Imidazopyridine-based inhibitors of glycogen synthase kinase 3: Synthesis and evaluation of amide isostere replacements of the carboxamide scaffold

Article abstract of DOI:10.1002/cbdv.201200308

In this study, we explored the effect of bioisostere replacement in a series of glycogen synthase kinase 3 (GSK3) inhibitors based on the imidazopyridine core. The synthesis and biological evaluation of a number of novel sulfonamide, 1,2,4-oxadiazole, and

Full text of DOI:10.1002/cbdv.201200308

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CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
Imidazopyridine-Based Inhibitors of Glycogen Synthase Kinase 3: Synthesis
and Evaluation of Amide Isostere Replacements of the Carboxamide Scaffold
by Ulrika Yngvea), Peter Sçdermana), Mats Svenssona), Susanne Rosqvistb), and
Per I. Arvidsson*c)d)e)
a) Medicinal Chemistry, iScience, CNSP iMed, AstraZeneca R&D Sçdertꢀlje, SE-15185 Sçdertꢀlje
b) Neuroscience, iScience, CNSP iMed, AstraZeneca R&D Sçdertꢀlje, SE-15185 Sçdertꢀlje
c) Project Management, CNSP iMed, AstraZeneca R&D Sçdertꢀlje, SE-15185 Sçdertꢀlje
(phone: þ46-8-55325923; fax: þ46-8-55328877; e-mail: Per.Arvidsson@astrazeneca.com;
Per.Arvidsson@orgfarm.uu.se)
d) Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Centre,
Uppsala University, Box 574, SE-75123 Uppsala
e) School of Pharmacy and Pharmacology, Westville Campus, University of KwaZulu-Natal, Private Bag
X54001, Durban 4000, South Africa
Dedicated to Professor Dr. Dieter Seebach, a role model and appreciated mentor who continues to
pioneer the area organic chemistry, on the occasion of his 75th birthday
In this study, we explored the effect of bioisostere replacement in a series of glycogen synthase kinase
3 (GSK3) inhibitors based on the imidazopyridine core. The synthesis and biological evaluation of a
number of novel sulfonamide, 1,2,4-oxadiazole, and thiazole derivates as amide bioisosteres, as well as a
computational rationalization of the obtained results are reported.
Introduction. – Glycogen synthase kinase 3 (GSK3), a serine/threonine protein
kinase, is known to play critical roles in a variety of cellular and physiological processes
[1]. GSK3 was originally identified as a regulator of glycogen metabolism through its
phosphorylation activity towards glycogen synthase [2]; however, the roles of GSK3
has since broadened widely, and the kinase is now known to be involved in regulatory
and proliferative signal transduction pathways, such as Wnt and Hedgehog signaling
[3], stem-cell renewal, cell-division cycle, differentiation, apoptosis, circadian rhythm,
transcription, and insulin action. Not surprisingly, dysregulation of GSK3 has been
associated with a multitude of diseases, such as diabetes [4], Alzheimerꢁs disease [5–7],
bipolar disorder [8], Downꢁs syndrome [9], and various cancers [10]. Thus, there is a
great interest in developing inhibitors for GSK3 as a potential therapeutic approach for
these diseases. The GSK3 enzyme is highly conserved from yeast to mammals; the
mammalian enzyme is expressed two isoforms, a and b, that exhibit 97% amino acid
sequence identity within their catalytic domains. Most ATP-competitive inhibitors of
GSK3 are reported to target GSK3b [11], but they are in fact equipotent on the a-
isoform; however, as the GSK3 enzyme is ubiquitously expressed, and the isoforms
seem functionally redundant in most, but not all, signaling pathways [12], this is
probably not of major concern.
ꢂ 2012 Verlag Helvetica Chimica Acta AG, Zꢃrich

CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
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We [13] and others [14] have reported that imidazopyridine-carboxamides with the
general formula I are potent GSK3b inhibitors (Fig. 1).
Fig. 1. Imidazopyridine carboxamides with general formula I are reported to be potent GSK3b inhibitors.
Representative structures from WO2007040439, Ia and Ib, and WO2007083978, Ic and Id, are shown
together with their potencies on GSK3b.
Recently, Lee et al. reported their optimization of such carboxamide derivatives as
GSK3b inhibitors with potential antidiabetic properties [15]. As part of our ongoing
effort to find disease-modifying treatments for Alzheimerꢁs disease [16], we undertook
optimization of GSK3b inhibitors based on the imidazopyridine-carboxamide core
[17]. Here, we report our efforts to probe various bioisosteres of the carboxamide
functionality.
Results and Discussion. – Chemistry. The imidazopyridine core is known to be
essential for interaction with the kinase, as the pyridine N-atom and the imidazo NH
function provide archetypical H-accepting/donating interactions with the kinase
backbone, similarly to binding of ATP in the native kinase. It is also known that the
carboxamide function can be replaced by aromatic moieties directly attached to the
imidazopyridine core without loss of potency. Based on these findings, we became
interested in developing alternative chemical lead series derived from the imidazopyr-
idine scaffold, in which the carboxamide function is replaced by a bioisostere.
Exploration of bioisosteres is a classical approach in drug discovery that may help
improve potency, modify physico-chemical properties, change metabolism, remove
toxicophores, expand intellectual-property scope, etc. [18]. Among the various
reported carboxamide isosteres, we chose sulfonamides, as well as heterocyclic amide
isosteres, of the imidazopyridine scaffold. This design led to sulfonamides, 1,2,4-
oxadiazoles, and thiazoles of the general formulae II–IV (Fig. 2).

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CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
Fig. 2. General formulae of novel sulfonamide, 1,2,4-oxadiazole, and thiazole derivatives, II–IV,
respectively, of the imidazopyridine scaffold
To the best of our knowledge, sulfonamide, thiazole, and 1,2,4-oxadiazole
derivatives of this kind have not been previously described in the literature. The
required intermediates [13], i.e., 1, 5, 9 (Schemes 1, 2, and 3, resp.) were available from
synthesis of other compounds within the project and were used as attractive building
blocks for the synthesis presented here.
We commenced the synthesis of sulfonamide derivatives of general formula I
starting from 7-chloro-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine (1) as
outlined in Scheme 1.
Scheme 1
i) PhCH2SH, tBuONa, DMF, 908, 16 h; 92%. ii) Cl2 (g), CH2Cl2, HCOOH, H2O, 08, 5 min, used as crude.
iii) R1a(R1b)NH, EtNiPr2, CH2Cl2, r.t., 16 h; 14–70% from 2. The structures and yields of products 4a–f
are shown in the Table.
Compound 1 was converted into 7-(benzylsulfanyl)-2-[4-(trifluoromethyl)phenyl]-
3H-imidazo[4,5-b]pyridine (2) in 92% yield via reaction with PhCH2SH in the presence
of tBuONa. Compound 2 was then further oxidized and chlorinated using Cl2 gas in a
biphasic system of HCOOH and CH2Cl2 to give 2-[4-(trifluoromethyl)phenyl]-3H-

CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
2445
imidazo[4,5-b]pyridine-7-sulfonyl chloride (3) in a CH2Cl2 solution, which was directly
used in the next step. The corresponding amine and EtNiPr2 were added to the solution,
the mixture was stirred at ambient temperature overnight, and the formed sulfon-
amides 4a–4f could be isolated in yields in the range of 16–70%. The poor aqueous
solubility of some of the target compounds might be a factor that lowered the yield,
since the compounds were isolated by reversed-phase chromatography.
1,2,4-Oxadiazole isosteres were prepared according to Scheme 2. The synthesis
started with the corresponding carboxylic ester, methyl 2-[4-(morpholin-4-ylmethyl)-
phenyl]-3H-imidazo[4,5-b]pyridine-7-carboxylate (5a) [13], which, after hydrolysis
with LiOH in H2O/THF to the carboxylic acid 5b, was reacted with the commercially
available hydroxyimidamides 6a–6c in the presence of TBTU as coupling reagent.
After removal of excess of TBTU through extraction, the resulting (carbonyloxy)imid-
amide was heated to 1208 to afford the products 7a–7c in 8–19% yield.
Scheme 2
i) LiOH, 10 equiv., THF/H2O 9 :1, 1008, 20 min. ii) O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluro-
nium tetrafluoroborate (TBTU), Et3N, r.t., 4 h. iii) DMF, 1208, 16 h; 8–25%.
Thiazole isostere analogs of general formula III were prepared as outlined in
Scheme 3. The iodo compound 9a was prepared from the corresponding chloro
compound 1 using a large excess of NaI in MeCN at 1608. Selected thiazole-boronic
Scheme 3
i) Na2CO3, [PdCl2(dppf)]ꢀCH2Cl2 adduct (dpff¼1,1’-bis(diphenylphosphino)ferrocene), THF, H2O,
MW heating, 1408, 30 min; 4–30%.

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CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
esters 8 were reacted with heterocyclic iodides 9 under standard Suzuki conditions with
[1,1’-bis(diphenylphosphino)ferrocene]palladium(II) as catalyst and Na2CO3 as base to
furnish the thiazole analogs 10a–10c in 4–30% yield after preparative HPLC.
Medicinal Chemistry. The potential for imidazopyridine-based compounds 4a–4f,
7a–7c, and 10a–10c to function as useful inhibitors of GSK3 were assessed by
determining a standard battery of drug-related properties. Thus, GSK3b potency,
aqueous solubility, and metabolic stability in human liver microsomes were evaluated;
data for a selected number of imidazopyridine-carboxamides I were compiled for
comparison in the Table. As can be seen in the Table, replacement of the amide
functionality by a sulfonamide results in a two-order-of-magnitude drop in GSK3b
potency (cf. the pairs 4c/Ia, 4d/Ie, and 4f/If). This surprisingly large drop in GSK3
inhibitory potency may be explained by a different binding mode of the substrate in the
GSK3b active site (vide infra). Aqueous solubility is generally poor for imidazo-
pyridine-based inhibitors bearing a non-ionizable group in R2 (i.e., CF3); despite the
higher polarity of the sulfonamide group, no drastic increase in aqueous solubility or
metabolic stability was noted upon this bioisostere replacement. Replacing the
carboxamide in I with the 1,2,4-oxadiazole bioisosteres again reduced GSK3b
potency 10–100-fold (cf. 7a/Ih in Table ; and 7c with related compound Ib (Fig. 1)).
Nevertheless, the 1,2,4-oxadiazoles reported here exhibit biologically useful GSK3b
potencies in the range of 100-nm in combination with good solubility and metabolic
stability. The thiazole isosteres 10a–10c also displayed GSK3b potencies in the
100-nm range; however, solubilities were too low to render them useful for further
evaluation.
To better understand the reduced GSK3 potencies observed upon replacing the
amide functionality with the reported bioisosteres in the imidazopyridine-based lead
series, we undertook some molecular-modeling studies [19].
A representative docking of 1,2,4-oxadiazole in the active site of the X-ray structure
reported for inhibitors of general class I [15] can be detected in Fig. 3. The 1,2,4-
oxadiazole and the thiazole bioisosteres appear to extend the R1 substituent in the
active site more and display less optimal H-bond interactions with an enzyme-bound
H2O molecule than the corresponding amide derivative, due to a rotation of the 1,2,4-
oxadiazole out of the plane vs. the amide.
Docking of the sulfonamide derivative 4b revealed the somewhat unexpected
structure in Fig. 4.
The docking suggests that the secondary sulfonamide functionality may replace the
imidazopyridine core as hinge-binding motif! Whether this, or the more polar nature of
the sulfonamide functionality, is the main cause for the decreased GSK3 potency
observed with this bioisostere remains unconfirmed in the absence of further
experimental data, but this information provokes further thoughts on new scaffolds
for ATP-competitive kinase inhibitors.
It should be noted that, in addition to the structural differences seen in the docking
experiments above, the GSK3 inhibitory activity of the amide bioisostere derivatives
reported here may be decreased (as compared to the parent amide) due to electronic
difference in H-bonding interaction potential for the imidazopyridine core upon
carboxamide replacement; however, such effects require quantum-chemical modeling
rather than the current force-field-based approach.

CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
2447
Table. Yields, Inhibitory Activity against GSK3b, Aqueous Solubility, Stability in Human Liver Microsomes of
Isostere-Containing Inhibitors 4, 7, and 10 together with Selected Comparative Data for the Corresponding
Amides of General Formula I
Compound X
R1
R2
Yield Ki (GSK3b) Solubility Clint (HLM)
[%] [nm]
[mm]
[ml/min/mg]
Ia
Ie
C¼O
CF3
–
–
17
13
49
52
C¼O
C¼O
CF3
CF3
6
65
If
–
7.7
<1
ND
Ig
Ih
C¼O
C¼O
(Morpholin-4-yl)-
methyl
–
–
25
4
ND
10
(Morpholin-4-yl)-
methyl
1.4
ND
4a
4b
ꢀS(O)2ꢀ
ꢀS(O)2ꢀ
CF3
CF3
70
28
750
940
<1
<1
ND
58
4c
ꢀS(O)2ꢀ
ꢀS(O)2ꢀ
CF3
CF3
32
14
1400
1600
10
4
40
46
4d
4e
4f
ꢀS(O)2ꢀ
ꢀS(O)2ꢀ
CF3
CF3
25
27
2500
7500
17
13
ND
16
7a
Pyridin-3-yl
(Morpholin-4-yl)- 17
methyl
120
6
ND

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CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
Table (cont.)
Compound
X
R1
iPr
R2
Yield Ki (GSK3b) Solubility Clint (HLM)
[%]
[nm]
[mm]
[ml/min/mg]
7b
(Morpholin-4-yl)- 25
methyl
190
33
47
7c
MeOCH2CH2 (Morpholin-4-yl)-
methyl
8
4
360
370
190
130
400
<1
<1
<1
27
10a
Piperidin-1-yl
CF3
ND
45
10b
Morpholin-4-yl CF3
19
10c
Piperidin-1-yl
(Morpholin-4-yl)- 30
methyl
ND
a) ND¼Not determined.
Fig. 3. Binding of 1,2,4-oxadiazole-based inhibitor 7a (grey) in the active site of GSK3b, compared to the
published structure of an amide containing inhibitor (green). Replacing the amide with the 1,2,4-
oxadiazole isostere leads to a general extension of the R1 group. Furthermore, rotation of the oxadiazole
ring leads to a less efficient H-bond interaction with the enzyme-bound H2O (seen interacting with the
carbonyl O-atom in the reference (green) structure).
Conclusions. – In summary, we have reported the design, synthesis, and biochemical
evaluation of a series of novel analogs of imidazopyridine-based GSK3b inhibitors in
which the original carboxamide motif was replaced with three different bioisosteres,
i.e., sulfonamides, 1,2,4-oxadiazoles, and thiazoles. Although all these modifications led

CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
2449
Fig. 4. Docking of sulfonamide-based inhibitor 4b in the active site of GSK3b gives rise to alternative
binding poses in which the secondary sulfonamide, rather than the imidazopyridine core, bind to the hinge
region of the kinase.
to decreased GSK3 inhibitory activities, the 1,2,4-oxadiazoles series still retained
biologically meaningful potencies in the 100-nm range in combination with good
solubility and metabolic stabilities. Further analysis by computation modeling
provoked the idea that the sulfonamide isostere itself may replace the imidazopyridine
core as a hinge-binding motif; this may offer new starting points for design of kinase
inhibitors.
Experimental Part
General. Commercially available anh. solvents were used for reactions. Commercially available
1
reagents were used as received. H-NMR Spectra: Varian Unityþ 400 NMR, Bruker Av400 NMR, or
Bruker 500 MHz ultrashield spectrometer; d in ppm rel. to the residual solvent signal as internal
reference (CDCl3, 7.27; (D6)DMSO, 2.50; CD3OD, 3.31); J in Hz. MS: Waters LC/MS and a ZQ single
quadrupole mass spectrometer equipped with an electrospray ion source (ESI); in m/z; alternatively,
Waters LC/MS system where the ZQ was equipped with a combined APPI/APCI ion source.
The experimental protocols for GSK3b activity measurements [13], dried DMSO solubility
measurements [20]1), and metabolic stability [21] have been described in the literature. Computational
studies were conducted with the Glide package from Schrçdinger [19].
The synthesis of amide derivatives I has been described in the patent literature [13][14], except Ie
and If, that are described below.
N-[3-(1H-Imidazol-1-yl)propyl]-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-7-car-
boxamide (Ie). 2-[4-(Trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-7-carboxylic acid [13]
(0.912 g, 2.97 mmol) and N,N,N’,N’-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (1.16 g,
5.41 mmol) were dissolved in DMF (29 ml), and Et3N (1.3 ml) was added. The mixture was stirred at r.t.
1
)
The method was modified by a pre-incubation step for 4 h at a fixed temp. of 18 with magnetic
stirrers at 500 rpm in order to generate the most stable solid form.

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CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
for 1 h. 3-(1H-Imidazol-1-yl)propan-1-amine (25 mg, 0.2 mmol) was dispensed in a 48-well plate, and
1 ml (0.10 mmol) of the reaction mixture was added. The mixture was shaken at r.t. for 16 h, and then
filtered and purified by prep. HPLC to give Ie as a dry film. 1H-NMR (400 MHz, (D6)DMSO) 9.49 (br. s.,
1 H); 8.49–8.62 (m, 3 H); 7.99 (d, J ¼ 8.0, 2 H); 7.81–7.65 (m, 2 H); 7.25 (s, 1 H); 6.91 (s, 1 H); 4.12 (t, J ¼
6.9, 2 H); 3.51–3.42 (m, 2 H); 2.12 (quint., J ¼ 6.8, 2 H). ESI-MS: 415 ([MþH]þ ).
N-[(1S)-2-hydroxy-1-phenylethyl]-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-7-car-
1
boxamide (If). Prepared with (2S)-2-amino-2-phenylethanol as described for Ie. H-NMR (400 MHz,
(D6)DMSO): 10.31 (d, J ¼ 7.3, 1 H); 8.61–8.50 (m, 3 H); 8.03 (d, J ¼ 8.3 , 2 H); 7.76 (d, J ¼ 5.1, 1 H);
7.53–7.45 (m, 2 H); 7.42–7.33 (m, 2 H); 7.33–7.23 (m, 1 H); 5.20 (dt, J ¼ 7.8, 5.1, 1 H); 3.91–3.76 (m,
2 H). ESI-MS: 427 ([MþH]þ ).
7-(Benzylsulfanyl)-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine (2). 7-Chloro-2-[4-(tri-
fluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine (1; 0.4 g, 1.34 mmol) and tBuONa (0.387 g, 4.03 mmol)
were dissolved in DMF (4 ml). PhCH2SH (0.317 ml, 2.69 mmol) was added, and the mixture was heated
to 908 under Ar for 16 h. The mixture was poured onto aq. NaHCO3 and ice. The solid was collected by
1
filtration. The solid was washed with H2O and dried under vacuum to give 2 (475 mg, 92%). H-NMR
(500 MHz, DMSO): 8.43 (d, J¼8.2, 2 H); 8.19 (d, J¼5.0, 1 H); 7.93 (d, J¼8.3, 2 H); 7.49 (d, J¼7.4, 2 H);
7.34 (t, J¼7.5, 2 H); 7.29–7.20 (m, 2 H); 4.58 (s, 2 H). ESI-MS: 386 ([MþH]þ ).
2-[4-(Trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-7-sulfonyl Chloride (3). Compound 2
(250 mg, 0.65 mmol) was dissolved in CH2Cl2 (50 ml) and HCOOH (25 ml). H2O (25 ml) was added,
and the mixture was cooled to 08. Cl2 (g) was bubbled through the vigorously stirred heterogeneous
mixture for 2 min. The mixture turned yellow. The mixture was stirred for an additional 3 min at 08. The
phases were separated. The aq. phase was extracted with CH2Cl2 (3ꢁ100 ml). The combined org. phases
were washed with 1m aq. NaOH, followed by brine. The org. phase was dried (Na2SO4), and the solvent
was evaporated until 25 ml remained. The soln. was used directly in the next step. ESI-MS: 362 ([Mþ
H]þ ).
3-[4-({2-[4-(Trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridin-7-yl}sulfonyl)piperazin-1-yl]propa-
nenitrile (4a). A soln. 3 (0.060 g, 0.17 mmol) in CH2Cl2 (10 ml) was added to 3-(piperazin-1-
yl)propanenitrile (0.035 g, 0.25 mmol). Hꢁnigꢁs base (0.087 ml, 0.50 mmol) was added, and the mixture
was stirred at r.t. for 16 h. The solvents were evaporated, and the residue was dissolved in DMSO (1.5 ml)
and purified by prep. HPLC. The fractions containing the product were pooled, concentrated, and aq.
NaHCO3 was added. The mixture was extracted with CH2Cl2 (3ꢁ ). The combined org. phases were dried
(Na2SO4), and the solvent was evaporated to give 4a (54 mg, 70%). Solid. 1H-NMR (400 MHz, CDCl3):
8.40 (br. s, 1 H); 8.31 (m, J ¼ 8.1, 2 H); 7.75 (m, J ¼ 7.8, 2 H); 7.59 (br. s, 1 H); 3.47–3.25 (m, 5 H); 3.18
(br. s, 2 H); 2.66–2.58 (m, 2 H); 2.55 (br. s, 4 H); 2.46–2.35 (m, 2 H). ESI-MS: 465 ([MþH]þ ).
N-Cyclopentyl-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-7-sulfonamide Hydro-
chloride (4b). Prepared with cyclopentylamine as described for 4a. The solid was dissolved in CH2Cl2
(2 ml) and MeOH (0.1 ml). HCl (1m in Et2O, 0.10 ml) was added. The solvents were evaporated to give
4b (28%). Dry film. 1H-NMR (400 MHz, (D6)DMSO): 8.60–8.53 (m, 3 H); 8.01 (d, J ¼ 8.2, 3 H); 7.61 (d,
J ¼ 5.1, 1 H); 3.84 (dq, J ¼ 12.9, 6.5, 1 H); 1.66–1.45 (m, 4 H); 1.43–1.29 (m, 4 H). ESI-MS: 411 ([Mþ
H]þ ).
N-(3-Methoxypropyl)-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-7-sulfonamide Hy-
drochloride (4c). Prepared with 3-methoxypropanamine as described for 4b. Yield: 32%. Dry film.
1H-NMR (400 MHz, (D6)DMSO): 8.61–8.53 (m, 3 H); 8.01 (d, J ¼ 8.2, 2 H); 7.91 (t, J ¼ 5.6, 1 H); 7.60
(d, J ¼ 5.1, 1 H); 3.25 (t, J ¼ 6.1, 2 H); 3.12–3.05 (m, 6 H); 1.61 (quint., J ¼ 6.6, 2 H). ESI-MS: 415 ([Mþ
H]þ ).
N-[3-(1H-Imidazol-1-yl)propyl]-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-7-sulfon-
amide Hydrochloride (4d). Prepared with 3-(1H-imidazol-1-yl)propan-1-amine as described for 4b.
Yield: 10 mg (14%). Dry film. 1H-NMR (400 MHz, (D6)DMSO): 9.11 (t, J ¼ 1.5, 1 H); 8.58 (d, J ¼ 4.9,
1 H); 8.55 (m, J ¼ 8.1, 2 H); 8.01 (m, J ¼ 8.2, 2 H); 7.75 (t, J ¼ 1.6, 1 H); 7.68 (t, J ¼ 1.6, 1 H); 7.60 (d, J ¼
4.9, 1 H); 4.26 (t, J ¼ 6.9, 2 H); 3.06 (q, J ¼ 6.2, 2 H); 2.01 (quint., J ¼ 6.8, 2 H). ESI-MS: 451 ([MþH]þ ).
N-(2-Methoxyethyl)-N-methyl-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-7-sulfon-
amide Hydrochloride (4e). Prepared with 2-methoxy-N-methylethanamine as described for 4b: Yield:

CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
2451
1
25%. Solid. H-NMR (400 MHz, CDCl3): 8.55 (br. s, 1 H); 8.38–8.28 (m, 3 H); 7.78 (d, J ¼ 8.1, 3 H);
7.68–7.59 (m, 1 H); 3.68–3.55 (m, 5 H); 3.31 (s, 3 H); 3.00 (br. s, 3 H). APCI-MS: 415 ([MþH]þ ).
N-[(1S)-2-Hydroxy-1-phenylethyl]-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-7-sul-
fonamide Hydrochloride (4f). Prepared with (2S)-2-amino-2-phenylethanol as described for 4b. Yield:
27%. Solid. 1H-NMR (400 MHz, (D6)DMSO): 8.54 (m, J ¼ 8.1, 2 H); 8.45–8.38 (m, 2 H); 8.03 (m, J ¼
8.3, 2 H); 7.45 (d, J ¼ 5.1, 1 H); 7.06 (dd, J ¼ 7.6, 1.3, 2 H); 6.96–6.86 (m, 3 H); 4.56–4.47 (m, 1 H); 3.58–
3.43 (m, 2 H). ESI-MS: 463 ([MþH]þ ).
2-[4-(Morpholin-4-ylmethyl)phenyl]-3H-imidazo[4,5-b]pyridine-7-carboxylic Acid (5b). Methyl 2-
[4-(Morpholin-4-ylmethyl)phenyl]-3H-imidazo[4,5-b]pyridine-7-carboxylate (5a; 2.4 g, 6.81 mmol) [13]
was dissolved in THF (36 ml) and H2O (4 ml). LiOH·H2O (2.86 g, 68.1 mmol) was added, and the
mixture was heated to 1008 for 15 min in a microwave reactor. The mixture was concentrated to ca. 1/2
volume by evaporation. The mixture was acidified with 6m aq. HCl. The solid was isolated by filtration
and washed with 1m aq. HCl. The solid was dried under vacuum to give 5b·HCl (2.4 g, 94%). ESI-MS:
339 ([MþH]þ ).
2-[4-(Morpholin-4-ylmethyl)phenyl]-7-[3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl]-3H-imidazo[4,5-b]-
pyridine Hydrochloride (7a). Compound 5b (0.2 g, 0.59 mmol) and 2-(2,5-dioxopyrrolidin-1-yl)-1,1,3,3-
tetramethylisouronium tetrafluoroborate (0.214 g, 0.71 mmol) were mixed in DMF (5 ml). Et3N
(0.330 ml, 2.36 mmol) was added, and the mixture was stirred at r.t. for 60 min. (Z)-N’-Hydroxy(pyridin-
3-yl)methanimidamide (6; R¼pyridin-3-yl; 0.084 g, 0.71 mmol) was added, and the mixture was stirred at
r.t. overnight. The mixture was diluted with aq. NaHCO3 and was extracted with CH2Cl2 (3ꢁ ). The org.
phase was dried (Na2SO4), and the solvent was evaporated to give the intermediate N’-[({2-[4-
(morpholin-4-ylmethyl)phenyl]-3H-imidazo[4,5-b]pyridin-7-yl}carbonyl)oxy]pyridine-3-carboximidamide
in a DMF soln. (ca. 5 ml). The DMF soln. was heated to 1208 for 5 h. The mixture was purified by prep.
HPLC. The fractions containing the product were pooled, and concentrated. aq. NaHCO3 was added, and
the mixture was extracted with CH2Cl2 (5ꢁ ). The org. phase was dried (Na2SO4), and the solvent was
evaporated. The residue was dissolved in CH2Cl2 and MeOH. HCl (1m in Et2O, 0.3 ml) was added. The
solvents were evaporated and to give a solid. The solid was dried under vacuum at 508 to give 7a·HCl
(54 mg, 17%). 1H-NMR (400 MHz, (D6)DMSO): 11.08 (br. s, 1 H); 9.37 (d, J ¼ 1.5, 1 H); 8.87 (dd, J ¼
4.9, 1.6, 1 H); 8.64 (d, J ¼ 5.1, 1 H); 8.57 (dt, J ¼ 8.0, 2.0, 1 H); 8.45 (m, J ¼ 8.3, 2 H); 8.04 (d, J ¼ 5.1,
1 H); 7.85 (m, J ¼ 8.3, 2 H); 7.73 (ddd, J ¼ 8.0, 4.9, 0.8, 1 H); 4.46 (d, J ¼ 4.0, 2 H); 3.97 (d, J ¼ 11.1, 2 H);
3.29 (d, J ¼ 11.9, 2 H); 3.22–3.07 (m, 2 H); 2 H under H2O signal. ESI-MS: 440 ([MþH]þ ).
2-[4-(Morpholin-4-ylmethyl)phenyl]-7-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]-3H-imidazo[4,5-
b]pyridine Hydrochloride (7b). Prepared with (Z)-N’-hydroxy-2-methylpropanimidamide (6, R¼iPr) as
described for 7a. Yield: 25%. Solid. 1H-NMR (400 MHz, (D6)DMSO): 10.80 (br. s, 1 H); 8.58 (d, J ¼ 5.1,
1 H); 8.42 (d, J ¼ 8.3, 2 H); 7.91 (d, J ¼ 5.1, 1 H); 7.81 (d, J ¼ 8.3, 2 H); 4.45 (d, J ¼ 4.8, 2 H); 3.97 (d, J ¼
10.9, 2 H); 3.33–3.10 (m, 5 H). ESI-MS: 406 ([MþH]þ ).
7-[3-(2-Methoxyethyl)-1,2,4-oxadiazol-5-yl]-2-[4-(morpholin-4-ylmethyl)phenyl]-3H-imidazo[4,5-
b]pyridine Hydrochloride (7c). Prepared with (Z)-N’-hydroxy-3-methoxypropanimidamide (6, R¼
MeOCH2CH2) as described for 7a. Yield: 8%. Solid. 1H-NMR (400 MHz, (D6)DMSO): 11.04 (br. s,
1 H); 8.58 (d, J ¼ 5.1, 1 H); 8.42 (m, J ¼ 8.3, 2 H); 7.91 (d, J ¼ 5.1, 1 H); 7.83 (m, J ¼ 8.3, 2 H); 4.45 (d,
J ¼ 5.1, 2 H); 3.96 (d, J ¼ 11.6, 2 H); 3.84–3.73 (m, 4 H); 3.32–3.24 (m, 5 H); 3.20–3.08 (m, 4 H). ESI-
MS: 421 ([MþH]þ ).
7-Iodo-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine (9a; R2 ¼CF3). Compound 1
(1.30 g, 3.89 mmol) was suspended in MeCN (19 ml). NaI (5.6 g, 38 mmol) was added, and the mixture
was heated at 1608 for 20 min. The mixture was poured onto sat. aq. NaHCO3 containing Na2S2O3. The
solid formed was collected by filtration and was washed with H2O. The solid was dried under vacuum to
give 9a (1.3 g, 85%). ESI-MS: 390 ([MþH]þ ).
7-[2-(Piperidin-1-yl)-1,3-thiazol-4-yl]-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine Hy-
drochloride (10a). Compound 9a (50 mg, 0.13 mmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
1,3-thiazol-2-yl]piperidine (8a; R1 ¼piperidin-1-yl; 49 mg, 0.17 mmol), Na2CO3 (54 mg, 0.51 mmol), and
PdCl2(dppf)ꢀCH2Cl2 adduct (16 mg, 0.02 mmol) were mixed in THF (3 ml) and H2O (0.33 ml). The
mixture was heated to 1408 in a microwave reactor for 30 min. H2O (10 ml) was added, and the
precipitate formed was isolated by filtration and washed with H2O. The solid was suspended in CH2Cl2

2452
CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
and MeOH. HCl (1m in Et2O, 0.2 ml) was added. The solvents were evaporated. The residue was
dissolved in DMSO and MeOH, and purified by prep. HPLC. The fractions were concentrated until a
precipitate formed. The precipitate was collected by filtration and was washed with H2O. The solid was
dried in a vacuum desiccator. The solid was dissolved in CH2Cl2 and MeOH. HCl (1m in Et2O, 0.05 ml)
was added. The solvents were evaporated to give 10·HCl. Yield: 5 mg (4%). Dry film. 1H-NMR
(400 MHz, CD3OD): 8.52 (d, J ¼ 6.1, 1 H); 8.47 (m, J ¼ 8.1, 2 H); 8.13–8.06 (m, 2 H); 7.97 (m, J ¼ 8.1,
2 H); 3.71 (d, J ¼ 5.6, 4 H); 1.85–1.72 (m, 6 H). ESI-MS: 430 ([MþH]þ ).
7-[2-(Morpholin-4-yl)-1,3-thiazol-4-yl]-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine
Hydrochloride (10b). Prepared with 8b (R1 ¼morpholin-4-yl) and 9a as described for 10a. Yield: 19%.
Solid. 1H-NMR (400 MHz, (D6)DMSO): 8.59–8.53 (m, 3 H); 8.43 (d, J ¼ 5.3, 1 H); 7.98 (d, J ¼ 8.1, 2 H);
7.85 (d, J ¼ 5.1, 1 H); 3.81–3.74 (m, 4 H); 3.57–3.48 (m, 4 H). ESI-MS: 432 ([MþH]þ ).
2-[4-(Morpholin-4-ylmethyl)phenyl]-7-[2-(piperidin-1-yl)-1,3-thiazol-4-yl]-3H-imidazo[4,5-b]pyri-
dine Hydrochloride (10c). Prepared with 8a and 9b (R2 ¼(morpholin-4-yl)methyl) as described for 10a.
1
Yield: 30%. Solid. H-NMR (400 MHz, (D6)DMSO): 11.43 (br. s, 1 H); 8.49 (s, 1 H); 8.43 (d, J ¼ 8.3,
3 H); 7.88–7.82 (m, 3 H); 4.43 (d, J ¼ 4.5, 2 H); 3.99–3.91 (m, 2 H); 3.87–3.77 (m, 2 H); 3.56 (br. s, 4 H);
3.30–3.21 (m, 2 H); 3.19–3.06 (m, 2 H); 1.65 (br. s, 6 H). ESI-MS: 461 ([MþH]þ ).
We thank our colleagues at the Physical Chemistry Characterization Team for solubility data and
colleagues at the DMPK department for metabolic stabilization data.
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Received August 16, 2012