Note: Descriptions are shown in the official language in which they were submitted.
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Solid dispersion product of N-aryl urea-based drugs
Many potent drugs belong to the class of compounds of N-aryl ureas and
compounds
of related structural types. Unfortunately, the crystalline forms of most N-
aryl urea-
based active agents are characterized by poor solubility in aqueous liquids.
Drugs of low water solubility, for example those classified as "practically
insoluble" or
"insoluble" according to United States Pharmacopeia (USP) 24 (2000), p. 10, i.
e., hav-
ing a solubility of less than about 1 part per 10,000 parts water (less than
about 100
g/ml) are notoriously difficult to formulate for oral delivery. Among other
problems,
bioavailability of such drugs, when administered by the oral route, tends to
be very low.
A specific illustrative small-molecule drug of low water solubility is the
compound N-[4-
(3-amino-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea (ABT-869),
a multi-
targeted protein tyrosine kinase (PTK) inhibitor. This compound, which has a
molecular
weight of 375.4 g/mol, is disclosed in International Patent Publication No.
WO 2004/113304 of Abbott Laboratories.
For a variety of reasons, such as patient compliance and taste masking, a
solid dosage
form is usually preferred over a liquid dosage form. In most instances,
however, oral
solid dosage forms of a drug provide a lower bioavailability than oral
solutions of the
drug.
There remains a need in the pharmaceutical art for a novel solid formulation
of N-aryl
urea-based active agents of low water solubility such as ABT-869 that is
suitable for
oral administration. More particularly and without limitation, there is a need
for such a
formulation having at least one of the following features, advantages or
benefits: ac-
ceptably high concentration of the drug; and acceptable bioavailability when
adminis-
tered orally.
The invention relates to a solid dispersion product comprising at least one
pharmaceu-
tically active agent, obtained by
a) preparing a liquid mixture containing the at least one active agent, at
least one
pharmaceutically acceptable matrix-forming agent, at least one
pharmaceutically
acceptable surfactant and at least one solvent, and
b) removing the solvent(s) from the liquid mixture to obtain the solid
dispersion
product.
The invention is particularly useful for water-insoluble or poorly water-
soluble (or "hy-
drophobic" or "lipophilic") compounds. Compounds are considered water-
insoluble or
poorly water-soluble when their solubility in water at 25 C is less than 1
g/100 ml, es-
pecially less than 0,1 g/100 ml.
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In the dosage forms of the invention, the active agent is present as a solid
dispersion
or, preferably, as a solid solution. The term "solid dispersion" defines a
system in a
solid state (as opposed to a liquid or gaseous state) comprising at least two
compo-
nents, wherein one component is dispersed evenly throughout the other
component or
components. For example, the active agent or combination of active agents is
dis-
persed in a matrix comprised of the matrix-forming agent(s) and
pharmaceutically ac-
ceptable surfactant(s). The term "solid dispersion" encompasses systems having
small
particles, typically of less than 1 m in diameter, of one phase dispersed in
another
phase. When said dispersion of the components is such that the system is
chemically
and physically uniform or homogenous throughout or consists of one phase (as
defined
in thermodynamics), such a solid dispersion will be called a "solid solution"
or a "glassy
solution". A glassy solution is a homogeneous, glassy system in which a solute
is dis-
solved in a glassy solvent. Glassy solutions and solid solutions are preferred
physical
systems. These systems do not contain any significant amounts of active agents
in
their crystalline or microcrystalline state, as evidenced by thermal analysis
(DSC) or X-
ray diffraction analysis (WAXS).
In an embodiment of the invention, at least one filler is added to the liquid
mixture be-
fore removing the solvent(s). It was found that incorporation of a filler into
the liquid
mixture before removing the solvent(s) increases the brittleness of the solid
dispersion
product obtained. This allows the solid dispersion product to be subjected to
a direct
tabletting process.
Preferably, the filler is essentially insoluble in the liquid mixture.
The choice of fillers is not particularly restricted. The filler may be
suitably selected
from inorganic particulate materials such as silica, calcium carbonate,
calcium phos-
phates, titanium dioxide; natural and pre-gelatinized starches such as corn
starch, ce-
real starch, potato starch; or the like.
However, the filler is preferably water-soluble. Useful fillers to that end
may be selected
from sugars such as lactose, sucrose; sugar alcohols such as mannitol,
sorbitol, xylitol;
or sugar alcohol derivatives.
The relative amounts of active agent, pharmaceutically acceptable matrix-
forming
agent and pharmaceutically acceptable surfactant are chosen with the following
condi-
tions in mind: (1) Essentially all of the active agent should be dispersed
evenly
throughout the matrix comprised of the matrix-forming agent(s) and
pharmaceutically
acceptable surfactant(s). (2) The matrix should have sufficient mechanical
integrity and
stability; in particular, the matrix should not exhibit cold flow. Generally,
the mass ratio
of active agent and pharmaceutically acceptable matrix-forming agent is from
0.01:1 to
1:3, preferably 0.05:1 to 0.2:1; generally the mass ratio of active agent and
pharmaceu-
tically acceptable surfactant(s) is from 0.1:1 to 1:7, preferably 1:4 to
1:6.5.
Generally, the solid dispersion product comprises
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from about 1 to 30 % by weight, preferably from about 4 to 15 % by weight, of
said at
least one pharmaceutically active agent,
from about 15 to 70 % by weight, preferably from about 20 to 55 % by weight,
of said at
least one pharmaceutically acceptable matrix-forming agent,
from about 2 to 70 % by weight, preferably from about 5 to 55 % by weight, of
said at
least one surfactant, and
from about 0 to 80 % by weight, preferably from about 0 to 60 % by weight, of
additives
such as fillers.
The matrix-forming agent may be any agent capable of embedding an active agent
and/or being loaded with an active agent and stabilizing an essentially
amorphous state
of the active agent. Mixtures of matrix-forming agents can, of course, be
used.
The pharmaceutically acceptable matrix-forming agent is suitably selected from
the
group consisting of cyclodextrines, pharmaceutically acceptable polymers,
lipids or
combinations of two or more thereof.
Cyclodextrins for the purpose of the invention are cyclic oligo- or
polysaccharides, for
example so-called cycloamyloses or cycloglucans, and analogous cyclic
carbohydrates
which are described, for example, in Angew. Chem. 92 (1980) p. 343 or F.
Vogtle, Su-
pramolekulare Chemie, 2nd Edition, (1992). Suitable and preferred are those
cyclodex-
trins which have a structure suitable for interactions with active agent
molecules, in
particular in the sense of host-guest systems. Particularly suitable
cyclodextrins are
those consisting of 6, 7, 8 or 9 a-1,4-glycosidically linked glucose units,
which are
called a-, R-, y- or 6-cyclodextrins. Higher structures analogous to
cyclodextrins and
composed of a larger number of glucoses or similar sugars are also conceivable
and
suitable.
Also suitable as cyclodextrins are modified cyclodextrins such as, for
example, prod-
ucts which can be prepared by reacting cyclodextrins with alkylene oxides,
alkyl hal-
ides, acid chlorides, epihalohydrins, isocyanates or halogenated carboxylic
acids.
Thus, suitable examples are products of the reaction of cyclodextrins with
alkylene ox-
ides such as ethylene oxide, propylene oxide, butylene oxide or styrene oxide.
One,
more than one or all hydroxyl groups in the cyclodextrin polyethers formed in
this way
may be substituted. Depending on the degree of substitution or the chain
lengths of the
polyether units, the average molar degree of substitution, that is to say the
number of
moles of alkylene oxide with which one mole of cyclodextrin is reacted, is
usually be-
tween 3 and 20,000, but there is in principle no upper limit. Particularly
suitable exam-
ples are the products of the reaction of cyclodextrins with alkylating agents
such as C,-
C22-alkyl halides, for example methyl chloride, ethyl chloride, isopropyl
chloride, n-butyl
chloride, isobutyl chloride, benzyl chloride, lauryl chloride, stearyl
chloride, methyl bro-
mide, ethyl bromide, n-butyl bromide and dialkyl sulfates such as, for
example, di-
methyl sulfate or diethyl sulfate. Reaction with alkylating reagents leads to
cyclodextrin
ethers in which one, more than one or all hydroxyl groups are substituted by
alkyl ether
groups. With the cyclodextrins composed of glucose units, the average degree
of eth-
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erification per glucose unit is usually in the range from 0.5 to 3, preferably
in the range
from 0.1 to 2.5 and particularly preferably in the range from 1 to 2.
Particular prefer-
ence is given to methylated, ethylated or propylated a-, R-, y-cyclodextrins
with an av-
erage degree of etherification of from 1.5 to 2.2. Also suitable are
cyclodextrin esters
which are obtainable by reacting cyclodextrins with acid chlorides such as
carbonyl or
sulfonyl chlorides. Particularly suitable are carbonyl chlorides such as
acetyl chloride,
acryloyl chloride, methacryloyl chloride or benzoyl chloride.
Also suitable are polymer-modified cyclodextrins, that is to say cyclodextrins
which are
incorporated into the main chain of polymers and/or cyclodextrins which have
been
attached to side chains of polymers or are themselves side chains of polymers.
Poly-
mer-modified cyclodextrins in which the cyclodextrin units are arranged in the
main
chain of the polymer can be obtained, for example, by reacting cyclodextrins
with or in
the presence of suitable coupling or crosslinking reagents, for example as
described in
Helv. Chim. Acta, Vol. 48, (1965), p. 1225. Polymer-modified cyclodextrins in
which the
cyclodextrin units are side chain constituents or act as side chains can be
obtained, for
example, by cyclodextrins modified with polymerizable groups being polymerized
with
other comonomers, for example by polymerizing cyclodextrin (meth)acrylates in
the
presence of other ethylenically unsaturated monomers or by free-radical
grafting of
cyclodextrin (meth)acrylates onto polymers with free hydroxyl groups such as,
for ex-
ample, polyvinyl alcohol. Another possibility for preparing polymer-modified
cyclodex-
trins with the cyclodextrin units on side groups or as side groups of polymers
is to react
cyclodextrins, deprotonated cyclodextrins or their alkali metal salts with
polymers which
have complementary reactive groups such as, for example, anhydride,
isocyanate, acid
halide or epoxy groups or halogens.
Preferred cyclodextrines are hydroxyalkyl-cyclodextrines, such as
hydroxypropyl-R-
cyclodextrin.
Suitable lipids may be selected from waxes, tri-, di-, and monoglycerides and
phospholipids.
The preferred matrix-forming agents are pharmaceutically acceptable polymers.
The pharmaceutically acceptable polymers may be selected from water-soluble
poly-
mers, water-dispersible polymers or water-swellable polymers or any mixture
thereof.
Polymers are considered water-soluble if they form a clear homogeneous
solution in
water. When dissolved at 20 C in an aqueous solution at 2 % (w/v), the water-
soluble
polymer preferably has an apparent viscosity of 1 to 5000 mPa.s, more
preferably of 1
to 700 mPa.s, and most preferably of 5 to 100 mPa.s. Water-dispersible
polymers are
those that, when contacted with water, form colloidal dispersions rather than
a clear
solution. Upon contact with water or aqueous solutions, water-swellable
polymers typi-
cally form a rubbery gel. Water-soluble polymers are preferred.
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Preferably, the pharmaceutically acceptable polymer employed in the invention
has a
Tg of at least 40 C, preferably at least +50 C, most preferably from 80 to
180. C.
"Tg" means glass transition temperature. Methods for determining Tg values of
the
organic polymers are described in "Introduction to Physical Polymer Science",
2nd Edi-
5 tion by L.H. Sperling, published by John Wiley & Sons, Inc., 1992. The Tg
value can be
calculated as the weighted sum of the Tg values for homopolymers derived from
each
of the individual monomers, i, that make up the polymer: Tg = E W; X; where W
is the
weight percent of monomer i in the organic polymer, and X is the Tg value for
the ho-
mopolymer derived from monomer i. Tg values for the homopolymers may be taken
from "Polymer Handbook", 2nd Edition by J. Brandrup and E.H. Immergut,
Editors,
published by John Wiley & Sons, Inc., 1975.
Various additives contained in the solid dispersion product or even the active
ingredi-
ent(s) itself may exert a plasticizing effect on the polymer and thus depress
the Tg of
the polymer such that the final solid dispersion product has a somewhat lower
Tg than
the starting polymer used for its preparation. In general, the final solid
dispersion prod-
uct has a Tg of 10 C or higher, preferably 15 C or higher, more preferably
20 C or
higher and most preferred 30 C or higher.
For example, preferred pharmaceutically acceptable polymers can be selected
from the
group comprising
homopolymers and copolymers of N-vinyl lactams, especially homopolymers and co-
polymers of N-vinyl pyrrolidone, e.g. polyvinylpyrrolidone (PVP), copolymers
of N-vinyl
pyrrolidone and vinyl acetate or vinyl propionate,
cellulose esters and cellulose ethers, in particular methylcellulose and
ethylcellulose,
hydroxyalkylcelluloses, in particular hydroxypropylcellulose,
hydroxyalkylalkylcellu-
loses, in particular hydroxypropylmethylcellulose, cellulose phthalates or
succinates, in
particular cellulose acetate phthalate and hydroxypropylmethylcellulose
phthalate, hy-
d roxypropylmethylcellulose succinate or hydroxypropylmethylcellulose acetate
succi-
nate;
high molecular polyalkylene oxides such as polyethylene oxide and
polypropylene ox-
ide and copolymers of ethylene oxide and propylene oxide,
polyvinyl alcohol-polyethylene glycol-graft copolymers (available as Kollicoat
IR from
BASF AG, Ludwigshafen, Germany);
polyacrylates and polymethacrylates such as methacrylic acid/ethyl acrylate
copoly-
mers, methacrylic acid/methyl methacrylate copolymers, butyl methacrylate/2-
dimethyl-
aminoethyl methacrylate copolymers, poly(hydroxyalkyl acrylates),
poly(hydroxyalkyl
methacrylates),
polyacrylamides,
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vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid,
partially
hydrolyzed polyvinyl acetate (also referred to as partially saponified
"polyvinyl alcohol"),
polyvinyl alcohol,
oligo- and polysaccharides such as carrageenans, galactomannans and xanthan
gum,
or mixtures of one or more thereof.
Among these, homopolymers or copolymers of N-vinyl pyrrolidone, in particular
a co-
polymer of N-vinyl pyrrolidone and vinyl acetate, are preferred. A
particularly preferred
polymer is a copolymer of 60 % by weight of the copolymer, N-vinyl pyrrolidone
and 40
% by weight of the copolymer, vinyl acetate.
A further polymer which can be suitably used is Kollidon SR (available from
BASF
AG, Ludwigshafen, Germany) which comprises a mixture of PVP and
polyvinylacetate.
The term "pharmaceutically acceptable surfactant" as used herein refers to a
pharma-
ceutically acceptable non-ionic surfactant. The surfactant may effectuate an
instanta-
neous emulsification of the active agent released from the dosage form and/or
prevent
precipitation of the active ingredient in the aqueous fluids of the
gastrointestinal tract. A
single surfactant as well as combinations of surfactants may be used.
According to an
embodiment of the invention, the solid dispersion product comprises a
combination of
two or more pharmaceutically acceptable surfactants.
Preferred surfactants are selected from sorbitan fatty acid esters,
polyalkoxylated fatty
acid esters such as, for example, polyalkoxylated glycerides, polyalkoxylated
sorbitan
fatty acid esters or fatty acid esters of polyalkylene glycols,
polyalkoxylated ethers of
fatty alcohols, tocopheryl compounds or mixtures of two or more thereof. A
fatty acid
chain in these compounds ordinarily comprises from 8 to 22 carbon atoms. The
polyal-
kylene oxide blocks comprise on average from 4 to 50 alkylene oxide units,
preferably
ethylene oxide units, per molecule.
Suitable sorbitan fatty acid esters are sorbitan monolaurate, sorbitan
monopalmitate,
sorbitan monostearate (Span 60), sorbitan monooleate (Span 80), sorbitan
tristearate, sorbitan trioleate, sorbitan monostearate, sorbitan monolaurate
or sorbitan
monooleate.
Examples of suitable polyalkoxylated sorbitan fatty acid esters are
polyoxyethylene
(20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate,
polyoxyethyl-
ene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate
(Tween
80), polyoxyethylene (20) sorbitan tristearate (Tween 65), polyoxyethylene
(20) sorbi-
tan trioleate (Tween 85), polyoxyethylene (4) sorbitan monostearate,
polyoxyethylene
(4) sorbitan monolaurate or polyoxyethylene (4) sorbitan monooleate.
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Suitable polyalkoxylated glycerides are obtained for example by alkoxylation
of natural
or hydrogenated glycerides or by transesterification of natural or
hydrogenated glyc-
erides with polyalkylene glycols. Commercially available examples are
polyoxyethylene
glycerol ricinoleate 35, polyoxyethylene glycerol tri hyd roxystea rate 40
(Cremophor
RH40, BASF AG) and polyalkoxylated glycerides like those obtainable under the
pro-
prietary names Gelucire and Labrafil from Gattefosse, e.g. Gelucire 44/14
(lauroyl
macrogol 32 glycerides prepared by transesterification of hydrogenated palm
kernel oil
with PEG 1500), Gelucire 50/13 (stearoyl macrogol 32 glycerides, prepared by
trans-
esterification of hydrogenated palm oil with PEG 1500) or Labrafil M1944 CS
(oleoyl
macrogol 6 glycerides prepared by transesterification of apricot kernel oil
with PEG
300).
A suitable fatty acid ester of polyalkylene glycols is, for example, PEG 660
hydroxy-
stearic acid (polyglycol ester of 12-hydroxystearic acid (70 mol%) with 30
mol% ethyl-
ene glycol).
Suitable polyalkoxylated ethers of fatty alcohols are, for example, PEG (2)
stearyl ether
(Brij 72), macrogol 6 cetylstearyl ether or macrogol 25 cetylstearyl ether.
In general, the tocopheryl compound corresponds to the formula below
Z- O(CHRl-CHR2O)nH
CH3
O
O CH3 CH3 CH3 CH3
H3C O CH3
CH3
wherein Z is a linking group, R1 and R2 are, independently of one another,
hydrogen or
C1-C4 alkyl and n is an integer from 5 to 100, preferably 10 to 50. Typically,
Z is the
residue of an aliphatic dibasic acid such as glutaric, succinic, or adipic
acid. Preferably,
both R1 and R2 are hydrogen.
The preferred tocopheryl compound is alpha tocopheryl polyethylene glycol
succinate,
which is commonly abbreviated as vitamin E TPGS. Vitamin E TPGS is a water-
soluble
form of natural-source vitamin E prepared by esterifying d-alpha-tocopheryl
acid succi-
nate with polyethylene glycol 1000. Vitamin E TPGS is available from Eastman
Chemi-
cal Company, Kingsport, TN, USA and is listed in the US pharmacopoeia (NF).
It was found that surfactants or combination of surfactants having a defined
HLB (hy-
drophilic lipophilic balance) value are preferred over other solubilizers.
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The HLB system (Fiedler, H.B., Encyclopedia of Excipients, 5th ed., Aulendorf:
ECV-
Editio-Cantor-Verlag (2002)) attributes numeric values to surfactants, with
lipophilic
substances receiving lower HLB values and hydrophilic substances receiving
higher
HLB values.
In preferred embodiments, the pharmaceutically acceptable surfactant comprises
at
least one surfactant having an HLB value of 10 or more.
Solubilizers having an HLB value of 10 or more may be selected from Gelucire
44/14
(HLB 14), Cremophor RH40 (HLB 13), Tween 65 (HLB 10.5), Tween 85 (HLB 11).
Preferred high HLB solubilizers are tocopheryl compounds having a polyalkylene
glycol
moiety.
In a preferred embodiment, a combination of solubilizers is used which
comprises (i) at
least one tocopheryl compound having a polyalkylene glycol moiety, preferably
alpha
tocopheryl polyethylene glycol succinate, and (ii) at least one
polyalkoxylated polyol
fatty acid ester. The tocopheryl compound preferably is alpha tocopheryl
polyethylene
glycol succinate. The polyalkoxylated polyol fatty acid ester preferably is a
polyalkoxy-
fated glyceride. The mass ratio of tocopheryl compound and polyalkoxylated
polyol
fatty acid ester preferably is in the range of from 0.2:1 to 1:1.
In an embodiment, the active agent is a N-aryl urea-based active agent. N-aryl
urea-
based active agents are biologically active compounds which comprise at least
one
urea moiety in their molecular structure wherein one or both nitrogen atoms
are substi-
tuted by an aryl group, and which exert a local physiological effect, as well
as those
which exert a systemic effect, after oral administration. The aryl group may
be a carbo-
cyclic or heterocyclic aromatic group or a fused carbocyclic or heterocyclic
aromatic
group. Attachment to the nitrogen atom is usually via a carbon atom of the
aryl group.
A fused aromatic group may be linked to the nitrogen atom via an aromatic or
non-
aromatic carbon atom. The aryl group may, of course, be substituted by further
sub-
stituents.
Generally, the N-aryl urea-based active agent is represented by the general
formula
` 0
Z/\ G2
G1 H H
wherein
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G1 and G2 are, independently from one another, a carbocyclic ring selected
from
phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, ben-
zocycloheptanyl, benzocycloheptenyl, indanyl and indenyl;
a ring system selected from benzoxazinyl, benzimidazolyl, indazolyl, benzo-
thiazolyl, benzooxazolyl, benzisoxazolyl, benzofuranyl, benzopyranyl, benzodi-
oxolyl, quinaldinyl, quinazolinyl, quinoxalinyl, isoquinolinyl, quinolinyl,
indolyl, iso-
indolyl, indolinyl, purinyl, tetrahydroquinolinyl, indazolyl, imidazo-
pyridinyl, pyra-
zolo-pyridinyl, pyrazolo-pyrimidinyl, pyrrolo-pyrimidinyl, pyrrolo-pyridinyl,
pyrido-
pyrazinyl, pyrido-pyrimidinyl, pyrido-oxazinyl, pyrido-thiazinyl, pyrido-
oxazolyl,
pyrido-thioxazolyl, pyrimido-pyrimidine, pteridinyl, cinnolinyl and
naphthyridinyl;
wherein G1 or G2 or both may be substituted by one or more substituents
selected from
the group consisting of C1_6 branched or unbranched alkyl, C1_6 haloalkyl,
C1_6
branched or unbranched acyl, C1_6 branched or unbranched alkoxy, halogen, C1_6
branched or unbranched alkyloxycarbonyl, hydroxy, amino, mono- or di-(C,_4 al-
kyl)amino, mono- or di-(C,_4 alkyl)amino-SO2, cyano, nitro or H2NSO2,
Z is 1,4-phenylene, and
n is0orl,
or the pharmaceutically acceptable salts, esters, isomers, hydrates or
solvates thereof
In an embodiment, the active agent is represented by the formula (I)
R3 R4
A
H2N R5
N1\
x R1 R2
(I),
or a therapeutically acceptable salt thereof, wherein
A is selected from the group consisting of indolyl, phenyl, pyrazinyl,
pyridazinyl,
pyridinyl, pyrimidinyl, and thienyl;
X is selected from the group consisting of 0, S, and NR9;
R1 and R2 are independently selected from the group consisting of hydrogen,
alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryl, arylalkyl, aryloxy,
aryloxyalkyl, halo,
haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,
heterocycly-
lalkyl, heterocyclyloxyalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl,
(NRaRb)alkoxy,
(NRaRb)alkenyl, (NRaRb)alkyl, (NRaRb)alkynyl, (NR aRb)carbonylalkenyl, and
(NRaRb)carbonylalkyl;
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R3, R4, and R5 are each independently selected from the group consisting of
hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo, haloalkoxy, haloalkyl, hydroxy,
and LR6;
provided that at least two of R3, R4, and R5 are other than LR6;
L is selected from the group consisting of (CH2),,N(R7)C(O)N(R8)(CH2)n and
5 CH2C(O)NR7, wherein m and n are independently 0 or 1, and wherein each group
is
drawn with its left end attached to A;
R6 is selected from the group consisting of hydrogen, aryl, cycloalkyl,
heterocy-
clyl, and 1,3-benzodioxolyl wherein the 1,3-benzodioxolyl can be optionally
substituted
with one, two, or three substituents independently selected from the group
consisting of
10 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,
arylalkoxy, arylal-
kyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a
second heterocy-
clyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR Rd, and (NR
Rd)alkyl;
R7 and R3 are independently selected from the group consisting of hydrogen
and alkyl;
R9 is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl,
alkyl,
alkylcarbonyl, aryl, heterocyclylalkyl, hydroxyalkyl, and (NRaRb)alkyl;
R a and Rb are independently selected from the group consisting of hydrogen,
alkenyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl,
arylsulfonyl,
haloalkylsulfonyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, and
heterocyclylsulfonyl;
and
Rc and Rd are independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, and hetero-
cyclylalkyl.
In another embodiment, the active agent is a compound of formula (II)
R11
L \Rio
R4
H2N R3
N
R1 R2
\
(II),
or a therapeutically acceptable salt thereof, wherein
X is selected from the group consisting of 0, S, and NR9;
R1 and R2 are independently selected from the group consisting of hydrogen,
alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo,
haloalkoxy, haloal-
kyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl,
heterocycly-
loxyalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NRaRb)alkoxy,
(NRaRb)alkenyl,
(NRaRb)alkyl, (NR aRb)carbonylalkenyl, and (NR aRb)carbonylalkyl;
R3 and R4 are independently selected from the group consisting of hydrogen,
alkoxy, alkyl, halo, haloalkoxy, haloalkyl, and hydroxy;
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L is selected from the group consisting of (CH2),,N(R7)C(O)N(R8)(CH2)n and
CH2C(O)NR7, wherein m and n are independently 0 or 1, and wherein each group
is
drawn with its left end attached to the ring substituted with R3 and R4;
R7 and R3 are independently selected from the group consisting of hydrogen
and alkyl;
R9 is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl,
alkyl,
alkylcarbonyl, aryl, heterocyclylalkyl, hydroxyalkyl, and (NRaRb)alkyl;
R10 and R" are independently selected from the group consisting of hydrogen,
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy,
cyano, halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR Rd;
R a and Rb are independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
heterocyclylsul-
fonyl; and
Rc and Rd are independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, and hetero-
cyclylalkyl.
In another embodiment, the present invention provides a compound of formula
(I) wherein X is 0 and A, R1, R2, R3, R4, and R5 are as defined in formula
(I).
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is 0; R5 is LR6; R6 is 1,3-benzodioxolyl optionally
substituted
with one, two, or three substituents independently selected from the group
consisting of
alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,
arylalkoxy, arylal-
kyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a
second heterocy-
clyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR Rd, and (NR
Rd)alkyl; L is
(CH2),N(R7)C(O)N(R3)(CH2)n; and m, n, Rc, Rd, R1, R2, R3, R4, R7, and R3 are
as de-
fined in formula (I).
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is 0; R5 is LR6; R6 is 1,3-benzodioxolyl optionally
substituted
with one, two, or three substituents independently selected from the group
consisting of
alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,
arylalkoxy, arylal-
kyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a
second heterocy-
clyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR Rd, and (NR
Rd)alkyl; L is
(CH2),N(R7)C(O)N(R3)(CH2)n; m and n are 0; R1 and R2 are independently
selected
from the group consisting of hydrogen and alkoxy; R3, R4, R7, and R$ are
hydrogen;
and Rc and Rd are selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is 0; R5 is LR6; R6 is 1,3-benzodioxolyl; L is
(CH2),N(R7)C(O)N(R3)(CH2)n; m and n are 0; R1 and R2 are independently
selected
from the group consisting of hydrogen and alkoxy; and R3, R4, R7, and R$ are
hydro-
gen.
In another embodiment, the present invention provides a compound of formula
(I) wherein X is S and A, R1, R2, R3, R4, and R5 are as defined in formula
(I).
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is S; R5 is LR6; R6 is 1,3-benzodioxolyl optionally
substituted
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with one, two, or three substituents independently selected from the group
consisting of
alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,
arylalkoxy, arylal-
kyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a
second heterocy-
clyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR Rd, and (NR
Rd)alkyl; L is
(CH2),N(R7)C(O)N(R8)(CH2)n; and m, n, Rc, Rd, R1, R2, R3, R4, R7, and R8 are
as de-
fined in formula (I).
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is S; R5 is LR6; R6 is 1,3-benzodioxolyl optionally
substituted
with one, two, or three substituents independently selected from the group
consisting of
alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,
arylalkoxy, arylal-
kyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a
second heterocy-
clyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR Rd, and (NR
Rd)alkyl; L is
(CH2),N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1 and R2 are independently
selected
from the group consisting of hydrogen and alkoxy; R3, R4, R7, and R8 are
hydrogen;
and Rc and Rd are selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is S; R5 is LR6; R6 is 1,3-benzodioxolyl; L is
(CH2),N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1 and R2 are independently
selected
from the group consisting of hydrogen and alkoxy; and R3, R4, R7, and R8 are
hydro-
gen.
In another embodiment, the present invention provides a compound of formula
(I) wherein X is NR9; and A, R1, R2, R3, R4, R5, and R9 are as defined in
formula (I).
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is NR9; R5 is LR6; R6 is 1,3-benzodioxolyl
optionally substi-
tuted with one, two, or three substituents independently selected from the
group con-
sisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,
aryl, ary-
lalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy,
haloalkyl, a
second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -
NR Rd, and
(NR Rd)alkyl; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; and m, n, Rc, Rd, R1, R2, R3,
R4, R7, R8,
and R9 are as defined in formula (I).
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is NR9; R5 is LR6; R6 is 1,3-benzodioxolyl
optionally substi-
tuted with one, two, or three substituents independently selected from the
group con-
sisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,
aryl, ary-
lalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy,
haloalkyl, a
second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -
NR Rd, and
(NR Rd)alkyl; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1 and R2 are
inde-
pendently selected from the group consisting of hydrogen and alkoxy; R3, R4,
R7, and
R8 are hydrogen; R9 is selected from the group consisting of hydrogen and
alkyl; and
Rc and Rd are selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is NR9; R5 is LR6; R6 is 1,3-benzodioxolyl; L is
(CH2),N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1 and R2 are independently
selected
from the group consisting of hydrogen and alkoxy; R3, R4, R7, and R8 are
hydrogen;
and R9 is selected from the group consisting of hydrogen and alkyl.
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In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is 0; R5 is LR6; R6 is cycloalkyl optionally
substituted with
one, two, or three substituents independently selected from the group
consisting of
alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,
cyano, halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR Rd, (NR Rd)alkyl, and oxo; L
is
(CH2),N(R7)C(O)N(R3)(CH2)n; and m, n, Rc, Rd, R1, R2, R3, R4, R7, and R3 are
as de-
fined in formula (I).
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is 0; R5 is LR6; R6 is cycloalkyl wherein the
cycloalkyl is se-
lected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl,
wherein the
cycloalkyl is optionally substituted with one, two, or three substituents
independently
selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkyl,
alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy,
hydroxyalkyl, -
NR Rd, (NR Rd)alkyl, and oxo; L is (CH2),,N(R7)C(O)N(R3)(CH2)n; m and n are 0;
R1 and
R2 are independently selected from the group consisting of hydrogen, alkoxy,
alkoxyalkoxy, alkyl, halo, hydroxy, (NRaRb)alkoxy, (NRaRb)alkyl, and
(NRaRb)carbonylalkenyl; R3 and R4 are independently selected from the group
consist-
ing of hydrogen, alkyl, alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy;
R7 and R$
are hydrogen; R a and Rb are independently selected from the group consisting
of hy-
drogen and alkyl; and Rc and Rd are independently selected from the group
consisting
of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is 0; R5 is LR6; R6 is cycloalkyl wherein the
cycloalkyl is
cyclopentyl; L is (CH2),,N(R7)C(O)N(R3)(CH2)n; m and n are 0; R1 and R2 are
independ-
ently selected from the group consisting of hydrogen and alkoxy; and R3, R4,
R7, and
R$ are hydrogen.
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is S; R5 is LR6; R6 is cycloalkyl optionally
substituted with
one, two, or three substituents independently selected from the group
consisting of
alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,
cyano, halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR Rd, (NR Rd)alkyl, and oxo; L
is
(CH2),N(R7)C(O)N(R3)(CH2)n; and m, n, Rc, Rd, R1, R2, R3, R4, R7, and R3 are
as de-
fined in formula (I).
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is S; R5 is LR6; R6 is cycloalkyl wherein the
cycloalkyl is se-
lected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl,
wherein the
cycloalkyl is optionally substituted with one, two, or three substituents
independently
selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkyl,
alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy,
hydroxyalkyl, -
NR Rd, (NR Rd)alkyl, and oxo; L is (CH2),,N(R7)C(O)N(R3)(CH2)n; m and n are 0;
R1 and
R2 are independently selected from the group consisting of hydrogen, alkoxy,
alkoxyalkoxy, alkyl, halo, hydroxy, (NRaRb)alkoxy, (NRaRb)alkyl, and
(NRaRb)carbonylalkenyl; R3 and R4 are independently selected from the group
consist-
ing of hydrogen, alkyl, alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy;
R7 and R$
are hydrogen; R a and Rb are independently selected from the group consisting
of hy-
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14
drogen and alkyl; and R and Rd are independently selected from the group
consisting
of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is S; R5 is LR6; R6 is cycloalkyl wherein the
cycloalkyl is
cyclopentyl; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1 and R2 are
independ-
ently selected from the group consisting of hydrogen and alkoxy; and R3, R4,
R7, and
R8 are hydrogen.
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is NR9; R5 is LR6; R6 is cycloalkyl optionally
substituted with
one, two, or three substituents independently selected from the group
consisting of
alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,
cyano, halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR Rd, (NR Rd)alkyl, and oxo; L
is
(CH2),N(R7)C(O)N(R8)(CH2)n; and m, n, Rc, Rd, R1, R2, R3, R4, R7, R8, and R9
are as
defined in formula (I).
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is NR9; R5 is LR6; R6 is cycloalkyl wherein the
cycloalkyl is
selected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl,
wherein
the cycloalkyl is optionally substituted with one, two, or three substituents
independ-
ently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl,
alkoxycarbonyl,
alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy,
hydroxyalkyl,
-NR Rd, (NR Rd)alkyl, and oxo; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are
0; R1
and R2 are independently selected from the group consisting of hydrogen,
alkoxy,
alkoxyalkoxy, alkyl, halo, hydroxy, (NRaRb)alkoxy, (NRaRb)alkyl, and
(NRaRb)carbonylalkenyl; R3 and R4 are independently selected from the group
consist-
ing of hydrogen, alkyl, alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy;
R7 and R8
are hydrogen; R9 is selected from the group consisting of hydrogen and alkyl;
R a and
Rb are independently selected from the group consisting of hydrogen and alkyl;
and Rc
and Rd are independently selected from the group consisting of hydrogen and
alkyl.
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is NR9; R5 is LR6; R6 is cycloalkyl wherein the
cycloalkyl is
cyclopentyl; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1 and R2 are
independ-
ently selected from the group consisting of hydrogen and alkoxy; R3, R4, R7,
and R8 are
hydrogen; and R9 is selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is 0; R5 is LR6; R6 is heterocyclyl optionally
substituted with
one, two, or three substituents independently selected from the group
consisting of
alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,
cyano, halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR Rd, (NR Rd)alkyl, and oxo; L
is
(CH2),N(R7)C(O)N(R8)(CH2)n; and m, n, Rc, Rd, R1, R2, R3, R4, R7, and R8 are
as de-
fined in formula (I).
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is 0; R5 is LR6; R6 is heterocyclyl wherein the
heterocyclyl is
selected from the group consisting of furyl, isoxazolyl, isothiazolyl,
oxazolyl, pyridinyl,
thiazolyl, and thienyl, wherein the heterocyclyl is optionally substituted
with one, two, or
three substituents independently selected from the group consisting of
alkenyl, alkoxy,
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alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo,
haloalkoxy,
haloalkyl, hydroxy, hydroxyalkyl, -NR Rd, (NR Rd)alkyl, and oxo; L is
(CH2),N(R7)C(O)N(R3)(CH2)n; m and n are 0; R1 and R2 are independently
selected
from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo,
hydroxy,
5 (NRaRb)alkoxy, (NRaRb)alkyl, and (NR aRb)carbonylalkenyl; R3 and R4 are
independently
selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkoxy,
halo,
haloalkoxy, and hydroxy; R7 and R3 are hydrogen; R a and Rb are independently
se-
lected from the group consisting of hydrogen and alkyl; and Rc and Rd are
independ-
ently selected from the group consisting of hydrogen and alkyl.
10 In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is 0; R5 is LR6; R6 is heterocyclyl wherein the
heterocyclyl is
thienyl; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R1 and R2 are
independently
selected from the group consisting of hydrogen and alkoxy; and R3, R4, R7, and
R$ are
hydrogen.
15 In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is S; R5 is LR6; R6 is heterocyclyl optionally
substituted with
one, two, or three substituents independently selected from the group
consisting of
alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,
cyano, halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR Rd, (NR Rd)alkyl, and oxo; L
is
(CH2),N(R7)C(O)N(R$)(CH2)n; and m, n, Rc, Rd, R1, R2, R3, R4, R7, and R$ are
as de-
fined in formula (I).
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is S; R5 is LR6; R6 is heterocyclyl wherein the
heterocyclyl is
selected from the group consisting of furyl, isoxazolyl, isothiazolyl,
oxazolyl, pyridinyl,
thiazolyl, and thienyl, wherein the heterocyclyl is optionally substituted
with one, two, or
three substituents independently selected from the group consisting of
alkenyl, alkoxy,
alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo,
haloalkoxy,
haloalkyl, hydroxy, hydroxyalkyl, -NR Rd, (NR Rd)alkyl, and oxo; L is
(CH2),N(R7)C(O)N(R3)(CH2)n; m and n are 0; R1 and R2 are independently
selected
from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo,
hydroxy,
(NRaRb)alkoxy, (NRaRb)alkyl, and (NR aRb)carbonylalkenyl; R3 and R4 are
independently
selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkoxy,
halo,
haloalkoxy, and hydroxy; R7 and R3 are hydrogen; R a and Rb are independently
se-
lected from the group consisting of hydrogen and alkyl; and Rc and Rd are
independ-
ently selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is S; R5 is LR6; R6 is heterocyclyl wherein the
heterocyclyl is
thienyl; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R1 and R2 are
independently
selected from the group consisting of hydrogen and alkoxy; and R3, R4, R7, and
R$ are
hydrogen.
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is NR9; R5 is LR6; R6 is heterocyclyl optionally
substituted with
one, two, or three substituents independently selected from the group
consisting of
alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,
cyano, halo,
d
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR R, (NR Rd)alkyl, and oxo; L
is
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16
(CH2),,N(R7)C(O)N(R8)(CH2)n; and m, n, Rc, Rd, R1, R2, R3, R4, R7, R8, and R9
are as
defined in formula (I).
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is NR9; R5 is LR6; R6 is heterocyclyl wherein the
heterocyclyl
is selected from the group consisting of furyl, isoxazolyl, isothiazolyl,
oxazolyl, pyridinyl,
thiazolyl, and thienyl, wherein the heterocyclyl is optionally substituted
with one, two, or
three substituents independently selected from the group consisting of
alkenyl, alkoxy,
alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo,
haloalkoxy,
haloalkyl, hydroxy, hydroxyalkyl, -NR Rd, (NR Rd)alkyl, and oxo; L is
(CH2),N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1 and R2 are independently
selected
from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo,
hydroxy,
(NRaRb)alkoxy, (NRaRb)alkyl, and (NR aRb)carbonylalkenyl; R3 and R4 are
independently
selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkoxy,
halo,
haloalkoxy, and hydroxy; R7 and R8 are hydrogen; R9 is selected from the group
con-
sisting of hydrogen and alkyl; R a and Rb are independently selected from the
group
consisting of hydrogen and alkyl; and Rc and Rd are independently selected
from the
group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(I) wherein A is phenyl; X is NR9; R5 is LR6; R6 is heterocyclyl wherein the
heterocyclyl
is thienyl; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1 and R2 are
independ-
ently selected from the group consisting of hydrogen and alkoxy; R3, R4, R7,
and R8 are
hydrogen; and R9 is selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a pharmaceutical com-
position comprising a compound of formula (I), or a therapeutically acceptable
salt
thereof, in combination with a therapeutically acceptable carrier.
In another embodiment, the present invention provides a method for inhibiting
protein kinase in a patient in recognized need of such treatment comprising
administer-
ing to the patient a therapeutically acceptable amount of a compound of
formula (I), or
a therapeutically acceptable salt thereof.
In another embodiment, the present invention provides a method for treating
cancer in a patient in recognized need of such treatment comprising
administering to
the patient a therapeutically acceptable amount of a compound of formula (I),
or a
therapeutically acceptable salt thereof.
In another embodiment, the present invention provides a compound of formula
(II) wherein L is CH2C(O)NR7; and X, R1, R2, R3, R4, R7, R10, and R" are as
defined in
formula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is CH2C(O)NR7; and R1, R2, R3, R4, R7, R9, R10, and
R11 are as
defined in formula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is CH2C(O)NR7; and R1, R2, R3, R4, R7, R9, R10, and
R11 are as
defined in formula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is CH2C(O)NR7; R1, R2, R3, R4, and R7 are hydrogen;
R9 is se-
lected from the group consisting of hydrogen and alkyl; R10 and R11 are as
defined in
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17
formula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is CH2C(O)NR7; R1, R2, R3, R4, and R7 are hydrogen;
R9 is se-
lected from the group consisting of hydrogen and alkyl; R10 and R"
independently se-
lected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl,
carboxy,
cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR Rd, and
aryloxy
wherein the aryloxy is phenoxy; and Rc and Rd are independently selected from
the
group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is CH2C(O)NR7; R1, R2, R3, R4, and R7 are hydrogen;
R9 is se-
lected from the group consisting of hydrogen and alkyl; R10 and R11
independently se-
lected from the group consisting of hydrogen, alkyl, halo, and haloalkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein L is (CH2),,N(R7)C(O)N(R8)(CH2)n; and m, n, X, R1, R2, R3, R4,
R7, R8, R10,
and R11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of for-
mula(II) wherein X is NR9; and L, R1, R2, R3, R4, R9, R10, and R11 are as
defined in for-
mula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; and m, n, R1, R2, R3,
R4, R7,
R8, R9, R10, and R11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R7 and
R8 are
hydrogen; R9 is selected from the group consisting of alkoxyalkyl, alkyl,
alkylcarbonyl,
aryl, heterocyclylalkyl, hydroxyalkyl, and (NRaRb)alkyl; and Ra, Rb, R1, R2,
R3 R4 R10,
and R11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R7 and
R8 are
hydrogen; R9 is hydrogen; and R1, R2, R3, R4, R10, and R11 are as defined in
formula
(II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R7 and
R8 are
hydrogen; R9 is hydrogen; one of R1 and R2 is selected from the group
consisting of
hydrogen and halo and the other is selected from the group consisting of
hydroxy, hy-
droxyalkyl, and (NRaRb)alkyl; and Ra, Rb, R3, R4, R10, and R11 are as defined
in formula
(II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R7 and
R8 are
hydrogen; R9 is hydrogen; one of R1 and R2 is selected from the group
consisting of
hydrogen and halo and the other is selected from the group consisting of
hydroxy, hy-
droxyalkyl, and (NRaRb)alkyl; one of R3 and R4 is hydrogen and the other is
selected
from the group consisting of alkoxyalkoxy, alkyl, halo, haloalkoxy, and
hydroxy; R10 and
R11 are independently selected from the group consisting of hydrogen, alkoxy,
alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo,
haloalkoxy,
haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR Rd; R a and Rb are
independently se-
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18
lected from the group consisting of hydrogen and alkyl; and Rc and Rd are
independ-
ently selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1,
R2, R3, R7,
R8, and R9 are hydrogen; R4 is selected from the group consisting of hydrogen
and
halo; R10 and R" are independently selected from the group consisting of
hydrogen,
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy,
cyano, halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR Rd; and Rc and Rd
are in-
dependently selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1,
R2, R3, R7,
R8, and R9 are hydrogen; R4 is selected from the group consisting of hydrogen
and
halo; R10 and R11 are independently selected from the group consisting of
hydrogen,
alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hy-
droxyalkyl, nitro, -NR Rd, and aryloxy wherein the aryloxy is phenoxy; and Rc
and Rd
are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1,
R2, R3, R7,
R8, and R9 are hydrogen; R4 is selected from the group consisting of hydrogen
and
halo; and R10 and R11 are independently selected from the group consisting of
hydro-
gen, alkyl, halo, and haloalkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1,
R2, R3, R7,
and R8 are hydrogen; R9 is alkyl; R4 is selected from the group consisting of
hydrogen
and halo; R10 and R11 are independently selected from the group consisting of
hydro-
gen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy,
cyano, halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR Rd; and Rc and Rd
are in-
dependently selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1,
R2, R3, R7,
and R8 are hydrogen; R9 is alkyl; R4 is selected from the group consisting of
hydrogen
and halo; R10 and R11 are independently selected from the group consisting of
hydro-
gen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy,
haloalkyl, hydroxy,
hydroxyalkyl, nitro, -NR Rd, and aryloxy wherein the aryloxy is phenoxy; and
Rc and Rd
are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1,
R2, R3, R7,
and R8 are hydrogen; R9 is alkyl; R4 is selected from the group consisting of
hydrogen
and halo; and R10 and R11 are independently selected from the group consisting
of hy-
drogen, alkyl, halo, and haloalkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R7 and
R8 are
hydrogen; R9 is hydrogen; one of R1 and R2 is hydrogen and the other is halo;
and R3,
R4, R10, and R11 are as defined in formula (II).
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19
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R7 and
R$ are
hydrogen; R9 is hydrogen; one of R1 and R2 is hydrogen and the other is halo;
R3 and
R4 are independently selected from the group consisting of hydrogen,
alkoxyalkoxy,
alkyl, halo, haloalkoxy, and hydroxy; R10 and R" are selected from the group
consisting
of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy,
haloalkyl,
hydroxy, hydroxyalkyl, nitro, -NR Rd, and aryloxy wherein the aryloxy is
phenoxy; and
Rc and Rd are independently selected from the group consisting of hydrogen and
alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9, L is (CH2),,N(R7)C(O)N(R$)(CH2)n, m and n are 0, R7 and
R$ are
hydrogen, R9 is hydrogen, one of R1 and R2 is hydrogen and the other is
heterocycly-
lalkoxy; and R3, R4, R10, and R11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9, L is (CH2),,N(R7)C(O)N(R$)(CH2)n, m and n are 0, R7 and
R$ are
hydrogen, R9 is hydrogen, one of R1 and R2 is hydrogen and the other is
heterocycly-
lalkoxy; R3 and R4 are independently selected from the group consisting of
hydrogen,
alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R10 and R11 are selected
from the
group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano,
halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR Rd, and aryloxy
wherein the
aryloxy is phenoxy; and Rc and Rd are independently selected from the group
consist-
ing of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9, L is (CH2),,N(R7)C(O)N(R$)(CH2)n, m and n are 0, R7 and
R$ are
hydrogen, R9 is hydrogen, one of R1 and R2 is hydrogen and the other is
heterocycly-
lalkoxy wherein the heterocyclyl is selected from the group consisting of
morpholinyl,
piperidinyl, pyridinyl, pyrrolyl, pyrrolidinyl optionally substituted with
oxo, and 3,4,4-
trimethyl-2,5-dioxo-1-imidazolidinyl; R3 and R4 are independently selected
from the
group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and
hydroxy; R10
and R11 are selected from the group consisting of hydrogen, alkoxy,
alkoxycarbonyl,
alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,
nitro, -NR Rd,
and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd are independently
selected
from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R7 and
R$ are
hydrogen; R9 is hydrogen; one of R1 and R2 is hydrogen and the other is
selected from
the group consisting of (NRaRb)carbonylalkenyl and (NRaRb)alkoxy; and Ra, Rb,
R3, R4,
R10, and R11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R7 and
R$ are
hydrogen; R9 is hydrogen; one of R1 and R2 is hydrogen and the other is
selected from
the group consisting of (NR aRb)carbonylalkenyl and (NRaRb)alkoxy; R3 and R4
are in-
dependently selected from the group consisting of hydrogen, alkoxyalkoxy,
alkyl, halo,
haloalkoxy, and hydroxy; R10 and R11 are selected from the group consisting of
hydro-
gen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy,
haloalkyl, hydroxy,
hydroxyalkyl, nitro, -NR Rd, and aryloxy wherein the aryloxy is phenoxy; R a
and Rb are
CA 02699301 2010-03-10
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independently selected from the group consisting of hydrogen, alkyl,
alkylsulfonyl, aryl-
sulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; and Rc and Rd are
independently
selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
5 (II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R7
and R$ are
hydrogen; R9 is hydrogen; one of R1 and R2 is hydrogen and the other is
selected from
the group consisting of (NR aRb)carbonylalkenyl and (NRaRb)alkoxy; R3 and R4
are in-
dependently selected from the group consisting of hydrogen, alkoxyalkoxy,
alkyl, halo,
haloalkoxy, and hydroxy; R10 and R" are selected from the group consisting of
hydro-
10 gen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy,
haloalkyl, hydroxy,
hydroxyalkyl, nitro, -NR Rd, and aryloxy wherein the aryloxy is phenoxy; R a
and Rb are
independently selected from the group consisting of hydrogen, alkyl,
alkylsulfonyl, aryl-
sulfonyl wherein the aryl is phenyl, haloalkylsulfonyl, and
heterocyclylsulfonyl wherein
the heterocyclyl is thienyl; and Rc and Rd are independently selected from the
group
15 consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R7 and
R$ are
hydrogen; R9 is hydrogen; one of R1 and R2 is hydrogen and the other is
selected from
the group consisting of aryloxyalkyl, heterocyclyl, heterocyclylalkyl and
heterocycly-
20 loxyalkyl; and R3, R4, R10, and R11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R7 and
R$ are
hydrogen; R9 is hydrogen; one of R1 and R2 is hydrogen and the other is
selected from
the group consisting of aryloxyalkyl, heterocyclyl, heterocyclylalkyl and
heterocycly-
loxyalkyl; R3 and R4 are independently selected from the group consisting of
hydrogen,
alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R10 and R11 are selected
from the
group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano,
halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR Rd, and aryloxy
wherein the
aryloxy is phenoxy; and Rc and Rd are independently selected from the group
consist-
ing of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R7 and
R$ are
hydrogen; R9 is hydrogen; one of R1 and R2 is hydrogen and the other is
aryloxyalkyl
wherein the aryl is phenyl optionally substituted with halo; R3 and R4 are
independently
selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo,
haloalkoxy,
and hydroxy; R10 and R11 are selected from the group consisting of hydrogen,
alkoxy,
alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy,
hydroxyal-
kyl, nitro, -NR Rd, and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd
are inde-
pendently selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R7 and
R$ are
hydrogen; R9 is hydrogen; one of R1 and R2 is hydrogen and the other is
heterocyclyl
wherein the heterocyclyl is selected from the group consisting of pyridinyl
and thienyl;
R3 and R4 are independently selected from the group consisting of hydrogen,
alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R10 and R11 are selected
from the
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group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano,
halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR Rd, and aryloxy
wherein the
aryloxy is phenoxy; and Rc and Rd are independently selected from the group
consist-
ing of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R7 and
R$ are
hydrogen; R9 is hydrogen; one of R1 and R2 is hydrogen and the other is
heterocycly-
lalkyl wherein the heterocyclyl is selected from the group consisting of
morpholinyl and
piperazinyl wherein the piperazinyl is optionally substituted with alkyl; R3
and R4 are
independently selected from the group consisting of hydrogen, alkoxyalkoxy,
alkyl,
halo, haloalkoxy, and hydroxy; R10 and R" are selected from the group
consisting of
hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy,
haloalkyl,
hydroxy, hydroxyalkyl, nitro, -NR Rd, and aryloxy wherein the aryloxy is
phenoxy; and
Rc and Rd are independently selected from the group consisting of hydrogen and
alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R7 and
R$ are
hydrogen; R9 is hydrogen; one of R1 and R2 is hydrogen and the other is
heterocycly-
loxyalkyl wherein the heterocyclyl is pyridinyl; R3 and R4 are independently
selected
from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy,
and hy-
droxy; R10 and R11 are selected from the group consisting of hydrogen, alkoxy,
alkoxy-
carbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy,
hydroxyalkyl, ni-
tro, -NR Rd, and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd are
independ-
ently selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R7 and
R$ are
hydrogen; R9 is hydrogen; one of R1 and R2 is hydrogen and the other is
selected from
the group consisting of alkoxy, alkoxyalkoxy, and alkyl; and R3, R4, R10, and
R11 are as
defined in formula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R7 and
R$ are
hydrogen; R9 is hydrogen; one of R1 and R2 is hydrogen and the other is
selected from
the group consisting of alkoxy, alkoxyalkoxy, and alkyl; R3 and R4 are
independently
selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo,
haloalkoxy,
and hydroxy; R10 and R11 are selected from the group consisting of hydrogen,
alkoxy,
alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy,
hydroxyal-
kyl, nitro, -NR Rd, and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd
are inde-
pendently selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R7 and
R8 are
hydrogen; R9 is hydrogen; R1 and R2 are hydrogen; and R3, R4, R10, and R11 are
as
defined in formula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R7 and
R$ are
hydrogen; R9 is hydrogen; R1 and R2 are hydrogen; one of R3 and R4 is hydrogen
and
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the other is selected from the group consisting of alkoxyalkoxy, alkyl, halo,
haloalkoxy,
and hydroxy; and R10 and R" are as defined in formula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R7 and
R8 are
hydrogen; R9 is hydrogen; R1 and R2 are hydrogen; one of R3 and R4 is hydrogen
and
the other is selected from the group consisting of alkoxyalkoxy, alkyl, halo,
haloalkoxy,
and hydroxy; and R10 and R11 are selected from the group consisting of
hydrogen,
alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hy-
droxyalkyl, nitro, -NR Rd, and aryloxy wherein the aryloxy is phenoxy; and Rc
and Rd
are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R7 and
R8 are
hydrogen; R9 is hydrogen; R1 and R2 are hydrogen; R3 and R4 are hydrogen; and
R10
and R11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R7 and
R8 are
hydrogen; R9 is hydrogen; R1 and R2 are hydrogen; R3 and R4 are hydrogen; and
R10
and R11 are selected from the group consisting of hydrogen, alkoxy,
alkoxycarbonyl,
alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,
nitro, -NR Rd,
and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd are independently
selected
from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is NR9; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R7 and
R8 are
hydrogen; R9 is hydrogen; R1 and R2 are hydrogen; R3 and R4 are alkyl; and R10
and
R11 are selected from the group consisting of hydrogen, alkoxy,
alkoxycarbonyl, alkyl,
carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR
Rd, and
aryloxy wherein the aryloxy is phenoxy; and Rc and Rd are independently
selected from
the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein R1 and R2 are independently selected from the group consisting of
hydro-
gen, alkoxy, alkoxyalkoxy, alkoxyalkyl, aryloxy, aryloxyalkyl, halo,
haloalkoxy, haloalkyl,
hydroxy, hydroxyalkoxy, hydroxyalkyl, (NRaRb)alkoxy, (NRaRb)alkenyl,
(NRaRb)alkyl,
(NRaRb)carbonylalkenyl, and (NR aRb)carbonylalkyl; and X, L, Ra, Rb, R3, R4,
R10, and
R11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of for-
mula(II) wherein X is 0 and L, R1, R2, R3, R4, R10, and R11 are as defined in
formula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is 0; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; and m, n, R1, R2, R3,
R4, R7, R8,
R10, and R11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is 0; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1, R2,
R3, R4, R7,
and R8 are hydrogen; R10 and R11 are independently selected from the group
consisting
of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl,
carboxy,
cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR aRb;
and Ra
and Rb are independently selected from the group consisting of hydrogen and
alkyl.
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In another embodiment, the present invention provides a compound of formula
(II) wherein X is 0; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1, R2,
R3, R4, R7,
and R8 are hydrogen; R10 and R" are independently selected from the group
consisting
of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy,
haloalkyl,
hydroxy, hydroxyalkyl, nitro, -NR aRb, and aryloxy wherein the aryloxy is
phenoxy; and
R a and Rb are independently selected from the group consisting of hydrogen
and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is 0; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1 is
heterocycly-
lalkoxy; R2, R3, R4, R7, and R8 are hydrogen; R10 and R11 are independently
selected
from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkyl, ary-
loxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy,
hydroxyalkyl, nitro,
and -NR aRb; and R a and Rb are independently selected from the group
consisting of
hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein Xis 0; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1 is
heterocycly-
lalkoxy wherein the heterocyclyl is morpholinyl; R2, R3, R4, R7, and R8 are
hydrogen;
R10 and R11 are independently selected from the group consisting of hydrogen,
alkoxy,
alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy,
hydroxyal-
kyl, nitro, -NR aRb, and aryloxy wherein the aryloxy is phenoxy; and R a and
Rb are inde-
pendently selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is 0; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1 is
selected
from the group consisting of alkoxy, alkyl, halo, and haloalkoxy; R2, R3, R4,
R7, and R8
are hydrogen; R10 and R11 are independently selected from the group consisting
of hy-
drogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy,
haloalkyl, hy-
droxy, hydroxyalkyl, nitro, -NR aRb, and aryloxy wherein the aryloxy is
phenoxy; and R a
and Rb are independently selected from the group consisting of hydrogen and
alkyl.
In another embodiment, the present invention provides a compound of for-
mula(II) wherein X is S and L, R1, R2, R3, R4, R10, and R11 are as defined in
formula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is S; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; and m, n, R1, R2, R3,
R4, R7, R8,
R10, and R11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of formula
(II) wherein X is S; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1, R2,
R3, R4, R7,
and R8 are hydrogen; R10 and R11 are independently selected from the group
consisting
of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl,
carboxy,
cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR aRb;
and R a
and Rb are independently selected from the group consisting of hydrogen and
alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is S; L is (CH2),,N(R7)C(O)N(R8)(CH2)n; m and n are 0; R1, R2,
R3, R4, R7,
and R8 are hydrogen; R10 and R11 are independently selected from the group
consisting
of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy,
haloalkyl,
hydroxy, hydroxyalkyl, nitro, -NR aRb, and aryloxy wherein the aryloxy is
phenoxy; and
R a and Rb are independently selected from the group consisting of hydrogen
and alkyl..
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24
In another embodiment, the present invention provides a compound of formula
(II) wherein X is S; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R1, R2,
R3, R4, R7,
and R3 are hydrogen; and R10 and R" are independently selected from the group
con-
sisting of hydrogen, alkyl, halo, and haloalkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is S; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R1 is
heterocycly-
lalkoxy; R2, R3, R4, R7, and R3 are hydrogen; R10 and R11 are independently
selected
from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkyl, ary-
loxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy,
hydroxyalkyl, nitro,
and -NR aRb; and R a and Rb are independently selected from the group
consisting of
hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is S; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R1 is
heterocycly-
lalkoxy wherein the heterocyclyl is morpholinyl; R2, R3, R4, R7, and R$ are
hydrogen;
R10 and R11 are independently selected from the group consisting of hydrogen,
alkoxy,
alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy,
hydroxyal-
kyl, nitro, -NR aRb, and aryloxy wherein the aryloxy is phenoxy; and R a and
Rb are inde-
pendently selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of formula
(II) wherein X is S; L is (CH2),,N(R7)C(O)N(R$)(CH2)n; m and n are 0; R1 is
selected
from the group consisting of alkoxy, alkyl, halo, and haloalkoxy; R2, R3, R4,
R7, and R$
are hydrogen; R10 and R11 are independently selected from the group consisting
of hy-
drogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy,
haloalkyl, hy-
droxy, hydroxyalkyl, nitro, -NR aRb, and aryloxy wherein the aryloxy is
phenoxy; and Ra
and Rb are independently selected from the group consisting of hydrogen and
alkyl.
In another embodiment, the present invention provides a pharmaceutical com-
position comprising a compound of formula (11), or a therapeutically
acceptable salt
thereof, in combination with a therapeutically acceptable carrier.
In another embodiment, the present invention provides a method for inhibiting
protein kinase in a patient in recognized need of such treatment comprising
administer-
ing to the patient a therapeutically acceptable amount of a compound of
formula (II), or
a therapeutically acceptable salt thereof.
In another embodiment, the present invention provides a method for treating
cancer in a patient in recognized need of such treatment comprising
administering to
the patient a therapeutically acceptable amount of a compound of formula (II),
or a
therapeutically acceptable salt thereof.
As used in the present specification the following terms have the meanings
indi-
cated:
The term "alkenyl," as used herein, refers to a straight or branched chain
group
of two to six carbon atoms containing at least one carbon-carbon double bond.
The term "alkoxy," as used herein, refers to an alkyl group attached to the
par-
ent molecular moiety through an oxygen atom.
The term "alkoxyalkoxy," as used herein, refers to an alkoxy group attached to
the parent molecular moiety through another alkoxy group.
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The term "alkoxyalkyl," as used herein, refers to an alkyl group substituted
with
at least one alkoxy group.
The term "alkoxycarbonyl," as used herein, refers to an alkoxy group attached
to the parent molecular moiety through a carbonyl group.
5 The term "alkyl," as used herein, refers to a group derived from a straight
or
branched chain saturated hydrocarbon of one to six carbon atoms. Preferred
alkyl
groups of the present invention are of one to three carbon atoms. Most
preferred alkyl
groups are methyl and ethyl.
The term "alkylcarbonyl," as used herein, refers to an alkyl group attached to
10 the parent molecular moiety through a carbonyl group.
The term "alkylsulfonyl," as used herein, refers to an alkyl group attached to
the
parent molecular moiety through a sulfonyl group.
The term "aryl," as used herein, refers to a phenyl group, or a bicyclic or
tricyclic
fused ring system wherein one or more of the fused rings is a phenyl group.
Bicyclic
15 fused ring systems are exemplified by a phenyl group fused to a monocyclic
cycloal-
kenyl group, as defined herein, a monocyclic cycloalkyl group, as defined
herein, or
another phenyl group. Tricyclic fused ring systems are exemplified by a
bicyclic fused
ring system fused to a monocyclic cycloalkenyl group, as defined herein, a
monocyclic
cycloalkyl group, as defined herein, or another phenyl group. Aryl groups
include, but
20 are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl,
naphthyl, phenyl,
and tetrahydronaphthyl. The aryl groups of the present invention can be
optionally
substituted with one, two, three, four, or five substituents independently
selected from
the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl,
a second aryl group, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano,
cycloalkyl, halo,
25 haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy,
hydroxyalkyl, nitro, -
NR Rd, (NR Rd)alkyl, and oxo; wherein the second aryl group, the aryl part of
the ary-
lalkoxy, the arylalkyl, and the aryloxy, the heterocyclyl, and the
heterocyclyl part of the
heterocyclylalkyl can be further optionally substituted with one, two, three,
four, or five
groups independently selected from the group consisting of alkenyl, alkoxy,
alkoxyalkyl,
alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and
oxo.
The term "arylalkyl," as used herein, refers to an alkyl group substituted
with at
least one aryl group.
The term "arylcarbonyl," as used herein, refers to an aryl group attached to
the
parent molecular moiety through a carbonyl group.
The term "arylalkoxy," as used herein, refers to an aryl group attached to the
parent molecular moiety through an alkoxy group.
The term "aryloxy," as used herein, refers to an aryl group attached to the
par-
ent molecular moiety through an oxygen atom.
The term "aryloxyalkyl," as used herein, refers to an aryloxy group attached
to
the parent molecular moiety through an alkyl group.
The term "arylsulfonyl," as used herein, refers to an aryl group attached to
the
parent molecular moiety through a sulfonyl group.
The term "carbonyl," as used herein, refers to -C(O)-.
The term "carboxy," as used herein, refers to -CO2H.
The term "cyano," as used herein, refers to -CN.
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The term "cycloalkenyl," as used herein, refers to a non-aromatic cyclic or bi-
cyclic ring system having three to ten carbon atoms and one to three rings,
wherein
each five-membered ring has one double bond, each six-membered ring has one or
two double bonds, each seven- and eight-membered ring has one to three double
bonds, and each nine-to ten-membered ring has one to four double bonds.
Examples
of cycloalkenyl groups include, but are not limited to, cyclohexenyl,
octahydronaphtha-
lenyl, and norbornylenyl.
The term "cycloalkyl," as used herein, refers to a saturated monocyclic,
bicyclic,
or tricyclic hydrocarbon ring system having three to twelve carbon atoms.
Examples of
cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl,
cyclohexyl,
bicyclo[3.1.1 ]heptyl, and adamantyl.
The cycloalkyl groups of the present invention can be optionally substituted
with
one, two, three, four, or five substituents independently selected from the
group con-
sisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,
carboxy,
cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR Rd, (NR
Rd)alkyl, and
oxo.
The terms "halo," and "halogen," as used herein, refer to F, Cl, Br, and I.
The term "haloalkoxy," as used herein, refers to a haloalkyl group attached to
the parent molecular moiety through an oxygen atom.
The term "haloalkyl," as used herein, refers to an alkyl group substituted by
one,
two, three, or four halogen atoms.
The term "haloalkylsulfonyl," as used herein, refers to a haloalkyl group at-
tached to the parent molecular moiety through a sulfonyl group.
The term "heterocyclyl," as used herein, represents a monocyclic, bicyclic, or
tricyclic ring system wherein one or more rings is a four-, five-, six-, or
seven-
membered ring containing one, two, or three heteroatoms independently selected
from
the group consisting of nitrogen, oxygen, and sulfur. Monocyclic ring systems
are ex-
emplified by any 3- or 4-membered ring containing a heteroatom independently
se-
lected from the group consisting of oxygen, nitrogen and sulfur; or a 5-, 6-
or 7-
membered ring containing one, two or three heteroatoms wherein the heteroatoms
are
independently selected from the group consisting of nitrogen, oxygen and
sulfur. The
3- and 4-membered rings have no double bonds, the 5-membered ring has from 0-2
double bonds and the 6- and 7-membered rings have from 0-3 double bonds. Repre-
sentative examples of monocyclic ring systems include, but are not limited to,
azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane,
furan, imida-
zole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine,
isoxazole,
isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline,
oxadiazolidine, oxa-
zole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine,
pyrazole, pyra-
zoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline,
pyrrolidine, tet-
rahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole,
thiadiazoline,
thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene,
thiomorpholine, thiomor-
pholine sulfone, thiopyran, triazine, triazole, and trithiane. Bicyclic ring
systems are
exemplified by any of the above monocyclic ring systems fused to phenyl ring,
a mono-
cyclic cycloalkyl group as defined herein, a monocyclic cycloalkenyl group, as
defined
herein, or another monocyclic heterocyclyl ring system. Representative
examples of
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bicyclic ring systems include but are not limited to, benzimidazole,
benzothiazole, ben-
zothiophene, benzoxazole, benzofuran, benzopyran, benzothiopyran,
benzodioxine,
1,3-benzodioxole, cinnoline, dihydrobenzimidazole, indazole, indole, indoline,
indoliz-
ine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline,
isoquino-
line, phthalazine, pyranopyridine, quinoline, quinolizine, quinoxaline,
quinazoline, tetra-
hydroisoquinoline, tetrahydroquinoline, and thiopyranopyridine. Tricyclic
rings systems
are exemplified by any of the above bicyclic ring systems fused to a phenyl
ring, a
monocyclic cycloalkyl group as defined herein, a monocyclic cycloalkenyl group
as
defined herein, or another monocyclic heterocyclyl ring system. Representative
exam-
ples of tricyclic ring systems include, but are not limited to, acridine,
carbazole, car-
boline, dibenzofuran, dibenzothiophene, naphthofuran, naphthothiophene,
oxanthrene,
phenazine, phenoxathin, phenoxazine, phenothiazine, thianthrene, thioxanthene,
and
xanthene. Heterocyclyl groups can be attached to the parent molecular moiety
through
a carbon atom or a nitrogen atom in the group.
The heterocyclyl groups of the present invention can be optionally substituted
with one, two, three, four, or five substituents independently selected from
the group
consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, aryl, ary-
lalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy,
haloalkyl, a
second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -
NR Rd,
(NR Rd)alkyl, and oxo; wherein the aryl, the aryl part of the arylalkoxy, the
arylalkyl, and
the aryloxy, the second heterocyclyl group, and the heterocyclyl part of the
heterocycly-
lalkyl can be further optionally substituted with one, two, three, four, or
five groups in-
dependently selected from the group consisting of alkenyl, alkoxy,
alkoxyalkyl, alkyl,
cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo.
The term "heterocyclylalkenyl," as used herein, refers to an alkenyl group sub-
stituted with at least one heterocyclyl group.
The term "heterocyclylalkoxy," as used herein, refers to a heterocyclyl group
attached to the parent molecular moiety through an alkoxy group.
The term "heterocyclylalkyl," as used herein, refers to an alkyl group
substituted
with at least one heterocyclyl group.
The term "heterocyclyloxy," as used herein, refers to a heterocyclyl group at-
tached to the parent molecular moiety through an oxygen atom.
The term "heterocyclyloxyalkyl," as used herein, refers to an alkyl group
substi-
tuted with at least one heterocyclyloxy group.
The term "heterocyclylsulfonyl," as used herein, refers to a heterocyclyl
group
attached to the parent molecular moiety through a sulfonyl group.
The term "hydroxy," as used herein, refers to -OH.
The term "hydroxyalkoxy," as used herein, refers to a hydroxy group attached
to
the parent molecular moiety through an alkoxy group.
The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted
with at least one hydroxy group.
The term "nitro," as used herein, refers to -NO2.
The term "-NRaRb"' as used herein, represents two groups, Ra and Rb, which
are attached to the parent molecular moiety through a nitrogen atom. R a and
Rb are
independently selected from the group consisting of hydrogen, alkenyl, alkyl,
alkylcar-
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bonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl,
haloalkylsulfonyl, cycloal-
kyl, heterocyclyl, heterocyclylalkyl, and heterocyclylsulfonyl, wherein the
aryl, the aryl
part of the arylalkyl and the arylcarbonyl, the heterocyclyl, the heterocyclyl
part of the
heterocyclylalkyl and the heterocyclylsulfonyl can be further optionally
substituted with
one, two, three, four, or five substituents independently selected from the
group con-
sisting of alkenyl, alkoxy, alkyl, cyano, halo, haloalkyl, haloalkoxy, nitro,
and oxo.
The term "(NRaRb)alkenyl," as used herein, represents an alkenyl group substi-
tuted with at least one -NR aRb group.
The term "(NRaRb)alkoxy," as used herein, represents an -NR aRb group at-
tached to the parent molecular moiety through an alkoxy group.
The term "(NRaRb)alkyl," as used herein, represents an alkyl group substituted
with at least one -NR aRb group.
The term "(NRaRb)alkynyl," as used herein, represents an alkynyl group substi-
tuted with at least one -NR aRb group.
The term "(NRaRb)carbonyl," as used herein, represents an (NRaRb) group at-
tached to the parent molecular moiety through a carbonyl group.
The term "(NRaRb)carbonylalkenyl," as used herein, represents an alkenyl
group substituted with at least one (NRaRb)carbonyl group.
The term "(NRaRb)carbonylalkyl," as used herein, represents an alkyl group
substituted with at least one (NRaRb)carbonyl group.
The term "-NR Rd" as used herein, represents two groups, Rc and Rd, which
are attached to the parent molecular moiety through a nitrogen atom. Rc and Rd
are
independently selected from the group consisting of hydrogen, alkyl,
alkylcarbonyl, aryl,
arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl,
wherein the
aryl, the aryl part of the arylalkyl, the heterocyclyl, and the heterocyclyl
part of the het-
erocyclylalkyl can be further optionally substituted with one, two, three,
four, or five
substituents independently selected from the group consisting of alkenyl,
alkoxy, alkyl,
cyano, halo, haloalkyl, haloalkoxy, nitro, and oxo.
The term "(NR Rd)alkyl," as used herein, represents an alkyl group substituted
with at least one -NR Rd group.
The term "oxo," as used herein, refers to =0.
The term "sulfonyl," as used herein, refers to -SO2.
The compounds of the present invention can exist as therapeutically acceptable
salts. The term "therapeutically acceptable salt," as used herein, represents
salts or
zwitterionic forms of the compounds of the present invention which are water
or oil-
soluble or dispersible, which are suitable for treatment of diseases without
undue toxic-
ity, irritation, and allergic response; which are commensurate with a
reasonable bene-
fit/risk ratio, and which are effective for their intended use. The salts can
be prepared
during the final isolation and purification of the compounds or separately by
reacting an
-NR aRb group with a suitable acid. Representative acid addition salts include
acetate,
adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,
butyrate,
camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, hep-
tanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-
hydroxyethansulfonate, lactate, maleate, mesitylenesulfonate,
methanesulfonate,
naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,
pectinate,
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persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate,
tartrate, tri-
chloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-
toluenesulfonate, and undecanoate. Also, -NR aRb groups in the compounds of
the
present invention can be quaternized with methyl, ethyl, propyl, and butyl
chlorides,
bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl,
lauryl,
myristyl, and steryl chlorides, bromides, and iodides; and benzyl and
phenethyl bro-
mides. Examples of acids which can be employed to form therapeutically
acceptable
addition salts include inorganic acids such as hydrochloric, hydrobromic,
sulfuric, and
phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
The present compounds can also exist as therapeutically acceptable prodrugs.
The term "therapeutically acceptable prodrug," refers to those prodrugs or
zwitterions
which are suitable for use in contact with the tissues of patients without
undue toxicity,
irritation, and allergic response, are commensurate with a reasonable
benefit/risk ratio,
and are effective for their intended use. The term "prodrug," refers to
compounds
which are rapidly transformed in vivo to parent compounds of formula (I) or
(II) for ex-
ample, by hydrolysis in blood.
Representative compounds of formulas (I) and (11) are:
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3,5-dimethoxyphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-bromo-4-methylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-phenylurea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-fluoro-4-methylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(2-fluorophenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(4-fluorophenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea;
N-{4-[3-amino-7-(4-morpholinylmethyl)-1 H-indazol-4-yl]phenyl}-N'-(3-
fluorophenyl)urea;
N-{4-[3-amino-7-(4-morpholinylmethyl)-1 H-indazol-4-yl]phenyl}-N'-(3-
methylphenyl)urea;
N-{4-[3-amino-7-(4-morpholinylmethyl)-1 H-indazol-4-yl]phenyl}-N'-[2-fluoro-5-
(trifluoromethyl)phenyl]urea;
N-{4-[3-amino-7-(4-morpholinylmethyl)-1 H-indazol-4-yl]phenyl}-N'-[4-fluoro-3-
(trifluoromethyl)phenyl]urea;
N-{4-[3-amino-7-(4-morpholinylmethyl)-1 H-indazol-4-yl]phenyl}-N'-[3-
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1 H-indazol-4-yl}phenyl)-N'-
(3-
chlorophenyl)urea;
N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1 H-indazol-4-yl}phenyl)-N'-
(3-
methylphenyl)urea;
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N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1 H-indazol-4-yl}phenyl)-N'-
(3-
fluorophenyl)urea;
N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1 H-indazol-4-yl}phenyl)-N'-
[3-
(trifluoromethyl)phenyl]urea;
5 N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1 H-indazol-4-yl}phenyl)-N'-
[2-fluoro-5-
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1 H-indazol-4-yl}phenyl)-N'-
(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea;
10 N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea;
N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-[3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea;
N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-cyanophenyl)urea;
N-(4-{3-amino-7-[(dimethylamino)methyl]-1 H-indazol-4-yl}phenyl)-N'-(2-fluoro-
5-
15 methylphenyl)urea;
N-(4-{3-amino-7-[(dimethylamino)methyl]-1 H-indazol-4-yl}phenyl)-N'-(3-
chlorophenyl)urea;
N-(4-{3-amino-7-[(dimethylamino)methyl]-1 H-indazol-4-yl}phenyl)-N'-[3-
(trifluoromethyl)phenyl]urea;
20 N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea;
N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-phenylurea;
N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-(2-methylphenyl)urea;
N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-(4-methylphenyl)urea;
N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-(3-methoxyphenyl)urea;
25 N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea;
N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea;
N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea;
N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-[3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
30 N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(3-methylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(3-fluorophenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(3,5-dimethylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(3-ethylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(3-chloro-4-
fluorophenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(3-fluoro-4-
methylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(3-chlorophenyl)urea;
N-[4-(3-amino-7-bromo-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea;
N-{4-[3-amino-1-(2-hydroxyethyl)-1 H-indazol-4-yl]phenyl}-N'-(3-
methylphenyl)urea;
2-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N-phenylacetamide;
2-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N-(3-chlorophenyl)acetamide;
2-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N-(4-fluoro-3-methylphenyl)acetamide;
2-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N-[3-(trifluoromethyl)phenyl]acetamide;
2-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N-(3-methylphenyl)acetamide;
N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea;
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N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-phenylurea;
N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea;
N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea;
N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-(3-fluoro-4-
methylphenyl)urea;
N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea;
N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-[3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea;
N-{4-[3-amino-7-(2-methoxyethoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-
methylphenyl)urea;
N-{4-[3-amino-7-(2-methoxyethoxy)-1 H-indazol-4-yl]phenyl}-N'-phenylurea;
N-{4-[3-amino-7-(2-methoxyethoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-
fluorophenyl)urea;
N-{4-[3-amino-7-(2-methoxyethoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-
bromophenyl)urea;
N-{4-[3-amino-7-(2-methoxyethoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-
chlorophenyl)urea;
N-{4-[3-amino-7-(2-methoxyethoxy)-1 H-indazol-4-yl]phenyl}-N'-[3-
(trifluoromethyl)phenyl]urea;
N-{4-[3-amino-7-(2-methoxyethoxy)-1 H-indazol-4-yl]phenyl}-N'-[2-fluoro-5-
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
methylphenyl)urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-
phenylurea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
fluorophenyl)urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
bromophenyl)urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
ethylphenyl)urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-[2-
fluoro-5-
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-[4-
fluoro-3-
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
chlorophenyl)urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-[3-
(trifluoromethyl)phenyl]urea;
(2E)-3-{3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1 H-
indazol-7-
yl}-N, N-dimethylacrylamide;
(2E)-3-{3-amino-4-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]-1 H-
indazol-7-
yl}-N, N-dimethylacrylamide;
(2E)-3-(3-amino-4-{4-[({[3-
(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1 H-
indazol-7-yl)-N, N-dimethylacrylamide;
N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-
phenylurea;
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32
N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
bromophenyl)urea;
N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
methylphenyl)urea;
N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
chlorophenyl)urea;
N-(4-{3-amino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-
(3-
methylphenyl)urea;
2-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N-(3-methylphenyl)acetamide.
N-[4-(3-amino-1 H-indazol-4-yl)-2-methylphenyl]-N'-(3-methylphenyl)urea;
N-(4-{3-amino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-
(3-
chlorophenyl)urea;
N-[4-(3-amino-l,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)urea;
N-[4-(3-amino-l,2-benzisoxazol-4-yl)phenyl]-N'-[2-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-l,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea;
N-[4-(3-amino-l,2-benzisoxazol-4-yl)phenyl]-N'-[3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-l,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-methoxy-l,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-methoxy-l,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)urea;
N-[4-(3-amino-7-methoxy-l,2-benzisoxazol-4-yl)phenyl]-N'-[3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-methoxy-l,2-benzisoxazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea;
N-[4-(3-amino-7-methoxy-l,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-[2-
fluoro-5-
(trifluoromethyl)phenyl]urea;
N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-[3-
(trifluoromethyl)phenyl]urea;
N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-
chlorophenyl)urea;
N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-
methylphenyl)urea;
N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(2-
fluoro-5-
methylphenyl)urea;
N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3,5-
dimethylphenyl)urea;
N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-
phenoxyphenyl)urea;
N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-
bromophenyl)urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-[3-
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-(2-
fluoro-5-
methylphenyl)urea;
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N-(4-{3-amino-7-[2-(4-morpholinyl )ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-[2-
fluoro-5-
(trifluorom ethyl) phenyl]urea;
N-(4-{3-amino-7-[2-(4-morpholinyl )ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-(3-
methylphenyl)urea;
N-{4-[3-amino-7-(2-methoxyethoxy)-1 H-indazol-4-yl]phenyl}-N'-(2-fluoro-5-
methylphenyl)urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(2-
fluoro-5-
methylphenyl)urea;
N-{4-[3-amino-7-(methoxymethoxy)-1 H-indazol-4-yl]phenyl}-N'-(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea;
N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea;
N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea;
N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea;
N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-[3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-phenylurea;
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-
phenylurea;
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
fluorophenyl)urea;
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(2-
fluoro-5-
methylphenyl)urea;
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
methylphenyl)urea;
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
bromophenyl)urea;
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-[2-
fluoro-5-
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
chlorophenyl)urea;
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-[3-
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-
phenylurea;
N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
fluorophenyl)urea;
N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(2-fluoro-
5-
methylphenyl)urea;
N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
methylphenyl)urea;
N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
bromophenyl)urea;
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34
N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-[2-fluoro-
5-
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
chlorophenyl)urea;
N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-[3-
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1 H-
indazol-4-
yl}phenyl)-N'-(3-methylphenyl)urea;
N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1 H-
indazol-4-
yl}phenyl)-N'-(3-chlorophenyl)urea;
N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1 H-
indazol-4-
yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea;
N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1 H-
indazol-4-
yl}phenyl)-N'-[3-(trifluoromethyl) phenyl]urea;
N-[4-(3-amino-1 H-indazol-4-yl)-2-ethylphenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)-2-ethylphenyl]-N'-[3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1 H-indazol-4-yl]phenyl}-N'-(2-fluoro-
5-
methylphenyl)urea;
N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1 H-indazol-4-yl]phenyl}-N'-[3-
(trifluoromethyl)phenyl]urea;
N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1 H-indazol-4-yl]phenyl}-N'-(3-
chlorophenyl)urea;
N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1 H-indazol-4-yl]phenyl}-N'-(3-
methylphenyl)urea;
N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1 H-indazol-4-yl]phenyl}-N'-(3-
fluorophenyl)urea;
N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1 H-indazol-4-yl}phenyl)-N'-(2-
fluoro-5-
methylphenyl)urea;
N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1 H-indazol-4-yl}phenyl)-N'-[3-
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1 H-indazol-4-yl}phenyl)-N'-(3-
chlorophenyl)urea;
N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1 H-indazol-4-yl}phenyl)-N'-(3-
methylphenyl)urea;
N-(4-{3-amino-7-[(3-pyridinyloxy)methyl]-1 H-indazol-4-yl}phenyl)-N'-[3-
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1 H-indazol-4-yl}phenyl)-N'-(2-fluoro-
5-
methylphenyl)urea;
N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1 H-indazol-4-yl}phenyl)-N'-(3-
fluorophenyl)urea;
N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1 H-indazol-4-yl}phenyl)-N'-(3-
chlorophenyl)urea;
N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1 H-indazol-4-yl}phenyl)-N'-[3-
(trifluoromethyl)phenyl]urea;
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N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1 H-indazol-4-yl}phenyl)-N'-(3-
methylphenyl)urea;
N-[4-(3-amino-6-bromo-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea;
N-[4-(3-amino-4-bromo-1 H-indazol-6-yl)phenyl]-N'-(3-methylphenyl)urea;
5 N-(4-{3-amino-1-[2-(dimethylamino)ethyl]-1 H-indazol-4-yl}phenyl)-N'-(2-
fluoro-5-
methylphenyl)urea;
N-(4-{3-amino-1-[2-(d imethylamino)ethyl]-1 H-indazol-4-yl}phenyl)-N'-(3-
chlorophenyl)urea;
N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1
H-
10 indazol-7-yl}oxy)ethyl]methanesulfonamide;
4-(1 H-indol-5-yl)-1 H-indazol-3-amine;
N-{4-[3-amino-1-(2-methoxyethyl)-1 H-indazol-4-yl]phenyl}-N'-(2-fluoro-5-
methylphenyl)urea;
N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)ethoxy]-1 H-
15 indazol-4-yl}phenyl)-N'-(3,5-dimethylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)-2,6-di methylphenyl]-N'-(2-fluoro-5-
methyl phenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)-2,6-di methylphenyl]-N'-[3-
(trifluoromethyl)phenyl]urea;
20 N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-hydroxyphenyl)urea;
N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1 H-
indazol-7-yl}oxy)ethyl]methanesulfonamide;
N-{2-[(3-amino-4-{4-[({[2-fluoro-5-
(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1 H-indazol-7-
25 yl)oxy]ethyl}methanesulfonamide;
N-[2-({3-amino-4-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]-1 H-
indazol-7-yl}oxy)ethyl]methanesulfonamide;
N-{2-[(3-amino-4-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-
1 H-indazol-7-yl)oxy]ethyl}methanesulfonamide;
30 N-[3-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea;
N-[4-(3-amino-7-methyl-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea;
N-[4-(3-amino-7-methyl-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea;
N-[4-(3-amino-7-methyl-1 H-indazol-4-yl)phenyl]-N'-[3-
(trifluoromethyl)phenyl]urea;
35 N-[4-(3-amino-7-methyl-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-methyl-1 H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea;
N-[4-(3-amino-7-methyl-1 H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea;
N-[4-(3-amino-7-methyl-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-7-methyl-1 H-indazol-4-yl)phenyl]-N'-(3-cyanophenyl)urea
N-[4-(3-amino-1 H-indazol-4-yl)-2-(trifluoromethoxy)phenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-
(trifluoromethyl)phenyl]urea;
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36
N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(4-fluorophenyl)urea;
N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(2-fluorophenyl)urea;
N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-fluoro-4-
methylphenyl)urea;
N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-phenylurea;
N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1 H-
indazol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide;
N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(4-bromo-2-fluorophenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(5-fluoro-2-methylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(4-fluoro-3-methylphenyl)urea;
N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-
phenylurea;
N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-
fluorophenyl)urea;
N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(2-
fluoro-
5-methylphenyl)urea;
N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-
methylphenyl)urea;
N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-[2-
fluoro-
5-(trifluoromethyl)phenyl]urea;
N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-
chlorophenyl)urea;
N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-[3-
(trifluoromethyl)phenyl]urea;
N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-
1 H-indazol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide;
N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1 H-
indazol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide;
N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-
1 H-indazol-7-yl}oxy)ethyl]benzenesulfonamide;
N-{2-[(3-amino-4-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-
1 H-indazol-7-yl)oxy]ethyl}benzenesulfonamide;
N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1 H-
indazol-7-yl}oxy)ethyl]benzenesulfonamide;
N-[2-({3-amino-4-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]-1 H-
indazol-7-yl}oxy)ethyl]benzenesulfonamide;
N-(4-{3-amino-7-[(isopropylamino)methyl]-1 H-indazol-4-yl}phenyl)-N'-(2-fluoro-
5-methylphenyl)urea;
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N-(4-{3-amino-7-[(isopropylamino)methyl]-1 H-indazol-4-yl}phenyl)-N'-(3-
chlorophenyl)urea;
N-(4-{3-amino-7-[(isopropylamino)methyl]-1 H-indazol-4-yl}phenyl)-N'-[3-
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[(isopropylamino)methyl]-1 H-indazol-4-yl}phenyl)-N'-(3-
methylphenyl)urea;
N-(4-{3-amino-7-[(isopropylamino)methyl]-1 H-indazol-4-yl}phenyl)-N'-(4-fluoro-
3-m ethylphenyl)urea;
N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1 H-indazol-4-yl}phenyl)-N'-(2-
fluoro-
5-methylphenyl)urea;
N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1 H-indazol-4-yl}phenyl)-N'-(3-
chlorophenyl)urea;
N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1 H-indazol-4-yl}phenyl)-N'-[3-
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1 H-indazol-4-yl}phenyl)-N'-(3-
methylphenyl)urea;
N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1 H-indazol-4-yl}phenyl)-N'-(4-
fluoro-
3-methylphenyl)urea;
N-(4-{3-amino-7-[3-(1 H-pyrrol-1-yl)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(2-
fluoro-5-methylphenyl)urea;
4-(1 H-indol-5-yl)-7-[3-(1 H-pyrrol-1-yl)propoxy]-1 H-indazol-3-amine;
N-(4-{3-amino-7-[3-(1 H-pyrrol-1-yl)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
methylphenyl)urea;
N-(4-{3-amino-7-[3-(1 H-pyrrol-1-yl)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
chlorophenyl)urea;
N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-
1 H-indazol-7-yl}oxy)ethyl]thiophene-2-sulfonamide;
N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1 H-
indazol-7-yl}oxy)ethyl]thiophene-2-sulfonamide;
N-(2-{[3-amino-4-(1 H-indol-5-yl)-1 H-indazol-7-yl]oxy}ethyl)thiophene-2-
sulfonamide
N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(2-
fluoro-
5-methylphenyl)urea;
N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
chlorophenyl)urea;
N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-[3-
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
fluorophenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-[3-(trifluoromethyl)-
phenyl]urea;
N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-[4-fluoro-3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-pyridin-3-yl-1 H-indazol-4-yl)phenyl]-N'-(4-fluoro-3-
methylphenyl)urea;
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38
N-[4-(3-amino-7-pyridin-3-yI-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea;
N-[4-(3-amino-7-pyridin-3-yI-1 H-indazol-4-yl)phenyl]-N'-[3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-pyridin-3-yI-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-7-pyridin-3-yI-1 H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
methylphenyl)urea;
N-(4-{3-amino-7-[3-(d imethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(2-
fluoro-5-methylphenyl)urea;
N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
fluorophenyl)urea;
N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(3-
chlorophenyl)urea;
N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-[3-
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(4-
fluoro-3-methylphenyl)urea;
N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-
bromophenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)-3-fluorophenyl]-N'-(3-methylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)-3-fluorophenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)-3-fluorophenyl]-N'-(3-chlorophenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)-3-fluorophenyl]-N'-(4-fluoro-3-
methylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)-3-fluorophenyl]-N'-[2-fluoro-5-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-1 H-indazol-4-yl)-3-fluorophenyl]-N'-[4-fluoro-3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-d imethylphenyl)urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-phenylurea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-methylphenyl)urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-cyanophenyl)urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-fluoro-3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-bromophenyl)urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluoro-4-methylphenyl)urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-di fluorophenyl)urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methoxyphenyl)urea;
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N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-methoxyphenyl)urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-nitrophenyl)urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-fluorophenyl)urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluorophenyl)urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chloro-4-fluorophenyl)urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chloro-4-methoxy-
phenyl)urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(dimethylamino)phenyl]urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-1,3-benzodioxol-5-ylurea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(trifluoromethoxy)-
phenyl]urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-(trifluoromethoxy)-
phenyl]urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)-
phenyl]urea;
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chloro-4-methylphenyl)urea;
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[3,5-
bis(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-
(trifluoromethoxy)phenyl]urea;
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea;
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methoxy-
phenyl)urea;
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-difluorophenyl)-
urea;
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-methylphenyl)-
urea;
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-bromophenyl)-
urea;
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-d imethyl-
phenyl)urea;
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(d imethylamino)-
phenyl]urea;
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-1,3-benzodioxol-5-
ylurea
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)urea;
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chIorophenyl)urea;
N-[4-(3-amino-7-methyl- 1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-7-methyl- 1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-methyl- 1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)-
phenyl]urea;
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N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-dimethyl-
phenyl)urea;
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea;
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-methylphenyl)urea;
5 N-[4-(3-amino-7-methyl- 1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(trifluoro-
methoxy)phenyl]urea;
N-[4-(3-amino-7-methyl- 1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluoro-4-
methylphenyl)urea;
N-[4-(3-amino-7-methyl- 1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methoxyphenyl)-
10 urea;
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-phenylurea;
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-[3,5-bis(trifluoro-
methyl)phenyl]urea;
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-bromophenyl)urea;
15 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-
fluorophenyl)urea;
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-fluoro-3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-fluoro-3-
methylphenyl)urea;
20 N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-
(trifluoromethyl)-
phenyl]urea;
N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-ch lorophenyl
)urea;
N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-fluoro-3-
(trifluorom ethyl) phenyl]urea;
25 N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methyl
phenyl)urea;
N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
30 N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-[2-
fluoro-5-
(trifluoromethyl)phenyl]urea;
N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-[3-
(trifluoromethyl)phenyl]urea;
N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-(2-fluoro-
5-
35 methylphenyl)urea;
N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-
chlorophenyl)urea;
N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-
bromophenyl)urea;
40 N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-[4-
fluoro-3-
(trifluoromethyl)phenyl]urea;
N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-(4-fluoro-
3-
methylphenyl)urea;
N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-(3,5-dimethyl phenyl)urea;
N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea;
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N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-(3-m ethylphenyl)urea;
N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-[3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(3-
chlorophenyl)urea;
N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1 H-indazol-4-yl}-2-
fluorophenyl)-N'-(2-fluoro-5-methylphenyl)urea;
N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1 H-indazol-4-yl}phenyl)-N'-
(3-methylphenyl)urea;
N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1 H-indazol-4-yl}phenyl)-N'-
(3-ch lorophenyl)urea;
N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1 H-indazol-4-yl}phenyl)-N'-
(4-fluoro-3-methylphenyl)urea;
N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-
chlorophenyl)urea;
N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-
methylphenyl)urea;
N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-[4-fluoro-
3-
(trifluoromethyl)phenyl]urea;
N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(4-fluoro-
3-
methylphenyl)urea;
N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-chloro-
4-
fluorophenyl)urea;
N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-[3-
(trifluoromethyl)phenyl]urea;
N-{4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(2-fluoro-
5-
methylphenyl)urea;
N-{4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-
methylphenyl)urea;
N-{4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-
chlorophenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)-2-(methoxymethoxy)phenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)-2-hydroxyphenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-
(hydroxymethyl)phenyl]urea;
N-[4-(3-amino-7-thien-3-yI-1 H-indazol-4-yl)phenyl]-N'-[3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-thien-3-yI-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-7-pyridin-4-yI-1 H-indazol-4-yl)phenyl]-N'-(4-fluoro-3-
methylphenyl)urea;
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N-[4-(3-amino-7-pyridin-4-yI-1 H-indazol-4-yl)phenyl]-N'-[3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-pyridin-4-yI-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea;
N-[4-(3-amino-7-pyridin-4-yI-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-7-pyridin-4-yI-1 H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-7-pyridin-4-yI-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea;
N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea;
N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-phenylurea;
N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-[3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-
(trifluoromethyl)phenyl]urea;
N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea;
N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-(4-fluoro-3-
methylphenyl)urea;
N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-chloro-4-
fluorophenyl)urea;
N-[4-(3-amino-7-bromo-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
3-[({[4-(3-amino-1 H-indazol-4-yl)phenyl]amino}carbonyl)amino]-4-fluorobenzoic
acid;
methyl 3-[({[4-(3-amino-1 H-indazol-4-yl)phenyl]amino}carbonyl)amino]-4-
fluorobenzoate;
N-[4-(3-amino-1 H-indazol-6-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1 H-
indazol-7-yl}oxy)ethyl]methanesulfonamide; and
N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-[4-
fluoro-3-(trifluoromethyl)phenyl]urea;
N-[4-(1-acetyl-3-amino-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(4-bromo-3-
methylphenyl)urea;
N-[4-(3-amino-1 -phenyl-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-
methylphenyl)urea;
N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(2-fluoro-
5-
methylphenyl)urea;
N-[4-(3-amino-1 H-indazol-6-yl)phenyl]-N'-phenylurea;
N-[4-(3-amino-1 H-indazol-6-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea;
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N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-thien-3-ylurea; and
N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-cyclopentylurea.
In an embodiment of the invention, the active agent is N-[4-(3-amino-1 H-
indazol-4-
yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea (ABT869) or salts or hydrates or
solvates
thereof.
Compounds of formula (I) or (II) are useful for inhibiting protein tyrosine
kinases. The
solid dispersion product or dosage forms containing the solid dispersion
product of the
invention are used in a method for treating cancer in a patient in recognized
need of
such treatment comprising administering to the patient a therapeutically
acceptable
amount of a compound.
The solid dispersion product is prepared by a process which comprises
a) preparing a liquid mixture containing the at least one active agent, at
least one
pharmaceutically acceptable matrix-forming agent, at least one
pharmaceutically
acceptable surfactant and at least one solvent, and
b) removing the solvent(s) from the liquid mixture to obtain the solid
dispersion
product.
As described above, at least one filler may advantageously be added to the
liquid mix-
ture before removing the solvent(s).
Suitable solvents are those which are capable of dissolving or solubilising
the matrix-
forming agent. Any such solvent may be used, however, pharmaceutically
acceptable
solvents are preferred because traces of solvent may remain in the dried solid
disper-
sion product. Suitably, the solvent may be selected from the group consisting
of alka-
nols, such as methanol, ethanol, isopropanol, n-propanol, isobutanol, n-
butanol; hydro-
carbons, such as pentane, hexane, cyclohexane, methylcyclohexane, toluene,
xylene;
halogenated hydrocarbons, such as dichloromethane, trichloromethane, dichloro-
ethane, chlorobenzene; ketones, such as acetone; esters, such as ethyl
acetate;
ethers, such as dioxane, tetrahydrofurane; and combinations of two or more
thereof.
Ethanol is particularly preferred due to its availability, dissolving power
and pharmaceu-
tical safeness.
The liquid mixture may be prepared by any suitable method of contacting the
essential
ingredients thereof, i. e. the pharmaceutically acceptable matrix-forming
agent, active
agent, the pharmaceutically acceptable surfactant and the solvent or
combination of
solvents. In an embodiment, the liquid mixture is prepared by dissolving the
pharma-
ceutically acceptable matrix-forming agent to obtain a matrix-forming agent
solution,
and adding the active agent and the pharmaceutically acceptable surfactant to
the so-
lution. The dissolved matrix-forming agent may exert an solubility-enhancing
effect on
the active agent; thus, the solubility of the active agent in the matrix-
forming agent solu-
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44
tion may be several times higher than its solubility in the solvent alone.
Preferably, the
active agent is essentially completely dissolved in the liquid mixture.
The liquid mixture has a dry matter content of up to 90 % by weight, for
example 0.5 to
90 % by weight, in most instances 2 to 60 % by weight, relative to the total
weight of
the liquid mixture.
The solvent(s) may be removed by any suitable method known in the art, such as
spray-drying, drum drying, belt drying, tray drying, fluid-bed drying or
combinations of
two or more thereof. For example, the primary solid dispersion powder obtained
by
spray-drying may be further dried by tray drying (optionally under vacuum) or
fluid-bed
drying (optionally under vacuum). In an embodiment, removal of the solvent
comprises
a spray-drying step, optionally in combination with one or more drying steps
other than
spray-drying.
The residual solvent content in the final solid dispersion product is
preferably 5% by
weight or less, more preferably 1 % by weight or less.
In spray-drying, the liquid to be dried is suspended in a gas flow, e. g.,
air, i. e. the liq-
uid is converted into a fog-like mist (atomized), providing a large surface
area. The at-
omized liquid is exposed to a flow of hot gas in a drying chamber. The
moisture evapo-
rates quickly and the solids are recovered as a powder consisting of fine,
hollow
spherical particles. Gas inlet temperatures of up to 250 C or even higher may
be used,
due to the evaporation the gas temperature drops very rapidly to a temperature
of
about 30 to 150 C (outlet temperature of the gas).
The principle of the drum drying process (roller drying) is that a thin film
of material is
applied to the smooth surface of a continuously rotating, heated metal drum.
The film of
dried material is continuously scraped off by a stationary knife located
opposite the
point of application of the liquid material. The dryer consists of a single
drum or a pair
of drums with or without "satellite" rollers. The drum(s) may be located in a
vacuum
chamber. Conveniently, the solvent vapours are collected and the solvent is
recovered
and recycled.
In a belt dryer, the liquid is spread or sprayed onto a belt which passes over
several
heated plates underneath the belt. The material is heated by steam-heated or
electri-
cally heated plates. The evaporation of the solvent can additionally be
fostered by infra-
red radiators or microwave radiators located over the belt. Belt drying may be
carried
out in a vacuum chamber.
In tray drying, the liquid mixture (or a dispersion product that has been pre-
dried by any
other method) is distributed over a number of trays. These are placed in an
oven, usu-
ally in a stream of hot gas, e. g. air. Vacuum may be applied additionally.
The dried solid dispersion product may then be grinded and/or classified
(sieved).
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The dried solid dispersion product may then be filled into capsules or may be
com-
pacted. Compacting means a process whereby a powder mass comprising the solid
dispersion product is densified under high pressure in order to obtain a
compact with
5 low porosity, e.g. a tablet. Compression of the powder mass is usually done
in a tablet
press, more specifically in a steel die between two moving punches.
At least one additive selected from flow regulators, disintegrants, bulking
agents and
lubricants is preferably used in compacting the granules. Disintegrants
promote a rapid
10 disintegration of the compact in the stomach and keep the liberated
granules separate
from one another. Suitable disintegrants are crosslinked polymers such as
crosslinked
polyvinyl pyrrolidone and crosslinked sodium carboxymethyl cellulose. Suitable
bulking
agents are selected from lactose, calcium hydrogen phosphate, microcrystalline
cellu-
lose (Avicel ), magnesium oxide, natural or pre-gelatinized potato or corn
starch, poly-
15 vinyl alcohol.
Suitable flow regulators are selected from highly dispersed silica (Aerosil ),
and animal
or vegetable fats or waxes.
20 A lubricant is preferably used in compacting the granules. Suitable
lubricants are se-
lected from polyethylene glycol (e.g., having a Mw of from 1000 to 6000),
magnesium
and calcium stearates, sodium stearyl fumarate, talc, and the like.
Various other additives may be used, for example dyes such as azo dyes,
organic or
25 inorganic pigments such as aluminium oxide or titanium dioxide, or dyes of
natural ori-
gin; stabilizers such as antioxidants, light stabilizers, radical scavengers,
or stabilizers
against microbial attack.
In order to facilitate the intake of such a dosage form by a mammal, it is
advantageous
30 to give the dosage form an appropriate shape. Large tablets that can be
swallowed
comfortably are therefore preferably elongated rather than round in shape.
A film coat on the tablet further contributes to the ease with which it can be
swallowed.
A film coat also improves taste and provides an elegant appearance. If
desired, the film
35 coat may be an enteric coat. The film coat usually includes a polymeric
film-forming
material such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, and
acrylate
or methacrylate copolymers. Besides a film-forming polymer, the film coat may
further
comprise a plasticizer, e.g. polyethylene glycol, a surfactant, e.g. a Tween
type, and
optionally a pigment, e.g. titanium dioxide or iron oxides. The film-coating
may also
40 comprise talc as anti-adhesive. The film coat usually accounts for less
than about 5 %
by weight of the dosage form.
The following examples will serve to further illustrate the invention without
limiting it.
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46
Example 1: Preparation of Solid Dispersion Products
Solid dispersion products wherein the matrix-forming agent is PVP are prepared
ac-
cording to the following protocol:
(1) Dissolve PVP in ethanol. For PVP K30 prepare a 30 % (w/w) solution, for
PVP
K12 prepare a 50 % (w/w) solution.
(2) Melt surfactants at 60 C in an oven and mix in the ratio indicated.
(3) Weigh PVP solution into amber glass bottle.
(4) Weigh active agent (ABT 869) and add to PVP solution; stir until
dissolved.
(5) Add surfactant and mix. If surfactant solidifies partially, warm again.
(6) If solution is still turbid after one hour, add further ethanol and
homogenize.
Solid dispersion products wherein the matrix-forming agent is hydroxypropyl-R-
cyclodextrin (HP-(3-CD) are prepared according to the following protocol:
(1) Weigh 8.5 g HP-(3-CD and dissolve in 60 g ethanol (anhydrous).
(2) Weigh active agent and dissolve in (1).
(3) Melt surfactant and add to (2).
(4) If surfactant solidifies partially, warm again until a clear solution is
obtained.
Spray drying was performed using a Buchi B-191 lab scale spray dryer. The
equipment
was pre-heated before the spray cycle was started. After spraying a final
drying was
conducted for 10-20 minutes before the cooling cycle was initiated. For
atomization of
the liquid a two-component nozzle (liquid plus air for atomization) has been
used.
Protocol for the oral bioavailability studies
For bioavailability evaluation, solid dispersion powder as obtained in example
were
screened and filled into capsules or compressed to tablets.
The studies were run in a randomized cross-over study design.
Dogs (beagle dogs, mixed sexes, weighing approximately 10 kg) received a
balanced
diet with 27 % fat and were permitted water ad libitum (non-fasted) or were
left without
diet overnight and water ad libitum (fasted). Each dog received a 100 g/kg
subcuta-
neous dose of histamine approximately 30 minutes prior to dosing. A single
dose of
ABT 869 was administered to each dog. The dose was followed by approximately
10
milliliters of water. Blood samples were obtained from each animal prior to
dosing and
0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 9, 12 and 24 hours after drug administration.
The plasma
was separated from the red cells by centrifugation and frozen (-30 C) until
analysis.
Concentrations of active ingredient were determined by reverse phase HPLC with
low
wavelength UV detection following liquid-liquid extraction of the plasma
samples. The
area under the curve (AUC) was calculated by the trapezoidal method over the
time
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47
course of the study. Each dosage form was evaluated in a group containing 3-6
dogs;
the values reported are averages for each group of dogs.
Following the procedures above, an ABT 869 solid dispersion product having the
fol-
lowing composition was prepared: 6% ABT-869: 54.8% K30: 23.4% Gelucire 44/14:
15.6% Vitamin E TPGS.
Bioavailability was tested as described above with 20 mg/dog. The studies were
run
with liquid clinical formulation as reference (4.0 % by weight ABT 869 in
ethanol-
surfactant solution) in a crossover study design. Each dosage form was
evaluated in a
group containing 5 dogs; the values reported are averages for each group of
dogs.
Cmax Tmax t112 AUCo-00 Cmax AUC
(pg/ml) (hr) (hr) (pg=hr/ml) Pt. est. Pt. est.
Clinical 0.35 1.2 0.7 0.62
Reference
Solid Dis- 0.42 0.9 0.8 0.74 1.07 1.04
persion
Example 2:
Following the procedures of Example 1 above, a liquid mixture is prepared,
containing
56.13 % by weight of ethanol, 15.36 % of PVP K30, 3.56 % of Gelucire 44/14,
1.92 %
of Vitamin E TPGS, 21.94 % of maltitol and 1.10 % of ABT-869.
The liquid mixture is fed to a twin-drum dryer. This dryer comprises a pair of
drums
which are rotated in the opposite direction to each other. The drums are
heated to a
temperature of about 60 C by circulating thermal oil. The space between the
drums
forms a liquid pool into which the liquid mixture is introduced. The liquid
mixture is be-
ing spread on the circumferential faces of the respective drums; the
adjustable gap
between the two drums acts as a means to control the film thickness. After
travelling
part of a revolution, the dried material is removed in the form of thin sheets
by scraper
knifes.
The drying drums are positioned in a vacuum chamber which is maintained at a
pres-
sure of 50mbar (absolute pressure). The ethanol vapours are drawn off and con-
densed.
