Note: Descriptions are shown in the official language in which they were submitted.
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WO 02/083642 PCT/USO1/12253
UREA COMPQUNDS USEFUL AS ANTI-INFLAMMATORY AGENTS
TECHNICAL FIELD OF THE INVENTION
This invention relates to novel compounds which inhibit production of
cytokines
involved in inflammatory processes and are thus useful for treating diseases
and
pathological conditions involving inflammation such as chronic inflammatory
disease.
This invention also relates to processes for preparing these compounds and to
l0 pharmaceutical compositions comprising these compounds.
BACKGROUND OF THE INVENTION
Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are important biological
entities
15 collectively referred to as proinflammatory cytokines. These, along with
several other
related molecules, mediate the inflammatory response associated with the
immunological
recognition of infectious agents. The inflammatory response plays an important
role in
limiting and controlling pathogenic infections.
2o Elevated levels of proinflammatory cytokines are also associated with a
number of
diseases of autoimmunity such as toxic shock syndrome, rheumatoid arthritis,
osteoarthritis, diabetes and inflammatory bowel disease (Dinarello, C.A., et
al., 1984,
Rev. Infect. Disease 6:51). In these diseases, chronic elevation of
inflammation
exacerbates or causes much of the pathophysiology observed. For example,
rheumatoid
25 synovial tissue becomes invaded with inflammatory cells that result in
destruction to
cartilage and bone (Koch, A.E., et al., 1995, J. Invest. Med. 43: 28-38). An
important
and accepted therapeutic approach for potential drug intervention in these
diseases is the
reduction of proinflammatory cytokines such as TNF (also referred to in its
secreted cell-
free form as TNFa) and IL-1(3. A number of anti-cytokine therapies are
currently in
30 clinical trials. Efficacy has been demonstrated with a monoclonal antibody
directed
against TNFa in a number of autoimmune diseases (Heath, P., "CDP571: An
Engineered
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WO 02/083642 PCT/USO1/12253
Human IgG4 Anti-TNFa Antibody" IBC Meeting on Cytokine Antagonists,
Philadelphia, PA, April 24-5, 1997). These include the treatment of rheumatoid
arthritis,
Crohn's disease and ulcerative colitis (Rankin, E.C.C., et al., 1997, British
J. Rheum. 35:
334-342 and Stack, W.A., et al., 1997, Lancet 349: 521-524). The monoclonal
antibody
is thought to function by binding to both soluble TNFa and to membrane bound
TNF.
A soluble TNFa receptor has been engineered that interacts with TNFa. The
approach is
similar to that described above for the monoclonal antibodies directed against
TNFa;
both agents bind to soluble TNFa, thus reducing its concentration. One version
of this
1o construct, called Enbrel (Immunex, Seattle, WA) recently demonstrated
efficacy in a
Phase III clinical trial for the treatment of rheumatoid arthritis (Brower et
al., 1997,
Nature Biotechholo~ 15: 1240). Another version of the TNFa receptor, Ro 45-
2081
(Hoffman-LaRoche Inc., Nutley, NJ) has demonstrated efficacy in various animal
models
of allergic lung inflammation and acute lung injury. Ro 45-2081 is a
recombinant
15 chimeric molecule constructed from the soluble 55 kDa human TNF receptor
fused to the
hinge region of the heavy chain IgGl gene and expressed in eukaryotic cells
(Renzetti, et
al., 1997, Inflamm. Res. 46: S 143).
IL-1 has been implicated as an immunological effector molecule in a large
number of
2o disease processes. IL-1 receptor antagonist (IL-lra) had been examined in
human
clinical trials. Efficacy has been demonstrated for the treatment of
rheumatoid arthritis
(Antril, Amgen). In a phase III human clinical trial IL-lra reduced the
mortality rate in
patients with septic shock syndrome (Dinarello, 1995, Nutrution 11, 492).
Osteoarthritis
is a slow progressive disease characterized by destruction of the articular
cartilage. IL-1
25 is detected in synovial fluid and in the cartilage matrix of osteoarthritic
joints.
Antagonists of IL-I have been shown to diminish the degradation of cartilage
matrix
components in a variety of experimental models of arthritis (Chevalier, 1997,
Biomed
Pharmacother. 51, 58). Nitric oxide (NO) is a mediator of cardiovascular
homeostasis,
neurotransmission and immune function; recently it has been shown to have
important
30 effects in the modulation of bone remodeling. Cytokines such as IL-1 and
TNF are
potent stimulators of NO production. NO is an important regulatory molecule in
bone
2
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with effects on cells of the osteoblast and osteoclast lineage (Evans, et al.,
1996, JBone
Miner Res. I1, 300). The promotion of beta-cell destruction leading to insulin
dependent
diabetes mellitus shows dependence on IL-1. Some of this damage may be
mediated
through other effectors such as prostaglandins and thromboxanes. IL-1 can
effect this
process by controlling the level of both cyclooxygenase II and inducible
nitric oxide
synthetase expression (McDaniel et al., 1996, Ps°oc Soc Exp Biol Med.
ill, 24).
Inhibitors of cytokine production are expected to block inducible
cyclooxygenase (COX-
2) expression. COX-2 expression has been shown to be increased by cytokines
and it is
to believed to be the isoform of cyclooxygenase responsible for inflammation
(M.K.
O'Banion et al., Proc. Natl. Acad. Sci. U.S.A, 1992, 89, 4888.) Accordingly,
inhibitors of
cytokines such as IL-1 would be expected to exhibit efficacy against those
disorders
currently treated with COX inhibitors such as the familiar NSAIDs. These
disorders
include acute and chronic pain as well as symptoms of inflammation and
cardiovascular
disease.
Elevation of several cytokines have been demonstrated during active
inflammatory bowel
disease (IBD). A mucosal imbalance of intestinal IL-1 and IL-lra is present in
patients
with IBD. Insufficient production of endogenous IL-lra may contribute to the
pathogenesis of IBD (Cominelli, et al., 1996, Aliment Pharmacol Ther. 10, 49).
Alzheimer disease is characterized by the presence of beta-amyloid protein
deposits,
neurofibrillary tangles and cholinergic dysfunction throughout the hippocampal
region.
The structural and metabolic damage found in Alzheimer disease is possibly due
to a
sustained elevation of IL-1 (Holden, et al., 1995, Med Hypotheses, 45, 559). A
role for
IL-1 in the pathogenesis of human immunodeficiency virus (HIV) has been
identified.
IL-lra showed a clear relationship to acute inflammatory events as well as to
the different
disease stages in the pathophysiology of HIV infection (Kreuzer, et al., 1997,
Clin Exp
Immunol. 109, 54). IL-1 and TNF are both involved in periodontal disease. The
destructive process associated with periodontal disease may be due to a
disregulation of
3o both IL-1 and TNF (Howells, 1995, Oral Dis. 1, 266).
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Proinflammatory cytokines such as TNFa and IL-1 (3 are also important
mediators of
septic shock and associated cardiopulmonary dysfunction, acute respiratory
distress
syndrome CARDS) and multiple organ failure. In a study of patients presenting
at a
hospital with sepsis, a correlation was found between TNFa and IL-6 levels and
septic
complications (Terregino et al., 2000, Ann. Emerg. Med., 35, 26). TNFa has
also been
implicated in cachexia and muscle degradation, associated with HIV infection
(Lahdiverta et al., 1988, Amer. J. Med., 85, 289). Obesity is associated with
an increase
incidence of infection, diabetes and cardiovascular disease. Abnormalities in
TNFa
expression have been noted for each of the above conditions (Loffreda, et al.,
1998,
to FASEB J. 12, 57). It has been proposed that elevated levels of TNFa are
involved in
other eating related disorders such as anorexia and bulimia nervosa.
Pathophysiological
parallels are drawn between anorexia nervosa and cancer cachexia (Holden, et
al., 1996,
Med Hypotheses 47, 423). An inhibitor of TNFa production, HU-211, was shown to
improve the outcome of closed brain injury in an experimental model (Shohami,
et al.,
1997, JNeuroimmunol. 72, 169). Atherosclerosis is known to have an
inflammatory
component and cytokines such as IL-1 and TNF have been suggested to promote
the
disease. In an animal model an IL-1 receptor antagonist was shown to inhibit
fatty streak
formation (Elhage et al., 1998, Circulation, 97, 242).
2o TNFa levels are elevated in airways of patients with chronic obstructive
pulmonary
disease and it may contribute to the pathogenesis of this disease (M.A. Higham
et al.,
2000, Eur. Respiratory J., I5, 281). Circulating TNFa may also contribute to
weight loss
associated with this disease (N. Takabatake et al., 2000, Amer. J. Resp. &
Crit. Care
Med., 161 (4 Pt 1), 1179). Elevated TNFa levels have also been found to be
associated
with congestive heart failure and the level has been correlated with severity
of the disease
(A.M. Feldman et al., 2000, J. Amer. College of Cardiology, 35, 537). In
addition, TNFa
has been implicated in reperfusion injury in lung (Borjesson et al., 2000,
Amer. J.
Physiol., 278, L3-12), kidney (Lemay et al., 2000, Transplantation, 69, 959),
and the
nervous system (Mitsui et al., 1999, Brain Res., 844, 192).
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WO 02/083642 PCT/USO1/12253
TNFa is also a potent osteoclastogenic agent and is involved in bone
resorption and
diseases involving bone resorption (Abu-Amer et al., 2000, J. Biol. Chem.,
275, 27307).
It has also been found highly expressed in chondrocytes of patients with
traumatic
arthritis (Melchiorri et al., 2000, Arthritis arad Rheumatism, 41, 2165). TNFa
has also
been shown to play a key role in the development of glomerulonephritis (Le Hir
et al.,
1998, Laboratory Investigation, 78, 1625).
The abnormal expression of inducible nitric oxide synthetase (iNOS) has been
associated
with hypertension in the spontaneously hypertensive rat (Chou et al., 1998,
Hypertension,
l0 31, 643). IL-1 has a role in the expression of iNOS and therefore may also
have a role in
the pathogenesis of hypertension (Singh et al., 1996, Amer. J. Hypertension,
9, 867).
IL-1 has also been shown to induce uveitis in rats which could be inhibited
with IL-1
blockers. (Xuan et al., 1998, J. Ocular Pharmacol. and Ther.,14, 31).
Cytokines
15 including IL-l, TNF and GM-CSF have been shown to stimulate proliferation
of acute
myelogenous leukemia blasts (Bruserud, 1996, Leukemia Res. 20, 65). IL-1 was
shown
to be essential for the development of both irritant and allergic contact
dermatitis.
Epicutaneous sensitization can be prevented by the administration of an anti-
IL-1
monoclonal antibody before epicutaneous application of an allergen (Muller, et
al., 1996,
20 Am J Contact Dermat. 7, 177). Data obtained from IL-1 knock out mice
indicates the
critical involvement in fever for this cytokine (I~luger et al., 1998, Clin
Exp Pharmacol
Physiol. 25, 141). A variety of cytokines including TNF, IL-l, IL-6 and IL-8
initiate the
acute-phase reaction which is stereotyped in fever, malaise, myalgia,
headaches, cellular
hypermetabolism and multiple endocrine and enzyme responses (Beisel, 1995, Am
J Clin
25 Nutr. 62, 813). The production of these inflammatory cytokines rapidly
follows trauma
or pathogenic organism invasion.
Other proinflammatory cytokines have been correlated with a variety of disease
states.
IL-8 correlates with influx of neutrophils into sites of inflammation or
injury. Blocking
30 antibodies against IL-8 have demonstrated a role for IL-8 in the neutrophil
associated
tissue injury in acute inflammation (Harada et al., 1996, Molecular Medicine
Today 2,
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WO 02/083642 PCT/USO1/12253
482). Therefore, an inhibitor of IL-8 production may be useful in the
treatment of
diseases mediated predominantly by neutrophils such as stroke and myocardial
infarction,
alone or following thrombolytic therapy, thermal injury, adult respiratory
distress
syndrome CARDS), multiple organ injury secondary to trauma, acute
glomerulonephritis,
dermatoses with acute inflammatory components, acute purulent meningitis or
other
central nervous system disorders, hemodialysis, leukopherisis, granulocyte
transfusion
associated syndromes, and necrotizing enterocolitis.
Rhinovirus triggers the production of various proinflammatory cytokines,
predominantly
IL-8, which results in symptomatic illnesses such as acute rhinitis (Winther
et al., 1998,
l0 Arn JRhinol. 12, 17).
Other diseases that are effected by IL-8 include myocardial ischemia and
reperfusion,
inflammatory bowel disease and many others.
The proinflammatory cytokine IL-6 has been implicated with the acute phase
response.
IL-6 is a growth factor in a number in ontological diseases including multiple
myeloma
and related plasma cell dyscrasias (Treon, et al., 1998, Current Opinion in
Hematology 5:
42). It has also been shown to be an important mediator of inflammation within
the
central nervous system. Elevated levels of IL-6 are found in several
neurological
2o disorders including AIDS dementia complex, Alzheimer's disease, multiple
sclerosis,
systemic lupus erythematosus, CNS trauma and viral and bacterial meningitis
(Gruol, et
al., 1997, Molecular Neurobiology 15: 307). IL-6 also plays a significant role
in
osteoporosis. In marine models it has been shown to effect bone resorption and
to induce
osteoclast activity (Ershler et al., 1997, Development and Comparative
Immunol. 21:
487). Marked cytokine differences, such as IL-6 levels, exist in vivo between
osteoclasts
of normal bone and bone from patients with Paget's disease (Mills, et al.,
1997, Calcif
Tissue Int. 61, 16). A number of cytokines have been shown to be involved in
cancer
cachexia. The severity of key parameters of cachexia can be reduced by
treatment with
anti IL-6 antibodies or with IL-6 receptor antagonists (Strassmann, et al.,
1995, Cytokins
Mol Ther. 1, 107). Several infectious diseases, such as influenza, indicate IL-
6 and IFN
alpha as key factors in both symptom formation and in host defense (Hayden, et
al.,
6
CA 02490819 2003-10-08
WO 02/083642 PCT/USO1/12253
1998, J Clin Invest. 101, 643). Overexpression of IL-6 has been implicated in
the
pathology of a number of diseases including multiple myeloma, rheumatoid
arthritis,
Castleman's disease, psoriasis and post-menopausal osteoporosis (Simpson, et
al., 1997,
Protein Sci. 6, 929). Compounds that interfered with the production of
cytokines
including IL-6, and TNF were effective in blocking a passive cutaneous
anaphylaxis in
mice (Scholz et al., 1998, J. Med. Chem., 41, 1050).
GM-CSF is another proinflammatory cytokine with relevance to a number of
therapeutic
diseases. It influences not only proliferation and differentiation of stem
cells but also
to regulates several other cells involved in acute and chronic inflammation.
Treatment with
GM-CSF has been attempted in a number of disease states including burn-wound
healing,
skin-graft resolution as well as cytostatic and radiotherapy induced mucositis
(Masucci,
1996, Medical Oncology 13: 149). GM-CSF also appears to play a role in the
replication
of human immunodeficiency virus (HIV) in cells of macrophage lineage with
relevance
15 to AIDS therapy (Crowe et al., 1997, Journal of Leukocyte Biology 62, 41).
Bronchial
asthma is characterised by an inflammatory process in lungs. Involved
cytokines include
GM-CSF amongst others (Lee, 1998, JR Coll Physicians Lond 32, 56).
Interferon y (IFN y) has been implicated in a number of diseases. It has been
associated
20 with increased collagen deposition that is a central histopathological
feature of graft-
versus-host disease (Parkman, 1998, Curr Opin Hematol. 5, 22). Following
kidney
transplantation, a patient was diagnosed with acute myelogenous leukemia.
Retrospective analysis of peripheral blood cytokines revealed elevated levels
of GM-CSF
and IFN y. These elevated levels coincided with a rise in peripheral blood
white cell
25 count (Burke, et al., 1995, Leuk Lymphoma. 19, 173). The development of
insulin-
dependent diabetes (Type 1) can be correlated with the accumulation in
pancreatic islet
cells of T-cells producing IFN y (Ablumunits, et al., 1998, JAutoimnaun. 11,
73). IFN y
along with TNF, IL-2 and IL-6 lead to the activation of most peripheral T-
cells prior to
the development of lesions in the central nervous system for diseases such as
multiple
3o sclerosis (MS) and AIDS dementia complex (Martino et al., 1998, Ann Neurol.
43, 340).
Atherosclerotic lesions result in arterial disease that can lead to cardiac
and cerebral
7
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WO 02/083642 PCT/USO1/12253
infarction. Many activated immune cells are present in these lesions, mainly T-
cells and
macrophages. These cells produce large amounts of proinflammatory cytokines
such as
TNF, IL-1 and IFN y. These cytokines are thought to be involved in promoting
apoptosis
or programmed cell death of the surrounding vascular smooth muscle cells
resulting in
the atherosclerotic lesions (Geng, 1997, Heart Vessels Suppl 12, 76). Allergic
subjects
produce mRNA specific for IFN y following challenge with Vespula venom (Bonay,
et
al., 1997, Clin Exp Immunol. 109, 342). The expression of a number of
cytokines,
including IFN y has been shown to increase following a delayed type
hypersensitivity
reaction thus indicating a role for IFN y in atopic dermatitis (Szepietowski,
et al., 1997,
Br' JDermatol. 137, 195). Histopathologic and immunohistologic studies were
performed in cases of fatal cerebral malaria. Evidence for elevated IFN y
amongst other
cytokines was observed indicating a role in this disease (Udomsangpetch et
al., 1997, Am
J Trop Med Hyg. 57, 501). The importance of free radical species in the
pathogenesis of
various infectious diseases has been established. The nitric oxide synthesis
pathway is
activated in response to infection with certain viruses via the induction of
proinflammatory cytokines such as IFN y (Akaike, et al., 1998, Proc Soc Exp
Biol Med.
217, 64). Patients, chronically infected with hepatitis B virus (HBV) can
develop
cirrhosis and hepatocellular carcinoma. Viral gene expression and replication
in HBV
transgenic mice can be suppressed by a post-transcriptional mechanism mediated
by IFN
y, TNF and IL-2 (Chisari, et al., 1995, Springer Semir~ Immunopathol. 17,
261). IFN y
can selectively inhibit cytokine induced bone resorption. It appears to do
this via the
intermediacy of nitric oxide (NO) which is an important regulatory molecule in
bone
remodeling. NO may be involved as a mediator of bone disease for such diseases
as: the
rheumatoid arthritis, tumor associated osteolysis and postmenopausal
osteoporosis
(Evans, et al., 1996, JBone Miner Res. 11, 300). Studies with gene deficient
mice have
demonstrated that the IL-12 dependent production of IFN y is critical in the
control of
early parasitic growth~ Although this process is independent of nitric oxide
the control of
chronic infection does appear to be NO dependent (Alexander et al., 1997,
Plailos Traps
R Soc Lond B Biol Sci 352, 1355). NO is an important vasodilator and
convincing
evidence exists for its role in cardiovascular shock (Kilbourn, et al., 1997,
Dis Mon. 43,
277). IFN y is required for progression of chronic intestinal inflammation in
such
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WO 02/083642 PCT/USO1/12253
diseases as Crohn's disease and inflammatory bowel disease (IBD) presumably
through
the intermediacy of CD4+ lymphocytes probably of the TH1 phenotype (Sartor
1996,
Aliment Pharmacol Ther. 10 Suppl 2, 43). An elevated level of serum IgE is
associated
with various atopic diseases such as bronchial asthma and atopic dermatitis.
The level of
IFN y was negatively correlated with serum IgE suggesting a role for IFN y in
atopic
patients (Teramoto et al., 1998, Clin Exp Allergy 28, 74).
WO 01/01986 discloses particular compounds alleged to having the ability to
inhibit
TNF-alpha. The specific inhibitors disclosed are structurally distinct from
the novel
l0 compounds disclosed in the present application disclosed hereinbelow.
Certain
compounds disclosed in WO 01/01986 are indicated to be effective in treating
the
following diseases: dementia associated with HIV infection, glaucoma, optic-
neuropathy,
optic neuritis, retinal ischemia, laser induced optic damage, surgery or
trauma-induced
proliferative vitreoretinopathy, cerebral ischemia, hypoxia-ischemia,
hypoglycemia,
domoic acid poisoning, anoxia, carbon monoxide or manganese or cyanide
poisoning,
Huntington's disease, Alzheimer's disease, Parkinson's disease, meningitis,
multiple
sclerosis and other demyelinating diseases, amyotrophic lateral sclerosis,
head and spinal
cord trauma, seizures, convulsions, olivopontocerebellar atrophy, neuropathic
pain
syndromes, diabetic neuropathy, HIV-related neuropathy, MERRF and MELAS
2o syndromes, Leber's disease, Wernicke's encephalophathy, Rett syndrome,
homocysteinuria, hyperprolinemia, hyperhomocysteinemia, nonketotic
hyperglycinemia,
hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems
disease,
lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drug
addiction, drug
tolerance, drug dependency, depression, anxiety and schizophrenia.
Compounds which modulate release of one or more of the aforementioned
inflammatory
cytokines can be useful in treating diseases associated with release of these
cytokines. For
example, WO 98/52558 discloses heteroaryl urea compounds which are indicated
to be
useful in treating cytokine mediated diseases. WO 99/23091 discloses another
class of
3o urea compounds which are useful as anti-inflammatory agents. WO 99/32463
relates to
aryl ureas amd their use in treating cytokine diseases and proteolytic enzyme
mediated
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disease. WO 00/41698 discloses aryl areas said to be useful in treating p38
MAP kinase
diseases.
U.S. Pat. No. 5,162,360 discloses N-substituted aryl-N'-heterocyclic
substituted urea
compounds which are described as being useful for treating
hypercholesterolemia and
atheroclerosis.
The work cited above supports the principle that inhibition of cytokine
production will be
beneficial in the treatment of various disease states. Some protein
therapeutics are in late
development or have been approved for use in particular diseases. Protein
therapeutics
to are costly to produce and have bioavailability and stability problems.
Therefore a need
exists for new small molecule inhibitors of cytokine production with optimized
efficacy,
pharmacokinetic and safety profiles.
BRIEF SUMMARY OF THE INVENTION
In view of the work cited above there is a clear need for compounds that
inhibit cytokine
production in order to treat various disease states.
It is therefore an object of the invention to provide novel compounds which
inhibit the
2o release of inflammatory cytokines such as interleukin-1 and tumor necrosis
factor.
It is a further object of the invention to provide methods for treating
diseases and
pathological conditions involving inflammation such as chronic inflammatory
disease,
using the novel compounds of the invention.
It is yet a further object of the invention to provide processes of
preparation of the above-
mentioned novel compounds.
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DETAILED DESCRIPTION OF THE INVENTION
In the first broadest generic aspect of the invention, there is provided
compounds of the
formula(I):
W
Gw /Ar X Y Z
E N
I
H
io
(I)
wherein:
E is chosen from -O-, -NH- and -S-;
Gis:
phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl,
2o benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl;
pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl,
isoquinolinyl,
tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl,
benzthiazolyl,
benzooxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl,
dihydrobenzofuranyl,
dibenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo[I,4]oxazin-3-
onyl,
benzodioxolyl, benzo[1,3]dioxol-2-onyl, benzofuran-3-onyl,
tetrahydrobenzopyranyl,
indolyl, 2,3-dihydro-1H-indolyl, indolinyl, indolonyl, indolinonyl,
phthalimidyl,
chromonyl;
oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl,
piperazinyl,
3o morpholino, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl,
tetramethylene
sulfoxidyl, oxazolinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, thiazolinyl,
imidazolinyl,
tertrahydropyridinyl, hornopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl,
11
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WO 02/083642 PCT/USO1/12253
decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholino, thiazolidinyl,
dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl;
wherein G is substituted by one R3 and further substituted by one or more Rl
or R2;
Ar is:
phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl,
tetrahydroquinolinyl,
tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl,
indolinyl,
benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl each being
optionally
l0 substituted by one or more R4 or R5;
X is:
a CS_8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo
groups or one
to three C1_4 alkyl, C1_4 alkoxy or C1_4 alkylamino chains each being branched
or
15 unbranched;
aryl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl,
pyrimidinyl, pyridinonyl,
dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole,
3H-
imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl; each being
optionally
2o independently substituted with one to three Cl_4 allcyl, C1_4 alkoxy,
hydroxy, nitrite,
amino, mono- or di-(C1_3 alkyl)amino, mono- or di-(Cl_3 alkylamino)carbonyl,
NH~C(O),
Ci-s alkyl-S(O)m or halogen;
Y is:
25 a bond or a C1_~o saturated or unsaturated branched or unbranched carbon
chain, wherein
one or more C atoms are optionally replaced by O, N, or S(O)m ; and wherein Y
is
optionally partially or fully halogenated and optionally independently
substituted with
one to two oxo groups, nitrite, amino, imino, phenyl or one or more C1_4 alkyl
optionally
substituted by one or more halogen atoms;
Z is:
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CA 02490819 2003-10-08
WO 02/083642 PCT/USO1/12253
aryl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl,
pyridazinyl, pyrazinyl,
imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl,
heterocycle
selected from tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxa- or
2-thia-
5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene
sulfoxidyl,
pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or
tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-
dioxolanonyl, 1,3-
dioxanonyl, 1,4-dioxanyl, morpholino, thiomorpholino, thiomorpholino
sulfoxidyl,
thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and
dioxolanyl,
each of the aforementioned Z are optionally substituted with one to three
halogen, C1_s
l0 alkyl, C1_6 alkoxy, C1_3 alkoxy-C1_3 alkyl, Cl_6 alkoxycarbonyl, aroyl,
CI_3 acyl, oxo,
hydroxy, pyridinyl-Cl_3 alkyl, imidazolyl-Cl_3 alkyl, tetrahydrofuranyl-C1_3
alkyl, nitrile-
CI_3 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally
substituted with
one to two halogen, C1-6 allcoxy, hydroxy or mono- or di-(C1_3 alkyl)amino,
Cl_6 alkyl-
S(O)m, or phenyl-S(O)m wherein the phenyl ring is optionally substituted with
one to two
halogen, C1_6 alkoxy, hydroxy, halogen or mono- or di-(C1_3 alkyl)amino;
or Z is optionally substituted with one to three amino or amino-Cl_3 alkyl
wherein the N
atom is optionally independently mono- or di-substituted by aminoCl_6 allcyl,
C1_3 alkyl,
arylCo_3 alkyl, C1_5 alkoxyCl_3 alkyl, C1_5 alkoxy, aroyl, C1_3 acyl, C1_3
alkyl-S(O)m- or
arylCo_3 alkyl-S(O)m each of the aforementioned allcyl and aryl attached to
the amino
2o group is optionally substituted with one to two halogen, C1_6 alkyl or Cl_6
allcoxy;
or Z is optionally substituted with one to three aryl, heterocycle or
heteroaryl as
hereinabove described in this paragraph each in turn is optionally substituted
by halogen,
C 1 _6 alkyl or C 1 _6 alkoxy;
or Z is hydroxy, halogen, nitrite, amino wherein the N atom is optionally
independently
mono- or di-substituted by C1_3 acyl, C1_6 alkyl or Ci_3 alkoxyCl_3 alkyl,
Cl_6 alkyl
branched or unbranched, C1_6 alkoxy, Cl_3 acylamino, nitrileCl_4 alkyl, Cl_6
alkyl-S(O)m,
and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one
to two
halogen, C1_6 alkoxy, hydroxy or mono- or di-(C1_3 alkyl)amino;
each R1 is independently:
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C1_lo alkyl branched or unbranched optionally partially or fully halogenated,
wherein one
or more C atoms are optionally independently replaced by O, N or S(O)m, and
wherein
said C1_io alkyl is optionally substituted with one to three C3_io cycloalkyl,
hydroxy, oxo,
phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,
pyrrolidinyl,
imidazolyl, pyrazolyl, thienyl, fiuyl, dioxolanyl, isoxazolyl or isothiazolyl;
each of the
aforementioned being optionally substituted with one to five groups selected
from
halogen, C1_6 alkyl which is optionally partially or fully halogenated, C3_8
cycloalkanyl,
CS_8 cycloalkenyl, hydroxy, nitrile, C1_3 alkoxy which is optionally partially
or fully
halogenated or NHZC(O), mono- or di(CI_3alkyl)amino, and mono- or
l0 di(C1_3alkyl)aminocarbonyl;
or Rl is
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or
cycloheptyloxy each
being optionally partially or fully halogenated and optionally substituted
with one to three
C1_3 alkyl groups optionally partially or fully halogenated, nitrite,
hydroxyCl_3 alkyl or
aryl;
phenyloxy or benzyloxy each being optionally partially or fully halogenated
and
optionally substituted with one to three Cl_3 alkyl groups optionally
partially or fully
halogenated, nitrite, hydroxyCl_3alkyl or aryl;
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
bicyclopentanyl,
bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully
halogenated
and optionally substituted with one to three C1_3 alkyl optionally partially
or fully
halogenated, nitrite, hydroxyCl_3alkyl or aryl;
C3-io branched or unbranced alkenyl each being optionally partially or fully
halogenated,
and optionally substituted with one to three Cl_5 branched or unbranched
alkyl, phenyl,
naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,
imidazolyl, pyrazolyl,
3o thienyl, furyl, isoxazolyl or isothiazolyl, each of the aforementioned
being substituted
with one to five halogen, C1_s alkyl which is optionally partially or fully
halogenated,
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cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrite, C1_3
alkyloxy
which is optionally partially or fully halogenated, NH2C(O), mono- or di(C1_
3alkyl)aminocarbonyl; the C3_lo branched or unbranced alkenyl being optionally
interrupted by one or more heteroatoms chosen from O, N and S(O)m;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,
bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is
optionally
substituted with one to three C1_3 alkyl groups;
oxo, nitrite, halogen;
silyl containing three C1_4 alkyl groups optionally partially or fully
halogenated; or
C3_6 alkynyl branched or unbranched carbon chain optionally partially or fully
halogenated, wherein one or more methylene groups are optionally replaced by
O, NH or
S(O)m and wherein said alkynyl group is optionally independently substituted
with one to
two oxo groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, one or more
C1_4 alkyl
optionally substituted by one or more halogen atoms, nitrite, morpholino,
piperidinyl,
piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, ormono- or
di(Cl_3alkyl)amino
optionally substituted by one or more halogen atoms;
each RZ, R4 and RS is
a C1_6 branched or unbranched alkyl optionally partially or fully halogenated,
C1_6 acyl,
amyl, C1_4 branched or unbranched alkoxy, each being optionally partially or
fully
halogenated, halogen, methoxycarbonyl, CI_3 alkyl-S(O)m optionally partially
or fully
halogenated, or phenyl-S(O)m;
3o Ci_6 alkoxy, hydroxy, carboxy, oxo, nitrite, nitro, halogen;
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or amino-S(O)m wherein the N atom is optionally independently mono- or di-
substituted
by C1_6alkyl or arylCo_3alkyl, or amino wherein the N atom is optionally
independently
mono- or di-substituted by C1_3 alkyl, arylCo_3 alkyl, C1_6 acyl, C1_6alkyl-
S(O)m- or arylCo_3
alkyl-S(O)m , each of the aforementioned alkyl and aryl in this subparagraph
are
optionally partially or fully halogenated and optionally substituted with one
to two Cl_6
alkyl or C1_6 alkoxy;
each R3 is independently:
(J)p L-S(o>m N(L)- ~ C(.~P L]ZN-s(o>m ~ C(.~p L]ZN-a
1 o wherein for R3:
J is:
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
bicyclopentanyl,
bicyclohexanyl or bicycloheptanyl;
cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,
cycloheptadienyl, bicyclohexenyl or bicycloheptenyl;
phenyl, naphthyl, morpholino, thiomorpholino, pyridinyl, piperadinyl,
piperazinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl,
pyrazolyl,
thiazolyl, oxazolyl, oxazoyl, [1,3,4]oxadiazol, triazolyl, tetrazolyl,
thienyl, furyl,
dioxolanyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl,
isoquinolinyl, indolyl,
benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl,
benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl,
quinoxalinyl,
quinazolinyl, purinyl or indazolyl,
a fused aryl selected from benzocyclobutanyl, indanyl, indenyl,
dihydronaphthyl,
tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl,
or J is a fused heteroaryl selected from cyclopentenopyridinyl,
cyclohexanopyridinyl,
cyclopentanopyrimidinyl, cyclohexanopyrimidinyl, cyclopentanopyrazinyl,
3o cyclohexanopyrazinyl, cyclopentanopyridazinyl, cyclohexanopyridazinyl,
cyclopentanoquinolinyl, cyclohexanoquinolinyl, cyclopentanoisoquinolinyl,
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cyclohexanoisoquinolinyl, cyclopentanoindolyl, cyclohexanoindolyl,
cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl,
cyclopentanobenzoxazolyl,
cyclohexanobenzoxazolyl, cyclopentanoimidazolyl, cyclohexanoimidazolyl,
cyclopentanothienyl and cyclohexanothienyl;
wherein each of the above J is optionally substituted by one to three R6;
each Rb is independently
C1_6 alkyl, Cl_6 alkoxy, arylCo_6 alkyl, heterocycleCo_6 alkyl, heteroarylCo_6
alkyl each
to optionally substituted by halogen, hydroxy, carboxy, oxo, nitro, nitrile or
amino
optionally mono- or di-substituted by C1_3 alkyl, or R6 is amino optionally
mono- or di-
substituted by C1_6 alkyl, C1_6 acyl, CO_6 alkylaryl, Co_6 alkylheterocycle or
Co_6
alkylheteroaryl, halogen, hydroxy, carboxy, oxo, nitro or nitrite; wherein
each of the
above heterocycle and heteroaryl in this paragraph are independently chosen
from those
15 hereinabove described for J;
L is
a bond, hydrogen, oxy, a Cl_6 saturated or unsaturated branched or unbranched
carbon chain, wherein one or more C atoms are optionally replaced by O, N, or
S(O)m ;
2o and wherein each L is optionally partially or fully halogenated and
optionally
independently substituted with one to two oxo groups, nitrite, amino, imino,
guanidino,
phenyl or one or more Cl_4 alkyl optionally substituted by one or more halogen
atoms;
and wherein for R3, the arrangement of covalent attachments shall be
understood to be as
25 follows:
For each [(J)p L] within [(J)P L]ZN-S(O)m or [(J)p L]2N-, it shall be
understood that
one or two [(J)p-L] can be covalently attached to the N atom as either [(J)P
L]2N-; or
[(J)p L]-NH- if one [(J)p L] is hydrogen and the other is a substituent as
defined herein;
or both can be hydrogen to form NH2. In any of the aforementioned embodiments
for R3,
30 J may be multiply attached to an L, for example (J)2L, or sequentially
attached, for
example, [J-J-L-] according to the value of p;
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and with the proviso that when R3 is [(gyp L]ZN-, the combination of L and N
cannot form:
O
NH- ~O~NH-
or ~O
s
m and p are each independently 0, 1 or 2;
WisOorSand
pharmaceutically acceptable derivatives thereof.
to
In another embodiment of the invention there is provided compounds of the
formula(I) as
described above and wherein:
E is -NH-;
15 W is O.
In yet another embodiment there are provided compounds of the formula(I) as
described
immediately above and wherein:
G is
phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl,
benzimidazolyl, benzooxazolyl, benzooxazolonyl, benzofuranyl, benzothiophenyl,
benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, 3,4-dihydro-2H-
benzo[1,4]oxazinyl, indanyl, indenyl, indolyl, indolinyl, indolonyl, 2,3-
dihydro-1H-
indolyl or indolinonyl, wherein G is substituted by one R3 and further
substituted by one
or more Rl or R2;
Ar is:
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naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, indanyl, indenyl or indolyl each being optionally
substituted by
one or more R4 or R5 groups;
X is:
phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl,
pyrimidinyl,
pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl,
piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently
substituted
with one to three C1_4 alkyl, C1_4allcoxy, hydroxy, nitrile, amino, mono- or
di-(C1_3
to alkyl)amino, mono- or di-(C1_3 alkylamino)carbonyl, NHZC(O), C1_6 alkyl-
S(O)m or
halogen;
and
Z is:
phenyl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl,
pyridazinyl,
pyrazinyl, imidazolyl, furanyl, thienyl and pyranyl, heterocycle selected from
2-oxa-5-
aza-bicyclo[2.2.1]heptanyl, tetrahydropyrimidonyl, pentamethylene sulfidyl,
pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl,
tetramethylene sulfoxidyl tetramethylene sulfonyl, tetrahydropyranyl,
tetrahydrofuranyl,
1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholino, thiomorpholino,
thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, dihydrothiazolyl,
dihydrothiazolyl
sulfoxidyl, pyrrolidinyl and dioxolanyl which are optionally substituted with
one to three
nitrite, Ci_3 alkyl, Cl_3 alkoxy, amino, mono- or di-(CI_3 alkyl)amino, CONHZ
or OH;
or Z is optionally substituted by phenyl, heterocycle or heteroaryl as
hereinabove
described in this paragraph each in turn is optionally substituted by halogen,
C1_3 alkyl or
C1_3 alkoxy; or Z is hydroxy, halogen, nitrite, amino wherein the N atom is
optionally
independently mono- or di-substituted by CI_3 acyl, C1_6 alkyl or C1_3
alkoxyCl_3 alkyl, C1_6
alkyl branched or unbranched, Cl_6 alkoxy, Cl_3 acylamino, nitrileCl_4 alkyl,
Cl_6 alkyl-
S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted
with one to
two halogen, Cl_6 alkoxy, hydroxy or mono- or di-(C1_3 allcyl)amino.
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In yet still another embodiment of the invention there is provided compounds
of the
formula(I) as described immediately above and wherein:
G is
phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl,
3,4-dihydro-
2H-benzo[1,4]oxazinyl, benzothiophenyl, dihydrobenzofuranyl,
dihydrobenzothiophenyl,
benzooxazolyl, indanyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein
G is
substituted by one R3 and further substituted by one or more Rl or R2;
to Ar is naphthyl;
X is
phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl,
pyridazinyl or
pyrazinyl each being optionally independently substituted with one to three
C1_4 alkyl, C1_
15 4alkoxy, hydroxy, nitrite, amino, mono- or di-(C1_3 alkyl)amino, mono- or
di-(C1_3
alkylamino)carbonyl, NH2C(O), C1_6 alkyl-S(O)m or halogen;
Y is:
a bond or
2o a Cl_4 saturated carbon chain wherein one or more of the C atoms is
optionally replaced
by O, N or S and wherein Y is optionally independently substituted with
nitrite or oxo;
Z is:
phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl,
dihydrothiazolyl,
25 dihydrothiazolyl sulfoxide, pyranyl, pyrrolidinyl, phenylpiperazinyl,
tetrahydropyranyl,
tetrahydrofuranyl, dioxolanyl, 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, morpholino,
thiomorpholino, thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl,
piperazinyl or
tetrahydropyrimidonyl each of which are optionally substituted with one to two
C1_Z alkyl
or C1_Z alkoxy; or
3o Z is hydroxy, C1_3 alkyl, Cl_3 alkoxy, C1_3 acylamino, C1_3 alkylsulfonyl,
nitrite C1_3 alkyl
or amino mono or di-substituted by Cl_3acyl, Cl_6alkyl or Ci_3alkoxyCl_3alkyl;
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each Ri is independently:
C1_5 alkyl branched or unbranched optionally partially or fully halogenated,
wherein one
or more C atoms are optionally independently replaced by O, N or S(O)m, and
wherein
said Ci_s alkyl is optionally substituted with oxo, dioxolanyl, pyrrolidinyl,
furyl or
phenyl each optionally substituted with one to three halogen, Ci_3 alkyl which
is
optionally partially or fully halogenated, hydroxy, nitrite and C1_3alkoxy
which is
optionally partially or fully halogenated;
l0 cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or
bicyclohexanyl, each being optionally partially or fully halogenated and
optionally
substituted with one to three Cl_3 alkyl groups optionally partially or fully
halogenated,
nitrite, hydroxyCl_3alkyl or phenyl; and an analog of cyclopropyl, cyclobutyl,
cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl;
15 oxo;
C2_4 alkynyl optionally partially or fully halogenated wherein one or more
methylene
groups are optionally replaced by O, and optionally independently substituted
with one to
two oxo groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, CI_4 alkyl
optionally
substituted by one or more halogen atoms, nitrite, morpholino, piperidinyl,
piperazinyl,
2o imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C1_3alkyl)amino
optionally
substituted by one or more halogen atoms;
or
silyl containing three C1_z alkyl groups optionally partially or fully
halogenated;
25 . each RZ is independently:
a Cite alkyl optionally partially or fully halogenated, Clue alkoxy optionally
partially or
fully halogenated, bromo, chloro, fluoro, methoxycarbonyl, methyl-S(O)m, ethyl-
S(O)m
each optionally partially or fully halogenated or phenyl-S(O)m;
or R2 is mono- or di-C1_3 acylamino, amino-S(O)m or S(O)~"amino wherein the N
atom is
3o mono- or di-substituted by C1_3 alkyl or phenyl, nitrite, nitro or amino;
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In yet a further embodiment of the invention there is provided compounds of
the
formula(I) as described immediately above and wherein:
G is:
phenyl, pyridinyl, pyridonyl, 2-naphthyl, quinolinyl, isoquinolinyl,
dihydrobenzofuranyl,
indanyl, 5-indolyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl, benzoxalolyl,
2,3-
dihydrobenzooxazol-7-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl, indolinyl,
indolonyl, or
indolinonyl , wherein G is substituted by one R3 and further substituted by
one or more
Rl or R2;
Ar is 1-naphthyl;
X is:
phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl,
pyridazinyl or
pyrazinyl and wherein X is attached to the 4-position of Ar;
Y is:
a bond or
-CH2-, -CH2CH2-, O-CH2CHa-, -C(O)-, -O-, -S-, -NH-CHaCH2CH2- , -N(CH3)-,
CH2(CN)CH2-NH-CH2 or -NH-;
Z is:
morpholino, dioxolanyl, tetrahydrofuranyl, pyridinyl, pyrrolidinyl, 2-oxa-5-
aza-
bicyclo[2.2.1]heptanyl, Cl_3 alkoxyphenylpiperazinyl, hydroxy, Cl_3 alkyl,
N,N-diCl_3 alkoxyCl_3 alkylamino, C1_3 acylamino, C1_6 dialkylamino, C1_3
alkylsulfonyl or
nitrileCl_3 alkyl;
Rl is:
C1_5 alkyl optionally partially or fully halogenated wherein one or more C
atoms are
optionally independently replaced by O or N, and wherein said Cl_5 alkyl is
optionally
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substituted with oxo, dioxolanyl, pyrrolidinyl, furyl or phenyl optionally
substituted by
C1_3alkoxy;
cyclopropyl, cyclopentanyl, cyclohexanyl and bicyclopentanyl optionally
substituted with
one to three methyl groups optionally partially or fully halogenated, nitrile,
hydroxymethyl or phenyl; or 2-tetrahydrofuranyl substituted by methyl; or
trimethyl silyl;
propynyl substituted hydroxy or tetrahydropyran-2-yloxy;
to
R~ is:
is C1_4 alkoxy optionally partially or fully halogenated, mono- or di-Cl_3
acylamino,
amino-S(O)m or S(O)m amino wherein the N atom is mono- or di-substituted by
Ci_3 alkyl
or phenyl, bromo, chloro, fluoro, nitrite, nitro, amino, methylsulfonyl
optionally partially
15 or fully halogenated or phenylsulfonyl;
and
J is:
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
bicyclopentanyl,
2o bicyclohexanyl or bicycloheptanyl,
phenyl, naphthyl, morpholino, thiomorpholino, piperidinyl, piperazinyl,
pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl,
pyrazolyl,
thiazolyl, isothiazolyl, thienyl, furyl, dioxolanyl, tetrahydrofixryl,
isoxazolyl and oxazolyl,
25 cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,
cycloheptadienyl, bicyclohexenyl or bicycloheptenyl; or an analog of each
thereof
wherein one to three ring methylene groups are independently replaced by O,
S(O)m,
CHOH, >C=O, >C=S or NH;
each of the above J is optionally substituted by one to two R6.
L is:
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Cl_6 alkyl wherein one or more C atoms are optionally independently replaced
by O or N,
optionally partially or fully halogenated and optionally substituted with oxo,
amino,
imino and hydroxy;
m is 2; and
p is 0, 1 or 2.
In yet still a further embodiment of the invention there are provided
compounds of the
l0 formula(I) as described immediately above and wherein:
G is:
phenyl, pyridinyl, 5-indolyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-~-yl,
benzoxalolyl,
2,3-dihydrobenzoxazol-7-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl or 2-naphthyl
wherein G
is substituted by one R3 and further substituted by one or more Rl or R2;
X is:
imidazolyl, pyridinyl, pyrimidinyl or pyrazinyl;
Y is:
a bond, -OCH2CH2-, -CHZCHZ-, -O-, CHa(CN)CH2-NH-CHZ, -CHI-, -NH-CH2CH2- or -
NH-;
Z is:
morpholin-4y1, dioxolan-2y1, tetrahydrofuranyl, pyridinyl, pyrrolidinyl, 2-oxa-
5-aza-
bicyclo[2.2.1]hept-5y1, methoxyphenylpiperazinyl, hydroxy, methyl, N,N-
dimethoxyethylamino, acetylamino, C1_3 dialkylamino, methylsulfonyl or
cyanoethyl;
Rl is:
tert-butyl, sec-butyl, tert-amyl, phenyl, tetrahydropyran-2-yloxypropynyl,
hydroxypropynyl, trihalomethyl, 2,2-diethylpropionyl or cyclohexanyl;
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RZ is:
is C1_3 alkoxy optionally partially or fully halogenated, mono- or di-C1_3
acylamino,
amino-S(O)m or S(O)m amino wherein the N atom is mono- or di-substituted by
C1_3 alkyl
or phenyl, bromo, chloro, fluoro, nitrile, nitro, amino, methylsulfonyl
optionally partially
or fully halogenated or phenylsulfonyl;
each R3 is independently:
l0 (J)o_1-L-S(O)a-N(L)- , [(J)o-i-L]2N-,
wherein for R3:
L is hydrogen, oxy, C1_6 alkyl, C1_S alkoxy, amidoCl_5 alkoxy, amidoCl_S
alkyl, Cl_
alkylimino or Cl_5 alkylsulfonyl;
J is as hereinabove described in the previous embodiment,
and R6 is halogen, nitro, nitrite, hydroxy, carboxy or oxo.
In yet still even a further embodiment of the invention there is provided
compounds of
2o the formula(I) as described immediately above and wherein:
G is phenyl substituted by one R3 and further substituted by one to two Rl or
R2;
X is pyridinyl;
J is
cyclopropyl, cyclobutenyl, phenyl, naphthyl, morpholino, pyridinyl,
pyrimidinyl,
pyrazinyl, pyrrolidinyl, oxazolyl, 4,5-dihydro-oxazol-2y1, isoxazolyl,
thienyl, furyl,
dioxolanyl, tetrahydrofuryl, thiazolyl, 4,5-dihydro-thiazolyl or isothiazolyl,
3o each of the above J being optionally substituted by one to two R6;
Y is:
a bond, -OCH2CH2-, -CHZCH2-, -O-, -CH2-, -NH-CH2CH2- or -NH-;
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Z 1S
morpholin-4y1, tetrahydrofuranyl or pyridinyl,
L is
hydrogen, C1_6 alkyl, C1_5 alkoxy, amidoCl_5 alkoxy, amidoCl_5 alkyl, C1-s
alkylimino or C1_5 alkylsulfonyl;
R6 is
thiomorpholino, morpholino, piperazinyl, piperidinyl or pyrrolindinyl each
optionally
substituted by halogen, hydroxy or amino optionally mono- or di-substituted by
Ci_3
alkyl, or R6 is C1_3 alkyl, C1_3 alkoxy, aminoCl_3 aryl, amino optionally mono-
or di-
substituted by C1_3 alkyl, benzylamino, halogen, nitro, nitrite, hydroxy,
carboxy or oxo.
In still even a further embodiment of the invention there is provided
compounds of the
formula(I) as provided immediately above and wherein:
X is pyridinyl attached to Ar via the 3-pyridinyl position;
and
J is
phenyl, morpholin-4y1, 4,5-dihydro-oxazol-2y1, dioxolanyl, tetrahydrofuryl,
isoxazolyl or
cyclobuten-1-enyl wherein said cyclobuten-1-enyl is optionally substituted by
methylamino, dimethylamino, dimethylaminoethyl, benzylamino, piperidin-lyl,
thiomorpholin-4y1, morpholin-4y1, morpholin-4ylethyl, pyrrolidin-lyl
optionally 3-
substituted by hydroxy or dimethylamino.
Table 1 shows representative compounds of the formula(I):
3o TABLE 1
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HOC °"bH~ ° ~ N~ N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-
morpholin-4-
o ° ~ ~ ~ N L.° ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido~-
phenyl)-
"'°-o.p ~ I p p I ~ methanesulfonamide;
"~°-° I
",° , -- ~ '1 2-[(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-
' / ' ~ ~ ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido)-phenyl)-
",° ~ ~ I ° ~ ' ~ v methanesulfonyl-amino]-acetamide;
° N~ p ' I
NH,
"~° ~ / i N~ 1-[5-tert-Butyl-3-(4,5-dihydro-oxazol-2-ylamino)-2-
I ' ° ° I ' N ~° methoxy-phenyl]-3-[4-(6-morpholin-4-
ylmethyl-pyridin-3-
~~N ° NON ' v yl)-naphthalen-1-yl]-urea;
~°.o ' I
",° ~ / i N~ N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-
I ' ' N ~'° Ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido~-
phenyl)-
"~C N / N N I ' acetamidine;
H °'O /
a
",° ~ N 1-[5-tert-Butyl-3-(2-dimethylamino-3,4-dioxo-cyclobut-1-
° ° / ~ ° ' ' I ~ enylamino)-2-methoxy-phenyl]-3-[4-(6-
morpholin-4-
~'N ' I N"N I I ' ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
"~°- ~ ~°.° /
and the pharmaceutically acceptable derivatives thereof.
In addition to the abovementioned compounds, the following prophetic compounds
of the
formula(I) may be made by the general methods described in the specification:
l0
[(5-tert-Butyl-2-methoxy-3- { 3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido~-phenyl)-methanesulfonyl-amino]-acetic acid methyl
ester;
1-[5-tert-Butyl-3-(4,5-dihydro-thiazol-2-ylamino)-2-methoxy-phenyl]-3-[4-(5-
morpholin-4-ylmethyl-pyridin-2-yl)-naphthalen-1-yl]-urea;
[(5-tent-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido}-phenyl)-methanesulfonyl-amino]-acetic acid;
[(5-tent-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido~-phenyl)-methanesulfonyl-amino]-acetic acid
tetrahydro-furan-3-yl ester;
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[(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido}-phenyl)-methanesulfonyl-amino]-acetic acid 2-
methoxy-ethyl ester;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido } -phenyl)-N-(2-morpholin-4-yl-2-oxo-ethyl)-
methanesulfonamide;
2-[(5-tert-Butyl-2-methoxy-3- {3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido}-phenyl)-methanesulfonyl-amino]-N,N-dimethyl-
acetamide;
1-[5-tert-Butyl-3-(4,5-dihydro-thiazol-2-ylamino)-2-methoxy-phenyl]-3-[4-(6-
morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
2-[(5-tert-Butyl-2-methoxy-3- {3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido } -phenyl)-methanesulfonyl-amino]-N-methyl-acetamide;
2-[(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido}-phenyl)-methanesulfonyl-amino]-N-(2-methoxy-
ethyl)-acetamide;
N-(5-tert-Butyl-2-methoxy-3- {3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido}-phenyl)-N-(2-oxo-2-pyrrolidin-1-yl-ethyl)-
methanesulfonamide;
2-[(5-tent-Butyl-2-methoxy-3- {3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido}-phenyl)-methanesulfonyl-amino]-N-
cyclopropylmethyl-acetamide;
N-(5-tert-Butyl-2-methoxy-3- {3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido}-phenyl)-N-methyl-methanesulfonamide;
N-(5-tert-Butyl-2-methoxy-3- {3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido } -phenyl)-N-ethyl-methanesulfonamide;
N-[5-(5-tert-Butyl-2-methoxy-3- { 3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido } -phenylsulfamoyl)-4-methyl-thiazol-2-yl] -acetamide;
Thiophene-2-sulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-
ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;
N-(5-tert-Butyl-2-methoxy-3- {3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido}-phenyl)-4-fluoro-benzenesulfonamide;
Propane-2-sulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-
ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;
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2-(5-tart-Butyl-2-methoxy-3- { 3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido } -phenylsulfamoyl)-N,N-dimethyl-acetamide;
2-Oxo-2-pyrrolidin-1-yl-ethanesulfonic acid (5-tart-butyl-2-methoxy-3-{3-[4-(6-
morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido } -phenyl)-amide;
1-[5-tart-Butyl-2-methoxy-3-( 1-methyl-4, 5-dihydro-1 H-imidazol-2-ylamino)-
phenyl]-3-[4-(6-morpholin-4-ylinethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
2-Morpholin-4-yl-2-oxo-ethanesulfonic acid (5-tart-butyl-2-methoxy-3-{3-[4-
(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-
amide;
3,5-I~imethyl-isoxazole-4-sulfonic acid (5-tart-butyl-2-methoxy-3-{3-[4-(6
morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido } -phenyl)-amide;
1-Methyl-1H-imidazole-4-sulfonic acid (5-tart-butyl-2-methoxy-3-{3-[4-(6-
morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido } -phenyl)-amide;
5-Bromo-thiophene-2-sulfonic acid (5-tent-butyl-2-methoxy-3-{3-[4-(6-
morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido } -phenyl)-amide;
N-(5-tart-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido } -phenyl)-3 -methoxy-benzenesulfonamide;
Cyclopropanesulfonic acid (5-tart-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-
ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido } -phenyl)-amide;
N-(5-tart-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido } -phenyl)-N-(2-morpholin-4-yl-ethyl)-
methanesulfonamide;
1-[5-tart-Butyl-3-(4,5-dihydro-thiazol-2-ylamino)-2-methoxy-phenyl]-3-[4-(6-
dimethylaminomethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tart-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido}-phenyl)-N-(2-dimethylamino-ethyl)-
methanesulfonamide;
N-(5-tart-Butyl-2-methoxy-3- { 3-[4-(6-piperidin-1-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido } -phenyl)-2-oxo-2-pyrrolidin-1-yl-acetamide;
N-(5-tart-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido}-phenyl)-2-oxo-2-pyrrolidin-1-yl-acetamide;
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N-(5-tert-Butyl-2-methoxy-3- f 3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido } -phenyl)-2-oxo-2-piperidin-1-yl-acetamide;
N-(5-tert-Butyl-2-methoxy-3- f 3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-ureido } -phenyl)-2-oxo-2-piperazin-1-yl-acetamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(4-morpholin-4-ylmethyl-phenyl)-
naphthalen-1-yl]-ureido } -phenyl)-2-oxo-2-piperazin-1-yl-acetamide;
1-[5-tert-Butyl-2-methoxy-3-(2-methylamino-3,4-dioxo-cyclobut-1-enylamino)-
phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-methoxy-3-(2-methylamino-3,4-dioxo-cyclobut-1-enylamino)-
phenyl]-3-[4-(6-diethylaminomethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[3-(2-Benzylamino-3,4-dioxo-cyclobut-1-enylamino)-5-tert-butyl-2-methoxy-
phenyl]-3-[4-(4-dimethylaminomethyl-phenyl)-naphthalen-1-yl]-urea;
1-[3-(2-Benzylamino-3,4-dioxo-cyclobut-1-enylamino)-5-tert-butyl-2-methoxy-
phenyl]-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(3,4-dioxo-2-thiomorpholin-4-yl-cyclobut-1-enylamino)-2-
methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-
urea;
1- f 5-tert-Butyl-2-methoxy-3-[2-(4-methyl-piperazin-1-yl)-3,4-dioxo-cyclobut-
1-
enylamino]-phenyl}-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
yl]-urea;
1-[5-tert-Butyl-2-methoxy-3-(2-morpholin-4-yl-3,4-dioxo-cyclobut-1-
enylamino)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
yl]-urea;
1-[5-tert-Butyl-2-methoxy-3-(2-morpholin-4-yl-3,4-dioxo-cyclobut-1-
enylamino)-phenyl]-3-[4-(6-diethylaminomethyl-pyridin-3-yl)-naphthalen-1-yl]-
urea;
1- f 5-tert-Butyl-3-[2-(3-hydroxy-pyrrolidin-1-yl)-3,4-dioxo-cyclobut-1-
enylamino]-2-methoxy-phenyl}-3- {4-[6-(2-dimethylamino-ethyl)-pyridin-3-yl]-
naphthalen-1-yl}-urea;
1- {5-tert-Butyl-3 -[2-(3-dimethylamino-pyrrolidin-1-yl)-3,4-dioxo-cyclobut-1-
enylamino]-2-methoxy-phenyl}-3- f 4-[6-(2-pyrrolidin-1-yl-ethyl)-pyridin-3-yl]-
naphthalen-1-yl}-urea;
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1-[5-tert-Butyl-3-(3,4-dioxo-2-pyrrolidin-1-yl-cyclobut-1-enylamino)-2-
methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-
urea;
1-[5-tert-Butyl-3-(3,4-dioxo-2-piperidin-1-yl-cyclobut-1-enylamino)-2-
methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-
urea;
1-[5-tert-Butyl-3-(3,4-dioxo-2-piperidin-1-yl-cyclobut-1-enylamino)-2-
methoxy-phenyl]-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
1-[5-tent-Butyl-3-(2-dimethylamino-3 ,4-dioxo-cyclobut-1-enylamino)-2-
methoxy-phenyl]-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
yl]-urea;
1-[5-tert-Butyl-3-(2-dimethylamino-3 ,4-dioxo-cyclobut-1-enylamino)-2-
methoxy-phenyl]-3-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-naphthalen-1-yl]-urea
and the pharmaceutically acceptable derivatives thereof.
In the second broadest generic aspect of the invention, there is provided
compounds of
the formula(I) as described hereinabove in the first broadest generic aspect
and it's
respective subgeneric embodiments, with the proviso that one or more of the
following
to compounds are hereby specifically excluded:
1-(3-Cyano-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-
urea;
1-(3-Fluoro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
yl]-urea;
1-(4-Chloro-2-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
1-(2-Chloro-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
1-(3,4-Dimethyl-phenyl)-3 -[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-
1-yl]-
urea;
1-(3-Iodo-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-
urea;
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1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-m-tolyl-urea;
1-(4-Methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3 -yl)-
naphthalen-1
yl]-urea;
1-(3-Chloro-4-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
io 1-(4-Chloro-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
1-(2, 5-Dichloro-phenyl)-3 -[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-
urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-naphthalen-2-yl-
urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3 -phenyl-urea;
1-(3-Chloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
yl]-urea;
1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2,4,6-trichloro-
phenyl)-
urea;
1-(2-Methyl-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
1-(4-Methyl-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
1-(2,3-Dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-
1-yl]-
urea;
1-(2-Methoxy-5-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-
1-yl]-urea;
1-(2-Chloro-6-methyl-phenyl)-3 -[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
1-(2,4-Dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-
1-yl]-
urea;
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1-(4-Methyl-3-vitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
1-(2,4-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-
1-yl]-
urea;
1-(2,3-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-
1-yl]-
urea;
1-(4-Cyano-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-
urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3 -(3,4, 5-
trimethoxy-
phenyl)-urea;
1-Biphenyl-4-yl-3 -[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-
urea;
1-(2,5-Difluoro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-
1-yl]-
urea;
2o 1-(3-Chloro-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-
1-yl]-urea;
1-(2-Fluoro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
1-(4-B enzyloxy-phenyl)-3 -[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-
1-yl]-
urea;
1-(2-Methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
1-(2-Fluoro-6-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
1-(4-Fluoro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2,4,5-trimethyl-
phenyl)-
urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-
trifluoromethyl-
phenyl)-urea;
1-(3-Methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
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1-(2-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
yl]-
urea;
1-(2-Fluoro-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
1-(4-Methoxy-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-
1-yl]-urea;
l 0 1-(2-Fluoro-5-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3 -yl)-
naphthalen-1-
yl]-urea;
1-(4-Ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
yl]-urea;
1-(2,5-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-
1-yl]-
urea;
1-(4,5-Dimethyl-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-
1-yl]-urea;
1-(5-Chloro-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
1-(2-Isopropyl-6-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
1-(2-Difluoromethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-
1-yl]-urea;
1-(4-Isopropyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
yl]-
urea;
1-(4-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
yl]-
urea;
1-(3-Ethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-
urea;
1-(2-Ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
yl]-urea;
1-(4-Butoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
yl]-urea;
4- f 3-[4-(6-Morpholin-4-ylinethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido~-
benzoic acid
ethyl ester;
1-(4-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
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1-(2,6-Dibromo-4-isopropyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
1-(3-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
yl]-
urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-
trifluoromethylsulfanyl-phenyl)-urea;
5-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido~-
isophthalic acid
dimethyl ester;
1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
i5 naphthalen-1-yl]-urea;
3- f 3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-
benzoic acid
ethyl ester;
1-(5-tert-Butyl-2-hydroxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
1-(2-Hydroxymethyl-4-phenyl-cyclohexyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
1-(2-Methylsulfanyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-
yl)-naphthalen-1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-pentyloxy-
biphenyl-3-
3o yl)-urea;
4-Methoxy-3- f 3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-
ureido}-
benzoic acid methyl ester;
1-(2,5-Diethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-
1-yl]-
urea;
1-Benzothiazol-6-yl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
yl]-urea;
4o N-(2,5-Diethoxy-4-~3-[4-(6-rnorpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
yl]-
ureido)-phenyl)-benzamide;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3 -phenoxy-
phenyl)-
urea;
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1-(5-Ethanesulfonyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
4-Methoxy-3- { 3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-
ureido ~ -N-
phenyl-benzamide;
1-(2-Methyl-1,3-dioxo-2, 3-dihydro-1 H-isoindol-5-yl)-3 -[4-(6-morpholin-4-
ylmethyl-
pyridin-3-yl)-naphthalen-1-yl]-urea;
l 0 1-(2, 3-Dimethyl-1 H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-naphthalen-
1-yl]-urea;
N-Butyl-4-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
yl]-
ureido } -benzenesulfonamide;
1-[3-(2-Methyl-[ 1,3]dioxolan-2-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-yl)-
naphthalen-1-yl]-urea;
1-(3-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
2o naphthalen-1-yl]-urea;
1-(2,4-Dimethoxy-phenyl)-3 -[4-(6-morpholin-4-ylmethyl-pyridin-3 -yl)-
naphthalen-1-yl]-
urea;
1-(2-Methyl-4-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
1-(2-Methoxy-4-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
1-(4-Chloro-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
1-(5-Chloro-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-
1-yl]-urea;
1-(3,5-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-
1-yl]-
urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-
trifluoromethoxy-
phenyl)-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-
trifluoromethylsulfanyl-phenyl)-urea;
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1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-I-yl]-3-(2-phenoxy-
phenyl)-
urea;
1-(2-Methoxy-5-nitro-phenyl)-3 -[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
l0 1-(3,5-Bis-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
1-(2-tert-Butyl-5-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
I5
1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
1-(3-tert-Butyl-phenyl)-3 -[4-(6-morpholin-4-ylmethyl-pyridin-3 -yl)-
naphthalen-1-yl]-
20 urea;
1-(4-Methyl-biphenyl-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
25 1-(4-tert-Butyl-biphenyl-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
I-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
1-(5-Isopropyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
1-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-3-propyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-yl)-
naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
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1-(5-tert-Butyl-2-methyl-phenyl)-3-(4- f 6-[(3-methoxy-propyl)-methyl-amino]-
pyridin-3-
yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-imidazol- I -yl)-
naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
l 0 1-(5-tert-Butyl-2-methyl-phenyl)-3- ~4-[6-(3-methoxy-propylamino)-pyridin-
3-yl]-
naphthalen-1-yl~-urea;
1-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-morpholin-4-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-
3-yl)-
naphthalen-1-yl]-urea;
1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-
2o yl)-naphthalen-I-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-
trifluoromethyl-
phenyl)-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-
trifluoromethoxy-
phenyl)-urea;
1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-
yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-yl)-
naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-morpholin-4-
ylmethyl-
pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-
yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(3-morpholin-4-yl-3-oxo-propyl)-phenyl]-3-[4-(6-morpholin-4-
ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-yl)-naphthalen-1-yl]-urea;
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N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yI)-
naphthalen-1-
yl]-ureido}-phenyl)-acetamide;
1-[4-(6- f [Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-
3-(5-tert-
butyl-2-methoxy-phenyl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3- f 4-[4-(2-methyl-3-oxo-piperazin-1-
ylmethyl)-
phenyl]-naphthalen-1-yl}-urea;
1-[4-(6- { [Bis-(2-methoxy-ethyl)-amino] -methyl} -pyridin-3 -yl)-naphthalen-1-
yl] -3-(5-
tert-butyl-2-methoxy-phenyl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3- f 4-[6-(2-methyl-3-oxo-piperazin-1-
ylmethyl)-
pyridin-3-yl]-naphthalen-1-yl}-urea;
is
1-(5-tert-Butyl-2-methoxy-phenyl)-3- f 4-[6-(1-oxo-114-thiomorpholin-4-
ylmethyl)-
pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(S-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-
yl)-
2o naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methyl-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylmethyl)-
pyridin-
3-yl]-naphthalen-1-yl}-urea;
25 1-(5-tert-Butyl-2-methyl-phenyl)-3- f 4-[6-(2-methyl-3-oxo-piperazin-1-
ylmethyl)-
pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[4-(1-oxo-11-thiomorpholin-4-ylmethyl)-
phenyl]-naphthalen-1-yl}-urea;
35
1-[4-(4- f [Bis-(2-cyano-ethyl)-amino]-methyl}-phenyl)-naphthalen-1-yl]-3-(5-
tert-butyl-
2-methoxy-phenyl)-urea;
1-(2-Methoxy-5-pentafluoroethyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-
1-yl)-
naphthalen-1-yl]-urea;
1-(2-Methoxy-5-trifluoromethyl-pyridin-3-yl)-3- {4-[2-(4-oxo-piperidin-1-
ylmethyl)-
pyrimidin-5-yl]-naphthalen-1-yl}-urea;
1-(2-Methoxy-5-trimethylsilanyl-phenyl)-3-{4-[4-(tetrahydro-pyran-4-ylamino)-
phenyl]-
4o naphthalen-1-yl}-urea;
1-(3-Methoxy-naphthalen-2-yl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl)-
naphthalen-1-yl]-urea;
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1-(3-Methyl-naphthalen-2-yl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-
yl]-
urea;
1-(3-tart-Butyl-5-methanesulfinyl-phenyl)-3- {4-[6-( 1-methyl-piperidin-4-
ylmethyl)-
pyridin-3-yl]-naphthalen-1-yl)-urea;
1-(3-tart-Butyl-phenyl)-3-[4-(3-pyridin-3-yl-propoxy)-naphthalen-1-yl]-urea;
1-(3-tart-Butyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-
urea;
1-(4-Methoxy-biphenyl-3-yl)-3- {4-[4-(tetrahydro-pyran-4-ylmethyl)-imidazol-1-
yl]-
naphthalen-1-yl~-urea;
1-(4-Methyl-biphenyl-3-yl)-3- {4-[4-(2-pyridin-4-yl-ethyl)-piperazin-1-yl]-
naphthalen-1-
yl}-urea;
1-(4-tart-Butyl-biphenyl-2-yl)-3-[4-(pyridin-4-ylmethoxy)-naphthalen-1-yl]-
urea;
1-(4-tart-Butyl-biphenyl-2-yl)-3-{4-[2-(1-oxo-114-thiomorpholin-4-ylmethyl)-3H-
imidazol-4-yl]-naphthalen-1-yl)-urea;
1-(5-tart-Butyl-2-hydroxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2-yl)-
naphthalen-1-yl]-urea;
1-(5-tent-Butyl-2-methoxy-3-propyl-phenyl)-3- {4-[4-(pyrrolidine-1-carbonyl)-
phenyl]-
naphthalen-1-yl~-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-
naphthalen-1-yl]-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-[4-(4-thiomorpholin-4-ylmethyl-phenyl)-
naphthalen-1-yl]-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-phenyl)-
naphthalen-1-
yl]-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-{4-[4-(tetrahydro-pyran-4-ylamino)-phenyl]-
naphthalen-1-yl}-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-
pyridin-3-
yl]-naphthalen-1-yl ) -urea;
1-(5-tart-Butyl-2-methoxy-pyridin-3-yl)-3-{4-[6-(4-oxo-piperidin-1-ylmethyl)-
pyridin-3-
yl]-naphthalen-1-yl)-urea;
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1-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-pyridin-4-ylmethyl-pyridin-
3-yl)-
naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-
naphthalen-1-
yl]-urea;
1-(5-tert-Butyl-2-phenoxy-phenyl)-3- {4-[6-(tetrahydro-pyran-4-yloxy)-pyridin-
3-yl]-
naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3 -[4-(4-methoxy-6-morpholin-4-
ylmethyl-
pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-
3-yl)-
naphthalen-1-yl]-urea;
1-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3- {4-[2-(2,6-dimethyl-morpholin-4-
ylmethyl)-pyrimidin-5-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-4'-dimethylamino-biphenyl-3-yl)-3-[4-(2-morpholin-4-ylmethyl-
pyrimidin-5-yl)-naphthalen-1-yl]-urea;
1-(6-Methoxy-3,3-dimethyl-indan-5-yl)-3- f 4-[4-(morpholine-4-carbonyl)-
phenyl]-
naphthalen-1-yl~-urea;
1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-thiomorpholin-4-
ylmethyl-
pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(6-tert-Butyl-benzo [ 1, 3 ] dioxol-4-yl)-3 - {4-[6-(morpholin-4-ylamino)-
pyridin-3-yl]-
naphthalen-1-yl~-urea;
1-(7-Methoxy-1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-3- f 4-[6-
(tetrahydro-
pyran-4-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(7-tert-Butyl-2,4-dimethyl-benzooxazol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-
yl)-naphthalen-1-yl]-urea;
1-[2-Methoxy-5-(1-methyl-1-phenyl-ethyl)-phenyl]-3- f 4-[6-(2-pyridin-4-yl-
ethyl)-
pyridazin-3-yl]-naphthalen-1-yl } -urea;
1-[2-Methoxy-5-(1-methyl-cyclohexyl)-phenyl]-3- f 4-[4-(1-methyl-piperidin-4-
ylsulfanyl)-phenyl]-naphthalen-1-yl}-urea;
1-[2-Methoxy-5-( 1-methyl-cyclopropyl)-phenyl]-3-[4-(2-morpholin-4-ylmethyl-
pyrimidin-5-yl)-naphthalen-1-yl]-urea;
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1-[2-Methoxy-5-(2-methyl-tetrahydro-furan-2-yl)-phenyl]-3-[4-(5-morpholin-4-
ylmethyl-
pyridin-2-yl)-naphthalen-1-yl]-urea;
1-[2-Methoxy-5-(3-trifluoromethyl-bicyclo [ 1.1.1 ]pent-1-yl)-phenyl]-3-[4-(4-
morpholin-
4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
1-[3-tart-Butyl-5-( 1-methyl-1 H-imidazol-4-yl)-phenyl]-3-[4-(5-morpholin-4-
ylmethyl-
pyridin-2-yl)-naphthalen-1-yl]-urea;
1o 1-[3-tart-Butyl-5-(2-pyrrolidin-1-yl-ethyl)-phenyl]-3- f 4-[6-(1-methyl-
piperidin-4-yloxy)-
pyridin-3-yl]-naphthalen-1-yl ~ -urea;
1-[3 -tart-Butyl-5-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenyl]-3 -[4-(6-morpholin-
4-ylmethyl-
pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[4-(6-Imidazol-1-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-[2-methoxy-5-( 1-
phenyl-
cyclopropyl)-phenyl]-urea;
1-[5-( 1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3 -[4-(4-thiomorpholin-4-
ylmethyl-
phenyl)-naphthalen-1-yl]-urea;
1-[5-( 1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(2-morpholin-4-ylmethyl-
pyrimidin-5-yl)-naphthalen-1-yl]-urea;
1-[5-( 1-Hydroxymethyl-cyclopropyl)-2-methoxy-phenyl]-3 -[4-(4-morpholin-4-
ylmethyl-
phenyl)-naphthalen-1-yl]-urea;
1-[5-tart-Butyl-1-(2-diethylamino-ethyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-3- f
4-[6-(1-
methyl-piperidin-4-yloxy)-pyridin-3-yl]-naphthalen-1-yl~-urea;
1-[5-tart-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-[4-(2-morpholin-4-yl-ethoxy)-
naphthalen-
1-yl]-urea;
1-[5-tart-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3- f 4-[4-(4-methyl-piperazine-1-
carbonyl)-
phenyl]-naphthalen-1-yl~-urea;
1-[5-tart-Butyl-2-(2,5-dioxo-pyrrolidin-1-yl)-phenyl]-3~ ~4-[6-( 1 H-imidazol-
2-ylmethyl)-
pyridin-3-yl]-naphthalen-1-yl~-urea;
4o 1-[5-tart-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(5-pyridin-4-
ylmethyl-pyridin-
2-yl)-naphthalen-1-yl]-urea;
1-[5-tart-Butyl-2-(2-morpholin-4-yl-2-oxo-ethoxy)-phenyl]-3- ~4-[6-(2-pyridin-
4-yl-
ethyl)-pyridazin-3-yl]-naphthalen-1-yl}-urea;
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1-[5-tert-Butyl-2-(2-morpholin-4-yl-2-oxo-ethylamino)-phenyl]-3- {4-[4-( 1-
methyl-
piperidin-4-ylamino)-piperidin-1-yl]-naphthalen-1-yl}-urea;
1-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-phenyl]-3-{4-[5-(2-pyrrolidin-1-yl-
ethyl)-
pyridin-2-yl]-naphthalen-1-yl}-urea;
1-[5-tert-Butyl-2-methoxy-3-(3-morpholin-4-yl-3-oxo-propenyl)-phenyl]-3-[4-(6-
pyrrolidin-1-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
l0 1-[5-tert-Butyl-3-(2-diethylamino-ethoxy)-2-methoxy-phenyl]-3- {4-[4-
(tetrahydro-pyran-
4-yloxy)-phenyl]-naphthalen-1-yl } -urea;
1-[5-tert-Butyl-3 -(2-pyrrolidin-1-yl-ethyl)-benzofuran-7-yl]-3-[4-(4-
morpholin-4-
ylmethyl-phenyl)-naphthalen-1-yl]-urea;
1-[6-tert-Butyl-4-(2-dimethylamino-ethyl)-3-oxo-3,4-dihydro-2H-benzo[
1,4]oxazin-8-
yl]-3-{4-[6-(thiomorpholin-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1- {5-tert-Butyl-2-methoxy-3-[2-( 1-methyl-piperidin-4-yloxy)-ethyl]-phenyl}-3-
[4-(4-
2o morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
2-(4-tent-Butyl-2-{3-[4-(5-pyrrolidin-1-ylmethyl-pyridin-2-yl)-naphthalen-1-
yl]-ureido}-
phenoxy)-N-methyl-acetamide;
2-[4-tert-Butyl-2-(3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-
naphthalen-1-yl}-ureido)-phenoxy]-acetamide;
35
3-(5-tert-Butyl-2-methoxy-3 - { 3-[4-(6-pyrrolidin-1-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-ureido}-phenyl)-acrylamide;
3 - { 3-tert-Butyl-5-[3-(4- {4-[2-( 1-oxo-114-thiazolidin-3-yl)-ethyl]-phenyl
} -naphthalen-1-
yl)-ureido]-phenyl } -N,N-dimethyl-propionamide;
3 - {4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl } -
benzamide;
4-tert-Butyl-2- { 3-[4-(2-chloro-4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-
yl]-
ureido } -benzamide;
N-(4-tert-Butyl-2-{3-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-naphthalen-1-yl]-
ureido}-
4o phenyl)-2-morpholin-4-yl-acetamide;
N-[3-tert-Butyl-5-(3-{4-[5-(tetrahydro-pyran-4-ylamino)-pyridin-2-yl]-
naphthalen-1-yl}-
ureido)-phenyl]-2-morpholin-4-yl-acetamide;
4.5 N-[4-tert-Butyl-2-(3-{4-[4-(1-methyl-piperidin-4-yloxy)-phenyl]-naphthalen-
1-yl}-
ureido)-phenyl]-acetamide;
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1-(4-tart-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-
1-yl]-
urea;
1-(5-tart-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl)-
naphthalen-1-yl]-urea;
1-(6-Chloro-4-trifluoromethyl-pyridin-2-yl)-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-yl)-
naphthalen-1-yl]-urea;
l0
1-(4-Difluoromethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-
1-yl]-urea;
1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
1-[2-Methoxy-5-( 1-methyl-1-phenyl-ethyl)-phenyl]-3 -[4-(6-morpholin-4-
ylmethyl-
pyridin-3-yl)-naphthalen-1-yl]-urea;
2o (S-tart-Butyl-2-methyl-phenyl)-carbamic acid 3-(5-{4-[3-(5-tart-butyl-2-
methyl-phenyl)-
ureido]-naphthalen-1-yl}-pyridin-2-ylamino)-propyl ester;
1-(6-tart-Butyl-benzo[ 1,3]dioxol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
30
N-(5-tent-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-ureido}-phenyl)-acetamide;
1,3-Bis-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tart-Butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-hydroxy-phenyl]-3-
[4-(6-
morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[ 5-tart-Butyl-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-[4-(6-morpholin-4-
ylmethyl-
pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tart-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-morpholin-4-
ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2,3-Dimethyl-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-
1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2-p-tolyloxy-5-
trifluoromethyl-phenyl)-urea;
1-[2-(2-Methoxy-phenoxy)-5-trifluoromethyl-phenyl]-3-[4-(6-morpholin-4-
ylmethyl-
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pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-naphthalen-1-yl-
urea;
1- f 5-tert-Butyl-2-methyl-3-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-
phenyl}-3-[4-(6-
morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1- { 5-tert-Butyl-2-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phenyl } -3 -[4-
(6-
morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
to
1-(5-Hydroxymethyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
1-(2-Methoxy-dibenzofuran-3-yl)-3-[4-(6-morpholin-4-ylinethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
1-(2, 5-Di-tert-butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3 -yl)-
naphthalen-1-
yl]-urea;
1-[3-(4-Bromo-1-methyl-1 H-pyrazol-3-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(3-Hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3 -yl)-naphthalen-1-yl]-urea;
1-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-oxazol-5-yl-
phenyl)-
urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-
[1,3,4]oxadiazol-2-yl-
phenyl)-urea;
1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
Furan-2-carboxylic acid (4-tert-butyl-2- f 3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-yl)-
naphthalen-1-yl]-ureido}-phenyl)-amide;
1-(2-Methoxy-4-phenylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
1-(5-Methoxy-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-
1-yl]-urea;
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1-(3-Hydroxy-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-
1-yl]-urea;
N,N-Diethyl-4-methoxy-3- {3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-ureido~-benzenesulfonamide;
1-(2,2-Difluoro-benzo [ 1,3 ] dioxol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-yl)-
naphthalen-1-yl]-urea;
l0 1-[5-( 1,1-Dimethyl-propyl)-2-phenoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-
yl)-naphthalen-1-yl]-urea;
1-[5-(2,2-Dimethyl-propionyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
pyridin-
3-yl)-naphthalen-1-yl]-urea;
2-Chloro-5-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-
ureido~-
benzoic acid isopropyl ester;
1-(4-Amino-3,5-dibromo-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin- 3-yl)-
naphthalen-1-yl]-urea;
1-[5-tart-Butyl-3-(3-hydroxy-prop-1-ynyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-
ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tent-Butyl-2-(3-hydroxy-prop-1-ynyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tart-Butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-methoxy-phenyl]-3-
[4-(6-
morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tart-Butyl-3-(2,3-dihydroxy-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-
ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tart-Butoxy-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
pyridin-
3-yl)-naphthalen-1-yl]-urea;
1-[5-tart-Butyl-3-(2-diethylamino-ethyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-
ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-[4-(6-[1,3]dioxolan-2-yl-pyridin-3-yl)-
naphthalen-
1-yl]-urea;
1-(5-tart-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-
3-yl)-
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naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-dimethylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-propoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
1-(5-tent-Butyl-2-methoxy-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-
naphthalen-1-
to yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3- f 4-[6-(2,6-dimethyl-morpholin-4-
ylmethyl)-
pyridin-3-yl]-naphthalen-1-yl}-urea;
15 2-(5-tert-Butyl-2-methoxy-phenyl)-N-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-acetamide;
1-(2-Methoxy-5-phenoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-cyclopentyloxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-
3-yl)-
naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3- f 4-[6-(3-pyridin-3-yl-pyrrolidin-1-
ylmethyl)-
pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-Cyclohexyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
1-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-
yl)-naphthalen-1-yl]-urea;
1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo [ 1,4] oxazin-7-yl)-3 -[4-(6-
morpholin-4-
ylmethyl-pyridin-3-yl)-naphthalen-1-yl)-urea;
1-(5-tent-Butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-
3-yl)-
4o naphthalen-1-yl]-urea;
1-(3-Amino-5-tent-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-
naphthalen-1-
yl]-urea;
N-Acetyl-N-(5-tert-butyl-2-methoxy-3-~3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl)-ureido}-phenyl)-acetamide;
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1-(6-tart-Butyl-4-methyl-3-oxo-3,4-dihydro-2H-benzo [ 1,4] oxazin-8-yl)-3-[4-
(6-
morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[6-tart-Butyl-4-(2-morpholin-4-yl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[
1,4]oxazin-8-
yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tart-Butyl-2-ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
to
1-(5-tart-Butyl-2-isopropoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
1-(5-tart-Butyl-2-imidazol-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
N-(5-tart-Butyl-2-methoxy-4-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-ureido}-phenyl)-methanesulfonamide;
1-(5-tart-Butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-
pyridin-
3-yl)-naphthalen-1-yl]-urea;
N-(5-tart-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-ureido}-phenyl)-bis(methanesulfon)amide;
1-[5-tart-Butyl-2-( 1-methyl-1 H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-
ylmethyl-
pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2-Methanesulfinyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-
3o yl)-naphthalen-1-yl]-urea;
1-(2-Ethanesulfonyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-
yl)-naphthalen-1-yl]-urea;
1-[4-(6-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-
3-(5-
tert-butyl-2-methoxy-phenyl)-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-dimethylamino-pyrrolidin-1-
ylmethyl)-
pyridin-3-yl]-naphthalen-1-yl} -urea;
N-[ 1-(5- {4-[3-(5-tart-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-
pyridin-2-
ylmethyl)-pyrrolidin-3-yl]-acetamide;
1-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-
ylmethyl-
pyridin-3-yl)-naphthalen-1-yl]-urea;
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N-(5-tart-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-ureido)-phenyl)-propionamide;
1-(5-tart-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-yl)-
naphthalen-1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3 -yl)-naphthalen-1-yl]-3-(3-
trifluoromethanesulfonyl-phenyl)-urea;
to N-(5-tart-Butyl-2-methoxy-3- f 3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-ureido ~ -phenyl)-isobutyramide;
2-(4-tart-Butyl-2-~3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-
ureido~-
phenoxy)-acetamide;
1-(5-tart-Butyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-3-[4-(6-morpholin-4-
ylmethyl-
pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(6-tart-Butyl-3-cyano-2-methoxymethoxy-pyridin-4-yl)-3-[4-(6-morpholin-4-
ylmethyl-
2o pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(6-tart-Butyl-3-cyano-2-hydroxy-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-
pyridin-
3-yl)-naphthalen-1-yl]-urea;
1-(5-tart-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-
3-yl)-
naphthalen-I-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(1,3,3-trimethyl-
2,3-
dihydro-1 H-indol-5-yl)-urea;
1-(5-tart-Butyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-urea;
N-(5-tart-Butyl-2-methoxy-3- ~ 3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-ureido}-phenyl)-benzenesulfonamide;
Ethanesulfonic acid (5-tart-butyl-2-methoxy-3- f 3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-
yl)-naphthalen-1-yl]-ureido]-phenyl)-amide;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl)-
naphthalen-1-yl]-urea;
1-[5-tart-Butyl-2-( I -methyl-1 H-pyrazol-4-yl)-phenyl]-3-[4-(4-morpholin-4-
ylmethyl-
piperidin-1-yl)-naphthalen-1-yl]-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylinethyl-pyrimidin-5-
yl)-
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naphthalen-1-yl]-urea;
1-(5-tart-Butyl-2-methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-
3-yl)-
naphthalen-1-yl]-urea;
1-(5-tart-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
2,2,2-Trifluoro-ethanesulfonic acid (5-tart-butyl-2-methoxy-3-{3-[4-(6-
morpholin-4-
to ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;
N-(5-{4-[3-(S-tart-Butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyrazin-2-
yl)-
methanesulfonamide;
15 1-[4-(6- { [Bis-(2-cyano-ethyl)-amino]-methyl} -pyridin-3-yl)-naphthalen-1-
yl]-3-(5-tert-
butyl-2-methoxy-phenyl)-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3- {4-[6-(4-methyl-piperazin-1-ylmethyl)-
pyridin-3-
yl]-naphthalen-1-yl}-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-piperidin-1-ylmethyl)-
pyridin-
3-yl]-naphthalen-1-yl}-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3- {4-[6-( 1-oxo-tetrahydro-thiopyran-4-
ylamino)-
pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3- {4-[6-(tetrahydro-pyran-4-ylamino)-
pyridin-3-yI]-
naphthalen-1-yl}-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-[4-(6- { [(2-cyano-ethyl)-(tetrahydro-
furan-2-
ylmethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3- {4-[6-(2-methoxymethyl-morpholin-4-
ylmethyl)-
pyridin-3-yl]-naphthalen-1-yl} -urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-morpholin-4-yl-ethylamino)-
methyl]-
pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-
ylmethyl)-
pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5- {4-[3-(5-tart-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl } -pyridin-
2-
ylinethyl)-piperidine-3-carboxylic acid amide;
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1-(5- {4-[3-(5-tart-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl } -pyri
din-2-
ylmethyl)-piperidine-4-carboxylic acid amide;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-~4-[6-(1-oxo-114-thiomorpholin-4-ylmethyl)-
pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(3, 3-Dimethyl-2-oxo-2,3 -dihydro-1 H-indol-5-yl)-3-[4-(6-morpholin-4-
ylmethyl-
pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3 - {4-[6-(3-oxo-piperazin-1-ylmethyl)-
pyridin-3-yl]-
naphthalen-1-yl}-urea;
1- f 4-[6-(4-Acetyl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-3-(5-
tart-butyl-
2-methoxy-phenyl)-urea;
4-(5-~4-[3-(5-tart-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-
ylmethyl)-piperazine-1-carboxylic acid ethyl ester;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-(4- { 6-[(2-pyridin-3-yl-ethylamino)-
methyl]-
pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-(4- { 6-[(tetrahydro-furan-3-ylamino)-
methyl]-
pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-[4-(6- { [(2-cyano-ethyl)-pyridin-3-
ylmethyl-amino]-
methyl } -pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-(4- f 6-[(2-methylsulfanyl-ethylamino)-
methyl]-
3o pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3- f 4-[6-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-
ylmethyl)-
pyridin-3-yl]-naphthalen-1-yl } -urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-
pyridin-3-yl]-naphthalen-1-yl } -urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3-(4- f 6-[(2-piperazin-1-yl-ethylamino)-
methyl]-
pyridin-3-yl} -naphthalen-1-yl)-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3- f 4-[6-(4-pyrimidin-2-yl-piperazin-1-
ylmethyl)-
pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tart-Butyl-2-methoxy-phenyl)-3- {4-[6-(4-pyridin-2-yl-piperazin-1-
ylmethyl)-
pyridin-3-yl]-naphthalen-1-yl}-urea;
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1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[4-(3-methoxy-phenyl)-piperazin-1-
ylmethyl]-pyridin-3-yl~-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[6-(morpholine-4-carbonyl)-pyridin-3-
yl]-
naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[6-(2-thia-5-aza-bicyclo[2.2.1 ]hept-5-
ylmethyl)-
pyridin-3-yl]-naphthalen-1-yl}-urea;
1o 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2-
yl)-
naphthalen-1-yl]-urea;
1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morpholin-
4-
ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-
3-yl)-
naphthalen-1-yl]-urea;
N-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl]-pyridin-2-
yl)-
2o acetamide;
N-(5-tert-Butyl-2-methoxy-3- {3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-ureido]-phenyl)-N-methyl-acetamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-ureido ) -phenyl)-2,2,2-trifluoro-acetamide;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-yloxy)-pyridin-3-yl]-
naphthalen-1-
yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-ylamino)-pyridin-3-yl]-
naphthalen-1-yl}-urea;
[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-carbamic acid 3-tert-
butyl-
phenyl ester;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-
yl]-ureido}-phenyl)-methanesulfonamide;
1-(5-tert-Butyl-2-methylsulfanyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-
yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-chloro-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
yl)-
naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methylamino-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-
pyridin-3-
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yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-3- f 3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
yl]-
ureido } -2-oxo-2H-pyridin-1-yl)-methanesulfonamide;
5-tert-Butyl-7- f 3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-
ureido}-
benzooxazole-2-carboxylic acid amide;
2-(5-tert-Butyl-7- { 3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
yl]-ureido } -
lo benzooxazol-2-yl)-acetamide and
5-tert-Butyl-2-methoxy-3- f 3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
naphthalen-1-yl]-
ureido } -benzamide.
Any compounds of this invention containing one or more asymmetric carbon atoms
may
occur as racemates and racemic mixtures, single enantiomers, diastereomeric
mixtures
and individual diastereomers. All such isomeric forms of these compounds are
expressly
2o included in the present invention. Each stereogenic carbon may be in the R
or S
configuration, or a combination of configurations.
Some of the compounds of formula (I) can exist in more than one tautomeric
form. The
invention includes all such tautomers.
All terms as used herein in this specification, unless otherwise stated, shall
be understood
in their ordinary meaning as known in the art. For example, "C1_4alkoxy" is a
Cl~alkyl
with a terminal oxygen, such as methoxy, ethoxy, propoxy and butoxy. All
alkyl, alkenyl
and alkynyl groups shall be understood as being branched or unbranched where
3o structurally possible and unless otherwise specified. Other more specif c
definitions are
as follows:
The term "amyl" as used in the present specification shall be understood to
mean
"benzoyl" or "naphthoyl".
The term "carbocycle" shall be understood to mean an aliphatic hydrocarbon
radical
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containing from three to twelve carbon atoms. Carbocycles include hydrocarbon
rings
containing from three to ten carbon atoms. These carbocycles may be either
aromatic
and non-aromatic ring systems. The non-aromatic ring systems may be mono- or
polyunsaturated. Preferred carbocycles include but are not limited to
cyclopropyl,
cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl,
cyclohexenyl,
cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutanyl,
dihydronaphthyl, tetrahydronaphthyl, naphthyl, decahydronaphthyl,
benzocycloheptanyl
and benzocycloheptenyl. Certain terms for cycloalkyl such as cyclobutanyl and
cyclobutyl shall be used inerchangeably.
to
The term "heterocycle" refers to a stable nonaromatic 4-8 membered (but
preferably, 5 or
6 membered) monocyclic or nonaromatic 8-11 membered bicyclic heterocycle
radical
which may be either saturated or unsaturated. Each heterocycle consists of
carbon atoms
and one or more, preferably from 1 to 4 heteroatoms selected from nitrogen,
oxygen and
15 sulfur. The heterocycle may be attached by any atom of the cycle, which
results in the
creation of a stable structure. Unless otherwise stated, heterocycles include
but are not
limited to, for example oxetanyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydrothiophenyl,
piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl,
tetramethylene
sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl,
2o tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl,
decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl,
dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl, dithianyl,
maleimidyl
or 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl and benzo or pyridino fused
derivatives
thereof.
The term "heteroaryl" shall be understood to mean an aromatic 3-8 membered
monocyclic or 8-14 membered bicyclic ring containing 1-4 heteroatoms such as
N,O and
S. Unless otherwise stated, such heteroaryls include: pyridinyl, pyridonyl,
quinolinyl,
dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl,
pyridazinyl,
pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzothienyl,
benzoxazolyl,
benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl,
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dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl,
benzodioxolyl,
benzo[1,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl,
indolonyl,
indolinonyl, phthalimidyl, and the mono or multiply saturated and benzo or
pyridino
fused derivatives thereof.
The term "aryl" as used herein shall be understood to mean aromatic carbocycle
or
heteroaryl as defined herein.
Terms which are analogs of the above cyclic moieties such as aryloxy or
heteroaryl
io amine shall be understood to mean an aryl, heteroaryl, heterocycle as
defined above
attached to it's respective group.
All of the above-defined terms, where chemically possible, shall be understood
to be
optionally halogenated with one or more halogen atoms as defined below.
The term "halogen" as used in the present specification shall be understood to
mean
bromine, chlorine, fluorine or iodine.
The term "heteroatom" as used herein shall be understood to mean atoms other
than
2o carbon such as O, N, S and P.
As used herein, "nitrogen" and "sulfur" include any oxidized form of nitrogen
and sulfur
and the quaternized form of any basic nitrogen.
The compounds of the invention are only those which are contemplated to be
'chemically
stable' as will be appreciated by those skilled in the art. For example, a
compound which
would have a 'dangling valency', or a 'carbanion' are not compounds
contemplated by
the invention.
3o The invention includes pharmaceutically acceptable derivatives of compounds
of formula
(I). A "pharmaceutically acceptable derivative" refers to any pharmaceutically
acceptable salt or ester of a compound of this invention, or any other
compound which,
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upon administration to a patient, is capable of providing (directly or
indirectly) a
compound of this invention, a pharmacologically active metabolite or
pharmacologically
active residue thereof. A pharmacologically active metabolite shall be
understood to
mean any compound of the invention capable of being metabolized enzymatically
or
chemically. This includes, for example, hydroxylated or oxidized derivative
compounds
of the formula(I).
Pharmaceutically acceptable salts of the compounds of this invention include
those
derived from pharmaceutically acceptable inorganic and organic acids and
bases.
1 o Examples of suitable acids include hydrochloric, hydrobromic, sulfuric,
nitric, perchloric,
fumaric, malefic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-
sulfuric,
tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic,
naphthalene-2-sulfuric
and benzenesulfonic acids. Other acids, such as oxalic acid, while not
themselves
pharmaceutically acceptable, may be employed in the preparation of salts
useful as
15 intermediates in obtaining the compounds of this invention and their
pharmaceutically
acceptable acid addition salts. Salts derived from appropriate bases include
alkali metal
(e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C1-C4
alkyl)4+ salts.
2o In addition, the compounds of this invention include prodrugs of compounds
of the
formula (I). Prodrugs include those compounds that, upon simple chemical
transformation, are modified to produce compounds of the invention. Simple
chemical
transformations include hydrolysis, oxidation and reduction. Specifically,
when a
prodrug of this invention is administered to a patient, the prodrug may be
transformed
25 into a compound of the invention, thereby imparting the desired
pharmacological effect.
3o METHODS OF USE
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WO 02/083642 PCT/USO1/12253
In accordance with the invention, there are provided methods of using the
compounds of
the formula (I). The compounds of the invention effectively block inflammatory
cytokine
production from cells. The inhibition of cytokine production is an attractive
means for
preventing and treating a variety of cytokine mediated diseases or conditions
associated
with excess cytokine production, e.g., diseases and pathological conditions
involving
inflammation. Thus, the compounds of the invention are useful for the
treatment of such
conditions. These encompass diseases including, but not limited to, rheumatoid
arthritis,
osteoarthritis, traumatic arthritis, multiple sclerosis, Guillain-Barre
syndrome, Crohn's
disease, ulcerative colitis, psoriasis, graft versus host disease, systemic
lupus
io erythematosus, glomerulonephritis, reperfusion injury, sepsis, bone
resorption diseases
including osteoporosis, chronic obstructive pulmonary disease, congestive
heart failure,
Alzheimer's disease, atherosclerosis, toxic shock syndrome, asthma, contact
dermatitis
and insulin-dependent diabetes mellitus.
15 In addition, the compounds of the invention being inhibitors of cytokine
production are
expected to block inducible cyclooxygenase (COX-2) expression. COX-2
expression has
been shown to be increased by cytokines and it is believed to be the isoform
of
cyclooxygenase responsible for inflammation (M.K. O'Banion et al., P~oc. Natl.
Acad.
Sci. U.S.A, 1992, 89, 4888.) Accordingly, the present novel compounds would be
2o expected to exhibit efficacy against those disorders currently treated with
COX inhibitors
such as the familiar NSAIDs. These disorders include acute and chronic pain as
well as
symptoms of inflammation and cardiovascular disease.
As discussed in the Background of the Invention, IL-8 plays a role in the
influx of
25 neutrophils into sites of inflammation or injury. Therefore, in a yet
further aspect of the
invention, the compounds of the invention may be useful in the treatment of
diseases
mediated predominantly by neutrophils such as stroke and myocardial
infarction, alone or
following thrombolytic therapy, thermal injury, adult respiratory distress
syndrome
CARDS), multiple organ injury secondary to trauma, acute glomerulonephritis,
30 dermatoses with acute inflammatory components, acute purulent meningitis or
other
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central nervous system disorders, hemodialysis, leukopherisis, granulocyte
transfusion
associated syndromes, and necrotizing entrerocolitis.
For therapeutic use, the compounds of the invention may be administered in any
conventional dosage form in any conventional manner. Routes of administration
include,
but are not limited to, intravenously, intramuscularly, subcutaneously,
intrasynovially, by
infusion, sublingually, transdermally, orally, topically or by inhalation. The
preferred
modes of administration are oral and intravenous.
io The compounds of this invention may be administered alone or in combination
with
adjuvants that enhance stability of the inhibitors, facilitate administration
of pharmaceutic
compositions containing them in certain embodiments, provide increased
dissolution or
dispersion, increase inhibitory activity, provide adjunct therapy, and the
like, including
other active ingredients. Advantageously, such combination therapies utilize
lower
15 dosages of the conventional therapeutics, thus avoiding possible toxicity
and adverse side
effects incurred when those agents are used as monotherapies. Compounds of the
invention may be physically combined with the conventional therapeutics or
other
adjuvants into a single pharmaceutical composition. Advantageously, the
compounds
may then be administered together in a single dosage form. In some
embodiments, the
20 pharmaceutical compositions comprising such combinations of compounds
contain at
least about 5%, but more preferably at least about 20%, of a compound of
formula (I)
(w/w) or a combination thereof. The optimum percentage (w/w) of a compound of
the
invention may vary and is within the purview of those skilled in the art.
Alternatively,
the compounds may be administered separately (either serially or in parallel).
Separate
25 dosing allows for greater flexibility in the dosing regime.
As mentioned above, dosage forms of the compounds of this invention include
pharmaceutically acceptable carriers and adjuvants known to those of ordinary
skill in the
art. These carriers and adjuvants include, for example, ion exchangers,
alumina,
3o aluminum stearate, lecithin, serum proteins, buffer substances, water,
salts or electrolytes
and cellulose-based substances. Preferred dosage forms include, tablet,
capsule, caplet,
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WO 02/083642 PCT/USO1/12253
liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable
powder, granule,
suppository and transdermal patch. Methods for preparing such dosage forms are
known
(see, for example, H.C. Ansel and N.G. Popovish, Pha~rnaceutical Dosage Forms
and
Df ug Delivery Systems, 5th ed., Lea and Febiger (1990)). Dosage levels and
requirements are well-recognized in the art and may be selected by those of
ordinary skill
in the art from available methods and techniques suitable for a particular
patient. In some
embodiments, dosage levels range from about 1-1000 mg/dose for a 70 kg
patient.
Although one dose per day may be sufficient, up to 5 doses per day may be
given. For
oral doses, up to 2000 mg/day may be required. As the skilled artisan will
appreciate,
lower or higher doses may be required depending on particular factors. For
instance,
specific dosage and treatment regimens will depend on factors such as the
patient's
general health profile, the severity and course of the patient's disorder or
disposition
thereto, and the judgment of the treating physician.
In order that this invention be more fully understood, the following examples
are set
forth. These examples are for the purpose of illustrating preferred
embodiments of this
invention, and are not to be construed as limiting the scope of the invention
in any way.
The examples which follow are illustrative and, as recognized by one skilled
in the art,
particular reagents or conditions could be modified as needed for individual
compounds
2o without undue experimentation. Starting materials used in the scheme below
are either
commercially available or easily prepared from commercially available
materials by
those skilled in the art.
GENERAL SYNTHETTC METHODS
The invention additionally provides for methods of making the compounds of the
formula
(I). The compounds of the invention may be prepared by the general methods and
examples presented below, and methods known to those of ordinary skill in the
art.
Further reference in this regard may be made to US application nos.
09/505,582,
3o 09/484,638, 09/714,539, 09/611,109, 09/698,442 and US provisional
application no.
60/216,283. Each of the aforementioned are incorporated herein by reference in
their
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WO 02/083642 PCT/USO1/12253
entirety. In all schemes "G" in the formulas shown below shall have the
meaning of "G"
in the formula (I) of the invention described hereinabove.
The compounds of the invention may be prepared by Method A, B, C or D as
illustrated
in Scheme I, preferably Method C.
Scheme I
Method A
G'-NCO
III O
G\NH2 G. ~L .G'
IV N
H H
I I a G' = Ar-X-Y-Z (I)
or a precursor of I
Method B
1 phosgene O
G. ~ .G'
G\NH2 H H
2. G' -NH2
IV G' = Ar-X-Y-Z ( I )
Ila or a precursor of I
Method C
O G'-NH2 O
CIC02Ph G~N~O.Ph IV G.N~N.G'
G~NH2
H H H
Ila V
G' = Ar-X-Y-Z (I)
or a precursor of I
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Method D
O G-NH2 O
CIC02Ph G~'N~J.~O,ph Ila G.N~N.G'
G ~NHZ ,
H H H
IV Va
G' = Ar-X-Y-Z (I)
or a precursor of I
In Method A, a mixture of an arylamine of formula IIa and an arylisocyanate of
formula
III is dissolved in a non-erotic, anhydrous solvent such as THF, ether,
toluene, dioxane or
ethyl acetate. The preferred solvent is THF. The mixture is stirred at between
0 - 45° C,
preferably at 25° C, for 2-24 h, and the volatiles are removed.
Purification of the residue
by recrystallization from an appropriate solvent such as ethyl
acetate/hexanes, ethyl
acetate/MeOH, THF/petroleum ether, EtOH/water or by silica gel chromatography,
using
for example, hexanes and ethyl acetate as eluents, provides the product of
formula I (E =
NH) or precursors thereof.
to In Method B, an arylamine of formula IIa is dissolved in a halogenated
solvent, such as
methylene chloride, chloroform or dichloroethane. The preferred solvent is
methylene
chloride. The mixture is diluted with aqueous alkali, such as sodium
bicarbonate or
potassium carbonate, cooled in an ice bath and phosgene is added. The mixture
is
vigorously stirred for 5 - 30 min, with 10 min being preferable. The organic
layer is
15 dried, with agents such as MgS04 or Na2S04, and the volatiles removed to
provide the
corresponding isocyanate. The isocyanate and arylamine IV are mixed in a non-
erotic,
anhydrous solvent such as THF, ether, toluene, dioxane, methylene chloride or
ethyl
acetate. The preferred solvent is THF. The mixture is stirred at between 0 -
45° C,
preferably at 25° C, for 2 - 24 h, and the volatiles are removed.
Purification of the residue
2o by recrystallization or by silica gel chromatography, as above, provides
the product of
formula I (E = NH) or precursors thereof.
The required isocyanate may also be prepared from the carboxylic acid G-COZH
by
reaction with a chloroformate, such as ethyl chloroformate, in the presence of
a suitable
base, such as triethylamine, in a suitable solvent, such as THF at about 0
°C. The
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resulting mixed anhydride is treated with an aqueous solution of sodium azide.
Heating a
solution of the resulting aryl azide in a suitable solvent, such as toluene,
at about reflux,
results in a Curtius rearrangement, providing the isocyanate G-N=C=O in situ.
In Method C, an arylamine of formula IIa is dissolved in a suitable solvent
such as a
halogenated solvent which includes methylene chloride, chloroform or
dichloroethane.
The preferred solvent is methylene chloride. A suitable base such as
triethylamine may
be added, followed by an alkyl or aryl chloroformate, such as t-butyl
chloroformate or
phenyl chloroformate (shown). The mixture is stirred at between 0 - 85°
C, preferably at
reflux temperature, for 2 - 24 h, and the volatiles are removed providing
carbamate V.
to The carbamate and arylamine IV are mixed in a non-protic, anhydrous solvent
such as
THF, ether, toluene, dioxane, methylene chloride or ethyl acetate. The
preferred solvent
is THF. The mixture is stirred at between 0 - 110 ° C, preferably at
reflux temperature,
for 2 - 24 h, and the volatiles are removed. Purification of the residue as
above provides
the product of formula I (E = NH) or precursors thereof. This process can also
be
performed in the reverse sense as illustrated by Method D.
In Method D an arylamine of formula IV is dissolved in a suitable solvent such
as a THF.
A suitable alkyl or aryl chloroformate, such as t-butyl chloroformate or
phenyl
chloroformate (shown), is added. The mixture is stirred at between 0 -
85° C, preferably
at 0° C, for 2 - 24 h, at which time the reaction is quenched with
aqueous, saturated
sodium bicarbonate. Extractions with a suitable solvent, such as ethyl
acetate, provide
carbamate Va upon concentration. The carbamate and arylamine IIa are mixed in
a non-
protic, anhydrous solvent such as THF, ether, toluene, dioxane, methylene
chloride or
ethyl acetate. The preferred solvent is THF. The mixture is stirred at between
0 - 110° C,
preferably at 0° C, for 2 - 48 h, in a sealed tube. PS-trisamine and PS-
isocynate resins are
added, and the reaction mixture was shaken for 3 days. Filtration and
concentration
provides the product of formula I (E = NH) or precursors thereof.
By using the appropriate starting material (G-EH), the above methods may also
be used
to prepare compounds of formula I with E = O or S (see for instance, Example
23).
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Arylamine intermediates of formula IIa are either commercially available or
can be made
by methods known to those skilled in the art. Some of these methods are
illustrated in the
Synthetic Examples section.
Methods by which some intermediates III and IV, G' = Ar-X-Y-Z (Scheme I) may
be
prepared are described below, and also illustrated in the Synthetic Examples
section. In
Method E (Scheme II), a bromoarylamine VI, which may be commercially available
or
easily prepared by one skilled in the art, is reacted with a cycloalkenone VII
in the
presence of a transition metal catalyst, for example a palladium(II) catalyst
such as
l0 bis(triphenylphosphine)palladium(II) chloride, in the presence of a
bis(triphenylphosphine) chelator, such as 1,2- bis(diphenylphosphino)ethane
(DPPE),
1,1'-bis(diphenylphosphino)ferrocene (DPPF) and 1,3-
bis(diphenylphosphino)propane
(DPPP), preferably DPPP, and a base, preferably sodiun bicarbonate, in a
suitable
solvent, preferably DMF at a temperature of about 150 °C to provide
VIII. VIII may then
be used (as IV) in Method B (Scheme I), or converted to isocyanate IX by
reaction with
phosgene or a phosgene equivalent in the presence of a base, such as sodium
bicarbonate
in a suitable solvent such as dichloromethane, at a temperature of about 0
°C, and used
(as III) in Method A. The resulting product X may be modified further by
methods
known by one skilled in the art to obtain the desired compound of formula I.
In Method F, bromide XI is reacted with a strong base, such as t-butyl
lithium, in a
suitable solvent, such as THF, with tributyltin chloride at a temperature of
about -50 °C
to -100 °C, preferably about -78 °C to give XII. XII is then
reacted with VT in a suitable
solvent, such as THF or 1,4-dioxane, in the presence of a transition metal
catalyst,
preferably tetrakis(triphenylphosphine)palladium(0), at a temperature of about
50 °C to
150 °C, preferably about 100 °C and in a sealed tube, providing
XIII. XIII may then be
used (as IV) in Method B or C (Scheme I), or converted to the corresponding
isocyanate
as described in Method E, and used (as III) in Method A.
3o Scheme II
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Method E
O Pd(Ph3)2CI2 O
DPPP
H2NXBr + '
NaHC03 H2N~X n
n DMF
150 ~C
VI VII VIII
n = 1-4
Method B or C
O
phosgene p
CH2C12 Method A
VIII ~- ~ N
aq ~NaCC03 OCN~ ~ ) G~ ~"~ ~X )n
o X n
IX X
Method F
1. t-BuLI V!
Br-X-G2 Bu3Sn-X-G2 H2NAr~ X-G2
XI 2. Bu3SnCl XII Pd(PPh3)4 XIII
G2=Y-Zor
a precursor
Methods by which Y and Z may be joined to X are known in the art, and two are
illustrated in Scheme III. As illustrated by Method G, if one desires a
product in which Y
includes an amino nitrogen bonded to X, an X containing a ketone may be
reacted with a
Y-Z containing a terminal primary or secondary amine under reductive amination
conditions. For example, ketone X is combined with a primary or secondary
amine, in a
suitable solvent such as THF. An acid, such as acetic acid, is added, followed
by a
suitable reducing agent, preferably sodium cyanoborohydride or sodium
(triacetoxy)borohydride, to provide the desired product XIV.
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Method H illustrates a procedure for obtaining a methylene group for Y and a
primary or
secondary amine for Z. An X group bearing an aldehyde and a halogen,
preferably
bromine (XV), may be reacted with a primary or secondary amine under reductive
amination conditions as described in Method G to provide XVI. This
intermediate may
then be used as described for XI in Method F.
Scheme III
Method G
O N(R)R'
RNHR'
,N N\ I ~ ~\ I
G ~ Ar ~)n G ~ Ar ~)n
reductive
O amination O
X XIV
n = 1-4 -N(R)R' _ -Y-Z
n=1-4
Method H
RNHR'
Br-X-CHO Br-X-CH2-N(R)R'
reductive
XV amination XVI
io -CH2N(R)R' _ _Y_Z
The synthesis of additional intermediates corresponding to IV and V may be
accomplished by methods similar to those described in the literature or known
to those
skilled in the art. Some of these methods are exemplified in the synthetic
examples
below.
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SYNTHETIC EXAMPLES
Intermediates IIa (G-NH2, Scheme I) may be commercially available or prepared
by
methods known to those skilled in the art. Examples 1-3 provide representative
procedures by which these intermediates may be synthesized.
EXAMPLE 1
5-tart-Butyl-2-methoxy-3-nitroaniline:
\ fuming HN03 ~ \
HOAc O N / NO
2 2
OMe OMe
Na2S.9Hz0 ( \
cat. Aliquat 336 O N / NH
a z
OMe
1
Fuming nitric acid (150 mL) was placed in a round bottom flask. A solution of
4-tert-
butylanisole (16.4 g, 0.1 mol) in acetic acid (15 mL) was placed in an
addition funnel and
added dropwise to the flask. The flask was intermittently immersed in a water
bath to
maintain the temperature below 40°C throughout the addition. Once the
addition was
complete, the reaction mixture was heated to 80°C, and maintained at
that temperature for
2 h. The reaction mixture was cooled to ambient temperature, and then poured
onto an
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ice/water mixture. A white solid soon formed, and the mixture was stirred for
30 min.
The solid was isolated by vacuum filtration, and the filter cake was washed
with water.
The solid was dried on the filter. Recrystallization from hot 2-propanol
provided 5-te~t-
butyl-2-methoxy-1,3-dinitrobenzene as white crystals (18.9 g, 75%).
To a suspension of 5-ter°t-butyl-2-methoxy-1,3-dinitrobenzene (10.2 g,
0.04 mol) in
EtOAc (150 mL) was added in a single portion a solution of sodium sulfide
nonahydrate
(19.2 g, 0.08 rnol) in water (200 mL). Aliquat~ 336 (0.8 g, 5 mole %) was
added in a
single portion, and the two-phase mixture was brought to a reflux. All solids
dissolved,
and the mixture became red/brown. After about 3 h, TLC (3:1 hexanes:EtOAc)
revealed
almost complete loss of starting material. The mixture was filtered warm
through a pad of
diatomaceous earth to remove insolubles, and the filter cake was washed with
fresh
EtOAc. The clarified two-phase mixture was separated, and the organic layer
was washed
with sodium carbonate solution, followed by water and then saturated sodium
chloride
solution. After drying over magnesium sulfate, the solution was concentrated
under
reduced pressure to a thick, dark oil. This oil was extracted three times with
refluxing
hexanes, leaving behind a dark residue. The orange extract deposited some more
dark oil,
from which the warm supernatant was decanted. The resulting orange solution
was
heated back to reflux, and treated with both activated charcoal and
diatomaceous earth.
The solution was filtered hot, and the filter cake washed with hot hexanes. Re-
heating the
orange filtrate resulted in a clear solution. Quickly cooling the solution in
an ice/acetone
bath and scratching the flask with a glass rod resulted in the deposition of
an
orangelyellow precipitate. The suspension was allowed to cool for 1 h, and
then filtered.
The filter cake was washed with a small portion of cold hexanes, and then
dried on the
filter, providing the title compound as a yellow/orange powder (2.6 g, 30%).
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EXAMPLE 2
5-tart-Butyl-3-methanesulfonamido-2-methoxyaniline
NOZBF4
\ CH3CN I \ MeSOZCI O O I \
HEN I ~ ~ H~N / NO~ ~ ~S~N / NOZ
H ,O H , H /O
NH4HC02 O \
Pd-C, EtOH O~II
/SAN I / N.H
H ,O H
2
5-tart-Butylanisole (5.38 g, 30.0 mmol, 1 equiv.) was dissolved in 80 mL
anhydrous
CH3CN and cooled to -35 °C under inert atmosphere. Nitronium
tetrafluoroborate (4.78
g, 36.0 mmol, 1.2 equiv.) was then added in one portion. The reaction was
stirred for 25
min, then quenched with a saturated aqueous solution of NaHC03 and extracted
with
dichloromethane (3 x 75 mL). The combined organic extracts were dried over
MgS04,
to filtered, and the solvents were removed in vacuo. The crude oil was
purified by column
chromatography on Si02, using 0-30% EtOAc in hexanes to afford 5.70 g of 5-
tert-
butyl-2-methoxy-3-nitro aniline (25.2 mmol, 84 % yield). (Example 1 describes
an
alternate synthesis of this intermediate.)
The nitro aniline (214 mg, 0.95 mmol, 1 equiv.) was dissolved in 1.0 mL
anhydrous
pyridine and cooled to 0 °C under inert atmosphere. Methane sulfonyl
chloride (146 uL,
1.90 mmol, 2 equiv.) was then added dropwise via syringe. The mixture was left
to stir
for 6 h at 0 °C, then poured over a mixture of 1 mL concentrated HCl
and ice. The
product was extracted with dichloromethane (3 x 20 mL) and dried over MgS04.
The
2o crude solution was filtered and the volatiles removed in vacuo.
Purification by column
chromatography on SiOa using 25-35 % EtOAc in hexanes as eluent afforded 270
mg of
nitro sulfonamide intermediate (0.89 mmol, 94 % yield).
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The nitro sulfonamide (270 mg, 0.89 mmol, 1 equiv.) was dissolved in 10 mL
EtOH.
Ammonium formate (288 mg, 4.56 mmol, 5.1 equiv.) and palladium-on-charcoal (10
Pd-C, ~ 150 mg) were added and the mixture was heated to 60 °C for 1 h.
The mixture
was then cooled, filtered through a pad of diatomaceous earth, and the solvent
removed in
vacuo. The aniline intermediate (220 mg, 88% yield) obtained was used in
subsequent
couplings without purification.
The same general procedure outlined above may be used to prepare other desired
alkyl or
aryl sulfonamide intermediates by substituting the appropriate alkyl or aryl
sulfonyl
to chloride for methane sulfonyl chloride. Also, by preparing a sulfonamide
with a reactive
functionality, one may use this reactive site to prepare additional compounds
of the
invention by methods known to those skilled in the art. This may be done
either in situ or
in a subsequent step. For example, as described by S. Vanwetswinkel et al. (J.
Antibiot.,
1994, 47, 1041), one may use the commercially available chlorosulfonylacetyl
chloride
and the desired amine (R'R"NH) ih situ to prepare amide-substituted
sulfonamide
intermediates as illustrated below. Selective reduction of the nitro group by
methods
known in the art, for example the catalytic reduction described above, gives
the desired
aniline intermediate.
~~ ~o
cl S'cl
H~N ~ NOZ R'R"NH
H , NEt3
CHzCl2
EXAMPLE 3
2-[(3-Amino-5-tent-butyl-2-methoxyphenyl)amino]oxazoline:
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CI(CH2)2NC0
\ DIPEA O ~ \ KF~AI203
CI~N~N / NO
H2N ~ ~N02 THF ~ ~ 2 CH3CN
OMe RT H H OMe
NH4+ HC02
O ~ \ Pd-C ~O ~ \
i~~ / /
N~N NO CH CN N N NH
3 I 2
H OMe ~ H OMe
3
5-tent-Butyl-2-methoxy-3-nitroaniline (338 mg, 1.5 mmol) was dissolved in 2 mL
THF
and diisopropylethylamine (0.26 mL, 1.5 mmol) was added. This mixture was
treated
with chloroethyl isocyanate (195 microL, 1.8 mmol) and was left stirring
overnight under
inert atmosphere. TLC analysis revealed starting amine was still present, so
the mixture
was treated with an additional 50 microL of isocyanate and stirred 4 h.
Volatiles were
then removed in vacuo and the resulting orange solid was purified by column
chromatography on Si02 using 0 - 50 % EtOAc in hexanes as eluent. The
chloroethyl
l0 urea was obtained as an orange solid (450 mg or 90 % yield).
The chloroethyl urea (189 mg, 0.57 mmol) was dissolved in 4 mL acetonitrile
and treated
with KF'A1203 (40 % wt., 332 mg, 2.29 mmol). The resulting mixture was heated
to
reflux and stirred overnight. After cooling to room temperature, the residue
was directly
loaded on a SiO2 column and the product eluted with 0 - 80 % EtOAc in hexanes
providing the desired amino-oxazoline (133 mg, 79 % yield).
The amino-oxazoline (133 mg, 0.46 mmol, 1 equiv) was suspended in 6.5 mL
acetonitrile. Palladium on carbon (10 % wt., 133 mg) was then added, followed
by
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ammonium formate (172 mg, 2.72 mmol). The mixture was refluxed for 1.75 h,
then
cooled to room temperature and filtered through a diatomaceous earth pad. The
solvent
was removed in vacuo to afford 107 mg of the title compound (89 % yield).
EXAMPLE 4
1-Amino-4-[5-(morpholin-4-ylmethyl)fur-2-yl]naphthalen-1-yl~ urea:
to
HN
1 ) t-BuLi
I ~ w0 ~O I ~ N
gr O O 2) Bu3SnCl
Br
AcOH, Na[HB(OAc)3]
Br
HZN ~ ~ N
~O
I ~ N
Bu3Sn
[Pd(PPh3)a]
4
To a mixture of 5-bromo-2-furaldehyde (1.76 g) and morpholine (1.00 ml) in 40
mL
anhydrous THF at room temperature was added acetic acid (0.60 mL) followed by
sodium triacetoxyborohydride (3.28 g). The mixture was stirred at room
temperature for
3 h and then poured into a saturated solution of sodium bicarbonate (100 mL).
After
stirring vigorously for 5 min the layers were separated and the aqueous layer
was
extracted with EtOAc. The combined organic layers were washed with brine,
dried
(Na2S04), filtered and evaporated to dryness. Purification of the residue by
flash
chromatography afforded 2.09 g (8.49 mmol, 84% yield) of 4-(5-bromo-2-
furylmethyl)morpholine.
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The above intermediate (0.678 g, 2.76 mmol) was dissolved in 10 mL anhydrous
THF
under inert gas atmosphere and the solution was cooled to at -78°C. t-
Butyllithium (4.0
mL of a 1.7 M solution in pentane) was added dropwise and the solution was
stirred at -
78°C for 30 min. Tributyltinchloride (0.60 mL, 0.72g, 2.2 mmol) was
added and the
solution was stirred for another 30 min at -78°C. pH7 Buffer
(NaH2P04/Na2HP04 sat.)
was added (10 mL) and the mixture was warmed to room temperature. The layers
were
separated and the aqueous layer was extracted with EtOAc. The combined organic
layers
were washed with brine, dried (NaZS04), filtered and evaporated to dryness.
Purification
of the residue by flash chromatography afforded 0.526 g (1.15 mmol, 42% yield)
of the
1o tributylstannane intermediate.
The above intermediate (0.399 g, 0.874 mmol) and 1-amino-4-bromonaphthalene
(0.200
g, 0.901 mmol) were dissolved in 10 mL anhydrous 1,4-dioxane in a sealable
tube under
inert gas atmosphere. The solution was degassed and purged with nitrogen (2x).
15 Tetrakis(triphenylphosphine)palladium(0) (0.057g, 0.049 mmol) was added and
the
solution was degassed and purged with nitrogen again (2x). The tube was sealed
and
heated to 100°C for 24 h. After cooling to room temperature the mixture
was diluted with
EtOAc, saturated aqueous potassium carbonate solution (10 mL) was added and
the
mixture was stirred for lh at room temperature. The mixture was filtered over
2o diatomaceous earth and the layers were separated. The aqueous layer was
extracted with
EtOAc. The combined organic layers were washed with brine, dried (Na2S04),
filtered an
evaporated to dryness. Purification of the residue by flash chromatography
afforded
0.314 g of a yellow oil, which contained the title compound along with
tributyltin
bromide. This mixture is suitable for use in Methods A-D without further
purification.
EXAMPLE 5
1-Amino-4-[3-(morpholin-4-yl)phenyl] naphthalene:
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O
/ 1 ) t-BuLi
/ Br Br
\ ~ Br \ I N 2) Bu3SnCl
Br NHz i-PrNEt2
\ Br
/ H2N \
\ ~ ~ / N
Bu3Sn N~ ~O
O [Pd(PPh3)al
3-Bromoaniline (3.0 mL, 4.7 g, 28 mmol), 2-bromoethylether (4.2 mL, 7.7 g, 33
mmol)
and diisopropylethylamine (15 mL, 11 g, 86 mmol) were dissolved in anhydrous
DMF
(20 mL) under inert gas atmosphere and heated to 100°C for 6 h. After
cooling to room
5 temperature the mixture was poured into water (300 mL) and extracted with
EtOAc. The
combined organic layers were washed with brine, dried (Na2SOa), filtered and
evaporated
to dryness. Purification of the residue by flash chromatography afforded 2.9 g
(12 mmol,
43% yield) of 4-(3-bromophenyl)morpholine.
4-(3-Bromophenyl)morpholine (1.73 g, 7.13 mmol) was dissolved in anhydrous THF
(30
mL) and cooled to -78°C, t-Butyllithium (10.0 mL of a 1.7 M solution in
pentane) was
added dropwise and the solution was stirred at -78 °C for 30 min.
Tributyltinchloride
(1.90 mL, 2.28 g, 7.00 mmol) was added and the solution was stirred for
another 45 min
at -78 °C. pH 7 Buffer (NaH2P04/Na2HPOa sat.) was added (10 mL) and the
mixture was
warmed to room temperature. The layers were separated and the aqueous layer
was
extracted with EtOAc. The combined organic layers were washed with brine,
dried
(Na2S04), filtered an evaporated to dryness. Purification of the residue by
flash
chromatography afforded 2.28 g (5.36 mmol, 77% yield) of the tributylstannane
intermediate.
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The above intermediate (1.49 g, 3.51 mmol) and 1-amino-4-bromonaphthalene
(0.69 g,
3.11 mmol) were dissolved in 20 mL anhydrous 1,4-dioxane in a sealable tube
under inert
gas atmosphere. The solution was degased and purged with nitrogen (2x).
Tetrakis(triphenylphosphine)palladium(0) (0.21 g, 0.18 mmol) was added and the
solution was degassed and purged with nitrogen again (2x). The tube was sealed
and
heated to 100 °C for 17 h. After cooling to room temperature the
mixture was diluted
with EtOAc, saturated aqueous potassium carbonate solution (10 mL) was added
and the
mixture was stirred for 1 h at room temperature. The mixture was filtered over
diatomaceous earth and the layers were separated. The aqueous layer was
extracted with
to EtOAc. The combined organic layers were washed with brine, dried (Na2SO4),
filtered
and evaporated to dryness. Purification of the residue by flash chromatography
afforded
0.363 g (1.19 mmol, 38%) oftitle compound.
EXAMPLE 6
5-(4-Aminonaphthalen-1-yl)-2-pyridin-3-ylmethylphenol:
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O Pd cat.
Br N HC03 O
H I + ~ H
~N /
DMF
H ~ I 150 °C
O
Boc-anhydride
NEt3 toluene
100 °C O O
--
O 1 ) t-BuOK
t-BuOH
reflux
2) TFA-DCM
H~N
H
6
To a tube containing a solution of 2.0 g of 1-amino-4-bromonaphthalene (9.0
mmol, 1
equiv.) in 70 mL DMF were added 1.75 mL of 2-cyclohexen-1-one (18.0 mmol, 2.0
equiv.), 2.3 g of sodium bicarbonate (27.0 mmol, 3.0 equiv.) and 186 mg of 1,3-
bis-
(diphenylphosphino)propane (dppp, 0.45 mmol, 0.05 equiv.). A stream of dry
nitrogen
gas was bubbled through the mixture for 15 min, then 316 mg of bis-
(triphenylphosphino)palladium(II) chloride (0.45 mmol, 0.05 equiv.) was added
and the
tube was sealed. The mixture was heated at 150 °C for 8 h, then cooled
to ambient
to temperature, diluted with EtOAc (150 mL) and filtered through diatomaceous
earth. The
mixture was washed with water, then brine. The organic layer was dried
(MgS04),
filtered and concentrated. The crude oil was purified by column chromatography
on SiOa
using 10 to 50% EtOAc in hexane mixtures as eluents to give 2.0 g of a thick
liquid
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consisting of 3-(4-aminonaphthalen-1-yl)cyclohex-2-enone and DMF (molar ratio
1:2
respectively, 5.22 mmol of naphthylamine, 58% of theoretical yield).
To a solution of 4.0 g of 3-(4-aminonaphthalen-1-yl)cycloxex-2-enone : DMF (1:
2, 10.4
s mmol, 1 equiv.) in 50 mL toluene was added 2.72 g of di-test-butyl
dicarbonate ( 12.5
mmol, 1.2 equiv.) and 1.5 mL triethylamine (10.4 mmol, 1 equiv.). The mixture
was
heated to 100 °C overnight, then cooled to ambient temperature. The
reaction mixture
was washed with 0.1% aqueous HCl (2 X 50 mL), water, brine, dried (MgS04),
filtered
and concentrated. The crude product precipitated and was washed with 10% EtOAc
in
to hexane to afford, after filtration, 2.5 g of desired tent-butyl carbamate
(7.4 mmol, 71% of
theoretical yield).
To a solution of 186 mg of the above tent-butyl carbamate (0.55 mmol, 1
equiv.) in 1.6
mL anhydrous test-butanol was added 52 uL of pyridine-3-carboxaldehyde (0.55
mmol, 1
15 equiv.) and 1.65 mL potassium test-butoxide solution (1.0 M, 1.32 mmol, 3
equiv.). The
mixture was heated to reflux overnight, then cooled. MeOH (5 mL) and HCl
solution in
dioxane (4.0 M) were added until pH ~ 1, the reaction was then stirred for 1.5
h at
ambient temperature. The mixture was then quenched with saturated NaHC03
aqueous
solution and extracted with EtOAc (2 x 50 mL). The aqueous layer was treated
with 4 N
2o NaOH aqueous solution until pH ~12 and extracted 2 more times. The combined
organic
extracts were washed with brine, dried (MgS04), filtered and concentrated to
afford a
mixture of crude products, including naphthylamine still protected as the
carbamate. The
residue was therefore taken up in dichloromethane (3 mL), treated with 2 mL
TFA and
left stirring over a weekend at ambient temperature. The mixture was quenched
and
25 neutralized with saturated aqueous NaHC03, extracted with dichloromethane
(3 x 50
mL), dried (MgS04) and filtered. The volatiles were removed in ~acuo and the
crude
product purified by column chromatography on SiOa using 50 to 100% EtOAc in
hexane
eluent mixtures giving 35 mg (0.11 mmol, 20% of theoretical yield) title
compound.
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EXAMPLE 7
5-(4-Aminonaphthalen-1-yl)-2-(tetrahydrofuran-3-ylmethyl)phenol:
O H H~N\HCI O O_ pibal-H O
O DCC, NEt3 N T 78 CI H
H
O CH2CI2 Oi O
cat DMAP
O
H
O O O
O N 1 ) t-BuOK
t-BuOH
reflux
2) TFA-DCM
RT
To a solution of 3.16 g of tetrahydro-3-furoic acid (27 mmol, 1 equiv.) in 25
mL
anhydrous dichloromethane was added 7.85 g of dicyclohexylcarbodiimide (38
mmol,
1.4 equiv.) and 4.54 mL triethylamine (32.6 mmol, 1.2 equiv.). N-methyl-
to methanolamine hydrochloride was then added, followed by 60 mg of DMAP (4-
dimethylamino)pyridine. An exothermic reaction ensued and a further 25 mL of
dichloromethane were added. The mixture was stirred at ambient temperature
overnight,
then filtered through diatomaceous earth and concentrated. The residue was
treated with
ether and the white solid filtered off and removed. The solvent was removed
from the
mother liquor and the residue purified by column chromatography on Si02 using
15-25%
EtOAc in hexanes as eluent mixtures to provide the desired amide as a
colorless oil (55%
of theoretical yield) that still contained 10% of dicyclohexyl urea. This was
used without
further purification in the next reaction.
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To a solution of 1.0 g of the above amide (6.28 mmol, 1 equiv.) in 60 mL
anhydrous THF
at -78 °C was added 12.6 mL of 1.0 M DIBAL-H solution in toluene
dropwise via
syringe (12.6 mmol, 2.0 equiv.). After stirring 30 min at -78 °C the
reaction mixture was
quenched with 50 mL MeOH and 50 mL water. The reaction mixture was transferred
to a
separatory funnel and 250 mL ether were added. 1 N HCl aqueous solution was
added
until all the solids had dissolved. The layers were separated and the aqueous
portion was
extracted further with 2 x 100 mL ether. The combined organics were washed
with
saturated aqueous NaHC03 solution, then brine, dried over Na2S04, filtered and
concentrated. The crude product was purified by chromatography on silica gel
using 0-
l0 5% MeOH in dichloromethane as eluent mixtures. The desired 3-
tetrahydrofuroic
aldehyde was obtained as a very volatile, impure colorless oil (200 mg).
To a solution of 200 mg of tent-butyl naphthyl carbamate (Example 6) (0.59
mmol, 1
equiv.) in 1.6 mL anhydrous tent-butanol was added 200 mg of 3-
tetrahydrofuroic
aldehyde from above (excess) and 1.78 mL potassium test-butoxide solution in
te~t-
butanol ( 1.0 M, 1.78 mmol, 3 equiv.). The mixture was heated to 40 °C
overnight, then
cooled and quenched with NH4C1 saturated aqueous solution. The product was
extracted
with a dichloromethane/MeOH mixture (3 x 100 mL). The combined extracts were
washed with brine, dried over MgSO4, and concentrated. 1H NMR analysis
revealed that
only 10% of the enone was consumed. The residue (300 mg) was dissolved in 4.0
mL
dichloromethane and treated with 4 mL of a 1 : 1 mixture dichloromethane :
TFA. The
mixture was stirred for 1.5 h, then neutralized with saturated NaHCO3 aqueous
solution,
basified with 4 N NaOH solution and extracted with dichloromethane / MeOH (3 x
100
mL). The combined organic extracts were washed with brine, dried (MgSO4) and
filtered
and concentrated. The crude product was purified by column chromatography on
silica
gel using 10 to 50% EtOAc in hexane eluent mixtures to give the title compound
(35 mg
0.11 mmol, 19% of theoretical yield).
EXAMPLE 8
4-[5-(4-Aminonaphthalen-1-yl)pyridin-2-yloxy] butyronitrile:
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OH
CBZNH ~ / B
~ON
Br Br
NaHMDS/THF
N gr DMSO N O~CN DME, 2M Na2C03
HO~CN Pd(PPh3)4, 90~C
CBZNH \ / \ / O~CN Fi2N \ ~ \ / 0'~/~CN
CZH50H, 10% Pd/C ~N
\ / 70 C
8
To 2,5-dibromopyridine (500 mg, 2.1 mmol) and 3-cyano-1-propanol (270 mg, 3.1
mmol) in DMSO (2 mL) was added 1M sodium hexamethyldisilazide (2.1 mL, 2.1
mmol). The reaction was stirred at room temperature overnight. EtOAc was added
to the
reaction and the mixture was washed with water (2 x 10 mL). The EtOAc fraction
was
dried over anhydrous sodium sulfate and evaporated on a rotary evaporator. The
crude
product was purified by flash column chromatography over silica gel using
40%EtOAc/hexanes to give 200 mg of 5-bromo-2-cyanopropyloxypyridine as a pale
yellow solid (39.3%).
To the above intermediate (100 mg, 0.4 mmol) and CBZ-protected naphthylboronic
acid
C (prepared as described for the Boc-analog Example 12) (200 mg, 0.62 mmol) in
DME
(4 mL) was added 2M sodium carbonate solution (2 mL). The solution was purged
with
nitrogen for 10 min and to this was added palladium tetrakistriphenylphosphine
(20 mg).
The reaction was heated at 90°C for 48 h and then cooled to room
temperature. EtOAc
was added to the reaction and the mixture was washed with water (2 x 10 mL).
The
EtOAc fraction was dried over anhydrous sodium sulfate, filtered and
concentrated. The
crude product was purified by flash column chromatography over silica gel
eluting with
40%EtOAc/hexanes to give 70 mg of the desired coupled intermediate (39%).
To the above coupled intermediate (70 mg, 0.16 mmol) in EtOH (5 mL) was added
cyclohexene (263 mg, 3.2 mmol) and 10%Pd/C (20 mg). The reaction was heated
under
nitrogen overnight and cooled to room temperature. The reaction was filtered
over
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diatomaceous earth, washed with MeOH and concentrated. The crude product was
purified by flash column chromatography over silica gel eluting with 50%
EtOAc/hexanes to give 15 mg of the title compound (31%).
EXAMPLE 9
[5-(4-Aminonaphthalen-1-yl)pyridin-2-yl]-(tetrahydrothiopyran-4-yl) amine
dihydrochloride:
l0
/OH
O N NHz Br
Br
NHZOH LIAIH4 Br
THF
EtOHC SJ SJ N
OH
BocNH ~ ~ B
~OH
HCI/dioxane
DME, 2M NazC03
(PPh3)zFdClz, 90oC
HzN
.2HC1
9
To tetrahydro-1,4-thiopyrone (2.0 g, 17.2 mmol) and hydroxylamine
hydrochloride (2.0
15 g, 28.7 mmol) in EtOH (10 mL) was added sodium acetate trihydrate (4.0 g,
29.4 mmol)
in 20 mL water. The reaction was heated at reflux for 3 h, cooled to room
temperature
and concentrated to 15 mL on a rotary evaporator. The residue was cooled in an
ice-bath
and filtered to give 2.0 g of the oxime product as a white solid m.p. 80-83
°C (88.7%).
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To a dry flask containing THF (20 mL) and 1M lithium aluminium hydride in
diethyl
ether (19 mL) at room temperature, was added the oxime from above (500 mg,
3.82
mmol). The reaction was heated at reflux for 3 h, cooled to room temperature
and the
excess LAH was quenched with ice/water. Extraction with EtOAc and
concentration gave
340 mg (76%) of the desired 4-aminotetrahydrothiopyran.
To the above amine (170 mg, 1.4 mmol) in dry pyridine (1 mL) was added 2,5-
dibromopyridine (250 mg, 1.1 mmol) and the reaction was heated at 110-120
°C for 5
days. The reaction was extracted with EtOAc, washed with water, dried over
anhydrous
l0 sodium sulfate and concentrated to give the crude product. The crude
product was
purified by flash column chromatography over silica gel using 30%
EtOAc/hexanes as
eluent to give 100 mg of pure product (33.3%).
To the above intermediate (80 mg, 0.293 mmol) and BOC-protected
naphthylboronic
15 acid (See Example 12) (140 mg, 0.488 mmol) in DME (4 mL) was added 2 M
sodium
carbonate (2 mL) and bis(triphenylphosphine)palladium chloride (15 mg). The
reaction
was heated at 90 °C under nitrogen for 18 h and cooled to room
temperature. The
reaction was extracted with EtOAc, washed with water, dried over anhydrous
sodium
sulfate and concentrated to give the crude product. The crude product was
purified by
2o flash column chromatography over silica gel using 30% EtOAc/hexanes as
eluent to give
110 mg of the coupled intermediate (86.0%)
To the coupled intermediate (35 mg, 0.08 mmol) in dioxane (1 mL) was added 4 M
HCl/dioxane (0.6 mL). The reaction was stirred at room temperature for 48 h.
Addition
25 of diethyl ether gave the product as the hydrochloride salt which was
filtered, giving 18
mg (55%) of the title compound.
EXAMPLE 10
30 [5-(4-Aminonaphthalen-1-yl)pyridin-2-yl]-(tetrahydropyran-4-yl) amine
dihydrochloride:
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OH
BocNH ~ ~ B
~OH
Br ~ ~ ~ O O O O
~ NHa CaHZCI2, CH3COOH
N NH2 DME, 2M NaaC03 ~N
(PPh3)aFdClz NaBH(OAC)3
O
O - - TFAlCH2Cl2 - ~-- N
O HZN ~ l ~ ~H~O
To 2-amino-5-bromopyridine (250 mg, 1.44 mmol) and BOC-protected
naphthylboronic
5 acid (Example 12) (688 mg, 2.4 mmol) in 5 mL DME was added 2 M sodium
carbonate
(2.5 mL) and bis(triphenylphosphine)palladium chloride (30 mg). The reaction
was
heated at 90 °C under nitrogen for 18 h and cooled to room temperature.
The reaction
mixture was extracted with EtOAc, washed with water, dried over anhydrous
sodium
sulfate and concentrated. The residue was purified by flash column
chromatography over
to silica gel eluting with 40% EtOAc/hexanes to give 370 mg coupled
intermediate
(76.4%).
To the above intermediate (200 mg, 0.597 mmol) and tetrahydropyranone (120 mg,
1.19
mmol) in dichloroethane (5 mL) was added glacial acetic acid (0.2 mL, 3.58
mmol) and
i5 sodium triacetoxyborohydride (380 mg, 1.79 mmol). The reaction was stirred
at room
temperature for 48 h and then extracted with EtOAc, washed with water, dried
over
anhydrous sodium sulfate and concentrated. The residue was purified by flash
column
chromatography over silica gel using 50% EtOAc/hexanes as eluent to give 120
mg Boc-
protected title compound (48.0%).
The Boc-protected title compound was dissolved in dichloromethane (3mL) and
treated
with trifluoroacetic acid ( 1 mL). The reaction was stirred for 3 h and
concentrated. The
residue was dissolved in EtOAc (20 mL), washed with sodium bicarbonate
solution, dried
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over anhydrous sodium sulfate concentrated to give 90 mg of the title compound
17
(98.5%).
EXAMPLE 11
[5-(4-Aminonaphthalen-1-yl)pyridin-2-yl]-(1-methylpiperidin-4-yl) amine:
0 0
~O~ O N- ~O-
H ~ ~ ~ / NHz ~ N ~ ~ ~ J~ N~
CZHZCIz, CH3COOH ~H~Nw
NaBH(OAC)3
TFA/CHZCIZ HzN ~ / ~ ~-H~N~
11
To a mixture of 5-(4-N-Boc-aminonaphthyl)pyridin-2-ylamine (Example 10) (110
mg,
0.33 mmol) and 1-methyl-4-piperidone (80 mg, 0.7 mmol) in dichloroethane (6
mL) was
added glacial acetic acid ( 120 mg, 2.0 mmol) and sodium triacetoxyborohydride
(220 mg,
1.03 mmol). The reaction was stirred at room temperature for 96 h and then
extracted
with EtOAc, washed with water, dried over anhydrous sodium sulfate and
concentrated.
The residue was purified by flash column chromatography over silica gel using
10%MeOH/ CH2Cl2/0.1%TEA as eluent to give 60 mg of the N-Boc-derivative of the
title compound (42%).
The above intermediate was dissolved in dichloromethane (3 mL) and treated
with
trifluoroacetic acid (1 mL). The reaction was stirred for 2.5 h and then
concentrated to
give 94 mg of the title compound (100%).
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The following are representative examples further illustrating procedures for
preparing
intermediates, as well as exemplifying methods in Scheme I for preparing
compounds of
fornzula I
EXAMPLE 12
4-[5-(4-Aminonaphthyl)pyridin-2-ylmethyl]morpholine
~o
NJ
Br H~O'B~O~H
1. 3 eq. n-BuLi N \
\ \ 2. B(OMe)3
3. 5% HCI ~ \ \
v
\\ I Br
~O~N'H O N'H
IOI Pd(PPh3)a
O 2 M Na2C03, DME
HCI, dioxane
NaOH
12
To a stirred solution of N-Boc-1-amino-4-bromo naphthalene (15.5 mmol) in
anhydrous
THF (40 mL) at -78 °C was added n-BuLi (47 mmol). The resultant
yellow-green
solution was stirred at -78 °C for two h then was transferred to a
solution of
trimethylborate (5.64 grams, 54.2 mmol) in anhydrous THF (25 mL) at -42
°C. The
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reaction was allowed to warm to room temperature overnight as the bath warmed.
After
stirring for 16 h, S% aqueous HCl was added (25 mL) and the mixture was
stirred for 15
min. The aqueous layer was saturated with NaCI and the layers were separated.
The
aqueous portion was extracted with diethyl ether (3 x 60 mL) and the combined
organics
were extracted with 0.5 M NaOH (6 x 30 mL). The combined basic extracts were
acidified to ~pH 2 with 3 M HCl (~30 mL) and the suspension was extracted with
diethyl
ether (3 x 100 mL). The combined ethereal extracts were dried (MgSOq.),
filtered and the
solvent was removed to afford the boronic acid as a beige solid (2.3 g) which
was used
without further purification.
This boronic acid (0.70 mmol) and 5-bromo-2-(morpholin-4-ylmethyl)pyridine
(0.70
mmol) were dissolved in a biphasic mixture of dimethoxyethane (2 mL) and 2 M
aq.
Na2C03 (1 mL). The reaction was purged with a stream of N2 for 15 min, the Pd
catalyst was added, and the mixture was heated at 85 °C for 16 h. The
reaction was
cooled to room temperature and was partitioned between water (10 mL) and EtOAc
(75
mL). The layers were separated and the organic portion was washed with brine
(20 rnL),
dried (MgS04), filtered and the solvent was removed to afford a brown solid.
Column
chromatography afforded the product as a beige solid.
This material (0.50 mmol) was dissolved in 2 mL anhydrous dioxane and HCl was
added
(2.5 mmol). The solution was stirred at room temperature for 16 h. To the
resultant
suspension was added diethyl ether (5 mL) and the mixture was chilled to 0
°C.
Neutralization with aq. NaOH and filtration afforded the title compound as a
light brown
solid (100 mg).
EXAMPLE 13
1-(5-tert-Butyl-3-(2-dimethylamino-3,4-dioxo-cyclobut-1-enylamino)-2-methoxy
phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea:
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Me0 O
10% Pd/C OMe O
O~N ~ NO~ NH4*HCOO
O CH3CN
w w
i
i w IN
OMe
O ~ NMe2 HzN
Me2NH_ O
O ~~ ~ ~NHZ THF ~ ~ NHZ Method
O~ O O\ B
1
0
O
13
5-tent-Butyl-2-methoxy-1,3-dinitro-benzene (see Example 1, 1.9 g, 0.0075 mol)
was
added to EtOH (40 mL) under nitrogen purge. To this mixture, ammonium formate
(4.9
g, 0.075 mol) was added in a single portion, followed by 10% palladium on
carbon (0.75
g, 10 mole %), also in a single portion. This resulted in an immediate
exotherm
(temperature climbs to 30°C), along with outgassing. Once the bubbling
subsided, the
mixture was slowly brought to reflux and maintained at this temperature for 3
h. An
to aliquot taken at this point -showed over 93% conversion to a new, polar
material. The
mixture was filtered hot through a pad of diatomaceous earth, which was then
washed
twice with hot EtOH. The filtrate was concentrated under reduce pressure to
obtain the
diamino compound as a light grey solid (1.3 g, 90%).
To a solution of the above diamine (0.313g, 1.61 mmol) in anhydrous MeOH (6
mL) at
0-5 °C was added 3,4-dimethoxycyclobutene-1,2-dione (0.29 g, 1.61
rnmol). The mixture
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was stirred 8 h and warmed to room temperature. After 18 h the mixture was
cooled in
an ice bath. The solid was filtered, washed with cold MeOH and dried in vacuo
which
afforded the desired intermediate.
To a solution of the above intermediate (0.182 g, 0.599 mmol) in THF (3 mL) at
0-5 °C
was added dimethylamine (0.33 mL of a 2.0 M solution in THF). The mixture was
stirred
h, warmed to room temperature, kept overnight and diluted with hexanes. The
solid was
filtered and dried ih vacuo to provide the dimethylamino intermediate.
to To a mixture of the above intermediate (0.091 g, 0.287 mmol) in 3 mL
methylene
chloride and 3 mL of saturated aqueous NaHC03 at 0-5 °C was added
phosgene (0.36 mL
of a 2.0 M solution in toluene). The mixture was rapidly stirred for 20
minutes and the
organic layer dried (MgS04). Removal of most of the volatiles in vacuo
provided a
residue that was added to 1-amino-4-(6-morpholin-4-yl-methyl-pyridin-3-
yl)naphthalene
(Example 12) (0.091 g, 0.287 mmol) in 3 mL anhydrous THF. The mixture was
stirred
overnight, diluted with ether and filtered. The filtrate was purified by
reverse phase
HPLC using acetonitrile and water as the eluents. Concentration in vacuo of
the product-
rich fractions provided the title compound as a solid, mp176-179 °C.
2p EXAMPLE 14
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tent-butyl-3-
methanesulfonamido-2-methoxyphenyl)-urea:
N~
1f coci2
\ N N
\ N ~O
I O\p ~ p \
I I
H~N / 2) ~ ~N N N
\ I H /O H H
o \o
14
%S~N / N.H
/O H
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4-[5-(4-Aminonaphthyl)pyridin-2-ylmethyl]morpholine (see Example 12) (293 mg,
0.915
mmol) was dissolved in 25 mL dichloromethane. To this solution was added 25 mL
of a
saturated aqueous solution of sodium bicarbonate and the mixture was cooled to
0 °C
while stirring vigorously. After 30 min, stirring was ceased and phosgene (~ 2
M in
toluene, 1.83 mL, 4 equiv.) was added to the organic layer in one portion via
syringe.
Stirring was resumed and continued for 20 min. The reaction mixture was then
transferred to a separatory funnel. The organic layer was collected and dried
over
Na2S04, filtered, and all but ~ 4 rnL of solvents were removed in vacuo. To
this
concentrated solution of isocyanate was added the aniline intermediate 2 (see
Example 2)
to (220 mg, 0.81 mmol) as a solution in 5 mL anh. THF and the mixture was
stirred at
ambient temperature under inert atmosphere overnight. The solvents were then
removed
in vacuo, and the crude urea was purified by column chromatography on Si02
using 0-5
MeOH in dichloromethane. The title compound was isolated as a foam (400 mg,
0.65
mmol, 80 % yield), which was crystallized from EtOAc/hexanes to afford 310 mg
of a
white powder (mp 177-179 °C).
EXAMPLE 15
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-
benzenesulfonamido-5-tent-butyl-2-methoxyphenyl) urea:
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O\/O NH4HCOz
\ Ph'S~CI O O \ EtOH O O I
I ~ \\// I
H N / NO ~ SAN / NOz I \ ~N NHz
z z
O I / H O ~ H
i
1
\ \ N ~ O \ \ N ~O
HzN I / CI/ 'CI OCN I /
\ I --~ \ I
I ~ ~s N ~ / NH ~ N
I
z
~o I O / \ \ IN ~O
al~ pII
O S~N \ I N~N I / _
H O~ H H ~
Nitroaniline 1 (Example 1) (350 mg, 1.54 mmol, 1 equiv.) was dissolved in 1.6
mL
anhydrous pyridine and cooled to 0 °C. Benzene sulfonyl chloride (212
uL, 1.66 mmol,
5 1.08 equiv.) was added dropwise via syringe. The mixture was stirred at 0-5
°C for 6 h,
then was poured over 10 g of ice and 3 mL of conc. HCI. The product was
extracted with
dichloromethane (3 x 50 mL) and the combined organics were dried (MgS04) and
filtered. Volatiles were removed in vacuo. The crude nitro sulfonamide (540
mg, 89
yield) was used in the subsequent step without purification.
to
The nitro sulfonamide (S00 mg, 1.37 mmol, 1 equiv.) was dissolved in 4 mL
absolute
EtOH and added to a slurry of palladium-on-carbon (10 %, 600 mg) in EtOH.
Ammonium formate (520 mg, 8.22 mmol, 6 equiv.) was added. The mixture was
heated
to 50 °C for 2 h. The mixture was cooled, filtered through diatomaceous
earth. The
15 volatiles were removed in vacuo. The resulting intermediate aniline was
obtained as a
brown solid (380 mg, 1.14 mmol, 83 % yield) and was used as is in the
subsequent step.
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4-[5-(4-Aminonaphthyl)pyridin-2-ylmethyl]morpholine (see Example 12) (319 mg,
1.0
mmol) was dissolved in 30 mL dichloromethane. To this solution was added 30 mL
of a
saturated aqueous solution of sodium bicarbonate and the mixture was cooled to
0 °C
while stirring vigorously. After 20 min, stirring was ceased and phosgene (~ 2
M in
toluene, 1.5 mL, 3.0 mmol, 3 equiv.) was added to the organic layer in one
portion via
syringe. Stirring was resumed and continued for 30 min. The reaction mixture
was then
transferred to a separatory funnel. The organic layer was collected and dried
over
Na2S04, filtered, and all but 6 mL of solvent were removed in vacuo. To one
third of this
to concentrated solution of isocyanate was added the intermediate aniline
above (117 mg,
0.35 mmol) as a solution in 5 mL anhydrous THF and the mixture was stirred at
ambient
temperature under inert atmosphere overnight. The solvents were then removed
in vacuo.
The crude urea was purified by column chromatography on Si02 using 0-4 % MeOH
in
dichloromethane. The resulting ftlm was recrystallized from EtOAc / hexanes to
give 60
mg of title compound as an off white solid (mp 206-207 °C).
EXAMPLE 16
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-[5-tent-butyl-3-
(N-
methanesulfonyl-N-aminocarboxymethylamino)-2-methoxyphenyl]-urea:
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O NH4HC02
~ ' Pd-C
O O ~ H N' v Br O O ~ EtOAc/Et01-
\\ // ~ Z
~S~N ~ NOz KzC03 ~ ~N ~ NOZ
H O CH3CN HzN' J O
O
1
0
m
HZN
N
~s~ ~ i ~O
N NHz
HZN' J ,O
~O
16
5-test-Butyl-1-methanesulfonamido-2-methoxy-3-nitrobenzene (see Example 2)
(108 mg,
0.36 mmol, 1 equiv.) was dissolved in 2 mL anhydrous CH3CN and KZCO3 (198 mg,
1.43
mmol, 4 equiv.) was added. alpha-Bromoacetamide (49 mg, 0.36 mmol, 1 equiv.)
was
then added and the reaction mixture was stirred at room temperature overnight.
The
mixture was then filtered. The filtrate was washed with aqueous 1M NH4Cl and
20 mL
dichloromethane. The product was extracted with 2 x 15 mL dichloromethane and
the
combined organics were dried (Na2S04) and filtered. Volatiles were removed in
vacuo.
l0 The crude oil was purified by column chromatography on Si02, using 10-50%
EtOAc in
hexanes to afford 71 mg of N-alkylated intermediate (0.20 mmol, 55 % yield).
The above intermediate (71 mg, 0.20 mmol, 1 equiv.) was dissolved in 4 mL EtOH
/
EtOAc (1:1) and added to a slurry of palladium-on-carbon (10%, 70 mg) in
EtOAc.
Ammonium formate (75 mg, 1.20 mmol, 6 equiv.) was added. The mixture was
heated to
60 °C for 1.5 h, then to 100 °C for 1.5 h. Finally the mixture
was cooled, filtered through
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diatomaceous earth, washed with 10 mL MeOH. The volatiles were removed in
vacuo.
The corresponding aniline was obtained (60 mg, 0.18 mmol, 91 % yield) and was
used as
is in the subsequent step.
4-[5-(4-Aminonaphthyl)pyridin-2-ylmethyl]morpholine (see Example 12) (58 rng,
0.18
mmol) was dissolved in 10 mL dichloromethane. To this solution was added 10 mL
of a
saturated aqueous solution of sodium bicarbonate and the mixture was cooled to
0 °C
while stirring vigorously. After 30 min, stirring was ceased and phosgene (2 M
in
toluene, 0.36 mL, 4 equiv.) was added to the organic layer in one portion via
syringe.
l0 Stirring was resumed and continued for 15 min. The reaction mixture was
then
transferred to a separatory funnel. The organic layer was collected and dried
over
Na2S04, filtered, and all but ~ 1 mL of solvent were removed in vacuo. To this
concentrated solution of isocyanate was added the aniline intermediate from
above (60
mg, 0.18 mmol) as a solution in 1.5 mL anh. THF and the mixture was stirred at
ambient
temperature under inert atmosphere overnight. The solvents were then removed
in vacuo.
The title compound was obtained following column chromatography on SiOz using
0-5
MeOH in dichloromethane.
2o ASSESSMENT OF BIOLOGICAL PROPERTIES
Inhibition of TNF Production in THP Cells
The inhibition of cytokine production can be observed by measuring inhibition
of TNFa
in lipopolysaccharide stimulated THP cells (for example, see W. Prichett et
al., 1995, J.
Inflammation, 45, 97). All cells and reagents were diluted in RPMI 1640 with
phenol red
and L-glutamine, supplemented with additional L-glutamine (total: 4 mM),
penicillin and
streptomycin (50 units/ml each) and fetal bovine serum (FBS, 3%) (GIBCO, all
conc.
final). Assay was performed under sterile conditions; only test compound
preparation was
nonsterile. Initial stock solutions were made in DMSO followed by dilution
into RPMI
1640 2-fold higher than the desired final assay concentration. Confluent THP.1
cells
(2x106 cells/ml, final cone; American Type Culture Company, Rockville, MD)
were
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added to 96 well polypropylene round bottomed culture plates (Costar 3790;
sterile)
containing 125 ~.1 test compound (2 fold concentrated) or DMSO vehicle
(controls,
blanks). DMSO concentration did not exceed 0.2% final. Cell mixture was
allowed to
preincubate for 30 min, 37°C, 5% C02 prior to stimulation with
lipopolysaccharide (LPS;
1 ~.g/ml anal; Siga L-2630, from E.coli serotype O111.B4; stored as 1 mg/ml
stock in
endotoxin screened distilled H20 at -80°C). Blanks (unstimulated)
received Hz0 vehicle;
final incubation volume was 250 ~1. Overnight incubation (18 - 24 hr)
proceeded as
described above. Assay was terminated by centrifuging plates 5 min, room
temperature,
1600 rpm (400 x g); supernatants were transferred to clean 96 well plates and
stored -
l0 80°C until analyzed for human TNFa by a commercially available ELISA
kit (Biosource
#KIIC3015, Camarillo, CA). Data was analyzed by non-linear regression (Hill
equation)
to generate a dose response curve using SAS Software System (SAS institute,
Inc., Cary,
NC). The calculated ICso value is the concentration of the test compound that
caused a
50% decrease in the maximal TNFa production.
Preferred compounds including those from the synthetic examples above were
evaluated
and had ICSO < 10 uM in this assay. Preferred prophetic compounds will also
have ICSO <
10 uM in this assay
2o Inhibition of other cytolcines
By similar methods using peripheral blood monocytic cells, appropriate
stimuli, and
commercially available ELISA kits (or other method of detection such as
radioimmunoassay), for a particular cytokine, inhibition of IL-l, G M -CSF, IL-
6 and
IL-8 can be demonstrated (for example, see J.C. Lee et al., 1988, Int. J.
Immuuopharmacol., 10, 835).
93
