Macroheterocylic compounds useful as kinase inhibitors

Details Macroheterocylic compounds useful as kinase inhibitors Macroheterocylic compounds useful as kinase inhibitors

2001-12-06

2004-12-07

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S403000, C514S410000, C540S469000, C540S472000

Reexamination Certificate

active

06828327

ABSTRACT:

FIELD OF THE INVENTION
This invention is directed to certain novel macroheterocyclic compounds, methods for producing such compounds and methods for treating or ameliorating a kinase or dual-kinase mediated disorder. More particularly, this invention is directed to macroheterocyclic 1H-indole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, and 1H-indazole compounds useful as selective kinase or dual-kinase inhibitors, methods for producing such compounds and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,624,949 to Heath, Jr., et. al., describes bis-indolemaleimide derivatives of the formula:
wherein W is —O—, —S—, —SO—, —SO
2
—, —CO—, C
2
-C
6
alkylene, substituted alkylene, C
2
-C
6
alkenylene, -aryl-, -aryl(CH
2
)
m
O—, -heterocycle-, -heterocycle-(CH
2
)
m
O—, -fused bicyclic-, -fused bicyclic-(CH
2
)
m
O—, —NR
3
—, —NOR
3
—, —CONH— or —NHCO—; X and Y are independently C
1
-C
4
alkylene, substituted alkylene, or together, X, Y and W combine to form (CH
2
)
n
—AA—; R
1
is independently hydrogen, halo, C
1
-C
4
alkyl, hydroxy, C
1
-C
4
alkoxy, haloalkyl, nitro, NR
4
R
5
or —NHCO(C
1
-C
4
)alkyl; R
2
is hydrogen, CH
3
CO—, NH
2
or hydroxy; R
3
is hydrogen, (CH
2
)
m
aryl, C
1
-C
4
alkyl, —COO(C
1
-C
4
alkyl), —CONR
4
R
5
, —C(C═NH)NH
2
, —SO(C
1
-C
4
alkyl), —SO
2
(NR
4
R
5
) or —SO
2
(C
1
-C
4
alkyl); R
4
and R
5
are independently hydrogen, C
1
-C
4
alkyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring; AA is an amino acid residue; m is independently 0, 1, 2 or 3; and n is independently 2, 3, 4 or 5 as PKC inhibitors and as selective PKC&bgr;-I and PKC&bgr;-II inhibitors.
It is an object of the present invention to provide macroheterocyclic 1H-indole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, and 1H-indazole compounds useful as a kinase or dual-kinase inhibitor (i.e., a compound capable of inhibiting two or more kinases such as, for example, a kinase selected from protein kinase C or glycogen synthase kinase-3; and, more particularly, a kinase selected from protein kinase C &agr;, protein kinase C &bgr;-II, protein kinase C &ggr; or glycogen synthase kinase-3&bgr;), methods for their production and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.
SUMMARY OF THE INVENTION
The present invention provides a macroheterocyclic compound of Formula (I):
wherein
A and E are independently selected from the group consisting of a hydrogen substituted carbon atom and a nitrogen atom; wherein
is independently selected from the group consisting of 1H-indole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine and 1H-indazole;
Z is selected from O; alternatively, Z is selected from dihydro; wherein each hydrogen atom is attached by a single bond;
R
4
and R
5
are independently selected from C
1-8
alkyl, C
2-8
alkenyl and C
2-8
alkynyl optionally substituted with oxo;
R
2
is selected from the group consisting of —C
1-8
alkyl-, —C
2-8
alkenyl-, —C
2-8
alkynyl-, —O—(C
1-8
)alkyl-O—, —O—(C
2-8
)alkenyl-O—, —O—(C
2-8
)alkynyl-O—, —C(O)—(C
1-8
)alkyl-C(O)— (wherein any of the foregoing alkyl, alkenyl and alkynyl linking groups are straight carbon chains optionally substituted with one to four substituents independently selected from the group consisting of C
1-8
alkyl, C
1-8
alkoxy, C
1-8
alkoxy(C
1-8
)alkyl, carboxyl, carboxyl(C
1-8
)alkyl, —C(O)O—(C
1-8
)alkyl, —C
1-8
alkyl-C(O)O—(C
1-8
)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C
1-4
alkyl), amino(C
1-8
)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C
1-4
alkyl), halogen, (halo)
1-3
(C
1-8
)alkyl, (halo)
1-3
(C
1-8
)alkoxy, hydroxy, hydroxy(C
1-8
)alkyl and oxo; and, wherein any of the foregoing alkyl, alkenyl and alkynyl linking groups are optionally substituted with one to two substituents independently selected from the group consisting of heterocyclyl, aryl, heteroaryl, heterocyclyl(C
1-8
)alkyl, aryl(C
1-8
)alkyl, heteroaryl(C
1-8
)alkyl, spirocycloalkyl and spiroheterocyclyl (wherein any of the foregoing cycloalkyl, heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C
1-8
alkyl, C
1-8
alkoxy, C
1-8
alkoxy(C
1-8
)alkyl, carboxyl, carboxyl(C
1-8
)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C
1-4
alkyl), amino(C
1-8
)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C
1-4
alkyl), halogen, (halo)
1-3
(C
1-8
)alkyl, (halo)
1-3
(C
1-8
)alkoxy, hydroxy and hydroxy(C
1-8
)alkyl; and, wherein any of the foregoing heterocyclyl substituents are optionally substituted with oxo)), cycloalkyl, heterocyclyl, aryl, heteroaryl (wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four substituents independently selected from the group consisting of C
1-8
alkyl, C
1-8
alkoxy, C
1-8
alkoxy(C
1-8
)alkyl, carboxyl, carboxyl(C
1-8
)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C
1-4
alkyl), amino(C
1-8
)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C
1-4
alkyl), halogen, (halo)
1-3
(C
1-8
)alkyl, (halo)
1-3
(C
1-8
)alkoxy, hydroxy and hydroxy(C
1-8
)alkyl; and, wherein heterocyclyl is optionally substituted with oxo), —(O—(CH
2
)
1-6
)
0-5
—O—, —O—(CH
2
)
1-6
—O—(CH
2
)
1-6
—O—, —O—(CH
2
)
1-6
—O—(CH
2
)
1-6
—O—(CH
2
)
1-6
—O—, —(O—(CH
2
)
1-6
)
0-5
—NR
6
—, —O—(CH
2
)
1-6
—NR
6
—(CH
2
)
1-6
—O—, —O—(CH
2
)
1-6
—O—(CH
2
)
1-6
—NR
6
—, —(O—(CH
2
)
1-6
)
0-5
—S—, —O—(CH
2
)
1-6
—S—(CH
2
)
1-6
—O—, —O—(CH
2
)
1-6
—O—(CH
2
)
1-6
—S—, —NR
6
—, —NR
6
—NR
7
—, —NR
6
—(CH
2
)
1-6
—NR
7
—, —NR
6
—(CH
2
)
1-6
—NR
7
—(CH
2
)
1-6
—NR
8
—, —NR
6
—C(O)—, —C(O)—NR
6
—, —C(O)—(CH
2
)
0-6
—NR
6
—(CH
2
)
0-6
—C(O)—, —NR
6
—(CH
2
)
0-6
—C(O)—(CH
2
)
1-6
—C(O)—(CH
2
)
0-6
—NR
7
—, —NR
6
—C(O)—, —C(O)—NR
6
—, —NR
6
—C(NR
7
)—NR
8
—, —O—(CH
2
)
1-6
—NR
6
—(CH
2
)
1-6
—S—, —S—(CH
2
)
1-6
—NR
6
—(CH
2
)
1-6
—O—, —S—(CH
2
)
1-6
—NR
6
—(CH
2
)
1-6
—S—, —NR
6
—(CH
2
)
1-6
—S—(CH
2
)
1-6
—NR
7
— and —SO
2
— (wherein R
6
, R
7
and R
8
are independently selected from the group consisting of hydrogen, C
1-8
alkyl, C
1-8
alkoxy(C
1-8
)alkyl, carboxyl(C
1-8
)alkyl, amino(C
1-8
)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C
1-4
alkyl), hydroxy(C
1-8
)alkyl, heterocyclyl(C
1-8
)alkyl, aryl(C
1-8
)alkyl and heteroaryl(C
1-8
)alkyl (wherein the foregoing heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C
1-8
alkyl, C
1-8
alkoxy, C
1-8
alkoxy(C
1-8
)alkyl, carboxyl, carboxyl(C
1-8
)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C
1-4
alkyl), amino(C
1-8
)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C
1-4
alkyl), halogen, (halo)
1-3
(C
1-8
)alkyl, (halo)
1-3
(C
1-8
)alkoxy, hydroxy and hydroxy(C
1-8
)alkyl; and, wherein heterocyclyl is optionally substituted with oxo));
with the proviso that, if A and E are selected from a hydrogen substituted carbon atom, then R
2
is selected from the group consisting of —C
2-8
alkynyl-, —O—(C
1-8
)alkyl-O—, —O—(C
2-8
)alkenyl-O—, —O—(C
2-8
)alkynyl-O—, —C(O)—(C
1-8
)alkyl-C(O)— (wherein any of the foregoing alkyl, alkenyl and alkynyl linking groups are straight carbon chains optionally substituted with one to four substituents independently selected from the group consisting of C
1-8
alkyl, C
1-8
alkoxy, C

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