Identification of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-ethylamine derivatives as novel GnRH receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2007.05.009

A novel series of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-ethylamine derivatives were designed and synthesized as GnRH receptor antagonists. SAR studies led to a series of highly active molecules against both the rat and human receptors. Furt

Full text of DOI:10.1016/j.bmcl.2007.05.009

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3845–3850
Identification of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-
3-yl)-ethylamine derivatives as novel GnRH receptor antagonists
Mi Chen,a Zhiqiang Guo,a Marion C. Lanier,a Liren Zhao,a Stephen F. Betz,b
Charles Q. Huang,a Colin J. Loweth,a Neil J. Ashweek,a Xin-Jun Liu,b R. Scott Struthers,b
Margaret J. Bradbury,c James W. Behan,c Jenny Wen,d Zhihong O’Brien,d
John Saundersa and Yun-Fei Zhua,*
aDepartment of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA
bDepartment of Endocrinology, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA
cDepartment of Neurosciences, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA
dDepartment of Preclinic Development, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA
Received 27 March 2007; revised 3 May 2007; accepted 4 May 2007
Available online 10 May 2007
Abstract—A novel series of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-ethylamine derivatives were designed and synthe-
sized as GnRH receptor antagonists. SAR studies led to a series of highly active molecules against both the rat and human receptors.
Furthermore, one potent compound, 17j, demonstrated dose-dependent LH suppression in castrated rats.
Ó 2007 Elsevier Ltd. All rights reserved.
Gonadotropin-releasing hormone (GnRH), also known
as luteinizing hormone-releasing hormone (LHRH), is a
decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-
Gly-NH2) which plays an important role in human
reproduction by regulating the levels of luteinizing hor-
mone (LH) and follicle-stimulating hormone (FSH).
GnRH is released from the hypothalamus and acts at
GnRH receptor on the pituitary gland to stimulate the
biosynthesis and release of LH and FSH. LH released
from the pituitary gland is responsible for the regulation
of gonadal steroid production in both males and
females, while FSH regulates spermatogenesis in males
and follicular development in females. Due to its biolog-
ical mechanism of action, it is believed that several dis-
ease states would benefit from the regulation of GnRH
function, particularly in antagonizing its activity. These
include sex hormone related diseases such as prostate
cancers, endometriosis, and uterine fibroids.
aryl-pyrrolo[1,2-a]pyrimid-4-ones1 (1) and 2-aryl-3-ami-
nomethyl-imidazolo[1,2-a]pyrimid-5-ones2 (2a–b, 3) and
uracils3 (4) as potent non-peptide human gonadotropin-
releasing hormone (hGnRH) receptor antagonists.
Furthermore, NBI-42902,
a
uracil-based analog,
demonstrated efficacy in both monkey4 and human sub-
jects.5 In general, these classes of molecules were found
to be highly species-selective. The binding affinities of
these molecules are usually >100-fold more potent for
the human receptor than for the rat receptor. Thus,
the most convenient and cost effective castrated rat
model cannot be applied for in vivo efficacy screening
to evaluate LH suppression. Interestingly, non-peptide
GnRH receptor antagonists from tryptamine class such
as 5 were reported to be less species-selective,6 presum-
ably they bind to a region of the receptor that is more
conservative among different species based on mutagen-
esis studies.7 To utilize castrated rats as efficient in vivo
screening tool, we report here the design, synthesis, and
SAR studies of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-
c]pyridine-3-yl)-ethylamine derivatives as novel potent
GnRH receptor antagonists for both human and rat
receptors. Furthermore, LH suppression in castrated
rats by one of the compounds is also demonstrated.
In earlier work, our group has disclosed SAR studies
over several series (Fig. 1) such as 6-aminomethyl-7-
Keywords: Non-peptide GnRH receptor antagonists; 12-(4,5,6,7-Tet-
rahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-ethylamine.
*
Scheme 1 illustrates the 5-step synthesis of the key inter-
mediate 9. 4-Oxo-piperidine-1-carboxylic acid tert-butyl
Corresponding author. Tel.: +1 858 617 7600; fax: +1 858 658
7619; e-mail: fzhu@neurocrine.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.05.009

3846
M. Chen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3845–3850
R1
N
R1
N
R2
O
R2
O
N
O
R6
R5
N
N
OR5
R3
R3
N
N
R4
X
R4
2a: R6=CO2R7, R5 = H
2b: R6=Ar, R5 =CH3
1: X=CN or H
R1
N
R2
O
O
R2
N
N
Ar
R1
Ar
N
Alkyl
R3
O
N
N
N
R4
3
R4
4
N
O
F
F
HN
O
N
F
N
O
N
H2N
O
N
H
5
NBI-42902
IC50: 0.6 nM ( human receptor binding)
IC50: 1.7 nM ( rat receptor whole cell binding)
Ki: 0.56 nM ( human receptor binding)
Ki: 3000 nM ( rat receptor binding)
Figure 1. General structures of GnRH antagonists.
NO2
HN
S
O
O
O
O
Boc
Boc
a, b, c
N
N
d
F3C
N
e
F3C
N
N
H
O
N
H
N
H
6
7
8
9
Scheme 1. Reagents and conditions: (a) pyrrolidine, toluene, reflux; (b) 3,5-dimethyl-a-bromoacetophenone, DIPEA, THF, reflux; (c) ammonium
acetate, EtOH, 60% from step a to step c; (d) TFA/DCM (1/1), then ethyl trifluoroacetate, MeOH, 78%; (e) BF3ÆEt2O, (S)-1-(4-nitro-benzene-
sulfonyl)-2-methyl-aziridine, DCM, 75%.
ester (6) was heated with pyrrolidine to form the corre-
sponding enamine intermediate, which directly reacted
with 3,5-dimethyl a-bromoacetophenone without fur-
ther manipulation to yield the crude 1,4-diketone prod-
uct, followed by ring closure with ammonium acetate to
afford the pyrrole dervative 7. N-protecting group of 7
was then switched to acid-stable trifluoroacetamide (8),
which reacted with the (S)-2-methyl-1-(4-nitro-
benzenesulfonyl)aziridine8 to produce the desired com-
pound 9 with orthogonal protections for both basic
amines. Two strategies were then adopted for the syn-
theses of the final compounds 13 and 17 depending on
the need for variation of substitutions on a particular
basic amino group. Scheme 2 shows the syntheses
involving the variation of substitutions on the basic ami-
no group on the bicyclic ring, while the substitution on
side chain basic amino group is locked with 2-(4-pyr-
idyl)-ethyl group, one of the preferred groups from
tryptamine class.6a 9 underwent Mitsunobu reaction
with 2-(4-pyridyl)-ethanol to yield 10. Selective hydroly-
sis of trifluoroacetamide afforded 11, which was coupled
either with a variety of acids or acyl chlorides to form
the corresponding amides. The final compounds 13 were
obtained after the hydrolysis of p-nitrobenzenesulfonyl
group under basic condition in the presence of 2-mer-
captoacetic acid. As indicated in Table 1, without substi-
tution on the ring nitrogen, compound 13a was not
active determined by the IP assay which measures the
inhibition of GnRH-stimulated [3H] inositol phosphate
hydrolysis using RBL cells stably transfected with the
gene for human GnRH receptors. Weaker activity was
observed with a simple acetamide (13b). Subsequently,
a variety of amides were examined. Increasing the size
of amide from the methyl to cyclopentyl gained about
2-fold activity (13c, 3480 nM). A bulky tetramethylcy-
clopropyl group (13d) bolstered the affinity nearly 10-
fold to 475 nM (IC50). However, further increase the
bulkiness using an adamantyl group did not help on

M. Chen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3845–3850
3847
N
NO2
N
N
NO2
NO2
N
S
O
N
S
O
N S
O
O
O
O
O
O
a
b
c
9
F3C
N
HN
R1
N
N
H
N
H
N
H
11
12
10
d
N
HN
O
R1
N
N
H
13
Scheme 2. Reagents: (a) 4-pyridyl-CH2CH2OH, Ph3P, DEAD, THF 30–80%; (b) K2CO3, MeOH, 60–80%; (c) amide formation (acyl chloride with
Et3N, DCM or acid with HBTU, DIEA, DCM), 60–95%; (d) LiOH, HSCH2CO2H, DMF, 50–70%.
the activity (13e, 546 nM). Surprisingly, benzamide (13f)
was inactive and the activity was regained by an inser-
tion of a methylene group between the phenyl and car-
bonyl moiety (10g, 1110 nM). Based on this lead (10g),
a variety of substitutions on the phenyl ring were ex-
plored. 2-substitution was evidently preferred over 3
and 4-substitutions, thus the discussion in this report
is focused on the variation of 2-substitution. Compound
13h with a 2-methoxyl group improved the affinity by 2-
fold, while 2-fluoro (13i) and 2-chloro (13j) analogs were
about 4-fold more potent than the non-substituted one
(13f). Mutagenesis studies7 implied that this moiety
might be interacting with Tyr283, Tyr284, Phe313 residues
on the receptor, suggesting that a electron-withdrawing
group should be preferred for facilitating a p–p interac-
tion. Indeed, a substantial improvement was observed
from the introduction of a 2-CF3 group (13k,
IC50 = 86 nM). A combination of 2-fluoro and 6-trifluo-
romethyl groups led to the most potent molecule (13l,
IC50 = 62 nM) from this part of the SAR studies. Subse-
quently, our attention was turned into optimizing the
substitution at the basic amino group on the side chain
using the 2-fluoro-6-trifluoromethylphenylacetyl group
as the preferred substituent for the central core amino
group. Scheme 3 describes the synthetic pathway to ob-
tain such compounds. Thus, 9 was subjected to selective
hydrolysis to remove trifluoroacetamide, followed by
coupling with 2-fluoro-6-trifluoromethylphenylacetyl
chloride to afford 14. Mitsunobu reactions with selected
alcohols (15b–n, Table 2) that were obtained either
through commercial sources or syntheses9 produced
16b–n. For 16b–d and 16n, a simple hydrolysis yielded
NO2
NO2
R2
N S
HN
S
O
F
F
O
O
a, b
O
O
O
c
9
N
N
CF3
CF3
N
H
N
H
16b-d, 16n
14
d
NO2
c
d
R2
NH
NH2
R2
N S
SEM
F
F
O
e, then d
F
O
O
O
O
N
N
N
CF3
N
H
CF3
N
H
CF3
N
H
17 a
17 b-n
16 e-m
Scheme 3. Reagents: (a) K2CO3, MeOH, 90%; (b) 2-fluoro-6-(trifluoromethyl)phenyl acetic acid, HBTU, DIPEA, DCM, 85%; (c) 4-R2OH, or SEM-
R2OH, Ph3P, DEAD, THF 30–80%; (d) LiOH, HSCH2CO2H, DMF, 50–60%; (e) concd HCl, EtOH, 90%.

3848
M. Chen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3845–3850
Table 1. In vitro activities of 13a–l
lysis of the sulfonamide group on 14. The inhibitions of
GnRH-stimulated [3H] inositol phosphate hydrolysis via
human GnRH receptors are summarized in Table 3.
While compound 17a with no N-substitution on the side
chain was inactive, attachment of 2-(tetrahydro-pyran-
4-yl)-ethyl group, a non-aromatic moiety with a hydro-
gen bond accepting capability (17b), regained some
activity, but was less potent than the 2-pyridin-4-yl-ethyl
analog (13l). While the N-methyl pyridinone (17c) im-
proved the activity by two-fold, the bicyclic quinoxaline
(17d) offered no advantage over the pyridyl compound
(13l). The 2-methylbenzimidazole (17e) and 3-ethyl-qui-
nazoline-2,4-dione (17f) were similarly potent as 17d
despite their additional hydrogen bond donating
capability. However, the benzotriazole analog (17g)
was more active (IC50 = 26 nM) than the benzimidazole
(17e, IC50 = 87 nM), which suggested that an acidic het-
erocycle might be preferred. Two triazole analogs (17h–
i) with increased acidity by either inserting a nitrogen or
substituting a fluoride on the benzotriazole indeed led to
a further improvement of activity. This SAR trend led
us to employ a tetrazole moiety which yielded the most
active molecule in these SAR studies (17j,
IC50 = 1.5 nM). Further manipulation by insertion of a
nitrogen to the phenyl ring (17k) decreased the activity
(IC50 = 10 nM). Attempt to further optimize the chain
length between the tetrazole substituted phenyl ring
and the basic amino group was not successful, while
insertion of an oxygen (17l) resulted in a loss of about
40-fold activity and shortening of the chain (17m) dras-
tically diminished the activity. Furthermore, replace-
ment of the tetrazole with a carboxylic acid (17n) also
reduced the activity, indicating the tetrazole group
may play additional roles beyond its acidity.
N
HN
R1
N
N
H
Compound R1
hIC50
(nM)
rKib (nM) rIC50
a
c,d
(nM)
13a
13b
H
>10,000 >10,000
n.d.
O
8090
3480
120
n.d.
O
13c
13d
18
250
96
O
475
546
1.3
O
13e
1.5
63
O
13f
>10,000
1110
660
n.d.
110
O
13g
4.5
O
F
O
O
All the compounds were also evaluated by rat binding
assay as shown in both Tables 1 and 3. As expected,
species selectivity was not an issue for this class of
molecules. The rat binding affinities were well corre-
lated with that in human. Rat pituitary cell-based as-
says measuring the inhibition of GnRH-stimulated LH
release were also undertaken before a compound was
chosen for in vivo LH suppression study in castrated
rats. It was found that this assay offered a better dif-
ferentiation among the potent binders. For example,
both 17d and 17j were highly potent rat receptor bind-
ers with similar Ki values at 0.3 and 0.2 nM. However,
the rat pituitary cell-based assay revealed that 17j was
far more potent than 17d as demonstrated by their
corresponding IC50 values (17j: 0.6 nM and 17d:
68 nM). With such small shift of potencies (0.2 nM
vs 0.6 nM) from the standard rat receptor binding as-
say to rat pituitary cell-based functional assay, it was
speculated that the binding affinity (Ki) of 17j was
underestimated and should be less than 0.2 nM. How-
ever, possibly due to lack of the equilibrium from the
standard binding assay condition, its true binding po-
tency was not determined adequately. The similar phe-
nomena were observed in uracil series.10
13h
13i
13j
462
271
267
5.6
1.8
2.6
n.d.
280
n.d.
Cl
O
CF3
O
13k
13l
86
62
1.5
0.5
47
57
CF3
O
F
a Inhibition of GnRH-stimulated [3H]inositol phosphate hydrolysis.
b Inhibition of [125I]Tyr5,DLeu6, NMeLeu7, Pro-N-Et-GnRH binding
to the cloned rat GnRH receptor.
c Inhibition of GnRH stimulated LH release from rat pituitary cells.
d n.d., not determined.
the desired products 17b–d and 17n. For 16e–m, which
carried a SEM protection group on the heterocycles,
an additional step to remove the SEM was employed,
followed by the hydrolysis of sulfonamide to yield
17e–m. Compound 17a was prepared by a direct hydro-
The in vivo efficacy of compound 17j was assessed by
measuring its ability to reduce LH concentrations in
rats that had been castrated approximately 4 weeks

M. Chen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3845–3850
3849
Table 2. The alcohols for Mitsunobu reactions in Scheme 3
Table 3. In vitro activities of 17a–n
R2
Compound
R2OH
HN
F
O
O
N
N
15b
HO
CF3
N
H
N
O
Compound R2
hIC50 rKib
rIC50
(nM)
a
c
15c
HO
(nM)
(nM)
N
13l
62
4180
205
0.5 57
15d6
15e6
HO
HO
N
17a
17b
H
470
n.d.
SEM
N
O
4.7 480
N
O
N
17c
17d
17e
32
60
87
0.4 n.d.
0.3 68
O
N
15f
HO
N
O
N
SEM
N
SEM
15g6
15h
15i
N
NH
1.0 n.d.
HO
HO
N
N
N
N
O
N
O
SEM
17f
91
26
1.8 n.d.
N
N
N
N
F
NH
N
17g
17h
17i
0.5 1.2
0.6 6.4
0.7 28
SEM
N
N
N
N
HO
HO
N
N
NH
N
9.0
SEM
N
N
N
F
15j
N
16
NH
N
SEM
N
N
H
N
N
N
N
N
15k
15l
N
HO
HO
N
17j
1.5
0.2 0.6
0.6 44
N
H
N
SEM
N
N
N
N
17k
7.0
N
N
N
N
O
HN
N
N
SEM
N
O
17l
63
6.2 n.d.
N
N
N
H
15m
15n
N
N
HO
HO
N
N
17m
17n
1600
22
1600
n.d.
N
O
O
O
2.0 n.d.
OH
n.d., not determined.
a Inhibition of GnRH-stimulated [3H]inositol phosphate hydrolysis.
b Inhibition of [125I]Tyr5,DLeu6, NMeLeu7, Pro-N-Et-GnRH binding
to the cloned rat GnRH receptor.
prior to the study. The castrated rats had elevated LH
concentrations that were stable over 24 h. Blood samples
from individually housed rats were withdrawn from pre-
c Inhibition of GnRH stimulated LH release from rat pituitary cells.

3850
M. Chen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3845–3850
9
8
7
6
5
4
3
2
1
0
1000
750
500
250
0
Vehicle
Cetrorelix
17j 1.5 mg/kg
17j, 4.5mg/kg
17j, 15mg/kg
0
4
8
12
16
20
24
0
4
8
12
16
20
24
Hours after ip dose
Hours after ip dose
Figure 2. (a) Pharmacokinetics of 17j in castrated rats via ip administration. (b) LH suppression of 17j in castrated rats via ip administration.
Gross, T. D.; Tucci, F.; Gao, Y.; Moorjani, M.;
Connors, P. J.; Rowbottom, M. R.; Chen, Y.; Struthers,
R. S.; Xie, Q.; Saunders, J.; Reinhart, G. J.; Chen, T.;
Bonneville, A. K.; Chen, C. J. Med. Chem. 2004, 47,
1259; (c) Rowbottom, M. R.; Tucci, F.; Zhu, Y.-F.;
Guo, Z.; Gross, T. D.; Reinhart, G. J.; Xie, Q.;
Struthers, R. S.; Saunders, J.; Chen, C. Bioorg. Med.
Chem. Lett. 2004, 14, 2269; (d) Tucci, F. C.; Zhu, Y.-F.;
Guo, Z.; Gross, T. D.; Connors, P. J., Jr.; Gao, Y.;
Rowbottom, M. W.; Struthers, R. S.; Reinhart, G. J.;
Xie, Q.; Chen, T. K.; Bozigian, H.; Bonneville, A. L.
K.; Fisher, A.; Jin, L.; Saunders, J.; Chen, C. J. Med.
Chem. 2004, 47, 3486.
viously implanted catheters prior to and up to 24 h after
intraperitoneal (ip) injection of 17j, vehicle, or subcutane-
ous injection of the peptide antagonist Cetrorelix at 10 lg/
kg. Compound 17j dose-dependently decreased LH con-
centrations as measured by radioimmunoassay with sig-
nificant effects observed at 1.5 mg/kg, the lowest dose
administered (p < 0.05, Two-way Repeated Measures
ANOVA, Fig. 2b). The highest dose, 15 mg/kg, reduced
plasma LH concentrations to the same degree as the posi-
tive control Cetrorelix. For all doses, suppression was sig-
nificant from 2 to 9 h. Plasma concentrations of 17j after
ip injection increased with dose (Fig. 2a). The AUCs
((ng h)/ml) of plasma concentration from rats completing
the 24-h study were 1290 221.8 (1.5 mg/kg),
2473.4 373.4 (4.5 mg/kg), and 6502.0 1094.6 (15 mg/
kg), respectively.
4. Tucci, F.; Zhu, Y.-F.; Struthers, R. S.; Guo, Z.; Gross, T.
D.; Rowbottom, M. R.; Acevedo, O.; Gao, Y.; Saunders,
S.; Xie, Q.; Reinhart, G. J.; Liu, X.; Ling, N.; Bonneville,
A. K.; Chen, T.; Bozigian, H.; Chen, C. J. Med. Chem.
2005, 48, 1169.
5. Struthers, R. S.; Chen, T.; Campbell, B.; Jimenez, R.; Pan,
P.; Yen, S. S. C.; Bozigian, H. P. J. Clin. Endocrino.
Metabl. 2006, 91, 3903.
In summary, we have developed a novel series of GnRH
receptor antagonists that were both potent against hu-
man and rat receptors in vitro. Effectiveness of such
class of molecules to suppress LH was demonstrated
in castrated rats.
6. (a) Ashton, W. T.; Sisco, R. M.; Kieczykowski, G. R.;
Yang, Y. T.; Yudkovitz, J. B.; Cui, J.; Mount, G. R.; Ren,
R. N.; Wu, T.-J.; Shen, X.; Lyons, K. A.; Mao, A.-H.;
Carlin, J. R.; Karanam, B. V.; Vincent, S. H.; Chang, K.;
Goulet, M. T. Bioorg. Med. Chem. Lett. 2001, 11, 2597,
and references therein; (b) Young, J. R.; Huang, S. X.;
Walsh, T. F.; Wyvratt, M. J., Jr.; Yang, Y. T.; Yudkovitz,
J. B.; Cui, J.; Mount, G. R.; Ren, E. N.; Wu, T.-J.; Shen,
X.; Lyons, K. A.; Mao, A.-H.; Carlin, J. R.; Karanam, B.
V.; Vincent, S. H.; Cheng, K.; Goulet, M. Bioorg. Med.
Chem. Lett. 2002, 12, 827.
7. Betz, S.; Reinhart, G. J.; Lio, F. M.; Chen, C.; Struthers,
R. S. J. Med. Chem. 2006, 49, 637.
8. Farr, R. N.; Alabaster, R. J.; Chung, J. Y. L.; Carig, B.;
Edwards, J. S.; Gibson, A. W.; Ho, G.-J.; Humphrey, G.
R.; Johnson, S. A.; Grabowski, E. J. J. Tetrahedron
Asymmetry 2003, 14, 3503.
References and notes
1. (a) Zhu, Y.-F.; Struthers, R. S.; Connors, P. J., Jr.; Gao,
Y.; Gross, T. D.; Saunders, J.; Wilcoxen, K.; Reinhart, G.
J.; Ling, N.; Chen, C. Bioorg. Med. Chem. Lett. 2002, 12,
339; (b) Zhu, Y.-F.; Wilcoxen, K.; Saunders, J.; Guo, Z.;
Gao, Y.; Connors, P. J., Jr.; Gross, T. D.; Tucci, F. C.;
Struthers, R. S.; Reinhart, G. J.; Xie, Q.; Chen, C. Bioorg.
Med. Chem. Lett. 2002, 12, 403.
2. (a) Wilcoxen, K.; Zhu, Y.-F.; Connors, P. J., Jr.; Saun-
ders, J.; Gross, T. D.; Gao, Y.; Reinhart, G. J.; Struthers,
R. S.; Chen, C. Bioorg. Med. Chem. Lett. 2002, 12, 2179;
(b) Gross, T. D.; Zhu, Y.-F.; Saunders, J.; Gao, Y.;
Connors, P. J., Jr.; Guo, Z.; Struthers, R. S.; Reinhart, G.
J.; Chen, C. Bioorg. Med. Chem. Lett. 2002, 12, 2185; (c)
Zhu, Y.-F.; Guo, Z.; Gross, T. D.; Gao, Y.; Connors, P.
J.; Struthers, R. S.; Xie, Q.; Tucci, F. C.; Reinhart, G. J.;
Wu, D.; Saunders, J.; Chen, C. J. Med. Chem. 2003, 46,
1769.
9. The general synthesis for alcohols 15c–m was performed
according to the following Scheme6:
a
OH
b, c
Ar Br
Ar
Ar
15c-m
Reagents and conditions: (a) Tributyl(vinyl)tin,
Pd(Ph3P)2Cl2, DMF; (b) 9-BBN, THF, reflux; (c) H2O2,
2 N NaOH, room temperature.
3. (a) Zhu, Y.-F.; Gross, T. D.; Guo, Z.; Connors, P. J.;
Gao, Y.; Tucci, F.; Struthers, R. S.; Reinhart, G. J.;
Saunders, J.; Chen, T. K.; Bonneville, A. K.; Chen, C.
J. Med. Chem. 2003, 46, 2023; (b) Guo, Z.; Zhu, Y.-F.;
10. Sullivan, S. K.; Hoare, S. R. J.; Fleck, B. A.; Zhu, Y.-F.;
Heise, C. E.; Struthers, R. S.; Crowe, P. D. Biochem.
Pharm. 2006, 72, 838.