Synthesis and biological activity of imidazopyridine anticoccidial agents: Part I

Article abstract of DOI:10.1016/j.ejmech.2007.02.006

Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance

Full text of DOI:10.1016/j.ejmech.2007.02.006

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 42 (2007) 1334e1357
http://www.elsevier.com/locate/ejmech
Original article
Synthesis and biological activity of imidazopyridine
anticoccidial agents: Part I
a
a
a
a
Andrew Scribner a, , Richard Dennis , Jean Hong , Shuliang Lee , Donald McIntyre ,
David Perrey a, Dennis Feng b, Michael Fisher b, Matthew Wyvratt b, Penny Leavitt b,
Paul Liberator c, Anne Gurnett c, Chris Brown c, John Mathew c,
*
Donald Thompson c, Dennis Schmatz c, Tesfaye Biftu b
a SCYNEXIS, Inc., Discovery Chemistry, P.O. Box 12878, Research Triangle Park, NC 27709-2878, United States
b Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, United States
c Department of Human and Animal Infectious Disease Research, Merck Research Laboratories, Merck & Co., Inc.,
Rahway, NJ 07065, United States
Received 29 November 2006; received in revised form 18 January 2007; accepted 12 February 2007
Available online 25 February 2007
Abstract
Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the
intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials
has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Antiparasitic activity is due to
inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we present the synthesis and biological activity of
imidazo[1,2-a]pyridine anticoccidial agents. From this series, several compounds showed subnanomolar in vitro activity and commercial levels
of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Coccidiosis; Antiparasitic; Antiprotozoal; Kinase; Imidazopyridine
1. Introduction
novel biochemical targets are needed. Genetic studies in Toxo-
plasma gondii, a protozoan parasite closely related to Eimeria,
demonstrate that cGMP-dependent protein kinase (PKG) is
essential for survival and represents a desirable therapeutic tar-
get [2]. It was reported recently that inhibition of a novel PKG,
isolated from these parasites, stops the parasite proliferation
by blocking parasite invasion [2,3]. High throughput screening
of known kinase inhibitors resulted in the discovery of imida-
zopyridine analogs as PKG inhibitors and broad spectrum
anticoccidial agents [4]. Herein, we report PKG inhibition,
synthesis, evaluation, optimization and in vivo anticoccidial
activities of such compounds with diversity introduced at the
imidazopyridine 2- and 3-positions. Future publications will
explore modifications introduced elsewhere on the imidazo-
pyridine scaffold.
Coccidiosis is a parasitic disease which is the major cause
of morbidity and mortality in the poultry industry. It is a dis-
ease of the avian intestinal lining due to invasion by protozoan
parasites of the genus Eimeria [1]. Some of the most signifi-
cant Eimeria species in poultry are Eimeria tenella, Eimeria
acervulina, Eimeria necartrix, Eimeria brunetti and Eimeria
maxima. Over 35 billion chickens are raised annually world-
wide, and all major poultry operations use anticoccidial agents
prophylactically. Resistance to current coccidiostats is becom-
ing widespread, and new broad spectrum drugs directed at
* Corresponding author. Tel.: þ1 919 544 8610; fax: þ1 919 544 8697.
E-mail address: andrew.scribner@scynexis.com (A. Scribner).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.02.006

A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
1335
2. Results and discussion
shown below in Scheme 3. Bromination of methyl 4-fluoro-
benzoylacetate with tetra-n-butylammonium tribromide gave
bromide 10, which was treated with (2-aminopyridin-4-yl)-
methanol to yield imidazopyridine 11 [7]. Esterification of
alcohol 11 with methanesulfonyl chloride and triethylamine
afforded methanesulfonate ester 12, which upon treatment
with dimethylamine and diisopropylethylamine produced ter-
tiary amine 13. The methyl ester of 13 was then converted to
the corresponding Weinreb amide (14) with N,O-dimethylhy-
droxylamine hydrochloride and isopropylmagnesium chloride
[15]. Treatment of Weinreb amide 14 with ethylmagnesium
bromide gave ethyl ketone 15 [15], which then reacted with
DMFDMA to yield enone 16 [16]. Subsequent treatment of
enone 16 with guanidine hydrochloride and sodium methoxide
yielded 2-amino-5-methylpyrimidine 17 [16].
5-Cyanopyrimidine (22) was synthesized in a similar fash-
ion, as shown in Scheme 4. Treatment of Weinreb amide 14
with methylmagnesium bromide gave methyl ketone 18 [15],
which reacted with bromine in acetic acid to give a-bromoke-
tone 19 [17]. Subsequent nucleophilic displacement with so-
dium cyanide afforded a-cyanoketone 20 [17]. Reaction of
ketone 20 with DMFDMA yielded enone 21 [16], which
upon treatment with guanidine hydrochloride and sodium
methoxide afforded 2-amino-5-cyanopyrimidine 22 [16].
Scheme 5 shows the synthesis of the 5-fluoropyrimidine
(25). Treatment of ketone 18 with DMFDMA gave enone 23
[16], which was fluorinated by N-fluorobenzenesulfonimide
to give 2-fluoroenone 24 [18]. Subsequent reaction with gua-
nidine hydrochloride and sodium methoxide afforded 2-
amino-5-fluoropyrimidine 25 [16].
2.1. Chemistry
Introduction of diversity on the amino group of the pyrim-
idine 2-position was accomplished as shown in Scheme 1.
First, 2-mercapto-4-methylpyrimidine hydrochloride was
refluxed with N,N-dimethylformamide dimethyl acetal
(DMFDMA) to give thiomethyl ether 1 [5]. Upon treatment
with lithium diisopropylamide (LDA), the anion of 1 reacted
with methyl 4-fluorobenzoate to yield 2, which exists as a mix-
ture of ketone and enol tautomers [6]. Subsequent bromination
with tetra-n-butylammonium tribromide gave a-bromoketone
3, which cyclized with (2-aminopyridin-4-yl)methanol to
give imidazopyridine 4 [7]. Treatment of alcohol 4 with meth-
anesulfonyl chloride and triethylamine afforded methanesulfo-
nate ester 5, which upon treatment with dimethylamine and
diisopropylethylamine gave benzylic dimethylamine 6. Treat-
ment of sulfide 6 with hydrogen peroxide, acetic acid, and
sodium tungsate dihydrate, followed by sulfur dioxide to
back-reduce any tertiary amine N-oxide [8], gave sulfone 7.
The desired 2-NHR-substituted pyrimidines (8aedd) were
ultimately prepared by heating sulfone 7 with an excess of
appropriate alkylamine, benzylamine, or arylamine [6].
Carbonyl- and sulfonyl-bearing substituents were also in-
stalled on the amino group at the pyrimidine 2-position as shown
in Scheme 2 below. Treatment of sulfone 7 with ammonia
afforded 2-aminopyrimidine 8ee [9], which was then treated
with appropriate acid chloride in pyridine to give amides 9aef
[10], or sulfonyl chloride in pyridine to give sulfonamides
9gei [11]. Alternatively, treatment of 2-aminopyrimidine 8ee
with formic acid and acetic anhydride gave formamide 9j
[12], while reaction of 8ee with t-butyl isocyanate and sodium
hydride gave urea 9k [13]. Likewise, treating 8ee with methyl
chloroformate and triethylamine yielded carbamate 9l [14].
In addition, functionality was introduced at the pyrimidine
5-position, including methyl (17), cyano (22), fluoro (25), and
bromo (26). The 5-methylpyrimidine (17) was synthesized as
Scheme 6 shows the synthesis of 5-bromopyrimidine 26 via
treatment of 2-aminopyrimidine 8ee with N-bromosuccini-
mide [19].
In addition, several modifications were made at the 2-aryl
ring. Substitutes for the 4-fluorophenyl ring included 3-
bromo-4-fluorophenyl (34a), 4-fluoro-3-methylphenyl (34b),
4-chlorophenyl (34c), 2,4-difluorophenyl (34d), and 2,4,6-tri-
fluorophenyl (43). Scheme 7 shows the synthesis of compounds
S
S
S
SH
N
N
N
N
N
N
S
a
b
c
d
N
N
Br
O
N
N
N
N
OH
O
HCl
1
F
F
F
2
3
4
e
R
N
HN
SO2
N
S
S
N
N
N
N
N
N
h
g
f
N
N
N
N
N
N
N
N
N
N
OSO2CH3
N
F
F
F
F
8a-dd
7
6
5
Scheme 1. Reagents: (a) DMFDMA; (b) LDA, methyl 4-fluorobenzoate; (c) n-Bu4NBr3; (d) (2-aminopyridin-4-yl)methanol; (e) CH3SO2Cl, Et3N; (f) HNMe2,
i-Pr2NEt; (g) (i) 30% H2O2, AcOH, Na2WO4-2H2O; (ii) SO2; (h) H2NR where R is defined in Table 1.

1336
A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
R
N
NH2
HN
N
N
N
a
c
b
e
N
N
N
N
7
N
N
F
F
8ee
9a-i
d
O
N
O
N
O
N
HN
H
HN
N
H
HN
O
N
N
N
N
N
N
N
N
N
N
N
N
F
F
F
9j
9k
9l
Scheme 2. Reagents: (a) NH3; (b) RC(]O)Cl or RSO2Cl, pyridine where R is defined in Table 2; (c) HCO2H, Ac2O; (d) (CH3)3CN]C]O, NaH; (e) ClCO2CH3,
Et3N.
34aed. Esterification of both 3-bromo-4-fluorobenzoic acid
and 4-fluoro-3-methylbenzoic acid with methanol and catalytic
sulfuric acid gave the corresponding methyl esters 27a and
27b. Subsequent treatment of these two esters, along with the
commercially available esters methyl 4-chlorobenzoate and
ethyl 2,4-difluorobenzoate, with the anion of 4-methyl-2-
(methylmercapto)pyrimidine (1) gave 28aed, which also exist
as ketone/enol mixtures [6]. This was followed by bromination
with tetra-n-butylammonium tribromide to give bromides
29aed, which were then cyclized with (2-aminopyridin-4-yl)-
methanol to give imidazopyridines 30aed [7]. Subsequent
oxidation with OXONEÒ gave sulfones 31aed, which were
O
O
O
Br
a
b
N
N
O
O
O
OH
O
O
F
F
F
10
11
c
O
O
O
O
e
d
N
N
N
N
N
N
O
O
N
N
OSO2CH3
N
F
F
F
14
12
13
f
NH2
N
O
O
N
g
h
N
N
N
N
N
N
N
N
N
N
CH3
F
F
F
15
16
17
Scheme 3. Reagents: (a) n-Bu4NBr3; (b) (2-aminopyridin-4-yl)methanol; (c) CH3SO2Cl, Et3N; (d) HNMe2, i-Pr2NEt; (e) Me(MeO)NHeHCl, i-PrMgCl; (f)
CH3CH2MgBr; (g) DMFDMA; (h) guanidineeHCl, NaOMe.

A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
1337
O
O
a
b
Br
N
N
N
N
N
N
14
F
F
18
19
c
NH2
N
O
O
N
d
e
N
NC
N
N
N
N
N
N
N
N
CN
N
CN
F
F
F
22
21
20
Scheme 4. Reagents: (a) CH3MgBr; (b) Br2, HOAc; (c) NaCN; (d) DMFDMA; (e) guanidineeHCl, NaOMe.
then treated with ammonia to give 2-aminopyrimidines 32aed
[6]. Benzylic oxidation with manganese(IV) oxide yielded alde-
hydes 33aed, which was followed by reductive amination with
dimethylamine and sodium triacetoxyborohydride to ultimately
yield benzylic amines 34aed.
2.2. Biology
The title compounds were tested for in vitro efficacy using
the Ten_K (Tenella Kinase) assay, and in vivo efficacy in the
ExMAC (Expanded Mini-Assay Coccidiosis) assay. The
Ten_K assay measures inhibition of E. tenella PKG enzyme
activity, and is reported as the amount of compound required
to inhibit activity by 50% (IC50, in nM). The ExMAC assay
measures antiparasitic activity after administration of com-
pound to infected chickens (ppm in feed). Birds are infected
with E. tenella (Et), E. acervulina (Ea), Eimeria mitis (Emi),
and E. maxima (Ema), and efficacy is reported using a score
of 0 through 4 based on percent of oocyte reduction relative
to an untreated control. Treatments that provide 100% reduc-
tion of oocyte production are scored with a ‘4’, those with 80e
99% reduction are scored ‘3’, those with 50e79% reduction
are scored ‘2’, and those with <50% reduction are scored
‘0’. Details of these procedures were published in early
work [3]. In some cases, not all 4 species of Eimeria were
tested.
The 2-(2,4,6-trifluorophenyl)imidazopyridine (43) was pre-
pared by a slightly different pathway, in which the pyrimidine
ring was constructed after the 7-(dimethylaminomethyl)imida-
zopyridine scaffold was assembled, shown in Scheme 8. Ethyl
hydrogen malonate was treated with 2 equivalents n-BuLi, and
then with 2,4,6-tifluorobenzoyl chloride to yield 1,3-ketoester
35 [20]. Subsequent bromination with tetra-n-butylammonium
tribromide gave bromide 36, which was cyclized with (2-
aminopyridin-4-yl)methanol to yield imidazopyridine 37 [7].
Functionalization of the imidazopyridine 7-position then
occurred via esterification with methanesulfonyl chloride and
triethylamine to methanesulfonate ester 38 followed by treat-
ment with dimethylamine and diisopropylethylamine to give
tertiary amine 39. Ethyl ester 39 was then treated with N,O-di-
methylhydroxylamine hydrochloride and isopropylmagnesium
chloride to yield Weinreb amide 40, which was then converted
to methyl ketone 41 with methylmagnesium bromide [15].
Methyl ketone 41 then reacted with DMFDMA to give enone
42, which was subsequently treated with guanidine hydrochlo-
ride and sodium methoxide to ultimately yield 2-aminopyrimi-
dine 43 [16].
The data presented in Table 1 summarizes the effect of sub-
stitution at the pyrimidine 2-NH-group on both in vitro and in
vivo efficacies. Regarding in vitro activity, it is seen that alkyl,
benzyl, aryl, and carbonyl-bearing functionality are all well
tolerated at the pyrimidine 2-position. However, the sulfon-
amides showed distinctly weaker potency, possibly due to
NH2
O
O
N
N
N
N
N
N
N
b
c
a
N
F
N
N
N
N
F
18
N
F
F
F
24
23
25
Scheme 5. Reagents: (a) DMFDMA; (b) (PhSO2)2NF; (c) guanidineeHCl, NaOMe.

1338
A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
NH2
N
corresponding isomeric NH-n-alkylpyrimidines, with potency
being the lowest in the n-hexyl analog, where alkyl chain
length reached 6 carbons. The NH-benzylpyrimidines, on the
other hand, generally showed weaker in vivo activity, with
only 2 examples out of 15 showing activity against all 4 spe-
cies of Eimeria at 25 ppm, and none of these showing the same
spectrum of activity at 12.5 ppm. One NH-aryl compound
(pyridin-2-yl) from this series showed significant in vivo activ-
ity. All 6 amides tested showed activity against all 4 species of
Eimeria at 25 ppm, and 2 of these showed such activity at
12.5 ppm. The three sulfonamides showed significantly
weaker in vivo activity, which again may be due to deprotona-
tion of the sulfonamide eNH under the assay condition. Be-
tween the formamide, urea, and carbamate, the formamide
showed the most promising activity; however, pH stability
studies (not shown) suggested that the formamide group could
be hydrolyzed to the active 2-aminopyrimidine at pH < 2.5.
N
a
N
N
8ee
N
Br
F
26
Scheme 6. Reagents: (a) N-bromosuccinimide.
deprotonation of the sulfonamide eNH under the assay condi-
tions. Efficacy in vivo, however, varied more significantly with
NH-substitution. The NH-alkylpyrimidines generally showed
good in vivo potency, as 8 out of 14 showed activity against
all 4 species of Eimeria at 25 ppm, and 3 of these showed
such activity at 12.5 ppm. It is noted that activity was often
slightly better with 2-NH-cycloalkylpyrimidines than the
S
OH
X
N
N
a
b
O
O
R3
R3
R1
R1
O
R2
R2
R3
R1
R2
R1 = H; R2 = Br; R3 = F (28a)
R1 = H; R2 = CH3; R3 = F (28b)
R1 = H; R2 = H; R3 = Cl (28c)
R1 = F; R2 = H; R3 = F (28d)
R1 = H; R2 = Br; R3 = F; X = OMe (27a)
R1 = H; R2 = CH3; R3 = F; X = OMe (27b)
R1 = H; R2 = H; R3 = Cl; X = OMe
R1 = F; R2 = H; R3 = F; X = OEt
R1 = H; R2 = Br; R3 = F
R1 = H; R2 = CH3; R3 = F
c
S
SO2
S
N
N
N
N
N
N
e
d
Br
O
N
N
N
N
OH
OH
R3
R3
R3
R1
R1
R1
R2
R2
R2
31a-d
30a-d
29a-d
f
NH2
N
NH2
N
NH2
N
H
O
N
N
N
g
h
N
N
N
N
N
N
OH
N
R3
R1
R3
R1
R3
R1
R2
R2
R2
32a-d
33a-d
R1 = H; R2 = Br; R3 = F (34a)
R1 = H; R2 = CH3; R3 = F (34b)
R1 = H; R2 = H; R3 = Cl (34c)
R1 = F; R2 = H; R3 = F (34d)
Scheme 7. Reagents: (a) MeOH, H2SO4; (b) LDA, 1; (c) n-Bu4NBr3; (d) (2-aminopyridin-4-yl)methanol; (e) OXONEÒ; (f) NH3; (g) MnO2; (h) HNMe2,
NaB(OAc)3H.

A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
1339
O
O
F
O
F
O
F
O
F
O
F
F
O
F
N
N
a
b
c
OH
Cl
O
O
Br
F
F
F
F
F
36
35
37
d
O
O
O
O
F
O
O
F
N
F
g
f
e
N
N
N
N
O
N
N
N
N
OSO2CH3
F
N
N
N
F
F
F
F
F
F
F
F
41
40
39
38
h
NH2
N
O
N
N
N
N
i
N
F
N
N
N
F
F
F
F
F
42
43
Scheme 8. Reagents: (a) n-BuLi, ethyl hydrogen malonate; (b) n-Bu4NBr3; (c) (2-aminopyridin-4-yl)methanol; (d) CH3SO2Cl, Et3N; (e) HNMe2, i-Pr2NEt; (f)
Me(MeO)NH-HCl, i-PrMgCl; (g) CH3MgBr; (h) DMFDMA; (i) guanidineeHCl, NaOMe.
The data presented in Table 2 summarizes the effect of in-
troducing a substituent at the pyrimidine 5-position on both in
vitro and in vivo efficacies. Here it is seen that only hydrogen
and fluorine at the pyrimidine 5-position are well tolerated.
Other compounds bearing sterically larger groups are consid-
erably less potent in both assays. It is possible that when
such a large group is present at the pyrimidine 5-position, it
forces conformational rigidity that prohibits the 3-aryl ring
from rotating out of an orthogonal position relative to the imi-
dazopyridine core. This may, in turn, adversely affect PKG
binding affinity.
The data presented in Table 3 summarizes the effect of sub-
stitution on the aryl ring at the imidazopyridine 2-position on
biological activity. All analogs showed subnanomolar in vitro
potency, suggesting some degree of tolerance of small substit-
uents on the 2-aryl ring. In vivo potency was also found to be
consistently strong in all compounds except in 4-chlorophenyl,
suggesting that fluorine at the phenyl 4-position is important
for bioavailability. It is noted that the 2,4-difluorophenyl ana-
log is the most active compound in this series, showing activ-
ity against all 3 species of Eimeria tested down to 6.25 ppm,
while the 2,4,6-trifluorophenyl analog shows weaker activity
than either the 4-fluorphenyl or 2,4-difluorophenyl analogs.
tolerance, however, for bulky substituents at the pyrimidine
5-position, which perhaps induce a conformational change on
the molecule that is detrimental for PKG binding. We have
also found there to be some freedom to vary substitution on
the 2-aryl ring, as long as a fluorine remains at the 4-position
of this ring, with both 4-fluoro-3-methylphenyl and 2,4-
difluorophenyl being optimal. Overall, there are 14 compounds
presented that show activity against all tested species of
Eimeria at 12.5 ppm (8c, 8d, 8f, 8g, 8h, 8k, 9b, 9c, 9e, 9j,
9k, 8ee, 34b, and 34d). Of these, compound 8ee was strongly
considered for further studies. However, the potential geno-
toxicity of this compound and others in this series precluded
them from further development [4a].
4. Experimental section
4.1. General
Reactions were monitored by thin-layer chromatography
(TLC) on precoated EMD silica gel (60 F254) plates (250 mm
thickness) and visualized using UV light (254 nm), or by
LCMS using a ThermoFinnigan AQA spectrometer with UV
detection (254 nm). Flash chromatography purification was
performed using Isco RediSep cartridges on an Isco OptiX10
or Companion automated flash chromatography system, or
using EMD silica gel (230e400 mesh). HPLC purification
was conducted on a Varian Dynamax HPLC Guard Column,
21.4 mm, Compression Module Microsorb Guard-8 C-18 (P/
3. Conclusion
We have prepared several 2-aryl-3-(2-aminopyrimidin-4-yl)
imidazopyridines with varying substitution on the 2-aryl and
3-aryl rings that have potent anticoccidial activity. We have
found that there is tolerance of alkyl groups, carbonyl groups,
and to a lesser extent, benzyl and aryl groups at the pyrimidine
2-NHR-position as long as this pyrimidine amino group
remains protonated at physiological pH. There is less
1
N R00083221G). H NMR spectra were recorded on a Varian
Unity INOVA 400 MHz spectrometer; the values of chemical
shifts (d) are given in ppm relative to the central peak of the
solvent, and the values of coupling constants (J ) are given in
hertz (Hz). Mass spectra were recorded on a ThermoFinnigan

1340
A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
Table 1
Biological activity of 3-(2-NHR)pyrimidin-4-yl)imidazopyridines
R
N
HN
N
N
N
N
F
Compound
R
Ten_K IC50 (nM)a
0.23; 0.28
ExMAC dose (ppm)
ExMAC rating
Et
Ea
Emi
Ema
8a
CH2CH3
25
12.5
6.25
3
3
0
3
3
0
3
0
0
3
3
3
8b
8c
CH2CH2OH
2.9; 0.3
25
12.5
6.25
3
2
0
3
0
0
3
0
0
3
3
2
c-Pr
0.08; 0.25
25
12.5
6.25
3
3
0
3
3
3
3
2
0
3
3
3
8d
8e
CH2CH2CH3
0.13
12.5
3
3
3
3
CH2CH2OCH3
0.47; 0.25
25
12.5
6.25
3
3
0
3
3
0
0
0
0
3
3
2
8f
CH2CH2CH2OH
0.33; 0.34
12.5
6.25
3
3
3
0
3
0
3
3
8g
CH2ec-Pr
0.064;
0.25
25
12.5
6.25
3
3
0
3
3
3
3
3
0
3
3
3
8h
c-Bu
0.22; 0.3
25
12.5
6.25
3
3
3
3
3
0
3
2
0
3
3
2
8i
CH2CH2CH2CH3
CH2CH2CH2OCH3
c-Pentyl
2.14
50
25
0
3
0
3
0
0
0
2
8j
8k
0.52; 0.25
0.102;
0.55
12.5
6.25
3
3
3
3
3
2
3
0
8l
CH2CH2CH2CH2CH3
0.1; 0.28
0.12; 0.3
25
0
3
2
3
8m
c-Hexyl
25
12.5
6.25
3
3
3
2
0
0
3
2
0
3
3
3
8n
8o
8p
8q
8r
8s
CH2CH2CH2CH2CH2CH3
CH2e2-FePh
0.13; 0.3
0.087
25
25
25
25
25
3
3
0
0
0
0
0
0
0
0
0
3
0
0
0
0
3
0
3
3
CH2e2-Fe3-FePh
CH2e2-Fe4-FePh
CH2e2-Fe5-FePh
CH2e2-Fe6-FePh
0.12; 0.3
0.15; 0.27
0.026; 0.25
0.06; 0.3
25
12.5
6.25
2
0
0
0
0
0
3
0
0
3
3
2
8t
CH2e2-ClePh
CH2e2-CH3ePh
CH2e3-FePh
0.056; 0.55
0.08; 0.28
0.09; 0.3
25
25
2
0
0
0
0
0
3
2
8u
8v
25
12.5
6.25
2
0
0
3
2
0
2
0
0
3
3
0

A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
1341
Table 1 (continued)
Compound
R
Ten_K IC50 (nM)a
ExMAC dose (ppm)
25
ExMAC rating
Et
Ea
Emi
Ema
8w
8x
CH2e3-Fe4-FePh
CH2e3-Fe5-FePh
0.06
0
0
0
0
0.11; 0.3
25
12.5
3
0
3
0
0
0
3
0
8y
CH2e3-ClePh
CH2e3-CH3ePh
CH2e4-FePh
0.18; 0.3
25
25
0
3
0
0
0
0
3
0
8z
0.083; 0.29
8aa
0.066;
0.29
25
12.5
3
0
3
0
3
0
3
0
8bb
8cc
CH2e4-ClePh
CH2e4-CH3ePh
Pyridin-2-yl
0.24; 0.3
0.121; 0.55
0.4; 0.45
25
25
0
0
0
2
0
0
0
3
8dd
25
12.5
3
3
0
0
3
3
3
2
9a
9b
C(]O)CH2CH3
C(]O)ec-Pr
0.73; 0.3
25
12.5
6.25
3
3
0
3
0
0
3
0
0
3
3
2
1.03; 0.42
25
12.5
6.25
3
3
2
3
3
3
3
3
0
2
3
0
9c
C(]O)CH2CH2CH3
C(]O)ec-Bu
0.63
12.5
6.25
3
0
3
0
3
0
3
3
9d
0.27; 0.42
25
12.5
6.25
3
3
3
3
0
0
3
3
0
3
3
0
9e
9f
C(]O)CH2CH2CH2CH3
C(]O)ec-pentyl
0.25; 0.42
0.21; 0.3
25
12.5
6.25
3
2
0
3
2
3
3
2
0
3
3
3
25
12.5
6.25
3
3
0
3
0
0
3
3
0
3
3
3
9g
9h
9i
SO2CH3
SO2CH2Ph
SO2Ph
40
25
25
25
2
0
0
2
0
0
0
0
0
0
0
0
40% Inhibition at 100 nM
9.4; 0.25
9j
C(]O)H
0.66; 0.45
12.5
6.25
3
3
3
3
2
0
3
3
9k
9l
C(]O)NC(CH3)3
4.39
12.5
3
3
3
3
CO2CH3
0.8; 0.45
25
12.5
3
3
3
3
0
0
3
3
a
In cases where a compound was tested more than once, all values obtained are reported.
AQA spectrometer. HPLC traces were recorded on an Agilent
1100 or Hewlett Packard 1050 instrument with a Phenomenex
Aqua C18 125A 5 mm column, 4.6 mm i.d. ꢀ 50 mm length.
All compounds tested biologically were found to be ꢁ90%
pure by HPLC at 254 nM.
reflux for 3.5 h, and then was concentrated under reduced pres-
sure. The residue was then treated with EtOAc (2 L), H2O
(2 L), and enough 10% (w/v) aqueous NaHSO4 solution to
reach a pH of 4.5. The aqueous layer was extracted with addi-
tional EtOAc (2 ꢀ2 L). All organic extracts were combined,
dried over Na2SO4, and concentrated under reduced pressure
to yield w1 L of a red oil, which was then purified by vacuum
distillation at <1 mm Hg. Yield of 1: 704 g (91%). H NMR
(400 MHz, CDCl3) d 2.38 (s, 3H), 2.49 (s, 3H), 6.75 (d,
J ¼ 5.2 Hz, 1H), 8.29 (d, J ¼ 5.2 Hz, 1H). MS (ESIþ) 141.1.
4.1.1. 4-Methyl-2-methylsulfanylpyrimidine (1)
1
A mixture of toluene (12 L), 4-methylpyrimidine-2-thiol hy-
drochloride (900 g, 5.53 mol), diisopropylethylamine (1.07 kg,
8.30 mol), and DMFDMA (1.61 kg, 12.7 mol) was heated to

1342
A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
Table 2
Biological activity of 3-(2-NH2-5-R-pyrimidin-4-yl)imidazopyridines
charged with LDA (7.5 mL of a 2.0 M solution in heptane/
THF/ethylbenzene, 15 mmol). After stirring for 1 h at
<ꢂ75 ꢃC, the reaction was treated with a cooled solution of
methyl 4-fluorobenzoate (1.21 g, 7.85 mmol) in THF
(10 mL) dropwise over 15 min, during which reaction temper-
ature was maintained at <ꢂ55 ꢃC. The reaction was allowed
to warm to room temperature while stirring for 12 h, and
was then diluted with a saturated aqueous NH4Cl solution
(50 mL), and extracted with EtOAc (3 ꢀ 50 mL). Organic ex-
tracts were pooled, dried over Na2SO4, and concentrated under
reduced pressure to give 2.15 g of crude solid, which was trit-
urated with pentane (50 mL) and filtered. Yield of 2: 809 mg
(43%) as a 1.7:1.0 mixture of enol:ketone tautomers. 1H
NMR (400 MHz, CDCl3) d enol tautomer: 2.60 (s, 3H), 5.91
(s, 1H), 6.63 (d, J ¼ 5.4 Hz, 1H), 7.10e7.18 (m, 2H), 7.78e
7.86 (m, 2H), 8.29 (d, J ¼ 5.4 Hz, 1H); ketone tautomer:
2.51 (s, 3H), 4.34 (s, 2H), 6.97 (d, J ¼ 5.0 Hz, 1H), 7.10e
7.18 (m, 2H), 8.03e8.11 (m, 2H), 8.45 (d, J ¼ 5.0 Hz, 1H).
MS (ESIþ) 263.
NH2
N
N
N
N
N
R
F
Compound
R
H
Ten_K IC50 (nM) ExMAC
ExMAC rating
dose (ppm)
Et Ea Emi Ema
8ee
0.11
25
3
3
3
3
0
2
0
3
3
3
2
3
3
3
3
0
0
0
4
4
2
0
3
3
0
0
3
0
0
2
0
0
0
3
3
0
12.5
6.25
25
17
CH3 10.35
12.5
6.25
25
22
25
CN
F
1.6
0.26
0
4
0
0
2
25
1.25
6.25
25
26
Br
5.8
4.1.3. 2-Bromo-1-(4-fluorophenyl)-2-
(2-methylsulfanylpyrimidin-4-yl)ethanone (3)
Ketone/enol mixture 2 (218 g, 0.833 mol) was slurried in
CCl4 (1.5 L), and charged with tetra-n-butylammonium tribro-
mide (402 g, 0.833 mol), then CH2Cl2 (3 L). After stirring at
room temperature for 2 h, the reaction was diluted with satu-
rated aqueous NaHCO3 solution (3 L), and stirred for an addi-
tional 30 min. The aqueous layer was then siphoned off,
and the organic layer was dried over Na2SO4, and concen-
trated under reduced pressure, and not purified further. Yield
4.1.2. 1-(4-Fluorophenyl)-2-(2-methylsulfanylpyrimidin-4-yl)
ethanone and 1-(4-fluorophenyl)-2-
(2-methylsulfanylpyrimidin-4-yl)ethenol (2)
A solution of 4-methylpyrimidine 1 (1.00 g, 7.13 mmol) in
THF (15 mL) was stirred at ꢂ78 ꢃC in a CO2/IPA bath, and
1
of 3: 284 g (100%). H NMR (400 MHz, CDCl3) d 2.43 (s,
Table 3
Biological activity of 2-arylimidazopyridines
3H), 6.19 (s, 1H), 7.09 (t, J ¼ 8.4 Hz, 2H), 7.35 (d,
J ¼ 4.8 Hz, 1H), 7.97e8.05 (m, 2H), 8.47e8.55 (m, 1H).
MS (ESIþ) 341.0.
NH2
N
N
N
N
N
4.1.4. [2-(4-Fluorophenyl)-3-(2-methylsulfanylpyrimidin-4-yl)
imidazo[1,2-a]pyridin-7-yl]methanol (4)
A suspension of bromide 3 (284 g, 0.833 mol) in ethanol
Ar
(3 L) was charged with (2-aminopyridin-4-yl)methanol
˚
Compound Ar
Ten_K IC50 ExMAC ExMAC rating
(nM)
(103 g, 0.833 mol), and 4 A molecular sieves (300 mL, acti-
dose
(ppm)
Et Ea Emi Ema
vated at 175 ꢃC overnight in a vacuum oven), and was then
heated 12 h at 60 ꢃC. The reaction was then filtered while
hot, and the resulting filtrate was allowed to cool to room tem-
perature. The solid that precipitated out was then collected and
dried in a vacuum oven at 40 ꢃC overnight, yielding 92 g of 4
(fraction #1). The resulting filtrate was then concentrated un-
der reduced pressure to an oil that was triturated with EtOH
(200 mL). The resulting precipitate was collected by filtration,
and was then washed with H2O (500 mL), and then dried in
a vacuum oven at 50 ꢃC for 3 h, yielding 41 g of 4 (fraction
8ee
4-FePh
0.11
25
3
3
3
3
3
3
3
3
0
3
4
3
3
3
0
2
3
3
3
3
3
3
3
2
0
4
4
4
3
3
2
0
3
3
0
0
3
3
3
2
0
3
3
2
0
0
2
2
3
3
0
3
12.5
6.25
25
34a
34b
3-Bre4-FePh
3-CH3e4-FePh
0.16
0.1
25
12.5
6.25
25
34c
34d
4-Cl-Ph
0.41
0.1
12.5
25
2-Fe4-FePh
12.5
6.25
25
1
#2). Overall yield of 4: 133 g (43%). H NMR (400 MHz,
CDCl3) d 2.56 (s, 3H), 4.60 (s, 2H), 6.85 (d, J ¼ 5.2 Hz,
1H), 7.07 (d, J ¼ 7.2 Hz, 1H), 7.27 (t, J ¼ 8.8 Hz, 2H),
7.58e7.66 (m, 3H), 8.43 (d, J ¼ 5.2 Hz, 1H), 9.30 (d,
J ¼ 7.2 Hz, 1H). MS (ESIþ) 367.2.
43
2-Fe4-Fe6-FePh 0.52
4
3
2
3
12.5
6.25
3.13

A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
1343
4.1.5. Methanesulfonic acid 2-(4-fluorophenyl)-3-
(2-methylsulfanylpyrimidin-4-yl)imidazo[1,2-a]pyridin-
7-ylmethyl ester (5)
4.2. General procedure for the synthesis of 2-NHR-
pyrimidines 8aeee
A solution of imidazopyridine 4 (161 g, 0.439 mol) in THF
(500 mL) and Et3N (66.7 g, 0.659 mol) was cooled to 5 ꢃC in
an ice water bath, then charged with the dropwise addition of
methanesulfonyl chloride (55.4 g, 0.484 mol), and the reaction
was warmed to room temperature and stirred for 1 h. The re-
action was then diluted with H2O (500 mL) and then extracted
with EtOAc (2 ꢀ 500 mL). The aqueous layer was then diluted
with saturated aqueous NaCl solution (500 mL) and extracted
with additional EtOAc (500 mL). All organic fractions were
pooled, dried over Na2SO4, and concentrated under reduced
pressure to yield a solid that was triturated with pentane
(500 mL), and the dried in a vacuum oven overnight at
Sulfone 7 was charged with 40 equivalents of appropriate
amine, and the reaction was heated neat at 60 ꢃC for 2 h.
The reaction was then diluted to 10 mL with MeOH, and
then purified by HPLC using a MeOH/H2O gradient, where
the aqueous phase was 98.9:1.0:0.1 H2O:CH3CN:Et3N. Any
modifications to this procedure are noted when applicable.
4.2.1. {4-[7-Dimethylaminomethyl-2-(4-fluorophenyl)
imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl}ethylamine (8a)
Amine 8a was prepared from sulfone 7 (50.0 mg, 0.118
mmol) and ethylamine (2.35 mL of a 2.0 M solution in THF,
4.70 mmol). Yield of 8a: 29.0 mg (63%). 1H NMR
(400 MHz, CDCl3) d 1.33 (t, J ¼ 7.2 Hz, 3H), 2.30 (s, 6H),
3.51 (s, 2H), 3.56 (dt, J ¼ 12.4, 7.2 Hz, 2H), 5.18 (bs, 1H),
6.43 (d, J ¼ 5.2 Hz, 1H), 7.01 (dd, J ¼ 7.2, 1.4 Hz, 1H), 7.13
(t, J ¼ 8.8 Hz, 2H), 7.55 (bs, 1H), 7.65e7.69 (m, 2H), 8.11
(d, J ¼ 5.2 Hz, 1H), 9.45e9.55 (m, 1H). MS (ESIþ) 390.7.
1
40 ꢃC. Yield of 5: 165 g (85%). H NMR (400 MHz, CDCl3)
d 2.64 (s, 3H), 3.07 (s, 3H), 5.32 (s, 2H), 6.82 (d,
J ¼ 5.2 Hz, 1H), 7.03 (dd, J ¼ 7.2, 1.6 Hz, 1H), 7.14 (t,
J ¼ 8.4 Hz, 2H), 7.57e7.65 (m, 2H), 7.73 (bs, 1H), 8.32 (d,
J ¼ 5.2 Hz, 1H), 9.59 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 445.2.
4.1.6. [2-(4-Fluorophenyl)-3-(2-methylsulfanylpyrimidin-4-yl)
imidazo[1,2-a]pyridin-7-ylmethyl]dimethylamine (6)
4.2.2. 2-{4-[7-Dimethylaminomethyl-2-(4-fluorophenyl)
imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamino}ethanol
(8b)
A solution of mesylate 5 (172 g, 0.389 mol) in CH3CN
(1.5 L) was charged with diisopropylethylamine (65.3 g,
0.505 mol) and dimethylamine (253 mL of a 2.0 M solution
in THF, 0.505 mol). After stirring for 15 min, the reaction
slurry was diluted with CH2Cl2 (2 L) and H2O (2 L), and
then stirred for 10 min. The organic layer was separated,
then dried over Na2SO4, filtered, concentrated under reduced
pressure, and dried in a vacuum oven for 5 h at 40 ꢃC. Yield
Amine 8b was prepared from sulfone 7 (50.0 mg, 0.118
mmol) and 2-aminoethanol (287 mg, 284 mL, 4.70 mmol).
Yield of 8b: 29.8 mg (62%). 1H NMR (400 MHz, CDCl3)
d 2.30 (s, 6H), 3.51 (s, 2H), 3.70 (dt, J ¼ 5.6, 4.8 Hz, 2H),
3.90 (t, J ¼ 4.8 Hz, 2H), 5.66 (bs, 1H), 6.46 (d, J ¼ 5.3 Hz,
1H), 7.01 (dd, J ¼ 7.2, 1.4 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H),
7.56 (bs, 1H), 7.61e7.67 (m, 2H), 8.09 (d, J ¼ 5.3 Hz, 1H),
9.42 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 407.2.
1
of 6: 145 g (95%). H NMR (400 MHz, CDCl3) d 2.31 (s,
6H), 2.63 (s, 3H), 3.54 (s, 2H), 6.79 (d, J ¼ 5.6 Hz, 1H),
7.08 (d, J ¼ 7.2 Hz, 1H), 7.13 (t, J ¼ 8.8 Hz, 2H), 7.57 (bs,
1H), 7.56e7.64 (m, 2H), 8.27 (d, J ¼ 5.6 Hz, 1H), 9.52 (d,
J ¼ 7.2 Hz, 1H). MS (ESIþ) 394.3.
4.2.3. Cyclopropyl{4-[7-dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}amine (8c)
Amine 8c was prepared from sulfone 7 (50.0 mg, 0.118
mmol) and cyclopropylamine (268 mg, 326 mL, 4.70 mmol).
Yield of 8c: 25.1 mg (53%). 1H NMR (400 MHz, CDCl3)
d 0.65e0.70 (m, 2H), 0.88e0.94 (m, 2H), 2.30 (s, 6H),
2.83e2.90 (m, 1H), 3.52 (s, 2H), 5.48 (bs, 1H), 6.50
(d, J ¼ 5.2 Hz, 1H), 7.01 (dd, J ¼ 7.2, 1.4 Hz, 1H), 7.14
(t, J ¼ 8.7 Hz, 2H), 7.56 (bs, 1H), 7.63e7.70 (m, 2H), 8.12
(d, J ¼ 5.2 Hz, 1H), 9.82 (bs, 1H). MS (ESIþ) 402.7.
4.1.7. [2-(4-Fluorophenyl)-3-(2-methanesulfonylpyrimidin-
4-yl)imidazo[1,2-a]pyridin-7-ylmethyl]dimethylamine (7)
A solution of sulfide 6 (40.0 g, 102 mmol) in MeOH (1.0 L)
was charged with AcOH (30.6 g, 510 mmol), H2O2 (46.0 g of
a 30% w/w aqueous solution, 41.2 mL, 407 mmol), then so-
dium tungstate dihydrate (10.1 g, 30.6 mmol). The reaction
was allowed to stir at room temperature overnight, and was
then chilled to <ꢂ70 ꢃC in a CO2/IPA bath, after which
56.3 g of SO2 was bubbled in over 15 min to reduce the N-ox-
ide back to the tertiary amine. The reaction was then allowed
to warm to room temperature while stirring for 5 h, after which
it was diluted slowly with a saturated aqueous NaHCO3 solu-
tion (500 mL), and stirred for 10 min. The resulting mixture
was then extracted with CH2Cl2 (1 ꢀ 1 L, then 3 ꢀ 500 mL).
The organic extracts were pooled, dried over Na2SO4, filtered,
and concentrated under reduced pressure. Yield of 7: 38.7 g
4.2.4. {4-[7-Dimethylaminomethyl-2-(4-fluorophenyl)
imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}propylamine (8d)
Amine 8d was prepared from sulfone 7 (50.0 mg, 0.118
mmol) and n-propylamine (278 mg, 386 mL, 4.70 mmol).
Yield of 8d: 30.7 mg (64%). 1H NMR (400 MHz, CDCl3)
d 1.05 (t, J ¼ 7.4 Hz, 3H), 1.67e1.78 (m, 2H), 2.30 (s, 6H),
3.43e3.51 (m, 2H), 3.51 (s, 2H), 5.25 (bs, 1H), 6.42
(d, J ¼ 5.2 Hz, 1H), 7.00 (dd, J ¼ 7.2, 1.4 Hz, 1H), 7.12
(t, J ¼ 8.7 Hz, 2H), 7.55 (bs, 1H), 7.63e7.69 (m, 2H), 8.10
(d, J ¼ 5.2 Hz, 1H), 9.45e9.55 (m, 1H). MS (ESIþ) 404.7.
1
(89%). H NMR (400 MHz, CDCl3) d 2.34 (s, 6H), 3.41 (s,
3H), 3.60 (s, 2H), 7.13e7.30 (m, 2H), 7.21 (t, J ¼ 8.8 Hz,
2H), 7.56e7.66 (m, 2H), 7.67 (bs, 1H), 8.49 (d, J ¼ 5.6 Hz,
1H), 9.79 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 426.3.

1344
A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
4.2.5. {4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}-(2-methoxyethyl)amine (8e)
(t, J ¼ 7.3 Hz, 3H), 1.49 (tq, J ¼ 7.3, 7.3 Hz, 2H), 1.69
(tt, J ¼ 7.3, 7.3 Hz, 2H), 2.30 (s, 6H), 3.51 (s, 2H), 3.52
(t, J ¼ 7.3 Hz, 2H), 5.21 (bs, 1H), 6.42 (d, J ¼ 5.2 Hz, 1H),
7.00 (dd, J ¼ 7.2, 1.4 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.55
(bs, 1H), 7.62e7.69 (m, 2H), 8.10 (d, J ¼ 5.2 Hz, 1H), 9.49
(bs, 1H). MS (ESIþ) 418.7.
Amine 8e was prepared from sulfone 7 (50.0 mg, 0.118
mmol) and 2-methoxyethylamine (353 mg, 409 mL, 4.70
mmol). Yield of 8e: 27.3 mg (53%). 1H NMR (400 MHz,
CDCl3) d 2.30 (s, 6H), 3.44 (s, 3H), 3.51 (s, 2H), 3.65 (t,
J ¼ 5.2 Hz, 2H), 3.72 (q, J ¼ 5.2 Hz, 2H), 5.55 (bs, 1H), 6.44
(d, J ¼ 5.3 Hz, 1H), 7.00 (dd, J ¼ 7.1, 1.5 Hz, 1H), 7.12 (t,
J ¼ 8.7 Hz, 2H), 7.55 (bs, 1H), 7.62e7.68 (m, 2H), 8.11 (d,
J ¼ 5.3 Hz, 1H), 9.46 (d, Je7.1 Hz, H). MS (ESIþ) 420.7.
4.2.10. {4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}-(3-methoxypropyl)amine (8j)
Amine 8j was prepared from sulfone 7 (50.0 mg, 0.118
mmol) and 3-methoxypropylamine (419 mg, 481 mL, 4.70
mmol). Yield of 8j: 25.6 mg (50%). 1H NMR (400 MHz,
CDCl3) d 1.93e2.01 (m, 2H), 2.30 (s, 6H), 3.39 (s, 3H),
3.51 (s, 2H), 3.57 (t, J ¼ 5.9 Hz, 2H), 3.63 (q, J ¼ 6.2 Hz,
2H), 5.55 (bs, 1H), 6.42 (d, J ¼ 5.3 Hz, 1H), 7.00 (dd,
J ¼ 7.2, 1.5 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.55 (bs, 1H),
7.62e7.69 (m, 2H), 8.10 (d, J ¼ 5.3 Hz, 1H), 9.49 (bs, 1H).
MS (ESIþ) 435.7.
4.2.6. 3-{4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-ylamino}propan-1-ol (8f)
Amine 8f was prepared from sulfone 7 (50.0 mg, 0.118
mmol) and 3-aminopropan-1-ol (353 mg, 359 mL, 4.70
mmol). Yield of 8f: 24.9 mg (51%). 1H NMR (400 MHz,
CDCl3) d 1.82e1.90 (m, 2H), 2.30 (s, 6H), 3.51 (s, 2H),
3.69 (q, J ¼ 6.4 Hz, 2H), 3.74 (t, J ¼ 5.5 Hz, 2H), 5.44 (bs,
1H), 6.44 (d, J ¼ 5.4 Hz, 1H), 7.01 (dd, J ¼ 7.2, 1.5 Hz, 1H),
7.13 (t, J ¼ 8.7 Hz, 2H), 7.56 (bs, 1H), 7.61e7.68 (m, 2H),
8.09 (d, J ¼ 5.4 Hz, 1H), 9.44 (d, J ¼ 7.2 Hz, 1H). MS
(ESIþ) 421.3.
4.2.11. Cyclopentyl{4-[7-dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}amine (8k)
Amine 8k was prepared from sulfone 7 (50.0 mg, 0.118
mmol) and cyclopentylamine (400 mg, 464 mL, 4.70 mmol).
Yield of 8k: 28.6 mg (56%). 1H NMR (400 MHz, CDCl3)
d 1.54e1.65 (m, 2H), 1.65e1.75 (m, 2H), 1.75e1.86 (m,
2H), 2.06e2.18 (m, 2H), 2.30 (s, 6H), 3.51 (s, 2H), 4.30e
4.44 (m, 1H), 5.21 (d, J ¼ 7.1 Hz, 1H), 6.42 (d, J ¼ 5.2 Hz,
1H), 7.01 (dd, J ¼ 7.2, 1.5 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H),
7.55 (bs, 1H), 7.62e7.71 (m, 2H), 8.09 (d, J ¼ 5.2 Hz, 1H),
9.53 (bs, 1H). MS (ESIþ) 431.4.
4.2.7. Cyclopropylmethyl{4-[7-dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}amine (8g)
Amine 8g was prepared from sulfone 7 (50.0 mg, 0.118
mmol) and cyclopropylmethylamine (334 mg, 408 mL, 4.70
mmol). Yield of 8g: 25.8 mg (53%). 1H NMR (400 MHz,
CDCl3) d 0.32 (q, J ¼ 4.8 Hz, 2H), 0.57e0.63 (m, 2H),
1.11e1.21 (m, 1H), 2.30 (s, 6H), 3.38 (dd, J ¼ 6.6, 5.7 Hz,
2H), 3.51 (s, 2H), 5.34 (bs, 1H), 6.43 (d, J ¼ 5.3 Hz, 1H),
7.01 (dd, J ¼ 7.1, 1.4 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.55
(bs, 1H), 7.62e7.69 (m, 2H), 8.11 (d, J ¼ 5.3 Hz, 1H), 9.49
(d, J ¼ 7.1 Hz, 1H). MS (ESIþ) 416.7.
4.2.12. {4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}pentylamine (8l)
Amine 8l was prepared from sulfone 7 (50.0 mg, 0.118
mmol) and n-pentylamine (410 mg, 535 mL, 4.70 mmol).
Yield of 8l: 27.2 mg (53%). 1H NMR (400 MHz, CDCl3)
d 0.95 (t, J ¼ 7.0 Hz, 3H), 1.35e1.50 (m, 4H), 1.71 (quintet,
J ¼ 7.2 Hz, 2H), 2.30 (s, 6H), 3.47e3.54 (m, 2H), 3.52 (s,
2H), 5.21 (bs, 1H), 6.42 (d, J ¼ 5.2 Hz, 1H), 7.00 (dd,
J ¼ 7.2, 1.5 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.55 (bs, 1H),
7.60e7.71 (m, 2H), 8.10 (d, J ¼ 5.2 Hz, 1H), 9.49 (bs, 1H).
MS (ESIþ) 432.8.
4.2.8. Cyclobutyl{4-[7-dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}amine (8h)
Amine 8h was prepared from sulfone 7 (50.0 mg, 0.118
mmol) and cyclobutylamine (334 mg, 401 mL, 4.70 mmol).
Yield of 8h: 24.1 mg (49%). 1H NMR (400 MHz, CDCl3)
d 1.73e1.90 (m, 2H), 1.94e2.06 (m, 2H), 2.31 (s, 6H),
2.45e2.55 (m, 2H), 3.52 (s, 2H), 4.49e4.57 (m, 1H), 5.40
(d, J ¼ 7.4 Hz, 1H), 6.43 (d, J ¼ 5.3 Hz, 1H), 7.02 (bd,
J ¼ 6.8 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.55 (bs, 1H),
7.62e7.69 (m, 2H), 8.09 (d, J ¼ 5.3 Hz, 1H), 9.49 (d,
J ¼ 6.8 Hz, 1H). MS (ESIþ) 416.8.
4.2.13. Cyclohexyl-{4-[7-dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}amine (8m)
Amine 8m was prepared from sulfone 7 (50.0 mg,
0.118 mmol) and cyclohexylamine (466 mg, 538 mL, 4.70
mmol). Yield of 8m: 33.9 (65%). 1H NMR (400 MHz,
CDCl3) d 1.22e1.39 (m, 2H), 1.39e1.54 (m, 2H), 1.61e
1.75 (m, 2H), 1.79e1.89 (m, 2H), 2.08e2.18 (m, 2H), 2.30
(s, 6H), 3.52 (s, 2H), 3.84e3.98 (m, 1H), 5.13 (d,
J ¼ 8.0 Hz, 1H), 6.41 (d, J ¼ 5.2 Hz, 1H), 7.00 (dd, J ¼ 7.2,
1.5 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.55 (s, 1H), 7.62e7.70
4.2.9. Butyl{4-[7-dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}amine (8i)
Amine 8i was prepared from sulfone 7 (50.0 mg, 0.118
mmol) and n-butylamine (344 mg, 465 mL, 4.70 mmol). Yield
1
of 8i: 23.5 mg (48%). H NMR (400 MHz, CDCl3) d 1.00

A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
1345
(m, 2H), 8.09 (d, J ¼ 5.2 Hz, 1H), 9.52 (s, 1H). MS (ESIþ)
4.70 mmol). Yield of 8r: 32.9 mg (58%). 1H NMR
(400 MHz, CDCl3) d 2.29 (s, 6H), 3.50 (s, 2H), 4.77 (d,
J ¼ 6.3 Hz, 2H), 5.65 (bs, 1H), 6.50 (d, J ¼ 5.3 Hz, 1H),
6.85 (bs, 1H), 6.93e7.02 (m, 1H), 7.03e7.09 (dd, J ¼ 8.8,
4.4 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.15e7.21 (m, 1H),
7.54 (bs, 1H), 7.61e7.69 (m, 2H), 8.13 (d, J ¼ 5.3 Hz, 1H),
9.22 (bs, 1H). MS (ESIþ) 488.7.
445.3.
4.2.14. {4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}hexylamine (8n)
Amine 8n was prepared from sulfone 7 (50.0 mg, 0.118
mmol) and n-hexylamine (577 mg, 754 mL, 4.70 mmol). Yield
1
of 8n: 31.5 mg (61%). H NMR (400 MHz, CDCl3) d 0.92 (t,
4.2.19. (2,6-Difluorobenzyl)-{4-[7-dimethylaminomethyl-
2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}amine (8s)
J ¼ 7.2 Hz, 3H), 1.32e1.40 (m, 4H), 1.41e1.51 (m, 2H), 1.69
(quintet, J ¼ 7.2 Hz, 2H), 2.30 (s, 6H), 3.46e3.55 (m, 2H),
3.51 (s, 2H), 5.21 (bt, J ¼ 5.2 Hz, 1H), 6.42 (d, J ¼ 5.2 Hz,
1H), 7.00 (dd, J ¼ 7.2, 1.5 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H),
7.55 (bs, 1H), 7.63e7.69 (m, 2H), 8.10 (d, J ¼ 5.2 Hz, 1H),
9.48 (bs, 1H). MS (ESIþ) 446.7.
Amine 8s was prepared from sulfone 7 (50.0 mg,
0.118 mmol) and 2,6-difluorobenzylamine (673 mg, 562 mL,
4.70 mmol). Yield of 8s: 29.2 mg (51%). 1H NMR
(400 MHz, CDCl3) d 2.30 (s, 6H), 3.52 (s, 2H), 4.87 (d,
J ¼ 6.0 Hz, 2H), 5.51 (bs, 1H), 6.47 (d, J ¼ 5.2 Hz, 1H),
6.95 (t, J ¼ 7.8 Hz, 2H), 7.01 (dd, J ¼ 7.1, 1.1 Hz, 1H), 7.12
(t, J ¼ 8.7 Hz, 2H), 7.25e7.34 (m, 1H), 7.56 (bs, 1H), 7.62e
7.69 (m, 2H), 8.12 (d, J ¼ 5.2 Hz, 1H), 9.49 (bs, 1H). MS
(ESIþ) 489.3.
4.2.15. {4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}-(2-fluorobenzyl)amine (8o)
Amine 8o was prepared from sulfone 7 (50.0 mg, 0.118
mmol) and 2-fluorobenzylamine (588 mg, 537 mL, 4.70
mmol). Yield of 8o: 32.9 mg (60%). 1H NMR (400 MHz,
CDCl3) d 2.28 (s, 6H), 3.49 (s, 2H), 4.80 (d, J ¼ 6.2 Hz,
2H), 5.64 (bs, 1H), 6.47 (d, J ¼ 5.2 Hz, 1H), 6.84 (bs, 1H),
7.06e7.18 (m, 4H), 7.28e7.35 (m, 1H), 7.45 (t, J ¼ 7.2 Hz,
1H), 7.54 (bs, 1H), 7.60e7.69 (m, 2H), 8.13 (d, J ¼ 5.2 Hz,
1H), 9.23 (bs, 1H). MS (ESIþ) 471.3.
4.2.20. (2-Chlorobenzyl)-{4-[7-dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}amine (8t)
Amine 8t was prepared from sulfone 7 (50.0 mg,
0.118 mmol) and 2-chlorobenzylamine (666 mg, 567 mL, 4.70
mmol). Yield of 8t: 30.0 mg (53%). 1H NMR (400 MHz,
CDCl3) d 2.29 (s, 6H), 3.49 (s, 2H), 4.83 (d, J ¼ 6.2 Hz,
2H), 5.73 (bs, 1H), 6.47 (d, J ¼ 5.2 Hz, 1H), 6.79 (bs, 1H),
7.12 (t, J ¼ 8.7 Hz, 2H), 7.24e7.31 (m, 1H), 7.42e7.51 (m,
3H), 7.53 (bs, 1H), 7.58e7.69 (m, 2H), 8.13 (d, J ¼ 5.2 Hz,
1H), 9.16 (s, 1H). MS (ESIþ) 487.3.
4.2.16. (2,3-Difluorobenzyl)-{4-[7-dimethylaminomethyl-
2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}amine (8p)
Amine 8p was prepared from sulfone 7 (50.0 mg,
0.118 mmol) and 2,3-difluorobenzylamine (673 mg, 550 mL,
4.70 mmol). Yield of 8p: 32.1 mg (56%). 1H NMR
(400 MHz, CDCl3) d 2.29 (s, 6H), 3.50 (s, 2H), 4.82 (d,
J ¼ 6.2 Hz, 2H), 5.66 (bs, 1H), 6.49 (d, J ¼ 5.3 Hz, 1H),
6.86 (bs, 1H), 7.04e7.17 (m, 2H), 7.12 (t, J ¼ 8.6 Hz, 2H),
7.22 (t, J ¼ 6.8 Hz, 1H), 7.55 (bs, 1H), 7.60e7.68 (m, 2H),
8.13 (d, J ¼ 5.3 Hz, 1H), 9.21 (bs, 1H). MS (ESIþ) 489.3.
4.2.21. {4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}-(2-methylbenzyl)amine (8u)
Amine 8u was prepared from sulfone 7 (50.0 mg,
0.118 mmol) and 2-methylbenzylamine (570 mg, 583 mL,
4.70 mmol). Yield of 8u: 33.0 mg (60%). 1H NMR
(400 MHz, CDCl3) d 2.28 (s, 6H), 2.42 (s, 3H), 3.48 (s, 2H),
4.69 (d, J ¼ 5.7 Hz, 2H), 5.51 (bs, 1H), 6.47 (d, J ¼ 5.3 Hz,
1H), 6.77 (bs, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.19e7.29 (m,
3H), 7.39 (d, J ¼ 6.9 Hz, 1H), 7.53 (bs, 1H), 7.61e7.70 (m,
2H), 8.13 (d, J ¼ 5.3 Hz, 1H), 9.15 (bs, 1H). MS (ESIþ)
466.7.
4.2.17. (2,4-Difluorobenzyl)-{4-[7-dimethylaminomethyl-
2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}amine (8q)
Amine 8q was prepared from sulfone 7 (50.0 mg,
0.118 mmol) and 2,4-difluorobenzylamine (673 mg, 559 mL,
4.70 mmol). Yield of 8q: 25.2 mg (44%). 1H NMR (400 MHz,
CDCl3) d 2.29 (s, 6H), 3.50 (s, 2H), 4.75 (d, J ¼ 6.1 Hz, 2H),
5.57 (bs, 1H), 6.49 (d, J ¼ 5.3 Hz, 1H), 6.84e6.92 (m, 1H),
6.88 (t, J ¼ 7.9 Hz, 2H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.37e7.48
(m, 1H), 7.55 (bs, 1H), 7.61e7.67 (m, 2H), 8.13 (d,
J ¼ 5.3 Hz, 1H), 9.27 (bs, 1H). MS (ESIþ) 489.3.
4.2.22. {4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}-(3-fluorobenzyl)amine (8v)
Amine 8v was prepared from sulfone 7 (50.0 mg,
0.118 mmol) and 3-fluorobenzylamine (588 mg, 536 mL,
4.70 mmol). Yield of 8v: 30.0 mg (55%). 1H NMR
(400 MHz, CDCl3) d 2.29 (s, 6H), 3.48 (s, 2H), 4.74 (d,
J ¼ 6.1 Hz, 2H), 5.68 (bs, 1H), 6.49 (d, J ¼ 5.3 Hz, 1H),
6.78 (bs, 1H), 6.98e7.06 (m, 1H), 7.11e7.17 (m, 1H), 7.12
(t, J ¼ 8.7 Hz, 2H), 7.21 (d, J ¼ 7.6 Hz, 1H), 7.33e7.41 (m,
4.2.18. (2,5-Difluorobenzyl)-{4-[7-dimethylaminomethyl-
2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}amine (8r)
Amine 8r was prepared from sulfone 7 (50.0 mg,
0.118 mmol) and 2,5-difluorobenzylamine (673 mg, 551 mL,

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A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
1H), 7.53 (bs, 1H), 7.64 (dd, J ¼ 8.6, 5.5 Hz, 2H), 8.13 (d,
J ¼ 5.3 Hz, 1H), 9.09 (bs, 1H). MS (ESIþ) 471.2.
4.70 mmol). Yield of 8aa: 27.6 mg (50%). 1H NMR
(400 MHz, CDCl3) d 2.29 (s, 6H), 3.49 (s, 2H), 4.71 (d,
J ¼ 5.9 Hz, 2H), 5.60 (bs, 1H), 6.48 (d, J ¼ 5.3 Hz, 1H),
6.82 (s, 1H), 7.08 (t, J ¼ 8.0 Hz, 2H), 7.12 (t, J ¼ 8.0 Hz,
2H), 7.37e7.43 (m, 2H), 7.54 (bs, 1H), 7.62e7.68 (m, 2H),
8.13 (d, J ¼ 5.3 Hz, 1H), 9.18 (bs, 1H). MS (ESIþ) 471.3.
4.2.23. (3,4-Difluorobenzyl)-{4-[7-dimethylaminomethyl-
2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}amine (8w)
Amine 8w was prepared from sulfone 7 (50.0 mg,
0.118 mmol) and 3,4-difluorobenzylamine (673 mg, 556 mL,
4.70 mmol). Yield of 8w: 28.8 mg (51%). 1H NMR
(400 MHz, CDCl3) d 2.29 (s, 6H), 3.49 (s, 2H), 4.70 (d,
J ¼ 6.1 Hz, 2H), 5.64 (bs, 1H), 6.50 (d, J ¼ 5.3 Hz, 1H),
6.83 (bs, 1H), 7.12 (t, J ¼ 8.8 Hz, 2H), 7.14e7.20 (m, 2H),
7.21e7.28 (m, 1H), 7.54 (bs, 1H), 7.61e7.68 (m, 2H), 8.13
(d, J ¼ 5.3 Hz, 1H), 9.15 (s, 1H). MS (ESIþ) 488.7.
4.2.28. (4-Chlorobenzyl)-{4-[7-dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}amine (8bb)
Amine 8bb was prepared from sulfone 7 (50.0 mg,
0.118 mmol) and 4-chlorobenzylamine (666 mg, 572 mL,
4.70 mmol). Yield of 8bb: 20.1 mg (35%). 1H NMR
(400 MHz, CDCl3) d 2.36 (s, 6H), 3.58 (s, 2H), 4.71 (d,
J ¼ 6.0 Hz, 2H), 5.67 (bs, 1H), 6.48 (d, J ¼ 5.3 Hz, 1H),
6.89 (bs, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.29e7.44 (m, 4H),
7.54 (bs, 1H), 7.64 (dd, J ¼ 8.7, 5.4 Hz, 2H), 8.13 (d,
J ¼ 5.3 Hz, 1H), 9.12 (bs, 1H). MS (ESIþ) 487.3.
4.2.24. (3,5-Difluorobenzyl)-{4-[7-dimethylaminomethyl-
2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}amine (8x)
Amine 8x was prepared from sulfone 7 (50.0 mg,
0.118 mmol) and 3,5-difluorobenzylamine (673 mg, 556 mL,
4.70 mmol). Yield of 8x: 21.8 mg (38%). 1H NMR
(400 MHz, CDCl3) d 2.29 (s, 6H), 3.49 (s, 2H), 4.72 (d,
J ¼ 6.2 Hz, 2H), 5.72 (bs, 1H), 6.51 (d, J ¼ 5.3 Hz, 1H),
6.67e6.84 (m, 1H), 6.80 (bs, 1H), 6.96 (bd, J ¼ 6.1 Hz, 2H),
7.12 (t, J ¼ 8.7 Hz, 2H), 7.54 (bs, 1H), 7.59e7.68 (m, 2H),
8.14 (d, J ¼ 5.3 Hz, 1H), 9.08 (bs, 1H). MS (ESIþ) 489.3.
4.2.29. {4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}-(4-methylbenzyl)amine (8cc)
Amine 8cc was prepared from sulfone 7 (50.0 mg,
0.118 mmol) and 4-methylbenzylamine (570 mg, 598 mL,
4.70 mmol). Yield of 8cc: 30.6 mg (56%). 1H NMR
(400 MHz, CDCl3) d 2.29 (s, 6H), 2.39 (s, 3H), 3.49 (s, 2H),
4.69 (d, J ¼ 5.8 Hz, 2H), 5.58 (bs, 1H), 6.46 (d, J ¼ 5.3 Hz,
1H), 6.80 (bs, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.21 (d,
J ¼ 7.9 Hz, 2H), 7.32 (d, J ¼ 7.9 Hz, 2H), 7.52 (bs, 1H),
7.61e7.69 (m, 2H), 8.13 (d, J ¼ 5.3 Hz, 1H), 9.18 (bs, 1H).
MS (ESIþ) 467.4.
4.2.25. (3-Chlorobenzyl)-{4-[7-dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}amine (8y)
Amine 8y was prepared from sulfone 7 (50.0 mg, 0.118
mmol) and 3-chlorobenzylamine (666 mg, 574 mL, 4.70
mmol). Yield of 8y: 32.8 mg (58%). 1H NMR (400 MHz,
CDCl3) d 2.29 (s, 6H), 3.49 (s, 2H), 4.72 (d, J ¼ 6.1 Hz,
2H), 5.68 (bs, 1H), 6.49 (d, J ¼ 5.3 Hz, 1H), 6.80 (bs, 1H),
7.12 (t, J ¼ 8.7 Hz, 2H), 7.29e7.38 (m, 3H), 7.42 (bs, 1H),
7.53 (bs, 1H), 7.61e7.68 (m, 2H), 8.13 (d, J ¼ 5.3 Hz, 1H),
9.08 (bs, 1H). MS (ESIþ) 487.3.
4.2.30. {4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}pyridin-2-ylamine (8dd)
Compound 8dd was prepared from sulfone 7 (72.0 mg,
0.169 mmol) and 2-aminopyridine (637 mg, 6.77 mmol) in di-
glyme (1.0 mL) by heating at 150 ꢃC for 3 h. Yield of 8dd:
1
17.9 mg (24%). H NMR (400 MHz, CDCl3) d 2.31 (s, 6H),
4.2.26. {4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}-(3-methylbenzyl)amine (8z)
3.53 (s, 2H), 6.70 (d, J ¼ 5.4 Hz, 1H), 6.96e7.03 (m, 2H),
7.15 (t, J ¼ 8.7 Hz, 2H), 7.60 (bs, 1H), 7.63e7.74 (m, 3H),
8.10 (bs, 1H), 8.31 (d, J ¼ 5.4 Hz, 1H), 8.33e8.39 (m, 2H),
9.48 (d, J ¼ 7.1 Hz, 1H). MS (ESIþ) 440.3.
Amine 8z was prepared from sulfone 7 (50.0 mg, 0.118
mmol) and 3-methylbenzylamine (570 mg, 590 mL, 4.70
mmol). Yield of 8z: 27.6 mg (50%). 1H NMR (400 MHz,
CDCl3) d 2.28 (s, 6H), 2.39 (s, 3H), 3.48 (s, 2H), 4.70 (d,
J ¼ 5.9 Hz, 2H), 5.63 (bs, 1H), 6.46 (d, J ¼ 5.3 Hz, 1H),
6.78 (bs, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.13e7.17 (m, 2H),
7.20e7.25 (m, 1H), 7.28e7.32 (m, 1H), 7.52 (bs, 1H),
7.61e7.71 (m, 2H), 8.13 (d, J ¼ 5.3 Hz, 1H), 9.14 (bs, 1H).
MS (ESIþ) 467.3.
4.2.31. 4-[7-Dimethylaminomethyl-2-(4-fluorophenyl)
imidazo[1,2,-a]pyridin-3-yl]pyrimidin-
2-ylamine (8ee)
A solution of sulfone 7 (21.6 g, 50.8 mmol) in THF
(200 mL) in a pressure reactor was chilled to <ꢂ70 ꢃC in
a CO2/IPA bath. Ammonia (27.9 g, 1.64 mol) was then bub-
bled in over 15 min, after which the pressure reactor was
sealed, and the reaction was allowed to warm to room temper-
ature and stir 12 h, during which the reaction pressure reached
55 psi. The pressure was then released, and the reaction was
concentrated under reduced pressure, then chromatographed
on SiO2 using a gradient that started with CH2Cl2 and ended
with 90:9:1 CH2Cl2:MeOH:concentrated NH4OH. Yield of
4.2.27. {4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}-(4-fluorobenzyl)amine (8aa)
Amine 8aa was prepared from sulfone 7 (50.0 mg,
0.118 mmol) and 4-fluorobenzylamine (588 mg, 537 mL,

A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
1347
8ee: 9.6 g (52%). 1H NMR (400 MHz, CDCl3) d 2.28 (s, 6H),
3.51 (s, 2H), 5.39 (bs, 2H), 6.49 (d, J ¼ 5.3 Hz, 1H), 7.00 (dd,
J ¼ 7.1, 1.6 Hz, 1H), 7.11 (t, J ¼ 8.8 Hz, 2H), 7.55 (bs, 1H),
7.59e7.67 (m, 2H), 8.08 (d, J ¼ 5.3 Hz, 1H), 9.40 (d,
J ¼ 7.1 Hz, 1H). MS (ESIþ) 363.3.
J ¼ 7.4 Hz, 2H), 3.53 (s, 2H), 6.84 (d, J ¼ 5.5 Hz, 2H), 7.13e
7.21 (m, 3H), 7.59 (bs, 1H), 7.59e7.67 (m, 2H), 8.26 (d,
J ¼ 5.5 Hz, 1H), 10.19 (d, J ¼ 6.8 Hz, 1H). MS (ESIþ) 433.4.
4.3.4. Cyclobutanecarboxylic acid {4-
[7-dimethylaminomethyl-2-(4-fluorophenyl)imidazo
[1,2-a]pyridin-3-yl]pyrimidin-2-yl}amide (9d)
4.3. General procedure for the synthesis of amides 9aef
and sulfonamides 9gei
Amide 9d was prepared from 2-aminopyrimidine 8ee
(50.0 mg, 0.138 mmol) and cyclobutanecarbonyl chloride
(18 mg, 17 mL, 0.15 mmol) in pyridine (0.5 mL). Additional
cyclobutanecarbonyl chloride (9.0 mg, 8.5 mL, 0.075 mmol)
A solution of 2-aminopyrimidine 8ee in pyridine was
charged with appropriate acid chloride or sulfonyl chloride,
and allowed to stir at room temperature for 24 h. Additional
portions of appropriate acid chloride or sulfonyl chloride
were added as needed at 24 h intervals until the reaction ap-
peared complete by LCMS. The reaction was then diluted to
10 mL with MeOH, and then purified by HPLC using
a MeOH/H2O gradient, where the aqueous phase was
98.9:1.0:0.1 H2O:CH3CN:Et3N. Any modifications to this pro-
cedure are noted when applicable.
1
was added after 24 h. Yield of 9d: 46.5 mg (76%). H NMR
(400 MHz, CDCl3) d 1.87e2.13 (m, 2H), 2.20e2.35 (m,
2H), 2.30 (s, 6H), 2.41e2.56 (m, 2H), 3.39e3.45 (m, 1H),
3.54 (s, 2H), 6.84 (d, J ¼ 5.5 Hz, 1H), 7.16 (t, J ¼ 8.5 Hz,
2H), 7.22 (d, J ¼ 7.0 Hz, 1H), 7.59 (bs, 1H), 7.58e7.66 (m,
2H), 8.02 (bs, 1H), 8.24 (d, J ¼ 5.5 Hz, 1H), 10.28 (d,
J ¼ 7.0 Hz, 1H). MS (ESIþ) 445.4.
4.3.5. Pentanoic acid {4-[7-dimethylaminomethyl-
4.3.1. N-{4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}propionamide (9a)
2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}amide (9e)
Amide 9e was prepared from 2-aminopyrimidine 8ee
(50.0 mg, 0.138 mmol) and pentanoyl chloride (18 mg,
18 mL, 0.15 mmol) in pyridine (0.5 mL). Additional penta-
nonyl chloride (9.0 mg, 9.0 mL, 0.075 mmol) was added after
24 h. Yield of 9e: 41.6 mg (67%). 1H NMR (400 MHz,
CDCl3) d 0.98 (t, J ¼ 7.2 Hz, 3H), 1.40e1.52 (m, 2H),
1.67e1.84 (m, 2H), 2.30 (s, 6H), 2.60 (t, J ¼ 7.2 Hz, 2H),
3.53 (s, 2H), 6.84 (d, J ¼ 5.6 Hz, 1H), 7.12e7.21 (m, 3H),
7.28 (s, 1H), 7.59 (bs, 1H), 7.60e7.66 (m, 2H), 8.26 (d,
J ¼ 5.6 Hz, 1H), 10.15e10.25 (m, 1H). MS (ESIþ) 447.4.
Amide 9a was prepared from 2-aminopyrimidine 8ee
(50.0 mg, 0.138 mmol) and propionyl chloride (14 mg,
13 mL, 0.15 mmol) in pyridine (0.5 mL). Additional propionyl
chloride (7.0 mg, 6.5 mL, 0.075 mmol) was added after 24 h.
Yield of 9a: 37.7 mg (65%). 1H NMR (400 MHz, CDCl3)
d 1.31 (t, J ¼ 7.5 Hz, 3H), 2.32 (s, 6H), 2.64 (q, J ¼ 7.5 Hz,
2H), 3.57 (s, 2H), 6.85 (d, J ¼ 5.5 Hz, 1H), 7.16 (t,
J ¼ 8.6 Hz, 2H), 7.21 (d, J ¼ 7.0 Hz, 1H), 7.60 (bs, 1H),
7.59e7.67 (m, 2H), 8.12 (s, 1H), 8.26 (d, J ¼ 5.5 Hz, 1H),
10.18 (d, J ¼ 7.0 Hz, 1H). MS (ESIþ) 419.3.
4.3.6. Cyclopentanecarboxylic acid
4.3.2. Cyclopropanecarboxylic acid {4-
[7-dimethylaminomethyl-2-(4-fluorophenyl)imidazo
[1,2-a]pyridin-3-yl]pyrimidin-2-yl}amide (9b)
Amide 9b was prepared from 2-aminopyrimidine 8ee
(50.0 mg, 0.138 mmol) and cyclopropanecarbonyl chloride
(16 mg, 14 mL, 0.15 mmol) in pyridine (0.5 mL). Additional
cyclopropanecarbonyl chloride (8.0 mg, 7.0 mL, 0.075 mmol)
{4-[7-dimethylaminomethyl-2-(4-fluorophenyl)imidazo[1,2-a]
pyridin-3-yl]pyrimidin-2-yl}amide (9f)
Amide 9f was prepared from 2-aminopyrimidine 8ee
(50.0 mg, 0.138 mmol) and cyclopentanecarbonyl chloride
(20 mg, 18 mL, 0.15 mmol) in pyridine (0.5 mL). Additional
cyclopentanecarbonyl chloride (10 mg, 9.0 mL, 0.075 mmol)
1
was added after 24 h. Yield of 9f: 47.4 mg (75%). H NMR
1
was added after 24 h. Yield of 9b: 43.8 mg (74%). H NMR
(400 MHz, CDCl3) d 1.63e1.73 (m, 2H), 1.78e1.89 (m,
2H), 1.96e2.05 (m, 4H), 2.30 (s, 6H), 2.85e3.00 (m, 1H),
3.54 (s, 2H), 6.84 (d, J ¼ 5.5 Hz, 1H), 7.16 (t, J ¼ 8.5 Hz,
2H), 7.22 (d, J ¼ 7.2 Hz, 1H), 7.58 (s, 1H), 7.59e7.67 (m,
2H), 8.04 (s, 1H), 8.25 (d, J ¼ 5.5 Hz, 1H), 10.32 (d,
J ¼ 7.2 Hz, 1H). MS (ESIþ) 459.3.
(400 MHz, CDCl3) d 0.92e0.99 (m, 2H), 1.20e1.26 (m,
2H), 1.90e2.05 (m, 1H), 2.29 (s, 6H), 3.53 (s, 2H), 6.84 (d,
J ¼ 5.5 Hz, 1H), 7.12e7.19 (m, 3H), 7.58 (bs, 1H), 7.59e
7.67 (m, 2H), 8.27 (d, J ¼ 5.5 Hz, 1H), 8.52 (bs, 1H), 10.17
(d, J ¼ 7.1 Hz, 1H). MS (ESIþ) 431.3.
4.3.3. N-{4-[7-Dimethylaminomethyl-2-
4.3.7. N-{4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}butyramide (9c)
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}methansulfonamide (9g)
Amide 9c was prepared from 2-aminopyrimidine 8ee
(50.0 mg, 0.138 mmol) and butyryl chloride (16 mg, 16 mL,
0.15 mmol) in pyridine (0.5 mL). Additional butyryl chloride
(8.0 mg, 8.0 mL, 0.075 mmol) was added after 24 h. Yield of
9c: 41.1 mg (69%). H NMR (400 MHz, CDCl3) d 1.06 (t,
J ¼ 7.4 Hz, 3H), 1.77e1.88 (m, 2H), 2.30 (s, 6H), 2.58 (t,
Sulfonamide 9g was prepared from 2-aminopyrimidine 8ee
(50.0 mg, 0.138 mmol) and methanesulfonyl chloride (17 mg,
12 mL, 0.15 mmol) in pyridine (1.5 mL). Additional portions
of methanesulfonyl chloride (8.5 mg, 6.0 mL, 0.075 mmol)
were added after 24 h, 48 h, and 72 h. Yield of 9g: 23.9 mg
1
1
(39%). H NMR (400 MHz, CDCl3) d 2.32 (s, 6H), 3.44 (s,

1348
A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
3H), 3.54 (s, 2H), 6.83 (d, J ¼ 5.7 Hz, 1H), 7.13e7.17 (m,
1H), 7.18 (t, J ¼ 8.8 Hz, 2H), 7.62 (s, 1H), 7.61e7.69 (m,
2H), 8.32 (d, J ¼ 5.7 Hz, 1H), 9.85 (d, J ¼ 7.2 Hz, 1H). MS
(ESIþ) 441.1.
a 60% w/w suspension in mineral oil, 0.29 mmol), then tert-
butyl isocyanate (36 mg, 42 mL, 0.36 mmol). After stirring
for 48 h at room temperature, the reaction was diluted to
10 mL with MeOH, and then purified by HPLC using
a MeOH/H2O gradient, where the aqueous phase was
98.9:1.0:0.1 H2O:CH3CN:Et3N. Yield of 9k: 69.6 mg (55%).
1H NMR (400 MHz, CDCl3) d 1.44 (s, 9H), 2.30 (s, 6H),
3.54 (s, 2H), 6.71 (d, J ¼ 5.5 Hz, 1H), 7.07 (d, J ¼ 7.1 Hz,
1H), 7.14 (t, J ¼ 8.7 Hz, 2H), 7.33 (s, 1H), 7.60 (bs, 1H),
7.61e7.67 (m, 2H), 8.20 (d, J ¼ 5.5 Hz, 1H), 8.95 (bs, 1H),
9.36 (d, J ¼ 7.1 Hz, 1H). MS (ESIþ) 462.4.
4.3.8. N-{4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}-C-phenylmethansulfonamide (9h)
Sulfonamide 9h was prepared from 2-aminopyrimidine 8ee
(50.0 mg, 0.138 mmol) and phenylmethanesulfonyl chloride
(29 mg, 0.15 mmol) in pyridine (1.5 mL). Additional portions
of phenylmethanesulfonyl chloride (15 mg, 0.075 mmol) were
added after 24 h, 48 h, and 72 h. Yield of 9h: 24.2 mg (34%).
1H NMR (400 MHz, CDCl3) d 2.34 (s, 6H), 3.57 (s, 2H), 4.81
(s, 2H), 6.83 (d, J ¼ 5.6 Hz, 1H), 7.10e7.20 (m, 1H), 7.20 (t,
J ¼ 8.7 Hz, 2H), 7.25e7.40 (m, 5H), 7.64 (bs, 1H), 7.62e7.70
(m, 2H), 8.21 (d, J ¼ 5.6 Hz, 1H), 9.90 (d, J ¼ 7.1 Hz, 1H).
MS (ESIþ) 517.2.
4.3.12. {4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl}
carbamic acid methyl ester (9l)
A
solution of 2-aminopyrimidine 8ee (100 mg,
0.276 mmol) in CH2Cl2 (3.0 mL) was charged with Et3N
(84.0 mg, 115 mL, 0.828 mmol) then methyl chloroformate
(52 mg, 42 mL, 0.55 mmol), and the reaction was allowed to
stir at room temperature for 24 h. Additional portions of
Et3N (84.0 mg, 115 mL, 0.828 mmol) and methyl chlorofor-
mate (52 mg, 42 mL, 0.55 mmol) were then added, and the re-
action stirred at room temperature for another 24 h, was then
diluted to 10 mL with MeOH, and then purified by HPLC us-
ing a MeOH/H2O gradient, where the aqueous phase was
98.9:1.0:0.1 H2O:CH3CN:Et3N. Yield of 9l: 49.9 mg (43%).
1H NMR (400 MHz, CDCl3) d 2.31 (s, 6H), 3.54 (s, 2H),
3.89 (s, 3H), 6.84 (d, J ¼ 5.6 Hz, 1H), 7.13e7.22 (m, 3H),
7.59 (bs, 1H), 7.59e7.67 (m, 2H), 8.26 (d, J ¼ 5.6 Hz, 1H),
8.46 (bs, 1H), 10.35 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 421.3.
4.3.9. N-{4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}benzenesulfonamide (9i)
Sulfonamide 9i was prepared from 2-aminopyrimidine 8ee
(50.0 mg, 0.138 mmol) and benzenesulfonyl chloride (27 mg,
19 mL, 0.15 mmol) in pyridine (1.5 mL). Additional portions
of benzenesulfonyl chloride (14 mg, 9.5 mL, 0.075 mmol)
were added after 24 h, 48 h, and 72 h. Yield of 9i: 38.9 mg
1
(56%). H NMR (400 MHz, CDCl3) d 2.33 (s, 6H), 3.57 (s,
2H), 6.75 (d, J ¼ 5.7 Hz, 1H), 7.13 (t, J ¼ 8.7 Hz, 2H), 7.18
(dd, J ¼ 7.2, 1.6 Hz, 1H), 7.40e7.48 (m, 2H), 7.50e7.60 (m,
3H), 7.61 (s, 1H), 8.08 (d, J ¼ 7.4 Hz, 2H), 8.26 (d,
J ¼ 5.7 Hz, 1H), 9.90 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 503.2.
4.3.13. 2-Bromo-3-(4-fluorophenyl)-3-oxopropionic
acid methyl ester (10)
A solution of 3-(4-fluorophenyl)-3-oxopropionic acid
4.3.10. N-{4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl}
formamide (9j)
methyl ester (19.1 g, 97.3 mmol) in CH2Cl2 (250 mL) was
charged with tetra-n-butylammonium tribromide (46.9 g,
97.3 mmol). The reaction stirred at room temperature for
7.5 h, and was then concentrated under reduced pressure,
and chromatographed on SiO2 using a gradient that started
with heptane and ended with 30:70 EtOAc:heptane. Yield of
10: 25.4 g (95%). 1H NMR (400 MHz, CDCl3) d 3.84 (s,
3H), 5.64 (s, 1H), 7.18 (t, J ¼ 8.7 Hz, 2H), 8.00e8.08 (m,
2H). MS (ESIþ) 274.8.
A solution of formic acid (10.2 g, 8.40 mL, 222 mmol), was
chilled to 0 ꢃC in an icewater bath, and then charged with 2-ami-
nopyrimidine 8ee (700 mg, 1.93 mmol) in small portions. After
20 min of stirring, acetic anhydride (2.80 mL, 3.03 g,
29.7 mmol) was added dropwise. The resulting yellow solution
was stirred at 0 ꢃC for 30 min, and then allowed towarm to room
temperature and stir for 3 days. The reaction was then concen-
trated under reduced pressure, then chromatographed on SiO2
using a gradient that started with CH2Cl2 and ended with
90:9:1 CH2Cl2:MeOH:concentrated NH4OH. Yield of 9j:
4.3.14. 2-(4-Fluorophenyl)-7-hydroxymethylimidazo
[1,2-a]pyridine-3-carboxylic acid methyl ester (11)
1
240 mg (32%). H NMR (400 MHz, CDCl3) d 2.31 (s, 6H),
A solution of bromide 10 (11.3 g, 41.1 mmol) in ethanol
(250 mL) was charged with (2-aminopyridin-4-yl)methanol
(5.10 g, 41.1 mmol) and NaHCO3 (3.45 g, 41.1 mmol), and
the reaction was heated at 60 ꢃC for 12 h, then concentrated un-
der reduced pressure and chromatographed on SiO2 first with
30:70 EtOAc:heptane, then with a gradient that started with
10:90 MeOH:CH2Cl2 and ended with 20:80 MeOH:CH2Cl2.
3.55 (s, 2H), 6.89 (d, J ¼ 5.5 Hz, 1H), 7.09 (dd, J ¼ 7.0,
1.5 Hz, 1H), 7.16 (t, J ¼ 8.7 Hz, 2H), 7.58e7.67 (m, 3H),
8.28 (d, J ¼ 5.5 Hz, 1H), 8.41 (d, J ¼ 9.8 Hz, 1H), 9.42 (d,
J ¼ 7.0 Hz, 1H), 9.59 (d, J ¼ 9.8 Hz, 1H). MS (ESIþ) 391.3.
4.3.11. 1-tert-Butyl-3-{4-[7-dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-yl}urea (9k)
A solution of 2-aminopyrimidine 8ee (100 mg, 0.276
mmol) in DMF (2.0 mL) was charged with NaH (7.0 mg of
1
Yield of 11: 4.1 g (33%). H NMR (400 MHz, CDCl3) d 3.84
(s, 3H), 4.82 (s, 2H), 7.05 (dd, J ¼ 7.1, 1.5 Hz, 1H), 7.15 (t,
J ¼ 8.8 Hz, 2H), 7.74 (bs, 1H), 7.72e7.80 (m, 2H), 9.34 (d,
J ¼ 7.1 Hz, 1H). MS (ESIþ) 300.9.

A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
1349
4.3.15. 2-(4-Fluorophenyl)-7-
methanesulfonyloxymethylimidazo[1,2-a]pyridine-
3-carboxylic acid methyl ester (12)
2.50 mmol), and allowed to stir at room temperature for
21 h. Additional portions of ethylmagnesium bromide
(5.00 mL of a 1.0 M solution in THF, 5.00 mmol) were then
added at t ¼ 21 h, 22 h, and 23 h since the start of the reaction,
after which starting material was consumed. The reaction was
then quenched with the dropwise addition of H2O (50 mL),
then concentrated under reduced pressure, then diluted with
a saturated aqueous NaHCO3 solution (100 mL), which was
then extracted into CH2Cl2 (3 ꢀ 200 mL), with filtering of
emulsions when necessary. The organic fractions were pooled,
dried over Na2SO4, filtered and concentrated under reduced
pressure, then chromatographed on SiO2 using a gradient
that started with CH2Cl2 and ended with 90:9:1
CH2Cl2:MeOH:concentrated NH4OH. Yield of 15: 320 mg
(39%). 1H NMR (400 MHz, CDCl3) d 1.03 (t, J ¼ 7.3 Hz,
3H), 2.28 (s, 6H), 2.45 (q, J ¼ 7.3 Hz, 2H), 3.52 (s, 2H),
7.12e7.15 (m, 1H), 7.17 (t, J ¼ 8.6 Hz, 2H), 7.50e7.58 (m,
2H), 7.58 (bs, 1H), 9.66 (d, J ¼ 7.1 Hz, 1H). MS (ESIþ)
326.0.
A solution of alcohol 11 (500 mg, 1.67 mmol) in THF
(100 mL) was charged with methanesulfonyl chloride
(285 mg, 193 mL, 2.49 mmol) and Et3N (337 mg, 464 mL,
3.33 mmol), and the reaction was allowed to stir at room tem-
perature overnight. The reaction was then concentrated under
reduced pressure, suspended with a saturated aqueous
NaHCO3 solution (50 mL), and extracted into CH2Cl2
(2 ꢀ 200 mL). The organic extracts were dried over Na2SO4,
filtered, and concentrated under reduced pressure, and the
product was not purified further. Yield of 12: 630 mg
1
(100%). H NMR (400 MHz, CDCl3) d 3.50 (s, 3H), 3.90 (s,
3H), 4.69 (s, 2H), 7.25 (t, J ¼ 8.8 Hz, 2H), 7.52 (dd, J ¼ 7.2,
1.0 Hz, 1H), 7.80e7.88 (m, 2H), 8.47 (bs, 1H), 9.55 (d,
J ¼ 7.2 Hz, 1H). MS (ESIþ) 378.8.
4.3.16. 7-Dimethylaminomethyl-2-(4-fluorophenyl)
imidazo[1,2-a]pyridine-3-carboxylic
acid methyl ester (13)
4.3.19. 3-Dimethylamino-1-[7-dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-
2-methylpropenone (16)
A solution of mesylate 12 (620 mg, 1.64 mmol) in CH3CN
(100 mL) was charged with diisopropylethylamine (265 mg,
357 mL, 2.04 mmol), then dimethylamine (1.07 mL of
a 2.0 M solution in THF, 2.13 mmol), and allowed to stir at
room temperature for 6 h. The reaction was then concentrated
under reduced pressure and chromatographed on SiO2 using
a gradient that started with CH2Cl2 and ended with 90:9:1
CH2Cl2:MeOH:concentrated NH4OH. Yield of 13: 340 mg
A solution of ketone 15 (360 mg, 1.11 mmol) in DMFDMA
(263 mg, 294 mL, 2.21 mmol) was heated to 100 ꢃC for 7 h to
give enone 16, which was not isolated, but instead was carried
onto the next step. 1H NMR (400 MHz, CDCl3) d 2.09 (s, 3H),
2.34 (s, 6H), 2.76 (s, 6H), 3.52 (s, 2H), 6.89 (s, 1H), 7.00 (d,
J ¼ 7.1 Hz, 1H), 7.09 (t, J ¼ 8.7 Hz, 2H), 7.52 (bs, 1H),
7.63e7.71 (m, 2H), 8.66 (d, J ¼ 7.1 Hz, 1H). MS (ESIþ)
381.0.
1
(63%). H NMR (400 MHz, CDCl3) d 2.30 (s, 6H), 3.54 (s,
2H), 3.83 (s, 3H), 7.09e7.17 (m, 3H), 7.60 (s, 1H), 7.72e
7.80 (m, 2H), 9.31 (d, J ¼ 7.1 Hz, 1H). MS (ESIþ) 328.0.
4.3.20. 4-[7-Dimethylaminomethyl-2-
4.3.17. 7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-
(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxylic acid
methoxymethylamide (14)
5-methylpyrimidin-2-ylamine (17)
Crude reaction mixture of enone 16 (theoretically 422 mg,
1.11 mmol) in DMFDMA (263 mg, 294 mL, 2.21 mmol) was
charged with 1-propanol (4.0 mL), guanidine hydrochloride
(157 mg, 1.65 mmol), and sodium methoxide (89.0 mg of a so-
lution 25% w/v in MeOH, 379 mL, 1.65 mmol), and was
heated to 80 ꢃC for 9 h. The reaction was then concentrated
under reduced pressure, then chromatographed on SiO2 using
a gradient that started with CH2Cl2 and ended with 90:9:1
CH2Cl2:MeOH:concentrated NH4OH. Yield of 17: 117 mg
A solution of ester 13 (8.90 g, 27.2 mmol) in THF
(500 mL) was charged with N,O-dimethylhydroxylamine hy-
drochloride (7.96 g, 81.6 mmol), and was then chilled to
0 ꢃC in an ice water bath. Isopropylmagnesium chloride
(122 mL of a 2.0 M solution in THF, 245 mmol) was then
added dropwise. After 30 min, the reaction was quenched
with the slow addition of a saturated aqueous NH4Cl solution
(250 mL), and extracted into EtOAc (3 ꢀ 250 mL). The or-
ganic extracts were pooled, dried over Na2SO4, filtered, and
concentrated under reduced pressure. Yield of 14: 8.00 g
1
(28% over 2 steps). H NMR (400 MHz, CDCl3) d 1.65 (s,
3H), 2.29 (s, 6H), 3.49 (s, 2H), 5.11e5.19 (m, 2H), 6.91
(dd, J ¼ 7.1, 1.1 Hz, 1H), 7.04 (t, J ¼ 8.7 Hz, 2H), 7.54 (bs,
1H), 7.56e7.64 (m, 2H), 8.16e8.30 (m, 2H). MS (ESIþ)
377.0.
1
(82%). H NMR (400 MHz, CDCl3) d 2.31 (s, 6H), 3.19 (s,
3H), 3.49 (s, 3H), 3.52 (s, 2H), 7.02 (d, J ¼ 7.1 Hz, 1H),
7.14 (t, J ¼ 8.7 Hz, 2H), 7.54 (bs, 1H), 7.74e7.82 (m, 2H),
8.49 (d, J ¼ 7.1 Hz, 1H). MS (ESIþ) 357.0.
4.3.21. 1-[7-Dimethylaminomethyl-2-(4-fluorophenyl)
imidazo[1,2-a]pyridin-3-yl]ethanone (18)
4.3.18. 1-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]propane-
1-one (15)
A solution of Weinreb amide 14 (892 mg, 2.50 mmol) in
THF (100 mL), was charged with the dropwise addition of eth-
ylmagnesium bromide (2.50 mL of a 1.0 M solution in THF,
A solution of Weinreb amide 14 (1.66 g, 4.66 mmol) in
THF (100 mL) was chilled to 0 ꢃC in an ice water bath,
then charged with the dropwise addition of methylmagnesium
bromide (16.7 mL of a 1.4 M solution in 3:1 toluene:THF,
23.3 mmol), and the reaction was allowed to stir at room

1350
A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
temperature overnight, after which it was quenched with the
slow addition of a saturated aqueous NH4Cl solution
(100 mL), and extracted into EtOAc (3 ꢀ 250 mL). The or-
ganic extracts were pooled, dried over Na2SO4, filtered, and
concentrated under reduced pressure, and the residue was
chromatographed on SiO2 using a gradient that started with
CH2Cl2 and ended with 90:9:1 CH2Cl2:MeOH:concentrated
4.3.25. 2-Amino-4-[7-dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine-
5-carbonitrile (22)
The crude reaction mixture of enone 21 (theoretically
231 mg, 0.583 mmol) in DMFDMA (139 mg, 154 mL,
1.17 mmol) was charged with 1-propanol (3.0 mL), guanidine
hydrochloride (83 mg, 0.87 mmol), and sodium methoxide
(47 mg of a 25% w/v solution in MeOH, 200 mL, 0.87 mmol),
and was heated to 80 ꢃC for 12 h. The reaction was then concen-
trated under reduced pressure, and then chromatographed on
SiO2 using a gradient that started with CH2Cl2 and ended with
90:9:1 CH2Cl2:MeOH:concentrated NH4OH, and then purified
by HPLC using a MeOH/H2O gradient, where the aqueous
phase was 98.9:1.0:0.1 H2O:CH3CN:Et3N. Yield of 22:
130 mg (58% over 2 steps). 1H NMR (400 MHz, CDCl3)
d 2.85 (s, 6H), 3.76 (s, 2H), 7.10 (t, J ¼ 8.6 Hz, 2H), 7.15e
7.30 (m, 1H), 7.47e7.55 (m, 2H), 7.58 (bs, 1H), 8.43 (s, 1H),
8.78 (d, J ¼ 6.8 Hz, 1H). MS (ESIþ) 388.0.
1
NH4OH. Yield of 18: 965 mg (67%). H NMR (400 MHz,
CDCl3) d 2.19 (s, 3H), 2.30 (s, 6H), 3.55 (s, 2H), 7.17 (dd,
J ¼ 7.1, 1,2 Hz, 1H), 7.20 (t, J ¼ 8.6 Hz, 2H), 7.54e7.62
(m, 2H), 7.61 (bs, 1H), 9.68 (d, J ¼ 7.1 Hz, 1H). MS
(ESIþ) 311.9.
4.3.22. 2-Bromo-1-[7-dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethanone (19)
A solution of ketone 18 (1.80 g, 5.78 mmol) in AcOH
(300 mL) was charged with the dropwise addition of a solution
of bromine (0.462 g, 148 mL, 2.89 mmol) in AcOH (30 mL),
and the reaction was heated to 90 ꢃC for 12 h. An additional
portion of bromine (0.231 g, 74.0 mL, 1.45 mmol) in AcOH
(20 mL) was then added, and heating at 90 ꢃC continued for
5 h, followed by a third portion of bromine (0.13 g, 37 mL,
0.72 mmol) in AcOH (10 mL) with heating for another 2 h,
then by a fourth portion of bromine (0.063 g, 19 mL,
0.36 mmol) in AcOH (10 mL) with heating for another 1 h, af-
ter which the reaction was concentrated and stored under vac-
uum for 12 h before proceeding to the next step without any
4.3.26. 3-Dimethylamino-1-[7-dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]propenone (23)
A solution of ketone 18 (8.06 g, 25.9 mmol) in DMFDMA
(9.25 g, 10.3 mL, 77.6 mmol) was heated to 90 ꢃC for 12 h.
The reaction was then concentrated under reduced pressure,
and chromatographed on SiO2 using a gradient that started
with CH2Cl2 and ended with 90:9:1 CH2Cl2:MeOH:concen-
trated NH4OH. Yield of 23: 6.89 g (73%). 1H NMR
(400 MHz, CDCl3) d 2.29 (s, 6H), 2.47 (bs, 3H), 3.04 (bs,
3H), 3.50 (s, 2H), 5.10 (d, J ¼ 12.4 Hz, 1H), 7.02 (dd,
J ¼ 7.2, 1.1 Hz, 1H), 7.13 (t, J ¼ 8.6 Hz, 2H), 7.52 (bs, 1H),
7.62 (d, J ¼ 12.4 Hz, 1H), 7.66e7.74 (m, 2H), 9.56 (d,
J ¼ 7.2 Hz, 1H). MS (ESIþ) 367.0.
1
further purification. H NMR (400 MHz, CDCl3) d 2.36 (s,
6H), 3.63 (s, 2H), 3.98 (s, 2H), 7.20e7.30 (m, 3H), 7.61e
7.69 (m, 2H), 7.68 (bs, 1H), 9.67 (d, J ¼ 7.1 Hz, 1H). MS
(ESIþ) 391.8.
4.3.23. 3-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-
3-oxopropionitrile (20)
4.3.27. 3-Dimethylamino-1-[7-dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-2-
fluoropropenone (24)
A solution of crude a-bromoketone 19 (theoretically 2.90 g,
5.78 mmol) in ethanol (450 mL) was chilled to 5 ꢃC in an ice
water bath, then charged with the dropwise addition of sodium
cyanide (3.60 g, 74.3 mmol) dissolved in H2O (70 mL). The
reaction was allowed to warm to room temperature and stir
for 4 h, and was then concentrated under reduced pressure,
then extracted into EtOAc (3 ꢀ 50 mL), dried over Na2SO4,
filtered, and concentrated under reduced pressure. Yield of
A solution of enone 23 (0.610 g, 1.67 mmol) in CH2Cl2
(15 mL) was cooled to ꢂ15 ꢃC, then charged with a solution
of N-fluorobenzensulfonimide (0.63 g) in CH3CN (20 mL),
and the reaction was allowed to warm to room temperature
while stirring for 12 h. The reaction was then concentrated un-
der reduced pressure, then chromatographed on SiO2 using
a gradient that started with CH2Cl2 and ended with 90:9:1
CH2Cl2:MeOH:concentrated NH4OH. Yield of 24: 0.35 g
(55%). The sample was carried directly onto the next step.
1
20: 1.70 g (71% over 2 steps). H NMR (400 MHz, CDCl3)
d 2.35 (s, 6H), 3.53 (s, 2H), 3.63 (s, 2H), 7.27 (t,
J ¼ 8.5 Hz, 2H), 7.33 (d, J ¼ 7.0 Hz, 1H), 7.54e7.62 (m,
2H), 7.70 (bs, 1H), 9.63 (d, J ¼ 7.0 Hz, 1H). MS (ESIþ)
336.9.
4.3.28. 4-[7-Dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-
5-fluoropyrimidin-2-ylamine (25)
A solution of enone 24 (170 mg, 0.442 mmol) in 1-propa-
nol (5 mL) was charged with guanidine hydrochloride
(63 mg, 0.66 mmol), then sodium methoxide (25% w/v in
MeOH, 143 mg, 151 mL, 0.662 mmol), and the reaction was
heated to 80 ꢃC for 2 h. The reaction was then concentrated
under reduced pressure, then chromatographed on SiO2 using
a gradient that started with CH2Cl2 and ended with 90:9:1
CH2Cl2:MeOH:concentrated NH4OH. The product mixture
4.3.24. 3-Dimethylamino-2-[7-dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridine-3-
carbonyl]acrylonitrile (21)
A solution of a-cyanoketone 20 (196 mg, 0.583 mmol) in
DMFDMA (139 mg, 154 mL, 1.17 mmol) was heated to
80 ꢃC for 6 h to give enone 21, which was not isolated, but in-
stead was carried onto the next step.

A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
1351
isolated was then purified by HPLC using a MeOH/H2O gra-
dient, where the aqueous phase was 98.9:1.0:0.1 H2O:CH3C-
appropriate ester dissolved in THF was then added, and the re-
action was allowed to warm to room temperature while stirring
for 12 h. The reaction was then concentrated under reduced
pressure, suspended in EtOAc and washed with a saturated
aqueous NH4Cl solution. The organic solution was dried
with Na2SO4, filtered, and concentrated under reduced pres-
sure. The solid obtained was washed with heptane, from which
additional batches of product could be obtained by crystalliza-
tion upon freezing. Any modifications to this procedure are
noted below.
1
N:Et3N. Yield of 25: 21.7 mg (13%). H NMR (400 MHz,
CD3OD) d 2.32 (s, 6H), 3.60 (s, 2H), 7.08 (dd, J ¼ 7.3,
1.7 Hz, 1H), 7.14 (t, J ¼ 8.8 Hz, 2H), 7.58e7.60 (m, 1H),
7.57e7.65 (m, 2H), 8.19 (d, J ¼ 2.5 Hz, 1H), 8.90 (d,
J ¼ 7.3 Hz, 1H). MS (ESIþ) 381.3.
4.3.29. 5-Bromo-4-[7-dimethylaminomethyl-2-
(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-ylamine (26)
A solution of 2-aminopyrimidine 8ee (50 mg, 0.14 mmol)
in ethanol (5.0 mL) was charged with N-bromosuccinimide
(25 mg, 0.14 mmol), and the reaction was stirred at room tem-
perature for 12 h. The reaction was then concentrated under
reduced pressure, then chromatographed on SiO2 using a gradi-
ent that started with CH2Cl2 and ended with 90:9:1
CH2Cl2:MeOH:concentrated NH4OH. Yield of 26: 24 mg
4.5.1. 1-(3-Bromo-4-fluorophenyl)-2-
(2-methylsulfanylpyrimidin-4-yl)ethanone and 1-
(3-bromo-4-fluorophenyl)-2-(2-methylsulfanylpyrimidin-
4-yl)ethenol (28a)
Ketone/enol mixture 28a was prepared from 4-methylpyri-
midine 1 (7.05 g, 50.3 mmol), ester 27a (12.9 g, 55.3 mmol),
and lithium diisopropylamide (27.7 mL of a 2.0 M solution
in THF, 55.3 mmol) in THF (20 mL). Yield of 28a: 6.78 g
(36%) as a 2.6:1.0 mixture of enol:ketone tautomers. 1H
NMR (400 MHz, CDCl3) d enol tautomer: 2.64 (s, 3H), 5.93
(s, 1H), 6.68 (d, J ¼ 5.4 Hz, 1H), 7.19 (t, J ¼ 8.4 Hz, 1H),
7.70e7.83 (m, 1H), 8.06 (dd, J ¼ 6.5, 1.9 Hz, 1H), 8.34 (d,
J ¼ 5.4 Hz, 1H); ketone tautomer: 2.54 (s, 3H), 4.34 (s, 2H),
6.99 (d, J ¼ 4.9 Hz, 1H), 7.21e7.25 (m, 1H), 7.70e7.83 (m,
1H), 7.99e8.05 (m, 1H), 8.48 (d, J ¼ 4.9 Hz, 1H). MS
(ESIþ) 342.5.
1
(40%). H NMR (400 MHz, CDCl3) d 2.32 (s, 6H), 3.53 (s,
2H), 5.37 (bs, 2H), 6.99 (dd, J ¼ 7.1, 1.2 Hz, 1H), 7.06 (t,
J ¼ 8.7 Hz, 2H), 7.57 (bs, 1H), 7.57e7.65 (m, 2H), 8.15 (d,
J ¼ 7.1 Hz, 1H), 8.47 (s, 1H). MS (ESIþ) 442.8.
4.4. General procedure for the synthesis of methyl esters
27aeb
A solution of appropriate benzoic acid in MeOH was
charged with concentrated H2SO4 and heated at 80 ꢃC for
the time specified. The reaction was then concentrated under
reduced pressure, suspended in a saturated aqueous NaHCO3
solution, and extracted into EtOAc. The organic extracts
were then pooled, dried over Na2SO4, filtered, and concen-
trated under reduced pressure.
4.5.2. 1-(4-Fluoro-3-methylphenyl)-2-
(2-methylsulfanylpyrimidin-4-yl)ethanone and 1-(4-fluoro-
3-methylphenyl)-2-(2-methylsulfanylpyrimidin-4-yl)ethenol
(28b)
Ketone/enol mixture 28b was prepared from 4-methylpyri-
midine 1 (10.0 g, 71.3 mmol), ester 27b (13.2 g, 78.5 mmol),
and lithium diisopropylamide (46.0 mL of a 2.0 M solution
in heptane/THF/ethylbenzene, 92.7 mmol) in THF (250 mL).
Yield of 28b: 7.22 g (37%) as a 1.3:1.0 mixture of enol:ketone
tautomers. 1H NMR (400 MHz, CDCl3) d enol tautomer: 2.34
(s, 3H), 2.62 (s, 3H), 5.91 (s, 1H), 6.63 (d, J ¼ 5.4 Hz, 1H),
7.05 (t, J ¼ 8.8 Hz, 1H), 7.61e7.67 (m, 1H), 7.68 (d,
J ¼ 7.3 Hz, 1H), 8.30 (d, J ¼ 5.4 Hz, 1H); ketone tautomer:
2.34 (s, 3H), 2.54 (s, 3H), 4.34 (s, 2H), 6.98 (d, J ¼ 5.1 Hz,
1H), 7.09 (t, J ¼ 8.8 Hz, 1H), 7.84e7.91 (m, 1H), 7.92
(d, J ¼ 7.3 Hz, 1H), 8.45 (d, J ¼ 5.1 Hz, 1H). MS (ESIþ)
276.9.
4.4.1. 3-Bromo-4-fluorobenzoic acid methyl ester (27a)
Methyl ester 27a was prepared from 3-bromo-4-fluoroben-
zoic acid (24.0 g, 110 mmol) and concentrated H2SO4
(1.0 mL) in MeOH (400 mL), with heating at 80 ꢃC for 36 h.
Yield of 27a: 23.7 g (92%). 1H NMR (400 MHz, CDCl3)
d 3.93 (s, 3H), 7.18 (t, J ¼ 8.3 Hz, 1H), 7.91e8.10 (m, 1H),
8.28 (dd, J ¼ 6.6, 2.1 Hz, 1H).
4.4.2. 4-Fluoro-3-methylbenzoic acid methyl ester (27b)
Methyl ester 27b was prepared from 4-fluoro-3-methylben-
zoic acid (15.0 g, 97.3 mmol) and concentrated H2SO4
(1.0 mL) in MeOH (200 mL), with heating to 80 ꢃC for
18 h. Yield of 27b: 13.4 g (82%). 1H NMR (400 MHz,
CDCl3) d 2.32 (s, 3H), 3.91 (s, 3H), 7.05 (t, J ¼ 8.9 Hz,
1H), 7.82e7.89 (m, 1H), 7.91 (d, J ¼ 7.4 Hz, 1H).
4.5.3. 1-(4-Chlorophenyl)-2-(2-methylsulfanylpyrimidin-4-yl)
ethanone and 1-(4-chlorophenyl)-2-
(2-methylsulfanylpyrimidin-4-yl)ethenol (28c)
Ketone/enol mixture 28c was prepared from 4-methylpyri-
midine 1 (10.1 g, 71.9 mmol), 4-chlorobenzoic acid methyl es-
ter (13.5 g, 79.1 mmol), and lithium diisopropylamide
(46.8 mL of 2.0 M solution in heptane/THF/ethylbenzene,
93.5 mmol) in THF (250 mL). Yield of 28c: 7.38 g (37%) as
a 2.7:1.0 mixture of enol:ketone tautomers. 1H NMR
(400 MHz, CDCl3) d enol tautomer: 2.62 (s, 3H), 5.96 (s,
1H), 6.66 (d, J ¼ 5.4 Hz, 1H), 7.41 (d, J ¼ 8.6 Hz, 2H), 7.99
4.5. General procedure for the synthesis of ketones
28aed
A solution of 4-methylpyrimidine 1 in THF was cooled to
ꢂ78 ꢃC in a CO2/IPA bath, then charged with the dropwise ad-
dition of lithium diisopropylamide (2.0 M in heptane/THF/eth-
ylbenzene), and allowed to stir at ꢂ78 ꢃC for 1 h. A solution of

1352
A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
(d, J ¼ 8.6 Hz, 2H), 8.33 (d, J ¼ 5.4 Hz, 1H); ketone tautomer:
2.52 (s, 3H), 4.35 (s, 2H), 6.98 (d, J ¼ 5.1 Hz, 1H), 7.46 (d,
J ¼ 8.6 Hz, 2H), 7.99 (d, J ¼ 8.6 Hz, 2H), 8.47 (d,
J ¼ 5.1 Hz, 1H). MS (ESIþ) 278.8.
4.6.3. 2-Bromo-1-(4-fluoro-3-methylphenyl)-2-
(2-methylsulfanylpyrimidin-4-yl)ethanone (29b)
Bromide 29b was prepared from ketone/enol mixture 28b
(7.20 g, 26.1 mmol) and tetra-n-butylammonium tribromide
(12.6 g, 26.1 mmol) in CH2Cl2 (200 mL). Yield of 29b:
4.60 g (50%).
4.5.4. 1-(2,4-Difluorophenyl)-2-(2-methylsulfanylpyrimidin-
4-yl)ethanone and 1-(2,4-difluorophenyl)-2-
(2-methylsulfanylpyrimidin-4-yl)ethenol (28d)
4.6.4. [2-(4-Fluoro-3-methylphenyl)-3-
Ketone/enol mixture 28d was prepared from 4-methylpyri-
midine 1 (10.0 g, 71.3 mmol), 2,4-difluorobenzoic acid methyl
ester (14.6 g, 78.4 mmol), and lithium diisopropylamide
(46.3 mL of a 2.0 M solution in heptane/THF/ethylbenzene,
92.7 mmol) in THF (250 mL). Yield of 28d: 9.90 g (50%) as
a 3.5:1.0 mixture of enol:ketone tautomers. 1H NMR
(400 MHz, CDCl3) d enol tautomer: 2.62 (s, 3H), 6.14 (s,
1H), 6.68 (d, J ¼ 5.4 Hz, 1H), 6.86e7.03 (m, 2H), 7.89e
7.97 (m, 1H), 8.35 (d, J ¼ 5.4 Hz, 1H); ketone tautomer:
2.49 (s, 3H), 4.37 (d, J ¼ 2.9 Hz, 2H), 6.86e7.03 (m, 3H),
7.95e8.04 (m, 1H), 8.48 (d, J ¼ 5.0 Hz, 1H). MS (ESIþ)
280.9.
(2-methylsulfanylpyrimidin-4-yl)imidazo[1,2-a]pyridin-
7-yl]methanol (30b)
Imidazopyridine 30b was prepared from bromide 29b
(4.50 g, 12.7 mmol), (2-aminopyridin-4-yl)methanol (1.58 g,
12.7 mmol), and Na2CO3 (2.13 g, 25.3 mmol) in ethanol
1
(100 mL). Yield of 30b: 2.10 g (44%). H NMR (400 MHz,
CDCl3) d 2.33 (s, 3H), 2.66 (s, 3H), 4.83 (s, 2H), 6.85 (d,
J ¼ 5.4 Hz, 1H), 6.99 (dd, J ¼ 7.2, 1.4 Hz, 1H), 7.06 (t,
J ¼ 8.9 Hz, 1H), 7.33e7.43 (m, 1H), 7.52 (d, 1H), 7.69 (bs,
1H), 8.29 (d, J ¼ 5.4 Hz, 1H), 9.57 (d, J ¼ 7.2 Hz, 1H). MS
(ESIþ) 380.9.
4.6.5. 2-Bromo-1-(4-chlorophenyl)-2-
4.6. General procedure for the synthesis of bromides
29aed and imidazopyridines 30aed
(2-methylsulfanylpyrimidin-4-yl)ethanone (29c)
Bromide 29c was prepared from ketone/enol mixture 28c
(7.38 g, 26.5 mmol) and tetra-n-butylammonium tribromide
(12.8 g, 26.5 mmol) in CH2Cl2 (250 mL). Yield of 29c:
4.65 g (49%).
A solution of appropriate ketone 28aed (1.0 equivalent) in
CH2Cl2 was charged with tetra-n-butylammonium tribromide
(1.0 equivalent). The reaction was stirred at room temperature
for 3 h, and was then concentrated under reduced pressure, and
chromatographed on SiO2 using a gradient that started with
heptane and ended with 25:75 EtOAc:heptane. A solution of
appropriate bromide 29aed (1.0 equivalent) in ethanol was
then charged with (2-aminopyridin-4-yl)methanol (1.0 equiva-
lent), and the reaction was heated to 60 ꢃC for 12 h. The reac-
tion was then concentrated under reduced pressure, then
chromatographed on SiO2 using a gradient that started
with CH2Cl2 and ended with 90:9:1 CH2Cl2:MeOH:concen-
trated NH4OH. Any modifications to this procedure are noted
below.
4.6.6. [2-(4-Chlorophenyl)-3-(2-methylsulfanylpyrimidin-
4-yl)imidazo[1,2-a]pyridin-7-yl]methanol (30c)
Imidazopyridine 30c was prepared from bromide 29c
(4.65 g, 13.0 mmol), (2-aminopyridin-4-yl)methanol (1.61 g,
13.0 mmol), and in this case NaHCO3 (2.18 g, 26.0 mmol)
1
in ethanol (100 mL). Yield of 30c: 2.13 g (43%). H NMR
(400 MHz, CDCl3) d 2.65 (s, 3H), 4.82 (s, 2H), 6.83 (d,
J ¼ 5.4 Hz, 1H), 6.98 (dd, J ¼ 7.3, 1.6 Hz, 1H), 7.43 (d,
J ¼ 8.5 Hz, 2H), 7.59 (d, J ¼ 8.5 Hz, 2H), 7.71 (bs, 1H),
8.32 (d, J ¼ 5.4 Hz, 1H), 9.52 (d, J ¼ 7.3 Hz, 1H). MS
(ESIþ) 382.8.
4.6.1. 2-Bromo-1-(3-bromo-4-fluorophenyl)-2-
(2-methylsulfanylpyrimidin-4-yl)ethanone (29a)
Bromide 29a was prepared from ketone/enol mixture 28a
(6.51 g, 19.1 mmol) and tetra-n-butylammonium tribromide
(9.20 g, 19.1 mmol) in CH2Cl2 (200 mL). Yield of 29a:
3.68 g (46%).
4.6.7. 2-Bromo-1-(2,4-difluorophenyl)-2-
(2-methylsulfanylpyrimidin-4-yl)ethanone (29d)
Bromide 29d was prepared from ketone/enol mixture 28d
(9.90 g, 35.3 mmol) and tetra-n-butylammonium tribromide
(17.0 g, 35.3 mmol) in CH2Cl2 (250 mL). Yield of 29d:
8.60 g (68%).
4.6.2. [2-(3-Bromo-4-fluorophenyl)-3-
(2-methylsulfanylpyrimidin-4-yl)imidazo[1,2-a]pyridin-
7-yl]methanol (30a)
4.6.8. [2-(2,4-Difluorophenyl)-3-
(2-methylsulfanyl)pyrimidin-4-yl)imidazo[1,2-a]pyridin-
7-yl]methanol (30d)
Imidazopyridine 30d was prepared from bromide 29d
(8.60 g, 23.9 mmol), (2-aminopyridin-4-yl)methanol (2.97 g,
23.9 mmol), and in this case NaHCO3 (2.00 g, 23.9 mmol)
Imidazopyridine 30a was prepared from bromide 29a
(3.68 g, 8.76 mmol) and (2-aminopyridin-4-yl)methanol
(1.08 g, 8.76 mmol) in ethanol (200 mL). Yield of 30a:
1
1.72 g (44%). H NMR (400 MHz, CDCl3) d 2.66 (s, 3H),
1
4.84 (s, 2H), 6.84 (d, J ¼ 5.4 Hz, 1H), 7.02 (d, J ¼ 7.0 Hz,
1H), 7.19 (t, J ¼ 8.4 Hz, 1H), 7.52e7.59 (m, 1H), 7.73 (bs,
1H), 7.92 (dd, J ¼ 6.5, 1.7 Hz, 1H), 8.36 (d, J ¼ 5.4 Hz, 1H),
9.50 (d, J ¼ 7.0 Hz, 1H). MS (ESIþ) 446.6.
in ethanol (100 mL). Yield of 30d: 3.50 g (38%). H NMR
(400 MHz, CDCl3) d 2.64 (s, 3H), 4.82 (s, 2H), 6.72 (dd,
J ¼ 5.4, 0.5 Hz, 1H), 6.90e6.96 (m, 1H), 7.01 (dd, J ¼ 7.3,
1.6 Hz, 1H), 7.05 (dt, J ¼ 8.4, 2.4 Hz, 1H), 7.65 (dd,

A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
1353
J ¼ 14.8, 8.4 Hz, 1H), 7.71 (bs, 1H), 8.32 (d, J ¼ 5.4 Hz, 1H),
9.66 (d, J ¼ 7.3 Hz, 1H). MS (ESIþ) 384.9.
reaching 40e50 psi. Pressure was then released, and the reac-
tion mixture was concentrated under reduced pressure, then
chromatographed on SiO2 using a gradient that started with
CH2Cl2 and ended with 90:9:1 CH2Cl2:MeOH:concentrated
NH4OH. Any modifications to this procedure are noted below.
4.7. General procedure for the synthesis of sulfones
31aed
A solution of appropriate sulfide (30aed) in MeOH/ace-
tone was charged with an aqueous solution of OXONEÒ and
the reaction was stirred at room temperature for 12 h. The re-
action was then concentrated under reduced pressure to re-
move as much organic solvent as possible, then diluted with
additional H2O, and filtered. The filter cake was then dried
in a vacuum oven at 60 ꢃC for 4 h. The filtrate was back ex-
tracted with CH2Cl2, which was then dried with Na2SO4, fil-
tered, and concentrated under reduced pressure to yield
additional product. Any modifications to this procedure are
noted below.
4.8.1. [3-(2-Aminopyrimidin-4-yl)-2-(3-bromo-
4-fluorophenyl)imidazo[1,2-a]pyridin-7-yl]methanol (32a)
2-Aminopyrimdine 32a was prepared from sulfone 31a
(1.59 g, 3.33 mmol) and ammonia (42.4 g, 2.49 mol) in THF
1
(100 mL). Yield of 32a: 920 mg (67%). H NMR (400 MHz,
CDCl3) d 4.84 (s, 2H), 5.48 (bs, 2H), 6.56 (d, J ¼ 5.5 Hz,
1H), 6.98e7.04 (m, 1H), 7.19 (t, J ¼ 8.4 Hz, 1H), 7.54e7.60
(m, 1H), 7.72 (bs, 1H), 7.94 (dd, J ¼ 6.5, 1.9 Hz, 1H), 8.13
(d, J ¼ 5.5 Hz, 1H), 9.47 (d, J ¼ 7.3 Hz, 1H). MS (ESIþ) 413.7.
4.8.2. [3-(2-Aminopyrimidin-4-yl)-2-(4-fluoro-
3-methylphenyl)imidazo[1,2-a]pyridin-7-yl]methanol (32b)
2-Aminopyrimdine 32b was prepared from sulfone 31b
(2.03 g, 4.92 mmol) and ammonia (18.2 g, 1.07 mol) in THF
4.7.1. [2-(3-Bromo-4-fluorophenyl)-3-
(2-methanesulfonylpyrimidin-4-yl)imidazo[1,2-a]pyridin-
7-yl]methanol (31a)
1
(200 mL). Yield of 32b: 1.10 g (64%). H NMR (400 MHz,
Sulfone 31a was prepared from sulfide 30a (1.72 g,
3.86 mmol) in MeOH (80 mL)/acetone (80 mL) that was
charged with OXONEÒ (7.12 g, 11.6 mmol) dissolved in
H2O (80 mL). Yield of 31a: 1.59 g (86%). MS (ESIþ) 478.7.
CDCl3) d 2.33 (s, 3H), 4.82 (s, 2H), 5.57 (bs, 2H), 6.55 (d,
J ¼ 5.5 Hz, 1H), 7.00 (d, J ¼ 7.4 Hz, 1H), 7.05 (t,
J ¼ 8.9 Hz, 1H), 7.35e7.41 (m, 1H), 7.52 (dd, J ¼ 7.4,
1.0 Hz, 1H), 7.73 (s, 1H), 8.05 (d, J ¼ 5.5 Hz, 1H), 9.52 (d,
J ¼ 7.4 Hz, 1H). MS (ESIþ) 349.9.
4.7.2. [2-(4-Fluoro-3-methylphenyl)-3-
(2-methanesulfonylpyrimidin-4-yl)imidazo[1,2-a]pyridin-
7-yl]methanol (31b)
Sulfone 31b was prepared from sulfide 30b (2.10 g,
5.52 mmol) in MeOH (125 mL)/acetone (100 mL) that was
charged with OXONEÒ (10.2 g, 16.6 mmol) dissolved in
H2O (90 mL). Yield of 31b: 2.03 g (89%). MS (ESIþ) 412.9.
4.8.3. [3-(2-Aminopyrimidin-4-yl)-2-
(4-chlorophenyl)imidazo[1,2-a]pyridin-7-yl]methanol (32c)
2-Aminopyrimdine 32c was prepared from sulfone 31c
(1.65 g, 3.98 mmol) and ammonia (15.0 g, 881 mmol) in
THF (200 mL). Yield of 32c: 0.75 g (54%). 1H NMR
(400 MHz, CDCl3) d 4.72 (s, 2H), 5.32 (bs, 2H), 6.50 (d,
J ¼ 5.4 Hz, 1H), 6.86 (dd, J ¼ 7.2, 1.3 Hz, 1H), 7.38 (d,
J ¼ 8.5 Hz, 2H), 7.57 (d, J ¼ 8.5 Hz, 2H), 7.62 (bs, 1H),
8.11 (d, J ¼ 5.4 Hz, 1H), 9.31 (d, J ¼ 7.2 Hz, 1H). MS
(ESIþ) 351.9.
4.7.3. [2-(4-Chlorophenyl)-3-(2-methanesulfonylpyrimidin-
4-yl)imidazo[1,2-a]pyridin-7-yl]methanol (31c)
Sulfone 31c was prepared from sulfide 30c (2.13 g,
5.56 mmol) in MeOH (100 mL)/acetone (75 mL) that was
charged with OXONEÒ (10.3 g, 16.7 mmol) dissolved in
H2O (90 mL). Yield of 31c: 1.65 g (71%). MS (ESIþ) 414.8.
4.8.4. [3-(2-Aminopyrimidin-4-yl)-2-(2,
4-difluorophenyl)imidazo[1,2-a]pyridin-7-yl]methanol
(32d)
4.7.4. [2-(2,4-Difluorophenyl)-3-
(2-methanesulfonylpyrimidin-4-yl)imidazo[1,2-a]pyridin-
7-yl]methanol (31d)
Sulfone 31d was prepared from sulfide 30d (3.50 g,
9.11 mmol) in MeOH (220 mL)/acetone (160 mL) that was
charged with OXONEÒ (16.8 g, 27.3 mmol) dissolved in
H2O (150 mL). Yield of 31d: 2.88 g (76%). MS (ESIþ) 416.8.
2-Aminopyrimdine 32d was prepared from sulfone 31d
(2.88 g, 6.92 mmol) and ammonia (11.5 g, 675 mmol) in
THF (100 mL). Yield of 32d: 1.29 g (53%). 1H NMR
(400 MHz, CDCl3) d 4.83 (s, 2H), 5.38 (bs, 2H), 6.43 (d,
J ¼ 5.4 Hz, 1H), 6.92 (t, J ¼ 9.2 Hz, 1H), 7.00 (d,
J ¼ 7.0 Hz, 1H), 7.01e7.08 (m, 1H), 7.61e7.69 (m, 1H),
7.71 (bs, 1H), 8.10 (d, J ¼ 5.4 Hz, 1H), 9.61 (d, J ¼ 7.0 Hz,
1H). MS (ESIþ) 353.9.
4.8. General procedure for the synthesis of
2-aminopyrimidines 32aed
4.9. General procedure for the synthesis of aldehydes
33aed
A mixture of appropriate sulfone (31aed) in THF in a pres-
sure bottlewas cooled to ꢂ78 ꢃC in a CO2/IPA bath, and charged
with excess ammonia gas that was bubbled in over 10e15 min.
The reaction vessel was then sealed, and the reaction was al-
lowed to warm to room temperature with stirring for 12 h, while
A solution of appropriate alcohol 32aed in CH2Cl2 was
charged with excess manganese(IV) oxide, and the reaction
was allowed to stir for 12 h at room temperature. The reaction
was then filtered through celite, and the celite filter cake was

1354
A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
then rinsed with additional CH2Cl2 and/or EtOAc. The com-
bined filtrates were concentrated under reduced pressure to
yield aldehydes 33aed, which were not purified further.
Any modifications to this procedure are noted below.
with CH2Cl2 and ended with 90:9:1 CH2Cl2:MeOH:concen-
trated NH4OH. Any modifications to this procedure are noted
below.
4.10.1. 4-[2-(3-Bromo-4-fluorophenyl)-
4.9.1. 3-(2-Aminopyrimidin-4-yl)-2-(3-bromo-
4-fluorophenyl)imidazo[1,2-a]pyridine-7-carbaldehyde
(33a)
7-dimethylaminomethylimidazo[1,2-a]pyridin-
3-yl]pyrimidin-2-ylamine (34a)
Amine 34a was prepared from aldehyde 33a (520 mg, 1.26
mmol), dimethylamine (945 mL of a 2.0 M solution in THF,
1.89 mmol), and sodium triacetoxyborohydride (401 mg,
1.89 mmol) in THF (100 mL). Yield of 34a: 250 mg (45%).
The product was then purified further by HPLC using
a MeOH/H2O gradient, where the aqueous phase was
98.9:1.0:0.1 H2O:CH3CN:Et3N. Final yield of 34a: 161 mg
Aldehyde 33a was prepared from alcohol 32a (910 mg,
2.20 mmol) and manganese(IV) oxide (4.77 g, 54.9 mmol).
1
Yield of 33a: 530 mg (58%). H NMR (400 MHz, CDCl3)
d 5.31 (bs, 2H), 6.60 (d, J ¼ 5.3 Hz, 1H), 7.20 (t, J ¼ 8.4 Hz,
1H), 7.45 (dd, J ¼ 7.3, 1.5 Hz, 1H), 7.50e7.64 (m, 1H), 7.97
(dd, J ¼ 6.6, 2.1 Hz, 1H), 8.17 (bs, 1H), 8.25 (d, J ¼ 5.3 Hz,
1H), 9.43 (d, J ¼ 7.3 Hz, 1H), 10.07 (s, 1H). MS (ESIþ) 411.7.
1
(29%). H NMR (400 MHz, CDCl3) d 2.30 (s, 6H), 3.52 (s,
2H), 5.25 (bs, 2H), 6.53 (d, J ¼ 5.3 Hz, 1H), 7.02 (dd,
J ¼ 7.2, 1.4 Hz, 1H), 7.15 (t, J ¼ 8.4 Hz, 1H), 7.48e7.61 (m,
2H), 7.94 (dd, J ¼ 6.6, 2.1 Hz, 1H), 8.16 (d, J ¼ 5.3 Hz, 1H),
9.35 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 440.7.
4.9.2. 3-(2-Aminopyrimidin-4-yl)-2-(4-fluoro-
3-methylphenyl)imidazo[1,2-a]pyridine-7-carbaldehyde
(33b)
Aldehyde 33b was prepared from alcohol 32b (730 mg,
2.09 mmol) and manganese(IV) oxide (4.54 g, 52.2 mmol).
1
Yield of 33b: 540 mg (75%). H NMR (400 MHz, CDCl3)
d 2.34 (s, 3H), 5.26 (bs, 2H), 6.60 (d, J ¼ 5.3 Hz, 1H), 7.07
(t, J ¼ 8.9 Hz, 1H), 7.38e7.46 (m, 2H), 7.57 (dd, J ¼ 7.2,
1.3 Hz, 1H), 8.17 (bs, 1H), 8.20 (d, J ¼ 5.3 Hz, 1H), 9.50 (d,
J ¼ 7.2 Hz, 1H), 10.06 (s, 1H). MS (ESIþ) 347.9.
4.10.2. 4-[7-Dimethylaminomethyl-2-(4-fluoro-
3-methylphenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-
2-ylamine (34b)
Amine 34b was prepared from aldehyde 33b (540 mg,
1.55 mmol),dimethylamine(1.17 mLofa2.0 MsolutioninTHF,
2.33 mmol), and sodium triacetoxyborohydride (493 mg,
2.33 mmol) in THF (100 mL). Yield of 34b: 389 mg (67%). 1H
NMR (400 MHz, CDCl3) d 2.30 (s, 6H), 2.31 (s, 3H), 3.51 (s,
2H), 5.25 (bs, 2H), 6.54 (d, J ¼ 5.3 Hz, 1H), 6.97e7.06 (m,
2H), 7.35e7.42 (m, 1H), 7.51e7.56 (m, 2H), 8.11 (d,
J ¼ 5.3 Hz, 1H), 9.42 (d, J ¼ 7.1 Hz, 1H). MS (ESIþ) 377.0.
4.9.3. 3-(2-Aminopyrimidin-4-yl)-2-
(4-chlorophenyl)imidazo[1,2-a]pyridine-7-carbaldehyde
(33c)
Aldehyde 33c was prepared from alcohol 32c (620 mg,
1.76 mmol) and manganese(IV) oxide (3.83 g, 44.1 mmol).
1
Yield of 33c: 290 mg (47%). H NMR (400 MHz, CDCl3)
4.10.3. 4-[2-(4-Chlorophenyl)-
d 5.63 (bs, 2H), 6.62 (d, J ¼ 5.5 Hz, 1H), 7.43e7.50 (m,
3H), 7.63 (d, J ¼ 8.4 Hz, 2H), 8.16 (d, J ¼ 5.5 Hz, 1H), 8.20
(bs, 1H), 9.52 (d, J ¼ 7.3 Hz, 1H), 10.08 (s, 1H). MS
(ESIþ) 349.8.
7-dimethylaminomethylimidazo[1,2-a]pyridin-
3-yl]pyrimidin-2-ylamine (34c)
Amine 34c was prepared from aldehyde 33c (290 mg,
0.829 mmol), dimethylamine (620 mL of a 2.0 M solution in
THF, 1.24 mmol), and sodium triacetoxyborohydride (352
mg, 1.66 mmol) in THF (100 mL). Yield of 34c: 185 mg
4.9.4. 3-(2-Aminopyrimidin-4-yl)-2-
(2,4-difluorophenyl)imidazo[1,2-a]pyridine-7-carbaldehyde
(33d)
Aldehyde 33d was prepared from alcohol 32d (970 mg,
2.75 mmol) and manganese(IV) oxide (5.98 g, 68.8 mmol).
1
Yield of 33d: 670 mg (70%). H NMR (400 MHz, CDCl3)
d 5.26 (bs, 2H), 6.48 (d, J ¼ 5.3 Hz, 1H), 6.90e6.99 (m,
1H), 7.07 (td, J ¼ 8.3, 1.6 Hz, 1H), 7.47 (dd, J ¼ 7.3, 1.6 Hz,
1H), 7.69 (td, J ¼ 8.3, 6.5 Hz, 1H), 8.17e8.23 (m, 2H), 9.63
(d, J ¼ 7.3 Hz, 1H), 10.08 (s, 1H). MS (ESIþ) 351.9.
1
(59%). H NMR (400 MHz, CDCl3) d 2.31 (s, 6H), 3.53 (s,
2H), 5.22 (bs, 2H), 6.53 (d, J ¼ 5.3 Hz, 1H), 7.02 (d,
J ¼ 7.1 Hz, 1H), 7.40 (d, J ¼ 8.4 Hz, 2H), 7.56 (bs, 1H),
7.61 (d, J ¼ 8.4 Hz, 2H), 8.14 (d, J ¼ 5.3 Hz, 1H), 9.37 (d,
J ¼ 7.1 Hz, 1H). MS (ESIþ) 379.0.
4.10.4. 4-[2-(2,4-Difluorophenyl)-
7-dimethylaminomethylimidazo[1,2-a]pyridin-
3-yl]pyrimidin-2-ylamine (34d)
Amine 34d was prepared from aldehyde 33d (670 mg,
1.91 mmol), dimethylamine (1.43 mL of a 2.0 M solution in
THF, 2.87 mmol), and sodium triacetoxyborohydride (810
mg, 3.82 mmol) in THF (250 mL). Yield of 34d: 340 mg
4.10. General procedure for the synthesis of tertiary
amines 34aed
1
A solution of appropriate aldehyde 33aed in THF was
charged with dimethylamine (2.0 M in THF) and sodium tria-
cetoxyborohydride. After stirring at room temperature for
12 h, the reaction was concentrated under reduced pressure,
then chromatographed on SiO2 using a gradient that started
(47%). H NMR (400 MHz, CDCl3) d 2.36 (s, 6H), 3.60 (s,
2H), 5.16 (bs, 2H), 6.41 (d, J ¼ 5.3 Hz, 1H), 6.88e6.95 (m,
1H), 7.00e7.06 (m, 1H), 7.12 (d, J ¼ 7.1 Hz, 1H), 7.58 (bs,
1H), 7.60e7.69 (m, 1H), 8.13 (d, J ¼ 5.3 Hz, 1H), 9.57 (d,
J ¼ 7.1 Hz, 1H). MS (ESIþ) 380.9.

A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
1355
4.10.5. 3-Oxo-3-(2,4,6-trifluorophenyl)propionic acid ethyl
ester (35)
29.7 mmol), then methanesulfonyl chloride (2.55 g, 1.73 mL,
22.3 mmol), and the reaction stirred at room temperature for
2 h, and was then concentrated under reduced pressure and
A solution of monoethyl malonate (1.19 g, 9.00 mmol) in
THF (200 mL) was cooled to ꢂ78 ꢃC in a CO2/IPA bath,
and charged with the dropwise addition of n-butyllithium
(11.2 mL of a 1.6 M solution in hexanes, 18.0 mmol). After
the addition, the reaction was allowed to warm to room tem-
perature for 40 min, and then cooled back to ꢂ78 ꢃC. A solu-
tion of 2,4,6-triflurobenzoyl chloride (1.00 g, 5.14 mmol) in
THF (50 mL) was then added dropwise. The reaction then
warmed to room temperature and stirred for 1.5 h, after which
it was concentrated under reduced pressure, suspended in 5:1
CH2Cl2:MeOH (600 mL), and washed with a saturated aque-
ous NaHCO3 solution (100 mL). The organic solution was
dried over Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was then chromatographed on
SiO2 using a gradient that started with heptane and ended
1
carried on to the next step without further purification. H
NMR (400 MHz, CDCl3) d 1.16 (t, J ¼ 7.2 Hz, 3H), 3.10 (s,
3H), 4.38 (q, J ¼ 7.2 Hz, 2H), 5.36 (s, 2H), 6.80 (dd,
J ¼ 8.4, 7.2 Hz, 2H), 7.17 (dd, J ¼ 7.2, 1.5 Hz, 1H), 7.85
(bs, 1H), 9.45 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 428.8.
4.10.9. 7-Dimethylaminomethyl-2-(2,4,6-trifluorophenyl)
imidazo[1,2-a]pyridine-3-carboxylic acid
ethyl ester (39)
A solution of crude mesylate 38 (theoretically 6.34 g,
14.8 mmol) in THF (250 mL) was charged with diisopropyle-
thylamine (2.49 g, 3.36 mL, 19.3 mmol) and dimethylamine
(9.65 mL of a 2.0 M solution in THF, 19.3 mmol), and the re-
action was allowed to stir at room temperature for 12 h. The
reaction was then concentrated under reduced pressure, then
chromatographed on SiO2 using a gradient that started with
CH2Cl2 and ended with 90:9:1 CH2Cl2:MeOH:concentrated
1
with 30:70 EtOAc:heptane. Yield of 35: 730 mg (57%). H
NMR (400 MHz, CDCl3) d ketone tautomer: 1.25 (t,
J ¼ 7.2 Hz, 3H), 3.89 (s, 2H), 4.20 (q, J ¼ 7.2 Hz, 2H),
6.63e6.90 (m, 2H); enol tautomer: 1.34 (t, J ¼ 7.2 Hz, 3H),
4.28 (q, J ¼ 7.2 Hz, 2H), 5.39 (s, 1H), 6.63e6.90 (m, 2H),
12.38 (s, 1H). MS (ESIþ) 246.8.
1
NH4OH. Yield of 39: 3.50 g (63% over 2 steps). H NMR
(400 MHz, CDCl3) d 1.15 (t, J ¼ 7.1 Hz, 3H), 2.35 (s, 6H),
3.59 (s, 2H), 4.26 (q, J ¼ 7.1 Hz, 2H), 6.78 (dd, J ¼ 8.5,
7.6 Hz, 2H), 7.15e7.30 (m, 1H), 7.65 (bs, 1H), 9.34 (d,
J ¼ 7.0 Hz, 1H). MS (ESIþ) 377.9.
4.10.6. 2-Bromo-3-oxo-3-(2,4,6-trifluorophenyl)propionic
acid ethyl ester (36)
A solution of ketone/enol mixture 35 (730 mg, 2.97 mmol)
in CH2Cl2 (50 mL) was charged with tetra-n-butylammonium
tribromide (1.43 g, 2.97 mmol). The reaction was stirred at
room temperature for 30 min, and was then chromatographed
on SiO2 using a gradient that started with heptane and ended
4.10.10. 7-Dimethylaminomethyl-2-(2,4,6-
trifluorophenyl)imidazo[1,2-a]pyridine-3-carboxylic acid
methoxymethylamide (40)
A solution of ethyl ester 39 (3.50 g, 9.27 mmol) and N,O-
dimethylhydroxylamine hydrochloride (2.71 g, 27.8 mmol) in
THF (250 mL) was cooled to 0 ꢃC in an ice water bath, then
charged with the dropwise addition of isopropylmagnesium
chloride (27.8 mL of a 2.0 M solution in THF, 55.6 mmol),
and the reaction was stirred at 0 ꢃC. After 1 h, additional por-
tions of both N,O-dimethylhydroxylamine (2.71 g, 27.8 mmol)
and isopropylmagnesium chloride (27.8 mL of a 2.0 M solu-
tion in THF, 55.6 mmol) were added, and stirring at 0 ꢃC con-
tinued for another 0.5 h. The reaction was then quenched with
the slow addition of a saturated aqueous NH4Cl solution
(200 mL). The layers were separated, and the organic layer
was washed again with a saturated aqueous NH4Cl solution
(100 mL). The organic layer was dried over Na2SO4, filtered,
and concentrated under reduced pressure, and carried onto the
next step without further purification. Yield of 40: 3.50 g
1
with 30:70 EtOAc:heptane. Yield of 36: 811 mg (84%). H
NMR (400 MHz, CDCl3) d 1.30 (t, J ¼ 7.1 Hz, 3H), 4.31 (q,
J ¼ 7.1 Hz, 2H), 5.48 (s, 1H), 6.79 (t, J ¼ 8.4 Hz, 2H). MS
(ESIþ) 324.2.
4.10.7. 7-Hydroxymethyl-2-(2,4,6-
trifluorophenyl)imidazo[1,2-a]pyridine-3-carboxylic acid
ethyl ester (37)
A solution of bromide 36 (12.8 g, 39.4 mmol) in ethanol
(100 mL) was charged with (2-aminopyridin-4-yl)methanol
(4.89 g, 39.4 mmol), and heated at 60 ꢃC for 36 h. The reac-
tion was then concentrated under reduced pressure and chro-
matographed on SiO2 first with a gradient that started with
heptane and ended with 30:70 EtOAc:heptane, and then with
a gradient that started with CH2Cl2 and ended with 40:60
MeOH:CH2Cl2. Yield of 37: 5.20 g (38%). 1H NMR
(400 MHz, CDCl3) d 1.14 (t, J ¼ 7.1 Hz, 3H), 4.25 (q,
J ¼ 7.1 Hz, 2H), 4.81 (s, 2H), 6.77 (t, J ¼ 8.0 Hz, 2H), 7.06
(dd, J ¼ 7.1, 0.9 Hz, 1H), 7.75 (bs, 1H), 9.31 (d, J ¼ 7.1 Hz,
1H). MS (ESIþ) 350.5.
1
(96%). H NMR (400 MHz, CDCl3) d 2.33 (s, 6H), 3.26 (s,
3H), 3.43 (s, 3H), 3.56 (s, 2H), 6.78 (t, J ¼ 8.2 Hz, 2H),
7.02e7.18 (m, 1H), 7.59 (bs, 1H), 8.72 (d, J ¼ 7.2 Hz, 1H).
MS (ESIþ) 392.9.
4.10.11. 1-[7-Dimethylaminomethyl-2-(2,4,6-
trifluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethanone (41)
A solution of crude Weinreb amide 40 (3.50 g, theoretically
8.92 mmol) in THF (250 mL) was cooled to 0 ꢃC in an ice wa-
ter bath, then charged with dropwise addition of methylmag-
nesium bromide (32.0 mL of a 1.4 M solution in 3:1
toluene:THF, 44.6 mmol). The reaction was then allowed to
4.10.8. 7-Methanesulfonyloxymethyl-2-(2,4,6-
trifluorophenyl)imidazo[1,2-a]pyridine-3-carboxylic
acid ethyl ester (38)
A solution of alcohol 37 (5.20 g, 14.8 mmol) in THF
(200 mL) was charged with Et3N (3.00 g, 4.13 mL,

1356
A. Scribner et al. / European Journal of Medicinal Chemistry 42 (2007) 1334e1357
molecular characterization of cGMP-dependent protein kinase from api-
complexan parasites: a novel chemotherapeutic target, J. Biol. Chem. 277
(2002) 15913e15922.
warm to room temperature and stirred for 12 h. The reaction
was then washed with a saturated aqueous NH4Cl solution
(2 ꢀ 150 mL), dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was then chroma-
tographed on SiO2 using a gradient that started with CH2Cl2
and ended with 90:9:1 CH2Cl2:MeOH:concentrated NH4OH.
Yield of 41: 1.37 g (44% over two steps). 1H NMR
(400 MHz, CDCl3) d 2.23 (s, 3H), 2.30 (s, 6H), 3.54 (s, 2H),
6.86 (dd, J ¼ 8.4, 7.2 Hz, 2H), 7.21 (dd, J ¼ 7.3, 1.5 Hz,
1H), 7.65 (bs, 1H), 9.70 (d, J ¼ 7.3 Hz, 1H). MS (ESIþ)
347.5.
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D. Thompson, J. Mathew, A. Misura, S. Samaras, T. Tamas, J.F. Sina,
K.A. McNulty, C.G. McKnight, D.M. Schmatz, M. Wyvratt, Synthesis
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P.S. Leavitt, P.A. Liberator, J. Mathew, A. Misura, S. Samaras,
T. Tamas, D.M. Schmatz, M. Wyvratt, T. Biftu, Synthesis and SAR of
2-(4-fluorophenyl)-3-pyrimidin-4-ylimidazo[1,2-a]pyridine derivatives
as anticoccidial agents, Bioorg. Med. Chem. Lett. 16 (2006) 5978e5981.
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E.J. Redford, J.E. Souness, N.E. Wilsher, RPR203494 a pyrimidine
analogue of the p38 inhibitor RPR200765A with an improved in vitro
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4.10.12. 3-Dimethylamino-1-[7-dimethylaminomethyl-2-
(2,4,6-trifluorophenyl)imidazo[1,2-a]pyridin-3-
yl]propenone (42)
(b) U. Urleb, B. Stanovnik, V. Stibilj, M. Tisler, Transformations of 2,4,5-
trisubstituted pyrimidines. The synthesis and transformations of pyri-
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a]pyrimidine, 1,2,4-triazolo[3,4-b]purine and tetrazolo[5,1-b]purine
derivatives, Heterocycles 24 (1986) 1899e1909.
A solution of ketone 41 (0.981 g, 2.82 mmol) in DMFDMA
(1.83 g, 1.88 mL, 14.1 mmol) was heated to 80 ꢃC for 12 h,
then chromatographed on SiO2 using a gradient that started
with CH2Cl2 and ended with 90:9:1 CH2Cl2:MeOH:concen-
trated NH4OH. Yield of 42: 750 mg (66%). 1H NMR
(400 MHz, CDCl3) d 2.31 (s, 6H), 2.46 (bs, 3H), 3.07 (bs,
3H), 3.54 (s, 2H), 5.01 (d, J ¼ 12.3 Hz, 1H), 6.82 (dd,
J ¼ 8.6, 7.2 Hz, 2H), 7.09 (d, J ¼ 7.1 Hz, 1H), 7.56 (bs, 1H),
7.68 (d, J ¼ 12.3 Hz, 1H), 9.67 (d, J ¼ 7.1 Hz, 1H). MS
(ESIþ) 402.9.
[6] N.J. Liverton, J.W. Butcher, C.F. Claiborne, D.A. Claremon, B.E. Libby,
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J.P. Vacca, S.L. Varga, L. Agarwal, K. Dancheck, A.J. Forsyth,
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