Note: Descriptions are shown in the official language in which they were submitted.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-1-
COMPOUND - 946
The present invention relates to morpholino pyrimidine compounds, processes
for
their preparation, pharmaceutical compositions containing them and their use
in therapy, for
example in the treatment of proliferative disease such as cancer and
particularly in disease
s mediated by an mTOR kinase and/or one or more P13K enzyme.
It is now well understood that deregulation of oncogenes and tumour-suppressor
genes
contributes to the formation of malignant tumours, for example by way of
increased cell
proliferation or increased cell survival. It is also known that signalling
pathways mediated by
the PI3K/mTOR families have a central role in a number of cell processes
including
io proliferation and survival, and deregulation of these pathways is a
causative factor in a wide
spectrum of human cancers and other diseases.
The mammalian target of the macrolide antibiotic Rapamycin (sirolimus) is the
enzyme mTOR. This enzymes belongs to the phosphatidylinositol (PI) kinase-
related kinase
(PIKK) family of protein kinases, which also includes ATM, ATR, DNA-PK and
hSMG-1.
is mTOR, like other PIKK family members, does not possess detectable lipid
kinase activity, but
instead functions as a serine/threonine kinase. Much of the knowledge of mTOR
signalling is
based upon the use of Rapamycin. Rapamycin first binds to the 12 kDa
immunophilin
FK506-binding protein (FKBP12) and this complex inhibits mTOR signalling (Tee
and
Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37). The mTOR
protein
20 consists of a catalytic kinase domain, an FKBP 12-Rapamycin binding (FRB)
domain, a
putative repressor domain near the C-terminus and up to 20 tandemly-repeated
HEAT motifs
at the N-terminus, as well as FRAP-ATM-TRRAP (FAT) and FAT C-terminus domain
(Huang and Houghton, Current Opinion in Pharmacology, 2003, 3, 371-377).
mTOR kinase is a key regulator of cell growth and has been shown to regulate a
wide
25 range of cellular functions including translation, transcription, mRNA
turnover, protein
stability, actin cytoskeleton reorganisation and autophagy (Jacinto and Hall,
Nature Reviews
Molecular and Cell Biology, 2005, 4, 117-126). mTOR kinase integrates signals
from growth
factors (such as insulin or insulin-like growth factor) and nutrients (such as
amino acids and
glucose) to regulate cell growth. mTOR kinase is activated by growth factors
through the
30 PI3K-Akt pathway. The most well characterised function of mTOR kinase in
mammalian
cells is regulation of translation through two pathways, namely activation of
ribosomal S6Kl
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-2-
to enhance translation of mRNAs that bear a 5'-terminal oligopyrimidine tract
(TOP) and
suppression of 4E-BPl to allow CAP-dependent mRNA translation.
Generally, investigators have explored the physiological and pathological
roles of
mTOR using inhibition with Rapamycin and related Rapamycin analogues based on
their
s specificity for mTOR as an intracellular target. However, recent data
suggests that
Rapamycin displays variable inhibitory actions on mTOR signalling functions
and suggest
that direct inhibition of the mTOR kinase domain may display substantially
broader anti-
cancer activities than that achieved by Rapamycin (Edinger et al., Cancer
Research, 2003, 63,
8451-8460). For this reason, potent and selective inhibitors of mTOR kinase
activity would
io be useful to allow a more complete understanding of mTOR kinase function
and to provide
useful therapeutic agents.
There is now considerable evidence indicating that the pathways upstream of
mTOR,
such as the P13K pathway, are frequently activated in cancer (Vivanco and
Sawyers, Nature
Reviews Cancer, 2002, 2, 489-501; Bjomsti and Houghton, Nature Reviews Cancer,
2004, 4,
is 335-348; Inoki et al., Nature Genetics, 2005, 37, 19-24). For example,
components of the
P13K pathway that are mutated in different human tumours include activating
mutations of
growth factor receptors and the amplification and/or overexpression of P13K
and Akt.
In addition there is evidence that endothelial cell proliferation may also be
dependent
upon mTOR signalling. Endothelial cell proliferation is stimulated by vascular
endothelial
20 cell growth factor (VEGF) activation of the PI3K-Akt-mTOR signalling
pathway (Dancey,
Expert Opinion on Investigational Drugs, 2005, 14, 313-328). Moreover, mTOR
kinase
signalling is believed to partially control VEGF synthesis through effects on
the expression of
hypoxia-inducible factor-la (HIF-la) (Hudson et al., Molecular and Cellular
Biology, 2002,
22, 7004-7014). Therefore, tumour angiogenesis may depend on mTOR kinase
signalling in
25 two ways, through hypoxia-induced synthesis of VEGF by tumour and stromal
cells, and
through VEGF stimulation of endothelial proliferation and survival through
PI3K-Akt-mTOR
signalling.
These findings suggest that pharmacological inhibitors of mTOR kinase should
be of
therapeutic value for treatment of the various forms of cancer comprising
solid tumours such
3o as carcinomas and sarcomas and the leukaemias and lymphoid malignancies. In
particular,
inhibitors of mTOR kinase should be of therapeutic value for treatment of, for
example,
cancer of the breast, colorectum, lung (including small cell lung cancer, non-
small cell lung
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-3-
cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile
duct, bone,
bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus,
ovary, pancreas,
skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including
ALL and CML),
multiple myeloma and lymphomas.
s In addition to tumourigenesis, there is evidence that mTOR kinase plays a
role in an
array of hamartoma syndromes. Recent studies have shown that the tumour
suppressor
proteins such as TSCl, TSC2, PTEN and LKBl tightly control mTOR kinase
signalling.
Loss of these tumour suppressor proteins leads to a range of hamartoma
conditions as a result
of elevated mTOR kinase signalling (Tee and Blenis, Seminars in Cell and
Developmental
io Biology, 2005, 16, 29-37). Syndromes with an established molecular link to
dysregulation of
mTOR kinase include Peutz-Jeghers syndrome (PJS), Cowden disease, Bannayan-
Riley-
Ruvalcaba syndrome (BRRS), Proteus syndrome, Lhermitte-Duclos disease and
Tuberous
Sclerosis (TSC) (Inoki et al., Nature Genetics, 2005, 37, 19-24). Patients
with these
syndromes characteristically develop benign hamartomatous tumours in multiple
organs.
15 Recent studies have revealed a role for mTOR kinase in other diseases
(Easton &
Houghton, Expert Opinion on Therapeutic Targets, 2004, 8, 551-564). Rapamycin
has been
demonstrated to be a potent immunosuppressant by inhibiting antigen-induced
proliferation of
T cells, B cells and antibody production (Sehgal, Transplantation Proceedings,
2003, 35, 7S-
14S) and thus mTOR kinase inhibitors may also be useful immunosuppressives.
Inhibition of
20 the kinase activity of mTOR may also be useful in the prevention of
restenosis, that is the
control of undesired proliferation of normal cells in the vasculature in
response to the
introduction of stents in the treatment of vasculature disease (Morice et al.,
New England
Journal of Medicine, 2002, 346, 1773-1780). Furthermore, the Rapamycin
analogue,
everolimus, can reduce the severity and incidence of cardiac allograft
vasculopathy (Eisen et
25 al., New England Journal of Medicine, 2003, 349, 847-858). Elevated mTOR
kinase activity
has been associated with cardiac hypertrophy, which is of clinical importance
as a major risk
factor for heart failure and is a consequence of increased cellular size of
cardiomyocytes (Tee
& Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37). Thus
mTOR
kinase inhibitors are expected to be of value in the prevention and treatment
of a wide variety
30 of diseases in addition to cancer.
It is also believed that a number of these morpholino pyrimidine derivatives
may have
inhibitory activity against the phosphatidylinositol (PI) 3-kinases family of
kinases.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-4-
Phosphatidylinositol (PI) 3-kinases (PI3Ks) are ubiquitous lipid kinases that
function
both as signal transducers downstream of cell-surface receptors and in
constitutive
intracellular membrane and protein trafficking pathways. All PI3Ks are dual-
specificity
enzymes with a lipid kinase activity that phosphorylates phosphoinositides at
the 3-hydroxy
position, and a less well characterised protein kinase activity. The lipid
products of P13K-
catalysed reactions comprising phosphatidylinosito13,4,5-trisphosphate
[PI(3,4,5)P3],
phosphatidylinosito13,4-bisphosphate [PI(3,4)P2] and phosphatidylinositol 3-
monophosphate
[PI(3)P] constitute second messengers in a variety of signal transduction
pathways, including
those essential to cell proliferation, adhesion, survival, cytoskeletal
rearrangement and vesicle
io trafficking. PI(3)P is constitutively present in all cells and its levels
do not change
dramatically following agonist stimulation. Conversely, PI(3,4)P2 and
PI(3,4,5)P3 are
nominally absent in most cells but they rapidly accumulate on agonist
stimulation.
The downstream effects of PI3K-produced 3-phosphoinositide second messengers
are
mediated by target molecules containing 3-phosphoinositide binding domains
such as the
is pleckstrin homology (PH) domain and the recently identified FYVE and phox
domains.
Well-characterised protein targets for P13K include PDKl and protein kinase B
(PKB). In
addition, tyrosine kinases like Btk and Itk are dependent on P13K activity.
The P13K family of lipid kinases can be classified into three groups according
to their
physiological substrate specificity (Vanhaesebroeck et al., Trends in Biol.
Sci., 1997, 22,
2o 267). Class III P13K enzymes phosphorylate PI alone. In contrast, Class II
P13K enzymes
phosphorylate both PI and PI 4-phosphate [PI(4)P]. Class I P13K enzymes
phosphorylate PI,
PI(4)P and PI 4,5-bisphosphate [PI(4,5)P2], although only PI(4,5)P2 is
believed to be the
physiological cellular substrate. Phosphorylation of PI(4,5)P2 produces the
lipid second
messenger PI(3,4,5)P3. More distantly related members of the lipid kinase
superfamily are
25 Class IV kinases such as mTOR (discussed above) and DNA-dependent kinase
that
phosphorylate serine/threonine residues within protein substrates. The most
studied and
understood of the P13K lipid kinases are the Class I P13K enzymes.
Class I PI3Ks are heterodimers consisting of a pl 10 catalytic subunit and a
regulatory
subunit. The family is further divided into Class Ia and Class lb enzymes on
the basis of
3o regulatory partners and the mechanism of regulation. Class Ia enzymes
consist of three
distinct catalytic subunits (pl 10a, p110(3 and p1106) that dimerise with five
distinct
regulatory subunits (p85a, p55a, p50a, p85(3 and p55y), with all catalytic
subunits being able
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-5-
to interact with all regulatory subunits to form a variety of heterodimers.
Class Ia PI3Ks are
generally activated in response to growth factor-stimulation of receptor
tyrosine kinases via
interaction of their regulatory subunit SH2 domains with specific phospho-
tyrosine residues
of activated receptor or adaptor proteins such as IRS-1. Both pl l0a and pl
10(3 are
s constitutively expressed in all cell types, whereas pl lOS expression is
more restricted to
leukocyte populations and some epithelial cells. In contrast, the single Class
lb enzyme
consists of a p1107 catalytic subunit that interacts with a p101 regulatory
subunit.
Furthermore, the Class lb enzyme is activated in response to G-protein coupled
receptor
systems (GPCRs) and its expression appears to be limited to leukocytes and
cardiomyocytes.
There is now considerable evidence indicating that Class Ia P13K enzymes
contribute
to tumourigenesis in a wide variety of human cancers, either directly or
indirectly (Vivanco
and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501). For example, the pl l0a
subunit is
amplified in some tumours such as those of the ovary (Shayesteh et al., Nature
Genetics,
1999, 21, 99-102) and cervix (Ma et al., Oncogene, 2000, 19, 2739-2744). More
recently,
is activating mutations within the catalytic site of the pl 10a catalytic
subunit have been
associated with various other tumours such as those of the colorectal region
and of the breast
and lung (Samuels et al., Science, 2004, 304, 554). Tumour-related mutations
in the p85a
regulatory subunit have also been identified in cancers such as those of the
ovary and colon
(Philp et al., Cancer Research, 2001, 61, 7426-7429). In addition to direct
effects, it is
2o believed that activation of Class Ia PI3Ks contributes to tumourigenic
events that occur
upstream in signalling pathways, for example by way of ligand-dependent or
ligand-
independent activation of receptor tyrosine kinases, GPCR systems or integrins
(Vara et al.,
Cancer Treatment Reviews, 2004, 30, 193-204). Examples of such upstream
signalling
pathways include over-expression of the receptor tyrosine kinase erbB2 in a
variety of
25 tumours leading to activation of PI3K-mediated pathways (Harari et al.,
Oncogene, 2000, 19,
6102-6114) and over-expression of the ras oncogene (Kauffmann-Zeh et al.,
Nature, 1997,
385, 544-548). In addition, Class Ia PI3Ks may contribute indirectly to
tumourigenesis
caused by various downstream signalling events. For example, loss of the
effect of the PTEN
tumour-suppressor phosphatase that catalyses conversion of PI(3,4,5)P3 back to
PI(4,5)P2 is
3o associated with a very broad range of tumours via deregulation of PI3K-
mediated production
of PI(3,4,5)P3 (Simpson and Parsons, Exp. Cell Res., 2001, 264, 29-41).
Furthermore,
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-6-
augmentation of the effects of other P13K-mediated signalling events is
believed to contribute
to a variety of cancers, for example by activation of Akt (Nicholson and
Anderson, Cellular
Signalling, 2002, 14, 381-395).
In addition to a role in mediating proliferative and survival signalling in
tumour cells,
s there is evidence that Class Ia P13K enzymes contribute to tumourigenesis in
tumour-
associated stromal cells. For example, P13K signalling is known to play an
important role in
mediating angiogenic events in endothelial cells in response to pro-angiogenic
factors such as
VEGF (Abid et al., Arterioscler. Thromb. Vasc. Biol., 2004, 24, 294-300). As
Class I P13K
enzymes are also involved in motility and migration (Sawyer, Expert Opinion
Investig. Drugs,
io 2004, 13, 1-19), P13K enzyme inhibitors should provide therapeutic benefit
via inhibition of
tumour cell invasion and metastasis. In addition, Class I P13K enzymes play an
important
role in the regulation of immune cells contributing to pro-tumourigenic
effects of
inflammatory cells (Coussens and Werb, Nature, 2002, 420, 860-867).
These findings suggest that pharmacological inhibitors of Class I P13K enzymes
will
15 be of therapeutic value for the treatment of various diseases including
different forms of the
disease of cancer comprising solid tumours such as carcinomas and sarcomas and
the
leukaemias and lymphoid malignancies. In particular, inhibitors of Class I
P13K enzymes
should be of therapeutic value for treatment of, for example, cancer of the
breast, colorectum,
lung (including small cell lung cancer, non-small cell lung cancer and
bronchioalveolar
20 cancer) and prostate, and of cancer of the bile duct, bone, bladder, head
and neck, kidney,
liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes,
thyroid, uterus, cervix
and vulva, and of leukaemias (including ALL and CML), multiple myeloma and
lymphomas.
PI3Ky, the Class lb P13K, is activated by GPCRs, as was finally demonstrated
in mice
lacking the enzyme. Thus, neutrophils and macrophages derived from PI3Ky-
deficient
25 animals failed to produce PI(3,4,5)P3 in response to stimulation with
various chemotactic
substances (such as IL-8, C5a, fMLP and MIP-la), whereas signalling through
protein
tyrosine kinase-coupled receptors to Class Ia PI3Ks was intact (Hirsch et al.,
Science, 2000,
287(5455), 1049-1053; Li et al., Science, 2002, 287(5455), 1046-1049; Sasaki
et al., Science
2002, 287(5455), 1040-1046). Furthermore, PI(3,4,5)P3-mediated phosphorylation
of PKB
30 was not initiated by these GPCR ligands in PI3Ky-null cells. Taken
together, the results
demonstrated that, at least in resting haematopoietic cells, PI3Ky is the sole
P13K isoform that
is activated by GPCRs in vivo. When murine bone marrow-derived neutrophils and
peritoneal
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-7-
macrophages from wild-type and PI3Ky /- mice were tested in vitro, a reduced,
but not
completely abrogated, performance in chemotaxis and adherence assays was
observed.
However, this translated into a drastic impairment of IL-8 driven neutrophil
infiltration into
tissues (Hirsch et al., Science, 2000, 287(5455), 1049-1053.). Recent data
suggest that PI3Ky
s is involved in the path finding process rather than in the generation of
mechanical force for
motility, as random migration was not impaired in cells that lacked PI3Ky
(Hannigan et al.,
Proc. Nat. Acad. of Sciences of U.S.A., 2002, 99(6), 3603-8). Data linking
PI3Ky to
respiratory disease pathology came with the demonstration that PI3Ky has a
central role in
regulating endotoxin-induced lung infiltration and activation of neutrophils
leading to acute
io lung injury (Yum et al., J. Immunology, 2001, 167(11), 6601-8). The fact
that although
PI3Ky is highly expressed in leucocytes, its loss seems not to interfere with
haematopoiesis,
and the fact that PI3Ky-null mice are viable and fertile further implicates
this P13K isoform as
a potential drug target. Work with knockout mice also established that PI3Ky
is an essential
amplifier of mast cell activation (Laffargue et al., Immunity, 2002, 16(3),
441-45 1).
is Thus, in addition to tumourigenesis, there is evidence that Class I P13K
enzymes play
a role in other diseases (Wymann et al., Trends in Pharmacological Science,
2003, 24, 366-
376). Both Class Ia P13K enzymes and the single Class lb enzyme have important
roles in
cells of the immune system (Koyasu, Nature Immunology, 2003, 4, 313-319) and
thus they
are therapeutic targets for inflammatory and allergic indications. Recent
reports demonstrate
20 that mice deficient in PI3Ky and PI3K6 are viable, but have attenuated
inflammatory and
allergic responses (Ali et al., Nature, 2004, 431(7011), 1007-11). Inhibition
of P13K is also
useful to treat cardiovascular disease via anti-inflammatory effects or
directly by affecting
cardiac myocytes (Prasad et al., Trends in Cardiovascular Medicine, 2003, 13,
206-212).
Thus, inhibitors of Class I P13K enzymes are expected to be of value in the
prevention and
25 treatment of a wide variety of diseases in addition to cancer.
Several compounds that inhibit PI3Ks and phosphatidylinositol (PI) kinase-
related
kinase (PI3KKs) have been identified, including wortmannin and the quercetin
derivative
LY294002. These compounds are reasonably specific inhibitors of PI3Ks and
PI3KKs over
other kinases but they lack potency and display little selectivity within the
P13K families.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-8-
Accordingly, it would be desirable to provide further effective mTOR and/or
P13K
inhibitors for use in the treatment of cancer, inflammatory or obstructive
airways diseases,
immune or cardiovascular diseases.
Morpholino pyrimidine derivatives and P13K inhibitors are known in the art.
s International Patent Application WO 2004/048365 discloses compounds that
possess
P13K enzyme inhibitory activity and are useful in the treatment of cancer.
These compounds
are arylamino- and heteroarylamino-substituted pyrimidines which differ from
the compounds
of the present invention by virtue of their arylamino- and heteroarylamino
substituents. WO
2004/048365 does not disclose compounds with the -XR' substituents of the
present
io invention. Inhibitors of P13K activity useful in the treatment of cancer
are also disclosed in
European Patent Application 1 277 738 which mentions 4-morpholino-substituted
bicyclic
heteroaryl compounds such as quinazoline and pyrido[3,2-d]pyrimidine
derivatives and 4-
morpholino-substituted tricyclic heteroaryl compounds but not monocyclic
pyrimidine
derivatives.
is W02007/080382, W02008/023180 and W02008/023159 disclose compounds that
possess mTOR and/or P13K enzyme inhibitory activity and are useful in the
treatment of
cancer.
A number of compounds such as 4-morpholin-4-yl-6-(phenylsulfonylmethyl)-2-
pyridin-4-yl-pyrimidine and 4-{6-[(phenylsulfonyl)methyl]-2-pyridin-2-
ylpyrimidin-4-
20 yl}morpholine have been registered in the Chemical Abstracts database but
no utility has been
indicated and there is no suggestion that these compounds have mTOR and/or
P13K inhibitory
activity or useful therapeutic properties.
Surprisingly, we have found that certain morpholino pyrimidine derivatives
possess
useful therapeutic properties. Without wishing to be bound by theoretical
constraints, it is
25 believed that the therapeutic usefulness of the derivatives is derived from
their inhibitory
activity against mTOR kinase and/or one or more P13K enzyme (such as the Class
Ia enzyme
and/or the Class lb enzyme). Because signalling pathways mediated by the
PI3K/mTOR
families have a central role in a number of cell processes including
proliferation and survival,
and because deregulation of these pathways is a causative factor in a wide
spectrum of human
30 cancers and other diseases, it is expected that the derivatives will be
therapeutically useful. In
particular, it is expected that the derivatives will have anti-proliferative
and/or apoptotic
properties which means that they will be useful in the treatement of
proliferative disease such
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-9-
as cancer. The compounds of the present invention may also be useful in
inhibiting the
uncontrolled cellular proliferation which arises from various non-malignant
diseases such as
inflammatory diseases, obstructive airways diseases, immune diseases or
cardiovascular
diseases.
s Generally, the compounds of the present invention possess potent inhibitory
activity
against mTOR kinase but the compound may also possess potent inhibitory
activity against
one or more P13K enzyme (such as the Class Ia enzyme and/or the Class lb
enzyme).
In accordance with one aspect of the present invention, there is provided a
compound
of formula (I)
col
CN1 R3
' YY2
R'~_'
X N Rz
formula (I)
or a pharmaceutically acceptable salt thereof; wherein
X is a linker group selected from -CR4=CR5-, -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -
C=C-, -
C=CCR6R7-, -CR6R'C=C-, -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R'-,
is -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R'-, -NR4C(O)NR5CR6R'-,
-NR4S(O)2CR6R'-, -S(O)2NR4CR6R7-, -C(O)NR4-, -NR4C(O)-, -NR4C(O)NR5-, -
S(O)2NR4-
and -NR4S(O)2-;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
2o R' is a group selected from C1_6alkyl, C2_6alkenyl, C2_6alkynyl,
carbocyclyl, carbocyc1y1C1_
6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group is optionally
substituted by one or
more substituent group selected from halo, cyano, nitro, R9, -OR9, -SR9, -
SOR9, -S02R9,
-COR9, -C02R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR1oR15
~
-NR9COCONR10R15 and -NR9SO2R10;
25 R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-10-
Ri i, -ORi i, -SRi i, -SORi i, -SOzRi i, -CORi i 11 11 12 11 iz
, -CO2R , -CONR R , -NR R , and -
NR"COCONR1zR16;
R3 is selected from halo, cyano, nitro, -R13, -OR'3, -SR'3, -SOR'3, -SOZR'3, -
COR'3, -COZR'3
,
-CONR13R14 -NR13R14 _NRI3COR14 -NR13COzR14 and -NR13SOzR14=
> > > >
s R4 and Rs are independently hydrogen or C1_6alkyl;
or R' and R4 together with the atom or atoms to which they are attached form a
4- to 10-
membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms
is optionally
replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloC1_6alkyl,
i o haloC l_6alkoxy, hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC
1_6alkyl, C 1_6alkoxyC 1_
6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoCi_6alkyl, cyanoCi_6alkyl, C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl,
bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl, C 1_
is 6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R6 and R' are independently selected from hydrogen, halo, cyano, nitro and
C1_6alkyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
20 substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloC1_6alkyl, haloC1_6alkoxy, hydroxyC1_6alkyl,
hydroxyC1_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino,
aminoCl_6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
2s 6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
Rii and Ri2 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
30 6alkyl, C 1_6alkoxy, haloC i_6alkyl, haloC i_6alkoxy, hydroxyC i_6alkyl,
hydroxyC i_6alkoxy, C 1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino,
aminoCl_6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-11-
6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino, carbamoyl,
C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R13 R14 Ris and R16 are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
s optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
1 o sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
for use as a medicament in the treatment of proliferative disease.
In accordance with one aspect of the present invention, there is provided a
compound
of formula (I)
O
CN1 R3
' YY2
R'~-'
X N
15 Rz
formula (I)
or a pharmaceutically acceptable salt thereof; wherein
X is a linker group selected from -CR4=CR5-, -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -
C=C-, -
20 C=CCR6R7-, -CR6R7C=C-, -NR4CR6R~-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)NRsCR6R'-, -S(O)2NR4CR6R'-, -C(O)NR4-,
-NR4C(O)-, -NR4C(O)NR5-, -S(O)2NR4- and -NR4S(O)2-;
iY and Y2 are independently N or CR8 provided that one of 'Y and Yz is N and
the other is
CRg ;
25 R' is a group selected from C1_6alkyl, C2_6alkenyl, C2_6alkynyl,
carbocyclyl, carbocyc1y1C1_
6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group is optionally
substituted by one or
more substituent group selected from halo, cyano, nitro, R9, -OR9, -SR9, -
SOR9, -S02R9,
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-12-
-COR9> -CO2R9> -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR1oRls
,
-NR9COCONR10Rls and -NR9SO2R10;
R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -
s R", -OR", -SRll, -SORll, -SOZRll, -CORll, -CO2R11, -CONR11R Iz, -NR11R lz
, and -
NR"COCONR1zR16;
R3is selected from halo, c ano nitro, '3 '3 '3 '3 '3 '3
y , , - , -OR , -SR , -SOR , -SOZR , -COR , -COZR ,
-CONR13R14 -NR13R14 -NRI3COR14 -NR13COzR14 and -NR13SOzR14=
> > > >
R4 and R5 are independently hydrogen or C1_6alkyl;
io or R' and R4 together with the atom or atoms to which they are attached
form a 4- to 10-
membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms
is optionally
replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl,
haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
is 6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoC1_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoCi_6alkyl, cyanoCi_6alkyl, C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl,
bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl, C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
2o R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and
C1_6alkyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
2s 6alkyl, C 1_6alkoxy, haloC i_6alkyl, haloC i_6alkoxy, hydroxyC i_6alkyl,
hydroxyC i_6alkoxy, C 1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino,
aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl, bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC1_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
30 carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
Rii and Ri2 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-13-
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino,
aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl, bis(C1_6alkyl)aminoCi_6alkyl,
cyanoCi_6alkyl, C1_
s 6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl, C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R13 R14 Ris and R16 are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
io hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
is 6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
for use as a medicament in the treatment of proliferative disease.
In accordance with one aspect of the present invention, there is provided a
compound
of formula (I)
col
CN1 R3
' YY2
Rl ~-' /\ ~
X N Rz
20 formula (I)
or a pharmaceutically acceptable salt thereof; wherein
X is a linker group selected from -CR4=CRs-, -CR4=CR5CR6R7-, -CR6R7CR5 =CR4-,
-C=C-, -C=CCR6R'-, -CR6R'C=C-, -NR4CR6R'-, -OCR6R'-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)NRsCR6R'-, -S(O)2NR4CR6R'-, -C(O)NR4-,
25 -NR4C(O)-, -NR4C(O)NR5-, -S(O)2NR4- and -NR4S(O)2-;
iY and Y2 are independently N or CR8 provided that one of 'Y and Yz is N and
the other is
CRg ;
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-14-
R' is a group selected from C1_6alkyl, carbocyclyl, carbocyc1y1C1_6alkyl,
heterocyclyl and
heterocyc1y1C1_6alkyl, which group is optionally substituted by one or more
substituent group
selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R'0 and -
NR9COR'0;
R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
s substituted by one or more substituent group independently selected from
halo, cyano, nitro, -
R", i-CORi 1-CONR11R12 and -NR11R12 =
> > > >
R3 is selected from halo, cyano, nitro, -R13, -OR13, -COR13, -CONR13R14, -
NR13R14 and
-NR13COR14;
R4 and R5 are independently hydrogen or C1_6alkyl;
io R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and
C1_6alkyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
15 hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
Rii and Ri2 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
2o hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
R13 and R14 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
25 hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
for use as a medicament in the treatment of proliferative disease.
In accordance with another aspect of the present invention, there is provided
the use of
a compound of formula (I)
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-15-
O
N R3
' Y/~Y 2
X N 2
formula (I)
or a pharmaceutically acceptable salt thereof; wherein
X is a linker group selected from -CR4=CRs-, -CR4=CRsCR6R7-, -CR6R7CRs=CR4-,
s-C=-C-, -C=CCR6R'-, -CR6R'C=C-, -NR4CR6R'-, -OCR6R'-, -SCR6R7-, -S(O)CR6R7-,
>
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R'-, -NR4C(O)NR5CR6R'-,
-NR4S(O)2CR6R'-, -S(O)2NR4CR6R7-, -C(O)NR4-, -NR4C(O)-, -NR4C(O)NR5-, -
S(O)zNR4-
and -NR4S(O)2-;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
io CRg;
R' is a group selected from C1_6alkyl, Cz_6alkenyl, Cz_6alkynyl, carbocyclyl,
carbocyc1y1C1_
6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group is optionally
substituted by one or
more substituent group selected from halo, cyano, nitro, -R9, -OR9, -SR9, -
SOR9, -S02R9,
-COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9C02Rlo, 9 lo is
-NRCONR R ,
is -NR9COCONR10Rls and -NR9SO2R10;
R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -
Rll, -ORll, - SRll, -SORll, -SOZRll, -CORll, -CO2R11, -CONR11R Iz, -NR11 lz
R and -
NR"COCONR1zR16;
2o R3 is selected from halo, c ano nitro, '3 '3 '3 '3 '3 '3
y , , - , -OR , -SR , -SOR , -SOZR , -COR , -COZR ,
-CONR13R14, -NR13R14, -NRI3COR14, -NR13COzR14 and -NR13SOzR14;
R4 and Rs are independently hydrogen or C1_6alkyl;
or R' and R4 together with the atom or atoms to which they are attached form a
4- to 10-
membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms
is optionally
25 replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloC1_6alkyl,
haloC1_6alkoxy, hydroxyC1_6alkyl, hydroxyC1_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-16-
6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCI-6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoCi_6alkyl, cyanoCi_6alkyl, C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl,
bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl, C 1_
s 6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and
C1_6alkyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
io substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino,
aminoCI-6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
is 6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
Rii and Ri2 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
20 6alkyl, C 1_6alkoxy, haloC i_6alkyl, haloC i_6alkoxy, hydroxyC i_6alkyl,
hydroxyC i_6alkoxy, C 1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino,
aminoCI-6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino, carbamoyl,
C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
25 R13 R14 Ris and R16 are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
30 6alkyl)amino, aminoCI-6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-17-
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
in the manufacture of a medicament for use in the treatment of proliferative
disease.
In accordance with another aspect of the present invention, there is provided
the use of
s a compound of formula (I)
col
CN1 R3
' Y/~Y2
Rl ~_, /\ ~
X N Rz
formula (I)
or a pharmaceutically acceptable salt thereof; wherein
X is a linker group selected from -CR4=CRs-, -CR4=CR5CR6R7-, -CR6R7CR5 =CR4-,
io -C=-C-, -C=CCR6R'-, -CR6R'C=C-, -NR4CR6R'-, -OCR6R'-, -SCR6R7-, -S(O)CR6R7-
,
>
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)NRsCR6R'-, -S(O)2NR4CR6R'-, -C(O)NR4-,
-NR4C(O)-, -NR4C(O)NR5-, -S(O)2NR4- and -NR4S(O)2-;
iY and Y2 are independently N or CR8 provided that one of 'Y and Yz is N and
the other is
CRg ;
is R' is a group selected from C1_6alkyl, C2_6alkenyl, C2_6alkynyl,
carbocyclyl, carbocyc1y1C1_
6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group is optionally
substituted by one or
more substituent group selected from halo, cyano, nitro, -R9, -OR9, -SR9, -
SOR9, -S02R9,
-COR9> -CO2R9> -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR1oR15
~
-NR9COCONR10Rls and -NR9SO2R10;
zo R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -
R", -OR", - SR", -SORll, -SOzRll, -CORll, -CO2R11, -CONR11R Iz, -NR11 lz
R and -
NR"COCONR1zR16;
R3 is selected from halo, c ano nitro, R' 3 ' 3 ' 3 ' 3 ' 3 ' 3 ' 3
y , - , -OR , -SR , -SOR , -SOZR , -COR , -COZR ,
25 -CONR13R14 -NR13R14 -NRI3COR14 -R13COzR14 and -NR13SOzR14=
> > > >
R4 and R5 are independently hydrogen or C1_6alkyl;
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-18-
or R' and R4 together with the atom or atoms to which they are attached form a
4- to 10-
membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms
is optionally
replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl,
s haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoCi_6alkyl, cyanoCi_6alkyl, C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl,
bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl, C 1_
io 6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and
C1_6alkyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
is substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino,
aminoCl_6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
20 6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
Rii and Ri2 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
2s 6alkyl, C 1_6alkoxy, haloC i_6alkyl, haloC i_6alkoxy, hydroxyC i_6alkyl,
hydroxyC i_6alkoxy, C 1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino,
aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl, bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC1_6alkyl, C1_
6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino, carbamoyl,
C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
3o R13 R14 Ris and R16 are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-19-
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl,
bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
s sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
in the manufacture of a medicament for use in the treatment of proliferative
disease.
In accordance with another aspect of the present invention, there is provided
the use of
a compound of formula (I)
col
CN1 R3
' Y/~Y2
R'~_,
X N Rz
formula (I)
or a pharmaceutically acceptable salt thereof; wherein
X is a linker group selected from -CR4=CRs-, -CR4=CR5CR6R7-, -CR6R7CR5 =CR4-,
-C=C-, -C=CCR6R'-, -CR6R'C=C-, -NR4CR6R'-, -OCR6R'-, -SCR6R7-, -S(O)CR6R7-,
1s -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)NRsCR6R'-, -S(O)2NR4CR6R'-, -C(O)NR4-
,
-NR4C(O)-, -NR4C(O)NR5-, -S(O)2NR4- and -NR4S(O)2-;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
R' is a group selected from C1_6alkyl, carbocyclyl, carbocyc1y1C1_6alkyl,
heterocyclyl and
2o heterocyc1y1C1_6alkyl, which group is optionally substituted by one or more
substituent group
selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R'0 and -
NR9COR'0;
R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -
R", i-CORi 1-CONR11R12 and -NR11R12 =
> > > >
25 R3 is selected from halo, cyano, nitro, -R13, -OR13, -COR13, -CONR13R14
NR13R14 and
~-
-NR13COR14;
R4 and R5 are independently hydrogen or C1_6alkyl;
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-20-
R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and
C1_6alkyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
s from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
Rii and Ri2 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
1 o from halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl,
haloC 1_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
R13 and R14 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
15 from halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl,
haloC 1_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
in the manufacture of a medicament for use in the treatment of proliferative
disease.
In accordance with a further aspect of the present invention, there is also
provided a
20 compound of formula (I)
O
N R3
I YY2
Rl~-' /\ ::'
X N Rz
formula (I)
or a pharmaceutically acceptable salt thereof; wherein
X is a linker group selected from -CR4=CR5-, -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -
C=C-, -
25 C=CCR6R7-, -CR6R'C=C-, -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R'-,
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-21-
-S(O)zCR6R'-, -C(O)NR4CR6R7-, -NR4C(O)CR6R'-, -NR4C(O)NRsCR6R7-,
-NR4S(O)2CR6R7-, -S(O)2NR4CR6R7-, -C(O)NR4-, -NR4C(O)-, -NR4C(O)NRs-, -(O)zNR4-
and -NR4S(O)2-;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
s CRg;
R' is a group selected from C1_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl,
carbocyc1y1C1_
6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group is optionally
substituted by one or
more substituent group selected from halo, cyano, nitro, -R9, -OR9, -SR9, -
SOR9, -02R9,
-COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9C02Rlo, 9 lo is
-NRCONR R ,
io -NR9COCONR10Rls and NR9SO2R10;
R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -
R", -OR", -SRll, -SORll, -SOZRll, -CORll, -CO2R11, -CONR11R Iz, -NR11 lz
R and -
NR"COCONR1zR16;
is R3 is selected from halo, c ano nitro, '3 '3 '3 '3 '3 '3
y , , - , -OR , -R , -SOR , -SOzR , -COR , -COzR , -
CONR13R14 -NR13R14 -NRI3COR14 -NR13C02R14 and -NR13SOzR14=
> > > >
R4 and R5 are independently hydrogen or C1_6alkyl;
or R' and R4 together with the atom or atoms to which they are attached form a
4- to 10-
membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms
is optionally
2o replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloC1_6alkyl,
haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoCi_6alkyl, cyanoCi_6alkyl, C1_6alkylsulfonyl, C1_
2s 6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl,
bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl, C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and
C1_6alkyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
3o R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-22-
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino,
aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl, bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC1_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
s 6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
Rii and Ri2 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino,
aminoCl_6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino, carbamoyl,
C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
is R13 R14 Ris and R16 are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
z0 6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In accordance with a further aspect of the present invention, there is also
provided a
25 compound of formula (I)
col
N R3
I YY2
Rl~-' /\ ::'
X N Rz
formula (I)
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-23-
or a pharmaceutically acceptable salt thereof; wherein
X is a linker group selected from -CR4=CRs-, -CR4=CRsCR6R7-, -CR6R7CRs=CR4-,
-C=C-, -C=CCR6R'-, -CR6R'C=C-, -NR4CR6R'-, -OCR6R'-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)NRsCR6R'-, -S(O)2NR4CR6R'-, -C(O)NR4-,
s -NR4C(O)-, -NR4C(O)NR5-, -S(O)2NR4- and -NR4S(O)2-;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
R' is a group selected from C1_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl,
carbocyc1y1C1_
6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group is optionally
substituted by one or
io more substituent group selected from halo, cyano, nitro, -R9, -OR9, -SR9, -
SOR9, -02R9,
-COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9C02Rlo, 9 lo is
-NRCONR R ,
-NR9COCONR10Rls and NR9SO2R10;
R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -
ls R", -OR", -SRll, -SORll, -SOZRll, -CORll, -CO2R11, -CONR11R Iz, -NR11 lz
R and -
NR"COCONR1zR16;
R3 is inde endentl selected from halo, c ano nitro, R' 3 ' 3 ' 3 ' 3 ' 3
p y y , - , -OR , -R , -SOR , -SOZR ,
-COR13> -CO2R13> -CONR13R14, -NR13R14, -NRI3COR14, -NR13C02R14 and -
NR13SOzR14;
R4 and R5 are independently hydrogen or C1_6alkyl;
20 or R' and R4 together with the atom or atoms to which they are attached
form a 4- to 10-
membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms
is optionally
replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl,
haloC1_6alkoxy, hydroxyC1_6alkyl, hydroxyC1_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
2s 6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoCi_6alkyl, cyanoCi_6alkyl, C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl,
bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl, C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
3o R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and
C1_6alkyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-24-
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
s 6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino,
aminoCl_6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
io Rii and Ri2 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino,
15 aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl, bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC1_6alkyl, C1_
6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino, carbamoyl,
C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R13 R14 Ris and R16 are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
20 optionally substituted by one or more substituent groups selected from
halo, cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloC1_6alkyl, haloC1_6alkoxy,
hydroxyC1_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
25 sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In accordance with a further aspect of the present invention, there is also
provided a
compound of formula (I)
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-25-
O
N R3
' Y/~Y 2
X N 2
formula (I)
or a pharmaceutically acceptable salt thereof; wherein
X is a linker group selected from -CR4=CRs-, -CR4=CRsCR6R7-, -CR6R7CRs=CR4-, -
C=C-, -
s C=CCR6R7-, -CR6R'C=C-, -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R'-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)NRsCR6R'-, -S(O)2NR4CR6R'-, -C(O)NR4-,
-NR4C(O)-, -NR4C(O)NR5-, -S(O)2NR4- and -NR4S(O)2-;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
io R' is a group selected from C1_6alkyl, carbocyclyl, carbocyc1y1C1_6alkyl,
heterocyclyl and
heterocyc1y1C1_6alkyl, which group is optionally substituted by one or more
substituent group
selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R'0 and -
R9COR'0;
R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -
is R", -ORii -CORii -CONR11R12 and -NR11R12 =
> > >
R3 is selected from halo, cyano, nitro, -R13 -OR13
-COR13, -CONR13R14, -NR13R14 and -NRI3COR14;
R4 and R5 are independently hydrogen or C1_6alkyl;
R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and
C1_6alkyl;
2o R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
2s 6alkylamino and bis(C1_6alkyl)amino;
Rii and Ri2 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-26-
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
R13 and R14 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
s heterocyclyl which group is optionally substituted by one or more
substituent groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino.
Certain compounds of formula (I) are capable of existing in stereoisomeric
forms. It
io will be understood that the invention encompasses all geometric and optical
isomers of the
compounds of formula (I) and mixtures thereof including racemates. Tautomers
and mixtures
thereof also form an aspect of the present invention. Solvates and mixtures
thereof also form
an aspect of the present invention. For example, a suitable solvate of a
compound of formula
(I) is, for example, a hydrate such as a hemi-hydrate, a mono-hydrate, a di-
hydrate or a
is tri-hydrate or an alternative quantity thereof.
The present invention relates to the compounds of formula (I) as herein
defined as
well as to salts thereof. Salts for use in pharmaceutical compositions will be
pharmaceutically
acceptable salts, but other salts may be useful in the production of the
compounds of formula
(I) and their pharmaceutically acceptable salts. Pharmaceutically acceptable
salts of the
20 invention may, for example, include acid addition salts of compounds of
formula (I) as herein
defined which are sufficiently basic to form such salts. Such acid addition
salts include but
are not limited to furmarate, methanesulfonate, hydrochloride, hydrobromide,
citrate and
maleate salts and salts formed with phosphoric and sulfuric acid. In addition
where
compounds of formula (I) are sufficiently acidic, salts are base salts and
examples include but
25 are not limited to, an alkali metal salt for example sodium or potassium,
an alkaline earth
metal salt for example calcium or magnesium, or organic amine salt for example
triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-
methylpiperidine, N-ethylpiperidine, dibenzylamine or amino acids such as
lysine.
The compounds of formula (I) may also be provided as in vivo hydrolysable
esters.
3o An in vivo hydrolysable ester of a compound of formula (I) containing
carboxy or hydroxy
group is, for example a pharmaceutically acceptable ester which is cleaved in
the human or
animal body to produce the parent acid or alcohol. Such esters can be
identified by
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-27-
administering, for example, intravenously to a test animal, the compound under
test and
subsequently examining the test animal's body fluid.
Suitable pharmaceutically acceptable esters for carboxy include
C1_6alkoxymethyl
esters for example methoxymethyl, C1_6alkanoyloxymethyl esters for example
s pivaloyloxymethyl, phthalidyl esters, C3_gcycloalkoxycarbonyloxyCl_6alkyl
esters for example
1-cyclohexylcarbonyloxyethyl, 1,3-dioxolen-2-onylmethyl esters for example
5-methyl-1,3-dioxolen-2-onylmethyl, and C1_6alkoxycarbonyloxyethyl esters for
example
1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in the
compounds of
this invention.
io Suitable pharmaceutically acceptable esters for hydroxy include inorganic
esters such
as phosphate esters (including phosphoramidic cyclic esters) and a-
acyloxyalkyl ethers and
related compounds which as a result of the in vivo hydrolysis of the ester
breakdown to give
the parent hydroxy group/s. Examples of a-acyloxyalkyl ethers include
acetoxymethoxy and
2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester
forming groups
15 for hydroxy include C1-ioalkanoyl, for example formyl, acetyl, benzoyl,
phenylacetyl,
substituted benzoyl and phenylacetyl; C1-ioalkoxycarbonyl (to give alkyl
carbonate esters), for
example ethoxycarbonyl; di-Cl-4alkylcarbamoyl and N-(di-Cl-4alkylaminoethyl)-N-
C1-4alkylcarbamoyl(to give carbamates); di-Cl-4alkylaminoacetyl and
carboxyacetyl.
Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl,
C1_
20 4alkylaminomethyl and di-(C1-4alkyl)aminomethyl, and morpholino or
piperazino linked from
a ring nitrogen atom via a methylene linking group to the 3- or 4- position of
the benzoyl ring.
Other interesting in vivo hydrolysable esters include, for example,
RAC(O)OC1_6alkyl-CO-,
wherein RA is for example, benzyloxy-Cl-4alkyl, or phenyl. Suitable
substituents on a phenyl
group in such esters include, for example, 4-C1-4piperazino-Cl-4alkyl,
piperazino-Cl-4alkyl
25 and morpholino-Cl-4alkyl.
The compounds of the formula (I) may be also be administered in the form of a
prodrug which is broken down in the human or animal body to give a compound of
the
formula (I). Various forms of prodrugs are known in the art. For examples of
such prodrug
derivatives, see:
3o a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods
in
Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press,
1985);
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-28-
b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and
H.
Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p.
113-191
(1991);
c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);
s d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);
and
e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).
In this specification the generic term "Cp_qalkyl" includes both straight-
chain and
branched-chain alkyl groups. However references to individual alkyl groups
such as "propyl"
are specific for the straight chain version only (i.e. n-propyl and isopropyl)
and references to
io individual branched-chain alkyl groups such as "tert-butyl" are specific
for the branched
chain version only.
The prefix Cp_q in Cp_qalkyl and other terms (where p and q are integers)
indicates the
range of carbon atoms that are present in the group, for example C1_4alkyl
includes Cialkyl
(methyl), C2alkyl (ethyl), C3alkyl (propyl as n-propyl and isopropyl) and
C4alkyl (n-butyl,
is sec-butyl, isobutyl and tert-butyl).
The term Cp_qalkoxy comprises -O-Cp_qalkyl groups.
The term Cp_qalkanoyl comprises -C(O)alkyl groups.
The term halo includes fluoro, chloro, bromo and iodo.
"Carbocyclyl" is a saturated, unsaturated or partially saturated monocyclic,
bicyclic or
20 tricyclic ring system containing from 3 to 14 ring atoms, wherein a ring
CH2 group may be
replaced with a C=O group. "Carbocyclyl" includes "aryl", "Cp_qcycloalkyl" and
"Cp_
qcycloalkenyl".
"aryl" is an aromatic monocyclic, bicyclic or tricyclic carbcyclyl ring
system.
"Cp_qcycloalkenyl" is an unsaturated or partially saturated monocyclic,
bicyclic or
25 tricyclic carbocyclyl ring system containing at least 1 C=C bond and
wherein a ring CH2
group may be replaced with a C=O group.
"Cp_qcycloalkyl" is a saturated monocyclic, bicyclic or tricyclic carbocyclyl
ring
system and wherein a ring CH2 group may be replaced with a C=O group.
"Heterocyclyl" is a saturated, unsaturated or partially saturated monocyclic,
bicyclic
30 or tricyclic ring system containing from 3 to 14 ring atoms of which 1, 2,
3 or 4 ring atoms are
chosen from nitrogen, sulfur or oxygen, which ring may be carbon or nitrogen
linked and
wherein a ring nitrogen or sulfur atom may be oxidised and wherein a ring CH2
group may be
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-29-
replaced with a C=O group. "Heterocyclyl" includes "heteroaryl",
"cycloheteroalkyl" and
"cycloheteroalkenyl".
"Heteroaryl" is an aromatic monocyclic, bicyclic or tricyclic heterocyclyl,
particularly
having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are chosen from
nitrogen, sulfur or
s oxygen where a ring nitrogen or sulfur may be oxidised.
"Cycloheteroalkenyl" is an unsaturated or partially saturated monocyclic,
bicyclic or
tricyclic heterocyclyl ring system, particularly having 5 to 10 ring atoms, of
which 1, 2, 3 or 4
ring atoms are chosen from nitrogen, sulfur or oxygen, which ring may be
carbon or nitrogen
linked and wherein a ring nitrogen or sulfur atom may be oxidised and wherein
a ring CH2
io group may be replaced with a C=O group.
"Cycloheteroalkyl" is a saturated monocyclic, bicyclic or tricyclic
heterocyclic ring
system, particularly having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring
atoms are chosen
from nitrogen, sulfur or oxygen, which ring may be carbon or nitrogen linked
and wherein a
ring nitrogen or sulfur atom may be oxidised and wherein a ring CH2 group may
be replaced
is with a C=O group.
This specification may make use of composite terms to describe groups
comprising
more than one functionality. Unless otherwise described herein, such terms are
to be
interpreted as is understood in the art. For example carbocyclylCp_qalkyl
comprises Cp_qalkyl
substituted by carbocyclyl, heterocyclylCp_qalkyl comprises Cp_qalkyl
substituted by
2o heterocyclyl, and bis(Cp_qalkyl)amino comprises amino substituted by 2
Cp_qalkyl groups
which may be the same or different.
HaloCp_qalkyl is a Cp_qalkyl group that is substituted by 1 or more halo
substituents and
particuarly 1, 2 or 3 halo substituents. Similarly, other generic terms
containing halo such as
haloCp_qalkoxy may contain 1 or more halo substituents and particluarly 1, 2
or 3 halo
25 substituents.
HydroxyCp_qalkyl is a Cp_qalkyl group that is substituted by 1 or more
hydroxyl
substituents and particularly by 1, 2 or 3 hydroxy substituents. Similarly
other generic terms
containing hydroxy such as hydroxyCp_qalkoxy may contain 1 or more and
particularly 1, 2 or
3 hydroxy substituents.
30 Cp_qalkoxyCp_qalkyl is a Cp_qalkyl group that is substituted by 1 or more
Cp_qalkoxy
substituents and particularly 1, 2 or 3 Cp_qalkoxy substituents. Similarly
other generic terms
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-30-
containing Cp_qalkoxy such as Cp_qalkoxyCp_qalkoxy may contain 1 or more
Cp_qalkoxy
substituents and particularly 1, 2 or 3 Cp_qalkoxy substituents.
Where optional substituents are chosen from "1 or 2", from "1, 2, or 3" or
from "1, 2,
3 or 4" groups or substituents it is to be understood that this definition
includes all
s substituents being chosen from one of the specified groups i.e. all
substitutents being the same
or the substituents being chosen from two or more of the specified groups i.e.
the substitutents
not being the same.
Compounds of the present invention have been named with the aid of computer
software (ACD/Name version 8.0).
io "Proliferative disease(s)" includes malignant disease(s) such as cancer as
well as non-
malignant disease(s) such as inflammatory diseases, obstracutive airways
diseases, immune
diseases or cardiovascular diseases.
Suitable values for any R group or any part or substitutent for such groups
include:
for C1_4alkyl: methyl, ethyl, propyl, butyl, 2-methylpropyl and tert-butyl;
is for C1_6alkyl: C1_4alkyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl and
hexyl;
for C3_6cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
for C3_6cyc1oa1kylCi_4alkyl: cyclopropylmethyl, cyclopropylethyl,
cyclobutylmethyl,
cyclopentylmethyl and cyclohexylmethyl;
20 for aryl: phenyl and naphthyl;
for ary1C1_4alkyl: benzyl, phenethyl, naphthylmethyl and naphthylethyl;
for carbocylyl: aryl, cyclohexenyl and C3_6cycloalkyl;
for halo: fluoro, chloro, bromo and iodo;
for C1_4alkoxy: methoxy, ethoxy, propoxy and isopropoxy;
25 for C1_6alkoxy: C1_4alkoxy, pentyloxy, 1-ethylpropoxy and hexyloxy;
for C1_6alkanoyl: acetyl, propanoyl and 2-methylpropanoyl;
for heteroaryl: pyridyl, imidazolyl, quinolinyl, cinnolyl, pyrimidinyl,
thienyl,
pyrrolyl, pyrazolyl, thiazolyl, thiazolyl, triazolyl, oxazolyl,
isoxazolyl, furanyl, pyridazinyl, pyrazinyl, indolyl,
30 benzofuranyl, dibenzofuranyl and benzothienyl;
for heteroarylCl_4alkyl: pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl,
imidazolylethyl, pyrazolylmethyl, pyrazolylethyl,
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-31-
furanylmethyl, furanylethyl, thienylmethyl, theinylethyl,
pyridylmethyl, pyridylethyl, pyrazinylmethyl, pyrazinylethyl,
pyrimidinylmethyl, pyrimidinylethyl, pyrimidinylpropyl,
pyrimidinylbutyl, imidazolylpropyl, imidazolylbutyl,
quinolinylpropyl, 1,3,4-triazolylpropyl and oxazolylmethyl;
for heterocyclyl: heteroaryl, pyrrolidinyl, isoquinolinyl, quinoxalinyl,
benzothiazolyl, benzoxazolyl, piperidinyl, piperazinyl,
azetidinyl, morpholinyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, indolinyl, dihydro-2H-pyranyl and
tetrahydrofuranyl.
It should be noted that examples given for terms used in the description are
not
limiting.
Particular values of m, X, 'Y and Y2XR1Ri X-Ri R2, Rs R6 R7, > > > > > > > > >
> > >
R'o, R" and R'2
are as follows. Such values may be used idividually or in combination where
appropriate, in connection with any aspect of the invention, or part thereof,
and with any of
the definitions, claims or embodiments defined herein.
x
In one aspect of the invention X is a linker group selected from -NR4CR6R'-,
-OCR6R'-, -SCR6R'-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-,
-NR4C(O)NR5CR6R7-, -S(O)2NR4CR6R7-, -NR4C(O)-, -C(O)NR4-, -S(O)2NR4- and
-NR4S(O)z-.
In another aspect X is a linker group selected from -NR4CR6R7-, -OCR6R7 -, -
SCR6R7
-,
-S(O)CR6R'-, -S(O)2CR6R7-, -C(O)NR4CR6R'-, -NR4C(O)NR5CR6R7-, -S(O)2NR4CR6R7
,
-C(O)NR4- and -NR4C(O)-.
In a further aspect X is a linker group selected from -NR4CR6R7 -, -OCR6R'-,
-SCR6R7-, -S(O)CR6R'-, -S(O)2CR6R7-, -C(O)NR4-, and -NR4C(O)-.
In a further aspect X is a linker group selected from -NR4CR6R7 -, -OCR6R'-,
-SCR6R7-, -S(O)CR6R7- and -S(O)2CR6R7-.
In yet another aspect X is a linker group selected from -SCR6R7-, -S(O)CR6R'-
and
-S(O)ZCR6R7-.
In another aspect X is a linker group selected from -NR4CH2-, -OCH2-, -SCH2-,
-S(O)CHz-, -S(O)zCHz-, -C(O)NR4-, and -NR4C(O)-.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-32-
In another aspect X is a linker group selected from -NR4CH2-, -OCH2-, -SCH2-,
-S(O)CH2- and -S(O)2CHz-.
In a further aspect X is a linker group selected from -NHCH2-, -N(CH3)CH2-, -
OCH2-,
-SCH2-, -S(O)CH2-, -S(O)zCHz-, -C(O)NH-, -C(O)N(CH3)-, -NHC(O)- and -
N(CH3)C(O)-.
s In yet a further aspect X is a linker group selected from -NHCH2-, -
N(CH3)CH2-,
-OCH2-, -SCH2- and -S(O)zCHz-.
In another aspect X is -SCH2- or -S(O)zCHz-.
In another aspect X is -S(O)zCHz-.
In a further aspect X is a linker group selected from -S(O)zCRV- and -C(O)NR4-
.
lY and Y2
In one aspect of the invention 'Y is N and Y2 is CRg.
In another aspect 'Y is N and Y2 is CH.
In yet another aspect 'Y is CR8 and Y2 is N.
In a further aspect 'Y is CH or CF and Y2 is N.
is In yet a further aspect 'Y is CH and Y2 is N.
R1
In one aspect of the invention R' is a group selected from C1_4alkyl,
C3_6cycloalkyl,
aryl, C3_6cyc1oa1ky1C1_4alkyl, ary1C1_4alkyl, cycloheteroalkyl, heteroaryl,
cycloheteroalkylCl_
4alkyl, heteroarylCl_4alkyl, which group is optionally substituted by one or
more substituent
group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R'0
and
-NR9CORlo
In another aspect, R' is a group selected from methyl, ethyl, propyl, butyl,
isobutyl,
tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl,
pyrrolyl,
imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl,
pyrrolidinylmethyl,
pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl,
imidazolylethyl,
pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl,
thienylethyl,
pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl,
pyrazinylmethyl and
pyrazinylethyl, which group is optionally substituted by 1, 2 or 3 substituent
group selected
from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10
In a further aspect, R' is a group selected from methyl, ethyl, propyl, butyl,
isobutyl,
tert-butyl, cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl,
furanylmethyl,
thienylmethyl, and pyrazinylethyl, which group is optionally substituted by 1
or 2 substituent
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-33-
group selected from halo, cyano, methyl, methoxy, trifluoromethyl,
trifluoromethoxy,
-NHCONHC6H5, -NHCOCH3, -CONH2 and -CONHCH3.
In a further aspect, R' is a group selected from methyl, ethyl, propyl, butyl,
isobutyl,
tert-butyl, cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl,
furanylmethyl,
s thienylmethyl, and pyrazinylethyl, which group is optionally substituted by
1 or 2 substituent
group selected from halo, cyano, methyl, methoxy, trifluoromethyl,
trifluoromethoxy,
-CONHz and -CONHCH3.
In yet another aspect R' is a group selected from methyl, ethyl, n-propyl,
isopropyl, n-
butyl, sec-butyl, isobutyl, tert-butyl, cyclohexyl, -CH2CN, -CH2C(O)NH2,
io -CH2CH2NC(O)CH3, phenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 2-
chloro-6-
fluorophenyl, 3-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl, 4-
trifluoromethylphenyl, 4-
trifluoromethoxyphenyl, 4-cyanophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-
dimethoxyphenyl, 4-(N-methylaminocarbonyl)phenyl, benzyl, 4-fluorobezyl, 2-
chlorobenzyl,
2-chloro-6-fluorobenzyl, 4-methoxybenzyl, phenethyl, 3-trifluorophenethyl,
furan-2ylmethyl,
is thien-2-ylmethyl, 2-pyrazin-2-ylethyl, pyidin-3-yl, 2-methylpyridin-3-yl, 2-
aminocarbonylpyridin-3-yl, 2-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-
methoxy-3-
trifluoromethylphenyl, 2-methoxypyridin-5-yl, 2-methoxypyridin-4-yl, 2-
methoxypyridin-4-
yl, 2-acetamidopyridin-5-yl, 2-acetamidopyridin-4-yl and 4-
[(anilinocarbonyl)amino]phenyl.
In yet another aspect R' is a group selected from methyl, ethyl, isopropyl,
sec-butyl,
20 isobutyl, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-fluoro-4-
methoxyphenyl, 4-
methoxy-3-trifluoromethylphenyl, 2-methoxypyridin-5-yl, 2-methoxypyridin-4-yl,
2-
methoxypyridin-4-yl, 2-acetamidopyridin-5-yl, 2-acetamidopyridin-4-yl and 4-
[(anilinocarbonyl)amino]phenyl.
-X-R1
25 In yet another aspect -XR' is a group selected from -CHzSOz-R' and -
C(CH3)2SO2-R'
wherein R' is methyl, ethyl, isopropyl, sec-butyl, isobutyl or phenyl.
In yet another aspect -XR' is -NHCO-R' wherein R' is 2-methoxyphenyl, 3-
methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-methoxy-3-trifluoromethylphenyl, 2-
methoxypyridin-5-yl, 2-methoxypyridin-4-yl, 2-methoxypyridin-4-yl, 2-
acetamidopyridin-5-
30 yl, 2-acetamidopyridin-4-yl or 4-[(anilinocarbonyl)amino]phenyl.
R2
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-34-
In one aspect of the invention R2 is selected from aryl and heteroaryl which
group is
optionally substituted by one or more substituent group independently selected
from halo,
cyano, nitro, -Ri i, -OR", -CORi i, -CONR11R12 and -NR11Riz
In another aspect R2 is selected from phenyl, naphthyl, pyrrolyl, imidazolyl,
pyrazolyl,
s furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, azaindolyl, indolyl,
quinolinyl,
benzimidazolyl, benzofuranyl, dibenzofuranyl, benzothienyl which group is
optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro,
-Ri i, -ORi i, -CORi i, -CONR11Riz and -NR11Riz
In another aspect R2 is selected from morpholinyl, piperidinyl, phenyl,
naphthyl,
io pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl,
pyridazinyl,
azaindolyl, indolyl, quinolinyl, benzimidazolyl, benzofuranyl, dibenzofuranyl,
benzothienyl
which group is optionally substituted by one or more substituent group
independently selected
from halo, methyl, methoxy, hydroxymethyl, cyanomethyl, phenoxy, pyrrolidinyl,
-CONH2,
-CONHCH3 and -CON(CH3)2.
is In another aspect R2 is selected from phenyl, naphthyl, pyrrolyl,
imidazolyl, pyrazolyl,
furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, azaindolyl, indolyl,
quinolinyl,
benzimidazolyl, benzofuranyl, dibenzofuranyl, benzothienyl which group is
optionally
substituted by one or more substituent group independently selected from halo,
methyl,
methoxy, hydroxymethyl, cyanomethyl, phenoxy, pyrrolidinyl, -CONH2, -CONHCH3
and
20 -CON(CH3)z.
In yet another aspect R2 is 3-(hydroxymethyl)phenyl, 4-(hydroxymethyl)phenyl,
4-
(cyanomethyl)phenyl, 3,4-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-
phenoxyphenyl, 3-
pyrrolidin-lylphenyl, 3-(aminocarbonyl)phenyl, 4-
(dimethylaminocarbonyl)phenyl, furan-3-
yl, thien-3-yl, 5-(hydroxymethyl)thien-2-yl, pyridin-2-yl, pyridin-4-yl, 2-
methoxypyridin-5-
25 yl, 2-methoxypyrimidin-5-yl, 2-methoxynaphth-6-yl, 5,7-
diazabicyclo[4.3.0]nona-2,4,8,10-
tetraenyl, azaindolyl, indol-5-yl, 1-methylindol-5-yl, quinolin-6-yl,
benzimidazolyl,
benzofuran-2-yl, dibenzofuran-l-yl and benzothien-3 -yl.
In yet a further aspect R2 is pyridin-2-yl, 3-hydroxyphenyl, 4-hydroxyphenyl,
3-
hydroxymethylphenyl, 4-hydroxymethylphenyl or indol-5-yl.
30 In another aspect R2 is phenyl, pyrazol-3y1, pyrazol-4-yl,
hydroxypiperidinyl, indol-5-
yl, azaindolyl, 3-(pyrazol-4-yl)phenyl, 4-(pyrazol-4-yl)phenyl, 2-
aminocarbonylindol-5-yl, 3-
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-35-
aminocarbonylindol-5-yl morpholinyl, 2-(pyrazol-4-yl)thiazol-5y1,
methylmorpholinyl or
dimethylmorpholinyl.
In another aspect R2 is (pyrazol-3y1)amino, hydroxypiperidinyl, indol-4-yl,
indol-5-yl,
indol-6-yl, azaindolyl, benzimidazol-5-yl, 3-(pyrazol-4-yl)phenyl, 4-(pyrazol-
4-yl)phenyl, 2-
s aminocarbonylindol-5-yl, 3-aminocarbonylindol-5-yl, 2-aminocarbonylindol-6-
yl, 3-
aminocarbonylindol-6-yl, morpholinyl, 2-(pyrazol-4-yl)thiazol-5y1 or
methylmorpholinyl.
In yet a further aspect R2 is azaindolyl, indol-5-yl, benzimidazolyl, 3-
hydroxyphenyl,
4-hydroxyphenyl, 3-hydroxymethylphenyl or 4-hydroxymethylphenyl
In another aspect R2 is pyridin-2-yl.
In a further aspect R2 is 3-hydroxyphenyl or 4-hydroxyphenyl.
In yet another aspect R2 is 3-hydroxymethylphenyl or 4-hydroxymethylphenyl.
In yet a further aspect R2 is indol-5-yl.
In one aspect R2 is morpholinyl.
In another aspect R2 is morpholinyl, methylmorpholinyl or dimethylmorpholinyl.
R3
In one aspect of the invention R3 is methyl.
R4
In one aspect of the invention R4 is hydrogen or methyl.
In another aspect R4 is hydrogen.
RS
In one aspect of the invention R 5 is hydrogen or methyl.
In another aspect R 5 is hydrogen.
R6
In one aspect of the invention R6 is hydrogen or methyl.
In another aspect R6 is hydrogen.
R'
In one aspect of the invention R7 is hydrogen or methyl.
In another aspect R7 is hydrogen.
In another aspect of the invention, when R6 is methyl, R7 is methyl.
Rg
In one aspect of the invention Rg is hydrogen or halo.
In another aspect Rg is hydrogen or fluoro.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-36-
In a further aspect Rg is hydrogen.
R9
In one aspect of the invention R9 is hydrogen or C1_4alkyl optionally
substituted by 1,
2 or 3 substituent groups selected from halo, cyano, nitro, hydroxy,
C1_4alkoxy, amino, C1_
s 4alkylamino and bis(C1_4alkyl)amino.
In another aspect R9 is hydrogen or C1_4alkyl optionally substituted by 1, 2
or 3 halo
substituents.
In a further aspect R9 is hydrogen, methyl or trifluoromethyl.
Rio
In one aspect of the invention R10 is hydrogen.
Rl l
In one aspect of the invention R" is hydrogen or a group selected from
C1_4alkyl, aryl
and cycloheteroalkyl which group is optionally substituted by 1, 2 or 3 groups
selected from
halo, hydroxy and cyano.
is In another aspect R" is hydrogen, methyl optionally substituted with
hydroxy or
cyano, phenyl or pyrrolidinyl.
In another aspect R" is hydrogen or methyl.
Ri2
In one aspect of the invention R'2 is hydrogen or methyl.
In a particular class of compound of formula (I), or a pharmaceutically
acceptable salt
thereof;
X is a linker group selected from -NR4CR6R7-,
-OCR6R'-, -SCR6R'-, -S(O)CR6R7-, -S(O)zCR6R'-, -C(O)NR4CR6R7-,
-NR4C(O)NR5CR6R7-, -S(O)2NR4CR6R7-, -NR4C(O)-, -C(O)NR4-, -S(O)2NR4- and
-NR4S(O)2-;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
R' is a group selected from C1_6alkyl, carbocyclyl, carbocyc1y1C1_6alkyl,
heterocyclyl and
heterocyc1y1C1_6alkyl, which group is optionally substituted by one or more
substituent group
selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R'0 and -
NR9COR'0;
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-37-
R2 is selected from aryl and heteroaryl which group is optionally substituted
by one or more
substituent group independently selected from halo, cyano, nitro, -R", -OR", -
COR", -
CONR11R12 and -NR11R12;
R3 is methyl;
s R4 and R5 are independently hydrogen or C1_6alkyl;
R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and
C1_6alkyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
1 o from halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl,
haloC 1_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
Rii and Ri2 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
15 from halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl,
haloC 1_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
R13 and R14 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
20 from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino.
In another particular class of compound of formula (I), or a pharmaceutically
acceptable salt thereof;
25 X is a linker group selected from -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -
S(O)CR6R7
-,
-S(O)2CR6R'-, -C(O)NR4CR6R7-, -NR4C(O)NRsCR6R'-, -S(O)2NR4CR6R7 , -C(O)NR4-
and -
NR4C(O)-;
1 YisCR8 andY2 isN;
R' is a group selected from C1_4alkyl, C3_6cycloalkyl, aryl,
C3_6cycloalkylCl_4alkyl, ary1C1_
30 4alkyl, cycloheteroalkyl, heteroaryl, cycloheteroalkylCl_4alkyl,
heteroarylCl_4alkyl, which
group is optionally substituted by one or more substituent group selected from
halo, cyano,
nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-38-
R2 is selected from aryl and heteroaryl which group is optionally substituted
by one or more
substituent group independently selected from halo, cyano, nitro, -R", -OR", -
COR",
-CONR11R12 and -NR11R12;
R3 is methyl;
s R4 and Rs are independently hydrogen or C1_6alkyl;
R6 and R' are independently selected from hydrogen, halo, cyano, nitro and
C1_6alkyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
1 o from halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl,
haloC 1_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
Rii and Ri2 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
15 from halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl,
haloC 1_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
R13 and R14 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
20 from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino.
In a further particular class of compound of formula (I), or a
pharmaceutically
acceptable salt thereof;
25 X is a linker group selected from -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -
S(O)CR6R7
-,
-S(O)2CR6R'-, -C(O)NR4-, and -NR4C(O)-;
iY is CH or CF and Y2 is N;
R' is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-
butyl, cyclohexyl,
phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl,
thienylmethyl, and
30 pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent
group selected from
halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCONHC6H5,
-NHCOCH3, -CONHz and -CONHCH3;
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-39-
R2 is selected from morpholinyl, piperidinyl, phenyl, naphthyl, pyrrolyl,
imidazolyl,
pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, azaindolyl,
indolyl, quinolinyl,
benzimidazolyl, benzofuranyl, dibenzofuranyl, benzothienyl which group is
optionally
substituted by one or more substituent group independently selected from halo,
methyl,
s methoxy, hydroxymethyl, cyanomethyl, phenoxy, pyrrolidinyl, -CONH2, -CONHCH3
and
-CON(CH3)2;
R3 is methyl;
R4 is hydrogen or methyl;
R6 is hydrogen or methyl;
io R7 is hydrogen or methyl.
In another particular class of compound of formula (I), or a pharmaceutically
acceptable salt thereof;
X is a linker group selected from -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R7
-,
-S(O)2CR6R'-, -C(O)NR4CR6R7-, -NR4C(O)NRsCR6R'-, -S(O)2NR4CR6R7 , -C(O)NR4-
and -
is NR4C(O)-;
1YisCR8 andY2 isN;
R' is a group selected from C1_4alkyl, C3_6cycloalkyl, aryl,
C3_6cycloalkylCl_4alkyl, ary1C1_
4alkyl, cycloheteroalkyl, heteroaryl, cycloheteroalkylCl_4alkyl,
heteroarylCl_4alkyl, which
group is optionally substituted by one or more substituent group selected from
halo, cyano,
2o nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10
R2 is selected from aryl and heteroaryl which group is optionally substituted
by one or more
substituent group independently selected from halo, cyano, nitro, -R", -OR", -
COR",
-CONR11R12 and -NR11R12;
R3 is methyl;
25 R4 and Rs are independently hydrogen or C1_6alkyl;
R6 and R' are independently selected from hydrogen, halo, cyano, nitro and
C1_6alkyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
30 from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-40-
Rii and Ri2 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloC1_6alkyl,
haloC1_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
s 6alkylamino and bis(C1_6alkyl)amino;
R13 and R14 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
io 6alkylamino and bis(C1_6alkyl)amino.
In a further particular class of compound of formula (I), or a
pharmaceutically
acceptable salt thereof;
X is a linker group selected from -S(O)zCRV-, -C(O)NR4- and -NR4C(O)-;
iY is CH or CF and Y2 is N;
is R' is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-
butyl, cyclohexyl,
phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl,
thienylmethyl, and
pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent
group selected from
halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCONHC6H5,
-NHCOCH3, -CONH2 and -CONHCH3;
2o R2 is selected from morpholinyl, piperidinyl, phenyl, naphthyl, pyrrolyl,
imidazolyl,
pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, azaindolyl,
indolyl, quinolinyl,
benzimidazolyl, benzofuranyl, dibenzofuranyl, benzothienyl which group is
optionally
substituted by one or more substituent group independently selected from halo,
methyl,
methoxy, hydroxymethyl, cyanomethyl, phenoxy, pyrrolidinyl, -CONH2, -CONHCH3
and
25 -CON(CH3)2;
R3 is methyl;
R4 is hydrogen or methyl;
R6 is hydrogen or methyl;
R7 is hydrogen or methyl.
30 In a further particular class of compound of formula (I), or a
pharmaceutically
acceptable salt thereof;
X is a linker group selected from -S(O)zCRV- and -C(O)NR4-;
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-41-
Y is CH and Y2 is N;
R' is a group selected from methyl, ethyl, isopropyl, sec-butyl, isobutyl,
phenyl, 2-
methoxyphenyl, 3-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-methoxy-3-
trifluoromethylphenyl, 2-methoxypyridin-5-yl, 2-methoxypyridin-4-yl, 2-
methoxypyridin-4-
s yl, 2-acetamidopyridin-5-yl, 2-acetamidopyridin-4-yl and 4-
[(anilinocarbonyl)amino]phenyl;
R2 is is (pyrazol-3y1)amino, hydroxypiperidinyl, indol-4-yl, indol-5-yl, indol-
6-yl, azaindolyl,
benzimidazol-5-yl, 3-(pyrazol-4-yl)phenyl, 4-(pyrazol-4-yl)phenyl, 2-
aminocarbonylindol-5-
yl, 3-aminocarbonylindol-5-yl, 2-aminocarbonylindol-6-yl, 3-aminocarbonylindol-
6-yl,
morpholinyl, 2-(pyrazol-4-yl)thiazol-5y1 or methylmorpholinyl;
io R3 is methyl;
R4 is hydrogen or methyl;
R6 is hydrogen or methyl;
R7 is hydrogen or methyl.
In a further particular class of compound of formula (I), or a
pharmaceutically
is acceptable salt thereof;
iY is CH and Y2 is N;
R' is a group selected from methyl, ethyl, isopropyl, sec-butyl, isobutyl,
phenyl, 2-
methoxyphenyl, 3-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-methoxy-3-
trifluoromethylphenyl, 2-methoxypyridin-5-yl, 2-methoxypyridin-4-yl, 2-
methoxypyridin-4-
20 yl, 2-acetamidopyridin-5-yl, 2-acetamidopyridin-4-yl and 4-
[(anilinocarbonyl)amino]phenyl;
R2 is is (pyrazol-3y1)amino, hydroxypiperidinyl, indol-4-yl, indol-5-yl, indol-
6-yl, azaindolyl,
benzimidazol-5-yl, 3-(pyrazol-4-yl)phenyl, 4-(pyrazol-4-yl)phenyl, 2-
aminocarbonylindol-5-
yl, 3-aminocarbonylindol-5-yl, 2-aminocarbonylindol-6-yl, 3-aminocarbonylindol-
6-yl,
morpholinyl, 2-(pyrazol-4-yl)thiazol-5y1 or methylmorpholinyl;
25 R3 is methyl;
R4 is hydrogen or methyl;
R6 is hydrogen or methyl;
R7 is hydrogen or methyl; and
-XRi is a group selected from -CHzSOz-R' and -C(CH3)2SO2-R' wherein R' is
methyl, ethyl,
30 isopropyl, sec-butyl, isobutyl or phenyl; or
-XRi is -NHCO-R' wherein R' is 2-methoxyphenyl, 3-methoxyphenyl, 3-fluoro-4-
methoxyphenyl, 4-methoxy-3-trifluoromethylphenyl, 2-methoxypyridin-5-yl, 2-
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-42-
methoxypyridin-4-yl, 2-methoxypyridin-4-yl, 2-acetamidopyridin-5-yl, 2-
acetamidopyridin-4-
yl or 4-[(anilinocarbonyl)amino]phenyl.
Another aspect of the invention provides a compound, or a combination of
compounds, selected from any of the Examples or a pharmaceutically acceptable
salt thereof.
s Another aspect of the invention provides a compound, or a combination of
compounds, selected from any of
N-[4,6-Bis[(3 S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]-4-methoxy-benzamide,
N- [2, 6-B is [(3 S)-3 -methylmorpho lin-4-yl]pyrimidin-4-yl] -4-methoxy-3 -
(trifluoromethyl)benzamide,
io N-[2,6-Bis[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]-3-methoxy-benzamide,
N- [4, 6-B is [(3 S)-3 -methylmorpho lin-4-yl]pyrimidin-2-yl] -4-methoxy-3 -
(trifluoromethyl)benzamide,
N-[4,6-Bis[(3 S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]-3-methoxy-benzamide,
N-[4,6-Bis[(3 S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]-6-methoxy-pyridine-3-
is carboxamide,
N-[2,6-Bis[(3 S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]-2-methoxy-pyridine-4-
carboxamide,
6-Acetamido-N-[2,6-bis [(3 S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]pyridine-3-
carboxamide,
2o N-[2,6-Bis[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]-2-methoxy-benzamide,
2-Acetamido-N-[2,6-bis [(3 S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]pyridine-4-
carboxamide,
N-[2,6-Bis[(3 S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]-3-fluoro-4-methoxy-
benzamide,
N-[4,6-Bis[(3 S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]-2-methoxy-pyridine-4-
2s carboxamide,
6-Acetamido-N-[4,6-bis [(3 S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]pyridine-3-
carboxamide,
N-[4,6-Bis[(3 S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]-2-methoxy-benzamide,
2-Acetamido-N-[4,6-bis [(3 S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]pyridine-4-
3o carboxamide,
N-[4,6-Bis[(3 S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]-3-fluoro-4-methoxy-
benzamide,
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-43-
N-[2,6-Bis[(3 S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]-4-
(phenylcarbamoylamino)benzamide,
N-[4,6-Bis[(3 S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]-4-
(phenylcarbamoylamino)benzamide,
s N-[2,6-Bis[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]-4-methoxy-benzamide,
2-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]-4-[(3 S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidine,
1-[4-[(3 S)-3-Methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-
yl]piperidin-3-ol,
4-[(3 S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)-2-morpholin-4-yl-
pyrimidine,
io 3-[4-[(3S)-3-Methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]-
5,7-
diazabicyclo[4.3.0]nona-1,3,5,8-tetraene,
5-[4-[(3 S)-3-Methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]-1
H-indole,
5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]-1 H-
indole,
5-[4-(Butan-2-ylsulfonylmethyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-2-
yl]-1 H-indole,
is 5-[4-(butan-2-ylsulfinylmethyl)-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-
yl]-1H-indole,
5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(propan-2-ylsulfonylmethyl)pyrimidin-2-
yl]-1 H-
indole,
5-[4-(ethylsulfonylmethyl)-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl]-1 H-
indole,
4-[(3 S)-3-Methylmorpholin-4-yl]-6-(methylsulfonylmethyl)-N-(1 H-pyrazol-3-
yl)pyrimidin-2-
2o amine,
4-[(3 S)-3-Methylmorpholin-4-yl]-6-(methylsulfonylmethyl)-2-[4-(1 H-pyrazol-4-
yl)phenyl]pyrimidine,
4-[(3S)-3-Methylmorpholin-4-yl]-6-(methylsulfonylmethyl)-2-[3- (1H-pyrazol-4-
yl)phenyl]pyrimidine,
25 5-[4-[(3S)-3-Methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]-
1H-indole-3-
carboxamide,
4-[(3 S)-3-Methylmorpholin-4-yl]-6-(methylsulfonylmethyl)-2-[2-(1 H-pyrazol-4-
yl)-1,3-
thiazol-5-yl]pyrimidine,
6-[4-[(3 S)-3-Methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]-1
H-indole,
3o 6-[4-[(3S)-3-Methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]-
1H-indole-3-
carboxamide,
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-44-
5-[4-[(3 S)-3-Methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]-1
H-indole-2-
carboxamide,
6-[4-[(3 S)-3-Methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]-1
H-indole-2-
carboxamide,
s 5-[4-[(3S)-3-Methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidin-
2-yl]-1H-
benzoimidazole,
3-[4-[(3 S)-3-Methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidin-2-
yl]-5,7-
diazabicyclo[4.3.0]nona-1,3,5,8-tetraene,
5-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidin-2-
yl]-1 H-
io indole,
4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidin-2-
yl]-1 H-
indole,
6-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidin-2-
yl]-1 H-
indole,
is 4-[4-(Benzenesulfonylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]-
1H-indole,
5-[4-(benzenesulfonylmethyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]-1
H-indole,
3-[4-(benzenesulfonylmethyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]-
5,7-
diazabicyclo[4.3.0]nona-1,3,5,8-tetraene,
6-[4-(benzenesulfonylmethyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]-1
H-indole,
2o and
5-[4-(benzenesulfonylmethyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]-1
H-
benzoimidazole,
or a pharmaceutically acceptable salt thereof.
In certain aspects of the invention such as a compound of formula (I) for use
as a
25 medicament for the treatment of proliferative disease; or the use of a
compound of formula (I)
in the manufacture of a medicament for use in the treatment of proliferative
disease.
The invention also provides processes for the preparation of a compound of
formula
(I) or a pharmaceutically acceptable salt thereof.
A compound of formula (I), wherein X=-S(O)zCR6~-, may be prepared by oxidising
3o a compound of the formula (I), wherein X = SCR6~-, for example by using
Oxone at room
temperature in a mixed solvent system of water and ethanol
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-45-
c~lR3 c~1R3
s ~
R I'N O O I~N
Ri'S N~R2 R1' N~R2
Rs R7 Rs
(I) (I)
A compound of formula (I), wherein R'X = R1OCR6R7-, may be prepared by the
reaction of a compound of formula (I), wherein R'X = HOCR6~-, with a compound
of
formula (II), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.)
optionally in the
s presence of a suitable base such as triethylamine and a solvent such as
tetrahydrofuran or
N,N-dimethylformamide.
C~1R3 C~1R3
s s
R? L1 R ~NI ~ R 'N
(II) HO I NRz R1'O I NRz
Rs R7 Rs R7
(I) (I)
A compound of formula (I), wherein R'X = R1R4NCR6R7-, may be prepared by the
reaction of a compound of formula (I), wherein R'X = HR4NCRV-, with a compound
of
io formula (II), wherein L1 is a leaving group (such as halo, tosyl, mesyl
etc.) optionally in the
presence of a suitable base such as triethylamine and a solvent such as
tetrahydrofuran or
N,N-dimethylformamide; or by the reaction of a compound of formula (I),
wherein R'X =
HR4NCR6R7-, with a compound of formula (III) in the presence of a suitable
reducing agent
such as NaCNBH3.
R' L
(II) cN01 J~R s N 01 s
J~R
R$ N ~ R$ N
~ H R\
I \
R R4,Ns NJ1R2 RINs N R2
ls (III) R R (I) R R (I)
A compound of formula (I), wherein Xl =-S(O)2CR6R7-, -SCRV-, -OCRV-, -
R4NCR6R7-, -S(O)CR6R7-, may be prepared by the reaction of a compound of
formula (IV),
wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with a
compound of formula
(V) optionally in the presence of a suitable base such as triethylamine and a
solvent such as
20 tetrahydrofuran or N,N-dimethylformamide.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-46-
c~lR3 c~lR3
R$ 30 R$
11
~ NI /
R' X'" L, ~\ N I
(V) NR2 RI'X NR2
R6 R R6 R7
(IV) (I)
A compound of formula (I), wherein X=-SCR6~-, may be prepared by the reaction
of a compound of formula (IV), wherein L1 is a leaving group (such as halo,
tosyl, mesyl
etc.), with thiourea in a suitable solvent such as ethanol to generate a
compound of formula
s(VI) which is then subsequently reacted with a compound of formula (II) in
the presence of a
suitable base such as sodium hydroxide and a solvent such as N,N-
dimethylformamide.
O
SH CNlRs CN1R3 R' L1 CN1R3
$ ~ $ (II~ $
H2N~NH R I~ N R I'N R I'N
1 u
L NJ~ R2 H2N S N R2 RI'S N R2
6 R7 II 6 R7 6 7
R (IV) NFf~ (VI) R R
(I)
A compound of formula (I), wherein X = -R4NC(O)-, may be prepared by the
reaction
of a compound of formula (VII) with an amine of formula RiR4NH following the
suitable
io activation of the carboxylic acid by methods known in the literature such
as the use of a
coupling agent such as HATU or the conversion to an acyl chloride.
C~lRs C~1Rs
8 ~ 8
R\ I
~N
HO 2 R~~N NJ~Rz
R ~N'!R
0 (VII) 0 (I)
A compound of formula (I), wherein X=-S(O)zCR6~-, may be prepared by the
sequential reaction of a compound of formula (I), wherein X=-S(O)zCHz-, with a
compound
is of formula (VIII) followed by reaction with a compound of formula (IX),
wherein L1 is a
leaving group (such as halo, tosyl, mesyl etc.), in the presence of a suitable
base such as
sodium hydride or potassium tert-butoxide in a suitable solvent such as
tetrahydrofuran or
N,N-dimethylformamide.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-47-
R6 L' coJ.Rs coJ.Rs
(VIII) $ ~ s
p NI O NI
R~ L R.S NJ, Rz R NJ~Rz
(IX) (I) R6 R~
(I)
A compound of formula (I), wherein R'X = HOCR6R7-, may be prepared by the
reaction of a compound of formula (X), with suitable organometallic reagents
of fomula (XI)
and formula (XII) such as the grignard reagent in a suitable solvent. Where R6
and R7 are
s different then it may be possible to use techniques known in the literature
such the conversion
of a compound of formula (X) to the Weinreb amide and reaction with an
organometallic
reagent of formula (XI) and then reaction with an organometallic reagent of
formula (XII) in a
subsequent step.
R M col Rs col Rs
(XI) R8
I N I N
R~ M I
(XII) R.OR$ NJ~Rz Hp N' Rz
p (X) R 6 R 7
(I)
A compound of formula (I) may be prepared from a compound of formula (XIII),
wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me
etc.), with a
suitable organometallic reagent (such as the boronic acid R2B(OH)2 or the
boronic ester
R2B(OR)2 etc.) in the presence of a suitable metal catalyst (such as palladium
or copper) in a
suitable solvent such as 1,4-dioxane. Alternatively where R2 connects to the
pyrimidine ring
through a nitrogen, oxygen or sulphur atom a compound of formula (I) may be
prepared from
a compound of formula (XIII), wherein L2 is a leaving group (such as halo,
tosyl, mesyl, -
SMe, -S(O)2Me etc.), by reaction with the required amine, alcohol or thiol in
the presence of a
suitable base such as potassium carbonate in a suitable solvent such as N,N-
dimethylformamide.
C~lRs C~lRs
s s
R X I N~Lz 0- RX I N11~' Rz
(XIII) (I)
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-48-
It will be appreciated that a compound of formula (XIII) may be transformed
into
another compound of formula (XIII) by techniques such as oxidation,
alkylation, reductive
amination etc., either listed above or otherwise known in the literature.
A compound of formula (XIII), wherein Xi =-S(O)zCR6R7-, -SCR6R7-, -OCRV-, -
s R4NCR6R7-, -S(O)CR6R7-, may be prepared by the reaction of a compound of
formula (XIV),
wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with a
compound of formula
(V) optionally in the presence of a suitable base such as triethylamine and a
solvent such as
tetrahydrofuran or N,N-dimethylformamide.
C~lRs C~1Rs
R ow R$
N
R X'H -I
(V) L1 I N R1.X1 ~ NL2
Rs R Rs R7
(XIV) (XIII)
io A compound of formula (XIII), wherein X=-SCR6~-, may be prepared by the
reaction of a compound of formula (XIV), wherein L1 is a leaving group (such
as halo, tosyl,
mesyl etc.), with thiourea in a suitable solvent such as ethanol to generate a
compound of
formula (XV) which is then subsequently reacted with a compound of formula
(II) in the
presence of a suitable base such as sodium hydroxide and a solvent such as N,N-
1 s dimethylformamide.
O
NR3 R' L' cN1R3
SH cNlR3 ( ~
$ ~ $ (II~ $
H2N~NH R N R 'N R 'N
L1 I N~L2 H2Nu S I N~L2 RI.S NJ,L2
Rs R7 NFRs R7 Rs R'7
(XIV) (XV) (XII I)
A compound of formula (XIII), wherein X=-R4NC(O)-, may be prepared by the
reaction of a compound of formula (XVI) with an amine of formula R1R4NH
following the
suitable activation of the carboxylic acid by methods known in the literature
such as the use of
2o a coupling agent such as HATU or the conversion to an acyl chloride.
C~lRs C~lRs
8 ~ 8
R ~N R\ R ~
HO I NJ~L2 R~'N I NL2
0 (XVI) 0 (XIII)
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-49-
A compound of formula (XIII), wherein X=-S(O)zCR6R7-, may be prepared by the
sequential reaction of a compound of formula (XIII), wherein X=-S(O)zCHz-,
with a
compound of formula (VIII) followed by reaction with a compound of formula
(IX), wherein
L1 is a leaving group (such as halo, tosyl, mesyl etc.), in the presence of a
suitable base such
s as sodium hydride or potassium tert-butoxide in a suitable solvent such as
tetrahydrofuran or
N,N-dimethylformamide.
Rs L' c~l Rs c~l Rs
(VIII) $ ~ $
O ~ N p N
R~ L R.S N~Lz R.S N~L2
(IX) R6 R~
(XIII) (XIII)
A compound of formula (XIII), wherein R'X = HOCR6~-, may be prepared by the
reaction of a compound of formula (XVII), with suitable organometallic
reagents of fomula
1o (XI) and formula (XII) such as the grignard reagent in a suitable solvent.
Where R6 and R7 are
different then it may be possible to use techniques known in the literature
such the conversion
of a compound of formula (XVII) to the Weinreb amide and reaction with an
organometallic
reagent of formula (XI) and then reaction with an organometallic reagent of
formula (XII) in a
subsequent step .
RL-M c~l Rs c~l Rs
(XI)
s ~ s
~ I I
R-M
XII R.OR NJ~Lz HO 7I N/~L2
( ) O R6
R
15 (XVII) (XIII)
A compound of formula (IV) may be prepared from a compound of formula (XIV),
wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)zMe
etc.) and L1 is a
leaving group (such as halo, tosyl, mesyl etc.), with a suitable
organometallic reagent (such as
the boronic acid R2 B(OH)z or the boronic ester R2B(OR)2 etc.) in the presence
of a suitable
20 metal catalyst (such as palladium or copper) in a suitable solvent such as
1,4-dioxane.
Alternatively where R2 connects to the pyrimidine ring through a nitrogen,
oxygen or sulphur
atom a compound of formula (IV) may be prepared from a compound of formula
(XIV),
wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)zMe
etc.), by reaction
with the required amine, alcohol or thiol in the presence of a suitable base
such as potassium
25 carbonate in a suitable solvent such as N,N-dimethylformamide.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-50-
C~lRs C~lRs
s N ~ R s
~R N
L N L N R R R R (XIV) (IV)
A compound of formula (X) may be prepared from a compound of formula (XVII),
wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)zMe
etc.) and R is a
hydrogen or C1_4 alkyl group, with a suitable organometallic reagent (such as
the boronic acid
s R2 B(OH)z or the boronic ester R2B(OR)2 etc.) in the presence of a suitable
metal catalyst
(such as palladium or copper) in a suitable solvent such as 1,4-dioxane.
Alternatively where
R2 connects to the pyrimidine ring through a nitrogen, oxygen or sulphur atom
a compound of
formula (X) may be prepared from a compound of formula (XVII), wherein L2 is a
leaving
group (such as halo, tosyl, mesyl, -SMe, -S(O)zMe etc.), by reaction with the
required amine,
io alcohol or thiol in the presence of a suitable base such as potassium
carbonate in a suitable
solvent such as N,N-dimethylformamide.
C~lRs C~1Rs
$ _ $
R I R I N
R~~ N N ~L2 R"ON~R2
0 (XVII) 0 (X)
A compound of formula (XVIII) may be prepared from a compound of formula
(XIX),
wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)zMe
etc.), with a
is suitable organometallic reagent (such as the boronic acid R2 B(OH)z or the
boronic ester
R2 B(OR)z etc.) in the presence of a suitable metal catalyst (such as
palladium or copper) in a
suitable solvent such as 1,4-dioxane. Alternatively where R2 connects to the
pyrimidine ring
through a nitrogen, oxygen or sulphur atom a compound of formula (XVIII) may
be prepared
from a compound of formula (XIX), wherein L2 is a leaving group (such as halo,
tosyl, mesyl,
20 -SMe, -S(O)zMe etc.), by reaction with the required amine, alcohol or thiol
in the presence of
a suitable base such as potassium carbonate in a suitable solvent such as N,N-
dimethylformamide.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-51-
C~lRs C~lRs
R8 ~ ~
N R8 ~N
NC I N~L2 NC I N-'-J1R2
(XIX) (XVIII)
A compound of formula (XX) may be prepared from a compound of formula (XXI),
wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)zMe
etc.), with a
suitable organometallic reagent (such as the boronic acid R2 B(OH)z or the
boronic ester
s R2 B(OR)z etc.) in the presence of a suitable metal catalyst (such as
palladium or copper) in a
suitable solvent such as 1,4-dioxane. Alternatively where R2 connects to the
pyrimidine ring
through a nitrogen, oxygen or sulphur atom a compound of formula (XX) may be
prepared
from a compound of formula (XXI), wherein L2 is a leaving group (such as halo,
tosyl, mesyl,
-SMe, -S(O)zMe etc.), by reaction with the required amine, alcohol or thiol in
the presence of
io a suitable base such as potassium carbonate in a suitable solvent such as
N,N-
dimethylformamide.
C~1Rs C~lRs
8 8
~
R2 I N N L2 R2 I N N R2
L (XX/I )\ (XXJ)\
A compound of formula (I), wherein L1 is a leaving group (such as halo, tosyl,
mesyl
etc.), may be prepared by the reaction of a compound of formula (XXII) with a
compound of
is formula (XXIII) optionally in the presence of a suitable base such as
triethylamine in a
suitable solvent such as N,N-dimethylformamide. C1 L' (01 NRs
~
Rs s N
N
CHJ~Rs R X ~ N I R2 RI X ~ N I R2
(XXIII) (XXIIJ)~ (1)J~
It will be appreciated that a compound of formula (XXII) may be transformed
into
another compound of formula (XXII) by techniques such as oxidation,
alkylation, reductive
2o amination etc., either listed above or otherwise known in the literature.
A compound of formula (IV), wherein L1 is a leaving group (such as halo,
tosyl, mesyl
etc.), may be prepared by the reaction of a compound of formula (XXIV) with a
compound of
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-52-
formula (XXIII) optionally in the presence of a suitable base such as
triethylamine in a
suitable solvent such as N,N-dimethylformamide.
0
L ~N~R3
s
O R \ ~ R \
I NI 1 I NI
H R3 L Rz L NJ~Rz
J~ R R
R R, N
(XXIII) (XXIV) (IV)
A compound of formula (X), wherein L1 is a leaving group (such as halo, tosyl,
mesyl
s etc.) and R is a hydrogen or a C1_4 alkyl group, may be prepared by the
reaction of a
compound of formula (XXV) with a compound of formula (XXIII) optionally in the
presence
of a suitable base such as triethylamine in a suitable solvent such as N,N-
dimethylformamide.
0
O L ~NJ~R3
s ~
HlR3 .OR I J- z .OR I J~ z
R N R R N R
(XXIII) 0 (Xxv) 0 (X)
A compound of formula (XVIII), wherein L1 is a leaving group (such as halo,
tosyl,
io mesyl etc.), may be prepared by the reaction of a compound of formula
(XXVI) with a
compound of formula (XXIII) optionally in the presence of a suitable base such
as
triethylamine in a suitable solvent such as N,N-dimethylformamide.
0
O L ~NJ~R3
s ~ s
Nl R3 R N R ~N
H z ~JI, z
(XXIII) NC N R NC N R
(XXVI) (XVI I I)
A compound of formula (XX), wherein L1 is a leaving group (such as halo,
tosyl,
is mesyl etc.) and L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -
S(O)zMe etc.), may
be prepared by the reaction of a compound of formula (XXVII) with a compound
of formula
(XXIII) optionally in the presence of a suitable base such as triethylamine in
a suitable solvent
such as N,N-dimethylformamide.
01
C0J~ 3 L1 NJ~R3
s
H R R ~N ~ R ~N
(XXIII) Lz I N~Rz Lz I N ~Rz
(XXVI I) (XX)
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-53-
A compound of formula (XIII), wherein L1 is a leaving group (such as halo,
tosyl,
mesyl etc.) and L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -
S(O)zMe etc.), may
be prepared by the reaction of a compound of formula (XXVIII) with a compound
of formula
(XXIII) optionally in the presence of a suitable base such as triethylamine in
a suitable solvent
s such as N,N-dimethylformamide.
O
O Li ~NJ~R3
s s
~
CNl R3 R X I NJ~L2 R X I N%~N
L2
H
(XXIII) (XXVIII) (xlll)
It will be appreciated that a compound of formula (XIII) may be transformed
into
another compound of formula (XIII) by techniques such as oxidation,
alkylation, reductive
amination etc., either listed above or otherwise known in the literature.
A compound of formula (XIV), wherein L1 is a leaving group (such as halo,
tosyl,
mesyl etc.) and L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -
S(O)zMe etc.), may
be prepared by the reaction of a compound of formula (XXIX) with a compound of
formula
(XXIII) optionally in the presence of a suitable base such as triethylamine in
a suitable solvent
such as N,N-dimethylformamide.
0
L ~N~R3
O $ ~ $
CN1R3 L R I NJ~L2 L1 R I N1 L2
H Rs R Rs R
1s (XXIII) (XXIX) (XIV)
A compound of formula (XVII), wherein L1 is a leaving group (such as halo,
tosyl,
mesyl etc.) and L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -
S(O)zMe etc.) and R
is a hydrogen or a C1_4 alkyl group, may be prepared by the reaction of a
compound of
formula (XXX) with a compound of formula (XXIII) optionally in the presence of
a suitable
2o base such as triethylamine in a suitable solvent such as N,N-
dimethylformamide.
0
O L ~NJ, R3
s 30
2
HlR3 .O N JR , L 2 ROR I N~/~
L
(XXIII) R 0 (XXX) 0 (xVI 1)
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-54-
A compound of formula (XIX), wherein L1 is a leaving group (such as halo,
tosyl,
mesyl etc.) and L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -
S(O)zMe etc.), may
be prepared by the reaction of a compound of formula (XXXI) with a compound of
formula
(XXIII) optionally in the presence of a suitable base such as triethylamine in
a suitable solvent
s such as N,N-dimethylformamide.
0
C Li ~N~R3
s s
Nl R3 R ~N ~ R N
H
~JII 2 I 2
(XXIII) NC N L NC N L
(XXXI) (XIX)
A compound of formula (XXI), wherein L1 is a leaving group (such as halo,
tosyl,
mesyl etc.) and L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -
S(O)zMe etc.), may
be prepared by the reaction of a compound of formula (XXXII) with a compound
of formula
io (XXIII) optionally in the presence of a suitable base such as triethylamine
in a suitable solvent
such as N,N-dimethylformamide.
01
C0J~ 3 L1 NJ~R3
s
H R R ~N ~ R N
(XXIII) L2 I N~L2 L2 NL2
(XXXII) (XXI)
A compound of formula (I), wherein R'X = H2NCH2-, may be prepared from a
compound of formula (XVIII) by a reduction such as hydrogenation with hydrogen
gas and a
is suitable catalyst such as Palladium on carbon in a suitable solvent such as
ethanol.
Col 3 (~1 R3
N R
R$ ~ s
N N
I ~ 2 H 2 N NR2
NC N R
(XVIII) (1)
A compound of formula (I), wherein R'X = H2NC(O)-, may be prepared from a
compound of formula (XVIII) by hydrolysis with, for example, sodium hydroxide
in a
suitable solvent such as a water ethanol mix.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-55-
C0/\ 3 c~l R3
N R $
Rs
N ~
N
H R -
~
NC N R2 2 N N R2
(XVIII) O (I)
A compound of formula (I), wherein R'X = H2NCR6R7-, may be prepared from a
compound of formula (XVIII) by reaction with organometallic reagents (XI) and
(XII).
0 0
Rs M
(XI) cNlRs NlRs
~ R$ ~ R$ ~ N
R-M 'N I
~ H N I J~ 2
(XII) NC N R2 2R6 R7 N R
(XVIII) (I)
A compound of formula (XIII), wherein R'X = H2NCH2-, may be prepared from a
compound of formula (XIX) by a reduction such as hydrogenation with hydrogen
gas and a
suitable catalyst such as Palladium on carbon in a suitable solvent such as
ethanol.
col 3 c~~R3
N R
$ ~ s
R N R ~N
I 2 H 2 N I N%, L2
NC N L
(XIX) (XIII)
A compound of formula (XIII), wherein R'X = H2NC(O)-, may be prepared from a
io compound of formula (XIX) by hydrolysis with, for example, sodium hydroxide
in a suitable
solvent such as a water ethanol mix.
(01 3 c~l R3
N R $
R N R ~N
s 30 .
~ H2N I N~L2
NC N L2
O
(XIX) (XII I)
A compound of formula (XIII), wherein R'X = H2NCR6~-, may be prepared from a
compound of formula (XIX) by reaction with organometallic reagents (XI) and
(XII).
0 0
R(XI) ~N~R3 ~N~R3
~ R$ ~ R$ N
R-M -N
I I
(XII) NC N~L2 H2R6 R7 NL2
(XIX) (XIII)
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-56-
It will be appreciated that the R2 group may be introduced and subsequently
converted
to another group of the formula R2 at a subsequent stage in the synthesis
using methods
known in the literature.
It will be appreciated that certain of the various ring substituents in the
compounds of
s the present invention may be introduced by standard aromatic substitution
reactions or
generated by conventional functional group modifications either prior to or
immediately
following the processes mentioned above, and as such are included in the
process aspect of
the invention. For example compounds of formula (I) my be converted into
further
compounds of formula (I) by standard aromatic substitution reactions or by
conventional
io functional group modifications. Such reactions and modifications include,
for example,
introduction of a substituent by means of an aromatic substitution reaction,
reduction of
substituents, alkylation of substituents and oxidation of substituents. The
reagents and
reaction conditions for such procedures are well known in the chemical art.
Particular
examples of aromatic substitution reactions include the introduction of a
nitro group using
15 concentrated nitric acid, the introduction of an acyl group using, for
example, an acyl halide
and Lewis acid (such as aluminium trichloride) under Friedel Crafts
conditions; the
introduction of an alkyl group using an alkyl halide and Lewis acid (such as
aluminium
trichloride) under Friedel Crafts conditions; and the introduction of a
halogen group.
Particular examples of modifications include the reduction of a nitro group to
an amino group
2o by for example, catalytic hydrogenation with a nickel catalyst or treatment
with iron in the
presence of hydrochloric acid with heating; oxidation of alkylthio to
alkylsulfinyl or
alkylsulfonyl.
It will also be appreciated that in some of the reactions mentioned herein it
may be
necessary/desirable to protect any sensitive groups in the compounds. The
instances where
25 protection is necessary or desirable and suitable methods for protection
are known to those
skilled in the art. Conventional protecting groups may be used in accordance
with standard
practice (for illustration see T.W. Green, Protective Groups in Organic
Synthesis, John Wiley
and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or
hydroxy it may
be desirable to protect the group in some of the reactions mentioned herein.
30 A suitable protecting group for an amino or alkylamino group is, for
example, an acyl
group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group,
for example a
methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an
arylmethoxycarbonyl
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-57-
group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
The
deprotection conditions for the above protecting groups necessarily vary with
the choice of
protecting group. Thus, for example, an acyl group such as an alkanoyl or
alkoxycarbonyl
group or an aroyl group may be removed for example, by hydrolysis with a
suitable base such
s as an alkali metal hydroxide, for example lithium or sodium hydroxide.
Alternatively an acyl
group such as a tert-butoxycarbonyl group may be removed, for example, by
treatment with a
suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic
acid and an
arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed,
for
example, by hydrogenation over a catalyst such as palladium-on-carbon, or by
treatment with
io a Lewis acid for example boron tris(trifluoroacetate). A suitable
alternative protecting group
for a primary amino group is, for example, a phthaloyl group which may be
removed by
treatment with an alkylamine, for example dimethylaminopropylamine, or with
hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl
group, for
example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl,
or an
is arylmethyl group, for example benzyl. The deprotection conditions for the
above protecting
groups will necessarily vary with the choice of protecting group. Thus, for
example, an acyl
group such as an alkanoyl or an aroyl group may be removed, for example, by
hydrolysis with
a suitable base such as an alkali metal hydroxide, for example lithium or
sodium hydroxide.
Alternatively an arylmethyl group such as a benzyl group may be removed, for
example, by
2o hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an
esterifying group,
for example a methyl or an ethyl group which may be removed, for example, by
hydrolysis
with a base such as sodium hydroxide, or for example a tert-butyl group which
may be
removed, for example, by treatment with an acid, for example an organic acid
such as
25 trifluoroacetic acid, or for example a benzyl group which may be removed,
for example, by
hydrogenation over a catalyst such as palladium-on-carbon.
The protecting groups may be removed at any convenient stage in the synthesis
using
conventional techniques well known in the chemical art.
Many of the intermediates defined herein are novel and these are provided as a
further
30 feature of the invention.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-58-
Biological Assays
The following assays can be used to measure the effects of the compounds of
the
present invention as mTOR kinase inhibitors, as P13 kinase inhibitors, as
inhibitors in vitro of
the activation of P13 kinase signalling pathways and as inhibitors in vitro of
the proliferation
s of MDA-MB-468 human breast adenocarcinoma cells.
(a)(i) In Vitro mTOR Kinase Assay
The assay used AlphaScreen technology (Gray et al., Analytical Biochemistry,
2003,
313: 234-245) to determine the ability of test compounds to inhibit
phosphorylation by
recombinant mTOR.
io A C-terminal truncation of mTOR encompassing amino acid residues 1362 to
2549 of
mTOR (EMBL Accession No. L34075) was stably expressed as a FLAG-tagged fusion
in
HEK293 cells as described by Vilella-Bach et al., Journal of Biochemistry,
1999, 274, 4266-
4272. The HEK293 FLAG-tagged mTOR (1362-2549) stable cell line was routinely
maintained at 37 C with 5% COz up to a confluency of 70-90% in Dulbecco's
modified
is Eagle's growth medium (DMEM; Invitrogen Limited, Paisley, UK Catalogue No.
41966-029)
containing 10% heat-inactivated foetal calf serum (FCS; Sigma, Poole, Dorset,
UK, Catalogue
No. F0392), 1% L-glutamine (Gibco, Catalogue No. 25030-024) and 2 mg/ml
Geneticin
(G418 sulfate; Invitrogen Limited, UK Catalogue No. 10131-027). Following
expression in
the mammalian HEK293 cell line, expressed protein was purified using the FLAG
epitope tag
20 using standard purification techniques.
Test compounds were prepared as 10 mM stock solutions in DMSO and diluted into
water as required to give a range of final assay concentrations. Aliquots (2
l) of each
compound dilution were placed into a well of a Greiner 384-well low volume
(LV) white
polystyrene plate (Greiner Bio-one). A 30 l mixture of recombinant purified
mTOR
25 enzyme, 1 M biotinylated peptide substrate (Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-
Val-Phe-
Leu-Gly-Phe-Thr-Tyr-Val-Ala-Pro-Ser-Val-Leu-Glu-Ser-Val-Lys-Glu-NHz; Bachem UK
Ltd), ATP (20 M) and a buffer solution [comprising Tris-HC1 pH7.4 buffer (50
mM), EGTA
(0.1 mM), bovine serum albumin (0.5 mg/mL), DTT (1.25 mM) and manganese
chloride (10
mM)] was agitated at room temperature for 90 minutes.
30 Control wells that produced a maximum signal corresponding to maximum
enzyme
activity were created by using 5% DMSO instead of test compound. Control wells
that
produced a minimum signal corresponding to fully inhibited enzyme were created
by adding
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-59-
EDTA (83 mM) instead of test compound. These assay solutions were incubated
for 2 hours
at room temperature.
Each reaction was stopped by the addition of 10 l of a mixture of EDTA (50
mM),
bovine serum albumin (BSA; 0.5 mg/mL) and Tris-HC1 pH7.4 buffer (50 mM)
containing
s p70 S6 Kinase (T389) lA5 Monoclonal Antibody (Cell Signalling Technology,
Catalogue
No. 9206B) and AlphaScreen Streptavidin donor and Protein A acceptor beads
(200 ng;
Perkin Elmer, Catalogue No. 6760002B and 6760137R respectively) were added and
the
assay plates were left for about 20 hours at room temperature in the dark. The
resultant
signals arising from laser light excitation at 680 nm were read using a
Packard Envision
1 o instrument.
Phosphorylated biotinylated peptide is formed in situ as a result of mTOR
mediated
phosphorylation. The phosphorylated biotinylated peptide that is associated
with
AlphaScreen Streptavidin donor beads forms a complex with the p70 S6 Kinase
(T389) lA5
Monoclonal Antibody that is associated with Alphascreen Protein A acceptor
beads. Upon
is laser light excitation at 680 nm, the donor bead : acceptor bead complex
produces a signal that
can be measured. Accordingly, the presence of mTOR kinase activity results in
an assay
signal. In the presence of an mTOR kinase inhibitor, signal strength is
reduced.
mTOR enzyme inhibition for a given test compound was expressed as an IC50
value.
(a)(ii) In Vitro mTOR Kinase Assay (Echo)
20 The assay used AlphaScreen technology (Gray et al., Analytical
Biochemistry, 2003,
313: 234-245) to determine the ability of test compounds to inhibit
phosphorylation by
recombinant mTOR.
A C-terminal truncation of mTOR encompassing amino acid residues 1362 to 2549
of
mTOR (EMBL Accession No. L34075) was stably expressed as a FLAG-tagged fusion
in
25 HEK293 cells as described by Vilella-Bach et al., Journal of Biochemistry,
1999, 274, 4266-
4272. The HEK293 FLAG-tagged mTOR (1362-2549) stable cell line was routinely
maintained at 37 C with 5% COz up to a confluency of 70-90% in Dulbecco's
modified
Eagle's growth medium (DMEM; Invitrogen Limited, Paisley, UK Catalogue No.
41966-029)
containing 10% heat-inactivated foetal calf serum (FCS; Sigma, Poole, Dorset,
UK, Catalogue
3o No. F0392), 1% L-glutamine (Gibco, Catalogue No. 25030-024) and 2 mg/ml
Geneticin
(G418 sulfate; Invitrogen Limited, UK Catalogue No. 10131-027). Following
expression in
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-60-
the mammalian HEK293 cell line, expressed protein was purified using the FLAG
epitope tag
using standard purification techniques.
Test compounds were prepared as 10 mM stock solutions in DMSO and diluted in
into
waterDMSO as required to give a range of final assay concentrations. Aliquots
(120n12 l)
s of each compound dilution were acoustically dispensedplaced using a Labcyte
Echo 550 into
a well of a Greiner 384-well low volume (LV) white polystyrene plate (Greiner
Bio-one). A
1230 l mixture of recombinant purified mTOR enzyme, 1 M biotinylated peptide
substrate
(Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly-Phe-Thr-Tyr-Val-Ala-Pro-Ser-
Val-Leu-
Glu-Ser-Val-Lys-Glu-NHz; Bachem UK Ltd), ATP (20 M) and a buffer solution
io [comprising Tris-HC1 pH7.4 buffer (50 mM), EGTA (0.1 mM), bovine serum
albumin (0.5
mg/mL), DTT (1.25 mM) and manganese chloride (10 mM)] was incubated at room
temperature for 12090 minutes.
Control wells that produced a maximum signal corresponding to maximum enzyme
activity were created by using 1005% DMSO instead of test compound. Control
wells that
is produced a minimum signal corresponding to fully inhibited enzyme were
created by adding
LY294002EDTA (100uM83 mM) compound. These assay solutions were incubated for 2
hours at room temperature.
Each reaction was stopped by the addition of 510 l of a mixture of EDTA (50
mM),
bovine serum albumin (BSA; 0.5 mg/mL) and Tris-HC1 pH7.4 buffer (50 mM)
containing
20 p70 S6 Kinase (T389) lA5 Monoclonal Antibody (Cell Signalling Technology,
Catalogue
No. 9206B) and AlphaScreen Streptavidin donor and Protein A acceptor beads
(200 ng;
Perkin Elmer, Catalogue No. 6760002B and 6760137R respectively) were added and
the
assay plates were left overnight at room temperature in the dark. The
resultant signals arising
from laser light excitation at 680 nm were read using a Packard Envision
instrument.
25 Phosphorylated biotinylated peptide is formed in situ as a result of mTOR
mediated
phosphorylation. The phosphorylated biotinylated peptide that is associated
with
AlphaScreen Streptavidin donor beads forms a complex with the p70 S6 Kinase
(T389) lA5
Monoclonal Antibody that is associated with Alphascreen Protein A acceptor
beads. Upon
laser light excitation at 680 nm, the donor bead : acceptor bead complex
produces a signal that
30 can be measured. Accordingly, the presence of mTOR kinase activity results
in an assay
signal. In the presence of an mTOR kinase inhibitor, signal strength is
reduced.
mTOR enzyme inhibition for a given test compound was expressed as an IC50
value.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-61-
(b)(i) In Vitro P13K Enzyme Assay
The assay used A1phaScreen technology (Gray et al., Analytical Biochemistry,
2003,
313: 234-245) to determine the ability of test compounds to inhibit
phosphorylation by
recombinant Type I P13K enzymes of the lipid PI(4,5)P2.
s DNA fragments encoding human P13K catalytic and regulatory subunits were
isolated
from cDNA libraries using standard molecular biology and PCR cloning
techniques. The
selected DNA fragments were used to generate baculovirus expression vectors.
In particular,
full length DNA of each of the pl 10a, pl 10(3 and pl 106 Type Ia human P13K
pl 10 isoforms
(EMBL Accession Nos. HSU79143, S67334, Y10055 for pl 10a, pl 10(3 and pl lOb
io respectively) were sub-cloned into a pDEST10 vector (Invitrogen Limited,
Fountain Drive,
Paisley, UK). The vector is a Gateway-adapted version of Fastbacl containing a
6-His
epitope tag. A truncated form of Type lb human P13K p1107 isoform
corresponding to amino
acid residues 144-1102 (EMBL Accession No. X8336A) and the full length human
p85a
regulatory subunit (EMBL Accession No. HSP13KIN) were also sub-cloned into
pFastBacl
is vector containing a 6-His epitope tag. The Type Ia pl 10 constructs were co-
expressed with
the p85a regulatory subunit. Following expression in the baculovirus system
using standard
baculovirus expression techniques, expressed proteins were purified using the
His epitope tag
using standard purification techniques.
DNA corresponding to amino acids 263 to 380 of human general receptor for
20 phosphoinositides (Grpl) PH domain was isolated from a cDNA library using
standard
molecular biology and PCR cloning techniques. The resultant DNA fragment was
sub-cloned
into a pGEX 4T1 E. coli expression vector containing a GST epitope tag
(Amersham
Pharmacia Biotech, Rainham, Essex, UK) as described by Gray et al., Analytical
Biochemistry, 2003, 313: 234-245). The GST-tagged Grpl PH domain was expressed
and
25 purified using standard techniques.
Test compounds were prepared as 10 mM stock solutions in DMSO and diluted into
water as required to give a range of final assay concentrations. Aliquots (2
l) of each
compound dilution were placed into a well of a Greiner 384-well low volume
(LV) white
polystyrene plate (Greiner Bio-one, Brunel Way, Stonehouse, Gloucestershire,
UK Catalogue
3o No. 784075). A mixture of each selected recombinant purified P13K enzyme
(15 ng), DiC8-
PI(4,5)P2 substrate (40 M; Cell Signals Inc., Kinnear Road, Columbus, USA,
Catalogue No.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-62-
901), adenosine triphosphate (ATP; 4 M) and a buffer solution [comprising
Tris-HC1 pH7.6
buffer (40 mM, 10 l), 3-[(3-cholamidopropyl)dimethylammonio]-l-
propanesulfonate
(CHAPS; 0.04%), dithiothreitol (DTT; 2 mM) and magnesium chloride (10 mM)] was
agitated at room temperature for 20 minutes.
Control wells that produced a minimum signal corresponding to maximum enzyme
activity were created by using 5% DMSO instead of test compound. Control wells
that
produced a maximum signal corresponding to fully inhibited enzyme were created
by adding
wortmannin (6 M; Calbiochem / Merck Bioscience, Padge Road, Beeston,
Nottingham, UK,
Catalogue No. 681675) instead of test compound. These assay solutions were
also agitated
io for 20 minutes at room temperature.
Each reaction was stopped by the addition of 10 l of a mixture of EDTA (100
mM),
bovine serum albumin (BSA, 0.045 %) and Tris-HC1 pH7.6 buffer (40 mM).
Biotinylated-DiC8-PI(3,4,5)P3 (50 nM; Cell Signals Inc., Catalogue No. 107),
recombinant purified GST-Grpl PH protein (2.5 nM) and AlphaScreen Anti-GST
donor and
is acceptor beads (100 ng; Packard Bioscience Limited, Station Road,
Pangboume, Berkshire,
UK, Catalogue No. 6760603M) were added and the assay plates were left for
about 5 to
20 hours at room temperature in the dark. The resultant signals arising from
laser light
excitation at 680 nm were read using a Packard AlphaQuest instrument.
PI(3,4,5)P3 is formed in situ as a result of P13K mediated phosphorylation of
20 PI(4,5)P2. The GST-Grpl PH domain protein that is associated with
AlphaScreen Anti-GST
donor beads forms a complex with the biotinylated PI(3,4,5)P3 that is
associated with
Alphascreen Streptavidn acceptor beads. The enymatically-produced PI(3,4,5)P3
competes
with biotinylated PI(3,4,5)P3 for binding to the PH domain protein. Upon laser
light
excitation at 680 nm, the donor bead : acceptor bead complex produces a signal
that can be
25 measured. Accordingly, P13K enzme activity to form PI(3,4,5)P3 and
subsequent competition
with biotinylated PI(3,4,5)P3 results in a reduced signal. In the presence of
a P13K enzyme
inhibitor, signal strength is recovered.
P13K enzyme inhibition for a given test compound was expressed as an IC50
value.
(b)(ii) In Vitro P13K Enzyme Assa,y (Echo)
30 The assay used AlphaScreen technology (Gray et al., Analytical
Biochemistry, 2003,
313: 234-245) to determine the ability of test compounds to inhibit
phosphorylation by
recombinant Type I P13K enzymes of the lipid PI(4,5)P2.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-63-
DNA fragments encoding human P13K catalytic and regulatory subunits were
isolated
from cDNA libraries using standard molecular biology and PCR cloning
techniques. The
selected DNA fragments were used to generate baculovirus expression vectors.
In particular,
full length DNA of each of the pl 10a, pl 10(3 and pl lOb Type Ia human P13K
pl 10 isoforms
s(EMBL Accession Nos. HSU79143, S67334, Y10055 for pl 10a, pl 10(3 and pl lOb
respectively) were sub-cloned into a pDEST10 vector (Invitrogen Limited,
Fountain Drive,
Paisley, UK). The vector is a Gateway-adapted version of Fastbacl containing a
6-His
epitope tag. A truncated form of Type lb human P13K p1107 isoform
corresponding to amino
acid residues 144-1102 (EMBL Accession No. X8336A) and the full length human
p85a
io regulatory subunit (EMBL Accession No. HSP13KIN) were also sub-cloned into
pFastBacl
vector containing a 6-His epitope tag. The Type Ia pl 10 constructs were co-
expressed with
the p85a regulatory subunit. Following expression in the baculovirus system
using standard
baculovirus expression techniques, expressed proteins were purified using the
His epitope tag
using standard purification techniques.
is DNA corresponding to amino acids 263 to 380 of human general receptor for
phosphoinositides (Grpl) PH domain was isolated from a cDNA library using
standard
molecular biology and PCR cloning techniques. The resultant DNA fragment was
sub-cloned
into a pGEX 4T1 E. coli expression vector containing a GST epitope tag
(Amersham
Pharmacia Biotech, Rainham, Essex, UK) as described by Gray et al., Analytical
2o Biochemistrv, 2003, 313: 234-245). The GST-tagged Grpl PH domain was
expressed and
purified using standard techniques.
Test compounds were prepared as 10 mM stock solutions in DMSO and diluted in
DMSO to wateras required to give a range of final assay concentrations.
Aliquots (120n12 l)
of each compound dilution were acoustically dispensed using a Labcyte Echo 550
placed into
25 a well of a Greiner 384-well low volume (LV) white polystyrene plate
(Greiner Bio-one,
Brunel Way, Stonehouse, Gloucestershire, UK Catalogue No. 784075). A mixture
of each
selected recombinant purified P13K enzyme (15 ng), DiC8-PI(4,5)P2 substrate
(40 M; Cell
Signals Inc., Kinnear Road, Columbus, USA, Catalogue No. 901), adenosine
triphosphate
(ATP; 4 M) and a buffer solution [comprising Tris-HC1 pH7.6 buffer (40 mM, 10
l), 3-[(3-
30 cholamidopropyl)dimethylammonio]-l-propanesulfonate (CHAPS; 0.04%),
dithiothreitol
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-64-
(DTT; 2 mM) and magnesium chloride (10 mM)] was agitatedincubated at room
temperature
for 20 minutes.
Control wells that produced a minimum signal corresponding to maximum enzyme
activity were created by using 1005% DMSO instead of test compound. Control
wells that
s produced a maximum signal corresponding to fully inhibited enzyme were
created by adding
Wwortmannin (6 M; Calbiochem / Merck Bioscience, Padge Road, Beeston,
Nottingham,
UK, Catalogue No. 681675) instead of test compound. These assay solutions were
also
incubatedagitated for 20 minutes at room temperature.
Each reaction was stopped by the addition of 10 10 1 of a mixture of EDTA (100
io mM), bovine serum albumin (BSA, 0.045 %) and Tris-HC1 pH7.6 buffer (40 mM).
Biotinylated-DiC8-PI(3,4,5)P3 (50 nM; Cell Signals Inc., Catalogue No. 107),
recombinant purified GST-Grpl PH protein (2.5 nM) and AlphaScreen Anti-GST
donor and
acceptor beads (100 ng; Packard Bioscience Limited, Station Road, Pangbourne,
Berkshire,
UK, Catalogue No. 6760603M) were added and the assay plates were left for
about 5 to
15 overnight
20 hours at room temperature in the dark. The resultant signals arising from
laser light
excitation at 680 nm were read using a Packard AlphaQuest instrument.
PI(3,4,5)P3 is formed in situ as a result of P13K mediated phosphorylation of
PI(4,5)P2. The GST-Grpl PH domain protein that is associated with AlphaScreen
Anti-GST
2o donor beads forms a complex with the biotinylated PI(3,4,5)P3 that is
associated with
Alphascreen Streptavidn acceptor beads. The enymatically-produced PI(3,4,5)P3
competes
with biotinylated PI(3,4,5)P3 for binding to the PH domain protein. Upon laser
light
excitation at 680 nm, the donor bead : acceptor bead complex produces a signal
that can be
measured. Accordingly, P13K enzme activity to form PI(3,4,5)P3 and subsequent
competition
25 with biotinylated PI(3,4,5)P3 results in a reduced signal. In the presence
of a P13K enzyme
inhibitor, signal strength is recovered.
P13K enzyme inhibition for a given test compound was expressed as an IC50
value.
(c) In Vitro phospho-Ser473 Akt assay
This assay determines the ability of test compounds to inhibit phosphorylation
of
30 Serine 473 in Akt as assessed using Acumen Explorer technology (Acumen
Bioscience
Limited), a plate reader that can be used to rapidly quantitate features of
images generated by
laser-scanning.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-65-
A MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem,
Teddington, Middlesex, UK, Catalogue No. HTB-132) was routinely maintained at
37 C with
5% COz up to a confluency of 70-90% in DMEM containing 10% heat-inactivated
FCS and
1% L-glutamine.
s For the assay, the cells were detached from the culture flask using
`Accutase'
(Innovative Cell Technologies Inc., San Diego, CA, USA; Catalogue No. AT 104)
using
standard tissue culture methods and resuspended in media to give 1.7x105 cells
per mL.
Aliquots (90 l) were seeded into each of the inner 60 wells of a black
Packard 96 well plate
(PerkinElmer, Boston, MA, USA; Catalogue No. 6005182) to give a density of -
15000 cells
io per well. Aliquots (90 l) of culture media were placed in the outer wells
to prevent edge
effects. The cells were incubated overnight at 37 C with 5% COz to allow them
to adhere.
On day 2, the cells were treated with test compounds and incubated for 2 hours
at
37 C with 5% COz. Test compounds were prepared as 10 mM stock solutions in
DMSO and
serially diluted as required with growth media to give a range of
concentrations that were 10-
is fold the required final test concentrations. Aliquots (10 l) of each
compound dilution were
placed in a well (in triplicate) to give the final required concentrations. As
a minimum
reponse control, each plate contained wells having a final concentration of
100 M LY294002
(Calbiochem, Beeston, UK, Catalogue No. 440202). As a maximum response
control, wells
contained 1% DMSO instead of test compound. Following incubation, the contents
of the
20 plates were fixed by treatment with a 1.6% aqueous formaldehyde solution
(Sigma, Poole,
Dorset, UK, Catalogue No. F1635) at room temperature for 1 hour.
All subsequent aspiration and wash steps were carried out using a Tecan 96
well
plate washer (aspiration speed 10 mm/sec). The fixing solution was removed and
the contents
of the plates were washed with phosphate-buffered saline (PBS; 50 l; Gibco,
Catalogue No.
25 10010015). The contents of the plates were treated for 10 minutes at room
temperature with
an aliquot (50 1) of a cell permeabilisation buffer consisting of a mixture
of PBS and 0.5%
Tween-20. The `permeabilisation' buffer was removed and non-specific binding
sites were
blocked by treatment for 1 hour at room temperature of an aliquot (50 1) of a
blocking buffer
consisting of 5% dried skimmed milk ['Marvel' (registered trade mark); Premier
Beverages,
30 Stafford, GB] in a mixture of PBS and 0.05% Tween-20. The `blocking' buffer
was removed
and the cells were incubated for 1 hour at room temperature with rabbit anti
phospho-Akt
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-66-
(Ser473) antibody solution (50 l per well; Cell Signalling, Hitchin, Herts,
U.K., Catalogue
No 9277) that had been diluted 1:500 in `blocking' buffer. Cells were washed
three times in a
mixture of PBS and 0.05% Tween-20. Subsequently, cells were incubated for 1
hour at room
temperature with Alexafluor488 labelled goat anti-rabbit IgG (50 l per well;
Molecular
s Probes, Invitrogen Limited, Paisley, UK, Catalogue No. Al 1008) that had
been diluted 1:500
in `blocking' buffer. Cells were washed 3 times with a mixture of PBS and
0.05% Tween-20.
An aliquot of PBS (50 l) was added to each well and the plates were sealed
with black plate
sealers and the fluorescence signal was detected and analysed.
Fluorescence dose response data obtained with each compound were analysed and
the
io degree of inhibition of Serine 473 in Akt was expressed as an ICso value.
(d) In Vitro MDA-MB-468 human breast adenocarcinoma Proliferation Assay
This assay determines the ability of test compounds to inhibit cell
proliferation as
assessed using Cellomics Arrayscan technology. A MDA-MB-468 human breast
adenocarcinoma cell line (LGC Promochem, Catalogue No. HTB-132) was routinely
is maintained as described in Biological Assay (b) herein.
For the proliferation assay, the cells were detached from the culture flask
using
Accutase and seeded into the inner 60 wells of a black Packard 96 well plate
at a density of
8000 cells per well in 100 l of complete growth media. The outer wells
contained 100 l of
sterile PBS. The cells were incubated overnight at 37 C with 5% COz to allow
them to
2o adhere.
On day 2, the cells were treated with test compounds and incubated for 48
hours at
37 C with 5% COz. Test compounds were prepared as 10 mM stock solutions in
DMSO and
serially diluted as required with growth media to give a range of test
concentrations. Aliquots
(50 l) of each compound dilution were placed in a well and the cells were
incubated for 2
25 days at 37 C with 5% COz. Each plate contained control wells without test
compound.
On day 4, BrdU labelling reagent (Sigma, Catalogue No. B9285) at a final
dilution of
1:1000 was added and the cells were incubated for 2 hours at 37 C. The medium
was
removed and the cells in each well were fixed by treatment with 100 l of a
mixture of
ethanol and glacial acetic acid (90% ethanol, 5% glacial acetic acid and 5%
water) for 30
30 minutes at room temperature. The cells in each well were washed twice with
PBS (100 l).
Aqueous hydrochloric acid (2M, 100 l) was added to each well. After 20
minutes at room
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-67-
temperature, the cells were washed twice with PBS. Hydrogen peroxide (3%, 50
l; Sigma,
Catalogue No. H1009) was added to each well. After 10 minutes at room
temperature, the
wells were washed again with PBS.
BrdU incorporation was detected by incubation for 1 hour at room temperature
with
s mouse anti-BrdU antibody (50 l; Caltag, Burlingame, CA, US; Catalogue No.
MD5200) that
was diluted 1:40 in PBS containing 1% BSA and 0.05% Tween-20. Unbound antibody
was
removed with two washes of PBS. For visualisation of incorporated BrdU, the
cells were
treated for 1 hour at room temperature with PBS (50 l) and 0.05% Tween-20
buffer
containing a 1:1000 dilution of Alexa fluor 488-labelled goat anti-mouse IgG.
For
io visualisation of the cell nucleus, a 1:1000 dilution of Hoechst stain
(Molecular Probes,
Catalogue No. H3570) was added. Each plate was washed in turn with PBS.
Subsequently,
PBS (100 l) was added to each well and the plates were analysed using a
Cellomics array
scan to assess total cell number and number of BrdU positive cells.
Fluorescence dose response data obtained with each compound were analysed and
the
is degree of inhibition of MDA-MB-468 cell growth was expressed as an IC50
value.
Although the pharmacological properties of the compounds of formula (I) vary
with
structural change as expected, in general, it is believed that activity
possessed by compounds
of formula (I) may be demonstrated at the following concentrations or doses in
one or more of
the above tests (a) to (d) :-
20 Test (a)(i):- IC50 versus mTOR kinase at less than 10 M, in particular
0.001 - 0.5
M for many compounds; for example 35 the IC50 was measured on
two occasions, the values were 0.566 and 0.404 uM.
Test (b)(i):- IC50 versus p110y Type lb human P13K at less than 10 M, in
particular 0.001 - 0.5 M for many compounds; and IC50 versus pl 10a
25 Type Ia human P13K at less than 10 M, in particular 0.00 1 - 0.5 M
for many compounds;
for example 35 the IC50 was measured on two occasions, the values
were 37 and >127 M.
Test (c):- IC50 versus Serine 473 in Akt at less than 10 M, in particular 0.1
- 20
30 M for many compounds); for example 35 the IC50 was measured on
one occasions, the value was 3.357 M.
Test (d):- IC50 at less than 20 M.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-68-
The following examples were tested in enzyme assay Test (a)(i):
Ex No. Test (a)(i) Ex No. Test (a)(i) Ex No. Test (a)(i)
IC50 ( M) IC50 ( M) IC50 ( M)
1 4.65 17 9.39 33 0.154
2 0.236 18 1.12 34 0.573
3 0.234 19 0.181 35 0.478
4 0.442 20 1.65 36 1.64
0.364 21 2.3 37 0.336
6 2.68 22 1.7 38 5.35
7 2.84 23 0.0377 39 0.192
8 1.78 24 0.303 40 0.588
9 0.894 25 0.385 41 0.117
26.4 26 1.38 42 0.335
11 3.58 27 1.17 43 0.88
12 4 28 0.626 44 0.366
13 1.58 29 0.351 45 0.119
14 0.886 30 0.897 46 0.932
9.55 31 0.99 47 0.512
16 2.47 32 0.437 48 0.108
In some cases, these values may represent the average of two or more
measurements.
By way of comparison, the corresponding unsubstituted morpholine compound (R3
is
hydrogen) has the following data: Test (a) 2.007and 0.650 M; Test (b)
131.992, 11.134,
s 79.939, 31.705, and 32.644 M; Test (c) 16.170 M.
The compounds of the present invention are advantageous in that they possess
pharmacological activity. In particular, the compounds of the present
invention modulate (in
particular, inhibit) mTOR kinase and/or phosphatidylinositol-3-kinase (P13K)
enzymes, such
as the Class Ia P13K enzymes (e.g. PI3Kalpha, PI3Kbeta and PI3Kdelta) and the
Class lb
io P13K enzyme (PI3Kgamma). More particularly compounds of the present
invention modulate
(in particular, inhibit) mTOR kinase. More particularly compounds of the
present invention
modulate (in particular, inhibit) one or more P13K enzyme. The inhibitory
properties of
compounds of formula (I) may be demonstrated using the test procedures set out
herein and in
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-69-
the experimental section. Accordingly, the compounds of formula (I) may be
used in the
treatment (therapeutic or prophylactic) of conditions/diseases in human and
non-human
animals which are mediated by mTOR kinase and/or one or more P13K enzyme(s),
and in
particular by mTOR kinase.
s The invention also provides a pharmaceutical composition comprising a
compound of
formula (I), or a pharmaceutically acceptable salt thereof, as defined herein
in association
with a pharmaceutically acceptable diluent or carrier.
The compositions of the invention may be in a form suitable for oral use (for
example
as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions,
emulsions, dispersible
io powders or granules, syrups or elixirs), for topical use (for example as
creams, ointments,
gels, or aqueous or oily solutions or suspensions), for administration by
inhalation (for
example as a finely divided powder or a liquid aerosol), for administration by
insufflation (for
example as a finely divided powder) or for parenteral administration (for
example as a sterile
aqueous or oily solution for intravenous, subcutaneous, intraperitoneal or
intramuscular
is dosing or as a suppository for rectal dosing).
The compositions of the invention may be obtained by conventional procedures
using
conventional pharmaceutical excipients, well known in the art. Thus,
compositions intended
for oral use may contain, for example, one or more colouring, sweetening,
flavouring and/or
preservative agents.
20 The amount of active ingredient that is combined with one or more
excipients to
produce a single dosage form will necessarily vary depending upon the host
treated and the
particular route of administration. For example, a formulation intended for
oral
administration to humans will generally contain, for example, from 1 mg to 1 g
of active
agent (more suitably from 1 to 250 mg, for example from 1 to 100 mg)
compounded with an
25 appropriate and convenient amount of excipients which may vary from about 5
to about 98
percent by weight of the total composition.
The size of the dose for therapeutic or prophylactic purposes of a compound of
formula I will naturally vary according to the nature and severity of the
disease state, the age
and sex of the animal or patient and the route of administration, according to
well known
30 principles of medicine.
In using a compound of formula (I) for therapeutic or prophylactic purposes it
will
generally be administered so that a daily dose in the range, for example, 1
mg/kg to 100
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-70-
mg/kg body weight is received, given if required in divided doses. In general,
lower doses
will be administered when a parenteral route is employed. Thus, for example,
for intravenous
administration, a dose in the range, for example, 1 mg/kg to 25 mg/kg body
weight will
generally be used. Similarly, for administration by inhalation, a dose in the
range, for
s example, 1 mg/kg to 25 mg/kg body weight will be used. Typically, unit
dosage forms will
contain about 10 mg to 0.5 g of a compound of this invention.
As stated herein, it is known that mTOR kinase and the P13K enzymes have roles
in
tumourigenesis as well as numerous other diseases. We have found that the
compounds of
formula (I) possess potent anti-tumour activity which it is believed is
obtained by way of
io inhibition of mTOR kinase and/or one or more of the P13K enzymes.
Accordingly, the compounds of the present invention are of value as anti-
tumour
agents. Particularly, the compounds of the present invention are of value as
anti-proliferative,
apoptotic and/or anti-invasive agents in the containment and/or treatment of
solid and/or
liquid tumour disease. Particularly, the compounds of the present invention
are expected to
15 be useful in the prevention or treatment of those tumours which are
sensitive to inhibition of
mTOR and/or one or more of the P13K enzymes such as the Class Ia P13K enzymes
and the
Class lb P13K enzyme. Further, the compounds of the present invention are
expected to be
useful in the prevention or treatment of those tumours which are mediated
alone or in part by
mTOR and/or one or more of the P13K enzymes such as the Class Ia P13K enzymes
and the
20 Class lb P13K enzyme. The compounds may thus be used to produce an mTOR
enzyme
inhibitory effect in a warm-blooded animal in need of such treatment. Certain
compounds
may be used to produce an P13K enzyme inhibitory effect in a warm-blooded
animal in need
of such treatment.
As stated herein, inhibitors of mTOR kinase and/or one or more P13K enzymes
should
25 be of therapeutic value for the treatment of proliferative disease such as
cancer and in
particular solid tumours such as carcinoma and sarcomas and the leukaemias and
lymphoid
malignancies and in particular for treatment of, for example, cancer of the
breast, colorectum,
lung (including small cell lung cancer, non-small cell lung cancer and
bronchioalveolar
cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and
neck, kidney,
30 liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes,
thyroid, uterus, cervix
and vulva, and of leukaemias [including acute lymphoctic leukaemia (ALL) and
chronic
myelogenous leukaemia (CML)], multiple myeloma and lymphomas.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-71-
According to a further aspect of the invention there is provided a compound of
formula (I), or a pharmaceutically acceptable salt thereof, as defined herein
for use as a
medicament in a warm-blooded animal such as man.
According to a further aspect of the invention, there is provided a compound
of
s formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein for use in the
production of an anti-proliferative effect in a warm-blooded animal such as
man.
According to a further aspect of the invention, there is provided a compound
of
formula (I), or a pharmaceutically acceptable salt thereof, as defined herein
for use in the
production of an apoptotic effect in a warm-blooded animal such as man.
According to a further feature of the invention there is provided a compound
of
formula (I), or a pharmaceutically acceptable salt thereof, as defined herein
for use in a warm-
blooded animal such as man as an anti-invasive agent in the containment and/or
treatment of
proliferative disease such as cancer.
According to a further aspect of the invention, there is provided the use of a
compound
is of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein for the
production of an anti-proliferative effect in a warm-blooded animal such as
man.
According to a further feature of this aspect of the invention there is
provided the use
of a compound of formula (I), or a pharmaceutically acceptable salt thereof,
as defined herein
in the manufacture of a medicament for use in the production of an anti-
proliferative effect in
2o a warm-blooded animal such as man.
According to a further aspect of the invention, there is provided the use of a
compound
of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein for the
production of an apoptotic effect in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention there is
provided the use
25 of a compound of formula (I), or a pharmaceutically acceptable salt
thereof, as defined herein
in the manufacture of a medicament for use in the production of an apoptotic
effect in a
warm-blooded animal such as man.
According to a further feature of the invention there is provided the use of a
compound
of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein in the
30 manufacture of a medicament for use in a warm-blooded animal such as man as
an anti-
invasive agent in the containment and/or treatment of proliferative disease
such as cancer.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-72-
According to a further feature of this aspect of the invention there is
provided a
method for producing an anti-proliferative effect in a warm-blooded animal,
such as man, in
need of such treatment which comprises administering to said animal an
effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt thereof, as
defined herein.
According to a further feature of this aspect of the invention there is
provided a
method for producing an anti-invasive effect by the containment and/or
treatment of solid
tumour disease in a warm-blooded animal, such as man, in need of such
treatment which
comprises administering to said animal an effective amount of a compound of
formula (I), or
a pharmaceutically acceptable salt thereof, as defined herein.
According to a further aspect of the invention there is provided the use of a
compound
of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein in the
manufacture of a medicament for use in the prevention or treatment of
proliferative disease
such as cancer in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention there is
provided a
method for the prevention or treatment of proliferative disease such as cancer
in a
warm-blooded animal, such as man, in need of such treatment which comprises
administering
to said animal an effective amount of a compound of formula (I), or a
pharmaceutically
acceptable salt thereof, as defined herein.
According to a further aspect of the invention there is provided a compound of
formula (I), or a pharmaceutically acceptable salt thereof, as defined herein
for use in the
prevention or treatment of those tumours which are sensitive to inhibition of
mTOR kinase
and/or one or more P13K enzymes (such as the Class Ia enzymes and/or the Class
lb P13K
enzyme) that are involved in the signal transduction steps which lead to the
proliferation,
survival, invasiveness and migratory ability of tumour cells.
According to a further feature of this aspect of the invention there is
provided the use
of a compound of formula (I), or a pharmaceutically acceptable salt thereof,
as defined herein
in the manufacture of a medicament for use in the prevention or treatment of
those tumours
which are sensitive to inhibition of mTOR kinase and/or one or more P13K
enzymes (such as
the Class Ia enzymes and/or the Class lb P13K enzyme) that are involved in the
signal
transduction steps which lead to the proliferation, survival, invasiveness and
migratory ability
of tumour cells.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-73-
According to a further feature of this aspect of the invention there is
provided a
method for the prevention or treatment of those tumours which are sensitive to
inhibition of
mTOR kinase and/or one or more P13K enzymes (such as the Class Ia enzymes
and/or the
Class lb P13K enzyme) that are involved in the signal transduction steps which
lead to the
s proliferation, survival, invasiveness and migratory ability of tumour cells
which comprises
administering to said animal an effective amount of a compound of formula (I),
or a
pharmaceutically acceptable salt thereof, as defined herein.
According to a further aspect of the invention there is provided a compound of
formula (I), or a pharmaceutically acceptable salt thereof, as defined herein
for use in
io providing a mTOR kinase inhibitory effect and/or a P13K enzyme inhibitory
effect (such as a
Class Ia P13K enzyme or Class lb P13K enzyme inhibitory effect).
According to a further feature of this aspect of the invention there is
provided the use
of a compound of formula (I), or a pharmaceutically acceptable salt thereof,
as defined herein
in the manufacture of a medicament for use in providing a mTOR kinase
inhibitory effect
is and/or a P13K enzyme inhibitory effect (such as a Class Ia P13K enzyme or
Class lb P13K
enzyme inhibitory effect).
According to a further aspect of the invention there is also provided a method
for
providing a mTOR kinase inhibitory effect and/or a P13K enzyme inhibitory
effect (such as a
Class Ia P13K enzyme or Class lb P13K enzyme inhibitory effect) which
comprises
2o administering an effective amount of a compound of formula I, or a
pharmaceutically
acceptable salt thereof, as defined herein.
According to a further feature of the invention there is provided a compound
of
formula I, or a pharmaceutically acceptable salt thereof, as defined herein
for use in the
treatment of cancer, inflammatory diseases, obstructive airways diseases,
immune diseases or
25 cardiovascular diseases.
According to a further feature of the invention there is provided a compound
of
formula I, or a pharmaceutically acceptable salt thereof, as defined herein
for use in the
treatment of solid tumours such as carcinoma and sarcomas and the leukaemias
and lymphoid
malignancies.
30 According to a further feature of the invention there is provided a
compound of
formula I, or a pharmaceutically acceptable salt thereof, as defined herein
for use in the
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-74-
treatment of cancer of the breast, colorectum, lung (including small cell lung
cancer, non-
small cell lung cancer and bronchioalveolar cancer) and prostate.
According to a further feature of the invention there is provided a compound
of
formula (I), or a pharmaceutically acceptable salt thereof, as defined herein
for use in the
s treatment of cancer of the bile duct, bone, bladder, head and neck, kidney,
liver,
gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid,
uterus, cervix and
vulva, and of leukaemias (including ALL and CML), multiple myeloma and
lymphomas.
According to a further feature of the invention there is provided the use of a
compound
of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein in the
io manufacture of a medicament for use in the treatment of cancer,
inflammatory diseases,
obstructive airways diseases, immune diseases or cardiovascular diseases.
According to a further feature of the invention there is provided the use of a
compound
of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein in the
manufacture of a medicament for use in the treatment of of solid tumours such
as carcinoma
15 and sarcomas and the leukaemias and lymphoid malignancies.
According to a further feature of the invention there is provided the use of a
compound
of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein in the
manufacture of a medicament for use in the treatment of cancer of the breast,
colorectum,
lung (including small cell lung cancer, non-small cell lung cancer and
bronchioalveolar
20 cancer) and prostate.
According to a further feature of the invention there is provided the use of a
compound
of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein in the
manufacture of a medicament for use in the treatment of cancer of the bile
duct, bone,
bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus,
ovary, pancreas,
25 skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias
(including ALL and CML),
multiple myeloma and lymphomas.
According to a further feature of the invention there is provided a method for
treating
cancer, inflammatory diseases, obstructive airways diseases, immune diseases
or
cardiovascular diseases in a warm blooded animal such as man that is in need
of such
30 treatment which comprises administering an effective amount of a compound
of formula (I),
or a pharmaceutically acceptable salt thereof, as defined herein.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-75-
According to a further feature of the invention there is provided a method for
treating
solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid
malignancies in a warm blooded animal such as man that is in need of such
treatment which
comprises administering an effective amount of a compound of formula (I), or a
s pharmaceutically acceptable salt thereof, as defined herein.
According to a further feature of the invention there is provided a method for
treating
cancer of the breast, colorectum, lung (including small cell lung cancer, non-
small cell lung
cancer and bronchioalveolar cancer) and prostate in a warm blooded animal such
as man that
is in need of such treatment which comprises administering an effective amount
of a
io compound of formula (I), or a pharmaceutically acceptable salt thereof, as
defined herein.
According to a further feature of the invention there is provided a method for
treating
cancer of the bile duct, bone, bladder, head and neck, kidney, liver,
gastrointestinal tissue,
oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva,
and of leukaemias
(including ALL and CML), multiple myeloma and lymphomas in a warm blooded
animal
15 such as man that is in need of such treatment which comprises administering
an effective
amount of a compound of formula (I), or a pharmaceutically acceptable salt
thereof, as
defined herein.
As stated herein, the in vivo effects of a compound of formula (I) may be
exerted in
part by one or more metabolites that are formed within the human or animal
body after
2o administration of a compound of formula (I).
The invention further relates to combination therapies wherein a compound of
formula (I), or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition or
formulation comprising a compound of formula (I) is administered concurrently
or
sequentially or as a combined preparation with another treatment of use in the
control of
25 oncology disease.
In particular, the treatment defined herein may be applied as a sole therapy
or may
involve, in addition to the compounds of the invention, conventional surgery
or radiotherapy
or chemotherapy. Accordingly, the compounds of the invention can also be used
in
combination with existing therapeutic agents for the treatment of cancer.
30 Suitable agents to be used in combination include :-
(i) antiproliferative/antineoplastic drugs and combinations thereof, as used
in medical
oncology such as alkylating agents (for example cis-platin, carboplatin,
cyclophosphamide,
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-76-
nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas);
antimetabolites (for
example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur,
raltitrexed,
methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumour
antibiotics (for
example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,
epirubicin,
s idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents
(for example
vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and
taxoids like
paclitaxel and taxotere); and topoisomerase inhibitors (for example
epipodophyllotoxins like
etoposide and teniposide, amsacrine, topotecan and camptothecins);
(ii) cytostatic agents such as antioestrogens (for example tamoxifen,
toremifene,
io raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators
(for example
fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide
and cyproterone
acetate), LHRH antagonists or LHRH agonists (for example goserelin,
leuprorelin and
buserelin), progestogens (for example megestrol acetate), aromatase inhibitors
(for example
as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-
reductase such as
15 finasteride;
(iii) anti-invasion agents (for example c-Src kinase family inhibitors like 4-
(6-chloro-
2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-
tetrahydropyran-
4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and
N-(2-chloro-6-methylphenyl)-2- {6-[4-(2-hydroxyethyl)piperazin-l-yl]-2-
methylpyrimidin-
2o 4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem.,
2004, 47, 6658-
6661), and metalloproteinase inhibitors like marimastat and inhibitors of
urokinase
plasminogen activator receptor function);
(iv) inhibitors of growth factor function: for example such inhibitors include
growth factor
antibodies and growth factor receptor antibodies (for example the anti-erbB2
antibody
25 trastuzumab [HerceptinTM] and the anti-erbBl antibody cetuximab [C225]);
such inhibitors
also include, for example, tyrosine kinase inhibitors, for example inhibitors
of the epidermal
growth factor family (for example EGFR family tyrosine kinase inhibitors such
as
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-
amine
(gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-
amine
30 (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-
morpholinopropoxy)quinazolin-4-amine (CI 1033) and erbB2 tyrosine kinase
inhibitors such
as lapatinib), inhibitors of the hepatocyte growth factor family, inhibitors
of the platelet-
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-77-
derived growth factor family such as imatinib, inhibitors of serine/threonine
kinases (for
example Ras/Raf signalling inhibitors such as famesyl transferase inhibitors,
for example
sorafenib (BAY 43-9006)) and inhibitors of cell signalling through MEK and/or
Akt kinases;
(v) antiangiogenic agents such as those which inhibit the effects of vascular
endothelial
s growth factor, [for example the anti-vascular endothelial cell growth factor
antibody
bevacizumab (AvastinTM) and VEGF receptor tyrosine kinase inhibitors such as 4-
(4-bromo-
2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline
(ZD6474;
Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-
(3-
pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212),
io vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), and
compounds
that work by other mechanisms (for example linomide, inhibitors of integrin
av(33 function
and angiostatin)];
(vi) vascular damaging agents such as combretastatin A4 and compounds
disclosed in
International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO
is 01/92224, WO 02/04434 and WO 02/08213;
(vii) antisense therapies, for example those which are directed to the targets
listed above,
such as ISIS 2503, an anti-ras antisense agent;
(viii) gene therapy approaches, including approaches to replace aberrant genes
such as
aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug
20 therapy) approaches such as those using cytosine deaminase, thymidine
kinase or a bacterial
nitroreductase enzyme and approaches to increase patient tolerance to
chemotherapy or
radiotherapy such as multi-drug resistance gene therapy; and
(ix) immunotherapeutic approaches, including ex-vivo and in-vivo approaches to
increase
the immunogenicity of patient tumour cells, such as transfection with
cytokines such as
25 interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating
factor, approaches
to decrease T-cell anergy, approaches using transfected immune cells such as
cytokine-transfected dendritic cells, approaches using cytokine-transfected
tumour cell lines
and approaches using anti-idiotypic antibodies.
The invention will now be further explained by reference to the following
illustrative
3o examples.
Unless stated otherwise, starting materials were commercially available. All
solvents
and commercial reagents were of laboratory grade and were used as received.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-78-
In the examples 'H NMR spectra were recorded on a Bruker DPX 300 (300 MHz),
Bruker DRX 400 (400 MHz) instrument or a Bruker DRX 500 (500 MHz) instrument.
The
central peaks of chloroform-d (8H 7.27 ppm), dimethylsulfoxide-d6 (8H 2.50
ppm) or acetone-
d6 (SH 2.05 ppm) were used as internal references. The following abbreviations
have been
s used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broad.
Column chromatography was carried out using silica gel (0.04-0.063 mm, Merck).
In
general, a Kromasil KR-100-5-C18 reversed-phase column (250 x 20 mm, Akzo
Nobel) was
used for preparative HPLC with mixtures of acetonitrile and water [containing
0.1 %
trifluoroacetic acid (TFA)] used as the eluent at a flow rate of 10 mL/min.
io The following methods were used for liquid chromatography (LC) / mass
spectral (MS)
analysis :-
HPLC: Agilent 1100 or Waters Alliance HT (2790 & 2795)
Mass Spectrometer: Waters ZQ ESCi
HPLC Column
15 The standard HPLC column used is the Phemonenex Gemini C18 5 m, 50 x 2 mm.
Acidic HPLC Methods
The mobile phases used are: Mobile phase A: Water
Mobile Phase B: Acetonitrile
Mobile Phase C: 1% Formic Acid in 50:50 Water:MeCN (v/v)
2o Each method is followed by a rapid equilibration using a 5 mL flow rate for
0.45 min.
Four uneric HPLC methods are available:
Minute Monitor Acidic method
Time Mobile Phase Mobile Phase Mobile Phase Curve Flow
/min A: B: C: Rate
/mL/min
0.00 95 0 5 1 1.1
4 0 95 5 6 1.1
4.5 0 95 5 6 1.1
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-79-
Early Acidic method for early elutini! compounds
Time Mobile Phase Mobile Phase Mobile Phase Curve Flow
/min A: B: C: Rate
/mL/min
0.00 95 0 5 1 1.1
4 57.5 37.5 5 6 1.1
4.5 57.5 37.5 5 6 1.1
Mid Acidic method for middle elutinl! compounds
Time Mobile Phase Mobile Phase Mobile Phase Curve Flow
/min A: B: C: Rate
/mL/min
0.00 95 0 5 1 1.1
0.01 67.5 27.5 5 6 1.1
4.5 27.5 67.5 5 6 1.1
s Late Acidic method for late elutinl! compounds
Time Mobile Phase Mobile Phase Mobile Phase Curve Flow
/min A: B: C: Rate
/mL/min
0.00 95 0 5 1 1.1
0.01 27.5 67.5 5 6 1.1
4.5 5 95 5 6 1.1
Basic HPLC methods
In some instances the standard acidic methods may be unsuitable for either the
compound
io ionisation or the chromatography separation required. In such cases four
comparable Basic
HPLC methods are available.
The mobile phases used are: Mobile phase A: Water
Mobile Phase B: Acetonitrile
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-80-
Mobile Phase D: 0.1% 880 Ammonia in acetonitrile
Each method is followed by a rapid equilibration using a 5 mL flow rate for
0.45 min.
Minute Monitor Basic method
Time Mobile Phase Mobile Phase Mobile Phase Curve Flow
/min A: B: D: Rate
/mL/min
0.00 95 0 5 1 1.1
4 0 95 5 6 1.1
4.5 0 95 5 6 1.1
Early Basic method for early elutinl! compounds
Time Mobile Phase Mobile Phase Mobile Phase Curve Flow
/min A: B: D: Rate
/mL/min
0.00 95 0 5 1 1.1
4 57.5 37.5 5 6 1.1
4.5 57.5 37.5 5 6 1.1
Mid Basic method for middle elutini! compounds
Time Mobile Phase Mobile Phase Mobile Phase Curve Flow
/min A: B: D: Rate
/mL/min
0.00 95 0 5 1 1.1
0.01 67.5 27.5 5 6 1.1
4.5 27.5 67.5 5 6 1.1
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-81-
Late Basic method for late elutini! compounds
Time Mobile Phase Mobile Phase Mobile Phase Curve Flow
/min A: B: C: Rate
/mL/min
0.00 95 0 5 1 1.1
0.01 27.5 67.5 5 6 1.1
4.5 5 95 5 6 1.1
The following method was used for liquid chromatography (LC) / mass spectral
(MS)
analysis :- Instrument: Agilent 1100; Column: Waters `Symmetry' 2.1 x 30 mm;
Mass
s Spectral analysis using chemical ionisation (APCI); Flow rate: 0.7 mL/min;
Absorption
Wavelength: 254 nm; Solvent A: water + 0.1 % TFA; Solvent B: acetonitrile +
0.1 % TFA ;
Solvent Gradient: 15-95% Solvent B for 2.7 minutes followed by 95% Solvent B
for 0.3
minutes.
The following methods were used for LC analysis :-
io Method A:- Instrument: Agilent 1100; Column: Kromasil C18 reversed-phase
silica,
100 x 3 mm, 5 m particle size; Solvent A: 0.1% TFA/water, Solvent B: 0.08%
TFA/acetonitrile; Flow Rate: 1 mL/min; Solvent Gradient: 10-100% Solvent B for
20 minutes
followed by 100% Solvent B for 1 minute; Absorption Wavelengths: 220, 254 and
280 nm.
In general, the retention time of the product was noted.
is Method B :- Instrument: Agilent 1100; Column: Waters `Xterra' C8 reversed-
phase
silica, 100 x 3 mm, 5 m particle size; Solvent A: 0.015M ammonia in water,
Solvent B:
acetonitrile; Flow Rate: 1 ml/min, Solvent Gradient: 10-100% Solvent B for 20
minutes
followed by 100% Solvent B for 1 minute; Absorption Wavelength: 220, 254 and
280 nm. In
general, the retention time of the product was noted.
20 The following abbreviations are used herein or within the following
illustrative
examples :-
HPLC High Performance Liquid Chromatography
HBTU O-(benzotriazol-l-yl)-N,N,N,N'-tetramethyluronium hexafluorophosphate;
HATU O-(7-azabenzotriazol-l-yl)-N,N,N',N-tetramethyluronium
hexafluorophosphate;
25 HOBT 1-hydroxybenzotriazole;
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-82-
HOAT 1-hydroxy-7-azabenzotriazole;
NMP N-methylpyrrolidin-2-one;
DMSO dimethylsulfoxide;
DMF N,N-dimethylformamide;
s DMA N,N-dimethylacetamide;
THF tetrahydrofuran;
DME 1,2-dimethoxyethane;
DCCI dicyclohexylcarbodiimide;
MeOH methanol;
io MeCN acetonitrile;
DCM dichloromethane;
DIPEA N,N-diisopropylethylamine
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene;
RT room temperature (approximately 17 to 25 C);
15 tR retention time;
m/z mass/charge ratio.
The chemical names were generated by software which used the Lexichem Toolkit
(v.
1.40) from OpenEye Scientific Software (www.eyesopen.com) to generate IUPAC
conforming names.
Example 1: N- f 4,6-Bis f(3S)-3-methylmorpholin-4-yll pyrimidin-2-yll -4-
methoxy-
benzamide
0
N
O N~
I
O NNN
O H ~O
4,6-Bis[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-amine (150 mg) was dissolved
in pyridine
(5 mL) and 4-methoxybenzoyl chloride (96 mg) added. The reaction was heated to
90 C for 1
hour. Further 4-methoxybenzoyl chloride (96 mg) was added and the reaction
heated at 90 C
for a further 3 hours. The reaction was allowed to cool, evaporated to dryness
then dissolved
in methanol. The material was passed down a SCX-2 column and eluted with 7N
ammonia in
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-83-
methanol. The fractions were concentrated in vacuo and chromatographed on
silica, eluting
with 2.5% methanol in DCM, to give the desired compound (107 mg) as a pale
blue solid.
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.11- 1.15 (6H, m), 3.01 - 3.08
(2H,
m), 3.40 (2H, q), 3.54 - 3.57 (2H, m), 3.68 (2H, d), 3.84 (3H, s), 3.87 - 3.91
(2H, m), 3.93
s(1H, s), 3.96 (1H, s), 4.35 (2H, t), 5.57 (1H, s), 6.98 - 7.02 (2H, m), 7.86 -
7.88 (2H, m), 9.79
(1 H, s)
Mass Spectrum; M+H+ 428.
The preparation of 4,6-bis[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-amine is
described
io below.
4,6-Bis[(3S)-3-methylmorpholin-4-yllbyrimidin-2-amine
0
N
N
H ~
a" ~ ~
2-Amino-4,6-dichloropyrimidine (3.28 g) and (3S)-3-methylmorpholine (4.44 g)
were
is dissolved in NMP (15 mL) under nitrogen. Calcium carbonate powder (4.4 g)
was added and
the stirred mixture heated to 200 C for 2.5 hours. The mixture was allowed to
cool and
partitioned between ethyl acetate and a saturated aqueous solution of sodium
hydrogen
carbonate. Solid residue was removed by filtration and the phases separated.
The aqueous
phase was washed with ethyl acetate and then the organics combined, washed
with 10%
2o aqueous brine (1 x 50 mL), 50% brine (1 x 50 mL) and brine (2 x 50 mL),
dried (MgS04) and
concentrated in vacuo. The residue was chromatographed on silica, eluting with
0 - 2%
isopropanol in DCM (with a few drops of triethylamine added), to give the
desired compound
as a colourless oil (2.76 g).
NMR Spectrum: 'H NMR (400.13 MHz, CDC13) b 1.22 - 1.28 (6H, d), 3.12 - 3.19
(2H, m),
25 3.51 - 3.57 (2H, m), 3.67 - 3.75 (4H, m), 3.81 - 3.85 (2H, m), 3.92 - 3.96
(2H, m), 4.26 (2H,
q), 4.46 (2H, br.s), 5.03 (1H, s)
Mass Spectrum; M+H+ 295
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-84-
Example 2: N- f 2,6-Bis f(3S)-3-methylmorpholin-4-yll pyrimidin-4-yll -4-
methoxy-3-
(trifluoromethyl)benzamide
0
N
F O I ~NI
F: F I~ H N NN~
O / ~ IO
2,6-Bis[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-amine)(120 mg) was dissolved
in pyridine
s(5 mL) and 4-methoxy-3 -(trifluromethyl)benzoyl chloride (196 mg) added. The
reaction was
heated at 90 C for 2 hours then the reaction allowed to cool and concentrated
in vacuo. The
residue was dissolved in methanol, passed down a SCX-2 column and the desired
material
eluted with 7N ammonia in methanol. The fractions were concentrated in vacuo
and the
residue purified by prep-HPLC (basic) to give the desired compound (97 mg) as
a white solid.
io NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.18 - 1.20 (6H, m), 3.07 -
3.10 (1H,
m),3.11-3.14(1H,m),3.40(1H,d),3.43(1H,d),3.55-3.61(1H,m),3.58-3.62(1H,m),
3.68 - 3.74 (2H, m), 3.87 - 3.95 (2H, m), 3.94 (1H, d), 3.99 (3H, s), 4.21 -
4.22 (1H, m), 4.25 -
4.28 (1H, m), 4.62 - 4.64 (1H, m), 6.93 (1H, s), 7.39 (1H, d), 8.24 (2H, d),
10.28 (1H, s)
Mass Spectrum; M+H+ 496.
is
The following compounds were made in an analogous fashion from 4,6-bis[(3S)-3-
methylmorpholin-4-yl]pyrimidin-2-amine or 2,6-bis[(3S)-3-methylmorpholin-4-
yl]pyrimidin-
2-amine and the appropriate acid chloride.
Example Structure NAME LCMS
MH+
3 ; ) -[2,6-Bis[(3S)-3-methylmorpholin-4- 428
" l]pyrimidin-4-yl]-3-methoxy-
o ~N
u N N~N~ enzamlde
I / H Lo
4 ; ) -[4,6-Bis[(3S)-3-methylmorpholin-4- 496
F O N " l]pyrimidin-2-yl]-4-methoxy-3-
~
(trifluoromethyl)benzamide
` F ~ ~ H " ~o
tF,
~
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-85-
Example Structure NAME LCMS
MH+
;, ) -[4,6-Bis[(3S)-3-methylmorpholin-4- 428
N l]pyrimidin-2-yl]-3-methoxy-
O N
I ~
~ NN N~ enzamlde
I / H ~O
Example 3: 'H NMR (400.13 MHz, DMSO-d6) b 1.19 (6H, t), 3.06 - 3.15 (2H, m),
3.36 -
3.40 (1H, m), 3.42 - 3.47 (1H, m), 3.53 - 3.62 (2H, m), 3.67 - 3.74 (2H, m),
3.85 (3H, s), 3.90
- 3.96 (2H, m), 4.23 (1H, d), 4.28 (1H, d), 4.61 - 4.63 (1H, m), 6.93 (1H, s),
7.15 - 7.18 (1H,
s m),7.42(1H,t),7.50(1H,t),7.54-7.57(1H,m),10.06(1H,s)
Example 4: 'H NMR (400.13 MHz, DMSO-d6) b 1.13 - 1.14 (6H, m), 3.04 (1H, d),
3.07 (1H,
s), 3.37 (1H, s), 3.40 (1H, d), 3.53 - 3.57 (2H, m), 3.67 (2H, d), 3.86 - 3.90
(2H, m), 3.92 -
3.95 (1H, m), 3.98 (4H, s), 4.34 (2H, t), 5.58 (1H, s), 7.35 (1H, d), 8.11
(1H, d), 8.14 - 8.17
(1 H, m), 10.15 (1 H, s)
io Example 5: 'H NMR (400.13 MHz, DMSO-d6) b 1.13 - 1.14 (6H, m), 3.01 - 3.07
(2H, m),
3.37 - 3.42 (2H, m), 3.53 - 3.57 (2H, m), 3.68 (2H, d), 3.82 (3H, s), 3.87 -
3.90 (2H, m), 3.92
(1H, s), 4.34 (2H, t), 5.58 (1H, s), 7.09 - 7.12 (1H, m), 7.37 (1H, d), 7.40 -
7.43 (1H, m), 7.39
- 7.45 (1H, m), 9.95 (1H, s)
is The preparation of 4,6-bis[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-amine
was described
earlier, the preparation of 2,6-bis[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-
amine is
described below.
2,6-Bis[(3S)-3-methylmorpholin-4-yllbyrimidin-4-amine
(~)',.
.
H2NN_!N~
`~
I,,~0
2o A mixture of 4-amino-2,6-dichloropyrimidine (4.33 g), (3S)-3-
methylmorpholine (6.00 g) and
calcium carbonate (5.81 g) in NMP (15 mL) was heated at 170-180 C for 3.5
hours under
nitrogen with a water-cooled condenser fitted to the flask. The mixture was
allowed to cool
and partitioned between ethyl acetate and a saturated aqueous solution of
sodium hydrogen
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-86-
carbonate. Solid residue was removed by filtration and the phases separated.
The aqueous
phase was washed with ethyl acetate and then the organics combined, washed
with 20%
aqueous brine (1 x 50 mL), 50% brine (1 x 50 mL) and brine (2 x 50 mL), dried
(MgS04) and
concentrated in vacuo. The residue was chromatographed on silica, eluting with
0 - 2.4%
s isopropanol in DCM (with a few drops of triethylamine added), to give the
desired compound
as a light brown gum (4.5 g).
NMR Spectrum: 'H NMR (400.13 MHz, CDC13) b 1.23 - 1.25 (6H, m), 3.13 - 3.21
(2H, m),
3.48 - 3.58 (2H, m), 3.65 - 3.75 (4H, m), 3.86 - 3.96 (3H, m), 4.14 - 4.17
(1H, m), 4.23 - 4.30
(3H, m), 4.59 - 4.64 (1H, m), 5.03 (1H, s)
io Mass Spectrum; M+H+ 295
Example 6: N- f 4,6-Bis f(3S)-3-methylmorpholin-4-yll pyrimidin-2-yll -6-
methoxy-
pyridine-3-carboxamide
0
N
O N-
N J<N N~
O
H
O N"
is 2-Methoxy-5-pyrdinecarboxylic acid (180 mg) was dissolved in DMA (2 mL) and
DIPEA
(0.216 mL) and HATU (350 mg) were added to the solution. The reaction was
allowed to stir
at room temperature for 10 minutes then 4,6-bis[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
amine (120 mg) added and the reaction stirred for 18 hours at 40 C. The
reaction was passed
down a SCX-2 column, washed with methanol and the desired material eluted with
7N
2o ammonia in methanol. The fractions were concentrated in vacuo and the
residue purified by
prep-HPLC (basic) to give the desired compound (28 mg) as a pale red solid.
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.10 - 1.14 (6H, m), 3.00 - 3.08
(2H,
m), 3.53 - 3.57 (2H, m), 3.67 (2H, d), 3.86 - 3.87 (1H, m), 3.88 (1H, d), 3.90
(1H, s), 3.93 -
3.95 (5H, m), 4.16 (1H, d), 4.33 (2H, d), 5.57 (1H, s), 7.18 (1H, d), 8.09 -
8.12 (1H, m), 8.65 -
25 8.66 (1H, m), 10.05 (1H, s)
Mass Spectrum; M+H+ 429.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-87-
The following compounds were made in an analogous fashion from 4,6-bis[(3S)-3-
methylmorpholin-4-yl]pyrimidin-2-amine or 2,6-bis[(3S)-3-methylmorpholin-4-
yl]pyrimidin-
2-amine and the appropriate carboxylic acid.
Example Structure NAME LCMS
MH+
7 On -[2,6-Bis[(3S)-3-methylmorpholin- 429
O N N 4-yl]pyrimidin-4-yl]-2-methoxy-
I
T H NN~ yridine-4-carboxamide
N / ~O
8 ; ) 6-Acetamido-N-[2,6-bis[(3S)-3- 456
O N ethylmorpholin-4-yl]pyrimidin-4-
N
N N",L ,N-~ 1]pyridine-3-carboxamide
A N N " ~1
H
9 ; ) -[2,6-Bis[(3S)-3-methylmorpholin- 428
N 4-yl]pyrimidin-4-yl]-2-methoxy-
O" O N
H N ~~ enzamlde
O
; ) 2-Acetamido-N-[2,6-bis[(3S)-3- 456
O N N ethylmorpholin-4-yl]pyrimidin-4-
-N ~ H NN' l]pyridine-4-carboxamide
O N / ~,O
11 ; ) -[2,6-Bis[(3S)-3-methylmorpholin- 446
o N N 4-yl]pyrimidin-4-yl]-3-fluoro-4-
" ):) H N N ethoxy-benzamide
o ~
12 ; ) -[4,6-Bis[(3S)-3-methylmorpholin- 429
N 4-yl]pyrimidin-2-yl]-2-methoxy-
i
~ H N~ yridine-4-carboxamide
N / ~O
13 ~ ) 6-Acetamido-N-[4,6-bis[(3S)-3- 456
N ethylmorpholin-4-yl]pyrimidin-2-
0 N
0N HI' N ~ 1]pyridine-3-carboxamide
H
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-88-
Example Structure NAME LCMS
MH+
14 ; ) -[4,6-Bis[(3S)-3-methylmorpholin- 428
O" O N " ` 4-yl]pyrimidin-2-yl]-2-methoxy-
I
NN N enzamlde
~O
H
15 ; ) 2-Acetamido-N-[4,6-bis[(3S)-3- 456
" ethylmorpholin-4-yl]pyrimidin-2-
0 '~
~" NN N') 1]pyridine-4-carboxamide
O N / H ~O
16 ; ) -[4,6-Bis[(3S)-3-methylmorpholin- 446
" 4-yl]pyrimidin-2-yl]-3-fluoro-4-
O N \,
F ~ ~ H~N~ ~~ ethoxy-benzamide
0
17 -[2,6-Bis[(3S)-3-methylmorpholin- 532
o N " 4-yl]pyrimidin-4-yl]-4-
I
~~
"k" H N ~o (phenylcarbamoylamino)benzamide
H H
18 ,c ) -[4,6-Bis[(3S)-3-methylmorpholin- 532
o N ~N, 4-yl]pyrimidin-2-yl]-4-
RJ, ~ N ~ N () HJ " ~
~ (phenylcarbamoylamino)benzamide
N
H H
Example 7: 'H NMR (400.13 MHz, DMSO-d6) b 0.94 (3H, d), 1.24 (3H, d), 2.67 -
2.69 (1H,
m), 2.96 (1H, d), 3.10 (1H, s), 3.13 - 3.21 (1H, m), 3.35 - 3.38 (1H, m), 3.39
- 3.45 (1H, m),
3.50 (1H, d), 3.57 - 3.60 (1H, m), 3.71 (1H, d), 3.90 (5H, s), 3.88 - 3.96
(1H, m), 4.33 (1H, d),
s 4.66 (1H, d), 6.80 (1H, d), 7.02 - 7.03 (1H, m), 7.50 (1H, s), 8.25 - 8.26
(1H, m)
Example 8: 'H NMR (400.13 MHz, DMSO-d6) b 0.97 (3H, d), 1.24 (3H, d), 2.14
(3H, s),
2.33 - 2.35 (1H, m), 2.61 (1H, s), 2.67 - 2.69 (1H, m), 2.96 (1H, d), 3.14 -
3.19 (2H, m), 3.39 -
3.46 (1H, m), 3.50 (1H, d), 3.57 - 3.60 (1H, m), 3.71 (1H, d), 3.87 (1H, s),
3.88 - 3.92 (1H,
m), 4.32 (1H, d), 4.64 (1H, d), 7.88 - 7.91 (1H, m), 7.50 (1H, s), 8.14 (1H,
d), 8.40 (1H, d),
io 10.74 (1H, s)
Example 9: 'H NMR (400.13 MHz, DMSO-d6) b 1.17 - 1.21 (6H, m), 3.05 - 3.15
(2H, m),
3.36 - 3.48 (2H, m), 3.54 - 3.62 (2H, m), 3.67 - 3.74 (2H, m), 3.86 - 3.95
(3H, m), 4.00 (3H,
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-89-
s), 4.17 - 4.21 (1H, m), 4.24 (1H, d), 4.54 (1H, d), 6.95 (1H, s), 7.11 - 7.15
(1H, m), 7.25 (1H,
d), 7.56 - 7.61 (1H, m), 7.88 - 7.90 (1H, m), 10.08 (1H, s)
Example 10: 'H NMR (400.13 MHz, DMSO-d6) b 0.94 (3H, d), 1.24 (3H, d), 2.10
(3H, s),
2.64 (1H, d), 2.68 (1H, q), 2.94 - 3.01 (1H, m), 2.98 (1H, d), 3.09 (1H, d),
3.14 - 3.21 (3H,
s m), 3.58 - 3.61 (1H, m), 3.71 (1H, d), 3.89 - 3.93 (2H, m), 4.33 (1H, d),
4.66 (1H, d), 7.14 -
7.16 (1H, m), 7.50 (1H, s), 8.17 (1H, s), 8.39 - 8.40 (1H, m), 10.59 (1H, s)
Example 11: 'H NMR (400.13 MHz, DMSO-d6) b 0.98 (3H, d), 1.23 (3H, d), 2.34
(1H, t),
2.53-2.57(1H,m),2.69(1H,q),2.71(1H,s),2.94(1H,s),3.13-3.18(1H,m),3.15-3.18
(1H, m), 3.34 (1H, d), 3.42 (1H, d), 3.50 (1H, d), 3.57 - 3.60 (1H, m), 3.71
(1H, d), 3.91 (3H,
io s), 4.29 (1H, d), 4.63 - 4.65 (1H, m), 7.23 (1H, t), 7.31 (1H, s), 7.33
(2H, d)
Example 12: 'H NMR (400.13 MHz, DMSO-d6) b 1.10 (6H, d), 2.97 - 3.04 (2H, m),
3.33 -
3.40 (2H, m), 3.50 - 3.53 (2H, m), 3.65 (2H, d), 3.84 - 3.85 (2H, m), 3.87 -
3.90 (5H, m), 4.24
(2H, t), 5.55 (1H, s), 7.08 (1H, s), 7.22 - 7.24 (1H, m), 8.24 - 8.26 (1H, m),
10.24 (1H, s)
Example 13: 'H NMR (400.13 MHz, DMSO-d6) b 1.10 - 1.14 (6H, m), 2.14 (3H, d),
3.00 -
is 3.08 (2H, m), 3.36 - 3.43 (2H, m), 3.53 - 3.56 (2H, m), 3.66 (2H, q), 3.84 -
3.94 (5H, m), 4.33
(2H, d), 5.57 (1H, s), 8.12 (1H, d), 8.17 - 8.20 (1H, m), 10.10 (1H, s), 10.75
(1H, s)
Example 14: 'H NMR (400.13 MHz, DMSO-d6) b 1.08 (6H, d), 2.95 - 2.99 (2H, m),
3.34 -
3.38 (1H, m), 3.48 - 3.51 (2H, m), 3.63 (2H, d), 3.76 (1H, s), 3.79 - 3.82
(6H, m), 3.84 (1H,
d), 3.86 (1H, s), 4.15 - 4.17 (2H, m), 5.49 (1H, s), 7.01 - 7.05 (1H, m), 7.09
- 7.11 (1H, m),
2o 7.43 (1H, d), 9.87 (1H, s)
Example 15: 'H NMR (400.13 MHz, DMSO-d6) b 1.08 - 1.13 (6H, m), 2.11 - 2.12
(3H, m),
2.99 - 3.03 (2H, m), 3.33 - 3.39 (2H, m), 3.48 - 3.52 (2H, m), 3.63 (2H, d),
3.80 - 3.87 (4H,
m), 4.21 (2H, d), 5.53 (1H, s), 7.28 - 7.29 (1H, m), 8.27 (1H, s), 8.36 - 8.37
(1H, m), 10.26
(1H, s), 10.60 (1H, s)
25 Example 16: 'H NMR (400.13 MHz, DMSO-d6) b 1.14 - 1.15 (6H, m), 3.01 - 3.09
(2H, m),
3.37 - 3.44 (2H, m), 3.54 - 3.58 (2H, m), 3.68 (2H, d), 3.87 - 3.94 (3H, m),
3.92 (4H, s), 4.36
(2H, t), 5.58 (1H, s), 7.25 (1H, t), 7.74 - 7.75 (1H, m), 7.77 (1H, s), 9.92
(1H, s)
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-90-
Example 19: N- f 2,6-Bis f(3S)-3-methylmorpholin-4-yll pyrimidin-4-yll -4-
methoxy-
benzamide
~0~
N
O ~
I ~ H NN
O ~'O
2,6-Bis[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-amine)( (150 mg) was dissolved
in
s pyridine (5 mL) and 4-methoxybenzoyl chloride (96 mg) was added to the
reaction and heated
to 90 C for 1 hour. Additional 4-methoxybenzoyl chloride (96 mg) was added and
heating
was continued for a further 1 hour. The reaction was left to cool and then
evaporated to
dryness and the compound dissolved in methanol and loaded onto a SCX-2 column
(20g). The
compound was removed with 7N ammonia in methanol, concentrated in vacuo and
the
io residue chromatographed on silica, eluting with 2.5% methanol in DCM, to
give the desired
material (136 mg) as a pale blue solid.
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.18 - 1.20 (6H, m), 3.08 - 3.14
(2H,
m), 3.37 - 3.43 (2H, m), 3.57 - 3.61 (3H, m), 3.69 (2H, d), 3.85 (3H, s), 3.87
- 3.94 (2H, m),
4.25 (2H, d), 4.61 - 4.64 (1H, m), 6.93 (1H, s), 7.03 - 7.05 (2H, m), 7.97 -
7.99 (2H, m), 9.87
is (1H, s)
Mass Spectrum; M+H+ 428.
Example 20: 2-f(2R,6S)-2,6-Dimethylmorpholin-4-yll-4-f(3S)-3-methylmorpholin-4-
yll-
6-(methylsulfonylmethyl)pyrimidine
(0)"',
N
O ,O
I
,S N J,
N~
20 I\i
A mixture of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidine
(150 mg), cis-2,6-dimethylmorpholine (0.263 mL) and sodium carbonate (104 mg)
in DMA
(3 mL) was heated at 180 C for 0.5 hours in a microwave reactor. The reaction
mixture was
loaded onto a SCX-2 column, the column washed with methanol then the desired
material
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-91-
eluted with 7N ammonia in methanol. The fractions were concentrated in vacuo
and the
residue purified by prep-HPLC (basic) to give the desired compound (151 mg) as
a solid.
NMR Spectrum: (DMSO-d6) 1.14 - 1.16 (6H, m), 1.18 - 1.19 (3H, m), 2.44 (2H,
d), 3.12 (4H,
s), 3.43 (1H, d), 3.52 - 3.58 (2H, m), 3.55 - 3.61 (1H, m), 3.72 - 3.75 (1H,
m), 3.96 (2H, s),
s 4.26 (3H, s), 4.42 - 4.45 (2H, m), 6.20 (1H, s)
Mass Spectrum; M+H+ 385.
The following compounds were made in an analogous fashion using the
appropriate amine.
Example Structure NAME LCMS
MH+
21 1-[4-[(3S)-3-Methylmorpholin-4-yl]- 371
N 6-(methylsulfonylmethyl)pyrimidin-2-
O,. .o I N
N, NO" yl]piperidin-3-ol
22 (0)4-[(3S)-3-methylmorpholin-4-yl]-6-
N ~~ (methylsulfonylmethyl)-2-morpholin-
O,.s.O I N
' No A.
4-yl-pyrimidine
0
io Example 21: 'H NMR (400.13 MHz, DMSO-d6) b 1.16 - 1.18 (3H, m), 1.35 (2H,
d), 1.68
(1H, s), 1.89 (1H, s), 2.73 - 2.79 (1H, m), 2.91 - 2.95 (1H, m), 3.09 (1H, s),
3.12 (3H, s), 3.40
- 3.45 (2H, m), 3.56 - 3.59 (1H, m), 3.72 (1H, d), 3.90 - 3.94 (2H, m), 4.06
(1H, q), 4.22 (2H,
s), 4.27 (1H, d), 4.39 - 4.43 (1H, m), 4.78 (1H, d), 6.12 (1H, s)
Example 22: 'H NMR (400.13 MHz, DMSO-d6) b 1.16 - 1.18 (3H, m), 3.12 (4H, s),
3.18
is (2H, d), 3.63 (8H, s), 3.71 (1H, d), 3.90 - 3.94 (2H, m), 4.25 (3H, s),
6.21 (1H, s)
The preparation of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidine is described below.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-92-
2-Chloro-4-f (3S)-3-methylmorpholin-4-yll-6-(methylsulfonylmethyl)pyrimidine
0
C N 1
O O lN
~S N~CI
2,4-Dichloro-6-(methylsulfonylmethyl)pyrimidine (30 g, 0.13 mol) was dissolved
in
dichloromethane and stirred (under nitrogen) at -5 C. Triethylamine (17.4 mL,
0.13 mol) was
s added to give a clear brown solution. (3S)-3-Methylmorpholine was dissolved
in
dichloromethane and added dropwise keeping the reaction below -5 C. The
cooling bath was
then removed and the mixture stirred for 1 hour. The reaction mixture was
heated at reflux for
2 hours, then the reaction mixture was washed with water, dried then
evaporated. The crude
material was purified by preparative HPLC to give the desired material as a
solid (19.3 g).
io NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.21 - 1.23 (m, 3H), 3.11 (s,
3H), 3.19
- 3.26 (m, 1 H), 3.42 - 3.49 (m, 1 H), 3.5 8- 3.62 (1 H, m), 3.73 (d, 1 H),
3.92 - 3.96 (m, 2H),
4.27 - 4.31 (m, 1 H), 4.45 (s, 2H), 6.92 (s, 1 H)
LCMS Spectrum: MH+ 306, retention time 1.42 min, Method 5 Min Acid
15 2,4-Dichloro-6-(methylsulfonylmethyl)pyrimidine
Ci
O p N
~S~ll`N~CI
6-(Methylsulfonylmethyl)-1H-pyrimidine-2,4-dione (132 g, 0.65 mol) was added
to
phosphorus oxychloride (1.2 L) and the mixture heated to reflux for 16 hours,
then cooled to
room temperature. The excess phosphorus oxychloride was removed in vacuo, the
residue
2o azeotroped with toluene (2 x 500 mL) and dissolved in dichloromethane. This
mixture was
then poured slowly onto ice (4 L) and stirred for 20 minutes, then extracted
with
dichloromethane (3 x 1 L) (the insoluble black material was filtered off and
discarded) and
ethyl acetate (2 x 1 L). The extracts were combined, dried, then evaporated to
leave the
desired material as a dark brown solid (51 g). The material was used without
further
25 purification.
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) 63.13 (s, 3H), 4.79 (s, 2H), 7.87
(s, 1H)
LCMS Spectrum: MH+ 239, retention time 1.21 min, Method 5 Min Acid
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-93-
6-(MethylsulfonylmethyI)-1 H-12yrimidine-2,4-dione
O
O O NH
is I N'J~' O
H
6-(Chloromethyl)-1H-pyrimidine-2,4-dione (175 g, 1.09 mol) was dissolved in
DMF (2L) and
methanesulphinic acid sodium salt (133.5 g, 1.31 mol) was added. The reaction
was heated to
s 125 C for 2 hours then allowed to cool and the suspension filtered and
concentrated in vacuo
to give a yellow solid. The crude material was washed with water, filtered,
then triturated with
toluene. The solid was filtered then triturated with isohexane to leave the
desired compound
as a yellow solid (250 g). The material was used without further purification.
io Example 23: 3- f 4- f(3S)-3-Methylmorpholin-4-yll -6-
(methylsulfonylmethyl)pyrimidin-2-
yll -5,7-diazabicyclo f 4.3.01 nona-1,3,5,8-tetraene
C0
N)''i
OO N
is I N
N..' N
H
A mixture of 5-bromo-lH-pyrrolo[2,3-b]pyridine (250 mg), potassium acetate
(374 mg) and
bis(pinacolato)diboron (387 mg) in 1,4 dioxane (12 mL) was degassed for 5
minutes then l,l'-
is bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane adduct
added (63
mg). The reaction was heated to 80 C for 4 hours. 2-Chloro-4-[(3S)-3-
methylmorpholin-4-yl]-
6-(methylsulfonylmethyl)pyrimidine (388 mg), ethanol (0.75 mL), 2M sodium
carbonate
solution (3.2 mL) and l,l'-
bis(diphenylphosphino)ferrocenedichloropalladium(II)
dichloromethane adduct (63 mg) were added and the heating continued for 16
hour. The
2o reaction mixture was allowed to cool and neutralised with 2M hydrochloric
acid. The reaction
mixture was passed through a SCX-2 column, the column washed with methanol
then the
desired material eluted with 7N ammonia in methanol. The fractions were
concentrated in
vacuo then chromatographed on silica, eluting with 2.5% methanol in DCM, to
give the
desired compound (176 mg) as a white solid.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-94-
NMR Spectrum: (DMSO-d6) 1.27 (3H, d), 3.23 (3H, s), 3.51 (1H, d), 3.67 (1H,
d), 3.80 (1H,
d), 4.01 (1H, d), 4.25 (1H, s), 4.52 (3H, s), 5.75 (1H, s), 6.59 (1H, s), 6.83
(1H, s), 7.52 (1H,
s), 8.85 (1H, s), 9.22 - 9.23 (1H, m), 11.83 (1H, s)
Mass Spectrum; M+H+ 388.
Example 24: 5- f 4- f(3S)-3-Methylmorpholin-4-yll -6-
(methylsulfonylmethyl)pyrimidin-2-
vll-lH-indole
N
O O ~N
~
N~
1! ON
H
To a solution of 5-[4-chloro-6-(methylsulfonylmethyl)pyrimidin-2-yl]-1H-indole
(97 mg,0.30
io mmol) and DIPEA (174.5 mg, 1.35 mmol) in THF (4 mL) was added, dropwise, 3S-
3-
Methylmorpholine (106 mg, 1.05 mmol) and the reaction warmed to 70 C
overnight. The
reaction mixture was evaporated to dryness and applied direct to a basic prep
HPLC system
for purification using a water/MeCN gradient. The title compound was obtained
as a cream
solid (38 mg).
is NMR Spectrum: 'H NMR (300.132 MHz, DMSO) 61.27 (3H, d), 3.24 (1H, s), 3.28
(3H, s),
3.52 (1H, td), 3.67 (1H, dd), 3.80 (1H, d), 4.01 (1H, dd), 4.21 (1H, d), 4.51
(3H, s), 6.55 (1H,
d), 6.77 (1H, s), 7.39 (1H, m), 7.45 (1H, d), 8.16 (1H, dd), 8.61 (1H, s),
11.24 (1H, s)
LCMS Spectrum: MH+ 387.5 Retention time 1.29 Method: Monitor Mid Basic
2o The following compound was prepared in an analogous fashion from 5-[4-
chloro-6-
(methylsulfonylmethyl)pyrimidin-2-yl]-1H-indole and the appropriate amine.
Example Structure NAME LCMS Retention
MH+ Time
25 5-[4-[(3R)-3- 387.6 1.27
N ethylmorpholin-4-yl]-6-
O,. .O N
's N ~ (methylsulfonylmethyl)pyrim
N
H idin-2-yl]-1H-indole
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-95-
Example 25: 'H NMR (300.132 MHz, DMSO) 8 1.26 (3H, d), 3.24 (3H, s), 3.43 -
3.55 (1H,
m), 3.67 (1H, dd), 3.80 (1H, d), 3.98 - 4.08 (2H, m), 4.21 (1H, d), 4.50 (3H,
s), 6.55 (1H, d),
6.77 (1H, s), 7.39 (1H, d), 7.45 (1H, d), 8.16 (1H, dd), 8.61 (1H, s), 11.24
(1H, s)
s The preparation of 5-[4-chloro-6-(methylsulfonylmethyl)pyrimidin-2-yl]-1H-
indole is
described below.
5-[4-chloro-6-(methylsulfonylmethyl)pyrimidin-2-yl1-1 H-indole
ci
O O ~N
I N I \ ~
1! ON
H
io 2-(1H-indol-5-yl)-6-(methylsulfonylmethyl)-3H-pyrimidin-4-one (626 mg, 2.06
mmol) was
refluxed in phosphorous oxychloride (15 mL) for 1 hour, the mixture allowed to
cool and the
phosphorous oxychloride removed under reduced pressure. The mixture was
azeotroped with
toluene, water added and the mixture made basic (pH= 10) with 6N sodium
hydroxide
solution. The mixture was extracted with ethyl acetate, washed with brine,
dried (MgSO4) and
is evaporated under reduced pressure to afford the desired material as yellow
gum which
solidified on standing (547 mg)
NMR Spectrum: 'H NMR (300.132 MHz, DMSO) S 3.23 (3H, s), 4.80 (2H, s), 6.61 -
6.62
(1H, m), 7.45 (1H, t), 7.53 (1H, d), 7.59 (1H, s), 8.16 (1H, dd), 8.66 (1H,
s), 11.40 (1H, s)
LCMS Spectrum: MH+ 322.43 Retention time 1.36 Method: Monitor Mid Acid
2-(1 H-indol-5-yl)-6-(methylsulfonylmethyl)-3H-gyrimidin-4-one
O
O O I NH
S N
N
H
2-Methylsulfanyl-6-(methylsulfonylmethyl)pyrimidin-4-ol (657 mg, 2.80 mmol), 5-
Indolyl
boronic acid (992 mg, 6.16 mmol), Copper (1) thiophene-2-carboxylate (1.39 g,
7.28 mmol)
and Palladium tetrakis triphenylphosphine (259 mg, 0.08 mmol) in 1,4 dioxane
(17 mL) were
placed in a microwave tube, degassed with nitrogen, sealed and irradiated at
130 C for
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-96-
45minutes. The reaction mixture was solubilised with NMP (8 mL) and applied to
a pre-
equilibrated SCX-2 column. The material was eluted using a gradient of 0-6%
ammonium
hydroxide in methanol. The residue was triturated with a small volume of ethyl
acetate,
filtered and the solid washed with diethyl ether to give the desired material
as a pale brown
s solid (626 mg).
NMR Spectrum: 'H NMR (300.132 MHz, DMSO-d6) 6 3.20 (3H, s), 4.47 (2H, s), 6.38
(1H,
s), 6.58 (1H, d), 7.47 (1H, t), 7.51 (1H, d), 7.91 (1H, d), 8.43 (1H, s),
11.43 (1H, s), 12.43
(1 H, s)
LCMS Spectrum: MH+ 304.5 Retention time 2.03 Method: Monitor Early Acid
lo
2-Methylsulfanyl-6-(methylsulfonylmethyl)pyrimidin-4-ol
OH
N - O
SN ,Si
O
6-(Chloromethyl)-2-methylsulfanyl-pyrimidin-4-ol (19.07 g, 100 mmol) was
suspended in
acetonitrile (400 ml). To this stirring suspension was added methanesulphinic
acid sodium
is salt (12.26 g, 120 mmol) and DMF (100 mL). The reaction was then heated to
100 C to give
a dark suspension and monitored by LCMS. Once complete, the solvents were
removed and
the resultant product added to 1:1 methanol:DCM (200 mL) and acidified with
acetic acid (10
mL). The resultant precipitate was collected, washed with water (200 mL) and
methanol (100
mL) and dried overnight in vacuo to afford the title compound as a white solid
(16.45 g).
2o NMR Spectrum: 'H NMR (300.132 MHz, DMSO-d6) 6 2.50 (s, 3H), 3.12 (s, 3H),
4.39 (s,
2H), 6.25 (s, 1H), 13.09 (s, 1H)
LCMS Spectrum: MH+ 235.2, Retention Time 0.5 minutes, Method: 5min Early Base
6-(Chloromethyl)-2-methylsulfanyl-12yrimidin-4-ol
OH
~N
CI I N
S-Methyl-2-thiopseudourea sulphate (20 g, 71.85 mmol), ethyl 4-
chloroacetoacetate (10.76
ml, 79.04 mmol) and sodium carbonate (13.93 g, 107.78 mmol) were dissolved in
water (100
mL) and stirred at RT overnight. The reaction was monitored by TLC, and once
complete, the
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-97-
reaction precipitate was collected and the supematant was neutralised with 6N
hydrochloric
acid to yield more reaction precipitate which was also collected. The
accumulated precipitate
was then washed with water and an off-white solid was obtained. This was dried
in vacuo at
60 C for 48 hours to yield the desired compound as a pale yellow/white solid
(43.2 g).
s NMR Spectrum: 'H NMR (300.132 MHz, CDC13) 6 2.59 (s, 3H), 4.35 (s, 2H), 6.41
(s, 1H),
12.70 (s, 1 H)
Mass Spectrum: M+ 190
Example 26: 5- f 4-(Butan-2-ylsulfonylmethyl)-6- f(3S)-3-methylmorpholin-4-
io yllnyrimidin-2-yll-lH-indole
N
y 0 O - N
~
S N~
1! ON
H
sec-Butyl thiol (25 mg, 0.28 mmol) was dissolved in DMF (1 mL) and sodium
hydride (60%
suspension in mineral oil) (12 mg, 0.3 mmol) was added. The reaction was
stirred for 10
minutes then 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonyloxymethyl)pyrimidin-2-
is yl]-1H-indole (101 mg, 0.25 mmol) was added. The reaction was stirred at RT
for a further 16
hours, to afford a solution of the sulphide intermediate. Water (1 mL) was
added to the
reaction followed by m-chloroperbenzoic acid (0.5 mmol) and the reaction
stirred at RT for 1
hour. The reaction mixture was diluted to 5 mL volume with acetonitrile and
purified by basic
prep HPLC to afford the desired product as a pale yellow solid (17 mg).
2o LCMS Spectrum: MH+ 429.52, Retention Time 1.77 Method: Monitor Base
The following compounds were prepared in an analogous fashion
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-98-
Example Structure NAME LCMS Retention
MH+ Time
(min)
27* (01, 5-[4-(butan-2-
N lsulfinylmethyl)-6-[(3R)-3-
0 N
~'s N ~ ethylmorpholin-4- 413.5 1.36
N
H yl]pyrimidin-2-yl]-IH-indole
28 5-[4-[(3R)-3-
N ethylmorpholin-4-yl]-6-
O. . N
~~
s N
~N (propan-2- 415.5 1.70
H ylsulfonylmethyl)pyrimidin-
2-yl]-IH-indole
29 (01, 5-[4-(ethylsulfonylmethyl)-6-
N [(3R)-3-methylmorpholin-4-
I N 401.5 1.69
1]pyrimidin-2-yl]-1H-indole
N
H
* This material was isolated from the same preparation which gave 5-[4-(butan-
2-
ylsulfonylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]-1H-indole.
The preparation of 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-
s (methylsulfonyloxymethyl)pyrimidin-2-yl]-1H-indole is described below.
5-[4- [(3 S)-3 -Methylmorpho lin-4-yll -6-(methylsulfonyloxymethyl)pyrimidin-2-
yll -1 H-indo le
C0
N)''i
I ~N
05:0 N I ~ ~
'!ON
H
[2-(1H-Indol-5-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methanol (340
mg, 1.05
io mmol) was suspended in DCM (8 mL) and treated with methane sulfonylchloride
(0.125 mL,
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-99-
1.57 mmol) and triethylamine (0.219 mL, 1.57 mmol). After 15 minutes the
suspension was
evaporated to give the desired product as a gummy solid (180 mg).
LCMS Spectrum: MH+ 403.61, Retention Time 2.26 Method: Monitor Base
s f2-(1H-Indol-5-yl)-6-[(3S)-3-methylmorpholin-4-yllbyrimidin-4-yllmethanol
C0
N)''i
'N
HO I N~
N
H
To 2-(1H-indol-5-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylic
acid (1 g, 2.96
mmol) suspended in dry THF (40 mL) was added borane-THF complex, (1M in THF,
18 mL,
18 mmol). The reaction mixture was heated slowly to 50 C for 20 minutes then
partitioned
io between ethyl acetate and aqueous sodium hydrogen carbonate solution. The
organics were
dried (MgS04), filtered and concentrated to give a dark oil. The oil was
chromatographed on
silica, eluting with 20-100% ethyl acetate in isohexane, to give the desired
material as a pale
white solid (350 mg).
NMR Spectrum: 'H NMR (300.132 MHz, DMSO-d6) 6 1.25 (3H, d), 3.21 (1H, td),
3.51 (1H,
is td), 3.66 (1H, dd), 3.79 (1H, d), 4.00 (1H, dd), 4.20 (1H, d), 4.48 (2H,
d), 4.51 - 4.57 (1H, m),
5.39 (1H, t), 6.54 (1H, dd), 6.66 (1H, s), 7.37 (1H, t), 7.42 (1H, d), 8.16
(1H, dd), 8.60 (1H,
s), 11.18 (1 H, s)
LCMS Spectrum: MH+ 325.49, Retention Time 1.72 Method: Monitor Base
2o 2-(1H-Indol-5-yl)-6-[(3S)-3-methylmorpholin-4-ylll2yrimidine-4-carboxylic
acid
C0
N)'',
N
HO I N~ \
O 1! ON
H
Methyl 2-chloro-6-[(3S)-3-methylmorpholin-4-yl] pyrmidine-4-carboxylate
(1 g, 3.68 mmol), indole-5-boronic acid (711 mg, 4.42 mmol) and
dichlorobis(triphenylphosphine)palladium (130 mg, 0.18 mmol) were dissolved in
18% DMF
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-100-
in 7:3:2 DME:Water:EtOH (15 mL) and aqueous sodium carbonate (2M, 5 mL) was
added.
The reaction was sealed and heated to 125 C for 30 minutes in the microwave
reactor. The
reaction was then evaporated and the mixture dissolved in 7:2:1
DMSO:Acetonitrile:Water
and acidified to pH=2 with hydrochloric acid. The resulting precipitate was
collected by
s filtration and dried to afford the title compound as a pale yellow solid
(1.l g).
NMR Spectrum: 'H NMR (300.132 MHz, DMSO-d6) 8 1.28 (3H, d), 3.14 - 4.85 (7H,
m),
6.57 (1H, s), 7.13 (1H, s), 7.30 - 7.86 (3H, m), 8.23 (1H, d), 8.70 (1H, s),
11.30 (1H, s)
LCMS Spectrum: MH+ 339.40, Retention Time 1.31 Method: Monitor Base
io Methyl2-chloro-6-[(3S)-3-methylmorpholin-4-yl]12yrimidine-4-carboxylate
C0
N)''i
I ~N
O N~CI
O
Methy12,6-dichloropyrimidine-4-carboxylate (4.4 g, 21.25 mmol) in DCM (20 mL)
was
cooled in ice and treated dropwise with 3S-3-methylmorpholine (2.37g, 23.4
mmol) and
DIPEA (8.15 mL, 46.8 mmol). After 3 hours polymer supported isocyanate
scavenger resin
15 (1 g) was added and the mixture was stirred for 30 minutes then filtered.
The solution was
evaporated and purified by flash silica chromatography, eluting with 5 - 20%
methanol in
DCM, to give the desired material as a white solid (5.0 g).
NMR Spectrum: 'H NMR (300.132 MHz, DMSO-d6) 8 1.23 (3H, d), 3.16 - 3.36 (2H,
m),
3.45 (1H, td), 3.59 (1H, dd), 3.71 (1H, d), 3.87 (3H, s), 3.93 (1H, dd), 4.33 -
4.56 (1H, m),
2o 7.28 (1H, s)
LCMS Spectrum: MH+ 272.38, Retention Time 1.52 Method: Monitor Base
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-101-
Example 30: 4-f(3S)-3-Methylmorpholin-4-yl1-6-(methylsulfonylmethyl)-N-(1H-
pyrazol-
3-yl)pyrimidin-2-amine
C0
ND' "
0~ 1- N
1, ZNH
N N N
H
2-Chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine
(1.00 g), 1H-
s pyrazol-3-amine (300 mg) and potassium carbonate (498 mg) were dissolved in
butyronitrile
(20 mL). The mixture was heated at reflux (117 C) for 24 hours. The reaction
was diluted
with ethyl acetate (20 mL) and washed with water (20 mL). The water was
extracted with
ethyl acetate (20 mL) and the combined organic extracts dried over magnesium
sulfate and
evaporated. The crude product was purified by chromatography on silica,
eluting with 0-5%
io methanol in DCM. The minor isomer was collected and gave the desired
material as a yellow
gum (45 mg).
NMR Spectrum: 'H NMR (400.13 MHz, CDC13) b 1.32 - 1.37 (3H, m), 1.68 (1H, s),
3.02
(3H, s), 3.07 (1H, m), 3.34 - 3.41 (1H, m), 3.55 - 3.62 (1H, m), 3.71 - 3.75
(1H, m), 3.81 (1H,
d), 4.02 - 4.06 (1H, m), 4.28 (2H, s), 4.31 (1H, m), 5.30 (1H, s), 5.51 (1H,
d), 5.75 (2H, s),
is 6.48 (1H, s), 7.48 (1H, d)
LCMS Spectrum: MH+ 353, Retention Time 1.01min, Method Monitor Acid
Example 31: 4-f(3S)-3-Methylmorpholin-4-yl1-6-(methylsulfonylmethyl)-2-f4-(1H-
pyrazol-4-yl)phenyll pyrimidine
N~--.,
0 0 ~N
~ N~ I
NH
Nitrogen was bubbled through a mixture of 2-chloro-4- [(3 S)-3 -
methylmorpholin-4-yl] -6-
(methylsulfonylmethyl)pyrimidine (210 mg, 0.69 mmol), tert-butyl 4-[4-(4,4,5,5-
tetramethyl-
1,3,2-dioxaborolan-2-yl)phenyl]pyrazole-1-carboxylate (270 mg, 0.73 mmol),
potassium
phosphate tribasic (511 mg, 2.4 mmol) in dioxane for 10 minutes. Bis(tri-tert-
butylphosphine)palladium(0) (18 mg) was added and the reaction was degassed
several times
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-102-
then heated at 80 C for 16 hours. After cooling the mixture was extracted with
ethyl acetate,
washed with water, dried (MgSO4), filtered and evaporated. The crude material
was
chromatographed on silica, eluting with 60-75% ethyl acetate in hexane, to
give the desired
material (71 mg) as a white solid.
s NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.26 (3H, d), 3.22 (2H, s),
3.25-3.30
(2H, m), 3.55 (1H.dd), 3.68 (1H, d), 3.78 - 3.81 (1H, d), 4.03 (1H, dd), 4.15
(1H, s), 4.50 (3H,
s), 6.84 (1H, s), 7.71 - 7.73 (2H, d), 8.00 (1H, s), 8.27 (1H, s), 8.30 - 8.33
(2H, d)
LCMS Spectrum; MH+414, retention time 1.81 mins, method monitor base.
io The preparation of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidine was described earlier.
The preparation of tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]pyrazole-l-carboxylate is described below.
is
tert-Buty14-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheUllbyrazole-1-
carboxylate
O,
~ N4
~N O
A mixture of tert-butyl 4-(4-bromophenyl)pyrazole-1-carboxylate (l.l g, 3.4
mmol),
bispinacolato diborane (1.04 g, 4.1 mmol), potassium acetate (1 g, 10.2 mmol),
1,l'-
2o bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane adduct
(167 mg) in
dioxane (15 mL), were heated at 90 C for 5 hours. The mixture was diluted with
water and
extracted into ethyl acetate. The organics were dried (MgS04), filtered and
evaporated and the
residue chromatographed on silica, eluting with 30% ethyl acetate in hexane,
to give the
desired material (835 mg).
25 NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.31 (12H, s), 1.61 (9H, s),
7.68 (2H,
d), 7.75 (2H, d), 8.30 (1H, s), 8.78 (1H, s).
LCMS Spectrum; no MH+ ion observed, retention time 2.82mins , method monitor
base
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-103-
tert-Buty14-(4-bromophenyl)pyrazole-1-carboxylate
Br
0
N4
O
A mixture of 4-(4-bromophenyl)-1H-pyrazole (800 mg, 3.6 mmol), (2-methylpropan-
2-
yl)oxycarbonyl tert-butyl carbonate (1.18 g, 5.38 mmol) and DMAP (100 mg), in
THF (20
s mL) were heated at 80 C for 3 hours. The mixture was evaporated, dissolved
in DCM and
chromatographed on silica, eluting with 40% ethyl acetate in hexane, to give
the desired
material (960 mg).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.61 (9H, s), 7.58 (2H, d), 7.70
(2H, s),
8.30 (1H, s), 8.80 (1H, s).
io LCMS Spectrum no MH+, retention time 2.8lmins, method monitor base.
Example 32: 4-f(3S)-3-Methylmorpholin-4-yll-6-(methylsulfonylmethyl)-2-f3- (1H-
pyrazol-4-yl)phenyll pyrimidine
N
N
0 0 N H
~ ~~N
N I \
/
is A mixture of tert-butyl 4-[3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]pyrazole-l-
carboxylate (270 mg, 0.73 mmol), 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidine (210 mg, 0.69 mmol), potassium phosphate
tribasic (511
mg, 2.4 mmol), bis(tri-tert-butylphosphine)palladium(0) (18 mg) in toluene (2
mL), ethanol (4
mL) and water (2 mL) was stirred at 80 C for 16 hours. After cooling the
mixture was
2o extracted with ethyl acetate, washed with water, the organics dried
(MgS04), filtered and
evaporated. The residue was chromatographed on silica, eluting with 70-100 %
ethyl acetate
in hexane, to give the desired material (116 mg).
NMR Spectrum 'H NMR (400.13 MHz, DMSO-d6) b 1.26 - 1.28 (3H, d), 3.24 (2H, s),
3.52
(2H, d), 3.55 (1H, dd), 3.66 - 3.69 (1H, dd), 3.80 (1H, d), 3.99 - 4.03 (1H,
dd), 4.20 (1H, s),
25 4.54 (3H, s), 6.88 (1H, s), 7.48 (1H, dd), 7.72 - 7.75 (1H, d), 7.95 (1H,
s), 8.16 (1H, d), 8.22
(2H, s), 8.50 (1H, s), 12.99 (1H, s)
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-104-
LCMS Spectrum MH+ 414, retention time 1.86 mins, method monitor base.
The preparation of tert-butyl4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]pyrazole-l-carboxylate is described below.
tert-Buty14-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]l2yrazole-l
-carboxylate
0
O N
B
O"
A mixture of tert-butyl4-(3-bromophenyl)pyrazole-l-carboxylate (l.l g, 3.4
mmol),
bispinacolatodiborane (1.038 g, 4 mmol), potassium acetate (1 g, 10.2 mmol),
l,l'-
io bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane adduct
(167 mg) in
dioxane (15 mL) was heated at 90 C for 5 hours. The mixture was diluted with
water and
extracted into ethyl acetate. The organics were dried (MgS04), filtered and
evaporated and the
residue chromatographed on silica, eluting with 30% ethyl acetate in hexane,
to give the
desired material (1.l g).
is NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.33 (12H, s), 1.62 (9H, s),
7.40 (1H,
dd), 7.60 (1H, d), 7.88 (1H, d), 7.92 (1H, d), 8.29 (1H, s), 8.70 (1H, s).
LCMS Spectrum; no MH+ ion observed, retention time 2.89mins, method monitor
base.
tert-Buty14-(3-bromophenyl)pyrazole- l -carboxylate
0
Br \ ~ ~N
I /
A mixture of 4-(3-bromophenyl)-1H-pyrazole (800 mg, 3.6 mmol), (2-methylpropan-
2-
yl)oxycarbonyl tert-butyl carbonate (1.18 g, 5.38 mmol) and DMAP (100 mg), in
THF (20
mL) were heated at 80 C for 3 hours. The mixture was evaporated, dissolved in
DCM and
chromatographed on silica, eluting with 40% ethyl acetate in hexane, to give
the desired
material (l.l g).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) 61.62 (9H, s) 7.35 (lHdd), 7.50
(1H, dd),
7.78 (1H, dd), 8.05 (1, d), 8.35 (1H, s), 8.84 (1H, s).
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-105-
LCMS Spectrum; no MH+ ion observed, retention time 2.67mins, method monitor
base.
Example 33: 5- f 4- f(3S)-3-Methylmorpholin-4-yll -6-
(methylsulfonylmethyl)pyrimidin-2-
yll-lH-indole-3-carboxamide
N
N H
H
Triethylamine (0.064 mL, 0.52 mmol) and HATU (95 mg, 0.25 mmol) were added to
a stirred
suspension of 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidin-2-yl]-
1H-indole-3-carboxylic acid (90 mg, 0.2 mmol), in DCM (8 mL) at RT. After 10
minutes an
aqueous solution of ammonia (1 mL) was added and the reaction stirred for 45
minutes. The
io mixture was washed with a saturated aqueous solution of sodium hydrogen
carbonate, the
organics dried (MgSO4), filtered and evaporated. The residue was
chromatographed on silica,
eluting with 0-10% methanol in ethyl acetate, and the solid obtained
triturated with a mixture
of diethyl ether and hexane to give the desired material (11 mg).
NMR Spectrum: 'H NMR (500.13 MHz, DMSO-d6) b 1.27 (3H, d), 3.27 - 3.28 (4H,
m), 3.6
is (1H, t), 3.69 (1H, d), 3.78 (1H, d), 4.0 (1H, d), 4.20 (1H, s), 4.49 (1H,
s), 4.51 (3H, s), 6.75
(2H, s), 7.48 (1H, s), 8.09 (1H, s), 8.18 (1H, d), 9.20 (1H, s), 11.62 (1H,
s).
LCMS Spectrum; MH+ 430, retention time 1.45mins, method monitor base.
The preparation of 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidin-
2o 2-yl]-1H-indole-3-carboxylic acid is described below.
5-[4-[(3S)-3-Methylmorpholin-4-yl1-6-(methylsulfonylmethyl)pyrimidin-2-yl1-1H-
indole-3-
carboxylic acid
N~-'-,
O O I~N OH
S N I \ ~
N
H
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-106-
A mixture of inethyl5-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidin-
2-yl]-1H-indole-3-carboxylate (177 mg, 0.4 mmol) in 2M sodium hydroxide
solution (3 mL),
methanol (7 mL) and THF (5 mL) was heated at 90 C for 4 hours then left to
stir at RT for 16
hours. The organics were removed in vacuo and the mixture washed with ethyl
acetate. The
s aqueous layer was acidified (pH = 4-6) and the product extracted with ethyl
acetate. The
organics were washed with water, dried (MgSO4) and evaporated to give the
desired material
(90 mg) which was used without further purification.
LCMS Spectrum MH+ 431, retention time 0.73mins, method monitor base.
io Methyl5-[4-[(3S)-3-methylmorpholin-4-yll-6-(methylsulfonylmethyl)pyrimidin-
2-yl1-1H-
indole-3-carboxvlate
N
O O I~N O O
N
N
H
A mixture of inethyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-
3-carboxylate
(250 mg, 0.83 mmol), 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-
is (methylsulfonylmethyl)pyrimidine (230 mg, 0.75 mmol), potassium phosphate
tribasic (560
mg), bis(tri-tert-butylphosphine)palladium(0) (24 mg) in toluene (2 mL),
ethanol (4 mL) and
water (2 mL) was stirred at 80 C for 16 hours. After cooling the mixture was
extracted with
ethyl acetate, washed with water, the organics dried (MgS04), filtered and
evaporated. The
residue was chromatographed on silica, eluting with 65 % ethyl acetate in
hexane, to give the
2o desired material (190 mg).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.28 (3H, d), 3.25 (4H, d), 3.53
(1H,
d), 3.66 (1H, d), 3.84 (4H, s), 4.03 (1H, d), 4.20 (1H, d), 4.55 (3H, s), 6.82
(1H, s), 7.55 (1H,
d), 8.13 (1H, d), 8.25 (1H, d), 9.09 (1H, d), 12.05 (1H, s)
LCMS Spectrum; MH+ 445, retention time 1.93mins, method monitor base.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-107-
Methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carboxylate
0 0\
o'B X
N
H
A mixture of methyl tert-butyl 5-bromoindole-1,3-dicarboxylate (600 mg, 1.7
mmol),
bispinacolatodiborane (516 mg, 2.3 mmol), potassium acetate (498 mg, 5.1
mmol), l,l'-
s bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane adduct
(83 mg) in
dioxane (10 mL) was degassed several times and heated at 90 C for 14 hours.
The reaction
was diluted with water and extracted with ethyl acetate, the organics dried
(MgSO4), filtered
and evaporated. The residue was chromatographed on silica, eluting with 50%
ethyl acetate in
hexane to give the desired material.
lo NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.32 (12H, s), 3.82 (3H, s),
7.46 (1H,
d), 7.50 (1H, d), 8.10 (1H, s), 8.43 (1H, s), 12.00 (1H, s)
LCMS Spectrum; MH+ 302, retention time 2.23mins, monitor base.
Methyl tert-butyl5-bromoindole-1,3-dicarboxylate
0
0
Br
N \
~O/~
15 0
A mixture of 5-bromo-l-[(2-methylpropan-2-yl)oxycarbonyl]indole-3-carboxylic
acid (1 g,
2.9 mmol), potassium carbonate (609 mg, 4.4 mmol) and iodomethane (626 mg,
4.4. mmol) in
DMF (15 mL) was heated at 70 C for 1.5 hours. The mixture was allowed to cool,
diluted
with water and extracted with ethyl acetate. The organics were washed with
water, dried
20 (MgS04), filtered and evaporated. The residue was chromatographed on
silica, eluting with
15-20% ethyl acetate in hexane, to give the desired material as a white solid
(600 mg).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b1.65 (9H, s), 3.89 (3H, s), 7.58
(1H,
dd), 8.07 (1H, d), 8.19 (1H, d), 8.26 (1H, s)
LCMS Spectrum; no MH+ ion observed, retention time 3.32mins, method monitor
base
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-108-
Example 34: 4-f(3S)-3-Methylmorpholin-4-yl1-6-(methylsulfonylmethyl)-2-f2-(1H-
pyrazol-4-yl)-1,3-thiazol-5-yll pyrimidine
C(0).",
O O I ~N
,S NSN
~ N ~N
A mixture of 2-(2-bromo-1,3-thiazol-5-yl)-4-[(3S)-3-methylmorpholin-4-yl]-6-
s(methylsulfonylmethyl)pyrimidine (150 mg, 0.346 mmol), 4-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.515 mmol), 2M aqueous solution of
sodium
hydrogen carbonate (1 mL), dichlorobis(triphenylphosphine)palladium(II) (20
mg) in DMF (2
mL), DME (4 mL), water (1.5 mL) and ethanol (2 mL) was degassed several times
then
heated at 95 C under a nitrogen atmosphere. The reaction was allowed to cool,
diluted with
io water and extracted with ethyl acetate. The organics were washed with
water, dried (MgSO4),
filtered and evaporated. The residue was chromatographed on silica, eluting
with ethyl
acetate, and the solid obtained was triturated with a mixture of ethyl acetate
and hexane to
give the desired material (50 mg).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.25 (3H, d), 3.20 (1H, d), 3.28
(3H, s),
is 3.50 (1H, dd), 3.62 (1H, dd), 3.78 (1H, d), 4.00 (1H, dd), 4.15 (1H, s),
4.40 (1H, s), 4.50 (2H,
s), 6.81 (1H, s), 8.05 (1H, s), 8.42 (1H, s), 8.46 (1H, s), 13.35 (1H, s).
LCMS Spectrum; MH+ 421, retention time 1.59mins, method monitor base.
The preparation of 2-(2-bromo-1,3-thiazol-5-yl)-4-[(3S)-3-methylmorpholin-4-
yl]-6-
20 (methylsulfonylmethyl)pyrimidine is described below.
2-(2-Bromo-1,3-thiazol-5-yl)-4-[(3S)-3-methylmorpholin-4-yll-6-
(methylsulfonylmethyl)pyrimidine
N
O O I ~N
~S N~ S
I ~~-Br
N
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-109-
tert-Butyl nitrite (0.921 mL) was added to a mixture of copper (I) bromide
(282 mg, 2 mmol),
in acetonitrile (8 mL). After stirring for 45 minutes, 5-[4-[(3S)-3-
methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidin-2-yl]-1,3-thiazol-2-amine (600 mg, 1.38 mmol)
was added.
The reaction was stirred for 45 minute then heated at 60 C for 2 hours. The
reaction was
s allowed to cool, partitioned between ethyl acetate and water, the organics
dried (MgSO4),
filtered, and evaporated. The residue was chromatographed on silica, eluting
with 50-60%
ethyl acetate in hexane, and the solid obtained triturated with a mixture of
diethyl ether and
hexane to give the desired material as a pale yellow solid (255 mg).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.24 (3H, d), 3.17 (3H, s), 3.23
(1H, d),
io 3.46 - 3.51 (1H, dd), 3.65 (1H, d), 3.77 (1H, d), 3.96 - 3.99 (1H, d), 4.12
(1H, s), 4.40 (1H, s),
4.49 (2H, s), 6.88 (1H, s), 8.30 (1H).
LCMS Spectrum; MH+ 435, retention time 2.1 lmins, method monitor base.
5-[4- [(3 S)-3 -Methylmorpho lin-4-yll -6-(methylsulfonylmethyl)pyrimidin-2-
yll -1, 3-thiaz o l-2-
1 s amine
N
0 0 I ~N
N
I N NH2
A solution of tert-butyl N-[5-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidin-2-yl]-1,3-thiazol-2-yl]-N-[(2-methylpropan-2-
yl)oxycarbonyl]carbamate (1.7 g, 2.9 mmol) and TFA (8 mL) in DCM (15 mL) was
stirred at
2o RT for 16 hours. The solvent was removed under reduced pressure and the
residue made basic
with aqueous ammonia solution. The product was extracted with ethyl acetate,
the organics
dried over sodium sulphate, filtered and evaporated to give the desired
material as a white
solid (1 g).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.16 - 1.22 (3H, m), 3.13 - 3.18
(1H,
25 m), 3.19 (3H, s), 3.43 - 3.50 (1H, m), 3.60 - 3.63 (1H, m), 3.75 (1H, d),
3.94 - 3.97 (1H, dd),
4.04 (1H, d), 4.37 (1H, s), 4.40 (2H, s), 5.75 (1H, s), 6.64 (1H, s), 7.40
(2H, s), 7.73 (1H, s)
LCMS Spectrum; MH+ 370, retention time 1.38 mins, method monitor base.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-110-
tert-Butyl N-[5-[4-[(3S)-3-methylmorpholin-4-yll-6-(methylsulfonylmethyI
pyrimidin-2-yll-
1,3-thiazol-2-yll-N-[(2-methylpropan-2-yl)oxycarbonyll carbamate
C(0).",
OSO I iN o-O
N S Y
I N N
>cO
O
A mixture of tert-butyl N-[(2-methylpropan-2-yl)oxycarbonyl]-N-(5-
tributylstannyl-1,3-
s thiazol-2-yl)carbamate (3 g, 5.1 mmol), 2-chloro-4-[(3S)-3-methylmorpholin-4-
yl]-6-
(methylsulfonylmethyl)pyrimidine (1 g, 3.2 mmol) and palladium tetrakis
(triphenylphosphine) (50 mg), in toluene (10 mL) was heated at 105 C for 2
hours under
nitrogen. The mixture was chromatographed on silica to give the desired
material (1.7 g).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.20 (3H, d), 1.53 (9H, s), 3.18
(3H, s),
io 3.55 (1H, t), 3.62 (1H, d), 3.75 (1H, d), 3.98 (1H, d), 4.10 (1H, s), 3.90
(1H, s), 3.98 (2H, s),
6.80 (1H, s), 8.18 (1H, s)
LCMS Spectrum; MH+ 570, retention time 2.89mins, method monitor base.
tert-Butyl N-[(2-methylpropan-2-yl)oxycarbonyll-N-(5-tributylstannyl-1,3-
thiazol-2-
is yI)carbamate
1-1~sn s o
N
>c0
O
n-Butyl lithium (1.6M in hexanes, 30 mL, 0.48 mol), was added to
diisopropylamine (6.7 mL,
0.48mo1) in THF (480 mL) at 0 C. The mixture was stirred at 0 C for 30 mins
then cooled to
-78 C. tert-Butyl N-[(2-methylpropan-2-yl)oxycarbonyl]-N-(1,3-thiazol-2-
yl)carbamate (12 g,
20 0.05 mol) was added and solution stirred for 30 minutes. Tributyltin
chloride (16.3 mL) was
added and solution stirred for 30minutes before allowing to warm to RT. The
reaction was
quenched with a saturated aqueous solution of ammonium chloride (20 mL) and
the product
extracted with ethyl acetate. The organics were dried over sodium sulphate,
concentrated in
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-111-
vacuo and chromatographed on silica, eluting with 5-15% ethyl acetate in
hexane, to give the
desired material as a clear oil (9 g).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.49 (18H, s), 7.50 (1H, d), 7.55
(1H,
d)
tert-Butyl N-[(2-methylpropan-2-yl)oxycarbonyll-N-(1,3-thiazol-2-YI)carbamate
s
CN N>c0
O
A solution of 2-aminothiazole (5 g, 0.05 mol), (2-methylpropan-2-
yl)oxycarbonyl tert-butyl
carbonate (27.8 g, 0.15 mol) and DMAP (100 mg) in THF (100 mL) was stirred at
reflux
io overnight. The mixture was allowed to cool and concentrated in vacuo. The
residue was
chromatographed on silica, eluting with 8% ethyl acetate in hexane, to give
the desired
material as a white solid (12 g).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.49 (18H, s), 7.50 (1H, d), 7.55
(1H,
d)
is LCMS Spectrum MH- 299, retention time 2.6 mins, method monitor base
Example 35: 6- f 4- f(3S)-3-Methylmorpholin-4-yll -6-
(methylsulfonylmethyl)pyrimidin-2-
yll-lH-indole
N~--.,
O O N
is I N I ~
20 H
A mixture of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidine
(350 mg, 1.15 mmol), 1H-indol-6-ylboronic acid (277 mg, 1.72 mmol), 2M aqueous
solution
of sodium hydrogen carbonate (1.5 mL),
dichlorobis(triphenylphosphine)palladium(II) (45
mg) in DMF (2 mL), DME (4 mL), water (2 mL) and ethanol (2 mL), was degassed
several
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-112-
times then heated at 95 C under a nitrogen atmosphere. The reaction was
allowed to cool,
diluted with water and extracted with ethyl acetate. The organics were washed
with water,
dried (MgSO4), filtered and evaporated. The residue was chromatographed on
silica, eluting
with ethyl acetate, and the solid obtained was triturated with a mixture of
ethyl acetate and
s hexane to give the desired material as a beige solid (390 mg).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.35 (3H, d), 3.18-3.28 (4H, m),
3.51
(1H, dd), 3.68 (1H, dd), 3.79 (1H, d), 4.00 (1H, dd), 4.20 (1H, d), 4.52 (3H,
s), 6.48 (1H, s),
6.79 (1H, s), 7.45 (1H, s), 7.58 (1H, d), 8.07 (1H, d), 8.45 (1H, s), 11.30
(1H, s).
LCMS Spectrum; MH+ 387, retention time (2.l2mins , method monitor base.
lo
Example 36: 6- f 4- f(3S)-3-Methylmorpholin-4-yll -6-
(methylsulfonylmethyl)pyrimidin-2-
yll-lH-indole-3-carboxamide
N
O O ~N
I N
O
N ~ NH2
H
A suspension of 6-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidin-2-
is yl]-1H-indole-3-carbonitrile (43 mg, 0.10 mmol), in a 30% solution of
hydrogen peroxide (2
mL), aqueous ammonia (1.5 mL) and ethanol (2 mL) was stirred at RT for 7
hours. The
reaction was diluted with water and extracted with ethyl acetate. The organics
were dried
(MgS04), filtered, evaporated and the residue triturated with a mixture of
diethyl ether and
hexane to give the desired material as a yellow solid (27 mg).
2o NMR Spectrum: 'H NMR (500.13 MHz, DMSO-d6) b 1.33 (3H, d), 3.19 (3H, s),
3.30 (1H,
dd), 3.40 (1H, t), 3.55 (1H, dd), 3.70 (1H, d), 3.75 (1H, d), 3.99 (1H, d),
4.18 (1H, d), 4.45
(2H, s), 4.53 (1H, s), 6.68 (1H, s), 6.72 (1H, s), 8.05 (1H, s), 8.12 (2H, s),
8.43 (1H, s), 9.80
(1H, s), 11.40 (1H, s).
LCMS Spectrum; MH+ 430, retention time 1.46mins, method monitor base.
The preparation of 6-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidin-
2-yl]-1H-indole-3-carbonitrile is described below.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-113-
6- [4- [(3 S)-3 -Methylmorpho lin-4-yll -6-(methylsulfonylmethyl)pyrimidin-2-
yll -1 H-indo le-3 -
carbonitrile
(0)" O O ~N
is I N
~ ~N
N
H
s A suspension of 6-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidin-2-
yl]-1H-indole (200 mg, 0.52 mmol), in dry acetonitrile (15 mL), was warmed
until all
material dissolved. The reaction was cooled to 0 C and chlorosulphonyl
isocyanate (0.045
mL) added, followed by dry DMF (3 mL). After 3.5 hours the mixture was
extracted into
ethyl acetate and the organics washed with water, dried (MgSO4), filtered and
evaporated.
io The residue was chromatographed on silica, eluting with 70% ethyl acetate
in hexane, to give
the desired material as a cream solid (45 mg).
LCMS Spectrum: 'H NMR (500.13 MHz, DMSO-d6) b 1.30 (3H, t), 3.15 (3H, s), 3.30
(1H,
dd), 3.58 (1H, dd), 3.70 (1H, d), 3.80 (1H, d), 4.0 (1H, dd), 4.18 (1H, d),
4.47 (2H, s), 4.53
(1H, s), 6.79 (1H, s), 7.68 (1H, d), 8.20 (1H, s), 8.25 (1H, d), 8.55 (1H, s),
12.0 (1H, s).
is LCMS Spectrum; MH+ 412, retention time 2.01mins, method monitor base.
The preparation of 6-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidin-
2-yl]-1H-indole was described earlier.
2o Example 37: 5- f 4- f(3S)-3-Methylmorpholin-4-yll -6-
(methylsulfonylmethyl)pyrimidin-2-
yll-lH-indole-2-carboxamide
N
O O I ~N
S N~ O
H NH2
Triethylamine (0.1 mL, 0.73 mmol) and HATU (222 mg, 0.58 mmol) were added to a
stirred
suspension of 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidin-2-yl]-
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-114-
1H-indole-2-carboxylic acid (210 mg, 0.48 mmol), in DCM (10 mL) at RT. After
10 minutes
an aqueous solution of ammonia (2 mL) was added and the reaction stirred for
45 minutes.
The mixture was washed with a saturated aqueous solution of sodium hydrogen
carbonate, the
organics dried (MgSO4), filtered and evaporated. The residue was
chromatographed on silica,
s eluting with 0-5% methanol in ethyl acetate, and the solid obtained
triturated with a mixture
of diethyl ether and hexane to give the desired material (85 mg).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.27 (3H, d), 3.24 - 3.26 (3H,
m), 3.55
(1H, dd), 3.68 (1H, dd), 3.80 (1H, d), 4.0 (1H, dd), 4.20 (1H, d), 4.5 (3H,
s), 6.80 (1H, s), 7.21
(1H, s), 7.35 (1H, s), 7.48 (1H, d), 7.95 (1H, s), 8.24 (1H, d), 8.65 (1H, s),
11.70 (1H, s).
io LCMS Spectrum; MH+ 430, retention time 1.59mins, method monitor base.
The preparation of 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidin-
2-yl]-1H-indole-2-carboxylic acid is described below.
15 5-[4-[(3S)-3-Methylmorpholin-4-yll-6-(methylsulfonylmethyl)pyrimidin-2-yll-
lH-indole-2-
carboxvlic acid
N
O O N
N O
I ~ N OH
H
A mixture of ethyl5-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidin-
2-yl]-1H-indole-2-carboxylate (390 mg, 0.85 mmol) in 2M aqueous sodium
hydroxide
20 solution (3 mL) and methanol (10 mL), was refuxed for 4 hours. The organics
were removed
in vacuo and the mixture adjusted to pH = 5 with 2M hydrochloric acid. The
mixture was
extracted with DCM and the organics dried (MgS04), filtered and evaporated.
The residue
was triturated with a mixture of diethyl ether and hexane to give the desired
material as a
cream solid (210 mg).
25 NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.22 (3H, d), 3.22 (3H, s),
3.38 (1H, t),
3, 50 (1H, dd), 3.68 (1H, dd), 3.80 (1H, d), 4.0 (1H, dd), 4.21' (1H, d), 4.51
(3H, s), 6.78 (1H,
s), 7.03 (1H, s), 7.45 (1H, d), 8.24 (1H, d), 8.65 (1H, s), 11.
LCMS Spectrum; MH+ 431, retention time 0.79mins, method monitor base.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-115-
Ethy15-[4-[(3S)-3-methylmorpholin-4-yll-6-(methylsulfonylmethyl)pyrimidin-2-
yll-1H-
indole-2-carboxylate
N
0 I ~N
N O
~
~
H
s A soln of ethyl tert-butyl 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidin-2-yl]indole-1,2-dicarboxylate (600 mg, 1.07
mmol) in TFA
(6 mL) and DCM (20 mL) was stirred at RT for 2 hours. The mixture was
concentrated in
vacuo and the residue made basic with aqueous ammonia. The mixture was
extracted with
ethyl acetate and the organics dried (MgSO4), filtered and evaporated. The
residue was
io triturated with diethyl ether and filtered to give the desired material as
a pale yellow solid
(450 mg).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.28 (3H, d), 1.36 31H, t), 3.23
(3H, s),
3.55 (1H, dd), 3.68 (1H, dd), 3.78 (1H, d), 3.89 (1H, s), 4.0 (1H, dd), 4.21
(1H, s), 4.38 (2H,
q), 4.52 (3H, s), 6.81 (1H, s), 7.29 (1H, s), 7.52 (1H, d), 8.31 (1H, d), 8.71
(1H, s).
is LCMS Spectrum; MH+ 459, retention time 2.26mins, method monitor base.
Ethyl tert-butyl5-[4-[(3S)-3-methylmorpholin-4-yll-6-(methylsulfonylmethyl
pyrimidin-2-
yllindole-1,2-dicarboxylate
N
0 ~N
is I N ~ 0
I '!O ~
0~--0
2o A mixture of ethyl tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)indole-1,2-
dicarboxylate (1.2 g, 2.9 mmol), 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidine (450 mg, 1.45 mmol), potassium phosphate
tribasic (1 g,
4.7 mmol) and bis(tri-tert-butylphosphine)palladium(0) (50 mg) in toluene (5
mL), ethanol
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-116-
(10 mL) and water (5 mL) was stirred at 80 C for 16 hours. After cooling the
mixture was
extracted with ethyl acetate, washed with water, the organics dried (MgSO4),
filtered and
evaporated. The residue was chromatographed on silica, eluting with 50-70 %
ethyl acetate in
hexane, to give the desired material contaminated with ethyl5-[4-[(3S)-3-
methylmorpholin-4-
s yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]-1H-indole-2-carboxylate (600
mg). The crude
mixture was used without further purification.
LCMS Spectrum MH+559, retention time 2.91 mins, method monitor base.
Ethyl tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1,2-
dicarboxylate
O
o-BI~ lo ION ~o
O
J ~
A mixture of ethyl tert-butyl 5 -chloroindole- 1,2-dicarboxylate (1.45 g, 4.5
mmol),
bispinacolatodiborane (1.4 g, 5.5 mmol) tricyclohexylphosphine (93 mg, 0.33
mol),
bis(dibenzylideneacetone)palladium (80 mg) and potassium acetate (684 mg, 6.97
mmol) in
dioxane (30 mL), was degassed several times, then heated at 90 C for 16 hours.
The mixture
was allowed to cool, diluted with water and extracted into ethyl acetate. The
organics were
washed with water, dried (MgS04), filtered and evaporated. The residue was
chromarographed on silica, eluting with 15% ethyl acetate in hexane, to give
the desired
material as a pale yellow solid (1.2 g).
LCMS Spectrum no MH+ ion observed, retention time 2.53mins, method monitor
base.
Example 38: 6- f 4- f(3S)-3-Methylmorpholin-4-yll -6-
(methylsulfonylmethyl)pyrimidin-2-
yll-lH-indole-2-carboxamide
N
O O I ~N H
is N~ N NH2
~ O
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-117-
Triethylamine (0.095 mL, 0.68 mmol) and HATU (205 mg, 0.54 mmol) were added to
a
stirred suspension of 6-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidin-2-yl]-lH-indole-2-carboxylic acid (195 mg,
0.43 mmol), in
DCM (10 mL) at RT. After 10 minutes an aqueous solution of ammonia (2 mL) was
added
s and the reaction stirred for 45 minutes. The mixture was washed with a
saturated aqueous
solution of sodium hydrogen carbonate, the organics dried (MgSO4), filtered
and evaporated.
The residue was chromatographed on silica, eluting with 0-10% methanol in
ethyl acetate, to
give the desired material as a yellow solid (10 mg).
NMR Spectrum: 'H NMR (500.13 MHz, DMSO-d6) b 1.28 (3H, d), 3.27 (4H, m), 3.55
(1H,
io dd), 3.68 (1H, s), 3.78 (1H, d), 4.0 (1H, d), 4.19 (1H, s), 4.52 (3H, s),
6.80 (1H, s), 7.14 (1H,
s), 7.35 (1H, s), 7.64 (1H, d), 7.95 (1H, s), 8.05 (1H, d), 8.48 (1H, s, ),
11.65 (1H, s).
LCMS Spectrum; MH+ 430, retention timel .72mins, method monitor base.
The preparation of 6-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidin-
is 2-yl]-1H-indole-2-carboxylic acid is described below.
6-[4-[(3S)-3-Methylmorpholin-4-yl1-6-(methylsulfonylmethyl)pyrimidin-2-yl1-1H-
indole-2-
carboxylic acid
N
O O N H
is N N OH
O
2o A mixture of ethyl6-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidin-
2-yl]-1H-indole-2-carboxylate (480 mg, 1 mmol) in 2M aqueous sodium hydroxide
solution
(3 mL) and methanol (15 mL), was refuxed for 4 hours. The organics were
removed in vacuo
and the mixture adjusted to pH = 5 with 2M hydrochloric acid. The mixture was
extracted
with DCM and the organics dried (MgS04), filtered and evaporated. The residue
was
25 triturated with a mixture of diethyl ether and hexane to give the desired
material as a cream
solid (200 mg).
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-118-
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.25 (3H, d), 3.26 (4H, s), 3.52
(1H,
dd), 3.69 (1H, d), 3.79 (1H, d), 4.0 (1H, dd), 4.20 (1H, d), 4.52 (3H, s),
6.82 (1H, s), 6.85 (1H,
s), 7.62 (1H, d), 8.09 (1H, d), 8.52 (1H, s), 11.40 (1H, s).
LCMS Spectrum; MH+ 431, retention time 0.91mins, method monitor base.
Ethy16-[4-[(3S)-3-methylmorpholin-4-yll-6-(methylsulfonylmethyl)pyrimidin-2-
yll-1H-
indole-2-carboxylate
N
OSO I iN H
N N O~
1O
A soln of ethyl tert-butyl 6-[4-[(3S)-3-methylmorpholin-4-yl]-6-
io (methylsulfonylmethyl)pyrimidin-2-yl]indole-1,2-dicarboxylate (800 mg, 1.43
mmol) in TFA
(4 mL) and DCM (10 mL) was stirred at RT for 2 hours. The mixture was
concentrated in
vacuo and the residue made basic with aqueous ammonia. The mixture was
extracted with
ethyl acetate and the organics dried (MgS04), filtered and evaporated. The
residue was
triturated with diethyl ether and filtered to give the desired material as a
white solid (480 mg).
is NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.28 (3H, d), 1.35 (3H, t),
3.25 (3H, s),
3.55 (1H, dd), 3.70 (1H, dd), 3.79 (1H, d), 4.02 (1H, dd), 4.20 (1H, d), 4.48
(1H, q), 4.55 (3H,
s), 6.85 (1H, s), 7.18 (1H, s), 7.72 (1H, d), 8.13 (1H, d), 8.55 (1H, s),
12.00 (1H, s).
LCMS Spectrum; MH+ 459, retention time 2.39mins, method monitor base.
2o Ethyl tert-butyl6-[4-[(3S)-3-methylmorpholin-4-yll-6-(methylsulfonylmethyl
pyrimidin-2-
yllindole-1,2-dicarboxylate
O
CN/=,~
O 0 I ~ N O\f:::IO /
is N N OJ
O
A mixture of ethyl tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)indole-1,2-
dicarboxylate (918 mg, 2.2 mmol), 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-
25 (methylsulfonylmethyl)pyrimidine (450 mg, 1.45 mmol), potassium phosphate
tribasic (1.l g,
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-119-
5.1 mmol) and bis(tri-tert-butylphosphine)palladium(0) (50 mg) in toluene (5
mL), ethanol
(10 mL) and water (5 mL) was stirred at 80 C for 16 hours. After cooling the
mixture was
extracted with ethyl acetate, washed with water, the organics dried (MgSO4),
filtered and
evaporated. The residue was chromatographed on silica, eluting with 50-70 %
ethyl acetate in
s hexane, to give the desired material as a white solid (800 mg).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.25 (3H, d), 1.32 (3H, t), 1.63
(9H, s),
3.28 (3H, s), 3.52 (1H, dd), 3.68 (1H, dd), 3.80 (1H, d), 3.88 (1H, s), 4.0
(1H, dd), 4.22 (1H,
d), 4.35 (1H, q), 4.52 (3H, s), 6.88 (1H, s), 7.32 (1H, s), 7.80 (1H, d), 8.34
(1H, d), 8.98 (1H,
s).
io LCMS Spectrum; MH+ 559, retention time 2.97mins, method monitor base.
Ethyl tert-butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1,2-
dicarboxylate
\1 r_- O /
O-B I ~ N OJ
~ O
A mixture of ethyl tert-butyl 6-bromoindole-1,2-dicarboxylate (3 g, 8.1 mmol),
is bispinacolatodiborane (2.48 g, 0.97 mmol), potassium acetate (3.2g,
0.032mo1), and 1,1'-
bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane adduct
(200 mg), in
dioxane (25 mL), was degassed several times, then heated at 90 C for 16 hours.
The mixture
was allowed to cool, diluted with water and extracted into ethyl acetate. The
organics were
washed with water, dried (MgS04), filtered and evaporated. The residue was
20 chromarographed on silica, eluting with 15% ethyl acetate in hexane, to
give the desired
material as a colourless gum (2.17 g).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.33 (15H, s), 1.57 (9H, s), 4.33
(2H,
q), 7.28 (1H, s), 7.58 (1H, d), 7.70 (1H, d), 8.89 (1H, s).
LCMS Spectrum; no MH+ ion observed, retention time 2.78mins, method monitor
base
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-120-
Example 39: 5- f 4- f(3S)-3-Methylmorpholin-4-yll -6-(2-methylsulfonylpropan-2-
yl)pyrimidin-2-yll -1H-benzoimidazole
C0
N)'',
O O N
I / `\
iS N
N
N/
H
Nitrogen was bubbled through a mixture of tert-butyl5-(4,4,5,5-tetramethyl-
1,3,2-
s dioxaborolan-2-yl)benzoimidazole-l-carboxylate (464 mg, 1.34 mmol),
2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-
yl)pyrimidine (250
mg, 0.75 mmol), sodium carbonate (397 mg, 3.75 mmol), palladium tetrakis
triphenylphosphine (50 mg) in DME (4 mL) and water (0.5 mL) for 15 minutes
then heated at
90 C for 16 hours. The mixture was concentrated in vacuo and dissolved in DCM.
TFA (6
io mL) was added and mixture heated at 40 C for 30 minutes before being
concentrated in vacuo
and partitioned between DCM and 2M hydrochloric acid. The aqueous layer was
made basic
with ammonia and extracted with DCM. The organic layer was dried (MgSO4),
filtered and
evaporated to give the desired material as a cream solid (280 mg).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.25 (3H, d), 1.78 (6H, s), 3.05
(3H, s),
is 3.25 (1H, m), 3.52 (1H, dd), 3.68 (1H, d), 3.78 (1H, d), 4.0 (1H, d), 4.25
(1H, d), 4.65 (1H, s),
6.78 (1H, s), 7.65 (1H, s), 8.30 (2h, S), 8.62 (1H, s), 12.55 (1H, s).
LCMS Spectrum; MH+ 416, retention time 1.84mins, method monitor base.
The preparation of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)benzoimidazole-
20 1-carboxylate is described below.
tert-Buty15-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoimidazole- l -
carboxylate
-~-O
O' aNN\
/!-O-
O
A mixture of tert-butyl 5-bromobenzoimidazole-1-carboxylate (2.5 g, 8.5 mmol),
25 bispinacolatodiboran (2.56 g, 10.07 mmol), potassium acetate (3.3 g, 33.67
mmol) and 1,1'-
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-121-
bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane adduct
(200 mg) in
dioxane (25 mL) was degassed several times then heated at 80 C for 16 hours.
The mixture
was evaporated and dissolved in DCM, filtered and the filtrate chromatographed
on silica,
eluting with 20%ethyl acetate in hexane, to give the desired material as a
pale yellow gum
s (2.65 g).
LCMS Spectrum M(-BOC)H+ 245, retention time 1.90mins, method monitor base.
tert-Butyl5-bromobenzoimidazole- l -carboxylate
Br
N`\
N\/
/TO-
O
io A solution of 5-bromo-lH-benzoimidazole (2 g, 10.1 mmol), (2-methylpropan-2-
yl)oxycarbonyl tert-butyl carbonate (3.3 g, 15.1 mmol) and DMAP (200 mg) in
THF (30 mL)
was heated at reflux for 16 hours. The reaction was allowed to cool, diluted
with ethyl acetate
and washed with water. The organics were dried (MgS04), filtered and
evaporated and the
residue chromatographed on silica, eluting with 20% ethyl acetate in hexane,
to give the
15 desired material as a mixture of isomers (2.5 g). The material was used
without further
purification.
LCMS Spectrum no MH+ ion observed, retention time 2.67mins, method monitor
base.
The preparation of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(2-
methylsulfonylpropan-2-
2o yl)pyrimidine is described below.
2-Chloro-4-[(3S)-3-methylmorpholin-4-yll-6-(2-methylsulfoulpropan-2-
yl)pyrimidine
(0)"',
O O I ~N
;S N-)
I CI
2-Chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine
(2.1 g, 6.87
25 mmol) was dissolved in DMF (20 mL) and the reaction cooled to -5 C. Sodium
tert-butoxide
(650 mg, 6.87 mmol) was added to the reaction, followed by iodomethane (0.4
mL, 6.87
mmol), maintaining the temperature at -5 C. A second equivalent of sodium tert-
butoxide
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-122-
(650 mg, 6.87 mmol) and iodomethane (0.4 mL, 6.87 mmol) were then added and
the reaction
stirred at -5 C for 1 hour, then at room temperature for 4 hours. DCM (20 mL)
was added and
the reaction washed with 2M aqueous hydrochloric acid (20 mL). The organic
phase was
dried over magnesium sulphate, filtered and concentrated in vacuo. The crude
solid was
s chromatographed on silica, eluting with 0-50% ethyl acetate in DCM to give
the desired
material (2.2 g).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) 61.21 (d, 3H), 1.68 (s, 6H), 2.74
(s, 3H),
3.21 (m, 1 H), 3.45 (m, 1 H), 3.59 (m, 1 H), 3.73 (d, 1 H), 3.94 (m, 1 H),
4.07 (d, 1 H), 4.45 (s,
1 H), 6.86 (s, 1 H)
io LCMS Spectrum: MH+ 334, retention time 1.85 min, Method 5 Min Base
is
Example 40: 3- f 4- f(3S)-3-Methylmorpholin-4-yll -6-(2-methylsulfonylpropan-2-
yl)pyrimidin-2-yll -5,7-diazabicyclo f 4.3.01 nona-1,3,5,8-tetraene
(0)"',
O O N
P
S I N I ~ ~
N N
H
A mixture of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(2-
methylsulfonylpropan-2-
2o yl)pyrimidine (150 mg, 0.45 mmol), 5,7-diazabicyclo[4.3.0]nona-1,3,5,8-
tetraen-3-ylboronic
acid (130 mg, 0.81 mmol), sodium carbonate (238 mg, 2.2 mmol) and palladium
tetrakis
triphenylphosphine (50 mg) in DME (4 mL) and water (0.6 mL) was heated for 4
hours at
90 C. The reaction was allowed to cool, diluted with water and extracted with
ethyl acetate.
The organics were washed with water, dried (MgS04), filtered and evaporated.
The residue
25 was purified by basic prep HPLC to give the desired material (148 mg).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.25 (3H.d), 1.80 (6H, s), 3.03
(3H, s),
3.25 (1H, m), 3.52 (1H, m), 3.68 (1H, dd), 3.80 (1H, d), 4.0 (1H, d), 4.30
(1H, d), 4.55 (1H,
s), 6.58 (1H, d), 6.80 (1H, s), 7.55-7.70 (2H, m), 8.87 (1H, s), 9.25 (1H, s),
11.85 (1H, s).
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-123-
LCMS Spectrum; MH+ 416, retention time 1.94mins, method monitor base.
The following compounds were prepared in an analogous fashion.
Example Structure NAME LCMS Retention
MH+ time
(min)
41 5-[4-[(3S)-3-methylmorpholin- 415 2.24
N 4-yl]-6-(2-
0 ~ `
s N ethylsulfonylpropan-2-
N
" 1)pyrimidin-2-yl]-1H-indole
42 ( ~ 4-[4-[(3S)-3-methylmorpholin- 415 2.14
N ~~ 4-yl]-6-(2-
0 0 I ~N -
's N ~ NH ethylsulfonylpropan-2-
~ 1)pyrimidin-2-yl]-1H-indole
43 6-[4-[(3S)-3-methylmorpholin- 415 2.32
N 4-yl]-6-(2-
o.s ~ ~
N N ethylsulfonylpropan-2-
1)pyrimidin-2-yl]-1H-indole
5
Example 41: 'H NMR (400.13MHz DMSO-d6) b 1.25 (3H, d), 1.75 (6H, s), 3.05 (3H,
s),
3.22 (1H, dd), 3.52 (1H, dd), 3.65 (1H, dd), 3.78 (1H, d), 4.0 (1H, dd), 4.28
(1H, d), 4.65 (1H,
s), 6.55 (1H, s), 6.72 (lh, S), 7.38 (1H, d), 7.42 (1H, d), 8.20 (1H, d), 8.62
(1H, s), 11.20 (1H,
s).
io Example 42: 'H NMR (400.13MHz DMSO-d6) b 1.28 (3H, d), 1.80 (6H, s), 3.0
(3H, s), 3.25
(1H, dd), 3.52 (1H, dd), 3.68 (1H, d), 3.80 (1H, d), 4.01 (1H, d), 4.25 (1H,
d), 4.65 (1H, s),
6.80 (1H, s), 7.18 (1H, dd), 7.82 (1H, d), 7.40 (1H, d), 7.52 (1H, d), 8.12
(1H, s), 11.20 (1H,
s).
Example 43: 'H NMR (400.13MHz DMSO-d6) b 1.25 (3H,d), 1.79 (6H,s), 3.08
(3H,s), 3.20-
is 3.30 (4H,m), 3.52 (1H,dd), 3.69 (1H,dd), 3.79 (1H,d), 4.02 (1H,d), 4.25
(1H,d), 4.64 (1H,s),
6.48 (1H,s), 6.79 (1H,s), 7.45 (1H,d), 7.61 (1H,d), 8.10 (1H,d), 8.47(1H,s),
11.25(1H,s).
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-124-
The preparation of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(2-
methylsulfonylpropan-2-
yl)pyrimidine was described earlier.
Example 44: 4-f4-(Benzenesulfonylmethyl)-6-f(3S)-3-methylmorpholin-4-
yllpyrimidin-2-
vll-lH-indole
N
O O N
c 'g NNH To a solution of 4-(benzenesulfonylmethyl)-2-chloro-6-[(3S)-3-
methylmorpholin-4-
io yl]pyrimidine (200 mg, 0.54 mmol) in ethanol was added toluene (1 mL),
water (1 mL), 1H-
indol-4-ylboronic acid (219 mg, 1.36 mmol), tri-potassium orthophosphate (404
mg, 1.90
mmol) and palladiumbis(tri-t-butylphoshine) (16.74 mg, 0.03 mmol). The
reaction was
degassed then purged with nitrogen and heated at 80 C for 2 hours.
The reaction mixture was cooled to RT diluted with ethyl acetate (10 mL) and
washed with
is water (5 mL). The organic layer was dried (MgSO4), filtered and evaporated.
The crude
product was purified by flash silica chromatography, elution gradient 0 to 10%
(3.5M
ammonia in methanol) in DCM, to give the desired material as a beige solid
(130 mg).
NMR Spectrum: 'H NMR (400.132 MHz, DMSO-d6) b 1.22 (3H, d), 3.22 (1H, m), 3.50
(1H,
t), 3.66 (1H, m), 3.79 (1H, d), 4.00 (1H, m), 4.06 (1H, m), 4.39 (1H, s), 4.75
(2H, s), 6.60
20 (1H, s), 7.08 (1H, t), 7.14 (1H, s), 7.36 (1H, t), 7.49 (1H, d), 7.61 (2H,
t), 7.71 (2H, t), 7.85
(2H, d), 11.15 (1 H, s)
LCMS Spectrum: MH+ 449, retention time 1.96 min
The following compounds were prepared in an analogous fashion from the
appropriate
25 boronic acid or boronic ester.
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-125-
Example Structure AME LCMS Retention
MH+ time (min)
45 ( l 5-[4- 449 2.23
N (benzenesulfonylmethyl)-6-
'N
O 'N
s N [(3S)-3-methylmorpholin-4-
~
" 1]pyrimidin-2-yl]-1H-indole
46 3-[4- 450 1.97
CN~..
(benzenesulfonylmethyl)-6-
'N
O 'N
s N [(3S)-3-methylmorpholin-4-
N N
" 1]pyrimidin-2-yl]-5,7-
diazabicyclo[4.3.0]nona-
1,3,5,8-tetraene
47 ( l 6-[4- 449 2.20
N (benzenesulfonylmethyl)-6-
'N ~ `N H
s N N [(3S)-3-methylmorpholin-4-
~
1]pyrimidin-2-yl]-1 H-indole
48 5-[4- 450 1.71
CN~..
(benzenesulfonylmethyl)-6-
'N
O 'N
s N N [(3S)-3-methylmorpholin-4-
.
N
" 1]pyrimidin-2-yl]-1H-
enzoimidazole
Example 45: 'H NMR (400.132 MHz, DMSO-d6) b 1.21 (3H, d), 3.22 (1H, m), 3.49
(1H, m),
3.64 (1H, m), 3.78 (1H, d), 3.99 (1H, m), 4.13 (1H, d), 4.40 (1H, s), 4.72
(2H, s), 6.49 (1H, s),
6.60 (1H, s), 7.32 (1H, d), 7.38 (1H, t), 7.64 (2H, t), 7.79 (2H, m), 7.85
(2H, d), 8.15 (1H, s),
s 11.17 (1 H, s)
Example 46: 'H NMR (400.132 MHz, DMSO-d6) b 1.24 (3H, d), 3.26 (1H, m), 3.50
(1H, m),
3.65 (1H, m), 3.78 (1H, d), 3.99 (1H, m), 4.15 (1H, d), 4.42 (1H, s), 4.74
(2H, s), 6.52 (1H,
m), 6.69 (1H, s), 7.50 (1H, t), 7.64 (2H, t), 7.77 (1H, m), 7.85 (2H, m), 8.36
(1H, d), 8.82 (1H,
d), 11.76 (1H, s)
io Example 47: 'H NMR (400.132 MHz, DMSO-d6) b 1.22 (3H, d), 3.19 (1H, m),
3.50 (1H, m),
3.65 (1H, m), 3.78 (1H, d), 3.99 (1H, m), 4.11 (1H, d), 4.38 (1H, s), 4.72
(2H, s), 6.45 (1H,
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-126-
m), 6.59 (1H, s), 7.44 (1H, t), 7.48 (2H, d), 7.64 (1H, t), 7.71 (1H, m), 7.76
(1H, m), 7.84 (2H,
m), 8.14 (1 H, s), 11.19 (1 H, s)
Example 48: 'H NMR (400.132 MHz, DMSO-d6) b 1.22 (3H, d), 3.20 (1H, m), 3.50
(1H, t),
3.65 (1H, d), 3.78 (1H, d), 3.99 (1H, d), 4.12 (1H, d), 4.40 (1H, s), 4.73
(2H, s), 6.64 (1H, s),
s 7.63 (3H, m), 7.75 (1H, m), 7.87 (3H, m), 8.25 (2H, m), 12.51 (1H, s)
The preparation of 4-(benzenesulfonylmethyl)-2-chloro-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidine is described below.
io 4-(Benzenesulfonylmethyl)-2-chloro-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidine
C0
N )"'i
dPJici
4-(Benzenesulfonylmethyl)-2,6-dichloro-pyrimidine (2.8 g, 9.24 mmol) was
dissolved in
DCM (20 mL) and stirred (under nitrogen) at -5 C. Triethylamine (1.42 mL,
10.17 mmol)
was added to give a clear brown solution. (3S)-3-methylmorpholine (935 mg,
9.24 mmol) was
is dissolved in DCM and added dropwise keeping the reaction below -5 C. The
cooling bath
was then removed and the reaction mixture stirred at room temperature for 1
hour. The
reaction mixture was then washed with water (50 mL), dried over magnesium
sulphate,
filtered and concentrated in vacuo. The crude material was chromatographed on
silica, eluting
with 0-50% ethyl acetate in DCM to give the desired material as a white solid
(2.6 g).
2o NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) 6 1.15 (d, 3H), 3.15 (m, 1H),
3.42 (m,
1 H), 3.5 6(m, 1 H), 3.72 (d, 1 H), 3.92 (m, 2H), 4.15 (s, 1 H), 4.62 (s, 2H),
6.66 (s, 1 H), 7.74 (t,
1 H), 7.76 (t, 1 H), 7.78 (d, 1 H), 7.80 (m, 2H)
LCMS Spectrum: MH+ 368, retention time 1.95 min, Method 5 Min Base
25 4-(Benzenesulfonylmethyl)-2,6-dichloro-12yrimidine
ci
O O 1- N
I ~ S N-1j, CI
CA 02692725 2010-01-06
WO 2009/007751 PCT/GB2008/050549
-127-
6-(Benzenesulfonylmethyl)-1H-pyrimidine-2,4-dione (13.3 g, 49 mmol) was added
to
phosphorus oxychloride (100 mL) and the mixture heated to reflux for 16 hours.
The reaction
was then cooled to room temperature and the excess phosphorus oxychloride was
removed in
vacuo. The residue was azeotroped with toluene (2 x 100 mL) and dissolved in
DCM. This
s mixture was then poured slowly onto ice (1 L) and stirred for 20 minutes,
then extracted with
DCM (3 x 500 mL) The extracts were combined, dried over magnesium sulphate,
then
concentrated in vacuo to give the desired material as a brown solid (12 g).
The material was
used without further purification.
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) 84.97 (s, 2H), 7.65 (t, 2H), 7.72
(s, 1H),
io 7.79 (m, 3H)
LCMS Spectrum: M-H 301, retention time 2.08 min, Method 5 Min Basic
6-(Benzenesulfonylmethyl)-1H-12yrimidine-2,4-dione
O
O O NH
alo~ H
is 6-(Chloromethyl)-1H-pyrimidine-2,4-dione (8 g, 50 mmol) was dissolved in
DMF (200 mL)
and benzenesulphinic acid sodium salt (9.8 g, 60 mmol) was added. The reaction
was heated
to 125 C for 2 hours then allowed to cool and the suspension filtered and
concentrated in
vacuo to give a yellow solid. The crude material was washed with water (100
mL), filtered,
then triturated with acetonitrileto give the desired material as a cream solid
(13.2 g). The
20 material was used without further purification.
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) 84.46 (s, 2H), 7.69 (t, 2H), 7.81
(m, 1H),
7.87 (m, 3H), 10.85 (s, 1H), 11.11 (s, 1H)
