Tricyclic-Carbocyclic RORγt Inverse Agonists - Discovery of BMS-986313

Article abstract of DOI:10.1021/acs.jmedchem.0c01992

SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound 1 (BMS-986251) led to tricyclic-carbocyclic analogues represented by 3-7 and culminated in the identification of 3d (BMS-986313), with structural differences distinct from 1. The X-ray co-crystal structure of 3d with the ligand binding domain of RORγt revealed several key interactions, which are different from 1. The in vitro and in vivo PK profiles of 3d are described. In addition, we demonstrate robust efficacy of 3d in two preclinical models of psoriasis - the IMQ-induced skin lesion model and the IL-23-induced acanthosis model. The efficacy seen with 3d in these models is comparable to the results observed with 1.

Full text of DOI:10.1021/acs.jmedchem.0c01992

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Article
Tricyclic-Carbocyclic RORγt Inverse AgonistsDiscovery of BMS-
986313
Michael G. Yang,* Myra Beaudoin-Bertrand, Zili Xiao, David Marcoux, Carolyn A. Weigelt,
Shiuhang Yip, Dauh-Rurng Wu, Max Ruzanov, John S. Sack, Jinhong Wang, Melissa Yarde, Sha Li,
David J. Shuster, Jenny H. Xie, Tara Sherry, Mary T. Obermeier, Aberra Fura, Kevin Stefanski,
Georgia Cornelius, Purnima Khandelwal, Ananta Karmakar, Mushkin Basha, Venkatesh Babu,
Arun Kumar Gupta, Arvind Mathur, Luisa Salter-Cid, Rex Denton, Qihong Zhao,
and T. G. Murali Dhar*
Cite This: J. Med. Chem. 2021, 64, 2714−2724
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*
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ABSTRACT: SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound 1 (BMS-
986251) led to tricyclic-carbocyclic analogues represented by 3−7 and culminated in the identification of 3d (BMS-986313), with
structural differences distinct from 1. The X-ray co-crystal structure of 3d with the ligand binding domain of RORγt revealed several
key interactions, which are different from 1. The in vitro and in vivo PK profiles of 3d are described. In addition, we demonstrate
robust efficacy of 3d in two preclinical models of psoriasisthe IMQ-induced skin lesion model and the IL-23-induced acanthosis
model. The efficacy seen with 3d in these models is comparable to the results observed with 1.
PoC for this mechanism has also been established for the
treatment of inflammatory bowel disease, rheumatoid arthritis,
and other autoimmune diseases.10−13
INTRODUCTION
■
The retinoid-related orphan receptor (ROR) is a member of
the nuclear hormone receptor family and consists of RORα, β,
and γ subfamilies. RORγt is a shorter isoform of RORγ,
differing by 24 amino acids at the N-terminal extension.1
Unlike RORγ,2 the expression of RORγt is restricted primarily
to lymphoid cells.3 RORγt is associated with the regulation of
CD4+ T cell differentiation into T helper 17 (TH17) cells
through cytokine signaling pathways including IL-17A/F and
IL-23.4 The activation of RORγt upregulates the expressions of
IL-23R, TH17 cells, and the production of pro-inflammatory
cytokines, such as IL-17A/F, IL-22, IL-26, and CCL20.5
Studies have shown that the overproduction of these pro-
inflammatory cytokines is linked to several human auto-
immune disorders such as psoriasis.6 This approach has been
validated in the clinic by marketed antibodies targeting IL-17
(secukinumab, ixekizumab), its receptor (brodalumab), and
the IL-23 p19 subunit (guselkumab), for the treatment of
psoriasis, ankylosing spondylitis, and active psoriatic arthri-
tis.7,8 In addition, clinical proof-of-concept (PoC) with small
molecule inverse agonists of RORγt has been achieved with
VTP-43742 for the treatment of psoriasis,9 and pre-clinical
In light of these findings, there has been significant interest
in academic institutions and pharmaceutical companies to
identify small molecule inverse agonists of RORγt.14−19
Recently, we reported the discovery of 1 and 2 as potent
and selective RORγt inverse agonists.20−23 Although com-
pound 2 was structurally differentiated from 1, the metabolic
stability (MetStab) profile was not optimal, and this prevented
its further development (Figure 1).22 In addition, for our
second generation series, we elected to stay away from acid
moieties (as in 1) because of the potential liabilities associated
with acyl glucuronide formation. Therefore, efforts to prepare
RORγt inverse agonists with an improved MetStab profile over
Received: November 17, 2020
Published: February 16, 2021
https://dx.doi.org/10.1021/acs.jmedchem.0c01992
© 2021 American Chemical Society
J. Med. Chem. 2021, 64, 2714−2724
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a
Figure 1. Development of orally bioavailable RORγt inverse agonists 3−7. LM t1/2: liver microsomes half-life in minutes, human (h), rat (r),
mouse (m), and dog (d).
a
Table 1. SAR Study of the Side Chains Presented in Molecules 3−7
RORγt GAL4 EC50
IL-17 hWB EC50
MetStab % rem
RORγt GAL4 EC50
IL-17 hWB EC50
MetStab % rem
a
b
a
b
compd
(nM)
(nM)
(h/m/r)
compd
(nM)
(nM)
(h/m/r)
c
3a
3b
3c
3d
3e
3f
3g
4a
4b
4c
4d
4e
5a
5b
5.4
8.5
8.6
3.6
2.5
1.4
7.4
30
48
26
63
2.2
4.5
15
120 16
116 21
64 32
50 13
54 20
67 31
ND /90/100
5c
5d
5e
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
1
20
96 29
48 29
134 22
157 48
127 36
28 13
50 24
36 17
291
ND/71/99
100/86/100
99/100/100
ND
82/65/34
71/70/14
100/92/100
97/86/90
50/56/22
100/75/66
80/100/100
98/85/89
100/88/83
74/78/97
0.3/0.3/0.4
100/93/10
61/67/100
5.4
12.3
7.3
9.9
6.7
8.7
1.9
24
3.7
2.5
3.1
9.1
12
ND
97/100/100
100/95/100
97/99/97
100/100/100
40/32/10
97/93/41
54/ND/42
ND
21
5
164 11
981 223
1940
101 67
65 28
ND
39
5
32
91
24
2
8
6
95 63
34 10
100/100/100
a
b
EC50 values reported as the average of two or more determinations. In vitro stability in the human (h), mouse (m), and rat (r) liver microsomes.
c
Not determined.
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Figure 2. Left panel: X-ray co-crystal structure of 1 (BMS-986251) in RORγt (pdb id: 6VQF); right panel: co-crystal structure of 3d (BMS-
986313) with the LBD of RORγt (pdb id: 7KQJ).
2 led to the identification of tricyclic N-cyclopentyl-derived
analogues 3−7 (Figure 1). This manuscript details the SAR
findings of 3−7 and reports the in vivo results of 3d in two
preclinical models of psoriasis: the imiquimod (IMQ)-induced
skin lesion model and IL-23-induced acanthosis model of
psoriasis.
group of polar amide analogues directed at engaging the polar
pocket of the ligand binding domain (LBD) of RORγt. Among
the alcohol derivatives 3b−g, compound 3g had the best hWB
potency (EC50 = 21 nM). However, only the tertiary alcohol
3d met the progression criteria [hWB EC50 = 50 nM and
MetStab % rem (h/r/m) = 100/92/100]. It is worth noting
that α-methyl substituents in 3c and 3d showed a trend toward
improvement in the hWB potency, as illustrated in Table 1.
Amine analogues 4a−e were generally weak in both the GAL4
and hWB assays, except 4e (hWB EC50 = 39 nM). However,
the MetStab profile of 4e was very poor [MetStab % rem (h/r/
m) = 0.3/0.3/0.4]. Among the amide analogues 5a to 5e, only
5b and 5d met the hWB criteria for progression. In addition,
5d exhibited good MetStab. Next, we examined a series of
sulfone and sulfonamide analogues 6a−e, as well as compound
6f as a representative carboxylic acid. Both 6a and 6b had a
weak hWB potency (EC50 > 120 nM). On the other hand,
compounds 6c−e were very potent in the hWB assay with
good MetStab, meeting the hWB and in vitro MetStab
progression criteria. It was somewhat surprising to see
carboxylic acid 6f to be ∼ 12- to 8-fold less potent than 6e
in the GAL4 and hWB assays, respectively. In the case of our
previously reported tricyclic pyrrolidine chemotype,20 the
difference in potency in the GAL4 and hWB assays was only
2−3 fold, suggesting a potentially different binding mode for
the sulfone and the carboxylic acid moieties in this chemotype.
Ureas 7a−c gave moderate to good potency in the hWB assay,
with 7c affording the best EC50 value of 32 nM. Compared to
urea 7c, carbamate 7d reduced the whole blood activity by 3-
fold (7c: EC50 = 32 nM vs 7d: EC50 = 91 nM). Unfortunately,
7c had poor MetStab in the in vitro microsomal assays which
prevented its further progression.
RESULTS AND DISCUSSION
■
Efforts aimed at improving the MetStab profile of 2 led to the
examination of a series of reverse amides 3−7, as listed in
Table 1. Compared to structure 2 (Figure 1), the side chain
amide nitrogen in the new series (compounds 3−7) is
sterically hindered because it is attached to the tricyclic core,
which could potentially alter or slow down metabolic processes
such as N-dealkylation. Because the reverse amide series was a
logical extension from our earlier tricyclic pyrrolidine series
where the nitrogen atom was a part of the ring system, as
illustrated in 1,20,21 a number of side chains studied earlier
were re-examined here. Molecular modeling studies revealed
that the trajectory of the side chains in both tricyclic
pyrrolidine and reverse amide series point toward the RORγt
polar pocket, consisting of a network of residues including
Glu286, Leu287, Arg364, and Arg367.
As part of the screening process, we tested all newly
synthesized compounds in both the GaL4-Luc reporter assay
(GAL4) and a physiologically relevant IL-17-stimulated human
whole blood (hWB) assay. Because the hWB EC50 of 1 was 24
nM,21 we required the EC50 cutoff value of newly synthesized
compounds to be ≤50 nM for further profiling. To assess
MetStab, we measured the percent of parent remaining (%
rem) following incubation with human, mouse, and rat liver
microsomes, aiming for >90% recovery in these assays (Table
1).24 These results are outlined in Table 1. Acetamide 3a
showed weak hWB activity (EC50 = 120 nM) but had good in
vitro MetStab in rodents relative to 2. Next, we examined a
Based on the activity profiles of compounds in the GAL4
and hWB assays and the in vitro liver microsomal data (Table
1), compounds 3d, 5d, and 6c−e were advanced for further
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profiling. The potency of 5d and 6c−e can be rationalized
based on information obtained from the X-ray co-crystal
structure of 1 with the LBD of RORγt (Figure 2, left panel).21
As shown in Figure 2, the acid moiety of 1 binds in the polar
pocket of RORγt and forms hydrogen bonds with the
backbone NH of Leu287 and Gln286 and with the side
chain of Arg367 and the backbone carbonyl of Ala327 via
water. In the design of 5d and 6c−e, it was our intention to
mimic the carboxylic acid moiety of 1 with the pyrrolidinone23
and sulfone motifs20 to achieve the desired interactions. The
potencies of 5d and 6c−e can potentially be explained based
on this rationale. However, we did not expect to see the potent
GAL4 and hWB activity for 3d (EC50’s of 3.6 and 50 nM,
respectively) because the 2-hydroxy-2-methylpropanamide side
chain is too short to fully extend into the polar pocket of
RORγt. In an effort to understand the observed potency, the X-
ray co-crystal structure of 3d with the LBD of RORγt was
acquired (Figure 2, right panel). Three things became evident
from the co-crystal structure: (1) the aryl sulfone forms an
intramolecular H-bond with the cyclopentylacetamide NH;
(2) the OH moiety of the 2-hydroxy-2-methylpropanamide
side chain forms hydrogen bonds with the CO of Phe377;
and (3) the CO group in the 2-hydroxy-2-methylpropana-
mide side chain interacts with the backbone carbonyl of
Gln286 through water. In addition, the α,α-dimethyl
substituents in 3d likely engages in lipophilic interactions
with the side chains of Gln286, Leu287, and Ala368 in the
RORγt LBD pocket. Taken together, these interactions
probably contribute to the potency enhancements seen with
compounds like 3d. It is worth mentioning that the
intramolecular H-bond between the amide NH and the
sulfone oxygen is likely the key interaction that preorganizes
the side chain of the molecule in the desired orientation to
engage in the important interactions described above. The
significant loss of potency observed with the N−Me analogue
(3d-Me, Figure 2) in both the Gal4 and hWB assays is
consistent with this hypothesis.
and 6e (orally dosed at 4 mg/kg) clearly indicated that 3d had
a higher oral exposure in terms of both Cmax (1.04 μM) and
area under the curve (AUC0−24h) (15.4 μM·h) compared to 6e
(Cmax 0.77 μM and AUC0−24h 11.1 μM·h). Therefore, 3d was
advanced for additional in vitro profiling and full PK studies in
mouse, rat, dog, and cyno.
In vitro liability profiling results for 3d are summarized in
Table 3. Compound 3d displayed excellent selectivity against
Table 3. In Vitro Profiling of Compound 3d
parameter
3d
1
RORγt GAL4 EC50 (nM)
IL-17 hWB EC50 (nM)
mouse Th17 EC50 (nM)
RORα GAL4 EC50 (nM)
RORβ GAL4 EC50 (nM)
3.6 2.3
50 13
2.7 0.3
>10,000
>10,000
all >5,000
19
12
24
11
6
6
2
>10,000
>10,000
all >5,000
>30
a
PXR/LXRα/LXRβ EC50 (nM)
hERG patch clamp IC50 (μM):
protein binding % free (h &; m):
0.5/0.6
1.2/1.6
b
CYP inhibition IC50 (μM)
1A2/2D6/2C9
3A4/2C8/2C19
20/20/12
11/12/19
20/20/20
20/16/20
a
b
PXR = pregnane X receptor; LXR = liver X receptor. CYP =
cytochrome P450.
RORα, RORβ, LXRα/β, and PXR, as well as a favorable IC50
in the hERG patch clamp assay and a clean CYP inhibition
profile (IC50 = 10−20 μM). As listed in Table 4, compound 3d
displays good oral bioavailability (65−100%) across the four
species studied, in addition to exhibiting low clearance,
consistent with the in vitro liver microsomal t1/2. The oral
exposures of 3d (both Cmax and AUC0−24h) were good across
species and were consistent with the permeability suggested by
the in vitro Caco-2 assay.
The efficacy of 3d in chronic disease models was assessed in
both the IMQ-induced skin lesion model and the IL-23-
induced acanthosis model of psoriasis (Figures 3 and 4). IMQ
activates pro-inflammatory signaling pathways and contributes
to the induction of clinical signs of psoriasis, such as skin
thickening. Skin thickness scores (% change) were measured
and recorded daily throughout the 8 day study. Doses of 3d at
5, 10 and 20 mg/kg BID inhibited skin thickening by 13.7,
39.6, and 57.7%, respectively, compared to the placebo arm
based on the area under the curve over the duration of the
study. In comparison, the αIL-23 mAb used as a positive
control inhibited skin thickening by 65% when dosed at 10
mg/kg (Figure 3B). At the end of the study, the skin was
collected and mRNA extracted for RT-PCR analysis. As shown
in Figure 3C, both IL-17A and IL-17F mRNA levels were
significantly reduced by compound 3d. At the 10 mg/kg dose,
the inhibition of IL-17A and IL-17F by 3d was comparable to
the results observed with the αIL-23 mAb.
Table 2 summarizes the liver microsome half-life (LM t1/2
)
and Caco-2 data for 3d, 5d, 6c−e, and 1. Based on the overall
Table 2. In Vitro Characterizations of RORγt Inverse
Agonist 3d, 5d, and 6c−e
b
IL-17 hWB EC50 LM t1/2 (min) h, m,
Caco-2 Pc, nm/s
(efflux ratio)
a
compd
(nM)
r, d, c
3d
50 13
120, 120, 120, 120,
120
106 (0.5)
5d
6c
6d
48 29
28 13
50 24
46, 38, 56, 120, 24
120, 120, 89, 120, 65
101, 120, 120, 120,
120
92 (0.7)
53 (1.4)
73 (1.4)
6e
1
36 17
120, 120, 120, 120,
120
120, 120, 120, 120,
120
46 (2.6)
24
6
240 (0.5)
a
Activation of IL-23R promotes the development of Th17
cells and the resulting production of cytokines such as IL-17A
and IL-17F, which are involved in mediating psoriasiform
changes. The IL-23-induced psoriasis model involves the
injection of IL-23 into the ear of C57BL/6 mice, which
contributes to the development of dermal inflammation and
epidermal hyperplasia (acanthosis). A starting “baseline”
measurement of the ear was made on day 0, and ear thickness
(% change) was measured every other day prior to the next ear
injection. In the IL-23-induced acanthosis study of 3d, all the
IC50 values reported as the average of two or more determinations.
Liver microsomes half-life in minutes.
b
profiles shown in Table 2, 3d and 6e became compounds of
interest. Of the two compounds, 3d was chosen for further
advancement based on its potency in the hWB assay, higher
Caco-2 value (A−B: 106 nm/s), lower efflux ratio (0.5), and
the desired in vitro MetStab profile across species. In addition,
the examination of results from mouse coarse PK studies of 3d
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a
Table 4. PK Profile of Compound 3d in Preclinical Species
IV
PO
species
dose (mg/kg) IV/PO
Cl (mL/min/kg)
Vss (L/kg)
Cmax (μM)
AUC24h (μM·h)
F (%)
b
mouse
rat
dog
2/4 (2/4)
3.7 (2.7)
4.2 (1.3)
0.8 (0.2)
3.0 (1.9)
2.9 (1.2)
3.2 (0.5)
2.7 (2.0)
2.2 (4.8)
1.0 (4.7)
1.3 (6.4)
1.1 (3.1)
33.2 (37)
17.0 (64)
59.8 (120)
18.0 (35)
100 (100)
65 (94)
83 (100)
75 (100)
2/4 (2/4)
1/2 (1/1)
1/2 (1/1)
cyno
2.7 (1.1)
a
b
Values are means obtained from three or more animals. Data in parenthesis are the PK data for compound 1.
Figure 3. Efficacy of 3d in an IMQ mouse model: (A) % change in skin thickness scores; (B) % inhibition of skin thickness based on AUC; and
a
(C) % inhibition of IL-17A and IL-17F. Steady-state (SS) exposures, C24h
.
Figure 4. Efficacy of 3d in an IL-23-induced mouse acanthosis model: (A) % change in ear thickness cores; (B) % inhibition of ear thickness based
a
on AUC; and (C) % inhibition of IL-17A and IL-17F. Steady-state (SS) exposures, C24h
.
a
Scheme 1. Synthesis of Compound 5d
a
Reagents and conditions: (a) DAST and CH2Cl2, 0 °C → rt, 94%; (b) RuO2·H2O, NaIO4, and EtOAc−H2O, rt, 63%; (c) 4 M HCl in dioxane
and DCM, rt, 81%; (d) Cs2CO3, ICD3, and MeCN, 45 °C → rt, ∼100%, crude used as such for next step; (e) LiOH and THF/MeOH/H2O, rt,
crude used as such for the next step; (f) TEA, toluene, and DPPA, 0 °C → rt, and then heated at 80 °C with TMSCH2CH2OH; (g) TFA and
CH2Cl2, rt, 28% over two steps; and (h) HATU, DIEA, and DMF, rt, 53%.
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N-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)acetamide (3a, Table 1). To a solution of 14 (40
mg, 0.078 mmol; see ref 25. for its synthesis) in CH2Cl2 (2 mL) was
treated with acetyl chloride (7.95 mg, 0.101 mmol) and triethylamine
(10.86 μL, 0.078 mmol) at rt and stirred at rt for 2 h. The reaction
mixture was diluted with water (10 mL), extracted with ethyl acetate
(10 × 2 mL) and the combined ethyl acetate extracts were dried over
Na2SO4 and concentrated under rotary evaporation. The crude
material was purified by preparative HPLC [Xbridge C18 19 × 200
mm, 5 μm (Waters Corp.); mobile phase A: 5:95 MeCN/water with
10 mΜ ammonium acetate; mobile phase B: 95:5 MeCN/water with
10 mΜ ammonium acetate; flow rate 20 mL/min; gradient:
increasing B, then isocratic at 100% B] to give 3a (21.2 mg, 49%
doses resulted in reduced ear thickness, as shown in Figure 4A.
Doses of 3, 6, and 15 mg/kg BID inhibited IL-23-induced ear
thickening by 42.3, 43.4, and 66.8%, respectively, compared to
the placebo arm based on the area under the curve over the
duration of the study (Figure 4B). At the end of the study on
day 10, the ear tissue was collected from all animals and
analyzed by qPCR for the expression of inflammatory cytokine
genes, such as IL-17A and IL-17F. As shown in Figure 4C,
compound 3d provided a dose-dependent inhibition in the
levels of IL-17A and IL-17F mRNAs in the ear tissue. These
reductions were statistically significant for the 6 and 15 mg/kg
doses. The results presented in Figures 3 and 4 show that 3d
demonstrates compelling efficacy in both preclinical models of
psoriasis, consistent with its in vitro profile.
1
yield). H NMR (500 MHz, DMSO-d6): δ 8.11 (br d, J = 7.6 Hz,
1H), 7.52−7.44 (m, 2H), 7.36 (s, 1H), 7.33−7.25 (m, 4H), 4.06−
3.86 (m, 1H), 3.08−2.92 (m, 1H), 2.80 (br d, J = 5.8 Hz, 1H), 2.71−
2.60 (m, 1H), 2.32−2.15 (m, 1H), 2.08−1.91 (m, 3H), 1.89−1.79
(m, 4H), 1.35−1.22 (m, 2H). ESI-MS: m/z 556.18 ([M + H+]).
HPLC: tR = 2.17 min.
CHEMISTRY
■
As a representative example for the preparation of 3−7, the
synthesis of 5d is outlined in Scheme 1. The DAST reaction of
8 led to the inversion of the configuration at the carbon
bearing the hydroxyl group to provide fluoro compound 9 in
94% yield. Ruthenium oxide-catalyzed oxidation of 9 followed
by deprotection of the Boc group yielded 10. Deuteromethy-
lation of 10 followed by saponification gave acid 11.23,25
DPPA-promoted Curtis rearrangement reaction of 1222 gave
tricyclic core 13, the Teoc group of which was deprotected
with TFA to give amine 14 in 28% yield over two steps.22,25
Finally, the HATU-promoted coupling reaction between acid
11 and amine 14 provided 5d in 53% yield (Scheme 1).
N-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)-2-hydroxyacetamide (3b, Table 1). To a
solution of 14 (26 mg, 0.042 mmol) in DMF (1 mL) was treated
with 2-hydroxyacetic acid (14.24 mg, 0.173 mmol), DIEA (0.096 mL,
0.549 mmol), and HATU (48.1 mg, 0.127 mmol). The reaction
mixture was stirred at rt for 30 min before water (10 mL) was added.
The resulting mixture was extracted with ethyl acetate (10 × 2 mL),
and the combined ethyl acetate extracts were dried over Na2SO4 and
concentrated under rotary evaporation. The crude material was
purified by preparative HPLC [Xbridge C18 19 × 200 mm, 5 μm
(Waters Corp.); mobile phase A: 5:95 MeCN/water with 10 mΜ
ammonium acetate; mobile phase B: 95:5 MeCN/water with 10 mΜ
ammonium acetate; flow rate 20 mL/min; gradient: increasing B, then
isocratic at 100% B] to give 3b (19.6 mg, 81% yield). 1H NMR (500
MHz, DMSO-d6): δ 7.94 (br d, J = 8.5 Hz, 1H), 7.58 (d, J = 8.5 Hz,
1H), 7.51 (br d, J = 8.2 Hz, 1H), 7.34−7.29 (m, 3H), 7.29−7.20 (m,
2H), 4.07−3.88 (m, 1H), 3.18−2.98 (m, 1H), 2.95−2.82 (m, 1H),
2.63 (br d, J = 16.2 Hz, 1H), 2.38−2.20 (m, 1H), 2.03−1.81 (m, 5H),
1.26 (m, 1H). ESI-MS: m/z 572.01 ([M + H+]). HPLC: tR = 2.14
min.
(R)-N-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(per-
fluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta-
[a]naphthalen-3-yl)-2-hydroxypropanamide (3c, Table 1). A
procedure similar to that described in the synthesis of 3b was used to
prepare 3c from 14 and (R)-2-hydroxypropanoic acid. 1H NMR (500
MHz, DMSO-d6): δ 7.89 (br d, J = 8.2 Hz, 1H), 7.60−7.49 (m, 2H),
7.36−7.23 (m, 5H), 4.05−3.90 (m, 2H), 3.63−3.40 (m, 1H), 3.07−
2.94 (m, 1H), 2.87 (br d, J = 8.2 Hz, 1H), 2.64 (br d, J = 16.2 Hz,
1H), 2.56−2.53 (m, 3H), 2.38−2.21 (m, 1H), 2.03−1.89 (m, 3H),
1.87−1.65 (m, 1H), 1.30−1.18 (m, 5H), 1.00 (m, 1H). ESI-MS: m/z
586.13 ([M + H+]). HPLC: tR = 2.10 min.
CONCLUSIONS
■
Our effort to identify potent, selective, and orally bioavailable
RORγt inverse agonists led to the discovery of clinical
compound 1. With the goal of preparing RORγt inverse
agonists structurally different from 1, SAR studies of tricyclic
N-cyclopentylamide-derived 3−7 were conducted, which led
to the identification of BMS-986313 (3d). Compound 3d in
addition to being structurally different from 1, also displayed
differential and distinct interactions with the LBD of RORγt, as
is evident from the X-ray co-crystal structures. 3d has a clean
liability profile and showed excellent PK in multiple preclinical
species. Furthermore, 3d was evaluated in two preclinical
models of psoriasis, the IMQ-induced skin lesion model and
the IL-23-induced acanthosis model, where it showed robust
efficacy comparable to that of an antibody (αIL-23 mAb),
thereby warranting further evaluation.
N-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)-2-hydroxy-2-methylpropanamide (3d, Table
1). A procedure similar to that described in the synthesis of 3b was
used to prepare 3d from 14 and 2-hydroxy-2-methylpropanoic acid.
1H NMR (500 MHz, DMSO-d6): δ 7.83 (br d, J = 8.2 Hz, 1H), 7.59
(br d, J = 8.5 Hz, 1H), 7.52 (br d, J = 8.2 Hz, 1H), 7.35−7.30 (m,
3H), 7.30−7.22 (m, 2H), 3.98 (br t, J = 7.3 Hz, 1H), 3.07−2.96 (m,
1H), 2.87 (br d, J = 7.9 Hz, 1H), 2.65 (br d, J = 15.9 Hz, 1H), 2.34−
2.19 (m, 1H), 2.03−1.90 (m, 3H), 1.89−1.72 (m, 1H), 1.28 (br d, J =
14.0 Hz, 6H). 13C NMR (126 MHz, methanol-d4): δ 179.56 (s, 1C),
167.62 (d, J = 256.1 Hz, 1C), 143.98 (d, J = 1.8 Hz, 1C), 138.08 (s,
1C), 134.44 (d, J = 9.1 Hz, 2C), 132.98 (d, J = 2.7 Hz, 1C), 132.68
(d, J = 1.8 Hz, 1C), 127.68 (d, J = 20.0 Hz, 1C), 126.32 (d, J = 10.0
Hz, 1C), 124.61−124.49 (m, 1C), 125.93−118.12 (m, 2C), 116.93
(d, J = 22.7 Hz, 2C), 94.28−91.30 (m, 1C), 77.17 (s, 1C), 73.86 (s,
1C), 57.85 (s, 1C), 48.92 (s, 1C), 35.66 (s, 1C), 32.23 (s, 1C), 29.40
(s, 1C), 28.23 (s, 1C), 27.96 (s, 1C), 27.84 (s, 1C). RHMS (ESI) m/
z: calcd for C26H26F8NO4S [M + H+], 600.1449; found, 600.1449.
EXPERIMENTAL SECTION
■
Chemistry. All commercially available chemicals and solvents were
used without further purification. Reactions are performed under an
atmosphere of nitrogen. All new compounds gave satisfactory 1H
nuclear magnetic resonance spectroscopy (NMR), liquid chromatog-
raphy/mass spectrometry and/or high-resolution mass spectrometry,
1
and mass spectrometry results. H NMR spectra were obtained on a
Bruker 400 MHz or a Jeol 500 MHz NMR spectrometer using the
residual signal of the deuterated NMR solvent as an internal reference.
Electrospray ionization (ESI) mass spectra were obtained on a Water
Micromass ESI-MS single quadrupole mass spectrometer. The purity
of the tested compounds determined by analytical HPLC was >95%
except as noted. The analytical HPLC conditions (except as noted)
are described as: Waters XBridge C18, 2.1 mm × 50 mm, 1.7 μm
particles; mobile phase A: 5:95 acetonitrile/water with 10 mΜ
ammonium acetate; mobile phase B: 95:5 acetonitrile/water with 10
mΜ ammonium acetate; gradient: 0% B to 100% B over 3 min, then a
0.75 min hold at 100% B; and flow rate: 1 mL/min.
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1
HPLC: tR = 2.23 min. Co-crystal structure of 3d (BMS-986313) with
the LBD of RORγt (pdb id: 7KQJ).
at 100% B] to give 4a (31.7 mg, 68% yield). H NMR (500 MHz,
DMSO-d6): δ 8.27 (br d, J = 7.4 Hz, 1H), 7.54−7.34 (m, 3H), 7.33−
7.23 (m, 3H), 3.99 (br t, J = 7.8 Hz, 1H), 3.54−3.36 (m, 2H), 3.12−
2.93 (m, 1H), 2.69 (br d, J = 16.1 Hz, 1H), 2.33−2.16 (m, 1H),
2.08−1.89 (m, 2H), 1.53 (br d, J = 12.8 Hz, 6H), 1.45 (br s, 2H).
ESI-MS: m/z 599.12 ([M + H+]). HPLC: tR = 1.89 min.
N-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)-2-hydroxy-N,2-dimethylpropanamide (3d-
1
Me, Figure 2). H NMR (500 MHz, chloroform-d): δ 7.63 (d, J =
8.5 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.26−7.07 (m, 3H), 6.94 (t, J =
8.2 Hz, 2H), 3.36−3.28 (m, 1H), 3.07 (br d, J = 5.7 Hz, 1H), 2.93−
2.86 (m, 2H), 2.61 (s, 3H), 2.56−2.41 (m, 1H), 2.06−1.84 (m, 5H),
1.76 (ddd, J = 15.9, 12.7, 3.6 Hz, 3H), 1.37−1.17 (m, 6H). ESI-MS:
m/z 614.5 ([M + H+]). HPLC: tR = 1.11 min. BEH C18 2.1 × 50 mm
1.7 u; mobile phase A: 100% water with 0.05% TFA; mobile phase B:
100% acetonitrile with 0.05% TFA; gradient: initial 98% A to 2% B,
and then 2% A to 98% B over 1.8 min, then a 0.75 min hold at 100%
B; flow rate: 0.8 mL/min.
3-Amino-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-
(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-
cyclopenta[a]naphthalen-3-yl)-3-methylbutanamide (4b,
Table 1). A procedure similar to that described in the synthesis of
4a was used to prepare 4b from 14 and 3-((tert-butoxycarbonyl)-
1
amino)-3-methylbutanoic acid. H NMR (500 MHz, DMSO-d6): δ
8.48 (br d, J = 7.9 Hz, 1H), 7.53−7.40 (m, 2H), 7.37 (s, 1H), 7.28 (d,
J = 6.7 Hz, 3H), 4.13−3.94 (m, 1H), 3.09−2.94 (m, 1H), 2.90−2.75
(m, 1H), 2.68 (br d, J = 15.0 Hz, 1H), 2.33−2.20 (m, 3H), 2.11−2.01
(m, 2H), 1.98 (br d, J = 5.5 Hz, 1H), 1.92−1.81 (m, 3H), 1.35−1.21
(m, 2H), 1.18 (s, 6H). ESI-MS: m/z 613.13 ([M + H+]). HPLC: tR =
1.88 min.
N-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)-3-hydroxy-3-methylbutanamide (3e, Table
1). A procedure similar to that described in the synthesis of 3b was
used to prepare 3e from 14 and 3-hydroxy-3-methylbutanoic acid. 1H
NMR (500 MHz, DMSO-d6): δ 8.13 (br d, J = 7.9 Hz, 1H), 7.52−
7.42 (m, 2H), 7.36 (s, 1H), 7.32−7.25 (m, 4H), 4.81 (s, 1H), 4.06−
3.90 (m, 1H), 3.06−2.93 (m, 1H), 2.80 (br d, J = 6.1 Hz, 1H), 2.72−
2.61 (m, 1H), 2.30−2.19 (m, 3H), 2.09−1.99 (m, 2H), 1.96 (br d, J =
5.2 Hz, 1H), 1.89−1.74 (m, 1H), 1.29 (br d, J = 10.1 Hz, 1H), 1.18
(s, 6H). ESI-MS: m/z 614.26 ([M + H+]). HPLC: tR = 2.28 min.
N-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)-1-hydroxycyclohexane-1-carboxamide (3f,
Table 1). A procedure similar to that described in the synthesis of
3b was used to prepare 3f from 14 and 1-hydroxycyclohexane-1-
carboxylic acid. 1H NMR (500 MHz, DMSO-d6): δ 7.87 (br d, J = 8.5
Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.52 (br d, J = 8.2 Hz, 1H), 7.35−
7.22 (m, 5H), 5.17 (s, 1H), 3.98 (br t, J = 7.5 Hz, 1H), 3.18 (d, J =
5.2 Hz, 1H), 3.06−2.94 (m, 1H), 2.94−2.80 (m, 1H), 2.74−2.60 (m,
1H), 2.28 (br dd, J = 13.9, 8.4 Hz, 1H), 2.07−1.88 (m, 3H), 1.86−
1.76 (m, 1H), 1.74−1.64 (m, 2H), 1.62−1.43 (m, 7H), 1.31−1.13
(m, 2H). ESI-MS: m/z 640.30 ([M + H+]). HPLC: tR = 2.38 min.
N-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)-4-hydroxytetrahydro-2H-pyran-4-carboxa-
mide (3g, Table 1). A procedure similar to that described in the
synthesis of 3b was used to prepare 3g from 14 and 4-
N-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)-4-hydroxypiperidine-4-carboxamide (4c,
Table 1). A procedure similar to that described in the synthesis of
4a was used to prepare 4c from 14 and 1-(tert-butoxycarbonyl)-4-
1
hydroxypiperidine-4-carboxylic acid. H NMR (500 MHz, DMSO-
d6): δ 8.00 (br d, J = 8.5 Hz, 1H), 7.59 (br d, J = 8.5 Hz, 1H), 7.52
(br d, J = 8.2 Hz, 1H), 7.32 (br s, 3H), 7.30−7.21 (m, 2H), 3.98 (br t,
J = 7.6 Hz, 1H), 3.18 (s, 1H), 3.09−2.95 (m, 1H), 2.91 (br s, 1H),
2.86 (br s, 3H), 2.75−2.59 (m, 1H), 2.38−2.22 (m, 1H), 2.00−1.82
(m, 8H), 1.80 (br s, 1H), 1.57−1.37 (m, 2H), 1.26 (br d, J = 9.5 Hz,
1H), 1.00 (d, J = 6.4 Hz, 1H). ESI-MS: m/z 641.18 ([M + H+]).
HPLC: tR = 1.80 min.
N-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)-2-methyl-2-(piperazin-1-yl)propanamideide
(4d, Table 1). A procedure similar to that described in the synthesis
of 4a was used to prepare 4d from 14 and 2-(4-(tert-butoxycarbonyl)-
piperazin-1-yl)-2-methylpropanoic acid. 1H NMR (500 MHz,
DMSO-d6): δ 8.24−8.06 (m, J = 8.2 Hz, 1H), 7.59 (br d, J = 8.5
Hz, 1H), 7.55−7.42 (m, J = 8.2 Hz, 1H), 7.33−7.18 (m, 4H), 4.05−
3.94 (m, 1H), 3.58−3.43 (m, 3H), 3.18 (br s, 1H), 3.08−2.87 (m,
2H), 2.70 (br s, 1H), 2.68−2.60 (m, 3H), 2.42−2.22 (m, 1H), 2.22−
2.01 (m, 1H), 1.99−1.88 (m, 2H), 1.88−1.71 (m, 1H), 1.18 (s, 3H),
1.13 (s, 3H). ESI-MS: m/z 668.32 ([M + H+]). HPLC: tR = 1.92 min.
N-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)-2-methyl-2-morpholinopropanamide (4e,
Table 1). A procedure similar to that described in the synthesis of
3b was used to prepare 4e from 9 and 2-methyl-2-morpholinopro-
1
hydroxytetrahydro-2H-pyran-4-carboxylic acid. H NMR (500 MHz,
DMSO-d6): δ 7.97 (br d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H),
7.52 (br d, J = 8.5 Hz, 1H), 7.34−7.22 (m, 5H), 3.98 (br t, J = 7.5 Hz,
1H), 3.72−3.59 (m, 2H), 3.09−2.97 (m, 1H), 2.93−2.82 (m, 1H),
2.73−2.59 (m, 1H), 2.44−2.24 (m, 1H), 2.02−1.88 (m, 6H), 1.87−
1.73 (m, 1H), 1.47−1.33 (m, 2H), 1.25 (m, 1H). ESI-MS: m/z
642.29 ([M + H+]). HPLC: tR = 2.22 min.
1
panoic acid. H NMR (500 MHz, DMSO-d6): δ 7.96 (br d, J = 8.4
Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.51 (br d, J = 8.4 Hz, 1H), 7.34−
7.20 (m, 5H), 4.14−3.96 (m, 1H), 3.71 (t, J = 4.4 Hz, 3H), 3.07−
2.94 (m, 1H), 2.94−2.81 (m, 1H), 2.65 (br d, J = 16.2 Hz, 1H),
2.46−2.40 (m, 2H), 2.39−2.22 (m, 1H), 2.06 (br dd, J = 13.4, 4.8 Hz,
1H), 2.01−1.90 (m, 2H), 1.80 (br dd, J = 12.5, 7.5 Hz, 1H), 1.36−
1.21 (m, 2H), 1.17 (s, 3H), 1.12 (s, 3H). ESI-MS: m/z 669.14 ([M +
H+]). HPLC: tR = 1.98 min.
2-Acetamido-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-
7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-
cyclopenta[a]naphthalen-3-yl)acetamide (5a, Table 1). A
procedure similar to that described in the synthesis of 3b was used
to prepare 5a from 14 and acetyl glycine. 1H NMR (500 MHz,
DMSO-d6): δ 7.95 (br d, J = 7.4 Hz, 2H), 7.54−7.43 (m, 2H), 7.36−
7.21 (m, 5H), 4.04−3.85 (m, 1H), 3.71 (d, J = 5.7 Hz, 2H), 3.13−
2.93 (m, 1H), 2.92−2.78 (m, 1H), 2.72−2.60 (m, 1H), 2.24 (br dd, J
= 14.4, 7.3 Hz, 1H), 2.10−1.92 (m, 3H), 1.92−1.82 (m, 4H), 1.30
(m, 1H). ESI-MS: m/z 613.28 ([M + H+]). HPLC: tR = 2.10 min.
1-Acetyl-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-
(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-
cyclopenta[a]naphthalen-3-yl)piperidine-4-carboxamide (5b,
Table 1). A procedure similar to that described in the synthesis of 3b
was used to prepare 5b from 14 and 1-acetylpiperidine-4-carboxylic
2-Amino-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)sulfonyl)-7-
(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-
cyclopenta[a]naphthalen-3-yl)-2-methylpropanamide (4a,
Table 1). To a solution of 14 (40 mg, 0.078 mmol), 2-((tert-
butoxycarbonyl)amino)-2-methylpropanoic acid (20.58 mg, 0.101
mmol), HATU (38.5 mg, 0.101 mmol) in DMF (2 mL) was added
triethylamine (32.6 μL, 0.234 mmol). The reaction mixture was
stirred at rt for 3 h before water (10 mL) was added. The resulting
mixture was basified with 1N NaOH solution (3 mL) and extracted
with ethyl acetate (10 × 2 mL), and the combined ethyl acetate
extracts were dried over Na2SO4 and concentrated under rotary
evaporation. The crude material was dissolved in CH2Cl2 (2 mL)
followed by TFA (1.5 mL). The reaction mixture was stirred at rt for
1 h before water (10 mL) was added. The resulting mixture was
extracted with ethyl acetate (10 × 2 mL) and the combined ethyl
acetate extracts were dried over Na2SO4 and concentrated under
rotary evaporation. The crude material was purified by preparative
HPLC [Xbridge C18 19 × 200 mm, 5 μm (Waters Corp.); mobile
phase A: 5:95 MeCN/water with 10 μM ammonium acetate; mobile
phase B: 95:5 MeCN/water with 10 mΜ ammonium acetate; flow
rate 20 mL/min; gradient: 29−69% B over 20 min, then a 4-min hold
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acid. 1H NMR (500 MHz, DMSO-d6): δ 8.07 (br d, J = 7.9 Hz, 1H),
7.52−7.43 (m, 2H), 7.35 (s, 1H), 7.28 (br d, J = 7.0 Hz, 4H), 4.36 (br
d, J = 11.0 Hz, 1H), 3.96−3.87 (m, 1H), 3.83 (br d, J = 11.6 Hz, 1H),
3.08−2.96 (m, 2H), 2.81 (br d, J = 6.4 Hz, 1H), 2.65 (br d, J = 15.6
Hz, 1H), 2.48−2.34 (m, 1H), 2.29−2.11 (m, 1H), 2.07−1.90 (m,
6H), 1.84−1.64 (m, 3H), 1.52 (br d, J = 12.2 Hz, 1H), 1.38 (br d, J =
11.9 Hz, 1H), 1.24 (m, 1H). ESI-MS: m/z 667.55 ([M + H+]).
HPLC: tR = 2.15 min.
(S)-1-(2-Cyanoethyl)-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)-
sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-
1H-cyclopenta[a]naphthalen-3-yl)-5-oxopyrrolidine-2-carbox-
amide (5c, Table 1). A procedure similar to that described in the
synthesis of 3b was used to prepare 5c from 14 and (S)-1-(2-
cyanoethyl)-5-oxopyrrolidine-2-carboxylic acid.25 1H NMR (500
MHz, DMSO-d6): δ 8.55 (br d, J = 7.6 Hz, 1H), 7.50−7.39 (m,
2H), 7.34 (s, 1H), 7.25 (d, J = 7.0 Hz, 4H), 4.27 (br dd, J = 7.5, 3.2
Hz, 1H), 4.01−3.91 (m, 1H), 3.81−3.63 (m, 1H), 3.50 (br d, J = 8.5
Hz, 1H), 3.17 (d, J = 5.2 Hz, 1H), 3.03 (br dd, J = 13.6, 6.6 Hz, 2H),
2.90 (br d, J = 8.9 Hz, 1H), 2.81−2.70 (m, 2H), 2.65 (br d, J = 15.9
Hz, 1H), 2.41−2.20 (m, 4H), 2.08 (br dd, J = 13.6, 5.6 Hz, 1H),
2.03−1.94 (m, 2H), 1.93−1.80 (m, 2H), 1.25 (br d, J = 10.1 Hz, 1H).
ESI-MS: m/z 678.45 ([M + H+]). HPLC: tR = 2.15 min.
(2S,4R)-4-Fluoro-N-((3R,3aS,9bS)-9b-((4-fluorophenyl)-
sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-
1H-cyclopenta[a]naphthalen-3-yl)-1-(methyl-d3)-5-oxopyrroli-
dine-2-carboxamide (5d, Table 1). A procedure similar to that
described in the synthesis of 3b was used to prepare 5d from 14 and
1125 (Scheme 1). 1H NMR (500 MHz, DMSO-d6): δ 8.73 (br d, J =
7.6 Hz, 1H), 7.51−7.37 (m, 2H), 7.34 (br s, 1H), 7.25 (br d, J = 7.0
Hz, 4H), 5.29 (t, J = 7.6 Hz, 1H), 5.18 (t, J = 7.5 Hz, 1H), 4.21 (br d,
J = 8.5 Hz, 1H), 4.06−3.91 (m, 1H), 3.17 (s, 1H), 3.03 (td, J = 7.2,
4.3 Hz, 1H), 2.92−2.76 (m, 1H), 2.73−2.59 (m, 1H), 2.48−2.32 (m,
1H), 2.32−2.18 (m, 1H), 2.10−1.95 (m, 3H), 1.95−1.84 (m, 2H),
1.24 (m, 1H). ESI-MS: m/z 659.96 ([M + H+]). HPLC: tR = 2.20
min.
(2S,4R)-N-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-
(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-
cyclopenta[a]naphthalen-3-yl)-4-hydroxy-1-(methyl-d3)-5-ox-
opyrrolidine-2-carboxamide (5e, Table 1). A procedure similar
to that described in the synthesis of 3b was used to prepare 5e from
14 and (2S,4R)-4-hydroxy-1-(methyl-d3)-5-oxopyrrolidine-2-carbox-
ylic acid.25 1H NMR (500 MHz, DMSO-d6): δ 8.56 (br d, J = 7.6 Hz,
1H), 7.52−7.40 (m, 2H), 7.35 (s, 1H), 7.27 (br d, J = 6.7 Hz, 3H),
4.21 (m, 1H), 4.06 (br d, J = 7.9 Hz, 1H), 4.00−3.92 (m, 1H), 3.09−
2.96 (m, 1H), 2.92−2.84 (m, 2H), 2.74 (s, 1H), 2.66 (br d, J = 15.0
Hz, 1H), 2.30−2.11 (m, 2H), 2.07−1.85 (m, 4H), 1.26 (m, 1H). ESI-
MS: m/z 658.10 ([M + H+]). HPLC: tR = 2.12 min.
carboxamide (6c, Table 1). A procedure similar to that described in
the synthesis of 3b was used to prepare 6c from 14 and 4-hydroxy-1-
(methylsulfonyl)piperidine-4-carboxylic acid, HCl. 1H NMR (500
MHz, DMSO-d6): δ 8.04 (br d, J = 8.2 Hz, 1H), 7.59 (d, J = 8.5 Hz,
1H), 7.52 (br d, J = 8.2 Hz, 1H), 7.35−7.23 (m, 5H), 4.04−3.94 (m,
1H), 3.90 (s, 1H), 3.46 (br s, 1H), 3.05−2.87 (m, 6H), 2.65 (br d, J =
15.9 Hz, 1H), 2.38−2.23 (m, 1H), 2.02−1.82 (m, 6H), 1.70−1.57
(m, 2H), 1.37−1.20 (m, 1H). ESI-MS: m/z 719.47 ([M + H+]).
HPLC: tR = 2.2 min.
N-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-
Dioxide (6d, Table 1). A procedure similar to that described in the
synthesis of 3b was used to prepare 6d from 14 and tetrahydro-2H-
thiopyran-4-carboxylic acid 1,1-dioxide. 1H NMR (500 MHz, DMSO-
d6): δ 8.23 (br d, J = 7.6 Hz, 1H), 7.52−7.40 (m, 2H), 7.33 (s, 1H),
7.25 (br d, J = 6.1 Hz, 4H), 4.04−3.85 (m, 1H), 3.62 (m, 1H), 3.19−
3.08 (m, 4H), 3.01 (td, J = 7.1, 4.1 Hz, 1H), 2.82 (br d, J = 6.7 Hz,
1H), 2.70−2.58 (m, 1H), 2.29−2.19 (m, 1H), 2.17−2.10 (m, 1H),
2.10−1.90 (m, 6H), 1.87−1.68 (m, 1H), 1.22 (s, 2H), 1.00 (d, J = 6.4
Hz, 1H). ESI-MS: m/z 674.03 ([M + H+]). HPLC: tR = 2.14 min.
N-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)-4-hydroxytetrahydro-2H-thiopyran-4-car-
boxamide 1,1-Dioxide (6e, Table 1). A procedure similar to that
described in the synthesis of 3b was used to prepare 6e from 14 and
4-hydroxytetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide. 1H
NMR (500 MHz, DMSO-d6): δ 8.14 (br d, J = 8.2 Hz, 1H), 7.63−
7.56 (m, J = 8.5 Hz, 1H), 7.56−7.49 (m, J = 8.5 Hz, 1H), 7.36−7.23
(m, 5H), 3.99 (br t, J = 7.5 Hz, 1H), 3.11−2.99 (m, 3H), 2.93 (br d, J
= 9.2 Hz, 1H), 2.76−2.59 (m, 1H), 2.48−2.27 (m, 3H), 2.05−1.83
(m, 6H), 1.26 (br d, J = 9.8 Hz, 1H). ESI-MS: m/z 690.43 ([M +
H+]). HPLC: tR = 2.15 min.
(1R,4r)-4-(((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-
(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-
cyclopenta[a]naphthalen-3-yl)carbamoyl)cyclohexane-1-car-
boxylic Acid (6f, Table 1). A procedure similar to that described in
the synthesis of 3b was used to prepare 6f from 14 and (1r,4r)-
cyclohexane-1,4-dicarboxylic acid. 1H NMR (500 MHz, DMSO-d6): δ
8.01 (br d, J = 7.9 Hz, 1H), 7.47 (s, 2H), 7.33 (s, 1H), 7.31−7.23 (m,
4H), 3.89 (br t, J = 7.6 Hz, 1H), 3.75−3.54 (m, 2H), 3.00 (br dd, J =
13.0, 5.6 Hz, 1H), 2.79 (br d, J = 6.1 Hz, 1H), 2.70−2.58 (m, 1H),
2.24−2.08 (m, 3H), 2.06−1.89 (m, 5H), 1.86−1.66 (m, 3H), 1.42−
1.20 (m, 5H). ESI-MS: m/z 668.07 ([M + H+]). HPLC: tR = 1.93
min.
1-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)-3-methylurea (7a, Table 1). To a solution of
14 (70 mg, 0.136 mmol) in CH2Cl2 (3 mL) was added phosgene (79
μL, 0.150 mmol) at 0 °C followed by triethylamine (76 μL, 0.545
mmol) and stirred at 0 °C for 0.5 h, and then warmed to rt for 0.5 h.
The solution was removed on the rotavapor, and the solid was
dissolved in CH2Cl2 (2 mL) followed by the addition of methenamine
(6.35 mg, 0.205 mmol), triethylamine (76 μL, 0.545 mmol), and
stirred at rt for 2 h. The reaction mixture was diluted with water, sat
NaHCO3 solution, and extracted with EtOAc. The organic layer was
collected and concentrated on a rotavapor to give the crude product,
which was then purified by preparative HPLC [Xbridge C18 19 × 200
mm, 5 μm (Waters Corp.); mobile phase A: 5:95 MeCN/water with
10 mΜ ammonium acetate; mobile phase B: 95:5 MeCN/water with
10 mΜ ammonium acetate; flow rate 20 mL/min; gradient:
increasing B, then isocratic at 100% B] to give 7a (18.5 mg, 24%
yield). 1H NMR (500 MHz, DMSO-d6): δ 7.52−7.40 (m, 2H), 7.34−
7.18 (m, 4H), 6.12 (br d, J = 8.2 Hz, 1H), 5.72 (br d, J = 3 9 Hz, 1H),
3.93−3.73 (m, 1H), 3.00 (br dd, J = 13.7, 6.8 Hz, 1H), 2.73−2.60 (m,
2H), 2.27−2.10 (m, 1H), 2.08−2.00 (m, 3H), 1.95 (br d, J = 8.6 Hz,
1H), 1.77−1.67 (m, 1H), 1.34−1.15 (m, 2H). ESI-MS: m/z 571.21
([M + H+]). HPLC: tR = 2.13 min.
N-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)methanesulfonamide (6a, Table 1). A proce-
dure similar to that described in the synthesis of 3a was used to
1
prepare 6a from 14 and methanesulfonyl chloride. H NMR (500
MHz, DMSO-d6): δ 7.53−7.41 (m, 3H), 7.38−7.25 (m, 4H), 3.52 (br
s, 1H), 3.18 (d, J = 4.9 Hz, 1H), 3.00 (br dd, J = 13.9, 7.2 Hz, 1H),
2.92 (s, 3H), 2.86−2.74 (m, 1H), 2.70−2.59 (m, 1H), 2.20−2.02 (m,
3H), 1.96−1.79 (m, 1H), 1.43−1.23 (m, 1H). ESI-MS: m/z 592.02
([M + H+]). HPLC: tR = 2.21 min.
N-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)-2-sulfamoylacetamide (6b, Table 1). A
procedure similar to that described in the synthesis of 3b was used
1
to prepare 6b from 14 and 2-sulfamoylacetic acid. H NMR (500
MHz, DMSO-d6): δ 8.49 (br d, J = 7.9 Hz, 1H), 7.51−7.37 (m, 2H),
7.34 (s, 1H), 7.30−7.21 (m, 4H), 4.03−3.87 (m, 2H), 3.81−3.62 (m,
2H), 3.03 (br dd, J = 14.8, 6.3 Hz, 1H), 2.81 (br d, J = 6.4 Hz, 1H),
2.63 (br d, J = 15.9 Hz, 1H), 2.32−2.18 (m, 1H), 2.12−2.02 (m, 1H),
2.02−1.94 (m, 2H), 1.86 (br dd, J = 10.5, 8.1 Hz, 1H), 1.32−1.16 (m,
1H). ESI-MS: m/z 634.88 ([M + H+]). HPLC: tR = 1.99 min.
N-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)-4-hydroxy-1-(methylsulfonyl)piperidine-4-
1-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)-3-(2-hydroxyethyl)urea (7b, Table 1). A
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pubs.acs.org/jmc
Article
procedure similar to that described in the synthesis of 7a was used to
prepare 7b from 14, phosgene, and 2-aminoethan-1-ol. 1H NMR (500
MHz, DMSO-d6): δ 7.46 (s, 2H), 7.34−7.19 (m, 5H), 6.23 (br d, J =
8.2 Hz, 1H), 5.87 (br t, J = 5.1 Hz, 1H), 3.95−3.79 (m, 1H), 3.51−
3.45 (m, 14H), 3.43 (br s, 1H), 3.09 (q, J = 5.6 Hz, 2H), 3.01 (br dd,
J = 13.7, 6.3 Hz, 1H), 2.72−2.59 (m, 2H), 2.18 (dt, J = 11.1, 7.2 Hz,
1H), 2.09−1.99 (m, 2H), 1.96 (br d, J = 4.9 Hz, 1H), 1.82−1.67 (m,
1H), 1.36−1.18 (m, 2H). ESI-MS: m/z 601.19 ([M + H+]). HPLC:
tR = 2.02 min.
United States; orcid.org/0000-0003-0738-1021;
Phone: 609-252-4158; Email: murali.dhar@bms.com
Authors
Myra Beaudoin-Bertrand − Research and Early Development,
Bristol Myers Squibb Company, Princeton, New Jersey
08543-4000, United States
Zili Xiao − Research and Early Development, Bristol Myers
Squibb Company, Princeton, New Jersey 08543-4000, United
States
David Marcoux − Research and Early Development, Bristol
Myers Squibb Company, Princeton, New Jersey 08543-4000,
United States; orcid.org/0000-0002-0295-7717
Carolyn A. Weigelt − Research and Early Development,
Bristol Myers Squibb Company, Princeton, New Jersey
08543-4000, United States
Shiuhang Yip − Research and Early Development, Bristol
Myers Squibb Company, Princeton, New Jersey 08543-4000,
United States
Dauh-Rurng Wu − Research and Early Development, Bristol
Myers Squibb Company, Princeton, New Jersey 08543-4000,
United States
Max Ruzanov − Research and Early Development, Bristol
Myers Squibb Company, Princeton, New Jersey 08543-4000,
United States
John S. Sack − Research and Early Development, Bristol Myers
Squibb Company, Princeton, New Jersey 08543-4000, United
States
Jinhong Wang − Research and Early Development, Bristol
Myers Squibb Company, Princeton, New Jersey 08543-4000,
United States
Melissa Yarde − Research and Early Development, Bristol
Myers Squibb Company, Princeton, New Jersey 08543-4000,
United States
Sha Li − Research and Early Development, Bristol Myers
Squibb Company, Princeton, New Jersey 08543-4000, United
States
David J. Shuster − Research and Early Development, Bristol
Myers Squibb Company, Princeton, New Jersey 08543-4000,
United States
Jenny H. Xie − Research and Early Development, Bristol
Myers Squibb Company, Princeton, New Jersey 08543-4000,
United States
Tara Sherry − Research and Early Development, Bristol Myers
Squibb Company, Princeton, New Jersey 08543-4000, United
States
Mary T. Obermeier − Research and Early Development,
Bristol Myers Squibb Company, Princeton, New Jersey
08543-4000, United States
Aberra Fura − Research and Early Development, Bristol Myers
Squibb Company, Princeton, New Jersey 08543-4000, United
States
1-((3R,3aS,9bS)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoro-
propan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]-
naphthalen-3-yl)-3-(2-hydroxy-2-methylpropyl)urea (7c,
Table 1). A procedure similar to that described in the synthesis of
7a was used to prepare 7c from 14, phosgene, and 1-amino-2-
1
methylpropan-2-ol. H NMR (500 MHz, DMSO-d6): δ 7.51−7.44
(m, 2H), 7.33 (s, 1H), 7.30−7.23 (m, 4H), 6.38 (br d, J = 8.5 Hz,
1H), 5.88 (br t, J = 5.6 Hz, 1H), 4.54 (s, 1H), 3.90−3.79 (m, 1H),
3.48 (br d, J = 5.5 Hz, 1H), 3.05−2.89 (m, 3H), 2.70−2.59 (m, 2H),
2.24−2.13 (m, 1H), 2.09−1.90 (m, 3H), 1.74 (br dd, J = 10.2, 8.1 Hz,
1H), 1.27 (br d, J = 10.7 Hz, 1H), 1.05 (s, 6H). ESI-MS: m/z 629.17
([M + H+]). HPLC: tR = 2.16 min.
2-Hydroxy-2-methylpropyl ((3R,3aS,9bS)-9b-((4-
Fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-
2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-3-yl)-
carbamate (7d, Table 1). A procedure similar to that described in
the synthesis of 7a was used to prepare 7d from 14, phosgene, and 2-
1
methylpropane-1,2-diol. H NMR (500 MHz, DMSO-d6): δ 7.55−
7.47 (m, 2H), 7.43 (br d, J = 7.6 Hz, 1H), 7.37−7.25 (m, 5H), 3.75
(s, 2H), 3.72−3.54 (m, 1H), 3.08−2.93 (m, 1H), 2.85 (br d, J = 6.7
Hz, 1H), 2.73−2.59 (m, 1H), 2.21 (ddd, J = 14.3, 11.0, 7.0 Hz, 1H),
2.06−1.91 (m, 3H), 1.87−1.76 (m, 1H), 1.35−1.19 (m, 2H), 1.12 (s,
6H). ESI-MS: m/z 630.25 ([M + H+]). HPLC: tR = 2.29 min.
Biological Methods. All procedures involving animals were
reviewed and approved by the Institutional Animal Care and Use
Committee and conformed to the “Guide for the Care and Use of
Laboratory Animals” published by the National Institutes of Health
(NIH publication no. 85−23, revised 2011). Detailed biological
experimental procedures, animal studies, and assay conditions used in
this study can be found in our recent publications, refs 20. and 21.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01992.
■
sı
Molecular formula strings (CSV)
SMILES representation of compounds with key data;
PDB ID 7KQJ for compound 3d, analytic experimental
HPLC methods; synthesis of compound 5d; synthetic
procedures and analytical data of 8−14; synthesis of
intermediates 16, 21, and compounds 3−7; HPLC
traces of compound 3d; biological experimental
procedures of the RORγt Gal4 Luc reporter gene
assay, RORγt hWB IL17 assay protocol, and RORγt
mouse whole blood IL17 assay protocol; and in vivo
experimental protocols of the IMQ-induced model of
skin inflammation and IL23-induced mouse model of
acanthosis (PDF)
Kevin Stefanski − Research and Early Development, Bristol
Myers Squibb Company, Princeton, New Jersey 08543-4000,
United States
Georgia Cornelius − Research and Early Development, Bristol
Myers Squibb Company, Princeton, New Jersey 08543-4000,
United States
Purnima Khandelwal − Research and Early Development,
Bristol Myers Squibb Company, Princeton, New Jersey
08543-4000, United States
AUTHOR INFORMATION
Corresponding Authors
■
Michael G. Yang − Research and Early Development, Bristol
Myers Squibb Company, Princeton, New Jersey 08543-4000,
United States; orcid.org/0000-0003-2908-4060;
Phone: 609-252-3234; Email: michael.yang@bms.com
T. G. Murali Dhar − Research and Early Development, Bristol
Myers Squibb Company, Princeton, New Jersey 08543-4000,
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pubs.acs.org/jmc
Article
transcription factor RORγt generates all human innate lymphoid cell
subsets. Immunity 2016, 44, 1140−1150.
Ananta Karmakar − Department of Discovery Synthesis,
Biocon Bristol-Myers Squibb Research Centre, Bengaluru
560099, India; orcid.org/0000-0003-3795-5807
Mushkin Basha − Department of Discovery Synthesis, Biocon
Bristol-Myers Squibb Research Centre, Bengaluru 560099,
India
Venkatesh Babu − Department of Discovery Synthesis, Biocon
Bristol-Myers Squibb Research Centre, Bengaluru 560099,
India
Arun Kumar Gupta − Department of Discovery Synthesis,
Biocon Bristol-Myers Squibb Research Centre, Bengaluru
560099, India
Arvind Mathur − Research and Early Development, Bristol
Myers Squibb Company, Princeton, New Jersey 08543-4000,
United States
Luisa Salter-Cid − Research and Early Development, Bristol
Myers Squibb Company, Princeton, New Jersey 08543-4000,
United States
Rex Denton − Research and Early Development, Bristol Myers
Squibb Company, Princeton, New Jersey 08543-4000, United
States
Qihong Zhao − Research and Early Development, Bristol
Myers Squibb Company, Princeton, New Jersey 08543-4000,
United States
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jmedchem.0c01992
Notes
The authors declare no competing financial interest.
(8) Leonardi, C.; Matheson, R.; Zachariae, C.; Cameron, G.; Li, L.;
Edson-Heredia, E.; Braun, D.; Banerjee, S. Anti-Interleukin-17
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ACKNOWLEDGMENTS
■
The authors would like to thank Qingjie Liu for providing
intermediate 11 and Douglas Batt for thorough review of the
manuscript.
ABBREVIATIONS
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Neufert, C.; Pouly, S.; Murphy, A. J.; Valenzuela, D. M.; Yancopoulos,
G. D.; Becher, B.; Littman, D. R.; Neurath, M. F. RORgamma-
expressing Th17 cells induce murine chronic intestinal inflammation
via redundant effects of IL-17A and IL-17F. Gastroenterology 2009,
136, 257−267.
■
AUC, area under the curve; bid, twice a day; Boc,
butyloxycarbonyl; CL, clearance; compd, compound; F,
bioavailability; hWB, human whole blood; IL, interleukin;
KO, knock-out; LM, liver microsome; MetStab, metabolic
stability; PD, pharmacodynamics; PK, pharmacokinetic; ROR,
retinoid-related orphan receptor; SAR, structure activity
relationship; SFC, supercritical fluid chromatography; Th17,
T helper 17 cells; THF, tetrahydrofuran; Vss, volume of
distribution
(11) Korn, T.; Bettelli, E.; Oukka, M.; Kuchroo, V. K. IL-17 and
Th17 Cells. Annu. Rev. Immunol. 2009, 27, 485−517.
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M.; Griffiths, A.; Dassopoulos, T.; Bitton, A.; Yang, H.; Targan, S.;
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K.; Barmada, M. M.; Rotter, J. I.; Nicolae, D. L.; Cho, J. H. A genome-
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J. Med. Chem. 2021, 64, 2714−2724

Journal of Medicinal Chemistry
pubs.acs.org/jmc
Article
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(24) Metabolic stability is defined as the percentage of parent
compound remaining over 10 min of incubation time in the presence
of human, rat and mouse liver microsomes, respectively. The initial
compound concentration was 0.5 μM; protein concentration 1 mg/
mL.
(25) The synthetic procedures and analytical data of 8−14 (Scheme
1) are described in the following patent: Marcoux, D.; Bertrand, M.
B.; Dhar, T. G. M.; Yang, M. G.; Xiao, Z.; Xiao, H. T.; Zhu, Y.;
Weigelt, C. A.; Batt, D. G. Tricyclic sulfones as ROR gamma
modulators. U.S. Patent 10,435,369 B2.
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https://dx.doi.org/10.1021/acs.jmedchem.0c01992
J. Med. Chem. 2021, 64, 2714−2724