3,3-Difluoro-3,4,5,6-tetrahydropyridin-2-amines: Potent and permeable BACE-1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2020.126999

Since its discovery in 1999, BACE-1, a membrane anchored aspartyl protease expressed primarily in the CNS, has been the target of numerous medicinal chemistry research programs. These efforts have produced highly potent inhibitors with nanomolar affinity

Full text of DOI:10.1016/j.bmcl.2020.126999

Journal Pre-proofs
3,3-Difluoro-3,4,5,6-tetrahydropyridin-2-amines: potent and permeable
BACE-1 inhibitors
Aldo Peschiulli, Daniel Oehlrich, Frederik Rombouts, Ann Vos, Harrie JM
Gijsen
PII:
S0960-894X(20)30062-7
DOI:
https://doi.org/10.1016/j.bmcl.2020.126999
BMCL 126999
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 November 2019
19 January 2020
24 January 2020
Please cite this article as: Peschiulli, A., Oehlrich, D., Rombouts, F., Vos, A., Gijsen, H.J., 3,3-Difluoro-3,4,5,6-
tetrahydropyridin-2-amines: potent and permeable BACE-1 inhibitors, Bioorganic & Medicinal Chemistry
Letters (2020), doi: https://doi.org/10.1016/j.bmcl.2020.126999
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3,3-Difluoro-3,4,5,6-tetrahydropyridin-2-
amines: potent and permeable BACE-1
inhibitors
Leave this area blank for abstract info.
Aldo Peschiulli, Daniel Oehlrich, Frederik Rombouts, Ann Vos and Harrie J. M. Gijsen
H
F
F
O
F
H2N
N
O
43
BACE-1 IC50: 1.5 nM
hA42 cell IC50: 3.5 nM
pKa: 6.6
HN
N
N
F
O

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
3,3-Difluoro-3,4,5,6-tetrahydropyridin-2-amines: potent and permeable BACE-1
inhibitors
Aldo Peschiulli, Daniel Oehlrich, Frederik Rombouts, Ann Vos and Harrie J. M. Gijsen
Discovery Sciences Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340, Beerse, Belgium.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Since its discovery in 1999, BACE-1, a membrane anchored aspartyl protease expressed primarily
in the CNS, has been the target of numerous medicinal chemistry research programs. These efforts
have produced highly potent inhibitors with nanomolar affinity and ever-increasing structural
complexity. However, only a handful of these molecules have been able to combine in vitro
potency with CNS permeability and progressed to the clinic. Herein, we describe a set of novel
piperidine-based inhibitors. This investigation culminated with the identification of 43, a highly
potent (IC50: 1.5 nM), permeable BACE-1 inhibitor with a low susceptibility to Pgp-
mediated efflux.
Keywords:
BACE inhibitor
β-secretase
Alzheimer’s disease
pKa
2009 Elsevier Ltd. All rights reserved.
amidine
———
 Corresponding author; e-mail address: apeschi@its.jnj.com (Aldo Peschiulli)

F
F
F
Alzheimer ’ s Disease (AD) is a neurodegenerative disorder
which is characterized by progressive memory loss and cognitive
decline.1 Approximately 50 million people worldwide live with
AD or a related form of dementia.2 AD is the sixth-leading cause
of death in the United States and, among the ten most prevalent
deadly diseases, the only that to date cannot be prevented, cured
or slowed.3
F
F
F
F
F
R
H2N
N
H2N
N
F
F
H2N
N
HN
N
HN
N
O
O
6
7
R = H
R = F
N
4
5
D3CO
NC
Pathologic and genetic evidence strongly suggest the
involvement of a protein known as Amyloid Precursor Protein
(APP) in the disease pathology.4-5 APP is processed sequentially
by -secretase (BACE-1) and -secretase to generate amyloid
fragments of various length, of which A1-40 and A1-42 are the
Figure 2. Piperidine derivatives by Lundbeck and our novel BACE inhibitors.
The synthesis of warhead 6 started from commercially available 2-
fluoroacetophenone (Scheme 1). Following literature procedures,
this was converted into the corresponding N-sulfinyl imine (70%
yield) which was then treated with allyl magnesium bromide, in
DCM at -40 ºC, to synthesize the corresponding tertiary amine 9
in 77% yield as a single diastereoisomer.24 Ozonolysis of 9
afforded the corresponding aldehyde in 67% yield. Intermediate
10 was reacted with triethyl 2-fluoro-2-phosphonoacetate and
NaH to yield the Horner-Wadsworth-Emmons product 11 in 45%
yield. Attempts to reduce the double bond of this intermediate by
catalytic hydrogenation led to low conversion levels. To optimize
the reduction, the sulfinyl group was removed, by treatment with
HCl in dioxane, and the amino group was BOC-protected.
Subsequent Pd-catalysed hydrogenation afforded 12 in excellent
isolated yield after column chromatography. TFA-mediated
deprotection of 12, followed by treatment of the resulting amino
ester with sodium bicarbonate, delivered lactam 13 in quantitative
yield. Intermediate 13 was BOC-protected and, in the next step,
deprotonated with LiHMDS and reacted with N-fluoro-
benzenesulfonimide (NFSI) generating 14 in 27% yield over the
two steps. After deprotection, the lactam was converted into the
corresponding amidine 6 in two steps, via initial formation of a
thioamide intermediate and subsequent reaction with ammonia
(82% yield over the three steps). Nitration of the aromatic ring
proceeded regioselectively and Zn-mediated reduction of the nitro
group yielded the corresponding aniline intermediate 15 (47%
over two steps). Finally, EDCI-mediated chemoselective coupling
between 15 and 4-fluoromethoxy pyrazine carboxylic acid
afforded final product 16 in 51% yield as a single enantiomer.
most prone to aggregate generating amyloid plaques,
a
characteristic feature of AD.6
Since its discovery as a potential disease modifying target,
BACE-1 has been the target of numerous medicinal chemistry
research programs.7-9 Early BACE-1 inhibitors were
peptidomimetics, polar transition state analogues with high MW,
which failed to reach significant CNS penetration levels.10 Then,
amidine- and guanidine-containing heterocycles, capable of
hydrogen-bonding interactions with the catalytic aspartic acid
residues of the enzyme, were identified and, after significant
optimisation efforts, developed as potent, selective and brain
penetrant inhibitors.11-12
A number of BACE inhibitors have been through clinical trial
studies in recent years.13 Notable examples are Elenbecestat14 (1,
E-2609, Eisai), Verubecestat15,16 (2, MK-8931, Merck) and
Atabecestat17 (3, (JNJ-911, Janssen) (Figure 1). Unfortunately,
compounds 1 and 2 failed in their phase III clinical trials due to
lack of efficacy,14,16 and the development of Atabecestat was
halted due to significant elevation of liver enzymes.18
O
O
H
S
F
S
S
N
O
H2N
N
F
H2N
N
O
H2N
N
F
HN
N
O
HN
HN
N
N
N
O
F
F
NC
1
2
3
Atabecestat
Elenbecestat
Verubecestat
F
O
S
S
a-b
c
d
O
NH
O
NH
(S)
Figure 1. BACE-1 inhibitors that entered clinical trials.
O
F
F
F
Patent applications by Lundbeck describe monocyclic 3-fluoro-
3-methylpiperidin-2-amine derivatives (Figure 2) as potent in vitro
BACE-1 inhibitors (e.g. Ki = 4.3 nM for compound 4).19-20
Additional fluorines on the piperidine ring are presumably
necessary to modulate the basicity of these compounds, thus
creating, at least for some analogues, multiple stereocenters.
8
9
10
(54%)
(67%)
O
S
e-g
h-i
O
NH
O
O
NH
O
E/Z
F
OEt
OEt
F
F
F
11
12
(45%)
(52%)
Many groups have commented on the importance of the pKa of
the amidine functionality in BACE inhibitors: values within the
6.5-7.5 range allow to align potency with desirable properties such
as high permeability, reduced propensity for P-gp efflux and low
hERG affinity.11,21-22 We wondered if a gem-difluoro substituent
alpha to the amidine group would lower its pKa to a value within
the optimal range, eliminating at the same time the need for
additional undesired chiral centers. Indeed, calculations predicted
the pKa of 6 (R = H) and 7 (R = F) to be 7.5 and 6.4 respectively
(Figure 2).23 To the best of our knowledge, no examples of 3,3-
difluoro-3,4,5,6-tetrahydropyridin-2-amine derivatives had been
reported in the literature. Intrigued by these findings, we decided
to synthesize these novel scaffolds and elaborate them to full
BACE inhibitors.
F
F
F
F
F
F
F
j-k
l-n
F
O
N
O
N
H2N
N
H
O
O
13
14
6
(82%)
(100%)
(27%)
F
F
F
F
H2N
N
F
F
o-p
q
H2N
N
HN
O
H2N
(47%)
N
15
16
(51%)
N
O
F

Scheme 1. Synthesis of monocyclic compound 16.
corresponding warheads, 7.6 for compound 16 and 6.3 for
compound 23. While compound 16 maintained potency in the
cellular assay (hAβ42 cell IC50 = 16.2 nM), derivative 23 suffered
from a 10-fold loss in cellular potency (hAβ42 cell IC50 > 90 nM).
This drop in cellular potency cannot be attributed to permeability
issues (A>B(+): 68.9, Table 1) and can perhaps be explained by
the rather low pKa of the compound that prevents accumulation in
the acidic intracellular compartments where BACE-1 exerts its
main activity.11
Reagents and conditions: (a) (R)-(+)-2-Methyl-2-propanesulfinamide,
Ti(OC2H5)4, THF, reflux, 16 h; (b) Allylmagnesium bromide (1 M in diethyl
ether), DCM, -40 ºC, 15 min; (c) O3, DCM, rt, 2 h; (d) Triethyl 2-fluoro-2-
phosphonoacetate, NaH, THF, 0 ºC to rt, 30 min; (e) HCl (4 M in dioxane), rt,
30 min; (f) BOC anhydride, NaHCO3 sat sol, THF, rt, 16 h; (g) H2, Pd/C,
MeOH, rt, 1 h; (h) TFA, DCM, rt, 1h (i) NaHCO3 sat sol, THF, rt, 3 h; (j) BOC
anhydride, DMAP, DCM, rt, 64 h; (k) LiHMDS (1 M in THF), NFSI, THF,
-78 ºC, 1 h; (l) TFA, DCM, rt, 1 h; (m) Lawesson’s reagent, toluene, 80 ºC,
1 h; (n) NH3 (6 M in MeOH), 75 ºC, 16 h; (o) HNO3, H2SO4, TFA, 0 ºC, 10
min; (p) Zn, HCl conc., rt, 1 h; (q) HCl (6 M in iPrOH), 4-fluoromethoxy
pyrazine carboxylic acid, EDCI, MeOH, rt, 1 h.
Encouraged by our findings on monocyclic derivative 16, we
sought to expand our exploration to target THP-fused bicyclic
derivatives 39 and 40 (predicted pKa 7.1 and 6.8 respectively)23
and 43-44 as depicted in Schemes 3 and 4. This expansion from
monocyclic to bicyclic systems has been performed in a number
of BACE medicinal chemistry programs26 as it gives the
possibility to access the S2’pocket of the enzyme and potentially
rigidify the inhibitor in its active conformation. Docking studies
on compound 44 (Figure 3) suggested a binding mode identical to
that of an analogous thiazine bicycle (24, PDB: 4WY6)27 with the
amidine group forming key H-bond interactions with the catalytic
aspartic acids Asp32 and Asp228 and the oxygen in the THP ring
interacting with Trp76 in the S2’ pocket via a water-mediated H-
bond.26,27 Conformational analysis showed the docking
conformation to be very close to the minimal energy conformation
for compound 44: the root-mean-square deviation (RMSD) of the
warhead atoms of the docked pose versus the lowest energy
conformation is 0.06.
A similar approach, starting from amino alcohol 17, already
described by our group,25 led to the synthesis of warhead 7
(Scheme 2). Amino alcohol 17 was treated with benzyl
chloroformate and the resulting N-protected hydroxy intermediate
was oxidized with Dess-Martin periodinane (DMP) to the
corresponding aldehyde (68% yield over two steps). Reaction
between 18 and triethyl 2-fluoro-2-phosphonoacetate yielded the
Horner-Wadsworth-Emmons product 19 in 78% isolated yield.
Intermediate 19 was hydrogenated in the presence of Pd/C as the
catalyst: this induced both the reduction of the double bond and
the removal of the CBZ protecting group. Cyclization to lactam 20
could be achieved by evaporating, at 60 ºC, the methanolic
solution from the hydrogenation reaction (48% overall yield).
Intermediate 20 was BOC-protected in the presence of DMAP as
catalyst. The corresponding N-BOC lactam was reacted with
LiHMDS and NFSI and then deprotected with TFA to yield 21 in
56% yield over the three steps. Lactam 21 was then elaborated to
the desired final compound 23 in a five steps sequence as already
described for 16.
Cbz
Cbz
NH2
NH
F
NH
a-b
c
E/Z
F
CO2Et
OH
O
F
F
F
F
F
17
18
19
(68%)
(78%)
F
F
F
F
F
F
F
F
F
e-g
d
h-i
F
F
O
N
H
O
N
H2N
N
H
20
21
7
(90%)
(48%)
(56%)
F
F
F
F
F
F
H2N
N
F
F
j-k
l
H2N
N
HN
N
O
H
F
H2N
H
F
F
F
22
23
(77%)
(42%)
S
F
O
F
H2N
N
O
N
O
F
H2N
N
O
F
HN
N
N
Scheme 2. Synthesis of monocyclic compound 23.
24
44
F
O
Figure 3. Docking pose of compound 44 superimposed with X-ray structure of
compound 24 (PDB: 4WY6).
Reagents and conditions: (a) Benzyl chloroformate, Na2CO3 sat sol, THF, 0 ºC
to rt, 16 h; (b) Dess-Martin periodinane, DCM, rt, 1 h; (c) Triethyl 2-fluoro-2-
phosphonoacetate, NaH, THF, 0 ºC to rt, 30 min; (d) H2, Pd/C (10%), MeOH,
1 h; Evaporation, 60 ºC; (e) BOC anhydride, DMAP, THF, rt, 48 h; (f)
LiHMDS (1 M in THF), NFSI, THF, -78 ºC, 1 h; (g) TFA, DCM, rt, 1 h; (h)
Lawesson’s reagent, toluene, 80 ºC, 1 h; (i) NH3 (6 M in MeOH), 75 ºC, 5 h;
(j) HNO3, H2SO4, TFA, 0 ºC, 5 min; (k) Zn, HCl conc., rt, 1 h; (l) HCl (6 M in
iPrOH), 4-fluoromethoxy pyrazine carboxylic acid, EDCI, MeOH, rt, 1 h.
Amino alcohols 25 and 26 were prepared as described in the
literature.28-29 These were N-protected with benzyl chloroformate
and then converted to aldehydes 27 and 28 by oxidation with DMP
(70% and 51% yield respectively over the two steps). The carbonyl
intermediates were then reacted with triethyl 2-fluoro-2-
phosphonoacetate to synthesize 29 and 30 (74-75% yield). As
described for intermediate 19, Pd-catalysed hydrogenation
reduced the double bond and simultaneously deprotected the
Both 16 and 23 were found to inhibit BACE-1 at nanomolar
concentrations in our enzymatic assay (IC50 = 11.5 and 8.9 nM
respectively, Table 1). Experimental pKa values were measured
and found to be close to that originally predicted for the

nitrogen. For both compounds, cyclisation to the amide was
achieved by simply evaporating the methanolic solution from the
hydrogenation reaction. Amides 31 and 32 were then converted to
the corresponding N-BOC derivatives and treated with LiHMDS
and NFSI to synthesize the desired gem-difluoro lactams (58% and
45% yield after N-deprotection). Conversion of the amides to the
corresponding amidines 35 and 36 was achieved in two steps as
described for the monocyclic analogues. The regioselective
nitration step proceeded in high yield as well as the following Zn-
catalyzed reduction of the nitro group. Racemic products 39 and
40 were obtained by reacting the appropriate aniline with 4-
fluoromethoxy pyrazine carboxylic acid, in the presence of EDCI,
in 76% and 79% yield respectively. Finally, chiral SFC
purification was used to separate the two enantiomers of the
products.
THP-fused compounds 39 and 43-44 proved highly potent
inhibitors in our BACE-1 enzymatic assay, with compound 43
displaying an IC50 of 1.5 nM (Table 1). This potency nicely
translated into inhibition of Aβ42 production in human
neuroblastoma cell lines (hAβ42 cell IC50 = 3.5 nM for compound
43). Regioisomeric THP-fused compound 40 was found to be
weakly active (BACE-1 IC50 = 79.4 nM), a result that can be
explained by its inability to form a water molecule-mediated H-
bond interaction with Trp 76 in the S2’ pocket of the enzyme as
depicted in Figure 3 for compound 44.
EtO2C
F
H
H
H
HO
H2N
Y
X
F
Y
X
F
O
Y
X
F
a-b
c
d-e
Table 1. Potency, selectivity and properties for final compounds.
CbzHN
CbzHN
Compound
16
11.5
16.2
126
11
23
39
3.5
40
79.4
170
1072
13.5
34.8
8.4
43
1.5
44
2.5
25
26
(X = -O-, Y = -CH2-)
(X = -CH2-, Y = -O-)
29
30
74%
75%
27
28
70%
51%
BACE-1 IC50 (nM)
8.9
hA42 cell IC50
H
H
H
F
F
F
93.3
138
15.5
68.9
1.86
6.3
7.1
3.5
4.8
F
Y
Y
X
F
Y
X
F
(nM)
F
f-h
i-j
X
O
N
O
N
H2N
N
F
H
H
BACE-2 IC50 (nM)
BACE-2/BACE-1
A>B(+)
10.2
3
6.8
8.9
33
34
58%
45%
35
36
55%
73%
4.5
3.6
31
32
62%
60%
H
F
Y
X
F
40.2
2.1
27.4
4.7
54.0
5.0
47.0
12.0
6.4
F
H
F
Y
X
F
H2N
N
O
F
k-l
m-n
AB(+)/AB(-)
H2N
N
HN
N
N
H2N
37
pKa
7.6
6.6
6.7
6.6
F
O
39
40
30% (X = -O-, Y = -CH2-)
25% (X = -CH2-, Y = -O-)
85%
89%
hLM Clint
38
10.1
10.2
1
<7.7
<7.7
>10
>10
46.2
15.5
>10
>10
35.3
11.8
>10
>10
119
18.6
>10
>10
24.9
<7.7
>10
>10
(L/min/mg)
dLM Clint
Scheme 3. Synthesis of isomeric THP-fused compounds 39 and 40.
(L/min/mg)
Reagents and conditions: (a) Benzyl chloroformate, NaHCO3 sat sol, THF, rt,
16 h; (b) Dess-Martin periodinane, DCM, rt, 2 h; (c) Triethyl 2-fluoro-2-
phosphonoacetate, NaH, THF, 0 ºC to rt; (d) H2, Pd/C, MeOH, rt, 1 h; (e) 50
ºC, evaporation; (f) BOC anhydride, DMAP, THF, rt, 16 h; (g) LiHMDS,
NFSI, THF, -78 ºC, 1 h; (h) TFA, DCM, rt, 1 h; (i) Lawesson’s reagent, toluene,
80 ºC, 90 min; (j) NH3 (6 M in MeOH), 75 ºC, 16 h; (k) HNO3, H2SO4, TFA, 0
ºC, 5 min; (l) Zn, HCl conc., rt, 1 h; (m) HCl (6 M in iPrOH), EDCI, 4-
fluoromethoxy pyrazine carboxylic acid, MeOH, rt 1 h; (n) Chiral SFC
purification.
2D6 IC50 (nM)
>10
hERG IC50 (M)
See Supplementary Material for assay details.
Interestingly, monocyclic derivatives 16 and 23 display a
degree of selectivity versus BACE-2, a highly homologous
transmembrane aspartic protease (10-15 fold selectivity in the
enzymatic assay, Table 1).30 This is in contrast to the bicyclic
systems 39, 43 and 44 which are only marginally selective. All
synthesised compounds exhibit good intrinsic permeability (A to
B (+)) and low potential for P-glycoprotein-mediated efflux
(MDCK assay). Further profiling revealed monocyclic 23 to have
good metabolic stability both in human (hLM) and dog (dLM)
liver microsomes (Table 1). Unfortunately, the more potent
bicyclic derivatives were found to be metabolically unstable in
hLM and dLM, except for fluoromethyl compound 44. Compound
23 shows a low potential to inhibit CYP2D6 and other major
Also, methyl- and fluoromethyl-substituted compounds 43 and
44 were synthesized (Scheme 4), using the synthetic route
described above, starting respectively from amino alcohols 41 and
42 and therefore obtaining the final compounds as single
enantiomers.26
H
F
R
F
H
R
O
F
HO
H2N
H2N
N
O
O
F
HN
N
N
cytochrome P450 isoforms (1A2, 3A4, 2C8, 2C9 and 2C19 IC50
>
F
O
41
42
43
44
10 M). The strong inhibition of the 2D6 isoform (IC50 = 1 M)
observed for compound 16 is presumably a result of its higher
basicity (measured pKa = 7.6).31 Finally, we tested the propensity
of all synthesized derivatives to inhibit hERG, Ca- and Na-
channels. Gratifyingly, we could not observe any signal, with IC50
R = -CH3
R = -CH2OBn
R = -CH3
R = -CH2F
Scheme 4. Synthesis of substituted compounds 43 and 44.

17. https://www.alzforum.org/therapeutics/atabecestat
18. The Janssen Pharmaceutical Campanies of Johnson & Johnson.
https://www.janssen.com/ja/node/45771 (accessed Dec 23, 2018).
19. Juhl, K.; Marigo, M.; Tagmose, L.; Jensen, T. PCT Int. Application
WO2015124576.
> 10 M for all compounds - this can be attributed to the optimal
pKa values that we have achieved for these systems.
In summary, we have reported the design and synthesis of a
novel class of BACE-1 inhibitors built around a 3,3-difluoro-
20. Juhl, K.; Tagmose, L.; Marigo, M. PCT Int. Application
WO2016075062.
3,4,5,6-tetrahydropyridin-2-amine
scaffold.
Monocyclic
21. Stachel, S. J.; Coburn, C. A.; Rush, D.; Jones, K. L. G.; Zhu, H.;
Rajapakse, H.; Graham, S. L.; Simon, A.; Holloway, K.; Allison, T.
J.; Munshi, S. K.; Espeseth, A. S.; Zuck, P.; Colussi, D.; Wolfe, A.;
Pietrak, B. L.; Lai, M.-T.; Vacca, J. P. Bioorg. Med. Chem. Lett.
2009, 19, 2977-2980.
22. Ginman, T.; Viklund, J.; Malmström, J.; Blid, J.; Emond, R.;
Forsblom, R.; Johansson, A.; Kers, A.; Lake, F.; Sehgelmeble, F.;
Sterky, K. J.; Bergh, M.; Lindgren, A.; Johansson, P.; Jeppsson, F.;
Fälting, J.; Gravenfors, Y.; Rahm, F. J. Med. Chem. 2013, 56, 4181-
4205.
derivative 23 emerged as the optimal compound among those
tested, combining enzymatic potency with excellent in vitro
permeability and metabolic stability. Further studies aimed at
determining the optimal amide substituent for this monocyclic
core, as well as efforts to increase the metabolic stability of the
bicyclic derivatives are currently underway in our laboratory and
will be reported in due course.
23. pKa values were calculated using Jaguar (Schrödinger Release
2019-2: Jaguar pKa, Schrödinger, LLC, New York, NY, 2019).
24. Fuchino, K.; Mitsuoka, Y.; Masui, M.; Kurose, N.; Yoshida, S.;
Komano. K.; Yamamoto, T.; Ogawa, M.; Unemura, C.; Hosono,
M.; Ito, H.; Sakaguchi, G.; Ando, S.; Ohnishi, S.; Kido, Y.;
Fukushima, T.; Miyajima, H.; Hiroyama, S.; Koyabu, K.;
Dhuyvetter, D.; Borghys, H.; Gijsen, H. J. M.; Yamano, Y.; Iso, Y.;
Kusakabe, K. J. Med. Chem. 2018, 61, 5122-5137.
Supplementary Material
Supplementary data to this article can be found online at
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