U.S. patent application number 14/076810 was filed with the patent office on 2014-03-06 for pyrimidine substituted purine derivatives.
This patent application is currently assigned to VERASTEM, INC.. The applicant listed for this patent is VERASTEM, INC.. Invention is credited to Harish K. Mysore, Meredith Williams.
Application Number | 20140066620 14/076810 |
Document ID | / |
Family ID | 40030252 |
Filed Date | 2014-03-06 |
United States Patent
Application |
20140066620 |
Kind Code |
A1 |
Mysore; Harish K. ; et
al. |
March 6, 2014 |
PYRIMIDINE SUBSTITUTED PURINE DERIVATIVES
Abstract
The present invention relates to purine compounds that are
useful as kinase inhibitors. More particularly, the present
invention relates to purine compounds, methods for their
preparation, pharmaceutical compositions containing these compounds
and uses of these compounds in the treatment of proliferative
conditions or disorders. These compounds may be useful as
medicaments for the treatment of a number of proliferative
conditions or disorders including tumours and cancers as well as
other disorders or conditions related to or associated with PI3
and/or mTOR kinases.
Inventors: |
Mysore; Harish K.;
(Singapore, SG) ; Williams; Meredith; (Singapore,
SG) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
VERASTEM, INC. |
Cambridge |
MA |
US |
|
|
Assignee: |
VERASTEM, INC.
Cambridge
MA
|
Family ID: |
40030252 |
Appl. No.: |
14/076810 |
Filed: |
November 11, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13554491 |
Jul 20, 2012 |
8609838 |
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14076810 |
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12681584 |
Jun 11, 2010 |
8247410 |
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PCT/SG2008/000379 |
Oct 3, 2008 |
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13554491 |
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61075532 |
Jun 25, 2008 |
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60977720 |
Oct 5, 2007 |
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Current U.S.
Class: |
544/118 |
Current CPC
Class: |
A61P 17/00 20180101;
A61P 35/00 20180101; A61P 1/00 20180101; A61P 29/00 20180101; C07D
473/32 20130101; A61P 35/02 20180101; A61P 37/02 20180101; A61P
11/00 20180101; A61P 43/00 20180101; A61P 37/06 20180101; A61P
37/00 20180101; A61P 27/02 20180101; A61P 37/08 20180101; C07D
473/40 20130101; A61P 21/04 20180101 |
Class at
Publication: |
544/118 |
International
Class: |
C07D 473/32 20060101
C07D473/32 |
Claims
1. (canceled)
2. A pharmaceutical composition comprising: ##STR00089##
##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094##
##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099## or
a pharmaceutically acceptable salt or prodrug thereof.
Description
FIELD
[0001] The present invention relates to purine compounds that may
be useful as kinase inhibitors. More particularly, the present
invention relates to 2-(morpholin-4-yl), 6-(pyrimidin-5-yl)
substituted purine derivatives, methods for their preparation,
pharmaceutical compositions containing these compounds and uses of
these compounds in the treatment of certain kinase related
disorders/conditions.
BACKGROUND
[0002] The search for kinase inhibitors has proven to be a fruitful
area for the development of useful pharmaceutically active
substances. Kinases, which are alternatively known as
phosphotransferases, are enzymes that transfer phosphate groups
from high energy donor molecules (for example ATP) to specific
target molecules (typically called substrates) in a process termed
phosphorylation. One of the largest groups of kinases are the
protein kinases which act on and modify the activity of specific
proteins.
[0003] As a result of this activity these kinases are involved in a
number of cellular processes such as in signalling and to prime the
cell for biochemical reactions in metabolism. Certain cellular
signalling processes have been implicated as important in a number
of medical conditions and the effective inhibition of certain cell
signalling processes therefore provides the potential to stop these
conditions developing. Accordingly, kinases represent an attractive
target for medicinal chemists as the provision of kinase inhibitors
potentially allows for certain signalling processes to be
controlled leading to the control of certain medical
conditions.
[0004] One family of kinases associated with undesirable medical
conditions in the body are the phosphoinositide 3-kinase (PI3)
family of kinases which are involved in a wide range of cellular
events such as cell migration, cell proliferation, oncogenic
transformation, cell survival, signal transduction and
intracellular trafficking of proteins. This family of kinases has
recently been the focus of much research aimed at developing
therapies for a range of indications such as proliferative
diseases, for example cancer, immune and inflammatory diseases,
diseases supported by excessive neovascularization and transplant
rejection.
[0005] The phosphoinositide 3-kinase (PI3K) family is a group of
enzymes that generate phosphatidylinositol `second messengers`.
These lipids are subsequently involved in a wide range of
physiological processes. In mammalian cells, the large PI3K family
has been categorized into three classes, referred to as 1, 11, and
III, each of which has its own characteristics in terms of
molecular structure and substrate specificity. Class I PI3K
preferred in vivo substrate is phosphatidylinositol-4,5
bisphosphate, which is phosphorylated to yield
phosphatidylinositol-3,4,5 trisphosphate. These are further
subdivided into Class IA and IB PI3Ks. Class IA enzymes consist of
any one of the `catalytic` subunits (p110.alpha., p110.beta., or
p110.delta.) complexed with any one of the `regulatory` subunits
(p85.alpha., p85.beta. or p55.gamma.). Only one Class IB PI3K
enzyme exists, and is made up of the p110.gamma. catalytic and the
p101 regulatory subunit. There are also three Class II PI3Ks
(CII.alpha., CII.beta., and CII.gamma.) and one Class III PI3K
(Vps34).
[0006] The class I PI3Ks are the best understood members of this
family and are key players of multiple intracellular signalling
networks that integrate a variety of signals initiated by many
growth factors. The Class IA enzymes are activated by tyrosine
kinases (e.g. growth factor receptors), antigen receptors, and
cytokine receptors, whilst the Class IB enzyme is activated by `G
Protein Coupled Receptors` (GPCRs). In response to activation, the
PI3Ks generate lipid second messengers, which bind to, and
activate, specific proteins in distinct signal transduction
pathways. The signal transduction pathways remain active until
phosphatase enzymes, in particular the oncogene PTEN,
dephosphorylate the PI3K lipid second messengers.
[0007] The PI3K signalling pathway is crucial to many aspects of
cell growth and survival via its regulation of widely divergent
physiological processes that include cell cycle progression,
differentiation, transcription, translation and apoptosis.
Constitutive activation of the PI3K pathway has been implicated in
both the pathogenesis and progression of a large variety of cancers
and there is now a rapidly accumulating body of evidence that
demonstrates conclusively that PI3K signalling is frequently
deregulated in cancer. The deregulation of PI3K signalling is
thought to occur in two different ways. The first is an increase in
PI3K signalling resulting from activating gene mutations,
amplification and over expression of PI3Ks or upstream receptors
that activate PI3Ks. For example, the PI3K.alpha. catalytic subunit
is amplified and over expressed in ovarian and cervical cancers.
Similarly, upstream receptor tyrosine kinases that activate PI3K
are commonly mutated, amplified and over expressed, e.g., EGFR in
breast, ovarian and lung cancer.
[0008] In addition, activation of the effectors downstream of PI3K
can also contribute to deregulation of the PI3K pathway, e.g.,
Akt/PKB (Protein Kinase B) is over expressed and activated in
breast, pancreatic and ovarian cancers among others. Also, the Ras
family members, which are involved in PI3K activation, are
frequently mutated, e.g. in colorectal and pancreatic cancer. The
second mechanism of PI3K deregulation involves loss of the tumor
suppressor phosphatase PTEN, which occurs in many aggressive brain
tumors, endometrial and breast cancers, and melanomas.
[0009] One specific cell signalling pathway mediated by the PI3
family of kinases is the phosphatidylinositol 3-kinase (PI3K)/Akt
pathway. This pathway is critically involved in the mediation of
cell survival and is a major signalling component downstream of
growth factor receptor tyrosine kinases (RTKs). Growth factor RTKs
engage the class-IA PI3K, which is a heterodimer comprised of the
p85 regulatory and p110 catalytic subunits. The small GTPase Ras
can also recruit and activate PI3K through direct binding to p110.
At the cell membrane, PI3K catalyzes the production of the lipid
second messenger phosphatidylinositol-3,4,5-triphosphate (PIP3).
Subsequently, PIP3 recruits other downstream
molecules--particularly the serine-threonine kinases Akt and
PDK1--via binding to their pleckstrin-homology (PH) domains. At the
membrane, Akt is partially activated through phosphorylation at
threonine 308 in its activation loop by PDK1. Additional
phosphorylation at serine 473 in the C terminus of Akt results in
its full activation. Akt in turn regulates a wide range of target
proteins, one of which is the mammalian target of Rapamycin
(commonly known as mTOR). The levels of PIP3 in the cell are
strictly regulated and several lipid phosphatases act to rapidly
remove it. Of particular interest is the phosphatase PTEN, which
converts PIP3 back to PIP2 and thus shuts off PI3K signalling. The
PI3K-Akt signalling pathway regulates many normal cellular
processes including cell proliferation, survival, growth, and
motility--processes that are critical for tumorigenesis.
[0010] The role of the PI3K/Akt pathway in oncogenesis has also
been extensively investigated and mutations or altered expression
of most of the pathway's components have been widely implicated in
many cancers. Gene amplification of p110 occurs in some cases of
human ovarian cancer, and amplification of Akt is found in ovarian,
breast, and colon cancer. In addition, activating mutations in p85
have been identified in ovarian and colon cancer. Most importantly
PTEN has been identified as a major tumor suppressor in humans and
loss-of-function mutations in the PTEN gene are extremely common
among sporadic glioblastomas, melanomas, prostate cancers, and
endometrial carcinomas, and a significant percentage of breast
tumors, lung cancers, and lymphomas also bear PTEN mutations. Thus,
through a variety of mechanisms, a high percentage of human cancers
possess activated PI3K signalling. Significantly, it has been shown
that mTOR is important for the oncogenic transformation induced by
PI3K and Akt.
[0011] In addition to the compelling correlative data presented
above, direct proof of the involvement of deregulated PI3K
signalling in cancer comes from mouse genetic models. For example,
mice with a constitutively activated p85 regulatory subunit of PI3K
progress to malignant lymphoma when crossed with p53-knockout mice.
Further, retroviral introduction of Akt and Ras caused
glioblastomas in mice. Taken together, all these data provide
strong validation for the development of novel anticancer
strategies targeted at PI3Ks. Indeed recent interest in PI3K
inhibitors has been intense with a number of compounds now in
development having demonstrated anti-tumor activity in animal
models. The most advanced compounds are now undergoing evaluation
in phase I clinical trials. Accordingly compounds that are PI3K
inhibitors would be expected to show interesting biological
activity as PI3K inhibitors have the potential to block the
PI3K/Akt signalling pathway and thereby form the basis of therapy
in disease involving deregulation of this pathway.
[0012] In addition, PI 3-kinase isoforms p110.delta. and
p110.gamma. regulate different aspects of immune and inflammatory
responses. Hence there is great interest in the role of PI 3-kinase
signaling in a range of immune and inflammatory diseases as well as
in transplant rejection.
[0013] Another area that has received attention has been the
serine/threonine kinases. One serine/threonine kinase that has
attracted significant interest is mTOR.
[0014] mTOR is a serine/threonine kinase of 289 kDa and is a
PI3K-like kinase that links mitogenic stimuli and nutrient status
to cell growth and division. mTOR was discovered during studies
conducted to understand the mechanism of action of rapamycin. Upon
entering cells, rapamycin binds to its intracellular target FKBP12
and the complex then binds to and specifically inhibits mTOR. mTOR
was, therefore, also named FKBP-RAP associated protein (FRAP), RAP
FKBP12 target (RAFT1) and RAP target (RAPT1). Cells responsible for
organ rejection stop growing due to rapamycin's ability to inhibit
the anabolic signals coordinated by mTOR. Since inhibition of cell
growth represents a valid target for treating cancer, designing new
drugs that inhibit mTOR will potentially have therapeutic
value.
[0015] In humans, mTOR mediates anabolic signals from 2 sources
namely nutrients that pass into the cell and activated growth
factor receptors. It exists in at least two distinct complexes: a
rapamycin-sensitive complex, referred to as mTOR complex 1
(mTORC1), defined by its interaction with the accessory protein
raptor (regulatory-associated protein of mTOR). The normal
activation of mTOR results in an increase in protein translation
because mTORC1 phosphorylates and activates the translation
regulators eukaryotic initiation factor 4E-binding protein 1 and
ribosomal p70 S6 kinase. Therefore, by inhibiting mTOR, rapamycin
causes a decrease in phosphorylation of these effectors, and a
decrease in protein synthesis, effectively blocking the pro-growth
actions of mTOR.
[0016] The second complex, mTOR complex 2 (mTORC2), is
rapamycin-insensitive and is defined by its interaction with rictor
(rapamycin-insensitive companion of mTOR). mTORC2 is involved in
the regulation of the pro-survival kinase Akt/PKB by
phosphorylating it on S473. Together with the phosphorylation of
T308 by PDK1, S473 phosphorylation is necessary for full Akt
activation. Recent reports indicate that prolonged treatment with
rapamycin in some cells also suppresses the assembly and function
of TORC2 to inhibit Akt and that this property of rapamycin
contributes to the anti-apoptotic effects of the drug. mTOR is also
one of the main downstream effectors in the phosphatidylinositol
3-kinase (PI3K)/Akt pathway and therefore inhibition of mTOR
provides a further opportunity to inhibit, at least in part, the
PI3K/Akt pathway.
[0017] An additional pathway influenced by mTOR that appears to be
particularly important in renal cell carcinoma involves the
hypoxia-inducible factor (HIF). With loss of Von Hippel-Lindau
(VHL) gene function commonly seen in clear cell renal cell cancer,
there is accumulation of the oxygen-sensitive transcription factors
HIF-1 and HIF-2. An accumulation of these factors yields increased
stimulation of vascular endothelial growth factor (VEGF),
platelet-derived growth factor, and transforming growth factor.
This effect is augmented by the activation of mTOR, which
stimulates both a protein stabilization function and a protein
translational function and, thus, increases HIF-1 activity.
[0018] It has also been determined that tuberous sclerosis complex
gene products, TSC1 and TSC2, function together to inhibit
mTOR-mediated downstream signalling. Mutations of these genes occur
in tuberous sclerosis and their loss of function yields yet another
pathway, which leads to increased activity of mTOR and induces VEGF
production. TSC2 also regulates HIF. Thus, studies evaluating the
impact of TSC1 and TSC2 mutations demonstrate the connection of
increased VEGF and activated mTOR pathways to angiogenesis.
[0019] So far, four mTOR inhibitors have been tested in clinical
trials: the prototype rapamycin and three rapamycin derivatives,
CCI-779 (temsirolimus), RAD001 (everolimus) and AP23573. Rapamycin,
also named sirolimus, is a natural antibiotic produced by
Streptomyces hygroscopicus. It was developed initially as an
anti-fungal drug directed against Candida albicans, Cryptococcus
neoformans, and Aspergillus fumigatus. Later, rapamycin was
developed as an immunosuppressive agent and those studies helped in
understanding the mechanism of action of this agent. As an
anti-cancer agent, rapamycin was shown to inhibit the growth of
several murine and human cancer cell lines in a
concentration-dependent manner, both in tissue culture and
xenograft models. In the sixty tumor cell lines screened at the
National Cancer Institute in the USA, general sensitivity to the
drug was seen at doses under 2000 ng/ml, more evident in leukemia,
ovarian, breast, central nervous system and small cell lung cancer
cell lines. In addition, rapamycin inhibits the oncogenic
transformation of human cells induced by either PI3K or Akt and has
shown metastatic tumor growth inhibition and anti-angiogenic
effects in in vivo mouse models.
[0020] Based on these pre-clinical results, clinical trials with
rapamycin as an anticancer drug were carried out and rapamycin
analogues with more favourable pharmaceutical properties were
developed. CCI-779, a more water-soluble ester derivative of
rapamycin was identified by investigators at Wyeth Ayerst as a
non-cytotoxic agent that delayed tumor cell proliferation. At
several non-toxic doses, CCI-779 demonstrated anti-tumor activity
alone or in combination with cytotoxic agents in a variety of human
cancer models such as gliomas, rhabdomyosarcoma, primitive
neuroectodermal tumor such as medulloblastoma, head and neck,
prostate, pancreatic and breast cancer cells. Treatment of mice
with CCI-779 inhibits p70S6K activity and reduces neoplastic
proliferation. As with rapamycin, PTEN-deficient human tumors are
more sensitive to CCI-779-mediated growth inhibition than PTEN
expressing cells. Specifically, studies in vitro in a panel of
eight human breast cancer cell lines showed that six of eight
cancer lines studied were inhibited by CCI-779 with IC.sub.50 in
the low nanomolar range. Two lines, however, were found to be
resistant with IC.sub.50>1 .mu.M. The sensitive cell lines were
estrogen receptor positive or over-expressed HER-2/Neu, or had lost
the tumor suppressor gene product PTEN. The main toxicities of
CCI-779 included dermatological toxicities and mild
myelosuppression (mainly thrombocytemia).
[0021] RAD001, 40-O-(2-hydroxyethyl)-rapamycin, is another analogue
of rapamycin that can be administrated orally. Its anti-neoplastic
activity has been evaluated in different human cancer cell lines in
vitro and in xenograft models in vivo with IC.sub.50 ranging from 5
to 1800 nM. p70S6K inhibition and anti-neoplastic effects have been
shown in these models, with an optimal effect being achieved with
2.5 mg/kg/day in melanoma, lung, pancreas and colon carcinoma.
Similarly, RAD001 demonstrated a concentration-dependent anti-tumor
activity in a syngenic rat pancreas carcinoma model with an
intermittent dosing schedule. RAD001 has also shown anti-angiogenic
activity and inhibits human vascular endothelial cell (HUVEC)
proliferation. The toxicity reported for RAD001 includes
hypercholesterolemia, hypertriglyceridemia, mild leukocytopenia and
thrombocytopenia. In a phase I trial performed in patients with
advanced cancer, RAD001 displayed a good safety profile with mild
to moderate skin and mucous toxicity up to 30 mg weekly.
Preliminary efficacy results showed an objective response in a
patient with non-small cell lung carcinoma.
[0022] AP23573 is the latest rapamycin analog to be reported in
clinical development. It is a phosphorus-containing compound
synthesized with the aid of computational modelling studies.
AP23573 was found to be stable in organic solvents, aqueous
solutions at a variety of pHs and in plasma and whole blood, both
in vitro and in vivo and has shown potent inhibition of diverse
human tumor cell lines in vitro and as xenografts implanted into
nude mice, alone or in combination with cytotoxic or targeted
agents. In phase I trials, AP23573 was administered intravenously
daily for 5 days every 2 weeks. Dose-limiting toxicity is severe
grade 3 oral mucositis occurring during the first cycle. Other side
effects seem to be moderate, including minor to moderate episodes
of mucositis, fatigue, nausea, rash, anaemia, neutropenia,
diarrhoea, hyperlipidemias and thrombocytopenia. Preliminary
anti-tumor activity is observed at all dose levels.
[0023] There is thus a plethora of studies that demonstrate that
mTOR inhibitors can improve cancer patient survival. However,
rapamycin and its analogues have not shown universal anti-tumor
activity in early clinical trials. Response rates vary among cancer
types from a low of less than 10% in patients with glioblastomas
and advanced renal-cell cancer to a high of around 40% in patients
with mantle-cell lymphoma. Knowledge of the status of PTEN and
PI3K/Akt/mTOR-linked pathways might help in the selection of tumor
types that will respond to mTOR inhibitors. Furthermore, because
many tumor types still do not respond to single agent therapy with
rapamycin derivatives, it is important to continue the search for
factors predictive of resistance or sensitivity to mTOR inhibitors.
Of particular interest will be molecules that directly inhibit mTOR
kinase activity, the assumption being that such molecules will
inhibit both mTORC1 and mTORC2. Such an inhibitor might be
beneficial for treating tumors with elevated Akt phosphorylation
and might down-regulate the growth, proliferation and survival
effects that are associated with Akt activation. If mTOR-rictor is
a crucial activator of Akt-dependent survival processes, such a
drug might promote apoptosis in tumor cells that have adapted to
Akt-dependent regulatory mechanisms.
[0024] In addition mTOR inhibitors have been shown to be very
effective in preventing organ rejection after transplantation
through an effect on immune responses, demonstrating a potential
for treatment of autoimmune and inflammatory diseases as well as
cancer.
[0025] Through the role of PI3 K isoforms as key compenents of the
down stream signalling pathways of angiogenic growth factors such
as VEGF, FGF and PDGF as well angiogenic cytokines and because of
the role of mTOR in the regulation of vascular endothelial growth
factor (VEGF), PI3 K and mTOR inhibitors also have potential to
treat diseases supported by pathological neovascularization. This
occurs during tumorigenesis, inflammatory conditions such as
rheumatoid arthritis and ocular neovascular diseases e.g.,
age-related macular degeneration (AMD), retinal vascular diseases
(vein occlusion and diabetic retinopathy) and other possible
proliferative vascular disorders.
[0026] mTOR and PI3 have been identified as protein kinases that
are involved in a number of disorders, and compounds that target
one or more of these kinases should display useful biological
activity. Accordingly, compounds that are mTOR and/or PI3K
inhibitors have the potential to provide further biologically
active compounds that would be expected to have useful, improved
pharmaceutical properties in the treatment of proliferative
disorders such as cancer, immune and inflammatory diseases,
diseases supported by excessive neovascularisation and organ
transplant rejection.
[0027] Compounds that inhibit both mTOR and PI3K simultaneously may
be expected to provide powerful anti-proliferative, anti-angiogenic
and antitumor activity since these compounds act at multiple points
in the PI3K/Akt/mTOR pathway. A number of inhibitors of this type
are now being investigated in a clinical setting for the first time
(e.g. BEZ235, XL765, GDC0941, PX866, SF1126).
SUMMARY
[0028] The present invention provides compounds of formula (I):
##STR00001##
wherein:
[0029] R.sup.1 is selected from the group consisting of: H, halogen
and optionally substituted C.sub.1-C.sub.6 alkyl;
[0030] R.sup.2 is selected from the group consisting of H, halogen,
OH, NO.sub.2, CN, NH.sub.2, optionally substituted
C.sub.1-C.sub.12alkyl, optionally substituted
C.sub.2-C.sub.12alkenyl, optionally substituted
C.sub.2-C.sub.12alkynyl, optionally substituted
C.sub.2-C.sub.12heteroalkyl, optionally substituted
C.sub.3-C.sub.12cycloalkyl, optionally substituted
C.sub.3-C.sub.12cycloalkenyl, optionally substituted
C.sub.2-C.sub.12heterocycloalkyl, optionally substituted
C.sub.2-C.sub.12heterocycloalkenyl, optionally substituted
C.sub.6-C.sub.18aryl, optionally substituted
C.sub.1-C.sub.18heteroaryl, optionally substituted
C.sub.1-C.sub.12alkyloxy, optionally substituted
C.sub.2-C.sub.12alkenyloxy, optionally substituted
C.sub.2-C.sub.12alkynyloxy, optionally substituted
C.sub.2-C.sub.10heteroalkyloxy, optionally substituted
C.sub.3-C.sub.12cycloalkyloxy, optionally substituted
C.sub.3-C.sub.12cycloalkenyloxy, optionally substituted
C.sub.2-C.sub.12heterocycloalkyloxy, optionally substituted
C.sub.2-C.sub.12heterocycloalkenyloxy, optionally substituted
C.sub.6-C.sub.18aryloxy, optionally substituted
C.sub.1-C.sub.18heteroaryloxy, optionally substituted
C.sub.1-C.sub.12alkylamino, SR.sup.8, SO.sub.3H,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8, SONR.sup.8R.sup.9,
SOR.sup.8, COR.sup.8, COOH, COOR.sup.8, CONR.sup.8R.sup.9,
NR.sup.8COR.sup.9, NR.sup.8COOR.sup.9, NR.sup.8SO.sub.2R.sup.9,
NR.sup.8CONR.sup.8R.sup.9, NR.sup.8R.sup.9, and acyl;
[0031] R.sup.3, and R.sup.4 are each independently selected from
the group consisting of H, F, Cl, Br, OH, optionally substituted
C.sub.1-C.sub.6alkyl, OR.sup.8, OCOR.sup.8, CH.sub.2OH, NH.sub.2,
NR.sup.8R.sup.9, NR.sup.8COR.sup.9, and
NR.sup.8SO.sub.2R.sup.9;
[0032] R.sup.6 is selected from the group consisting of H, OH,
OR.sup.8, OP.sub.g.sup.O, OCOR.sup.8, CH.sub.2OH, NH.sub.2,
NR.sup.8R.sup.9, NR.sup.8P.sub.g.sup.N, N(P.sub.g.sup.N).sub.2,
NR.sup.8COR.sup.9, and NR.sup.8SO.sub.2R.sup.9;
[0033] each R.sup.8 and R.sup.9 is independently selected from the
group consisting of H, optionally substituted
C.sub.1-C.sub.12alkyl, optionally substituted
C.sub.2-C.sub.12alkenyl, optionally substituted
C.sub.2-C.sub.12alkynyl, optionally substituted
C.sub.2-C.sub.10heteroalkyl, optionally substituted
C.sub.3-C.sub.12cycloalkyl, optionally substituted
C.sub.3-C.sub.12cycloalkenyl, optionally substituted
C.sub.2-C.sub.12 heterocycloalkyl, optionally substituted
C.sub.2-C.sub.12 heterocycloalkenyl, optionally substituted
C.sub.6-C.sub.18aryl, and optionally substituted
C.sub.1-C.sub.18heteroaryl; or
[0034] R.sup.8 and R.sup.9 when taken together with the atoms to
which they are attached form an optionally substituted cyclic
moiety;
[0035] P.sub.g.sup.O is a protecting group for oxygen;
[0036] each P.sub.g.sup.N is independently a protecting group for
nitrogen;
[0037] each R.sup.z is independently selected from the group
consisting of C.sub.1-C.sub.6alkyl, halo-C.sub.1-C.sub.6alkyl,
hydroxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
cyanoC.sub.1-C.sub.6alkyl, aminoC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylaminoC.sub.1-C.sub.6alkyl, and
di(C.sub.1-C.sub.6alkyl)aminoC.sub.1-C.sub.6alkyl;
[0038] q is an integer selected from the group consisting of 0, 1,
2, 3, and 4;
[0039] X is a group of formula (CR.sup.10.sub.2).sub.m;
[0040] each R.sup.10 is independently selected from the group
consisting of: H and optionally substituted C.sub.1-C.sub.6
alkyl;
[0041] m is an integer selected from the group consisting of 0, 1,
2, 3 and 4;
[0042] or a pharmaceutically acceptable salt, N-oxide, or prodrug
thereof.
[0043] As with any group of structurally related compounds which
possess a particular utility, certain embodiments of variables of
the compounds of the Formula (I), are particularly useful in their
end use application.
[0044] In various embodiments q is an integer selected from the
group consisting of 0, 1, 2, 3, and 4. In some embodiments q is 4.
In some embodiments q is 3. In some embodiments q is 2. In some
embodiments q is 1. In some embodiments q is 0.
[0045] In some embodiments wherein q is other than 0 each R.sup.z
may be selected from the group consisting of F, Cl, Br, methyl,
trifluoromethyl, and ethyl. The R.sup.Z substituent may be attached
at the 2, 3, 5 or 6 position of the morpholine ring and in
circumstances where there are multiple R.sup.z substituents each
R.sup.z substituent is located independently of the others such
that where there are multiple R.sup.z substituents then two of the
R.sup.z substituents may be located on the same carbon on the
morpholine ring or each substituent may be located on a different
carbon.
[0046] In some embodiments q is 1 and the R.sup.z substituent is
located at the 3 position of the morpholine ring. This provides
compounds of formula (Ia).
##STR00002##
[0047] or a pharmaceutically acceptable salt or prodrug
thereof;
[0048] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.z
and X are as defined above.
[0049] In some embodiments of the compounds of the invention q is
0. This provides compounds of formula (Ib).
##STR00003##
[0050] or a pharmaceutically acceptable salt or prodrug
thereof;
[0051] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6 and X
are as defined above.
[0052] In some embodiments R.sup.3 is selected from the group
consisting of H, OR.sup.8, and optionally substituted
C.sub.1-C.sub.6 alkyl.
[0053] In some embodiments R.sup.3 is OR.sup.8 where R.sup.8 is
optionally substituted C.sub.1-C.sub.6alkyl. Examples of R.sup.3
groups of this type include methoxy, trifluoro-methoxy, ethoxy,
isopropoxy, propoxy, and butoxy. In some embodiments R.sup.3 is
methoxy.
[0054] In some embodiments R.sup.3 is optionally substituted
C.sub.1-C.sub.6alkyl. Examples of R.sup.3 groups of this type
include methyl, trifluoro-methyl, ethyl, propyl, isopropyl, and
butyl. In some embodiments R.sup.3 is methyl.
[0055] In some embodiments R.sup.3 is selected from the group
consisting of H, methoxy and methyl. In some embodiments R.sup.3 is
H.
[0056] In some embodiments R.sup.4 is selected from the group
consisting of H, F, Cl, Br, OH and NH.sub.2. In some embodiments
R.sup.4 is H.
[0057] In some embodiments of the compounds and specifically the
compounds of formula (I), (Ia) and (Ib), R.sup.3 and R.sup.4 are
both H.
[0058] In some embodiments of the invention q=0, R.sup.3 is H and
R.sup.4 is H. This provides compounds of formula (Ic):
##STR00004##
[0059] or a pharmaceutically acceptable salt or prodrug
thereof;
[0060] wherein R.sup.1, R.sup.2, R.sup.6, and X are as defined
above.
[0061] In some embodiments of the compounds containing the group
R.sup.8, R.sup.8 is selected from H and C.sub.1-C.sub.6alkyl. In
some embodiments R.sup.8 is methyl. In some embodiments R.sup.8 is
H.
[0062] In some embodiments of the compounds containing the group
R.sup.9, R.sup.9 is selected from H and C.sub.1-C.sub.6alkyl. In
some embodiments R.sup.9 is methyl. In some embodiments R.sup.9 is
H.
[0063] As stated previously X is a group of formula
(CR.sup.10.sub.2).sub.m. In some embodiments of the compounds of
formula (I), (Ia), (Ib) and (Ic) m is selected from the group
consisting of 0, 1, and 2. In some embodiments m is 0 or 1. In some
embodiments m is 0. In some embodiments m is 1.
[0064] In some embodiments q=0, R.sup.3 is H, R.sup.4 is H and m is
0. This provides compounds of formula (II):
##STR00005##
[0065] or a pharmaceutically acceptable salt or prodrug
thereof;
[0066] wherein R.sup.1, R.sup.2, and R.sup.6, are as defined
above.
[0067] In some embodiments q=0, R.sup.3 is H, R.sup.4 is H and m is
1. This provides compounds of formula (III):
##STR00006##
[0068] or a pharmaceutically acceptable salt or prodrug
thereof;
[0069] wherein R.sup.1, R.sup.2, R.sup.6 and R.sup.10 are as
defined above.
[0070] In some embodiments of the compounds of formula (I), (Ia),
(Ib), (Ic) and (III) each R.sup.10 is H. In some embodiments each
R.sup.10 is independently an optionally substituted
C.sub.1-C.sub.6alkyl. In some embodiments one R.sup.10 is H and the
other is CH.sub.3. In some embodiments one R.sup.10 is H and the
other R.sup.10 is H or optionally substituted
C.sub.1-C.sub.6alkyl.
[0071] In some embodiments of the compounds of formula (I), (Ia),
(Ib), (Ic) and (III) m is 1, one R.sup.10 is H and X is a group of
the formula:
##STR00007##
In some embodiments of the invention R.sup.3 and R.sup.4 are H, m
is 1, q is 0 and one R.sup.10 is H. This provides compounds of the
formula (IV):
##STR00008##
[0072] or a pharmaceutically acceptable salt or prodrug
thereof,
[0073] wherein R.sup.1, R.sup.2, R.sup.6 and R.sup.10 are as
defined above.
[0074] In some embodiments of the compounds containing R.sup.10 and
specifically compounds of formula (I), (Ia), (Ib), (Ic), (III) and
(IV) R.sup.10 is selected from the group consisting of H,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl and
C.sub.1-C.sub.6alkyl. In some embodiments R.sup.10 is selected from
the group consisting of methyl, ethyl, propyl, isopropyl, and
butyl. In some embodiments R.sup.10 is selected from the group
consisting of H, methyl and ethyl.
[0075] In some embodiments of the compounds of the invention and
specifically the compounds of formula (I), (Ia), (Ib), (Ic), (II),
(III) and (IV) R.sup.1 is selected from the group consisting of H,
Br, methyl, ethyl, isopropyl, propyl, 3,3-dimethyl-propyl, butyl,
isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, and hexyl. In
some embodiments R.sup.1 is selected from the group consisting of
H, methyl and ethyl. In some embodiments R.sup.1 is H. In some
embodiments R.sup.1 is methyl. In some embodiments R.sup.1 is
ethyl. In some embodiments R.sup.1 is Br.
[0076] In some embodiments of the compounds of the invention and
specifically the compounds of formula (I), (Ia), (Ib), (Ic), (II),
(III) and (IV) R.sup.6 is selected from the group consisting of H,
NH.sub.2 and NR.sup.8R.sup.9 wherein R.sup.8 and R.sup.9 are as
defined above. In some embodiments R.sup.6 is NH.sub.2.
[0077] In some embodiments of the compounds of the invention and
specifically the compounds of (I), (Ia), (Ib), (Ic), (II), (III)
and (IV) R.sup.2 is selected from the group consisting of H, cyano,
optionally substituted C.sub.1-C.sub.12alkyl, optionally
substituted C.sub.2-C.sub.12 alkenyl, optionally substituted
C.sub.2-C.sub.12heteroalkyl, optionally substituted
C.sub.3-C.sub.12 cycloalkyl, optionally substituted
C.sub.2-C.sub.12heterocycloalkyl, optionally substituted
C.sub.6-C.sub.18 aryl, and optionally substituted
C.sub.1-C.sub.18heteroaryl.
[0078] In some embodiments R.sup.2 is an optionally substituted
C.sub.6-C.sub.18 aryl. In some embodiments of R.sup.2 the
optionally substituted C.sub.6-C.sub.18 aryl is a group of the
formula:
##STR00009##
[0079] wherein p is an integer selected from the group consisting
of 0, 1, 2, 3, 4, and 5;
[0080] each R.sup.13 is independently selected from the group
consisting of H, halogen, OH, NO.sub.2, CN, NH.sub.2, optionally
substituted C.sub.1-C.sub.12alkyl, optionally substituted
C.sub.2-C.sub.12 alkenyl, optionally substituted
C.sub.2-C.sub.12alkynyl, optionally substituted C.sub.2-C.sub.1
heteroalkyl, optionally substituted C.sub.3-C.sub.12cycloalkyl,
optionally substituted C.sub.2-C.sub.12 heterocycloalkyl,
optionally substituted C.sub.2-C.sub.12heterocycloalkenyl,
optionally substituted C.sub.6-C.sub.18 aryl, optionally
substituted C.sub.1-C.sub.18heteroaryl, optionally substituted
C.sub.1-C.sub.12alkyloxy, optionally substituted
C.sub.2-C.sub.12alkenyloxy, optionally substituted
C.sub.2-C.sub.12alkynyloxy, optionally substituted
C.sub.2-C.sub.10heteroalkyloxy, optionally substituted
C.sub.3-C.sub.12cycloalkyloxy, optionally substituted
C.sub.3-C.sub.12cycloalkenyloxy, optionally substituted
C.sub.2-C.sub.12heterocycloalkyloxy, optionally substituted
C.sub.2-C.sub.12heterocycloalkenyloxy, optionally substituted
C.sub.6-C.sub.18 aryloxy, optionally substituted
C.sub.1-C.sub.18heteroaryloxy, optionally substituted
C.sub.1-C.sub.12 alkylamino, SR.sup.8, SO.sub.3H, SO.sub.2NH.sub.2,
SO.sub.2R.sup.8, SONH.sub.2, SOR.sup.8, COR.sup.S, COOH,
COOR.sup.S, CONR.sup.8R.sup.9, NR.sup.8COR.sup.9,
NR.sup.8COOR.sup.9, NR.sup.8SO.sub.2R.sup.9,
NR.sup.8CONR.sup.8R.sup.9, NR.sup.8R.sup.9, and acyl;
[0081] where R.sup.8 and R.sup.9 are as defined above.
[0082] The phenyl group may be unsubstituted or may be optionally
substituted with one or more suitable substituent groups. If the
phenyl group is substituted then there may be 1, 2, 3, 4 or 5
substituent groups. In some embodiments p is 0, 1 or 2. In some
embodiments p is 1. In some embodiments p is 2.
[0083] In some embodiments of R.sup.2 the optionally substituted
C.sub.6-C.sub.18 aryl is a group of the formula:
##STR00010##
[0084] wherein R.sup.13 is as defined above;
[0085] s is an integer selected from the group consisting of 0, 1,
2, 3 and 4;
[0086] r is an integer selected from the group consisting of 1, 2,
and 3.
[0087] In some embodiments r is 1 and the optionally substituted
C.sub.6-C.sub.18 aryl is a group of the formula:
##STR00011##
[0088] wherein R.sup.13 and s are as defined above.
[0089] In some embodiments r is 2 and the optionally substituted
C.sub.6-C.sub.18 aryl is a group of the formula:
##STR00012##
[0090] wherein R.sup.13 and s are as defined above.
[0091] In some embodiments s is selected from the group consisting
of 0, 1, and 2. In some embodiments s is 1. In some embodiments s
is 1. In some embodiments s is 2.
[0092] Each R.sup.13 substituent may be selected from any suitable
substituent. In some embodiments each R.sup.13 is independently
selected from the group consisting of H, F, CH.sub.3,
CH.sub.2CH.sub.3, OCH.sub.3, CN, OCF.sub.3, CO.sub.2CH.sub.3,
NO.sub.2, NH.sub.2, NHCOCH.sub.3, NHSO.sub.2CH.sub.3,
NHCH.sub.2CH.sub.3, and CF.sub.3.
[0093] In some embodiments R.sup.1 is H, R.sup.3 is H, R.sup.4 is
H, R.sup.6 is NH.sub.2, X is (CH.sub.2).sub.m wherein m is 0, and
R.sup.2 is a group of the formula:
##STR00013##
[0094] This provides compounds of formula (V):
##STR00014##
[0095] or a pharmaceutically acceptable salt or prodrug
thereof;
[0096] wherein R.sup.13 and p are as defined above.
[0097] In some embodiments R.sup.1 is H, R.sup.3 is H, R.sup.4 is
H, R.sup.6 is NH.sub.2, X is (CH.sub.2).sub.m wherein m is 1, and
R.sup.2 is a group of the formula:
##STR00015##
[0098] This provides compounds of formula (Va):
##STR00016##
[0099] or a pharmaceutically acceptable salt or prodrug
thereof;
[0100] wherein R.sup.13, R.sup.10 and p are as defined above.
[0101] In some embodiments of the compounds of formula (I), (Ia),
(Ib), (Ic), (II), (III) and (IV) R.sup.2 is selected from the group
consisting of cyano, optionally substituted C.sub.1-C.sub.12 alkyl,
and optionally substituted C.sub.2-C.sub.12heteroalkyl.
[0102] In some embodiments of the compounds of formula (I), (Ia),
(Ib), (Ic), (II), (III) and (IV) R.sup.2 is selected from the group
consisting of methyl, ethyl, isopropyl, propyl, butyl, sec-butyl,
isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, hexyl, heptyl,
and octyl.
[0103] In some embodiments of the compounds of formula (I), (Ia),
(Ib), (Ic), (II), (III) and (IV) R.sup.2 is an optionally
substituted methyl group of the formula:
##STR00017##
[0104] wherein R.sup.20, R.sup.21 and R.sup.22 are each
independently selected from the group consisting of H, Cl, Br, F,
OH, NO.sub.2, CN, NH.sub.2, optionally substituted
C.sub.1-C.sub.12alkyl, optionally substituted
C.sub.2-C.sub.12heteroalkyl, optionally substituted
C.sub.3-C.sub.12cycloalkyl, optionally substituted
C.sub.2-C.sub.12heterocycloalkyl, optionally substituted
C.sub.6-C.sub.18aryl, and optionally substituted
C.sub.1-C.sub.18heteroaryl; or any two or more of R.sup.20,
R.sup.21 and R.sup.22 when taken together with the carbon atom to
which they are attached form a cyclic moiety.
[0105] In some embodiments each R.sup.20, R.sup.21 and R.sup.22 is
independently selected from the group consisting of H, Cl, Br, F,
OH, NO.sub.2, CN, NH.sub.2, methyl, ethyl, propyl, isopropyl,
butyl, pentyl, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl,
2-ethoxyethyl, 3-ethoxypropyl, aminomethyl, 2-aminoethyl,
3-aminopropyl, 4-aminobutyl, 5 aminopentyl, methylaminomethyl,
2-methylaminoethyl, 3-methylaminopropyl. 4-methylaminobutyl,
5-methylaminopentyl, ethylaminomethyl, 2-ethylaminoethyl,
3-ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl,
dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,
4-dimethylaminobutyl, 5-dimethylaminopentyl, diethylaminomethyl,
2-diethylaminoethyl, 3-diethylaminopropyl, 4-diethylaminobutyl and
5-diethylaminopentyl.
[0106] In some embodiments R.sup.2 is optionally substituted
C.sub.3-C.sub.12cycloalkyl. In some embodiments R.sup.2 is selected
from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl
and cyclohexyl. In some embodiments R.sup.2 is cyclopropyl.
[0107] In some embodiments R.sup.2 is optionally substituted
C.sub.2-C.sub.12heterocycloalkyl.
[0108] In some embodiments R.sup.2 is selected from the group
consisting of optionally substituted pyrrolidin-1-yl, optionally
substituted pyrrolidin-2-yl, optionally substituted
pyrrolidin-3-yl, optionally substituted dioxolane-2-yl, optionally
substituted dioxolane-3-yl, optionally substituted
tetrahydrofuran-2-yl, optionally substituted tetrahydrofuran-3-yl,
optionally substituted piperidine-1-yl, optionally substituted
piperidine-2-yl, optionally substituted piperidine-3-yl, optionally
substituted piperidine-4-yl, optionally substituted
morpholine-2-yl, optionally substituted morpholine-3-yl, optionally
substituted 1,4,dioxolane-2-yl, optionally substituted
thiomorpholine-2-yl, optionally substituted thiomorpholine-3-yl,
optionally substituted thiomorpholine-4-yl, optionally substituted
piperazine-1-yl and optionally substituted piperazine-2-yl.
[0109] In some embodiments the optionally substituted
C.sub.2-C.sub.12heterocycloalkyl group is selected from the group
consisting of:
##STR00018##
[0110] wherein R.sup.23 is independently selected from the group
consisting of H, optionally substituted C.sub.1-C.sub.12alkyl,
optionally substituted C.sub.2-C.sub.12alkenyl, optionally
substituted C.sub.2-C.sub.12alkynyl, optionally substituted
C.sub.2-C.sub.12heteroalkyl, optionally substituted
C.sub.3-C.sub.12cycloalkyl, optionally substituted
C.sub.3-C.sub.12cycloalkenyl, optionally substituted
C.sub.2-C.sub.12heterocycloalkyl, optionally substituted
C.sub.2-C.sub.12heterocycloalkenyl, optionally substituted
C.sub.6-C.sub.18aryl, optionally substituted
C.sub.1-C.sub.18heteroaryl, optionally substituted
C.sub.1-C.sub.12alkyloxy, optionally substituted
C.sub.2-C.sub.12alkenyloxy, optionally substituted
C.sub.2-C.sub.12alkynyloxy, optionally substituted
C.sub.2-C.sub.10heteroalkyloxy, optionally substituted
C.sub.3-C.sub.12cycloalkyloxy, optionally substituted
C.sub.3-C.sub.12cycloalkenyloxy, optionally substituted
C.sub.2-C.sub.12heterocycloalkyloxy, optionally substituted
C.sub.2-C.sub.12 heterocycloalkenyloxy, optionally substituted
C.sub.6-C.sub.18aryloxy, optionally substituted
C.sub.1-C.sub.18heteroaryloxy, optionally substituted
C.sub.1-C.sub.12alkylamino, SO.sub.2NR.sup.24R.sup.25, SOR.sup.24,
SO.sub.2R.sup.24, SONR.sup.24R.sup.25, SOR.sup.24, COR.sup.24,
COOH, COOR.sup.24, and CONR.sup.24R.sup.25;
[0111] each R.sup.24 and R.sup.25 is independently selected from
the group consisting of H, optionally substituted
C.sub.1-C.sub.12alkyl, optionally substituted
C.sub.2-C.sub.12alkenyl, optionally substituted
C.sub.2-C.sub.12alkynyl, optionally substituted
C.sub.2-C.sub.10heteroalkyl, optionally substituted
C.sub.3-C.sub.12cycloalkyl, optionally substituted
C.sub.3-C.sub.12cycloalkenyl, optionally substituted
C.sub.2-C.sub.12 heterocycloalkyl, optionally substituted
C.sub.2-C.sub.12 heterocycloalkenyl, optionally substituted
C.sub.6-C.sub.18aryl, and optionally substituted
C.sub.1-C.sub.18heteroaryl.
[0112] In some embodiments the optionally substituted
C.sub.2-C.sub.12heterocycloalkyl group is selected from the group
consisting of:
##STR00019##
[0113] wherein R.sup.23 is as defined above.
[0114] In some embodiments R.sup.23 is selected from the group
consisting of H, COR.sup.24, and COOR.sup.24.
[0115] In some embodiments R.sup.24 is selected from the group
consisting of H, optionally substituted C.sub.1-C.sub.12alkyl,
optionally substituted C.sub.6-C.sub.18aryl, and optionally
substituted C.sub.1-C.sub.18heteroaryl. In some embodiments
R.sup.24 is C.sub.1-C.sub.6 alkyl.
[0116] In some embodiments R.sup.2 is an optionally substituted
C.sub.2-C.sub.1 heteroalkyl group. In some embodiments the
C.sub.2-C.sub.12 heteroalkyl group is selected from the group
consisting of hydroxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
aminoC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylaminoC.sub.1-C.sub.6alkyl, and
di(C.sub.1-C.sub.6alkyl)aminoC.sub.1-C.sub.6alkyl. Examples of
possible values of R.sup.2 as C.sub.2-C.sub.12 heteroalkyl include
hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl,
hydroxypentyl, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl,
2-ethoxyethyl, 3-ethoxypropyl, aminomethyl, 2-aminoethyl,
3-aminopropyl, 4-aminobutyl, 5 aminopentyl, methylaminomethyl,
2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl,
5-methylaminopentyl, ethylaminomethyl, 2-ethylaminoethyl,
3-ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl,
dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,
4-dimethylaminobutyl, 5-dimethylaminopentyl, diethylaminomethyl,
2-diethylaminoethyl, 3-diethylaminopropyl, 4-diethylaminobutyl and
5-diethylaminopentyl.
[0117] In some embodiments R.sup.2 is COOR.sup.8 wherein R.sup.8 is
as defined above. In some embodiments R.sup.2 is COOR.sup.8 and
R.sup.8 is C.sub.1-C.sub.12alkyl. Examples of groups of this type
include COOCH.sub.3, COOCH.sub.2CH.sub.3 and the like.
[0118] In some embodiments R.sup.2 is CONR.sup.8R.sup.9 wherein
each R.sup.8 and R.sup.9 is independently selected from the group
consisting of H, optionally substituted C.sub.1-C.sub.12alkyl,
optionally substituted C.sub.2-C.sub.12alkenyl, optionally
substituted C.sub.2-C.sub.12alkynyl, optionally substituted
C.sub.2-C.sub.10heteroalkyl, optionally substituted
C.sub.3-C.sub.12cycloalkyl, optionally substituted
C.sub.3-C.sub.12cycloalkenyl, optionally substituted
C.sub.2-C.sub.12heterocycloalkyl, optionally substituted
C.sub.2-C.sub.12heterocycloalkenyl, optionally substituted
C.sub.6-C.sub.18aryl, and optionally substituted
C.sub.1-C.sub.18heteroaryl, or
[0119] R.sup.8 and R.sup.9 when taken together with the atoms to
which they are attached form an optionally substituted cyclic
moiety;
[0120] In some embodiments where R.sup.2 is CONR.sup.8R.sup.9 then
R.sup.8 and R.sup.9 are each independently selected from the group
consisting of H, C.sub.1-C.sub.12alkyl, C.sub.3-C.sub.12 cycloalkyl
and C.sub.1-C.sub.18aryl. Examples of R.sup.2 groups of this type
include CONHCH(CH.sub.3).sub.2, CONHcyclopropyl, and
CONHphenyl.
[0121] In some embodiments where R.sup.2 is CONR.sup.8R.sup.9 then
R.sup.8 and R.sup.9 when taken together with the atoms to which
they are attached form a cyclic moiety. Examples of R.sup.2 groups
of this type include:
##STR00020##
[0122] Wherein R.sup.26 is independently selected from the group
consisting of H, optionally substituted C.sub.1-C.sub.12alkyl,
optionally substituted C.sub.2-C.sub.12alkenyl, optionally
substituted C.sub.2-C.sub.12alkynyl, optionally substituted
C.sub.2-C.sub.12heteroalkyl, optionally substituted
C.sub.3-C.sub.12cycloalkyl, optionally substituted
C.sub.3-C.sub.12cycloalkenyl, optionally substituted
C.sub.2-C.sub.12heterocycloalkyl, optionally substituted
C.sub.2-C.sub.12 heterocycloalkenyl, optionally substituted
C.sub.6-C.sub.18aryl, optionally substituted
C.sub.1-C.sub.18heteroaryl, optionally substituted
C.sub.1-C.sub.12alkyloxy, optionally substituted
C.sub.2-C.sub.12alkenyloxy, optionally substituted
C.sub.2-C.sub.12alkynyloxy, optionally substituted
C.sub.2-C.sub.10heteroalkyloxy, optionally substituted
C.sub.3-C.sub.12cycloalkyloxy, optionally substituted
C.sub.3-C.sub.12cycloalkenyloxy, optionally substituted
C.sub.2-C.sub.12heterocycloalkyloxy, optionally substituted
C.sub.2-C.sub.12 heterocycloalkenyloxy, optionally substituted
C.sub.6-C.sub.18aryloxy, optionally substituted
C.sub.1-C.sub.18heteroaryloxy, optionally substituted
C.sub.1-C.sub.12 alkylamino, H, SO.sub.2NR.sup.27R.sup.28,
SO.sub.2R.sup.27, SONR.sup.27R.sup.28, SOR.sup.27, COR.sup.27,
COOH, COOR.sup.27, and CONR.sup.27R.sup.28;
[0123] each R.sup.27 and R.sup.28 is independently selected from
the group consisting of H, optionally substituted
C.sub.1-C.sub.12alkyl, optionally substituted
C.sub.2-C.sub.12alkenyl, optionally substituted
C.sub.2-C.sub.12alkynyl, optionally substituted
C.sub.2-C.sub.10heteroalkyl, optionally substituted
C.sub.3-C.sub.12cycloalkyl, optionally substituted
C.sub.3-C.sub.12cycloalkenyl, optionally substituted
C.sub.2-C.sub.12 heterocycloalkyl, optionally substituted
C.sub.2-C.sub.12 heterocycloalkenyl, optionally substituted
C.sub.6-C.sub.18aryl, and optionally substituted
C.sub.1-C.sub.18heteroaryl.
[0124] In some embodiments R.sup.2 is selected from the group
consisting of methyl, ethyl, isopropyl, propyl,
3,3-dimethyl-propyl, cyclopropyl, cyclopentyl, 3-methycyclopentyl,
cyclohexyl, 4-methylcyclohexyl, butyl, sec-butyl, isobutyl,
3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, pent-4-enyl, hexyl,
heptyl, octyl, cyano, methoxymethyl, butoxymethyl, t-butoxymethy
and tetrahydrofuran-3-yl,
[0125] Many if not all of the variables discussed above may be
optionally substituted. If the variable is optionally substituted
then in some embodiments each optional substituent is independently
selected from the group consisting of halogen, .dbd.O, .dbd.S,
--CN, --NO.sub.2, --CF.sub.3, --OCF.sub.3, alkyl, alkenyl, alkynyl,
haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl,
cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl,
heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl,
heteroarylalkyl, arylalkyl, cycloalkylalkenyl,
heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl,
cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,
arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl,
alkyloxy, alkyloxyalkyl, alkyloxycycloalkyl,
alkyloxyheterocycloalkyl, alkyloxyaryl, alkyloxyheteroaryl,
alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy,
cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy,
heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy,
arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino,
sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl,
arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl,
aminosulfinylaminoalkyl, --C(.dbd.O)OH, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, C(.dbd.O)NR.sup.aR.sup.b, C(.dbd.NOH)R.sup.a,
C(.dbd.NR.sup.a)NR.sup.bR.sup.c, NR.sup.aR.sup.b,
NR.sup.aC(.dbd.O)R.sup.b, NR.sup.aC(.dbd.O)OR.sup.b,
NR.sup.aC(.dbd.O)NR.sup.bR.sup.c,
NR.sup.aC(.dbd.NR.sup.b)NR.sup.cR.sup.d, NR.sup.aSO.sub.2R.sup.b,
--SR.sup.a, SO.sub.2NR.sup.aR.sup.b, --OR.sup.a,
OC(.dbd.O)NR.sup.aR.sup.b, OC(.dbd.O)R.sup.a and acyl,
[0126] wherein R.sup.a, R.sup.b, R.sup.c and R.sup.d are each
independently selected from the group consisting of H,
C.sub.1-C.sub.12alkyl, C.sub.1-C.sub.12haloalkyl,
C.sub.2-C.sub.12alkenyl, C.sub.2-C.sub.12alkynyl, heteroalkyl,
C.sub.3-C.sub.12cycloalkyl, C.sub.3-C.sub.12cycloalkenyl,
C.sub.1-C.sub.12heterocycloalkyl, C.sub.1-C.sub.12
heterocycloalkenyl, C.sub.6-C.sub.18aryl,
C.sub.1-C.sub.18heteroaryl, and acyl, or any two or more of
R.sup.a, R.sup.b, R.sup.c and R.sup.d, when taken together with the
atoms to which they are attached form a heterocyclic ring system
with 3 to 12 ring atoms.
[0127] Alternatively, two adjacent optional; substituents may, when
taken together with the atoms to which they are attached, form a
cyclic moiety such as an optionally substituted C.sub.3-C.sub.12
cycloalkyl moiety or an optionally substituted C.sub.2-C.sub.12
heterocycloalkyl moiety.
[0128] In some embodiments each optional substituent is
independently selected from the group consisting of: F, Cl, Br,
.dbd.O, .dbd.S, --CN, --NO.sub.2, alkyl, alkenyl, heteroalkyl,
haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,
hydroxy, hydroxyalkyl, alkoxy, alkylamino, aminoalkyl, acylamino,
phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl,
aminosulfonyl, --C(O)OR.sup.a, COOH, SH, and acyl.
[0129] In some embodiments each optional substituent is
independently selected from the group consisting of: F, Br, Cl,
.dbd.O, .dbd.S, --CN methyl, trifluoro-methyl, ethyl,
2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl,
3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl,
2-ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl,
octyl, phenyl, NH.sub.2, --NO.sub.2, phenoxy, hydroxy, methoxy,
trifluoro-methoxy, ethoxy, and methylenedioxy.
[0130] In addition to compounds of Formula I, the embodiments
disclosed are also directed to pharmaceutically acceptable salts,
pharmaceutically acceptable N-oxides, pharmaceutically acceptable
prodrugs, and pharmaceutically active metabolites of such
compounds, and pharmaceutically acceptable salts of such
metabolites.
[0131] The invention also relates to pharmaceutical compositions
including a compound of the invention with a pharmaceutically
acceptable carrier, diluent or excipient.
[0132] In a further aspect the invention provides a method of
inhibiting a protein kinase selected from the group consisting of a
serine/threonine protein kinase or a fragment or a complex thereof
or a functional equivalent thereof and a PI3 kinase or a fragment
or a complex thereof or a functional equivalent thereof, the method
including exposing the protein kinase or a fragment or complex
thereof or a functional equivalent thereof and/or co-factor(s)
thereof to an effective amount of a compound of the invention.
[0133] The compounds disclosed herein may act directly and solely
on the kinase molecule or a complex or fragment thereof to inhibit
biological activity. However, it is understood that the compounds
may also act at least partially on co-factors that are involved in
the phosphorylation process. Known kinase co-factors include ionic
species (such as zinc and calcium), lipids (such as
phosphatidylserine), and diacylglycerols.
[0134] In some embodiments the protein kinase is a serine/threonine
protein kinase or a fragment or a complex thereof or a functional
equivalent thereof. In some embodiments the serine/threonine
protein kinase or a fragment or complex thereof is an mTOR protein
kinase or a fragment thereof, or a complex thereof or a functional
equivalent thereof. In some embodiments the serine/threonine
protein kinase is mTORC1 or a fragment or complex thereof or a
functional equivalent thereof.
[0135] In some embodiments the protein kinase is a PI3 kinase or a
fragment thereof or a complex thereof or a functional equivalent
thereof. In some embodiments the PI3 kinase or a fragment thereof
or a complex thereof or a functional equivalent thereof, is a class
I PI3K or a fragment thereof or a complex thereof or a functional
equivalent thereof.
[0136] In one embodiment of the method exposing the one or more
protein kinase(s) to the compound includes administering the
compound to a mammal containing the one or more protein
kinase(s).
[0137] In an even further aspect the invention provides the use of
a compound of the invention to inhibit one or more protein
kinase(s) selected from the group consisting of a serine/threonine
protein kinase or a fragment or a complex thereof or a functional
equivalent thereof and a PI3 kinase or a fragment or a complex
thereof or a functional equivalent thereof.
[0138] In some embodiments the protein kinase is a serine/threonine
protein kinase or a fragment or a complex thereof or a functional
equivalent thereof. In some embodiments the serine/threonine
protein kinase or a fragment or complex thereof is an mTOR protein
kinase or a fragment thereof, or a complex thereof or a functional
equivalent thereof. In some embodiments the serine/threonine
protein kinase is mTORC1 or a fragment or complex thereof or a
functional equivalent thereof.
[0139] In some embodiments the protein kinase is a PI3 kinase or a
fragment thereof or a complex thereof or a functional equivalent
thereof. In some embodiments the PI3 kinase or a fragment thereof
or a complex thereof or a functional equivalent thereof, is a class
I PI3K or a fragment thereof or a complex thereof or a functional
equivalent thereof.
[0140] In an even further aspect the invention provides a method of
treating or preventing a condition in a mammal in which inhibition
of one or more protein kinase(s) selected from the group consisting
of a serine/threonine protein kinase or a fragment or a complex
thereof or a functional equivalent thereof and a PI3 kinase or a
fragment or a complex thereof or a functional equivalent thereof,
prevents, inhibits or ameliorates a pathology or a symptomology of
the condition, the method including administration of a
therapeutically effective amount of a compound of the
invention.
[0141] In some embodiments the protein kinase is a serine/threonine
protein kinase or a fragment or a complex thereof or a functional
equivalent thereof. In some embodiments the serine/threonine
protein kinase or a fragment or complex thereof is an mTOR protein
kinase or a fragment thereof, or a complex thereof or a functional
equivalent thereof. In some embodiments the serine/threonine
protein kinase is mTORC1 or a fragment or complex thereof or a
functional equivalent thereof.
[0142] In some embodiments the protein kinase is a PI3 kinase or a
fragment thereof or a complex thereof or a functional equivalent
thereof. In some embodiments the PI3 kinase or a fragment thereof
or a complex thereof or a functional equivalent thereof, is a class
I PI3K or a fragment thereof or a complex thereof or a functional
equivalent thereof.
[0143] In some embodiments the condition is cancer. In some
embodiments the cancer is selected from the group consisting of
Hematologic cancer such as myeloproliferative disorders (idiopathic
myelofibrosis, polycythemia vera, essential thrombocythemia,
chronic myeloid leukemia), myeloid metaplasia, chronic
myelomonocytic leukemia, acute lymphocytic leukemia, acute
erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease,
B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes,
plasma cell disorder, hairy cell leukemia, kaposi's sarcoma,
lymphoma and hyperproliferative conditions such as psoriasis and
restenosis; gynaecologic cancer such as breast carcinoma, ovarian
cancer, cervical cancer, vaginal and vulva cancer, endometrial
hyperplasia; gastrointestinal tract cancer such as colorectal
carcinoma, polyps, liver cancer, gastric cancer, pancreatic cancer,
gall bladder cancer; urinary tract cancer such as prostate cancer,
kidney and renal cancer; urinary bladder cancer, urethral cancer,
penile cancer; skin cancer such as melanoma; brain tumour such as
glioblastoma, neuroblastoma, astrocytoma, ependynoma, brain-stem
gliomas, medulloblastoma, menigiomas, astrocytoma,
oligodendroglioma; head and neck cancer such as nasopharyngeal
carcinoma, laryngeal carcinoma; respiratory tract cancer such as
lung carcinoma (NSCLC and SCLC), mesothelioma; eye disease such as
retinoblastoma; musculo-skeleton diseases such as osteosarcoma,
musculoskeleletal neoplasm; Squamous cell carcinoma and fibroid
tumour. In other embodiments, compounds of this invention can be
used to treat pre-cancer conditions or hyperplasia including
familial adenomatous polyposis, colonic adenomatous polyps, myeloid
dysplasia, endometrial dysplasia, endometrial hyperplasia with
atypia, cervical dysplasia, vaginal intraepithelial neoplasia,
benign prostatic hyperplasia, papillomas of the larynx, actinic and
solar keratosis, seborrheic keratosis and keratoacanthoma.
[0144] In some embodiments the condition is an autoimmune or
inflammatory disease or a disease supported by excessive
neovascularisation. Diseases that have been attributed with some
degree of autoimmune etiology, or that involve pathological
inflammatory and neovascularization responses, include the
following: acute disseminated encephalomyelitis, Addison's disease,
agammaglobulinemia, agranulocytosis, allergic asthma, allergic
encephalomyelitis, allergic rhinitis, alopecia greata, alopecia
senilis, anerythroplasia, ankylosing spondylitis, antiphospholipid
antibody syndrome, aortitis syndrome, aplastic anemia, atopic
dermatitis, autoimmune haemolytic anemia, autoimmune hepatitis,
autoimmune oophoritis, Balo disease, Basedow's disease, Behcet's
disease, bronchial asthma, Castleman's syndrome, celiac disease,
Chagas disease, chronic inflammatory demyelinating polyneuropathy,
Churg-Strauss syndrome, Cogans syndrome, comical cornea, comical
leukoma, Coxsackie myocarditis, CREST disease, Crohn's disease,
cutaneous eosinophilia, cutaneous T-cell lymphoma, dermatitis
erythrema multiforme, dermatomyositis, diabetic retinopathy,
Dressler's syndrome, dystrophia epithelialis corneae, eczematous
dermatitis, eosinophilic fasciitis, eosinophilic gastroenteritis,
epidermolysis bullosa, Evans syndrome, fibrosing alveolitis,
gestational pemphigoid, glomerulonephritis, Goodpasture's syndrome,
graft-versus-host disease, Graves' disease, Guillain-Barre
Syndrome, Hashimoto's disease, haemolytic-uretic syndrome, herpetic
keratitis, ichthyosis vulgaris, idiopathic intersititial pneumonia,
idiopathic thrombocytopenic purpura, inflammatory bowel diseases,
Kawasaki's disease, keratitis, keratoconjunctivitis, Lambert-Eaton
syndrome, leukoderma vulgaris, lichen planus, lichen sclerosus,
Lyme disease, linear IgA disease, macular degeneration,
megaloblastic anemia, Meniere's disease, Mooren's ulcer,
Mucha-Habermann disease, multiple myositis, multiple sclerosis,
myasthenia gravis, necrotizing enterocolitis, neuromyelitis optica,
ocular pemphigus, opsoclonus myoclonus syndrome, Ord's thyroiditis,
paroxysmal nocturnal hemoglobinuria, Parsonnage-Turner syndrome,
pemphigus, periodontitis, pernicious anemia, pollen allergies,
polyglandular autoimmune syndrome, posterior uveitis, primary
biliary cirrhosis, proctitis, pseudomembranous colitis, psoriasis,
pulmonary emphysema, pyoderma, Reiter's syndrome, reversible
obstructive airway disease, rheumatic fever, rheumatoid arthritis,
sarcoidosis, scleritis, Sezary's syndrome, Sjogren's syndrome,
subacute bacterial endocarditis, systemic lupus erythematosus,
Takayasu's arteritis, temporal arteritis, Tolosa-Hunt syndrome,
Type I diabetes mellitus, ulcerative colitis, urticaria, vernal
conjunctivitis, vitiligo, Vogy-Koyanagi-Harada syndrome and
Wegener's granulomatosis.
[0145] In an even further aspect the invention provides use of a
compound of the invention in the preparation of a medicament for
treating a condition in an animal in which inhibition of one or
more protein kinase(s) selected from the group consisting of a
serine/threonine protein kinase or a fragment or a complex thereof
or a functional equivalent thereof and a PI3 kinase or a fragment
or a complex thereof or a functional equivalent thereof, prevents,
inhibits or ameliorates a pathology or a symptomology of the
condition.
[0146] In another aspect the present invention provides the use of
a compound of the invention or a pharmaceutically acceptable salt,
N-oxide or prodrug thereof in the treatment of a condition in which
inhibition of one or more protein kinase(s) selected from the group
consisting of a serine/threonine protein kinase or a fragment or a
complex thereof or a functional equivalent thereof and a PI3 kinase
or a fragment or a complex thereof or a functional equivalent
thereof, prevents, inhibits or ameliorates a pathology or a
symptomology of the condition
[0147] In some embodiments the protein kinase is a serine/threonine
protein kinase or a fragment or a complex thereof or a functional
equivalent thereof. In some embodiments the serine/threonine
protein kinase or a fragment or complex thereof is an mTOR protein
kinase or a fragment thereof, or a complex thereof or a functional
equivalent thereof. In some embodiments the serine/threonine
protein kinase is mTORC1 or a fragment or complex thereof or a
functional equivalent thereof.
[0148] In some embodiments the protein kinase is a PI3 kinase or a
fragment thereof or a complex thereof or a functional equivalent
thereof. In some embodiments the PI3 kinase or a fragment thereof
or a complex thereof or a functional equivalent thereof, is a class
I PI3K or a fragment thereof or a complex thereof or a functional
equivalent thereof.
[0149] In another aspect the present invention provides a method of
prevention or treatment of a proliferative condition in a subject,
the method including administration of a therapeutically effective
amount of a compound of the invention.
[0150] In another aspect the present invention provides the use of
a compound of the invention in the preparation of a medicament for
treating a proliferative condition in a subject.
[0151] In some embodiments the condition is cancer. In some
embodiments the cancer is selected from the group consisting of
Hematologic cancer such as myeloproliferative disorders (idiopathic
myelofibrosis, polycythemia vera, essential thrombocythemia,
chronic myeloid leukemia), myeloid metaplasia, chronic
myelomonocytic leukemia, acute lymphocytic leukemia, acute
erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease,
B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes,
plasma cell disorder, hairy cell leukemia, kaposi's sarcoma,
lymphoma; gynaecologic cancer such as breast carcinoma, ovarian
cancer, cervical cancer, vaginal and vulva cancer, endometrial
hyperplasia; gastrointestinal tract cancer such as colorectal
carcinoma, polyps, liver cancer, gastric cancer, pancreatic cancer,
gall bladder cancer; urinary tract cancer such as prostate cancer,
kidney and renal cancer; urinary bladder cancer, urethral cancer,
penile cancer; skin cancer such as melanoma; brain tumour such as
glioblastoma, neuroblastoma, astrocytoma, ependynoma, brain-stem
gliomas, medulloblastoma, menigiomas, astrocytoma,
oligodendroglioma; head and neck cancer such as nasopharyngeal
carcinoma, laryngeal carcinoma; respiratory tract cancer such as
lung carcinoma (NSCLC and SCLC), mesothelioma; eye disease such as
retinoblastoma; musculo-skeleton diseases such as osteosarcoma,
musculoskeleletal neoplasm; Squamous cell carcinoma and fibroid
tumour.
[0152] These and other features of the present teachings are set
forth herein.
DETAILED DESCRIPTION
[0153] In this specification a number of terms are used which are
well known to a skilled addressee. Nevertheless for the purposes of
clarity a number of terms will be defined.
[0154] As used herein, the term "unsubstituted" means that there is
no substituent or that the only substituents are hydrogen.
[0155] The term "optionally substituted" as used throughout the
specification denotes that the group may or may not be further
substituted or fused (so as to form a condensed polycyclic system),
with one or more non-hydrogen substituent groups. In certain
embodiments the substituent groups are one or more groups
independently selected from the group consisting of halogen,
.dbd.O, .dbd.S, --CN, --NO.sub.2, --CF.sub.3, --OCF.sub.3, alkyl,
alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl,
cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl,
aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl alkyl,
heteroarylalkyl, arylalkyl, cycloalkylalkenyl,
heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl,
cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,
arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl,
alkyloxy, alkyloxyalkyl, alkyloxycycloalkyl,
alkyloxyheterocycloalkyl, alkyloxyaryl, alkyloxyheteroaryl,
alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy,
cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy,
heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy,
arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino,
sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl,
arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl,
aminosulfinylaminoalkyl, --C(.dbd.O)OH, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, C(.dbd.O)NR.sup.aR.sup.b, C(.dbd.NOH)R.sup.a,
C(.dbd.NR.sup.a)NR.sup.bR.sup.c, NR.sup.aR.sup.b,
NR.sup.aC(.dbd.O)R.sup.b, NR.sup.aC(.dbd.O)OR.sup.b,
NR.sup.aC(.dbd.O)NR.sup.bR.sup.c,
NR.sup.aC(.dbd.NR.sup.b)NR.sup.cR.sup.d, NR.sup.aSO.sub.2R.sup.b,
--SR.sup.a, SO.sub.2NR.sup.aR.sup.b, --OR.sup.a,
OC(.dbd.O)NR.sup.aR.sup.b, OC(.dbd.O)R.sup.a and acyl,
[0156] wherein R.sup.a, R.sup.b, R.sup.c and R.sup.d are each
independently selected from the group consisting of H,
C.sub.1-C.sub.12alkyl, C.sub.1-C.sub.12haloalkyl,
C.sub.2-C.sub.12alkenyl, C.sub.2-C.sub.12alkynyl, C.sub.2-C.sub.10
heteroalkyl, C.sub.3-C.sub.12cycloalkyl,
C.sub.3-C.sub.12cycloalkenyl, C.sub.2-C.sub.12heterocycloalkyl,
C.sub.2-C.sub.12 heterocycloalkenyl, C.sub.6-C.sub.18aryl,
C.sub.1-C.sub.18heteroaryl, and acyl, or any two or more of
R.sup.a, R.sup.b, R.sup.c and R.sup.d, when taken together with the
atoms to which they are attached form a heterocyclic ring system
with 3 to 12 ring atoms.
[0157] In some embodiments each optional substituent is
independently selected from the group consisting of: halogen,
.dbd.O, .dbd.S, --CN, --NO.sub.2, --CF.sub.3, --OCF.sub.3, alkyl,
alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl,
cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl,
aryl, heteroaryl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl,
alkyloxyaryl, alkyloxyheteroaryl, alkenyloxy, alkynyloxy,
cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy,
heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl,
heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino,
aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl,
aminosulfonyl, aminoalkyl, --COOH, --SH, and acyl.
[0158] Examples of particularly suitable optional substituents
include F, Cl, Br, I, CH.sub.3, CH.sub.2CH.sub.3, OH, OCH.sub.3,
CF.sub.3, OCF.sub.3, NO.sub.2, NH.sub.2, and CN.
[0159] In the definitions of a number of substituents below it is
stated that "the group may be a terminal group or a bridging
group". This is intended to signify that the use of the term is
intended to encompass the situation where the group is a linker
between two other portions of the molecule as well as where it is a
terminal moiety. Using the term alkyl as an example, some
publications would use the term "alkylene" for a bridging group and
hence in these other publications there is a distinction between
the terms "alkyl" (terminal group) and "alkylene" (bridging group).
In the present application no such distinction is made and most
groups may be either a bridging group or a terminal group.
[0160] "Acyl" means an R--C(.dbd.O)-- group in which the R group
may be an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl
group as defined herein. Examples of acyl include acetyl and
benzoyl. The group may be a terminal group or a bridging group. If
the group is a terminal group it is bonded to the remainder of the
molecule through the carbonyl carbon.
[0161] "Acylamino" means an R--C(.dbd.O)--NH-- group in which the R
group may be an alkyl, cycloalkyl, heterocycloalkyl, aryl or
heteroaryl group as defined herein. The group may be a terminal
group or a bridging group. If the group is a terminal group it is
bonded to the remainder of the molecule through the nitrogen
atom.
[0162] "Alkenyl" as a group or part of a group denotes an aliphatic
hydrocarbon group containing at least one carbon-carbon double bond
and which may be straight or branched preferably having 2-12 carbon
atoms, more preferably 2-10 carbon atoms, most preferably 2-6
carbon atoms, in the normal chain. The group may contain a
plurality of double bonds in the normal chain and the orientation
about each is independently E or Z. Exemplary alkenyl groups
include, but are not limited to, ethenyl, propenyl, butenyl,
pentenyl, hexenyl, heptenyl, octenyl and nonenyl. The group may be
a terminal group or a bridging group.
[0163] "Alkenyloxy" refers to an alkenyl-O-- group in which alkenyl
is as defined herein. Preferred alkenyloxy groups are
C.sub.1-C.sub.6 alkenyloxy groups. The group may be a terminal
group or a bridging group. If the group is a terminal group it is
bonded to the remainder of the molecule through the oxygen
atom.
[0164] "Alkyl" as a group or part of a group refers to a straight
or branched aliphatic hydrocarbon group, preferably a
C.sub.1-C.sub.12 alkyl, more preferably a C.sub.1-C.sub.10 alkyl,
most preferably C.sub.1-C.sub.6 unless otherwise noted. Examples of
suitable straight and branched C.sub.1-C.sub.6 alkyl substituents
include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl,
t-butyl, hexyl, and the like. The group may be a terminal group or
a bridging group.
[0165] "Alkylamino" includes both mono-alkylamino and dialkylamino,
unless specified. "Mono-alkylamino" means a Alkyl-NH-- group, in
which alkyl is as defined herein. "Dialkylamino" means a
(alkyl).sub.2N-- group, in which each alkyl may be the same or
different and are each as defined herein for alkyl. The alkyl group
is preferably a C.sub.1-C.sub.6 alkyl group. The group may be a
terminal group or a bridging group. If the group is a terminal
group it is bonded to the remainder of the molecule through the
nitrogen atom.
[0166] "Alkylaminocarbonyl" refers to a group of the formula
(Alkyl).sub.x(H).sub.yNC(.dbd.O)-- in which alkyl is as defined
herein, x is 1 or 2, and the sum of X+Y=2. The group may be a
terminal group or a bridging group. If the group is a terminal
group it is bonded to the remainder of the molecule through the
carbonyl carbon.
[0167] "Alkyloxy" refers to an alkyl-O-- group in which alkyl is as
defined herein. Preferably the alkyloxy is a
C.sub.1-C.sub.6alkyloxy. Examples include, but are not limited to,
methoxy and ethoxy. The group may be a terminal group or a bridging
group.
[0168] "Alkyloxyalkyl" refers to an alkyloxy-alkyl- group in which
the alkyloxy and alkyl moieties are as defined herein. The group
may be a terminal group or a bridging group. If the group is a
terminal group it is bonded to the remainder of the molecule
through the alkyl group.
[0169] "Alkyloxyaryl" refers to an alkyloxy-aryl- group in which
the alkyloxy and aryl moieties are as defined herein. The group may
be a terminal group or a bridging group. If the group is a terminal
group it is bonded to the remainder of the molecule through the
aryl group.
[0170] "Alkyloxycarbonyl" refers to an alkyl-O--C(.dbd.O)-- group
in which alkyl is as defined herein. The alkyl group is preferably
a C.sub.1-C.sub.6 alkyl group. Examples include, but are not
limited to, methoxycarbonyl and ethoxycarbonyl. The group may be a
terminal group or a bridging group. If the group is a terminal
group it is bonded to the remainder of the molecule through the
carbonyl carbon.
[0171] "Alkyloxycycloalkyl" refers to an alkyloxy-cycloalkyl- group
in which the alkyloxy and cycloalkyl moieties are as defined
herein. The group may be a terminal group or a bridging group. If
the group is a terminal group it is bonded to the remainder of the
molecule through the cycloalkyl group.
[0172] "Alkyloxyheteroaryl" refers to an alkyloxy-heteroaryl- group
in which the alkyloxy and heteroaryl moieties are as defined
herein. The group may be a terminal group or a bridging group. If
the group is a terminal group it is bonded to the remainder of the
molecule through the heteroaryl group.
[0173] "Alkyloxyheterocycloalkyl" refers to an
alkyloxy-heterocycloalkyl- group in which the alkyloxy and
heterocycloalkyl moieties are as defined herein. The group may be a
terminal group or a bridging group. If the group is a terminal
group it is bonded to the remainder of the molecule through the
heterocycloalkyl group.
[0174] "Alkylsulfinyl" means an alkyl-S--(.dbd.O)-- group in which
alkyl is as defined herein. The alkyl group is preferably a
C.sub.1-C.sub.6 alkyl group. Exemplary alkylsulfinyl groups
include, but not limited to, methylsulfinyl and ethylsulfinyl. The
group may be a terminal group or a bridging group. If the group is
a terminal group it is bonded to the remainder of the molecule
through the sulfur atom.
[0175] "Alkylsulfonyl" refers to an alkyl-S(.dbd.O).sub.2-- group
in which alkyl is as defined above. The alkyl group is preferably a
C.sub.1-C.sub.6alkyl group. Examples include, but not limited to
methylsulfonyl and ethylsulfonyl. The group may be a terminal group
or a bridging group. If the group is a terminal group it is bonded
to the remainder of the molecule through the sulfur atom.
[0176] "Alkynyl" as a group or part of a group means an aliphatic
hydrocarbon group containing a carbon-carbon triple bond and which
may be straight or branched preferably having from 2-12 carbon
atoms, more preferably 2-10 carbon atoms, more preferably 2-6
carbon atoms in the normal chain. Exemplary structures include, but
are not limited to, ethynyl and propynyl. The group may be a
terminal group or a bridging group.
[0177] "Alkynyloxy" refers to an alkynyl-O-- group in which alkynyl
is as defined herein. Preferred alkynyloxy groups are
C.sub.1-C.sub.6alkynyloxy groups. The group may be a terminal group
or a bridging group. If the group is a terminal group it is bonded
to the remainder of the molecule through the oxygen atom.
[0178] "Aminoalkyl" means an NH.sub.2-alkyl- group in which the
alkyl group is as defined herein. The group may be a terminal group
or a bridging group. If the group is a terminal group it is bonded
to the remainder of the molecule through the alkyl group.
[0179] "Aminosulfonyl" means an NH.sub.2--S(.dbd.O).sub.2-- group.
The group may be a terminal group or a bridging group. If the group
is a terminal group it is bonded to the remainder of the molecule
through the sulfur atom.
[0180] "Aryl" as a group or part of a group denotes (i) an
optionally substituted monocyclic, or fused polycyclic, aromatic
carbocycle (ring structure having ring atoms that are all carbon)
preferably having from 5 to 12 atoms per ring. Examples of aryl
groups include phenyl, naphthyl, and the like; (ii) an optionally
substituted partially saturated bicyclic aromatic carbocyclic
moiety in which a phenyl and a C.sub.5-7 cycloalkyl or C.sub.5-7
cycloalkenyl group are fused together to form a cyclic structure,
such as tetrahydronaphthyl, indenyl or indanyl. The group may be a
terminal group or a bridging group. Typically an aryl group is a
C.sub.6-C.sub.18 aryl group.
[0181] "Arylalkenyl" means an aryl-alkenyl- group in which the aryl
and alkenyl are as defined herein. Exemplary arylalkenyl groups
include phenylallyl. The group may be a terminal group or a
bridging group. If the group is a terminal group it is bonded to
the remainder of the molecule through the alkenyl group.
[0182] "Arylalkyl" means an aryl-alkyl- group in which the aryl and
alkyl moieties are as defined herein. Preferred arylalkyl groups
contain a C.sub.1-5alkyl moiety. Exemplary arylalkyl groups include
benzyl, phenethyl, 1-naphthalenemethyl and 2-naphthalenemethyl. The
group may be a terminal group or a bridging group. If the group is
a terminal group it is bonded to the remainder of the molecule
through the alkyl group.
[0183] "Arylalkyloxy" refers to an aryl-alkyl-O-- group in which
the alkyl and aryl are as defined herein. The group may be a
terminal group or a bridging group. If the group is a terminal
group it is bonded to the remainder of the molecule through the
oxygen atom.
[0184] "Arylamino" includes both mono-arylamino and di-arylamino
unless specified. Mono-arylamino means a group of formula arylNH--,
in which aryl is as defined herein. di-arylamino means a group of
formula (aryl).sub.2N-- where each aryl may be the same or
different and are each as defined herein for aryl. The group may be
a terminal group or a bridging group. If the group is a terminal
group it is bonded to the remainder of the molecule through the
nitrogen atom.
[0185] "Arylheteroalkyl" means an aryl-heteroalkyl- group in which
the aryl and heteroalkyl moieties are as defined herein. The group
may be a terminal group or a bridging group. If the group is a
terminal group it is bonded to the remainder of the molecule
through the heteroalkyl group.
[0186] "Aryloxy" refers to an aryl-O-- group in which the aryl is
as defined herein. Preferably the aryloxy is a
C.sub.6-C.sub.18aryloxy, more preferably a C.sub.6-C.sub.10aryloxy.
The group may be a terminal group or a bridging group. If the group
is a terminal group it is bonded to the remainder of the molecule
through the oxygen atom.
[0187] "Arylsulfonyl" means an aryl-S(.dbd.O).sub.2-- group in
which the aryl group is as defined herein. The group may be a
terminal group or a bridging group. If the group is a terminal
group it is bonded to the remainder of the molecule through the
sulfur atom.
[0188] A "bond" is a linkage between atoms in a compound or
molecule. The bond may be a single bond, a double bond, or a triple
bond.
[0189] "Cycloalkenyl" means a non-aromatic monocyclic or
multicyclic ring system containing at least one carbon-carbon
double bond and preferably having from 5-10 carbon atoms per ring.
Exemplary monocyclic cycloalkenyl rings include cyclopentenyl,
cyclohexenyl or cycloheptenyl. The cycloalkenyl group may be
substituted by one or more substituent groups. A cycloalkenyl group
typically is a C.sub.3-C.sub.12 alkenyl group. The group may be a
terminal group or a bridging group.
[0190] "Cycloalkyl" refers to a saturated monocyclic or fused or
spiro polycyclic, carbocycle preferably containing from 3 to 9
carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and the like, unless otherwise specified. It includes
monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic
systems such as decalin, and polycyclic systems such as adamantane.
A cycloalkyl group typically is a C.sub.3-C.sub.12 alkyl group. The
group may be a terminal group or a bridging group.
[0191] "Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which
the cycloalkyl and alkyl moieties are as defined herein. Exemplary
monocycloalkylalkyl groups include cyclopropylmethyl,
cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. The
group may be a terminal group or a bridging group. If the group is
a terminal group it is bonded to the remainder of the molecule
through the alkyl group.
[0192] "Cycloalkylalkenyl" means a cycloalkyl-alkenyl- group in
which the cycloalkyl and alkenyl moieties are as defined herein.
The group may be a terminal group or a bridging group. If the group
is a terminal group it is bonded to the remainder of the molecule
through the alkenyl group.
[0193] "Cycloalkylheteroalkyl" means a cycloalkyl-heteroalkyl-
group in which the cycloalkyl and heteroalkyl moieties are as
defined herein. The group may be a terminal group or a bridging
group. If the group is a terminal group it is bonded to the
remainder of the molecule through the heteroalkyl group.
[0194] "Cycloalkyloxy" refers to a cycloalkyl-O-- group in which
cycloalkyl is as defined herein. Preferably the cycloalkyloxy is a
C.sub.1-C.sub.6cycloalkyloxy. Examples include, but are not limited
to, cyclopropanoxy and cyclobutanoxy. The group may be a terminal
group or a bridging group. If the group is a terminal group it is
bonded to the remainder of the molecule through the oxygen
atom.
[0195] "Cycloalkenyloxy" refers to a cycloalkenyl-O-- group in
which the cycloalkenyl is as defined herein. Preferably the
cycloalkenyloxy is a C.sub.1-C.sub.6cycloalkenyloxy. The group may
be a terminal group or a bridging group. If the group is a terminal
group it is bonded to the remainder of the molecule through the
oxygen atom.
[0196] "Haloalkyl" refers to an alkyl group as defined herein in
which one or more of the hydrogen atoms has been replaced with a
halogen atom selected from the group consisting of fluorine,
chlorine, bromine and iodine. A haloalkyl group typically has the
formula C.sub.nH.sub.(2n+1-m)X.sub.m wherein each X is
independently selected from the group consisting of F, Cl, Br and
I. In groups of this type n is typically from 1 to 10, more
preferably from 1 to 6, most preferably 1 to 3. m is typically 1 to
6, more preferably 1 to 3. Examples of haloalkyl include
fluoromethyl, difluoromethyl and trifluoromethyl.
[0197] "Haloalkenyl" refers to an alkenyl group as defined herein
in which one or more of the hydrogen atoms has been replaced with a
halogen atom independently selected from the group consisting of F,
Cl, Br and I.
[0198] "Haloalkynyl" refers to an alkynyl group as defined herein
in which one or more of the hydrogen atoms has been replaced with a
halogen atom independently selected from the group consisting of F,
Cl, Br and I.
[0199] "Halogen" represents chlorine, fluorine, bromine or
iodine.
[0200] "Heteroalkyl" refers to a straight- or branched-chain alkyl
group preferably having from 2 to 12 carbons, more preferably 2 to
6 carbons in the chain, in which one or more of the carbon atoms
(and any associated hydrogen atoms) are each independently replaced
by a heteroatomic group selected from S, O, P and NR' where R' is
selected from the group consisting of H, optionally substituted
C.sub.1-C.sub.12alkyl, optionally substituted
C.sub.3-C.sub.12cycloalkyl, optionally substituted
C.sub.6-C.sub.18aryl, and optionally substituted
C.sub.1-C.sub.18heteroaryl. Exemplary heteroalkyls include alkyl
ethers, secondary and tertiary alkyl amines, amides, alkyl
sulfides, and the like. Examples of heteroalkyl also include
hydroxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
aminoC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylaminoC.sub.1-C.sub.6alkyl, and
di(C.sub.1-C.sub.6alkyl)aminoC.sub.1-C.sub.6alkyl. The group may be
a terminal group or a bridging group.
[0201] "Heteroalkyloxy" refers to an heteroalkyl-O-- group in which
heteroalkyl is as defined herein. Preferably the heteroalkyloxy is
a C.sub.2-C.sub.6heteroalkyloxy. The group may be a terminal group
or a bridging group.
[0202] "Heteroaryl" either alone or part of a group refers to
groups containing an aromatic ring (preferably a 5 or 6 membered
aromatic ring) having one or more heteroatoms as ring atoms in the
aromatic ring with the remainder of the ring atoms being carbon
atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur.
Examples of heteroaryl include thiophene, benzothiophene,
benzofuran, benzimidazole, benzoxazole, benzothiazole,
benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine,
xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine,
pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole,
1H-indazole, purine, quinoline, isoquinoline, phthalazine,
naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine,
acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole,
isooxazole, furazane, phenoxazine, 2-, 3- or 4-pyridyl, 2-, 3-, 4-,
5-, or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolinyl 1-, 2-, or
3-indolyl, and 2-, or 3-thienyl. A heteroaryl group is typically a
C.sub.1-C.sub.18 heteroaryl group. The group may be a terminal
group or a bridging group.
[0203] "Heteroarylalkyl" means a heteroaryl-alkyl group in which
the heteroaryl and alkyl moieties are as defined herein. Preferred
heteroarylalkyl groups contain a lower alkyl moiety. Exemplary
heteroarylalkyl groups include pyridylmethyl. The group may be a
terminal group or a bridging group. If the group is a terminal
group it is bonded to the remainder of the molecule through the
alkyl group.
[0204] "Heteroarylalkenyl" means a heteroaryl-alkenyl- group in
which the heteroaryl and alkenyl moieties are as defined herein.
The group may be a terminal group or a bridging group. If the group
is a terminal group it is bonded to the remainder of the molecule
through the alkenyl group.
[0205] "Heteroarylheteroalkyl" means a heteroaryl-heteroalkyl-
group in which the heteroaryl and heteroalkyl moieties are as
defined herein. The group may be a terminal group or a bridging
group. If the group is a terminal group it is bonded to the
remainder of the molecule through the heteroalkyl group.
[0206] "Heteroaryloxy" refers to a heteroaryl-O-- group in which
the heteroaryl is as defined herein. Preferably the heteroaryloxy
is a C.sub.1-C.sub.18heteroaryloxy. The group may be a terminal
group or a bridging group. If the group is a terminal group it is
bonded to the remainder of the molecule through the oxygen
atom.
[0207] "Heterocyclic" refers to saturated, partially unsaturated or
fully unsaturated monocyclic, bicyclic or polycyclic ring system
containing at least one heteroatom selected from the group
consisting of nitrogen, sulfur and oxygen as a ring atom. Examples
of heterocyclic moieties include heterocycloalkyl,
heterocycloalkenyl and heteroaryl.
[0208] "Heterocycloalkenyl" refers to a heterocycloalkyl group as
defined herein but containing at least one double bond. A
heterocycloalkenyl group typically is a C.sub.2-C.sub.12
heterocycloalkenyl group. The group may be a terminal group or a
bridging group.
[0209] "Heterocycloalkyl" refers to a saturated monocyclic,
bicyclic, or polycyclic ring containing at least one heteroatom
selected from nitrogen, sulfur, oxygen, preferably from 1 to 3
heteroatoms in at least one ring. Each ring is preferably from 3 to
10 membered, more preferably 4 to 7 membered. Examples of suitable
heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl,
tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl,
morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and
1,4-oxathiapane. A heterocycloalkyl group typically is a
C.sub.2-C.sub.12 heterocycloalkyl group. The group may be a
terminal group or a bridging group.
[0210] "Heterocycloalkylalkyl" refers to a heterocycloalkyl-alkyl-
group in which the heterocycloalkyl and alkyl moieties are as
defined herein. Exemplary heterocycloalkyl alkyl groups include
(2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl) methyl. The
group may be a terminal group or a bridging group. If the group is
a terminal group it is bonded to the remainder of the molecule
through the alkyl group.
[0211] "Heterocycloalkylalkenyl" refers to a
heterocycloalkyl-alkenyl- group in which the heterocycloalkyl and
alkenyl moieties are as defined herein. The group may be a terminal
group or a bridging group. If the group is a terminal group it is
bonded to the remainder of the molecule through the alkenyl
group.
[0212] "Heterocycloalkylheteroalkyl" means a
heterocycloalkyl-heteroalkyl- group in which the heterocycloalkyl
and heteroalkyl moieties are as defined herein. The group may be a
terminal group or a bridging group. If the group is a terminal
group it is bonded to the remainder of the molecule through the
heteroalkyl group.
[0213] "Heterocycloalkyloxy" refers to a heterocycloalkyl-O-- group
in which the heterocycloalkyl is as defined herein. Preferably the
heterocycloalkyloxy is a C.sub.1-C.sub.6heterocycloalkyloxy. The
group may be a terminal group or a bridging group. If the group is
a terminal group it is bonded to the remainder of the molecule
through the oxygen atom.
[0214] "Heterocycloalkenyloxy" refers to a heterocycloalkenyl-O--
group in which heterocycloalkenyl is as defined herein. Preferably
the Heterocycloalkenyloxy is a C.sub.1-C.sub.6
Heterocycloalkenyloxy. The group may be a terminal group or a
bridging group. If the group is a terminal group it is bonded to
the remainder of the molecule through the oxygen atom.
[0215] "Hydroxyalkyl" refers to an alkyl group as defined herein in
which one or more of the hydrogen atoms has been replaced with an
OH group. A hydroxyalkyl group typically has the formula
C.sub.nH.sub.(2n+1-x)(OH).sub.x. In groups of this type n is
typically from 1 to 10, more preferably from 1 to 6, most
preferably 1 to 3. x is typically 1 to 6, more preferably 1 to
3.
[0216] "Lower alkyl" as a group means unless otherwise specified,
an aliphatic hydrocarbon group which may be straight or branched
having 1 to 6 carbon atoms in the chain, more preferably 1 to 4
carbons such as methyl, ethyl, propyl (n-propyl or isopropyl) or
butyl (n-butyl, isobutyl or tertiary-butyl). The group may be a
terminal group or a bridging group.
[0217] "Sulfinyl" means an R--S(.dbd.O)-- group in which the R
group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or
heteroaryl group as defined herein. The group may be a terminal
group or a bridging group. If the group is a terminal group it is
bonded to the remainder of the molecule through the sulfur
atom.
[0218] "Sulfinylamino" means an R--S(.dbd.O)--NH-- group in which
the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or
heteroaryl group as defined herein. The group may be a terminal
group or a bridging group. If the group is a terminal group it is
bonded to the remainder of the molecule through the nitrogen
atom.
[0219] "Sulfonyl" means an R--S(.dbd.O).sub.2-- group in which the
R group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or
heteroaryl group as defined herein. The group may be a terminal
group or a bridging group. If the group is a terminal group it is
bonded to the remainder of the molecule through the sulfur
atom.
[0220] "Sulfonylamino" means an R--S(.dbd.O).sub.2--NH-- group. The
group may be a terminal group or a bridging group. If the group is
a terminal group it is bonded to the remainder of the molecule
through the nitrogen atom.
[0221] It is understood that included in the family of compounds of
Formula (I) are isomeric forms including diastereoisomers,
enantiomers, tautomers, and geometrical isomers in "E" or "Z"
configurational isomer or a mixture of E and Z isomers. It is also
understood that some isomeric forms such as diastereomers,
enantiomers, and geometrical isomers can be separated by physical
and/or chemical methods and by those skilled in the art.
[0222] Some of the compounds of the disclosed embodiments may exist
as single stereoisomers, racemates, and/or mixtures of enantiomers
and/or diastereomers. All such single stereoisomers, racemates and
mixtures thereof, are intended to be within the scope of the
subject matter described and claimed.
[0223] Additionally, Formula (I) is intended to cover, where
applicable, solvated as well as unsolvated forms of the compounds.
Thus, each formula includes compounds having the indicated
structure, including the hydrated as well as the non-hydrated
forms.
[0224] The term "pharmaceutically acceptable salts" refers to salts
that retain the desired biological activity of the above-identified
compounds, and include pharmaceutically acceptable acid addition
salts and base addition salts. Suitable pharmaceutically acceptable
acid addition salts of compounds of Formula (I) may be prepared
from an inorganic acid or from an organic acid. Examples of such
inorganic acids are hydrochloric, sulfuric, and phosphoric acid.
Appropriate organic acids may be selected from aliphatic,
cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic
classes of organic acids, examples of which are formic, acetic,
propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,
citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Additional
information on pharmaceutically acceptable salts can be found in
Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing
Co., Easton, Pa. 1995. In the case of agents that are solids, it is
understood by those skilled in the art that the inventive
compounds, agents and salts may exist in different crystalline or
polymorphic forms, all of which are intended to be within the scope
of the present invention and specified formulae.
[0225] "Prodrug" means a compound that undergoes conversion to a
compound of formula (I) within a biological system, usually by
metabolic means (e.g. by hydrolysis, reduction or oxidation). For
example an ester prodrug of a compound of formula (I) containing a
hydroxyl group may be convertible by hydrolysis in vivo to the
parent molecule. Suitable esters of compounds of formula (I)
containing a hydroxyl group, are for example acetates, citrates,
lactates, tartrates, malonates, oxalates, salicylates, propionates,
succinates, fumarates, maleates,
methylene-bis-.beta.-hydroxynaphthoates, gestisates, isethionates,
di-p-toluoyltartrates, methanesulphonates, ethanesulphonates,
benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and
quinates. As another example an ester prodrug of a compound of
formula (I) containing a carboxy group may be convertible by
hydrolysis in vivo to the parent molecule. (Examples of ester
prodrugs are those described by F. J. Leinweber, Drug Metab. Res.,
18:379, 1987). Similarly, an acyl prodrug of a compound of formula
(I) containing an amino group may be convertible by hydrolysis in
vivo to the parent molecule (Many examples of prodrugs for these
and other functional groups, including amines, are described in
Prodrugs: Challenges and Rewards (Parts 1 and 2); Ed V. Stella, R.
Borchardt, M. Hageman, R. Oliyai, H. Maag and J Tilley; Springer,
2007)
[0226] The term "oxygen protecting group" means a group that can
prevent the oxygen moiety reacting during further derivatisation of
the protected compound and which can be readily removed when
desired. In one embodiment the protecting group is removable in the
physiological state by natural metabolic processes. Examples of
oxygen protecting groups include acyl groups (such as acetyl),
ethers (such as methoxy methyl ether (MOM), B-methoxy ethoxy methyl
ether (MEM), p-methoxy benzyl ether (PMB), methylthio methyl ether,
Pivaloyl (Piv), Tetrahydropyran (THP)), and silyl ethers (such as
Trimethylsilyl (TMS) tert-butyl dimethyl silyl (TBDMS) and
triisopropylsilyl (TIPS).
[0227] The term "nitrogen protecting group" means a group that can
prevent the nitrogen moiety reacting during further derivatisation
of the protected compound and which can be readily removed when
desired. In one embodiment the protecting group is removable in the
physiological state by natural metabolic processes. Examples of
suitable nitrogen protecting groups that may be used include
formyl, trityl, phthalimido, acetyl, trichloroacetyl, chloroacetyl,
bromoacetyl, iodoacetyl; urethane-type blocking groups such as
benzyloxycarbonyl (`CBz`), 4-phenyl benzyloxycarbonyl,
2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,
3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,
2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,
3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
4-cyanobenzyloxycarbonyl, t-butoxycarbonyl (`tBoc`),
2-(4-xenyl)-isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl,
1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,
2-(p-toluoyl)-prop-2-yloxycarbonyl, cyclopentanyloxy-carbonyl,
1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl,
1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl,
2-(4-toluylsulfono)-ethoxycarbonyl,
2-(methylsulfono)ethoxycarbonyl,
2-(triphenylphosphino)-ethoxycarbonyl, fluorenylmethoxycarbonyl
("FMOC"), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,
1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,
5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,
cyclopropylmethoxycarbonyl, 4-(decycloxy)benzyloxycarbonyl,
isobornyloxycarbonyl, 1-piperidyloxycarbonlyl and the like;
benzoylmethylsulfono group, 2-nitrophenylsulfenyl,
diphenylphosphine oxide, and the like. The actual nitrogen
protecting group employed is not critical so long as the
derivatised nitrogen group is stable to the condition of subsequent
reaction(s) and can be selectively removed as required without
substantially disrupting the remainder of the molecule including
any other nitrogen protecting group(s). Further examples of these
groups are found in: Greene, T. W. and Wuts, P. G. M., Protective
Groups in Organic Synthesis, Second edition; Wiley-Interscience:
1991; Chapter 7; McOmie, J. F. W. (ed.), Protective Groups in
Organic Chemistry, Plenum Press, 1973; and Kocienski, P. J.,
Protecting Groups, Second Edition, Theime Medical Pub., 2000.
[0228] The term "therapeutically effective amount" or "effective
amount" is an amount sufficient to effect beneficial or desired
clinical results. An effective amount can be administered in one or
more administrations. An effective amount is typically sufficient
to palliate, ameliorate, stabilize, reverse, slow or delay the
progression of the disease state.
[0229] The term "functional equivalent" is intended to include
variants of the specific protein kinase species described herein.
It will be understood that kinases may have isoforms, such that
while the primary, secondary, tertiary or quaternary structure of a
given kinase isoform is different to the protoypical kinase, the
molecule maintains biological activity as a protein kinase.
Isoforms may arise from normal allelic variation within a
population and include mutations such as amino acid substitution,
deletion, addition, truncation, or duplication. Also included
within the term "functional equivalent" are variants generated at
the level of transcription. Many kinases (including JAK2 and CDK2)
have isoforms that arise from transcript variation. It is also
known that FLT3 has an isoform that is the result of exon-skipping.
Other functional equivalents include kinases having altered
post-translational modification such as glycosylation.
[0230] Specific compounds of the invention include the
following:
##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025##
##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030##
##STR00031##
[0231] or a pharmaceutically acceptable salt or prodrug
thereof.
[0232] The compounds of the invention have the ability to inhibit
the activity of certain protein kinases. The ability to inhibit
kinase activity may be a result of the compounds of the invention
acting directly and solely on the kinase molecule to inhibit
biological activity. However, it is understood that the compounds
may also act at least partially on co-factors of the kinase in
question that are involved in the phosphorylation process.
[0233] The compounds may have activity against PI3 protein kinases
or a fragment or a complex or a functional equivalent thereof.
[0234] The compounds may have activity against certain
serine/threonine kinases such as mTOR or a fragment or complex or
functional equivalent thereof.
[0235] The inhibition of the protein kinase may be carried out in
any of a number of well known ways in the art. For example if
inhibition of the protein kinase in vitro is desired an appropriate
amount of the compound of the invention may be added to a solution
containing the kinase. In circumstances where it is desired to
inhibit the activity of the kinase in a mammal the inhibition of
the kinase typically involves administering the compound to a
mammal containing the kinase.
[0236] Accordingly the compounds of the invention may find a
multiple number of applications in which their ability to inhibit
protein kinases of the type mentioned above can be utilised. For
example the compounds may be used to inhibit serine/threonine
protein kinases. The compounds may also be used in treating or
preventing a condition in a mammal in which inhibition of a protein
kinase and/or co-factor thereof prevents, inhibits or ameliorates a
pathology or a symptomology of the condition.
[0237] The compounds disclosed have the ability to be used in the
treatment of proliferative disorders. An example of such a disorder
is cancer. It is anticipated that the compounds will have the
ability to treat both solid and liquid tumors. In some embodiments
the cancers that may be treated by compounds of the present
invention include solid tumors and hematological cancers.
[0238] As used herein, the term "cancer" is a general term intended
to encompass the vast number of conditions that are characterized
by uncontrolled abnormal growth of cells. It is anticipated that
the compounds of the invention will be useful in treating various
cancers including but not limited to bone cancers, brain and CNS
tumours, breast cancers, colorectal cancers, endocrine cancers
including adrenocortical carcinoma, pancreatic cancer, pituitary
cancer, thyroid cancer, parathyroid cancer, thymus cancer,
gastrointestinal cancers, Liver cancer, extra hepatic bile duct
cancer, gastrointestinal carcinoid tumour, gall bladder cancer,
genitourinary cancers, gynaecological cancers, head and neck
cancers, leukemias, myelomas, hematological disorders, lung
cancers, lymphomas, eye cancers, skin cancers, soft tissue
sarcomas, adult soft tissue sarcoma, Kaposi's sarcoma, urinary
system cancers.
[0239] Exemplary cancers that may be treated by compounds of this
invention include Hematologic cancer such as myeloproliferative
disorders (idiopathic myelofibrosis, polycythemia vera, essential
thrombocythemia, chronic myeloid leukemia), myeloid metaplasia,
chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute
erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease,
B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes,
plasma cell disorder, hairy cell leukemia, kaposi's sarcoma,
lymphoma and hyperproliferative conditions such as psoriasis and
restenosis; gynaecologic cancer such as breast carcinoma, ovarian
cancer, cervical cancer, vaginal and vulva cancer, endometrial
hyperplasia; gastrointestinal tract cancer such as colorectal
carcinoma, polyps, liver cancer, gastric cancer, pancreatic cancer,
gall bladder cancer; urinary tract cancer such as prostate cancer,
kidney and renal cancer; urinary bladder cancer, urethral cancer,
penile cancer; skin cancer such as melanoma; brain tumour such as
glioblastoma, neuroblastoma, astrocytoma, ependynoma, brain-stem
gliomas, medulloblastoma, menigiomas, astrocytoma,
oligodendroglioma; head and neck cancer such as nasopharyngeal
carcinoma, laryngeal carcinoma; respiratory tract cancer such as
lung carcinoma (NSCLC and SCLC), mesothelioma; eye disease such as
retinoblastoma; musculo-skeleton diseases such as osteosarcoma,
musculoskeleletal neoplasm; Squamous cell carcinoma and fibroid
tumour. Compounds of this invention may also be used to treat
pre-cancer conditions or hyperplasia including familial adenomatous
polyposis, colonic adenomatous polyps, myeloid dysplasia,
endometrial dysplasia, endometrial hyperplasia with atypia,
cervical dysplasia, vaginal intraepithelial neoplasia, benign
prostatic hyperplasia, papillomas of the larynx, actinic and solar
keratosis, seborrheic keratosis and keratoacanthoma.
[0240] It is also anticipated that the compounds of the invention
will be useful in treating autoimmune or inflammatory diseases or
diseases supported by excessive neovascularisation. Diseases that
have been attributed with some degree of autoimmune etiology, or
that involve pathological inflammatory and neovascularization
responses, include, but are not limited to, the following: acute
disseminated encephalomyelitis, Addison's disease,
agammaglobulinemia, agranulocytosis, allergic asthma, allergic
encephalomyelitis, allergic rhinitis, alopecia greata, alopecia
senilis, anerythroplasia, ankylosing spondylitis, antiphospholipid
antibody syndrome, aortitis syndrome, aplastic anemia, atopic
dermatitis, autoimmune haemolytic anemia, autoimmune hepatitis,
autoimmune oophoritis, Balo disease, Basedow's disease, Behcet's
disease, bronchial asthma, Castleman's syndrome, celiac disease,
Chagas disease, chronic inflammatory demyelinating polyneuropathy,
Churg-Strauss syndrome, Cogans syndrome, comical cornea, comical
leukoma, Coxsackie myocarditis, CREST disease, Crohn's disease,
cutaneous eosinophilia, cutaneous T-cell lymphoma, dermatitis
erythrema multiforme, dermatomyositis, diabetic retinopathy,
Dressler's syndrome, dystrophia epithelialis corneae, eczematous
dermatitis, eosinophilic fasciitis, eosinophilic gastroenteritis,
epidermolysis bullosa, Evans syndrome, fibrosing alveolitis,
gestational pemphigoid, glomerulonephritis, Goodpasture's syndrome,
graft-versus-host disease, Graves' disease, Guillain-Barre
Syndrome, Hashimoto's disease, haemolytic-uretic syndrome, herpetic
keratitis, ichthyosis vulgaris, idiopathic intersititial pneumonia,
idiopathic thrombocytopenic purpura, inflammatory bowel diseases,
Kawasaki's disease, keratitis, keratoconjunctivitis, Lambert-Eaton
syndrome, leukoderma vulgaris, lichen planus, lichen sclerosus,
Lyme disease, linear IgA disease, macular degeneration,
megaloblastic anemia, Meniere's disease, Mooren's ulcer,
Mucha-Habermann disease, multiple myositis, multiple sclerosis,
myasthenia gravis, necrotizing enterocolitis, neuromyelitis optica,
ocular pemphigus, opsoclonus myoclonus syndrome, Ord's thyroiditis,
paroxysmal nocturnal hemoglobinuria, Parsonnage-Turner syndrome,
pemphigus, periodontitis, pernicious anemia, pollen allergies,
polyglandular autoimmune syndrome, posterior uveitis, primary
biliary cirrhosis, proctitis, pseudomembranous colitis, psoriasis,
pulmonary emphysema, pyoderma, Reiter's syndrome, reversible
obstructive airway disease, rheumatic fever, rheumatoid arthritis,
sarcoidosis, scleritis, Sezary's syndrome, Sjogren's syndrome,
subacute bacterial endocarditis, systemic lupus erythematosus,
Takayasu's arteritis, temporal arteritis, Tolosa-Hunt syndrome,
Type I diabetes mellitus, ulcerative colitis, urticaria, vernal
conjunctivitis, vitiligo, Vogy-Koyanagi-Harada syndrome and
Wegener's granulomatosis.
[0241] The compounds of the invention may also be used the
preparation of a medicament for treating a condition in an animal
in which inhibition of a protein kinase can prevent, inhibit or
ameliorate the pathology or symptomology of the condition. The
compounds of the invention may also be used in the preparation of a
medicament for the treatment or prevention of a kinase-related
disorder.
[0242] Administration of compounds within Formula (I) to humans can
be by any of the accepted modes for enteral administration such as
oral or rectal, or by parenteral administration such as
subcutaneous, intramuscular, intravenous and intradermal routes.
Injection can be bolus or via constant or intermittent infusion.
The active compound is typically included in a pharmaceutically
acceptable carrier or diluent and in an amount sufficient to
deliver to the patient a therapeutically effective dose. In various
embodiments the inhibitor compound may be selectively toxic or more
toxic to rapidly proliferating cells, e.g. cancerous tumours, than
to normal cells.
[0243] In using the compounds of the invention they can be
administered in any form or mode which makes the compound
bioavailable. One skilled in the art of preparing formulations can
readily select the proper form and mode of administration depending
upon the particular characteristics of the compound selected, the
condition to be treated, the stage of the condition to be treated
and other relevant circumstances. We refer the reader to Remingtons
Pharmaceutical Sciences, 19.sup.th edition, Mack Publishing Co.
(1995) for further information.
[0244] The compounds of the present invention can be administered
alone or in the form of a pharmaceutical composition in combination
with a pharmaceutically acceptable carrier, diluent or excipient.
The compounds of the invention, while effective themselves, are
typically formulated and administered in the form of their
pharmaceutically acceptable salts as these forms are typically more
stable, more easily crystallised and have increased solubility.
[0245] The compounds are, however, typically used in the form of
pharmaceutical compositions which are formulated depending on the
desired mode of administration. As such in some embodiments the
present invention provides a pharmaceutical composition including a
compound of Formula (I) and a pharmaceutically acceptable carrier,
diluent or excipient. The compositions are prepared in manners well
known in the art.
[0246] The invention in other embodiments provides a pharmaceutical
pack or kit comprising one or more containers filled with one or
more of the ingredients of the pharmaceutical compositions of the
invention. In such a pack or kit can be found a container having a
unit dosage of the agent(s). The kits can include a composition
comprising an effective agent either as concentrates (including
lyophilized compositions), which can be diluted further prior to
use or they can be provided at the concentration of use, where the
vials may include one or more dosages. Conveniently, in the kits,
single dosages can be provided in sterile vials so that the
physician can employ the vials directly, where the vials will have
the desired amount and concentration of agent(s). Associated with
such container(s) can be various written materials such as
instructions for use, or a notice in the form prescribed by a
governmental agency regulating the manufacture, use or sale of
pharmaceuticals or biological products, which notice reflects
approval by the agency of manufacture, use or sale for human
administration.
[0247] The compounds of the invention may be used or administered
in combination with one or more additional drug(s) for the
treatment of the disorder/diseases mentioned. The components can be
administered in the same formulation or in separate formulations.
If administered in separate formulations the compounds of the
invention may be administered sequentially or simultaneously with
the other drug(s).
[0248] In addition to being able to be administered in combination
with one or more additional drugs, the compounds of the invention
may be used in a combination therapy. When this is done the
compounds are typically administered in combination with each
other. Thus one or more of the compounds of the invention may be
administered either simultaneously (as a combined preparation) or
sequentially in order to achieve a desired effect. This is
especially desirable where the therapeutic profile of each compound
is different such that the combined effect of the two drugs
provides an improved therapeutic result.
[0249] Pharmaceutical compositions of this invention for parenteral
injection comprise pharmaceutically acceptable sterile aqueous or
nonaqueous solutions, dispersions, suspensions or emulsions as well
as sterile powders for reconstitution into sterile injectable
solutions or dispersions just prior to use. Examples of suitable
aqueous and nonaqueous carriers, diluents, solvents or vehicles
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils (such as olive oil), and injectable organic
esters such as ethyl oleate. Proper fluidity can be maintained, for
example, by the use of coating materials such as lecithin, by the
maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0250] These compositions may also contain adjuvants such as
preservative, wetting agents, emulsifying agents, and dispersing
agents. Prevention of the action of micro-organisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid, and the
like. It may also be desirable to include isotonic agents such as
sugars, sodium chloride, and the like. Prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents that delay absorption such as aluminium
monostearate and gelatin.
[0251] If desired, and for more effective distribution, the
compounds can be incorporated into slow release or targeted
delivery systems such as polymer matrices, liposomes, and
microspheres.
[0252] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions that can be dissolved or dispersed in sterile water or
other sterile injectable medium just prior to use.
[0253] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0254] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like.
[0255] The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and can also be of a composition that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions which can be used
include polymeric substances and waxes.
[0256] The active compounds can also be in microencapsulated form,
if appropriate, with one or more of the above-mentioned
excipients.
[0257] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compounds, the liquid
dosage forms may contain inert diluents commonly used in the art
such as, for example, water or other solvents, solubilizing agents
and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures
thereof.
[0258] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0259] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminium metahydroxide, bentonite,
agar-agar, and tragacanth, and mixtures thereof.
[0260] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at room temperature but liquid at
body temperature and therefore melt in the rectum or vaginal cavity
and release the active compound.
[0261] Dosage forms for topical administration of a compound of
this invention include powders, patches, sprays, ointments and
inhalants. The active compound is mixed under sterile conditions
with a pharmaceutically acceptable carrier and any needed
preservatives, buffers, or propellants which may be required.
[0262] The amount of compound administered will preferably treat
and reduce or alleviate the condition. A therapeutically effective
amount can be readily determined by an attending diagnostician by
the use of conventional techniques and by observing results
obtained under analogous circumstances. In determining the
therapeutically effective amount a number of factors are to be
considered including but not limited to, the species of animal, its
size, age and general health, the specific condition involved, the
severity of the condition, the response of the patient to
treatment, the particular compound administered, the mode of
administration, the bioavailability of the preparation
administered, the dose regime selected, the use of other
medications and other relevant circumstances.
[0263] A preferred dosage will be a range from about 0.01 to 300 mg
per kilogram of body weight per day. A more preferred dosage will
be in the range from 0.1 to 100 mg per kilogram of body weight per
day, more preferably from 0.2 to 80 mg per kilogram of body weight
per day, even more preferably 0.2 to 50 mg per kilogram of body
weight per day. A suitable dose can be administered in multiple
sub-doses per day.
Synthesis of Compounds of the Invention
[0264] The agents of the various embodiments may be prepared using
the reaction routes and synthesis schemes as described below,
employing the techniques available in the art using starting
materials that are readily available. The preparation of particular
compounds of the embodiments is described in detail in the
following examples, but the artisan will recognize that the
chemical reactions described may be readily adapted to prepare a
number of other agents of the various embodiments. For example, the
synthesis of non-exemplified compounds may be successfully
performed by modifications apparent to those skilled in the art,
e.g. by appropriately protecting interfering groups, by changing to
other suitable reagents known in the art, or by making routine
modifications of reaction conditions. A list of suitable protecting
groups in organic synthesis can be found in T. W. Greene's
Protective Groups in Organic Synthesis, 3.sup.rd Edition, John
Wiley & Sons, 1991. Alternatively, other reactions disclosed
herein or known in the art will be recognized as having
applicability for preparing other compounds of the various
embodiments.
[0265] Reagents useful for synthesizing compounds may be obtained
or prepared according to techniques known in the art.
General Synthetic Scheme
[0266] A wide range of trisubstituted purines can be prepared in a
straightforward three step procedure starting from
2,6-dichloropurine which is commercially available from a number of
sources or may be prepared from purine itself using, for example,
phosphorylchloride. The general representative procedure is shown
in scheme 1.
##STR00032##
[0267] As shown initial reaction of 2,6-dichloropurine or its 8
derivative with an alkyl halide results in alkylation predominately
at the 9 position (Tetrahedron Letters 1995, 36, 11, 1945). A
typical procedure uses an alkyl bromide in the presence of a
suitable base such as potassium carbonate. Alternatively, an
alcohol may be reacted with the 2,6-dichloropurine in the presence
of a phosphine and an activating agent, such as
diethylazodicarboxylate, so as to effect a similar alkylation.
N-arylation may also be carried out at the 9 position of the
dichloropurine. Copper catalysed couplings of this type have been
described by Gundersen et al. in Tetrahedron Letters 2003, 44,
3359-3362. Subsequent palladium catalysed coupling of 2 with a
suitable aryl boronic acid or ester then delivers intermediate 3
(Collect. Czech. Chem. Commun. 2002, 67, 325). Addition of
morpholine can then be carried out at elevated temperature, in a
suitable solvent such as DMA, DMF or THF, to give the desired
trisubstituted purine. In cases where a substituted morpholine
group is being added the reaction has been shown to be facilitated
by the use of microwave irradiation. The R.sup.1 substituent may be
varied either by using an 8-substituted dichloropurine as starting
material (Scheme 1) or can be introduced later in the synthetic
sequence (Scheme 2). For example chemistry may be carried out on
the 8-position after completion of the sequence illustrated in
scheme 1 above. For example, the 8-position of 4 may be brominated
to give 5. The bromide may then be displaced by, for example, an
organometallic agent, such as an organozinc, to install R.sup.1 as
in 6.
##STR00033##
EXAMPLES
[0268] In the examples described below, unless otherwise indicated,
all temperatures in the following description are in degrees
Celsius and all parts and percentages are by weight, unless
indicated otherwise.
[0269] Various starting materials and other reagents were purchased
from commercial suppliers, such as Aldrich Chemical Company or
Lancaster Synthesis Ltd., and used without further purification,
unless otherwise indicated. Tetrahydrofuran (THF) and
N,N-dimethylformamide (DMF) were purchased from Aldrich in SureSeal
bottles and used as received. All solvents were purified by using
standard methods in the art, unless otherwise indicated.
[0270] The reactions set forth below were performed under a
positive pressure of nitrogen, argon or with a drying tube, at
ambient temperature (unless otherwise stated), in anhydrous
solvents, and the reaction flasks are fitted with rubber septa for
the introduction of substrates and reagents via syringe. Glassware
was oven-dried and/or heat-dried. Analytical thin-layer
chromatography was performed on glass-backed silica gel 60 F 254
plates (E Merck (0.25 mm)) and eluted with the appropriate solvent
ratios (v/v). The reactions were assayed by TLC and terminated as
judged by the consumption of starting material.
[0271] The TLC plates were visualized by UV absorption or with a
p-anisaldehyde spray reagent or a phosphomolybdic acid reagent
(Aldrich Chemical, 20 wt % in ethanol) which was activated with
heat, or by staining in an iodine chamber.
[0272] Work-ups were typically done by doubling the reaction volume
with the reaction solvent or extraction solvent and then washing
with the indicated aqueous solutions using 25% by volume of the
extraction volume (unless otherwise indicated). Product solutions
were dried over anhydrous sodium sulfate prior to filtration, and
evaporation of the solvents was under reduced pressure on a rotary
evaporator and noted as solvents removed in vacuo.
[0273] Flash column chromatography [Still et al, J. Org. Chem., 43,
2923 (1978)] was conducted using E Merck-grade flash silica gel
(47-61 mm) and a silica gel:crude material ratio of about 20:1 to
50:1, unless otherwise stated. Hydrogenolysis was done at the
pressure indicated or at ambient pressure.
[0274] .sup.1H NMR spectra were recorded on a Bruker instrument
operating at 400 MHz, and .sup.13C-NMR spectra was recorded
operating at 100 MHz. NMR spectra were obtained as CDCl.sub.3
solutions (reported in ppm), using chloroform as the reference
standard (7.27 ppm and 77.00 ppm) or CD.sub.3OD (3.4 and 4.8 ppm
and 49.3 ppm), or an internal tetramethylsilane standard (0.00 ppm)
when appropriate. Other NMR solvents were used as needed. When peak
multiplicities are reported, the following abbreviations are used:
s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened,
dd=doublet of doublets, dt=doublet of triplets. Coupling constants,
when given, are reported in Hertz. Mass spectra were obtained using
LC/MS either in ESI or APCI. All melting points are uncorrected.
All final products had greater than 90% purity (by HPLC at
wavelengths of 220 nm and 254 nm).
[0275] The following examples are intended to illustrate the
embodiments disclosed and are not to be construed as being
limitations thereto. Additional compounds, other than those
described below, may be prepared using the following described
reaction scheme or appropriate variations or modifications
thereof.
[0276] Scheme 3 depicts three variations on the three step
procedure in which different conditions are used in the first step
so as to introduce diverse substituents at the 9-position of the
purine scaffold. In principle, however, a skilled addressee could
modify the general reaction scheme shown in scheme one where the
nitrogen moiety at the 9 position of the purine may be reacted with
a moiety containing a suitable leaving group (such as a halide) in
a reaction whereby the nitrogen displaces the leaving group to form
the compound in which the nitrogen at the 9 position is then
functionalised with the moiety. Suitable leaving groups for use in
reactions of this type which can be displaced by nitrogen in such
reactions are known in the art and in general the synthesis of
moieties containing leaving groups of this type for use in these
types of reactions are also well known to a skilled worker in the
field.
[0277] As shown in Scheme 3 the three simplest routes to the
compounds of the invention involve reaction of the dichloropurine
with either an arylalkyl halide (such as benzyl halide) or a
heteroarylalkyl halide to introduce an aryl or heteroaryl
substituted methyl group at the 9 position, an alcohol (to
introduce a di-substituted methyl group at the 9 position) or an
aryl or heteroaryl boronic acid (to introduce an aryl or heteroaryl
group directly.
##STR00034##
Example 1
Compound 1
Synthesis of 2,6-Dichloro-9-(2,6-difluoro-benzyl)-9H-purine
##STR00035##
[0279] To a stirred solution of 2,6-dichloropurine (5.3 mmol) in 10
ml anhydrous DMSO at room temperature was added anhydrous potassium
carbonate (6.34 mmol) and 2,6-difluorobenzylbromide (6.34 mmol).
The reaction mixture was maintained at this temperature for 20 hrs.
The reaction can be monitored using either TLC or LC/MS. The
reaction mixture was poured in to a beaker containing ice-cold
water. The aqueous layer was acidified to pH 5-6. Extraction of the
aqueous layer, using 3.times.75 ml portions of ethyl acetate,
afforded the crude product. This was purified on the silica gel
column (10-70% ethyl acetate in petroleum ether, step-gradient), to
give the desired compound in a yield of 61%.
Synthesis of
5-[2-chloro-(2,6-difluoro-benzyl)-9H-purin-6-yl]-pyrimidin-2-ylamine
##STR00036##
[0281] A solution of 2,6-dichloro-9-(2,6-difluoro-benzyl)-9H-purine
(1.59 mmol), 5-(4,4,5,5-tetremethyl-[1,3,2]dioxaborolan-2-ylamine
(1.59 mmol) and 1,1'-bis(diphenylphosphino) ferrocene palladium
(II) chloride, complexed with dichloromethane (0.15 mmol), was
taken up in a mixture of peroxide free dioxane (40 ml) and added 2M
aqueous solution of sodium carbonate (6.4 mmol). The reaction mix
was degassed and purged with nitrogen. This reaction mix was then
stirred on an oil bath maintained at 65.degree. C. for 3 h. The
reaction was monitored by LC/MS for the disappearance of the
starting purine.
[0282] The reaction mixture was cooled to room temperature and the
solvents removed under reduced pressure. The residue was taken up
in ethyl acetate and water. The organic phase was separated and the
aqueous layer further extracted with 3.times.100 ml portions of
ethyl acetate. The combined ethyl acetate layers were washed once
with brine solution (25 ml). The organics were dried over sodium
sulfate and the solvents removed under vacuum to give
5-[2-chloro-(2,6-difluoro-benzyl)-9H-purin-6-yl]-pyrimidin-2-ylamine
in 60% yield.
Synthesis of
5-[2-chloro-(2,6-difluoro-benzyl)-2-morpholin-4-yl-9H-purin-6-yl]-pyrimid-
in-2-ylamine
##STR00037##
[0284] To a solution of
5-[2-chloro-(2,6-difluoro-benzyl)-9H-purin-6-yl]-pyrimidin-2-ylamine
(1.12 mmol) in dimethyl acetamide (18 ml) was added morpholine (3.5
mmol). The reaction mix was heated on an oil bath maintained at
94.degree. C. for 12 h. The reaction was monitored for the absence
of the
5-[2-chloro-(2,6-difluoro-benzyl)-9H-purin-6-yl]-pyrimidin-2-ylamine,
by LC-MS. The crude material was directly loaded onto a preparative
HPLC column and purified by chromatography to get the title
compound in a yield of 70%. .sup.1H NMR, DMSO: 9.48 (s, 2H); 8.29
(s, 1H); 7.45 (m, 2H); 7.31 (s, 2H); 7.14 (t, 1H); 5.42 (s, 2H);
3.75 (m, 4H); 3.67 (m, 4H). m/z: 425.27 [MH].sup.+.
Example 2
Compound 2
Synthesis of 9-sec-butyl-2,6-dichloro-9H-purine
##STR00038##
[0286] 2,6-dichloropurine (5.3 mmol), 2-Butanol (9.01 mmol),
triphenylphosphine (7.95 mmol) in 40 ml anhydrous tetrahydrofuran,
to which was added drop-wise diisoproplyazidodicarboxylate (7.95
mmol) at room temperature over a period of 30 minutes. The reaction
mixture was stirred at room temperature for 24 hrs. The reaction is
monitored by TLC or LC/MS. The reaction mixture was poured in to a
beaker containing ice-cold water. Extraction of the aqueous layer,
using 3.times.100 ml portions of ethyl acetate, afforded the crude
product. This was purified on the silica gel column (10-80% ethyl
acetate in petroleum ether, gradient elution), to give the desired
compound in a yield of 50%.
Synthesis of
5-(9-sec-butyl-2-chloro-9H-purin-6-yl)-pyrimidin-2-ylamine
##STR00039##
[0288] A solution of 9-sec-butyl-2,6-dichloro-9H-purine (1.59
mmol), 5-(4,4,5,5-tetremethyl-[1,3,2]dioxaborolan-2-ylamine (1.59
mmol) and 1,1'-bis(diphenylphosphino) ferrocene palladium (II)
chloride, complexed with dichloromethane (0.15 mmol) were taken up
in a mixture of peroxide free dioxane (40 ml) and added 2M aqueous
solution of sodium carbonate (6.4 mmol). The reaction mix was
degassed and purged with nitrogen. This reaction mix was then
stirred on an oil bath maintained at 80.degree. C. for 3 h. The
reaction was monitored by LC/MS for the disappearance of the
starting purine.
[0289] The reaction mixture was cooled to room temperature and the
solvents removed under reduced pressure. The residue was taken up
in ethyl acetate and water. The organic phase was separated and the
aqueous layer further extracted with 3.times.100 ml portions of
ethyl acetate. The organics were dried over sodium sulfate and the
solvents removed under vacuum to give
5-(9-sec-butyl-2-chloro-9H-purin-6-yl)-pyrimidin-2-ylamine in 60%
yield.
Synthesis of
5-(9-sec-butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine
##STR00040##
[0291] To a solution of
5-(9-sec-butyl-2-chloro-9H-purin-6-yl)-pyrimidin-2-ylamine (1.12
mmol) in dimethyl acetamide (18 ml) was added morpholine (3.5
mmol). The reaction mix was heated on an oil bath maintained at
94.degree. C. for 12 h. The reaction was monitored for the absence
of the give
5-(9-sec-butyl-2-chloro-9H-purin-6-yl)-pyrimidin-2-ylamine, by
LC-MS. The crude material was directly loaded onto a preparative
HPLC column and purified by chromatography to get the title
compound in a yield of 70%. .sup.1H NMR, DMSO-d6: 9.52 (s, 2H);
8.27 (s, 1H); 7.28 (s, 2H); 4.5 (m, 2H); 3.8 (m, 4H); 3.70 (m, 4H);
2.0 (m, 1H); 1.9 (m, 1H); 1.6 (d, 3H); 0.79 (t, 3H). m/z: 355.45
[MH].sup.+.
Example 3
Compound 27
Synthesis of 2,6-Dichloro-9-m-tolyl-9H-purine
##STR00041##
[0293] 2,6-Dichloropurine (1.3 mmol), m-Tolyl boronic acid (4.0
mmol), anhydrous cupric acetate (1.32 mmol), 4 .ANG. molecular
sieves (1 g) [1,10]-Phenanthroline (2.64 mmol) in 25 ml of
anhydrous dichloromethane were stirred at room temperature in a
round bottomed flask. The reaction mixture was stirred at room
temperature and monitored by TLC, LC-MS. Reaction was complete
after 24 h. The molecular sieves and inorganic material were
removed by filtration through a celite bed. The bed was thoroughly
washed with methanol. The combined organics were purified by flash
chromatography to yield 50% of the desired compound as a solid.
m/z: 279.02 [MH].sup.+.
Synthesis of
5-(2-chloro-9-m-tolyl-9H-purin-6-yl)-pyrimidin-2-yl-amine
##STR00042##
[0295] 2,6-Dichloro-9-m-tolyl-9H-purine (0.182 mmol),
5-(4,4,5,5-tetremethyl-[1,3,2]dioxaborolan-2-ylamine (0.182 mmol)
and 1,1'-bis(diphenylphosphino) ferrocene palladium (II) chloride,
complexed with dichloromethane (0.018 mmol) were taken up in a
mixture of peroxide free dioxane (40 ml) and added 2M aqueous
solution of sodium carbonate (0.730 mmol). The reaction mix was
degassed and purged with nitrogen. This reaction mix was then
stirred on an oil bath maintained at 40.degree. C. for 2 h. The
reaction was monitored by LC/MS for the disappearance of the
starting purine. The reaction mixture was cooled to room
temperature and the solvents removed under reduced pressure. The
residue was taken up in ethyl acetate and water. The organic phase
was separated and the aqueous layer further extracted with
3.times.100 ml portions of ethyl acetate. The organics were dried
over sodium sulfate and the solvents removed under vacuum to give
5-(2-chloro-9-m-tolyl-9H-purin-6-yl)-pyrimidin-2-yl-amine. This
crude material was taken directly to the next step without further
purification.
Synthesis of
5-(2-morpholin-4-yl-9-m-tolyl-9H-purin-6-yl)-pyrimidin-2-yl-amine
##STR00043##
[0297] To a solution of
5-(2-chloro-9-m-tolyl-9H-purin-6-yl)-pyrimidin-2-yl-amine (0.182
mmolmmol) in dimethyl acetamide (4 ml) was added morpholine (0.4
mmol). The reaction mix was heated on an oil bath maintained at
94.degree. C. for 12 h. The reaction was monitored for the absence
of the give
5-(2-chloro-9-m-tolyl-9H-purin-6-yl)-pyrimidin-2-yl-amine, by
LC-MS. The crude material was directly loaded onto a preparative
HPLC column and purified by chromatography to give the title
compound. m/z: 389.2 [MH].sup.+.
Example 4
Compound 33
Synthesis of
{3-[6-(2-Amino-pyrimidin-5-yl)-2-morpholin-4-yl-purin-9-yl]-pyrrolidin-1--
yl}-(5-methyl-thiophen-2-yl)-methanone
##STR00044##
[0299]
{3-[6-(2-Amino-pyrimidin-5-yl)-2-morpholin-4-yl-purin-9-yl]pyrrolid-
in-1-yl}-(5-methyl-thiophen-2-yl)-methanone was prepared from the
corresponding Boc protected compound
(3-[6-(2-amino-pyrimidin-5-yl)-2-morpholin-4-yl-purin-9-yl]-pyrrolidine-1-
-carboxylic acid tert-butyl ester) using a standard deprotection
protocol. This intermediate was in turn prepared using the same
three step procedure employed in the synthesis of
5-(9-sec-butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine
(compound 2) starting from the commercially available Boc protected
aminoalcohol 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl
ester.
[0300] To a solution of
5-(2-morpholin-4-yl-9-pyrrolidin-3-yl-9H-purin-6-yl)-pyrimidin-2-ylamine
(37 mg, 0.08 mmol) in DMF was added 5-methyl-thiophene-2-carboxylic
acid (15 mg, 0.104 mmol, 1.3 eq), EDC (20 mg, 0.104 mmol, 1.3 eq),
HOBt (14 mg, 0.104 mmol, 1.3 eq) and diisopropylethylamine (32
.mu.L, 0.184 mmol, 2.3 eq). The mixture was stirred at 50.degree.
C. for 16 hrs. Then NaHCO.sub.3 was added and the mixture extracted
twice with ethyl acetate. The combined organic layers were further
washed with brine before drying over Na.sub.2SO.sub.4. The crude
product was purified by chromatography to afford the title compound
as yellow solid (14.4 mg).
[0301] .sup.1H NMR, CDCl.sub.3: 9.74 (2H, s), 7.80 (1H, s), 7.39
(3H, s), 6.77 (1H, d, J=3.3), 5.19-5.13 (1H, m), 4.33 (1H, b s),
4.24-4.19 (1H, m), 4.09-4.04 (1H, m), 4.00 (1H, b s), 3.87-3.79
(8H, m), 2.61-2.56 (2H, m), 2.52 (3H, s). m/z: 492 [MH].sup.+.
Example 5
Compound 40
Synthesis of
5-(8-Bromo-9-sec-butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamin-
e
##STR00045##
[0303] To a solution of
5-(9-sec-Butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine,
(200 mg, 0.57 mmol) in 15 ml of chloroform, was added slowly NBS,
(120 mg, 0.68 mmol) at a temperature of 5.degree. C. The reaction
was continued for 2 hours at this temperature. After simple
work-up, the product
5-(8-Bromo-9-sec-butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamin-
e was purified by flash column (solvent system: 50% ethyl acetate
in hexane) to deliver the desired compound. in a yield of 49% (120
mg).
Synthesis of
5-(9-sec-Butyl-8-methyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylami-
ne
##STR00046##
[0305] To a solution of
5-(8-Bromo-9-sec-butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamin-
e, (20 mg, 0.046 mmol), Pd(dppf)Cl.sub.2, (3 mg, 8% mmol) in 3 ml
of anhydrous dioxane, was added slowly dimethyl zinc (230 .mu.l,
1.0M in heptane solution). The mixture was heated to about
65.degree. C. until in the sealed tube. MeOH was added dropwise and
solvents were removed in vacuo. EtOAc was added to the residue and
the resulting solution washed with 1 M HCl, water, brine and then
dried over Na.sub.2SO.sub.4. The solvent was removed and the crude
mixture was subjected to flash chromatography to obtain
5-(9-sec-Butyl-8-methyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylami-
ne 8 mg in a yield of 47%. .sup.1H NMR, MeOD: 9.45 (s, 2H); 4.55
(m, 1H); 3.87 (m, 4H); 3.80 (s, 4H); 2.69 (s, 3H); 2.43 (m, 1H);
2.02 (m, 1H); 1.71 (d, 3H); 0.86 (t, 3H). m/z: 369.22
[MH].sup.+.
[0306] The compounds outlined in Table 1 were synthesized following
the procedures outlined above or variations thereof typically by
variation of the starting materials used.
TABLE-US-00001 TABLE 1 Synthesised compounds Cmpd No Structure
1H-NMR MS(M + 1) 1 ##STR00047## (DMSO-d6) .delta. 9.48(s, 2H);
8.29(s, 1H); 7.45(m, 2H); 7.31(s, 2H); 7.14(t, 1H); 5.42(s, 2H);
3.75(m, 4H); 3.67(m, 4H). 425.27 2 ##STR00048## (DMSO-d6) .delta.
9.52(s, 2H); 8.27(s, 1H); 7.28(s, 2H); 4.5(m, 2H); 3.8(m, 4H);
3.70(m, 4H); 2.0(m, 1H); 1.9(m, 1H); 1.6(d, 3H); 0.79(t, 3H).
355.45 3 ##STR00049## (DMSO-d6) .delta. 9.52(s, 2H); 8.27(s, 1H);
7.28(s, 2H); 4.01(m, 2H); 3.8(m, 4H); 3.70(m, 4H), 1.3(m, 1H);
0.54(m, 2H); 0.52(m, 2H). 353.40 4 ##STR00050## (CDCl.sub.3)
.delta. 10.0(s, 2H); 9.4(s, 1H); 7.9(s, 1H); 7.45-7.35(m, 5H);
5.4(s, 2H); 3.9(m, 4H); 3.8(m, 4H). 374.32 5 ##STR00051## (DMSO-d6)
.delta. 9.54(s, 2 H); 8.27(s, 1H); 7.28(s, 2H); 4.6(m, 2H); 3.8(m,
4H); 3.70(m, 4H); 3.65(m, 2H); 1.55(d, 3H); 0.9(s, 9H). 413.41 6
##STR00052## (DMSO-d6) .delta. 9.97(s, 2H); 9.34(s, 1H); 8.50(s,
1H); 4.5(m, 1H); 3.9(m, 4H); 3.8(m, 4H); 2.0(m, 1H); 1.9(m, 1H);
1.6(d, 3H); 0.79(t, 3H). 340.50 7 ##STR00053## (MeOD) .delta. 9.28
(s, 2H), 8.08 (s, 1H), 5.03 (m, 1H), 4.34 (m, 4H), 3.85 (m, 4H),
2.30 (m, 2H), 2.03 (m, 4H), 1.85 (m, 2H). 367 8 ##STR00054##
(DMSO-d6) .delta. 8.74(s, 1H); 8.4(s, 1H); 7.6(bs, 2H); 4.5(m, 1H);
4.0(s, 3H); 3.8(m, 4H); 3.7(m, 4H); 2.0(m, 1H); 1.9(m, 1H); 1.6(d,
3H); 0.79(t, 3H). 385.46 9 ##STR00055## (DMSO-d6) .delta. 9.54(s,
2H); 8.45(s, 1H); 7.42-7.22(m, 5H); 5.8(m, 1H); 3.8(m, 4H); 3.7(m,
4H); 2.0(d, 3H). 403.39 10 ##STR00056## (DMSO-d6) .delta. 9.53(s,
2H); 8.35(s, 1H); 7.28(s, 2H); 3.86(m, 1H); 3.78(m, 4H); 3.72(m,
4H); 1.62(d, 3H); 1.5(m, 1H); 0.7(m, 1H); 0.5(m, 2H); 0.4(m, 1H).
367.46 11 ##STR00057## (DMSO-d6) .delta. 8.73(s, 1H); 8.5(s, 1H);
7.28(s, 2H); 4.0(s, 3H); 3.86(m, 1H); 3.78(m, 4H); 3.72(m, 4H);
1.62(d, 3H); 1.5(m, 1H); 0.7(m, 1H); 0.5(m, 2H); 0.4(m, 1H). 397.41
12 ##STR00058## (DMSO-d.sub.6) .delta. 9.53 (s, 2H), 8.26 (s, 1H),
4.81 (m, 1H), 3.84 (m, 4H), 3.71 (m, 4H), 3.62 (m, 2H), 3.23 (s,
3H), 1.50 (d, 3H). 371 13 ##STR00059## (DMSO-d6) .delta. 8.72(s,
1H); 8.34(s, 1H); 7.66(bs, 2H); 4.8(m, 1H); 4.0(s, 3H); 3.9(m, 1H);
3.8-3.7(m, 8H); 3.6(m, 1H); 3.3(s, 3H); 1.5(d, 3H). 401.41 14
##STR00060## (CDCl.sub.3) .delta. 9.16(s, 1H); 7.84(s, 1H); 4.6(m,
1H); 3.86(m, 8H); 2.88(s, 3H); 2.0(m, 2H); 1.65(d, 3H); 0.94(t,
3H). 369.31 15 ##STR00061## (CDCl.sub.3) .delta. 9.16(s, 1H);
7.84(s, 1H); 3.86(m, 8H); 2.88(s, 3H); 1.65(d, 3H); 1.4(m, 2H);
0.81(m, 1H); 0.6(m, 1H); 0.46(m, 2H); 381.29 16 ##STR00062##
(CDCl.sub.3) .delta. 9.13(s, 1H); 7.99(s, 1H); 7.6(bs, 2H); 4.75(m,
1H); 3.9(m, 1H); 3.8-3.7(m, 8H); 3.6(m, 1H); 3.4(s, 3H); 2.8(s,
3H); 1.6(d, 3H). 385.3 17 ##STR00063## (CDCl.sub.3) .delta. 9.16(s,
1H); 7.84(s, 1H); 7.4(m, 5H); 5.9(m, 1H); 3.86(m, 8H); 2.88(s, 3H);
2.0(d, 3H). 417.31 18 ##STR00064## (DMSO-d6) .delta. 9.52(s, 2H);
8.2(s, 1H); 7.3(s, 2H); 5.2(m, 1H); 4.2(m, 1H); 4.1(m, 2H); 3.9(m,
1H); 3.8(m, 4H); 3.7(m, 4H); 2.4(m, 2H). 369.24 19 ##STR00065##
(MeOD) .delta. 9.68 (s, 2H), 8.27 (s, 1H), 4.65 (m, 1H), 4.28 (m,
2H), 3.91 (m, 4H), 3.80 (m, 4H), 3.01 (m, 2H), 2.23 (m, 2H), 2.10
(m, 2H), 1.51 (s, 9H). 482 20 ##STR00066## (CDCl.sub.3) .delta.
10.4(bs, 1H); 9.9(s, 1H); 9.6(s, 1H); 7.9(s, 1H); 4.6(m, 1H);
3.9(m, 4H); 3.8(m, 4H); 3.3(d, 3H); 2.0(m, 2H); 1.6(d, 3H); 1.0(t,
3H). 369.30 21 ##STR00067## (MeOD) .delta. 9.46 (s, 2H), 8.07 (s,
1H), 4.74 (m, 2H), 4.01 (m, 1H), 3.77 (m, 4H), 3.68 (m, 4H), 2.75
(m, 1H), 2.34 (m, 2H), 2.10 (m, 5H), 1.57 (m, 2H), 0.91 (m, 3H).
452 22 ##STR00068## (DMSO-d6) .delta. 9.53(s, 2H); 8.3(s, 1H);
7.33(bs, 2H); 4.31(m, 1H); 3.77(m, 4H); 3.72(m, 4H); 2.4(m, 1H);
1.5(d, 3H); 1.0(m, 3H); 0.7(m, 3H). 369.28 23 ##STR00069##
(DMSO-d6) .delta. 9.56(s, 2H); 8.35(s, 1H); 7.40(bs, 2H); 5.81(t,
1H); 3.9(m, 4H); 3.8(m, 4H); 2.4(m, 2H); 0.9(t, 3H). 366.18 24
##STR00070## (DMSO-d6) .delta. 9.54(s, 2H); 8.28(s, 1H); 7.37(bs,
2H); 4.3(m, 1H); 3.8(m, 4H); 3.7(m, 4H); 2.0(m, 4H); 0.7(t, 6H).
369.21 25 ##STR00071## (DMSO-d6) .delta. 9.52(s, 2H); 8.27(s, 1H);
7.28(s, 2H); 4.5(m, 2H); 3.8(m, 4H); 3.70(m, 4H); 2.0(m, 1H);
1.9(m, 1H); 1.6(d, 3H); 0.79(t, 3H). 355.45 26 ##STR00072##
(DMSO-d6) .delta. 9.52(s, 2H); 8.27(s, 1H); 7.28(s, 2H); 4.5(m,
2H); 3.8(m, 4H); 3.70(m, 4H); 2.0(m, 1H); 1.9(m, 1H); 1.6(d, 3H);
0.79(t, 3H). 355.45 27 ##STR00073## (DMSO-d6) .delta. 9.56(s, 2H);
8.64(s, 1H); 7.73(m, 2H); 7.50(t, 1H); 7.36(s, 2H); 7.28(m, 1H);
3.78(m, 4H); 3.73(m, 4H); 2.38(s, 3H). 389.14 28 ##STR00074##
(DMSO-d6) .delta. 9.46 (2 H, s); 8.25 (1 H, s); 7.35 (2H, brs);
5.21-5.14 (1H, m); 3.73-3.60 (10H, m); 3.58- 3.50 (1H, m); 3.39-
3.30 (1H, m); 2.46 (2H, overlapping). 368.17 29 ##STR00075##
(DMSO-d6) .delta. 9.54(s, 2H); 8.18(s, 1H); 3.66(s, 2H); 3.78(m,
4H); 3.73(m, 4H). 369.15 30 ##STR00076## (DMSO-d6) .delta. 9.54(s,
2H); 8.32 (s, 1H); 7.34(bs, 2H); 7.16(m, 4H); 4.82(m, 1H); 3.78(m,
4H); 3.43(m, 4H); 3.21-3.0(m, 6H). 429.19 31 ##STR00077## (DMSO-d6)
.delta. 9.52(s, 2H); 8.21 (s, 1H); 7.33(bs, 2H); 7.24(m, 4H);
5.35(m, 1H); 3.78(m, 4H); 3.63(m, 4H); 3.58-3.40 (m, 4H). 415.15 32
##STR00078## na 472.18 33 ##STR00079## (CDCl3) .delta. 9.74 (2 H,
s); 7.80 (1 H, s); 7.39 (3H, s); 6.77 (1H, d); 5.19-5.13 (1H, m);
4.33 (1H, b s); 4.24-4.19 (1H, m); 4.09- 4.04 (1H, m); 4.00 (1H, b
s); 3.87-3.79 (8H, m); 2.61-2.56 (2H, m); 2.52 (3H, s). 492.19 34
##STR00080## (DMSO-d6): .delta. 12.83 (1H, bs, D.sub.2O
exchangeable proton); 9.51 (2H, s); 8.15 (1H, s); 7.25 (2H, s,
D.sub.2O exchangeable protons); 3.73-3.74 (4H, d); 3.69- 3.70 (4H,
d). 299.00 35 ##STR00081## (DMSO-d6): .delta. 9.51 (2H, s);
8.27-8.25 (1H, d); 7.25 (2H, s, D.sub.2O exchangeable proton);
4.72-4.70 (1H, d); 4.51- 4.46 (1H, m); 4.37-4.35 (1H, d); 3.96-3.95
(1H, d), 3.77-3.74 (1H, d); 3.65-3.63 (1H, d); 3.51- 3.48 (1H, t);
3.23-3.19 (1H, m); 2.05-1.85 (2H, m); 1.54-1.52 (3H, q); 1.22-1.20
(3H, q); 0.78- 0.74 (3H, q). 369.10 36 ##STR00082## (DMSO-d6)
.delta. 9.53 (2 H, s); 8.35 (1 H, s); 7.37 (2H, bs); 4.37-4.31 (1H,
m); 3.77 (4H, m); 3.72 (4H, m); 2.31-2.21 (2H, m); 1.99-1.91 (1H,
m); 1.78- 1.65 (4H, m); 1.57- 1.52 (2H, m); 1.07 (3H, d, J = 7.1).
295.21 37 ##STR00083## Mixture of Diastereomers (2:1): (DMSO-d6):
.delta. 9.50 (2H, s), 9.50 (2H, s); 8.26 (1H, s), 8.28 (1H, s);
7.26 (2H, s), 7.26 (2H, s); 4.95- 4.92 (1H, m), 4.83-4.80 (1H, m);
3.77 (4H, s), 3.77 (4H, s); 3.71-3.69 (4H, t), 3.71-3.69 (4H, t);
2.40- 2.35 (1H, m), 2.40-2.35 (1H, m); 2.30-2.13 (2H, m), 2.30-2.13
(2H, m); 2.08-2.02 (3H, m), 1.89- 1.88 (1H, m), 1.77-1.70 (2H, m);
1.55-1.53 (1H, m), 1.32-1.21 (1H, m); 1.10-1.08 (3H, d), 1.04- 1.02
(3H, d). 381.20 38 ##STR00084## (DMSO-d6) .delta. 9.53(s, 2H);
8.55(s, 1H); 8.20(s, 2H); 7.90(d, 2H); 7.56(t, 2H); 7.40(t, 1H);
3.77(m, 4H); 3.70(m, 4H). 375.15 39 ##STR00085## (DMSO-d6) .delta.
9.52(s, 2H); 8.20(s, 1H); 7.29(s, 2H); 5.18(m, 1H); 4.16(m, 1H);
3.96(m, 2H); 3.86(m, 1H); 3.79(m, 4H); 3.68(m, 4H); 2.43(m, 2H).
369.10 40 ##STR00086## (MeOD) .delta. 9.45 (s, 2H), 4.55 (m, 1H),
3.87 (m, 4H), 3.80 (m, 4H), 2.69 (s, 3H), 2.43 (m, 1H), 2.02 (m,
1H), 1.71 (d, 3H), 0.86 (t, 3H). 369.22 41 ##STR00087## (MeOD)
.delta. 9.44 (s, 2H), 4.64 (m, 1H), 3.77 (m, 4H), 3.69 (m, 4H),
2.89 (m, 2H), 1.61 (d, 6H), 1.21 (t, 3H). 369.21 42 ##STR00088##
(MeOD) .delta. 9.58 (s, 2H), 4.64 (m, 1H), 3.87 (m, 4H), 3.80 (m,
4H), 2.46 (m, 1H), 2.00 (m, 1H), 1.71 (d, 3H), 0.82 (t, 3H).
434
Biological Testing
[0307] mTOR Assay
[0308] Truncated mTOR kinase and His-tagged 4eBP1 were produced
in-house. [.gamma..sup.33P]-ATP was purchased from Amersham (GE
Healthcare). All chemicals, unless otherwise stated, were from
Sigma-Aldrich.
[0309] Phosphorylation assays were initially performed in a final
volume of 20 .mu.L in 384-well polypropylene plate (Greiner).
Compounds were typically tested over the range from 100 .mu.M to
0.006 .mu.M, in 8 step dilutions, in duplicate. 10 .mu.L/well of
2.times. Enzyme-Substrate solution (1.5 .mu.g/mL mTOR, 40 .mu.g/mL
4eBP1 in 1.times. assay buffer: 10 mM Hepes pH 7.5, 50 mM NaCl and
10 mM MnCl.sub.2) were first added to the sample plate containing 1
.mu.L/well of test compound in neat DMSO. The reaction was
initiated by adding 10 .mu.L/well of 20 .mu.M ATP solution (final
assay concentration 10 .mu.M ATP and 0.4 .mu.Ci/well of [.gamma.hu
33P]-ATP). After 1 hour incubation at room temperature, the
reaction was terminated with 40 .mu.L/well of 20 mM EDTA/1 mM ATP
solution.
[0310] 50 .mu.L/well of the stopped reaction mix was then
transferred to 384-well MultiScreenHTS-PH filter plate (Millipore)
pre-added with 50 .mu.L/well of 1% phosphoric acid. The plate was
washed 4 times with 120 .mu.L/well of 0.5% phosphoric acid via
vacuum filtration. Finally, 10 .mu.L/well of Optiphase.TM. SuperMix
liquid scintillation cocktail (Perkin Elmer) was added. After
minimum 1 hour of incubation, counting was performed in a Wallac
MicroBeta TriLux scintillation counter using coincidence counting
mode with crosstalk correction. IC.sub.50 is defined as the
concentration of compound required for 50% inhibition of kinase
enzyme activity. IC.sub.50 data are shown in Table 2 below.
PI3K Assay
[0311] Recombinant PI3K p110.alpha./p85 was prepared in-house.
Phosphatidylinositol (PtdIns), phosphotidylserine (PtdSer) and all
other unspecified chemicals were purchased from Sigma-Aldrich.
[.gamma..sup.33P]ATP and Optiphase scintillant were obtained from
Perkin Elmer.
[0312] Assays were performed in a final assay volume of 25 .mu.L in
384-well Maxisorp plates (Nunc). Compounds were tested at 8
concentrations in 3-fold serial dilution, generally starting from
10 .mu.M. Maxisorp plates were coated with 20 .mu.L/well of a 1:1
mixture of PtdIns and PtdSer [0.1 mg/mL each dissolved in
chloroform:ethanol (3:7)] and left overnight in a fume hood at room
temperature (RT) to dry.
[0313] The enzyme reaction was created by pipetting 5 .mu.L/well of
compound (in 2.5% DMSO), 10 .mu.L/well of enzyme (0.5 .mu.g/mL
p110.alpha.+1 .mu.g/mL p85), and 10 .mu.L/well of 5 .mu.M ATP with
5 .mu.Ci/mL [.gamma..sup.33P]ATP in assay buffer (final
concentrations: 0.2 .mu.g/mL p110.alpha., 2 .mu.M ATP, 0.05
.mu.Ci/well [.gamma..sup.33P]ATP in 1.times. assay buffer: 100 mM
Tris-HCl pH 7.0, 200 mM NaCl, 8 mM MgCl.sub.2). The reaction was
incubated for 1 hour at RT and terminated with 30 .mu.L/well of 50
mM EDTA solution. The plate was then washed twice with TBS, dried,
and added with 30 .mu.L/well of scintillant before it was counted
in a MicroBeta Trilux. IC.sub.50 is defined as the concentration of
compound required for 50% inhibition of kinase enzyme activity.
IC.sub.50 data are shown in Table 2 below.
TABLE-US-00002 TABLE 2 In vitro mTOR and PI3K inhibition activity
assay IC.sub.50 data Compound IC.sub.50 IC.sub.50 Number (mTOR)*
(PI3K.alpha.)* 1 ++ +++ 2 +++ +++ 3 +++ +++ 4 + +++ 5 ++ +++ 6 ++
+++ 7 +++ +++ 8 +++ +++ 9 ++ +++ 10 +++ +++ 11 ++ +++ 12 +++ +++ 13
++ +++ 14 + +++ 15 + +++ 16 + +++ 17 + +++ 18 +++ +++ 19 +++ +++ 20
+++ +++ 21 +++ +++ 22 +++ +++ 23 +++ +++ 24 +++ +++ 25 +++ +++ 26
+++ +++ 27 +++ +++ 28 ++ na 29 +++ +++ 30 +++ +++ 31 +++ +++ 32 +++
+++ 33 +++ +++ 34 ++ +++ 35 +++ +++ 36 +++ +++ 37 +++ +++ 38 +++
+++ *+++ <1 .mu.M ++ 1 .mu.M-5 .mu.M + >5 .mu.M na not
available
Cell-Based Proliferation Assay
[0314] The biological efficacy of the invention was demonstrated by
the following assay. Human cancer cell lines PC3 and DU145 (human
prostate cancer cell lines), were obtained from ATCC. They were
cultured in the media according to the ATCC work instructions. PC3
and DU145 cells were seeded at 1,000 cells per well in 96-well
plates, respectively. The plates were incubated at 37.degree. C.,
5% CO.sub.2, for 24 h. Cells were treated with compounds at various
concentrations for 96 h. Cell proliferation was then quantified
using Celltiter96 Aqueous One Solution Cell Proliferation Assay
from Promega (Madison Wis.). Dose response curves were plotted to
determine IC.sub.50 values for the compounds using XL-fit (ID
Business Solution, Emeryville, Calif.). IC.sub.50 is defined as the
concentration of compound required for 50% inhibition of cell
proliferation. The compounds of this invention inhibited cell
proliferation as shown in Table 3 below. The data indicated that
the compounds of this invention are active in the inhibition of
tumour cell growth. IC.sub.50 data are shown in Table 3 below.
TABLE-US-00003 TABLE 3 Cell-based proliferation assay IC.sub.50
data Compound No. PC3 DU145 2 +++ NT 3 NT ++ 10 +++ NT 18 +++ NT 19
+++ NT 21 +++ NT 22 +++ NT 23 +++ NT 25 +++ NT 26 +++ NT 29 +++ NT
35 +++ NT 37 +++ NT 42 +++ NT NT = not tested IC.sub.50 .ltoreq. 1
.mu.M +++ 1 .mu.M < IC.sub.50 .ltoreq. 5 .mu.M ++ IC.sub.50 >
5 .mu.M +
In Vivo Antineoplastic (or Anti-Tumour) Effect:
[0315] The efficacy of the compounds of the invention can then be
determined using in vivo animal xenograft studies. The animal
xenograft model is one of the most commonly used in vivo cancer
models.
[0316] In these studies, female athymic nude mice, 12-14 weeks of
age would be implanted subcutaneously in the flank with
5.times.10.sup.6 cells of PC-3 human prostate cancer cell line in
50% Matrigel (BD Biosciences). When the tumour reaches the size 100
mm.sup.3, the xenograft nude mice would be paired-match into
various treatment groups. The selected kinase inhibitors would be
dissolved in appropriate vehicles and administered to the xenograft
nude mice intraperitoneally or orally daily for 28 days. The dosing
volume will be 0.01 ml/g body weight. Tumour volume will be
calculated twice weekly post-injection using the formula: Volume
(mm.sup.3)=(w.sup.2.times.l)/2, where w=width and l=length in mm of
a MV4-11tumour. Compounds of this invention that have been tested
show significant reduction in tumour volume relative to controls
treated with vehicle only. The result will therefore indicate that
compounds of this invention are efficacious in treating a
proliferative disease such as cancer.
[0317] The details of specific embodiments described in this
invention are not to be construed as limitations. Various
equivalents and modifications may be made without departing from
the essence and scope of this invention, and it is understood that
such equivalent embodiments are part of this invention.
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