Design and optimization of tricyclic gamma-secretase modulators

Article abstract of DOI:10.1016/j.bmcl.2015.06.020

Beginning with a diaminotriazine screening hit, several series of novel, tricyclic gamma-secretase modulators (GSMs) were designed. The SAR of several related series of GSMs is presented, and the in vivo profile of a lead molecule from the series is described.

Full text of DOI:10.1016/j.bmcl.2015.06.020

Accepted Manuscript
Design and optimization of tricyclic gamma-secretase modulators
Jianliang Shi, Dmitry Zuev, Li Xu, Kimberley A. Lentz, James E. Grace, Jeremy
H. Toyn, Richard E. Olson, John E. Macor, Lorin A. Thompson
PII:
S0960-894X(15)00613-7
DOI:
http://dx.doi.org/10.1016/j.bmcl.2015.06.020
BMCL 22810
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 April 2015
2 June 2015
4 June 2015
Please cite this article as: Shi, J., Zuev, D., Xu, L., Lentz, K.A., Grace, J.E., Toyn, J.H., Olson, R.E., Macor, J.E.,
Thompson, L.A., Design and optimization of tricyclic gamma-secretase modulators, Bioorganic & Medicinal
Chemistry Letters (2015), doi: http://dx.doi.org/10.1016/j.bmcl.2015.06.020
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Design and optimization of tricyclic gamma-secretase Leave this area blank for abstract info.
modulators
Jianliang Shi∗, Dmitry Zuev, Li Xu, Kimberley A. Lentz, James E. Grace , Jeremy H. Toyn, Richard E. Olson,
John E. Macor, and Lorin A. Thompson
N
S
N
N
H
N
Compound 6
Abeta1-42 IC50 = 35 nM

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
Design and optimization of tricyclic gamma-secretase modulators
Jianliang Shi∗, Dmitry Zuev, Li Xu, Kimberley A. Lentz , James E. Grace , Jeremy H. Toyn, Richard E.
Olson, John E. Macor, and Lorin A. Thompson
Discovery, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Beginning with a diaminotriazine screening hit, several series of novel, tricyclic gamma-
secretase modulators (GSMs) were designed. The SAR of several related series of GSMs is
presented, and the in vivo profile of a lead molecule from the series is described.
Revised
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Alzheimer’s Disease
Gamma-secretase modulators
CYP3A4 inhibition
1. Introduction
continued development of additional treatment options. A recent
additional approach is to target the γ-secretase complex with
Alzheimer’s disease (AD) is an age-related, chronically
progressive neurodegenerative disorder affecting more than 35
million people worldwide and an estimated 5.5 million in the
US.1 Current marketed drugs such as acetylcholinesterase
inhibitors and the NMDA antagonist memantine only treat
disease symptoms and don’t slow or reverse the underlying
progression of the disease. Thus, the development of disease-
molecules that change the length of the Αβ peptides produced.
This class of molecules, known as γ-secretase modulators
(GSMs), are believed to change the processing of APP-CTFβ
(the substrate for γ-secretase) so that shorter, more soluble
peptides (such as Αβ1-38) are produced instead of the highly
insoluble and neurotoxic Αβ1-42.5 Because they do not block γ-
secretase processing, GSMs do not interfere with Notch
signaling,6 and it is possible that they may avoid some of the
issues of nonselective GSIs. The first generation of GSMs,
including NSAID derivatives such as ibuprofen, indomethacin
and tarenflurbil generally have weak in-vitro potency (Αβ1-42
IC50 = 25-200 µM) and were not effective in the clinic. Second
generation GSMs have been disclosed by a number of companies
and have demonstrated effacy in a number of preclinical AD
animal models.7
modifying treatments remains
pharmaceutical industry.
a major interest in the
Pathological examination of AD brain tissue has revealed two
underlying disease components, neurofibilliary tangles and
amyloid plaques. Plaques are formed from the precipitation of the
amyloid beta peptides (Αβ), which range from 37 to 42 amino
acids in length and are produced from sequential cleavages of the
amyloid precursor protein (APP) by β-secretase 1 (BACE 1) and
γ-secretase.1 While the exact cause of the disease is still an active
area of research, a current prevailing hypothesis suggests that
oligomers of the 42-amino acid form of the beta amyloid peptide
(Αβ1-42) are central to the disease process.2 Efforts to reduce
Αβ1-42 production by interfering with the action of γ-secretase
have led to the identification of full inhibitors of the enzyme
complex (γ-secretase inhibitors, or GSIs), several of which have
been advenced into clinical trials.3 This approach, however, is
complicated by issues including inhibition of Notch processing
by unselective GSIs and the clinical failure of the GSIs
semagacestat and avagacestat.4 These issues have led to the
———
Based on the interesting biological profile of the GSM class,
we screened the BMS compound collection for compounds that
inhibit Αβ1-42 production in
a
cellular assay.8
Active
compounds were then rescreened for their effect on total Αβ
production to identify potential GSMs. To our delight, a class of
diaminotriazines represented by compound 1 was identified as
having modest potency for inhibition of Αβ1-42 production (IC50
= 180 nM) with no effect on total Αβ production (Figure 1).9
Our initial efforts to optimize the diaminotriazine scaffold
have already been described, including the observation that
∗ Corresponding author. Tel.: 203-677-7891; e-mail: jianling.shi@bms.com

lengthening the triazine aryl substituent to a benzyl substituent
and changing the triazole group to a methyl imidazole as in
inhibitor of Αβ1-42 production (IC50 = 35 nM). Additional
assays (data not shown) demonstrated that compound 6 had no
effect on total Αβ production, confirming the GSM mechanism
for this chemotype. We observed that 4-methylimidazole was
the most potent heretocycle at the R1 position in the thiazole
series, with similar activity observed with the 3-methyl-4-pyridyl
group (12, IC50 = 50 nM). There was an approximate 4-fold loss
of potency for the related 3-methyl triazole (7, IC50 = 140 nM) or
4-chloroimidazole (8, IC50 = 140 nM). The nitrile (9) and 5-
methylimidazole (11) groups were poorly tolerated. Adding a 4-
fluoro substituent on the ring led to little change in potency
(compare examples 6 and 10 or examples 12 and 13), while 3,4-
difluoro was slightly less well tolerated (14, IC50 = 120 nM).
N
O
HN
O
HN
N
N
N
N
N
N
N
N
N
H
N
N
H
N
screening hit
program lead
2
1
Aβ42 IC50 = 180 nM
Aβ42 IC50 = 29 nM
Figure 1. Triazine GSMs
compound 2 resulted in a nearly 10-fold increase in potency.
We were also able to incorporate heterocycles other than triazine
as the core of the molecule.9 In an effort to increase potency by
conformational restriction, we questioned whether an additional
ring could be constructed linking the aniline ring back to the
triazine or other heterocycle. The resulting compounds would be
somewhat related to the well-known tricyclic antidepressants,
and might be expected to have reasonable brain penetration
(Figure 2).
Table 1. Activity of tricyclic thiazoles
R2
S
R1
N
H
N
IC50 Αβ1-42
Ex.
R1
R2
H4(nM)a
N
N
6
7
H
H
35
N
140
N
N
N
Figure 2. Tricyclic GSM concept
N
8
9
H
H
140
1200
20
Cl
We selected a thiazole ring as the first heterocycle simply for
the synthetic ease of using the well-established Hantszch
cyclization to construct the ring. The synthesis of these initial
analogs is outlined in Scheme 1.
N
N
N
10
4-F
H
N
O
H
N
O
a
b
Br
Br
N
I
N
11
12
13
14
4-F
H
1800
50
3
4
R2
R2
N
S
c
S
I
R1
N
H
N
N
H
N
N
4-F
80
5
6-11
d
N
R2
3,4-di-F
120
N
S
12-14
aActivity assayed in H4 cells according to reference 7 with n >/= 2.
N
H
N
Having successfully designed compounds that showed potent
GSM activity in cells, we further profiled compound 6. The
compound showed good metabolic stability when incubated with
human liver microsomes (rate of metabolism 0.035
nmol/min/mg) and was not a hERG blocker in our high-
throughput assay,10 however it did show some broad µM
inhibition of CYPs in fluorescence assays, including inhibition of
CYP3A4 with an IC50 = 0.7 µM. The compound was also highly
protein bound (> 99.8%) in both human and mouse plasma. We
then tested compound 6 in 3xTg-AD mice.11 These animals,
which overproduce human Αβ1-42, are a convenient model
because of the increased ability to detect the otherwise low brain
Αβ1-42 concentration. Compound 6 was dosed orally in a
vehicle consisting of 84% PEG-400/15% ethanol/1% Tween 80
at doses of 1, 3, 10, 30, and 100 mpk and Αβ1-42 levels were
Scheme 1. Reagents and conditions: (a) excess ICl, AcOH, 100%, rt; (b)
benzyl thioamides, EtOH, 25-40%, rt; (c) heterocycle or ZnCN, CuI, N, N-
dimethylglycine, K2CO3, DMSO, 125 °C, 13-30%; (d) 2-methylpyridin-4-
ylboronic acid, Pd(dppf)Cl2, Na2CO3, DME/ H2O, 80 °C, 31-42%.
Iodination of commercially available 3 with excess ICl in
AcOH gave a quantitative yield of 4, which was cyclized with
benzyl thioamides to give the 2-benzyl-9,10-dihydro-4H-1-thia-
3,4-diaza-benzo[f]azulenes 5. Coupling of the iodides 5 with
heterocycles including imidazoles, triazoles, or zinc cyanide
using Ullman conditions provided the final molecules (6-11).
Alternatively, coupling of 5 with 2-methylpyridin-4-ylboronic
acid under standard Suzuki conditions provided examples 12-14.
The activity of compounds 6-14 is summarized in Table 1. We
were immediately gratified to see compound 6 was a potent

collected 3 hours post dose. Plasma drug levels were determined
at all doses, and brain drug levels were determined at 30 mpk.
As is shown in Table 2, compound concentrations increased with
dose
of 180 and 40 nM, respectively. Profiling of the pyrazoles,
however, revealed that compounds 22 and 23 were both stronger
inhibitors of CYP3A4 (IC50’s = 0.3 µM), discouraging further
work in this series.
Table 2. Exposure and efficacy of compound 6 in 3xTg-AD mice
DMB
DMB
H
N
O
S
O
N
N
a
b
Brain Αβ 1-
42
(% Veh)
Plasma total Brain total
(nM)
Brain/
Plasma
I
I
Dose
I
(nM)
17
15
16
Bn
N
1 mpk
3 mpk
10 mpk
210
480
NT
NT
110
100
70
NT
NT
NT
1.1
NT
DMB
DMB
S
N
c,d
e
O
H
N
N
3800
8000
25,000
NT
I
I
30 mpk
100 mpk
8900
NT
60
18
19
Bn
N
50
H
N
f,g
NT = Not tested
N
N
N
N
19
R1
20, 22 R1
21, 23 R1
=
=
N
and overall exposure was quite high.
At 30 mpk, the
20-21
brain/plasma ratio of the compound was 1.1, indicating
significant brain penetration. As enumerated in Table 2 and
shown graphically in Figure 3, compound 6 significantly reduced
brain Αβ1-42 concentrations at doses of 10 mpk and higher, with
an ED50 at the 100 mpk dose. No inhibition of total Αβ
production was seen at any dose (data not shown).
N
H
N
N
N
h,i,f,g
Cl
18
R1
22-23
Scheme 2. Reagents and conditions: (a) NaH, DMF, DMB-Br, rt 79%; (b)
Lawesson’s reagent, toluene, reflux, 69%; (c) neat Bredereck’s reagent, 115
°C, 7 h, 58%; (d) MeI, K2CO3, AcCN, rt, 98%; (e) neat BnNHNH2, 70 °C, 20
h, 84%; (f) 3-methyl-1,2,4-triazole or 4-chloro-imidazole, CuI, K3PO4, trans-
1,2-bis(methylamino)cyclohexane, DMF, 130 °C, 34-71%; (g) neat TFA, rt,
53-80%; (h) NH2NH2, THF, 81%; (i) BnBr, KHMDS, THF, rt, 88%.
In order to address the Cyp inhibition issue, we tested the
possibility of further changes in the heterocycle combined with
reducing the electron density in the ring system by swapping the
central aniline nitrogen atom for a ketone. Scheme 3 details the
synthesis of these analogs, which started with
bromobenzosuberone.13 Oxime installation followed by
7-
O
O
N
Figure 3. Activity of compound 6 in 3xTg-AD mouse brain
a,b
Br
O
While these results represent a good starting point, it was clear
that to move a molecule toward clinical development we must
improve efficacy, achieve these results at a lower overall dose
and exposure, and we must remove the CYP3A4 inhibition
liability in compound 6. In order to more broadly assess the
potential of this new series of GSMs, we investigated synthesis
of related compounds with different heterocycles in place of the
thiazole ring.
Br
24
OMe
25
c
O
N
O
N
d,e
d,c
O
26
O
First, we turned to pyrazoles. As shown in Scheme 2, the
pyrazoles were constructed beginning with 7-iodo-4,5-dihydro-
N
N
1H-benzo[b]azepin-2(3H)-one 15.12
dimethoxybenzyl group followed by conversion of the amide to
the thioamide produced intermediate 17. Installation of an α-
Protection with
a
N
O
N
N
OMe
27
N
aldehyde
bis(dimethylamino)methane) followed by thione methylation
gave cyclization precursor 18. Direct cyclization with
using
Bredereck’s
reagent
(tert-butoxy-
N
OMe
28
benzylhydrazine produced the 1-benzyl-7-methyl-1,4,5,10-
tetrahydrobenzo[b]pyrazolo[4,3-f]azepine core intermediate 19,
which was coupled with heterocycles as before to produce
compounds 20 and 21 after acidic deprotection. Alternatively,
cyclization of 18 with hydrazine followed by benzylation
produced the alternate 2-benzyl core, allowing production of
compounds 22 and 23 where the position of the benzyl group is
more analogous to the thiazole series. Indeed, compounds 20 and
21 were inactive, while compounds 22 and 23 had Αβ1-42 IC50’s
Scheme 3. Reagents and conditions: (a) isopentyl nitrite, 2.0 M HCl/Et2O, rt,
73%; (b) 4-methoxyphenylacetic anhydride, 4-methoxyphenylacetic acid, 4-
methoxyphenylacetyl chloride, 85 °C, 53%; (c) 2-methylpyridin-4-ylboronic
acid, Pd(dppf)Cl2, Na2CO3, DME/H2O, 100 °C, 31-75%; (d) MeNH2, THF,
µwave, 100 °C, 6 h, 79%; (e) 4-methylimidiazole, CuI, N, N-dimethylglycine,
K2CO3, DMSO, 125 °C, 12%.
cyclization with 4-methoxyphenylacetic acid produced the
tricyclic 2-(4-methoxy-benzyl)-7-methyl-9,10-dihydro-1-oxa-3-
aza-benzo[f]azulen-4-one core 25. Suzuki coupling produced

93%; (d) 4-methylimidazole, 4-chloroimidazole, or 4-methyltriazole, K2CO3,
DMSO, 65 °C, 28-96%; (e) H2 balloon, Pd/C, MeOH, rt, 79-89%; (f) 36 or
37, tetramethylenesulfone, 145-165 °C, 16 h, 3-53%.
tricyclic 26 (IC50 = 0.30 µM) , while addition of methylamine
into intermediate 25 produced the corresponding tricyclic
imidazole core which allowed production of analogs 27 and 28
(IC50’s = 1.1 µM and 0.38 µM respectively). All three analogs
were modest GSMs with IC50’s > 300 nM. Unfortunately, all
three analogs remained potent CYP3A4 inhibitors (IC50’s = 0.3
– 0.5 µM). While the 4-methoxybenzyl substituent did not allow
direct comparison of activity to the thiazole series, we were
encouraged that the first analogs containing the central ketone
were modestly active and wanted to test expanding the
heterocyclic ring to a 6-membered pyridyl ring.
A first pyridyl analog was synthesized using the suberone
core using a slight variant of established chemistry (Scheme 4).14
Negishi coupling of 29 and 30 was followed by N-oxidation and
rearrangement to the pyridyl 2-nitrile 32.15 Formation of the tert-
butyl amide followed by deprotonation and alkylation of the
pyridyl methyl group gave 33. Dehydration back to the nitrile
followed by acid-catalyzed cyclization and Ullman coupling gave
the desired compound 34. This initial 6-membered ring analog
had an Αβ1-42 IC50 = 1 µM and was still a CYP3A4 inhibitor
(IC50 = 0.3 µM).
accessed the desired analogs by selectively installing a 6-benzyl
group on 2,6-dichloronicotinc acid 35 using a Negishi coupling
protocol. In order to test steric blocking of the pyridyl group, 36
was bismethylated and then saponified to produce 37.
Separately, the left-hand heterocycle was installed on 4-
fluoronitro intermediates 38. Reduction to the diamine followed
by thermal condensation with the preformed chloronicotinic
acids produced the desired analogs 40-45, albeit in modest
chemical yield. The desired regioisomer was typically favored,
but purification was necessary to produce pure material.
The Αβ1-42 activity and inhibition of CYP3A4 for
compounds 40-45 is summarized in Table 3. The parent 4-
methylimidazole analog 40 was the most potent inhibitor in the
series (IC50 = 50 nM), with activity similar to that of the more
potent compounds in the thiazine series 6-14 (IC50 = 35 nM).
The inhibition of CYP3A4, however, was not improved by
changing to this core (IC50 = 0.15 µM). In this particular series,
the chloroimidazole 41 was 2-3 fold more active than the
O-
N
Br
N+
corresponding methyltriazole 42.
Somewhat surprisingly,
c
a,b
Br
+
fluorine was poorly tolerated at R1, with over a 10-fold loss in
Αβ1-42 potency and an increase in CYP3A4 inhibition.
Interestingly, the chloroimidazoles 41 and 45 had a dramatically
improved CYP3A4 profile (IC50 > 13 µM). This is not solely
the result of a solubility change, as the assay is monitored for
drug precipitation. The data suggest that in this series the
CYP3A4 SAR closely tracks with heterocycle basicity, with the
methyl imidazole being most potent, follwed by the triazole,
while the weakly basic chloroimidazole is a poor binder. More
analogs would be needed to confirm these observations, however
the series overall suffered from modest potency at Αβ 1-42, so
F
F
29
30
31
O
N
N
NC
N
H
d,e
Br
F
F
32
33
O
N
f,g,h
F
N
N
additional analogs were not prepared. As
a benchmark,
34
Scheme 4. Reagents and conditions: (a) Zn, BrCH2CH2Br, 4-
fluorobenzylbromide, then (Ph3P)4Pd, THF, 0 °C to rt, 92%; (b) H2O2, AcOH,
reflux; (c) TMS-CN, dimethylcarbamic chloride, DCM, rt, 34% for two steps;
(d) H2SO4, t-BuOH, 70 °C, 100%; (e) LDA, 1-bromo-3-
(bromomethyl)benzene, THF, -70 °C to rt, 24%; (f) POCl3, DMF, toluene,
115°C, 99%; (g) triflic acid, MeOH/H2O, 65-85 °C, 62%; (h) 4-
methylimidiazole, CuI, N, N-dimethylglycine, K2CO3, DMSO, 125 °C, 12%.
compound 40 was also examined at 30 mpk in the 3xTg-AD
mouse model, but no activity was observed.
Table 3. Activity of tricyclic GSMs.
R3
R1
R2
H
N
N
Hoping to both improve the potency of the analogs and
further improve the Cyp inhibitor profile we next moved to the
HN
O
well-established
6,11-dihydro-5H-benzo[b]pyrido[2,3-
XX
e][1,4]diazepin-5-one core,16 where existing chemistry would
allow for additional modifications of both the steric and
electronic environment of the inhibitor. Synthetically we
IC50 Aβ1-42 CYP3A4
H4(nM)a
Ex.
40
R1
R2
R3
IC50 (µM)
N
N
H
H
50
0.15
O
O
O
(b,c)
a
N
HO
HO
HO
N
41
42
43
H
H
H
H
190
460
> 13
2.0
Cl
Cl
N
Cl
Cl
N
Bn
Cl
N
R3
R3
37
36
35
N
N
N
N
N
N
N
NH2
R2
NH2
NH2
F
R1
R1
R2
H
N
f
N
d,e
F
H
820
100
0.03
0.2
NO2
R1
38
39
HN
O
40-46
(+/-)
44
H
Me
Scheme 5. Reagents and conditions: (a) 9-Bn-9-BNN, (Ph3P)4Pd, K2CO3,
THF, 85 °C, 44%; (b) MeI, NaH, DMF, rt, 42%; (c) LiOH, THF/H2O, rt,

Bulter, T.; Kang, D. E.; Marquez-Steriling, N.; Golde, T. E.;
Koo, E. H., A subset of NSAIDs lower amyloidogenic Ab42
independently of cyclooxygenase activity. Nature 2001, 414
N
(+/-)
45
N
H
Me
200
> 13
Cl
aActivity assayed in H4 cells according to reference 7 with n >/= 2.
NT = not tested
(6860), 212-216.
6.
Toyn, J. H.; Thompson, L. A.; Lentz, K. A.; Meredith, J. E. Jr;
Burton C. R.; Sankaranararyanan, S.; Guss, V.; Hall, T.; Iben,
L. G.; Krause, C. M.; Krause, R.; Lin, X. A.;
Pierdomenico, M.; Polson, C.; Robertson, A. S.; Denton,
In summary, starting from a class of aniline triazines GSMs, we
designed multiple series of conformationally restriained, tricyclic
GSMs.
The 2-benzyl-9,10-dihydro-4H-1-thia-3,4-diaza-
R. R.; Grace, J. E.; Morrison, J.; Raybon, J.; Zhuo, X.;
Snow, K.; Padmanabha, R.; Agler, M.; Esposito, K.;
Harden, D.; Prack, M.; Varma, S.; Wong, V.; Zhu, Y.;
Zvyaga, T.; Gerritz, S.; Marcin, L. R.; Higgins, M. A.;
Shi, J.; Wei, C.; Cantone, J. L.; Drexler, D. M.; Macor,
J. E.; Olson, R. E.; Ahlijanian, M. K.; and Albright, C.
F. Identification and preclinical pharmacology of the γ-
secretase modulator BMS-869780. Int J Alzheimers
Dis. 2014, 2014:431858.
benzo[f]azulenes including compound 6 were effective in an
animal model of Αβ1-42 production at high exposure. In an
efffort to explore the SAR and separate efficacy from inhibition
of CYP3A4 activity, a variety of additional tricyclic cores was
explored. While we were able to construct additional scaffolds
with moderate to good in vitro potency, the combination of high
potency without inhibition of CYP3A4 remains an issue to be
addressed.
7.
a. Oehlrich, D.; Berthelot, D. J. C.; Gijsen, H. J. M., g-
Secretase Modulators as Potential Disease Modifying Anti-
Alzheimer's Drugs. J. Med. Chem. 2011, 54 (3), 669-698. b.
Golde, T. E.; Koo, E. H., Felsenstein, F. M.; Osborne, B. A.;
Miele, L. γ-secretase inhibitors and modulators. Biochim
Biophys Acta 2013, 1828 (12), 2898-2907. c. Hall, A.; Patel,
T. R.; Prog. Med. Chem. 2014, 53, 101-145.
Acknowledgements
The authors appreciate the contributions of Tracey Fiedler and
Jason Corsa who conducted the rat and mouse in vivo
experiments. Rudy Krause and Alan Lin executed the
accompanying Αβ assays.
8.
Gillman, K. W.; Starrett, J. E.; Parker, M. F.; Xie, K.;
Bronson, J. J.; Marcin, L. R.; McElhone, K. E.; Bergstrom, C.
P.; Mate, R. A.; Williams, R.; Meredith, J. E.; Burton, C. R.;
Barten, D. M.; Toyn, J. H.; Roberts, S. B.; Lentz, K. A.;
Houston, J. G.; Zaczek, R.; Albright, C. F.; Decicco, C. P.;
Macor, J. E.; Olson, R. E., Discovery and Evaluation of BMS-
708163, a Potent, Selective and Orally Bioavailable g-
Secretase Inhibitor. ACS Medicinal Chemistry Letters 2010, 1
(3), 120-124.
References and notes
All new compounds reported herein gave satisfactory analytical
data including parent mass, proton NMR spectral integrity, and
high purity by HPLC characterization.
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2.
3.
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a. Marcin, L.R.; Thompson, L. A. III; Boy, K. M.; guernon, J.
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