Keeping it small, polar, and non-flat: diversely functionalized building blocks containing the privileged 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]- and [1,5-a]pyridine cores

Article abstract of DOI:10.1016/j.tetlet.2016.01.094

Six sets of functionalized building blocks based on 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine as well as 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine cores have been prepared. These compounds are non-flat, bicyclic heterocycles that are likely to find utility as privileged motifs for lead-like compound design. One set of building blocks, (5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-6-ylmethyl)amines, proved useful as a scaffold for developing compounds that stimulate glucagon-like peptide-1 (GLP-1) secretion and are novel anti-diabetes drug leads.

Full text of DOI:10.1016/j.tetlet.2016.01.094

Tetrahedron Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Keeping it small, polar, and non-flat: diversely functionalized
building blocks containing the privileged 5,6,7,8-tetrahydro
[1,2,4]triazolo[4,3-a]- and [1,5-a]pyridine cores
Alexander Mishchuk a, Natalia Shtil b, Mykola Poberezhnyk c, Konstiantyn Nazarenko a,b
,
Timur Savchenko a, Andrey Tolmachev a, Mikhail Krasavin d,
⇑
a Enamine Ltd, 78 Chervonotkatska, Kyiv 02094, Ukraine
b Institute of Organic Chemistry of the NAS of Ukraine, 5, Murmanska Str., Kyiv 02660, Ukraine
c Taras Shevchenko National University of Kyiv, 64/13, Volodymyrska Street, Kyiv 01601, Ukraine
d Institute of Chemistry, St. Petersburg State University, Peterhof 198504, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Six sets of functionalized building blocks based on 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine as well
as 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine cores have been prepared. These compounds are non-
flat, bicyclic heterocycles that are likely to find utility as privileged motifs for lead-like compound design.
One set of building blocks, (5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-6-ylmethyl)amines, proved
useful as a scaffold for developing compounds that stimulate glucagon-like peptide-1 (GLP-1) secretion
and are novel anti-diabetes drug leads.
Received 27 November 2015
Revised 22 January 2016
Accepted 26 January 2016
Available online xxxx
Keywords:
Ó 2016 Elsevier Ltd. All rights reserved.
Lead-oriented synthesis
Non-flat heterocycles
Hydrogenation
Dimroth rearrangement
Anti-diabetes drugs
The modern design of small molecules for bioactivity screening
appears to be significantly be influenced by two major concepts,
namely, those of lead-likeness and ‘non-flatness’. Lead-like com-
pounds1 conform to more stringent criteria of lipophilicity (logP)
and molecular weight (MW) compared to the Lipinski ‘rule-of-five’
chemical space.2 Lead-likeness offers ample room for medicinal
chemistry optimization, which normally results in increasing a
molecule’s size and lipophilicity. Noticeably, compounds in current
screening collections (proprietary or commercially available) fill
the higher-end space of the Lipinski boundaries while the lead-like
space is scarcely populated.3 In response to this obvious void, the
term ‘lead-oriented synthesis’ (LOS) was coined by a GlaxoSmithK-
line team4 to signify the synthetic organic chemistry methodolo-
gies capable of primarily delivering lead-like compounds. While
being a technically more challenging concept to implement,5 LOS
has become a necessary challenge for organic chemists to face, as
the current productivity crisis in pharmaceutical industry6 is fre-
quently linked to the lack of quality drug leads emerging from
screening.7 The concept of ‘non-flatness’, that is, increasing a mole-
cule’s three-dimensional character by reducing the number of flat
aromatic rings (or increasing the fraction of sp3-hybridized heavy
atoms, Fsp3) has also gained a particular importance after it was
noted that, on a statistical level, compounds become more satu-
rated as they progress through the drug development cycle.8
Besides this pure statistical significance, more ‘shapeliness’ for a
compound means being more complimentary to its protein target,
more selective against off-targets, less toxic, and, ultimately, more
successful in the drug development cycle.
The 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine core (1) as
well as its bioisosteric 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyri-
dine counterpart (2) clearly incorporate the aforementioned fea-
tures, considering their low molecular weight (123), high
hydrophilicity (cLogP ꢀÀ0.179), and the saturation of the pyridine
ring, while preserving the essential 1,2,4-triazole moiety (Fig. 1).
While preparation of these cores by partial reduction of their fully
aromatic congeners was well established several decades ago,10,11
only recently have we seen their advent (of 1 in particular) in var-
ious drug leads. Notable examples include modulators of c-secre-
tase (an important target in Alzheimer’s disease) from Janssen
Pharmaceutica (3)12 and Takeda (4),13 multi-target anti-inflamma-
tory compound 514 from Pharmacia & Upjohn, as well as inhibitors
of dipeptidyl peptidase IV (DPPIV) from Merck (6)15 and The
⇑
Corresponding author. Tel.: +7 931 3617872; fax: +7 812 428 6939.
E-mail address: m.krasavin@spbu.ru (M. Krasavin).
http://dx.doi.org/10.1016/j.tetlet.2016.01.094
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mishchuk, A.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.01.094

2
A. Mishchuk et al. / Tetrahedron Letters xxx (2016) xxx–xxx
N
N
group could only be achieved by high-pressure (100 atm) hydro-
N
N
genation over Raney nickel in 7 M methanolic ammonia. On the
contrary, reduction under the reported literature conditions
(which normally involve Pd/C),12,14 produced a complex mixture
of products mostly consisting of the de-amination product 10.
Notably, the 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine core
of building blocks 8a–e remained intact over the course of the
reduction and did not undergo the Dimroth rearrangement, as
was confirmed by 1H–15N HMBC spectroscopy (vide infra).
In the preparation of a set of carboxylic acids 11a–d, Pd(OH)2
rather than Pd/C was identified as the optimal catalyst for the
hydrogenation step, which allowed the reduction of the pyrido ring
in 12 without decarboxylation, which was the case when Pd/C was
used. Remarkably, the efficient three-step synthesis from readily
available 6-chloronicotinic acid did not require protecting the car-
boxylic acid functionality (Scheme 2).
Building blocks 8a–e and 11a–d are noteworthy as in the course
of their synthesis, the formation of the [1,2,4]triazolo[4,3-a]pyri-
dine cycle was not accompanied by Dimroth rearrangement. This
was despite the fact that in both cases, the pyridine ring was sub-
stituted with an electron-withdrawing substituent, which has been
shown to increase the tendency for the Dimroth rearrange-
ment.18,19 The latter, however, was the sole course of the reaction
during the 1,2,4-triazole ring formation step involving 3- and 5-
nitro-substituted 2-hydrazinopyridines. In both cases, only the
N
N
1
2
Figure 1. Lead-like, non-flat cores 1–2 that are the subjects of the present study.
University of Nottingham (7),16 both of which are related to the
FDA-approved anti-diabetic drug sitagliptin (Fig. 2).17
In light of these latest developments, it is particularly desirable
to gain convenient access to a series of building blocks based on
core motifs 1 and 2. On first viewing, the task may seem simple,
considering the usual way to access these by the reduction of the
triazolopyridine precursors (vide supra). However, core 1 appears
to be a lot more challenging, in light of its known propensity for
a Dimroth rearrangement.18 In this Letter, we describe a conve-
nient, scalable synthesis of a series of diversely functionalized
cores 1 and 2 and demonstrate the application of one of them for
anti-diabetic drug lead generation.
A series of (5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-6-
ylmethyl)amine building blocks 8a–e was synthesized starting
from commercially available 2-chloro-5-cyanopyridine (Scheme 1).
Elaboration of the fully aromatic precursor 9 presented no issues.
However, simultaneous reduction of the pyrido ring and the cyano
N
O
F3C
MeO
N
N
N
N
N
N
N
N
Cl
N
N
O
O
3
4
F3C
N
N
F
N
F
N
NH3+ TFA-
N
N
F
F
F
N
N
NH2
F
NH2
O
F
F
5
6
7
N
N
O
Figure 2. Examples of biologically active compounds based on scaffold 1.
R
N
N
+ other minor products
c
N
R
10
CN
CN
a
b
CN
N
N
N
N
80%
d
Cl
HN
NH2
N
NH2
8a
, R = H, 81%
8b, R = Me, 93%
8c
R
9a, 63%
9b
, 71%
N
N
, R = Et, 77%
8d, R = i-Pr, 68%
8e
9c, 65%
9d, 79%
N
, R = CHF2,73%
9e
, 73%
Scheme 1. Synthesis of (5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-6-ylmethyl)amines 8a–e. Reagents and conditions: (a) hydrazine hydrate (5 equiv), i-PrOH, reflux,
24 h; (b) RCO2H, 110 °C, 48 h; (c) H2, Pd/C, 100 atm, 60 °C; (d) H2, Raney Ni, 7 M NH3 in MeOH, 100 atm, 60 °C.
R
R
COOH
COOH
a
11a
b
COOH
, R = H, 85%
11b, R = Me, 63%
11c
COOH
c
N
N
N
N
N
N
85%
Cl
HN
NH2
N
N
, R = cyclo-Pr, 72%
11d, R = CHF2, 82%
12a, 55%
12b, 48%
12c
, 77%
12d, 66%
Scheme 2. Synthesis of 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acids 11a–d. Reagents and conditions: (a) hydrazine hydrate (10 equiv), EtOH, reflux,
72 h, then AcOH; (b) RCO2H, 110 °C, 48 h; (c) H2, Pd(OH)2, 100 atm, 100 °C.
Please cite this article in press as: Mishchuk, A.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.01.094

A. Mishchuk et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
R
6
N
NO2
N
N
8
X
5
5
a
N
N
13
NO2
NO2
88-92%
Cl
HN
NH2
b
3
3
6
6
N
N
N
N
N
c
N
NO2
R
NH2
R
8
8
14a
14b
(8-NO 2):
(6-NO2):
6-NH2:
8-NH2:
15a
16a
R = H, 75%
R = Me, 88%
R = Et, 92%
R = i-Pr, 63%
R = H, 73%
R = Me, 80%
R = Et, 56%
R = i-Pr, 58%
, R = H, 79%
15b, R = Me, 68%
15c
, R = H, 66%
16b, R = Me, 72%
16c
, R = Et, 69%
15d, R = i-Pr, 48%
15e
, R = Et, 82%
16d, R = i-Pr, 57%
16e
, R = MeOCH2, 49%
R = MeOCH2, 68% R = MeOCH2, 70%
, R = MeOCH2, 63%
Scheme 3. Dimroth rearrangement observed on attempted preparation of 6- and 8-nitro-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridines 13. Reagents and conditions: (a)
hydrazine hydrate (5 equiv), i-PrOH, rt; (b) RCO2H, 110 °C, 48 h; (c) H2, 10% Pd/C, 7 M NH3 in MeOH, 100 atm, 100 °C, 48 h.
5
5
R
R
5
N
N
N
a
6
6
b
c
NO2
NH2
d
NO2
R' = Ac
R' = H
N
N
e
NHAc
NHR'
N
N
HN
NH
HN
NH
HN
NH2
3
3
3
N
N
R
R
8
8
6-NH2:
8-NH2:
O
O
17a
18a
, R = H, 57%
18b, R = Me, 71%
R = Me (5-NO2), 89%
R = Et (5-NO2), 86%
R = i-Pr (5-NO2), 90%
R = H (3-NO2), 90%
R = Me (3-NO2), 91%
R = Me (5-NO2), 65%
R = Et (5-NO2), 63%
R = i-Pr (5-NO2), 60%
R = H (3-NO2), 65%
R = Me (3-NO2), 70%
R = Me (6-NO2), 80%
R = Et (6-NO2), 73%
R = i-Pr (6-NO2), 71%
R = H (8-NO2), 80%
R = Me (8-NO2), 70%
, R = Me, 68%
17b, R = Et, 58%
17c
, R = i-Pr, 49%
(yields shown are over last two steps)
Scheme 4. Preparation of 6- and 8-amino-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridines 17a–c and 18a–b via sequential reduction of the nitro group and the pyridine ring.
Reagents and conditions: (a) RCOCl (1.1 equiv), pyridine (2 equiv), DMF, 0 °C ? rt; (b) H2, Pd/C, MeOH, 1 atm, rt; (c) AcOH, reflux, 48 h; (d) H2, Pd/C, MeOH, 100 atm, 70 °C; (e)
aq HCl (10 M), reflux, 24 h.
Clearly, the preparation of the targeted 6- and 8-nitro precur-
sors 13 for subsequent reduction would require a substantial
change in synthetic strategy. We reasoned that the tendency of
the 2-hydrazinopyridine precursors to undergo the Dimroth rear-
rangement would be suppressed if the nitro functional group
was converted to an electron-donating amino group prior to the
formation of the 1,2,4-tiazolo ring. As presented in Scheme 4, this
reasoning proved correct. The synthetic route included the protec-
tion of the amino group and delivered two isomeric sets of 6- and
8-amino-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridines 17a–c
and 18a–b.
N
N
N
N
N
H3C
N
N
NH2
N
N
NH2
COOH
H3C
H3C
8b
11b
15b
NH2
NH2
N
N
N
N
N
N
N
N
H3C
NH2
N
H3C
H3C
16b
17a
18b
The identity of the heterocyclic cores in 8, 11, 17, and 18 (‘non-
rearranged’) as well as in 15 and 16 (‘Dimroth rearranged’) was
unequivocally established by the correlations observed in the
1H–15N HMBC spectra of representative compounds in each series
(Fig. 3).
The utility of the 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyri-
dine core which were developed as building blocks in this work
for application in antidiabetic drug design is clearly exemplified
by compounds 6 and 7 which are DPPIV inhibitors (vide supra).
Inhibition of DPPIV leads to an increase in the levels of glucagon-
Figure 3. 1H–15N HMBC correlations observed for compounds 8b, 11b, 15b, 16b,
17a, and 18b.
respective sets of compounds 14a–b were obtained (incorporating
various substituents at position 3 of the 1,2,4-triazole ring). Hydro-
genation over Pd/C using 100 atm of hydrogen gas in methanolic
ammonia yielded the products of concomitant reduction of the
pyrido ring and the nitro group (Scheme 3).
N
N
R
R
N
N
N
N
F
F
N
N
N
N
R'
HN
H2N
NH2
O
F
7
8
19
180 compounds
synthesized
and tested
Figure 4. Library of GLP-1 secretion stimulators inspired by compound 7.
Please cite this article in press as: Mishchuk, A.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.01.094

4
A. Mishchuk et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Table 1
Supplementary data
GLP-1 release stimulation in mSTC-1 and NCI-H716 cell lines by compounds 19a–c
Compound Structure
EC50 (mSTC-1) EC50 (NCI-H716)
M) M)
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.01.
094.
(l
(l
Ph
N
N
N
19a
4.19
>40
>40
H
N
N
N
N
References and notes
Ph
N
N
H
1. Hann, M. M.; Oprea, T. I. Curr. Opin. Chem. Biol. 2004, 8, 255–263.
2. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Deliv. Rev.
2001, 46, 3–26.
3. Chuprina, A.; Lukin, O.; Demoiseaux, R.; Buzko, A.; Shivanyuk, A. J. Chem. Inf.
Model. 2010, 50, 470–479.
19b
12.6
12.2
N
N
Ph
N
N
H
N
N
19c
>40
4. Nadin, A.; Hattotuwagama, C.; Churcher, I. Angew. Chem., Int. Ed. 2012, 51,
1114–1122.
5. Tosatti, P.; Horn, J.; Campbell, A. J.; House, D.; Nelson, A.; Marsden, S. P. Adv.
Synth. Catal. 2010, 352, 3152–3157.
6. Pammolli, F.; Magazzini, L.; Riccaboni, M. Nat. Rev. Drug Disc. 2011, 10, 428–
438.
7. Harvey, A. L.; Edrada-Ebel, R.; Quinn, R. J. Nat. Rev. Drug Disc. 2015, 14, 111–129.
8. Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752–6756.
9. Calculated using ACD/Labs 6.00 Software.
like peptide-1 (GLP-1) and results in the lowering of the blood glu-
cose levels.20 The structure of the aminomethyl-substituted core 8
is clearly recognizable in compound 7 (Fig. 4) and this led to the
design of a focused library of 180 compounds 19 (see ESI for exact
structures)21 which was synthesized and tested as part of the Eli
Lilly Open Innovation Drug Discovery program.22 To our delight,
three compounds tested (19a–c) selectively stimulated GLP-1
secretion in mouse enteroendocrine-like STC-1 cells (relevant cel-
lular model)23 but not in NCI-H716 cells (Table 1).24
In conclusion, we have described a facile synthesis of six types
of functionalized building blocks based on 5,6,7,8-tetrahydro
[1,2,4]triazolo[4,3-a]pyridine and 5,6,7,8-tetrahydro[1,2,4]triazolo
[1,5-a]pyridine cores. Both of these non-flat bicyclic heterocycles
are attractive from the standpoint of lead-likeness and represent
emerging privileged motifs for drug design. We have exemplified
the latter aspect by designing new GLP-1 secretion stimulators
based on a set of (5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-
6-ylmethyl)amines 8.
10. Bonanomi, M.; Baiocchi, L. J. Heterocycl. Chem. 1983, 20, 1657–1660.
11. Bouteau, B.; Lancelot, J. C.; Robba, M. J. Heterocycl. Chem. 1990, 27, 1649–1651.
12. Bischoff, F. P.; Velter, A. I.; Rombouts, F. J. R.; De Cleyn, M. A. J.; Van Brandt, S. F.
A.; Gijsen, H. J. M.; Zavattaro, C.; Van den Keybus, F. A. M. PCT Int. Appl. WO
2,014,111,457, A1 (2014); Chem. Abstr. 2014, 161, 1199038.
13. Takai, T.; Hoashi, Y.; Tomata, Y.; Morimoto, S.; Nakamura, M.; Watanabe, T.;
Igari, T.; Koike, T. Bioorg. Med. Chem. Lett. 2015, 25, 4245–4249.
14. Rucker, P. V.; Jerome, K. D.; Selness, S. R.; Baldus, J. E.; Xing, L. PCT Int. Appl. WO
2,006,018,727, A2 (2006); Chem. Abstr. 2006, 144, 164479.
15. Edmondson, S. D.; Mastracchio, A.; Cox, J. M.; Eiermann, G. J.; He, H.; Lyons, K.
A.; Patel, R. A.; Patel, S. B.; Petrov, A.; Scapin, G.; Wu, J. K.; Xu, S.; Zhu, B.;
Thornberry, N. A.; Roy, R. S.; Weber, A. E. Bioorg. Med. Chem. Lett. 2009, 19,
4097–4101.
16. Schwehm, C.; Li, J.; Song, H.; Hu, X.; Kellam, B.; Stocks, M. J. ACS Med. Chem. Lett.
2015, 6, 324–328.
17. Thornberry, N. A.; Weber, A. E. Curr. Top. Med. Chem. 2007, 7, 557–568.
18. (a) Oehlrich, D.; Rombouts, F. J. R.; Berthelot, D.; Bischoff, F. P.; De Cleyn, M. A.
J.; Jaroskova, L.; Macdonald, G.; Mercken, M.; Surkyn, M.; Trabanco, A. A.;
Tresadern, G.; Van Brandt, S.; Velter, A. I.; Wu, T.; Gijsen, H. J. M. Bioorg. Med.
Chem. Lett. 2013, 23, 4794–4800; (b) Schmidt, M. A.; Qian, X. Tetrahedron Lett.
2013, 54, 5721–5726.
19. Kost, A. N.; Gromov, S. P.; Sagitullin, R. S. Tetrahedron 1981, 37, 3423–3454.
20. McIntosh, C.; Demuth, H.; Pospisilik, J.; Pederson, R. Regul. Pept. 2005, 128, 159–
165.
Acknowledgements
21. The screening and the building block collection of Enamine, Ltd can be
obtained at https://www.enaminestore.com/catalog.
22. https://openinnovation.lilly.com/dd/.
23. Rindi, G.; Grant, S. G. N.; Yiangou, Y.; Ghatei, M. A.; Bloom, S. R.; Bautch, V. L.;
Solcia, E.; Polak, J. M. Am. J. Pathol. 1990, 136, 1349–1363.
24. Le Neve, B.; Daniel, H. Regul. Pept. 2011, 167, 14–20.
OIDD screening data supplied courtesy of Eli Lilly and Com-
pany—used with Lilly’s permission. To learn more about the Lilly
Open Innovation Drug Discovery program, please visit the program
website at https://openinnovation.lilly.com (last accessed on 11-
05-2015). M.K. gratefully acknowledges support from the Russian
Scientific Fund (Project Grant 14-50-00069).
Please cite this article in press as: Mishchuk, A.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.01.094