
8-methylnonanamide, hydrochloride salt (23)
2.58e2.66 (m, 1 H), 2.67e2.75 (m, 1 H), 3.25e2.28 (m, 1H), 3.34 (s, 3
H), 3.58 (t, 2 H, J ¼ 6.0 Hz), 3.60e3.65 (m, 1 H), 3.70e3.76 (m, 1 H),
3.79 (s, 3 H), 4.07 (t, 2 H, J ¼ 6.0 Hz), 6.75e6.90 (m, 3 H), 7.90e8.05
(m, 2 H), 8.53 (t, 1 H, J ¼ 5 Hz), 8.76 (d, 1 H, J ¼ 5 Hz). 13C NMR
Following a similar procedure for the preparation of 16, 23 was
prepared starting from 23a (40 mg, 0.058 mmol). Solid (35 mg,
97%). Purity ¼ 95.9% (HPLC eluent: 60% aqueous containing 0.1%
(125 MHz, CD3OD) d 18.4, 19.4, 20.4, 21.2, 30.7, 30.8, 32.0, 32.8, 34.7,
35.0, 38.2, 39.1, 42.9, 50.8, 56.7, 57.0, 58.9, 67.4, 69.8, 70.4, 113.7,
116.2, 123.0, 126.5, 129.2, 134.8, 142.8, 147.8, 149.4, 150.0, 156.2,
177.8. ESI-MS m/z 558.4 [MþH]þ. HRMS calcd for C32H52N3O5
[MþH]þ m/z 558.3907, found 558.3911.
trifluoroacetic acid).
(500 MHz, CD3OD)
[a
]25 D-11.5 (c 0.15, CH3OH). 1H NMR
0.85e1.00 (m, 12 H), 1.38e1.46 (m, 1 H),
d
1.50e1.60 (m, 2 H), 1.67e1.80 (m, 4 H), 1.95e2.05 (m, 2 H),
2.15e2.22 (m, 1 H), 2.42e2.50 (m, 1 H), 2.58e2.65 (m, 1 H),
2.67e2.75 (m, 1 H), 2.76e2.81 (m, 2 H), 3.28e3.30 (m, 1 H),
3.32e3.37 (m, 4 H), 3.47e3.55 (m, 1 H), 3.57 (t, 2 H, J ¼ 6.2 Hz), 3.77
(s, 3 H), 3.78 (s, 3 H), 4.05 (t, 2 H, J ¼ 6.3 Hz), 6.73e6.78 (m, 2 H),
6.78e6.83 (m, 3 H), 6.83e6.87 (m, 1 H), 7.18 (m, 1 H). 13C NMR
4.3.23. (2S,4S,5S,7S)-5-Amino-N-((R)-1-(4-chlorophenyl)ethyl)-4-
hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-
8-methylnonanamide, hydrochloride salt (27)
(125 MHz, CD3OD)
d
18.5, 19.2, 20.5, 21.2, 30.7, 32.0, 32.8, 35.0, 36.8,
Following a similar procedure for the preparation of 16, 27 was
prepared starting from 27a (20 mg, 28.9 mmol). Solid (16.0 mg,
38.1, 41.9, 42.9, 51.2, 55.6, 56.7, 56.8, 58.9, 67.4, 69.8, 70.4, 112.8,
113.7,115.5,116.2,122.0,122.9,130.5,134.8,141.9,149.4,149.9,161.3,
177.3. ESI-MS m/z 587.4 [MþH]þ. HRMS calcd for C34H55N2O6
[MþH]þ m/z 587.4060, found 587.4065.
94%). Purity ¼ 97.3%. [
a
]25 Dþ18.5 (c 0.46, CH3OH). 1H NMR
(500 MHz, CD3OD)
d
0.80e1.00 (m, 12 H), 1.25e1.35 (m, 1 H),
1.35e1.50 (m, 5 H), 1.60e1.70 (m, 3 H), 1.70e1.80 (m, 1 H), 1.97e2.05
(m, 2 H), 2.27e2.40 (m, 2 H), 2.50e2.65 (m, 2 H), 3.10e3.20 (m, 1 H),
3.33 (s, 3 H), 3.57 (t, 2 H, J ¼ 5.5 Hz), 3.79 (s, 3 H), 4.05 (t, 2 H,
J ¼ 5.5 Hz), 4.95e5.05 (m, 1 H), 6.60e6.68 (m, 1 H), 6.75e6.85 (m, 2
4.3.20. (2S,4S,5S,7S)-5-Amino-N-(3,4-dimethoxyphenethyl)-4-
hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-
8-methylnonanamide, hydrochloride salt (24)
H), 7.25e7.40 (m, 4 H). 13C NMR (125 MHz, CD3OD)
d 18.2, 19.4, 20.7,
Following a similar procedure for the preparation of 16, 24 was
prepared starting from 24a (20 mg, 27.9 mmol). Solid (16.7 mg,
21.2, 22.7, 30.7, 30.8, 32.1, 33.1, 35.4, 38.3, 42.8, 50.9, 51.0, 56.7, 56.8,
58.9, 67.4, 70.0, 70.4, 113.7, 116.1, 122.8, 129.0, 129.6, 133.5, 134.8,
144.5, 149.4, 150.0, 176.5. ESI-MS m/z 591.4 [MþH]þ. HRMS calcd for
97%). Purity ¼ 96.8%. [
a
]25 D-16.8 (c 0.36, CH3OH). 1H NMR
(300 MHz, CD3OD) 0.80e1.00 (m, 12 H), 1.35e1.60 (m, 3 H),
d
C
33H52N2O5Cl [MþH]þ m/z 591.3565, found 591.3568.
1.65e1.82 (m, 4 H), 1.95e2.05 (m, 2 H), 2.15e2.25 (m, 1 H),
2.40e2.50 (m, 1 H), 2.58e2.80 (m, 4 H), 3.24e3.32 (m, 2 H), 3.34 (s,
3 H), 3.45e3.53 (m,1 H), 3.57 (t, 2 H, J ¼ 6.3 Hz), 3.78 (s, 3 H), 3.79 (s,
3 H), 3.82 (s, 3 H), 4.05 (t, 2 H, J ¼ 6.3 Hz), 6.73e6.80 (m, 2 H),
4.3.24. (2S,4S,5S,7S)-5-Amino-N-((S)-1-(4-chlorophenyl)ethyl)-4-
hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-
8-methylnonanamide, hydrochloride salt (28)
6.80e6.90 (m, 4 H). 13C NMR (75 MHz, CD3OD)
d 18.5, 19.3, 20.6,
21.3, 30.7, 32.0, 32.8, 35.0, 36.4, 38.2, 42.1, 42.9, 51.3, 56.6, 56.7, 56.9,
58.9, 67.3, 69.8, 70.4, 113.4, 113.6, 114.0, 116.1, 122.2, 122.9, 133.4,
134.8, 149.2, 149.4, 149.9, 150.5, 177.3. ESI-MS m/z 617.4 [MþH]þ.
HRMS calcd for C35H57N2O7 [MþH]þ m/z 617.4166, found 617.4171.
Following a similar procedure described for the preparation of
16, 28 was prepared starting from 28a (23 mg, 33.3 mmol). Solid
(18.7 mg, 95%). Purity ¼ 96.5%. [
a
]25 D-34.7 (c 0.38, CH3OH). 1H
NMR (500 MHz, CD3OD) 0.75e1.00 (m, 12 H), 1.25e1.35 (m, 1 H),
d
1.43 (d, 3 H, J ¼ 6.0 Hz), 1.50e1.59 (m, 2 H), 1.65e1.80 (m, 4 H),
1.95e2.05 (m, 2 H), 2.22e2.31 (m, 1 H), 2.40e2.50 (m, 1 H),
2.60e2.75 (m, 2 H), 3.25e3.30 (m, 1 H), 3.33 (s, 3 H), 3.58 (t, 2 H,
J ¼ 5.5 Hz), 3.80 (s, 3H), 4.07 (t, 2H, J ¼ 5.0 Hz), 4.95e5.05 (m, 1H),
6.75e6.90 (m, 3H), 7.25e7.35 (m, 4H). 13C NMR (125 MHz, CD3OD)
4.3.21. (2S,4S,5S,7S)-5-Amino-N-(2-(benzo[d][1,3]dioxol-5-yl)
ethyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-8-methylnonanamide, hydrochloride salt
(25)
Following a similar procedure for the preparation of 16, 25 was
prepared starting from 25a (19 mg, 0.027 mmol). Solid (15.3 mg,
d 18.5, 19.3, 20.5, 21.3, 22.3, 30.7, 30.8, 32.2, 32.8, 34.9, 38.1, 42.9,
51.0, 56.8, 56.9, 58.9, 67.5, 69.9, 70.4, 113.8, 116.3, 123.0, 129.1, 129.4,
133.7, 134.8, 144.0, 149.5, 149.9, 176.6. ESI-MS m/z 591.4 [MþH]þ.
HRMS calcd for C33H52N2O5Cl [MþH]þ m/z 591.3565, found
591.3569.
94%). Purity ¼ 93.5%. [
a
]25 D-11.0 (c 0.29, CH3OH). 1H NMR
(300 MHz, CD3OD) 0.80e1.02 (m, 12 H), 1.35e1.45 (m, 1 H),
d
1.50e1.60 (m, 2 H), 1.65e1.80 (m, 4 H), 1.97e2.05 (m, 2 H),
2.12e2.22 (m, 1 H), 2.40e2.50 (m, 1 H), 2.58e2.66 (m, 1 H),
2.67e2.75 (m, 3 H), 3.22e2.30 (m, 2 H), 3.34 (s, 3 H), 3.43e2.50 (m,
1 H), 3.57 (t, 2 H, J ¼ 6.0 Hz), 3.79 (s, 3 H), 4.05 (t, 2 H, J ¼ 6.3 Hz),
5.88 (s, 2 H), 6.63e6.80 (m, 4 H), 6.80e6.88 (m, 2 H). 13C NMR
4.3.25. (2S,4S,5S,7S)-5-Amino-N-((R)-1-(4-bromophenyl)ethyl)-4-
hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-
8-methylnonanamide, hydrochloride salt (29)
(75 MHz, CD3OD)
d 18.5, 19.3, 20.6, 21.2, 30.7, 32.0, 32.8, 35.0, 36.5,
38.1, 42.2, 42.9, 51.3, 56.6, 56.8, 58.9, 67.3, 69.8, 70.4, 102.1, 109.1,
110.0, 113.6, 116.1, 122.7, 122.9, 134.2, 134.8, 147.6, 149.1, 149.4, 149.9,
177.3. ESI-MS m/z 601.4 [MþH]þ. HRMS calcd for C34H53N2O7
[MþH]þ m/z 601.3853, found 601.3859.
Following a similar procedure for the preparation of 16, 29 was
prepared starting from 29a (20 mg, 27.2 mmol). Solid (16.8 mg,
97%). Purity ¼ 93.6%. [
a
]25 Dþ13.5 (c 0.36, CH3OH). 1H NMR
(500 MHz, CD3OD)
d
0.80e1.00 (m, 12H), 1.40e1.46 (m, 6H),
1.60e1.70 (m, 3H), 1.75e1.82 (m, 1H), 1.97e2.05 (m, 2H), 2.27e2.40
(m, 2H), 2.50e2.65 (m, 2H), 3.13e3.17 (m, 1H), 3.34 (s, 3H), 3.58 (t,
2H, J ¼ 6.0 Hz), 3.79 (s, 3H), 4.05 (t, 2H, J ¼ 6.0 Hz), 4.95e5.05 (m,
1H), 6.60e6.68 (m, 1H), 6.75e6.85 (m, 2H), 7.25e7.32 (m, 2H),
4.3.22. (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-(4-
methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl-N-(2-(pyridin-2-
yl)ethyl)nonanamide, hydrochloride salt (26)
Following a similar procedure for the preparation of 16, 26 was
prepared starting from 26a (60 mg, 0.091 mmol). Solid (53 mg,
7.42e7.48 (m, 2H). 13C NMR (125 MHz, CD3OD)
d 18.3, 19.4, 20.6,
21.2, 22.6, 22.7, 28.8, 30.7, 30.8, 32.1, 33.2, 35.4, 38.2, 42.8, 49.8, 49.9,
51.0, 51.1, 56.7, 56.8, 58.9, 67.4, 70.0, 70.4, 113.8, 116.2, 121.6, 122.9,
129.3, 132.6, 134.7, 144.9, 149.5, 149.9, 176.5. ESI-MS m/z 635.3
[MþH]þ. HRMS calcd for C33H52N2O5Br [MþH]þ m/z 635.3060,
found 635.3067.
98%). Purity ¼ 99.3%. [
a
]25 D-4.5 (c 0.40, CH3OH). 1H NMR
(500 MHz, CD3OD) 0.80e0.90 (m, 6 H), 0.90e1.00 (m, 6 H),
d
1.28e1.32 (m, 1 H), 1.35e1.42 (m, 1 H), 1.45e1.65 (m, 3 H), 1.65e1.85
(m, 4 H), 1.97e2.05 (m, 2 H), 2.22e2.30 (m, 1 H), 2.42e2.52 (m, 1 H),

284
X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
4.3.26. (2S,4S,5S,7S)-5-Amino-N-((S)-1-(4-bromophenyl)ethyl)-4-
hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-
8-methylnonanamide, hydrochloride salt (30)
(m, 2H), 2.39e2.41 (m, 1H), 2.46e2.50 (m, 1H), 2.60e2.64 (m, 1H),
2.71e2.73 (m, 1H), 2.80 (t, 2H, J ¼ 6 Hz), 3.13e3.22 (m, 2H),
3.30e3.33 (m, 1H), 3.35 (s, 3H), 3.59 (t, 2H, J ¼ 6 Hz), 3.81 (s, 3H),
4.08 (t, 2H, J ¼ 6 Hz), 4.30e4.38 (m, 2H), 6.76e6.89 (m, 3H), 8.22 (s,
Following a similar procedure for the preparation of 16, 30 was
prepared starting from 30a (21 mg, 28.6 mmol). Solid (17.6 mg,
1H). 13C NMR (125 MHz, CD3OD)
d 14.0, 18.4, 19.3, 20.5, 21.3, 23.1,
97%). Purity ¼ 98.4%. [
a
]25 D-31.4 (c 0.40, CH3OH). 1H NMR
23.8, 30.7, 30.7, 32.1, 34.9, 37.9, 38.1, 42.8, 48.0, 51.1, 56.7, 56.9, 58.9,
60.1, 67.4, 69.9, 70.4, 113.7, 116.2, 122.9, 126.9, 134.7, 147.5, 149.4,
149.9, 178.0. ESI-MS m/z 646.5 [MþH]þ. HRMS calcd for C36H64N5O5
[MþH]þ m/z 646.4907, found 646.4910.
(500 MHz, CD3OD) 0.80e1.00 (m, 12H), 1.25e1.35 (m, 1H),
d
1.40e1.45 (m, 3H), 1.50e1.60 (m, 2H), 1.60e1.80 (m, 4H), 1.95e2.05
(m, 2H), 2.20e2.30 (m, 1H), 2.40e2.50 (m, 1H), 2.60e2.80 (m, 2H),
3.25e3.30 (m, 1H), 3.33 (s, 3H), 3.57 (t, 2H, J ¼ 5.5 Hz), 3.79 (s, 3H),
4.07 (t, 2H, J ¼ 5.5 Hz), 4.95e5.05 (m, 1H), 6.60e6.68 (m, 1H),
6.75e6.90 (m, 2H), 7.25e7.30 (m, 2H), 7.40e7.50 (m, 2H). 13C NMR
4.3.30. (2S,4S,5S,7S)-5-Amino-N-(3-(4-hexyl-1H-1,2,3-triazol-1-
yl)-2,2-dimethylpropyl)-4-hydroxy-2- isopropyl-7-(4-methoxy-3-
(3-methoxypropoxy)benzyl)-8-methylnonanamide, hydrochloride
salt (34)
(125 MHz, CD3OD) d 18.5, 19.3, 20.5, 21.3, 22.3, 30.6, 30.7, 32.2, 32.8,
34.9, 38.1, 42.9, 50.9, 56.7, 56.8, 58.9, 67.5, 69.9, 70.4, 113.8, 116.3,
121.7,123.0,129.4,132.5,134.8,144.6,149.5,150.0,176.5. ESI-MS m/z
635.3 [MþH]þ. HRMS calcd for C33H52N2O5Br [MþH]þ m/z
635.3060, found 635.3068.
Following a similar procedure for the preparation of 16, 34 was
prepared starting from starting with 34a (50 mg, 0.065 mmol).
Solid (43 mg, 98%). Purity ¼ 98.8%. [
a
]25 D-13.00 (c 0.2, CH2Cl2). 1H
NMR (500 MHz, CD3OD) 0.83e0.99 (m, 20H), 1.25e1.33 (m, 9H),
d
4.3.27. (2S,4S,5S,7S)-5-Amino-N-(3-(4-cyclopropyl-1H-1,2,3-
triazol-1-yl)-2,2-dimethylpropyl)-4-hydroxy-2-isopropyl-7-(4-
methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnonanamide,
hydrochloride salt (31)
1.44e1.49 (m, 1H), 1.65e1.68 (m, 3H), 1.73e1.78 (m, 3H), 2.00e2.03
(m, 2H), 2.29e2.33 (m, 1H), 2.42e2.50 (m, 3H), 2.69 (t, 2H, J ¼ 5 Hz),
3.02e3.18 (m, 2H), 3.30e3.33 (m, 1H), 3.34 (s, 3H), 3.58 (t, 2H,
J ¼ 5 Hz), 3.79 (s, 3H), 4.06 (t, 2H, J ¼ 5 Hz), 4.20e4.23 (m, 2H),
Following a similar procedure for the preparation of 16, 31 was
prepared starting from 31a (56 mg, 0.077 mmol). Solid (49 mg,
6.72e6.84 (m, 3H), 7.84 (s, 1H). 13C NMR (75 MHz, CD3OD)
d 12.9,
16.5, 18.6, 19.3, 20.0, 22.1, 22.5, 22.6, 24.8, 28.4, 29.1, 29.2, 30.7, 31.2,
33.8, 34.2, 36.5, 37.1, 41.8, 46.6, 50.4, 54.1, 55.3, 57.3, 57.4, 65.9, 69.0,
72.7, 112.1, 114.7, 121.4, 123.2, 134.4, 147.5, 147.7, 148.3, 177.0. ESI-MS
m/z 674.5 [MþH]þ. HRMS calcd for C38H68N5O5 [MþH]þ m/z
674.5220, found 674.5223.
99%). Purity ¼ 98.6%. [
a
]25 D-15.5 (c 0.2, CH2Cl2). 1H NMR
(300 MHz, CD3OD) 0.80e1.00 (m, 20H), 1.05e1.10 (m, 2H),
d
1.41e1.65 (m, 4H), 1.73e1.85 (m, 4H), 1.95e2.05 (m, 3H), 2.33e2.36
(m, 1H), 2.41e2.47 (m, 1H), 2.60e2.64 (m, 1H), 2.69e2.70 (m, 1H),
3.07e3.10 (m, 1H), 3.14e3.16 (m, 1H), 3.34 (s, 3H), 3.58 (t, 2H,
J ¼ 6.0 Hz), 3.80 (s, 3H), 4.07 (t, 2H, J ¼ 6.3 Hz), 4.18e4.25 (m, 2H),
4.3.31. (2S,4S,5S,7S)-5-Amino-N-(2,2-dimethyl-3-(4-phenyl-1H-
1,2,3-triazol-1-yl)propyl)-4-hydroxy-2- isopropyl-7-(4-methoxy-3-
(3-methoxypropoxy)benzyl)-8-methylnonanamide, hydrochloride
salt (35)
6.75e6.88 (m, 3H), 7.82 (s, 1H). 13C NMR (125 MHz, CD3OD)
d 6.4,
8.6, 18.4, 19.3, 20.5, 22.3, 23.8, 23.9, 30.7, 30.7, 32.1, 32.8, 34.9, 37.8,
38.1, 42.8, 43.4, 48.0, 51.1, 56.7, 56.9, 58.8, 60.2, 67.4, 68.1, 69.9, 70.4,
83.6, 87.7, 113.8, 116.2, 122.9, 125.5, 125.5, 134.8, 149.4, 150.1, 178.0.
ESI-MS m/z 630.5 [MþH]þ. HRMS calcd for C35H60N5O5 [MþH]þ m/z
630.4594, found 630.4597.
Following a similar procedure for the preparation of 16, 35 was
prepared starting from 35a (62 mg, 0.081 mmol). Solid (56 mg,
98%). Purity ¼ 95.1%. [
a
]25 D-7.67 (c 0.49, CH3OH). 1H NMR
(300 MHz, CD3OD) 0.87e0.90 (m, 6H), 0.98e1.00 (m, 12H),
d
4.3.28. (2S,4S,5S,7S)-5-Amino-N-(3-(4-tert-butyl-1H-1,2,3-triazol-
1-yl)-2,2-dimethylpropyl)-4-hydroxy-2- isopropyl-7-(4-methoxy-3-
(3-methoxypropoxy)benzyl)-8-methylnonanamide, hydrochloride
salt (32)
1.28e1.55 (m, 4H), 1.73e1.85 (m, 4H), 1.98e2.02 (m, 2H), 2.39e2.49
(m, 2H), 2.56e2.61 (m, 1H), 2.71 (s, 1H), 3.12 (s, 2H), 3.33 (s, 3H),
3.57 (t, 2H, J ¼ 6.1 Hz), 3.78 (s, 3H), 4.05 (t, 2H, J ¼ 6.2 Hz), 4.37 (s,
2H), 6.73e6.86 (m, 3H), 7.38e7.48 (m, 3H), 7.83e7.86 (m, 2H), 8.59
Following a similar procedure for the preparation of 16, 32 was
prepared starting from 32a (59 mg, 0.079 mmol). Solid (53 mg,
(s, 1H). 13C NMR (75 MHz, CD3OD)
d 18.4, 19.3, 20.5, 21.4, 23.9, 24.1,
30.6, 30.7, 32.2, 32.8, 35.0, 37.9, 38.2, 42.8, 48.1, 51.2, 56.7, 56.9, 58.9,
59.5, 67.3, 70.0, 70.3, 113.6, 116.1, 122.9, 124.5, 126.9, 129.8, 130.1,
130.7, 134.7, 148.0, 149.4, 149.9, 178.1. ESI-MS m/z 666.5 [MþH]þ.
98%). Purity ¼ 96.0%. [
a
]25 D-4.81 (c 0.47, CH3OH). 1H NMR
(500 MHz, CD3OD) 0.90e0.92 (m, 6H), 0.98 (s, 12H), 1.42 (s, 10H),
d
1.54e1.59 (m, 2H), 1.72e1.85 (m, 4H), 2.02 (t, 2H, J ¼ 5.7 Hz),
2.40e2.49 (m, 2H), 2.59e2.63 (m, 1H), 2.72 (s, 1H), 3.14e3.23 (dd,
2H, J ¼ 13.7 Hz, J ¼ 10.6 Hz), 3.30e3.32 (m, 1H), 3.34 (s, 3H), 3.59 (t,
2H, J ¼ 5.9 Hz), 3.80 (s, 3H), 4.07 (t, 2H, J ¼ 5.9 Hz), 4.39 (s, 2H),
HRMS calcd for
666.4600.
C
38H60N5O5 [MþH]þ m/z 666.4594, found
4.3.32. (2S,4S,5S,7S)-5-Amino-N-(2,2-dimethyl-3-(4-p-tolyl-1H-
1,2,3-triazol-1-yl)propyl)-4-hydroxy-2- isopropyl-7-(4-methoxy-3-
(3-methoxypropoxy)benzyl)-8-methylnonanamide, hydrochloride
salt (36)
6.76e6.88 (m, 3H), 8.39 (s, 1H). 13C NMR (125 MHz, CD3OD)
d 18.4,
19.4, 20.5, 21.4, 23.8, 23.9, 30.2, 30.7, 30.8, 32.2, 32.8, 34.9, 37.9, 38.2,
42.8, 48.0, 51.1, 56.7, 56.9, 58.9, 60.6, 67.4, 69.9, 70.4, 113.7, 116.2,
122.9, 125.9, 134.8, 149.5, 149.9, 156.1, 178.2. ESI-MS m/z 646.5
[MþH]þ. HRMS calcd for C36H64N5O5 [MþH]þ m/z 646.4907, found
646.4913.
Following a similar procedure for the preparation of 16, 36 was
prepared starting from 36a (63 mg, 0.081 mmol). Solid (52 mg,
90%). Purity ¼ 95.8% (HPLC eluent: 60% aqueous acetonitrile con-
taining 0.1% trifluoroacetic acid). [
NMR (500 MHz, CD3OD)
a
]25 D-11.86 (c 0.28, CH3OH). 1H
0.86 (t, 6H, J ¼ 6.5 Hz), 0.97e0.99 (m,
4.3.29. (2S,4S,5S,7S)-5-Amino-N-(3-(4-butyl-1H-1,2,3-triazol-1-
yl)-2,2-dimethylpropyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-
(3-methoxypropoxy)benzyl)-8-methylnonanamide, hydrochloride
salt (33)
d
12H), 1.27e1.49 (m, 4H), 1.65e1.85 (m, 4H), 1.97e2.03 (m, 2H), 2.36
(s, 4H), 2.44e2.59 (m, 3H), 3.17e3.18 (m, 2H), 3.33 (s, 3H), 3.56 (t,
2H, J ¼ 6.3 Hz), 3.78 (s, 3H), 4.05 (t, 2H, J ¼ 6.3 Hz), 4.30 (s, 2H),
6.72e6.84 (m, 3H), 7.23e7.25 (m, 2H), 7.70e7.72 (m, 2H), 8.39 (s,
Following a similar procedure for the preparation of 16, 33 was
prepared starting from 33a (50 mg, 0.067 mmol). Solid (43 mg,
1H). 13C NMR (75 MHz, CD3OD)
d 18.2, 19.7, 20.6, 21.3, 21.4, 23.9,
98%). Purity ¼ 98.4%. [
(500 MHz, CD3OD) 0.91e0.99 (m, 21H), 1.41e1.47 (m, 3H),
1.50e1.60 (m, 2H), 1.71e1.77 (m, 5H), 1.84e1.85 (m, 1H), 2.02e2.04
a
]25 D-6.2 (c 0.60, CH3OH). 1H NMR
24.1, 30.7, 32.2, 35.1, 37.9, 38.3, 43.1, 48.1, 51.5, 56.2, 56.7, 58.9, 59.0,
67.3, 68.1, 70.4, 72.1, 113.7, 116.2, 122.9, 123.4, 126.6, 128.8, 130.6,
135.3, 139.4, 148.6, 149.3, 149.8, 178.3. ESI-MS m/z 680.5 [MþH]þ.
d

X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
285
HRMS calcd for C39H62N5O5 [MþH]þ m/z 680.4751, found 680.4756.
73%). Purity ¼ 97.9%. [
(300 MHz, CD3OD)
a
]25 D-7.13 (c 0.30, CH3OH). 1H NMR
d
0.90e0.92 (m, 6H), 0.97 (s, 12H), 1.28e1.57 (m,
4.3.33. (2S,4S,5S,7S)-5-Amino-N-(2,2-dimethyl-3-(4-(pyridin-2-
yl)-1H-1,2,3-triazol-1-yl)propyl)-4-hydroxy-2-isopropyl-7-(4-
methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnonanamide,
hydrochloride salt (37)
7H), 1.72e1.80 (m, 4H), 2.02 (t, 2H, J ¼ 5.4 Hz), 2.43e2.51 (m, 2H),
2.60e2.70 (m, 2H), 3.12e3.24 (m, 2 H), 3.34 (s, 3H), 3.58 (t, 2H,
J ¼ 5.7 Hz), 3.84 (s, 3H), 4.07 (t, 2H, J ¼ 5.6 Hz), 4.43 (s, 2H), 5.09 (s,
1H), 6.76e6.88 (m, 3H), 8.49 (s, 1H). 13C NMR (75 MHz, CD3OD)
Following a similar procedure for the preparation of 16, 37 was
prepared starting from 37a (50 mg, 0.065 mmol). Solid (43 mg,
d 16.9, 17.9, 19.1, 19.9, 22.4, 22.5, 29.2, 29.3, 30.8, 31.4, 33.5, 36.5,
36.7, 41.3, 46.5, 49.6, 55.3, 55.4, 57.5, 59.4, 61.0, 65.9, 68.5, 68.9,
112.2, 114.7, 121.5, 125.4, 133.4, 147.9, 148.5, 149.7, 176.7. ESI-MS m/z
634.5 [MþH]þ. HRMS calcd for C34H60N5O6 [MþH]þ m/z 634.4544,
found 634.4549.
99%). Purity ¼ 97.5%. [
a
]25 D-2.00 (c 0.2, CH2Cl2). 1H NMR
(500 MHz, CD3OD) 0.89e0.91 (m, 6H), 0.99e1.02 (m, 12H),
d
1.44e1.49 (m, 1H), 1.51e1.60 (m, 2H), 1.70e1.74 (m, 3H), 1.78e1.87
(m, 1H), 1.99e2.03 (m, 2H), 2.42e2.50 (m, 2H), 2.57e2.61 (m, 1H),
2.74e2.75 (m, 1H), 3.19e3.22 (m, 2H), 3.34 (s, 3H), 3.37e3.40 (m,
1H), 3.58 (t, 2H, J ¼ 6.5 Hz), 3.79 (s, 3H), 4.06 (t, 2H, J ¼ 6.0 Hz), 4.45
(s, 2H), 6.72e6.90 (m, 3H), 7.91 (t,1H, J ¼ 6.0 Hz), 8.45e8.46 (m,1H),
8.56 (t, 1H, J ¼ 7.0 Hz), 8.75e8.76 (m, 1H), 9.10 (s, 1H). 13C NMR
4.3.37. (2S,4S,5S,7S)-5-Amino-4-hydroxy-N-(3-(4-(1-
hydroxycyclopentyl)-1H-1,2,3-triazol-1-yl)-2,2-dimethylpropyl)-2-
isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-
methylnonanamide, hydrochloride salt (41)
(125 MHz, CD3OD) d 18.3, 19.4, 20.5, 21.3, 23.9, 23.9, 30.6, 32.2, 32.8,
Following a similar procedure for the preparation of 16, 41 was
prepared starting from 41a (50 mg, 0.065 mmol). Solid (42 mg,
35.0, 38.0, 38.2, 42.8, 48.1, 48.2, 51.1, 56.7, 56.9, 58.8, 59.5, 67.3, 68.1,
69.9, 70.3, 113.7, 116.1, 122.9, 125.2, 126.6, 128.9, 134.7, 140.6, 143.3,
145.4, 147.7, 149.4, 149.9, 178.1. ESI-MS m/z 667.5 [MþH]þ. HRMS
calcd for C37H59N6O5 [MþH]þ m/z 667.4547, found 667.4550.
96%). Purity ¼ 98.3%. [
a
]25 D-9.67 (c 0.30, CH3OH). 1H NMR
(300 MHz, CD3OD) 0.84e0.88 (m, 6H), 0.94e1.00 (m, 12H),
d
1.21e1.50 (m, 4H), 1.67e1.81 (m, 6H), 1.96e2.09 (m, 8H), 2.28e2.50
(m, 4H), 3.14e3.16 (m, 2H), 3.35 (s, 3H), 3.59 (t, 2H, J ¼ 6.2 Hz), 3.80
(s, 3H), 4.08 (t, 2H, J ¼ 6.2 Hz), 4.25 (s, 2H), 6.73e6.86 (m, 3H), 7.93
4.3.34. (2S,4S,5S,7S)-5-Amino-4-hydroxy-N-(3-(4-
(s, 1H). 13C NMR (75 MHz, CD3OD)
d 17.9, 20.1, 20.8, 21.5, 23.9, 24.0,
(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-2,2-dimethylpropyl)-2-
isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-
methylnonanamide, hydrochloride salt (38)
24.5, 30.5, 30.7, 32.2, 35.2, 35.6, 37.9, 38.5, 41.9, 43.2, 48.0, 51.8, 55.5,
56.7, 58.8, 67.2, 70.4, 74.2, 79.5, 113.5, 116.0, 122.8, 124.0, 135.8,
149.1, 149.7, 155.4, 178.5. ESI-MS m/z 674.5 [MþH]þ. HRMS calcd for
Following a similar procedure for the preparation of 16, 38 was
prepared starting from 38a (70 mg, 0.097 mmol). Solid (63 mg,
C
37H64N5O6 [MþH]þ m/z 674.4857, found 674.4862.
99%). Purity ¼ 98.2%. [
a
]25 D-10.80 (c 0.40, CH3OH). 1H NMR
(300 MHz, CD3OD) 0.90e0.92 (m, 6H), 0.97 (s, 12H), 1.29e1.54 (m,
d
4.3.38. (2S,4S,5S,7S)-5-Amino-N-(3-(4-((dimethylamino)methyl)-
1H-1,2,3-triazol-1-yl)-2,2-dimethylpropyl)-4-hydroxy-2-isopropyl-
7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-
methylnonanamide, hydrochloride salt (42)
Following a similar procedure for the preparation of 16, 42 was
prepared starting from 42a (54 mg, 0.072 mmol). Solid (50 mg,
5H), 1.72e1.86 (m, 4H), 1.98e2.02 (m, 2H), 2.39e2.51 (m, 2H),
2.58e2.72 (m, 2H), 3.11e3.23 (dd, 2H, J ¼ 13.9 Hz, J ¼ 8.2 Hz), 3.34
(s, 3H), 3.59 (t, 2H, J ¼ 6.2 Hz), 3.80 (s, 3H), 4.07 (t, 2H, J ¼ 6.3 Hz),
4.40 (s, 2H), 4.47 (s, 2H), 6.76e6.88 (m, 3H), 8.38 (s, 1H). 13C NMR
(75 MHz, CD3OD)
d 18.3, 19.4, 20.5, 21.4, 23.8, 23.9, 30.7, 30.8, 32.2,
32.8, 34.9, 37.9, 38.2, 42.8, 48.0, 51.0, 55.5, 56.7, 56.9, 58.9, 60.3, 67.4,
69.9, 70.4, 113.7, 116.1, 122.9, 127.2, 134.8, 149.3, 149.4, 149.9, 171.2.
ESI-MS m/z 620.4 [MþH]þ. HRMS calcd for C33H58N5O6 [MþH]þ m/z
620.4387, found 620.4392.
99%). Purity ¼ 98.1%. [
a
]25 D-13.06 (c 0.34, CH3OH). 1H NMR
0.85 (t, 6H, J ¼ 6.2 Hz), 0.91e0.99 (m, 12H),
(300 MHz, CD3OD)
d
1.21e1.36 (m, 5H), 1.64e1.84 (m, 4H), 1.97e2.06 (m, 2H), 2.26 (s,
7H), 2.39e2.51 (m, 3H), 3.08e3.20 (m, 3H), 3.34 (s, 3H), 3.58 (t, 2H,
J ¼ 6.2 Hz), 3.79 (s, 3H), 4.06 (t, 2H, J ¼ 6.3 Hz), 4.27 (s, 2H),
4.3.35. (2S,4S,5S,7S)-5-Amino-4-hydroxy-N-(3-(4-(2-
hydroxyethyl)-1H-1,2,3-triazol-1-yl)-2,2- dimethylpropyl)-2-
isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-
methylnonanamide, hydrochloride salt (39)
6.72e6.85 (m, 3H), 8.01 (s, 1H). 13C NMR (75 MHz, CD3OD)
d 16.5,
18.7, 19.3, 20.0, 22.4, 22.5, 29.0, 29.2, 30.7, 33.7, 34.2, 36.5, 37.1, 41.8,
43.4, 46.6, 50.4, 52.8, 54.0, 55.2, 57.5, 65.8, 68.9, 72.3, 112.0, 114.6,
121.4, 125.4, 134.4, 142.8, 147.7, 148.3, 177.1. ESI-MS m/z 647.5
[MþH]þ. HRMS calcd for C35H63N6O5 [MþH]þ m/z 647.4860, found
647.4865.
Following a similar procedure for the preparation of 16, 39 was
prepared starting from 39a (45 mg, 0.062 mmol). Solid (39 mg,
99%). Purity ¼ 99.5%. [
a
]25 D-5.8 (c 0.15, CH3OH). 1H NMR
(500 MHz, CD3OD) 0.76e0.90 (m, 18H), 1.18e1.23 (m, 1H),
d
1.28e1.50 (m, 3H), 1.60e1.80 (m, 4H), 1.86e1.96 (m, 2H), 2.28e2.40
(m, 2H), 2.48e2.55 (m, 1H), 2.58e2.65 (m, 1H), 2.82e2.92 (m, 2H),
3.00e3.12 (m, 2H), 3.20e3.22 (m, 2H), 3.23 (s, 3H), 3.58 (t, 2H,
J ¼ 6.5 Hz), 3.70 (s, 3H), 4.06 (t, 2H, J ¼ 6.0 Hz), 4.20e4.35 (m, 2H),
6.63e6.70 (m, 1H), 6.72e6.80 (m, 2H), 8.24 (s, 1H). 13C NMR
4.3.39. (2S,4S,5S,7S)-5-Amino-N-(3-(4-((diethylamino)methyl)-
1H-1,2,3-triazol-1-yl)-2,2-dimethylpropyl)-4-hydroxy-2-isopropyl-
7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-
methylnonanamide, hydrochloride salt (43)
Following a similar procedure for the preparation of 16, 43 was
prepared starting from 43a (30 mg, 0.038 mmol). Solid (26 mg,
(75 MHz, CD3OD)
d 16.0, 18.1, 18.8, 19.5, 22.0, 22.1, 27.9, 28.6, 28.7,
30.2, 33.5, 41.3, 46.1, 49.8, 53.7, 54.7, 56.9, 60.2, 65.3, 68.5, 72.1,111.6,
114.1, 120.9, 123.6, 133.9, 143.9, 147.2, 147.8, 176.5. ESI-MS m/z 634.5
[MþH]þ. HRMS calcd for C34H60N5O6 [MþH]þ m/z 634.4544, found
634.4546.
99%). Purity ¼ 99.4%. [
a
]25 D-5.0 (c 0.2, CH2Cl2). 1H NMR (300 MHz,
CD3OD) 0.87e0.99 (m, 18H), 1.25e1.28 (m, 1H), 1.39e1.40 (m, 8H),
d
1.49e1.55 (m, 3H), 1.72e1.80 (m, 4H), 2.00e2.04 (m, 2H), 2.38e2.43
(m, 2H), 2.58e2.65 (m, 1H), 2.70e2.75 (m, 1H), 3.11e3.24 (m, 4H),
3.34 (s, 3H), 3.58 (t, 2H, J ¼ 6.0 Hz), 3.80 (s, 3H), 4.07 (t, 2H,
J ¼ 6.6 Hz), 4.25e4.40 (m, 2H), 4.45e4.55 (m, 2H), 6.75e6.89 (m,
4.3.36. (2S,4S,5S,7S)-5-Amino-4-hydroxy-N-(3-(4-(1-
hydroxyethyl)-1H-1,2,3-triazol-1-yl)-2,2- dimethylpropyl)-2-
isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-
methylnonanamide, hydrochloride salt (40)
Following a similar procedure for the preparation of 16, 40 was
prepared starting from 40a (42 mg, 0.057 mmol). Solid (28 mg,
3H), 8.41 (s, 1H). 13C NMR (75 MHz, CD3OD)
d 9.5, 18.4, 19.3, 20.5,
21.4, 23.9, 24.0, 30.7, 30.8, 32.1, 32.9, 34.9, 37.9, 38.1, 42.8, 46.9, 51.0,
56.7, 56.9, 58.9, 59.3, 67.4, 69.9, 70.4, 113.8, 116.3, 122.9, 129.7, 134.8,
137.2, 149.5, 149.9, 178.0. ESI-MS m/z 673.5 [M-H]-. HRMS calcd for
C
37H65N6O5 [M-H]- m/z 673.5016, found 673.5018.

286
X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
4.3.40. (2S,4S,5S,7S)-5-Amino-N-(3-(4-((diisopropylamino)
methyl)-1H-1,2,3-triazol-1-yl)-2,2- dimethylpropyl)-4-hydroxy-2-
isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-
methylnonanamide, hydrochloride salt (44)
Following a similar procedure for the preparation of 16, 44 was
prepared starting from 44a (57 mg, 0.071 mmol). Solid was ob-
rennin solution; 3) positive controls containing 3
buffer and 10 L of the human recombinant rennin solution; 4)
substrate controls containing 13 L of the assay buffer. The plate
was incubated for 30 min at 37 ꢂC. Meanwhile, the rennin substrate
solution (20
M) was pre-incubated at 37 ꢂC. Into each well was
added 17 L of the pre-incubated rennin substrate solution to
mL of the assay
m
m
m
m
tained (50 mg, 95%). Purity ¼ 96.7%. [
a
]25 D-9.94 (c 0.31, CH3OH).
initiate the enzymatic reaction. The plate was gently shaked for no
more than 30 s to mix the reagents completely and incubated for
15 min at 37 ꢂC. The fluorescence intensity for each well was
measured at Ex/Em ¼ 490 nm/520 nm and expressed in relative
fluorescence units (RFU) with the fluorescence intensity of sub-
strate controls as the background. The IC50 values were determined
by using non-linear regression analysis.
1H NMR (300 MHz, CD3OD)
d
0.90e0.99 (m, 18H), 1.45e1.55 (m,
16H), 1.72e1.80 (m, 4H), 2.00e2.04 (m, 2H), 2.41e2.51 (m, 2H),
2.58e2.63 (m, 1H), 2.70 (s, 1H), 3.10e3.23 (m, 2H), 3.35 (s, 3H), 3.59
(t, 2H, J ¼ 6.2 Hz), 3.79 (s, 3H), 3.84e3.86 (m, 2H), 4.08 (t, 2H,
J ¼ 6.2 Hz), 4.34 (s, 2H), 4.53 (s, 2H), 6.76e6.89 (m, 3H), 8.39 (s, 1H).
13C NMR (75 MHz, CD3OD)
d 16.4, 16.9, 17.6, 17.9, 19.1, 19.9, 22.5,
22.6, 29.2, 29.3, 30.7, 32.4, 33.6, 36.5, 36.7, 41.3, 46.6, 49.7, 55.2, 55.3,
55.4, 57.4, 57.7, 65.9, 68.5, 68.9, 112.2, 114.6, 121.5, 127.4, 133.3,137.9,
148.0, 148.5, 176.6. ESI-MS m/z 703.5 [MþH]þ. HRMS calcd for
In similar fashions, the inhibitory activity of 39 against the hu-
man rennin (Anaspec, catalog 72040), cathepsin D (Enzo, catalog
SE199-0025) and cathepsin E (R&D, catalog 1294-AS-010) was
assayed.
C
39H71N6O5 [MþH]þ m/z 703.5486, found 703.5492.
4.3.41. (2S,4S,5S,7S)-5-Amino-N-(2,2-dimethyl-3-(4-(piperidin-1-
ylmethyl)-1H-1,2,3-triazol-1-yl)propyl)-4-hydroxy-2-isopropyl-7-
(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnonanamide,
hydrochloride salt (45)
4.5. In vivo evaluation
Male and female hypertensive dTGMs (19e26 g, >20 weeks)
carrying both human angiotensinogen (hAOGEN) and human renin
(hREN) genes were randomly divided into two groups: group of
compound 1 (n ¼ 7) and group of compounds 39 (n ¼ 7). The mean
arterial pressure (MAP) of animals was measured using a pro-
grammable sphygmomanometer BP-98A (Softron, Tokyo, Japan) by
the tail-cuff method. Baseline values were recorded for 24 h prior to
administration of vehicle (physiological saline). Following vehicle
oral administration, mice MAP values were monitored for 24 h.
After a rest of two days, mice were then administrated orally by
Following a similar procedure for the preparation of 16, 45 was
prepared starting from 45a (56 mg, 0.072 mmol). Solid (49 mg,
99%). Purity ¼ 95.4%. [
a
]25 D-14.0 (c 0.2, CH2Cl2). 1H NMR
(500 MHz, CD3OD) 0.82e0.88 (m, 18H), 1.25e1.27 (m, 1H),
d
1.32e1.37 (m, 2H), 1.46e1.50 (m, 3H), 1.64e1.73 (m, 5H), 1.85e1.93
(m, 4H), 2.31e2.39 (m, 2H), 2.51e2.63 (m, 2H), 2.93e3.11 (m, 4H),
3.25 (s, 3H), 3.35e3.45 (m, 3H), 3.49 (m, 2H), 3.71 (s, 3H), 3.98 (m,
2H), 4.20e4.30 (m, 2H), 4.30e4.40 (m, 2H), 6.67e6.79 (m, 3H), 8.30
(s, 1H). 13C NMR (125 MHz, CD3OD)
d
7.9, 18.4, 19.3, 20.5, 21.4, 22.6,
gavages with 1 or 39 at doses of 8.5, 17.0 and 34.0 mmol/kg,
24.0, 24.1, 24.2, 30.6, 30.7, 32.1, 32.8, 35.0, 37.9, 38.1, 42.7, 48.2, 51.1,
52.2, 53.8, 54.3, 56.7, 56.8, 58.9, 59.4, 67.4, 69.5, 70.4, 113.7, 116.2,
122.9, 130.0, 134.7, 137.3, 149.4, 149.9, 178.1. ESI-MS m/z 685.5 [M-
H]-. HRMS calcd for C38H65N6O5 [M-H]- m/z 685.5016, found
685.5018.
respectively, and animals were also monitored for a further 24 h
post-dose. The experimental interval of each dose is two days. The
MAP values are reported as changes from the corresponding time-
matched baseline values per hour.
4.6. Molecular dynamic modeling
4.3.42. (2S,4S,5S,7S)-5-Amino-N-(2,2-dimethyl-3-(4-
(morpholinomethyl)-1H-1,2,3-triazol-1-yl)propyl)-4- hydroxy-2-
isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-
methylnonanamide, hydrochloride salt (46)
Following a similar procedure for the preparation of 16, 46 was
prepared starting from 46a (70 mg, 0.089 mmol). Solid (63 mg,
The conformational search was performed in MOE software
(version 2012.10, Chemical Computing Group Inc., Montreal, QC,
Canada) under the MMFF94x force field. Aliskiren in the complex
structure (PDB code: 2V0Z) was modified to 4 and 39, and pro-
tonated at pH 7.0. The stochastic method was used to explore
conformation space to find reasonable conformations. With re-
98%). Purity ¼ 99.1%. [
a
]23 D-3.35 (c 0.62, CH3OH). 1H NMR
0.93 (t, 6H, J ¼ 6.2 Hz), 1.00e1.04 (m, 12H),
0
(300 MHz, CD3OD)
d
straint on the renin0 protein and the P3eP1 portions of the in-
0
1.36e1.57 (m, 4H), 1.74e1.86 (m, 4H), 2.06e2.10 (m, 3H), 2.25e2.75
(m, 8H), 3.16e3.27 (m, 3H), 3.41 (s, 3H), 3.65 (t, 2H, J ¼ 6.1 Hz), 3.74
(s, 4H), 3.87 (s, 3H), 4.14 (t, 2H, J ¼ 6.1 Hz), 4.34 (s, 2H), 6.79e6.89
hibitors, only the P2 eP3 portions were submitted to stochastic
conformational search. To obtain conformations with lowest en-
ergy, further conformational search was performed by the Low-
ModeMD method. Rejection limit and iteration limit were set to
100 and 10,000 with maximum energy minimization iteration at
500, respectively. The conformation with the lowest energy for
each compound was chosen for further studies.
The complex structures were refined via molecular dynamic
simulation in Amber software (version 9). The force field parame-
ters of ligands derived from GAFF force field with BCC charges were
obtained by Antechamber module. The AMBER FF03 force field
parameters were applied. Each complex model was soaked into a
periodic box of TIP3P water with a margin of 10 Å for each
dimension and then Naþ ion was added to neutralize the whole
systems. During simulation, Partical Mesh Ewald (PME) with 10 Å
cutoff was employed in the computation of electrostatic in-
teractions. The Langevin thermostat with a collision frequency of
2 psꢃ1 and isotropic position scaling barostat with a pressure
relaxation time of 2 ps were used. The SHAKE algorithm was used
to constrain all covalent bonds connecting hydrogen atoms.
(m, 3H), 8.10 (s, 1H). 13C NMR (75 MHz, CD3OD)
d 17.9, 20.1, 20.8,
21.5, 23.9, 24.0, 30.5, 30.7, 32.2, 35.2, 35.7, 38.0, 38.5, 43.3, 48.0, 51.8,
53.9, 54.2, 55.5, 56.7, 58.9, 67.3, 67.6, 70.4, 74.3, 84.5, 113.5, 116.1,
122.8, 126.9, 135.9, 144.0, 149.7, 178.5. ESI-MS m/z 689.5 [MþH]þ.
HRMS calcd for C37H65N6O6 [MþH]þ m/z 689.4966, found 689.4972.
4.4. In vitro assay
The inhibitory activity of test compounds against the human
recombinant rennin was measured by using the Sensolyte® 520
Renin Assay Kits. Into microplate wells were added 3
compound solutions (100 nM, 20 nM, 4 nM, 0.8 nM and 0.16 nM)
and 10 L of the human recombinant rennin solution. At the same
time, the following controls were set up: 1) inhibitor controls
containing 3 L of the Ac-HPFV-(Sta)-LF-NH2 solution (10 M) and
10 L of the human recombinant rennin solution; 2) vehicle con-
trols containing 3 L of vehicle and 10 L of the human recombinant
mL of the test
m
m
m
m
m
m

X. Sun et al. / European Journal of Medicinal Chemistry 103 (2015) 269e288
once daily dosing in marmosets, J. Med. Chem. 50 (2007) 4832e4844.
287
The systems were firstly minimized by 500 steps via the
steepest descent method and 500 steps via the conjugate gradient
method with 5 kcal/mol$Å2 restraint on the complexes. Similar
1000-step minimization was performed without restraint on the
complexes. Then, the models with restraint were heated from 0 K to
300 K within 50 ps and maintained at 300 K for 50 ps by the NVT
method. The systems were further equipoised over 500 ps without
any restraint by the NPT method and finally run a 5 ns simulation at
a constant temperature of 300 K and under a constant pressure of
1 atm. The snapshots with the lowest RMSD to the average struc-
tures in MD were retrieved from the simulation trajectories. The
complexes after MD simulation were further subjected to a round
of energy minimization in MOE, and then taken as the final models.
To validate the computational method, the renin-aliskiren
complex structure (PDB code: 2V0Z) was refined by MD simula-
tion. The final model gave a RMSD 1.4 Å to the alpha-carbon of
protein and the interactions between the ligand and the protein
kept well during the MD simulations, indicating that the MD
simulation could help to refine the modeling structure for the
designed inhibitors.
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This project was financially supported by the “111 Project” from
the Ministry of Education of China, the State Administration of
Foreign Expert Affairs of China (No. 111-2-07), Program for
Changjiang Scholars and Innovative Research Team in University
(IRT1193), Changjiang Scholars Program of China (No. 02410601)
and the Priority Academic Program Development of Jiangsu Higher
Education Institutions. We thank Zhixiong Zhao from the State Key
Laboratory of Bioorganic & Natural Products Chemistry at Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, for his
help in molecular modeling computation.
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Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
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