Triazolopiperazine-amides as dipeptidyl peptidase IV inhibitors: Close analogs of JANUVIA (sitagliptin phosphate)

Article abstract of DOI:10.1016/j.bmcl.2007.03.098

A series of β-aminoamides bearing triazolopiperazines has been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. Efforts at optimization of the β-aminoamide series, which ultimately led to the discovery

Full text of DOI:10.1016/j.bmcl.2007.03.098

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3373–3377
Triazolopiperazine-amides as dipeptidyl peptidase IV
inhibitors: Close analogs of JANUVIATM (sitagliptin phosphate)
Dooseop Kim,a,* Jennifer E. Kowalchick,a Scott D. Edmondson,a
Anthony Mastracchio,a Jinyou Xu,a George J. Eiermann,b Barbara Leiting,b
Joseph K. Wu,b KellyAnn D. Pryor,b Reshma A. Patel,b Huaibing He,a
Kathryn A. Lyons,a Nancy A. Thornberryb and Ann E. Webera
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
bDepartment of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 6 March 2007; revised 22 March 2007; accepted 29 March 2007
Available online 5 April 2007
Abstract—A series of b-aminoamides bearing triazolopiperazines has been prepared and evaluated as potent, selective, orally active
dipeptidyl peptidase IV (DPP-4) inhibitors. Efforts at optimization of the b-aminoamide series, which ultimately led to the discovery
of JANUVIATM (sitagliptin phosphate, compound 1), are described.
Ó 2007 Elsevier Ltd. All rights reserved.
The discovery of a biological function of dipeptidyl pep-
tidase IV (DPP-4), a serine protease, has spurred recent
intense research efforts directed toward the development
of DPP-4 inhibitors as new potential anti-diabetic
agents.1 DPP-4 inhibitors function as indirect stimula-
tors of insulin secretion and this effect is believed to be
mediated primarily by enhancing the action of the incre-
tin hormone glucagon-like peptide 1 (GLP-1).2 This hor-
mone is released in the gut in response to food intake.
GLP-1, in turn, stimulates the pancreas to synthesize
and secrete insulin, while inhibiting the release of gluca-
gon. GLP-1 regulates insulin in a strictly glucose-depen-
dent manner, thus posing little or no risk of
hypoglycemia. Other beneficial effects of GLP-1 therapy
include the slowing of gastric emptying3 and reduction
of appetite.4 Furthermore, recent data suggesting a po-
tential role for GLP-1 in restoration of b-cell function
in rodents indicate that this mechanism might even slow
or reverse disease progression.5 However, GLP-1 is rap-
idly degraded in vivo through the action of DPP-4,
which cleaves a dipeptide from the N-terminus to give
the inactive GLP-1[9–36]amide.6 Thus, inhibition of
DPP-4 would increase the half-life of GLP-1 and pro-
long the beneficial effects of this incretin hormone. Com-
pound 1, JANUVIATM (sitagliptin phosphate), a potent,
selective, and orally active DPP-4 inhibitor, has recently
been approved by the U.S. Food and Drug Administra-
tion (FDA) for the treatment of type 2 diabetes (Fig. 1).
Several other DPP-4 inhibitors are currently being eval-
uated in late stage human clinical trials, including
vildagliptin (2) and saxagliptin (3).7
Extensive structure–activity relationship (SAR) studies
around the left side phenyl ring and the right side triaz-
olopiperazine moiety in the b-aminoamide series
F
OH
F
NH2
O
O
CN
N
N
NH
N
N
H3PO4
F
N
CF3
1 JANUVIATM (sitagliptin phosphate)
2 Vildagliptin (LAF-237)
OH
O
CN
N
NH2
Keywords: Close analogs of Januvia; Sitagliptin; Type 2 diabetes;
Triazolopiperazine-amides; Dipeptidyl peptidase IV inhibitors; DPP-4
inhibitor; GLP-1; DPP-8; DPP-9.
3 Saxagliptin (BMS477118)
Figure 1. DPP-4 inhibitors.
*
Corresponding author. E-mail: dooseop_kim@merck.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.03.098

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D. Kim et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3373–3377
provided various close analogs of sitagliptin (1).8 While
the discovery of sitagliptin (1) was previously reported,9
herein, our initial efforts at optimization of b-aminoa-
mide series are described in detail.
N
HN
N
N
14
R
X
a,b
The b-amino acid derived DPP-4 inhibitors in this
report were prepared by standard peptide coupling of
b-amino acids (7 and 12, Scheme 1) with fused heterocy-
cles (14–19, Scheme 2) as reported earlier.9 Two different
approaches to non-commercially available b-amino
acids are described in Scheme 1.
H
N
N
N
N
c,d,b
h,b
e,d,b
HN
HN
N
N
NH2
HN
HN
N
N
N
N
N
N
N
13
16
F
15
F
f,g
N
N
First, using Scholkopf’s bis-lactam strategy,10 the start-
ing dihydropyrazine 4 was converted to a-amino acid
6 with the requisite (R)-stereochemistry following the
procedure similar to those previously reported (Route
1, Scheme 1).8a,9 Subsequent one-carbon extension gave
rise to the desired b-amino acid 7 for the synthesis of
DPP-4 inhibitors. In a second approach (Route 2,
Scheme 1), 2,4-difluorophenylacetic acid was converted
to b-ketoester 9 in three steps according to the known
procedure.11 Treatment of b-ketoester 9 with (S)-phe-
nylglycine amide followed by asymmetric hydrogenation
provided compound 11a. Enantiomeric excess (ee) of
methyl ester 11b was determined to be 98.5% using chi-
ral HPLC (ChiralPak AD column). Boc-protection of
11a followed by hydrolysis afforded b-aminoacid 12.
b
N
N
N
N
NH
CO2Et
CO2Et
19
O
17
18
Scheme 2. Reagents and conditions: (a) fluorobenzoic acid or isoni-
cotinic acid, PPA, 150 °C, 18 h, 8–16%; (b) H2, 10% Pd/C, EtOH, rt,
18 h, 80–93%; (c) cyclopropanecarbonyl chloride, py, reflux, 47%; (d)
PPA, 150 °C, 18 h, 57–74%; (e) (CHF2CO)2O, Et3N, CH2Cl2, 0 °C to
rt, 2 h, 100%; (f) ethyl oxalyl chloride, Et3N, CH3CN, 27%; (g) PTSA,
toluene, reflux, 6 h, 31%; (h) t-BuNH2, 35%.
sponding fluorobenzoic acid or isonicotinic acid in
polyphosphoric acid (PPA) followed by catalytic hydro-
genation afforded aryl-substituted triazolopiperazine 14.
Several approaches for the variation of the substituents
on triazolopiperazines are described in Scheme 2. First,
direct condensation of hydrazinopyrazine 13 with corre-
Acylation of starting hydrazinopyrazine 13 with cyclo-
propanecarbonyl chloride or difluoroacetic anhydride
followed by PPA cyclization and hydrogenation affor-
ded 15 and 16, respectively. Similarly, hydrazinopyr-
azine 13 was acylated with ethyl oxalyl chloride and
then cyclized under mild conditions to give 17,12 which
was hydrogenated to afford 18 or converted to tert-butyl
amide 19 by treatment with tert-butyl amine.
Route 1:
R
Boc
N
OMe
N
OMe
a
NH
CO2H
b,c,d
O
R
MeO
N
MeO
R
N
Compounds in Tables 1 and 2 were evaluated in vitro
for their inhibition of DPP-4.13 The inhibitors were also
tested against DPP-4 structural homologs in the DPP-4
gene family, including DPP8,14 DPP9,15 fibroblast acti-
vation protein (FAP, also called seprase),16 and other
proline specific enzymes with DPP-4 like activity, includ-
ing quiescent cell proline dipeptidase (QPP, also known
as DPP-II),13,17 amino peptidase P, and prolidase. Since
significant QPP off-target activity was often observed for
the b-amino acid derived DPP-4 inhibitors reported
from these laboratories earlier,8 QPP data are presented
for comparison. Safety studies using a DPP8/9 selective
inhibitor suggest that inhibition of DPP8 and/or DPP9
is associated with profound toxicity in preclinical
species.18 Although the relevance of these findings to
human toxicity is unknown, treatment-related dermato-
logical toxicity in monkeys was observed with a
non-selective DPP-4, DPP8, and DPP9 inhibitor.19
Thus, selectivity profiles against DPP8 and DPP9 were
also obtained for safety reasons.
5
4
6
Boc
NH
e,f,
OH
7
Route 2:
F
CONH2
F
F
NH
O
O
O
O
j
g,h,i
OH
OMe
OMe
F
F
F
9
10
8
F
R
F
Boc
k,l
NH
O
NH
O
n
OMe
OH
F
F
11a R = H
12
m
11b R = Boc
Scheme 1. Reagents and conditions: (a) n-BuLi, THF, À78 °C, BnBr,
75–80%; (b) i—1 N HCl, rt, 16 h, ii—MeOH; (c) (Boc)2O, Et3N,
CH2Cl2; (d) LiOH, 1:1 THF/H2O, 62–70% (3 steps); (e) Et3N, iso-butyl
chloroformate, À30 °C, CH2N2; (f) silver benzoate, 1,4-dioxane/H2O
(5:1), sonication, 81–86% (2 steps); (g) (COCl)2, cat. DMF, CH2Cl2;
(h) 2,4,6-collidine, Meldrum’s acid, 45% (2 steps); (i) MeOH, reflux,
4 h, 81%; (j) (S)-phenylglycine amide, MeOH, AcOH, 40 °C, 2 h, 87%;
(k) 90 psi H2, THF/MeOH = 5:1, PtO2, 42%; (l) MeOH/AcOH/H2O,
Pearlman’s catalyst; (m) (Boc)2O, Et3N, CH2Cl2, 59% (2 steps); (n) 1 N
aqueous LiOH, THF, 87%.
In the course of the SAR development of this triazolo-
piperazine series, an interesting fluorine effect on DPP-
4 activity was observed. The trend was consistent with
the SAR observed with a previously reported thiazoli-
dine series.8 In the case of mono-fluoro substitution,

D. Kim et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3373–3377
Table 1. Effects of R1 substituent on inhibitory properties of selected DPP-4 inhibitorsa
3375
NH2
O
R1
N
N
N
N
CF3
Compound
R1
DPP-4 IC50 (nM)
QPP IC50 (nM)
DPP-8 IC50 (nM)
DPP-9 IC50 (nM)
20
21
2-F
3-F
98
135
272
128
82
14,000
31,000
75,000
>100,000
65,000
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
72,000
22
23
4-F
>100,000
98,000
3,4-Di-F
2,4-Di-F
2,5-Di-F
2,3,5-Tri-F
2,3,6-Tri-F
2,4,6-Tri-F
2,4,5-Tri-F
2,3,4,5,6-Penta-F
2-CF3
46,000
83,000
69,000
24
25
>100,000
>100,000
42,000
27
26
27
805
151
87
>100,000
>100,000
>100,000
48,000
>100,000
>100,000
>100,000
66,000
28
1 (Sitagliptin)
18
29
30
31
32
33
34
35
36
37
38
39
40
41
1018
486
366
511
145
59
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
26,000
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
46,000
3-CF3
4-CF3
2-Cl
3-Cl
4-Cl
264
1580
23
3,4-Di-Cl
2,4-Di-Cl
2,5-Di-Cl
2-F, 5-Cl
2,5-Di-F, 4-Cl
2-Cl-, 4,5-di-F
>100,000
30,000
>100,000
49,000
180
21
>100,000
>100,000
49,000
>100,000
98,000
76
84
>100,000
>100,000
>100,000
>100,000
a Unless otherwise noted, values reported are means of a minimum of two experiments with a standard deviation <25% of the mean.
2-fluoro analog 20 was slightly more potent than 3-flu-
oro analog 21, and 4-fluoro analog 22 was the least
active. Sequential addition of one or two more fluorine
atoms further increased the DPP-4 potency. In the case
of difluoro-analogs (23–25), highest DPP-4 potency was
achieved with the addition of fluorine atoms at the
2- and 5-positions (25, IC50 = 27 nM). Interestingly,
reordering of three fluorine atoms on the phenyl of the
most potent 2,4,5-trifluoro-compound 1 (sitagliptin)
resulted in a significant decrease in the DPP-4 potency
(P5-fold, 26–28). It was notable that pentafluoro-ana-
log 29 was the least active in the fluorine-substitution
series (DPP-4 IC50 = 1018 nM). Trifluoromethyl substi-
tuted analogs (30–32) were uniformly less active than
their corresponding fluoro-analogs (21–23). Unlike the
fluorine series, the preferred positions for chlorine atoms
changed in both mono- and di-substitution cases. In the
case of mono-chloro substitution, the 3-position is the
optimal position for DPP-4 potency (35; DPP-4
IC50 = 59 nM). Compound 34 was ca. 2-fold more
potent than the corresponding 3-fluoro compound 21.
Among three dichloro-substituted compounds (36–38)
the 2,4-dichloro compound 37exhibited the highest
potency (DPP-4 IC50 = 23 nM). Compound 37 was ca.
4-fold more potent than the corresponding 2,4-diflu-
oro-compound 24 and was as potent as 2,5-difluoro
compound 25. Interestingly, compound 39 with mixed
halides (2-F, 5-Cl) exhibited a similar activity as
2,5-difluoro-compound 25. Displacement of a fluorine
atom with a chlorine atom at either the 2- or 4-position
of compound 1 (sitagliptin) resulted in a 4- to 5-fold
decrease in the DPP-4 potency (40 and 41). In general,
most of the triazolopiperazine analogs exhibited high
selectivity over counterscreens.
In order to improve DPP-4 potency as well as pharma-
cokinetic properties, the effects of substituents on the
triazolopiperazine moiety were investigated. Both aryl
and heteroaryl substituents were found to be as effective
as alkyl or perfluoroalkyl substituents in terms of DPP-4
potency. However, these analogs (42–44) displayed
unacceptable DPP8 activity (IC50: 1–4 lM), whereas
the effects of aryl and heteroaryl substituents on DPP9
activity were insignificant. Since inhibition of DPP8
and/or DPP9 is associated with significant toxicity in
preclinical species, further development of a series of
compounds with aryl or heteroaryl substituent was dis-
continued. While ethyl ester and tert-butyl amide ana-
logs (45, 50, and 51) showed moderate DPP-4 activity,
hydroxyl analog 46 exhibited a 3-fold increase in DPP-
4 potency over these analogs.20 Ethyl analog 47 was
equipotent to cyclopropyl analog 48. Deletion of one
fluorine from a CF3-group at R2 resulted in a slight
decrease in potency (49: DPP-4 IC50 = 29 nM).
Representative potent compounds were selected for the
evaluation in rat pharmacokinetic studies (Table 3).
While both 2,4-dichloro- and 2-fluoro-, 5-chloro-ana-
logs (37 and 39) are comparable to compound 1 (sitag-
liptin) in terms of DPP-4 potency, they showed faster
clearance and disappointing oral bioavailability
compared to compound 1. Additional halo-substituted
analogs 40 and 41 also exhibited decreased oral

3376
D. Kim et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3373–3377
Table 2. Effects of R1 and R2 substituents on inhibitory properties of selected DPP-4 inhibitorsa
NH2
O
R1
N
N
N
N
R2
Compound
R1
R2
DPP-4 IC50 (nM)
QPP IC50 (nM)
38,000
DPP-8 IC50 (nM)
979
DPP-9 IC50 (nM)
>100,000
42
2,5-Di-F
60
F
43
44
45
46
47
48
49
50
51
2,5-Di-F
30
65
95,000
>100,000
>100,000
>100,000
>100,000
83,000
1010
4200
58,000
84,000
F
F
2,5-Di-F
N
O
2,5-Di-F
190
69
37,000
>100,000
39,000
54,000
86,000
22,000
63,000
78,000
O
2,5-Di-F
>100,000
>100,000
>100,000
>100,000
78,000
OH
2,4,5-Tri-F
2,4,5-Tri-F
2,4,5-Tri-F
2,4,5-Tri-F
2,4,5-Tri-F
Et
37
30
F
29
>100,000
>100,000
46,000
F
O
219
O
O
NH
234
>100,000
a Unless otherwise noted, values reported are means of a minimum of two experiments with a standard deviation <25% of the mean.
Table 3. Pharmacokinetic properties of selected DPP-4 inhibitors in
the rat (iv, 1 mg/kg; po, 2 mg/kg)
one fluorine atom from the CF3-substituent in
compound 1 resulted in a significant decrease in oral
exposure and oral bioavailability (49).
Compound CL
(mL/min/kg)
t1/2 (h) AUC norm
(lM h kg mgÀ1
F (%)
)
In summary, we have discovered a series of novel triaz-
olopiperazine-based DPP-4 inhibitors, which are among
the most selective DPP-4 inhibitors reported to date.
Reordering of three fluorine atoms (26–28), displace-
ment of a fluorine atom with a chlorine (40 and 41) in
the left side phenyl ring of compound 1 (sitagliptin),
and deletion of a fluorine from triazolopiperazine ring
(49) gave rise to several close analogs of compound 1.
Among these analogs compound 40 was found to
possess the best pharmacokinetic profile, however, its
DPP-4 activity was suboptimal. Decreased DPP-4
potency and oral bioavailability of des-fluoro-analog
49 demonstrated that the CF3 group on the triazolopip-
1
37
39
40
41
47
48
49
60
1.7
2.6
1.7
2.1
1.7
1.7
1.8
1.3
0.523
0.144
0.180
0.371
0.238
0.016
0.016
0.251
76
36
43
54
47
2
98
99
58
78
70
68
66
3
39
bioavailability in the rat comparable to compound 1
(sitagliptin). Replacement of CF3 in compound 1 with
an ethyl or cyclopropyl substituent resulted in a loss of
oral bioavailability (47 and 48: F = 2–3%). Deletion of

D. Kim et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3373–3377
3377
Han, S.; Parker, R. A.; Hamann, L. G. J. Med. Chem.
2004, 47, 2587.
erazine moiety of compound 1 is optimal. Importantly,
it was discovered that some substituents on the triazolo-
piperazine moiety often afford the unacceptable DPP8
activity (42–44). This result suggests that we need to
take precautions in designing DPP-4 inhibitors even in
highly selective series such as the triazolopiperazine
series.
8. For earlier studies, see: (a) Xu, J.; Ok, H. O.; Gonzalez, E.
J., ; Colwell, L. F., Jr.; Habulihaz, B.; He, H.; Leiting, B.;
Lyona, K. A.; Marsilio, F.; Patel, R. A.; Wu, J. K.;
Thornberry, N. A.; Weber, A. E.; Parmee, E. R. Bioorg.
Med. Chem. Lett. 2004, 14, 4759; (b) Brockunier, L.; He, J.;
Colwell, L. F., Jr.; Habulihaz, B.; He, H.; Leiting, B.;
Lyons, K. A.; Marsilio, F.; Patel, R.; Teffera, Y.; Wu, J. K.;
Thornberry, N. A.; Weber, A. E.; Parmee, E. R. Bioorg.
Med. Chem. Lett. 2004, 14, 4763; (c) Edmondson, S. D.;
Mastracchio, A.; Beconi, M.; Colwell, L., Jr.; Habulihaz,
H.; He, H.; Kumar, S.; Leiting, B.; Lyons, K.; Mao, A.;
Marsilio, F.; Patel, R. A.; Wu, J. K.; Zhu, L.; Thornberry,
N. A.; Weber, A. E.; Parmee, E. R. Bioorg. Med. Chem.
Lett. 2004, 14, 5151.
9. (a) Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.;
Fisher, M. H.; He, H.; Hickey, G. J.; Kowalchick, J. E.;
Leiting, B.; Lyons, K.; Marsilio, F.; McCann, M. E.;
Patel, R. A.; Petrov, A.; Scapin, G.; Patel, S. B.; Sinha
Roy, R.; Wu, J. K.; Wyvratt, M. J.; Zhang, B. B.; Zhu, L.;
Thornberry, N. A.; Weber, A. E. J. Med. Chem. 2005, 48,
141; (b) U.S. Patent 6,699,871 B2, 2004.
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20. For the synthesis of compound 46, the coupling product
52 was employed as shown below.
F
Boc
1) LiBH4/THF, 0oC
60%
NH
O
N
N
46
N
F
N
2) HCl/MeOH, 56%
CO2Et
52