U.S. patent application number 17/328618 was filed with the patent office on 2022-02-10 for compounds and methods for inhibiting mitotic progression.
The applicant listed for this patent is Millennium Pharmaceuticals, Inc.. Invention is credited to Richard J. Boyce, Christopher F. Claiborne, Lloyd J. Payne, Todd B. Sells, Stephen G. Stroud, Stuart Travers, Tricia J. Vos, Gabriel S. Weatherhead.
Application Number | 20220041605 17/328618 |
Document ID | / |
Family ID | 1000005918266 |
Filed Date | 2022-02-10 |
United States Patent
Application |
20220041605 |
Kind Code |
A1 |
Claiborne; Christopher F. ;
et al. |
February 10, 2022 |
COMPOUNDS AND METHODS FOR INHIBITING MITOTIC PROGRESSION
Abstract
This invention relates to compounds and methods for the
treatment of cancer. In particular, the invention provides
compounds that inhibit Aurora kinase, pharmaceutical compositions
comprising the compounds, and methods of using the compounds for
the treatment of cancer.
Inventors: |
Claiborne; Christopher F.;
(Binningen, CH) ; Payne; Lloyd J.; (Cambridge,
GB) ; Boyce; Richard J.; (Boxworth, GB) ;
Sells; Todd B.; (Bellingham, MA) ; Stroud; Stephen
G.; (Medford, MA) ; Travers; Stuart;
(Meppershall, GB) ; Vos; Tricia J.; (Medford,
MA) ; Weatherhead; Gabriel S.; (Cambridge,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Millennium Pharmaceuticals, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
1000005918266 |
Appl. No.: |
17/328618 |
Filed: |
May 24, 2021 |
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11014928 |
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17328618 |
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14810225 |
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13644216 |
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14810225 |
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12472583 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 513/14 20130101;
C07D 495/14 20130101; C07D 491/14 20130101; C07D 487/14 20130101;
C07D 487/04 20130101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 487/14 20060101 C07D487/14; C07D 491/14 20060101
C07D491/14; C07D 495/14 20060101 C07D495/14; C07D 513/14 20060101
C07D513/14 |
Claims
1. A compound of formula (A): ##STR00647## or a pharmaceutically
acceptable salt thereof; wherein: R.sup.f1 is hydrogen, or R.sup.f1
and R.sup.f2 together form a bond; R.sup.f2 is hydrogen, or
R.sup.f2 forms a bond with either R.sup.f1 or R.sup.x; 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; or R.sup.x and R.sup.f2 together form a bond; G is hydrogen,
an optionally substituted aliphatic or Ring B when R.sup.f1 is
hydrogen; and G is hydrogen, --OR.sup.5, --N(R.sup.4).sub.2,
--SR.sup.5, an optionally substituted aliphatic, or Ring B when
R.sup.f1 and R.sup.f2 together form a bond; 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, heterocyclyl, or cycloaliphatic ring; Ring C is a
substituted or unsubstituted aryl, heteroaryl, heterocyclyl, or
cycloaliphatic ring; R.sup.a is hydrogen, --C(O)R.sup.1,
--CO.sub.2R.sup.1, --SO.sub.2R.sup.1, or a C.sub.1-3 aliphatic
having 0-2 substituents independently selected from R.sup.3 or
R.sup.7; R.sup.e is hydrogen, --OR.sup.5, --N(R.sup.4).sub.2,
--SR.sup.5, --NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--NR.sup.4CO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2N(R.sup.4).sub.2, or a C.sub.1-3 aliphatic
optionally substituted with R.sup.3 or R.sup.7; R.sup.1 is
C.sub.1-6 aliphatic or an optionally substituted aryl, heteroaryl,
or heterocyclyl group; 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; each R.sup.6 independently is an optionally substituted
aliphatic or aryl group; and each R.sup.7 independently is an
optionally substituted aryl, heterocyclyl, or heteroaryl group.
2. The compound of claim 1, wherein: each of R.sup.x and R.sup.y
independently is hydrogen, fluoro, or a C.sub.1-6 aliphatic
optionally substituted with one or two R.sup.3; 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; R.sup.e is hydrogen, --OH, --NHR.sup.4, --SH,
or a C.sub.1-3 aliphatic optionally substituted with R.sup.3 or
R.sup.7; R.sup.f1 and R.sup.f2 together form a bond; G is --H,
--OH, --NH.sub.2, --O(C.sub.1-3 alkyl), --NH(C.sub.1-3 alkyl),
--N(C.sub.1-3 alkyl).sub.2, C.sub.1-3 alkyl, C.sub.1-3 fluoroalkyl,
--O-L.sup.1-R.sup.7, --N(C.sub.1-3 alkyl)-L.sup.1-R.sup.7, or
-L.sup.1-R.sup.7; and L.sup.1 is a covalent bond or C.sub.1-3
alkylene.
3. The compound of claim 1, having formula (A-1): ##STR00648## 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.1-3alkyl), --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.
4. The compound of claim 3, having formula (C): ##STR00649## or a
pharmaceutically acceptable salt thereof, wherein: 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; 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; 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; R.sup.2c
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).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; each R.sup.7C
independently is an optionally substituted aryl, heterocyclyl, or
heteroaryl group; 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; 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; 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--, --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; 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)--,
--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.3 or a portion thereof
optionally forms part of a 3-7 membered ring; V is
--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)--, --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)--; R.sup.2d 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.3R.sup.5, --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(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5,
--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; each R.sup.7d
independently is an optionally substituted aryl, heterocyclyl, or
heteroaryl group; 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.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; 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; each R.sup.6 independently is an optionally substituted
aliphatic or aryl group; each R.sup.7 independently is an
optionally substituted aryl, heterocyclyl, or heteroaryl group; and
each R.sup.10 independently is --CO.sub.2R.sup.5 or
--C(O)N(R.sup.4).sub.2.
5. The compound of claim 3, wherein each of R.sup.x and R.sup.y
independently is hydrogen, fluoro, or a C.sub.1-6 aliphatic
optionally substituted with one or two R.sup.3; 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.
6. The compound of claim 5, wherein Ring A is a substituted or
unsubstituted ring selected from the group consisting of 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.
7. The compound of claim 6 wherein Ring A is a substituted or
unsubstituted ring selected from the group consisting of furano,
thieno, pyrrolo, oxazolo, thiazolo, imidazolo, pyrazolo, isoxazolo,
isothiazolo, triazolo, benzo, pyridino, pyridazino, pyrimidino, and
pyrazino.
8. The compound of claim 3, wherein: each substitutable saturated
ring carbon atom in Ring A is unsubstituted or 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; 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 substituted with
--R.sup.9b; one ring nitrogen atom in Ring A optionally is
oxidized; each R.sup.b 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).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, --P(O)(OR.sup.5).sub.2, 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; 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 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; each R.sup.6
independently is an optionally substituted aliphatic or aryl group;
each R.sup.7 independently is an optionally substituted aryl,
heterocyclyl, or heteroaryl group; 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; and each
R.sup.10 independently is --CO.sub.2R.sup.5 or
--C(O)N(R.sup.4).sub.2.
9. The compound of claim 8, wherein: each R.sup.b independently is
selected from the group consisting of C.sub.1-6 aliphatic,
C.sub.1-6 fluoroaliphatic, --R.sup.2b, --R.sup.7b,
-T.sup.1-R.sup.2b, and -T.sup.1-R.sup.7b; 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; 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; 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;
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), --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; and each R.sup.7b
independently is an optionally substituted aryl, heteroaryl, or
heterocyclyl group.
10. The compound of claim 9, wherein Ring A is selected from the
group consisting of: ##STR00650## ##STR00651## any of which groups
optionally is substituted on any substitutable ring carbon atom and
any substitutable ring nitrogen atom.
11. The compound of claim 10, wherein Ring A is selected from the
group consisting of: ##STR00652## any of which groups optionally is
substituted on any substitutable ring carbon atom and any
substitutable ring nitrogen atom.
12. The compound of claim 10, having formula (B): ##STR00653## or a
pharmaceutically acceptable salt thereof; wherein: Ring A is
substituted with 0-3 R.sup.b; Ring B is a substituted or
unsubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic
ring; and Ring C is a substituted or unsubstituted aryl,
heteroaryl, heterocyclyl, or cycloaliphatic ring.
13. The compound of claim 12, wherein: Ring B is a mono- or
bicyclic aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring;
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, or R.sup.c; each substitutable unsaturated
ring carbon atom in Ring B is unsubstituted or is substituted with
R.sup.c; each substitutable ring nitrogen atom in Ring B is
unsubstituted or substituted with R.sup.9c; 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; 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; R.sup.2c
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).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; each R.sup.7C
independently is an optionally substituted aryl, heterocyclyl, or
heteroaryl group; 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; and Ring C is a mono- or
bicyclic aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring;
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, or R.sup.d; each substitutable unsaturated
ring carbon atom in Ring C is unsubstituted or is substituted with
R.sup.d; each substitutable ring nitrogen atom in Ring C is
unsubstituted or is substituted with R.sup.9d; 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;
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; 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)--,
--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.3 or a portion thereof
optionally forms part of a 3-7 membered ring; V is
--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)--, --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)--; R.sup.2d 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.3R.sup.5, --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(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5,
--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; each R.sup.7d
independently is an optionally substituted aryl, heterocyclyl, or
heteroaryl group; and 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.
14. The compound of claim 1, having formula (I): ##STR00654## or a
pharmaceutically acceptable salt thereof; wherein: Ring A is
substituted with 0-3 R.sup.b; Ring B is a substituted or
unsubstituted aryl or heteroaryl ring; Ring C is a substituted or
unsubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic
ring; R.sup.a is hydrogen, --C(O)R.sup.1, --CO.sub.2R.sup.1,
--SO.sub.2R.sup.1, or a C.sub.1-3 aliphatic having 0-2 substituents
independently selected from R.sup.3 or R.sup.7; R.sup.1 is
C.sub.1-6 aliphatic or an optionally substituted aryl, heteroaryl,
or heterocyclyl group; each R.sup.b independently is -halo,
--NO.sub.2, --CN, --C(R.sup.5).dbd.C(R.sup.5).sub.2,
--C.ident.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, --P(O)(OR.sup.5).sub.2, an optionally
substituted aliphatic, or an optionally substituted aryl,
heterocyclyl, or heteroaryl group; R.sup.e is hydrogen or a
C.sub.1-3 aliphatic optionally substituted with R.sup.3 or R.sup.7;
each R.sup.f1 and R.sup.f2 each are hydrogen, or R.sup.f1 and
R.sup.f2 together form a bond; 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; each R.sup.6 independently is an optionally
substituted aliphatic or aryl group; and each R.sup.7 independently
is an optionally substituted aryl, heterocyclyl, or heteroaryl
group.
15. The compound of claim 14, having formula (II): ##STR00655## or
a pharmaceutically acceptable salt thereof; wherein: R.sup.e is
hydrogen or a C.sub.1-3 aliphatic optionally substituted with
R.sup.3 or R.sup.7; Ring A is substituted with 0-3 R.sup.b; 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; each R.sup.2b independently is -halo,
--NO.sub.2, --CN, --C(R.sup.5).dbd.C(R.sup.5).sub.2,
--C.ident.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; each R.sup.7b
independently is an optionally substituted aryl, heterocyclyl, or
heteroaryl group; Ring B is an aryl or heteroaryl ring substituted
with 0-2 independently selected R.sup.c and 0-3 independently
selected R.sup.2c or C.sub.1-6 aliphatic groups; 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; each R.sup.2c independently is -halo,
--NO.sub.2, --CN, --C(R.sup.5).dbd.C(R.sup.5).sub.2,
--C.ident.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; each R.sup.7C
independently is an optionally substituted aryl, heterocyclyl, or
heteroaryl group; 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; Ring C is
aryl or heteroaryl ring substituted with 0-2 independently selected
R.sup.d and 0-3 independently selected R.sup.2d or C.sub.1-6
aliphatic groups; 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; 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; 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)--,
--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.3 or a portion thereof
optionally forms part of a 3-7 membered ring; V is
--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)--, --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)--; R.sup.2d is -halo, --NO.sub.2,
--CN, --C(R.sup.5).dbd.C(R.sup.5).sub.2, --C.ident.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 each R.sup.7d
independently is an optionally substituted aryl, heterocyclyl, or
heteroaryl group. 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.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; 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;
each R.sup.5 independently is hydrogen or an optionally substituted
aliphatic, aryl, heteroaryl, or heterocyclyl group; each R.sup.6
independently is an optionally substituted aliphatic or aryl group;
and each R.sup.7 independently is an optionally substituted aryl,
heterocyclyl, or heteroaryl group.
16. The compound of claim 15, wherein 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.
17. The compound of claim 15, wherein Ring B is a substituted or
unsubstituted phenyl or pyridyl ring.
18. The compound of claim 17, having formula (IIa): ##STR00656##
wherein: Ring A is substituted with 0-2 independently selected
R.sup.b; and Ring B is substituted with 0-2 independently selected
R.sup.c.
19-56. (canceled)
57. A pharmaceutical composition comprising a compound according to
claim 1 and a pharmaceutically acceptable carrier.
58. (canceled)
59. A method for treating an Aurora kinase-mediated disorder in a
patient in need thereof, comprising administering to the patient a
therapeutically effective amount of a compound according to claim
1.
60-62. (canceled)
Description
PRIORITY CLAIM
[0001] This application claims priority from U.S. Provisional
Patent Application Ser. No. 60/571,653, filed on May 14, 2004, and
U.S. Provisional Patent Application Ser. No. 60/617,221, filed on
Oct. 8, 2004, each of which is hereby incorporated by reference in
its entirety.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] This invention relates to compounds and methods for the
treatment of cancer. In particular, the invention provides
compounds that inhibit Aurora kinase enzymes, pharmaceutical
compositions comprising the compounds, and methods of using the
compounds for the treatment of cancer.
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, 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 (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.
There is thus a need for new Aurora kinase inhibitors.
DESCRIPTION OF THE INVENTION
[0005] This invention provides compounds that inhibit Aurora
kinase. These compounds are useful for inhibiting Aurora kinase in
vitro or in vivo, and are especially useful for the treatment of
cell proliferative disorders, including cancer. The Aurora kinase
inhibitors of the invention have the formula (A):
##STR00001##
[0006] or a pharmaceutically acceptable salt thereof, wherein Ring
A, Ring C, and each of the variables R.sup.a, R.sup.e, R.sup.f1,
R.sup.f2, R.sup.x, R.sup.y, and G have the values described below.
[0007] R.sup.f1 is hydrogen, or R.sup.f1 and R.sup.f2 together form
a bond. [0008] R.sup.f2 is hydrogen, or R.sup.f2 forms a bond with
either R.sup.f1 or R.sup.x. [0009] 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; or R.sup.x and
R.sup.f2 together form a bond. [0010] G is hydrogen, an optionally
substituted aliphatic, or Ring B when R.sup.f1 is hydrogen; and G
is hydrogen, --OR.sup.5, --N(R.sup.4).sub.2, --SR.sup.5, an
optionally substituted aliphatic, or Ring B when R.sup.f1 and
R.sup.f2 together form a bond. [0011] Ring A is a substituted or
unsubstituted 5- or 6-membered aryl, heteroaryl, cycloaliphatic, or
heterocyclyl ring. [0012] Ring B is a substituted or unsubstituted
aryl, heteroaryl, cycloaliphatic, or heterocyclyl ring. [0013] Ring
C is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl,
or cycloaliphatic ring. [0014] R.sup.a is hydrogen, --C(O)R.sup.1,
--CO.sub.2R.sup.1, --SO.sub.2R.sup.1, or a C.sub.1-3 aliphatic
having 0-2 substituents independently selected from R.sup.3 or
R.sup.7. [0015] R.sup.e is hydrogen, --OR.sup.5,
--N(R.sup.4).sub.2, --SR.sup.5, --NR.sup.4C(O)R.sup.5,
--NR.sup.4C(O)N(R.sup.4).sub.2, --NR.sup.4CO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
or a C.sub.1-3 aliphatic optionally substituted with R.sup.3 or
R.sup.7. [0016] R.sup.1 is C.sub.1-6 aliphatic or an optionally
substituted aryl, heteroaryl, or heterocyclyl group. [0017] 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). [0018] 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. [0019] Each
R.sup.5 independently is hydrogen or an optionally substituted
aliphatic, aryl, heteroaryl, or heterocyclyl group. [0020] Each
R.sup.6 independently is an optionally substituted aliphatic or
aryl group. [0021] Each R.sup.7 independently is an optionally
substituted aryl, heterocyclyl, or heteroaryl group.
[0022] The invention further provides pharmaceutical compositions
comprising a compound of formula (A), as well as uses of the
claimed compounds for inhibiting Aurora kinase activity and for
treating Aurora kinase-mediated disorders.
[0023] Compounds of this invention include those described
generally above, and are further illustrated by the classes,
subclasses, and species disclosed herein. Terms used herein shall
be accorded the following defined meanings, unless otherwise
indicated.
[0024] 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, p 53, 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.
[0025] The term "Aurora kinase inhibitor" or "inhibitor of Aurora
kinase" is used to signify a compound having a structure as defined
herein, 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.
[0026] 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.
[0027] 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%.
[0028] As used herein, the term "comprises" means "includes, but is
not limited to."
[0029] The term "aliphatic", as used herein, means straight-chain,
branched or cyclic C.sub.1-12 hydrocarbons which are completely
saturated or which contain one or more units of unsaturation, but
which are not aromatic. For example, suitable aliphatic groups
include substituted or unsubstituted linear, branched or cyclic
alkyl, alkenyl, or alkynyl groups and hybrids thereof, such as
(cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. In
various embodiments, the aliphatic group has 1 to 12, 1 to 8, 1 to
6, 1 to 4, or 1 to 3 carbons.
[0030] 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.
[0031] 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.
[0032] 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.
[0033] The terms "cycloaliphatic", "carbocycle", "carbocyclyl",
"carbocyclo", or "carbocyclic", used alone or as part of a larger
moiety, refer 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. Cycloaliphatic
groups include, without limitation, cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,
cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In
some embodiments, the cycloalkyl has 3 to 6 carbons. The terms
"cycloaliphatic", "carbocycle", "carbocyclyl", "carbocyclo", or
"carbocyclic" also include aliphatic rings that are fused to one or
more aromatic or nonaromatic rings, such as decahydronaphthyl or
tetrahydronaphthyl, where the radical or point of attachment is on
the aliphatic ring.
[0034] The terms "haloaliphatic", "haloalkyl", "haloalkenyl" and
"haloalkoxy" refer to an aliphatic, alkyl, alkenyl or alkoxy group,
as the case may be, substituted with one or more halogen atoms. As
used herein, the term "halogen" or "halo" means F, Cl, Br, or
I.
[0035] The terms "aryl" and "ar-", used alone or as part of a
larger moiety, e.g., "aralkyl", "aralkoxy", or "aryloxyalkyl",
refer to a C.sub.6 to C.sub.1-4 aromatic moiety comprising one to
three aromatic rings, which are optionally substituted. Preferably,
the aryl group is a C.sub.6-10 aryl group. Aryl groups include,
without limitation, phenyl, naphthyl, and anthracenyl. The term
"aryl", as used herein, also 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 ring", and
"aromatic ring".
[0036] 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, including, without
limitation, benzyl, phenethyl, and naphthylmethyl.
[0037] The terms "heteroaryl" and "heteroar-", used alone or as
part of a larger moiety, e.g., heteroaralkyl, or "heteroaralkoxy",
refer to aromatic groups having 5 to 14 ring atoms, preferably 5,
6, 9, or 10 ring atoms; having 6,10, or 14 n electrons shared in a
cyclic array; and having, in addition to one or more 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. 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.
[0038] 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 saturated or
partially unsaturated ring having 0-3 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).
[0039] 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. The terms
"heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic
group", "heterocyclic moiety", and "heterocyclic radical", are used
interchangeably herein, and also 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.
[0040] 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.
[0041] The term "linker group" or "linker" means an organic moiety
that connects two parts of a compound. Linkers typically comprise
an atom such as oxygen or sulfur, a unit such as --NH--,
--CH.sub.2--, --C(O)--, --C(O)NH--, or a chain of atoms, such as an
alkylene chain. The molecular mass of a linker is typically in the
range of about 14 to 200, preferably in the range of 14 to 96 with
a length of up to about six atoms. In some embodiments, the linker
is a C.sub.1-6 alkylene chain.
[0042] 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.
[0043] An alkylene chain also can be optionally interrupted by a
functional group. An alkylene chain is "interrupted" by a
functional group when an internal methylene unit is replaced with
the functional group. Examples of suitable "interrupting functional
groups" include --C(R*).dbd.C(R{circumflex over ( )})--,
--C.ident.C--, --O--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2N(R.sup.+)--, --N(R*)--, --N(R.sup.+)CO--,
--N(R.sup.+)C(O)N(R.sup.+)--, --N(R.sup.+)CO.sub.2--,
--C(O)N(R.sup.+)--, --C(O)--, --C(O)--C(O)--, --CO.sub.2--,
--OC(O)--, --OC(O)O--, --OC(O)N(R.sup.+)--, --C(NR.sup.+).dbd.N,
--C(OR*).dbd.N--, --N(R.sup.+)--N(R.sup.+)--, or
--N(R.sup.+)S(O).sub.2--. 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{circumflex over ( )}
independently is hydrogen --CO.sub.2R*, --C(O)N(R.sup.+).sub.2, or
an optionally substituted aliphatic, aryl, heteroaryl, or
heterocyclyl group.
[0044] Examples of C.sub.3-6 alkylene chains that have been
"interrupted" with --O-- include --CH.sub.2OCH.sub.2--,
--CH.sub.2O(CH.sub.2).sub.2--, --CH.sub.2O(CH.sub.2).sub.3--,
--CH.sub.2O(CH.sub.2).sub.4--, --(CH.sub.2).sub.2OCH.sub.2--,
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2O(CH.sub.2).sub.3--,
--(CH.sub.2).sub.3O(CH.sub.2)--,
--(CH.sub.2).sub.3O(CH.sub.2).sub.2--, and
--(CH.sub.2).sub.4O(CH.sub.2)--. Other examples of alkylene chains
that are "interrupted" with functional groups include
--CH.sub.2GCH.sub.2-, --CH.sub.2G(CH.sub.2).sub.2--,
--CH.sub.2G(CH.sub.2).sub.3--, --CH.sub.2G(CH.sub.2).sub.4--,
--(CH.sub.2).sub.2GCH.sub.2-,
--(CH.sub.2).sub.2G(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2G(CH.sub.2).sub.3--,
--(CH.sub.2).sub.3G(CH.sub.2)--,
--(CH.sub.2).sub.3G(CH.sub.2).sub.2--, and
--(CH.sub.2).sub.4G(CH.sub.2)--, wherein G is one of the
"interrupting" functional groups listed above.
[0045] The term "substituted", as used herein, means that one or
more hydrogens of the designated moiety are replaced, provided that
the substitution results in a stable or chemically feasible
compound. A stable compound or chemically feasible compound is one
in which the chemical structure is not substantially altered when
kept at a temperature from about -80.degree. C. to about
+40.degree. C., in the absence of moisture or other chemically
reactive conditions, for at least a week, or a compound which
maintains its integrity long enough to be useful for therapeutic or
prophylactic administration to a patient. 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.
[0046] 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*)(R{circumflex over ( )}),
--C.ident.C--R{circumflex over ( )}, --OR*, --SR.sup..smallcircle.,
--S(O)R.sup..smallcircle., --SO.sub.2R.sup.0, --SO.sub.3R*,
--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..smallcircle., --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..smallcircle.,
--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. In such
substituents, R.sup..smallcircle. is an optionally substituted
aliphatic or aryl group, and R.sup.+, R*, and R{circumflex over (
)} are as defined above.
[0047] 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--NHR*, .dbd.N--N(R*).sub.2, .dbd.N--OR*, .dbd.N--NHC(O)R*,
.dbd.N--NHCO.sub.2R.sup..smallcircle.,
.dbd.N--NHSO.sub.2R.sup..smallcircle., or .dbd.N--R*, where each R*
and R.sup..smallcircle. is as defined above.
[0048] 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*).sub.2,
--C(.dbd.NH)--N(R*).sub.2, and --NR*SO.sub.2R*; wherein each R* is
as defined above.
[0049] It will be apparent to one skilled in the art that certain
compounds of this invention 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. By way of example, the compounds of formula
(A) wherein R.sup.f1 is hydrogen can have R or S configuration at
the carbon atom bearing Ring B. Both the R and the S stereochemical
isomers, as well as all mixtures thereof, are included within the
scope of the invention.
[0050] Unless otherwise stated, structures depicted herein are also
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.
[0051] Unless otherwise stated, structures depicted herein are also
meant to include solvated and hydrated forms of the depicted
compounds. Also included within the scope of the invention are
pharmaceutically acceptable salts of compounds of formula (A), as
well as solvated and hydrated forms of such salts.
[0052] Some embodiments of the invention relate to compounds of
formula (A) where R.sup.e is hydrogen, --OR.sup.5,
--N(R.sup.4).sub.2, --SR.sup.5, --NR.sup.4C(O)R.sup.5,
--NR.sup.4C(O)N(R.sup.4).sub.2, --NR.sup.4CO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
or a C.sub.1-3 aliphatic optionally substituted with R.sup.3 or
R.sup.7. In some embodiments, R.sup.e is hydrogen or a C.sub.1-3
aliphatic optionally substituted with one R.sup.3 or R.sup.7. In
certain embodiments, R.sup.e is hydrogen.
[0053] In some embodiments, R.sup.x and R.sup.y are each
independently selected from hydrogen, fluoro, or a C.sub.1-6
aliphatic optionally substituted with one or two R.sup.3. In some
other embodiments, 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. In some other
embodiments, R.sup.x and R.sup.f2 together form a bond. In some
embodiments, R.sup.x and R.sup.y are each hydrogen. In certain
embodiments, R.sup.x, R.sup.y, and R.sup.e are each hydrogen.
[0054] Some embodiments of the invention relate to compounds of
formula (A) where R.sup.f1 is hydrogen, R.sup.f2 is hydrogen or
R.sup.f2 and R.sup.x together form a bond, and G is hydrogen, an
optionally substituted aliphatic, or Ring B.
[0055] Some other embodiments relate to compounds of formula (A),
where R.sup.f1 and R.sup.f2 together form a bond, and G is
hydrogen, --SR.sup.5, --OR.sup.5, --N(R.sup.4).sub.2, or an
optionally substituted aliphatic. In such embodiments, G preferably
is hydrogen, --OR.sup.5, --N(R.sup.4).sub.2, or an optionally
substituted aliphatic. More preferably, G is --H, --OH, --NH.sub.2,
--O(C.sub.1-3 alkyl), --NH(C.sub.1-3 alkyl), --N(C.sub.1-3
alkyl).sub.2, C.sub.1-3 alkyl, C.sub.1-3 fluoroalkyl,
--O-L.sup.1-R.sup.7, --N(C.sub.1-3 alkyl)-L.sup.1-R.sup.7, or
-L.sup.1-R.sup.7, where L.sup.1 is a covalent bond or C.sub.1-3
alkylene.
[0056] Other embodiments of the invention relate to a subgenus of
the compounds of formula (A) characterized by formula (A-1):
##STR00002##
[0057] or a pharmaceutically acceptable salt thereof, where the
variables R.sup.e, R.sup.x, and R.sup.y are as defined above for
formula (A). Values and preferred values for Rings A, B, and C in
formulae (A) and (A-1) are described below.
[0058] 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.
[0059] 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.
[0060] Each 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.
[0061] Each R.sup.26 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), --OC--R.sup.5,
--OC--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.
[0062] 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).
[0063] 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.
[0064] Each R.sup.5 independently is hydrogen or an optionally
substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
[0065] Each R.sup.6 independently is an optionally substituted
aliphatic or aryl group;
[0066] Each R.sup.7 independently is an optionally substituted
aryl, heterocyclyl, or heteroaryl group;
[0067] Each R.sup.10 independently is --CO.sub.2R.sup.5 or
--C(O)N(R.sup.4).sub.2.
[0068] In some embodiments, each R.sup.6 independently is selected
from the group consisting of C.sub.1-6 aliphatic, C.sub.1-6
fluoroaliphatic, --R.sup.2b, --R.sup.7b, -T.sup.1-R.sup.2b, and
--H--R.sup.7b; or two adjacent R.sup.6, 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. The
variable R.sup.2b is as described above, and T.sup.1 and R.sup.7b
are described below. [0069] 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.
[0070] 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). [0071] 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. [0072] Each R.sup.7b independently is an
optionally substituted aryl, heteroaryl, or heterocyclyl group.
[0073] In some embodiments, Ring A is substituted with 0-3, 0-2, or
0-1 substituents R.sup.b, wherein the substituents R.sup.b may be
the same or different. In some embodiments, each R.sup.b
independently is selected from the group consisting of C.sub.1-3
aliphatic, R.sup.2b, R.sup.7b, -T.sup.1-R.sup.2b, and
-T.sup.1-R.sup.7b, where T.sup.1 is a C.sub.1-3 alkylene chain
optionally substituted with fluoro. In some embodiments, two
adjacent R.sup.b, taken together with the intervening ring carbon
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. In some embodiments, each
R.sup.b independently is selected from the group consisting of
C.sub.1-3 aliphatic, R.sup.2b, and -T.sup.1-R.sup.2b, where T.sup.1
is a C.sub.1-3 alkylene chain, optionally substituted with fluoro.
In some such embodiments, 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.ident.C--R.sup.5,
--OR.sup.5, and --N(R.sup.4).sub.2.
[0074] 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, --OC--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.
[0075] Certain examples of Ring A moieties are shown in Table 1.
For ease of viewing, the optional substituents R.sup.b on ring
carbon atoms and R.sup.9b on ring nitrogen atoms are not shown.
TABLE-US-00001 TABLE 1 Examples of Ring A Moieties ##STR00003## A-1
##STR00004## A-2 ##STR00005## A-3 ##STR00006## A-4 ##STR00007## A-5
##STR00008## A-6 ##STR00009## A-7 ##STR00010## A-8 ##STR00011## A-9
##STR00012## A-10 ##STR00013## A-11 ##STR00014## A-12 ##STR00015##
A-13 ##STR00016## A-14 ##STR00017## A-15 ##STR00018## A-16
##STR00019## A-17 ##STR00020## A-18 ##STR00021## A-19 ##STR00022##
A-20 ##STR00023## A-21 ##STR00024## A-22 ##STR00025## A-23
##STR00026## A-24 ##STR00027## A-25 ##STR00028## A-26 ##STR00029##
A-27 ##STR00030## A-28 ##STR00031## A-29 ##STR00032## A-30
##STR00033## A-31 ##STR00034## A-32 ##STR00035## A-33 ##STR00036##
A-34 ##STR00037## A-35 ##STR00038## A-36 ##STR00039## A-37
##STR00040## A-38 ##STR00041## A-39 ##STR00042## A-40 ##STR00043##
A-41 ##STR00044## A-42 ##STR00045## A-43 ##STR00046## A-44
##STR00047## A-45 ##STR00048## A-46 ##STR00049## A-47
[0076] In some embodiments, two adjacent R.sup.b on one of the
above Ring A moieties, taken together with the intervening ring
atoms, form an optionally substituted fused 4- to 8-membered
aromatic or nonaromatic fused ring, so that Ring A is a bicyclic
moiety. Certain examples of such bicyclic moieties are shown in
Table 2, any of which moieties optionally is substituted on any
substitutable ring carbon atom and any substitutable ring nitrogen
atom.
TABLE-US-00002 TABLE 2 Examples of Bicyclic Ring A Moieties
##STR00050## A-48 ##STR00051## A-49 ##STR00052## A-50 ##STR00053##
A-51 ##STR00054## A-52 ##STR00055## A-53 ##STR00056## A-54
##STR00057## A-55 ##STR00058## A-56 ##STR00059## A-57 ##STR00060##
A-58 ##STR00061## A-59 ##STR00062## A-60 ##STR00063## A-61
##STR00064## A-62 ##STR00065## A-63 ##STR00066## A-64
[0077] In some embodiments, the invention relates to a compound of
formula (B):
##STR00067##
or a pharmaceutically acceptable salt thereof, wherein Ring A is
substituted with 0-3 R.sup.b. Rings B and C, and the variables
R.sup.e, R.sup.x, and R.sup.y are as defined above for formula
(A).
[0078] In certain such embodiments, Ring A has the formula A-i:
##STR00068##
[0079] wherein each of R.sup.b2 and R.sup.b3 independently is
hydrogen or R.sup.b. In some embodiments, each of R.sup.b2 and
R.sup.b3 independently is selected from the group consisting of
hydrogen, -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 embodiments, each of R.sup.b2 and R.sup.b3 independently
is selected from the group consisting of hydrogen, chloro, fluoro,
bromo, methyl, trifluoromethyl, and methoxy. In some other
embodiments, R.sup.b2 and R.sup.b3, taken together with the
intervening ring carbon 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.
[0080] In the compounds of formulae (A), (A-1), and (B) above, Ring
B is a mono-, bi-, or tricyclic ring system. In some embodiments,
the point of attachment for Ring B to the rest of the formula is on
an aryl or heteroaryl ring of the Ring B moiety. In other
embodiments, the point of attachment is on an heterocyclyl or
cycloaliphatic ring. Preferably, Ring B is mono- or bicyclic.
[0081] 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.9c, 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.
[0082] 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.
[0083] 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).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.
[0084] In some embodiments, 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.4-R.sup.2c, and -T.sup.1-R.sup.7c, where R.sup.2c
is as described above and T.sup.1 and R.sup.7c are described below.
[0085] 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. [0086] 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). [0087] 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. [0088] Each
R.sup.7c independently is an optionally substituted aryl,
heterocyclyl, or heteroaryl group.
[0089] In some embodiments, each R.sup.c independently is selected
from the group consisting of C.sub.1-3 aliphatic, R.sup.2c,
R.sup.7c, -T.sup.4-R.sup.2c, and -T.sup.1-R.sup.7c, where T.sup.1
is a C.sub.1-3 alkylene chain optionally substituted with fluoro.
In some embodiments, each R.sup.c independently is selected from
the group consisting of C.sub.1-3 aliphatic, R.sup.2c, and
-T.sup.1-R.sup.2c, where T.sup.1 is a C.sub.1-3 alkylene chain
optionally substituted with fluoro. In some such embodiments, 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,
--OC--R.sup.5, --OR.sup.5, and --N(R.sup.4).sub.2.
[0090] 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.
[0091] 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.
[0092] 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, --OC--R.sup.5,
--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.
[0093] In some embodiments, Ring B has the formula B-i:
##STR00069##
[0094] wherein each of R.sup.c1 and R.sup.c5 independently is
hydrogen or R.sup.c. In some embodiments, each of R.sup.c1 and
R.sup.c5 independently is selected from the group consisting of
hydrogen, -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 embodiments, each of R.sup.c1 and R.sup.c5 independently
is selected from the group consisting of hydrogen, chloro, fluoro,
bromo, methyl, trifluoromethyl, and methoxy.
[0095] In the compounds of formulae (A), (A-1), and (B) above, Ring
C is a substituted or unsubstituted mono-, bi-, or tricyclic ring
system. In some embodiments, the point of attachment for Ring C to
the rest of the formula is on an aryl or heteroaryl ring of the
Ring C moiety. In other embodiments, the point of attachment is on
a heterocyclyl or cycloaliphatic ring. Preferably, Ring C is mono-,
or bicyclic.
[0096] 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.
[0097] Each R.sup.d independently is R.sup.2d, an optionally
substituted aliphatic, or an optionally substituted aryl,
heteroaryl, or heterocyclyl group.
[0098] 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.
[0099] In some embodiments, 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, wherein R.sup.2d is
as described above, and T.sup.2, T.sup.3, V, and R.sup.7d are
described below. [0100] 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. [0101] 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)--, --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.3 or a portion thereof optionally forms part of a 3-7
membered ring. [0102] V is --C(R.sup.5).dbd.C(R.sup.5)--, --OC--,
--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)--. [0103] 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. [0104] Each R.sup.7d
independently is an optionally substituted aryl, heterocyclyl, or
heteroaryl group.
[0105] In some embodiments, each R.sup.2d independently is selected
from the group consisting of -halo, --OR.sup.5, --N(R.sup.4).sub.2,
--N(R.sup.4)C(O)--, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2, and
--SO.sub.2N(R.sub.4).sub.2. In some other embodiments, each
R.sup.2d independently is -halo, --OR.sup.5, --N(R.sup.4).sub.2,
--N(R.sup.4)C(O)--, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2, and
--SO.sub.2N(R.sub.4).sub.2,
--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.
[0106] In some embodiments, T.sup.2 is a C.sub.1-6 alkylene chain,
which optionally is substituted with one or two substituents
R.sup.3b independently selected from the group consisting of -halo,
--C.sub.1-3 aliphatic, --OH, and --O(C.sub.1-3 aliphatic), 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. In some embodiments, T.sup.2 optionally is
interrupted by --C(R.sup.5).dbd.C(R.sup.5)--, --C.ident.C--, --O--,
--C(O)--, --C(O)N(R.sup.4)--, --N(R.sup.4)C(O)-- or
--N(R.sup.4)--.
[0107] In some embodiments, V is --C(R.sup.5).dbd.C(R.sup.5)--,
--C.ident.C--, --O--, --N(R.sup.4)--, --C(O)--, --N(R.sup.4)C(O)--,
or --C(O)N(R.sup.4)--. In some embodiments, T.sup.3 is a C.sub.1-4
alkylene chain, which optionally is substituted with one or two
R.sup.3b independently selected from the group consisting of -halo,
--C.sub.1-3 aliphatic, --OH, and --O(C.sub.1-3 aliphatic), 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. In some embodiments, T.sup.3 is a C.sub.1-4
alkylene chain, which optionally is interrupted by
--C(R.sup.5).dbd.C(R.sup.5)--, --C.ident.C--, --O--, --C(O)--,
--C(O)N(R.sup.4)--, --N(R.sup.4)C(O)-- or --N(R.sup.4)--.
[0108] In some embodiments, each R.sup.d independently is selected
from the group consisting of C.sub.1-3 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, where R.sup.2d is
selected from the group consisting of -halo, --OR.sup.5,
--N(R.sup.4).sub.2, --N(R.sup.4)C(O)--, --CO.sub.2R.sup.5,
--C(O)N(R.sup.4).sub.2, and --SO.sub.2N(R.sub.4).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.
[0109] In some embodiments, Ring C is substituted with at least one
R.sup.7d selected from the group consisting of:
##STR00070##
[0110] any of which groups optionally is substituted on any
substitutable ring carbon or ring nitrogen atom.
[0111] In some embodiments, Ring C is substituted with at least one
-T.sup.2-R.sup.2d or -T.sup.2-R.sup.7d, where:
[0112] T.sup.2 is a C.sub.1-6 alkylene chain, wherein T.sup.2
optionally is substituted with one or two substituents R.sup.3b
independently selected from the group consisting of -halo,
--C.sub.1-3 aliphatic, --OH, and --O(C.sub.1-3 aliphatic), 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, and wherein T.sup.2 optionally is interrupted by
--C(R.sup.5).dbd.C(R.sup.5)--, --C.ident.C--, --O--, --C(O)--,
--NR.sup.4C(O)R.sup.5, --N(R.sup.4)C(O)-- or --N(R.sup.4)--;
and
[0113] R.sup.2d is selected from the group consisting of -halo,
--OR.sup.5, --N(R.sup.4).sub.2, --N(R.sup.4)C(O)--,
--CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--SO.sub.2N(R.sub.4).sub.2,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, and
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5.
[0114] In certain such embodiments, Ring C is substituted with one
-T.sup.2-R.sup.2d or -T.sup.2-R.sup.7d, and optionally one other
substituent selected from the group consisting of hydrogen, -halo,
C.sub.1-3 aliphatic, and --OR.sup.5, where R.sup.5 is hydrogen or
C.sub.1-3 aliphatic. In some embodiments, T.sup.2 is a C.sub.1-6
alkylene chain, which optionally is interrupted by
--C(O)N(R.sup.4)-- or --N(R.sup.4)C(O)--.
[0115] In some embodiments, Ring C is substituted with at least one
--V-T.sup.3-R.sup.2d or --V-T.sup.3-R.sup.7d, where:
[0116] V is --N(R.sup.4)--, --O--, --C(O)N(R.sup.4)--, --C(O)--, or
--OC--;
[0117] T.sup.3 is a C.sub.1-4 alkylene chain, which is optionally
substituted by one or two substituents R.sup.3b independently
selected from the group consisting of -halo, --C.sub.1-3 aliphatic,
--OH, and --O(C.sub.1-3 aliphatic), 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;
and
[0118] R.sup.2d is selected from the group consisting of -halo,
--OR.sup.5, --N(R.sup.4).sub.2, --NR.sup.4C(O)R.sup.5,
--CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2, and
--SO.sub.2N(R.sub.4).sub.2.
[0119] In certain such embodiments, Ring C is substituted with one
--V-T.sup.3-R.sup.2d or --V-T.sup.3-R.sup.7d, and optionally one
other substituent selected from the group consisting of hydrogen,
-halo, C.sub.1-3 aliphatic, and --OR.sup.5, where R.sup.5 is
hydrogen or C.sub.1-3 aliphatic.
[0120] In some embodiments, Ring C is substituted with
--V-T.sup.3-R.sup.2d, where V is --C(O)N(R.sup.4)--, T.sup.3 is a
C.sub.2-4 alkylene chain, and R.sup.2d is --N(R.sup.4).sub.2. Each
R.sup.4 independently is hydrogen or C.sub.1-3 aliphatic, or
--N(R.sup.4).sub.2 is an optionally substituted 5- to 6-membered
heteroaryl or 4- to 8-membered heterocyclyl ring having, in
addition to the nitrogen, 0-2 ring heteroatoms selected from N, O,
and S. In certain such embodiments, --N(R.sup.4).sub.2 is an
optionally substituted heterocyclyl selected from the group
consisting of piperidinyl, piperazinyl, and morpholinyl. In certain
other such embodiments, --N(R.sup.4).sub.2 is an optionally
substituted heterocyclyl selected from pyrrolidinyl and
azetidinyl.
[0121] In other embodiments, Ring C is substituted with
--V-T.sup.3-R.sup.7d, where V is --C(O)N(R.sup.4)--, T.sup.3 is a
C.sub.2-4 alkylene chain, and R.sup.7d is an optionally substituted
4- to 8-membered heterocyclyl or an optionally substituted 5- to
6-membered heteroaryl. In certain such embodiments, R.sup.7d is
selected from the group consisting of pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, pyrrolyl, oxazolyl, imidazolyl, and
pyrazolyl. In certain other such embodiments, R.sup.7d is a 6- to
8-membered bicyclic heterocyclyl.
[0122] In some embodiments, Ring C is substituted with one or two
substituents independently selected from the group consisting of
C.sub.1-3 aliphatic, -halo, --OR.sup.5, --CO.sub.2R.sup.5,
--C(O)N(R.sup.4).sub.2, and --SO.sub.2N(R.sup.4).sub.2. Additional
selections possible for Ring C substituents in these embodiments
include --C(.dbd.NR.sup.4)N(R.sup.4).sub.2, --NR.sup.4C(O)R.sup.5,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2 and
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5. In some
embodiments, Ring C is substituted with at least one substituent
selected from the group consisting of --CO.sub.2R.sup.5,
--C(O)N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5, and
--NR.sup.4C(O)R.sup.5. In certain embodiments, Ring C is
substituted with at least one --CO.sub.2R.sup.5, where R.sup.5 is
hydrogen or C.sub.1-6 aliphatic.
[0123] In some embodiments, Ring C is substituted with at least one
--C(O)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)N(R.sup.4).sub.2, or
--NR.sup.4C(O)R.sup.5, where --N(R.sup.4).sub.2 is an optionally
substituted 4- to 8-membered heterocyclyl ring having, in addition
to the nitrogen atom, 0-2 ring heteroatoms selected from N, O, and
S, and R.sup.5 is an optionally substituted 4- to 8-membered
nitrogen-containing heterocyclyl ring. In some such embodiments,
--N(R.sup.4).sub.2 is an optionally substituted heterocyclyl
selected from the group consisting of piperidinyl, piperazinyl,
morpholinyl, pyrrolidinyl, and azetidinyl. In some other such
embodiments, --N(R.sup.4).sub.2 is a bridged or spiro bicyclic
heterocyclyl.
[0124] In certain embodiments, Ring C is substituted with at least
one substituent having the formula D-i:
##STR00071## [0125] wherein: [0126] Ring D optionally is
substituted on one or two ring carbon atoms; [0127] X is O or NH;
[0128] W.sup.1 is hydrogen, --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 an optionally substituted aliphatic, aryl, heteroaryl, or
heterocyclyl group.
[0129] In some embodiments, Ring D in formula D-i is substituted
with one or two substituents selected from the group consisting of
C.sub.1-3 aliphatic, --CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2, and
-T.sup.5-R.sup.m, where T.sup.5 is a C.sub.1-3 alkylene chain and
R.sup.m is --OR.sup.5, --N(R.sup.4).sub.2, --CO.sub.2R.sup.5, or
--C(O)N(R.sup.4).sub.2. In some such embodiments, Ring D in formula
D-1 is substituted with one or two substituents selected from the
group consisting of C.sub.1-3 aliphatic, --CO.sub.2H,
--CO.sub.2(C.sub.1-3 alkyl), --C(O)N(C.sub.1-3 alkyl).sub.2,
--C(O)NH(C.sub.1-3 alkyl), --C(O)NH.sub.2, --(C.sub.1-3 alkyl)-OH,
--(C.sub.1-3 alkylene)-O(C.sub.1-3 alkyl), --(C.sub.1-3
alkylene)-NH.sub.2, --(C.sub.1-3 alkylene)-NH(C.sub.1-3 alkyl),
--(C.sub.1-3 alkylene)-N(C.sub.1-3 alkyl).sub.2, --(C.sub.1-3
alkylene)-CO.sub.2H, --(C.sub.1-3 alkylene)-CO.sub.2(C.sub.1-3
alkyl), --(C.sub.1-3 alkylene)-C(O)NH.sub.2, --(C.sub.1-3
alkylene)-C(O)NH(C.sub.1-3 alkyl), and --(C.sub.1-3
alkylene)-C(O)N(C.sub.1-3 alkyl).sub.2.
[0130] In certain other embodiments, Ring C is substituted with at
least one substituent having one of the formulae D-ii to D-v
below:
##STR00072## [0131] wherein: [0132] Ring D optionally is
substituted on one or two substitutable ring carbon atoms; [0133] X
is O or NH; [0134] W.sup.2 is R.sup.n or -T.sup.6-R.sup.n; [0135]
T.sup.6 is a C.sub.1-3 alkylene chain optionally substituted with
R.sup.3 or R.sup.3b; and [0136] R.sup.n is --N(R.sup.4).sub.2 or
--C(O)N(R.sup.4).sub.2; and [0137] R.sup.z is hydrogen,
--CO.sub.2R.sup.5, C(O)N(R.sup.4).sub.2; --C(O)R.sup.5, or a
C.sub.1-3 aliphatic optionally substituted with R.sup.3 or R.sup.7;
or R.sup.z and W.sup.2, taken together with the carbon atom to
which they are attached, form a 4- to 7-membered cycloaliphatic or
heterocyclyl ring.
[0138] In some embodiments, Ring D in formulae D-ii to D-v is
substituted with one or two substituents selected from the group
consisting of C.sub.1-3 aliphatic, --CO.sub.2R.sup.5,
--C(O)N(R.sup.4).sub.2, --OR.sup.5, --N(R.sup.4).sub.2, and
-T.sup.5-R.sup.m, where T.sup.5 is a C.sub.1-3 alkylene chain and
R.sup.m is --OR.sup.5, --N(R.sup.4).sub.2, --CO.sub.2R.sup.5, or
--C(O)N(R.sup.4).sub.2.
[0139] In certain embodiments, at least one substituent on Ring C
is selected from the group consisting of:
##STR00073## ##STR00074##
[0140] where X is O or NH.
[0141] In certain other embodiments, at least one substituent on
Ring C is selected from the group consisting of:
##STR00075##
[0142] where X is O or NH, and each R.sup.4z independently is
hydrogen or --CH.sub.3.
[0143] In certain other embodiments, at least one substituent on
Ring C is selected from the group consisting of:
##STR00076## ##STR00077##
[0144] where X is O or NH, and each R.sup.4z independently is
hydrogen or --CH.sub.3.
[0145] In some embodiments, Ring C is substituted with at least one
--C(O)N(R.sup.4).sub.2 or --C(.dbd.NH)N(R.sup.4).sub.2, where one
R.sup.4 is hydrogen or C.sub.1-3 alkyl, and the other R.sup.4 is an
optionally substituted heterocyclyl or heterocyclylalkyl. In some
such embodiments, Ring C is substituted with at least one
substituent selected from the group consisting of:
##STR00078##
[0146] where X is O or NH.
[0147] In some other such embodiments, Ring C is substituted with
at least one substituent selected from the group consisting of:
##STR00079##
where X is O or NH, and each R.sup.4z independently is H or
CH.sub.3.
[0148] In some embodiments, Ring C is a bicyclic aryl group, which
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. In
some such embodiments, Ring C is a phenyl ring fused to a 5- or
6-membered carbocyclic, heteroaryl, or heterocyclyl ring, wherein
each ring independently is substituted or unsubstituted. In certain
such embodiments, Ring C is an optionally substituted benzodioxanyl
or benzodioxolyl ring. In certain other such embodiments, Ring C is
an optionally substituted benzimidazolyl, benzthiazolyl,
benzoxazolyl, or phthalimidyl ring, wherein Ring C is attached to
the rest of formula (A), (A-1), or (B) at the benzo ring of the
bicyclic Ring C moiety.
[0149] In some other 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.
[0150] In yet 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.
[0151] Some embodiments of the invention relate to a subgenus of
formula (A) defined by formula (I):
##STR00080##
[0152] or a pharmaceutically acceptable salt thereof, wherein Ring
A, Ring B, Ring C, and each of the variables R.sup.a, R.sup.b,
R.sup.e, R.sup.f1, and R.sup.f2 have the values described below.
[0153] Ring A is substituted with 0-3 R.sup.b. [0154] Ring B is a
substituted or unsubstituted aryl or heteroaryl ring. [0155] Ring C
is a substituted or unsubstituted aryl or heteroaryl ring.
Additionally, Ring C can be a heterocyclyl, or cycloaliphatic ring.
[0156] R.sup.a is hydrogen, --C(O)R.sup.1, --CO.sub.2R.sup.1,
--SO.sub.2R.sup.1, or a C.sub.1-3 aliphatic having 0-2 substituents
independently selected from R.sup.3 or R.sup.7. [0157] R.sup.1 is
an optionally substituted C.sub.1-6 aliphatic or an optionally
substituted aryl, heteroaryl, or heterocyclyl group. [0158] Each
independently is R.sup.2b, an optionally substituted aliphatic, or
an optionally substituted aryl, heteroaryl, or heterocyclyl group.
In some embodiments each R.sup.6 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. In some embodiments, two
adjacent R.sup.6, taken together with the intervening carbon 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. [0159] 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. [0160] 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), --C.ident.C--R.sup.5,
--OC--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. [0161] 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.
[0162] Each R.sup.7b independently is an optionally substituted
aryl, heterocyclyl, or heteroaryl group. [0163] R.sup.e is hydrogen
or a C.sub.1-3 aliphatic optionally substituted with R.sup.3 or
R.sup.7. [0164] R.sup.f1 and R.sup.f2 each are hydrogen, or
R.sup.f1 and R.sup.f2 together form a bond. [0165] 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). [0166] 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 4- to 8-membered or 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. [0167] Each R.sup.5
independently is hydrogen or an optionally substituted aliphatic,
aryl, heteroaryl, or heterocyclyl group. [0168] Each R.sup.6
independently is an optionally substituted aliphatic or aryl group.
[0169] Each R.sup.7 independently is an optionally substituted
aryl, heterocyclyl, or heteroaryl group. [0170] Each R.sup.10
independently is --CO.sub.2R.sup.5 or --C(O)N(R.sup.4).sub.2.
[0171] In some embodiments, the compound of formula (I) is
characterized by at least one, two, or three of the following
features (a)-(f): [0172] (a) R.sup.a is hydrogen or C.sub.1-3
alkyl; [0173] (b) R.sup.f1 and R.sup.f2 together form a bond;
[0174] (c) Ring A is substituted with 0-2 R.sup.b, where each
R.sup.b independently is selected from the group consisting of
C.sub.1-3 aliphatic, R.sup.2b, R.sup.7b, -T.sup.1-R.sup.2b, and
-T.sup.1-R.sup.7b, where T.sup.1 is a C.sub.1-3 alkylene chain;
[0175] (d) Ring B is a monocyclic 5- or 6-membered aryl or
heteroaryl ring, which is substituted with 0-2 R.sup.c, where each
R.sup.c independently is selected from the group consisting of
C.sub.1-3 aliphatic, R.sup.2c, R.sup.7c, -T.sup.1-R.sup.2c, and
-T.sup.1-R.sup.7c, where T.sup.1 is a C.sub.1-3 alkylene chain;
[0176] (e) Ring C is a mono- or bicyclic aryl or heteroaryl ring,
which is substituted with 0-2 independently selected R.sup.d and
0-2 independently selected R.sup.2d or C.sub.1-6 aliphatic groups;
and [0177] (f) R.sup.e is hydrogen.
[0178] In some embodiments, the compound of formula (I) is
characterized by all six of the features (a)-(f) above.
[0179] Some embodiments of the invention relate to a subgenus of
formula (A) defined by formula (B) or (II):
##STR00081##
[0180] wherein each of R.sup.e, R.sup.x, R.sup.y, and Rings A, B,
and C have the values and preferred values described above for
formulae (B) and (1). In some such embodiments, Ring B is a mono-
or bicyclic aryl or heteroaryl ring, which 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, and Ring C as a mono- or
bicyclic aryl, heteroaryl, heterocyclyl or cycloaliphatic ring,
which is substituted with 0-2 independently selected R.sup.d and
0-2 independently selected R.sup.2d or C.sub.1-6 aliphatic
groups.
[0181] In some embodiments, the compound of formula (II) is defined
by formula (IIa):
##STR00082##
[0182] wherein Ring A is substituted with 0-2 independently
selected R.sup.b, and Ring B is substituted with 0-2 independently
selected R.sup.c. In some embodiments, the compound of formula
(IIa) is characterized by at least one of the following features
(a)-(c):
[0183] (a) each R.sup.b independently is selected from the group
consisting of C.sub.1-3 aliphatic, R.sup.2b, R.sup.7b,
-T.sup.1-R.sup.2b, and -T.sup.1-R.sup.7b, where T.sup.1 is a
C.sub.1-3 alkylene chain optionally substituted with fluoro, 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.ident.C--R.sup.5, --OR.sup.5, and --N(R.sup.4).sub.2;
[0184] (b) each R.sup.c independently is selected from the group
consisting of C.sub.1-3 aliphatic, R.sup.2c, R.sup.7c,
-T.sup.1-R.sup.2c, and -T.sup.1-R.sup.7c, where T.sup.1 is a
C.sub.1-3 alkylene chain optionally substituted with fluoro, 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,
--C.ident.C--R.sup.5, --OR.sup.5, and --N(R.sup.4).sub.2; and
[0185] (c) R.sup.e is hydrogen.
[0186] Some embodiments of the invention relate to a subgenus of
the compounds of formula (IIa) defined by formula (III):
##STR00083##
[0187] wherein each of R.sup.b, R.sup.c, R.sup.e, and Ring C have
the values or preferred values described above for any preceding
formula.
[0188] Some embodiment of the invention relate to a subgenus of the
compounds of formula (IIa) defined by formula (Ilia):
##STR00084##
[0189] wherein: each of R.sup.b2 and R.sup.b3 independently is
hydrogen or R.sup.b; each of R.sup.c1 and R.sup.c5 independently is
hydrogen or R.sup.c; and each of Ring C, R.sup.b, R.sup.c, and
R.sup.e have the values and preferred values described above for
any preceding formula.
[0190] In some embodiments, each R.sup.b in formula (III) or (Ilia)
is selected from the group consisting of C.sub.1-3 aliphatic,
C.sub.1-3 fluoroaliphatic, and R.sup.2b; and each R.sup.c is
selected from the group consisting of C.sub.1-3 aliphatic,
C.sub.1-3 fluoroaliphatic, and R.sup.2c. In certain such
embodiments, each of R.sup.2b and 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, --OC--R.sup.5, --OR.sup.5, and
--N(R.sup.4).sub.2.
[0191] In some embodiments, the invention relates to a compound of
formula (Ilia), wherein R.sup.e is hydrogen; each of R.sup.b2 and
R.sup.b3 independently is selected from the group consisting of
hydrogen, -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;
and each of R.sup.c1 and R.sup.c5 independently is selected from
the group consisting of hydrogen, -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 some embodiments, each of
R.sup.b3 and R.sup.c1 independently is selected from the group
consisting of -halo, C.sub.1-3aliphatic, C.sub.1-3 fluoroaliphatic,
and --OR.sup.5, where R.sup.5 hydrogen or C.sub.1-3 aliphatic. In
certain such embodiments, R.sup.b2 is hydrogen, R.sup.c5 is
selected from the group consisting of hydrogen, -halo,
C.sub.1-3aliphatic, C.sub.1-3 fluoroaliphatic, and --OR.sup.5, and
each of R.sup.b3 and R.sup.c1 independently is selected from the
group consisting of -halo, C.sub.1-3aliphatic, C.sub.1-3
fluoroaliphatic, and --OR.sup.5, where R.sup.5 hydrogen or
C.sub.1-3 aliphatic. In certain embodiments, R.sup.b2 is hydrogen,
R.sup.c2 is hydrogen, chloro, fluoro, bromo, methyl,
trifluoromethyl, or methoxy, and each of R.sup.b3 and R.sup.c1
independently is chloro, fluoro, bromo, methyl, trifluoromethyl, or
methoxy.
[0192] Some embodiments of the invention relate to a subgenus of
the compounds of formula (A) defined by formula (IV):
##STR00085##
[0193] wherein: [0194] Ring A is substituted with 0-2 R.sup.b;
[0195] Ring B is a mono- or bicyclic aryl or heteroaryl ring, which
optionally 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; [0196] R.sup.e is hydrogen or a C.sub.1-3 aliphatic
optionally substituted with R.sup.3 or R.sup.7; [0197] R.sup.g is
selected from the group consisting of hydrogen, C.sub.1-6
aliphatic, and R.sup.2d; and [0198] each of R.sup.h and R.sup.k
independently is hydrogen or R.sup.d.
[0199] In some such embodiments, the invention relates to a
compound of formula (IV), wherein: [0200] each R.sup.4 in R.sup.d
or R.sup.2d is hydrogen, C.sub.1-3 alkyl, or a 5- or 6-membered
aryl or heteroaryl ring; 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; and [0201] each R.sup.5
in R.sup.d or R.sup.2d is hydrogen, C.sub.1-3 alkyl, or a 5- or
6-membered aryl or heteroaryl ring.
[0202] In some such embodiments, two R.sup.4 on the same nitrogen
atom in R.sup.d or R.sup.2d, taken together with the nitrogen atom,
form an optionally substituted piperidinyl, piperazinyl, or
morpholinyl ring.
[0203] In some embodiments, the invention relates to a compound of
formula (IV) wherein: [0204] Ring A is substituted with 0-2
R.sup.b, where each R.sup.b independently is selected from the
group consisting of C.sub.1-3 aliphatic, R.sup.2b, R.sup.7b,
-T.sup.1-R.sup.2b, and -T.sup.1-R.sup.7b, where T.sup.1 is a
C.sub.1-3 alkylene chain; [0205] Ring B is a monocyclic 5- or
6-membered aryl or heteroaryl ring, which is substituted with 0-2
independently selected R.sup.c, where each R.sup.c independently is
selected from the group consisting of C.sub.1-3 aliphatic,
R.sup.2c, R.sup.7c, -T.sup.1-R.sup.2c, and -T.sup.1-R.sup.7c, where
T.sup.1 is a C.sub.1-3 alkylene chain; and [0206] R.sup.e is
hydrogen.
[0207] In some such embodiments, each R.sup.b independently is
selected from the group consisting of C.sub.1-3 aliphatic,
R.sup.2b, and -T.sup.1-R.sup.2b, and each R.sup.c independently is
selected from the group consisting of C.sub.1-3 aliphatic,
R.sup.2c, and -T.sup.1-R.sup.2c. In some embodiments, 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, --OC--R.sup.5,
--OR.sup.5, and --N(R.sup.4).sub.2, 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, --OC--R.sup.5, --OR.sup.5, and
--N(R.sup.4).sub.2.
[0208] In some embodiments, the invention is directed to the
compound of formula (IV), wherein one of R.sup.h and R.sup.k is
R.sup.7d. In some such embodiments, R.sup.g is hydrogen, and
R.sup.7d is tetrazolyl.
[0209] In some embodiments, the invention relates to a compound of
formula (IV), wherein R.sup.g is hydrogen, one of R.sup.h and
R.sup.k has the formula -T.sup.2-R.sup.2d or -T.sup.2-R.sup.7d, and
the other of R.sup.h and R.sup.k is selected from the group
consisting of hydrogen, -halo, C.sub.1-3 aliphatic, and --OR.sup.5,
where R.sup.5 is hydrogen or C.sub.1-3 aliphatic. In some
embodiments, T.sup.2 is a C.sub.1-6 alkylene chain, which
optionally is interrupted by --C(O)N(R.sup.4)-- or
--N(R.sup.4)C(O)--.
[0210] In some embodiments, the invention is directed to a compound
of formula (IV) wherein R.sup.g is hydrogen, one of R.sup.h and
R.sup.k has the formula --V-T.sup.3-R.sup.2d, and the other of
R.sup.h and R.sup.k is selected from the group consisting of
hydrogen, -halo, C.sub.1-3 aliphatic, and --OR.sup.5, where R.sup.5
is hydrogen or C.sub.1-3 aliphatic. In some such embodiments, V is
--C(O)N(R.sup.4)--, T.sup.3 is a C.sub.2-4 alkylene chain, and
R.sup.2d is --N(R.sup.4).sub.2, where each R.sup.4 independently is
hydrogen or C.sub.1-3 aliphatic, or --N(R.sup.4).sub.2 is an
optionally substituted 5- to 6-membered heteroaryl or 4- to
8-membered heterocyclyl ring having, in addition to the nitrogen,
0-2 ring heteroatoms selected from N, O, and S. In certain such
embodiments, --N(R.sup.4).sub.2 is an optionally substituted
heterocyclyl selected from the group consisting of piperidinyl,
piperazinyl, and morpholinyl. In certain other such embodiments,
--N(R.sup.4).sub.2 is an optionally substituted heterocyclyl
selected from pyrrolidinyl and azetidinyl.
[0211] In some other embodiments, the invention relates to a
compound of formula (IV), wherein R.sup.k is hydrogen, one of
R.sup.h and R.sup.k has the formula --V-T.sup.3-R.sup.7d, and the
other of R.sup.h and R.sup.k is selected from the group consisting
of hydrogen, -halo, C.sub.1-3 aliphatic, and --OR.sup.5, where
R.sup.5 is hydrogen or C.sub.1-3 aliphatic. In certain such
embodiments, V is --C(O)N(R.sup.4)--, T.sup.3 is a C.sub.2-4
alkylene chain, and R.sup.7d is an optionally substituted 4- to
8-membered heterocyclyl or an optionally substituted 5- to
6-membered heteroaryl. In certain such embodiments, R.sup.7d is an
optionally substituted heteroaryl selected from the group
consisting of pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
pyrrolyl, oxazolyl, imidazolyl, and pyrazolyl. In certain other
such embodiments, R.sup.7d is a 6- to 8-membered bridged bicyclic
heterocyclyl.
[0212] In some embodiments, the invention is directed to a compound
of formula (IV) wherein R.sup.g is hydrogen, and at least one of
R.sup.h and R.sup.k is selected from the group consisting of
--CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(.dbd.NR.sup.4)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5, or
--NR.sup.4C(O)R.sup.5. In some such embodiments, at least one of
R.sup.h and R.sup.k is --CO.sub.2R.sup.5, where R.sup.5 is hydrogen
or C.sub.1-6 aliphatic. In some embodiments, each of R.sup.g and
R.sup.k is hydrogen, and R.sup.h is --CO.sub.2R.sup.5.
[0213] In some embodiments, R.sup.g is hydrogen, and one of R.sup.h
and R.sup.k is --C(O)--N(R.sup.4).sub.2 or
--C(.dbd.NR.sup.4)N(R.sup.4).sub.2, where --N(R.sup.4).sub.2 is an
optionally substituted heterocyclyl selected from the group
consisting of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl,
and azetidinyl. In some such embodiments, one of R.sup.h and
R.sup.k has one of the formulae D-i to D-v, as defined above. In
certain such embodiments, one of R.sup.h or R.sup.k has one of the
formulae D-1 to D-51, or has the formula embodied at the relevant
position of any of the compounds depicted in Table 3 below.
[0214] Some embodiment of the invention relate to a subgenus of the
compounds of formula (A) defined by formula (C):
##STR00086##
[0215] wherein: [0216] Ring A is a substituted or unsubstituted 5-
or 6-membered aryl, heteroaryl, cycloaliphatic, or heterocyclyl
ring; [0217] 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; [0218] Ring C is substituted 0-2 independently
selected R.sup.d and 0-3 independently selected R.sup.2d or
C.sub.1-6 aliphatic groups; and [0219] each of R.sup.e, R.sup.x,
and R.sup.y has the values and preferred values described
above.
[0220] In some embodiments, the invention relates to a subgenus of
formula (C) defined by formula (V):
##STR00087##
[0221] wherein: [0222] R.sup.e is hydrogen or a C.sub.1-3 aliphatic
optionally substituted with R.sup.3 or R.sup.7; [0223] Ring A is
substituted with 0-3 R.sup.b; [0224] 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; and [0225] Ring C is
substituted or unsubstituted.
[0226] In some embodiments, the compound of formula (V) is defined
by formula (Va):
##STR00088## [0227] wherein: [0228] R.sup.e is hydrogen; [0229]
each of R.sup.b2 and R.sup.b3 independently is selected from the
group consisting of hydrogen, -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; [0230] each of R.sup.c1 and R.sup.c5
independently is selected from the group consisting of hydrogen,
-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;
[0231] R.sup.g is selected from the group consisting of hydrogen,
C.sub.1-6 aliphatic, and R.sup.2d; and [0232] each of R.sup.h and
R.sup.k independently is hydrogen or R.sup.d.
[0233] In some embodiments, the invention relates to a compound of
formula (Va) wherein at least one of R.sup.h and R.sup.k has the
formula --V-T.sup.3-R.sup.2d or --V-T.sup.3-R.sup.7d, where: [0234]
V is --C(O)N(R.sup.4)--; [0235] T.sup.3 is a C.sub.2-4 alkylene
chain; [0236] R.sup.2d is --N(R.sup.4).sub.2, where R.sup.4 is
hydrogen or C.sub.1-3 aliphatic, or two R.sup.4 on the same
nitrogen atom, taken together with the nitrogen atom, form an
optionally substituted 4- to 8-membered heterocyclyl or an
optionally substituted 5- to 6-membered heteroaryl ring having, in
addition to the nitrogen, 0-2 ring heteroatoms selected from N, O,
and S; and [0237] R.sup.7d is an optionally substituted 4- to
8-membered heterocyclyl or an optionally substituted 5- to
6-membered heteroaryl.
[0238] In some other embodiments, the invention relates to a
compound of formula (Va), wherein R.sup.g is hydrogen, and at least
one of R.sup.h and R.sup.k is selected from the group consisting of
--CO.sub.2R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(.dbd.NR.sup.4)N(R.sup.4).sub.2,
--C(O)N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4)--C(O)R.sup.5, or
--NR.sup.4C(O)R.sup.5.
[0239] In a particular embodiment, the invention relates to a
compound of formula (Va), wherein: [0240] R.sup.e, R.sup.b2,
R.sup.g, and R.sup.k are each hydrogen; [0241] R.sup.b3 and
R.sup.c1 are each independently 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;
[0242] R.sup.c5 is selected from the group consisting of hydrogen,
-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; and
[0243] R.sup.h is --CO.sub.2H, --C(O)N(R.sup.4).sub.2,
--C(.dbd.NR.sup.4)N(R.sup.4).sub.2,
--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, where
R.sup.5 is an optionally substituted 4- to 8-membered
nitrogen-containing heterocyclyl ring, and --N(R.sup.4).sub.2 is an
optionally substituted 4- to 8-membered heterocyclyl ring having in
addition to the nitrogen atom 0-2 heteroatoms selected from N, O,
and S.
[0244] Compounds embodying any combination of the preferred values
for the variables described herein are considered to be within the
scope of the present invention.
[0245] Table 3 shows specific examples of compounds of formula
(V).
TABLE-US-00003 TABLE 3 Aurora Kinase Inhibitors ##STR00089## I-1
##STR00090## I-2 ##STR00091## I-3 ##STR00092## I-4 ##STR00093## I-5
##STR00094## I-6 ##STR00095## I-7 ##STR00096## I-8 ##STR00097## I-9
##STR00098## I-10 ##STR00099## I-11 ##STR00100## I-12 ##STR00101##
I-13 ##STR00102## I-14 ##STR00103## I-15 ##STR00104## I-16
##STR00105## I-17 ##STR00106## I-18 ##STR00107## I-19 ##STR00108##
I-20 ##STR00109## I-21 ##STR00110## I-22 ##STR00111## I-23
##STR00112## I-24 ##STR00113## I-25 ##STR00114## I-26 ##STR00115##
I-27 ##STR00116## I-28 ##STR00117## I-29 ##STR00118## I-30
##STR00119## I-31 ##STR00120## I-32 ##STR00121## I-33 ##STR00122##
I-34 ##STR00123## I-35 ##STR00124## I-36 ##STR00125## I-37
##STR00126## I-38 ##STR00127## I-39 ##STR00128## I-40 ##STR00129##
I-41 ##STR00130## I-42 ##STR00131## I-43 ##STR00132## I-44
##STR00133## I-45 ##STR00134## I-46 ##STR00135## I-47 ##STR00136##
I-48 ##STR00137## I-49 ##STR00138## I-50 ##STR00139## I-51
##STR00140## I-52 ##STR00141## I-53 ##STR00142## I-54 ##STR00143##
I-55 ##STR00144## I-56 ##STR00145## I-57 ##STR00146## I-58
##STR00147## I-59 ##STR00148## I-60 ##STR00149## I-61 ##STR00150##
I-62 ##STR00151## I-63 ##STR00152## I-64 ##STR00153## I-65
##STR00154## I-66 ##STR00155## I-67 ##STR00156## I-68 ##STR00157##
I-69 ##STR00158## I-70 ##STR00159## I-71 ##STR00160## I-72
##STR00161## I-73 ##STR00162## I-74 ##STR00163## I-75 ##STR00164##
I-76 ##STR00165## I-77 ##STR00166## I-78 ##STR00167## I-79
##STR00168## I-80 ##STR00169## I-81 ##STR00170## I-82 ##STR00171##
I-83 ##STR00172## I-84 ##STR00173## I-85 ##STR00174## I-86
##STR00175## I-87 ##STR00176## I-88 ##STR00177## I-89 ##STR00178##
I-90 ##STR00179## I-91 ##STR00180## I-92 ##STR00181## I-93
##STR00182## I-94 ##STR00183## I-95 ##STR00184## I-96 ##STR00185##
I-97 ##STR00186## I-98 ##STR00187## I-99 ##STR00188## I-100
##STR00189## I-101 ##STR00190## I-102 ##STR00191## I-103
##STR00192## I-104 ##STR00193## I-105 ##STR00194## I-106
##STR00195## I-107 ##STR00196## I-108 ##STR00197## I-109
##STR00198## I-110 ##STR00199## I-111 ##STR00200## I-112
##STR00201## I-113 ##STR00202## I-114 ##STR00203## I-115
##STR00204## I-116 ##STR00205## I-117 ##STR00206## I-118
##STR00207## I-119 ##STR00208## I-120 ##STR00209## I-121
##STR00210## I-122 ##STR00211## I-123
##STR00212## I-124 ##STR00213## I-125 ##STR00214## I-126
##STR00215## I-127 ##STR00216## I-128 ##STR00217## I-129
##STR00218## I-130 ##STR00219## I-131 ##STR00220## I-132
##STR00221## I-133 ##STR00222## I-134 ##STR00223## I-135
##STR00224## I-136 ##STR00225## I-137 ##STR00226## I-138
##STR00227## I-139 ##STR00228## I-140 ##STR00229## I-141
##STR00230## I-142 ##STR00231## I-143 ##STR00232## I-144
##STR00233## I-145 ##STR00234## I-146 ##STR00235## I-147
##STR00236## I-148 ##STR00237## I-149 ##STR00238## I-150
##STR00239## I-151 ##STR00240## I-152 ##STR00241## I-153
##STR00242## I-154 ##STR00243## I-155 ##STR00244## I-156
##STR00245## I-157 ##STR00246## I-158 ##STR00247## I-159
##STR00248## I-160 ##STR00249## I-161 ##STR00250## I-162
##STR00251## I-163 ##STR00252## I-164 ##STR00253## I-165
##STR00254## I-166 ##STR00255## I-167 ##STR00256## I-168
##STR00257## I-169 ##STR00258## I-170 ##STR00259## I-171
##STR00260## I-172 ##STR00261## I-173 ##STR00262## I-174
##STR00263## I-175 ##STR00264## I-176 ##STR00265## I-177
##STR00266## I-178 ##STR00267## I-179 ##STR00268## I-180
##STR00269## I-181 ##STR00270## I-182 ##STR00271## I-183
##STR00272## I-184 ##STR00273## I-185 ##STR00274## I-186
##STR00275## I-187 ##STR00276## I-188 ##STR00277## I-189
##STR00278## I-190 ##STR00279## I-191 ##STR00280## I-192
##STR00281## I-193 ##STR00282## I-194 ##STR00283## I-195
##STR00284## I-196 ##STR00285## I-197 ##STR00286## I-198
##STR00287## I-199 ##STR00288## I-200 ##STR00289## I-201
##STR00290## I-202 ##STR00291## I-203 ##STR00292## I-204
##STR00293## I-205 ##STR00294## I-206 ##STR00295## I-207
##STR00296## I-208 ##STR00297## I-209 ##STR00298## I-210
##STR00299## I-211 ##STR00300## I-212 ##STR00301## I-213
##STR00302## I-214 ##STR00303## I-215 ##STR00304## I-216
##STR00305## I-217 ##STR00306## I-218 ##STR00307## I-219
##STR00308## I-220 ##STR00309## I-221 ##STR00310## I-222
##STR00311## I-223 ##STR00312## I-224 ##STR00313## I-225
##STR00314## I-226 ##STR00315## I-227 ##STR00316## I-228
##STR00317## I-229 ##STR00318## I-230 ##STR00319## I-231
##STR00320## I-232 ##STR00321## I-233 ##STR00322## I-234
##STR00323## I-235 ##STR00324## I-236 ##STR00325## I-237
##STR00326## I-238 ##STR00327## I-239 ##STR00328## I-240
##STR00329## I-241 ##STR00330## I-242 ##STR00331## I-243
##STR00332## I-244 ##STR00333## I-245 ##STR00334## I-246
##STR00335## I-247 ##STR00336## I-248
##STR00337## I-249 ##STR00338## I-250 ##STR00339## I-251
##STR00340## I-252 ##STR00341## I-253 ##STR00342## I-254
##STR00343## I-255 ##STR00344## I-256 ##STR00345## I-257
##STR00346## I-258 ##STR00347## I-259 ##STR00348## I-260
##STR00349## I-261 ##STR00350## I-262 ##STR00351## I-263
##STR00352## I-264 ##STR00353## I-265 ##STR00354## I-266
##STR00355## I-267 ##STR00356## I-268 ##STR00357## I-269
##STR00358## I-270 ##STR00359## I-271 ##STR00360## I-272
##STR00361## I-273 ##STR00362## I-274 ##STR00363## I-275
##STR00364## I-276 ##STR00365## I-277 ##STR00366## I-278
##STR00367## I-279 ##STR00368## I-280 ##STR00369## I-281
##STR00370## I-282 ##STR00371## I-283 ##STR00372## I-284
##STR00373## I-285 ##STR00374## I-286 ##STR00375## I-287
##STR00376## I-288 ##STR00377## I-289 ##STR00378## I-290
##STR00379## I-291 ##STR00380## I-292 ##STR00381## I-293
##STR00382## I-294 ##STR00383## I-295 ##STR00384## I-296
##STR00385## I-297 ##STR00386## I-298 ##STR00387## I-299
##STR00388## I-300 ##STR00389## I-301 ##STR00390## I-302
##STR00391## I-303 ##STR00392## I-304 ##STR00393## I-305
##STR00394## I-306 ##STR00395## I-307 ##STR00396## I-308
##STR00397## I-309 ##STR00398## I-310 ##STR00399## I-311
##STR00400## I-312 ##STR00401## I-313 ##STR00402## I-314
##STR00403## I-315 ##STR00404## I-316 ##STR00405## I-317
##STR00406## I-318 ##STR00407## I-319 ##STR00408## I-320
##STR00409## I-321 ##STR00410## I-322 ##STR00411## I-323
##STR00412## I-324 ##STR00413## I-325 ##STR00414## I-326
##STR00415## I-327 ##STR00416## I-328 ##STR00417## I-329
##STR00418## I-330 ##STR00419## I-331 ##STR00420## I-332
##STR00421## I-333 ##STR00422## I-334 ##STR00423## I-335
##STR00424## I-336 ##STR00425## I-337 ##STR00426## I-338
##STR00427## I-339 ##STR00428## I-340 ##STR00429## I-341
##STR00430## I-342 ##STR00431## I-343 ##STR00432## I-344
##STR00433## I-345 ##STR00434## I-346 ##STR00435## I-347
##STR00436## I-348 ##STR00437## I-349 ##STR00438## I-350
##STR00439## I-351 ##STR00440## I-352 ##STR00441## I-353
##STR00442## I-354 ##STR00443## I-355 ##STR00444## I-356
##STR00445## I-357 ##STR00446## I-358 ##STR00447## I-359
##STR00448## I-360 ##STR00449## I-361 ##STR00450## I-362
##STR00451## I-363 ##STR00452## I-364 ##STR00453## I-365
##STR00454## I-366 ##STR00455## I-367 ##STR00456## I-368
##STR00457## I-369 ##STR00458## I-370 ##STR00459## I-371
##STR00460## I-372 ##STR00461## I-373 ##STR00462## I-374
##STR00463## I-375 ##STR00464## I-376 ##STR00465## I-377
##STR00466## I-378 ##STR00467## I-379 ##STR00468## I-380
##STR00469## I-381 ##STR00470## I-382 ##STR00471## I-383
##STR00472## I-384 ##STR00473## I-385 ##STR00474## I-386
##STR00475## I-387 ##STR00476## I-388 ##STR00477## I-389
##STR00478## I-390 ##STR00479## I-391 ##STR00480## I-392
##STR00481## I-393 ##STR00482## I-394 ##STR00483## I-395
##STR00484## I-396 ##STR00485## I-397 ##STR00486## I-398
##STR00487## I-399 ##STR00488## I-400 ##STR00489## I-401
##STR00490## I-402 ##STR00491## I-403 ##STR00492## I-404
##STR00493## I-405 ##STR00494## I-406 ##STR00495## I-407
##STR00496## I-408 ##STR00497## I-409 ##STR00498## I-410
##STR00499## I-411 ##STR00500## I-412 ##STR00501## I-413
##STR00502## I-414 ##STR00503## I-415 ##STR00504## I-416
##STR00505## I-417 ##STR00506## I-418 ##STR00507## I-419
##STR00508## I-420 ##STR00509## I-421 ##STR00510## I-422
##STR00511## I-423 ##STR00512## I-424 ##STR00513## I-425
##STR00514## I-426 ##STR00515## I-427 ##STR00516## I-428
##STR00517## I-429 ##STR00518## I-430 ##STR00519## I-431
##STR00520## I-432 ##STR00521## I-433 ##STR00522## I-434
##STR00523## I-435 ##STR00524## I-436 ##STR00525## I-437
##STR00526## I-438 ##STR00527## I-439 ##STR00528## I-440
##STR00529## I-441 ##STR00530## I-442 ##STR00531## I-443
##STR00532## I-444 ##STR00533## I-445 ##STR00534## I-446
##STR00535## I-447 ##STR00536## I-448 ##STR00537## I-449
##STR00538## I-450 ##STR00539## I-451 ##STR00540## I-452
##STR00541## I-453 ##STR00542## I-454 ##STR00543## I-455
##STR00544## I-456 ##STR00545## I-457 ##STR00546## I-458
##STR00547## I-459 ##STR00548## I-460 ##STR00549## I-461
##STR00550## I-462 ##STR00551## I-463 ##STR00552## I-464
##STR00553## I-465 ##STR00554## I-466 ##STR00555## I-467
##STR00556## I-468 ##STR00557## I-469 ##STR00558## I-470
##STR00559## I-471 ##STR00560## I-472 ##STR00561## I-473
##STR00562## I-474 ##STR00563## I-475 ##STR00564## I-476
##STR00565## I-477 ##STR00566## I-478 ##STR00567## I-479
##STR00568## I-480 ##STR00569## I-481 ##STR00570## I-482
##STR00571## I-483 ##STR00572## I-484 ##STR00573## I-485
##STR00574## I-486 ##STR00575## I-487 ##STR00576## I-488
##STR00577## I-489 ##STR00578## I-490 ##STR00579## I-491
##STR00580## I-492 ##STR00581## I-493 ##STR00582## I-494
##STR00583## I-495 ##STR00584## I-496 ##STR00585## I-497
##STR00586## I-498 ##STR00587## I-499
##STR00588## I-500 ##STR00589## I-501 ##STR00590## I-502
##STR00591## I-503 ##STR00592## I-504 ##STR00593## I-505
##STR00594## I-506 ##STR00595## I-507 ##STR00596## I-508
##STR00597## I-509 ##STR00598## I-510 ##STR00599## I-511
##STR00600## I-512 ##STR00601## I-513 ##STR00602## I-514
##STR00603## I-515 ##STR00604## I-516 ##STR00605## I-517
##STR00606## I-518 ##STR00607## I-519 ##STR00608## I-520
##STR00609## I-521 ##STR00610## I-522 ##STR00611## I-523
##STR00612## I-524 ##STR00613## I-525 ##STR00614## I-526
##STR00615## I-527 ##STR00616## I-528 ##STR00617## I-529
##STR00618## I-530 ##STR00619## I-531 ##STR00620## I-532
##STR00621## I-533 ##STR00622## I-534 ##STR00623## I-535
[0246] The compounds in Table 3 above also may be identified by the
following chemical names: [0247] I-1:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-(2-methylamino-ethyl)-benzamide [0248] I-2:
N-(2-Amino-ethyl)-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido-[4,-
5-e]azepin-2-ylamino]-N-methyl-benzamide [0249] I-3:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-methyl-N-(2-methylamino-ethyl)-benzamide [0250] I-4:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-(2-dimethylamino-ethyl)-benzamide [0251] I-5:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-(2-dimethylamino-ethyl)-N-methyl-benzamide [0252] I-6:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-(3-dimethylamino-propyl)-benzamide [0253] I-7:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-(3-dimethylamino-propyl)-N-methyl-benzamide [0254] I-8:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-piperazin-1-yl-methanone [0255] I-9:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-(4-methyl-piperazin-1-yl)-methanone [0256] I-10:
{4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-(4-methyl-piperazin-1-yl)-methanone [0257] I-11:
[4-(9-Chloro-7-o-tolyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-phenyl-
]-(4-methyl-piperazin-1-yl)-methanone [0258] I-12:
{4-[9-Chloro-7-(2-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylam-
ino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone [0259] I-13:
{4-[9-Chloro-7-(4-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-(4-methyl-piperazin-1-yl)-methanone [0260] I-14:
{4-[7-(2-Fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-(4-methyl-piperazin-1-yl)-methanone [0261] I-15:
2-{3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yla-
mino]-phenyl}-1-(4-methyl-piperazin-1-yl)-ethanone [0262] I-16:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-piperidin-4-yl-benzamide [0263] I-17:
(4-Amino-piperidin-1-yl)-{4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyri-
mido[4,5-e]azepin-2-ylamino]-phenyl}-methanone [0264] I-18:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-(4-dimethylamino-piperidin-1-yl)-methanone [0265] I-19:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide [0266] I-20:
4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide [0267] I-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 [0268] I-22:
4-[9-Chloro-7-(2-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide [0269] I-23:
4-[9-Chloro-7-(4-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide [0270] I-24:
4-[7-(2-Fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide [0271] I-25:
2-{3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yla-
mino]-phenyl}-N-[3-(4-methyl-piperazin-1-yl)-propyl]-acetamide
[0272] I-26:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
-ylamino]-phenyl}-morpholin-4-yl-methanone [0273] I-27:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N,N-bis-(2-hydroxy-ethyl)-benzamide [0274] I-28:
{4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-morpholin-4-yl-methanone [0275] I-29:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-(2-morpholin-4-yl-ethyl)-benzamide [0276] I-30:
4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-(2-morpholin-4-yl-ethyl)-benzamide [0277] I-31:
4-(9-Chloro-7-o-tolyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-N-(2-mo-
rpholin-4-yl-ethyl)-benzamide [0278] I-32:
4-[9-Chloro-7-(2-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-N-(3-morpholin-4-yl-propyl)-benzamide [0279] I-33:
4-[9-Chloro-7-(4-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-(2-morpholin-4-yl-ethyl)-benzamide [0280] I-34:
4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-2-hydroxy-N-(2-morpholin-4-yl-ethyl)-benzamide [0281] I-35:
[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-pyri-
din-2-yl-amine [0282] I-36:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,5-
-dichloro-phenyl)-amine [0283] I-37:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-m-
ethoxy-phenyl)-amine [0284] I-38:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-e-
thoxy-phenyl)-amine [0285] I-39:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3-m-
ethoxy-phenyl)-amine [0286] I-40:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(2-m-
ethoxy-phenyl)-amine [0287] I-41:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-c-
hloro-phenyl)-amine [0288] I-42:
[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-c-
hloro-phenyl)-amine [0289] I-43:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3-c-
hloro-phenyl)-amine [0290] I-44:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(2-c-
hloro-phenyl)-amine [0291] I-45:
4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-phenol [0292] I-46:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-m-
orpholin-4-yl-phenyl)-amine [0293] I-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 [0294] I-48:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-p-
yridin-4-ylmethyl-phenyl)-amine [0295] I-49:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzonitrile [0296] I-50:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-n-
itro-phenyl)-amine [0297] I-51:
4-[7-(2-Fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoi-
c acid [0298] I-52:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzoic acid [0299] I-53:
4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzoic acid [0300] I-54:
4-(9-Chloro-7-o-tolyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-benzoic
acid [0301] I-55:
4-[9-Chloro-7-(2-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-benzoic acid [0302] I-56:
4-[9-Chloro-7-(4-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzoic acid [0303] I-57:
4-[9-Fluoro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzoic acid [0304] I-58:
4-[7-(2-Fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzoic acid [0305] I-59:
4-[10-Fluoro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-benzoic acid [0306] I-60:
4-[10-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-benzoic acid [0307] I-61:
4-[10-Bromo-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzoic acid [0308] I-62:
4-[7-(2-Fluoro-phenyl)-10-methoxy-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylam-
ino]-benzoic acid [0309] I-63:
4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzamide [0310] I-64:
3-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzamide [0311] I-65:
{3-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-acetic acid [0312] I-66:
2-{3-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yla-
mino]-phenyl}-acetamide [0313] I-67:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzenesulfonic acid [0314] I-68:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzenesulfonamide [0315] I-69:
4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-(5-methyl-isoxazol-3-yl)-benzenesulfonamide [0316] I-70:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-t-
rifluoromethanesulfonyl-phenyl)-amine [0317] I-71:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,4-
-dimethoxy-phenyl)-amine [0318] I-72:
[9-Chloro-7-(2-fluoro-phenyl)-6,7-dihydro-5H-benzo[c]pyrimido-[4,5-e]azep-
in-2-yl]-(3,4-dimethoxy-phenyl)-amine [0319] I-73:
[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,4-
-dimethoxy-phenyl)-amine [0320] I-74:
(9-Chloro-7-o-tolyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl)-(3,4-dimethoxy-
-phenyl)-amine [0321] I-75:
(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[-
4,5-e]azepin-2-yl]-amine [0322] I-76:
(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-9-isopropyl-5H-benzo[c]pyrimi-
do[4,5-e]azepin-2-yl]-amine [0323] I-77:
(3,4-Dimethoxy-phenyl)-[10-fluoro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-yl]-amine [0324] I-78:
[10-Bromo-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,4-
-dimethoxy-phenyl)-amine [0325] I-79:
(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-10-trifluoromethyl-5H-benzo[c-
]pyrimido[4,5-e]azepin-2-yl]-amine [0326] I-80:
(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-10-methyl-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-yl]-amine [0327] I-81:
(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-10-methoxy-5H-benzo[c]pyrimid-
o[4,5-e]azepin-2-yl]-amine [0328] I-82:
(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-11-methyl-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-yl]-amine [0329] I-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 [0330] I-84:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-f-
luoro-3-methoxy-phenyl)-amine [0331] I-85:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-2-hydroxy-benzoic acid [0332] I-86:
4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-2-hydroxy-benzoic acid [0333] I-87:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,4-
-dichloro-phenyl)-amine [0334] I-88:
[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,5-
-dimethoxy-phenyl)-amine [0335] I-89:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,5-
-dimethyl-phenyl)-amine [0336] I-90:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-phen-
yl-amine [0337] I-91:
4-[9-Chloro-7-(2,5-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
amino]-benzoic acid [0338] I-92:
4-[9-Chloro-7-(2,3-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
amino]-benzoic acid [0339] I-93:
(3-Dimethylamino-pyrrolidin-1-yl)-{4-[7-(2-fluoro-phenyl)-9-methoxy-5H-be-
nzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-methanone [0340]
I-94:
4-[9-Chloro-7-(2,5-dimethoxy-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2--
ylamino]-benzoic acid [0341] I-95:
4-[7-(2-Fluoro-phenyl)-9-methoxy-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-N,N-bis-(2-hydroxy-ethyl)-benzamide [0342] I-96:
4-[9-Chloro-7-(2,4-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
amino]-benzoic acid [0343] I-97:
4-[9-Chloro-7-(2,4-difluoro-phenyl)-7H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
amino]-benzoic acid [0344] I-98:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-(3-dimethylamino-azetidin-1-yl)-methanone [0345] I-99:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-methyl-N-(1-methyl-pyrrolidin-3-yl)-benzamide [0346] I-100:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-(3-dimethylamino-pyrrolidin-1-yl)-methanone [0347]
I-101:
4-[9-Chloro-7-(2,4-dimethoxy-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2--
ylamino]-benzoic acid [0348] I-102:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-(3-methylamino-pyrrolidin-1-yl)-methanone [0349] I-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 [0350]
I-104:
4-[9-Chloro-7-(2,3-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-:
ylamino]-benzoic acid methyl ester [0351] I-105:
4-[9-Chloro-7-(2,5-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
amino]-benzoic acid methyl ester [0352] I-106
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-phosphonic acid [0353] I-107:
N-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yla-
mino]-phenyl}-methanesulfonamide [0354] I-108:
N-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yla-
mino]-phenyl}-N-methyl-acetamide [0355] I-109:
2-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yla-
mino]-benzoylamino}-succinic acid [0356] I-110:
[9-Chloro-7-(2-fluoro-phenyl)-4-methyl-5H-benzo[c]pyrimido-[4,5-e]azepin--
2-yl]-(3,4-dimethoxy-phenyl)-amine [0357] I-111:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone [0358] I-112:
1-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yla-
mino]-benzoyl}-pyrrolidine-2-carboxylic acid [0359] I-113:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-(3-methyl-piperazin-1-yl)-methanone [0360] I-114:
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-[4-(-
2H-tetrazol-5-yl)-phenyl]-amine [0361] I-115:
N-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yla-
mino]-phenyl}-acetamide [0362] I-116:
5-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-2-fluoro-benzoic acid [0363] I-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 [0364] I-118:
2-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yla-
mino]-benzoylamino}-propionic acid [0365] I-119:
5-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-pyridine-2-carboxylic acid [0366] I-120:
2-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yla-
mino]-phenyl}-N-(2-morpholin-4-yl-ethyl)-acetamide [0367] I-121:
5-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-2-methoxy-benzoic acid [0368] I-122:
5-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-2-methyl-benzoic acid [0369] I-123:
6-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-nicotinic acid [0370] I-124:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-(2-morpholin-4-yl-ethyl)-benzenesulfonamide [0371] I-125:
2-Chloro-5-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepi-
n-2-ylamino]-benzoic acid [0372] I-126:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-acetic acid [0373] I-127:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-2-trifluoromethyl-benzoic acid
[0374] I-128:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide [0375] I-129:
N-(3-Amino-propyl)-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,-
5-e]azepin-2-ylamino]-benzamide [0376] I-130:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-(3-methylamino-propyl)-benzamide [0377] I-131:
N-(2-Amino-2-methyl-propyl)-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]py-
rimido[4,5-e]azepin-2-ylamino]-benzamide [0378] I-132:
2-(3,4-Dimethoxy-phenylamino)-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-
-e]azepine-10-carboxylic acid [0379] I-133:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-2-methyl-benzoic acid [0380] I-134:
2-Chloro-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepi-
n-2-ylamino]-benzoic acid [0381] I-135:
4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-13-
5: ylamino]-benzoic acid [0382] I-136:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-2-fluoro-benzoic acid [0383] I-137:
4-[7-(2-Fluoro-phenyl)-9-methoxy-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-benzoic acid [0384] I-138:
(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-9-methoxy-5H-benzo[c]pyrimido-
[4,5-e]azepin-2-yl]-amine [0385]
I-139:[9,10-Dichloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-
-2-yl]-(3,4-dimethoxy-phenyl)-amine [0386] I-140:
4-[9,10-Dichloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-y-
lamino]-benzoic acid [0387] I-141:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-2-methoxy-benzoic acid [0388] I-142:
N-(2-Amino-ethyl)-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido-[4,-
5-e]azepin-2-ylamino]-benzamide [0389] I-143:
4-(9-Chloro-7-phenyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-benzoic
acid [0390] I-144:
[7-(2-Bromo-phenyl)-9-chloro-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,4--
dimethoxy-phenyl)-amine [0391] I-145:
2-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yla-
mino]-phenyl}-1-(4-methyl-piperazin-1-yl)-ethanone [0392] I-146:
3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzoic acid [0393] I-147:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-[2-(1H-imidazol-4-yl)-ethyl]-benzamide [0394] I-148:
4-[7-(2-Fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-(2-morpholin-4-yl-ethyl)-benzamide [0395] I-149:
{3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-acetic acid [0396] I-150:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-(2-pyridin-4-yl-ethyl)-benzamide [0397] I-151:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-(2-pyridin-3-yl-ethyl)-benzamide [0398]
I-152:(9-Chloro-7-phenyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl)-(3,4-dime-
thoxy-phenyl)-amine [0399] I-153:
4-[7-(2-Fluoro-phenyl)-10-methyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-benzoic acid [0400] I-154:
(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido-[4,5-e]az-
epin-2-yl]-amine [0401] I-155:
4-[9-Chloro-7-(4-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-benzoic acid [0402] I-156:
4-[9-Chloro-7-(3-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-benzoic acid [0403] I-157:
4-[9-Chloro-7-(3-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide [0404] I-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 [0405] I-159:
{4-[9-Chloro-7-(3-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-(4-methyl-piperazin-1-yl)-methanone [0406] I-160:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-methyl-N-(2-pyridin-2-yl-ethyl)-benzamide [0407] I-161:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-N-(2-pyridin-2-yl-ethyl)-benzamide [0408] I-162:
4-[9-Chloro-7-(3-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzoic acid [0409] I-163:
{3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-(4-methyl-piperazin-1-yl)-methanone [0410] I-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 [0411] I-165:
9-Chloro-7-(2-fluorophenyl)-N-(4-{[4-(2-morpholin-4-yl-2-oxoethyl)piperaz-
in-1-yl]carbonyl}phenyl)-5H-pyrimido-[5,4-d][2]benzazepin-2-amine
[0412] I-166:
9-Chloro-7-(2-fluorophenyl-N-(4-{[4-(2-furoyl)piperazin-1-yl]carbo-
nyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0413] I-167:
Benzyl-4-(4-{[9-chloro-7-(2-fluorophenyl)-5H-pyrimido-[5,4-d][2]benzazepi-
n-2-yl]amino}benzoyl)piperazine-1-carboxylate [0414] I-168:
Ethyl-4-(4-{[9-chloro-7-(2-fluorophenyl)-5H-pyrimido-[5,4-d][2]benzazepin-
-2-yl]amino}benzoyl)piperazine-1-carboxylate [0415] I-169:
2-[4-(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-y-
l]amino}benzoyl)piperazin-1-yl]benzoic acid [0416] I-170:
2-[4-(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-y-
l]amino}benzoyl)piperazin-1-yl]-N-isopropylacetamide [0417] I-171:
9-Chloro-7-(2-fluorophenyl)-N-(4-{[4-(2-pyrrolidin-1-ylethyl)piperazin-1--
yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0418]
I-172:
N-[2-(aminocarbonyl)phenyl]-4-{[9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5-
,4-d][2]benzazepin-2-yl]amino}benzamide [0419] I-173:
9-Chloro-7-(2-fluorophenyl)-N-{4-[(4-pyrimidin-2-ylpiperazin-1-yl)carbony-
l]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0420] I-174:
4-{[9-Chloro-7-(2-chloro-6-fluorophenyl)-5H-pyrimido-[5,4-d][2]benzazepin-
-2-yl]amino}benzoic acid [0421] I-175:
9-Chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-yl)carbony-
l]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0422] I-176:
9-Chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino)pyrrolidin-1-yl]c-
arbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0423]
I-177:
9-Chloro-N-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-7-(2-fluoro-6-
-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0424]
I-178:
9-Chloro-N-(4-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-7-(2-fl-
uoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0425] I-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
[0426] I-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 [0427]
I-181:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-[4-(3-piperidin-1-yl-propyl)-piperazin-1-yl]-methanone
[0428] I-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
[0429] I-183:
{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-y-
lamino]-phenyl}-(4-dimethylamino-piperidin-1-yl)-methanone [0430]
I-184:
{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-y-
lamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone [0431] I-185:
4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
amino]-N-(3-dimethylamino-propyl)-N-methyl-benzamide [0432] I-186:
{4-[9-Chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimido-[4,5-e]aze-
pin-2-ylamino]-phenyl}-(4-dimethylamino-piperidin-1-yl)-methanone
[0433] I-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
[0434] I-188:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-[4-(3-pyrrolidin-1-yl-propyl)-piperazin-1-yl]-methanone
[0435] I-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
[0436] I-190:
4-[9-Chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepi-
n-2-ylamino]-benzoic acid [0437] I-191:
{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-y-
lamino]-phenyl}-(3(S)-methyl-piperazin-1-yl)-methanone [0438]
I-192:
(3-Amino-azetidin-1-yl)-{4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrim-
ido[4,5-e]azepin-2-ylamino]-phenyl}-methanone [0439] I-193:
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-phenyl}-(3-dimethylaminomethyl-azetidin-1-yl)-methanone [0440]
I-194:
{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-y-
lamino]-phenyl}-(3(R)-methyl-piperazin-1-yl)-methanone [0441]
I-195:
{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-y-
lamino]-phenyl}-piperazin-1-yl-methanone [0442] I-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 [0443] I-197:
{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-y-
lamino]-phenyl}-(3-methylamino-pyrrolidin-1-yl)-methanone [0444]
I-198:
4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
amino]-N-methyl-N-(3-methylamino-propyl)-benzamide [0445] I-199:
{4-[9-Chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep-
in-2-ylamino]-phenyl}-(3-methylamino-pyrrolidin-1-yl)-methanone
[0446] I-200:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
-ylamino]-cyclohexanecarboxylic acid [0447] I-201:
9-chloro-N-(4-{[4-(2-ethoxyphenyl)piperazin-1-yl]carbonyl}phenyl)-7-(2-fl-
uorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0448] I-202:
N-[amino(imino)methyl]-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,-
4-d][2]benzazepin-2-yl]amino}benzamide [0449] I-203:
3-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}benzoic acid [0450] I-204:
9-chloro-7-(2,6-difluorophenyl)-N-(3-{[3-(dimethylamino)azetidin-1-yl]car-
bonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0451] I-205:
9-chloro-7-(2,6-difluorophenyl)-N-(3-{[4-(dimethylamino)piperidin-1-yl]ca-
rbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0452]
I-206:
9-chloro-7-(2,6-difluorophenyl)-N-(3-{[3-(dimethylamino)pyrrolidin-1-yl]c-
arbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0453]
I-207:
N-[2-(aminomethyl)-1,3-benzoxazol-5-yl]-9-chloro-7-(2,6-difluorophenyl)-5-
H-pyrimido[5,4-d][2]benzazepin-2-amine [0454] I-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 [0455]
I-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 [0456]
I-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 [0457]
I-211:
9-chloro-7-(2-fluorophenyl)-N-[4-({4-[(1-methylpiperidin-3-yl)methyl]pipe-
razin-1-yl}carbonyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0458] I-212:
9-chloro-7-(2,6-difluorophenyl)-N-(4-nitrophenyl)-5H-pyrimido[5,4--
d][2]benzazepin-2-amine [0459] I-213:
9-chloro-N-(3-chloro-4-{[4-(2-pyrrolidin-1-ylethyl)piperazin-1-yl]carbony-
l}phenyl)-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0460] I-214:
9-chloro-N-{3-chloro-4-[(3-methylpiperazin-1-yl)carbonyl]phenyl}-7-(2-flu-
orophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0461] I-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
[0462] I-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
[0463] I-217:
N-[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-
-2-yl]benzene-1,4-diamine [0464] I-218: methyl
2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaze-
pin-2-yl]amino}benzoate [0465] I-219:
1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}benzoyl)piperazine-2-carboxylic acid [0466] I-220:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[4-(methylamino)piperidin-1-yl]carb-
onyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0467] I-221:
N-{4-[(3-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2,6-difluorophe-
nyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0468] I-222:
9-chloro-7-(2,6-difluorophenyl)-N-{3-[(3,5-dimethylpiperazin-1-yl)carbony-
l]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0469] I-223:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-N-[[4-(dimethylamino)piperidin-1-yl](imino)methyl]benzamide
[0470] I-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 [0471]
I-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 [0472]
I-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 [0473]
I-227:
9-chloro-N-(3-{[3-(dimethylamino)azetidin-1-yl]carbonyl}phenyl)-7-(2-fluo-
ro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0474]
I-228:
9-chloro-N-{3-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-7-(2-fluoro-6-
-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0475]
I-229:
9-chloro-N-(3-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-7-(2-flu-
oro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0476]
I-230:
N-(4-{[3-(aminomethyl)azetidin-1-yl]carbonyl}phenyl)-9-chloro-7-(2-fluoro-
phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0477] I-231:
9-chloro-N-(3-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-7-(2-fl-
uoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0478] I-232:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-{4-[(3-methylpiperazin-1-y-
l)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0479]
I-233:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-{4-[(4-methylpiperazin-1-yl)carbo-
nyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0480] I-234:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(methylamino)azetidin-1-yl]carbo-
nyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0481] I-235:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[3-(methylamino)azetidin-1-yl-
]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0482]
I-236:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}benzonitrile [0483] I-237:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-N-[[3-(dimethylamino)pyrrolidin-1-yl](imino)methyl]benzamide
[0484] I-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
[0485] I-239:
N-{4-[(4-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2,6-difluorophe-
nyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0486] I-240:
N-{4-[(3-aminopyrrolidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2-fluoro-6-met-
hoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0487] I-241:
N-{4-[(4-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2-fluoro-6-meth-
oxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0488] I-242:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[4-(methylamino)piperidin-1-y-
l]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0489]
I-243:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-[4-(piperazin-1-ylcarbonyl)phenyl-
]-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0490] I-244:
9-chloro-7-(2,6-difluorophenyl)-N-{4-[[4-(dimethylamino)piperidin-1-yl](i-
mino)methyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0491]
I-245:
N-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}phenyl)guanidine [0492] I-246:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-N-methyl-N-[2-(methylamino)ethyl]benzamide [0493] I-247:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-N-[2-(dimethylamino)ethyl]-N-methylbenzamide [0494] I-248:
methyl
4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}benzoyl)piperazine-2-carboxylate [0495] I-249:
2-[(4-carboxyphenyl)amino]-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzaz-
epine-9-carboxylic acid [0496] I-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 [0497]
I-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 [0498]
I-252:
N-(2-aminoethyl)-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2-
]benzazepin-2-yl]amino}-N-methylbenzamide [0499] I-253:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(methylamino)piperidin-1-yl]carb-
onyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0500] I-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 [0501]
I-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 [0502]
I-256:
7-(2-fluorophenyl)-2-[(3-methoxyphenyl)amino]-5H-pyrimido[5,4-d][2]benzaz-
epine-9-carboxylic acid [0503] I-257:
N-(3-aminopropyl)-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][-
2]benzazepin-2-yl]amino}-N-methylbenzamide [0504] I-258:
2-chloro-5-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaze-
pin-2-yl]amino}benzoic acid [0505] I-259:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-N-[[3-(dimethylamino)azetidin-1-yl](imino)methyl]benzamide
[0506] I-260:
N-(2-amino-2-methylpropyl)-4-{[9-chloro-7-(2,6-difluorophenyl)-5H--
pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzamide [0507] I-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 [0508]
I-262:
N-{4-[(3-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2-fluoro-6-meth-
oxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0509] I-263:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[3-(methylamino)piperidin-1-y-
l]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0510]
I-264:
N-(3-aminopropyl)-4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5-
,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide [0511] I-265:
N-(2-aminoethyl)-4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,-
4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide [0512] I-266:
4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}benzoyl)piperazine-2-carboxylic acid [0513] I-267:
9-chloro-7-(2,6-difluorophenyl)-N-{4-[[3-(dimethylamino)azetidin-1-yl](im-
ino)methyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0514]
I-268:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{imino[3-(methylamino)pyrrolidin-1-y-
l]methyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0515]
I-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
[0516] I-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
[0517] I-271:
N-[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-
-2-yl]-N'-pyrimidin-2-ylbenzene-1,4-diamine [0518] I-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 [0519] I-273:
9-bromo-7-(2,6-difluorophenyl)-N-(3-methoxyphenyl)-5H-pyrimido[5,4-d][2]b-
enzazepin-2-amine [0520] I-274:
4-{[9-bromo-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]a-
mino}benzoic acid [0521] I-275:
7-(2,6-difluorophenyl)-N-(3-methoxyphenyl)-9-(3-pyrrolidin-1-ylprop-1-yn--
1-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0522] I-276:
9-(3-aminoprop-1-yn-1-yl)-7-(2,6-difluorophenyl)-N-(3-methoxyphenyl)-5H-p-
yrimido[5,4-d][2]benzazepin-2-amine [0523] I-277:
4-({9-chloro-7-[2-(trifluoromethyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepi-
n-2-yl}amino)benzoic acid [0524] I-278:
N-{4-[(3-aminoazetidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2,6-difluorophen-
yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0525] I-279:
4-[(9-chloro-7-pyridin-2-yl-5H-pyrimido[5,4-d][2]benzazepin-2-yl)amino]be-
nzoic acid [0526] I-280:
N-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}phenyl)-4-methylpiperazine-1-carboxamide [0527] I-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
[0528] I-282:
9-chloro-N-(4-chloro-3-{[4-(methylamino)piperidin-1-yl]carbonyl}ph-
enyl)-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0529] I-283:
2-chloro-5-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaze-
pin-2-yl]amino}-N-methyl-N-[2-(methylamino)ethyl]benzamide [0530]
I-284:
N-{4-[(3-aminopyrrolidin-1-yl)(imino)methyl]phenyl}-9-chloro-7-(2,6-diflu-
orophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0531] I-285:
2-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}phenyl)-1,4,5,6-tetrahydropyrimidin-5-ol [0532] I-286:
N-{4-[(3-aminoazetidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2-fluoro-6-metho-
xyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0533] I-287:
N-{4-[(4-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-[2-(trifluoromet-
hyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0534] I-288:
9-chloro-N-(4-{[4-(methylamino)piperidin-1-yl]carbonyl}phenyl)-7-[2-(trif-
luoromethyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0535]
I-289:
N-{4-[(3-aminopyrrolidin-1-yl)carbonyl]phenyl}-9-chloro-7-[2-(trifluorome-
thyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0536] I-290:
9-chloro-N-(4-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)-7-[2-(tri-
fluoromethyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0537]
I-291:
9-chloro-N-(4-chloro-3-{[3-(methylamino)azetidin-1-yl]carbonyl}phenyl)-7--
(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0538]
I-292:
N-{3-[(4-aminopiperidin-1-yl)carbonyl]-4-chlorophenyl}-9-chloro-7-(2,6-di-
fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0539] I-293:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino)piperidin-1-yl]ca-
rbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0540]
I-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 [0541]
I-295:
4-amino-1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benza-
zepin-2-yl]amino}benzoyl)piperidine-4-carboxylic acid [0542] I-296:
N-{4-[(3-aminoazetidin-1-yl)carbonyl]phenyl}-9-chloro-7-[2-(trifluorometh-
yl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0543] I-297:
9-chloro-N-(4-{[3-(methylamino)azetidin-1-yl]carbonyl}phenyl)-7-[2-(trifl-
uoromethyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0544]
I-298:
N-{4-[(4-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-pyridin-2-yl-5H--
pyrimido[5,4-d][2]benzazepin-2-amine [0545] I-299:
N-{4-[(3-aminopyrrolidin-1-yl)carbonyl]phenyl}-9-chloro-7-pyridin-2-yl-5H-
-pyrimido[5,4-d][2]benzazepin-2-amine [0546] I-300: ethyl
2-amino-4-[(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benz-
azepin-2-yl]amino}benzoyl)amino]butanoate [0547] I-301:
4-{[9-chloro-7-(3-fluoropyridin-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-y-
l]amino}benzoic acid [0548] I-302:
9-{[3-(dimethylamino)azetidin-1-yl]carbonyl}-7-(2-fluorophenyl)-N-(3-meth-
oxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0549] I-303:
7-(2-fluorophenyl)-2-[(3-methoxyphenyl)amino]-N-methyl-N-[3-(methylamino)-
propyl]-5H-pyrimido[5,4-d][2]benzazepine-9-carboxamide [0550]
I-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 [0551] I-305:
N-{4-[(3-aminopyrrolidin-1-yl)carbonyl]phenyl}-9-chloro-7-(3-fluoropyridi-
n-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0552] I-306:
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-carboxylic acid [0553]
I-307:
N-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}phenyl)-2-(dimethylamino)acetamide [0554] I-308:
2-amino-N-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benza-
zepin-2-yl]amino}phenyl)-2-methylpropanamide [0555] I-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 [0556] I-310:
4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}benzoyl)-N-methylpiperazine-2-carboxamide [0557] I-311:
7-(2-fluorophenyl)-2-[(3-methoxyphenyl)amino]-N-(3-morpholin-4-ylpropyl)--
5H-pyrimido[5,4-d][2]benzazepine-9-carboxamide [0558] I-312:
9-[(3,5-dimethylpiperazin-1-yl)carbonyl]-7-(2-fluorophenyl)-N-(3-methoxyp-
henyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0559] I-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
[0560] I-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 [0561]
I-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 [0562] I-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 [0563] I-317:
4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}benzoyl)piperazine-2-carboxamide [0564] I-318:
N-{4-[(3-aminopyrrolidin-1-yl)carbonyl]-3-chlorophenyl}-9-chloro-7-(2,6-d-
ifluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0565]
I-319:
N-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}phenyl)piperidine-4-carboxamide [0566] I-320:
4-{[9-chloro-7-(2-fluoro-6-{methyl[2-(methylamino)ethyl]amino}phenyl)-5H--
pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoic acid [0567] I-321:
9-chloro-7-(2,4-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-yl)carbony-
l]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0568] I-322:
9-chloro-7-(2,4-dimethoxyphenyl)-N-{4-[(3,5-dimethylpiperazin-1-yl)carbon-
yl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0569] I-323:
9-chloro-7-(2-chloro-6-fluorophenyl)-N-{4-[(3-methylpiperazin-1-yl)carbon-
yl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0570] I-324:
9-chloro-7-(2-chloro-6-fluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-yl)ca-
rbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0571]
I-325:
9-chloro-7-(2-chloro-6-fluorophenyl)-N-(4-{[4-(methylamino)piperidin-1-yl-
]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0572]
I-326:
9-chloro-7-(2-chloro-6-fluorophenyl)-N-(4-{[3-(methylamino)piperidin-1-yl-
]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0573]
I-327:
9-chloro-7-(2-chloro-6-fluorophenyl)-N-(4-{[3-(methylamino)pyrrolidin-1-y-
l]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0574]
I-328:
9-chloro-N-(3,4-dimethoxyphenyl)-7-{2-[(dimethylamino)methyl]phenyl}-5H-p-
yrimido[5,4-d][2]benzazepin-2-amine [0575] I-329:
9-chloro-7-(2-methoxyphenyl)-N-{4-[(3-methylpiperazin-1-yl)carbonyl]pheny-
l}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0576] I-330:
9-chloro-N-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-7-(2-methoxyp-
henyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0577] I-331:
9-chloro-7-(2-methoxyphenyl)-N-(4-{[4-(methylamino)piperidin-1-yl]carbony-
l}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0578] I-332:
9-chloro-7-(2-methoxyphenyl)-N-(4-{[3-(methylamino)pyrrolidin-1-yl]carbon-
yl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0579] I-333:
9-chloro-7-(2-methoxyphenyl)-N-(4-{[3-(methylamino)piperidin-1-yl]carbony-
l}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0580] I-334:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-N-methylbenzamide [0581] I-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 [0582] I-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 [0583]
I-337:
1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}phenyl)ethanone [0584] I-338:
N-[3-(3-aminoprop-1-yn-1-yl)phenyl]-9-chloro-7-(2,6-difluorophenyl)-5H-py-
rimido[5,4-d][2]benzazepin-2-amine [0585] I-339:
4-[(9-chloro-7-{2-fluoro-6-[(2-hydroxyethyl)amino]phenyl}-5H-pyrimido[5,4-
-d][2]benzazepin-2-yl)amino]-N-methylbenzamide [0586] I-340:
4-[(7-{2-[(2-aminoethyl)amino]-6-fluorophenyl}-9-chloro-5H-pyrimido[5,4-d-
][2]benzazepin-2-yl)amino]-N-methylbenzamide [0587] I-341:
4-amino-1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benza-
zepin-2-yl]amino}benzoyl)-N-methylpiperidine-4-carboxamide [0588]
I-342:
4-[(9-chloro-7-{2-[4-(dimethylamino)piperidin-1-yl]-6-fluorophenyl}-5H-py-
rimido[5,4-d][2]benzazepin-2-yl)amino]-N-methylbenzamide [0589]
I-343:
9-chloro-7-(2,6-difluorophenyl)-N-{3-[3-(dimethylamino)prop-1-yn-1-yl]phe-
nyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0590] I-344:
9-chloro-7-(2,6-difluorophenyl)-N-(3-iodophenyl)-5H-pyrimido[5,4-d][2]ben-
zazepin-2-amine [0591] I-345:
4-{[9-chloro-7-(2-{[2-(dimethylamino)ethyl]amino}-6-fluorophenyl)-5H-pyri-
mido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide [0592]
I-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
[0593] I-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
[0594] I-348:
4-({7-[2-(4-aminopiperidin-1-yl)-6-fluorophenyl]-9-chloro-5H-pyrim-
ido[5,4-d][2]benzazepin-2-yl}amino)-N-methylbenzamide [0595] I-349:
7-(2-fluorophenyl)-2-[(3-methoxyphenyl)amino]-N-methyl-N-[2-(methylamino)-
ethyl]-5H-pyrimido[5,4-d][2]benzazepine-9-carboxamide [0596] I-350:
4-amino-1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benza-
zepin-2-yl]amino}benzoyl)piperidine-4-carboxamide [0597] I-351:
9-chloro-7-(2-chloro-6-fluorophenyl)-N-(4-{[3-(methylamino)azetidin-1-yl]-
carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0598]
I-352:
9-chloro-7-(2,6-difluorophenyl)-N-(4-methyl-1,3-thiazol-2-yl)-5H-pyrimido-
[5,4-d][2]benzazepin-2-amine
[0599] I-353:
7-(2,6-difluorophenyl)-2-[(3-methoxyphenyl)amino]-5H-pyrimido[5,4-d][2]be-
nzazepine-9-carboxylic acid [0600] I-354:
4-({9-chloro-7-[2-fluoro-6-(methylamino)phenyl]-5H-pyrimido[5,4-d][2]benz-
azepin-2-yl}amino)-N-methylbenzamide [0601] I-355:
2-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-N-methyl-1,3-thiazole-4-carboxamide [0602] I-356:
N-1H-benzimidazol-2-yl-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d]-
[2]benzazepin-2-amine [0603] I-357:
7-(2,6-difluorophenyl)-2-[(4-methyl-1,3-thiazol-2-yl)amino]-5H-pyrimido[5-
,4-d][2]benzazepine-9-carboxylic acid [0604] I-358:
3-amino-1-(3-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benza-
zepin-2-yl]amino}phenyl)propan-1-one [0605] I-359:
1-(3-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}phenyl)-3-(dimethylamino)propan-1-one [0606] I-360:
2-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-1,3-thiazole-4-carboxylic acid [0607] I-361: ethyl
2-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-1,3-thiazole-4-carboxylate [0608] I-362:
9-chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-yl)carbony-
l]-1,3-thiazol-2-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0609]
I-363: ethyl
2-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-
-2-yl]amino}-1,3-oxazole-5-carboxylate [0610] I-364:
2-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-1,3-oxazole-5-carboxylic acid [0611] I-365:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[(3R)-3-methylpiperazin-1-yl]carbon-
yl}-1,3-thiazol-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0612] I-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 [0613]
I-367:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(methylamino)pyrrolidin-1-yl]car-
bonyl}-1,3-thiazol-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0614] I-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 [0615] I-369:
9-chloro-7-(2,6-difluorophenyl)-N-{5-[(3,5-dimethylpiperazin-1-yl)carbony-
l]-1,3-oxazol-2-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0616]
I-370:
9-chloro-7-(2,6-difluorophenyl)-N-(5-{[3-(methylamino)pyrrolidin-1-yl]car-
bonyl}-1,3-oxazol-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0617] I-371:
4-{[9-chloro-7-(2,6-difluorophenyl)-5-methyl-5H-pyrimido[5,4-d][2]-
benzazepin-2-yl]amino}benzoic acid [0618] I-372:
9-chloro-7-(2,6-difluorophenyl)-N-{3-[3-(dimethylamino)propyl]phenyl}-5H--
pyrimido[5,4-d][2]benzazepin-2-amine [0619] I-373:
N-[3-(3-aminopropyl)phenyl]-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5-
,4-d][2]benzazepin-2-amine [0620] I-374:
9-chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-yl)carbony-
l]-1,3-oxazol-2-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0621]
I-375:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(methylamino)pyrrolidin-1-yl]car-
bonyl}-1,3-oxazol-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0622] I-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
[0623] I-377:
2-{[4-(aminocarbonyl)phenyl]amino}-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-
-d][2]benzazepine-9-carboxylic acid [0624] I-378:
1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4d][2]benzazepin-2-y-
l]amino}benzoyl)-N-methyl-4-(methylamino)piperidine-4-carboxamide
[0625] I-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
[0626] I-380:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-methyl-3-(methylamino)pyr-
rolidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0627] I-381:
1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}benzoyl)-4-(methylamino)piperidine-4-carboxamide [0628]
I-382:
9-chloro-7-(2,6-difluorophenyl)-N-{4-[(3,3,5-trimethylpiperazin-1-yl)carb-
onyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0629] I-383:
N-1-azabicyclo[2.2.2]oct-3-yl-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyri-
mido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide [0630]
I-384:
N-1-azabicyclo[2.2.2]oct-3-yl-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyri-
mido[5,4-d][2]benzazepin-2-yl]amino}benzamide [0631] I-385:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-N-hydroxybenzamide [0632] I-386:
N-{4-[(aminooxy)carbonyl]phenyl}-9-chloro-7-(2,6-difluorophenyl)-5H-pyrim-
ido[5,4-d][2]benzazepin-2-amine [0633] I-387:
4-{[9-chloro-7-(2,6-difluorophenyl)-7H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}benzoic acid [0634] I-388:
4-{[9-chloro-7-(2,3-difluorophenyl)-7H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}benzoic acid [0635] I-389:
3-amino-1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benza-
zepin-2-yl]amino}benzoyl)-N-methylpyrrolidine-3-carboxamide [0636]
I-390:
3-amino-1-(2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d-
][2]benzazepin-2-yl]amino}benzoyl)pyrrolidine-3-carboxamide [0637]
I-391:
9-chloro-7-(2,6-difluorophenyl)-N-{4-[(3,3-dimethylpiperazin-1-yl)carbony-
l]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0638] I-392:
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)benzamide [0639]
I-393:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino)-3-methylpyrrolid-
in-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0640] I-394:
9-chloro-7-(2,6-difluorophenyl)-N-(3-methyl-1H-pyrazol-5-yl)-5H-py-
rimido[5,4-d][2]benzazepin-2-amine [0641] I-395:
2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzaze-
pin-2-yl]amino}benzoic acid [0642] I-396:
4-amino-1-(2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d-
][2]benzazepin-2-yl]amino}benzoyl)-N-methylpiperidine-4-carboxamide
[0643] I-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-carboxa-
mide [0644] I-398:
4-[(9-methoxy-7-oxo-6,7-dihydro-5H-pyrimido[5,4-d][2]benzazepin-2-yl)amin-
o]benzoic acid [0645] I-399:
2-({4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}amino)-9-methoxy-5,6-d-
ihydro-7H-pyrimido[5,4-d][2]benzazepin-7-one [0646] I-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 [0647] I-401:
4-[(8-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[5,4-c]pyrrolo[3,2-e]azepin--
2-yl)amino]benzoic acid [0648] I-402:
2-({4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}amino)-8-methyl-5,8-di-
hydropyrimido[5,4-c]pyrrolo[3,2-e]azepin-7(6H)-one [0649] I-403:
2-[(3-methoxyphenyl)amino]-8-methyl-5,8-dihydropyrimido[5,4-c]pyrrolo[3,2-
-e]azepin-7(6H)-one [0650] I-404:
9-chloro-2-[(3,4-dimethoxyphenyl)amino]-5,6-dihydro-7H-pyrimido[5,4-d][2]-
benzazepin-7-one [0651] I-405:
4-{[4-amino-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazep-
in-2-yl]amino}benzoic acid [0652] I-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
[0653] I-407:
9-chloro-N-(3-chloro-4-{[4-(methylamino)piperidin-1-yl]carbonyl}ph-
enyl)-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0654] I-408:
4-{[9-chloro-7-(2-fluoro-6-hydroxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-
-2-yl]amino}benzoic acid [0655] I-409:
9-chloro-N-[4-(1,7-diazaspiro[4.4]non-7-ylcarbonyl)phenyl]-7-(2,6-difluor-
ophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0656] I-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
[0657] I-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
[0658] I-412:
1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}benzoyl)-3-(methylamino)pyrrolidine-3-carboxamide [0659]
I-413:
1-(2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benz-
azepin-2-yl]amino}benzoyl)-N-methyl-3-(methylamino)piperidine-3-carboxamid-
e [0660] I-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
[0661] I-415:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[3-methyl-3-(methylami-
no)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0662] I-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)-met-
hanone [0663] I-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
[0664] I-418:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[4-(dimethylamino)-4-methylp-
iperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0665] I-419:
N-{4-[(4-amino-4-methylpiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2,6-di-
fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0666] I-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
[0667] I-421:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[4-methyl-4-(methylamino)pipe-
ridin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0668] I-422:
2-Chloro-4-[9-chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyri-
mido[4,5-e]azepin-2-ylamino]-phenyl}-(4-methyl-4-methylamino-piperidin-1-y-
l)-methanone [0669] I-423:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(3-fluoro-4-{[4-methyl-4-(methyla-
mino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-ami-
ne [0670] I-424:
9-chloro-N-{3-chloro-4-[(3,3,5,5-tetramethylpiperazin-1-yl)carbonyl]pheny-
l}-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0671] I-425:
N-1-azabicyclo[2.2.2]oct-3-yl-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyri-
mido[5,4-d][2]benzazepin-2-yl]amino}-2-fluoro-N-methylbenzamide
[0672] I-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
[0673] I-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
[0674] I-428:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(methylamino)-8-azabicycl-
o[3.2.1]oct-8-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine
[0675] I-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
[0676] I-430:
4-{[7-(2,6-difluorophenyl)-9-methyl-5H-pyrimido[5,4-c]thieno[2,3-e]azepin-
-2-yl]amino}benzoic acid [0677] I-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 [0678] I-432:
N-{4-[(3-amino-3-methylpyrrolidin-1-yl)carbonyl]phenyl}-7-(2,6-difluoroph-
enyl)-10-methyl-5,10-dihydropyrimido[5,4-c]pyrrolo[2,3-e]azepin-2-amine
[0679] I-433:
7-(2,6-difluorophenyl)-9-methyl-N-(4-{[3-(methylamino)pyrrolidin-1-yl]car-
bonyl}phenyl)-5H-furo[2,3-c]pyrimido[4,5-e]azepin-2-amine [0680]
I-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-amin-
e [0681] I-435:
N-{4-[(3-amino-3-methylpyrrolidin-1-yl)carbonyl]phenyl}-7-(2-fluoro-6-met-
hoxyphenyl)-5,9-dihydropyrimido[5,4-c]pyrrolo[3,4-e]azepin-2-amine
[0682] I-436:
4-{[4-(2,6-difluorophenyl)-1-methyl-1,6-dihydropyrazolo[4,3-c]pyri-
mido[4,5-e]azepin-9-yl]amino}benzoic acid [0683] I-437:
1-{4-[4-(2,6-Difluoro-phenyl)-2-methyl-6H-3-thia-5,8,10-triaza-benzo[e]az-
ulen-9-ylamino]-benzoyl}-4-dimethylamino-piperidine-4-carboxylic
acid methylamide [0684] I-438:
4-(4-{[7-(2,6-difluorophenyl)-5H-furo[3,2-c]pyrimido[4,5-e]azepin-2-yl]am-
ino}benzoyl)-N-methylpiperazine-2-carboxamide [0685] I-439:
4-(4-{[4-(2,6-difluorophenyl)-6H-isoxazolo[4,5-c]pyrimido[4,5-e]azepin-9--
yl]amino}benzoyl)-N-methylpiperazine-2-carboxamide [0686] I-440:
4-(2,6-difluorophenyl)-9-[(4-{[3-methyl-3-(methylamino)pyrrolidin-1-yl]ca-
rbonyl}phenyl)amino]-3,6-dihydroimidazo[4,5-c]pyrimido[4,5-e]azepin-2(1H)--
one [0687] I-441:
2-amino-N-(3-{[7-(2,6-difluorophenyl)-8,10-dimethyl-5H-pyrimido[5,4-c]thi-
eno[3,4-e]azepin-2-yl]amino}phenyl)-N,2-dimethylpropanamide [0688]
I-442:
9-chloro-7-(2,6-difluorophenyl)-N-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)-
oxy]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0689] I-443:
4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}phenyl)-N-methyl-1-(methylamino)cyclohexanecarboxamide
[0690] I-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
[0691] I-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 [0692]
I-446:
1-(3-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}phenyl)-3,5,5-trimethylpiperazin-2-one [0693] I-447:
9-chloro-N-[4-(2,6-dimethylpiperidin-4-yl)phenyl]-7-(2-fluoro-6-methoxyph-
enyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0694] I-448:
N-[4-(1-amino-1-methylethyl)phenyl]-9-chloro-7-(2,6-difluorophenyl)-5H-py-
rimido[5,4-d][2]benzazepin-2-amine [0695] I-449:
N-[4-(2,5-diazaspiro[3.4]oct-2-ylcarbonyl)phenyl]-7-(2,6-difluorophenyl)--
10-methyl-5H-isothiazolo[5,4-c]pyrimido[4,5-e]azepin-2-amine [0696]
I-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 [0697] I-451:
4-(2,6-difluorophenyl)-N-[4-(1H-imidazol-2-yl)phenyl]-1-methyl-1,6-dihydr-
oimidazo[4,5-c]pyrimido[4,5-e]azepin-9-amine [0698] I-452:
4-{[7-(2,6-difluorophenyl)-5H-[1]benzofuro[2,3-c]pyrimido[4,5-e]azepin-2--
yl]amino}benzoic acid [0699] I-453:
7-(2-fluorophenyl)-N-{4-[(3,3,5,5-tetramethylpiperazin-1-yl)carbonyl]phen-
yl}-8,9,10,11-tetrahydro-5H-pyrido[4',3':4,5]thieno[3,2-c]pyrimido[4,5-e]a-
zepin-2-amine [0700] I-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
[0701] I-455:
7-(2-fluorophenyl)-N-(3-methyl-1H-indazol-6-yl)-5,12-dihydropyrimi-
do[4',5':5,6]azepino[4,3-b]indol-2-amine [0702] I-456:
1-(4-{[7-(2,6-difluorophenyl)-9,10-dimethyl-5,8-dihydropyrimido[5,4-c]pyr-
rolo[3,2-e]azepin-2-yl]amino}benzoyl)-3-(methylamino)pyrrolidine-3-carboxa-
mide [0703] I-457:
{3-[9-Chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimido-[4,5-e]aze-
pin-2-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone [0704]
I-458:
[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]--
(2-methylaminomethyl-benzothiazol-6-yl)-amine [0705] I-459:
4-[9-Chloro-7-(2-isopropoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
amino]-benzoic acid [0706] I-460:
4-[9-Chloro-7-(2-fluoro-6-isopropoxy-phenyl)-5H-benzo[c]pyrimido-[4,5-e]a-
zepin-2-ylamino]-benzoic acid [0707] I-461:
4-[9-Chloro-7-(2-ethoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzoic acid
[0708] I-462:
4-[9-Chloro-7-(2-ethoxy-6-fluoro-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepi-
n-2-ylamino]-benzoic acid [0709] I-463:
4-[9-Chloro-7-(2-fluoro-6-methyl-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepi-
n-2-ylamino]-benzoic acid [0710] I-464:
4-[9-Chloro-7-(2-trifluoromethoxy-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azep-
in-2-ylamino]-benzoic acid [0711] I-465:
4-[9-Chloro-7-(2-fluoro-6-trifluoromethoxy-phenyl)-5H-benzo[c]pyrimido[4,-
5-e]azepin-2-ylamino]-benzoic acid [0712] I-466:
4-[9-Chloro-7-(3-fluoro-2-trifluoromethoxy-phenyl)-5H-benzo[c]pyrimido[4,-
5-e]azepin-2-ylamino]-benzoic acid [0713] I-467:
4-[9-Chloro-7-(2,3-dimethoxy-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2--
ylamino]-benzoic acid [0714] I-468:
4-[9-Chloro-7-(2-isobutyl-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylam-
ino]-benzoic acid [0715] I-469:
4-(7-Benzofuran-2-yl-9-chloro-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-
-benzoic acid [0716] I-470:
4-[9-Chloro-7-(1-methyl-1H-pyrrol-2-yl)-5H-benzo[c]pyrimido-[4,5-e]azepin-
-2-ylamino]-benzoic acid [0717] I-471:
4-[9-Chloro-7-(1-methyl-1H-imidazol-2-yl)-5H-benzo[c]pyrimido-[4,5-e]azep-
in-2-ylamino]-benzoic acid [0718] I-472:
4-(9-Chloro-7-thiophen-2-yl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-b-
enzoic acid [0719] I-473:
4-[9-Chloro-7-(2H-pyrazol-3-yl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzoic acid [0720] I-474:
4-[9-Chloro-7-(2-ethynyl-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-benzoic acid [0721] I-475:
4-[7-(2-Aminomethyl-phenyl)-9-chloro-5H-benzo[c]pyrimido-[4,5-e]azepin-2--
ylamino]-benzoic acid [0722] I-476:
4-[9-Chloro-7-(5-fluoro-2-methoxy-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azep-
in-2-ylamino]-benzoic acid [0723] I-477:
4-[9-Chloro-7-(3-methoxy-pyridin-2-yl)-5H-benzo[c]pyrimido-[4,5-e]azepin--
2-ylamino]-benzoic acid [0724] I-478:
4-[8-Fluoro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzoic acid [0725] I-479:
4-[8-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzoic acid [0726] I-480:
4-[11-Fluoro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-benzoic acid [0727] I-481:
4-[11-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylami-
no]-benzoic acid [0728] I-482:
6-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-pyridazine-3-carboxylic acid [0729] I-483:
2-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-1H-imidazole-4-carboxylic acid [0730] I-484:
4-[9-Chloro-7-(2-fluoro-phenyl)-4-methyl-5H-benzo[c]pyrimido-[4,5-e]azepi-
n-2-ylamino]-benzoic acid [0731] I-485:
4-[4-Aminomethyl-9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido-[4,5-e]-
azepin-2-ylamino]-benzoic acid [0732] I-486:
4-(9-Aminomethyl-7-phenyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-ben-
zoic acid [0733] I-487:
9-Chloro-7-(2-fluorophenyl)-N-{4-[(2-methylpiperazin-1-yl)carbonyl]phenyl-
}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0734] I-488:
4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amin-
o}-N-[{3-[(dimethylamino)methyl]azetidin-1-yl}(imino)methyl]benzamide
[0735] I-489:
4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amin-
o}-N-[imino(piperazin-1-yl)methyl]benzamide [0736] I-490:
4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amin-
o}-N-[imino(3-methylpiperazin-1-yl)methyl]benzamide [0737] I-491:
4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amin-
o}-N-[[3-(dimethylamino)pyrrolidin-1-yl](imino)methyl]benzamide
[0738] I-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 [0739]
I-493:
4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amin-
o}-N-[(3,5-dimethylpiperazin-1-yl)(imino)methyl]benzamide [0740]
I-494:
1-[[(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl-
]amino}benzoyl)amino](imino)methyl]pyrrolidine-3-carboxamide [0741]
I-495:
1-[[(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl-
]amino}benzoyl)amino](imino)methyl]piperidine-3-carboxamide [0742]
I-496:
4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amin-
o}-N-[{4-[(cyclopropylcarbonyl)amino]piperidin-1-yl}(imino)methyl]benzamid-
e [0743] I-497:
4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amin-
o}-N-[(dimethylamino)(imino)methyl]benzamide [0744] I-498:
N-[[(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl-
]amino}phenyl)amino](imino)methyl]cyclopropanecarboxamide [0745]
I-499:
N-[[(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl-
]amino}phenyl)amino](imino)methyl]-3-(dimethylamino)cyclopentanecarboxamid-
e [0746] I-500:
4-({9-Chloro-7-[2-fluoro-6-(trifluoromethyl)phenyl]-5H-pyrimido-[5,4-d][2-
]benzazepin-2-yl}amino)benzoic acid [0747] I-501:
4-{[9-Chloro-7-(2,6-dichlorophenyl)-5H>-pyrimido[5,4-d][2]benzazepin-2-
-yl]amino}benzoic acid [0748] I-502:
4-{[9-Chloro-7-(2-fluoro-6-methylphenyl)-5H-pyrimido-[5,4-d][2]benzazepin-
-2-yl]amino}benzoic acid [0749] I-503:
4-{[7-(2-Bromo-6-chlorophenyl)-9-chloro-5H-pyrimido-[5,4-d][2]benzazepin--
2-yl]amino}benzoic acid [0750] I-504:
9-Chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-yl)carbony-
l]-3-fluorophenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0751]
I-505:
4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-N-[(3,5-dimethylpiperazin-1-yl)(imino)methyl]-N-methylbenzamide
[0752] I-506:
4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-N-[[3-(dimethylamino)azetidin-1-yl](imino)methyl]-N-methylbenzamide
[0753] I-507:
3-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-N-[(3,5-dimethylpiperazin-1-yl)(imino)methyl]benzamide
[0754] I-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
[0755] I-509:
9-Chloro-7-(2,6-difluorophenyl)-N-{3-[(3,5-dimethylpiperazin-1-yl)carbony-
l]-4-fluorophenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0756]
I-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)cyclopentanecarbo-
xamide [0757] I-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)cyclopen-
tanecarboxamide [0758] I-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)cyclopen-
tanecarboxamide [0759] I-513:
N-(4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}phenyl)-3,5-dimethylpiperazine-1-carboximidamide [0760]
I-514:
4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-N-[[3-(dimethylamino)pyrrolidin-1-yl](imino)methyl]-N-methylbenzami-
de [0761] I-515:
N-(3-{[9-Chloro-7-(2,6-difluorophenyl)-5<i>H</i>-pyrimido-[5,-
4-d][2]benzazepin-2-yl]amino}phenyl)-3,5-dimethylpiperazine-1-carboximidam-
ide [0762] I-516:
N-(3-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}phenyl)-N,3,5-trimethylpiperazine-1-carboximidamide [0763]
I-517:
3-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-N-[[3-(dimethylamino)azetidin-1-yl](imino)methyl]benzamide
[0764] I-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-carboximidami-
de [0765] I-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)cyclopentanecarbo-
xamide [0766] I-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 [0767]
I-521:
N-(4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}phenyl)-N,3,5-trimethylpiperazine-1-carboximidamide [0768]
I-522:
N-(4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}-2-fluorophenyl)-3,5-dimethylpiperazine-1-carboximidamide
[0769] I-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
[0770] I-524:
5-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-
amino}-2-(2,6-dimethylpiperidin-4-yl)-1H-isoindole-1,3(2H)-dione
[0771] I-525:
N-[2-(Aminomethyl)-1H-benzimidazol-6-yl]-9-chloro-7-(2-fluoropheny-
l)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0772] I-526:
9-Chloro-7-(2-fluorophenyl)-N-{2-[(methylamino)methyl]-1H-benzimidazol-6--
yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0773] I-527:
9-Chloro-N-{2-[(dimethylamino)methyl]-1H-benzimidazol-6-yl}-7-(2-fluoroph-
enyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0774] I-528:
9-Chloro-7-(2-fluorophenyl)-N-{2-[(methylamino)methyl]-1,3-benzothiazol-6-
-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0775] I-529:
9-Chloro-7-(2,6-difluorophenyl)-N-{2-[(methylamino)methyl]-1H-benzimidazo-
l-6-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0776] I-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 [0777] I-531:
9-Chloro-7-(2-fluorophenyl)-N-{2-[(methylamino)methyl]-1,3-benzoxazol-6-y-
l}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0778] I-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
[0779] I-533:
9-Chloro-7-(2,6-difluorophenyl)-N-{2-[(methylamino)methyl]-1,3-ben-
zothiazol-6-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0780]
I-534:
{3-[9-Chloro-7-(2,6-difluorophenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
amino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone [0781] I-535:
3-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
amino]-N-methyl-N-(4-methyl-pentyl)-benzamide
[0782] In one embodiment, the invention relates to a compound
selected from the group consisting of: [0783] I-52:
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamin-
o]-benzoic acid [0784] I-135:
4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
amino]-benzoic acid [0785] I-174:
4-{[9-Chloro-7-(2-chloro-6-fluorophenyl)-5H-pyrimido-[5,4-d][2]benzazepin-
-2-yl]amino}benzoic acid [0786] I-175:
9-Chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-yl)carbony-
l]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0787] I-177:
9-Chloro-N-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-7-(2-fluoro-6-
-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0788]
I-179:
9-Chloro-N-(4-{[3-(dimethylamino)azetidin-1-yl]carbonyl}phenyl)-7-(2-fluo-
ro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0789]
I-183:
{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-y-
lamino]-phenyl}-(4-dimethylamino-piperidin-1-yl)-methanone [0790]
I-190:
4-[9-Chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepi-
n-2-ylamino]-benzoic acid [0791] I-191:
{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-y-
lamino]-phenyl}-(3(S)-methyl-piperazin-1-yl)-methanone [0792]
I-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 [0793] I-197:
{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-y-
lamino]-phenyl}-(3-methylamino-pyrrolidin-1-yl)-methanone [0794]
I-199:
{4-[9-Chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep-
in-2-ylamino]-phenyl}-(3-methylamino-pyrrolidin-1-yl)-methanone
[0795] I-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 [0796]
I-232:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-{4-[(3-methylpiperazin-1-yl)carbo-
nyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0797] I-234:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(methylamino)azetidin-1-yl]carbo-
nyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0798] I-235:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[3-(methylamino)azetidin-1-yl-
]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0799]
I-240:
N-{4-[(3-aminopyrrolidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2-fluoro-6-met-
hoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0800] I-241:
N-{4-[(4-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2-fluoro-6-meth-
oxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0801] I-242:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[4-(methylamino)piperidin-1-y-
l]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0802]
I-263:
9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[3-(methylamino)piperidin-1-y-
l]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0803]
I-286:
N-{4-[(3-aminoazetidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2-fluoro-6-metho-
xyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0804] I-293:
9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino)piperidin-1-yl]ca-
rbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0805]
I-310:
4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}benzoyl)-N-methylpiperazine-2-carboxamide [0806] I-318:
N-{4-[(3-aminopyrrolidin-1-yl)carbonyl]-3-chlorophenyl}-9-chloro-7-(2,6-d-
ifluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0807]
I-326:
9-chloro-7-(2-chloro-6-fluorophenyl)-N-(4-{[3-(methylamino)piperidin-1-yl-
]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine [0808]
I-341:
4-amino-1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benza-
zepin-2-yl]amino}benzoyl)-N-methylpiperidine-4-carboxamide [0809]
I-383:
N-1-azabicyclo[2.2.2]oct-3-yl-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyri-
mido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide [0810]
I-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
[0811] I-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
[0812] The compounds of the present invention can be prepared by
methods known to one of ordinary skill in the art and/or by
reference to the synthetic routes set forth in Schemes 1, 2, and 3
below. One of ordinary skill in the art will recognize that
variations in reaction conditions, including variations in solvent,
reagents, catalysts, and reaction temperature, may be possible for
each of the reactions described below. Alternate synthetic routes
also are possible.
[0813] Scheme 1 depicts a general synthetic route for preparation
of compounds of formula (I) wherein each of rings A and B is an
optionally substituted phenyl ring. One of ordinary skill in the
art will appreciate that certain compounds of formula (I) wherein
one or both of rings A and B is other than phenyl can be prepared
by a route analogous to that outlined in Scheme 1, by appropriate
selection of the ketone starting material in Method G.
[0814] Methods for the synthesis of
dimethylaminomethylene-benzo[c]azepin-5-ones of the formula v (see
Scheme 1) have been described in U.S. Pat. Nos. 3,947,585,
4,022,801 and 4,028,381. Methods for the conversion of compounds of
formula v to pyrimido[5,4-d][2]benzazepines lacking a Ring C
substituent also are known and have been described, e.g., in U.S.
Pat. Nos. 4,318,854 and 4,547,581. Compounds of the present
invention (formula Ha), which include Ring C, can be prepared by
the reaction of compounds of formula v with aryl or heteroaryl
guanidines, as illustrated in Scheme 1.
##STR00624##
[0815] Methods for the synthesis of amino-substituted diaryl
ketones of formula (i) are known, and exemplary synthetic
procedures are described in the Examples. Conversion of (i) to the
iodo-substituted diaryl ketone of formula (ii) can be accomplished
by diazotization of the amine and iodide displacement, as
exemplified in Method G. Compound (iii) can be prepared from (ii)
by cross-coupling of the aryl iodide with a protected propargyl
amine, according to Method I. In Scheme 1, an iodo-substituted
diaryl ketone is coupled with N-Boc-propargylamine, but those of
ordinary skill in the art will recognize that other
halogen-substituted diaryl ketones and other protected
propargylamines may be used. Additionally, a variety of catalysts,
bases, solvents and temperatures may be employed for the
cross-coupling reaction. For compounds wherein Ring B is other than
phenyl, the preparation of (iii) may alternatively be accomplished
by Method J, in which the Weinreb amide of a 2-iodobenzoic acid is
coupled with N-Boc-propargylamine, followed by a lithiated Ring
B.
[0816] Stepwise conversion of (iii) to (iv) can be effected by
sequential treatment with mercury (II) sulfate, HCl/dioxane, and
N,N-diisopropylethylamine, according to Method K. Alternatively,
(iii) can be converted to (iv) by sequential treatment with aqueous
HCl/dioxane and sodium carbonate, according to Method L. Those of
ordinary skill in the art will recognize that aryl alkynes can be
hydrated with a variety of other strong acids, such as
trifluoroacetic acid and sulfuric acid. Additionally, a variety of
basic conditions can promote the azepine imine bond formation.
[0817] Treatment of (iv) with N,N-dimethylformamide dimethyl acetal
in various solvents and at various temperatures affords (v).
Example 11 illustrates the conversion of (iv) to (v) in toluene at
80.degree. C. The conversion of (v) to the pyrimido compound (IIa)
is accomplished by treatment with an aryl or heteroaryl guanidine.
The reaction may be performed by submitting a reaction mixture
containing (v), an aryl or heteroaryl guanidine, and
N,N-diisopropylethylamine in DMF to microwave irradiation,
according to Method Q. Alternatively, the latter reaction may be
performed in the presence of potassium carbonate in refluxing
ethanol, according to Method R.
[0818] In some embodiments, preparation of (IIa) may alternatively
be accomplished by Method S, in which (v) is first treated with
guanidine hydrochloride to form a
5H-benzo[c]pyrimido[4,5-e]azepin-2-yl amine. Conversion of the
amine to the corresponding iodide, followed by cross-coupling with
a heteroaryl amine then affords compound (IIa), in which Ring C is
heteroaryl.
##STR00625##
[0819] Scheme 2 depicts a general synthetic route for preparation
of compounds of formula (A-1) wherein Ring A is an optionally
substituted 5- or 6-membered aryl, heteroaryl, or heterocyclyl
ring, Ring B is an optionally substituted aryl, heterocyclyl,
cycloaliphatic, or heteroaryl ring, and Ring C is a substituted or
unsubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic
ring.
[0820] Methods for the synthesis of heterocyclic-substituted
.beta.-ketonitriles of formula (vi) are known and described in the
literature e.g., Katritzky et id, JOC (2003), 68(12), 4932-4934 and
Bergman et al, Synthesis (2004), 16, 2760-2765. Treatment of
compounds (vi) with N,N-dimethylformamide dimethyl acetal in
various solvents and at various temperatures affords intermediate
enaminone (vii). Methods for the synthesis of intermediate
enaminones of formula (vii) have been further described in PCT Int.
Appl. WO 00/78731.
[0821] The preparation of cyanopyrimidine (viii) may be
accomplished by treatment of enaminone (vii) with a
mono-substituted guanidine, as shown in Step 2. The reaction may be
performed by refluxing a reaction mixture containing (vii) and a
guanidine in ethanol in the presence of potassium carbonate.
Methods for the synthesis of intermediate pyrimidines of formula
(viii) have been further described in PCT Int. Appl. WO
00/78731.
[0822] As shown in Step 3, compound (viii) may be reduced to amine
(ix) by hydrogenation in the presence of a metal catalyst, for
example Raney nickel, as described by Price et al, J. Am. Chem.
Soc. 68:766-9 (1946). Alternatively, the reduction may be carried
out with a reducing agent such as LiAlH.sub.4 as described by
Thurkauf et al, Bioorg. & Med. Chem. Letters 13(17):2921-2924,
(2003).
[0823] Conversion of amine (ix) to amide (x) can be accomplished by
reaction of (ix) with an acid chloride in the presence of a base,
or alternatively, with a carboxylic acid in the presence of a
coupling reagent. Amide (x) may then be converted to the desired
compound of formula (A-1) by heating with a cyclodehydration
reagent such as polyphosphoric acid, phosphorus
pentoxide/methanesulfonic acid, phosphorus oxychloride, or
phosphorus oxychloride/tin(IV) chloride.
##STR00626##
[0824] Scheme 3 depicts another general synthetic route for
preparation of compounds of formula (A-1) wherein Ring A is an
optionally substituted 5- or 6-membered aryl, heteroaryl, or
heterocyclyl ring, Ring B is an optionally substituted aryl,
heterocyclyl, cycloaliphatic, or heteroaryl ring, and Ring C is a
substituted or unsubstituted aryl, heteroaryl, heterocyclyl, or
cycloaliphatic ring.
[0825] Methods for the synthesis of heterocyclic-substituted
carboxylic acids of formula (xii) are well-known and are widely
described in the literature. Condensation of compound (xii) with a
.beta.-alanine ester affords amide (xiii). Methods for the
synthesis of intermediate amides of formula (xiii) have been
further described in the literature, e.g., Portevin et al,
Tetrahedron Letters, 44(52):9263-9265 (2003) and El-Naggar et al,
J. Indian Chem. Soc., 59(6):783-6 (1982).
[0826] The preparation of acid (xiv) may be accomplished by
treatment of ester (xiii) with a dilute aqueous solution of an
alkali-metal hydroxide, e.g., sodium or lithium hydroxide. Examples
of this transformation have been described by Portevin et al,
Tetrahedron Letters, 44(52):9263-9265 (2003)
[0827] Compound (xiv) may be cyclized to azepinedione (xv) by
treatment with a cyclodehydration reagent, for example
polyphosphoric acid (PPA), as described by Annoura et al,
Tetrahedron Letters 36(3):413-16 (1995).
[0828] The preparation of enaminones (xvi) may be accomplished by
treatment of compounds (xv) with N,N-dimethylformamide dimethyl
acetal. The reaction may be performed in various solvents and at
various temperatures.
[0829] The preparation of pyrimidinoazepinone (xvii) may be
accomplished by treatment of enaminone (xvi) with a
mono-substituted guanidine. The reaction may be performed by
refluxing a reaction mixture containing (xvi) and a guanidine in an
alcoholic solvent in the presence of potassium carbonate.
[0830] Conversion of pyrimidinoazepinone (xvii) to imidoyl chloride
(xviii) may be accomplished by reaction of (xvii) with a
chlorinating reagent, typically POCl.sub.3 or SOCl.sub.2. Compound
(xviii) may then be cross-coupled with an organoboronic acid using
palladium catalysis to yield azepine (xi), following the method of
Nadin et al, J. Org. Chem., 68(7), 2844-2852 (2003).
[0831] The compounds of this invention 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 described
in the Examples and/or are known in the art.
[0832] In another aspect, therefore, the invention provides a
method for inhibiting Aurora kinase activity in a cell, comprising
contacting a cell in which inhibition of Aurora kinase is desired
with an Aurora kinase inhibitor of formula (I). In some
embodiments, the Aurora kinase inhibitor interacts with and reduces
the activity of all enzymes of the Aurora kinase family in the
cell. In some other embodiments, the Aurora kinase inhibitor
interacts with and reduces the activity of fewer than all Aurora
kinase enzymes in the cell. In certain preferred embodiments, the
Aurora kinase inhibitor selectively inhibits one Aurora kinase
enzyme in the cell.
[0833] Preferably, the method according to this aspect of 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 to inhibit
cell number or cell growth in contacted cells as compared to cells
not contacted with the inhibitor. An assessment of cell
proliferation can be made by counting cells using a cell counter or
by an assay of cell viability, e.g., an MTT, XTT, 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.
[0834] Preferably, the growth of cells contacted with the inhibitor
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 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.
[0835] In another aspect, the invention provides a pharmaceutical
composition comprising a compound of formula (I) as defined above,
or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
[0836] If pharmaceutically acceptable salts of the compounds of the
invention are utilized in these compositions, the salts preferably
are derived from inorganic or organic acids and bases. 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.
[0837] 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.
[0838] 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, f-butylamine, ethylene diamine, ethanolamine,
and choline, and salts with amino acids such as arginine, lysine,
and so forth. For example, compounds of formula (V), wherein Ring C
is substituted with --CO.sub.2H may be formulated as the
corresponding sodium salts.
[0839] Also, basic nitrogen-containing groups may be quaternized
with such agents as lower alkyl halides, such as methyl, ethyl,
propyl, and butyl chloride, 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.
[0840] 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.
[0841] 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 stabilizers, pH
modifiers, surfactants, bioavailability modifiers and combinations
of these.
[0842] Pharmaceutical formulations may be prepared as liquid
suspensions or solutions using a liquid, such as, but not limited
to, an oil, water, an alcohol, and combinations of these.
Pharmaceutically suitable surfactants, suspending agents, or
emulsifying agents, may be added for oral or parenteral
administration. Suspensions may include oils, such as but not
limited to, peanut oil, sesame oil, cottonseed oil, corn oil and
olive oil. Suspension preparation may also contain esters of fatty
acids such as ethyl oleate, isopropyl myristate, fatty acid
glycerides and acetylated fatty acid glycerides. Suspension
formulations may include alcohols, such as, but not limited to,
ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and
propylene glycol. Ethers, such as but not limited to, poly
(ethyleneglycol), petroleum hydrocarbons such as mineral oil and
petrolatum; and water may also be used in suspension
formulations.
[0843] Pharmaceutically acceptable carriers that may be used in
these compositions include, but are not limited to, ion exchangers,
alumina, aluminum stearate, lecithin, serum proteins, such as human
serum albumin, buffer substances such as phosphates, glycine,
sorbic acid, potassium sorbate, partial glyceride mixtures of
saturated vegetable fatty acids, water, salts or electrolytes, such
as protamine sulfate, disodium hydrogen phosphate, potassium
hydrogen phosphate, sodium chloride, zinc salts, colloidal silica,
magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based
substances, polyethylene glycol, sodium carboxymethylcellulose,
polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,
polyethylene glycol and wool fat.
[0844] 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.
[0845] Sterile injectable forms of the compositions of this
invention may be aqueous or oleaginous suspension. These
suspensions may be formulated according to techniques known in the
art using suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic 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 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 may be employed including synthetic
mono- or di-glycerides. Fatty acids, such as oleic acid and its
glyceride derivatives are useful in the preparation of injectables,
as are natural pharmaceutically-acceptable oils, such as olive oil
or castor oil, especially in their polyoxyethylated versions. These
oil solutions or suspensions may also contain a long-chain alcohol
diluent or dispersant, such as carboxymethyl cellulose or similar
dispersing agents which are commonly used in the formulation of
pharmaceutically acceptable dosage forms including emulsions and
suspensions. Other commonly used surfactants, such as Tweens, Spans
and other emulsifying agents or bioavailability enhancers which are
commonly used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for the
purposes of formulation. Compounds may be formulated for parenteral
administration by injection such as by bolus injection or
continuous infusion. A unit dosage form for injection may be in
ampoules or in multi-dose containers.
[0846] The pharmaceutical compositions of this invention may be
orally administered in any orally acceptable dosage form including,
but not limited to, capsules, tablets, aqueous suspensions or
solutions. In the case of tablets for oral use, carriers that are
commonly used include lactose and corn starch. Lubricating agents,
such as magnesium stearate, are also typically added. For oral
administration in a capsule form, useful diluents include lactose
and dried cornstarch. When aqueous suspensions are required for
oral use, the active ingredient is combined with emulsifying and
suspending agents. If desired, certain sweetening, flavoring or
coloring agents may also be added.
[0847] Alternatively, the pharmaceutical compositions of this
invention may be administered in the form of suppositories for
rectal administration. These may be prepared by mixing the agent
with a suitable non-irritating excipient which is solid at room
temperature but liquid at rectal temperature and therefore will
melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0848] The pharmaceutical compositions of this invention may also
be administered topically, especially when the target of treatment
includes areas or organs readily accessible by topical application,
including diseases of the eye, the skin, or the lower intestinal
tract. Suitable topical formulations are readily prepared for each
of these areas or organs.
[0849] Topical application for the lower intestinal tract may be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches may also
be used. For topical applications, the pharmaceutical compositions
may be formulated in a suitable ointment containing the active
component suspended or dissolved in one or more carriers. Carriers
for topical administration of the compounds of this invention
include, but are not limited to, mineral oil, liquid petrolatum,
white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the pharmaceutical compositions may be formulated in
a suitable lotion or cream containing the active components
suspended or dissolved in one or more pharmaceutically acceptable
carriers. Suitable carriers include, but are not limited to,
mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters
wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and
water.
[0850] For ophthalmic use, the pharmaceutical compositions may be
formulated as micronized suspensions in isotonic, pH adjusted
sterile saline, or, preferably, as solutions in isotonic, pH
adjusted sterile saline, either with our without a preservative
such as benzylalkonium chloride. Alternatively, for ophthalmic
uses, the pharmaceutical compositions may be formulated in an
ointment such as petrolatum.
[0851] The pharmaceutical compositions of this invention may also
be administered by nasal aerosol or inhalation. Such compositions
are prepared according to techniques well known in the art of
pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons,
and/or other conventional solubilizing or dispersing agents.
[0852] The pharmaceutical compositions of this invention are
particularly useful in therapeutic applications relating to an
Aurora kinase-mediated disorder. As used herein, the term "Aurora
kinase-mediated disorder" includes any disorder, disease or
condition which is caused or characterized by an increase in Aurora
kinase expression or activity, or which requires Aurora kinase
activity. The term "Aurora kinase-mediated disorder" also includes
any disorder, disease or condition in which inhibition of Aurora
kinase activity is beneficial. Aurora kinase-mediated disorders
include proliferative disorders. Non-limiting examples of
proliferative disorders include chronic inflammatory proliferative
disorders, e.g., psoriasis and rheumatoid arthritis; proliferative
ocular disorders, e.g., diabetic retinopathy; benign proliferative
disorders, e.g., hemangiomas; and cancer.
[0853] Preferably, the composition is formulated for administration
to a patient having or at risk of developing or experiencing a
recurrence of an Aurora kinase-mediated disorder. The term
"patient", as used herein, means an animal, preferably a mammal,
more preferably a human. Preferred pharmaceutical compositions of
the invention are those formulated for oral, intravenous, or
subcutaneous administration. However, any of the above dosage forms
containing a therapeutically effective amount of a compound of the
invention are well within the bounds of routine experimentation and
therefore, well within the scope of the instant invention. In some
embodiments, the pharmaceutical composition of the invention may
further comprise another therapeutic agent. Preferably, such other
therapeutic agent is one normally administered to patients with the
disease or condition being treated.
[0854] By "therapeutically effective amount" is meant an amount
sufficient to cause a detectable decrease in Aurora kinase activity
or the severity of an Aurora kinase-mediated disorder. The amount
of Aurora kinase inhibitor needed will depend on the effectiveness
of the inhibitor for the given cell type and the length of time
required to treat the disorder. It should also be understood that a
specific dosage and treatment regimen for any particular patient
will depend upon a variety of factors, including the activity of
the specific compound employed, the age, body weight, general
health, sex, and diet of the patient, time of administration, rate
of excretion, drug combinations, the judgment of the treating
physician, and the severity of the particular disease being
treated. The amount of additional therapeutic agent present in a
composition of this invention typically will be no more than the
amount that would normally be administered in a composition
comprising that therapeutic agent as the only active agent.
Preferably, the amount of additional therapeutic agent will range
from about 50% to about 100% of the amount normally present in a
composition comprising that agent as the only therapeutically
active agent.
[0855] In another aspect, the invention provides a method for
treating a patient having or at risk of developing or experiencing
a recurrence of an Aurora kinase-mediated disorder. The method
comprises the step of administering to the patient a compound or
pharmaceutical composition according to the invention. The
compounds and pharmaceutical compositions of the invention can be
used to achieve a beneficial therapeutic or prophylactic effect,
for example, in a patient with a proliferative disorder, as
discussed above. The compounds and pharmaceutical compositions of
the invention are particularly useful for the treatment of
cancer.
[0856] As used herein, the term "cancer" refers to a cellular
disorder characterized by uncontrolled or disregulated cell
proliferation, decreased cellular differentiation, inappropriate
ability to invade surrounding tissue, and/or ability to establish
new growth at ectopic sites. The term "cancer" includes, but is not
limited to, solid tumors and bloodborne tumors. The term "cancer"
encompasses diseases of skin, tissues, organs, bone, cartilage,
blood, and vessels. The term "cancer" further encompasses primary
and metastatic cancers.
[0857] Non-limiting examples of solid tumors that can be treated by
the methods of the invention include pancreatic cancer; bladder
cancer; colorectal cancer; breast cancer, including metastatic
breast cancer; prostate cancer, including androgen-dependent and
androgen-independent prostate cancer; renal cancer, including,
e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung
cancer, including, e.g., non-small cell lung cancer (NSCLC),
bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung;
ovarian cancer, including, e.g., progressive epithelial or primary
peritoneal cancer; cervical cancer; gastric cancer; esophageal
cancer; head and neck cancer, including, e.g., squamous cell
carcinoma of the head and neck; melanoma; neuroendocrine cancer,
including metastatic neuroendocrine tumors; brain tumors,
including, e.g., glioma, anaplastic oligodendroglioma, adult
glioblastoma multiforme, and adult anaplastic astrocytoma; bone
cancer; and soft tissue sarcoma.
[0858] In some other embodiments, the cancer is a hematologic
malignancy. Non-limiting examples of hematologic malignancy include
acute myeloid leukemia (AML); chronic myelogenous leukemia (CML),
including accelerated CML and CML blast phase (CML-BP); acute
lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL);
Hodgkin's disease (HD); non-Hodgkin's lymphoma (NHL), including
follicular lymphoma and mantle cell lymphoma; B-cell lymphoma;
T-cell lymphoma; multiple myeloma (MM); Waldenstrom's
macroglobulinemia; 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.
[0859] In some embodiments, the compound or composition of the
invention is used to treat a cancer in which the activity of an
Aurora kinase is amplified. In some embodiments, the compound or
composition of the invention is used to treat a patient having or
at risk of developing or experiencing a recurrence in a cancer
selected from the group consisting of colorectal cancer, ovarian
cancer, breast cancer, gastric cancer, prostate cancer, and
pancreatic cancer. In certain embodiments, the cancer is selected
from the group consisting of breast cancer, colorectal cancer, and
pancreatic cancer.
[0860] In some embodiments, the Aurora kinase inhibitor of the
invention is administered in conjunction with another therapeutic
agent. The other therapeutic agent may also inhibit Aurora kinase
or may operate by a different mechanism. In some embodiments, the
other therapeutic agent is one that is normally administered to
patients with the disease or condition being treated. The Aurora
kinase inhibitor of the invention may be administered with the
other therapeutic agent in a single dosage form or as a separate
dosage form. When administered as a separate dosage form, the other
therapeutic agent may be administered prior to, at the same time
as, or following administration of the Aurora kinase inhibitor of
the invention.
[0861] In some embodiments, the Aurora kinase inhibitor of the
invention is administered in conjunction with a therapeutic agent
selected from the group consisting of cytotoxic agents,
radiotherapy, and immunotherapy. Non-limiting examples of cytotoxic
agents suitable for use in combination with the Aurora kinase
inhibitors of the invention include: antimetabolites, including,
e.g., capecitibine, gemcitabine, 5-fluorouracil or
5-fluorouracil/leucovorin, fludarabine, cytarabine, mercaptopurine,
thioguanine, pentostatin, and methotrexate; topoisomerase
inhibitors, including, e.g., etoposide, teniposide, camptothecin,
topotecan, irinotecan, doxorubicin, and daunorubicin; vinca
alkaloids, including, e.g., vincristine and vinblastin; taxanes,
including, e.g., paclitaxel and docetaxel; platinum agents,
including, e.g., cisplatin, carboplatin, and oxaliplatin;
antibiotics, including, e.g., actinomycin D, bleomycin, mitomycin
C, adriamycin, daunorubicin, idarubicin, doxorubicin and pegylated
liposomal doxorubicin; alkylating agents such as melphalan,
chlorambucil, busulfan, thiotepa, ifosfamide, carmustine,
lomustine, semustine, streptozocin, decarbazine, and
cyclophosphamide; thalidomide and related analogs, including, e.g.,
CC-5013 and CC-4047; protein tyrosine kinase inhibitors, including,
e.g., imatinib mesylate and gefitinib; antibodies, including, e.g.,
trastuzumab, rituximab, cetuximab, and bevacizumab; mitoxantrone;
dexamethasone; prednisone; and temozolomide.
[0862] In order that this invention be more fully understood, the
following preparative and testing examples are set forth. These
examples illustrate how to make or test specific compounds, and are
not to be construed as limiting the scope of the invention in any
way.
EXAMPLES
Definitions
[0863] AcOH acetic acid [0864] ATP adenosine triphosphate [0865]
BSA bovine serum albumin [0866] Boc tert-butoxycarbonyl [0867] DMF
N,N-dimethylformamide [0868] DTT dithiothreitol [0869] EDTA
ethylenediaminetetraacetic acid [0870] EtOAc ethyl acetate [0871]
Et.sub.2O diethyl ether [0872] MeOH methanol [0873] MTT
methylthiazoletetrazolium [0874] XTT
2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide
inner salt [0875] WST
(4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene
disulfonate sodium salt [0876] PKA cAMP-dependent protein kinase
[0877] PPA polyphosphoric acid [0878] TBTU
O-Benzolriazol-1-yl-N,N,N',N'-tetramethyluronium [0879]
tetrafluoroborate [0880] THF tetrahydrofuran [0881] h hours [0882]
min minutes [0883] m/z mass to charge [0884] MS mass spectrum
[0885] HRMS high resolution mass spectrum
Example 1: Method A for the Synthesis of Compounds of Formula (i)
(See Scheme 1)
##STR00627##
[0886] (2-Amino-4-methoxy-phenyl)-(2-fluoro-phenyl)-methanone
(1h)
[0887] 3-Anisidine (1.0 g, 8.0 mmol) was added dropwise to a
stirred solution of BCl.sub.3 (1M in CH.sub.2Cl.sub.2, 8.8 mL, 8.8
mmol) in anhydrous CH.sub.2Cl.sub.2 (20 mL) at 0.degree. C.
AlCl.sub.3 (1.15 g, 8.8 mmol) was added in one portion followed by
2-fluorobenzonitrile (1.6 mL, 16.0 mmol). The mixture was refluxed
for 16 h and then cooled to 0.degree. C. HCl (2N, 30 mL) was added
and the mixture was heated to 80.degree. C. and stirred vigorously
for 30 min. Upon cooling to room temperature, the mixture was
extracted with CH.sub.2Cl.sub.2 (3.times.50 mL). The combined
organic portions were washed with brine, dried over MgSO.sub.4,
filtered and evaporated in vacuo. The resulting brown oil was
purified by column chromatography (silica gel, Hexanes:EtOAc, 4:1)
to provide 1h (1.1 g, 56%), MS m/z=246 (M+H).
(2-Amino-3-methyl-phenyl)-(2-fluoro-phenyl)-methanone (1b)
[0888] In a manner similar to that described above for compound 1h,
o-tolylamine and 2-fluorobenzonitrile were converted to 1b (20%
yield) MS m/z=230 (M+H).
(2-Amino-4-fluoro-phenyl)-(2-fluoro-phenyl)-methanone (1c)
[0889] In a manner similar to that described above for compound 1h,
3-fluoro-phenylamine and 2-fluorobenzonitrile were converted to 1c
(25% yield) MS m/z=234 (M+H).
(2-Amino-4-bromo-phenyl)-(2-fluoro-phenyl)-methanone (1e)
[0890] In a manner similar to that described above for compound 1h,
3-bromo-phenylamine and 2-fluorobenzonitrile were converted to 1e
(15% yield) MS m/z=294/296 (M+H).
(2-Amino-4-methyl-phenyl)-(2-fluoro-phenyl)-methanone (1g)
[0891] In a manner similar to that described above for compound 1h,
m-tolylamine and 2-fluorobenzonitrile were converted to 1g (44%
yield) MS m/z=230 (M+H).
(2-Amino-4,5-dichloro-phenyl)-(2-fluoro-phenyl)-methanone (1ad)
[0892] In a manner similar to that described above for compound 1h,
3,4-dichloroaniline and 2-fluorobenzonitrile were converted to 1ad
(17% yield) MS m/z=284 (M+H).
(2-Amino-5-isopropyl-phenyl)-(2-fluoro-phenyl)-methanone (1ag)
[0893] In a manner similar to that described above for compound 1h,
4-isopropylaniline and 2-fluorobenzonitrile were converted to 1ag
(22% yield) MS m/z=258 (M+H).
Example 2: Method B for the Synthesis of Compounds of Formula
(i)
##STR00628##
[0894] (2-Amino-5-methyl-phenyl)-(2-fluoro-phenyl)-methanone
(1af)
[0895] 2-Iodofluorobenzene (2.0 mL, 17 mmol) was dissolved in
anhydrous THF (20 mL) under an argon atmosphere and cooled to
-20.degree. C. A solution of isopropyl magnesium chloride (8.5 mL,
17.0 mmol) was slowly added, and the solution was stirred for 20
min. 2-Nitro-5-methylbenzaldehyde (2.7 g, 16.5 mmol) in THF (20 mL)
was then added, and the mixture was stirred for 20 min at
-20.degree. C. and then quenched with saturated aqueous NH.sub.4Cl.
The mixture was partitioned between EtOAc (100 mL) and H.sub.2O
(100 mL). The organic portion was collected, dried over MgSO.sub.4,
filtered and evaporated in vacuo. This material was dissolved in
anhydrous CH.sub.2Cl.sub.2 (80 mL). Silica gel (20.3 g) and
pyridinium chlorochromate (5.4 g, 25 mmol) were then added and the
suspension was stirred at room temperature for 3 h. The mixture was
then filtered through silica gel. The filtrate was concentrated in
vacuo and the resulting residue was purified by column
chromatography (silica gel, hexanes:EtOAc, 3:2) to provide the
2-nitro-benzophenone (3.7 g, 14 mmol). The benzophenone was
dissolved in glacial acetic acid (50 mL), MeOH (50 mL) and
deionized H.sub.2O (10 mL). Iron powder (<10 micron, 1.0 g) was
added with vigorous stirring and the suspension heated to
60.degree. C. After 20 min, additional iron powder (2.0 g) was
added and the mixture was stirred at 60.degree. C. for 3 h. After
cooling, silica gel (12.5 g) was added and the volatile components
were removed in vacuo. The resulting powder was suspended in EtOAc
(100 mL) and carefully treated with 1N NaOH until basic to litmus.
The suspension was filtered and the organic portion was separated,
washed with brine, dried over MgSO.sub.4, filtered and evaporated
in vacuo. The resulting residue was purified by column
chromatography (silica gel, hexanes:EtOAc, 1:3) to provide 1af (3.1
g, 94%) MS m/z=230 (M+H).
(2-Amino-4-trifluoromethyl-phenyl)-(2-fluoro-phenyl)-methanone
(1f)
[0896] In a manner similar to that described above for compound
1af, 2-nitro-4-trifluoromethyl-benzaldehyde was converted to 1f
(46% yield) MS m/z=230 (M+H).
(2-Amino-5-fluoro-phenyl)-(2-fluoro-phenyl)-methanone (1j)
[0897] In a manner similar to that described above for compound
1af, 5-Fluoro-2-nitro-benzaldehyde was converted to 1j (60% yield)
MS m/z=234 (M+H).
(2-Amino-5-methoxy-phenyl)-(2-fluoro-phenyl)-methanone (1ah)
[0898] In a manner similar to that described above for compound
1af, 5-methoxy-2-nitro-benzaldehyde was converted to 1ah (62%
yield) MS m/z=246 (M+H).
Example 3: Method C for the Synthesis of Compounds of the Formula
(i)
##STR00629##
[0899] (2-Amino-5-chloro-phenyl)-(2-methyl-phenyl)-methanone
(1m)
[0900] Benzoyl chloride (5.3 mL, 45 mmol) was added dropwise to a
suspension of Na.sub.2CO.sub.3 (3.8 g, 36 mmol) and
2-amino-5-chloro-benzoic acid (3.1 g, 18 mmol) in THF (60 mL). The
mixture was allowed to stir for 16 h and then H.sub.2O (200 mL) was
added. The resulting precipitate was collected by filtration,
washed with MeOH/H.sub.2O (1/1,100 mL) and then dried in vacuo to
provide 6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one (4.3 g, 92%).
To a suspension of the benzoxazinone (5.0 g, 19 mmol) in
CH.sub.2Cl.sub.2 (100 mL) at -78.degree. C. was added
o-tolylmagnesium chloride (2 M in THF, 48 mmol) dropwise. The
mixture was allowed to warm to -30.degree. C. and stir for 1 h. 1N
HCl (100 mL) was then added. The organic phase was collected and
the aqueous phase was washed with CH.sub.2Cl.sub.2 (2.times.50 mL).
The combined organic portions were washed with 0.1 N NaOH
(2.times.50 mL), dried over MgSO.sub.4, filtered and concentrated
in vacuo to provide
N-[4-chloro-2-(2-methyl-benzoyl)-phenyl]-benzamide (6.3 g, 93%).
The acylated amino-benzophenone (3.5 g, 10 mmol) was dissolved in
MeOH (50 mL) containing KOH (3 M, 30 mmol) and was refluxed for 16
h. The solution was then cooled to room temperature and diluted
with H.sub.2O (50 mL) and EtOAc (100 mL). The organic phase was
collected, washed with H.sub.2O (3.times.50 mL), dried over
MgSO.sub.4, filtered and evaporated to dryness in vacuo to provide
1m (2.4 g, 98%) MS m/z=246 (M+H).
(2-Amino-5-chloro-phenyl)-(2-methoxy-phenyl)-methanone (In)
[0901] In a manner similar to that described above for compound 1m,
6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one was converted to 1n
(84% yield) MS m/z=262 (M+H).
(2-Amino-5-chloro-phenyl)-(2-dimethylaminomethyl-phenyl)-methanone
(1q)
[0902] To a solution of
N-[4-chloro-2-(2-methyl-benzoyl)-phenyl]-benzamide (5.1 g, 14.6
mmol) and N-bromosuccinimide (2.85 g, 16 mmol) in CCl.sub.4 (150
mL) was added 2,2'-azobisisobutrylnitrile (0.2 g, 1.5 mmol). The
solution was refluxed for 4 h. The solution was then cooled to room
temperature, diluted with CH.sub.2Cl.sub.2 (150 mL) and washed with
H.sub.2O (3.times.50 mL). The organic portion was dried over
Na.sub.2SO.sub.4 and evaporated to dryness in vacuo to provide
N-[2-(2-bromomethyl-benzoyl)-4-chloro-phenyl]-benzamide (4.6 g,
74%). A solution of the benzamide (2.3 g, 5.4 mmol) in
CH.sub.2Cl.sub.2 (50 mL) was saturated with dimethylamine, stirred
for 16 h and evaporated to dryness in vacuo. The resulting residue
was dissolved in MeOH (50 mL) and KOH (0.9 g, 16 mmol) in H.sub.2O
(5 mL) was added. The solution was refluxed for 24 h. The solution
was concentrated in vacuo and then diluted with EtOAc (150 mL) and
H.sub.2O (50 mL). The organic portion was washed with H.sub.2O
(3.times.50 mL), dried over Na.sub.2SO.sub.4 and purified by column
chromatography (silica gel, 18:80:2 MeOH:CH.sub.2C.sub.1-2:NHOH) to
provide 1q (0.9 g, 53% yield) MS m/z=289 (M+H).
(2-Amino-5-chloro-phenyl)-(3-fluoro-phenyl)-methanone (1r)
[0903] In a manner similar to that described above for compound 1m,
6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one was converted to 1r
(36% yield) MS m/z=250 (M+H).
(2-Amino-5-chloro-phenyl)-(3-methoxy-phenyl)-methanone (1s)
[0904] In a manner similar to that described above for compound 1m,
6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one was converted to 1s
(64% yield) MS m/z=262 (M+H).
(2-Amino-5-chloro-phenyl)-(2,4-dimethoxy-phenyl)-methanone (1x)
[0905] In a manner similar to that described above for compound 1m,
6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one was converted to
1.times.(63% yield) MS m/z=292 (M+H).
(2-Amino-5-chloro-phenyl)-(2,5-dimethoxy-phenyl)-methanone (1z)
[0906] In a manner similar to that described above for compound 1m,
6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one was converted to 1z
(62% yield) MS m/z=292 (M+H).
Example 4: Method D for the Synthesis of Compounds of the Formula
(i)
##STR00630##
[0907]
(2-Amino-5-chloro-phenyl)-(2-fluoro-6-methoxy-phenyl)-methanone
(1ac)
[0908] To a solution of 1-fluoro-3-methoxy-benzene (19.6 g, 155
mmol) in THF (180 mL), at -78.degree. C., was added dropwise 2.5 M
n-butyllithium in hexanes (62 mL, 155 mmol). The solution was
stirred at -78.degree. C. for 3 h and then added to a suspension of
6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one (38.8 g, 150 mmol) in
THF (280 mL) at -20.degree. C. The mixture was allowed to gradually
warm until the solution became homogenous. 1N HCl (150 mL) followed
by EtOAc (250 mL) were then added and the solution allowed to warm
to room temperature. The organic portion was collected and washed
with H.sub.2O (250 mL), saturated NaHCO.sub.3 (2.times.250 mL) and
H.sub.2O (250 mL). The organic portion was then dried over
Na.sub.2SO.sub.4 and evaporated to dryness, in vacuo, to provide
the N-[4-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-phenyl]-benzamide as
an orange solid (42.7 g). To a solution of
N-[4-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-phenyl]-benzamide (42.7
g, 110 mmol) in MeOH (540 mL) was added KOH (56.4 g, 1 mole) in
H.sub.2O (100 mL). The solution was allowed to reflux for 16 h. The
solution was then allowed to cool to room temperature and the
resulting precipitate removed by filtration. The filtrate was
concentrated in vacuo, diluted with EtOAc (250 mL) and washed with
H.sub.2O (3.times.100 mL). The organic portion was then dried over
Na.sub.2SO.sub.4, concentrated in vacuo and then purified by column
chromatography (silica gel, 0 to 15% EtOAc/hexanes) to provide 1ac
(19.6 g, 47%) MS m/z=280 (M+H).
Example 5: Method E for the Synthesis of Compounds of the Formula
(i)
##STR00631##
[0909] (2-Amino-5-chloro-phenyl)-(4-fluoro-phenyl)-methanone
(1t)
[0910] To p-fluorobenzoyl chloride (49.7 g, 314 mmol), heated to
120.degree. C., was added p-chloroaniline (17.8 g, 139 mmol) over
10 min. The mixture was then heated to 180.degree. C. and
ZnCl.sub.2 (23.8 g, 174 mmol) was added over 10 min. The resulting
mixture was heated at 205.degree. C. for 2 h. After cooling to
120.degree. C., 3N HCl (125 mL) was added cautiously and the
mixture was maintained at 120.degree. C. for 1 h. The hot aqueous
portion was then decanted and the remaining residue was washed with
hot 3N HCl (2.times.125 mL). The residue was poured onto ice and
extracted with CH.sub.2Cl.sub.2 (3.times.100 mL). The combined
organic portions were washed with 3N HCl (2.times.50 mL), 5N NaOH
(2.times.50 mL) and H.sub.2O (3.times.50 mL) and were then dried
over MgSO.sub.4, filtered and concentrated in vacuo to provide 15 g
(29%) of the
N-[4-chloro-2-(4-fluoro-benzoyl)-phenyl]-4-fluoro-benzamide as a
dark yellow powder. To a flask containing the acylated
amino-benzophenone (6.7 g, 18 mmol) was added 1:1 cone. HCl:AcOH
(700 mL) and the resulting mixture was heated to 105.degree. C. and
stirred for 16 h. The mixture was cooled to room temperature and
concentrated in vacuo. The residue was poured onto ice and
extracted with CH.sub.2Cl.sub.2 (3.times.100 mL). The combined
organic portions were washed with 5N NaOH (2.times.50 mL) and
H.sub.2O (3.times.50 mL) and then dried over MgSO.sub.4, filtered
and evaporated in vacuo. The resulting residue was purified by
column chromatography (silica gel, 5 to 25% EtOAc/hexanes) and
recrystallized from hexanes to provide 1t (3.4 g, 76%) MS m/z=250
(M+H).
(2-Amino-5-chloro-phenyl)-(4-methoxy-phenyl)-methanone (1u)
[0911] To a solution of
N-[4-chloro-2-(4-fluoro-benzoyl)-phenyl]-4-fluoro-benzamide (6.0 g,
16 mmol), prepared as described above for compound 1s, in MeOH (400
mL) was added 5N NaOH (50 mL) and the resulting solution was
allowed to reflux for 16 h. The solution was cooled to room
temperature and concentrated in vacuo. The aqueous portion was
extracted with CH.sub.2Cl.sub.2 (2.times.100 mL). The combined
organic portions were washed with H.sub.2O (3.times.50 mL), dried
over MgSO.sub.4, filtered and evaporated in vacuo. The resulting
residue was purified by column chromatography (silica gel, 5 to 25%
EtOAc/hexanes) and recrystallized from MeOH to provide 1u (3.5 g,
83%) as a light yellow powder MS m/z=262 (M+H).
(2-Amino-5-methyl-phenyl)-(2,6-difluoro-phenyl)-methanone (1aj)
[0912] In a manner similar to that described above for compound 1t,
p-toluidine and 2,6-difluorobenzoyl chloride were converted to 1aj
(16% yield) MS m/z=248 (M+H).
Example 6: Method F for the Synthesis of Compounds of Formula
(i)
##STR00632##
[0913] (2-Amino-5-chloro-phenyl)-(2,6-difluoro-phenyl)-methanone (1
aa)
[0914] 4-Chloro-N-Boc-aniline (3.4 g, 15 mmol) was dissolved in dry
inhibitor-free THF (40 mL) under argon and cooled to -78.degree. C.
t-BuLi (1.7 M in pentane, 20 mL, 34 mmol) was cooled in a dry
ice/acetone bath and added to the Boc-aniline solution, via a
cannula, over 20 min. The yellow solution was stirred at
-78.degree. C. for 30 min, warmed to -30.degree. C. for an
additional 2.5 h, and then cooled to -78.degree. C.
2,6-Difluorobenzoyl chloride (2.8 g, 16 mmol) was dissolved in dry
THF (30 mL) and cooled to -78.degree. C. under argon. The
o-lithiated aniline was added, via a cannula, to the acid chloride
solution over 30 min. The solution was stirred for an additional 20
min before quenching with 1N HCl (50 mL). The solution was diluted
with EtOAc and the organic portion was separated, dried over
MgSO.sub.4 and concentrated to dryness in vacuo. The resulting
orange oil was purified by column chromatography (silica gel,
Hexanes:EtOAc 4:1) to provide the Boc protected amino-benzophenone
(3.3 g, 60%). The N-Boc-aminobenzophenone was dissolved in dry
CH.sub.2Cl.sub.2 (50 mL) and trifluoroacetic acid (50 mL) was
added. After stirring for 1 h, the solution was evaporated to
dryness in vacuo. The resulting residue was dissolved in EtOAc (100
mL) and water (100 mL) containing NaHCO.sub.3. The organic portion
was washed with a saturated aqueous NaHCO.sub.3 solution, dried
over MgSO.sub.4, and concentrated to dryness in vacuo to provide,
quantitatively, 1aa MS m/z=268 (M+H).
(2-Amino-5-chloro-phenyl)-(2,3-difluoro-phenyl)-methanone (1v)
[0915] In a manner similar to that described above for compound
1aa, 4-Chloro-N-Boc-aniline and 2,3-difluoro-benzoyl chloride were
converted to 1v (14% yield) MS m/z=268 (M+H).
(2-Amino-5-chloro-phenyl)-(2,4-difluoro-phenyl)-methanone (1w)
[0916] In a manner similar to that described above for compound
1aa, 4-Chloro-N-Boc-aniline and 2,4-difluoro-benzoyl chloride were
converted to 1w (20% yield) MS m/z=268 (M+H).
(2-Amino-5-chloro-phenyl)-(2,5-difluoro-phenyl)-methanone (1y)
[0917] In a manner similar to that described above for compound
1aa, 4-Chloro-N-Boc-aniline and 2,4-difluoro-benzoyl chloride were
converted to 1y (10% yield) MS m/z=268 (M+H).
(2-Amino-5-chloro-phenyl)-(2-chloro-6-fluoro-phenyl)-methanone
(1ab)
[0918] In a manner similar to that described above for compound
1aa, 4-Chloro-N-Boc-aniline and 2-chloro-6-fluoro-benzoyl chloride
were converted to 1ab (42% yield) MS m/z=284 (M+H).
(2-amino-5-chlorophenyl)-(2-(trifluoromethyl)phenyl)methanone
(1o)
[0919] In a manner similar to that described above for compound
1aa, 4-Chloro-N-Boc-aniline and 2-(trifluoromethyl)benzoyl chloride
were converted to 1o (% yield) MS m/z=(M+H).
Example 7: Method G and Method H for the Synthesis of Compounds of
Formula ii (See Scheme 1)
##STR00633##
[0920] (5-Chloro-2-iodo-phenyl)-(2,6-difluoro-phenyl)-methanone
(2aa)
[0921] Method G:
(2-Amino-5-chloro-phenyl)-(2,6-difluoro-phenyl)-methanone (1aa)
(2.6 g, 9.7 mmol) was dissolved in acetic acid (10 mL) and
concentrated HCl (4 mL) and the solution was cooled to 0.degree. C.
A solution of NaNO.sub.2 (0.7 g, 10.7 mmol) in H.sub.2O (6 mL) was
added dropwise so as to maintain a temperature of between
0-5.degree. C. Following this addition, the reaction mixture was
stirred at 0.degree. C. for 30 min. Cold EtOAc (20 mL) was added
dropwise and the solution was stirred for 20 min. Iodine (1.5 g,
5.8 mmol) and potassium iodide (1.9 g, 11.6 mmol) in H.sub.2O (10
mL) were added dropwise and the mixture was warmed to room
temperature and stirred for 1 h. The reaction mixture was diluted
with EtOAc (200 mL) and washed with saturated aqueous sodium
thiosulfate (4.times.100 mL). The combined aqueous portions were
extracted with EtOAc (3.times.50 mL). The combined organic portions
were then washed with a saturated aqueous NaHCO.sub.3 solution
(3.times.50 mL), H.sub.2O (2.times.50 mL), dried over
Na.sub.2SO.sub.4, filtered and evaporated in vacuo to afford 2aa
(3.3 g, 90%) as a light yellow solid.
4-(2-Fluoro-benzoyl)-3-iodo-benzoic acid methyl ester (2i)
[0922] Method H: To a solution of 2g (1 g, 3 mmol) in t-butanol (25
mL) and H.sub.2O (25 mL) was added KMnO.sub.4 (3.8 g, 24 mmol). The
solution was refluxed for 18 h. THF (50 mL) was added and the
solution was refluxed for 30 min, cooled to room temperature and
filtered. The filtrate was concentrated in vacuo, diluted with MeOH
(20 mL) and acidified with concentrated HCl. The solution was
diluted with H.sub.2O (10 mL) and the resulting precipitate was
collected to provide 4-(2-fluoro-benzoyl)-3-iodo-benzoic acid (1 g,
92%) as a white solid. The 4-(2-fluoro-benzoyl)-3-iodo-benzoic acid
(0.5 g, 1.4 mmol) in MeOH (6 mL) containing concentrated HCl (100
.mu.L) was submitted to microwave irradiation (300 W) for 30 min at
140.degree. C. The resulting precipitate was collected to provide
2i (0.4 g, 79%) as a white solid MS m/z=385 (M+H).
2-(5-Chloro-2-iodo-benzoyl)-benzoic acid methyl ester (2p)
[0923] In a manner similar to that described above for compound 2i,
2m was converted to 2p (81% yield) MS m/z=401 (M+H).
3-(2-Fluorobenzoyl)-4-iodobenzoic acid methyl ester (2ai)
[0924] In a manner similar to that described above for compound 2i,
2af was converted to 2ai (60% yield) MS m/z=385 (M+H).
3-(2,6-Difluorobenzoyl)-4-iodobenzoic acid methyl ester (2ak)
[0925] In a manner similar to that described above for compound 2i,
2aj was converted to 2ak (58% yield) MS m/z=403 (M+H).
[0926] The illustrative compounds of the formula 2, set forth in
Table 4 below, were prepared in a similar manner to that
illustrated by Method G or Method H, as described above for
compounds 2aa and 2i.
TABLE-US-00004 TABLE 4 Illustrative Examples of Compounds of
Formulae 1-5 1-5 Substituent Mass Spectra (M + H) R.sup.b1 R.sup.b2
R.sup.b3 R.sup.c1 R.sup.c2 R.sup.c3 R.sup.c4 R.sup.c5 2 3 4 5 a H H
H H H H H H 309 336 236 291 b Me H H F H H H H 341 368 268 323 c H
F H F H H H H 345 372 272 327 d H Cl H F H H H H 361 388 288 343 e
H Br H F H H H H 405/407 432/434 332/334 387/389 f H CF.sub.3 H F H
H H H 395 422 322 377 g H Me H F H H H H 341 368 268 323 h H OMe H
F H H H H 357 384 284 339 i H CO.sub.2Me H F H H H H 385 412 312
367 j H H F F H H H H 345 372 272 327 k H H Cl F H H H H 361 388
288 343 1 H H Cl Cl H H H H 377 404 304 359 m H H Cl Me H H H H 357
384 284 339 n H H Cl OMe H H H H 373 400 300 355 o H H Cl CF.sub.3
H H H H 411 438 338 393 p H H Cl CO.sub.2Me H H H H 401 428 328 383
q H H Cl CH.sub.2N(Me).sub.2 H H H H 400 427 327 382 r H H Cl H F H
H H 361 388 288 343 s H H Cl H OMe H H H 373 400 300 355 t H H Cl H
H F H H 361 388 288 343 u H H Cl H H OMe H H 373 400 300 355 v H H
Cl F F H H H -- 406 306 361 w H H Cl F H F H H -- 406 306 361 x H H
Cl OMe H OMe H H 403 430 330 385 y H H Cl F H H F H -- 406 306 361
z H H Cl OMe H H OMe H 403 430 330 385 aa H H Cl F H H H F -- 406
306 361 ab H H Cl F H H H Cl -- 422 322 377 ac H H Cl F H H H OMe
-- 418 318 373 ad H Cl Cl F H H H H 395 422 322 377 ae H H H F H H
H H -- 354 254 309 af H H Me F H H H H 341 368 268 323 ag H H iPr F
H H H H 369 -- -- -- ah H H OMe F H H H H 357 384 284 339 ai H H
CO.sub.2Me F H H H H 385 412 312 367 aj H H CH.sub.3 F H H H F 359
ak H H CO.sub.2Me F H H H F 403 430 330 385 al H H Cl -- H H H H --
371 271 326 (pyridyl) am H H Cl -- H H H F -- 389 289 344
(pyridyl)
Example 8: Method I for the Synthesis of Compounds of Formula iii
(See Scheme 1)
##STR00634##
[0927]
{3-[4-Chloro-2-(2,6-difluoro-benzoyl)-phenyl]-prop-2-ynyl}-carbamic
acid tert-butyl ester (3aa)
[0928] (5-Chloro-2-iodo-phenyl)-(2,6-difluoro-phenyl)-methanone
(2aa) (5.5 g, 14.5 mmol), prop-2-ynyl-carbamic acid tert-butyl
ester (2.5 g, 16 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (0.6 g, 0.9
mmol) and Cu(I)I (0.2 g, 0.9 mmol) were suspended in anhydrous
CH.sub.2Cl.sub.2 (50 mL) and the mixture was sparged with nitrogen
for 30 min. Diethylamine (8 mL) was added and the solution was
stirred at room temperature for 16 h. The solution was concentrated
in vacuo and the resulting residue purified by column
chromatography (silica gel, 0 to 15% EtOAc/hexanes) to afford 3aa
(3.6 g, 61%) as a white solid, MS m/z=406 (M+H).
[0929] The illustrative compounds of the formula 3, set forth in
Table 4, were prepared in a similar manner to that illustrated by
Method I, as described above for compounds 3aa.
Example 9: Method J for the Synthesis of Compounds of Formula iii
(See Scheme 1)
##STR00635##
[0930] tert-Butyl
3-(4-chloro-2-picolinoylphenyl)prop-2-ynylcarbamate (3al)
[0931] 5-Chloro-2-iodobenzoic acid (2.8 g, 10 mmol) was taken up in
dry methylene chloride (80 mL) and DMF (50 .mu.L, cat.) followed by
thionyl chloride (2.4 g, 20 mmol) were added. The mixture was
stirred at reflux for 12 h, cooled to room temperature and
evaporated in vacuo. The residue was azeotroped with toluene
(2.times.10 mL) and used without further purification. The
5-chloro-2-iodobenzoyl chloride (10 mmol) was taken up in dry
methylene chloride (50 mL) and N,O-dimethylhydroxylamine
hydrochloride (1.1 g, 11 mmol) was added. The mixture was cooled to
0.degree. C., and pyridine (2.4 g, 30 mmol) was added. The mixture
was allowed to warm to room temperature, stir for 12 h, and was
then quenched with saturated brine (20 mL). The organic phase was
separated and the water phase was extracted with methylene chloride
(2.times.10 mL). The combined organic extracts were dried with
anhydrous MgSO.sub.4, filtered and evaporated in vacuo. The residue
was purified using flash chromatography on silica gel (50 g) using
methylene chloride as eluent to provide
5-chloro-2-iodo-N-methoxy-N-methylbenzamide (3.1 g, 95%) MS m/z=326
(M+H).
[0932] The Weinreb amide (3.1 g, 9.5 mmol) and prop-2-ynyl-carbamic
acid tert-butyl ester (2.9 g, 19 mmol) were coupled according to
method H to provide
3-(4-chloro-2-(methoxy(methyl)carbamoyl)phenyl)prop-2-ynylcarbami-
c acid tert-butyl ester (2.7 g, 80%), MS m/z=353 (M+H). To this
product, dissolved in dry THF (40 mL) and cooled to -78.degree. C.,
was added lithiated pyridine, prepared from 2-bromopyridine (4.2 g,
26.6 mmol) and n-butyllithium (14.3 mL of 1.6 M solution in
hexanes, 22.8 mmol) in dry THF (40 mL) under argon atmosphere at
-78.degree. C. The resulting mixture was gradually warmed to
-40.degree. C. over 1 h and then quenched with brine (20 mL). After
warming to room temperature, the mixture was extracted with ethyl
acetate (3.times.20 mL). The organic extracts were dried with
MgSO.sub.4, filtered and evaporated. The residue was purified using
flash chromatography on silica gel (100 g) using methylene chloride
to 10% ethyl acetate in methylene chloride as eluent to give 3al
(2.14 g, 76%): MS m/z=371 (M+H).
tert-Butyl
3-(4-chloro-2-(3-fluoropicolinoyl)phenyl)prop-2-ynylcarbamate
(3am)
[0933] In a manner similar to that described above for compound
3al,
3-(4-chloro-2-(methoxy(methyl)carbamoyl)phenyl)prop-2-ynylcarbamic
acid tert-butyl ester and 2-bromo-3-fluoropyridine were converted
to 3am (45% yield): MS m/z=389 (M+H).
[0934] The illustrative compounds of the formula 3, set forth in
Table 4, were prepared in a similar manner to that illustrated by
Method J, as described above for compounds 3al and 3am.
Example 10: Method K and Method L for the Synthesis of Compounds of
Formula iv (See Scheme 1)
##STR00636##
[0935]
8-Chloro-1-(2-fluoro-phenyl)-3,4-dihydro-benzo[c]azepin-5-one
(4k)
[0936] Method K: A solution of
{3-[4-chloro-2-(2-fluoro-benzoyl)-phenyl]-prop-2-ynyl}-carbamic
acid tert-butyl ester (9.2 g, 23 mmol) in CH.sub.2Cl.sub.2 (100 mL)
containing formic acid (9.18 mL) was cooled to 0.degree. C.
Mercury(II) sulphate (2.1 g, 7.1 mmol) was added and the reaction
stirred for 2 h at 0.degree. C. The mixture was diluted with
H.sub.2O (20 mL) and NH.sub.4OH (20 mL). The organic phase was
collected and the aqueous phase was extracted with EtOAc
(3.times.100 mL). The combined organic portions were washed with
H.sub.2O, dried over MgSO.sub.4, filtered and the solvents
evaporated in vacuo to afford
[3-[4-chloro-2-(2-fluorobenzoyl)-phenyl]-3-oxopropyl]-carbamic acid
tert-butyl ester 8.9 g (95%) as a brown solid. This material (8.9
g, 22 mmol) was dissolved in HCl (4N in dioxane, 185 mL) and
stirred at room temperature for 30 min. The solution was then
evaporated in vacuo. The residue was dissolved in CH.sub.2Cl.sub.2
(250 mL) and diisopropylethylamine amine (18 mL) was added. The
solution was stirred at room temperature for 2 h. The solution was
evaporated in vacuo and the residue purified by column
chromatography (silica gel, 10 to 50% EtOAc/hexanes) to provide 4k
(2.9 g, 46%) as a brown solid MS m/z=288 (M+H).
8-Chloro-1-(2,6-difluoro-phenyl)-3,4-dihydro-benzo[c]azepin-5-one
(4aa)
[0937] Method L: A solution of
{3-[4-chloro-2-(2,6-difluoro-benzoyl)-phenyl]-prop-2-ynyl}-carbamic
acid tert-butyl ester (5.6 g, 15 mmol) was dissolved in dioxane
(200 mL). 5N HCl (aq) (200 mL) was added and the solution was
stirred at room temperature for 14 h and then at 60.degree. C. for
2 h. The solution was diluted with CH.sub.2Cl.sub.2 (200 mL) and
Na.sub.2CO.sub.3 was added until the solution pH was basic to
litmus. The mixture was allowed to stir for 2 h. The organic
portion was separated and the aqueous portion was extracted with
CH.sub.2Cl.sub.2 (2.times.100 mL). The combined organic portions
were washed with H.sub.2O (3.times.50 mL), dried over
Na.sub.2SO.sub.4, filtered and evaporated in vacuo to provide 4aa
(4.2 g, 100%) MS m/z=306 (M+H).
[0938] The illustrative compounds of formula 4, set forth in Table
4, were prepared in a similar manner to that illustrated by Method
K and Method L, as described above for compounds 4k and 4aa.
Example 11: Method M for the Synthesis of Compounds of the Formula
v (See Scheme 1)
##STR00637##
[0939]
8-Chloro-4-dimethylaminomethylene-1-(2,6-difluoro-phenyl)-3,4-dihyd-
ro-benzo[c]azepin-5-one (5aa)
[0940]
8-Chloro-1-(2,6-difluoro-phenyl)-3,4-dihydro-benzo[c]azepin-5-one
(4aa) (4.2 g, 15 mmol) was dissolved in toluene (100 mL) and
N,N-dimethylformamide dimethyl acetal (19 mL) and heated at
80.degree. C. for 2 h. The solution was evaporated in vacuo and the
resulting residue was purified by column chromatography (silica
gel, 0 to 75% EtOAc/hexanes) to afford 5aa (2.6 g, 78%) as a pale
brown solid MS m/z=361 (M+H).
[0941] The illustrative compounds of formula 5, set forth in Table
4, were prepared in a similar manner to that illustrated by Method
M, as described above for 5aa.
Example 12: Preparation of Aryl or Heteroaryl Guanidines by Methods
N, O or P
##STR00638##
[0942] N-(3,4-Dimethoxy-phenyl)-guanidine
[0943] Method N: To a vigorously stirred solution of
3,4-dimethoxyaniline (15.3 g, 0.1 mol) in EtOH (60 mL) at 0.degree.
C. was added nitric acid (69%, 9.0 mL, 0.1 mol) dropwise. A
solution of cyanamide (4.6 g, 0.1 mol) in H.sub.2O (8.5 mL) was
added and the solution was heated at reflux for 3 h. The mixture
was then diluted with EtOH (50 mL), chilled to 4.degree. C. and the
resulting golden needles were collected and dried in vacuo to
provide N-(3,4-dimethoxy-phenyl)-guanidine as the nitric acid salt
(14.7 g, 57%) MS m/z=196 (M+H).
N-Pyridin-3-yl-guanidine
[0944] Method O: To a mixture of 3-aminopyridine (1.0 g, 10.6
mmol), 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (4.0
g, 13.8 mmol) and Et.sub.3N (15 mL) in CH.sub.2Cl.sub.2 (100 mL)
was added mercuric chloride (4.0 g, 14.8 mmol). The resulting
mixture was stirred under a nitrogen atmosphere at room temperature
for 16 h, during which time a dense white precipitate formed. The
mixture was filtered through Celite.RTM., and washed with
Et.sub.2O. The combined filtrates were evaporated to dryness in
vacuo and the resulting white solid purified by column
chromatography (silica gel, 15% EtOAc/hexanes) to yield the bis-Boc
protected guanidine (3.1 g, 88%). To a solution of this material
(3.1 g, 9.3 mmol) in MeOH (2 mL) was added HCl (4N in dioxane, 60
mmol). The resulting solution was refluxed for 16 h, cooled to room
temperature and triturated with Et.sub.2O to provide the
N-pyridin-3-yl-guanidine as the hydrochloride salt (1.2 g, 74%) MS
m/z=173 (M+H).
t-Butyl guanidinobenzoate, HCl salt
[0945] Method P: To a solution of t-butyl 4-aminobenzoate (2.0 g,
10.3 mmol) in CH.sub.2Cl.sub.2 (20 mL) was added
1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea (5.6 g, 15.5
mmol), Et.sub.3N (5.0 mL, 36 mmol), and mercuric chloride (3.37 g,
12.4 mmol). The reaction mixture was stirred overnight at room
temperature. The reaction mixture was filtered through Celite.RTM.,
and the filtrates were concentrated in vacuo and purified by column
chromatography (1:1 CH.sub.2Cl.sub.2/hexanes to 100%
CH.sub.2Cl.sub.2, and then 10% EtOAc/CH.sub.2Cl.sub.2) to provide
tert-butyl 4-(2,3-bis(benzyloxycarbonyl)guanidino)benzoate (3.9 g,
75%). To a pressure bottle was charged 20% palladium hydroxide on
carbon (2 g) followed by a solution of t-butyl
4-(2,3bis(benzyloxycarbonyl)guanidine)benzoate (3.9 g, 7.7 mmol) in
EtOAc (80 mL). The mixture was stirred under hydrogen at 50 psi at
room temperature overnight. The solution was filtered through
Celite.RTM. and the filtrate evaporated in vacuo to provide t-butyl
guanidinobenzoate (1.8 g, 100%). To the guanidine (855 mg, 3.6
mmol) in EtOAc (50 mL) was add 2M HCl in Et.sub.2O (1.9 mL, 3.8
mM). The solution was concentrated and the precipitate was
collected by filtration, washed with Et.sub.2O and dried in vacuo
to yield (840 mg, 85%) of the HCl salt.
Example 13: Method Q, Method R and Method S for the Synthesis of
Compounds of Formula (I)
##STR00639##
[0946]
4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2--
ylamino]-benzoic acid (I-52)
[0947] Method Q: A solution of
8-chloro-4-dimethylaminomethylene-1-(2-fluoro-phenyl)-3,4-dihydro-benzo[c-
]azepin-5-one (5k) (0.22 g, 0.64 mmol), 4-guanidino-benzoic acid
hydrochloride (0.15 g, 0.70 mmol) and diisopropylethylamine
(i-Pr.sub.2EtN) (0.23 mL, 1.32 mmol) in DMF (2.5 mL) was submitted
to microwave irradiation (300 W) for 300 sec at 250.degree. C. The
mixture was cooled and then poured into H.sub.2O (100 mL). While
stirring, 1N HCl was added dropwise to pH=3 followed by EtOAc (50
mL). The resulting precipitate was collected by filtration and
dried under vacuum to yield I-52 as a tan solid (0.13 g, 47%).
4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yla-
mino]-benzoic acid (I-135)
[0948] Method R:
8-Chloro-4-dimethylaminomethylene-1-(2,6-difluoro-phenyl)-3,4-dihydro-ben-
zo[c]azepin-5-one (5aa) (2.6 g, 7.1 mmol), 4-guanidino-benzoic acid
hydrochloride (1.7 g, 7.8 mmol) and K.sub.2CO.sub.3.1.5H.sub.2O
(2.6 g, 15.6 mmol) in EtOH (50 mL) were refluxed for 14 h. The
mixture was cooled and then poured into H.sub.2O (400 mL). While
stirring, 1N HCl was added dropwise to pH=3. EtOAc (400 mL) was
then added and the organic portion was washed with H.sub.2O
(2.times.100 mL), dried over Na.sub.2SO.sub.4 and concentrated to
dryness in vacuo. The residue was suspended in CH.sub.2Cl.sub.2 and
filtered. The solids were dissolved in EtOAc, filtered through
silica gel, concentrated to dryness in vacuo and dried under vacuum
to yield I-135 as a white solid (1.4 g, 42%).
[0949]
4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepi-
n-2-ylamino]-benzoic acid (I-135) (1.5 g, 2.95 mol) was added to a
solution of ethanol (8.86 mL) and water (1.2 mL), and the mixture
was heated to 50.degree. C. An aqueous NaOH solution (0.02458 g/mL)
was added to a target solution pH of 11.6. Additional water was
added to a total of 4.26 mL/g of free acid. The resultant slurry
was heated to 70.degree. C. and rapidly filtered, maintaining a
solution temperature of 65-70.degree. C. Warm ethanol (9.15 mL,
7.21 g) was added, and the solution cooled to 65.degree. C. Seed
crystals of the sodium salt of I-135 (7.1 mg, 0.014 mol) were added
as a slurry in 10% (wt) solution of 75:25 ethanol: water. The
mixture was maintained at 65.degree. C. for one hour, and then was
cooled to 35.degree. C. at a rate of 12.degree. C./hour. At
35.degree. C., a second addition of ethanol (4.72 g, 5.98 mL) was
performed. The mixture was cooled to 0.degree. C. at a rate of
12.degree. C./hour, and then held at 0.degree. C. for one hour. The
resultant thick slurry was filtered, and the wet filter cake was
rinsed with cold ethanol (5.52 g, 7 mL) to afford a 72% yield of
the sodium salt of I-135, as a hydrate.
2-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yla-
mino]-oxazole-5-carboxylic acid (I-364)
[0950] Method S:
8-Chloro-4-dimethylaminomethylene-1-(2,6-difluorophenyl)-3,4-dihydrobenzo-
[c]azepin-5-one (5aa) (3.6 g, 10 mmol), guanidine hydrochloride
(1.06 g, 11 mmol), potassium carbonate (4.6 g, 33 mmol), and
ethanol (100 mL) were combined in a 100-mL round-bottomed flask and
stirred at reflux for 3 hours. The reaction mixture was poured into
500 mL water with stirring. The mixture was extracted with ethyl
acetate (4.times.200 mL). The organic extracts were combined,
washed with saline, dried (Na.sub.2SO.sub.4), filtered, and
evaporated to leave a brown solid. The solid was stirred with
diethyl ether, filtered, washed with ether, then dried in vacuo to
provide
9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl
amine (3.16 g, 89%) as a light brown solid MS m/z=357 (M+H). The
amine (2.0 g, 5.6 mmol), diiodomethane (7.7 g, 28.6 mmol), copper
(I) iodide (1.1 g, 5.6 mmol), dry tetrahydrofuran (40 mL), and
isoamyl nitrite (2.0 g, 16.8 mmol) were combined in a
round-bottomed flask and stirred at reflux for 1 hour. The dark
purple solution was cooled to room temperature and then transferred
to a separatory funnel containing 1N HCl (250 mL) and ethyl acetate
(150 mL). The organic layer was separated and the aqueous layer was
extracted with ethyl acetate (100 mL). The organic extracts were
combined, washed with ammonium hydroxide (3%), saturated ammonium
chloride, and saturated saline, and then dried (Na.sub.2SO.sub.4),
filtered, and concentrated to leave a dark oil. Purification by
column chromatography (silica gel, CH.sub.2Cl.sub.2 to 10% ethyl
acetate in CH.sub.2Cl.sub.2) afforded
9-Chloro-7-(2,6-difluoro-phenyl)-2-iodo-5H-benzo[c]pyrimido[4,5-e]azepine
as a pale yellow solid (1.3 g, 50%) MS m/z=468 (M+H).
[0951] A mixture of
9-Chloro-7-(2,6-difluoro-phenyl)-2-iodo-5H-benzo[c]pyrimido[4,5-e]azepine
(200 mg, 0.43 mmol), ethyl 2-aminooxazole-5-carboxylate (81.2 mg,
0.52 mmol), tris(dibenzylideneacetone)dipalladium(0)
(Pd.sub.2(dba).sub.3) (935 mg, 0.034 mmol), Xantphos (30 mg, 0.052
mmol), powdered K.sub.3PO.sub.4 (183 mg, 0.86 mmol), and degassed
toluene were submitted to microwave irradiation (300 W) for 20
minutes at 145.degree. C. The mixture was cooled to room
temperature and then evaporated to leave a brown solid which was
purified by column chromatography (silica gel, CH.sub.2Cl.sub.2 to
50% diethyl ether in CH.sub.2Cl.sub.2) to yield
2-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
amino]-oxazole-5-carboxylic acid ethyl ester as a yellow powder
(103 mg, 48%) MS m/z=496 (M+H).
2-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
amino]-oxazole-5-carboxylic acid ethyl ester (91 mg, 0.18 mmol),
methanol (1 mL), tetrahydrofuran (3 mL), and 1N LiOH (3.7 mL, 3.7
mmol) were stirred at room temperature for 3 hours. Water (50 mL)
was added with stirring, and the resulting clear yellow solution
was acidified by slowly adding 1N HCl. A yellow precipitate formed.
Diethyl ether (10 mL) was added and the precipitate was collected
by filtration, washed with water, diethyl ether and then dried in
vacuo to yield I-364 as a yellow powder (78 mg, 93% yield) MS
m/z=468 (M+H).
Example 14: Method T for the Synthesis of Compounds of Formula
(I)
##STR00640##
[0952]
{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone (I-9)
[0953] 1-Methyl-piperazine (0.03 mL, 0.3 mmole) was added to a
solution of I-52 (0.1 g, 0.2 mmole), TBTU (0.08 g, 0.2 mmole) and
Et.sub.3N (0.06 mL, 0.4 mmole) in DMF (5 mL). The solution was
allowed to stir for 30 min and then diluted with 0.1 N NaOH (50 mL)
and EtOAc (50 mL). The organic portion was separated, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The resulting residue
was purified by column chromatography (Silica Gel,
CH.sub.2C.sub.1-2:MeOH:NH.sub.4OH, 94:5:1) to yield I-9 (0.07 g,
47%).
Example 15: Method U for the Synthesis of Compounds of Formula
(I)
##STR00641##
[0954]
4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepi-
n-2-ylamino]-N-[(3-dimethylamino-pyrrolidin-1-yl)-imino-methyl]-benzamide
(I-237)
[0955] A mixture of I-135 (4.8 g, 10 mmol) and DMF (100 mL) was
stirred and fluoro-N,N,N',N'-tetramethylformamidinium
hexafluorophosphate (2.9 g, 11 mmol) was added in one portion,
followed by diisopropylethylamine (3.9 g, 30 mmol). The mixture was
stirred at room temperature for 10 minutes.
2-Methyl-2-thiopseudourea sulfate (3.2 g, 11 mmol) was then added
as a solid and the reaction mixture was stirred at room temperature
overnight. The reaction was quenched into saline (500 mL) and the
off-white precipitate was collected by filtration, washed with
water, and dried in vacuo to yield
1-{4-[9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-
-ylamino]-benzoyl}-2-methyl-isothiourea as a pale yellow solid
(5.81 g, 100%) MS m/z=549 (M+H).
[0956] A solution of the benzoyl-methylisothiourea (250 mg, 0.5
mmol), 3-dimethylaminopyrrolidine (58 mg, 0.5 mmol), triethylamine
(50 mg, 0.5 mmol), and toluene (10 mL) was stirred at reflux for 8
hours. The volatiles were then removed in vacuo and the brown
residue was purified by column chromatography (silica gel, 1% 7N
NH.sub.3 in MeOH/CH.sub.2Cl.sub.2 to 5% NH.sub.3 in
MeOH/CH.sub.2Cl.sub.2) to yield I-237 as a yellow solid (154 mg,
54%) MS m/z=615 (M+H).
Example 16: Method V for the Synthesis of Compounds of Formula
(I)
##STR00642##
[0957]
[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin--
2-yl]-{4-[(3,5-dimethyl-piperazin-1-yl)-imino-methyl]-phenyl}-amine
(I-251)
[0958] Anhydrous HCl gas was added to a stirred suspension of I-236
(1.9 g, 4.4 mmol) in absolute ethanol (75 mL) at 0.degree. C. until
a homogeneous solution resulted. The solution was allowed to warm
to room temperature and sit for three days. Diethyl ether (100 mL)
was added and the resulting precipitate collected by filtration,
washed with diethyl ether, and dried in vacuo to yield
4-[9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
amino]-benzimidic acid ethyl ester HCl salt as a bright yellow
powder (2.4 g, 94%) MS m/z=504 (M+H).
[0959] A mixture of the ethyl benzimidate (100 mg, 0.17 mmol),
2,6-dimethylpiperazine (200 mg, 8.8 mmol), and absolute ethanol (1
mL) was submitted to microwave irradiation (300 W) for 7.5 minutes
at 120.degree. C. The reaction solution was cooled to room
temperature and slowly poured into a stirring saline solution (10
mL). The resulting precipitate was collected and purified by column
chromatography (silica gel, 0.25% NH.sub.4OH/2% MeOH/97.75%
CH.sub.2C.sub.1-2 to 2.5% NH.sub.4OH/20% MeOH/77.5%
CH.sub.2Cl.sub.2) to yield I-251 as a pale yellow solid (30 mg,
30%).
Example 17: Method W for the Synthesis of Compounds of Formula
(I)
##STR00643##
[0960] 4-Methyl-piperazine-1-carboxylic acid
{4-[9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-y-
lamino]-phenyl}-amide (I-280)
[0961] A mixture of
[9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]--
(4-nitro-phenyl)-amine (I-212,500 mg, 1.05 mmol), stannous chloride
dihydrate (1.42 g, 6.3 mmol) and ethyl acetate (15 mL) was refluxed
for 28 hours, then cooled to room temperature and allowed to sit
overnight. The mustard-yellow reaction mixture was poured onto
.about.50 g cracked ice with stirring, and sat. NaHCO.sub.3
solution was added to adjust the pH to 8. The mixture was extracted
with ethyl acetate (3.times.100 mL). The extracts were combined,
dried (Na.sub.2SO.sub.4), filtered and evaporated in vacuo to
provide
N-[9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]-benzene-1,4-diamine as an orange/yellow solid (500 mg, 100%) MS
m/z=448 (M+H). A solution of this product (50 mg, 0.1 mmol),
4-methylpiperazine-1-carbonylchloride (89 mg, 0.6 mmol),
diisopropylethylamine (142 mg, 1.1 mmol), in dioxane (0.5 mL) was
submitted to microwave irradiation (300 W) for 60 minutes at
160.degree. C. The reaction solution was cooled to room temperature
and slowly poured into a stirring saline solution (10 mL). The
resulting precipitate was collected by filtration, washed with
water and purified by RP-HPLC (C.sub.18, 0 to 100% CH.sub.3CN in
0.1% aqueous HCO.sub.2H) to yield I-280 as a pale yellow solid (6
mg, 10%) MS m/z=574 (M+H).
Example 18: Method X for the Synthesis of Compounds of Formula
(I)
##STR00644##
[0962]
4-[(7-{2-[(2-aminoethyl)amino]-6-fluorophenyl}-9-chloro-5H-pyrimido-
[5,4-d][2]benzazepin-2-yl)amino]-N-methylbenzamide (I-340)
[0963] A solution of I-334 (49 mg, 0.1 mmol) in ethylene diamine
(200 .mu.L) was submitted to microwave irradiation (300 W) for 20
minutes at 140.degree. C. The reaction solution was cooled to room
temperature and slowly poured into a stirring saline solution (10
mL). The resulting precipitate was collected by filtration, washed
with water and purified by column chromatography (silica gel, 1%
NH.sub.4OH/2% MeOH/97% CH.sub.2Cl.sub.2 to 2.5% NH.sub.4OH/20%
MeOH/77.5% CH.sub.2Cl.sub.2) to yield I-340 as a pale yellow solid
(46 mg, 87%) MS m/z=530 (M+H).
[0964] Certain exemplary compounds of the invention were prepared
by methods Q through X, employing procedures analogous to those
described above for I-52, I-135, I-236, I-237, I-280, and I-340.
HRMS data were collected on a Sciex Qstar.RTM. time of flight mass
spectrometer coupled to an Agilent HPLC. Experimentally determined
(M+H).sup.+ for certain exemplary compounds are presented in Table
5, and were within 10 ppm error of calculated (M+H).sup.+.
Example 19: Method Y for the Synthesis of Compounds of the Formula
(I)
##STR00645##
[0965]
[9-Chloro-7-(2-fluoro-phenyl)-6,7-dihydro-5H-benzo[c]pyrimido[4,5-e-
]azepin-2-yl]-(3,4-dimethoxy-phenyl)-amine (I-72)
[0966]
[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl-
]-(3,4-dimethoxy-phenyl)-amine (I-71, 49 mg, 0.10 mmol) was
dissolved in dichloromethane (1.8 mL). Acetic acid (0.43 mL) was
added and the solution was stored and cooled to 0.degree. C. Zinc
dust (20 mg, 0.31 mmol) was then added and the mixture was stirred
at 0.degree. C. for 1 hour and then allowed to warm to room
temperature and stir for 4 hours. Additional zinc dust (10 mg, 0.15
mmol) and acetic acid (0.22 mL) was added and the mixture was
stirred at room temperature for 20 hours. The reaction mixture was
diluted with dichloromethane. The organic layer was separated and
washed with 1N NaOH, brine and then dried over magnesium sulfate,
filtered and concentrated in vacuo. The yellow powder was purified
by column chromatography (silica gel, ethyl acetate) to afford
[9-Chloro-7-(2-fluoro-phenyl)-6,7-dihydro-5H-benzo[c]pyrimido[4,5-e]azepi-
n-2-yl]-(3,4-dimethoxy-phenyl)-amine (I-72) as an orange solid (32
mg, 65%): MS m/z=477.
Example 20: Method Z for the Synthesis of Compounds of the Formula
(I)
##STR00646##
[0968]
4-[9-Chloro-7-(2,6-difluoro-phenyl)-7H-benzo[c]pyrimido[4,5-e]azepi-
n-2-ylamino]-benzoic acid (I-387). To a solution of I-135 (1.0 g,
2.1 mmol) in THF (20 mL) was added potassium tert-butoxide (1M in
THF, 21 mmol). The solution was allowed to stir for 1 hr and then
the pH was adjusted to 3 with 1N HCl. The solution was then diluted
with water (100 mL) and extracted with EtOAc (3.times.50 mL). The
organic portion was dried (Na.sub.2SO.sub.4), concentrated in vacuo
and the resulting brown oil purified by RP-HPLC (08, 0 to 100%
CH.sub.3CN in water containing 0.1% formic acid) to provide, after
lyophilization, I-387 (0.3 g, 30%).
TABLE-US-00005 TABLE 5 High Resolution Mass Spectra of Exemplary
Compounds of Formula (A) Compound HRMS I-1: 515.1739 I-2: 515.1775
I-3: 529.1881 I-4: 529.1889 I-5: 543.2054 I-6: 543.2066 I-7:
557.2233 I-8: 527.1769 I-9: 541.1910 I-10: 557.1613 I-11: 537.2175
I-12: 553.2114 I-13: 541.1881 I-14: 521.2463 I-15: 555.2072 I-16:
541.1897 I-17: 541.1908 I-18: 569.2207 I-19: 598.2473 I-20:
614.2190 I-21: 594.2742 I-22: 610.2708 I-23: 598.2503 I-24:
578.3039 I-25: 612.2655 I-26: 528.1619 I-27: 546.1722 I-28:
544.1313 I-29: 571.2018 I-30: 587.1709 I-31: 567.2256 I-32:
597.2367 I-33: 571.2046 I-34: 603.1674 I-35: 432.0783 I-36:
483.0332 I-37: 445.1213 I-38: 459.1367 I-39: 445.1213 I-40:
445.1215 I-41: 449.0731 I-42: 465.0443 I-43: 449.0728 I-44:
449.0727 I-45: 447.0789 I-46: 500.1630 I-47: 513.1947 I-48:
506.1558 I-49: 440.1073 I-50: 460.0966 I-51: 425.1431 I-52:
459.1014 I-53: 475.0752 I-54: 455.1261 I-55: 471.1210 I-56:
459.1027 I-57: 443.1332 I-58: 439.1550 I-59: 443.1286 I-60:
459.1016 I-61: 503.0516 I-62: 455.1496 I-63: 474.0871 I-64:
474.0879 I-65: 489.0889 I-66: 488.1034 I-67: 495.0690 I-68:
494.0832 I-69: 591.0810 I-70: 547.0605 I-71: 475.1339 I-72:
477.1491 I-73: 491.1031 I-74: 471.1579 I-75: 455.1873 I-76:
483.2202 I-77: 459.1602 I-78: 519.0851 I-79: 509.1604 I-80:
455.1873 I-81: 471.1830 I-82: 455.1872 I-83: 473.1168 I-84:
463.1152 I-85: 475.1000 I-86: 491.0677 I-87: 483.0331 I-88:
491.1035 I-89: 443.1442 I-90: 477.093 I-91: 477.0928 I-92: 551.2557
I-93: 501.1302 I-94: 542.2212 I-95: 477.0929 I-96: 477.0931 I-97:
541.1928 I-98: 555.2058 I-99: 555.208 I-100: 501.134 I-101:
541.1905 I-102: 527.1755 I-103: 491.1094 I-104: 477.1084 I-105:
495.0789 I-106: 508.105 I-107: 486.1508 I-108: 574.1296 I-109:
489.1484 I-110: 555.2063 I-111: 556.1545 I-112: 541.1925 I-113:
483.1249 I-114: 472.1352 I-115: 477.0961 I-116: 529.1913 I-117:
530.1387 I-118: 585.217 I-119: 489.1156 I-120: 473.1179 I-121:
460.0964 I-122: 607.1699 I-123: 493.0631 I-124: 473.1161 I-128:
569.221 I-129: 515.1759 I-130: 529.1927 I-131: 529.1929 I-132:
485.1637 I-134: 493.0633 I-135: 477.0955 I-136: 477.0929 I-137:
455.1529 I-138: 471.1842 I-139: 509.0987 I-140: 493.0648 I-141:
489.1129 I-142: 501.1594 I-143: 441.1137 I-144: 535.0517 I-145:
554.2076 I-146: 459.1021 I-147: 552.1697 I-148: 551.2548 I-150:
563.1742 I-151: 563.175 I-152: 457.1424 I-153: 439.1575 I-154:
441.1735 I-155: 471.1229 I-156: 471.1243 I-157: 598.2497 I-158:
571.2015 I-159: 541.1905 I-160: 577.1898 I-161: 563.1744 I-162:
459.1019 I-163: 541.1911 I-164: 604.2055 I-165: 654.2409 I-166:
621.1838 I-167: 661.2162 I-168: 599.2003 I-169: 647.1998 I-170:
626.2448 I-171: 624.2685 I-172: 577.1576 I-173: 605.2002 I-174:
493.0656 I-175: 573.1983 I-176: 573.1986 I-177: 585.2192 I-178:
585.2203 I-179: 571.2037 I-180: 559.1851 I-181: 652.2994 I-182:
638.2822 I-183: 587.2117 I-184: 559.1845 I-185: 575.2131 I-186:
599.2348 I-187: 654.3136 I-188: 638.2832 I-189: 640.2628 I-190:
489.1142 I-191: 559.1845 I-192: 513.1625 I-193: 555.2103 I-194:
559.1843 I-195: 545.1683 I-196: 545.1693 I-197: 559.1814 I-198:
561.2004 I-199: 571.2047 I-200: 465.1514 I-201: 647.2340 I-202:
518.1331 I-203: 477.0943 I-204: 559.1814 I-205: 587.2156 I-206:
573.2001 I-207: 503.1197 I-208: 640.2953 I-209: 626.2832 I-210:
612.2649 I-211: 638.2782 I-212: 478.0905 I-213: 658.2264 I-214:
575.1556 I-215: 607.1598 I-216: 593.1427 I-217: 448.1154 I-218:
525.0715 I-219: 589.1588 I-220: 573.1994 I-221: 559.1807 I-222:
573.1989 I-223: 629.2331 I-224: 587.1893 I-225: 587.2358 I-226:
587.2364 I-227: 571.2031 I-228: 585.2198 I-229: 599.2352 I-230:
527.1765 I-231: 585.2195 I-232: 571.2033 I-233: 571.2028 I-234:
545.1676 I-235: 557.1849 I-236: 458.0994 I-237: 615.2217 I-238:
615.2214 I-239: 559.1851 I-240: 557.1880 I-241: 571.2035 I-242:
585.2169 I-243: 557.1893 I-244: 586.2295 I-245: 490.1365 I-246:
547.1831 I-247: 561.2004 I-248: 603.1714 I-249: 469.1317
I-250: 572.2137 I-251: 572.2140 I-252: 533.1689 I-253: 573.1966
I-254: 559.2009 I-255: 573.2187 I-256: 455.1499 I-257: 547.1803
I-258: 511.0542 I-259: 601.2042 I-260: 547.1813 I-261: 573.2173
I-262: 571.2009 I-263: 585.2164 I-264: 559.2041 I-265: 545.1858
I-266: 589.1555 I-267: 558.1969 I-268: 558.1982 I-269: 621.1760
I-270: 529.1733 I-271: 526.1345 I-272: 496.1588 I-273: 507.0622
I-274: 521.0448 I-275: 536.2267 I-276: 482.1776 I-277: 509.0967
I-278: 531.1524 I-279: 442.1091 I-280: 574.1943 I-281: 593.1419
I-282: 607.1584 I-283: 581.1453 I-284: 544.1826 I-285: 531.1529
I-286: 543.1704 I-287: 591.1867 I-288: 605.2016 I-289: 577.1710
I-290: 591.1900 I-291: 579.1263 I-292: 593.1439 I-293: 587.2139
I-294: 617.1853 I-295: 603.1746 I-296: 563.1593 I-297: 577.1714
I-298: 524.1949 I-299: 510.1813 I-300: 605.1879 I-301: 460.0978
I-302: 537.2438 I-303: 539.2562 I-304: 542.1863 I-305: 528.1737
I-306: 545.1308 I-307: 533.1642 I-308: 533.1680 I-309: 605.1894
I-310: 602.1863 I-311: 581.2652 I-312: 551.2576 I-313: 621.1731
I-314: 573.1610 I-315: 524.1979 I-316: 538.2110 I-317: 588.1727
I-318: 579.1300 I-319: 559.1850 I-320: 545.1876 I-321: 573.1971
I-322: 597.2403 I-323: 575.1523 I-324: 589.1704 I-325: 589.1678
I-326: 589.1680 I-327: 575.1517 I-328: 514.1995 I-329: 553.2092
I-330: 567.2287 I-331: 567.2301 I-332: 553.2124 I-333: 567.2288
I-334: 490.1270 I-335: 559.2007 I-336: 572.2352 I-337: 475.1144
I-338: 486.1287 I-339: 531.1727 I-340: 530.1895 I-341: 616.2019
I-342: 598.2501 I-343: 514.1631 I-344: 558.9984 I-345: 558.2185
I-346: 572.2341 I-347: 558.2203 I-348: 570.2169 I-349: 525.2404
I-350: 602.1911 I-351: 561.1395 I-352: 454.0727 I-353: 473.1430
I-354: 501.1626 I-355: 497.0780 I-356: 473.1106 I-357: 464.1012
I-358: 504.1412 I-359: 532.1712 I-360: 484.0467 I-361: 512.0783
I-362: 580.1487 I-363: 496.0996 I-364: 468.0686 I-365: 566.1355
I-366: 559.1852 I-367: 566.1333 I-368: 468.0684 I-369: 564.1728
I-370: 550.1549 I-371: 491.1096 I-372: 518.1921 I-373: 490.1603
I-374: 564.1736 I-375: 550.1579 I-376: 596.2613 I-377: 486.1401
I-378: 630.2207 I-379: 559.1829 I-380: 573.1978 I-381: 616.2039
I-382: 587.2132 I-383: 599.2158 I-384: 585.1999 I-385: 492.106
I-386: 492.1055 I-387: 477.095 I-388: 477.0948 I-389: 602.1900
I-390: 588.1738 I-301: 573.1996 I-392: 599.2152 I-393: 587.2156
I-394: 437.1107 I-395: 511.0564 I-396: 650.1655 I-397: 664.1835
Example 21: Expression and Purification of Aurora Kinase
Enzymes
Aurora A Enzyme Expression and Purification
[0969] Recombinant mouse Aurora A with an amino-terminus
hexahistidine tag (His-Aurora A) was expressed using a standard
baculovirus vector and insect cell expression system
(Bac-to-Bac.RTM., Invitrogen).
[0970] Soluble, recombinant mouse Aurora A was purified from insect
cells using Ni-NTA agarose (Qiagen) as described by the
manufacturer and further purified over an S75 size exclusion column
(Amersham Pharmacia Biotech).
Aurora B Enzyme Expression and Purification
[0971] Recombinant mouse Aurora B with an amino-terminus
hexahistidine tag (His-Aurora B) was expressed using a standard
baculovirus vector and insect cell expression system
(Bac-to-Bac.RTM., Invitrogen).
[0972] Soluble, recombinant mouse Aurora B was purified from insect
cells using Ni-NTA agarose (Qiagen) as described by the
manufacturer.
Example 22: Aurora Kinase Enzyme Assays
Aurora A DELFIA.RTM. Kinase Assay
[0973] The mouse Aurora A enzymatic reaction totaled 25 .mu.L and
contained 25 mM Tris-HCl (pH 8.5), 2.5 mM MgCl.sub.2, 0.05%
Surfact-AMPS-20, 5 mM Sodium Fluoride, 5 mM DTT, 250 .mu.M ATP, 10
.mu.M peptide substrate (Biotin-.beta.-Ala-QTRRKSTGGKAPR-NH.sub.2),
and 500 .mu.M recombinant murine Aurora A enzyme. The enzymatic
reaction mixture, with and without Aurora inhibitors, was incubated
for 15 minutes at room temperature before termination with 100
.mu.L of stop buffer (1% BSA, 0.05% Surfact-AMPS-20, and 100 mM
EDTA). A total of 100 .mu.L of the enzyme reaction mixture was
transferred to wells of a Neutravidin-coated 96-well plate (Pierce)
and incubated at room temperature for 30 minutes. The wells were
washed with wash buffer (25 mM Tris, 150 mM sodium chloride, and
0.1% Tween 20) and incubated for 1 hour with 100 .mu.L of antibody
reaction mixture containing 1% BSA, 0.05% Surfact-AMPS-20,
anti-phospho-PKA rabbit polyclonal antibody (1:2000, New England
Biolabs), and europium labeled anti-rabbit IgG (1:2000, Perkin
Elmer). The wells were washed and then the bound europium was
liberated using 100 .mu.L of Enhancement Solution (Perkin Elmer).
Quantification of europium was done using a Wallac.TM. EnVision
(Perkin Elmer).
[0974] Compounds I-1 to I-12, I-14 to I-32, I-34, I-37, I-39, I-45,
I-52 to I-55, I-57 to I-59.1-63 to I-69, I-73 to I-75, I-80, I-85,
I-86, I-91, I-93 to I-96, I-98 to I-103, I-109, I-111 to I-113,
I-117, I-118, I-120, I-126, I-128 to I-131, I-134 to I-138, I-142,
I-145, I-147 to I-151, I-157, I-160 to [0975] I-163, I-165, I-166,
I-168 to I-171, I-173 to I-199, I-202 to I-211, I-213 to I-217,
I-219 to I-235, I-237 to I-301, I-304 to I-310, I-313 to I-327,
I-329 to I-335, I-337 to I-341, I-343, I-350 to I-355, I-357 to
I-360, and I-362 to I-376 exhibited IC.sub.50 values less than or
equal to 1.0 .mu.M in this assay.
[0976] Compounds I-1 to I-12, I-14 to I-22, I-24 to I-32, I-52 to
I-55, I-57, I-58, I-63, I-65 to I-67, I-69, I-73, I-86, I-93, I-98
to I-100, I-102, I-103, I-111 to I-113, I-117, I-128, I-130, I-135,
I-145, I-147, I-148, I-160, I-161, I-163, I-171, I-174 to I-199,
I-204 to I-206, I-208 to I-211, I-213 to I-217.1-219 to I-229,
I-231 to I-235, I-237 to I-244, I-246 to I-257, I-259 to I-270,
I-272, I-274, I-277, I-278, I-280 to I-301, I-304 to I-310, I-313
to I-319, I-321, I-323 to I-327, I-329 to I-334, I-337, I-338,
I-341, I-343, I-350, I-351, I-353, I-355, I-357, I-359, I-362,
I-365 to I-368, and I-371 to I-376 exhibited IC.sub.50 values less
than or equal to 100 nM in this assay.
Aurora B DELFIA.RTM. Kinase Assay
[0977] The mouse Aurora B enzymatic reaction totaling 25 .mu.L
contained 25 mM Tris-HCl (pH 8.5), 2.5 mM MgCl.sub.2, 0.025%
Surfact-AMPS-20 (Pierce), 1% Glycerol, 1 mM DTT, 1 mM ATP, 3 .mu.M
peptide substrate (Biotin-.beta.-Ala-QTRRKSTGGKAPR-NH.sub.2), and
20 nM recombinant murine Aurora B enzyme. The enzymatic reaction
mixture, with or without Aurora inhibitors, was incubated for 3
hours at room temperature before termination with 100 .mu.L of stop
buffer (1% BSA, 0.05% Surfact-AMPS-20, and 100 mM EDTA). A total of
100 .mu.L of the enzyme reaction mixture was transferred to wells
of a Neutravidin-coated 96-well plate (Pierce) and incubated at
room temperature for 30 minutes. The wells were washed with wash
buffer (25 mM Tris, 150 mM sodium chloride, and 0.1% Tween 20) and
incubated for 1 hour with 100 .mu.L of antibody reaction mix
containing 1% BSA, 0.05% Surfact-AMPS-20, anti-phospho-PKA rabbit
polyclonal antibody (1:2000, New England Biolabs), and europium
labeled anti-rabbit IgG (1:2000, Perkin Elmer). The wells were
washed and then the bound europium was liberated using 100 .mu.L of
Enhancement Solution (Perkin Elmer). Quantification of europium was
done using a Wallac.TM. EnVision (Perkin Elmer).
Example 23: Cellular Assay
Aurora Phosphorylation Assays
[0978] Inhibition of Aurora A or Aurora B activity in whole cell
systems can be assessed by determination of decreased
phosphorylation of Aurora substrates. For example, determining
decreased phosphorylation of histone H.sub.3 on Serine 10, an
Aurora B substrate can be used to measure inhibition of Aurora B
activity in a whole cell system. Alternatively, any known Aurora B
substrate can be used in similar assay methods to assess inhibition
of Aurora B activity. Similarly, Aurora A inhibition can be
determined using analogous methods and known Aurora A substrates
for detection.
[0979] In a specific example, HeLa cells were seeded in a 96-well
cell culture plate (10.times.10.sup.3 cells/well) and incubated
overnight at 37.degree. C. Cells were incubated with Aurora
inhibitors for 1 hour at 37.degree. C., fixed with 4%
paraformaldehyde for 10 minutes and then permeabilized with 0.5%
TritonX-100 in PBS. Cells were incubated with mouse anti-pHisH3
(1:120, Cell Signaling Technologies) and rabbit anti-mitotic marker
(1:120, Millennium Pharmaceuticals Inc.) antibodies for 1 hour at
room temperature. After washing with PBS the cells were stained
with anti-rabbit IgG Alexa 488 (1:180, Molecular Probes) and
anti-mouse IgG Alexa 594 (1:180) for 1 hour at room temperature.
DNA was then stained with Hoechst solution (2 .mu.g/ml). The
percentage of pHisH3 and anti-mitotic positive cells were
quantified using Discovery I and MetaMorph (Universal Imaging
Corp.). Aurora B inhibition was determined by calculating the
decrease of pHisH3 positive cells.
Anti-Proliferation Assays
[0980] HCT-116 (1000) or other tumor cells in 100 .mu.L of
appropriate cell culture medium (McCoy's 5A for HCT-116,
Invitrogen) supplemented with 10% fetal bovine serum (Invitrogen)
was seeded in wells of a 96-well cell culture plate and incubated
overnight at 37.degree. C. Aurora inhibitors were added to the
wells and the plates were incubated for 96 hours at 37.degree. C.
MTT or WST reagent (10 .mu.L, Roche) was added to each well and
incubated for 4 hours at 37.degree. C. as described by the
manufacturer. For MTT the metabolized dye was solubilized overnight
according to manufacturer's instructions (Roche). The optical
density for each well was read at 595 nm (primary) and 690 nm
(reference) for the MTT and 450 nm for the WST using a
spectrophotometer (Molecular Devices). For the MTT the reference
optical density values were subtracted from the values of the
primary wavelength. Percent inhibition was calculated using the
values from a DMSO control set to 100%.
Example 24: In Vivo Assays
In Vivo Tumor Efficacy Model
[0981] HCT-116 (1.times.10.sup.6) or other tumor cells in 100 .mu.L
of phosphate buffered saline were aseptically injected into the
subcutaneous space in the right dorsal flank of female CD-1 nude
mice (age 5-8 weeks, Charles River) using a 23-ga needle. Beginning
at day 7 after inoculation tumors were measured twice weekly using
a vernier caliper. Tumor volumes were calculated using standard
procedures (0.5.times.(length*width.sup.2)). When the tumors
reached a volume of approximately 200 mm.sup.3 mice were injected
i.v. in the tail vein with Aurora inhibitors (100 .mu.L) at various
doses and schedules. All control groups received vehicle alone.
Tumor size and body weight was measure twice a week and the study
was terminated when the control tumors reached approximately 2000
mm.sup.3.
[0982] 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.
[0983] 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.
* * * * *