U.S. patent application number 12/638018 was filed with the patent office on 2010-07-22 for combination of aurora kinase inhibitors and anti-cd20 antibodies.
This patent application is currently assigned to Millennium Pharmaceuticals, Inc.. Invention is credited to Mark Manfredi.
Application Number | 20100183601 12/638018 |
Document ID | / |
Family ID | 41664630 |
Filed Date | 2010-07-22 |
United States Patent
Application |
20100183601 |
Kind Code |
A1 |
Manfredi; Mark |
July 22, 2010 |
Combination of Aurora Kinase Inhibitors and Anti-CD20
Antibodies
Abstract
The present invention relates to methods for the treatment of
hematological malignancies. In particular, the invention provides
methods for treatment of hematological malignancies by
administering Aurora kinase inhibitors in combination with
anti-CD20 antibodies.
Inventors: |
Manfredi; Mark; (Newton,
MA) |
Correspondence
Address: |
MILLENNIUM PHARMACEUTICALS, INC.
40 Landsdowne Street
CAMBRIDGE
MA
02139
US
|
Assignee: |
Millennium Pharmaceuticals,
Inc.
Cambridge
MA
|
Family ID: |
41664630 |
Appl. No.: |
12/638018 |
Filed: |
December 15, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61203509 |
Dec 22, 2008 |
|
|
|
Current U.S.
Class: |
424/133.1 ;
424/158.1 |
Current CPC
Class: |
A61K 39/395 20130101;
A61K 39/3955 20130101; A61P 35/00 20180101; A61K 39/395 20130101;
A61K 31/55 20130101; C07K 16/2887 20130101; A61K 39/00 20130101;
A61P 35/02 20180101; A61K 45/06 20130101; C07K 2317/24 20130101;
A61K 31/55 20130101; A61K 2300/00 20130101; A61K 2039/505 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
424/133.1 ;
424/158.1 |
International
Class: |
A61K 39/395 20060101
A61K039/395; A61P 35/00 20060101 A61P035/00; A61P 35/02 20060101
A61P035/02 |
Claims
1. A method of treating a patient suffering from a hematological
malignancy, comprising administering to the subject a
therapeutically effective amount of an Aurora kinase inhibitor
simultaneously with or consecutively with an anti-CD20
antibody.
2. The method of claim 1, wherein the hematological malignancy is
selected from the group consisting of lymphoma, leukemia and
multiple myeloma.
3. The method of claim 2, wherein the lymphoma is selected from the
group consisting of B-cell lymphoma, Non-Hodgkin's lymphoma and
mantle cell lymphoma.
4. The method of claim 1, wherein the anti-CD20 antibody is
rituximab.
5. The method of claim 4, wherein the patient was treated
previously with an anti-CD20 antibody.
6. The method of claim 1, wherein the Aurora kinase inhibitor is an
Aurora A kinase specific inhibitor.
7. The method of claim 6, wherein the Aurora A kinase specific
inhibitor is characterized by formula (I): ##STR00004## or a
pharmaceutically acceptable salt thereof; wherein: Ring A is a
substituted or unsubstituted 5- or 6-membered aryl, heteroaryl,
cycloaliphatic, or heterocyclyl ring; Ring B is a substituted or
unsubstituted aryl, heteroaryl, cycloaliphatic, or heterocyclyl
ring; Ring C is a substituted or unsubstituted aryl, heteroaryl,
heterocyclyl, or cycloaliphatic ring; R.sup.e is hydrogen,
--OR.sup.5, --N(R.sup.4).sub.2, --SR.sup.5, or a C.sub.1-3
aliphatic optionally substituted with R.sup.3 or R.sup.7; each of
R.sup.x and R.sup.y independently is hydrogen, fluoro, or an
optionally substituted C.sub.1-6 aliphatic; or R.sup.x and R.sup.y,
taken together with the carbon atom to which they are attached,
form an optionally substituted 3- to 6-membered cycloaliphatic
ring; each R.sup.3 independently is selected from the group
consisting of -halo, --OH, --O(C.sub.1-3 alkyl), --CN,
--N(R.sup.4).sub.2, --C(O)(C.sub.1-3 alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-3 alkyl), --C(O)NH.sub.2, and --C(O)NH(C.sub.1-3
alkyl); each R.sup.4 independently is hydrogen or an optionally
substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or
two R.sup.4 on the same nitrogen atom, taken together with the
nitrogen atom, form an optionally substituted 5- to 6-membered
heteroaryl or 4- to 8-membered heterocyclyl ring having, in
addition to the nitrogen atom, 0-2 ring heteroatoms selected from
N, O, and S; each R.sup.5 independently is hydrogen or an
optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl
group; and each R.sup.7 independently is an optionally substituted
aryl, heterocyclyl, or heteroaryl group.
8. The method of claim 6, wherein the Aurora A kinase specific
inhibitor is characterized by formula (III): ##STR00005## or a
pharmaceutically acceptable salt thereof; wherein: R.sup.a is
selected from the group consisting of C.sub.1-3 aliphatic,
C.sub.1-3 fluoroaliphatic, --R.sup.2, and -T-R.sup.2; T is a
C.sub.1-3 alkylene chain optionally substituted with fluoro;
R.sup.1 is an optionally substituted aryl, heteroaryl, or
heterocyclyl group; R.sup.2 is selected from the group consisting
of halo, --C.dbd.C--R.sup.3, --CH.dbd.CH--R.sup.3,
--N(R.sup.4).sub.2, and --OR.sup.5; R.sup.3 is hydrogen or an
optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl
group; each R.sup.4 independently is hydrogen or an optionally
substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or
two R.sup.4 on the same nitrogen atom, taken together with the
nitrogen atom form an optionally substituted 5- to 6-membered
heteroaryl or 4- to 8-membered heterocyclyl ring having, in
addition to the nitrogen atom, 0-2 ring heteroatoms selected from
N, O, and S; R.sup.5 is hydrogen or an optionally substituted
aliphatic, aryl, heteroaryl, or heterocyclyl group; and R.sup.b is
selected from the group consisting of fluoro, chloro, --CH.sub.S,
--CF.sub.3, --OH, --OCH.sub.3, --OCF.sub.3, --OCH.sub.2CH.sub.3,
and --OCH.sub.2CF.sub.3.
9. The method of claim 6, wherein the Aurora A kinase specific
inhibitor is
4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzaze-
pin-2-yl]amino}-2-methoxybenzoic acid.
Description
RELATED APPLICATIONS
[0001] The present application claims the benefit of U.S.
Provisional Application Ser. No. 61/203,509, filed Dec. 22, 2008
(pending), the contents of which are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] This invention relates to methods for the treatment of
hematological malignancies. In particular, the invention provides
methods for treatment of hematological malignancies by
administering Aurora kinase inhibitors in combination with
anti-CD20 antibodies.
BACKGROUND OF THE INVENTION
[0003] According to the American Cancer Society, an estimated 1.4
million Americans were newly-diagnosed with cancer in 2004 and
about 560,000 victims died from the disease. While medical advance
have improved cancer survival rates, there is a continuing need for
new and more effective treatment.
[0004] Cancer is characterized by uncontrolled cell reproduction.
Mitosis is a stage in the cell cycle during which a series of
complex events ensure the fidelity of chromosome separation into
two daughter cells. Several current cancer therapies, including the
taxanes and vinca alkaloids, act to inhibit the mitotic machinery.
Mitotic progression is largely regulated by proteolysis and by
phosphorylation events that are mediated by mitotic kinases. Aurora
kinase family members (e.g., Aurora A, Aurora B, Aurora C) regulate
mitotic progression through modulation of centrosome separation,
spindle dynamics, spindle assembly checkpoint, chromosome
alignment/segregation, and cytokinesis (Dutertre et al., Oncogene,
21: 6175 (2002); Berdnik et al., Curr. Biol., 12: 640 (2002)).
Overexpression and/or amplification of Aurora kinases have been
linked to oncogenesis in several tumor types including those of
colon and breast (Warner et al., Mol. Cancer. Ther., 2: 589 (2003);
Bischoff et al., EMBO, 17: 3062 (1998); Sen et al., Cancer Res.,
94: 1320 (2002)). Moreover, Aurora kinase inhibition in tumor cells
results in mitotic arrest and apoptosis, suggesting that these
kinases are important targets for cancer therapy (Manfredi et al.,
PNAS., 104: 4106 (2007); Ditchfield, J. Cell Biol., 161: 267
(2003); Harrington et al., Nature Med., 1 (2004)). Given the
central role of mitosis in the progression of virtually all
malignancies, inhibitors of the Aurora kinases are expected to have
application across a broad range of human tumors.
[0005] CD20 (also known as Bp35) is a B-lymphocyte-restricted
differentiation antigen that is expressed during early pre-B-cell
development and remains until plasma cell differentiation. CD20 is
a useful target for B-cell lymphomas as this antigen is expressed
at very high densities on the surface of malignant B-cells, i.e.,
B-cells wherein unabated proliferation can lead to B-cell
lymphomas. The Food and Drug Administration has approved the
therapeutic use of an anti-CD20 antibody, rituximab (RITUXAN.RTM.),
for use in relapsed and previously treated low-grade non-Hodgkin's
lymphoma (NHL). Rituximab acts by binding to the CD20 antigen on B
cells which results in the lysis of the B cell by a mechanism
thought to involve complement-dependent cytotoxicity (CDC) and
antibody-dependent cell mediated cytotoxicity (ADCC).
[0006] However, while anti-CD20 antibodies and, in particular,
rituximab, have been reported to be effective for treatment of
B-cell lymphomas, such as non-Hodgkin's lymphoma, the treated
patients are often subject to disease relapse. Therefore, it would
be beneficial if more effective treatment regimens could be
developed. Combined treatment regimens could be helpful for
patients suffering from B cell related tumors or other
hematological malignancies, and might potentially even decrease the
rate of relapse or overcome the resistance to a particular
anticancer agent sometime seen in these patients. Additionally,
combinations of anticancer agents may have additive, or even
synergistic, therapeutic effects.
[0007] There is thus a need for new cancer treatment regimens,
including combination therapies.
DESCRIPTION OF THE INVENTION
[0008] The present invention provides new combination therapies for
the treatment of hematological malignancies. In particular, the
present invention provides a method to treat a patient suffering
from a hematological malignancy comprising administering to said
patient a therapeutically effective amount of a Aurora kinase
inhibitor simultaneously with or consecutively with (e.g., before
or after) an anti-CD20 antibody.
[0009] Terms used herein shall be accorded the following defined
meanings, unless otherwise indicated.
[0010] As used herein, the term "Aurora kinase" refers to any one
of a family of related serine/threonine kinases involved in mitotic
progression. A variety of cellular proteins that play a role in
cell division are substrates for phosphorylation by Aurora kinase
enzymes, including, without limitation, histone H3, p53, CENP-A,
myosin II regulatory light chain, protein phosphatase-1, TPX-2,
INCENP, survivin, topoisomerase II alpha, vimentin, MBD-3,
MgcRacGAP, desmin, Ajuba, XIEg5 (in Xenopus), Ndc10p (in budding
yeast), and D-TACC (in Drosophila). Aurora kinase enzymes also are
themselves substrates for autophosphorylation, e.g., at Thr288.
Unless otherwise indicated by context, the term "Aurora kinase" is
meant to refer to any Aurora kinase protein from any species,
including, without limitation, Aurora A, Aurora B, and Aurora C,
preferably Aurora A or B. Preferably, the Aurora kinase is a human
Aurora kinase.
[0011] The term "Aurora kinase inhibitor" or "inhibitor of Aurora
kinase" is used to signify a compound which is capable of
interacting with an Aurora kinase and inhibiting its enzymatic
activity. Inhibiting Aurora kinase enzymatic activity means
reducing the ability of an Aurora kinase to phosphorylate a
substrate peptide or protein. In various embodiments, such
reduction of Aurora kinase activity is at least about 50%, at least
about 75%, at least about 90%, at least about 95%, or at least
about 99%. In various embodiments, the concentration of Aurora
kinase inhibitor required to reduce an Aurora kinase enzymatic
activity is less than about 1 .mu.M, less than about 500 nM, less
than about 100 nM, or less than about 50 nM.
[0012] In some embodiments, such inhibition is selective, i.e., the
Aurora kinase inhibitor reduces the ability of an Aurora kinase to
phosphorylate a substrate peptide or protein at a concentration
that is lower than the concentration of the inhibitor that is
required to produce another, unrelated biological effect, e.g.,
reduction of the enzymatic activity of a different kinase. In some
embodiments, the Aurora kinase inhibitor also reduces the enzymatic
activity of another kinase, preferably one that is implicated in
cancer.
[0013] The term "about" is used herein to mean approximately, in
the region of, roughly, or around. When the term "about" is used in
conjunction with a numerical range, it modifies that range by
extending the boundaries above and below the numerical values set
forth. In general, the term "about" is used herein to modify a
numerical value above and below the stated value by a variance of
10%.
[0014] As used herein, the term "comprises" means "includes, but is
not limited to."
[0015] A "CD20" antigen is a 35 kDa, non-glycosylated
phosphoprotein found on the surface of greater than 90% of B cells
from peripheral blood or lymphoid organs. CD20 is expressed during
early pre-B cell development and remains until plasma cell
differentiation. CD20 is present on both normal B cells as well as
malignant B cells. Other names for CD20 in the literature include
"B-lymphocyte-restricted antigen" and "Bp35".
[0016] The CD20 antigen is described in, e.g., Clark et al. PNAS
(USA) 82:1766 (1985).
[0017] The term "antibody" herein is used in the broadest sense and
specifically covers intact monoclonal antibodies, polyclonal
antibodies, humanized antibodies, human antibodies, chimeric
antibodies, multispecific antibodies (e.g., bispecific antibodies)
formed from at least two intact antibodies, and antibody fragments,
so long as they exhibit the desired biological activity. Antibodies
may be produced by one of skill in the art using conventional
methods.
[0018] The term "monoclonal antibody" as used herein refers to an
antibody obtained from a population of substantially homogeneous
antibodies, i.e., the individual antibodies comprising the
population are identical except for possible naturally occurring
mutations that may be present in minor amounts. Monoclonal
antibodies are highly specific, being directed against a single
antigenic site. Furthermore, in contrast to conventional
(polyclonal) antibody preparations, which typically include
different antibodies directed against different determinants
(epitopes), each monoclonal antibody is directed against a single
determinant on the antigen. In addition to their specificity, the
monoclonal antibodies are advantageous in that they are synthesized
by the hybridoma culture, uncontaminated by other immunoglobulins.
The modifier "monoclonal" indicates the character of the antibody
as being obtained from a substantially homogeneous population of
antibodies, and is not to be construed as requiring production of
the antibody by any particular method. For example, the monoclonal
antibodies to be used in accordance with the present invention may
be made by the hybridoma method first described by Kohler et al.,
Nature, 256:495 (1975), or may be made by recombinant DNA methods
(see, e.g., U.S. Pat. No. 4,816,567). The "monoclonal antibodies"
may also be isolated from phage antibody libraries using the
techniques described in Clackson et al., Nature, 352:624-628 (1991)
and Marks et al, J. Mol. Biol., 222:581-597 (1991), for example.
The monoclonal antibodies herein specifically include but are not
limited to "chimeric" or "humanized" forms.
[0019] The term "aliphatic" or "aliphatic group", as used herein,
means a substituted or unsubstituted straight-chain, branched or
cyclic C.sub.1-12 hydrocarbon, which is completely saturated or
which contains one or more units of unsaturation, but which is not
aromatic. For example, suitable aliphatic groups include
substituted or unsubstituted linear, branched or cyclic alkyl,
alkenyl, alkynyl groups and hybrids thereof, such as
(cylcoalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
[0020] The terms "alkyl", "alkenyl", and "alkynyl", used alone or
as part of a larger moiety, refer to a straight and branched chain
aliphatic group having from 1 to 12 carbon atoms. For purposes of
the present invention, the term "alkyl" will be used when the
carbon atom attaching the aliphatic group to the rest of the
molecule is a saturated carbon atom. However, an alkyl group may
include unsaturation at other carbon atoms. Thus, alkyl groups
include, without limitation, methyl, ethyl, propyl, allyl,
propargyl, butyl, pentyl, and hexyl.
[0021] For purposes of the present invention, the term "alkenyl"
will be used when the carbon atom attaching the aliphatic group to
the rest of the molecule forms part of a carbon-carbon double bond.
Alkenyl groups include, without limitation, vinyl, 1-propenyl,
1-butenyl, 1-pentenyl, and 1-hexenyl.
[0022] For purposes of the present invention, the term "alkynyl"
will be used when the carbon atom attaching the aliphatic group to
the rest of the molecule forms part of a carbon-carbon triple bond.
Alkynyl groups include, without limitation, ethynyl, 1-propynyl,
1-butynyl, 1-pentynyl, and 1-hexynyl.
[0023] The term "cycloaliphatic", used alone or as part of a larger
moiety, refers to a saturated or partially unsaturated cyclic
aliphatic ring system having from 3 to about 14 members, wherein
the aliphatic ring system is optionally substituted. In some
embodiments, the cycloaliphatic is a monocyclic hydrocarbon having
3-8 or 3-6 ring carbon atoms. Nonlimiting examples include
cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,
cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl,
and cyclooctadienyl. In some embodiments, the cycloaliphatic is a
bridged or fused bicyclic hydrocarbon having 6-12, 6-10, or 6-8
ring carbon atoms, wherein any individual ring in the bicyclic ring
system has 3-8 members.
[0024] In some embodiments, two adjacent substituents on the
cycloaliphatic ring, taken together with the intervening ring
atoms, form an optionally substituted fused 5- to 6-membered
aromatic or 3- to 8-membered non-aromatic ring having 0-3 ring
heteroatoms selected from the group consisting of O, N, and S.
Thus, the term "cycloaliphatic" includes aliphatic rings that are
fused to one or more aryl, heteroaryl, or heterocyclyl rings.
Nonlimiting examples include indanyl,
5,6,7,8-tetrahydroquinoxalinyl, decahydronaphthyl, or
tetrahydronaphthyl, where the radical or point of attachment is on
the aliphatic ring. The term "cycloaliphatic" may be used
interchangeably with the terms "carbocycle", "carbocyclyl",
"carbocyclo", or "carbocyclic".
[0025] The terms "aryl" and "ar-", used alone or as part of a
larger moiety, e.g., "aralkyl", "aralkoxy", or "aryloxyalkyl",
refer to a C6 to C14 aromatic hydrocarbon, comprising one to three
rings, each of which is optionally substituted. Preferably, the
aryl group is a C.sub.6-10 aryl group. Aryl groups include, without
limitation, phenyl, naphthyl, and anthracenyl. In some embodiments,
two adjacent substituents on the aryl ring, taken together with the
intervening ring atoms, form an optionally substituted fused 5- to
6-membered aromatic or 4- to 8-membered non-aromatic ring having
0-3 ring heteroatoms selected from the group consisting of O, N,
and S. Thus, the term "aryl", as used herein, includes groups in
which an aromatic ring is fused to one or more heteroaryl,
cycloaliphatic, or heterocyclyl rings, where the radical or point
of attachment is on the aromatic ring. Nonlimiting examples of such
fused ring systems include indolyl, isoindolyl, benzothienyl,
benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,
benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl,
phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, fluorenyl, indanyl, phenanthridinyl,
tetrahydronaphthyl, indolinyl, phenoxazinyl, benzodioxanyl, and
benzodioxolyl. An aryl group may be mono-, bi-, tri-, or
polycyclic, preferably mono-, bi-, or tricyclic, more preferably
mono- or bicyclic. The term "aryl" may be used interchangeably with
the terms "aryl group", "aryl moiety", and "aryl ring".
[0026] An "aralkyl" or "arylalkyl" group comprises an aryl group
covalently attached to an alkyl group, either of which
independently is optionally substituted. Preferably, the aralkyl
group is C.sub.6-10 aryl(C.sub.1-6)alkyl, C.sub.6-10
aryl(C.sub.1-4)alkyl, or C.sub.6-10 aryl(C.sub.1-3)alkyl,
including, without limitation, benzyl, phenethyl, and
naphthylmethyl.
[0027] The terms "heteroaryl" and "heteroar-", used alone or as
part of a larger moiety, e.g., heteroaralkyl, or "heteroaralkoxy",
refer to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or
10 ring atoms; having 6, 10, or 14 .pi. electrons shared in a
cyclic array; and having, in addition to carbon atoms, from one to
four heteroatoms. The term "heteroatom" refers to nitrogen, oxygen,
or sulfur, and includes any oxidized form of nitrogen or sulfur,
and any quaternized form of a basic nitrogen. Heteroaryl groups
include, without limitation, thienyl, furanyl, pyrrolyl,
imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,
naphthyridinyl, and pteridinyl. In some embodiments, two adjacent
substituents on the heteroaryl, taken together with the intervening
ring atoms, form an optionally substituted fused 5- to 6-membered
aromatic or 4- to 8-membered non-aromatic ring having 0-3 ring
heteroatoms selected from the group consisting of O, N, and S.
Thus, the terms "heteroaryl" and "heteroar-", as used herein, also
include groups in which a heteroaromatic ring is fused to one or
more aryl, cycloaliphatic, or heterocyclyl rings, where the radical
or point of attachment is on the heteroaromatic ring. Nonlimiting
examples include indolyl, isoindolyl, benzothienyl, benzofuranyl,
dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl,
isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,
phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and
pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be
mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or
tricyclic, more preferably mono- or bicyclic. The term "heteroaryl"
may be used interchangeably with the terms "heteroaryl ring",
"heteroaryl group", or "heteroaromatic", any of which terms include
rings that are optionally substituted. The term "heteroaralkyl"
refers to an alkyl group substituted by a heteroaryl, wherein the
alkyl and heteroaryl portions independently are optionally
substituted.
[0028] As used herein, the terms "heterocycle", "heterocyclyl",
"heterocyclic radical", and "heterocyclic ring" are used
interchangeably and refer to a stable 3- to 7-membered monocyclic,
or to a fused 7- to 10-membered or bridged 6- to 10-membered
bicyclic heterocyclic moiety that is either saturated or partially
unsaturated, and having, in addition to carbon atoms, one or more,
preferably one to four, heteroatoms, as defined above. When used in
reference to a ring atom of a heterocycle, the term "nitrogen"
includes a substituted nitrogen. As an example, in a heterocyclyl
ring having 1-3 heteroatoms selected from oxygen, sulfur or
nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH
(as in pyrrolidinyl) or .sup.+NR (as in N-substituted
pyrrolidinyl). A heterocyclic ring can be attached to its pendant
group at any heteroatom or carbon atom that results in a stable
structure, and any of the ring atoms can be optionally substituted.
Examples of such saturated or partially unsaturated heterocyclic
radicals include, without limitation, tetrahydrofuranyl,
tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl,
pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl,
dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and
quinuclidinyl.
[0029] In some embodiments, two adjacent substituents on a
heterocyclic ring, taken together with the intervening ring atoms,
for an optionally substituted fused 5- to 6-membered aromatic or 3-
to 8-membered non-aromatic ring having 0-3 ring heteroatoms
selected from the group consisting of O, N, and S. Thus, the terms
"heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic
group", "heterocyclic moiety", and "heterocyclic radical", are used
interchangeably herein, and include groups in which a heterocyclyl
ring is fused to one or more aryl, heteroaryl, or cycloaliphatic
rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl,
or tetrahydroquinolinyl, where the radical or point of attachment
is on the heterocyclyl ring. A heterocyclyl group may be mono-,
bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more
preferably mono- or bicyclic. The term "heterocyclylalkyl" refers
to an alkyl group substituted by a heterocyclyl, wherein the alkyl
and heterocyclyl portions independently are optionally
substituted.
[0030] As used herein, the term "partially unsaturated" refers to a
ring moiety that includes at least one double or triple bond
between ring atoms. The term "partially unsaturated" is intended to
encompass rings having multiple sites of unsaturation, but is not
intended to include aryl or heteroaryl moieties, as herein
defined.
[0031] The terms "haloaliphatic", "haloalkyl", "haloalkenyl" and
"haloalkoxy" refer to an aliphatic, alkyl, alkenyl or alkoxy group,
as the case may be, which is substituted with one or more halogen
atoms. As used herein, the term "halogen" or "halo" means F, Cl,
Br, or I. The term "fluoroaliphatic" refers to a haloaliphatic
wherein the halogen is fluoro.
[0032] The term "alkylene" refers to a bivalent alkyl group. An
"alkylene chain" is a polymethylene group, i.e.,
--(CH.sub.2).sub.n--, wherein n is a positive integer, preferably
from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
A substituted alkylene chain is a polymethylene group in which one
or more methylene hydrogen atoms is replaced with a substituent.
Suitable substituents include those described below for a
substituted aliphatic group. An alkylene chain also may be
substituted at one or more positions with an aliphatic group or a
substituted aliphatic group.
[0033] The term "substituted", as used herein, means that a
hydrogen radical of the designated moiety is replaced with the
radical of a specified substituent, provided that the substitution
results in a stable or chemically feasible compound. The phrase
"one or more substituents", as used herein, refers to a number of
substituents that equals from one to the maximum number of
substituents possible based on the number of available bonding
sites, provided that the above conditions of stability and chemical
feasibility are met. Unless otherwise indicated, an optionally
substituted group may have a substituent at each substitutable
position of the group, and the substituents may be either the same
or different.
[0034] An aryl (including the aryl moiety in aralkyl, aralkoxy,
aryloxyalkyl and the like) or heteroaryl (including the heteroaryl
moiety in heteroaralkyl and heteroaralkoxy and the like) group may
contain one or more substituents. Examples of suitable substituents
on the unsaturated carbon atom of an aryl or heteroaryl group
include -halo, --NO.sub.2, --CN, --R*, --C(R*).dbd.C(R*).sub.2,
--C.ident.C--R*, --OR*, --SR.sup.o, --S(O)R.sup.o,
--SO.sub.2R.sup.o, --SO.sub.3R.sup.o, --SO.sub.2N(R.sup.+).sub.2,
--N(R.sup.+).sub.2, --NR.sup.+C(O)R*,
--NR.sup.+C(O)N(R.sup.+).sub.2, --NR.sup.+CO.sub.2R.sup.o,
--O--CO.sub.2R*, --OC(O)N(R.sup.+).sub.2, --O--C(O)R*,
--CO.sub.2R*, --C(O)--C(O)R*, --C(O)R*, --C(O)N(R.sup.+).sub.2,
--C(O)N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+).sub.2,
--N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+)--C(O)R*,
--C(.dbd.NR.sup.+)--N(R.sup.+).sub.2, --C(.dbd.NR.sup.+)--OR*,
--N(R.sup.+)--N(R.sup.+).sub.2,
--N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+).sub.2,
--NR.sup.+SO.sub.2R.sup.o, --NR.sup.+SO.sub.2N(R.sup.+).sub.2,
--P(O)(R*).sub.2, --P(O)(OR*).sub.2, --O--P(O)--OR*, and
--P(O)(NR.sup.+)--N(R.sup.+).sub.2; or two adjacent substituents,
taken together with their intervening atoms, form a 5-6 membered
unsaturated or partially unsaturated ring having 0-3 ring atoms
selected from the group consisting of N, O, and S.
[0035] An aryl (including the aryl moiety in aralkyl, aralkoxy,
aryloxyalkyl and the like) or heteroaryl (including the heteroaryl
moiety in heteroaralkyl and heteroaralkoxy and the like) group may
contain one or more substituents. Examples of suitable substituents
on the unsaturated carbon atom of an aryl or heteroaryl group
include -halo, --NO.sub.2, --CN, --R*, --C(R*).dbd.C(R*).sub.2,
--C.ident.C--R*, --OR*, --SR.sup.o, --S(O)R.sup.o,
--SO.sub.2R.sup.o, --SO.sub.3R.sup.o, --SO.sub.2N(R.sup.+).sub.2,
--N(R.sup.+).sub.2, --NR.sup.+C(O)R*,
--NR.sup.+C(O)N(R.sup.+).sub.2, --NR.sup.+CO.sub.2R.sup.o,
--O--CO.sub.2R*, --OC(O)N(R.sup.+).sub.2, --O--C(O)R*,
--CO.sub.2R*, --C(O)--C(O)R*, --C(O)R*, --C(O)N(R.sup.+).sub.2,
--C(O)N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+).sub.2,
--N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+)--C(O)R*,
--C(.dbd.NR.sup.+)--N(R.sup.+).sub.2, --C(.dbd.NR.sup.+)--OR*,
--N(R.sup.+)--N(R.sup.+).sub.2,
--N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+).sub.2,
--NR.sup.+SO.sub.2R.sup.o, --NR.sup.+SO.sub.2N(R.sup.+).sub.2,
--P(O)(R.sup.+).sub.2, --P(O)(OR*).sub.2, --O--P(O)--OR*, and
--P(O)(NR.sup.+)--N(R.sup.+).sub.2; or two adjacent substituents,
taken together with their intervening atoms, form a 5-6 membered
unsaturated or partially unsaturated ring having 0-3 ring atoms
selected from the group consisting of N, O, and S.
[0036] Each R.sup.+, independently, is hydrogen or an optionally
substituted aliphatic, aryl, heteroaryl, or heterocyclyl group, or
two R.sup.+ on the same nitrogen atom, taken together with the
nitrogen atom, form a 5-8 membered aromatic or non-aromatic ring
having, in addition to the nitrogen atom, 0-2 ring heteroatoms
selected from N, O, and S. Each R* independently is hydrogen or an
optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl
group. Each R.sup.o is an optionally substituted aliphatic or aryl
group.
[0037] An aliphatic group or a non-aromatic heterocyclic ring may
be substituted with one or more substituents. Examples of suitable
substituents on the saturated carbon of an aliphatic group or of a
non-aromatic heterocyclic ring include, without limitation, those
listed above for the unsaturated carbon of an aryl or heteroaryl
group and the following: .dbd.O, .dbd.S, .dbd.C(R*).sub.2,
.dbd.N--N(R*).sub.2, .dbd.N--OR*, .dbd.N--NHC(O)R*,
.dbd.N--NHCO.sub.2R.sup.o, .dbd.N--NHSO.sub.2R.sup.o, or
.dbd.N--R*, where each R* and R.sup.o is as defined above.
[0038] Suitable substituents on the nitrogen atom of a non-aromatic
heterocyclic ring include --R*, --N(R*).sub.2, --C(O)R*,
--CO.sub.2R*, --C(O)--C(O)R*--C(O)CH.sub.2C(O)R*, --SO.sub.2R*,
--SO.sub.2N(R*).sub.2, --C(.dbd.S)N(R.sup.+).sub.2,
--C(.dbd.O--NH)--N(R*).sub.2, and --NR*SO.sub.2R*; wherein each R*
is as defined above.
[0039] Unless otherwise stated, structures depicted herein are
meant to include compounds which differ only in the presence of one
or more isotopically enriched atoms. For example, compounds having
the present structure except for the replacement of a hydrogen atom
by a deuterium or tritium, or the replacement of a carbon atom by a
.sup.13C- or .sup.14C-enriched carbon are within the scope of the
invention.
[0040] It will be apparent to one skilled in the art that certain
compounds described herein may exist in tautomeric forms, all such
tautomeric forms of the compounds being within the scope of the
invention. Unless otherwise stated, structures depicted herein are
also meant to include all stereochemical forms of the structure;
i.e., the R and S configurations for each asymmetric center.
Therefore, single stereochemical isomers as well as enantiomeric
and diastereomeric mixtures of the present compounds are within the
scope of the invention.
[0041] Any compound capable of inhibiting the enzymatic activity of
an Aurora kinase may be used in the methods of the instant
invention. In particular, Aurora kinase inhibitors include the
compounds described herein, as well as compounds disclosed in, for
example, WO 05/111039, US2005/0256102, US2007/0185087, WO
08/021,038, US2008/0045501, WO 08/063,525, US2008/0167292, WO
07/113,212, EP1644376, US2005/0032839, WO 05/005427, WO 06/070192,
WO 06/070198, WO 06/070202, WO 06/070195, WO 06/003440, WO
05/002576, WO 05/002552, WO 04/071507, WO 04/058781, WO 06/055528,
WO 06/055561, WO 05/118544, WO 05/013996, WO 06/036266,
US2006/0160874, US2007/0142368, WO 04/043953, WO 07/132,220, WO
07/132,221, WO 07/132,228, WO 04/00833 and WO 07/056,164, each of
which is hereby incorporated by reference in its entirety. Also
suitable for use in the methods of the invention are solvated and
hydrated forms of any of these compounds. Also suitable for use in
the methods of the invention are pharmaceutically acceptable salts
of any of the compounds, and solvated and hydrated forms of such
salts. These Aurora kinase inhibitors can be prepared in a number
of ways well known to one skilled in the art of organic synthesis,
including, but not limited to, the methods of synthesis described
in detail in the above references.
[0042] In some embodiments, the Aurora kinase inhibitor is a
compound represented by formula (I):
##STR00001##
[0043] or a pharmaceutically acceptable salt thereof;
[0044] wherein: [0045] Ring A is a substituted or unsubstituted 5-
or 6-membered aryl, heteroaryl, cycloaliphatic, or heterocyclyl
ring; [0046] Ring B is a substituted or unsubstituted aryl,
heteroaryl, cycloaliphatic, or heterocyclyl ring; [0047] Ring C is
a substituted or unsubstituted aryl, heteroaryl, heterocyclyl, or
cycloaliphatic ring; [0048] R.sup.e is hydrogen, --OR.sup.5,
--N(R.sup.4).sub.2, --SR.sup.5, or a C.sub.1-3 aliphatic optionally
substituted with R.sup.3 or R.sup.7; [0049] each of R.sup.x and
R.sup.y independently is hydrogen, fluoro, or an optionally
substituted C.sub.1-6 aliphatic; or R.sup.x and R.sup.y, taken
together with the carbon atom to which they are attached, form an
optionally substituted 3- to 6-membered cycloaliphatic ring; [0050]
each R.sup.3 independently is selected from the group consisting of
-halo, --OH, --O(C.sub.1-3 alkyl), --CN, --N(R.sup.4).sub.2,
--C(O)(C.sub.1-3 alkyl), --CO.sub.2H, --CO.sub.2(C.sub.1-3 alkyl),
--C(O)NH.sub.2, and --C(O)NH(C.sub.1-3 alkyl); [0051] each R.sup.4
independently is hydrogen or an optionally substituted aliphatic,
aryl, heteroaryl, or heterocyclyl group; or two R.sup.4 on the same
nitrogen atom, taken together with the nitrogen atom, form an
optionally substituted 5- to 6-membered heteroaryl or 4- to
8-membered heterocyclyl ring having, in addition to the nitrogen
atom, 0-2 ring heteroatoms selected from N, O, and S; [0052] each
R.sup.5 independently is hydrogen or an optionally substituted
aliphatic, aryl, heteroaryl, or heterocyclyl group; and [0053] each
R.sup.7 independently is an optionally substituted aryl,
heterocyclyl, or heteroaryl group.
[0054] Ring A is a substituted or unsubstituted 5- or 6-membered
aryl, heteroaryl, cycloaliphatic, or heterocyclyl ring. Examples of
Ring A include furano, dihydrofurano, thieno, dihydrothieno,
cyclopenteno, cyclohexeno, 2H-pyrrolo, pyrrolo, pyrrolino,
pyrrolidino, oxazolo, thiazolo, imidazolo, imidazolino,
imidazolidino, pyrazolo, pyrazolino, pyrazolidino, isoxazolo,
isothiazolo, oxadiazolo, triazolo, thiadiazolo, 2H-pyrano,
4H-pyrano, benzo, pyridino, piperidino, dioxano, morpholino,
dithiano, thiomorpholino, pyridazino, pyrimidino, pyrazino,
piperazino, and triazino, any of which groups may be substituted or
unsubstituted. Preferred values for Ring A include, without
limitation, substituted or unsubstituted rings selected from the
group consisting of furano, thieno, pyrrolo, oxazolo, thiazolo,
imidazolo, pyrazolo, isoxazolo, isothiazolo, triazolo, benzo,
pyridino, pyridazino, pyrimidino, and pyrazino.
[0055] Ring A may be substituted or unsubstituted. In some
embodiments, each substitutable saturated ring carbon atom in Ring
A is unsubstituted or is substituted with .dbd.O, .dbd.S,
.dbd.C(R.sup.5).sub.2, .dbd.N--N(R.sup.4).sub.2, .dbd.N--OR.sup.5,
.dbd.N--NHC(O)R.sup.5, .dbd.N--NHCO.sub.2R.sup.6,
.dbd.N--NHSO.sub.2R.sup.6, .dbd.N--R.sup.5 or --R.sup.b, where
R.sup.b, R.sup.4, R.sup.5, and R.sup.6 are as defined below. Each
substitutable unsaturated ring carbon atom in Ring A is
unsubstituted or substituted with --R.sup.b. Each substitutable
ring nitrogen atom in Ring A is unsubstituted or is substituted
with --R.sup.9b, and one ring nitrogen atom in Ring A optionally is
oxidized. Each R.sup.9b independently is --C(O)R.sup.5,
--C(O)N(R.sup.4).sub.2, --CO.sub.2R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sub.2, or a C.sub.1-4 aliphatic optionally
substituted with R.sup.3 or R.sup.7.
[0056] Each R.sup.b independently is R.sup.2b, an optionally
substituted aliphatic, or an optionally substituted aryl,
heterocyclyl, or heteroaryl group; or two adjacent R.sup.b, taken
together with the intervening ring atoms, form an optionally
substituted fused 4- to 8-membered aromatic or non-aromatic ring
having 0-3 ring heteroatoms selected from the group consisting of
O, N, and S.
[0057] Each R.sup.2b independently is -halo, --NO.sub.2, --CN,
--C(R.sup.5).dbd.C(R.sup.5).sub.2,
--C(R.sup.5).dbd.C(R.sup.5)(R.sup.10), --OR.sup.5, --SR.sup.6,
--S(O)R.sup.6, --SO.sub.2R.sup.6, --SO.sub.2N(R.sup.4).sub.2,
--N(R.sup.4).sub.2, --NR.sup.4C(O)R.sup.5,
--NR.sup.4C(O)N(R.sup.4).sub.2, --NR.sup.4CO.sub.2R.sup.6,
--O--CO.sub.2R.sup.5, --OC(O)N(R.sup.4).sub.2, --O--C(O)R.sup.5,
--CO.sub.2R.sup.5, --C(O)--C(O)R.sup.5, --C(O)R.sup.5,
--C(O)N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--C(.dbd.NR.sup.4)--OR.sup.5, --N(R.sup.4)--N(R.sup.4).sub.2,
N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--P(O)(R.sup.5).sub.2, or --P(O)(OR.sup.5).sub.2, where the
variables R.sup.4, R.sup.5, and R.sup.7 have the values described
above; each R.sup.6 independently is an optionally substituted
aliphatic or aryl group; and each R.sup.10 independently is
--CO.sub.2R.sup.5 or --C(O)N(R.sup.4).sub.2.
[0058] In some embodiments, Ring A is substituted by 0-2
substituents R.sup.b. In some such embodiments, each R.sup.b
independently is C.sub.1-3 aliphatic or R.sup.2b, and each R.sup.2b
independently is selected from the group consisting of -halo,
--NO.sub.2, --C(R.sup.5).dbd.C(R.sup.5).sub.2, --C.dbd.C--R.sup.5,
--OR.sup.5, and --N(R.sup.4).sub.2. In some embodiments, each
R.sup.b independently is selected from the group consisting of
-halo, C.sub.1-3 aliphatic, C.sub.1-3 fluoroaliphatic, and
--OR.sup.5, where R.sup.5 is hydrogen or C.sub.1-3 aliphatic. In
certain preferred embodiments, Ring A is substituted with 0, 1, or
2 substituents, preferably 0 or 1 substituents, independently
selected from the group consisting of chloro, fluoro, bromo,
methyl, trifluoromethyl, and methoxy.
[0059] In some embodiments, Ring B is a substituted or
unsubstituted mono- or bicyclic aryl or heteroaryl ring selected
from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl,
thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
oxadiazolyl, triazolyl, thiadiazolyl, phenyl, pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl,
isoindolyl, indazolyl, benzo[b]furanyl, benzo[b]thienyl,
benzimidazolyl, benzthiazolyl, benzoxazolyl, purinyl, quinolyl,
isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, and pteridinyl.
[0060] Each substitutable saturated ring carbon atom in Ring B is
unsubstituted or is substituted with .dbd.O, .dbd.S,
.dbd.C(R.sup.5).sub.2, .dbd.N--N(R.sup.4).sub.2, .dbd.N--OR.sup.5,
.dbd.N--NHC(O)R.sup.5, .dbd.N--NHCO.sub.2R.sup.6,
.dbd.N--NHSO.sub.2R.sup.6, .dbd.N--R.sup.5 or --R.sup.c. Each
substitutable unsaturated ring carbon atom in Ring B is
unsubstituted or substituted with --R.sup.c. Each substitutable
ring nitrogen atom in Ring B is unsubstituted or is substituted
with --R.sup.9e, and one ring nitrogen atom in Ring B optionally is
oxidized. Each R.sup.9c independently is --C(O)R.sup.5,
--C(O)N(R.sup.4).sub.2, --CO.sub.2R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sub.2, or a C.sub.1-4 aliphatic optionally
substituted with R.sup.3 or R.sup.7. Ring B may be unsubstituted or
may be substituted on any one or more of its component rings,
wherein the substituents may be the same or different. In some
embodiments, Ring B is substituted with 0-2 independently selected
R.sup.c and 0-3 independently selected R.sup.2c or C.sub.1-6
aliphatic groups. The variables R.sup.3, R.sup.4, R.sup.5, R.sup.6,
and R.sup.7 are as defined above for Ring A, and R.sup.c and
R.sup.2c are defined below.
[0061] Each R.sup.c independently is R.sup.2c, an optionally
substituted C.sub.1-6 aliphatic, or an optionally substituted aryl,
heteroaryl, or heterocyclyl group.
[0062] Each R.sup.2c independently is -halo, --NO.sub.2, --CN,
--C(R.sup.5).dbd.C(R.sup.5).sub.2,
--C(R.sup.5).dbd.C(R.sup.5)(R.sup.10), --C.ident.C--R.sup.5,
--C.ident.C--R.sup.10, --OR.sup.5, --SR.sup.6, --S(O)R.sup.6,
--SO.sub.2R.sup.6, --SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--NR.sup.4CO.sub.2R.sup.6, --O--CO.sub.2R.sup.5,
--OC(O)N(R.sup.4).sub.2, --O--C(O)R.sup.5, --CO.sub.2R.sup.5,
--C(O)--C(O)R.sup.5, --C(O)R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(.dbd.NR.sup.4)--N(R.sup.4).sup.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--N(R.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--P(O)(R.sup.5).sub.2, or --P(O)(OR.sup.5).sub.2.
[0063] In some embodiments, Ring B is a monocyclic 5- or 6-membered
aryl or heteroaryl ring, substituted with 0-2 independently
selected R.sup.c and 0-2 independently selected R.sup.2c or
C.sub.1-6 aliphatic groups. In certain such embodiments, Ring B is
a substituted or unsubstituted phenyl or pyridyl ring.
[0064] In some embodiments, Ring B is substituted with 0-2
substituents R.sup.c. In some such embodiments, each R.sup.c
independently is C.sub.1-3 aliphatic or R.sup.2c, and each R.sup.2c
independently is selected from the group consisting of -halo,
--NO.sub.2, --C(R.sup.5).dbd.C(R.sup.5).sub.2, --OR.sup.5, and
--N(R.sup.4).sub.2. In some embodiments, each R.sup.c independently
is selected from the group consisting of -halo, C.sub.1-3
aliphatic, C.sub.1-3 haloaliphatic, and --OR.sup.5, where R.sup.5
is hydrogen or C.sub.1-3 aliphatic. In certain preferred
embodiments, Ring B is substituted with 0, 1, or 2 substituents,
independently selected from the group consisting of chloro, fluoro,
bromo, methyl, trifluoromethyl, and methoxy.
[0065] Each substitutable saturated ring carbon atom in Ring C is
unsubstituted or is substituted with .dbd.O, .dbd.S,
.dbd.C(R.sup.5).sub.2, .dbd.N--N(R.sup.4).sub.2, .dbd.N--OR.sup.5,
.dbd.N--NHC(O)R.sup.5, .dbd.N--NHCO.sub.2R.sup.6,
.dbd.N--NHSO.sub.2R.sup.6, .dbd.N--R.sup.5 or --R.sup.d. Each
substitutable unsaturated ring carbon atom in Ring C is
unsubstituted or substituted with --R.sup.d. Each substitutable
ring nitrogen atom in Ring C is unsubstituted or is substituted
with --R.sup.9d, and one ring nitrogen atom in Ring C optionally is
oxidized. Each R.sup.9d independently is --C(O)R.sup.5,
--C(O)N(R.sup.4).sub.2, --CO.sub.2R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sub.2, or a C.sub.1-4 aliphatic optionally
substituted with R.sup.3 or R.sup.7. Ring C may be unsubstituted or
may be substituted on any one or more of its component rings,
wherein the substituents may be the same or different. In some
embodiments, Ring C is substituted with 0-2 independently selected
R.sup.d and 0-3 independently selected R.sup.2d or C.sub.1-6
aliphatic groups. The variables R.sup.3, R.sup.4, R.sup.5, R.sup.6,
and R.sup.7 are as described above for Rings A and B. The variables
R.sup.d and R.sup.2d are described below.
[0066] Each R.sup.d independently is R.sup.2d, an optionally
substituted aliphatic, or an optionally substituted aryl,
heteroaryl, or heterocyclyl group.
[0067] Each R.sup.2d independently is -halo, --NO.sub.2, --CN,
--C(R.sup.5).dbd.C(R.sup.5).sub.2,
--C(R.sup.5).dbd.C(R.sup.5).sub.2(R.sup.10), --C.ident.C--R.sup.5,
--C.ident.C--R.sup.10, --OR.sup.5, --SR.sup.6, --S(O)R.sup.6,
--SO.sub.2R.sup.6, --SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--NR.sup.4CO.sub.2R.sup.6, --O--CO.sub.2R.sup.5,
--OC(O)N(R.sup.4).sub.2, --O--C(O)R.sup.5, --CO.sub.2R.sup.5,
--C(O)--C(O)R.sup.5, --C(O)R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--N(R.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--P(O)(R.sup.5).sub.2, or --P(O)(OR.sup.5).sub.2. Additionally,
R.sup.2d can be --SO.sub.3R.sup.5,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2 or
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5.
[0068] In some embodiments, Ring C is a monocyclic 5- or 6-membered
aryl or heteroaryl ring, which is substituted with 0-2
independently selected substituents R.sup.d and 0-2 independently
selected R.sup.2d or C.sub.1-6 aliphatic groups. In some such
embodiments, Ring C is an optionally substituted heteroaryl ring
selected from the group consisting of pyridyl, pyrimidinyl,
pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, and oxazolyl. In
some other embodiments, Ring C is a substituted or unsubstituted
phenyl ring. In some embodiments, Ring C is a monocyclic 5- or
6-membered aryl or heteroaryl ring, which is substituted with 0, 1,
or 2 substituents R.sup.d, as defined above.
[0069] In some other embodiments, Ring C is a monocyclic 5- or
6-membered heterocyclyl or cycloaliphatic ring, which is
substituted with 0-2 independently selected substituents R.sup.d
and 0-2 independently selected R.sup.2d or C.sub.1-6 aliphatic
groups.
[0070] In some embodiments, the Aurora kinase inhibitor is a
compound represented by formula (II):
##STR00002##
[0071] or a pharmaceutically acceptable salt thereof;
[0072] wherein: [0073] R.sup.e is hydrogen or a C.sub.1-3 aliphatic
optionally substituted with R.sup.3 or R.sup.7; [0074] Ring A is
substituted with 0-3 R.sup.b; [0075] each R.sup.b independently is
selected from the group consisting of C.sub.1-6 aliphatic,
R.sup.2b, R.sup.7b, -T.sup.1-R.sup.2b, and -T.sup.1-R.sup.7b;
[0076] each R.sup.2b independently is -halo, --NO.sub.2, --CN,
--C(R.sup.5).dbd.C(R.sup.5).sub.2, --OR.sup.5, --SR.sup.6,
--S(O)R.sup.6, --SO.sub.2R.sup.6, --SO.sub.2N(R.sup.4).sub.2,
--N(R.sup.4).sub.2, --NR.sup.4C(O)R.sup.5,
--NR.sup.4C(O)N(R.sup.4).sub.2, --NR.sup.4CO.sub.2R.sup.6,
--O--CO.sub.2R.sup.5, --OC(O)N(R.sup.4).sub.2, --O--C(O)R.sup.5,
--CO.sub.2R.sup.5, --C(O)--C(O)R.sup.5, --C(O)R.sup.5,
--C(O)N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--C(.dbd.NR.sup.4)--OR.sup.5, --N(R.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--P(O)(R.sup.5).sub.2, or --P(O)(OR.sup.5).sub.2; [0077] each
R.sup.7b independently is an optionally substituted aryl,
heterocyclyl, or heteroaryl group; [0078] Ring B is substituted
with 0-2 independently selected R.sup.c and 0-2 independently
selected R.sup.2c or C.sub.1-6 aliphatic groups; [0079] each
R.sup.c independently is selected from the group consisting of
C.sub.1-6 aliphatic, R.sup.2c, R.sup.7c, -T.sup.1-R.sup.2c, and
-T.sup.1-R.sup.7c; [0080] each R.sup.2c independently is -halo,
--NO.sub.2, --CN, --C(R.sup.5).dbd.C(R.sup.5).sub.2, --OR.sup.5,
--SR.sup.6, --S(O)R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--NR.sup.4CO.sub.2R.sup.6, --O--CO.sub.2R.sup.5,
--OC(O)N(R.sup.4).sub.2, --O--C(O)R.sup.5, --CO.sub.2R.sup.5,
--C(O)--C(O)R.sup.5, --C(O)R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--N(R.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--P(O)(R.sup.5).sub.2, or --P(O)(OR.sup.5).sub.2; [0081] each
R.sup.7c independently is an optionally substituted aryl,
heterocyclyl, or heteroaryl group; [0082] T.sup.1 is a C.sub.1-6
alkylene chain optionally substituted with R.sup.3 or R.sup.3b,
wherein T.sup.1 or a portion thereof optionally forms part of a 3-
to 7-membered ring; [0083] Ring C is substituted with 0-2
independently selected R.sup.d and 0-3 independently selected
R.sup.2d or C.sub.1-6 aliphatic groups; [0084] each R.sup.d
independently is selected from the group consisting of C.sub.1-6
aliphatic, R.sup.2d, R.sup.7d, -T.sup.2-R.sup.2d,
-T.sup.2-R.sup.7d, --V-T.sup.3-R.sup.2d, and --V-T.sup.3-R.sup.7d;
[0085] T.sup.2 is a C.sub.1-6 alkylene chain optionally substituted
with R.sup.3 or R.sup.3b, wherein the alkylene chain optionally is
interrupted by --C(R.sup.5).dbd.C(R.sup.5)--, --C.ident.C--, --O--,
--S--, --S(O)--, --S(O).sub.2--, --SO.sub.2N(R.sup.4)--,
--N(R.sup.4)--, --N(R.sup.4)C(O)--, --NR.sup.4C(O)N(R.sup.4)--,
--N(R.sup.4)CO.sub.2--, --C(O)N(R.sup.4)--, --C(O)--,
--C(O)--C(O)--, --CO.sub.2--, --OC(O)--, --OC(O)O--,
--OC(O)N(R.sup.4)--, --N(R.sup.4)--N(R.sup.4)--,
--N(R.sup.4)SO.sub.2--, or --SO.sub.2N(R.sup.4)--, and wherein
T.sup.2 or a portion thereof optionally forms part of a 3-7
membered ring; [0086] T.sup.3 is a C.sub.1-6 alkylene chain
optionally substituted with R.sup.3 or R.sup.3b, wherein the
alkylene chain optionally is interrupted by
--C(R.sup.5).dbd.C(R.sup.5)--, --O--, --S--, --S(O)--,
--S(O).sub.2--, --SO.sub.2N(R.sup.4)--, --N(R.sup.4)--,
--N(R.sup.4)C(O)--, --NR.sup.4C(O)N(R.sup.4)--,
--N(R.sup.4)CO.sub.2--, --C(O)N(R.sup.4)--, --C(O)--,
--C(O)--C(O)--, --CO.sub.2--, --OC(O)--, --OC(O)O--,
--OC(O)N(R.sup.4)--, --N(R.sup.4)--N(R.sup.4)--,
--N(R.sup.4)SO.sub.2--, or --SO.sub.2N(R.sup.4)--, and wherein
T.sup.3 or a portion thereof optionally forms part of a 3-7
membered ring; [0087] V is --C(R.sup.5).dbd.C(R.sup.5)--, --O--,
--S--, --S(O)--, --S(O).sub.2--, --SO.sub.2N(R.sup.4)--,
--N(R.sup.4)--, --N(R.sup.4)C(O)--, --NR.sup.4C(O)N(R.sup.4)--,
--N(R.sup.4)CO.sub.2--, --C(O)N(R.sup.4)--, --C(O)--,
--C(O)--C(O)--, --CO.sub.2--, --OC(O)--, --OC(O)O--,
--OC(O)N(R.sup.4)--, --C(NR.sup.4).dbd.N--, --C(OR.sup.5).dbd.N--,
--N(R.sup.4)--N(R.sup.4)--, --N(R.sup.4)SO.sub.2--,
--N(R.sup.4)SO.sub.2N(R.sup.4)--, --P(O)(R.sup.5)--,
--P(O)(OR.sup.5)--O--, --P(O)--O--, or
--P(O)(NR.sup.5)--N(R.sup.5)--; [0088] R.sup.2d is -halo,
--NO.sub.2, --CN, --C(R.sup.5).dbd.C(R.sup.5).sub.2,
--C.dbd.C--R.sup.5, --OR.sup.5, --SR.sup.6, --S(O)R.sup.6,
--SO.sub.2R.sup.6, --SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--NR.sup.4CO.sub.2R.sup.6, --O--CO.sub.2R.sup.5,
--OC(O)N(R.sup.4).sub.2, --O--C(O)R.sup.5, --CO.sub.2R.sup.5,
--C(O)--C(O)R.sup.5, --C(O)R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--N(R.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--P(O)(R.sup.5).sub.2, or --P(O)(OR.sup.5).sub.2; and [0089] each
R.sup.7d independently is an optionally substituted aryl,
heterocyclyl, or heteroaryl group. [0090] each R.sup.3
independently is selected from the group consisting of -halo, --OH,
--O(C.sub.1-3 alkyl), --CN, --N(R.sup.4).sub.2, --C(O)(C.sub.1-3
alkyl), --CO.sub.2H, --CO.sub.2(C.sub.1-3 alkyl), --C(O)NH.sub.2,
and --C(O)NH(C.sub.1-3 alkyl); [0091] each R.sup.3b independently
is a C.sub.1-3 aliphatic optionally substituted with R.sup.3 or
R.sup.7, or two substituents R.sup.3b on the same carbon atom,
taken together with the carbon atom to which they are attached,
form a 3- to 6-membered carbocyclic ring; [0092] each R.sup.4
independently is hydrogen or an optionally substituted aliphatic,
aryl, heteroaryl, or heterocyclyl group; or two R.sup.4 on the same
nitrogen atom, taken together with the nitrogen atom, form an
optionally substituted 5- to 8-membered heteroaryl or heterocyclyl
ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms
selected from N, O, and S; [0093] each R.sup.5 independently is
hydrogen or an optionally substituted aliphatic, aryl, heteroaryl,
or heterocyclyl group; [0094] each R.sup.6 independently is an
optionally substituted aliphatic or aryl group; and [0095] each
R.sup.7 independently is an optionally substituted aryl,
heterocyclyl, or heteroaryl group.
[0096] Table 1 provides the chemical names for specific examples of
compounds of formula (II).
TABLE-US-00001 TABLE 1 Examples of Compounds of Formula (II) II-1:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-N-(2-methylamino-ethyl)-benzamide II-2:
N-(2-Amino-ethyl)-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimid-
o- [4,5-e]azepin-2-ylamino]-N-methyl-benzamide II-3:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-N-methyl-N-(2-methylamino-ethyl)-benzamide II-4:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-N-(2-dimethylamino-ethyl)-benzamide II-5:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-N-(2-dimethylamino-ethyl)-N-methyl-benzamide II-6:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-N-(3-dimethylamino-propyl)-benzamide II-7:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-N-(3-dimethylamino-propyl)-N-methyl-benzamide II-8:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-phenyl}-piperazin-1-yl-methanone II-9:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-10:
{4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-11:
[4-(9-Chloro-7-o-tolyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)--
phenyl]- (4-methyl-piperazin-1-yl)-methanone II-12:
{4-[9-Chloro-7-(2-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-13:
{4-[9-Chloro-7-(4-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-14:
{4-[7-(2-Fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-15:
2-{3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-
-2- ylamino]-phenyl}-1-(4-methyl-piperazin-1-yl)-ethanone II-16:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-N-piperidin-4-yl-benzamide II-17:
(4-Amino-piperidin-1-yl)-{4-[9-chloro-7-(2-fluoro-phenyl)-5H-
benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-methanone II-18:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-phenyl}-(4-dimethylamino-piperidin-1-yl)-methanone
II-19:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide II-20:
4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide II-21:
4-(9-Chloro-7-o-tolyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-N-
-[3- (4-methyl-piperazin-1-yl)-propyl]-benzamide II-22:
4-[9-Chloro-7-(2-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide II-23:
4-[9-Chloro-7-(4-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide II-24:
4-[7-(2-Fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide II-25:
2-{3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-
-2-
ylamino]-phenyl}-N-[3-(4-methyl-piperazin-1-yl)-propyl]-acetamide
II-26:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-phenyl}-morpholin-4-yl-methanone II-27:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-N,N-bis-(2-hydroxy-ethyl)-benzamide II-28:
{4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-phenyl}-morpholin-4-yl-methanone II-29:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-N-(2-morpholin-4-yl-ethyl)-benzamide II-30:
4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-N-(2-morpholin-4-yl-ethyl)-benzamide II-31:
4-(9-Chloro-7-o-tolyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-N-
-(2- morpholin-4-yl-ethyl)-benzamide II-32:
4-[9-Chloro-7-(2-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-N-(3-morpholin-4-yl-propyl)-benzamide II-33:
4-[9-Chloro-7-(4-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-N-(2-morpholin-4-yl-ethyl)-benzamide II-34:
4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-2-hydroxy-N-(2-morpholin-4-yl-ethyl)-benzamide II-35:
[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]- pyridin-2-yl-amine II-36:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]- (3,5-dichloro-phenyl)-amine II-37:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]-(4- methoxy-phenyl)-amine II-38:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]-(4- ethoxy-phenyl)-amine II-39:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]-(3- methoxy-phenyl)-amine II-40:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]-(2- methoxy-phenyl)-amine II-41:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]-(4- chloro-phenyl)-amine II-42:
[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]-(4- chloro-phenyl)-amine II-43:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]-(3- chloro-phenyl)-amine II-44:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]-(2- chloro-phenyl)-amine II-45:
4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-phenol II-46:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]-(4- morpholin-4-yl-phenyl)-amine II-47:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]-[4- (4-methyl-piperazin-1-yl)-phenyl]-amine II-48:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]-(4- pyridin-4-ylmethyl-phenyl)-amine II-49:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-benzonitrile II-50:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]-(4- nitro-phenyl)-amine II-51:
4-[7-(2-Fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-
benzoic acid II-52:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-benzoic acid II-53:
4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-benzoic acid II-54:
4-(9-Chloro-7-o-tolyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-
benzoic acid II-55:
4-[9-Chloro-7-(2-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-benzoic acid II-56:
4-[9-Chloro-7-(4-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-benzoic acid II-57:
4-[9-Fluoro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-benzoic acid II-58:
4-[7-(2-Fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-benzoic acid II-59:
4-[10-Fluoro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-benzoic acid II-60:
4-[10-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-benzoic acid II-61:
4-[10-Bromo-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-benzoic acid II-62:
4-[7-(2-Fluoro-phenyl)-10-methoxy-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-benzoic acid II-63:
4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-benzamide II-64:
3-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-benzamide II-65:
{3-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-phenyl}-acetic acid II-66:
2-{3-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-
-2- ylamino]-phenyl}-acetamide II-67:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-benzenesulfonic acid II-68:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-benzenesulfonamide II-69:
4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-N-(5-methyl-isoxazol-3-yl)-benzenesulfonamide II-70:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]-(4- trifluoromethanesulfonyl-phenyl)-amine II-71:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]- (3,4-dimethoxy-phenyl)-amine II-72:
[9-Chloro-7-(2-fluoro-phenyl)-6,7-dihydro-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-yl]-(3,4-dimethoxy-phenyl)-amine II-73:
[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]- (3,4-dimethoxy-phenyl)-amine II-74:
(9-Chloro-7-o-tolyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl)-(3,4-
dimethoxy-phenyl)-amine II-75:
(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-9-methyl-5H-
benzo[c]pyrimido[4,5-e]azepin-2-yl]-amine II-76:
(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-9-isopropyl-5H-
benzo[c]pyrimido[4,5-e]azepin-2-yl]-amine II-77:
(3,4-Dimethoxy-phenyl)-[10-fluoro-7-(2-fluoro-phenyl)-5H-
benzo[c]pyrimido[4,5-e]azepin-2-yl]-amine II-78:
[10-Bromo-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]- (3,4-dimethoxy-phenyl)-amine II-79:
(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-10-trifluoromethyl-5H-
benzo[c]pyrimido[4,5-e]azepin-2-yl]-amine II-80:
(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-10-methyl-5H-
benzo[c]pyrimido[4,5-e]azepin-2-yl]-amine II-81:
(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-10-methoxy-5H-
benzo[c]pyrimido[4,5-e]azepin-2-yl]-amine II-82:
(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-11-methyl-5H-
benzo[c]pyrimido[4,5-e]azepin-2-yl]-amine II-83:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]- (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine II-84:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]-(4- fluoro-3-methoxy-phenyl)-amine II-85:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-2-hydroxy-benzoic acid II-86:
4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-2-hydroxy-benzoic acid II-87:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]- (3,4-dichloro-phenyl)-amine II-88:
[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]- (3,5-dimethoxy-phenyl)-amine II-89:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]- (3,5-dimethyl-phenyl)-amine II-90:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]- phenyl-amine II-91:
4-[9-Chloro-7-(2,5-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepi-
n-2- ylamino]-benzoic acid II-92:
4-[9-Chloro-7-(2,3-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepi-
n-2- ylamino]-benzoic acid II-93:
(3-Dimethylamino-pyrrolidin-1-yl)-{4-[7-(2-fluoro-phenyl)-9-methoxy-
- 5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-methanone
II-94: 4-[9-Chloro-7-(2,5-dimethoxy-phenyl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-benzoic acid II-95:
4-[7-(2-Fluoro-phenyl)-9-methoxy-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-N,N-bis-(2-hydroxy-ethyl)-benzamide II-96:
4-[9-Chloro-7-(2,4-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepi-
n-2- ylamino]-benzoic acid II-97:
4-[9-Chloro-7-(2,4-difluoro-phenyl)-7H-benzo[c]pyrimido[4,5-e]azepi-
n-2- ylamino]-benzoic acid II-98:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-phenyl}-(3-dimethylamino-azetidin-1-yl)-methanone II-99:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino]-N-methyl-N-(1-methyl-pyrrolidin-3-yl)-benzamide II-100:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-phenyl}-(3-dimethylamino-pyrrolidin-1-yl)-methanone
II-101: 4-[9-Chloro-7-(2,4-dimethoxy-phenyl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-benzoic acid II-102:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-phenyl}-(3-methylamino-pyrrolidin-1-yl)-methanone
II-103:
(3-Amino-pyrrolidin-1-yl)-{4-[9-chloro-7-(2-fluoro-phenyl)-5H-
benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-methanone II-104:
4-[9-Chloro-7-(2,3-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep-
in-2- ylamino]-benzoic acid methyl ester II-105:
4-[9-Chloro-7-(2,5-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep-
in-2- ylamino]-benzoic acid methyl ester II-106:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-phenyl}-phosphonic acid II-107:
N-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepi-
n-2- ylamino]-phenyl}-methanesulfonamide II-108:
N-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepi-
n-2- ylamino]-phenyl}-N-methyl-acetamide II-109:
2-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepi-
n-2- ylamino]-benzoylamino}-succinic acid II-110:
[9-Chloro-7-(2-fluoro-phenyl)-4-methyl-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-yl]-(3,4-dimethoxy-phenyl)-amine II-111:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone II-112:
1-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepi-
n-2- ylamino]-benzoyl}-pyrrolidine-2-carboxylic acid II-113:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-phenyl}-(3-methyl-piperazin-1-yl)-methanone II-114:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-y-
l]-[4- (2H-tetrazol-5-yl)-phenyl]-amine II-115:
N-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepi-
n-2- ylamino]-phenyl}-acetamide II-116:
5-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-2-fluoro-benzoic acid II-117:
N-(3-Amino-propyl)-4-[9-chloro-7-(2-fluoro-phenyl)-5H-
benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-methyl-benzamide II-118:
2-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepi-
n-2- ylamino]-benzoylamino}-propionic acid II-119:
5-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-pyridine-2-carboxylic acid II-120:
2-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepi-
n-2- ylamino]-phenyl}-N-(2-morpholin-4-yl-ethyl)-acetamide II-121:
5-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-2-methoxy-benzoic acid II-122:
5-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-2-methyl-benzoic acid II-123:
6-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-nicotinic acid II-124:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-N-(2-morpholin-4-yl-ethyl)-benzenesulfonamide II-125:
2-Chloro-5-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-benzoic acid II-126:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-phenyl}-acetic acid II-127:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-2-trifluoromethyl-benzoic acid II-128:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide II-129:
N-(3-Amino-propyl)-4-[9-chloro-7-(2-fluoro-phenyl)-5H-
benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzamide II-130:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-N-(3-methylamino-propyl)-benzamide II-131:
N-(2-Amino-2-methyl-propyl)-4-[9-chloro-7-(2-fluoro-phenyl)-5H-
benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzamide II-132:
2-(3,4-Dimethoxy-phenylamino)-7-(2-fluoro-phenyl)-5H-
benzo[c]pyrimido[4,5-e]azepine-10-carboxylic acid II-133:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-2-methyl-benzoic acid II-134:
2-Chloro-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-benzoic acid II-135:
4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep-
in-2- ylamino]-benzoic acid II-136:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-2-fluoro-benzoic acid II-137:
4-[7-(2-Fluoro-phenyl)-9-methoxy-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-benzoic acid II-138:
(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-9-methoxy-5H-
benzo[c]pyrimido[4,5-e]azepin-2-yl]-amine II-139:
[9,10-Dichloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepi-
n-2- yl]-(3,4-dimethoxy-phenyl)-amine II-140:
4-[9,10-Dichloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]aze-
pin- 2-ylamino]-benzoic acid II-141:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-2-methoxy-benzoic acid II-142:
N-(2-Amino-ethyl)-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrim-
ido- [4,5-e]azepin-2-ylamino]-benzamide II-143:
4-(9-Chloro-7-phenyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-
benzoic acid II-144:
[7-(2-Bromo-phenyl)-9-chloro-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]- (3,4-dimethoxy-phenyl)-amine II-145:
2-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepi-
n-2- ylamino]-phenyl}-1-(4-methyl-piperazin-1-yl)-ethanone II-146:
3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-benzoic acid II-147:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-N-[2-(1H-imidazol-4-yl)-ethyl]-benzamide II-148:
4-[7-(2-Fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-N-(2-morpholin-4-yl-ethyl)-benzamide II-149:
{3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-phenyl}-acetic acid II-150:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-N-(2-pyridin-4-yl-ethyl)-benzamide II-151:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-N-(2-pyridin-3-yl-ethyl)-benzamide II-152:
(9-Chloro-7-phenyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl)-(3,4-
dimethoxy-phenyl)-amine II-153:
4-[7-(2-Fluoro-phenyl)-10-methyl-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-benzoic acid II-154:
(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-yl]-amine II-155:
4-[9-Chloro-7-(4-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-benzoic acid II-156:
4-[9-Chloro-7-(3-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-benzoic acid II-157:
4-[9-Chloro-7-(3-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide II-158:
4-[9-Chloro-7-(3-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-N-(2-morpholin-4-yl-ethyl)-benzamide II-159:
{4-[9-Chloro-7-(3-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-160:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-N-methyl-N-(2-pyridin-2-yl-ethyl)-benzamide II-161:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-N-(2-pyridin-2-yl-ethyl)-benzamide II-162:
4-[9-Chloro-7-(3-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-benzoic acid II-163:
[3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-164:
9-Chloro-7-(2-fluorophenyl)-N-{4-[(4-pyridin-2-ylpiperazin-1-
yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-165:
9-Chloro-7-(2-fluorophenyl)-N-(4-{[4-(2-morpholin-4-yl-2-
oxoethyl)piperazin-1-yl]carbonyl}phenyl)-5H-pyrimido-
[5,4-d][2]benzazepin-2-amine II-166:
9-Chloro-7-(2-fluorophenyl-N-(4-{[4-(2-furoyl)piperazin-1-
yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-167:
Benzyl-4-(4-{[9-chloro-7-(2-fluorophenyl)-5H-pyrimido-
[5,4-d][2]benzazepin-2-yl]amino}benzoyl)piperazine-1-carboxylate
II-168: Ethyl-4-(4-{[9-chloro-7-(2-fluorophenyl)-5H-pyrimido-
[5,4-d][2]benzazepin-2-yl]amino}benzoyl)piperazine-1-carboxylate
II-169:
2-[4-(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzaze-
pin-2- yl]amino}benzoyl)piperazin-1-yl]benzoic acid II-170:
2-[4-(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzaze-
pin-2- yl]amino}benzoyl)piperazin-1-yl]-N-isopropylacetamide
II-171:
9-Chloro-7-(2-fluorophenyl)-N-(4-{[4-(2-pyrrolidin-1-ylethyl)piper-
azin-1- yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-172:
N-[2-(aminocarbonyl)phenyl]-4-{[9-chloro-7-(2-fluorophenyl)-5H-
pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzamide II-173:
9-Chloro-7-(2-fluorophenyl)-N-{4-[(4-pyrimidin-2-ylpiperazin-1-
yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-174:
4-{[9-Chloro-7-(2-chloro-6-fluorophenyl)-5H-pyrimido-
[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-175:
9-Chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-
yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-176:
9-Chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino)pyrrolidin-
-1- yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-177:
9-Chloro-N-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-7-(2-f-
luoro- 6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-178:
9-Chloro-N-(4-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)--
7-(2-
fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-179:
9-Chloro-N-(4-{[3-(dimethylamino)azetidin-1-yl]carbonyl}phenyl)-7--
(2- fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-180:
9-Chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino)azetidin-1-
- yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-181:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2-
ylamino]-phenyl}-[4-(3-piperidin-1-yl-propyl)-piperazin-1-yl]-methanone
II-182:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2-
ylamino]-phenyl}-[4-(2-piperidin-1-yl-ethyl)-piperazin-1-yl]-methanone
II-183:
{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]aze-
pin- 2-ylamino]-phenyl}-(4-dimethylamino-piperidin-1-yl)-methanone
II-184:
{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]aze-
pin- 2-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-185:
4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep-
in-2- ylamino]-N-(3-dimethylamino-propyl)-N-methyl-benzamide
II-186:
{4-[9-Chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-phenyl}-(4-dimethylamino-piperidin-1-yl)-
methanone II-187:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2-
ylamino]-phenyl}-[4-(2-dipropylamino-ethyl)-piperazin-1-yl]-methanone
II-188:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-phenyl}-[4-(3-pyrrolidin-1-yl-propyl)-piperazin-1-yl]-
methanone II-189:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2-
ylamino]-phenyl}-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]-methanone
II-190:
4-[9-Chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-
e]azepin-2-ylamino]-benzoic acid II-191:
{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]aze-
pin- 2-ylamino]-phenyl)-(3(S)-methyl-piperazin-1-yl)-methanone
II-192:
(3-Amino-azetidin-1-yl)-{4-[9-chloro-7-(2-fluoro-phenyl)-5H-
benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-methanone II-193:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-phenyl}-(3-dimethylaminomethyl-azetidin-1-yl)-methanone
II-194:
{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]aze-
pin- 2-ylamino]-phenyl}-(3(R)-methyl-piperazin-1-yl)-methanone
II-195:
{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]aze-
pin- 2-ylamino]-phenyl}-piperazin-1-yl-methanone II-196:
(3-Amino-pyrrolidin-1-yl)-{4-[9-chloro-7-(2,6-difluoro-phenyl)-5H-
benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-methanone II-197:
{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]aze-
pin- 2-ylamino]-phenyl}-(3-methylamino-pyrrolidin-1-yl)-methanone
II-198:
4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep-
in-2- ylamino]-N-methyl-N-(3-methylamino-propyl)-benzamide II-199:
{4-[9-Chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-
- e]azepin-2-ylamino]-phenyl}-(3-methylamino-pyrrolidin-1-yl)-
methanone II-200:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-cyclohexanecarboxylic acid II-201:
9-chloro-N-(4-{[4-(2-ethoxyphenyl)piperazin-1-yl]carbonyl}phenyl)--
7-(2- fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-202:
N-[amino(imino)methyl]-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-
pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzamide II-203:
3-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}benzoic acid II-204:
9-chloro-7-(2,6-difluorophenyl)-N-(3-{[3-(dimethylamino)azetidin-1-
- yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-205:
9-chloro-7-(2,6-difluorophenyl)-N-(3-{[4-(dimethylamino)piperidin--
1- yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-206:
9-chloro-7-(2,6-difluorophenyl)-N-(3-{[3-(dimethylamino)pyrrolidin-
-1- yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-207:
N-[2-(aminomethyl)-1,3-benzoxazol-5-yl]-9-chloro-7-(2,6-difluoroph-
enyl)- 5H-pyrimido[5,4-d][2]benzazepin-2-amine II-208:
9-chloro-N-[4-({4-[3-(diethylamino)propyl]piperazin-1-
yl}carbonyl)phenyl]-7-(2-fluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-209:
9-chloro-N-[4-({4-[2-(diethylamino)ethyl]piperazin-1-
yl}carbonyl)phenyl]-7-(2-fluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-210:
9-chloro-N-[4-({4-[3-(dimethylamino)propyl]piperazin-1-
yl}carbonyl)phenyl]-7-(2-fluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-211:
9-chloro-7-(2-fluorophenyl)-N-[4-({4-[(1-methylpiperidin-3-
yl)methyl]piperazin-1-yl}carbonyl)phenyl]-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-212:
9-chloro-7-(2,6-difluorophenyl)-N-(4-nitrophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-213:
9-chloro-N-(3-chloro-4-{[4-(2-pyrrolidin-1-ylethyl)piperazin-1-
yl]carbonyl}phenyl)-7-(2-fluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-214:
9-chloro-N-{3-chloro-4-[(3-methylpiperazin-1-yl)carbonyl]phenyl}-7-
-(2- fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-215:
9-chloro-N-(3-chloro-4-{[3-(dimethylamino)pyrrolidin-1-
yl]carbonyl}phenyl)-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-216:
9-chloro-N-{3-chloro-4-[(3-methylpiperazin-1-yl)carbonyl]phenyl}-7-
-(2,6- difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-217:
N-[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-
-2- yl]benzene-1,4-diamine II-218: methyl
2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}benzoate II-219:
1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}benzoyl)piperazine-2-carboxylic acid II-220:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[4-(methylamino)piperidin-1-
yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-221:
N-{4-[(3-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2,6-
difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-222:
9-chloro-7-(2,6-difluorophenyl)-N-{3-[(3,5-dimethylpiperazin-1-
yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-223:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}-N-[[4-(dimethylamino)piperidin-1-
yl](imino)methyl]benzamide II-224:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}-N-[imino(piperazin-1-yl)methyl]benzamide II-225:
4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}-N-[3-(dimethylamino)propyl]-N-
methylbenzamide II-226:
3-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}-N-[3-(dimethylamino)propyl]-N-
methylbenzamide II-227:
9-chloro-N-(3-{[3-(dimethylamino)azetidin-1-yl]carbonyl}phenyl)-7--
(2- fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-228:
9-chloro-N-{3-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-7-(2-f-
luoro- 6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-229:
9-chloro-N-(3-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-7-
-(2-
fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-230:
N-(4-{[3-(aminomethyl)azetidin-1-yl]carbonyl}phenyl)-9-chloro-7-(2-
- fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-231:
9-chloro-N-(3-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)--
7-(2-
fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-232:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-{4-[(3-methylpiperazin-1-
yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-233:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-{4-[(4-methylpiperazin-1-
yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-234:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(methylamino)azetidin-1-
yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-235:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[3-(methylamino)azetid-
in- 1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-236:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}benzonitrile II-237:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}-N-[[3-(dimethylamino)pyrrolidin-1-
yl](imino)methyl]benzamide II-238:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2-
yl]amino}-N-[(3,5-dimethylpiperazin-1-yl)(imino)methyl]benzamide
II-239:
N-{4-[(4-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2,6-
difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-240:
N-{4-[(3-aminopyrrolidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2-fluor-
o-6- methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-241:
N-{4-[(4-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2-fluoro-
-6- methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-242:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[4-(methylamino)piperi-
din- 1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-243: 9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-[4-(piperazin-1-
ylcarbonyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-244:
9-chloro-7-(2,6-difluorophenyl)-N-{4-[[4-(dimethylamino)piperidin--
1- yl](imino)methyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-245:
N-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}phenyl)guanidine II-246:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}-N-methyl-N-[2-(methylamino)ethyl]benzamide II-247:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}-N-[2-(dimethylamino)ethyl]-N-methylbenzamide II-248:
methyl 4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}benzoyl)piperazine-2-carboxylate II-249:
2-[(4-carboxyphenyl)amino]-7-(2-fluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepine-9-carboxylic acid II-250:
9-chloro-7-(2,6-difluorophenyl)-N-{4-[[3-(dimethylamino)pyrrolidin-
-1-
yl](imino)methyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-251:
9-chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-
yl)(imino)methyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-252:
N-(2-aminoethyl)-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5-
,4- d][2]benzazepin-2-yl]amino}-N-methylbenzamide II-253:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(methylamino)piperidin-1-
yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-254:
4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}-N-methyl-N-[2-
(methylamino)ethyl]benzamide II-255:
4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}-N-[2-(dimethylamino)ethyl]-N-
methylbenzamide II-256:
7-(2-fluorophenyl)-2-[(3-methoxyphenyl)amino]-5H-pyrimido[5,4-
d][2]benzazepine-9-carboxylic acid II-257:
N-(3-aminopropyl)-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[-
5,4- d][2]benzazepin-2-yl]amino}-N-methylbenzamide II-258:
2-chloro-5-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}benzoic acid II-259:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2-
yl]amino}-N-[[3-(dimethylamino)azetidin-1-yl](imino)methyl]benzamide
II-260:
N-(2-amino-2-methylpropyl)-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-
pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzamide II-261:
4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}-N-methyl-N-[3-
(methylamino)propyl]benzamide II-262:
N-{4-[(3-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2-fluoro-
-6- methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-263:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[3-(methylamino)piperi-
din- 1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-264:
N-(3-aminopropyl)-4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-
pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide II-265:
N-(2-aminoethyl)-4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-
pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide II-266:
4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}benzoyl)piperazine-2-carboxylic acid
II-267:
9-chloro-7-(2,6-difluorophenyl)-N-{4-[[3-(dimethylamino)azetidin-1-
- yl](imino)methyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-268:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{imino[3-(methylamino)pyrroli-
din- 1-yl]methyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-269: 9-chloro-N-(4-chloro-3-{[4-(dimethylamino)piperidin-1-
yl]carbonyl}phenyl)-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-270:
9-chloro-7-(2,6-difluorophenyl)-N-[4-(5,5-dimethyl-4,5-dihydro-1H-
imidazol-2-yl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-271:
N-[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-
-2- yl]-N'-pyrimidin-2-ylbenzene-1,4-diamine II-272:
4-{[9-(3-aminoprop-1-yn-1-yl)-7-(2,6-difluorophenyl)-5H-pyrimido[5-
,4- d][2]benzazepin-2-yl]amino}benzoic acid II-273:
9-bromo-7-(2,6-difluorophenyl)-N-(3-methoxyphenyl)-5H-pyrimido[5,4-
- d][2]benzazepin-2-amine II-274:
4-{[9-bromo-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-
-2- yl]amino}benzoic acid II-275:
7-(2,6-difluorophenyl)-N-(3-methoxyphenyl)-9-(3-pyrrolidin-1-ylpro-
p-1- yn-1-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-276:
9-(3-aminoprop-1-yn-1-yl)-7-(2,6-difluorophenyl)-N-(3-methoxypheny-
l)- 5H-pyrimido[5,4-d][2]benzazepin-2-amine II-277:
4-({9-chloro-7-[2-(trifluoromethyl)phenyl]-5H-pyrimido[5,4-
d][2]benzazepin-2-yl}amino)benzoic acid II-278:
N-{4-[(3-aminoazetidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2,6-
difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-279:
4-[(9-chloro-7-pyridin-2-yl-5H-pyrimido[5,4-d][2]benzazepin-2-
yl)amino]benzoic acid II-280:
N-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}phenyl)-4-methylpiperazine-1-carboxamide II-281:
9-chloro-N-(4-chloro-3-{[3-(methylamino)pyrrolidin-1-
yl]carbonyl}phenyl)-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-282:
9-chloro-N-(4-chloro-3-{[4-(methylamino)piperidin-1-
yl]carbonyl}phenyl)-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-283:
2-chloro-5-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}-N-methyl-N-[2-
(methylamino)ethyl]benzamide II-284:
N-{4-[(3-aminopyrrolidin-1-yl)(imino)methyl]phenyl}-9-chloro-7-(2,-
6- difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-285:
2-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}phenyl)-1,4,5,6-tetrahydropyrimidin-5-ol II-286:
N-{4-[(3-aminoazetidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2-fluoro--
6- methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-287:
N-{4-[(4-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-[2-
(trifluoromethyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-288:
9-chloro-N-(4-{[4-(methylamino)piperidin-1-yl]carbonyl}phenyl)-7-[-
2- (trifluoromethyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-289:
N-{4-[(3-aminopyrrolidin-1-yl)carbonyl]phenyl}-9-chloro-7-[2-
(trifluoromethyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-290:
9-chloro-N-(4-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)-7--
[2-
(trifluoromethyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-291:
9-chloro-N-(4-chloro-3-{[3-(methylamino)azetidin-1-yl]carbonyl}phe-
nyl)-
7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-292:
N-{3-[(4-aminopiperidin-1-yl)carbonyl]-4-chlorophenyl}-9-chloro-7--
(2,6- difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-293:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino)piperidin--
1- yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-294: methyl
4-amino-1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}benzoyl)piperidine-4-carboxylate II-295:
4-amino-1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}benzoyl)piperidine-4-carboxylic acid
II-296: N-{4-[(3-aminoazetidin-1-yl)carbonyl]phenyl}-9-chloro-7-[2-
(trifluoromethyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-297:
9-chloro-N-(4-{[3-(methylamino)azetidin-1-yl]carbonyl}phenyl)-7-[2-
- (trifluoromethyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-298:
N-{4-[(4-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-pyridin-2-
-yl- 5H-pyrimido[5,4-d][2]benzazepin-2-amine II-299:
N-{4-[(3-aminopyrrolidin-1-yl)carbonyl]phenyl}-9-chloro-7-pyridin--
2-yl- 5H-pyrimido[5,4-d][2]benzazepin-2-amine II-300: ethyl
2-amino-4-[(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}benzoyl)amino]butanoate II-301:
4-{[9-chloro-7-(3-fluoropyridin-2-yl)-5H-pyrimido[5,4-d][2]benzaze-
pin-2- yl]amino}benzoic acid II-302:
9-{[3-(dimethylamino)azetidin-1-yl]carbonyl}-7-(2-fluorophenyl)-N--
(3- methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-303:
7-(2-fluorophenyl)-2-[(3-methoxyphenyl)amino]-N-methyl-N-[3-
(methylamino)propyl]-5H-pyrimido[5,4-d][2]benzazepine-9-carboxamide
II-304:
N-{(4-[(4-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-(3-
fluoropyridin-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-305:
N-{4-[(3-aminopyrrolidin-1-yl)carbonyl]phenyl}-9-chloro-7-(3-
fluoropyridin-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-306:
2-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}phenyl)-4,5-dihydro-1H-imidazole-5-carboxylic acid
II-307:
N-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}phenyl)-2-(dimethylamino)acetamide II-308:
2-amino-N-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}phenyl)-2-methylpropanamide II-309:
ethyl (2R)-4-amino-2-[(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-
pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)amino]butanoate
II-310:
4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}benzoyl)-N-methylpiperazine-2-carboxamide II-311:
7-(2-fluorophenyl)-2-[(3-methoxyphenyl)amino]-N-(3-morpholin-4-
ylpropyl)-5H-pyrimido[5,4-d][2]benzazepine-9-carboxamide II-312:
9-[(3,5-dimethylpiperazin-1-yl)carbonyl]-7-(2-fluorophenyl)-N-(3-
methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-313:
9-chloro-N-(3-chloro-4-{[4-(dimethylamino)piperidin-1-
yl]carbonyl}phenyl)-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-314: ethyl
2-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}phenyl)-4,5-dihydro-1H-imidazole-5-
carboxylate II-315:
9-chloro-N-(4-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)-7-
pyridin-2-yl-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-316:
9-chloro-N-(4-{[4-(methylamino)piperidin-1-yl]carbonyl}phenyl)-7-
pyridin-2-yl-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-317:
4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}benzoyl)piperazine-2-carboxamide II-318:
N-{4-[(3-aminopyrrolidin-1-yl)carbonyl]-3-chlorophenyl}-9-chloro-7-
-(2,6- difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-319:
N-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}phenyl)piperidine-4-carboxamide II-320:
4-{[9-chloro-7-(2-fluoro-6-{methyl[2-(methylamino)ethyl]amino}phen-
yl)- 5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoic acid
II-321:
9-chloro-7-(2,4-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-
yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-322:
9-chloro-7-(2,4-dimethoxyphenyl)-N-{4-[(3,5-dimethylpiperazin-1-
yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-323:
9-chloro-7-(2-chloro-6-fluorophenyl)-N-{4-[(3-methylpiperazin-1-
yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-324:
9-chloro-7-(2-chloro-6-fluorophenyl)-N-{4-[(3,5-dimethylpiperazin--
1- yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-325:
9-chloro-7-(2-chloro-6-fluorophenyl)-N-(4-{[4-(methylamino)piperid-
in-1- yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-326:
9-chloro-7-(2-chloro-6-fluorophenyl)-N-(4-{[3-(methylamino)piperid-
in-1- yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-327:
9-chloro-7-(2-chloro-6-fluorophenyl)-N-(4-{[3-(methylamino)pyrroli-
din-1- yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-328: 9-chloro-N-(3,4-dimethoxyphenyl)-7-{2-
[(dimethylamino)methyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-
amine II-329:
9-chloro-7-(2-methoxyphenyl)-N-{4-[(3-methylpiperazin-1-
yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-330:
9-chloro-N-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-7-(2-
methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-331:
9-chloro-7-(2-methoxyphenyl)-N-(4-{[4-(methylamino)piperidin-1-
yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-332:
9-chloro-7-(2-methoxyphenyl)-N-(4-{[3-(methylamino)pyrrolidin-1-
yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-333:
9-chloro-7-(2-methoxyphenyl)-N-(4-{[3-(methylamino)piperidin-1-
yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-334:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}-N-methylbenzamide II-335:
4-{[9-chloro-7-(2-fluoro-6-{methyl[3-
(methylamino)propyl]amino}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-
2-yl]amino}benzoic acid II-336:
4-{[9-chloro-7-(2-fluoro-6-{methyl[3-
(methylamino)propyl]amino}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-
2-yl]amino}-N-methylbenzamide II-337:
1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}phenyl)ethanone II-338:
N-[3-(3-aminoprop-1-yn-1-yl)phenyl]-9-chloro-7-(2,6-difluorophenyl-
)-5H- pyrimido[5,4-d][2]benzazepin-2-amine II-339:
4-[(9-chloro-7-{2-fluoro-6-[(2-hydroxyethyl)amino]phenyl}-5H-
pyrimido[5,4-d][2]benzazepin-2-yl)amino]-N-methylbenzamide II-340:
4-[(7-{2-[(2-aminoethyl)amino]-6-fluorophenyl}-9-chloro-5H-
pyrimido[5,4-d][2]benzazepin-2-yl)amino]-N-methylbenzamide II-341:
4-amino-1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}benzoyl)-N-methylpiperidine-4-carboxamide
II-342:
4-[(9-chloro-7-{2-[4-(dimethylamino)piperidin-1-yl]-6-fluorophenyl-
}-5H- pyrimido[5,4-d][2]benzazepin-2-yl)amino]-N-methylbenzamide
II-343:
9-chloro-7-(2,6-difluorophenyl)-N-{3-[3-(dimethylamino)prop-1-yn-1-
- yl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-344:
9-chloro-7-(2,6-difluorophenyl)-N-(3-iodophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-345:
4-{[9-chloro-7-(2-{[2-(dimethylamino)ethyl]amino}-6-fluorophenyl)--
5H- pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide
II-346:
4-[(9-chloro-7-{2-[[2-(dimethylamino)ethyl](methyl)amino]-6-
fluorophenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-yl)amino]-N-
methylbenzamide II-347:
4-{[9-chloro-7-(2-fluoro-6-{methyl[2-(methylamino)ethyl]amino}phen-
yl)- 5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide
II-348:
4-({7-[2-(4-aminopiperidin-1-yl)-6-fluorophenyl]-9-chloro-5H-
pyrimido[5,4-d][2]benzazepin-2-yl}amino)-N-methylbenzamide II-349:
7-(2-fluorophenyl)-2-[(3-methoxyphenyl)amino]-N-methyl-N-[2-
(methylamino)ethyl]-5H-pyrimido[5,4-d][2]benzazepine-9-carboxamide
II-350:
4-amino-1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}benzoyl)piperidine-4-carboxamide II-351:
9-chloro-7-(2-chloro-6-fluorophenyl)-N-(4-{[3-(methylamino)azetidi-
n-1- yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-352:
9-chloro-7-(2,6-difluorophenyl)-N-(4-methyl-1,3-thiazol-2-yl)-5H-
pyrimido[5,4-d][2]benzazepin-2-amine II-353:
7-(2,6-difluorophenyl)-2-[(3-methoxyphenyl)amino]-5H-pyrimido[5,4-
d][2]benzazepine-9-carboxylic acid II-354:
4-({9-chloro-7-[2-fluoro-6-(methylamino)phenyl]-5H-pyrimido[5,4-
d][2]benzazepin-2-yl}amino)-N-methylbenzamide II-355:
2-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}-N-methyl-1,3-thiazole-4-carboxamide II-356:
N-1H-benzimidazol-2-yl-9-chloro-7-(2,6-difluorophenyl)-5H-
pyrimido[5,4-d][2]benzazepin-2-amine II-357:
7-(2,6-difluorophenyl)-2-[(4-methyl-1,3-thiazol-2-yl)amino]-5H-
pyrimido[5,4-d][2]benzazepine-9-carboxylic acid II-358:
3-amino-1-(3-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}phenyl)propan-1-one II-359:
1-(3-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}phenyl)-3-(dimethylamino)propan-1-one II-360:
2-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}-1,3-thiazole-4-carboxylic acid II-361: ethyl
2-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}-1,3-thiazole-4-carboxylate II-362:
9-chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-
yl)carbonyl]-1,3-thiazol-2-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-363: ethyl 2-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}-1,3-oxazole-5-carboxylate II-364:
2-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}-1,3-oxazole-5-carboxylic acid II-365:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[(3R)-3-methylpiperazin-1-
yl]carbonyl}-1,3-thiazol-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-366:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[(2R)-2-methylpiperazin-1-
yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-367:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(methylamino)pyrrolidin-1-
-
yl]carbonyl}-1,3-thiazol-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-368:
2-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}-1,3-oxazole-4-carboxylic acid II-369:
9-chloro-7-(2,6-difluorophenyl)-N-{5-[(3,5-dimethylpiperazin-1-
yl)carbonyl]-1,3-oxazol-2-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-370:
9-chloro-7-(2,6-difluorophenyl)-N-(5-{[3-(methylamino)pyrrolidin-1-
-
yl]carbonyl}-1,3-oxazol-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-371:
4-{[9-chloro-7-(2,6-difluorophenyl)-5-methyl-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}benzoic acid II-372:
9-chloro-7-(2,6-difluorophenyl)-N-{3-[3-(dimethylamino)propyl]phen-
yl}- 5H-pyrimido[5,4-d][2]benzazepin-2-amine II-373:
N-[3-(3-aminopropyl)phenyl]-9-chloro-7-(2,6-difluorophenyl)-5H-
pyrimido[5,4-d][2]benzazepin-2-amine II-374:
9-chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-
yl)carbonyl]-1,3-oxazol-2-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-375:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(methylamino)pyrrolidin-1-
-
yl]carbony}-1,3-oxazol-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-376: 7-(2,6-difluorophenyl)-2-({4-[(3,5-dimethylpiperazin-1-
yl)carbonyl]phenyl}amino)-N-methyl-5H-pyrimido[5,4-d][2]benzazepine-
9-carboxamide II-377:
2-{[4-(aminocarbonyl)phenyl]amino}-7-(2,6-difluorophenyl)-5H-
pyrimido[5,4-d][2]benzazepine-9-carboxylic acid II-378:
1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4d][2]benzaze-
pin-2-
yl]amino}benzoyl)-N-methyl-4-(methylamino)piperidine-4-carboxamide
II-379:
N-{4-[(3-amino-3-methylpyrrolidin-1-yl)carbonyl]phenyl}-9-chloro-7-
-(2,6- difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-380: 9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-methyl-3-
(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-381:
1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}benzoyl)-4-(methylamino)piperidine-4-carboxamide
II-382:
9-chloro-7-(2,6-difluorophenyl)-N-{4-[(3,3,5-trimethylpiperazin-1-
yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-383:
N-1-azabicyclo[2.2.2]oct-3-yl-4-{[9-chloro-7-(2,6-difluorophenyl)--
5H- pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide
II-384:
N-1-azabicyclo[2.2.2]oct-3-yl-4-{[9-chloro-7-(2,6-difluorophenyl)--
5H- pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzamide II-385:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}-N-hydroxybenzamide II-386:
N-{4-[(aminooxy)carbonyl]phenyl}-9-chloro-7-(2,6-difluorophenyl)-5-
H- pyrimido[5,4-d][2]benzazepin-2-amine II-387:
4-{[9-chloro-7-(2,6-difluorophenyl)-7H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}benzoic acid II-388:
4-{[9-chloro-7-(2,3-difluorophenyl)-7H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}benzoic acid II-389:
3-amino-1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}benzoyl)-N-methylpyrrolidine-3-
carboxamide II-390:
3-amino-1-(2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimid-
o[5,4- d][2]benzazepin-2-yl]amino}benzoyl)pyrrolidine-3-carboxamide
II-391:
9-chloro-7-(2,6-difluorophenyl)-N-{4-[(3,3-dimethylpiperazin-1-
yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-392:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)benzamide
II-393: 9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino)-3-
methylpyrrolidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-394:
9-chloro-7-(2,6-difluorophenyl)-N-(3-methyl-1H-pyrazol-5-yl)-5H-
pyrimido[5,4-d][2]benzazepin-2-amine II-395:
2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}benzoic acid II-396:
4-amino-1-(2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimid-
o[5,4- d][2]benzazepin-2-yl]amino}benzoyl)-N-methylpiperidine-4-
carboxamide II-397:
4-amino-1-(2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimid-
o[5,4-
d][2]benzazepin-2-yl]amino}benzoyl)-N,N-dimethylpiperidine-4-
carboxamide II-398:
4-[(9-methoxy-7-oxo-6,7-dihydro-5H-pyrimido[5,4-d][2]benzazepin-2-
yl)amino]benzoic acid II-399:
2-({4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}amino)-9-methox-
y- 5,6-dihydro-7H-pyrimido[5,4-d][2]benzazepin-7-one II-400:
9-methoxy-2-[(4-{[3-(methylamino)pyrrolidin-1-
yl]carbonyl}phenyl)amino]-5,6-dihydro-7H-pyrimido[5,4-
d][2]benzazepin-7-one II-401:
4-[(8-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[5,4-c]pyrrolo[3,2-
e]azepin-2-yl)amino]benzoic acid II-402:
2-({4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}amino)-8-methyl-
-5,8- dihydropyrimido[5,4-c]pyrrolo[3,2-e]azepin-7(6H)-one II-403:
2-[(3-methoxyphenyl)amino]-8-methyl-5,8-dihydropyrimido[5,4-
c]pyrrolo[3,2-e]azepin-7(6H)-one II-404:
9-chloro-2-[(3,4-dimethoxyphenyl)amino]-5,6-dihydro-7H-pyrimido[5,-
4- d][2]benzazepin-7-one II-405:
4-{[4-amino-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}benzoic acid II-406:
9-chloro-N-(3-chloro-4-{[4-(methylamino)piperidin-1-
yl]carbonyl}phenyl)-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-407:
9-chloro-N-(3-chloro-4-{[4-(methylamino)piperidin-1-
yl]carbonyl}phenyl)-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-408:
4-{[9-chloro-7-(2-fluoro-6-hydroxyphenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}benzoic acid II-409:
9-chloro-N-[4-(1,7-diazaspiro[4.4]non-7-ylcarbonyl)phenyl]-7-(2,6-
difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-410:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[2-(methylamino)-7-
azabicyclo[2.2.1]hept-7-yl]carbonyl}phenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-411:
1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}benzoyl)-N-methyl-3-(methylamino)pyrrolidine-3-
carboxamide II-412:
1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}benzoyl)-3-(methylamino)pyrrolidine-3-carboxamide
II-413:
1-(2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}benzoyl)-N-methyl-3-
(methylamino)piperidine-3-carboxamide II-414:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-methyl-3-
(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-415:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[3-methyl-3-
(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-416:
{2-Chloro-4-[9-chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-
benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(3-methyl-3-
methylamino-piperidin-1-yl)-methanone II-417:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[4-methyl-4-
(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-418:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[4-(dimethylamino)-4-
methylpiperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-419:
N-{4-[(4-amino-4-methylpiperidin-1-yl)carbonyl]phenyl}-9-chloro-7--
(2,6- difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-420:
9-chloro-N-(3-chloro-4-{[4-methyl-4-(methylamino)piperidin-1-
yl]carbonyl}phenyl)-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-421:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[4-methyl-4-
(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-422:
2-Chloro-4-[9-chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-
benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(4-methyl-4-
methylamino-piperidin-1-yl)-methanone II-423:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(3-fluoro-4-{[4-methyl-4-
(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-424:
9-chloro-N-{3-chloro-4-[(3,3,5,5-tetramethylpiperazin-1-
yl)carbonyl]phenyl}-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-425:
N-1-azabicyclo[2.2.2]oct-3-yl-4-{[9-chloro-7-(2,6-difluorophenyl)--
5H-
pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-fluoro-N-methylbenzamide
II-426:
N-1-azabicyclo[2.2.2]oct-3-yl-4-{[9-chloro-7-(2-fluoro-6-methoxyph-
enyl)-
5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide
II-427:
N-8-azabicyclo[3.2.1]oct-3-yl-4-{[9-chloro-7-(2,6-difluorophenyl)--
5H- pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide
II-428: 9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(methylamino)-8-
azabicyclo[3.2.1]oct-8-yl]carbonyl}phenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-429:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[3-(methylamino)-8-
azabicyclo[3.2.1]oct-8-yl]carbonyl}phenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-amine II-430:
4-{[7-(2,6-difluorophenyl)-9-methyl-5H-pyrimido[5,4-c]thieno[2,3-
e]azepin-2-yl]amino}benzoic acid II-431:
7-(2,6-difluorophenyl)-N-{4-[(3,3,5,5-tetramethylpiperazin-1-
yl)carbonyl]phenyl}-5H-pyrimido[5,4-c]thieno[2,3-e]azepin-2-amine
II-432:
N-{4-[(3-amino-3-methylpyrrolidin-1-yl)carbonyl]phenyl}-7-(2,6-
difluorophenyl)-10-methyl-5,10-dihydropyrimido[5,4-c]pyrrolo[2,3-
e]azepin-2-amine II-433:
7-(2,6-difluorophenyl)-9-methyl-N-(4-{[3-(methylamino)pyrrolidin-1-
- yl]carbonyl}phenyl)-5H-furo[2,3-c]pyrimido[4,5-e]azepin-2-amine
II-434: 4-(2,6-difluorophenyl)-2-methyl-N-(4-{[3-methyl-3-
(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)-6H-pyrimido[5,4-
c][1,3]thiazolo[4,5-e]azepin-9-amine II-435:
N-{4-[(3-amino-3-methylpyrrolidin-1-yl)carbonyl]phenyl}-7-(2-fluor-
o-6-
methoxyphenyl)-5,9-dihydropyrimido[5,4-c]pyrrolo[3,4-e]azepin-2-amine
II-436:
4-{[4-(2,6-difluorophenyl)-1-methyl-1,6-dihydropyrazolo[4,3-
c]pyrimido[4,5-e]azepin-9-yl]amino}benzoic acid II-437:
1-{4-[4-(2,6-Difluoro-phenyl)-2-methyl-6H-3-thia-5,8,10-triaza-
benzo[e]azulen-9-ylamino]-benzoyl}-4-dimethylamino-piperidine-4-
carboxylic acid methylamide II-438:
4-(4-{[7-(2,6-difluorophenyl)-5H-furo[3,2-c]pyrimido[4,5-e]azepin--
2- yl]amino}benzoyl)-N-methylpiperazine-2-carboxamide II-439:
4-(4-{[4-(2,6-difluorophenyl)-6H-isoxazolo[4,5-c]pyrimido[4,5-e]az-
epin-9- yl]amino}benzoyl)-N-methylpiperazine-2-carboxamide II-440:
4-(2,6-difluorophenyl)-9-[(4-{[3-methyl-3-(methylamino)pyrrolidin--
1- yl]carbonyl}phenyl)amino]-3,6-dihydroimidazo[4,5-c]pyrimido[4,5-
e]azepin-2(1H)-one II-441:
2-amino-N-(3-{[7-(2,6-difluorophenyl)-8,10-dimethyl-5H-pyrimido[5,-
4- c]thieno[3,4-e]azepin-2-yl]amino}phenyl)-N,2-dimethylpropanamide
II-442:
9-chloro-7-(2,6-difluorophenyl)-N-{3-[(2,2,6,6-tetramethylpiperidi-
n-4- yl)oxy]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-443:
4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin-
2-yl]amino}phenyl)-N-methyl-1-(methylamino)cyclohexanecarboxamide
II-444:
7-(3-{[7-(2-fluoro-6-methoxyphenyl)-9-methoxy-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}phenyl)-1,7-diazaspiro[4.4]nonan-6-one
II-445:
9-chloro-N-[4-(3,8-diazabicyclo[3.2.1]oct-3-ylcarbonyl)phenyl]-7-(-
2,6- difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-446:
1-(3-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}phenyl)-3,5,5-trimethylpiperazin-2-one II-447:
9-chloro-N-[4-(2,6-dimethylpiperidin-4-yl)phenyl]-7-(2-fluoro-6-
methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-448:
N-[4-(1-amino-1-methylethyl)phenyl]-9-chloro-7-(2,6-difluorophenyl-
)-5H- pyrimido[5,4-d][2]benzazepin-2-amine II-449:
N-[4-(2,5-diazaspiro[3.4]oct-2-ylcarbonyl)phenyl]-7-(2,6-difluorop-
henyl)-
10-methyl-5H-isothiazolo[5,4-c]pyrimido[4,5-e]azepin-2-amine
II-450: 4-(2,6-difluorophenyl)-1-methyl-9-[(4-{[4-methyl-4-
(methylamino)piperidin-1-yl]carbonyl}phenyl)amino]-1,6-dihydro-2H-
pyrimido[5,4-c][1,3]thiazolo[4,5-e]azepin-2-one II-451:
4-(2,6-difluorophenyl)-N-[4-(1H-imidazol-2-yl)phenyl]-1-methyl-1,6-
- dihydroimidazo[4,5-c]pyrimido[4,5-e]azepin-9-amine
II-452:
4-{[7-(2,6-difluorophenyl)-5H-[1]benzofuro[2,3-c]pyrimido[4,5-e]az-
epin-2- yl]amino}benzoic acid II-453:
7-(2-fluorophenyl)-N-{4-[(3,3,5,5-tetramethylpiperazin-1-
yl)carbonyl]phenyl}-8,9,10,11-tetrahydro-5H-pyrido[4',3':4,5]thieno[3,2-
c]pyrimido[4,5-e]azepin-2-amine II-454:
9-bromo-7-(2-fluorophenyl)-N-(4-{[3-(methylamino)pyrrolidin-1-
yl]carbonyl}phenyl)-5,8-dihydropyrimido[5,4-c]pyrrolo[3,2-e]azepin-2-
amine II-455: 7-(2-fluorophenyl)-N-(3-methyl-1H-indazol-6-yl)-5,12-
dihydropyrimido[4',5':5,6]azepino[4,3-b]indol-2-amine II-456:
1-(4-{[7-(2,6-difluorophenyl)-9,10-dimethyl-5,8-dihydropyrimido[5,-
4-
c]pyrrolo[3,2-e]azepin-2-yl]amino}benzoyl)-3-(methylamino)pyrrolidine-
3-carboxamide II-457:
{3-[9-Chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone
II-458:
[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-
-2- yl]-(2-methylaminomethyl-benzothiazol-6-yl)-amine II-459:
4-[9-Chloro-7-(2-isopropoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep-
in- 2-ylamino]-benzoic acid II-460:
4-[9-Chloro-7-(2-fluoro-6-isopropoxy-phenyl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-benzoic acid II-461:
4-[9-Chloro-7-(2-ethoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-benzoic acid II-462:
4-[9-Chloro-7-(2-ethoxy-6-fluoro-phenyl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-benzoic acid II-463:
4-[9-Chloro-7-(2-fluoro-6-methyl-phenyl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-benzoic acid II-464:
4-[9-Chloro-7-(2-trifluoromethoxy-phenyl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-benzoic acid II-465:
4-[9-Chloro-7-(2-fluoro-6-trifluoromethoxy-phenyl)-5H-
benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-466:
4-[9-Chloro-7-(3-fluoro-2-trifluoromethoxy-phenyl)-5H-
benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-467:
4-[9-Chloro-7-(2,3-dimethoxy-phenyl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-benzoic acid II-468:
4-[9-Chloro-7-(2-isobutyl-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-
-2- ylamino]-benzoic acid II-469:
4-(7-Benzofuran-2-yl-9-chloro-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino)-benzoic acid II-470:
4-[9-Chloro-7-(1-methyl-1H-pyrrol-2-yl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-benzoic acid II-471:
4-[9-Chloro-7-(1-methyl-1H-imidazol-2-yl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-benzoic acid II-472:
4-(9-Chloro-7-thiophen-2-yl-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino)-benzoic acid II-473:
4-[9-Chloro-7-(2H-pyrazol-3-yl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-benzoic acid II-474:
4-[9-Chloro-7-(2-ethynyl-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-benzoic acid II-475:
4-[7-(2-Aminomethyl-phenyl)-9-chloro-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-benzoic acid II-476:
4-[9-Chloro-7-(5-fluoro-2-methoxy-phenyl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-benzoic acid II-477:
4-[9-Chloro-7-(3-methoxy-pyridin-2-yl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-benzoic acid II-478:
4-[8-Fluoro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-benzoic acid II-479:
4-[8-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-benzoic acid II-480:
4-[11-Fluoro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-benzoic acid II-481:
4-[11-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2- ylamino]-benzoic acid II-482:
6-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-pyridazine-3-carboxylic acid II-483:
2-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
- ylamino]-1H-imidazole-4-carboxylic acid II-484:
4-[9-Chloro-7-(2-fluoro-phenyl)-4-methyl-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-benzoic acid II-485:
4-[4-Aminomethyl-9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-ylamino]-benzoic acid II-486:
4-(9-Aminomethyl-7-phenyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-
ylamino)-benzoic acid II-487:
9-Chloro-7-(2-fluorophenyl)-N-{4-[(2-methylpiperazin-1-
yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-488:
4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-
yl]amino}-N-[{3-[(dimethylamino)methyl]azetidin-1-
yl}(imino)methyl]benzamide II-489:
4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-
yl]amino}-N-[imino(piperazin-1-yl)methyl]benzamide II-490:
4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-
yl]amino}-N-[imino(3-methylpiperazin-1-yl)methyl]benzamide II-491:
4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-
yl]amino}-N-[[3-(dimethylamino)pyrrolidin-1-
yl](imino)methyl]benzamide II-492:
4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-
yl]amino}-N-[imino(4-methylpiperazin-1-yl)methyl]benzamide II-493:
4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-
yl]amino}-N-[(3,5-dimethylpiperazin-1-yl)(imino)methyl]benzamide
II-494:
1-[[(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazep-
in-2-
yl]amino}benzoyl)amino](imino)methyl]pyrrolidine-3-carboxamide
II-495:
1-[[(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazep-
in-2- yl]amino}benzoyl)amino](imino)methyl]piperidine-3-carboxamide
II-496:
4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-
yl]amino}-N-[{4-[(cyclopropylcarbonyl)amino]piperidin-1-
yl}(imino)methyl]benzamide II-497:
4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-
yl]amino}-N-[(dimethylamino)(imino)methyl]benzamide II-498:
N-[[(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazep-
in-2- yl]amino}phenyl)amino](imino)methyl]cyclopropanecarboxamide
II-499:
N-[[(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazep-
in-2- yl]amino}phenyl)amino](imino)methyl]-3-
(dimethylamino)cyclopentanecarboxamide II-500:
4-({9-Chloro-7-[2-fluoro-6-(trifluoromethyl)phenyl]-5H-pyrimido-
[5,4-d][2]benzazepin-2-yl}amino)benzoic acid II-501:
4-{[9-Chloro-7-(2,6-dichlorophenyl)-5H>-pyrimido[5,4-d][2]benza-
zepin-2- yl]amino}benzoic acid II-502:
4-{[9-Chloro-7-(2-fluoro-6-methylphenyl)-5H-pyrimido-
[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-503:
4-{[7-(2-Bromo-6-chlorophenyl)-9-chloro-5H-pyrimido-
[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-504:
9-Chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-
yl)carbonyl]-3-fluorophenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-505:
4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}-N-[(3,5-dimethylpiperazin-1-yl)(imino)methyl]-N-
methylbenzamide II-506:
4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}-N-[[3-(dimethylamino)azetidin-1-yl](imino)methyl]-N-
methylbenzamide II-507:
3-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2-
yl]amino}-N-[(3,5-dimethylpiperazin-1-yl)(imino)methyl]benzamide
II-508:
3-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2- yl]amino}-N-[[3-(dimethylamino)pyrrolidin-1-
yl](imino)methyl]benzamide II-509:
9-Chloro-7-(2,6-difluorophenyl)-N-{3-[(3,5-dimethylpiperazin-1-
yl)carbonyl]-4-fluorophenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-510: N-[[(4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido-
[5,4-d][2]benzazepin-2-yl]amino}phenyl)amino](imino)methyl]-3-
(dimethylamino)cyclopentanecarboxamide II-511:
N-[[(4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido-
[5,4-d][2]benzazepin-2-yl]amino}-2-fluorophenyl)amino](imino)methyl]-
3-(dimethylamino)cyclopentanecarboxamide II-512:
N-[[(5-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido-
[5,4-d][2]benzazepin-2-yl]amino)}-2-fluorophenyl)amino](imino)methyl]-
3-(dimethylamino)cyclopentanecarboxamide II-513:
N-(4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}phenyl)-3,5-dimethylpiperazine-1-carboximidamide
II-514:
4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2-
yl]amino}-N-[[3-(dimethylamino)pyrrolidin-1-yl](imino)methyl]-N-
methylbenzamide II-515:
N-(3-{[9-Chloro-7-(2,6-difluorophenyl)-5<i>H</i>-pyrim-
ido-
[5,4-d][2]benzazepin-2-yl]amino}phenyl)-3,5-dimethylpiperazine-1-
carboximidamide II-516:
N-(3-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin-
2-yl]amino}phenyl)-N,3,5-trimethylpiperazine-1-carboximidamide
II-517:
3-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2-
yl]amino}-N-[[3-(dimethylamino)azetidin-1-yl](imino)methyl]benzamide
II-518:
N-(5-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin- 2-yl]amino}-2-fluorophenyl)-N,3,5-trimethylpiperazine-1-
carboximidamide II-519:
N-[[(3-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido-
[5,4-d][2]benzazepin-2-yl]amino}phenyl)amino](imino)methyl]-3-
(dimethylamino)cyclopentanecarboxamide II-520:
9-Chloro-7-(2,6-difluorophenyl)-N-{3-[(3,5-dimethylpiperazin-1-
yl)(imino)methyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine
II-521:
N-(4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin-
2-yl]amino}phenyl)-N,3,5-trimethylpiperazine-1-carboximidamide
II-522:
N-(4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin-
2-yl]amino}-2-fluorophenyl)-3,5-dimethylpiperazine-1-carboximidamide
II-523:
9-Chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-
yl)(imino)methyl]-3-fluorophenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-
amine II-524:
5-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepi-
n-2-
yl]amino}-2-(2,6-dimethylpiperidin-4-yl)-1H-isoindole-1,3(2H)-dione
II-525:
N-[2-(Aminomethyl)-1H-benzimidazol-6-yl]-9-chloro-7-(2-fluoropheny-
l)- 5H-pyrimido[5,4-d][2]benzazepin-2-amine II-526:
9-Chloro-7-(2-fluorophenyl)-N-{2-[(methylamino)methyl]-1H-
benzimidazol-6-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-527:
9-Chloro-N-{2-[(dimethylamino)methyl]-1H-benzimidazol-6-yl}-7-(2-
fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-528:
9-Chloro-7-(2-fluorophenyl)-N-{2-[(methylamino)methyl]-1,3-
benzothiazol-6-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-529:
9-Chloro-7-(2,6-difluorophenyl)-N-{2-[(methylamino)methyl]-1H-
benzimidazol-6-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-530:
9-Chloro-7-(2,6-difluorophenyl)-N-{2-[(methylamino)methyl]-1,3-
benzoxazol-6-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-531:
9-Chloro-7-(2-fluorophenyl)-N-{2-[(methylamino)methyl]-1,3-
benzoxazol-6-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-532:
9-Chloro-7-(2,6-difluorophenyl)-N-{3-[(3,5-dimethylpiperazin-1-
yl)(imino)methyl]-4-fluorophenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-
amine II-533:
9-Chloro-7-(2,6-difluorophenyl)-N-{2-[(methylamino)methyl]-1,3-
benzothiazol-6-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-534:
{3-[9-Chloro-7-(2,6-difluorophenyl)-5H-benzo[c]pyrimido[4,5-e]azep-
in-2- ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-535:
3-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep-
in-2- ylamino]-N-methyl-N-(4-methyl-pentyl)-benzamide
[0097] In some embodiments, the Aurora kinase inhibitor is
represented by formula (III):
##STR00003##
[0098] or a pharmaceutically acceptable salt thereof;
[0099] wherein: [0100] R.sup.a is selected from the group
consisting of C.sub.1-3 aliphatic, C.sub.1-3 fluoroaliphatic,
-T-R.sup.1, --R.sup.2, and -T-R.sup.2; [0101] T is a C.sub.1-3
alkylene chain optionally substituted with fluoro; [0102] R.sup.1
is an optionally substituted aryl, heteroaryl, or heterocyclyl
group; [0103] R.sup.2 is selected from the group consisting of
halo, --C.ident.C--R.sup.3, --CH.dbd.CH--R.sup.3,
--N(R.sup.4).sub.2, and --OR.sup.5; [0104] R.sup.3 is hydrogen or
an optionally substituted aliphatic, aryl, heteroaryl, or
heterocyclyl group; [0105] each R.sup.4 independently is hydrogen
or an optionally substituted aliphatic, aryl, heteroaryl, or
heterocyclyl group; or two R.sup.4 on the same nitrogen atom, taken
together with the nitrogen atom form an optionally substituted 5-
to 6-membered heteroaryl or 4- to 8-membered heterocyclyl ring
having, in addition to the nitrogen atom, 0-2 ring heteroatoms
selected from N, O, and S; [0106] R.sup.5 is hydrogen or an
optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl
group; and [0107] R.sup.b is selected from the group consisting of
fluoro, chloro, --CH.sub.3, --CF.sub.3, --OH, --OCH.sub.3,
--OCF.sub.3, --OCH.sub.2CH.sub.3, and --OCH.sub.2CF.sub.3.
[0108] In some embodiments, R.sup.1 is a 5- or 6-membered aryl,
heteroaryl, or heterocyclyl ring optionally substituted with one or
two substituents independently selected from the group consisting
of halo, C.sub.1-3 aliphatic, and C.sub.1-3 fluoroaliphatic. In
certain embodiments, R.sup.1 is a phenyl, furyl, pyrrolidinyl, or
thienyl ring optionally substituted with one or two substituents
independently selected from the group consisting of halo, C.sub.1-3
aliphatic, and C.sub.1-3 fluoroaliphatic.
[0109] In some embodiments, R.sup.3 is hydrogen, C.sub.1-3
aliphatic, C.sub.1-3 fluoroaliphatic, or --CH.sub.2--OCH.sub.3.
[0110] In some embodiments, R.sup.5 is hydrogen, C.sub.1-3
aliphatic, or C.sub.1-3 fluoroaliphatic.
[0111] In certain embodiments, R.sup.a is halo, C.sub.1-3
aliphatic, C.sub.1-3 fluoroaliphatic, --OH, --O(C.sub.1-3
aliphatic), --O(C.sub.1-3 fluoroaliphatic), --C.dbd.C--R.sup.3,
--CH.dbd.CH--R.sup.3, or an optionally substituted pyrrolidinyl,
thienyl, furyl, or phenyl ring, wherein R.sup.3 is hydrogen,
C.sub.1-3 aliphatic, C.sub.1-3 fluoroaliphatic, or
--CH.sub.2--OCH.sub.3. In certain particular embodiments, R.sup.a
is selected from the group consisting of chloro, fluoro, C.sub.1-3
aliphatic, C.sub.1-3 fluoroaliphatic, --OCH.sub.3, --OCF.sub.3,
--C.ident.C--CH.sub.3, --C.ident.C--CH.sub.2OCH.sub.3,
--CH.dbd.CH.sub.2, --CH.dbd.CHCH.sub.3, N-methylpyrrolidinyl,
thienyl, methylthienyl, furyl, methylfuryl, phenyl, fluorophenyl,
and tolyl.
[0112] Table 2 provides the chemical names for specific examples of
compounds of formula (III).
TABLE-US-00002 TABLE 2 Examples of Compounds of Formula (III)
Chemical Name III-1
4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benza-
zepin-2- yl]amino}-2-methoxybenzoic acid III-2
4-{[9-ethynyl-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benz-
azepin- 2-yl]amino}-2-methoxybenzoic acid III-3
4-({9-chloro-7-[2-fluoro-6-(trifluoromethoxy)phenyl]-5H-pyrimido[5,4-
- d][2]benzazepin-2-yl}amino)-2-methoxybenzoic acid III-4
4-{[7-(2-fluoro-6-methoxyphenyl)-9-(1-methyl-1H-pyrrol-2-yl)-5H-
pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid
III-5
4-{[7-(2-fluoro-6-methoxyphenyl)-9-(4-methyl-3-thienyl)-5H-pyrimido[-
5,4- d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-6
4-{[7-(2-fluoro-6-methoxyphenyl)-9-(3-methyl-2-furyl)-5H-pyrimido[5,-
4- d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-7
4-({9-ethynyl-7-[2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl]-5H-pyrimi-
do[5,4- d][2]benzazepin-2-yl}amino)-2-methoxybenzoic acid III-8
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin--
2- yl]amino}-2-methoxybenzoic acid III-9
4-{[7-(2-fluoro-6-methoxyphenyl)-9-(2-methylphenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-10
4-{[7-(2-fluoro-6-methoxyphenyl)-9-prop-1-yn-1-yl-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-11
4-{[7-(2-fluoro-6-methoxyphenyl)-9-vinyl-5H-pyrimido[5,4-d][2]benza-
zepin-2- yl]amino}-2-methoxybenzoic acid III-12
4-{[7-(2-fluoro-6-methoxyphenyl)-9-(2-fluorophenyl)-5H-pyrimido[5,4-
- d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-13
4-{[7-(2-fluoro-6-methoxyphenyl)-9-(3-methoxyprop-1-yn-1-yl)-5H-
pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid
III-14
4-({7-(2-fluoro-6-methoxyphenyl)-9-[(1E)-prop-1-en-1-yl]-5H-pyrimid-
o[5,4- d][2]benzazepin-2-yl}amino)-2-methoxybenzoic acid III-15
4-({9-chloro-7-[2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl]-5H-pyrimi-
do[5,4- d][2]benzazepin-2-yl}amino)-2-methoxybenzoic acid III-16
4-{[7-(2-fluoro-6-methoxyphenyl)-9-(2-furyl)-5H-pyrimido[5,4-d][2]b-
enzazepin- 2-yl]amino}-2-methoxybenzoic acid III-17
4-{[9-chloro-7-(2-fluoro-6-hydroxyphenyl)-5H-pyrimido[5,4-d][2]benz-
azepin-2- yl]amino}-2-methoxybenzoic acid III-18
4-{[7-(2-fluoro-6-methoxyphenyl)-9-phenyl-5H-pyrimido[5,4-d][2]benz-
azepin- 2-yl]amino}-2-methoxybenzoic acid
[0113] In one embodiment, the compound of formula (III) is
4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-
-2-yl]amino}-2-methoxybenzoic acid or a pharmaceutically acceptable
salt thereof. In a particular embodiment, the compound of formula
(III) is sodium
4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]ben-
zazepin-2-yl]amino}-2-methoxybenzoate.
[0114] Any antibody capable of binding the CD20 antigen may be used
in the methods of the instant invention. Antibodies which bind the
CD20 antigen include, for example: C2138 (rituximab; RITUXAN.RTM.)
(U.S. Pat. No. 5,736,137, expressly incorporated herein by
reference); the yttrium-[90]-labeled 2138 murine antibody
designated Y2B8 (U.S. Pat. No. 5,736,137, expressly incorporated
herein by reference); murine IgG2a 131 optionally labeled with 131
1 to generate the 131 1-B1 antibody (BEXXAR.RTM.) (U.S. Pat. No.
5,595,721, expressly incorporated herein by reference); murine
monoclonal antibody 1F5 (Press et al. Blood 69(2): 584-591 (1987));
chimeric 2H7 antibody (U.S. Pat. No. 5,677,180 expressly
incorporated herein by reference); and monoclonal antibodies L27,
G28-2, 93-1 133, B--Cl or NU-B2 available from the International
Leukocyte Typing Workshop (Valentine et al., In: Leukocyte Typing
III (McMichael, Ed., p. 440, Oxford University Press (1987)).
[0115] In some embodiments, the anti-CD20 antibody is rituximab.
Rituximab is a genetically engineered chimeric murine/human
monoclonal antibody. Rituximab is an IgG, kappa immunoglobulin
containing murine light and heavy chain variable region sequences
and human constant region sequences. Rituximab has a binding
affinity for the CD20 antigen of approximately 8.0 nM. It is
commercially available, e.g., from Genentech (South San Francisco,
Calif.).
[0116] In some embodiments, the anti-CD20 antibody used in the
present invention may be administered along with standard of care
chemotherapeutic agents/combinations, such as, for example, CHOP
chemotherapy regimen, which is a regimen consisting of the
combination of cyclophosphamide, doxorubicin, vincristine and
prednisolone. Rituximab has been approved in combination with CHOP
chemotherapy for the treatment of certain types of lymphomas and
this combination has become known as RCHOP chemotherapy.
[0117] Compounds of formulas (I), (II) and (III), as well as
compounds disclosed in, for example, WO 05/111039, US2005/0256102,
US2007/0185087, WO 08/021,038, US2008/0045501, WO 08/063,525,
US2008/0167292, WO 07/113,212, EP1644376, US2005/0032839, WO
05/005427, WO 06/070192, WO 06/070198, WO 06/070202, WO 06/070195,
WO 06/003440, WO 05/002576, WO 05/002552, WO 04/071507, WO
04/058781, WO 06/055528, WO 06/055561, WO 05/118544, WO 05/013996,
WO 06/036266, US2006/0160874, US2007/0142368, WO 04/043953, WO
07/132,220, WO 07/132,221, WO 07/132,228, WO 04/00833 and WO
07/056,164 are inhibitors of Aurora kinase. The compounds can be
assayed in vitro or in vivo for their ability to bind to and/or
inhibit an Aurora kinase. In vitro assays include assays to
determine inhibition of the ability of an Aurora kinase to
phosphorylate a substrate protein or peptide. Alternate in vitro
assays quantitate the ability of the compound to bind to an Aurora
kinase. Inhibitor binding may be measured by radiolabelling the
inhibitor prior to binding, isolating the inhibitor/Aurora kinase
complex and determining the amount of radiolabel bound.
Alternatively, inhibitor binding may be determined by running a
competition experiment in which new inhibitors are incubated with
Aurora kinase bound to a known radioligand. The compounds also can
be assayed for their ability to affect cellular or physiological
functions mediated by Aurora kinase activity. Assays for each of
these activities are known in the art.
[0118] In another aspect, therefore, the invention provides a
method for inhibiting cellular growth/cellular proliferation
comprising contacting a cell with an Aurora kinase inhibitor in
combination with an anti-CD20 antibody, such as, e.g., rituximab.
In an another embodiement, the invention provides a method for
inhibiting cellular growth/cellular proliferation comprising
contacting a cell with an Aurora kinase inhibitor in combination
RCHOP chemotherapy.
[0119] Preferably, the method according to the invention causes an
inhibition of cell proliferation of the contacted cells. The phrase
"inhibiting cell proliferation" is used to denote an ability of an
inhibitor of Aurora kinase and/or anti-CD20 antibody to inhibit
cell number or cell growth in contacted cells as compared to cells
not contacted with the inhibitor and/or antibody. An assessment of
cell proliferation can be made by counting cells using a cell
counter or by an assay of cell viability, e.g., a BrdU, MTT, XIT,
or WST assay. Where the cells are in a solid growth (e.g., a solid
tumor or organ), such an assessment of cell proliferation can be
made by measuring the growth, e.g., with calipers, and comparing
the size of the growth of contacted cells with non-contacted
cells.
[0120] Preferably, the growth of cells contacted with an Aurora
kinase inhibitor and an anti-CD20 antibody is retarded by at least
about 50% as compared to growth of non-contacted cells. In various
embodiments, cell proliferation of contacted cells is inhibited by
at least about 75%, at least about 90%, or at least about 95% as
compared to non-contacted cells. In some embodiments, the phrase
"inhibiting cell proliferation" includes a reduction in the number
of contacted cells, as compare to non-contacted cells. Thus, an
inhibitor of Aurora kinase and/or an anti-CD20 antibody that
inhibits cell proliferation in a contacted cell may induce the
contacted cell to undergo growth retardation, to undergo growth
arrest, to undergo programmed cell death (i.e., apoptosis), or to
undergo necrotic cell death.
[0121] In another aspect, the invention provides a pharmaceutical
composition comprising i) an Aurora kinase inhibitor; and ii) an
anti-CD20 antibody. In some embodiments the Aurora kinase inhibitor
is selected from the group consisting of i) the compounds of
formulas (I), (II) and (III); ii) the compounds disclosed in, for
example, WO 05/111039, US2005/0256102, US2007/0185087, WO
08/021,038, US2008/0045501, WO 08/063,525, US2008/0167292, WO
07/113,212, EP1644376, US2005/0032839, WO 05/005427, WO 06/070192,
WO 06/070198, WO 06/070202, WO 06/070195, WO 06/003440, WO
05/002576, WO 05/002552, WO 04/071507, WO 04/058781, WO 06/055528,
WO 06/055561, WO 05/118544, WO 05/013996, WO 06/036266,
US2006/0160874, US2007/0142368, WO 04/043953, WO 07/132,220, WO
07/132,221, WO 07/132,228, WO 04/00833 and WO 07/056,164; and
pharmaceutically acceptable salts thereof.
[0122] If a pharmaceutically acceptable salt of the Aurora kinase
inhibitor is utilized in these compositions, the salt preferably is
derived from an inorganic or organic acid or base. For reviews of
suitable salts, see, e.g., Berge et al, J. Pharm. Sci. 66:1-19
(1977) and Remington: The Science and Practice of Pharmacy, 20th
Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000.
[0123] Nonlimiting examples of suitable acid addition salts include
the following: acetate, adipate, alginate, aspartate, benzoate,
benzene sulfonate, bisulfate, butyrate, citrate, camphorate,
camphor sulfonate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, fumarate, lucoheptanoate,
glycerophosphate, hemisulfate, heptanoate, hexanoate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
lactate, maleate, methanesulfonate, 2-naphthalenesulfonate,
nicotinate, oxalate, pamoate, pectinate, persulfate,
3-phenyl-propionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, tosylate and undecanoate.
[0124] Suitable base addition salts include, without limitation,
ammonium salts, alkali metal salts, such as sodium and potassium
salts, alkaline earth metal salts, such as calcium and magnesium
salts, salts with organic bases, such as dicyclohexylamine,
N-methyl-D-glucamine, t-butylamine, ethylene diamine, ethanolamine,
and choline, and salts with amino acids such as arginine, lysine,
and so forth.
[0125] Also, basic nitrogen-containing groups may be quaternized
with such agents as lower alkyl halides, such as methyl, ethyl,
propyl, and butyl chlorides, bromides and iodides; dialkyl
sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates,
long chain halides such as decyl, lauryl, myristyl and stearyl
chlorides, bromides and iodides, aralkyl halides, such as benzyl
and phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0126] The term "pharmaceutically acceptable carrier" is used
herein to refer to a material that is compatible with a recipient
subject, preferably a mammal, more preferably a human, and is
suitable for delivering an active agent to the target site without
terminating the activity of the agent. The toxicity or adverse
effects, if any, associated with the carrier preferably are
commensurate with a reasonable risk/benefit ratio for the intended
use of the active agent.
[0127] The terms "carrier", "adjuvant", or "vehicle" are used
interchangeably herein, and include any and all solvents, diluents,
and other liquid vehicles, dispersion or suspension aids, surface
active agents, isotonic agents, thickening or emulsifying agents,
preservatives, solid binders, lubricants and the like, as suited to
the particular dosage form desired. Remington: The Science and
Practice of Pharmacy, 20th Ed., ed. A. Gennaro, Lippincott Williams
& Wilkins, 2000 discloses various carriers used in formulating
pharmaceutically acceptable compositions and known techniques for
the preparation thereof. Except insofar as any conventional carrier
medium is incompatible with the compounds of the invention, such as
by producing any undesirable biological effect or otherwise
interacting in a deleterious manner with any other component(s) of
the pharmaceutically acceptable composition, its use is
contemplated to be within the scope of this invention. Some
examples of materials which can serve as pharmaceutically
acceptable carriers include, but are not limited to, ion
exchangers, alumina, aluminum stearate, lecithin, serum proteins,
such as human serum albumin, buffer substances such as disodium
hydrogen phosphate, potassium hydrogen phosphate, sodium carbonate,
sodium bicarbonate, potassium carbonate, potassium bicarbonate,
magnesium hydroxide and aluminum hydroxide, glycine, sorbic acid,
or potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, pyrogen-free water, salts or
electrolytes such as protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, and zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, wool fat, sugars such
as lactose, glucose, sucrose, starches such as corn starch and
potato starch, cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate,
powdered tragacanth; malt, gelatin, talc, excipients such as cocoa
butter and suppository waxes, oils such as peanut oil, cottonseed
oil, safflower oil, sesame oil, olive oil, corn oil and soybean
oil, glycols such as propylene glycol and polyethylene glycol,
esters such as ethyl oleate and ethyl laurate, agar, alginic acid,
isotonic saline, Ringer's solution, alcohols such as ethanol,
isopropyl alcohol, hexadecyl alcohol, and glycerol, cyclodextrins,
lubricants such as sodium lauryl sulfate and magnesium stearate,
petroleum hydrocarbons such as mineral oil and petrolatum. Coloring
agents, releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition, according to the judgment of the
formulator.
[0128] The pharmaceutical compositions of the invention can be
manufactured by methods well known in the art such as conventional
granulating, mixing, dissolving, encapsulating, lyophilizing, or
emulsifying processes, among others. Compositions may be produced
in various forms, including granules, precipitates, or
particulates, powders, including freeze dried, rotary dried or
spray dried powders, amorphous powders, tablets, capsules, syrup,
suppositories, injections, emulsions, elixirs, suspensions or
solutions. Formulations may optionally contain solvents, diluents,
and other liquid vehicles, dispersion or suspension aids, surface
active agents, pH modifiers, isotonic agents, thickening or
emulsifying agents, stabilizers and preservatives, solid binders,
lubricants and the like, as suited to the particular dosage form
desired.
[0129] According to a preferred embodiment, the compositions of
this invention are formulated for pharmaceutical administration to
a mammal, preferably a human being. Such pharmaceutical
compositions of the present invention may be administered orally,
parenterally, by inhalation spray, topically, rectally, nasally,
buccally, vaginally or via an implanted reservoir. The term
"parenteral" as used herein includes subcutaneous, intravenous,
intramuscular, intra-articular, intra-synovial, intrasternal,
intrathecal, intrahepatic, intralesional and intracranial injection
or infusion techniques. Preferably, the compositions are
administered orally, intravenously, or subcutaneously. The
formulations of the invention may be designed to be short-acting,
fast-releasing, or long-acting. Still further, compounds can be
administered in a local rather than systemic means, such as
administration (e.g., by injection) at a tumor site.
[0130] Liquid dosage forms for oral administration include, but are
not limited to, pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for
example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, cyclodextrins,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof. Besides inert diluents,
the oral compositions can also include adjuvants such as wetting
agents, emulsifying and suspending agents, sweetening, flavoring,
and perfuming agents.
[0131] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables. The
injectable formulations can be sterilized, for example, by
filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use. Compositions
formulated for parenteral administration may be injected by bolus
injection or by timed push, or may be administered by continuous
infusion.
[0132] In order to prolong the effect of a compound of the present
invention, it is often desirable to slow the absorption of the
compound from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of
absorption of the compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered compound form is accomplished by
dissolving or suspending the compound in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the
compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the compound in liposomes or microemulsions that are
compatible with body tissues.
[0133] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or Vagina
cavity and release the active compound.
[0134] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents such as
phosphates or carbonates.
[0135] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polyethylene
glycols and the like.
[0136] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose or starch. Such dosage forms may also comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions that can be used include polymeric
substances and waxes.
[0137] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, and
eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use
of transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0138] Formulation of an antibody or fragment to be administered
will vary according to the route of administration and formulation
(e.g., solution, emulsion, capsule) selected. An appropriate
pharmaceutical composition comprising an antibody or functional
fragment thereof to be administered can be prepared in a
physiologically acceptable vehicle or carrier. A mixture of
antibodies and/or fragments can also be used. For solutions or
emulsions, suitable carriers include, for example, aqueous or
alcoholic/aqueous solutions, emulsions or suspensions, including
saline and buffered media. Parenteral vehicles can include sodium
chloride solution, Ringer's dextrose, dextrose and sodium chloride,
lactated Ringer's or fixed oils. A variety of appropriate aqueous
carriers are known to the skilled artisan, including water,
buffered water, buffered saline, polyols (e.g., glycerol, propylene
glycol, liquid polyethylene glycol), dextrose solution and glycine.
Intravenous vehicles can include various additives, preservatives,
or fluid, nutrient or electrolyte replenishers (See, generally,
Remington's Pharmaceutical Science, 16th Edition, Mack, Ed. 1980).
The compositions can optionally contain pharmaceutically acceptable
auxiliary substances as required to approximate physiological
conditions such as pH adjusting and buffering agents and toxicity
adjusting agents, for example, sodium acetate, sodium chloride,
potassium chloride, calcium chloride and sodium lactate. The
antibodies and fragments of this invention can be lyophilized for
storage and reconstituted in a suitable carrier prior to use
according to art-known lyophilization and reconstitution
techniques. The optimum concentration of the active ingredient(s)
in the chosen medium can be determined empirically, according to
procedures well known to the skilled artisan, and will depend on
the ultimate pharmaceutical formulation desired. For inhalation,
the antibody or fragment can be solubilized and loaded into a
suitable dispenser for administration (e.g., an atomizer, nebulizer
or pressurized aerosol dispenser).
[0139] The antibody or fragment can be administered in a single
dose or multiple doses. The dosage can be determined by methods
known in the art and is dependent, for example, upon the antibody
or fragment chosen, the subject's age, sensitivity and tolerance to
drugs, and overall well-being. Antibodies and antigen-binding
fragments thereof, such as human, humanized and chimeric antibodies
and antigen-binding fragments can often be administered with less
frequency than other types of therapeutics. For example, an
effective amount of an antibody can range from about 0.01 mg/kg to
about 5 or 10 mg/kg administered daily, weekly, biweekly or
monthly.
[0140] The present invention provides new combination therapies for
the treatment of hematological malignancies. As used herein, the
term "hematological malignancies" includes any malignancy
associated with cells in the bloodstream; bone marrow; and the
lymphoid system including in the liver, spleen, and lymph nodes.
Nonlimiting examples of hematological malignancies include B and T
cell lymphomas and leukemias. Nonlimiting examples of B and T cell
lymphomas include, for example, low grade/follicular non-Hodgkin's
lymphoma (NHL), small lymphocytic (SL) NHL, T or B prolymphocytic
leukemia, diffuse large B cell NHL, peripheral T cell lymphomas,
mantle cell lymphoma, marginal zone lymphomas, B or T cell
lymphoblastic lymphoma, Burkitt's lymphoma, primary thyroid
lymphoma, Waldenstrom's Macroglobulinemia or lymphoplamacytic
lymphoma. Nonlimiting examples of leukemia include, for example,
chronic leukocytic leukemia, acute myelogenous leukemia (AML),
acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL),
chronic myelogenous leukemia, lymphoblastic leukemia, lymphocytic
leukemia, monocytic leukemia, myelogenous leukemia and
promyelocytic leukemia. Nonlimiting examples of hematological
malignancies additionally include, for example, multiple myeloma,
myelodysplastic syndromes (MDS), including refractory anemia (RA),
refractory anemia with ringed siderblasts (RARS), (refractory
anemia with excess blasts (RAEB), and RAEB in transformation
(RAEB-T); and myeloproliferative syndromes. It should be clear to
those of skill in the art that these pathological conditions may
often have different names due to differing/changing classification
systems.
[0141] In some embodiments, the hematological malignancy to be
treated by the method of the invention is one in which the activity
of an Aurora kinase is amplified and in which the CD20 antigen is
expressed. In some embodiments, the hematological malignancy is
selected from the group consisting of lymphoma, leukemia and
multiple myeloma. In certain embodiments, the lymphoma is selected
from the group consisting of B cell lymphoma, non-Hodgkin's
lymphoma and mantle cell lymphoma.
[0142] The term "patient", as used herein, means an animal,
preferably a mammal, more preferably a human. In some embodiments,
the patient has been treated with an agent, e.g., an Aurora kinase
inhibitor or an anti-CD20 antibody, prior to initiation of
treatment according to the method of the invention. In some
embodiments, the patient is a patient at risk of developing or
experiencing a recurrence of a hematological malignancy.
[0143] The expression "therapeutically effective amount" refers to
an amount of a drug substance (e.g., Aurora kinase inhibitor and/or
anti-CD20 antibody) effective for treatment or prophylaxis or
amelioration of symptoms of a hematological malignancy discussed
herein.
[0144] Compositions for use in the method of the invention may be
formulated in unit dosage form for ease of administration and
uniformity of dosage. The expression "unit dosage form" as used
herein refers to a physically discrete unit of agent appropriate
for the patient to be treated. It will be understood, however, that
the total daily usage of the compounds and compositions of the
present invention w111 be decided by the attending physician within
the scope of sound medical judgment. A unit dosage form for
parenteral administration may be in ampoules or in multi-dose
containers.
[0145] The Aurora kinase inhibitor may be administered with the
anti-CD20 antibody in a single dosage form or as a separate dosage
form. When administered as a separate dosage form, the anti-CD20
antibody may be administered prior to, at the same time as, or
following administration of the Aurora kinase inhibitor of the
invention.
[0146] As specifically contemplated herein, the instant invention
includes the following methods: A method to treat a patient
suffering from a hematological malignancy comprising administering
to said patient a therapeutically effective amount of a Aurora
kinase inhibitor simultaneously with or consecutively with (e.g.,
before or after) an anti-CD20 antibody; A method to treat a patient
suffering from a hematological malignancy comprising administering
to said patient a therapeutically effective amount of a Aurora
kinase inhibitor simultaneously with or consecutively with (e.g.
before or after) rituximab; A method to treat a patient suffering
from lymphoma comprising administering to said patient a
therapeutically effective amount of a Aurora kinase inhibitor
simultaneously with or consecutively with (e.g. before or after) an
anti-CD20 antibody; A method to treat a patient suffering from
lymphoma comprising administering to said patient a therapeutically
effective amount of a Aurora kinase inhibitor simultaneously with
or consecutively with (e.g. before or after) rituximab; A method to
treat a patient suffering from leukemia comprising administering to
said patient a therapeutically effective amount of a Aurora kinase
inhibitor simultaneously with or consecutively with (e.g. before or
after) an anti-CD20 antibody; A method to treat a patient suffering
from leukemia comprising administering to said patient a
therapeutically effective amount of a Aurora kinase inhibitor
simultaneously with or consecutively with (e.g. before or after)
rituximab; A method to treat a patient suffering from multiple
myeloma comprising administering to said patient a therapeutically
effective amount of a Aurora kinase inhibitor simultaneously with
or consecutively with (e.g. before or after) an anti-CD20 antibody;
and A method to treat a patient suffering from multiple myeloma
comprising administering to said patient a therapeutically
effective amount of a Aurora kinase inhibitor simultaneously with
or consecutively with (e.g. before or after) rituximab.
[0147] In some particular embodiments, the method of the invention
comprises administering to a patient suffering from a hematological
malignancy a therapeutically effective amount of an Aurora kinase
inhibitor of Formula (I), (II) or (III) as defined herein
simultaneously with or consecutively with (e.g., before or after)
rituximab.
[0148] Additionally, the invention relates to use of an Aurora
kinase inhibitor for the manufacture of a medicament for the
treatment of a hematological malignancy. In other particular
embodiments, the invention relates to the use of an Aurora kinase
inhibitor of Formula (I), (II) or (III) as defined herein, in the
manufacture of a medicament for use in combination therapy with
rituximab for the treatment of a hematological malignancy.
[0149] Unless defined otherwise, all technical and scientific terms
used herein have the same meanings as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, the preferred methods, devices and materials are herein
described. All publications mentioned herein are hereby
incorporated by reference in their entirety for the purpose of
describing and disclosing the materials and methodologies that are
reported in the publication which might be used in connection with
the invention.
EXAMPLES
Definitions
[0150] ANOVA Analysis of variance [0151] .DELTA.AUC difference in
the area under the curve [0152] BID twice daily [0153] DLBCL
diffuse large B-cell lymphoma [0154] IV intravenous(ly) [0155] MTD
maximum tolerated dose [0156] SCID severe combined immunodeficiency
[0157] po. Orally (by mouth, per os) [0158] QD once daily [0159] QW
or Q7D once weekly [0160] SC subcutaneous(ly) [0161] TG treatment
group [0162] TGI tumor growth inhibition
Experimental Overview
[0163] The Ly19-Luc, WSU-DLBCL2-Luc and PHTX-22-06 models described
in these studies are human DLBCL cell lines, transfected with
luciferase. These models were grown in immunocompromised mice
subcutaneously on the flank, or disseminated throughout the body by
tail vain injection.
4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-
-2-yl]amino}-2-methoxybenzoic acid (III-1) was administered orally
in both daily and twice daily dosing regimens and rituximab was
administered by IV injection QD7.times.3. The efficacy, tumor
growth and post-treatment survival of mice treated with Compound
III-4 and rituximab were compared as single agents or in
combination.
Sub-Cutaneous Models
Example 1
Combination of Aurora A Kinase Specific Inhibitor (Compound III-1)
and Rituximab in a Sub-Cutaneous Ly19 Lymphoma Model Grown in
Female SCID Mice
Experimental Overview
[0164] This is an in vivo experiment looking at tumor volume after
treatment with the combination of Compound III-1 and rituximab.
Tumor growth was monitored with vernier calipers. The mean tumor
volume was calculated using the formula V=W.sup.2.times.L/2. When
the mean tumor volume reached approximately 200 mm.sup.3, the
animals were randomized into the following eight treatment groups,
with each cohort made up of ten mice:
[0165] Vehicle
[0166] 3 mg/kg Compound III-1 (qd)
[0167] 10 mg/kg Compound III-1 (qd)
[0168] 10 mg/kg Compound III-1 (bid)
[0169] 10 mg/kg rituximab (qw)
[0170] 3 mg/kg Compound III-1 (qd)+10 mg/kg rituximab (qw)
[0171] 10 mg/kg Compound III-1 (qd)+10 mg/kg rituximab (qw)
[0172] 10 mg/kg Compound III-1 (bid)+10 mg/kg rituximab (qw)
[0173] The animals were inoculated with 4.0.times.10.sup.6 cells
from cell line Ly-19 at implant site Flank (cell suspension).
Compounds were administered for 21 days, and tumor volumes were
measured on days 0, 5, 13, 15, 18, and 21. After treatment ended,
the surviving mice continued to be evaluated on days 25, 28, 33,
36, 40, 43, 47, 50, 54, 60, and 62.
[0174] There were several endpoints in this experiment. The primary
goal was to determine whether the combination of Compound III-1 and
rituximab was more effective at reducing tumor volume than either
treatment alone. The second endpoint was to evaluate the rates of
tumor regrowth among the groups after treatment was completed.
Statistical Methodology
[0175] Statistical analysis was performed using a linear mixed
effects regression model. This model takes into account the
differences in trends of tumor growth between control and treated
samples. The statistical modeling was conducted in two steps: model
fitting and model selection. In the first step, a family of ten
closely related mixed-effects regression models was fitted to the
study data. Data from all time points in the study were used,
including mice that were sacrificed before the end of the study.
Each treatment group was fitted to a quadratic trend line for tumor
growth that consisted of up to three terms for tumor growth:
zero-order (intercept), first-order (slope) and second-order
(curvature). Each drug treatment was then modeled by up to two
interaction terms, one describing the difference in slope and the
other describing the difference in curvature due to drug
treatments. In addition, mouse-specific variability was accounted
for by including random effects for each mouse with up to three
terms: a mouse-specific intercept, slope or curvature effect.
Repeated measurements of tumor growth for a given mouse were
modeled using a compound symmetry covariance structure.
[0176] Model selection was performed by first filtering models that
the model-fitting algorithm was unable to fit in a numerically
stable way (specifically by removing models that demonstrated
sensitivity to the starting value of the autocorrelation
coefficient, and those for whom the variance-covariance matrix of
random effects was not positive definite). The best fit model was
then selected using a statistical criterion called the Bayes
Information Criterion (BIC), which is a measure of a model's
goodness of fit that takes into account the number of parameters
used by the model and the magnitude of the residuals--the
difference between fitted and observed values. The BIC favors
models that are parsimonious and that fit the underlying data
well.
[0177] The model fitting and selection procedure were performed
twice, once on the original (untransformed) data, and once on
log.sub.10-transformed data. Once the automated model-fitting and
selection procedure were completed, two best-fit models were
generated, one on log-transformed data and the other on
untransformed data. An investigator then studied the diagnostic
plots generated by the two statistical models and chose one of them
as the appropriate model for the study. This choice was made on the
basis of the distribution of the residuals as well as their
behavior with respect to the fitted values. Obvious trends in the
residuals were indicative of a poor model fit, suggesting trends
remaining in the data that the model had failed to take into
account.
[0178] Once an appropriate statistical model was selected, the
effect size was calculated as the difference between areas under
the model-fitted curves (.DELTA.AUC) for treated and control
groups, relative to the area under the model-fitted curve for the
control group. A MAUL of 0 meant that the curves for the treatment
and control groups were the same, whereas a negative .DELTA.AUC
indicated tumor growth inhibition upon treatment.
[0179] The significance of an effect size for a given pairwise
comparison was assessed using permutation analysis. During this
procedure, the assignment of mice to treatment and control groups
were randomly shuffled. The .DELTA.AUC metric was calculated for
comparisons between these new simulated groups, and the process was
repeated .about.2000 times. This gave rise to an empirical
distribution of the .DELTA.AUC values for the null hypothesis,
which stated that there was no difference in .DELTA.AUC values
between treatment and control groups. The reported p-value was the
proportion of permuted .DELTA.AUC values which were greater than
the .DELTA.AUC of the original group assignments. P-values <0.05
were considered significant.
[0180] For combination studies a synergy measure was also reported
(in addition to the measures of tumor growth inhibition for each
arm of the trial relative to control). For the synergy measure, the
approach and the results described here were essentially
equivalent, except that effect size was defined differently and
permutation testing was performed over four groups rather than two.
The effect size for combinations was defined as:
.DELTA.AUC=[AUC.sub.AxB-AUC.sub.ctl-(AUC.sub.A-AUC.sub.ctl+AUC.sub.B--
AUC.sub.ctl)]/AUC.sub.ctl (where AxB is the combination treatment,
ctl is the control, and A and B are the agents used singly). A
.DELTA.AUC of less than zero meant that a combination treatment led
to a greater decrease in area under the curve than the sum of
individual treatments, indicating a synergistic tumor growth
inhibition. Permutation testing was performed to compare the
difference between control and combination treatment against the
difference that would have been observed if the treatments were
purely additive. Synergy measures disclosed herein are provided
based on .DELTA.AUC calculations and based on TGI calculations.
Because .DELTA.AUC calculations capture the entire treatment period
within an experiment, such calculations are deemed more
comprehensive and more accurate than the TGI calculations.
Results
[0181] In this study, all animals in all of the treatment groups
endured the 21 days of treatment.
[0182] The average tumor volume in the vehicle group increased
almost sixteen fold from 180 mm.sup.3 at day 0 to over 2850
mm.sup.3 on day 21, and this resulted in a mean area under the
log(fold change) over time curve (AUC) of 12.9. The AUCs, and
therefore the tumor volumes, were smaller in each of the treatment
groups compared to vehicle (Table 3a). The results of the linear
regression model revealed that all of these differences relative to
the vehicle group were significant (Table 3b).
TABLE-US-00003 TABLE 3a Efficacy Analysis (Days 0 through 21) Pct
Decrease in AUC Relative to Mean Vehicle Treatment AUC Vehicle --
Compound III-1 (3 mg/kg qd) 22.9 Compound III-1 (10 mg/kg qd) 79.3
Compound III-1 (10 mg/kg bid) 105.6 Rituximab (10 mg/kg) 71.8
Compound III-1 (3 mg/kg qd) + Rituximab 130.0 (10 mg/kg) Compound
III-1 (10 mg/kg qd) + Rituximab 151.4 (10 mg/kg) Compound III-1 (10
mg/kg bid) + Rituximab 186.2 (10 mg/kg) Average percent change in
the area under the log.sub.10 fold change vs day curves (AUC)
relative to the mean AUC of the vehicle group.
TABLE-US-00004 TABLE 3b Efficacy Analysis (Days 0 through 21)
Treatment Group Reference P-value Compound III-1 (3 mg/kg qd)
Vehicle <0.01 Compound III-1 (10 mg/kg qd) <0.01 Compound
III-1 (10 mg/kg bid) <0.01 Rituximab (10 mg/kg) <0.01
Compound III-1 (3 mg/kg qd) + Rituximab <0.01 (10 mg/kg)
Compound III-1 (10 mg/kg qd) + Rituximab <0.01 (10 mg/kg)
Compound III-1 (10 mg/kg bid) + Rituximab <0.01 (10 mg/kg)
Compound III-1 (3 mg/kg) + Rituximab Compound III-1 <0.01 (10
mg/kg) (3 mg/kg) Rituximab <0.01 (10 mg/kg) Compound III-1 (10
mg/kg qd) + Rituximab Compound III-1 <0.01 (10 mg/kg) (10 mg/kg
qd) Rituximab <0.01 (10 mg/kg) Compound III-1 (10 mg/kg bid) +
Rituximab Compound III-1 <0.01 (10 mg/kg) (10 mg/kg bid)
Rituximab <0.01 (10 mg/kg) Summary of mixed-effects linear
regression results.
[0183] The three combination groups showed consistent decreases in
tumor volume and were all significantly lower than their respective
single agents alone. The Compound III-1 (3 mg/kg qd)+rituximab (10
mg/kg) group was synergistic, while the other two combinations were
additive when examining AUC values (Table 4). All three
combinations were sub-additive when looking at tumor growth
inhibition (Table 5, Table 6).
TABLE-US-00005 TABLE 4 Synergy Analysis (AUC, Days 0 through 21)
Synergy 95% Confidence Combination Score Interval Assessment
Compound III-1 -0.35 (-0.55, -0.15) Synergistic (3 mg/kg qd) +
Rituximab (10 mg/kg) Compound III-1 0.00 (-0.19, 0.18) Additive (10
mg/kg qd) + Rituximab (10 mg/kg) Compound III-1 -0.09 (-0.32, 0.14)
Additive (10 mg/kg bid) + Rituximab (10 mg/kg) Synergistic: score
< 0, Additive: score = 0, Sub-additive: score > 0. Assessment
based on whether 95% confidence interval included the value 0.
TABLE-US-00006 TABLE 5 Tumor Growth Inhibition (Day 21) Pct Tumor
Growth Inhibition Treatment Relative to Vehicle Mean Vehicle --
Compound III-1 (3 mg/kg qd) 54.7 Compound III-1 (10 mg/kg qd) 97.1
Compound III-1 (10 mg/kg bid) 102.2 Rituximab (10 mg/kg) 94.5
Compound III-1 (3 mg/kg qd) + Rituximab 103.7 (10 mg/kg) Compound
III-1 (10 mg/kg qd) + Rituximab 105.3 (10 mg/kg) Compound III-1 (10
mg/kg bid) + Rituximab 105.8 (10 mg/kg) Average percent decrease in
tumor growth relative to the mean tumor volume of the vehicle
group.
TABLE-US-00007 TABLE 6 Synergy Analysis (Tumor Growth Inhibition,
Day 21 95% Synergy Confidence Combination Score Interval Assessment
Compound III-1 (3 mg/kg qd) + 0.46 (0.35, 0.56) Sub-Additive
Rituximab (10 mg/kg) Compound III-1 (10 mg/kg qd) + 0.86 (0.81,
0.91) Sub-Additive Rituximab (10 mg/kg) Compound III-1 (10 mg/kg
bid) + 0.91 (0.86, 0.96) Sub-Additive Rituximab (10 mg/kg)
Synergistic: score < 0, Additive: score = 0, Sub-additive: score
> 0. Assessment based on whether 95% confidence interval
included the value 0.
[0184] To determine if tumors began to regrow after treatment
ended, mixed-effects piecewise linear regression models were built
to compare the slope of the log tumor volume between days 9 and day
21 to the slope between days 21 and 62 (or earlier if all animals
in a group died). All of the examined groups showed increases in
slope after treatment which were at least marginally significant
(Table 7), suggesting that tumor volumes stopped shrinking or, in
the cases of Compound III-1 (10 mg/kg qd) and rituximab (10 mg/kg),
began to grow again.
TABLE-US-00008 TABLE 7 Difference in Tumor Growth Rates Change in
Treatment Group Slope P-value Compound III-1 (10 mg/kg qd) 0.040
0.05 Compound III-1 (10 mg/kg bid) 0.018 <0.01 Rituximab (10
mg/kg) 0.039 <0.01 Compound III-1 (3 mg/kg qd) + Rituximab 0.012
0.02 (10 mg/kg) Compound III-1 (10 mg/kg qd) + Rituximab 0.053
<0.01 (10 mg/kg) Compound III-1 (10 mg/kg bid) + Rituximab 0.091
<0.01 (10 mg/kg) Breakpoint was set at day 21. Change in slope
was calculated as slope (day 21 to 62) - slope (day 13 to 21).
P-values <0.05 indicate that the difference in slope was
significantly different than zero.
Conclusions
[0185] The effects of Compound III-1 in combination with rituximab
upon tumor volumes were investigated in an in vivo sub-cutaneous
xenograft study. 3 mg/kg Compound III-1 dosed qd, 10 mg/kg Compound
III-1 dosed qd, and 10 mg/kg Compound III-1 dosed bid were
administered as both single agents and in combination with 10 mg/kg
of rituximab. All treatment groups had significantly lower mean
areas under the log(fold change) vs time curves relative to the
vehicle group during the first 21 days. Additionally, the mean AUC
of the 3 mg/kg Compound III-1 rituximab combination group was
significantly lower than that for the respective individual
treatment groups. Surprisingly, the combination of Compound III-1
with rituximab was demonstrated to have a synergistic therapeutic
effect in this sub-cutaneous lymphoma model. Once treatment was
completed, tumor volumes ceased to continue diminishing, and in
some cases began to regrow.
Example 2
Combination of Aurora A Kinase Specific Inhibitor (Compound III-1)
and Rituximab in a Subcutaneous WSU-Luc Lymphoma Model Grown in
Female SCID Mice
Experimental Overview
[0186] This is an in vivo experiment looking at tumor volume after
treatment with the combination of Compound III-1 and rituximab.
Tumor growth was monitored with vernier calipers. The mean tumor
volume was calculated using the formula V=W.sup.2.times.L/2. When
the mean tumor volume reached approximately 250 mm.sup.3, the
animals were randomized into the following six treatment groups,
with each group made up of ten mice:
[0187] Vehicle
[0188] 3 mg/kg Compound III-1 (P.O., qd)
[0189] 10 mg/kg Compound III-1 (P.O., qd)
[0190] 10 mg/kg rituximab (I.V., q7d)
[0191] 3 mg/kg Compound III-4+10 mg/kg rituximab
[0192] 10 mg/kg Compound III-1+10 mg/kg rituximab
[0193] The animals were inoculated with 4.0.times.10.sup.6 cells
from cell line WSU-DLCL2 at implant site Flank (cell suspension).
Compounds were administered for 21 days, and tumor volumes were
measured on days 0, 4, 7, 11, 15, 18, and 20. The primary goal was
to investigate whether the combination of Compound III-4 and
Rituximab was synergistic.
Statistical Methodology
[0194] The statistical methodology used in these experiments was
the same as that described in Example 1 above.
Results
[0195] The average tumor volume in the vehicle group increased over
nine-fold from 201 mm.sup.3 at day 0 to 1903 mm.sup.3 on day 20.
The tumor volumes were smaller in each of the treatment groups
compared to vehicle (Table 8).
TABLE-US-00009 TABLE 8 Efficacy Analysis (Days 0 through 20) Pct
Decrease in AUC Relative to Mean Treatment Vehicle AUC Vehicle --
Compound III-1 (3 mg/kg, PO, qd) 19.4 Compound III-1 (10 mg/kg, PO,
48.5 qd) Rituximab (10 mg/kg, IV, q7d) 43.2 Compound III-1 (3
mg/kg) + 60.5 Rituximab (10 mg/kg, IV, q7d) Compound III-1 (10
mg/kg) + 86.6 Rituximab (10 mg/kg, IV, q7d) Average percent change
in the area under the log.sub.10 fold change vs day curves (AUC)
relative to the mean AUC of the vehicle group.
[0196] Both combination groups were additive relative to their
respective individual treatments when comparing AUC values (Table
9).
TABLE-US-00010 TABLE 9 Synergy Analysis of AUC values (Days 0
through 20) Approx. 95% Synergy Confidence Combination Score
Interval Assessment Compound III-1 (3 mg/kg) + 0.02 (-0.12, 0.16)
Additive Rituximab (10 mg/kg, IV, q7d) Compound III-1 (10 mg/kg) +
0.05 (-0.08, 0.18) Additive Rituximab (10 mg/kg, IV, q7d)
Synergistic: score < 0, Additive: score = 0, Sub-additive: score
> 0. Assessment based on whether 95% confidence interval
included the value 0
[0197] Both treatment groups were sub-additive when looking at
tumor growth inhibition (Table 10, and Table 11).
TABLE-US-00011 TABLE 10 Tumor Growth Inhibition (Day 20) Pct Tumor
Growth Inhibition Treatment Relative to Vehicle Mean Vehicle --
Compound III-1 (3 mg/kg, PO, qd) 33.1 Compound III-1 (10 mg/kg, PO,
qd) 68.9 Rituximab (10 mg/kg, IV, q7d) 67.1 Compound III-1 (3
mg/kg) + 78.5 Rituximab (10 mg/kg, IV, q7d) Compound III-1 (10
mg/kg) + 95.5 Rituximab (10 mg/kg, IV, q7d) Average percent
decrease in tumor growth relative to the mean tumor volume of the
vehicle group.
TABLE-US-00012 TABLE 11 Synergy Analysis of Tumor Growth Inhibition
(Day 20) Approx. 95% Synergy Confidence Combination Score Interval
Assessment Compound (3 mg/kg) + 0.21 (0.08, 0.35) Sub-Additive
Rituximab (10 mg/kg, IV, q7d) Compound (10 mg/kg) + 0.40 (0.30,
0.51) Sub-Additive Rituximab (10 mg/kg, IV, q7d) Synergistic: score
< 0, Additive: score = 0, Sub-additive: score > 0. Assessment
based on whether 95% confidence interval included the value 0.
Conclusions
[0198] The effects of Compound III-1 in combination with rituximab
upon tumor volumes were investigated in an in vivo sub-cutaneous
xenograft study. 3 mg/kg and 10 mg/kg Compound III-1, dosed PO and
qd, and 10 mg/kg rituximab, dosed IV and q7d, were administered as
both single agents and in combination. Neither combination group
showed a synergistic interaction relative to their respective
single agents when looking at AUC or tumor growth inhibition.
Example 3
Combination of Aurora A Kinase Specific Inhibitor (Compound III-1)
and Rituximab in a Sub-Cutaneous Primary Diffuse Large B-Cell
Lymphoma Model (PHTX-22-06) Grown in Female SCID Mice
Experimental Overview
[0199] This is an in vivo experiment looking at tumor volume after
treatment with the combination of Compound III-1, and rituximab.
Tumor growth was monitored with vernier calipers. The mean tumor
volume was calculated using the formula V=W.sup.2.times.L/2. When
the mean tumor volume reached approximately 200 mm.sup.3, the
animals were randomized into the following six treatment groups,
with each group made up of ten mice:
[0200] Vehicle
[0201] 10 mg/kg Compound III-4 (P.O., bid)
[0202] 20 mg/kg Compound III-1 (P.O., bid)
[0203] 10 mg/kg rituximab (I.V., q7d)
[0204] 10 mg/kg Compound III-1+10 mg/kg rituximab
[0205] 20 mg/kg Compound III-1+10 mg/kg rituximab
[0206] The animals were inoculated with 2.times.5 mm.sup.3 tumor
mass from primary PHTX-22L-6 tumor chunk at implant site Flank
(trocar). Compounds were administered for 21 days, and tumor
volumes taken on days 0, 3, 7, 10, 14, 17, 21, 24, and 27 were
analyzed. The primary goal was to investigate whether the
combination of Compound III-1 and rituximab was synergistic.
Statistical Methodology
[0207] The statistical methodology used in these experiments was
the same as that described in Example 1 above.
Results
[0208] The average tumor volume in the vehicle group increased over
nine-fold from 268 mm.sup.3 at day 0 to 2563 mm.sup.3 on day 27.
The tumor volumes were smaller in each of the treatment groups
compared to vehicle (Table 12).
TABLE-US-00013 TABLE 12 Efficacy Analysis (Days 0 through 27) Pct
Decrease in AUC Relative to Mean Treatment Vehicle AUC Vehicle --
Compound III-1 (10 mg/kg, PO, bid) 52.3 Compound III-1 (20 mg/kg,
PO, bid) 79.3 Rituximab (10 mg/kg, IV, q7d) 41.9 Compound III-1 (10
mg/kg) + Rituximab (10 mg/kg, 75.8 IV, q7d) Compound III-1 (20
mg/kg) + Rituximab (10 mg/kg, 146.8 IV, q7d) Average percent change
in the area under the log.sub.10 fold change vs day curves (AUC)
relative to the mean AUC of the vehicle group.
[0209] Both combinations groups were additive relative to their
respective individual treatments when comparing AUC values (Table
13).
TABLE-US-00014 TABLE 13 Synergy Analysis of AUC values (Days 0
through 27) Approx. 95% Synergy Confidence Combination Score
Interval Assessment Compound III-1 (3 mg/kg) + 0.18 (-0.05, 0.42)
Additive Rituximab (10 mg/kg, IV, q7d) Compound III-1 (10 mg/kg) +
-0.26 (-0.80, 0.29) Additive Rituximab (10 mg/kg, IV, q7d)
Synergistic: score < 0, Additive: score = 0, Sub-additive: score
> 0. Assessment based on whether 95% confidence interval
included the value 0.
[0210] Both treatment groups were sub-additive when looking at
tumor growth inhibition (Table 14, and Table 15).
TABLE-US-00015 TABLE 14 Tumor Growth Inhibition (Days 0 through 27)
Pct Tumor Growth Inhibition Treatment Relative to Vehicle Mean
Vehicle -- Compound III-1 (10 mg/kg, PO, bid) 86.3 Compound III-1
(20 mg/kg, PO, bid) 95.1 Rituximab (10 mg/kg, IV, q7d) 57.3
Compound III-1 (10 mg/kg) + 97.3 Rituximab (10 mg/kg, IV, q7d)
Compound III-1 (20 mg/kg) + 105.1 Rituximab (10 mg/kg, IV, q7d)
Average percent decrease in tumor growth relative to the mean tumor
volume of the vehicle group.
TABLE-US-00016 TABLE 15 Synergy Analysis of Tumor Growth Inhibition
(Days 0 through 27) Approx. 95% Synergy Confidence Combination
Score Interval Assessment Compound III-1 (10 mg/kg) + 0.46 (0.26,
0.67) Sub- Rituximab (10 mg/kg, Additive IV, q7d) Compound III-1
(20 mg/kg) + 0.47 (0.27, 0.68) Sub- Rituximab (10 mg/kg, Additive
IV, q7d) Synergistic: score < 0, Additive: score = 0,
Sub-additive: score > 0. Assessment based on whether 95%
confidence interval included the value 0.
Conclusions:
[0211] The effects of Compound III-4 in combination with rituximab
upon tumor volumes were investigated in an in vivo sub-cutaneous
xenograft study. 10 mg/kg and 20 mg/kg Compound dosed PO and bid,
and 10 mg/kg rituximab, dosed IV and q7d, were administered as both
single agents and in combination. Neither combination examined
showed a synergistic interaction relative to their respective
single agents when looking at AUC or tumor growth inhibition, which
may be attributable to the significant single agent activity
observed in this model.
Disseminated Models
Example 4
Combination of Aurora A Kinase Specific Inhibitor (Compound III-1)
and Rituximab in a Disseminated Lymphoma Model of Ly19-Luc Cell
Line Grown in Female SCID Mice
Experimental Overview
[0212] The in vivo experiments using the disseminated Ly19-Luc
lymphoma model were performed in duplicate. The experiments
consisted of looking at tumor volume after treatment with the
combination of Compound III-1 and rituximab. Tumor volumes were
estimated once weekly throughout the inoculation and treatment
period using the Xenogen IVIS.RTM. imaging system (Xenogen
Corporation, Alameda, Calif.). To image the mice, an
intraperitoneal (IP) injection of luciferase (15 mg/ml), was
administered 10 minutes prior to procedure and mice were
anesthetized with 2% isofluorane 2-5 minutes throughout the
scanning procedure. For Xenogen imaging, each mouse was imaged on
dorsal and ventral views. The sum of 2 photon flux measurements was
used for the analysis.
[0213] The antitumor effects of each treatment group were
determined by calculating the percent TGI ([.DELTA. control mean
tumor volume-.DELTA. treated mean tumor volume].times.100/.DELTA.
control mean tumor volume) at the end of treatment. Mice were
weighed once weekly for the duration of the study and the maximal
percent body weight change was determined during the treatment
period. Animals were monitored for survival up to 132 days
following treatment. Animals were removed from the study when they
reached humane endpoints (>20%, body weight loss or paralysis of
either both front or hind limbs), the medial survival for each
group was determined and the survival rate of treatment groups were
compared to control. Treatment groups were evaluated to determine
if the effects of combination treatment were synergistic, additive
or sub-additive relative to control.
Statistical Analysis
[0214] Tumor growth inhibition (TGI): The photon flux data was
log.sub.10 transformed, and these values over the treatment period
were compared across treatment groups to assess if the differences
in the trends over time were statistically significant. A
mixed-effects linear regression model using a restricted maximum
likelihood was fit to the data. An ANOVA test was performed to
determine if there was a statistically significant difference
between the treatment groups and control.
[0215] Area under the curve (AUC): Log.sub.10-transformed fold
change photon flux values (tumor burden) from baseline were also
used to calculate AUC values for each animal. The AUC values from
the mice in a given treatment group were then averaged together to
generate mean AUC values and associated standard errors.
[0216] Synergy Effects: A synergy score calculation was used to
address the question of whether the effects of the combination
treatment were synergistic, additive, or sub-additive relative to
the individual treatments. The effect of the combination treatment
was considered synergistic if the synergy score was less than 0,
additive if the synergy score equaled 0, and sub-additive if the
synergy score was greater than O, Standard errors and 95%
confidence intervals (calculated as 2*SE) were used to determine if
the synergy scores were significantly different from zero.
[0217] Tumor Regrowth: To compare the tumor regrowth rates after
stopping treatment, mixed-effects piecewise linear regression
models were built separately for each treatment group with mice
monitored beyond treatment period. All P-values <0.05 were
called significant in this report.
[0218] Survival Rate: The survival rates of the animals in each
treatment group were plotted using Kaplan-Meier curves and the log
rank test was used to compare survival rates among pairs of
treatment groups.
Experiment #1
Disseminated Ly19-Luc Lymphoma Model
[0219] Animals bearing Ly19-Luc xenografts were treated with
Compound III-1 and rituximab as single agents and in combination.
The TGI, calculated on Day 24 was similar between treatment groups
(89.6%-100.3%). Tumor growth was significantly inhibited in all
single agent and combination treatment groups compared to vehicle
(p<0.001, Table 16).
TABLE-US-00017 TABLE 16 Dosing regimen for mice in first
disseminated Ly19 experimental group Maximum Survival Study/
Percent Body TGI Median Treatment Dose Route and Weight Mean.sup.c
Survival Group.sup.a (mg/kg).sup.b Dose Regimen Change (%) (%) p
Value.sup.d (Days) p Value.sup.e Vehicle 0 Po/QD .times. 21 -5.9,
Day 24 N/A N/A 25 N/A days Compound 3 Po/QD .times. 21 +6.2, Day 24
89.6, Day 24 <0.001 40 <0.001 III-1 days Compound 10 Po/QD
.times. 21 +3.3, Day 24 100, Day 24 <0.001 63.5 <0.001 III-1
days Compound 3 po/QD .times. 21 +8.7, Day 24 100, Day 24 <0.001
>100 <0.001* III-1 days Rituximab 10 IV/QW .times. 3 doses
Compound 10 po/QD .times. 21 +4.5, Day 24 100.3, Day 24 <0.001
>100 <0.001* III-1 days Rituximab 10 IV/QW .times. 3 doses
Rituximab 10 IV/QW .times. 3 +9.4, Day 24 99.6, Day 24 <0.001 66
<0.001 doses .sup.aThere were 10 mice in each treatment group.
.sup.bFor each dose, mice received 100 .mu.L of Compound III-1
and/or rituximab dosing solution prepared at 0.75, 2.5, 5.0 and 7.5
mg/mL (3, 10, 20, 30 mg/kg Compound III-1) or 2.0 mg/mL (10 mg/kg
rituximab). These dosing solutions were prepared routinely based on
historical mouse body weights of 25 or 20 grams respectively. All
doses were approximate. .sup.cMean tumor volumes, and TGI values
were calculated on Day 24 of treatment. .sup.dTGI = TGI calculation
B - tumor growth inihibition (TGI = [(.DELTA. control average
volume - .DELTA. treated average volume) .times. 100/.DELTA.
control average volume]. p values were calculated with an ANOVA, p
< 0.05 considered statistically significant. TGI values will be
greater than 100% when the average volume of the treatment group is
smaller at the end of treatment than at the beginning of treatment
.sup.eLog-rank analysis was used to compare the survival rate of
each treatment group to the vehicle group test, p < 0.05
considered statistically significant. *= Combination treatment
groups had significantly longer survival than the corresponding
individual treatment groups (p .ltoreq. 0.004). .sup.fAnimals dosed
with Compound III-1 at 10 mg/kg BID and 30 mg/kg QD received a 5
day dose holiday from Day 13 to Day 17. .sup.gThe vehicle used in
TG1 and the treatment groups was 10% HP-.beta.-CD plus 1%
NaHCO.sub.3. The vehicle used in the rituximab treatment groups was
0.9% saline
[0220] Individual whole body bioluminescence images were taken of
all mice in all treatment groups using the Xenogen IVIS.RTM.
imaging system. Any bioluminescence observed in these whole body
images represents tumor presence in the mouse model. Tumor
presence/growth in each mouse was assessed using this system prior
to treatment on Day 0; after the end of treatment on Day 24; and of
mice remaining in the study on Day 52. On Day 24 there is a
striking reduction in the fluorescent signal of the tumor as a
result of treatment with Compound III-1 at 10 mg/kg, with the
combination Compound III-1 at 3 mg/kg with rituximab and with the
combination Compound III-1 at 10 mg/kg with rituximab. Mice
receiving combination treatments show little or no evidence of the
disseminated lymphoma tumor. At Day 52 however, tumor growth was
evident in the mice remaining in the single agent Compound III-1 10
mg/kg and rituximab 10 mg/kg groups.
[0221] Photon flux values (tumor burden) from baseline to Day 24
were also used to calculate AUC values for each animal and the
percent decrease in the AUC relative to the mean vehicle AUC was
calculated (Table 17a). A synergy score calculation was applied to
the AUC data to determine whether the effects of the combination
treatment were synergistic, additive or sub-additive relative to
the individual treatments. This analysis showed that the
combination treatment of Compound III-1 at 3 mg/kg QD with
rituximab at 10 mg/kg QW was synergistic when comparing the
log.sub.10-transformed fold changes and the combination treatment
of Compound III-1 at 10 mg/kg with rituximab at 10 mg/kg QW
displayed an additive effect (Table 17b).
TABLE-US-00018 TABLE 17a Percent Decrease in AUC Relative to
Treatment Mean Vehicle AUC Vehicle N/A Compound III-1 (3 mg/kg-QD)
59.3 Compound III-1 (10 mg/kg-QD) 108.2 Rituximab (10 mg/kg-QW)
103.3 Compound III-1 (3 mg/kg) + 121.2 Rituximab (10 mg/kg)
Compound III-1 (10 mg/kg) + 121.4 Rituximab (10 mg/kg) Average
percent change in the area under the log.sub.10 fold change versus
day curves (AUC) relative to the mean AUC of the vehicle group for
each treatment group. Values greater than 100 indicate decreased
tumor burden.
TABLE-US-00019 TABLE 17b Synergy 95% Confidence Combination Score
Interval Assessment Compound III-1 (3 mg/kg) + -25.5 (-35.9, -15.0)
Synergistic Rituximab (10 mg/kg) Compound III-1 (10 mg/kg) + -4.3
(-11.5, 2.9) Additive Rituximab (10 mg/kg) Synergistic: score <
0, Additive: score = 0, Sub-Additive: score > 0. Assessment
based on whether 95% confidence interval included the value 0.
[0222] All vehicle treated mice reached the pre-defined endpoint of
paralysis and were euthanized between Day 21 and Day 31, however
all mice in the two combination treatment groups were alive up to
Day 132. By the end of the study (Day 132), the number of mice
remaining in the single agent Compound III-1 3 mg/kg, Compound
III-1 10 mg/kg and rituximab 10 mg/kg groups was 1 out of 10, 3 out
of 10 and 1 out of 10 respectively. The median survival in days for
each group is presented in Table 18. Log rank analysis, conducted
to compare the survival rates between groups, showed that all
treatment groups had significantly longer survival than the vehicle
group, and all combination groups had significantly longer survival
than each of the individual treatments (Table 16). Table 16 also
shows the mean maximum body weight change of the groups from Day 0
to Day 24. The maximum body weight loss for vehicle group was 5.9%
on Day 24. All other treatment groups gained weight during the
study, including the single agent and combination agent groups.
Treatment with Compound III-1 at 3 or 10 mg/kg on a QD schedule or
rituximab at 10 mg/kg on a QW schedule was well tolerated.
TABLE-US-00020 TABLE 18 Method of Study/Cell Dose Administration/
Noteworthy Line/Treatment (mg/kg) Frequency Endpoints Findings
Ly19-Luc 0 po/QD .times. 21 days TGI.sup.a N/A Vehicle (10%
HP-.beta.-CD Median Survival (Days) 25 plus 1% NaHCO.sub.3) BW
change.sup.b -5.9, Day 24 Compound III-1 3 po/QD .times. 21 days
TGI 89.6, p < 0.001 Median Survival (Days) 40, p < 0.01.sup.c
BW change +6.2, Day 24 Compound III-1 10 po/QD .times. 21 days TGI
100, p < 0.001 Median Survival (Days) 63.5, p < 0.01 BW
change +3.3%, Day 24 Compound III-1 + 3 po/QD .times. 21 days TGI
100, p < 0.001 Rituximab 10 IV/QW .times. 3 doses Median
Survival (Days) >100, p < 0.01 BW change +8.7%, Day 24
Compound III-1 + 10 po/QD .times. 21 days TGI 100.3, p < 0.001
Rituximab 10 IV/QW .times. 3 doses Median Survival (Days) >100,
p < 0.01 BW change +4.5%, Day 24 Rituximab 10 IV/QW .times. 3
doses TGI 99.6, p < 0.001 Median Survival (Days) 66, p < 0.01
BW change +9.4%, Day 24 .sup.aTGI was calculated on Day 24, p
values were calculated using a one-way ANOVA with p < 0.05
considered statistically significant .sup.bMaximum body-weight
change. .sup.cLog-rank analysis was used to compare the survival
rate of each treatment group to the vehicle group, p < 0.05
considered statistically significant,
Experiment #2
Disseminated Ly19-Luc Lymphoma Model
[0223] Mice were dosed according to the following treatment
groups:
TABLE-US-00021 TABLE 19 Dosing regimen for mice in second
disseminated Ly19 experimental group. Dose Dose Animals/ Dose Dose
Dose Solution Volume Group Test Article group Route (mg/kg) Regimen
(mg/ml) (ml) 1 Vehicle 10 PO 0 QD 100 2 Compound 10 PO 3 QD 0.75
100 III-1 3 Compound 10 PO/IV 3/10 QD/Q7D .times. 3 0.75/2.5 100
III-1 + Rituximab 4 Rituximab 10 IV 10 Q7D .times. 3 2.5 100 5
Rituximab 10 IV 5 Q7D .times. 3 1.25 100 6 Rituximab 10 IV 1 Q7D
.times. 3 0.25 100 7 Rituximab 10 IV 0.5 Q7D .times. 3 0.025
100
Results
[0224] Mice were weighed and tumor volumes were estimated with
Xenogen signal (average photon flux) calculation once a week
throughout the inoculation and the treatment period and after the
treatment until the end of study.
[0225] Treatment started 7 days following the inoculation of tumor
cells into the tail vein, with an average photon flux measurement
of 1.times.10.sup.7 on treatment Day 0. The TGI, calculated on Day
23 (2 days post dose) was similar between treatment groups
(75.8-100%). Tumor growth was significantly inhibited (P<0.001)
in all groups including the single agents (Compound III-1 or
rituximab) the combination of Compound III-1+rituximab treatment
group when compared to control (Table 20).
TABLE-US-00022 TABLE 20 TGI, tumor growth inhibition (TGI = 100 -
[(MTV treated/MTV control) .times. 100]; Mean Group/Test Dose Route
& Photon Flux TGI Article (mg/kg) N Schedule (Day 23) Day 23
P-value Group -- 10 PO QD .times. 3 wks 1.84E+09 -- 1/Vehicle Group
3 mg/kg 10 PO QD .times. 3 wks 2.34E+08 87.7% P < 0.001
2/Compound III-1 Group 3/ 3/10 mg/kg 10 PO QD .times. 3 wks
9.13E+05 100% P < 0.001 Compound IV Q7D .times. 3 wks III-1/
Rituximab Group 10 mg/kg 10 IV Q7D .times. 3 dose 8.43E+07 95.9% P
< 0.001 4/Rituximab Group 5 mg/kg 10 IV Q7D .times. 3 dose
1.57E+08 91.9% P < 0.001 5/Rituximab Group 1 mg/kg 10 IV Q7D
.times. 3 dose 3.52E+08 81.3% P < 0.001 6/Rituximab Group 0.1
mg/kg 10 IV Q7D .times. 3 dose 4.52E+08 75.8 P < 0.001
7/Rituximab P < 0.001 as determined by ANOVA
[0226] To better compare tumor growth and the response to treatment
between groups, mean AUC values were calculated for each group
based on photon flux levels representing tumor burden. The AUC
values from each group during the treatment period up to Day 23 (2
days post-treatment) are summarized in Table 21a.
TABLE-US-00023 TABLE 21a Mean Treatment AUC Vehicle 30.4 Rituximab
(0.5 mg/kg Q7D) 24.7 Rituximab (1 mg/kg Q7D) 18.8 Rituximab (5
mg/kg Q7D) 8.1 Rituximab (10 mg/kg Q7D)) 8.4 Compound III-1 (3
mg/kg QD) 18.2 Compound III-1 (3 mg/kg QD + -20.0 Rituximab 10
mg/kg Q7D) Mean area under the log.sub.10 fold change vs day curves
(AUC) for each treatment group. Negative values indicate decreased
tumor burden.
[0227] Average photon flux measurements increased approximately two
logs in the vehicle group during the 23-day period, which was an
average increase in tumor burden of nearly two-fold and resulted in
a mean AUC of 30.4 (Table 21a). The AUCs, and therefore the tumor
burden, were smaller in each of the treatment groups compared to
vehicle. A clear dose response in the AUC values was observed in
the rituximab treatment groups. The results of the linear
regression model revealed that all of these differences relative to
the vehicle group were significant (P<0.01, Table 21b).
Additionally, the combination treatment group (Compound III-1 3
mg/kg+rituximab 10 mg/kg) showed a consistent decrease in tumor
burden (-20.0), that was significantly lower than either of the
respective single agents alone (Compound III-1 3 mg/kg and
rituximab 10 mg/kg, P<0.01). In fact, the mice in this group had
photon flux values that were in the un-inoculated, baseline range
(photon flux=4-7.times.10 5), suggesting the tumors had
disappeared.
TABLE-US-00024 TABLE 21b Summary of mixed-effects linear regression
results Treatment Group Reference P-value Compound III-1 (3
mg/kg-QD) Vehicle <0.01 Rituximab (0.5 mg/kg Q7D) 0.02 Rituximab
(1 mg/kg Q7D) 0.01 Rituximab (5 mg/kg Q7D) <0.01 Compound III-1
(3 mg/kg QD) + <0.01 Rituximab (10 mg/kg Q7D) Compound III-1 (3
mg/kg QD) + Compound III-1 (3 mg/kg <0.01 Rituximab (10 mg/kg
Q7D) QD) Compound III-1 (3 mg/kg QD) + Rituximab (10 mg/kg Q7D)
<0.01 Rituximab (10 mg/kg Q7D)
[0228] A synergy score calculation was applied to these data to
determine whether the effects of the combination treatment were
synergistic, additive or sub-additive relative to the individual
treatments. This analysis showed that the combination treatment
with Compound III-1 at 3 mg/kg plus rituximab at 10 mg/kg was
synergistic when comparing the log.sub.10-transformed fold changes
(Table 22).
TABLE-US-00025 TABLE 22 Synergy 95% Confidence Combination Score
Interval Assessment Compound III-1 (3 mg/kg + -46.6 (-56.2, -37.0)
Synergistic Rituximab 10 mg/kg Synergistic: score < 0, Additive:
score = 0, Sub-Additive: score > 0. Assessment based on whether
95% confidence interval included the value 0.
[0229] Following treatment, tumor growth was monitored in remaining
mice up to Day 125 to determine if tumors would re-grow after
treatment ended. Mixed-effects piecewise linear regression models
were built to compare the slope of the log flux between Days 9 and
23 to the slope between Days 23 and 125 (or earlier if all animals
in a group died). Due to loss of mice from paralysis in many
groups, only the combination Compound III-1 and rituximab group and
the rituximab 10 and 5 mg/kg groups were evaluated. None of the
groups had significantly different changes in slopes after
treatment stopped on Day 23 (Table 23), indicating that tumor
growth/inhibition did not significantly change following the
cessation of treatment. These data suggest that the inhibitory
effects of each of the respective treatments appear to continue up
to 104 days following treatment.
TABLE-US-00026 TABLE 23 Breakpoint was set at Day 23. Difference
was calculated as slope (Day 23 to 125) - slope (Day 9 to 23).
Difference Treatment Group in Slope P-value Rituximab (5 mg/kg)
-0.01 0.49 Rituximab (10 mg/kg) -0.01 0.40 Compound III-1 (3 mg/kg
+ 0.00 0.86 Rituximab 10 mg/kg) P-values <0.05 indicate that the
difference in slope was significantly different than zero.
[0230] Individual whole body bioluminescence images were taken of
all mice in all treatment groups using the Xenogen IVIS.RTM.
imaging system. Tumor presence/growth in each mouse was assessed
using this system prior to treatment on Day 0; 3 days before the
end of treatment (Day 18); and 104 days following the end of
treatment (Day 125). On Day 18 there is a striking reduction in the
fluorescent signal of the tumor as a result of treatment with the
combination Compound III-1 at 3 mg/kg with rituximab as compared to
any of the other treatment groups or control group. Mice receiving
combination treatments show little or no evidence of the
disseminated lymphoma tumor, whereas tumor growth was evident in
the single agent Compound III-1 3 mg/kg group and all of the single
agent rituximab treatment groups. Bioluminescence images of mice in
the combination treatment group, i.e., Compound III-1 at 3 mg/kg
with rituximab, on Day 125, show no evidence of tumor growth. Due
to the loss of mice from paralysis in the other treatment groups,
bioluminescence imaging was not conducted in these groups.
[0231] All vehicle treated mice reached the pre-defined endpoint of
paralysis and were euthanized between Day 21 and Day 31. A dose
response was observed in the survival rate of rituximab treated
mice with 3/10, 1/10, 1/10 and 0/10 mice remaining by Day 125 in
the 10, 5, 1 and 0.5 mg/kg groups respectively. Log rank analysis,
conducted to compare the survival rates between groups,
demonstrates that all treatment groups had significantly longer
survival than the vehicle group, and the combination group had
significantly longer survival than each of the individual
treatments. None of the mice in the combination treatment group
were removed during the 125 days of the study
[0232] Table 24 shows the mean maximum body weight change of the
groups from Day 0 to Day 22 of the study. The maximum body weight
loss for vehicle group was 1.75% on Day 22. All other treatment
groups gained weight during the study, including the single agent
and combination agent groups. Treatment with Compound III-1 at 3
mg/kg on a QD schedule, or rituximab up to 10 mg/kg on a Q7D
schedule, were well tolerated.
TABLE-US-00027 TABLE 24 Body weight (BW) change Mean Test Dose
Route & BW Mean BW Maximum BW Article (mg/kg) N Schedule Day 0
Day 22 Change (%) Day 22 Vehicle -- 10 PO QD .times. 19.46 19.12
-1.75 3 wks Compound 3 mg/kg 10 PO QD .times. 19.20 19.81 +3.1
III-1 3 wks Compound 3 mg/kg 10 PO QD .times. 18.02 18.21 +1.05
III-1/ 3 wks/ Rituximab 10 mg/kg IV Q7D .times. 3 dose Rituximab 10
mg/kg 10 IV Q7D .times. 3 19.11 19.72 +3.19 dose Rituximab 5 mg/kg
10 IV Q7D .times. 3 18.55 19.55 +5.39 dose Rituximab 1 mg/kg 10 IV
Q7D .times. 3 19.43 20.25 +4.22 dose Rituximab 0.5 mg/kg 10 IV Q7D
.times. 3 19.30 20.27 +5.02 dose
Conclusions
[0233] In vivo imaging experiments in SCID mice bearing Ly19-Luc
disseminated lymphoma tumors were performed in duplicate in order
to confirm the effects of Compound III-1 and rituximab as single
agents and as combination treatment. Tumor burden and TGI were
determined using quantitative Xenogen imaging in mice receiving
various doses of Compound III-1 with and without 10 mg/kg of
rituximab. Tumor growth was significantly inhibited in all
treatment groups (P<0.001). Tumor burden, presented as the AUC
of photon flux values during the treatment period, was
significantly lower in all treatment groups compared to control.
Combination treatment with Compound III-1 at 3 mg/kg and rituximab
at 10 mg/kg appears to provide a synergistic effect that
significantly lowered tumor burden when compared to either of the
agents alone, thereby corroborating the synergistic effect observed
in the sub-cutaneous Ly19 lymphoma model discussed above (refer to
Example 1). The survival of the animals was significantly higher in
each of the treatment groups compared to the vehicle group and
significantly higher in the combination groups compared to the
respective individual treatments. Following treatment, there were
no significant changes in tumor growth rates in any of the groups
up to 52 days in the first replicate and 125 days in the second
replicate. In summary, results from the two experiments are
consistent with one another and these data confirm that a
combination of Compound III-1 and rituximab is the most effective
treatment for disseminated Ly19-Luc lymphoma in SCID mice,
resulting in a reduction of tumor burden to undetectable
levels.
Experiment 5
Combination of Aurora A kinase Specific Inhibitor (Compound III-1)
and Rituximab in a Disseminated Lymphoma Model of WSU-DLBCL2-luc
Cell Line Grown in Female SCID Mice
Experimental Overview
[0234] Two separate studies were conducted in the WSU-DLBCL2-luc
model. Compound III-1 was administered initially at low doses (3 or
10 mg/kg on a QD schedule) alone and in combination with rituximab,
or at higher doses (10 or 20 mg/kg on a BID schedule) alone or in
combination with rituximab. After treatment, animals were monitored
up to Day 132 to compare the survival between treatment groups and
vehicle.
[0235] In the first WSU-DLBCL2 study, Compound III-4 when dosed
alone at either 3 mg/kg or 10 mg/kg QD did not significantly
inhibit tumor growth in this model (TGI=50.9%, p>0.05,
TGI=88.2%, p>0.05 respectively). Rituximab dosed alone (10 mg/kg
QW) or in combination with Compound III-1 at 3 or 10 mg/kg
significantly inhibited tumor growth (TGI=83.6%, p<0.05,
TGI=91.8%, p<0.05, TGI=99.0%, p<0.001 respectively) in SCID
mice bearing WSU-DLCL2-Luc xenografts (Table 25). In the second
study, when Compound III-1 was dosed alone at either 10 mg/kg or 20
mg/kg BID, tumor growth was significantly inhibited in this model
(TGI=99.7%, p<0.001, for both groups). Rituximab dosed alone at
10 mg/kg QW (TGI=88.4%, p<0.001) and in combination with
Compound III-4 at 10 or 20 mg/kg BID resulted in significant tumor
growth inhibition (TGI=99.6% and 99.9% respectively, p<0.001 for
both), (Table 25).
TABLE-US-00028 TABLE 25 Tumor Growth Inhibition, Body Weight Change
and Survival Maximum Percent Survival Body TGI Median Dose Route
and Dose Weight p Survival p (mg/kg).sup.b Regimen Change (%) Mean
(%).sup.c Value.sup.d (Days) Value.sup.d 1st WSU- DLBCL2
Study/Treatment Group.sup.a Vehicle.sup.f 0 po/QD .times. 21 days
-0.3, Day 21 N/A N/A 37 N/A Compound 3 po/QD .times. 21 days -3.1,
Day 21 50.9, Day 21 >0.05 46.5 0.040 III-1 Compound 3 po/QD
.times. 21 days -2.4, Day 21 91.8, Day 21 <0.05 73 0.003 III-1
10 IV/QW .times. 3 doses Rituximab Compound 10 po/QD .times. 21
days -4.5, Day 21 88.2, Day 21 >0.05 44 0.017 III-1 Compound 10
po/QD .times. 21 days -2.8, Day 21 99.0, Day 21 <0.001 52.5
<0.001 III-1 10 IV/QW .times. 3 doses Rituximab Rituximab 10
IV/QW .times. 3 doses +1.7, Day 21 83.6, Day 21 <0.05 61
<0.001 2nd WSU- DLBCL2 study Vehicle 0 po/BID .times. 21 days
+2.5, Day 22 N/A N/A 45 N/A Compound 10 po/BID .times. 21 days
-3.9, Day 19 99.7, Day 22 <0.001 70 <0.001 III-1 Compound 20
po/QD .times. 21 days -8.9, Day 9 99.7, Day 22 <0.001 111.5
<0.001 III-1g Compound 10 po/BID .times. 21 days -1.7, Day 19
99.6, Day 22 <0.001 121 <0.001 III-1 10 IV/QW .times. 3 doses
Rituximab Compound 20 po/BID .times. 21 days -12.2, Day 9 99.9, Day
22 <0.001 >128 <0.001 III-1g 10 IV/QW .times. 3 doses
Rituximab Rituximab 10 IV/QW .times. 3 doses +6.3, Day 22 88.4, Day
22 <0.001 59 >0.05 .sup.aThere were 10 mice in each treatment
group. .sup.bFor each dose, mice received 100 .mu.L of Compound
III-1 and/or rituximab dosing solution prepared at 0.75, 2.5, 5.0
and 7.5 mg/mL (3, 10, 20, 30 mg/kg Compound III-1) or 2.0 mg/mL (10
mg/kg rituximab). These dosing solutions were prepared routinely
based on historical mouse body weights of 25 or 20 grams
respectively. All doses were approximate. .sup.cMean tumor volumes,
and TGI values were calculated on Day 21 (1.sup.st study) and Day
22 (2.sup.nd study) of treatment. .sup.dTGI = TGI calculation B -
tumor growth inhibition (TGI = [(.DELTA. control average volume -
.DELTA. treated average volume) .times. 100/.DELTA. control average
volume]. p values were calculated with an ANOVA, p < 0.05
considered statistically significant .sup.eLog-rank analysis was
used to compare the survival rate of each treatment group to the
vehicle group, p < 0.05 considered statistically significant,
.sup.fThe vehicle used in TG1 and the treatment groups was 10%
HP-.beta.-CD plus 1% NaHCO. The vehicle used in the rituximab
treatment groups was 0.9% saline. .sup.gAnimals dosed with Compound
III-1 at 20 mg/kg BID, and animals in the combination group dosed
with 20 mg/kg Compound III-1 and rituximab at 10 mg/kg QW received
a dose holiday for 5 days, from Day 9 to Day 13.
[0236] After treatment, animals were monitored for survival up to
Day 125 (1.sup.st study) or Day 130 (2.sup.nd study). The median
survival in days for each group is presented in Table 25 and the
mean survival rate of the treatment groups were compared to the
vehicle group. In the 1st study, all vehicle animals were
euthanized at the humane endpoint (paralysis) by Day 44 and all
treatment groups showed significantly longer survival relative to
the vehicle group (p<0.04-0.001, Table 25). By the end of the
study (Day 125), 1 out of 10 mice remained in the single agent
rituximab group and in the 10 mg/kg Compound III-1 combination
treatment group. In the 2.sup.nd study, all vehicle animals were
euthanized at the humane endpoint by Day 68. With the exception of
rituximab treatment alone (p>0.05), all treatment groups showed
significantly longer survival relative to the vehicle group
(p<0.001, Table 25). The number of mice remaining at the end of
the study (Day 130) was 1 out of 10 in the 10 mg/kg single agent
Compound III-1 and rituximab groups, 5 out of 10 in the 20 mg/kg
Compound III-1 single agent group and the 10 mg/kg Compound III-1
combination group, and 8 out of 10 mice in the mg/kg Compound III-1
combination group.
[0237] The tumor volumes were smaller in each of the treatment
groups in the first study compared to vehicle (Table 26a). Both
combinations groups were additive relative to their respective
individual treatments when comparing AUC values (Table 26b).
TABLE-US-00029 TABLE 26a Area Under the Curve Efficacy and Synergy
Analysis (Days 0 Through 21) for first study. Average percent
change in the area under the log.sub.10 photon flux vs day curves
(AUC) relative to the mean AUC of the vehicle group. Pct Decrease
in AUC Relative to Mean Treatment Vehicle AUC Vehicle -- Compound
III-1 (3 mg/kg, PO, QD) 21.1 Compound III-1 (10 mg/kg, PO, QD) 42.0
Rituximab 10 (mg/kg, IV, QW) 44.4 Compound III-1 (3 mg/kg) + 48.6
Rituximab (10 mg/kg) Compound III-1 (10 mg/kg) + 75.0 Rituximab (10
mg/kg)
TABLE-US-00030 TABLE 26b Area Under the Curve Efficacy and Synergy
Analysis (Days 0 Through 21) for first study. 95% Synergy
Confidence P Combination Score Interval Value Assessment Compound
III-1 (3 mg/kg 16.9 (-10.8, 44.6) 0.22 Additive QD) + Rituximab
Compound III-1 (10 mg/kg 11.3 (-12.5, 35.1) 0.33 Additive QD) +
Rituximab Synergistic: score < 0, Additive: score = 0,
Sub-additive: score > 0. Assessment based on whether the synergy
score was significantly different from 0.
[0238] The tumor volumes were smaller in each of the treatment
groups in the second study compared to vehicle (Table 27a). Both
combinations groups were sub-additive relative to their respective
individual treatments when comparing AUC values (Table 27b).
TABLE-US-00031 TABLE 27a Area Under the Curve Efficacy and Synergy
Analysis (Days 0 Through 21) for second study. Average percent
change in the area under the log.sub.10 photon flux vs day curves
(AUC) relative to the mean AUC of the vehicle group. Pct Decrease
in AUC Relative to Mean Treatment Vehicle AUC Vehicle -- Compound
III-1 (10 mg/kg, PO, BID) 94.0 Compound III-1 (20 mg/kg, PO, BID)
96.6 Rituximab (10 mg/kg, IV, QW) 41.3 Compound III-1 (10 mg/kg) +
98.5 Rituximab (10 mg/kg) Compound III-1 (20 mg/kg) + 100.2
Rituximab (10 mg/kg)
TABLE-US-00032 TABLE 27b Area Under the Curve Efficacy and Synergy
Analysis (Days 0 Through 21) for second study. 95% Synergy
Confidence P Combination Score Interval Value Assessment Compound
III-1 (10 mg/kg 36.8 (12.4, 61.2) 0.005 Sub-Additive QD) +
Rituximab Compound III-1 (20 mg/kg 37.7 (15.5, 59.9) 0.003
Sub-Additive QD) + Rituximab Synergistic: score < 0, Additive:
score = 0, Sub-additive: score > 0. Assessment based on whether
the synergy score was significantly different from 0.
[0239] At the end of dosing on Day 21 of the 1st study, body weight
loss was less than 5% for all groups (Table 25). In the second
study, however, treatment with Compound III-1 at 20 mg/kg on a BID
schedule and the combination treatment of Compound III-1 at 20
mg/kg BID with rituximab at 10 mg/kg QW resulted in mean maximum
body weight losses of 8.9% (Day 9) and 12.2% (Day 9) respectively.
This effect was managed by giving all animals in these groups a 5
day dose holiday (Day 9 through Day 13); animals then regained body
weight. No other treatment group exhibited a maximum body weight
loss greater than 3.9% (Table 25).
[0240] While the foregoing invention has been described in some
detail for purposes of clarity and understanding, these particular
embodiments are to be considered as illustrative and not
restrictive. It will be appreciated by one skilled in the art from
a reading of this disclosure that various changes in form and
detail can be made without departing from the true scope of the
invention, which is to be defined by the appended claims rather
than by the specific embodiments.
[0241] The patent and scientific literature referred to herein
establishes knowledge that is available to those with skill in the
art. Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. The
issued patents, applications, and references that are cited herein
are hereby incorporated by reference to the same extent as if each
was specifically and individually indicated to be incorporated by
reference. In the case of inconsistencies, the present disclosure,
including definitions, will control.
* * * * *