Pyrazole-based arylalkyne Cathepsin S inhibitors. Part III: Modification of P4 region

Article abstract of DOI:10.1016/j.bmcl.2012.12.014

Novel classes of tetrahydropyrido-pyrazole thioether amines and arylalkynes that display potency against human Cathepsin S have been previously reported. Here, key pharmacophoric elements of these two classes are merged, and SAR investigations of the P4 region are described, in conjunction with re-optimization of the P5 and P1/P1′/P3 regions. Identification of meta-substituted arylalkynes with good potency and improved solubility is described.

Full text of DOI:10.1016/j.bmcl.2012.12.014

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1070–1074
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Pyrazole-based arylalkyne Cathepsin S inhibitors. Part III:
Modification of P4 region
⇑
John J. M. Wiener , Alvah Tyson Wickboldt, Steven Nguyen, Siquan Sun, Raymond Rynberg,
Michele Rizzolio, Lars Karlsson, James P. Edwards, Cheryl A. Grice
Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel classes of tetrahydropyrido-pyrazole thioether amines and arylalkynes that display potency
against human Cathepsin S have been previously reported. Here, key pharmacophoric elements of these
two classes are merged, and SAR investigations of the P4 region are described, in conjunction with re-
optimization of the P5 and P1/P10/P3 regions. Identification of meta-substituted arylalkynes with good
potency and improved solubility is described.
Received 23 August 2012
Revised 28 November 2012
Accepted 10 December 2012
Available online 21 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cathepsin S
Pyrazole
Autoimmune
Alkyne
The lysosomal cysteine protease Cathepsin S (CatS) mediates
cleavage of major histocompatibility class II (MHC II)-associated
invariant chain (Ii), a key step in the immune response to an anti-
gen.1 The invariant chain prevents loading of the antigen into the
MHC II binding groove for subsequent presentation on the cell
surface to CD4+ T-cells. By preventing the degradation of the
invariant chain, inhibition of CatS reduces antigen presentation.
CatS inhibitors have thus been proposed for treatment of various
autoimmune disorders and other inflammatory diseases. Both
covalent-binding active site modifiers and noncovalent inhibitors
of CatS have been disclosed.2–5
Thioether molecules illustrated by compound 1, though quite
potent, are limited by poor oral bioavailability in rat PK studies.
On the other hand, arylalkyne molecules such as 2 tend to display
good PK properties but possess sub-optimal cellular potency. In
general, both series suffer from poor equilibrium solubility at pH
7, complicating potential development of molecules within either
series. Additional investigation into the SAR of the arylalkynes
was undertaken, specifically through incorporation of various P4
P3
In preceding papers,5 the synthesis and biological evaluation of
novel classes of noncovalent thioether amine- and arylalkyne-con-
taining tetrahydropyrido-pyrazoles led to the identification of two
series of molecules (e.g., 1 and 2, Fig. 1) with good in vitro potency
against human CatS, as measured in an enzymatic assay (hCatS
IC50) and in an invariant chain degradation cellular assay (JY Ii
IC50).3a,3c Computational studies and preliminary X-ray crystal
structure analysis have given insight into the potential binding
mode of these compounds. The alkyne portion of molecules such
as 2 is hypothesized to access the S1/S10 binding pocket of the en-
zyme, and the oxamide substituent of compounds such as 1 is be-
lieved to make beneficial interactions with the S4 region of the
enzyme.
linker
F
CF3
S
N
N
N
N
P5
OH
N
O
hCatS IC50 = 0.07 µM
JY Ii IC50 = 0.19 µM
Eq.sol. (pH 7) < 1 µM
linker
P4
NH2
O
1
P1/P1'
Cl
N
N
N
Cl
P5
O
H
N
N
P4
SO2CH3
hCatS IC50 = 0.14 µM
JY Ii IC50 = 1.5 µM
Eq.sol. (pH 7) < 1 µM
2
⇑
Corresponding author.
E-mail address: Jwiener1@its.jnj.com (J.J.M. Wiener).
Figure 1. Reported tetrahydropyrido-pyrazole cathepsin S inhibitors.5
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.12.014

J. J. M. Wiener et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1070–1074
1071
removal of the substituent altogether (9) leads to a loss of potency,
a primary urea (10), a sulfonyl urea (13), substituted acetamides
(15 and 16), and oxamides (17 and 18) afford comparable enzy-
matic potency. As is further evident from these data, the primary
oxamide (17) and urea (10) substituents additionally offer im-
proved cellular potency and were chosen for further optimization
studies.
Variation of the P5 amine architecture was subsequently ex-
plored, in conjunction with these two P4 moieties using the revised
synthetic route shown in Scheme 4. This modified approach in-
volved incorporation of the P4 substituent earlier in the synthetic
sequence. Deprotection of intermediate 4 was followed by intro-
duction of the P4 substituent. Sonogoshira coupling of the biaryl al-
kyne fragment proceeded in good yield, and the desired P5 amine
substituent was incorporated via an oxidation/reductive amination
sequence.
Cl
Cl
N
N
a
N
HN
HO
I
I
N
N
BOC
BOC
3
4
Cl
N
N
b,c
N
I
O
N
5
BOC
Scheme 1. Reagents and conditions: (a) 1-bromopropanol, Cs2CO3, DMF, 0 °C to rt
(74%); (b) Dess–Martin, CH2Cl2, rt; (c) morpholine, AcOH, CH2Cl2, then NaBH(OAc)3
after 30 min, rt (69% from 4).
An assortment of P5 substituents were used in conjunction with
these two P4 substituents, with representative data shown in
Table 2. Generally, enzymatic and cellular potency were un-
changed across a variety of P5 structures, including unsubstituted
O
O
a
b
H
N
NH
CF3
Table 1
Arylalkynes: variation of P4 substituent
6
8
7
Cl
Cl
N
Cl
N
N
Scheme 2. Reagents and conditions: (a) benzyl amine, NaBH(OAc)3, AcOH, CH2Cl2,
rt (75%); (b) TFAA, iPr2NEt, CH2Cl2, rt (95%).
O
N
R1
H
N
Cl
N
O
Entry R1
hCatS IC50
JY Ii IC50
M)
Eq. Soln (pH 7,
a
a,b
(lM)
(
l
l
M)b,c
N
N
MeO2S
CF3
Cl
O
N
2
9
0.14
2.5
1.5
nd
nd
nd
Cl
N
H
N
R1
a, b, c, d
O
8
10
11
0.09
0.79
0.44
nd
nd
nd
H2N
Cl
O
N
N
I
MeHN
NH
O
O
N
12
13
4.56
0.18
nd
nd
nd
BOC
5
Me2N
Cl
Me2NO2S
O
5.0
Scheme 3. Reagents and conditions: (a) PdCl2(PPh3)2, CuI, Et3N, THF, rt (69%); (b)
3:1 CH2Cl2:TFA, 0 °C to rt; (c) R1-X, Cs2CO3, DMF, rt or R1-OH, HATU, HOAT, iPr2NEt,
DMF, 80 °C or TMSNCO, CH2Cl2 or R1NCO, CH2Cl2, rt; (d) aq K2CO3/MeOH, rt.
14
1.63
nd
nd
N
O
O
binding elements in an attempt to improve potency and physical
properties.
15
16
0.26
0.16
nd
nd
nd
H2N
O
Incorporation of P4 changes into the arylalkyne series was
accomplished using the synthetic route shown in Scheme 1, from
intermediate 3 (reported previously).5c Alkylation with bromopro-
panol was followed by an oxidation/reductive amination sequence
to install the morpholine substituent of intermediate 5. The pro-
tected diaryl alkyne fragment 8 was prepared as shown in
Scheme 2 via a reductive amination protocol. Sonogashira condi-
tions were used to couple iodide 5 and alkyne 8 as shown in
Scheme 3. Removal of the BOC protecting group allowed introduc-
tion of the P4 substituent, and removal of the trifluoroacetamide
protecting group under basic conditions subsequently afforded
the target compounds.
1.1
AcHN
O
H2N
17
18
0.06
0.11
0.51
1.75
<1
<1
O
O
Me2N
O
a
CatS IC50 and JY Ii degradation IC50 values are the mean of n P2 runs and
determined as described previously.3a,c All IC50 values were within a twofold range.
b
‘nd’ Denotes data not determined.
c
This route allowed for facile modification of the P4 region, and a
selection of the analogs prepared is shown in Table 1. Whereas
pH
7 Phosphate buffer equilibrium solubility determination using LCMS
quantification.

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J. J. M. Wiener et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1070–1074
piperidine (25), phenyl piperazine (27), thiomorpholine (28), and
methyl-morpholine (29). As well, these analogs display only
negligible, if any, changes in solubility.
Cl
N
N
a, b
HO
I
4
At this stage of the CatS program, analogs 28a and 29b were ta-
ken into advanced profiling assays, as they provided optimal com-
binations of in vitro and in vivo potency, suitable rat PK profiles,
and minimal hERG binding as measured by a patch clamp assay.6,7
Importantly, the thiomorpholine analog 28a displayed comparable
in vitro metabolic stability and in vivo rat half-life to the morpho-
line analog 29b. Concurrent with those advanced profiling studies,
medicinal chemistry efforts were directed towards potentially
realizing a more drastic modulation of physical properties. As such,
modification to the right-hand side amine portion of analogs 28a
and 29b was undertaken. Ethereal and amido alkyne fragments
were incorporated in both a para and meta orientation around
the phenyl ring relative to the alkyne. Compounds were again pre-
pared utilizing Sonogashira coupling conditions as shown in
Scheme 5, incorporating arylalkyne fragments constructed as
shown in Scheme 6. The data for a representative selection of these
compounds are shown in Table 3; in the interests of brevity, only
those analogs derived from analog 28a, which contains a thi-
omorpholine P5 and urea P4, are shown, as trends for analogs of
both 28a and 29b were similar.
N
20, 21
R1
O
O
20,23: R1=
21,24: R1=
NH2
NH2
c
d
NBOC
NH
O
22
7
Cl
Cl
Cl
N
N
HO
Cl
N
R1
23, 24
NBOC
e,f,g
Cl
The basic amine functionality of analog 28a was replaced with
an amide connection in analog 30, and cellular potency was elim-
inated while enzymatic potency remained, in accord with previous
findings concerning the role of basic amine functionality in
pyrazole-based CatS inhibitors.5b,d Neither terminal pyridyl- nor
pyrrolidinyl-containing compounds (31 and 32), designed to incor-
porate basicity, were able to restore cellular potency. These results
N
N
R2R3N
Cl
N
R1
NH
Scheme 4. Reagents and conditions: (a) 3:1 CH2Cl2:TFA, rt (89%); (b) TMSNCO,
CH2Cl2, rt or H2NCOCO2H, HATU, HOAT, iPr2NEt, DMF, 80 °C; (c) (BOC)2O, CH2Cl2, rt;
(d) PdCl2(PPh3)2, CuI, Et3N, THF, rt (88%); (e) (b) Dess–Martin, CH2Cl2, rt; (f) HNR2R3,
AcOH, CH2Cl2, then NaBH(OAc)3 after 30 min, rt; (g) 3:1 CH2Cl2:TFA, 0 °C to rt.
S
N
Cl
N
N N
N
N
I
S
Table 2
Cl
N
N
a, b
Arylalkynes: variation of P5 substituent
NH2
R5
O
NH2
O
Cl
N
N
R2R3N
R5
R4
R4
N
R1
H
N
Cl
Scheme 5. Reagents and conditions: (a) PdCl2(PPh3)2, CuI, Et3N, THF; (b) (only if R4
or R5 in starting material contain N-BOC) 3:1 CH2Cl2:TFA, 0 °C to rt.
O
O
a: R1=
NH2
b: R1=
NH2
O
a
a,b
Entry
25a
25b
26a
26b
27a
27b
28a
28b
NR2R3
hCatS IC50
M)
JY Ii IC50
M)
Eq. Soln (pH 7,
HNR2
l
M)b,c
ONa
(l
(l
NR2
CDI, DMF
O
O
0.06
0.10
0.20
0.30
nd
nd
N
1. CBr4
PPh3, CH2Cl2
2. NaH
TBAI, THF
0 °C to RT
0.06
0.10
0.69
1.77
<1
<1
F3C
N
OH
O
0.04
0.01
0.71
0.56
nd
<1
N
N
R
0.07
0.03
0.87
0.27
<1
<1
S
N
O
O
(
)
HNR
R
1.
2.
2
29a
29b
0.11
0.05
1.54
0.96
3
<1
I
OH
NR2
CDI, DMF
TMS
PdCl2(PPh3)2
CuI, Et3N, THF
O
N
Cl
Cl
a
CatS IC50 and JY Ii degradation IC50 values are the mean of n P2 runs and
determined as described previously.3a,c All IC50 values were within a twofold range.
b
3. K2CO3, MeOH
‘nd’ Denotes data not determined.
c
pH
7 Phosphate buffer equilibrium solubility determination using LCMS
quantification.
Scheme 6.

J. J. M. Wiener et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1070–1074
1073
Table 3
Reinforcing the notion that factors beyond lysosomal accumula-
tion may be relevant to potency of these basic inhibitors is the
observation that repositioning the amide from the para to the meta
orientation as in 35–38 led not only to increased enzymatic
potency but also to significant cellular potency. Comparing
para-compound 32 and meta-compound 35 highlights this differ-
ential potency based on connectivity. The potency of these meta
analogs appears unaffected by positioning of the basic amine and
extent of basicity. It has been hypothesized that, in contrast to
thioethers such as 1 which occupy the S3 pocket and arylalkynes
such as 2 which extend into the S1 and S10 pockets, these meta
alkynes may interact with both S1 and S3 pockets.
Arylalkynes: replacement of P1/P10 amine substituent
Cl
N
N
N
S
R4
N
NH2
O
Entry R4
hCatS
JY Ii
Eq. Soln (pH
7,
M)b,c
a
a,b
IC50
IC50
M)
l
(l
M)
(l
Significantly, many of the analogs in Table 3 are markedly more
soluble than the compounds in Tables 1 and 2. This observed
improvement may owe to replacing the amine RHS with amido
or ethereal functionality or to elimination of the terminal aromatic
substituent.
These studies with pyrazole-based arylalkyne CatS inhibitors
have provided an expanded understanding of SAR within the P4,
P5 and P1/P10/P3 regions. The meta-substituted pyrollidinyl alkyne
35, containing thiomorpholine P5 and urea P4 moieties, displays
not only excellent potency but remarkable solubility improvement.
These data warrant further structural optimization studies with
the more soluble meta-alkyne CatS inhibitors, as well as investiga-
tions into the nature of their potential alternative binding mode.
Cl
H
N
30
31
32
0.12
0.09
0.07
>10
>10
>10
nd
nd
81
O
O
O
H
N
N
N
HN
(S)
H
N
33
34
0.07
0.12
>10
>10
nd
46
O
O
References and notes
O
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NH
rac
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H
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N
H
35
36
0.03
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0.62
0.51
175
nd
(S
)
Cl
O
rac
N
H
NH
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Cl
O
O
N
37
38
N
H
0.04
0.13
0.61
0.63
9
Cl
O
N
66
NH
Cl
a
CatS IC50 and JY Ii degradation IC50 values are the mean of n P2 runs and
determined as described previously.3a,c All IC50 values were within a twofold range.
b
‘nd’ Denotes data not determined
c
pH
7 Phosphate buffer equilibrium solubility determination using LCMS
quantification.
highlight a limit to the flexibility in position of the basic amine that
had been identified previously.5d Ether linkages (33 and 34) led to
similar results.
Indeed, while accumulation of basic, lipophilic inhibitors of
lysosomal cysteine proteases in the acidic lysosomal compartment
has been reported, such lysosomotropism typically results in en-
hanced cellular inhibition relative to the inhibition observed in
purified enzyme assays.4f,8 In the case of the inhibitors reported
here, no such disparity is observed; in fact, the cellular IC50s of
these inhibitors are typically 3- to 12-fold higher than their enzy-
matic IC50s. Nonetheless, the possibility that lysosomal accumula-
tion has a role in the cellular potency of these basic inhibitors must
be considered, in regard to selectivity over other cathepsins as well
as in the potential for phospholipidosis.

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