Synthesis of isoquinolinone-based tricycles as novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2014.04.061

The isoquinolinone-based tricyclic compounds were designed and synthesized. Preliminary biological study of these compounds provided potent compounds 17a, 33b, 33c, 33d, and 33g with low nanomolar IC₅₀s against PARP-1 enzyme.

Full text of DOI:10.1016/j.bmcl.2014.04.061

Accepted Manuscript
Synthesis of isoquinolinone-based tricycles as novel poly(ADP-ribosyl) poly-
merase-1 (PARP-1) inhibitors
Jianyang Chen, Haixia Peng, Jinxue He, Xiajuan Huan, Zehong Miao, Chunhao
Yang
PII:
S0960-894X(14)00409-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.04.061
BMCL 21554
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 February 2014
3 April 2014
16 April 2014
Please cite this article as: Chen, J., Peng, H., He, J., Huan, X., Miao, Z., Yang, C., Synthesis of isoquinolinone-based
tricycles as novel poly(ADP-ribosyl) polymerase-1 (PARP-1) inhibitors, Bioorganic & Medicinal Chemistry
Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.2014.04.061
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Synthesis of isoquinolinone-based
tricycles as novel poly(ADP-ribosyl) polymerase-1
(PARP-1) inhibitors
Jianyang Chen, Haixia Peng, Jinxue He, Xiajuan Huan, Zehong Miao,* and Chunhao Yang*
1

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
Synthesis of isoquinolinone-based tricycles as novel poly(ADP-ribosyl)
polymerase-1 (PARP-1) inhibitors
Jianyang Chen a, Haixia Peng a, Jinxue He b, Xiajuan Huan b, Zehong Miao b,*, and Chunhao Yang a,*
aDepartment of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555
5 Zuchongzhi Road, Shanghai, 201203, P.R. China.
bDivision of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555
Zuchongzhi Road, Shanghai, 201203, P.R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
The isoquinolinone-based tricyclic compounds were designed and synthesized. Preliminary
biological study of these compounds provided potent compound 17a, 33b, 33c, 33d, 33g with
low nanomolar IC50s against PARP-1 enzyme.
Revised
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Isoquinolinone-based tricycles
PARP-1 inhibitors
antitumor
10
Poly(ADP-ribose) polymerase-1 (PARP-1) is the most
single-agent therapy to kill tumors with mutation in BRCA1- and
abundant and best-characterized member of the PARP family of 35 BRCA2-dependent DNA double stranded repair mechanisms
nuclear enzymes, with an important role in the cellular life
cycle.1 It is involved in various cellular processes including DNA
repair, telomere regulation, transcription, genomic stability and
(homologous recombination HR).5 More than half-a-dozen of
PARP-1 inhibitors are being pursued into different stages of
clinical trials, including AZD2281 (olaparib),6 BMN673,7 MK-
4827 (Niraparib),8 and AG014699 (Rucaparib)9 (1-4, Fig.1).
15 regulation of cell death. It is widely accepted that the catalytic
activity of PARP-1 is stimulated by DNA damage caused by
peroxidation, irradiation and DNA-damaging chemicals, for
example, chemotherapeutic agent.2 During poly(ADP)
ribosylation (PARylation), PARP-1 can utilize NAD+ as the
20 substrate to construct polymers of ADP-ribose on histones and
other nuclear acceptor proteins including the auto-modification
domain of PARP-1 itself. The negatively charged PARylated
nuclear target proteins cause chromatin decondensation and
dynamic nucleosome remodeling that tend to increase the
25 accessibility of base excision repair (BER) proteins such as
XRCC1, DNA ligase III and DNA polymerase β (pol β) to
damaged DNA, resulting in repair.3
40
Figure. 1 PARP-1 inhibitors.
Most currently available structure of PARP-1 inhibitors is
based on the benzamide as pharmacophore, which mimics the
substrate-protein interaction of NAD+ with PARP-1. Early
45 PARP-1 inhibitors are structurally analogous of 3-amino-
benzamide (5, Fig.1,).10 The rest majority of PARP-1 inhibitors
are bicyclic or polycyclic scaffolds where the key carboxamido
In view of the key role of the PARP-1 in maintaining the
genomic integrity, particularly in the repair of single-strand DNA
30 lesions which caused by ionizing radiation, chemotherapy, or
products of cellular and oxidative metabolism, PARP-1 has
emerged as an attractive anticancer drug target.4 Another major
breakthrough highlights that PARP-1 inhibitors can be used as
———
moiety is restricted into a ring system to form a lactam (6-7,
Fig.1).9,
11
The key interactions between these inhibitors and
* Corresponding authors. For C.Yang: Tel./fax: +86 21 50806770; e-mail: chyang@simm.ac.cn.
For Z.Miao.: Tel./fax: +86 21 50806820; e-mail: zhmiao@simm.ac.cn.
2

PARP-1 include the H-bonding networks formed between the
carboxamido component and Ser 904 and Gly 863 of PARP-1,
and the π-π stacking between the aryl ring and Tyr 907.
Meanwhile, these inhibitors should have a large hydrophobic
group that can access the adenosine site of the PARP-1 active
site.12
5
Scheme 1. : a) CH3I, K2CO3, acetone, r.t., 94%; b) Pd/C, H2, r.t., 62%; c) o-bromobenzoic acid, SOCl2, THF, 50%; d) NaH, BOMCl, DMF, 88%; e) Pd(PPh3)4,
KOAc, DMF, 110 ℃, 60%; f) BBr3, toluene, -15 ℃, 50%; g) 3N NaOH, r.t., 80 %; h) SOCl2, amine, THF, 40- 90%; i) NBS or NCS, acetone, 80 ℃, M.W., 30%.
10
.
Scheme 2. : a) ClSO2NCO, DMF, acetonitrile, 35%; b) 60 % NaH, DMF, CH3I, 78%; c) Raney Ni, Ammonium Hydroxide, H2, 55%; d) o-bromobenzoyl
chloride, DIPEA, acetonitrile, 69%; e) EOMCl, NaH, DMF, 80%; f) Pd(OAc)2, PPh3, KOAc, DMAc, 150 ℃, N2, 74%; g) i. 1 N HCl, dioxane, 80 ℃, 74% ; ii.
NaOH, EtOH: H2O = 4: 1, reflux, 80%; h) amine, HOBt, EDCI, DIPEA, DCM, 40-70%.
15 Scheme 3. a) Pd(OAc)2, Ag2CO3, PCy3, Dioxane: DMSO = 17: 3, 62%; b) Ac2O, HNO3, 45%; c) Fe, con. HCl, 74%; d) i. NaOH, EtOH+H2O; ii. amine, HOBt,
EDCI, DIPEA, DMF, 50-60%.
Our laboratory has been working on the project aiming at 17a. Replacement of methyl substituent with bulkier alkyls, such
developing high potent, low toxicity PARP-1 inhibitors. Herein, 45 as i-propyl compound 17c and benzyl derivative 17d displayed a
20 we describe the synthesis, SAR study and preliminary biological
evaluation of a novel series of isoquinolinone-based tricycles 8.
We took 5-membered heterocycle ring (pyrrole or thiophene)
instead of phenyl ring (6) and pyrazole (7). Considering the poor
significant drop in PARP-1 potency. Interestingly, the electron-
donating group (methoxyl group, 17e) was tolerated for PARP-1
activity, displaying IC50 = 0.4 µМ, while the electron-
withdrawing group (nitro group, 17f) was inactive (IC50 > 10
solubility of the tricyclic compounds in both organic and aqueous 50 µМ). Both the sulfonyl substitution and 1,4-diazepane derivatives
25 solvents owing to its planarity, we speculated that introducing
basic amino functional group into the ortho-position of 5-
membered ring might be a good choice.
showed a less potent activity (IC50 ranging from 0.1 to 0.6 µМ ,
17g-i). Aliphatic derivatives 17k-l showed only moderate
potency, while 17j was 10-fold less active, indicating that the
three-carbon length between the amide nitrogen and the basic
55 nitrogen was better than two-carbon length. Compounds 18a-b,
in which halogen Cl/Br was introduced to the 3-position of 8,
almost have the same potency as the unhalogenated compound
17i.
To verify the hypothesis, the first class of tricycles containing
pyrrole ring were synthesized outlined in Scheme 1.13
30 Methylation and hydrogenation of methyl 4-nitro-1H-pyrrole-2-
carboxylate 9 provided corresponding amine 11 in 58% yield,
which was further coupled with o-bromobenzoyl chloride to
obtain 12 in 50% yield. Protection by BOMCl of amide 12 and
Reported literature showed that tricycles containing [5,6,7]
intra-molecular cylization of 13 afforded the tricycles 14 in 53% 60 system would exhibit the most favorable physical properties
35 yield. Deprotection and hydrolysis of 14 provided corresponding
acid 16 in 40% yield. Amides 17a-l were prepared by
condensation of 16 and different amines in 40-90% yields and
18a-b were prepared by halogenation of 17i in microwave
(solubility) and still maintain the potency targeting PARP-1.9 So
we further designed and synthesized a series of tricycle structure:
4,5-dihydrobenzo[c]pyrrolo[2,3-e]azepin-6(1H)-one, outlined in
Scheme 2.14 Cyanidation of pyrrole 19 afforded 20 and its
condition in 30% yield. All compounds were tested in the PARP- 65 regiomer methyl 5-cyano-1H-pyrrole-2-carboxylate in 1:1 ratio
40 1 enzyme assay shown in Table 1. To our delight, piperazine
derivative 17a showed good activity (IC50 = 0.044 µМ)
comparable to 6 (IC50 = 0.52 µМ)11c. Methyl substituted
piperazine 17b provided a 2.7-fold less potency with respect to
in 35% yield. Amide 23 was prepared by condensation of amine
22 and o-bromobenzoyl chloride in 69% yield. Protection of 23
and intra-molecular cyclization of 24 afforded tricycle 25 in 55%
yield. Deprotection and hydrolysis of 25 provided corresponding
3

acid 26 in 56% yield, which was further condensed with amines
to obtain the corresponding amides 27a-e in 40-70% yields. As
shown in Table 2, most compounds 27a-e caused an obvious
drop in activity compared to 17a. The detrimental effect of
synthesized and outlined in Scheme 3.15 Pd-catalyzed oxidative
cross-coupling of methyl 2-iodobenzoate 28 and methyl 3-
methylthiophene-2-carboxylate 29 provided 30 in 62% yield.
Nitration of 30 afforded nitro compound 31 in 45% yield.
5
expanding the ring size of the isoquinolinone was even more 25 Tricycle 32 was prepared by hydrogenation of 31 in 74% yield.
evident that produced 27a, 27d with an IC50 > 10 µМ.
Amides 33 a-h were prepared by condensation of corresponding
acid and amines in 50-60% yields.
Table 1. PARP-1 Enzymatic Assays of Compounds 17a-l and
18a-ba
Table 2. PARP-1 Enzymatic Assays of Compounds 27a-e a
O
O
NH
X
NH
R3
N
N
O
O
R4
X
H
R3
IC50 ( M)b
0.044
Compd
17a
b
Compd
R4
IC50
(
)
NH
N
N
N
N
27a
27b
>10
N
N
17b
17c
H
H
0.119
0.83
6.429
N
F
N
27c
27d
1.673
10
N
N
N
17d
17e
H
H
0.86
0.4
N
N
N
O
N
N
N
27e
8.167
0.006
N
N
H
17f
H
H
>10
0.6
N
NO2
1. AZD2281
O
S
O
17g
N
30
a,bSee the footnotes in table 1,
N
Table 3. PARP-1 Enzymatic Assays of Compounds 33a-h a
17h
H
0.1
0.2
NH
H
N
N
R5
O
N
S
O
17i
17j
H
H
N
b
R5
Compd
33a
IC50
(
)
N
1.1
0.3
N
H
N
0.231
H
N
17k
17l
H
H
N
N
N
N
33b
33c
0.079
0.086
O
H
0.1
0.1
0.1
N
N
N
N
N
N
18a
Cl
Br
N
N
N
33d
33e
0.029
0.133
18b
N
F
1. AZD2281
0.006
N
(0.005c)
H
N
a
N
10
IC50s were calculated by Logit method from the results with
six concentrations each (standard deviations were within 25% of
the mean values).
33f
0.284
0.083
N
H
N
N
33g
O
b The assays were performed as described in Ref. 11a.
c. data from Ref 6.
H
N
33h
0.248
0.006
N
1. AZD2281
15
Based on the above disappointing results, we think keeping
the planarity of the tricyclic ring is important to maintain the
potency. So we envisaged the possibility to replace the pyrrole
ring by thiophene ring in order to increase the electron density of
the tricycle scaffold for improving the π-π stacking between the
a,b See the footnotes in Table 1.
As shown in Table 3, most compounds displayed high
35 potency with IC50 ranging from 0.029 to 0.284 µМ. Compound
33a containing methyl substituent showed moderated potency
20 aryl ring and Tyr 907. This series of compounds were
4

55 Chambon and G. de Murcia, Proceedings of the National Academy of
Sciences, 1997, 94, 7303; (b) C. Szabo, B. Zingarelli, M. O'Connor and A. L.
SALzMAN, Proceedings of the National Academy of Sciences, 1996, 93,
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(IC50 = 0.231 µМ). Replacement of methyl group with bulkier
alkyl, such as ethyl derivative 33b and i-propyl product 33c,
displayed a 3-fold more potent compared to 33a, and equipotent
to 17a. A further improvement in activity was achieved with
N,N-dimethylpiperidin-4-amine derivative 33d (IC50 = 0.029 µМ)
as the most potent compound., presumably due to a beneficial
interaction of the amine with the adenosine binding site of
PARP-1. Arylated piperidine 33e displayed a drop in PARP-1
potency (IC50 = 0.133 µМ). Aliphatic derivatives 33f, 33h
10 showed moderate activity while 33g containing morpholine as
basic nitrogen displayed nanomolar potency (IC50 = 0.083 µМ).
From the results above, some compounds with IC50 values lower
than 0.100 µM were further evaluated for their inhibition on cell
proliferation (as shown in Table 4). Unfortunately, these
15 compounds showed no proliferation inhibition to the BRCA2-
deficient V-C8 cells (CC50 > 10 µМ). However, these compounds
were further evaluated in human breast cancer MDA-MB-436
cells carrying natural BRCA1 mutation. Both 17h and 33b
showed moderate potency against the BRCA1-deficient MDA-
20 MB-436 cells, whereas 33c and 33d were inactive in both lines.
3 F. Dantzer, G. de la Rubia, J. Ménissier-de Murcia, Z. Hostomsky, G. de
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R. N. Mansour, K. E. Zhang, A. Ekker, C. R. Calabrese, N. J. Curtin, S. Kyle,
80 H. D. Thomas, L.-Z. Wang, A. H. Calvert, B. T. Golding, R. J. Griffin, D. R.
Newell, S. E. Webber and Z. Hostomsky, J. Med. Chem., 2002, 45, 4961.
10 M. Banasik and K. Ueda, Mol. Cell Biochem., 1994, 138, 185.
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Q. Liu, Y. Chen, J. Ding, Y. Xu, Z.-H. Miao and A. Zhang, J. Med. Chem.,
85 2013, 56, 2885; (b) F. Orvieto, D. Branca, C. Giomini, P. Jones, U. Koch, J.
M. Ontoria, M. C. Palumbi, M. Rowley, C. Toniatti and E. Muraglia, Bioorg.
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Table 4. Cell Proliferation Inhibition of Compounds on
BRCA1 and BRCA2 Deficient Cellsa,b
90 12 D. V. Ferraris, J. Med. Chem., 2010, 53, 4561.
13 Analytical data for selected final compound 17a: 1H NMR (300 MHz,
CD3OD) δ: 8.46 (d, J = 8.1 Hz, 1H), 8.28 (d, J = 8.1 Hz, 1H), 7.84 - 7.78 (m,
1H), 7.54 - 7.48 (m, 1H), 6.33 (s, 1H), 4.12(s, 3H), 3.72 (t, J = 4.5 Hz, 4H),
3.01 (s, 1H), 2.90 (t, J = 4.5 Hz, 4H); 13C NMR (125 MHz, DMSO-d6) δ
95 161.77, 160.91, 132.90, 130.68, 130.04, 129.38, 126.44, 125.12, 124.22,
120.71, 116.12, 96.30, 46.10, 35.71. LC-MS [ESI]: m/z 311.2 [M+H]+. 17b:
1H NMR (300 MHz, CD3OD) δ: 8.46 (d, J = 8.1 Hz, 1H), 8.30 (d, J = 8.7 Hz,
1H), 7.84 - 7.78 (m, 1H), 7.54 - 7.48 (m, 1H), 6.34 (s, 1H), 4.12 (s, 3H), 3.77
(m, 4H), 2.51 (m, 4H), 2.35 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ
100 161.31, 160.45, 132.43, 130.00, 129.55, 128.92, 125.95, 124.70, 123.80,
120.27, 115.80, 96.05, 54.58, 45.56, 35.27. LC-MS [ESI]: m/z 325.2 [M+H]+.
18a: 1H NMR (300 MHz, DMSO-d6) δ: 11.59 (s, 1H), 8.36 (d, J = 8.2 Hz,
1H), 8.21 (d, J = 8.2 Hz, 1H), 7.88 - 7.81 (m, 1H), 7.59 - 7.52 (m, 1H), 4.01
(s, 3H), 3.85 - 3.80 (m, 1H), 3.72 - 3.65 (m, 3H), 3.53 - 3.48 (m, 2H), 3.08 -
105 3.02 (m, 2H), 2.73 (s, 3H), 2.15 - 2.00 (m, 2H); 13C NMR (125 MHz, DMSO-
d6) δ 161.78, 161.31, 133.21, 129.56, 129.43, 125.76, 125.71, 125.42, 124.36,
123.89, 120.98, 115.41, 57.61, 56.45, 55.72, 47.85, 45.39, 36.92, 25.91. LC-
MS [ESI]: m/z, 317.1 [M+H]+, 319.1 [M+3H]+. 18b: white solid 1H NMR
(300 MHz, CD3OD) δ: 8.46 (d, J = 8.1 Hz, 1H), 8.32 - 8.29 (m, 1H), 7.88 -
110 7.81 (m, 1H), 7.59 - 7.52 (m, 1H), 4.12 (s, 3H), 4.00-3.95 (m, 1H), 3.80-3.74
(m, 1H), 3.60 - 3.40 (m, 6H), 3.00 (s, 3H), 2.92-2.90 (m, 2H). 13C NMR (125
MHz, DMSO-d6) δ 161.78, 161.31, 134.21, 130.56, 129.43, 125.76, 125.71,
125.42, 124.36, 123.89, 120.98, 115.41, 56.91, 56.05, 55.22, 46.85, 44.99,
36.52, 24.91. LC-MS [ESI]: m/z, 373.2 [M+H]+, 375.2 [M+3H]+.
a
Cytotoxic effect (CC50) means the concentration required to
25 reduce cell proliferation and growth by 50%. Values were
calculated by Logit method from the results with six
concentrations each (standard deviations were within 25% of the
mean values).
b The assays were performed as described in Ref. 11a
30
In summary, we reported the synthesis and biological
evaluation of novel isoquinolinone-based tricycles as PARP-1
inhibitors. Preliminary SAR study of isoquinolinone-based
tricycles containing pyrrole ring identified submicromolar
inhibitor 17a (IC50 = 44 nМ). Enlarging the ring system was not
35 tolerated. Further structural modification lead to a novel class of
thieno[3,2-c]isoquinolin-5(4H)-one scaffold, which provided
nanomolar PARP-1 inhibiors. Compound 33b, 33c, 33d and 33g
displayed IC50 values of 79, 86, 29 and 83 nM, respectively.
Although these compounds showed lower potency against the
40 BRCA2-deficient V-C8 cells and BRCA1-deficient MDA-MB-
436 cells than AZD-2281, they provided a clue to design novel
PARP1 inhibitors.
1
115 14 Analytical data for selected final compound 27a: H NMR (300 MHz,
CDCl3) δ:8.01 (dd, J = 6.3, 1.9Hz, 1H), 7.59 - 7.51 (m, 1H), 7.46 - 7.39 (m,
2H), 7.18 (t, J = 6.4Hz, 1H, CONH), 6.25 (s, 1H), 4.00 - 3.72 (m, 4H), 3.79 (s,
3H), 3.60 - 3.54 (m, 1H, CONH-CH2), 3.42 - 3.36 (m, 1H, CONH-CH2), 2.48
(m, 4H), 2.36 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 162.69, 160.78, 134.26,
120 134.20, 131.51, 130.53, 128.40, 127.43, 127.40, 127.31, 123.30, 109.33,
55.15, 45.94, 37.83, 34.89, 29.70. LC-MS [ESI]: m/z, 325.2 [M+H]+. 27b: 1H
NMR (300 MHz, CDCl3) δ: 8.00 (d, J = 8.0 Hz, 1H), 7.59 - 7.50 (m, 1H),
7.41 (dd, J = 11.6, 4.4 Hz, 2H), 7.29 (t, J = 6.4 Hz, 1H, CONH), 6.25 (s, 1H),
4.60-4.52 (m, 2H), 3.94 - 3.88 (m, 2H), 3.78 (s, 3H), 3.04 - 2.90 (m, 2H), 2.60
125 - 2.54 (m, 1H), 2.39 (s, 6H), 1.52 - 1.35 (m, 4H); 13C NMR (125 MHz, CDCl3)
δ 162.69, 160.78, 134.26, 134.20, 131.51, 130.53, 128.40, 127.43, 127.40,
127.31, 123.30, 109.33, 71.72, 42.80, 42.10, 34.90, 29.71, 27.40. LC-MS
[ESI]: m/z, 353.2 [M+H]+.
Acknowledgments
This work was supported by National Science & Technology
45 Major Project “Key New Drug Creation and Manufacturing
Program” 2012ZX09301001-001, 2012ZX09103101-071 and the
National Natural Science Foundation of China (21072205 and
81025020) and SIMM1203ZZ-0103.
References and notes
15 Analytical data for selected final compound 33b: 1H NMR (300 MHz,
130 CDCl3) δ: 11.41 (s, 1H), 8.49 (d, J = 7.5 Hz, 1H), 7.78 – 7.68 (m, 2H), 7.54
(ddd, J = 8.2, 6.2, 2.1 Hz, 1H), 3.77 - 3.63 (m, 4H), 2.49 (s, 3H), 2.57 – 2.48
(m,4H), 2.46 (q, J = 7.2 Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H); 13C NMR (125
MHz, DMSO-d6) δ 163.26, 162.38, 137.51, 133.85, 132.87, 130.07, 128.70,
50 1 (a) S.-W. Yu, H. Wang, M. F. Poitras, C. Coombs, W. J. Bowers, H. J.
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2 (a) J. M. de Murcia, C. Niedergang, C. Trucco, M. Ricoul, B. Dutrillaux, M.
Mark, F. J. Oliver, M. Masson, A. Dierich, M. LeMeur, C. Walztinger, P.
5

127.71, 127.59, 124.68, 123.11, 115.88, 52.66, 42.79, 12.84, 11.81. LC-MS
[ESI]: m/z, 356.2 [M+H]+. 33c: 1H NMR (300 MHz, CDCl3) δ: 12.06 (s, 1H),
8.49 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 6.0 Hz, 2H,), 7.56 - 7.49 (m, 1H), 3.77 -
3.63 (m, 4H), 2.82 - 2.70 (m, 1H), 2.63 - 2.54 (m, 4H), 2.52 (s, 3H),1.07 (d, J
5 = 6.6 Hz, 6H); 13C NMR (125 MHz, DMSO-d6) δ 163.56, 162.18, 137.31,
133.85, 132.87, 130.07, 128.70, 127.71, 127.59, 124.68, 123.11, 115.88,
1
54.67, 45.89, 18.21, 12.84. LC-MS [ESI]: m/z 370.2 [M+H]+. 33d: H NMR
(300 MHz, CDCl3) δ: 11.46 (s, 1H), 8.49 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 6.3
Hz, 2H), 7.59 – 7.46 (m, 1H), 4.38 - 4.25 (m, 2H), 3.01 (t, J = 13.0 Hz, 2H),
10 2.49 (brs, 3H), 2.46 - 2.38 (m, 1H) 2.32 (br s, 6H), 1.98 – 1.90 (m, 2H), 1.60 -
1.43 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 163.88, 163.36, 136.44, 133.31,
133.23, 131.04, 128.73, 126.97, 126.35, 124.06, 122.58, 117.22, 61.92, 41.72,
29.66, 12.08. LC-MS [ESI]: m/z, 370.2 [M+H]+.
15
6