Novel tetrahydropyran analogs as dipeptidyl peptidase IV inhibitors: Profile of clinical candidate (2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2- (methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran- 3-amine (23)

Article abstract of DOI:10.1016/j.bmcl.2013.07.061

A series of novel tri-2,3,5-substituted tetrahydropyran analogs were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the series provided inhibitors with good DPP-4 potency and selectivity over other peptidases (QPP, DPP8, and FAP). Compound 23, which is very potent, selective, efficacious in the diabetes PD model, and has an excellent pharmacokinetic profile, is selected as a clinical candidate.

Full text of DOI:10.1016/j.bmcl.2013.07.061

Accepted Manuscript
Novel tetrahydropyran analogs as dipeptidyl peptidase IV inhibitors: Profile of
clinical candidate (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfon‐
yl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine
(23)
Tesfaye Biftu, Xiaoxia Qian, Ping Chen, Dennis Feng, Giovanna Scapin, Ying-
Duo Gao, Jason Cox, Ranabir Sinha Roy, George Eiermann, Huabing He, Kathy
Lyons, Gino Salituro, Sangita Patel, Alexander Petrov, Feng Xu, Shiyao Sherrie
Xu, Bei Zhang, Charles Caldwell, Joseph K. Wu, Kathy Lyons, Ann E. Weber
PII:
S0960-894X(13)00906-2
DOI:
http://dx.doi.org/10.1016/j.bmcl.2013.07.061
BMCL 20726
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
11 June 2013
22 July 2013
24 July 2013
Please cite this article as: Biftu, T., Qian, X., Chen, P., Feng, D., Scapin, G., Gao, Y-D., Cox, J., Roy, R.S., Eiermann,
G., He, H., Lyons, K., Salituro, G., Patel, S., Petrov, A., Xu, F., Xu, S.S., Zhang, B., Caldwell, C., Wu, J.K., Lyons,
K., Weber, A.E., Novel tetrahydropyran analogs as dipeptidyl peptidase IV inhibitors: Profile of clinical candidate
(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-
yl]tetrahydro-2H-pyran-3-amine (23), Bioorganic & Medicinal Chemistry Letters (2013), doi: http://dx.doi.org/
10.1016/j.bmcl.2013.07.061
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Novel tetrahydropyran analogs as dipeptidyl
peptidase 4 inhibitors: Profile of clinical
candidate (2R,3S,5R)-2-(2,5-Difluorophenyl)-
5-[2-(methylsulfonyl)-2,6-
Leave this area blank for abstract info.
dihydropyrrolo[3,4-c]pyrazol-5(4H)-
yl]tetrahydro-2H-pyran-3-amine (23)
Tesfaye Biftu, Xiaoxia Qian, Ping Chen, Dennis Feng, Giovanna Scapin, Ying-Duo Gao, Jason Cox,
Ranabir Sinha Roy, George Eiermann, Huabing He, Kathy Lyons, Gino Salituro, Sangita Patel,
Alexander Petrov, Feng Xu, Shiyao Sherrie Xu, Bei Zhang, Charles Caldwell, Joseph K. Wu, and Ann
E. Weber

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Novel tetrahydropyran analogs as dipeptidyl peptidase IV inhibitors: Profile of
clinical candidate (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-
dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine (23)
Tesfaye Biftua, Xiaoxia Qiana, Ping Chena, Dennis Fenga, Giovanna Scapinb, Ying-Duo Gaoc, Jason Coxa,
Ranabir Sinha Royd,George Eiermannd, Huabing Hee, Kathy Lyonse, Gino Salituroe, Sangita Patelb,
Alexander Petrovd, Feng Xuf, Shiyao Sherrie Xue, Bei Zhangd, Charles Caldwella, Joseph K. Wud, Kathy
Lyonse, and Ann E. Webera
a Discovery Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
b Structural Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
c Chemical Modeling and Informatics, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
d In Vivo Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
e PPDM Bioanalytics, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
f Process Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A series of novel tri-2,3,5-substituted tetrahydropyran analogs were synthesized and evaluated
as inhibitors of dipeptidyl peptidase 4 (DPP-4) for the treatment of type 2 diabetes.
Optimization of the series provided inhibitors with good DPP-4 potency and selectivity over
other peptidases (QPP, DPP8, and FAP). Compound 23, which is very potent, selective,
efficacious in the diabetes PD model, and has an excellent pharmacokinetic profile, is selected as
a clinical candidate.
2013 Elsevier Ltd. All rights reserved.
Keywords:
DPP-IV
Tetrahydropyran, DPP-4 inhibitors, diabetes
Type 2 diabetes mellitus is a growing epidemic
affecting approximately 220 million people worldwide.1
Commercial proof of concept for DPP-4 inhibitors has been
established with sitagliptin, Merck's lead DPP-4 inhibitor (1),
which was the first DPP-4 inhibitor approved by the FDA in
October 2006. Subsequently, additional DPP4i have entered the
market. These include vildagliptin (2), saxagliptin (3), linagliptin
(4) and alogliptin (5).
DPP-4 inhibitors prolong the circulating half-life of
glucagon-like peptide
1
(GLP-1) and glucose-dependant
incretin hormones that
insulinotropic polypeptide (GIP),2
stimulate insulin secretion in a glucose-dependent manner.
Additionally, GLP-1 has been shown to inhibit glucagon release,
decrease gastric emptying, and promote the regeneration and
differentiation of islet β-cells.3 By increasing the circulating
concentration GLP-1 and GIP, DPP-4 inhibitors improve glucose
control in patients with type 2 diabetes.
was the development of cyclohexylamine (6),4 a structurally
distinct rigid analog of sitagliptin (1). The cyclohexylamine
analogs are potent and selective against other related proteases
with excellent pharmacokinetic profiles; however, they block the
human potassium channel hERG at low micromolar
concentrations, resulting in QTc prolongation in a cardiovascular
dog model (CV-dog).5 The current tetrahydropyran (23) analogs
have reduced basicity compared to the cyclohexylamines, and
Given the clinical success of sitagliptin (1), our
laboratories have been interested in generating structurally
diverse, best-in-class DPP-4 inhibitors. Over the course of our
studies, several lead classes have evolved. Critical to this work

thereby reduced hERG potency. In addition, they do not affect
QTc (a measure of the time between the start of the Q wave and
the end of the T wave in the heart's electrical cycle) prolongation
in the cardiovascular (CV)-dog model. Following systematic
Structure-activity-studies, tetrahydropyran (23a) was selected as
a clinical candidate. In this paper, we describe the discovery,
synthesis, SAR studies, and pharmacokinetic properties of the
clinical candidate 23a.
column (Chiralpak 1A, hexane/ethanol 90:10). The nitro-
substituted pyran 17a was then reduced using zinc and
hydrochloric acid, and the resulting amine 18a was protected as
its BOC derivative by treatment with di-tert-butyl dicarbonate to
give 19a. Treatment of 19a with osmium tetroxide and N-
methylmorpholine N-oxide gave the diol 20a, which upon further
treatment with sodium periodate or lead tetraacetate gave ketone
21a. The desired ketone 21a could alternatively be made directly
from 19a by treatment with ruthenium chloride and sodium
periodate. All the other isomers 21b, 21c and 21d were made
from 17b, 17c and 17d by a similar method.
The synthesis of tetrahyrdopyran analogs (23) depicted
in this manuscript is illustrated in Schemes 1-3.
The pyrrolopyrazole intermediate 10 (Scheme 1) was
made from the commercially available Boc-protected ketone 8.
Stirring a mixture of neat N,N-dimethylformamide dimethyl
acetal (DMF-DMA) and ketone 8 gave the enamine 9. Heating
enamine 9 with hydrazine and ethanol under pressure followed
by dehydration by treatment with hydrogen chloride in dry ethyl
acetate gave the salt of the desired pyrrolopyrazole 10. Upon
neutralization with aqueous ammonium hydroxide, the free base
pyrrolopyrazole 10 was obtained. The pyrrolopyrimidines 10a
were prepared from gem-dimethyl substituted 8 and substituted
amidines in a similar manner. The other heterocycles 10d used to
prepare analogs 23 were prepared from pyrrolidine 10b, by
acylation to form intermediates 10c and final cyclization to the
desired heterocycle 10d.
Scheme 2.
Synthetic of tetrahydropyranone
Ar
Cl
Ar
O
83%
CH NO
3
O
O
2
I
I
11
12
Ar
70%
NO
2
40-50%
O
Jones 50%
CH NO
3
Ar
13
2
Ar
H
NO
2
OH
or Dess-Martin 65%
O
15
14
NH
2
NO
2
1. NaBH
2. DBU
NO
2
Zn / HCl
4
Ar
Ar
Ar
O
70% trans
O
O
(17a + 17b)
18a
17a
16
30% cis
(Boc) O
2
(17c + 17d)
80%
NHBoc
ChrialCel AD
NaIO
4
Ar
or Pb(OAc)
4
OH
OH
90%, 2 steps
O
OsO / NMMO
4
NHBoc
NHBoc
Ar
20a
Ar
O
O
O
RhCl / NaIO
3
4
19a
21a
40%
Reductive amination of tetrahydropyranone 21a with
pyrrolopyrazole 10 in the presence of decaborane in methanol
gave intermediate 22a as the major product and 22b as the minor
product. Separation of the two isomers was carried out on a silica
column by eluting with ethanol (8.5% containing 10%
ammonium hydroxide) in hexane. Deprotection with hydrogen
chloride in dry ethyl acetate gave 23a and its other
diastereoisomer 23b, respectively. The other six isomers of 23
were made from ketones 21b, 21c and 21d by using a similar
method. Other analogs of 23 were also made in a similar manner
from their respective heterocyclic amines. The relative
configurations of trans-isomers 21a/21b and cis-isomers 21c/21d
were confirmed by NMR spectroscopy. The absolute
configurations of each enantiomers 21a-d were determined by
Vibrational Circular Dichroism (VCD) spectroscopy and
confirmed by x-ray crystallography of 23w.
The synthesis of tetrahydropyranone intermediate 21a is
illustrated in Scheme 2. Substituted benzoyl halide 11 was treated
with phenol in the presence of N,N-diisopropylethylamine to
form the ester 12. Treatment of 12 with the anion generated from
nitromethane using sodium hydride gave the nitroketone 13.
Alternatively, the nitroketone 13 was made by reacting aldehyde
14 with nitromethane in the presence of catalytic amount of
sodium hydroxide as a base and oxidizing the resulting
nitroalcohol 15 with Jones or Dess-Martin reagent. Heating the
nitroketone 13 with 3-iodo-2-(iodomethyl)prop-1-ene gave the
pyran 16, which was reduced with sodium borohydride to
provide a mixture of trans and cis pyrans 17a/17b and 17c/17d,
respectively. Separation of the cis and trans isomers was carried
on a silica column by using gradient elution with ethyl acetate (0-
36%) in hexane. The trans isomer is the less polar
diastereoisomer. 17c/17d could be isomerized to 17a/17b by
stirring
a
methanol solution in the presence of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU). The enantiomers of
17a/17b and 17c/17d were separated by HPLC using a chiral

Compounds 23a-w were examined for their in vitro
inhibition of human DPP-4 and related enzymes6 such as QPP,7
DPP8,8 and FAP.9 Inhibition of DPP8 and DPP910 has been
associated with toxicity in preclinical species.11 While the
relevance of this toxicity to humans is not known, it is of
particular importance to avoid DPP8/9 off target activity. DPP9
inhibition typically tracks closely with DPP8 and thus was not
reported for this series. The compounds were also evaluated in
the hERG (human-Ether-a-go-go Related Gene) assay.
Table 1. Blocking the site of metabolism
F
NH
2
F
O
R
IC (nM)
50
DPP-4
R
DPP8
FAP
Compd
QPP
The cyclohexyamine analog 6a reported in our earlier
publications has excellent DPP-4 inhibition activity (IC50 = 0.5
nM). However selectivity against IKr (IC50 = 4.8 µM) was below
the desired standard (IC50 > 30µM). In addition, in the CV-dog
model, 6a was found to prolong QTc (>5% at 3 mpk).
Replacement of the cyclohexylamine with tetrahydropyran (e.g.
23i and 23j) reduced the pKa of the primary amine from 8.6 to
7.3 and the hERG selectivity improved accordingly (IC50 = 23µM
and >30µM, respectively). In addition, pyrans 23i and 23j are
devoid of any QTc prolongation in the CV dog at doses up to 30
mg/kg. However, we noticed 23j was unstable and observed
undesirable circulating 23k upon dosing 23j in both rats (~50%)
and dogs (~30%). The metabolite 23k has weaker potency in
DPP4 (140 nM) and reduced selectivity against related proteases,
QPP (IC50 = 160 nM).
N
N
23l
37
>100,000 >100,000 100,000
N
N
CF
N
N
N
23m
27
15,000
>100,000 75,000
N
N
N
23n
12,600 3,900
>100,000 >100,000
O
N
23o
720
>100,000 >100,000
>100,000
N
O
65,000
125
23p
39,000 >100,000
We then considered evaluation of several 5,5-
heterocycles. Pyrrolooxazole 23q is less potent. Pyrroloimidazole
23r has good potency, but selectivity against DPP-8 is poor.
However, pyrrolopyrazole 23 gave compounds with good
potency and selectivity. In addition, 23 was found to be stable
and no oxidation product was observed when dosed to rats or
dogs.
F
NH
2
F
O
R
IC (nM)
50
DPP-4
R
DPP8
FAP
Compd
QPP
N
O
23q
11
>100,000 >100,000 >100000
N
CH
N
NH
23r
1.6
>100,000
220
>100,000
N
CF
Several attempts were made to circumvent the
N
metabolism on the right hand side amine. The tetrahydropyran
NH
N
23
1.4
34,000 >100,000 22,000
analog 23l
has the same left hand heterocycle
(triazolopiperazine) as sitagliptin. However, in the DPP-4
enzyme assay, its potency is lower (34 nM) than sitagliptin (18
nM). Attempts to block the oxidation sites with gem-dimethyl
groups as shown for 23m and 23n gave compounds with much
reduced potency. Introduction of lactam 23o or other 5-member
rings such as the iso-oxazole 23p resulted in much reduced
potency.
Replacement of the left hand side diflurophenyl group
of 23a with other substituents 23s-23v resulted in reduced
potency. The trifluoro analog 23w has comparable DPP-4i
activity to 23a, however, selectivity against FAP is lower.

trans and 2,3 trans > 2,3 cis.
The best analog in this series, 23 was evaluated at Panlabs and
in-house for off-target interactions including hERG potassium
channel, Cav1.2 channel, and various P450 enzyme (Cyps)
activities and found to be inactive.
The pharmacokinetic profile of DPP-4i 23 was
determined in rat, dog and rhesus monkey (Table 6). This
compound displayed a low clearance (2.7 to 9.7 mL/min/kg),
long half-life (6.3 to 13 h), and excellent bioavailability (70 to
83%).
Table 6. Mean pharmacokinetic parameters of 23 in nonclinical
species
Parametera
Rat
1/2
Dog
1/2
2.7
3.0
13
Rhesus
1/2
Dose IV/P.O. (mg/kg)
Cl (mL/min/kg)b
Vdss (L/kg)
9.7
5.2
4.9
4.2
T1/2 (hr)
6.3
9.7
Cmax (µM)
0.800
0.5
1.92
3.5
83
1.48
1.1
T
max (hr)
oral (%)
nAUC (µM•hr/(mg/kg))
Since the best analog in the series 23 has three chiral
centers, all the possible eight stereoisomers were made and
evaluated in the DPP-4 and counter assays. As shown in Table 5,
the 2R, 3S, 5R isomer is found to be the most potent isomer while
the 2R, 3R, 5R isomer is the least potent (>100,000 nM). In
general, the order of potency is as follows: 3S>3R; 3,5 cis > 3,5
F
70
72
3.72
16.1
7.33
aBlood clearance in the mouse, plasma clearance in the rat, dog and monkey.
bCl, clearance; Vdss, volume of distribution at steady state; T1/2, terminal half-life; Cmax, maximum
plasma concentration following oral dosing; Tmax time to maximum concentration; Foral oral
,
,
bioavailability; nAUC, dose-normalized area under the plasma concentration vs. time curve following
oral dosing. Pharmacokinetic parameters were obtained following administration of the free base in
ethanol:water (5:95; v/v) to rats, and the di-hydrochloride salt in saline to mice, beagle dogs and
rhesus monkeys.
Table 5.
Activities of Stereoisomers of 2,3,5-substituted Tetrahydropyrans
F
NH2
F
O
The lead candidate 23 was assessed for its ability to
improve glucose tolerance in lean mice. In lean animals, 23,
orally administered 1 hour prior to dextrose challenge in an oral
glucose tolerance test (OGTT), significantly reduced blood
glucose excursion in a dose-dependent manner from 0.1 mg/kg
(27% reduction in glucose AUC) to 3 mg/kg (47% reduction).
N
NH
N
IC50 (nM )*
DP P8
DP P-4
Com pd
23
R
FA P
Q PP
F
NH2
2R
O
3S
1.4
56
42,000
6,600
> 100,000 >100,000
45,800 >100,000
5 R
N
F
F
NH
The efficacy of glucose lowering in this model was
N
NH2
comparable to that achieved with sitagliptin.
In the
23b
F
F
O
O
O
corresponding pharmacodynamic (PD) assay, 23-mediated DPP-
4 inhibition and plasma compound concentrations were dose-
dependent 10 minutes following dextrose challenge. At the 0.3
mg/kg dosage, plasma DPP-4 activity was inhibited by >80%, the
targeted inhibition associated with maximal glucose lowering
efficacy, with a corresponding plasma concentration of 260 nM.
The administration of 23 also dose-dependently increased plasma
concentrations of active GLP-1 in this assay with the maximal
increase observed at the 1 mg/kg dosage. The augmentation of
active GLP-1 levels achieved at these dosages (up to 4-fold) was
similar to the elevation in circulating hormone observed in DPP-
4–deficient (Dpp4-/-) mice12 (3-8-fold) relative to wild type
animals.
N
N
N
NH
N
NH2
24,400 >100,000 > 100,000 >100,000
23c
F
NH
N
F
NH2
23d
23e
23f
38,000 100,000
28,000
100,000
F
F
NH
N
NH2
NH2
NH2
2,800 >100,000 > 100,000 >100,000
26,600 >100,000 > 100,000 > 100000
F
O
N
NH
N
F
F
O
N
NH
N
F
The effect of DPP-4i 23 on blood glucose during an
OGTT was investigated in DPP-4 deficient and comparably aged
wild type lean mice. 23 administered at 3 mg/kg, 1 hour prior to
dextrose challenge, significantly inhibited blood glucose
excursion by 53% in the control lean mice. In contrast, the
administration of 23 at 3 mg/kg did not significantly inhibit blood
glucose excursion compared to vehicle controls in the DPP-4
deficient mice.
23g
23h
13,100
15,400
>100000
51000
F
O
N
NH
N
F
NH2
> 100000
>100,000 >100000 >100000
F
O
N
NH
N
*Purity of each isomer is >99.0%. Activity could be affected by minor im purity

In summary, we have discovered a series of structurally
diverse tetrahydropyrans that are potent and selective DPP-4
inhibitors. The optimal side-chain for this series was determined
to be a tetrahydropyrrolopyrazole. Compound 23 is a potent,
selective DPP-4 inhibitor with an excellent pharmacokinetic
profile, and efficacy in an oral glucose tolerance test in mice,
and emerged as the lead clinical candidate.
Acknowledgments
We like to acknowledge Drs. Raman Bakshi and Uday
Sharma for scale-up of ketone intermediates 21a-21d. We also
like to thank Dr. George Doss, Claire Lee, Ed Sherer and Joe
Shpunginfor for structural determination of the absolute
configuration of these ketones and other compounds in this
manuscript.
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Novel tetrahydropyran analogs as dipeptidyl
peptidase 4 inhibitors: Profile of clinical
candidate (2R,3S,5R)-2-(2,5-Difluorophenyl)-
5-[2-(methylsulfonyl)-2,6-
dihydropyrrolo[3,4-c]pyrazol-5(4H)-
yl]tetrahydro-2H-pyran-3-amine (23)
Leave this area blank for abstract info.
Tesfaye Biftu, Xiaoxia Qian, Ping Chen, Dennis Feng, Giovanna Scapin, Ying-Duo Gao, Ranabir
Sinha Roy, George Eiermann, Huabing He, Kathy Lyons, Gino Salituro, Sangita Patel, Alexander
Petrov, Feng Xu, Shiyao Sherrie Xu, Bei Zhang, Charles Caldwell, Joseph K. Wu, and Ann E. Weber
A series of novel tri-2,3,5-substituted tetrahydropyran analogs were synthesized and evaluated as inhibitors of dipeptidyl
peptidase 4 (DPP-4) for the treatment of type 2 diabetes. Optimization of the series provided inhibitors with good DPP-4
potency and selectivity over other peptidases (QPP, DPP8, and FAP). Compound 23, which is very potent, selective,
efficacious in the diabetes PD model, and has an excellent pharmacokinetic profile, is selected as a clinical candidate.