Synthesis and structure-activity relationship studies of 3,6-diazabicyclo[3.2.0]heptanes as novel α4β2 nicotinic acetylcholine receptor selective agonists

Article abstract of DOI:10.1021/jm070755h

A series of novel, potent neuronal nicotinic acetylcholine receptor (nAChR) ligands derived from 3,6-diazabicyclo[3.2.0]heptane have been synthesized and evaluated for binding affinity and agonist activity at the α4β2 nAChR subtype. Structure-activity relationship studies of these novel nAChR ligands focused on substitution effects on the pyridine ring, as well as stereo- and regiochemical influences of the 3,6-diazabicyclo[3.2.0]heptane core. Small 5-substituents on the pyridine ring had a modest impact on the binding affinities and functional activities. 6-Bromo, 6-chloro, and 6-methyl substituents on the pyridine ring led to increased binding affinities and improved functional activities. Most of the 6-N-pyridinyl-substituted 3,6-diazabicyclo[3.2.0]heptanes are selective for the α4β2 nAChR subtype. Compounds (1R,5S)-25, (1R,5S)-55, and (1R,5S)-56 were virtually inactive as agonists at the hα3β4 nAChR but retained potency and efficacy at the hα4β2 nAChR subtype. 3-N-Pyridinyl-substituted series demonstrated more complex SAR. (1R,5R)-39, (1R,5R)-41, and (1R,5R)-42 were found to be much more potent at the hα3β4 nAChR subtype, whereas (1R,5R)-38 and (1R,5R)-40 were very selective at the hα4β2 nAChR subtype. The SAR studies of these novel ligands led to the discovery of several compounds with interesting in vitro pharmacological profiles.

Full text of DOI:10.1021/jm070755h

J. Med. Chem. 2007, 50, 5493-5508
5493
Synthesis and Structure-Activity Relationship Studies of 3,6-Diazabicyclo[3.2.0]heptanes as
Novel r4â2 Nicotinic Acetylcholine Receptor Selective Agonists
Jianguo Ji,*,† Michael R. Schrimpf,† Kevin B. Sippy,† William H. Bunnelle,† Tao Li,† David J. Anderson,† Connie Faltynek,†
Carol S. Surowy,† Tino Dyhring,‡ Philip K. Ahring,‡ and Michael D. Meyer†
Neuroscience Research, R47W, AP9A-1, Abbott, Abbott Park, Illinois 60064, and NeuroSearch A/S, Ballerup, Denmark
ReceiVed June 26, 2007
A series of novel, potent neuronal nicotinic acetylcholine receptor (nAChR) ligands derived from 3,6-
diazabicyclo[3.2.0]heptane have been synthesized and evaluated for binding affinity and agonist activity at
the R4â2 nAChR subtype. Structure-activity relationship studies of these novel nAChR ligands focused on
substitution effects on the pyridine ring, as well as stereo- and regiochemical influences of the
3,6-diazabicyclo[3.2.0]heptane core. Small 5-substituents on the pyridine ring had a modest impact on the
binding affinities and functional activities. 6-Bromo, 6-chloro, and 6-methyl substituents on the pyridine
ring led to increased binding affinities and improved functional activities. Most of the 6-N-pyridinyl-substituted
3,6-diazabicyclo[3.2.0]heptanes are selective for the R4â2 nAChR subtype. Compounds (1R,5S)-25, (1R,5S)-
55, and (1R,5S)-56 were virtually inactive as agonists at the hR3â4 nAChR but retained potency and efficacy
at the hR4â2 nAChR subtype. 3-N-Pyridinyl-substituted series demonstrated more complex SAR. (1R,5R)-
39, (1R,5R)-41, and (1R,5R)-42 were found to be much more potent at the hR3â4 nAChR subtype, whereas
(1R,5R)-38 and (1R,5R)-40 were very selective at the hR4â2 nAChR subtype. The SAR studies of these
novel ligands led to the discovery of several compounds with interesting in Vitro pharmacological profiles.
Introduction
pain relievers was not appreciated until the early 1990s when
epibatidine (2), a novel nAChR agonist isolated from the skin
of a poisonous Ecuadorian tree frog, demonstrated potent
analgesic effects,10 surpassing even opioids such as morphine
(3).8,11 Epibatidine demonstrates poor binding selectivity among
nAChR subtypes (especially R4â2 vs R3â4 nAChR),12 and its
toxicity profile is unacceptable for clinical use.13 In the search
for nAChR analgesics with an improved therapeutic window,
the structural diversity of nAChR ligands, primarily comprising
series of nicotine and epibatidine analogues, has been exten-
sively studied over the past decade with a focus on the
identification of R4â2 nAChR subtype selective agonists.4b For
an example, tebanicline (4), a potent nAChR agonist with
moderate enhancement of R4â2 (vs R3â4) nAChR subtype
selectivity as compared to 2, demonstrated analgesic effects
across a broad range of preclinical models of nociceptive and
neuropathic pain.14 However, tebanicline exhibited only a
modest therapeutic window and showed dose-limiting gas-
trointestinal side effects. To identify novel nAChR agonists with
superior R4â2 nAChR subtype selectivity and with reduced
adverse effects, our ongoing efforts focused on novel nAChR
pharmacophores and their structure-activity relationships (SARs)
for further exploration of analgesic agents with clinical potential.
Commonly prescribed analgesic agents, such as nonsteroidal
anti-inflammatory drugs (NSAIDs) and opioids,1 have safety
concerns, as well as unpleasant side effects.2 To satisfy
significant unmet medical need and achieve optimal analgesic
efficacy without undesirable side effects, the search for novel
and efficacious analgesics with improved therapeutic window
continues to receive considerable attention.3 Among a number
of novel approaches to pain relief currently under investigation,
nicotinic acetylcholine receptors (nAChRs) hold considerable
potential as therapeutic targets for the development of analgesic
drugs.4 nAChRs are pentameric ligand-gated ion channel
proteins that are widely expressed throughout the central and
peripheral nervous systems (CNS and PNS). nAChRs are
derived from multiple R (R2-R10) and â (â2-â4) subunit genes.
Each distinct subunit gene composition defines a certain nAChR
subtype with characteristic pharmacological and biophysical
properties.5 Accordingly, drug discovery efforts have been
focused on the development of subtype-selective nAChR ligands
for the potential treatment of Alzheimer’s disease (AD),
Parkinson’s disease, Tourette’s syndrome, schizophrenia, de-
pression, and pain.6 Of particular interest is the R4â2 receptor
subtype, a major target involved in the analgesic response
elicited by nAChR agonists.7 On the other hand, the R3â4
nAChR subtype that predominates in the autonomic ganglia and
mediates the systemic release of multiple neurotransmitters is
correlated to adverse events.8 Consequently, the discovery of
potent R4â2 nAChR subtype selective (vs R3â4) agonists has
been critical for the advancement of novel nAChR-based
analgesics with improved safety profiles.4b
A few pharmacophore models for R4â2 nAChR ligands have
been proposed to integrate binding interactions of nAChR
ligands.15 However, these are generally not useful for novel
ligand design.15b According to Beers and Reich’s early
hypothesis,15f nicotinic agonists require a Columbic interaction
involving the cationic center and a hydrogen bond acceptor
feature that interacts with a receptor-based hydrogen bond donor
site. Glennon et al. suggested an improved vector pharmaco-
phore model stating that the spatial relationship between these
two pharmacophoric elements is very important for ligand
binding affinities toward R4â2 nAChR.15c From structural
analysis of various nAChR ligands developed during the past
decade, one simple conclusion is that most of the nAChR ligands
Despite the mild analgesic effects of nicotine (1) (Scheme
1) reported decades ago,9 the potential of nAChR ligands as
* To whom correspondence should be addressed. Tel: 847-935-3579.
Fax: 847-937-9195. E-mail: jianguo.ji@abbott.com.
† Abbott.
‡ NeuroSearch.
10.1021/jm070755h CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/11/2007

5494 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22
Ji et al.
Scheme 1
Scheme 2
providing (()-15 in an overall 90% yield. The optimized six-
step process from 10 to (()-15 required neither distillation nor
chromatographic purification.
Resolution of (()-15 with (R)-mandelic acid was then
investigated. According to the procedure reported by Ohta,23
amino alcohol (()-15 was initially treated with (R)-mandelic
acid in cyclohexanone at -20 °C for 48 h. The reaction
consistently gave enantiomerically enriched salt in 35-44%
yield with maximal 94% ee. Replacing cyclohexanone with
anhydrous acetone under identical conditions gave (S,S)-16 with
excellent enantioselectivity (>98% ee) but with much lower
chemical yield (<10%). After additional optimization, the
recovery of (S,S)-16 was improved to 44% (>98% ee) by simply
pretreating (()-15 with 2-methoxypropene. This modification
also allows the chiral resolution to proceed at ambient temper-
ature without sacrificing optical purity or chemical yield. The
enantiomeric excess was determined by chiral high-performance
liquid chromatography (HPLC) assay of the corresponding
amino-alcohol intermediate (3S,4S)-17. The latter was easily
obtained by acidic hydrolysis of salt (S,S)-16, followed by
treatment with Boc2O under basic conditions. Although the role
of 2-methoxypropene in the reaction is not very clear at the
present time, the formation of the fused 1,3-oxazinane that is
actually resolved through chiral salt (S,S)-16 was accelerated.
The best resolution condition involved premixing 2 equiv of
2-methoxypropene with (()-15 for 1.0 h followed by treatment
with 1 equiv of (R)-mandelic acid in anhydrous acetone at
ambient temperature for 48 h. Crystalline (S,S)-16 was isolated
in 44% yield (vs maximal 50%) with over 98% enantiomeric
excess. The crystallization of (S,S)-16 also served as the first
purification in the seven-step sequence from 10.
(S,S)-16 was hydrolyzed with aqueous H2SO4, then basified
to pH 10, and treated with di-tert-butyldicarbonate to give
(3S,4S)-17 in excellent chemical yield. The reaction of (3S,4S)-
17 with methanesulfonyl chloride gave mesylate (3S,4S)-18,
which was smoothly transformed to (1S,5S)-19a (R ) Cbz) by
removal of the N-Boc-protecting group under acidic conditions,
followed by basification to liberate the nucleophilic amine. The
five-step process from (S,S)-16 to (1S,5S)-19a did not require
chromatographic purification and gave (1S,5S)-19a in 90%
overall yield. (1S,5S)-19a was transformed to (1R,5S)-20 by
initial 6-N-Boc protection of (1S,5S)-19a with di-tert-butyldi-
carbonate and then N-Cbz deprotection under catalytic hydro-
genation conditions with Pd/C. (1S,5S)-19a was also converted
to (1R,5S)-19b (R ) Boc) through a sequence involving 6-N-
CF3CO protection of (1S,5S)-19a with (CF3CO)2O, a swap of
3-N-Cbz for the 3-N-Boc-protecting group under catalytic
hydrogenation conditions with Pd/C, and last the deprotection
of azetidine nitrogen with K2CO3 in MeOH. The opposite
are generally composed of an sp3 nitrogen atom, a heteroaryl
group possibly containing an sp2 nitrogen atom, and a linker
that connects the sp3 nitrogen atom to the heteroaryl group. The
linkers play an important role by determining the internitrogen
3
2
(Nsp -Nsp ) distance and orientation in the ligand’s binding
conformation. The structural motif of many unique linkers often
3
is constructed with a rigidified skeleton of Nsp -(C)n-X-,
wherein -(C)n-X- can be a simple -C- (nicotine 1), -CC-
(epibatidine 2,10 varenicline 516), -CCC- (dianicline, 617),
-CCCC- (ispronicline 718), -CCO- (tebanicline 4),14 and
-CCN- (8).19 With regards to the ligands with the -NCCN-
motif, compound 8 shows potent binding affinity ([3H]cytisine,
IC50 ) 1.9 nM)19b but holds a relatively flexible homopiperazine
linker, which provides the ligand with multiple conformational
3
2
possibilities varying the internitrogen (Nsp -Nsp ) distance and
orientation. To gain more insight into the SAR of ligands with
the -NCCN- motif, we proposed that a rigidified -NCCN-
motif linker, such as 3,6-diazabicyclo[3.2.0]heptane (9), should
reduce the conformational complexity of ligands and might lead
to novel R4â2 nAChR agonists with enhanced subtype selectiv-
ity. This paper describes the chiral synthesis and pharmacologi-
cal profiles of 3,6-diazabicyclo[3.2.0]heptane-derived pyridine
analogues A (6-N-pyridinyl-substituted series) and B (3-N-
pyridinyl-substituted series) (Scheme 2).
Results and Discussion
Chemistry. Scheme 3 outlines the chiral synthesis of
intermediates (1S,5S)-19 and (1R,5S)-20.20 Oxime 13 was
synthesized through a convenient process21 including the N-Cbz
protection of 2,2-dimethoxyethylamine (10) and the subsequent
N-allylation to offer dimethyl acetal 11, hydrolysis of 11 to
produce aldehyde 12, and oxime formation with hydroxyamine.
Intramolecular 1,3-dipolar cycloaddition of oxime 13 afforded
the racemic intermediate isoxazolidine (()-14, which was then
converted to (cis)-3-amino-4-(hydroxymethyl)pyrrolidine (()-
15 by reductive cleavage of the N-O bond in (()-14 using
Zn/HOAc. To minimize the facile air oxidation of 14 to
isoxazoline22 impurities as often detected by LC/MS, cyclization
of 13 and reduction of 14 were carried out in a single pot

3,6-Diazabicyclo[3.2.0]heptanes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22 5495
Scheme 3. Synthesis of Optically Pure 3,6-Diazabicyclo[3.2.0]heptanea
a Reagents and conditions: (a) CbzCl, NaOH (aqueous), toluene, r.t., 4 h, 91%. (b) Allyl-Br, KOH, Et3BnN+Cl-, r.t., 14 h, 96%. (c) HCO2H, r.t., 15 h,
99%. (d) HONH2‚HCl, NaOAc, MeCN, r.t., 20 h, 98%. (e) Xylene, 130 °C, 10 h. (f) Zn/HOAc, r.t., 3 h, 90%. (g) (1) 2-Methoxypropene, acetone, r.t., 1
h; (2) (R)-mandelic acid, r.t., 48 h, 44% yield, >98% ee. (h) (1) H2SO4 (aqueous), EtOH, r.t., 16 h; (2) NaOH (aqueous), Boc2O, 65 °C, 4 h, 98%. (i) MsCl,
Et3N, CH2Cl2, -10 °C, 0.5 h, 97%. (j) (1) CF3CO2H, CH2Cl2, 0-20 °C, 1 h; (2) NaOH (aqueous), EtOH, pH)10, 60 °C, 10 h, 95%. (k) Boc2O, CH2Cl2,
Et3N, r.t., 10 h, 95%. (l) Pd/C, H2, EtOH, r.t. 4 h, 89%. (m) (1) (CF3CO)2O, Et3N, THF, -20 to 0 °C, 4 h, 96%; (2) Pd/C, H2, Boc2O, MeOH, r.t., 10 h, 82%;
(3) K2CO3, MeOH, 65 °C, 1 h, 80%.
Scheme 4. Synthesis of Pyridine-Substituted
Scheme 5a
3,6-Diazabicyclo[3.2.0]heptanesa
a Reagents and conditions: (a) Pd/C, H2, EtOH, r.t., 10 h, >87%. (b)
CF3CO2H, CH2Cl2, r.t., 1 h, 85%.
hydrogenation conditions (Pd/C-H2 for the deprotection of
N-Cbz group). 5-Methyl-substituted analogues 32 and 43 can
be prepared through a convenient palladium-mediated hydro-
genation of 30 and 41, respectively (Scheme 5).
Scheme 6 illustrates the further transformation of the Buch-
wald-Hartwig coupling products 3-N-Boc-23 and 3-N-Cbz-23.
Under standard Sonogashira reaction conditions,25 reaction of
3-N-Boc-23 with ethynyltrimethylsilane, followed by the depro-
tection of trimethylsilyl and N-Boc groups, provided 44. Under
typical Stille coupling conditions,26 reaction of 3-N-Cbz-23 with
2-(tributylstannyl)oxazole or 1-methyl-4-(tributylstannyl)imid-
azole installed oxazole or imidazole groups on the 5-position,
leading to 45 and 46.
Several of the Buchwald-Hartwig coupling products (Scheme
7) could be further elaborated with a 6-bromo substituent by
the reaction with NBS in MeCN to provide compounds 47-49
and 51-54. The directive effect of the 3-amino group dominates,
so that bromination at the 6-position was the major product
regardless of the 5-substitutents. Minor amounts of 2-bromo
and 2,6-dibromo byproducts were observed in some cases. These
could be minimized by control of reaction temperature, amount,
and rate of addition of NBS. These byproducts were easily
removed by chromatography. Compound 50 was prepared by
the reaction of 3-N-Boc-48 with urea‚H2O2 and the deprotection
of the N-Boc group with CF3CO2H in CH2Cl2.
a Reagents and conditions: (a) Compound 19a (1.0 equiv), 21 (1.5 equiv),
Pd2(dba)3 (0.02 equiv), rac-BINAP or xantphos (0.06 equiv), BuONa or
Cs2CO3 (1.5 equiv) in toluene (0.2 M), at 100-110 °C, 10-40 h. (b)
CF3CO2H, or TsOH, or Pd/C-H2. (c) Compound 20 (1.0 equiv), 21 (1.5
equiv), Pd2(dba)3 (0.02 equiv), rac-BINAP or xantphos (0.06 equiv), tBuONa
or Cs2CO3 (1.5 equiv) (1.5 equiv) in toluene (0.2 M), at 100-110 °C, 10-
40 h.
t
enantiomers, (1R,5R)-19 and (1S,5R)-20, were obtained by
resolution of (()-15 with (S)-mandelic acid and using the same
sequence described above.
Scheme 4 outlines the synthesis of 3,6-diazabicyclo[3.2.0]-
heptanyl pyridine analogues 22-31 and 33-42. Monoprotected
3,6-diazabicyclo[3.2.0]heptanes 19a or 20 were condensed with
halopyridines 21 via a palladium-mediated procedure initially
developed by Buchwald and Hartwig.24 The Buchwald and
Hartwig amination of numerous pyridines 21 with a variety of
5- and/or 6-substitutents, including bromo, chloro, cyano,
methoxy, and methyl, proceeded smoothly and provided the
corresponding coupling products with moderate-to-excellent
chemical yield (40-95%). The protecting groups of the coupling
products were then removed under acidic conditions (CF3CO2H
for the removal of N-Boc or N-Cbz groups) or catalytic
Scheme 8 outlines the further transformation of (1S,5S)-tert-
butyl 6-(5-cyanopyridin-3-yl)-3,6-diazabicyclo[3.2.0]heptane-

5496 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22
Scheme 6. Transformation of 5-Bromopyridinesa
Ji et al.
Scheme 8a
a Reagents and conditions: (a) NH2OH‚HCl, Et3N, EtOH, r.t., 10 h, 76%.
(b) CF3CO2H, CH2Cl2, r.t., 1 h. (c) m-CPBA (1.28 equiv), MeCN, r.t., 10
h, 97%.
Biology. The predominant receptor with high affinity for
[3H]nicotine and (-)-[3H]cytisine in rodent brain is composed
of R4 and â2 subunits.27 As a primary screen, the binding
affinities of ligands at nAChRs were determined by assessing
their ability to compete with (-)-[3H]cytisine in binding to rat
brain membranes (n g 3).28 In addition to (-)-[3H]cytisine
binding, fluorometric imaging plate reader (FLIPR) cellular
assays29 using recombinant human receptors were employed to
evaluate the functional activities and subtype nAChR selectivity
in all lines expressing recombinant human receptors.30 Serial
log dilutions of test compound were applied, and the corre-
sponding changes in intracellular calcium were assessed. Data
were normalized to the response evoked by 100 µM nicotine,
and EC50 and maximal efficacy values were determined.
Exploration of SARs for the 3,6-diazabicyclo[3.2.0]heptane
was focused on 6-N- and 3-N-pyridin-3-yl-substituted 3,6-diaza-
bicyclo[3.2.0]heptanes (structures A and B, Scheme 2), espe-
cially on the extensive variations of substitutions on the 5- and/
or 6-positions of pyridine ring. The results are shown in Tables
1 and 2. Typically, only those nAChR ligands with high affinity
(Ki < 50 nM) were selected for functional evaluation. In
functional assays, compounds with EC50 > 100 µM or less than
20% maximal peak response were generally considered to be
weak or partial agonists. Comparison of EC50 and efficacy at
recombinant hR4â2 and hR3â4 nAChR subtypes provides an
estimate of nAChR subtype selectivity. Ideally, selective hR4â2
nAChR agonists should give high efficacy and potency at
hR4â2 but not at hR3â4 nAChRs. As noted earlier, compounds
with optimal subtype selectivity (hR4â2 vs hR3â4) hold the
potential for achieving analgesic efficacy with a low incidence
of undesired side effects.
a Reagents and conditions: (a) (1) TMSCtCH (2.5 equiv), PdCl2(PPh3)2,
(0.02 equiv), CuI (0.1 equiv), Et3N, DMF, 70 °C, 10 h, >60%; (2) Bu4N+F-,
THF, r.t., 1 h; (3) CF3CO2H, CH2Cl2, r.t., 2 h, 94%. (b) R2SnBu3 (2.0 equiv),
PdCl2(PPh3)2, (0.02 equiv), MeCN, 80 °C, 6 h, 99%. (c) Pd/C, H2, EtOH,
r.t., 2 h, >60%.
Scheme 7. Preparation of 6-Bromopyridin-3-yl-Substituted
3,6-Diazabicyclo[3.2.0]heptanesa
Examination of the (-)-[3H]cytisine binding indicated that
most of the 6-N-substituted 3,6-diazabicyclo[3.2.0]heptanes
(structure A) demonstrated comparable binding affinities (0.2-
29 nM) to (S)-nicotine 1 (0.96 nM) and much weaker than
epibatidine 2 (0.05 nM) (Table 1). Small substituents on the
5-position of the pyridine ring, such as hydrogen (22), bromo
(23), chloro (24), nitrile (25), methoxy (26), methyl (32), and
ethynyl (44), had little impact on binding affinities (Ki ) 0.6-
7.2 nM) (Table 1). On the other hand, placement of oxazol-2-
yl and 1-methyl-imidazol-4-yl on 5-position (45 and 46,
respectively) diminished binding affinities 15-20-fold (45 and
46 vs 22, Table 1). 6-Chloro analogue 29 exhibited comparable
binding affinities to 22. With regards to 5,6-disubstituted
pyridin-3-yl analogues, 6-halo (chloro or bromo) substituents
boost binding affinities 4-15-fold, as exemplified by com-
pounds with a 6-chloro substitutent, (1R,5S)-31 (Ki ) 0.3 nM)
vs (1R,5S)-24 (Ki ) 3.0 nM) and (1R,5S)-30 (Ki ) 0.2 nM) vs
(1R,5S)-32 (Ki ) 1.1 nM), as well as compounds with a 6-bromo
substitutent, (1R,5S)-47 (Ki ) 0.5 nM) vs (1R,5S)-23 (Ki ) 3.1
a Reagents and conditions: (a) NBS (1.0 equiv), MeCN, -20 to 20 °C,
0.5-1 h. (b) For deprotection of N-Boc group: CF3CO2H, CH2Cl2, r.t., 1
h; for deprotection of N-Cbz group: CF3CO2H, 65 °C, 1 h. (c) 3-N-Boc 48
(1.0 equiv), urea‚H2O2 (10.1 equiv), K2CO3 (0.1 equiv), acetone-water,
r.t., 10 h, 51%.
3-carboxylate (3-N-Boc-25). The reaction of (1S,5S)-3-N-Boc-
25 with hydroxylamine gave N-hydroxynicotinimidamide, and
the deprotection of N-Boc with CF3CO2H provided 5-
[(1R,5S)-3,6-diazabicyclo[3.2.0]heptan-6-yl]-N-hydroxynicotinimid-
amide 55. Oxidation of (1S,5S)-3-N-Boc-25 with m-CPBA,
followed by the deprotection of N-Boc group, afforded 3-[(1R,5S)-
3,6-diazabicyclo[3.2.0]heptan-6-yl]-5-cyanopyridine 1-oxide 56.

3,6-Diazabicyclo[3.2.0]heptanes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22 5497
Table 1. Binding and Functional Activity of 6-N-Substituted 3,6-Diazabicyclo[3.2.0]heptanes
a Displacement studies with [3H]cytisine using rat brain homogenates. The Ki represents mean values obtained from independent experiments where n g
3. b Values represents mean potencies of compounds, as assessed by measuring fluorescence changes using FLIPR technology in HEK 293 cell lines expressing
human R4â2 and R3â4 nAChRs. c Max values represent the maximal response of the ligand relative to the peak response for the positive control of 100 µM
nicotine. d nc, EC50 not reliably calculable for agonists with a maximal response below 20%.

5498 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22
Ji et al.
Table 2. Binding and Functional Activity of 3-N-Substituted 3,6-Diazabicyclo[3.2.0]heptanes
Ca2+ flux (FLIPR)
[3H]-cytisine binding
hR4â2
hR3â4
compd
R1
R2
pKi ( SEM
Kia (nM)
pEC50 ( SEM
EC50b (µM)
max (%)c
pEC50 ( SEM
EC50b (µM)
max (%)c
(1S,5S)-33
(1R,5R)-33
(1S,5S)-34
(1R,5R)-34
(1S,5S)-35
(1S,5S)-36
(1R,5R)-36
(1S,5S)-37
(1R,5R)-37
(1S,5S)-38
(1R,5R)-38
(1S,5S)-39
(1R,5R)-39
(1S,5S)-40
(1R,5R)-40
(1S,5S)-41
(1R,5R)-41
(1S,5S)-42
(1R,5R)-42
(1S,5S)-43
(1S,5S)-51
(1S,5S)-52
(1S,5S)-53
(1S,5S)-54
(1R,5R)-54
H
H
H
H
H
H
H
H
H
H
Br
Br
8.92 ( 0.06
9.96 ( 0.02
8.84 ( 0.04
10.20 ( 0.10
8.72 ( 0.04
8.77 ( 0.06
9.92 ( 0.05
8.52 ( 0.06
9.96 ( 0.06
8.65 ( 0.13
9.59 ( 0.08
9.20 ( 0.03
10.22 ( 0.62
9.24 ( 0.11
9.77 ( 0.04
10.10 ( 0.10
10.40 ( 0.04
9.53 ( 0.05
10.40 ( 0.06
8.61 ( 0.04
9.52 ( 0.05
9.62 ( 0.09
9.51 ( 0.04
8.71 ( 0.21
10.15 ( 0.05
1.2
0.1
1.4
0.1
1.9
1.7
0.1
3.0
0.1
2.2
0.3
0.6
0.06
0.6
0.2
0.08
0.04
0.3
0.04
2.5
0.3
0.2
0.3
1.9
0.07
5.81 ( 0.04
6.53 ( 0.08
5.21 ( 0.07
5.97 ( 0.05
5.03 ( 0.02
4.88 ( 0.08
6.38 ( 0.17
4.88 ( 0.13
6.04 ( 0.06
5.93 ( 0.02
6.68 ( 0.02
6.14 ( 0.09
7.36 ( 0.07
6.79 ( 0.02
7.61 ( 0.08
6.52 ( 0.03
7.14 ( 0.02
6.35 ( 0.21
7.38 ( 0.05
4.51 ( 0.15
5.93 ( 0.07
6.41 ( 0.09
6.11 ( 0.05
5.66 ( 0.05
6.83 ( 0.01
1.6
0.3
6.5
1.1
11.4
14.6
0.6
15.8
1.0
1.2
0.2
0.8
0.5
0.2
0.03
0.3
0.7
0.4
0.4
39.9
1.2
0.4
0.8
2.2
0.2
122 ( 5
181 ( 14
53 ( 5
5.22 ( 0.02
6.22 ( 0.03
5.04 ( 0.02
6.62 ( 0.03
4.60 ( 0.03
5.15 ( 0.03
6.49 ( 0.02
4.33 ( 0.04
5.99 ( 0.02
5.49 ( 0.01
5.49 ( 0.01
6.04 ( 0.03
7.06 ( 0.02
6.35 ( 0.02
7.46 ( 0.03
6.17 ( 0.01
6.75 ( 0.06
5.84 ( 0.07
7.27 ( 0.04
4.42 ( 0.03
5.90 ( 0.02
6.23 ( 0.08
6.24 ( 0.01
5.40 ( 0.03
7.00 ( 0.01
6.1
0.6
9.1
0.2
25.3
7.1
0.3
48.1
1.0
3.3
3.3
0.9
0.09
0.4
0.4
0.7
0.2
1.5
0.05
38.5
1.3
0.6
0.6
4.0
0.1
90 ( 3
119 ( 4
68 ( 2
115 ( 4
57 ( 2
84 ( 3
102 ( 2
44 ( 3
99 ( 4
85 ( 3
96 ( 2
94 ( 3
101 ( 2
110 ( 3
105 ( 2
100 ( 2
119 ( 4
92 ( 1
98 ( 2
74 ( 2
90 ( 3
92 ( 2
91 ( 2
72 ( 1
113 ( 5
161 ( 6
66 ( 6
Cl
CN
CN
OMe
OMe
Me
Me
CN
CN
H
102 ( 6
123 ( 5
55 ( 5
130 ( 7
76 ( 2
124 ( 4
119 ( 4
136 ( 7
162 ( 6
126 ( 2
134 ( 6
228 ( 9
110 ( 5
162 ( 6
76 ( 7
H
Me
Me
Me
Me
Cl
Cl
Cl
Cl
Cl
Cl
H
Br
Br
Br
Br
Br
H
Me
Me
Cl
Cl
Me
Br
122 ( 6
108 ( 5
146 ( 9
64 ( 2
Cl
CN
OMe
OMe
159 ( 6
a Displacement studies with [3H]cytisine using rat brain homogenates. The Ki represents mean values obtained from independent experiments where n g
3. b Values represents mean potencies of compounds, as assessed by measuring fluorescence changes using FLIPR technology in HEK 293 cell lines expressing
human R4â2 and R3â4 nAChRs. c Max values represent the maximal response of the ligand relative to the peak response for the positive control of 100 µM
nicotine
nM) and (1R,5S)-48 (Ki ) 0.3 nM) vs (1R,5S)-25 (Ki ) 3.2
nM) and (1R,5S)-49 (Ki ) 0.2 nM) vs (1R,5S)-26 (Ki ) 0.8
nM). On the other hand, the 6-methyl substituent revealed
similar binding affinity [for example, (1R,5S)-28 (Ki ) 1.1 nM)
vs (1R,5S)-25 (Ki ) 3.2 nM)]. Slight differences in binding
affinities between (1R,5S)- and (1S,5R)-enantiomers were
sometimes noted, but no clear SAR trends of stereochemical
effect on binding affinities could be predicted.
imidazol-4-yl substituents at the 5-position of the pyridine ring,
lacked agonist activity at either hR4â2 or hR3â4 nAChR
subtypes. A 6-chloro substituent (29) increased agonist activity
at both recombinant hR4â2 and hR3â4 nAChR subtypes relative
to 22. Similar trends were observed for other 6-chloro, 6-methyl,
and 6-bromo analogues (27-31 and 47-50). In spite of the
modest stereochemical influence of 3,6-diazabicyclo[3.2.0]-
heptane core on [3H]cytisine binding Ki values, ligands of
structure A with (1R,5S)-stereochemistry, with the exception
of compounds 27-29, demonstrated substantially more potent
agonist activity at recombinant hR4â2 nAChR subtypes relative
to (1S,5R)-enantiomers. On the basis of the functional data in
Table 1, several compounds deserve particular attention because
of the significant differentiation between functional activities
at hR4â2 and hR3â4 nAChR subtypes. (1R,5S)-22 and (1R,5S)-
50 showed full agonist activity at both hR4â2 and hR3â4
nAChR subtypes, but EC50 values at recombinant hR4â2 nAChR
subtype were approximately 15-19-fold more potent than at
the hR3â4 nAChR subtype. Compounds (1R,5S)-25, (1R,5S)-
55, and (1R,5S)-56 were virtually inactive as agonists at the
hR3â4 nAChR but retained potency and efficacy at the hR4â2
nAChR subtype. (1R,5S)-25, (1R,5S)-55, and (1R,5S)-56 offered,
thus far, the highest degree of subtype selective for agonist
activity at hR4â2 nAChR with very weak hR3â4 nAChR agonist
activity.
As shown in Table 1, functional data from the 6-N-substituted
3,6-diazabicyclo[3.2.0]heptanes showed that all compounds,
with the exception of 45 and 46, demonstrated substantial
agonist activities at recombinant human R4â2 and/or R3â4
nAChR subtypes. (1R,5S)-22 was slightly more potent (EC50
) 1.9 µM) and efficacious (maximal response, 116%) at the
recombinant hR4â2 nAChR subtype than (S)-nicotine 1 (EC50
) 6.6 µM; maximal response, 101%) but is weaker (EC50
)
29.4 µM) and less efficacious (maximal response, 62%) than
(S)-nicotine 1 (EC50 ) 8.0 µM; maximal response, 89%) at the
recombinant hR3â4 nAChR subtype. As compared to 22, 5-Cl,
5-MeO, 5-Me, and 5-ethynyl analogues (24, 26, 32, and 44)
revealed slightly weaker agonist activities at the recombinant
hR4â2 nAChR subtypes. 5-Br and 5-nitrile analogues (23 and
25) showed stereochemical effects of 3,6-diazabicyclo[3.2.0]-
heptane core on nAChR subtype selectivity. Both (1S,5R)-23
and (1S,5R)-25 demonstrated weak and nonselective agonist
activity at the recombinant hR4â2 and hR3â4 nAChR subtypes.
However, enantiomers (1R,5S)-23 and (1R,5S)-25 showed
agonist activity at hR4â2 nAChR subtype but did not show
detectable functional potency at hR3â4 nAChR subtype due to
low efficacy. Ligands 45 and 46, with oxazol-2-yl and 1-methyl-
Likewise, 3-N-substituted 3,6-diazabicyclo[3.2.0]heptanes
(structure B) have also been tested in [3H]cytisine binding and
FLIPR functional assays (Table 2). As compared to the ligands
of structure A, many of the compounds with chemical structure
B showed more potent binding affinities (0.04-3.0 nM) and

3,6-Diazabicyclo[3.2.0]heptanes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22 5499
agonist activity. Monosubstitution on the 5-position of the
pyridine ring (34-37 and 43 vs 33) had little influence on
binding affinities (0.1-3.0 vs 0.1-1.2 nM) but reduced
functional agonist activities at both hR4â2 and hR3â4 nAChR
subtypes. 6-Methyl-, 6-chloro-, and 6-bromo-substituted pyridine
analogues (38-42 and 51-54) demonstrated more potent
binding affinities and agonist activities relative to the corre-
sponding 6-unsubstituted pyridine analogues (33-37 and 43).
In contrast to the 6-N-substituted series (structure A), the 3-N-
substituted series (structure B) showed significant stereochemical
effects on binding affinity and functional potency. (1R,5R)-
Enantiomers demonstrated approximately 5-30-fold more
potent binding affinity than (1S,5S)-enantiomers. In many cases,
(1R,5R)-enantiomers also exhibited more potent functional
agonist activities than (1S,5S)-enantiomers. For instance, (1S,5S)-
33 showed an approximately 12-fold weaker Ki value (Ki )
1.2 nM) and 5-fold less potent EC50 value at hR4â2 nAChR
subtype (EC50 ) 1.6 µM; maximal response, 122%), as well as
The 3-N-substituted series, especially those ligands with a
(1R,5R)-3,6-diazabicyclo[3.2.0]heptane stereochemical skeleton,
demonstrated complex SARs. (1R,5R)-38 and (1R,5R)-40 pref-
erentially activated hR4â2 (vs hR3â4) nAChR subtypes with
excellent potency and high efficacy. On the other hand, (1R,5R)-
34, (1R,5R)-39, (1R,5R)-41, and (1R,5R)-42 demonstrated
substantially stronger potency at hR3â4 (vs hR4â2) nAChR
subtype. (1R,5R)-42 and (1R,5R)-41 are compounds with the
lowest Ki values (Ki ) 0.04 nM) in the entire 3,6-diazabicyclo-
[3.2.0]heptane series. (1R,5R)-40 is the most potent hR4â2
nAChR (EC50 ) 0.03 µM; maximal response, 126%) agonist.
The SAR studies of novel 3,6-diazabicyclo[3.2.0]heptane nAChR
ligands led to the identification of several nAChR subtype
selective compounds that were advanced to in vivo testing in
models of efficacy and tolerability. Examples of such prototypes
will be reported elsewhere.
Experimental Section
a 10-fold higher EC50 value at hR3â4 nAChR subtype (EC50
)
Chemistry General. 1H NMR spectra were recorded on GE QE-
300 (300 MHz) and Bruker AMX-400 (400 MHz) spectrometers.
Chemical shifts are reported in parts per million (ppm) downfield
from tetramethylsilane (TMS) as an internal standard. Data are
reported as follows: chemical shift, multiplicity (s ) singlet, d )
doublet, t ) triplet, q ) quartet, dd ) doublets of doublets, m )
multiplet, and br ) broad), coupling constant(s), integration, and
peak assignment. 13C NMR spectra were recorded on a GE QE-
300 (75 MHz) spectrometer using broad band proton decoupling.
Chemical shifts are reported in ppm downfield from TMS, using
the middle resonance of CDCl3 (77.0 ppm) or MeOH-d4 (49.0 ppm)
as an internal standard. Mass spectra were acquired on a Jeol JMS-
SX-102 spectrometer. HPLC analyses were carried out on Hitachi
system model D-7000. Elemental analyses were performed by QTI
Quantitative Technologies Inc. (Whitehouse, NJ). Unless otherwise
specified, all reagents and solvents were obtained from commercial
suppliers.
Benzyl Allyl-(2,2-dimethoxyethyl)carbamate (11).31,32 Step
1: Benzyl chloroformate (95%, 231.3 g, 1.29 mol) was added
gradually to a mixture of aminoacetaldehyde dimethyl acetal (10)
(152.0 g, 1.45 mol) in toluene (750 mL) and aqueous NaOH (72.8
g, 1.82 mol, in 375 mL of water) at 10-20 °C. After the addition
was completed, the mixture was stirred at ambient temperature for
4 h. The organic layer was separated and washed with brine (2 ×
100 mL). It was then concentrated to afford benzyl 2,2-dimethoxy-
ethyl-carboxylate as an oil (281.5 g, 91.0% yield). 1H NMR (CDCl3,
300 MHz): δ 3.33 (t, J ) 6.0 Hz, 2H), 3.39 (s, 6H), 4.37 (t, J )
6.0 Hz, 1H), 5.11 (s, 2H), 7.30 (m, 5H). MS (DCI/NH3) m/z 257
(M + NH4)+, 240 (M + H)+.
Step 2: Under N2, powdered KOH (291.2 g, 5.20 mol) and
triethyl-benzylammonium chloride (4.40 g, 19.4 mmol) were added
to a 2 L three-necked flask containing the solution of benzyl 2,2-
dimethoxyethylcarbamate (281.0 g, 1.18 mol) in dry toluene (1.0
L). A solution of allyl bromide (188.7 g, 1.56 mol) in toluene (300
mL) was then added dropwise over 1 h at 20-30 °C. The mixture
was stirred at ambient temperature for 14 h. The reaction was slowly
quenched with water (300 mL) at 20-30 °C over 20 min. The
organic layer was separated, and the aqueous phase was extracted
with toluene (2 × 300 mL). The combined organic extracts were
washed with brine (2 × 100 mL) and concentrated to give 11 as
an oil (315.6 g, 96% yield). 1H NMR (CD3OD, 300 MHz): δ 3.32
(s, 3H), 3.37 (m, 5H), 3.97 (d, J ) 5.40 Hz, 2H), 4.45 (m, 1H),
5.15 (m, 4H), 5.75 (m, 1H), 7.23 (m, 5H). MS (DCI/NH3) m/z 297
(M + NH4)+, 280 (M + H)+.
Benzyl Allyl-(2-oxo-ethyl)carbamate (12).32 A solution of 11
(314.0 g, 1.125 mol) in formic acid (88%, 350 mL) was stirred
under N2 at ambient temperature for 15 h. Most of the formic acid
was then removed under reduced pressure at 40-50 °C. The residue
was extracted with EtOAc (3 × 500 mL). The combined extracts
were washed with brine until the wash had a pH of 6-7. The
6.1 µM; maximal response, 90%) than (1R,5R)-33 (Ki ) 0.1
nM; hR4â2 nAChR: EC50 ) 0.3 µM; maximal response, 181%;
hR3â4 nAChR: EC50 ) 0.6 µM; maximal response, 119%)
(Table 2). Similar trends were noticed for compounds 34 and
36-42 as well. With regard to subtype selectivity, it is apparent
that most of the ligands with (1S,5S)-absolute stereochemistry
are generally hR4â2 nAChR subtype selective (see Table 2).
Compounds with (1R,5R)-absolute stereochemistry, on the other
hand, gave a more complex SAR. For example, (1R,5R)-38 and
(1R,5R)-40 are potent and efficacious hR4â2 nAChR subtype
selective agonists. (1R,5R)-34, (1R,5R)-39, (1R,5R)-41, and
(1R,5R)-42 revealed substantially more potent hR3â4 (vs hR4â2)
nAChR agonist activity (Table 2). Additionally, several other
ligands with (1R,5R)-absolute chemistry, such as (1R,5R)-33
and (1R,5R)-37, showed low to moderate hR4â2 nAChR subtype
selectivity. At the present time, the prediction of subtype
selectivity resulting from substitution on the pyridine ring of
(1R,5R)-stereoisomers remains difficult.
Data presented in Tables 1 and 2 also indicate a few other
important SAR trends for stereo- and regiochemistry effects of
the 3,6-diazabicyclo[3.2.0]heptane core. The 3-N-pyridinyl-
substituted 3,6-diazabicyclo[3.2.0]heptanes (structure B) are, in
general, more potent than the 6-N-substituted series (structure
A) in the [3H]cytisine binding assay. The 3-N-substituted series
also demonstrate more potent agonist activities (Table 2) than
the corresponding 6-N-substituted series (Table 1) at both hR4â2
and hR3â4 nAChR subtypes. The 6-N-substituted series gener-
ally has a preference for activation of the hR4â2 nAChR
subtype.
In conclusion, we have explored 3,6-diazabicyclo[3.2.0]-
heptane as a useful core for the optimization of novel selective
hR4â2 nAChR agonists. Both absolute enantiomers of 3,6-
diazabicyclo[3.2.0]heptane have been synthesized and employed
to prepare 6-(N)- and 3-(N)-pyridin-3-yl-substituted analogues
(structures A and B). SAR studies of these novel nAChR ligands
explored substitution effects of the pyridine ring and stereo-
and regiochemical influences of the 3,6-diazabicyclo[3.2.0]-
heptane core. Small 5-substituents on the pyridine ring had
modest impact on the binding affinities and functional activities.
6-Bromo and 6-chloro substituents on the pyridine led to an
increase in binding affinities and functional activities. 6-N-
Pyridinyl-substituted 3,6-diazabicyclo[3.2.0]heptanes were typi-
cally found to be hR4â2 nAChR subtype selective. (1R,5S)-25,
(1R,5S)-55, and (1R,5S)-56 are hR4â2 nAChR subtype selective
agonists with almost no agonist efficacy at the hR3â4 nAChR.

5500 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22
Ji et al.
organic solution was then concentrated to provide 12 as an oil (260.0
g, 98.8% yield). H NMR (CDCl3, 300 MHz): δ 3.20 (m, 1H),
3.97 (m, 2H), 4.10 (m, 1H), 5.10 (m, 4H), 5.75 (m, 1H), 7.45 (m,
5H), 9.50 (d, J ) 6.40 Hz, 1H). MS (DCI/NH3) m/z 234 (M +
H)+.
(3 × 500 mL). The combined extracts were washed with brine (2
× 100 mL) and concentrated to give (S,S)-17 as a solid (43.7 g,
98% yield). The optical purity (>98% ee) was determined by HPLC
(HPLC conditions: Chiracel AD column; eluents, EtOH/hexanes
) 20/80; flow rate, 1.0 mL/min; UV, 215 nm; retention time for
(S,S)-17 as the more mobile isomer, 10.8 min; and retention time
for (R,R)-17 as the less mobile isomer, 13.9 min); mp 149.0-150.8
°C. 1H NMR (CD3OD, 400 MHz): δ 1.46 (s, 9 H), 2.50 (m, 1 H),
3.25 (m, 1 H), 3.40 (m, 1 H), 3.50-3.75 (m, 4 H), 4.20 (m, 1 H),
5.10 (s, 2 H), 7.35 (m, 5 H) ppm. 13C NMR (CD3OD, 75 MHz):
δ 158.4, 156.7, 138.2, 129.5, 129.0, 128.8, 80.6, 68.1, 60.8, 53.1,
52.9, 52.1, 48.0, 47.8, 45.7, 44.9, 28.7 ppm. MS (DCI/NH3) m/z
1
Benzyl Allyl-(2-hydroxyiminoethyl)carbamate (13). A solution
of NaOAc‚3H2O (170.6 g, 1.254 mol, in 0.75 L of water) was added
to a flask containing the solution of 12 (260.0 g, 1.115 mol) and
NH2OH‚HCl (98.0 g, 1.41 mol) in MeCN (1.5 L) and then stirred
at ambient temperature for 20 h. The volatiles were then removed
under reduced pressure, and the residue was extracted with EtOAc
(2 × 750 mL). The combined extracts were washed with brine until
the wash had a pH of 7. The organic solution was concentrated to
368 (M + NH4)+, 351 (M + H)+; [R]D ) 17.50° (c ) 0.67,
20
1
MeOH). Anal. (C18H26N2O5) C, H, N.
provide 13 as an oil (271.0 g 97.6% yield). H NMR (CD3OD,
300 MHz): δ 3.94 (m, 2H), 3.98 (d, J ) 5.43 Hz, 1H), 4.17 (d, J
) 4.41 Hz, 1H), 5.30 (m, 4H), 5.62 (m, 1H), 7.27-7.36 (m, 6H)
ppm. 13C NMR (CDCl3, 75 MHz): δ 156.1, 155.9, 149.8, 149.4,
147.0, 136.2, 132.8, 132.6, 128.4, 128.0, 127.8, 118.1, 117.8, 117.5,
117.3, 67.5, 50.8, 50.4, 49.5, 49.0, 45.4, 45.1, 42.4, 42.0 ppm. MS
(DCI/NH3) m/z 266 (M + NH4)+, 249 (M + H)+. Anal. (C13H16N2O3)
C, H, N.
Benzyl (3S,4S)-3-tert-Butoxycarbonylamino-4-methylsulfon-
yloxymethyl-pyrrolidine-1-carboxylate (18).34 A solution of
methanesulfonyl chloride (12.6 mL, 163 mmol) in anhydrous
CH2Cl2 (50 mL) was added to the solution of (S,S)-17 (43.7 g, 125
mmol) and Et3N (25.2 g, 250 mmol) in anhydrous CH2Cl2 (600
mL) at -10 °C over 30 min. The reaction was then allowed to
warm to ambient temperature and stirred for 1 h and quenched with
water (100 mL). The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (2 × 400 mL). The combined
organic solution was washed with brine (2 × 100 mL) and
concentrated to give (S,S)-18 as an oil (52.0 g, 97% yield). 1H NMR
(CDCl3, 300 MHz): δ 1.46 (s, 9H), 2.80 (m, 1 H), 3.08 (s, 3 H),
3.40 (m, 2 H), 3.70 (m, 2 H), 4.10 (m, 2 H), 4.75 (m, 1 H), 5.16
(s, 2 H), 7.30 (m, 5 H). MS (DCI/NH3) m/z 446 (M + NH4)+, 429
(M + H)+.
(()-Benzyl 3-Amino-4-hydroxymethyl-pyrrolidine-1-carbox-
ylate [(()-15].23,33 A solution of 13 (20.0 g, 80.6 mmol) in xylene
(100 mL) was stirred under N2 at 130 °C for 10 h. The brown
solution was cooled to ambient temperature, and HOAc (100 mL)
was then added. Zinc powder (10.0 g, 154 mmol) was added
gradually at 10 °C. After the addition was completed, the reaction
mixture was stirred at ambient temperature for 3 h. The inorganic
solid was removed by filtration. The xylene solution was then stirred
with water (100 mL) for 10 min and separated. The aqueous layer
was extracted with xylene (4 × 40 mL). The combined extracts
were concentrated under reduced pressure. The residue was basified
to pH 9-10 by cautious addition of saturated aqueous Na2CO3.
The precipitated white solid was removed by filtration. The aqueous
solution was extracted with CHCl3 (3 × 60 mL). The combined
extracts were washed with saturated aqueous Na2CO3 (2 × 10 mL)
and dried over anhydrous Na2CO3. The mixture was then filtered
through a short column of diatomaceous earth and concentrated to
provide (()-15 as an oil (18.2 g, 90.3% yield). 1H NMR (CD3OD,
300 MHz): δ 2.40 (m, 1H), 3.32 (m, 2H), 3.52-3.80 (m, 5H),
5.10 (s, 2H), 7.35 (m, 5H) ppm. 13C NMR (CD3OD, 75 MHz):
156.7, 138.2, 19.4, 129.0, 128.8, 67.9, 60.6, 55.4, 55.1, 52.8, 52.0,
47.9, 47.7, 46.1, 45.3 ppm. MS (DCI/NH3) m/z 251 (M + H)+.
(3S,4S)-Benzyl2,2-Dimethyl-hexahydro-pyrrolo[3,4-d]1,3oxazine-
6-carboxylate (16) [(R)-Mandelate].23 2-Methoxypropene (5.5 mL,
56.0 mmol) was added to the solution of (()-15 (7.0 g, 28.0 mmol)
in anhydrous acetone (10 mL). The solution was stirred at ambient
temperature for 1 h and subsequently concentrated under reduced
pressure to remove the volatiles. The residue was then dissolved
in anhydrous acetone (140 mL) and stirred with (R)-mandelic acid
(4.25 g, 28.0 mmol) at ambient temperature for 48 h. The precipitate
was obtained by filtration and dried under reduced pressure to
provide (3S,4S)-16 as a white solid (5.46 g, 44% yield); mp 113.7-
Benzyl (1S,5S)-3,6-Diaza-bicyclo[3.2.0]heptane-3-carboxylate
(19a). A solution of (S,S)-18 (43.7 g, 125 mmol) in CH2Cl2 (150
mL) was stirred with CF3CO2H (50 mL) at 0-20 °C for 1 h. It
was then concentrated under reduced pressure. The residue was
dissolved in EtOH (250 mL), basified to pH ∼10 with 10% aqueous
NaOH, and stirred at 60 °C for 10 h. It was cooled to ambient
temperature and concentrated under reduced pressure to remove
most of the volatiles. The residue was extracted with CHCl3 (2 ×
500 mL). The combined extracts were washed with brine (3 × 50
mL) and then passed through a short column of diatomaceous earth.
The filtrate was concentrated to give (1S,5S)-19a (28.0 g, 95%
yield). 1H NMR (CD3OD, 300 MHz): δ 3.16-3.30 (m, 3 H), 3.36
(m, 1 H), 3.75-3.86 (m, 3 H), 4.55 (m, 1 H), 5.20 (s, 2 H), 7.36
(m, 5 H). 13C NMR (CD3OD, 75 MHz): δ 157.4, 138.2, 129.5,
129.1, 129.0, 68.2, 63.6, 54.8, 52.9, 50.6, 38.3. MS (DCI/NH3) m/z
250 (M + NH4)+, 233 (M + H)+; [R]D ) -18.97° (c ) 0.39,
20
MeOH). Anal. (C13H16N2O2) C, H, N.
Synthesis of tert-Butyl (1S,5S)-3,6-Diaza-bicyclo[3.2.0]heptane-
3-carboxylate (19b). Step 1: A solution of (CF3CO)2O (2.77 g,
13.2 mmol) in tetrahydrofuran (THF) (anhydrous, 10 mL) was
slowly added to a flask containing the solution of (1S,5S)-19a (2.80
g, 12 mmol) and Et3N (1.82 g, 18 mmol) in anhydrous THF (20
mL) under N2 at -20 °C. The reaction was then warmed to 0 °C
and stirred for 4 h. The volatiles were removed under reduced
pressure. The residue was diluted with EtOAc (100 mL), washed
with brine (2 × 10 mL), and concentrated to give benzyl (1S,5S)-
6-trifluoroacetyl-3,6-diaza-bicyclo[3.2.0]heptane-3-carboxylate (3.80
g, 96.5% yield). 1H NMR (CDCl3, 400 MHz): δ 3.11-3.42 (m, 3
H), 3.56-3.77 (m, 0.7 H, rotamer), 3.79-4.05 (m, 1.3 H, rotamer),
4.09-4.33 (m, 1.7 H, rotamer) 4.47 (t, J ) 8.75 Hz, 0.3 H, rotamer),
4.85 (t, J ) 5.98 Hz, 0.7 H, rotamer), 4.93 (t, J ) 6.00 Hz, 0.3 H,
rotamer), 5.03-5.33 (m, 2 H), 7.18-7.44 (m, 5 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ 162.0, 155.2, 136.2, 128.4, 128.1, 127.8,
105.4, 67.4, 67.3, 56.1, 52.8, 50.4, 49.9, 48.3 ppm. MS (DCI/NH3)
1
115.8 °C. H NMR (CD3OD, 300 MHz): δ 1.30 [s (br.), 3 H],
2.09 (s, 3 H), 3.30 (m, 1 H), 3.48-3.75 (m, 6 H), 4.20 (m, 1 H),
5.10 (m, 3 H), 7.25-7.52 (m, 10 H) ppm. 13C NMR (DMSO-d6,
75 MHz): δ 206.4, 174.4, 141.5, 137.1, 128.3, 127.7, 127.6, 127.5,
127.4, 126.9, 126.4, 82.7, 72.8, 65.9, 65.6, 58.9, 58.0, 57.6, 53.3,
53.2, 52.7, 51.0, 50.4, 50.2, 49.5, 48.6, 46.2, 45.6, 45.5, 45.0, 42.9,
42.0, 35.1, 34.3, 30.6, 30.0, 28.9, 20.3, 18.4 ppm. MS (DCI/NH3)
20
m/z 291 (M + H)+; [R]D ) -45.70° (c ) 0.37, MeOH). Anal.
(C16H22N2O3‚1.0C8H8O3) C, H, N.
Benzyl (3S,4S)-3-tert-Butoxycarbonylamino-4-hydroxymethyl-
pyrrolidine-1-carboxylate (17). A solution of (3S,4S)-16 (56.0 g,
127 mmol) in EtOH (50 mL) was stirred with aqueous H2SO4 (5%,
100 mL) at ambient temperature for 16 h. It was then basified to
pH ∼10 with 20% aqueous NaOH (50 mL). A solution of di-tert-
butyl dicarbonate (41.5 g, 190 mmol) in EtOH (50 mL) was
cautiously added at 10-20 °C. After the addition was completed,
it was allowed to stir at 65 °C for 4 h. The volatiles were removed
under reduced pressure, and the residue was extracted with EtOAc
20
m/z 346 (M + NH4)+, 329 (M + H)+. [R]D ) -85.87° (c )
0.39, MeOH).
Step 2: A solution of benzyl (1S,5S)-6-trifluoroacetyl-3,6-diaza-
bicyclo[3.2.0]heptane-3-carboxylate (3.77 g, 11.5 mmol) in MeOH
(50 mL) was stirred with Pd/C (10 wt %, 0.38 g) under H2 at
ambient temperature for 2 h. It was then degassed and purged with
N2 three times. Boc2O (4.36 g, 22 mmol) was added, and the
mixture was stirred at ambient temperature for 10 h. The catalyst

3,6-Diazabicyclo[3.2.0]heptanes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22 5501
was cautiously removed by filtration through a short column of
diatomaceous earth. The filtrate was concentrated to give tert-butyl
(1S,5S)-6-trifluoroacetyl-3,6-diazabicyclo[3.2.0]heptane-3-carbox-
ylate as an oil (2.80 g, 82.6% yield). 1H NMR (CDCl3, 400 MHz):
δ 1.48 (s, 9 H), 3.22 (dd, J ) 12.12, 6.29 Hz, 1 H), 3.29 (dd, J )
13.96, 5.37 Hz, 1 H), 3.32-3.43 (m, 1 H), 3.71 (dd, J ) 10.74,
5.52 Hz, 1 H), 3.80 (d, J ) 11.97 Hz, 1 H), 4.12-4.30 (m, 2 H),
4.90 (t, J ) 6.14 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ
162.4, 154.8, 80.8, 63.2, 50.2, 49.7, 48.3, 35.9, 28.2 ppm. MS (DCI/
solution of (1S,5S)-3-N-Cbz-22 (190 mg) in methanol (10 mL) was
stirred with Pd/C (wt 10%, 100 mg) under H2 for 2 h. The catalyst
was cautiously removed by filtration through a short column of
diatomaceous earth. The filtrate was concentrated to give (1R,5S)-
22 (100 mg, 94% yield).
N-Cbz Deprotection: Representative Procedure “D(b)”. A
solution of (1S,5S)-3-N-Cbz-23 (180 mg, 0.46 mmol) in trifluoro-
acetic acid (3.0 mL) was stirred at 65 °C for 1 h. It was then
concentrated under reduced pressure. The residue was treated with
NaOH aqueous solution (5%) to pH 8-9. It was subsequently
extracted with CHCl3 (3 × 10 mL). The combined extracts were
washed with brine (2 × 10 mL) and concentrated. The residue was
purified by chromatography (SiO2, solvent: v. CH2Cl2:MeOH:NH3‚
H2O ) 90:10:2) to give (1R,5S)-23 (Rf ) 0.15, 80 mg, 69% yield).
N-Boc Deprotection: Representative Procedure “D(c)”. A
solution of (1R,5S)-6-N-Boc-33 (430 mg, 1.56 mmol) in CH2Cl2
(5 mL) was stirred with trifluoroacetic acid (1 mL) at ambient
temperature for 1 h. It was then concentrated, and the residue was
purified with chromatography on silica gel (solvent: v. CH2Cl2:
MeOH:NH3‚H2O ) 90:10:2) to give (1S,5S)-33 (Rf ) 0.1, 230 mg,
84%).
20
NH3) m/z 312 (M + NH4)+, 295 (M + H)+; [R]D ) -22.32° (c
) 0.36, MeOH).
Step 3: The solution of (tert-butyl (1S,5S)-6-trifluoroacetyl-3,6-
diazabicyclo[3.2.0]heptane-3-carboxylate (2.70 g, 9.2 mmol) in
MeOH (20 mL) was stirred with saturated K2CO3 (aqueous, 5 mL)
at 65 °C for 1 h. It was then extracted with CHCl3 (3 × 50 mL).
The combined extracts were washed with brine (2 × 10 mL), passed
through a short column of diatomaceous earth, and then concen-
trated to give (1S,5S)-19b (1.50 g, 79.8% yield). 1H NMR (CD3OD,
300 MHz): δ 1.49 (s, 9 H), 3.09-3.29 (m, 4 H), 3.62-3.73 (m, 2
H), 3.77 (t, J)7.97 Hz, 1 H), 4.38 (m, 1 H) ppm. 13C NMR
(CD3OD, 100 MHz): δ 157.06, 80.99, 63.45, 54.82, 52.68, 50.69,
39.14, 28.80, 25.34 ppm. MS (DCI/NH3) m/z 199 (M + H)+; [R]D
20
N-Boc Deprotection: Representative Procedure “D(d)”. A
solution of (1R,5S)-6-N-Boc-38 (280 mg, 0.92 mmol) in EtOAc
(10 mL) was stirred with TsOH‚H2O (351 mg, 1.85 mmol) at 80
°C for 6 h. The precipitate was filtered and dried to give (1S,5S)-
38 tosylate (320 mg, 81% yield).
) -32.14° (c ) 0.28, MeOH). Anal. (C10H18N2O2) C, H, N.
(1R,5S)-3-Benzyl 6-tert-Butyl 3,6-Diazabicyclo[3.2.0]heptane-
3,6-dicarboxylate (3-N-Cbz-20). A solution of (1S,5S)-19a (6.96
g, 30.0 mmol) in CH2Cl2 (100 mL) was stirred with Et3N (4.04 g,
40 mmol) and Boc2O (8.72 g, 40.0 mmol) at ambient temperature
for 10 h. It was then concentrated, and the residue was purified
with chromatography on silica gel (EtOAc/hexanes, v. 1/1, Rf )
0.4) to provide (1R,5S)-3-benzyl 6-tert-butyl 3,6-diazabicyclo[3.2.0]-
heptane-3,6-dicarboxylate [(1R,5S)-3-N-Cbz-20] (9.50 g, yield,
Salt Formation: Representative Procedure “S(a)” for Fu-
marate Formation. A solution of fumaric acid (66 mg, 0.57 mmol)
in EtOH (1 mL) was added to a solution of (1R,5S)-22 (100 mg,
0.57 mmol) in EtOAc (10 mL). The mixture was then stirred at
ambient temperature for 16 h. The white precipitate was filtered
and dried to give (1R,5S)-22-fumarate (120 mg, 73% yield).
Salt Formation: Representative Procedure “S(b)” for Tosyl-
ate Formation. (1R,5S)-25 (1.40 g, 7 mmol) was dissolved in iPrOH
(50 mL) and heated to 80 °C. The solution of TsOH‚H2O (2.66 g,
14.0 mmol) in EtOAc (50 mL) was slowly added to the above
solution at 80 °C over 0.5 h. After the addition was finished, the
mixture was cooled to ambient temperature and stirred for 10 h.
The solid was filtered and dried to give (1R,5S)-25 bis(tosylate) as
a white solid (3.20 g, 84.0% yield).
Salt Formation: Representative Procedure “S(c)” for Tri-
fluoroacetate Formation. A solution of (1R,5S)-6-N-Boc-41 (480
mg, 1.48 mmol) in CH2Cl2 (5 mL) was stirred with trifluoroacetic
acid (5 mL) at ambient temperature for 2 h. It was then concentrated,
and the residue was stirred in i-PrOAc (5 mL) at ambient
temperature overnight. The precipitate was filtered and dried to
give (1S,5S)-41 trifluoroacetate (310 mg, 62% yield).
1
95.4%). H NMR (CD3OD, 400 MHz): δ 1.41 (s, 9 H), 2.98-
3.17 (m, 2 H), 3.21-3.29 (m, 1 H), 3.39-3.52 (m, 1 H), 3.86 (d,
J ) 11.9 Hz, 1 H), 3.95-4.11 (m, 2 H), 4.67 (dd, J ) 6.4, 4.4 Hz,
1 H), 5.05-5.26 (m, 2 H), 7.08-7.62 (m, 5 H) ppm. MS (DCI/
NH3) m/z 350 (M + NH4)+, 333 (M + H)+.
(1R,5S)-tert-Butyl 3,6-Diazabicyclo[3.2.0]heptane-6-carbox-
ylate (20). A solution of [(1R,5S)-3-N-Cbz-20] (7.5 g, 22.6 mmol)
in EtOH (50 mL) was stirred with Pd/C (10 wt %, 0.75 g) under
H2 for 4 h. The catalyst was cautiously removed by filtration through
a short column of diatomaceous earth. The filtrate was concentrated
to give (1R,5S)-tert-butyl 3,6-diazabicyclo[3.2.0]heptane-6-car-
1
boxylate (20) as an oil (4.0 g, yield, 89.4%). H NMR (CD3OD,
400 MHz): δ 1.43 (s, 9 H), 2.46 (dd, J ) 12.9, 3.7 Hz, 1 H), 2.62
(dd, J ) 12.2, 6.1 Hz, 1 H), 2.90-3.00 (m, 1 H), 3.03 (d, J ) 12.5
Hz, 1 H), 3.22 (d, J ) 12.9 Hz, 1 H), 3.37-3.57 (m, 1 H), 3.95 (t,
J ) 7.6 Hz, 1 H), 4.64 (dd, J ) 6.1, 3.7 Hz, 1 H) ppm. MS (DCI/
NH3) m/z 199 (M + H)+.
(1R,5S)-6-Pyridin-3-yl-3,6-diaza-bicyclo[3.2.0]heptane (22) Fu-
marate. This was prepared according to the representative proce-
dures C(a), D(a), and S(a) using (1S,5S)-19a and 3-bromopyridine.
1H NMR (CD3OD, 300 MHz): δ 3.18 (dd, J ) 12.6, 3.4 Hz, 1 H),
3.35 (m, 1 H), 3.46 (m, 1 H), 3.75 (m, 3 H), 4.04 (t, J ) 7.8 Hz,
1 H), 4.90 (m, 1 H), 6.58(s, 2.5 H), 7.04 (ddd, J ) 8.2, 2.7, 1.3
Hz, 1 H), 7.27 (dd, J ) 8.2, 4.8 Hz, 1 H), 7.87 (d, J ) 2.7 Hz, 1
H), 7.95 (dd, J ) 4.8, 1.1 Hz, 1 H) ppm. MS (DCI/NH3) m/z 176
(M + H)+. Anal. (C10H13N3‚1.25C4H4O4‚0.30H2O) C, H, N.
(1S,5R)-6-Pyridin-3-yl-3,6-diaza-bicyclo[3.2.0]heptane (22) Fu-
marate. This was prepared according to the representative proce-
dures C(a), D(a), and S(a) using (1R,5R)-19a and 3-bromopyridine.
1H NMR (CD3OD, 300 MHz): δ 3.18 (dd, J ) 12.2, 3.4 Hz, 1 H),
3.35 (m, 1 H), 3.46 (m, 1 H), 3.75 (m, 3 H), 4.04 (t, J ) 7.5 Hz,
1 H), 4.90 (m, 1 H), 6.58(s, 2.7 H), 7.04 (ddd, J ) 8.2, 2.7, 1.3
Hz, 1 H), 7.27 (dd, J ) 8.2, 4.8 Hz, 1 H), 7.87 (d, J ) 2.7 Hz, 1
H), 7.95 (dd, J ) 4.8, 1.1 Hz, 1 H) ppm. MS (DCI/NH3) m/z 176
(M + H)+. Anal. (C10H13N3‚1.36C4H4O4‚0.24H2O) C, H, N.
(1R,5S)-6-(5-Bromopyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (23) Fumarate. This was prepared according to the
representative procedures C(a), D(b), and S(a) using (1S,5S)-19a
Buchwald-Hartwig Coupling Reaction: Representative Pro-
cedure “C(a)”. The mixture of (1S,5S)-19a (230 mg, 1.0 mmol),
3-bromopyridine (236 mg, 1.50 mmol), and tBuONa (144 mg, 1.50
mmol) in anhydrous toluene (10.0 mL) was degassed and purged
with nitrogen three times before the addition of rac-BINAP (37.3
mg, 0.06 mmol) and Pd2(dba)3 (18.3 mg, 0.02 mmol). It was then
heated to 110 °C and stirred at this temperature for 10 h. After it
was cooled down to ambient temperature, it was diluted with EtOAc
(20.0 mL) and washed with brine (2 × 5.0 mL). The organic
solution was concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (v. EtOAc:hexanes ) 4:1)
to give (1S,5S)-3-N-Cbz-22 (Rf ) 0.30, 190 mg, 61% yield).
Buchwald-Hartwig Coupling Reaction: Representative Pro-
cedure “C(b)”. A mixture of (1S,5S)-19a (460 mg, 2.0 mmol),
5-bromo-nicotinonitrile (550 mg, 3.0 mmol), Cs2CO3 (1312 mg,
4.0 mmol), rac-BINAP (74.8 mg, 0.12 mmol), and Pd2(dba)3 (36.6
mg, 0.04 mmol) in anhydrous toluene (20 mL) was stirred under
N2 at 110 °C for 40 h. After it was cooled to ambient temperature,
it was then diluted with EtOAc (50.0 mL), washed with brine (2 ×
5.0 mL), and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (v. EtOAc:hexanes ) 4:1)
to give (1S,5S)-3-N-Cbz-25 (Rf ) 0.30, 610 mg, 91.3% yield).
N-Cbz Deprotection: Representative Procedure “D(a)”. A
1
and 3,5-dibromopyridine. H NMR (CD3OD, 300 MHz): δ 3.15
(dd, J ) 12.6, 3.4 Hz, 1 H), 3.30 (m, 1 H), 3.45 (m, 1 H), 3.67 (d,
J ) 11.5 Hz, 1 H), 3.75 (m, 2 H), 4.06 (t, J ) 8.1 Hz, 1 H), 4.94

5502 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22
Ji et al.
(m, 1 H), 6.30 (s, 2.0 H), 7.22 (t, J ) 2.3 Hz, 1 H), 7.84 (d, J ) 2.3
Hz, 1 H), 8.04 (d, J ) 1.7 Hz, 1 H) ppm. MS (DCI/NH3) m/z 256
(M + H)+, 254 (M + H)+. Anal. (C10H12BrN3‚1.00C4H4O4) C, H,
N.
representative procedures C(b), D(a), and S(b) using (1S,5S)-19a
and 3-bromo-5,6-dimethylpyridine. 1H NMR (CD3OD, 300
MHz): δ 2.27 (s, 3 H), 2.36 (s, 3 H), 2.37 (s, 3 H), 3.16 (dd, J )
12.5, 3.4 Hz, 1 H), 3.30-3.50 (m, 2 H), 3.70 (d, J ) 12.5 Hz, 2
H), 3.73 (dd, J ) 7.8, 2.0 Hz, 1 H), 3.96 (t, J ) 8.0 Hz, 1H),
4.81-4.84 (m, 1 H), 6.87 (d, J ) 3.1 Hz, 1 H), 7.22 (d, J ) 7.8
Hz, 2 H), 7.55 (d, J ) 2.4 Hz, 1 H), 7.70 (d, J ) 8.5 Hz, 2 H)
ppm. MS (DCI/NH3) m/z 204 (M + H)+. Anal. (C12H17N3‚
1.00C7H8SO3) C, H, N.
(1S,5R)-6-(5,6-Dimethylpyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (27) Tosylate. This was prepared according to the
representative procedures C(b), D(a), and S(b) using (1R,5R)-19a
and 3-bromo-5,6-dimethylpyridine. 1H NMR (CD3OD, 300
MHz): δ 2.27 (s, 3.3 H), 2.37 (s, 3 H), 2.38 (s, 3 H), 3.16 (dd, J
) 12.7, 3.6 Hz, 1 H), 3.32-3.46 (m, 2 H), 3.70 (d, J ) 11.5 Hz,
2 H), 3.75 (dd, J ) 7.8, 2.4 Hz, 1 H), 3.96 (t, J ) 7.8 Hz, 1 H),
4.76-4.87 (m, 1 H), 6.89 (d, J ) 1.7 Hz, 1 H), 7.23 (d, J ) 8.1
Hz, 2.2 H), 7.56 (d, J ) 2.7 Hz, 1 H), 7.70 (d, J ) 8.5 Hz, 2.2 H)
ppm. MS (DCI/NH3) m/z 204 (M + H)+. Anal. (C12H17N3‚
1.11C7H8SO3) C, H, N.
(1R,5S)-6-(5-Cyano-6-methylpyridin-3-yl)-3,6-diazabicyclo-
[3.2.0]heptane (28) Trifluoroacetate. This was prepared according
to the representative procedures C(b), D(b), and S(c) using (1S,5S)-
19a and 3-bromo-5-cyano-6-methylpyridine. 1H NMR (CD3OD, 300
MHz): δ 2.60 (s, 3 H), 3.14 (dd, J ) 12.7, 3.6 Hz, 1 H), 3.33-
3.56 (m, 2 H), 3.70 (d, J ) 12.4 Hz, 1 H), 3.72 (d, J ) 12.4 Hz,
1 H), 3.77 (dd, J ) 8.1, 3.1 Hz, 1 H), 4.04 (t, J ) 8.1 Hz, 1 H),
4.92 (dd, J ) 6.4, 3.7 Hz, 1 H), 7.31 (d, J ) 3.1 Hz, 1 H), 7.99 (d,
J ) 3.1 Hz, 1 H) ppm. MS (DCI/NH3) m/z 215 (M + H)+. Anal.
(C12H14N4‚1.00CF3CO2H) C, H, N.
(1S,5R)-6-(5-Bromopyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (23) Bisfumarate. This was prepared according to the
representative procedures C(a), D(b), and S(a) using (1R,5R)-19a
1
and 3,5-dibromopyridine. H NMR (CD3OD, 300 MHz): δ 3.20
(dd, J ) 12.7, 3.7 Hz, 1 H), 3.30-3.45 (m, 2 H), 3.70-3.82 (m,
3 H), 4.05 (t, J ) 8.1 Hz, 1 H), 4.96 (dd, J ) 6.6, 3.7 Hz, 1 H),
6.30 (s, 4.9 H), 7.22 (t, J ) 2.3 Hz, 1 H), 7.84 (d, J ) 2.3 Hz, 1
H), 8.04 (d, J ) 1.7 Hz, 1 H) ppm. MS (DCI/NH3) m/z 256 (M +
H)+, 254 (M + H)+. Anal. (C10H12BrN3‚2.45C4H4O4‚1.00H2O) C,
H, N.
(1R,5S)-6-(5-Chloropyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (24) Fumarate. This was prepared according to the
representative procedures C(a), D(b), and S(a) using (1S,5S)-19a
1
and 3-bromo-5-chloropyridine. H NMR (CD3OD, 300 MHz): δ
3.14 (dd, J ) 12.9, 3.4 Hz, 1 H), 3.31-3.36 (m, 1 H), 3.39-3.52
(m, 1 H), 3.65-3.74 (m, 2 H), 3.77 (dd, J ) 8.1, 3.1 Hz, 1 H),
4.05 (t, J ) 8.0 Hz, 1 H), 4.93 (dd, J ) 6.6, 3.6 Hz, 1 H), 6.69 (s,
2 H), 7.07 (t, J ) 2.2 Hz, 1 H), 7.79 (d, J ) 2.4 Hz, 1 H), 7.93 (d,
J ) 2.0 Hz, 1 H) ppm. MS (DCI/NH3) m/z 212 (M + H)+, 210 (M
+ H)+. Anal. (C10H12ClN3‚1.00C4H4O4‚0.30H2O) C, H, N.
(1R,5S)-6-(5-Cyanopyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (25) Bis(tosylate). This was prepared according to the
representative procedures C(b), D(b), and S(b) using (1S,5S)-19a
1
and 5-bromo-nicotinonitrile; mp 240-243 °C. H NMR (MeOH-
d4, 400 MHz): δ 2.36 (s, 6 H), 3.23 (dd, J ) 13.0, 3.8 Hz, 1 H),
3.34 (dd, J ) 12.6, 7.1 Hz, 1 H), 3.73 (d, J ) 12.3 Hz, 1 H),
3.82-3.98 (m, 3 H), 4.18 (t, J ) 8.6 Hz, 1 H), 5.13 (dd, J ) 6.4,
3.7 Hz, 1 H), 7.21 (d, J ) 8.0 Hz, 4 H), 7.64 (d, J ) 8.0 Hz, 4 H),
7.83 (dd, J ) 2.6, 1.4 Hz, 1 H), 8.22 (d, J ) 2.5 Hz, 1 H), 8.42 (d,
J ) 0.9 Hz, 1 H) ppm. 13C NMR (CD3OD, 100 MHz): δ 148.0,
143.3, 141.9, 133.2, 130.2, 129.9, 129.3, 126.8, 115.2, 113.9, 68.7,
56.0, 50.9, 35.4, 25.3, 21.3. MS (DCI/NH3) m/z 218 (M + NH4)+,
201 (M + H)+; [R]D25 ) -108.0° (0.47, MeOH). Anal. (C11H12N4‚
2.00C7H8SO3) C, H, N.
(1S,5R)-6-(5-Cyano-6-methylpyridin-3-yl)-3,6-diazabicyclo-
[3.2.0]heptane (28) Fumarate. This was prepared according to the
representative procedures C(b), D(b), and S(a) using (1R,5R)-19a
1
and 3-bromo-5-cyano-6-methylpyridine. H NMR (CD3OD, 300
MHz): δ 2.60 (s, 3 H), 3.15 (dd, J ) 12.9, 3.4 Hz, 1 H), 3.27-
3.36 (m, 1 H), 3.45 (ddd, J ) 14.3, 7.4, 2.7 Hz, 1 H), 3.71 (dd, J
) 12.4, 10.3 Hz, 2 H), 3.77 (dd, J ) 8.1, 3.1 Hz, 1 H), 4.03 (t, J
) 8.0 Hz, 1 H), 4.92 (dd, J ) 6.4, 3.4 Hz, 1 H), 6.67 (s, 2 H), 7.31
(d, J ) 2.7 Hz, 1 H), 7.99 (d, J ) 3.1 Hz, 1 H) ppm. MS (DCI/
NH3) m/z 215 (M + H)+. Anal. (C12H14N4‚1.00C4H4O4) C, H, N.
(1R,5S)-6-(6-Chloropyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (29) Fumarate. This was prepared according to the
representative procedures C(a), D(b), and S(a) using (1S,5S)-19a
(1S,5R)-6-(5-Cyanopyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (25) Bisfumarate. This was prepared according to the
representative procedures C(b), D(b), and S(a) using (1R,5R)-19a
and 5-bromo-nicotinonitrile. 1H NMR (CD3OD, 400 MHz): δ 3.20
(dd, J ) 12.7, 3.7 Hz, 1 H), 3.38 (m, 1 H), 3.50 (m, 1H), 3.70-
3.85 (m, 3 H), 4.10 (t, J ) 8.1 Hz, 1 H), 5.00 (dd, J ) 6.5, 3.8 Hz,
1 H), 6.70 (s, 5.0 H), 7.36 (d, J ) 2.7, 1.7 Hz, 1 H), 8.10 (d, J )
3.0 Hz, 1 H), 8.26 (d, J ) 1.4 Hz, 1 H) ppm. MS (DCI/NH3) m/z
218 (M + NH4)+, 201 (M + H)+. Anal. (C11H12N4‚2.50C4H4O4‚
0.70H2O) C, H, N.
1
and 5-bromo-2-chloropyridine. H NMR (CD3OD, 300 MHz): δ
3.15 (dd, J ) 12.8, 3.7 Hz, 1 H), 3.35 (m, 1 H), 3.40 (m, 1 H),
3.45 (m, 1 H), 3.76 (m, 2 H), 4.00 (t, J ) 7.8 Hz, 1 H), 4.88 (m,
1 H), 6.70 (s, 2.9 H), 7.05 (dd, J ) 8.8, 3.0 Hz, 1 H), 7.28 (d, J )
8.4 Hz, 1 H), 7.68 (d, J ) 3.0 Hz, 1 H) ppm. MS (DCI/NH3) m/z
212 (M + H)+, 210 (M + H)+. Anal. (C10H12ClN3‚1.45C4H4O4)
C, H, N.
(1R,5S)-6-(5-Methoxypyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (26) Tosylate. This was prepared according to the
representative procedures C(a), D(a), and S(b), using (1S,5S)-19a
(1S,5R)-6-(6-Chloropyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (29) Fumarate. This was prepared according to the
representative procedures C(a), D(b), and S(a) using (1R,5R)-19a
1
and 3-bromo-5-methoxypyridine. H NMR (CD3OD, 300 MHz):
δ 2.37 (s, 3 H), 3.20 (dd, J ) 12.6, 3.7 Hz, 1 H), 3.35 (m, 1 H),
3.45 (m, 1 H), 3.72 (m, 3 H), 3.83 (s, 3 H), 4.16 (t, J ) 8.2 Hz, 1
H), 4.90 (dd, J ) 6.5, 3.8 Hz, 1 H), 6.54 (t, J ) 2.4 Hz, 1 H), 7.22
(d, J ) 6.0 Hz, 2 H), 7.47 (d, J ) 2.8 Hz, 1 H), 7.67 (d, J ) 2.8
Hz, 1 H), 7.69 (d, J ) 6.0 Hz, 2 H) ppm. MS (DCI/NH3) m/z 206
(M + H)+. Anal. (C11H15N3O‚1.00C7H8SO3) C, H, N.
1
and 5-bromo-2-chloropyridine. H NMR (CD3OD, 300 MHz): δ
3.15 (dd, J ) 12.8, 3.7 Hz, 1 H), 3.35 (m, 1 H), 3.40 (m, 1 H),
3.45 (m, 1 H), 3.76 (m, 2 H), 4.00 (t, J ) 7.8 Hz, 1 H), 4.88 (m,
1 H), 6.70 (s, 2.8 H), 7.05 (dd, J ) 8.8, 3.0 Hz, 1 H), 7.28 (d, J )
8.4 Hz, 1 H), 7.68 (d, J ) 3.0 Hz, 1 H) ppm. MS (DCI/NH3) m/z
212 (M + H)+, 210 (M + H)+. Anal. (C10H12ClN3‚1.38C4H4O4)
C, H, N.
(1S,5R)-6-(5-Methoxypyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (26) Tosylate. This was prepared according to the
representative procedures C(a), D(a), and S(b), using (1R,5R)-19a
(1R,5S)-6-(6-Chloro-5-methylpyridin-3-yl)-3,6-diazabicyclo-
[3.2.0]heptane (30) Tosylate. This was prepared according to the
representative procedures C(a), D(b), and S(b) using (1S,5S)-19a
1
and 3-bromo-5-methoxypyridine. H NMR (CD3OD, 300 MHz):
δ 2.36 (s, 3 H), 3.18 (dd, J ) 12.5, 3.4 Hz, 1 H), 3.32-3.38 (m,
1 H), 3.38-3.50 (m, 1 H), 3.66-3.80 (m, 3 H), 3.84 (s, 3 H), 4.01
(t, J ) 8.0 Hz, 1 H), 4.90 (dd, J ) 6.4, 3.4 Hz, 1 H), 6.55 (t, J )
2.4 Hz, 1 H), 7.22 (d, J ) 7.8 Hz, 2 H), 7.47 (d, J ) 2.4 Hz, 1 H),
7.67 (d, J ) 2.8 Hz, 1 H), 7.69 (d, J ) 6.0 Hz, 2 H) ppm. MS
(DCI/NH3) m/z 206 (M + H)+. Anal. (C11H15N3O‚1.00C7H8SO3)
C, H, N.
1
and 5-bromo-2-chloro-3-methylpyridine. H NMR (CD3OD, 300
MHz): δ 2.31 (s, 3 H), 2.36 (s, 3 H), 3.17 (dd, J ) 12.5, 3.4 Hz,
1 H), 3.33-3.37 (m, 1 H), 3.43 (ddd, J ) 14.3, 7.5, 2.9 Hz, 1 H),
3.69 (d, J ) 2.7 Hz, 1 H), 3.74 (dd, J ) 8.3, 2.9 Hz, 2 H), 3.98 (t,
J ) 8.0 Hz, 1 H), 4.87 (dd, J ) 6.4, 3.4 Hz, 1 H), 6.97 (d, J ) 3.1
Hz, 1 H), 7.21 (d, J ) 7.8 Hz, 2 H), 7.49 (d, J ) 2.7 Hz, 1 H),
7.69 (d, J ) 8.1 Hz, 2 H) ppm. MS (DCI/NH3) m/z 226 (M + H)+,
224 (M + H)+. Anal. (C11H14ClN3‚1.00C7H8SO3) C, H, N.
(1R,5S)-6-(5,6-Dimethylpyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (27) Tosylate. This was prepared according to the

3,6-Diazabicyclo[3.2.0]heptanes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22 5503
(1S,5R)-6-(6-Chloro-5-methylpyridin-3-yl)-3,6-diazabicyclo-
[3.2.0]heptane (30) Tosylate. This was prepared according to the
representative procedures C(b), D(b), and S(b) using (1R,5R)-19a
(m, 1 H), 3.66 (dd, J ) 10.7, 4.9 Hz, 1 H), 3.90 (d, J ) 10.5 Hz,
1 H), 4.09 (d, J ) 12.2 Hz, 1 H), 4.20 (dd, J ) 10.7, 8.3 Hz, 1 H),
4.98 (dd, J ) 7.0, 4.9 Hz, 1 H), 6.66 (s, 1 H), 7.47-7.59 (m, 1 H),
8.07 (d, J ) 2.0 Hz, 1 H), 8.16 (d, J ) 2.4 Hz, 1 H) ppm. MS
(DCI/NH3) m/z 256 (M + H)+, 254 (M + H)+. Anal. (C10H12BrN3‚
0.50C4H4O4) C, H, N.
1
and 5-bromo-2-chloro-3-methylpyridine. H NMR (CD3OD, 300
MHz): δ 2.31 (s, 3 H), 2.36 (s, 3 H), 3.17 (dd, J ) 12.5, 3.4 Hz,
1 H), 3.32-3.37 (m, 1 H), 3.43 (ddd, J ) 14.1, 7.5, 2.9 Hz, 1 H),
3.69 (d, J ) 3.1 Hz, 1 H), 3.74 (dd, J ) 8.0, 2.9 Hz, 2 H), 3.98 (t,
J ) 7.8 Hz, 1 H), 4.87 (dd, J ) 6.4, 3.4 Hz, 1 H), 6.97 (d, J ) 3.1
Hz, 1 H), 7.21 (d, J ) 7.8 Hz, 2 H), 7.49 (d, J ) 2.4 Hz, 1 H),
7.69 (d, J ) 8.1 Hz, 2 H) ppm. MS (DCI/NH3) m/z 226 (M + H)+,
224 (M + H)+. Anal. (C11H14ClN3‚1.00C7H8SO3) C, H, N.
(1R,5S)-6-(5,6-Dichloropyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (31) Fumarate. This was prepared according to the
representative procedures C(a), D(b), and S(a) using (1S,5S)-19a
and 2,3-dichloro-5-iodopyridine. 1H NMR (CD3OD, 300 MHz): δ
3.14 (dd, J ) 12.9, 3.7 Hz, 1 H), 3.32-3.35 (m, 1 H), 3.45 (ddd,
J ) 14.5, 7.4, 3.2 Hz, 1 H), 3.70 (dd, J ) 12.4, 10.3 Hz, 2 H),
3.76 (dd, J ) 8.0, 3.2 Hz, 1 H), 4.04 (t, J ) 8.1 Hz, 1 H), 4.92 (dd,
J ) 6.4, 3.4 Hz, 1 H), 6.67 (s, 2 H), 7.20 (d, J ) 2.7 Hz, 1 H),
7.63 (d, J ) 2.7 Hz, 1 H) ppm. MS (DCI/NH3) m/z 246 (M + H)+,
244, (M + H)+. Anal. (C10H11Cl2N3‚1.00C4H4O4) C, H, N.
(1S,5R)-6-(5,6-Dichloropyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (31) Fumarate. This was prepared according to the
representative procedures C(a), D(b), and S(a) using (1R,5R)-19a
and 2,3-dichloro-5-iodopyridine. 1H NMR (CD3OD, 300 MHz): δ
3.14 (dd, J ) 12.9, 3.4 Hz, 1 H), 3.32-3.34 (m, 1 H), 3.45 (ddd,
J ) 14.2, 7.4, 3.2 Hz, 1 H), 3.64-3.73 (m, 2 H), 3.76 (dd, J )
8.0, 3.2 Hz, 1 H), 4.04 (t, J ) 8.1 Hz, 1 H), 4.92 (dd, J ) 6.4, 3.4
Hz, 1 H), 6.67 (s, 2 H), 7.21 (d, J ) 2.7 Hz, 1 H), 7.63 (d, J ) 2.7
Hz, 1 H) ppm. MS (DCI/NH3) m/z 246 (M + H)+, 244, (M + H)+.
Anal. (C10H11Cl2N3‚1.00C4H4O4) C, H, N.
(1S,5R)-6-(5-Methylpyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (32) Hydrochloride. A solution of (1S,5R)-30 (0.62 g,
2.77 mmol) in EtOH (15 mL) was stirred with Pd/C (10 wt %, 0.2
g) under H2 (1 atm) at ambient temperature for 10 h. The catalyst
was filtered off, and the organic solution was concentrated to give
(1S,5R)-32 hydrochloride (0.54 g, 87% yield). 1H NMR (CD3OD,
300 MHz): δ 2.30 (s, 3 H), 3.18 (dd, J ) 12.5, 3.4 Hz, 1 H),
3.31-3.39 (m, 1 H), 3.44 (ddd, J ) 14.2, 7.5, 2.7 Hz, 1 H), 3.71
(dd, J ) 12.2, 2.4 Hz, 2 H), 3.77 (dd, J ) 7.8, 3.1 Hz, 1 H), 4.00
(t, J ) 7.8 Hz, 1 H), 4.89 (dd, J ) 6.3, 3.6 Hz, 1 H), 6.84-6.94
(m, 1 H), 7.67 (d, J ) 2.4 Hz, 1 H), 7.81 (d, J ) 1.0 Hz, 1 H)
ppm. MS (DCI/NH3) m/z 190 (M + H)+. Anal. (C11H15N3‚1.00HCl‚
0.25H2O) C, H, N.
(1S,5S)-3-(Pyridin-3-yl)-3,6-diazabicyclo[3.2.0]heptane (33)
Bis(tosylate). This was prepared according to the representative
procedures C(a), D(c), and S(b) using (1R,5S)-20 and 3-bromo-
pyridine. 1H NMR (CD3OD, 300 MHz): δ 2.36 (s, 6 H), 3.23 (dd,
J ) 10.5, 6.4 Hz, 1 H), 3.36 (dd, J ) 10.8, 5.5 Hz, 1 H), 3.50-
3.67 (m, 1 H), 3.76 (dd, J ) 11.2, 5.1 Hz, 1 H), 4.00 (d, J ) 10.8
Hz, 1 H), 4.19-4.37 (m, 2 H), 5.11 (dd, J ) 6.8, 5.4 Hz, 1 H),
7.22 (d, J ) 7.8 Hz, 4 H), 7.69 (d, J ) 8.5 Hz, 4 H), 7.81 (dd, J
) 8.8, 5.1 Hz, 1 H), 7.92 (ddd, J ) 8.8, 2.7, 1.0 Hz, 1 H), 8.18 (d,
J ) 5.4 Hz, 1 H), 8.32 (d, J ) 2.7 Hz, 1 H) ppm. MS (DCI/NH3)
m/z 176 (M + H)+. Anal. (C10H13N3‚2.00C7H8SO3) C, H, N.
(1R,5R)-3-(Pyridin-3-yl)-3,6-diazabicyclo[3.2.0]heptane (33)
Tosylate. This was prepared according to the representative
procedures C(a), D(c), and S(b) using (1S,5R)-20 and 3-bromo-
pyridine. 1H NMR (CD3OD, 300 MHz): δ 2.36 (s, 3 H), 3.01 (dd,
J ) 10.3, 5.9 Hz, 1 H), 3.11 (dd, J ) 12.4, 4.9 Hz, 1 H), 3.43-
3.56 (m, 1 H), 3.74 (dd, J ) 11.0, 5.3 Hz, 1 H), 3.92 (d, J ) 10.5
Hz, 1 H), 4.14 (d, J ) 12.2 Hz, 1 H), 4.26 (dd, J ) 10.9, 8.5 Hz,
1 H), 5.04 (dd, J ) 7.1, 4.7 Hz, 1 H), 7.22 (d, J ) 7.8 Hz, 2 H),
7.30-7.44 (m, 2 H), 7.70 (d, J ) 8.5 Hz, 2 H), 8.04 (dd, J ) 4.4,
1.4 Hz, 1 H), 8.21 (d, J ) 2.7 Hz, 1 H) ppm. MS (DCI/NH3) m/z
176 (M + H)+. Anal. (C10H13N3‚1.00C7H8SO3) C, H, N.
(1R,5R)-3-(5-Bromopyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (34) Tosylate. This was prepared according to the
representative procedures C(a), D(c), and S(b) using (1S,5R)-20
1
and 3,5-dibromopyridine. H NMR (CD3OD, 300 MHz): δ 2.32
(s, 3H), 3.06 (dd, J ) 10.5, 6.1 Hz, 1 H), 3.16 (dd, J ) 12.5, 5.1
Hz, 1 H), 3.43-3.60 (m, 1 H), 3.73 (dd, J ) 11.2, 5.1 Hz, 1 H),
3.91 (d, J ) 10.5 Hz, 1 H), 4.13 (d, J ) 12.2 Hz, 1 H), 4.26 (dd,
J ) 11.2, 8.5 Hz, 1 H), 5.05 (dd, J ) 7.1, 5.1 Hz, 1 H), 7.22 (d,
J ) 7.8 Hz, 1 H), 7.49-7.56 (m, 1 H), 7.69 (d, J ) 8.5 Hz, 2 H),
8.09 (d, J ) 2.0 Hz, 1 H), 8.16 (d, J ) 2.4 Hz, 1 H) ppm. MS
(DCI/NH3) m/z 256 (M + H)+, 254 (M + H)+. Anal. (C10H12BrN3‚
1.00C7H8SO3) C, H, N.
(1S,5S)-3-(5-Chloropyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (35) Fumarate. This was prepared according to the
representative procedures C(a), D(c), and S(a) using (1R,5S)-20 and
1
3-bromo-5-chloropyridine. H NMR (CD3OD, 300 MHz): δ 3.08
(dd, J ) 10.5, 6.1 Hz, 1 H), 3.17 (dd, J ) 12.4, 4.9 Hz, 1 H),
3.44-3.59 (m, 1 H), 3.71 (dd, J ) 11.2, 5.1 Hz, 1 H), 3.92 (d, J
) 10.5 Hz, 1 H), 4.13 (d, J ) 12.5 Hz, 1 H), 4.25 (dd, J ) 11.0,
8.6 Hz, 1 H), 5.03 (dd, J ) 7.1, 4.7 Hz, 1 H), 6.67 (s, 2 H), 7.39
(t, J ) 2.2 Hz, 1 H), 8.00 (d, J ) 2.0 Hz, 1 H), 8.13 (d, J ) 2.7
Hz, 1 H) ppm. MS (DCI/NH3) m/z 212 (M + H)+, 210 (M + H)+.
Anal. (C10H12ClN3‚1.05C4H4O4) C, H, N.
(1S,5S)-5-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)nicotinonitrile (36)
Tosylate. This was prepared according to the representative
procedures C(a), D(c), and S(b) using (1R,5S)-20 and 5-bromo-
1
nicotinonitrile. H NMR (CD3OD, 300 MHz): δ 2.30 (s, 4.2 H),
3.16 (dd, J ) 10.7, 6.3 Hz, 1 H), 3.25 (dd, J ) 12.8, 7.8 Hz, 1 H),
3.47-3.62 (m, 1 H), 3.74 (dd, J ) 11.2, 5.1 Hz, 1 H), 3.98 (d, J
) 10.5 Hz, 1 H), 4.20 (d, J ) 12.5 Hz, 1 H), 4.28 (dd, J ) 11.0,
8.6 Hz, 1 H), 5.08 (dd, J ) 6.8, 5.1 Hz, 1 H), 7.22 (d, J ) 8.1 Hz,
2.8 H), 7.69 (d, J ) 8.5 Hz, 2.8 H), 7.76 (dd, J ) 2.7, 1.7 Hz, 1
H), 8.39 (d, J ) 1.7 Hz, 1 H), 8.47 (d, J ) 2.7 Hz, 1 H) ppm. MS
(DCI/NH3) m/z 201 (M + H)+. Anal. (C11H12N4‚1.40C7H8SO3) C,
H, N.
(1R,5R)-5-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)nicotinonitrile (36)
Fumarate. This was prepared according to the representative
procedures C(a), D(c), and S(a) using (1S,5R)-20 and 5-bromo-
1
nicotinonitrile. H NMR (CD3OD, 300 MHz): δ 3.14 (dd, J )
10.6, 6.2 Hz, 1 H), 3.24 (dd, J ) 12.8, 5.0 Hz, 1 H), 3.55 (m, 1 H),
3.75 (dd, J ) 11.0, 5.0 Hz, 1 H), 3.96 (d, J ) 10.6 Hz, 1 H), 4.18
(d, J ) 12.2 Hz, 1 H), 4.28 (dd, J ) 10.9, 8.4 Hz, 1 H), 5.00 (dd,
J ) 6.8, 4.8 Hz, 1 H), 6.40 (s, 2 H), 7.65 (dd, J ) 2.9, 1.2 Hz, 1
H), 8.33 (d, J ) 1.2 Hz, 1 H), 8.45 (d, J ) 2.8 Hz, 1 H) ppm. MS
(DCI/NH3) m/z 201 (M + H)+. Anal. (C11H12N4‚1.00C4H4O4‚
0.50H2O) C, H, N.
(1S,5S)-3-(5-Methoxypyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (37) Tosylate. This was prepared according to the
representative procedures C(a), D(c), and S(b) using (1R,5S)-20
and 3-bromo-5-methoxypyridine. 1H NMR (MeOH-d4, 300 MHz):
δ 2.36 (s, 4.2 H), 3.13 (dd, J ) 10.7, 6.3 Hz, 1 H), 3.23 (dd, J )
12.5, 5.1 Hz, 1 H), 3.45-3.61 (m, 1 H), 3.75 (dd, J ) 11.2, 5.1
Hz, 1 H), 3.87-4.01 (m, 4 H), 4.18 (d, J ) 12.5 Hz, 1 H), 4.27
(dd, J ) 11.0, 8.6 Hz, 1 H), 5.07 (dd, J ) 7.3, 5.3 Hz, 1 H), 7.13
(t, J ) 2.4 Hz, 1 H), 7.22 (d, J ) 8.1 Hz, 2.8 H), 7.69 (d, J ) 8.1
Hz, 2.8 H), 7.85 (d, J ) 2.4 Hz, 1 H), 7.90 (d, J ) 2.4 Hz, 1 H)
ppm. MS (DCI/NH3) m/z 206 (M + H)+. Anal. (C11H15N3O‚
1.40C7H8SO3‚0.10H2O) C, H, N.
(1R,5R)-3-(5-Methoxypyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (37) Tosylate. This was prepared according to the
representative procedures C(a), D(c), and S(b) using (1S,5R)-20
(1S,5S)-3-(5-Bromopyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (34) Hemifumarate. This was prepared according to the
representative procedures C(a), D(c), and S(a) using (1R,5S)-20 and
3,5-dibromopyridine. 1H NMR (CD3OD, 300 MHz): δ 3.08 (dd, J
) 10.3, 6.3 Hz, 1 H), 3.15 (dd, J ) 12.2, 5.1 Hz, 1 H), 3.43-3.56
1
and 3-bromo-5-methoxypyridine. H NMR (CD3OD, 300 MHz):
δ 2.36 (s, 3.5 H), 3.08 (dd, J ) 10.7, 5.9 Hz, 1 H), 3.18 (dd, J )
12.5, 5.1 Hz, 1 H), 3.44-3.59 (m, 1 H), 3.75 (dd, J ) 11.0, 4.9
Hz, 1 H), 3.86-3.98 (m, 4 H), 4.15 (d, J ) 12.5 Hz, 1 H), 4.26

5504 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22
Ji et al.
(dd, J ) 11.0, 8.3 Hz, 1 H), 5.05 (dd, J ) 7.1, 5.1 Hz, 1 H), 7.02
(t, J ) 2.4 Hz, 1 H), 7.22 (d, J ) 8.5 Hz, 2.3 H), 7.69 (d, J ) 8.1
Hz, 2.3 H), 7.81 (d, J ) 2.4 Hz, 1 H), 7.86 (d, J ) 2.4 Hz, 1 H)
ppm. MS (DCI/NH3) m/z 206 (M + H)+. Anal. (C11H15N3O‚
1.15C7H8SO3‚0.60H2O) C, H, N.
(1S,5S)-3-(6-Chloro-5-methylpyridin-3-yl)-3,6-diaza-bicyclo-
[3.2.0]heptane (41) Trifluoroacetate. This was prepared according
to the representative procedures C(a) and S(c) using (1R,5S)-20
1
and 2-chloro-3-methyl-5-bromopyridine. H NMR (CD3OD, 300
MHz): δ 2.37 (s, 3 H), 3.00 (dd, J ) 10.5, 6.1 Hz, 1 H), 3.10 (dd,
J ) 12.4, 4.9 Hz, 1 H), 3.41-3.58 (m, 1 H), 3.72 (dd, J ) 11.2,
5.1 Hz, 1 H), 3.89 (d, J ) 10.5 Hz, 1 H), 4.09 (d, J ) 12.5 Hz, 1
H), 4.25 (dd, J ) 11.0, 8.6 Hz, 1 H), 5.03 (dd, J ) 7.3, 5.3 Hz, 1
H), 7.34 (d, J ) 3.1 Hz, 1 H), 7.83 (d, J ) 3.1 Hz, 1 H) ppm. MS
(DCI/NH3) m/z 226 (M + H)+, 224 (M + H)+. Anal. (C11H14-
ClN3‚1.00CF3CO2H) C, H, N.
(1R,5R)-3-(6-Chloro-5-methylpyridin-3-yl)-3,6-diaza-bicyclo-
[3.2.0]heptane (41) Tosylate. This was prepared according to the
representative procedures C(a) and D(d) using (1S,5R)-20 and
2-chloro-3-methyl-5-bromopyridine. 1H NMR (CD3OD, 300
MHz): δ 2.36 (s, 6 H), 2.99 (dd, J ) 10.3, 5.9 Hz, 1 H), 3.09 (dd,
J ) 12.5, 4.7 Hz, 1 H), 3.40-3.58 (m, 1 H), 3.73 (dd, J ) 11.2,
5.1 Hz, 1 H), 3.88 (d, J ) 10.5 Hz, 1 H), 4.09 (d, J ) 12.5 Hz, 1
H), 4.25 (dd, J ) 11.0, 8.6 Hz, 1 H), 5.03 (dd, J ) 7.0, 4.9 Hz, 1
H), 7.22 (d, J ) 7.8 Hz, 2 H), 7.32 (d, J ) 3.1 Hz, 1 H), 7.69 (d,
J ) 8.5 Hz, 2 H), 7.82 (d, J ) 2.7 Hz, 1 H) ppm. MS (DCI/NH3)
m/z 226 (M + H)+, 224 (M + H)+. Anal. (C11H14ClN3‚
1.01C7H8SO3) C, H, N.
(1S,5S)-3-(5,6-Dimethylpyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (38) Tosylate. This was prepared according to the
representative procedures C(a) and D(d) using (1R,5S)-20 and
1
3-bromo-5,6-dimethylpyridine. H NMR (CD3OD, 300 MHz): δ
2.30 (s, 3 H), 2.36 (s, 3.8 H), 2.40 (s, 3 H), 2.93 (dd, J ) 10.3, 5.9
Hz, 1 H), 3.02 (dd, J ) 12.2, 4.7 Hz, 1 H), 3.40-3.54 (m, 1 H),
3.72 (dd, J ) 10.8, 5.1 Hz, 1 H), 3.86 (d, J ) 10.2 Hz, 1 H), 4.07
(d, J ) 12.2 Hz, 1 H), 4.23 (dd, J ) 10.8, 8.8 Hz, 1 H), 4.99 (dd,
J ) 7.1, 4.7 Hz, 1 H), 7.19 (d, J ) 2.7 Hz, 1 H), 7.22 (d, J ) 7.8
Hz, 2.5 H), 7.70 (d, J ) 8.1 Hz, 2.5 H), 7.87 (d, J ) 2.7 Hz, 1 H)
ppm. MS (DCI/NH3) m/z 204 (M + H)+. Anal. (C12H17N3‚
1.27C7H8SO3‚0.20H2O) C, H, N.
(1R,5R)-3-(5,6-Dimethylpyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (38) Fumarate. This was prepared according to the
representative procedures C(a), D(c), and S(a) using (1S,5R)-20 and
1
3-bromo-5,6-dimethylpyridine. H NMR (CD3OD, 300 MHz): δ
2.31 (s, 3 H), 2.40 (s, 3 H), 2.95 (dd, J ) 10.3, 5.9 Hz, 1 H), 3.04
(dd, J ) 12.2, 4.7 Hz, 1 H), 3.40-3.57 (m, 1 H), 3.74 (dd, J )
11.0, 5.3 Hz, 1 H), 3.88 (d, J ) 10.5 Hz, 1 H), 4.09 (d, J ) 12.2
Hz, 1 H), 4.25 (dd, J ) 11.0, 8.6 Hz, 1 H), 5.02 (dd, J ) 6.8, 5.1
Hz, 1 H), 6.68 (s, 2.6 H), 7.22 (d, J ) 2.7 Hz, 1 H), 7.88 (d, J )
2.7 Hz, 1 H) ppm. MS (DCI/NH3) m/z 204 (M + H)+. Anal.
(C12H17N3‚1.30C4H4O4‚0.20H2O) C, H, N.
(1S,5S)-3-(5,6-Dichloropyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]-
heptane (42) Tosylate. This was prepared according to the
representative procedures C(a) and D(d) using (1R,5S)-20 and
1
3-bromo-5,6-dichloropyridine. H NMR (CD3OD, 300 MHz): δ
2.36 (s, 3 H), 3.06 (dd, J ) 10.3, 6.3 Hz, 1 H), 3.17 (dd, J ) 12.5,
5.1 Hz, 1 H), 3.41-3.61 (m, 1 H), 3.72 (dd, J ) 10.8, 5.4 Hz, 1
H), 3.90 (d, J ) 10.5 Hz, 1 H), 4.10 (d, J ) 12.5 Hz, 1 H), 4.26
(dd, J ) 11.0, 8.6 Hz, 1 H), 5.04 (dd, J ) 7.1, 5.1 Hz, 1 H), 7.22
(d, J ) 7.8 Hz, 2 H), 7.52 (d, J ) 2.7 Hz, 1 H), 7.69 (d, J ) 8.1
Hz, 2 H), 7.95 (d, J ) 2.7 Hz, 1 H) ppm. MS (DCI/NH3) m/z 248
(M + H)+, 246 (M + H)+, 244 (M + H)+. Anal. (C10H11Cl2N3‚
1.00C7H8SO3) C, H, N.
(1S,5S)-3-(5-Cyano-6-methylpyridin-3-yl)-3,6-diazabicyclo-
[3.2.0]heptane (39) Fumarate. This was prepared according to the
representative procedures C(a), D(c), and S(a) using (1R,5S)-20 and
3-bromo-5-cyano-6-methylpyridine. 1H NMR (CD3OD, 300
MHz): δ 2.63 (s, 3 H), 3.05 (dd, J ) 10.5, 6.1 Hz, 1 H), 3.15 (dd,
J ) 12.4, 4.9 Hz, 1 H), 3.43-3.56 (m, 1 H), 3.73 (dd, J ) 11.2,
5.1 Hz, 1 H), 3.93 (d, J ) 10.5 Hz, 1 H), 4.14 (d, J ) 12.5 Hz, 1
H), 4.26 (dd, J ) 11.2, 8.5 Hz, 1 H), 5.04 (dd, J ) 7.0, 4.9 Hz, 1
H), 6.68 (s, 2 H), 7.62 (d, J ) 3.1 Hz, 1 H), 8.33 (d, J ) 3.1 Hz,
1 H) ppm. MS (DCI/NH3) m/z 215 (M + H)+. Anal. (C12H14N4‚
1.00C4H4O4‚0.10H2O) C, H, N.
(1R,5R)-3-(5-Cyano-6-methylpyridin-3-yl)-3,6-diazabicyclo-
[3.2.0]heptane (39) Fumarate. This was prepared according to the
representative procedures C(a), D(c), and S(a) using (1S,5R)-20 and
3-bromo-5-cyano-6-methylpyridine. 1H NMR (CD3OD, 300
MHz): δ 2.63 (s, 3 H), 3.05 (dd, J ) 10.5, 6.1 Hz, 1 H), 3.14 (dd,
J ) 12.4, 4.9 Hz, 1 H), 3.42-3.59 (m, 1 H), 3.72 (dd, J ) 11.2,
5.1 Hz, 1 H), 3.93 (d, J ) 10.5 Hz, 1 H), 4.13 (d, J ) 12.5 Hz, 1
H), 4.25 (dd, J ) 11.0, 8.6 Hz, 1 H), 5.04 (dd, J ) 6.8, 5.1 Hz, 1
H), 6.67 (s, 2 H), 7.62 (d, J ) 3.1 Hz, 1 H), 8.33 (d, J ) 2.7 Hz,
1 H) ppm. MS (DCI/NH3) m/z 215 (M + H)+. Anal. (C12H14N4‚
1.00C4H4O4) C, H, N.
(1S,5S)-3-(6-Chloropyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]-
heptane (40) Fumarate. This was prepared according to the
representative procedures C(a), D(c), and S(a) using (1R,5S)-20 and
2-chloro-5-iodopyridine. 1H NMR (CD3OD, 300 MHz): δ 3.02 (dd,
J ) 10.5, 6.1 Hz, 1 H), 3.12 (dd, J ) 12.4, 4.9 Hz, 1 H), 3.43-
3.59 (m, 1 H), 3.72 (dd, J ) 11.0, 4.9 Hz, 1 H), 3.89 (d, J ) 10.5
Hz, 1 H), 4.10 (d, J ) 12.2 Hz, 1 H), 4.25 (dd, J ) 11.0, 8.6 Hz,
1 H), 5.03 (dd, J ) 7.0, 4.9 Hz, 1 H), 6.68 (s, 2 H), 7.27-7.45 (m,
2 H), 7.98 (d, J ) 2.7 Hz, 1 H) ppm. MS (DCI/NH3) m/z 212 (M
+ H)+, 211 (M + H)+. Anal. (C10H12ClN3‚1.00C4H4O4): C, H, N.
(1R,5R)-3-(6-Chloropyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]-
heptane (40) Fumarate. This was prepared according to the
representative procedures C(a), D(c), and S(a) using (1S,5R)-20 and
2-chloro-5-iodopyridine. 1H NMR (CD3OD, 300 MHz): δ 3.05 (dd,
J ) 10.1, 5.1 Hz, 1 H), 3.15 (dd, J ) 12.6, 5.1 Hz, 1 H), 3.50 (m,
1 H), 3.75 (dd, J ) 11.2, 3.10 Hz, 1 H), 3.90 (d, J ) 10.5 Hz, 1
H), 4.10 (d, J ) 12.2 Hz, 1 H), 4.25 (dd, J ) 11.2, 8.8 Hz, 1 H),
5.05 (dd, J ) 6.8, 4.8 Hz, 1 H), 6.68 (s, 2.4 H), 7.34 (d, J ) 8.5
Hz, 1 H), 7.38 (dd, J ) 8.9, 3.1 Hz, 1 H), 7.96 (d, J ) 2.7 Hz, 1
H) ppm. MS (DCI/NH3) m/z 212 (M + H)+, 210 (M + H)+. Anal.
(C10H12ClN3‚1.20C4H4O4) C, H, N.
(1R,5R)-3-(5,6-Dichloropyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]-
heptane (42) Tosylate. This was prepared according to the
representative procedure C(a) and D(d) using (1S,5R)-20 and 2,3-
dichloro-5-iodopyridine. 1H NMR (CD3OD, 300 MHz): δ 2.36 (s,
3 H), 3.06 (dd, J ) 10.5, 6.1 Hz, 1 H), 3.16 (dd, J ) 12.5, 5.1 Hz,
1 H), 3.42-3.59 (m, 1 H), 3.72 (dd, J ) 11.2, 5.1 Hz, 1 H), 3.89
(d, J ) 10.5 Hz, 1 H), 4.10 (d, J ) 12.5 Hz, 1 H), 4.26 (dd, J )
11.2, 8.5 Hz, 1 H), 5.05 (dd, J ) 7.1, 4.7 Hz, 1 H), 7.21 (d, J )
8.1 Hz, 2 H), 7.51 (d, J ) 2.7 Hz, 1 H), 7.69 (d, J ) 8.1 Hz, 2 H),
7.94 (d, J ) 2.7 Hz, 1 H) ppm. MS (DCI/NH3) m/z 248 (M + H)+,
246 (M + H)+, 244 (M + H)+. Anal. (C10H11Cl2N3‚1.00C7H8SO3)
C, H, N.
(1R,5S)-tert-Butyl 3-(5-Methylpyridin-3-yl)-3,6-diazabicyclo-
[3.2.0]heptane-6-carboxylate (6-N-Boc-43) Hydrochloride. A
solution of (1R,5S)-6-N-Boc-41 (350 mg, 1.00 mmol) in EtOH (20
mL) was stirred with Pd/C (10 wt %, 100 mg) under H2 (1 atm) at
ambient temperature for 10 h. The catalyst was filtered off, and
the organic solution was concentrated to give (1R,5S)-6-N-Boc-
1
43‚HCl (300 mg, 92% yield). H NMR (CD3OD, 300 MHz): δ
1.44 (s, 9 H), 2.49 (s, 3 H), 3.10-3.19 (m, 1 H), 3.20-3.29 (m, 2
H), 3.53-3.67 (m, 1 H), 3.88 (d, J ) 10.5 Hz, 1 H), 3.98 (d, J )
11.5 Hz, 1 H), 4.13 (t, J ) 8.0 Hz, 1 H), 4.90 (dd, J ) 6.6, 4.6 Hz,
1 H), 7.77 (s, 1 H), 7.96 (s, 1 H), 8.07 (s, 1 H) ppm. MS (DCI/
NH3) m/z 290 (M + H)+.
(1S,5S)-3-(5-Methylpyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (43) Fumarate. This was prepared according to the
representative procedures D(c) and S(a) using (1R,5S)-6-N-Boc-
43‚HCl. 1H NMR (CD3OD, 300 MHz): δ 2.34 (s, 3 H), 3.00 (dd,
J ) 10.5, 6.1 Hz, 1 H), 3.09 (dd, J ) 12.2, 4.7 Hz, 1 H), 3.41-
3.60 (m, 1 H), 3.73 (dd, J ) 10.8, 5.1 Hz, 1 H), 3.91 (d, J ) 10.8
Hz, 1 H), 4.13 (d, J ) 12.5 Hz, 1 H), 4.25 (dd, J ) 11.0, 8.6 Hz,
1 H), 5.03 (dd, J ) 7.3, 4.9 Hz, 1 H), 6.68 (s, 2.2 H), 7.22 (s, 1 H),
7.17-7.29 (m, 1 H), 7.89 (s, 1 H), 7.89 (d, J ) 1.0 Hz, 1 H), 8.01
(d, J ) 3.1 Hz, 1 H) ppm. MS (DCI/NH3) m/z 190 (M + H)+.
Anal. (C11H15N3‚1.08C4H4O4) C, H, N.

3,6-Diazabicyclo[3.2.0]heptanes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22 5505
(1S,5S)-tert-Butyl 6-(5-Bromopyridin-3-yl)-3,6-diazabicyclo-
[3.2.0]heptane-3-carboxylate (3-N-Boc-23). This was prepared
according to the representative procedure C(a) using (1S,5S)-19b
(0.20 g, 1.0 mmol) and 3,5-dibromopyridine (0.35 g, 1.5 mmol) to
provide (1S,5S)-3-N-Boc-23 (0.16 g, 45.7% yield). 1H NMR
(CD3OD, 300 MHz): δ 1.40 [s(br.), 9 H], 3.12 (dd, J ) 12.7, 3.7
Hz, 1 H), 3.20-3.35 (m, 2 H), 3.65 (m, 1 H), 3.80-4.05 (m, 3 H),
4.73-4.76 (m, 1 H), 7.06 (t, J ) 2.0 Hz, 1 H), 7.70 (d, J ) 2.7
Hz, 1H), 7.90 (d, J ) 1.7 Hz, 1 H) ppm. MS (DCI/NH3) m/z 356
(M + H)+, 354 (M + H)+.
(1S,5S)-tert-Butyl 6-{5-[(Trimethylsilyl)ethynyl]pyridin-3-yl}-
3,6-diazabicyclo[3.2.0]heptane-3-carboxylate (TMS-3-N-Boc-44).
A solution of (1S,5S)-3-N-Boc-23 (140 mg, 0.40 mmol), ethynyl-
trimethylsilane (100 mg, 1.0 mmol), Et3N (122 mg, 1.2 mmol),
PdCl2(PPh3)2 (5.6 mg, 0.008 mmol), and CuI (7.6 mg, 0.004 mmol)
in anhydrous DMF (5 mL) was stirred under N2 at 60-70 °C for
10 h. It was then cooled to ambient temperature, quenched with
water (10 mL), and extracted with EtOAc (3 × 50 mL). The
combined extracts were concentrated, and the residue was purified
by chromatography on silica gel (v. EtOAc:hexanes ) 1:1) to
provide (1S,5S)-TMS-3-N-Boc-44 (Rf ) 0.50, 90 mg, 60% yield).
1H NMR (CD3OD, 300 MHz): δ 0.05 (s, 9 H), 1.40 [s (br.), 9 H],
3.16 (dd, J ) 12.6, 3.6 Hz, 1H), 3.20-3.35 (m, 2 H), 3.65 (m,
1H), 3.85-4.05 (m, 3 H), 4.70 (m, 1 H), 6.68 (m, 1 H), 7.48 (d, J
) 2,7 Hz, 1 H), 7.67 (d, J ) 1.7 Hz, 1 H) ppm. MS (DCI/NH3)
m/z 372 (M + H)+.
6.68 (m, 1 H), 7.48 (d, J ) 2.7 Hz, 1 H), 7.67 (d, J ) 1.7 Hz, 1 H)
ppm. MS (DCI/NH3) m/z 372 (M + H)+.
(1S,5R)-6-(5-Ethynylpyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (44). This was prepared according to the procedure for
(1R,5S)-44 using (1R,5R)-TMS-3-N-Boc-44 (120 mg, 0.32 mmol)
to give (1S,5R)-44 (60 mg, 93.7%). 1H NMR (CD3OD, 300 MHz):
δ 2.57 (dd, J ) 12.6, 4.1 Hz, 1 H), 2.75 (dd, J ) 12.5, 6.4 Hz, 1
H), 3.10-3.30 (m, 3 H), 3.60 (dd, J ) 7.8, 3.4 Hz, 1 H), 3.70 (s,
1H), 3.96 (t, J ) 7.8 Hz, 1 H), 4.70 (dd, J ) 6.1, 3.3 Hz, 1 H),
6.94 (dd, J ) 2.7, 1.7 Hz, 1 H), 7.72 (d, J ) 2.7 Hz, 1 H), 7.90 (d,
J ) 1.7 Hz, 1 H) ppm. MS (DCI/NH3) m/z 200 (M + H)+.
(1S,5R)-6-(5-Ethynylpyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (44) Fumarate. This was prepared according to the
representative procedure S(a) using (1S,5R)-44 (60 mg, 0.30 mmol)
to give (1S,5R)-44 fumarate (86 mg, 92% yield). 1H NMR (CD3OD,
300 MHz): δ 3.16 (dd, J ) 12.6, 3.4 Hz, 1 H), 3.35-3.40 (m, 2
H), 3.45 (m, 1 H), 3.70-3.85 (m, 3 H), 4.05 (t, J ) 7.8 Hz, 1 H),
4.96 (dd, J ) 6.4, 3.3 Hz, 1 H), 6.70 (s, 2.8 H), 7.10 (dd, J ) 2.3,
1.7 Hz, 1 H), 7.85 (d, J ) 2.7 Hz, 1 H), 8.00 (d, J ) 1.7 Hz, 1 H)
ppm. MS (DCI/NH3) m/z 200 (M + H)+. Anal. (C12H13N3‚
1.42C4H4O4‚0.30H2O) C, H, N.
(1S,5S)-Benzyl 6-(5-(Oxazol-2-yl)pyridin-3-yl)-3,6-diazabicyclo-
[3.2.0]heptane-3-carboxylate (3-N-Cbz-45). A solution of (1S,5S)-
3-N-Cbz-23 (125 mg, 0.32 mmol), 2-(tributylstannyl)oxazole (230
mg, 0.64 mmol), and PdCl2(PPh3)2 (5.6 mg, 0.008 mmol) in
anhydrous MeCN (10 mL) was stirred under N2 at 80 °C for 4 h.
It was then cooled down to ambient temperature, concentrated under
reduced pressure, and purified by chromatography on silica gel (v.
EtOAc:hexanes ) 4:1) to provide (1S,5S)-3-N-Cbz-45 (Rf ) 0.40,
120 mg, 99% yield). 1H NMR (CD3OD, 300 MHz): δ 3.25 (dd, J
) 12.5, 3.7 Hz, 1 H), 3.31-3.42 (m, 1 H), 3.69 (dd, J ) 7.8, 3.4
Hz, 1 H), 3.93-4.29 (m, 4 H), 4.73-4.81 (m, 1 H), 5.01-5.23
(m, 2 H), 7.04-7.30 (m, 3 H), 7.25-7.49 (m, 4 H), 7.86 (d, J )
2.7 Hz, 1 H), 8.04 (s, 1 H), 8.49 (d, J ) 2.0 Hz, 1 H) ppm. MS
(DCI/NH3) m/z 377 (M + H)+.
(1R,5S)-6-(5-Ethynylpyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (44). A solution of (1S,5S)-TMS-3-N-Boc-44 (90 mg, 0.24
mmol) in THF (5 mL) was stirred with Bu4N+F- (1 M in THF, 2
mL, 2.0 mmol) at ambient temperature for 1 h. It was then diluted
with EtOAc (50 mL), washed with water (2 × 5 mL), and
concentrated. The residue was dissolved in CH2Cl2 (5 mL) and
stirred with trifluoroacetic acid (1 mL) at ambient temperature for
2 h. The volatiles were removed under reduced pressure, and the
residue was purified by chromatography on silica gel (v. CH2Cl2:
MeOH:NH3‚H2O ) 90:10:2) to give (1R,5S)-44 (Rf ) 0.2, 45 mg,
2-{5-[(1R,5S)-3,6-Diazabicyclo[3.2.0]heptan-6-yl]pyridin-3-
yl}oxazole (45) Bisfumarate. This was prepared according to the
representative procedures D(a) and S(a) using (1S,5S)-3-N-Cbz-
1
94%). H NMR (CD3OD, 300 MHz): δ 2.75 (dd, J ) 12.9, 3.4
Hz, 1 H), 2.90 (dd, J ) 12.25, 6.4 Hz, 1 H), 3.10 (m, 1 H), 3.30
(d, J ) 12.6 Hz, 1 H), 3.40 (d, J ) 12.9 Hz, 1 H), 3.70 (dd, J )
7.8, 3.3 Hz, 1 H), 3.76 (s, 1H), 3.96 (t, J ) 7.8 Hz, 1 H), 4.70 (dd,
J ) 6.1, 3.3 Hz, 1 H), 6.94 (dd, J ) 2.7, 1.7 Hz, 1 H), 7.77 (d, J
) 2.7 Hz, 1 H), 7.94 (d, J ) 1.7 Hz, 1 H) ppm. MS (DCI/NH3)
m/z 200 (M + H)+.
1
45. H NMR (CD3OD, 300 MHz): δ 3.22 (dd, J ) 12.5, 3.4 Hz,
1 H), 3.38 (d, J ) 7.5 Hz, 1 H), 3.43-3.56 (m, 1 H), 3.74 (d, J )
12.5 Hz, 1 H), 3.80 (d, J ) 12.5 Hz, 1 H), 3.84 (dd, J ) 8.1, 3.1
Hz, 1 H), 4.12 (t, J ) 8.0 Hz, 1 H), 5.01 (dd, J ) 6.4, 3.4 Hz, 1
H), 6.70 (s, 4 H), 7.36 (d, J ) 1.0 Hz, 1 H), 7.54 (dd, J ) 2.7, 1.7
Hz, 1 H), 8.00 (d, J ) 3.1 Hz, 1 H), 8.06 (s, 1 H), 8.59 (d, J ) 1.7
Hz, 1 H) ppm. MS (DCI/NH3) m/z 243 (M + H)+. Anal.
(C13H14N4O‚2.00C4H4O4) C, H, N.
(1R,5S)-6-(5-Ethynylpyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane(44) Fumarate. This was prepared according to the
representative procedure S(a) using (1R,5S)-44. 1H NMR (MeOH-
d4, 300 MHz): δ 3.16 (dd, J ) 12.6, 3.7 Hz, 1 H), 3.35-3.40 (m,
2 H), 3.45 (m, 1 H), 3.70-3.85 (m, 3 H), 4.05 (t, J ) 7.8 Hz, 1
H), 4.96 (dd, J ) 6.1, 3.4 Hz, 1 H), 6.70 (s, 2.4 H), 7.10 (dd, J )
2.4, 2.0 Hz, 1 H), 7.85 (d, J ) 3.0 Hz, 1 H), 7.96 (d, J ) 1.7 Hz,
1 H) ppm. MS (DCI/NH3) m/z 200 (M + H)+. Anal. (C12H13N3‚
1.20C4H4O4‚1.00H2O) C, H, N.
(1R,5R)-tert-Butyl 6-(5-Bromopyridin-3-yl)-3,6-diazabicyclo-
[3.2.0]heptane-3-carboxylate (3-N-Boc-23). A solution of (1S,5R)-
23 (510 mg, 2.0 mmol), di-tert-butyl dicarbonate (660 mg, 3.0
mmol), and Et3N (404 mg, 4.0 mmol) in CH2Cl2 (20 mL) was stirred
at ambient temperature for 10 h and then concentrated. The residue
was purified by chromatography on silica gel (v. EtOAc:hexanes
) 1:1) to give (1R,5R)-3-N-Boc-23 (Rf ) 0.5, 700 mg, 98% yield).
1H NMR (CD3OD, 300 MHz): δ 1.40 [s(br.), 9 H], 3.14 (dd, J )
12.9, 4.0 Hz, 1 H), 3.20-3.35 (m, 2 H), 3.65 (m, 1 H), 3.85-4.05
(m, 3 H), 4.74 (dd, J ) 5.4, 3.7 Hz, 1 H), 7.07 (t, J ) 2.0 Hz, 1
H), 7.68 (d, J ) 2.7 Hz, 1H), 7.90 (d, J ) 1.7 Hz, 1 H) ppm. MS
(DCI/NH3) m/z 356 (M + H)+, 354 (M + H)+.
(1S,5S)-Benzyl 6-[5-(1-Methyl-1H-imidazol-5-yl)pyridin-3-yl]-
3,6-diazabicyclo[3.2.0]heptane-3-carboxylate (3-N-Cbz-46). This
was prepared according to the procedure for the synthesis of (1S,5S)-
3-N-Cbz-45 using (1S,5S)-3-N-Cbz-23 (200 mg, 0.52 mmol) and
1-methyl-5-(tributylstannyl)-1H-imidazole (385 mg, 1.04 mmol) to
provide (1S,5S)-3-N-Cbz-46 (200 mg, 99% yield). 1H NMR
(CD3OD, 300 MHz): δ 3.23 (dd, J ) 12.7, 3.9 Hz, 1 H), 3.30-
3.41 (m, 1 H), 3.62-3.84 (m, 5 H), 3.89-4.26 (m, 3 H), 4.78 (dd,
J ) 6.3, 3.9 Hz, 1 H), 5.00-5.24 (m, 2 H), 6.92 (dd, J ) 2.7, 2.0
Hz, 1 H), 7.11 (s, 1 H), 7.16-7.46 (m, 5 H), 7.74 (s, 1 H), 7.77 (d,
J ) 2.7 Hz, 1 H), 7.96 (d, J ) 1.7 Hz, 1 H) ppm. MS (DCI/NH3)
m/z 390 (M + H)+.
(1R,5S)-6-(5-(1-Methyl-1H-imidazol-5-yl)pyridin-3-yl)-3,6-
diazabicyclo[3.2.0]heptane (46) Bisfumarate. This was prepared
according to the representative procedures D(a) and S(a) using
(1S,5S)-3-N-Cbz-46. 1H NMR (CD3OD, 300 MHz): δ 3.19 (dd, J
) 12.5, 3.4 Hz, 1 H), 3.32-3.39 (m, 1 H), 3.41-3.57 (m, 1 H),
3.75 (t, J ) 12.7 Hz, 2 H), 3.74 (s, 3 H), 3.82 (dd, J ) 8.1, 3.1 Hz,
1 H), 4.09 (t, J ) 7.8 Hz, 1 H), 4.98 (dd, J ) 6.4, 3.4 Hz, 1 H),
6.71 (s, 4 H), 7.08 (dd, J ) 2.7, 2.0 Hz, 1 H), 7.16 (d, J ) 1.0 Hz,
1 H), 7.81 (d, J ) 0.7 Hz, 1 H), 7.90 (d, J ) 2.7 Hz, 1 H), 8.07 (d,
J ) 2.0 Hz, 1 H) ppm. MS (DCI/NH3) m/z 256 (M + H)+. Anal.
(C14H17N5‚2.00C4H4O4) C, H, N.
(1R,5R)-tert-Butyl 6-{5-[(Trimethylsilyl)ethynyl]pyridin-3-yl}-
3,6-diazabicyclo[3.2.0]heptane-3-carboxylate (TMS-3-N-Boc-44).
This was prepared according to the procedure for (1S,5S)-TMS-3-
N-Cbz-44 using (1R,5R)-3-N-Boc-23 (140 mg, 0.40 mmol) to
provide (1R,5R)-TMS-3-N-Boc-44 (120 mg, 80%). 1H NMR
(CD3OD, 300 MHz): δ 0.05 (s, 9 H), 1.40 [s (br.), 9 H], 3.16-
3.35 (m, 3 H), 3.50 (m, 1H), 3.85-4.05 (m, 3 H), 4.50 (m, 1 H),
(1S,5S)-Benzyl 6-(5,6-Dibromopyridin-3-yl)-3,6-diazabicyclo-
[3.2.0]heptane-3-carboxylate (3-N-Cbz-47): Representative Pro-

5506 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22
Ji et al.
cedure for Bromination. A solution of N-bromosuccinimide (92
mg, 0.52 mmol) in MeCN (5 mL) was slowly added to the solution
of (1S,5S)-3-N-Cbz-23 (200 mg, 0.52 mmol) in MeCN (10 mL) at
-20 to 0 °C over 5 min. The mixture was then stirred at 0-20 °C
for 1 h and quenched with water (5 mL). It was extracted with
EtOAc (3 × 20 mL). The combined extracts were washed with
brine (2 × 5 mL) and then concentrated. The residue was purified
by chromatography on silica gel (v. EtOAc:hexanes ) 1:1) to
1 H), 3.16 (dd, J ) 12.4, 4.9 Hz, 1 H), 3.43-3.60 (m, 1 H), 3.71
(dd, J ) 11.0, 5.3 Hz, 1 H), 3.89 (d, J ) 10.5 Hz, 1 H), 4.09 (d,
J ) 12.2 Hz, 1 H), 4.25 (dd, J ) 11.2, 8.8 Hz, 1 H), 5.03 (dd, J )
7.0, 5.3 Hz, 1 H), 6.69 (s, 2 H), 7.63 (d, J ) 2.7 Hz, 1 H), 7.99 (d,
J ) 3.1 Hz, 1 H) ppm. MS (DCI/NH3) m/z 336 (M + H)+, 334 (M
+ H)+, 332 (M + H)+. Anal. (C10H11Br2N3‚1.00C4H4O4) C, H, N.
(1S,5S)-3-(6-Bromo-5-chloropyridin-3-yl)-3,6-diazabicyclo-
[3.2.0]heptane (52) Fumarate. This was prepared according to the
representative procedures D(c) and S(a) using (1R,5S)-6-N-Boc-
1
provide (1S,5S)-3-N-Cbz-47 (Rf ) 0.5, 100 mg, 42% yield). H
1
NMR (CD3OD, 300 MHz): δ 3.11-3.23 (m, 2 H), 3.33-3.43 (m,
1 H), 3.59 (dd, J ) 8.0, 3.6 Hz, 1 H), 3.90-4.12 (m, 3 H), 4.72
(dd, J ) 6.1, 4.1 Hz, 1 H), 4.99-5.33 (m, 2 H), 7.13 (d, J ) 2.4
Hz, 1 H), 7.17-7.44 (m, 5 H), 7.52 (d, J ) 2.4 Hz, 1 H) ppm. MS
(DCI/NH3) m/z 470 (M + H)+, 468 (M + H)+, 466 (M + H)+.
(1R,5S)-6-(5,6-Dibromopyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (47) Bis(tosylate). This was prepared according to the
representative procedures D(b) and S(b) using (1S,5S)-3-N-Cbz-
52. H NMR (CD3OD, 300 MHz): δ 3.07 (dd, J ) 10.5, 6.4 Hz,
1 H), 3.17 (dd, J ) 12.5, 5.1 Hz, 1 H), 3.44-3.59 (m, 1 H), 3.71
(dd, J ) 11.2, 5.1 Hz, 1 H), 3.90 (d, J ) 10.5 Hz, 1 H), 4.09 (d,
J ) 12.5 Hz, 1 H), 4.24 (dd, J ) 11.2, 8.5 Hz, 1 H), 5.03 (dd, J )
7.1, 5.1 Hz, 1 H), 6.68 (s, 2 H), 7.50 (d, J ) 2.7 Hz, 1 H), 7.96 (d,
J ) 2.7 Hz, 1 H) ppm. MS (DCI/NH3) m/z 292 (M + H)+, 290 (M
+ H)+, 288 (M + H)+. Anal. (C10H11BrClN3‚1.00C4H4O4) C, H,
N.
1
47. H NMR (CD3OD, 300 MHz): δ 2.37 (s, 6 H), 3.17 (dd, J )
5-[(1S,5S)-3,6-Diazabicyclo[3.2.0]heptan-3-yl]-2-bromonico-
tinonitrile (53) Tosylate. This was prepared according to the
representative procedures D(c) and S(b) using (1R,5S)-6-N-Boc-
12.7, 3.2 Hz, 1 H), 3.33-3.38 (m, 1 H), 3.40-3.52 (m, 1 H), 3.65-
3.80 (m, 3 H), 4.03 (t, J ) 8.0 Hz, 1 H), 4.89-4.98 (m, 1 H), 7.23
(d, J ) 8.5 Hz, 4 H), 7.31 (d, J ) 2.7 Hz, 1 H), 7.66 (d, J ) 2.7
Hz, 1 H), 7.70 (d, J ) 8.1 Hz, 4 H) ppm. MS (DCI/NH3) m/z 336
(M + H)+, 334 (M + H)+, 332 (M + H)+. Anal. (C10H11Br2N3‚
2.00C7H8SO3‚0.48H2O) C, H, N.
1
53. H NMR (CD3OD, 300 MHz): δ 2.37 (s, 3 H), 3.10 (dd, J )
11.0, 6.3 Hz, 1 H), 3.21 (dd, J ) 12.7, 5.3 Hz, 1 H), 3.45-3.62
(m, 1 H), 3.72 (dd, J ) 10.8, 5.4 Hz, 1 H), 3.93 (d, J ) 10.5 Hz,
1 H), 4.13 (d, J ) 12.2 Hz, 1 H), 4.26 (dd, J ) 11.2, 8.8 Hz, 1 H),
5.06 (dd, J ) 6.8, 4.7 Hz, 1 H), 7.22 (d, J ) 7.8 Hz, 2 H), 7.63-
7.84 (m, 3 H), 8.22 (d, J ) 3.1 Hz, 1 H) ppm. MS (DCI/NH3) m/z
281 (M + H)+, 279 (M + H)+. Anal. (C11H11BrN4‚1.03C7H8SO3‚
0.70H2O) C, H, N.
(1R,5S)-6-(6-Bromo-5-cyano-pyridin-3-yl)-3,6-diaza-bicyclo-
[3.2.0]heptane (48) Bisfumarate. This was prepared according to
the representative procedures D(c) and S(a) using (1S,5S)-3-N-Boc-
1
48. H NMR (CD3OD, 300 MHz): δ 3.20 (dd, J ) 12.0, 3.0 Hz,
1 H), 3.28-3.38 (m, 2 H), 3.45 (m, 1 H), 3.68-3.72 (m, 2 H),
4.08 (t, J ) 8.8 Hz, 1 H), 4.95 (m, 1 H), 6.70 (s, 4.00 H), 7.40 (d,
J ) 3.0 Hz, 1 H), 7.90 (d, J ) 3.0 Hz, 1 H) ppm. MS (DCI/NH3)
m/z 281 (M + H)+, 279 (M + H)+. Anal. (C11H11BrN4‚2.00C4H4O4)
C, H, N.
(1S,5S)-3-(6-Bromo-5-methoxypyridin-3-yl)-3,6-diazabicyclo-
[3.2.0]heptane (54) Fumarate. This was prepared according to the
representative procedures D(c) and S(a) using (1R,5S)-6-N-Boc-
1
54. H NMR (CD3OD, 300 MHz): δ 3.06 (dd, J ) 10.3, 5.9 Hz,
1 H), 3.15 (dd, J ) 12.4, 4.9 Hz, 1 H), 3.41-3.59 (m, 1 H), 3.73
(dd, J ) 11.2, 5.1 Hz, 1 H), 3.93 (d, J ) 12.5 Hz, 1 H), 3.94 (s,
3 H), 4.11 (d, J ) 12.2 Hz, 1 H), 4.26 (dd, J ) 11.0, 8.6 Hz, 1 H),
5.03 (dd, J ) 7.1, 5.1 Hz, 1 H), 6.68 (s, 2 H), 6.94 (d, J ) 2.7 Hz,
1 H), 7.58 (d, J ) 2.4 Hz, 1 H) ppm. MS (DCI/NH3) m/z 286 (M
+ H)+, 284 (M + H)+. Anal. (C11H14BrN3O‚1.02C4H4O4‚0.80H2O)
C, H, N.
(1R,5S)-6-(6-Bromo-5-methoxy-pyridin-3-yl)-3,6-diaza-bicyclo-
[3.2.0]heptane (49) Trifluoroacetate. This was prepared according
to the representative procedures D(b) and S(c) using (1S,5S)-3-N-
1
Cbz-49. H NMR (CD3OD, 300 MHz): δ 3.18 (dd, J ) 12.5, 3.7
Hz, 1 H), 3.32-3.39 (m, 2 H), 3.46 (ddd, J ) 14.1, 7.3, 2.7 Hz, 1
H), 3.66-3.81 (m, 3 H), 3.90 (s, 3 H), 4.04 (t, J ) 8.0 Hz, 1 H),
4.93 (dd, J ) 6.4, 3.4 Hz, 1 H), 6.58 (d, J ) 2.4 Hz, 1 H), 7.25 (d,
J ) 2.4 Hz, 1 H) ppm. MS (DCI/NH3) m/z 286 (M + H)+, 284 (M
+ H)+. Anal. (C11H14N3OBr‚1.00CF3CO2H‚0.50H2O) C, H, N.
(1S,5S)-tert-Butyl 6-(6-Bromo-5-carbamoylpyridin-3-yl)-3,6-
diazabicyclo[3.2.0]heptane-3-carboxylate (3-N-Boc-50). A solu-
tion of (1S,5S)-3-N-Boc-48 (383 mg, 1.0 mmol), urea hydrogen
peroxide (953 mg, 10.1 mmol), and K2CO3 (14 mg, 0.1 mmol) in
acetone-water (v., 1:1, 10 mL) was stirred at ambient temperature
for 10 h. It was then diluted with CH2Cl2 (50 mL) and washed
with saturated aqueous NH4Cl solution (2 × 5 mL) and brine (2 ×
5 mL). The organic solution was concentrated, and the residue was
purified by chromatography on silica gel (v. EtOAc:hexanes ) 1:1)
to provide (1S,5S)-3-N-Boc-50 (Rf ) 0.3, 203 mg, 51% yield). 1H
NMR (CD3OD, 300 MHz): δ 1.44 (s, 9 H), 3.14 (dd, J ) 13.6,
4.1 Hz, 1 H), 3.27-3.40 (m, 2 H), 3.66 (dd, J ) 8.1, 3.1 Hz, 1 H),
3.87 (d, J ) 10.5 Hz, 1 H), 3.93 (d, J ) 12.9 Hz, 1 H), 4.01 (t, J
) 8.0 Hz, 1 H), 4.71 (dd, J ) 5.8, 3.7 Hz, 1 H), 6.92 (d, J ) 3.1
Hz, 1 H), 7.60 (d, J ) 3.1 Hz, 1 H) ppm. MS (DCI/NH3) m/z 399
(M + H)+, 397 (M + H)+.
(1R,5R)-3-(6-Bromo-5-methoxypyridin-3-yl)-3,6-diazabicyclo-
[3.2.0]heptane (54) Fumarate. This was prepared according to the
representative procedures D(c) and S(a) using (1S,5R)-6-N-Boc-
1
54. H NMR (CD3OD, 300 MHz): δ 3.05 (dd, J ) 10.5, 6.1 Hz,
1 H), 3.15 (dd, J ) 12.5, 5.1 Hz, 1 H), 3.44-3.60 (m, 1 H), 3.73
(dd, J ) 10.8, 5.1 Hz, 1 H), 3.93 (d, J ) 12.5 Hz, 1 H), 3.94 (s,
3 H), 4.12 (d, J ) 12.5 Hz, 1 H), 4.26 (dd, J ) 11.0, 8.6 Hz, 1 H),
5.03 (dd, J ) 7.1, 5.1 Hz, 1 H), 6.68 (s, 2 H), 6.94 (d, J ) 2.7 Hz,
1 H), 7.57 (d, J ) 2.7 Hz, 1 H) ppm. MS (DCI/NH3) m/z 286 (M
+ H)+, 284 (M + H)+. Anal. (C11H14BrN3O‚1.00C4H4O4‚0.40H2O)
C, H, N.
5-[(1R,5S)-3,6-Diazabicyclo[3.2.0]heptan-6-yl]-N-hydroxy-
nicotinimidamide (55) Fumarate. This was prepared according
to the representative procedures D(c) and S(a) using (1S,5S)-3-N-
1
Boc-55. H NMR (CD3OD, 300 MHz): δ 3.15 (dd, J ) 12.5, 3.4
Hz, 1 H), 3.32-3.36 (m, 1 H), 3.38-3.50 (m, 1 H), 3.70 (d, J )
12.2 Hz, 1 H), 3.74 (d, J ) 12.6 Hz, 1 H), 3.79 (dd, J ) 7.8, 3.1
Hz, 1 H), 4.06 (t, J ) 8.0 Hz, 1 H), 4.93 (dd, J ) 6.4, 3.4 Hz, 1
H), 6.68 (s, 2 H), 7.20 (dd, J ) 2.7, 2.0 Hz, 1 H), 7.89 (d, J ) 2.7
Hz, 1 H), 8.24 (d, J ) 1.7 Hz, 1 H) ppm. MS (DCI/NH3) m/z 234
(M + H)+. Anal. (C11H15N5O‚1.00C4H4O4) C, H, N.
5-[(1R,5S)-3,6-Diazabicyclo[3.2.0]heptan-6-yl]-2-bromonico-
tinamide (50) Fumarate. This was prepared according to the
representative procedures D(c) and S(a) using (1S,5S)-3-N-Boc-
3-{(1R,5S)-3,6-Diazabicyclo[3.2.0]heptan-6-yl}-5-cyanopyri-
dine 1-oxide (56) Fumarate. This was prepared according to the
representative procedure D(c) and S(a) using 3-N-Boc-56. 1H NMR
(CD3OD, 300 MHz): δ 3.18 (dd, J ) 12.5, 3.4 Hz, 1 H), 3.33-
3.38 (m, 1 H), 3.39-3.51 (m, 1 H), 3.66-3.86 (m, 3 H), 4.06 (t,
J ) 8.0 Hz, 1 H), 4.94 (dd, J ) 6.3, 3.6 Hz, 1 H), 6.68 (s, 2 H),
7.21 (dd, J ) 2.7, 2.0 Hz, 1 H), 7.89 (d, J ) 2.7 Hz, 1 H), 8.25 (d,
J ) 1.7 Hz, 1 H) ppm. MS (DCI/NH3) m/z 234 (M + NH4)+. Anal.
(C11H12N4O‚1.10C4H4O4‚1.05H2O) C, H, N.
1
50. H NMR (D2O, 300 MHz): δ 3.22 (dd, J ) 12.7, 3.2 Hz, 1
H), 3.32-3.44 (m, 1 H), 3.45-3.61 (m, 1 H), 3.77-3.83 (m, 3 H),
4.08 (t, J ) 8.0 Hz, 1 H), 4.99 (dd, J ) 5.9, 3.2 Hz, 1 H), 6.57 (s,
2 H), 7.10 (d, J ) 3.1 Hz, 1 H), 7.74 (d, J ) 2.7 Hz, 1 H) ppm.
MS (DCI/NH3) m/z 299 (M + H)+, 297 (M + H)+. Anal. (C11H13-
BrN4O‚1.00C4H4O4‚0.20H2O) C, H, N.
(1S,5S)-3-(5,6-Dibromopyridin-3-yl)-3,6-diazabicyclo[3.2.0]-
heptane (51) Fumarate. This was prepared according to the
representative procedures D(c) and S(a) using (1R,5S)-6-N-Boc-
Binding Assay. Binding assay conditions were modified from
1
51. H NMR (CD3OD, 300 MHz): δ 3.06 (dd, J ) 10.5, 6.1 Hz,
the procedures described in Pabreza et al.28b Membrane-enriched

3,6-Diazabicyclo[3.2.0]heptanes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22 5507
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DE) were slowly thawed at 4 °C, washed, and resuspended in 30
volumes of BSS-Tris buffer (120 mM NaCl/5 mM KCl/2 mM
CaCl2/2 mM MgCl2/50 mM Tris-Cl, pH 7.4, 4 °C). Samples
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were incubated in a final volume of 500 µL for 75 min at 4 °C.
Seven log-dilution concentrations of each compound were tested
in duplicate. Nonspecific binding was determined in the presence
of 10 µM (-)-nicotine. Bound radioactivity was isolated by vacuum
filtration onto prewetted glass fiber filter plates (Millipore, Bedford,
MA) using a 96-well filtration apparatus (Packard Instruments,
Meriden, CT) and were then rapidly rinsed with 2 mL of ice-cold
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Packard MicroScint-20 scintillation cocktail (40 µL) was added to
each well, and radioactivity was determined using a Packard
TopCount instrument. The IC50 values were determined by nonlinear
regression in Microsoft Excel software. Ki values were calculated
from the IC50 values using the Cheng-Prusoff equation, where Ki
) IC50/(1 + [ligand]/KD).
Functional Assay. HEK-293 cell lines expressing the recom-
binant human nAChRs R4â2 and R3â4 subunit combinations were
used in the determination of functional nAChR agonist activity by
measuring intracellular calcium changes using the fluorometric
imaging plate reader (FLIPR; Molecular Devices, Sunnyvale, CA).
Cells were plated at densities of 25000-50000 cells/well in
Dulbecco’s modified Eagle’s medium (Gibco) supplemented with
10% fetal bovine serum (Gibco) in 96-well clear bottom black-
walled plates precoated with poly-D-lysine (Sigma, 75 µL/well of
0.01 g/L solution g 30 min) and allowed to incubate for 24-48 h
at 37 °C in 5% CO2 in a humidified environment. After the media
were aspirated off, the cell lines were incubated in the dark at room
temperature for ∼0.75-1 h with 2-4 µM Fluo-4 AM calcium
indicator dye (Molecular Probes, Eugene, OR) dissolved in 0.1-
0.2% v/v of DMSO (Sigma, United Kingdom) in NMDG Ringer
buffer (in mM: 140 NMDG, 5 KCl, 1 MgCl2, 10 HEPES, and 10
CaCl2, pH 7.4). Cells were placed in the FLIPR, and 50 µL of 3×
stock concentrations of test compounds or buffer prepared in the
same NMDG ringer buffer was added. Raw fluorescence data were
corrected by subtracting fluorescence values from wells that
received buffer-only additions. Peak fluorescent values were
exported to Microsoft Excel, corrected for background signal, and
expressed as a percentage of the reference peak response for the
positive control of 100 µM nicotine. Dose-response data were fitted
using a single sigmoidal function in GraphPad Prism (San Diego,
CA) for determination of EC50 and maximum response. Data are
expressed as means ( SEM (n of six represents two replicates
across three separate plates).
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Acknowledgment. We thank Drs. Murali Gopalakrishnan
and Lance Lee for assistance with the preparation of this
manuscript.
Supporting Information Available: Experimental details and
spectra data for (1R,5R)-19a, (1S,5R)-20, and intermediates of 22-
31, 33-43, 45-49, and 51-56 as well as elemental analysis for
final compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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