Discovery of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent and selective PI3Kδ inhibitors

Article abstract of DOI:10.1016/j.bmcl.2017.01.016

As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.

Full text of DOI:10.1016/j.bmcl.2017.01.016

Accepted Manuscript
Discovery of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine
derivatives as highly potent and selective PI3Kδ inhibitors
Lan-Ying Qin, Zheming Ruan, Robert J. Cherney, T.G. Murali Dhar, James
Neels, Carolyn A. Weigelt, John S. Sack, Anurag S. Srivastava, Lyndon A.M.
Cornelius, Joseph A. Tino, Kevin Stefanski, Xiaomei Gu, Jenny Xie, Vojkan
Susulic, Xiaoxia Yang, Melissa Yarde-Chinn, Stacey Skala, Ruth Bosnius,
Christine Goldstein, Paul Davies, Stefan Ruepp, Luisa Salter-Cid, Rajeev S.
Bhide, Michael A. Poss
PII:
S0960-894X(17)30028-8
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.01.016
BMCL 24592
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 December 2016
6 January 2017
7 January 2017
Please cite this article as: Qin, L-Y., Ruan, Z., Cherney, R.J., Murali Dhar, T.G., Neels, J., Weigelt, C.A., Sack, J.S.,
Srivastava, A.S., Cornelius, L.A.M., Tino, J.A., Stefanski, K., Gu, X., Xie, J., Susulic, V., Yang, X., Yarde-Chinn,
M., Skala, S., Bosnius, R., Goldstein, C., Davies, P., Ruepp, S., Salter-Cid, L., Bhide, R.S., Poss, M.A., Discovery
of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent and selective
PI3Kδ inhibitors, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.
2017.01.016
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Discovery of 7-(3-(piperazin-1-
yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-
amine derivatives as highly potent and
selective PI3Kδ inhibitors
Leave this area blank for abstract info.
Lan-Ying Qin, Zheming Ruan, Robert J. Cherney, T. G. Murali Dhar, James Neels, Carolyn A.
Weigelt, John S. Sack, Anurag S. Srivastava, Lyndon A.M. Cornelius, Joseph A. Tino, Kevin
Stefanski, Xiaomei Gu, Jenny Xie, Vojkan Susulic, Xiaoxia Yang, Melissa Yarde-Chinn, Stacey
Skala, Ruth Bosnius, Christine Goldstein, Paul Davies, Stefan Ruepp, Luisa Salter-Cid, Rajeev S.
Bhide, Michael A. Poss

Bioorganic & Medicinal Chemistry Letters
Discovery of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine
derivatives as highly potent and selective PI3Kδ inhibitors
Lan-Ying Qin, Zheming Ruan, Robert J. Cherney, T. G. Murali Dhar, James Neels, Carolyn A. Weigelt,
John S. Sack, Anurag S. Srivastava, Lyndon A. M. Cornelius, Joseph A. Tino, Kevin Stefanski, Xiaomei
Gu, Jenny Xie, Vojkan Susulic, Xiaoxia Yang, Melissa Yarde-Chinn, Stacey Skala, Ruth Bosnius,
Christine Goldstein, Paul Davies, Stefan Ruepp, Luisa Salter-Cid, Rajeev S. Bhide, Michael A. Poss
Bristol-Myers Squibb, Rt. 206 & Province Line Road, Princeton, NJ 08540
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Abstract: As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or
its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of
PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and
Accepted
respiratory ailments.
Herein, we disclose the identification of 7-(3-(piperazin-1-
Available online
yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally
bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse
KLH model.
Keywords:
PI3Kδ
2009 Elsevier Ltd. All rights reserved.
7-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine
Autoimmune diseases
Rheumatoid arthritis
Phosphoinositide 3-kinases
———
 Corresponding author. Tel.: +1-609-252-6374; fax: +1-609-252-3993; e-mail: lan-ying.qin@bms.com

Phosphoinositide 3-kinases (PI3Ks) are lipid kinases that
phosphorylate the 3-hydroxyl position of the inositol ring of
phosphatidylinositol (PI) substrate within the plasma membrane
and intracellular compartments. Phosphoinositide 3-kinases are
divided into two classes: class IA and class IB. PI3K class IA
includes PI3Kα, PI3Kβ and PI3Kδ, and PI3K class IB includes
PI3Kγ. PI3Kα and PI3Kβ are both involved in insulin signaling.
PI3Kα also protects the heart against myocardial infarction-
induced heart failure and PI3Kβ functions in platelet activation.
PI3Kδ is involved in early signaling events of leukocytes
responding to a wide variety of stimuli. Its expression is mainly
in leukocytes, and its signaling function is via the production of
phosphoinositide 3,4,5-triphosphate at the proximity of activated
receptors for recruiting other signaling molecules.1-3 PI3Kδ is the
main PI3K isoform responsible for B cell development and
activation. It is also responsible for T cell differentiation,
activation and function. PI3Kγ takes over only some B cell
functions in the absence of PI3Kδ.3-5 Therefore, PI3Ks are
preferentially studied to potentially provide new cures for various
diseases mediated by one or more PI3K isoforms. Many non-
specific PI3K inhibitors have been reported.6-13 Recently, the
search for selective inhibitors of PI3K isoforms has been
increased. Mechanistically, PI3Kδ plays a critical role in
mediating immune cell function that makes it a research priority
in the search for treatments for autoimmune diseases and B-Cell
malignacies.14-18 Inhibition of PI3Kδ leads to a decrease of
immune responses which has been validated in animal disease
models for rheumatoid arthritis (RA) and systemic lupus
erythematosus (SLE).19-21 The study of PI3Kδ mRNA and protein
expression levels in RA patients also provides solid evidence that
selective inhibition of PI3Kδ may result in potential treatments
for inflammatory diseases.22 However, recent articles also
describe situations where inhibition of PI3Kδ can activate the
immune system.23 There are some reports about relatively potent
and selective PI3Kδ inhibitors,24-31 but it still remains a
significant challenge to identify a PI3Kδ inhibitor that is both
highly potent and selective against all other PI3K isoforms.
Described herein is our efforts to identify a potent and selective
PI3Kδ inhibitor.
In our previous report, compound I (Figure 1) was efficacious at
30 mg/kg in a mouse collagen induced arthritis model.32
However, the compound showed acute toxicity in an exploratory
tox study in mice at 300 mg/kg/day dose. Therefore, finding a
replacement of I became our mission.
PI3Kδ (IC50) = 2 nM
Selectivity:
δ/α = 665; δ/γ = 130; δ/β = 800
CD86 WB (IC50) = 118 nM
hERG (Patch clamp) = 65% @ 10 µM
Na+(Patch clamp) = 17% @ 10 µM (1Hz)
Microsomal stability in mouse:
58% remaining @ 0.5µM 10 min. incubation
Figure 1. Profile of Compound I

Computational modeling of our HTS hit in PI3Kδ (Figure 2),
suggested two important binding interactions, one between C4-
NH2 and Glu826 on the hinge, and the other between N-3 of the
triazine ring and Val828. When bound in this manner, the
cyclohexyl ring sits next to the gatekeeper residue, Ile825.
tetrahydropyran at N-1 of the C-5 pyrazole resulted in both
improved selectivity against other PI3K isoforms and improved
metabolic stability.32 Based on these results, continued C-7
optimization was conducted with 4-tetrahydropyran on the C-5
pyrazole. Compared to the HTS hit, compounds 1 and 4-6
(Table 1), which incorporated a piperazinyl moiety at the meta
position on the pyridine ring, exhibited better δ activity and
improved selectivity against the other PI3K isoforms. In addition,
when the pyridine moiety was replaced by a phenyl ring (2 and 7-
9), the resultant compounds were equipotent (<5 nM) with the
pyridine derivatives (1 and 4-6), but were more selective against
the α and γ isoforms. As indicated in Table 1, PI3Kβ selectivity
was generally not an issue for this chemotype. Substitution on N-
1 of the C-5 pyrazole ring was then investigated (Table 2). Here,
the data suggested that the steric and electronic effects of the R
group did not have a significant impact on PI3Kδ enzyme
potency and selectivity, although the 4-tetrahydropyran (9)
provided better cellular potency than the other R groups that were
studied.
Figure 2. The computational model of HTS hit in PI3Kδ
Table 1. Initial optimization
B-cell
selectivity
PI3Kδ
IC50
(nM)
CD86/C69
WB IC50
(nM)b
prolif
IC50
(nM)a
R
δ vs.α
δ vs.γ
δ vs.β
10
11
2.5
5.0
66
37
25
1017
-
681/-
422/-
selectivity
PI3K δ
134
136
1001
755
26
R
X
N
IC50 (nM)a
δ vs. α
δ vs. γ
δ vs. β
12
1
H
1.8
47
6
338
6.6
27
-
-/1208
4
5
N
N
4.7
0.8
39
72
10
6
184
13
9
5.5
2.4
134
73
25
22
914
17
-/143
1323
6
2
N
C
5.2
5.0
46
70
10
23
1778
129
1247
2.2
66/4.0
H
7
8
C
C
C
2.0
0.9
2.4
197
252
73
35
55
22
1001
1984
1247
Table 2. SAR study of the R group on N1 of the C5-pyrazole
a
Inhibition of human B-cell proliferation was measured by thymidine
incorporation.
b
9
Human whole blood assay measuring suppression of CD86 or CD69
expression
a
All PI3K isoform assays were performed in ADP Glo format
Compound 9 was highly active in the human B cell proliferation
assay (IC50: 2.2 nM), and in the human whole blood CD69 assay
(IC50: 3.5 nM), and was moderately active in the human whole
blood CD86 assay (IC50: 66 nM). Using 9, an X-ray co-crystal
structure was obtained with the kinase domain of PI3K (Figure
3) that displayed similar hinge binding as the HTS hit (Figure 2).
In addition, it was observed that the acyl piperazine of 9 stacks
with Trp760 which allows the acyl oxygen to form a hydrogen
bond with Thr750. In contrast, an X-ray co-crystal structure of 9
obtained with PI3Kα indicated that Arg770 moves to allow the
acyl piperazine to stack with Trp780 (Figure 4) which provides
no opportunity for the acyl oxygen to be involved in a similar
hydrogen bond interaction with PI3Kα, and likely provides an
explanation for the observed PI3K selectivity. Fixing C-5 as 4-
tetrahydropyran-pyrazole, a SAR study of substitution of the
piperazine attached to the C-7 phenyl was conducted (Table 3).
New compounds 14-24 (Table 3) were all very potent in the
There is a selectivity pocket between Trp760 and Thr750, and the
model suggested substitutions on the pyridine ring that project
into this pocket might improve selectivity against other PI3K
isoforms. Furthermore, the lack of hydrogen bonding between the
nitrogen of the pyridine ring and PI3Kδ suggested that the
pyridine could be replaced by a phenyl ring. Additional analysis
of the model indicated that the pyridine ring was in the same
plane as the pyrrolotriazine. Therefore, an ortho substituent on
the pyridine which forced the aminopyrrolotriazine and pyridine
rings to rotate out of plane would likely interfere with the binding
of C4-NH2 and N-3 with the hinge residues. In contrast, the para
position was directed into an open space where a substituent
might have a more limited impact on selectivity. Based on these
observations, optimization of the substituent at the meta position
on the C-7 aryl group was initiated. In preliminary SAR studies,
replacement of the cyclohexyl ring with an isosteric 4-

PI3Kδ enzyme assay, and selectivity against the other PI3K
isoforms improved with the size of the R group. Although
compound 18,
but lost ~10 fold potency in the B-cell proliferation assay, and
were less selective compared to the corresponding 2 and/or 6
regio-isomers (16, 17 and 19). Compared to 9, compound 23
Table 3. SAR study of piperazine moiety at the meta position of the C-7
phenyl
exhibited
similar
δ
PI3Kδ
IC50
(nM)
B-cell
Prolif. IC50
(nM)
selectivity
R
δ vs. α δ vs. γ
δ vs. β
9
2.4
73
22
1247
2.2
14
15
1.7
0.8
139
256
33
44
950
316
2.5
8.2
Figure 3. X-ray crystal structure of 9 in PI3Kδ (PDB code 5UBT)
16
17
18
0.9
0.5
1.3
292
755
75
143
159
34
600
1359
70
4.3
1.7
---
19
20
21
1.3
1.4
4.3
611
275
69
44
213
6
1443
3000
95
5.8
50
36
Figure 4. X-ray crystal structure of 9 in PI3Kα (PDB code 5UBR)
activity and selectivity against the other PI3K isoforms.
Importantly, introduction of the carbonyl group in 23 improved
metabolic stability. Furthermore, addition of a dimethyl group
next to the carbonyl (24), significantly improved PI3Kδ activity
and selectivity against α, β and γ. However, compound 24
showed poor permeability in Caco-2 assay. Next, the functional
group attached to N-4 of the piperazine ring was studied (Table
4). Compounds in this series (3, 19 and 25-29) were very potent
in the PI3δ enzyme assay, and selectivity against PI3Kα
increased with the size of the R group. In this set, 19 displayed
the best human whole blood CD86 cellular potency which
showed better correlations with further in vivo test results than
other in vitro assay measurements. Keeping the 4-acyl-cis-2,6-
dimethyl piperazinyl moiety at the meta position fixed, additional
substitution on the C-7 aromatic ring was then investigated
(Table 5). From this study, it was observed that substitution at
the 5 position of the phenyl ring (30 and 31) or replacement of
the phenyl with a 5-pyridine ring (32) improved selectivity
against all of the other PI3K isoforms, but resulted in poor mouse
liver microsomal stability. Based on the SAR outlined in Tables
1-5, compound 19 was selected for further characterization.
Overall, 19 exhibited a favorable profile based on the results
22
1.2
5.5
0.3
117
72
20
12
93
598
470
24
64
23*
24*
251
2300
4.2
*Prepared via procedure b in Scheme 2.
(R=4-chlorophenyl) was still very potent against PI3Kδ, its
selectivity against α and β dropped significantly. One explanation
for these observed results could be that the hydrophobic
substitution at 2 position of the piperazine enhances the stacking
interaction between acyl piperazine and Trp760. However, when
the substitution becomes too big, it collides with Trp760, which
disrupts the stacking interaction and the hydrogen bond
interaction between acyl oxygen and Thr750. Compounds 20-22,
which incorporated an R group at the 3 and/or 5 position of the
piperazine ring were also very potent in the PI3Kδ enzyme assay,

from in vitro liability assays (Table 6), and selectivity observed
in both the enzyme and cellular PI3K assays. In mouse PK
studies (Table 7), 19 exhibited sustained exposure that was equal
to its IC50 in the CD86 whole blood assay (WB) at 3 mg/kg.
Based on its favorable PK profile, 19 was then evaluated in a
mouse KLH model to measure IgM antibody response. The
compound was dosed twice a day (BID) and 250 µg of KLH was
administered i.p. to BALB/c mice to induce an antibody
response. In this study, compound 19 was efficacious at 3 mg/kg,
reducing the IgM response by 63% (Figure 5). Compound 19
was then further evaluated in a 4-day exploratory toxicity study
in mice at doses up to 300 mg/kg/day (QD), and found to be well
tolerated at all doses (Day 4 AUC ≤ 520 µM●h; Cmax ≤ 55 µM).
No morbidity/mortality was observed.
To support the SAR studies, a robust synthetic route was
developed to efficiently access pyrrolo[2,1-f][1,2,4]triazine-4-
amine derivatives (Scheme 1).33,34 The route began with mono
CBZ-protected hydrazine (33) which was reacted with
Table 6. Profile of compound 19
In vitro IC50
δ (nM)
Cellular assay IC50
B cell prolif. (δ) (nM)
CD86 WB (δ) (nM)
1.3
57
6
γ (nM)
α (nM)
24
13
4
795
CD69 WB (δ) (nM)
β (nM)
1,876 CD86 Mo spleen (δ) (nM)
Table 4. SAR study of the R group on cis-2,6-dimethylpiperazine N-4
Met Stab (mouse)
54%
Protein Binding
(mouse, % free)
13.4
hERG
(patch clamp)
18% @ 10 µM
Na+
(patch clamp)
-2.6% @ 10 µM (1 Hz)
B-cell
Prolif.
IC50
CD86
WB
IC50
(nM)
selectivity
PI3Kδ
IC50
(nM)
R
Table 7. Exposures of 19 in Mouse KLH study (P.O.)
δ vs.α
δ vs.γ
δ vs.β
(nM)
3
H
10.7
6.4
109
108
32
40
1053
1609
-
314
239
25
12
26
19
9.6
1.3
234
611
85
44
3140
1443
39
193
24
5.8
0.6 mg/kg
3 mg/kg
15 mg/kg
27
28
29
4.5
1.5
3.9
370
390
475
45
64
37
1115
1850
1269
-
81
39
Time
Ca (nM) Ratiob Ca (nM) Ratiob Ca (nM) Ratiob
2.3
28
7h
<6.4
<5.6
0.3
0.2
24.9
<3.9
97.8
<7.0
4
291
24 h
0.16
0.3
a
Table 5. SAR study of the C-7 aryl group
Concentration of compound 19 at noted time and dose
Conc. of compound 19/CD86 WB IC50
b
Mouse liver
microsomal
stability (%
remaining)a
selectivity
PI3Kδ
IC50
(nM)
R
δ vs. α δ vs. γ
δ vs. β
19
1.3
611
44
1443
54
30
31
0.9
1.2
628
56
2048
2409
35
14
1244
190
Figure 5. Compound 19 in KLH dependent antibody response
32
0.6
1036
148
1001
48
Bromoacetaldehyde dimethyl acetal to give 34. Intermediate 34
was then reacted with the sodium salt of diethyl oxalacetate
followed by cyclization in the presence of para-toluenesulfonic
acid to give compound 35 in one pot. The CBZ group was
a
Mouse liver microsomal stability assay at concentration of 0.5 µM for 10
min in a high throughput mode.

removed before treatment with formamidine gave 36. Compound
36 was brominated with NBS to give 37, which was then treated
with thionyl chloride followed by displacement with ammonia to
which was then treated with thionyl chloride followed by
displacement with ammonia to provide 38. Next, ester 38 was
hydrolyzed, and converted to Weinreb amide 39, which was
treated with n-butyl lithium and TMS-acetylene to furnish 40.
Compound 40 was treated with dimethylamine, and then reacted
with R1-NHNH2 to give 41 which was coupled with 45 to provide
42. Finally, the Boc group was removed to furnish compounds 1-
3, or the free amine was further derivatized to give 4-32.
Incorporation of a piperazinyl moiety onto the C-7 aryl group
was achieved via a Buchwald or Ullman coupling (Scheme 2).
Intermediate 44 was converted to a pinacol boronic ester 45,
which was then used to synthesize the desired analogs as shown
in Scheme 1.
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Pattaropong V, Pettus LH, Reichelt A, Rzasa RM, Seganish J,
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29. Gopal AK, Kahl BS, de Vos S, Wagner-Johnson ND, Schuster SJ,
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The identification and subsequent optimization of a novel class
of
7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-
amine derivatives as potent and selective PI3Kδ inhibitors have
been described. Compound 19, a highly potent and selective
PI3Kδ inhibitor with improved hERG and ion channel profiles
and an improved CD86 whole blood potency compared to
compound I, showed efficacy in a mouse KLH model when
dosed at 3 mg/kg BID. In a 4-day toxicity study in mice, no
morbidity/mortality was observed, and compound 19 was well
tolerated when dosed at 300 mg/kg (QD). Further evaluation and
improvements in the physical and pharmacokinetic properties of
compound 19 will be reported.
Acknowledgment
31. Meadows SA, Vega F, Kashishian A, Johnson D, Diehl V, Miller
LL, Younes A, Lannutti BJ. Blood 2012; 119(8): 1897-1900
32. Bhide RS, Neels J, Qin L, Ruan Z, Stachura S, Weigelt C, Sack
JS, Stefanski K, Gu X, Xie JH, Goldstine GB, Skala S, Pedicord
DL, Ruepp R, Dhar M, Carter PH, Salter-Cid LM, Poss MA,
We would like to thank Proteros Biostructures GmbH for the X-
ray structures of compound B6 in complex with PI3Kα and
PI3Kδ.

Davies P. Bioorganic & Medicinal Chemistry Letters 2016;
26(17): 4256-4260
34. Bhide RS, Cherney RJ, Cornelius LAM, Dhar TGM, Gong H,
Marcoux D, Poss MA, Qin L, Ruan Z, Shi Q, Tino JA.
WO2016064958 A1
33. Bhide RS, Batt DG, Cherney RJ, Cornelius LAM, Liu Q, Marcoux
D, Neels J, Poss MA, Qin L, Ruan Z, Shi Q, Srivatava AS, Tino
JA, Wattterson SH. WO2016064957 A1