Discovery of novel pyrazole-containing benzamides as potent RORγ inverse agonists

Article abstract of DOI:10.1016/j.bmcl.2015.05.028

The nuclear receptor RORγ plays a central role in controlling a pro-inflammatory gene expression program in several lymphocyte lineages including TH17 cells. RORγ-dependent inflammation has been implicated in the pathogenesis of several major autoimmune diseases and thus RORγ is an attractive target for therapeutic intervention in these diseases. Starting from a lead biaryl compound 4a, replacement of the head phenyl moiety with a substituted aminopyrazole group resulted in a series with improved physical properties. Further SAR exploration led to analogues (e.g., 4j and 5m) as potent RORγ inverse agonists.

Full text of DOI:10.1016/j.bmcl.2015.05.028

Bioorganic & Medicinal Chemistry Letters 25 (2015) 2985–2990
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of novel pyrazole-containing benzamides as potent ROR
inverse agonists
c
Tao Wang a, , Daliya Banerjee , Tonika Bohnert , Jianhua Chao , Istvan Enyedy , Jason Fontenot ,
⇑
b
a
a
a
b
a
a
a
a
a
a
Kevin Guertin , Howard Jones , Edward Y. Lin , Douglas Marcotte , Tina Talreja , Kurt Van Vloten
a
Chemistry and Molecular Therapeutics, Biogen, 12 Cambridge Center, Cambridge, MA 02142, USA
Immunology Discovery, Biogen, 12 Cambridge Center, Cambridge, MA 02142, USA
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 March 2015
Revised 8 May 2015
Accepted 12 May 2015
Available online 22 May 2015
The nuclear receptor ROR
gram in several lymphocyte lineages including TH17 cells. ROR
implicated in the pathogenesis of several major autoimmune diseases and thus ROR
get for therapeutic intervention in these diseases. Starting from a lead biaryl compound 4a, replacement
c
plays a central role in controlling a pro-inflammatory gene expression pro-
c-dependent inflammation has been
c
is an attractive tar-
of the head phenyl moiety with a substituted aminopyrazole group resulted in a series with improved
physical properties. Further SAR exploration led to analogues (e.g., 4j and 5m) as potent RORc inverse
agonists.
This Letter is dedicated to Professor Iwao
Ojima for the occasion of his 70th birthday
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
ROR
c
inverse agonist
IL-17
Inflammation
Autoimmune disease
Th17 cell
Recently, the nuclear receptor Retinoic Acid Receptor (RAR)-
active in the mouse splenocyte IL-17 assay (895 nM). With a clogP
value greater than 5.0, compound 4a has poor kinetic aqueous sol-
related orphan receptor C (NR1F3; RORC; ROR
c) has emerged as
an attractive target for therapeutic intervention in human autoim-
ubility (0.3 lg/mL) and is highly bound to human and rat plasma
1
,2
mune diseases. ROR
tions including T cells,
and its activity has been demonstrated to be critical for driving a
c
is expressed in several lymphocyte popula-
proteins (0.3% and 0.2% free, respectively). It is reasoned that a
replacement of the phenyl head ring with a heteroaryl group
would lower the lipophilicity of the molecule and might help
improve the physical properties such as solubility. For example,
the clogP of compound 4b at 4.0 is one log unit lower than its phe-
nyl counterpart 4a. As shown in Table 1, pyrazole analogue 4b
c
d T cells, and group 3 innate lymphoid cells
3
–5
pro-inflammatory gene expression response in these cells.
These cells produce several pro-inflammatory cytokines, including
IL-17a, IL-17f, GM-CSF and IL-22. These cytokines are implicated in
autoimmune disease, and their expression is regulated by ROR
c
indeed has an improved aqueous solubility of 32 lg/mL and has
activity. Biologics targeting these cytokines, most notably IL-17a
and IL-17f, have demonstrated efficacy in human disease. Small
single digit free unbound fractions against human/rat plasma pro-
teins. However, there is a significant drop of biochemical and cel-
lular potency for 4b. We sought to explore more SAR around this
newly installed pyrazole ring. Two regioisomers 4c and 4d that
do not contain the primary amide groups were made. Compound
4c has a weaker potency as compared to that of 4b. This result is
expected as the carbonyl group from the primary amide of com-
pound 4a is believed to make an important hydrogen bond interac-
6
molecule inhibitors of ROR
animal models.
c
have also demonstrated efficacy in
Examples of recently reported ROR inverse
agonists include TMP778 (1), GSK805 (2) and compound 3.
We herein report the discovery of a series of novel pyrazole-con-
taining benzamides as potent ROR inverse agonists (Fig. 1).
We have recently identified compound 4a from a biaryl benza-
7
–14
c
1
5,16
c
17
mide series as an ROR
ROR biochemical FRET assay (IC50: 29 nM), moderately potent
in ROR
c
inverse agonist (Table 1). It is potent in
tion with backbone NH of Glu379 of human RORc protein based on
18
c
docking analysis (see Fig. 2B in the crystal structure section).
Compound 4d, also devoid of this H-bond interaction, somehow
is in the similar potency range to that of 4a. As 5-membered pyra-
zole ring is smaller in size as to a 6-membered phenyl ring, ana-
logue 4e was synthesized and it appears that one extra
19
c
GAL4 cellular reporter assay (EC50: 98 nM) and is weakly
⇑
Corresponding author.
E-mail address: taowang2@gmail.com (T. Wang).
http://dx.doi.org/10.1016/j.bmcl.2015.05.028
960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
0

2
986
T. Wang et al. / Bioorg. Med. Chem. Lett. 25 (2015) 2985–2990
OCF
3
Cl
O
O
O
OH
O
S
O
N
H
Cl
N
H
O
N
1
(TMP778)
2 (GSK805)
O
O
O
Cl
S
S
O
N
N
H
Cl
3
Figure 1. Recent RORc inverse agonists with in vivo activities.
Figure 2. (A) Structure of ROR
binding site. (C) Central ring orienting azabicyclo[3.1.0] into the hydrophobic subpocket. (D) Tail benzamide sitting in the hydrophobic pocket made by the junction of helix 3,
, 7 and 11 while the amide carbonyl makes a hydrogen bond with H479.
c bound to 4j. (B) Backbone interaction between the acetamide carbonyl of 4j and the backbone amide of E379 at the entrance of the ligand
6
methylene spacer did not bring the potency back to the level of 4a.
However, acetamide 4f showed comparable potency in both bio-
chemical and cellular reporter assays. In addition, 4f exhibited an
improved solubility of 27 lg/mL.
With 4f in hand, we went to investigate the substitutions off the
middle phenyl ring (Table 2). A cyclobutylmethoxyl analogue 4g
Compound 4j has an oral exposure of 1045 ng h/mL when dosed
in rats at 10 mpk (0–7 h, CMC/Tween) and 2834 ng h/mL when
dosed in mouse at 25 mpk (CMC/Tween). The oral exposure in
rat is comparable to that of 4a (3134 ng.hr/mL). Pyrrolidine and
piperidine analogues 4k and 4l both showed excellent cellular
potencies. A pheny analogue 4m has slightly decreased cellular
potency compared to 4j.
showed a 5-fold improvement in the ROR
as compared to 4f but had weak activity in the mouse splenocyte
IL-17 assay (3.1 M). It is not clear what is causing the larger-
than-expected potency shift from Gal4 assay to the mouse spleno-
cyte assay. 4g has reasonable isoform selectivity over ROR /RORb
c GAL4 reporter assay
Next, we fixed the middle ring substitution with the azabicy-
clo[3.1.0]hexane moiety and checked the SAR around the tail ben-
l
3
zamide region (Table 3). Regarding R substitution, incorporation
a
of deuterium atoms has attracted a growing interest as it has
potential for benefits on profiles (such as reduced metabolism or
change of ratio between the metabolites) from the deuterium
based on cellular reporter assays. Closely related oxygen-linked
analogues such as 4h and 4i both have comparable potency to that
of 4f. The nitrogen-linked substitutions, however, resulted in more
potent compounds. Azabicyclo[3.1.0]hexane substituted analogue
2
0
3
kinetic isotope effect. In our hands, the profile of 4n (R equals
to CH ) tracks well with that of 4j and the 3-fold decrease in the
splenocyte activity for 4n could be within experimental error. For
3
4
3
ROR
j has single digit nM potency in the ROR
8 nM in the splenocyte IL-17 assay. It has good selectivity over
/RORb and PXR receptor. Physical properties (e.g., solubility)
and plasma binding are both improved as to biaryl analogue 4a.
c reporter assay and is
4
5
R /R , Cl/Cl and F/Me substitutions gave analogues 4o and 4p with
similar ROR GAL4 activities but with reduced mouse splenocyte
potencies. Incorporation of a nitrogen atom to the central ring
a
c

T. Wang et al. / Bioorg. Med. Chem. Lett. 25 (2015) 2985–2990
2987
Table 1
Replacement of phenyl head ring with a pyrazole
Cl
O
N
O
F
CD
3
R1
4a-f
CF
3
Compd ID
R1
ROR
29
c
Fret IC50 (nM)
ROR
c
Gal4 EC50 (nM)
Splenocyte IL17 EC50 (nM)
895
Solubility (
lg/mL)
PPB fu% Human/rat
O
4
a
H
2
N
98
0.3
0.3/0.2
Cl
O
4b
4c
4d
4e
4f
H N
N
240
530
38
570
1700
160
2000
—
32
—
5.9/3.1
—/—
2
N
N
N
N
818
—
<0.1
—
0.9/0.6
—/—
N
H N
N
610
26
1200
160
2
N
N
O
HN
—
27
—/—
N
O
Table 2
SAR at R2 position
Cl
O
N
F
CD
3
H
R2
N
N
N
O
4g-m
Compd
ID
R2
ROR
(nM)
c
Fret IC50
ROR
(nM)
c
Gal4 EC50
Splenocyte IL17 EC50
(nM)
ROR
a
/RORb EC50
PXR act. EC50
Solubility
g/mL)
PPB fu%
Human/rat
(
lM)
(
lM)
(
l
O
O
4
g
18
30
3110
1.2/0.9
>10
—
—/—
4
4
h
i
76
54
180
130
—
—
—/—
—/—
—
—
—
—
0.3/0.2
—/—
O
4
4
j
N
N
N
3.0
8.6
8.1
18
38
17
1.6/1.3
1.4/1.0
9.9
0.8
2.1
12
1.4/0.2
1.7/0.9
k
4
4
l
3.8
15
6.0
49
11
—
1.1/0.8
2.1/1.1
>10
>10
1.3
—
0.4/0.1
0.4/0.4
m

2
988
T. Wang et al. / Bioorg. Med. Chem. Lett. 25 (2015) 2985–2990
Table 3
SAR at middle ring and R /R /R
3
4
5
R4
O
A
N
N
R5
R3
H
N
N
N
O
4n-q
Compd
ID
A/R3
R4/R5
ROR
(nM)
c
Fret IC50
ROR
(nM)
c
Gal4 EC50
Splenocyte IL17 EC50 ROR
a
/RORb EC50
PXR act. EC50
M)
Solubility
g/mL)
PPB fu%
Human/rat
(nM)
(lM)
(
l
(
l
4n
4o
4p
4q
CH/CH
3
F/Cl
4.9
3.4
4.8
9.2
10
6.1
12
33
110
73
355
—
1.9/1.7
1.5/0.6
2.0/1.5
>10/6.2
—
—
0.9/0.2
0.4/0.1
1.1/0.2
5.6/2.2
CH/CD
CH/CD
3
Cl/Cl
F/Me
F/Cl
0.5
>10
1.3
0.8
17
48
3
N/CD
3
(
ortho- to the aniline nitrogen) yielded 4q with excellent kinetic
Table 4
SAR at R6 position
solubility (48 g/mL) and free levels against plasma proteins albeit
with slight decrease in cellular potency.
l
Since the methyl group of acetamide head group is predicted to
point to the open region based on docking studies (Data not
shown), it is reasoned that introduction of additional groups at this
Cl
O
6
N
N
F
position (R ) might retain potencies. In Table 4, a series of amides
CD
3
(4r–y), ureas (4z, 5a–d) and carbamates (5e–f) were synthesized.
HN
These analogues showed comparable potencies to 4j in the ROR
c
R6
N
N
GAL4 assay but were in general less potent in the splenocyte assay
with the exception of 4s.
O
4
r-z, 5a-f
Based on docking studies, substitutions off pyrazole ring at the
R position occupy the same space as chlorine atom on 4a does.
R6
Compd
ID
ROR
IC50 (nM)
c
Fret
ROR
EC50 (nM)
c
Gal4
Splenocyte IL17
EC50 (nM)
7
However, due to the ring difference (pyrazole vs phenyl) a methyl
group (similar in size to Cl) off pyrazole scaffold does not provide
comparable potency (data not shown). A number of analogues
were made and their profiles were shown in Table 5. Cyclopentyl
analogue 5g is equally potent to 4j but with inferior physical prop-
erties that may be due to the higher lipophilicity of a cyclopentyl
group as to an isopropyl group. Both cyclobutyl and cyclopropyl-
methylene analogues 5h and 5k had 5-fold decreases in potencies
4
4s
4t
r
H
Et
4.9
4.9
22
14
7.6
15
—
33
88
128
Cyclopropyl 5.0
i
4u
Pr
—
4v
HO
—
15
134
4w
4x
HO
HOCH
12
12
15
134
120
2
–
3.3
N
4y
70
93
25
—
7
in the splenocyte vs. 4j. The isopropyl group at this position (R )
H
N
offers a balance between potency and physical properties.
A combination of pyridine central ring with a piperidine substi-
4z
6.0
354
5
5
a
O
N
16
22
21
148
—
2
tution at R gave 5m with reasonable profile (Table 6). It has 34 nM
b
HO
N
9.4
in the mouse splenocyte assay, selective over ROR
a/RORb and PXR
H
N
receptor, and has good kinetic aqueous solubility (37.4
l
g/mL) and
5
5
c
18
—
37
71
—
—
HO
free unbound levels in plasma proteins (Human: 7.6%; Rat: 1.3%).
Compound 5m has an oral exposure of 927 ng h/mL when dosed
in rats at 10 mpk (0–7 h, CMC/Tween) and 2259 ng h/mL when
dosed in mouse at 25 mpk (CMC/Tween). A thiazole analogue 5n
with the same substitution (isopropyl and acetamide) is equally
potent but has poor physical property as well as PXR activation.
Neither triazole (5o) nor imidazole (5p) showed activity in the con-
centration range tested.
H
N
d
HO
HO
5e
21
—
57
—
—
O
O
5f
150
A representative synthesis is shown in Scheme 1. Nucleophilic
aromatic substitution of 6 with amine 7 gave 8. Reduction of 8 fol-
lowed by amide formation yielded 10, which was then methylated
and converted to the corresponding boronic ester 11. The other key
intermediate 12 was prepared in 6 steps. Regioselective alkylation
of 3-nitropyrazole 13 gave 15. Iron powder reduction of 15 fol-
lowed by protection of the newly installed amino group yielded
intermediate 17. Bromination of 17 followed by deprotection and
acetylation produced aminopyrazole 12. Cross coupling of 11 with
An X-ray structure of human ROR
c ligand binding domain in
complex with 4j to 2.2 Å was generated (PDB Code: 4ZOM,
Fig. 2A). The structure shows the carbonyl group on the pyrazole
head group makes a hydrogen bond interaction with the backbone
NH of Glu379 at the entrance of the ligand binding site (Fig. 2B).
The middle phenyl ring is sandwiched between Phe358 and
Met365, while the azabicyclo[3.1.0]hexane substituent travels into
sub-pocket making hydrophobic interactions with the side chains
of Phe388, Ile397, Ile400 and Phe401 (Fig. 2C). The Cl/F benzamide
1
2 furnished the target 4j.

T. Wang et al. / Bioorg. Med. Chem. Lett. 25 (2015) 2985–2990
2989
Table 5
SAR at R7 position
Cl
O
N
N
F
CD
3
H
N
N
N
R7
O
5g-l
Compd
ID
R7
ROR
(nM)
c
Fret IC50
ROR
(nM)
c
Gal4 EC50
Splenocyte IL17 EC50
(nM)
ROR
a
/RORb EC50
PXR act. EC50
M)
Solubility
g/mL)
PPB fu% Human/
rat
(lM)
(
l
(
l
5
g
5.1
9.5
60
1.3/1.3
0.5
0.1
0.2/<0.05
5
5
h
i
5.2
15
13
55
199
—
—/—
—/—
—
—
0.5
0.8
0.3/0.04
—/—
5
5
5
j
40
76
12
17
—
—/—
—
—
—/—
O
k
l
6.4
8.4
201
—
1.8/1.8
9.3/1.3
8.8
0.9
10.1
0.5
0.5/0.2
—/—
Table 6
Other 5-membered heteroaryls
Cl
O
N
N
N
F
R1
5m-p
Compd
ID
R1
ROR
(nM)
c
Fret IC50
ROR
(nM)
c
Gal4 EC50
Splenocyte IL17 EC50
(nM)
ROR
a
/RORb EC50
PXR act. EC50
M)
Solubility
g/mL)
PPB fu%
Human/rat
(lM)
(
l
(
l
H
N
5
5
5
5
m
n
o
6.2
13
34
—
9.3/2.3
2.2/0.8
—/—
5.4
0.4
—
37.4
0.3
—
7.6/1.3
NiPr
N
O
H
N
S
3.2
10
0.3/0.2
—/—
N
iPr
O
H
N
N
>5000
4800
>1000
>1000
—
N
N
iPr
O
H
N
N
p
—
—/—
—
—
—/—
NiPr
O
tail piece travels towards the junction of helix 3, 6, 7 and 11 of
ROR and is buried in a pocket composed of Trp317, Leu483,
Phe486, Leu396, Cys393, Ile397 and Leu392. The carbonyl of the
linker amide makes a hydrogen bond with the imidazole NH of
His479 (Fig. 2D).
crystal structure His479 is seen in an alternate conformation from
the 25-hydroxycholesterol agonist structure where it now makes a
hydrogen bond with the carbonyl of the benzamide (Fig. 3A).
Additionally, Trp317 of helix 3 is seen in an alternate conformation
where the head piece of the benzamide pushes tryptophan side
chain out towards helix 12 where it clashes with Tyr502
(Fig. 3B). Both interactions disrupt the His479 and Tyr502 hydro-
gen bond unlocking the agonist conformation and might explain
how 4j achieves inverse agonism.
c
By superimposing the ROR
holesterol agonist co-crystal structure (PBD code: 3L0L),
hypothesis can be generated for how 4j achieves inverse agonism.
ROR has a signature hydrogen bond between His479 of helix 11
and Tyr502 of helix 12 which locks RORs in the agonist conforma-
c 4j structure with the 25-hydroc-
2
1
a
c
In summary we have identified a series of novel pyrazole con-
taining benzamides as potent RORc inverse agonists. We have
19
tion creating part of the co-activator binding pocket. In the 4j co-

2
990
T. Wang et al. / Bioorg. Med. Chem. Lett. 25 (2015) 2985–2990
Cl
Cl
Cl
O
O
O
12, Na
2 3
CO ,
2
HN
NO
N
NO
2
2
1. NaH,
3
N
F
Pd(dppf)Cl
N
F
CD
3
7
1. iron, AcOH
Cl
NH
N
F
CD
I, DMF
CD
3
Br
F
Br
O
N
2.
2.
B
O
N
DMF/H
2
O (3:1),
HN
O
2
Cs CO
3
, DMF
Br
O
O
O
o
N
N
O
B B
100 C, 16 h
95%
O
9
F
Cl
pyridine, CH
3% for two steps
6
8
10
11
61% from 10
4j
2 2
KOAc, Pd(dppf) Cl
2
Cl
2
7
1
. n-BuLi, THF,
O
Br
N
1. HO-NH .HCl, KOH
EtOH, 80 C, 12 h
H
N
H
N
O
o
2
Br
N
-78 C,
2. BrCN, rt, 4 h
N
N
o
Br
1
4
iron
N
N
N
N
N
O
N
N
. NaH, DMF, 0 oC, 1 h
. 100 C, 1 h
N
1
2
TsOH
EtOH,
2. Ac
CH Cl
67% for two steps
2
O, DIPEA,
2
NO
2
o
NH2 toluene, 130 oC, 4 h
81%
N
80 oC, 1 h
, RT
NO
2
2
7
8%
85%
67-78%
13
15
16
17
18
12
Scheme 1.
Figure 3. Superposition of ROR
c/4j Cocrystal structure (Green/Magenta) with the 25-hydroxycholesterol structure (3L0L, Yellow). (A) His479 shifts away from agonist
conformation to hydrogen bond with carbonyl of 4j. (B) Tail benzamide of 4j moves Trp317 towards Helix 12 clashing with Tyr502.
improved the cellular potency as well as physical properties.
Compounds such as 4j and 5m are potent and selective and have
adequate profiles that would allow them to be used as probe com-
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