Note: Descriptions are shown in the official language in which they were submitted.
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
Substituted Pyridine Derivatives Useful
in the Treatment of Cancer and other Disorders
s Field of the Invention
This invention relates to novel compounds, pharmaceutical compositions
containing such compounds and the use of those compounds or compositions for
treating hyper-proliferative and angiogenesis disorders, as a sole agent or in
combination with other active ingredients, e.g., cytotoxic therapies.
to
Background of the Invention
Activation of the ras signal transduction pathway indicates a cascade of
events that have a profound impact on cellular proliferation, differentiation,
and
transformation. Raf kinase, a downstream effector of ras, is recognized as a
key
is mediator of these signals from cell surface receptors to the cell nucleus
(Lowy, D. R.;
Willumsen, B. M. Ann. Rev. Biochem. 1993, 62, 851; Bos, J. L. Cancer Res.
1989,
49, 4682). It has been shown that inhibiting the effect of active ras by
inhibiting the
raf kinase signaling pathway by administration of deactivating antibodies to
raf kinase
or by co-expression of dominant negative raf kinase or dominant negative MEK,
the
2o substrate of raf kinase, leads to the reversion of transformed cells to the
normal
growth phenotype (see: Daum et al. Trends Biochem. Sci. 1994, 19, 474-80;
Fridman
et al. J. Bi~I. Chem. 1994, 269, 30105-8. Kolch et al. (Nature 1991, 349, 426-
28)
have further indicated that inhibition of raf expression by antisense RNA
blocks cell
proliferation in membrane-associated oncogenes. Similarly, inhibition of raf
kinase
2s (by antisense oligodeoxynucleotides) has been correlated in vitro and in
vivo with
inhibition of the growth of a variety of human tumor types (Monia et al., Nat.
Med.
1996, 2, 668-75). Some examples of small molecule inhibitors of Raf kinase
activity
are important agents for the treatment of cancer. (Naumann, U.; Eisenmann-
Tappe,
I.; Rapp, U. R. Recent Results Cancer Res. 1997, 143, 237; Monia, B. P.;
Johnston,
3o J. F.; Geiger, T.; Muller, M.; Fabbro, D. Nature Medicine 1996, 2, 668).
1
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To support progressive tumor growth beyond the size of 1-2 mm3, it is
recognized that tumor cells require a functional stroma, a support structure
consisting
of fibroblast, smooth muscle cells, endothelial cells, extracellular matrix
proteins, and
soluble factors (Folkman, J., Semin Oncol, 2002. 29(6 Suppl 16), 15-8). Tumors
s induce the formation of stromal tissues through the secretion of soluble
growth
factors such as PDGF and transforming growth factor-beta (TGF-beta), which in
turn
stimulate the secretion of complimentary factors by host cells such as
fibroblast
growth factor (FGF), epidermal growth factor (EGF), and vascular endothelial
growth
factor (VEGF). These stimulatory factors induce the formation of new blood
vessels,
to or angiogenesis, which brings oxygen and nutrients to the tumor and allows
it to grow
and provides a route for metastasis. It is believed some therapies directed at
inhibiting stroma formation will inhibit the growth of epithelial tumors from
a wide
variety of histological types. (George, D. Semin Oncol, 2001. 28(5 Suppl 17),
27-33;
Shaheen, R.M., et al., Cancer Res, 2001. 61 (4), 1464-8; Shaheen, R.M., et al.
is Cancer Res, 1999. 59(21 ), 5412-6). However, because of the complex nature
and
the multiple growth factors involved in angiogenesis process and tumor
progression,
an agent fiargeting a single pafihway may have limited efficacy. It is
desirable to
provide treatment against a number of key signaling pathways utilized by
tumors to
induce angiogenesis in the host stroma. These include PDGF, a potent
stimulator of
2o stroma formation (Ostman, A. and C.H. Heldin, Adv Cancer Res, 2001, 80, 1-
38),
FGF, a chemo-attractant and mitogen for fibroblasts and endothelial cells, and
VEGF, a potent regulator of vascularization.
PDGF is another key regulator of stromal formation which is secreted by many
2s tumors in a paracrine fashion and is believed to promote the growth of
fibroblasts,
smooth muscle and endothelial cells, promoting stroma formation and
angiogenesis.
PDGF was originally identified as the v-sis oncogene product of the simian
sarcoma
virus (Heldin, C.H., et al., J Cell Sci Suppl, 1985, 3, 65-76). The growth
factor is
made up of two peptide chains, referred to as A or B chains which share 60%
3o homology in their primary amino acid sequence. The chains are disulfide
cross linked
2
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
to form the 30 kDa mature protein composed of either AA, BB or AB homo- or
heterodimmers. PDGF is found at high levels in platelets, and is expressed by
endothelial cells and vascular smooth muscle cells. In addition, the
production of
PDGF is up regulated under low oxygen conditions such as those found in poorly
s vascularized tumor tissue (Kourembanas, S., et al., Kidney Int, 1997, 51
(2), 438-43).
PDGF binds with high affinity to the PDGF receptor, a 1106 amino acid 124 kDa
transmembrane tyrosine kinase receptor (Heldin, C.H., A. Ostman, and L.
Ronnstrand, Biochim Biophys Acta, 1998. 1378(1 ), 79-113). PDGFR is found as
homo- or heterodimer chains which have 30% homology overall in their amino
acid
to sequence and 64% homology between their kinase domains (Heldin, C.H., et
al..
Embo J, 1988, 7(5), 1387-93). PDGFR is a member of a family of tyrosine kinase
receptors with split kinase domains that includes VEGFR2 (KDR), VEGFR3 (FIt4),
c-
Kit, and FLT3. The PDGF receptor is expressed primarily on fibroblast, smooth
muscle cells, and pericytes and to a lesser extent. on neurons, kidney
mesangial,
is Leydig, and Schwann cells of the central nervous system. Upon binding to
the
receptor, PDGF induces receptor dimerization and undergoes auto- and trans-
phosphorylation of tyrosine residues which increase the receptors' kinase
activity and
promotes the recruitment of downstream effectors through the activation of SH2
protein binding domains. A number of signaling molecules form complexes with
2o activated PDGFR including Pl-3-kinase, phospholipase C-gamma, src and GAP
(GTPase activating protein for p21-ras) (Soskic, V., et al. Biochemistry,
1999, 38(6),
1757-64). Through the activation of PI-3-kinase, PDGF activafies the Rho
signaling
pathway inducing cell motility and migration, and through the activation of
GAP,
induces mitogenesis through the activation of p21-ras and the MAPK signaling
Zs pathway.
In adults, it is believed the major function of PDGF is to facilitate and
increase
the rate of wound healing and to maintain blood vessel homeostasis (Baker,
E.A. and
D.J. Leaper, Wound Repair Regen, 2000. 8(5), 392-8; Yu, J., A. Moon, and H.R.
3o Kim, Biochem Biophys Res Commun, 2001. 282(3), 697-700). PDGF is found at
high
3
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
concentrations in platelets and is a potent chemoattractant for fibroblast,,
smooth
muscle cells, neutrophils and macrophages. In addition to its role in wound
healing
PDGF is known to help maintain vascular homeostasis. During the development of
new blood vessels, PDGF recruits pericytes and smooth muscle cells that are
s needed for the structural integrity of the vessels. PDGF is thought to play
a similar
role during tumor neovascularization. As part of its role in angiogenesis PDGF
controls interstitial fluid pressure, regulating the permeability of vessels
through its
regulation of the interaction between connective tissue cells and the
extracellular
matrix. Inhibiting PDGFR activity can lower interstitial pressure and
facilitate the
to influx of cytotoxics into tumors improving the anti-tumor efficacy of these
agents
(Pietras, K., et al. Cancer Res, 2002. 62(19), 5476-84; Pietras, K., et al.
Cancer Res,
2001. 61 (7), 2929-34).
PDGF can promote tumor growth through either the paracrine or autocrine
is stimulation of PDGFR receptors on stromal cells or tumor cells directly, or
through
the amplification of the receptor or activation of the receptor by
recombination. Over
expressed PDGF can transform human melanoma cells and keratinocytes (Forsberg,
K., et al. Proc Natl Acad Sci U S A., 1993. 90(2), 393-7; Strobe, M. and N.E.
Fusenig,
Proc Natl Acad Sci U S A, 1998. 95(3), 1050-5), two cell types that do not
express
2o PDGF receptors, presumably by the direct effect of PDGF on stroma formation
and
induction of angiogenesis. This paracrine stimulation of tumor stroma is else
observed in carcinomas of the colon, lung, breast, and prostate (Bhardwaj, B.,
et al.
Clin Caneer Res, 1996, 2(4), 773-82; Nakanishi, K., et al. Mod Pathol, 1997,
10(4),
341-7; Sundberg, C., et al. Am J Pathol, 1997, 151(2), 479-92; Lindmark, G.,
et al.
2s Lab Invest, 1993, 69(6), 682-9; Vignaud, J.M., et al, Cancer Res, 1994,
54(20), 5455-
63) where the tumors express PDGF, but not the receptor. The autocrine
stimulation
of tumor cell growth, where a large faction of tumors analyzed express both
the
ligand PDGF and the receptor, has been reported in glioblastomas (Fleming,
T.P., et
al. Cancer Res, 1992, 52(16), 4550-3), soft tissue sarcomas (Wang, J., M.D.
3o Coltrera, and A.M. Gown, Cancer Res, 1994, 54(2), 560-4) and cancers of the
ovary
4
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
(Henriksen, R., et al. Cancer Res, 1993, 53(19), 4550-4), prostate (Fudge, K.,
C.Y.
Wang, and M.E. Stearns, Mod Pathol, 1994, 7(5), 549-54), pancreas (Funs, K.,
et al.
Cancer Res, 1990, 50(3), 748-53) and lung (Antoniades, H.N., et al., Proc Natl
Acad
Sci U S A, 1992, 89(9), 3942-6). Ligand independent activation of the receptor
is
s found to a lesser extent but has been reported in chronic myelomonocytic
leukemia
(CMML) where the a chromosomal translocation event forms a fusion protein
between the Ets-like transcription factor TEL and the PDGF receptor. In
addition,
activating mutations in PDGFR have been found in gastrointestinal stromal
tumors in
which c-Kit activation is not involved (Heinrich, M.C., et al., Science, 2003,
9, 9).
io Certain PDGFR inhibitors will interfere with tumor stromal development and
are
believed to inhibit tumor growth and metastasis.
Another major regulator of angiogenesis and vasculogenesis in both
embryonic 'development and some angiogenic-dependent diseases is vascular
is endothelial growth factor (VEGF; also called vascular permeability factor,
VPF).
VEGF represents a family of isoforms of mitogens existing in homodimeric forms
due
to alternative RNA splicing. The VEGF isoforms are reported to be highly
specific for
vascular endothelial cells (for reviews, see: Farrara et al. Endocr. Rev.
1992, 13, 18;
Neufield et al. FASEB J. 1999, 13, 9).
VEGF expression is reported to be induced by hypoxia (Shweiki et al. Nature
1992, 359, 843), as well as by a variety of cytokines and growth factors, such
as
interleukin-1, interleukin-6, epidermal growth factor and transforming growth
factor.
To date, VEGF and the VEGF family members have been reported to bind to one or
2s more of three transmembrane receptor tyrosine kinases (Mustonen et al. J.
Cell Biol.,
1995, 129, 895), VEGF receptor-1 {also known as flt-1 (fms-like tyrosine
kinase-1 )),
VEGFR-2 (also known as kinase insert domain containing receptor (KDR); the
murine analogue of KDR is known as fetal liver kinase-1 (flk-1 )), and VEGFR-3
(also
known as flt-4). KDR and flt-1 have been shown to have different signal
transduction
3o properties (Waltenberger et al. J. Biol. Chem. 1994, 269, 26988); Park et
al.
5
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
Oncogene 1995, 10, 135). Thus, KDR undergoes strong ligand-dependant tyrosine
phosphorylation in intact cells, whereas flt-1 displays a weak response. Thus,
binding to KDR is believed to be a critical requirement for induction of the
full
spectrum of VEGF-mediated biological responses.
s
In vivo, VEGF plays a central role in vasculogenesis, and induces
angiogenesis and permeabilization of blood vessels. Deregulated VEGF
expression
contributes to the development of a number of diseases that are characterized
by
abnormal angiogenesis andlor hyperpermeability processes. It is believed
regulation
to of the VEGF-mediated signal transduction cascade by some agents can provide
a
useful mode for control of abnormal angiogenesis andlor hyperpermeability
processes.
Angiogenesis is regarded as an important prerequisite for growth of tumors
is beyond about 1-2 mm. Oxygen and nutrients may be supplied to cells in tumor
smaller than this limit through diffusion. However, it is believed every tumor
is
dependent on angiogenesis for continued growth after it has reached a certain
size.
Tumorigenic cells within hypoxic regions of tumors respond by stimulation of
VEGF
production, which triggers activation of quiescent endothelial cells to
stimulate new
ao blood vessel formation. (Shweiki et al. Proc. Nat'G Acad. Sci., 1995, 92,
768). In
addition, VEGF production in tumor regions where there is no angiogenesis may
proceed through the ras signal transduction pathway (Grugel et al. J. Siol.
Chem.,
1995, 270, 25915; Rak et al. Cancer Res. 1995, 55, 4575). In situ
hybridization
studies have demonstrated VEGF mRNA is strongly upregulated in a wide variety
of
2s human tumors, including lung (Mattern et al. Br. J. Cancer 1996, 73, 931 ),
thyroid
(Viglietto et al. Oncogene 1995, 17, 1569), breast (Brown et al. Human Pathol.
1995,
26, 86), gastrointestinal tract (Brown et al. Cancer Res. 1993, 53, 4727;
Suzuki et al.
Cancer Res. 1996, 56, 3004), kidney and bladder (Brown et al. Am. J. Pathol.
1993,
1431, 1255), ovary (Olson et al. Cancer Res. 1994, 54, 1255), and cervical
(Guidi et
3o al. J. Nat'/ Cancer Inst. 1995, 87, 12137) carcinomas, as well as
angiosacroma
6
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
(Hashimoto et al. Lab. Invest. 1995, 73, 859) and several intracranial tumors
(Plate et
ai. Nature 1992, 359, 845; Phillips et al. Int. J. Oncol. 1993, 2, 913;
Berkman et al. J.
Clin. Invest., 1993, 97, 153). Neutralizing monoclonal antibodies to KDR have
been
shown to be efficacious in blocking tumor angiogenesis (Kim et al. Nature
1993, 362,
s 841; Rockwell et al. Mol. Cell. Differ. 1995, 3, 315).
Over expression of VEGF, for example under conditions of extreme hypoxia,
can lead to intraocular angiogenesis, resulting in hyperproliferation of blood
vessels,
leading eventually to blindness. Such a cascade of events has been observed
for a
to number of retinopathies, including diabetic retinopathy, ischemic retinal-
vein
occlusion, and retinopathy of prematurity (Aiello et al. New Engl. J. Med.
1994, 331,
1480; Peer et al. Lab. Invest. 1995, 72, 638), and age-related macular
degeneration
(AMD; see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855).
is In rheumatoid arthritis (RA), the in-growth of vascular pannus may be
mediated by production of angiogenic factors. ~.evels -of immunoreactive VEGF
are
high in the synoviaf fluid of RA patients, while VEGF levels were low in the
synovial
fluid of patients with other forms of arthritis of with degenerative joint
disease (Koch
et al. J. Immunol. 1994, 152, 4149). The angiogenesis inhibitor AGM-170 has
been
ao shown to prevent neovascularization of the joint in the rat collagen
arthritis model
(Peacock et al. J. Exper. Med. 1992, 175, 1135).
Increased VEGF expression has also been shown in psoriatic skin, as well as
bullous disorders associated with subepidermal blister formation, such as
bullous
2s pemphigoid, erythema multiforme, and dermatitis herpetiformis (Brown et al.
J.
Invest. Dermatol. 1995, 104, 744).
The vascular endothelial growth factors (VEGF, VEGF-C, VEGF-D) and their
receptors (VEGFR2, VEGFR3) are not only key regulators of tumor angiogenesis,
3o but also lymphangiogenesis. VEGF, VEGF-C and VEGF-D are expressed in most
z
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
tumors, primarily during periods of tumor growth and, often at substantially
increased
levels. VEGF expression is stimulated by hypoxia, cytokines, oncogenes such as
ras,
or by inactivation of tumor suppressor genes (McMahon, G. Oncologisf 2000,
5(Suppl. 7), 3-10; McDonald, N.Q.; Hendrickson, W.A. Cell 1993, 73, 421-424).
s
The biological activities of the VEGFs are mediated through binding to their
receptors. VEGFR3 (also called Flt-4) is predominantly expressed on lymphatic
endothelium in normal adult tissues. VEGFR3 function is needed for new
lymphatic
vessel formation, but not for maintenance of the pre-existing lymphatics.
VEGFR3 is
to also upregulated on blood vessel endothelium in tumors. Recently VEGF-C and
VEGF-D, ligands for VEGFR3, have been identified as regulators of
lymphangiogenesis in mammals. Lymphangiogenesis induced by tumor-associated
lymphangiogenic factors could promote the growth of new vessels into the
tumor,
providing tumor cells access to systemic circulation. Cells that invade the
lymphatics
is could find their way into the bloodstream via the thoracic duct. Tumor
expression
studies have allowed a direct comparison of VEGF-C, VEGF-D and VEGFR3
expression with clinicopathological factors that relate directly to the
ability of primary
tumors to spread (e.g., lymph node involvement, lymphatic invasion, secondary
metastases, and disease-free survivall. In many instanc~sthPSP Ct11fI1PC
2o demonstrate a statistical correlation between the expression of
lymphangiogenic
factors and the ability of a primary solid tumor to metastasise (Skobe, M. et
al.
Nature Med. 2001, 7(2), 192-198; Stacker, S.A. et al.. Nature Med. 2001, 7(2),
186
191; Makinen, T. et al. Nature Med. 2001, 7(2), 199-205; Mandriota, S.J. et
al. EM80
J. 2001, 20(4), 672-82; Karpanen, T. et al. CancerRes. 2001, 67(5), 1786-90;
Kubo,
2s H. et al. Blood 2000, 96(2), 546-53).
Hypoxia appears to be an important stimulus for VEGF production in
malignant cells. Activation of p38 MAP kinase is required for VEGF induction
by
tumor cells in response to hypoxia (Blaschke, F. et al. Biochem. Biophys. Res.
3o Commun. 2002, 296, 890-896; Shemirani, B. et al. Oral Oncology 2002, 38,
251-
s
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
257). In addition to its involvement in angiogenesis through regulation of
VEGF
secretion, p38 MAP kinase promotes malignant cell invasion, and migration of
different tumor types through regulation of collagenase activity and urokinase
plasminogen activator expression (Laferriere, J. et al. J. Biol. Chem. 2001,
276,
s 33762-33772; Westermarck, J. et al. Cancer Res. 2000, 60, 7156-7162; Huang,
S.
et al. J. Biol. Chem. 2000, 275, 12266-12272; Simon, C. et al. Exp. Cell Res.
2001,
271, 344-355).
Some diarylureas have been described as having activity as serine-threonine
io kinase andlor as tyrosine kinase inhibitors. The ultility of these
diarylureas as an
active ingredient in pharmaceutical compositions for the treatment of cancer,
angiogenesis disorders, and inflammatory disorders has been demonstated. See
Redman et al., Bioorg. Med. Chem. Lett. 2001, 11, 9-12; Smith et al., Bioorg.
Med.
Chem. Lett. 2001, 11, 2775-2778; Dumas et al., Bioorg. Med. Chem. Lett. 2000,
10,
is 2047-2050; Dumas et al., Bioorg. Med. Chem. Lett. 2000, 10, 2051-2054;
Ranges
et al., Book of Abstracts, 220t" ACS National Meeting, hVashingt~n, DC, USA,
MEDI
149; Dumas et al., Bioorg. Med. Chem. Lett. 2002, 12, 1559-1562; Lowinger et
al.,
Clin. Cancer Res. 2000, 6(suppl.), 335; Lyons et al., Endocr.-Relat. Cancer
2001, 8,
219-225; Riedl et al., Book of Abstracts, 92"d AACR Meeting, New Orleans, LA,
2o USA, abstract 4956; Khire et al., Book of Abstracts, 93rdAACR Meeting, San
Francisco, CA, USA, abstract 4211; Lowinger et al., Curr. Pharm. Design 2002,
8,
99-110; Regan et al., J. Med. Chem. 2002, 45, 2994-3008; Pargellis et al.,
Nature
Sfruct. Biol. 2002, 9(4), 268-272; Carter et al., Book of Abstracts, 92"dAACR
Meeting, New Orleans, LA, USA, abstract 4954; Vincent et al., Book of
Abstracts,
2s 38t" ASCO Meeting, Orlando, FL, USA, abstracf 1900; Hilger et al., Book of
Absfracfs, 38t" ASCO Meeting, Orlando, FL, USA, abstract 1916; Moore et al.,
Book
of Abstracts, 38f" ASCO Meeting, Orlando, FL, USA, abstract 1816; Strumberg et
al., Book of Abstracts, 38~" ASCO Meeting, Orlando, FL, USA, abstract 121;
Madwed JB: Book of Abstracts, Protein Kinases: Novel Target Identification and
3o Validation for Therapeutic Development, San Diego, CA, USA, March 2002;
Roberts
9
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
et al., Book of Abstracfs, 38th ASCO Meeting, Orlando, FL, USA, abstract 473;
Tolcher et al., Book of Abstracts, 38th ASCO Meeting, Orlando, FL, USA,
abstract
334; and Karp et al,, Book of Abstracts, 38th AACR Meefing, San Francisco, CA,
USA, abstract 2753.
s
Despite the advancements in the art, there remains a need for cancer
treatments and anti-cancer compounds.
Description of the Invention
io The present invention pertains to:
(i) novel compounds, salts, metabolites and prodrugs thereof, including
diastereoisomeric forms,
(ii) pharmaceutical compositions containing any of such compounds, and
is (iii) use of those compounds or compositions for treating diseases, e.g.,
hyper-
proliferative and angiogenesis disorders, as a sole agent or in combination
with other
active ingredients, e.g., cytotoxic therapies.
The compounds of formula (I), salts, metabolites and prodrugs thereof,
2o including diastereoisomeric forms (both isolated stereoisomers and mixtures
of
stereoisomers) are collectively referred to herein as the "compounds of the
invention", Formula I is as follows:
O
W/
N N L Q
H H I
A is phenyl, naphthyl, mono- or bi-cyclic heteroaryl, or a group of the
formula
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
o ° ° ~'° ~° ° I
° ~ ~ or
'''
optionally substituted with 1-4 substituents which are independently R~, ORS,
S(O)pR~, C(O)RD, C(O)OR', C(O)NR'R2, halogen, hydroxy, amino, cyano, or nitro;
s B is phenyl, naphthyl, or pyridyl, optionally substituted with 1-4
substituents which are
independently C~-C5 linear or branched alkyl, C~-C5 linear or branched
haloalkyl, C~-
C3 alkoxy, hydroxy, amino, C~-Cs alkyiamino, C~-C6 dialkylamino, halogen,
cyano, or
nitro.
to B is preferably phenyl or pyridyl, optionally substituted with 1-4
substituents which
are independently C~-C5 linear or branched alkyl, C~-C5 linear or branched
haloalkyl,
C~-C3 alkoxy, hydroxy, amino, C~-C3 alkylamino, C~-C6 dialkylamino, halogen,
cyano,
or nitro.
is L is a bridging group which is;
(a) -(CH2)m-O-(CH2),-,
(b) -(CH~)m-(CHZO-,
(c) _(CH2)m_C(~)-(CE.12O-
20 (d) -(CH2)m-NR3-(CH2O-,
(e) -(CH2)m- NR3C(O)-(CHzO-,
(f) -(CHZ)m-S-(CH2)n,
(g) -(CHZ)m-C(O)NR3 -(CHZ)i-, or
(h) a single bond.
The integers m and I are independently selected from 0-4 and are typically
selected
from 0-2.
11
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
L is most preferably -O- or -S-.
M is a pyridine ring, optionally substituted with 1-3 substituents which are
s independently C1-C5 linear or branched alkyl, C1-C5 linear or branched
haloalkyl, C1-
C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-Cg dialkyiamino, halogen, or
nitro.
Q is:
io (1 ) C(S)NR4R~;
(2) C(O)NR7-NR4R~; '
(3) tetrazolyl;
(4) imidazoiyl;
(5) imidazoline-2~yl;
is (6) 1,3,4-oxadiazoline-2-yl;
(7) 1,3~thiazoline-2-yl;
(8) 5-thioxo-4,5-dihydro-1,3,4-thiazoline-2-yl;
(9) 5-oxo-4,5-dihydro-1,3,4-oxadiazoline-2-yl; or
(10) a group of the formula
R6
N~
R5
~N~
R4
and is preferably (1 ), (2) or (10).
2s Each of R1, R2 , R13, R4 and R5 is independently
(a) hydrogen,
12
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
(b) C1-C5 linear, branched, or cyclic alkyl,
(c) phenyl,
(d) C1-C3 phenyl-alkyl,
(e) up to per-halo substituted C1-C5 linear or branched alkyl, or
s (f) -(CH2)q-X.
The substituent X is a 5 or 6 membered heterocyclic ring, containing at least
one atom selected from oxygen, nitrogen and sulfur, which is saturated,
partially
saturated, or aromatic, or a 8-10 membered bicyclic heteroaryl having 1-4
io heteroatoms selected from the group consisting of O, N and S.
In addition, R4 and R5 taken together may form a 5 or 6 membered aliphatic
ring, which may be interrupted by an atom selected from N, O or S. This is
optionally
substituted with 1-3 substituents which are independently C1-C5 linear or
branched
is alkyl, up to perhalo substituted C1-C5 linear or branched alkyl, C1-C3
alkoxy, hydroxy,
oxo, carboxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen, cyano, or
nitro.
R6 is independently:
20 (a) hydrogen,
(b) C1-G5 linear, branched, or cyclic alkyl,
(c) cyano,
(d) nitro,
(e) up to per-halo substituted C1-C5 linear or branched alkyl. or
2s (f) -C(O)R', where R' is C1-C5 linear, branched, or cyclic alkyl.
R6 is preferably independently:
(a) hydrogen,
30 (b) C1-C5 linear, branched, or cyclic alkyl, or
13
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
(c) cyano or
(d) nitro, and most preferably,R6 is independently:
(a) hydrogen,
(b) C1-C5 linear, branched, or cyclic alkyl, or
s (c) cyano.
R~ is hydrogen, or C1-C5 linear, branched, or cyclic alkyl.
The variable q is an integer 0, 1, 2, 3, or 4. The variable p is an integer 0,
1, or
l0 2
A group of compounds of interest are compounds of formula (I), salts,
metabolites and prodrugs thereof, including diastereoisomeric forms (both
isolated
stereoisomers and mixtures of stereoisomers) wherein
is
A is
~O O O~O
O
O
/ , _
' ' or
~O
O
14
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WO 2004/078128 PCT/US2004/006295
wherein A is substituted on any carbon atom by 0-4 substituents
independently R1, OR1, S(O)pRl, C(O)R1, C(O)OR1, C(O)NR1R2, halogen, hydroxy,
amino, cyano, or nitro; and B, L ,M and Q of formula I are as defined above.
s For these compounds,
B is preferably phenyl or pyridyl, optionally substituted with 1-4
substituents which
are independently C1-C5 linear or branched alkyl, C1-C5 linear or branched
haloalkyl,
C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, C1-C6 dialkylamino, halogen,
cyano,
to or nitro.
L is preferably -O-,
M is preferably a pyridine ring substituted only by Q, and
Q is preferably
Ls C(S)NR4R5;
C(O)NR~-NR4R5;
or
a group of the formula
R6
N~
Rs
~N~
R4
2Q
wherein each of R1, R2, R4 and R5 is preferably, independently:
(a) hydrogen,
(b) C1-C5 linear, branched, or cyclic alkyl,
2s (c) phenyl,
(d) C1-C3 phenyl-alkyl,
(e) up to per-halo substituted C1-C5 linear or branched alkyl, or
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
(f) -(CH2)q-X, where the substituent X is pyridinyl and the variable q is
preferably an
integer 0 or 1,
R6 is preferably independently:
s
(a) hydrogen,
(b) C1-Cg linear, branched, or cyclic alkyl, or
(c) cyano.
to Another group of compounds of interest are compounds of formula (I), salts,
metabolites and prodrugs thereof, including diastereoisomeric forms (both
isolated
stereoisomers and mixtures of stereoisomers) wherein
A is
O O ~N
N
~ \ O
I ~ or
is
and B, L, M and Q of formula I are as defined above, and the preferred values
for B, L, M and C~ of formula I are as defined above.
When any moiety is "substituted", it can have up to the highest number of
2o indicated substituents, and each substituent can be located at any
available position
on the moiety and can be attached through any available atom on the
substituent.
"Any available position" means any position on the moiety that is chemically
accessible through means known in the art or taught herein and that does not
create
an unduly unstable molecule. When there are two or more substituents on any
16
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
moiety, each substituent is defined independently of any other substituent and
can,
accordingly, be the same or different.
The term "optionally substituted" means that the moiety so modified may be
s either unsubstituted, or substituted with the identified substituent(s).
It is understood that since M is pyridine, the term "hydroxy" as a pyridine
substituent includes 2-, 3-, and 4-hydroxypyridine, but also includes those
structures
referred to in the art as 1-oxo-pyridine, 1-hydroxy-pyridine and pyridine N-
oxide.
to
Where the plural form of the word compounds, salts, and the like, is used
herein, this is taken to mean also a single compound, salt, or the like.
The term C1-CSalkyl means straight or branched chain alkyl groups having
15 from one to five carbon atoms, which may be linear or branched with single
or
multiple branching. Such groups include methyl, ethyl, n-propyl, isopropyl, n-
butyl,
isobutyl, sec-butyl, fief butyl, and the like.
The term haloCl-C5 alkyl means a saturated hydrocarbon radical having up to
2o five carbon atoms, which is substituted with a least one halogen atom, up
to perhalo.
The radical may be linear or branched with single or multiple branching. The
halo
substituent(s) include fluoro, chloro, bromo, or iodo. Fluoro, chloro and
bromo are
preferred, and fluoro and chloro are more preferred. The halogen
substituent(s) can
be located on any available carbon. When more than one halogen substituent is
2s present on this moiety, they may be the same or different. Examples of such
halogenated alkyl substituents include but are not limited to chloromethyl,
dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, 2,2,2-
trifluoroethyl, and 1,1,2,2-tetrafluoroethyl, and the like.
3o The term C1-C3 alkoxy means straight or branched chain alkoxy group having
17
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WO 2004/078128 PCT/US2004/006295
from one to three saturated carbon atoms which may be linear or branched with
single or multiple branching, and includes such groups as methoxy, ethoxy, n-
propoxy, isopropoxy, and the like. It also includes halogenated groups such as
2,2-
dichloroethoxy, trifluoromethoxy, and the like.
s
Hafo or halogen means fluoro, chloro, bromo, or iodo. Fluoro, chloro and
bromo are preferred, and fluoro and chloro are more preferred.
C1-C3alkylamine means methylamino, ethylamino, propyfamino or
to isopropylamino.
Examples of C1-C6 dialkylamine include but are not limited to diethylamino,
ethyl-isopropylamino, methyl-isobytulamino and dihexylamino.
is The term heteroaryl refers to both monocyclic and bicyclic heteroaryl
rings.
Monocyclic heteroaryl means an aromatic monocyclic rings having 5 to 6 ring
atoms,
at least one of which is a hetero atom selected from N, O and S, the remaining
atoms
being carbon. When more than one hetero atom is present in the moiety, they
are
selected independently from the others) so that they may be the same or
different.
2o Monocyclic heteroaryl rings include, but are not limited to pyrrole, furan,
thiophene,
imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole,
tetrazole,
thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, and
triazine.
Bicyclic heteroaryl means fused bicyclic moieties where one of the rings is
2s chosen from the monocyclic heteroaryl rings described above and the second
ring is
either benzene or another monocyclic heteroaryl ring described above. When
both
rings in the bicyclic moiety are heteroaryl rings, they may be the same or
different, as
long as they are chemically accessible by means known in the art. Bicyclic
heteroaryl rings include synthetically accessible 5-5, 5-6, or 6-6 fused
bicyclic
3o aromatic structures including, for example but not by way of limitation,
benzoxazole
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WO 2004/078128 PCT/US2004/006295
(fused benzene and oxazole), indazole (fused benzene and pyrazole), quinoline
(fused phenyl and pyridine), quinazoline (fused pyrimidine and benzene),
imidazopyrimidine (fused imidazole and pyrimidine), naphtyridine (two fused
pyridines), and the like.
The term "5 or 6 membered heterocyclic ring, containing at least one atom
selected from oxygen, nitrogen and sulfur, which is saturated, partially
saturated, or
aromatic" includes, by no way of limitation, tetrahydropyrane,
tetrahydrofurane, 1,3-
dioxolane, 1,4-dioxane, morpholine, thiomorpholine, piperazine, piperidine,
lo piperidinone, tetrahydropyrimidone, pentamethylene sulfide, tetramethylene
sulfide,
dihydropyrane, dihydrofurane, dihydrothiophene, pyrrole, furan, thiophene,
imidazole,
pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, pyridine,
pyrimidine,
pyridazine, pyrazine, triazine, and the like.
is Non-limiting examples of Q substituents where R4 and R5 taken together may
form a 5 or 6 membered aliphatic ring, which may be interrupted by an atom
selected
from N, ~ or S, which is optionally substituted include:
/CN ,N02
NH N N N CF3
N ~ N~~~ ~ N ~ , N
~O 0 ~ N W
CH3
HsC CH3
The term "C1-C3 phenyl-alkyl" includes, by no way of limitation, 3-phenyl-
propyl, 2-phenyl-1-methyl-ethyl. Substituted examples include 2-[2-
chlorophenyl]ethyl, 3,4-dimethylphenyl-methyl, and the like.
2s The compounds of Formula 4 may contain one or more asymmetric centers,
depending upon the location and nature of the various substituents desired.
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WO 2004/078128 PCT/US2004/006295
Asymmetric carbon atoms may be present in the (R) or (S) configuration or
(R,S)
configuration. In certain instances, asymmetry may also be present due to
restricted
rotation about a given bond, for example, the central bond adjoining two
substituted
aromatic rings of the specified compounds. Substituents on a ring may also be
s present in either cis or traps form. It is intended that all such
configurations
(including enantiomers and diastereomers), are included within the scope of
the
present invention. Preferred compounds are those with the absolute
configuration of
the compound of Formula I which produces the more desirable biological
activity.
Separated, pure or partially purified isomers or racemic mixtures of the
compounds
to of this invention are also included within the scope of the present
invention. The
purification of said isomers and the separation of said isomeric mixtures can
be
accomplished by standard techniques known in the art.
The optical isomers can be obtained by resolution of the racemic mixtures
is according to conventional processes, for example, by the formation of
diastereoisomeric salts using an optically active acid or base or formation of
covalent
diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric,
ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can
be
separated into their individual diastereomers on the basis of their physical
and/or
ao chemical differences by methods known in the art, for example, by
chromatography
or fractional crystallization. The optically active bases or acids are then
liberafied
from the separated diastereomeric salts. A different process for separation of
optical
isomers involves the use of chiral chromatography (e.g., chiral HPLC columns),
with
or without conventional derivation, optimally chosen to maximize the
separation of
2s the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel,
e.g.,
Chiracel OD and Chiracel OJ among many others, all routinely selectable.
Enzymatic
separations, with or without derivitization, are also useful. The optically
active
compounds of Formula I can likewise be obtained by chiral syntheses utilizing
optically active starting materials.
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
The present invention also relates to useful forms of the compounds as
disclosed herein, such as pharmaceutically acceptable salts, metabolites and
prodrugs of all the compounds Formula (I). The term "pharmaceutically
acceptable
salt'" refers to a relatively non-toxic, inorganic or organic acid addition
salt of a
s compound of the present invention. For example, see S. M. Bergs, et al.
"Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19. Pharmaceutically
acceptable
salts include those obtained by reacting the main compound, functioning as a
base,
with an inorganic or organic acid to form a salt, for example, salts of
hydrochloric
acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic
acid,
to oxalic acid, malefic acid, succinic acid and citric acid. Pharmaceutically
acceptable
salts also include those in which the main compound functions as an acid and
is
reacted with an appropriate base to form, e.g., sodium, potassium, calcium,
magnesium, ammonium, and choline salts. Those skilled in the art will further
recognize that acid addition salts of the claimed compounds may be prepared by
is reaction of the compounds with the appropriate inorganic or organic acid
via any of a
number of known methods. Alternatively, alkali and alkaline earth metal salts
are
prepared by reacting the compounds of the invention with the appropriate base
via a
variety of known methods.
2o Representative salts of the compounds of this invention include the
conventional non-toxic salts and the quaternary ammonium salts which are
formed,
for example, from inorganic or organic acids or bases by means well known in
fibs
art. For example, such acid addition salts include acetate, adipate, alginate,
ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,
citrate,
2s camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate,
digluconate,
dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,
2-
hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate,
methanesulfonate,
2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate,
persulfate,
30 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate,
tartrate,
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WO 2004/078128 PCT/US2004/006295
thiocyanate, tosylate, and undecanoate.
Base salts include alkali metal salts such as potassium and sodium salts,
alkaline earth metal salts such as calcium and magnesium salts, and ammonium
s salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine.
Additionally, basic nitrogen containing groups may be quaternized with such
agents
as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides,
bromides
and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and
diamyl
sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl
chlorides,
to bromides and iodides, aralkyl halides like benzyl and phenethyl bromides
and others.
Certain compounds of this invention can be further modified with labile
functional groups that are cleaved after in vivo administration to furnish the
parent
active agent and the pharmacologically inactive derivatizing (functional)
group.
is These derivatives, commonly referred to as prodrugs, can be used, for
example, to
alter the physicochemical properties of the active agent, to target the active
agent to
a specific tissue, to alter the pharmacokinetic and pharmacodynamic properties
of
the active agent, and to reduce undesirable side effects
2o Prodrugs of the invention include, e.g., the esters of appropriate
compounds
of this invention are well-tolerated, pharmaceutically acceptable esters such
as alkyl
esters including methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl
esters.
Additional esters such as phenyl-C~-~5 alkyl may be used, although methyl
ester is
preferred.
Methods for synthesizing prodrugs are described in the following reviews on
the subject, which are incorporated herein by reference for their description
of these
methods:
22
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WO 2004/078128 PCT/US2004/006295
~ Higuchi, T.; Stella, V. eds. Prodrugs As Novel Drug Delivery Systems. ACS
Symposium Series. American Chemical Society: Washington, DC (1975).
~ Roche, E. B. Design of Biopharmaceutical Properties through Prodrugs and
s Analogs. American Pharmaceutical Association: Washington, DC (1977).
~ Sinkula, A. A.; Yalkowsky, S. H. J Pharm Sci. 1975, 64, 181-210.
~ Stella, V. J.; Charman, W. N. Naringrekar, V. H. Drugs 1985, 29, 455-473.
~ Bundgaard, H., ed. Design of Prodrugs. Elsevier: New York (1985).
~ Stelfa, V. J.; Himmelstein, K. J. J. Med. Chem. 1980, 23, 1275-1282.
to ~ Han, H-K; Amidon, G. L. AAPS Pharmsci 2000, 2, 1- 11.
~ Denny, W. A. Eur. J. Med. Chem. 2001, 36, 577-595.
~ Wermuth, C. G. in Wermuth, C. G. ed. The Practice of Medicinal Chemistry
Academic Press: San Diego (1996), 697-715.
~ Balant, L. P.; Doelker, E. in Wolff, M. E. ed. Burgers Medicinal Chemistry
And
is Drug Discovery John Wiley & Sons: New York (1997), 949-982.
The metabolites of the compounds of this invention include oxidized
derivatives of the compounds of Formula l, wherein one or more of the
nitrogens are
substituted with a hydroxy group; which includes derivatives where the
nitrogen atom
zo of the pyridine group is in the oxide form, referred to in the art as 1-oxo-
pyridine or
has a hydroxy substituent, referred to in the art as 1-hydroxy-pyridine.
General Preparative Methods
The particular process to be utilized in the preparation of the compounds used
2s in this embodiment of the invention depends upon the specific compound
desired.
Such factors as the selection of the specific substituents play a role in the
path to be
followed in the preparation of the specific compounds of this invention. Those
factors
are readily recognized by one of ordinary skill in the art.
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CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
The compounds of the invention may be prepared by use of known chemical
reactions and procedures. Nevertheless, the following general preparative
methods
are presented to aid the reader in synthesizing the compounds of the present
invention; with more detailed particular examples being presented below in the
s experimental section describing the working examples.
All variable groups of these methods are as described in the generic
description if they are not specifically defined below. When a variable group
or
substituent with a given symbol is used more than once in a given structure,
it is to
to be understood that each of these groups or substituents may be
independently
varied within the range of definitions for that symbol. It is recognized that
compounds
of the invention with each claimed optional functional group cannot be
prepared with
each of the below-listed methods. Within the scope of each method optional
substituents are used which are stable to the reaction conditions, or the
functional
is groups which may participate in the reactions are present in protected form
where
necessary, and the removal of such protective groups is completed at
appropriate
stages by methods well known to those skilled in the art.
The compounds of the invention can be made according to conventional
2o chemical methods, and/or as disclosed below, from starting materials which
are
either commercially available or producible according to routine, conventional
chemical methods. General methods for fihe preparation of the compounds are
given
below, and the preparation of representative compounds is specifically
illustrated in
examples.
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CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
s General Method
a
L-M O
I ~~
A-NCO + H2N-B -w~' A~N~,N~B~~,M'Q
H H
to The compounds (I) can be synthesized according to the reaction sequence
shown in the General Method above. Thus, the compounds (I) can be synthesized
by reacting amino compounds (III) with isocyante compounds (II).
The compounds (II) are commercially available or can be synthesized
is according to methods commonly known to those skilled in the art [e.g. from
treatment
of an amine with phosgene or a phosgene equivalent such as trichloromethyl
chloroformate (diphosgene), bis(trichloromethyl)carbonate (triphosgene), or
N,N'-
carbonyldiimidazole (CDI); or, alternatively by a Curtius-type rearrangement
of an
amide, or a carboxylic acid derivative, such as an ester, an acid halide or an
2o anhydride]. The compounds (III) are commercially available or can be
synthesized
according methods commonly known to those skilled in the art.
In addition, specific preparations of diaryl ureas are already described in
the
patent literature, and can be adapted to the compounds of the present
invention. For
2s example, Miller S. et al, "Inhibition of p38 Kinase using Symmetrical and
Unsymmetrical biphenyl Ureas" PCT Int. App/. WO 99 32463, Miller, S et al.
"Inhibition of raf Kinase using Symmetrical and Unsymmetrical Substituted
biphenyl
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
Ureas" PCT Int. Appl., WO 99 32436, Dumas, J. et al., "Inhibition of p38
Kinase
Activity using Substituted Heterocyclic Ureas" PCT Int. Appl., WO 99 3211'!,
Dumas,
J. et al., "Method for the Treatment of Neoplasm by Inhibition of raf Kinase
using N-
Heteroaryl-N'-(hetero)arylureas" PCT Inf. Appl., WO 99 32106, Dumas, J. et
al.,
s "Inhibition of p38 Kinase Activity using Aryl- and Heteroaryl- Substituted
Heterocyclic
Ureas" PCT Int. Appl., WO 99 32110, Dumas, J., et al., "Inhibition of raf
Kinase using
Aryl- and Heteroaryl- Substituted Heterocyclic Ureas" PCT Int. Appl., WO 99
32455,
Riedl, B., et al., "O-Carboxy Aryl Substituted biphenyl Ureas as raf Kinase
Inhibitors"
PCT Inf. Appl., WO 00 42012, Riedl, B., et al., "O-Carboxy Aryl Substituted
biphenyl
to Ureas as p38 Kinase Inhibitors" PCT Int. Appl., WO 00 41698, Dumas, J. et
al.
"Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinase inhibitors"
U. S. Pat.
Appl. Publ., US 20020065296, Dumas, J. et al. "Preparation of N-aryl-N'-
[(acylphenoxy) phenyl]ureas as raf kinase inhibitors" PCT Int. Appl., WO 02
62763,
Dumas, J. et al. "Inhibition of raf kinase using quinolyi, isoquinolyl or
pyridyl ureas"
is PCT Int. Appl., WO 02 85857, Dumas, ,!. et al. "Preparation of quinolyl,
isoquinolyl or
pyridyl-ureas as inhibitors of raf kinase for the treatment of tumors and/or
cancerous
cell growth" U. S. Pat. Appl. Publ., US 20020165394. All the preceding patenfi
applications are hereby incorporated by reference.
2o The reaction of the compounds (II) with (1!i) is carried out preferably in
a
solvent. Suitable solvents comprise the customary organic solvents which are
inert
under the reaction conditions. Non-limiting examples include ethers such as
diefihyl
ether, dioxane, tetrahydrofuran, 1,2-dimethoxy ethane; hydrocarbons such as
benzene, toluene, xylene, hexane, cyclohexane, mineral oil fractions;
halogenated
2s hydrocarbons such as dichloromethane, trichloromethane, carbon
tetrachloride,
dichloroethane, trichloroethylene, chlorobenzene; alcohols such as methanol,
ethanol, n-propanol, isopropanol; esters such as ethyl acetate; ketones such
as
acetone; nitrites such as acetonitrile; heteroaromatics such as pyridine;
polar
solvents such as dimethyl formamide and hexamethyl phosphoric acid tris-amide;
26
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
and mixtures of the above-mentioned solvents. Toluene, benzene, and
dichloramethane are preferred.
The compounds (Ill} are generally employed in an amount of from 1 to 3 mol
s per mol of compounds (II); an equimolar amount or slight excess of compounds
(lll)
is preferred.
The reacfiion of the compounds (II) with (III) is generally carried out within
a
relatively wide temperature range. In general, they are carried out in a range
of from -
l0 20 to 200°C, preferably from 0 to 100°C, and more preferably
from 25 to 50°C. The
steps of this reaction are. generally carried out' under atmospheric pressure.
However, it is also possible to carry them out under superatmospheric pressure
or
under reduced pressure (for example, in a range ~of from 0.5 to 5 bar). The
reaction
time can generally be varied within a relatively wide range. In general, the
reaction is
is finished after a period of from 2 to 24 hours, preferably from 6 to 12
hours.
Synthetic firansformations that may be employed in the synthesis of
compounds of Formula I and in the synthesis of intermediates involved in the
synthesis of compounds of Formula I are known by or accessible to one skilled
in the
2o art. Collections of synthetic transformations may be found in compilations;
such as:
~ J. March. Advanced Organic Chemistry, 4th ed.; John Wiley: New York (1992)
~ R.C. Larock. Comprehensive Organic Transformations, 2nd ed.; Wlley-VCH: New
York (1999)
2s ~ F.A. Corey; R.J. Sundberg. Advanced Organic Chemistry, 2nd ed.; Plenum
Press: New York (1984)
~ T.W. Greener P.G.M. Wuts. Protective Groups in Organic Synthesis, 3rd ed.;
John Wiley: New York (1999)
~ L.S. Hegedus. Transition Metals in the Synthesis of Complex Organic
Molecules,
30 2nd ed.; University Science Books: Mill Valley, CA (1994)
27
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
~ L.A. Paquette, Ed. The Encyclopedia of Reagents for Organic Synthesis; John
Wiley: New York (1994)
~ A.R. Katritzky; O. Meth-Cohn; C.W. Rees, Eds. Comprehensive Organic
Functional Group Transformations; Pergamon Press: Oxford, UK (1995)
s ~ G. Wilkinson; F.G A. Stone; E.W. Abel, Eds. Comprehensive Organometallic
Chemistry; Pergamon Press: Oxford, UK (1982)
~ B.M. Trost; I. Fleming. Comprehensive Organic Synthesis; Pergamon Press;
Oxford, UK (1991 )
~ A.R. Katritzky; C.W. Rees Eds. Comprehensive Heferocylic Chemistry;
io Pergamon Press: Oxford, UK (1984)
~ A.R. Katritzky; C.W. Rees; E.F.V. Scriven, Eds. Comprehensive Heterocylic
Chemistry II; Pergamon Press: Oxford, UK (1996)
~ C. Hansch; P.G. Sammes; J.B. Taylor, Eds. Comprehensive Medicinal
Chemistry: Pergamon Press: Oxford, UK (1990).
is
In addition, recurring reviews of synthetic methodology and related topics
include Organic Reactions; John Wiley: New York; Organic Syntheses; John
Wiiey:
New York; Reagents for Organic Synthesis: John Wiley: New York; The Total
Synthesis of Natural Products; John Wiley: New York; The Organic Chemistry of
Zo Drug Synthesis; John Wiley: New York; Annual Reports in Organic Synthesis;
Academic Press: San Diego CA; and Methoden der Organischen Chemie (Houben
Weyl); Thieme: Stuttgart, Germany. Furthermore, databases of synthetic
transformations include Chemical Abstracts, which may be searched using either
CAS Online or SciFinder, Handbuch der Organischen Chemie(Beilstein), which may
2s be searched using SpotFire, and REACCS.
Compositions of the compounds of this inyention
This invention also relates to pharmaceutical compositions containing one or
more compounds of the present invention. These compositions can be utilized to
3o achieve the desired pharmacological effect by administration to a patient
in need
2a
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WO 2004/078128 PCT/US2004/006295
thereof. A patient, for the purpose of this invention, is a mammal, including
a human,
in need of treatment for the particular condition or disease. Therefore, the
present
invention includes pharmaceutical compositions which are comprised of a
pharmaceutically acceptable carrier and a pharmaceutically effective amount of
a
s compound, or salt thereof, of the present invention. A pharmaceutically
acceptable
carrier is preferably a carrier which is relatively non-toxic and innocuous to
a patient
at concentrations consistent with effective activity of the active ingredient
so that any
side effects ascribable to the carrier do not vitiate the beneficial effects
of the active
ingredient. A pharmaceutically effective amount of compound is preferably that
to amount which produces a result or exerts an influence on the particular
condition
being treated. The compounds of the present invention can be administered with
pharmaceutically-acceptable carriers well known in the art using any effective
conventional dosage unit forms, including immediate, slow and timed release
preparations, orally, parenterally, topically, nasally, ophthalmically,
optically,
is sublingually, rectally, vaginally, and the like.
For oral administration, the compounds can be formulated into solid or liquid
preparations such as capsules, pills, tablets, troches, lozenges, melts,
powders,
solutions, suspensions, or emulsions, and may be prepared according to methods
2o known to the art for the manufacture of pharmaceutical compositions. The
solid unit
dosage forms can be a capsule which can be of the ordinary hard- or soft-
shelled
gelatin type containing, for example, surfactants, lubricants, and inert
fillers such as
lactose, sucrose, calcium phosphate, and corn starch.
2s In another embodiment, the compounds of this invention may be tableted with
conventional tablet bases such as lactose, sucrose and cornstarch in
combination
with binders such as acacia, corn starch or gelatin, disintegrating agents
intended to
assist the break-up and dissolution of the tablet following administration
such as
potato starch, alginic acid, corn starch, and guar gum, gum tragacanth,
acacia,
30 lubricants intended to improve the flow of tablet granulation and to
prevent the
2s
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
adhesion of tablet material to the surfaces of the tablet dies and punches,
for
example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes,
coloring
agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry
flavoring, intended to enhance the aesthetic qualities of the tablets and make
them
s more acceptable to the patient. Suitable excipients for use in oral liquid
dosage forms
include dicalcium phosphate and diluents such as water and alcohols, for
example,
ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the
addition
of a pharmaceutically acceptable surfactant, suspending agent or emulsifying
agent.
Various other materials may be present as coatings or to otherwise modify the
to physical form of the dosage unit. For instance tablets, pills or capsules
may be
coated with shellac, sugar or both.
Dispersible powders and granules are suitable for the preparation of an
aqueous suspension. They provide the active ingredient in admixture with a
is dispersing or wetting agent, a suspending agent and one or more
preservatives.
Suitable dispersing or wetting agents and suspending agents are exemplified by
those already mentioned above. Additional excipients, for example those
sweetening, flavoring and coloring agents described above, may also be
present.
2o The pharmaceutical compositions of this invention may also be in the form
of
oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid
paraffin
or a mixture of vegetable oils. Suitable emulsifying agents may be (1 )
naturally
occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring
phosphatides such as soy bean and lecithin, (3) esters or partial esters
derived form
2s fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4)
condensation products of said partial esters with ethylene oxide, for example,
polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening
and flavoring agents.
3o Oily suspensions may be formulated by suspending the active ingredient in a
CA 02516627 2005-08-19
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vegetable oil such as, for example, arachis oil, olive oil, sesame oil or
coconut oil, or
in a mineral oil such as liquid paraffin. The oily suspensions may contain a
thickening
agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The
suspensions may also contain one or more preservatives, for example, ethyl or
n-
s propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring
agents; and one or more sweetening agents such as sucrose or saccharin.
Syrups and elixirs may be formulated with sweetening agents such as, for
example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations
may also
to contain a demulcent, and preservative, such as methyl and propyl parabens
and
flavoring and coloring agents.
The compounds of this invention may also be administered parenterally, that
is, subcutaneously, intravenously, intraocularly, intrasynovially,
intramuscularly, or
is interperitoneally, as injectable dosages of the compound in preferably a
physiologically acceptable diluent with a pharmaceutical carrier which can be
a
sterile liquid or mixture of liquids such as water, saline, aqueous dextrose
and related
sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl
alcohol,
glycols such as propylene glycol or polyethylene glycol, glycerol ketals such
as 2,2-
ao dimethyl-1,1-dioxolane-4-methanol, ethers such as polyethylene glycol) 400,
an oil,
a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated
fatty acid
glyceride, with or without the addition of a pharmaceutically acceptable
surfactant
such as a soap or a detergent, suspending agent such as pectin, carbomers,
methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or
2s emulsifying agent and other pharmaceutical adjuvants.
Illustrative of oils which can be used in the parenteral formulations of this
invention are those of petroleum, animal, vegetable, or synthetic origin, for
example,
peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil,
petrolatum and
3o mineral oil. Suitable fatty acids include oleic acid, stearic acid,
isostearic acid and
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myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and
isopropyl
myristate. Suitable soaps include fatty acid alkali metal, ammonium, and
triethanolamine salts and suitable detergents include cationic detergents, for
example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and
alkylamine
s acetates; anionic detergents, for example, alkyl, aryl, and olefin
sulfonates, alkyl,
olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic
detergents,
to
for example, fatty amine oxides, fatty acid alkanolamides, and
poly(oxyethylene-
oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric
detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline
quarternary ammonium salts, as well as mixtures.
The parenteral compositions of this invention will typically contain from
about
0.5% to about 25% by weight of the active ingredient in solution.
Preservatives and
buffers may also be used advantageously. In order to minimize or eliminate
irritation
is at the site of injection, such compositions may contain a non-ionic
surfactant having
a hydrophile-iipophiie balance (HLB) preferably of from about 12 to about 17.
The
quantity of surFactant in such formulation preferably ranges from about 5% to
about
15% by weight. The surfactant can be a single component having the above HLB
or
can be a mixture of two or more components having the desired HLB.
Illustrative of surfactants used in parenteral formulations are the class of
polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and
the
high molecular weight adducts of ethylene oxide with a hydrophobic base,
formed by
the condensation of propylene oxide with propylene glycol.
The pharmaceutical compositions may be in the form of sterile injectable
aqueous suspensions. Such suspensions may be formulated according to known
methods using suitable dispersing or wetting agents and suspending agents such
as,
for example, sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethyl-
3o cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum
acacia;
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dispersing or wetting agents which may be a naturally occurring phosphatide
such as
lecithin, a condensation product of an alkylene oxide with a fatty acid, for
example,
polyoxyethylene stearate, a condensation product of ethylene oxide with a long
chain
aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation
s product of ethylene oxide with a partial ester derived form a fatty acid and
a hexitol
such as polyoxyethylene sorbitol monooleate, or a condensation product of an
ethylene oxide with a partial ester derived from a fatty acid and a hexitol
anhydride,
for example polyoxyethylene sorbitan monooleate.
io The sterile injectable preparation may also be a sterile injectable
solution or
suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents
and
solvents that may be employed are, for example, water, Ringer's solution,
isotonic
sodium chloride solutions and isotonic glucose solutions. In addition, sterile
fixed oils
are conventionally employed as solvents or suspending media. For this purpose,
any
is bland, fixed oil may be employed including synthetic mono- or diglycerides.
In
addition, fatty acids such as oleic acid can be used in the preparation of
injectables.
A composition of the invention may also be administered in the form of
suppositories for rectal administration of the drug. These compositions can be
2o prepared by mixing the drug with a suitable non-irritation excipient which
is solid at
ordinary temperatures but liquid at the rectal temperature and will therefore
melt in
the rectum to release the drug. Such material are, for example, cocoa butter
and
polyethylene glycol.
Zs Another formulation employed in the methods of the present invention
employs transdermal delivery devices ("patches"). Such transdermal patches may
be
used to provide continuous or discontinuous infusion of the compounds of the
present invention in controlled amounts. The construction and use of
transdermal
patches for the delivery of pharmaceutical agents is well known in the art
(see, e.g.,
3o US Patent No. 5,023,252, issued June 11, 1991, incorporated herein by
reference).
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Such patches may be constructed for continuous, pulsatile, or on demand
delivery of
pharmaceutical agents.
Controlled release formulations for parenteral administration include
s liposomal, polymeric microsphere and polymeric gel formulations which are
known in
the art.
It may be desirable or necessary to introduce the pharmaceutical composition
to the patient via a mechanical delivery device. The construction and use of
to mechanical delivery devices for the delivery of pharmaceutical agents is
well known
in the art. Direct techniques for, for example, administering a drug directly
to the
brain usually involve placement of a drug delivery catheter into the patient's
ventricular system to bypass the blood-brain barrier. One such implantable
delivery
system, used for the transport of agents to specific anatomical regions of the
body, is
is described in US Patent No. 5,011,472, issued April 30, 1991.
The compositions of the invention can also contain other- conventional
pharmaceutically acceptable compounding ingredients, generally referred to as
carriers or diluents, as necessary or desired. Conventional procedures for
preparing
ao such compositions in appropriate dosage forms can be utilized. Such
ingredients
and procedures include those described in the following references, each of
which is
incorporated herein by reference: Powell, M.F. et al, "Compendium of
Excipients for
Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology
1998, 52(5), 238-311; Strickley, R.G "Parenteral Formulations of Small
Molecule
2s Therapeutics Marketed in the United States (1999)-Part-1" PDA Journal of
Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et al,
"Excipients and Their Use in Injectable Products" PDA Journal of
Pharmaceutical
Science & Technology 1997, 51 (4), 166-171.
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Commonly used pharmaceutical ingredients which can be used as appropriate
to formulate the composition for its intended route of administration include:
acidifying agents (examples include but are not limited to acetic acid, citric
s acid, fumaric acid, hydrochloric acid, nitric acid);
alkalinizing agents (examples include but are not limited to ammonia
solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium
hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine,
trolamine);
to adsorbents (examples include but are not limited to powdered cellulose and
activated charcoal);
aerosol propellants (examples include but are not limited to carbon dioxide,
CCI2F2, F2CIC-CCIF2 and CCIF3)
air displacement agents (examples include but are not limited to nitrogen
is and argon);
antifungal preservatives (examples include but are not limited to benzoic
acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium
benzoate);
antimicrobial preservatives (examples include but are not limited to
benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium
ao chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric
nitrate and
thimerosal);
antio~zidants (examples include but are not limified to ascorbic acid,
ascorbyl
palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus
acid,
monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium
2s formaldehyde sulfoxylate, sodium metabisulfite);
binding materials (examples include but are not limited to block polymers,
natural and synthetic rubber, polyacrylates, polyurethanes, silicones,
polysiloxanes
and styrene-butadiene copolymers);
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buffering agents (examples include but are not limited to potassium
metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous
and sodium citrate dihydrate)
carrying agents (examples include but are not limited to acacia syrup,
s aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup,
syrup, corn
oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride
injection and
bacteriostatic water for injection)
chelating agents (examples include but are not limited to edetate disodium
and edetic acid)
to colorants (examples include but are not limited to FD&C Red No. 3, FD&C
Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange
No. 5, D&C Red No. 8, caramel and ferric oxide red);
clarifying agents (examples include but are not limited to bentonite);
emulsifying agents (examples include but are not limited to acacia,
is cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan
monooleate,
polyoxyethylene 50 monostearate);
encapsulating agents (examples include but are not limited to gelatin and
cellulose acetate phthalate)
flavorants (examples include but are not limited to anise oil, cinnamon oil,
2o cocoa, menthol, orange oil, peppermint oil and vanillin);
humectants (examples include but are not limited to glycerol, propylene
glycol and sorbitol);
levigating agents (examples include but are not limited to mineral oil and
glycerin);
2s oils (examples include but are not limited to arachis oil, mineral oil,
olive oil,
peanut oil, sesame oil and vegetable oil);
ointment bases (examples include but are not limited to lanolin, hydrophilic
ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum,
white
ointment, yellow ointment, and rose water ointment);
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penetration enhancers (transdermal delivery) (examples include but are
not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent
alcohols,
saturated or unsaturated fatty alcohols, saturated or unsaturated fatty
esters,
saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl
derivatives,
s cephalin, terpenes, amides, ethers, ketones and ureas)
plasticizers (examples include but are not limited to diethyl phthalate and
glycerol);
solvents (examples include but are not limited to ethanol, corn oil,
cottonseed
oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified
water, water for
to injection, sterile water for injection and sterile water for irrigation);
stiffening agents (examples include but are not limited to cetyl alcohol,
cetyl
esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and
yellow
wax);
suppository bases (examples include but are not limited to cocoa butter and
is polyethylene glycols (mixtures));
surfactants (examples include but are not limited to benzalkonium chloride,
nonoxynol 10, oxtoxynol 9, polysorbate $0, sodium lauryl sulfate and sorbitan
mono-
palmitate);
suspending agents (examples include but are not limited to agar, bentonite,
2,o carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose,
hydroxypropyl
cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth
and
veegum);
sweetening agents (examples include but are not limited to aspartame,
dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and
2s sucrose);
tablet anti-adherents (examples include but are not limited to magnesium
stearate and talc);
tablet binders (examples include but are not limited to acacia, alginic acid,
carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin,
liquid
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glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and
pregelatinized
starch);
tablet and capsule diluents (examples include but are not limited to dibasic
calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose,
powdered
s cellulose, precipitated calcium carbonate, sodium carbonate, sodium
phosphate,
sorbitol and starch);
tablet coating agents (examples include but are not limited to liquid glucose,
hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose,
methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac);
to tablet direct compression excipients (examples include but are not limited
to dibasic calcium phosphate);
tablet disintegrants (examples include but are not limited to alginic acid,
carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin
potassium,
cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate
.and
is starch);
tablet glidants (examples include but are not limited to colloidal silica,
corn
starch and talc);
tablet lubricants (examples include but are not limited to calcium stearate,
magnesium stearate, mineral oil, stearic acid and zinc stearate);
2o tablet/capsule opaquants (examples include but are not limited to titanium
dioxide);
tablet polishing agents (examples include but are not limited to carnuba wax
and white wax);
thickening agents (examples include but are not limited to beeswax, cetyl
2s alcohol and paraffin);
tonicity agents (examples include but are not limited to dextrose and sodium
chloride);
viscosity increasing agents (examples include but are not limited to alginic
acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose,
3o polyvinyl pyrrolidone, sodium alginate and tragacanth); and
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wetting agents (examples include but are not limited to heptadecaethylene
oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol
monooleate, and
polyoxyethylene stearate).
Pharmaceutical compositions according to the present invention can be
s illustrated as follows:
Sterile IV Solution: A 5 mg/ml solution of the desired compound of this
invention
can be made using sterile, injectable water, and the pH is adjusted if
necessary. The
solution is diluted for administration to 1 - 2 mg/ml with sterile 5% dextrose
and is
to administered as an IV infusion over 60 minutes.
Lyophilized powder for IV administration: A sterile preparation can be
prepared
with (i) 100 - 1000 mg of the desired compound of this invention as a
lypholized
powder, (ii) 32- 327 mg/ml sodium citrate, and (iii) 300 - 3000 mg Dextran 40.
The
1s, formulation is reconstituted with sterile, injectable saline or dextrose
5% to a
concentration of 10 to 20 mg/ml, which is further diluted with saline or
dextrose 5% to
0.2 - 0.4 mg/ml, and is administered either IV bolus or by IV infusion over 15
- 60
minutes.
ao Intramuscular suspension: The following solution or suspension can be
prepared,
for intramuscular injection:
50 mg/ml of the desired, water-insoluble compound of this invention
mg/ml sodium carboxymethylcellulose
4 mg/ml TWEEN 80
2s 9 mg/ml sodium chloride
9 mg/ml benzyl alcohol
Hard Shell C Josules: A large number of unit capsules are prepared by filling
standard two-piece hard galantine capsules each with 100 mg of powdered active
3o ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium
stearate.
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Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such
as
soybean oil, cottonseed oil or olive oil is prepared and injected by means of
a
positive displacement pump into molten gelatin to form soft gelatin capsules
s containing 100 mg of the active ingredient. The capsules are washed and
dried.
The active ingredient can be dissolved in a mixture of polyethylene glycol,
glycerin
and sorbitol to prepare a water miscible medicine mix.
Tablets: A large number of tablets are prepared by conventional procedures so
that
io the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal
silicon dioxide, 5
mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of
starch,
and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be
applied to increase palatability, improve elegance and stability or delay
absorption.
is Immediate Release TabletslCapsules: These are solid oral dosage forms made
by
conventional and novel processes. These units are taken orally without water
for
immediate dissolution and delivery of the medication. The active ingredient is
mixed
in a liquid containing ingredient such as sugar, gelatin, pectin and
sweeteners.
These liquids are solidified into solid tablets or caplets by freeze drying
and solid
2o state extraction techniques. The drug compounds may be compressed with
viscoelastic and thermoelastic sugars and polymers or effervescent components
to
produce porous matrices intended for immediafie release, without the need of
water.
Method of treating hy~er-~roliferative disorders
as The present invention relates to a method for using the compounds described
above (Compounds of Formula I), including salts and esters thereof and
compositions thereof, to treat mammalian hyper-proliferative disorders. This
method
comprises administering to a mammal in need thereof, including a human, an
amount of a compound of this invention, or a pharmaceutically acceptable salt
or
3o ester thereof, which is effective to treat the disorder. Hyper-
proliferative disorders
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include but are not limited to solid tumors, such as cancers of the breast,
respiratory
tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver,
skin, head
and neck, thyroid, parathyroid and their distant metastases. Those disorders
also
include lymphomas, sarcomas, and leukemias.
s
Examples of breast cancer include, but are not limited to invasive ductal
carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular
carcinoma in situ.
to Examples of cancers of the respiratory tract include, but are not limited
to
small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and
pleuropulmonary blastoma.
Examples of brain cancers include, but are not limited to brain stem and
is hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma,
ependymoma, as well as neuroectodermal and pineal tumor.
Tumors of the male reproductive organs include, but are not limited to
prostate
and testicular cancer. Tumors of the female reproductive organs include, but
are not
20 limited to endometrial, cervical, ovarian, vaginas, and vulvar cancer, as
well as
sarcoma of the uterus.
Tumors of the digestive tract include, but are not limited to anal, colon,
colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-
intestine, and
2s salivary gland cancers.
Tumors of the urinary tract include, but are not limited to bladder, penile,
kidney, renal pelvis, ureter, and urethral cancers.
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Eye cancers include, but are not limited to intraocular melanoma and
retinoblastoma.
Examples of liver cancers include, but are not limited to hepatocellular
s carcinoma (liver cell carcinomas with or without fibrolamellar variant),
cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed
hepatocellular
cholangiocarcinoma.
Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's
io sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin
cancer.
Head-and-neck cancers include, but are not limited to laryngeal /
hypopharyngeal / nasopharyngeal / oropharyngeal cancer, and lip and oral
cavity
is cancer.
Lymphomas include, but are not limited to AIDS-related lymphoma, non-
Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and
lymphoma of the central nervous system.
Sarcomas include, but are not limited to sarcoma of the soft tissue,
osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and
rhabdomyosarcoma.
2s Leukemias include, but are not limited to acute myeloid leukemia, acute
lymphoblastic Leukemia, chronic lymphocytic leukemia, chronic myelogenous
leukemia, and hairy cell leukemia.
These disorders have been well characterized in humans, but also exist with a
3o similar etiology in other mammals, and can be treated by administering
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pharmaceutical compositions of the present invention.
Based upon standard laboratory techniques known to evaluate compounds
useful for the treatment of hyper-proliferative disorders, by standard
toxicity tests and
s by standard pharmacological assays for the determination of treatment of the
conditions identified above in mammals, and by comparison of these results
with the
results of known medicaments that are used to treat these conditions, the
effective
dosage of the compounds of this invention can readily be determined for
treatment of
each desired indication. The amount of the active ingredient to be
administered in
to the treatment of one of these conditions can vary widely according to such
considerations as the particular compound and dosage unit employed, the mode
of
administration, the period of treatment, the age and sex of the patient
treated, and
the nature and extent of the condition treated.
is The total amount of the active ingredient to be administered will generally
range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and
preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. It
should
be noted that the choice of dosing schedules is particularly important to
maximize the
efficacy and safety of drugs for the treatment of proliferative disorders such
as
ao cancer. Clinically useful dosing schedules will range from three times a
day dosing to
once every four weeks dosing. In addition, "drug holidays" in which a patient
is not
dosed with a drug for a certain period of time, may be beneficial to the
overall
balance between pharmacological effect and tolerability. A unit dosage may
contain
from about 0.5 mg to about 1500 mg of active ingredient, and can be
administered
2s one or more times per day or less than once a day. The average daily dosage
for
administration by injection, including intravenous, intramuscular,
subcutaneous and
parenteral injections, and use of infusion techniques will preferably be from
0.01 to
200 mg/kg of total body weight. The average daily rectal dosage regimen will
preferably be from 0.01 to 200 mg/kg of total body weight. The average daily
vaginal
3o dosage regimen will preferably be from 0.01 to 200 mg/kg of total body
weight. The
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average daily topical dosage regimen will preferably be from 0.1 to 200 mg
administered between one to four times daily. The transdermal concentration
will
preferably be that required to maintain a daily dose of from 0.01 to 200
mg/kg. The
average daily inhalation dosage regimen will preferably be from 0.01 to 100
mg/kg of
s total body weight.
Of course the specific initial and continuing dosage regimen for each patient
will vary according to the nature and severity of the condition as determined
by the
attending diagnostician, the activity of the specific compound employed, the
age and
to general condition of the patient, time of administration, route of
administration, rate of
excretion of the drug, drug combinations, and the like. The desired mode of
treatment and number of doses of a compound of the present invention or a
pharmaceutically acceptable salt or ester or composition thereof can be
ascertained
by those skilled in the art using conventional treatment tests.
The compounds of this invention can be administered as the sole
pharmaceufiical agent or in combination with one or more other pharmaceutical
agents where the combination causes no unacceptable adverse effects. For
example, the compounds of this invention can be combined with known anti-hyper-
2o proliferative or other indication agents, and the like, as well as with
admixtures and
combinations thereof.
Optional anti-hyper-proliferative agents which can be added to the
composition include but are not limited to compounds listed on the cancer
2s chemotherapy drug regimens in the 11th Edition of the Merck Index, (1996),
which is
hereby incorporated by reference, such as asparaginase, bleomycin,
carboplatin,
carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine,
dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine),
epirubicin,
etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide,
irinotecan,
30 leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna,
methotrexate,
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mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen,
streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and
vindesine.
s Other anti-hyper-proliferative agents suitable for use with the composition
of
the invention include but are not limited to those compounds acknowledged to
be
used in the treatment of neoplastic diseases in Goodman and Gilman's The
Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al.,
publ. by
McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by
reference,
io such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine
cladribine,
busulfan, diethylstilbestrol, 2', 2'-difluorodeoxycytidine, docetaxel,
erythrohydroxynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-
fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone,
flutamide, hydroxyprogesterone caproate, idarubicin, interferon,
is medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane,
paclitaxel,
pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine,
teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and
vinorelbine.
~o Other anti-hyper-proliferative agents suitable for use with the composition
of
the invention include but are not limited to other anti-cancer agents such as
epothilone and its derivatives, irinotecan, raloxifen and fiopotecan.
Generally, the use of cytotoxic and/or cytostatic agents in combination with a
2s compound or composition of the present invention will serve to:
(1 ) yield better efficacy in reducing the growth of a tumor or even eliminate
the
tumor as compared to administration of either agent alone,
(2) provide for the administration of lesser amounts of the administered
3o chemotherapeutic agents,
CA 02516627 2005-08-19
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(3) provide for a chemotherapeutic treatment that is well tolerated in the
patient with fewer deleterious pharmacological complications than observed
with
single agent chemotherapies and certain other combined therapies,
(4) provide for treating a broader spectrum of different cancer types in
s mammals, especially humans,
(5) provide for a higher response rate among treated patients,
(6) provide for a longer survival time among treated patients compared to
standard chemotherapy treatments,
(7) provide a longer time for tumor progression, and/or
io (8) yield efficacy and tolerability results at least as good as those of
the agents
used alone, compared to known instances where other cancer agent combinations
produce antagonistic effects.
Preparation of synthetic intermediates
is
Abbreviations used in this specification
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DMF N,N-dimethyl formamide
DCM Dichloromethane
DCE 1,2-dichloroethane
DMS~ dimethyl sulphoxide
HPLC High pressure liquid chromatography
MPLC . Medium pressure liquid chromatography
LC-MS liquid chromatography - coupled mass
spectroscopy
RT retention time
MP melting point
NMR nuclear resonance spectroscopy
TLC thin layer chromatography
46
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ES electrospray
DMA N,N-dimethylacetamide
HRMS high resolution mass spectroscopy
CDI 1,1'-carbonyldiimidazole
HOBT 1-hydroxybenzotriazole
EDCI 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide
hydrochloride
TMSCI Trimethylsilyl chloride
m-CPBA 3-chloroperbenzoic acid
HEPES N-(2-hydroxyethyl)-piperazine-N'-(2-ethane
sulphonic acid)
Tris/hydrochloric Iris(hydroxymethyl)-aminomethane hy-
acid
drochloride
T""Triton X-100~ tert.-octyl-phenoxypolyethoxyethanol, Rohm &
Haas, USA
The yield percentages ofi the fiollowing examples refer to the starting
component which was used in the lowest molar amount.
s LC-MS conditions: HPLC - electrospray mass spectra (HPLC ES-MS) were
obtained
using a Gilson HPLC system equipped with two Gilson 306 pumps, a Gilson 215
Autosampler, a Gilson diode array detector, a 1'MC Pro C-18 column (2 x 23mm,
120
A), and a Micromass LCZ single quadrupole mass spectrometer with z-spray
efectrospray ionization. Spectra were scanned from 120-1000 amu over 2
seconds.
io ELSD (Evaporative Light Scattering Detector) data was also acquired as an
analog
channel. Gradient elution was used with Buffer A as 2% acetonitrile in water
with
0.02% TFA and Buffer B as 2% water in Acetonitrile with 0.02% TFA at 1.5
mL/min.
Samples were eluted as follows: 90% A for D.5 minutes tamped to 95% B over 3.5
minutes and held at 95% B for 0.5 minutes and then the column is brought back
to
is initial conditions over 0.1 minutes. Total run time is 4.8 minutes.
47
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Preparative HPLC; Preparative HPLC was obtained using a Gilson HPLC system
epuipped with two Gilson 322 pumps, a Gilson 215 Autosampler, a Gilson diode
array detector, a YMC Pro C-18 column (20 x 150 mm, 120 A). Gradient elution
was
s used with Buffer A as water with 0.1 % TFA and Buffer B as acetonifirile
with 0.1
TFA. Sample was dissolved in MeOH or MeOH/DMSO with concentration about 50
mg/ml. Injection volume was aboufi 2-3 mL/injection. Sample was eluted as
follows:
10-90% B over 15 minutes with flow rate of 25 mL/min, hold 2 minutes, back to
10%
B. Desired fraction was collected with UV at 254 or 220 nm and evaporated with
to GeneVac speed vacuum.
Preparation of 4-(4-Amino-phenoxY)pyridine-2-carboxylic acid methyl ester
o
0 ~ ~i
i I ~N
NH2
Step 1: Preparation of 4-Chlor~~yridine-2-carbonyl chloride hydrochloride
c1
1w
N~ c~
Hc~ o
2o Anhydrous DMF (6.0 mL) was slowly added to SOC12 (180 mL) between 40
°C
and 50 °C. The solution was stirred in that temperature range for 10
min., then
picolinic acid (60.0 g, 487 mmol) was added in portions over 30 min. The
resulting
solution was heated at 72 °C for 16h to generate a yellow solid
precipitate. The
resulting mixture was cooled to RT, diluted with toluene (500 mL) and
concentrated
2s to half its volume. The resulting residue was filtered and the solids were
washed with
~a
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toluene and dried under high vacuum for 4h to afford 4-chloropyridine-2-
carbonyl
chloride HCI salt as a yellow solid (92.0 g, 89%).
Step 2: Preparation of 4-Chloro~yridine-2-carboxylic acid methylamide
s
cl
H
N NCH
3
0
A suspension of methyl 4-chloropyridine-2-carboxylate HCI salt (89.0 g, 428
mmol) in MeOH (75 mL) at 0 °C was treated with a 2.0 M methylamine
solution in
to THF (1 L). The resulting mixture was stored at 3 °C for 5h, then
concentrated under
reduced pressure. The resulting solids were suspended in EtOAc (1 L) and
filtered.
The filtrate was washed with a saturated NaCI solution (500 mL), dried over
Na2S04,
and concentrated under reduced pressure to afford 4-chloro-N-methyl-2-
pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%). ~H-NMR (DMSO-ds) 8
is 2.81 (s, 3H), 7.74 (dd, J = 5.1, 2.2 Hz, 1 H), 8.00 (d, J = 2.2 Hz, 1 H),
8.61 (d, J = 5.1
Hz, 1 H), 8.85 (br d, 1 H); CI-MS m/z 171 (MH+); m.p. 41-43 °C.
Step 3: Preparation of 4-(4-Aminophenoxy)pyridine-2-carboxylic acid
methLrlamide
0
NHMe
~N
20 H2N
A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anhydrous DMF (150 mL)
was treated with potassium tent-butoxide (10.29 g, 91.7 mmol), and the reddish-
2s brown mixture was stirred at RT for 2h. The contents were treated with 4-
chloropyridine-2-carboxylic acid methylamide (15.0 g, 87.9 mmol) and K2C03
(6.50 g,
47.0 mmol) and then heated at 80 °C for 8h. The mixture was cooled to
RT and
49
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partitioned between EtOAc (500 mL) and a saturated NaCI solution (500 mL). The
aqueous phase was back-extracted with EtOAc (300 mL). The combined organic
layers were washed with brine, dried over Na2S04, and concentrated under
reduced
pressure. The resulting solids were dried under reduced pressure at 35
°C for 3h to
s afford the title compound (17.9 g, 84%) as a light-brown solid. ~H-NMR (DMSO-
d6)
8 2.77 (d, J = 4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA'BB' quartet, J =
8.4 Hz,
4H), 7.06 (dd, J = 5.5, 2.5 Hz, 1 H), 7.33 (d, J = 2.5 Hz, 1 H), 8.44 (d, J =
5.5 Hz, 1 H),
8.73 (br d, 1 H); HPLC ES-MS m/z 244 (MH+).
to Step 4: Preparation of the title compound 4- 4-Amino-~henoxy)pyridine-2-
carboxylic
acid meth Irk ester
A mixture of 4-(4-aminophenoxy)pyridine-2-carboxylic acid methylamide (15.0
g, 61.7 mmol) and potassium hydroxide (34.6 g, 617 mmol) in ethanol (400 mL)
and
water (40 mL) was stirred at 90 °C for 48h. After cooling to RT, 2.0 N
hydrochloric
is acid was slowly added to the reaction mixture until pH = 5. The solvent was
removed
completely and the residue redissolved in MeOH (400 mL). After slow addition
of
trimethylsilylchloride (178 mL, 140 mmol, 2.27 eq) at 0 °C, the
reaction mixture was
stirred at reflux for 24h and cooled to RT. The mixture was filtered, and the
filtrate
concentrated under reduced pressure and then partitioned between DCM and
water.
2o The organic layer was then washed with 1 M aqueous sodium bicarbonate
solution,
dried over Na2SO4, filtered, and evaporated under reduced pressure. The
resulting
residue was washed further with H2O and reextracted with EtOAc/ Hex (1:2 v/v)
to
afford the desired ester (6.27 g, 42%) as a light brown solid. 'H-NMR (DMSO-
d6) ~
8.51 (d, J = 5.7 Hz,1 H), 7.35 (d, J = 2.4 Hz, 1 H), 7.10 (dd, J = 5.7, 2.7
Hz, 1 H), 6.86
2s (dt, J = 9.0, 2.4 Hz, 2H), 6.63 (dt, J = 8.7, 2.4 Hz, 2H), 5.18 (br s, 2H),
3.86 (s, 3H);
MS LC-MS [M+H]+ = 245, RT = 1.04 min; TLC (75% EtOAc/hex), Rf = 0.20.
Preparation of 4-(3-Aminophenox~~pyridine-2-carboxylic acid
CA 02516627 2005-08-19
WO 2004/078128 PCT/US2004/006295
O
H2N ~ O
OH
/ I ~N
Step 1: Preparation of 4-(3-AminophenoxY~pyridine-2-carboxylic acid
methylamide
O
H2N ~ O
N
~N H
The title compound was prepared in the same manner described for 4-(4-
aminophenoxy)pyridine-2-carboxylic acid methylamide, substituting 3-
aminophenol
to for 4-aminophenol. 1H-NMR (DMSO-ds) 8 8.75 (br q, J = 4.8 Hz, 1 H), 8.48
(d, J =
6.3 Hz, 1 H), 7.39 (d, J = 2.1 Hz, 1 H), 7.15 to 7.07 (m, 2H), 5.51 to 6.47
(m, 1 H), 6.31
to 6.24 (m, 2H), 5.40 (s, 2H), 2.77 (d, J = 5.1 Hz, 3H).
Step 2: Preparation of the title compound 4-(3-Aminophenoxy)pyridine-2-
carboxylic
aCld
A mixture of 4-(3-aminophenoxy)pyridine-2-carboxylic acid methylamide (5.64
g, 23.81 mmol) and potassium hydroxide (13.01 g, 232 mmol) in EtOHlH2O (55 mL,
10:1 ) was stirred at 90 °C for 48 h. The mixture was concentrated in
vacuo, and the
crude residue was dissolved in HBO (100 mL). The solution was carefully
adjusted to
2o pH = 6-7 with aq. 1 N HCI, and the resultant precipitate was filtered. The
filtrate was
then concentrated in vacuo, and the crude material was diluted with MeOH (150
mL),
and the solid was collected. The combined filtered solids were washed with
CH2C12
to give 5.25 g (98°I°) of 4-(3-amino-phenoxy)pyridine-2-
carboxylic acid. 1H-NMR
(CD30D) ~ 8.45 (d, 1 H), 7.60 (d, 1 H), 7.17 (t, 1 H), 7.09 (d, 1 H), 6.64
(dd, 1 H), 6.47
2s 6.45 (m, 1 H), 6.40 (dd, 1 H); MS LC-MS [M+H]+ = 231.
Preparation of 4-(3-Aminophenoxy~pyridine-2-carboxylic acid methyl ester
51
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O
H2N \ O \ Oi
I i I ~N
To a 0 °C MeOH solution (100 mL) containing TMSCI (4.72 g, 43.4
mmol) was
s slowly added 4-(3-aminophenoxy)pyridine-2-carboxylic acid (0.5 g, 2.17 mmol)
in
MeOH (5 mL), and the reaction mixture heated to reflux for 12 h. The solvent
was
removed in vacuo, and residue partitioned between CH2CIa and H20. The organic
layer was dried over NaaS04, filtered, and concentrated in vacuo. The crude
residue
was purified by silica gel chromatography eluting with hexanes/EtOAc (gradient
- 3/7
to to 2/3) to obtain the desired product, 0.25 g (48%). ~H-NMR (CD30D) b 8.49
(d, 1 H),
7.20 (d, 1 H), 7.14 (dd, 1 H), 6.64 (dd, 1 H), 6.45 (t, 1 H), 6.40 (dd, 1 H),
3.92 (s, 3H);
MS LG-MS [M+H]~ = 245.1, RT = 0.52 min.
Preparation of 4-(2-f 1,3 4]Oxadiazol-2-~rl-p rLridin-4- loxy)phen lad mine
HaN
O
O ~ NO
c.
N-N
Step 1: Preparation of 4-chloropyridine-2-carbox lic acid methyl ester
c
,o I NJ
O
A mixture of 4-chloropyridine-2-carbonyl chloride HCI (1.75 g, 8.22 mmol) and
52
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triethylamine (3.8 mL, 24.14 mmol, 3.3 eq) in THF (16 mL) and MeOH (4 mL) was
stirred at 0 °C for 2h until all of the SM has been consumed. The
solvent was
concentrated under reduced pressure, and the resultant crude material was
purified
using MPLC (biotage) eluted with 25 to 50% EtOAc-hexane to afFord 878 mg
(60.7%)
s of the methyl ester as a light tan crystalline solid. ~H-NMR (DMSO-d6) 8
8.69 (d, J =
5.4 Hz, 1 H), 8.07 (d, J = 2.1 Hz, 1 H), 7.82 (dd, J = 5.4, 2.1 Hz, 1 H), 3.89
(s, 3H); TLC
(50% EtOAc/Hex), Rf = 0.40.
Step 2: Preparation of 4-Chlorot~yridine-2-carboxylic acid hydrazide
io
cl
N.N
HZ ~N
O
To 4-chloro-pyridine-2-carboxylic acid methyl (850 mg, 4.95 mmol) in
anhydrous MeOH (50 mL) was added hydrazine hydrate (2.48 g, 49.5 mmol)
is dropwise, and the reaction mixture was stirred under argon at RT for 18 h.
The
mixture was diluted with EtOAc (200 mL), and the organic layer was washed with
water and brine, dried over Na2S04, filtered, and concentrated under reduce
pressure. Recrystallization from MeOH afforded 500 mg (59%) of 4-
chloropyridine-2-
carboxylic acid hydrazide. ~H-NMR (Acetone-ds) 8 9.38 (s, 1 H), 8.60 (d, 1 H),
8.08
20 (d, 1 H), 7.64 (dd, 1 H), 4.46 (s, 2H); MS LC-MS [M+H]+ = 172, RT = 0.86
min; TLC
(100% EtOAc), Rf = 0.35.
Step 3: Preparation of 4-Chloro-2-L 3 4loxadiazol-2- l-pyridine
C~
O ' N
c.
25 N-N
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A mixture of 4-chloro-pyridine-2-carboxylic acid hydrazide (550 mg, 2.91
mmol) in triethyl orthoformate (10 mL) was refluxed under argon for 48 h. The
mixture was diluted with EtOAc (200 mL), and the organic layer was washed with
s water and brine, dried over Na2S04, filtered, and concentrated under reduce
pressure. The crude residue was purified by flash chromatography eluted with
50%
EtOAc/Hex to give 360 mg (68%) of 4-chloro-2-[1,3,4]oxadiazol-2-yl-pyridine.
~H-
NMR (Acetone-d6) 8 9.16 (s, 1 H), 8.76 (d, 1 H), 8.26 (d, 1 H), 7.74 (dd, 1
H); MS LC-
MS [M+H]+ = 182, RT = 1.36 min; TLC (100°l° EtOAc), Rf =
0.70
to
Step 4: Preparation of the title compound 4-(2-~1 3 410xadiazol-2-yl-~ ridin-4
yloxY phenylamine
The title compound was prepared in the same manner as 4-(4
aminophenoxy)pyridine-2-carboxylic acid methylamide mentioned above,
substituting
is 4-chloro-2-[1,3,4]oxadiazol-2-yl-pyridine for 4-chloropyridine-2-carboxylic
acid. ~H
NMR (Acetone-d6) 5 9.04 (s, 1 H), 8.59 (d, J= 6.0 Hz, 1 H), 7.62 (d, J = 2.4
Hz, 1 H),
7.06 (dd, J = 2.4 Hz, 5.7 Hz, 1 H), 6.96 (d, J = 6.9 Hz, 2H), 6.78 (d, J = 6.9
Hz, 2H),
4.81 (s, 2H); MS LC-MS [M+H]+ = 255, RT = 0.95 min; TLC (100% EtOAc) = 0.55.
2o Preparation of N-f4-Chloro-3-(trifluoromethyl)phenyll-N'-f4 f(2
cyanopyridin 4
yl)oxylphenyl~urea
CI
O I ~ CN
N J~ ~ N
H H
2s Step 1: Preparation of N [4-Chloro-3-(trifluoromethyl)phenyl]-N'-[4-
(pyridin-4-
yloxy)phenyl]-urea
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CA 02516627 2005-08-19
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CF3
CI / ~ C
\ N- 'N / i N
H H
To a solution of 4-(4-aminophenoxy)pyridine (2 g, 10.74 mmol) in DCM (10
mL) was added 4-chloro-3-trifluoromethyl isocyanate (2.4 g, 10.74 mmol). The
s solution was stirred overnight at room temperature. The solvent was removed
by
distillation, and the resultant solid was washed with EtOAc to give 3.6 g (82
%) of the
title product; MS LC-MS [M+H]+ = 408.
Step 2: Preparation of N-[4-Chloro-3-(trifluoromethyl)phenyl]-N'-{4-[(1-
oxidopyridin-4-
to yl)oxy]-phenyl~urea
CF3
CI / ~ C ~ \ C ~ \
\ N~N /
H H
To a solution of N [4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-(pyridin-4-
yloxy)phenyl]-urea (3.1 g, 7.6 mmol) in DCM (40 mL) and acetone (10 mL) was
is added m-CPBA (1.5 g). The mixture was stirred at room temperature for 12 h,
followed by addition of another portion of m-CPBA (1.5 g) and the solution was
sfiirred for another 12 h at RT. The solution was then washed with 10% aqueous
sodium carbonate. The solvent was removed to give the title product, 2.9 g (90
%);
MS LC-MS [M+H]+ = 424.
Step 3: Preparation of the title compound N-[4-Chloro-3-
(trifluoromethyl)phenyl]-N'-
(4-[(2-cyanopyridin-4-yl)oxy]phenyl}urea
To a solution of N [4-chloro-3-(trifluoromethyl)phenyl]-N'-~4-[(1-oxidopyridin-
4
yl)oxy]-phenyl}urea (2 g, 4.72 mmol) in anhydrous DMF (50 mL) was added
2s trimethylsilyl cyanide (0.7 g, 7.1 mmol) at room temperature, followed by
dropwise
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addition of dimethyl carbamyl chloride (1.27 g, 11.8 mmol) in DMF (10 mL) over
30
min. The mixture was stirred at room temperature for 24 h. A solution of 10
°l°
aqueous sodium carbonate (50 mL) was added dropwise and stirred for 10 min,
followed by extraction with EtOAc (3x). The extracts were combined, dried over
s MgS04, and evaporated under reduced pressure. The residue was purified by
flash
to
chromatography (EtOAc:Hexane:MeOH 45:45:10) to afford 1.8 g (88%) of the title
product. ~H-NMR (DMSO-d6) 8 9.20 (s, 1 H), 9.01 (s, 1 H), 8.57 (d, J = 5.7 Hz,
1 H),
8.10 (d, J = 2.4 Hz, 1 H), 7.66 to 7.56 (m, 5H), 7.19 to 7.14 (m, 3H); MS LC-
MS
[M+H]+ = 433, RT = 3.56 min; TLC (75% EtOAc/Hex), Rf = 0.53.
Preparation of N-~4-[(2-Cyanop~iridin-4-yl)oxy]phen~~N'2,2,4,4-tetrafluoro-4H-
1,3-
benzodioxin-6-yl)urea
F FO , O \ O \ CN
~O \ I ~ I / I ~N
~N N
15 F F H H
Step 1: Preparation of 4-(4-Aminophenoxy~pyridine-2-carbonitrile
\ O \ CN
~N
H2N
A solution of 4-aminophenol (1.0 g, 9.16 mmol) in anhydrous DMF (9.2 mL)
was treated with potassium terf butoxide (1.08 g, 9.62 mmol, 1.05 eq), and the
orange-brown reaction mixture was stirred at RT for 1 h. The contents were
treated
with 2-cyano-4-chloropyridine (1.27 g, 9.16 mmol, 1.0 eq) and K2C03 (497 mg,
5.04
2s mmol, 0.55 eq) and then heated at 90 °C for 17h. The mixture was
cooled to RT and
partitioned between EtOAc (250 mL) and a saturated NaCI solution (100 mL). The
aqueous phase was back-extracted with EtOAc (300 mL). The combined organic
layers were washed with brine, dried over Na2S04, and concentrated under
reduced
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WO 2004/078128 PCT/US2004/006295
pressure. Purification on MPLC (biotage) eluted with 30% EtOAc - hexanes
afforded
1.83 g (94.6%) of 4-(4-aminophenoxy)pyridine-2-carbonitrile as a yellow solid.
~H
NMR (DMSO- d6) ~ 8.52 (d, J = 6.3 Hz, 1 H), 7.54 (d, J = 2.4 Hz, 1 H), 7.07
(dd, J =
5.4, 2.4 Hz, 1 H), 6.86 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 8.7 Hz, 2H), 5.21
(s, 2H); MS
s LC-MS [M+H]~ = 212, RT = 0.98 min; TLC (50% EtOAc/Hex), Rf= 0.28.
Step 2: Preparation of the title compound N-~4 j(2-C anopyridin-4-
yl~ox~~phenyl -N'-
(2,2,4,4-tetrafluoro-4H-1 3-benzodioxin-6-yl urea
A solution of 4-(4-aminophenoxy)pyridine-2-carbonitrile (300 mg, 1.42 mmol)
io and 2,2,4,4-tetrafluoro-6-isocyanate-1,3-benzodioxene (389.2 mg, 1.56 mmol,
1.1
eq) in anhydrous 1,2-dichloroethane (7.1 mL) was stirred at 80 °C under
argon for
17h, where upon a white solid precipitated out during the course of the
reaction. The
reaction mixture was cooled to RT, and the precipitate was collected and
washed
with DCM (3.0 mL) and ether (3 x 5 mL) to give 355 mg (54.3 °l°)
of the title
is compound. ~H-NMR (DMSO-d6) 89.14 (s, 1 H), 9.03 (s, 1 H), 8.57 (d, J = 6.0
Hz, 1 H),
8.11 (d, J = 2.7 Hz, 1 H), 7.66 to 7.57 (m, 4H), 7.43 (d, J = 9.0 Hz, 1 H),
7.19 to 7.14
(m, 3H); MS LC-MS [M+H]+ = 461, RT = 3.59 min; TLC (75% EtOAc/Hex), Rf = 0.29.
Preparation of N-f4-f(2-cyanopyridin-4-yl)oxylphenyl -N'- 1-meth~H-indazol 5
I urea
~ O ~ GN
O
N ~ '~ I J-'. I / I ~ N
N N
H H
To a solution of 1-methyl-5-aminoindazole (230 mg, 1.56 mmol) in anhydrous
2s DCE (2.4 mL) was added 1,1'-carbonyldiimidazole (281.5 mg, 1.70 mmol, 1.2
eq),
and the reaction mixture was stirred at 65 °C under argon. After 16h a
solution of 5
(4-aminophenoxy)pyridine-2-carbonitrile (300 mg, 1.42 mmol, 0.91 eq) in
anhydrous
THF (4.0 mL) was added at ambient temperature, and the reaction mixture was
stirred at 65 °C under argon for 7h. The reaction mixture was
partitioned between
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EtOAc and water, and the organic layer was washed with water and brine, dried
over
Na2S04, filtered, and concentrated under reduced pressure. The crude residue
was
triturated in DCM (10 mL) to afford 382.4 mg (70 °l°) of the
title compound as a white
solid. ~H-NMR (DMSO-d6) 88.84 (s, 1 H), 8.70 (s, 1 H), 8.57 (d, J = 6.0 Hz, 1
H), 7.95
s (d, J = 1.0 Hz, 1 H), 7.90 (d, J = 1.8 Hz, 1 H), 7.60 to 7.54 (m, 4H), 7.36
(dd, J = 9.3,
2.1 Hz, 1 H), 7.18 to 7.14 (m, 3H), 4.01 (s, 3H); MS LC-MS [M+H]+ = 385, RT =
2.64
min; TLC (100% EtOAc), Rf= 0.22.
Preparation of N-f4-ff2-cyanop rids in-4-yl oxylphenyl~-N'-cpinolin-6-yurea
to
N~ ~ O \ O ~ CN
~N
N N
H H
The title compound was prepared in the same manner described for N-~4-[(2-
cyanopyridin-4-yl)oxy]phenyl}-N-(1-methyl-1 H-indazol-5-yl)urea, substituting
h-
is aminoquino-line for 1-methyl-5-aminoindazole. ~H-NMR (DMSO-d6) 8 8.76 (dd,
J =
2.7, 7.2 Hz, 1 H), 8.58 (dd, J = 0.6, 5.7 Hz, 1 H), 8.51 (s, 1 H), 8.44 (s, 1
H), 8.28 (d, J =
2.7 Hz, 1 H), 8.21 (dd, J = 0.6, 7.8 Hz, 1 H), 7.96 (d, J = 9.3 Hz, 1 H), 7.78-
7.71 (m,
3H), 7.49-7.42 (m, 2H), 7.22-7.17 (m, 3H); MS LC-MS [M+H]+ = 382, RT = 2.03
min;
TLC (100% EtOAc), Rf = 0.38.
Preparation of Methyl 41f3-(~,[~1-methyl-1 H-indazol-5
yl)aminolcarbonyl}amino)phenoxyl-p~tridine-2-carboxylate
O \ / N
N~ \ ~ ~ ~ / \ I
N N O
2s N H O
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To a solution of 4-(3-amino-phenoxy)-pyridine-2-carboxylic acid methyl ester
(0.79 g, 5.35 mmol) in DCM (3 mL) was added 1,1'-carbonyldiimidazole (0.87 g,
5.35
mmol), and the reaction mixture was stirred at room temperature for 12 h. A
solution
of 1-methyl-5-aminoindazol (1.02 g, 6.96 mmol) in DCM (4 mL) was added, and
the
s mixture stirred at room temperature an additional 8 h. The mixture was
concentrated
in vacuo. Purification of the crude product by column chromatography eluted
with
5% MeOH - DCM gave 850 mg (38%) of the title compound. ~H-NMR (CD30D)
8 8.57 (dd, 1 H), 7.95 (d, 1 H),7.87 (d, 1 H), 7.54 (d, 1 H), 7.53-7.51 (m,
2H), 7.47-7.32
(m, 2H), 7.32 (d, 1 H), 7.21 (dd, 1 H), 6.86 (dd, 1 H). 4.07 (s, 3H), 3.96 (s,
3H); MS
to LC-MS [M+H]+ = 418, RT = 2.91 min.
Preparation of Methyl 4-f3-(f~(2 2 4,4-tetrafluoro-4H-1 3-benzodioxin-6-
yl)aminol-carbonylamino)phenoxyl~yridine-2-carboxylate
is
F F H H O
F O I ~ N~N I ~. O ~ I Oi
O ~ IOI ~ w N
F
To a stirring solution of 2,2,4,4-tetrafluoro-6-isocyanato-1,3-benzodioxene
(0.816 g, 3.28 mmol) was added 4-(3-aminophenoxy)pyridine-2-carboxylic acid
2o methyl ester (0.800 g, 3.28 mmol) in DCM (13 mL) in portions. The
homogenous
contents turned white and opaque within 1 min. of addition, and were allowed
to stir
at room temperature for 12 h. The heteroaenous mixture way fIItPYP~ an~a ~"n,a
product repeatedly washed with DCM to remove residual starting material. The
desired product was collected as a white powder, 1.36 g (83%). ~H-NMR (DMSO-
d6)
2s 8 9.08 (d, 2H), 8.59 (s, 1 H), 8.07 (s, 1 H), 7.60 (dd, 1 H), 7.37 (m, 4H),
7.25 (d, 1 H),
7.20 (dd, 1 H), 6.80 (d, 1 H), 3.82 (s, 3H); MS LC MS [M+H]+ = 494.1, RT =
3.23 min.
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Preparation of Methyl 4-~4-(~~(4-Chloro-3-trifluoromethyl-
phenyl)aminolcarbonyl}amino)-phenox ridine-2-carbox IrLate
CF3 O
CJ \ ~ ~ ~ \ O / N O/
w
N N
H H
The title compound was prepared in the same manner described for methyl 4-
[3-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]-
carbonyl}amino)phenoxy]pyridine-2-carboxylate, substituting 4-chloro-3-
(trifluoromethyl)phenyl isocyanate for 2,2,4,4-tetrafluoro-6-isocyanate-1,3-
~o benzodioxene, and 4-(4-aminophenoxy)pyridine-2-carboxylic acid methyl ester
for 4-
(3-aminophenoxy)pyridine-2-carboxylic acid methyl ester. ~H-NMR (DMSO-d6) 8
9.21 (s, 1 H), 9.00 (s, 1 H), 8.57 (d, J = 6.0 Hz, 1 H), 8.11 (d, J = 2.1 Hz,
1 H), 7.64 to
7.56 (m, 4H), 7.41 (d, J = 3.0 Hz, 1 H), 7.19 to 7.15 (m, 3H), 3.83 (s, 3H);
MS LC-MS
[M+H]~ = 466.
1s
Preparation of Methyl 4-f4-(~2 2 4 4-tetrafluoro-4H-1 3-benzodioxin-6
yl)aminolcarbon~}amino)phenoxylpyridine-2-carboxLrlate
F F
O
F F O
O
O \ ~ ~ ~ \ O / N /
N N
H H
2Q
The title compound was prepared in the same manner described for methyl 4-
[3-(~[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]-
carbonyl}amino)phenoxy]pyridine-2-carboxylate, substituting 4-(4-
aminophenoxy)pyridine-2-carboxylic acid methyl ester for 4-(3-
2s aminophenoxy)pyridine-2-carboxylic acid methyl ester. ~H-NMR (Acetone-ds) 8
8.85
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(broad s, 1 H), 8.73 (broad s, 1 H), 8.56 (d, J = 5.7 Hz, 1 H), 8.17 (d, J =
2.7 Hz, 1 H),
7.75 (dd, J = 9.0, 2.4 Hz, 1 H), 7.67 (dt, J = 9.0, 3.6 Hz, 2H), 7.55 (d, J =
2.4 Hz, 1 H),
7.26 (dd, J = 9.0, 1.2 Hz, 1 H), 7.15 to 7.08 (m, 3H), 3.90 (s, 3H); MS LC-MS
[M+H]+
= 494.
Preparation of 4-f3-(~j(1-Methyl-1 H-indazol-5-
yUamino]carbonyl'~amino phenoxylpyridine-2-carboxylic acid
i
N\ / ~ O ~ \ / ~ OH
N_ 'N ~ O \'
H H I
O
A mixture of methyl 4-[3-(~[(1-methyl-1 H-indazol-5-yl)amino]carbonyl)amino)-
phenoxy]pyridine-2-carboxylate (0.08 g, 0.19 mmol). and potassium hydroxide
(0.03
g, 0.56 mmol) in MeOH/H20 (4 mL, 3:1 ) was heated at 40 °C for 3 hours.
The
solvent was removed under reduced pressure, and the crude residue was
dissolved
is in H2O (5 mL). The aqueous solution was neutralized with aq. 1 N HCI. The
precipitated solid was then washed with water followed by DCM to give 0.55 g
(70°I°)
of the title compound. 1H-NMR (DMSO-d6) 8 9.97 (s, 1 H), 9.77 (s, 1 H), 8.46
(d, 1 H),
7.93 (s, 1 H), 7.90 (s, 1 H), 7.51 (d, 1 H), 7.43-7.34 (m, 5H), 7.07 (dd, 1
H), 6.73 (dd,
1 H), 3.97 (s, 3H); MS LC-MS [M+H] ~ - 404.
Preparation of ~4-f3-(2 2,4 4-Tetrafluoro-4H-benzof 1131dioxin-6
r~l)phenoxyll7heny~acetic acid
F F H H O
F O I \ N~N ~ 4 O 4 \ OH
O \ iN
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The title compound was prepared in the same manner described for 4-[3-(~((1-
methyl-1 H-indazol-5-yl)amino]carbonyl)amino)phenoxy]pyridine-2-carboxylic
acid,
substituting methyl 4-[3-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-
yl)amino]-
carbonyl)amino)phenoxy]-pyridine-2-carboxylate for methyl 4-[3-({[(1-methyl-1
H-
s indazol-5-yl)amino]carbonyl}amino)-phenoxy]-pyridine-2-carboxylate. ~H-NMR
(DMSO-ds) ~ 9.58 (s, 1 H), 9.39 (s, 1 H), 8.58 .(d, 1 H), 8.08 (d, 1 H), 7.62
(dd, 1 H),
7.38-7.47 (m, 4H), 7.32 (dd, 1 H), 7.18 (dd, 1 H), 6.83 (dd, 1 H); MS LC-MS
[M+H]+ -
480.
to
Preparation of 4-~3~~4-chloro-3-trifluoromethyl-
phenyl amino]carbonyl~amino phenoxVl ~Yridine-2-carboxylic acid
H H O
F3C ~ N~N / O
OH
O ~ I I ~N
CI
The title compound was prepared in the same manner described for 4-[4-(~[(4-
Chloro-3-trifluoromethylphenyl)amino]carbonyl}amino)phenoxy]pyridine-2-
carboxylate, substituting 4-(3-aminophenoxy)pyridine-2-carboxylic acid for 4-
(4-
aminophenoxy)pyridine-2-carboxylic acid methyl ester. ~H-NMR (CD3~~) 8 8.66
(d,
J = 4.2 Hz, 1 H), 8.03 (d, J = 2.7 Hz, 1 H), 7.77 (d, J = 2.2 Hz, 1 H), 7.67
(dd, J = 1.8,
5.4 Hz, 1 H), 7.60 (t, J = 2.7 Hz, 1 H), 7.59 to 7.49 (m, 2H), 7.41 to 7.37
(m, 2H), 6.06
(dd, J = 2.4 Hz, 1 Hz, 1 H); MS LC-MS [M+H]+ = 452, RT = 2.54 min.
Zs The present invention provides, but is not limited, to the embodiments
defined
in the following paragraphs:
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Examples
Example 1
Preparation of 4 ~4-((1'(4-Chloro-3-
s Ctrifluoromethyl~phenyliaminolcarbonyl~aminolphenoxy~~yridine-2-
carboximidamide
CF3 NH
CI / ~ O ~ ~ O ~ \ NH2
\ N~N / ~- N
H H
To a mixture of ammonium chloride (1.73 mmol) in toluene at 0 °C
was added
to trimethylaluminum (1.73 mmol, 0.87 mL of 2 M in toluene), and the mixture
was
stirred at RT until the reacfiion becomes clear. N-[4-Chloro-3-
(trifluoromethyl)phenyl]-
N~{'4-[(2-cyanopyridin-4-yl)oxy]phenyl}urea (0.35 mmol, 150 mg) was then added
and the mixture was heated at 90 °C for 18 h. The solvent was removed
and the
residue was purified by flash chromatography (35:9:5:1 v/v
is EfiOAc:MeCH:hexane:NH4~H) to give 18 mg (17°/~) of the title product
as a white
solid. ~H-NMR (CD30D) 88.61 (s, 1 H), 8.00 (s, 1 H), 7.79 (s, 1 H), 7.58 (m,
3H), 7.52
(m, 3H), 7.10 (m, 3H); MS LC-MS [M+H]~ = 450, RT = 3.13 min.
2o Example 2
Preparation of 4-~4-[~~(4-Chloro-3
(trifluoromethyl)phenyllamino)carbonyl)aminolphenox~~-N-methylpyridine-2
carboximidamide
CF3 NH
CI / ~ p ( \ O ~ \ H
\ N"N / i N
25 H H
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To a mixture of methylamine hydrochloride (117 mg, 1.73 mmol) in anhydrous
toluene at 0 °C was added trimethylaluminum (1.73 mmol, 0.87 mL of 2 M
in
toluene), and the reaction mixture was stirred at RT until the reaction
becomes clear.
N-[4-Chloro-3-(trifluoromethyl)phenyl]-N-(4-[(2-cyanopyridin-4-
yl)oxy]phenyl)urea
s (0.35 mmol, 150 mg) was then added, and the mixture heated at 90 °C
for 17 h. The
solvent was then removed and the residue was purified by flash chromatography
(35:10:4:1 v/v EtOAc:MeOH:Hexane:NH40H) to give 79 mg (49%) of the title
product
as a yellow solid. ~ H-NMR (DMSO-d6) 8 10.14 (s, 1 H), 9.80 (s, 1 H), 10.05 to
9.20
(broad s, 2H), 8.62 (d, J = 5.4 Hz, 1 H), 8.10 (s, 1 H), 7.89 (d, J = 2.4 Hz,
1 H), 7.62 to
l0 7.52 (m, 4H), 7.19 to 7.15 (m, 3H), 3,02 (s, 3H); MS LC-MS [M+H]+ = 464, RT
= 2.54
min.
Example 3
Preparation of N-Methyl-4-f4-~f f(2,2 4 4-tetrafluoro-4H-1 3-benzodioxin-6-
ls y!)aminolcarbonyl -amino)~heno~lwridine-2-carboximidamide
F O F
F~ F NH
O / ~ ~O ~ \ O ~ \ H
\ N"N / ~ N
H H
The title compound was prepared in the same manner described for 4-{4-[({[4-
20 chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-
methylpyridine-2-
carboximid-amide, substituting N-{4-[(2-cyanopyridin-4-yl)oxy]phenyl}-N'-
(2,2,4,4-
tetrafluoro-4H-1,3-benzodioxin-6-yl)urea for N-[4-chloro-3-
(trifluoromethyl)phenyl]-N=
~4-[(2-cyanopyridin-4-yl)-oxy]phenyl}urea. ~H-NMR (DMSO-d6) 89.84 (s, 1 H),
9.59
(s, 1 H), 8.64 (d, J = 5.4 Hz, 1 H), 8.10 (d, J = 2.4 Hz, 1 H), 7.86 (d, J =
2.4 Hz, 1 H),
2s 7.67 to 7.58 (m, 3H), 7.43 (d, J = 9.0 Hz, 1 H), 7.20 to 7.16 (m, 3H), 3.01
(s, 3H); MS
LC-MS [M+H]+ = 492, RT = 2.57 min.
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Example 4
Preparation of N-Methyl-4-(4-f~guinolin-6-
ylamino)carbonyllamino}phenoxy)pyridine-
2-carboximidamide
\ NH
N / ~ O ~ \ O
~~ I
\ N~N / ~ N
H H
The title compound was prepared in the same manner described for 4-~4-[({[4-
chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy)-N-
methylpyridine-2-
carboximid-amide, substituting N-{4-[(2-cyanopyridin-4-yl)oxy]phenyl}-N'-
quinolin-6-
lo ylurea for N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-f4-[(2-cyanopyridin-4-
yl)-
oxy]phenyl~urea. ~H-NMR (DMSO-d6) 8 9.68 (s, 1 H), 9.60 (s, 1 H), 8.72 (dd, J
= 1.2,
3.9 Hz, 1 H), 8.64 (d, J= 5.71 H, 1 H), 8.25 (d, J = 0.69 Hz, 1 H), 8.16 (d, J
= 2.4 Hz,
1 H), 7.94 (d, J = 9.0 Hz, 1 H), 7.87 (d, J = 1.8 Hz, 1 H), 7.73 (dd, J = 2.4
Hz, 9.0 Hz,
1 H), 7.66 to 7.62 (m, 2H), 7.46 to 7.42 (m, 1 H), 7.21 to 7.17 (m, 3H), 3.02
(s, 3H);
is MS LC-MS [M+H]~ = 413, RT = 1.58 min; TLC (EtOAc:MeOH:Hexanes:NH40H v/v
35:10:4:1 ), R f = 0.22.
Example 5
Preparafiion of 4-f4-[(f f4-Chloro-3-
20 (trifluoromethyl)phenyllamino)carbon rLaminolphenoxy~pyridine-2-
carbothioamide
CF3 S
CI / ~ O ~ ~ O ~ ~ NH2
\ N~N / ~N
H H
Hydrogen sulfide gas was bubbled into a solution of N-[4-chloro-3-
2s (trifluoromethyl)phenyl]-N~~4-[(2-cyanopyridin-4-yl)-oxy]phenyl)urea (230
mg, 0.53
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mmol) in anhydrous DMF (30 mL) at RT. After 10 minutes diethylamine (58 mg,
0.80
mmol) was added, and the reaction mixture was heated to 60 °C for 1 h.
The mixture
was poured into EtOAc (200 mL), and the organic phase was washed with water (2
x
200 mL), brine (1 x 200 mL), dried over Na2S04, and concentrated in vacuo. The
s residue was purified by flash chromatography eluted with 50% EtOAcI hexane
to give
180 mg (73%) of the title product as a yellow solid. ~H-NMR (DMSO-d6) 8 10.2
(broad s, 1 H), 9.93 (broad s, 1 H), 9.23 (s, 1 H), 9.02 (s, 1 H), 8.47 (d, J
= 5.7 Hz, 1 H),
8.11 (d, J = 2.1 Hz, 1 H), 7.95 (d, J = 2.4 Hz, 1 H), 7.67 to 7.57 (m, 4H),
7.19 to 7.11
(m, 3H); MS LC-MS [M+H]+ = 467, RT = 3.47 min.
to
Example 6
Preparation of 4-(4-f f(Quinolin-6- lamino~carbonyllamino phenox~ ridine-2
carbothioamide
N~ I O I \ O I \ NH2
~~ I
\ N~N / ~ N
15 H H
The title compound was prepared in the same manner described for 4-{4-[(~[4-
chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy)pyridine-2-
carbothioamide, substituting N-~4-[(2-cyanopyridin-4-yl)oxy]phenyl}-N'-
quinolin-6-
2o ylurea for N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-~4-[(2-cyanopyridin-4-
yl)-
oxy]phenyl)urea. 'H-NMR (DMSO-d6) 8 10.19 (s, 1 H), 9.92 (s, 1 H), 9.08 (s, 1
H),
8.95 (s, 1 H), 8.73 (dd, J = 2.4, 4.5 Hz, 1 H), 8.47 (d, J = 5.4 Hz, 1 H),
8.24 (dd, J = 0.9,
7.8 Hz, 1 H), 8.17 (d, J = 2.4 Hz, 1 H), 7.97 to 7.92 (m, 2H), 7.71 (dd, J =
2.7, 9.0 Hz,
1 H), 7.64 to 7.59 (m, 2H), 7.47 to 7.43 (m, 1 H), 7.20 to 7.11 (m, 3H); MS LC-
MS
2s [M+H]+ = 416, RT = 2.08 min; TLC (EtOAc:MeOH:Hexanes:NH40H vlv 35:10:4:1 ),
Rf
= 0.75.
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Example 7
Preparation of 4-f4-~~[(1-Methyl-1 H-indazol-5-
yl)aminoLcarbony~amino~henox rLlpyridine-2-carbothioamide
s
N, S
i
iN / ~ O ~ \ O ~ \ NH2
\ N~N / ~ N
H H
The title compound was prepared in the same manner described for 4-~4-[({[4-
chloro-3-(trifluoromethyl)phenyl]amino~carbonyl)amino]phenoxy)pyridine-2-
to carbothioamide, substituting N-~4-[(2-cyanopyridin-4-yl)oxy]phenyl}-N'-(1-
methyl-1 H-
indazol-5-yl)urea for N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-~4-[(2-
cyanopyridin-4-
yl)-oxy]phenyl}urea. ~H-NMR (DMSO-d6) 8 10.18 (s, 1 H), 9.92 (s, 1 H), 8.80
(s, 1 H),
8.68 (s, 1 H), 8.46 (d, J = 5.7 Hz, 1 H), 7.96 to 7.89 (m, 3H), 7.60 to 7.54
(m, 3H), 7.36
(dd, J = 1.8, 9.0 Hz, 1 H), 7.18 to 7.10 (m, 3H), 4.00 (s, 3H); MS LC-MS
[M+H]~ -
is 419, RT = 2.62 min.
Example 8
Preparation of N-f4-Chloro-3-~trifluoromethyl)~hen I~r 1_N' (~f2-
20 (hydrazinocarbonyl)pyridin-4-yllox~r;phenyl)urea
CF3 O
CI / ~ O ~ \ O ~ \ H_NH2
~ I
\ N' _N / ~N
H H
A mixture of methyl 4-[4-({[(4-chloro-3-trifluoromethyl-
2s phenyl)amino]carbonyl}amino)-phenoxy] pyridine-2-carboxylate (600 mg, 1.29
mmol)
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and hydrazine hydrate (645 mg, 12.9 mmol) in anhydrous MeOH (50 mL) was
stirred
at RT under argon for 18h. The reaction mixture was diluted with EtOAc (200
mL),
washed With water and brine. The organic layer was dried over Na2S04,
filtered, and
concentrated under reduced pressure. The crude product was purified by flash
s chromotography eluted with 100% EtOAc to give 580 mg (97%) of the title
compound. ~H-NMR (DMSO-d6) 8 9.88 (s, 1 H), 9.26 (s, 1 H), 9.08 (s, 1 H), 8.48
(d,
1 H), 8.10 (d, 1 H), 7.66-7.58 (m, 4H), 7.36 (d, 1 H), 7.18-7.08 (m, 3H), 4.50
(s, 2H);
MS LC-MS [M+H]~ = 466, RT = 2.83 min; TLC (100% EtOAc), Rf = 0.15.
io
Example 9
Preparation of N-(4-~f2-lH~inocarbonyl)pyridin-4-ylloxy}phen~ -N'- 2,2,4,4-
tetrafluoro-4H-1,3-benzodioxin-6- rLl)urea
F O F
F--~ F O
~ / I O I \ O I \ H_NH2
\ N~N / ~N
H H
The title compound was prepared in the same manner described for N-[4-
chloro-3-(trifluoromethyl)phenyl]-N'-(4-~[2-(hydrazinocarbonyl)pyridin-4-
yl]oxy}phenyl)urea, substituting methyl 4-[4-({[(2,2,4,4-tetrafluoro-4H-1,3-
2o benzodioxin-6-yl)amino]carbonyl}-amino)phenoxy]pyridine-2-carboxylate for
methyl
4-[4-({[(4-chloro-3-trifluoromethylphenyl)-amino]-
carbonyl)amino}phenoxy]pyridine-2-
carboxylate. ~H-NMR (DMSO-ds) b 9.89 to 9.86 (m, 1 H), 9.17 (s, 1 H), 9.03 (s,
1 H),
8.46 (d, J = 6.0 Hz, 1 H), 8.10 (d, J = 2.4 Hz, 1 H), 7.66 (dd, J = 2.1, 9.0
Hz, 1 H), 7.60
to 7.56 (m, 2H), 7.41 (d, J = 9.0 Hz, 1 H), 7.32 (d, J = 2.7 Hz, 1 H), 7.17 to
7.09 (m,
2s 3H), 4.52 (d, J = 4.5 Hz, 2H); MS LC-MS [M+H]+ = 494, RT = 2.88 min; TLC
(100%
EtOAc), Rf = 0.15.
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Example 10
Preparation of N f4-Chloro-3-(trifluoromethyl)phen Il-~~2 ~2,2-
dimethylhydrazino)-carbonyl]p rids in-4-yl~oxy~phenyllurea
C F3
CI / ~ O I ~
H
\ ~ ~/ \ N
N N O
H H O
To a solution of 4-[3-(f[(4-chioro-3-trifluoromethyl-
phenyl)amino]carbonyl}amino)-phenoxy]pyridine-2-carboxylic acid (120 mg, 0.27
mmol) in anhydrous DMF (3 mL) was added 1,1-dimethylhydrazine (20 mg, 0.27
io mmol), HOBT (80 mg, 0.58 mmol), EDCI (80 mg, 0.40 mmol) and N-
methylmorphine
(60 mg, 0.58 mmol). The reaction mixture was stirred at room temperature
overnight. The solvent was removed under reduced pressure. The crude product
was purified by HPLC and neutralized with aqueous sodium bicarbonate (1 N) to
give
100 mg (75.5°l°) of the title compound. ~H-NMR (CD30D) 8 8.48
(d, J = 5.4 Hz, 1 H),
~5 7.97 (d, J = 2.4 Hz, 1 H), 7.63 (dd, J = 5.4, 2.4 Hz, 1 H), 7.51 (d, J =
3.0 Hz, 1 H), 7.48
to 7.39 (m, 3H), 7.32 to 7.31 (m, 1 H), 7.13 (dd, J = 5.7, 3.0 Hz, 1 H), 6.84
(dd, J = 7.2,
1.5 Hz, 1 H), 2.68 (s, 6H); MS LC-MS [M+H]+ = 494, RT = 3.46 min.
Example 11
2o Preparation of 4-~3-f(~f4-Chloro-3-{trifluorometh~l phen~Lamino~carbon
,aminol-
phenoxy~-N-f2-(dimethylamino)ethyllpyridine-2-carboxamide
CF3
CI /
/ \\I H
N N O NON
H H O
2s The title compound was prepared in the same manner described for N-[4-
chloro-3-(trifluoromethyl)phenyl]-N'-[3-((2-[(2,2-dimethylhydrazino)-
carbonyl]pyridin-4-
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yl~oxy)phenyl]-urea, substituting N-aminopiperidine for 1,1-dimethylhydrazine.
'H-
NMR (DMSO-d6) 8 9.53 (s, 1 H), 9.22 (s, 1 H), 9.10 (s, 1 H), 8.51 (d, J = 5.7
HZ, 1 H),
8.05 (d, J = 1.8 Hz, 1 H), 7.60 to 7.58 (m, 2H), 7.47 to 7.17 (m, 4H), 6.82
(dd, J = 7.2,
1.5 Hz, 1 H), 2.78 to 2.74 (m, 4H), 1.57 to 1.54 (m, 4H), 1.32 to 1.30 (m,
2H); MS LC-
s MS [M+H]~ = 534, RT = 3.28 min.
Example 12
Preparation of 4-(3-[~~[4-Chloro-3-
(trifluoromethYl)phenylamino~carbonyl)aminol-
phenoxy~-N-morpholin-4-ylpyridine-2-carboxamide
io
CF3
Cl / ~ O
w H
~/'w. \ Nw
H H O N
O ~O
The title compound was prepared in the same manner described for N-[4-
is chloro-3-(trifluoromethyl)phenyl]-N-[3-({2-[(2,2-dimethylhydrazino)-
carbonyl]pyridin-4-
yl]oxy)phenyl]-urea, substituting N-aminopiperidine for 1,1-dimethylhydrazine.
~H-
NMR (CD30D) 8 8.48 (d, J = 4.8 Hz, 1 H), 7.97 (d, J = 2.4 Hz, 1 H), 7.65 to
7.57 (m,
2H), 7.48 to 7.30 (m, 4H), 7.11 to 7.09 (m, 1 H), 6.82 (dd, J = 2.1, 1.0 Hz, 1
H), 3.81 to
3.78 (m, 4H), 2.92 to 2.89 (m, 4H); MS LC-MS [M+H]+ = 536, RT = 3.10 min.
Example 13
Preparation of N-Piperidin-1-yl-4-f3-(~[ 2 2,4 4-tetrafluoro-4H-1 3-
benzodioxin-6
y~aminol-carbonyl~amino)~henox~~ridine-2-carboxamide
H
O N'N
F O
F~' /I O I\ I~N
O \ N"N ~ O /
F F H H
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To a mixture of (4-[3-(2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-
y()phenoxy]phenyl}-acetic acid (100 mg, 0.21 mmol) in DMF (3 mL) at RT was
added
1-aminopiperidine (20 mg, 0.21 mmol), HOBT (60 mg, 0.46 mmol), EDCI (60 mg,
s 0.31 mmol), and N-methylmorpholine (50 mg, 0.46 mmol). The mixture was
stirred at
RT overnight. The solvent was removed and the residue diluted with DCM (10
mL),
and then washed with H20 (3 mL). The crude product was purified by HPLC and
neutralized with NaHC03 to give 56 mg (45%) of the title product. ~H-NMR (DMSO-
d6) 8 9.65 (s, 1 H), 9.19 (s, 1 H), 9.14 (s, 1 H), 8.51 (d, 1 H), 8.07 (d, 1
H), 7.62 (dd, 1 H),
l0 7.38 to 7.49 (m, 4H), 7.30 (dd, 1 H), 7.21 (dd, 1 H), 6.85 (dd, 1 H), 2.72
to 2.79 (m,
4H), 1.55 to 1.59 (m, 4H), 1.34 (m, 2H); MS LC-MS [M+H]+ = 562, RT = 3.28 min.
Example 14
Preparation of N-Morpholin-4-yl-4-f3-(~j~2,2L4,4-tetrafluoro-4H-113-
benzodioxin-6-
15 y1 amino]-carbon~~amino~phenoxyj~ ridine-2-carboxamide
H
O N~N
1F
F \/O / ~ O ~ ~ ~ ~N O
N"N ~ O
F~ F H H
The title compound was prepared in the same manner described for N
2o piperidin-1-yl-4-[3-(f[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]-
carbonyl}amino)phenoxy]pyridine-2-carboxamide, substituting 4-aminomorpholine
for
N-aminopiperidine. ~H-NMR (DMSO-d6) 8 9.81 (s, 1 H), 9.17 (s, 1 H), 9.12 (s, 1
H),
8.50 (d, 1 H), 8.06 (d, 1 H), 7.60 (dd, 1 H), 7.37-7.48 (m, 4H), 7.29 (dd, 1
H), 7.21 (dd,
1 H), 6.83 (dd, 1 H), 3.61-3.64 (m, 4H), 2.71-2.87 (m, 4H); MS LC-MS [M+H]~ =
564,
2s RT = 3.20 min.
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Example 15
Preparation of 4-f3-(f f(1-methyl-1 H-indazol-5-yl)amino]'carbonyl}amino
phenoxy~'-N
morpholin-4-ylpyridine-2-carboxamide
H
O N,N
O \ ~N ~O
N~ I ~ I I
\ N N ~ O
H H
To a mixture of 4-[3-({[(1-methyl-1 H-indazol-5-
yl)amino]carbonyl}amino)phenoxy]-pyridine-2-carboxylic acid (70 mg, 0.7 7
mmol) in
DMF (3 mL) at RT was added 4-aminomorpholine (20 mg, 0.17 mmol), HOBT (50
to mg, 0.38 mmol), EDCI (50 mg, 0.26 mmol), and N-methylmorpholine (40 mg,
0.38
mmol). The reaction mixture was stirred at RT overnight. The solvent was
removed
and the residue diluted with methylene DCM (10 mL) and then washed with H20 (3
mL). The crude product was purified by HPLC and neutralized with NaHC03 to
give
38 mg (44%) of the title product. ~H-NMR (CD3OD) 8 8.46 (d, 1 H), 7.89 (s, 1
H), 7.83
is (d, 1 H), 7.57 (d, 1 H), 7.45-7.50 (m, 2H), 7.35-740 (m, 2H), 7.26 (dd, 1
H), 7.08 (dd,
1 H), 6.76 (dd, 1 H), 4.04 (s, 3H), 3.76-3.79 (m, 4H), 2.84-2.91 (m, 4H); MS
LC-MS
[M+H]+ = 488, RT = 2.86 min.
Example 16
2o Preparation of N-f4-Chloro-3-(firifluoromethyllphe~fl-N'-(4-f f2 (1 H
tetrazol 5
yl)pyridin-4-yll-oxy phenyl)urea
CF3 N -N
CI / O \ O \ I ~N
~ I ~ I N 'H
N N
N H
z2
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A mixture of the N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-{4-[(2-cyanopyridin-
4-yl)oxy]phenyl~urea (300 mg, 0.23 mmol), sodium azide (1.5 mmol, 67.6 mg),
and
triethylamine hydrochloride (143 mg, 1.5 mmol) in toluene (20 mL) was heated
at 80
°C for 2 days. The solvent was removed, and the residue was purified by
flash
s chromatography (40:30:28:2 v/v EtOAc:hexane:MeOH:NH40H) to give 210 mg (63%)
of the desired product. ~H-NMR (DMSO-d6) 8 9.55 (s, 1 H), 9.21 (s, 1 H), 8.42
(d, 1 H),
8.19 (s, 2H), 7.65 (m, 1 H), 7.60 (m, 3H), 7.42 (s, 1 H), 7.20 (m, 2H), 6.95
(s, 1 H); MS
LC-MS [M+H]+ = 476, RT = 3.11 min.
to Example 17
Preparation of 1 N-f4-chloro-3-(trifluorometh~il phen~rl]-N= ~'f2-(4 5-dihydro-
1 H
imidazol-2-yl~ rid-4ylloxy phen~ urea
CF3 N
I
CI / I C I ~ O I \
\ N J'' N / i N
H H
A mixture of N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-{4-[(2-cyanopyridin-4-
yl)oxy]-phenyl~urea (100 mg, 0.23 mmol), ethylenediamine (42 mg, 0.69 mmol),
and
sulfur (22 mg, 0.69 mmol) in DMF (3 mL) was heated at 80 °C overnight.
The solvent
was removed, and the residue was purified by preparative HPLC to give 81 mg
(73%) of the desired product. 'H-NMR (DMSO-ds) S 9.22 (s, 1 H), 9.05 (s, 1 H),
8.50
(d, 1 H), 7.60 (m, 5H), 7.39 (s, 1 H), 7.19 (m, 3H), 3.65 (s, 4H); MS LC-MS
[M+H]+ -
476, RT = 2.74 min.
Example 18
2s Preparation of N-f4-Chloro-3-(trifluoromethyl)phen 1y 1-N'-~4-f f2 ~1 3~4-
oxadiazol 2
yl)pyridin-4-ylloxy)phenyl)urea
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CF3 N'
CI / ~ O ~ \ O ~ \ O
\ N~N / ~ N
H H
The title compound was prepared in the same manner described for 4-[4-({[(4-
s Chloro-3-trifluoromethylphenyl)amino]carbonyl)amino)phenoxy]pyridine-2-
carboxylate, substituting 4-(2-[1,3,4]oxadiazol-2-yl-pyridin-4-
yloxy)phenylamine for 4-
(4-aminophenoxy)pyridine-2-carboxylic acid methyl ester. ~H-NMR (Acetone-d6) 8
9.06 (s, 1 H), 8.70 (s, 1 H), 8.63 (d, J = 6.0 Hz, 1 H), 8.54 (s, 1 H), 8.17
(d, J = 2.7 Hz,
1 H), 7.79 to 7.58 (m, 4H), 7.55 (d, J = 9.3 Hz, 1 H), 7.24 to 7.20 (m, 2H),
7.14 to 7.10
to (m, 1 H); MS LC-MS [M+H]+ = 476, RT = 3.37 min; TLC (100% EtOAc), Rf =
0.45.
Examt~le 19
Preparation of N-f4-chloro-3-(trifluorometh rLl~~phenyll N'- 4~[~4-methyl-1,3-
thiazol-2-
is yl)pyridin-4-ylloxy}phenyl urea
CF3 N
Cl / O \ O \ i S
\ ~ N~N ~ / ~ ~ N
H H
To 4-{4-[({[4-Chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy~-
pyri-
ao dine-2-carbothioamide (150 mg, 0.32 mmol) in anhydrous EtOH (20 mL) was
added
chloroacetyl chloride (30.6 ~.L, 0.38 mmol, 1.2 eq), and the reaction mixture
was
refluxed under argon for 18h. The mixture was poured into diethyl ether (100
mL);
and the organic layer was washed with water and brine, dried over Na2S04,
filtered,
and concentrated at reduced pressure. The crude residue was purified by MPLC
2s (biotage) eluted with 50% ethyl acetate - hexane to afford 145 mg (89%) of
the title
product, ~H-NMR (Acetone-d6) 8 8.60 (s, 1 H), 8.45 (d, J = 2.4 Hz, 1 H), 8.43
(s, 1 H),
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8.17 (d, J = 2.4 Hz, 1 H), 7.79 to 7.68 (m, 3H), 7.58 to 7.55 (m, 2H), 7.26 to
7.18 (m,
3H), 7.01 to 6.99 (m, 1 H), 2.40 (s, 3H); MS LC-MS [M+H]+ = 505, RT = 3.79
min;
TLC (50% EtOAc/Hexane), Rf= 0.25.
s Example 20
Preparation of N-quinolin-6-yl-N=(~[~5-thioxo-4,5-di~dro-1,3,4-thiadiazol-2
yl)p ridy_ in-4-~Loxy~phen I)y urea
-NH
N I O Nl e""S
O ~ \ ~ ~ ~S
\ N~N / i N
H H
To 4-(4-{[(quinolin-6-ylamino)carbonyl]amino~phenoxy)pyridine-2-
carbothioamide (50 mg, 0.12 mmol) in anhydrous MeOH (20 mL) was added
hydrazine hydrate (60 mg, 1.20 mmol), and the reaction mixture was stirred
under Ar
is at RT for 18h. The mixture was poured into diethyl ether (100 mL), and the
organic
layer was washed with water and brine, dried over Na2S0~., filtered, and
concentrated at reduced pressure. To the crude hydrazine amide was added
anhydrous MeOH (30 mL) followed by carbon disulfide (55 mg, 0.73 mmol). The
reaction mixture was stirred under Ar at room temperature for 18h and then
taken up
ao in ethyl acetate (100 mL). The reaction mixture was washed with water and
brine,
dried over Na2SO4, filfiered, and concentrated at reduced pressure.
Purification of
the residue using preparative TLC (100% EtOAc) afforded 2 mg (6%) of the title
product. ~H-NMR (Acetone-d6) 8 8.74 (d, 1 H), 8.44 (d, 1 H), 8.40 (s, 1 H),
7.96 to
7.84 (m, 4H), 7.44 to 7.38 (m, 2H), 7.18 to 7.14 (m, 2H), 7.18 (d, J = 9.0 Hz,
2H),
2s 7.08 to 7.00 (m, 2H); MS LC-MS [M+H]+ = 473, RT = 3.16 min; TLC (100%
EtOAc),
Rf= 0.15.
Example 21
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Preparation of N-f4-Chloro-3-(trifluoromethyl~ henyll-N'- 4-J~j~5-oxo-4 5-
dihydro
1,3,4-oxadiazol-2-yl)pyridin-4-ylloxy)pheny~urea
CF3 N-NH
~O
CI / ~ O ~ \ O ~ \ O
~~ i
\ N~N / i N
H H
The title compound was prepared in the same manner described for N-
quinolin-6-yl-N'-(4-{[2-(5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)pyridin-4-
yl]oxy~phenyl)urea, substituting, 4-{4-[({[4-chloro-3-
(trifluoromethyl)phenyl]amino~carbonyl)amino]phenoxy}-pyridine-2-carbo-
thioamide
1o for 4-(4-{[(quinolin-6-ylamino)carbonyl]amino~phenoxy)pyridine-2-
carbothioamide,
and substituting phosgene for carbon disulfide. ~H-NMR (DMSO-d6) S 12.75 (s, 1
H),
9.21 (s, 1 H), 8.99 (s, 1 H), 8.55 (d, J = 5.7 Hz, 1 H), 8.10 (d, J = 2.4 Hz,
1 H), 7.66 to
7.55 (m, 4H), 7.23 (d, J = 2.4 Hz, 1 H), 7.20 to 7.16 (m, 2H), 7.11 to 7.08
(m, 1 H); MS
LC-MS [M+H]+ = 492, RT = 3.16 min; TLC (10% MeOHIDCM), Rf= 0.84.
is
Example 22
Preparation of N-(4-~f2-(5-oxo-4 5-dihydro-1 3 4-oxadiazol-2-yl~p rLridin-4
rLlloxy~phenyl)-N=(2,2 4 4-tetrafluoro-4H-1,3-benzodioxin-6-y~urea
F O F
F~ F N-NH
I ~O
O / ~ ~O ~ \ 0 ~ \ O
\ NI 'N / ~ N
20 H H
The title compound was prepared in the same manner described for N-[4-
Chloro-3-(trifluoromethyl)phenyl]-N'-(4-{[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-
2-
yl)pyridin-4-yl]oxy}-phenyl)urea, substituting 4-[3-({[(2,2,4,4-tetrafluoro-4H-
1,3-
2s benzodioxin-6-yl)amino]carbonyl}-amino)phenoxy]pyridine-2-carboxamide for 4-
{4
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[({[4-chloro-3-(trifluoromethyl)phenyl]amino}-carbonyl)amino]phenoxy}pyridine-
2-
carbothioamide. ~H-NMR (DMSO-d6) 8 12.75 (s, 1 H), 9.15 (s, 1 H), 9.01 (s, 1
H), 8.55
(d, J = 6.0 Hz, 1 H), 8.10 (d, J = 2.7 Hz, 1 H), 7.68 to 7.57 (m, 3H), 7.42
(d, J = 8.7 Hz,
1 H), 7.23 (d, J = 2.7 Hz, 1 H), 7.19 to 7.16 (m, 2H), 7.11 to 7.08 (m, 1 H);
MS LC-MS
s [M+H]~ = 520, RT = 3.20 min; TLC (10°l° MeOHIDCM), Rf= 0.72.
It is believed that one skilled in the art, using the preceding information
and
information available in the art, can utilize the present invention to its
fullest extent.
to It should be apparent to one of ordinary skill in the art that changes and
modifications can be made to this invention without departing from the spirit
or scope
of the invention as it is set forth herein.
The topic headings set forth above and below are meant as guidance where
is certain information can be found in the application, but are not intended
to be the
only source in the application where information on such topic can be found.
All publications and patents cited above are incorporated herein by reference.
~o
77
