Discovery and optimization of novel constrained pyrrolopyridone BET family inhibitors

Article abstract of DOI:10.1016/j.bmcl.2018.04.020

Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin

Full text of DOI:10.1016/j.bmcl.2018.04.020

Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery and optimization of novel constrained pyrrolopyridone BET
family inhibitors
Steven D. Fidanze a, ,b, Dachun Liu a, ,b, Robert A. Mantei a, Lisa A. Hasvold a, John K. Pratt a,
George S. Sheppard a, Le Wang a, James H. Holms a, Yujia Dai a, Ana Aguirre a, Andrew Bogdan a,
Justin D. Dietrich a, Jasmina Marjanovic a, Chang H. Park a,c, Charles W. Hutchins a, Xiaoyu Lin a, Mai H. Bui a,
⇑
⇑
Xiaoli Huang a, Denise Wilcox a, Leiming Li a, Rongqi Wang a, Peter Kovar a, Terrance J. Magoc a,c
Ganesh Rajaraman a,c, Daniel H. Albert a, Yu Shen a, Warren M. Kati a, Keith F. McDaniel a
,
a AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors
were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7
(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated
excellent activity in binding and cellular assays, and lead compounds from each series demonstrated sig-
nificant efficacy in in vivo tumor xenograft models.
Received 31 October 2017
Revised 5 April 2018
Accepted 10 April 2018
Available online xxxx
Ó 2018 Published by Elsevier Ltd.
Reversible lysine acetylation plays a central role in regulating
gene transcription. Acetylated lysines are recognized by conserved
protein structural folds known as bromodomains. 1 The BET family
is a subset of related bromodomain-containing proteins that
includes BRD2, BRD3, BRD4, and BRDT. BET family members con-
tain two N-terminal tandem bromodomains (BDI and BDII), as well
as a C-terminal extra terminal (ET) domain and interact with other
proteins to activate transcription of proximal genes into RNA.2 In
recent years, inhibitors of BET family proteins have received much
interest as potential therapeutics against several types of
malignancies.3
Studies performed at several academic and industrial sites have
resulted in the discovery of a variety of structurally diverse BET
family inhibitors. Several of these compounds have entered clinical
studies for oncology indications. OTX015/MK-8628 (1), I-BET762
(2), and CPI-0610 (3) share many structural similarities with the
probe compound JQ-1 (4).4–6 Recently, the structurally distinct
inhibitor ABBV-075 (mivebresib)7,8 (5) has also entered into clini-
cal trials (Fig. 1).9 This compound is characterized by the novel
4-substituted 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one struc-
tural motif,10,11 (designated as the N-methyl pyridone core in
Fig. 1), one of the most potent BET inhibitor cores generated to
date. In the course of medicinal chemistry efforts leading to the
discovery of mivebresib, several other modifications of the
pyrrolopyridone motif were also examined, including 3-substi-
tuted 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (designated
as the N-methyl pyrrole core, Fig. 1).12 This manuscript describes
the optimization of each of these cores via the incorporation of
conformationally constrained ring systems to generate BET inhibi-
tors with substantially improved potency.
Both variants of the pyrrolopyridone core exhibited strong
binding to the BET family, and share similar interactions with
BRD4. This similarity in binding can be noted by examination of
X-ray co-crystallography structures of representative compounds
6 (PDB code: 5UVS, N-methyl pyridone core) and 7 (PDB code:
5UEO, N-methyl pyrrole core) in BRD4 BDII. There are four key
interactions which together provide optimal activity. First, each
core forms a bidentate interaction with the side chain amide of
ASN 433 (Figs. 2a and 3a). In compound 6, this interaction is medi-
ated by the carbonyl of the pyridone and the NH of the pyrrole. In
compound 7, these hydrogen bonds are formed by the amide of the
pyridone. Second, each core also contains a methyl group that
resides in an amphoteric water pocket, as is common for many
BET inhibitors.13 Third, a hydrophobic group, a cyclopropylmethyl
moiety in the case of compound 6 and a difluorophenyl ring as in
mivebresib in the case of compound 7, lies in a pocket conserved
throughout the BET family which is defined by the WPF shelf.14
Finally, the sulfone substituent of 6 and the sulfonamide of 7 each
form a key hydrogen bond to the backbone NH of ASP 381.
⇑
Corresponding authors.
E-mail addresses: steve.fidanze@abbvie.com (S.D. Fidanze), dachun.liu@abbvie.
com (D. Liu).
b
These authors contributed equally to this work.
Former Abbvie employee.
c
https://doi.org/10.1016/j.bmcl.2018.04.020
0960-894X/Ó 2018 Published by Elsevier Ltd.
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2
S.D. Fidanze et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Fig. 1. Examples of BET Family Inhibitors.
Fig. 2. a: X-ray Co-crystal Structure of 6 with BRD4 BDII. b: Overlay of 6 with a modelled constrained compound.
Fig. 3. a: X-ray Co-crystal Structure of 7 with BRD4 BDII. b: Overlay of 7 with a modelled constrained compound.
For both cores, the biaryl bond between the core and the phenyl
potency. The use of pre-organization in medicinal chemistry opti-
mization, presumably to minimize entropic considerations for
binding, is well precedented,15 although practical application of
conformational constraints can be challenging.16
In order to quickly examine this hypothesis, preparation of con-
formationally constrained seven-membered ring analogs of both
cores were generated readily in a single synthetic step from uncy-
clized analogs by reaction with paraformaldehyde and hydrochlo-
ric acid. Initial characterization of novel compounds was
performed using three key assays. The first assay was a TR-FRET-
group is free to rotate prior to binding to the protein. Examination
of the co-crystal structures of 6 and 7 suggested that a conforma-
tional constraint might provide improved potency (Figs. 2b and
3b, green structures). Specifically, molecular modeling indicated
that restricting rotation around the above mentioned biaryl bond
with the incorporation of a bridging methylene group to form a
seven-membered ring would pre-organize the hydrophobic group
bound in the WPF pocket in the desired conformation. Thus,
cyclization of each core was expected to provide improved
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S.D. Fidanze et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
3
based binding assay to determine binding of the compound to
BRD4. The second assay was a cellular proliferation assay using
an MX-1 breast cancer cell line. The third assay was a positive
readout BRD4 engagement assay in H1299 cells to establish on-tar-
get cellular activity of compounds.17
As hypothesized, incorporation of conformational constraints
provided increased potency in both cores (Table 1). For example,
conformational restriction of the N-methyl pyridone core, exempli-
fied by the cyclization of aniline 8 to generate constrained N-
methyl pyridone 9, provided a 42-fold improvement in binding
activity, as well as an 82-fold improvement in cellular target
engagement. Similarly, the corresponding constrained N-methyl
pyrrole 11 showed a 35-fold increase in binding activity, along
with a 52-fold increase in BRD4 engagement when compared to
uncyclized variant 10. Thus, pre-organization of the molecule pro-
vided a clear boost in activity. These two examples are particularly
noteworthy because both lack a moiety required to form a hydro-
gen bond to the backbone NH of ASP 381. In fact, constrained N-
methyl pyridone 9, which incorporates only three of the four bind-
ing motifs required for maximum activity, matches the potency of
non-constrained analog 12, which does contain moieties satisfying
all four binding interactions.
Furthermore, cyclization of N-methyl pyridone 12 to provide 13
demonstrated an 8-fold improvement in binding activity, and a 13-
fold improvement in target engagement. Similarly, cyclization of
N-methyl pyrrole 14 to give 15 provided an 18-fold increase in
binding activity, as well as a 9-fold increase in BRD4 engagement.
Examination of the X-ray co-crystal structure of N-methyl pyri-
done 13 (PDB code: 5UVU) with BRD4 BDII reveals the key interac-
tions leading to the high potency of the compound, as shown in
Fig. 4. The compound retains all four of the key protein interactions
seen in compound 6. The bidentate hydrogen bonds from the core
to ASN 433 are preserved. The methyl group of the pyridone retains
an optimal location in the water network. The methylene group
leading to the sulfone–backbone NH hydrogen bond provides con-
formational flexibility, which appears to allow both the formation
of a strong hydrogen bond to Asp381 and also optimal placement
of the hydrophobic cyclopropylmethyl group in the WPF region.
Fig. 4. X-ray Co-crystal Structure of 13 with BRD4 BDII.
Surprisingly, cyclization of either core with a directly-linked
sulfone binding to ASP 381 (compounds 16 to 17, and 18 to 19)
demonstrated no improvement in activity upon addition of the
conformational constraint. For example, 19, which incorporates a
sulfone directly linked to the aryl ring, shows little difference in
activity compared to the uncyclized variant 18. While conforma-
tionally constrained direct-linked sulfones often exhibited very
good activity, they rarely provided an improvement over their
uncyclized counterparts.
The failure of direct-linked sulfone analogs 17 and 19 to demon-
strate a boost in activity upon formation of the conformationally
constrained seven-membered rings can be explained by the con-
formations adopted in X-ray co-crystals with BRD4 BDII. A compar-
ison of uncyclized compound 6 and cyclized compound 20 (PDB
code: 5UVV) demonstrates many clear similarities between the
two structures (Fig. 5). For both compounds, the key hydrogen
bonds from the pyrrolopyridone core to ASN 433 are preserved.
Both pyridone methyl groups reside in the amphoteric water
pocket. Also, the two cyclopropyl methyl groups are oriented to
occupy the same hydrophobic pocket. Further, both compounds
form hydrogen bonds with the backbone NH of ASP 381. However,
minor differences were observed for interactions between the inhi-
Table 1
Activity in TR-FRET Binding, Proliferation, and BRD4 Engagement Assays of Early Constrained Compounds.
Compound
R
BRD4 TR-FRET (nM)
MX-1 Proliferation (nM)
BRD4 Engagement (nM)
8
9
H
680
16
1400
7.3
1900
23
10
11
1500
43
3300
57
5000
95
12
13
14
15
69
43
58
8.4
220
12
2.0
140
19
4.6
200
23
16
17
18
19
13
26
80
180
17
15
140
140
20
28
150
190
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S.D. Fidanze et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Fig. 5. X-ray Co-crystal Structures of 6 (green) and 20 (blue) with BRD4 BDII.
bitors and the WPF shelf. It appears that the direct-linked sulfone
does not allow as much conformational flexibility of the phenyl
or cyclopropyl rings. Indeed, the phenyl ring of 20 is pulled away
from Pro 375 by approximately 0.6 Å (3.7 vs. 4.3 Å, respectively).
Thus, any improvement in entropic factors by pre-organization
likely has been offset by a loss of hydrophobic binding, resulting
in similar potency between 6 and 20. For both the N-methyl pyri-
done and the N-methyl pyrrole series, the most highly potent com-
pounds typically contained a one atom spacer from the aryl ring to
an SO2 moiety, which forms a hydrogen bond to ASP 381, either
through a methylene sulfone or a sulfonamide.
with higher clearance in mouse liver microsomes, as well as
acceptable permeability. These analogs were advanced into mouse
pharmacokinetic studies. Compounds with alkyl groups in the
hydrophobic WPF shelf, such as 13 and 23, exhibited high clear-
ance resulting in low free exposures (AUCu, po) upon oral dosing.
Aryl substituents generally showed improved clearance and oral
exposure. The potent monofluorophenyl compound 24 had unac-
ceptably high clearance, as well as limited oral exposure. The
2,4-difluorophenyl and 2-pyridyl methylene sulfone analogs 25
and 26, respectively, exhibited lower clearance (Clp,u) and higher
bioavailability (F) which resulted in greatly improved free oral
exposure.
With the methylene sulfone aryl substituent providing optimal
activity for the constrained analogs in both cores, the pocket
defined by the WPF shelf was next explored in this context. The
incorporation of both polar and hydrophobic groups was examined
in this region, and many of these substituents provided extremely
potent inhibitors. In the N-methyl pyridone series, amides and car-
bamates such as 21 and 22, respectively, demonstrated good bind-
ing affinity (Table 2), as well as excellent cellular potency.
Incorporation of a cycloalkyl group, as in 23, also provided strong
binding affinity. Aryl rings in this area were also closely examined.
4-Fluorophenyl analog 24 provided sub-nanomolar activity in the
TR-FRET binding assay, as well as sub-nanomolar to low single
digit nanomolar activity in cell-based assays. 2,4-Difluorophenyl
compound 25 provided subnanomolar binding, albeit with slightly
weaker activity in cellular assays compared to 24. Heteroaryl 2-
pyridine 26 afforded excellent activity across all assays. Changing
the central phenyl ring to a pyridyl group, as in 27, also provided
a highly potent compound. Several of these compounds demon-
strate improved in vitro activity compared to the clinical candidate
5 (mivebresib).
For the N-methyl pyrrole series, a similar pattern was revealed.
Amides and carbamates, such as 28 and 29, respectively, demon-
strated good activity in the TR-FRET assay, but somewhat weaker
activity in cellular assays (Table 2). As was the case with the N-
methyl pyridone series, incorporation of a 4-fluorophenyl sub-
stituent (30) provided further improved activity, particularly in
cellular assays. Use of the 2,4-difluorophenyl moiety in 31 or the
2-pyridyl analog 32 provided excellent TR-FRET and cellular activ-
ities. Changing the R1 substituent from a methylene-linked sulfone
to a sulfonamide (33) also provided excellent binding activity.
However, the R1 sulfonamide combined with the R2 2-pyridyl moi-
ety suffered from a loss in demonstrated on-target cellular activity
in the BRD4 engagement assay compared to the corresponding
methylene sulfone (32 vs. 34). Replacing the central phenyl ring
with a pyridine (33 vs. 35) resulted in a further loss of cellular
activity.
Similarly, microsomal stability and permeability were also suit-
able for several inhibitors in the N-methyl pyrrole series. Again,
there was a trend toward higher clearance in mouse microsomes
compared to human, but both were still in acceptable ranges. Sev-
eral compounds were then advanced to mouse pharmacokinetic
testing. Despite low clearance in mouse and human liver micro-
somes, methylene sulfone 15 showed unacceptably high clearance
in vivo, along with low oral exposure and bioavailability. Methy-
lene sulfone 32, incorporating a pyridyl moiety in the WPF shelf,
showed improved exposure upon oral dosing. Compound 30
demonstrated moderate clearance and higher absorption leading
to acceptable free oral exposure.
Compounds 25, 26 and 30 were further characterized for bind-
ing to a series 24 of bromodomain-containing proteins. Compound
25 showed significant binding to ATAD2a, BRPF1, CREBBP, EP300,
and TAF1. Compound 26 was slightly more selective, with signifi-
cant binding to BRPF1, CREBBP, EP300, and TAF1. The N-methyl-
pyrrole 30 was more selective, with strong binding only to
CREBBP. Selectivity data can be found in the Supporting
Information.
The combination of excellent potency and cellular activity,
along with acceptable pharmacokinetic properties, provided the
opportunity to examine key compounds from each series in
in vivo tumor xenograft studies. N-methylpyridone 26 and N-
methylpyrrole 30 were each tested in an OPM-2 mouse xenograft
model of multiple myeloma and demonstrated dose dependent
activity in this model (Fig. 6). Once daily oral dosing (QD PO) of
tumor bearing mice with compound 26 at 0.625 and 0.313 mg/
kg, respectively, produced dose-effective tumor growth inhibition
(TGI) of 94% and 60%, respectively, when compared with the drug
vehicle treated control group. Similarly, at a QD PO dose of 7.5 mg/
kg, N-methyl pyrrole analog 30 exhibited similar dose-dependent
activity, albeit at higher dose levels (68% and 84% TGI at 3.75 mg/
kg and 7.5 mg/kg, respectively). These results are comparable to
mivebresib.8 The activity shown by both of these compounds
demonstrates their potential as valuable agents for hematology-
based oncology indications.
The excellent activity demonstrated in multiple analogs in both
of these series prompted evaluation of the DMPK properties of a
variety of compounds (Table 3), in preparation for in vivo efficacy
studies. Several N-methyl pyridone analogs (13, 23, 24, 25, 26)
exhibited reasonable clearance in human liver microsomes, albeit
The preparation of compounds from both of these series relied
upon two crucial synthetic transformations. First, a Suzuki cou-
pling reaction was utilized to generate the biaryl linkage between
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S.D. Fidanze et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
5
Table 2
Activity in TR-FRET Binding, Proliferation, and BRD4 Engagement Assays.
Compound
X
R1
R2
BRD4 TR-FRET (nM)
7.1
MX-1 Proliferation (nM)
7.8
BRD4 Engagement (nM)
21
21
CH
22
23
7.3
4.7
4.7
1.4
9.0
3.7
24
25
26
0.87
0.87
0.62
0.72
3.4
1.5
3.6
1.7
1.3
27
28
N
4.1
7.7
7.0
16
4.1
31
CH
29
30
17
78
48
3.3
1.4
2.5
31
32
2.7
2.9
4.0
5.5
6.5
2.3
33
CH
4.8
5.6
4.3
34
35
CH
N
2.7
4.4
4.9
18
18
32
5 (mivebresib)
1.5
13
20
Table 3
ADME and Pharmacokinetic Properties of Selected Compounds.
Compound
In Vitro ADME
Mouse PK (10 mg/kg, PO)
Clint,u (Human, L/Hr/kg)
Clint,u (Mouse, L/Hr/kg)
PAMPA (10À6 cm/s)
Clp,u (L/Hr/kg)
AUC oral (lM*Hr)
F (%)
13
23
24
25
26
15
32**
30
11
4.0
18
16
84
32
4.3
7.3
6.6
13
6.0
2.5
5.9
5.1
27
0.16
0.13
0.67
12
8.2
48
23
93
32
23
ND
34
290
310
45
9.4
44
<2.5
<3.1
3.0
<2.7
3.9
14
3.5*
0.64
1.2
<8.0
8.4
19
ND
78
5.5
2.8
*
Dose normalized. Dosed at 1 mpk.
Not dosed IV, only a PO PK screen.
**
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6
S.D. Fidanze et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Fig. 6. Efficacy of Compound 26 (left) and Compound 30 (right) in a Multiple Myeloma Xenograft (OPM-2) Model.
the N-methylpyridone core or the N-methylpyrrole core and the
biaryl amine or its precursor. Second, an acid-catalyzed cyclization
incorporating formaldehyde generated the critical seven-mem-
bered ring. Syntheses of the key aniline intermediates 40 and 44
common to both cores and required for the key Suzuki reaction
are described in Scheme 1. Starting from the commercially avail-
able benzylic bromide 36, displacement with sodium methyl sulfi-
nate provided the corresponding methylene-linked sulfone 37.
Reduction of the nitro group in 37 provided aniline 38 in good
yield. Subsequent iodination of 38 to generate 39, followed by
reductive amination gave aniline intermediate 40. Similarly, dis-
placement of the benzylic bromide of 41 with sodium methyl sul-
finate provided methylene sulfone 42. Treatment of 42 with a
variety of anilines or heterocyclic amines under Buchwald-Hartwig
arylation conditions provided bis-aryl amines 43 in good yields.
Subsequent bromination afforded the key intermediates 44.
Assembly of the final compounds is described in Scheme 2.
Suzuki coupling of the aryl halides from Scheme 1 with the known
boronate 459 provided compounds 46. Tosylate deprotection under
phase transfer conditions provided compounds 47 in good yield.
The key conformational constraint was then introduced by treat-
ment of anilines 47 with paraformaldehyde under acidic condi-
tions to give the constrained compounds. In the case where R2 =
H, further elaboration by acylation of 48 to provide 21 and 22
was also readily achieved. Compounds in the N-methylpyrrole ser-
ies were prepared in a similar manner. The key cyclization of 49
with paraformaldehyde was successful in providing the com-
pounds in this series.
In conclusion, guided by X-ray co-crystallography of BRD4 BDII
with previously developed inhibitors, two new series of tetracyclic
pyrrolopyridone BET inhibitors were designed and prepared. These
inhibitors demonstrated excellent activity in binding and cellular
assays, which in most cases was superior to their acyclic analogs.
Several compounds demonstrated superior in vitro activity to
mivebresib. Furthermore, several compounds from each series
had acceptable pharmacokinetic properties, and were examined
in in vivo tumor models. Examples from both series demonstrated
excellent activity in these in vivo models, similar to mivebresib,8,9
and provide excellent cores suitable for continued examination as
BET inhibitor templates.
Scheme 1. Synthesis of Common Intermediates. a) MeSO2Na, DMF, 65 °C, 93–95%; b) 5% Pd/C, H2 (30 psi), THF, 50 °C, 88%; c) NIS, DMF, RT, 83%; d) AcOH,
cyclpropanecarbaldehyde, MP-CNBH3, CH2Cl2, MeOH, 50 °C, 66%; e) Ar-NH2, Pd(OAc)2, X-Phos, Cs2CO3, toluene, tert-butanol, microwave 150 °C, 89–94%; f) NBS, AcOH, RT,
81–88%.
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S.D. Fidanze et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
7
Scheme 2. Representative Synthesis of Final Compounds. a) Pd2(dba)3, 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane, Na2CO3, 4:1 dioxane:water, 60 °C,
75–100%; b) n-C16H33(Me3)NBr, KOH, 3:1 dioxane:water, 90 °C, 44–85%; c) paraformaldehyde, 4 N HCl in dioxane, MeOH, 18–99%; d) R3COCl, Et3N, DMA, 34–43%.
Acknowledgments
Supplementary data
This research used resources at the Industrial Macromolecular
Crystallography Association Collaborative Access Team (IMCA-
CAT) beamline 17-ID, supported by the companies of the Industrial
Macromolecular Crystallography Association through a contract
with Hauptman-Woodward Medical Research Institute.
This research used resources of the Advanced Photon Source, a
U.S. Department of Energy (DOE) Office of Science User Facility
operated for the DOE Office of Science by Argonne National Labo-
ratory under Contract No. DE-AC02-06CH11357.
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.bmcl.2018.04.020.
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support for this research were provided by AbbVie. AbbVie partic-
ipated in the interpretation of data, review, and approval of the
publication.
Please cite this article in press as: Fidanze S.D., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.04.020