Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity

Article abstract of DOI:10.1016/j.bmcl.2011.02.101

A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.

Full text of DOI:10.1016/j.bmcl.2011.02.101

Bioorganic & Medicinal Chemistry Letters 21 (2011) 2278–2282
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic
stability and potent cell-proliferation activity
Christoph W. Zapf a, , Jonathan D. Bloom a, Jamie L. McBean a, Russell G. Dushin a, Thomas Nittoli a,
⇑
Charles Ingalls a, Alan G. Sutherland a, John P. Sonye a, Clark N. Eid a, Jennifer Golas b, Hao Liu b,
Frank Boschelli b, Yongbo Hu c, Erik Vogan d, Jeremy I. Levin a
a Medicinal Chemistry, Pfizer, 401 N. Middletown Road, Pearl River, NY 10965, USA
b Oncology Research, Pfizer, 401 N. Middletown Road, Pearl River, NY 10965, USA
c Structural Biology & Computational Chemistry, Pfizer, 401 N. Middletown Road, Pearl River, NY 10965, USA
d Structural Biology & Computational Chemistry, Pfizer, 200 Cambridge Park Drive, Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen
within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to
compounds with good physical properties. Important structure–activity relationship information was
obtained from this series which led to the discovery of a soluble and stable compound which is potent
in an Hsp90 binding and cell-proliferation assay.
Received 12 January 2011
Revised 23 February 2011
Accepted 24 February 2011
Available online 28 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Hsp90 inhibitors
Chaperon inhibitors
ortho-Aminobenzamides
N-terminal ATP-binding site
Macrocycles
Buchwald–Hartwig cyclization
Modern cancer chemotherapy generally suffers from the emer-
gence of drug resistance.1,2 The selective silencing of a specific cell
signaling pathway by a chemotherapeutic is arguably at the origin
of this problem. By up-regulating alternative pathways, tumors are
able to adapt to the drug treatment and continue their growth. Tar-
geting chaperone proteins offers a promising solution to this tradi-
tional chemotherapy dilemma since it allows the simultaneous
inhibition of multiple pathways with a single agent.3,4
The ATP-dependent 90 kDa molecular chaperone Hsp90 has be-
come an attractive target for cancer therapy.5,6 It plays a critical
role in maintaining the function of a wide range of client proteins
many of which are intimately involved in cancer pathology.7 Inhi-
bition of Hsp90 leads to the destabilization and ultimately degra-
dation of the clients which results in the inhibition of cell growth
and apoptosis.8
The first Hsp90 inhibitor reported in the literature was the mac-
rocyclic natural product Geldanamycin 1 (Fig. 1) which belongs to
the class of the ansamycins.13 Clinical studies established this com-
pound’s unacceptable toxicology profile preventing it from further
development.14 Optimization studies led to the discovery of 17-
AAG 2 and 17-DMAG 315 which are currently in clinical trials but
which are characterized by poor solubility and a narrow therapeu-
tic window, respectively.
Vernalis recently disclosed resorcinol 416 which entered clinical
trials in 2007. Isoxazole 4 is one of many small molecules which
have been described in the literature as potential novel Hsp90
inhibitors with clinical application and is part of a recent summary
on this topic.17
Serenex (acquired by Pfizer) recently disclosed their own efforts
to discover potent small-molecule Hsp90 inhibitors that would be
devoid of drawbacks associated with Geldanamycin.18 Their stud-
ies culminated in a series of 2-aminobenzamides which exhibited
low-nanomolar potencies in a proliferation assay. Among the re-
ported compounds, glycine pro-drug SNX-5422 5 was forwarded
to clinical trials.19
Using structure-based drug design, a series of potent benzisox-
azoles as Hsp90 inhibitors was recently discovered.20 In continua-
tion of seeking potent small molecule inhibitors of Hsp90 and
guided by X-ray crystallography using a structural analog of 5,
Different ATP-competitive chemotypes have evolved as potent
N-terminal Hsp90 inhibitors, several of which have transitioned
into clinical trials.9–11 While many of these clinical trials focus on
Hsp90 inhibitors as single agents for cancer therapy, combination
studies with established chemotherapeutics have been designed
and were reported recently as well.12
⇑
Corresponding author. Tel.: +1 617 665 5602; fax: +1 617 665 5682.
E-mail address: christoph.zapf@pfizer.com (C.W. Zapf).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.02.101

C. W. Zapf et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2278–2282
2279
O
O
CONH2
R
O
H
O
N
N
O
N
H
NH2
O
HO
N
MeO
N
OH
O
MeO
CF3
OH
O
N
HN
OCONH2
O
1 Geldanamycin: R = OMe
2 17-AAG: R = NHallyl
4 NVP-AUY922
5 SNX-5422
3 17-DMAG: R = NHCH2CH2NMe2
Figure 1. Structure of Geldanamycin 1, clinically relevant ansamycins 17-AAG 2, 17-DMAG 3, Vernalis’ clinical candidate NVP-AUY922 4 and Serenex0 clinical candidate
SNX-5422 5.
we were able to design structurally unique macrocyclic ortho-
aminobenzamides that are potent inhibitors of Hsp90 in an en-
zyme and cell-proliferation assay. In this Letter, we wish to dis-
close a series of macrocycles which show good to excellent
solubility and microsomal stability.
bered macrocycle is outlined in Scheme 2. To this end, aldehyde 10
was reduced to the alcohol with NaBH4 followed by conversion to
the corresponding mesylate which was displaced with excess
bis(2-aminoethyl)ether to produce diamine 24. The macrocycliza-
tion was carried out with moderate yield using the same Pd-med-
iated conditions as before followed by the hydrolysis of the
benzonitrile under basic conditions providing the ether linked
macrocycle 25.
The synthesis of two structurally related 12-membered analogs
is highlighted in Scheme 3. For this purpose the allyl side-chain in
26 was isomerized to the methylvinyl substituent in 27 by treat-
ment with Grubbs 2nd generation catalyst in methanol at elevated
temperature.26 Following the arylation of pyrrole 28, the obtained
olefine 28 was dihydroxylated as before providing diol 29 which
was converted to aldehyde 30 by treatment with sodium perio-
date. The target compounds 33 and 34 were prepared by reductive
amination of aldehyde 30 using the mono-protected 1,4-diamino
butane building blocks 31 or 32, deprotection, Buchwald–Hartwig
cyclization and hydrolysis.
The synthesis of our macrocyclic target structures commenced
with allyl tetrahydroindolone 6 or the corresponding homoallyl
derivative 7 (Scheme 1). Dihydroxylation and cleavage21 of diols 8
or 9 yielded aldehydes 10 or 11, respectively. Reductive amination
of these aldehydes with
a
variety of mono-Boc protected22
diamines 12 provided amines 13 following the removal of the pro-
tecting group with TFA. The intramolecular cyclization was accom-
plished in moderate to very good yields using Buchwald–Hartwig
conditions for the arylation of amines23 which was followed by
hydrolysis of the benzonitriles to the benzamides 14–23 under
either basic19 or acidic conditions. While the synthesis of macrocy-
clic rings using palladium-mediated chemistry has been demon-
strated to some extend before24,25, this present work represents to
the best of our knowledge the first application of the Buchwald–
Hartwig reaction to access complex macrocyclic anilines.
To access another set of 12-membered amine-containing mac-
rocycles, homoallyl derivative 7 was successfully subjected to
Wacker oxidation conditions providing the corresponding methyl
Several 11- to 13-membered macrocycles were prepared using
the approach illustrated in Scheme 1. The synthesis of a 14-mem-
CN
N
CN
CN
Br
Br
Br
a
b
N
N
m
m
m
CHO
OH
HO
O
O
O
m = 1: 6
m = 2: 7
m = 1: 8
m = 2: 9
m = 1: 10
m = 2: 11
R
R'
BocHN
NH2
c, d
n
X
Y
#
m
n
X
Y
R
R'
12
14
15
16
17
18
19
20
21
22
23
1
1
2
2
2
2
1
2
1
1
1
0
1
0
0
0
1
0
1
1
H
H
H
H
H
H
H
H
H
H
H
CONH2
CN
N
H
R'
Me Me H
Me Me H
R
Br
R'
R
N
NH2
H
H
H
H
Me H
OH H
H
H
H
H
H
X
e, f
X
n
Y
Me H
Me H
Me Me
H
H
Y
N
NH
n
m
NH
m
H
H
O
O
14 - 23
13
Scheme 1. Reagents and condition: (a) OsO4, NMO, tBuOH, 70–80%; (b) NaIO4/SiO2, DCM, quant.; (c) NaBH(OAc)3, DCE, 14–95%; (d) 10% TFA, DCM, quant.; (e) Pd2dba3, BINAP,
NaOtBu, dioxane, toluene, 110 °C, 15–93%; (f) 90% H2SO4, 60 °C 19–48% or 5 M NaOH, 30% H2O2, DMSO, EtOH, 21–99%.

2280
C. W. Zapf et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2278–2282
CN
N
tion of deprotected diamine 36b was separated at this stage by
chromatography. Hydrolysis of the benzonitriles provided the
three macrocyclic target structures 37–39.
CONH2
NH2
H
Br
N
O
O
d, e
a, b, c
Further derivatization of macrocycles 19 and 20 by alkylation
with iodomethane and acetic anhydride, respectively, yielded the
corresponding tertiary amine 40 and acetamide 41 (Scheme 5).
Correlating the biologic activity of these macrocycles with their
ring size was an important question at the outset of this project
that needed to be addressed. This class of compounds forms two
critical hydrogen bonds with Hsp90: the benzamide interacts with
Asp93 while the carbonyl on the tetrahydroindolone moiety en-
gages Tyr139 (see Fig. 2). Simple molecular modeling consider-
ations suggest an optimal dihedral angle range for the aromatic
moieties allowing these two hydrogen bonds to be accessible. It
was expected that the tether length would influence this dihedral
angle and thus the biologic activity of the macrocycle.
10
N
NH
NH
O
O
24
25
Scheme 2. Reagents and condition: (a) NaBH4, THF, 0 °C, 71%; (b) MeSO2Cl, Et3N,
DCM; (c) bis(2-aminoethyl)ether, 40 °C, 64%; (d) Pd2dba3, BINAP, NaOtBu, toluene,
110 °C, 69%; (e) 5 M NaOH, 30% H2O2, DMSO, EtOH, quant.
ketone which after reductive amination with Boc-protected ethyl-
ene diamines 35a (R = H) or 35b (R = Me) gave rise to racemic dia-
mine 36a or 36b as a 1:1 mixture of diastereomers (Scheme 4).
Both intermediates were deprotected and cyclized as before. The
diastereomeric mixture of macrocycles obtained after the cycliza-
Target compounds were prepared in which the length of the
tether had been varied. A comparison reveals that the 11-mem-
bered ring 15 is much less active than the corresponding 12-mem-
bered analog 14 (Table 1). While 13-membered analog 16 is more
CN
Br
H
N
H
N
a
b
N
O
O
26
27
O
28
CONH2
H
N
c
NH2
BocHN
CN
N
CN
N
N
31
N
H
Br
Br
e, f, g, h
d
OH
O
33
CHO
CONH2
HO
H
NH2
N
PhthN
O
O
32
30
29
N
e, i, g, h
N
H
O
34
Scheme 3. Reagents and condition: (a) Grubbs 2nd generation catalyst, MeOH, 60 °C, 70%; (b) NaH, 2-bromo-4-fluorobenzonitrile, DMF, 80 °C, 70%; (c) OsO4, NMO, dioxane
61%; (d) NaIO4, DCM, 82%; (e) NaBH(OAc)3, DCE, 31: 67%, 32: 23%; (f) 10% TFA, DCM, quant.; (g) Pd2dba3, BINAP, NaOtBu, dioxane, toluene, 110 °C, for 33: 11%, for 34: 50%; (h)
5 M NaOH, 30% H2O2, DMSO, EtOH, 33: 84%, 34: 69%; (i) hydrazine, THF, 63%.
CONH2
CN
N
H
R
Br
R
N
NHBoc
NHBoc
H2N
35a,b
a,b
R
NH
7
NH
R'
N
c, d, e
R'
O
O
36a,b
R = H, R' = Me: 37
R = Me, R' = (R)-Me: 38
R = Me, R' = (S)-Me: 39
Scheme 4. Reagents and condition: (a) PdCl2, CuCl, O2, DMF, H2O 78%; (b) 35a or 35b, NaBH(OAc)3, DCE; R = H: 79%, R = Me: 83%; (c) 10% TFA, DCM, quant.; (d) Pd2dba3, BINAP,
NaOtBu, dioxane, toluene, 110 °C, for 36a: 52%, for 36b: 50% (ꢀ1:1 mixture of separable diastereomers); (e) 5 M NaOH, 30% H2O2, DMSO, EtOH, 37: 36%, 38: 69%, 39: 78%.

C. W. Zapf et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2278–2282
Table 1
2281
CONH2
CONH2
H
H
Biologic activities, profiling data, and selected calculated properties for Geldanamycin
N
N
and macrocycles 14–41
Compd Ring size Hsp90a HCT116b Sol.c
Stab.d MWe c log Pf
a
N
b
20
19
1g
19
12
11
13
12
12
12
12
12
12
12
14
12
12
12
12
12
12
12
0.04
0.40
12.44
0.29
0.14
0.92
0.11
0.21
0.83
0.36
0.32
0.57
>5.00
>5.00
1.24
0.09
0.43
0.15
0.11
0.03
8.14
NT
NT
NT
NT
NT
561
395
380
437
423
395
409
409
423
409
411
425
395
409
409
423
423
423
451
2.1
3.3
3.1
4.7
4.4
3.6
4.1
3.8
4.6
3.8
2.6
2.9
3.3
3.8
4.1
4.6
4.6
4.4
2.8
N
NAc
N
14
15
16
17
18
19
20
21
22
23
25
33
34
37
38
39
40
41
>100 15
6
52
35
0.21
0.08
0.82
0.09
0.16
0.62
0.25
0.60
0.83
>5.00
>5.00
0.94
0.03
0.36
0.08
0.15
3
15
>30
O
O
40
41
>100 >30
Scheme 5. (a) MeI, Hünig0s base, DCM, 27%; (b) Ac2O, Et3N, DCM, 85%.
67
45
39
70
73
18
16
69
14
>30
5
10
28
18
7
26
>100 15
58
31
19
7
11
9
For experimental details see Ref. 20.
a
Enzyme IC50
(
l
M).
Cell-proliferation EC50
Solubility ( g/mL).
b
c
d
e
f
(lM).
l
t1/2 in rat microsomes (min).
Molecular weight.
Calculated partition ratio.
In-house data.
g
methyl compounds 16 and 17, presumably due to a lack of suffi-
cient rigidity in the linker.
With respect to optimizing the position of the heteroatom with-
in the tether, compound 19 is about twice as potent as 20 in bind-
ing and proliferation. Shifting the position of the nitrogen another
position in the tether, however, leads to a complete loss of activity
of the target structure irrespective whether the chiral methyl
group is absent (33) or present (34).
Figure 2. X-ray crystal structure of macrocycle 19 (pink) bound to the N-terminal
ATP-binding site of Hsp90. Water mediated hydrogen bonds to the protein are
highlighted in red. Selected water molecules are displayed as red spheres.
Analog 38 which contains two chiral methyl substituents shows
a three-fold improvement in cell-proliferation potency compared
to compound 19. A comparison of 38 with 37 and 39 implies that
the number and stereochemical nature of the substituents within
the tether can have a dramatic effect on the biologic activity of
the macrocycles. Lastly, modifications of the basic nitrogen in the
macrocyclic tether that result in an altering of its hydrogen-bond-
ing properties (40) or its basicity (41) is possible without signifi-
cant change in potency.
Table 1 also highlights the great variability in solubility that
was determined for these macrocycles which ranged from poor
to excellent. Likewise but without much correlation, wide ranging
rat microsomal stability was measured. Fortunately, compound 19,
which is among this series0 most active compounds in the binding
active than 14 in binding and proliferation activity, we also recog-
nized that the gem-dimethyl substituents within the ring could be
responsible for a favorable reduction in flexibility of the tether. The
analogous 12-membered analog 17 also containing
a gem-
dimethyl unit was prepared leading to an increase in binding and
cell-proliferation activity thus substantiating the need for a rigidi-
fying element within the tether. This finding is underscored when
comparing compound 17 with 18 which lacks the gem-dimethyl
group and shows reduced biologic activity. Increasing the ring size
from a 13- (16) to a 14-membered ring (25) leads to a further de-
crease in biologic activity. Together, these results led us to investi-
gate 12-membered macrocycles containing substituents within the
tether that contribute to a reduction of the compound’s overall
flexibility.
(IC50 = 0.11
high aqueous solubility (>100
somes (t1/2 > 30 min). Similarly, analog 38 is also highly potent
(binding IC50 = 0.09 M, proliferation IC50 = 0.03 M) and soluble
(>100 g/mL), however its rat microsomal stability is moderate
lM) and proliferation assay (IC50 = 0.09
lM), shows
In a related series of analogs27 we discovered the benefit of a
properly configured chiral methyl group adjacent to the aniline
nitrogen atom. To evaluate the effect of this substituent in the het-
eroatom-linked series of macrocycles, analogs 19 and 20 were pre-
pared. As can be seen in Table 1, 17 and 19 are about equipotent in
the binding and cell-proliferation assays underscoring that this
chiral substituent provides the same effect on the biologic activity
as the gem-dimethyl unit. Removing the chirality in the macrocy-
cle by the addition of a methyl group (21) reduces the biologic
activity. This finding confirms the stereochemical preference for
substituents at this position of the ring.
lg/mL) and is stable in rat micro-
l
l
l
(t1/2 = 15 min).
An X-ray crystal structure for macrocycle 19 bound to the N-
terminal ATP-binding site of Hsp90 was obtained.28 As can be seen
in Figure 2, the carbonyl of the tetrahydroindolone engages in a
hydrogen bond with Tyr139 while the benzamide interacts with
Asp93 in a direct and a water-mediated hydrogen bond. The nitro-
gen of the tether forms an additional water-mediated interaction
to the main chain carbonyl of Asn51 (the side-chain is omitted in
Fig. 2). Figure 2 shows a second water molecule proximal to the
benzamide interacting with Ser52, Ile91, Asp93 and Thr184
Macrocycles featuring tethers with only one substituent are
represented by racemic compounds 22 (X = Me) and 23 (X = OH).
These compounds are less active when compared to the gem-di-

2282
C. W. Zapf et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2278–2282
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representing the dense network of conserved water molecules
characteristic for the N-terminal ATP-binding site of Hsp90. Addi-
tional water molecules were observed in the crystal structure but
were omitted in Figure 2 for clarity.
The X-ray structure of 19 confirms that the macrocyclic tether
linking the aminobenzamide to the tetrahydroindolone is indeed
oriented toward the solvent exposed region of the binding site.
This will allow further functionalization and derivatization of the
tether enabling the fine-tuning of biologic and physical properties.
Improved analogs of these novel macrocycles which display excel-
lent biomarker activity will be reported in due course.27
Acknowledgments
17. Biamonte, M. A.; Van de Water, R.; Arndt, J. W.; Scannevin, R. H.; Perret, D.; Lee,
W. C. J. Med. Chem. 2010, 53, 3.
18. Barta, T. E.; Veal, J. M.; Rice, J. W.; Partridge, J. M.; Fadden, R. P.; Ma, W.; Jenks,
M.; Geng, L.; Hanson, G. J.; Huang, K. H.; Barabasz, A. F.; Foley, B. E.; Otto, J.;
Hall, S. E. Bioorg. Med. Chem. Lett. 2008, 18, 3517.
19. Huang, K. H.; Veal, J. M.; Fadden, R. P.; Rice, J. W.; Eaves, J.; Strachan, J. P.;
Barabasz, A. F.; Foley, B. E.; Barta, T. E.; Ma, W.; Silinski, M. A.; Hu, M.; Partridge,
J. M.; Scott, A.; DuBois, L. G.; Freed, T.; Steed, P. M.; Ommen, A. J.; Smith, E. D.;
Hughes, P. F.; Woodward, A. R.; Hanson, G. J.; McCall, W. S.; Markworth, C. J.;
Hinkley, L.; Jenks, M.; Geng, L.; Lewis, M.; Otto, J.; Pronk, B.; Verleysen, K.; Hall,
S. E. J. Med. Chem. 2009, 52, 4288.
We are deeply indebted to our dedicated co-workers in the
Discovery Analytic Chemistry Group in Pearl River especially Mark
Tischler, Joe Ashcroft, Hui Tong, Mairead Young, Keiko Tabai,
Elwira Muszynska. Continued managerial support of this work
came from Tarek Mansour, Will Somers, Kim Arndt and Robert
Abraham, who are also gratefully acknowledged.
20. Gopalsamy, A.; Shi, M.; Golas, J.; Vogan, E.; Jacob, J.; Johnson, M.; Lee, F.;
Nilakantan, R.; Petersen, R.; Svenson, K.; Chopra, R.; Tam, M. S.; Wen, Y.;
Ellingboe, J.; Arndt, K.; Boschelli, F. J. Med. Chem. 2008, 51, 373.
21. Zhong, Y. L.; Shing, T. K. J. Org. Chem. 1997, 62, 2622.
22. Pittelkow, M.; Lewinsky, R.; Christensen, J. B. Org. Syn. 2007, 84, 209.
23. Muci, A. R.; Buchwald, S. L. In Topics in Current Chemistry; Miyaura, N., Ed.;
Springer-Verlag: Berlin, Germany, 2002; Vol. 219, p 131.
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27. manuscript in preparation
28. The structure has been assigned PDB ID code 3QTF.