Discovery of 3-morpholino-imidazole[1,5-a]pyrazine BTK inhibitors for rheumatoid arthritis

Article abstract of DOI:10.1016/j.bmcl.2017.03.040

8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.

Full text of DOI:10.1016/j.bmcl.2017.03.040

Accepted Manuscript
Discovery of 3-morpholino-imidazole[1,5-a]pyrazine BTK inhibitors for rheu-
matoid arthritis
Sobhana Babu Boga, Abdul-Basit Alhassan, Jian Liu, Deodial Guiadeen, Arto
Krikorian, Xiaolei Gao, James Wang, Younong Yu, Rajan Anand, Shilan Liu,
Chundao Yang, Hao Wu, Jiaqiang Cai, Hugh Zhu, Jagdish Desai, Kevin
Maloney, Ying-Duo Gao, Thierry O. Fischmann, Jeremy Presland, My
Mansueto, Zangwei Xu, Erica Leccese, Ian Knemeyer, Charles G. Garlisi,
Nathan Bays, Peter Stivers, Philip E. Brandish, Alexandra Hicks, Alan Cooper,
Ronald M. Kim, Joseph A. Kozlowski
PII:
S0960-894X(17)30266-4
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.03.040
BMCL 24792
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 February 2017
13 March 2017
15 March 2017
Please cite this article as: Boga, S.B., Alhassan, A-B., Liu, J., Guiadeen, D., Krikorian, A., Gao, X., Wang, J., Yu,
Y., Anand, R., Liu, S., Yang, C., Wu, H., Cai, J., Zhu, H., Desai, J., Maloney, K., Gao, Y-D., Fischmann, T.O.,
Presland, J., Mansueto, M., Xu, Z., Leccese, E., Knemeyer, I., Garlisi, C.G., Bays, N., Stivers, P., Brandish, P.E.,
Hicks, A., Cooper, A., Kim, R.M., Kozlowski, J.A., Discovery of 3-morpholino-imidazole[1,5-a]pyrazine BTK
inhibitors for rheumatoid arthritis, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/
j.bmcl.2017.03.040
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Discovery of 3-morpholino-imidazole[1,5-
a]pyrazine BTK inhibitors for rheumatoid
arthritis
Sobhana Babu Boga a, *, Abdul-Basit Alhassan a, Jian Liu a, Deodial Guiadeen a, Arto Krikorian a, Xiaolei Gao a, James Wang a, Younong Yu a, Rajan
Anand a, Shilan Liu b, Chundao Yang b, Hao Wu b, Jiaqiang Caib, Hugh Zhu a, Jagdish Desai a, Kevin Maloney a, Ying-Duo Gao a, Thierry O. Fischmann
a, Jeremy Presland a, My Mansueto a, Zangwei Xu a, Erica Leccese a, Ian Knemeyer a, Charles G. Garlisi a, Nathan Bays a, Peter Stivers a, Philip E.
Brandish a, Alexandra Hicks a, Alan Cooper a, Ronald M. Kim a, Joseph A. Kozlowski a

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
Discovery of 3-morpholino-imidazole[1,5-a]pyrazine BTK inhibitors for
rheumatoid arthritis#
Sobhana Babu Boga*, a, Abdul-Basit Alhassan a, Jian Liu a, Deodial Guiadeen a, Arto Krikorian a, Xiaolei Gao a, James Wang a, Younong Yu a, Rajan Anand a,
b
Shilan Liu b, Chundao Yang b, Hao Wu , Jiaqiang Caib, Hugh Zhu a, Jagdish Desai a, Kevin Maloney a, Ying-Duo Gao a, Thierry O. Fischmann a, Jeremy
Presland a, My Mansueto a, Zangwei Xu a, Erica Leccese a, Ian Knemeyer a, Charles G. Garlisi a, Nathan Bays a, Peter Stivers a, Philip E. Brandish a, Alexandra
Hicks a, Alan Cooper a, Ronald M. Kima, Joseph A. Kozlowski a
a Department of Early Development and Discovery Sciences, MRL, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065 USA
b WuXi PharmaTech Co. Ltd, 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. China
#Dedicated to Professor Léon Ghosez, Emeritus Professor UCL, Belgium & visiting scientist IECB, France on the occasion of his 80th birthday
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
8-Amino-imidazo[1,5-a]pyrazine-based Bruton’s tyrosine kinase (BTK) inhibitors, such as 6,
exhibited potent inhibition of BTK but required improvements in both kinase and hERG
selectivity.1 In an effort to maintain the inhibitory activity of these analogs and improve their
selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine
compound 6. This effort led to the discovery of the morpholine group as an optimized
pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and
hERG selectivities, and pharmacokinetic profiles.
Keywords:
BTK inhibitor
2009 Elsevier Ltd. All rights reserved
.
ATP ribose pocket
Rheumatoid Arthritis
Kinase selectivity
Immunology
Bruton’s tyrosine kinase (BTK) is a TEC family kinase
expressed in B cells, mast cells and macrophages, but not in T
cells or natural killer cells2. BTK is important in cell signaling
pathways such as B cell antigen receptor (BCR) and Fc receptor
(FcR) signaling cascades3. Mutations in the human BTK gene
cause X-linked agammaglobulinemia (XLA), a disease which is
characterized by a deficit of peripheral B cells and low levels of
serum Ig4. In mice, point mutation or deletion of BTK causes X-
linked immunodeficiency (xid) where fewer B cells and reduced
serum Ig levels are observed5. Xid mice have been shown to be
resistant to collagen-induced arthritis (CIA). Thus, a connection
between the pathogenesis of rheumatoid arthritis (RA) and
systemic lupus erythematosus (SLE) and BTK has been
postulated as RA is characterized, in part, as being an outcome of
autoreactive B cell activation, which in turn gives rise to
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expansion of
B cells and the subsequent production of
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autoantibodies. Given that rituximab, a therapeutic anti-CD20
antibody, impacts B cell levels of patients with autoimmune
diseases such as RA, multiple sclerosis (MS) and SLE, a
significant interest in pursuing small molecule inhibitors of BTK
has emerged5. Extensive research efforts6 have focused on the
development of both reversible (i.e. 4, 5) and irreversible BTK
inhibitors (i.e. 1-3) as represented in Figure-1. The irreversible
inhibitors form a covalent bond with cysteine-481 of the BTK
enzyme. Several irreversible BTK inhibitors have progressed to
the clinic and Ibrutinib was approved.7
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Figure 1. Representative structures of BTK inhibitors.

We recently described reversible BTK inhibitors, such as 8-
amino-imidazo[1,5-a]pyrazines 6, with good kinase selectivity
and acceptable oral bioavailability.1 In an effort to further
optimize potency, selectivity and PK parameters of this series
we now report the SAR and optimization surrounding 3-
substitution of the 8-amino-imidazo[1,5-a]pyrazine series.
Early SAR indicated that substitution off the 3-position
significantly impacted BTK inhibitory activity and kinase
selectivity. Therefore we focused our efforts on expanding SAR
in this region. To that end, as compared to compound 6,
tolerability for various substitutions was probed (Table 1). Initial
effort focused upon replacing the chiral piperidine ring with an
achiral methyl morpholine group, compound 7, caused
significant loss in BTK inhibitory activity compared to lead
compound 6.
Table 1. Exploration at the 3-position of 8-Amino-imidazo[1,5-a]pyrazine
towards BTK, hPBMC and hERG.
BTK
hPBMC
hERG/ikra
#.
R1
IC50 (nM)
IC50 (nM)
IC50 (µM)
6
7
0.3
8
3.5
We next systematically modified the ring size of the groups
appended at the 3-position of the pyrazine. Evaluation of the ring
size was initially tested by maintaining a common pendant group,
the methyl oxetane amide as in the lead compound 6. The 4-
membered azetadine 8, as well as the 5-membered pyrrolidine 9
maintained BTK inhibitory activity but unfortunately lost 5-20
fold in hPBMC (human peripheral blood mononuclear cell)1
cellular potency. Significant loss of BTK inhibitory activity was
also observed with the 6-membered rings, (e.g., piperidine analog
10 with para-orientation, and the cyclohexyl amine analog 11).
Increasing the ring as exemplified with 7-membered heptane
analogue 12, suffered ten-fold loss of BTK inhibitory activity
compared to the lead piperidine analog 6.
132
1225
ND
8
9
5.9
1.2
167
37
0.4
2.5
10
11
3.4
80
ND
ND
Next we explored replacement of the 6-membered piperidine
motif of 6 with a morpholine, compound 13, which resulted in
BTK inhibitory activity comparable to 6 while the cell based
activity was slightly weaker but showed improvement in hERG
inhibition. Further modifications of morpholine analogue 14 such
as thiomorpholine analog 15, sulfone morpholine analog 16, and
piperazine analog 17 resulted in reduced BTK inhibitory activity.
10.7
ND
12
13
5.3
0.9
ND
48
ND
14.4
14
15
16
17
3.3
6.6
58
5.8
1.8
ND
ND
ND
ND
ND
294
377
a ikr channel or MK-499 assay11; ND Not Determined

ꢆ
While several compounds in Table 1 emerged more similar to
or slightly weaker than 6 for either enzyme or cell potency,
morpholine analogue 13 showed greater than four-fold
improvement in hERG selectivity. We then focused on the
morpholine compound 13 for further exploration. Compound 13
was modeled in the BTK active site using the X-ray crystal
structure of 61 and the BTK complex (PDB Code 5FBO). One
hundred conformations of compound 13 were generated using the
method described by Feuston et al.8 and docked into the BTK
active site using the SQ procedure developed by Miller et al.9
The binding mode of 13 is predicted to be very similar to the
conformation of compound 6 depicted in the crystal structure.
Similarly, 13 bound in the catalytic subunit of BTK showed
typical binding of 8-amino-imidazo[1,5-a]pyrazine to the hinge
region via amino pyridine hydrogen bonding with Ser538 and
Asp539, trifluoromethyl pyridine chain extending deep into the
hydrophobic back pocket while the morpholine ring
demonstrated close binding interactions with the ribose pocket.
(Figure-2). With respect to the water molecule that binds to the
pyrazine core, the morpholine oxygen is approximately 3.7 Å
from the water and is not believed to be making any hydrogen
bond interactions. Our model indicates that the morpholine
oxygen does not provide additional interactions for better activity
through a water bridge, but rather enhances desolvation. Hence
the BTK potency drops approximately 2-3 fold compared with
piperidine analog 6.
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Table 2. Comparison of Piperidine and morpholine analogs of 8-Amino-
imidazo[1,5-a]pyrazine series towards BTK, hPBMC and hERG.
BTK
hPBMC
hERG/ikrb
#.
R1
IC50 (nM)
IC50 (nM)
IC50 (µM)
18
19
X=CH2; 0.3
X=O; 0.7
7
35
ND
14
20
21
X=CH2; 0.1
X=O; 0.4
11
6
2.4
19
22
23
X=CH2; 0.3
X=O; 0.4
5
26
2.8
15
24
25
X=CH2; 0.2
X=O; 0.4
13
14
4.5
24
26
27
X=CH2; 0.8
X=O; 0.6
65
13
0.1
4.6
b ikr channel or MK-499 assay11; ND Not Determined
The synthesis of morpholine based BTK inhibitors is similar to
the synthetic routes described in an earlier report1 which involves
preparation of bromide 33 from commercially available (R)-4-
(tert-butoxycarbonyl)morpholine-2-carboxylic acid 29 as shown
in Scheme-1. Coupling of boronate 34 with 33 lead to the
common morpholine intermediate 36 after deprotection using
TFA. The final morpholine based BTK inhibitors were
synthesized using HATU as coupling reagent for the amide
formation with the corresponding pendant carboxylic groups to
give compounds 19, 21, 23, and 25. Reductive amination with
tetrahydro-4H-pyran-4-one 37 using Na(OAc)3BH gave the N-
alkyl morpholine analog 27. The corresponding piperidine
analogs were synthesized using commercially available (R)-1-
(tert-butoxycarbonyl)-piperidine-3-carboxylic acid replacing (R)-
4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid 29 in the
scheme 1.12
Figure 2. Morpholine compound 13 modeled in the BTK active site using the
X-Ray crystal structure of 6 and BTK complex (PDB code: 5FBO). The
hydrogen bond interactions with the key residues are indicated.
It was reported in our previous communication1 that 2-F
substitution on the middle phenyl ring, of piperidine compound
18 improved BTK inhibition and cellular hPBMC potency. We
explored an analogous approach in the morpholine series in an
effort to optimize the back pocket region. As depicted in Table 2,
morpholine compounds 19, 21, 23, and 25 displayed comparable
or slightly decreased BTK inhibition compared to the
corresponding piperidine analogs 18, 20, 22, and 24,
respectively. However, it was observed that morpholine series of
compounds 19, 21, 23, and 25 consistently offered an
improvement in hERG inhibition ranging from 3-6 fold,
depending upon the pendant group attached to it compared to the
piperidine analogues. Interestingly, the N-alkyl morpholine
analog 27 was slightly more potent in the cellular functional
assay, but also showed significant improvement in hERG activity
over the piperidine analog 26.

(3576)
74
(296)
646
(2584)
350
(4327)
100
(227)
1045
(2375)
173
(853)
11
(51)
74
(335)
60
(1544)
28
(75)
268
(723)
77
(127)
7
(9)
115
(138)
48
(420)
21
(35)
399
(676)
113
LCK
LYNB
PTK6
SRC
(1400)
265
(393)
512
(273)
55
(209)
123
(58)
77
(191)
112
(1060)
84
(336)
378
(1512)
132
(1164)
103
(234)
428
(973)
464
(251)
19
(86)
63
(287)
45
(333)
76
(205)
232
(626)
256
(93)
50
(189)
65
(110)
191
(323)
282
SRMS
TEC
(60)
170
(205)
231
(278)
32
TXK
(528)
189
(1055)
266
(203)
37
(691)
73
(478)
60
YES1
(756)
(605)
(167)
(198)
(38)
(102)
Based on their potency and improved kinase selectivity profiles
compounds 23, 25, and 27 were further profiled in rat and dog
pharmacokinetic studies as summarized in Table-4. Morpholine
compound 23 displayed low clearance and good bioavailability in
both rat and dog. Replacing the amide group with methoxy acetyl
25 and N-alkyl morpholine 27 resulted in bioavailability of 42%
Scheme 1. Reagents. i. HATU, TEA, CH2Cl2,; ii POCl3, CH3CN, 57% two
steps; iii. NBS, DMF, rt, 95%; iv. 2,4-DMB, DIEA, RT, 97%; vi.
PdCl2(dppf).CH2Cl2, 2M K3PO4 (aq.), DMF, 80 oC, ON, 80%; vi. Pd/C(10%),
H2 (atom), EtOH, 95%; vii. HATU, DIEA, DMF, 0 oC, 1hr, 60-70%; viii.
Na(OAc)3BH, MeOH, 90%
and 75%, and decreased t of 0.8 and 1.1 hour in rats
½
respectively. For comparison, compound 38 was also synthesized
(scheme-2), which included an alpha methyl substitution in the
morpholine ring and with cyclopropyl amide. Compound 38
maintained excellent potency (BTK IC50 = 0.4 nM; hPBMC IC50=
5.3 nM) and resulted in an acceptable overall PK profile both in
The morpholine class of BTK inhibitors were further evaluated
across a battery of Tec and Src family kinases and compared to
piperidine analogs. Kinase selectivity was assessed relative to
BTK inhibitory activity and summarized in Table 3. In general,
the kinase selectivity of morpholine analogs 23, 25 and 27
trended higher than the corresponding piperidine analogs 22, 24,
and 26 respectively.
rat with total clearance of 4.2 mL/min/kg,
t
½
of 3.9 h,
bioavailability 40% and in dog with total clearance of 1.6
mL/min/kg, t of 8.8 h, bioavailability 88%.
½
Table 4. Pharmacokinetic parameters of morpholine based BTK
inhibitors, 23, 25, 27 & 38
R1 =
Table 3. Comparison of piperidine and morpholine BTK analogs towards
selectivity over SRC family kinases.
23
27
25
38
Kinase
Compound #
IC50 (nM)
(fold selectivity)
Compound #
IC50 (nM)
(fold selectivity)
Compound #
IC50 (nM)
(fold selectivity)
Rat PK @ 10 mpk
Clp (mL/min/kg)
t½ (h)
1.4
2.3
87
8.2
0.8
42
23
1.1
75
4.2
3.9
40
22
23
24
25
26
27
F %
BTK
BLK
0.25
53
0.44
280
0.22
9
(39)
0.37
78
(212)
331
(895)
626
(2232)
169
(457)
69
(187)
0.83
29
0.59
50
Dog PK @ 2 mpk
Clp (mL/min/kg)
t½ (h)
4.8
3.9
89
13.8a
2.5a
ND
5.9a
3.1a
ND
1.6
8.8
88
(212)
(636)
(35)
127
(153)
455
(548)
59
(84)
200
(339)
665
(1466)
BMX
CSK
83
703
20
(332)
1154
(4616)
230
(920)
203
(1598)
2145
(4875)
514
(1168)
268
(93)
261
(1185)
71
F %
a Dog cassette PK study at 0.5 mpk ; ND Not Determined
ERBB4
FGR
76
Synthesis of enantiomerically pure morpholine BTK inhibitor 38
involves the preparation of key intermediate 43 in accordance to
the literature report10 by the addition of (S)-2-((4-
methoxybenzyl)amino)propan-1-ol 39 to (S)-(+)-epichlorohydrin
40 in the presence of LiClO4, subsequent deprotection and
protection of PMB to Boc and oxidation with TEMPO (Scheme-
(322)
(71)
22
(128)
39
28
(812)
472
(1888)
(610)
706
(1605)
(127)
151
(687)
188
(26)
85
(66)
132
FRK
214
(578)
571
(102)
105
(224)
248
FYN
894
1904

2). Morpholine intermediate 44 was then synthesized following
the steps described as depicted in scheme 1 and final amidation
using HATU with cyclo propyl carboxylic acid 45 gave the
compound 38 in 70%.12
C.: Kosaka, Y.: Takada, H.: Imai, K.: Kanegane, H.: Mizutani, S.:
Burg, M.: Zelm, M. C.: Ohara, O.; Morio, T. Int. J. of Hematol,
2015, 101(3), 305
5. (a) Lou, Y.; Owens, T. D.; Kuglstatter, A.; Kondru, R. K.;
Goldstein, D. M. J. Med. Chem. 2012, 55, 4539.; (b) Xu, D.; Kim,
Y.; Postelnek, J.; Vu, M. D.; Hu, D. Q.; Liao, C.; Bradshaw, M.;
Hsu, J.; et al J. Pharmacol. Exp. Ther. 2012, 341, 90.; (c)
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Scheme 2. Reagents. i. LiClO4, NaOMe, rt, 3d, 84%; ii. BOC2O, 10% Pd/C,
1-methyl-1,4-cyclohexadiene/BHT, EtOH, reflux, 3h, 80%; iii. TEMPO,
PhI(OAc)2, CH2Cl2; iv. HATU, DIEA, DMF, 0 oC, 1hr, 70%
In summary, exploration of the 3-position of the 8-amino-
imidazo[1,5-a]pyrazine series 6 led to the discovery of the
morpholine moiety as a replacement for piperidine. These
morpholine based BTK inhibitors (23, 25 and 27) displayed good
BTK inhibitory activity and moderate hPBMC cellular potency,
and offered advantages over the corresponding piperidine series
with respect to kinase selectivity and hERG ion channel activity.
Additionally the morpholines 23 and 38 demonstrated acceptable
pharmacokinetic profiles. This demonstrates the utility of the
morpholine 8-amino-imidazo[1,5-a]pyrazine series as BTK
inhibitors and will be reported in due course.
−271.
7. Cameron, F.; Sanford, M. Drugs 2014, 74 (2), 263
8. Feuston B. P., Miller M. D., Culberson J. C., Nachbar R. B.,
Kearsley S. K. J. Comput. Info. Comput. Sci. 2001, 41, 754
9. Miller M. D., Sheridan R. P., Kearsley S. K. J. Med. Chem.1999,
42, 1505
10. Matthias, B; Malte, W; Melanie, S. Eur. J. Org. Chem. 2007, 2100
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M. C. Proc. Natl. Acad. Sci. U.S.A., 2000, 97, 12329
(Radiolabeled [35S]MK-499 or iKr assay used in in vitro binding
study as a measure of potential hERG liability).
12. Experimental procedure and characterization of compounds are
reported in the patent application ; (a) De, M.; Adrianus, P.A.;
Sterrenburg, J-G.; Raaijmakers, H. C. A.; Kaptein, A.; Oubrie, A.
A.; Rewinkel, J. B. M.; Jans, C. G. J. Maria,; Wijkmans, J. C. H.
M.; Barf, T. A.; Gao, X.; Boga, S. B.; Yao, X.; Zhu, H. Y.;
Cooper, A. B.; Kim, R. M. “Bicyclic heterocycles as BTK
inhibitors and their preparation” Eur. Pat. Appl. (2013), EP
2548877 A1 (b) Liu, J.; Kozlowski, J. A.; Boga, S. B.; Guiadeen,
D. Yu, W.; Cai, J.; Liu, S. “ Imidazo[1,5-a]pyrazines as Btk
inhibitors and their preparation” PCT Int. Appl. (2016), WO
2016109217 A2
Acknowledgments
We thank Drs. Jeffrey J. Hale, Petr Vachal and Joseph L.
Duffy at MRL, Merck & Co., Inc., Kenilworth, NJ USA for their
support and encouragement.
References and notes
1. (a) Liu, J.; Guiadeen, D.; Krikorian, A.; Gao, X.; Wang, J.; Boga,
S. B.; Alhassan, A-B.; Yu, Y.; Vaccaro, H.; Liu, S.; Yang, C.; Wu,
H.; Cooper, A.; de Man, J. ; Kaptein, A.; Maloney, K.; Hornak,
V.; Gao, Y-D.; Fischmann, T.; Raaijmakers, H.; Vu-Pham, D.;
Presland, J.; Mansueto, M.; Xu, Z.; Leccese, E.; Zhang-Hoover, J.;
Knemeyer, I.; Garlisi, C. G.; Bays, N.; Stivers, P.; Brandish, P. E.;
Hicks, A.; Kim, R.; Kozlowski, J. A. ACS Med. Chem. Lett. 2016,
7, 198 (b) Gao, X.; Wang, J.; Liu, J.; Guiadeen, D.; Krikorian, A.;
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