U.S. patent application number 10/272651 was filed with the patent office on 2003-05-08 for irreversible inhibitors of tyrosine kinases.
Invention is credited to Bridges, Alexander James.
Application Number | 20030087881 10/272651 |
Document ID | / |
Family ID | 21988531 |
Filed Date | 2003-05-08 |
United States Patent
Application |
20030087881 |
Kind Code |
A1 |
Bridges, Alexander James |
May 8, 2003 |
Irreversible inhibitors of tyrosine kinases
Abstract
The present invention provides compounds that are irreversible
inhibitors of tyrosine kinases. Also provided is a method of
treating cancer, restenosis, atherosclerosis, endometriosis, and
psoriasis and a pharmaceutical composition that comprises a
compound that is an irreversible inhibitor of tyrosine kinases.
Inventors: |
Bridges, Alexander James;
(Saline, MI) |
Correspondence
Address: |
Rosanne Goodman
Warner-Lambert Company
2800 Plymouth Road
Ann Arbor
MI
48105
US
|
Family ID: |
21988531 |
Appl. No.: |
10/272651 |
Filed: |
October 17, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10272651 |
Oct 17, 2002 |
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09656331 |
Sep 6, 2000 |
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09656331 |
Sep 6, 2000 |
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09269647 |
Mar 25, 1999 |
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6153617 |
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09269647 |
Mar 25, 1999 |
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PCT/US98/15592 |
Jul 29, 1998 |
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60054061 |
Jul 29, 1997 |
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Current U.S.
Class: |
514/80 ;
514/266.3; 514/266.4; 544/244; 544/287; 544/293 |
Current CPC
Class: |
C07D 495/04 20130101;
C07D 401/04 20130101; C07D 471/04 20130101; C07D 487/04 20130101;
C07D 403/04 20130101 |
Class at
Publication: |
514/80 ;
514/266.3; 514/266.4; 544/244; 544/287; 544/293 |
International
Class: |
A61K 031/675; A61K
031/517; C07D 239/72 |
Claims
What is claimed is:
1. A compound having the Formula I 51wherein X is -D-E-F and Y is
--SR.sup.4, halogen, --OR.sup.4, --NHR.sup.3 or hydrogen, or X is
--SR.sup.4, halogen, --OR.sup.4, --NHR.sup.3 or hydrogen, and Y is
-D-E-F; 52each R.sup.a is independently hydroxy, amino. N-mono- or
N,N-di-(C.sub.1-C.sub.4) alkylamino, sulfo, or
(C.sub.1-C.sub.4)alkoxy (provided that such groups are not attached
to a ring carbon which is adjacent to an oxy, thio, or --N--), or
R.sup.a is independently carboxy, hydroxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4) alkyl,
amino(C.sub.1-C.sub.4)alkyl, mono-N-- or di-N,N-(C.sub.1-C.sub.4)
alkylamino(C.sub.1-C.sub.4)alkyl, morpholino(C.sub.1-C.sub.4)alkyl,
4-(C.sub.1-C.sub.4)alkyl-piperazin-1-yl(C.sub.1-C.sub.4)alkyl,
carboxy(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxycarbonyl,
sulfo(C.sub.1-C.sub.4)alkyl or (C.sub.1-C.sub.4)alkyl; each R.sup.b
is independently mono-, di-, or trifluoromethyl, halo, nitro,
hydroxy, amino, axido, isothiocyano, (C.sub.1-C.sub.4)alkyl,
phenyl, thienyl, (C.sub.1-C.sub.4)alkoxy, benzyloxy, phenoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.4)alkylenedioxy, cyano, benzoylamino,
trifluoromethylcarbonylamino, (C.sub.1-C.sub.4)alkanoylamin- o,
(C.sub.1-C.sub.4)alkanoyl, N-mono- or
N,N-di-(C.sub.1-C.sub.4)alkylamin- o,
(C.sub.1-C.sub.4)alkylsulfonylamino, trifluoromethylsulfonylamino,
(C.sub.1-C.sub.4)alkylthio, (C.sub.1-C.sub.4)alkylsulfinyl or
(C.sub.1-C.sub.4)alkylsulfonyl, pyrrol-1-yl, piperidin-1-yl or
pyrrolidin-1-yl, said phenyl, benzyloxy, phenoxy, and benzoylamino
optionally monosubstituted with halo, nitro, trifluoromethyl,
hydroxy, or (C.sub.1-C.sub.4)alkyl and said
(C.sub.1-C.sub.4)alkylenedioxy is linked at both ends to adjacent
carbons on the benzene moiety, or R.sup.b is -Z.sup.aR.sup.77; J is
--CH.sub.2--, thio, --N(H)--, or oxy; g is 0, 1, or2; h is 0 to4; k
is 0, 1, or 2; S completes a 5- or 6-membered aromatic or partially
saturated ring that can contain an oxygen or sulfur atom; T is
--CH.sub.2, --N(H)--, thio, or oxy; S.sup.a is --CH.sub.2--, oxy,
or thio; A.sup.1 completes a 7- to 9-membered mono-unsaturated
mono-aza ring; Q.sup.a is a 9- or 10-membered bicyclic heterocyclic
moiety, or a hydrogenated derivative thereof, containing one or two
nitrogen heteroatoms and optionally containing a further heteroatom
selected from nitrogen, oxygen and sulfur, or Q.sup.a is a 9- or
10-membered bicyclic aryl moiety, or a hydrogenated derivative
thereof, which heterocyclic or aryl moiety, or hydrogenated
derivatives thereof, may optionally bear one or two substituents
selected from halogen, hydroxy, oxo, amino, nitro, carbamoyl,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkylamino, di-[(C.sub.1-C.sub.4)alkyl]amino, and
(C.sub.2-C.sub.4)alkanoyl amino; R.sup.1 is hydrogen, halogen, or
C.sub.1-C.sub.6 alkyl; R.sup.2, R.sup.3, and R.sup.4 are
independently hydrogen, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1piperazinyl-
[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n-imidazoyl,
--(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--(CH.sub.2).sub.n--N-hexahydroazep- ine or substituted
C.sub.1-C.sub.6alkyl, wherein the substituents are selected from
--OH, NH.sub.2, or 53A and B are independently hydrogen,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.nOH,
--(CH.sub.2).sub.n--N-piperi- dinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-pipe-
razinyl[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl- , --(CH.sub.2).sub.n--N-pyridyl,
--(CH.sub.2).sub.n-imidazoyl, or --(CH.sub.2).sub.n--N-imidazoyl;
Z.sup.1, Z.sup.2, or Z.sup.3 are independently hydrogen, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6
alkoxy, C.sub.3-C.sub.8 cycloalkoxy, nitro, C.sub.1-C.sub.6
perfluoroalkyl, hydroxy, C.sub.1-C.sub.6 acyloxy, --NH.sub.2,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NH(C.sub.3-C.sub.8 cycloalkyl), --N(C.sub.3-C.sub.8
cycloalkyl).sub.2, hydroxymethyl, C.sub.1-C.sub.6 acyl, cyano,
azido, C.sub.1-C.sub.6 thioalkyl, C.sub.1-C.sub.6 sulfinylalkyl,
C.sub.1-C.sub.6 sulfonylalkyl, C.sub.3-C.sub.8 thiocycloalkyl,
C.sub.3-C.sub.8 sulfinylcycloalkyl, C.sub.3-C.sub.8
sulfonylcycloalkyl, mercapto, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.3-C.sub.8 cycloalkoxycarbonyl, C.sub.2-C.sub.4 alkenyl,
C.sub.4-C.sub.8 cycloalkenyl, or C.sub.2-C.sub.4 alkynyl; Z.sup.a
is a bond, --CH.sub.2--, --S--, SO.sub.2, --NH--, --O--,
--OCH.sub.2--, --S--CH.sub.2--, --SO.sub.2--, or
--CH.sub.2CH.sub.2--; R.sup.77 is phenyl, substituted phenyl, or a
5- to 10-membered optionally substituted heterocyclic aromatic
ring; R.sup.5 is hydrogen, halogen, C.sub.1-C.sub.6 perfluoroalkyl,
1,1-difluoro(C.sub.1-C.sub.6)alkyl, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.n--N-piperidinyl, --(CH.sub.2).sub.n-piperazinyl,
--(CH.sub.2).sub.n-piperazinyl[N.sub.4--(- C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2)n--N-imidazoyl, --(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
54--CH.dbd.CH--(C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.n--N-hexahydroaze- pine,
--(CH.sub.2).sub.nNH.sub.2,--(CH.sub.2).sub.nNH
(C.sub.1-C.sub.6alkyl),
--(CH.sub.2).sub.nN(C.sub.1-C.sub.6alkyl).sub.2,
-1-oxo(C.sub.1-C.sub.6)alkyl, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl,
N--(C.sub.1-C.sub.6)alkylcarbamoyl, phenyl or substituted phenyl,
wherein the substituted phenyl can have from one to three
substituents independently selected from Z.sup.1, Z.sup.2, Z.sup.3
or a monocyclic heteroaryl group, and each C.sub.1-C.sub.6 alkyl
group can be substituted with --OH, --NH.sub.2 or --NAB, where A
and B are as defined above; and n is 1 to 4, and the
pharmaceutically acceptable salts, esters, amides, and prodrugs
thereof.
2. A compound of claim 1 wherein 55and Y is hydrogen, or X is
hydrogen, and Y 56
3. A compound of claim 1 wherein Y is -D-E-F and -D-E-F is 57
4. A compound of claim 1 wherein X is -D-E-F and -D-E-F is 58
5. A compound of claim 3 wherein R.sup.2 is hydrogen.
6. A compound of claim 4 wherein R.sup.2 is hydrogen.
7. A compound of claim 3 wherein R.sup.2 is
--(CH.sub.2).sub.n-morpholino.
8. A compound of claim 4 wherein R.sup.2 is
--(CH.sub.2).sub.n-morpholino.
9. A compound of claim 3 wherein R.sup.5 is carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl or C.sub.1-C.sub.6 alkyl.
10. A compound of claim 1 wherein Y is -D-E-F, and X is
--O--(CH.sub.2).sub.n-morpholino.
11. A compound of claim 1 wherein Y is -D-E-F, and X is
--O--(CH.sub.2).sub.n--N.sub.1-piperazinyl[N.sub.4--(C.sub.1-C.sub.6)alky-
l].
12. A compound of claim I wherein Y is -D-E-F and X is
--O--(CH.sub.2).sub.n-imidazoyl.
13. A compound having the Formula II Q-Z II wherein Q is 59X is
-D-E-F and Y is --SR.sup.4, --OR.sup.4, --NHR.sup.3 or hydrogen, or
X is --SR.sup.4, --OR.sup.4, --NHR.sup.3 or hydrogen, and Y is
-D-E-F; 60each R.sup.a is independently hydroxy, amino, N-mono- or
N,N-di-(C.sub.1-C.sub.4) alkylamino, sulfo, or
(C.sub.1-C.sub.4)alkoxy (provided that such groups are not attached
to a ring carbon which is adjacent to an oxy, thio, or --N--), or
R.sup.a is independently carboxy, hydroxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4) alkyl,
amino(C.sub.1-C.sub.4)alkyl, mono-N-- or di-N,N--(C.sub.1-C.sub.4)
alkylamino(C.sub.1-C.sub.4)alkyl, morpholino(C.sub.1-C.sub.4)alkyl,
4-(C.sub.1-C.sub.4)alkyl-piperazin-1-yl(C.sub.1-4)alkyl,
carboxy(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxycarbonyl,
sulfo(C.sub.1-C.sub.4)alkyl or (C.sub.1-C.sub.4)alkyl; each R.sup.b
is independently mono-, di-, or trifluoromethyl, halo, nitro,
hydroxy, amino, axido, isothiocyano, (C.sub.1-C.sub.4)alkyl,
phenyl, thienyl, (C.sub.1-C.sub.4)alkoxy, benzyloxy, phenoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.4)alkylenedioxy, cyano, benzoylamino,
trifluoromethylcarbonylamino, (C.sub.1-C.sub.4)alkanoylamin- o,
(C.sub.1-C.sub.4)alkanoyl, N-mono- or
N,N-di-(C.sub.1-C.sub.4)alkylamin- o,
(C.sub.1-C.sub.4)alkylsulfonylamino, trifluoromethylsulfonylamino,
(C.sub.1-C.sub.4)alkylthio, (C.sub.1-C.sub.4)alkylsulfinyl or
(C.sub.1-C.sub.4)alkylsulfonyl, pyrrol-1-yl, piperidin-1-yl or
pyrrolidin-1-yl, said phenyl, benzyloxy, phenoxy, and benzoylamino
optionally monosubstituted with halo, nitro, trifluoromethyl,
hydroxy, or (C.sub.1-C.sub.4)alkyl and said
(C.sub.1-C.sub.4)alkylenedioxy is linked at both ends to adjacent
carbons on the benzene moiety, or R.sup.b is -Z.sup.aR.sup.77; J is
--CH.sub.2--, thio, --N(H)--, or oxy; g is 0, 1, or2; h is 0 to 4;
k is 0, 1, or 2; S completes a 5- or 6-membered aromatic or
partially saturated ring that can contain an oxygen or sulfur atom:
T is --CH.sub.2, --N(H)--, thio, or oxy; S.sup.a is --CH.sub.2--,
oxy, or thio; A.sup.1 completes a 7- to 9-membered mono-unsaturated
mono-aza ring; Q.sup.a is a 9- or 10-membered bicyclic heterocyclic
moiety, or a hydrogenated derivative thereof, containing one or two
nitrogen heteroatoms and optionally containing a further heteroatom
selected from nitrogen, oxygen and sulfur, or Q.sup.a is a 9- or
10-membered bicyclic aryl moiety, or a hydrogenated derivative
thereof, which heterocyclic or aryl moiety, or hydrogenated
derivatives thereof, may optionally bear one or two substituents
selected from halogen, hydroxy, oxo, amino, nitro, carbamoyl,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkylamino, di-[(C.sub.1-C.sub.4)alkyl]amino, and
(C.sub.2-C.sub.4)alkanoylamino; R.sup.1 is hydrogen, halogen, or
C.sub.1-C.sub.6 alkyl; R.sup.2, R.sup.3, and R.sup.4 are
independently hydrogen, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1piperazinyl[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n-imidazoyl,
--(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--(CH.sub.2).sub.n--N-hexahydroazepine or substituted
C.sub.1-C.sub.6 alkyl, wherein the substituents are selected from
--OH NH.sub.2, or 61A and B are independently hydrogen,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.nOH,
--(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-piperaziny-
l[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl. --(CH.sub.2).sub.n--N-pyridyl,
--(CH.sub.2).sub.n-imidazoyl, or --(CH.sub.2).sub.n--N-imidazoyl:
E.sup.1, E.sup.2, or E.sup.3 are independently hydrogen, halogen.
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6
alkoxy, C.sub.3-C.sub.8 cycloalkoxy, nitro, C.sub.1-C.sub.6
perfluoroalkyl, hydroxy, C.sub.1-C.sub.6 acyloxy, --NH.sub.2,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NH(C.sub.3-C.sub.8 cycloalkyl), --N(C.sub.3-C.sub.8
cycloalkyl).sub.2, hydroxymethyl, C.sub.1-C.sub.6 acyl, cyano,
azido, C.sub.1-C.sub.6 thioalkyl, C.sub.1-C.sub.6 sulfinylalkyl,
C.sub.1-C.sub.6 sulfonylalkyl, C.sub.3-C.sub.8 thiocycloalkyl,
C.sub.3-C.sub.8 sulfinylcycloalkyl, C.sub.3-C.sub.8
sulfonylcycloalkyl, mercapto, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.3-C.sub.8 cycloalkoxycarbonyl, C.sub.2-C.sub.4 alkenyl,
C.sub.4-C.sub.8 cycloalkenyl, or C.sub.2-C.sub.4 alkynyl; Z.sup.a
is a bond, --CH.sub.2--, --S--, SO.sub.2, --NH--, --O--,
--OCH.sub.2--, --S--CH.sub.2--, --SO.sub.2--, or
--CH.sub.2CH.sub.2--; R.sup.77 is phenyl, substituted phenyl, or a
5- to 10-membered optionally substituted heterocyclic aromatic
ring; R.sup.5 is hydrogen, halogen, C.sub.1-C.sub.6 perfluoroalkyl,
1,1-difluoro(C.sub.1-C.sub.6)alkyl, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.n--N-piperidinyl, --(CH.sub.2).sub.n-piperazinyl,
--(CH.sub.2).sub.n-piperazinyl[N.sub.4--(- C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2)n-N-imidazoyl, --(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
62--CH.dbd.CH--(C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.n--N-hexahydroaze- pine,
--(CH.sub.2).sub.nNH.sub.2,--(CH.sub.2).sub.nNH
(C.sub.1-C.sub.6alkyl),
--(CH.sub.2).sub.nN(C.sub.1-C.sub.6alkyl).sub.2,
-1-oxo(C.sub.1-C.sub.6)alkyl, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl,
N--(C.sub.1-C.sub.6)alkylcarbamoyl, phenyl or substituted phenyl,
wherein the substituted phenyl can have from one to three
substituents independently selected from E.sup.1, E.sup.2, E.sup.3
or a monocyclic heteroaryl group, and each C.sub.1-C.sub.6 alkyl
group can be substituted with --OH, --NH.sub.2 or --NAB, where A
and B are as defined above; and n is 1 to 4, and the
pharmaceutically acceptable salts, esters, amides, and prodrugs
thereof.
14. A compound of claim 13 wherein Q is 63
15. A compound of claim 13 wherein Q is 64
16. A compound of claim 13 wherein Q is 65
17. A compound of claim 13 wherein Q is 66
18. A compound of claim 15 wherein X is 67
19. A compound of claim 16 wherein X is 68
20. A compound of claim 16 wherein X is 69
21. A compound of claim 14 wherein X is 70and Y is hydrogen.
22. A compound having the Formula II Q-Z II wherein Q is 71X is
-D-E-F and Y is --SR.sup.4, --OR.sup.4, --NHR.sup.3 or hydrogen, or
X is --SR.sup.4, --OR.sup.4, --NHR.sup.3 or hydrogen, and Y is
-D-E-F; 72each R.sup.a is independently hydroxy, amino, N-mono- or
N,N-di-(C.sub.1--C.sub.4) alkylamino, sulfo, or
(C.sub.1-C.sub.4)alkoxy (provided that such groups are not attached
to a ring carbon which is adjacent to an oxy, thio, or --N--), or
R.sup.a is independently carboxy, hydroxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4) alkyl,
amino(C.sub.1-C.sub.4)alkyl, mono-N-- or di-N,N--(C.sub.1-C.sub.4)
alkylamino(C.sub.1-C.sub.4)alkyl, morpholino(C.sub.1-C.sub.4)alkyl,
4-(C.sub.1-C.sub.4)alkyl-piperazin-1-yl(C.sub.1--C.sub.4)alkyl,
carboxy(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxycarbonyl,
sulfo(C.sub.1-C.sub.4)alkyl or (C.sub.1-C.sub.4)alkyl; each R.sup.b
is independently mono-, di-, or trifluoromethyl, halo, nitro,
hydroxy, amino, axido, isothiocyano, (C.sub.1-C.sub.4)alkyl,
phenyl, thienyl, (C.sub.1-C.sub.4)alkoxy, benzyloxy, phenoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.4)alkylenedioxy, cyano, benzoylamino,
trifluoromethylcarbonylamino. (C.sub.1-C.sub.4)alkanoylamin- o,
(C.sub.1-C.sub.4)alkanoyl, N-mono- or
N,N-di-(C.sub.1-C.sub.4)alkylamin- o,
(C.sub.1-C.sub.4)alkylsulfonylamino, trifluoromethylsulfonylamino,
(C.sub.1--C.sub.4)alkylthio, (C.sub.1-C.sub.4)alkylsulfinyl or
(C.sub.1-C.sub.4)alkylsulfonyl, pyrrol-1-yl, piperidin-1-yl or
pyrrolidin-1-yl, said phenyl, benzyloxy, phenoxy, and benzoylamino
optionally monosubstituted with halo, nitro, trifluoromethyl,
hydroxy, or (C.sub.1-C.sub.4)alkyl and said
(C.sub.1-C.sub.4)alkylenedioxy is linked at both ends to adjacent
carbons on the benzene moiety, or R.sup.b is -Z.sup.aR.sup.77; J is
--CH.sub.2--, thio, --N(H)--, or oxy; g is 0, 1, or 2; h is 0 to 4;
k is 0, 1, or 2; S completes a 5- or 6-membered aromatic or
partially saturated ring that can contain an oxygen or sulfur atom;
T is --CH.sub.2, --N(H)--, thio, or oxy; S.sup.a is --CH.sub.2--,
oxy, or thio; A.sup.1 completes a 7- to 9-membered mono-unsaturated
mono-aza ring; Q.sup.a is a 9- or 10-membered bicyclic heterocyclic
moiety, or a hydrogenated derivative thereof, containing one or two
nitrogen heteroatoms and optionally containing a further heteroatom
selected from nitrogen, oxygen and sulfur, or Q.sup.a is a 9- or
10-membered bicyclic aryl moiety, or a hydrogenated derivative
thereof, which heterocyclic or aryl moiety, or hydrogenated
derivatives thereof, may optionally bear one or two substituents
selected from halogen, hydroxy, oxo, amino, nitro, carbamoyl,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkylamino, di-[(C.sub.1-C.sub.4)alkyl]amino, and
(C.sub.2-C.sub.4)alkanoylamino; R.sup.1 is hydrogen, halogen, or
C.sub.1-C.sub.6 alkyl; R.sup.2, R.sup.3, and R.sup.4 are
independently hydrogen, C.sub.1-C.sub.6 alkyl.
--(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl.
--(CH.sub.2).sub.n--N.sub.1piperazinyl[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n-imidazoyl,
--(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--(CH.sub.2).sub.n--N-hexahydroazepine or substituted
C.sub.1-C.sub.6 alkyl, wherein the substituents are selected from
--OH, --NH.sub.2, or 73A and B are independently hydrogen,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.nOH,
--(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-piperaziny-
l[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n--N-pyridyl,
--(CH.sub.2).sub.n-imidazoyl, or --(CH.sub.2).sub.n--N-imidazoyl;
E.sup.1, E.sup.2, or E.sup.3 are independently hydrogen, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6
alkoxy, C.sub.3-C.sub.8 cycloalkoxy, nitro, C.sub.1-C.sub.6
perfluoroalkyl, hydroxy, C.sub.1-C.sub.6 acyloxy, --NH.sub.2,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NH(C.sub.3-C.sub.8 cycloalkyl), --N(C.sub.3-C.sub.8
cycloalkyl).sub.2, hydroxymethyl, C.sub.1-C.sub.6 acyl, cyano,
azido, C.sub.1-C.sub.6 thioalkyl, C.sub.1-C.sub.6 sulfinylalkyl,
C.sub.1-C.sub.6 sulfonylalkyl, C.sub.3-C.sub.8 thiocycloalkyl,
C.sub.3-C.sub.8 sulfinylcycloalkyl, C.sub.3-C.sub.8
sulfonylcycloalkyl, mercapto, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.3-C.sub.8 cycloalkoxycarbonyl, C.sub.2-C.sub.4 alkenyl,
C.sub.4-C.sub.8 cycloalkenyl, or C.sub.2-C.sub.4 alkynyl; Z.sup.a
is a bond, --CH.sub.2--, --S--, SO.sub.2, --NH--, --O--,
--OCH.sub.2-, -S--CH.sub.2--, --SO.sub.2--, or
--CH.sub.2CH.sub.2--; R.sup.77 is phenyl, substituted phenyl, or a
5- to 10-membered optionally substituted heterocyclic aromatic
ring; R.sup.5 is hydrogen, halogen, C.sub.1-C.sub.6 perfluoroalkyl,
1,1-difluoro(C.sub.1-C.sub.6)alkyl, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.n--N-piperidinyl, --(CH.sub.2).sub.n-piperazinyl,
--(CH.sub.2).sub.n-piperazinyl[N.sub.4--(- C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2)n-N-imidazoyl, --(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
74--CH.dbd.CH--(C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.n--N-hexahydroaze- pine,
--(CH.sub.2).sub.nNH.sub.2,--(CH.sub.2).sub.nNH
(C.sub.1-C.sub.6alkyl),
--(CH.sub.2).sub.nN(C.sub.1-C.sub.6alkyl).sub.2,
-1-oxo(C.sub.1-C.sub.6)alkyl, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl,
N--(C.sub.1-C.sub.6)alkylcarbamoyl, phenyl or substituted phenyl,
wherein the substituted phenyl can have from one to three
substituents independently selected from E.sup.1, E.sup.2, E.sup.3
or a monocyclic heteroaryl group, and each C.sub.1-C.sub.6 alkyl
group can be substituted with --OH, --NH.sub.2 or --NAB, where A
and B are as defined above; and n is 1 to 4, and the
pharmaceutically acceptable salts, esters, amides, and prodrugs
thereof.
23. A compound of claim 22 wherein Q is 75
24. A compound of claim 22 wherein Q is 76
25. A compound of claim 23 wherein X is 77
26. A compound of claim 24 wherein X is 78
27. A pharmaceutically acceptable composition that comprises a
compound of claim 1.
28. A pharmaceutically acceptable composition that comprises a
compound of claim 13.
29. A pharmaceutically acceptable composition that comprises a
compound of claim 22.
30. A method of treating cancer, the method comprising
administering to a patient having cancer a therapeutically
effective amount of a compound of claim 1.
31. A method of treating or preventing restenosis, the method
comprising administering to a patient having restenosis or at risk
of having restenosis a therapeutically effective amount of a
compound of claim 1.
32. A method of treating cancer, the method comprising
administering to a patient having cancer a therapeutically
effective amount of a compound of claim 13.
33. A method of treating or preventing restenosis, the method
comprising administering to a patient having restenosis or at risk
of having restenosis a therapeutically effective amount of a
compound of claim 13.
34. A method of treating cancer, the method comprising
administering to a patient having cancer a therapeutically
effective amount of a compound of claim 22.
35. A method of treating or preventing restenosis, the method
comprising 5administering to a patient having restenosis or at risk
of having restenosis, a therapeutically effective amount of a
compound of claim 22.
36. A method of irreversibly inhibiting tyrosine kinases, the
method comprising administering to a patient a tyrosine kinase
inhibition a tyrosine kinase inhibiting amount of a compound of
claim 1.
37. A method of irreversibly inhibiting tyrosine kinases, the
method comprising administering to a patient in need of tyrosine
kinase inhibition a amount of tyrosine kinase inhibiting amount of
a compound of claim 13.
38. A method of irreversibly inhibiting tyrosine kinases, the
method comprising administering to a patient in need of tyrosine
kinase inhibition a tyrosine kinase inhibiting amount of a compound
of claim 22.
39. A method of treating psoriasis, the method comprising
administering to a patient having psoriasis a therapeutically
effective amount of a compound of claim 1.
40. A method of treating psoriasis, the method comprising
administering to a patient having psoriasis a therapeutically
effective amount of a compound of claim 13.
41. A method of treating psoriasis, the method comprising
administering to a patient having psoriasis a therapeutically
effective amount of a compound of claim 22.
42. A method of treating atherosclerosis, the method comprising
administering to a patient having atherosclerosis a therapeutically
effective amount of a compound of claim 1.
43. A method of treating atherosclerosis, the method comprising
administering to a patient having atherosclerosis a therapeutically
effective amount of a compound of claim 13.
44. A method of treating atherosclerosis, the method comprising
administering to a patient having atherosclerosis a therapeutically
effective amount of a compound of claim 22.
45. A method of treating endometriosis, the method comprising
administering to a patient having endometriosis a therapeutically
effective amount of a compound of claim 1.
46. A method of treating endometriosis, the method comprising
administering to a patient having endometriosis a therapeutically
effective amount of a compound of claim 13.
47. A method of treating endometriosis, the method comprising
administering to a patient having endometriosis a therapeutically
effective amount of a compound of claim 22.
48. A compound according to claim 1 wherein X is -D-E-F and F is
79and R.sup.5 is 1,1-difluoro(C.sub.1-C.sub.6)alkyl,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n-piperazinyl,
--(CH.sub.2).sub.n-piperazinyl[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--CH.dbd.CH--(C.sub.1-C.sub.6)alkyl- ,
--(CH.sub.2).sub.n--N-hexahydroazepine,
--(CH.sub.2).sub.nNH.sub.2,--(CH- .sub.2).sub.nNH(C.sub.1-C.sub.6
alkyl), --(CH.sub.2).sub.nN(C.sub.1-C.sub.- 6 alkyl).sub.2,
-1-oxo(C.sub.1-C.sub.6)alkyl, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl,
N--(C.sub.1-C.sub.6)alkylcarbamoyl, and each C.sub.1-C.sub.1 alkyl
group of 1,1-difluoro(C.sub.1-C.sub.6)alky- l, C.sub.1-C.sub.6
alkyl, --CH.dbd.CH--(C.sub.1-C.sub.6)alkyl,
-1-oxo(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, or
--N--(C.sub.1-C.sub.6)alkylcarbamoyl is substituted with --OH,
--NH.sub.2, or --NAB, where A and B are as defined above; or Y is
-D-E-F and F is 80and R.sup.5 is
1,1-difluoro(C.sub.1-C.sub.6)alkyl, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.n--N-piperidinyl, --(CH.sub.2).sub.n-piperazinyl,
--(CH.sub.2).sub.n-piperazinyl[N.sub.4--(- C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--CH.dbd.CH--(C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.n--N-hexahydroazepi- ne,
--(CH.sub.2).sub.nNH.sub.2,--(CH.sub.2).sub.nNH(C.sub.1-C.sub.6
alkyl), --(CH.sub.2).sub.nN(C.sub.1-C.sub.6 alkyl).sub.2,
-1-oxo(C.sub.1-C.sub.6)alkyl, carboxy, (C.sub.1-C.sub.6
)alkyloxycarbonyl, N--(C.sub.1-C.sub.6)alkylcarbamoyl, and each
C.sub.1-C.sub.1 alkyl group of 1,1-difluoro(C.sub.1-C.sub.6)alkyl,
C.sub.1-C.sub.6 alkyl, --CH.dbd.CH--(C.sub.1-C.sub.6)alkyl,
-1-oxo(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, or
--N--(C.sub.1-C.sub.6)alkylcarbamoyl is substituted with --OH,
--NH.sub.2, or --NAB, where A and B are as defined above.
49. A compound according to claim 13 wherein X is -D-E-F and F is
81and R.sup.5 is 1,1-difluoro(C.sub.1-C.sub.6)alkyl,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n-piperazinyl,
--(CH.sub.2).sub.n-piperazinyl[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--CH.dbd.CH--(C.sub.1-C.sub.6)alkyl- ,
--(CH.sub.2).sub.n--N-hexahydroazepine,
--(CH.sub.2).sub.nNH.sub.2,--(CH- .sub.2).sub.nNH(C.sub.1-C.sub.6
alkyl), --(CH.sub.2).sub.nN(C.sub.1-C.sub.- 6 alkyl).sub.2,
-1-oxo(C.sub.1-C.sub.6)alkyl, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl,
N--(C.sub.1-C.sub.6)alkylcarbamoyl, and each C.sub.1-C.sub.1 alkyl
group of 1,1-difluoro(C.sub.1-C.sub.6)alky- l, C.sub.1-C.sub.6
alkyl, --CH.dbd.CH--(C.sub.1-C.sub.6)alkyl,
-1-oxo(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, or
--N--(C.sub.1-C.sub.6)alkylcarbamoyl is substituted with --OH,
--NH.sub.2, or --NAB, where A and B are as defined above; or Y is
-D-E-F and F is 82and R.sup.5 is
1,1-difluoro(C.sub.1-C.sub.6)alkyl, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.n--N-piperidinyl, --(CH.sub.2).sub.n-piperazinyl,
--(CH.sub.2).sub.n-piperazinyl[N.sub.4--(- C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--CH.dbd.CH--(C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.n--N-hexahydroazepi- ne,
--(CH.sub.2).sub.nNH.sub.2,--(CH.sub.2).sub.nNH(C.sub.1-C.sub.6
alkyl), --(CH.sub.2).sub.nN(C.sub.1-C.sub.6 alkyl).sub.2,
-1-oxo(C.sub.1-C.sub.6)alkyl, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl,
N--(C.sub.1-C.sub.6)alkylcarbamoyl, and each C.sub.1-C.sub.1 alkyl
group of 1,1-difluoro(C.sub.1-C.sub.6)alkyl, C.sub.1-C.sub.6 alkyl,
--CH.dbd.CH--(C.sub.1-C.sub.6)alkyl, -1-oxo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyloxycarbonyl, or
--N--(C.sub.1-C.sub.6)alkylcarbamoy- l is substituted with --OH,
--NH.sub.2, or --NAB, where A and B are as defined above.
50. A compound according to claim 22 wherein X is -D-E-F and F is
83and R.sup.5 is 1,1-difluoro(C.sub.1-C.sub.6)alkyl,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n-piperazinyl,
--(CH.sub.2).sub.n-piperazinyl[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--CH.dbd.CH--(C.sub.1-C.sub.6)alkyl- ,
--(CH.sub.2).sub.n--N-hexahydroazepine,
--(CH.sub.2).sub.nNH.sub.2,--(CH- .sub.2).sub.nNH(C.sub.1-C.sub.6
alkyl), --(CH.sub.2).sub.nN(C.sub.1-C.sub.- 6 alkyl).sub.2,
-1-oxo(C.sub.1-C.sub.6)alkyl, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl,
N--(C.sub.1-C.sub.6)alkylcarbamoyl, and each C.sub.1-C.sub.1 alkyl
group of 1,1-difluoro(C.sub.1-C.sub.6)alky- l, C.sub.1-C.sub.6
alkyl, --CH.dbd.CH--(C.sub.1-C.sub.6)alkyl,
-1-oxo(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, or
--N--(C.sub.1-C.sub.6)alkylcarbamoyl is substituted with --OH,
--NH.sub.2, or --NAB, where A and B are as defined above; or Y is
-D-E-F and F is 84and R.sup.5 is
1,1-difluoro(C.sub.1-C.sub.6)alkyl, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.n--N-piperidinyl. --(CH.sub.2).sub.n-piperazinyl,
--(CH.sub.2).sub.n-piperazinyl[N.sub.4--(- C.sub.1-C.sub.6)alkyl].
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--CH.dbd.CH--(C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.n--N-hexahydroazepi- ne,
--(CH.sub.2).sub.nNH.sub.2,--(CH.sub.2).sub.nNH(C.sub.1-C.sub.6
alkyl), --(CH.sub.2).sub.nN(C.sub.1-C.sub.6 alkyl).sub.2,
-1-oxo(C.sub.1-C.sub.6)alkyl, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl,
N--(C.sub.1-C.sub.6)alkylcarbamoyl, and each C.sub.1-C.sub.1 alkyl
group of 1,1-difluoro(C.sub.1-C.sub.6)alkyl, C.sub.1-C.sub.6 alkyl,
--CH.dbd.CH--(C.sub.1-C.sub.6)alkyl, -1-oxo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyloxycarbonyl, or
--N--(C.sub.1-C.sub.6)alkylcarbamoy- l is substituted with --OH,
--NH.sub.2, or --NAB, where A and B are as defined above.
51. A compound according to claim 1 wherein X is -D-E-F; Y is
--SR.sup.4, --OR.sup.4, or --NHR.sup.3; and R.sup.3 and R.sup.4 are
--(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1--piperazinyl[N.sub.4--(C.sub.1-C.sub.6)alkyl]-
, --(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n-imidazoyl,
--(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--(CH.sub.2).sub.n--N-hexahydroazepine or substituted
C.sub.1-C.sub.6 alkyl, wherein the substituents are selected from
--OH, --NH.sub.2, or 85A and B are independently hydrogen,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.nOH,
--(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-piperaziny-
l[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n--N-pyridyl,
--(CH.sub.2).sub.n-imidazoyl, or --(CH.sub.2).sub.n--N-imidazoyl;
or Y is -D-E-F; X is --SR.sup.4, --OR.sup.4, or --NHR.sup.3; and
R.sup.3 and R.sup.4 are --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1piperazinyl[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n-imidazoyl,
--(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--(CH.sub.2).sub.n--N-hexahydroazepine or substituted
C.sub.1-C.sub.6 alkyl, wherein the substituents are selected from
--OH, --NH.sub.2, or 86A and B are independently hydrogen,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.nOH,
--(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
-(CH.sub.2).sub.n--N.sub.1-piperazinyl-
[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n--N-pyridyl,
--(CH.sub.2).sub.n-imidazoyl, or
--(CH.sub.2).sub.n--N-imidazoyl.
52. A compound according to claim 13 wherein X is -D-E-F; Y is
--SR.sup.4, --OR.sup.4, or --NHR.sup.3; and R.sup.3 and R.sup.4 are
--(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1--piperazinyl[N.sub.4--(C.sub.1-C.sub.6)alkyl]-
, --(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n-imidazoyl,
--(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--(CH.sub.2).sub.n--N-hexahydroazepine or substituted
C.sub.1-C.sub.6 alkyl, wherein the substituents are selected from
--OH, --NH.sub.2, or 87A and B are independently hydrogen,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.nOH,
--(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-piperaziny-
l[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n--N-pyridyl,
--(CH.sub.2).sub.n-imidazoyl, or --(CH.sub.2).sub.n--N-imidazoyl;
or Y is -D-E-F; X is --SR.sup.4, --OR.sup.4, or --NHR.sup.3; and
R.sup.3 and R.sup.4 are --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1--piperazinyl[N.sub.4--(C.sub.1-C.sub.6)alkyl]-
, --(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n-imidazoyl,
--(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--(CH.sub.2).sub.n--N-hexahydroazepine or substituted
C.sub.1-C.sub.6 alkyl, wherein the substituents are selected from
--OH, --NH.sub.2, or 88A and B are independently hydrogen,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.nOH,
--(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-piperaziny-
l[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n--N-pyridyl,
--(CH.sub.2).sub.n-imidazoyl, or
--(CH.sub.2).sub.n--N-imidazoyl.
53. A compound according to claim 22 wherein X is -D-E-F; Y is
--SR.sup.4, --OR.sup.4, or --NHR.sup.3; and R.sup.3 and R.sup.4 are
--(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1--piperazinyl[N.sub.4--(C.sub.1-C.sub.6)alkyl]-
, --(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n-imidazoyl,
--(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--(CH.sub.2).sub.n--N-hexahydroazepine or substituted
C.sub.1-C.sub.6 alkyl, wherein the substituents are selected from
--OH, --NH.sub.2, or 89A and B are independently hydrogen,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.nOH,
--(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-piperaziny-
l[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n--N-pyridyl,
--(CH.sub.2).sub.n-imidazoyl, or --(CH.sub.2).sub.n--N-imidazoyl;
or Y is -D-E-F; X is --SR.sup.4, --OR.sup.4, or --NHR.sup.3; and
R.sup.3 and R.sup.4 are --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1--piperazinyl[N.sub.4--(C.sub.1-C.sub.6)alkyl]-
, --(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n-imidazoyl,
--(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--(CH.sub.2).sub.n--N-hexahydroazepine or substituted
C.sub.1-C.sub.6 alkyl, wherein the substituents are selected from
--OH, --NH.sub.2, or 90A and B are independently hydrogen,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.nOH,
--(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-piperaziny-
l[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n--N-pyridyl,
--(CH.sub.2).sub.n-imidazoyl, or
--(CH.sub.2).sub.n--N-imidazoyl.
54. The compounds:
N-[4-(6-Bromo-2,3-dihydroindol-1-yl)quinazolin-6-yl]acr- ylamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]acrylamide;
N-[4-(7-Chloro-3,4-dihydro-2H-quinolin-1-yl)quinazolin-6-yl]acrylamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-7-yl]acrylamide;
N-[4-(7-Chloro-3,4-dihydro-2H-quinolin-1-yl)quinazolin-7-yl]acrylamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]propynamide;
N-[4-(7-Trifluoromethyl-3,4-dihydro-2H-quinolin-1-yl)quinazolin-6-yl]prop-
ynamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-7-yl]propynamide;
N-[4-(7-Trifluoromethyl-3,4-dihydro-2H-quinolin-1-yl)quinazolin-7-yl]prop-
ynamide;
N-[4-(4-6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]but-2-ynam-
ide;
N-[4-(6-Bromo-5-fluoro-2,3-dihydroindol-1-yl)quinazolin-6-yl]but-2-yn-
amide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]buta-2,3-diena-
mide;
N-[4-(6-Bromo-5-fluoro-2,3-dihydroindol-1-yl)quinazolin-6-yl]buta-2,-
3-dienamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]but-2-en-
amide;
N-[4-(6-Ethynyl-2,3-dihydroindol-1-yl)quinazolin-6-yl]but-2-enamide-
;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4,4,4-trifluorobut-
-2-enamide;
N-[4-(6-Nitro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4,4,4-tri-
fluorobut-2-enamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-
-3-chloroacryl-amide;
N-[4-(6-Nitro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-
-3-chloroacrylamide;
6-(S-Vinylsulfonamido)-4-(6-chloro-2,3-dihydroindol-1-
-yl)quinazoline;
6-(S-Vinylsulfonamido)-4-(6-pyrrol-1-yl-2,3-dihydroindol--
1-yl)quinazoline;
N-[7-[3-(4-Morpholino)propoxy]-4-(6-chloro-2,3-dihydroin-
dol-1-yl)quinazolin-6-yl]acrylamide;
N-[4-(6-Pyrrol-1-yl-2,3-dihydroindol--
1-yl)-7-[4-(N,N-dimethylamino)butoxy]quinazolin-6-yl]acrylamide
N-[7-[4-(N,N-dimethylamino)butoxy]-4-(6-chloro-2,3-dihydroindol-1-yl)quin-
azolin-6-yl]acrylamide;
N-[4-(Octahydroindol-1-yl)-7-[3-(4-morpholino)prop-
oxy]-quinazolin-6-yl]acrylamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quin-
azolin-6-yl]-4-oxopent-2-enamide;
N-[4-(Octahydroindol-1-yl)quinazolin-6-y- l]-4-oxopent-2-enamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6--
yl]-4-hydroxy-4-oxobut-2-enamide;
N-[4-(6,7-Dihydro-5H-[1,3]dioxolo[4,5-f]-
indol-5-yl)quinazolin-6-yl]-4-hydroxy-4-oxobut-2-enamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-ethoxy-4-oxobut-2-
-enamide;
N-[4-(6,7-Dihydro-5H-[1,3]dioxolo[4,5-f]indol-5-yl)quinazolin-6--
yl]-4-ethoxy-4-oxobut-2-enamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quin-
azolin-6-yl]-4-(3-(N,N-dimethylamino)propoxy)-4-oxobut-2-enamide;
N-[4-(6-Methyl-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-(3-(N,N-dimethyla-
mino)propoxy)-4-oxobut-2-enamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)qui-
nazolin-6-yl]-4-(3-(N,N-dimethylamino)propylamino)-4-oxobut-2-enamide;
N-[4-(6-Methyl-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-(3-(N,N-dimethyla-
mino)propylamino)-4-oxobut-2-enamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl-
)quinazolin-6-yl]-4-(3-(4-morpholino)propoxy)-4-oxobut-2-enamide;
N-[4-(6-Azido-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-(3-(4-morpholino)p-
ropoxy)-4-oxobut-2-enamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazoli-
n-6-yl]-4-(3-(4-morpholino)propylamino)-4-oxobut-2-enamide;
N-[4-(6-Azido-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-(3-(4-morpholino)p-
ropylamino)-4-oxobut-2-enamide;
4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(6-chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]amide;
4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(5-benzyloxy-2,3-dihydr- oindol-1-yl)quinazolin-6-yl]amide;
Pent-2-enedioic acid
1{[4-(5-benzyloxy-2,3-dihydroindol-1-yl)quinazolin-6-yl]amide}5-[(3-morph-
olin-4-ylpropyl)amide]; Pent-2-enedioic acid
1{[4-(6-chloro-2,3-dihydroind-
ol-1-yl)quinazolin-6-yl]amide}5-[(3-morpholin-4-ylpropyl)amide];
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-(3-(morpholin-4-y-
l)propylthio)but-2-enamide;
N-[4-(5-Methoxy-2,3-dihydroindol-1-yl)quinazol-
in-6-yl]-4-(3-(morpholin-4-yl)propylthio)but-2-enamide;
7-Morpholin-4-ylhept-2-ynoic
acid[4-(6-chloro-2,3-dihydroindol-1-yl)quina- zolin-6-yl]amide;
7-Morpholin-4-ylhept-2-ynoic acid[4-(5-methoxy-2,3-dihyd-
roindol-1-yl)quinazolin-6-yl]amide; 4-Morpholin-4-ylbut-2-ynoic
acid[4-(6-chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]amide;
4-Morpholin-4-ylbut-2-ynoic
acid[4-(2,3,4,5-tetrahydro-1H-benzoazepin-1-y-
l)quinazolin-6-yl]amide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d-
]pyrimid-6-yl]acrylamide;
N-[4-(2,3,4,5-Tetrahydro-1H-benzoazepin-1-yl)pyr-
ido[3,4-d]-pyrimid-6-yl]acrylamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)p-
yrido[4,3-d]pyrimid-7-yl]acrylamide;
N-[4-(5-Hydroxy-2,3-dihydroindol-1-yl-
)pyrido[4,3-d]pyrimid-7-yl]propynamide;
N-[4-(6-Chloro-2,3-dihydroindol-1--
yl)pyrido[3,4-d]pyrimid-6-yl]propynamide;
N-[4-(5-Hydroxy-2,3-dihydroindol-
-1-yl)pyrido[3,4-d]pyrimid-6-yl]propynamide;
N-[4-(6-Chloro-2,3-dihydroind-
ol-1-yl)pyrido[4,3-d]pyrimid-7-yl]propynamide;
N-[4-(5-Amino-2,3-dihydroin-
dol-1-yl)pyrido[4,3-d]pyrimid-7-yl]propynamide;
N-[4-(6-Chloro-2,3-dihydro- indol-1-yl)pyrido
[3,4-d]pyrimid-6-yl]but-2-ynamide;
N-[4-(5-Amino-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]but-2-ynami-
de; N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido
[3,4-d]pyrimid-6-yl]buta-2- ,3-dienamide;
N-[4-(1,2,3,4,5,6-Hexahydrobenzo[b]azocin-1-yl)pyrido[3,4-d]-
-pyrimid-6-yl]buta-2,3-dienamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyr-
ido[3,4-d]pyrimid-6-yl]but-2-enamide;
N-[4-(1,2,3,4,5,6-Hexahydrobenzo[b]a-
zocin-1-yl)pyrido[3,4-d]-pyrimid-6-yl]but-2-enamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4,4,4-tri-
fluorobut-2-enamide;
N-[4-(6-Fluoro-7-methyl-2,3-dihydroindol-1-yl)pyrido[-
3,4-d]-pyrimid-6-yl]-4,4,4-trifluorobut-2-enamide;
N-[4-(6-Chloro-2,3-dihy-
droindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-3-chloroacrylamide;
N-[4-(6-Fluoro-7-methyl-2,3-dihydroindol-1-yl)pyrido[3,4-d]-pyrimid-6-yl]-
-3-chloroacrylamide;
6-(S-Vinylsulfonamido)-4-(6-chloro-2,3-dihydroindol-1-
-yl)-pyrido[3,4-d]pyrimidine;
6-(S-Vinylsulfonamido)-4-(2,3,6,7,8,9-hexahy-
dro-1H-benzo[g]indol-1-yl)pyrido[3,4-d]pyrimidine.
N-[4-(6-Chloro-2,3-dihy-
droindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4-oxopent-2-enamide;
N-[4-(2,3,6,7,8,9-Hexahydro-1H-benzo[g]indol-1-yl)pyrido[3,4d]-pyrimid-6--
yl]-4-oxopent-2-enamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d-
]pyrimid-6-yl]-4-hydroxy-4-oxobut-2-enamide;
N-[4-(6-Ethynyl-2,3-dihydroin-
dol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4-hydroxy-4-oxobut-2-enamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4-ethoxy--
4-oxobut-2-enamide;
N-[4-(6-Ethynyl-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyr-
imid-6-yl]-4-ethoxy-4-oxobut-2-enamide;
N-[4-(6-Chloro-2,3-dihydroindol-1--
yl)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(N,N-dimethylamino)propoxy)-4-oxobut-2--
enamide;
N-[4-(6-Ethynyl-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]--
4-(3-(N,N-dimethylamino)propoxy)-4-oxobut-2-enamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(N,N-
-dimethylamino)propylamino)-4-oxobut-2-enamide;
N-[4-(6-Ethynyl-2,3-dihydr-
oindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(N,N-dimethylamino)propylamino-
)-4-oxobut-2-enamide;
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]py-
rimid-6-yl]-4-(3-(4-morpholino)propoxy)-4-oxobut-2-enamide;
N-[4-(6-Ethynyl-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(4--
morpholino)propoxy)-4-oxobut-2-enamide;
N-[4-(6-Chloro-2,3-dihydroindol-1--
yl)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(4-morpholino)propylamino)-4-oxobut-2-e-
namide;
N-[4-(6-Ethynyl-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4-
-(3-(4-morpholino)propylamino)-4-oxobut-2-enamide;
4,4-Difluoro-8-(morphol- in-4-yl)oct-2-enoic
acid[4-(6-chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]py-
rimid-6-yl]amide; 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(6-Ethynyl-2.3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]amide;
Pent-2-enedioic acid
1{[4-(2,3-dihydropyrrolo[2,3-f]indol-7-yl)pyrido[3,4-
-d]pyrimid-6-yl]amide}5-[(3-morpholin-4-ylpropyl)amide];
Pent-2-enedioic acid
1{[4-(6-chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]amide-
}5-[(3-morpholin-4-ylpropyl)amide];
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)p-
yrido[3,4-d]pyrimid-6-yl]-4-(3-(morpholin-4-yl)propylthio)but-2-enamide;
N-[4-(2,3-Dihydropyrrolo[2,3-f]indol-7-yl)pyrido[3,4-d]pyrimid-6-yl]-4-(3-
-(morpholin-4-yl)propylthio)but-2-enamide;
7-Morpholin-4-ylhept-2-ynoic
acid[4-(6-chloro-2,3-dihydroindol-1-yl)pyrido
[3,4-d]pyrimid-6-yl]amide; 7-Morpholin-4-ylhept-2-ynoic
acid[4-(2,3,5,6-tetrahydropyrrolo[2,3-f]indo-
l-1-yl)pyrido[3,4-d]pyrimid-6-yl]amide; 4-Morpholin-4-ylbut-2-ynoic
acid[4-(6-chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]amide;
4-Morpholin-4-ylbut-2-ynoic
acid[4-(2,3,5,6-tetrahydropyrrolo[2,3-f]indol-
-1-yl)pyrido[3,4-d]pyrimid-6-yl]amide;
N-[4-(6-Chloro-2,3-dihydroindol-1-y-
l)benzo[b]thieno[3,2-d]-pyrimid-6-yl]acrylamide;
N-[4-(6-Ethynyl-2,3-dihyd-
roindol-1-yl)benzo[b]thieno[3,2-d]-pyrimid-6-yl]acrylamide;
[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]acrylate;
[4-(2,3,5,6-Tetrahydropyrrolo[2,3-f]indol-1-yl)quinazolin-6-yl]acrylate;
[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-7-yl]acrylate;
[4-(6-Ethynyl-2,3-dihydroindol-1-yl)quinazolin-7-yl]acrylate;
[7-[3-(4-Morpholino)propoxy]-4-(6-chloro-2,3-dihydroindol-1-yl)quinazolin-
-6-yl]acrylate;
[4-(-(2,3-Dihydropyrrolo[2,3-f]indol-7-yl)-7-[4-(N,N-dimet-
hylamino)butoxy]quinazolin-6-yl]acrylate;
[7-[4-(N,N-dimethylamino)butoxy]-
-4-(6-chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]acrylate;
[4-(6-Ethynyl-2,3-dihydroindol-1-yl)-7-[3-(4-morpholino)-propoxy]quinazol-
in-6-yl]acrylate;
N-(3-(4-Morpholino)propylamino)-4,O-[4-(6-chloro-2,3-dih-
ydroindol-1-yl)quinazolin-6-yl]-4-oxobut-2-enamide;
N-(3-(4-Morpholino)propylamino)-4,O-[4-(2,3,4,5-tetrahydro-1H-benzoazepin-
-1-yl)quinazolin-6-yl]-4-oxobut-2-enamide;
4,4-Difluoro-8-(morpholin-4-yl)- oct-2-enoic
acid[4-(6-chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]ester;
4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(6-bromo-2,3-dihydroind- ol-1-yl)quinazolin-6-yl]ester;
Pent-2-enedioic acid
1{[4-(6-methyl-2,3-dihydroindol-1-yl)quinazolin-6-yl]ester}5-[(3-morpholi-
n-4-ylpropyl)amide]; Pent-2-enedioic acid
1{[4-(6-chloro-2,3-dihydroindol--
1-yl)quinazolin-6-yl]ester}5-[(3-morpholin-4-ylpropyl)amide];
[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-(3-(morpholin-4-yl)-
propylthio)but-2-enoate;
[4-(6-Fluoro-2,3-dihydroindol-1-yl)quinazolin-6-y-
l]-4-(3-(morpholin-4-yl)propylthio)but-2-enoate;
7-Morpholin-4-ylhept-2-yn- oic
acid[4-(6-chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]ester;
7-Morpholin-4-ylhept-2-ynoic
acid[4-(6-chloro-7-fluoro-2,3-dihydroindol-1-
-yl)quinazolin-6-yl]ester; 4-Morpholin-4-ylbut-2-ynoic
acid[4-(6-chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]ester;
4-Morpholin-4-ylbut-2-ynoic
acid[4-(6-ethynyl-2,3-dihydroindol-1-yl)quina- zolin-6-yl]ester;
N-[4-(Quinol-2-ylamino)quinazolin-6-yl]acrylamide;
N-[4-(Indol-5-ylamino)quinazolin-6-yl]acrylamide;
N-[4-(Quinol-2-ylamino)- quinazolin-7-yl]acrylamide;
N-[4-(Indol-5-ylamino)quinazolin-7-yl]acrylami- de;
N-[4-(Quinol-3-ylamino)quinazolin-6-yl]propynamide;
N-[4-(Indol-5-ylamino)quinazolin-6-yl]propynamide;
N-[4-(Quinol-3-ylamino)quinazolin-7-yl]propynamide;
N-[4-(Indol-5-ylamino)quinazolin-7-yl]propynamide;
N-[4-(Quinol-5-ylamino)quinazolin-6-yl]but-2-ynamide;
N-[4-(Indol-5-ylamino)quinazolin-6-yl]but-2-ynamide;
N-[4-(Quinol-5-ylamino)quinazolin-6-yl]buta-2,3-dienamide;
N-[4-(Indol-5-ylamino)quinazolin-6-yl]buta-2,3-dienamide;
N-[4-(Quinol-6-ylamino)quinazolin-6-yl]but-2-enamide;
N-[4-(Indol-5-ylamino)quinazolin-6-yl]but-2-enamide;
N-[4-(Quinol-6-ylamino)quinazolin-6-yl]4,4,4-trifluorobut-2-enamide;
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-4,4,4-trifluorobut-2-enamide;
N-[4-(Quinol-7-ylamino)quinazolin-6-yl]-3-chloroacrylamide;
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-3-chloroacrylamide;
6-(S-Vinylsulfonamido)-4-(quinol-7-ylamino)quinazoline;
6-(S-Vinylsulfonamido)-4-(indol-5-ylamino)quinazoline;
N-[7-[3-(4-Morpholino)propoxy]-4-(quinol-8-ylamino)quinazolin-6-yl]acryla-
mide;
N-[4-(Indol-5-ylamino)-7-[4-(N,N-dimethylamino)butoxy]-quinazolin-6--
yl]acrylamide;
N-[7-[4-(N,N-dimethylamino)butoxy]-4-(quinol-8-ylamino)-qui-
nazolin-6-yl]acrylamide;
N-[4-(Indol-5-ylamino)-7-[3-(4-morpholino)propoxy-
]quinazolin-6-yl]acrylamide;
N-[4-(Isoquinol-1-ylamino)quinazolin-6-yl]-4-- oxopent-2-enamide;
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-4-oxopent-2-enam- ide;
N-[4-(Isoquinol-1-ylamino)quinazolin-6-yl]-4-hydroxy-4-oxobut-2-enami-
de;
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-4-hydroxy-4-oxobut-2-enamide;
N-[4-(Isoquinol-5-ylamino)quinazolin-6-yl]-4-ethoxy-4-oxobut-2-enamide;
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-4-ethoxy-4-oxobut-2-enamide;
N-[4-(Isoquinol-5-ylamino)quinazolin-6-yl]-4-(3-(N,N-dimethylamino)propox-
y)-4-oxobut-2-enamide;
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-4-(3-(N,N-di-
methylamino)-propoxy)-4-oxobut-2-enamide;
N-[4-(Indol-4-ylamino)quinazolin-
-6-yl]-4-(3-(N,N-dimethylamino)propylamino)-4-oxobut-2-enamide;
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-4-(3-(N,N-dimethylamino)propylamin-
o)-4-oxobut-2-enamide;
N-[4-(Indol-4-ylamino)quinazolin-6-yl]-4-(3-(4-morp-
holino)propoxy)-4-oxobut-2-enamide;
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-
-4-(3-(4-morpholino)propoxy)-4-oxobut-2-enamide;
N-[4-(Indol-6-ylamino)qui-
nazolin-6-yl]-4-(3-(4-morpholino)propylamino)-4-oxobut-2-enamide;
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-4-(3-(4-morpholino)propylamino)-4--
oxobut-2-enamide; 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(indol-6-ylamino)quinazolin-6-yl]amide;
4,4-Difluoro-8-(morpholin-- 4-yl)oct-2-enoic
acid[4-(indol-5-ylamino)quinazolin-6-yl]amide; Pent-2-enedioic acid
1{[4-(indol-5-ylamino)quinazolin-6-yl]amide}5-[(3-mo-
rpholin-4-ylpropyl)amide]; Pent-2-enedioic acid
1{[4-(1H-indazol-6-ylamino-
)quinazolin-6-yl]amide}5-[(3-morpholin-4-ylpropyl)amide];
N-[4-(1H-Indazol-6-ylamino)quinazolin-6-yl]-4-(3-(morpholin-4-yl)propylth-
io)but-2-enamide;
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-4-(3-(morpholin-4-
-yl)propylthio)but-2-enamide; 7-Morpholin-4-ylhept-2-ynoic
acid[4-(1H-indazol-5-ylamino)quinazolin-6-yl]amide;
7-Morpholin-4-ylhept-2-ynoic
acid[4-(indol-5-ylamino)quinazolin-6-yl]amid- e;
4-Morpholin-4-ylbut-2-ynoic
acid[4-(1H-indazol-5-ylamino)quinazolin-6-y- l]amide;
4-Morpholin-4-ylbut-2-ynoic acid[4-(4-benzyloxyphenylamino)-quina-
zolin-6-yl]amide;
N-[4-(1H-Indazol-4-ylamino)pyrido[3,4-d]pyrimid-6-yl]acr- ylamide;
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]acrylamide;
N-[4-(1H-Indazol-4-ylamino)pyrido[4,3-d]pyrimid-7-yl]acrylamide;
N-[4-(Indol-5-ylamino)pyrido[4,3-d]pyrimid-7-yl]propynamide;
N-[4-(1H-Indazol-4-ylamino)pyrido[3,4-d]pyrimid-6-yl]propynamide;
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]propynamide;
N-[4-(1H-Benzotriazol-5-ylamino)pyrido[4,3-d]pyrimid-7-yl]propynamide;
N-[4-(Indol-5-ylamino)pyrido[4,3- d]pyrimid-7-yl]propynamide;
N-[4-(1H-Benzotriazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]but-2-ynamide;
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]but-2-ynamide;
N-[4-(1H-Benzotriazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]buta-2,3-dienam-
ide;
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]buta-2,3-dienamide;
N-[4-(1H-Benzotriazol-7-ylamino)pyrido[3,4-d]pyrimid-6-yl]but-2-enamide;
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid -6-yl]but-2-enamide;
N-[4-(1H-Benzotriazol-7-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4,4,4-trifluor-
obut-2-enamide;
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4,4,4-tri-
fluorobut-2-enamide;
N-[4-(1H-Benzotriazol-7-ylamino)pyrido[3,4-d]pyrimid--
6-yl]-3-chloroacrylamide;
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-
-3-chloroacrylamide;
6-(S-Vinylsulfonamido)-4-(benzothiazol-5-ylamino)pyri-
do[3,4-d]-pyrimidine;
6-(S-Vinylsulfonamido)-4-(indol-5-ylamino)pyrido
[3,4-d]-pyrimidine;
N-[4-(Benzothiazol-5-ylamino)pyrido[3,4-d]pyrimid-6-y-
l]-4-oxopent-2-enamide;
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-
-oxopent-2-enamide;
N-[4-(Benzothiazol-6-ylamino)pyrido[3,4-d]pyrimid-6-yl-
]-4-hydroxy-4-oxobut-2-enamide;
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-
-6-yl]-4-hydroxy-4-oxobut-2-enamide;
N-[4-(Benzothiazol-6-ylamino)pyrido[3-
,4-d]pyrimid-6-yl]-4-ethoxy-4-oxobut-2-enamide;
N-[4-(Indol-5-ylamino)pyri-
do[3,4-d]pyrimid-6-yl]-4-ethoxy-4-oxobut-2-enamide;
N-[4-(Indan-4-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(N,N-dimethylamino)-
propoxy)-4-oxobut-2-enamide;
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6--
yl]-4-(3-(N,N-dimethylamino)propoxy)-4-oxobut-2-enamide;
N-[4-(Indan-4-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(N,N-dimethylamino)-
propylamino)-4-oxobut-2-enamide;
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimi-
d-6-yl]-4-(3-(N,N-dimethylamino)propylamino)-4-oxobut-2-enamide;
N-[4-(Indan-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(4-morpholino)propo-
xy)-4-oxobut-2-enamide;
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-
-(3-(4-morpholino)propoxy)-4-oxobut-2-enamide;
N-[4-(Indan-5-ylamino)pyrid-
o[3,4-d]pyrimid-6-yl]-4-(3-(4-morpholino)propylamino)-4-oxobut-2-enamide;
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(4-morpholino)propy-
lamino)-4-oxobut-2-enamide;
4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(1,2,3,4-tetrahydronaphth-1-ylamino)pyrido[3,4-d]pyrimid-6-yl]amid-
e; 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(indol-5-ylamino)pyri- do[3,4-d]pyrimid-6-yl]amide;
Pent-2-enedioic acid 1{[4-(indol-5-ylamino)py-
rido[3,4-d]pyrimid-6-yl]amide}5-[(3-morpholin-4-ylpropyl)amide];
Pent-2-enedioic acid
1{[4-(1,2,3,4-tetrahydronaphth-1-ylamino)pyrido[3,4--
d]pyrimid-6-yl]amide}5-[(3-morpholin-4-ylpropyl)amide];
N-[4-(1,2,3,4-Tetrahydronaphth-2-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3--
(morpholin-4-yl)propylthio)but-2-enamide;
N-[4-(Indol-5-ylamino)pyrido[3,4-
-d]pyrimid-6-yl]-4-(3-(morpholin-4-yl)propylthio)but-2-enamide;
7-Morpholin-4-ylhept-2-ynoic
acid[4-(1,2,3,4-tetrahydronaphth-2-ylamino)p-
yrido[3,4-d]pyrimid-6-yl]amide; 7-Morpholin-4-ylhept-2-ynoic
acid[4-(indol-5-ylamino)-pyrido[3,4-d]pyrimid-6-yl]amide;
4-Morpholin-4-ylbut-2-ynoic
acid[4-(benzo[c][2,1,3]thiadiazol-4-ylamino)p-
yrido[3,4-d]pyrimid-6-yl]amide: 4-Morpholin-4-ylbut-2-ynoic
acid[4-(indol-5-ylamino)-pyrido[3,4-d]pyrimid-6-yl]amide;
N-[4-(Benzo[c][2,1,3]thiadiazol-4-ylamino)benzo[b]thieno[3,2-d]-pyrimid-6-
-yl]acrylamide;
N-[4-(Indol-5-ylamino)benzo[b]thieno[3,2-d]pyrimid-6-yl]ac-
rylamide; [4-(Benzimidazol-5-ylamino)quinazolin-6-yl]acrylate;
[4-(Indol-5-ylamino)quinazolin-6-yl]acrylate.
[4-(Benzimidazol-5-ylamino)- quinazolin-7-yl]acrylate;
[4-(Indol-5-ylamino)quinazolin-7-yl]acrylate;
[7-[3-(4-Morpholino)propoxy]-4-(benzimidazol-5-ylamino)-5quinazolin-6-yl]-
acrylate;
[4-(Indol-5-ylamino)-7-[4-(N,N-dimethylamino)butoxy]-quinazolin--
6-yl]acrylate;
[7-[4-(N,N-dimethylamino)butoxy]-4-(6-methoxyquinol-8-ylami-
no)quinazolin-6-yl]acrylate;
[4-(Indol-5-ylamino)-7-[3-(4-morpholino)propo-
xy]quinazolin-6-yl]acrylate;
N-(3-(4-Morpholino)propylamino)-4,O-[4-(6-met-
hoxyquinol-8-ylamino)quinazolin-6-yl]-4-oxobut-2-enamide;
N-(3-(4-Morpholino)propylamino)-4,O-[4-(indol-5-ylamino)-quinazolin-6-yl]-
-4-oxobut-2-enamide; 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(1-methylindol-5-ylamino)quinazolin-6-yl]ester;
4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(indol-5-ylamino)quinaz- olin-6-yl]ester; Pent-2-enedioic
acid 1{[4-(indol-5-ylamino)quinazolin-6-y-
l]ester}5-[(3-morpholin-4-ylpropyl)amide]; Pent-2-enedioic acid
1{[4-(1-methylindol-5-ylamino)quinazolin-6-yl]ester}5-[(3-morpholin-4-ylp-
ropyl)amide];
[4-(2-Methylindol-5-ylamino)quinazolin-6-yl]-4-(3-(morpholin-
-4-yl)propylthio)but-2-enoate;
[4-(Indol-5-ylamino)quinazolin-6-yl]-4-(3-(-
morpholin-4-yl)-propylthio)but-2-enoate;
7-Morpholin-4-ylhept-2-ynoic
acid[4-(3-cyanoindol-5-ylamino)-quinazolin-6-yl]ester;
7-Morpholin-4-ylhept-2-ynoic
acid[4-(indol-5-ylamino)-quinazolin-6-yl]est- er;
4-Morpholin-4-ylbut-2-ynoic
acid[4-(benzothien-5-ylamino)-quinazolin-6- -yl]ester;
4-Morpholin-4-ylbut-2-ynoic acid[4-(indol-5-ylamino)quinazolin--
6-yl]ester;
N-[4-(1-Benzylindol-5-ylamino)quinazolin-6-yl]acrylamide;
N-[4-(2-Benzylbenzimidazol-5-ylamino)quinazolin-6-yl]acrylamide;
N-[4-( l -Benzylindol-5-ylamino)quinazolin-7-yl]acrylamide;
N-[4-(2-Benzylbenzimidazol-5-ylamino)quinazolin-7-yl]acrylamide;
N-[4-(2-Benzylbenzindazol-5-ylamino)quinazolin-6-yl]propynamide;
N-[4-(1-Benzylbenzindazol-5-ylamino)quinazolin-6-yl]propynamide;
N-[4-(2-Benzylbenzindazol-5-ylamino)quinazolin-7-yl]propynamide;
N-[4-(2-Benzylbenzindazol-5-ylamino)quinazolin-7-yl]propynamide;
N-[4-(1-Phenylsulfonylindol-5-ylamino)quinazolin-6-yl]but-2-ynamide;
N-[4-(1-Phenylsulfonylindol-5-ylamino)quinazolin-6-yl]buta-2,3-dienamide;
N-[4-(1-Benzylindol-5-ylamino)quinazolin-6-yl]but-2-enamide;
N-[4-(2-Benzylbenzindazol-5-ylamino)quinazolin-6-yl]-4,4,4-trifluorobut-2-
-enamide;
N-[4-(1-Benzylindol-5-ylamino)quinazolin-6-yl]-4,4,4-trifluorobu-
t-2-enamide;
N-[4-(1-Benzylindol-6-ylamino)quinazolin-6-yl]-3-chloroacryla-
mide;
6-(S-Vinylsulfonamido)-4-(2-benzylbenzindazol-5-ylamino)quinazoline;
N-[7-[3-(4-Morpholino)propoxy]-4-(2-benzylbenzindazol-5-ylamino)quinazoli-
n-6-yl]acrylamide;
N-[4-(1-Benzylindol-6-ylamino)-7-[4-(N,N-dimethylamino)-
-butoxy]quinazolin-6-yl]acrylamide;
N-[4-(2-Phenylbenzimidazol-5-ylamino)--
7-[3-(4-morpholino)-propoxy]quinazolin-6-yl]acrylamide;
N-[4-(2-Phenylbenzimidazol-5-ylamino)quinazolin-6-yl]-4-oxopent-2-enamide-
;
N-[4-(3-Benzylbenzimidazol-5-ylamino)quinazolin-6-yl]-4-hydroxy-4-oxobut-
-2-enamide;
N-[4-(3-Benzylbenzimidazol-5-ylamino)quinazolin-6-yl]-4-ethoxy-
-4-oxobut-2-enamide;
N-[4-(2-Benzylbenzindazol-5-ylamino)quinazolin-6-yl]--
4-(3-(N,N-dimethylamino)propoxy)-4-oxobut-2-enamide;
N-[4-(2-Benzylbenzindazol-5-ylamino)quinazolin-6-yl]-4-(3-(N,N-dimethylam-
ino)propylamino)-4-oxobut-2-enamide;
N-[4-(1-Benzylbenzimidazol-5-ylamino)-
quinazolin-6-yl]-4-(3-(N,N-dimethylamino)propylamino)-4-oxobut-2-enamide;
N-[4-(1-Benzylbenzimidazol-5-ylamino)quinazolin-6-yl]-4-(3-(4-morpholino)-
propoxy)-4-oxobut-2-enamide;
N-[4-(2-Benzylbenzindazol-5-ylamino)quinazoli-
n-6-yl]-4-(3-(4-morpholino)propoxy)-4-oxobut-2-enamide;
N-[4-(42-Benzylbenzindazol-5-ylamino)quinazolin-6-yl]-4-(3-(4-morpholino)-
propylamino)-4-oxobut-2-enamide;
N-[4-(2-Benzylbenzotriazol-5-ylamino)quin-
azolin-6-yl]-4-(3-(4-morpholino)propylamino)-4-oxobut-2-enamide;
4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(2-benzylbenzotriazol-5- -ylamino)quinazolin-6-yl]amide;
4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(2-benzylbenzindazol-5-ylamino)quinazolin-6-yl]amide;
Pent-2-enedioic acid
1{[4-(2-benzylbenzindazol-5-ylamino)quinazolin-6-yl]- amide
}5-[(3-morpholin-4-ylpropyl)amide]; Pent-2-enedioic acid
1{[4-(2-benzylbenzindazol-5-ylamino)quinazolin-6-yl]amide}5-[(3-morpholin-
-4-ylpropyl)amide];
N-[4-(1-Benzylbenzotriazol-5-ylamino)quinazolin-6-yl]--
4-(3-(morpholin-4-yl)propylthio)but-2-enamide;
N-[4-(2-Benzylbenzindazol-5-
-ylamino)quinazolin-6-yl]-4-(3-(morpholin-4-yl)propylthio)but-2-enamide;
7-Morpholin-4-ylhept-2-ynoic
acid[4-(1-Benzylbenzotriazol-5-ylamino)quina- zolin-6-yl]amide;
4-Morpholin-4-ylbut-2-ynoic acid[4-(3-benzylbenzotriazol-
-5-ylamino)quinazolin-6-yl]amide; 4-Morpholin-4-ylbut-2-ynoic
acid[4-(2-benzylbenzindazol-5-ylamino)quinazolin-6-yl]amide;
N-[4-(2-Benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]acrylamide;
N-[4-(3-Benzylbenzotriazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]acrylamide-
;
N-[4-(2-{Pyrid-2-yl}benzotriazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]pro-
pynamide;
N-[4-(2-Benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]pr-
opynamide;
N-[4-(2-{Pyrid-2-yl}benzotriazol-5-ylamino)pyrido[3,4-d]pyrimid-
-6-yl]but-2-ynamide;
N-[4-(2-Benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyri-
mid-6-yl]buta-2,3-dienamide;
N-[4-(2-Phenethylbenzindazol-5-ylamino)pyrido-
[3,4-d]pyrimid-6-yl]but-2-enamide;
N-[4-(2-Phenethylbenzindazol-5-ylamino)-
pyrido[3,4-d]pyrimid-6-yl]-4,4,4-trifluorobut-2-enamide;
N-[4-(2-Benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4,4,4-trif-
luorobut-2-enamide;
N-[4-(1-Phenethylbenzindazol-5-ylamino)pyrido[3,4-d]py-
rimid-6-yl]-3-chloroacrylamide; 6-(
S-Vinylsulfonamido)-4-(1-phenethylbenz-
indazol-5-ylamino)pyrido[3,4-d]pyrimidine;
6-(S-Vinylsulfonamido)-4-(2-ben-
zylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimidine;
N-[4-(2-Benzylbenzindazo-
l-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-hydroxy-4-oxobut-2-enamide;
N-[4-(2-Benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(N,N--
dimethylamino)propylamino)-4-oxobut-2-enamide;
N-[4-(2-Benzyloxyindol-5-yl-
amino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(4-morpholino)propoxy)-4-oxobut-2-en-
amide;
N-[4-(2-Benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-
-(4-morpholino)propoxy)-4-oxobut-2-enamide;
N-[4-(2-Benzylbenzindazol-5-yl-
amino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(4-morpholino)propylamino)-4-oxobut--
2-enamide;
N-[4-(2-Benzyloxyindol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(-
3-(4-morpholino)propylamino)-4-oxobut-2-enamide;
4,4-Difluoro-8-(morpholin- -4-yl)oct-2-enoic
acid[4-(2-benzyloxybenzimidazol-5-ylamino)pyrido[3
4-d]pyrimid-6-yl]amide; 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(2-benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]amide;
Pent-2-enedioic acid
1{[4-(2-benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyr-
imid-6-yl]amide}5-[(3-morpholin-4-ylpropyl)amide]; Pent-2-enedioic
acid 1{[4-(2-benzylsulfonylbenzimidazol-5-ylamino)
pyrido[3,4-d]pyrimid-6-yl]a-
mide}5-[(3-morpholin-4-ylpropyl)amide];
N-[4-(4-benzyloxybenzimidazol-5-yl-
amino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(morpholin-4-yl)propylthio)but-2-ena-
mide;
N-[4-(2-Benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3--
(morpholin-4-yl)propylthio)but-2-enamide;
7-Morpholin-4-ylhept-2-ynoic
acid[4-(2-benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]amide;
7-Morpholin-4-ylhept-2-ynoic
acid[4-(2-benzylsulfonylbenzimidazol-5-ylami-
no)pyrido[3,4-d]pyrimid-6-yl]amide:
N-[4-(2-Benzylbenzindazol-5-ylamino)be- nzo[b]thieno
[3,2-d]-pyrimid-6-yl]acrylamide; N-[4-(1-Benzylbenzindazol-5--
ylamino)benzo[b]thieno[3,2-d]-pyrimid-6-yl]acrylamide;
[4-(2-Benzylbenzindazol-5-ylamino)quinazolin-6-yl]acrylate;
N-(3-(4-Morpholino)propylamino)-4,O-[4-(2-benzylbenzindazol-5-ylamino)qui-
nazolin-6-yl]-4-oxobut-2-enamide;
4,4-Difluoro-8-(morpholin-4-yl)oct-2-eno- ic
acid[4-(2-benzylbenzindazol-5-ylamino)quinazolin-6-yl]ester;
Pent-2-enedioic acid
1{[4-(2-benzylbenzindazol-5-ylamino)quinazolin-6-yl]-
ester}5-[(3-morpholin-4-ylpropyl)amide];
[4-(2-Benzylbenzindazol-5-ylamino-
)quinazolin-6-yl]-4-(3-(morpholin-4-yl)propylthio)but-2-enoate; and
7-Morpholin-4-ylhept-2-ynoic
acid[4-(2-benzylbenzindazol-5-ylamino)quinaz- olin-6-yl]ester.
Description
FIELD OF THE INVENTION
[0001] This invention relates to compounds that are irreversible
inhibitors of tyrosine kinases. This invention also relates to a
method of treating cancer, atherosclerosis, restenosis,
endometriosis, and psoriasis, and to a pharmaceutical composition
that comprises a compound that is an irreversible inhibitor of
tyrosine kinases.
BACKGROUND OF THE INVENTION
[0002] Cancer has been viewed as a disease of the intracellular
signalling system, or signal transduction mechanism. Cells receive
instructions from many extracellular sources, instructing them to
either proliferate or not to proliferate. The purpose of the signal
transduction system is to receive these and other signals at the
cell surface, get them into the cell, and then pass the signal on
to the nucleus, the cytoskeleton, and transport and protein
synthesis machinery.
[0003] The most common cause of cancer is a series of defects,
either in these proteins, when they are mutated, or in the
regulation of the quantity of the position in the cell such that it
over or under produced. Most often, there are key lesions in the
cell which lead to a constitutive state whereby the cell nucleus
receives a signal to proliferate, when this signal is not actually
present. This can occur through a variety of mechanisms. Sometimes
the cell may start to produce an authentic growth factor for its
own receptors when it should not, the so-called autocrine loop
mechanism. Mutations to the cell surface receptors, which usually
signal into the cell by means of tyrosine kinases, can lead to
activation of the kinase in the absence of ligand, and passing of a
signal which is not really there. Alternatively, many surface
kinases can be overexpressed on the cell surface leading to an
inappropriately strong response to a weak signal. There are many
levels inside the cell at which mutation or overexpression can lead
to the same spurious signal arising in the cell, and there are many
other kinds of signalling defects involved in cancer. This
invention touches upon cancers which are driven by the three
mechanisms just described, and which involve cell surface receptors
of the epidermal growth factor receptor tyrosine kinase family
(EGFR). This family consists of the EGF receptor (also known as
Erb-B1), the Erb-B2 receptor, and its constitutively active
oncoprotein mutant Neu, the Erb-B3 receptor and the Erb-B4
receptor. Additionally, other biological processes driven through
members of the EGF family of receptors can also be treated by
compounds of the invention described below.
[0004] The EGFR has as its two most important ligands Epidermal
Growth Factor (EGF) and Transforming Growth Factor alpha (TGF
alpha). The receptors appear to have only minor functions in adult
humans, but are apparently implicated in the disease process of a
large portion of all cancers, especially colon and breast cancer.
The closely related Erb-B2, Erb-B3, and Erb-B4 receptors have a
family of Heregulins as their major ligands, and receptor
overexpression and mutation have been unequivocally demonstrated as
the major risk factor in poor prognosis breast cancer.
Additionally, it has been demonstrated that all four of the members
of this family of receptors can form heterodimeric signalling
complexes with other members of the family, and that this can lead
to synergistic transforming capacity if more than one member of the
family is overexpressed in a malignancy. Overexpression of more
than one family member has been shown to be relatively common in
human malignancies.
[0005] In addition to cancer, restenosis is also a disease in which
undesired cellular proliferation occurs. Restenosis involves the
proliferation of vascular smooth muscle cells. Restenosis is a
major clinical problem associated with coronary angioplasty and
other medical procedures. Restenosis generally occurs within about
0 to 6 months in about 30% to 50% of patients who undergo balloon
angioplasty to clear clogged coronary arteries in an effort to
treat heart disease due to occluded arteries. The resulting
restenosis causes substantial patient morbidity and health care
expense.
[0006] The process of restenosis is initiated by injury of the
blood vessel, including arteries and veins, with the subsequent
release of thrombogenic, vasoactive, and mitogenic factors.
Endothelial and deep vessel injury leads to platelet aggregation,
thrombus formation, inflammation, and activation of macrophages and
smooth muscle cells. These events induce the production of and
release of growth factors and cytokines, which in turn may promote
their own synthesis and release from target cells. Thus, a
self-perpetuating process involving growth factors such as EGF,
platelet derived growth factor (PDGF) or fibroblast growth factor
(FGFs) is initiated. Thus, it would be useful to have irreversible
inhibitors of signal transduction pathways, particularly of
tyrosine kinases like EGF, PDGF, FGF, or src tyrosine kinases.
[0007] The proliferative skin disease psoriasis has no good cure at
present. It is often treated by anticancer agents such as
methotrexate, which have very serious side effects, and which are
not very effective at the toxicity limited doses which have to be
used. It is believed that TGF alpha is the major growth factor
overproduced in psoriasis, since 50% of transgenic mice which over
express TGF alpha develop psoriasis. This suggests that a good
inhibitor of EGFR signalling could be used as antipsoriatic agent,
preferably, but not necessarily, by topical dosing.
[0008] It is especially advantageous to have irreversible tyrosine
kinase inhibitors when compared to reversible inhibitors, because
irreversible inhibitors can be used in prolonged suppression of the
tyrosine kinase, limited only by the normal rate of receptor
resynthesis, also called turnover.
[0009] Additional information on the role of src tyrosine kinases
in biological processes relating to cancer and restenosis can be
found in the following documents, which are all hereby incorporated
by reference.
[0010] Benjamin C. W. and Jones D. A., Platelet-Derived Growth
Factor Stimulates Growth Factor Receptor Binding Protein-2
Association With Src In Vascular Smooth Muscle Cells, JBC,
1994;269:30911-30916.
[0011] Kovalenko M., et al., Selective Platelet-Derived Growth
Factor Receptor Kinase Blockers Reverse Cis-transformation, Cancer
Res, 1994;54:6106-6114.
[0012] Schwartz R. S., et al., The Restenosis Paradigm Revisted: An
Alternative Proposal for Cellular Mechanisms, J Am Coll Cardiol,
1992;20:1284-1293.
[0013] Libby P., et al., Cascade Model for Restenosis--A Special
Case of Atherosclerosis Progression, Circulation,
1992;86:47-52.
[0014] Additional information on the role of EGF tyrosine kinases
in biological processes relating to cancer and restenosis can be
found in the following document which is hereby incorporated by
reference.
[0015] Jonathan Blay and Morley D. Hollenberg, Heterologous
Regulation Of EGF Receptor Function In Cultured Aortic Smooth
Muscle Cells, Eur J Pharmacol, Mol Pharmacol Sect, 1989;
172(1):1-7.
[0016] Information that shows that antibodies to EGF or EGFR show
in vivo antitumor activity can be found in the following documents
which are hereby incorporated by reference.
[0017] Modjtahedi H., Eccles S., Box G., Styles J., Dean C.,
Immunotherapy Of Human Tumour Xenografts Overexpressing The EGF
Receptor With Rat Antibodies That Block Growth Factor-Receptor
Interaction, Br J Cancer, 1993;67:254-261.
[0018] Kurachi H., Morishige K. I., Amemiya K., Adachi H., Hirota
K., Miyake A., Tanizawa O., Importance Of Transforming Growth
Factor Alpha/Epidermal Growth Factor Receptor Autocrine Growth
Mechanism In An Ovarian Cancer Cell Line In Vivo, Cancer Res,
1991-;51:5956-5959.
[0019] Masui H., Moroyama T., Mendelsohn J., Mechanism Of Antitumor
Activity In Mice For Anti-Epidermal Growth Factor Receptor
Monoclonal Antibodies With Different Isotypes, Cancer Res,
1986;46:5592-5598.
[0020] Rodeck U., Herlyn M., Herlyn D., Molthoff C., Atkinson B.,
Varello M., Steplewski Z., Koprowski H., Tumor Growth Modulation By
A Monoclonal Antibody To The Epidermal Growth Factor Receptor:
Immunologically Mediated And Effector Cell-Independent Effects,
Cancer Res, 1987;47:3692-3696.
[0021] Guan E., Zhou T., Wang J., Huang P., Tang W., Zhao M., Chen
Y., Sun Y., Growth Inhibition Of Human Nasopharyngeal Carcinoma In
Athymic Mice By Anti-Epidermal Growth Factor Receptor Monoclonal
Antibodies, Internat J Cell Clon, 1989;7:242-256.
[0022] Masui H., Kawamoto T., Sato J. D., Wolf B., Sato G.,
Mendelsohn J., Growth Inhibition Of Human Tumor Cells In Athymic
Mice By Anti-Epidermal Growth Factor Receptor Monoclonal
Antibodies. Cancer Res, 1984;44:1002-1007.
[0023] In addition, the following documents show the antitumor
activity of protein tyrosine kinase inhibitors. The documents are
hereby incorporated by reference.
[0024] Buchdunger E., Trinks U., Mett H., Regenass U., Muller M.,
Meyer T., McGlynn E., Pinna L. A., Traxler P., Lydon N. B.,
4,5-Dianilinophthalimide: A Protein Tyrosine Kinase Inhibitor With
Selectivity For The Epidermal Growth Factor Receptor Signal
Transduction Pathway And Potent In Vivo Antitumor Activity, Proc
Natl Acad Sci USA, 1994;91:2334-2338.
[0025] Buchdunger E., Mett H., Trinks U., Regenass U., Muller M.,
Meyer T., Beilstein P., Wirz B., Schneider P., Traxler P., Lydon
N., 4,5-Bis (4-Fluoroanilino)Phthalimide: A Selective Inhibitor Of
The Epidermal Growth Factor Receptor Signal Transduction Pathway
With Potent In Vivo Mdd Antitumor Activity, Clinical Cancer
Research, 1995;1:813-821.
[0026] Compounds that are reversible inhibitors of tyrosine kinases
have been described in U.S. Pat. Nos. 5,457,105, 5,475,001, and
5,409,930 and in PCT publication Numbers WO 9519774, WO 9519970, WO
9609294, and WO 9523141. The presently disclosed compounds, which
are structurally different from the tyrosine kinase inhibitors
described in the above-identified documents, are irreversible
inhibitors of tyrosine kinases.
SUMMARY OF THE INVENTION
[0027] The present invention provides compounds having the Formula
I 1
[0028] wherein X is -D-E-F and Y is --SR.sup.4, halogen,
--OR.sup.4, --NHR.sup.3, or hydrogen, or X is --SR.sup.4, halogen,
--OR.sup.4, --NHR.sup.3, or hydrogen, and Y is -D-E-F; 2
[0029] each R.sup.a is independently hydroxy, amino, N-mono- or
N,N-di-(C.sub.1-C.sub.4) alkylamino, sulfo, or
(C.sub.1-C.sub.4)alkoxy (provided that such groups are not attached
to a ring carbon which is adjacent to an oxy, thio, or --N--), or
R.sup.a is independently carboxy, hydroxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4) alkyl,
amino(C.sub.1-C.sub.4)alkyl, mono-N-- or di-N,N--(C.sub.1-C.sub.4)-
alkylamino(C.sub.1-C.sub.4)alkyl, morpholino(C.sub.1-C.sub.4)alkyl,
4-(C.sub.1-C.sub.4)alkyl-piperazin-1-yl(C.sub.1-C.sub.4)alkyl,
carboxy(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxycarbonyl,
sulfo(C.sub.1-C.sub.4)alkyl, or (C.sub.1-C.sub.4)alkyl;
[0030] each R.sup.b is independently mono-, di-, or
trifluoromethyl, halo, nitro, hydroxy, amino, axido, isothiocyano,
(C.sub.1-C.sub.4)alkyl, phenyl, thienyl, (C.sub.1-C.sub.4)alkoxy,
benzyloxy, phenoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.4)alkylenedioxy, cyano,
benzoylamino, trifluoromethylcarbonylamino,
(C.sub.1-C.sub.4)alkanoylamino, (C.sub.1-C.sub.4)alkanoyl, N-mono-
or N,N-di-(C.sub.1-C.sub.4)alkylamino,
(C.sub.1-C.sub.4)alkylsulfonylamino, trifluoromethylsulfonylamino,
(C.sub.1-C.sub.4)alkylthio, (C.sub.1-C.sub.4)alkylsulfinyl or
(C.sub.1-C.sub.4)alkylsulfonyl, pyrrol-1-yl, piperidin-1-yl or
pyrrolidin-1-yl, said phenyl, benzyloxy, phenoxy, and benzoylamino
optionally mono-substituted with halo, nitro, trifluoromethyl,
hydroxy, or (C.sub.1-C.sub.4)alkyl and said
(C.sub.1-C.sub.4)alkylenedioxy is linked at both ends to adjacent
carbons on the benzene moiety, or R.sup.b is -Z.sup.aR.sup.77;
[0031] J is --CH.sub.2--, thio, --N(H)--, or oxy;
[0032] g is 0, 1, or 2;
[0033] h is 0 to 4;
[0034] k is 0, 1, or2;
[0035] S completes a 5- or 6-membered aromatic or partially
saturated ring that can contain an oxygen or sulfur atom;
[0036] T is --CH.sub.2, --N(H)--, thio, or oxy;
[0037] S.sup.a is --CH.sub.2--, oxy, or thio;
[0038] A.sup.1completes a 7- to 9-membered mono-unsaturated
mono-aza ring;
[0039] R.sup.1is hydrogen, halogen, or C.sub.1-C.sub.6 alkyl;
[0040] Q.sup.a is a 9- or 10-membered bicyclic heterocyclic moiety,
or a hydrogenated derivative thereof, containing one or two
nitrogen heteroatoms and optionally containing a further heteroatom
selected from nitrogen, oxygen and sulfur, or Q.sup.a is a 9- or
10-membered bicyclic aryl moiety, or a hydrogenated derivative
thereof, which heterocyclic or aryl moiety, or hydrogenated
derivatives thereof, may optionally bear one or two substituents
selected from halogen, hydroxy, oxo, amino, nitro, carbamoyl,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkylamino, di-[(C.sub.1-C.sub.4)alkyl]amino, and
(C.sub.2-C.sub.4)alkanoylamino;
[0041] R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-piperaziny-
l[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n-imidazoyl,
--(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--(CH.sub.2).sub.n--N-hexahydroazep- ine or substituted
C.sub.1-C.sub.6 alkyl, wherein the substituents are selected from
--OH, --NH.sub.2, or 3
[0042] A and B are independently hydrogen, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.nOH, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-piperaziny-
l[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n--N-pyridyl,
--(CH.sub.2).sub.n-imidazoyl, or
--(CH.sub.2).sub.n--N-imidazoyl;
[0043] Z.sup.1, Z.sup.2, or Z.sup.3 are independently hydrogen,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.8 cycloalkoxy, nitro,
C.sub.1-C.sub.6 perfluoroalkyl, hydroxy, C.sub.1-C.sub.6 acyloxy,
--NH.sub.2, --NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, --NH(C.sub.3-C.sub.8 cycloalkyl), --N(C.sub.3-C.sub.8
cycloalkyl).sub.2, hydroxymethyl, C.sub.1-C.sub.6 acyl, cyano,
azido, C.sub.1-C.sub.6 thioalkyl, C.sub.1-C.sub.6 sulfinylalkyl,
C.sub.1-C.sub.6 sulfonylalkyl, C.sub.3-C.sub.8 thiocycloalkyl,
C.sub.3-C.sub.8 sulfinylcycloalkyl, C.sub.3-C.sub.8
sulfonylcycloalkyl, mercapto, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.3-C.sub.8 cycloalkoxycarbonyl, C.sub.2-C.sub.4 alkenyl,
C.sub.4-C.sub.8 cycloalkenyl, or C.sub.2-C.sub.4 alkynyl;
[0044] Z.sup.a is a bond, --CH.sub.2--, --S--, SO.sub.2, --NH--,
--O--, --OCH.sub.2--, --S--CH.sub.2--, --SO.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2--;
[0045] R.sup.5 is hydrogen, halogen, C.sub.1-C.sub.6
perfluoroalkyl, 1,1-difluoro(C.sub.1-C.sub.6)alkyl, C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n-piperazinyl,
--(CH.sub.2).sub.n-piperazinyl[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino, 4
[0046] --CH.dbd.CH--(C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.n--N-hexahydr- oazepine,
--(CH.sub.2).sub.nNH.sub.2,--(CH.sub.2).sub.nNH(C.sub.1-C.sub.6a-
lkyl), --(CH.sub.2).sub.nN(C.sub.1-C.sub.6alkyl).sub.2,
-1-oxo(C.sub.1-C.sub.6)alkyl, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl,
N--(C.sub.1-C.sub.6)alkylcarbamoyl, phenyl or substituted phenyl,
wherein the substituted phenyl can have from one to three
substituents independently selected from Z.sup.1, Z.sup.2, Z.sup.3
or a monocyclic heteroaryl group, and each C.sub.1-C.sub.6 alkyl
group above in R.sup.5 can be substituted with --OH, --NH.sub.2 or
--NAB, where A and B are as defined above;
[0047] R.sup.77 is phenyl, substituted phenyl, or a 5- to
10-membered optionally substituted heterocyclic aromatic ring;
[0048] R.sup.13 is hydrogen or halogen; and
[0049] n is 1 to 4, and the pharmaceutically acceptable salts,
esters, amides, and prodrugs thereof.
[0050] In a preferred embodiment of the compounds of Formula I,
5
[0051] and Y is hydrogen, or
[0052] X is hydrogen, and Y is 6
[0053] In another preferred embodiment of the compounds of Formula
I, Y is -D-E-F, and -D-E-F is 7
[0054] In another preferred embodiment of the compounds of Formula
I, X is -D-E-F, and -D-E-F is 8
[0055] In another preferred embodiment of the compounds of Formula
I, R.sup.2 is hydrogen.
[0056] In another preferred embodiment of the compounds of Formula
I, Y is -D-E-F and X is --O(CH.sub.2).sub.n-morpholino.
[0057] In another preferred embodiment of the compounds of Formula
I, R.sup.5 is carboxy, (C.sub.1-C.sub.6 alkyl)oxycarbonyl or
C.sub.1-C.sub.6 alkyl.
[0058] In another preferred embodiment of the compounds of Formula
I, Y is -D-E-F and X is --O(CH.sub.2).sub.nmorpholino.
[0059] In another preferred embodiment of the compounds of Formula
I, Y is -D-E-F and X is
--O--(CH.sub.2).sub.n--N.sub.1-piperazinyl[N.sub.4--(C.su-
b.1-C.sub.6)alkyl].
[0060] In another preferred embodiment of the compounds of Formula
I, Y is -D-E-F and X is --O--(CH.sub.2).sub.n-imidazoyl.
[0061] In another embodiment, the present invention provides
compounds having the Formula II
Q-Z II
[0062] wherein Q is 9
[0063] p is 0 or 1;
[0064] X is -D-E-F and Y is --SR.sup.4, --OR.sup.4, --NHR.sup.3 or
hydrogen, or X is --SR.sup.4, --OR.sup.4, --NHR.sup.3 or hydrogen,
and Y is -D-E-F; 10
[0065] each R.sup.a is independently hydroxy, amino, N-mono- or
N,N-di-(C.sub.1-C.sub.4) alkylamino, sulfo, or
(C.sub.1-C.sub.4)alkoxy (provided that such groups are not attached
to a ring carbon which is adjacent to an oxy, thio, or --N--), or
R.sup.a is independently carboxy, hydroxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4) alkyl,
amino(C.sub.1-C.sub.4)alkyl, mono-N-- or di-N,N--(C.sub.1-C.sub.4)-
alkylamino(C.sub.1-C.sub.4)alkyl, morpholino(C.sub.1-C.sub.4)alkyl,
4-(C.sub.1-C.sub.4)alkyl-piperazin-1-yl(C.sub.1-C.sub.4)alkyl,
carboxy(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxycarbonyl,
sulfo(C.sub.1-C.sub.4)alkyl, or (C.sub.1-C.sub.4)alkyl;
[0066] each R.sup.b is independently mono-, di-, or
trifluoromethyl, halo, nitro, hydroxy, amino, axido, isothiocyano,
(C.sub.1-C.sub.4)alkyl, phenyl, thienyl, (C.sub.1-C.sub.4)alkoxy,
benzyloxy, phenoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.4)alkylenedioxy, cyano,
benzoylamino, trifluoromethylcarbonylamino,
(C.sub.1-C.sub.4)alkanoyl amino, (C.sub.1-C.sub.4)alkanoyl, N-mono-
or N,N-di-(C.sub.1-C.sub.4)alkylamino,
(C.sub.1-C.sub.4)alkylsulfonylamino, trifluoromethylsulfonylamino,
(C.sub.1-C.sub.4)alkylthio, (C.sub.1-C.sub.4)alkylsulfinyl or
(C.sub.1-C.sub.4)alkylsulfonyl, pyrrol-1-yl, piperidin-1-yl or
pyrrolidin-1-yl, said phenyl, benzyloxy, phenoxy, and benzoylamino
optionally mono-substituted with halo, nitro, trifluoromethyl,
hydroxy, or (C.sub.1-C.sub.4)alkyl and said
(C.sub.1-C.sub.4)alkylenedioxy is linked at both ends to adjacent
carbons on the benzene moiety, or R.sup.b is -Z.sup.aR.sup.77;
[0067] J is --CH.sub.2--, thio, --N(H)--, or oxy;
[0068] g is 0, 1, or 2;
[0069] h is 0 to 4;
[0070] k is 0, 1, or 2;
[0071] S completes a 5- or 6-membered aromatic or partially
saturated ring that can contain an oxygen or sulfur atom;
[0072] T is --CH.sub.2, --N(H)--, thio, or oxy;
[0073] S.sup.a is --CH.sub.2--, oxy, or thio;
[0074] A.sup.1 completes a 7- to 9-membered mono-unsaturated
mono-aza ring;
[0075] Q.sup.a is a 9- or 10-membered bicyclic heterocyclic moiety,
or a hydrogenated derivative thereof, containing one or two
nitrogen heteroatoms and optionally containing a further heteroatom
selected from nitrogen, oxygen and sulfur, or Q.sup.a is a 9- or
10-membered bicyclic aryl moiety, or a hydrogenated derivative
thereof, which heterocyclic or aryl moiety, or hydrogenated
derivatives thereof, may optionally bear one or two substituents
selected from halogen, hydroxy, oxo, amino, nitro, carbamoyl,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkylamino, di-[(C.sub.1-C.sub.4)alkyl]amino, and
(C.sub.2-C.sub.4)alkanoylamino;
[0076] R.sup.1 is hydrogen, halogen, or C.sub.1-C.sub.6 alkyl;
[0077] R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-piperaziny-
l[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n-imidazoyl,
--(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--(CH.sub.2).sub.n--N-hexahydroazep- ine or substituted
C.sub.1-C.sub.6 alkyl, wherein the substituents are selected from
--OH, --NH.sub.2, or 11
[0078] A and B are independently hydrogen, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.nOH, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-piperaziny-
l[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n--N-pyridyl,
--(CH.sub.2).sub.n-imidazoyl, or
--(CH.sub.2).sub.n--N-imidazoyl;
[0079] E.sup.1, E.sup.2, or E.sup.3 are independently hydrogen,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.8 cycloalkoxy, nitro,
C.sub.1-C.sub.6 perfluoroalkyl, hydroxy, C.sub.1-C.sub.6 acyloxy,
--NH.sub.2, --NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, --NH(C.sub.3-C.sub.8 cycloalkyl), --N(C.sub.3-C.sub.8
cycloalkyl).sub.2, hydroxymethyl, C.sub.1-C.sub.6 acyl, cyano,
azido, C.sub.1-C.sub.6 thioalkyl, C.sub.1-C.sub.6 sulfinylalkyl,
C.sub.1-C.sub.6 sulfonylalkyl, C.sub.3-C.sub.8 thiocycloalkyl,
C.sub.3-C.sub.8 sulfinylcycloalkyl, C.sub.3-C.sub.8
sulfonylcycloalkyl, mercapto, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.3-C.sub.8 cycloalkoxycarbonyl, C.sub.2-C.sub.4 alkenyl,
C.sub.4-C.sub.8 cycloalkenyl, or C.sub.2-C.sub.4 alkynyl;
[0080] Z.sup.a is a bond, --CH.sub.2--, --S--, SO.sub.2, --NH--,
--O--, --OCH.sub.2--, --S--CH.sub.2--, --SO.sub.2--, or
--CH.sub.2CH.sub.2--;
[0081] R.sup.77 is phenyl, substituted phenyl, or a 5- to
10-membered optionally substituted heterocyclic aromatic ring;
[0082] R.sup.5 is hydrogen, halogen, C.sub.1-C.sub.6
perfluoroalkyl, 1,1-difluoro(C.sub.1-C.sub.6)alkyl, C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.7).sub.n-piperazinyl,
--(CH.sub.2).sub.n-piperazinyl[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino, 12
[0083] --CH.dbd.CH--(C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.n--N-hexahydr- oazepine,
--(CH.sub.2).sub.nNH.sub.2,--(CH.sub.2).sub.nNH(C.sub.1-C.sub.6a-
lkyl), --(CH.sub.2).sub.nN(C.sub.1-C.sub.6alkyl).sub.2,
-1-oxo(C.sub.1-C.sub.6)alkyl, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl,
N--(C.sub.1-C.sub.6)alkylcarbamoyl, phenyl or substituted phenyl,
wherein the substituted phenyl can have from one to three
substituents independently selected from E.sup.1, E.sup.2, E.sup.3
or a monocyclic heteroaryl group, and each C.sub.1-C.sub.6 alkyl
group can be substituted with --OH, --NH.sub.2 or --NAB, where A
and B are as defined above; and
[0084] n is 1to 4, and the pharmaceutically acceptable salts,
esters, amides, and prodrugs thereof.
[0085] In another preferred embodiment of the compounds of Formula
II, Q is 13
[0086] In another preferred embodiment of the compounds of Formula
II, Q is 14
[0087] In another preferred embodiment of the compounds of Formula
II, Q is 15
[0088] In another preferred embodiment of the compounds of Formula
II, Q is 16
[0089] In another preferred embodiment of the compounds of Formula
II, X is 17
[0090] In another preferred embodiment of the compounds of Formula
II, X is 18
[0091] In another embodiment, the present invention provides
compounds having the Formula II
Q-Z II
[0092] wherein Q is 19
[0093] p is 0 or 1;
[0094] X is -D-E-F, and Y is --SR.sup.4, --OR.sup.4, --NHR.sup.3 or
hydrogen, or X is --SR.sup.4, --OR.sup.4, --NHR.sup.3 or hydrogen,
and Y is -D-E-F; 20
[0095] each R.sup.a is independently hydroxy, amino, N-mono- or
N,N-di-(C.sub.1-C.sub.4) alkylamino, sulfo, or
(C.sub.1-C.sub.4)alkoxy (provided that such groups are not attached
to a ring carbon which is adjacent to an oxy, thio, or --N--), or
R.sup.a is independently carboxy, hydroxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4) alkyl,
amino(C.sub.1-C.sub.4)alkyl, mono-N-- or di-N,N--(C.sub.1-C.sub.4)-
alkylamino(C.sub.1-C.sub.4)alkyl, morpholino(C.sub.1-C.sub.4)alkyl,
4-(C.sub.1-C.sub.4)alkyl-piperazin-1-yl(C.sub.1-C.sub.4)alkyl,
carboxy(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxycarbonyl,
sulfo(C.sub.1-C.sub.4)alkyl, or (C.sub.1-C.sub.4)alkyl;
[0096] each R.sup.b is independently mono-, di-, or
trifluoromethyl, halo, nitro, hydroxy, amino, axido, isothiocyano,
(C.sub.1-C.sub.4)alkyl, phenyl, thienyl, (C.sub.1-C.sub.4)alkoxy,
benzyloxy, phenoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.4)alkylenedioxy, cyano,
benzoylamino, trifluoromethylcarbonylamino,
(C.sub.1-C.sub.4)alkanoylamino, (C.sub.1-C.sub.4)alkanoyl, N-mono-
or N,N-di-(C.sub.1-C.sub.4)alkylamino,
(C.sub.1-C.sub.4)alkylsulfonylamino, trifluoromethylsulfonylamino,
(C.sub.1-C.sub.4)alkylthio, (C.sub.1-C.sub.4)alkylsulfinyl or
(C.sub.1-C.sub.4)alkylsulfonyl, pyrrol-1-yl, piperidin-1-yl or
pyrrolidin-1-yl, said phenyl, benzyloxy, phenoxy, and benzoylamino
optionally mono-substituted with halo, nitro, trifluoromethyl,
hydroxy, or (C.sub.1-C.sub.4)alkyl and said
(C.sub.1-C.sub.4)alkylenedioxy is linked at both ends to adjacent
carbons on the benzene moiety, or R.sup.b is -Z.sup.aR.sup.77;
[0097] J is --CH.sub.2--, thio, --N(H)--, or oxy;
[0098] g is 0, 1, or 2;
[0099] h is 0 to 4;
[0100] k is 0, 1, or 2;
[0101] S completes a 5- or 6-membered aromatic or partially
saturated ring that can contain an oxygen or sulfur atom;
[0102] T is --CH.sub.2, --N(H)--, thio, or oxy;
[0103] S.sup.a is --CH.sub.2--, oxy, or thio;
[0104] A.sup.1completes a 7- to 9-membered mono-unsaturated
mono-aza ring;
[0105] Q.sup.a is a 9- or 10-membered bicyclic heterocyclic moiety,
or a hydrogenated derivative thereof, containing one or two
nitrogen heteroatoms and optionally containing a further heteroatom
selected from nitrogen, oxygen and sulfur, or Q.sup.a is a 9- or
10-membered bicyclic aryl moiety, or a hydrogenated derivative
thereof, which heterocyclic or aryl moiety, or hydrogenated
derivatives thereof, may optionally bear one or two substituents
selected from halogen, hydroxy, oxo, amino, nitro, carbamoyl,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkylamino, di-[(C.sub.1-C.sub.4)alkyl]amino, and
(C.sub.2-C.sub.4)alkanoylamino;
[0106] R.sup.1is hydrogen, halogen, or C.sub.1-C.sub.6 alkyl;
[0107] R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH,).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-piperazinyl[N.s-
ub.4--(C.sub.1-C.sub.6)alkyl], --(CH.sub.2).sub.n--N-pyrrolidyl,
--(CH.sub.2).sub.n-pyridinyl, --(CH.sub.2).sub.n--N-imidazoyl,
--(CH-).sub.n-imidazoyl, --(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--(CH.sub.2).sub.n--N-hexahydroazep- ine or substituted
C.sub.1-C.sub.6 alkyl, wherein the substituents are selected from
--OH, --NH.sub.2, or 21
[0108] A and B are independently hydrogen, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.nOH, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-piperaziny-
l[N.sub.4--(C.sub.1-C.sub.6)alkyl], --(CH,).sub.n--N-pyrrolidyl,
--(CH.sub.2).sub.n--N-pyridyl, --(CH.sub.2).sub.n-imidazoyl, or
--(CH.sub.2).sub.n--N-imidazoyl;
[0109] E.sup.1, E.sup.2, or E.sup.3 are independently hydrogen,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.8 cycloalkoxy, nitro,
C.sub.1-C.sub.6 perfluoroalkyl, hydroxy, C.sub.1-C.sub.6 acyloxy,
--NH.sub.2, --NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, --NH(C.sub.3-C.sub.8 cycloalkyl), --N(C.sub.3-C.sub.8
cycloalkyl).sub.2, hydroxymethyl, C.sub.1-C.sub.6 acyl, cyano,
azido, C.sub.1-C.sub.6 thioalkyl, C.sub.1-C.sub.6 sulfinylalkyl,
C.sub.1-C.sub.6 sulfonylalkyl, C.sub.3-C.sub.8 thiocycloalkyl,
C.sub.3-C.sub.8 sulfinylcycloalkyl, C.sub.3-C.sub.8
sulfonylcycloalkyl, mercapto, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.3-C.sub.8 cycloalkoxycarbonyl, C.sub.2-C.sub.4 alkenyl,
C.sub.4-C.sub.8 cycloalkenyl, or C.sub.2-C.sub.4 alkynyl;
[0110] Z.sup.a is a bond, --CH.sub.2--, --S--, SO.sub.2, --NH--,
--O--, --OCH.sub.2--, --S--CH.sub.2--, --SO.sub.2--, or
--CH.sub.2CH.sub.2--;
[0111] R.sup.77 is phenyl, substituted phenyl, or a 5- to
10-membered optionally substituted heterocyclic aromatic ring;
[0112] R.sup.5 is hydrogen, halogen, C.sub.1-C.sub.6
perfluoroalkyl, 1,1-difluoro(C.sub.1-C.sub.6)alkyl, C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n-piperazinyl,
--(CH.sub.2).sub.n-piperazinyl[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino, 22
[0113] --CH.dbd.CH--(C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.n--N-hexahydr- oazepine,
--(CH.sub.2).sub.nNH.sub.2,--(CH.sub.2).sub.nNH(C.sub.1-C.sub.6a-
lkyl), --(CH.sub.2).sub.nN(C.sub.1-C.sub.6alkyl).sub.2,
-1-oxo(C.sub.1-C.sub.6)alkyl, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl,
N--(C.sub.1-C.sub.6)alkylcarbamoyl, phenyl or substituted phenyl,
wherein the substituted phenyl can have from one to three
substituents independently selected from E.sup.1, E.sup.2, E.sup.3
or a monocyclic heteroaryl group, and each C.sub.1-C.sub.6 alkyl
group can be substituted with --OH, --NH.sub.2 or --NAB, where A
and B are as defined above; and
[0114] n is 1 to 4, and the pharmaceutically acceptable salts,
esters, amides, and prodrugs thereof.
[0115] In another preferred embodiment of the compounds of Formula
III, Q is 23
[0116] In another preferred embodiment of the compounds of Formula
III, Q is 24
[0117] In another preferred embodiment of the compounds of Formula
III, X is 25
[0118] In another preferred embodiment of the compounds of Formula
III, X is 26
[0119] In another preferred embodiment, Q is a 6-substituted
benzothieno[3,2-d]pyrmid-4-yl.
[0120] The present invention also provides a pharmaceutically
acceptable composition that comprises a compound of Formula I or
II.
[0121] The present invention also provides a method of treating
cancer, the method comprising administering to a patient having
cancer a therapeutically effective amount of a compound of Formula
I or II.
[0122] The present invention also provides a method of treating or
preventing restenosis, the method comprising administering to a
patient having restenosis or at risk of having restenosis, a
therapeutically effective amount of a compound of Formula I or
II.
[0123] The present invention also provides a method of treating
psoriasis, the method comprising administering to a patient having
psoriasis a therapeutically effective amount of a compound of
Formula I or II.
[0124] The present invention also provides a method of treating
atherosclerosis, the method comprising administering to a patient
having atherosclerosis a therapeutically effective amount of a
compound of Formula I or II.
[0125] The present invention also provides a method of treating
endometriosis, the method comprising administering to a patient
having endometroisis a therapeutically effective amount of a
compound of Formula I or II.
[0126] The present invention also provides a method of irreversibly
inhibiting tyrosine kinases, the method comprising administering to
a patient in need of tyrosine kinase inhibition a tyrosine kinase
inhibiting amount of a compound of Formula I or II.
[0127] In a most preferred embodiment the present invention
provides the following compounds:
[0128]
N-[4-(6-Bromo-2,3-dihydroindol-1-yl)quinazolin-6-yl]acrylamide;
[0129]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]acrylamide;
[0130]
N-[4-(7-Chloro-3,4-dihydro-2H-quinolin-1-yl)quinazolin-6-yl]acrylam-
ide;
[0131]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]propynamide;
[0132]
N-[4-(7-Chloro-3,4-dihydro-2H-quinolin-1yl)quinazolin-7-yl]acrylami-
de;
[0133]
N-[4-(6-Chloro-2,3-dihydroindol-1yl)quinazolin-6-yl]propynamide;
[0134]
N-[4-(7-Trifluoromethyl-3,4-dihydro-2H-quinolin-1-yl)quinazolin-6-y-
l]propynamide;
[0135]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-7-yl]propynamide;
[0136]
N-[4-(7-Trifluoromethyl-3,4-dihydro-2H-quinolin-1-yl)quinazolin-7-y-
l]propynamide;
[0137]
N-[4-(4-6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]but-2-ynamid-
e;
[0138]
N-[4-(6-Bromo-5-fluoro-2,3-dihydroindol-1-yl)quinazolin-6-yl]but-2--
ynamide;
[0139]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]buta-2,3-diena-
mide;
[0140]
N-[4-(6-Bromo-5-fluoro-2,3-dihydroindol-1-yl)quinazolin-6-yl]buta-2-
,3-dienamide;
[0141]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]but-2-enamide;
[0142]
N-[4-(6-Ethynyl-2,3-dihydroindol-1-yl)quinazolin-6-yl]but-2-enamide-
;
[0143]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4,4,4-trifluo-
robut-2-enamide;
[0144]
N-[4-(6-Nitro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4,4,4-trifluor-
obut-2-enamide;
[0145]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-3-chloroacryl-
-amide;
[0146]
N-[4-(6-Nitro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-3-chloroacryl--
amide;
[0147]
6-(S-Vinylsulfonamido)-4-(6-chloro-2,3-dihydroindol-1-yl)quinazolin-
e;
[0148]
6-(S-Vinylsulfonamido)-4-(6-pyrrol-1-yl-2,3-dihydroindol-1-yl)quina-
zoline;
[0149]
N-[7-[3-(4-Morpholino)propoxy]-4-(6-chloro-2,3-dihydroindol-1-yl)qu-
inazolin-6-yl]acrylamide;
[0150]
N-[4-(6-Pyrrol-1-yl-2,3-dihydroindol-1-yl)-7-[4-(N,N-dimethylamino)-
butoxy]quinazolin-6-yl]acrylamide
[0151]
N-[7-[4-(N,N-dimethylamino)butoxy]-4-(6-chloro-2,3-dihydroindol-1-y-
l)quinazolin-6-yl]acrylamide;
[0152]
N-[4-(Octahydroindol-1-yl)-7-[3-(4-morpholino)propoxy]quinazolin-6--
yl]acrylamide;
[0153]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-oxopent-2-e-
namide;
[0154]
N-[4-(Octahydroindol-1-yl)quinazolin-6-yl]-4-oxopent-2-enamide;
[0155]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-hydroxy-4-o-
xobut-2-enamide;
[0156]
N-[4-(6,7-Dihydro-5H-[1,3]dioxolo[4,5-f]indol-5-yl)quinazolin-6-yl]-
-4-hydroxy-4-oxobut-2-enamide;
[0157]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-ethoxy-4-ox-
obut-2-enamide;
[0158]
N-[4-(6,7-Dihydro-5H-[1,3]dioxolo[4,5-f]indol-5-yl)quinazolin-6-yl]-
-4-ethoxy-4-oxobut-2-enamide;
[0159]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-(3-(N,N-dim-
ethylamino)propoxy)-4-oxobut-2-enamide;
[0160]
N-[4-(6-Methyl-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-(3-(N,N-dim-
ethylamino)propoxy)-4-oxobut-2-enamide;
[0161]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-(3-(N,N-dim-
ethylamino)propylamino)-4-oxobut-2-enamide;
[0162]
N-[4-(6-Methyl-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-(3-(N,N-dim-
ethylamino)propylamino)-4-oxobut-2-enamide;
[0163]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-(3-(4-morph-
olino)propoxy)-4-oxobut-2-enamide;
[0164]
N-[4-(6-Azido-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-(3-(4-morpho-
lino)propoxy)-4-oxobut-2-enamide;
[0165]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-(3-(4-morph-
olino)propylamino)-4-oxobut-2-enamide;
[0166]
N-[4-(6-Azido-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-(3-(4-morpho-
lino)propylamino)-4-oxobut-2-enamide;
[0167] 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(6-chloro-2,3-dih- ydroindol-1-yl)quinazolin-6-yl]amide;
[0168] 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(5-benzyloxy-2,3--
dihydroindol-1-yl)quinazolin-6-yl]amide;
[0169] Pent-2-enedioic acid
1{[4-(5-benzyloxy-2,3-dihydroindol-1-yl)quinaz-
olin-6-yl]amide}5-[(3-morpholin-4-ylpropyl)amide];
[0170] Pent-2-enedioic acid
1{[4-(6-chloro-2,3-dihydroindol-1-yl)quinazoli-
n-6-yl]amide}5-[(3-morpholin-4-ylpropyl)amide];
[0171]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-(3-(morphol-
in-4-yl)propylthio)but-2-enamide;
[0172] N-[4-(5-Methoxy-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4,
-(3-(morpholin-4-yl)propylthio)but-2-enamide;
[0173] 7-Morpholin-4-ylhept-2-ynoic
acid[4-(6-chloro-2,3-dihydroindol-1-yl- )quinazolin-6-yl]amide;
[0174] 7-Morpholin-4-ylhept-2-ynoic
acid[4-(5-methoxy-2,3-dihydroindol-1-y-
l)quinazolin-6-yl]amide;
[0175] 4-Morpholin-4-ylbut-2-ynoic
acid[4-(6-chloro-2,3-dihydroindol-1-yl)- quinazolin-6-yl]amide;
[0176] 4-Morpholin-4-ylbut-2-ynoic
acid[4-(2,3,4,5-tetrahydro-1H-benzoazep-
in-1-yl)quinazolin-6-yl]amide;
[0177]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]acry-
lamide;
[0178]
N-[4-(2,3,4,5-Tetrahydro-1H-benzoazepin-1-yl)pyrido[3,4-d]pyrimid-6-
-yl]acrylamide;
[0179]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[4,3-d]pyrimid-7-yl]acry-
lamide;
[0180]
N-[4-(5-Hydroxy-2,3-dihydroindol-1-yl)pyrido[4,3-d]pyrimid-7-yl]pro-
pynamide;
[0181]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]prop-
ynamide;
[0182]
N-[4-(5-Hydroxy-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]pro-
pynamide;
[0183]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[4,3-d]pyrimid-7-yl]prop-
ynamide;
[0184]
N-[4-(5-Amino-2,3-dihydroindol-1-yl)pyrido[4,3-d]pyrimid-7-yl]propy-
namide;
[0185]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]but--
2-ynamide;
[0186]
N-[4-(5-Amino-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]but-2-
-ynamide;
[0187]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]buta-
-2,3-dienamide;
[0188]
N-[4-(1,2,3,4,5,6-Hexahydrobenzo[b]azocin-1-yl)pyrido[3,4-d]pyrimid-
-6-yl]buta-2,3-dienamide;
[0189]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]but--
2-enamide;
[0190]
N-[4-(1,2,3,4,5,6-Hexahydrobenzo[b]azocin-1-yl)pyrido[3,4-d]pyrimid-
-6-yl]but-2-enamide;
[0191]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4,4-
,4-trifluorobut-2-enamide;
[0192]
N-[4-(6-Fluoro-7-methyl-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid--
6-yl]-4,4,4-trifluorobut-2-enamide;
[0193]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-3-c-
hloroacrylamide;
[0194]
N-[4-(6-Fluoro-7-methyl-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid--
6-yl]-3-chloroacrylamide;
[0195]
6-(S-Vinylsulfonamido)-4-(6-chloro-2,3-dihydroindol-1-yl)pyrido[3,4-
-d]pyrimidine;
[0196]
6-(S-Vinylsulfonamido)-4-(2,3,6,7,8,9-hexahydro-1H-benzo[g]indol-1--
yl)pyrido[3,4-d]pyrimidine;
[0197]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4-o-
xopent-2-enamide;
[0198]
N-[4-(2,3,6,7,8,9-Hexahydro-1H-benzo[g]indol-1-yl)pyrido[3,4-d]pyri-
mid-6-yl]-4-oxopent-2-enamide;
[0199]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4-h-
ydroxy-4-oxobut-2-enamide;
[0200]
N-[4-(6-Ethynyl-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4--
hydroxy-4-oxobut-2-enamide;
[0201]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4-e-
thoxy-4-oxobut-2-enamide;
[0202]
N-[4-(6-Ethynyl-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4--
ethoxy-4-oxobut-2-enamide;
[0203]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4-(-
3-(N,N-dimethylamino)propoxy)-4-oxobut-2-enamide;
[0204]
N-[4-(6-Ethynyl-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4--
(3-(N,N-dimethylamino)propoxy)-4-oxobut-2-enamide;
[0205]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4-(-
3-(N,N-dimethylamino)propylamino)-4-oxobut-2-enamide;
[0206]
N-[4-(6-Ethynyl-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4--
(3-(N,N-dimethylamino)propylamino)-4-oxobut-2-enamide;
[0207]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4-(-
3-(4-morpholino)propoxy)-4-oxobut-2-enamide;
[0208]
N-[4-(6-Ethynyl-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4--
(3-(4-morpholino)propoxy)4-oxobut-2-enamide;
[0209]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4-(-
3-(4-morpholino)propylamino)-4-oxobut-2-enamide;
[0210]
N-[4-(6-Ethynyl-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4--
(3-(4-morpholino)propylamino)-4-oxobut-2-enamide;
[0211] 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(6-chloro-2,3-dih-
ydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]amide;
[0212] 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(6-Ethynyl-2,3-di-
hydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]amide;
[0213] Pent-2-enedioic acid
1{[4-(2,3-dihydropyrrolo[2,3-f]indol-7-yl)pyri-
do[3,4-d]pyrimid-6-yl]amide}5-[(3-morpholin-4-ylpropyl)amide];
[0214] Pent-2-enedioic acid
1{[4-(6-chloro-2,3-dihydroindol-1-yl)pyrido[3,-
4-d]pyrimid-6-yl]amide}5-[(3-morpholin-4-ylpropyl)amide];
[0215]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)pyrido[3,4-d]pyrimid-6-yl]-4-(-
3-(morpholin-4-yl)propylthio)but-2-enamide;
[0216]
N-[4-(2,3-Dihydropyrrolo[2,3-f]indol-7-yl)pyrido[3,4-d]pyrimid-6-yl-
]-4-(3-(morpholin-4-yl)propylthio)but-2-enamide;
[0217] 7-Morpholin-4-ylhept-2-ynoic
acid[4-(6-chloro-2,3-dihydroindol-1-yl-
)pyrido[3,4-d]pyrimid-6-yl]amide;
[0218] 7-Morpholin-4-ylhept-2-ynoic
acid[4-(2,3,5,6-tetrahydropyrrolo[2,3--
f]indol-1-yl)pyrido[3,4-d]pyrimid-6-yl]amide;
[0219] 4-Morpholin-4-ylbut-2-ynoic
acid[4-(6-chloro-2,3-dihydroindol-1-yl)-
pyrido[3,4-d]pyrimid-6-yl]amide;
[0220] 4-Morpholin-4-ylbut-2-ynoic
acid[4-(2,3,5,6-tetrahydropyrrolo[2,3-f-
]indol-1-yl)pyrido[3,4-d]pyrimid-6-yl]amide;
[0221]
N-[4-(6-Chloro-2,3-dihydroindol-1-yl)benzo[b]thieno[3,2-d]pyrimid-6-
-yl]acrylamide;
[0222]
N-[4-(6-Ethynyl-2,3-dihydroindol-1-yl)benzo[b]thieno[3,2-d]pyrimid--
6-yl]acrylamide;
[0223]
[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]acrylate;
[0224]
[4-(2,3,5,6-Tetrahydropyrrolo[2,3-f]indol-1-yl)quinazolin-6-yl]acry-
late;
[0225]
[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-7-yl]acrylate;
[0226]
[4-(6-Ethynyl-2,3-dihydroindol-1-yl)quinazolin-7-yl]acrylate;
[0227]
[7-[3-(4-Morpholino)propoxy]-4-(6-chloro-2,3-dihydroindol-1-yl)quin-
azolin-6-yl]acrylate;
[0228]
[4-(-(2,3-Dihydropyrrolo[2,3-f]indol-7-yl)-7-[4-(N,N-dimethylamino)-
butoxy]quinazolin-6yl]acrylate;
[0229]
[7-[4-(N,N-dimethylamino)butoxy]-4-(6-chloro-2,3-dihydroindol-1-yl)-
quinazolin-6yl]acrylate;
[0230]
[4-(6-Ethynyl-2,3-dihydroindol-1-yl)-7-[3-(4-morpholino)propoxy]qui-
nazolin-6-yl]acrylate;
[0231]
N-(3-(4-Morpholino)propylamino)-4,O-[4-(6-chloro-2,3-dihydroindol-1-
-yl)quinazolin-6-yl]-4-oxobut-2-enamide;
[0232]
N-(3-(4-Morpholino)propylamino)-4,O-[4-(2,3,4,5-tetrahydro-1H-benzo-
azepin-1-yl)quinazolin-6-yl]-4-oxobut-2-enamide;
[0233] 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(6-chloro-2,3-dih- ydroindol-1-yl)quinazolin-6-yl]ester;
[0234] 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(6-bromo-2,3-dihy- droindol-1-yl)quinazolin-6-yl]ester;
[0235] Pent-2-enedioic acid
1{[4-(6-methyl-2,3-dihydroindol-1-yl)quinazoli-
n-6-yl]ester}5-[(3-morpholin-4-ylpropyl)amide];
[0236] Pent-2-enedioic acid
1{[4-(6-chloro-2,3-dihydroindol-1-yl)quinazoli-
n-6-yl]ester}5-[(3-morpholin-4-ylpropyl)amide];
[0237]
[4-(6-Chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-(3-(morpholin-
-4-yl)propylthio)but-2-enoate;
[0238]
[4-(6-Fluoro-2,3-dihydroindol-1-yl)quinazolin-6-yl]-4-(3-(morpholin-
-4-yl)propylthio)but-2-enoate;
[0239] 7-Morpholin-4-ylhept-2-ynoic
acid[4-(6-chloro-2,3-dihydroindol1- yl)quinazolin-6-yl]ester;
[0240] 7-Morpholin-4-ylhept-2-ynoic
acid[4-(6-chloro-7-fluoro-2,3-dihydroi-
ndol-1-yl)quinazolin-6-yl]ester;
[0241] 4-Morpholin-4-ylbut-2-ynoic
acid[4-(6-chloro-2,3-dihydroindol-1-yl)- quinazolin-6-yl]ester;
[0242] 4-Morpholin-4-ylbut-2-ynoic
acid[4-(6-ethynyl-2,3-dihydroindol-1-yl-
)quinazolin-6-yl]ester;
[0243] N-[4-(Quinol-2-ylamino)quinazolin-6-yl]acrylamide;
[0244] N-[4-(Indol-5-ylamino)quinazolin-6-yl]acrylamide;
[0245] N-[4-(Quinol-2-ylamino)quinazolin-7-yl]acrylamide;
[0246] N-[4-(Indol-5-ylamino)quinazolin-7-yl]acrylamide;
[0247] N-[4-(Quinol-3-ylamino)quinazolin-6-yl]propynamide;
[0248] N-[4-(Indol-5-ylamino)quinazolin-6-yl]propynamide;
[0249] N-[4-(Quinol-3-ylamino)quinazolin-7-yl]propynamide;
[0250] N-[4-(Indol-5-ylamino)quinazolin-7-yl]propynamide;
[0251] N-[4-(Quinol-5-ylamino)quinazolin-6-yl]but-2-ynamide;
[0252] N-[4-(Indol-5-ylamino)quinazolin-6-yl]but-2-ynamide;
[0253]
N-[4-(Quinol-5-ylamino)quinazolin-6-yl]buta-2,3-dienamide;
[0254]
N-[4-(Indol-5-ylamino)quinazolin-6-yl]buta-2,3-dienamide;
[0255] N-[4-(Quinol-6-ylamino)quinazolin-6-yl]but-2-enamide;
[0256] N-[4-(Indol-5-ylamino)quinazolin-6-yl]but-2-enamide;
[0257]
N-[4-(Quinol-6-ylamino)quinazolin-6-yl]-4,4,4-trifluorobut-2-enamid-
e;
[0258]
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-4,4,4-trifluorobut-2-enamide-
;
[0259]
N-[4-(Quinol-7-ylamino)quinazolin-6-yl]-3-chloroacrylamide;
[0260]
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-3-chloroacrylamide;
[0261] 6-(S-Vinylsulfonamido)-4-(quinol-7-ylamino)quinazoline;
[0262] 6-(S-Vinylsulfonamido)-4-(indol-5-ylamino)quinazoline;
[0263]
N-[7-[3-(4-Morpholino)propoxy]-4-(quinol-8-ylamino)quinazolin-6-yl]-
acrylamide;
[0264]
N-[4-(Indol-5-ylamino)-7-[4-(N,N-dimethylamino)butoxy]quinazolin-6--
yl]acrylamide;
[0265]
N-[7-[4-(N,N-dimethylamino)butoxy]-4-(quinol-8-ylamino)quinazolin-6-
-yl]acrylamide;
[0266]
N-[4-(Indol-5-ylamino)-7-[3-(4-morpholino)propoxy]quinazolin-6-yl]a-
crylamide;
[0267]
N-[4-(Isoquinol-1-ylamino)quinazolin-6-yl]-4-oxopent-2-enamide;
[0268]
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-4-oxopent-2-enamide;
[0269]
N-[4-(Isoquinol-1-ylamino)quinazolin-6-yl]-4-hydroxy-4-oxobut-2-ena-
mide;
[0270]
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-4-hydroxy-4-oxobut-2-enamide-
;
[0271]
N-[4-(Isoquinol-5ylamino)quinazolin-6yl]-4-oxobut-2-enamide;
[0272]
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-4-ethoxy-4-oxobut-2-enamide;
[0273]
N-[4-(Isoquinol-5-ylamino)quinazolin-6-yl]-4-(3-(N,N-dimethylamino)-
propoxy)-4-oxobut-2-enamide;
[0274]
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-4-(3-(N,N-dimethylamino)prop-
oxy)-4-oxobut-2-enamide;
[0275]
N-[4-(Indol-4-ylamino)quinazolin-6-yl]-4-(3-(N,N-dimethylamino)prop-
ylamino)-4-oxobut-2-enamide;
[0276]
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-4-(3-(N,N-dimethylamino)prop-
ylamino)-4-oxobut-2-enamide;
[0277]
N-[4-(Indol-4-ylamino)quinazolin-6-yl]-4-(3-(4-morpholino)propoxy)--
4-oxobut-2-enamide;
[0278]
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-4-(3-(4-morpholino)propoxy)--
4-oxobut-2-enamide;
[0279]
N-[4-(Indol-6-ylamino)quinazolin-6-yl]-4-(3-(4-morpholino)propylami-
no)-4-oxobut-2-enamide;
[0280]
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-4-(3-(4-morpholino)propylami-
no)-4-oxobut-2-enamide;
[0281] 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(indol-6-ylamino)- quinazolin-6-yl]amide;
[0282] 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(indol-5-ylamino)- quinazolin-6-yl]amide;
[0283] Pent-2-enedioic acid
1{[4-(indol-5-ylamino)quinazolin-6-yl]amide}5--
[(3-morpholin-4-ylpropyl)amide];
[0284] Pent-2-enedioic acid
1{[4-(1H-indazol-6-ylamino)quinazolin-6-yl]ami-
de}5-[(3-morpholin-4-ylpropyl)amide];
[0285]
N-[4-(1H-Indazol-6-ylamino)quinazolin-6-yl]-4-(3-(morpholin-4-yl)pr-
opylthio)but-2-enamide;
[0286]
N-[4-(Indol-5-ylamino)quinazolin-6-yl]-4-(3-(morpholin-4-yl)propylt-
hio)but-2-enamide;
[0287] 7-Morpholin-4-ylhept-2-ynoic
acid[4-(1H-indazol-5-ylamino)quinazoli- n-6-yl]amide;
[0288] 7-Morpholin-4-ylhept-2-ynoic
acid[4-(indol-5-ylamino)quinazolin-6-y- l]amide;
[0289] 4-Morpholin-4-ylbut-2-ynoic
acid[4-(1H-indazol-5-ylamino)quinazolin- -6-yl]amide;
[0290] 4-Morpholin-4-ylbut-2-ynoic
acid[4-(4-benzyloxyphenylamino)quinazol- in-6-yl]amide;
[0291]
N-[4-(1H-Indazol-4-ylamino)pyrido[3,4-d]pyrimid-6-yl]acrylamide;
[0292]
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]acrylamide;
[0293]
N-[4-(1H-Indazol-4-ylamino)pyrido[4,3-d]pyrimid-7-yl]acrylamide;
[0294]
N-[4-(Indol-5-ylamino)pyrido[4,3-d]pyrimid-7-yl]propynamide;
[0295]
N-[4-(1H-Indazol-4-ylamino)pyrido[3,4-d]pyrimid-6-yl]propynamide;
[0296]
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]propynamide;
[0297]
N-[4-(1H-Benzotriazol-5-ylamino)pyrido[4,3-d]pyrimid-7-yl]propynami-
de;
[0298]
N-[4-(Indol-5-ylamino)pyrido[4,3-d]pyrimid-7-yl]propynamide;
[0299]
N-[4-(1H-Benzotriazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]but-2-yna-
mide;
[0300] N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid
-6-yl]but-2-ynamide;
[0301]
N-[4-(1H-Benzotriazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]buta-2,3--
dienamide;
[0302]
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]buta-2,3-dienamide;
[0303]
N-[4-(1H-Benzotriazol-7-ylamino)pyrido[3,4-d]pyrimid-6-yl]but-2-ena-
mide;
[0304]
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]but-2-enamide,
[0305]
N-[4-(1H-Benzotriazol-7-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4,4,4-tr-
ifluorobut-2-enamide;
[0306]
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl)-4,4,4-trifluorobut-
-2-enamide;
[0307]
N-[4-(1H-Benzotriazol-7-ylamino)pyrido[3,4-d]pyrimid-6-yl]-3-chloro-
acrylamide;
[0308]
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-3-chloroacrylamide-
;
[0309]
6-(S-Vinylsulfonamido)4-(benzothiazol-5-ylamino)pyrido[3,4-d]-pyrim-
idine;
[0310] 6-(S-Vinylsulfonamido)-4-(indol-5-ylamino)
pyrido[3,4-d]pyrimidine;
[0311]
N-[4-(Benzothiazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-oxopent-2-
-enamide;
[0312]
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-oxopent-2-enamid-
e;
[0313]
N-[4-(Benzothiazol-6-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-hydroxy-4-
-oxobut-2-enamide;
[0314]
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-hydroxy-4-oxobut-
-2-enamide;
[0315]
N-[4-(Benzothiazol-6-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-ethoxy-4--
oxobut-2-enamide;
[0316]
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-ethoxy-4-oxobut--
2-enamide;
[0317]
N-[4-(Indan-4-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(N,N-dimethyl-
amino)propoxy)-4-oxobut-2-enamide;
[0318]
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(N,N-dimethyl-
amino)propoxy)-4-oxobut-2-enamide;
[0319]
N-[4-(Indan-4-ylamino)pyrido[3,4-d]pyrimid-6yl]-4-(3-(N,N-dimethyla-
mino)propylamino)-4-oxobut-2-enamide;
[0320]
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(N,N-dimethyl-
amino)propylamino-4-oxobut-2-enamide;
[0321]
N-[4-(Indan-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(4-morpholino-
)propoxy)-4-oxobut-2-enamide;
[0322]
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(4-morpholino-
)propoxy)-4-oxobut-2-enamide;
[0323]
N-[4-(Indan-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(4-morpholino-
)propylamino)-4-oxobut-2-enamide;
[0324]
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(4-morpholino-
)propylamino)-4-oxobut-2-enamide;
[0325] 4,4-Difluoro-8-(morpholin-4yl)oct-2-enoic
acid[4-(1,2,3,4-tetrahydr-
onaphth-1-ylamino)pyrido[3,4-d]pyrimid-6-yl]amide;
[0326] 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(indol-5-ylamino)- pyrido[3,4-d]pyrimid-6-yl]amide;
[0327] Pent-2-enedioic acid
1{[4-(indol-5-ylamino)pyrido[3,4-d]pyrimid-6-y-
l]amide}5-[(3-morpholin-4-ylpropyl)amide];
[0328] Pent-2-enedioic acid
1{[4-(1,2,3,4-tetrahydronaphth-1-ylamino)pyrid-
o[3,4-d]pyrimid-6-yl]amide}5-[(3-morpholin-4-ylpropyl)amide];
[0329]
N-[4-(1,2,3,4-Tetrahydronaphth-2-ylamino)pyrido[3,4-d]pyrimid-6-yl]-
-4-(3-(morpholin-4-yl)propylthio)but-2-enamide;
[0330]
N-[4-(Indol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(morpholin-4--
yl)propylthio)but-2-enamide;
[0331] 7-Morpholin-4-ylhept-2-ynoic
acid[4-(1,2,3,4-tetrahydronaphth-2-yla-
mino)pyrido[3,4-d]pyrimid-6-yl]amide;
[0332] 7-Morpholin-4-ylhept-2-ynoic
acid[4-(indol-5-ylamino)pyrido[3,4-d]p- yrimid-6-yl]amide;
[0333] 4-Morpholin-4-ylbut-2-ynoic
acid[4-(benzo[c][2,1,3]thiadiazol-4-yla-
mino)pyrido[3,4-d]pyrimid-6-yl]amide;
[0334] 4-Morpholin-4-ylbut-2-ynoic
acid[4-(indol-5-ylamino)pyrido[3,4-d]py- rimid-6-yl]amide;
[0335]
N-[4-(Benzo[c][2,1,3]thiadiazol-4-ylamino)benzo[b]thieno[3,2-d]pyri-
mid-6-yl]acrylamide;
[0336]
N-[4-(Indol-5-ylamino)benzo[b]thieno[3,2-d]pyrimid-6-yl]acrylamide;
[0337] [4-(Benzimidazol-5-ylamino)quinazolin-6-yl]acrylate;
[0338] [4-(Indol-5-ylamino)quinazolin-6-yl]acrylate;
[0339] [4-(Benzimidazol-5-ylamino)quinazolin-7-yl]acrylate;
[0340] [4-(Indol-5-ylamino)quinazolin-7-yl]acrylate;
[0341]
[7-[3-(4-Morpholino)propoxy]-4-(benzimidazol-5-ylamino)quinazolin-6-
-yl]acrylate;
[0342]
[4-(Indol-5-ylamino)-7-[4-(N,N-dimethylamino)butoxy]quinazolin-6-yl-
]acrylate;
[0343]
[7-[4-(N,N-dimethylamino)butoxy]-4-(6-methoxyquinol-8-ylamino)quina-
zolin-6-yl]acrylate;
[0344]
[4-(Indol-5-ylamino)-7-[3-(4-morpholino)propoxy]quinazolin-6-yl]acr-
ylate;
[0345]
N-(3-(4-Morpholino)propylamino)-4,O-[4-(6-methoxyquinol-8-ylamino)q-
uinazolin-6-yl]-4-oxobut-2-enamide;
[0346]
N-(3-(4-Morpholino)propylamino)-4,O-[4-(indol-5-ylamino)quinazolin--
6-yl]-4-oxobut-2-enamide;
[0347] 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(1-methylindol-5-- ylamino)quinazolin-6-yl]ester;
[0348] 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(indol-5-ylamino)- quinazolin-6-yl]ester;
[0349] Pent-2-enedioic acid
1{[4-(indol-5-ylamino)quinazolin-6-yl]ester)}5-
-[(3-morpholin-4-ylpropyl)amide];
[0350] Pent-2-enedioic acid
1{[4-(1-methylindol-5-ylamino)quinazolin-6-yl]-
ester}5-[(3-morpholin-4-ylpropyl)amide];
[0351]
[4-(2-Methylindol-5-ylamino)quinazolin-6-yl]-4-(3-(morpholin-4-yl)p-
ropylthio)but-2-enoate;
[0352]
[4-(Indol-5-ylamino)quinazolin-6-yl]-4-(3-(morpholin-4-yl)propylthi-
o)but-2-enoate;
[0353] 7-Morpholin-4-ylhept-2-ynoic
acid[4-(3-cyanoindol-5-ylamino)quinazo- lin-6-yl]ester;
[0354] 7-Morpholin-4-ylhept-2-ynoic
acid[4-(indol-5-ylamino)quinazolin-6-y- l]ester;
[0355] 4-Morpholin-4-ylbut-2-ynoic
acid[4-(benzothien-5-ylamino)quinazolin- -6-yl]ester;
[0356] 4-Morpholin-4-ylbut-2-ynoic
acid[4-(indol-5-ylamino)quinazolin-6-yl- ]ester;
[0357]
N-[4-(1-Benzylindol-5-ylamino)quinazolin-6-yl]acrylamide;
[0358]
N-[4-(2-Benzylbenzimidazol-5-ylamino)quinazolin-6-yl]acrylamide;
[0359]
N-[4-(1-Benzylindol-5-ylamino)quinazolin-7-yl]acrylamide;
[0360]
N-[4-(2-Benzylbenzimidazol-5-ylamino)quinazolin-7-yl]acrylamide;
[0361]
N-[4-(2-Benzylbenzindazol-5-ylamino)quinazolin-6-yl]propynamide;
[0362]
N-[4-(1-Benzylbenzindazol-5-ylamino)quinazolin-6-yl]propynamide;
[0363]
N-[4-(2-Benzylbenzindazol-5-ylamino)quinazolin-7-yl]propynamide;
[0364]
N-[4-(2-Benzylbenzindazol-5-ylamino)quinazolin-7-yl]propynamide;
[0365]
N-[4-(1-Phenylsulfonylindol-5-ylamino)quinazolin-6-yl]but-2-ynamide-
;
[0366]
N-[4-(1-Phenylsulfonylindol-5-ylamino)quinazolin-6-yl]buta-2,3-dien-
amide;
[0367]
N-[4-(1-Benzylindol-5-ylamino)quinazolin-6-yl]but-2-enamide;
[0368]
N-[4-(2-Benzylbenzindazol-5-ylamino)quinazolin-6-yl]-4,4,4-trifluor-
obut-2-enamide;
[0369]
N-[4-(1-Benzylindol-5-ylamino)quinazolin-6-yl]-4,4,4-trifluorobut-2-
-enamide;
[0370]
N-[4-(1-Benzylindol-6-ylamino)quinazolin-6-yl]-3-chloroacrylamide;
[0371]
6-(S-Vinylsulfonamido)-4-(2-benzylbenzindazol-5-ylamino)quinazoline-
;
[0372]
N-[7-[3-(4-Morpholino)propoxy]-4-(2-benzylbenzindazol-5-ylamino)qui-
nazolin-6-yl]acrylamide;
[0373]
N-[4-(1-Benzylindol-6-ylamino)-7-[4-(N,N-dimethylamino)butoxy]-quin-
azolin-6-yl]acrylamide;
[0374]
N-[4-(2-Phenylbenzimidazol-5-ylamino)-7-[3-(4-morpholino)propoxy]-q-
uinazolin-6-yl]acrylamide;
[0375]
N-[4-(2-Phenylbenzimidazol-5-ylamino)quinazolin-6-yl]-4-oxopent-2-e-
namide;
[0376]
N-[4-(3-Benzylbenzimidazol-5-ylamino)quinazolin-6-yl]-4-hydroxy-4-o-
xobut-2-enamide;
[0377]
N-[4-(3-Benzylbenzimidazol-5-ylamino)quinazolin-6-yl]-4-ethoxy-4-ox-
obut-2-enamide;
[0378]
N-[4-(2-Benzylbenzindazol-5-ylamino)quinazolin-6-yl]-4-(3-(N,N-dime-
thylamino)propoxy)-4-oxobut-2-enamide;
[0379]
N-[4-(2-Benzylbenzindazol-5-ylamino)quinazolin-6-yl]-4-(3-(N,N-dime-
thylamino)propylamino)-4-oxobut-2-enamide;
[0380]
N-[4-(1-Benzylbenzimidazol-5-ylamino)quinazolin-6-yl]-4-(3-(N,N-dim-
ethylamino)propylamino)-4-oxobut-2-enamide;
[0381]
N-[4-(1-Benzylbenzimidazol-5-ylamino)quinazolin-6-yl]-4-(3-(4-morph-
olino)propoxy)-4-oxobut-2-enamide;
[0382]
N-[4-(2-Benzylbenzindazol-5-ylamino)quinazolin-6-yl]-4-(3-(4-morpho-
lino)propoxy)-4-oxobut-2-enamide;
[0383]
N-[4-(42-Benzylbenzindazol-5-ylamino)quinazolin-6-yl]-4-(3-(4-morph-
olino)propylamino)-4-oxobut-2-enamide;
[0384]
N-[4-(2-Benzylbenzotriazol-5-ylamino)quinazolin-6-yl]-4-(3-(4-morph-
olino)propylamino)-4-oxobut-2-enamide;
[0385] 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(2-benzylbenzotri- azol-5-ylamino)quinazolin-6-yl]amide;
[0386] 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(2-benzylbenzinda- zol-5-ylamino)quinazolin-6-yl]amide;
[0387] Pent-2-enedioic acid
1{[4-(2-benzylbenzindazol-5-ylamino)quinazolin-
-6-yl]amide}5-[(3-morpholin-4-ylpropyl)amide];
[0388] Pent-2-enedioic acid
1{[4-(2-benzylbenzindazol-5-ylamino)quinazolin-
-6-yl]amide}5-[(3-morpholin-4-ylpropyl)amide];
[0389]
N-[4-(1-Benzylbenzotriazol-5-ylamino)quinazolin-6-yl]-4-(3-(morphol-
in-4-yl)propylthio)but-2-enamide;
[0390]
N-[4-(2-Benzylbenzindazol-5-ylamino)quinazolin-6-yl]-4-(3-(morpholi-
n-4-yl)propylthio)but-2-enamide;
[0391] 7-Morpholin-4-ylhept-2-ynoic
acid[4-(1-Benzylbenzotriazol-5-ylamino- )quinazolin-6-yl]amide;
[0392] 4-Morpholin-4-ylbut-2-ynoic
acid[4-(3-benzylbenzotriazol-5-ylamino)- quinazolin-6-yl]amide;
[0393] 4-Morpholin-4-ylbut-2-ynoic
acid[4-(2-benzylbenzindazol-5-ylamino)q- uinazolin-6-yl]amide;
[0394]
N-[4-(2-Benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]acryl-
amide;
[0395]
N-[4-(3-Benzylbenzotriazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]acry-
lamide;
[0396]
N-[4-(2-{Pyrid-2-yl}benzotriazol-5-ylamino)pyrido[3,4-d]pyrimid-6-y-
l]propynamide;
[0397]
N-[4-(2-Benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]propy-
namide;
[0398]
N-[4-(2-{Pyrid-2-yl}benzotriazol-5-ylamino)pyrido[3,4-d]pyrimid-6-y-
l]but-2-ynamide;
[0399]
N-[4-(2-Benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]buta--
2,3-dienamide;
[0400]
N-[4-(2-Phenethylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]bu-
t-2-enamide;
[0401]
N-[4-(2-Phenethylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-
,4,4-trifluorobut-2-enamide;
[0402]
N-[4-(2-Benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4,4,-
4-trifluorobut-2-enamide;
[0403]
N-[4-(1-Phenethylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-3-
-chloroacrylamide;
[0404]
6-(S-Vinylsulfonamido)-4-(1-phenethylbenzindazol-5-ylamino)-pyrido[-
3,4-d]pyrimidine;
[0405]
6-(S-Vinylsulfonamido)-4-(2-benzylbenzindazol-5-ylamino)-pyrido[3,4-
-d]pyrimidine;
[0406]
N-[4-(2-Benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-hy-
droxy-4-oxobut-2-enamide;
[0407]
N-[4-(2-Benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-
-(N,N-dimethylamino)propylamino)-4-oxobut-2-enamide;
[0408]
N-[4-(2-Benzyloxyindol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(4-
-morpholino)propoxy)-4-oxobut-2-enamide;
[0409]
N-[4-(2-Benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-
-(4-morpholino)propoxy)-4-oxobut-2-enamide;
[0410]
N-[4-(2-Benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-
-(4-morpholino)propylamino)-4-oxobut-2-enamide;
[0411]
N-[4-(2-Benzyloxyindol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-(4-
-morpholino)propylamino)-4-oxobut-2-enamide;
[0412] 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(2-benzyloxybenzi-
midazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]amide;
[0413] 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(2-benzylbenzinda-
zol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]amide;
[0414] Pent-2-enedioic acid
1{[4-(2-benzylbenzindazol-5-ylamino)pyrido[3,4-
-d]-pyrimid-6-yl]amide}5-[(3-morpholin-4-ylpropyl)amide];
[0415] Pent-2-enedioic acid
1{[4-(2-benzylsulfonylbenzimidazol-5-ylamino)--
pyrido[3,4-d]pyrimid-6-yl]amide}5-[(3-morpholin-4-ylpropyl)amide];
[0416]
N-[4-(4-benzyloxybenzimidazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]--
4-(3-(morpholin-4-yl)propylthio)but-2-enamide;
[0417]
N-[4-(2-Benzylbenzindazol-5-ylamino)pyrido[3,4-d]pyrimid-6-yl]-4-(3-
-(morpholin-4-yl)propylthio)but-2-enamide;
[0418] 7-Morpholin-4-ylhept-2-ynoic
acid[4-(2-benzylbenzindazol-5-ylamino)-
pyrido[3,4-d]pyrimid-6-yl]amide;
[0419] 7-Morpholin-4-ylhept-2-ynoic
acid[4-(2-benzylsulfonylbenzimidazol-5-
-ylamino)pyrido[3,4-d]pyrimid-6-yl]amide;
[0420]
N-[4-(2-Benzylbenzindazol-5-ylamino)benzo[b]thieno[3,2-d]pyrimid-6--
yl]acrylamide;
[0421]
N-[4-(1-Benzylbenzindazol-5-ylamino)benzo[b]thieno[3,2-d]pyrimid-6--
yl]acrylamide;
[0422]
[4-(2-Benzylbenzindazol-5-ylamino)quinazolin-6-yl]acrylate;
[0423]
N-(3-(4-Morpholino)propylamino)-4,O-[4-(2-benzylbenzindazol-5-ylami-
no)quinazolin-6-yl]-4-oxobut-2-enamide;
[0424] 4,4-Difluoro-8-(morpholin-4-yl)oct-2-enoic
acid[4-(2-benzylbenzinda- zol-5-ylamino)quinazolin-6-yl]ester;
[0425] Pent-2-enedioic acid
1{[4-(2-benzylbenzindazol-5-ylamino)quinazolin-
-6-yl]ester}5-[(3-morpholin-4-ylpropyl)amide];
[0426]
[4-(2-Benzylbenzindazol-5-ylamino)quinazolin-6-yl]-4-(3-(morpholin--
4-yl)propylthio)but-2-enoate; and
[0427] 7-Morpholin-4-ylhept-2-ynoic
acid[4-(2-benzylbenzindazol-5-ylamino)- quinazolin-6-yl]ester.
DETAILED DESCRIPTION OF THE INVENTION
[0428] The present invention provides compounds having the Formula
I 27
[0429] wherein X is -D-E-F and Y is --SR.sup.4, halogen,
--OR.sup.4, --NHR.sup.3, or hydrogen, or X is --SR.sup.4, halogen,
--OR.sup.4, --NHR.sup.3, or hydrogen, and Y is -D-E-F; 28
[0430] each R.sup.a is independently hydroxy, amino, N-mono- or
N,N-di-(C.sub.1-C.sub.4) alkylamino, sulfo, or
(C.sub.1-C.sub.4)alkoxy (provided that such groups are not attached
to a ring carbon which is adjacent to an oxy, thio, or --N--), or
R.sup.a is independently carboxy, hydroxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4) alkyl,
amino(C.sub.1-C.sub.4)alkyl, mono-N-- or di-N,N-(C.sub.1-C.sub.4)a-
lkylamino(C.sub.1-C.sub.4)alkyl, morpholino(C.sub.1-C.sub.4)alkyl,
4-(C.sub.1-C.sub.4)alkyl-piperazin-1-yl(C.sub.1-C.sub.4)alkyl,
carboxy(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxycarbonyl,
sulfo(C.sub.1-C.sub.4)alkyl, or (C.sub.1-C.sub.4)alkyl;
[0431] each R.sup.b is independently mono-, di-, or
trifluoromethyl, halo, nitro, hydroxy, amino, axido, isothiocyano,
(C.sub.1-C.sub.4)alkyl, phenyl, thienyl, (C.sub.1-C.sub.4)alkoxy,
benzyloxy, phenoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.4)alkylenedioxy, cyano,
benzoylamino, trifluoromethylcarbonylamino,
(C.sub.1-C.sub.4)alkanoylamino, (C.sub.1-C.sub.4)alkanoyl, N-mono-
or N,N-di-(C.sub.1-C.sub.4)alkylamino,
(C.sub.1-C.sub.4)alkylsulfonylamino, trifluoromethylsulfonylamino,
(C.sub.1-C.sub.4)alkylthio, (C.sub.1-C.sub.4)alkylsulfinyl or
(C.sub.1-C.sub.4)alkylsulfonyl, pyrrol-1-yl, piperidin-1-yl or
pyrrolidin-1-yl, said phenyl, benzyloxy, phenoxy, and benzoylamino
optionally mono-substituted with halo, nitro, trifluoromethyl,
hydroxy, or (C.sub.1-C.sub.4)alkyl and said
(C.sub.1-C.sub.4)alkylenedioxy is linked at both ends to adjacent
carbons on the benzene moiety, or R.sup.b is -Z.sup.aR.sup.77; p1 J
is --CH.sub.2--, thio, --N(H)--, or oxy;
[0432] g is 0, 1, or 2;
[0433] h is 0 to 4;
[0434] k is 0, 1, or2;
[0435] S completes a 5- or 6-membered aromatic or partially
saturated ring that can contain an oxygen or sulfur atom;
[0436] T is --CH.sub.2--, --N(H)--, thio, or oxy;
[0437] S.sup.a is --CH.sub.2--, oxy, or thio;
[0438] A.sup.1completes a 7- to 9-membered mono-unsaturated
mono-aza ring.
[0439] Q.sup.a is a 9- or 10-membered bicyclic heterocyclic moiety,
or a hydrogenated derivative thereof, containing one or two
nitrogen heteroatoms and optionally containing a further heteroatom
selected from nitrogen, oxygen and sulfur, or Q.sup.a is a 9- or
10-membered bicyclic aryl moiety, or a hydrogenated derivative
thereof, which heterocyclic or aryl moiety, or hydrogenated
derivatives thereof, may optionally bear one or two substituents
selected from halogen, hydroxy, oxo, amino, nitro, carbamoyl,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkylamino, di-[(C.sub.1-C.sub.4)alkyl]amino, and
(C.sub.2-C.sub.4)alkanoylamino;
[0440] R.sup.1is hydrogen, halogen, or C.sub.1-C.sub.6 alkyl;
[0441] R.sup.2, R.sup.3, and R.sup.4are independently hydrogen,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-piperaziny-
l[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n-imidazoyl,
--(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--(CH.sub.2).sub.n--N-hexahydroazep- ine or substituted
C.sub.1-C.sub.6alkyl, wherein the substituents are selected from
--OH, --NH.sub.2, or 29
[0442] A and B are independently hydrogen, C.sub.1-C.sub.6alkyl,
--(CH.sub.2).sub.nOH, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-piperaziny-
l[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n--N-pyridyl,
--(CH.sub.2).sub.n-imidazoyl, or
--(CH.sub.2).sub.n--N-imidazoyl;
[0443] Z.sup.1, Z.sup.2, or Z.sup.3are independently hydrogen,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.8 cycloalkoxy, nitro,
C.sub.1-C.sub.6 perfluoroalkyl, hydroxy, C.sub.1-C.sub.6 acyloxy,
--NH.sub.2, --NH(C.sub.1-C.sub.6alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2,--NH(C.sub.3- -C.sub.8 cycloalkyl),
--N(C.sub.3-C.sub.8 cycloalkyl).sub.2, hydroxymethyl,
C.sub.1-C.sub.6 acyl, cyano, azido, C.sub.1-C.sub.6 thioalkyl,
C.sub.1-C.sub.6 sulfinylalkyl, C.sub.1-C.sub.6 sulfonylalkyl,
C.sub.3-C.sub.8 thiocycloalkyl. C.sub.3-C.sub.8 sulfinylcycloalkyl,
C.sub.3-C.sub.8 sulfonylcycloalkyl, mercapto. C.sub.1-C.sub.6
alkoxycarbonyl, C.sub.3-C.sub.8 cycloalkoxycarbonyl,
C.sub.2-C.sub.4 alkenyl, C.sub.4-C.sub.8 cycloalkenyl, or
C.sub.2-C.sub.4 alkynyl;
[0444] Z.sup.a is a bond, --CH.sub.2--, --S--, SO.sub.2, --NH--,
--O--, --OCH.sub.2--, --S--CH.sub.2--, --SO.sub.2--, or
--CH.sub.2CH.sub.2--;
[0445] R.sup.77 is phenyl, substituted phenyl, or a 5- to
10-membered optionally substituted heterocyclic aromatic ring;
[0446] R.sup.5 is hydrogen, halogen, C.sub.1-C.sub.6
perfluoroalkyl, 1,1-difluoro(C.sub.1-C.sub.6)alkyl, C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n-piperazinyl,
--(CH.sub.2).sub.n-piperazinyl[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2)n-N-imidazoyl, --(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino, 30
[0447] --CH.dbd.CH--(C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.n--N-hexahydr- oazepine,
--(CH.sub.2).sub.nNH.sub.2,--(CH.sub.2).sub.nNH(C.sub.1-C.sub.6a-
lkyl),
--(CH.sub.2).sub.nN(C.sub.1-C.sub.6alkyl).sub.2,-1-oxo(C.sub.1-C.su-
b.6)alkyl, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl,
N--(C.sub.1-C.sub.6)alkylcarbamoyl, phenyl or substituted phenyl,
wherein the substituted phenyl can have from one to three
substituents independently selected from Z.sup.1, Z.sup.2, Z.sup.3
or a monocyclic heteroaryl group, and each C.sub.1-C.sub.6 alkyl
group can be substituted with --OH, --NH.sub.2 or --NAB, where A
and B are as defined above, R.sup.6 is hydrogen or C.sub.1-C.sub.6
alkyl; R.sup.13 is hydrogen or halogen; and
[0448] n is 1 to 4, p is 0 or 1, and the pharmaceutically
acceptable salts, esters, amides, and prodrugs thereof.
[0449] In another preferred embodiment, present invention also
provides compounds having the Formula II
Q-Z II
[0450] wherein Q is 31
[0451] p is 0 or 1;
[0452] X is -D-E-F, and Y is --SR.sup.4, --OR.sup.4, --NHR.sup.3 or
hydrogen, or X is --SR.sup.4, --OR.sup.4, --NHR.sup.3 or hydrogen,
and Y is -D-E-F; 32
[0453] each R.sup.a is independently hydroxy, amino, N-mono- or
N,N-di-(C.sub.1-C.sub.4) alkylamino, sulfo, or
(C.sub.1-C.sub.4)alkoxy (provided that such groups are not attached
to a ring carbon which is adjacent to an oxy, thio, or --N--), or
R.sup.a is independently carboxy, hydroxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4) alkyl,
amino(C.sub.1-C.sub.4)alkyl, mono-N-- or di-N,N-(C.sub.1-C.sub.4)a-
lkylamino(C.sub.1-C.sub.4)alkyl, morpholino(C.sub.1-C.sub.4)alkyl,
4-(C.sub.1-C.sub.4)alkyl-piperazin-1-yl(C.sub.1-C.sub.4)alkyl,
carboxy(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxycarbonyl,
sulfo(C.sub.1-C.sub.4)alkyl, or (C.sub.1-C.sub.4)alkyl;
[0454] each R.sup.b is independently mono-, di-, or
trifluoromethyl, halo, nitro, hydroxy, amino, axido, isothiocyano,
(C.sub.1-C.sub.4)alkyl, phenyl, thienyl, (C.sub.1-C.sub.4)alkoxy,
benzyloxy, phenoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.4)alkylenedioxy, cyano,
benzoylamino, trifluoromethylcarbonylamino,
(C.sub.1-C.sub.4)alkanoylamino, (C.sub.1-C.sub.4)alkanoyl, N-mono-
or N,N-di-(C.sub.1-C.sub.4)alkylamino,
(C.sub.1-C.sub.4)alkylsulfonylamino, trifluoromethylsulfonylamino,
(C.sub.1-C.sub.4)alkylthio, (C.sub.1-C.sub.4)alkylsulfinyl or
(C.sub.1-C.sub.4)alkylsulfonyl, pyrrol-1-yl, piperidin-1-yl or
pyrrolidin-1-yl, said phenyl, benzyloxy, phenoxy, and benzoylamino
optionally mono-substituted with halo, nitro, trifluoromethyl,
hydroxy, or (C.sub.1-C.sub.4)alkyl and said
(C.sub.1-C.sub.4)alkylenedioxy is linked at both ends to adjacent
carbons on the benzene moiety, or R.sup.b is -Z.sup.aR.sup.77;
[0455] J is --CH.sub.2--, thio, --N(H)--, or oxy;
[0456] g is 0, 1, or2;
[0457] h is 0 to 4;
[0458] k is 0, 1, or 2;
[0459] S completes a 5- or 6-membered aromatic or partially
saturated ring that can contain an oxygen or sulfur atom;
[0460] T is --CH.sub.2, --N(H)--, thio, or oxy;
[0461] S.sup.a is --CH.sub.2--, oxy, or thio;
[0462] A.sup.1 completes a 7- to 9-membered mono-unsaturated
mono-aza ring;
[0463] Q.sup.a is a 9- or 10-membered bicyclic heterocyclic moiety,
or a hydrogenated derivative thereof, containing one or two
nitrogen heteroatoms and optionally containing a further heteroatom
selected from nitrogen, oxygen and sulfur, or Q.sup.a is a 9- or
10-membered bicyclic aryl moiety, or a hydrogenated derivative
thereof, which heterocyclic or aryl moiety, or hydrogenated
derivatives thereof, may optionally bear one or two substituents
selected from halogen, hydroxy, oxo, amino, nitro, carbamoyl,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkylamino, di-[(C.sub.1-C.sub.4)alkyl]amino, and
(C.sub.2-C.sub.4)alkanoylamino;
[0464] R.sup.1is hydrogen, halogen, or C.sub.1-C.sub.6 alkyl;
[0465] R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1--piperazin-
yl[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n-imidazoyl,
--(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--(CH.sub.2).sub.n--N-hexahydroazep- ine or substituted
C.sub.1-C.sub.6 alkyl, wherein the substituents are selected from
--OH, --NH.sub.2, or 33
[0466] A and B are independently hydrogen, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.nOH, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-piperaziny-
l[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n--N-pyridyl,
--(CH.sub.2).sub.n-imidazoyl, or
--(CH.sub.2).sub.n--N-imidazoyl;
[0467] E.sup.1, E.sup.2, or E.sup.3 are independently hydrogen,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.8 cycloalkoxy, nitro,
C.sub.1-C.sub.6 perfluoroalkyl, hydroxy, C.sub.1-C.sub.6 acyloxy,
--NH.sub.2, --NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, --NH(C.sub.3-C.sub.8 cycloalkyl), --N(C.sub.3-C.sub.8
cycloalkyl).sub.2, hydroxymethyl, C.sub.1-C.sub.6 acyl, cyano,
azido, C.sub.1-C.sub.6 thioalkyl, C.sub.1-C.sub.6 sulfinylalkyl,
C.sub.1-C.sub.6 sulfonylalkyl, C.sub.3-C.sub.8 thiocycloalkyl,
C.sub.3-C.sub.8 sulfinylcycloalkyl, C.sub.3-C.sub.8
sulfonylcycloalkyl, mercapto, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.3-C.sub.8 cycloalkoxycarbonyl, C.sub.2-C.sub.4 alkenyl,
C.sub.4-C.sub.8 cycloalkenyl, or C.sub.2-C.sub.4 alkynyl;
[0468] Z.sup.1 is a bond, --CH.sub.2--, --S--, SO.sub.2, --NH--,
--O--, --OCH.sub.2--, --S--CH.sub.2--, --SO.sub.2--, or
--CH.sub.2CH.sub.2--;
[0469] R.sup.77 is phenyl, substituted phenyl, or a 5- to
10-membered optionally substituted heterocyclic aromatic ring;
[0470] R.sup.5 is hydrogen, halogen, C.sub.1-C.sub.6
perfluoroalkyl, 1,1-difluoro(C.sub.1-C.sub.6)alkyl, C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n-piperazinyl,
--(CH.sub.2).sub.n-piperazinyl[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino, 34
[0471] --CH.dbd.CH--(C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.n--N-hexahydr- oazepine,
--(CH.sub.2).sub.nNH.sub.2,--(CH.sub.2).sub.nNH(C.sub.1-C.sub.6a-
lkyl), --(CH.sub.2).sub.nN(C.sub.1-C.sub.6alkyl).sub.2,
-1-oxo(C.sub.1-C.sub.6)alkyl, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl,
N--(C.sub.1-C.sub.6)alkylcarbamoyl, phenyl or substituted phenyl,
wherein the substituted phenyl can have from one to three
substituents independently selected from E.sup.1, E.sup.2, E.sup.3
or a monocyclic heteroaryl group, and each C.sub.1-C.sub.6 alkyl
group can be substituted with --OH, --NH.sub.2 or --NAB, where A
and B are as defined above or C.sub.1-C.sub.6 alkyl; and
[0472] n is 1 to 4, and the pharmaceutically acceptable salts,
esters, amides, and prodrugs thereof.
[0473] In another embodiment, the present invention provides
compounds having the Formula II
Q-Z II
[0474] wherein Q is 35
[0475] p is0 or 1;
[0476] X is -D-E-F, and Y is --SR.sup.4, --OR.sup.4, --NHR.sup.3 or
hydrogen, or X is --SR.sup.4, --OR.sup.4, --NHR.sup.3 or hydrogen,
and Y is -D-E-F; 36
[0477] each R.sup.a is independently hydroxy, amino, N-mono- or
N,N-di-(C.sub.1-C.sub.4) alkylamino, sulfo, or
(C.sub.1-C.sub.4)alkoxy (provided that such groups are not attached
to a ring carbon which is adjacent to an oxy, thio, or --N--), or
R.sup.a is independently carboxy, hydroxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4) alkyl,
amino(C.sub.1-C.sub.4)alkyl, mono-N-- or di-N,N-(C.sub.1-C.sub.4)a-
lkylamino(C.sub.1-C.sub.4)alkyl, morpholino(C.sub.1-C.sub.4)alkyl,
4-(C.sub.1-C.sub.4)alkyl-piperazin-1-yl(C.sub.1-C.sub.4)alkyl,
carboxy(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxycarbonyl,
sulfo(C.sub.1-C.sub.4)alkyl, or (C.sub.1-C.sub.4)alkyl;
[0478] each R.sup.b is independently mono-, di-, or
trifluoromethyl, halo, nitro, hydroxy, amino, axido, isothiocyano,
(C.sub.1-C.sub.4)alkyl, phenyl, thienyl, (C.sub.1-C.sub.4)alkoxy,
benzyloxy, phenoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.4)alkylenedioxy, cyano,
benzoylamino, trifluoromethylcarbonylamino,
(C.sub.1-C.sub.4)alkanoylamino, (C.sub.1-C.sub.4)alkanoyl, N-mono-
or N,N-di-(C.sub.1-C.sub.4)alkylamino,
(C.sub.1-C.sub.4)alkylsulfonylamino, trifluoromethylsulfonylamino,
(C.sub.1-C.sub.4)alkylthio, (C.sub.1-C.sub.4)alkylsulfinyl or
(C.sub.1-C.sub.4)alkylsulfonyl, pyrrol-1-yl, piperidin-1-yl or
pyrrolidin-1-yl, said phenyl, benzyloxy, phenoxy, and benzoylamino
optionally mono-substituted with halo, nitro, trifluoromethyl,
hydroxy, or (C.sub.1-C.sub.4)alkyl and said
(C.sub.1-C.sub.4)alkylenedioxy is linked at both ends to adjacent
carbons on the benzene moiety, or R.sup.b is -Z.sup.aR.sup.77;
[0479] J is --CH.sub.2--, thio, --N(H)--, or oxy;
[0480] g is 0, 1, or 2;
[0481] h is 0 to 4;
[0482] k is 0, 1, or 2;
[0483] S completes a 5- or 6-membered aromatic or partially
saturated ring that can contain an oxygen or sulfur atom;
[0484] T is --CH.sub.2--, --N(H)--, thio, or oxy;
[0485] S.sup.a is --CH.sub.2--, oxy, or thio;
[0486] A.sup.1 completes a 7- to 9-membered mono-unsaturated
mono-aza ring;
[0487] Q.sup.a is a 9- or 10-membered bicyclic heterocyclic moiety,
or a hydrogenated derivative thereof, containing one or two
nitrogen heteroatoms and optionally containing a further heteroatom
selected from nitrogen, oxygen and sulfur, or Q.sup.a is a 9- or
10-membered bicyclic aryl moiety, or a hydrogenated derivative
thereof, which heterocyclic or aryl moiety, or hydrogenated
derivatives thereof, may optionally bear one or two substituents
selected from halogen, hydroxy, oxo, amino, nitro, carbamoyl,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkylamino, di-[(C.sub.1-C.sub.4)alkyl]amino, and
(C.sub.2-C.sub.4)alkanoylamino;
[0488] R.sup.1 is hydrogen, halogen, or C.sub.1-C.sub.6 alkyl;
[0489] R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1--piperazin-
yl[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2).sub.n--N-imidazoyl, --(CH.sub.2).sub.n-imidazoyl,
--(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino,
--(CH.sub.2).sub.n--N-hexahydroazep- ine or substituted
C.sub.1-C.sub.6 alkyl, wherein the substituents are selected from
--OH, --NH.sub.2, or 37
[0490] A and B are independently hydrogen, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.nOH, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2).sub.n--N.sub.1-piperaziny-
l[N.sub.4--(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n--N-pyridyl,
--(CH.sub.2).sub.n-imidazoyl, or
--(CH.sub.2).sub.n--N-imidazoyl;
[0491] E.sup.1, E.sup.2, or E.sup.3 are independently hydrogen,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.8 cycloalkoxy, nitro,
C.sub.1-C.sub.6 perfluoroalkyl, hydroxy, C.sub.1-C.sub.6 acyloxy,
--NH.sub.2, --NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, --NH(C.sub.3-C.sub.8 cycloalkyl), --N(C.sub.3-C.sub.8
cycloalkyl).sub.2,hydroxymethyl, C.sub.1-C.sub.6 acyl, cyano,
azido, C.sub.1-C.sub.6 thioalkyl, C.sub.1-C.sub.6 sulfinylalkyl,
C.sub.1-C.sub.6 sulfonylalkyl, C.sub.3-C.sub.8 thiocycloalkyl,
C.sub.3-C.sub.8 sulfinylcycloalkyl, C.sub.3-C.sub.8
sulfonylcycloalkyl, mercapto, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.3-C.sub.8 cycloalkoxycarbonyl, C.sub.2-C.sub.4 alkenyl,
C.sub.4-C.sub.8 cycloalkenyl, or C.sub.2-C.sub.4 alkynyl;
[0492] Z.sup.a is a bond, --CH.sub.2--, --S--, SO.sub.2, --NH--,
--O--, --OCH.sub.2--, --S--CH.sub.2--, --SO.sub.2--, or
--CH.sub.2CH.sub.2--;
[0493] R.sup.77 is phenyl, substituted phenyl, or a 5- to
10-membered optionally substituted heterocyclic aromatic ring;
[0494] R.sup.5 is hydrogen, halogen, C.sub.1-C.sub.6
perfluoroalkyl, 1,1-difluoro(C.sub.1-C.sub.6)alkyl, C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n-piperazinyl,
--(CH.sub.2).sub.n-piperazinyl[N.sub.4-(C.sub.1-C.sub.6)alkyl],
--(CH.sub.2).sub.n--N-pyrrolidyl, --(CH.sub.2).sub.n-pyridinyl,
--(CH.sub.2)n-N-imidazoyl, --(CH.sub.2).sub.n--N-morpholino,
--(CH.sub.2).sub.n--N-thiomorpholino, 38
[0495] --CH.dbd.CH--(C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.n--N-hexahydr- oazepine,
--(CH.sub.2).sub.nNH.sub.2,--(CH.sub.2).sub.nNH(C.sub.1-C.sub.6a-
lkyl), --(CH.sub.2).sub.nN(C.sub.1-C.sub.6alkyl).sub.2,
-1-oxo(C.sub.1-C.sub.6)alkyl, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl,
N--(C.sub.1-C.sub.6)alkylcarbamoyl, phenyl or substituted phenyl,
wherein the substituted phenyl can have from one to three
substituents independently selected from E.sup.1, E.sup.2,
E.sup.3or a monocyclic heteroaryl group, and each C.sub.1-C.sub.6
alkyl group above in R.sup.5 can be substituted with --OH,
--NH.sub.2 or --NAB, where A and B are as defined above or
C.sub.1-C.sub.6 alkyl; and
[0496] n is 1 to 4, and the pharmaceutically acceptable salts,
esters, amides, and prodrugs thereof.
[0497] The term "alkyl" means a straight or branched chain
hydrocarbon. Representative examples of alkyl groups are methyl,
ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl,
pentyl, and hexyl.
[0498] The term "alkoxy" means an alkyl group attached to an oxygen
atom. Representative examples of alkoxy groups include methoxy,
ethoxy, tert-butoxy, propoxy, and isobutoxy.
[0499] The term "halogen" includes chlorine, fluorine, bromine, and
iodine.
[0500] The term "alkenyl" means a branched or straight chain
hydrocarbon having one or more carbon-carbon double bond.
[0501] The term "cycloalkyl" means a cyclic hydrocarbon. Examples
of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,
and cyclohexyl.
[0502] The term "cycloalkoxy" means a cycloalkyl group attached to
an oxygen atom.
[0503] The term "perfluoroalkyl" means an alkyl group in which all
the hydrogen atoms have been replaced by fluorine atoms.
[0504] The term "acyl" means a group derived from an organic acid
by removal of the hydroxy group (--OH).
[0505] The term "acyloxy" means an acyl group attached to an oxygen
atom.
[0506] The term "thioalkyl" means an alkyl group attached to a
sulfur atom.
[0507] The term "sulfinylalkyl" means a sulfinyl group attached to
an alkyl group.
[0508] The term "sulfonylalkyl" means a sulfonyl group attached to
an alkyl group.
[0509] The term "thiocycloalkyl" means a cycloalkyl group attached
to a sulfur atom.
[0510] The term "sulfinylcycloalkyl" means a sulfinyl group
attached to a cycloalkyl group.
[0511] The term "sulfonylcycloalkyl" means a sulfonyl group
attached to a cycloalkyl group.
[0512] The term "mercapto" means a --SH group.
[0513] The term "alkoxycarbonyl" means an alkoxy group attached to
a carbonyl group.
[0514] The term "cycloalkoxycarbonyl" means a cycloalkyoxy group
attached to a carbonyl group.
[0515] The term "cycloalkenyl" means a cyclic hydrocarbon
containing one or more carbon-carbon double bond.
[0516] The term "alkynyl" means a hydrocarbon having one or more
carbon-carbon triple bond.
[0517] The term "monocyclic heteroaryl" mean a heterocyclic aryl
compound having only one ring structure. The cyclic compound is
aromatic and contains one or more heteroatom. Examples of
heteroatoms include, but are not limited to, nitrogen, oxygen,
sulfur, and phosphorus. Examples of monocyclic heteroaryl groups
include, but are not limited to, pyridyl, thienyl, and
imidazoyl.
[0518] The symbol "--" represents a covalent bond.
[0519] The compounds of Formulas I or II are irreversible
inhibitors of tyrosine kinases, particularly EGF tyrosine kinase. A
therapeutically effective amount of the compounds of Formula I or
II can be administered to a patient having cancer or a patient
having restenosis or at risk of having restenosis or a patient
having psoriasis, atherosclerosis, or endometriosis. Those skilled
in the art are readily able to identify patients having cancer,
restenosis, psoriasis, atherosclerosis, or endometriosis, and
patients who are at risk of developing restenosis. The term
"patient" means animals such as dogs, cats, cows, sheep, and also
includes humans.
[0520] The compounds of the present invention can be administered
to humans and animals either orally, rectally, parenterally
(intravenously, intramuscularly or subcutaneously),
intracisternally, intravaginally, intraperitoneally,
intravesically, locally (powders, ointments, or drops), or as a
buccal or nasal spray. The compounds can be administered alone or
as part of a pharmaceutically acceptable composition that includes
pharmaceutically acceptable excipients. It is noted that more than
one compound of Formula I or II can be administered either
concurrently or sequentially.
[0521] Compositions suitable for parenteral injection may comprise
physiologically acceptable sterile aqueous or nonaqueous solutions,
dispersions, suspensions or emulsions, and sterile powders for
reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents, or vehicles include water, ethanol, polyols
(propyleneglycol, polyethyleneglycol, glycerol, and the like),
suitable mixtures thereof, vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate. Proper fluidity can
be maintained, for example, by the use of a coating such as
lecithin, by the maintenance of the required particle size in the
case of dispersions and by the use of surfactants.
[0522] These compositions may also contain adjuvants such as
preserving. wetting, emulsifying, and dispensing agents. Prevention
of the action of microorganisms can be ensured by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be
desirable to include isotonic agents, for example sugars, sodium
chloride, and the like. Prolonged absorption of the injectable
pharmaceutical form can be brought about by the use of agents
delaying absorption, for example, aluminum monostearate and
gelatin.
[0523] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is admixed with at least one inert customary
excipient (or carrier) such as sodium citrate or dicalcium
phosphate or (a) fillers or extenders, as for example, starches,
lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders,
as for example, carboxymethylcellulose, alignates, gelatin,
polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for
example, glycerol; (d) disintegrating agents, as for example,
agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain complex silicates, and sodium carbonate; (e) solution
retarders, as for example paraffin; (f) absorption accelerators, as
for example, quaternary ammonium compounds; (g) wetting agents, as
for example, cetyl alcohol and glycerol monostearate; (h)
adsorbents, as for example, kaolin and bentonite; and (i)
lubricants, as for example, talc, calcium stearate, magnesium
stearate, solid polyethylene glycols, sodium lauryl sulfate, or
mixtures thereof. In the case of capsules, tablets, and pills, the
dosage forms may also comprise buffering agents.
[0524] Solid compositions of a similar type may also be employed as
fillers in soft- and hard-filled gelatin capsules using such
excipients as lactose or milk sugar, as well as high molecular
weight polyethylene-glycols, and the like.
[0525] Solid dosage forms such as tablets, dragees, capsules,
pills, and granules can be prepared with coatings and shells, such
as enteric coatings and others well-known in the art. They may
contain opacifying agents, and can also be of such composition that
they release the active compound or compounds in a certain part of
the intestinal tract in a delayed manner. Examples of embedding
compositions which can be used are polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if
appropriate, with one or more of the above-mentioned
excipients.
[0526] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs. In addition to the active compounds, the
liquid dosage forms may contain inert diluents commonly used in the
art, such as water or other solvents, solubilizing agents and
emulsifiers, as for example, ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in
particular, cottonseed oil, groundnut oil, corn germ oil, olive
oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl
alcohol, polyethyleneglycols and fatty acid esters of sorbitan or
mixtures of these substances, and the like.
[0527] Besides such inert diluents, the composition can also
include adjuvants, such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0528] Suspensions, in addition to the active compounds, may
contain suspending agents, as for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, or mixtures of these substances, and the
like.
[0529] Compositions for rectal administrations are preferably
suppositories which can be prepared by mixing the compounds of the
present invention with suitable non-irritating excipients or
carriers such as cocoa butter, polyethyleneglycol or a suppository
wax, which are solid at ordinary temperatures but liquid at body
temperature and therefore, melt in the rectum or vaginal cavity and
release the active component.
[0530] Dosage forms for topical administration of a compound of
this invention include ointments, powders, sprays, and inhalants.
The active component is admixed under sterile conditions with a
physiologically acceptable carrier and any preservatives, buffers,
or propellants as may be required. Ophthalmic formulations, eye
ointments, powders, and solutions are also contemplated as being
within the scope of this invention.
[0531] The term "pharmaceutically acceptable salts, esters, amides,
and prodrugs" as used herein refers to those carboxylate salts,
amino acid addition salts, esters. amides, and prodrugs of the
compounds of the present invention which are, within the scope of
sound medical judgement, suitable for use in contact with the
tissues of patients without undue toxicity, irritation, allergic
response, and the like, commensurate with a reasonable benefit/risk
ratio, and effective for their intended use, as well as the
zwitterionic forms, where possible, of the compounds of the
invention. The term "salts" refers to the relatively non-toxic,
inorganic and organic acid addition salts of compounds of the
present invention. These salts can be prepared in situ during the
final isolation and purification of the compounds or by separately
reacting the purified compound in its free base form with a
suitable organic or inorganic acid and isolating the salt thus
formed. Representative salts include the hydrobromide,
hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate,
valerate, oleate, palmitate, stearate, laurate, borate, benzoate,
lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, naphthylate, mesylate, glucoheptonate,
lactobionate and laurylsulphonate salts, and the like. These may
include cations based on the alkali and alkaline earth metals, such
as sodium, lithium, potassium, calcium, magnesium, and the like, as
well as non-toxic ammonium, quaternary ammonium, and amine cations
including, but not limited to ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine and the like (see, for example, S. M.
Berge, et al., "Pharmaceutical Salts," J Pharm Sci, 1977;66:1-19
which is incorporated herein by reference).
[0532] Examples of pharmaceutically acceptable, non-toxic esters of
the compounds of this invention include C.sub.1-C.sub.6 alkyl
esters wherein the alkyl group is a straight or branched chain.
Acceptable esters also include C.sub.5-C.sub.7 cycloalkyl esters as
well as arylalkyl esters such as, but not limited to benzyl.
C.sub.1-C.sub.4 alkyl esters are preferred. Esters of the compounds
of the present invention may be prepared according to conventional
methods.
[0533] Examples of pharmaceutically acceptable, non-toxic amides of
the compounds of this invention include amides derived from
ammonia, primary C.sub.1-C.sub.6 alkyl amines and secondary
C.sub.1-C.sub.6 dialkyl amines wherein the alkyl groups are
straight or branched chain. In the case of secondary amines, the
amine may also be in the form of a 5- or 6-membered heterocycle
containing one nitrogen atom. Amides derived from ammonia,
C.sub.1-C.sub.3 alkyl primary amines and C.sub.1-C.sub.2 dialkyl
secondary amines are preferred. Amides of the compounds of the
invention may be prepared according to conventional methods.
[0534] The term "prodrug" refers to compounds that are rapidly
transformed in vivo to yield the parent compound of the above
formulas, for example, by hydrolysis in blood. A thorough
discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as
Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series,
and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987, both
of which are incorporated herein by reference.
[0535] The compounds of the present invention can be administered
to a patient at dosage levels in the range of about 0.1 to about
1,000 mg per day. For a normal human adult having a body weight of
about 70 kg, a dosage in the range of about 0.01 to about 100 mg
per kilogram of body weight per day is sufficient. The specific
dosage used, however, can vary. For example, the dosage can depend
on a number of factors including the requirements of the patient,
the severity of the condition being treated, and the
pharmacological activity of the compound being used. The
determination of optimum dosages for a particular patient is
well-known to those skilled in the art.
[0536] The compounds of the present invention can exist in
different stereoisometric forms by virtue of the presence of
asymmetric centers in the compounds. It is contemplated that all
stereoisometric forms of the compounds as well as mixtures thereof,
including racemic mixtures, form part of this invention.
[0537] In addition, the compounds of the present invention can
exist in unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like. In
general, the solvated forms are considered equivalent to the
unsolvated forms for the purposes of the present invention.
[0538] It is intended that the compounds of Formula I, II, or III
be either synthetically produced or biologically produced.
[0539] The following examples illustrate particular embodiments of
the invention and are not intended to limit the specification,
including the claims, in any manner.
GENERAL SYNTHETIC SCHEMES
[0540] Amine-Linked Alkylating Michael Acceptor Sidechains
[0541] The amine is acylated either by an acid in the presence of a
coupling agent such as EDAC, or by an acid chloride. The amine in
turn can be made by reduction of the corresponding nitro compound,
displacement of a halogen by an amine or ammonia equivalent, or in
the case of pyrido[4,3-d]pyrimidines by direct incorporation during
the synthesis. 2-Haloalkylsulfonyl halides form vinyl sulfonamides
when treated with the aryl amine and excess tertiary amine base.
39
[0542] CIN means either a carbon or nitrogen atom is present at
that location.
[0543] -- means a bond or no bond.
[0544] Oxygen-Linked Alkylating Michael Acceptor Sidechains
[0545] The hydroxyl group is acylated either by an acid in the
presence of a coupling agent such as EDAC, or by an acid chloride.
The hydroxyl compound can in turn can be made by cleavage of the
corresponding methyl ether. 3-Methylthioalkanoic acid or their acid
chlorides can be used to acylate the oxygen followed by
S-alkylation or oxidation and basic or thermal elimination. 40
[0546] Ar and R denote an aryl group and R denotes an organic group
as exemplified herein.
[0547] Carbon-Linked Alkylating Michael Acceptor Sidechains
[0548] A Stille or Suzuki coupling can be used to couple the
sidechain to an appropriately substituted
quinazoline/pyridopyrimidine/pyrimidinopyrim- idine/tricycle. These
in turn can be made as aryl halides by methods known in the art, or
as aryl triflates by triflation of the hydroxyl compounds described
above, as aryl stannanes by reaction of the abovementioned
triflates with hexamethyl distannane, or as arylboronic acids by
conversion of aryl iodides to arylorgano-metallics, followed by
treatment with borate esters and hydrolysis. Alternatively, aryl
iodides can be converted to the arylzinc species and coupled with
activated halides. 41
[0549] Sulfur-Linked Alkylating Michael Acceptor Sidechains
[0550] Activated halides in pyridopyrimidines and
pyrimidinopyrimidines can be displaced by suitable
2-hydroxythiolates, and these in turn can be oxidized to sulfones,
and then water eliminated by treatment with mesyl chloride and
several equivalents of a base. For quinazolines, and claimed
tricycles, either an activated halogen especially fluorine can be
used in the sequence just described for pyridopyrimidines, or an
aryl iodide precursor can be metalated, quenched with sulfur or a
suitable sulfur electrophilic progenitor and then the resultant
aryl thiol used to open a terminal epoxide, giving a 2-hydroxy
thioether which can be converted onto a vinyl sulfone by oxidation
and water elimination as described above. 42
[0551] Hydrazino-Linked Alkylating Michael Acceptor Sidechains
[0552] Activated halides in pyridopyrimidines and
pyrimidinopyrimidines and appropriately substituted quinazolines
can be displaced by a (N-alkyl) hydrazine. Alternatively, an
amino-derivative of the desired ring nucleus can be diazotized, and
then reduced to the hydrazine. The distal nitrogen of the hydrazine
can then be acylated, sulfonylated or phosphorylated, by methods
well-known to one skilled in the art. 43
[0553] Hydroxylamino-O-Linked Alkylating Michael Acceptor
Sidechains
[0554] Activated halides in pyridopyrimidines and
pyrimidinopyrimidines and appropriately substituted quinazolines
can be displaced by a suitably O-protected (N-alkyl) hydroxylamine.
Alternatively, a nitro-derivative of the desired ring nucleus can
be synthesized, and then reduced to the hydroxylamine under
appropriate mildly reducing conditions. The oxygen of the
hydroxylamine can then be acylated, sulfonylated or phosphorylated,
by methods well-known to one skilled in the art. 44
[0555] Methyleneamino-N-Linked Alkylating Michael Acceptor
Sidechains
[0556] Activated halides in pyridopyrimidines and
pyrimidinopyrimidines and appropriately substituted quinazolines
can be displaced by cyanide, preferably in the presence of copper
or nickel salt catalysis. Alternatively, an amino-derivative of the
desired ring nucleus can be diazotized, and then converted to the
nitrile as described above. In some cases, the nitrile
functionality can be incorporated into the heterocycle earlier in
the synthesis, either as itself, or via a carboxylic acid or
aldehyde, both of which can readily be turned into nitrile
compounds by one skilled in the art. Reduction of the nitrile to a
methyleneamine is followed by nitrogen acylation, sulfonylation or
phosphorylation, by methods well-known to one skilled in the art.
45
[0557] Methyleneoxy-O-Linked Alkylating Michael Acceptor
Sidechains
[0558] Hydroxymethyl compounds can be incorporated into appropriate
heterocycles in many ways obvious to one skilled in the art. For
example, iodoquinazolines may be carbonylated in a Heck reaction,
and then reduced with NaBH.sub.4 to the desired precursor.
Aminopyridopyrimidines may be diazotized, converted to the nitrile,
partially reduced to an imine, hydrolysed, and the resultant
aldehyde reduced to hydroxymethyl. The oxygen of the hydroxymethyl
can then be acylated, sulfonylated or phosphorylated, by methods
well-known to one skilled in the art. 46
[0559] Ethano-Linked Alkylating Michael Acceptor Sidechains
[0560] Michael addition of a cuprate, derived via an organozincate
from an iodoquinazoline, to a divinylketone, or appropriately
mono-masked derivative, followed by unmasking of the second
unsaturated functionality, if required, will give compounds of the
desired type. Aldehydes derived from pyridopyrimidines or
pyrimidopyrimidnes as described above can be homologated to the
desired compounds by a wide variety of techniques such as the one
illustrated, by one skilled in the art. 47
[0561] Aminomethyl-C-Linked Alkylating Michael Acceptor
Sidechains
[0562] Amino-heterocycles of the type described throughout this
application can be alkylated by various double bond-masked
equivalents of 1-bromobut-3-en-2-one, followed by unmasking of the
unsaturation by methods known to one skilled in the art. 48
[0563] Hydroxymethyl-C-Linked Alkylating Michael Acceptor
Sidechains
[0564] Hydroxy-heterocycles made as described previously from
methoxy-heterocycles can be alkylated by various double bond-masked
equivalents of 1-bromobut-3-en-2-one, followed by unmasking of the
unsaturation by methods known to one skilled in the art.
Alternatively, alkylation of the phenol can be accomplished with
chloroacetic acid, followed by conversion to an acyl chloride and
Stille coupling of that acyl halide with an appropriate alkenyl
stannane. 49
[0565] Thiomethyl-C-Linked Alkylating Michael Acceptor
Sidechains
[0566] Appropriate mercapto-heterocycles, made by displacement of
activated halides on the heteroaromatic ring, can be alkylated by
various double bond-masked equivalents of 1-bromobut-3-en-2-one,
followed by unmasking of the unsaturation by methods known to one
skilled in the art. Alternatively, alkylation of the thiol can be
accomplished with chloroacetic acid, followed by conversion to an
acyl chloride and Stille coupling of that acyl halide with an
appropriate alkenyl stannane. 50
EXAMPLE 1
N-[4-(6-Bromo-2,3-dihydroindol-1-yl)quinazolin-6-yl]acrylamide
[0567] Step (a) 6-Nitro-4-(1-(6-bromo-indolinyl))-quinazoline
[0568] A suspension of 6-bromo-indoline (490 mg, 2.47 mmol) (Miyake
Y., Kikugawa Y., J. Het. Chem., 1983;20:349),
4-chloro-6-nitro-quinazoline (660 mg, 2.47 mmol), and
N,N-dimethylaniline (0.63 mL. 4.9 mmol) in 15 mL of isopropyl
alcohol was heated under reflux for 1 hour. The suspension was
concentrated to give a solid, which was shaken with a mixture of
ethyl acetate and saturated aqueous sodium bicarbonate. The solid
was collected by filtration and recrystallized from a boiling
mixture of ethanol (100 mL) and dimethylformamide (25 mL) to give
the product as a yellow solid (290 mg, 32%), mp 249-251.degree.
C.
[0569] Anal. Calcd. for C.sub.16H.sub.11Br.sub.1N.sub.4O.sub.2: C,
51.77; H, 2.99; N, 15.09.
[0570] Found: C, 51.58; H, 2.91; N, 15.01.
[0571] MS (APCI): Calcd. for M+1, 371.0; Found, 371.0
[0572] Step (b) 6-Amino-4-(1-(6-bromo-indolinyl))-quinazoline
[0573] To a suspension of
6-nitro-4-(1-(6-bromo-indolinyl))-quinazoline (240 mg, 6.5 mmol)
and acetic acid (1.04 mL, 18 mmol) in H.sub.2O (75 mL) and ethanol
(100 mL), heated under reflux, was added iron powder (washed with
1N HCl, then H.sub.2O, and dried; 180 mg, 3.23 mmol). After 30
minutes of heating, more iron powder (320 mg, 5.73 mmol) was added,
and heating was continued for another 30 minutes. The reaction was
filtered while hot and the solids washed with ethanol. To the
filtrate and washings was added concentrated NH.sub.4OH (10 mL),
and a small amount of solid was removed by filtration. The fitrate
was concentrated, and the resulting residue was purified by flash
silica gel chromatography dichloromethane/methanol, 10:1) to give a
yellow foam.
[0574] MS (APCI): Calcd. for C.sub.16H.sub.13Br.sub.1N.sub.4:
M+1,341.0; Found, 341.1
[0575] The NMR spectrum showed the presence of an acetate species.
This was removed by dissolving the solid in diethylether, and
washing the solution consecutively with H.sub.2O, saturated aqueous
NaHCO.sub.3, and brine. The solution was dried (MgSO.sub.4) and
concentrated to give the product as a brown solid (220 mg,
100%).
[0576] Step (c)
[0577] To a suspension of
6-amino-4-(1-(6-bromo-indolinyl))-quinazoline (200 mg, 0.6 mmol)
and N-ethyl-N'-(3-N,N-dimethylaminopropylcarbodiimide
hydrochloride) (450 mg, 2.3 mmol) in dimethylformamide (1 mL) and
tetrahydrofuran (3 mL), cooled in an ice-bath and under nitrogen,
was added acrylic acid (0.16 mL, 2.3 mmol), followed by
diisopropylethylamine (0.40 mL, 2.3 mmol). The ice-bath was
removed, and the suspension was stirred at room temperature for 18
hours. The resulting solution was poured into cold H.sub.2O, and
the suspension was extracted with dicholoromethane (4.times.25 mL).
The extracts were dried (MgSO.sub.4), concentrated, and purified by
flash silica gel chromatography (dichloromethane/methanol, 9:1) to
give the product as a light yellow solid (110 mg, 41%), mp
214-216.degree. C. This material contained 0.3 mol of
dimethylformamide (substantiated by NMR) and 0.3 mol H.sub.2O by
C,H,N analysis.
[0578] Anal. Calcd. for
C.sub.19H.sub.15Br.sub.1N.sub.4O.sub.1.0.3DMF.0.3H- .sub.2O: C,
56.56; H, 4.22; N, 14.25.
[0579] Found: C, 56.37; H, 4.14: N, 14.01.
[0580] MS (APCI): Calcd. for M+1, 395.0; Found, 395.1
BIOLOGICAL METHODS
[0581] Tissue Culture
[0582] A431 human epidermoid carcinoma cells were obtained from the
American Type Culture Collection, Rockville, Md. and maintained as
monolayers in dMEM (Dulbecco's modified eagle medium)/F12, 50:50
(Gibco/BRL) containing 10% fetal bovine serum. For growth
inhibition assays, dilutions of the designated compound in 10 .mu.L
were placed in 24-well Linbro plates (1.7.times.1.6 cm, flat
bottom) followed by the addition of cells (2.times.10.sup.4) in 2
mL of media. The plates were incubated for 72 hours at 37.degree.
C. in a humidified atmosphere containing 5% CO.sub.2, in air. Cell
growth was determined by cell count with a Coulter Model AM
electronic cell counter (Coulter Electronics, Inc., Hialeah,
Fla.).
[0583] Purification of Epidermal Growth Factor Receptor Tyrosine
Kinase
[0584] Human EGF receptor tyrosine kinase was isolated from A431
human epidermoid carcinoma cells by the following method. Cells
were grown in roller bottles in dMEM/F12 media (Gibco/BRL)
containing 10% fetal calf serum. Approximately 10.sup.9 cells were
lysed in 2 volumes of buffer containing 20mM
N-[2-hydroxyethyl]piperazine-N'-[2-ethane sulfonic acid](Hepes), pH
7.4, 5 mM ethylene glycol-bis(.beta.-aminoethyl ether)
N,N,N',N'-tetraacetic acid (EGTA), 1% Triton X-100, 10% glycerol,
0.1 mM sodium orthovanadate, 5 mM sodium fluoride, 4 mM
pyrophosphate, 4 mM benzamide, 1 mM dithiothreitol (DTT), 80
.mu.g/mL aprotinin, 40 .mu.g/mL leupeptin, and 1 mM phenylmethyl
sulfonyl fluoride (PMSF). After centrifugation at 25,000.times.g
for 10 minutes, the supernatant was applied to a fast Q sepharose
column (Pharmacia Biotech., Inc., Piscataway, N.J.) and eluted with
a linear gradient from 0.1 M NaCl to 0.4 M NaCl in 50 mM Hepes, 10%
glycerol, pH 7.4. Enzyme active fractions were pooled, divided into
aliquots, and stored at -100.degree. C. Fibroblast growth factor
receptor (FGFR), platelet-derived growth factor (PDGF), insulin,
and c-src tyrosine kinases were obtained by methods well-known in
the art. For example, see Fry et al., "Strategies For The Discovery
Of Novel Tyrosine Kinase Inhibitors With Anticancer Activity,
Anticancer Drug Design, 1994;9:331-351.
[0585] Tyrosine Kinase Assays
[0586] Enzyme assays for IC.sub.50determinations were performed in
96-well filter plates (Millipore MADVN6550, Millipore, Bedford,
Mass.). The total volume was 0.1 mL containing 20 mM Hepes, pH 7.4,
50 .mu.M sodium vanadate, 40 mM magnesium chloride, 10 .mu.M
adenosine triphosphate (ATP) containing 0.5 .mu.Ci of
[.sup.32P]ATP, 20 .mu.g of poly Glutamic acid/tyrosine (Sigma
Chemical Co., St. Louis, Mo.), 10 ng of EGF receptor tyrosine
kinase and appropriate dilutions of inhibitor. All components
except the ATP are added to the well and the plate incubated with
shaking for 10 minutes at 25.degree. C. The reaction is started by
adding [.sup.32P]ATP, and the plate is incubated at 25.degree. C.
for 10 minutes. The reaction is terminated by addition of 0.1 mL of
20% trichloroacetic acid (TCA). The plate is kept at 4.degree. C.
for at least 15 minutes to allow the substrate to precipitate. The
wells are then washed 5 times with 0.2 mL of 10% TCA and .sup.32P
incorporation determined with a Wallac beta plate counter (Wallac,
Inc., Gaithersburg, Pa.). Assays using intracellular kinase domains
of PDGF, FGF, and insulin receptors, as well as those for c-src,
were performed as described for the EGF receptor except that 10 mM
Manganese chloride was included in the reaction.
[0587] Western Blotting Procedure
[0588] Extracts were made by lysing the monolayers in 0.2 mL of
boiling Laemlli buffer (2% sodium dodecyl sulfate, 5%
beta-mercaptoethanol, 10% glycerol and 50 mM
tris[hydroxymethyl]aminomethane (Tris), pH 6.8), and the lysates
were heated to 100.degree. C. for 5 minutes. Proteins in the lysate
were separated by polyacrylamide gel electrophoresis and
electrophoretically transferred to nitrocellulose. The membrane was
washed once in 10 mM Tris, pH 7.2, 150 mM NaCl, 0.01% Azide (TNA),
and blocked overnight in TNA containing 5% bovine serum albumin and
1% ovalbumin. The membrane was blotted for 2 hours with
antiphosphotyrosine antibody (UBI, 1 .mu.g/mL in blocking buffer)
and then washed twice in TNA, once in TNA containing 0.05% Tween-20
detergent and 0.05% nonidet P-40 detergent and twice in TNA. The
membranes were then incubated for 2 hours in blocking buffer
containing 0.1 .mu.Ci/mL of [.sup.125I]protein A and then washed
again as above. After the blots were dry, they were loaded into a
film cassette and exposed to X-AR X-ray film (Eastman Kodak Co.,
Rochester, N.Y.) for 1 to 7 days. Band intensities were determined
with a Molecular Dynamics laser densitometer.
[0589] Autophosphorylation Assay
[0590] A431 human epidermoid carcinoma cells were grown in 6-well
plates to about 80% confluency and then incubated in serum-free
media for 18 hours. Duplicate sets of cells were treated with a
range of concentrations of the designated compound to be tested as
an inhibitor for 15 minutes. The cells were then stimulated with
100 ng/mL of EGF for 5 minutes and extracts made as described under
the Western Blotting Procedure.
[0591] Irreversibility Test Protocol
[0592] A431 human epidermoid carcinoma cells were grown in 6-well
plates to about 80% confluency and then incubated in serum-free
media for 18 hours. Duplicate sets of cells were treated with 2
.mu.M of designated compound to be tested as an irreversible
inhibitor for either 1 or 2 hours. One set of cells was then
stimulated with 100 ng/mL of EGF for 5 minutes and extracts made as
described under the western blotting procedure. The other set of
cells were washed free of the compound with warmed serum-free
media, incubated for 2 hours, washed again, incubated another 2
hours, washed again, and then incubated a further 4 hours. This set
of cells was then stimulated with EGF and extracts made similar to
the first set of cells.
1 IC.sub.50 (nM) IC.sub.50 (nM) A431 EGFr Cell Example (isolated
enzyme Autophosphorylation Irreversibility Number assay) Assay Test
1 0.4 9.9 yes, irreversible
* * * * *