Discovery of potent and muscle selective androgen receptor modulators through scaffold modifications

Article abstract of DOI:10.1021/jm070312d

A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle selective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro potency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the lead compound 11a (AR K_i = 0.9 nM, EC₅₀ = 1.8 nM) for 14 days induced muscle growth with an ED₅₀ of 0.09 mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model. Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65% and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series are expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.

Full text of DOI:10.1021/jm070312d

J. Med. Chem. 2007, 50, 3015-3025
3015
Discovery of Potent and Muscle Selective Androgen Receptor Modulators through Scaffold
Modifications
James J. Li,|,* James C. Sutton,|,§ Alexandra Nirschl,| Yan Zou,| Haixia Wang,| Chongqing Sun,| Zulan Pi,| Rebecca Johnson,|,‡
Stanley R. Krystek, Jr., Ramakrishna Seethala,X Rajasree Golla,X Paul G. Sleph,X Blake C. Beehler,X Gary J. Grover,X,†
Aberra Fura,# Viral P. Vyas,# Cindy Y. Li,@ Jack Z. Gougoutas,∇ Michael A. Galella,∇ Robert Zahler,| Jacek Ostrowski,X and
Lawrence G. Hamann|
DiscoVery Chemistry, Computer Assisted Drug Design, Metabolic Disease Research, Metabolism and Pharmacokinetics,
DiscoVery Analytical Sciences, and Analytical Research and DeVelopment, Bristol-Myers Squibb Pharmaceutical Research Institute,
P.O. Box 5400, Princeton, New Jersey 08543-5400
ReceiVed March 19, 2007
A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle
selective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro
potency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the lead
compound 11a (AR Ki ) 0.9 nM, EC50 ) 1.8 nM) for 14 days induced muscle growth with an ED50 of 0.09
mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model.
Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65%
and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series are
expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.
Introduction
As men age beyond the third decade of life, they experience
a slow steady decrease in serum testosterone levels.1 The
physiological impact of testosterone decline in elderly men is
associated with reduced muscle mass and strength, decreased
bone mass, low energy, diminished sexual function, an increased
risk of osteoporosis and fracture, and an increased incidence of
depression, all of which can have a significant negative impact
on quality of life.2-4 Testosterone replacement therapy (TRT)a
has been shown in clinical studies to significantly increase lean
body mass and bone density, decrease adipose tissue, and in
some studies, increase muscle strength.5-9 However, the use of
long-term TRT is limited, mainly due to concerns about
accelerating benign prostatic hypertrophy (BPH) and/or prostate
cancer.10-11 As such, there exists considerable unmet medical
need for a novel therapy that would retain the beneficial anabolic
effects on muscle and bone with minimal androgenic effects
on prostate. Consequently, discovery of an orally active,
Figure 1. Representative examples of nonsteroidal androgen agonists.
nonsteroidal, and selective androgen receptor modulator (SARM)
4 (LGD-2226), 5, and 6 have been reported in the literature
(Figure 1).19-36 As compared to endogenous testosterone, these
new agents have demonstrated, to varying degrees, potent and
efficacious anabolic activity on muscle and/or bone with
significantly improved selectivity versus prostate in preclinical
rodent models and therefore have the potential to provide safer
treatment options with fewer side-effects as compared to
conventional TRT.
As reported recently by our group, N-aryl hydroxybicyclo-
hydantoin 3 is as an orally active, highly potent SARM that
had advanced to clinical studies.28 Most of our first generation
SARMs, including 3, have a hydantoin moiety embedded within
the [5.5] bicyclic scaffold.28-30 During the course of structure-
activity relationship (SAR) optimization, a trace amount of the
potentially mutagenic 4-cyanonaphtylamine metabolite was
detected in dog and cynomolgus monkey urine upon oral dosing
of early lead compound 7 (Table 1).29 Two complementary
approaches were taken to circumvent this issue. The first focused
on the evaluation of various alternative aryl amines. This
continues to be an area of high interest among the biomedical
research community.12-18 Several distinct series of orally active
compounds such as 1 (LG-121071), 2 (S-4), 3 (BMS-564929),
* Corresponding author: Telephone: 609-818-7124, e-mail: James.Li@
bms.com.
| Discovery Chemistry.
Computer Assisted Drug Design.
X Metabolic Disease Research.
# Metabolism and Pharmacokinetics.
@ Discovery Analytical Sciences.
∇ Analytical Research and Development.
§ Current address: Novartis Institutes of Biomedical Research, 4560
Horton St., Emeryville, CA 94608. email: james.sutton@novartis.com.
‡ Current address: Department of Defense, 200 MacDill Blvd., Wash-
ington, D.C. 20340. e-mail: rejohns@dia.mil.
† Current address: Product Safety Laboratories, 2394 Rt. 130, Dayton,
NJ 08810. email: garygrover@productsafetylabs.com.
a Abbreviations: SARM, selective androgen receptor modulator; AR,
androgen receptor; TRT, testosterone replacement therapy; BPH, benign
prostatic hypertrophy; LBD, ligand binding domain; ADME, absorption,
distribution, metabolism, and excretion; DHT, dihydrotestosterone; IA,
intrinsic activity.
10.1021/jm070312d CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/07/2007

3016 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Li et al.
Figure 2. Overall strategy for hydantoin core modification from lead 3.
Scheme 1a
of benzoyl ester protecting group to provide 9 as single
enantiomer. The absolute stereochemistry of 9 was determined
by single-crystal X-ray crystallography.
Simple methyl- and ethyl-substituted imidazolidin-2-one
analogues 10a-c and 11a-d were prepared from N-Boc
pyrrolidine aldehyde 17a (Scheme 2). Reaction of methyl- or
ethylmagnesium bromide with 17a gave the corresponding
diastereomeric alcohols 18a,b, which were then oxidized with
4-methyl morpholine N-oxide (NMO) in the presence of
catalytic tetrapropylammonium perruthenate (TPAP) to provide
ketone 19. Treatment of 19 with hydroxylamine gave the oxime
intermediate which was hydrogenated to furnish amine 20a as
the only diastereomer isolated. N-Arylation of 20a with 16 under
Buchwald conditions38 provided aniline 21. Removal of N-Boc
protecting group in 21, followed by reaction with phosgene,
provided the tert-butyldimethylsilyl (TBS)-protected 10a or 11a.
The TBS group was then removed by treatment with tetrabu-
tylammonium fluoride (TBAF) to give compounds 10a and 11a.
Alternatively, diastereomeric alcohols 18a and 18b could be
separated by silica gel chromatography, and the first eluting
isomer 18a was allowed to react with methanesulfonyl chloride
to form a mesylate intermediate. Azide displacement of the
mesylate group, followed by reduction of the resulting azo
intermediate, gave diastereomeric amine 20b. With 20b in hand,
it was readily converted to 10b or 11b in a similar manner.
With respect to the 7-hydroxyl diastereomers 10c, 11c, or 11d,
they were prepared via Mitsunobu reaction from 10a, 11a, or
11b, respectively, to give the benzoyl ester intermediates.
Hydrolysis of the resulting respective benzoyl esters under basic
conditions provided the isomers 10c, 11c, and 11d.
a Reagents and conditions: (a) LiEt3BH, -78 °C; (b) Et3SiH, BF3Et2O,
-78 °C to 0 °C, 6%; (c) CuI, K3PO4, 1,2-cyclohexyldiamine, 21%; (d) 1
M KOH, 88%.
approach led to the successful identification and incorporation
of the nonmutagenic 3-chloro-4-cyano-2-methylaniline moiety
to provide compound 3, which surpasses the highly potent and
muscle selective AR agonist profile of earlier leads.30 In parallel
to the search for nonmutagenic aryl amine replacements, a
second approach entailing systematic modification of the
hydantoin core structure to reduce the likelihood of aryl amine
release (Figure 2) was also undertaken. Throughout these efforts,
both the optimized [5.5] bicyclic scaffold and the newly
discovered 3-chloro-4-cyano-2-methylphen-1-yl group were
retained as the key pharmacophoric features for potent AR
binding and functional activity. Herein we wish to report the
results of these scaffold modification efforts, leading to the
identification of advanced preclinical candidates (such as 11a)
with favorable pharmaceutics properties.
Trifluoromethyl-substituted imidazolidin-2-one analogues
12a-d were prepared employing a slightly different cyclization
strategy (Scheme 3). Cesium fluoride-mediated trifluoromethyl
addition to 17b provided diastereomeric alcohols 22a,b, which
were readily separated and carried forward individually. Re-
moval of the N-Boc group of 22a, followed by reaction with
isocyanate 23, provided urea intermediate 24a. Treatment of
24a with potassium tert-butoxide and p-toluenesulfonyl chloride
afforded compound 12d after removal of TBS group. Likewise,
compound 12c was prepared from alcohol 22b, and 12a,b from
aldehyde 17a as shown in Scheme 3. It was later found that
compound 11a could also be prepared from 18b (R ) Et) using
conditions described in steps b-e of Scheme 3, giving an
improved overall yield. Furthermore, alcohol isomer 18a (R )
Et) can be converted to 18b (R ) Et) in a two-step sequence
involving Mitsunobu inversion followed by hydrolysis of the
resulting ester as shown in steps l and m of Scheme 2. The
stereochemistry of these alkyl-substituted imidazolidinones
Chemistry
The primary objective of the hydantoin core modifications
(Figure 2) was to minimize the potential for aryl amine release
in vivo while maintaining potent SARM activity. Conceptually,
these modifications included replacement of one of the two
potentially labile N-acyl bonds of 3 with an alternative N-alkyl
fragment as in compounds 8-13, as well as obviation of an
aniline fragment altogether as in 14. Toward that end, general
synthetic approaches for preparation of the scaffolds in com-
pounds 8 to 14 were developed using 3 or other available
advanced intermediates as outlined in Schemes 1-4. Reduction
of the amide carbonyl in 3 was achieved by a two-step sequence
as an expedient entry to the des-oxo compound 8. Pyrrolidin-
2-one 9 was prepared by a copper(I)-catalyzed N-arylation of
1537 with 16, followed by two sequential chromatographic
separations on ChiralPak AD and OD columns, and removal

Androgen Receptor Modulators
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 3017
Scheme 2a
a Reagents and conditions: (a) MeMgBr or EtMgBr, -60 to -78 °C, 50-60%; (b) NMO, n-Pr4NRuO4, 87%; (c) NH2OHHCl, NaOAc, ∼98%; (d) H2,
Raney Ni, 10% Pd/C, 95%; (e) compd 16, Pd2(dba)3, (R)-N,N-dimethyl-1-[(R)-2-(diphenyphosphino)ferrocenyl]-ethylamine, Cs2CO3, 21%; (f) 15% TFA/
CH2Cl2; (g) COCl2, i-Pr2NEt, 86%; (h) Bu4NF, 68%; (i) MeSO2Cl, i-Pr2NEt, DMAP, 78%; (j) NaN3, 77%; (k) H2, 5% Pd/C, 98%; (l) PhCO2H, Ph3P,
diisopropyl azodicarboxylate, 94%; (m) 1 N NaOH, 88%.
Scheme 3a
a
Reagents and conditions: (a) CF3SiMe3, CsF, isomers separated and carried forward individually, 50% and 8%; (b) ∼30% TFA/CH2Cl2; (c) i-Pr2Net,
93%; (d) tert-BuOK, p-TolSO2Cl, 69%; (e) Bu4NF, 86%.
Scheme 4a
a Reagents and conditions: (a) 10% TFA/CH2Cl2; (b) PyBroP, i-Pr2NEt, 36%; (c) piperidine, 7%; (d) HF pyridine, 73%.
10a-c, 11a-d, and 12a-d were confirmed by NOE analysis,
and in the case of 12d, by X-ray crystal structural analysis.
The aniline nitrogen replacement analogue pyrrol-2-one 14
was prepared from ketone 19 (Scheme 4). Deprotection of the
N-Boc group in 19, followed by amide formation with acid 25
in the presence of bromo tris-(pyrrolidinophosphonium) hexafluo-
rophosphate (PyBroP), provided amide intermediate 26. Pip-
eridine-assisted intramolecular cyclization, followed by removal
of the TBS group with HF-pyridine, provided pyrrol-2-one 14.
Biological Results and Discussion
Our previous SAR investigations demonstrated a strong
preference for a [5.5] fused bicyclic scaffold substituted with a
3-chloro-4-cyano-2-methylphenyl moiety for potent and muscle

3018 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Li et al.
Table 1. Androgen Receptor Binding (Ki) and Functional (EC50)
Potencya
Figure 3. (a) X-ray cocrystal structure of 3 bound to the human
androgen receptor ligand binding domain at 3.0 Å resolution. Key
residues in the active site are displayed and colored by atom type (C,
beige, N blue, O red). Dashed lines indicate potential hydrogen bonds
with distance between heavy atoms shown. A portion of the backbone
green ribbon was removed for clarity. (b) Docking model of 11a in
human androgen receptor ligand binding domain. Key residues in the
active site are displayed and colored by atom type (C, white, N blue,
O red). Key contacts are a bifurcated hydrogen bond between hydroxyl
group to Asn-705 and Thr-877, and cyano group with Arg-752. Dashed
lines indicate potential hydrogen bonds with distance between heavy
atoms shown. The π-edge-face interaction of aryl ring with Phe-764
also provides another key interaction. A portion of the backbone green
ribbon was removed for clarity.
a In vitro data are at lease two separate measurements using DHT as a
control in both AR binding (Ki ) 0.25 ( 0.03 nM) and functional agonist
assay (EC50 ) 2.8 ( 0.5 nM). Unless otherwise noted, all compounds are
full AR agonist (IA > 85%) relative to DHT control (IA ) 100%). b Ar is
4-cyanonaphen-1-yl for compound 7; 3-chloro-4-cyano-2-methylphen-1-yl
for compounds 3, 8-14.
selective in vivo activity.28-30 Modification to either the
corresponding [5.6] or [6.5] bicyclic ring systems resulted in a
dramatic loss of activity.39 Analysis of the X-ray cocrystal
structure of compound 3 bound to the AR ligand binding domain
(LBD) reveals some key interactions within the binding site
(Figure 3a).28 There are hydrogen bonds between the 7-hydroxyl
and aryl nitrile groups of compound 3 to Asn-705 (2.7 Å) and
Arg-752 (3.2 Å), respectively, and a π-edge-face interaction of
the aryl group of 3 with Phe-764. In addition, it is noted that
there are no direct contacts for the amide carbonyl group of the
hydantoin ring with residues in the binding site. This carbonyl
is projected instead to a small hydrophobic cavity surrounded
by the Trp-741, Met-742, and Met-745 residues. The dihedral
angle between the aryl group and the hydantoin ring is 62°,
which appears to provide an optimal conformation to ensure
that key interactions are achieved within the binding pocket.
Proton NMR analysis of compound 3 also indicates there are
two distinguishable rotamers around the N-aryl bond, which are
interconvertible. Taken together these data suggest a small
hydrophobic group in place of the amide carbonyl may fit in
the hydrophobic pocket and induce a similar conformational
arrangement. Furthermore, crystal lattice analysis of compound
3 reveals an intermolecular hydrogen bond between the amide
carbonyl of one molecule to the 7-hydroxyl group of another
molecule, which may result in tight crystal lattice packing, that
in turn likely contributes to 3 having a low aqueous solubility
of 19 µg/mL. It was hypothesized that removal of the amide
carbonyl from the hydantoin core could eliminate the intermo-
lecular hydrogen bonding and thereby improve aqueous solubil-
ity to facilitate formulation work.
In Vitro Activity. Based on these rationales, the simple
imidazolin-2-one 8 was first prepared as a baseline des-oxo
analogue and was shown to be a fully efficacious AR agonist
with an EC50 of 15 nM. This initial finding indicated that
removal of the amide carbonyl of hydantoin ring was tolerated
but that additional optimization to find a more suitable amide
carbonyl replacement was needed in order to retain the AR
functional potency of the parent molecule 3. Our attention then
turned to the alkyl-substituted imidazolin-2-ones such as
compounds 10-13 (Figure 2) in order to investigate the
feasibility of small hydrophobic groups as the more optimal
surrogates for the amide carbonyl group. Methyl- and ethyl-
substituted imidazolin-2-ones 10a-c and 11a-d were highly
potent in the AR binding assay with Kis in the range of 0.9 to

Androgen Receptor Modulators
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 3019
4 nM, whereas the ethyl analogues 11a-c demonstrated a 3 to
12-fold enhanced functional potency versus the corresponding
methyl analogues 10a-c (i.e., 11c, EC50 ) 2.6 nM vs 10c, EC50
) 13.2 nM). Trifluoromethyl-substituted imidazolin-2-ones
12a-d were also evaluated since the trifluoromethyl group was
considered to be comparable in size to an ethyl group but might
be more metabolically stable in vivo. In both AR binding and
functional assays, compounds 12a-d were found to have in
vitro activity similar to that of ethyl analogues 11a-d, confirm-
ing that the trifluoromethyl group can function as a suitable
steric replacement with Van der Waals interactions to the
neighboring residues in the binding pocket.
and Met-745. However, the larger isopropyl group in 13, which
leads to 10-15-fold reduced potency compared to 11 or 12 in
the in vitro assay, exceeds the available space in the hydrophobic
pocket and thus causes unfavorable helical deformation of the
LBD.
A preliminary assessment of aqueous solubility was conducted
for compounds 8 (245 µg/mL), 10a (613 µg/mL), 11a (242 µg/
mL), and 12d (1140 µg/mL) using crystalline or amorphous
solid.41 Despite the higher log P values for these imidazolin-
2-ones, all showed an improvement in aqueous solubility
compared with hydantoin 3 (19 µg/mL). These results are
consistent with our initial hypothesis that removal of the amide
carbonyl from the hydantoin core would eliminate intermolecular
hydrogen bonding between 7-hydroxyl in one molecule to amide
carbonyl group of another molecule in the crystal lattice, thus
obviating the potential for tight crystal lattice packing. Ac-
companying these observations is the fact that the melting points
for 8, 10a, 11a, and 12d are at least 50 °C lower than that of 3,
suggesting looser crystal packing as a likely reason for the
improved aqueous solubility.41
As was recently shown for the N-aryl hydroxybicyclohydan-
toin series, both the relative and absolute stereochemical
configuration of the 7-hydroxyl and ring juncture 7a-hydrogen
can have a significant impact on biological activity, particularly
in the AR functional assay.29 It is also noted that there is a slight
preference for the R-configuration with respect to 7a-hydrogen.
Four sets of imidazolin-2-one diastereomers, varying the 7-hy-
droxyl and 1-alkyl positions, were evaluated with 7a-hydrogen
being fixed in the R-configuration (Figure 2). The effects of
the 7-hydroxyl configuration for these alkyl-substituted imida-
zolin-2-ones 10-12 were found to have little impact on activity.
This is most readily illustrated in the comparison of examples
10a, 11a, or 12a versus 10c, 11c, or 12c, respectively, where
the potency difference between the pairs is generally within
2-fold (Table 1). On the other hand, there is a slight preference
for the S-stereochemistry for 1-alkyl substitution. For example,
compound 10a (EC50 ) 5.2 nM) is 16-fold more potent than
10b (EC50 ) 87 nM), and 11c (EC50 ) 2.6 nM) is 3-fold more
potent than 11d (EC50 ) 7.4 nM). Size limitations at this
position were also apparent, as the larger isopropyl group in
imidazolin-2-one 13 resulted in a substantial loss of both AR
binding and functional potency.
In Vivo Pharmacological Evaluation. On the basis of in
vitro pharmacological activity as well as data from a panel of
pharmaceutical profiling assays (including Caco-2 permeability,
CYP inhibition, liver microsomal stability, human hepatotocyte
toxicity, hERG inhibition, etc.), compounds 8, 9, 10a, 11a, 12c,
and 12d were selected for evaluation of their in vivo pharmacol-
ogy. The compounds were assessed for efficacy and selectivity
in the stimulation of muscle vs prostate tissue growth in castrated
male rats, a pharmacological model that has been widely used
for the assessment of anabolic and androgenic activities.42,43 In
this model, mature male rats were castrated two weeks prior to
oral administration of test compounds. After an additional two
weeks of treatment, both levator ani muscle and ventral prostate
tissues were weighed and compared to those from a sham-
operated, vehicle-treated control group. In addition, plasma
concentrations of testing compounds were measured following
a single 10 mg/kg oral dose to gain understanding of pharma-
cokinetic/pharmacodynamic relationships. As summarized in
Table 2, compounds 8, 9, 10a, and 12c showed approximately
40-66% recovery of muscle weight with minimal effect on
prostate tissue at a once-daily oral screening dose of 1 or 3
mg/kg. Conversely, a somewhat weaker response was observed
Carbon replacement of the ring juncture nitrogen in 8 was
also assessed with corresponding pyrrolidinone 9, which was
found to exhibit comparable in vitro potency to that of
compound 8. Replacement of the sp2 aniline nitrogen with an
sp2 carbon, as in pyrrol-2-one 14, was also evaluated as a means
of obviating metabolic release of an aniline, and compound 14
was a very potent AR agonist. However, because compound
14 slowly eliminated water under mildly acidic conditions to
form an olefinated byproduct, no further optimization was
attempted with the pyrrol-2-one scaffold.
for trifluoromethyl-substituted imidazolin-2-one 12d (EC50
)
2.1 nM), which is likely due at least in part to its poor systemic
exposure. In contrast, ethyl-substituted 11a (EC50 ) 1.8 nM)
achieved maximum muscle recovery at a dose of 1 mg/kg. A
subsequent full dose response study determined that 11a had
an ED50 of 0.09 mg/kg for levator ani muscle and an ED50 of
approximate 4.6 mg/kg for prostate tissue which amounts to
50-fold selectivity favoring muscle (Figure 4).44 For comparison,
testosterone propionate exhibited only 2-fold muscle selectivity
in this model when given subcutaneously.29 Pharmacokinetic
studies in rats with 11a indicate that this compound has an oral
bioavailability of 65% and a plasma half-life of 5.5 h.45
Compound 11a is selective versus other steroid hormone
receptors (PR, ERR, ERâ, GR), as well as for SHBG binding
and aromatase inhibition, is clean in human hepatocyte toxicity
assays, and has only weak inhibition of CYP450 isozymes and
hERG (patch clamp).46 Furthermore, compound 11a is negative
in an exploratory Ames genotoxicity assay.47
In order to gain insight into the molecular interactions of these
alkyl-substituted imidazolin-2-ones within the AR-LBD, mo-
lecular docking studies were conducted using 11a as a probe.
Much like those key interactions observed in the X-ray cocrystal
structure of hydantoin 3, the binding model of 11a was also
dominated by the interaction between the cyano group with the
guanidinium moiety of Arg-752 to form a nonclassical hydrogen
bond of 2.6 Å length (Figure 3b). However, unlike the case of
3, the 7-hydroxyl group of 11a appeared capable of forming a
bifurcated hydrogen bond with both Asn-705 (3.0 Å) and Thr-
877 (2.8 Å). A similar bifurcated hydrogen bond to both Asn-
705 and Thr-877 was also observed in the endogenous steroid
ligand DHT cocrystal structure.40 The dihedral angle between
the aryl and imidazolin-2-one ring of 11a was determined to
be 58°, likely inducing the aryl group into a favorable orientation
for the π-edge-face interaction with the Phe-764 residue. The
docking studies also suggested that replacing the amide carbonyl
in 3 with small alkyl groups such as methyl, ethyl or trifluo-
romethyl, as in compounds 10, 11, or 12, respectively, fit well
in the hydrophobic pocket surrounded by Trp-741, Met-742,
In summary, based on pharmacophore modeling studies which
emerged from the cocrystal structure of our first generation
SARM 3, a systematic SAR exploration of the hydantoin
scaffold was carried out to provide a novel series of imidazolin-

3020 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Li et al.
Table 2. In Vivo Evaluation of Muscle and Prostate Tissue Growth and Oral Exposure in Rats
in vivo results
oral exposure at 10 mg/kg
Cmax (nM) AUC(0-4h) (nM·h)
compda
EC50 (nM)
dose (mg/kg)
muscleb
prostateb
3
8
9
10a
11a
12c
12d
TP
0.7
15
20
5.2
1.8
2.9
2.1
2.8
0.01
1
1
3
1
1
1
0.3
59 ( 3
66 ( 3
45 ( 2
44 ( 2
101 ( 4
40 ( 2
30 ( 1
70 ( 4
3 ( 1
14 ( 4
6 ( 1
6896
3972
NDc
1625
3096
819
8797
6378
NDc
2893
6078
1182
630
4 ( 1
24 ( 3
3 ( 0
1 ( 0
245
68 ( 5
NDc
NDc
a All compounds were administrated orally once a day at dose indicated. Testosterone propionate (TP) was dosed subcutaneously. A historical result of
compound 3 was included for comparison; see ref 28 for details. b The percent weight of rat levator ani muscle or ventral prostate tissue compared to intact
control group ( SEM (%). c Not determined.
mg, 0.5 mmol) in anhydrous THF (12 mL) was added LiEt3BH
(0.5 mL, 0.5 mmol, 1.0 M in THF) at -78 °C. The reaction was
stirred at -78 °C for 4 h and then quenched with a saturated
aqueous solution of Na2CO3 (5 mL). The reaction mixture was
allowed to warm to 0 °C, a solution of 30% H2O2 (∼ 0.5 mL) was
added, and the stirring was continued at 0 °C for another 30 min
before being extracted with CH2Cl2 (3×). The combined extracts
were washed with brine, dried (Na2SO4), and concentrated. The
residue (120 mg) was dissolved in anhydrous CH2Cl2, and trieth-
ylsilane (0.5 mL, 3.1 mmol) was added at -78 °C followed by
BF3Et2O (0.5 mL, 3.9 mmol). After the mixture was stirred at -78
°C for 2 h, additional triethylsilane (0.3 mL, 1.88 mmol) and
BF3Et2O (0.3 mL, 2.35 mmol) were added, and the stirring was
continued at 0 °C overnight. The reaction was quenched with a
saturated aqueous solution of Na2CO3 (10 mL), and extracted with
CH2Cl2 (3×). The combined extracts were washed with brine, dried
(Na2SO4), and concentrated. Purification by reverse phase prepara-
tive HPLC followed by chiral preparative HPLC (Chiralpak OD,
1
Figure 4. Effects of once daily treatment with compound 11a on
levator ani muscle and prostate tissue growth in a 14-day dose-response
study.
20% IPA in hexanes) afforded 8 (9 mg, 6%). HPLC: 98%; H
NMR (CD3OD) δ 2.04-2.13 (m, 2 H), 2.34 (s, 3 H), 3.22 (ddd, J
) 10.8, 9.0, 3.1 Hz, 1 H), 3.64 (ddd, J ) 10.0, 10.0, 8.6 Hz, 1 H),
3.90 (d, J ) 2.6 Hz, 1 H), 3.91 (s, 1 H), 3.99-4.03 (m, 1 H),
2-ones 10-12 as highly potent and orally active AR agonists.
4.16-4.19 (m, 1 H), 7.39 (d, J ) 8.3 Hz, 1 H), 7.66 (d, J ) 8.3
Hz, 1 H); LC-MS m/z 292 [M+H]+; HRMS calcd for (M+H)
The lead compound in the new series, 11a, had a Ki of 0.9 nM
and EC50 of 1.8 nM in the AR binding and functional assays,
respectively, and exhibited 50-fold selectivity for muscle growth
in a mature orchidectomized rat model. The overall pharma-
cological, ADME, and pharmaceutics profile of this potent
SARM suggests that 11a is a suitable SARM drug candidate
for further development.
292.0843, found 292.0843.
2-Chloro-4-((3aR,4R,6aS)-4-hydroxy-1-oxo-hexahydrocyclo-
penta[c]pyrrol-2(1H)-yl)-3-methylbenzonitrile (9). Step 1. N-
Arylation. To a vial containing compound 1537 (100 mg, 0.4 mmol)
in dioxane (1 mL) were added CuI (15.6 mg, 0.08 mmol), K3PO4
(174 mg, 0.82 mmol), 1,2-cyclohexyldiamine (4.7 mg, 0.08 mmol),
and 16 (136 mg, 0.49 mmol). The vial was sealed, heated at 110
°C for 14 h, and cooled to room temperature. The solid was filtered
and the filtrate concentrated. Purification by silica gel chromatog-
raphy (eluting with 5-100% EtOAc in hexanes and then 10%
MeOH in EtOAc), followed by chiral preparative HPLC (Chiralpak
AD, 20% IPA in heptane and then Chiralpak OD, 6% MeOH and
6% EtOH in heptane) provided N-arylated benzoyl ester (24 mg,
21%). 1H NMR (CD3OD) δ 1.94-2.00 (m, 1H), 2.03-2.18 (m, 3
H), 2.20 (s, 3 H), 3.25-3.35 (m, 2H), 3.72 (d, J ) 9.9 Hz, 1H),
3.80 (dd, J ) 2.2, 8.2 Hz, 1H), 5.50 (q, J ) 6.0 Hz, 1H), 7.20 (d,
J ) 8.2 Hz, 1H), 7.41 (t, J ) 7.7 Hz, 2H), 7.52 (d, J ) 8.2 Hz,
1H), 7.56 (t, J ) 7.7 Hz, 1H), 7.92 (d, J ) 7.7 Hz, 2H); LC/MS
(m/z) 395 [M+H]+.
Step 2. Hydrolysis of Benzoyl Ester. To a stirred solution of
benzoyl ester obtained from step 1 (24 mg, 0.06 mmol) in THF (2
mL) was added KOH (0.09 mL, 1 M in MeOH) at 0 °C, and the
stirring was continued at 0 °C for 3 h. The reaction was quenched
with 1 N HCl (0.09 mL) and diluted with EtOAc and water. The
organic layer was separated, washed with water, dried (Na2SO4),
and concentrated. Purification by silica gel chromatography, eluting
with 5-80% EtOAc in hexanes, provided 9 (15 mg, 88%). 1H NMR
(CDCl3) δ 1.73 (ddd, J ) 12.9, 12.9, 6.6 Hz, 1H), 1.91 (ddd, J )
20.5, 7.3, 4.7 Hz, 1H), 2.00-2.10 (m, 1H), 2.11-2.20 (m, 1H),
2.29 (s, 3 H), 2.85-2.92 (m, 1H), 3.14 (ddd, J ) 9.6, 9.6, 4.4 Hz,
1H), 3.90 (dd, J ) 9.9, 2.2 Hz, 1H), 4.41 (q, J ) 5.5 Hz, 1H), 7.22
Experimental Section
General Chemistry Methods. Proton and carbon-13 NMR
spectra were recorded on Jeol 400 MHz or 500 MHz instrument.
Analytical HPLC was performed on a Shimadzu HPLC using YMC
C18 5 µm 4.6 × 50 mm column with a 4 min gradient of 0-100%
solvent A (90% MeOH/90% H2O/0.2% H3PO4) and 100-0% of
solvent B (10% MeOH/90% H2O/0.2% H3PO4) with a 1 min hold.
LC-MS spectra were obtained on a Shimadzu HPLC and Micromass
Platform using electrospray ionization. HRMS were obtained on a
Micromass LCT in lockspray with electrospray ionization. The
preparative HPLC was done on an automated Shimadzu system
using YMC ODS C18 5 micron preparative columns with mixtures
of solvent C (90% MeOH/10% H2O/0.2% TFA) and solvent D
(10% MeOH/90% H2O/0.2% TFA) or mixtures of solvent E (90%
CH3CN/10%H2O/0.2% TFA) and solvent F (10% CH3CN/90%
H2O/0.2% TFA). Melting point (°C) was measured on the Mel-
Temp II device and was uncorrected. Preparation of intermediates
16, 17a, 17b, 23, and 25 are described in Supporting Information,
and other reagents and solvent were obtained from commercial
sources and were used without further purification. All reactions
were carried out under a nitrogen atmosphere unless otherwise
noted.
(7R,7aR)-2-Chloro-4-(7-hydroxy-3-oxotetrahydropyrrolo[1,2-
c]imidazol-2-yl)3-methylbenzonitrile (8). To a solution of 3 (150

Androgen Receptor Modulators
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 3021
(d, J ) 8.2 Hz, 1H), 7.52 (d, J ) 8.2 Hz, 1H); LC-MS m/z 291
[M+H]+; HRMS calcd for [M+H] 291.0900, found 290.0897; [R]D
) +80.7° (589 nm, c ) 0.091 w/v% in MeOH); Anal. (C15H15-
ClN2O2) C, H, N.
2-Chloro-4-((1S,7S,7aR)-1-ethyl-7-hydroxy-3-oxo-tetrahydro-
1H-pyrrolo[1,2-e]imidazol-2(3H)-yl)-3-methylbenzonitrile (11a)
is described as a typical procedure for 10a, 10b, and 11b (Scheme
2).
(CDCl3) δ 0.05 (s, 6H), 0.84 (s, 9H), 0.94 (t, J ) 7.5 Hz, 3H),
1.41 (s, 9H), 1.78-1.89 (m, 2H), 1.91-2.01 (m, 1H), 2.21 (s, 3H),
3.17-3.31 (m, 3H), 3.43-3.58 (m, 1H), 3.90 (d, J ) 9.7 Hz, 1H),
4.19 (J ) 2.6 Hz, 1H), 5.53 (d, J ) 4.8 Hz, 1H), 6.38 (d, J ) 8.4
Hz, 1H), 7.31 (d, J ) 8.4 Hz, 1H); LC-MS m/z 508 [M+H]+.
Step 6. Boc Deprotection and Cyclization. Aniline 21 (177 mg,
0.35 mmol) was dissolved in 15% TFA/CH2Cl2 (8 mL) and stirred
at room temperature for 3 h. The reaction was quenched with 1 N
NaOH and diluted with CH2Cl2. The organic layer was washed
with water, dried (Na2SO4), and concentrated. The residue was
dissolved in THF (3 mL) and cooled to 0 °C. i-Pr2NEt (183 µL,
1.00 mmol) was added followed by a phosgene solution (220 µL,
0.42 mmol, 1.9 M in toluene), and the stirring was continued for
10 min at 0 °C and then room temperature for 60 min before being
quenched with water. The mixture was concentrated, diluted with
EtOAc, washed with water, dried (Na2SO4), and concentrated.
Purification by silica gel chromatography, eluting with 10-30%
EtOAc in hexanes, provided TBS-protected 11a (130 mg, 86%) as
a solid. 1H NMR (CDCl3) δ 0.10 (s, 6H), 0.88 (t, J ) 7.0 Hz, 3H),
0.90 (s, 9H), 1.46-1.55 (m, 1H), 1.86 (dddd, J ) 12.8, 8.8, 8.6,
8.4 Hz, 1H), 2.18 (dddd, J ) 12.1, 8.2, 7.9, 4.2 Hz, 1H), 2.30 (s,
3H), 3.34 (ddd, J ) 13.2, 9.7, 4.0 Hz, 1H), 3.40 (dd, J ) 6.8, 2.9
Hz, 1H), 3.67 (ddd, J ) 11.9, 8.4, 8.4 Hz, 1H), 3.90 (br s, 1H),
4.00 (q, J ) 7.5 Hz, 1H), 7.11 (br s, 1H), 7.52 (d, J ) 8.3 Hz,
1H); LC-MS m/z 435 [M+H]+.
Step 7. Compound 11a. To a solution of TBS-protected 11a (130
mg, 0.3 mmol) from previous step in THF (2 mL) was added Bu4NF
(0.7 mL, 0.7 mmol, 1.0 M in THF), and the reaction was stirred at
room temperature for 60 min. The reaction was quenched with water
and then concentrated. The residue was diluted with EtOAc, washed
with water, dried (Na2SO4), and concentrated. Purification by silica
gel chromatography, eluting with 50-100% EtOAc in hexanes,
followed by reverse phase preparative HPLC (YMC S5 ODS-A
30 × 75 mm C18 column) provided 11a (65 mg, 68%) as a white
solid. 1H NMR (CDCl3) δ 0.90 (t, J ) 7.4 Hz, 3H), 1.46-1.66 (m,
2H), 1.90 (dddd, J ) 14.0, 7.1, 7.1, 6.9 Hz, 1H), 2.24 (dddd, J )
13.0, 8.0, 6.5, 6.3 Hz, 1H), 2.30 (s, 3H), 3.34 (ddd, J ) 14.0, 8.6,
5.1 Hz, 1H), 3.46 (dd, J ) 5.9, 5.6 Hz, 1H), 3.72 (ddd, J ) 15.1,
7.9, 7.9 Hz, 1H), 4.01 (t, J ) 2.8 Hz, 1H), 4.13 (q, J ) 6.9 Hz,
1H), 7.12 (d, J ) 7.9 Hz, 1H), 7.51 (d, J ) 8.2 Hz, 1H); 13C NMR
(CDCl3) δ 8.7, 16.3, 26,1, 34.3, 43.9, 62.9, 67.7, 75.6, 111.6, 116.2,
123.2, 131.2, 136.6, 138.4, 142.0, 160.0; LC-MS m/z 320 [M+H]+;
HRMS calcd for (M-H)- 318.1009, found 318.0994; [R]D ) -92.3
(c ) 0.6667 w/v% in MeOH, 23.9 °C); Anal. (C16H18ClN3O2‚0.7
H2O) C, H, N.
Step 1. Alcohols 18a (R ) Et) and 18b (R ) Et). To a stirred
solution of aldehyde 17a (13.0 g, 39.5 mmol) in anhydrous THF
(100 mL) was added dropwise EtMgBr (79.0 mL, 79.0 mmol, 1.0
M in THF) under nitrogen, and the temperature was kept below
-60 °C during the addition. The reaction was stirred at 0 °C for 2
h and then quenched with HOAc (4.5 mL, 79 mmol) at 0 °C. The
mixture was concentrated and then diluted with EtOAc. The organic
layer was washed with brine, dried (Na2SO4), and concentrated.
Purification by silica gel chromatography, eluting with 10% EtOAc
in hexanes, provided 18a (4.1 g, 29%; first eluting isomer) and
18b (4.0 g, 28%; second eluting isomer), both as oils. Alcohol 18a.
1H NMR (CDCl3) δ 0.05 and 0.06 (s, total 6H), 0.85 and 0.86 (s,
total 9H), 1.01 (t, J ) 7.3 Hz, 3H), 1.46 (s, 9H), 1.52-1.65 (m,
2H), 1.68-1.80 (m, 1H), 1.85-2.05 (m, 1H), 3.20-3.40 (m, 1H),
3.45-3.62 (m, 1H), 3.64-3.73 (m, 1H), 4.07-4.14 (m, 1H).
Step 2. Ketone 19 (R ) Et). To the mixtures of 18a and 18b
(1.9 g, 5.3 mmol) in 50 mL of CH3CN and CH2Cl2 (1:9) at room
temperature was added 4-methyl morpholine N-oxide (1.50 g, 12.8
mmol), followed by tetrapropylammonium perruthenate (95 mg,
0.27 mmol). The reaction was stirred at room temperature for 2 h
and then diluted with hexanes (50 mL). The mixture was filtered
through a pad of silica gel and concentrated. Purification by silica
gel chromatography, eluting with 10% EtOAc in hexanes, provided
1
ketone 19 (1.66 g, 87%) as an oil. H NMR (CDCl3) δ 0.06 and
0.07 (s, total 6H), 0.86 (s, 9H), 1.04 and 1.05 (t, J ) 7.1 Hz, total
3H), 1.74-1.79 (m, 1H), 1.88-1.93 (m, 1H), 2.49 and 2.57 (q, J
) 8.0 Hz, total 2H), 3.46-3.64 (m, 2H), 4.09 and 4.23 (d, J ) 2.8
Hz, total 2H), 4.17-4.21 (m, 1H).
Step 3. Oxime Intermediate. To a solution of ketone 19 (1.66 g,
4.6 mmol) in MeOH (15 mL) were added NH2OH HCl (960 mg,
13.8 mmol) and NaOAc (1.13 g, 13.8 mmol) at room temperature.
The suspension was stirred at room temperature for 2 h, filtered,
washed with EtOAc, and concentrated. Purification by silica gel
chromatography, eluting with 10% EtOAc in hexanes, provided
the oxime intermediate (1.7 g, 100%) as an oil. 1H NMR (CDCl3)
δ 0.06 and 0.07 (s, total 6H), 0.86 and 0.87 (s, total 9H), 0.99-
1.20 (m, total 3H), 1.42 and 1.46 (s, total 9H), 1.68-1.85 (m, 1H),
1.96-2.08 (m, 1H), 2.10-2.31 (m, 1H), 2.39-2.54 (m, 1H), 3.39-
3.70 (m, 2H), 4.12 and 4.23 (s, total 1H).
(2R,3S)-N-tert-Butyloxycarbonyl-3-(tert-butyldimethylsilanyl-
oxy)-2-((1R)-1-aminopropyl)pyrrolidine (20b, R ) Et). Step 1.
Mesylate formation. To a solution of alcohol 18a (1.25 g, 3.5 mmol)
in CH2Cl2 (20 mL) were added i-Pr2NEt (2.44 mL, 14.0 mmol)
and DMAP (21 mg, 0.17 mmol) at room temperature, and the
mixture was cooled to 0 °C. CH3SO2Cl (0.54 mL, 6.9 mmol) was
added at 0 °C, and the reaction was stirred at 0 °C for 20 min
followed by room temperature for 3 h. The reaction was quenched
with water and then concentrated. The residue was diluted with
EtOAc, washed with water, dried (Na2SO4) and concentrated.
Purification by silica gel chromatography, eluting with 10% EtOAc
in hexanes, provided mesylate intermediate (1.20 g, 78%) as a
Step 4. Amine 20a (R ) Et). To a 100 mL pressure reaction
vessel containing oxime (1.7 g, 4.6 mmol) from the previous step
in MeOH (40 mL) were added a slurry of Raney Ni (ca. 4.3 g, in
water), 10% Pd/C (200 mg, Degussa type), ammonia in MeOH
(2.0 M, 10 mL), and water (2 mL). The vessel was carefully
evacuated under vacuum until the solvent bubbled gently. Hydro-
genation (80 psi H2) was carried out at room temperature overnight.
The catalyst was removed by filtration, washed with additional
MeOH, and concentrated. Purification by silica gel chromatography,
eluting with 5-20% MeOH in CH2Cl2, provided 20a (1.55 g, 95%)
1
1
colorless oil. H NMR (CDCl3) δ 0.06 (s, 3H), 0.07 (s, 3H), 0.85
as an oil. H NMR (CDCl3) δ 0.05 (s, 6H), 0.85 (s, 9H), 1.00 (br
(s, 9 H), 1.03 (t, J ) 7.3 Hz, 3H), 1.44 and 1.47 (s, total 9 H),
1.58-1.73 (m, 1H), 1.73-1.88 (m, 1H), 1.89-2.02 (m, 1H), 2.99
and 3.04 (s, total 3H), 3.52 and 3.62 (ddd, J ) 9.8, 9.8, 7.7 Hz,
total 1H), 3.85-3.98 (m, 1H), 4.23-4.32 (m, 1H), 4.57-4.80 (m,
1H).
s, 3H), 1.45 (s, 9H), 1.85-2.05 (m, 4H), 2.30-2.55 (m, 1H), 3.34
(br s, 1H), 3.24-3.73 (m, 3H), 4.11 (br s, 1H).
Step 5. Aniline 21 (R ) Et). To a solution of amine 20a (600.0
mg, 1.7 mmol) in anhydrous toluene (7 mL) were added 16 (700
mg, 2.5 mmol), Pd2(dba)3 (154 mg, 0.17 mmol), (R)-N,N-dimethyl-
1-[(R)-2-(diphenyphosphino)ferrocenyl]ethylamine (225 mg, 0.51
mmol), Cs2CO3 (850 mg, 3.4 mmol), and DMSO (1 mL) at room
temperature. After the solution was degassed with N2 for 10 min,
the reaction mixture was heated at 100 °C for 48 h and then cooled
to room temperature. The reaction was diluted with EtOAc (50 mL),
washed with water, dried (Na2SO4), filtered, and concentrated.
Purification by silica gel chromatography, eluting with 0-10%
EtOAc in hexanes, provided 21 (177 mg, 21%) as an oil. 1H NMR
Step 2. Sodium Azide Displacement. To a solution of the above
mesylate intermediate (1.20 g, 2.74 mmol) in DMF (20 mL) was
added NaN3 (890 mg, 13.7 mmol), and the reaction was heated at
80 °C overnight. The reaction was quenched with water and then
concentrated. The residue was diluted with EtOAc, washed with
water, dried (Na2SO4), and concentrated. Purification by silica gel
chromatography, eluting with 10% EtOAc in hexanes, provided
1
the azide intermediate (810 mg, 77%) as a colorless oil. H NMR

3022 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Li et al.
(CDCl3) δ 0.04 (s, 6 H), 0.84 (s, 9 H), 1.03 (t, J ) 7.3 Hz, 3H),
1.45 and 1.55 (s, total 9 H), 1.50-1.61 (m, 1H), 1.67-1.80 (m,
1H), 2.03-2.15 (m, 1H), 3.30-3.44 (m, 1H), 3.44-3.55 (m, 1H),
3.55-3.66 (m, 1H), 3.66-3.71 (m, 1H), 3.87-3.96 (m, 1H), 4.21-
4.31 (m, 1H); LC-MS m/z 385 [M+H]+.
NMR (CD3OD) δ 0.89 (t, J ) 7.5 Hz, 3H), 1.60 (br s, 2H), 1.99-
2.20 (m, 2H), 2.34 (s, 3H), 3.20 (ddd, J ) 10.0, 10.0, 1.5 Hz, 1H),
3.54-3.68 (m, 2H), 4.18 (t, J ) 2.9 Hz, 1H), 4.41 (br s, 4H), 7.38
(d, J ) 7.5 Hz, 1H), 7.66 (d, J ) 8.3 Hz, 1H); LC-MS m/z 320
[M+H]+; HRMS calcd for [M+H] 320.1166, found 320.1152;
Anal. (C16H18ClN3O2) C, H, N.
Step 3. Amine 20b (R ) Et). To a solution of the above azide
intermediate (810 mg, 2.1 mmol) in MeOH (15 mL) was added
10% Pd-C (160 mg, 5% dry basis), and the reaction was stirred
under a H2 balloon for 3 h. The catalyst was removed by filtration,
washed with MeOH, and concentrated to give 20b (740 mg, 98%)
2-Chloro-4-((1S,7R,7aR)-7-hydroxy-1-methyl-3-oxo-tetrahy-
dro-1H-pyrrolo[1,2-e]imidazol-2(3H)-yl)-3-methylbenzonitrile
1
(10c). H NMR (CD3OD, 400 MHz) δ 1.24 (d, J ) 6.2 Hz, 3H),
1.99-2.20 (m, 2H), 2.33 (s, 3H), 3.15-3.25 (m ,1H), 3.55 (t, J )
2.4 Hz, 1H), 3.62 (q, J ) 9.4 Hz, 1H), 4.22 (s, 1H), 4.49 (bs, 1H),
7.36 (d, J ) 7.9 Hz, 1H), 7.67 (d, J ) 8.4 Hz, 1H); LC-MS m/z
306 [M+H]+; HRMS calcd for [M+H]+ 306.1009, found 306.1011;
Anal. (C15H16ClN3O2‚0.1 H2O) C, H, N.
1
as a colorless oil. H NMR (CDCl3) δ 0.04 (s, 3H), 0.05 (s, 3H),
0.84 (s, 9 H), 0.96 (t, J ) 7.3 Hz, 3H), 1.15-1.36 (m, 2H), 1.49-
1.63 (m, 1H), 1.73 (br s, 1H), 2.02 (dddd, J ) 13.1, 8.7, 8.7, 4.6
Hz, 1H), 2.90 and 3.09 (br s, total 1H), 3.32 (t, J ) 7.9 Hz, 1H),
3.49 (br s, 1H), 3.61 (br s, 1H), 4.34 (br s, 1H); LC-MS m/z 359
[M+H]+.
2-Chloro-4-((1R,7R,7aR)-1-ethyl-7-hydroxy-3-oxo-tetrahydro-
1H-pyrrolo[1,2-e]imidazol-2(3H)-yl)-3-methylbenzonitrile (11d).
1
2-Chloro-4-((1S,7S,7aR)-7-hydroxy1-methyl-3-oxo-tetrahydro-
1H-pyrrolo[1,2-e]imidazol-2(3H)-yl)-3-methylbenzonitrile (10a)
HPLC purity: 97%; H NMR (DMSO6) δ 0.88 (t, J ) 7.4 Hz,
3H), 1.29-1.42 (m, 1H), 1.82-1.92 (m, 2H), 1.92-2.06 (m, 1H),
2.27 (s, 3H), 3.05 (ddd, J ) 10.9, 8.1, 3.0 Hz, 1H), 3.52-3.56 (m,
J ) 9.3 Hz, 1H), 3.61 (d, J ) 7.7 Hz, 1H), 4.24-4.29 (m, 1H),
4.35 (t, J ) 10.2 Hz, 1H), 4.83 (br s, 1H), 7.18 and 7.46 (d, J )
7.7 Hz, total 1H), 7.79 (d, J ) 8.2 Hz, 1H), 7.82 (d, J ) 8.2 Hz,
1H); LC-MS m/z 320 [M+H]+, HRMS calcd for [M+H] 320.1166,
found 320.1168.
1
is prepared using amine 20a (R ) Me). H NMR (CD3OD, 400
MHz) δ 1.25 (d, J ) 6.6 Hz, 3H), 1.82-1.92 (m, 1H), 2.15-2.25
(m, 1H), 2.30 (s, 3H), 3.39 (s, 1H), 3.54-2.65 (m, 1H), 4.13 (q, J
) 6.6 Hz, 1H), 4.33 (bs, 1H), 7.35 (d, J ) 8.3 Hz, 1H), 7.69 (d, J
) 8.3 Hz, 1H); 13C NMR (CD3OD, 125 MHz) δ 16.2, 19.9, 34.7,
44.8, 71.7, 75.7, 116.8, 132.7, 137.9, 138.5, 143.1; LC-MS m/z
306 [M+H]+; HRMS calcd for [M+H] 306.1009, found 306.1002;
Anal. (C15H16ClN3O2‚0.1 H2O) C, H, N.
2-Chloro-4-((1S,7R,7aR)-7-hydroxy-3-oxo-1-(trifluoromethyl)-
tetrahydro-1H-pyrrolo[1,2-e]imidazol-2(3H)-yl)-3-methylben-
zonitrile (12d) is described as a typical procedure for 12a, 12b,
12c, and 13 (Schemes 3).
2-Chloro-4-((1R,7S,7aR)-7-hydroxy1-methyl-3-oxo-tetrahydro-
1H-pyrrolo[1,2-e]imidazol-2(3H)-yl)-3-methylbenzonitrile (10b)
1
is prepared using amine 20b (R ) Me). HPLC purity: 98%; H
Step 1. Alcohols 22a and 22b. To aldehyde 17b (2.10 g, 6.38
mmol) were added trimethyl(trifluoromethyl)silane (0.80 mL, 6.6
mmol) and CsF (10.0 mg, 0.066 mmol, dried under high vacuum
at 130 °C for 12 h). The reaction was stirred at room temperature
for 24 h and then heated at 50 °C for 5 h. After cooling to room
temperature, an aqueous HCl solution (10 mL, 40 mmol, 4 N) was
added, and the mixture was stirred overnight. The aqueous layer
was decanted and the remaining waxy yellow solid was dried under
high vacuum overnight and then recrystallized from hexanes to
provide 22a (1.19 g) as a white solid. The mother liquor was
concentrated and purified by silica gel chromatography eluting with
5-20% EtOAc in hexanes to provide additional 22a (100 mg, total
51%) and 22b (192 mg, 8%) as an oil. Alcohol 22a. 1H NMR (CD3-
OD) δ 0.12 (s, 3 H), 0.16 (s, 3 H), 0.92 (s, 9 H), 2.07-2.18 (m,
1H), 2.26 (dddd, J ) 13.7, 9.9, 9.9, 3.8 Hz, 1H), 3.32-3.48 (m,
2H), 3.73 (dd, J ) 8.5, 3.0 Hz, 1H), 4.44 (ddd, J ) 14.8, 6.6, 6.6
Hz, 1H), 4.57 (br s, 1H).
NMR (CD3OD) δ 1.23 (d, J ) 6.6 Hz, 3H), 1.79-1.92 (m, 1H),
2.23-2.35 (m, 1H), 2.31 (s, 3H), 3.26-3.35 (m, 1H), 3.55-3.70
(m, 2H), 4.09 and 4.24 (q, J ) 7.9 Hz, total 1H), 4.47 (br s, 1H),
7.37 (d, J ) 8.3 Hz, 1H), 7.71 (d, J ) 8.3 Hz, 1H); LC-MS m/z
306 [M+H]+; HRMS calcd for [M+H] 306.1009, found 306.1010.
2-Chloro-4-((1R,7S,7aR)-1-ethyl-7-hydroxy-3-oxo-tetrahydro-
1H-pyrrolo[1, 2-e]imidazol-2(3H)-yl)-3-methylbenzonitrile (11b)
is prepared using amine 20b (R ) Et). 1H NMR (CDCl3) δ 0.96 (t,
J ) 7.5 Hz, 3H), 1.45-1.57 (dddd, J ) 21.3, 7.7, 7.7, 4.2 Hz,
1H), 1.68 (dddd, J ) 20.8, 10.2, 7.1, 7.1 Hz, 1H), 1.78-1.89 (m,
1H), 2.24-2.34 (m, 1H), 2.28 (s, 3H), 3.29 (ddd, J ) 12.0, 9.4,
5.1 Hz, 1H), 3.71 (t, J ) 7.5 Hz, 1H), 3.76 (ddd, J ) 12.1, 8.8, 6.6
Hz, 1H), 4.08 (br s, 1H), 4.32 (q, J ) 7.5 Hz, 1H), 7.11 and 7.15
(d, J ) 8.2 Hz, total 1H), 7.53 (d, J ) 8.2 Hz, 1H); LC-MS m/z
320 [M+H]+; HRMS calcd for [M+H] 320.1166, found 320.1152;
Anal. (C16H18ClN3O2) C, H, N.
2-Chloro-4-((1S,7R,7aR)-1-ethyl-7-hydroxy-3-oxo-tetrahydro-
1H-pyrrolo[1, 2-e]imidazol-2(3H)-yl)-3-methylbenzonitrile (11c)
is described as a typical procedure for 10c and 11d. Step 1.
Mitsunobu Reaction. To a solution of compound 11a (51 mg, 0.16
mmol) in THF (2 mL) were added PPh3 (84 mg, 0.32 mmol) and
benzoic acid (39 mg, 0.32 mmol) followed by diisopropyl azodi-
carboxylate (65 mg, 0.32 mmol), and the mixture was stirred at
room temperature for 2 h. The reaction was concentrated and then
diluted with EtOAc. The organic layer was washed with water,
dried (Na2SO4) and concentrated. Purification by silica gel column
chromatography, eluting with 5-50% EtOAc in hexanes, yielded
Step 2. Urea 24a. To alcohol 22a (1.29 g, 3.23 mmol) in CH2-
Cl2 (24 mL) was added TFA (8 mL). After stirring for 30 min at
room temperature, toluene (ca. 5 mL) was added, the reaction was
concentrated, and the brown oil residue was dried under high
vacuum overnight. The resulting Boc-deprotected intermediate was
dissolved in CH2Cl2 (32 mL) and cooled to -78 °C. i-Pr2NEt (1.13
mL, 6.49 mmol) was added, and the mixture was stirred for 15
min at -78 °C. Isocyanate 23 (621 mg, 3.23 mmol) in CH2Cl2 (5
mL) was added, and the reaction was allowed to warm to room
temperature and stirred for 2 h. The reaction was quenched with
water and then diluted with CH2Cl2. The organic layer was washed
with brine, dried (MgSO4), filtered, and concentrated. Purification
by silica gel chromatography, eluting with 30-75% EtOAc in
1
the benzoyl ester (64 mg, 94%) as a solid. H NMR (CDCl3) δ
0.87 (t, J ) 7.5 Hz, 3H), 1.55-1.64 (m, 2H), 2.27 (br s, 3H), 2.25-
2.34 (m, 2H), 3.36 (ddd, J ) 11.6, 8.1, 3.5 Hz, 1H), 3.77 (t, J )
2.9 Hz, 1H), 3.85 (ddd, J ) 11.1, 8.8, 8.8 Hz, 1H), 4.14 (ddd, J )
5.9, 5.9, 2.4 Hz, 1H), 5.59-5.65 (m, 1H), 6.81 (br s, 1H), 7.18-
7.25 (m, 1H), 7.38 (t, J ) 7.8 Hz, 2H), 7.58 (t, J ) 7.6 Hz, 1H),
7.91 (dd, J ) 8.3, 1.3 Hz, 2H).
1
hexanes, provided 24a (1.47 g, 93%) as a white solid. H NMR
(CDCl3) δ 0.08 (s, 3 H), 0.10 (s, 3H), 0.89 (s, 9 H), 1.98-2.06 (m,
2H), 2.21 (s, 3 H), 3.49-3.58 (m, 1H), 3.72-3.83 (m, 1H), 3.92
(br s, 1H), 4.26 (t, J ) 6.4, Hz, 1H), 4.46-4.55 (m, 2H), 7.12 (br
s, 1H), 7.42 (d, J ) 8.8 Hz, 1H), 7.84 (d, J ) 8.8 Hz, 1H); LC-
MS: m/z 492 [M+H]+.
Step 3. Cyclization. To urea 24a (1.44 g, 2.93 mmol) in THF
(49 mL) at 0 °C was added tert-BuOK (8 mL, 8 mmol, 1 M in
THF) followed by p-toluenesulfonyl chloride (720 mg, 3.8 mmol)
in THF (5 mL). The cold bath was removed, and the reaction was
stirred at room temperature for 90 min and then heated at 60 °C
for 4 h. The reaction was quenched with water and then diluted
with EtOAc. The aqueous layer was acidified to pH 1 with 1 N
Step 2. Benzoyl ester (64 mg, 0.15 mmol) from the previous
step was dissolved in THF (1.5 mL) and then treated with KOH
(0.32 mL, 0.32 mmol, 1 N in MeOH) at room temperature for 2 h.
The reaction mixture with diluted with water and EtOAc. The
organic layer was washed with saturated NaHCO3 solution and
brine, dried (MgSO4), filtered, and concentrated. Purification by
reverse phase preparative HPLC (Phenominex Luna 30 × 250 mm
1
S5 C18 column) provided 11c (43 mg, 88%) as a while solid. H

Androgen Receptor Modulators
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 3023
HCl and extracted with EtOAc. The combined organics were
washed with brine, dried (MgSO4), filtered, and concentrated.
Purification by silica gel chromatography, eluting with 30-75%
EtOAc in hexanes, provided TBS-protected 12d (956 mg, 69%) as
diluted with EtOAc. The organic layer was washed with water,
dried (Na2SO4), and concentrated. Purification by silica gel chro-
matography, eluting with 30% EtOAc in hexanes, provided 26 (220
1
mg, 36%). H NMR (CDCl3) δ 0.08 and 0.10 (s, total 3H), 0.09
1
a yellow foam. H NMR (CDCl3) δ 0.06 and 0.08 (s, total 3 H),
and 0.11 (s, total 3H), 0.86 (s, 9 H), 1.91 (dddd, J ) 12.8, 6.2, 3.3,
3.0 Hz, 1H), 2.07 (dddd, J ) 13.0, 8.8, 8.8, 4.1 Hz, 1H), 2.24 and
2.26 (s, total 3H), 2.27 and 2.31 (s, total 3H), 3.68 (dd, J ) 8.8,
3.3 Hz, 2H), 3.66-3.78 (m, 2H), 4.27 and 4.33 (ddd, J ) 4.0, 2.1,
2.1 Hz, 1H), 4.48 (s, 1H), 7.08 and 7.17 (d, J ) 7.7 Hz, total 1H),
7.41 and 7.44 (d, J ) 7.7 Hz, total 1H); LC/MS (ES) m/z 435
[M+H]+.
0.12 (s, 3 H), 0.89 (s, 9 H), 1.86-2.17 (m, 2H), 2.29 and 2.40 (s,
total 3 H), 3.23-3.34 (m, 1H), 3.72 (ddd, J ) 10.4, 10.4, 7.7 Hz,
1H), 3.84 and 3.89 (dd, J ) 9.2, 1.8 Hz, total 1H), 4.54 and 4.85
(ddd, J ) 16.9, 7.7, 7.5 Hz, 1H), 7.16 and 7.28 (d, J ) 8.8 Hz,
total 1H), 7.52 (d, J ) 8.3 Hz, 1H); LC-MS: m/z 474 [M+H]+.
Step 4. Compound 12d. To TBS-protected 12d (956 mg, 2.0
mmol) in THF (20 mL) was added Bu4NF (2.5 mL, 2.5 mmol, 1
M in THF), and the reaction was stirred at room temperature for 2
h, quenched with saturated aqueous NH4Cl, and then diluted with
EtOAc. The organic layer was washed with brine, dried (MgSO4),
filtered, and concentrated. Purification by reverse phase preparative
HPLC (YMC ODS C-18, 30 × 250 mm, eluting) provided 12d
Step 2. Cyclization and Dehydration. To a 15 mL pressure
reaction vessel containing 26 (210 mg, 0.48 mmol) in anhydrous
THF (8 mL) was added piperidine (0.24 mL, 2.4 mmol). The vessel
was sealed, heated at 100 °C for 15 h, and cooled to room
temperature. Purification by silica gel chromatography, eluting with
10-30% EtOAc in hexanes, provided TBS-protected 14 (15 mg,
7%). 1H NMR (CDCl3) δ 0.06 (s, 3H), 0.08 (s, 3H), 0.87 (s, 9 H),
1.98 (s, 3H), 1.99-2.06 (m, 1H), 2.15 (dt, J ) 20.3, 6.5 Hz, 1H),
2.48 (s, 3H), 3.80 (ddd, J ) 11.6, 7.3, 6.2 Hz, 1H), 3.91 (d, J )
4.4 Hz, 1H), 4.42 (q, J ) 5.3 Hz, 1H), 4.45 (br s, 1H), 7.06 and
7.13 (d, J ) 7.9 Hz, total 1H), 7.46 and 7.51 (d, J ) 7.9 Hz, total
1H); LC-MS m/z 417 [M+H]+.
1
(617 mg, 86%) as a white solid. H NMR (CD3OD) δ 1.98-2.12
(m, 1H), 2.34 and 2.39 (s, total 3H), 3.24 (ddd, J ) 10.8, 8.0, 3.2
Hz, 1H), 3.62 and 3.71 (ddd, J ) 10.0, 10.0, 8.8 Hz, total 1H),
3.97 and 4.03 (dd, J ) 8.9, 2.0 Hz, total 1H), 4.39 (br s, 1H), 4.96
and 5.29 (ddd, J ) 16.5, 8.2, 8.0 Hz, total 1H), 7.30 and 7.48 (d,
J ) 8.4 Hz, total 1H), 7.69 (d, J ) 8.4 Hz, 1H); LC-MS: m/z 360
[M+H]+; HRMS calcd for (M+H)+ 360.0727, found 360.0738;
Anal. (C15H13ClF3N3O2) C, H, N, Cl.
Step 3. Compound 14. To TBS-protected 14 (14 mg, 0.036
mmol) in anhydrous THF (0.3 mL) in a plastic vial was added HF
pyridine (0.05 mL), and the reaction was stirred at room temperature
overnight. The reaction was concentrated and purified by reverse
phase preparative HPLC to provide 14 (8 mg, 73%) as a white
2-Chloro-4-((1R,7S,7aR)-7-hydroxy-3-oxo-1-(trifluoromethyl)-
tetrahydro-1H-pyrrolo[1,2-e]imidazol-2(3H)-yl)-3-methylben-
zonitrile (12a). 1H NMR (CD3OD) δ 1.86-1.96 (m, 1H), 2.26 (ddd,
J ) 16.4, 8.4, 3.7 Hz, 1H), 2.31 and 2.35 (s, total 3H), 3.32-3.40
(m, 1H), 3.63 and 3.67 (dd, J ) 7.1, 2.5 Hz, total 1H), 4.20 (q, J
) 7.3 Hz, 1H), 5.04-5.11 (m, 1H), 7.33 and 7.49 (d, J ) 8.7 Hz,
total 1H), 7.72 (d, J ) 8.7 Hz, 1H); LC-MS: m/z 360 [M+H]+;
HRMS calcd for (M+H)+ 360.0733, found 360.0733; Anal. (C15H13-
ClF3N3O2) C, H, N.
1
solid. HPLC purity 95%.; H NMR (CDCl3) δ 1.98 and 2.03 (s,
total 3H), 2.16-2.34 (m, 1H), 2.22 and 2.29 (s, total 3H), 2.50-
2.60 (m, 1H), 3.40-3.50 (m, 1H), 3.63 (ddd, J ) 16.8, 11.8, 8.3
Hz, 1H), 3.85-3.97 (m, 1H), 4.06 (d, J ) 7.5 Hz, 1H), 4.09 (d, J
) 7.5 Hz, 1H), 7.05 and 7.13 (d, J ) 8.3 Hz, total 1H), 7.52 (t, J
) 7.7 Hz, 1H); LC-MS m/z 303 [M+H]+; HRMS calcd for
[M+H]+ 303.0900, found 303.0898.
2-Chloro-4-((1S,7S,7aR)-7-hydroxy-3-oxo-1-(trifluoromethyl)-
tetrahydro-1H-pyrrolo[1,2-e]imidazol-2(3H)-yl)-3-methylben-
Androgen receptor binding, functional assays, and an in vivo
pharmacological rat model have been reported previously.28
Molecular Modeling and Docking. Molecular modeling and
docking were performed using ICM software.48,49 The docking of
ligands into AR LBD was performed in a two-step process. Initial
docking was carried out using multiple grid representation of the
receptor and flexible ligand. Five grid potentials were used to
describe the shape, hydrophobicity, electrostatics, and hydrogen-
bonding potential of AR LDB. The ligand conformations from the
grid-based docking were then optimized with a full atom repre-
sentation of the receptor and flexible ligand, using ICM stochastic
global optimization algorithm.
1
zonitrile (12b). H NMR (CD3OD) δ 1.88-2.01 (m, 1H), 2.25
(ddd, J ) 20.3, 7.7, 5.5 Hz, 1H), 2.35 (s, 3H), 3.31-3.35 (m, 1H),
3.63 (ddd, J ) 11.1, 7.7, 7.6 Hz, 1H), 4.11 (dd, J ) 8.5, 6.9 Hz,
1H), 4.50 (q, J ) 6.6 Hz, 1H), 5.17 (br s, 1H), 7.50 (br s, 1H),
7.71 (d, J ) 8.2 Hz, 1H); HRMS calcd for (M+H)+ 360.0727,
found 360.0726; Anal. (C15H13ClF3N3O2) C, H, N.
2-Chloro-4-((1R,7R,7aR)-7-hydroxy-3-oxo-1-(trifluoromethyl)-
tetrahydro-1H-pyrrolo[1,2-e]imidazol-2(3H)-yl)-3-methylben-
1
zonitrile (12c). HPLC purity 99%; H NMR (CD3OD) δ 2.03-
2.22 (m, 2H), 2.34 and 2.42 (s, total 3H), 3.23 (ddd, J ) 10.3,
10.3, 1.9 Hz, 1H), 3.68 (ddd, J ) 10.2, 9.3, 9.1 Hz, 1H), 3.94 and
3.99 (t, J ) 2.7 Hz, total 1H), 4.31 (t, J ) 3.0 Hz, 1H), 5.07 (ddd,
J ) 13.7, 7.1, 2.2 Hz, 1H), 7.31 and 7.49 (d, J ) 8.2 Hz, total
1H), 7.69 (d, J ) 8.2 Hz, 1H); HRMS calcd for (M+H)+ 360.0727,
found 360.0731; Anal. (C15H13ClF3N3O2) Cl.
Acknowledgment. The authors would like to thank Gerry
Everlof for performing aqueous solubility and log P determi-
nation, and James Johnson for conducting exploratory Ames
assay.
2-Chloro-4-((1R,7R,7aR)-7-hydroxy-1-isopropyl-3-oxo-tet-
rahydro-1H-pyrrolo[1,2-e]imidazol-2(3H)-yl)-3-methylbenzoni-
trile (13). 1H NMR (CD3OD) δ 0.42 and 0.45 (d, J ) 6.6 Hz, total
3H), 1.03 and 1.08 (m, J ) 6.6 Hz, total 3H), 1.92-2.07 (m, 2H),
2.32 and 2.41 (s, total 3H), 2.45-2.54 (m, 1H), 2.63 (dddd, J )
9.9, 6.5, 6.5, 3.5 Hz, 1H), 3.13-3.20 (m, 1H), 3.67-3.77 (m, 2H),
4.12 (dd, J ) 10.2, 8.0 Hz, 1H), 4.43 and 4.52 (br s, total 1H),
7.38 and 7.42 (dd, J ) 8.3, 3.5 Hz, total 1H), 7.65 (dd, J ) 8.3,
3.5 Hz, 1H); MS: m/z 665 [2M-H]-; HRMS calcd for (M+H)+
334.1322, found 334.1333. Anal. (C17H20ClN3O2) C, H, N.
2-Chloro-4-((7S,7aR)-7-hydroxy-1-methyl-3-oxo-5,6,7,7a-tet-
rahydro-3H-pyrrolizin-2-yl)-3-methylbenzonitrile (14). Step 1.
Amide 26. To compound 19 (480 mg, 1.4 mmol) was added 10%
TFA/CH2Cl2 solution (7 mL) at room temperature, and the mixture
was stirred for 4 h. Toluene (7 mL) was added, and the reaction
was concentrated to give a pale brown residue which was then
dissolved in CH2Cl2 (5 mL). A solution of PyBrop (1.2 g, 2.5 mmol)
and acid 25 (210 mg, 1 mmol) in THF (3 mL) was added followed
by i-Pr2NEt (0.52 mL, 3 mmol), and stirring was continued for 3
h at room temperature. The reaction was concentrated and then
Supporting Information Available: Preparation of intermediate
compounds 16, 17a, 17b, 23, and 25. This material is available
free of charge via the Internet at http://pubs.acs.org.
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µM; aromatase inhibition IC50 > 100 µM. Human hepatotoxicity
JM070312D