Design and synthesis of diazatricyclodecane agonists of the G-protein-coupled receptor 119

Article abstract of DOI:10.1021/jm301626p

A series of GPR119 agonists based on a 2,6-diazatricyclo[3.3.1.1～3, 7～]decane ring system is described. Also provided is a detailed account of the development of a multigram scale synthesis of the diazatricyclic ring system, which was achieved using a Hofmann-L?ffler-Freytag reaction as the key step. The basis for the use of this complex framework lies in an attempt to constrain one end of the molecule in the agonist conformation as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]nonanes. Optimization of carbamate analogues of the diazatricylic compounds led to the identification of 32i as a potent agonist of the GPR119 receptor with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE) termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility limited absorption and poor exposure reduced further interest in these molecules.

Full text of DOI:10.1021/jm301626p

Article
pubs.acs.org/jmc
Design and Synthesis of Diazatricyclodecane Agonists of the
G‑Protein-Coupled Receptor 119
Etzer Darout,‡ Ralph P. Robinson,† Kim F. McClure,*,‡ Matthew Corbett,† Bryan Li,† Andrei Shavnya,†
Melissa P. Andrews,† Christopher S. Jones,† Qifang, Li,† Martha L. Minich,† Vincent Mascitti,†
Cristiano R. W. Guimaraes,‡ Michael J. Munchhof,† Kevin B. Bahnck,† Cuiman Cai,† David A. Price,‡
̃
Spiros Liras,‡ Paul D. Bonin,† Peter Cornelius,† Ruduan Wang,† Victoria Bagdasarian,† Colleen P. Sobota,†
Sam Hornby,† Victoria M. Masterson,† Reena M. Joseph,† Amit S. Kalgutkar,‡ and Yue Chen†
†Departments of Medicinal Chemistry, Discovery Biology, Drug Metabolism, and Pharmaceutical Sciences, Pfizer Worldwide
Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
‡Departments of Medicinal Chemistry, Discovery Biology, Drug Metabolism, and Pharmaceutical Sciences, Pfizer Worldwide
Research and Development, 620 Memorial Drive, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
ABSTRACT: A series of GPR119 agonists based on a 2,6-
diazatricyclo[3.3.1.1∼3,7∼]decane ring system is described.
Also provided is a detailed account of the development of a
multigram scale synthesis of the diazatricyclic ring system,
which was achieved using a Hofmann−Loffler−Freytag
̈
reaction as the key step. The basis for the use of this complex
framework lies in an attempt to constrain one end of the
molecule in the “agonist conformation” as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]nonanes. Optimization of
carbamate analogues of the diazatricylic compounds led to the identification of 32i as a potent agonist of the GPR119 receptor
with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE)
termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility
limited absorption and poor exposure reduced further interest in these molecules.
intestinal tract.8,9 In addition, stimulation of GPR119 receptors
INTRODUCTION
■
in the islet is proposed to have beneficial effects on the health of
islets.10 These theoretical attributes have thus far been a
challenge to demonstrate clinically, and the potential of
GPR119 agonists remains unanswered.11−13
The incidence of diabetes continues to grow globally with
recent estimates of 384 million cases worldwide.1 Generally
diagnosis is determined by measurement of fasting plasma
glucose (FPG), but recently an international recommendation
has been made for the use of glycosylated hemoglobin (HbA1c)
as a time integrated marker of glucose levels.2 Current
pharmacologic treatment of diabetes is largely characterized
by modulation of the pathway for the endogenous hormone
insulin either by increasing its secretion or by sensitizing the
target tissues to its action.3,4 Although an orthogonal
mechanism that addresses glucose directly by increasing its
disposal in urine is currently in development,5 the insulin
pathway continues to receive attention, particularly with respect
to achieving glycemic control with reduced risk of hypo-
glycemia or for exhausting the ability of the pancreas to secrete
insulin.
Interest in the non-peptide G-protein-coupled receptor 119
(GPR119) can be traced to the success of glucagon-like peptide
1 (GLP-1) injectable drugs such as exenatide6 and the oral
small molecule inhibitors that act by increasing the circulating
levels of active GLP-1 by blocking its enzymatic degradation by
dipetidyl dipeptidase IV (DPPIV).7 Theoretically a GPR119
agonist could provide the benefits of the former in an oral agent
through the stimulation of GPR119 receptors in the gastro-
Although early GPR119 structures showed a high prevalence
of a piperidine carbamate on one end of the molecule (the
“head”) and a sulfone on the other (the “tail”), it is now
apparent that other structural motifs are tolerated.14−18
Interestingly, synthetic agonist ligands are structurally distinct
from the growing number of “endogenous” ligands of the
receptor.19,20Accompanying the evolution of GPR119 agonist
structures has been an increasing understanding of the
structural features that drive an agonist response. Previously
we described a conformational hypothesis to explain the
differences in human agonist pharmacology for
oxaazabicyclo[3.3.1]nonane head pieces.21 Herein we describe
the extension of this hypothesis to a novel series of bridged
cyclic structures.
Received: November 3, 2012
© XXXX American Chemical Society
A
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of intermediate 6b.23 In turn, this intermediate would arise
from chlorination of the corresponding aminal 6a. An oxidation
of the hydroxyl group in 7 and reductive amination with
hydride delivery from the convex face would be required to
produce 6a. Bicyclic 7 would then be accessed via a double
Mannich reaction on the iminium species formed from 8 and
10 (Scheme 1).
RESULTS AND DISCUSSION
Design and Synthesis of the “Cage”. As shown in Figure
1, the approach was to constrain the piperidine head piece as in
■
As shown in Scheme 2, the synthetic sequence used to
pursue this approach began with the Mannich reaction of
a
Scheme 2. Mannich/Reductive Amination Approach
Figure 1. Functional profile for bridged cyclic vs unbridged structures.
the oxoazabicyclo[3.2.1]octanes 1 and 2.21 At the same time
the aim was to ensure that the preferred conformation locks
this part of the molecule into the “agonist conformation”. The
ring system we planned to use for achieving this was a 2,6-
diazatricyclo[3.3.1.1∼3,7∼]decane, informally referred to as the
“cage”.22 While the carbamate placement would closely match
that of compound 1 and provide a level of confidence in
achieving an agonist profile, the switch to a nitrogen linkage
between the headgroup and the “core” central pyrimidine ring
would have less predictable consequences. One of the concerns
with the change centered on the added carbons near the
pyrimidine ring and the impact they may have on the torsion to
the central pyrimidine, particularly one bearing a methyl group
as in 3a. From a calculated physicochemical perspective, the
diazatricyclo[3.3.1.1∼3,7∼]decane system has a similar ClogP
to the oxoazabicyclo[3.2.1]octane in the context of structures
1−3 (ClogP(3a) = ClogP(1) = 3.3). By far the biggest concern
with the proposal, however, was how to address the synthesis
challenge presented by the complex cage structure.
a
Reagents and conditions: (a) 1,3-acetonedicarboxylic acid, BnNH2,
conc HCl, H2O, 50 °C (35%); (b) H2, Pd(OH)2, Boc2O, MeOH, 23
°C (quant).
bisaldehyde 8a,24 benzylamine, and acetone-1,3-dicarboxylic
acid.25 This provided a 3:1 mixture of isomers favoring the
enolate addition to the face of the iminium opposite that of the
benzyl ether. Hydrogenolysis of the major isomer 11a in the
presence of di-tert-butyl dicarbonate provided bicyclic ketone
12.
Installation of the second nitrogen via a two-step reductive
amination protocol was then attempted following the
conditions shown in Table 1. Only recovered starting material
Table 1. Reductive Amination Conditions
To fully test how well the cage structures fit our
conformational hypothesis, we needed to enable an efficient
and scalable synthesis of a versatile intermediate such as 5
(Scheme 1) to access bridged-cyclic structures such as 3a
(Figure 1). Several synthetic strategies for the synthesis of the
requisite cage intermediate were explored. Our first attempt is
outlined retrosynthetically in Scheme 1. In this scheme the cage
template 5 would ultimately result from a hydrodechlorination
pressure
(bar)
temp
reducing
agent
step a
step b
EtOH
(°C)
NH3/EtOH
40
70
10
40
Raney Ni
Raney Ni
PtO2
BnNH2/EtOH
MeNH2/EtOH
EtOH
70
EtOH/NH4OAc
THF
25
NH2OH·HCl,
NaOAc/MeOH
30−40
LiAlH4
Scheme 1. Retrosynthetic Analysis of the 2,6-
Diazatricyclo[3.3.1.1∼3,7∼]decane Ring System
was obtained after attempted reductive amination via sequential
treatment of 12 with NH3/MeOH and Raney nickel.26 The use
of benzylamine27 or methylamine with PtO2 as catalyst28
yielded similar results. Condensation of the C-3 ketone with
hydroxylamine followed by LAH reduction of the oxime
resulted in decomposition of the oxime to a complex mixture
that was not investigated further.29 The lack of success in
installing the C-3 amine in this fashion necessitated exploring a
different approach to the cage intermediate.
An alternative approach was to exploit the work of Rassat et
al. who, in 1974, disclosed the synthesis of a 2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane (2,6-diazaadamantane) derivative via
Hofmann−Loffler−Freytag (HLF) ring closure (Scheme 3).30
̈
B
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Despite the fact that Li31 failed to reproduce the Rassat work,
the simplicity of the approach compelled us to further explore
this free radical chain cyclization process.
As shown in Scheme 5, treatment of commercially available
endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane 19 with t-
Scheme 5. Optimization of the Hofmann−Loffler−Freytag
̈
a
Reaction
Scheme 3. Rassat’s Route to 2,6-Diazaadamantane
a
Derivatives
a
Reagents and conditions: (a) t-BuOCl, Et2O, 23 °C, 15 min; then hν,
35 °C, 60 min, (68%) of 3:1 mix 20/19; (b) Boc2O, Et3N, MeOH, 23
°C, 30 min (54%, steps a and b); (c) 1-methylcyclopropyl 4-
nitrophenylcarbonate, Et3N, CH2Cl2, 16 h, (44%, steps a and c); (d)
KMnO4, NaOH (1.5 N), THF, 68 h (90%); (e) ACE-Cl, 1,2-DCE, 90
°C, 1.5 h; MeOH, 90 °C, 1.5 h (93%).
a
Reagents and conditions: (a) Br2, cyclohexane, 0 °C; (b) 84% H2SO4,
65 °C, 30 min (15, 30%, 18, 33%).
Consistent with the work of Li, our attempts to follow the
sequence in Scheme 3 using the published conditions with Br2
or N-bromosuccinimide failed to provide any of the desired 17.
In both cases, the compounds isolated from the reaction were
benzaldimine 18 arising from the formal loss of HBr and
recovered starting material. Presumably if 18 was formed from
the aminyl radical derived from homolytic cleavage of the N−
Br bond, the rate of hydrogen atom abstraction from the
benzylic methylene must be greater than that of the cross-ring
abstraction required to form 17. It is also possible that under
the reaction conditions in Scheme 3, no homolytic bond
cleavage occurs, only elimination of HBr.
Although studies have shown that homolytic cleavage of N-
chloroamines under acidic conditions leads to protonated
aminyl radicals that are less prone to disproportionation/
dimerization and undergo more efficient HLF reaction,32 we
did not try this acidic halide variation. Instead, we explored the
acid free conditions reported by Ban as shown in Scheme 4.33
BuOCl, followed by ultraviolet irradiation of the mixture,
provided a 68% yield of a 3:1 mixture of 20 and starting
material as a hygroscopic solid. Switching to t-BuOCl
eliminated the succinimide byproduct formed when N-
chlorosuccinimide was used as the chloronium source and
simplified the isolation of the product. The cage intermediate
20 was easily converted to the tert-butyl (21a) and 1-
methylcyclopropyl (21b) carbamate derivatives in 54% and
44% yield, respectively, from 19. To complete the synthesis of
the cage intermediate needed for our analogue work, we
needed to demethylate 21a and 21b. Compound 21b was
demethylated with 1-chloroethyl chloroformate (ACE-Cl)
using the standard conditions to provide 5b in 93% yield.35
For the demethylation of 21a, we used an alternative method
because of concerns with the HCl content of commercial
sources of ACE-Cl and the acid instability of the Boc group.
Thus, intermediate 21a was demethylated under oxidative
conditions with KMNO4 to afford 5a in 90% yield.36
a
Scheme 4. Initial Hofmann−Loffler−Freytag Reaction
̈
Synthesis and SAR of Cage Analogues. With an efficient
and scalable method to prepare 2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane derivatives we were ready to investigate
the impact of this novel piperidine surrogate on human
GPR119 pharmacology. The compounds shown in Table 2
were synthesized using the general sequence shown in Scheme
6. The synthesis of 25a−c began with the addition of 2-fluoro-
4-(methylsulfonyl)phenol to 4,6-dichloro-5-methylpyrimidine
a
Reagents and conditions: (a) NCS, Et2O, 0 °C, 5 min; then Et3N, hν,
0 °C, 45 min (17, 29%; 18, 40%).
Table 2. In Vitro Human GPR119 Pharmacology for 25a−c
In this case N-chlorosuccinimide was used to N-chlorinate 15
and homolysis was achieved by first addition of triethylamine
followed by photolysis. Substantial amounts of the benzaldi-
mine 18 were still obtained. However, for the first time, small
amounts of the desired cage compound 17 were produced.
While this was an encouraging result, significant improvements
in yield would be needed to supply sufficient quantities of 17
for the rapid synthesis of analogues.
To improve the yield of the cyclization step, we needed to
identify an HLF precursor less prone to unproductive side
reactions. One possibility was to replace the troublesome N-
benzyl with a more inert protective group. The more efficient
approach was to forego a protective group altogether.34
and 26
a
a
b
compd cAMP EC50 (nM)
IA (%)
Ki (nM)
ClogP (ElogD)
25a
25b
25c
26
40 12
n = 6
87
74
91
49
8
4
8
7
41 24
3.2
n = 5
(4.6)
2.8
121 34
n = 9
141 71
n = 5
(4.4)
2.8
169 49
n = 4
131 45
n = 4
(4.3)
2.8
29 28
n = 24
53 56
n = 9
(4.5)
a
b
See ref 21 for assay conditions. See ref 38.
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a
Scheme 6. Addition of the 2,6-Diazatricyclo[3.3.1.1∼3,7∼]decane to Biaryl Chloropyrimidine via SNAr
a
Reagents and conditions: (a) 2-fluoro-4-(methylsulfonyl)phenol, Cs2CO3, CH3CN, microwave 120 °C, 1.5 h (57%); (b) 2-methyl-2,6-
diazatricyclo[3.3.1.1∼3,7∼]decane, Cs2CO3, CH3CN, microwave 180 °C, 1 h (57%); (c) ACE-Cl, 1,2-DCE, 90 °C, 1.5 h; MeOH, 90 °C, 1.5 h; (d)
Boc2O, Et3N, CH2Cl2, 23 °C, 30 min (17%, steps c and d); (e) isopropyl chloroformate, DIPEA, CH2Cl2, 23 °C, 18 h (74%); (f) 1-
methylcyclopropyl 4-nitrophenylcarbonate, DIPEA, CH2Cl2, 16 h (57%).
22a. The resulting biaryl ether 2337 underwent nucleophilic
aromatic substitution with the Boc-cage derivative 20 followed
by N-demethylation to provide pyrimidine 24. The desired
carbamates derivatives 25a−c were then obtained by standard
acylation. The pharmacology of these analogues was compared
with that of the unbridged piperidine analogue 2637 (Figure 2).
nitrogens. In effect this places the carbamate in the same area as
the “agonist” conformation of 1.
To make the comparison with analogues in the
oxoazabicyclo[3.2.1]octane series, we next wanted to incorpo-
rate the methylpyridyloxy tail. Our experience showed that the
methylpyridyloxy group generally provides a lower agonist
response relative to the fluoro(methylsulfonyl)phenoxy group.
Having a baseline comparator with near 50% of the maximal
response would allow both positive and negative changes in
intrinsic activity (IA) to be readily assessed, thus revealing the
contribution of various cage groups on agonist response. Also,
methylpyridyloxy analogues exhibit superior aqueous solubility
relative to those having fluoro(methylsulfonyl)phenoxy
tails.21,39
Figure 2. Piperidinol comparator.
The synthesis of the methylpyridyloxy analogues is shown in
Scheme 7. Nucleophilic aromatic substitution reaction between
Consistent with our hypothesis, direct comparison of 25b
and 26 showed that the cage analogue indeed elicits a greater
agonist response than its piperidinol counterpart in our 3′,5′-
cyclic adenosine monophosphate (cAMP) functional assay. To
investigate whether the conformational disposition of the cage
group resembles the conformation of the oxoazabicyclo[3.2.1]-
octane headgroup we explored earlier, we obtained a single
crystal X-ray structure for 25b.
Scheme 7. Synthesis of 2,6-
Diazatricyclo[3.3.1.1∼3,7∼]decane Pyridyloxypyrimidine
a
Analogues
As seen in Figure 3, the cage structure places the “crown”
methine in a similar torsional arrangement as in the case of the
piperidinol,21 just out of plane with one of the pyrimidine
a
Reagents and conditions: (a) tert-butyl 2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate 5a, Na2CO3, CH3CN, 1200 °C,
42 h (53%); (b) 4 N HCl/1,4-dioxane, MeOH, 20 °C, 16 h; (c)
R1OC(O)X, Et3N, CH2Cl2, 23 °C, 12−16 h (31−94%, steps b and c).
5a and commercially available chloropyrimidine 27a followed
by Boc cleavage provided the pyrimidine derivative 28a, which
was used for the synthesis of the carbamate analogues 3a−i in
Table 3.
Given the apparent positional contribution of the carbamate
on the functional profiles of 1 and 2, enforced by their distinct
conformations, we also wanted to explore the nature of the
Figure 3. ORTEP of 25b with ellipsoids drawn at the 50% confidence
level.
D
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Table 3. In Vitro Human GPR119 Pharmacology for 3a−i
a
b
compd
R1, Scheme 7
isopropyl
cAMP EC50 (nM)
IA (%)
64 16
Ki (nM)
ClogP (ElogD)
3a
559 1128
n = 10
2233 1608
n = 5
3.3
(3.8)
3.0
3b
3c
3d
3e
3f
Et
5562 2223
n = 3
56% at 10 μM
1970 914
n = 4
1-methylcyclopropyl
cyclobutyl
tert-butyl
636 1201
n = 21
81 10
586 668
n = 4
3.4
(4.0)
3.4
130 59
n = 5
53
6
682 409
n = 3
40 11
n = 3
61 13
486 204
n = 3
3.7
(4.3)
3.9
isobutyl
88 75
n = 7
27
44
45
46
5
7
4
3
231 78
n = 5
(4.5)
3.9
3g
3h
3i
(R)-sec-butyl
(S)-sec-butyl
145 59
n = 3
290 53
n = 3
(4.4)
3.9
155 62
n = 3
493 24
n = 3
(4.4)
3.9
1-methylcyclobutyl
75 19
n = 3
136 41
n = 3
(4.5)
a
b
See ref 21 for assay conditions. See ref 38.
carbamate on the functional response. As shown in Table 3,
branching near the carbamate oxygen led to the compounds
with the highest agonist response. Interestingly, the methyl-
pyridyloxy tail did not lower the IA relative to the sulfone-based
tail to the extent anticipated with some overlap remaining in
the standard deviation for the maximal agonist response. With
the exception of 3b, a lower agonist response could not be
ascribed to reduced binding affinity. The aqueous solubility of
the representative 3c (0.5 μg/mL, phosphate buffered saline,
pH 7.4, and 6.8 mg/mL at pH 1.2) suggested the potential for
good aqueous solubility at low pH. The in vitro human liver
microsomal clearance for the compounds tracked with
lipophilicity. Of the compounds tested in Table 3, only
compounds with ClogP greater than 3.7 demonstrated scaled
apparent intrinsic clearance (Clint,app,scaled) greater than 30 mL
min−1 kg−1 in human liver microsomes.
Unfortunately, when straightforward changes to the terminal
nitrogen of the cage headgroup were employed, it was not
possible to obtain a sufficiently potent full agonist using the
methylpyridyloxy tail. While we had demonstrated that the cage
was beneficial for eliciting an agonist response, it was at the cost
of adding molecular weight and limited options for easy
substitutions. Unable to overcome the lower IA for the
methylpyridyloxy tail with changes to the cage head, alternative
tail−core combinations would be needed to achieve the desired
pharmacologic profile and would potentially limit options for
retaining desirable physicochemical properties.
Next we explored the impact of different substitution on the
core pyrimidine ring. As mentioned previously, there was
concern that such changes would create a more congested
environment around the cage headgroup relative to the
piperidinol.
Scheme 8 describes the synthesis of the modified core
analogues. As shown in Table 4, changes to R2 on the central
pyrimidine ring generally resulted in weaker agonists compared
to compounds where R2 is methyl. In certain cases, such as
when R is H, this is a consequence of a loss in binding affinity
to the receptor. No additional effort was applied to this region
of the molecule.
Scheme 8. Synthesis of C-5 Substituted Pyrimidine
Derivatives
a
a
Reagents and conditions: (a) 2-methylpyridin-3-ol, KO-t-Bu, THF/
DMF, 0−23 °C (81−90%); (b) tert-butyl 2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate 5a, Na2CO3 or NaHCO3, DMF
or DMA, 80−120 °C, 1−16.5 h (51−87%); (c) 4 N HCl/1,4-dioxane,
MeOH or TFA, CH2Cl2, 23 °C, 1.25−3 h; (d) R1OC(O)X, Et3N,
CH2Cl2, 23 °C, 12−16 h (7−93%, steps c and d).
Finally, the tail portion of the molecule was explored starting
with 22a, attaching the tail piece and then coupling to cage 5a
(Scheme 9). Cage 5a was selected because removal of a Boc
group rather than a methyl was anticipated to provide greater
flexibility in the choices of tail groups. As shown in Table 5, we
explored a number of phenoxy groups terminated with motifs
that would project a hydrogen bond acceptor in a position
similar to that of the sulfonyl compounds 25a−c. With the
possible exception of the 4-cyano-2-fluorophenoxy group, the
changes led to a higher maximal agonist response than that
associated with the methylpyridyloxy tail. Indeed, in some
instances the IA was greater than that seen for the prototype
sulfone analogues 25a−c. In comparing the various five-
membered heterocycles examined, both the tetrazole and
triazole isomers led to examples with some of the better agonist
profiles. Interestingly, methyl substitution on the 1,2,4-triazole
was poorly tolerated (see 32m; cf. 32g). The reduced binding
affinity and corresponding loss in functional activity with this
change suggest a disruption to the coplanarity of the phenyl
E
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Table 4. In Vitro Human GPR119 Pharmacology for 29a−j
a
b
compd
R1, Scheme 8
R2, Scheme 8
H
cAMP EC50 (nM)
IA (%)
Ki (nM)
>8148
ClogP (ElogD)
29a
1-methylcyclopropyl
>10000
n = 3
2.9
n = 1
29b
29c
29d
29e
29f
29g
29h
29i
tert-butyl
H
>10000
n = 3
>8148
n = 2
3.2
isopropyl
Et
164 153
n = 3
36 0.2
197 55
n = 3
3.9
(4.3)
3.9
1-methylcyclopropyl
tert-butyl
Et
49 21
n = 6
52
37
5
4
123 33
n = 3
(4.4)
4.3
Et
16
7
18
6
n = 5
n = 3
1-methylcyclopropyl
tert-butyl
F
>10000
n = 3
>7318 1027
n = 3
2.8
3.2
F
>3014 4665
n = 4
47
28
43
35
3
5
4
7
814 569
n = 3
isopropyl
OMe
OMe
OMe
691 184
n = 3
1496 103
n = 3
3.0
(3.6)
3.1
1-methylcyclopropyl
1028 482
n = 3
3123
n = 1
29j
tert-butyl
144 71
n = 3
163 33
n = 3
3.4
a
b
See ref 21 for assay conditions. See ref 38.
limitations of such efficiency measures when applied to agonist
programs. We also present an agonist weighted alternative.42
Over the past decade a number of calculated terms that
integrate physicochemical or molecular properties and primary
pharmacology have been reported. These include ligand
efficiency (LE),43,44 LLE, and the related term LipE.45,46 The
widespread use of these terms can be understood from the way
in which they indirectly relate to efficacious concentration and
unbound clearance, two major determinants of dose. Although
the increased use of these properties has made for “ready
reckoners”44 or easier visualization of superior compounds in
plots and tables of compounds, it has increased the potential for
users of these concepts to forget the parameters that form their
basis.
Scheme 9. Synthesis of 2,6-Diazatricyclo[3.3.1.1−
a
3,7∼]decane Analogues with Tail Variations
a
Reagents and conditions: (a) R3OH, Cs2CO3 or K2CO3, CH3CN or
LipE, although introduced with an agonist program using the
agonist EC50 for the potency contribution, was done in the
context of the unusual situation where all the compounds
apparently achieved the same full agonist response (100%
IA).45 No correction would therefore be needed. The concept
of LLE was originally introduced specifically using pIC50 and
pKi presumably to avoid the complication of agonist
pharmacology. However, it was later15 expanded to include
pEC50 as well and in so doing exposed the issue of how to
appropriately treat partial agonists.
Clearly, the weighing of the agonist response can be applied
in different ways, but penalizing poor agonists would have to be
the consistent outcome of any correction factor. As recently
introduced,42 one solution is to correct LLE for IA to derive the
“agonist lipophilic ligand efficiency” (AgLLE) as shown in eq 1.
DMF, 23−120 °C, 1−24 h (43−90%); (b) tert-butyl 2,6-diazatricyclo-
[3.3.1.1−3,7∼]decane-2-carboxylate 5a, NaHCO3, Cs2CO3, or DIPEA,
DMF, DMSO, or CH3CN, 60−120 °C, 2−64 h, (13−72%); (c) TFA,
CH2Cl2, 23 °C, 3 h; (d) R1OC(O)Cl, Et3N, CH2Cl2, 23 °C, 12−16 h
(24−72%, steps c and d).
ring and the terminal triazole and/or a steric clash between the
added methyl group and the receptor.
Selection and Characterization of Compound 32i as a
Potential Candidate. Ultimately, identifying the most
compelling agonist in the cage series was not difficult since
relatively few full agonists with EC50 below 100 nM were
identified. The tetrazole-containing compounds (32d,e,f,h,i,j)
proved to be the best at providing a low EC50 and a relatively
full agonist response. Among these, 32i was one of the most
potent agonists that retained good human liver microsomal
stability (Clint,app,scaled < 9.5 mL min−1 kg−1).
agonist LLE = AgLLE = (pEC50 − ClogP)(IA/100%)
(1)
Others have reportedly15,39 optimized their GPR119 agonists
by tracking a property termed ligand lipophilic efficiency
(LLE),40,41 a combined measure of potency and lipophilicity.
Although we did not use this methodology to identify our best
agonists, we performed a retrospective analysis of the
compounds in this manuscript using LLE to highlight the
As with many agonist programs, our GPR119 functional data
were derived from a comparison to control agonists having the
same pharmacology. The IA of a test compound is thus the
fractional efficacy47 relative to the maximum response of the
control agonist chosen. The choice of control agonist is an
important decision particularly for an orphan G-protein-
F
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Table 5. In Vitro Human GPR119 Pharmacology for 32a−n
a
b
See ref 21 for assay conditions. See ref 38.
coupled receptor (GPCR) where the endogenous ligand is not
firmly established or unknown. In the case of our GPR119
program the control molecules we selected achieve the same
maximal response as oleleoylethanolamide (OEA).48
The results of the analysis for the compounds reported in
this manuscript are plotted Figure 4. The 45° lines trace the
indicated LLE values. On the basis of a straightforward LLE
analysis, better compounds should map to the upper left
quadrant of the plot. However, from an accounting for the
agonist response, a very different picture emerges and it is no
longer true that only better agonists will be found in the upper
left region. This can be visualized in Figure 4 where the
diameters of the circles are sized according to AgLLE. Bigger
circles equate to better agonists and better (larger) AgLLE
values; smaller circles equate to poor agonists and smaller
AgLLE values. The upper left quadrant is, in fact, populated
with compounds with poor IA, thereby underscoring why LLE
should not be used in agonist programs for assessing
compounds. The use of AgLLE correctly distinguishes agonists
from partial agonists and antagonists. In fact, the full spectrum
of functional activity from inverse agonists (negative AgLLE) to
superagonists (IA > 100%) can be accommodated by this term.
Interestingly, 32i has the highest AgLLE value (4.4) of all the
cage compounds,49 as well as having one of the top LLE values
(4.3). On the basis of LLE, the top compound in the data set is
actually 26 (LLE = 4.7; AgLLE = 2.3), a partial agonist. It is
perhaps not surprising to have partial agonists result in high
LLE scores. For two compounds that trace the same agonist
response curves, differing only in their maximum response, the
lower EC50 will be associated with the compound with the
lower IA.
Having profiled 32i as a compound of interest in vitro, we
proceeded to characterize the molecule in vivo. Given the
inherent risks associated with species differences in pharmacol-
ogy, especially translation of agonism to human, our priorities
were to project human oral exposure and prepare for high dose
toxicology studies rather than to demonstrate preclinical
efficacy.50 On the basis of our own experience, as well as the
work of others working on GPR119 agonists, the potential for
low solubility and hence solubility limited absorption was a
concern.39,51 Thus, before in vivo studies were run, it was
Figure 4. Plot of pEC50 vs ClogP sized by AgLLE with lines of
constant LLE.
G
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Table 6. Oral and Intravenous Pharmacokinetics for 32i in Sprague−Dawley Rats
a
bh
,
h
h
h
bh
,
h
c
route and formulation dose (mpk) AUC
(ng·h/mL)
T1/2 (h)
Cl (mL min−1 kg−1
)
Vss (L/kg) Cmax
(ng/mL)
Tmax (h)
F
(%)
d
iv
1
1360 592
312 139
4.34 0.79
13.2 5.6
3.96 2.0
e
po 0.5% MC
3
24.2 8.5
255 75.0
912 39.0
484 172
3490 825
3.00 1.41
4.7 1.2
6.0 0.0
4.7 1.2
4.0 0.0
7.6
f
nanomilled
3
3180 695
12533 289
6137 1577
49133 9279
78
nanomilled
30
3
31
g
SDD
>100
>100
g
SDD
30
a
b
c
Milligram per kilogram (mpk). All concentrations are reported as total drug; the fraction unbound in rat plasma is 1.0%. F calculations are based
d
e
on 1 mpk rat iv PK data. iv vehicle = 10% N-methylpyrrolidone and 90% sulfobutyl ether−β-cyclodextrin (SBE-CD) solution prepared at 30%. Per
os (po) dosing in 0.5% methylcellulose (MC). po dosing of milled material in 0.5% MC. po at 0.6 mL/kg as 25% SDD in 20 mM Tris buffer with
0.5% MC + 0.5% HPMCAS-HF, pH 7.4. Data reported are the mean SD for studies conducted in three animals.
f
g
h
a
Table 7. Oral and Intravenous Pharmacokinetics for 32i in Male Beagle Dogs
b
c
c
d
route and formulation
dose (mpk)
AUC (ng·h/mL)
T1/2 (h)
Cl (mL min−1 kg−1
1.74
)
Vss (L/kg)
Cmax (ng/mL)
Tmax (h)
F
(%)
e
iv
1
3
4730
8580
26.8
20.0
3.7
515
812
f
po SDD
1
60
g
po SDD
10
41000
76800
151000
1950
3750
6030
1
87
54
32
g
po SDD
30
1
g
po SDD
100
1.5
a
b
c
PK parameters reported are the mean values obtained from two animals. Milligram per kilogram (mpk). All concentrations are reported as total
d
e
drug; the fraction unbound in dog plasma is 1.4%. F calculations are based on 1 mpk dog IV pk data. 1 mg/kg iv at 2 mL/kg in 5%
dimethylacetamide (DMA)/75% polyethylene glycol 200 (PEG200)/20% (30% SBE-CD). po at 0.6 mL/kg as 25% SDD in 20 mM Tris buffer with
0.5% MC + 0.5% HPMCAS-HF, pH 7.4. 10, 30, or 100 mpk po at 5 mL/kg as 25% SDD in 20 mM Tris buffer in 0.5% MC and 0.5% HPMCAS-
f
g
HF, pH 7.4.
important to first check the thermodynamic solubility of
crystalline 32i. Consistent with the high melting point (234 °C,
determined by differential scanning calorimetry) the thermody-
namic solubility of 32i in aqueous media was poor (solubility at
pH 7.4 is 0.7 μg/mL; that at pH 1.2 is 4.8 μg/mL). This
suggested a need for using solubilizing formulations to
administer the compound.
The baseline intravenous (iv) and oral rat pharmacokinetics
(PK) for 32i are shown in Table 6. The poor bioavailability (F)
at the lowest oral dose could be overcome by reducing the
average particle size by milling (2−25 μm premilling to
approximately 190 nm postmilling). This was consistent with a
problem of poor solubility and not permeability. This notion is
supported by the apparent permeability (Papp) for 32i, which at
3.5 × 10−6 cm/s was indicative of moderate flux.52
Unfortunately, there was a limit to the increases in exposure
and bioavailability achievable using nanomilled material.
Further increases in exposure with increasing dose was achieved
by preparing an amorphous spray dried dispersion (SDD)53 of
the molecule with HPMCAS-HF (hydroxypropylmethylcellu-
lose acetate succinate high fine). By use of SDD, an added 3-
fold increase in maximum plasma concentrations (Cmax) and
area under the curve (AUC) over nanomilled material was
achieved.
A similar PK evaluation was conducted in dog as shown in
Table 7. In this instance SDD was used straight away. In
general the exposure was similar to rat. As another indicator of
solubility-driven exposure, the best bioavailability was achieved
at low doses with the larger dosing volumes. Disappointingly,
the bioavailability in dog was substantially reduced with
increasing dose (cf. 10−100 mpk).
The major concern with these exposure data was how they
compared to our projected efficacious concentration for human.
On a free exposure basis, the 30 mpk SDD doses in rat and dog
only achieve between 69 and 104 nM free drug at Cmax. Absent
actual human efficacy data for comparison and mindful of the
theoretical risk of receptor desensitization, our target trough
efficacious drug concentration was set at approximately 75%
receptor activation from the cAMP assay. For compound 32i
this is estimated to be 50−70 nM. Therefore, even at the
highest dose used in dog (100 mpk) only an approximate 3-fold
margin above our projected efficacious concentration was
achieved at Cmax (167 nM free drug). Furthermore, the decline
in bioavailability with increasing dose would make it hard to
achieve greater multiples over the projected efficacious
concentration. Given the challenge of trying to further develop
this compound, we chose to abandon the cage series.
In summary we have described an efficient synthesis of the
complex 2,6-diazatricyclo[3.3.1.1∼3,7∼]decane system and
have demonstrated the benefits of this conformationally
restricted framework on eliciting an agonist response from
the human GPR119 receptor. In spite of the advantages of this
cage group, achieving the desired overlap in agonist
pharmacology and metabolic stability was only possible with
larger substituents on the tail end of the molecule. Smaller
compounds such as 3c with superior solubility characteristics
did not have the desired agonist properties. It was also shown
that the direct use of LLE is not sufficient to identify more
desirable agonists. The application of AgLLE, which applies a
simple correction for IA to LLE, makes it possible to use this
concept to triage potentially more interesting compounds.
Compound 32i was shown to be one of the better cage agonists
overall. However, interest in this cage series diminished when it
was established that it would be difficult to progress 32i
because of challenges in achieving adequate exposure relative to
the projected efficacious concentration.
EXPERIMENTAL SECTION
■
Commercial reagents were used without further purification. All final
compounds were purified using flash chromatography on Isco
Combiflash systems or by preparative HPLC on a Waters Sunfire
C18 column (19 mm × 100 mm, 5 μm particle size), eluting with a
H
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H2O/CH3CN, using NH4OH or TFA as a modifiers. Compounds of
pharmacologic interest are greater than 95% pure as judged by five
separate UPLC methods, using the method reporting the largest
percent impurity. Except where indicated, reactions were magnetically
stirred and monitored by thin-layer chromatography using Merck silica
gel 60 F254 by fluorescence quenching under UV light or by LC/MS
detection. NMR spectra were obtained on a Varian INOVA
spectrometer (400 or 500 MHz). Chemical shifts are expressed in δ
(ppm) units relative to solvent residual peak, and peak multiplicities
are expressed as follows: singlet (s), doublet (d), doublet of doublets
(dd), triplet (t), quartet (q), multiplet (m), broad singlet (br s).
Chemical shifts (δ) are reported in ppm downfield from internal
tetramethylsilane (TMS), and coupling constants (J) are in hertz (Hz).
The synthesis of representative compounds is given below.
sulfuric acid, 20 mL of H2O). The solution was then heated at 65−70
°C for 30 min. After cooling, the mixture was added to 200 mL of ice−
water, rendered strongly alkaline with 50% NaOH solution, and then
extracted with CH2Cl2. The extracts were dried over Na2SO4, filtered,
and the filtrate was concentrated to yield 4 g of a crude viscous oil.
This crude mixture was purified by silica gel chromatography using 1:7
Et3N/EtOAc to give SM 15 (1.56 g, 30%) as a clear oil and 18 (1.70 g,
1
33%) as an off-white gel. H NMR (CDCl3, 400 MHz) δ 1.09−1.13
(m, 2H), 1.49−1.55 (m, 1H), 1.66−1.74 (m, 2H), 1.97−2.05 (m, 2H),
2.18−1.25 (m, 2H), 2.30−2.41 (m, 1H), 2.54 (s, 3H), 3.06 (d, J =
10.98 Hz, 2H), 3.74−3.81 (m, 1H), 7.40 (dd, J = 3.17 Hz, 3H), 7.74−
7.75 (m, 2H), 8.36 (s, 1H). GCMS (m/z): 242.
2-Benzyl-6-methyl-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane
(17). To N-benzyl-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine 15
(5.15 g, 21.1 mmol) dissolved in Et2O (250 mL) in a Pyrex flask,
under nitrogen, was added recrystallized N-chlorosuccinimide (5.68 g,
42.1 mmol) at 23 °C with stirring. After 13 min, Et3N (11.7 mL, 84.3
mmol) was added rapidly and the mixture was irradiated for 50 min
using a mercury lamp (450 W). The mixture was cooled to 23 °C and
filtered through a Pall GHP filter (0.45 μm). The solid was rinsed with
Et2O, and the filtrate was concentrated to dryness under vacuum. The
residue was purified by chromatography on 120 g silica gel (50−100%
ethyl acetate in heptanes for 3 min, followed by 1:7 Et3N/EtOAc) to
afford the title compound as a yellow oil (1.46 g, 29%). 1H NMR (500
MHz, CDCl3) δ 1.83−1.97 (m, 8H), 2.57 (s, 3H), 2.88 (br s, 2H),
2.92 (br s, 2H), 3.87 (s, 2H), 7.17−7.44 (m, 5H). GCMS (m/z): 242.
2-Methyl-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane·2HCl (20).
To a stirred, cold (0 °C) solution of endo-3-amino-9-methylazabicyclo-
[3,3,1]nonane 19 (4.85 g, 31.47 mmol) in Et2O (1 L) in a 2 L Pyrex
round-bottom flask was added tert-butyl hypochlorite dropwise under
a nitrogen atmosphere. During the addition the mixture became a
milky color. The bath was removed, and the mixture was stirred for 15
min at 23 °C. The flask was equipped with a reflux condenser and
placed in a plastic bucket that was wrapped in aluminum foil. The
mercury lamp (450 W) photoreactor equipped with a quartz jacketed
cooling condenser was placed next to the 2 L flask inside the bucket. A
pump was used to circulate ice cold H2O through the inner well of the
photoreactor and the reflux condenser of the flask. Aluminum foil was
used to wrap the bucket and condenser to prevent light exposure. The
mixture was irradiated for 45 min over which time the mixture became
light orange with some solids present. The power supply was shut off,
and after 5 min a small aliquot of the reaction mixture was taken and
analyzed by GCMS. The mixture was filtered, and the resulting filter
cake (somewhat hygroscopic) was collected, dried, and analyzed by
GCMS. The crude material contained a 3:1 mixture of the title
compound 20 to SM. A small aliquot was purified by silica gel
chromatography using 1:7 Et3N/EtOAc for characterization. 1H NMR
(500 MHz, DMSO-d6) δ 1.87 (d, J = 12.93 Hz, 4H), 2.07 (d, J = 12.93
Hz, 4H), 2.44 (s, 3H), 2.87 (br s, 2H), 3.60 (br s, 2H), 9.13 (br s, 1H).
GCMS (m/z): 152.
(1R,5S,7r)-9-Benzyl-7-(benzyloxy)-9-azabicyclo[3.3.1]nonan-
3-one (11a) and (1R,5S,7s)-9-Benzyl-7-(benzyloxy)-9-
azabicyclo[3.3.1]nonan-3-one (11b). To a stirred solution of 4-
(benzyloxy)cyclopentane-1,2-diol16 (8.50 g, 40.82 mmol) in H2O
(88.0 mL) was added NaIO4 (4.41 mg, 20.4 mmol) at 23 °C. After 18
h, CH3CN (60 mL) was added and stirring was continued for an
additional 30 min. The mixture was filtered, and the filtrate was
concentrated. Acetonitrile (60 mL) was added. The mixture was
filtered and the filtrate was concentrated to provide a clear oil. To the
crude oil in H2O (40 mL) were added acetone-1,3-dicarboxylic acid
(6.15 g, 40.8 mmol) and concentrated HCl (2.2 mL), followed by
dropwise addition of benzylamine (3.6 mL, 33.6 mmol). The mixture
was stirred for 1.5 h at 23 °C, then heated at 50 °C for 6 h. After
cooling, the mixture was placed in an ice bath and basified to pH >9
using 1 N NaOH. The basic solution was extracted 3× with CH2Cl2
(60 mL). The organic phase was dried over K2CO3, filtered, and the
filtrate was concentrated to dryness. The resulting brown viscous oil
was purified by silica gel chromatography using 40% EtOAc/heptanes
1
to provide 11a (3.59 g, 10.7 mmol) as a semisolid. H NMR (CDCl3,
400 MHz) δ 1.85−1.95 (m, 4H), (m, 2H), 2.31 (d, J = 16.4 Hz, 2H),
2.73 (dd, J = 6.8 Hz, J = 16.6 Hz, 2H), 3.45 (br s, 2H), 3.64−3.75 (m,
1H), 3.92 (s, 2H), 4.47 (s, 2H), 4.69 (d, J = 5.87 Hz), 7.24−7.39 (m,
10 H). 13C NMR (CDCl3, 100 MHz) δ 34.7, 44.9, 53.7, 56.6, 65.6,
70.1, 127.2, 127.9, 128.6, 128.8, 138.7, 139.2, 141.1, 210.3. LCMS:
336.1 (M + 1). Compound 11b (1.198 g, 3.57 mmol) as a yellow solid.
1H NMR (CDCl3, 400 MHz) δ 1.80 (d, J = 13.7 Hz, 2H), 1.95−2.05
(m, 2H), 2.37 (d, J = 17.8 Hz, 2H), 2.62 (dd, J = 7.3 Hz, J = 17.6 Hz,
2H), 3.28 (br s, 2H), 3.77 (s, 1H), 3.88 (s, 2H), 4.40 (s, 2H), 7.20−
7.40 (m, 10 H). 13C NMR (CDCl3, 100 MHz) δ 32.2, 42.4, 50.5, 57.0,
69.2, 70.9, 127.4, 127.6, 127.9, 128.5, 128.7, 138.7, 206.5. LCMS:
336.1 (M + 1).
(1R,3r,5S)-tert-Butyl 3-Hydroxy-7-oxo-9-azabicyclo[3.3.1]-
nonane-9-carboxylate (12). To a solution of 11a (3.20 g, 9.54
mmol) in EtOH (48 mL) was added di-tert-butyl dicarbonate (4.21 g,
19.1 mmol). Hydrogenolysis of the material was achieved via a
continuous flow process on an ThalesNano H-Cube apparatus with a
long Pd(OH)2 cartridge as the metal catalyst at 70 bar and 70 °C for 1
h. The mixture was concentrated and purified by silica gel
chromatography using a gradient elution of 10−90% EtOAc/heptanes
tert-Butyl 6-Methyl-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-
2-carboxylate (21a). To a stirred solution of crude (3:1) 2-
methyl-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane·2HCl 20 (3.25 g, 21.4
mmol) in MeOH (100 mL) was added Et3N (6.72 mL, 48 mmol)
followed by di-tert-butyl dicarbonate (5.10 g, 23.4 mmol). The
reaction was complete after 1 h, but the mixture was stirred at 23 °C
under nitrogen for 13 h. The yellow suspension was reduced to
dryness under vacuum and diluted with 1 N NaOH (30 mL). The
resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The
combined extracts were washed with brine, dried over Na2SO4, filtered,
and the filtrate was concentrated to dryness under vacuum. The
residue was purified by silica gel chromatography with a gradient
elution (20% of (1:9) Et3N/EtOAc solution in heptanes to 100% (1:9)
Et3N/EtOAc) to give the title compound as a light yellow oil that
solidified under vacuum (2.91 g, 54%). Product Rf = 0.23 in 75% (1:9,
1
over 40 min to give 12 (2.4 g, 9.50 mmol) as a white solid. H NMR
(CDCl3, 400 MHz) δ 1.43 (s, 9H), 1.55−1.65 (m, 2H), 1.90−2.00 (m,
2H), 2.32 (s, 2H), 2.36 (s, 2H), 2.48−2.61 (m, 3H), 3.89 (m, 1H). 13C
NMR (CDCl3, 100 MHz) δ 28.6, 40.0, 45.7, 45.8, 47.6, 48.7, 80.9,
153.8, 208.6. LCMS: 256.1 (M + 1).
(1R,3r,5S,Z)-N-Benzylidene-9-methyl-9-azabicyclo[3.3.1]-
nonan-3-amine (18). To a solution of 15 (5.2 g, 21.3 mmol) in
cyclohexane (100 mL) and 12% NaOH (15 mL) was added a solution
of Br2 (1 mL) in cyclohexane (150 mL) dropwise over 1.5 h. During
the addition the mixture was cooled in an ice bath. The cyclohexane
solution of the bromoamine intermediate was separated, and the
aqueous layer was extracted with cyclohexane (20 mL). The extracts
were combined, washed with 12% NaOH (50 mL), dried over
anhydrous Na2SO4, and filtered, and the filtrate was concentrated
under reduced pressure. The N-bromoamine 16 (6.2 g) thus obtained
was used in the next step without purification. The N-bromoamine 16
was dissolved in 70 mL of cold 84% H2SO4 (80 mL of concentrated
1
Et3N/EtOAc)/heptane. H NMR (500 MHz, CDCl3) δ 1.47 (s, 9H),
1.66 (d, 4H), 2.04 (t, 4H), 2.56 (s, 3H), 2.93 (br s, 2H), 4.28 (br s,
1H), 4.39 (br s, 1H). 13C NMR (500 MHz,CDCl3) δ 28.5, 30.6, 31.8,
41.2, 45.2, 46.4, 51.8, 79.2, 154.3. GCMS (m/z): 252.
I
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tert-Butyl 2,6-Diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxy-
late (5a). tert-Butyl 6-methyl-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-
2-carboxylate 21a (2.59 g, 10.28 mmol) was dissolved in THF (8.6
mL) and cooled to 0 °C. A solution of 1.5 N NaOH (206 mL, 308
mmol) was added slowly by addition funnel. To the resulting white
suspension was added in four portions solid KMNO4 (12.20 g, 77.10
mmol). The mixture was stirred at 0 °C for 10 min and then stirred at
23 °C for 68 h. Additional KMNO4 (3.05 g, 19.28 mmol) and H2O
(50 mL) were added, and the reaction mixture was stirred for another
8 h. The mixture was then extracted with CH2Cl2 (3 × 75 mL). The
combined extracts were washed with brine, dried over Na2SO4, filtered,
and the filtrate was concentrated to dryness under vacuum to afford
the title compound as a colorless oil that became a white solid under
vacuum (2.207 g, 90%). 1H NMR (500 MHz, CDCl3) δ 1.47 (s, 9H),
1.77−2.00 (m, 8H), 3.30 (s, 2H), 4.36 (s, 1H), 4.48 (s, 1H). 13C NMR
(500 MHz, CDCl3) δ 28.5, 35.6, 35.7, 45.4, 45.9, 46.8, 79.2, 154.6.
GCMS (m/z): 238. LCMS (ES+): 239.3 (M + 1).
(m, 2H), 8.35 (s, 1H). 13C NMR (CDCl3, 125 MHz) δ 12.1, 44.8,
116.9, 117.1, 117.4, 124.6, 125.2, 154.8, 161.9. LCMS: 317.0 (M + 1).
2-{6-[2-Fluoro-4-(methylsulfonyl)phenoxy]-5-methylpyrimi-
din-4-yl}-6-methyl-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane (24).
A solution of 2-benzyl-6-methyl-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane
17 (456 mg, 1.88 mmol) in MeOH (12.0 mL) was passed through a
long Pd/C cartridge on a ThalesNano H-Cube apparatus at full
hydrogen pressure and 60 °C. The mixture was circulated through the
instrument for a total of 4 h. The mixture was concentrated to give 288
mg of hydrogenolysis product (crude). A 0.1 M solution of the crude
material and 4-chloro-6-[2-fluoro-4-(methylsulfonyl)phenoxy]-5-
methylpyrimidine 23 in CH3CN (14 mL) was prepared in a 20 mL
microwave vial, and Cs2CO3 (766 mg, 2.35 mmol) was added. The vial
was capped and irradiated in the microwave at 180 °C for 1 h. The
crude material was concentrated and purified by silica gel
chromatography using 14% Et3N/EtOAc as the eluent to give the
title compound as an off-white foam (387 mg, 57%). Product Rf = 0.2
in 14% Et3N/EtOAc. LCMS (ES+): 433.2 (M + 1).
1-Methylcyclopropyl-6-methyl-2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate (21b). To a stirred solution
of crude 2-methyl-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane 20 in
CH2Cl2 (525 mL) at 0 °C was added Et3N (26.4 mL, 189 mmol),
followed by 1-methylcyclopropyl 4-nitrophenylcarbonate (37.4 g, 158
mmol). After 15 h, the mixture was concentrated under reduced
pressure. The resulting residue was dissolved in CH2Cl2, poured into a
2 L separatory funnel, followed by the addition of a 1:1 mixture of 1 N
NaOH and saturated NH4Cl (500 mL). The mixture was shaken, and
the CH2Cl2 layer was removed. More CH2Cl2 (200 mL) was added,
and the procedure was repeated twice. The combined organic phase
was concentrated to dryness under reduced pressure and adsorbed
onto silica gel. This silica gel was loaded atop a 330 g ISCO column
and eluted using 9:1 (EtOAc/10% NH4OH in MeOH) to give 17 g
tert-Butyl 6-{6-[2-Fluoro-4-(methylsulfonyl)phenoxy]-5-
methylpyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-
2-carboxylate (25a). To a stirred, cold (0 °C) solution of 2-{6-[2-
fluoro-4-(methylsulfonyl)phenoxy]-5-methylpyrimidin-4-yl}-6-methyl-
2,6-diazatricyclo[3.3.1.1∼3,7∼]decane 24 (361 mg, 0.835 mmol) in
1,2-dichloroethane (8.35 mL) was added dropwise 1-chloroethyl
chloroformate (244 mg, 1.67 mmol). The solution was stirred for 10
min, and the ice bath was removed. The mixture was placed in a
DrySyn heating vessel and heated at reflux for 2 h. The mixture was
cooled and concentrated. Methanol (10.0 mL) was added, and the
mixture was heated at reflux for 2 h. The crude mixture was
concentrated to dryness. Dichloromethane (10.0 mL) was added,
followed by di-tert-butyl dicarbonate (552 mg, 2.50 mL) and
triethylamine (422 mg, 4.18 mmol) at 23 °C. After 2 h, the mixture
was concentrated to dryness. Purification of the crude residue was
performed on silica gel using 50% EtOAc/heptanes as the eluent to
give the title compound as a white solid (84 mg, 17%). 1H NMR (500
MHz, CDCl3) δ 1.47 (s, 9H), 1.87 (app t, J = 12.1 Hz, 4H), 1.98−2.08
(m, 4H), 2.18 (s, 3H), 3.07 (s, 3H), 4.27 (s, 2H), 4.43 (s, 2H), 4.56 (s,
1H), 7.4 (t, J = 7.80 Hz, 1H,), 7.72−7.78 (m, 2H), 8.19 (s, 1H). 13C
NMR (125 MHz, CDCl3) δ 12.6, 28.7, 34.0, 34.2, 44.8, 46.4, 49.3,
79.8, 102.0, 116.7, 116.9, 124.4, 125.1, 138.2, 138.3, 145.7, 145.9,
153.2, 154.2, 154.5, 155.8, 166.3, 167.2. LCMS (ES+): 519.0 (M + 1).
Isopropyl-6-{5-methyl-6-[(2-fluoro-4-methanesulfonyl-
phenyl)oxy]pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]-
decane-2-carboxylate (25b). To a stirred suspension of tert-butyl 6-
{5-methyl-6-[(2-fluoro-4-methanesulfonylphenyl)oxy]pyrimidin-4-yl}-
2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate (28 mg, 0.054
mmol) in MeOH (0.50 mL) was added 2.0 M HCl in Et2O (0.40
mL, 0.80 mmol). The resulting solution was stirred for 16 h at 23 °C.
The solvents were removed under vacuum to give the amine
intermediate as a white solid (29.5 mg) which was used without
1
(44%) of the title compound 21b as an amber oil. H NMR (500
MHz, CDCl3) δ 0.64 (dd, J = 5.85, 7.07 Hz, 2H), 0.88 (t, J = 6.59 Hz,
2H), 1.57 (t, 3H), 1.6−1.7 (m, 4H), 2.01−2.10 (m, 4H), 2.57 (s, 3H),
2.94 (br s, 2H), 4.24 (br s, 1H), 4.42 (br s, 1H). GCMS (m/z): 250.
Preparation of 1-Methylcyclopropyl-2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate (5b). To a stirred, cold (0
°C) solution of 1-methylcyclopropyl-6-methyl-2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate 21b (17.0, 64.8 mmol) in 1,2-
dichloroethane (324 mL) was added dropwise 1-chloroethyl
chloroformate (8.47 mL, 77.7 mmol). After 10 min at 0 °C, the ice
bath was removed and the yellow reaction mixture was allowed to
warm to 23 °C over 5 min. The reaction mixture was heated at reflux
(∼90 °C) for 1.5 h and then allowed to cool to 23 °C. The solvent was
removed under reduced pressure, and MeOH (324 mL) was added.
The mixture was heated at 90 °C for 1 h. The reaction mixture was
cooled to 23 °C and concentrated under reduced pressure. To the
resulting residue was added a 1:9 mixture of MeOH/Et2O. Upon
addition a tan solid began to precipitate. The solid was collected and
washed with Et2O to give the title compound 5b as a tan solid, 14 g
(93% yield). 1H NMR (500 MHz, CDCl3) δ 0.67 (t, J = 7.32 Hz, 2H),
0.88 (t, J = 6.34 Hz, 2H), 1.50−1.65 (m, 7H) 1.86−1.96 (m, 4H) 2.90
(br s, 2H), 3.52 (s, 1H) 4.35 (br s, 1H), 4.55 (br s, 1H). GCMS (m/
z): 236.
1
further purification. H NMR (500 MHz, CD3OD) δ 2.28 (s, 3H),
2.29−2.38 (m, 8H), 3.15 (s, 3H), 3.93 (br s, 2H), 4.36 (br s, 2H), 7.49
(t, J = 7.81 Hz, 1H), 7.53 (d, J = 2.20 Hz, 1H), 7.78−7.85 (m, 2H),
8.24 (s, 1H). LCMS (ES+): 419.5 (M + 1).
To a stirred suspension of crude 2-{5-methyl-6-[(2-fluoro-4-
methanesulfonylphenyl)oxy]pyrimidin-4-yl}-2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane·HCl 25a (14 mg, 0.028 mmol) in CH2Cl2 (0.5
mL) was added N,N-diisopropylethylamine (20.0 μL, 0.112 mmol),
and the resulting solution was stirred at 23 °C for 10 min. Isopropyl
chloroformate (31.00 mL, 0.031 mmol) was added, and the yellow
mixture was stirred at 23 °C for 1 h. The solvent was evaporated to
give 20 mg (92%) of a pale yellow solid which was purified by silica gel
chromatography, eluting with a linear gradient of 40−80% EtOAc/
heptanes to afford the title compound as a white solid (10.5 mg, 74%).
1H NMR (500 MHz, CDCl3) δ 1.28 (d, 6H), 1.92 (d, J = 9.27 Hz,
4H), 2.02−2.12 (m, 4H), 2.22 (s, 3H), 3.11 (s, 3H), 4.31 (br s, 2H),
4.53 (br s, 1H), 4.63 (br s, 1H), 4.9−5.04 (m, 1H), 7.41−7.47 (m,
1H), 7.80 (ddd, J = 2.07, 6.34, 8.42 Hz, 2H), 8.22 (s, 1H). LCMS (ES
+): 505.5 (M + 1).
4-Chloro-6-(2-fluoro-4-(methylsulfonyl)phenoxy)-5-methyl-
pyrimidine (23).37 To a solution of 4,6-dichloro-5-methylpyrimidine
(700 mg, 4.29 mmol) and 2-fluoro-4-methylsulfonylphenol (743 mg,
3.91 mmol) and CH3CN (15.8 mL) in a 20 mL microwave vial was
added Cs2CO3 (1.65 g, 5.07 mmol). The vial was capped and
irradiated at 120 °C for 40 min using a microwave. The reaction
mixture was passed through a pad of Celite, and the filtrate was diluted
with EtOAc (25 mL) and H2O (15 mL). The layers were separated
and the organic phase was washed with brine, dried over MgSO4,
filtered, and the filtrate was evaporated. The crude material was
purified by flash chromatography using an 80 g ISCO column with a
gradient elution of 20−50% EtOAc/heptanes over 20 min and then an
isocratic elution of 50% EtOAc/heptanes to afford the title compound
1
23 (775 mg, 57%) as a white solid. H NMR (500 MHz, CDCl3) δ
2.44 (s, 3H), 3.10 (s, 3H), 7.44 (dd, J = 6.64, 8.40 Hz, 1H), 7.78−7.83
J
dx.doi.org/10.1021/jm301626p | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Article
1-Methylcyclopropyl-6-{5-methyl-6-[(2-fluoro-4-methane-
sulfonyl-phenyl)oxy]pyrimidin-4-yl}-2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate (25c). To a stirred suspen-
sion of 2-{5-methyl-6-[(2-fluoro-4-methanesulfonylphenyl)oxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane·HCl (14 mg,
0.028 mmol) in CH2Cl2 (0.5 mL) was added N,N-diisopropylethyl-
amine (20.0 μL, 0.112 mmol), and the resulting solution was stirred at
23 °C for 10 min. 1-Methylcyclopropyl 4-nitrophenylcarbonate (7.5
mg, 0.031 mmol) was added, and the yellow mixture was stirred at 23
°C for 18 h. Additional N,N-diisopropylethylamine (10.0 μL, 0.056
mmol) and 1-methylcyclopropyl 4-nitrophenyl carbonate (3.6 mg,
0.015 mmol) were added, and the mixture was stirred at 23 °C for
another 18 h. The reaction was quenched with 0.5 N NaOH (2 mL),
and extraction was with CH2Cl2 (4 mL). The aqueous layer was
extracted two additional times with CH2Cl2 (4 mL). The combined
organic layers were washed with a 0.5 N NaOH. The organic layer was
dried over Na2SO4, filtered, and the filtrate was evaporated to give 15.5
mg of a pale yellow solid which was purified by preparative reverse
phase HPLC on a Waters Sunfire C18 column (19 mm × 100 mm, 5
μm particle size), eluting with a gradient of H2O/CH3CN (0.05% TFA
modifier) to afford 8.1 mg (57%) of the title compound. Analytical
LCMS: retention time 3.35 min (Atlantis C18 4.6 mm × 50 mm, 5 μm
particle size; 95% H2O/CH3CN linear gradient to 5% H2O/CH3CN
for 4.0 min with a hold at 5% H2O/CH3CN to 5.0 min; 0.05% TFA
modifier; flow rate 2.0 mL/min). LCMS (ES+): 517.25 (M + 1).
4-Chloro-5-methyl-6-((2-methylpyridin-3-yl)oxy)pyrimidine
(27a). To a stirred solution of 2-methylpyridin-3-ol (6.29 g, 57.6
mmol) in THF (45 mL) and DMF (30 mL) at 23 °C was added KO-t-
Bu (57.6 mmol, 57.6 mL) in one portion to give a brown solution. In a
separate flask, a stirred solution of 4,6-dichloro-5-methylpyrimidine
(8.95 g, 54.9 mmol) in THF (120 mL) under N2 was heated to 70 °C.
The potassium salt solution was added via cannula to the stirred
pyrimidine solution in a slow steady stream. After the addition was
complete, the mixture became brownish white. After 1.5 h at 70 °C,
the heating bath was removed and the mixture was allowed to cool to
23 °C. The solvents were removed under reduced pressure, and the
remaining residue was diluted with 0.1 M KOH (100 mL) and MTBE
(150 mL). The layers were separated, and the basic aqueous layer was
extracted with MTBE (2 × 50 mL). The MTBE layers were combined,
washed with brine, dried over Na2SO4), filtered, and the filtrate was
concentrated under reduced pressure to a clear colorless oil. The
colorless oil was crystallized from heptanes to give the title compound
as a white solid (5.5 g, 43%). 1H NMR (500 MHz, CDCl3) δ 2.41 (s, 3
H), 2.48 (s, 3H), 7.25−7.28 (m, 1 H), 7.41 (d, J = 10.0 Hz, 1 H), 8.36
(s, 1 H), 8.47 (d, J = 4.64 Hz, 1H). LCMS (ES+): 236.2 (M + 1).
tert-Butyl 6-{5-Methyl-6-[(2-methylpyridin-3-yl)oxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-car-
boxylate (3e). To a mixture of tert-butyl 2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate (400 mg, 1.70 mmol) 5a, 4-
chloro-5-methyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidine (404 mg,
1.70 mmol), and Na2CO3 (214 mg, 2.55 mmol) in a 10 mL
microwave vial was added N,N-dimethylacetamide (4.2 mL). The vial
was sealed, and the resulting suspension was stirred at 120 °C for 42 h.
The mixture was cooled to 23 °C and then poured into H2O (80 mL)
that was externally cooled by an ice bath. After the resulting mixture
was stirred for 5 min, the ice bath was removed and stirring was
continued for an additional 90 min. The solids that formed were
collected by filtration on a Pall GHP filter (0.45 μm), rinsed with H2O,
and dried for 30 min under a stream of nitrogen. The solid was
dissolved in EtOAc and saturated brine. The aqueous mixture was
extracted with EtOAc (2 × 20 mL), and the combined extracts were
dried over Na2SO4, filtered, and the filtrate was dried under vacuum to
give an off-white solid that was purified by chromatography on silica
gel (40−100% EtOAc/heptanes, followed by a period of 2% MeOH/
EtOAc) to give the title compound as a white solid (391 mg, 53%).
Product Rf = 0.36 in 70% EtOAc/heptanes. 1H NMR (500 MHz,
CDCl3) δ 1.50 (s, 9H), 1.80−1.98 (m, 4H), 1.99−2.14 (m, 4 H), 2.22
(s, 3 H), 2.43 (s, 3 H), 4.27 (br s, 2 H), 4.46 (br s, 1 H), 4.59 (br s,
1H), 7.21 (dd, J = 8.05, 4.88 Hz, 1 H), 7.39 (d, J = 7.07 Hz, 1 H), 8.22
(s, 1 H), 8.40 (d, J = 3.66 Hz, 1 H). LCMS (ES+): 438.4 (M + 1).
2-{5-Methyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidin-4-yl}-
2,6-diazatricyclo[3.3.1.1∼3,7∼]decane·HCl (28a). To a stirred
solution of tert-butyl 6-{5-methyl-6-[(2-methylpyridin-3-yl)oxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate
3e (132 mg, 0.30 mmol) in MeOH (2.3 mL) was added 4 N HCl in
1,4-dioxane (1.13 mL, 4.53 mmol), dropwise. The mixture was stirred
for 16 h at 20 °C before the solvents were removed under vacuum to
give the title compound as a hygroscopic, yellow solid (165 mg). This
1
material was used without further purification. H NMR (500 MHz,
CDCl3) δ 2.03−2.19 (m, 8H), 2.22 (s, 3H), 2.43 (s, 3H), 3.56 (br s,
2H), 4.29 (br s, 2H), 7.21 (dd, J = 4.64, 8.05 Hz, 1H), 7.39 (d, J = 8.05
Hz, 1H), 8.22 (s, 1H), 8.40 (d, J = 3.66 Hz, 1H). LCMS (ES+): 338.3
(M + 1).
The free base of the above compound was prepared as follows.
To a stirred solution of tert-butyl 6-{5-methyl-6-[(2-methylpyridin-
3-yl)oxy]pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-car-
boxylate 3e (389 mg, 0.89 mmol) in dichloromethane (3 mL) was
added trifluoroacetic acid (0.9 mL, 11.6 mmol). The reaction mixture
was stirred at 23 °C for 5 h and then concentrated to dryness under
vacuum. The residue was dissolved in 1 N NaOH solution and
extracted with CH2Cl2 (3 × 20 mL) and then with 2-butanol (3 × 20
mL). The combined extracts were pooled, dried over a mixture of
MgSO4, filtered, and the filtrate was concentrated to dryness under
vacuum. The resulting solid was dissolved in a mixture of EtOAc and
THF and was filtered. The filtrate was concentrated to give the title
compound as a white solid (306 mg), which was used in the
1
subsequent steps without purification. H NMR (500 MHz, CD3OD)
δ 2.20 (d, J = 13.42 Hz, 4H), 2.29 (s, 3H), 2.31−2.43 (m, 7H), 3.94
(br s, 2H), 4.33 (br s, 2H), 7.36 (dd, J = 4.88, 8.29 Hz, 1H), 7.54 (d, J
= 8.05 Hz, 1H), 8.15 (s, 1H), 8.33 (d, J = 4.63 Hz, 1H). LCMS (ES+):
338.3 (M + 1).
Isobutyl 6-{5-Methyl-6-[(2-methylpyridin-3-yl)oxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-car-
boxylate (3f). To a stirred suspension of 2-{5-methyl-6-[(2-
methylpyridin-3-yl)oxy]pyrimidin-4-yl}-2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane·HCl salt (20 mg, 0.05 mmol) in dichloro-
methane (0.25 mL) was added triethylamine (27 mg, 0.27 mmol)
followed by isobutyl chloroformate (7 μL, 0.05 mmol). The mixture
was stirred at 23 °C for 2 h. Water was added to the reaction mixture,
and it was extracted with dichloromethane (3 × 2 mL). The combined
extracts were washed with half saturated brine, dried over sodium
sulfate, filtered, and the filtrate was concentrated to dryness under
1
vacuum to give the title compound as a tan solid (17.8 mg, 72%). H
NMR (500 MHz, CDCl3) δ 0.96 (d, J = 6.83 Hz, 6H), 1.86−2.03 (m,
5H), 2.10 (d, J = 12.20 Hz, 4H), 2.22 (s, 3H), 2.43 (s, 3H), 3.93 (d, J
= 6.59 Hz, 2H), 4.29 (br s, 2H), 4.55 (br s, 1H), 4.64 (br s, 1H), 7.21
(dd, J = 4.64, 8.05 Hz, 1H), 7.39 (d, J = 7.81 Hz, 1H), 8.22 (s, 1H),
8.40 (d, J = 4.15 Hz, 1H). LCMS (ES+): 438.3 (M + 1).
Alternatively, the crude material was purified by preparative reverse
phase HPLC on a Waters Sunfire C18 column (19 mm × 100 mm, 5
μm particle size), eluting with a gradient of H2O/CH3CN (0.05% TFA
modifier) to afford the title compound as the TFA salt. Analytical
LCMS: retention time 2.59 min (Atlantis C18 4.6 mm × 50 mm, 5 μm
particle size; 95% H2O/CH3CN linear gradient to 5% H2O/CH3CN
for 4.0 min with a hold at 5% H2O/CH3CN to 5.0 min; 0.05% TFA
modifier; flow rate 2.0 mL/min). LCMS (ES+): 438.2 (M + 1).
Ethyl 6-{5-Methyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidin-4-
yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate (3a).
The title compound was prepared from 2-{5-methyl-6-[(2-methylpyr-
idin-3-yl)oxy]pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane
(12 mg, 0.03 mmol) in a manner similar to that described for the
preparation of isobutyl 6-{5-methyl-6-[(2-methylpyridin-3-yl)oxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate
3f. The crude material was purified by preparative reverse phase HPLC
on a Waters Sunfire C18 column (4.6 mm × 100 mm, 5 μm particle
size), eluting with a gradient of H2O/CH3CN (0.05% formic acid
modifier) to afford 4.8 mg of the title compound. Analytical LCMS:
retention time 2.31 min (Atlantis C18 4.6 mm × 50 mm, 5 μm particle
size; 95% H2O/CH3CN linear gradient to 5% H2O/CH3CN for 4.0
K
dx.doi.org/10.1021/jm301626p | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Article
min with a hold at 5% H2O/CH3CN to 5.0 min; 0.05% formic acid
modifier; flow rate 2.0 mL/min). LCMS (ES+): 410.1 (M + 1).
Isopropyl 6-{5-Methyl-6-[(2-methylpyridin-3-yl)oxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-car-
boxylate (3b). To a mixture of isopropyl 2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate (50 mg, 0.22 mmol), 4-chloro-5-
methyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidine (53 mg, 0.22 mmol),
and Na2CO3 (28 mg, 0.36 mmol) in a 5 mL microwave vial was added
N,N-dimethylformamide (1.1 mL). The vial was sealed, and the
resulting suspension was stirred at 120 °C for 45 h. The mixture was
cooled to 23 °C, diluted with H2O (20 mL) and aqueous 10% LiCl
solution (5 mL), and extracted with EtOAc (3 × 15 mL). The
combined extracts were washed with aqueous 10% LiCl solution (15
mL), dried over Na2SO4, filtered, and the filtrate was dried under
vacuum to yield a white solid that was purified by silica gel
chromatography (with a gradient elution of 50−100% EtOAc/
heptanes, followed by a period of 2% MeOH/EtOAc) to give the
title compound as a white solid (56 mg). This material was further
purified by stirring the solid in 50% EtOAc/heptanes (3 mL) for 3
days, filtering, and rinsing the solid with 50% EtOAc/heptanes (2 × 1
h. The crude material was purified by preparative reverse phase HPLC
on a Waters Sunfire C18 column (19 mm × 100 mm, 5 μm particle
size), eluting with a gradient of H2O in CH3CN (0.05% TFA
modifier) to afford 17.3 mg of the title compound as the mono-TFA
salt. Analytical LCMS: retention time 2.55 min (Atlantis C18 4.6 mm ×
50 mm, 5 μm particle size; 95% H2O/CH3CN linear gradient to 5%
H2O/CH3CN for 4.0 min with a hold at 5% H2O/CH3CN to 5.0 min;
0.05% TFA modifier; flow rate 2.0 mL/min). LCMS (ES+): 436.3 (M
+ 1).
3-Methyl-1-({[(1R)-1-methylpropyl]oxy}carbonyl)-1H-imida-
zol-3-ium Iodide. To a stirred solution of (R)-2-butanol (80 mg,
1.08 mmol) in toluene (2.8 mL) was added 1,1′-carbonyldiimidazole
(175 mg, 1.08 mmol). The mixture was stirred 1 h at 23 °C. The
mixture was then diluted with Et2O (20 mL), and the organic layer was
washed with 0.1 N HCl solution (23 mL). The aqueous layer was
again extracted with Et2O (2 × 10 mL). The combined organic
extracts were dried over Na2SO4, filtered, and the filtrate was
concentrated under reduced pressure to give 1-({[(1R)-1-
methylpropyl]oxy}carbonyl)-1H-imidazole as a clear, colorless oil
(60 mg, 32%). 1H NMR (500 MHz, CDCl3) δ 1.00 (t, J = 7.44 Hz, 3
H), 1.41 (d, J = 6.34 Hz, 3 H), 1.65−1.88 (m, 2 H), 5.08 (m, 1 H),
7.08 (s, 1 H), 7.43 (s, 1 H), 8.14 (s, 1 H). GCMS (m/z): 168. To a
solution of crude imidazole (22 mg, 0.13 mmol) in CH3CN (0.5 mL)
in a sealable vial, under an N2 atmosphere, was added methyl iodide
(0.1 mL, 2.0 mmol). The vial was sealed and heated at 50 °C for 42 h.
The solvent was removed under vacuum to give a light yellow solid
that was used without further purification. 1H NMR (500 MHz,
CDCl3) δ 1.05 (t, J = 7.44 Hz, 3H), 1.54 (d, J = 6.10 Hz, 3H), 1.78−
1.89 (m, 1H), 1.92−2.03 (m, 1H), 4.34 (s, 3H), 5.21 (m, 1H), 7.47 (s,
1H), 7.77 (s, 1H), 10.83 (s, 1H). LCMS (ES+): 183.1 (M).
(1R)-1-Methylpropyl 6-{5-Methyl-6-[(2-methylpyridin-3-yl)-
oxy]pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-
carboxylate (3g). To a stirred solution of the crude 3-methyl-1-
({[(1R)-1-methylpropyl]oxy}carbonyl)-1H-imidazol-3-ium iodide (22
mg, 0.12 mmol) in CH2Cl2 (0.5 mL) was added Et3N (0.028 mL, 0.20
mmol) followed by 2-{5-methyl-6-[(2-methylpyridin-3-yl)oxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane (41 mg, 0.12
mmol). The amber colored solution was stirred for 2 h, diluted with
H2O, and extracted with CH2Cl2 (3 × 3 mL). The combined extracts
were dried over Na2SO4, filtered, and the filtrate was concentrated to
dryness under vacuum to give a tan solid that was purified by
preparative reverse phase HPLC on a Waters Sunfire C18 column (19
mm × 100 mm, 5 μm particle size), eluting with a gradient of H2O/
CH3CN (0.05% TFA modifier) to afford 22.5 mg of the title
compound as the mono-TFA salt. Analytical LCMS: retention time
2.81 min (Atlantis C18 4.6 mm × 50 mm, 5 μm particle size; 95%
H2O/CH3CN linear gradient to 5% H2O/CH3CN for 4.0 min with a
hold at 5% H2O/CH3CN to 5.0 min; 0.05% TFA modifier; flow rate
2.0 mL/min). LCMS (ES+): 452.4 (M + 1).
1
mL) to give the title compound as a white solid (30 mg, 31%). H
NMR (500 MHz, CDCl3) δ 1.28 (d, J = 6.10 Hz, 6H), 1.81−2.00 (m,
4H), 2.02−2.15 (m, 4H), 2.22 (s, 3H), 2.43 (s, 3H), 4.28 (br s, 2H),
4.52 (br s, 1H), 4.63 (br s, 1 H), 4.91−5.07 (m, 1H), 7.21 (dd, J =
4.88, 8.05 Hz, 1H), 7.39 (d, J = 7.81 Hz, 1H), 8.22 (s, 1H), 8.40 (d, J =
4.39 Hz, 1H). LCMS (ES+): 424.3 (M + 1).
1-Methylcyclopropyl 6-{5-Methyl-6-[(2-methylpyridin-3-yl)-
oxy]pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-
carboxylate (3c). To a stirred solution of tert-butyl 6-{5-methyl-6-
[(2-methylpyridin-3-yl)oxy]pyrimidin-4-yl}-2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate 3e (400 mg, 0.91 mmol) in
CH2Cl2 (3 mL) was slowly added TFA (1.0 mL) at 23 °C. After 2
h, toluene (10 mL) was added and the reaction mixture was reduced to
dryness under vacuum. The residue was diluted with 6 mL of toluene,
and the mixture was sonicated. The solvent was again removed under
vacuum to give a light yellow residue. This residue was dissolved in
CH2Cl2 (5 mL), and to the resulting solution were added Et3N (0.67
mL, 4.81 mmol) and 1-methylcyclopropyl 4-nitrophenylcarbonate
(251 mg, 1.06 mmol). The mixture was stirred for 16 h at 40 °C. The
mixture was cooled to 23 °C, and additional Et3N (0.3 mL) and 1-
methylcyclopropyl 4-nitrophenylcarbonate (46 mg, 0.18 mmol) were
added. The mixture was heated at 40 °C for another 3.5 h. The
mixture was cooled to 23 °C, diluted with 1 N NaOH solution (20
mL), stirred for 10 min, and extracted with CH2Cl2 (three times, 20
mL). The combined extracts were washed with brine, dried over
Na2SO4, filtered, and the filtrate was reduced to dryness under
vacuum, giving a light yellow solid which was purified by silica gel
chromatography (with a gradient elution of 40−100% EtOAc/
heptanes, followed by a period of 2% MeOH/EtOAc) to give the
title compound as a white solid (395 mg, 94%). This solid was
suspended in EtOAc (4 mL) and was stirred for 20 h. The mixture was
filtered through a Pall GHP 0.45 μm membrane. The solid was rinsed
with cold EtOAc (3 mL) and dried under a stream of nitrogen for 30
min. The solid was further dried under vacuum to give the title
compound as a white, crystalline solid (309 mg, 74%). 1H NMR (500
MHz, CDCl3) δ 0.60−0.73 (m, 2H), 0.84−0.97 (m, 2H), 1.59 (s, 3H),
1.76−1.98 (m, 4H), 1.99−2.14 (m, 4H), 2.21 (s, 3H), 2.42 (s, 3H),
4.27 (br s, 2H), 4.41 (br s, 1H), 4.61 (br s, 1H), 7.21 (dd, J = 4.88,
8.05 Hz, 1H), 7.38 (d, J = 7.81 Hz, 1H), 8.21 (s, 1H), 8.39 (d, J = 3.90
Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 12.3, 13.0, 19.5, 21.7, 33.8,
34.0, 45.3, 46.2, 48.9, 56.5, 102.1, 121.9, 129.5, 145.8, 148.2, 151.9,
154.3, 154.6, 166.1, 167.5. LCMS (ES+): 436.4 (M + 1).
(1S)-1-Methylpropyl 6-{5-Methyl-6-[(2-methylpyridin-3-yl)-
oxy]pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-
carboxylate (3h). The title compound was prepared from crude 3-
methyl-1-({[(1S)-1-methylpropyl]oxy}carbonyl)-1H-imidazol-3-ium
iodide and 2-{5-methyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidin-4-yl}-
2,6-diazatricyclo[3.3.1.1∼3,7∼]decane 28a (41 mg, 0.12 mmol) in a
manner similar to that of 1-methylpropyl 6-{5-methyl-6-[(2-methyl-
pyridin-3-yl)oxy]pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]-
decane-2-carboxylate 3g. The crude material was purified by
chromatography on silica gel, eluting with EtOAc/heptanes to give
1
the title compound as a white solid (22 mg, 42%). H NMR (500
MHz, CDCl3) δ 0.94 (t, J = 7.44 Hz, 3H), 1.26 (d, J = 6.34 Hz, 3H),
1.50−1.73 (m, 2H), 1.82−2.00 (m, 4H), 2.08 (d, J = 8.05 Hz, 4H),
2.22 (s, 3H), 2.46 (s, 3H), 4.29 (br s, 2H), 4.54 (br s, 1H), 4.63 (br s,
1H), 4.82 (m, 1H), 7.22−7.29 (m, 1H), 7.44 (d, J = 7.81 Hz, 1H),
8.21 (s, 1H), 8.40 (d, J = 4.64 Hz, 1H). LCMS (ES+): 438.2.
1-Methylcyclobutyl 6-{5-methyl-6-[(2-methylpyridin-3-yl)-
oxy]pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-
carboxylate (3i). To a stirred suspension of 2-{5-methyl-6-[(2-
methylpyridin-3-yl)oxy]pyrimidin-4-yl}-2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane·HCl salt 28a (20 mg, 0.05 mmol) in CH2Cl2
Cyclobutyl 6-{5-Methyl-6-[(2-methylpyridin-3-yl)oxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-car-
boxylate (3d). The title compound was prepared from 2-{5-methyl-
6-[(2-methylpyridin-3-yl)oxy]pyrimidin-4-yl}-2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane 28a (15 mg, 0.05 mmol) in a manner similar to
that described for the preparation of 1-methylcyclobutyl 6-{5-methyl-
6-[(2-methylpyridin-3-yl)oxy]pyrimidin-4-yl}-2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate 3c but with a heating time of 18
L
dx.doi.org/10.1021/jm301626p | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Article
(0.25 mL) was added Et3N (27 mg, 0.27 mmol) followed by 1-
methylcyclobutyl 4-nitrophenylcarbonate (14 mg, 0.05 mmol). After
4.5 h at 45 °C the reaction mixture was cooled to 23 °C, diluted with 1
N NaOH, and extracted with CH2Cl2 (3 × 2 mL). The combined
extracts were washed with brine, dried over Na2SO4, filtered, and the
filtrate was concentrated to dryness to produce a yellow solid. The
crude material was purified by preparative reverse phase HPLC on a
Waters Sunfire C18 column (19 mm × 100 mm, 5 μm particle size),
eluting with a gradient of H2O/CH3CN (0.05% TFA modifier) to
afford 14.1 mg of the title compound as the mono-TFA salt. Analytical
LCMS: retention time 2.63 min (Atlantis C18 4.6 mm × 50 mm, 5 μm
particle size; 95% H2O/CH3CN linear gradient to 5% H2O/CH3CN
for 4.0 min with a hold at 5% H2O/CH3CN to 5.0 min; 0.05% TFA
modifier; flow rate 2.0 mL/min). LCMS (ES+): 450.2 (M + 1).
tert-Butyl 6-{6-[(2-Methylpyridin-3-yl)oxy]pyrimidin-4-yl}-
2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate (29b). To
a 5 mL microwave vial charged with tert-butyl 2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate (200 mg, 0.90 mmol) 5a, 4-
chloro-5-methyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidine (215 mg,
0.90 mmol), and Na2CO3 (114 mg, 1.35 mmol) was added N,N-
dimethylformamide (4.5 mL). The mixture was stirred, put under an
N2 atmosphere, sealed, and heated at 120 °C for 16.5 h. The mixture
was cooled to 23 °C, diluted with H2O (80 mL), 10% aqueous LiCl
(20 mL), and extracted with EtOAc (3 × 30 mL). The combined
organic extracts were washed with 10% aqueous LiCl (40 mL), dried
over Na2SO4, filtered, and the filtrate was reduced to dryness under
vacuum. The residue was suspended in heptane, and the solvent was
removed under vacuum. The process was repeated to give 393 mg of
crude material as an orange solid. The crude material was purified by
chromatography on 25 g silica, eluting with EtOAc/heptanes using a
linear gradient from 25% to 85% EtOAc over 18.5 min, followed by a
linear gradient from 85% to 100% EtOAc over 2.6 min, then a period
of EtOAc for 10 min to give the title compound as a white foam (332
Isopropyl 6-{5-Ethyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidin-
4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate
(29c). To a stirred solution of tert-butyl 6-{5-ethyl-6-[(2-methylpyr-
idin-3-yl)oxy]pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-
2-carboxylate 29e (20 mg, 0.044 mmol) in MeOH (0.3 mL) was
added 4 N HCl in 1,4-dioxane (0.33 mL, 1.32 mmol), and the mixture
was stirred for 75 min. The solvent was removed under vacuum, and
the residue was dissolved in CH2Cl2 (1 mL) and Et3N (0.031 mL, 0.22
mmol). The reaction mixture was cooled to 0 °C, at which point 1 M
isopropyl chloroformate in toluene (0.048 mL, 0.048 mmol) was
added dropwise. The mixture was stirred for 1 h at 0 °C and then
allowed to warm to 23 °C. After a total of 15 h, the reaction mixture
was diluted with 1 N NaOH and extracted with CH2Cl2 (2×). The
combined extracts were pooled, dried over Na2SO4, filtered, and the
filtrate was concentrated to dryness. The residue was dissolved in
DMSO (0.9 mL) and purified by preparative reverse-phase HPLC on a
Waters Sunfire C18 19 mm × 100 mm, 0.005 mm column, eluting with
a linear gradient of 90% H2O/CH3CN (0.05% TFA modifier) to 0%
H2O/CH3CN in 8.5 min and holding at 0% H2O/CH3CN for 1.5 min
(flow rate, 25 mL/min) to give the title compound as the mono-TFA
salt (19 mg, 78%). Analytical LCMS: retention time 2.61 min (Waters
Atlantis C18 4.6 mm × 50 mm, 0.005 mm column; 95% H2O/CH3CN
linear gradient to 5% H2O/CH3CN over 4.0 min and held at 5% H2O/
CH3CN for 1.0 min; 0.05% TFA modifier; flow rate 2.0 mL/min).
LCMS (ES+): 438.1 (M + 1).
1-Methylcyclopropyl 6-{5-Ethyl-6-[(2-methylpyridin-3-yl)-
oxy]pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-
carboxylate (29d). The title compound was prepared using tert-butyl
6-{5-ethyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidin-4-yl}-2,6-
diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate 29e (20 mg, 0.044
mmol) in a manner similar to that used to prepare 1-
methylcyclopropyl 6-{5-methyl-6-[(2-methylpyridin-3-yl)oxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate
3c. The residue was dissolved in DMSO (0.9 mL) and purified by
preparative reverse-phase HPLC on a Waters Sunfire C18 19 mm ×
100 mm, 0.005 mm column, eluting with a linear gradient of 90%
H2O/CH3CN (0.05% TFA modifier) to 0% H2O/CH3CN in 8.5 min
and holding at 0% H2O/CH3CN for 1.5 min (flow rate, 25 mL/min)
to give the title compound as the mono-TFA salt (23.1 mg, 93%).
Analytical LCMS: retention time 2.60 min (Waters Atlantis C18 4.6
mm × 50 mm, 0.005 mm column; 95% H2O/CH3CN linear gradient
to 5% H2O/CH3CN over 4.0 min and held at 5% H2O/CH3CN for
1.0 min; 0.05% TFA modifier; flow rate 2.0 mL/min). LCMS (ES+):
450.1 (M + 1).
1
mg, 87%). Product Rf = 0.24 in 70% EtOAc/heptanes. H NMR (500
MHz, CDCl3) δ 1.51 (s, 9H), 1.85−2.00 (m, 8H), 2.43 (s, 3H), 4.46
(br s, 1H), 4.59 (br s, 1 H), 6.02 (s, 1H), 7.21 (dd, J = 4.88, 8.05 Hz,
1H), 7.39 (d, J = 7.07 Hz, 1H), 8.28 (s, 1H), 8.41 (d, J = 3.66 Hz, 1H).
LCMS (ES+): 424.3 (M + 1).
1-Methylcyclopropyl 6-{6-[(2-Methylpyridin-3-yl)oxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-car-
boxylate (29a). The title compound was prepared from 29b in a
1
manner similar to 3c from 3e. H NMR (500 MHz, CDCl3) δ 0.60−
0.73 (m, 2H), 0.84−0.97 (m, 2H), 1.60 (s, 3H), 1.75−1.98 (m, 8H),
2.46 (s, 3H), 4.42 (br s, 1H), 4.62 (br s, 1H), 6.02 (s, 1H), 7.21 (dd, J
= 4.88, 8.05 Hz, 1H), 7.38 (d, J = 7.81 Hz, 1H), 8.28 (s, 1H), 8.39 (d, J
= 3.90 Hz, 1H). LCMS (ES+): 422.3 (M + 1).
4-Chloro-5-fluoro-6-[(2-methylpyridin-3-yl)oxy]pyrimidine
(27c). The title compound was prepared from 4,6-dichloro-5-
fluoropyrimidine (300 mg, 1.77 mmol) in a manner similar to that
used to prepare 4-chloro-5-methyl-6-((2-methylpyridin-3-yl)oxy)-
pyrimidine. The title compound was obtained as a clear, colorless oil
4-Chloro-5-ethyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidine
(27b). The title compound was prepared from 4,6-dichloro-5-
ethylpyrimidine (783 mg, 4.42 mmol) in a manner similar to that
used to prepare 4-chloro-5-methyl-6-((2-methylpyridin-3-yl)oxy)-
pyrimidine. The title compound was obtained as a tan solid (892
1
(382 mg, 90%). H NMR (500 MHz, CDCl3) δ 2.46 (s, 3H), 7.22−
1
7.33 (m, 1H), 7.47 (d, J = 8.05 Hz, 1H), 8.29 (s, 1H), 8.50 (d, J = 4.88
Hz, 1H). LCMS (ES+): 240.1 (M + 1).
mg, 81%). H NMR (500 MHz, CDCl3) δ 1.32 (t, J = 7.56 Hz, 3H),
2.42 (s, 3H), 2.95 (q, J = 7.40 Hz, 2H), 7.22−7.30 (m, 1H), 7.41 (d, J
= 8.05 Hz, 1H), 8.35 (s, 1H), 8.47 (d, J = 4.64 Hz, 1H). LCMS (ES+):
250.2 (M + 1).
tert-Butyl 6-{5-Fluoro-6-[(2-methylpyridin-3-yl)oxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-car-
boxylate (29g). To a microwave vial charge with tert-butyl 2,6-
diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate 5a (47 mg, 0.20
mmol), 4-chloro-5-fluoro-6-[(2-methylpyridin-3-yl)oxy]pyrimidine
27c (47 mg, 0.20 mmol), and NaHCO3 (25 mg, 0.29 mmol) was
added N,N-dimethylformamide (0.49 mL). The vial was capped, and
the resulting suspension was stirred at 90 °C for 1 h, then 80 °C for 6
h. The mixture was cooled to 23 °C, diluted with H2O (25 mL), and
extracted with EtOAc (3 × 15 mL). The combined organic extracts
were washed with 10% aqueous LiCl (15 mL), dried over Na2SO4,
filtered, and the filtrate was dried under vacuum to give an off-white
solid that was purified using silica gel chromatography, eluting with an
EtOAc/heptanes gradient. The title compound was obtained as a
tert-Butyl 6-{5-Methoxy-6-[(2-methylpyridin-3-yl)oxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-car-
boxylate (29e). The title compound was prepared from 4-chloro-5-
ethyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidine (100 mg, 0.40 mmol)
in a manner similar to that used to prepare tert-butyl 6-{5-methyl-6-
[(2-methylpyridin-3-yl)oxy]pyrimidin-4-yl}-2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate 3e. Silica gel chromatography was
carried out using EtOAc/heptanes followed by a second chromatog-
raphy using EtOAc/CH2Cl2. The title compound was isolated as a
white solid (107 mg, 59%). 1H NMR (500 MHz, CDCl3) δ 1.36 (t, J =
7.32 Hz, 3H), 1.50 (s, 9H), 1.85−1.98 (m, 3H), 2.02−2.14 (m, 3H),
2.54 (br s, 2H), 2.63 (d, J = 7.56 Hz, 2H), 3.50 (d, J = 2.20 Hz, 3H),
4.27 (br s, 2H), 4.41−4.50 (m, 1H), 4.54−4.64 (m, 1H), 7.21−7.37
(m, 1H), 7.44−7.61 (m, 1H), 8.19 (s, 1H), 8.42 (d, J = 4.88 Hz, 1H).
LCMS (ES+): 452.2 (M + 1).
1
white solid (67 mg, 77%). H NMR (500 MHz, CDCl3) δ 1.51 (s,
9H), 1.90−2.06 (m, 8H), 2.50 (s, 3H), 4.46 (br s, 1H), 4.59 (br s,
1H), 4.90 (br s, 2H), 7.25 (br s, 1H), 7.42−7.54 (m, 1H), 7.99 (s,
M
dx.doi.org/10.1021/jm301626p | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
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1
1H), 8.43 (br s, 1H). LCMS (ES+): 442.3 (M + 1). Product Rf = 0.20
in 60% EtOAc/heptanes.
mg, 48%). H NMR (500 MHz, CDCl3) δ 1.28 (d, J = 6.34 Hz, 6H),
1.87−2.15 (m, 8H), 2.55 (br s, 3H), 3.87 (s, 3H), 4.47−4.55 (m, 1H),
4.57−4.65 (m, 1H), 4.95−5.06 (m, 3H), 7.22−7.33 (m, 1 H), 7.43−
7.58 (m, 1H), 8.02 (s, 1H), 8.42 (d, J = 4.63 Hz, 1H). LCMS (ES+):
440.2 (M + 1).
1-Methylcyclopropyl 6-{5-Fluoro-6-[(2-methylpyridin-3-yl)-
oxy]pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-
carboxylate (29f). To a stirred solution of tert-butyl 6-{5-fluoro-6-
[(2-methylpyridin-3-yl)oxy]pyrimidin-4-yl}-2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate 29g (15 mg, 0.034 mmol) in
CH2Cl2 (0.5 mL) was added TFA (0.2 mL). After being stirred at 23
°C for 3 h, the mixture was concentrated to dryness under vacuum.
The residue was dissolved in CH2Cl2 (0.5 mL) and Et3N (0.024 mL,
0.13 mmol). 1-Methylcyclopropyl 4-nitrophenylcarbonate (10 mg,
0.044 mmol) was added, and the mixture was heated to 45 °C. After
18 h, the reaction mixture was cooled to 23 °C, diluted with 1 N
NaOH, and extracted with CH2Cl2 (3 × 2 mL). The combined
extracts were pooled, dried over Na2SO4, filtered, and the filtrate was
concentrated to dryness under vacuum. The residue was dissolved in
DMSO (0.9 mL) and purified by preparative reverse-phase HPLC on a
Waters XBridge C18 19 mm × 100 mm, 0.005 mm column, eluting
with 60% H2O/CH3CN (0.03% NH4OH modifier) holding for 1 min,
then a linear gradient of 60% H2O/CH3CN to 40% H2O/CH3CN in
5.75 min, followed by a linear gradient of 40% H2O/CH3CN to 0%
H2O/CH3CN in 0.25 min and holding at 0% H2O/CH3CN for 1.0
min (flow rate 30 mL/min) to obtain the title compound (3.4 mg,
23%). Analytical LCMS: retention time 2.58 min (Waters Atlantis
dC18 4.6 mm × 50 mm, 0.005 mm column; 95% H2O/CH3CN linear
gradient to 5% H2O/CH3CN over 4.0 min and a hold at 5% H2O/
CH3CN for 1 min; 0.05% TFA modifier; flow rate 2.0 mL/min).
LCMS (ES+): 440.1 (M + 1).
1-Methylcyclopropyl 6-{5-Methoxy-6-[(2-methylpyridin-3-
yl)oxy]pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-
2-carboxylate (29i). To a stirred solution of tert-butyl 6-{5-methoxy-
6-[(2-methylpyridin-3-yl)oxy]pyrimidin-4-yl}-2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate 29j (20 mg, 0.045 mmol) in
CH2Cl2 (0.3 mL) was added TFA (0.1 mL). After being stirred at 23
°C for 3 h, the mixture was concentrated to dryness under vacuum.
The residue was dissolved in CH2Cl2 (0.5 mL) and Et3N (0.031 mL,
0.23 mmol) before 1-methylcyclopropyl 4-nitrophenylcarbonate (13
mg, 0.054 mmol) was added. The mixture was heated to 50 °C for 19
h. The reaction mixture was cooled to 23 °C, diluted with 1 N NaOH,
and extracted with CH2Cl2 (2×). The combined organic extracts were
pooled, dried over Na2SO4, filtered, and the filtrate was concentrated
to dryness under vacuum. The residue was dissolved in DMSO (0.9
mL) and purified by preparative reverse-phase HPLC on a Waters
XBridge C18 19 mm × 100 mm, 0.005 mm column, eluting with a
linear gradient of 85% H2O/CH3CN (0.03% NH4OH modifier) to 0%
H2O/CH3CN in 8.5 min and holding at 0% H2O/CH3CN for 1.5
min; flow rate 25 mL/min, to obtain the title compound (1.4 mg, 7%).
Analytical LCMS: retention time 2.43 min (Waters Atlantis C18 4.6
mm × 50 mm, 0.005 mm column; 95% H2O/CH3CN linear gradient
to 5% H2O/CH3CN over 4.0 min and a hold at 5% H2O/CH3CN for
1 min; 0.05% TFA modifier (flow rate 2.0 mL/min). LCMS (ES+):
452.2 (M + 1).
4-Chloro-5-methoxy-6-[(2-methylpyridin-3-yl)oxy]-
pyrimidine (27d). The title compound was prepared from 4,6-
dichloro-5-methoxypyrimidine (500 mg, 2.79 mmol) in a manner
similar to that used to prepare 4-chloro-5-methyl-6-((2-methylpyridin-
3-yl)oxy)pyrimidine. The title compound was obtained as a white solid
(607 mg, 87%). 1H NMR (500 MHz, CDCl3) δ 2.45 (s, 3H), 4.10 (s,
3H), 7.24−7.29 (m, 1 H), 7.44 (d, J = 8.05 Hz, 1 H), 8.23 (s, 1H),
8.48 (dd, J = 1.22, 4.64 Hz, 1H). LCMS (ES+): 252.1 (M + 1).
tert-Butyl 6-{5-Methoxy-6-[(2-methylpyridin-3-yl)oxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-car-
boxylate (29j). To a microwave vial charged with tert-butyl 2,6-
diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate (95 mg, 0.40 mmol)
5a, 4-chloro-5-methoxy-6-[(2-methylpyridin-3-yl)oxy]pyrimidine 27d
(100 mg, 0.40 mmol), and NaHCO3 (50 mg, 0.60 mmol) was added
N,N-dimethylacetamide (1.0 mL). The vial was capped, and the
resulting suspension was stirred at 120 °C for 15 h. The mixture was
cooled to 23 °C, diluted with H2O, and extracted with EtOAc (3 × 20
mL). The combined organic extracts were washed with 10% aqueous
LiCl, dried over Na2SO4, filtered, and the filtrate was dried under
vacuum. The residue was purified by silica gel chromatography, eluting
with an EtOAc/heptanes gradient. The title compound was obtained
tert-Butyl 6-[6-(4-Cyano-2-fluorophenoxy)-5-methylpyrimi-
din-4-yl)]-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate
(32b). Step 1: 4-(6-Chloro-5-methylpyrimidin-4-yloxy)-3-fluoroben-
zonitrile. To a stirred solution of 4,6-dichloro-5-methylpyrimidine
(3.92 g, 24.1 mmol) and 3-fluoro-4-hydroxybenzonitrile (3.0 g, 22.0
mmol) in CH3CN (75 mL) was added Cs2CO3 (9.27 g, 28.4 mmol).
The reaction mixture was heated at reflux under nitrogen for 18 h. The
reaction mixture was cooled to 23 °C, filtered, and the filtrate was
evaporated under reduced pressure. The residue was taken up in
EtOAc (200 mL) and H2O (100 mL), and the aqueous layer was
extracted with EtOAc (2 × 50 mL). The combined organic extracts
were washed with brine (50 mL), dried over Na2SO4, filtered, and the
filtrate was evaporated to a cream-colored solid. This material was
purified by silica chromatography (120 g silica, 25% EtOAc/heptanes
as eluent, using a 25g silica precolumn) to give the title compound as a
1
white solid. H NMR (500 MHz, CDCl3) δ 2.47 (s, 3H), 7.39 (t, J =
8.0 Hz, 1H), 7.53−7.58 (m, 1H), 8.37 (s, 1H). LCMS (ES+): 305.1
(M + 1 + formic acid).
Step 2. A microwave vial was charged with tert-butyl 2,6-
diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate 5a (125 mg, 0.52
mmol), 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-3-fluorobenzonitrile
(138 mg, 0.52 mmol), NaHCO3 (66.0 mg, 0.786 mmol), and dry
N,N-dimethylformamide (2.5 mL). The vial was sealed and heated at
120 °C for 18 h. The mixture was cooled to 23 °C and diluted with
EtOAc (50 mL) and H2O (50 mL). The aqueous layer was separated
and extracted with EtOAc (2 × 20 mL). The combined organic
extracts were washed with brine, dried over Na2SO4, filtered, and the
filtrate was concentrated under reduced pressure. The residue was
purified by silica chromatography (12 g silica, eluting with 25%
EtOAc/heptanes). The product fractions were combined and
evaporated to a white solid (126.7 mg, 51.9%). 1H NMR (400
MHz, CDCl3) δ 1.47 (s, 9H), 1.84−1.90 (m, 4H), 2.00−2.04 (m, 4H),
2.18 (s, 3H), 4.26 (br s, 2H), 4.43 (br s, 1H), 4.56 (br s, 1H), 7.32 (t, J
= 8.4 Hz, 1H), 7.45−7.50 (m, 2H), 8.17 (s, 1H). LCMS (ES+): 466.2
(M + 1).
1
as an off-white solid (90 mg, 51%). H NMR (500 MHz, CDCl3) δ
1.50 (s, 9H), 1.85−2.10 (m, 8 H), 2.52 (s, 3H), 3.87 (s, 3H), 4.36−
4.48 (m, 1H), 4.51−4.63 (m, 1H), 5.01 (br s, 2H), 7.23−7.30 (m,
1H), 7.43−7.51 (m, 1H), 8.02 (s, 1H), 8.41 (d, J = 4.88 Hz, 1 H).
LCMS (ES+): 454.2 (M + 1). Product Rf = 0.17 in 75% EtOAc/
heptanes.
Isopropyl 6-{5-Methoxy-6-[(2-methylpyridin-3-yl)oxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-car-
boxylate (29h). To a stirred solution of tert-butyl 6-{5-methoxy-6-
[(2-methylpyridin-3-yl)oxy]pyrimidin-4-yl}-2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate 29j (21 mg, 0.047 mmol) in
CH2Cl2 (0.3 mL) was added TFA (0.1 mL). After being stirred at 23
°C for 3 h, the mixture was concentrated to dryness under vacuum.
The residue was dissolved in CH2Cl2 (0.5 mL) and Et3N (0.040 mL,
0.24 mmol) before isopropyl chloroformate (1 M in toluene, 0.056
mL, 0.056 mmol) was added. After 2 h, the reaction mixture was
cooled to 23 °C, diluted with 1 N NaOH, and extracted with CH2Cl2
(2×). The combined organic extracts were pooled, dried over Na2SO4,
filtered, and the filtrate was concentrated to dryness under vacuum.
The residue was purified using silica gel chromatography, eluting with
EtOAc/heptanes. The title compound was isolated as a white solid (10
Isopropyl 6-[6-(4-Cyano-2-fluorophenoxy)-5-methylpyrimi-
din-4-yl]-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate
(32a). To a stirred solution of 4-[6-(2,6-diazatricyclo[3.3.1.1∼3,7∼]-
dec-2-yl)-5-methylpyrimidin-4-yloxy]-3-fluorobenzonitrile·HCl (pre-
pared from Boc cleavage of 32b) (40 mg, 0.10 mmol) in dry
CH2Cl2 (1.0 mL) and diisopropylethylamine (51.7 mg, 0.40 mmol)
N
dx.doi.org/10.1021/jm301626p | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Article
was added isopropyl chloroformate (1 M in toluene, 0.12 mL, 0.12
mmol) at 23 °C. The reaction vessel was sealed, and the mixture was
stirred for 2.5 h. The reaction mixture was diluted with CH2Cl2 and
H2O and shaken. The organic layer was separated and filtered through
an Alltech filter, and the filtrate was concentrated under reduced
pressure. The residue was purified by preparative reverse-phase HPLC
on a Waters Sunfire C18 column (19 mm × 100 mm, 5 μm particle
size), eluting with a gradient of H2O/CH3CN (0.05% TFA modifier)
to afford the title compound (10.9 mg, 24%). Analytical LCMS:
retention time 3.72 min (Atlantis C18 4.6 mm × 50 mm, 5 μm particle
size; 95% H2O/CH3CN linear gradient to 5% H2O/CH3CN for 4.0
min with a hold at 5% H2O/CH3CN to 5.0 min; 0.05% TFA modifier;
flow rate 2.0 mL/min). LCMS (ES+): 452.1 (M + 1).
mL/min) to give the title compound (9.2 mg). Analytical LCMS:
retention time 2.83 min (Waters XBridge C18 4.6 mm × 50 mm, 0.005
mm column; 95% H2O/CH3CN linear gradient to 5% H2O/CH3CN
over 4.0 min and a hold at 5% H2O/CH3CN for 1 min; 0.03%
NH4OH modifier; flow rate 2.0 mL/min). LCMS (ES+): 490.2 (M +
1).
Isopropyl 6-[5-Methyl-6-(4-[1,2,3]triazol-1-ylphenoxy)-
pyrimidin-4-yl]-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-car-
boxylate (32c). A sealed 8 dram tube charged with 4-chloro-5-
methyl-6-(4-[1,2,3]triazol-1-yl-phenoxy)pyrimidine (29.6 mg, 0.10
mmol), isopropyl 2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate
(23 mg, 0.1 mmol), NaHCO3 (13 mg, 0.16 mmol), and dry N,N-
dimethylformamide (0.5 mL) was heated at 120 °C for 18 h. The
mixture was cooled to 23 °C and diluted with EtOAc (20 mL) and
H2O (20 mL). The layers were separated, and the aqueous layer was
extracted with EtOAc (10 mL). The combined organic extracts were
washed with brine (5 mL), dried over Na2SO4, filtered, and the filtrate
was evaporated to a yellow solid (53 mg). This solid was purified by
preparative reverse-phase HPLC on a Waters Sunfire C18 column (19
mm × 100 mm, 5 μm particle size), eluting with a gradient of H2O/
CH3CN (0.05% TFA modifier) to give the title compound (19.8 mg,
41%). Analytical LCMS: retention time 3.28 min (Atlantis C18 4.6 mm
× 50 mm, 5 μm particle size; 95% H2O/CH3CN linear gradient to 5%
H2O/CH3CN for 4.0 min with a hold at 5% H2O/CH3CN to 5.0 min;
0.05% TFA modifier (flow rate 2.0 mL/min). LCMS (ES+): 476.1 (M
+ 1).
tert-Butyl 6-{5-Methyl-6-[4-(1H-tetrazol-1-yl)phenoxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-car-
boxylate (32f). Step 1: 4-Chloro-5-methyl-6-[4-(1H-tetrazol-1-
yl)phenoxy]pyrimidine. A mixture of 4-(1H-tetrazol-1-yl)phenol
(4.80 g, 30 mmol), 4,6-dichloro-5-methylpyrimidine (5.71 g, 33
mmol), and potassium carbonate (8.50 g, 62 mmol) in N,N-
dimethylformamide (60 mL) was stirred at 23 °C for 18 h. The
mixture was then diluted with EtOAc (500 mL), washed with brine (2
× 100 mL), dried over Na2SO4, and filtered. While the filtrate was
concentrated under vacuum, a solid began to precipitate. The solid was
triturated with petroleum ether and was filtered. The filter cake was
washed with 10% EtOAc/petroleum ether, and the collected solid was
further dried under vacuum to afford the title compound as a brown
solid (5 g, 59%). 1H NMR (400 MHz, CDCl3) δ 2.46 (s, 3H), 7.39 (d,
J = 8.8 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 8.39 (s, 1H), 9.00 (s, 1H).
GCMS: m/z 288.8.
tert-Butyl 6-{5-Methyl-6-[4-(3-methyl-4H-1,2,4-triazol-4-yl)-
phenoxy]pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]-
decane-2-carboxylate (32m). Step1: 4-Chloro-5-methyl-6-[4-(3-
methyl-4H-1,2,4-triazol-4-yl)phenoxy]pyrimidine. The title com-
pound was prepared from 4-(3-methyl-4H-1,2,4-triazol-4-yl)phenol
(234 mg, 1.34 mmol) in a manner similar to that used to prepare 4-
chloro-5-methyl-6-[4-(4H-1,2,4-triazol-4-yl)phenoxy]pyrimidine (step
1 of 32g preparation). Heating was carried out at 100 °C for 1 h. The
1
title compound was obtained as a white solid (360 mg, 90%). H
NMR (500 MHz, CD3OD) δ 2.46 (s, 3H), 2.54 (s, 3H), 7.44−7.50
(m, 2H), 7.60−7.66 (m, 2H), 8.35 (s, 1H), 8.90 (s, 1H). LCMS (ES
+): 302.0 (M + 1). TLC: Rf = 0.27 in 5% MeOH/CH2Cl2.
Step 2. A mixture of 4-chloro-5-methyl-6-[4-(3-methyl-4H-1,2,4-
triazol-4-yl)phenoxy]pyrimidine (100 mg, 0.33 mmol), tert-butyl 2,6-
diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate 5a (79 mg, 0.33
mmol), and N,N-diisopropylethylamine (0.115 mL, 0.66 mmol) in
CH3CN (0.33 mL) was heated at 100 °C for 24 h in a sealed tube. The
reaction mixture was cooled to 23 °C, diluted with H2O and brine, and
extracted with EtOAc (3 × 20 mL). The combined organic extracts
were washed with brine, dried over Na2SO4, filtered, and the filtrate
was concentrated under reduced pressure. A portion of the orange
residue was dissolved in DMSO (0.9 mL) and purified by preparative
reverse-phase HPLC on a Waters XBridge C18 19 mm × 100 mm,
0.005 mm column, eluting with a linear gradient of 85% H2O/CH3CN
(0.03% NH4OH modifier) to 0% H2O/CH3CN in 8.5 min and
holding at 0% H2O/CH3CN for 1.5 min (flow rate, 25 mL/min) to
give the title compound (6.0 mg). Analytical LCMS: retention time
2.85 min (Waters XBridge C18 4.6 mm × 50 mm, 0.005 mm column;
95% H2O/CH3CN linear gradient to 5% H2O/CH3CN over 4.0 min
and a hold at 5% H2O/CH3CN for 1 min; 0.03% NH4OH modifier;
flow rate 2.0 mL/min). LCMS (ES+): 504.2 (M + 1). TLC Rf = 0.16
in 10% MeOH/CH2Cl2.
Step 2. A microwave vial was charged with tert-butyl 2,6-
diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate 5a (41 mg, 0.17
mmol), 4-chloro-5-methyl-6-[4-(1H-tetrazol-1-yl)phenoxy]pyrimidine
(50 mg, 0.17 mmol), NaHCO3 (22 mg, 0.26 mmol), and N,N-
dimethylformamide (0.43 mL), capped, and heated at 90 °C for 16 h.
After cooling to 23 °C, the reaction mixture was diluted with H2O (25
mL) and a 10% aqueous LiCl (5 mL) and extracted with EtOAc (2 ×
20 mL). The combined organic extracts were washed with 10%
aqueous LiCl (15 mL), dried over Na2SO4, filtered, and the filtrate was
concentrated to dryness under vacuum. The residue was purified by
silica gel chromatography, eluting with an EtOAc/CH2Cl2 gradient.
The title compound was isolated as an off-white solid (18 mg, 21%).
1H NMR (500 MHz, CDCl3) δ 1.51 (s, 9H), 1.84−1.99 (m, 4H),
tert-Butyl 6-{5-Methyl-6-[4-(4H-1,2,4-triazol-4-yl)phenoxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-car-
boxylate (32g). Step 1: 4-Chloro-5-methyl-6-[4-(4H-1,2,4-triazol-4-
yl)phenoxy]pyrimidine. To a mixture of 4,6-dichloromethylpyrimidine
(212 mg, 1.30 mmol) and 4-(4H-1,2,4-triazol-4-yl)phenol (200 mg,
1.24 mmol) in CH3CN (5 mL) in a 2−5 mL microwave vial was added
Cs2CO3 (526 mg, 1.61 mmol). The vial was sealed and heated at 80
°C for 2 h. The reaction mixture was cooled to 23 °C and adsorbed
onto 2 g of silica gel. This silica was place on top of a silica gel column
and eluted with a MeOH/CH2Cl2 gradient to give the title compound
1
as a white solid (316 mg, 89%). H NMR (500 MHz, CDCl3) δ 2.47
2.01−2.13 (m, 4H), 2.22 (s, 3H), 4.32 (br s, 2H), 4.42−4.52 (m, 1H),
4.55−4.66 (m, 1H), 7.33−7.39 (m, 2H), 7.71−7.78 (m, 2H), 8.29 (s,
1H), 8.97 (s, 1H). LCMS (ES+): 491.2 (M + 1). Product Rf = 0.16 in
30% EtOAc/CH2Cl2.
(s, 3H), 7.34−7.41 (m, 2H), 7.55 (d, J = 7.32 Hz, 2H), 8.40 (s, 1H),
8.71 (br s, 2H). LCMS (ES+): 288.2 (M + 1). TLC: Rf = 0.22 in 5%
MeOH/CH2Cl2.
Step 2. The title compound was prepared using 4-chloro-5-methyl-
6-[4-(4H-1,2,4-triazol-4-yl)phenoxy]pyrimidine (100 mg, 0.35 mmol)
in a manner similar to that used to prepare tert-butyl 6-{5-methyl-6-[4-
(3-methyl-4H-1,2,4-triazol-4-yl)phenoxy]pyrimidin-4-yl}-2,6-
diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate 32m (step 2 of 32 m
preparation). This mixture was heated for 64 h instead of 24 h. A small
portion of the crude product was dissolved in DMSO (0.9 mL) and
purified by preparative reverse-phase HPLC on a Waters XBridge C18
19 mm × 100 mm, 0.005 mm column, eluting with a linear gradient of
85% H2O/CH3CN (0.03% NH4OH modifier) to 0% H2O/CH3CN in
8.5 min and holding at 0% H2O/CH3CN for 1.5 min (flow rate, 25
Isopropyl 6-{5-Methyl-6-[4-(1H-tetrazol-1-yl)phenoxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-car-
boxylate (32d). The title compound was prepared from tert-butyl 6-
{5-methyl-6-[4-(1H-tetrazol-1-yl)phenoxy]pyrimidin-4-yl}-2,6-
diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate 32f (15 mg, 0.031
mmol) in a manner similar to that used to prepare isopropyl 6-{5-
methoxy-6-[(2-methylpyridin-3-yl)oxy]pyrimidin-4-yl}-2,6-
diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate 29h. The residue was
dissolved in DMSO (0.9 mL) and purified by preparative reverse-
phase HPLC on a Waters XBridge C18 19 mm × 100 mm, 0.005 mm
column, eluting with a linear gradient of 60% H2O/CH3CN (0.03%
O
dx.doi.org/10.1021/jm301626p | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Article
NH4OH modifier) to 40% H2O/CH3CN in 10.5 min, linear to 0%
H2O/CH3CN for 0.5 min, and a hold at 0% H2O/CH3CN for 1.0 min
(flow rate 25 mL/min) to give the title compound (5.0 mg, 33%).
Analytical LCMS: retention time 3.25 min (Waters Atlantis dC18 4.6
mm × 50 mm, 0.005 mm column; 95% H2O/CH3CN linear gradient
to 5% H2O/CH3CN over 4.0 min and a hold at 5% H2O/CH3CN for
1 min; 0.05% TFA modifier; flow rate 2.0 mL/min). LCMS (ES+):
477.2 (M + 1).
TFA modifier) to 30% H2O/CH3CN in 10.5 min, linear to 0% H2O/
CH3CN in 0.5 min, and holding at 0% H2O/CH3CN for 1 min (flow
rate 25 mL/min) to give the title compound as the free base (10 mg,
59%). Analytical LCMS: retention time 3.36 min (Waters Atlantis
dC18 4.6 mm × 50 mm, 0.005 mm column; 95% H2O/CH3CN linear
gradient to 5% H2O/CH3CN over 4.0 min and held at 5% H2O/
CH3CN for 1.0 min; 0.05% TFA modifier (flow rate 2.0 mL/min).
LCMS (ES+): 495.2 (M + 1).
1-Methylcyclopropyl 6-{5-Methyl-6-[4-(1H-tetrazol-1-yl)-
phenoxy]pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]-
decane-2-carboxylate (32e). The title compound was prepared
from tert-butyl 6-{5-methyl-6-[4-(1H-tetrazol-1-yl)phenoxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate
32f (14 mg, 0.029 mmol) in a manner similar to that used to prepare
1-methylcyclopropyl 6-{5-methoxy-6-[(2-methylpyridin-3-yl)oxy]-
pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate
29i. The residue was dissolved in DMSO (0.9 mL) and purified by
preparative reverse-phase HPLC on a Waters XBridge C18 19 mm ×
100 mm, 0.005 mm column, eluting with a linear gradient of 85%
H2O/CH3CN (0.03% NH4OH modifier) to 0% H2O/CH3CN in 8.5
min and holding at 0% H2O/CH3CN for 1.5 min (flow rate 25 mL/
min) to give the title compound (5.3 mg, 37%). Analytical LCMS:
retention time 3.23 min (Waters Atlantis dC18 4.6 mm × 50 mm,
0.005 mm column; 95% H2O/CH3CN linear gradient to 5% H2O/
CH3CN over 4.0 min and a hold at 5% H2O/CH3CN for 1 min;
0.05% TFA modifier (flow rate 2.0 mL/min). LCMS (ES+): 489.2 (M
+ 1).
1-Methylcyclopropyl 6-{6-[2-Fluoro-4-(1H-tetrazol-1-yl)-
phenoxy]-5-methylpyrimidin-4-yl}-2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate (32i). Step 1: 4-(6-Chloro-5-
methylpyrimidin-4-yloxy)-3-fluoroaniline. To a stirred mixture of
4,6-dichloro-5-methylpyrimidine (24.3 g, 149 mmol) and Cs2CO3
(48.7 g, 149 mmol) in CH3CN (299 mL) was added 4-amino-2-
fluorophenol (19.0 g, 149 mmol) at 23 °C. The mixture was allowed
to stir at 23 °C for 4 h. The mixture was then filtered through Celite,
rinsing the filter cake with EtOAc. The filtrate was concentrated to
dryness and adsorbed onto silica. The charged silica was place on top
of a 330 g silica gel column and purified by chromatography using an
isocratic elution with 30% EtOAc/heptanes to give 19 g (50%) of the
title compound as a tan solid. 1H NMR (500 MHz, CDCl3) δ 2.40 (s,
3H), 3.80 (br s, 2H), 6.49 (dd, J = 11.7 Hz, 21.5 1H), 6.97 (t, J = 17.6
Hz, 1H), 8.38 (s, 1H). LCMS (ES+): 254.0 (M + 1). TLC: Rf = 0.30
in 30% EtOAc/heptanes.
Step 2: 1-Methylcyclopropyl 6-(6-{4-[Amino]-2-fluorophenoxy}-5-
methylpyrimidin-4-yl)-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-car-
boxylate. A 250 mL flask was charged with 4-(6-chloro-5-
methylpyrimidin-4-yloxy)-3-fluoroaniline (17.8 g, 82.5 mmol), 1-
methylcyclopropyl-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxy-
late (19.5 g, 82.5 mmol), NaHCO3 (17.9 g, 211 mmol), and DMSO
(82.6 mL). The reaction mixture was equipped with a reflux condenser
and heated at 160 °C for 18 h. The reaction mixture was cooled to 23
°C, and H2O was added. A tan solid precipitated from the solution.
This solid was filtered and dried. The solid material was adsorbed onto
silica gel with the aid of CH2Cl2. The charged silica was loaded on top
of a silica gel column and was purified by chromatography using 50%
EtOAc/CH2Cl2 to give the title compound as an off-white solid (23 g,
tert-Butyl 6-{6-[2-Fluoro-4-(1H-tetrazol-1-yl)phenoxy]-5-
methylpyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-
2-carboxylate (32j). Step 1: 4-Chloro-5-methyl-6-[2-fluoro-4-(1H-
tetrazol-1-yl)phenoxy]pyrimidine. A mixture of 2-fluoro-4-(1H-
tetrazol-1-yl)phenol (1.00 g, 5.6 mmol), 4,6-dichloro-5-methylpyr-
imidine (1.09 g, 6.7 mmol), and K2CO3 (1.20 g, 8.4 mmol) in N,N-
dimethylformamide (15 mL) was stirred at 70 °C for 3 h. The mixture
was then diluted with EtOAc, washed with H2O and brine, dried over
Na2SO4, filtered, and the filtrate was concentrated to dryness under
vacuum. The residue was purified by silica gel chromatography, eluting
with EtOAc/petroleum ether. The title compound was obtained as a
1
72%). H NMR (500 MHz, DMSO-d6) δ 0.58−0.65 (m, 2H), 0.76−
1
white solid (1.00 g, 59%). H NMR (400 MHz, CDCl3) δ 2.49 (s,
0.83 (m, 2H), 1.50 (s, 3H), 1.67−1.82 (m, 4H), 1.89−2.02 (m, 4H),
2.11 (s, 3H), 4.18 (br s, 2H), 4.25 (br s, 1H), 4.37 (br s, 1H), 5.27 (s,
2H), 6.35 (dd, J = 2.44, 8.54 Hz, 1H), 6.42 (dd, J = 2.56 Hz, 13.05,
1H), 6.87 (t, J = 8.90 Hz, 1H), 8.12 (s, 1H). LCMS (ES+): 454.3 (M
+ 1). TLC: Rf = 0.21 in 60% EtOAc/heptanes.
3H), 7.62 (m, 1H), 7.83 (m, 1H), 7.96 (m, 1H), 8.36 (s, 1H), 9.82 (s,
1H). GCMS: m/z 306.8.
Step 2. A mixture of tert-butyl 2,6-diazatricyclo[3.3.1.1∼3,7∼]-
decane-2-carboxylate (78 mg, 0.33 mmol), 4-chloro-5-methyl-6-[2-
fluoro-4-(1H-tetrazol-1-yl)phenoxy]pyrimidine (100 mg, 0.33 mmol),
and NaHCO3 (41 mg, 0.49 mmol) was suspended in N,N-
dimethylformamide (0.82 mL) in a microwave vial. The vial was
capped and heated at 60 °C for 14 h. The temperature was increased
to 70 °C, and the mixture was heated an additional 26 h. The mixture
was cooled to 23 °C, diluted with H2O and 10% aqueous LiCl, and
extracted with EtOAc (2 × 20 mL). The organic extracts were
combined, washed with 10% aqueous LiCl (15 mL), dried over
Na2SO4, filtered, and the filtrate was concentrated to dryness under
vacuum. The residue was purified by silica gel chromatography, eluting
with an EtOAc/heptanes gradient. The title compound was isolated as
Step 3. A mixture of 1-methylcyclopropyl 6-[6-(4-amino-2-
fluorophenoxy)-5-methylpyrimidin-4-yl]-2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate (23.0 g, 50.7 mmol), NaN3 (3.64
g, 55.8 mmol), triethyl orthoformate (25.8 mL, 152 mmol), and acetic
acid (23.3 mL, 406 mmol) was heated at 80 °C. After 2 h, the
suspension became a yellow solution before transitioning to a very
thick slurry, which was loosened with the addition of acetic acid (20
mL). The mixture was heated at 80 °C for an additional 2 h. After
cooling to 23 °C, the mixture was diluted with H2O and was extracted
with EtOAc (200 mL). The aqueous layer was extracted again with
EtOAc (2 × 100 mL), and the combined organic extracts were washed
with brine, dried over Na2SO4, filtered, and the filtrate was
concentrated to dryness under vacuum. The crude residue was
purified by silica gel chromatography using 40% EtOAc/CH2Cl2 as the
1
a white solid (36 mg, 22%). H NMR (500 MHz, CDCl3) δ 1.51 (s,
9H), 1.84−1.98 (m, 4H), 2.00−2.13 (m, 4H), 2.24 (s, 3H), 4.31 (br s,
2H), 4.46 (br s, 1H), 4.60 (br s, 1H), 7.46 (d, J = 8.05 Hz, 1H), 7.52−
7.58 (m, 1H), 7.64 (dd, J = 2.56, 9.88 Hz, 1H), 8.23 (s, 1H), 8.99 (s,
1H). LCMS (ES+): 509.2 (M + 1).
1
eluent to give 19 g (75%) of the title compound as a white solid. H
NMR (500 MHz, CDCl3) δ 0.63−0.70 (m, 2H), 0.87−0.94 (m, 2H),
1.59 (s, 3H), 1.80−1.98 (m, 4H), 2.00−2.13 (m, 4H), 2.23 (s, 3H),
4.29 (br s, 2H), 4.42 (br s, 1H), 4.62 (br s, 1H), 7.42−7.48 (m, 1H),
7.52−7.58 (m, 1H), 7.63 (dd, J = 2.44, 9.76 Hz, 1H), 8.22 (s, 1H),
8.99 (s, 1H). LCMS (ES+): 507.3 (M + 1). TLC Rf = 0.70 in EtOAc/
CH2Cl2.
tert-Butyl 6-{6-[2-Fluoro-4-(4H-1,2,4-triazol-4-yl)phenoxy]-5-
methylpyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-
2-carboxylate (32l). The title compound was prepared using 4-
chloro-5-methyl-6-[2-fluoro-4-(4H-1,2,4-triazol-4-yl)phenoxy]-
pyrimidine (88 mg, 0.29 mmol) in a manner similar to that used to
prepare tert-butyl 6-{5-methyl-6-[4-(3-methyl-4H-1,2,4-triazol-4-yl)-
Isopropyl 6-{6-[2-Fluoro-4-(1H-tetrazol-1-yl)phenoxy]-5-
methylpyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-
2-carboxylate (32h). The title compound was prepared from tert-
butyl 6-{5-methyl-6-[2-fluoro-4-(1H-tetrazol-1-yl)phenoxy]pyrimidin-
4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate 32j (18 mg,
0.035 mmol) in a manner similar to that used to prepare isopropyl 6-
{5-ethyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidin-4-yl}-2,6-
diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate 29c. The residue was
dissolved in DMSO (0.9 mL) and purified by preparative reverse-
phase HPLC on a Waters Sunfire C18 19 mm × 100 mm, 0.005 mm
column, eluting with a linear gradient of 70% H2O/CH3CN (0.05%
P
dx.doi.org/10.1021/jm301626p | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Article
phenoxy]pyrimidin-4-yl}-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-2-car-
boxylate 32g. This mixture was heated for 64 h instead of 24 h. A small
portion of this residue was dissolved in DMSO (0.9 mL) and purified
by preparative reverse-phase HPLC on a Waters XBridge C18 19 mm
× 100 mm, 0.005 mm column, eluting with a linear gradient of 85%
H2O/CH3CN (0.03% NH4OH modifier) to 0% H2O/CH3CN in 8.5
min and holding at 0% H2O/CH3CN for 1.5 min (flow rate 25 mL/
min) to give the title compound (10 mg). Analytical LCMS: retention
time 2.93 min (Waters XBridge C18 4.6 mm × 50 mm, 0.005 mm
column; 95% H2O/CH3CN linear gradient to 5% H2O/CH3CN over
4.0 min and a hold at 5% H2O/CH3CN for 1 min; 0.03% NH4OH
modifier; flow rate 2.0 mL/min). LCMS (ES+): 508.1 (M + 1).
tert-Butyl 6-{6-[2-Fluoro-4-(3-methyl-4H-1,2,4-triazol-4-yl)-
phenoxy]-5-methylpyrimidin-4-yl}-2,6-diazatricyclo-
[3.3.1.1∼3,7∼]decane-2-carboxylate (32n). The title compound
was prepared using 4-chloro-5-methyl-6-[2-fluoro-4-(3-methyl-4H-
1,2,4-triazol-4-yl)phenoxy]pyrimidine (74 mg, 0.31 mmol) in a
manner similar to that used to prepare tert-butyl 6-{5-methyl-6-[4-
(3-methyl-4H-1,2,4-triazol-4-yl)phenoxy]pyrimidin-4-yl}-2,6-
diazatricyclo[3.3.1.1∼3,7∼]decane-2-carboxylate 32m. A small portion
of this residue was dissolved in DMSO (0.9 mL) and purified by
preparative reverse- phase HPLC on a Waters XBridge C18 19 mm ×
100 mm, 0.005 mm column, eluting with a linear gradient of 85%
H2O/CH3CN (0.03% NH4OH modifier) to 0% H2O/CH3CN in 8.5
min and holding at 0% H2O/CH3CN for 1.5 min (flow rate, 25 mL/
min) to give the title compound (6.3 mg). Analytical LCMS: retention
time 2.93 min (Waters XBridge C18 4.6 mm × 50 mm, 0.005 mm
column; 95% H2O/CH3CN linear gradient to 5% H2O/CH3CN over
4.0 min and a hold at 5% H2O/CH3CN for 1 min; 0.03% NH4OH
modifier; flow rate 2.0 mL/min). LCMS (ES+): 522.2 (M + 1).
Isopropyl 6-[6-(4-Dimethylcarbamoyl-2-fluorophenoxy)-5-
methylpyrimidin-4-yl]-2,6-diazatricyclo[3.3.1.1∼3,7∼]decane-
2-carboxylate (32k). Step 1: 4-(6-Chloro-5-methylpyrimidin-4-yl
oxy)-3-fluoro-N,N-dimethylbenzamide. To a solution of 4,6-dichloro-
5-methylpyrimidine (202 mg, 1.24 mmol) and 3-fluoro4-hydroxy-N,N-
dimethylbenzamide (205 mg, 1.12 mmol) in CH3CN (5.0 mL) was
added Cs2CO3 (476 mg, 1.46 mmol). The reaction mixture was heated
at reflux under nitrogen for 18 h. The mixture was cooled to 23 °C and
diluted with H2O (30 mL) and EtOAc (40 mL). The aqueous layer
was separated and extracted once with EtOAc (20 mL). The combined
organic extracts were washed with brine (5 mL), dried over Na2SO4,
filtered, and the filtrate was evaporated. The residue was purified by
silica gel chromatography (12 g silica, 30% EtOAc/heptanes linear
gradient to 70% EtOAc/heptanes). The product fractions were
combined, evaporated, and dried under high vacuum to give the title
compound as an off-white solid (150.8 mg, 43%). 1H NMR (400
MHz, CDCl3) δ 2.46 (s, 3H), 3.07 (s, 3H), 3.17 (s, 3H), 7.25−7.33
(m, 4H). LCMS (ES+): 310.2 (M + 1).
ASSOCIATED CONTENT
* Supporting Information
X-ray experimental conditions for the structure determination
of 25b and the results. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*Phone: +1-617-551-3516. Fax: +1-617-551-3082. E-mail: kim.
f.mcclure@pfizer.com.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Brian Samas for the X-ray structure
determination of 25b.
ABBREVIATIONS USED
■
GPR119, G-protein-coupled receptor 119; GLP-1, glucagon-
like peptide 1; DPPIV, dipetidyl dipeptidase IV; FPG, fasting
plasma glucose; HbA1c, hemoglobin A1c; GPCR, G-protein-
coupled receptor; cAMP, 3′,5′-cyclic adenosine monophos-
phate; IA, intrinsic activity; OEA, oleoylethanolamide; LLE,
ligand lipophilic efficiency; LE, ligand efficiency; AgLLE,
agonist ligand lipophilic efficiency; Cmax, maximum plasma
concentration; AUC, area under the curve; iv, intravenous; po,
per os; UPLC, ultrahigh pressure liquid chromatography; mpk,
milligram per kilogram; F, bioavailability; SDD, spray dried
dispersion; HPMCAS-HF, hydroxypropylmethylcellulose ac-
etate succinate high fine; MC, methylcellulose; DMA,
dimethylacetamide; PEG200, polyethylene glycol 200
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