Note: Descriptions are shown in the official language in which they were submitted.
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~-Carboxyaryl substituted diphenyl ureas as raf kinase
inhibitors
Field of the Invention
This invention relates to the use of a group of
aryl ureas in treating raf mediated diseases, and
pharmaceutical compositions for use in such therapy.
Background of the Invention
The p2lras oncogene is a major contributor to the
development and progression of human solid cancers and is
mutated in 30% of all human cancers (Bolton et al. Ann. Rep.
Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49,
4682-9). In its normal, unmutated form, the ras protein is
a key element of the signal transduction cascade directed by
growth factor receptors in almost all tissues (Avruch et al.
Trends Biochem. Sci. 1994, 19, 279-83). Biochemically, ras
is a guanine nucleotide binding protein, and cycling between
a GTP-bound activated and a GDP-bound resting form is
strictly controlled by ras' endogenous GTPase activity and
other regulatory proteins. In the ras mutants in cancer
cells, the endogenous GTPase activity is alleviated and,
therefore, the protein delivers constitutive growth signals
to downstream effectors such as the enzyme raf kinase. This
leads to the cancerous growth of the cells which carry these
mutants (Magnuson et al. Semin. Cancer Biol. 1994, 5,
247-53). It has been shown that inhibiting the effect of
active ras by inhibiting the raf kinase signaling pathway by
administration of deactivating antibodies to raf kinase or
by co-expression of dominant negative raf kinase or dominant
negative MEK, the substrate of
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raf kinase, leads to the reversion of transformed cells to the normal growth
phenotype (see:
Daum et al. Trends Biochem. Sci. 1994, 19, 474-80; Fridman et al. J. Biol.
Chem. 1994, 269,
30105-8. Kolch et al. (Nature 1991, 349, 426-28) have further indicated that
inhibition of raf
expression by antisense RNA blocks cell proliferation in membrane-associated
oncogenes.
Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) has
been correlated in
vitro and in vivo with inhibition of the growth of a variety of human tumor
types (Monia et
al., Nat. Med. 1996, 2, 668-75).
Summary of the Invention
1o The present invention provides compounds which are inhibitors of the enzyme
raf kinase.
Since the enzyme is a downstream effector of p21'as, the inhibitors are useful
in
pharmaceutical compositions for human or veterinary use where inhibition of
the raf kinase
pathway is indicated, e.g., in the treatment of tumors and/or cancerous cell
growth mediated
by raf kinase. In particular, the compounds are useful in the treatment of
human or animal
solid cancers, e.g., murine cancer, since the progression of these cancers is
dependent upon
the ras protein signal transduction cascade and therefore susceptible to
treatment by
interruption of the cascade, i.e., by inhibiting raf kinase. Accordingly, the
compounds of the
invention are useful in treating cancers, including solid cancers, such as,
for example,
carcinomas (e.g., of the lungs, pancreas, thyroid, bladder or colon), myeloid
disorders (e.g.,
2o myeloid leukemia) or adenomas (e.g., villous colon adenoma).
The present invention therefore provides compounds generally described as aryl
ureas,
including both aryl and heteroaryl analogues, which inhibit the raf kinase
pathway. The
invention also provides a method for treating a raf mediated disease state in
humans or
mammals. Thus, the invention is directed to compounds which inhibit the enzyme
raf kinase
and also compounds, compositions and methods for the treatment of cancerous
cell growth
mediated by raf kinase wherein a compound of Formula I is administered or
pharmaceutically
acceptable salt thereof.
°'-D-B (I)
~o In forn~ula I, D is -NH-C(O)-NH-,
2
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A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L ~
)q , .
where L is a 5 or 6 membered cyclic structure bound directly to D, L'
comprises a
substituted cyclic moiety having at least 5 members, M is a bridging group
having at least
one atom, q is an integer of from 1-3; and each cyclic structure of L and L'
contains 0-4
members of the group consisting of nitrogen, oxygen and sulfur, and
B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety
of up to
30 carbon atoms with at least one 6-member cyclic structure bound directly to
D containing
0-4 members of the group consisting of nitrogen, oxygen and sulfur,
wherein L' is substituted by at least one substituent selected from the group
consisting
to of -SOZRx, -C(O)RX and -C(NRy) RZ,
RY is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally
containing heteroatoms selected from N, S and O and optionally
halosubstituted, up to per
halo,
RZ is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally
containing heteroatoms selected from N, S and O and optionally substituted by
halogen,
hydroxy and carbon based substituents of up to 24 carbon atoms, which
optionally contain
heteroatoms selected from N, S and O and are optionally substituted by
halogen;
RX is RZ or NRaRb where Ra and Rb are
a) independently hydrogen,
2o a carbon based moiety of up to 30 carbon atoms optionally containing
heteroatoms selected from N, S and O and optionally substituted by halogen,
hydroxy and
carbon based substituents of up to 24 carbon atoms, which optionally contain
heteroatoms
selected from N, S and O and are optionally substituted by halogen, or
-OSi(Rf)3 where R,~ is hydrogen or a carbon based moiety of up to 24 carbon
?5 atoms optionally containing heteroatoms selected from N, S and O and
optionally substituted
by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms,
which
optionally contain heteroatoms selected from N, S and O and are optionally
substituted by
halogen; or
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b) Ra and Rb together form a S-7 member heterocyclic structure of 1-3
heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic
structure of
1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or
carbon based
substituents of up to 24 carbon atoms, which optionally contain heteroatoms
selected from N,
S and O and are optionally substituted by halogen; or
c) one of Ra or Rb is -C(O)-, a C~-CS divalent alkylene group or a substituted
C,-
CS divalent alkylene group bound to the moiety L to form a cyclic structure
with at least 5
members, wherein the substituents of the substituted Cl-CS divalent alkylene
group are
selected from the group consisting of halogen, hydroxy, and carbon based
substituents of up
to to 24 carbon atoms, which optionally contain heteroatoms selected from N, S
and O and are
optionally substituted by halogen;
where B is substituted, L is substituted or L' is additionally substituted,
the
substituents are selected from the group consisting of halogen, up to per-
halo, and Wn, where
n is 0-3;
wherein each W is independently selected from the group consisting of -CN, -
COZR',
-C(O)NR'R', -C(O)-R', -NOz, -OR', -SR', -NR'R', -NR'C(O)OR', -NR'C(O)R', -Q-
Ar, and
carbon based moieties of up to 24 carbon atoms, optionally containing
heteroatoms selected
from N, S and O and optionally substituted by one or more substituents
independently
selected from the group consisting of -CN, -COzR', -C(O)R', -C(O)NR'R', -OR', -
SR', -
2o NR'R', -NOz, -NR'C(O)R', -NR'C(O)OR' and halogen up to per-halo; with each
R'
independently selected from H or a carbon based moiety of up to 24 carbon
atoms, optionally
containing heteroatoms selected from N, S and O and optionally substituted by
halogen,
wherein Q is -O-, -S-, -N(R')-, -(CHz)m , -C(O)-, -CH(OH)-, -(CHz)m0-, -
(CHz)mS-,
-(CHz)mN(R')-, -O(CHz)m- CHXa-, -CXaz-, -S-(CHz)m and -N(R')(CHz)m , where m=
1-3,
and Xa is halogen; and
Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from
the
group consisting of nitrogen, oxygen and sulfur, which is optionally
substituted by halogen,
up to per-halo, and optionally substituted by Z",, wherein n1 is 0 to 3 and
each Z is
independently selected from the group consisting of -CN, -COzR', -C(O)RD, -
C(O)NR-R .
',~IO~, -OR'. - SR' -NR'R', -NR'C(O)OR', -NR'C(O)R', and a carbon based moiety
of up to
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24 carbon atoms, optionally containing heteroatoms selected from N, S and O
and optionally
substituted by one or more substituents selected from the group consisting of -
CN, -CO~R', -
COR', -C(O)NR'R', -OR', -SR', -N02, -NR'R', -NR'C(O)R', and -NR'C(O)OR', with
R' as
def ned above.
In formula I, suitable hetaryl groups include, but are not limited to, 5-12
carbon-atom
aromatic rings or ring systems containing 1-3 rings, at least one of which is
aromatic, in
which one or more, e.g., 1-4 carbon atoms in one or more of the rings can be
replaced by
oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms. For
example, B can be
2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-
, 4- or 5-imidazolyl,
1-, 3-,.4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4-
or 5-thiazolyl, 3-,
4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-
triazol-1-, -4- or -S-
yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -
5-yl, 1,2,4-
oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -S-yl, 1,2,4-oxadiazol-3- or -5-
yl, 1,3,4-
thiadiazol-2- or -5-yl, 1,3,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -
5-yl, 2-, 3-, 4-, S-
or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl,
pyrazinyl, 2-, 3-, 4-, 5-,
6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-,
6- or 7-indolyl, 1-, 2-,
4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6-
or 7-benzoxazolyl,
3-, 4-, 5- 6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-,
4-, 5-, 6- or 7-
2o benzisothiazolyl, 2-, 4-, 5-, 6- or 7-bent-1,3-oxadiazolyl, 2-, 3-, 4-, 5-,
6-, 7- or 8-quinolinyl,
1-, 3-, 4-, 5-, 6-, 7-, 8- isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-,
2-, 3-, 4-, 5-, 6-, 7-, 8-
or 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or additionally
optionally substituted
phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-
thiazolyl or 5-thiazolyl,
etc. For example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-
thienyl, I-
Z5 methyl-3-pyrryl, 1-methyl-3-pyrazolyl, S-methyl-2-thiazolyl or 5-methyl-
1,2,4-thiadiazol-2-
y1.
Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy, etc.
throughout
include methyl, ethyl, propyl, butyl, etc., including all straight-chain and
branched isomers
such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc.
;rr Suitable aryl groups which do not contain heteroatoms include, for
example. phcnvl
and 1- an~i _'-naphthvl.
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The term "cycloalkyl", as used herein, refers to
cyclic structures with or without alkyl substituents such
that, for example, "C9 cycloalkyl" includes methyl
substituted cyclopropyl groups as well as cyclobutyl groups.
The term "cycloalkyl", as used herein also includes
saturated heterocyclic groups.
Suitable halogen groups include F, Cl, Br,
and/or I, from one to per-substitution (i.e. all H atoms on
a group replaced by a halogen atom) being possible where an
alkyl group is substituted by halogen, mixed substitution of
halogen atom types also being possible on a given moiety.
The invention also relates to compounds per se, of
formula I.
The present invention is also directed to
pharmaceutically acceptable salts of formula I. Suitable
pharmaceutically acceptable salts are well known to those
skilled in the art and include basic salts of inorganic and
organic acids, such as hydrochloric acid, hydrobromic acid,
sulfuric acid, phosphoric acid, methanesulphonic acid,
trifluoromethanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, 1-naphthalenesulfonic acid,
2-naphthalenesulfonic acid, acetic acid, trifluoroacetic
acid, malic acid, tartaric acid, citric acid, lactic acid,
oxalic acid, succinic acid, furmaric acid, malefic acid,
benzoic acid, salicylic acid, phenylacetic acid, and
mandelic acid. In addition, pharmaceutically acceptable
salts include acid salts of inorganic bases, such as salts
containing alkaline cations (e. g., Li+, Na+ or K+), alkaline
earth cations (e . g. , Mg+2, Ca+2 or Ba+2) , the ammonium canon,
as well as acid salts of organic bases, including aliphatic
and aromatic substituted ammonium, and quaternary ammonium
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rations, such as those arising from protonation or
peralkylation of triethylamine, N,N-diethylamine,
N,N-dicyclohexylamine, lysine,
pyridine, N,N-dimethylaminopyridine (DMAP),
1,4-diazabicyclo[2.2.2]octane (DABCO),
1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and
1,8-diazabicyclo[5.4.0]under-7-ene (DBU).
According to another aspect of the present invention, there
is provided a compound selected from the group consisting
of: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-
carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-
(trifluoromethyl) phenyl) -N'- (3- (2- (N-methylcarbamoyl) -4-
pyridyloxy)phenyl)urea, N-(4-chloro-3-
(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-
pyridyloxy)phenyl)urea, N-(4-chloro-3-
(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)phenyl)urea, N-(4-chloro-3
(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-
methylcarbamoyl)(4-pyridyloxy))phenyl)urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-
methylcarbamoyl)-4-pyridyloxy)phenyl)urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-
methylcarbamoyl)-4-pyridyloxy)phenyl)urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-
methylcarbamoyl)-4-pyridylthio)phenyl)urea, N-(4-bromo-3-
(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-
methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(4-bromo-3-
(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-
methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(2-methoxy-4-
chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-
methylcarbamoyl)-4-pyridyloxy)phenyl)urea, and N-(2-methoxy-
4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-
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methylcarbamoyl)(4-pyridyloxy))phenyl)urea, or a
pharmaceutically acceptable salt thereof.
A number of the compounds of Formula I possess
asymmetric carbons and can therefore exist in racemic and
optically active forms. Methods of separation of
enantiomeric and diastereomeric mixtures are well known to
one skilled in the art. The present invention encompasses
any isolated racemic or optically active form of compounds
described in Formula I which possess raf inhibitory
activity.
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General Preparative Methods
The compounds of Formula I may be prepared by the use of known chemical
reactions and
procedures, some from starting materials which are commercially available.
Nevertheless,
general preparative methods are provided below to aid one skilled in the art
in synthesizing
these compounds, with more detailed examples being provided in the
Experimental section
which follows.
Substituted anilines may be generated using standard methods (March. Advanced
Organic
Chemistry, 3'd Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic
Transformations; VCH Publishers: New York (1989)). As shown in Scheme I, aryl
amines
are commonly synthesized by reduction of nitroaryls using a metal catalyst,
such as Ni, Pd, or
Pt, and HZ or a hydride transfer agent, such as formate, cyclohexadiene, or a
borohydride
(Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)).
Nitroaryls may
also be directly reduced using a strong hydride source, such as LiAlH4 (Seyden-
Penne.
Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH
Publishers: New
York ( 1991 )), or using a zero valent metal, such as Fe, Sn or Ca, often in
acidic media. Many
methods exist for the synthesis of nitroaryls (March. Advanced Organic
Chemistry, 3'd Ed.;
John Wiley: New York (1985). Larock. Comprehensive Organic Transformations;
VCH
Publishers: New York (1989)).
H21 catalyst
(eg. Ni, Pd, Pt)
ArN02 ~H ~ ArNH2
M(0)
(eg. Fe, Sn, Ca)
Scheme I Reduction of Nitroaryls to Aryl Amines
Nitroaryls are commonly formed by electrophilic aromatic nitration using HNO:,
or an
alternative NO,' source. Nitroaryls may be further elaborated prior to
reduction. Thus.
nitroaryls substituted with
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HN03
Ar-H ArN02
potential leaving groups (e.g. F, Cl, Br, etc.) may undergo substitution
reactions on treatment
with nucleophiles, such as thiolate (exemplified in Scheme II) or phenoxide.
Nitroaryls may
also undergo Ullman-type coupling reactions (Scheme II).
OzN
ArSH
\~F
base
1 02N \
R j ~ S-Ar
02N
Br-Ar
j~SH
R Cu0 / base
3
Scheme II Selected Nucleophilic Aromatic Substitution using Nitroaryls
Nitroaryls may also undergo transition metal mediated cross coupling
reactions. For
example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or
triflates, undergo
palladium mediated cross coupling reactions with aryl nucleophiles, such as
arylboronic acids
(Suzuki reactions, exemplified below), aryltins (Stifle reactions) or
arylzincs (Negishi
reaction) to afford the biaryl (5).
02N ~ ~ ArB(OR')2 02N
R j~X Pd(0) j- Ar
R
4 5
Either nitroaryls or anilines may be converted into the corresponding
arenesulfonyl chloride
(7) on treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride
with a fluoride
source, such as KF then affords sulfonyl fluoride (8). Reaction of sulfonyl
fluoride 8 with
trimethylsilyl trifluoromethane in the presence of a fluoride source, such as
tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF) leads to the
corresponding
trifluoromethylsulfone (9). Alternatively, sulfonyl chloride 7 may be reduced
to the
arenethiol ( 10), for example with zinc amalgum. Reaction of thiol 10 with
CHC1F~ in the
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presence of base gives the difluoromethyl mercaptam (11), which may be
oxidized to the
sulfone (12) with any of a variety of oxidants, including Cr03-acetic
anhydride (Sedova et al.
Zh. Org. Khim. 1970, 6; (568).
SOZCI
/ CIS03H
R ~ ; R 7
KF \ Zn(H9)
S02F SH
R 8 ~ ~ R 10
(Me2N)3S Me3SiF2 CHCIF2
Me3SiCF3 base
SOZCF3 SCHF2
R 9 v R 11
[O]
S02CHF2
R 12
Scheme III Selected Methods of Fluorinated Aryl Sulfone Synthesis
As shown in Scheme IV, non-symmetrical urea formation may involve reaction of
an aryl
isocyanate (14) with an aryl amine (13). The heteroaryl isocyanate may be
syntnesizea from
a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such
as
trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate
(triphosgene), or
!o N.N'-carbonyldiimidazole (CDI). The isocyanate may also be derived from a
heterocyclic
carboxylic acid derivative, such as an ester, an acid halide or an anhydride
by a Curtius-type
rearrangement. Thus, reaction of acid derivative 16 with an azide source,
followed by
rearrangement affords the isocyanate. The corresponding carboxylic acid ( 17)
may also be
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subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPPA)
or a
similar reagent.
Are-NH2 13
COCI2
H2N-Ar2 O
Are-NCO. --~. Ar~~N~N.Ar~
14 H H
N3 DPPA
O O
Ar~~X Ar~~OH
16 17
Scheme IV Selected Methods of Non-Symmetrical Urea Formation
5 Finally, ureas may be further manipulated using methods familiar to those
skilled in the art.
The invention also includes pharmaceutical compositions including a compound
of Formula
I, and a physiologically acceptable carrier.
to The compounds may be administered orally, topically, parenterally, by
inhalation or spray or
rectally in dosage unit formulations. The term 'administration by injection'
includes
intravenous, intramuscular, subcutaneous and parenteral injections, as well as
use of infusion
techniques. One or. more compounds may be present in association with one or
more non-
toxic pharmaceutically acceptable carriers and if desired other active
ingredients.
Compositions intended for oral use may be prepared according to any suitable
method known
to the art for the manufacture of pharmaceutical compositions. Such
compositions may
contain one or more agents selected from the group consisting of diluents,
sweetening agents,
flavoring agents, coloring agents and preserving agents in order to provide
palatable
'u preparations. Tablets contain the active ingredient in admixture with non-
toxic
pharmaceutically acceptable excipients which are suitable for the manufacture
of tablets.
These excipients may be, for example, inert diluents, such as calcium
carbonate, sodium
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carbonate, lactose, calcium phosphate or sodium phosphate; granulating and
disintegrating
agents, for example, corn starch, or alginic acid; and binding agents, for
example magnesium
stearate, stearic acid or talc. The tablets may be uncoated or they may be
coated by known
techniques to delay disintegration and adsorption in the gastrointestinal
tract and thereby
provide a sustained action over a longer period. For example, a time delay
material such as
glyceryl monostearate or glyceryl distearate may be employed. These compounds
may also
be prepared in solid, rapidly released form.
Formulations for oral use may also be presented as hard gelatin capsules
wherein the active
to ingredient is mixed with an inert solid diluent, for example, calcium
carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient
is mixed with
water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients
suitable for
the manufacture of aqueous suspensions. Such excipients are suspending agents,
for example
sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose,
sodium
alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents
may be a naturally occurring phosphatide, for example, lecithin, or
condensation products or
an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or
condensation
2o products of ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethylene
oxycetanol, or condensation products of ethylene oxide with partial esters
derived from fatty
acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation
products of
ethylene oxide with partial esters derived from fatty acids and hexitol
anhydrides, for
example polyethylene sorbitan monooleate. The aqueous suspensions may also
contain one
or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one
or more
coloring agents, one or more flavoring agents, and one or more sweetening
agents, such as
sucrose or saccharin.
Dispersible powders and granules suitable for preparation of an aqueous
suspension by the
:u addition of water provide the active ingredient in admixture with a
dispersing or wetting
agent, suspending agent and one or more preservatives. Suitable dispersing or
wetting agents
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and suspending agents are exemplified by those already mentioned above.
Additional
excipients, for example, sweetening, flavoring and coloring agents, may also
be present.
The compounds may also be in the form of non-aqueous liquid formulations,
e.g., oily
suspensions which may be formulated by suspending the active ingredients in a
vegetable oil,
for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral
oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for example
beeswax, hard
paraffin or cetyl alcohol. Sweetening agents such as those set forth above,
and flavoring
agents may be added to provide palatable oral preparations. These compositions
may be
to preserved by the addition of an anti-oxidant such as ascorbic acid.
Pharmaceutical compositions of the invention may also be in the form of oil-in-
water
emulsions. The oily phase may be a vegetable oil, for example olive oil or
arachis oil, or a
mineral oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents
may be naturally-occurring gums, for example gum acacia or gum tragacanth,
naturally-
occurnng phosphatides, for example soy bean, lecithin, and esters or partial
esters derived
from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and
condensation
products of the said partial esters with ethylene oxide, for example
polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example
glycerol,
propylene glycol, sorbitol or sucrose. Such formulations may also contain a
demulcent, a
preservative and flavoring and coloring agents.
The compounds may also be administered in the form of suppositories for rectal
administration of the drug. These compositions can be prepared by mixing the
drug with a
suitable non-irntating excipient which is solid at ordinary temperatures but
liquid at the rectal
temperature and will therefore melt in the rectum to release the drug. Such
materials include
cocoa butter and polyethylene glycols.
For all regimens of use disclosed herein for compounds of Formula I, the daily
ural ~iosa~~r
regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The
daily ~iosa~~e
12
CA 02359510 2006-05-23
69676-8
for administration by injection, including intravenous,
intramuscular, subcutaneous and parenteral injections, and
use of infusion techniques will preferably be from 0.01
to 200 mg/Kg of total body weight. The daily rectal dosage
regime will preferably be from 0.01 to 200 mg/Kg of total
body weight. The daily topical dosage regime will
preferably be from 0.1 to 200 mg administered between one to
four times daily. The daily inhalation dosage regime will
preferably be from 0.01 to 10 mg/Kg of total body weight.
It will be appreciated by those skilled in the art
that the particular method of administration will depend on
a variety of factors, all of which are considered routinely
when administering therapeutics. It will also be
appreciated by one skilled in the art that the specific dose
level for a given patient depends on a variety of factors,
including specific activity of the compound administered,
age, body weight, health, sex, diet, time and route of
administration, rate of excretion, etc. It will be further
appreciated by one skilled in the art that the optimal
course of treatment, i.e., the mode of treatment and the
daily number of doses of a compound of Formula I or a
pharmaceutically acceptable salt thereof given for a defined
number of days, can be ascertained by those skilled in the
art using conventional treatment tests.
It will be understood, however, that the specific
dose level for any particular patient will depend upon a
variety of factors, including the activity of the specific
compound employed, the age, body weight, general health,
sex, diet, time of administration, route of administration,
and rate of excretion, drug combination and the severity of
the condition undergoing therapy.
13
CA 02359510 2006-05-23
69676-8
The compounds can be produced from known compounds
(or from starting materials which, in turn, can be produced
from known compounds), e.g., through the general preparative
methods shown below. The activity of a given compound to
inhibit raf kinase can be routinely assayed, e.g., according
to procedures disclosed below. The following examples
13a
CA 02359510 2001-07-12
WO 00/42012 PCT/US00/00648
are for illustrative purposes only and are not intended, nor should they be
construed to limit
the invention in any way.
EXAMPLES
All reactions were performed in flame-dried or oven-dried glassware under a
positive
pressure of dry argon or dry nitrogen, and were stirred magnetically unless
otherwise
indicated. Sensitive liquids and solutions were transferred via syringe or
cannula, and
introduced into reaction vessels through rubber septa. Unless otherwise
stated, the term
'concentration under reduced pressure' refers to use of a Buchi rotary
evaporator at
to approximately 15 mmHg. Unless otherwise stated, the term 'under high
vacuum' refers to a
vacuum of 0.4 - 1.0 mmHg.
All temperatures are- reported uncorrected in degrees Celsius (°C).
Unless otherwise
indicated, all parts and percentages are by weight.
Commercial grade reagents and solvents were used without further purification.
N
cyclohexyl-N'-(methylpolystyrene)carbodiimide was purchased from Calbiochem-
Novabiochem Corp. 3-tert-Butylaniline, 5-tert-butyl-2-methoxyaniline, 4-bromo-
3-
(trifluoromethyl)aniline, 4-chloro-3-(trifluoromethyl)aniline 2-methoxy-5-
(trifluoromethyl)aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-naphthol,
ethyl 4-
isocyanatobenzoate, N acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline and
4-chloro-3-
(trifluoromethyl)phenyl isocyanate were purchased and used without further
purification.
Syntheses of 3-amino-2-methoxyquinoline (E. Cho et al. WO 98/00402; A. Cordi
et al. EP
542,609; IBID Bioorg. Med. Chem.. 3, 1995, 129), 4-(3-carbamoylphenoxy)-1-
nitrobenzene
(K. Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 3-
tert-
butylphenyl isocyanate (O. Rohr et al. DE 2,436,108) and 2-methoxy-5-
(trifluoromethyl)phenyl isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo
Kagaku
Zasshi 70, 1967, 491 ) have previously been described.
3o Thin-layer chromatography (TLC) was performed using Whatman~ pre-coated
glass-backed
silica gel 60A F-254 250 pm plates. Visualization of plates was effected by
one or more of
the following techniques: (a) ultraviolet illumination, (b) exposure to iodine
vapor, (c)
14
CA 02359510 2001-07-12
WO 00/42012 PCT/US00/00648
immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol
followed by
heating, (d) immersion of the plate in a cerium sulfate solution followed by
heating, and/or
(e) immersion of the plate in an acidic ethanol solution of
2,4=dinitrophenylhydrazine
followed by heating. Column chromatography (flash chromatography) was
performed using
s 230-400 mesh EM Science~ silica gel.
Melting points (mp) were determined using a Thomas-Hoover melting point
apparatus or a
Mettler FP66 automated melting point apparatus and are uncorrected. Fourier
transform
infrared spectra were obtained using a Mattson 4020 Galaxy Series
spectrophotometer.
to Proton (tH) nuclear magnetic resonance (NMR) spectra were measured with a
General
Electric GN-Omega 300 (300 MHz) spectrometer with either Me4Si (8 0.00) or
residual
protonated solvent (CHC13 8 7.26; MeOH 8 3.30; DMSO 8 2.49) as standard.
Carbon (~3C)
NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz)
spectrometer
with solvent (CDCl3 8 77.0; MeOD-d3; 8 49.0; DMSO-d6 8 39.5) as standard. Low
resolution
15 mass spectra (MS) and high resolution mass spectra (HRMS) were either
obtained as electron
impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra.
Electron impact
mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass
spectrometer
equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample
introduction.
The ion source was maintained at 250 °C. Electron impact ionization was
performed with
2o electron energy of 70 eV and a trap current of 300 ~tA. Liquid-cesium
secondary ion mass
spectra (FAB-MS), an updated version of fast atom bombardment were obtained
using a
Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were
obtained
using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the
reagent gas
( 1 x 10-4 torr to 2.5x 10~ torr). The direct insertion desorption chemical
ionization (DCI) probe
25 (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at
l0.amps until all
traces of the sample disappeared ( ~l-2 min). Spectra were scanned from 50-800
amu at 2
sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained
using a
Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable
wavelength
detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with
electrosprav
_'~0 ionization. Spectra were scanned from 120-800 amu using a variable ion
time accor~lin~~ to
the number of ions in the source. Gas chromatography - ion selective mass
spectra 1 CJ(~-~1S ~
l5
CA 02359510 2001-07-12
WO 00/42012 PCT/US00/00648
were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an
HP-1
methyl silicone column (0.33 mM coating; 25 m x 0.2 mm) and a Hewlett Packard
5971
Mass Selective Detector (ionization energy 70 eV). Elemental analyses are
conducted by
Robertson Microlit Labs, Madison NJ.
All compounds displayed NMR spectra, LRMS and either elemental analysis or
HRMS
consistent with assigned structures.
List of
Abbreviations
and Acronyms:
1o AcOH acetic acid
anh anhydrous
atm atmospheres)
BOC tent-butoxycarbonyl
CDI l,l'-carbonyl diimidazole
t 5 conc concentrated
d days)
dec decomposition
DMAC N,N dimethylacetamide
DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
2o DMF N,N dimethylformamide
DMSO dimethylsulfoxide
DPPA diphenylphosphoryl azide
EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
EtOAc ethyl acetate
25 EtOH ethanol ( 100%)
EtZQ diethyl ether
Et3N triethylamine
h hours)
HOBT 1-hydroxybenzotriazole
o nr-CPBA 3-chloroperoxybenzoic acid
YIeOH methanol
pct. ether petroleum ether (boiling range 30-60
C)
16
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WO 00/42012 PCT/US00/00648
temp. temperature
THF tetrahydrofuran
TFA trifluoroAcOH
Tf trifluoromethanesulfonyl
S
A. General Methods for Synthesis of Substituted Anilines
Al. General Method for Aryl Amine Formation via Ether Formation
Followed by Ester Saponification, Curtius Rearrangement, and
Carbamate Deprotection. Synthesis of 2-Amino-3-methoxynaphthalene.
i
C02Me
OMe
Step 1. Methyl 3-methoxy-2-naphthoate
A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and KZC03 (7.96
g, 57.6
mmol) in DMF (200 mL) was stirred at room temp. for 15 min., then treated with
iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at room
temp.
I S overnight, then was treated with water (200 mL). The resulting mixture was
extracted with
EtOAc (2 x 200 mL). The combined organic layers were washed with a saturated
NaCI
solution (100 mL), dried (MgS04), concentrated under reduced pressure
(approximately 0.4
mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil ( 10.30
g): ~ H
NMR (DMSO-db) 8 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J--8.09 Hz, 1H), 7.44
(s, 1H), 7.53
(app t, J--8.09 Hz, 1H), 7.84 (d, J--8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).
i
C02H
OMe
Step 2. 3-Methoxy-2-naphthoic acid
A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10
mL) in
MeOH ( 100 mL) at room temp. was treated with a 1 N NaOH solution (33.4 mL, 3
,.-l mmol ).
?a The mixture was heated at the reflux temp. for 3 h, cooled to room temp.,
and magic ardnr
with a 10°,'o citric acid solution. The resulting solution was
extracted with EtO.-~r 1 ~ v 1 m ~
CA 02359510 2001-07-12
WO 00/42012 PCT/US00/00648
mL). The combined organic layers were washed with a saturated NaCI solution,
dried
(MgS04) and concentrated under reduced pressure. The residue was triturated
with hexane
then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a
white solid
(5.40 g, 92%): 'H-NMR (DMSO-db) 8 3.88 (s, 3H), 7.34-7.41 (m, ZH), 7.49-7.54
(m, 1H),
7.83 (d, J--8.09 Hz, 1 H), 7.91 (d, J--8.09 Hz, 1 H), 8.19 (s, 1 H), 12.83 (br
s, 1 H).
I~
i
I OII
H ~O I W
OMe
Step 3. 2-(N (Carbobenzyloxy)amino-3-methoxynaphthalene
A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et3N (2.59
mL, 18.6
mmol) in anh toluene ~ (70 mL) was stirred at room temp. for 15 min., then
treated with a
to solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette. The
resulting mixture
was heated at 80 °C for 2 h. After cooling the mixture to room temp.,
benzyl alcohol (2.06
mL, 20 mmol)~was added via syringe. The mixture was then warmed to 80
°C overnight. The
resulting mixture was cooled to room temp., quenched with a 10% citric acid
solution, and
extracted with EtOAc (2 x 100 mL). The combined organic layers were washed
with a
saturated NaCI solution, dried (MgS04) and concentrated under reduced
pressure. The
residue was purified by column chromatography (14% EtOAc/86% hexane) to give 2-
(N
(carbobenzyloxy)amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%):
'H-NMR
(DMSO-db) 8 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, SH), 7.72-7.75 (m, 2H),
8.20 (s, 1 H),
8.76 (s, 1 H).
I~
i
NH2
OMe
Step 4. 2-Amino-3-methoxynaphthalene
A slurry of 2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol)
and 10%
Pd/C (0.5 g) in EtOAc (70 mL) was maintained under a HZ atm (balloon) at room
temp.
overnight. The resulting mixture was filtered through Celite~' and
concentrated under
reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder
(?..10
18
CA 02359510 2001-07-12
WO 00/42012 PCT/US00/00648
85%): 'H-NMR (DMSO-db) 8 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43
(d, J--8.0
Hz, 1H), 7.56 (d, J--8.0 Hz, 1H); EI-MS m/z 173 (M+).
A2. Synthesis of ~-Carbamyl Anilines via Formation of a Carbamylpyridine
Followed by Nucleophilic Coupling with an Aryl Amine. Synthesis of 4-
(2-N Methylcarbamyl-4-pyridyloxy)aniline
O
CI ~ NHMe
~N
Step la. Synthesis of 4-chloro-N methyl-2-pyridinecarboxamide via the Menisci
reaction
to Caution: this is a highly hazardous, potentially explosive reaction. To a
stirring solution of
4-chloropyridine (10.0 g) in N methylformamide (250 mL) at room temp. was
added conc.
HZS04 (3.55 mL) to generate an exotherm. To this mixture was added H202 (30%
wt in HzO,
17 mL) followed by FeS04~7H20 (0.56 g) to generate another exothenm. The
resulting
mixture was stirred in the dark at room temp. for 1 h, then warmed slowly over
4 h to 45 °C.
When bubbling had subsided, the reaction was heated at 60 °C for 16 h.
The resulting
opaque brown solution was diluted with H20 (700 mL) followed by a 10% NaOH
solution
(250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The
organic
phases were washed separately with a saturated NaCI solution (3 x 150 mL),
then they were
combined, dried (MgS04) and filtered through a pad of silica gel with the aid
of EtOAc. The
2o resulting brown oil was purified by column chromatography (gradient from
50% EtOAc/50%
hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0
°C over 72 h to
give 4-chloro-N methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50%
EtOAc/50%
hexane) Rf 0.50; 'H NMR (CDC13) 8 3.04 (d, J--S.1 Hz, 3H), 7.43 (dd, J--5.4,
2.4 Hz, 1H),
7.96 (br s, 1H), 8.21 (s, 1H), 8.44 (d, J--5.1 Hz, 1 H); CI-MS m/z 171
((M+H)+).
O
CI ~ CI
I
~ N HCI
Step 1 b. Synthesis of 4-chloropyridine-2-carbonyl chloride HCI salt via
picolinic
acid
19
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WO 00/42012 PCT/US00/00648
Anhydrous DMF (6.0 mL) was slowly added to SOC12 (180 mL) between 40°
and 50 °C.
The solution was stirred in that temperature range for 10 min. then picolinic
acid (60.0 g, 487
mmol) was added in portions over 30 min. The resulting solution was heated at
72 °C
(vigorous SOZ evolution) for 16 h to generate a yellow solid precipitate. The
resulting
mixture was cooled to room temp., diluted with toluene (500 mL) and
concentrated to 200
mL. The toluene addition/concentration process was repeated twice. The
resulting nearly
dry residue was filtered and the solids were washed with toluene (2 x 200 mL)
and dried
under high vacuum for 4 h to afford 4-chloropyridine-2-carbonyl chloride HC1
salt as a
yellow-orange solid (92.0 g, 89%).
O
CI
home
~ N HCI
Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate HC1 salt
Anh DMF (10.0 mL) was slowly added to SOC12 (300 mL) at 40-48 °C. The
solution was
stirred at that temp. range for 10 min., then picolinic acid (100 g, 812 mmol)
was added over
30 min. The resulting solution was heated at 72 °C (vigorous SOZ
evolution) for 16 h to
generate a yellow solid. The resulting mixture was cooled to room temp.,
diluted with
toluene (S00 mL) and concentrated to 200 mL. The toluene
addition/concentration process
was repeated twice. The resulting nearly dry residue was filtered, and the
solids were washed
with toluene (SO mL) and dried under high vacuum for 4 hours to afford 4-
chloropyridine-2-
carbonyl chloride HCl salt as an off white solid (27.2 g, 16%). This material
was set aside.
The red filtrate was added to MeOH (200 mL) at a rate which kept the internal
temperature
below 55 °C. The contents were stirred at room temp. for 45 min.,
cooled to S °C and treated
with Et20 (200. mL) dropwise. The resulting solids were filtered, washed with
Et~O (200
mL) and dried under reduced pressure at 35 °C to provide methyl 4-
chloropyridine-2-
carboxylate HCl salt as a white solid (110 g, 65%): mp 108-112 °C; 'H-
NMR (DMSO-db) 8
3.88 (s, 3H); 7.82 (dd, J--5.5, 2.2 Hz, 1H); 8.08 (d, J--2.2 Hz, 1H); 8.68 (d,
J--S.5 Hz, IH);
10.68 (br s, 1H); HPLC ES-MS m/z 172 ((M+H)+).
CA 02359510 2001-07-12
WO 00/42012 PCT/US00/00648
O
NHMe
~N
Step 3a. Synthesis of 4-chloro-N methyl-2-pyridinecarboxamide from methyl 4-
chloropyridine-2-carboxylate
A suspension of methyl 4-chloropyridine-2-carboxylate HCl salt (89.0 g, 428
mmol) in
s MeOH (75 mL) at 0 °C was treated with a 2.0 M methylamine solution in
THF ( 1 L) at a rate
which kept the internal temp. below S °C. The resulting mixture was
stored at 3 °C for 5 h,
then concentrated under reduced pressure. The resulting solids were suspended
in EtOAc ( 1
L) and filtered. The filtrate was washed with a saturated NaCI solution (500
mL), dried
(Na2S04) and concentrated under reduced pressure to afford 4-chloro-N methyl-2-
to pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43
°C; ~H-NMR (DMSO-
db) 8 2.81 (s, 3H), 7.74 (dd, J 5.1, 2.2 Hz, 1 H), 8.00 (d, J 2.2, 1 H), 8.61
(d, J--5.1 Hz, 1 H),
8.85 (br d, 1H); CI-MS m/z 171 ((M+H)+).
O
CI
~NHMe
~N
Step 3b. Synthesis of 4-chloro-N methyl-2-pyridinecarboxamide from 4-
15 chloropyridine-2-carbonyl chloride
4-Chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) was added in
portions to
a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at
0 °C.
The resulting mixture was stored at 3 °C for 4 h, then concentrated
under reduced pressure.
The resulting nearly dry solids were suspended in EtOAc (100 mL) and filtered.
The filtrate
2o was washed with a saturated NaCI solution (2 x 100 mL), dried (NazS04) and
concentrated
under reduced pressure to provide 4-chloro-N-methyl-2-pyridinecarboxamide as a
yellow,
crystalline solid (4.95 g, 88%): mp 37-40 °C.
O
O
NHMe
H2N
Step 4. Synthesis of 4-(2-(N methylcarbamoyl)-4-pyridyloxy)aniline
2s A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF ( 150 mL) was
treated with
potassium tent-butoxide ( 10.29 g, 91.7 mmol), and the reddish-brown mixture
was stirred at
2t
CA 02359510 2001-07-12
WO 00/42012 PCT/US00/00648
room temp. for 2 h. The contents were treated with 4-chloro-N methyl-2-
pyridinecarboxamide (15.0 g, 87.9 mmol) and KZC03 (6.50 g, 47.0 mmol) and then
heated at
80 °C for 8 h. The mixture was cooled to room temp. and separated
between EtOAc (S00
mL) and a saturated NaCI solution (500 mL). The aqueous phase was back-
extracted with
EtOAc (300 mL). The combined organic layers were washed with a saturated NaCI
solution
(4 x 1000 mL), dried (NaZS04) and concentrated under reduced pressure. The
resulting solids
were dried under reduced pressure at 35 °C for 3 h to afford 4-(2-(N
methylcarbamoyl)-4-
pyridyloxy)aniline as a light-brown solid 17.9 g, 84%): 1H-NMR (DMSO-db) 8
2.77 (d, J--4.8
Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA'BB' quartet, J--8.4 Hz, 4H), 7.06
(dd, J--5.5, 2.5 Hz,
l0 1H), 7.33 (d, J--2.5 Hz, 1H), 8.44 (d, J--S.5 Hz, 1H), 8.73 (br d, 1H);
HPLC ES-MS m/z 244
((M+H)+).
A3. General Method for the Synthesis of Anilines by Nucleophilic Aromatic
Addition Followed by Nitroarene Reduction. Synthesis of 5-(4-
Aminophenoxy)isoindoline-1,3-dione
O
'N H
HO
O
Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione
To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL)
was
slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture
was heated
2o at 120 °C for 45 min., then the clear, bright yellow mixture was
heated at 160 °C for 2 h. The
resulting mixture was maintained at 160 °C and was concentrated to
approximately 15 mL,
then was cooled to room temp. and adjusted pH 10 with a 1N NaOH solution. This
mixture
was cooled to 0 °C and slowly acidified to pH 5 using a 1N HCl
solution. The resultant
precipitate was collected by filtration and dried under reduced pressure to
yield 5-
hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%):
~H NMR
(DMSO-db) 8 7.00-7.03 (m, 2H), 7.56 (d, J--9.3Hz, 1 H).
22
CA 02359510 2001-07-12
WO 00/42012 PCT/US00/00648
02N ~ O
NH
O
Step 2. Synthesis of 5-(4-nitrophenoxy)isoindoline-1,3-dione
To a stirnng slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 °C
was added a solution
of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise.
The bright
yellow-green mixture was allowed to return to room temp. and was stirred for 1
h, then 1
fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4
portions. The
resulting mixture was heated at 70 °C overnight, then cooled to room
temp. and diluted
slowly with water ( 150 mL), and extracted with EtOAc (2 x 100 mL). The
combined organic
layers were dried (MgS04) and concentrated under reduced pressure to give 5-(4-
nitrophenoxy)isoindoline-1,3-dione as a yellow solid (3.3 g, 62%): TLC (30%
EtOAc/70%
hexane) Rf 0.28; 1H NMR (DMSO-db) 8 7.32 (d, J--12 Hz, 2H), 7.52-7.57 (m, 2H),
7.89(d,
J--7.8 Hz, 1H), 8.29 (d, J--9 Hz, 2H), 11.43 (br s, 1H); CI-MS m/z 285
((M+H)+, 100%).
i ~ i
H2N ~ O
NH
O
Step 3. Synthesis of 5-(4-aminophenoxy)isoindoline-1,3-dione
A solution of 5-(4-nitrophenoxy)isoindoline-1,3-dione (0.6 g, 2.11 mmol) in
conc. AcOH (12
mL) and water (0.1 mL) was stirred under stream of argon while iron powder
(0.59 g, 55.9
mmol) was added slowly. This mixture stirred at room temp. for 72 h, then was
diluted with
water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic
layers were
dried (MgS04) and concentrated under reduced pressure to give S-(4-
2o aminophenoxy)isoindoline-1,3-dione as a brownish solid (0.4 g, 75%): TLC
(5O%
EtOAc/50% hexane) Rf0.27; iH NMR (DMSO-db) 8 5.14 (br s, 2H), 6.62 (d, J--8.7
Hz, 2H),
6.84 (d, J--8.7 Hz, 2H), 7.03 (d, J 2.1 Hz, 1 H), 7.23 (dd, 1 H), 7.75 (d, J
8.4 Hz, 1 H), 11.02
(s, 1 H); HPLC ES-MS m/z 255 ((M+H)+, 100%).
A4. General Method for the Synthesis of Pyrrolylanilines. Synthesis of 5-tert-
Butyl-2-(2,5-dimethylpyrrolyl)aniline
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WO 00/42012 PCT/US00/00648
N02
N
Step 1. Synthesis of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole
To a stirring solution of 2-nitro-4-tert-butylaniline (0.5 g, 2.57 mmol) in
cyclohexane (10
mL) was added AcOH (O.ImL) and acetonylacetone (0.299 g, 2.63 mmol) via
syringe. The
reaction mixture was heated at 120 °C for 72 h with azeotropic removal
of volatiles. The
reaction mixture was cooled to room temp., diluted with CHZC12 (10 mL) and
sequentially
washed with a 1 N HCl solution ( 15 mL), a 1 N NaOH solution ( 15 mL) and a
saturated NaCI
solution (lSmL), dried ( MgS04) and concentrated under reduced pressure. The
resulting
orange-brown solids were purified via column chromatography (60 g Si02;
gradient from 6%
to EtOAc/94% hexane to 25% EtOAc/75% hexane) to give 1-(4-tert-butyl-2-
nitrophenyl)-2,5-
dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc/85%
hexane) Rf
0.67; ~H NMR (CDC13) d 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m,
1H), 7.62
(dd, 1H), 7.88 (d, J--2.4 Hz, 1H); CI-MS mlz 273 ((M+H)+, 50%).
NH2
N
Step 2. Synthesis of 5-tert--Butyl-2-(2,5-dimethylpyrrolyl)aniline
A slurry of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25
mmol),
10%Pd/C (0.056 g) and EtOAc (SO mL) under an HZ atmosphere (balloon) was
stirred for 72
h, then filtered through a pad of Celite°. The filtrate was
concentrated under reduced
pressure to give 5-tert--butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish
solids (0.30 g,
99%): TLC (10% EtOAc/90% hexane) Rf0.43; ~H NMR (CDC13) 8 1.28 (s, 9H), 1.87-
1.91
(m, 8H), 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, 1H).
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A5. General Method for the Synthesis of Anilines from Anilines by
Nucleophilic Aromatic Substitution. Synthesis of 4-(2-(N
Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HCl Salt
O
NHMe
HZN / . ~ N
HCI
Me
A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry
dimethylacetamide (75
mL) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol) and the
black mixture
was stirred at room temp. until the flask had reached room temp. The contents
were then
treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52
g, 44.2
mmol) and heated at 110 °C for 8 h. The mixture was cooled to room
temp. and diluted with
1o water (75 mL). The organic layer was extracted with EtOAc (5 x 100 mL). The
combined
organic layers were washed with a saturated NaCI solution (200 mL), dried
(MgSO~) and
concentrated under reduced pressure. The residual black oil was treated with
Et~O (50 mL)
and sonicated. The solution was then treated with HCl (1 M in Et20; 100 mL)
and stirred at
room temp. for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was
removed by
filtration from solution and stored under anaerobic conditions at 0 °C
prior to use: ' H NMR
(DMSO-d6) b 2.41 (s, 3H), 2.78 (d, J--4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd,
J--8.5, 2.6 Hz,
1H), 7.23 (dd, J--5.5, 2.6 Hz, 1H), 7.26 (d, J 2.6 Hz, 1H), 7.55 (d, J--2.6
Hz, 1H), 7.64 (d,
J--8.8 Hz, 1,H), 8.55 (d, J--5.9 Hz, 1 H), 8.99 (q, J--4.8 Hz, 1 H).
2o A6. General Method for the Synthesis of Anilines from Hydroxyanilines by N-
Protection, Nucleophilic Aromatric Substitution and Deprotectioa.
Synthesis of 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline
O ~ OH
F3C~H
CI
Step 1: Synthesis of 3-Chloro-4-(2,2,2-trifluoroacetylamino)pheno!
?5 Iron (3.24 ~, 58.00 mmol) was added to stirring TFA (200 mL). To this
slurry was added ?-
chloro--t-nitrophenol ( 10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20
mL). This ~~rav
slum was stirred at room temp. for 6 d. The iron was filtered from solution
and the
CA 02359510 2001-07-12
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remaining material was concentrated under reduced pressure. The resulting gray
solid was
dissolved in water (20 mL). To the resulting yellow solution was added a
saturated NaHCOz
solution (SO mL). The solid which precipitated from solution was removed. The
filtrate was
slowly quenched with the sodium bicarbonate solution until the product visibly
separated
from solution (determined was using a mini work-up vial). The slightly cloudy
yellow
solution was extracted with EtOAc (3 x 125 mL). The combined organic layers
were washed
with a saturated NaCI solution (125 mL), dried (MgS04) and concentrated under
reduced
pressure. The 'H NMR (DMSO-db) indicated a 1:1 ratio of the nitrophenol
starting material
and the intended product 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol. The
crude material
1o was taken on to the next step without further purification.
O
NHMe
~N
CI
Step 2: Synthesis of 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl
(222-trifluoro)acetamide
A solution of crude 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol (5.62 g,
23.46 mmol) in
t s dry dimethylacetamide (50 mL) was treated with potassium tert-butoxide
(5.16 g, 45.98
mmol) and the brownish black mixture was stirred at room temp. until the flask
had cooled to
room temp. The resulting mixture was treated with 4-chloro-N methyl-2-
pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100
°C under
argon for 4 d. The black reaction mixture was cooled to room temp. and then
poured into
20 cold water ( 100 mL). The mixture was extracted with EtOAc (3 x 75 mL) and
the combined
organic layers were concentrated under reduced pressure. The residual brown
oil was
purified by column chromatography (gradient from 20% EtOAc/pet. ether to 40%
EtOAc/pet.
ether) to yield 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-
trifluoro)acetamide as a yellow solid (8.59 g, 23.0 mmol).
O
O ~ NHMe
i I ~N
H2N CI
Step 3. Synthesis of 4-(2-(N-h~tethylcarbamoyl)-4-pyridyloxy)-2-chloroaniline
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A solution of crude 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-
trifluoro)acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated
with a 1N
NaOH solution (20 mL). This brown solution was allowed to stir for 8 h. To
this solution
was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3 x
40 mL)
and the solvent was concentrated to yield 4-(2-(N Methylcarbamoyl)-4-
pyridyloxy)-2-
chloroaniline as a green oil that solidified upon standing (2.86 g, 10.30
mmol): 'H NMR
(DMSO-d6) 8 2.77 (d, J--4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, J--8.5, 2.6 Hz,
1H), 6.76 (d,
J--2.6 Hz, 1H), 7.03 (d, J--8.5 Hz, 1H), 7.07 (dd, J--5.5, 2.6, Hz, 1H), 7.27
(d, J--2.6 Hz, 1H),
8.46 (d, J--5.5 Hz, 1H), 8.75 (q, J--4.8, 1H).
A7. General Method for the Deprotection of an Acylated Aniline. Synthesis of
4-Chloro-2-methoxy-5-(trifluoromethyl)aniline
CF3
CI
NH2
OMe
A suspension of 3-chloro-6-(N-acetyl)-4-(trifluoromethyl)anisole (4.00 g,
14.95
mmol) in a 6M HCl solution (24 mL) was heated at the reflux temp. for 1 h. The
resulting solution was allowed to cool to room temp. during which time it
solidified
slightly. The resulting mixture was diluted with water (20 mL) then treated
with a
combination of solid NaOH and a saturated NaHC03 solution until the solution
was
basic. The organic layer was extracted with CHZC12 (3 x 50 mL). The combined
organics were dried (MgSOa) and concentrated under reduced pressure to yield 4-
chloro-2-methoxy-5-(trifluoromethyl)aniline as a brown oil (3.20 g, 14.2
mmol): 'H
NMR (DMSO-db) b 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).
A8. General Method for Synthesis of w-Alkoxy-c~-carboxyphenyl Anilines.
Synthesis of 4-(3-(N Methylcarbamoly)-4-methoxyphenoxy)aniline.
O
O OMe
i
OZN OMe
Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene:
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To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-1-nitrobenzene (prepared from
2,5- .
dihydroxybenzoic acid in a manner analogous to that described in Method A13,
Step l, 12
mmol) in acetone (50 mL) was added KzC03 (S g) and dimethyl sulfate (3.5 mL).
The
resulting mixture was heated at the reflux temp. overnight, then cooled to
room temp. and
s filtered through a pad of Celite~. The resulting solution was concentrated
under reduced
pressure, absorbed onto Si02, and purified by column chromatography (50% EtOAc
i 50%
hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene as a
yellow
powder (3 g): mp 115-118 °C.
O
O OH
I
OZN OMe
1o Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-1-nitrobenzene:
A mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene (1.2 g),
KOH (0.33
g) and water (5 mL) in MeOH (45 mL) was stirred at room temp. overnight and
then heated
at the reflux temp. for 4 h. The resulting mixture was cooled to room temp.
and concentrated
under reduced pressure. The residue was dissolved in water (50 mL), and the
aqueous
15 mixture was made acidic with a 1N HCl solution. The resulting mixture was
extracted with
EtOAc (50 mL). The organic layer was ~ dried (MgS04) and concentrated under
reduced
pressure to give 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (1.04 g).
O
O NHMe
02N OMe
Step 3. 4-(3-(lV Methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene:
2o To a solution of 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (0.50 g,
1.75 mmol) in
CHzCIZ ( 12 mL) was added SOC12 (0.64 mL, 8.77 mmol) in portions. The
resulting solution
was heated at the reflux temp. for 18 h, cooled to room temp., and
concentrated under
reduced pressure. The resulting yellow solids were dissolved in CHZCIz (3 mL)
then the
resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5
mL, 7.02
?, mmol) in portions (CAUTION: gas evolution), and stirred at room temp. for 4
h. The
resulting mixture was treated with a 1N NaOH solution, then extracted with
CH~CI~ (25 mL).
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The organic layer was dried (NazS04) and concentrated under reduced pressure
to give 4-(3-
(N-methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene as a yellow solid (0.50
g, 95%).
O
O
NHMe
H2N OMe
Step 4. 4-(3-(N Methylcarbamoly)-4-methoxyphenoxy)aniline:
A slurry of 4-(3-(N methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene (0.78 g,
2.60
mmol) and 10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under 1 atm of Hz
(balloon) for
2.5 d, then was filtered through a pad of Celite~. The resulting solution was
concentrated
under reduced pressure to afford 4-(3-(N methylcarbamoly)-4-
methoxyphenoxy)aniline as an
off white solid (0.68 g, 96%): TLC (0.I% Et3N/99.9% EtOAc) Rf0.36.
A9. General Method for Preparation of w-Alkylphthalimide-containing
Anilines. Synthesis of 5-(4-Aminopheuoxy)-2-methylisoindoline-1,3-dione
O
O
N-Me
02N
O
Step 1. Synthesis of 5-(4-Nitrophenoxy)-2-methylisoindoline-1,3-dione:
A slurry of 5-(4-nitrophenoxy)isoindoline-1,3-dione (A3 Step 2; 1.0 g, 3.52
mmol) and NaH
(0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp. for 1 h, then
treated with
methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room
temp.
overnight, then was cooled to °C and treated with water ( 10 mL). The
resulting solids were
collected and dried under reduced pressure to give 5-(4-nitrophenoxy)-2-
methylisoindoline-
1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% hexane)
Rf0.61.
O
O
~ N-Me
H2N
O
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Step 2. Synthesis of 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione:
A slurry of nitrophenoxy)-2-methylisoindoline-1,3-dione (0.87 g, 2.78 mmol)
and 10% Pd/C
(0.10 g) in MeOH was stirred under 1 atm of HZ (balloon) overnight.' The
resulting mixture
was filtered through a pad of Celite~ and concentrated under reduced pressure.
The resulting
yellow solids were dissolved in EtOAc (3 mL) and filtered through a plug of
Si02 (60%
EtOAc/40% hexane) to afford 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione
as a
yellow solid (0.67 g, 86%): TLC (40% EtOAc/60% hexane) Rf0.27.
A10. General Method for Synthesis of w-Carbamoylaryl Anilines Through
1o Reaction of w-Alkoxycarbonylaryl Precursors with Amines. Synthesis of
4-(2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline
O
CI
~O
~ N N~N
Step 1. Synthesis of 4-Chloro-2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridine
~s To a solution of methyl 4-chloropyridine-2-carboxylate HCl salt (Method A2,
Step 2; 1.01 g,
4.86 mmol) in THF (20 mL) was added 4-(2-aminoethyl)morpholine (2.55 mL, 19.4
mmol)
dropwise and the resulting solution was heated at the reflux temp. for 20 h,
cooled to room
temp., and treated with water (50 mL). The resulting mixture was extracted
with EtOAc (SO
mL). The organic layer was dried (MgS04) and concentrated under reduced
pressure to
2o afford 4-chloro-2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow
oil (1.25 g,
95%): TLC (10% MeOH/90% EtOAc) Rf0.50.
O
O
~ N N~.N
H2N
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Step 2. Synthesis of 4-(2-(N (2-Morpholin-4-
ylethyl)carbamoyl)pyridyloxy)aniline.
A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide
(0.53 g, 4.75
mol) in DMF (8 mL) was stirred at room temp. for 2 h, then was sequentially
treated with 4-
s chloro-2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52 mmol)
and KZC03
(0.31 g, 2.26 mmol). The resulting mixture was heated at 75 °C
overnight, cooled to room
temp., and separated between EtOAc (25 mL) and a saturated NaCI solution (2s
mL). The
aqueous layer was back extracted with EtOAc (25 mL). The combined organic
layers were
washed with a saturated NaCI solution (3 x 25 mL) and concentrated under
reduced pressure.
1o The resulting brown solids were purified by column chromatography (58 g;
gradient from
100% EtOAc to 25% MeOH/75% EtOAc) to afford 4-(2-(N (2-morpholin-4-
ylethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%): TLC (10% MeOH/90% EtOAc)
Rf0.32.
A11. General Method for the Reduction of Nitroarenes to Arylamines.
15 Synthesis of 4-(3-Carboxyphenoxy)aniline.
O
O OH
H2N
A slurry of 4-(3-carboxyphenoxy)-1-nitrobenzene (5.38 g, 20.7 mmol) and 10%
Pd/C (0.50
g) in MeOH (120 mL) was stirred under an Hz atmosphere (balloon) for 2 d. The
resulting
mixture was filtered through a pad of Celite~, then concentrated under reduced
pressure to
2o afford 4-(3-carboxyphenoxy)aniline as a brown solid (2.26 g, 48%): TLC (10%
MeOH/90%
CHzCIz) Rf 0.44 (streaking).
A12. General Method for the Synthesis of Isoindolinone-Containing Anilines.
Synthesis of 4-(1-Oxoisoindolin-5-yloxy)aniline.
HO
'NH
O
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Step 1. Synthesis of 5-hydroxyisoindolin-1-one
To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was
slowly
added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated at
the reflux
temp. for 40 min., filtered hot, and concentrated under reduced pressure. The
reaction was
repeated on the same scale and the combined oily residue was purified by
column
chromatography (1.1 Kg Si02; gradient from 60% EtOAc/40% hexane to 25%
MeOH/75%
EtOAc) to give 5-hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) Rf0.17;
HPLC ES-
MS m/z 150 ((M+H)+).
I \ I NH
02N \\
O
1o Step 2. Synthesis of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene
To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0 °C was added 5-
hydroxyisoindolin-1-
one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm
to room temp.
and was stirred for 45 min., then 4-fluoro-1-nitrobenzene was added and then
mixture was
heated at 70 °C for 3 h. The mixture was cooled to 0 °C and
treated with water dropwise
until a precipitate formed. The resulting solids were collected to give 4-(1-
isoindolinon-5-
yloxy)-1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc)
Rf0.35.
~ I NH
H2N
O
Step 3. Synthesis of 4-(1-oxoisoindolin-5-yloxy)aniline
A slurry of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene (2.12 g, 7.8 mmol) and
10% Pd/C
(0.20 g) in EtOH (50 mL) was stirred under an HZ atmosphere (balloon) for 4 h,
then filtered
through a pad of Celite~. The filtrate was concentrated under reduced pressure
to afford 4-( 1-
oxoisoindolin-5-yloxy)aniline as a dark yellow solid: TLC ( 100% EtOAc} Rf
0.15.
A13. General Method for the Synthesis of c~-Carbamoyl Anilines via EDCI-
Mediated Amide Formation Followed by Nitroarene Reduction.
Synthesis of 4-(3-N Methylcarbamoylphenoxy)aniline.
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O
O ~ OEt
02N
Step 1. Synthesis of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene
A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-
hydroxybenzoate 25 g,
150 mmol) and KZC03 (41 g, 300 mmol) in DNiF (125 mL) was heated at the reflux
temp.
overnight, cooled to room temp. and treated with water (250 mL). The resulting
mixture was
extracted with EtOAc (3 x 150 mL). The combined organic phases were
sequentially washed
with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried
(NazS04) and
concentrated under reduced pressure. The residue was purified by column
chromatography
1o (10% EtOAc/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene
as an oil
(38 g).
O
O ~ OH
~ i
02N
Step 2. Synthesis of 4-(3-carboxyphenoxy)-1-nitrobenzene
To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene
(5.14 g, 17.9
mmol) in a 3:1 THF/water solution (75 mL) was added a solution LiOH~HZO (1.50
g, 35.8
mmol) in water (36 mL). The resulting mixture was heated at SO °C
overnight, then cooled to
room temp., concentrated under reduced pressure, and adjusted to pH 2 with a
1M HC1
2o solution. The resulting bright yellow solids were removed by filtration and
washed with
hexane to give 4-(3-carboxyphenoxy)-1-nitrobenzene (4.40 g, 95%).
O
NHMe
~ i
02N
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Step 3. Synthesis of 4-(3-(N methylcarbamoyl)phenoxy)-1-nitrobenzene
A mixture of 4-(3-carboxyphenoxy)-1-nitrobenzene (3.72 g, 14.4 mmol), EDCI~HC1
(3.63 g,
18.6 mmol), N methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in
THF; 8
mL, 16 mmol) in CHZC12 (45 mL) was stirred at room temp. for 3 d, then
concentrated under
reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting
mixture
was extracted with a 1M HCI solution (50 mL). The aqueous layer was back-
extracted with
EtOAc (2 x SO mL). The combined organic phases were washed with a saturated
NaCI
solution (50 mL), dried (NaZSOa), and concentrated under reduced pressure to
give 4-(3-(N-
methylcarbamoyl)phenoxy)-1-nitrobenzene as an oil (1.89 g).
O
O ~ NHMe
i
H2N
Step 4. Synthesis of 4-(3-(N methylcarbamoyl)phenoxy)aniline
A slurry of 4-(3-(N methylcarbamoyl)phenoxy)-1-nitrobenzene (1.89 g, 6.95
mmol) and 5%
Pd/C (0.24 g) in EtOAc (20 mL) was stirred under an Hz atm (balloon)
overnight. The
a 5 resulting mixture was filtered through a pad of Celite~ and concentrated
under reduced
pressure. The residue was purified by column chromatography (5% MeOH/95%
CHZCIZ).
The resulting oil solidified under vacuum overnight to give 4-(3-(N
methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%).
2o A14. General Method for the Synthesis of w-Carbamoyl Anilines via EDCI-
Mediated Amide Formation Followed by Nitroarene Reduction.
Synthesis of 4-3-(5-Methylcarbamoyl)pyridyloxy)aniline
O
O ~ I OMe
02N N
2, Step 1. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene
To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of
methyl S-
hvdroxvnicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture was
added to a
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solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the
resulting
mixture was heated at 70 °C overnight, cooled to room temp., and
treated with MeOH (5 mL)
followed by water (50 mL). The resulting mixture was extracted with EtOAc (
100 mL). The
organic phase was concentrated under reduced pressure. The residue was
purified by column
chromatography (30% EtOAc/70% hexane) to afford 4-(3-(5-
methoxycarbonyl)pyridyloxy)-
1-nitrobenzene (0.60 g).
O
O ~ OMe
HZN N
Step 2. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline
A slurry of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g, 2.20
mmol) and
10% Pd/C in MeOH/EtOAc was stirred under an HZ atmosphere (balloon) for 72 h.
The
resulting mixture was filtered and the filtrate was concentrated under reduced
pressure. The
residue was purified by column chromatography (gradient from 10% EtOAc/90%
hexane to
30% EtOAc/70% hexane to 50% EtOAc/50% hexane) to afford 4-(3-(5
methoxycarbonyl)pyridyloxy)aniline (0.28 g, 60%): 1H NMR (CDC13) 8 3.92 (s,
3H), 6.71 (d,
~ 5 2H), 6.89 (d, 2H), 7.73 (, 1 H), 8.51 (d, 1 H), 8.87 (d, 1 H).
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A15. Synthesis of an Aniline via Electrophilic Nitration Followed by Reduction
Synthesis of 4-(3-Methylsulfamoylphenoxy)aniline.
O~ ,O
S~NHMe
Step 1. Synthesis of N methyl-3-bromobenzenesulfonamide
To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15
mL) at 0
°C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting
solution was
allowed to warm to room temp. and was stirred at room temp. overnight. The
resulting
mixture was separated between EtOAc (25 mL) and a 1 M HCl solution (25 mL).
The
aqueous phase was back-extracted with EtOAc (2 x 25 mL). The combined organic
phases
1o were sequentially washed with water (2 x 25 mL) and a saturated NaCI
solution (25 mL),
dried (MgS04) and concentrated under reduced pressure to give N methyl-3-
bromobenzenesulfonamide as a white solid (2.8 g, 99%).
O ,O
~ O , I S~NHMe
Step 2. Synthesis of 4-(3-(N methylsulfamoyl)phenyloxy)benzene
To a slurry of phenol (1.9 g, 20 mmol), KZC03 (6.0 g, 40 mmol), and CuI (4 g,
20 mmol) in
DMF (25 mL) was added N methyl-3-bromobenzenesulfonamide (2.5 g, l Ommol), and
the
resulting mixture was stirred at the reflux temp. overnight, cooled to room
temp., and
separated between EtOAc (50 mL) and a 1 N HCl solution (50 mL). The aqueous
layer was
back-extracted with EtOAc (2 x 50 mL). The combined organic phases were
sequentially
2o washed with water (2 x 50 mL) and a saturated NaCI solution (50 mL), dried
(MgS04), and
concentrated under reduced pressure. The residual oil was purified by column
chromatography (30% EtOAc/70% hexane) to give 4-(3-(N-
methylsulfamoyl)phenyloxy)benzene (0.30 g).
O~ ,O
O , I S~NHMe
OzN
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Step 3. Synthesis of 4-(3-(N methylsulfamoyl)phenyloxy)-1-nitrobenzene
To a solution of 4-(3-(N methylsulfamoyl)phenyloxy)benzene (0.30 g, 1.14 mmol)
in TFA (6
mL) at -10°C was added NaN02 (0.097 g, 1.14 mmol) in portions over 5
min. The resulting
solution was stirred at -10 °C for 1 h, then was allowed to warm to
room temp., and was
concentrated under reduced pressure. The residue was separated between EtOAc
(10 mL)
and water (10 mL). The organic phase was sequentially washed with water (10
mL) and a
saturated NaCI solution (10 mL), dried (MgS04) and concentrated under reduced
pressure to
give 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.20 g). This material
carned on
to the next step without further purification.
OSO
NHMe
H2N
Step 4. Synthesis of 4-(3-(N methylsulfamoyl)phenyloxy)aniline
A slurry of 4-(3-(N methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.30 g) and 10%
Pd/C
(0.030 g) in EtOAc (20 mL) was stirred under an HZ atmosphere (balloon)
overnight. The
resulting mixture was filtered through a pad of Celite~. The filtrate was
concentrated under
reduced pressure. The residue was purified by column chromatography (30%
EtOAc/70%
hexane) to give 4-(3-(N methylsulfamoyl)phenyloxy)aniline (0.070 g).
A16. Modification of w-ketones. Synthesis of 4-(4-(1-(N
methoxy)iininoethyl)phenoxyaniline HCI salt.
N.O~
HCI
H2N
O
To a slurry of 4-(4-acetylphenoxy)aniline HC1 salt (prepared in a manner
analogous to
Method A13, step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and
pyridine ( 1.0 mL)
was added O-methylhydroxylamine HC1 salt (0.65 g, 7.78 mmol, 2.0 equiv.). The
resulting
solution was heated at the reflux temperature for 30 min, cooled to room
temperature and
3a concentrated under reduced pressure. The resulting solids were triturated
with water ( 10 mL)
and washed with water to give 4-(4-(1-(N-methoxy)iminoethyl) phenoxyaniline
HCI salt as a
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yellow solid (0.85 g): TLC (50% EtOAc/50% pet. ether) Rf0.78; ~H NMR (DMSO-d6)
8 3.90
(s, 3H), 5.70 (s, 3H); HPLC-MS m/z 257 ((M+H)+).
A17. Synthesis of N (w-Silyloxyalkyl)amides. Synthesis of 4-(4-(2-(N (2-
Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline.
O
CI , N~O.Si
\ N
Step 1. 4-Chloro-N (2-triisopropylsilyloxy)ethylpyridine-2-carboxamide
To a solution of 4-chloro-N (2-hydroxyethyl)pyridine-2-carboxamide (prepared
in a manner
analogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) was added
to triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole
(1.12 g, 16.4 mmol,
2.2 equiv.). The resulting yellow solution was stirred for 3 h at room temp,
then was
concentrated under reduced pressure. The residue was separated between water (
10 mL) and
EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The
combined
organic phases were dried (MgS04), and concentrated under reduced pressure to
afford 4-
chloro-2-(N (2-triisopropylsilyloxy)ethyl)pyridinecarboxamide as an orange oil
(2.32 g,
88%). This material was used in the next step without further purification.
O
\ O ~ N~O'Si
N
H2N
Step 2. 4-(4-(2-(N (2-Triisopropylsilyloxy)ethylcarbamoyl)pyriidyloxyaniline
To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anh DMF (8 mL) was
added
2o potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) in one portion
causing an exotherm.
When this mixture had cooled to room temperature, a solution of 4-chloro-2-(N-
(2
triisopropylsilyloxy)ethyl)pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv.) in
DMF (4 mL)
was added followed by KZC03 (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting
mixture was
heated at 80 °C overnight. An additional portion of potassium tert-
butoxide (0.34 g, 3 mmol,
0.5 equiv.) was then added and the mixture was stirred at 80 °C an
additional 4 h. T'he
mixture was cooled to 0 °C with an ice/water bath, then water (approx.
1 mL) was slowly
added dropwise. The organic layer was extracted with EtOAc (3 x 10 mL).
The~combined
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organic layers were washed with a saturated NaCI solution (20 mL), dried
(MgS04) and
concentrated under reduced pressure. The brown oily residue was purified by
column
chromatography (SiOz; 30% EtOAc/ 70% pet ether) to afford 4-(4-(2-(N-(2
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as a clear light brown
oil (0.99 g,
38%).
A18. Synthesis of 2-Pryidinecarboxylate Esters via Oxidation of 2-
Methylpyridines. Synthesis of 4-(5-(2-
methoxycarbonyl)pyridyloxy)aniline.
~ o i
02N N
Step 1. 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene.
A mixture of S-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), 1-fluoro-4-
nitrobenzene (9.8
mL, 91.6 mmol, 1.0 equiv.), KZC03 (25 g, 183 mmol, 2.0 equiv.) in DMF (100 mL)
was
heated at the reflux temperature overnight. The resulting mixture was cooled
to room
temperature, treated with water (200 mL), and extracted with EtOAc (3 x 100
mL). The
combined organic layers were sequentially washed with water (2 x 100 mL) and a
saturated
NaCI solution ((100 mL), dried (MgS04) and concentrated under reduced pressure
to give 4-
(5-(2-methyl)pyridyloxy)-1-nitrobenzene as a brown solid (12.3 g).
O
I / ~ I oMe
02N N
O
2o Step 2. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)-1-nitrobenzene.
A mixture of 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene (1.70 g, 7.39 mmol) and
selenium
dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) in pyridine (20 mL) was heated at the
reflux
temperature for 5 h, then cooled to room temperature. The resulting slurry was
filtered , then
concentrated under reduced pressure. The residue was dissolved in MeOH ( 100
mL). The
solution was treated with a conc HCI solution (7 mL), then heated at the
reflux temperature
for 3 h, cooled to room temperature and concentrated under reduced pressure.
The residue
was separated between EtOAc (50 mL) and a 1 N NaOH solution (50 mL). The
aqueous layer
was extracted with EtOAc (2 x 50 mL). The combined organic layers were
sequentially
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washed with water (2 x 50 mL) and a saturated NaCI solution (50 mL), dried
(MgS04) and
concentrated under reduced pressure. The residue was purified by column
chromatography
(Si02; 50% EtOAc/50% hexane) to afford 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-
nitrobenzene (0.70 g).
W
OMe
H2N N.
O
Step 3. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)aniline.
A slurry of 4-(S-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.50 g) and
10% Pd/C
(0.050 g) in a mixture of EtOAc (20 mL) and MeOH (5 mL) was placed under a HZ
atmosphere (balloon) overnight. The resulting mixture was filtered through a
pad of Celite'~,
to and the filtrate was concentrated under reduced pressure. The residue was
purified by
column chromatography (Si02; 70% EtOAc/30% hexane) to give 4-(S-(2-
methoxycarbonyl)pyridyloxy)aniline (0.40 g).
A19. Synthesis of w-Sulfonylphenyl Anilines. Synthesis of 4-(4-
Methylsulfonylphenyoxy)aniline.
O
i ,Me
02N O S~O
Step 1. 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene: To a solution of 4-(4-
methylthiophenoxy)-1-nitrobenzene (2.0 g, 7.7 mmol) in CHZCIz (75 mL) at 0
°C was slowly
added m-CPBA (57-86%, 4.0 g), and the reaction mixture was stirred at room
temperature for
5 h. The reaction mixture was treated with a 1 N NaOH solution (25 mL). The
organic layer
was sequentially washed with a 1N NaOH solution (25 mL), water (25 mL) and a
saturated
NaCI solution (25 mL), dried (MgS04), and concentrated under reduced pressure
to give 4-
(4-methylsulfonylphenoxy)-1-nitrobenzene as a solid (2.1 g).
z5 Step 2. 4-(4-Methylsulfonylphenoxy)-1-aniline: 4-(4-Methylsulfonylphenoxy)-
1-
nitrobenzene was reduced to the aniline in a manner analogous to that
described Wlethod
-~ 1 S, strp 3.
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B. Synthesis of Urea Precursors
B1. General Method for the Synthesis of Isocyanates from Anilines Using
CDI. Synthesis of 4-Bromo-3-(trifluoromethyl)phenyl Isocyanate.
CF3
Br
NH2~HCI
Step 1. Synthesis of 4-bromo-3-(trifluoromethyl)aniline HCl salt
To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 267 mmol) in Et20
(500 mL) was
added an HC1 solution (1 M in Et20; 300 mL) dropwise and the resulting mixture
was stirred
at room temp. for 16 h. The resulting pink-white precipitate was removed by
filtration and
washed with Et20 (50 mL) and to afford 4-bromo-3-(trifluoromethyl)aniline HCl
salt (73 g ,
l0 98%).
CF3
Br
i
NCO
Step 2. Synthesis of 4-bromo-3-(trifluoromethyl)phenyl isocyanate
A suspension of 4-bromo-3-(trifluoromethyl)aniline HCl salt (36.8 g, 133 mmol)
in toluene
(278 mL) was treated with trichloromethyl chloroformate dropwise and the
resulting mixture
was heated at the reflux temp. for 18 h. The resulting mixture was
concentrated under
reduced pressure. The residue was treated with toluene (500 mL), then
concentrated under
reduced pressure. The residue was treated with CHZCIZ (500 mL), then
concentrated under
reduced pressure. The CHZCIz treatment/concentration protocol was repeated and
resulting
2o amber oil was stored at -20 °C for 16 h, to afford 4-bromo-3-
(trifluoromethyl)phenyl
isocyanate as a tan solid (35.1 g, 86%): GC-MS m/z 265 (M+).
C. Methods of Urea Formation
Cla. General Method for the Synthesis of Ureas by Reaction of an Isocyanate
with an Aniline. Synthesis of N (4-Chloro-3-(trifluoromethyl)phenyl)-N'-
(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) Urea
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CF3 O
CI ~ I 0 ~ I O I w NHMe
~N
N N
H H
A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (14.60 g, 65.90
mmol) in CHZCIz
(35 mL) was added dropwise to a suspension of 4-(2-(N methylcarbamoyl)-4-
pyridyloxy)aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CHzCl2 (35 mL)
at 0 °C. The
resulting mixture was stirred at room temp. for 22 h. The resulting yellow
solids were
removed by filtration, then washed with CHZCIZ (2 x 30 mL) and dried under
reduced
pressure (approximately 1 mmHg) to afford N (4-chloro-3-
(trifluoromethyl)phenyl)-N'-(4-(2-
(N methylcarbamoyl)-4-pyridyloxy)phenyl) urea as an off white solid (28.5 g,
93%): mp
207-209 °C; ~H-NMR (DMSO-db) 8 2.77 (d, J--4.8 Hz, 3H), 7.16 (m, 3H),
7.37 (d, J--2.5 Hz,
t o 1 H), 7.62 (m, 4H), 8.11 (d, .l--2. S Hz, 1 H), 8.49 (d, J--S .S Hz, 1 H),
8.77 (br d, 1 H), 8.99 (s,
1H), 9.21 (s, 1H); HPLC ES-MS m/z 465 ((M+H)+).
Clb. General Method for the Synthesis of Ureas by Reaction of an Isocyanate
with an Aniline. Synthesis of N (4-Bromo-3-(trifluoromethyl)phenyl)-N'-
(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) Urea
CF3 O
Br / I O / I O I ~ NHMe
W ~ ~ iN
N N
H H
A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method B1, Step 2;
8.0 g, 30.1
mmol) in CHzCIz (80 mL) was added dropwise to a solution of 4-(2-(N
methylcarbamoyl)-4-
pyridyloxy)aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CHZC12 (40 mL) at
0 °C. The
2o resulting mixture was stirred at room temp. for 16 h. The resulting yellow
solids were
removed by filtration, then washed with CHZC12 (2 x 50 mL) and dried under
reduced
pressure (approximately 1 mmHg) at 40 °C to afford N (4-bromo-3-
(trifluoromethyl)phenyl)-
N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a pale-yellow solid
( 13.2 g,
90%): mp 203-205 °C; 'H-NMR (DMSO-db) 8 2.77 (d, J--4.8 Hz, 3H), 7.16
(m, 3H), 7.37 (d,
J--2.5 Hz, IH), 7.58 (m, 3H), 7.77 (d, J--8.8 Hz, 1H), 8.11 (d, J--2.5 Hz, 1
H), 8..19 (ci, ,l=>.s
Hz; 1 H), 8.77 (br d, I H), 8.99 (s, 1 H), 9.21 (s, 1 H); HPLC ES-MS m/_ 509
((:~~t~H )~ 1
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Clc. General Method for the Synthesis of Ureas by Reaction of an Isocyanate
with an Aniline. Synthesis of N (4-Chloro-3-(trifluoromethyl)phenyl)-N'-
(2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) Urea
CF3 O
CI w O ~ O ~ NHMe
N~N ~ I ~ , N
H H Me
A solution of 2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))aniline (Method
A5; 0.11 g,
0.45 mmol) in CHZCIz (1 mL) was treated with Et3N (0.16 mL) and 4-chloro-3-
(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown
solution was
stirred at room temp. for 6 d, then was treated with water (S mL). The aqueous
layer was
back-extracted with EtOAc (3 x 5 mL). The combined organic layers were dried
(MgS04)
1o and concentrated under reduced pressure to yield N (4-chloro-3-
(trifluoromethyl)phenyl)-N'
(2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea as a brown oil
(0.11 g, 0.22
mmol): 'H NMR (DMSO-db) 8 2.27 (s, 3H), 2.77 (d, J--4.8 Hz, 3H), 7.03 (dd, J--
8.5, 2.6 Hz,
1H), 7.11 (d, J--2.9 Hz, 1H), 7.15 (dd, J--5.5, 2.6, Hz, 1H), 7.38 (d, J--2.6
Hz, 1H), 7.62 (app
d, J--2.6 Hz, 2H), 7.84 (d, J--8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H); 8.50
(d, J--5.5 Hz, 1H),
8.78 (q, J--5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m/z 479 ((M+H)+).
Cld. General Method for the Synthesis of Ureas by Reaction of an Isocyanate
with an Aniline. Synthesis of N (4-Chloro-3-(trifluoromethyl)phenyl)-N'-
(4-aminophenyl) Urea
CF3
CI ~ O , NH2
I
N N
H H
To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (2.27 g, 10.3
mmol) in
CHZCIz (308 rizL) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one
part. The
resulting mixture was stirred at room temp. for 1 h, treated with CHZC12 ( 100
mL), and
concentrated under reduced pressure. The resulting pink solids were dissolved
in a mixture
of EtOAc ( 110 mL) and MeOH ( 1 SmL), and the clear solution was washed with a
0.05 '
HCl solution. The organic layer was concentrated under reduced pressure to
afford impure
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N (4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-aminophenyl) urea (3.3 g): TLC (
100°ro
EtOAc) Rj 0.72.
Cle. General Method for the Synthesis of Ureas by Reaction of an Isocyanate
s with an Aniline. Synthesis of N (4-Chloro-3-(trifluoromethyl)phenyl)-N'
(4-ethoxycarbonylphenyl) Urea
CF3 O
CI I ~ O ~ I OEt
N~N
H H
To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CHZCIZ (30
mL) was
added 4-chloro-3-(trifluoromethyl)aniline (3.21 g, 16.4 mmol), and the
solution was stirred at
to room temp. overnight. The resulting slurry was diluted with CHZC12 (50 mL)
and filtered to
afford N (4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-ethoxycarbonylphenyl) urea
as a white
solid (s.93 g, 97%): TLC (40% EtOAc/60% hexane) Rf0.44.
Clf. General Method for the Synthesis of Ureas by Reaction of an Isocyanate
1s with an Aniline. Synthesis ofN (4-Chloro-3-(trifluoromethyl)phenyl)-N'
(3-carboxyphenyl) Urea
CF3 O
CI I ~ O , I O I ~ OH
N N
H H
To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.21g, 5.46
mmol) in CHZCIZ
(8 mL) was added 4-(3-carboxyphenoxy)aniline (Method All; 0.81 g, 5.76 mmol)
and the
2o resulting mixture was stirred at room temp. overnight, then treated with
MeOH (8 mL), and
stirred an additional 2 h. The resulting mixture was concentrated under
reduced pressure.
The resulting brown solids were triturated with a 1:1 EtOAc/hexane solution to
give N (4-
chloro-3-(trifluoromethyl)phenyl)-N'-(3-carboxyphenyl) urea as an off white
solid (1.21 g,
76%).
C2a. General Method for Urea Synthesis by Reaction of an Aniline with lV,:'V'-
Carbonyl Diimidazole Followed by Addition of a Second Aniline.
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Synthesis of N (2-Methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N
methylcarbamoyl)-4-pyridyloxy)phenyl) Urea
CF3 O
O I ~ O I ~ NHMe
W ~ ~ ~N
N N
OMe H H
To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CHZCIz
(15 mL) at 0 °C
was added CDI (0.13 g). The resulting solution was allowed to warm to room
temp. over 1 h,
was stirred at room temp. for 16 h, then was treated with 4-(2-(N
methylcarbamoyl)-4
pyridyloxy)aniline (0.18 g). The resulting yellow solution was stirred at room
temp. for 72 h,
then was treated with H20 (125 mL). The resulting aqueous mixture was
extracted with
EtOAc (2 x 150 mL). The combined organics were washed with a saturated NaCI
solution
(100 mL), dried (MgS04) and concentrated under reduced pressure. The residue
was
triturated (90% EtOAc/10% hexane). The resulting white solids were collected
by filtration
and washed with EtOAc. The filtrate was concentrated under reduced pressure
and the
residual oil purified by column chromatography (gradient from 33% EtOAc/67%
hexane to
50% EtOAc/50% hexane to 100% EtOAc) to give N (2-methoxy-5-
(trifluoromethyl)phenyl)-
N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a light tan solid
(0.098 g, 30%):
TLC (100% EtOAc) Rf 0.62; 'H NMR (DMSO-db) 8 2.76 (d, J--4.8 Hz, 3H), 3.96 (s,
3H),
7.1-7.6 and 8.4-8.6 (m, 11 H), 8.75 (d, J--4.8 Hz, 1 H), 9.55 (s, 1 H); FAB-MS
m/z 461
((M+H)+)~
Zo C2b. General Method for Urea Synthesis by Reaction of an Aniline with N,/V'-
Carbonyl Diimidazole Followed by Addition of a Second Aniline.
Symmetrical Urea's as Side Products of a N,N'-Carbonyl Diimidazole
Reaction Procedure. Synthesis of Bis(4-(2-(N methylcarbamoyl)-4-
pyridyloxy)phenyl) Urea
O O
MeHN ~ ~ O ~ I O I ~ O I ~ NHMe
N ~ ~ ~ ~ ~N
N N
H H
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To a stirnng solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous
CHZCIz ( 15 mL)
at 0 C was added CDI (0.13 g). The resulting solution was allowed to warm to
room temp.
over 1 h then was stirred at room temp. for 16 h. The resulting mixture was
treated with 4-(2-
(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yellow
solution stirred at
room temp. for 72 h, then was treated with water (125 mL). The resulting
aqueous mixture
was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed
with a
saturated NaCI solution (100 ml), dried (MgS04) and concentrated under reduced
pressure.
The residue was triturated (90% EtOAc/10% hexane). The resulting white solids
were
collected by filtration and washed with EtOAc to give bis(4-(2-(N
methylcarbamoyl)-4-
pyridyloxy)phenyl) urea (0.081 g, 44%): TLC (100% EtOAc) Rf0.50;'H NMR (DMSO-
db) b
2.76 (d, J--5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J--5.4 Hz, 1H), 8:75 (d, J-
-4.8 Hz, 2H),,
8.86 (s, 2H); HPLC ES-MS m/z 513 ((M+H)+).
C2c. General Method for the Synthesis of Ureas by Reaction of an Isocyanate
with an Aniline. Synthesis of N (2-Methoxy-5-(trifluoromethyl)phenyl-N'-
(4-(1,3-dioxoisoindolin-5-yloxy)phenyl) Urea
CF3
O
~N N ~O
OMe H H NH
O
To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10
g, 0.47 mmol)
in CHZC12 (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-1,3-dione (Method
A3, Step
3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for 12
h, then was
treated with CHZC12 (10 mL) and MeOH (5 mL). The resulting mixture was
sequentially
washed with a 1 N HCl solution ( 15 mL) and a saturated NaCI solution ( 1 S
mL), dried
(MgS04) and concentrated under reduced pressure to afford N (2-methoxy-5-
(trifluoromethyl)phenyl-N'-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl) urea as a
white solid (0.2
g, 96%): TLC (70% EtOAc/30% hexane) Rf0.50;'H NMR (DMSO-db) 8 3.95 (s, 3H),
7.31-
7.10 (m, 6H), 7.57 (d, J=9.3Hz, 2H), 7.80 (d, J=8.7 Hz, 1H), 8.53 (br s, 2H),
9.57 (s, 1H),
1 I .27 (br s, 1 H); HPLC ES-MS 472.0 ((M+H)r, 100%).
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C2d. General Method for Urea Synthesis by Reaction of an Aniline with N,N'-
Carbonyl Diimidazole Followed by Addition of a Second Aniline.
Synthesis of N (5-(tert-Butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N'-(4-(2-
(N methylcarbamoyl)-4-pyridyloxy)phenyl) Urea
0
O i I 0 I ~ NHMe
/ ~ ~ iN
~N N
N H H
To a stirring solution of CDI (0.21g, 1.30 mmol) in CHZCIz (2 mL) was added 5-
(tert-butyl)-
2-(2,5-dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in one
portion. The
resulting mixture was stirred at room temp. for 4 h, then 4-(2-(N-
methylcarbamoyl)-4-
pyridyloxy)aniline (0.065 g, 0.267mmo1) was then added in one portion. The
resulting
1o mixture was heated at 36 °C overnight, then cooled to room temp. and
diluted with EtOAc (5
mL). The resulting mixture was sequentially washed with water (15 mL) and a 1N
HC1
solution ( lSmL), dried (MgSOa), and filtered through a pad of silica gel (50
g) to afford N-(5-
(tert-butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-
pyridyloxy)phenyl) urea as a yellowish solid (0.033 g, 24%): TLC (40%
EtOAc/60% hexane)
Rf 0.24; 'H NMR (acetone-d6) 8 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J--4.8Hz,
3H), 5.83 (s,
2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J--5.4Hz,
1H), 8.57 (d,
J--2.1 Hz, 1 H), 8.80 (br s, 1 H); HPLC ES-MS 512 ((M+H)+, 100%).
C3. Combinatorial Method for the Synthesis of biphenyl Ureas Using
2o Triphosgene
One of the anilines to be coupled was dissolved in dichloroethane (0.10 M).
This solution
was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this
was added a
bis(trichloromethyl) carbonate solution (0.12 M in dichloroethane, 0.2 mL, 0.4
equiv.),
followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2
equiv.). The vial
z5 was capped and heat at 80 °C for 5 h, then allowed to cool to room
temp for approximately
10 h. The second aniline was added (0.10 M in dichloroethane, 0.5 mL, 1.0
equiv.). followed
by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The
resulting
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mixture was heated at 80 °C for 4 h, cooled to room temperature and
treated with MeOH (0.5
mL). The resulting mixture was concentrated under reduced pressure and the
products were
purified by reverse phase HPLC.
C4. General Method for Urea Synthesis by Reaction of an Aniline with Phosgene
Followed by Addition of a Second Aniline. Synthesis of N (2-Methoxy-5-
(trifluoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl)
Urea
CF3 O
O ~ O ~ NHMe
i ~ w I ~ ~N
~N N
OMe H H
To a stirnng solution of phosgene (1.9 M in toluene; 2.07 mL0.21g, 1.30 mmol)
in CHZC12
(20 mL) at 0 °C was added anh pyridine (0.32 mL) followed by 2-methoxy-
5-
(trifluoromethyl)aniline (0.75 g). The yellow solution was allowed to warm to
room temp
during which a precipitate formed. The yellow mixture was stirred for 1 h,
then concentrated
under reduced pressure. The resulting solids were treated with anh toluene (20
mL) followed
by 4-(2-(N methylcarbamoyl)-4-pyridyloxy)aniline (prepared as described in
Method A2;
0.30 g) and the resulting suspension was heated at 80 °C for 20 h, then
allowed to cool to
room temp. The resulting mixture was diluted with water (100 mL), then was
made basic
with a saturated NaHC03 solution (2-3 mL). The basic solution was extracted
with EtOAc (2
x 250 mL). The organic layers were separately washed with a saturated NaCI
solution,
combined, dried (MgS04), and concentrated under reduced pressure. The
resulting prok-
2o brown residue was dissolved in MeOH and absorbed onto Si02 (100 g). Column
chromatography (300 g Si02; gradient from 1% Et3N/33% EtOAc/66% hexane to 1%
Et3N/99% EtOAc to 1 % Et3N/20% MeOH/79% EtOAc) followed by concentration under
reduced pressure at 45 °C gave a warm concentrated EtOAc solution,
which was treated with
hexane ( 10 mL) to slowly form crystals of N (2-methoxy-5-
(trifluoromethyl)phenyl)-N'-(4-
(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea (0.44 g): TLC ( 1 % Et3N/99%
EtOAc) Rf
0.40.
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D. Interconversion of Ureas
Dla. Conversion of w-Aminophenyl Ureas into w-(Aroylamino)phenyl Ureas.
Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-
methoxycarbonylphenyl)carboxyaminophenyl) Urea
CF3
CI ~ O , N ~ I OMe
I / ~ W I O O
N N
H H
To a solution of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-aminophenyl)
urea (Method
Cld; 0.050 g, 1.52 mmol), mono-methyl isophthalate (0.25 g, 1.38 mmol),
HOBT~Hz0 (0.41
g, 3.03 mmol) and N methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) was
added
EDCI ~HCl (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temp.
overnight;
to diluted with EtOAc (25 mL) and sequentially washed with water (25 mL) and a
saturated
NaHC03 solution (25 mL). The organic layer was dried (Na2S04) and concentrated
under
reduced pressure. The resulting solids were triturated with an EtOAc solution
(80%
EtOAc/20% hexane) to give N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-
methoxycarbonylphenyl)carboxyaminophenyl) urea (0.27 g, 43%): mp 121-122; TLC
(80%
EtOAc/20% hexane) Rf 0.75.
Dlb. Conversion of w-Carboxyphenyl Ureas into w-(Arylcarbamoyl)phenyl
Ureas. Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-
methylcarbamoylphenyl)carbamoylphenyl) Urea
CF3 O
CI ~ O , N w I NHMe
N~N ~ I H O
H H
To a solution of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-
methylcarbamoylphenyl)
carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080
g, 0.53
mmol), HOBT~HZO (0.14 g, 1.07 mmol), and N-methylmorpholine (O.SmL, 1.07 mmol)
in
DMF (3 mL) at 0 °C was added EDCI~HC1 (0.10 g, 0.53 mmol). The
resulting mixture was
allowed to warm to room temp. and was stirred overnight. The resulting mixture
was treated
with water ( l OmL), and extracted with EtOAc (25 mL). The organic phase was
concentrated
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under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3
mL) then
filtered through a pad of silica gel (17 g, gradient from 70% EtOAc/30% hexane
to 10%
MeOH/90% EtOAc) to give N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3
methylcarbamoylphenyl)carbamoylphenyl) urea as a white solid (0.097 g, 41%):
mp 225
229; TLC ( 100% EtOAc) Rf 0.23.
Dlc. Combinatorial Approach to the Conversion of w-Carboxyphenyl Ureas
into w-(Arylcarbamoyl)phenyl Ureas. Synthesis of N (4-Chloro-3-
((trifluoromethyl)phenyl)-N'-(4-(N-(3-(N-(3-
1o pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) Urea
CF3 O
CI ~ O , N W I N ~N
~ ~ ~ I H o I ~
N N
H H
A mixture of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(3-carboxyphenyl) urea
(Method
Clf; 0.030 g, 0.067 mmol) and N cyclohexyl-N'-(methylpolystyrene)carbodiimide
(55 mg) in
1,2-dichloroethane ( 1 mL) was treated with a solution of 3-aminopyridine in
CHZC12 ( 1 M;
0.074 mL, 0.074 mmol). (In cases of insolubility or turbidity, a small amount
of DMSO was
also added.) The resulting mixture was heated at 36 °C overnight.
Turbid reactions were then
treated with THF (1 mL) and heating was continued for 18 h. The resulting
mixtures were
treated with poly(4-(isocyanatomethyl)styrene) (0.040 g) and the resulting
mixture was
2o stirred at 36 °C for 72 h, then cooled ~to room temp. and filtered.
The resulting solution was
filtered through a plug of silica gel (1 g). Concentration under reduced
pressure afforded N-
(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(N-(3-(N-(3-
pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) urea (0.024 g, 59%): TLC (70%
EtOAc/30%
hexane) Rf 0.12.
D2. Conversion of w-Carboalkoxyaryl Ureas into w-Carbamoylaryl Ureas.
Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-
methylcarbamoylphenyl)carboxyaminophenyl) Urea
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CF3 H
CI ~ O ~ N w I NHMe
i ~ ~ ( O O
N N
H H
To a sample of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-
carbomethoxyphenyl)
carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in
THF; 1 mL,
1.7 mmol) and the resulting mixture was stirred at room temp. overnight, then
concentrated
under reduced pressure to give N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-
(3-
methylcarbamoylphenyl)carboxyaminophenyl) urea as a white solid: mp 247; TLC (
100%
EtOAc) Rf0.35.
D3. Conversion of w-Carboalkoxyaryl Ureas into w-Carboxyaryl Ureas.
to Synthesis ofN=(4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-
carboxyphenyl) Urea
CF3 O
CI I ~ O / I OH
N~N
H H
To a slurry of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-
ethoxycarbonylphenyl) urea
(Method Cle; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous KOH
solution
~ 5 (2.5 N, 10 mL, 23 mmol). The resulting mixture was heated at the reflux
temp. for 12 h,
cooled to room temp., and concentrated under reduced pressure. The residue was
diluted
with water (50 mL), then treated with a 1 N HCI solution to adjust the pH to 2
to 3. The
resulting solids were collected and dried under reduced pressure to give N (4-
chloro-3-
((trifluoromethyl)phenyl)-N'-(4-carboxyphenyl) urea as a white solid (5.0S g,
92%).
2o
D4. General Method for the Conversion of cu-Alkoxy Esters into w-Alkyl Amides.
Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-
dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) Urea
CF3 O
CI \ I ~ I j O \ I OH
N N N
H H
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Step 1. Synthesis of N (4-Chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-
carboxypyridyl) oxyphenyl) Urea
N (4-Chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-
methoxycarbonylpyridyl)oxyphenyl)
urea was synthesized from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and 4-
(3-(5-
methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) in a manner analogous
to Method
Cla. A suspension of N (4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-
methoxycarbonylpyridyl)oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was
treated
with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL) and was stirred at
room temp. for
1 h. The resulting mixture was adjusted to pH 5 with a 1 N HCl solution. The
resulting
1o precipitate was removed by filtration and washed with water. The resulting
solids were
dissolved in EtOH (10 mL) and the resulting solution was concentrated under
reduced
pressure. The EtOH/concentration procedure was repeated twice to give N (4-
chloro-3-
(trifluoromethyl)phenyl)-N'-((4-(3-(5-carboxypyridyl) oxyphenyl) urea (0.18 g,
71%).
CF3 O
CI \ I O I j O , I H~N~
N N N
H H
Step 2. Synthesis of N (4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-
dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea
A mixture of N (4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-
carboxypyridyl)oxyphenyl) urea (0.050 g, 0.011 mmol), N,N
dimethylethylenediamine (0.22
mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), N methylmorpholine (0.035 g, 0.28
mmol),
2o and EDCI~HCl (0.032 g, 0.17 mmol) in DMF (2.5 mL) was stirred at room temp.
overnight.
The resulting solution was separated between EtOAc (50 mL) and water (50 mL).
The
organic phase was washed with water (35 mL), dried (MgS04) and concentrated
under
reduced pressure. The residue was dissolved in a minimal amount of CH2C12
(approximately
2 mL). The resulting solution was treated with Et20 dropwise to give N (4-
chloro-3-
(trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-
dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl)
urea as a white precipitate (0.48 g, 84%:'H NMR (DMSO-db) b 2.10 s, 6H), 3.26
(s, H), 7.03
(d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, 1H), 8.43 (s, 1H), 8.58 (t, 1H),
8.69 (s, 1 H), 8.90
(s, 1 H), 9.14 (s, 1 H); HPLC ES-MS m/z 522 ((M+H)+).
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D5. General Method for the Deprotection of N (w-Silyloxyalkyl)amides.
Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N (2-
hydroxy)ethylcarbamoyl)pyridyloxyphenyl) Urea.
CF3 O
CI / O \ O / I N~O~gi
\ N H
N N
H H
To a solution of N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N (2-
triisopropylsilyloxy) ethylcarbamoyl)pyridyloxyphenyl) urea (prepared in a
manner
analogous to Method C 1 a; 0.25 g, 0.37 mmol) in anh THF (2 mL) was
tetrabutylammonium
fluoride (1.0 M in THF; 2 mL). The mixture was stirred at room temperature for
5 min, then
was treated with water (10 mL). The aqueous mixture was extracted with EtOAc
(3 x 10
to mL). The combined organic layers were dried (MgS04) and concentrated under
reduced
pressure. The residue was purified by column chromatography (Si02; gradient
from 100%
hexane to 40% EtOAc/60% hexane) to give N (4-chloro-3-
((trifluoromethyl)phenyl)-N'-(4-
(4-(2-(N (2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea as a white solid
(0.019 g, 10%).
Listed below are compounds listed in the Tables below which have been
synthesized
according to the Detailed Experimental Procedures given above:
Syntheses of Exemplified Compounds
(see Tables for compound characterization)
Entry 1: 4-(3-N Methylcarbamoylphenoxy)aniline was prepared according to
Method A13.
According to Method C3, 3-tert-butylaniline was reacted with
bis(trichloromethyl)carbonate
followed by 4-(3-N Methylcarbamoylphenoxy)aniline to afford the urea.
Entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted
according to
Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4-
Acetylphenoxy)-
1-nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-
acetylphenoxy)aniline. According to Method C3, 3-tert-butylaniline was reacted
with
bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to
afford the urea.
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Entry 3: According to Method C2d, 3-tert-butylaniline was treated with CDI,
followed by 4-
(3-N methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared
according to
Method A8, to afford the urea.
Entry 4: 5-tert-Butyl-2-methoxyaniline was converted to 5-tert-butyl-2-
methoxyphenyl
isocyanate according to Method B 1. 4-(3-N Methylcarbamoylphenoxy)aniline,
prepared
according to Method A 13, was reacted with the isocyanate according to Method
C 1 a to
afford the urea.
1o Entry 5: According to Method C2d, 5-tert-butyl-2-methoxyaniline was reacted
with CDI
followed by 4-(3-N methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been
prepared
according to Method A8, to afford the urea.
Entry 6: 5-(4-Aminophenoxy)isoindoline-1,3-dione was prepared according to
Method A3.
According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI
followed by 5
(4-aminophenoxy)isoindoline-1,3-dione to afford the urea.
Entry 7: 4-(1-Oxoisoindolin-S-yloxy)aniline was synthesized according to
Method A12.
According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI
followed by 4
(1-oxoisoindolin-5-yloxy)aniline to afford the urea.
Entry 8: 4-(3-N Methylcarbamoylphenoxy)aniline was synthesized according to
Method
AI3. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted
with CDI
followed by 4-(3-N methylcarbamoylphenoxy)aniline to afford the urea.
Entry 9: 4-Hydroxyacetophenone was reacted with 2-chloro-S-nitropyridine to
give 4-(4-
acetylphenoxy)-5-nitropyridine according to Method A3, Step 2. According to
Method A8,
Step 4, 4-(4-acetylphenoxy)-5-nitropyridine was reduced to 4-(4-acetylphenoxy)-
5-
aminopyridine. 2-Methoxy-5-(trifluoromethyl)aniline was converted to 2-methoxy-
5-
(trifluoromethyl)phenyl isocyanate according to Method B1. The isocyanate was
reacted
with 4-(4-acetylphenoxy)-5-aminopyridine according to Method Cla to afford the
urea.
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Entry 10: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted
according to
Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4-
Acetylphenoxy)-
1-nitrobenzene was reduced according to Method A13, Step 4 to afford ~ 4-(4-
acetylphenoxy)aniline: According to Method C3, S-(trifluoromethyl)-2-
methoxybutylaniline
was reacted with bis(trichloromethyl) carbonate followed by 4-(4-
acetylphenoxy)aniline to
afford the urea.
Entry 11: 4-Chloro-N methyl-2-pyridinecarboxamide, which was synthesized
according to
Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2,
Step 4 using
to DMAC in place of DMF to give 3-(-2-(N methylcarbamoyl)-4-
pyridyloxy)aniline. According
to Method C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene
followed by
3-(-2-(N methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 12: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with
ammonia
according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-
Chloro-2-
pyridinecarboxamide was reacted with 3-aminophenol according to Method A2,
Step 4 using
DMAC in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to
Method
C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed
by 3-(2-
carbamoyl-4-pyridyloxy)aniline to afford the urea.
Entry 13: 4-Chloro-N methyl-2-pyridinecarboxamide was synthesized according to
Method
A2, Step 3b. 4-Chloro-N methyl-2-pyridinecarboxamide was reacted with 4-
aminophenol
according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(N-
methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-
(trifluoromethyl)aniline was reacted with CDI followed by 4-(2-(N
methylcarbamoyl)-4-
pyridyloxy)aniline to afford the urea.
Entry 14: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with
ammonia
according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-
Chloro-2-
o pyridinecarboxamide was reacted with 4-aminophenol according to Method A2,
Step :1 using
DMAC in place of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. According to
~letho~l
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C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by
4-(2-
carbamoyl-4-pyridyloxy)aniline to afford the urea.
Entry 1S: According to Method C2d, S-(triflouromethyl)-2-methoxyaniline was
reacted with
CDI followed by 4-(3-N methylcarbamoyl)-4-methoxyphenoxy)aniline, which had
been
prepared according to Method A8, to afford the urea.
Entry 16: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was
synthesized
according to Method AS. 5-(Trifluoromethyl)-2-methoxyaniline was converted
into S-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. The
isocyanate was
reacted with 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-2-methylaniline according
to Method
C 1 c to afford the urea.
Entry 17: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was
synthesized
~ 5 according to Method A6. S-(Trifluoromethyl)-2-methoxyaniline was converted
into S-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-
(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N
methylcarbamoyl)-
4-pyridyloxy)-2-chloroaniline according to Method Cla to afford the urea.
2o Entry 18: According to Method A2, Step 4, S-amino-2-methylphenol was
reacted with 4-
chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to
Method
A2, Step 3b, to give 3-(2-(N methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. S-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl
isocyanate according to Method B 1. S-(Trifluoromethyl)-2-methoxyphenyl
isocyanate was
25 reacted with 3-(2-(N methylcarbamoyl)-4-pyridyloxy)-4-methylaniline
according to Method
C 1 a to afford the urea.
Entry 19: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine
according to
Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was
reacted
3o with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-
ethylcarbamoyl)-4-
pyridyloxy)aniline. S-(Trifluoromethyl)-2-methoxyaniline was converted into S-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. S-
(Trifluoromethyl)-
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2-methoxyphenyl isocyanate was reacted with 4-(2-(N ethylcarbamoyl)-4-
pyridyloxy)aniline
according to Method C 1 a to afford the urea.
Entry 20: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted
with 4-
chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to
Method
A2, Step 3b, to give 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. S-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl
isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl
isocyanate was
reacted with 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline according
to Method
1 o C 1 a to afford the urea.
Entry 21: 4-(4-Methylthiophenoxy)-1-nitrobenzene was oxidized according to
Method A19,
Step 1 to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene
was reduced
according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-1-aniline.
According
to Method C 1 a, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted
with 4-(4-
methylsulfonylphenoxy)-1-aniline to afford the urea.
Entry 22: 4-(3-carbamoylphenoxy)-1-nitrobenzene was reduced to 4-(3-
carbamoylphenoxy)aniline according to Method A15, Step 4. According to Method
C 1 a, S-
(trifluoroinethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-
carbamoylphenoxy)aniline to afford the urea.
Entry 23: 5-(4-Aminophenoxy)isoindoline-1,3-dione was synthesized according to
Method
A3. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method B 1. S-(Trifluoromethyl)-2-
methoxyphenyl
isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione according
to Method
C 1 a to afford the urea.
Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine
according
3o to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-
pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give .1-t ~-
~.~'..~'-
dimethylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluoromethyl)-2-methoxyaniline
was
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converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to
Method B 1. 5-
(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N,N-
dimethylcarbamoyl)-4-pyridyloxy)aniline according to Method C 1 a to afford
the urea.
Entry 25: 4-(I-Oxoisoindolin-5-yloxy)aniline was synthesized according to
Method A12. 5-
(Trifluoromethyl)-2-methoxyaniline was treated with CDI, followed by 4-(1-
oxoisoindolin-5-
yloxy)aniline according to Method C2d to afford the urea.
Entry 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene
according to
to Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The
nitrobenzene was
reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline,
which was
converted to the 4-(4-(I-(N methoxy)iminoethyl)phenoxyaniline HCI salt
according to
Method A16. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-
2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-
methoxyphenyl
isocyanate was reacted with 4-(4-(1-(N methoxy)iminoethyl)phenoxyaniline HC1
salt to
Method C 1 a to afford the urea.
Entry 27: 4-Chloro-N methylpyridinecarboxamide was synthesized as described in
Method
A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according
to Method
2o A2, Step 4 to give 4-(4-(2-(N methylcarbamoyl)phenylthio)aniline. 5-
(Trifluoromethyl)-2-
methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl
isocyanate
according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was
reacted with
4-(4-(2-(N methylcarbamoyl)phenylthio)aniline according to Method C 1 a to
afford the urea.
Entry 28: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized
according to
Method A9. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-
methoxyphenyl
isocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione
according to
Method C 1 a to afford the urea.
Entry 29: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in
Vlethocl
A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according
to :~lethocl
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A2, Step 4 to give 3-(4-(2-(N methylcarbamoyl)phenylthio)aniline. 5-
(Trifluoromethyl)-2-
methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl
isocyanate
according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was
reacted with
3-(4-(2-(N methylcarbamoyl)phenylthio)aniline according to Method C 1 a to
afford the urea.
Entry 30: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine
according
to Method A2, Step 3b. The resulting 4-chloro-N isopropyl-2-
pyridinecarboxamide .was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N
isopropylcarbamoyl)-4-pyridyloxy)aniline. S-(Trifluoromethyl)-2-methoxyaniline
was
to converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to
Method B1. 5-
(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N
isopropylcarbamoyl)-4-pyridyloxy)aniline according to Method Cla to afford the
urea.
Entry 31: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according
to Method
t5 A14. S-(Trifluoromethyl)-2-methoxyaniline was converted into S-
(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-
methoxyphenyl
isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline
according to
Method C 1 a to afford the urea. N (5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-
(3-(5-
methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4,
Step 1,
2o and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to
afford the
amide according to Method D4, Step 2.
Entry 32: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according
to Method
A14. S-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-2-
25 methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-
methoxyphenyl
isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline
according to
Method C 1 a to afford the urea. N (5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-
(3-(S-
methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4,
Step l,
and the corresponding acid was coupled with methylamine according to Method
D4, Step 2
3o to afford the amide.
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Entry 33: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according
to Method
A14. S-(Trifluoromethyl)-2-methoxyaniline was converted into S-
(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method B1. S-(Trifluoromethyl)-2-
methoxyphenyl
isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline
according to
Method C 1 a to afford the urea. N (5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-
(3-(5-
methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4,
Step 1,
and the corresponding acid was coupled with N,N dimethylethylenediamine
according to
Method D4, Step 2 to afford the amide.
1o Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method
A11. S
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl
isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted
with 5
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford
N (5
(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was
coupled with 3
t 5 aminopyridine according to Method D 1 c.
Entry 35: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl
isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted
with 5-
20 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C 1 f to
afford N (S-
(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was
coupled with N
(4-fluorophenyl)piperazine according to Method Dlc.
Entry 36: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11.
5-
25 (Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl
isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted
with 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C 1 f to
afford N (5-
(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was
coupled with 4-
fluoroaniline according to Method Dlc.
Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
~-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl
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isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted
with 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C 1 f to
afford N-(5-
(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was
coupled with 4-
(dimethylamino)aniline according to Method Dlc.
Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl
isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted
with 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to afford
N-(5-
to (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was
coupled with 5-
amino-2-methoxypyridine according to Method D 1 c.
Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11.
5-
(Trifluoromethyl)-2-methoxyaniline was converted into S-(trifluoromethyl)-2-
methoxyphenyl
isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline was reacted
with 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C 1 f to
afford N-(5-
(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was
coupled with 4-
morpholinoaniline according to Method D 1 c.
2o Entry 40: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method
A11. 5
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl
isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted
with 5
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford
N-(5
(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was
coupled with N
(2-pyridyl)piperazine according to Method D 1 c.
Entry 41: 4-(3-(N Methylcarbamoyl)phenoxy)aniline was synthesized according to
Method
A 13. According to Method C3, 4-chloro-3-(trifluoromethyl)aniline was
converted to the
isocyanate, then reacted with 4-(3-(N Methylcarbamoyl)phenoxy)aniline to
afford the urea.
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Entry 42: 4-(2-N Methylcarbamyl-4-pyridyloxy)aniline was synthesized according
to
Method A2. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-
N-
methylcarbamyl-4-pyridyloxy)aniline according to Method C 1 a to afford the
urea.
Entry 43: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with
ammonia
according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-
Chloro-2-
pyridinecarboxamide was reacted with 4-aminophenol according to Method A2,
Step 4 to
form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C 1 a, 4-chloro-
3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-carbamoyl-4-
pyridyloxy)aniline to
afford the urea.
Entry 44: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with
ammonia
according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-
Chloro-2-
pyridinecarboxamide was reacted with 3-aminophenol according to Method A2,
Step 4 to
form 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C 1 a, 4-chloro-
3-
(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-carbamoyl-4-
pyridyloxy)aniline to
afford the urea.
Entry 45: 4-Chloro-N methyl-2-pyridinecarboxamide, which was synthesized
according to
2o Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2,
Step 4 to
form 3-(-2-(N methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C 1
a, 4-chloro-
3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(N methylcarbamoyl)-
4-
pyridyloxy)aniline to afford the urea.
Entry 46: 5-(4-Aminophenoxy)isoindoline-1,3-dione was synthesized according to
Method
A3. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was
reacted
with 5-(4-aminophenoxy)isoindoline-1,3-dione to afford the urea.
Entry 47: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was
synthesized
,o according to Method A5. According to Method Clc, 4-chloro-3-
(trifluoromethyl)phenyl
isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione to afford
the urea.
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Entry 48: 4-(3-N Methylsulfamoyl)phenyloxy)aniline was synthesized according
to Method
A15. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate
was reacted
with 4-(3-N methylsulfamoyl)phenyloxy)aniline to afford the urea.
Entry 49: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was
synthesized
according to Method A6. According to Method C 1 a, 4-chloro-3-
(trifluoromethyl)phenyl
isocyanate was reacted with 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-2-
chloroaniline to
afford the urea.
to Entry 50: According to Method A2, Step 4, 5-amino-2-methylphenol was
reacted with 4-
chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to
Method
A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline.
According to
Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-
(2-(N-
methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea.
Entry 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine
according to
Method A2, Step 3b. The resulting 4-chloro-N ethyl-2-pyridinecarboxamide was
reacted
with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N
ethylcarbamoyl)-4-
pyridyloxy)aniline. According to Method Cla, 4-chloro-3-
(trifluoromethyl)phenyl
2o isocyanate was reacted with 4-(2-(N ethylcarbamoyl)-4-pyridyloxy)aniline to
afford the urea.
Entry 52: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted
with 4-
chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to
Method
A2, Step 3b, to give 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline.
According to
Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-
(2-(N-
methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.
Entry 53: 4-(4-Methylthiophenoxy)-1-nitrobenzene was oxidized according to
Method A 19,
Step 1 to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene
was reduced
3o according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-1-
aniline. According
to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with -
1-j.l-
methylsulfonylphenoxy)-1-aniline to afford the urea.
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Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine
according to
Method A15, Step 1 to afford N methyl-4-bromobenzenesulfonamide. N Methyl-4-
bromobenzenesulfonamide was coupled with phenol according to Method A15, Step
2 to
afford 4-(4-(N methylsulfamoyl)phenoxy)benzene. 4-(4-(N
Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(N
methylsulfamoyl)phenoxy)-
1-nitrobenzene according to Method A15, Step 3. 4-(4-(N
Methylsulfamoyl)phenoxy)-1-
nitrobenzene was reduced to 4-(4-N methylsulfamoyl)phenyloxy)aniline according
to
Method A15, Step 4. According to Method Cla, 4-chloro-3-
(trifluoromethyl)phenyl
isocyanate was reacted with 4-(3-N methylsulfamoyl)phenyloxy)aniline to afford
the urea.
to
Entry 55: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene
according
to Method A18, Step 1 to give 4-(S-(2-Methyl)pyridyloxy)-1-nitrobenzene. The
methylpyridine was oxidized according to the carboxylic acid, then esterified
according to
Method A18, Step 2 to give 4-(5-(2-methoXycarbonyl)pyridyloxy)-1-nitrobenzene.
The
t5 nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2-
methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3-
(trifluoromethyl)phenyl isocyanate according to Method C 1 a to afford the
urea.
Entry 56: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene
according
to Method A18, Step 1 to give 4-(S-(2-Methyl)pyridyloxy)-1-nitrobenzene. The
rriethylpyridine was oxidized according to the carboxylic acid, then
esterified according to
Method A18, Step 2 to give 4-(S-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene.
The
nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2-
methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3-
25 (trifluoromethyl)phenyl isocyanate according to Method Cla to give N (4-
chloro-3-
(trifluoromethyl)phenyl)-N'-(4-(2-(methoxycarbonyl)-5-pyridyloxy)phenyl) urea.
The
methyl ester was reacted with methylamine according to Method D2 to afford N-
(4-chloro-3-
(trifluoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-5-pyridyloxy)phenyl)
urea.
:o Entry ~7: lV-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea
was prepared
according to Method Cld. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-
aminophenyl) urea
was coupled with mono-methyl isophthalate according to Method Dla to afford
the urea.
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Entry 58: N (4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was
prepared
according to Method Cld. N (4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-
aminophenyl) urea
was coupled with mono-methyl isophthalate according to Method Dla to afford N
(4-chloro-
3-(trifluoromethyl)phenyl-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl)
urea.
According to Method D2, N (4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-
methoxycarbonylphenyl)carboxyaminophenyl) urea was reacted with methylamine to
afford
the corresponding methyl amide.
1o Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted with
dimethylamine according
to Method A2, Step 3b. The resulting 4-chloro-N,N dimethyl-2-
pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N
dimethylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N,N
dimethylcarbamoyl)-4
ts pyridyloxy)aniline to afford the urea.
Entry 60: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene
according to
Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene
was
reduced according to Method 13, Step 4 to afford 4-(4-acetylphenoxy)aniline,
which was
2o converted to the 4-(4-(1-(N methoxy)iminoethyl) phenoxyaniline HCl salt
according to
Method A 16. According to Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was
reacted with 4-(4-acetylphenoxy)aniline to afford the urea.
Entry 61: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to
Method A13,
25 Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was . coupled with 4-(2-
aminoethyl)morpholine according to Method A13, Step 3 to give 4-(3-(N (2-
morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13
Step 4, 4-
(3-(N (2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-
(3-(N-(2-
morpholinylethyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chloro-
3-
o (trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(2-
morpholinylethyl)carbamoyl)phenoxy)aniline to afford the urea.
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Entry 62: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to
Method A13,
Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 1-(2-
aminoethyl)piperidine
according to Method A13, Step 3 to give 4-(3-(N-(2-
piperidylethyl)carbamoyl)phenoxy)-1-
nitrobenzene. According to Method A13 Step 4, 4-(3-(N-(2-
piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(2-
piperidylethyl)carbamoyl)phenoxy)aniline. According to Method C 1 a, 4-chloro-
3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(2-
piperidylethyl)carbamoyl)phenoxy)aniline to afford the urea.
1o Entry 63: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to
Method A13,
Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with
tetrahydrofurfurylamine
according to Method A13, Step 3 to give 4-(3-(N-
(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method
A13 Step
4, 4-(3-(N (tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene was
reduced to 4-(3-
(N (tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline. According to Method Cla,
4-chloro-
3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-
(tetrahydrofurylmethyl)carbamoyl) phenoxy)aniline to afford the urea.
Entry 64: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to
Method A13,
2o Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 2-aminomethyl-
1-
ethylpyrrolidine according to Method A13, Step 3 to give 4-(3-(N-(( 1-
methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene. According to
Method A13
Step 4, 4-(3-(N ((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-
nitrobenzene was
reduced to 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline.
According to
Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-
(3-(N-(( 1-
methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline to afford the urea.
Entry 65: 4-Chloro-N methylpyridinecarboxamide was synthesized as described in
Method
A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according
to Method
3o A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According
to Method
Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with -l-1-1-(?-
1:'~'-
methylcarbamoyl)phenylthio)aniline to afford the urea.
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Entry 66: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine
according
to Method A2, Step 3b. The resulting 4-chloro-N isopropyl-2-
pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N
isopropylcarbamoyl)-4-pyridyloxy)aniline. According to Method C 1 a, 4-chloro-
3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N
isopropylcarbamoyl)-4-
pyridyloxy)aniline to afford the urea.
Entry 67: N (4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-ethoxycarbonylphenyl)
urea was
1 o synthesized according to Method C 1 e. N (4-Chloro-3-
(trifluoromethyl)phenyl-N'-(4-
ethoxycarbonylphenyl) urea was saponified according to Method D3 to give N (4-
chloro-3-
(trifluoromethyl)phenyl-N'-(4-carboxyphenyl) urea. N (4-Chloro-3-
(trifluoromethyl)phenyl-
N'-(4-carboxyphenyl) urea was coupled with 3-methylcarbamoylaniline according
to Method
Dlb to give N (4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-
methylcarbamoylphenyl)carbamoylphenyl) urea.
Entry 68: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized
according to
Method A9. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was
reacted with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione to afford the
urea.
Entry 69: 4-Chloro-N methylpyridinecarboxamide was synthesized as described in
Method
A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according
to Method
A2, Step 4 to give 3-(4-(2-(N methylcarbamoyl)phenylthio)aniline. According to
Method
C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-
(N
methylcarbamoyl)phenylthio)aniline to afford the urea.
Entry 70: 4-(2-(N (2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was
synthesized
according to Method A10. According to Method Cla, 4-chloro-3-
(trifluoromethyl)phenyl
isocyanate was reacted with 4-(2-(N (2-morpholin-4-
ylethyl)carbamoyl)pyridyloxy)aniline to
3o afford the urea.
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Entry 71: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according
to Method
A14. 4-Chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with
4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline according to Method Cl a to afford the
urea. N-(4-
Chloro-3-(trifluoromethyl)phenyl)-N'-(4-(3-(5-
methoxycarbonylpyridyl)oxy)phenyl) urea
was saponified according to Method D4, Step l, and the corresponding acid was
coupled with
4-(2-aminoethyl)morpholine to afford the amide.
Entry 72: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according
to Method
A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline according to Method C l a to afford the
urea. N-(5-
(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-
methoxycarbonylpyridyl)oxy)phenyl) urea
was saponified according to Method D4, Step 1, and the corresponding acid was
coupled with
methylamine according to Method D4, Step 2 to afford the amide.
Entry 73: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according
to Method
A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5
methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea.
N-(5
(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-
methoxycarbonylpyridyl)oxy)phenyl) urea
was saponified according to Method D4, Step l, and the corresponding acid was
coupled with
2o N,N dimethylethylenediamine according to Method D4, Step 2 to afford the
amide.
Entry 74: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with 2-
hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-N-(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide. - 4-Chloro-N-(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with
triisopropylsilyl chloride,
followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(N-(2
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method C 1
a, 4-chloro
3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(,'V-(?
triisopropylsilyloxy)ethylcarbamoyl) pyridyloxyaniline to afford N-(4-chloro-3
3o ((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2-triisopropylsilyloxy)
ethylcarbamoyl)pyridyloxyphenyl) urea.
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Entry 75: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
4-
Chloi=o-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(S-
methoxycarbonyl)pyridyloxy)aniline according to Method Clf to afford the urea,
which was
coupled with 3-aminopyridine according to Method Dlc.
Entry 76: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A
11. 4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-
carboxyphenoxy)aniline
according to Method C 1 f to afford the urea, which was coupled with N-(4-
acetylphenyl)piperazine according to Method D 1 c.
Entry 77: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-
carboxyphenoxy)aniline
according to Method C 1 f to afford the urea, which was coupled with 4-
fluoroaniline
according to Method D 1 c.
Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-
carboxyphenoxy)aniline
according to Method C 1 f to afford the urea, which was coupled with 4-
(dimethylamino)aniline according to Method D 1 c.
Entry 79: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-
carboxyphenoxy)aniline
according to Method Clf to afford the urea, which was coupled with N
phenylethylenediamine according to Method Dlc.
Entry 80: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-
carboxyphenoxy)aniline
according to Method C 1 f to afford the urea, which was coupled with 2-
methoxyethylamine
according to Method Dlc.
Entry 81: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-
carboxyphenoxy)aniline
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according to Method C 1 f to afford the urea, which was coupled with S-amino-2-
methoxypyridine according to Method Dlc.
Entry 82: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11.
4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-
carboxyphenoxy)aniline
according to Method Clf to afford the urea, which was coupled with 4-
morpholinoaniline
according to Method D 1 c.
Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A l
1. 4-
1o Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-
carboxyphenoxy)aniline
according to Method Clf to afford the urea, which was coupled with N (2-
pyridyl)piperazine
according to Method D 1 c.
Entry 84: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with 2-
t5 hydroxyethylamine according to Method A2, Step 3b to form ' 4-chloro-N (2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-Chloro-N (2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with
triisopropylsilyl chloride,
followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(N (2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method C 1
a, 4-chloro-
20 3-(trifluoromethyl)phenyl isocyanate was reacted. with 4-(4-(2-(N (2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline to give N (4-chloro-3-
((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N (2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl) urea. The urea was
deprotected
according to Method D5 to afford N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-
(4-(2-(N (2-
25 hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea.
Entry 85: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized
according to
Method A2. 4-Bromo-3-(trifluoromethyl)aniline was converted to 4-bromo-3-
(trifluoromethyl)phenyl isocyanate according to Method B 1. According to
Method C 1 a, 4-
30 bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-
methylcarbamoyl)-4-
pyridyloxy)aniline to afford the urea.
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Entry 86: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was
synthesized
according to Method A6. 4-Bromo-3-(trifluoromethyl)aniline was converted into
4-bromo-3-
(trifluoromethyl)phenyl isocyanate according to Method B 1. According to
Method C 1 a, 4-
bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N
methylcarbamoyl)-4-
pyridyloxy)-2-chloroaniline to afford the urea.
Entry 87: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted
with 4-
chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to
Method
A2, Step 3b, to give 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-
Bromo-3-
to (trifluoromethyl)aniline was converted into 4-bromo-3-
(trifluoromethyl)phenyl isocyanate
according to Method B 1. According to Method C 1 a, 4-bromo-3-
(trifluoromethyl)phenyl
isocyanate was reacted with 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-
chloroaniline to
afford the urea.
Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine
according to
Method A2, Step 3b. The resulting 4-chloro-N ethyl-2-pyridinecarboxamide was
reacted
with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N
ethylcarbamoyl)-4-
pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-
bromo-3-
(trifluoromethyl)phenyl isocyanate according to Method B 1. According to
Method C 1 a, 4-
2o bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N
ethylcarbamoyl)-4-
pyridyloxy)aniline to afford the urea.
Entry 89: 4-Chloro-N methyl-2-pyridinecarboxamide, which was synthesized
according to
Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2,
Step 4 to
form 3-(-2-(N methylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-
(trifluoromethyl)aniline
was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to
Method B 1.
According to Method C 1 a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was
reacted with 3-
(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
3o Entry 90: According to Method A2, Step 4, S-amino-2-methylphenol was
reacted with -l-
chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to
Method
A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. -
1-Bromo-:-
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(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl
isocyanate
according to Method B 1. According to Method C 1 a, 4-bromo-3-
(trifluoromethyl)phenyl
isocyanate was reacted with 3-(2-(lV methylcarbamoyl)-4-pyridyloxy)-4-
methylaniline to
afford the urea.
Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine
according
to Method A2, Step 3b. The resulting 4-chloro-N,N dimethyl-2-
pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N
dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline
was
1o converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to
Method B1.
According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was
reacted with 4-
(2-(N,N dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 92: 4-Chloro-N methylpyridinecarboxamide was synthesized as described in
Method
t5 A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol
according to Method
A2, Step 4 to give 4-(4-(2-(N methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-
(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl
isocyanate
according to Method B 1. According to Method C 1 a, 4-bromo-3-
(trifluoromethyl)phenyl
isocyanate was reacted with 4-(4-(2-(N methylcarbamoyl)phenylthio)aniline to
afford the
20 urea.
Entry 93: 4-Chloro-N methylpyridinecarboxamide was synthesized as described in
Method
A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according
to Method
A2, Step 4 to give 3-(4-(2-(N methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-
25 (trifluoromethyl)aniline was converted into 4-bromo-3-
(trifluoromethyl)phenyl isocyanate
according to Method B 1. According to Method C 1 a, 4-bromo-3-
(trifluoromethyl)phenyl
isocyanate was reacted with 3-(4-(2-(N methylcarbamoyl)phenylthio)aniline to
afford the
urea.
3o Entry 94: 4-(2-(N (2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was
synthesized
according to Method A10. 4-Bromo-3-(trifluoromethyl)aniline was convened into
4-bromo-
3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to
Method C 1 a, ~1-
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bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N (2-
Morpholin-4-
ylethyl)carbamoyl)pyridyloxy)aniline to afford the urea.
Entry 95: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized
according to
Method A2. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized
according to
Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-
chloro-2-
methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B 1.
According to
Method C 1 a, 4-chloro-2-methoxy-S-(trifluoromethyl)phenyl isocyanate was
reacted with 4-
(2-(N methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
to
Entry 96: 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was
synthesized
according to Method A6. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was
synthesized
according to Method A7. 4-Chloro-2-methoxy-S-(trifluoromethyl)aniline was
converted into
4-chloro-2-methoxy-S-(trifluoromethyl)phenyl isocyariate according to Method B
1.
According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl
isocyanate was
reacted with 4-(2-(N=methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline afford the
urea.
Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted
with 4-
chloro-N methyl-2-pyridinecarboxamide, which had been synthesized according to
Method
2o A2, Step 3b, to give 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-
chloroaniline. 4-Chloro-2-
methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-
Chloro-2-
methoxy-S-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxv-5-
(trifluoromethyl)phenyl isocyanate according to Method B 1. According to
Method C l a, 4
chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N
methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.
Entry 98: 4-Chloro-N methyl-2-pyridinecarboxamide, which was synthesized
according to
Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2,
Step 4 to
form 3-(-2-(N methylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxv-s-
(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-?-
methoxv-s-
(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-
(trifluoromethyl)ph~nvl
isocyanate according to Method B 1. According to Method C 1 a, 4-chloro-2-
methoxy-s-
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(trifluoromethyl)phenyl isocyanate as was reacted with 3-(-2-(N
methylcarbamoyl)-4-
pyridyloxy)aniline to afford the urea.
Entry 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine
according to
Method A2, Step 3b. The resulting 4-chloro-N ethyl-2-pyridinecarboxamide was
reacted
with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N
ethylcarbamoyl)-4-
pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was
synthesized
according to Method A7. 4-Chloro-2-methoxy-S-(trifluoromethyl)aniline was
converted into
4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B
1.
to According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl
isocyanate was
reacted with 4-(2-(N ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 100: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine
according
to Method A2, Step 3b. The resulting 4-chloro-N,N dimethyl-2-
pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N-
dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-
(trifluoromethyl)aniline
was synthesized according to Method A7. 4-Chloro-2-methoxy-5-
(trifluoromethyl)aniline
was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate
according to
Method B 1. According to Method C 1 a, 4-chloro-2-methoxy-5-
(trifluoromethyl)phenyl
2o isocyanate was reacted with 4-(2-(N,N dimethylcarbamoyl)-4-
pyridyloxy)aniline to afford the
urea.
Entry 101: 4-Chloro-N methyl-2-pyridinecarboxamide, which was synthesized
according to
Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2,
Step 4 to
form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. 2-Amino-3-
methoxynaphthalene was
synthesized as described Method A1. According to Method C3, 2-amino-3-
methoxynaphthalene was reacted with bis(trichloromethyl) carbonate followed by
3-(-2-(N-
methylcarbamoyl)-4-pyridyloxy)aniline to form the urea.
3o Entry 102: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized
according to
Method A2. 5-rert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was synthesized
according to
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Method A4. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was reacted with CDI
followed by
4-(2-(N methylcarbamoyl)-4-pyridyloxy)aniline according to Method C2d to
afford the urea.
Entry 103: 4-Chloro-N methyl-2-pyridinecarboxamide was synthesized according
to Method
A2, Step 3b. 4-Chloro-N methyl-2-pyridinecarboxamide was reacted with 4-
aminophenol
according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(N
methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2b, reaction of 3-
amino-2-
methoxyquinoline with CDI followed by 4-(2-(N methylcarbamoyl)-4-
pyridyloxy)aniline
afforded bis(4-(2-(N methylcarbamoyl)-4-pyridlyoxy)phenyl)urea.
Listed in the Tables below are compounds which have been synthesized according
to
the Detailed Experimental Procedures given above:
Tables
2o The compounds listed in Tables 1-6 below were synthesized according to the
general
methods shown above, and the more detailed exemplary procedures are in the
entry listings
above and characterizations are indicated in the tables.
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Table 1. 3-tert-Butylphenyl Ureas
O ~ w
R.N~N /
H H
TLC Mass
mp HPLC TLC SolventSpec. Synth.
En R C min. R S Source Method
stem
I O 0.2250% 418 A 13
C3
NH EtOAc(M+H)+
Me / (HPLC
50% ES-MS)
hexane
2 O 0.5850% 403 A13
~ O ~ ~ EtOAc(M+H)+ C3
Me /50% (HPLC
hexaneES-MS
3 O 133- 0.68100% 448 A8
C2d
NH 135 EtOAc(M+H)+
- Me (FAB)
~O ~ ~ OMe
Table 2. 5-tert-Butyl-2-methoxyphenyl Ureas
O
R.N~N /
H H OMe
TLC Mass
mp HPLCTLC SolventSpec. Synth.
En R C min.R S Source Method
stem
4 O 5.93 448 A 13
NH (M+H)+ B1
Me (HPLC Cla
ES-MS)
O 120- 0.67 100% 478 A8
NH 122 EtOAc(M+H)+ C2d
/ ~ - Me (FAB)
~O ~ ~ OMe
6 ~ ~ - ~ 0.40 50% 460 A 3
I
O ~ ~ EtOAc(MTH)+ C2d
NH /50% (HPLC
hexaneES-MS)
O
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7 / \ -O - 0.7950% 446 A 12
O \ ~ EtOAc (M+H)+C2d
NH / 50% (HPLC
hexaneES-MS
Table 3. 5-(Trifluoromethyl)-2-methoxyphenyl Ureas
F F F
O'' ~ W
R.N~N /
H H OMe
TLC Mass
mp HPLC TLC SolventSpec. Synth.
En R C min. R S stemSourceMethod
8 O 250 460 A 13
NH (dec) (M+H)+C2a
/ \ - Me (FAB)
~O \
9 O 206- 0.5410% 446 A3
O 208 MeOH (M+H)+step
2,
N \ / Me / 90% (HPLC A8
step
CH2Cl ES-MS)4,
2 BI,
Cla
O 0.3350% 445 A13
\ O \ ~ EtOAc (M+H)+C3
Me / 50% (HPLC
pet ES-MS)
ether
11 O 0.202% 461 A2
/ \ Et3N/ (M+H)+C4
NH
~Me 98% (HPLC
O \ /N
EtOAc ES-MS)
12 O 0.271% 447 A2
/ \ Et3N/ (M+H)+C4
NH2
_ 99% (HPLC
O \ /N
EtOAc ES-MS)
13 O 0.62100% 461 A2
C2a
NH EtOAc (M+H)+
Me (FAB)
\ O \ /N
14 O . 114- 0.401% 447 A2
NH2 117 Et3N/ (M+H)+C4
_ 99% (FAB)
~ O N EtOAc
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15 O 232- 0.54 100% 490 A8 C2d
NH 235 EtOAc (M+H)+
- Me (FAB)
~O ~ ~ OMe
16 O 210- 0.29 5% 475 A5
Me NH 213 MeOH (M+H)+ B1 Clc
_ j~e / 45% (HPLC
/ ~ O ~ / N 50 oc ES-MS)
0
pet
ether
17 O 187- 0.17 50% 495 A6
CI NH 188 EtOAc (M+H)+ B1 Cla
_ j~e / 50% (HPLC
/ ~ O ~ / N pet ES-MS)
ether
18 / ~ O 0.48 100% 475 A2 step
Me NHy EtOAc (M+H)+ 4,
_ (HPLC B1 Cla
ES-MS)
O ~ /N
19 O 194- 0.31 5% 475 A2
NH 196 MeOH (M+H)+ BI Cla
~Et / 45% (HPLC
/ ~ O ~ /N, E5~ ac ES-MS)
°
pet
ether
20 O 214- 0.25 5% 495 A2 C 1 a
CI NH 216 MeOH (M+H)+
_ j~e /45% (HPLC
~ O \N EtOAc ES-MS)
/ 50%
pet
ether
21 O 208- 0.30 50% 481 A 19 C2a
/ ~ O ~ ~ S~O 210 EtOAc (M+H)+
Me /50% (HPLC
hexane ES-MS
22 O 188- 0.30 70% 447 A 15,
NH2 190 EtOAc (M+H)+ step 4,
_ / 50% (HPLC C 1 a
/ ~ O \ / hexane ES-MS)
23 / ~ - O 0.50 70% 472 A3
O ~ ~ EtOAc (M+H)+ B 1 C 1 a
NH / 30% (FAB)
hexane
O
24 O Me 203- 0.13 100% 479 A2 E31
N 205 EtOAc (M+H)+ Cla
~Me (HPLC
/ ~. O N ES-;~1S)
78.
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25 ~ - O 0.09 75% 458 A12
~ O ~ ~ EtOAc (M+H)+ C2d
NH / 25% (HPLC
hexane ES-MS
26 Me0 169- 0.67 50% 474 A 13
_ N 171 EtOAc (M+H)+ stepl,
/ 50% (HPLC A 13 step
Me pet ES-MS) 4,
ether A 16,
B1
Cla
27 O 218- 0.40 50% 477 A2 step
NH 219 EtOAc (M+H)+ 3b,
_ jyle / 50% (HPLC A2 step
~ S N pet ES-MS) 4,
ether B 1,
Cla
28 ~ ~ - O 212- 0.30 40% A9
O ~ ~ 214 EtOAc BI Cla
NMe / 60%
hexane
O
29 / ~ O 0.33 50% 474 A2 step
NH EtOAc (M+H)+ 3b,
~Me / 50% (HPLC A2 step
w
S ~ / N pet ES-MS) 4,
ether B 1,
Cla
30 O 210- A2
NH 211 B1
- ~Pr-i Cla
~O ~ /N
31 O 210- 0.43 10% A 14
NH 204 MeOH B1
O ~ / N CH2CI D4a
N 2
O
32 O 247- 0.57 10% A14
NH 249 MeOH B1
/ Me CH2C1 D4a
N 2
33 ~ O 217- 0.07 10% A14
NH 219 MeOH B 1
O ~ / ~N-M CH2CI D4a
N Me 2
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34 O 0.11 70% A 11
N H EtOAc B 1
/ 30% Clf
~ O ~ ~ ~ ~ N hexane D 1 c
35 F 0.38 70% A11
EtOAc B 1
/ 30% C l f
hexane D 1 c
N
'-N
O
O ~
36 ~ ~ 0.77 70% All
F~NH EtOAc BI
O / 30% C l f
- hexane D 1 c
~O ~
37 Me~ 0.58 70% Al I
N ~ ~ N H EtOAc B 1
Me O / 30% Clf
_ hexane D 1 c
38 N 0.58 70% All
Me0 / ~ NH EtOAc B1
p / 30% Clf
_ hexane D 1 c
O ~
39 /~ ~ ~ 0.17 70% All
~N NH EtOAc B1
O / 30% Clf
- hexane D 1 c
O ~
40 N ~---1 0.21 70% A 11
N N . ~ ~ NH EtOAc B 1
U O / 30% Clf
_ hexane D 1 c
~ O
Table 4. 3-(Trifluoromethyl)-4-cbloropbenyl Ureas
F F F
O ~ CI
R.N~N
H H
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TLC Mass
mp HPLC TLC Solvent Spec. Synth.
En R °C min. R S stem Source Method
41 O. 163- 0.08 50% 464 A 13
NH 165 EtOAc/ (M+H)+ C3
- [yle 50% pet (HPLC
O ~ / ether ES-MS)
42 O 215 0.06 50% 465 A2
N H EtOAc/ (M+H)+ C 1 a
_ j~e 50% pet (HPLC
~ / N ether ES-MS)
43 O 0.10 50% 451 A2
NHZ EtOAc/ (M+H)+ Cla
_ 50% pet (HPLC
~ / N ether ES-MS)
44 / ~ O 0.25 30% 451 A2
NH2 EtOAc/ (M+H)+ Cla
_ 70% pet (HPLC
O ~ / N ether ES-MS)
45 / \ O 0.31 30% 465 A2
N H EtOAc/ (M+H)+ C 1 a
~Me 70% pet (HPLC
O N ether ES-MS)
46 ~ ~ - O 176- 0.23 40% 476 A3
O ~ ~ 179 EtOAc/ (M+H)+ C 1 a
NH 60% (FAB)
hexane
O
47 O 0.29 5% 478 A5
Me NH MeOH/ (M+H)+ Clc
~ / N Me EtOAc/ ESPMS)
50 /o pet
ether
48 O' ~O 206- A 15
~S-NH 209 Cla
~ ~ - Me
~O
49 O 147- 0.22 50% 499 A6
CI NH 151 EtOAc/ (M+H)+ Cla
_ j~e 50% pet (HPLC
~ O \N ether ES-MS)
50 / \ O 0.54 100% 479 A2
Me NH EtOAc (MtH)+ Cta
Me (HPLC I
ES-VIS)
O ~ /N
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51 O 187- 0.33 5% 479 A2
N H 189 MeOH/ (M+H)+ C 1 a
/ ~ - ~Et 45% (HPLC
~O N EtOAc/ ES-MS)
/ 50% pet
ether
52 O 219 0.18 5% 499 A2
CI NH MeOH/ (M+H)+ Cla
/ \ Me 45% (HPLC
O N EtOAc/ ES-MS)
50% pet
ether
53 O 246- 0.30 50% 485 A19, Cla
/ ~ O ~S~O 248 EtOAc/ (M+H)+
/ ,
Me 50% (HPLC
hexane ES-MS
54 O~ 196- 0.30 70% 502 A15
/ ~ O ~ / S~O 200 EtOAc/ (M+H)+ Cia
~NH 30% (HPLC
Me hexane) ES-MS)
55 O 228- 0.30 30% 466
O 230 EtOAc/ (M+H)+
/ ~ Me 70% (HPLC
~O ~ ~N CH2C12 ES-MS)
56 N O 238
/ ~ O ~ / 245
NH
Me
57 O 221- 0.75 80% 492 Cld
O 222 EtOAc/ (M+H)+ D 1 a
H O fv~e 20% (FAB)
~N ~ / hexane
58 O 247 0.35 100% Cld
N H EtOAc D 1 a
H O Me D2
~N ~ /
59 O Me 198- 0.09 100% 479 A2
N 200 EtOAc (M+H)+ C 1 a
/ ~ - Me (HPLC
ES-MS)
~O ~ ~N
60 Me0 158- 0.64 50%
N 160 EtOAc/
/ ~ O ~ / / 50% pet
Me ether
61 O 195- 0.39 10% A 13
NH 197 MeOH/ Cla
- CH2C1
O ~ / N~ 2
'O
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62 O 170- 0.52 10% A13
NH 172 MeOH/ C 1 a
- CH2C1
O ~ ~ ~N 2
63 O 168- 0.39 10% A 13
N~ 171 MeOH/ C I a
- CH2C1
O ~ ~ 2
64 O Et 176- 0.35 10% A13
NH N 177 MeOH/ Cla
/ ~ CH2C1
O. 2
65 O 130- 487 A2
NH 133
(M+H)+ B 1
- Me (HPLC Cla
S ~ / N ES-MS)
66 O 155 A2
NH Cla
- ~Pr-i
O ~ /N
67 O 225- 0.23 100% C 1 a
NH 229 EtOAc D3
H O -~ Me Dlb
~N
68 ~ ~ - O 234- 0.29 40% A9
O ~ ~ 236 EtOAc/ C I a
NMe 60%
hexane
O
69 / \ O 0.48 50% 481
NH EtOAc/ (M+H)+
Me 50% pet (HPLC
-v
S N ether ES-MS)
70 O 0.46 5% 564 A 10
NH MeOH/ (M+H)+ C 1 a
- ~ 95% (HPLC
O ~ / N N~ CH2C12 ES-MS)
>O
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71 O 199- 0.50 10% A 14
NH 201 MeOH/ Cla
CH2C 1 D4
~O ~ / N 2
N
O
72 O 235- 0.55 10% A14
NH 237 MeOH/ Cla
/ ~ Me CH2C1 D4
O ~ / 2
/ N
73 O 200- 0.21 50% A 14
NH 201 MeOH/ Cla
CH2C1 D4
O ~ / N-Me 2
N Me
74 O 145
NH 148
O ~ ~ OSi(Pr-i)3
N
75 N \ 0.12 70%
527 A11
~NH EtOAc/ (M+H)+ Clf
O 30% (HPLC D 1 c
_ hexane ES-MS)
/ ~ O ~ /
76 O 0.18 70% A 11
Me EtOAc/ C 1 f
30% Dlc
/ hexane
N
~N
O
/ ~ O ~ /
77 / \ - 0.74 70% A 11
F~ N H EtOAc/ C 1 f
O 30% Dlc
/ ~ - hexane
O ~ /
78 Me 0.58 70% A 11
'N / ~ NH EtOAc/ Clf
Me O 30% Dlc
hexane
/ ~ O
/
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79 O 0.47 70% 569 A11
NH EtOAc/ (M+H)+ Cif
_ 30% (HPLC Dlc
/ \ O \ / ~NH hexane ES-MS)
\ /
80 O 0.18 70% 508 All
NH EtOAc/ (M+H)+ Clf
_ 30% (HPLC Dlc
/ \ O \ / OMe hexane ES-MS)
0.58 70% 557 A11
81 N
Me0 ~ \ NH EtOAc/ (M+H)+ Clf
O 30% (HPLC Dlc
_ hexane ES-MS)
/ \ O \ /
g2 ~--~ 0.37 70% 611 All
~N / \ NH EtOAc/ (M+H)+ Clf
O 30% (HPLC Dlc
hexane ES-MS)
\ O \ /
g3 0.19 70% A11
~N EtOAc/ C 1 f
30% Dlc
N~ hexane
'N
O
\ O \
84 O 179- A2
NH 183 A17
/ \ - Cla
DS
~O \ /N OH
Table 5. 3-(Trifluoromethyl)-4-bromophenyl Ureas
F F F
~ Br
O
R.N~N /
H H
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TLC Mass
mp HPLC TLC Solvent Spec. Synth.
En R °C min. R S stem Source Method
85 O 186- 0.13 50% 509 A2
NH 187 EtOAc/ (M+H)+ B1
_ jyle 50% pet (HPLC ES- C 1 a
ether MS)
O ~ /N
86 O 150- 0.31 50% 545 A6
CI NH 152 EtOAc/ (M+H)+ B1
_ jig 50% pet (HPLC ES- Cla
~ O ~ / N ether MS)
87 O 217- 0.16 50% 545 A2
CI NH 219 EtOAc/ (M+H)+ B1
_ j~e 50% pet (HPLC ES- Cla
ether MS)
O ~ /N
88 O 183- 0.31 50% 525 A2
NH 184 EtOAc/ (M+H)+ B1
~Et 50% pet (HPLC ES- C 1 a
~ O ~ / N ether MS)
89 / \ O 0.21 50% 511 A2
NH EtOAc/ (M+H)+ B1
_ j~e . 50% pet (HPLC ES- C 1 a
O \N ether MS)
90 / \ O 0.28 50% 525 A2
Me NH EtOAc/ (M+H)+ B1
~Me 50% pet (HPLC ES- C 1 a
O \N ether MS)
91 O Me 214- 0.28 50% 522 A2
N 216 EtOAc/ (M+H)+ B 1
~Me 50% pet (HPLC ES- C 1 a
/ N ether MS)
92 O 0.47 50% 527 A2 step
NH EtOAc/ (M+H)+ 3b,
jig 50% pet (HPLC ES- A2 step
~S ~ /N ether MS) g1,
Cla
93 / \ O 0.46 50% 527 A2 step
NH EtOAc/ (M+H)+ 3b.
~Me 50% pet (HPLC ES- A2 step
ether MS) 4.
S ~ /N B1,
Cla
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94 O 145- 0.415% A10
NH 150 MeOH/ B1
95% Cla
~O . \ /N N CH2C12
O
Table 6. 5-(Trifluoromethyl)-4-chloro-2-methoxyphenyl Ureas
F F F
O ~ CI
R.N~N I /
H H OMe
TLC Mass
mp HPLC TLC Solvent Spec. Synth.
En R °C min. R S stem Source Method
95 O 140- 0.29 5% 495 A2
NH 144 MeOH/ (M+H)+ A7
\ O \ ~ N Me EtOAc/ ESPMS) C 1 a
50 /o pet
ether
96 O 244- 0.39 5% 529 A6
CI NH 245 MeOH/
(M+H)+ A7
\ - Me 45% (HPLC B 1
O ~N EtOAc/ ES-MS) Cla
\ ~ 50% pet
ether
97 O 220- 0.25 5% 529 A2
CI NH 221 MeOH/ (M+H)+ A7
\ - [~e 45% (HPLC B1
O N EtOAc/ ES-MS) Cla
\ ~ 50% pet
ether
98 / \ O 0.27 5% 495 A2
NH MeOH/
(M+H)+ A7
Alle 45% (HPLC B 1
O N EtOAc/ ES-MS) C 1 a
50% pet
ether
'99 O 180- 0.52 5% 509 A2
NH 181 MeOH/ (M+H)+ A7
\ - ~Et 45% (HPLC B 1
~O N EtOAc/ ES-MS) Cla
\ ~ 50% pet
ether
100 O 162- . A2
NH 165 A7
\ - ~P r-i B 1
~O \ /N Cla
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Table 7. Additional Ureas
TLC Mass
mp HPLC TLC Solvent Spec. Synth.
En R °C min. R S stem Source Method
101 I ~ O 162- A 1
O 165 A2
N~N ~ ~ ~ ~ Me C3
OMe H H
102 0.10 50% 442 A2
EtOAc/ (M+H)+ A4
NH 50% (HPLC C2d
N N ~ ~ N Me hexane ES-MS)
H H
Me \N/ Me
103 O 125- 0.24 40% 512 A2
(M+H)+ C2b
HN ~ NH 130 EtOAc/
60% (FAB)
\ hexane
O O
/ \ ~ \
O O
NH-Me Me-NH
The preceding examples can be repeated with similar success by substituting
the generically
or specifically described reactants and/or operating conditions of this
invention for those used
in the preceding examples.
1 o From the foregoing description, one skilled in the art can easily
ascertain the essential
characteristics of this invention and, without departing from the spirit and
scope thereof, can
make various changes and modifications of the invention to adapt it to various
usages and
conditions.
88
