U.S. patent application number 11/684173 was filed with the patent office on 2007-07-05 for methods of treating cytokine mediated diseases.
Invention is credited to Neil MOSS, John Robinson Regan.
Application Number | 20070155724 11/684173 |
Document ID | / |
Family ID | 23240282 |
Filed Date | 2007-07-05 |
United States Patent
Application |
20070155724 |
Kind Code |
A1 |
MOSS; Neil ; et al. |
July 5, 2007 |
Methods of Treating Cytokine Mediated Diseases
Abstract
Disclosed are methods of treating acute and chronic inflammation
in the lung caused by inhalation of smoke, endometriosis, Behcet's
disease, uveitis, ankylosing spondylitis, pancreatitis, cancer,
Lyme disease, sepsis, chronic obstructive pulmonary disease,
traumatic arthritis, congestive heart failure and restenosis
following percutaneous transluminal coronary angioplasty, known to
be cytokine mediated, using aromatic heterocyclic compounds
described in WO 00/55139.
Inventors: |
MOSS; Neil; (Ridgefield,
CT) ; Regan; John Robinson; (Larchmont, NY) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P O BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Family ID: |
23240282 |
Appl. No.: |
11/684173 |
Filed: |
March 9, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10237306 |
Sep 9, 2002 |
7211575 |
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11684173 |
Mar 9, 2007 |
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60318958 |
Sep 13, 2001 |
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Current U.S.
Class: |
514/217.11 ;
514/227.5; 514/230.5; 514/237.5; 514/247; 514/252.1; 514/275;
514/310; 514/313; 514/347; 514/352; 514/365; 514/374; 514/394;
514/418; 514/419; 514/426; 514/449; 514/471 |
Current CPC
Class: |
A61P 11/00 20180101;
A61P 9/02 20180101; Y02A 50/30 20180101; A61P 9/10 20180101; A61P
31/04 20180101; A61K 31/547 20130101; A61K 31/496 20130101; A61P
35/00 20180101; Y02A 50/401 20180101; A61K 31/4439 20130101; A61K
31/497 20130101; A61P 19/02 20180101; A61K 31/5377 20130101; A61P
21/00 20180101; A61K 31/537 20130101; A61P 25/28 20180101; A61K
31/44 20130101; A61K 31/4433 20130101; A61K 31/4545 20130101; A61K
31/443 20130101; A61P 1/18 20180101; A61P 15/00 20180101 |
Class at
Publication: |
514/217.11 ;
514/227.5; 514/237.5; 514/247; 514/230.5; 514/252.1; 514/275;
514/313; 514/365; 514/374; 514/426; 514/394; 514/449; 514/471;
514/418; 514/419; 514/310; 514/352; 514/347 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61K 31/54 20060101 A61K031/54; A61K 31/538 20060101
A61K031/538; A61K 31/5375 20060101 A61K031/5375; A61K 31/505
20060101 A61K031/505; A61K 31/50 20060101 A61K031/50; A61K 31/4965
20060101 A61K031/4965; A61K 31/4706 20060101 A61K031/4706 |
Claims
1. A method of treating cancer, said method comprising
administering to a patient a therapeutically effective amount of a
compound of the formula (III): ##STR5## wherein: E is carbon or a
heteroatom group chosen from --O--, --NH-- and --S--; G is: an
aromatic C.sub.6-10 carbocycle or a nonaromatic
C.sub.3-10carbocycle saturated or unsaturated; a 6-14 membered
monocyclic, bicyclic or tricyclic heteroaryl containing 1 or more
heteroatoms chosen from O, N and S; a 6-8 membered monocyclic
heterocycle containing one or more heteroatoms chosen from O, N and
S; or an 8-11 membered bicyclic heterocycle, containing one or more
heteroatoms chosen from O, N and S; wherein G is optionally
substituted by one or more R.sub.1, R.sub.2 or R.sub.3; Ar is:
phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl,
benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl,
dihydrobenzothienyl, indanyl, indenyl or indolyl each being
optionally substituted by one or more R.sub.4 or R.sub.5; X is: a
C.sub.5-8 cycloalkyl or cycloalkenyl optionally substituted with
one to two oxo groups or one to three C.sub.1-4 alkyl, C.sub.1-4
alkoxy or C.sub.1-4 alkylamino chains each being branched or
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 independently substituted with
one to three C.sub.1-4 alkyl, C.sub.1-4alkoxy, hydroxy, nitrile,
amino, mono- or di-(C.sub.1-3 alkyl)amino, mono- or di-(C.sub.1-3
alkylamino)carbonyl, NH.sub.2C(O), C.sub.1-6 alkyl-S(O).sub.m or
halogen; Y is: a bond or a C.sub.1-4 saturated or unsaturated
branched or unbranched carbon chain optionally partially or fully
halogenated, wherein one or more C atoms are optionally replaced by
O, N, or S(O).sub.m and wherein Y is optionally independently
substituted with one to two oxo groups, nitrile, phenyl or one or
more C.sub.1-4 alkyl optionally substituted by one or more halogen
atoms; Z is: 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, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-3
alkoxy-C.sub.1-3 alkyl, C.sub.1-6 alkoxycarbonyl, aroyl,
C.sub.1-3acyl, oxo, hydroxy, pyridinyl-C.sub.1-3 alkyl,
imidazolyl-C.sub.1-3 alkyl, tetrahydrofuranyl-C.sub.1-3 alkyl,
nitrile-C.sub.1-3 alkyl, nitrile, carboxy, phenyl wherein the
phenyl ring is optionally substituted with one to two halogen,
C.sub.1-6 alkoxy, hydroxy or mono- or di-(C.sub.1-3 alkyl)amino,
C.sub.1-6 alkyl-S(O).sub.m, or phenyl-S(O).sub.m wherein the phenyl
ring is optionally substituted with one to two halogen, C.sub.1-6
alkoxy, hydroxy, halogen or mono- or di-(C.sub.1-3 alkyl)amino; or
Z is optionally substituted with one to three amino or
amino-C.sub.1-3 alkyl wherein the N atom is optionally
independently mono- or di-substituted by aminoC.sub.1-6alkyl,
C.sub.1-3alkyl, arylC.sub.0-3alkyl, C.sub.1-5 alkoxyC.sub.1-3
alkyl, C.sub.1-5 alkoxy, aroyl, C.sub.1-3acyl,
C.sub.1-3alkyl-S(O).sub.m-- or arylC.sub.0-3alkyl-S(O).sub.m-- each
of the aforementioned alkyl and aryl attached to the amino group is
optionally substituted with one to two halogen, C.sub.1-6 alkyl or
C.sub.1-6 alkoxy; 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.sub.1-6 alkyl or C.sub.1-6 alkoxy; or Z is hydroxy, halogen,
nitrile, amino wherein the N atom is optionally independently mono-
or di-substituted by C.sub.1-3acyl, C.sub.1-6alkyl or
C.sub.1-3alkoxyC.sub.1-3alkyl, C.sub.1-6alkyl branched or
unbranched, C.sub.1-6alkoxy, C.sub.1-3acylamino, nitrileC.sub.1-4
alkyl, C.sub.1-6 alkyl-S(O).sub.m, and phenyl-S(O).sub.m, wherein
the phenyl ring is optionally substituted with one to two halogen,
C.sub.1-6 alkoxy, hydroxy or mono- or di-(C.sub.1-3 alkyl)amino;
each R.sub.1 is independently: C.sub.1-10 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).sub.m, and wherein said C.sub.1-10 alkyl is optionally
substituted with one to three C.sub.3-10 cycloalkyl, hydroxy, oxo,
phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thienyl, furyl,
dioxolanyl, isoxazolyl or isothiazolyl; each of the aforementioned
being optionally substituted with one to five groups selected from
halogen, C.sub.1-6 alkyl which is optionally partially or fully
halogenated, C.sub.3-8 cycloalkanyl, C.sub.5-8 cycloalkenyl,
hydroxy, nitrile, C.sub.1-3 alkoxy which is optionally partially or
fully halogenated or NH.sub.2C(O), mono- or di(C.sub.1-3
alkyl)amino, and mono- or di(C.sub.1-3alkyl)aminocarbonyl; or
R.sub.1 is cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,
cyclohexyloxy, or cycloheptyloxy each being optionally partially or
fully halogenated and optionally substituted with one to three
C.sub.1-3 alkyl groups optionally partially or fully halogenated,
nitrile, hydroxyC.sub.1-3alkyl or aryl; or an analog of such
cycloalkyl group wherein one to three ring methylene groups are
independently replaced by O, S(O).sub.m, CHOH, >C.dbd.O,
>C.dbd.S or NH; phenyloxy or benzyloxy each being optionally
partially or fully halogenated and optionally substituted with one
to three C.sub.1-3 alkyl groups optionally partially or fully
halogenated, nitrile, hydroxyC.sub.1-3alkyl or aryl; or an analog
of such cycloaryl group wherein one to two ring methyne groups are
independently replaced by N; cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, bicyclopentanyl, bicyclohexanyl or
bicycloheptanyl, each being optionally partially or fully
halogenated and optionally substituted with one to three C.sub.1-3
alkyl optionally partially or fully halogenated, nitrile,
hydroxyC.sub.1-3alkyl or aryl; or an analog of such cycloalkyl
group wherein one to three ring methylene groups are independently
replaced by O, S(O).sub.m, CHOH, >C.dbd.O, >C.dbd.S or NH;
C.sub.3-10 branched or unbranced alkenyl each being optionally
partially or fully halogenated, and optionally substituted with one
to three C.sub.1-5 branched or unbranched alkyl, phenyl, naphthyl,
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,
imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl,
each of the aforementioned being substituted with one to five
halogen, C.sub.1-6 alkyl which is optionally partially or fully
halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl,
cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and
bicycloheptanyl, hydroxy, nitrile, C.sub.1-3 alkyloxy which is
optionally partially or fully halogenated, NH.sub.2C(O), mono- or
diC.sub.1-3alkyl)aminocarbonyl; the C.sub.3-10 branched or
unbranced alkenyl being optionally interrupted by one or more
heteroatoms chosen from O, N and S(O).sub.m; cyclopentenyl,
cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,
bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group
is optionally substituted with one to three C.sub.1-3 alkyl groups;
oxo, nitrile, halogen; silyl containing three C.sub.1-4 alkyl
groups optionally partially or fully halogenated; or C.sub.3-6
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).sub.m and wherein said alkynyl
group is optionally independently substituted with one to two oxo
groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, one or
more C.sub.1-4 alkyl optionally substituted by one or more halogen
atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl,
phenyl, pyridinyl, tetrazolyl, or mono- or di(C.sub.1-3alkyl)amino
optionally substituted by one or more halogen atoms; each R.sub.2,
R.sub.4, and R.sub.5 is a C.sub.1-6 branched or unbranched alkyl
optionally partially or fully halogenated, C.sub.1-6acyl, aroyl,
C.sub.1-4 branched or unbranched alkoxy, each being optionally
partially or fully halogenated, halogen, methoxycarbonyl, C.sub.1-3
alkyl-S(O).sub.m optionally partially or fully halogenated, or
phenyl-S(O).sub.m; OR.sub.6, C.sub.1-6 alkoxy, hydroxy, nitrile,
nitro, halogen; or amino-S(O).sub.m-- wherein the N atom is
optionally independently mono- or di-substituted by C.sub.1-6alkyl
or arylC.sub.0-3alkyl, or amino wherein the N atom is optionally
independently mono- or di-substituted by C.sub.1-3alkyl,
arylC.sub.0-3alkyl, C.sub.1-6acyl, C.sub.1-6alkyl-S(O).sub.m-- or
arylC.sub.0-3alkyl-S(O).sub.m--, each of the aforementioned alkyl
and aryl in this subparagraph are optionally partially or fully
halogenated and optionally substituted with one to two C.sub.1-6
alkyl or C.sub.1-6 alkoxy; each R.sub.3 is independently: phenyl,
naphthyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl,
pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl,
thiazolyl, oxazoyl, [1,3,4]oxadiazol, triazolyl, tetrazolyl,
thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl,
quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,
benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl,
cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl,
quinoxalinyl, quinazolinyl, purinyl or indazolyl, each of the
aforementioned is optionally substituted with one to three phenyl,
naphthyl, heterocycle or heteroaryl as hereinabove described in
this paragraph, C.sub.1-6 branched or unbranched alkyl which is
optionally partially or fully halogenated, cyclopropanyl,
cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C.sub.1-5
alkyl, naphthyl C.sub.1-5 alkyl, halogen, hydroxy, oxo, nitrile,
C.sub.1-3 alkoxy optionally partially or fully halogenated,
phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein
the heterocyclic or heteroaryl moiety is as hereinabove described
in this paragraph, nitro, amino, mono- or di-(C.sub.1-3alky)lamino,
phenylamino, naphthylamino, heteroaryl or heterocyclic amino
wherein the heteroaryl heterocyclic moiety is as hereinabove
described in this paragraph, NH.sub.2C(O), a mono- or
di-(C.sub.1-3alkyl)aminocarbonyl, C.sub.1-5 alkyl-C(O)--C.sub.1-4
alkyl, amino-C.sub.1-5 alkyl, mono- or di-(C.sub.1-5alkyl)amino,
mono- or di-(C.sub.1-3alkyl)amino-C.sub.1-5 alkyl,
amino-S(O).sub.2, di-(C.sub.1-3alkyl)amino-S(O).sub.2,
R.sub.7--C.sub.1-5 alkyl, R.sub.8--C.sub.1-5 alkoxy,
R.sub.9--C(O)--C.sub.1-5 alkyl, R.sub.10--C.sub.1-5
alkyl(R.sub.11)N, carboxy-mono- or di-(C.sub.1-5alkyl)-amino; a
fused aryl selected from benzocyclobutanyl, indanyl, indenyl,
dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and
benzocycloheptenyl, or a fused heteroaryl selected from
cyclopentenopyridinyl, cyclohexanopyridinyl,
cyclopentanopyrimidinyl, cyclohexanopyrimidinyl,
cyclopentanopyrazinyl, cyclohexanopyrazinyl,
cyclopentanopyridazinyl, cyclohexanopyridazinyl,
cyclopentanoquinolinyl, cyclohexanoquinolinyl,
cyclopentanoisoquinolinyl, cyclohexanoisoquinolinyl,
cyclopentanoindolyl, cyclohexanoindolyl,
cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl,
cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl,
cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl
and cyclohexanothienyl; wherein the fused aryl or fused heteroaryl
ring is independently substituted with zero to three phenyl,
naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,
imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl,
C.sub.1-6 alkyl which is optionally partially or fully halogenated,
halogen, nitrile, C.sub.1-3 alkyloxy which is optionally partially
or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or
heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as
hereinabove described in this paragraph, nitro, amino, mono- or
di-(C.sub.1-3alkyl)amino, phenylamino, naphthylamino, heteroaryl or
heterocyclic amino wherein the heteroaryl or heterocyclic moiety is
as hereinabove described in this paragraph, NH.sub.2C(O), mono- or
di-(C.sub.1-3alkyl)aminocarbonyl, C.sub.1-4 alkyl-OC(O), C.sub.1-5
alkyl-C(O)--C.sub.1-4 alkyl, amino-C.sub.1-5 alkyl, mono- or
di-(C.sub.1-3)alkylamino-C.sub.1-5 alkyl, R.sub.12--C.sub.1-5
alkyl, R.sub.13--C.sub.1-5 alkoxy, R.sub.14--C(O)--C.sub.1-5 alkyl
or R.sub.15--C.sub.1-5 alkyl(R.sub.16)N; cyclopropanyl,
cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being
optionally be partially or fully halogenated and optionally
substituted with one to three C.sub.1-3 alkyl groups, or an analog
of such cycloalkyl group wherein one to three ring methylene groups
are independently replaced by O, S, CHOH, >C.dbd.O, >C.dbd.S
or NH; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,
cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each
optionally substituted with one to three C.sub.1-3 alkyl groups;
C.sub.1-4 alkyl-phenyl-C(O)--C.sub.1-4 alkyl-, C.sub.1-4
alkyl-C(O)--C.sub.1-4 alkyl- or C.sub.1-4
alkyl-phenyl-S(O).sub.m--C.sub.1-4 alkyl-; C.sub.1-6 alkyl or
C.sub.1-6 branched or unbranched alkoxy each of which is optionally
partially or fully halogenated or optionally substituted with
R.sub.17; OR.sub.18 or C.sub.1-6 alkyl optionally substituted with
OR.sub.18; amino or mono- or di-(C.sub.1-5alkyl)amino optionally
substituted with R.sub.19; R.sub.20C(O)N(R.sub.21)--, R.sub.22O--
or R.sub.23R.sub.24NC(O)--;
R.sub.26(CH.sub.2).sub.mC(O)N(R.sub.21)--,
R.sub.23R.sub.24NC(O)--C.sub.1-3alkoxy or
R.sub.26C(O)(CH.sub.2).sub.mN(R.sub.21)--; C.sub.2-6alkenyl
substituted by R.sub.23R.sub.24NC(O)--; C.sub.2-6 alkynyl branched
or unbranched carbon chain, optionally partially or fully
halogenated, wherein one or more methylene groups are optionally
replaced by O, NH, S(O).sub.m and wherein said alkynyl group is
optionally independently substituted with one to two oxo groups,
pyrroldinyl, pyrrolyl, morpholino, piperidinyl, piperazinyl,
imidazolyl, phenyl, pyridinyl, tetrazolyl one or more C.sub.1-4
alkyl optionally substituted by one or more halogen atoms, nitrile,
morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl,
pyridinyl, tetrazolyl, or mono- or di(C
.sub.1-4 alkyl)amino optionally substituted by one or more halogen
atoms; C.sub.1-6acyl or aroyl; R.sub.6 is a: C.sub.1-4 alkyl
optionally partially or fully halogenated and optionally
substituted with R.sub.26; each R.sub.7, R.sub.8, R.sub.9,
R.sub.10, R.sub.12, R.sub.13, R.sub.14, R.sub.15, R.sub.17,
R.sub.19, R.sub.25 and R.sub.26 is independently: nitrile, phenyl,
morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl,
tetrazolyl, amino or mono- or di-(C.sub.1-4alkyl)amino optionally
partially or fully halogenated; each R.sub.11 and R.sub.16 is
independently: hydrogen or C.sub.1-4 alkyl optionally partially or
fully halogenated; R.sub.18 is independently: hydrogen or a
C.sub.1-4 alkyl optionally independently substituted with oxo or
R.sub.25; R.sub.20 is independently: C.sub.1-10 alkyl optionally
partially or fully halogenated, phenyl, or pyridinyl; R.sub.21 is
independently: hydrogen or C.sub.1-3 alkyl optionally partially or
fully halogenated; each R.sub.22, R.sub.23 and R.sub.24 is
independently: hydrogen, C.sub.1-6 alkyl optionally partially or
fully halogenated, said C.sub.1-6 alkyl is optionally interrupted
by one or more O, N or S, said C.sub.1-6 alkyl also being
independently optionally substituted by mono- or
di-(C.sub.1-3alkyl)aminocarbonyl, phenyl, pyridinyl, amino or mono-
or di-(C.sub.1-4alkyl)amino each of which is optionally partially
or fully halogenated and optionally substituted with mono- or
di-(C.sub.1-3alkyl)amino; or R.sub.23 and R.sub.24 taken together
optionally form a heterocyclic or heteroaryl ring; m=0, 1 or 2; W
is O or S and the pharmaceutically acceptable salts thereof.
2. The method according to claim 1 wherein E is --CH.sub.2--,
--NH-- or --O--; W is O; and G is: phenyl, naphthyl,
benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl,
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[1,4]oxazin-3-onyl, benzodioxolyl,
benzo[1,3]dioxol-2-onyl, benzofuran-3-onyl, tetrahydrobenzopyranyl,
indolyl, 2,3-dihydro-1H-indolyl, indolinyl, indolonyl, indolinonyl,
phthalimidyl, chromoyl; oxetanyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholino,
tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl,
tetramethylene sulfoxidyl, oxazolinyl,
3,4-dihydro-2H-benzo[1,4]oxazinyl, thiazolinyl, imidazolinyl,
tertrahydropyridinyl, homopiperidinyl, pyrrolinyl,
tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl,
thiomorpholino, thiazolidinyl, dihydrooxazinyl, dihydropyranyl,
oxocanyl, heptacanyl, thioxanyl or dithianyl; wherein G is
optionally substituted by one or more R.sub.1, R.sub.2 or
R.sub.3.
3. The method according to claim 2 wherein E is --NH--; 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 optionally substituted by one or more
R.sub.1, R.sub.2 or R.sub.3; Ar is: naphthyl, quinolinyl,
isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, indanyl, indenyl or indolyl each being
optionally substituted by one or more R.sub.4 or R.sub.5 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 C.sub.1-4 alkyl, C.sub.1-4alkoxy, hydroxy, nitrile,
amino, mono- or di-(C.sub.1-3 alkyl)amino, mono- or di-(C.sub.1-3
alkylamino)carbonyl, NH.sub.2C(O), C.sub.1-6 alkyl-S(O).sub.m or
halogen; Y is: a bond or a C.sub.1-4 saturated or unsaturated
carbon chain wherein one or more of the C atoms is optionally
replaced by O, N, or S(O).sub.m and wherein Y is optionally
independently substituted with one to two oxo groups, nitrile,
phenyl or one or more C.sub.1-4 alkyl optionally substituted by one
or more halogen atoms; 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 nitrile, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, amino,
mono- or di-(C.sub.1-3 alkyl)amino, CONH.sub.2 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, C.sub.1-3 alkyl or C.sub.1-3 alkoxy; or Z
is nitrile, nitrileC.sub.1-3 alkyl, C.sub.1-6 alkyl-S(O).sub.m,
halogen, hydroxy, C.sub.1-3 alkyl, C.sub.1-3 acylamino, C.sub.1-4
alkoxy, amino, mono- or di-(C.sub.1-3 alkyl)aminocarbonyl, or amino
mono or di-substituted by aminoC.sub.1-6 alkyl or
C.sub.1-3alkoxyC.sub.1-3alkyl; each R.sub.1 is independently:
C.sub.1-6 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).sub.m, and wherein said
C.sub.1-6 alkyl is optionally substituted with one to three
C.sub.3-6cycloalkyl, oxo, phenyl, dioxolanyl, pyrrolidinyl, furyl,
isoxazolyl or isothiazolyl; each of the aforementioned being
optionally substituted with one to three groups selected from
halogen, C.sub.1-3 alkyl which is optionally partially or fully
halogenated, hydroxy, nitrile and C.sub.1-3alkoxy which is
optionally partially or fully halogenated; cyclopropyl, cyclobutyl,
cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl,
each being optionally partially or fully halogenated and optionally
substituted with one to three C.sub.1-3 alkyl groups optionally
partially or fully halogenated, nitrile, hydroxyC.sub.1-3alkyl or
phenyl; or an analog of such cycloalkyl group wherein one to three
ring methylene groups are independently replaced by O, S, CHOH,
>C.dbd.O, >C.dbd.S or NH; oxo; C.sub.3-6 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).sub.m and wherein said alkynyl group is optionally
independently substituted with one to two oxo groups, hydroxy,
pyrroldinyl, pyrrolyl, tetrahydropyranyl, C.sub.1-4 alkyl
optionally substituted by one or more halogen atoms, nitrile,
morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl,
pyridinyl, tetrazolyl, or mono- or di(C.sub.1-3alkyl)amino
optionally substituted by one or more halogen atoms; or silyl
containing three C.sub.1-4 alkyl groups optionally partially or
fully halogenated; R.sub.2 is independently: a C.sub.1-5 branched
or unbranched alkyl optionally partially or fully halogenated,
acetyl, aroyl, C.sub.1-4 branched or unbranched alkoxy, each being
optionally partially or fully halogenated, halogen,
methoxycarbonyl, C.sub.1-2 alkyl-S(O).sub.m optionally partially or
fully halogenated, or phenyl-S(O).sub.m; C.sub.1-3 alkoxy, hydroxy,
nitrile, nitro, halogen; or amino-S(O).sub.m-- wherein the N atom
is optionally independently mono- or di-substituted by
C.sub.1-3alkyl or arylC.sub.0-3alkyl, or amino wherein the N atom
is optionally independently mono- or di-substituted by
C.sub.1-3alkyl, arylC.sub.0-3alkyl, C.sub.1-3acyl,
C.sub.1-4alkyl-S(O).sub.m-- or arylC.sub.0-3alkyl-S(O).sub.m--,
each of the aforementioned alkyl and aryl in this subparagraph are
optionally partially or fully halogenated and optionally
substituted with one to two C.sub.1-3 alkyl or C.sub.1-3 alkoxy;
R.sub.3 is independently: phenyl, morpholino, pyridinyl,
pyrimidinyl, pyrazinyl, pyrrolyl, pyrrolidinyl, imidazolyl,
[1,3,4]oxadiazol, pyrazolyl, each is optionally substituted with
one to three phenyl, naphthyl, heterocycle or heteroaryl as
hereinabove described in this paragraph, C.sub.1-6 alkyl which is
optionally partially or fully halogenated, cyclopropanyl,
cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C.sub.1-5
alkyl, naphthyl C.sub.1-5 alkyl, halogen, oxo, hydroxy, nitrile,
C.sub.1-3 alkoxy optionally partially or fully halogenated,
phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein
the heteroaryl or heterocyclic moiety is as hereinabove described
in this paragraph, nitro, amino, mono- or di-(C.sub.1-3alkyl)amino,
phenylamino, naphthylamino, heteroaryl or heterocyclic amino
wherein the heteroaryl or heterocyclic moiety is as hereinabove
described in this paragraph, NH.sub.2C(O), a mono- or
di-(C.sub.1-3alkyl)aminocarbonyl, C.sub.1-5 alkyl-C(O)--C.sub.1-4
alkyl, mono- or di-(C.sub.1-3alkyl)amino, mono- or
di-(C.sub.1-3)alkylamino-C.sub.1-5 alkyl, mono- or
di-(C.sub.1-3alkyl)amino-S(O).sub.2, R.sub.7--C.sub.1-5 alkyl,
R.sub.8--C.sub.1-5 alkoxy, R.sub.9--C(O)--C.sub.1-5 alkyl,
R.sub.10--C.sub.1-5 alkyl(R.sub.11)N, carboxy-mono- or
di-(C.sub.1-5)-alkyl-amino; C.sub.1-3 alkyl or C.sub.1-4 alkoxy
each being optionally partially or fully halogenated or optionally
substituted with R.sub.17; OR.sub.18 or C.sub.1-6 alkyl optionally
substituted with OR.sub.18; amino or mono- or di-(C.sub.1-5
alkyl)amino optionally substituted with R.sub.19;
R.sub.20C(O)N(R.sub.21)--, R.sub.22O--; R.sub.23R.sub.24NC(O)--;
R.sub.26CH.sub.2C(O)N(R.sub.21)--,
R.sub.23R.sub.24NC(O)--C.sub.1-2alkoxy or
R.sub.26C(O)CH.sub.2N(R.sub.21)--; C.sub.2-4alkenyl substituted by
R.sub.23R.sub.24NC(O)--; or C.sub.2-4 alkynyl branched or
unbranched carbon chain optionally partially or fully halogenated
wherein one of the methylene groups is optionally replaced by O,
and optionally independently substituted with one to two oxo
groups, pyrroldinyl, pyrrolyl, morpholino, piperidinyl,
piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl or one or
more C.sub.1-4 alkyl optionally substituted by one or more halogen
atoms; C.sub.1-3acyl; and R.sub.23 and R.sub.24 taken together
optionally form imidazolyl, piperidinyl, morpholino, piperazinyl or
a pyridinyl ring.
4. The method according to claim 3 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
optionally substituted by one or more R.sub.1, R.sub.2 or R.sub.3;
Ar is naphthyl; X is phenyl, imidazolyl, pyridinyl, pyrimidinyl,
piperdinyl, piperazinyl, pyridazinyl or pyrazinyl each being
optionally independently substituted with one to three C.sub.1-4
alkyl, C.sub.1-4alkoxy, hydroxy, nitrile, amino, mono- or
di-(C.sub.1-3 alkyl)amino, mono- or di-(C.sub.1-3
alkylamino)carbonyl, NH.sub.2C(O), C.sub.1-6 alkyl-S(O).sub.m or
halogen; Y is: a bond or a C.sub.1-4 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 nitrile or
oxo; Z is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,
imidazolyl, dihydrothiazolyl, 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 C.sub.1-2 alkyl or
C.sub.1-2 alkoxy; or Z is hydroxy, C.sub.1-3 alkyl, C.sub.1-3
alkoxy, C.sub.1-3 acylamino, C.sub.1-3 alkylsulfonyl, nitrile
C.sub.1-3 alkyl or amino mono or di-substituted by C.sub.1-3
alkoxyC.sub.1-3 alkyl; each R.sub.1 is independently: C.sub.1-5
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).sub.m, and wherein said
C.sub.1-5 alkyl is optionally substituted with oxo, dioxolanyl,
pyrrolidinyl, furyl or phenyl each optionally substituted with one
to three halogen, C.sub.1-3 alkyl which is optionally partially or
fully halogenated, hydroxy, nitrile and C.sub.1-3alkoxy which is
optionally partially or fully halogenated; cyclopropyl, cyclobutyl,
cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl,
each being optionally partially or fully halogenated and optionally
substituted with one to three C.sub.1-3 alkyl groups optionally
partially or fully halogenated, nitrile, hydroxyc.sub.1-3alkyl or
phenyl; and an analog of cyclopropyl, cyclobutyl, cyclopentanyl,
cyclohexanyl, bicyclopentanyl or bicyclohexanyl wherein one ring
methylene group is replaced by O; oxo; C.sub.2-4 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, C.sub.1-4 alkyl optionally substituted
by one or more halogen atoms, nitrile, morpholino, piperidinyl,
piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or
di(C.sub.1-3 alkyl)amino optionally substituted by one or more
halogen atoms; or silyl containing three C.sub.1-2 alkyl groups
optionally partially or fully halogenated; each R.sub.2 is
independently: a C.sub.1-4 alkyl optionally partially or fully
halogenated, C.sub.1-4 alkoxy optionally partially or fully
halogenated, bromo, chloro, fluoro, methoxycarbonyl,
methyl-S(O).sub.m, ethyl-S(O).sub.m each optionally partially or
fully halogenated or phenyl-S(O).sub.m; or R.sub.2 is mono- or
di-C.sub.1-3 acylamino, amino-S(O).sub.m or S(O).sub.mamino wherein
the N atom is mono- or di-substituted by C.sub.1-3alkyl or phenyl,
nitrile, nitro or amino; each R.sub.3 is independently: phenyl,
morpholino, pyridinyl, pyrimidinyl, pyrrolidinyl,
2,5-pyrrolidin-dionyl, imidazolyl, [1,3,4]oxadiazol, pyrazolyl,
each of the aforementioned is optionally substituted with one to
three C.sub.1-3 alkyl which is optionally partially or fully
halogenated, halogen, oxo, hydroxy, nitrile and C.sub.1-3 alkoxy
optionally partially or fully halogenated; C.sub.1-3 alkyl or
C.sub.1-3 alkoxy optionally partially or fully halogenated or
optionally substituted with R.sub.17; OR.sub.18 or C.sub.1-3 alkyl
optionally substituted with OR.sub.18; amino or mono- or
di-(C.sub.1-3 alkyl)amino optionally substituted with R.sub.19;
R.sub.20C(O)N(R.sub.21)--, R.sub.22O--; R.sub.23R.sub.24NC(O)--;
R.sub.26CH.sub.2C(O)N(R.sub.21)--, NH.sub.2C(O)methoxy or
R.sub.26C(O)CH.sub.2N(R.sub.21)--; C.sub.2-4 alkenyl substituted by
R.sub.23R.sub.24NC(O)--; or C.sub.2-4 alkynyl substituted with
pyrroldinyl or pyrrolyl; C.sub.1-3acyl and R.sub.23 and R.sub.24
taken together optionally form morpholino.
5. The method according to claim 4 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, benzooxalolyl,
2,3-dihydrobenzooxazol-7-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl,
indolinyl, indolonyl, or indolinonyl, wherein G is optionally
substituted by one or more R.sub.1, R.sub.2 or R.sub.3; Ar is
1-naphthyl; X is: phenyl, imidazolyl, pyridinyl, pyrimidinyl,
piperdinyl, piperazinyl, pyridazinyl or pyrazinyl; Y is: a bond or
--CH.sub.2--, --CH.sub.2CH.sub.2--, --C(O)--, --O--, --S--,
--NH--CH.sub.2CH.sub.2CH.sub.2--, --N(CH.sub.3)--,
CH.sub.2(CN)CH.sub.2--NH--CH.sub.2 or --NH--; Z is morpholino,
dioxolanyl, tetrahydrofuranyl, pyridinyl,
2-oxa-5-aza-bicyclo[2.2.1]heptanyl,
C.sub.1-3alkoxyphenylpiperazinyl, hydroxy, C.sub.1-3alkyl,
N,N-diC.sub.1-3alkoxyC.sub.1-3alkylamino, C.sub.1-3acylamino,
C.sub.1-3alkylsulfonyl or nitrileC.sub.1-3alkyl; each R.sub.1 is
independently: C.sub.1-5 alkyl optionally partially or fully
halogenated wherein one or more C atoms are optionally
independently replaced by 0 or N, and wherein said C.sub.1-5 alkyl
is optionally substituted with oxo, dioxolanyl, pyrrolidinyl, furyl
or phenyl optionally substituted by C.sub.1-3alkoxy; 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; R.sub.2 is
is mono- or di-C.sub.1-3acylamino, amino-S(O).sub.m or S(O).sub.m
amino wherein the N atom is mono- or di-substituted by
C.sub.1-3alkyl or phenyl, bromo, chloro, fluoro, nitrile, nitro,
amino, methylsulfonyl optionally partially or fully halogenated or
phenylsulfonyl; each R.sub.3 is independently: phenyl, morpholino,
pyridinyl, pyrimidinyl, pyrrolidinyl, 2,5-pyrrolidin-dionyl,
imidazolyl, [1,3,4]oxadiazol or pyrazolyl, each is optionally
substituted with C.sub.1-2 alkyl which is optionally partially or
fully halogenated; C.sub.1-3 alkyl or C.sub.1-3 alkoxy each being
optionally partially or fully halogenated or optionally substituted
with diethylamino; OR.sub.18 or C.sub.1-3 alkyl optionally
substituted with OR.sub.18; amino or mono- or di-(C.sub.1-3
alkyl)amino optionally substituted with R.sub.19; CH.sub.3C(O)NH--,
R.sub.22O--; R.sub.23R.sub.24NC(O)--;
R.sub.26CH.sub.2C(O)N(R.sub.21)--, NH.sub.2C(O)methoxy or
R.sub.26C(O)CH.sub.2N(R.sub.21)--; C.sub.2-4alkenyl substituted by
R.sub.23R.sub.24NC(O)--; or C.sub.2-4 alkynyl substituted with
pyrroldinyl or pyrrolyl; C.sub.1-2acyl; and R.sub.23 and R.sub.24
are H or R.sub.23 and R.sub.24 taken together optionally form
morpholino; and R.sub.26 is morpholino.
6. The method according to claim 5 wherein G is phenyl, pyridinyl,
5-indolyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl,
benzooxalolyl, 2,3-dihydrobenzooxazol-7-yl,
2-oxo-2,3-dihydro-1H-indol-5-yl or 2-naphthyl wherein G is
optionally substituted by one or more R.sub.1, R.sub.2 or R.sub.3;
X is: imidazolyl, pyridinyl, pyrimidinyl or pyrazinyl; Y is: a
bond, CH.sub.2(CN)CH.sub.2--NH--CH.sub.2, --CH.sub.2--,
--NH--CH.sub.2CH.sub.2CH.sub.2-- or --NH--; Z is morpholin-4yl,
dioxolan-2yl, tetrahydrofuranyl, pyridinyl,
2-oxa-5-aza-bicyclo[2.2.1]hept-5yl, methoxyphenylpiperazinyl,
hydroxy, methyl, N,N-dimethoxyethylamino, acetylamino,
methylsulfonyl or cyanoethyl; each R.sub.1 is independently:
tert-butyl, sec-butyl, tert-amyl, phenyl,
tetrahydropyran-2-yloxypropynyl, hydroxypropynyl, trihalomethyl,
2,2-diethylpropionyl or cyclohexanyl; R.sub.2 is chloro, nitro,
amino, nitrile, methylsulfonylamino, diacetylamino,
phenylsulfonylamino, N,N-di(methylsulfonyl)amino, methylsulfonyl or
trihalomethylsulfonyl; R.sub.3 is independently: methyl, C.sub.1-3
alkoxy, methoxymethyl, hydroxypropyl, dimethylamino,
C.sub.1-4alkylamino, NH.sub.2C(O)methoxy, acetyl, pyrrolidinyl,
imidazolyl, pyrazolyl, morpholino or morpholinocarbonyl.
7. The method according to claim 6 wherein X is pyridinyl.
8. The method according to claim 7 wherein the pyridinyl is
attached to Ar via the 3-pyridinyl position.
9. A method of treating cancer, said method comprising
administering to a patient a therapeutically effective amount of a
compound chosen from:
1-(4-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphth-
alen-1-yl]-urea;
1-(5-tert-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;
1-(4-Difluoromethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-urea;
1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-urea;
1-[2-Methoxy-5-(1-methyl-1-phenyl-ethyl)-phenyl]-3-[4-(6-morpholin-4-ylme-
thyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
(5-tert-Butyl-2-methyl-phenyl)-carbamic acid
3-(5-{4-[3-(5-tert-butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyridi-
n-2-ylamino)-propyl ester;
1-(6-tert-Butyl-benzo[1,3]dioxol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-acetamide;
1,3-Bis-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-hydroxy-pheny-
l]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-[4-(6-morpholin-4--
ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-morpho-
lin-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-tolylo-
xy-5-trifluoromethyl-phenyl)-urea;
1-[2-(2-Methoxy-phenoxy)-5-trifluoromethyl-phenyl]-3-[4-(6-morpholin-4-yl-
methyl-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-{5-tert-Butyl-2-methyl-3-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phe-
nyl}-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;
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-ylmethyl-pyridin-3-yl-
)-naphthalen-1-yl]-urea;
1-(2,5-Di-tert-butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-urea;
1-[3-(4-Bromo-1-methyl-1H-pyrazol-3-yl)-phenyl]-3-[4-(6-morpholin-4-ylmet-
hyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(3-Hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylme-
thyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-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]o-
xadiazol-2-yl-phenyl)-urea;
1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea; Furan-2-carboxylic acid
(4-tert-butyl-2-{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;
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)-napht-
halen-1-yl]-ureido}-benzenesulfonamide;
1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea;
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-ylmeth-
yl-pyridin-3-yl)-naphthalen-1-yl]-urea;
2-Chloro-5-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-u-
reido}-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-tert-Butyl-3-(3-hydroxy-prop-1-ynyl)-2-methyl-phenyl]-3-[4-(6-morpho-
lin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(3-hydroxy-prop-1-ynyl)-phenyl]-3-[4-(6-morpholin-4-ylm-
ethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-methoxy-pheny-
l]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-methoxy-phenyl]-3-[4-(6-morpho-
lin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-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-tert-Butyl-3-(2-diethylamino-ethyl)-2-methoxy-phenyl]-3-[4-(6-morpho-
lin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-[1,3]dioxolan-2-yl-pyridin-3-yl-
)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-dimethylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyri-
din-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-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-nap-
hthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmet-
hyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
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-ylme-
thyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-cyclopentyloxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyr-
idin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-pyridin-3-yl-pyrrolidin-1-yl-
methyl)-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-p-
yridin-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-morph-
olin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea;
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-na-
phthalen-1-yl]-urea;
N-Acetyl-N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide;
1-(6-tert-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-tert-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-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-isopropoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-
-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-imidazol-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyri-
din-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-4-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide;
1-(5-tert-Butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmeth-
yl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-bis(methanesulfon)amide;
1-[5-tert-Butyl-2-(1-methyl-1H-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-ylmeth-
yl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2-Ethanesulfonyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethy-
l-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-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-dimethylamino-pyrrolidin-1-y-
lmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
N-[1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-py-
ridin-2-ylmethyl)-pyrrolidin-3-yl]-acetamide;
1-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-y-
lmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-propionamide;
1-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-p-
yridin-3-yl)-naphthalen-1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluor-
omethanesulfonyl-phenyl)-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-isobutyramide;
2-(4-tert-Butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen--
1-yl]-ureido}-phenoxy)-acetamide;
1-(5-tert-Butyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-3-[4-(6-morpholin-4-y-
lmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(6-tert-Butyl-3-cyano-2-methoxymethoxy-pyridin-4-yl)-3-[4-(6-morpholin--
4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(6-tert-Butyl-3-cyano-2-hydroxy-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmet-
hyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(1,3,3-trim-
ethyl-2,3-dihydro-1H-indol-5-yl)-urea;
1-(5-tert-Butyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3--
yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-benzenesulfonamide; Ethanesulfonic
acid
(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-nap-
hthalen-1-yl]-ureido}-phenyl)-amide;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin--
1-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-3-[4-(4-morpholin-4--
ylmethyl-piperidin-1-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin--
5-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyr-
idin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyri-
din-3-yl)-naphthalen-1-yl]-urea; 2,2,2-Trifluoro-ethanesulfonic
acid
(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-nap-
hthalen-1-yl]-ureido}-phenyl)-amide;
N-(5-{4-[3-(5-tert-Butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyrazi-
n-2-yl)-methanesulfonamide;
1-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-y-
l]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-
-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-piperidin-1-ylmet-
hyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-tetrahydro-thiopyran-4-y-
lamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-py-
ridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-(tetrahydro-f-
uran-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxymethyl-morpholin-4-yl-
methyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-morpholin-4-yl-ethylamino)--
methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylm-
ethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyrid-
in-2-ylmethyl)-piperidine-3-carboxylic acid amide;
1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyrid-
in-2-ylmethyl)-piperidine-4-carboxylic acid amide;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylme-
thyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylme-
thyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-oxo-piperazin-1-ylmethyl)-py-
ridin-3-yl]-naphthalen-1-yl}-urea;
1-{4-[6-(4-Acetyl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-3--
(5-tert-butyl-2-methoxy-phenyl)-urea;
4-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyrid-
in-2-ylmethyl)-piperazine-1-carboxylic acid ethyl ester;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-pyridin-3-yl-ethylamino)-me-
thyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(tetrahydro-furan-3-ylamino)-m-
ethyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-pyridin-3-ylm-
ethyl-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-methylsulfanyl-ethylamino)--
methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-oxa-5-aza-bicyclo[2.2.1]hept-
-5-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmet-
hyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-piperazin-1-yl-ethylamino)--
methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-pyrimidin-2-yl-piperazin-1-y-
lmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-pyridin-2-yl-piperazin-1-ylm-
ethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
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]hep-
t-5-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
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-morph-
olin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyrid-
in-2-yl)-acetamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-N-methyl-acetamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-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-y-
l]-naphthalen-1-yl}-urea;
[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-carbamic
acid 3-tert-butyl-phenyl ester and
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide or the
pharmaceutically acceptable salts thereof.
10. A method of treating cancer, said method comprising
administering to a patient a therapeutically effective amount of a
compound chosen from:
1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-acetamide;
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-morpho-
lin-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-{5-tert-Butyl-2-methyl-3-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phe-
nyl}-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea;
1-[5-(2,2-Dimethyl-propionyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmeth-
yl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(3-hydroxy-prop-1-ynyl)-2-methyl-phenyl]-3-[4-(6-morpho-
lin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(3-hydroxy-prop-1-ynyl)-phenyl]-3-[4-(6-morpholin-4-ylm-
ethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-methoxy-pheny-
l]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-methoxy-phenyl]-3-[4-(6-morpho-
lin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-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-tert-Butyl-3-(2-diethylamino-ethyl)-2-methoxy-phenyl]-3-[4-(6-morpho-
lin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-[1,3]dioxolan-2-yl-pyridin-3-yl-
)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-dimethylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyri-
din-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-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-nap-
hthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmet-
hyl)-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-p-
yridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea;
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-na-
phthalen-1-yl]-urea;
N-Acetyl-N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide;
1-(6-tert-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-(5-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-y-
l)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-isopropoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-
-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-imidazol-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyri-
din-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmeth-
yl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-bis(methanesulfon)amide;
1-[5-tert-Butyl-2-(1-methyl-1H-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-ylmeth-
yl-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;
N-[1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-py-
ridin-2-ylmethyl)-pyrrolidin-3-yl]-acetamide;
1-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-y-
lmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-propionamide;
1-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-p-
yridin-3-yl)-naphthalen-1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluor-
omethanesulfonyl-phenyl)-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-isobutyramide;
2-(4-tert-Butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen--
1-yl]-ureido}-phenoxy)-acetamide;
1-(5-tert-Butyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-3-[4-(6-morpholin-4-y-
lmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3--
yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-benzenesulfonamide; Ethanesulfonic
acid
(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-nap-
hthalen-1-yl]-ureido}-phenyl)-amide;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin--
5-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyr-
idin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyri-
din-3-yl)-naphthalen-1-yl]-urea; 2,2,2-Trifluoro-ethanesulfonic
acid
(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-nap-
hthalen-1-yl]-ureido}-phenyl)-amide;
N-(5-{4-[3-(5-tert-Butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyrazi-
n-2-yl)-methanesulfonamide;
1-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-y-
l]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-
-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-piperidin-1-ylmet-
hyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-tetrahydro-thiopyran-4-y-
lamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-py-
ridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-(tetrahydro-f-
uran-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxymethyl-morpholin-4-yl-
methyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylm-
ethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyrid-
in-2-ylmethyl)-piperidine-3-carboxylic acid amide;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylme-
thyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylme-
thyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-oxo-piperazin-1-ylmethyl)-py-
ridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(tetrahydro-furan-3-ylamino)-m-
ethyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-pyridin-3-ylm-
ethyl-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-oxa-5-aza-bicyclo[2.2.1]hept-
-5-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmet-
hyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
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-(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-morph-
olin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyrid-
in-2-yl)-acetamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-N-methyl-acetamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-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;
[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-carbamic
acid 3-tert-butyl-phenyl ester and
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide and or the
pharmaceutically salts thereof.
11. A method of treating cancer, said method comprising
administering to a patient a therapeutically effective amount of a
compound chosen from:
1-(5-tert-Butyl-2-methylsulfanyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmeth-
yl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-chloro-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methylamino-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl--
pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen--
1-yl]-ureido}-2-oxo-2H-pyridin-1-yl)-methanesulfonamide;
5-tert-Butyl-7-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-y-
l]-ureido}-benzooxazole-2-carboxylic acid amide;
2-(5-tert-Butyl-7-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen--
1-yl]-ureido}-benzooxazol-2-yl)-acetamide;
5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naph-
thalen-1-yl]-ureido}-benzamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide;
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea and
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-morpho-
lin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea or the
pharmaceutically acceptable salts thereof.
12. The method according to claims 1, 9, 10 or 11 wherein the
cancer is chosen from cancer cachexia, multiple myeloma, acute
myelogenous leukemia and Castleman's disease.
13. The method according to claims 1, 9, 10 or 11 wherein the
method involves inhibiting proliferation of acute myelogenous
leukemia blasts.
14. The method according to claims 1, 9, 10 or 11 wherein the
cancer is a plasma cell dyscrasias.
15. The method according to claim 1, 9, 10 or 11 wherein treament
is done in conjunction with genotoxic therapy.
16. The method according to claim 1, 9, 10 or 11 wherein the method
involves treating tumor cells.
Description
APPLICATION DATA
[0001] This application is a divisional application of U.S. Ser.
No. 10/237,306 filed Sep. 9, 2002 which claims benefit to U.S.
provisional application Ser. No. 60/318,958 filed Sep. 13, 2001,
the entirety of each is incorporated herein by reference.
TECHNICAL FIELD OF THE INVENTION
[0002] This invention relates to methods of treating acute and
chronic inflammation in the lung caused by inhalation of smoke,
endometriosis, Behcet's disease, uveitis, ankylosing spondylitis,
pancreatitis, cancer, Lyme disease, percutaneous transluminal
coronary angioplasty, Alzheimer's disease, traumatic arthritis,
sepsis, chronic obstructive pulmonary disease and congestive heart
failure indicated to be cytokine mediated diseases using aromatic
heterocyclic compounds disclosed in PCT publication WO
00/55139.
BACKGROUND OF THE INVENTION
[0003] In WO 00/55139 there are described aromatic heterocyclic
compounds useful in treating certain cytokine mediated diseases.
Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are important
biological entities 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.
[0004] 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 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).
Studies suggest that inflammatory changes mediated by cytokines may
be involved in the pathogenesis of restenosis after percutaneous
transluminal coronary angioplasty (PTCA) (Tashiro, H., et al., 2001
Mar, Coron Artery Dis 12(2):107-13). 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 TNF.alpha.) and
IL-1.beta.. A number of anti-cytokine therapies are currently in
clinical trials. Efficacy has been demonstrated with a monoclonal
antibody directed against TNF.alpha. in a number of autoimmune
diseases (Heath, P., "CDP571: An Engineered Human IgG4
Anti-TNF.alpha. Antibody" IBC Meeting on Cytokine Antagonists,
Philadelphia, Pa., Apr. 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
TNF.alpha. and to membrane bound TNF.
[0005] A soluble TNF.alpha. receptor has been engineered that
interacts with TNF.alpha.. The approach is similar to that
described above for the monoclonal antibodies directed against
TNF.alpha.; both agents bind to soluble TNF.alpha., thus reducing
its concentration. One version of this construct, called Enbrel
(Immunex, Seattle, Wash.) recently demonstrated efficacy in a Phase
III clinical trial for the treatment of rheumatoid arthritis
(Brower et al., 1997, Nature Biotechnology 15: 1240). Another
version of the TNF.alpha. receptor, Ro 45-2081 (Hoffman-LaRoche
Inc., Nutley, N.J.) has demonstrated efficacy in various animal
models of allergic lung inflammation and acute lung injury. Ro
45-2081 is a recombinant chimeric molecule constructed from the
soluble 55 kDa human TNF receptor fused to the hinge region of the
heavy chain IgG1 gene and expressed in eukaryotic cells (Renzetti,
et al., 1997, Inflamm. Res. 46: S143).
[0006] IL-1 has been implicated as an immunological effector
molecule in a large number of disease processes. IL-1 receptor
antagonist (IL-1ra) 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-1ra 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 is detected in synovial fluid and in the
cartilage matrix of osteoarthritic joints. Antagonists of IL-1 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
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 with effects on cells of the
osteoblast and osteoclast lineage (Evans, et al, 1996, J Bone Miner
Res. 11, 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, Proc Soc
Exp Biol Med. 211, 24).
[0007] 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., 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.
[0008] Elevation of several cytokines have been demonstrated during
active inflammatory bowel disease (IBD). A mucosal imbalance of
intestinal IL-1 and IL-1ra is present in patients with IBD.
Insufficient production of endogenous IL-1ra may contribute to the
pathogenesis of IBD (Cominelli, et al., 1996, Aliment Pharmacol
Ther. 10, 49).
[0009] 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-1ra
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 both IL-1 and TNF (Howells, 1995, Oral Dis. 1,
266).
[0010] Proinflammatory cytokines such as TNF.alpha. and IL-1.beta.
are also important mediators of septic shock and associated
cardiopulmonary dysfunction, acute respiratory distress syndrome
(ARDS) and multiple organ failure. In a study of patients
presenting at a hospital with sepsis, a correlation was found
between TNF.alpha. and IL-6 levels and septic complications
(Terregino et al., 2000, Ann. Emerg. Med., 35, 26). TNF.alpha. 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
TNF.alpha. expression have been noted for each of the above
conditions (Loffreda, et al., 1998, FASEB J. 12, 57). It has been
proposed that elevated levels of TNF.alpha. 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 TNF.alpha. production, HU-211, was shown to improve
the outcome of closed brain injury in an experimental model
(Shohami, et al., 1997, J Neuroimmunol. 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).
[0011] TNF.alpha. 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., 15, 281). Circulating TNF.alpha. 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 TNF.alpha. 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, TNF.alpha.
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).
[0012] TNF.alpha. 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 and
Rheumatism, 41, 2165). TNF.alpha. has also been shown to play a key
role in the development of glomerulonephritis (Le Hir et al., 1998,
Laboratory Investigation, 78, 1625).
[0013] The abnormal expression of inducible nitric oxide synthetase
(iNOS) has been associated with hypertension in the spontaneously
hypertensive rat (Chou et al., 1998, Hypertension, 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).
[0014] 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 including IL-1, 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, Am J Contact Dermat. 7, 177). Data obtained from IL-1 knock
out mice indicates the critical involvement in fever for this
cytokine (Kluger et al., 1998, Clin Exp Pharmacol Physiol. 25,
141). A variety of cytokines including TNF, IL-1, 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 Nutr. 62,
813). The production of these inflammatory cytokines rapidly
follows trauma or pathogenic organism invasion.
[0015] 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
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, 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 (ARDS),
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, Am J Rhinol. 12, 17).
[0016] Other diseases that are effected by IL-8 include myocardial
ischemia and reperfusion, inflammatory bowel disease and many
others.
[0017] The proinflammatory cytokine IL-6 has been implicated with
the acute phase response. IL-6 is a growth factor in a number in
oncological 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 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 murine 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., 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).
[0018] 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 regulates
several other cells involved in acute and chronic inflammation.
Treatment with GM-CSF has been attempted in a number of disease
states including bum-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 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, J R Coll
Physicians Lond 32, 56).
[0019] Interferon .gamma. (IFN.gamma.) has been implicated in a
number of diseases. It has been associated 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.gamma..
These elevated levels coincided with a rise in peripheral blood
white cell 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.gamma. (Ablumunits, et al., 1998, J
Autoimmun. 11, 73). IFN.gamma. 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 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
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.gamma.. 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.gamma. following challenge with Vespula venom
(Bonay, et al., 1997, Clin Exp Immunol. 109, 342). The expression
of a number of cytokines, including IFN.gamma. has been shown to
increase following a delayed type hypersensitivity reaction thus
indicating a role for IFN.gamma. in atopic dermatitis
(Szepietowski, et al., 1997, Br J Dermatol. 137, 195).
Histopathologic and immunohistologic studies were performed in
cases of fatal cerebral malaria. Evidence for elevated IFN.gamma.
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.gamma. (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 .gamma., TNF
and IL-2 (Chisari, et al., 1995, Springer Semin Immunopathol 17,
261). IFN.gamma. 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, J
Bone Miner Res. 11, 300). Studies with gene deficient mice have
demonstrated that the IL-12 dependent production of IFN.gamma. 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,
Philos Trans R Soc Lond B Biol Sci 352, 1355). NO is an important
vasodilator and convincing evidence exists for its role in
cardiovascular shock (Kilboum, et al., 1997, Dis Mon. 43, 277).
IFN.gamma. is required for progression of chronic intestinal
inflammation in such 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.gamma. was negatively
correlated with serum IgE suggesting a role for IFN.gamma. in
atopic patients (Teramoto et al., 1998, Clin Exp Allergy 28,
74).
[0020] 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 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 syndromes, Leber's disease,
Wemicke'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. WO 02/32862 discloses that
inhibitors of pro-inflammatory cytokines including TNF.alpha. are
allegedly useful for treating acute and chronic inflammation in the
lung caused by inhalation of smoke such as cigarette smoke.
TNF.alpha. anatagonists are apparently also useful for the
treatment of endometriosis, see EP 1022027 A1. Infliximab, in
clinical trials for RA, has also been indicated to be useful for
treating various inflammatory diseases including Behcet's disease,
uveitis and ankylosing spondylitis. Pancreatitis may also be
regulated by inflammatory mediator production, see J Surg Res 2000
May 15 90(2)95-101; Shock 1998 September. 10(3):160-75.
p38MAPkinase pathway plays an role in B.burgdorferi-elicited
infammation and may be useful in treating inflammation induced by
the Lyme disease agent. Anguita, J. et. al., The Journal of
Immunology, 2002, 168:6352-6357.
[0021] Anti-cytokine drugs may also have therapeutic utility in
treating tumor cells. Drug Resistance Updates 4(4):253-267, 2001
August. WO 02/38143 discloses the use of p38 inhibitors to enhance
the efficacy and safety of genotoxic therapy for treating, for
example, aging, cancer and certain types of heart failure.
[0022] 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 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 disease. WO 00/41698 discloses aryl ureas said to be
useful in treating p38 MAP kinase diseases.
[0023] 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.
[0024] The work cited above supports the principle that inhibition
of cytokine production will be beneficial in the treatment acute
and chronic inflammation in the lung caused by inhalation of smoke,
endometriosis, Behcet's disease, uveitis, ankylosing spondylitis,
pancreatitis, cancer, Lyme disease, restenosis following
percutaneous transluminal coronary angioplasty, Alzheimer's
disease, traumatic arthritis, sepsis, chronic obstructive pulmonary
disease and congestive heart failure. None of these specific
diseases have been taught or described in WO 00/55139 as being
possible indications for the compounds taught therein. Therefore a
need exists for small molecule inhibitors for treating these
diseases with optimized efficacy, pharmacokinetic and safety
profiles.
BRIEF SUMMARY OF THE INVENTION
[0025] The present invention is directed a method of treating a
cytokine mediated disease or condition chosen from: acute and
chronic inflammation in the lung caused by inhalation of smoke,
endometriosis, Behcet's disease, uveitis, ankylosing spondylitis,
pancreatitis, cancer, Lyme Disease, restenosis following
percutaneous transluminal coronary angioplasty, Alzheimer's
disease, traumatic arthritis, sepsis, chronic obstructive pulmonary
disease and congestive heart failure, said method comprising
administering to a patient in need of such treatment a
therapeutically effective amount of compounds disclosed in in WO
00/55139.
DETAILED DESCRIPTION OF THE INVENTION
[0026] In a first broad generic aspect, the present invention is
directed a method of treating a cytokine mediated disease or
condition chosen from: acute and chronic inflammation in the lung
caused by inhalation of smoke, endometriosis, Behcet's disease,
uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme
disease, restenosis following percutaneous transluminal coronary
angioplasty, Alzheimer's disease, traumatic arthritis, sepsis,
chronic obstructive pulmonary disease and congestive heart failure,
said method comprising administering to a patient in need of such
treatment a therapeutically effective amount of a compound of the
formula (I) disclosed in WO 00/55139 which is the PCT case of U.S.
application Ser. No. 09/505,582 (both of which are incorporated by
reference herein in it their entirety): ##STR1## [0027] wherein:
[0028] Ar.sub.1 is selected from the group consisting of: pyrrole,
pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and
thiophene; wherein Ar.sub.1 may be substituted by one or more
R.sub.1, R.sub.2 or R.sub.3; [0029] Ar.sub.2 is: phenyl, naphthyl,
quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline,
tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl
or indole each being optionally substituted with zero to three
R.sub.2 groups; [0030] X is: [0031] a) a C.sub.5-8 cycloalkyl or
cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3
C.sub.1-4 branched or unbranched alkyl, C.sub.1-4 alkoxy or
C.sub.1-4 alkylamino chains; [0032] b) phenyl, furan, thiophene,
pyrrole, imidazolyl, pyridine, pyrimidine, pyridinone,
dihydropyridinone, maleimide, dihydromaleimide, piperdine,
piperazine or pyrazine each being optionally independently
substituted with 0-3 C.sub.1-4 branched or unbranched alkyl,
C.sub.1-4alkoxy, hydroxy, nitrile, mono- or di-(C.sub.1-3
alkyl)amino, C.sub.1-6 alkyl-S(O).sub.m, or halogen; [0033] Y is: a
bond or a C.sub.1-4 saturated or unsaturated branched or unbranched
carbon chain optionally partially or fully halogenated, wherein one
or more methylene groups are optionally replaced by O, NH, S(O),
S(O).sub.2 or S and wherein Y is optionally independently
substituted with 0-2 oxo groups and one or more C.sub.1-4 branched
or unbranched alkyl which may be substituted by one or more halogen
atoms; [0034] Z is: [0035] a) phenyl, pyridine, pyrimidine,
pyridazine, imidazole, furan, thiophene, pyran, which are
optionally substituted with one to three groups consisting of
halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, mono- or
di-(C.sub.1-3 alkyl)amino, C.sub.1-6 alkyl-S(O).sub.m, COOH and
phenylamino wherein the phenyl ring is optionally substituted with
one to two groups consisting of halogen, C.sub.1-6 alkyl and
C.sub.1-6 alkoxy; [0036] b) tetrahydropyran, tetrahydrofuran,
1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxane, morpholine,
thiomorpholine, thiomorpholine sulfoxide, piperidine, piperidinone,
piperazine, tetrahydropyrimidone, cyclohexanone, cyclohexanol,
pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene
sulfone, tetramethylene sulfide, tetramethylene sulfoxide or
tetramethylene sulfone which are optionally substituted with one to
three groups consisting of nitrile, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, hydroxy, mono- or di-(C.sub.1-3 alkyl)amino-C.sub.1-3
alkyl, phenylamino-C.sub.1-3 alkyl and C.sub.1-3 alkoxy-C.sub.1-3
alkyl; [0037] c) C.sub.1-6 alkoxy, secondary or tertiary amine
wherein the amino nitrogen is covalently bonded to groups selected
from the group consisting of C.sub.1-3 alkyl, C.sub.1-5
alkoxyalkyl, pyridinyl-C.sub.1-3 alkyl, imidazolyl-C.sub.1-3 alkyl,
tetrahydrofuranyl-C.sub.1-3 alkyl, phenylamino, wherein the phenyl
ring is optionally substituted with one to two halogen, C.sub.1-6
alkoxy, hydroxy or mono- or di-(C.sub.1-3 alkyl)amino, C.sub.1-6
alkyl-S(O).sub.m, and phenyl-S(O).sub.m, wherein the phenyl ring is
optionally substituted with one to two halogen, C.sub.1-6 alkoxy,
hydroxy or mono- or di-(C.sub.1-3 alkyl)amino; [0038] R.sub.1 is:
[0039] (a) C.sub.3-10 branched or unbranched alkyl optionally
partially or fully halogenated and optionally substituted with one
to three phenyl, naphthyl or heterocyclic groups selected from the
group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and
isothiazolyl; each such phenyl, naphthyl or heterocycle selected
from the group hereinabove described in this paragraph, and being
substituted with 0 to 5 groups selected from the group consisting
of halogen, C.sub.1-6 branched or unbranched alkyl which is
optionally partially or fully halogenated, C.sub.3-8 cycloalkyl,
C.sub.5-8 cycloalkenyl, hydroxy, nitrile, C.sub.1-3 alkyloxy which
is optionally partially or fully halogenated, NH.sub.2C(O) and
di(C.sub.1-3)alkylaminocarbonyl; [0040] (b) C.sub.3-7 cycloalkyl
selected from the group consisting of cyclopropyl, cyclobutyl,
cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,
bicyclohexanyl and bicycloheptanyl each being optionally be
partially or fully halogenated and optionally substituted with one
to three C.sub.1-3 alkyl groups, or an analog of such cycloalkyl
group wherein one to three ring methylene groups are replaced by
groups independently selected from the group consisting of O, S,
CHOH, >C.dbd.O, >C.dbd.S and NH; [0041] (c) C.sub.3-10
branched alkenyl optionally partially or fully halogenated and
optionally substituted with one to three C.sub.1-5 branched or
unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with
each such heterocyclic group being independently selected from the
group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and
isothiazolyl, and each such phenyl, naphthyl or heterocyclic group
being substituted with 0 to 5 groups selected from the group
consisting of halogen, C.sub.1-6 branched or unbranched alkyl which
is optionally partially or fully halogenated, cyclopropyl,
cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, nitrile,
C.sub.1-3 alkoxy which is optionally partially or fully
halogenated, NH.sub.2C(O) and mono- or
di(C.sub.1-3)alkylaminocarbonyl; [0042] (d) a C.sub.5-7
cycloalkenyl selected from the group consisting of cyclopentenyl,
cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,
bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group
is optionally substituted with one to three C.sub.1-3 alkyl groups;
[0043] (e) nitrile; or [0044] (f) C.sub.1-6 branched or unbranched
alkoxycarbonyl, C.sub.1-6 branched or unbranched
alkylaminocarbonyl, C.sub.1-6 branched or unbranched
alkylcarbonylamino-C.sub.1-3-alkyl; [0045] R.sub.2 is: a C.sub.1-6
branched or unbranched alkyl optionally partially or fully
halogenated, acetyl, aroyl, C.sub.1-4 branched or unbranched alkoxy
optionally partially or fully halogenated, halogen, methoxycarbonyl
or phenylsulfonyl; [0046] R.sub.3 is: [0047] a) phenyl, naphthyl or
heterocyclic group selected from the group consisting of pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,
pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl,
isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,
benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl,
benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl,
naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and
indazolyl, wherein such phenyl, naphthyl or heterocyclic group is
optionally substituted with one to five groups selected from the
group consisting of phenyl, naphthyl, heterocycle selected from the
group hereinabove described in this paragraph, C.sub.1-6 branched
or unbranched alkyl which is optionally partially or fully
halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl
C.sub.1-5 alkyl, naphthyl C.sub.1-5 alkyl, halogen, hydroxy,
nitrile, C.sub.1-3 alkyloxy which may optionally be partially or
fully halogenated, phenyloxy, naphthyloxy, heteraryloxy wherein the
heterocyclic moiety is selected from the group hereinabove
described in this paragraph, nitro, amino, mono- or
di-(C.sub.1-3)alkylamino, phenylamino, naphthylamino,
heterocyclylamino wherein the heterocyclyl moiety is selected from
the group hereinabove described in this paragraph, NH.sub.2C(O), a
mono- or di-(C.sub.1-3)alkyl aminocarbonyl, C.sub.1-5
alkyl-C(O)--C.sub.1-4 alkyl, amino-C.sub.1-5 alkyl, mono- or
di-(C.sub.1-3)alkylamino-C.sub.1-5 alkyl, amino-S(O).sub.2,
di-(C.sub.1-3)alkylamino-S(O).sub.2, R.sub.4--C.sub.1-5 alkyl,
R.sub.5--C.sub.1-5 alkoxy, R.sub.6--C(O)--C.sub.1-5 alkyl and
R.sub.7--C.sub.1-5 alkyl(R.sub.8)N, carboxy-mono- or
di-(C.sub.1-5)-alkyl-amino; [0048] b) a fused aryl selected from
the group consisting of benzocyclobutanyl, indanyl, indenyl,
dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and
benzocycloheptenyl, or a fused heterocyclyl selected from the group
consisting of cyclopentenopyridine, cyclohexanopyridine,
cyclopentanopyrimidine, cyclohexanopyrimidine,
cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine,
cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline,
cyclopentanoisoquinoline, cyclohexanoisoquinoline,
cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole,
cyclohexanobenzimidazole, cyclopentanobenzoxazole,
cyclohexanobenzoxazole, cyclopentanoimidazole,
cyclohexanoimidazole, cyclopentanothiophene and
cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl
ring is substituted with 0 to 3 groups independently selected from
the group consisting of phenyl, naphthyl and heterocyclyl selected
from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl,
pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,
isoxazolyl, and isothiazolyl, C.sub.1-6 branched or unbranched
alkyl which is optionally partially or fully halogenated, halogen,
nitrile, C.sub.1-3 alkoxy which is optionally partially or fully
halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the
heterocyclyl moiety is selected from the group hereinabove
described in this paragraph, nitro, amino, mono- or
di-(C.sub.1-3)alkylamino, phenylamino, naphthylamino,
heterocyclylamino wherein the heterocyclyl moiety is selected from
the group hereinabove described in this paragraph, NH.sub.2C(O), a
mono- or di-(C.sub.1-3)alkyl aminocarbonyl, C.sub.1-4 alkyl-OC(O),
C.sub.1-5 alkyl-C(O)-C.sub.1-4 branched or unbranched alkyl, an
amino-C.sub.1-5 alkyl, mono- or di-(C.sub.1-3)alkylamino-C.sub.1-5
alkyl, R.sub.9--C.sub.1-5 alkyl, R.sub.10--C.sub.1-5 alkoxy,
R.sub.11--C(O)--C.sub.1-5 alkyl, and R.sub.12--C.sub.1-5
alkyl(R.sub.13)N; [0049] c) cycloalkyl selected from the group
consisting of cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl,
bicyclohexyl and bicycloheptyl, wherein the cycloalkyl is
optionally partially or fully halogenated and optionally
substituted with one to three C.sub.1-3 alkyl groups; [0050] d)
C.sub.5-7 cycloalkenyl selected from the group consisting of
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,
cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such
cycloalkenyl group is optionally substituted with one to three
C.sub.1-3 alkyl groups; [0051] e) acetyl, aroyl,
alkoxycarbonylalkyl or phenylsulfonyl; or [0052] f) C.sub.1-6
branched or unbranched alkyl optionally partially or fully
halogenated; or R.sub.1 and R.sub.2 taken together may optionally
form a fused phenyl or pyridinyl ring; [0053] each R.sub.8 and
R.sub.13 is independently selected from the group consisting of:
hydrogen and C.sub.1-4 branched or unbranched alkyl optionally be
partially or fully halogenated; [0054] each R.sub.4, R.sub.5,
R.sub.6, R.sub.7, R.sub.9, R.sub.10, R.sub.11 and R.sub.12 is
independently selected from the group consisting of morpholine,
piperidine, piperazine, imidazole and tetrazole; [0055] m is 0, 1
or 2; [0056] W is O or S and the pharmaceutically acceptable
derivatives thereof.
[0057] A preferred subgeneric aspect of the invention comprises a
method of using the compounds of the formula (I) as provided above
and wherein: [0058] Ar.sub.2 is naphthyl, tetrahydronaphthyl,
indanyl or indenyl and [0059] W is O.
[0060] A more preferred subgeneric aspect of the invention
comprises a method of using the compounds of the formula (I) as
provided above and wherein: [0061] Ar.sub.1 is selected from
thiophene and pyrazole; [0062] X is C.sub.5-7 cycloalkyl or
C.sub.5-7cycloalkenyl optionally substituted with 0-2 oxo groups or
0-3 C.sub.1-4 branched or unbranched alkyl, C.sub.1-4 alkoxy or
C.sub.1-4 alkylamino; or X is phenyl, pyridine, tetrahydropyridine,
pyrimidine, furan or thiophene each being optionally independently
substituted with 0-3 C.sub.1-4 branched or unbranched alkyl,
C.sub.1-4alkoxy, hydroxy, nitrile, mono- or di-(C.sub.1-3
alkyl)amino, C.sub.1-6 alkyl-S(O).sub.m or halogen; [0063] R.sub.1
is C.sub.1-4alkyl branched or unbranched, cyclopropyl or cyclohexyl
optionally partially or fully halogenated and optionally
substituted with one to three C.sub.1-3 alkyl groups; [0064]
R.sub.3 is C.sub.1-4alkyl branched or unbranched, phenyl,
pyrimidinyl, pyrazolyl or pyridinyl each being optionally
substituted as described hereinabove in the broadest generic
aspect, alkoxycarbonylalkyl or cyclopropyl or cyclopentyl
optionally substituted as described hereinabove in the broadest
generic aspect.
[0065] A yet more preferred subgeneric aspect of the invention
comprises a method of using the compounds of the formula (I), as
described in the immediate previous paragraph, wherein: [0066]
Ar.sub.1 is pyrazole; [0067] X is cyclopentenyl, cyclohexenyl or
cycloheptenyl, optionally substituted with an oxo group or 0-3
C.sub.1-4 branched or unbranched alkyl, C.sub.1-4alkoxy or
C.sub.1-4alkylamino; or X is phenyl, pyridine, furan or thiophene
each being optionally independently substituted with 0-3 C.sub.1-4
branched or unbranched alkyl, C.sub.1-4alkoxy, hydroxy, nitrile,
mono- or di-(C.sub.1-3 alkyl)amino, C.sub.1-6 alkyl-S(O).sub.m or
halogen.
[0068] A yet further preferred subgeneric aspect of the invention
comprises a method of using the compounds of the formula (I), as
described in the immediate previous paragraph, and wherein: [0069]
Y is --CH2--, --CH2CH2--, --CH2NH--, --CH2CH2NH-- or a bond; and
[0070] Z is phenyl, imidazole, furan, piperazine, tetrahydropyran,
morpholine, thiomorpholine, thiomorpholine sulfoxide, piperidine,
pyridine, secondary or tertiary amine wherein the amino nitrogen is
covalently bonded to groups selected from the group consisting of
C.sub.1-3 alkyl and C.sub.1-5 alkoxyalkyl, phenylamino wherein the
phenyl ring is optionally substituted with one to two halogen,
C.sub.1-6 alkoxy, hydroxy or mono- or di-(C.sub.1-3 alkyl)amino,
C.sub.1-6 alkyl-S(O).sub.m and phenyl-S(O).sub.m wherein the phenyl
ring is optionally substituted with one to two halogen, C.sub.1-6
alkoxy, hydroxy or mono- or di-(C.sub.1-3 alkyl)amino.
[0071] A further preferred subgeneric aspect of the invention
comprises a method of using the compounds of the formula (I), as
described in the immediate previous paragraph, and wherein: [0072]
Ar.sub.1 is 5-tert-butyl-pyrazol-3-yl; wherein the pyrazole ring
may be substituted by R.sub.3; [0073] R.sub.3 is C.sub.1-4alkyl
branched or unbranched, phenyl, pyrimidinyl, pyrazolyl, pyridinyl
each being optionally substituted as described hereinabove in the
broadest generic aspect, alkoxycarbonylalkyl or cyclopropyl or
cyclopentyl optionally substituted as described hereinabove in the
broadest generic aspect.
[0074] A still yet further preferred subgeneric aspect of the
invention comprises a method of using the compounds of the formula
(I), as described in the immediate previous paragraph, and
wherein:
[0075] X is pyridinyl.
[0076] A still yet further preferred subgeneric aspect of the
invention comprises a method of using the compounds of the formula
(I), as described in the immediate previous paragraph, and
wherein:
the pyridinyl is attached to Ar.sub.1 via the 3-pyridinyl
position.
[0077] The following compounds are representative of the compounds
of formula (I) which may be useful in the novel methods described
herein: [0078]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-y-
l)phenyl)naphthalen-1-yl]urea; [0079]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl-
)phenyl)naphthalen-1-yl]urea; [0080]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(morpholin-4-yl)eth-
yl)phenyl)naphthalen-1-yl]urea; [0081]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-dimethylaminophenyl)na-
phthalen-1-yl]urea; [0082]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)phenyl-
)naphthalen-1-yl]urea; [0083]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl-
)phenyl)naphthalen-1-yl]urea; [0084]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-p-
yridin-3-yl)naphthalen-1-yl]urea; [0085]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-p-
yridin-2-yl)naphthalen-1-yl]urea; [0086]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-f-
ur-2-yl)naphthalen-1-yl]urea; [0087]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-morpho-
lin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea; [0088]
1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)naphthalen-1-yl]urea; [0089]
1-[5-tert-butyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(4-piperdin-1-ylmethyl-phe-
nyl)naphthalen-1-yl]urea; [0090]
1-[5-tert-butyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(4-(4-methylpiperazin-1-yl-
)methylphenyl)naphthalen-1-yl]urea; [0091]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3,4-di(morpholin-4-yl-me-
thyl)phenyl)naphthalen-1-yl]urea; [0092]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-pyridi-
n-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea; [0093]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-
- thiomorpholin-4-ylmethyl)pyridin-3-yl)naphthalen-1-yl]urea;
[0094]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-
-ylmethyl)pyridin-3-yl)naphthalen-1-yl]urea; [0095]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-tetrah-
ydropyran-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea; [0096]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-
-tetrahydrothiophen-3-ylmethyl)pyridin-3-yl)naphthalen-1-yl]urea;
[0097]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(imida-
zol-1-ylmethyl)pyridin-3-yl)naphthalen-1-yl]urea; [0098]
1-[2-(3-dimethylaminomethylphenyl)-5-(1-methyl-cyclohexyl)-2H-pyrazol-3-y-
l]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;
[0099]
1-[2-(5-(1-methyl-cyclohexyl)-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-
-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;
[0100]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylmethyl-p-
yrimidin-5-yl)naphthalen-1-yl]urea; [0101]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-methox-
y-5-(2-morpholin-4-yl-ethoxy)phenyl)naphthalen-1-yl]urea; [0102]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-mor-
pholin-4-yl-ethoxy)phenyl)naphthalen-1-yl]urea; [0103]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-3-(dimeth-
ylamino)phenyl)naphthalen-1-yl]urea; [0104]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-3-(methyl-
sulfonyl)phenyl)naphthalen-1-yl]urea; [0105]
5-tert-butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl-
]ureido}thiophene-2-carboxylic acid methyl ester; [0106]
5-tert-butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl-
]ureido}thiophene-2-carboxylic acid methylamide; [0107]
5-tert-butyl-1-methyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphth-
alen-1-yl]ureido}-1H-pyrrole-2-carboxylic acid methyl ester; [0108]
5-tert-butyl-1-methyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphth-
alen-1-yl]ureido}-1H-pyrrole-2-carboxylic acid methylamide; [0109]
2-acetylamino
N-(5-tert-butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-
-yl]ureido}thiophen-2-ylmethyl)acetamide; [0110]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-cyclohe-
x-1-enyl)naphthalen-1-yl]urea; [0111]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-cylohep-
t-1-enyl)naphthalen-1-yl]urea; [0112]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(2-morpholin-4-yl-ethy-
lamino)cyclohex-1-enyl)naphthalen-1-yl]urea; [0113]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-cyclohe-
pt-1-enyl)naphthalen-1-yl]urea; [0114]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(pyrid-
in-4-yl-methylamino)cyclohex-1-enyl)naphthalen-1-yl]urea; [0115]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(dimet-
hylaminoethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea; [0116]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(pyrid-
in-3-yl-methylamino)cyclohex-1-enyl)naphthalen-1-yl]urea; [0117]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(pheny-
l-methylamino)cyclohex-1-enyl)naphthalen-1-yl]urea; [0118]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-phe-
nylethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea; [0119]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(furan-
-2-yl-methylamino)cyclohex-1-enyl)naphthalen-1-yl]urea; [0120]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-pyr-
idin-2-yl-ethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea; [0121]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-pip-
erdin-1-yl-ethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea; [0122]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-imi-
dazol-4-yl-ethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea; [0123]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(pyrid-
in-2-yl- methylamino)cyclohex-1-enyl)naphthalen-1-yl]urea; [0124]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(4--
methoxyphenyl)ethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;
[0125]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-ylmethyl-3-
-oxo-cyclohex-1-enyl)naphthalen-1-yl]urea; [0126]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(1-oxo-tetrahydrothiop-
hen-3-ylmethyl)-3-oxo-cyclohex-1-enyl)naphthalen-1-yl]urea; [0127]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(1-oxo-thiomorpholin-4-
-ylmethyl)-3-oxo-cyclohex-1-enyl)naphthalen-1-yl]urea; [0128]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-methylpiperazin-1-ylme-
thyl)-3-oxo-cyclohex-1-enyl)naphthalen-1-yl]urea; [0129]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-{6-oxo-1--
(tetrahydro-pyran-4-ylmethyl)-1,2,3,6-tetrahydro-pyridin-4-yl}naphthalen-1-
-yl]urea; [0130]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-oxo-1--
pyridin-4-ylmethyl-piperdin-4-yl)naphthalen-1-yl]urea; [0131]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-oxo-1-pyridin-4-yl-1,2-
,3,6-tetrahydro-pyridin-4-yl)naphthalen-1-yl]urea; [0132]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-oxo-1--
pyridin-4-yl-1,2,3,6-tetrahydro-pyridin-4-yl)naphthalen-1-yl]urea;
[0133]
5-tert-butyl-3-{3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydro-pyridin-4--
yl)naphthalen-1-yl]ureido}thiophene-2-carboxylic acid methyl ester;
[0134]
5-tert-butyl-1-methyl-3-{3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetra-
hydro-pyridin-4-yl)naphthalen-1-yl]ureido}pyrrole-2-carboxylic acid
methyl ester; [0135]
5-tert-butyl-1-methyl-3-{3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydro-py-
ridin-4-yl)naphthalen-1-yl]ureido}pyrrole-2-carboxylic acid methyl
amide; [0136]
5-tert-butyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-1-enyl)naphthalen-
-1-yl]ureido}thiophene-2-carboxylic acid methyl ester; [0137]
5-tert-butyl-1-methyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-1-enyl)naphthale-
n-1-yl]ureido}pyrrole-2-carboxylic acid methyl ester; and [0138]
5-tert-butyl-1-methyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-1-enyl)naphthale-
n-1-yl]ureido}pyrrole-2-carboxylic acid methyl amide and the
pharmaceutically acceptable derivatives thereof.
[0139] In another embodiment of the invention there are provided
the following compounds of formula (I) which may be useful in the
novel methods described herein: [0140]
1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morph-
olin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea; [0141]
1-[5-tert-butyl-2-(2-methylthiopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(-
morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0142]
1-[5-tert-butyl-2-(2-methoxypyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(mor-
pholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0143]
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morp-
holin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0144]
1-[3-tert-butyl-1'H-[1,4']bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)-
pyridin-3-yl)naphthalen-1-yl]-urea; [0145]
1-[3-tert-butyl-1'-methyl-1'H-[1,4']bipyrazol-5-yl]-3-[4-(6-(morpholin-4--
yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0146]
1-[3-tert-butyl-1'-(3-methylsulfanylpropyl)-1'H-[1,4']bipyrazol-5-yl]-3-[-
4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
[0147]
1-[3-tert-butyl-1'-methyl-1'H-[1,4']bipyrazol-5-yl]-3-[4-(6-(morpholin-4--
yl-methyl)phenyl)naphthalen-1-yl]-urea; [0148]
1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morph-
olin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea; [0149]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(pyrid-
in-3-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0150]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl-
)phenyl)naphthalen-1-yl]urea; [0151]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(morpholin-4-yl)eth-
yl)phenyl)naphthalen-1-yl]urea; [0152]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl-
)phenyl)naphthalen-1-yl]urea; [0153]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-p-
yridin-3-yl)naphthalen-1-yl]urea; [0154]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-p-
yridin-2-yl)naphthalen-1-yl]urea; [0155]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-f-
ur-2-yl)naphthalen-1-yl]urea; [0156]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-morpho-
lin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea; [0157]
1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)naphthalen-1-yl]urea and the pharmaceutically acceptable
derivatives thereof.
[0158] In a second broad generic aspect, there is provided a method
of treating a cytokine mediated disease or condition chosen from:
acute and chronic inflammation in the lung caused by inhalation of
smoke, endometriosis, Behcet's disease, uveitis, ankylosing
spondylitis, pancreatitis, cancer, Lyme disease, restenosis
following percutaneous transluminal coronary angioplasty,
Alzheimer's disease, traumatic arthritis, sepsis, chronic
obstructive pulmonary disease and congestive heart failure, said
method comprising administering to a patient in need of such
treatment a therapeutically effective amount of a compound of the
formula (Ia) disclosed in WO 00/55139 which is the PCT case of U.S.
application Ser. No. 09/505,582: ##STR2## [0159] wherein: [0160]
Ar.sub.1 is: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole,
thiazole, furan and thiophene; wherein Ar.sub.1 is optionally
substituted by one or more R.sub.1, R.sub.2 or R.sub.3; [0161]
Ar.sub.2 is: phenyl, naphthyl, quinoline, isoquinoline,
tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline,
benzimidazole, benzo furan, indanyl, indenyl and indole each being
optionally substituted with zero to three R.sub.2 groups; [0162] X
is: a C.sub.5-8 cycloalkyl or cycloalkenyl optionally substituted
with one to two oxo groups or one to three C.sub.1-4 alkyl,
C.sub.1-4 alkoxy or C.sub.1-4 alkylamino chains each being branched
or unbranched; phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl,
imidazolyl, pyridinyl, tetrahydropyridinyl, pyrimidinyl,
pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl,
piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl,
pyridazinyl or pyrazinyl; each being optionally independently
substituted with one to three C.sub.1-4 alkyl, C.sub.1-4alkoxy,
hydroxy, nitrile, amino, mono- or di-(C.sub.1-3 alkyl)amino, mono-
or di-(C.sub.1-3 alkylamino)carbonyl, NH.sub.2C(O), C.sub.1-6
alkyl-S(O).sub.m or halogen; [0163] Y is: a bond or a C.sub.1-4
saturated or unsaturated branched or unbranched carbon chain
optionally partially or fully halogenated, wherein one or more C
atoms are optionally replaced by O, N, or S(O).sub.m and wherein Y
is optionally independently substituted with one to two oxo groups,
nitrile, phenyl, hydroxy or one or more C.sub.1-4 alkyl optionally
substituted by one or more halogen atoms; [0164] Z is: aryl,
indanyl, heteroaryl selected from benzimidazolyl, pyridinyl,
pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl,
triazolyl, tetrazolyl, furanyl, thienyl and pyranyl, heterocycle
selected from piperazinyl, 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, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-3
alkoxy-C.sub.1-3 alkyl, C.sub.1-6 alkoxycarbonyl, aroyl,
heteroaroyl, heterocycleC.sub.1-3acyl wherein the heteroaryl and
heterocycle are as defined hereinabove in this paragraph,
C.sub.1-3acyl, oxo, hydroxy, pyridinyl-C.sub.1-3 alkyl,
imidazolyl-C.sub.1-3 alkyl, tetrahydrofuranyl-C.sub.1-3 alkyl,
nitrile-C.sub.1-3 alkyl, nitrile, carboxy, phenyl wherein the
phenyl ring is optionally substituted with one to two halogen,
C.sub.1-6 alkoxy, hydroxy or mono- or di-(C.sub.1-3 alkyl)amino,
amino-S(O).sub.m, C.sub.1-6 alkyl-S(O).sub.m or phenyl-S(O).sub.m
wherein the phenyl ring is optionally substituted with one to two
halogen, C.sub.1-6 alkoxy, hydroxy, halogen or mono- or
di-(C.sub.1-3 alkyl)amino; or Z is optionally substituted with one
to three amino, aminocarbonyl or amino-C.sub.1-3 alkyl wherein the
N atom is optionally independently mono- or di-substituted by
aminoC.sub.1-6alkyl, C.sub.1-3alkyl, arylC.sub.0-3alkyl, C.sub.1-5
alkoxyC.sub.1-3 alkyl, C.sub.1-5 alkoxy, aroyl, C.sub.1-3acyl,
C.sub.1-3alkyl-S(O).sub.m-- or arylC.sub.0-3alkyl-S(O).sub.m-- each
of the aforementioned alkyl and aryl attached to the amino group is
optionally substituted with one to two halogen, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, hydroxy or mono- or di-(C.sub.1-3 alkyl)amino; 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.sub.1-6 alkyl or C.sub.1-6
alkoxy; or Z is hydroxy, hydroxyC.sub.1-3alkyl, halogen, nitrile,
amino wherein the N atom is optionally independently mono- or
di-substituted by C.sub.1-6alkyl, aminoC.sub.1-6alkyl,
arylC.sub.0-3alkyl, C.sub.1-5 alkoxyC.sub.1-3 alkyl, C.sub.1-5
alkoxy, aroyl, C.sub.1-3acyl, C.sub.1-3alkyl-S(O).sub.m--,
arylC.sub.0-3alkyl-S(O).sub.m--, nitrileC.sub.1-4alkyl or
C.sub.1-3alkoxyC.sub.1-3alkyl, each of the aforementioned alkyl and
aryl attached to the amino group is optionally substituted with one
to two halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy or mono-
or di-(C.sub.1-3 alkyl)amino, C.sub.1-6
alkoxyheteroarylC.sub.0-3alkyl, heteroarylC.sub.0-3alkyl or
heterocycyleC.sub.0-3alkyl wherein the heteroaryl and heterocycle
is hereinabove described in this paragraph, or Z is C.sub.1-6alkyl
branched or unbranched, C.sub.1-6alkoxy, C.sub.1-3acylamino,
nitrileC.sub.1-4alkyl, C.sub.1-6 alkyl-S(O).sub.m, and
phenyl-S(O).sub.m, wherein the phenyl ring is optionally
substituted with one to two halogen, C.sub.1-6 alkoxy, hydroxy or
mono- or di-(C.sub.1-3 alkyl)amino; [0165] R.sub.1 is: [0166] a)
C.sub.1-10 branched or unbranched alkyl optionally partially or
fully halogenated, and optionally substituted with one to three
phenyl, naphthyl or heterocyclic groups selected from the group
consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and
isothiazolyl; each such phenyl, naphthyl or heterocycle, selected
from the group hereinabove described, being substituted with 0 to 5
groups selected from the group consisting of halogen, C.sub.1-6
branched or unbranched alkyl which is optionally partially or fully
halogenated, C.sub.3-8 cycloalkyl, C.sub.5-8 cycloalkenyl, hydroxy,
nitrile, C.sub.1-3 alkyloxy which is optionally partially or fully
halogenated, NH.sub.2C(O) and di(C.sub.1-3)alkylaminocarbonyl;
[0167] b) C.sub.3-7 cycloalkyl selected from the group consisting
of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
bicyclopentyl, bicyclohexyl and bicycloheptyl, each optionally
partially or fully halogenated and optionally substituted with one
to three C.sub.1-3 alkyl groups, or an analog of such cycloalkyl
group wherein one to three ring methylene groups are replaced by
groups independently selected from the group consisting of O, S,
CHOH, >C.dbd.O, >C.dbd.S and NH; [0168] c) C.sub.3-10
branched alkenyl optionally partially or fully halogenated and
optionally substituted with one to three C.sub.1-5 branched or
unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with
each such heterocyclic group being independently selected from the
group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and
isothiazolyl, and each such phenyl, naphthyl or heterocyclic group
being substituted with 0 to 5 groups selected from the group
consisting of halogen, C.sub.1-6 branched or unbranched alkyl which
is optionally partially or fully halogenated, cyclopropyl,
cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, nitrile,
C.sub.1-3 alkoxy which is optionally partially or fully
halogenated, NH.sub.2C(O) and mono- or
di(C.sub.1-3)alkylaminocarbonyl; [0169] d) a C.sub.5-7 cycloalkenyl
selected from the group consisting of cyclopentenyl, cyclohexenyl,
cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl
and bicycloheptenyl, wherein such cycloalkenyl group is optionally
substituted with one to three C.sub.1-3 alkyl groups; [0170] e)
nitrile; or [0171] f) C.sub.1-6 branched or unbranched
alkoxycarbonyl, C.sub.1-6 branched or unbranched
alkylaminocarbonyl, C.sub.1-6 branched or unbranched
alkylcarbonylamino-C.sub.1-3-alkyl; [0172] R.sub.2 is: a C.sub.1-6
branched or unbranched alkyl optionally partially or fully
halogenated and optionally substituted with nitrile, or R.sub.2 is
acetyl, aroyl, C.sub.1-4 branched or unbranched alkoxy optionally
partially or fully halogenated, halogen, methoxycarbonyl or
phenylsulfonyl; [0173] R.sub.3 is: [0174] a) phenyl, naphthyl or
heterocyclic group selected from the group consisting of pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,
pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl,
isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,
benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl,
benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl,
naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and
indazolyl, wherein such phenyl, naphthyl or heterocyclic group is
optionally substituted with one to five groups selected from the
group consisting of a phenyl, naphthyl, heterocycle selected from
the group hereinabove described in this paragraph, C.sub.1-6
branched or unbranched alkyl which is optionally partially or fully
halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl
C.sub.1-5 alkyl, naphthyl C.sub.1-5 alkyl, halogen, hydroxy, oxo,
nitrile, C.sub.1-3 alkoxy optionally partially or fully
halogenated, C.sub.1-3 alkoxyC.sub.1-5alkyl, C.sub.1-3thioalkyl,
C.sub.1-3thioalkylC.sub.1-5alkyl, phenyloxy, naphthyloxy,
heteraryloxy wherein the heterocyclic moiety is selected from the
group hereinabove described in this paragraph, nitro, amino, mono-
or di-(C.sub.1-3)alkylamino, phenylamino, naphthylamino,
heterocyclylamino wherein the heterocyclyl moiety is selected from
the group hereinabove described in this paragraph, NH.sub.2C(O), a
mono- or di-(C.sub.1-3)alkyl aminocarbonyl, C.sub.1-5
alkyl-C(O)--C.sub.1-4 alkyl, amino-C.sub.1-5 alkyl, mono- or
di-(C.sub.1-3)alkylamino-C.sub.1-5 alkyl, amino-S(O).sub.2,
di-(C.sub.1-3)alkylamino-S(O).sub.2, R.sub.4--C.sub.1-5 alkyl,
R.sub.5--C.sub.1-5 alkoxy, R.sub.6--C(O)--C.sub.1-5 alkyl and
R.sub.7--C.sub.1-5 alkyl(R.sub.8)N, carboxy-mono- or
di-(C.sub.1-5)-alkyl-amino; [0175] b) a fused aryl selected from
the group consisting of benzocyclobutanyl, indanyl, indenyl,
dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and
benzocycloheptenyl, or a fused heterocyclyl selected from the group
consisting of cyclopentenopyridine, cyclohexanopyridine,
cyclopentanopyrimidine, cyclohexanopyrimidine,
cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine,
cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline,
cyclopentanoisoquinoline, cyclohexanoisoquinoline,
cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole,
cyclohexanobenzimidazole, cyclopentanobenzoxazole,
cyclohexanobenzoxazole, cyclopentanoimidazole,
cyclohexanoimidazole, cyclopentanothiophene and
cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl
ring is substituted with 0 to 3 groups independently selected from
the group consisting of phenyl, naphthyl and heterocyclyl selected
from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl,
pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,
isoxazolyl, and isothiazolyl, C.sub.1-6 branched or unbranched
alkyl which is optionally partially or fully halogenated, halogen,
nitrile, C.sub.1-3 alkoxy which is optionally partially or fully
halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the
heterocyclyl moiety is selected from the group hereinabove
described, nitro, amino, mono- or di-(C.sub.1-3)alkylamino,
phenylamino, naphthylamino, heterocyclylamino wherein the
heterocyclyl moiety is selected from the group hereinabove
described, NH.sub.2C(O), a mono- or di-(C.sub.1-3)alkyl
aminocarbonyl, C.sub.1-4 alkyl-OC(O), C.sub.1-5
alkyl-C(O)--C.sub.1-4 branched or unbranched alkyl, an
amino-C.sub.1-5 alkyl, mono- or di-(C.sub.1-3)alkylamino-C.sub.1-5
alkyl, R.sub.9--C.sub.1-5 alkyl, R.sub.10--C.sub.1-5 alkoxy,
R.sub.11--C(O)--C.sub.1-5 alkyl and R.sub.12--C.sub.1-5
alkyl(R.sub.13)N; [0176] c) cycloalkyl selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, wherein
the cycloalkyl is optionally partially or fully halogenated and
optionally substituted with one to three C.sub.1-3 alkyl groups;
[0177] d) C.sub.5-7 cycloalkenyl selected from the group consisting
of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,
cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such
cycloalkenyl group is optionally substituted with one to three
C.sub.1-3 alkyl groups; [0178] e) acetyl, aroyl,
C.sub.1-6alkoxycarbonylC.sub.1-6alkyl or phenylsulfonyl; or [0179]
f) C.sub.1-6 branched or unbranched alkyl optionally partially or
fully halogenated; or R.sub.1 and R.sub.2 taken together optionally
form a fused phenyl or pyridinyl ring; [0180] each R.sub.8 and
R.sub.13 is independently selected from the group consisting of:
hydrogen and C.sub.1-4 branched or unbranched alkyl optionally
partially or fully halogenated; [0181] each R.sub.4, R.sub.5,
R.sub.6, R.sub.7, R.sub.9, R.sub.10, R.sub.11 and R.sub.12 is
independently selected from the group consisting of morpholine,
piperidine, piperazine, imidazole and tetrazole; [0182] m is 0, 1
or 2; [0183] W is O or S; wherein X is directly attached to one or
two --Y-Z, and the pharmaceutically acceptable derivatives
thereof.
[0184] A preferred subgeneric aspect of the invention comprises a
method of using the compounds of the formula (Ia) as provided above
and wherein: [0185] Ar.sub.2 is naphthyl, tetrahydronaphthyl,
indanyl or indenyl and [0186] W is O.
[0187] A more preferred subgeneric aspect of the invention
comprises a method of using the compounds of the formula (Ia) as
provided above and wherein: [0188] Ar.sub.1 is thiophene or
pyrazole each substituted independently by one to three R.sub.1,
R.sub.2 or R.sub.3; [0189] X is: a C.sub.5-7 cycloalkyl or
cycloalkenyl optionally substituted with one to two oxo groups or
one to three C.sub.1-4 alkyl, C.sub.1-4 alkoxy or C.sub.1-4
alkylamino chains each being branched or unbranched; phenyl,
indanyl, furanyl, thienyl, imidazolyl, pyridinyl, pyrazinyl,
tetrahydrapyridinyl, pyrimidinyl, pyridinonyl, piperdinyl,
benzimidazole or piperazinyl; each being optionally independently
substituted with one to three C.sub.1-4 alkyl, C.sub.1-4alkoxy,
hydroxy, nitrile, amino, mono- or di-(C.sub.1-3 alkyl)amino, mono-
or di-(C.sub.1-3 alkylamino)carbonyl, NH.sub.2C(O), C.sub.1-6
alkyl-S(O).sub.m or halogen; [0190] Y is: a bond or a C.sub.1-4
saturated or unsaturated branched or unbranched carbon chain
optionally partially or fully halogenated, wherein one or more C
atoms are optionally replaced by O or N, and wherein Y is
optionally independently substituted with one to two oxo groups,
nitrile, phenyl, hydroxy or one or more C.sub.1-4 alkyl optionally
substituted by one or more halogen atoms; [0191] Z is: phenyl,
heteroaryl selected from pyridinyl, imidazolyl, furanyl and
thienyl, heterocycle selected from piperazinyl,
2-oxa-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl,
pentamethylene sulfoxidyl, pentamethylene sulfonyl,
tetrahydrofuranyl, morpholino, thiomorpholino and piperidinyl, each
of the aforementioned Z are optionally substituted with one to
three halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-3
alkoxy-C.sub.1-3 alkyl, C.sub.1-6 alkoxycarbonyl, aroyl,
morpholinocarbonyl, C.sub.1-3acyl, oxo, hydroxy,
pyridinyl-C.sub.1-3 alkyl, imidazolyl-C.sub.1-3 alkyl,
tetrahydrofuranyl-C.sub.1-3 alkyl, nitrile-C.sub.1-3 alkyl,
nitrile, carboxy, phenyl wherein the phenyl ring is optionally
substituted with one to two halogen, C.sub.1-6 alkoxy, hydroxy or
mono- or di-(C.sub.1-3 alkyl)amino, amino-S(O).sub.m, C.sub.1-6
alkyl-S(O).sub.m or phenyl-S(O).sub.m wherein the phenyl ring is
optionally substituted with one to two halogen, C.sub.1-6 alkoxy,
hydroxy, halogen or mono- or di-(C.sub.1-3 alkyl)amino; or Z is
optionally substituted with one to three amino, aminocarbonyl or
amino-C.sub.1-3 alkyl wherein the N atom is optionally
independently mono- or di-substituted by aminoC.sub.1-6alkyl,
C.sub.1-3alkyl, arylC.sub.0-3alkyl, C.sub.1-5 alkoxyC.sub.1-3
alkyl, C.sub.1-5 alkoxy, aroyl, C.sub.1-3acyl,
C.sub.1-3alkyl-S(O).sub.m-- or arylC.sub.0-3alkyl-S(O).sub.m-- each
of the aforementioned alkyl and aryl attached to the amino group
are optionally substituted with one to two halogen, C.sub.1-6 alkyl
or C.sub.1-6 alkoxy; 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.sub.1-6 alkyl or C.sub.1-6 alkoxy; or Z is hydroxy,
hydroxyC.sub.1-3alkyl, halogen, nitrile, amino wherein the N atom
is optionally independently mono- or di-substituted by aroyl,
C.sub.1-3acyl, C.sub.1-6alkyl, C.sub.1-5 alkoxyC.sub.1-3 alkyl,
pyridinylC.sub.1-3alkyl, tetrahydrafuranylC.sub.1-3alkyl,
nitrileC.sub.1-4alkyl or phenyl wherein the phenyl ring is
optionally substituted with one to two halogen, C.sub.1-6 alkoxy,
hydroxy or mono- or di-(C.sub.1-3 alkyl)amino, or Z is
C.sub.1-6alkyl branched or unbranched, C.sub.1-6alkoxy or
nitrileC.sub.1-4alkyl; [0192] R.sub.1 is: C.sub.1-4 branched or
unbranched alkyl optionally partially or fully halogenated;
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl
optionally partially or fully halogenated and optionally
substituted with one to three C.sub.1-3 alkyl groups, or an 30
analog of such cycloalkyl group wherein one to three ring methylene
groups are replaced by groups independently selected from the group
consisting of O, S and NH; C.sub.3-10 branched alkenyl optionally
partially or fully halogenated and optionally substituted with one
to three C.sub.1-5 branched or unbranched alkyl; cyclopentenyl and
cyclohexenyl optionally substituted with one to three C.sub.1-3
alkyl groups; [0193] R.sub.2 is: a C.sub.1-6 branched or unbranched
alkyl optionally partially or fully halogenated and optionally
substituted with nitrile; [0194] R.sub.3 is: phenyl or heterocyclic
group selected from the group consisting of pyridinyl, pyrimidinyl,
pyrazinyl, pyridazinyl and pyrazolyl, wherein such phenyl or
heterocyclic group is optionally substituted with one to five
groups selected from the group consisting of a phenyl, heterocycle
selected from the group hereinabove described in this paragraph,
C.sub.1-6 branched or unbranched alkyl which is optionally
partially or fully halogenated, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl,
bicycloheptyl, phenyl C.sub.1-5 alkyl, naphthyl C.sub.1-5 alkyl,
halogen, hydroxy, oxo, nitrile, C.sub.1-3 alkoxy optionally be
partially or fully halogenated, C.sub.1-3 alkoxyC.sub.1-5alkyl,
C.sub.1-3thioalkyl, C.sub.1-3thioalkylC.sub.1-5alkyl, phenyloxy,
naphthyloxy, heteraryloxy wherein the heterocyclic moiety is
selected from the group hereinabove described in this paragraph,
nitro, amino, mono- or di-(C.sub.1-3)alkylamino, phenylamino,
naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is
selected from the group hereinabove described in this paragraph,
NH.sub.2C(O), a mono- or di-(C.sub.1-3)alkyl aminocarbonyl,
C.sub.1-5 alkyl-C(O)--C.sub.1-4 alkyl, amino-C.sub.1-5 alkyl, mono-
or di-(C.sub.1-3)alkylamino-C.sub.1-5 alkyl, amino-S(O).sub.2,
di-(C.sub.1-3)alkylamino-S(O).sub.2, R.sub.4--C.sub.1-5 alkyl,
R.sub.5--C.sub.1-5 alkoxy, R.sub.6--C(O)--C.sub.1-5 alkyl and
R.sub.7--C.sub.1-5 alkyl(R.sub.8)N, carboxy-mono- or
di-(C.sub.1-5)-alkyl-amino; a fused aryl selected from the group
consisting of benzocyclobutanyl, indanyl, indenyl; wherein the
fused aryl is substituted with 0 to 3 groups independently selected
from the group consisting of phenyl, naphthyl and heterocyclyl
selected from the group consisting of pyridinyl, pyrimidinyl,
pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl,
furyl, isoxazolyl, and isothiazolyl, C.sub.1-6 branched or
unbranched alkyl which is optionally partially or fully
halogenated, halogen, nitrile, C.sub.1-3 alkoxy which is optionally
partially or fully halogenated, phenyloxy, naphthyloxy,
heterocyclyloxy wherein the heterocyclyl moiety is selected from
the group hereinabove described in this paragraph, nitro, amino,
mono- or di-(C.sub.1-3)alkylamino, phenylamino, naphthylamino,
heterocyclylamino wherein the heterocyclyl moiety is selected from
the group hereinabove described in this paragraph, NH.sub.2C(O), a
mono- or di-(C.sub.1-3)alkyl aminocarbonyl, C.sub.1-4 alkyl-OC(O),
C.sub.1-5 alkyl-C(O)--C.sub.1-4 branched or unbranched alkyl, an
amino-C.sub.1-5 alkyl, mono- or di-(C.sub.1-3)alkylamino-C.sub.1-5
alkyl, R.sub.9--C.sub.1-5 alkyl, R.sub.10--C.sub.1-5 alkoxy,
R.sub.11--C(O)--C.sub.1-5 alkyl and
R.sub.12--C.sub.1-5alkyl(R.sub.13)N; cycloalkyl selected from the
group consisting of cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, wherein the cycloalkyl is optionally
partially or fully halogenated and optionally substituted with one
to three C.sub.1-3 alkyl groups;
C.sub.1-6alkoxycarbonylC.sub.1-6alkyl; or R.sub.1 and R.sub.2 taken
together optionally form a fused phenyl or pyridinyl ring; [0195]
each R.sub.8 and R.sub.13 is independently selected from the group
consisting of: hydrogen and C.sub.1-4 branched or unbranched alkyl
optionally partially or fully halogenated; and [0196] each R.sub.4,
R.sub.5, R.sub.6, R.sub.7, R.sub.9, R.sub.10, R.sub.11 and R.sub.12
is independently selected from the group consisting of morpholine,
piperidine, piperazine, imidazole and tetrazole; wherein X is
directly attached to one --Y-Z. [0197] A yet more preferred
subgeneric aspect of the invention comprises a method of using the
compounds of the formula (Ia), as described in the immediate
previous paragraph, wherein: [0198] Ar.sub.1 is pyrazole; [0199] X
is: cyclopentenyl, cyclohexenyl, cycloheptenyl, optionally
substituted with an oxo group or one to three C.sub.1-4 alkyl,
C.sub.1-4 alkoxy or C.sub.1-4 alkylamino chains each being branched
or unbranched; phenyl, furanyl, thienyl, pyridinyl, pyrazinyl
piperidinyl or pyrimidinyl each being optionally independently
substituted with one to three C.sub.1-2 alkyl, C.sub.1-2alkoxy,
hydroxy or halogen; [0200] Z is: phenyl, heteroaryl selected from
pyridinyl, imidazolyl and furanyl, heterocycle selected from
2-oxa-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl,
pentamethylene sulfoxidyl, pentamethylene sulfonyl,
tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholino,
thiomorpholino, thiomorpholino sulfoxide and piperidinyl, each of
the aforementioned Z are optionally substituted with one to three
halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-3
alkoxy-C.sub.1-3 alkyl, C.sub.1-6 alkoxycarbonyl, aroyl,
morpholinocarbonyl, C.sub.1-3acyl, oxo, hydroxy,
pyridinyl-C.sub.1-3 alkyl, imidazolyl-C.sub.1-3 alkyl,
tetrahydrofuranyl-C.sub.1-3 alkyl, nitrile-C.sub.1-3 alkyl,
nitrile, carboxy, phenyl wherein the phenyl ring is optionally
substituted with one to two halogen, C.sub.1-6 alkoxy, hydroxy or
mono- or di-(C.sub.1-3 alkyl)amino, amino-S(O).sub.m, C.sub.1-6
alkyl-S(O).sub.m, or phenyl-S(O).sub.m wherein the phenyl ring is
optionally substituted with one to two halogen, C.sub.1-6 alkoxy,
hydroxy, halogen or mono- or di-(C.sub.1-3 alkyl)amino; or Z is
optionally substituted with one to three amino, aminocarbonyl or
amino-C.sub.1-3 alkyl wherein the N atom is optionally
independently mono- or di-substituted by aminoC.sub.1-6alkyl,
C.sub.1-3alkyl, arylC.sub.0-3alkyl, C.sub.1-5 alkoxyC.sub.1-3
alkyl, C.sub.1-5 alkoxy, aroyl, C.sub.1-3acyl,
C.sup.1-3alkyl-S(O).sub.m--, pyridinylC.sub.0-3alkyl,
tetrahydrafuranylC.sub.0-3alkyl, or arylC.sub.0-3alkyl-S(O).sub.m--
each of the aforementioned alkyl and aryl attached to the amino
group is optionally substituted with one to two halogen, C.sub.1-6
alkyl or C.sub.1-6 alkoxy; or Z is hydroxy, hydroxyc.sub.1-3alkyl,
halogen, nitrile, amino wherein the N atom is optionally
independently mono- or di-substituted by C.sub.1-6alkyl,
pyridinylC.sub.0-3alkyl, tetrahydrafuranylC.sub.0-3alkyl, C.sub.1-5
alkoxyC.sub.1-3 alkyl, C.sub.1-3acyl, nitrileC.sub.1-4alkyl or
phenyl wherein the phenyl ring is optionally substituted with one
to two halogen, C.sub.1-6 alkoxy, hydroxy or mono- or di-(C.sub.1-3
alkyl)amino, or Z is C.sub.1-6alkyl branched or unbranched,
C.sub.1-6alkoxy or nitrileC.sub.1-4alkyl; [0201] R.sub.1 is:
C.sub.1-4 branched or unbranched alkyl optionally partially or
fully halogenated; cyclopropyl, cyclobutyl, cyclopentanyl,
cyclohexanyl and cycloheptanyl optionally partially or fully
halogenated and optionally substituted with one to three C.sub.1-3
alkyl groups, or an analog of such cycloalkyl group wherein one to
three ring methylene groups are replaced by groups independently
selected from the group consisting of O, S and NH; C.sub.3-10
branched alkenyl optionally partially or fully halogenated and
optionally substituted with one to three C.sub.1-3 branched or
unbranched alkyl; cyclopentenyl and cyclohexenyl optionally
substituted with one to three C.sub.1-3 alkyl groups; [0202]
R.sub.2 is: a C.sub.1-6 branched or unbranched alkyl optionally
partially or fully halogenated and optionally substituted with
nitrile; [0203] R.sub.3 is: phenyl or heterocyclic group selected
from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl
and pyrazolyl, wherein such phenyl or heterocyclic group is
optionally substituted with one to five groups selected from the
group consisting of a phenyl, heterocycle selected from the group
hereinabove described in this paragraph, C.sub.1-6 branched or
unbranched alkyl which is optionally partially or fully
halogenated, phenyl C.sub.1-5 alkyl, halogen, hydroxy, oxo,
nitrile, C.sub.1-3 alkoxy optionally partially or fully
halogenated, C.sub.1-3thioalkyl, C.sub.1-3thioalkylC.sub.1-5alkyl,
amino, mono- or di-(C.sub.1-3)alkylamino, NH.sub.2C(O) or a mono-
or di-(C.sub.1-3)alkyl aminocarbonyl,
C.sub.1-6alkoxycarbonylC.sub.1-6alkyl; or R.sub.3 is cyclopropyl or
cyclopentyl each optionally partially or fully halogenated and
optionally substituted with one to three C.sub.1-3 alkyl groups or
R.sub.1 and R.sub.2 taken together optionally form a fused phenyl
or pyridinyl ring.
[0204] A yet further preferred subgeneric aspect of the invention
comprises a method of using the compounds of the formula (Ia), as
described in the immediate previous paragraph, and wherein: [0205]
Y is --CH.sub.2--, --O--(CH.sub.2).sub.0-3--, --CH.sub.2CH.sub.2--,
--CH.sub.2NH--, --CH.sub.2CH.sub.2--NH--, NH--CH.sub.2CH.sub.2--,
--CH.sub.2--NH--CH.sub.2--, --NH--, --NH--C(O)--, --C(O)--,
--CH(OH)--, --CH.sub.2(CH.sub.2CH.sub.3)-- or a bond; [0206] X is:
cyclohexenyl optionally substituted with an oxo group or one to
three C.sub.1-4 alkyl, C.sub.1-4 alkoxy or C.sub.1-4 alkylamino
chains each being branched or unbranched; phenyl, pyridinyl,
pyrazinyl, piperidinyl or pyrimidinyl each being optionally
independently substituted with one to three C.sub.1-2 alkyl,
C.sub.1-2alkoxy, hydroxy or halogen; [0207] Z is: phenyl,
heteroaryl selected from pyridinyl, imidazolyl and furanyl,
heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1]heptanyl,
pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene
sulfonyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl,
morpholino, thiomorpholino, thiomorpholino sulfoxide and
piperidinyl, each of the aforementioned Z are optionally
substituted with one to three halogen, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, C.sub.1-3 alkoxy-C.sub.1-3 alkyl, C.sub.1-6 alkoxycarbonyl,
aroyl, morpholinocarbonyl, C.sub.1-3acyl, oxo, hydroxy,
pyridinyl-C.sub.1-3 alkyl, imidazolyl-C.sub.1-3 alkyl,
tetrahydrofuranyl-C.sub.1-3 alkyl, nitrile-C.sub.1-3 alkyl,
nitrile, carboxy, phenyl wherein the phenyl ring is optionally
substituted with one to two halogen, C.sub.1-6 alkoxy, hydroxy or
mono- or di-(C.sub.1-3 alkyl)amino, amino-S(O).sub.m, C.sub.1-6
alkyl-S(O).sub.m, or phenyl-S(O).sub.m wherein the phenyl ring is
optionally substituted with one to two halogen, C.sub.1-6 alkoxy,
hydroxy, halogen or mono- or di-(C.sub.1-3 alkyl)amino; or Z is
optionally substituted with one to three amino or aminocarbonyl
wherein the N atom is optionally independently mono- or
di-substituted by aminoC.sub.1-6alkyl, C.sub.1-3alkyl,
arylC.sub.0-3alkyl, C.sub.1-5 alkoxyC.sub.1-3 alkyl, C.sub.1-5
alkoxy, aroyl, C.sub.1-3acyl, C.sub.1-3alkyl-S(O).sub.m-- or
arylC.sub.0-3alkyl-S(O).sub.m-- each of the aforementioned alkyl
and aryl attached to the amino group is optionally substituted with
one to two halogen, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; or Z is
hydroxy, hydroxyC.sub.1-3alkyl, halogen, nitrile, amino wherein the
N atom is optionally independently mono- or di-substituted by
C.sub.1-3alkyl, pyridinylC.sub.1-2alkyl,
tetrahydrafuranylC.sub.1-2alkyl, C.sub.1-3 alkoxyC.sub.1-3 alkyl,
C.sub.1-3acyl, nitrileC.sub.1-4alkyl, phenyl wherein the phenyl
ring is optionally substituted with one to two halogen, C.sub.1-6
alkoxy, hydroxy or mono- or di-(C.sub.1-3 alkyl)amino, or Z is
C.sub.1-6alkyl branched or unbranched, C.sub.1-6alkoxy or
nitrileC.sub.1-4alkyl; [0208] R.sub.1 is: C.sub.1-4 branched or
unbranched alkyl optionally partially or fully halogenated; [0209]
R.sub.2 is: a C.sub.1-3 branched or unbranched alkyl optionally
partially or fully halogenated and optionally substituted with
nitrile; [0210] R.sub.3 is: phenyl or heterocyclic group selected
from the group consisting of pyridinyl, pyrimidinyl, and pyrazolyl,
wherein such phenyl or heterocyclic group is optionally substituted
with one to five groups selected from the group consisting of
C.sub.1-3 branched or unbranched alkyl which is optionally
partially or fully halogenated, C.sub.1-3 alkoxy which optionally
partially or fully halogenated, C.sub.1-3thioalkyl,
C.sub.1-3thioalkylC.sub.1-5alkyl, amino or NH.sub.2C(O);
C.sub.1-3alkoxycarbonyl; or R.sub.3 is cyclopropyl or cyclopentyl
each optionally partially or fully halogenated and optionally
substituted with one to three C.sub.1-3 alkyl groups.
[0211] A further preferred subgeneric aspect of the invention
comprises a method of using the compounds of the formula (Ia), as
described in the immediate previous paragraph, and wherein: [0212]
Ar.sub.1 is 5-tert-butyl-pyrazol-3-yl; wherein the pyrazole ring is
substituted independently by one to two R.sub.2 or R.sub.3; [0213]
X is: cyclohexenyl; phenyl, pyridinyl, pyrazinyl, piperidinyl or
pyrimidinyl each being optionally independently substituted with
C.sub.1-2alkoxy or hydroxy; [0214] Z is: phenyl, heteroaryl
selected from pyridinyl and furanyl, heterocycle selected from
2-oxa-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl,
pentamethylene sulfoxidyl, tetrahydrofuranyl, piperazinyl,
morpholino, thiomorpholino and piperidinyl, each of the
aforementioned Z are optionally substituted with one to three
C.sub.1-3 alkyl, C.sub.1-3 alkoxy, oxo, hydroxy or NH.sub.2C(O)--;
or Z is hydroxyc.sub.1-3alkyl, amino wherein the N atom is
optionally independently mono- or di-substituted by
pyridinylmethyl, tetrahydrafuranylmethyl, C.sub.1-3 alkoxyC.sub.1-3
alkyl, C.sub.1-3acyl or nitrileC.sub.1-4alkyl, or Z is
nitrileC.sub.1-4alkyl; [0215] R.sub.3 is: phenyl or heterocyclic
group selected from the group consisting of pyridinyl, pyrimidinyl,
and pyrazolyl, wherein such phenyl or heterocyclic group is
optionally substituted with one to two groups selected from the
group consisting of C.sub.1-2 alkyl which is optionally partially
or fully halogenated, C.sub.1-2 alkoxy which optionally partially
or fully halogenated, C.sub.1-2thioalkyl,
C.sub.1-2thioalkylC.sub.1-3alkyl, amino or NH.sub.2C(O);
C.sub.1-3alkoxycarbonyl; or R.sub.3 is cyclopropyl or cyclopentyl
each optionally partially or fully halogenated and optionally
substituted with one to three C.sub.1-3 alkyl groups.
[0216] A still yet further preferred subgeneric aspect of the
invention comprises a method of using the compounds of the formula
(Ia), as described in the immediate previous paragraph, and wherein
X is pyridinyl.
[0217] A still yet further preferred subgeneric aspect of the
invention comprises a method of using the compounds of the formula
(Ia), as described in the immediate previous paragraph, and
wherein:
the pyridinyl is attached to Ar.sub.1 via the 3-pyridinyl
position.
[0218] The following compounds are representative of the compounds
of formula (Ia) which are useful in the novel methods described
herein: [0219]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-yl-
-methylphenyl)-naphthalen-1-yl]-urea; [0220]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[3-(4-morpholin-4-yl-methylp-
henyl)-naphthalen-1-yl]-urea; [0221]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-yl-methylf-
uran-2-yl)- naphthalen-1-yl]-urea; [0222]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl-
)cyclohexenyl)-naphthalen-1-yl]-urea; [0223]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(4-morpholin-4-yl)ethy-
lphenyl)-naphthalen-1-yl]-urea; [0224]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-dimethylaminomethylphe-
nyl)-naphthalen-1-yl]-urea; [0225]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-methyl-
)pyridin-2-yl)-naphthalen-1-yl]-urea; [0226]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl-
)pyridin-3-yl)- naphthalen-1-yl]-urea; [0227]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morph-
olin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea; [0228]
1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)-
pyridin-3-yl)-naphthalen-1-yl]-urea; [0229]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(mo-
rpholin-4-yl)ethylamino)cyclohexenyl)-naphthalen-1-yl]-urea; [0230]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3,4-(morpholin-4-yl-meth-
yl)phenyl)-naphthalen-1-yl]-urea; [0231]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-methylpiperzin-1-yl-me-
thyl)phenyl)- naphthalen-1-yl]-urea; [0232]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(piperdin-1-yl-methyl)phe-
nyl)-naphthalen-1-yl]-urea; [0233]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(py-
ridin-2-yl)ethylamino)cyclohexenyl)-naphthalen-1-yl]-urea;
[0234]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(pyridin-4-y-
l)ethylaminomethyl)phenyl)naphthalen-1-yl]-urea; [0235]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(pyridin-3-yl-methylam-
inomethyl)phenyl)naphthalen-1-yl]-urea; [0236]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3,4-d-
imethoxyphenylmethyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea; [0237]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-oxo-1,6-dihydro-pyridi-
n-3-yl)naphthalen-1-yl]-urea; [0238]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morph-
olin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea; [0239]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morph-
olin-4-yl-methyl)imidazol-1-yl)naphthalen-1-yl]-urea; [0240]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl-
)imidazol-1-yl)naphthalen-1-yl]-urea; [0241]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-
-3-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea; [0242]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4-hyd-
roxybutylamino)pyridin-3-yl)-naphthalen-1-yl]-urea; [0243]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(pyrid-
in-3-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea; [0244]
1-[5-tert-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(6-(m-
orpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0245]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(imida-
zol-2-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea; [0246]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3-hyd-
roxymorpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea; [0247]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-2-m-
ethoxyethy-N-methylaminomethyl)phenyl)naphthalen-1-yl]-urea; [0248]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(4-hyd-
roxymorpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea; [0249]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(morph-
olin-4-yl-methyl)cyclohexenyl)-naphthalen-1-yl]-urea; [0250]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(tetra-
hydrofuran-3-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;
[0251]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-d-
i-(2-methoxyethyl)aminomethyl)phenyl)naphthalen-1-yl]-urea; [0252]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(3-cya-
nopropoxy)pyridin-3-yl)naphthalen-1-yl]-urea; [0253]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-morpho-
lin-4-yl-methyl-piperdinyl)naphthalen-1-yl]-urea; [0254]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-d-
i-(2-cyanoethyl)aminomethyl)phenyl)naphthalen-1-yl]-urea; [0255]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(1-morpholin-4-yl-indan-5-
-yl)-naphthalen-1-yl]-urea; [0256]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-
-2-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea; [0257]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(thiom-
orpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea; [0258]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3-car-
boxamidomorpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea; [0259]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(2-met-
hyl-3-oxo-piperzin-1-yl-methyl)phenyl)naphthalen-1-yl]-urea; [0260]
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morp-
holin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0261]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4-hyd-
roxybutyloxy)pyridin-3-yl)-naphthalen-1-yl]-urea; [0262]
1-[3-tert-butyl-1'H-[1,4']bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)-
pyridin-3-yl)naphthalen-1-yl]-urea; [0263]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-
-2-yl-methyl)-3-methoxyphenyl)naphthalen-1-yl]-urea; [0264]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(morph-
olin-4carbonyl)pyrazin-2-yl)naphthalen-1-yl]-urea; [0265]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetra-
hydrothiopyran-4-yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
[0266]
1-[5-tert-butyl-2-(2-cyanoethyl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-
-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea; [0267]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2,6-d-
imethylmorpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
[0268]
1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morph-
olin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea; [0269]
1-[5-tert-butyl-2-(2-aminoypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpho-
lin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea; [0270]
1-[5-tert-butyl-2-(6-oxo-1,6-dihydropyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(-
6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
[0271]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morph-
olin-4-yl-4-carbonyl)pyridin-3-yl)-naphthalen-1-yl]-urea; [0272]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2-oxa-
-5-aza-bicyclo[2.2.1]hept-5-yl-methyl)pyridin-3-yl)-
naphthalen-1-yl]-urea; [0273]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(3-carbamylphenyl)naph-
thalen-1-yl]-urea; [0274]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2--
cyanoethyl)-N-(pyridin-3-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-ur-
ea; [0275]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2--
cyanoethyl)-N-(pyridin-2-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-ur-
ea; [0276]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2--
cyanoethyl)-N-(tetrahydrofuran-2-yl-methyl)aminomethyl)phenyl)-naphthalen--
1-yl]-urea; [0277]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morph-
olin-4-yl-methyl)-4-methoxypyridin-3-yl)-naphthalen-1-yl]-urea;
[0278]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-mor-
pholin-4-yl-propyl)pyridin-3-yl)-naphthalen-1-yl]-urea; [0279]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(N-(3--
methoxypropyl)amino)pyridin-3-yl)-naphthalen-1-yl]-urea; [0280]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(N-(3--
methoxypropyl)-N-methylamino)pyridin-3-yl)-naphthalen-1-yl]-urea;
[0281]
1-[3-tert-butyl-1'-methyl-1'H-[1,4']bipyrazol-5-yl]-3-[4-(6-(morpholin-4--
yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0282]
1-[5-tert-butyl-2-benzyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)-
pyridin-3-yl)-naphthalen-1-yl]-urea; [0283]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-N-d-
i-(2-cyanoethyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea; [0284]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(4-carbamylphenyl)naph-
thalen-1-yl]-urea; [0285]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-
-tetrahydrothiopyran-4yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
[0286]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(-
6-(tetrahydropyran-4yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
[0287]
1-[3-tert-butyl-1'-(3-cyanopropyl)-1'H-[1,4']bipyrazol-5-yl]-3-[4-(6-(mor-
pholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0288]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-methanesulfinylphenyl)-
naphthalen-1-yl]-urea; [0289]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-methanesulfonylphenyl)-
naphthalen-1-yl]-urea; [0290]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-sulfonamidophenyl)naph-
thalen-1-yl]-urea; [0291]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)carbon-
ylphenyl)naphthalen-1-yl]-urea; [0292]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(tetra-
hydrothiopyran-4yl-amino)pyrazin-2-yl)-naphthalen-1-yl]-urea;
[0293]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(methy-
lcarbonylamino)pyridin-3-yl)-naphthalen-1-yl]-urea; [0294]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-4-carb-
onyl)phenyl) -naphthalen-1-yl]-urea; [0295]
1-[3-tert-butyl-1'-(3-methylsulfanylpropyl)-1'H-[1,4']bipyrazol-5-yl]-3-[-
4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
[0296]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-carbon-
yl)pyridin-3-yl)-naphthalen-1-yl]-urea; [0297]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(morph-
olin-4-yl-methyl)pyrazin-2-yl)-naphthalen-1-yl]-urea; [0298]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-aminop-
yridin-3-yl)naphthalen-1-yl]-urea; [0299]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-met-
hylpiperdin-4-yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea; [0300]
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2-me-
thyl-3-oxo-piperzin-1-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
[0301]
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4--
(6-(morpholin-4-yl-carbonyl)pyridin-3-yl)naphthalen-1-yl]-urea;
[0302]
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(N,N--
di-(2-methoxyethyl)aminomethyl)pyridin-3-yl)naphthalen-1-yl]-urea;
[0303]
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-o-
xo-thiomorpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
[0304]
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetr-
ahydropyran-4-yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea; [0305]
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(5-(morp-
holin-4-yl-methyl)pyrazin-2-yl)naphthalen-1-yl]-urea; [0306]
1-[5-tert-butyl-2-(2-methylthiopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(-
morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0307]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(2-methyl-3-oxo-piperz-
in-1-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0308]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-oxy)pyri-
din-3-yl)naphthalen-1-yl]-urea [0309]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-amino)py-
ridin-3-yl)naphthalen-1-yl]-urea; [0310]
1-[5-tert-butyl-2-(2-methoxypyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(mor-
pholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0311]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-carbamylpyridin-3-yl)n-
aphthalen-1-yl]-urea; [0312]
1-[5-tert-butyl-2-(2-aminopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morph-
olin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0313]
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morp-
holin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea; [0314]
1-[3-tert-butyl-1'-methyl-1'H-[1,4']bipyrazol-5-yl]-3-[4-(6-(morpholin-4--
yl-methyl)phenyl)naphthalen-1-yl]-urea; [0315]
1-[5-tert-butyl-2-(2-cyclopropylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6--
(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0316]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(pyridin-3-yl-amino)py-
rimidin-5-yl)naphthalen-1-yl]-urea; [0317]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-tetrahydrothiop-
yran-4-yl- amino)pyridin-3-yl)naphthalen-1-yl]-urea; [0318]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(thiomorpholin-4-yl-me-
thyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0319]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-benzyl-3H-imidazo[4,5--
b]pyridin-6-yl)naphthalen-1-yl]-urea; [0320]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(pyrid-
in-3-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0321]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-carbon-
yl)pyrimidin-5-yl)naphthalen-1-yl]-urea; [0322]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-methyl-
)pyrimidin-5-yl)naphthalen-1-yl]-urea; [0323]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-amino-4-carbamylphenyl-
)naphthalen-1-yl]-urea; [0324]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-
-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0325]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-methyl)p-
yridin-3-yl)naphthalen-1-yl]-urea; [0326]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(hydroxy-pyridin-3-yl--
methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0327]
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(morp-
holin-4-yl-methyl)pyrimidin-5-yl)naphthalen-1-yl]-urea; and the
pharmaceutically acceptable derivatives thereof.
[0328] In another embodiment of the invention there are provided
the following compounds of formula (Ia) which are useful in the
novel methods described herein: [0329]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-methyl-
)pyridin-2-yl)-naphthalen-1-yl]-urea; [0330]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl-
)pyridin-3-yl)-naphthalen-1-yl]-urea; [0331]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(py-
ridin-2-yl)ethylamino)cyclohexenyl)-naphthalen-1-yl]-urea; [0332]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(pyridin-3-yl-methylam-
inomethyl)phenyl)naphthalen-1-yl]-urea; [0333]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morph-
olin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea; [0334]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4-hyd-
roxybutylamino)pyridin-3-yl)-naphthalen-1-yl]-urea; [0335]
1-[5-tert-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(6-(m-
orpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0336]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3-hyd-
roxypiperidin-1-yl-methyl)phenyl)naphthalen-1-yl]-urea; [0337]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(4-hyd-
roxymorpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea; [0338]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(morph-
olin-4-yl-methyl)cyclohexenyl)-naphthalen-1-yl]-urea; [0339]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(tetra-
hydrofuran-3-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;
[0340]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-d-
i-(2-methoxyethyl)aminomethyl)phenyl)naphthalen-1-yl]-urea; [0341]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(3-cya-
nopropoxy)pyridin-3-yl)naphthalen-1-yl]-urea; [0342]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-morpho-
lin-4-yl-methyl-piperdinyl)naphthalen-1-yl]-urea; [0343]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-d-
i-(2-45 cyanoethyl)aminomethyl)phenyl)naphthalen-1-yl]-urea; [0344]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-
-2-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea; [0345]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(thiom-
orpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea; [0346]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3-car-
boxamidopiperidin-1-yl-methyl)phenyl)naphthalen-1-yl]-urea; [0347]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(2-met-
hyl-3-oxo-piperzin-1-yl-methyl)phenyl)naphthalen-1-yl]-urea; [0348]
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morp-
holin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0349]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4-hyd-
roxybutyloxy)pyridin-3-yl)-naphthalen-1-yl]-urea; [0350]
1-[3-tert-butyl-1'H-[1,4']bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)-
pyridin-3-yl)naphthalen-1-yl]-urea; [0351]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetra-
hydrothiopyran-4-yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
[0352]
1-[5-tert-butyl-2-(2-cyanoethyl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-
-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea; [0353]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2,6-d-
imethylmorpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
[0354]
1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morph-
olin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea; [0355]
1-[5-tert-butyl-2-(2-aminoypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpho-
lin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea; [0356]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morph-
olin-4-yl-4-carbonyl)pyridin-3-yl)-naphthalen-1-yl]-urea; [0357]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2-oxa-
-5-aza-bicyclo[2.2.1]hept-5-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
[0358]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4--
(4-(N-(2-cyanoethyl)
-N-(pyridin-3-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;
[0359]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(-
4-(N-(2-cyanoethyl)-N-(tetrahydrofuran-2-yl-methyl)aminomethyl)phenyl)-nap-
hthalen-1-yl]-urea; [0360]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morph-
olin-4-yl-methyl)-4-methoxypyridin-3-yl)-naphthalen-1-yl]-urea;
[0361]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-mor-
pholin-4-yl-propyl)pyridin-3-yl)-naphthalen-1-yl]-urea; [0362]
1-[3-tert-butyl-1'-methyl-1'H-[1,4']bipyrazol-5-yl]-3-[4-(6-(morpholin-4--
yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0363]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-
-tetrahydrothiopyran-4yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
[0364]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(-
6-(tetrahydropyran-4yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
[0365]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(tetra-
hydrothiopyran-4yl-amino)pyrazin-2-yl)-naphthalen-1-yl]-urea;
[0366]
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(methy-
lcarbonylamino)pyridin-3-yl)-naphthalen-1-yl]-urea; [0367]
1-[3-tert-butyl-1'-(3-methylsulfanylpropyl)-1'H-[1,4']bipyrazol-5-yl]-3-[-
4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
[0368]
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-ox-
o-thiomorpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
[0369]
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetr-
ahydropyran-4-yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea; [0370]
1-[5-tert-butyl-2-(2-methylthiopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(-
morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0371]
1-[5-tert-butyl-2-(2-aminopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morph-
olin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0372]
1-[3-tert-butyl-1'-methyl-1'H-[1,4']bipyrazol-5-yl]-3-[4-(6-(morpholin-4--
yl-methyl)phenyl)naphthalen-1-yl]-urea; [0373]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-tetrahydrothiop-
yran-4-yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea; [0374]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(thiomorpholin-4-yl-me-
thyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0375]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-carbon-
yl)pyrimidin-5-yl)naphthalen-1-yl]-urea; [0376]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-methyl-
)pyrimidin-5-yl)naphthalen-1-yl]-urea; [0377]
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-
-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; [0378]
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(morp-
holin-4-yl-methyl)pyrimidin-5-yl)naphthalen-1-yl]-urea and the
pharmaceutically acceptable derivatives thereof.
[0379] In a third broad generic aspect, there is provided a method
of treating a cytokine mediated disease or condition chosen from:
acute and chronic inflammation in the lung caused by inhalation of
smoke, endometriosis, Behcet's disease, uveitis, ankylosing
spondylitis, pancreatitis, cancer, Lyme disease, restenosis
following percutaneous transluminal coronary angioplasty,
Alzheimer's disease, traumatic arthritis, sepsis, chronic
obstructive pulmonary disease and congestive heart failure, said
method comprising administering to a patient in need of such
treatment a therapeutically effective amount of a compound of the
formula (II) disclosed in WO 00/55139 which is the PCT case of U.S.
application Ser. No. 09/505,582: ##STR3## [0380] wherein: [0381] G
is: an aromatic C.sub.6-10 carbocycle or a nonaromatic C.sub.3-10
carbocycle saturated or unsaturated; a 6-10 membered heteroaryl
containing 1 or more heteroatoms chosen from O, N and S; a 5-8
membered monocyclic heterocycle containing one or more heteroatoms
chosen from O, N and S; or an 8-11 membered bicyclic heterocycle,
containing one or more heteroatoms chosen from O, N and S; wherein
G is substituted by one or more R.sub.1, R.sub.2 or R.sub.3; [0382]
Ar is: phenyl, naphthyl, quinolinyl, isoquinolinyl,
tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl,
benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl each
being optionally substituted by one or more R.sub.4 or R.sub.5;
[0383] X is: a C.sub.5-8 cycloalkyl or cycloalkenyl optionally
substituted with one to two oxo groups or one to three C.sub.1-4
alkyl, C.sub.1-4 alkoxy or C.sub.1-4 alkylamino chains; phenyl,
furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl,
pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl,
dihydromaleimidyl, piperdinyl, benzimidazole,
3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl;
[0384] Y is: a bond or a C.sub.1-4 saturated or unsaturated
branched or unbranched carbon chain optionally partially or fully
halogenated, wherein one or more methylene groups are optionally
replaced by O, N, or S(O).sub.m and wherein Y is optionally
independently substituted with one to two oxo groups, phenyl or one
or more C.sub.1-4 alkyl optionally substituted by one or more
halogen atoms; [0385] Z is: phenyl, pyridinyl, pyrimidinyl,
pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl,
tetrazolyl, furanyl, thienyl, pyranyl each being optionally
substituted with one to three halogen, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, hydroxy, amino, mono- or di-(C.sub.1-3 alkyl)amino,
C.sub.1-6 alkyl-S(O).sub.m, CN, CONH.sub.2, COOH or phenylamino
wherein the phenyl ring is optionally substituted with one to two
halogen, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; tetrahydropyranyl,
tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl,
morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl,
thiomorpholino sulfonyl, piperidinyl, piperidinonyl, piperazinyl,
tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl,
pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene
sulfonyl, tetramethylene sulfide, tetramethylene sulfoxidyl or
tetramethylene sulfonyl each being optionally substituted with one
to three nitrile, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy,
amino, mono- or di-(C.sub.1-3 alkyl)amino-C.sub.1-3 alkyl,
CONH.sub.2, phenylamino-C.sub.1-3 alkyl or C.sub.1-3
alkoxy-C.sub.1-3 alkyl; halogen, C.sub.1-4 alkyl, nitrile, amino,
hydroxy, C.sub.1-6 alkoxy, NH.sub.2C(O), mono- or
di(C.sub.1-3alkyl) aminocarbonyl, mono- or di(C.sub.1-6
alkyl)amino, secondary or tertiary amine wherein the amino nitrogen
is covalently bonded to C.sub.1-3 alkyl or C.sub.1-5 alkoxyalkyl,
pyridinyl-C.sub.1-3 alkyl, imidazolyl-C.sub.1-3 alkyl,
tetrahydrofuranyl-C.sub.1-3 alkyl, nitrile-C.sub.1-3 alkyl,
carboxamide-C.sub.1-3 alkyl, phenyl, wherein the phenyl ring is
optionally substituted with one to two halogen, C.sub.1-6 alkoxy,
hydroxy or mono- or di-(C.sub.1-3 alkyl)amino, C.sub.1-6
alkyl-S(O).sub.m, or phenyl-S(O).sub.m, wherein the phenyl ring is
optionally substituted with one to two halogen, C.sub.1-6 alkoxy,
hydroxy, halogen or mono- or di-(C.sub.1-3 alkyl)amino; C.sub.1-6
alkyl-S(O).sub.m, and phenyl-S(O).sub.m, wherein the phenyl ring is
optionally substituted with one to two halogen, C.sub.1-6 alkoxy,
hydroxy or mono- or di-(C.sub.1-3 alkyl)amino; [0386] each R.sub.1
is independently: C.sub.1-10 alkyl optionally be partially or fully
halogenated, and optionally substituted with one to three
C.sub.3-10 cycloalkanyl, hydroxy, phenyl, naphthyl, pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,
pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl; each of the
aforementioned being optionally substituted with one to five groups
selected from halogen, C.sub.1-6 alkyl which is optionally
partially or fully halogenated, C.sub.3-8 cycloalkanyl, C.sub.5-8
cycloalkenyl, hydroxy, nitrile, C.sub.1-3 alkoxy which is
optionally partially or fully halogenated or NH.sub.2C(O), mono- or
di(C.sub.1-3alkyl)amino, and mono- or
di(C.sub.1-3alkyl)aminocarbonyl; cyclopropyloxy, cyclobutyloxy,
cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy each being
optionally partially or fully halogenated and optionally
substituted with one to three C.sub.1-3 alkyl groups optionally
partially or fully halogenated, CN, hydroxyC.sub.1-3alkyl or aryl;
or an analog of such cycloalkyl group wherein one to three ring
methylene groups are independently replaced by O, S(O).sub.m, CHOH,
>C.dbd.O, >C.dbd.S or NH; phenyloxy or benzyloxy each being
optionally partially or fully halogenated and optionally
substituted with one to three C.sub.1-3 alkyl groups optionally
partially or fully halogenated, CN, hydroxyC.sub.1-3alkyl or aryl;
or an analog of such cycloaryl group wherein one to two ring
methyne groups are independently replaced by N; cyclopropanyl,
cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being
optionally partially or fully halogenated and optionally
substituted with one to three C.sub.1-3 alkyl groups optionally
partially or fully halogenated, CN, hydroxyC.sub.1-3alkyl or aryl;
or an analog of such cycloalkyl group wherein one to three ring
methylene groups are independently replaced by O, S(O).sub.m, CHOH,
>C.dbd.O, >C.dbd.S or NH; C.sub.3-10 branched or unbranced
alkenyl each being optionally partially or fully halogenated, and
optionally be substituted with one to three C.sub.1-5 branched or
unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl,
pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl,
furyl, isoxazolyl or isothiazolyl, each of the aforementioned being
substituted with zero to five halogen, C.sub.1-6 alkyl which is
optionally partially or fully halogenated, cyclopropanyl,
cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy,
nitrile, C.sub.1-3 alkyloxy which is optionally partially or fully
halogenated, NH.sub.2C(O), mono- or
di(C.sub.1-3alkyl)aminocarbonyl; the C.sub.3-10 branched or
unbranced alkenyl being optionally interrupted by one or more
heteroatoms chosen from O, N and S(O).sub.m; cyclopentenyl,
cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,
bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group
is optionally substituted with one to three C.sub.1-3 alkyl groups;
nitrile, halogen; methoxycarbonyl, ethoxycarbonyl and
propoxycarbonyl; silyl containing three C.sub.1-4 alkyl groups
optionally partially or fully halogenated; C.sub.3-6 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).sub.m and wherein said alkynyl group is
optionally independently substituted with one to two oxo groups,
pyrrolidinyl, pyrrolyl, one or more C.sub.1-4 alkyl optionally
substituted by one or more halogen atoms, nitrile, morpholino,
piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl,
tetrazolyl, or mono- or di(C.sub.1-3 alkyl)amino optionally
substituted by one or more halogen atoms; each R.sub.2, R.sub.4,
and R.sub.5 is a C.sub.1-6 branched or unbranched alkyl optionally
partially or fully halogenated, acetyl, aroyl, C.sub.1-4 branched
or unbranched alkoxy, each being optionally partially or fully
halogenated, halogen, nitrile, methoxycarbonyl, C.sub.1-3
alkyl-S(O).sub.m optionally partially or fully halogenated, or
phenylsulfonyl; C.sub.1-6 alkoxy, hydroxy, amino, or mono- or
di-(C.sub.1-4 alkyl)amino, nitrile, halogen; OR.sub.6; nitro; or
mono- or di-(C.sub.1-4 alkyl)amino-S(O).sub.2 optionally partially
or fully halogenated, or H.sub.2NSO.sub.2; [0387] each R.sub.3 is
independently: phenyl, naphthyl, morpholinyl, pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl,
imidazolyl, pyrazolyl, thiazolyl, oxazoyl, triazolyl, tetrazolyl,
thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl,
quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,
benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl,
cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl,
quinoxalinyl, quinazolinyl, purinyl or indazolyl, each of the
aforementioned is optionally substituted with one to three phenyl,
naphthyl, heterocycle or heteroaryl as hereinabove described in
this paragraph, C.sub.1-6 branched or unbranched alkyl which is
optionally partially or fully halogenated, cyclopropanyl,
cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C.sub.1-5
alkyl, naphthyl C.sub.1-5 alkyl, halogen, hydroxy, oxo, nitrile,
C.sub.1-3 alkyloxy optionally partially or fully halogenated,
phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein
the heterocyclic or heteroaryl moiety is as hereinabove described
in this paragraph, nitro, amino, mono- or di-(C.sub.1-3alkyl)amino,
phenylamino, naphthylamino, heteroaryl or heterocyclic amino
wherein the heteroaryl heterocyclic moiety is as hereinabove
described in this paragraph, NH.sub.2C(O), a mono- or
di-(C.sub.1-3alkyl) aminocarbonyl, C.sub.1-5 alkyl-C(O)--C.sub.1-4
alkyl, amino-C.sub.1-5 alkyl, mono- or
di-(C.sub.1-3alkyl)amino-C.sub.1-5 alkyl, amino-S(O).sub.2,
di-(C.sub.1-3alkyl)amino-S(O).sub.2, R.sub.7--C.sub.1-5 alkyl,
R.sub.8--C.sub.1-5 alkoxy, R.sub.9--C(O)--C.sub.1-5 alkyl,
R.sub.10--C.sub.1-5 alkyl(R.sub.11)N, carboxy-mono- or
di-(C.sub.1-5alkyl)-amino; a fused aryl selected from
benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl,
tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a
fused heteroaryl selected from cyclopentenopyridinyl,
cyclohexanopyridinyl, cyclopentanopyrimidinyl,
cyclohexanopyrimidinyl, cyclopentanopyrazinyl,
cyclohexanopyrazinyl, cyclopentanopyridazinyl,
cyclohexanopyridazinyl, cyclopentanoquinolinyl,
cyclohexanoquinolinyl, cyclopentanoisoquinolinyl,
cyclohexanoisoquinolinyl, cyclopentanoindolyl, cyclohexanoindolyl,
cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl,
cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl,
cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl
and cyclohexanothienyl; wherein the fused aryl or fused heteroaryl
ring is independently substituted with zero to three phenyl,
naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,
imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl,
C.sub.1-6 alkyl which is optionally partially or fully halogenated,
halogen, nitrile, C.sub.1-3 alkyloxy which is optionally partially
or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or
heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as
hereinabove described in this paragraph, nitro, amino, mono- or
di-(C.sub.1-3alkyl)amino, phenylamino, naphthylamino, heteroaryl or
heterocyclic amino wherein the heteroaryl or heterocyclic moiety is
as hereinabove described in this paragraph, NH.sub.2C(O), mono- or
di-(C.sub.1-3alkyl)aminocarbonyl, C.sub.1-4 alkyl-OC(O), C.sub.1-5
alkyl-C(O)--C.sub.1-4 alkyl, amino-C.sub.1-5 alkyl, mono- or
di-(C.sub.1-3)alkylamino-C.sub.1-5 alkyl, R.sub.12--C.sub.1-5
alkyl, R.sub.13--C.sub.1-5 alkoxy, R.sub.14--C(O)--C.sub.1-5 alkyl
or R.sub.15--C.sub.1-5 alkyl(R.sub.16)N; cyclopropanyl,
cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being
optionally partially or fully halogenated and optionally
substituted with one to three C.sub.1-3 alkyl groups, or an analog
of such cycloalkyl group wherein one to three ring methylene groups
are independently replaced by O, S, CHOH, >C.dbd.O, >C.dbd.S
or NH; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,
cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each
optionally substituted with one to three C.sub.1-3 alkyl groups;
C.sub.1-4 alkyl-phenyl-C(O)--C.sub.1-4 alkyl-, C.sub.1-4
alkyl-C(O)--C.sub.1-4 alkyl- or C.sub.1-4
alkyl-phenyl-S(O).sub.m--C.sub.1-4 alkyl-; C.sub.1-6 alkyl or
C.sub.1-6 branched or unbranched alkoxy each of which is optionally
partially or fully halogenated or optionally substituted with
R.sub.17; OR.sub.18 or C.sub.1-6 alkyl optionally substituted with
OR.sub.18; amino or mono- or di-(C.sub.1-5alkyl)amino optionally
substituted with R.sub.19; R.sub.20C(O)N(R.sub.21)--, R.sub.22O--
or R.sub.23R.sub.24NC(O)--;
R.sub.26(CH.sub.2).sub.mC(O)N(R.sub.21)-- or
R.sub.26C(O)(CH.sub.2).sub.mN(R.sub.21)--; --C.sub.2-6alkenyl
substituted by R.sub.23R.sub.24NC(O)--; C.sub.2-6 alkynyl branched
or unbranched carbon chain, optionally partially or fully
halogenated, wherein one or more methylene groups are optionally
replaced by O, NH, S(O).sub.m and wherein said alkynyl group is
optionally independently substituted with one to two oxo groups,
pyrroldinyl, pyrrolyl, morpholinyl, piperidinyl, piperazinyl,
imidazolyl, phenyl, pyridinyl, tetrazolyl one or more C.sub.1-4
alkyl optionally substituted by one or more halogen atoms, nitrile,
morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl,
pyridinyl, tetrazolyl, or mono- or di(C.sub.1-4 alkyl)amino
optionally substituted by one or more halogen atoms; or aroyl;
[0388] R.sub.6 is a: C.sub.1-4 alkyl optionally partially or fully
halogenated and optionally substituted with R.sub.26; [0389] each
R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.12, R.sub.13, R.sub.14,
R.sub.15, R.sub.17, R.sub.19, R.sub.25 and R.sub.26 is
independently: nitrile, phenyl, morpholino, piperidinyl,
piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or
di-(C.sub.1-4alkyl)amino optionally partially or fully halogenated;
[0390] each R.sub.11 and R.sub.16 is independently: hydrogen or
C.sub.1-4 alkyl optionally partially or fully halogenated; [0391]
R.sub.18 is independently: hydrogen or a C.sub.1-4
alkyl optionally independently substituted with oxo or R.sub.25;
[0392] R.sub.20 is independently: C.sub.1-10 alkyl optionally
partially or fully halogenated, phenyl, or pyridinyl; [0393]
R.sub.21 is independently: hydrogen or C.sub.1-3 alkyl optionally
partially or fully halogenated; [0394] each R.sub.22, R.sub.23 and
R.sub.24 is independently: hydrogen, C.sub.1-6 alkyl optionally
partially or fully halogenated, said C.sub.1-6 alkyl is optionally
interrupted by one or more O, N or S, said C.sub.1-6 alkyl also
being independently optionally substituted by mono- or
di-(C.sub.1-3alkyl)aminocarbonyl, phenyl, pyridinyl, amino or mono-
or di-(C.sub.1-4alkyl)amino each of which is optionally partially
or fully halogenated and optionally substituted with mono- or
di-(C.sub.1-3alkyl)amino; or R.sub.23 and R.sub.24 taken together
optionally form a heterocyclic or heteroaryl ring; [0395] m=0, 1 or
2; [0396] W is O or S and the pharmaceutically acceptable
derivatives thereof.
[0397] A preferred subgeneric aspect of the invention comprises a
method of using the compounds of the formula (II) as provided above
and wherein:
G is:
phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl,
tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl,
indanyl, indenyl;
[0398] pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl,
tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl,
pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl,
benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl,
dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl,
benzo[1,4]oxazin-3-onyl, benzodioxolyl, benzo[1,3]dioxol-2-onyl,
benzofuran-3-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl,
indolonyl, indolinonyl, phthalimidyl;
[0399] oxetanyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl,
tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl,
tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl,
tertrahydropyridinyl, homopiperidinyl, pyrrolinyl,
tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl,
thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl,
oxocanyl, heptacanyl, thioxanyl or dithianyl;
wherein G is substituted by one or more R.sub.1, R.sub.2 or
R.sub.3;
[0400] A more preferred subgeneric aspect of the invention
comprises a method of using the compounds of the formula (II) as
provided above and wherein:
[0401] G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl,
isoquinolinyl, pyrazinyl, benzimidazolyl, benzoxazolyl,
benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl,
dihydrobenzothiophenyl, indanyl, indenyl, indolyl, indolinyl,
indolonyl or indolinonyl, wherein G is substituted by one or more
R.sub.1, R.sub.2 or R.sub.3; [0402] Ar is: naphthyl, quinolinyl,
isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, indanyl, indenyl or indolyl each being
optionally substituted by one or more R.sub.4 or R.sub.5 groups;
[0403] X is: phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl,
imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl,
dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl,
piperazinyl, pyridazinyl or pyrazinyl [0404] Y is: a bond or a
C.sub.1-4 saturated or unsaturated carbon chain wherein one of the
carbon atoms is optionally replaced by O, N, or S(O).sub.m and
wherein Y is optionally independently substituted with one to two
oxo groups, phenyl or one or more C.sub.1-4 alkyl optionally
substituted by one or more halogen atoms; [0405] Z is: phenyl,
pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl,
furanyl, thienyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl,
pyranyl, pyrrolidinyl which are optionally substituted with one to
three nitrile, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, amino, mono- or
di-(C.sub.1-3 alkyl)amino, CONH.sub.2 or OH; tetrahydropyranyl,
tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl,
morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl,
piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl,
pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene
sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or
tetramethylene sulfonyl which are optionally substituted with one
to three nitrile, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, amino, mono-
or di-(C.sub.1-3 alkyl)amino, CONH.sub.2, or OH; nitrile, C.sub.1-6
alkyl-S(O).sub.m, halogen, hydroxy, C.sub.1-4 alkoxy, amino, mono-
or di-(C.sub.1-6 alkyl)amino, mono- or di-(C.sub.1-3
alkyl)aminocarbonyl or NH.sub.2C(O); [0406] each R.sub.1 is
independently: C.sub.3-6 alkyl optionally partially or fully
halogenated, and optionally substituted with one to three
C.sub.3-6cycloalkyl, phenyl, thienyl, furyl, isoxazolyl or
isothiazolyl; each of the aforementioned being optionally
substituted with one to three groups selected from halogen,
C.sub.1-3 alkyl which is optionally partially or fully halogenated,
hydroxy, nitrile or C.sub.1-3alkoxy which is optionally partially
or fully halogenated; cyclopropyl, cyclobutyl, cyclopentanyl,
cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each being
optionally partially or fully halogenated and optionally
substituted with one to three C.sub.1-3 alkyl groups optionally
partially or fully halogenated, CN, hydroxyC.sub.1-3alkyl or
phenyl; or an analog of such cycloalkyl group wherein one to three
ring methylene groups are independently replaced by O, S, CHOH,
>C.dbd.O, >C.dbd.S or NH; or silyl containing three C.sub.1-4
alkyl groups optionally partially or fully halogenated; [0407]
R.sub.2 is independently: halogen, C.sub.1-3 alkoxy, C.sub.1-3
alkyl-S(O).sub.m optionally partially or fully halogenated,
phenylsulfonyl or nitrile; [0408] R.sub.3 is independently: phenyl,
morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl,
pyrrolylidinyl, imidazolyl, pyrazolyl, each being optionally
substituted with one to three phenyl, naphthyl, heterocycle or
heteroaryl as hereinabove described in this paragraph, C.sub.1-6
alkyl which is optionally partially or fully halogenated,
cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl,
cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl,
phenyl C.sub.1-5 alkyl, naphthyl C.sub.1-5 alkyl, halogen, oxo,
hydroxy, nitrile, C.sub.1-3 alkyloxy optionally partially or fully
halogenated, phenyloxy, naphthyloxy, heteroaryloxy or
heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as
hereinabove described in this paragraph, nitro, amino, mono- or
di-(C.sub.1-3alkyl)amino, phenylamino, naphthylamino, heteroaryl or
heterocyclic amino wherein the heteroaryl or heterocyclic moiety is
as hereinabove described in this paragraph, NH.sub.2C(O), a mono-
or di-(C.sub.1-3alkyl)aminocarbonyl, C.sub.1-5
alkyl-C(O)--C.sub.1-4 alkyl, mono- or di-(C.sub.1-3alkyl)amino,
mono- or di-(C.sub.1-3)alkylamino-C.sub.1-5 alkyl, mono- or
di-(C.sub.1-3alkyl)amino-S(O).sub.2, R.sub.7--C.sub.1-5 alkyl,
R.sub.8--C.sub.1-5 alkoxy, R.sub.9--C(O)--C.sub.1-5 alkyl,
R.sub.10--C.sub.1-5 alkyl(R.sub.11)N, carboxy-mono- or
di-(C.sub.1-5)-alkyl-amino; C.sub.1-3 alkyl or C.sub.1-4 alkoxy
each being optionally partially or fully halogenated or optionally
substituted with R.sub.17; OR.sub.18 or C.sub.1-6 alkyl optionally
substituted with OR.sub.18; amino or mono- or di-(C.sub.1-5
alkyl)amino optionally substituted with R.sub.19;
R.sub.20C(O)N(R.sub.21)--, R.sub.22O--; R.sub.23R.sub.24NC(O)--;
R.sub.26CH.sub.2C(O)N(R.sub.21)-- or
R.sub.26C(O)CH.sub.2N(R.sub.21)--; C.sub.2-4alkenyl substituted by
R.sub.23R.sub.24NC(O)--; or C.sub.2-4 alkynyl branched or
unbranched carbon chain optionally partially or fully halogenated
and optionally independently substituted with one to two oxo
groups, pyrroldinyl, pyrrolyl, morpholinyl, piperidinyl,
piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl or one or
more C.sub.1-4 alkyl optionally substituted by one or more halogen
atoms; and R.sub.23 and R.sub.24 taken together optionally form
imidazolyl, piperidinyl, morpholinyl, piperazinyl or a pyridinyl
ring.
[0409] A yet more preferred subgeneric aspect of the invention
comprises a method of using the compounds of the formula (II), as
described in the immediate previous paragraph, wherein:
[0410] G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl,
isoquinolinyl, pyrazinyl, benzothiophenyl, dihydrobenzofuranyl,
dihydrobenzothiophenyl, indanyl, indolyl, indolinyl, indolonyl or
indolinonyl, wherein G is substituted by one or more R.sub.1,
R.sub.2 or R.sub.3; [0411] Ar is naphthyl; [0412] X is phenyl,
imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl,
pyridazinyl or pyrazinyl each being optionally independently
substituted with one to three C.sub.1-4 alkyl, C.sub.1-4alkoxy,
hydroxy, nitrile, amino, mono- or di-(C.sub.1-3 alkyl)amino, mono-
or di-(C.sub.1-3 alkylamino)carbonyl, NH.sub.2C(O), C.sub.1-6
alkyl-S(O).sub.m or halogen; [0413] Y is: a bond or a C.sub.1-4
saturated carbon chain wherein one of the carbon atoms is
optionally replaced by O, N or S and wherein Y is optionally
independently substituted with an oxo group; [0414] Z is: phenyl,
pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl,
dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl or
pyrrolidinyl which are optionally substituted with one to two
C.sub.1-2 alkyl or C.sub.1-2 alkoxy; tetrahydropyranyl,
morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl,
piperidinyl, piperidinonyl, piperazinyl or tetrahydropyrimidonyl
which are optionally substituted with one to two C.sub.1-2 alkyl or
C.sub.1-2 alkoxy; or C.sub.1-3 alkoxy; [0415] each R.sub.1 is
independently: C.sub.3-5 alkyl optionally partially or fully
halogenated, and optionally substituted with phenyl substituted
with zero to three halogen, C.sub.1-3 alkyl which is optionally
partially or fully halogenated, hydroxy, nitrile or C.sub.1-3alkoxy
which is optionally partially or fully halogenated; cyclopropyl,
cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or
bicyclohexanyl, each being optionally partially or fully
halogenated and optionally substituted with one to three C.sub.1-3
alkyl groups optionally partially or fully halogenated, CN,
hydroxyC.sub.1-3alkyl or phenyl; and an analog of cyclopropyl,
cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or
bicyclohexanyl wherein one ring methylene group is replaced by O;
and silyl containing three C.sub.1-2 independently alkyl groups
optionally partially or fully halogenated; [0416] each R.sub.2 is
independently: bromo, chloro, fluoro, methoxy, methylsulfonyl or
nitrile; [0417] each R.sub.3 is independently: phenyl, morpholino,
pyridinyl, pyrimidinyl, pyrrolylidinyl, 2,5-pyrrolidin-dionyl,
imidazolyl, pyrazolyl, each of the aforementioned is optionally
substituted with one to three C.sub.1-3 alkyl which is optionally
partially or fully halogenated, halogen, oxo, hydroxy, nitrile and
C.sub.1-3 alkyloxy optionally partially or fully halogenated;
C.sub.1-3 alkyl or C.sub.1-3 alkoxy each being optionally partially
or fully halogenated or optionally substituted with R.sub.17;
OR.sub.18 or C.sub.1-3 alkyl optionally substituted with OR.sub.18;
amino or mono- or di-(C.sub.1-3 alkyl)amino optionally substituted
with R.sub.19; R.sub.20C(O)N(R.sub.21)--, R.sub.22O--;
R.sub.23R.sub.24NC(O)--; R.sub.26CH.sub.2C(O)N(R.sub.21)-- or
R.sub.26C(O)CH.sub.2N(R.sub.21)--; C.sub.2-4 alkenyl substituted by
R.sub.23R.sub.24NC(O)--; or C.sub.2-4 alkynyl substituted with
pyrroldinyl or pyrrolyl; and R.sub.23 and R.sub.24 taken together
optionally form morpholino.
[0418] A yet further preferred subgeneric aspect of the invention
comprises a method of using the compounds of the formula (II), as
described in the immediate previous paragraph, and wherein:
G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl,
isoquinolinyl, dihydrobenzofuranyl, indanyl, indolinyl, indolonyl,
or indolinonyl, wherein G is substituted by one or more R.sub.1,
R.sub.2 or R.sub.3;
[0419] Ar is 1-naphthyl; [0420] X is: phenyl, imidazolyl,
pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or
pyrazinyl; [0421] Y is: a bond or --CH.sub.2--,
--CH.sub.2CH.sub.2--, --C(O)--, --O--, --S--,
--NH--CH.sub.2CH.sub.2CH.sub.2--, --N(CH.sub.3)--, or --NH--;
[0422] each R.sub.1 is independently: C.sub.3-5 alkyl optionally
partially or fully halogenated, and optionally substituted with
phenyl; cyclopropyl, cyclopentanyl, cyclohexanyl and
bicyclopentanyl optionally substituted with one to three methyl
groups optionally partially or fully halogenated, CN, hydroxymethyl
or phenyl; or 2-tetrahydrofuranyl substituted by methyl; or
trimethyl silyl; [0423] each R.sub.3 is independently: phenyl,
morpholinyl, pyridinyl, pyrimidinyl, pyrrolylidinyl,
2,5-pyrrolidin-dionyl, imidazolyl or pyrazolyl, wherein any of the
aforementioned is optionally substituted with C.sub.1-2 alkyl which
is optionally partially or fully halogenated; C.sub.1-3 alkyl or
C.sub.1-3 alkoxy each being optionally partially or fully
halogenated or optionally substituted with diethylamino; OR.sub.18
or C.sub.1-3 alkyl optionally substituted with OR.sub.18; amino or
mono- or di-(C.sub.1-3 alkyl)amino optionally substituted with
R.sub.19; CH.sub.3C(O)NH--, R.sub.22O--; R.sub.23R.sub.24NC(O)--;
R.sub.26CH.sub.2C(O)N(R.sub.21)-- or
R.sub.26C(O)CH.sub.2N(R.sub.21)--; C.sub.2-4alkenyl substituted by
R.sub.23R.sub.24NC(O)--; or C.sub.2-4 alkynyl substituted with
pyrroldinyl or pyrrolyl; R.sub.23 and R.sub.24 are H or R.sub.23
and R.sub.24 taken together optionally form morpholino; and
R.sub.26 is morpholino.
[0424] A further preferred subgeneric aspect of the invention
comprises a method of using the compounds of the formula (II), as
described in the immediate previous paragraph, and wherein: [0425]
G is phenyl, pyridinyl or naphthyl wherein G is substituted by one
or more R.sub.1, R.sub.2 or R.sub.3; [0426] X is: imidazolyl or
pyridinyl; [0427] Y is: --CH.sub.2-,
--NH--CH.sub.2CH.sub.2CH.sub.2-- or --NH--; [0428] Z is morpholino;
[0429] each R.sub.1 is independently: tert-butyl, sec-butyl,
tert-amyl or phenyl; [0430] R.sub.2 is chloro; [0431] R.sub.3 is
independently: methyl, methoxy, methoxymethyl, hydroxypropyl,
acetamide, morpholino or morpholinocarbonyl.
[0432] A still yet further preferred subgeneric aspect of the
invention comprises a method of using the compounds of the formula
(II), as described in the immediate previous paragraph, and wherein
X is pyridinyl.
[0433] A still yet further preferred subgeneric aspect of the
invention comprises a method of using the compounds of the formula
(II), as described immediately above, and wherein the pyridinyl is
attached to Ar via the 3-pyridinyl position.
[0434] The following compounds are representative of the compounds
of formula (II) which are useful in the novel methods described
herein: [0435]
1-(3-Cyano-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-nap-
hthalen-1-yl]-urea; [0436]
1-(3-Fluoro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-
-1-yl]-urea; [0437]
1-(4-Chloro-2-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-urea; [0438]
1-(2-Chloro-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-urea; [0439]
1-(3,4-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphth-
alen-1-yl]-urea; [0440]
1-(3-Iodo-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-
-yl]-urea; [0441]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-m-tolyl-ure-
a; [0442]
1-(4-Methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-na-
phthalen-1-yl]-urea; [0443]
1-(3-Chloro-4-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-urea; [0444]
1-(4-Chloro-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-na-
phthalen-1-yl]-urea; [0445]
1-(2,5-Dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphth-
alen-1-yl]-urea; [0446]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-naphthalen--
2-yl-urea; [0447]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-phenyl-urea-
; [0448]
1-(3-Chloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)--
naphthalen-1-yl]-urea; [0449]
1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-urea; [0450]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2,4,6-tric-
hloro-phenyl)-urea; [0451]
1-(2-Methyl-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-na-
phthalen-1-yl]-urea; [0452]
1-(4-Methyl-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-na-
phthalen-1-yl]-urea; [0453]
1-(2,3-Dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphth-
alen-1-yl]-urea; [0454]
1-(2-Methoxy-5-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)--
naphthalen-1-yl]-urea; [0455]
1-(2-Chloro-6-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-urea; [0456]
1-(2,4-Dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphth-
alen-1-yl]-urea; [0457]
1-(4-Methyl-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-na-
phthalen-1-yl]-urea; [0458]
1-(2,4-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphth-
alen-1-yl]-urea; [0459]
1-(2,3-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphth-
alen-1-yl]-urea; [0460]
1-(4-Cyano-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen--
1-yl]-urea; [0461]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3,4,5-trim-
ethoxy-phenyl)-urea; [0462]
1-Biphenyl-4-yl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-y-
l]-urea; [0463]
1-(2,5-Difluoro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphth-
alen-1-yl]-urea; [0464]
1-(3-Chloro-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)--
naphthalen-1-yl]-urea; [0465]
1-(2-Fluoro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-urea; [0466]
1-(4-Benzyloxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphtha-
len-1-yl]-urea; [0467]
1-(2-Methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-na-
phthalen-1-yl]-urea; [0468]
1-(2-Fluoro-6-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-urea; [0469]
1-(4-Fluoro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-urea; [0470]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2,4,5-trim-
ethyl-phenyl)-urea; [0471]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluor-
omethyl-phenyl)-urea; [0472]
1-(3-Methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-na-
phthalen-1-yl]-urea; [0473]
1-(2-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthale-
n-1-yl]-urea; [0474]
1-(2-Fluoro-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-urea; [0475]
1-(4-Methoxy-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)--
naphthalen-1-yl]-urea; [0476]
1-(2-Fluoro-5-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-na-
phthalen-1-yl]-urea; [0477]
1-(4-Ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-
-1-yl]-urea; [0478]
1-(2,5-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht-
halen-1-yl]-urea; [0479]
1-(4,5-Dimethyl-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl-
)-naphthalen-1-yl]-urea; [0480]
1-(5-Chloro-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-urea; [0481]
1-(2-Isopropyl-6-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl-
)-naphthalen-1-yl]-urea; [0482]
1-(2-Difluoromethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-urea; [0483]
1-(4-Isopropyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphtha-
len-1-yl]-urea; [0484]
1-(4-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthale-
n-1-yl]-urea; [0485]
1-(3-Ethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen--
1-yl]-urea; [0486]
1-(2-Ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-
-1-yl]-urea; [0487]
1-(4-Butoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-
-1-yl]-urea; [0488]
4-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-be-
nzoic acid ethyl ester; [0489]
1-(4-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-na-
phthalen-1-yl]-urea; [0490]
1-(2,6-Dibromo-4-isopropyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
-yl)-naphthalen-1-yl]-urea; [0491]
1-(3-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthale-
n-1-yl]-urea; [0492]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluor-
omethylsulfanyl-phenyl)-urea; [0493]
5-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-is-
ophthalic acid dimethyl ester; [0494]
1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-urea; [0495]
3-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-be-
nzoic acid ethyl ester; [0496]
1-(5-tert-Butyl-2-hydroxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3--
yl)-naphthalen-1-yl]-urea; [0497]
1-(2-Hydroxymethyl-4-phenyl-cyclohexyl)-3-[4-(6-morpholin-4-ylmethyl-pyri-
din-3-yl)-naphthalen-1-yl]-urea; [0498]
1-(2-Methylsulfanyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethy-
l-pyridin-3-yl)-naphthalen-1-yl]-urea; [0499]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-pentylox-
y-biphenyl-3-yl)-urea; [0500]
4-Methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]--
ureido}-benzoic acid methyl ester; [0501]
1-(2,5-Diethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphth-
alen-1-yl]-urea; [0502]
1-Benzothiazol-6-yl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-
-1-yl]-urea; [0503]
N-(2,5-Diethoxy-4-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen--
1-yl]-ureido}-phenyl)-benzamide; [0504]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-phenoxy--
phenyl)-urea; [0505]
1-(5-Ethanesulfonyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-urea; [0506]
4-Methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]--
ureido}-N-phenyl-benzamide; [0507]
1-(2-Methyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)-3-[4-(6-morpholin-4-y-
lmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0508]
1-(2,3-Dimethyl-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
-naphthalen-1-yl]-urea; [0509]
N-Butyl-4-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthale-
n-1-yl]-ureido}-benzenesulfonamide; [0510]
1-[3-(2-Methyl-[1,3]dioxolan-2-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-p-
yridin-3-yl)-naphthalen-1-yl]-urea; [0511]
1-(3-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea; [0512]
1-(2,4-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht-
halen-1-yl]-urea; [0513]
1-(2-Methyl-4-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-na-
phthalen-1-yl]-urea; [0514]
1-(2-Methoxy-4-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-urea; [0515]
1-(4-Chloro-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-na-
phthalen-1-yl]-urea; [0516]
1-(5-Chloro-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)--
naphthalen-1-yl]-urea; [0517]
1-(3,5-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht-
halen-1-yl]-urea; [0518]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluor-
omethoxy-phenyl)-urea; [0519]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluor-
omethylsulfanyl-phenyl)-urea; [0520]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2-phenoxy--
phenyl)-urea; [0521]
1-(2-Methoxy-5-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-urea; [0522]
1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3--
yl)-naphthalen-1-yl]-urea; [0523]
1-(3,5-Bis-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
-yl)-naphthalen-1-yl]-urea; [0524]
1-(2-tert-Butyl-5-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea; [0525]
1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-urea; [0526]
1-(3-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphth-
alen-1-yl]-urea; [0527]
1-(4-Methyl-biphenyl-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-nap-
hthalen-1-yl]-urea; [0528]
1-(4-tert-Butyl-biphenyl-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
-naphthalen-1-yl]-urea; [0529]
1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3--
yl)-naphthalen-1-yl]-urea; [0530]
1-(5-Isopropyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl-
)-naphthalen-1-yl]-urea; [0531]
1-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-y-
l)-naphthalen-1-yl]-urea; [0532]
1-(5-tert-Butyl-2-methoxy-3-propyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-p-
yridin-3-yl)-naphthalen-1-yl]-urea; [0533]
1-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyri-
din-3-yl)-naphthalen-1-yl]-urea; [0534]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3--
yl)-naphthalen-1-yl]-urea; [0535]
1-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-amino-
]-pyridin-3-yl}-naphthalen-1-yl)-urea; [0536]
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-imidazol-1--
yl)-naphthalen-1-yl]-urea; [0537]
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-y-
l)-naphthalen-1-yl]-urea; [0538]
1-(5-tert-Butyl-2-methyl-phenyl)-3-{4-[6-(3-methoxy-propylamino)-pyridin--
3-yl]-naphthalen-1-yl}-urea; [0539]
1-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea; [0540]
1-(5-tert-Butyl-2-morpholin-4-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyr-
idin-3-yl)-naphthalen-1-yl]-urea; [0541]
1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmet-
hyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0542]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluor-
omethyl-phenyl)-urea; [0543]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluor-
omethoxy-phenyl)-urea; [0544]
1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
-pyridin-3-yl)-naphthalen-1-yl]-urea; [0545]
1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl--
pyridin-3-yl)-naphthalen-1-yl]-urea; [0546]
1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-morpholin-4-y-
lmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0547]
1-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
-pyridin-3-yl)-naphthalen-1-yl]-urea; [0548]
1-[5-tert-Butyl-2-(3-morpholin-4-yl-3-oxo-propyl)-phenyl]-3-[4-(6-morphol-
in-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0549]
1-[5-tert-Butyl-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholin-4-ylm-
ethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0550]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-acetamide; [0551]
2-(5-tert-Butyl-2-methoxy-phenyl)-N-[4-(6-morpholin-4-ylmethyl-pyridin-3--
yl)-naphthalen-1-yl]-acetamide; [0552]
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-na-
phthalen-1-yl]-urea; [0553]
1-(5-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-y-
l)-naphthalen-1-yl]-urea; [0554]
N-(5-tert-Butyl-2-methoxy-4-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide; [0555]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin--
1-yl)-naphthalen-1-yl]-urea; [0556]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin--
5-yl)-naphthalen-1-yl]-urea; [0557]
1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyri-
din-3-yl)-naphthalen-1-yl]-urea; [0558]
2,2,2-Trifluoro-ethanesulfonic acid
(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl-
)-naphthalen-1-yl]-ureido}-phenyl)-amide and the pharmaceutically
acceptable derivatives thereof.
[0559] In addtion to the abovementioned representative compounds
the following prophetic compounds of the formula (II) may be useful
in the novel methods described herein: [0560]
1-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-y-
l]-3-(5-tert-butyl-2-methoxy-phenyl)-urea [0561]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[4-(2-methyl-3-oxo-piperazin-1-ylm-
ethyl)-phenyl]-naphthalen-1-yl}-urea [0562]
1-[4-(6-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-
-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea [0563]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylm-
ethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0564]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylme-
thyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0565]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-urea; [0566]
1-(5-tert-Butyl-2-methyl-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylmet-
hyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0567]
1-(5-tert-Butyl-2-methyl-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylme-
thyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0568]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[4-(1-oxo-11-thiomorpholin-4-ylmet-
hyl)-phenyl]-naphthalen-1-yl}-urea; [0569]
1-[4-(4-{[Bis-(2-cyano-ethyl)-amino]-methyl}-phenyl)-naphthalen-1-yl]-3-(-
5-tert-butyl-2-methoxy-phenyl)-urea; [0570]
1-(2-Methoxy-5-pentafluoroethyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-pipe-
ridin-1-yl)-naphthalen-1-yl]-urea; [0571]
1-(2-Methoxy-5-trifluoromethyl-pyridin-3-yl)-3-{4-[2-(4-oxo-piperidin-1-y-
lmethyl)-pyrimidin-5-yl]-naphthalen-1-yl}-urea; [0572]
1-(2-Methoxy-5-trimethylsilanyl-phenyl)-3-{4-[4-(tetrahydro-pyran-4-ylami-
no)-phenyl]-naphthalen-1-yl}-urea; [0573]
1-(3-Methoxy-naphthalen-2-yl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl-
)-naphthalen-1-yl]-urea; [0574]
1-(3-Methyl-naphthalen-2-yl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphtha-
len-1-yl]-urea; [0575]
1-(3-tert-Butyl-5-methanesulfinyl-phenyl)-3-{4-[6-(1-methyl-piperidin-4-y-
lmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0576]
1-(3-tert-Butyl-phenyl)-3-[4-(3-pyridin-3-yl-propoxy)-naphthalen-1-yl]-ur-
ea; [0577]
1-(3-tert-Butyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-
-yl]-urea; [0578]
1-(4-Methoxy-biphenyl-3-yl)-3-{4-[4-(tetrahydro-pyran-4-ylmethyl)-imidazo-
l-1-yl]-naphthalen-1-yl}-urea; [0579]
1-(4-Methyl-biphenyl-3-yl)-3-{4-[4-(2-pyridin-4-yl-ethyl)-piperazin-1-yl]-
-naphthalen-1-yl}-urea; [0580] 1-(4-tert-Butyl-biphenyl-2-yl)-3-[4-
pyridin-4-ylmethoxy)-naphthalen-1-yl]-urea; [0581]
1-(4-tert-Butyl-biphenyl-2-yl)-3-{4-[2-(1-oxo-114-thiomorpholin-4-ylmethy-
l)-3H-imidazol-4-yl]-naphthalen-1-yl}-urea; [0582]
1-(5-tert-Butyl-2-hydroxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2--
yl)-naphthalen-1-yl]-urea; [0583]
1-(5-tert-Butyl-2-methoxy-3-propyl-phenyl)-3-{4-[4-(pyrrolidine-1-carbony-
l)-phenyl]-naphthalen-1-yl}-urea; [0584]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin--
5-yl)-naphthalen-1-yl]-urea; [0585]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-thiomorpholin-4-ylmethyl-phenyl-
)-naphthalen-1-yl]-urea; [0586]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-phenyl)-na-
phthalen-1-yl]-urea; [0587]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[4-(tetrahydro-pyran-4-ylamino)-ph-
enyl]-naphthalen-1-yl}-urea; [0588]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-
-pyridin-3-yl]-naphthalen-1-yl}-urea; [0589]
1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-{4-[6-(4-oxo-piperidin-1-ylmeth-
yl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0590]
1-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-pyridin-4-ylmethyl-pyr-
idin-3-yl)-naphthalen-1-yl]-urea; [0591]
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-nap-
hthalen-1-yl]-urea; [0592]
1-(5-tert-Butyl-2-phenoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-yloxy)-pyri-
din-3-yl]-naphthalen-1-yl}-urea; [0593]
1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(4-methoxy-6-morpholin-4-y-
lmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0594]
1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea; [0595]
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; [0596]
1-(5-tert-Butyl-4'-dimethylamino-biphenyl-3-yl)-3-[4-(2-morpholin-4-ylmet-
hyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea; [0597]
1-(6-Methoxy-3,3-dimethyl-indan-5-yl)-3-{4-[4-(morpholine-4-carbonyl)-phe-
nyl]-naphthalen-1-yl}-urea; [0598]
1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-thiomorpholin-4-y-
lmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0599]
1-(6-tert-Butyl-benzo[1,3]dioxol-4-yl)-3-{4-[6-(morpholin-4-ylamino)-pyri-
din-3-yl]-naphthalen-1-yl}-urea; [0600]
1-(7-Methoxy-1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-3-{4-[6-(t-
etrahydro-pyran-4-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea;
[0601]
1-(7-tert-Butyl-2,4-dimethyl-benzooxazol-5-yl)-3-[4-(6-morpholin-4-ylmeth-
yl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0602]
1-[2-Methoxy-5-(1-methyl-1-phenyl-ethyl)-phenyl]-3-{4-[6-(2-pyridin-4-yl--
ethyl)-pyridazin-3-yl]-naphthalen-1-yl}-urea; [0603]
1-[2-Methoxy-5-(1-methyl-cyclohexyl)-phenyl]-3-{4-[4-(1-methyl-piperidin--
4-ylsulfanyl)-phenyl]-naphthalen-1-yl}-urea; [0604]
1-[2-Methoxy-5-(1-methyl-cyclopropyl)-phenyl]-3-[4-(2-morpholin-4-ylmethy-
l-pyrimidin-5-yl)-naphthalen-1-yl]-urea; [0605]
1-[2-Methoxy-5-(2-methyl-tetrahydro-furan-2-yl)-phenyl]-3-[4-(5-morpholin-
-4-ylmethyl-pyridin-2-yl)-naphthalen-1-yl]-urea; [0606]
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; [0607]
1-[3-tert-Butyl-5-(1-methyl-1H-imidazol-4-yl)-phenyl]-3-[4-(5-morpholin-4-
-ylmethyl-pyridin-2-yl)-naphthalen-1-yl]-urea; [0608]
1-[3-tert-Butyl-5-(2-pyrrolidin-1-yl-ethyl)-phenyl]-3-{4-[6-(1-methyl-pip-
eridin-4-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0609]
1-[3-tert-Butyl-5-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenyl]-3-[4-(6-morphol-
in-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0610]
1-[4-(6-Imidazol-1-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-[2-methoxy-5-
-(1-phenyl-cyclopropyl)-phenyl]-urea; [0611]
1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(4-thiomorpholin-4-ylme-
thyl-phenyl)-naphthalen-1-yl]-urea; [0612]
1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(2-morpholin-4-ylmethyl-
-pyrimidin-5-yl)-naphthalen-1-yl]-urea; [0613]
1-[5-(1-Hydroxymethyl-cyclopropyl)-2-methoxy-phenyl]-3-[4-(4-morpholin-4--
ylmethyl-phenyl)-naphthalen-1-yl]-urea; [0614]
1-[5-tert-Butyl-1-(2-diethylamino-ethyl)-2-oxo-1,2-dihydro-pyridin-3-yl]--
3-{4-[6-(1-methyl-piperidin-4-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea;
[0615]
1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-[4-(2-morpholin-4-y-
l-ethoxy)-naphthalen-1-yl]-urea; [0616]
1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-{4-[4-(4-methyl-piperazine--
1-carbonyl)-phenyl]-naphthalen-1-yl}-urea; [0617]
1-[5-tert-Butyl-2-(2,5-dioxo-pyrrolidin-1-yl)-phenyl]-3-{4-[6-(1H-imidazo-
l-2-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0618]
1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(5-pyridin-4-ylm-
ethyl-pyridin-2-yl)-naphthalen-1-yl]-urea; [0619]
1-[5-tert-Butyl-2-(2-morpholin-4-yl-2-oxo-ethoxy)-phenyl]-3-{4-[6-(2-pyri-
din-4-yl-ethyl)-pyridazin-3-yl]-naphthalen-1-yl}-urea; [0620]
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;
[0621]
1-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-phenyl]-3-{4-[5-(2-pyrr-
olidin-1-yl-ethyl)-pyridin-2-yl]-naphthalen-1-yl}-urea; [0622]
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;
[0623]
1-[5-tert-Butyl-3-(2-diethylamino-ethoxy)-2-methoxy-phenyl]-3-{4-[4-(tetr-
ahydro-pyran-4-yloxy)-phenyl]-naphthalen-1-yl}-urea; [0624]
1-[5-tert-Butyl-3-(2-pyrrolidin-1-yl-ethyl)-benzofuran-7-yl]-3-[4-(4-morp-
holin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea; [0625]
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; [0626]
1-{5-tert-Butyl-2-methoxy-3-[2-(1-methyl-piperidin-4-yloxy)-ethyl]-phenyl-
}-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
[0627]
2-(4-tert-Butyl-2-{3-[4-(5-pyrrolidin-1-ylmethyl-pyridin-2-yl)-naphthalen-
-1-yl]-ureido}-phenoxy)-N-methyl-acetamide; [0628]
2-[4-tert-Butyl-2-(3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3--
yl]-naphthalen-1-yl}-ureido)-phenoxy]-acetamide; [0629]
3-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-pyrrolidin-1-ylmethyl-pyridin-3-yl)--
naphthalen-1-yl]-ureido}-phenyl)-acrylamide; [0630]
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;
[0631]
3-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-benzamid-
e; [0632]
4-tert-Butyl-2-{3-[4-(2-chloro-4-morpholin-4-ylmethyl-phenyl)-naphthalen--
1-yl]-ureido}-benzamide; [0633]
N-(4-tert-Butyl-2-{3-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-naphthalen-1-yl]-
-ureido}-phenyl)-2-morpholin-4-yl-acetamide; [0634]
N-[3-tert-Butyl-5-(3-{4-[5-(tetrahydro-pyran-4-ylamino)-pyridin-2-yl]-nap-
hthalen-1-yl}-ureido)-phenyl]-2-morpholin-4-yl-acetamide; [0635]
N-[4-tert-Butyl-2-(3-{4-[4-(1-methyl-piperidin-4-yloxy)-phenyl]-naphthale-
n-1-yl}-ureido)-phenyl]-acetamide and the pharmaceutically
acceptable derivatives thereof.
[0636] In another embodiment of the invention there are provided
the following compounds of formula (II) which are useful in the
novel methods described herein: [0637]
1-(2-tert-Butyl-5-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea; [0638]
1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-urea; [0639]
1-(3-tert-Butyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-
-yl]-urea; [0640]
1-(3-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphth-
alen-1-yl]-urea; [0641]
1-(4-Methyl-biphenyl-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-nap-
hthalen-1-yl]-urea; [0642]
1-(4-tert-Butyl-biphenyl-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
-naphthalen-1-yl]-urea; [0643]
1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3--
yl)-naphthalen-1-yl]-urea; [0644]
1-(5-Isopropyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl-
)-naphthalen-1-yl]-urea; [0645]
1-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-y-
l)-naphthalen-1-yl]-urea; [0646]
1-(5-tert-Butyl-2-methoxy-3-propyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-p-
yridin-3-yl)-naphthalen-1-yl]-urea; [0647]
1-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyri-
din-3-yl)-naphthalen-1-yl]-urea; [0648]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin--
5-yl)-naphthalen-1-yl]-urea; [0649]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-thiomorpholin-4-ylmethyl-phenyl-
)-naphthalen-1-yl]-urea; [0650]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3--
yl)-naphthalen-1-yl]-urea; [0651]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-phenyl)-na-
phthalen-1-yl]-urea; [0652]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[4-(tetrahydro-pyran-4-ylamino)-ph-
enyl]-naphthalen-1-yl}-urea; [0653]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-
-pyridin-3-yl]-naphthalen-1-yl}-urea; [0654]
1-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-amino-
]-pyridin-3-yl}-naphthalen-1-yl)-urea; [0655]
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-imidazol-1--
yl)-naphthalen-1-yl]-urea; [0656]
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-nap-
hthalen-1-yl]-urea; [0657]
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-y-
l)-naphthalen-1-yl]-urea; [0658]
1-(5-tert-Butyl-2-methyl-phenyl)-3-{4-[6-(3-methoxy-propylamino)-pyridin--
3-yl]-naphthalen-1-yl}-urea; [0659]
1-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea; [0660]
1-(5-tert-Butyl-2-morpholin-4-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyr-
idin-3-yl)-naphthalen-1-yl]-urea; [0661]
1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmet-
hyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0662]
1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-thiomorpholin-4-y-
lmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0663]
1-[2-Methoxy-5-(1-methyl-cyclopropyl)-phenyl]-3-[4-(2-morpholin-4-ylmethy-
l-pyrimidin-5-yl)-naphthalen-1-yl]-urea; [0664]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluor-
omethyl-phenyl)-urea; [0665]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluor-
omethoxy-phenyl)-urea; [0666]
1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(4-thiomorpholin-4-ylme-
thyl-phenyl)-naphthalen-1-yl]-urea; [0667]
1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
-pyridin-3-yl)-naphthalen-1-yl]-urea; [0668]
1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(2-morpholin-4-ylmethyl-
-pyrimidin-5-yl)-naphthalen-1-yl]-urea; [0669]
1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl--
pyridin-3-yl)-naphthalen-1-yl]-urea; [0670]
1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(5-pyridin-4-ylm-
ethyl-pyridin-2-yl)-naphthalen-1-yl]-urea; [0671]
1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-morpholin-4-y-
lmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0672]
1-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
-pyridin-3-yl)-naphthalen-1-yl]-urea; [0673]
1-[5-tert-Butyl-2-(3-morpholin-4-yl-3-oxo-propyl)-phenyl]-3-[4-(6-morphol-
in-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0674]
1-[5-tert-Butyl-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholin-4-ylm-
ethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0675]
2-[4-tert-Butyl-2-(3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3--
yl]-naphthalen-1-yl}-ureido)-phenoxy]-acetamide; [0676]
3-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-benzamid-
e; [0677]
4-tert-Butyl-2-{3-[4-(2-chloro-4-morpholin-4-ylmethyl-phenyl)-naphthalen--
1-yl]-ureido}-benzamide; and the pharmaceutically acceptable
derivatives thereof.
[0678] In another embodiment of the invention there are provided
the following compounds of formula (II) which are useful in the
novel methods described herein: [0679]
1-(2-tert-Butyl-5-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea; [0680]
1-(3-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphth-
alen-1-yl]-urea; [0681]
1-(4-Methyl-biphenyl-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-nap-
hthalen-1-yl]-urea; [0682]
1-(4-tert-Butyl-biphenyl-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
-naphthalen-1-yl]-urea; [0683]
1-(5-Isopropyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl-
)-naphthalen-1-yl]-urea; [0684]
1-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-y-
l)-naphthalen-1-yl]-urea; [0685]
1-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyri-
din-3-yl)-naphthalen-1-yl]-urea; [0686]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3--
yl)-naphthalen-1-yl]-urea; [0687]
1-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-amino-
]-pyridin-3-yl}-naphthalen-1-yl)-urea; [0688]
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-y-
l)-naphthalen-1-yl]-urea; [0689]
1-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea; [0690]
1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
-pyridin-3-yl)-naphthalen-1-yl]-urea; [0691]
1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl--
pyridin-3-yl)-naphthalen-1-yl]-urea; [0692]
1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-morpholin-4-y-
lmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0693]
1-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
-pyridin-3-yl)-naphthalen-1-yl]-urea; [0694]
1-[5-tert-Butyl-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholin-4-ylm-
ethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0695]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-acetamide and the pharmaceutically
acceptable derivatives thereof.
[0696] In a fourth broad generic aspect, there is provided a method
of treating a cytokine mediated disease or condition chosen from:
acute and chronic inflammation in the lung caused by inhalation of
smoke, endometriosis, Behcet's disease, uveitis, ankylosing
spondylitis, pancreatitis, cancer, Lyme disease, restenosis
following percutaneous transluminal coronary angioplasty,
Alzheimer's disease, traumatic arthritis, sepsis, chronic
obstructive pulmonary disease and congestive heart failure, said
method comprising administering to a patient in need of such
treatment a therapeutically effective amount of a compound of the
formula (III) disclosed in WO 00/55139 which is the PCT case of
U.S. application Ser. No. 09/505,582: ##STR4## [0697] wherein:
[0698] E is carbon or a heteroatom group chosen from --O--, --NH--
and --S--; [0699] G is: an aromatic C.sub.6-10 carbocycle or a
nonaromatic C.sub.3-10carbocycle saturated or unsaturated; a 6-14
membered monocyclic, bicyclic or tricyclic heteroaryl containing 1
or more heteroatoms chosen from O, N and S; a 6-8 membered
monocyclic heterocycle containing one or more heteroatoms chosen
from O, N and S; or an 8-11 membered bicyclic heterocycle,
containing one or more heteroatoms chosen from O, N and S; wherein
G is optionally substituted by one or more R.sub.1, R.sub.2 or
R.sub.3; [0700] Ar is: phenyl, naphthyl, quinolinyl, isoquinolinyl,
tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl,
benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl each
being optionally substituted by one or more R.sub.4 or R.sub.5;
[0701] X is: a C.sub.5-8 cycloalkyl or cycloalkenyl optionally
substituted with one to two oxo groups or one to three C.sub.1-4
alkyl, C.sub.1-4 alkoxy or C.sub.1-4 alkylamino chains each being
branched or 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 independently substituted with
one to three C.sub.1-4 alkyl, C.sub.1-4alkoxy, hydroxy, nitrile,
amino, mono- or di-(C.sub.1-3 alkyl)amino, mono- or di-(C.sub.1-3
alkylamino)carbonyl, NH.sub.2C(O), C.sub.1-6 alkyl-S(O).sub.m or
halogen; [0702] Y is: a bond or a C.sub.1-4 saturated or
unsaturated branched or unbranched carbon chain optionally
partially or fully halogenated, wherein one or more C atoms are
optionally replaced by O, N, or S(O).sub.m and wherein Y is
optionally independently substituted with one to two oxo groups,
nitrile, phenyl or one or more C.sub.1-4 alkyl optionally
substituted by one or more halogen atoms; [0703] Z is: 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, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-3
alkoxy-C.sub.1-3 alkyl, C.sub.1-6 alkoxycarbonyl, aroyl,
C.sub.1-3acyl, oxo, hydroxy, pyridinyl-C.sub.1-3 alkyl,
imidazolyl-C.sub.1-3 alkyl, tetrahydrofuranyl-C.sub.1-3 alkyl,
nitrile-C.sub.1-3 alkyl, nitrile, carboxy, phenyl wherein the
phenyl ring is optionally substituted with one to two halogen,
C.sub.1-6 alkoxy, hydroxy or mono- or di-(C.sub.1-3 alkyl)amino,
C.sub.1-6 alkyl-S(O).sub.m, or phenyl-S(O).sub.m wherein the phenyl
ring is optionally substituted with one to two halogen, C.sub.1-6
alkoxy, hydroxy, halogen or mono- or di-(C.sub.1-3 alkyl)amino; or
Z is optionally substituted with one to three amino or
amino-C.sub.1-3 alkyl wherein the N atom is optionally
independently mono- or di-substituted by aminoC.sub.1-6alkyl,
C.sub.1-3alkyl, arylC.sub.0-3alkyl, C.sub.1-5 alkoxyC.sub.1-3
alkyl, C.sub.1-5 alkoxy, aroyl, C.sub.1-3acyl,
C.sub.1-3alkyl-S(O).sub.m-- or arylC.sub.0-3alkyl-S(O).sub.m-- each
of the aforementioned alkyl and aryl attached to the amino group is
optionally substituted with one to two halogen, C.sub.1-6 alkyl or
C.sub.1-6 alkoxy; 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.sub.1-6 alkyl or C.sub.1-6 alkoxy; or Z is hydroxy, halogen,
nitrile, amino wherein the N atom is optionally independently mono-
or di-substituted by C.sub.1-3acyl, C.sub.1-6alkyl or
C.sub.1-3alkoxyC.sub.1-3alkyl, C.sub.1-6alkyl branched or
unbranched, C.sub.1-6alkoxy, C.sub.1-3acylamino,
nitrileC.sub.1-4alkyl, C 1.sub.6 alkyl-S(O).sub.m, and
phenyl-S(O).sub.m, wherein the phenyl ring is optionally
substituted with one to two halogen, C.sub.1-6 alkoxy, hydroxy or
mono- or di-(C.sub.1-3 alkyl)amino; [0704] each R.sub.1 is
independently: C.sub.1-10 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).sub.m, and
wherein said C.sub.1-10 alkyl is optionally substituted with one to
three C.sub.3-10 cycloalkyl, hydroxy, oxo, phenyl, naphthyl,
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,
pyrrolidinyl, imidazolyl, pyrazolyl, thienyl, furyl, dioxolanyl,
isoxazolyl or isothiazolyl; each of the aforementioned being
optionally substituted with one to five groups selected from
halogen, C.sub.1-6 alkyl which is optionally partially or fully
halogenated, C.sub.3-8 cycloalkanyl, C.sub.5-8 cycloalkenyl,
hydroxy, nitrile, C.sub.1-3 alkoxy which is optionally partially or
fully halogenated or NH.sub.2C(O), mono- or di(C.sub.1-3
alkyl)amino, and mono- or di(C.sub.1-3alkyl)aminocarbonyl; or
R.sub.1 is cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,
cyclohexyloxy, or cycloheptyloxy each being optionally partially or
fully halogenated and optionally substituted with one to three
C.sub.1-3 alkyl groups optionally partially or fully halogenated,
nitrile, hydroxyC.sub.1-3alkyl or aryl; or an analog of such
cycloalkyl group wherein one to three ring methylene groups are
independently replaced by O, S(O).sub.m, CHOH, >C.dbd.O,
>C.dbd.S or NH; phenyloxy or benzyloxy each being optionally
partially or fully halogenated and optionally substituted with one
to three C.sub.1-3 alkyl groups optionally partially or fully
halogenated, nitrile, hydroxyC.sub.1-3alkyl or aryl; or an analog
of such cycloaryl group wherein one to two ring methyne groups are
independently replaced by N; cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, bicyclopentanyl, bicyclohexanyl or
bicycloheptanyl, each being optionally partially or fully
halogenated and optionally substituted with one to three C.sub.1-3
alkyl optionally partially or fully halogenated, nitrile,
hydroxyC.sub.1-3alkyl or aryl; or an analog of such cycloalkyl
group wherein one to three ring methylene groups are independently
replaced by O, S(O).sub.m, CHOH, >C.dbd.O, >C.dbd.S or NH;
C.sub.3-10 branched or unbranced alkenyl each being optionally
partially or fully halogenated, and optionally substituted with one
to three C.sub.1-5 branched or unbranched alkyl, phenyl, naphthyl,
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,
imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl,
each of the aforementioned being substituted with one to five
halogen, C.sub.1-6 alkyl which is optionally partially or fully
halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl,
cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and
bicycloheptanyl, hydroxy, nitrile, C.sub.1-3 alkyloxy which is
optionally partially or fully halogenated, NH.sub.2C(O), mono- or
di(C.sub.1-3alkyl)aminocarbonyl; the C.sub.3-10 branched or
unbranced alkenyl being optionally interrupted by one or more
heteroatoms chosen from O, N and S(O).sub.m; cyclopentenyl,
cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,
bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group
is optionally substituted with one to three C.sub.1-3 alkyl groups;
oxo, nitrile, halogen; silyl containing three C.sub.1-4 alkyl
groups optionally partially or fully halogenated; or C.sub.3-6
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).sub.m and wherein said alkynyl
group is optionally independently substituted with one to two oxo
groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, one or
more C.sub.1-4 alkyl optionally substituted by one or more halogen
atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl,
phenyl, pyridinyl, tetrazolyl, or mono- or di(C.sub.1-3 alkyl)amino
optionally substituted by one or more halogen atoms; [0705] each
R.sub.2, R.sub.4, and R.sub.5 is a C.sub.1-6 branched or unbranched
alkyl optionally partially or fully halogenated, C.sub.1-6acyl,
aroyl, C.sub.1-4 branched or unbranched alkoxy, each being
optionally partially or fully halogenated, halogen,
methoxycarbonyl, C.sub.1-3 alkyl-S(O).sub.m optionally partially or
fully halogenated, or phenyl-S(O).sub.m; OR.sub.6, C.sub.1-6
alkoxy, hydroxy, nitrile, nitro, halogen; or amino-S(O).sub.m--
wherein the N atom is optionally independently mono- or
di-substituted by C.sub.1-6alkyl or arylC.sub.0-3alkyl, or amino
wherein the N atom is optionally independently mono- or
di-substituted by C.sub.1-3alkyl, arylC.sub.0-3alkyl,
C.sub.1-6acyl, C.sub.1-6alkyl-S(O).sub.m-- or
arylC.sub.0-3alkyl-S(O).sub.m--, each of the aforementioned alkyl
and aryl in this subparagraph are optionally partially or fully
halogenated and optionally substituted with one to two C.sub.1-6
alkyl or C.sub.1-6 alkoxy; [0706] each R.sub.3 is independently:
phenyl, naphthyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl,
pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl,
thiazolyl, oxazoyl, [1,3,4]oxadiazol, triazolyl, tetrazolyl,
thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl,
quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,
benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl,
cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl,
quinoxalinyl, quinazolinyl, purinyl or indazolyl, each of the
aforementioned is optionally substituted with one to three phenyl,
naphthyl, heterocycle or heteroaryl as hereinabove described in
this paragraph, C.sub.1-6 branched or unbranched alkyl which is
optionally partially or fully halogenated, cyclopropanyl,
cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C.sub.1-5
alkyl, naphthyl C.sub.1-5 alkyl, halogen, hydroxy, oxo, nitrile,
C.sub.1-3 alkoxy optionally partially or fully halogenated,
phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein
the heterocyclic or heteroaryl moiety is as hereinabove described
in this paragraph, nitro, amino, mono- or di-(C.sub.1-3alky)lamino,
phenylamino, naphthylamino, heteroaryl or heterocyclic amino
wherein the heteroaryl heterocyclic moiety is as hereinabove
described in this paragraph, NH.sub.2C(O), a mono- or
di-(C.sub.1-3alkyl) aminocarbonyl, C.sub.1-5 alkyl-C(O)--C.sub.1-4
alkyl, amino-C.sub.1-5 alkyl, mono- or di-(C.sub.1-5alkyl)amino,
mono- or di-(C.sub.1-3alkyl)amino-C.sub.1-5 alkyl,
amino-S(O).sub.2, di-(C.sub.1-3alkyl)amino-S(O).sub.2,
R.sub.7--C.sub.1-5 alkyl, R.sub.8--C.sub.1-5 alkoxy,
R.sub.9--C(O)--C.sub.1-5 alkyl, R.sub.10--C.sub.1-5
alkyl(R.sub.11)N, carboxy-mono- or di-(C.sub.1-5alkyl)-amino; a
fused aryl selected from benzocyclobutanyl, indanyl, indenyl,
dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and
benzocycloheptenyl, or a fused heteroaryl selected from
cyclopentenopyridinyl, cyclohexanopyridinyl,
cyclopentanopyrimidinyl, cyclohexanopyrimidinyl,
cyclopentanopyrazinyl, cyclohexanopyrazinyl,
cyclopentanopyridazinyl, cyclohexanopyridazinyl,
cyclopentanoquinolinyl, cyclohexanoquinolinyl,
cyclopentanoisoquinolinyl, cyclohexanoisoquinolinyl,
cyclopentanoindolyl, cyclohexanoindolyl,
cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl,
cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl,
cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl
and cyclohexanothienyl; wherein the fused aryl or fused heteroaryl
ring is independently substituted with zero to three phenyl,
naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,
imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl,
C.sub.1-6 alkyl which is optionally partially or fully halogenated,
halogen, nitrile, C.sub.1-3 alkyloxy which is optionally partially
or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or
heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as
hereinabove described in this paragraph, nitro, amino, mono- or
di-(C.sub.1-3alkyl)amino, phenylamino, naphthylamino, heteroaryl or
heterocyclic amino wherein the heteroaryl or heterocyclic moiety is
as hereinabove described in this paragraph, NH.sub.2C(O), mono- or
di-(C.sub.1-3alkyl)aminocarbonyl, C.sub.1-4 alkyl-OC(O), C.sub.1-5
alkyl-C(O)--C.sub.1-4 alkyl, amino-C.sub.1-5 alkyl, mono- or
di-(C.sub.1-3)alkylamino-C.sub.1-5 alkyl, R.sub.12--C.sub.1-5
alkyl, R.sub.13--C.sub.1-5 alkoxy, R.sub.14--C(O)--C.sub.1-5 alkyl
or R.sub.15--C.sub.1-5 alkyl(R.sub.16)N; cyclopropanyl,
cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being
optionally be partially or fully halogenated and optionally
substituted with one to three C.sub.1-3 alkyl groups, or an analog
of such cycloalkyl group wherein one to three ring methylene groups
are independently replaced by O, S, CHOH, >C.dbd.O, >C.dbd.S
or NH; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,
cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each
optionally substituted with one to three C.sub.1-3 alkyl groups;
C.sub.1-4 alkyl-phenyl-C(O)--C.sub.1-4 alkyl-, C.sub.1-4
alkyl-C(O)--C.sub.1-4 alkyl- or C.sub.1-4
alkyl-phenyl-S(O).sub.m--C.sub.1-4 alkyl-; C.sub.1-6 alkyl or
C.sub.1-6 branched or unbranched alkoxy each of which is optionally
partially or fully halogenated or optionally substituted with
R.sub.17; OR.sub.18 or C.sub.1-6 alkyl optionally substituted with
OR.sub.18; amino or mono- or di-(C.sub.1-5alkyl)amino optionally
substituted with R.sub.19; R.sub.20C(O)N(R.sub.21)--, R.sub.22
O-- or R.sub.23R.sub.24NC(O)--;
R.sub.26(CH.sub.2).sub.mC(O)N(R.sub.21)--,
R.sub.23R.sub.24NC(O)--C.sub.1-3alkoxy or
R.sub.26C(O)(CH.sub.2).sub.mN(R.sub.21)--; C.sub.2-6alkenyl
substituted by R.sub.23R.sub.24NC(O)--; C.sub.2-6 alkynyl branched
or unbranched carbon chain, optionally partially or fully
halogenated, wherein one or more methylene groups are optionally
replaced by O, NH, S(O).sub.m and wherein said alkynyl group is
optionally independently substituted with one to two oxo groups,
pyrroldinyl, pyrrolyl, morpholino, piperidinyl, piperazinyl,
imidazolyl, phenyl, pyridinyl, tetrazolyl one or more C.sub.1-4
alkyl optionally substituted by one or more halogen atoms, nitrile,
morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl,
pyridinyl, tetrazolyl, or mono- or di(C.sub.1-4 alkyl)amino
optionally substituted by one or more halogen atoms; C.sub.1-6acyl
or aroyl; [0707] R.sub.6 is a: C.sub.1-4 alkyl optionally partially
or fully halogenated and optionally substituted with R.sub.26;
[0708] each R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.12,
R.sub.13, R.sub.14, R.sub.15, R.sub.17, R.sub.19, R.sub.25 and
R.sub.26 is independently: nitrile, phenyl, morpholino,
piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino
or mono- or di-(C.sub.1-4alkyl)amino optionally partially or fully
halogenated; [0709] each R.sub.11 and R.sub.16 is independently:
hydrogen or C.sub.1-4 alkyl optionally partially or fully
halogenated; [0710] R.sub.18 is independently: hydrogen or a
C.sub.1-4 alkyl optionally independently substituted with oxo or
R.sub.25; [0711] R.sub.20 is independently: C.sub.1-10 alkyl
optionally partially or fully halogenated, phenyl, or pyridinyl;
[0712] R.sub.21 is independently: hydrogen or C.sub.1-3 alkyl
optionally partially or fully halogenated; [0713] each R.sub.22,
R.sub.23 and R.sub.24 is independently: hydrogen, C.sub.1-6 alkyl
optionally partially or fully halogenated, said C.sub.1-6 alkyl is
optionally interrupted by one or more O, N or S, said C.sub.1-6
alkyl also being independently optionally substituted by mono- or
di-(C.sub.1-3alkyl)aminocarbonyl, phenyl, pyridinyl, amino or mono-
or di-(C.sub.1-4alkyl)amino each of which is optionally partially
or fully halogenated and optionally substituted with mono- or
di-(C.sub.1-3alkyl)amino; or R.sub.23 and R.sub.24 taken together
optionally form a heterocyclic or heteroaryl ring; [0714] m=0, 1 or
2; [0715] W is 0 or S and the pharmaceutically acceptable
derivatives thereof.
[0716] A preferred subgeneric aspect of the invention comprises a
method of using the compounds of the formula (III) as provided
above and wherein: [0717] E is --CH.sub.2--, --NH-- or --O--;
[0718] W is O; and [0719] G is: phenyl, naphthyl,
benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl,
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[1,4]oxazin-3-onyl, benzodioxolyl,
benzo[1,3]dioxol-2-onyl, benzofuran-3-onyl, tetrahydrobenzopyranyl,
indolyl, 2,3-dihydro-1H-indolyl, indolinyl, indolonyl, indolinonyl,
phthalimidyl, chromoyl; oxetanyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholino,
tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl,
tetramethylene sulfoxidyl, oxazolinyl,
3,4-dihydro-2H-benzo[1,4]oxazinyl, thiazolinyl, imidazolinyl,
tertrahydropyridinyl, homopiperidinyl, pyrrolinyl,
tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl,
thiomorpholino, thiazolidinyl, dihydrooxazinyl, dihydropyranyl,
oxocanyl, heptacanyl, thioxanyl or dithianyl; wherein G is
optionally substituted by one or more R.sub.1, R.sub.2 or
R.sub.3.
[0720] A more preferred subgeneric aspect of the invention
comprises a method of using the compounds of the formula (III) as
provided above and wherein: [0721] E is --NH--; [0722] 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 optionally substituted by one or more
R.sub.1, R.sub.2 or R.sub.3; [0723] Ar is: naphthyl, quinolinyl,
isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, indanyl, indenyl or indolyl each being
optionally substituted by one or more R.sub.4 or R.sub.5 groups;
[0724] 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 C.sub.1-4 alkyl,
C.sub.1-4alkoxy, hydroxy, nitrile, amino, mono- or di-(C.sub.1-3
alkyl)amino, mono- or di-(C.sub.1-3 alkylamino)carbonyl,
NH.sub.2C(O), C.sub.1-6 alkyl-S(O).sub.m or halogen; [0725] Y is: a
bond or a C.sub.1-4 saturated or unsaturated carbon chain wherein
one or more of the C atoms is optionally replaced by O, N, or
S(O).sub.m and wherein Y is optionally independently substituted
with one to two oxo groups, nitrile, phenyl or one or more
C.sub.1-4 alkyl optionally substituted by one or more halogen
atoms; [0726] 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 nitrile, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, amino,
mono- or di-(C.sub.1-3 alkyl)amino, CONH.sub.2 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, C.sub.1-3 alkyl or C.sub.1-3 alkoxy; or Z
is nitrile, nitrileC.sub.1-3 alkyl, C.sub.1-6 alkyl-S(O).sub.m,
halogen, hydroxy, C.sub.1-3 alkyl, C.sub.1-3 acylamino, C.sub.1-4
alkoxy, amino, mono- or di-(C.sub.1-3 alkyl)aminocarbonyl, or amino
mono or di-substituted by aminoC.sub.1-6 alkyl or
C.sub.1-3alkoxyC.sub.1-3alkyl; [0727] each R.sub.1 is
independently: C.sub.1-6 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).sub.m, and
wherein said C.sub.1-6 alkyl is optionally substituted with one to
three C.sub.3-6cycloalkyl, oxo, phenyl, dioxolanyl, pyrrolidinyl,
furyl, isoxazolyl or isothiazolyl; each of the aforementioned being
optionally substituted with one to three groups selected from
halogen, C.sub.1-3 alkyl which is optionally partially or fully
halogenated, hydroxy, nitrile and C.sub.1-3alkoxy which is
optionally partially or fully halogenated; cyclopropyl, cyclobutyl,
cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl,
each being optionally partially or fully halogenated and optionally
substituted with one to three C.sub.1-3 alkyl groups optionally
partially or fully halogenated, nitrile, hydroxyC.sub.1-3alkyl or
phenyl; or an analog of such cycloalkyl group wherein one to three
ring methylene groups are independently replaced by O, S, CHOH,
>C.dbd.O, >C.dbd.S or NH; oxo; C.sub.3-6 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).sub.m and wherein said alkynyl group is optionally
independently substituted with one to two oxo groups, hydroxy,
pyrroldinyl, pyrrolyl, tetrahydropyranyl, C.sub.1-4 alkyl
optionally substituted by one or more halogen atoms, nitrile,
morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl,
pyridinyl, tetrazolyl, or mono- or di(C.sub.1-3alkyl)amino
optionally substituted by one or more halogen atoms; or silyl
containing three C.sub.1-4 alkyl groups optionally partially or
fully halogenated; [0728] R.sub.2 is independently: a C.sub.1-5
branched or unbranched alkyl optionally partially or fully
halogenated, acetyl, aroyl, C.sub.1-4 branched or unbranched
alkoxy, each being optionally partially or fully halogenated,
halogen, methoxycarbonyl, C.sub.1-2 alkyl-S(O).sub.m optionally
partially or fully halogenated, or phenyl-S(O).sub.m; C.sub.1-3
alkoxy, hydroxy, nitrile, nitro, halogen; or amino-S(O).sub.m--
wherein the N atom is optionally independently mono- or
di-substituted by C.sub.1-3alkyl or arylC.sub.0-3alkyl, or amino
wherein the N atom is optionally independently mono- or
di-substituted by C.sub.1-3alkyl, arylC.sub.0-3alkyl,
C.sub.1-3acyl, C.sub.1-4alkyl-S(O).sub.m-- or
arylC.sub.0-3alkyl-S(O).sub.m--, each of the aforementioned alkyl
and aryl in this subparagraph are optionally partially or fully
halogenated and optionally substituted with one to two C.sub.1-3
alkyl or C.sub.1-3 alkoxy; [0729] R.sub.3 is independently: phenyl,
morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl,
pyrrolidinyl, imidazolyl, [1,3,4]oxadiazol, pyrazolyl, each is
optionally substituted with one to three phenyl, naphthyl,
heterocycle or heteroaryl as hereinabove described in this
paragraph, C.sub.1-6 alkyl which is optionally partially or fully
halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl,
cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl,
bicycloheptanyl, phenyl C.sub.1-5 alkyl, naphthyl C.sub.1-5 alkyl,
halogen, oxo, hydroxy, nitrile, C.sub.1-3 alkoxy optionally
partially or fully halogenated, phenyloxy, naphthyloxy,
heteroaryloxy or heterocyclicoxy wherein the heteroaryl or
heterocyclic moiety is as hereinabove described in this paragraph,
nitro, amino, mono- or di-(C.sub.1-3alkyl)amino, phenylamino,
naphthylamino, heteroaryl or heterocyclic amino wherein the
heteroaryl or heterocyclic moiety is as hereinabove described in
this paragraph, NH.sub.2C(O), a mono- or
di-(C.sub.1-3alkyl)aminocarbonyl, C.sub.1-5 alkyl-C(O)--C.sub.1-4
alkyl, mono- or di-(C.sub.1-3alkyl)amino, mono- or
di-(C.sub.1-3)alkylamino-C.sub.1-5 alkyl, mono- or
di-(C.sub.1-3alkyl)amino-S(O).sub.2, R.sub.7--C.sub.1-5 alkyl,
R.sub.8--C.sub.1-5 alkoxy, R.sub.9--C(O)--C.sub.1-5 alkyl,
R.sub.10--C.sub.1-5 alkyl(R.sub.11)N, carboxy-mono- or
di-(C.sub.1-5)-alkyl-amino; C.sub.1-3 alkyl or C.sub.1-4 alkoxy
each being optionally partially or fully halogenated or optionally
substituted with R.sub.17; OR.sub.18 or C.sub.1-6 alkyl optionally
substituted with OR.sub.18; amino or mono- or di-(C.sub.1-5
alkyl)amino optionally substituted with R.sub.19;
R.sub.20C(O)N(R.sub.21)--, R.sub.22O--; R.sub.23R.sub.24NC(O)--;
R.sub.26CH.sub.2C(O)N(R.sub.21)--,
R.sub.23R.sub.24NC(O)--C.sub.1-2alkoxy or
R.sub.26C(O)CH.sub.2N(R.sub.21)--; C.sub.2-4alkenyl substituted by
R.sub.23R.sub.24NC(O)--; or C.sub.2-4 alkynyl branched or
unbranched carbon chain optionally partially or fully halogenated
wherein one of the methylene groups is optionally replaced by O,
and optionally independently substituted with one to two oxo
groups, pyrroldinyl, pyrrolyl, morpholino, piperidinyl,
piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl or one or
more C.sub.1-4 alkyl optionally substituted by one or more halogen
atoms; C.sub.1-3acyl; and R.sub.23 and R.sub.24 taken together
optionally form imidazolyl, piperidinyl, morpholino, piperazinyl or
a pyridinyl ring.
[0730] A yet more preferred subgeneric aspect of the invention
comprises a method of using the compounds of the formula (III), as
described in the immediate previous paragraph, wherein:
[0731] 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 optionally substituted by one or more
R.sub.1, R.sub.2 or R.sub.3; [0732] Ar is naphthyl; [0733] X is
phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl,
piperazinyl, pyridazinyl or pyrazinyl each being optionally
independently substituted with one to three C.sub.1-4 alkyl,
C.sub.1-4alkoxy, hydroxy, nitrile, amino, mono- or di-(C.sub.1-3
alkyl)amino, mono- or di-(C.sub.1-3 alkylamino)carbonyl,
NH.sub.2C(O), C.sub.1-6 alkyl-S(O).sub.m or halogen; [0734] Y is: a
bond or a C.sub.1-4 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 nitrile or oxo; [0735] Z
is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,
imidazolyl, dihydrothiazolyl, 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 C.sub.1-2 alkyl or
C.sub.1-2 alkoxy; or Z is hydroxy, C.sub.1-3 alkyl, C.sub.1-3
alkoxy, C.sub.1-3 acylamino, C.sub.1-3 alkylsulfonyl, nitrile
C.sub.1-3 alkyl or amino mono or di-substituted by C.sub.1-3
alkoxyC.sub.1-3 alkyl; [0736] each R.sub.1 is independently:
C.sub.1-5 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).sub.m, and wherein said
C.sub.1-5 alkyl is optionally substituted with oxo, dioxolanyl,
pyrrolidinyl, furyl or phenyl each optionally substituted with one
to three halogen, C.sub.1-3 alkyl which is optionally partially or
fully halogenated, hydroxy, nitrile and C.sub.1-3alkoxy which is
optionally partially or fully halogenated; cyclopropyl, cyclobutyl,
cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl,
each being optionally partially or fully halogenated and optionally
substituted with one to three C.sub.1-3 alkyl groups optionally
partially or fully halogenated, nitrile, hydroxyC.sub.1-3alkyl or
phenyl; and an analog of cyclopropyl, cyclobutyl, cyclopentanyl,
cyclohexanyl, bicyclopentanyl or bicyclohexanyl wherein one ring
methylene group is replaced by O; oxo; C.sub.2-4 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, C.sub.1-4 alkyl optionally substituted
by one or more halogen atoms, nitrile, morpholino, piperidinyl,
piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or
di(C.sub.1-3alkyl)amino optionally substituted by one or more
halogen atoms; or silyl containing three C.sub.1-2 alkyl groups
optionally partially or fully halogenated; [0737] each R.sub.2 is
independently: a C.sub.1-4 alkyl optionally partially or fully
halogenated, C.sub.1-4 alkoxy optionally partially or fully
halogenated, bromo, chloro, fluoro, methoxycarbonyl,
methyl-S(O).sub.m, ethyl-S(O).sub.m each optionally partially or
fully halogenated or phenyl-S(O).sub.m; or R.sub.2 is mono- or
di-C.sub.1-3acylamino, amino-S(O).sub.m or S(O).sub.mamino wherein
the N atom is mono- or di-substituted by C.sub.1-3alkyl or phenyl,
nitrile, nitro or amino; [0738] each R.sub.3 is independently:
phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolidinyl,
2,5-pyrrolidin-dionyl, imidazolyl, [1,3,4]oxadiazol, pyrazolyl,
each of the aforementioned is optionally substituted with one to
three C.sub.1-3 alkyl which is optionally partially or fully
halogenated, halogen, oxo, hydroxy, nitrile and C.sub.1-3 alkoxy
optionally partially or fully halogenated; C.sub.1-3 alkyl or
C.sub.1-3 alkoxy optionally partially or fully halogenated or
optionally substituted with R.sub.1.sub.7; OR.sub.18 or C.sub.1-3
alkyl optionally substituted with OR.sub.18; amino or mono- or
di-(C.sub.1-3 alkyl)amino optionally substituted with R.sub.19;
R.sub.20C(O)N(R.sub.21)--, R.sub.22O--; R.sub.23R.sub.24NC(O)--;
R.sub.26CH.sub.2C(O)N(R.sub.21)--, NH.sub.2C(O)methoxy or
R.sub.26C(O)CH.sub.2N(R.sub.21)--; C.sub.2-4 alkenyl substituted by
R.sub.23R.sub.24NC(O)--; or C.sub.2-4 alkynyl substituted with
pyrroldinyl or pyrrolyl; C.sub.1-3acyl and R.sub.23 and R.sub.24
taken together optionally form morpholino.
[0739] A yet further preferred subgeneric aspect of the invention
comprises a method of using the compounds of the formula (III), as
described in the immediate previous paragraph, and wherein:
[0740] 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, benzooxalolyl,
2,3-dihydrobenzooxazol-7-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl,
indolinyl, indolonyl, or indolinonyl, wherein G is optionally
substituted by one or more R.sub.1, R.sub.2 or R.sub.3; [0741] Ar
is 1-naphthyl; [0742] X is: phenyl, imidazolyl, pyridinyl,
pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl;
[0743] Y is: a bond or --CH.sub.2--, --CH.sub.2CH.sub.2--,
--C(O)--, --O--, --S--, --NH--CH.sub.2CH.sub.2CH.sub.2--,
--N(CH.sub.3)--, CH.sub.2(CN)CH.sub.2--NH--CH.sub.2 or --NH--;
[0744] Z is morpholino, dioxolanyl, tetrahydrofuranyl, pyridinyl,
2-oxa-5-aza-bicyclo[2.2.1]heptanyl,
C.sub.1-3alkoxyphenylpiperazinyl, hydroxy, C.sub.1-3alkyl,
N,N-diC.sub.1-3alkoxyC.sub.1-3alkylamino, C.sub.1-3acylamino,
C.sub.1-3alkylsulfonyl or nitrileC.sub.1-3alkyl; each R.sub.1 is
independently: C.sub.1-5 alkyl optionally partially or fully
halogenated wherein one or more C atoms are optionally
independently replaced by O or N, and wherein said C.sub.1-5 alkyl
is optionally substituted with oxo, dioxolanyl, pyrrolidinyl, furyl
or phenyl optionally substituted by C.sub.1-3alkoxy; 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; [0745]
R.sub.2 is is mono- or di-C.sub.1-3acylamino, amino-S(O).sub.m or
S(O).sub.m amino wherein the N atom is mono- or di-substituted by
C.sub.1-3alkyl or phenyl, bromo, chloro, fluoro, nitrile, nitro,
amino, methylsulfonyl optionally partially or fully halogenated or
phenylsulfonyl; [0746] each R.sub.3 is independently: phenyl,
morpholino, pyridinyl, pyrimidinyl, pyrrolidinyl,
2,5-pyrrolidin-dionyl, imidazolyl, [1,3,4]oxadiazol or pyrazolyl,
each is optionally substituted with C.sub.1-2 alkyl which is
optionally partially or fully halogenated; C.sub.1-3 alkyl or
C.sub.1-3 alkoxy each being optionally partially or fully
halogenated or optionally substituted with diethylamino; OR.sub.18
or C.sub.1-3 alkyl optionally substituted with OR.sub.18; amino or
mono- or di-(C.sub.1-3 alkyl)amino optionally substituted with
R.sub.19; CH.sub.3C(O)NH--, R.sub.22O--; R.sub.23R.sub.24NC(O)--;
R.sub.26CH.sub.2C(O)N(R.sub.21)--, NH.sub.2C(O)methoxy or
R.sub.26C(O)CH.sub.2N(R.sub.21)--; C.sub.2-4alkenyl substituted by
R.sub.23R.sub.24NC(O)--; or C.sub.2-4 alkynyl substituted with
pyrroldinyl or pyrrolyl; C.sub.1-2acyl; and R.sub.23 and R.sub.24
are H or R.sub.23 and R.sub.24 taken together optionally form
morpholino; and R.sub.26 is morpholino.
[0747] A further preferred subgeneric aspect of the invention
comprises a method of using the compounds of the formula (III), as
described in the immediate previous paragraph, and wherein: [0748]
G is phenyl, pyridinyl, 5-indolyl,
3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl, benzooxalolyl,
2,3-dihydrobenzooxazol-7-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl or
2-naphthyl wherein G is optionally substituted by one or more
R.sub.1, R.sub.2 or R.sub.3; [0749] X is: imidazolyl, pyridinyl,
pyrimidinyl or pyrazinyl; [0750] Y is: a bond,
CH.sub.2(CN)CH.sub.2--NH--CH.sub.2, --CH.sub.2--,
--NH--CH.sub.2CH.sub.2CH.sub.2-- or --NH--; [0751] Z is
morpholin-4yl, dioxolan-2yl, tetrahydrofuranyl, pyridinyl,
2-oxa-5-aza-bicyclo[2.2.1]hept-5yl, methoxyphenylpiperazinyl,
hydroxy, methyl, N,N-dimethoxyethylamino, acetylamino,
methylsulfonyl or cyanoethyl; [0752] each R.sub.1 is independently:
tert-butyl, sec-butyl, tert-amyl, phenyl,
tetrahydropyran-2-yloxypropynyl, hydroxypropynyl, trihalomethyl,
2,2-diethylpropionyl or cyclohexanyl; [0753] R.sub.2 is chloro,
nitro, amino, nitrile, methylsulfonylamino, diacetylamino,
phenylsulfonylamino, N,N-di(methylsulfonyl)amino, methylsulfonyl or
trihalomethylsulfonyl; [0754] R.sub.3 is independently: methyl,
C.sub.1-3 alkoxy, methoxymethyl, hydroxypropyl, dimethylamino,
C.sub.1-4alkylamino, NH.sub.2C(O)methoxy, acetyl, pyrrolidinyl,
imidazolyl, pyrazolyl, morpholino or morpholinocarbonyl.
[0755] A still yet further preferred subgeneric aspect of the
invention comprises a method of using the compounds of the formula
(III), as described in the immediate previous paragraph, and
wherein: [0756] X is pyridinyl.
[0757] A still yet further preferred subgeneric aspect of the
invention comprises a method of using the compounds of the formula
(III), as described immediately above, and wherein [0758] the
pyridinyl is attached to Ar via the 3-pyridinyl position.
[0759] The following compounds are representative of the compounds
of formula (II) which are useful in the novel methods described
herein: [0760]
1-(4-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl-
)-naphthalen-1-yl]-urea; [0761]
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-
-yl)-naphthalen-1-yl]-urea; [0762]
1-(6-Chloro-4-trifluoromethyl-pyridin-2-yl)-3-[4-(6-morpholin-4-ylmethyl--
pyridin-3-yl)-naphthalen-1-yl]-urea; [0763]
1-(4-Difluoromethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-urea; [0764]
1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-urea; [0765]
1-[2-Methoxy-5-(1-methyl-1-phenyl-ethyl)-phenyl]-3-[4-(6-morpholin-4-ylme-
thyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0766]
(5-tert-Butyl-2-methyl-phenyl)-carbamic acid
3-(5-{4-[3-(5-tert-butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyridi-
n-2-ylamino)-propyl ester; [0767]
1-(6-tert-Butyl-benzo[1,3]dioxol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea; [0768]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-acetamide; [0769]
1,3-Bis-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
[0770]
1-[5-tert-Butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-hydro-
xy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ure-
a; [0771]
1-[5-tert-Butyl-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-[4-(6-morpholin-4--
ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0772]
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-morpho-
lin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0773]
1-(2,3-Dimethyl-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
-naphthalen-1-yl]-urea; [0774]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2-p-tolylo-
xy-5-trifluoromethyl-phenyl)-urea; [0775]
1-[2-(2-Methoxy-phenoxy)-5-trifluoromethyl-phenyl]-3-[4-(6-morpholin-4-yl-
methyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0776]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-naphthalen--
1-yl-urea; [0777]
1-{5-tert-Butyl-2-methyl-3-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phe-
nyl}-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
[0778]
1-{5-tert-Butyl-2-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phen-
yl}-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
[0779]
1-(5-Hydroxymethyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl--
pyridin-3-yl)-naphthalen-1-yl]-urea; [0780]
1-(2-Methoxy-dibenzofuran-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl-
)-naphthalen-1-yl]-urea; [0781]
1-(2,5-Di-tert-butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-urea; [0782]
1-[3-(4-Bromo-1-methyl-1H-pyrazol-3-yl)-phenyl]-3-[4-(6-morpholin-4-ylmet-
hyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0783]
1-(3-Hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylme-
thyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0784]
1-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea; [0785]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-oxazol-5-
-yl-phenyl)-urea; [0786]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-[1,3,4]o-
xadiazol-2-yl-phenyl)-urea; [0787]
1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea; [0788] Furan-2-carboxylic acid
(4-tert-butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1--
yl]-ureido}-phenyl)-amide; [0789]
1-(2-Methoxy-4-phenylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
-yl)-naphthalen-1-yl]-urea; [0790]
1-(5-Methoxy-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)--
naphthalen-1-yl]-urea; [0791]
1-(3-Hydroxy-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)--
naphthalen-1-yl]-urea; [0792] N,N-Diethyl-4-methoxy-3-{3-[4-(6-
morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzenesulfon-
amide; [0793]
1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea; [0794]
1-[5-(1,1-Dimethyl-propyl)-2-phenoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
-pyridin-3-yl)-naphthalen-1-yl]-urea; [0795]
1-[5-(2,2-Dimethyl-propionyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmeth-
yl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0796]
2-Chloro-5-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-u-
reido}-benzoic acid isopropyl ester; [0797]
1-(4-Amino-3,5-dibromo-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
-naphthalen-1-yl]-urea; [0798]
1-[5-tert-Butyl-3-(3-hydroxy-prop-1-ynyl)-2-methyl-phenyl]-3-[4-(6-morpho-
lin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0799]
1-[5-tert-Butyl-2-(3-hydroxy-prop-1-ynyl)-phenyl]-3-[4-(6-morpholin-4-ylm-
ethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0800]
1-[5-tert-Butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-methoxy-pheny-
l]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
[0801]
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-methoxy-phenyl]-3-[4-(-
6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0802]
1-(5-tert-Butoxy-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
-yl)-naphthalen-1-yl]-urea; [0803]
1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
-pyridin-3-yl)-naphthalen-1-yl]-urea; [0804]
1-[5-tert-Butyl-3-(2-diethylamino-ethyl)-2-methoxy-phenyl]-3-[4-(6-morpho-
lin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0805]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-[1,3]dioxolan-2-yl-pyridin-3-yl-
)-naphthalen-1-yl]-urea; [0806]
1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea; [0807]
1-(5-tert-Butyl-2-dimethylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyri-
din-3-yl)-naphthalen-1-yl]-urea; [0808]
1-(5-tert-Butyl-2-propoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3--
yl)-naphthalen-1-yl]-urea; [0809]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-nap-
hthalen-1-yl]-urea; [0810]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmet-
hyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0811]
2-(5-tert-Butyl-2-methoxy-phenyl)-N-[4-(6-morpholin-4-ylmethyl-pyridin-3--
yl)-naphthalen-1-yl]-acetamide; [0812]
1-(2-Methoxy-5-phenoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
-naphthalen-1-yl]-urea; [0813]
1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-7-yl)-3-[4-(6-morpholin-4-ylme-
thyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0814]
1-(5-tert-Butyl-2-cyclopentyloxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyr-
idin-3-yl)-naphthalen-1-yl]-urea; [0815]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-pyridin-3-yl-pyrrolidin-1-yl-
methyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0816]
1-(5-Cyclohexyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3--
yl)-naphthalen-1-yl]-urea; [0817]
1-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-p-
yridin-3-yl)-naphthalen-1-yl]-urea; [0818]
1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-3-[4-(6-morph-
olin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0819]
1-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea; [0820]
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-na-
phthalen-1-yl]-urea; [0821]
N-Acetyl-N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide; [0822]
1-(6-tert-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;
[0823]
1-[6-tert-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; [0824]
1-(5-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-y-
l)-naphthalen-1-yl]-urea; [0825]
1-(5-tert-Butyl-2-isopropoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-
-3-yl)-naphthalen-1-yl]-urea; [0826]
1-(5-tert-Butyl-2-imidazol-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyri-
din-3-yl)-naphthalen-1-yl]-urea; [0827]
N-(5-tert-Butyl-2-methoxy-4-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide; [0828]
1-(5-tert-Butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmeth-
yl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0829]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-bis(methanesulfon)amide; [0830]
1-[5-tert-Butyl-2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4--
ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0831]
1-(2-Methanesulfinyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmeth-
yl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0832]
1-(2-Ethanesulfonyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethy-
l-pyridin-3-yl)-naphthalen-1-yl]-urea; [0833]
1-[4-(6-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-
-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea; [0834]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-dimethylamino-pyrrolidin-1-y-
lmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0835]
N-[1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-py-
ridin-2-ylmethyl)-pyrrolidin-3-yl]-acetamide; [0836]
1-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-y-
lmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0837]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-propionamide; [0838]
1-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-p-
yridin-3-yl)-naphthalen-1-yl]-urea; [0839]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluor-
omethanesulfonyl-phenyl)-urea; [0840]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-isobutyramide; [0841]
2-(4-tert-Butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen--
1-yl]-ureido}-phenoxy)-acetamide; [0842]
1-(5-tert-Butyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-3-[4-(6-morpholin-4-y-
lmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0843]
1-(6-tert-Butyl-3-cyano-2-methoxymethoxy-pyridin-4-yl)-3-[4-(6-morpholin--
4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0844]
1-(6-tert-Butyl-3-cyano-2-hydroxy-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmet-
hyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0845]
1-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea; [0846]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(1,3,3-trim-
ethyl-2,3-dihydro-1H-indol-5-yl)-urea; [0847]
1-(5-tert-Butyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3--
yl)-naphthalen-1-yl]-urea; [0848]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-benzenesulfonamide; [0849]
Ethanesulfonic acid
(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-nap-
hthalen-1-yl]-ureido}-phenyl)-amide; [0850]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin--
1-yl)-naphthalen-1-yl]-urea; [0851]
1-[5-tert-Butyl-2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-3-[4-(4-morpholin-4--
ylmethyl-piperidin-1-yl)-naphthalen-1-yl]-urea; [0852]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin--
5-yl)-naphthalen-1-yl]-urea; [0853]
1-(5-tert-Butyl-2-methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyr-
idin-3-yl)-naphthalen-1-yl]-urea; [0854]
1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyri-
din-3-yl)-naphthalen-1-yl]-urea; [0855]
2,2,2-Trifluoro-ethanesulfonic acid
(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl-
)-naphthalen-1-yl]-ureido}-phenyl)-amide; [0856]
N-(5-{4-[3-(5-tert-Butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyrazi-
n-2-yl)-methanesulfonamide; [0857]
1-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-y-
l]-3-(5-tert-butyl-2-methoxy-phenyl)-urea; [0858]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-
-pyridin-3-yl]-naphthalen-1-yl}-urea; [0859]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-urea; [0860]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-piperidin-1-ylmet-
hyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0861]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-tetrahydro-thiopyran-4-y-
lamino)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0862]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-py-
ridin-3-yl]-naphthalen-1-yl}-urea; [0863]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-(tetrahydro-f-
uran-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
[0864]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxymethyl-morpho-
lin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0865]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-morpholin-4-yl-ethylamino)--
methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea; [0866]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylm-
ethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0867]
1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyrid-
in-2-ylmethyl)-piperidine-3-carboxylic acid amide; [0868]
1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyrid-
in-2-ylmethyl)-piperidine-4-carboxylic acid amide; [0869]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylme-
thyl)-pyridin-pg,120 3-yl]-naphthalen-1-yl}-urea; [0870]
1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylme-
thyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0871]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-oxo-piperazin-1-ylmethyl)-py-
ridin-3-yl]-naphthalen-1-yl}-urea; [0872]
1-{4-[6-(4-Acetyl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-3--
(5-tert-butyl-2-methoxy-phenyl)-urea; [0873]
4-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyrid-
in-2-ylmethyl)-piperazine-1-carboxylic acid ethyl ester; [0874]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-pyridin-3-yl-ethylamino)-me-
thyl]-pyridin-3-yl}-naphthalen-1-yl)-urea; [0875]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(tetrahydro-furan-3-ylamino)-m-
ethyl]-pyridin-3-yl}-naphthalen-1-yl)-urea; [0876]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-pyridin-3-ylm-
ethyl-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea; [0877]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-methylsulfanyl-ethylamino)--
methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea; [0878]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-oxa-5-aza-bicyclo[2.2.1]hept-
-5-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0879]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmet-
hyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0880]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-piperazin-1-yl-ethylamino)--
methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea; [0881]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-pyrimidin-2-yl-piperazin-1-y-
lmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
[0882]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-pyridin-2-yl-piperaz-
in-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0883]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[4-(3-methoxy-phenyl)-piperazin-
-1-ylmethyl]-pyridin-3-yl}-naphthalen-1-yl)-urea; [0884]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(morpholine-4-carbonyl)-pyridin-
-3-yl]-naphthalen-1-yl}-urea; [0885]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-thia-5-aza-bicyclo[2.2.1]hep-
t-5-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0886]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2--
yl)-naphthalen-1-yl]-urea; [0887]
1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morph-
olin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0888]
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea; [0889]
N-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyrid-
in-2-yl)-acetamide; [0890]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-N-methyl-acetamide; [0891]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-2,2,2-trifluoro-acetamide; [0892]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-yloxy)-pyridin-3-yl]-
-naphthalen-1-yl}-urea; [0893]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-ylamino)-pyridin-3-y-
l]-naphthalen-1-yl}-urea; [0894]
[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-carbamic
acid 3-tert-butyl-phenyl ester; [0895]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide and the
pharmaceutically acceptable derivatives thereof.
[0896] In another embodiment of the invention there are provided
the following compounds of formula (III) which are useful in the
novel methods described herein: [0897]
1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-urea; [0898]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-acetamide; [0899]
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-morpho-
lin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0900]
1-(2,3-Dimethyl-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-
-naphthalen-1-yl]-urea; [0901]
1-{5-tert-Butyl-2-methyl-3-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phe-
nyl}-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
[0902]
1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmeth-
yl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0903]
1-[5-(2,2-Dimethyl-propionyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmeth-
yl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0904]
1-[5-tert-Butyl-3-(3-hydroxy-prop-1-ynyl)-2-methyl-phenyl]-3-[4-(6-morpho-
lin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0905]
1-[5-tert-Butyl-2-(3-hydroxy-prop-1-ynyl)-phenyl]-3-[4-(6-morpholin-4-ylm-
ethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0906]
1-[5-tert-Butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-methoxy-pheny-
l]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
[0907]
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-methoxy-phenyl]-3-[4-(-
6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0908]
1-(5-tert-Butoxy-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-
-yl)-naphthalen-1-yl]-urea; [0909]
1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-
-pyridin-3-yl)-naphthalen-1-yl]-urea; [0910]
1-[5-tert-Butyl-3-(2-diethylamino-ethyl)-2-methoxy-phenyl]-3-[4-(6-morpho-
lin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0911]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-[1,3]dioxolan-2-yl-pyridin-3-yl-
)-naphthalen-1-yl]-urea; [0912]
1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea; [0913]
1-(5-tert-Butyl-2-dimethylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyri-
din-3-yl)-naphthalen-1-yl]-urea; [0914]
1-(5-tert-Butyl-2-propoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3--
yl)-naphthalen-1-yl]-urea; [0915]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-nap-
hthalen-1-yl]-urea; [0916]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmet-
hyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0917]
1-(5-Cyclohexyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3--
yl)-naphthalen-1-yl]-urea; [0918]
1-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-p-
yridin-3-yl)-naphthalen-1-yl]-urea; [0919]
1-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea; [0920]
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-na-
phthalen-1-yl]-urea; [0921]
N-Acetyl-N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide; [0922]
1-(6-tert-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;
[0923]
1-(5-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-y-
l)-naphthalen-1-yl]-urea; [0924]
1-(5-tert-Butyl-2-isopropoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-
-3-yl)-naphthalen-1-yl]-urea; [0925]
1-(5-tert-Butyl-2-imidazol-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyri-
din-3-yl)-naphthalen-1-yl]-urea; [0926]
1-(5-tert-Butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmeth-
yl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0927]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-bis(methanesulfon)amide; [0928]
1-[5-tert-Butyl-2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4--
ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0929]
1-(2-Methanesulfinyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmeth-
yl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0930]
1-[4-(6-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-
-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea; [0931]
N-[1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-py-
ridin-2-ylmethyl)-pyrrolidin-3-yl]-acetamide; [0932]
1-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-y-
lmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0933]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-propionamide; [0934]
1-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-p-
yridin-3-yl)-naphthalen-1-yl]-urea; [0935]
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluor-
omethanesulfonyl-phenyl)-urea; [0936]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-isobutyramide; [0937]
2-(4-tert-Butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen--
1-yl]-ureido}-phenoxy)-acetamide; [0938]
1-(5-tert-Butyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-3-[4-(6-morpholin-4-y-
lmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0939]
1-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea; [0940]
1-(5-tert-Butyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3--
yl)-naphthalen-1-yl]-urea; [0941]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-benzenesulfonamide; [0942]
Ethanesulfonic acid
(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-nap-
hthalen-1-yl]-ureido}-phenyl)-amide; [0943]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin--
5-yl)-naphthalen-1-yl]-urea; [0944]
1-(5-tert-Butyl-2-methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyr-
idin-3-yl)-naphthalen-1-yl]-urea; [0945]
1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyri-
din-3-yl)-naphthalen-1-yl]-urea; [0946]
2,2,2-Trifluoro-ethanesulfonic acid
(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl-
)-naphthalen-1-yl]-ureido}-phenyl)-amide; [0947]
N-(5-{4-[3-(5-tert-Butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyrazi-
n-2-yl)-methanesulfonamide; [0948]
1-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-y-
l]-3-(5-tert-butyl-2-methoxy-phenyl)-urea; [0949]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-
-pyridin-3-yl]-naphthalen-1-yl}-urea; [0950]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridi-
n-3-yl)-naphthalen-1-yl]-urea; [0951]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-piperidin-1-ylmet-
hyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0952]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-tetrahydro-thiopyran-4-y-
lamino)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0953]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-py-
ridin-3-yl]-naphthalen-1-yl}-urea; [0954]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-(tetrahydro-f-
uran-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
[0955]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxymethyl-morpho-
lin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0956]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylm-
ethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0957]
1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyrid-
in-2-ylmethyl)-piperidine-3-carboxylic acid amide; [0958]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylme-
thyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0959]
1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylme-
thyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0960]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-oxo-piperazin-1-ylmethyl)-py-
ridin-3-yl]-naphthalen-1-yl}-urea; [0961]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(tetrahydro-furan-3-ylamino)-m-
ethyl]-pyridin-3-yl}-naphthalen-1-yl)-urea; [0962]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-pyridin-3-ylm-
ethyl-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea; [0963]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-oxa-5-aza-bicyclo[2.2.1]hept-
-5-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0964]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmet-
hyl)-pyridin-3-yl]-naphthalen-1-yl}-urea; [0965]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[4-(3-methoxy-phenyl)-piperazin-
-1-ylmethyl]-pyridin-3-yl}-naphthalen-1-yl)-urea; [0966]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(morpholine-4-carbonyl)-pyridin-
-3-yl]-naphthalen-1-yl}-urea; [0967]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2--
yl)-naphthalen-1-yl]-urea; [0968]
1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morph-
olin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0969]
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-py-
ridin-3-yl)-naphthalen-1-yl]-urea; [0970]
N-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyrid-
in-2-yl)-acetamide; [0971]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-N-methyl-acetamide; [0972]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-2,2,2-trifluoro-acetamide; [0973]
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-yloxy)-pyridin-3-yl]-
-naphthalen-1-yl}-urea; [0974]
[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-carbamic
acid 3-tert-butyl-phenyl ester; [0975]
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-n-
aphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide and the
pharmaceutically acceptable derivatives thereof.
[0976] In addtion to the abovementioned compounds the following
prophetic compounds of the formula (III) may be useful in the novel
methods described herein: [0977]
1-(5-tert-Butyl-2-methylsulfanyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmeth-
yl-pyridin-3-yl)-naphthalen-1-yl]-urea; [0978]
1-(5-tert-Butyl-2-chloro-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyrid-
in-3-yl)-naphthalen-1-yl]-urea; [0979]
1-(5-tert-Butyl-2-methylamino-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl--
pyridin-3-yl)-naphthalen-1-yl]-urea; [0980]
N-(5-tert-Butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen--
1-yl]-ureido}-2-oxo-2H-pyridin-1-yl)-methanesulfonamide; [0981]
5-tert-Butyl-7-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-y-
l]-ureido}-benzooxazole-2-carboxylic acid amide; [0982]
2-(5-tert-Butyl-7-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen--
1-yl]-ureido}-benzooxazol-2-yl)-acetamide; [0983]
5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naph-
thalen-1-yl]-ureido}-benzamide and the pharmaceutically acceptable
derivatives thereof.
[0984] The invention includes the use of any compounds of described
above 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 included in the present invention.
Each stereogenic carbon may be in the R or S configuration, or a
combination of configurations.
[0985] Some of the compounds of formulas (I), (Ia), (II) and (III)
can exist in more than one tautomeric form. The invention includes
methods using all such tautomers.
[0986] 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, "C.sub.1-4alkoxy" is a
C.sub.1-4alkyl with a terminal oxygen, such as methoxy, ethoxy,
propoxy, pentoxy and hexoxy. All alkyl, alkenyl and alkynyl groups
shall be understood as being branched or unbranched where
structurally possible and unless otherwise specified. Other more
specific definitions are as follows:
[0987] The term "aroyl" as used in the present specification shall
be understood to mean "benzoyl" or "naphthoyl".
[0988] The term "carbocycle" shall be understood to mean an
aliphatic hydrocarbon radical 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, 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.
[0989] 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 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,
tertrahydropyridinyl, homopiperidinyl, pyrrolinyl,
tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl,
thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl,
oxocanyl, heptacanyl, thioxanyl, dithianyl or 2-oxa- or
2-thia-5-aza-bicyclo[2.2.1]heptanyl.
[0990] The term "heteroaryl" shall be understood to mean an
aromatic 5-8 membered monocyclic or 8-11 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, benzoxazolyl, benzofuranyl,
benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl,
dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl,
benzodioxolyl, benzo[1,3]dioxol-2-onyl, tetrahydrobenzopyranyl,
indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl.
[0991] The invention includes methods of using pharmaceutically
acceptable derivatives of compounds of formula (I), (Ia), (II) and
(III). A "pharmaceutically acceptable derivative" refers to any
pharmaceutically acceptable salt or ester, or any other compound
which, upon administration to a patient, is capable of providing
(directly or indirectly) a compound useful for the invention, or 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
formulas (I), (Ia), (II) or (III).
[0992] Pharmaceutically acceptable salts include those derived from
pharmaceutically acceptable inorganic and organic acids and bases.
Examples of suitable acids include hydrochloric, hydrobromic,
sulfuric, nitric, perchloric, fumaric, maleic, 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
intermediates in obtaining the compounds 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--(C.sub.1-C.sub.4
alkyl).sub.4.sup.+ salts.
[0993] In addition, within the scope of the invention is use of
prodrugs of compounds of the formula (I), (Ia), (II) and (III).
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 is administered to a
patient, the prodrug may be transformed into a compound disclosed
hereinabove, thereby imparting the desired pharmacological
effect.
Methods of Use
[0994] In accordance with the invention, there are provided novel
methods of using the compounds of the formulas (I), (Ia), (II) and
(III). as described in WO 00/55139 and U.S. application Ser. No.
09/505,582. The compounds disclosed therein 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
are described in WO 00/55139 as being useful for the treatment of
the following conditions and diseases: osteoarthritis, multiple
sclerosis, Guillain-Barre syndrome, Crohn's disease, ulcerative
colitis, psoriasis, graft versus host disease, systemic lupus
erythematosus and insulin-dependent diabetes mellitus, rheumatoid
arthritis, Alzheimer's disease, toxic shock syndrome, diabetes,
inflammatory bowel diseases, acute and chronic pain as well as
symptoms of inflammation and cardiovascular disease, stroke,
myocardial infarction, alone or following thrombolytic therapy,
thermal injury, adult respiratory distress syndrome (ARDS),
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 entrerocolitis.
[0995] Suprisingly, it has been discovered for the first time that
the compounds disclosed in WO 00/55139 are useful in methods for
treating: acute and chronic inflammation in the lung caused by
inhalation of smoke, endometriosis, Behcet's disease, uveitis,
ankylosing spondylitis, pancreatitis, cancer, Lyme disease,
restenosis following percutaneous transluminal coronary
angioplasty, Alzheimer's disease, traumatic arthritis, sepsis,
chronic obstructive pulmonary disease and congestive heart
failure.
[0996] For therapeutic use, the compounds 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.
[0997] The compounds 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 dosages of the conventional
therapeutics, thus avoiding possible toxicity and adverse side
effects incurred when those agents are used as monotherapies. The
above described compounds may be physically combined with the
conventional therapeutics or other adjuvants into a single
pharmaceutical composition. Reference is this regard may be made to
Cappola et al.: U.S. patent application Ser. No. 09/902,822 and
PCT/US 01/21860 each incorporated by reference herein in their
entirety. Advantageously, the compounds may then be administered
together in a single dosage form. In some embodiments, the
pharmaceutical compositions comprising such combinations of
compounds contain at least about 5%, but more preferably at least
about 20%, of a compound of formulas (I), (Ia), (II) and (III)
(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
dosing allows for greater flexibility in the dosing regime.
[0998] As mentioned above, dosage forms of the compounds described
herein 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, aluminum
stearate, lecithin, serum proteins, buffer substances, water, salts
or electrolytes and cellulose-based substances. Preferred dosage
forms include, tablet, capsule, caplet, 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, Pharmaceutical Dosage Forms and Drug 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.
General Synthetic Methods
[0999] The compounds described hereinabove may be prepared by
Method A, B, or C as illustrated in Scheme I, preferably method C,
in WO 00/55139. Starting materials used are either commercially
available or easily prepared from commercially available materials
known by those skilled in the art. Further reference in this regard
may be made to U.S. application Ser. Nos. 09/505,582, 09/484,638,
09/714,539, 09/611,109, 09/698,442 and U.S. provisional application
No. 60/216,283. Each of the aforementioned incorporated herein by
reference in their entirety.
Assessment of Biolocical Properties
Inhibition of TNF Production in THP Cells
[1000] The inhibition of cytokine production can be observed by
measuring inhibition of TNF.alpha. 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
(2.times.10.sup.6 cells/ml, final conc.; American Type Culture
Company, Rockville, Md.) were added to 96 well polypropylene round
bottomed culture plates (Costar 3790; sterile) containing 125 .mu.l
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.degree. C., 5% CO.sub.2
prior to stimulation with lipopolysaccharide (LPS; 1 .mu.g/ml
final; Siga L-2630, from E.coli serotype 0111. B4; stored as 1
mg/ml stock in endotoxin screened distilled H.sub.2O at -80.degree.
C.). Blanks (unstimulated) received H.sub.2O vehicle; final
incubation volume was 250 .mu.l. Overnight incubation (18-24 hr)
proceeded as described above. Assay was terminated by centrifuging
plates 5 min, room temperature, 1600 rpm (400.times.g);
supernatants were transferred to clean 96 well plates and stored
-80.degree. C. until analyzed for human TNF.alpha. by a
commercially available ELISA kit (Biosource #KHC3015, Camarillo,
Calif.). 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 IC50 value is the
concentration of the test compound that caused a 50% decrease in
the maximal TNF.alpha. production.
[1001] Preferred compounds including those from the synthetic
examples above were evaluated and had IC.sub.50<10 uM in this
assay.
Inhibition of Other Cytokines
[1002] 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-1beta, GM-CSF, IL-6 and IL-8
can be demonstrated for preferred compounds (for example, see J. C.
Lee et al., 1988, Int. J. Immunopharmacol., 10,835).
* * * * *