Discovery of (5S,6S,9R)-5-aqmino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro- 5H-cyclohepta[b]pyridin-9-yl4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl) piperidine-1-carboxylate (BMS-927711): An oral Calcitonin Gene-Related Peptide (CGRP) antagonist in cinical trials for treating migraine

Article abstract of DOI:10.1021/jm3013147

Calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated clinical efficacy in the treatment of acute migraine. Herein, we describe the design, synthesis, and preclinical characterization of a highly potent, oral CGRP receptor antagonist BMS-927711 (8). Compound 8 has good oral bioavailability in rat and cynomolgus monkey, attractive overall preclinical properties, and shows dose-dependent activity in a primate model of CGRP-induced facial blood flow. Compound 8 is presently in phase II clinical trials.

Full text of DOI:10.1021/jm3013147

Subscriber access provided by UNIV OF WISCONSIN - MADISON
Article
Discovery of (5S,6S,9R)-5-Amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-
cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-
yl)piperidine-1-carboxylate (BMS-927711) – An Oral Calcitonin Gene-
related Peptide (CGRP) Antagonist in Clinical Trials for Treating Migraine
Guanglin Luo, Ling Chen, Charles M. Conway, Rex Denton, Deborah Keavy, Laura
Signor, Walter A. Kostich, Kimberley A. Lentz, Kenneth S. Santone, Richard Schartman,
Marc Browning, Gary Tong, John G. Houston, Gene M. Dubowchik, and John E. Macor
J. Med. Chem., Just Accepted Manuscript • Publication Date (Web): 02 Nov 2012
Downloaded from http://pubs.acs.org on November 6, 2012
Just Accepted
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Journal of Medicinal Chemistry is published by the American Chemical Society. 1155
Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

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Journal of Medicinal Chemistry
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Discovery of (5S,6S,9R)ꢀ5ꢀAminoꢀ6ꢀ(2,3ꢀ
difluorophenyl)ꢀ6,7,8,9ꢀtetrahydroꢀ5Hꢀ
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cyclohepta[b]pyridinꢀ9ꢀyl 4ꢀ(2ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀ
imidazo[4,5ꢀb]pyridinꢀ1ꢀyl)piperidineꢀ1ꢀcarboxylate
(BMSꢀ927711) – An Oral Calcitonin Geneꢀrelated
Peptide (CGRP) Antagonist in Clinical Trials for
Treating Migraine
Guanglin Luo*, Ling Chen, Charles M. Conway, Rex Denton, Deborah Keavy, Laura Signor, Walter
Kostich, Kimberley A. Lentz, Kenneth S. Santone, Richard Schartman, Marc Browning, Gary Tong,
John G. Houston, Gene M. Dubowchik, and John E. Macor.
Molecular Sciences and Candidate Optimization, Disease Sciences and Biologics, BristolꢀMyers Squibb
Research & Development, 5 Research Parkway, Wallingford, CT, 06492.
Guanglin.luo@bms.com
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
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ABSTRACT: Calcitonin geneꢀrelated peptide (CGRP) receptor antagonists have demonstrated clinical
efficacy in the treatment of acute migraine. Herein, we describe the design, synthesis, and preclinical
characterization of a highly potent, oral CGRP receptor antagonist BMSꢀ927711 (8). Compound 8 has
good oral bioavailability in rat and cynomolgus monkey, attractive overall preclinical properties, and
shows doseꢀdependent activity in a primate model of CGRPꢀinduced facial blood flow. Compound 8 is
presently in Phase II clinical trials.
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KEYWORDS (Word Style “BG_Keywords”). If you are submitting your paper to a journal that requires
keywords, provide significant keywords to aid the reader in literature retrieval.
BRIEFS (WORD Style “BH_Briefs”). If you are submitting your paper to a journal that requires a brief,
provide a oneꢀsentence synopsis for inclusion in the Table of Contents.
INTRODUCTION
Migraine is a painful, incapacitating disease, that affects a large portion (12%) of the adult population
and imposes a substantial economic burden on society (estimated to be $13 billion per year).1 It is
characterized by recurrent unilateral headaches often accompanied by nausea, vomiting, photophobia
and phonophobia. Much remains to be learned about the underlying pathophysiology of migraine. One
prominent hypothesis is that migraine headache is initiated with the dilation of cranial blood vessels.2
Additional contemporary work has focused on neural processes and the potential roles of peripheral3
and possibly central sensitization4 in the neurobiology of headache. The current standard of care is the
triptan class of 5ꢀHT1B/1D receptor agonists which are believed to act by constriction of the cranial blood
vessels.3 However, because they cause nonselective smooth muscle vasoconstriction, they are
associated with a number of unpleasant, and potentially dangerous, cardiovascular side effects, and the
triptans have labeled contraindications against use in patients with heart disease and hypertension.4 A
novel class of drugs for migraine treatment that are devoid of direct vasoconstriction would offer a
significant therapeutic advantage over the current standard of care.
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Journal of Medicinal Chemistry
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CGRP is a 37 aminoꢀacid peptide that is widely distributed in the nervous system.5 It is an extremely
potent vasodilator that has been directly implicated in the pathogenesis of migraine.6 Studies have
shown that plasma levels of CGRP are elevated during migraine attacks, and these levels are normalized
by sumatriptan in connection with the relief of headache.4 CGRP receptors are Gꢀcoupled cell surface
receptors composed of: the calcitonin receptorꢀlike receptor (CLR), receptor activity modifying protein
1 (RAMP1), and the receptor component protein (RCP).7
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CGRP receptor antagonists are a new therapeutic target for the treatment of migraine. Proof of
mechanism in the clinic was first demonstrated with intravenous administration of olcegepant
(BIBN4096BS) (1, Figure 1), where alleviation of pain in migraneurs was significantly superior over
placebo.8 Importantly, cardiovascular side effects associated with sumatriptan were not observed with
the CGRP receptor antagonist 1. More recently, an oral CGRP receptor antagonist, telcagepant (MKꢀ
0974)10 (2, Figure 1), showed efficacy in multiple Phase II and Phase III trials, but was discontinued
following a larger study.11 Two later oral CGRP receptor antagonists, MKꢀ320712 and BIꢀ4437013 (3
and 4, Figure 1), were efficacious in various Phase II trials, but are not currently in clinical
development.14
A recent publication from our laboratory disclosed the potent, oral CGRP receptor antagonist, BMSꢀ
846372, which contained a cyclohepta[b]pyridine core, (5, Figure 1) and was an attractive preclinical
lead.15 However, the compound was highly crystalline with very low aqueous solubility (< 2 ꢁg/ml),
and this created a significant challenge for further clinical development. Formation of useful salts of the
core pyridine (pKa ~ 4) was not feasible since strong acids led to hydrolysis of the carbamate. A limited
number of phosphateꢀrelated prodrugs were attempted, but they were not progressable.16 We realized
that one way to increase the aqueous solubility of an organic molecule was to add hydrophilic groups.
We hypothesized that the addition of small, polar groups such as OH or NH2 would provide “helpful
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polarity,” improving the solubility while maintaining the attractive properties of 5. In this vein, two
target alcohols, 6 and 7 (Figure 2) were prepared to test this hypothesis. These more polar analogs of 5
(6 and 7) maintained their potency as CGRP receptor antagonists, and this encouraged us to make the
primary amine analog 8 (Figure 2). A primary amine would also allow salt formation that might not
facilitate decomposition of the carbamate linker. Accordingly, herein we describe the discovery of a
potent, aqueous soluble, orally active CGRP receptor antagonist BMSꢀ927711 (8) (Figure 2) which is
presently in Phase II clinical trials.
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Figure 1. Selected CGRP Receptor Antagonists
Figure 2. Proposed target CGRP receptor antagonists 6, 7, and 8
CHEMISTRY
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We recently reported a stereoselective synthesis of 5,17 in which ketone 9 (Scheme 1) was prepared as
1
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a key intermediate. It was also useful for the formation of our present targets, compounds 6, 7, and 8.
The syntheses of the desired alcohols, 6 and 7, are shown in Scheme 1. Careful deprotection of 9 by
TBAF afforded the rather unstable hydroxyl ketone intermediate 10 in 62% yield. Carbamate formation
with 11 under previously reported conditions18 using NaHMDS as the base at low temperature afforded
the intermediate ketone 12 in 29% yield. Reduction of the ketone 12 by NaBH4 afforded three alcohols,
6, 7, and 13, after careful purifications using preparative HPLC and flash column chromatography.
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Scheme 1. Synthesis of alcohols 6 and 7
o
Reagents and Conditions: (a) THF, TBAF, -15 °C, 1h (62%); (b) DMF, NaHMDS, -15 to -5 C, 1.5h (29%); (c) MeOH, NaBH4, rt,
30min, 6 (14%), 7 (12%), 13 (6%).
In order to assign relative stereochemistry, ketone mixture 9 was directly reduced by NaBH4 to the
diastereomeric mixture 14 (Scheme 2). Treatment of 14 with TBAF at room temperature left 16
untouched, while removing the TIPS protecting group from the major and minor diastereomers, 15 and
17. All three components were easily separable at this stage. The major diastereomer, 15, was obtained
in 65% yield. An Xꢀray structure of 15 was obtained and identified its relative stereochemistry (as
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shown in Scheme 2).19 The protected diasteromer 16 was further treated with TBAF at elevated
temperature to afford the diol 18. An Xꢀray structure of 18 was also obtained, showing its relative
stereochemistry (as shown in Scheme 2).19 The relative stereochemistry of diol 17 was not
determined.20
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Scheme 2. Absolute stereochemistry of diols 15 and 18
Reagents and Conditions: (a) MeOH, NaBH4, rt, 1h (96%); (b) THF, TBAF, rt, 2h, 15 (65%), 16 (17%), 17 (12%); (c) THF, TBAF
(2.5 equiv.), 50 °C, 18h, (94%).
Based on the stereochemical information and product distribution ratio (compounds 6 and 15 were
major products from both NaBH4 reductions) obtained from 15 and 18, the absolute stereochemistry of
compound 6 was assigned as shown in Scheme 1. To further confirm the stereochemistry of 6, a
stereoselective synthesis of compound 6 was carried out (Scheme 3). Enantiomerically pure 19 was
available from ketone 9 through dynamic resolution and diastereoselective reduction.17 Protection of
alcohol 19 as the acetate afforded 20, which after TBAF deprotection, afforded the desired alcohol 21.
When 21 was subjected to the coupling conditions described in Scheme 1, compound 22 was obtained.
Under the basic conditions, partial hydrolysis of 22 occurred to generate the final product 6. After
separation, treatment of 22 with K2CO3 in MeOH resulted in complete conversion to compound 6,
which was identical in every respect with that generated in Scheme 1.
Scheme 3. The stereospecific synthesis of 6
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Journal of Medicinal Chemistry
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Reagents and Conditions: (a) CH2Cl2, Ac2O, Et3N, DMAP, rt, 2h; (b) THF, TBAF, rt, 2h (87% for 2 steps); (c) 11, DMF, NaHMDS, -
15 to 0 oC, 2h (30% + 13% of 6); (d) MeOH, K2CO3, rt, 1h (56%).
With the absolute stereochemistry of the more active alcohol 6 established (Table 1), we prepared the
primary amine analog with the same configuration. The stereospecific synthesis of 8 was achieved as
shown in Scheme 4.20 Based on the stereochemistry of alcohol 19, a double inversion strategy was used
to preserve the absolute configuration of 6. Thus, alcohol 19 was first converted to the chloride 23 with
inversion of the chiral center. The second inversion was achieved by treating 23 with NaN3 to obtain
24. After TIPS removal, the alcohol 25 was coupled with 11, as described in Scheme 1, to give the
azide 26. This was converted to the amine 8 by treatment with Me3P (Scheme 4).
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Scheme 4. The stereospecific synthesis of 8a
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Reagents and Conditions: (a) NCS, Ph3P, THF, rt, 5h (83%); (b) NaN3, DMF, 50 C, 15h; (c) TBAF, THF, rt, 1.5h; (d) 11, DMF,
a.
NaHMDS, -15 oC to rt, 4h (73% for 3 steps); (e) PMe3, THF, H2O, rt, 5h (85%).
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RESULTS AND DISCUSSION
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Binding affinities for the human CGRP receptor were determined by inhibition of 125IꢀCGRP binding
to SKꢀNꢀMC cell membranes, which endogenously express receptor.21 Alcohol 6 demonstrated potent
CGRP receptor binding (Ki = 0.081 ± 0.034 nM (n=8), Table 1), comparable to previously reported
antagonist 515 (Ki = 0.070 ± 0.021 nM). In addition, the presence of the hydroxyl group in 6 improved
aqueous solubility (66 ꢁg/mL), reduced human plasma protein binding (fu = 4.1%), and improved
human microsomal stability (HLM T1/2 = 70 min.) relative to 5. The diastereomeric alcohols 13 and 7
(Ki = 0.67 and 4.3 nM, respectively) were successively less potent than 5 (Table 1).
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The corresponding primary amine 8 demonstrated even better in vitro properties relative to 5 (Table
1). Due to its higher human plasma free fraction and more potent CGRP receptor binding, the proteinꢀ
adjusted Ki for 8 was improved by 8ꢀfold in comparison with 5. There was also a further improvement
in HLM stability (T1/2 = 83 min). Functional receptor antagonism for 8 was determined by measuring
inhibition of CGRPꢀstimulated cAMP production in SKꢀNꢀMC cells. Compound 8 was shown to be a
full, competitive antagonist with IC50 = 0.14 ± 0.01 nM (n = 2). Despite the additional polarity of the
primary amine, permeability of 8 in the parallel artificial membrane permeability assay (PAMPA) was
excellent (190 and 320 nm/sec at pH 5.5 and 7.4, respectively). The solubility of crystalline 8 was very
good (50 ꢀg/mL) and a good portent of a straightforward pharmaceutics development.
Table 1. In Vitro Data for hCGRP Receptor Antagonists
Aq.Sol.(crystalline)
(ꢁg/ml)
HMetStab
T1/2(min)
Protein
adjusted Ki
(nM)a
cAMP
Human
fu (%)
Compound
i
hCGRP K (nM)
EC50(nM)
515
6
0.070(±0.021)
0.081(±0.034)
0.22
ꢀ
2.3
4.1
3.0
2.0
<2
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66b
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Journal of Medicinal Chemistry
4.3(±0.7)
0.027 (±0.009)
0.67(±0.01)
ꢀ
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6.9
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ꢀ
ꢀ
50
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ꢀ
83
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8
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0.14
0.39
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0.066(±0.018)
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a. Protein adjusted Ki was defined as Ki/Human fu; b. Amorphous.
A novel nonꢀinvasive marmoset recovery model for in vivo efficacy assessment of CGRP receptor
antagonists was developed in our laboratories, which utilizes laser Doppler facial blood flow as a
surrogate for intracranial artery diameter.15,21 Briefly, marmosets were anesthetized and facial blood
flow was increased by four intravenous (IV) administrations of hαCGRP (10 ꢁg/kg) delivered at 45 min
intervals (ꢀ30, 15, 60 & 105 min). The effect of antagonist, delivered subcutaneously (SC) at 0 min, on
the hαCGRPꢀinduced changes in facial blood flow was measured by laser Doppler flowmetry. In this
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model, compound 8 inhibited hαCGRPꢀinduced increases in marmoset facial blood flow upon
subcutaneous (SC) dosing.22 Compared to preꢀdose hCGRP control (ꢀ30 min), strong (> 50%)
inhibition of CGRPꢀinduced effects on facial blood flow was observed with 8 dosed sc at 7 mg/kg at 15,
60 and 105 min postꢀdose (Figure 2). Comparing activity versus exposure 15 min postꢀdose, plasma
levels of approximately 400 nM were associated with strong in vivo efficacy (> 65% inhibition). In
comparison, plasma levels of 5 above 1000 nM were needed for similar efficacy in this model.15,21
Peak inhibition for 8 was very strong at 75 ꢀ 80% at 60 and 105 min postꢀdose with corresponding
plasma levels just below 800 nM (Figure 2).22
Figure 2. Marmoset Facial Blood Flow at 7 mg/kg, SC. ꢀ30 min represents the increased facial blood
flow caused for hCGRP (10 ꢁg/kg IV). 7 mg/kg 8 (SC) delivered at time = 0 min. At 15, 60, and 105
min, hCGRP challenge (10 ꢁg/kg IV) was administered and reduction of facial blood flow and plasma
levels of 8 were measured.
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Compound 8 exhibited good oral bioavailability in the rat (FPO = 45%) and cynomolgus monkey (FPO
= 67% as a solution). When dosed as a free base suspension of crystalline material, the oral
bioavailability of 8 in the monkey remained good at 48%.
Against a panel of eight recombinant hCYP isoforms, 8 showed low levels of inhibition: IC50 ≥ 20
ꢁM for all except CYP3A4 (IC50 = 17 ꢁM). In addition, 8 showed no significant potential for offꢀtarget
liabilities in a panel of 45 receptor and ion channel binding, and enzyme activity assays. No
cardiovascular liability was identified in vitro. At 10 and 30 ꢂM, 8 caused less than 30% inhibition of
the hERG potassium channel alpha subunit expressed in HEKꢀ293 cells, and no significant effect was
seen on Lꢀtype sodium or calcium channels expressed in these cells. The compound was not mutagenic
in an exploratory Ames study.
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Journal of Medicinal Chemistry
On the basis of favorable preꢀnomination and preꢀIND toxicological studies, 8 was chosen for clinical
development. Initial Phase I human PK results have been in good agreement with preclinical human PK
projections, giving exposures at a 75 mg dose that are expected to prove efficacious. No significant
adverse effects were encountered up to 600 mg. Compound 8 is presently in Phase II studies and the
results of those studies will be reported in due course.
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CONCLUSION
Compound 8 is a highly potent CGRP receptor antagonist, with very good metabolic stability,
acceptable CYP inhibition profile, good animal PK, and a favorable predictive toxicological profile.
The presence of a primary amino group greatly improved aqueous solubility without compromising
bilayer permeability, resulting in enhanced ADME properties. More detailed pharmacological and
clinical results for 8 will be reported in due course.
EXPERIMENTAL PROCEDURES
General Procedures. All commercially available reagents and solvents were used without further
purification unless otherwise stated. All reactions were carried out under an inert atmosphere of dry
nitrogen in oven or flameꢀdried glassware unless otherwise stated. Flash column chromatography was
performed using 40ꢀ60 ꢂm Silica Gel 60 (EMD Chemicals, Inc.) as the stationary phase, or preꢀpacked
1
columns from ISCO Inco., Biotage, or Thomson Instrument Co. H NMR spectra were recorded on a
Bruker 400 or 500 MHz machine with tetramethylsilane or residual protiated solvent used as a
reference. 13C NMR were recorded on a Bruker DRXꢀ500 instrument operating at 125 MHz with
residual 12C solvent used as a reference. Low resolution mass spectra were recorded using a Waters
Micromass ZQ with electrospray ionization. High resolution mass spectra were recorded using a Waters
Micromass LCT time of flight mass spectrometer with electrospray ionization. The purity of all
compounds was determined by either Liquid chromatography–mass spectrometry (LCMS) or analytical
HPLC and was confirmed to be greater than 95% purity.
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(5S,6S,9R)-6-(2,3-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-
(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (6), (5R,6S,9R)-6-(2,3-
difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-
9
1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate
(7),
and
(5S,6R,9R)-6-(2,3-
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difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-
1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (13). In a 100 mL roundꢀbottom flask was
dissolved 12 (44.4 mg, 0.083 mmol) in MeOH (1 mL) to give a colorless solution. NaBH4 (6.30 mg,
0.166 mmol) was added, and the mixture was stirred at rt for 30 min. LCMS indicated complete
conversion, showing three peaks, all with the desired MW (M+H = 536). The mixture was concentrated
and directly purified by prepꢀHPLC (0.1% TFAꢀMeOHꢀWater system) to afford three components.
They were individually purified by flash column chromotagraphy using 0 ꢀ 10% MeOH/CH2Cl2 to
afford the products 6 (6.7 mg, 14%), 7 (5.5 mg, 12%), and 13 (3.0 mg, 6%) as white solids. The relative
stereochemistry was not strictly assigned at this stage. Product 6: 1H NMR (400 MHz,
CHLOROFORMꢀd) δ ppm 10.21 (br. s., 1 H) 8.52 (d, J=3.53 Hz, 1 H) 7.97 ꢀ 8.16 (m, 2 H) 7.47 (br. s.,
1 H) 7.27 ꢀ 7.37 (m, 1 H) 6.90 ꢀ 7.22 (m, 4 H) 5.97 (d, J=10.32 Hz, 1 H) 5.32 (d, J = 10.4 Hz, 1 H) 4.26
19
ꢀ 4.74 (m, 3 H) 2.55 ꢀ 3.29 (m, 3 H) 2.18 ꢀ 2.49 (m, 4 H) 2.07 ꢀ 2.17 (m, 1 H) 1.59 ꢀ 2.02 (m, 4 H); F
NMR (376 MHz, CHLOROFORMꢀd) δ ppm ꢀ137.26 ꢀ ꢀ136.84 (m, 1 F) ꢀ142.46 ꢀ ꢀ142.13 (m, 1 F).
Product 7: 1H NMR (400 MHz, CHLOROFORMꢀd) δ ppm 10.04 (br. s., 1 H) 8.60 (dd, J=4.78, 1.26 Hz,
1 H) 8.05 (br. s., 1 H) 7.66 (d, J=6.55 Hz, 1 H) 7.31 (dd, J=7.43, 4.91 Hz, 3 H) 7.03 ꢀ 7.17 (m, 2 H) 6.91
ꢀ 7.03 (m, 1 H) 6.25 (d, J=5.79 Hz, 1 H) 4.80 (d, J=8.56 Hz, 1 H) 4.18 ꢀ 4.66 (m, 3 H) 3.38 ꢀ 3.58 (m, 2
H) 3.02 (d, J=6.29 Hz, 2 H) 2.68 (d, J=13.60 Hz, 2 H) 2.05 ꢀ 2.45 (m, 3 H) 1.93 (br. s., 3 H);19F NMR
1
(376 MHz, CHLOROFORMꢀd) δ ppm ꢀ138.28 (m, 1 F) 143.94 (m, 1 F). Product 13: H NMR (400
MHz, CHLOROFORMꢀd) δ ppm 9.47 (br. s., 1 H) 8.50 (dd, J=4.78, 1.26 Hz, 1 H) 8.03 (dd, J=5.16,
1.13 Hz, 1 H) 7.35 ꢀ 7.55 (m, 3 H) 7.04 ꢀ 7.15 (m, 3 H) 7.00 (dd, J=7.55, 5.29 Hz, 1 H) 6.58 (br. s., 1 H)
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Journal of Medicinal Chemistry
4.85 (s, 1 H) 4.61 (br. s., 3 H) 3.36 (br. s., 1 H) 2.55 ꢀ 3.15 (m, 3 H) 2.35 (br. s., 1 H) 1.83 ꢀ 2.04 (m, 3
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H) 1.57 ꢀ 1.80 (m, 4 H); F NMR (376 MHz, CHLOROFORMꢀd) δ ppm ꢀ138.49 (br. s., 1 F) ꢀ144.30
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(m, 1 F).
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(5S,6S,9R)-6-(2,3-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-
(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (6). In a 250 mL
roundꢀbottom flask was dissolved 22 (51 mg, 0.088 mmol) (acetateꢀprotected product from above) in
MeOH (1 mL) to give a colorless solution. K2CO3 (122 mg, 0.883 mmol) was added, and the mixture
was stirred at rt for 1h. LCMS indicated complete conversion. MeOH was removed in vacuo. The
residue was partitioned between water and EtOAc. The phases were separated. The organic layer was
washed with brine, dried, and concentrated to a white solid. Purification by flash column
chromotagraphy using 0 ꢀ 10% MeOH/CH2Cl2 afforded the desire product (28 mg, 56%) as a light
1
yellow solid. H and 19F NMRs were obtained and matched that of the previous product 6.
(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-
(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (8). In a 100 mL
roundꢀbottom flask was dissolved 26 (620 mg, 1.106 mmol) in THF (5 mL) to give a colorless solution.
Trimethylphosphine (3.32 mL, 3.32 mmol, 1.0M in toluene) was added. The mixture was stirred at rt.
After 2 h, LCMS indicated complete conversion. Water (0.080 mL, 4.42 mmol) was added, and the
mixture was stirred for another 3 h. LCMS showed complete conversion to the desired product.
Volatile components were removed in vacuo and the residue was directly purified by flash column
chromotagraphy using 0 ꢀ 10% MeOH in CH2Cl2 to afford the product (510 mg, 85%) as a white solid,
which was recrystallized from EtOH: MS(ESI)[M+H+] = 535.23; 1H NMR (400 MHz,
CHLOROFORMꢀd) δ ppm 10.39 (br. s., 1 H) 8.52 (d, J=3.78 Hz, 1 H) 8.09 (d, J=5.04 Hz, 2 H) 7.46
(br. s., 1 H) 7.26 ꢀ 7.38 (m, 1 H) 7.06 ꢀ 7.20 (m, 3 H) 6.94 ꢀ 7.05 (m, 1 H) 6.06 ꢀ 6.23 (m, 1 H) 4.31 ꢀ
4.78 (m, 4 H) 4.05 (spt, J=6.13 Hz, 1 H) 2.57 ꢀ 3.25 (m, 3 H) 2.17 ꢀ 2.38 (m, 3 H) 1.42 ꢀ 2.04 (m, 6 H);
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Journal of Medicinal Chemistry
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23
19F NMR (376 MHz, CHLOROFORMꢀd) δ ppm ꢀ136.90 (br. s., 1 F) ꢀ142.48 ꢀ ꢀ142.21 (m, 1 F); [α]D
= ꢀ86.36° (c 5.71 mg/mL, methanol); Elemental Analysis: Calcd for C28H28N6•0.01 EtOH: C 62.90, H
5.29, N 15.70; Observed: C 63.03, H 5.26, N 15.62.
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(9R)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (10).
In a 250 mL roundꢀbottom flask was dissolved 9 (0.218 g, 0.49 mmol) in THF (5 mL) to give a
colorless solution. After cooling to ꢀ15°C (ice/MeOH bath) under nitrogen, TBAF (0.490 mL, 0.490
mmol) was added, and the resulting bright yellow solution was stirred at ꢀ15°C for 1h. The reaction was
quenched with NaHCO3 solution and diluted with EtOAc. The phases were separated and the aqueous
layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and
concentrated to give a tan oil. Purification by flash column chromotagraphy using EtOAc/hexane
1
afforded a mixture of two diastereomers (87 mg, 62%). Major component: H NMR (400 MHz,
CHLOROFORMꢀd) δ ppm 8.53 (dd, J=4.91, 1.64 Hz, 1 H) 7.85 (dd, J=7.68, 1.64 Hz, 1 H) 7.34 (dd,
J=7.68, 4.91 Hz, 1 H) 7.00 ꢀ 7.16 (m, 3 H) 5.32 (s, 1 H) 4.94 ꢀ 5.04 (m, 1 H) 4.48 (dd, J=11.83, 3.02 Hz,
1 H) 2.14 ꢀ 2.48 (m, 4 H); 19F NMR (376 MHz, CHLOROFORMꢀd) δ ppm ꢀ138.24 ꢀ ꢀ138.07 (m, 1 F) ꢀ
140.70 ꢀ ꢀ140.50 (m, 1 F).
(9R)-6-(2,3-difluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-
dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (12). In an ovenꢀdried 100 mL
roundꢀbottom flask was added 10 (112 mg, 0.389 mmol) (azeotroped with dry benzene) and 1117 (224
mg, 0.583 mmol) in DMF (3 mL) to give a light yellow suspension under nitrogen. After cooling to ꢀ
15°C (ice/MeOH bath), NaHMDS (1.55 mL, 1.55 mmol, 1.0 M in THF) was added dropwise. The
resulting yellow solution was stirred under nitrogen at ꢀ15°C for 1h. After gradually warming to ꢀ5°C
over 30 min, the reaction was quenched with NaHCO3 solution and diluted with EtOAc. The phases
were separated and the aqueous layer was extracted with EtOAc twice. The combined organic layers
were washed with brine, dried with Na2SO4, and concentrated to give a yellow oil. Purification by flash
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Journal of Medicinal Chemistry
column chromotagraphy using 0 ꢀ 10% MeOH/CH2Cl2 afforded the product (60 mg, 29%) as a white
solid. Major component: 1H NMR (400 MHz, CHLOROFORMꢀd) δ ppm 11.35 (br. s., 1 H) 8.76 (br. s.,
1 H) 8.00 ꢀ 8.17 (m, 1 H) 7.88 ꢀ 8.00 (m, 1 H) 7.29 ꢀ 7.55 (m, 2 H) 6.82 ꢀ 7.19 (m, 4 H) 6.20 (br. s., 1 H)
4.58 (br. s., 1 H) 4.24 ꢀ 4.51 (m, 2 H) 4.12 (q, J=7.22 Hz, 1 H) 2.75 ꢀ 3.17 (m, 2 H) 2.02 ꢀ 2.68 (m, 6 H)
1.89 (br. s., 2 H).
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(9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-
5-ol (14). In a 100 mL roundꢀbottom flask was dissolved ketone 9 (510 mg, 1.144 mmol) (mainly trans
with a trans/cis ratio of ~6/1) in MeOH (5 mL) to give a colorless solution. NaBH4 (87 mg, 2.289
mmol) was added, and the mixture was stirred at rt for 1h. LCMS indicated complete conversion.
MeOH was removed in vacuo and the residue was partitioned between water and EtOAc. The phases
were separated. The organic layer was washed with brine, dried, and concentrated to 14 (492 mg, 96%)
as a light yellow oil. The crude product was carried onto next reaction without further purification and
characterization.
(5S,6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-5,9-diol
(5R,6S,9R)-6-(2,3-difluorophenyl)-9-((triisopropylsilyl)oxy)-6,7,8,9-tetrahydro-5H-
(15),
cyclohepta[b]pyridin-5-ol (16), and (5S,6R,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-
cyclohepta[b]pyridine-5,9-diol (17). In a 100 mL roundꢀbottom flask was dissolved 14 (224.3 mg,
0.501 mmol) in THF (4 mL) to give a colorless solution. TBAF (0.752 mL, 0.752 mmol) was added,
and the mixture was stirred at rt for 2h. LCMS indicated complete conversion of the major component
while the minor one did not change. THF was removed in vacuo and the residue was partitioned
between water and EtOAc. The phases were separated and the aqueous layer was extracted with
EtOAc. The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to
give a tan oil. Flash column chromotagraphy using 0 ꢀ 50% EtOAc/hexane afforded intermediate 16
unchanged (38 mg, 17%) as a white crystalline solid, and intermediate 15 (95 mg, 65%) as a colorless
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Journal of Medicinal Chemistry
Page 16 of 26
oil that solidified upon standing. Further elution up to 100% EtOAc afforded 17 (17.3 mg, 12%) as a
colorless oil. Intermediate 15 was further crystallized and single crystals were obtained. Its relative
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stereochemistry was proven by xꢀray studies. 15: MS(ESI)[M+H+] = 292.26; H NMR (400 MHz,
7
8
9
CHLOROFORMꢀd) δ ppm 8.45 (dd, J=4.78, 1.26 Hz, 1 H) 8.10 (d, J=7.81 Hz, 1 H) 7.24 ꢀ 7.36 (m, 1
H) 6.97 ꢀ 7.18 (m, 3 H) 5.77 ꢀ 6.44 (m, 1 H) 5.08 (d, J=10.07 Hz, 1 H) 4.70 ꢀ 4.84 (m, 1 H) 2.93 ꢀ 3.08
(m, 1 H) 2.55 (br. s., 1 H) 2.17 ꢀ 2.38 (m, 2 H) 2.04 ꢀ 2.13 (m, 1 H) 1.39 ꢀ 1.58 (m, 1 H); 19F NMR (376
MHz, CHLOROFORMꢀd) δ ppm ꢀ137.35 ꢀ ꢀ136.88 (m, 1 F) ꢀ142.50 ꢀ ꢀ142.13 (m, 1 F); 13C NMR (101
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MHz, CHLOROFORMꢀd) δ ppm 157.58 (s, 1 C) 150.05 ꢀ 152.35 (dd, J = 12.5 and 199 Hz, 1 C) 147.63
ꢀ 149.87 (dd, J = 13.0 and 197 Hz, 1 C) 145.43 (s, 1 C) 136.62 (s, 1 C) 133.15 (s, 1 C) 132.69 (d,
J=11.56 Hz, 1 C) 124.36 ꢀ 124.79 (m, 1 C) 123.71 (br. s., 1 C) 122.74 (s, 1 C) 115.75 (d, J=16.96 Hz, 1
C) 71.37 (s, 1 C) 71.12 (s, 1 C) 46.21 (br. s., 1 C) 35.70 (s, 1 C) 32.83 (s, 1 C). 16: MS(ESI)[M+H+] =
1
448.43; H NMR (400 MHz, CHLOROFORMꢀd) δ ppm 8.34 ꢀ 8.48 (m, 1 H) 7.62 (d, J=7.55 Hz, 1 H)
7.15 (dd, J=7.81, 4.78 Hz, 1 H) 6.89 ꢀ 7.05 (m, 1 H) 6.67 ꢀ 6.82 (m, 1 H) 6.24 (br. s., 1 H) 5.81 (br. s., 1
H) 5.38 (d, J=4.78 Hz, 1 H) 3.93 (br. s., 1 H) 2.59 (br. s., 1 H) 2.31 (d, J=4.53 Hz, 1 H) 2.13 ꢀ 2.25 (m, 1
H) 2.01 ꢀ 2.12 (m, J=14.20, 7.07, 7.07, 3.65 Hz, 1 H) 1.85 ꢀ 2.01 (m, 1 H) 1.10 ꢀ 1.23 (m, 3 H) 1.02 ꢀ
1
1.08 (m, 9 H) 0.93 ꢀ 1.00 (m, 9 H). 17: H NMR (400 MHz, CHLOROFORMꢀd) δ ppm 8.11 (dd,
J=5.04, 1.51 Hz, 1 H) 7.55 (dd, J=7.55, 1.51 Hz, 1 H) 7.43 ꢀ 7.51 (m, 1 H) 7.28 (s, 1 H) 6.99 ꢀ 7.16 (m,
3 H) 5.92 (br. s., 1 H) 5.12 (d, J=6.04 Hz, 1 H) 4.63 (br. s., 1 H) 3.40 (d, J=12.09 Hz, 1 H) 2.76 ꢀ 2.98
(m, 1 H) 2.33 ꢀ 2.54 (m, 1 H) 1.90 ꢀ 2.03 (m, 1 H) 1.76 ꢀ 1.90 (m, 1 H); 19F NMR (376 MHz,
CHLOROFORMꢀd) δ ppm ꢀ138.96 ꢀ ꢀ138.49 (m, 1 F) ꢀ145.03 ꢀ ꢀ144.50 (m, 1 F).
((5R,6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-5,9-diol (18). In
a 100 mL roundꢀbottom flask was dissolved 16 in THF (2 mL) to give a colorless solution. TBAF
(0.407 mL, 0.407 mmol) was added, and the mixture was heated at 50°C for 18h. LCMS showed
complete conversion. The mixture was diluted with EtOAc and water. The phases were separated and
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Journal of Medicinal Chemistry
the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine,
dried with Na2SO4, and concentrated to give a tan oil. Flash column chromotagraphy using 0 ꢀ 50%
EtOAc/hexane afforded the desired product (56 mg, 94%) as a white crystalline solid. Intermediate 18
was further crystallized and single crystals were obtained. Its relative stereochemistry was proven by xꢀ
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ray studies. MS(ESI)[M+H+] = 292.26; H NMR (400 MHz, CHLOROFORMꢀd) δ ppm 8.37 (dd,
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J=5.04, 1.51 Hz, 1 H) 7.52 (dd, J=7.55, 1.51 Hz, 1 H) 7.37 ꢀ 7.49 (m, 1 H) 7.19 (dd, J=7.30, 5.04 Hz, 1
H) 7.00 ꢀ 7.15 (m, 2 H) 5.96 (br. s., 1 H) 5.23 (dd, J=11.58, 2.27 Hz, 1 H) 4.78 (s, 1 H) 3.22 ꢀ 3.32 (m, 1
H) 3.10 (br. s., 1 H) 2.74 ꢀ 2.89 (m, 1 H) 2.29 (dddd, J=13.60, 5.16, 2.77, 2.64 Hz, 1 H) 1.77 ꢀ 1.91 (m,
1 H) 1.47 ꢀ 1.67 (m, 1 H); 19F NMR (376 MHz, CHLOROFORMꢀd) δ ppm ꢀ138.73 ꢀ ꢀ138.11 (m, 1 F) ꢀ
144.45 ꢀ ꢀ144.03 (m, 1 F); 13C NMR (101 MHz, CHLOROFORMꢀd) δ ppm 160.75 (s, 1 C) 149.14 ꢀ
151.82 (dd, J = 14.0 and 246 Hz, 1 C) 146.49 ꢀ 149.15 (dd, J = 12.0 and 244 Hz, 1 C) 146.14 (s, 1 C)
136.75 (s, 1 C) 135.45 (s, 1 C) 134.93 (d, J=10.79 Hz, 1 C) 123.79 ꢀ 124.30 (m, 1 C) 123.38 (s, 1 C)
122.20 (s, 1 C) 115.24 (d, J=16.96 Hz, 1 C) 77.94 (s, 1 C) 70.62 (s, 1 C) 40.42 (s, 1 C) 36.62 (s, 1 C)
26.81 (s, 1 C).
(5S,6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-
cyclohepta[b]pyridin-5-yl acetate (20). In a 250 mL roundꢀbottom flask was dissolved 19 (1.0 g,
2.243 mmol) in CH2Cl2 (20 mL) to give a colorless solution. Acetic anhydride (0.423 mL, 4.49 mmol)
and triethylamine (0.938 mL, 6.73 mmol) were added, followed by DMAP (0.055 g, 0.449 mmol). The
mixture was stirred at rt under nitrogen. After 2h, LCMS showed complete conversion. The mixture
was quenched with NaHCO3 solution and diluted with EtOAc. The phases were separated. The organic
layer was washed with brine, dried and concentrated to give a colorless oil (100%), which was
immediately carried onto the next reaction without further purification and characterization.
MS(ESI)[M+H+] = 490.26.
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(5S,6S,9R)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-yl
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acetate (21). In a 100 mL roundꢀbottom flask was dissolved 20 (1.1 g, 2.243 mmol) (azeotroped with
dry benzene) in THF (20 mL) to give a colorless solution. TBAF (2.69 mL, 2.69 mmol) was added, and
the resulting light yellow solution was stirred at rt for 2h. LCMS indicated complete conversion. THF
was removed in vacuo and the residue was diluted with water and EtOAc. The phases were separated.
The organic layer was washed with brine, dried, and concentrated to give a colorless oil. Purification by
flash column chromotagraphy using 0 ꢀ 70% EtOAc/hexane afforded the desired product (648 mg, 87%
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for 2 steps) as a colorless oil. MS(ESI)[M+H+] = 334.21; H NMR (400 MHz, CHLOROFORMꢀd) δ
ppm 8.47 (dd, J=4.78, 1.51 Hz, 1 H) 7.69 (d, J=7.30 Hz, 1 H) 7.28 (dd, J=7.81, 5.04 Hz, 1 H) 6.94 ꢀ
7.10 (m, 3 H) 6.20 (d, J=10.32 Hz, 1 H) 5.95 (br. s., 1 H) 4.95 (dd, J=11.21, 1.64 Hz, 1 H) 3.16 ꢀ 3.31
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(m, 1 H) 2.27 ꢀ 2.41 (m, 2 H) 2.06 ꢀ 2.19 (m, 1 H) 1.80 (s, 3 H) 1.48 ꢀ 1.63 (m, 1 H); C NMR (101
MHz, CHLOROFORMꢀd) δ ppm 168.96 (s, 1 C) 157.96 (s, 1 C) 149.66 ꢀ 151.75 (d, J = 12.6 and 199
Hz, 1 C) 147.21 ꢀ 149.29 (d, J = 13 and 198 Hz, 1 C) 146.00 (s, 1 C) 133.43 (s, 1 C) 132.23 (d, J=11.56
Hz, 1 C) 131.99 (s, 1 C) 123.90 ꢀ 124.24 (m, 1 C) 122.89 (br. s., 1 C) 122.66 (s, 1 C) 115.36 (d, J=16.95
Hz, 1 C) 72.77 (s, 1 C) 71.14 (s, 1 C) 42.12 (br. s., 1 C) 35.66 (s, 1 C) 32.68 (s, 1 C) 20.28 (s, 1 C); 19F
NMR (376 MHz, CHLOROFORMꢀd) δ ppm ꢀ138.20 ꢀ ꢀ137.93 (m, 1 F) ꢀ143.38 ꢀ ꢀ143.16 (m, 1 F).
(5S,6S,9R)-5-acetoxy-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-
(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (22). In an ovenꢀdried
100 mL roundꢀbottom flask was added 21 (96.7 mg, 0.290 mmol) (azeotroped with dry benzene) and 4ꢀ
nitrophenyl 4ꢀ(2ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀimidazo[4,5ꢀb]pyridinꢀ1ꢀyl)piperidineꢀ1ꢀcarboxylate (167 mg,
0.435 mmol) in DMF (3 mL) to give a light yellow suspension under nitrogen. After cooling to ꢀ15°C
(ice/MeOH bath), NaHMDS (0.870 mL, 0.870 mmol) was added dropwise. The resulting darkꢀred
solution was stirred under nitrogen at ꢀ15°C ~ 0°C for 1h. LCMS showed the desired product along
with possible hydrolyzed product. After another 1h at rt, complete hydrolysis was not achieved. The
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reaction was quenched with NaHCO3 solution and volatile components removed in vacuo. The mixture
was diluted with EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc
twice. The combined organic layers were washed with brine, dried with Na2SO4, and concentrated to
give a yellow oil. Purification by flash column chromotagraphy using 0 ꢀ 10% MeOH/CH2Cl2 afforded
the acetateꢀprotected product (51 mg, 30%) as well as the final product alcohol 6 (20 mg, 13%).
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(5R,6S,9R)-5-chloro-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-
cyclohepta[b]pyridine (23).
In an ovenꢀdried 250 mL roundꢀbottom flask was added Nꢀ
chlorosuccinimide (0.751 g, 5.62 mmol) in THF (15 mL) to give a colorless suspension. Ph3P (1.475 g,
5.62 mmol) was added. After stirring under nitrogen for 5min, 19 (1.0 g, 2.250 mmol) was added in one
portion to the gray suspension. The resulting reddish suspension was stirred at rt. The solids gradually
dissolved to give a tan solution. After 5h, LCMS indicated complete conversion. THF was removed in
vacuo. The remaining red oil was directly purified by flash column chromotagraphy (240 g silica
column) using 10 – 100% EtOAc/hexane, and then using 10% MeOH (with 2.0 M NH4OH) in CH2Cl2.
The product fractions were combined and reꢀpurified by flash column chromotagraphy using 0 ꢀ 50%
EtOAc/hexane to afford the desired product as a colorless oil (869 mg, 83%). MS(ESI)[M+H+] =
466.22; 1H NMR (400 MHz, CHLOROFORMꢀd) δ ppm 8.55 (d, J=3.53 Hz, 1 H) 7.63 (br. s., 1 H) 7.20
(dd, J=7.68, 4.91 Hz, 1 H) 7.01 ꢀ 7.15 (m, 1 H) 6.90 ꢀ 7.01 (m, 1 H) 6.66 ꢀ 6.90 (m, 1 H) 5.55 ꢀ 5.85 (m,
1 H) 5.40 ꢀ 5.56 (m, 1 H) 3.96ꢀ4.33 (m, 1 H) 2.33 (br. s., 3 H) 2.09 ꢀ 2.20 (m, 1 H) 1.14 ꢀ 1.23 (m, 3 H)
1.04 ꢀ 1.14 (m, 9 H) 1.01 (d, J=7.30 Hz, 9 H).
(5S,6S,9R)-5-azido-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-
cyclohepta[b]pyridine (24). In a 100 mL roundꢀbottom flask was dissolved 23 (566 mg, 1.214 mmol)
in DMF (5 mL) to give a colorless solution. Sodium azide (474 mg, 7.29 mmol) was added, and the
mixture was stirred at rt under nitrogen for 2.5h. LCMS indicated only very little reaction. The mixture
was heated at 50°C overnight. After 15h, LCMS indicated complete conversion with some elimination
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product. The mixture was diluted with water and EtOAc. The phases were separated. The organic
layer was washed with brine, dried, and concentrated to a colorless oil. The crude product was carried
onto the next reaction without further purification and characterization. Smaller scale purification
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afforded an analytical sample: MS(ESI)[M+H+] = 473.27; H NMR (400 MHz, CHLOROFORMꢀd) δ
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ppm 8.52 ꢀ 8.63 (m, 1 H) 7.75 (d, J=7.81 Hz, 1 H) 7.23 ꢀ 7.36 (m, 1 H) 6.95 ꢀ 7.17 (m, 2 H) 6.89 (br. s.,
1 H) 5.28 (d, J=4.03 Hz, 1 H) 4.90 (d, J=9.07 Hz, 1 H) 3.79 (t, J=9.44 Hz, 1 H) 1.86 ꢀ 2.23 (m, 4 H)
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1.16 ꢀ 1.30 (m, 3 H) 0.98 ꢀ 1.15 (m, 18 H); F NMR (376 MHz, CHLOROFORMꢀd) δ ppm ꢀ137.68 ꢀ ꢀ
137.36 (m, 1 F) ꢀ141.78 ꢀ ꢀ141.54 (m, 1 F).
(5S,6S,9R)-5-azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (25).
In a 100 mL roundꢀbottom flask was dissolved 24 (0.732 g, 1.549 mmol) (crude) in THF (8 mL) to give
a colorless solution. TBAF (1.859 mL, 1.859 mmol) was added, and the resulting light yellow solution
was stirred at rt for 1.5 h. LCMS indicated complete conversion. THF was removed in vacuo and the
residue was diluted with water and EtOAc. The phases were separated. The organic layer was washed
with brine, dried, and concentrated to a light yellow oil. Purification by flash column chromatography
using 0 ꢀ 60% EtOAc/hexane afforded the desired product (crude weight 480 mg) as a colorless oil.
1
Smaller scale purification afforded an analytical sample: MS(ESI)[M+H+] = 317.22; H NMR (400
MHz, CHLOROFORMꢀd) δ ppm 8.51 (dd, J=4.91, 1.38 Hz, 1 H) 7.99 (d, J=7.30 Hz, 1 H) 7.35 (dd,
J=7.81, 5.04 Hz, 1 H) 7.06 ꢀ 7.20 (m, 2 H) 6.94 ꢀ 7.05 (m, 1 H) 5.91 (br. s., 1 H) 5.03 (d, J=10.32 Hz, 1
H) 4.92 (dd, J=11.21, 2.39 Hz, 1 H) 2.84 ꢀ 3.02 (m, 1 H) 2.37 ꢀ 2.49 (m, 1 H) 2.25 ꢀ 2.36 (m, 1 H) 2.07 ꢀ
2.17 (m, J=14.38, 4.94, 3.05, 3.05 Hz, 1 H) 1.40 ꢀ 1.64 (m, 1 H); 13C NMR (101 MHz,
CHLOROFORMꢀd) δ ppm 158.48 (s, 1 C) 152.19 ꢀ 149.87 (dd, J=13.10 and 221Hz, 1 C) 149.72 ꢀ
147.42 (dd, J=13.87 and 219 Hz, 1 C) 146.16 (s, 1 C) 133.67 (s, 1 C) 133.23 (s, 1 C) 132.66 (d, J=10.79
Hz, 1 C) 124.43 (dd, J=6.94, 3.85 Hz, 1 C) 123.84 (br. s., 1 C) 122.89 (s, 1 C) 115.98 (d, J=17.73 Hz, 1
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C) 70.94 (s, 1 C) 65.67 (s, 1 C) 45.43 (br. s., 1 C) 35.71 (s, 1 C) 33.45 (s, 1 C); F NMR (376 MHz,
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CHLOROFORMꢀd) δ ppm ꢀ137.55 ꢀ ꢀ137.20 (m, 1 F) ꢀ142.28 ꢀ ꢀ141.89 (m, 1 F).
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(5S,6S,9R)-5-azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-
oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (26). In a 100 mL roundꢀ
bottom flask was added 25 (0.490 g, 1.549 mmol) (azeotroped with dry benzene) and 4ꢀnitrophenyl 4ꢀ
(2ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀimidazo[4,5ꢀb]pyridinꢀ1ꢀyl)piperidineꢀ1ꢀcarboxylate (0.713 g, 1.859 mmol) in
DMF (8 mL) to give a light yellow suspension under nitrogen. After cooling to ꢀ15°C (ice/MeOH bath),
NaHMDS (4.18 mL, 4.18 mmol) was added dropwise. The resulting tan solution was stirred under
nitrogen at ꢀ10°C ~ 0°C for 2h and at rt for 2h. LCMS showed complete conversion. The reaction was
quenched with NaHCO3 solution. The mixture was diluted with EtOAc. The phases were separated and
the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water,
brine, dried with Na2SO4, and concentrated to give a tan oil. Purification by flash column
chromotagraphy using 0 ꢀ 8% MeOH/CH2Cl2 afforded the desired product (632 mg, 73% for 3 steps) as
a light yellow foam. MS(ESI)[M+H+] = 561.27; 1H NMR (400 MHz, CHLOROFORMꢀd) δ ppm 11.50
(br. s., 1 H) 8.58 (d, J=3.78 Hz, 1 H) 8.11 (d, J=5.04 Hz, 1 H) 7.91 (d, J=7.30 Hz, 1 H) 7.33 (br. s., 2 H)
7.07 ꢀ 7.19 (m, 2 H) 6.92 ꢀ 7.06 (m, 2 H) 6.10 (d, J=9.32 Hz, 1 H) 5.23 (d, J=10.07 Hz, 1 H) 4.26 ꢀ 4.84
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(m, 3 H) 2.46 ꢀ 3.34 (m, 4 H) 2.20 ꢀ 2.43 (m, 3 H) 2.01 ꢀ 2.13 (m, 1 H) 1.94 (d, J=12.34 Hz, 3 H); F
NMR (376 MHz, CHLOROFORMꢀd) δ ppm ꢀ137.30 ꢀ ꢀ137.01 (m, 1 F) ꢀ142.32 ꢀ ꢀ142.03 (m, 1 F).
ACKNOWLEDGMENT A generous supply of alcohol 19 from our Process group is greatly
appreciated; We thank Ms. Alicia Ng and Dr. Qi Gao for the Xꢀray structures of diols 15 and 18, and the
members of Discovery Analytical Sciences for detailed characterizations.
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SUPPORTING INFORMATION AVAILABLE Xꢀray structures of intermediates 15 and 18, and
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biology experimental. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION Corresponding author: Phone: 203ꢀ677ꢀ6640. Fax: 203ꢀ677ꢀ7702. Eꢀ
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mail: guanglin.luo@bms.com.
ANCILLARY INFORMATION Abbreviations used: CGRP (Calcitonin geneꢀrelated peptide); CLP
(Clacitonin receptorꢀlike receptor); RAMP1 (Receptor activity modifying protein 1); RCP (Receptor
component protein); TBAF (Tetrabutylammonium fluoride); PAMPA (Parallel artificial membrane
permeability assay); IV (Intravenous); Fpo (Oral Bioavailability); SC (Subcutaneous).
REFERENCES
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(6) (a) Goadsby, P.J. Calcitonin geneꢀrelated peptide antagonists as treatments of migraine and other
primary headaches. Drugs 2005, 65, 2557ꢀ2567. (b) Edvinsson L. Blockade of CGRP receptors in the
intracranial vasculature: a new target in the treatment of headache. Cephalalgia. 2004, 24, 611ꢀ622. (c)
Williamson D.J.; Hargreaves R.J. Neurogenic inflammation in the context of migraine. Microsc. Res.
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(7) Recober, A.; Russo, A.F. Calcitonin geneꢀrelated peptide: An update on the biology. Curr. Opin.
Neurol. 2009, 22, 241ꢀ246.
(8) Olesen, J.; Diener, H.C.; Husstedt, I.W.; Goadsby, P.J.; Hall, D.; Meier, U.; Pollentier, S.; Lesko,
L.M. Calcitonin gene related peptide receptor antagonist BIBN 4096 BS for the acute treatment of
migraine. N. Engl. J. Med. 2004, 350, 1104ꢀ1110.
(9) IDDB, Thomson Scientific reports that development of BIBN4096BS has been discontinued.
(10) Paone, D.V.; Shaw, A.W.; Nguyen, D.N.; Burgey, C.S.; Deng, J.Z.; Kane, S.A.; Koblan, K.S.;
Salvatore, C.A.; Mosser, S.D.; Johnston, V.K.; Wong, B.K.; MillerꢀStein, C.M.; Hershey, J.C.; Graham,
S.L.; Vacca, J.P.; Williams, T.M. Potent, Orally Bioavailable Calcitonin GeneꢀRelated Peptide Receptor
Antagonists for the Treatment of Migraine: Discovery of Nꢀ[(3R,6S)ꢀ6ꢀ(2,3ꢀDifluorophenyl)ꢀ2ꢀoxoꢀ1ꢀ
(2,2,2ꢀtrifluoroethyl)azepanꢀ3ꢀyl]ꢀ4ꢀ (2ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀimidazo[4,5ꢀb]pyridinꢀ 1ꢀyl)piperidineꢀ1ꢀ
carboxamide (MKꢀ0974). J. Med. Chem. 2007, 50, 5564ꢀ5567.
(11) (a) Hewitt, D.J.; Martin, V.; Lipton, R.B.; Brandes, J.; Ceesay, P.; Gottwald, R.; Schaefer, E.;
Lines, C.; Ho, T.W. Randomized Controlled Study of Telcagepant Plus Ibuprofen or Acetaminophen in
Migraine. Headache 2011, 51, 533ꢀ543. (b) TfeltꢀHansen, P. Excellent Tolerability but Relatively Low
Initial Clinical Efficacy of Telcagepant in Migraineheadache. Headache 2011, 51, 118ꢀ123. (c) Merck
recently discontinued the development of telcagepant.
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(12) Bell, I.M.; Gallicchio, S.N.; Wood, M.R.; Quigley, A.G. Craig A. Stump, C.A.; C. Blair Zartman,
C.B; John F. Fay, J.F.; ChiꢀChung Li, C.ꢀC.; Joseph J. Lynch, J.J.; Eric L. Moore, E.L.; Scott D.
Mosser, S.D.; Thomayant Prueksaritanont, T.; Christopher P. Regan, C.P.; Shane Roller, S.; Christopher
A. Salvatore, C.A.; Stefanie A. Kane, S.A.; Joseph P. Vacca, J.P.; Harold G. Selnick, H.G. Discovery of
MKꢀ3207: A Highly Potent, Orally Bioavailable CGRP Receptor Antagonist. ACS Med. Chem. Lett.
2010, 1, 24ꢀ29.
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(13) Diener, H.ꢀC; Barbanti, P.; Dahlöf, C.; Reuter, U.; Habeck, J.; Podhorna, J. BI 44370 TA, an oral
CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia,
2011, 31, 573ꢀ584.
(14) Merck publicly anounced the discontinuation of MKꢀ3207 due to toxicity while there was no
further public news about BI 44370.
(15) Luo, G.; Chen, L.; Conway, C. M.; Keavy, D.; Denton, R.; Kostich, W.; Mercer, S.; Schartman,
R.; Signor, L.; Lentz, K.; Browning, M.; Macor, J.E.; Dubowchik, G.M. Discovery of BMSꢀ846372, a
Potent and Orally Active Human CGRP Receptor Antagonist for the Treatment of Migraine. ACS Med.
Chem. Lett. 2012, 3, 337ꢀ341.
(16) Luo, G.; Conway, C.M.; Everlof, G. Lentz, K.A.; Schartman, R.; Macor, J.E.; Dubowchik,
G.M.Unpublished results.
(17) Leahy, D.K.; Fan, Y.; Desai, L.V.; Chan, C.; Zhu, J.; Luo, G.; Chen, L.; Hanson, R.L.; Sugiyama,
M.; Rosner, T.; Cuniere, N.; Guo, Z.; Gao, Q. Efficient and Scalable Enantioselective Synthesis of a
CGRP antagonist. Org. Lett. 2012, 14, 4938ꢀ4941.
(18) Luo, G.; Chen, L.; Civiello, R.; Pin, S.S.; Xu, C.; Kostich, W.; Kelley, M.; Conway, C.M.;
Macor, J.E.; Dubowchik, G.M. Calcitonin Geneꢀrelated Peptide (CGRP) Receptor Antagonists: Pyridine
as a Replacement for a Core Amide Group. Bioorg. Med. Chem. Lett. 2012, 22, 2917ꢀ2921.
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(19) See supported information for details.
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(20) The relative stereochemistry of 17 and 13 were not rigorously established. The absolute
stereochemistry of 8 was established through extensive xꢀray analysis of 8 and intermediate 23, Qi, G.
Unpublished results.
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(21) Compound 8 had marmoset CGRP receptor Ki of 0.0921±1.5 nM (n=2). For the description of all
biologic assays, see also: Degnan, A.P.; Chaturvedula, P.V.; Conway, C.M.; Cook, D.; Davis, C.D.;
Denton, R.; Han, X.; Macci, R.; Mathias, N.R.; Moench, P.; Pin, S.S.; Ren, S.X.; Schartman, R.; Signor,
L.; Thalody, G.; Widmann, K.A.; Xu, C.; Macor, J.E.; Dubowchik, G.M. Discovery of (R)ꢀ4ꢀ(8ꢀFluoroꢀ
2ꢀoxoꢀ1,2ꢀdihydroquinazolinꢀ3(4H)ꢀyl)ꢀNꢀ(3ꢀ(7ꢀmethylꢀ1Hꢀindazolꢀ5ꢀyl)ꢀ1ꢀoxoꢀ1ꢀ(4ꢀ(piperidinꢀ1ꢀ
yl)piperidinꢀ1ꢀyl)propanꢀ2ꢀyl)piperidineꢀ1ꢀcarboxamide (BMSꢀ694153): A Potent Antagonist of the
Human Calcitonin Geneꢀ Related Peptide Receptor for Migraine with Rapid and Efficient Intranasal
Exposure. J. Med. Chem. 2008, 51, 4858ꢀ4861.
(22) Conway, C.M.; Dubowchik, G.M.; Cook, D.A.; Signor, L. J.; Thalody, G.; Kostich, W.A.;
Gulianello, M.; Huang, Y.; Denton, R.; Lentz, K.A.; Schartman, R.;Johnson, B.M.; Browning, M.; Luo,
G.; Chen, L.; Macor, J.E.Unpublished results.
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