Evaluation of WO2014075392 and WO2014075393, Merck's first PI3Kδ inhibitor filings

Article abstract of DOI:10.1517/13543776.2014.969710

Introduction: There is considerable interest in the development of selective PI3Kδ inhibitors for the treatment of inflammatory diseases and haematological cancers. Merck has no previous filings in this field but licensed Exelixis' programme, including its lead compound XL-499, in December 2011.Areas covered: Both applications claim novel 9-alkyl-6,8-disubstituted purine derivatives as selective δ inhibitors for the treatment of asthma, obstructive airways disease, arthritis and cancer. The two applications differ in the range of exemplified substituents, the first focusing on 8-heteroaryl substituted purines, the second on 8-aminopurine derivatives. Many of the exemplified compounds have IC50 values < 10 nM against PI3Kδ with a number having sub-nanomolar potency.Expert Opinion: The compounds appear to be XL-499 derivatives, some of which are more potent than XL-499. The compounds claimed by Merck are some of the most potent PI3Kδ inhibitors yet described but it is unclear whether a development compound has been identified.

Full text of DOI:10.1517/13543776.2014.969710

Patent Evaluation
Evaluation of WO2014075392 and
WO2014075393, Merck’s first
PI3Kd inhibitor filings
1. Introduction
2. Chemistry
3. Biology
Peter Norman
Norman Consulting, Bucks, UK
Introduction: There is considerable interest in the development of selective
PI3K inhibitors for the treatment of inflammatory diseases and haematologi-
cal cancers. Merck has no previous filings in this field but licensed Exelixis’
programme, including its lead compound XL-499, in December 2011.
Areas covered: Both applications claim novel 9-alkyl-6,8-disubstituted purine
derivatives as selective d inhibitors for the treatment of asthma, obstructive
airways disease, arthritis and cancer. The two applications differ in the range
of exemplified substituents, the first focusing on 8-heteroaryl substituted
purines, the second on 8-aminopurine derivatives. Many of the exemplified
compounds have IC50 values < 10 nM against PI3Kd with a number having
sub-nanomolar potency.
Expert Opinion: The compounds appear to be XL-499 derivatives, some of
which are more potent than XL-499. The compounds claimed by Merck are
some of the most potent PI3K inhibitors yet described but it is unclear
whether a development compound has been identified.
Keywords: asthma, idelalisib, lymphoma, phosphatidylinositol 3-kinase delta inhibitor,
rheumatoid arthritis, XL-499
Expert Opin. Ther. Patents (2014) 24(11):1277-1282
1. Introduction
The lipid kinase phosphatidylinositol 3-kinase (PI3K) plays a pivotal role in the
PI3K/Akt/mTOR signalling pathway [1,2]. Four distinct catalytic isoforms of this
class I PI3K are known, each differing in cellular expression and pathophysiological
roles. The isoform PI3Kd appears to be exclusively expressed in leukocytes and plays
a significant role in regulating leukocyte signalling and function [3,4]. Its selective
expression has highlighted the potential of using selective PI3Kd inhibitors to treat
leukocyte-mediated diseases and has prompted a steady increase in activity focused
on the identification and development of such inhibitors for the treatment of both
inflammatory diseases and haematological cancers [5]. The first selective PI3Kd
inhibitors, based on a quinazolinone scaffold, were described in 2003 by a group
at Icos (subsequently Calistoga and then Gilead) [6]. Optimisation and development
of this series of compounds led to idelalisib (Cal-101/GS-1101) (Figure 1) [7],
which was approved as Zydelig by the FDA on the 23 July 2014, gaining approval
for the treatment of relapsed chronic lymphocytic leukaemia (CLL), relapsed
follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic
lymphoma [8].
A number of other selective PI3Kd inhibitors are now in development for the
treatment of blood cancers and inflammatory diseases (Figure 1). These include
Gilead’s GS-9820 for the treatment of lymphoid malignancies [9], Infinity
Pharmaceuticals’ duvesilib (IPI-145) for the treatment of CLL, non-Hodgkin’s
lymphoma and asthma [10], Amgen’s AMG-319 for the treatment of haemotological
malignancies [11], GlaxoSmithKline’s GSK-2269557 for the treatment of COPD
10.1517/13543776.2014.969710 © 2014 Informa UK, Ltd. ISSN 1354-3776, e-ISSN 1744-7674
All rights reserved: reproduction in whole or in part not permitted
1277

P. Norman
F
O
N
O
N
Cl
O
N
F
N
N
N
HN
HN
HN
HN
HN
N
N
N
N
N
N
H N
N
N
N
Idealisib
GS-9820
Duvelisib
H
N
O
N
H
N
N
N
N
O
N
N
N
N
N
O
N
N
N
S
O
O
GSK-2269557
GNE-293
Cl
N
O
O
O
S
N
N
F
O
O
N
N
H2N
N
N
N
N
O
N
O
O
O
N
N
HO
RV-1729
MSC-2364588
Figure 1. Selective PI3Kd inhibitors in development.
and asthma [12], Respivert’s RV-1729 for the treatment of
COPD [13,14], Genentech’s GNE-293 for the treatment of
N
H
N
O
rheumatoid
arthritis
[15]
and
Merck
Serono’s
N
O
N
N
N
N
MSC-2364588 for the treatment of lupus [16]. A number of
other companies have shown an interest as judged by patent
filings [5] but have yet to progress identified selective PI3Kd
inhibitors into development. (N.B. both duvesilib and
RV-1729 are dual PI3Kd/ PI3Kg inhibitors.)
Exelixis also identified the development compound
XL-499. It described the profile of this inhibitor prior to
the publication of any patent application related to such
inhibitors. At the 2010 EORTC-NCI-AACR meeting,
XL-499 was described as a highly selective PI3Kd inhibitor
identified from a HTS campaign [17]. XL-499 combines an
IC50 value of 7.5 nM, with 100-fold selectivity over PI3Ka
N
N
N
H
N
N
HN
N
N
O
N
CF3
N
N
N
H
N
(1)
(2)
Figure 2. Selective PI3Kd inhibitors previously claimed by
Exelixis [16,17].
1278
Expert Opin. Ther. Patents (2014) 24(11)

Evaluation of WO2014075392 and WO2014075393, Merck’s first PI3Kd inhibitor filings
and PI3Kb, 200-fold over PI3Kg and > 1000-fold against
The final 11 claims are common to both applications.
These encompass composition claims, the use of com-
pounds (3) as PI3Kd inhibitors, and their use for the treat-
ment of asthma, arthritis, obstructive airways disease and
cancer.
138 other kinases. Two patent applications, claiming
compounds such as 1 and 2 (Figure 2), were subsequently
published in 2012 [18-20], following the licensing of
this programme to Merck in December 2011 [21]. The two
patent filings that form the subject of this evaluation [22,23]
are the first from Merck since the announcement of
this deal.
2.1 WO2014075392
The first application exemplifies 387 compounds. In the
majority of these, the 8-substituent (R2-X-) is a directly
attached heteroaryl group (generally pyridyl, pyrimidinyl or
pyrrolyl). And, in spite of the broad claims provided for the
group Y-A, in nearly all the examples Y is O and A is
either a piperidine or, more commonly, a pyrrolidine ring.
A small number of examples are provided in which Y is S,
with four where it is methylene and just one where it is sulfo-
nyl, in each case forming the linker to a monocyclic amine
ring.
2. Chemistry
R3
A
Y
N
N
X
R2
The synthesis of the exemplified compounds, for example, 4,
follows the basic strategy shown in Figure 3. N-arylation of a
4,5-diaminopyrimidine is followed by cyclisation and
introduction of the second substituent. In some cases, the pre-
formed purine ring is subjected to nucleophilic substitution at
C6, followed by iodination at C8 and Suzuki coupling with an
arylboronic acid to give the desired substitution pattern. Both
methods are those employed in the previous filing from
Exelixis [19], which is cited as a reference.
N
N
R1
(3)
R1 = H, alkyl, cycloalkyl, heteroalkyl or heterocyclalkyl.
R2 = H, hal, alkyl, cycloalkyl, heteroalkyl, heterocyclalkyl,
alkynyl, aryl or heteroaryl.
R3 includes hal, NH2, CN, SO2CF3 and
alkoxycarbonylalkyl.
A = cycloalkyl, heterocycloalkyl or spirocycle.
X = bond, NH, O, CO, CH2, N-dialkyl, S, SO2, CONHalkylene
or alkynylene.
2.2 WO2014075393
The second application provides 288 examples. All the com-
pounds exemplified in the second application incorporate an
amino linker group, attached to a heterocyclic amine, nor-
mally pyrrolidine or piperidine. A few examples are presented
where the linker X is an alkyne, but in most cases, the group
R2 is directly attached to the purine ring. The majority of
the examples are of R2 as a pyrimidin-4-yl or 1-ethyl-5-meth-
ylpyrrol-3-yl substituents. But, a moderate number of exam-
ples are with R2 alkyl or acyl groups.
A broadly similar synthetic approach was employed to
prepare the compounds, for example, 5, exemplified in the
second application. In most instances, as shown in Figure 4,
the heteroaryl group was coupled to the diaminopyrimidine
by amination of the aroyl aldehyde and in situ oxidation to
the purine ring. In some cases, the alternative strategy of
employing Suzuki coupling was employed.
Y= O, S, SO2 or CH2.
The two applications share their claim structure and (some-
what unusually) both provide the same Markush structure
(3) for their primary claim. The second claim of each
application specifically claims all compounds exemplified in
the application. These two claims are followed by secondary
claims that define different options for certain of the
Markush variable groups in claims 3 -- 9, but they are not
written as dependent claims.
The first application successively claims:
3. X = bond
4. Y = O
5. Y = S or SO2
6. Y = CH2
7. A is one of 8 defined ring systems, either cycloalkyl or
mono or bicyclic azaalkyl rings.
8. R3 is one of 33 specified variables (H, I, alkyl, cycloalkyl
or heterocycle).
3. Biology
The second application successively claims:
3. X = CO, CONMe, CONMeCH2, CH2, O, -C=C- or
CONH2
4. X = bond
5. Y= NH or N(chloroalkyl)
6. Y= CH2
7. A = cycloalkyl or heterocycloalkyl
8. A = spirocycle
Compounds were tested as inhibitors of each of the four iso-
forms of PI3K using Upstate kits and by measuring the decay
of a HTRF (Homogeneous Time-Resolved Fluorescence
energy transfer) complex is formed consisting of europium-
labeled anti-GST, GST-tagged GRP1 pleckstrin homology
domain, biotin-phosphatidyl-(3,4,5)-triphosphate and strep-
tavidin-conjugated allophycocyanin. IC50 values were deter-
mined in 1536-well plate assays after optimising the assay
Expert Opin. Ther. Patents (2014) 24(11)
1279

P. Norman
Cl
Cl
Cl
N
N
N
N
N
N
H
N
a
d
b, c
H2N
H2N
O
H
N
O
N
HN
H2N
O
N
O
Cl
N
O
N
O
e
N
O
+
O
N
N
O
N
N
N
N
N
HO
N
O
H
N
N
O
O
g
N
N
f
N
O
N
N
N
O
N
N
N
N
(4)
Figure 3. The preparation of compound (4) (Examples 2 -- 89 in the application).
a) EtNH2.HCl, K2CO3, EtOH, 50ꢀC, 39 h.
b) 6-methoxy-5-methyl-nicotinic acid.
c) NaOt-Bu, Me2O, 25ꢀC, 2 h.
d) N-(trimethylsilyl)acetimidate, 55ꢀC, 1 h.
e) NaH, THF, DMF, 25ꢀC, 20 h.
f) c.HCl, dioxan, 90ꢀC, 3 h.
g) EtCOCl, Et3N, DMF, 25ꢀC, 20 h.
conditions for both high-throughput screening and structure-
-- activity analysis. However, data are only presented for the
compounds as inhibitors of PI3Kd, together with their selec-
tivity relative to PI3Ka.
compounds are reported to have IC50 values in excess of
100 nM but none > 800 nM.
These data are presented in tabular form in both applica-
tions and show that many of the compounds inhibit PI3Kd
with IC50 values of < 10 nM. In the first application, com-
pound 4 is one of the two most potent compounds for which
specific IC50 values are given (0.5 nM). But 18 other com-
pounds are stated to have IC50 values < 1.0 nM, while a few
have IC50 values in excess of 1000 nM. In almost all the
examples, the selectivity is simply stated to be > 10, with
only a few examples reported as less selective.
In the second application, compound 5 is one of the most
potent compounds for which a specific IC50 value is provided
(1.1 nM), with 46 compounds simply described as having
IC50 values < 1.0 nM. In this application, only a few
4 Expert opinion
These two applications are significant because they are the
first applications filed by Merck since it struck its deal with
Exelixis. Both applications describe a number of compounds
that show superior potency, as PI3Kd inhibitors, and appar-
ently with at least as good isoform selectivity. (None of the
applications provide details of activity against all four PI3K
isoforms.) The two applications clearly seek to expand the
decoration of the scaffold described in the earlier filings.
The key difference from the earlier filing [19] is that it specifies
that cyclic amino groups are attached to the purine ring.
Evidently, this application encompassed XL-499 within the
claims because all the modifications claimed in the new
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Expert Opin. Ther. Patents (2014) 24(11)

Evaluation of WO2014075392 and WO2014075393, Merck’s first PI3Kd inhibitor filings
Cl
N
Cl
N
N
+
a
b
O
H
N
N
H2N
H2N
N
HN
H2N
O
O
N
Cl
N
O
N
N
c
HN
N
N
N
O
N
+
N
N
N
N
N
N
H2N
(5)
Figure 4. The preparation of compound (5) (Examples 1 -- 14 in the application).
a) EtNH2.HCl, K2CO3, EtOH, 50ꢀC, 39 h.
b) FeCl3, 6H2O, O2, DMF, 90ꢀC, 14 h.
c) iPr2NEt, DMF, 80ꢀC, 48 h.
applications focus on this scaffold rather than that described
in the other filing [18].
The claims cover all the indications for which other compa-
nies are currently developing PI3Kd inhibitors. Although
any development is some way behind that of other companies,
the data presented in these applications suggests that Merck
has some of the most potent PI3Kd inhibitors yet described.
These could, therefore, provide some therapeutically useful
inhibitors now that this target is clinically validated, at least
for oncology indications. Only subsequent filings will clarify
which of these two applications is the more significant.
Considering the compounds claimed in the current appli-
cations, it is clear that the use of a purine scaffold distin-
guishes them from most of the better documented PI3Kd
inhibitors shown in Figure 1. Only GNE-293 also features a
purine scaffold, and GNE-293 is a slightly less potent inhibi-
tor (Ki 3.1 nM) of PI3Kd than some of the compounds
claimed in these applications [22,23]. GNE-293 is claimed inter
alia in an application, from Genentech’s parent co. Roche,
that covers a large number of 8-alkoxy-6-morpholinopurine
derivatives [24] which are not encompassed by the Markush
structure (3) of the current applications.
It is apparent from Roche’s patent filings [24] and the
publications from the Genentech group that its primary focus
for its PI3Kd programme is the treatment of rheumatoid
arthritis [15,25]. It has multiple PI3K inhibitors, of varying spe-
cificities, in development for the treatment of cancer.
The indication for which Merck wishes to pursue the
development of the claimed PI3Kd inhibitors is unclear.
Declaration of interest
The author has received an honorarium from Informa for the
preparation of this article. The author has no other relevant
affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript.
This includes employment, consultancies, honoraria, stock
ownership or options, expert testimony, grants or patents
received or pending, or royalties.
Expert Opin. Ther. Patents (2014) 24(11)
1281

P. Norman
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Affiliation
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Norman Consulting, 18 Pink Lane, Burnham,
Bucks, SL1 8JW, UK
PressAnnouncements/ucm406387.htm
E-mail: peter.norman2@btinternet.com
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Expert Opin. Ther. Patents (2014) 24(11)