|
Cancer Patent Abstract
The present invention relates to 2-substituted 4-heteroaryl-pyrimidines,
their preparation, pharmaceutical compositions containing them and
their use as inhibitors of cyclin-dependent kinases (CDKs) and hence
their use in the treatment of proliferative disorders such as cancer,
leukaemia, psoriasis and the like.
Cancer Patent Claims
The invention claimed is:
1. A compound of general formula I: ##STR00013## wherein: X.sup.1
is CR.sup.9; X.sup.2 is NR.sup.10; Z is NH; R.sup.1, R.sup.2, R.sup.3,
R.sup.9 and R.sup.10 are independently H, alkyl, aryl, aralkyl,
heterocycle, halogeno, NO.sub.2, CN, OH, alkoxy, aryloxy, (R''')nNH.sub.2,
(R''')nNH--R', (R''')nN--(R')(R''), NH-aryl, N-(aryl).sub.2, COOH,
COO--R', COO-aryl, CONH.sub.2, CONH--R', CON--(R')(R''), CONH-aryl,
CON-(aryl).sub.2, SO.sub.3H, SO.sub.2NH.sub.2, CF.sub.3, CO--R',
or CO-aryl, wherein alkyl, aryl, aralkyl and heterocycle groups
may be further substituted with one or more groups selected from
halogeno, NO.sub.2, CN, OH, O-methyl, NH.sub.2, COOH, CONH.sub.2
and CF.sub.3; R.sup.4, R.sup.5, R.sup.7, and R.sup.8 are independently
from each other H, substituted or unsubstituted lower alkyl, halogeno,
NO.sub.2, CN, OH, substituted or unsubstituted alkoxy, NH.sub.2,
NH--R', N--(R')(R''), COOH, COO--R', CONH.sub.2, CONH--R', CON--(R')(R''),
SO.sub.3H, SO.sub.2NH.sub.2, or CF.sub.3; R.sub.6 is H, substituted
or unsubstituted lower alkyl, halogeno, NO.sub.2, CN, OH, substituted
or unsubstituted alkoxy, NH.sub.2, NH--R', N--(R')(R''), COOH, COO--R',
SO.sub.3H, SO.sub.2NH.sub.2, or CF.sub.3; wherein R'R'' and R'''
are each independently alkyl groups that may be the same or different
and n is 0 or 1; and wherein at least two or three of R.sup.1, R.sub.2
and R.sub.9 are not hydrogen; or a pharmaceutically acceptable salts
thereof.
2. A compound according to claim 1, wherein; R.sup.1, R.sup.2,
R.sup.3 and R.sup.9 are each independently selected from H, alkyl,
aryl, aralkyl, heterocycle, halogeno, NO.sub.2, CN, OH, alkoxy,
aryloxy, (R''')nNH.sub.2, (R''')nNH--R', (R''')nN--(R')(R''), COOH,
COO--R', CONH.sub.2, CONH--R', CON--(R')(R''), SO.sub.3H, SO.sub.2NH.sub.2,
CF.sub.3, and CO--R'wherein alkyl, aryl and aralkyl groups may be
further substituted with one or more groups selected from halogeno,
NO.sub.2, CN, OH, O-methyl, NH.sub.2, COOH, CONH.sub.2 and CF.sub.3.
3. A compoundaccording to claim 1, wherein said compound is selected
from 2-[N-(phenyl)]-4-(2,4-dimethylpyrrol-3-yl)pyrimidineamines
in which the phenyl group is 2-, 3-, 4-or 5-substituted by at least
one of F, NH.sub.2, NO.sub.2, OH, Cl, Br, I, CN, CH.sub.2OH, CF.sub.3
or OMe.
4. A compound according to claim 3, wherein the phenyl group is
mono-substituted by F, NH.sub.2, NO.sub.2, OH, Cl, Br, I, CH.sub.2OH,
CN, CF.sub.3 or OMe at any of the 2,3,4 or 5-positions, or di-substituted
by 2,4-difluoro, 3,5-difluoro, 3,4-difluoro, 2,4-dichloro, 3,5-dichloro,
3,4-dichloro or 4-chloro-3-trifluoromethyl.
5. A compound according to claim 1, wherein said compound is selected
from 2-[N-(phenyl)]-4-(3,5-dimethyl-1H-pyrrole-2-carbonitrile)pyrimidinea-
mines in which the phenyl group is 2-, 3- or 4-substituted by at
least one of F, NH(CH.sub.3).sub.2, NO.sub.2, OH, Cl, Br, I or CF.sub.3.
6. A compound according to claim 5, wherein the phenyl group is
mono-substituted by F, NH(CH.sub.3).sub.2, NO.sub.2, OH, I or CF.sub.3
at any of the 3 or 4-positions, or di-substituted by 4-methyl-3-nitro,
3-iodo-4-methyl, 4-chloro-3-methyl, 3-hydroxy-4-methyl, 4-fluoro-3-methyl
or 4-methyl-3-fluoro.
7. A compound according to claim 1, wherein said compound is selected
from 2-[N-(phenyl)]-4-(2,4-dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidinamin-
es wherein the phenyl group is mono-substituted by F, NIH(CH.sub.3).sub.2,
NO.sub.2, OH, I or CF.sub.3 at the 4-position.
8. A compound according to claim 7, wherein the phenyl group is
substituted by a fluoro or NH(CH.sub.3).sub.2 group.
9. A compound according to claim 1, wherein said compound is selected
from 2-[N-(phenyl)]-4-(2,4-dimethyl-5-halogeno-1H-pyrrol-3-yl)-pyrimidina-
mines wherein the phenyl group is mono-substituted by F, NH(CH.sub.3).sub.2,
NO.sub.2, OH, I or CF.sub.3 at the 3 or 4-positions.
10. A compound according to claim 9, wherein the phenyl group is
substituted by a 4-fluoro or 3-nitro group, the halogeno group being
chloro or bromo.
11. A compound according to claim 1, selected from 2-[N-(phenyl)]-4-(2,4-dimethyl-5-dialkylaminoalkyl-1H-pyrrol-3-yl)-pyrimi-
dinamines wherein the phenyl group is mono-substituted by F, NH(CH.sub.3).sub.2,
NO.sub.2, OH, I or CF.sub.3 at the 4-position.
12. A compound according to claim 11, wherein the phenyl group
is substituted by fluoro, and the dialkylaminoalkyl group is diethylaminomethyl
or dimethylaminomethyl.
13. A compound according to claim 1, selected from 2-[N-(phenyl)]-4-(2,4-dimethyl-5-(heterocycle)-1H-pyrrol-3-yl)-pyrimidina-
mines wherein the phenyl group is mono-substituted by F, NH(CH.sub.3).sub.2,
NO.sub.2, OH, I or CF.sub.3 at the 4-position.
14. A compound according to claim 13, wherein the phenyl group
is substituted by fluoro, and the heterocycle group is 5-morpholin-4-ylmethyl
or 4-methyl-piperazin-1-ylmethyl.
15. A compound selected from: [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine;
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-iodo-phenyl)-amine;
(3,4-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-am-
ine; (4-Chloro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-am-
ine; (3,5-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl-
]-amine; 4-[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-ylamino]-phenol;
3-[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-ylamino]-phenol;
(2,4-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-am-
ine; (2,4-Dichloro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl-
]-amine; (4-Chloro-3-trifluoromethyl-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3--
yl)-pyrimidin-2-yl]-amine; [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-trifluoromethyl-pheny-
l)-amine; [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-trifluoromet-
hyl-phenyl)-amine; (3-Chloro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-amine;
N-[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-N',N'-dimethyl-benzene-
-1,4-diamine; (3-Chloro-4-iodo-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-
-amine; [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-fluoro-4-iodo--
phenyl)-amine; 3,5-Dimethyl-4-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carb-
onitrile; 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-.sub.3 ,5-dimethyl-1H-pyrrole-2-carbonitrile;
4-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-.sub.3 ,5-dimethyl-1H-pyrrole-2-carbonitrile;
3,5-Dimethyl-4-[2-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1H-pyrr-
ole-2-carbonitrile; 4-[2-(4-Iodo-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbo-
nitrile; 4-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-.sub.3 ,5-dimethyl-1H-pyrrole-2-carbonitrile;
3,5-Dimethyl-4-[2-(4-methyl-3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrro-
le-2-carbonitrile; 4-[2-(3-Iodo-4-methyl-phenylamino)-pyrimidin-4-yl]-.sub.3,5-dimethyl-1H-p-
yrrole-2-carbonitrile; 4-[2-(4-Chloro-3-methyl-phenylamino)-pyrimidin-4-yl]-.sub.3
,5-dimethyl-1H-pyrrole-2-carbonitrile; 4-[2-(3-Hydroxy-4-methyl-phenylamino)-pyrimidin-4-yl]-.sub.3,5-dimethyl-1-
H-pyrrole-2-carbonitrile; 4-[2-(4-Fluoro-3-methyl-phenylamino)-pyrimidin-4-y.sub.1]-3,5-dimethyl-1H-
-pyrrole-2-carbonitrile; 4-[2-(3-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile; 4-[2-(4-Dimethylamino-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrol-
e-2-carbonitrile; 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-car-
boxylic acid amide; [4-(3,5-Dimethyl-1H-pyrrol-2-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;
(4-Fluoro-phenyl)-[4-(1,2,4-trimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-ami-
ne; [4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phe-
nyl)-amine; N-[4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-N',Nt-dimethyl-
-benzene-1,4-diamine; [4-(5-Amino-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl-
)-amine; [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluor-
o-phenyl)-amine; [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-
-amine; [4(5-Chloro-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-
-phenyl)-amine; [4-(5-Diethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4--
fluoro-phenyl)-amine; [4-(5-Dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-
-fluoro-phenyl)-amine; [4-(2,4-Dimethyl-5-morpholin-4-ylmethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(-
4-fluoro-phenyl)-amine; and {4-[2,4-Dimethyl-5-(4-methyl-piperazin-1-ylmethyl)-1H-pyrrol-3-yl)-pyrimi-
din-2-yl}-(4-fluoro-phenyl)-amine.
16. A compound according to claim 15 selected from; [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine;
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-iodo-phenyl)-amine;
(3,4-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-am-
ine; (4-Chioro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-am-
ine; (3,5-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl-
]-amine; 4-[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-ylamino]-phenol;
3-[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-ylamino]-phenol;
[4-(2,4-Dimethyl- .sub.1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-trifluoromethyl-phenyl)-amine;
(3-Chloro-4-iodo-phenyl)-4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]--
amine; [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-fluoro-4-iodo-p-
henyl)-amine; 3,5-Dimethyl-4-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carb-
onitrile; 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile; 4-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-ca-
rbonitrile; 3,5-Dimethyl-4-[2-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1H-pyrr-
ole-2-carbonitrile; 4-[2-(4-Iodo-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbo-
nitrile; 4-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile; 3,5-Dimethyl-4-[2-(4-methyl-3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrro-
le-2-carbonitrile; 4-[2-(3-Iodo-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrol-
e-2-carbonitrile; 4-[2-(4-Chloro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile; 4-[2-(3-Hydroxy-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyr-
role-2-carbonitrile; 4-[2-(4-Fluoro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2carbonitrile; 4-[2-(3-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2carbonitrile; 4-[2-(4-Dimethylamino-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrol-
e-2-carbonitrile; 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-car-
boxylic acid amide; (4-Fluoro-phenyl)-[4-(1,2,4-trimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-ami-
ne; [4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phe-
nyl)-amine; N-[4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-N',N'-dimethyl-
-benzene-1,4-diamine; [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl-
)-amine; [4- (5-Bromo-2,4-dimethyl- lH-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine;
[4-(5-Chloro-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-pheny-
l)-amine; [4-(5-Diethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin--
2-yl]-(4-fluoro-phenyl)-amine; [4-(5-Dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-
-fluoro-phenyl)-amine; [4-(2,4-Dimethyl-5-morpholin-4-ylmethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(-
4-fluoro-phenyl)-amine, and {4-[2,4-Dimethyl-5-(4-methyl-piperazin-1-ylmethyl)-1H-pyrrol-3-yl)-pyrimi-
din-2-yl}-(4-fluoro-phenyl)-amine.
17. A compound according to claim 16 selected from; [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine;
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-iodo-phenyl)-amine;
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-trifluoromethyl-pheny-
l)-amine; 3,5-Dimethyl-4-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrro-
le-2-carbonitrile; 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-car-
bonitrile; 4-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-py-
rrole-2-carbonitrile; 3,5-Dimethyl-4-[2-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1H-pyrr-
ole-2-carbonitrile; 4-[2-(4-Iodo-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbo-
nitrile; 4-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile; 3,5-Dimethyl-4-[2-(4-methyl-3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrro-
le-2-carbonitrile; 4-[2-(3-Iodo-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrol-
e-2-carbonitrile; 4-[2-(4-Chloro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile; 4-[2-(3-Hydroxy-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyr-
role-2-carbonitrile; 4-[2-(4-Fluoro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile; 4-[2-(3-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile; 4-[2-(4-Dimethylamino-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrol-
e-2-carbonitrile; 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-car-
boxylic acid amide; [4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl-
)-amine; N-[4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-N',N''-
-dimethyl-benzene-1,4-diamine; [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl-
)-amine; [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-
-phenyl)-amine; [4-(5-Chloro-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-pheny-
l)-amine; [4-(5-Diethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin--
2-yl]-(4-fluoro-phenyl)-amine; [4-(5-Dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-
-fluoro-phenyl)-amine, and [4-(2,4-Dimethyl-5-morpholin-4-ylmethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(-
4-fluoro-phenyl)-amine.
18. A compound according to claim 17 selected from; [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine;
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-iodo-phenyl)-amine;
3,5-Dimethyl-4-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carb-
onitrile; 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile; 4-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-ca-
rbonitrile; 3,5-Dimethyl-4-[2-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1H-pyrr-
ole-2-carbonitrile; 4-[2-(4-Iodo-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbo-
nitrile; 4-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile; 3,5-Dimethyl-4-[2-(4-methyl-3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrro-
le-2-carbonitrile; 4-[2-(3-Hydroxy-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyr-
role-2-carbonitrile; 4-[2-(4-Fluoro-3-methyl-phenylamino)-pyrimidin-4-yI]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile; 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-car-
boxylic acid amide; [4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl-
)-amine; 4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro--
phenyl)-amine, and [4-(5-Dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-
-fluoro -phenyl)-amine.
19. A compound of general formula I: ##STR00014## wherein: one
of X.sup.1 and X.sup.2 is NR.sup.10 and the other of X.sup.1 and
X.sup.2 is CR.sup.9; Z is NHCO, NHSO.sub.2, NHCH.sub.2, CH.sub.2,
CH.sub.2CH.sub.2, or CH.dbd.CH; R.sup.1, R.sup.2, R.sup.3 R.sup.9
and R.sup.10 are independently H, alkyl, aryl, aralkyl, heterocycle,
halogeno, NO.sub.2, CN, OH, alkoxy, aryloxy, (R''')nNH.sub.2, (R''').sub.nNH--R',
(R''').sub.nN--(R')(R''), NH-aryl, N-(aryl).sub.2, COOH, COO--R',
COO-aryl, CONH.sub.2, CONH--R', CON--(R')(R''), CONH-aryl, CON-(aryl).sub.2,
SO.sub.3H, SO.sub.2NH.sub.2, CF.sub.3, CO--R', or CO-aryl, wherein
alkyl, aryl, aralkyl and heterocycle groups may be further substituted
with one or more groups selected from halogeno, NO.sub.2, CN, OH,
O-methyl, NH.sub.2, COOH, CONH.sub.2 and CF.sub.3; R.sup.4, R.sup.5,
R.sup.6, R.sup.7, and R.sup.8 are independently from each other
H, substituted or unsubstituted lower alkyl, halogeno, NO.sub.2,
CN, OH, substituted or unsubstituted alkoxy, NH.sub.2, NH--R', N--(R')(R''),
COOH, COO--R', CONH.sub.2, CONH--R', CON--(R')(R''), SO.sub.3H,
SO.sub.2NH.sub.2, or CF.sub.3; wherein R'R''and R''' are each independently
alkyl groups that may be the same or different and n is 0 or 1,
or a pharmaceutically acceptable salt thereof.
20. A compound of general formula I: ##STR00015## wherein: X.sup.1
is NH; X.sub.2 is CR.sup.9; Z is NH; R.sup.1, R.sup.2, R.sup.3 and
R.sup.9 are each independently selected from H, alkyl, aryl, aralkyl,
heterocycle, halogeno, NO.sub.2, CN, OH, alkoxy, aryloxy, (R''').sub.nNH.sub.2,
(R''').sub.nNH--R', (R''').sub.nN--(R')(R''), COOH, COO--R', CONH.sub.2,
CONH--R', CON--(R')(R''), SO.sub.3H, SO.sub.2NH.sub.2, CF.sub.3,
and CO--R'wherein alkyl, aryl and aralkyl groups may be further
substituted with one or more groups selected from halogeno, NO.sub.2,
CN, OH, O-methyl, NH.sub.2, COOH, CONH.sub.2 and CF.sub.3; R.sup.4,
R.sup.5 and R.sup.8 are each independently selected from H, halogeno,
nitro, amino, aminoalkyl, hydroxy, alkoxy, carbamoyl, sulfamyl,
N(R')(R''), C.sub.1-4 alkyl and substituted C.sub.1-4 alkyl; R.sup.6
is selected from H, halogeno, nitro, amino, aminoalkyl, hydroxy,
alkoxy, carbamoyl, sulfamyl, N(R')(R''), butyl and substituted C.sub.1-4
alkyl; R.sup.7 is selected from H, halogeno, nitro, amino, aminoalkyl,
hydroxy, carbamoyl, sulfamyl, N(R')(R'') C.sub.2-4 alkyl and substituted
C.sub.1-4 alkyl; wherein R'R'' and R''' are each independently alkyl
groups that may be the same or different and n is 0 or 1, wherein
at least two or three of R.sup.1, R.sup.2, and R.sup.9 are not hydrogen,
or a pharmaceutically acceptable salt thereof.
21. A compound according to claim 1 or 19, wherein R.sup.3 is H.
22. A compound according to claim 21, wherein R.sup.1, R.sup.2
and R.sup.9 are each independently H, halogeno, CN, NO.sub.2, CO(NH.sub.2),
(R''')NH(R')(R'') a C.sub.1-4 alkyl group or a heterocyclic group.
23. A compound according to claim 22, wherein when R.sup.1 is halogeno,
it is selected from chloro or bromo; when R.sup.1 is alkylamino,
it is diethylaminomethyl or dimethylaminomethyl; when R.sup.1 is
a heterocyclic group it is morpholin-4-ylmethyl or 4-methyl-piperazin-1-ylmethyl.
24. A compound according to claim 1 or 19, wherein R is H or CN,
and R.sup.2 and R.sup.9 are both methyl.
25. A compound according to claim 24, wherein R.sup.1 is H.
26. A compound according to claim 25, wherein R.sup.1 is CN.
27. A compound according to claim 1 or 19, wherein; R.sup.4, R.sup.5,
R.sup.6, R.sup.7, and R.sup.8 are independently from each other
H, unsubstituted lower alkyl, halogeno, NO.sub.2, CN, OH, N--(R')(R''),
or CF.sub.3; wherein R'R'' and R''' are each independently alkyl
groups that may be the same or different and n is 0 or 1.
28. A compound according to claim 27, wherein R.sup.4 to R.sup.8are
selected independently from H, F, NH.sub.2, NO.sub.2, OH, Cl, Br,
I, CN, CH.sub.2OH, CF.sub.3 and dimethylamino.
29. A compound according to claim 27, wherein R.sup.4 and R.sup.8
are both hydrogen.
30. A compound according to claim 19, wherein; X.sup.1 and X.sup.2
are NH and CR.sup.9 respectively; Rhu 1, R.sup.2, R.sup.3 and R.sup.9
are each independently selected from H, alkyl, aryl, aralkyl, heterocycle,
halogene, NO.sub.2, CN, OH, alkoxy, aryloxy, (R''')nNH.sub.2,(R''')nNH--R',
(R''')nN--(R')(R''), COOH, COO--R', CONH.sub.2, CONH--R', CON--(R')(R''),
SO.sub.3H, SO.sub.2NH.sub.2, CF.sub.3, and CO--R' wherein alkyl,
aryl and aralkyl groups may be firther substituted with one or more
groups selected from halogene, NO.sub.2, CN, OH, O-methyyl, NH.sub.2,
COOH, CONH.sub.2 and CF.sub.3; Z is selected from NHSO.sub.2 and
NHCH.sub.2; R.sup.4, R.sup.5 and R.sup.8 are each independently
selected from H, halogeno, nitro, amino, aminoalkyl, hydroxy, alkoxy,
carbamoyl, sulfamyl, N(R')(R''), C.sub.1-4 alkyl and substituted
C.sub.1-4 alkyl; R6 is selected from H, halogeno, nitro, amino,
aminoalkyl, hydroxy, alkoxy, carbamoyl, sulfamyl, N(R')(R''), methyl,
propyl, butyl and substituted C.sub.1-4 alkyl; R7 is selected from
H, halogeno, nitro, amino, aminoalkyl, hydroxy, carbamoyl, sulfamyl,
N(R')(R''C.sub.2-4 alkyl and substituted C.sub.1-4 alkyl.
31. A pharmaceutical composition comprising a compound of claim
1 or a pharmaceutically acceptable salt thereof together with a
pharmaceutically acceptable excipient.
32. A pharmaceutical composition comprising a compound of claim
19 or 20 or a pharmaceutical acceptable salt thereof together with
a pharmaceutically acceptable excipient.
33. A method of treating a subject for a CDK dependent proliferative
disorder, comprising administering to a subject a compound of claim
1 or a pharmaceutically acceptable salt thereof, such that said
CDK dependent proliferative disorder in said subject is treated,
wherein said CDK dependent proliferative disorder is lung cancer,
cervical cancer, colon cancer, breast cancer, or bone cancer.
34. The method of claim 33, wherein said compound is administered
in an amount sufficient to inhibit at least one CDK enzyme.
35. The method of claim 34, wherein the CDK enzyme is CDK2 andlor
CDK4.
36. A method of treating a subject for a CDK dependent proliferative
disorder, comprising administering to a subject a compound of claim
19 or 20 or a pharmaceutically acceptable salt thereof, such that
said CDK dependent proliferative disorder in said subject is treated,
wherein said CDK dependent proliferative disorder is lung cancer,
cervical cancer, colon cancer, breast cancer, or bone cancer.
37. The method of claim 36, wherein said compound is administered
in an amount sufficient to inhibit at least one CDK enzyme.
38. The method of claim 37, wherein the CDK enzyme is CDK2 and/or
CDK4.
39. A method of treating a subject for lung cancer, cervical cancer,
colon cancer, breast cancer, or bone cancer, comprising administering
to a subject a compound of general formula 1 or a pharmaceutically
acceptable salt thereof such that said lung cancer, cervical cancer,
colon cancer, breast cancer, or bone cancer in said subject is treated,
wherein said compound of general formula 1 is. ##STR00016## wherein:
one of X.sup.1 and X.sup.2 is NR.sup.10 and the other of X.sup.1
and X.sup.2 is CR.sup.9; Z is NH, NHCO, NHSO.sub.2, NHCH.sub.2,
CH.sub.2, CH.sub.2CH.sub.2, or CH.dbd.CH; R.sup.1, R.sup.2, R.sup.3
R.sup.9 and R.sub.10 are independently H, alkyl, aryl, aralkyl,
heterocycle, halogeno, NO.sub.2, CN, OH, alkoxy, aryloxy, (R''')nNH.sub.2,
(R''')nNH--R', (R''')nN--(R')(R''), NH-aryl, N-(aryl).sub.2, COOH,
COO--R', COO-aryl, CONH.sub.2, CONH--R', CON--(R')(R''), CONH-aryl,
CON-(aryl).sub.2, SO.sub.3H, SO.sub.2NH.sub.2, CF.sub.3, CO--R',
or CO-aryl, wherein alkyl, aryl, aralkyl and heterocycle groups
may be further substituted with one or more groups selected from
halogeno, NO.sub.2, CN, OH, O-methyl, NH.sub.2, COOH, CONH.sub.2
and CF.sub.3; R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
independently from each other H, substituted or unsubstituted lower
alkyl, halogeno, NO.sub.2, CN, OH, substituted or unsubstituted
alkoxy, NH.sub.2, NH--R', N--(R')(R''), COOH, COO--R', CONH.sub.2,
CONH--R', CON--(R')(R''), SO.sub.3H, SO.sub.2NIH.sub.2, or CF.sub.3;
wherein R'R'' and R''' are each independently alkyl groups that
may be the same or different and n is 0 or 1, wherein at least two
or three of R.sup.1, R.sup.2, and R.sub.9 are not hydrogen; or a
pharmaceutically acceptable salte thereof.
40. The method of claim 39, wherein said compound is administered
in an amount sufficient to inhibit at least one CDK enzyme.
41. The method of claim 40, wherein the CDK enzyme is CDK2 and/or
CDK4.
Cancer Patent Description
The present invention relates to 2-substituted 4-heteroaryl-pyrimidines,
their preparation, pharmaceutical compositions containing them,
and their use in the treatment of proliferative disorders such as
cancer, leukemia, psoriasis and the like.
INTRODUCTION AND SUMMARY OF THE PRIOR ART
Certain 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidineamines
having anti-asthmatic properties are disclosed in EP-A-233,461.
Certain 4-heteroaryl-N-(3-substituted-phenyl)-2-pyridineamines possessing
anti-proliferative properties and inhibiting protein kinases C,
epidermal growth factor receptor-associated tyrosine protein kinase
(EGF-R-TPK), as well as CDK1/cyclin B have been disclosed in WO95/09847
wherein the exemplified heteroaryl are pyridyl and indolyl.
J. Med. Chem. (1993) Vol. 36, pages 2716 2725, Paul, R. et al:
discloses a further class of phenyl amino-pyrimidines possessing
anti-inflammatory activity. These compounds include unsubstituted
pyrrol groups, mono-substituted 2-thienyl groups and dimethyl-3-furyl
groups at the 4-position of the pyrimidine ring.
It is an aim of the present invention to provide a further class
of N-phenyl-2-pyrimidine anti-proliferative compounds. The compounds
of the present invention have surprisingly been found to not to
be inhibitors of protein kinase C. As discussed hereinafter, their
activity may be demonstrated by inhibition of cell proliferation
in cell lines and/or inhibition of cyclin dependent kinase enzymes.
SUMMARY OF THE INVENTION
The first aspect of the present invention relates to compounds
of general formula I:
##STR00001## wherein: one of X.sup.1 and X.sup.2 is NR.sup.10 and
the other of X.sup.1 and X.sup.2 is CR.sup.9; Z is NH, NHCO, NHSO.sub.2,
NHCH.sub.2, CH.sub.2, CH.sub.2CH.sub.2, or CH.dbd.CH; R.sup.1, R.sup.2,
R.sup.3, R.sup.9 and R.sup.10 are independently H, alkyl, aryl,
aralkyl, heterocycle, halogeno, NO.sub.2, CN, OH, alkoxy, aryloxy,
(R''').sub.nNH.sub.2, (R''').sub.nNH--R', (R''').sub.nN--(R')(R''),
NH-aryl, N-(aryl).sub.2, COOH, COO--R', COO-aryl, CONH.sub.2, CONH--R',
CON--(R')(R''), CONH-aryl, CON-(aryl).sub.2, SO.sub.3H, SO.sub.2NH.sub.2,
CF.sub.3, CO--R', or CO-aryl, wherein alkyl, aryl, aralkyl and heterocycle
groups may be further substituted with one or more groups selected
from halogeno, NO.sub.2, CN, OH, O-methyl, NH.sub.2, COOH, CONH.sub.2
and CF.sub.3; R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
independently from each other H, substituted or unsubstituted lower
alkyl, halogeno, NO.sub.2, CN, OH, substituted or unsubstituted
alkoxy, NH.sub.2, NH--R', N--(R')(R''), COOH, COO--R', CONH.sub.2,
CONH--R', CON--(R')(R''), SO.sub.3H, SO.sub.2NH.sub.2, or CF.sub.3;
wherein R'R'' and R''' are each independently alkyl groups that
may be the same or different and n is 0 or 1; with the proviso that
when R.sup.1 and R.sup.2 are H, X.sup.1 is NH, X.sup.2 is CH, and
R.sup.3 is H, the phenyl group is not unsubstituted, 4-ethyl, 3-methyl,
3-(1,1,2,2-tetrafluoroethoxy), 3,4,5-trimethoxy, when the other
groups R.sup.4 R.sup.8 are H; and pharmaceutically acceptable salts
thereof.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
As used herein the term "alkyl" includes both straight
chain and branched alkyl groups having from 1 to 8 carbon atoms,
e.g. methyl, ethyl propyl, isopropyl, butyl, isobutyl, tert-butyl,
pentyl, hexyl etc and the term "lower alkyl" is similarly
used for groups having from 1 to 4 carbon atoms.
The term "aryl" is used to include groups having from
6 to 10 carbon atoms, e.g. phenyl, naphthyl etc.
The term "aralkyl" is used as a conjunction of the terms
alkyl and aryl as given above.
Preferred compounds of formula I are those bearing a mono-, di-
or trisubstituted pyrrol radical, attached to the pyrimidine ring
through one of the ring carbon atoms. Preferably, the pyrrol radical
is a pyrrol-3-yl group (i.e. X.sup.1 is CR.sup.9 and X.sup.2 is
NR.sup.10, preferably NH) and is di- or tri-substituted.
The pyrrol group may be substituted by R.sup.1, R.sup.2, R.sup.9
and R.sup.10. Preferably, R.sup.1, R.sup.2 and where appropriate
R.sup.9 and R.sup.10 are independently H, alkyl, aryl, aralkyl,
heterocycle, halogeno, NO.sub.2, CN, OH, alkoxy, aryloxy, (R''')nNH.sub.2,
(R''').sub.nNH--R', (R''')nN--(R')(R''), NH-aryl, N-(aryl).sub.2,
COOH, COO--R', COO-aryl, CONH.sub.2, CONH--R', CON--(R')(R''), CONH-aryl,
CON-(aryl).sub.2, SO.sub.3H, SO.sub.2NH.sub.2, CF.sub.3, CO--R',
or CO-aryl, wherein alkyl, aryl, aralkyl and heterocycle groups
may be further substituted with one or more groups selected from
halogeno, NO.sub.2, CN, OH, O-methyl, NH.sub.2, COOH, CONH.sub.2
and CF.sub.3. Most preferably R.sup.10 is H.
More preferably, R.sup.1, R.sup.2 and R.sup.9 are each independently
selected from H, halogeno, NO.sub.2, CN, (R''')nN--(R')(R''), CONH.sub.2,
a C.sub.1-4 alkyl group and a heterocyclic group. Preferably, at
least one, more preferably at least two or three of R.sup.1, R.sup.2
and R.sup.9 are not hydrogen.
Preferably, R.sup.1 is H, CN, halogeno, nitro, alkylamino or a
heterocyclic group. When R.sup.1 is halogeno, it is preferably selected
from chloro or bromo. When R.sup.1 is alkylamino, it is preferably
diethylaminomethyl or dimethylaminomethyl When R.sup.1 is a heterocyclic
group it is preferably morpholin-4-ylmethyl or 4-methyl-piperazin-1-ylmethyl.
Most preferably, R.sup.1 is H or CN.
Even more preferably, when R.sup.1 is as preferably described,
R.sup.2 and R.sup.9 are both lower alkyl, preferably methyl.
The group Z is preferably NH, NHSO.sub.2 or NHCH.sub.2, most preferably
NH.
The phenyl substituents R.sup.4 R.sup.8 are each independently
selected from H, halogeno, nitro, amino, aminoalkyl, hydroxy, alkoxy,
carbamoyl, sulfamyl, CN, N(R')(R''), C.sub.1-4 alkyl and substituted
C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8
are independently from each other H, unsubstituted lower alkyl,
halogeno, NO.sub.2, CN, OH, N--(R')(R''), or CF.sub.3;
wherein R' R'' and R''' are each independently alkyl groups that
may be the same or different and n is 0 or 1;
Even more preferably, R.sup.4 to R.sup.8 are selected independently
from H, F, NH.sub.2, NO.sub.2, OH, Cl, Br, I, CN, CH.sub.2OH, CF.sub.3
and dimethylamino. Within the preferences for R.sup.4 to R.sup.8,
R.sup.4 and R.sup.8 are most preferably hydrogen.
Thus, particularly preferred embodiments include 2-[N-(phenyl)]-4-(2,4-dimethylpyrrol-3-yl)pyrimidineamines
in which the phenyl group is 2-, 3- or 4-substituted by at least
one of H, F, NH.sub.2, NO.sub.2, OH, Cl, Br, I, CN, CH.sub.2OH,
CF.sub.3 or OMe.
Within this particular embodiment, the phenyl group is preferably
mono-substituted by F, NH.sub.2, NO.sub.2, OH, Cl, Br, I, CH.sub.2OH,
CN, CF.sub.3 or OMe at any of the 2, 3 or 4-positions, or di-substituted
by 2,4-difluoro, 3,5-difluoro, 3,4-difluoro, 2,4-dichloro, 3,5-dichloro,
3,4-dichloro or 4-chloro-3-trifluoromethyl.
Further particularly preferred embodiments include 2-[N-(phenyl)]-4-(3,5-dimethyl-1H-pyrrole-2-carbonitrile)pyrimidineamines
in which the phenyl group is 2-, 3- or 4-substituted by at least
one of F, NH(CH.sub.3).sub.2, NO.sub.2, OH, Cl, Br, I or CF.sub.3.
Within this particular embodiment, the phenyl group is preferably
mono-substituted by F, NH(CH.sub.3).sub.2, NO.sub.2, OH, I or CF.sub.3
at any of the 3 or 4-positions, or di-substituted by 4-methyl-3-nitro,
3-iodo-4-methyl, 4-chloro-3-methyl, 3-hydroxy-4-methyl, 4-fluoro-3-methyl
or 4-methyl-3-fluoro.
Further more particularly preferable embodiments include; 2-[N-(phenyl)]-4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidinamines
wherein the phenyl group is preferably mono-substituted by F, NH(CH.sub.3).sub.2,
NO.sub.2, OH, I at the 4-position, preferably by a fluoro or NH(CH.sub.3).sub.2
group. 2-[N-(phenyl)]-4-(2,4-dimethyl-5-halogeno-1H-pyrrol-3-yl)-pyrimidinamines
wherein the phenyl group is preferably mono-substituted by F, NH(CH.sub.3).sub.2,
NO.sub.2, OH, I or CF.sub.3 at the 3 or 4-positions, preferably
by a 4-fluoro or 3-nitro group, the halogeno group preferably being
chloro or bromo. 2-[N-(phenyl)]-4-(2,4-dimethyl-5-dialkylaminoalkyl-1H-pyrrol-3-yl)-pyrimi-
dinamines wherein the phenyl group is preferably mono-substituted
by F, NH(CH.sub.3).sub.2, NO.sub.2, OH, I or CF.sub.3 at the 4-position,
preferably by fluoro, the dialkylaminoalkyl group preferably being
diethylaminomethyl or dimethylaminomethyl. 2-[N-(phenyl)]-4-(2,4-dimethyl-5-(heterocycle)-1H-pyrrol-3-yl)-pyrimidina-
mines wherein the phenyl group is preferably mono-substituted by
F, NH(CH.sub.3).sub.2, NO.sub.2, OH, I or CF.sub.3 at the 4-position,
preferably by fluoro, the heterocycle group preferably being 5-morpholin-4-ylmethyl
or 4-methyl-piperazin-1-ylmethyl.
Most preferably, the compounds of the present invention are selected
from; [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-iodo-phenyl)-amine
(3,4-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-am-
ine (4-Chloro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-ami-
ne (3,5-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]--
amine 4-[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-ylamino]-phenol
3-[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-ylamino]-phenol (2,4-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-am-
ine (2,4-Dichloro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-
-amine (4-Chloro-3-trifluoromethyl-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl-
)-pyrimidin-2-yl]-amine [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-trifluoromethyl-pheny-
l)-amine [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-trifluorometh-
yl-phenyl)-amine (3-Chloro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-amine
N-[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-N',N'-dimethyl-benzene-
-1,4-diamine (3-Chloro-4-iodo-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-
-amine [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-fluoro-4-iodo-p-
henyl)-amine 3,5-Dimethyl-4-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carb-
onitrile 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrro-
le-2-carbonitrile 4-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-ca-
rbonitrile 3,5-Dimethyl-4-[2-(4-trifluoromethyl-phenylamino)-pyrimidin-4-y-
l]-1H-pyrrole-2-carbonitrile 4-[2-(4-Iodo-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbo-
nitrile 4-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrro-
le-2-carbonitrile 3,5-Dimethyl-4-[2-(4-methyl-3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrro-
le-2-carbonitrile 4-[2-(3-Iodo-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrol-
e-2-carbonitrile 4-[2-(4-Chloro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile 4-[2-(3-Hydroxy-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyr-
role-2-carbonitrile 4-[2-(4-Fluoro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile 4-[2-(3-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile 4-[2-(4-Dimethylamino-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrol-
e-2-carbonitrile 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-car-
boxylic acid amide [4-(3,5-Dimethyl-1H-pyrrol-2-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine
(4-Fluoro-phenyl)-[4-(1,2,4-trimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-ami-
ne [4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phen-
yl)-amine N-[4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-N',N'-
-dimethyl-benzene-1,4-diamine [4-(5-Amino-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl-
)-amine [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-
-phenyl)-amine [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-
-amine [4-(5-Chloro-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-
-phenyl)-amine [4-(5-Diethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4--
fluoro-phenyl)-amine [4-(5-Dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-
-fluoro-phenyl)-amin [4-(2,4-Dimethyl-5-morpholin-4-ylmethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(-
4-fluoro-pheny {4-[2,4-Dimethyl-5-(4-methyl-piperazin-1-ylmethyl)-1H-pyrrol-3-yl]-pyrimi-
din-2-yl}-(4-fluoro-phenyl)-amine
The structures of the above-mentioned compounds are illustrated
in FIG. 1.
Particularly preferred compounds observed are those to be CDK inhibitors
having IC.sub.50 for cdk2/cyclinE of less than 5 .mu.M (.+-.0.05),
including; [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-iodo-phenyl)-amine
(3,4-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-am-
ine (4-Chloro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-ami-
ne (3,5-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]--
amine 4-[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-ylamino]-phenol
3-[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-ylamino]-phenol [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-trifluoromethyl-pheny-
l)-amine (3-Chloro-4-iodo-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimid-
in-2-yl]-amine [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-fluoro-4-iodo-phenyl)-
-amine 3,5-Dimethyl-4-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrrole--
2-carbonitrile 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-car-
bonitrile 4-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyr-
role-2-carbonitrile 3,5-Dimethyl-4-[2-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1H-pyrr-
ole-2-carbonitrile 4-[2-(4-Iodo-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbo-
nitrile 4-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrro-
le-2-carbonitrile 3,5-Dimethyl-4-[2-(4-methyl-3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrro-
le-2-carbonitrile 4-[2-(3-Iodo-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrol-
e-2-carbonitrile 4-[2-(4-Chloro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile 4-[2-(3-Hydroxy-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyr-
role-2-carbonitrile 4-[2-(4-Fluoro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile 4-[2-(3-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile 4-[2-(4-Dimethylamino-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrol-
e-2-carbonitrile 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-car-
boxylic acid amide (4-Fluoro-phenyl)-[4-(1,2,4-trimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-ami-
ne [4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phen-
yl)-amine N-[4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-N',N'-
-dimethyl-benzene-1,4-diamine [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl-
)-amine [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro--
phenyl)-amine [4-(5-Chloro-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-pheny-
l)-amine [4-(5-Diethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-
-yl]-(4-fluoro-phenyl)-amine [4-(5-Dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-
-fluoro-phenyl)-amin [4-(2,4-Dimethyl-5-morpholin-4-ylmethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(-
4-fluoro-pheny and {4-[2,4-Dimethyl-5-(4-methyl-piperazin-1-ylmethyl)-1H-pyrrol-3-yl]-pyrimi-
din-2-yl}-(4-fluoro-phenyl)-amine.
Of these compounds, more preferred are those to be CDK inhibitors
having IC.sub.50 for cdk2/cyclinE of less than 1 .mu.M (.+-.0.05),
including; [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-iodo-phenyl)-amine
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-trifluoromethyl-pheny-
l)-amine 3,5-Dimethyl-4-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrrol-
e-2-carbonitrile 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-car-
bonitrile 4-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyr-
role-2-carbonitrile 3,5-Dimethyl-4-[2-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1H-pyrr-
ole-2-carbonitrile 4-[2-(4-Iodo-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbo-
nitrile 4-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrro-
le-2-carbonitrile 3,5-Dimethyl-4-[2-(4-methyl-3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrro-
le-2-carbonitrile 4-[2-(3-Iodo-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrol-
e-2-carbonitrile 4-[2-(4-Chloro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile 4-[2-(3-Hydroxy-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyr-
role-2-carbonitrile 4-[2-(4-Fluoro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile 4-[2-(3-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile 4-[2-(4-Dimethylamino-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrol-
e-2-carbonitrile 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-car-
boxylic acid amide [4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl-
)-amine N-[4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-N',N'-d-
imethyl-benzene-1,4-diamine [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl-
)-amine [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro--
phenyl)-amine [4-(5-Chloro-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-pheny-
l)-amine [4-(5-Diethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-
-yl]-(4-fluoro-phenyl)-amine [4-(5-Dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-
-fluoro-phenyl)-amine, and [4-(2,4-Dimethyl-5-morpholin-4-ylmethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(-
4-fluoro-phenyl)-amine.
Of these, even more preferred are compounds are those having IC.sub.50
for cdk2/cyclinE of less than 0.5 .mu.M (.+-.0.05), being; [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-iodo-phenyl)-amine
3,5-Dimethyl-4-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carb-
onitrile 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrro-
le-2-carbonitrile 4-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-ca-
rbonitrile 3,5-Dimethyl-4-[2-(4-trifluoromethyl-phenylamino)-pyrimidin-4-y-
l]-1H-pyrrole-2-carbonitrile 4-[2-(4-Iodo-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbo-
nitrile 4-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrro-
le-2-carbonitrile 3,5-Dimethyl-4-[2-(4-methyl-3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrro-
le-2-carbonitrile 4-[2-(3-Hydroxy-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyr-
role-2-carbonitrile 4-[2-(4-Fluoro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-car-
boxylic acid amide [4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl-
)-amine [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro--
phenyl)-amine, and [4-(5-Dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-
-fluoro-phenyl)-amine.
The following compounds are observed to be particularly effective
anti-proliferative agents, as demonstrated by cell-based assays:
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-trifluoromethyl-pheny-
l)-amine (3-Chloro-4-iodo-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimid-
in-2-yl]-amine 3,5-Dimethyl-4-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carb-
onitrile 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrro-
le-2-carbonitrile 4-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-ca-
rbonitrile 3,5-Dimethyl-4-[2-(4-trifluoromethyl-phenylamino)-pyrimidin-4-y-
l]-1H-pyrrole-2-carbonitrile 4-[2-(4-Iodo-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbo-
nitrile 4-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrro-
le-2-carbonitrile 3,5-Dimethyl-4-[2-(4-methyl-3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrro-
le-2-carbonitrile 4-[2-(3-Iodo-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrol-
e-2-carbonitrile 4-[2-(4-Chloro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile 4-[2-(3-Hydroxy-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyr-
role-2-carbonitrile 4-[2-(4-Fluoro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile 4-[2-(3-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile 4-[2-(4-Dimethylamino-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrol-
e-2-carbonitrile 4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-car-
boxylic acid amide (4-Fluoro-phenyl)-[4-(1,2,4-trimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-ami-
ne [4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phen-
yl)-amine N-[4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-N',N'-
-dimethyl-benzene-1,4-diamine [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-
-amine [4-(5-Diethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-y-
l]-(4-fluoro-phenyl)-amine [4-(5-Dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-
-fluoro-phenyl)-amine, and {4-[2,4-Dimethyl-5-(4-methyl-piperazin-1-ylmethyl)-1H-pyrrol-3-yl]-pyrimi-
din-2-yl}-(4-fluoro-phenyl)-amine.
The compounds of formula I have been found to possess anti-proliferative
activity and are therefore believed to be of use in the treatment
of proliferative disorders such as cancers, leukaemias and other
disorders associated with uncontrolled cellular proliferation such
as psoriasis and restenosis. As defined herein, an anti-proliferative
effect within the scope of the present invention may be demonstrated
by the ability to inhibit cell proliferation in an in vitro whole
cell assay, for example using any of the cell lines A549, HT29,
Saos-2, HeLa or MCF-7, or by showing inhibition of a CDK enzyme
(such as CDK2 or CDK4) in an appropriate assay. These assays, including
methods for their performance, are described in more detail in Example
3. Using such cell line and enzymes assays it may be determined
whether a compound is anti-proliferative in the context of the present
invention.
Without wishing to be bound by theory, the compounds of the present
invention are believed to exert their anti-proliferative effect
in a non-protein kinase C (PKC) dependent manner. Many of the compounds
inhibit cyclin-dependent kinase enzymes (CDKs) that have been shown
to be involved in cell cycle control. These CDKs include CDK2 and
CDK4 and particularly their respective interactions with cyclin
E and cyclin D1. These compounds of the present invention are further
believed to be advantageous in being selective for CDK enzymes implicated
in proliferative diseases. By the term "selective" it
is meant that although possible having some inhibitory effect on
another enzyme (such as PKC), the compound is preferentially effective
against an enzyme implicated in proliferative diseases.
The compounds of the invention may inhibit any of the steps or
stages in the cell cycle, for example, formation of the nuclear
envelope, exit from the quiescent phase of the cell cycle (G0),
G1 progression, chromosome decondensation, nuclear envelope breakdown,
START, initiation of DNA replication, progression of DNA replication,
termination of DNA replication, centrosome duplication, G2 progression,
activation of mitotic or meiotic functions, chromosome condensation,
centrosome separation, microtubule nucleation, spindle formation
and function, interactions with microtubule motor proteins, chromatid
separation and segregation, inactivation of mitotic functions, formation
of contractile ring, and cytokinesis functions. In particular, the
compounds of the invention may influence certain gene functions
such as chromatin binding, formation of replication complexes, replication
licensing, phosphorylation or other secondary modification activity,
proteolytic degradation, microtubule binding, actin binding, septin
binding, microtubule organising centre nucleation activity and binding
to components of cell cycle signalling pathways.
A further embodiment of the present invention therefore relates
to the use of one or more compounds of formula I in the treatment
of proliferative disorders. Preferably, the proliferative disorder
is a cancer or leukaemia. The term proliferative disorder is used
herein in a broad sense to include any disorder that requires control
of the cell cycle, for example cardiovascular disorders such as
restenosis and cardiomyopathy, auto-immune disorders such as glomerulonephritis
and rheumatoid arthritis, dermatological disorders such as psoriasis,
anti-inflammatory, anti-fungal, antiparasitic disorders such as
malaria, emphysema and alopecia. In these disorders, the compounds
of the present invention may induce apoptosis or maintain stasis
within the desired cells as required.
In a particularly preferred embodiment, the invention relates to
the use of one or more compounds of formula I in the treatment of
a CDK dependent or sensitive disorder. CDK dependent disorders are
associated with an above normal level of activity of one or more
CDK enzymes. Such disorders preferably associated with an abnormal
level of activity of CDK2 and/or CDK4. A CDK sensitive disorder
is a disorder in which an aberration in the CDK level is not the
primary cause, but is downstream of the primary metabolic aberration.
In such scenarios, CDK2 and/or CDK4 can be said to be part of the
sensitive metabolic pathway and CDK inhibitors may therefore be
active in treating such disorders. Such disorders are preferably
cancer or leukaemic disorders.
A second aspect of the present invention relates to the use of
a compound of formula
##STR00002## wherein: one of X.sup.1 and X.sup.2 is NH and the
other of X.sup.1 and X.sup.2 is CR.sup.9; Z is NH, NHCO, NHSO.sub.2,
NHCH.sub.2, CH.sub.2, CH.sub.2CH.sub.2, or CH.dbd.CH; R.sup.1, R.sup.2,
R.sup.3 and R.sup.9 are independently H, alkyl, aryl, aralkyl, heterocycle,
halogeno, NO.sub.2, CN, OH, alkoxy, aryloxy, NH.sub.2, NH--R', N--(R')(R''),
NH-aryl, N-(aryl).sub.2, COOH, COO--R', COO-aryl, CONH.sub.2, CONH--R',
CON--(R')(R''), CONH-aryl, CON-(aryl).sub.2, SO.sub.3H, SO.sub.2NH.sub.2,
CF.sub.3, CO--R', or CO-aryl, wherein alkyl, aryl, aralkyl and heterocycle
groups may be further substituted with one or more groups selected
from halogeno, NO.sub.2, CN, OH, O-methyl, NH.sub.2, COOH, CONH.sub.2
and CF.sub.3; R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
independently from each other H, substituted or unsubstituted lower
alkyl, halogeno, NO.sub.2, CN, OH, substituted or unsubstituted
alkoxy, NH.sub.2, NH--R', N--(R')(R''), COOH, COO--R', CONH.sub.2,
CONH--R', CON--(R')(R''), SO.sub.3H, SO.sub.2NH.sub.2, or CF.sub.3;
wherein R' and R'' are each independently alkyl groups that may
be the same or different; with the proviso that when R.sup.1 and
R.sup.2 are H, X.sup.1 is NH, X.sup.2 is CH, and R.sup.3 is H, the
phenyl group is not 3-(1,1,2,2-tetrafluoroethoxy), or 3,4,5-trimethoxy,
when the other groups R.sup.4 R.sup.8 are H; and pharmaceutically
acceptable salts thereof, in the manufacture of a medicament for
use in the treatment of a proliferative disease.
The term "proliferative disorder" has been previously
discussed and the same definition applies to the second aspect of
the invention.
A further aspect of the present invention relates to the use of
the compounds of formula II in the manufacture of a medicament for
use in the treatment of antiviral infections. Such viral infections
include VZV, HSV type 1 and 2 and HIV. Preferably, the compounds
are of use in the treatment of HIV and HIV related disorders.
The preferred embodiments of these further aspects of the invention
are identical to those described above in respect of the first aspect.
In a particularly preferred embodiment, the one or more compounds
of the invention are administered in combination with one or more
other anticancer agents. In such cases, the compounds of the invention
may be administered consecutively, simultaneously or sequentially
with the one or more other anticancer agents.
As used herein the phrase "manufacture of a medicament"
includes the use of a compound of formula I directly as the medicament
in addition to its use in a screening programme for further anti-proliferative
agents or in any stage of the manufacture of such a medicament.
The compounds of the present invention (first and seconds aspects)
can be present as salts or esters, in particular pharmaceutically
acceptable salts or esters.
Pharmaceutically acceptable salts of the compounds of the invention
(first and seconds aspects) include suitable acid addition or base
salts thereof. A review of suitable pharmaceutical salts may be
found in Berge et al, J Pharm Sci, 66, 1 19 (1977). Salts are formed,
for example with strong inorganic acids such as mineral acids, e.g.
sulphuric acid, phosphoric acid or hydrohalic acids; with strong
organic carboxylic acids, such as alkanecarboxylic acids of 1 to
4 carbon atoms which are unsubstituted or substituted (e.g., by
halogen), such as acetic acid; with saturated or unsaturated dicarboxylic
acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic
or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic,
glycolic, lactic, malic, tartaric or citric acid; with aminoacids,
for example aspartic or glutamic acid; with benzoic acid; or with
organic sulfonic acids, such as (C.sub.1 C.sub.4)-alkyl- or aryl-sulfonic
acids which are unsubstituted or substituted (for example, by a
halogen) such as methane- or p-toluene sulfonic acid.
Esters are formed either using organic acids or alcohols/hydroxides,
depending on the functional group being esterified. Organic acids
include carboxylic acids, such as alkanecarboxylic acids of 1 to
12 carbon atoms which are unsubstituted or substituted (e.g., by
halogen), such as acetic acid; with saturated or unsaturated dicarboxylic
acid, for example oxalic, malonic, succinic, maleic, fumaric, phthalic
or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic,
glycolic, lactic, malic, tartaric or citric acid; with aminoacids,
for example aspartic or glutamic acid; with benzoic acid; or with
organic sulfonic acids, such as (C.sub.1 C.sub.4)-alkyl- or aryl-sulfonic
acids which are unsubstituted or substituted (for example, by a
halogen) such as methane- or p-toluene sulfonic acid. Suitable hydroxides
include inorganic hydroxides, such as sodium hydroxide, potassium
hydroxide, calcium hydroxide, aluminium hydroxide. Alcohols include
alkanealcohols of 1 12 carbon atoms which may be unsubstituted or
substituted, e.g. by a halogen).
In all aspects of the present invention previously discussed, the
invention includes, where appropriate all enantiomers and tautomers
of compounds of formula I. The man skilled in the art will recognise
compounds that possess an optical properties (one or more chiral
carbon atoms) or tautomeric characteristics. The corresponding enantiomers
and/or tautomers may be isolated/prepared by methods known in the
art.
The invention furthermore relates to the compounds of or of use
in the present invention (first and seconds aspects) in their various
crystalline forms, polymorphic forms and (an)hydrous forms. It is
well established within the pharmaceutical industry that chemical
compounds may be isolated in any of such forms by slightly varying
the method of purification and or isolation form the solvents used
in the synthetic preparation of such compounds.
The invention further includes the compounds (first and seconds
aspects) of or of use in the present invention in prodrug form.
Such prodrugs are generally compounds of formula I wherein one or
more appropriate groups have been modified such that the modification
may be reversed upon administration to a human or mammalian subject.
Such reversion is usually performed by an enzyme naturally present
in such subject, though it is possible for a second agent to be
administered together with such a prodrug in order to perform the
reversion in vivo. Examples of such modifications include ester
(for example, any of those described above), wherein the reversion
may be carried out be an esterase etc. Other such systems will be
well known to those skilled in the art.
The present invention also encompasses pharmaceutical compositions
comprising the compounds of the invention (first and seconds aspects).
In this regard, and in particular for human therapy, even though
the compounds of the present invention (including their pharmaceutically
acceptable salts, esters and pharmaceutically acceptable solvates)
can be administered alone, they will generally be administered in
admixture with a pharmaceutical carrier, excipient or diluent selected
with regard to the intended route of administration and standard
pharmaceutical practice.
Thus, the present invention also relates to pharmaceutical compositions
comprising one or more compounds of formula I or II or pharmaceutically
acceptable salts or esters thereof, together with at least one pharmaceutically
acceptable excipient, diluent or carrier.
By way of example, in the pharmaceutical compositions of the present
invention, the compounds of the invention may be admixed with any
suitable binder(s), lubricant(s), suspending agent(s), coating agent(s),
and/or solubilising agent(s). Examples of such suitable excipients
for the various different forms of pharmaceutical compositions described
herein may be found in the "Handbook of Pharmaceutical Excipients,
2.sup.nd Edition, (1994), Edited by A Wade and P J Weller.
The pharmaceutical compositions of the present invention may be
adapted for oral, rectal, vaginal, parenteral, intramuscular, intraperitoneal,
intraarterial, intrathecal, intrabronchial, subcutaneous, intradermal,
intravenous, nasal, buccal or sublingual routes of administration.
For oral administration, particular use is made of compressed tablets,
pills, tablets, gellules, drops, and capsules. Preferably, these
compositions contain from 1 to 250 mg and more preferably from 10
100 mg, of active ingredient per dose.
Other forms of administration comprise solutions or emulsions which
may be injected intravenously, intraarterially, intrathecally, subcutaneously,
intradermally, intraperitoneally or intramuscularly, and which are
prepared from sterile or sterilisable solutions. The pharmaceutical
compositions of the present invention may also be in form of suppositories,
pessaries, suspensions, emulsions, lotions, ointments, creams, gels,
sprays, solutions or dusting powders.
An alternative means of transdermal administration is by use of
a skin patch. For example, the active ingredient can be incorporated
into a cream consisting of an aqueous emulsion of polyethylene glycols
or liquid paraffin. The active ingredient can also be incorporated,
at a concentration of between 1 and 10% by weight, into an ointment
consisting of a white wax or white soft paraffin base together with
such stabilisers and preservatives as may be required.
Injectable forms may contain between 10 1000 mg, preferably between
10 250 mg, of active ingredient per dose.
Compositions may be formulated in unit dosage form, i.e., in the
form of discrete portions containing a unit dose, or a multiple
or sub-unit of a unit dose.
A person of ordinary skill in the art can easily determine an appropriate
dose of one of the instant compositions to administer to a subject
without undue experimentation. Typically, a physician will determine
the actual dosage which will be most suitable for an individual
patient and it will vary with the age, weight and response of the
particular patient. The dosages disclosed herein are exemplary of
the average case. There can of course be individual instances where
higher or lower dosage ranges are merited, and such are within the
scope of this invention.
In an exemplary embodiment, one or more doses of 10 to 150 mg/day
will be administered to the patient for the treatment of malignancy.
The pharmaceutical compositions of the invention may further comprise
one or more additional anticancer agents, for example, existing
anticancer drugs available on the market.
Anticancer drugs in general are more effective when used in combination.
In particular, combination therapy is desirable in order to avoid
an overlap of major toxicities, mechanism of action and resistance
mechanism(s). Furthermore, it is also desirable to administer most
drugs at their maximum tolerated doses with minimum time intervals
between such doses. The major advantages of combining chemotherapeutic
drugs are that it may promote additive or possible synergistic effects
through biochemical interactions and also may decrease the emergence
of resistance in early tumor cells which would have been otherwise
responsive to initial chemotherapy with a single agent. An example
of the use of biochemical interactions in selecting drug combinations
is demonstrated by the administration of leucovorin to increase
the binding of an active intracellular metabolite of 5-fluorouracil
to its target, thymidylate synthase, thus increasing its cytotoxic
effects.
Numerous combinations are used in current treatments of cancer
and leukemia. A more extensive review of medical practices may be
found in "Oncologic Therapies" edited by E. E. Vokes and
H. M. Golomb, published by Springer.
Beneficial combinations may be suggested by studying the growth
inhibitory activity of the test compounds with agents known or suspected
of being valuable in the treatment of a particular cancer initially
or cell lines derived from that cancer. This procedure can also
be used to determine the order of administration of the agents,
i.e. before, simultaneously, or after delivery. Such scheduling
may be a feature of all the cycle acting agents identified herein.
The compounds of this invention (I) can be synthesised, for example,
by an adaptation of the Traube synthesis (A. R. Katritzky, I. Taher,
Can. J. Chem. 1986, 64, 2087 and references cited therein), i.e.
by condensation between 1,3-dicarbonyl compounds 1 or acrylates
2 or 3, and amidine 4, as shown in Scheme 1.
##STR00003##
The dicarbonyl compounds I in turn can be prepared by many methods
known in the art (J. March, In: Advanced Organic Chemistry: Reactions,
Mechanism, and Structure, 4.sup.th Ed., John Wiley & Sons, Inc.,
New York, 1992, p. 1283). Acrylates 2 and 3, which are particularly
suitable for the purposes of this invention, are obtained from heterocyclic
methyl ketones 5 by condensation with tert-butoxybis(dimethylamino)methane
6 (Scheme 2).
##STR00004##
The diamino compounds 4 will be amidines 4a or guanidines 4b, depending
on the definition of Z in general structure I. Amidines (HN.dbd.CRNH.sub.2)
can be obtained from readily available amine precursors by condensation
with e.g. ketenimines, or by addition of ammonia to suitable nitriles
or imidates. Guanidines 4b (Scheme 3) can be elaborated by a number
of methods known in the art. For the purposes of this invention,
the most useful route is amination of cyanamide 8 with anilines
9.
##STR00005##
In the case where 5 is a pyrrole, two systems can apply (refer
Scheme 4), i.e. the acetyl group which is used to generate the pyrimidine
precursors 2 and 3 is either in the pyrrole 3-position (5: X.sup.1=CR.sup.9,
X.sup.2=NH; i.e. structure 5b) or in the pyrrole 2-position (X.sup.1=NH,
X.sup.2=CR.sup.9; i.e. structure 5c).
##STR00006##
In both cases the pyrrole rings can be assembled using methods
known in the art. Particularly relevant is a modification of the
Knorr synthesis (refer, e.g J. A. Joule, G. F. Smith, Heterocyclic
Chemistry, 2.sup.nd Ed., Van Nostrand Reinhold (UK) Co. Ltd., 1978,
pp.213 215). For the pyrrol-3-yl system, activated (i.e. R.sup.1=COOEt,
CN, etc.) carbonyl compounds 10 are first nitrosylated. The resulting
oximes 11 are condensed with dicarbonyl compounds 12 in the presence
of e.g. zinc-acetic acid or aqueous dithionate, with formation of
the reactive .quadrature.-aminocarbonyl intermediate 13. The R.sup.1
substituent (e.g. COOEt, CN) in the resulting 3-acetylpyrroles 5b
can be further manipulated, either directly, or in the context of
intermediates 2 or 3, or in the pyrrolopyrimidine products I. Thus
decarboxylation (R.sup.1=COOEt) will give products with R.sup.1=H,
oxidation (R.sup.1=CN) will afford products with R.sup.1=CONH.sub.2,
etc. Furthermore, products with R.sup.1=H can be transformed into
various derivatives, particularly through electrophilic substitution.
Thus derivatives where R.sup.1 is, for example, a halogen, nitro,
amino, alkyl, alkylamino, etc., group can be obtained readily. In
the case of the pyrrol-2-yl system an analogous situation arises,
here an activating group needs to be present in the carbonyl component
15 (e.g. R.sup.9=COOEt, CN, etc.). This is condensed with oximes
16 (derived from dicarbonyl compounds 14), again with formation
of the intermediate 17. The R.sup.9 substituent in products 5c or
derivatives can be manipulated in the same way as the R.sup.1 group
in the pyrrol-3-yl system discussed above.
Alternatively, compounds of general structure I can be obtained
from suitable pyrimidine precursors directly, e.g. from 2,4-disubstituted
(halogen, amine, etc.) pyrimidines by successive substitution reactions.
BRIEF DESCRIPTION OF DRAWINGS
The present invention will now be described by way of example and
with reference to the following FIGURE:
FIG. 1 shows the chemical structure of compounds according to the
invention.
EXAMPLES
Abbreviations
LC-MS, liquid chromatography-mass spectrometry; NMR, nuclear magnetic
resonance spectroscopy; r.t. room temperature; PE, petroleum ether
(40 60.degree. C. boiling fraction); DMSO, dimethylsulfoxide.
General
NMR spectra were recorded using a Bruker DPX-300 instrument. Chemical
shifts are reported in ppm (.delta.) from tetramethylsilane. EM
Kieselgel 60 (0.040 0.063 mm) was used for flash column chromatography.
Melting points were determined with a LEICA testo-720 electrothermometer
and are uncorrected. Compound numbers are shown in brackets, where
appropriate.
Example 1
3-Dimethylamino-1-(2,4-dimethyl-1H-pyrrol-3-yl)-propenone
##STR00007##
A mixture of 1-(2,4-dimethyl-1H-pyrrol-3-yl)-ethanone (2 g, 15
mmol) in 5 mL of 1,1-bis-dimethylamino-3,3-dimethyl-butan-2-one
was heated at 100.degree. C. for 22 h. The precipitates of the reaction
mixture were slurried in EtOAc/PE with chilling. The crude product
was filtered, washed with EtOAc/PE, and dried in vacuo to afford
the title compound as a purple solid (2.6 g). .sup.1H-NMR (CDCl.sub.3)
.delta.: 2.25 (s, 6H, CH.sub.3), 2.45 (s, 6H, CH.sub.3), 5.46 (d,
1H, J=12.6 Hz, CH), 6.35 (s, 1H, pyrrolyl-H), 7.63 (d, 1H, J=12.6
Hz, CH).
Example 2
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine
[1]
To a mixture of 3-dimethylamino-1-(2,4-dimethyl-1H-pyrrol-3-yl)-propenone
(1 mmol, 0.19 g) and 4-fluorophenyl guanidine nitrate (2 mmol, 0.44
g) in 2-methoxyethanol (5 mL) was added NaOH (40 mg). The reaction
mixture was heated at 100 120.degree. C. under N.sub.2 for 6 h.
The solvent was evaporated to dryness and the residue was purified
by flash chromatography (1:2 EtOAc/PE). Recrystallisation from EtOAc/PE
afforded the title compound (174 mg, 62%) as brown crystals. .sup.1H-NMR
(CDCl.sub.3) .delta.: 2.21 (s, 3H, CH.sub.3), 2.43 (s, 3H, CH.sub.3),
6.33 (s, 1H, pyrrolyl-H), 6.73 (d, 1H, J=5.3 Hz, pyrimidinyl-H),
7.00 (m, 2H, Ph-H), 7.79 (m, 2H, Ph-H), 8.28 (d, 1H, J=5.3 Hz, pyrimidinyl-H),
9.16 (s, 1H, NH), 10.59 (s, 1H, NH).
The following compounds were prepared in a manner analogous to
that described above:
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl-(3-nitro-phenyl)-amine
[2]
Yellow-orange solid. M.p. 197 199.degree. C. LC-MS: m/z=310 (M+1).
C.sub.16H.sub.15N.sub.5O.sub.2 requires C, 62.12; H, 4.89; N, 22.64;
found C, 62.61; H, 4.99; N, 22.20. .sup.1H-NMR (CDCl.sub.3) .delta.:
2.71 (d, 6H, CH.sub.3), 7.05 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.47
(m, 2H, Ph-H), 7.78 (m, 1H, Ph-H), 7.81 (s, 1H, Ar--H), 8.07 (m,
1H, Ph-H), 8.51 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 8.99 (br. s, 1H,
NH), 9.91 (br. s, 1H, NH).
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-iodo-phenyl)-amine
[3]
.sup.1H-NMR (CDCl.sub.3) .delta.: 2.26 (s, 3H, CH.sub.3), 2.48
(s, 3H, CH.sub.3), 6.80 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.47 (m,
2H, Ph-H), 7.57 (m, 2H, Ph-H), 7.23 (s, 1H, pyrrolyl-H), 8.32 (d,
1H, J=5.3 Hz, pyrimidinyl-H).
(3,4-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-ami-
ne [4]
.sup.1H-NMR (CDCl.sub.3) .delta.: 2.23 (s, 3H, CH.sub.3), 2.46
(s, 3H, CH.sub.3), 6.42 (m, 1H, pyrrolyl-H), 6.77 (d, 1H, J=5.3
Hz, pyrimidinyl-H), 7.11 (m, 1H, Ph-H), 7.41 (m, 1H, Ph-H), 8.05
(m, 1H, Ph-H), 8.29 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 9.21 (s, 1H,
Ph-H), 10.46 (br. s, 1H, NH).
(4-Chloro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-amine
[5]
M.p. 219 223.degree. C. MS: [M+H].sup.+=299.4 (C.sub.16H.sub.15ClN.sub.4
requires 298.8). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.19 (s, 3H,
CH.sub.3), 2.42 (s, 3H, CH.sub.3), 6.48 (s, 1H, pyrrolyl-H), 6.82
(d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.31 (d, 2H, J=8.7 Hz, Ph-H),
7.84 (d, 2H, J=8.7 Hz, Ph-H), 8.34 (d, 1H, J=5.3 Hz, pyrimidinyl-H),
9.45 (s, 1H, Ph-H), 10.72 (br. s, 1H, NH).
(3,5-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-ami-
ne [6]
M.p. 153.3 156.8.degree. C. MS: [M+H].sup.+=303.6 (C.sub.16H.sub.14F.sub.2N.sub.4
requires 300.3). .sup.1H-NMR (CD.sub.3OD) .delta.: 2.25 (s, 3H,
CH.sub.3), 2.47 (s, 3H, CH.sub.3), 6.42 6.48 (m, 2H, pyrrolyl-H
and Ph-H), 6.80 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.44 7.48 (m,
2H, Ph-H), 8.31 (d, 1H, J=5.5 Hz, pyrimidinyl-H).
4-[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-ylamino]-phenol
[7]
M.p. 189.5 193.4.degree. C. MS: [M+H].sup.+=281.9 (C.sub.16H.sub.16N.sub.4O
requires 280.3). .sup.1H-NMR (CD.sub.3OD) .delta.: 2.23 (s, 3H,
CH.sub.3), 2.43 (s, 3H, CH.sub.3), 6.44 (s, 1H, pyrrolyl-H), 6.75
6.78 (m, 3H, pyrimidinyl-H and Ph-H), 7.39 (d, 2H, J=8.8 Hz, Ph-H),
8.17 (d, 1H, J=5.3 Hz, pyrimidinyl-H).
3-[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-ylamino]-phenol
[8]
M.p. 169.0 174.6.degree. C. MS: [M+H].sup.+=281.3 (C.sub.16H.sub.16N.sub.4O
requires 280.3). .sup.1H-NMR (CD.sub.3OD) .delta.: 2.26 (s, 3H,
CH.sub.3), 2.47 (s, 3H, CH.sub.3), 6.44 6.48 (m, 2H, pyrrolyl-H,
Ph-H 6.84 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.05 7.10 (m, 2H, Ph-H),
7.32 (m, 1H, Ph-H), 8.25 (d, 1H, J=5.3 Hz, pyrimidinyl-H).
(2,4-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-ami-
ne [9]
M.p. 219 220.degree. C. MS: [M+H].sup.+=302.6 (C.sub.16H.sub.14F.sub.2N.sub.2
requires 300.3). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.10 (s, 3H,
CH.sub.3), 2.36 (s, 3H, CH.sub.3), 6.43 (s, 1H, pyrrolyl-H), 6.77
(d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.06 (m, 1H, Ph-H), 7.27 (m, 1H,
Ph-H), 7.66 (m, 1H, Ph-H), 8.25 (d, 1H, J=5.3 Hz, pyrimidinyl-H),
8.71 (s, 1H, Ph-H), 10.70 (br. s, 1H, NH).
(2,4-Dichloro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-ami-
ne [10]
M.p. 158.5 159.7.degree. C. MS: [M+H].sup.+=335.4 (C.sub.16H.sub.14Cl.sub.2N.sub.4
requires 333.2). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.18 (s, 3H,
CH.sub.3), 2.38 (s, 3H, CH.sub.3), 6.51 (s, 1H, pyrrolyl-H), 6.90
(d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.46 (m, 1H, Ph-H), 7.71 (m, 1H,
Ph-H), 8.05 (m, 1H, Ph-H), 8.36 (d, 1H, J=5.3 Hz, pyrimidinyl-H),
8.49 (s, 1H, Ph-H), 10.80 (br. s, 1H, NH).
(4-Chloro-3-trifluoromethyl-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrim-
idin-2-yl]-amine [11]
M.p. 187.7 190.7.degree. C. MS: [M+H].sup.+=368.6 (C.sub.17H.sub.14ClF.sub.3N.sub.4
requires 366.8). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.19 (s, 3H,
CH.sub.3), 2.42 (s, 3H, CH.sub.3), 6.50 (s, 1H, pyrrolyl-H), 6.89
(d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.61 (m, 1H, Ph-H), 8.08 (m, 1H,
Ph-H), 8.39 8.42 (m, 2H, Ph-H and pyrimidinyl-H), 9.79 (s, 1H),
10.80 (br. s, 1H, NH).
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-trifluoromethyl-phenyl-
)-amine [12]
M.p. 165.6 167.9.degree. C. MS: [M+H].sup.+=332.9 (C.sub.17H.sub.15F.sub.3N.sub.4
requires 332.3). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.26 (s, 3H,
CH.sub.3), 2.49 (s, 3H, CH.sub.3), 6.56 (s, 1H, pyrrolyl-H), 6.94
(d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.67 (d, 2H, J=8.5 Hz, Ph-H),
8.09 (d, 2H, J=8.5 Hz, Ph-H), 8.45 (d, 1H, J=5.3 Hz, pyrimidinyl-H),
9.82 (s, 1H, NH).
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-trifluoromethyl-phenyl-
)-amine [13]
M.p. 152.7 154.3.degree. C. MS: [M+H].sup.+=332.6 (C.sub.17H.sub.15F.sub.3N.sub.4
requires 332.3). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.26 (s, 3H,
CH.sub.3), 2.48 (s, 3H, CH.sub.3), 6.56 (s, 1H, pyrrolyl-H), 6.92
(d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.29 (m, 1H, Ph-H), 7.55 (m, 1H,
Ph-H), 8.03 (m, 1H, Ph-H), 8.42 7.45 (m, 2H, pyrimidinyl-H and Ph-H),
9.73 (s, 1H, NH), 10.83 (br. s, 1H, NH).
(3-Chloro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-amine
[14]
M.p. 140.4 144.2.degree. C. MS: [M+H].sup.+=299.5 (C.sub.16H.sub.15ClN.sub.4
requires 298.8). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.21 (s, 3H,
CH.sub.3), 2.44 (s, 3H, CH.sub.3), 6.51 (s, 1H, pyrrolyl-H), 6.85
(d, 1H, J=5.3 Hz, pyrimidinyl-H), 6.94 (d, 1H, J=7.6 Hz, Ph-H),
7.28 (t, 1H, J=8.1 Hz, Ph-H), 7.61 (d, 1H, J=8.2 Hz, Ph-H), 8.19
(s, 1H, Ph-H), 8.37 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 9.55 (s, 1H,
NH), 10.78 (br. s, 1H, NH).
N-[4-(2,4-Dimethyl-H-pyrrol-3-yl)-pyrimidin-2-yl]-N',N'-dimethyl-benzene-1-
,4-diamine [15]
M.p. 179.9 182.1.degree. C. MS: [M+H].sup.+=307.3 (C.sub.18H.sub.21N.sub.5
requires 307.4). .sup.1H-NMR (CDCl.sub.3) .delta.: 2.25 (s, 3H,
CH.sub.3), 2.46 (s, 3H, CH.sub.3), 2.91 (s, 6H, CH.sub.3), 6.46
(s, 1H, pyrrolyl-H), 6.70 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 6.78
(dd, 2H, J=6.8, 2.2 Hz, Ph-H), 6.79 (br. s, 1H, NH), 7.45 (dd, 2H,
J=6.8, 2.2 Hz, Ph-H), 7.80 (br. s, 1H, NH), 8.28 (d, 1H, J=5.1 Hz,
pyrimidinyl-H).
(3-Chloro-4-iodo-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]--
amine [16]
M.p. 185.0 187.4.degree. C. MS: [M+H].sup.+=423.9 (C.sub.16H.sub.14ClIN.sub.4
requires 424.7). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.18 (s, 3H,
CH.sub.3), 2.41 (s, 3H, CH.sub.3), 6.48 (s, 1H, pyrrolyl-H), 6.84
(d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.40 (dd, 1H, J=8.8, 2.4 Hz, Ph-H),
7.75 (d, 1H, J=8.8 Hz, Ph-H), 8.34 (m, 1H, Ph-H), 8.36 (d, 1H, J=5.4
Hz, pyrimidinyl-H), 9.61 (s, 1H, NH), 10.75 (s, 1H, NH).
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-fluoro-4-iodo-phenyl)--
amine [17]
M.p. 200 202.degree. C. MS: [M+H].sup.+=407.4 (C.sub.16H.sub.14FIN.sub.4
requires 408.2). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.18 (s, 3H,
CH.sub.3), 2.40 (s, 3H, CH.sub.3), 6.48 (s, 1H, pyrrolyl-H), 6.84
(d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.35 (m, 1H, Ph-H), 7.64, (t,
1H, J=8.0 Hz, Ph-H), 8.02 (dd, 1H, J=12.0, 2.2 Hz, Ph-H), 8.36 (d,
1H, J=5.4 Hz, pyrimidinyl-H), 9.65 (s, 1H, NH), 10.75 (s, 1H, NH).
Example 3
4-(3-Dimethylamino-acryloyl)-3,5-dimethyl-1H-pyrrole-2-carbonitrile
##STR00008##
Ethyl cyanoacetate (10 mL, 94 mmol) was diluted with AcOH (20 mL)
and the solution was cooled to -10.degree. C. (ice-MeOH bath). NaNO.sub.2
(6.5 g, 94 mmol) was dissolved in H.sub.2O (10 mL) and the solution
was added dropwise over a period of 40 min, keeping the internal
temperature <0.degree. C. After completion of the addition, the
reaction mixture was stirred for 1 h with cooling. It was then warmed
to room temperature and stirred for a further 3 h. The mixture was
diluted with acetic acid (50 mL) and H.sub.2O (50 mL). Pentane-2,4-dione
(10.6 mL, 103 mmol) was added and the mixture heated to .about.75.degree.
C. To this reaction mixture Zn powder (6.9 g, 105 mmol) was added
in portions over a period of 30 min at such a rate as to maintain
the internal temperature <90.degree. C. The reaction mixture
was then heated for a further 30 min before pouring into H.sub.2O
(1 mL). From the reaction mixture 3,5-dimethyl-1H-pyrrole-2-carbonitrile
(3.67 g) was filtered as an off-white solid. The filtrate was extracted
with EtOAc (3.times.500 mL). The combined organic extracts were
washed (brine) and dried (MgSO.sub.4). The solvent was evaporated
to a brown oil, which was purified by chromatography (100 g SiO.sub.2,
eluted with 4:1 heptane/EtOAc) to afford a further crop (4.41 g)
of this product as a pale yellow solid (total yield 72%).
3,5-Dimethyl-1H-pyrrole-2-carbonitrile (1.2 g, 10 mmol) was dissolved
in anhydrous 1,2-dichloroethane (15 mL) and AlCl.sub.3 (2.93 g,
22 mmol) was added proportion-wise. The reaction vessel was purged
with N.sub.2 and was cooled in an ice-water bath. AcCl (0.71 mL,
10 mmol) was added dropwise and the mixture was stirred for 1 h
with cooling and for a further 3 h at room temperature. The reaction
mixture was quenched by careful addition of 2 M aq HCl. The acidity
of the mixture was adjusted to approximately pH 6 by addition of
NaHCO.sub.3. After separation of the organic phase, the aqueous
phase was extracted with EtOAc (3.times.100 mL). The combined organic
phases were washed (H.sub.2O, then brine), dried (MgSO.sub.4), and
filtered. The solvent was evaporated to afford of 4-acetyl-3,5-dimethyl-1H-pyrrole-2-carbonitrile
(1.42 g, 88%) as a pale tan solid. .sup.1H-NMR (CDCl.sub.3) .delta.:
2.44 (s, 3H, CH.sub.3), 2.45 (s, 3H, CH.sub.3), 2.54 (s, 3H, CH.sub.3),
8.75 (br. s, 1H, NH).
4-Acetyl-3,5-dimethyl-1H-pyrrole-2-carbonitrile (1.38 g, 8.51 mmol)
was suspended in 1,1-bis-dimethylamino-3,3-dimethyl-butan-2-one
(1.3 mL) and heated at 75.degree. C. for 42 h. The reaction mixture
was evaporated to dryness and the residue was purified by SiO.sub.2
chromatography (heptane/EtOAc) to afford the title compound (1.2
g, 65%) as a pale tan solid. .sup.1H-NMR (DMSO-d.sub.6) .delta.:
2.21 (s, 3H, CH.sub.3), 2.31 (s, 3H, CH.sub.3), 3.32 (s, 6H, CH.sub.3),
5.22 (d, 1H, J=12.4 Hz, CH), 7.47 (d 1H, J=12.4 Hz, CH), 11.96 (br.
s, 1H, NH).
Example 4
3,5-Dimethyl-4-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carbo-
nitrile [31]
To a mixture of 4-(3-dimethylamino-acryloyl)-3,5-dimethyl-1H-pyrrole-2-carbonitrile
(1.0 mmol, 0.22 g) and 3-nitrophenyl guanidine nitrate (1.5 mmol,
0.36 g) in 2-methoxyethanol (5 mL) was added K.sub.2CO.sub.3 (138
mg, 1.0 mmol). The reaction mixture was heated at 120.degree. C.
under N.sub.2 for 18 h. The solvent was evaporated to dryness and
the residue was purified by flash chromatography (1:2 EtOAc/heptane)
to afford the title compound as a light-yellow solid. M.p. 258 259.degree.
C. MS: [M+H].sup.+=336.1 (C.sub.17H.sub.14N.sub.6O.sub.2 requires
334.3). .sup.1H-NMR (CD.sub.3OD) .delta.: 2.39 (s, 3H, CH.sub.3),
2.49 (s, 3H, CH.sub.3), 6.94 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 7.50
(t, 1H, J=8.3 Hz, Ph-H), 7.81 (m, 1H, Ph-H), 7.94 (m, 1H, Ph-H),
8.45 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 8.94 (t, 1H, J=2.2 Hz, Ph-H).
The following compounds were prepared in a manner analogous to
that described above:
4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carb-
onitrile [32]
MS: [M+H].sup.+=307.7 (C.sub.17H.sub.14FN.sub.5 requires 307.3).
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.30 (s, 3H, CH.sub.3), 2.40
(s, 3H, CH.sub.3), 6.84 (d, 1H, J=5.0 Hz, pyrimidinyl --H), 7.00
(m, 2H, Ph-H), 7.73 (m, 2H, Ph-H), 8.40 (d, 1H, J=5.5 Hz, pyrimidinyl
--H), 9.46 (s, 1H, NH), 12.19 (br. s, 1H, NH).
4-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-car-
bonitrile [33]
M.p. 272 276.degree. C. MS: [M+H].sup.+=305.8 (C.sub.17H.sub.15N.sub.5O
requires 305.3). .sup.1H-NMR (CD.sub.3OD) .delta.: 2.33 (s, 3H,
CH.sub.3), 2.41 (s, 3H, CH.sub.3), 6.74 6.56 (m, 3H, pyrimidinyl-H/Ph-H),
7.36 (d, 2H, J=8.5 Hz, Ph-H), 8.25 (d, 1H, J=5.4 Hz, pyrimidinyl-H).
3,5-Dimethyl-4-[2-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-H-pyrrol-
e-2-carbonitrile [34]
M.p. 195.6 198.9.degree. C. MS: [M+H].sup.+=357.7 (C.sub.18H.sub.14F.sub.3N.sub.5
requires 357.3). .sup.1H-NMR (CDCl.sub.3) .delta.: 2.33 (s, 3H,
CH.sub.3), 2.44 (s, 3H, CH.sub.3), 6.75 (d, 1H, J=5.1 Hz, pyrimidinyl-H),
7.20 (br. s, 1H, NH), 7.50 (d, 2H, J=8.8 Hz, Ph-H), 7.71 (d, 2H,
J=8.8 Hz, Ph-H), 8.39 (d, 1H, J=5.1 Hz, pyrimidinyl), 8.40 (br.
s, 1H, NH).
4-[2-(4-Iodo-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbon-
itrile [35]
M.p. 178.3 181.2.degree. C. MS: [M+H].sup.+=416.6 (C.sub.18H.sub.141N.sub.5
requires 415.2). .sup.1H-NMR (CDCl.sub.3) .delta.: 2.39 (s, 3H,
CH.sub.3), 2.49 (s, 3H, CH.sub.3), 6.76 (d, 1H, J=5.1 Hz, pyrimidinyl-H),
7.10 (br. s, 1H, NH), 7.44 (d, 2H, J=8.8 Hz, Ph-H), 7.61 (d, 2H,
J=8.8 Hz, Ph-H), 8.42 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 8.45 (br.
s, 1H, NH).
4-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-car-
bonitrile [36]
M.p. 247 250.degree. C. MS: [M+H].sup.+=305.8 (C.sub.17H.sub.15N.sub.5O
requires 305.3). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.31 (s, 3H,
CH.sub.3), 2.41 (s, 3H, CH.sub.3), 6.33 (m, 1H, Ph-H), 6.82 (d,
1H, J=5.1 Hz, pyrimidinyl-H), 7.01 (t, 1H, J=8.1 Hz, Ph-H), 7.11
(m, 1H, Ph-H), 7.33 (t, 1H, J=2.1 Hz, Ph-H), 8.40 (d, 1H, J=5.4
Hz, pyrimidinyl-H), 9.18 (s, 1H), 9.30 (s, 1H), 12.20 (br. s, 1H,
NH).
3,5-Dimethyl-4-[2-(4-methyl-3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrrol-
e-2-carbonitrile [37]
M.p. 233 237.degree. C. MS: [M+H].sup.+=350.0 (C.sub.18H.sub.16N.sub.6O.sub.2
requires 348.6). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.31 (s, 3H,
CH.sub.3), 2.42 (s, 3H, CH.sub.3), 2.44 (s, 3H, CH.sub.3), 6.92
(d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.39 (d, 1H, J=8.5 Hz, Ph-H),
7.87 (dd, 1H, J=8.1, 1.7 Hz, Ph-H), 8.48 (d, 1H, J=5.1 Hz, pyrimidinyl-H),
8.63 (d, 1H, J=1.7 Hz, Ph-H), 9.87 (s, 1H, NH), 12.21 (br. s, 1H,
NH).
4-[2-(3-Iodo-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-
-2-carbonitrile [38]
M.p. 189.5 191.7.degree. C. MS: [M+H].sup.+=431.5 (C.sub.18H.sub.161N.sub.5
requires 429.6). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.29 (s, 3H,
CH.sub.3), 2.32 (s, 3H, CH.sub.3), 2.43 (s, 3H, CH.sub.3), 6.85
(d, 1H, J=5.1 Hz, pyrimidinyl-H), 7.20 (d, 1H, J=8.1 Hz, Ph-H),
7.57 (m, 1H, Ph-H), 8.41 8.43 (m, 2H, Ph-H, pyrimidinyl-H), 9.48
(s, 1H, NH), 12.20 (br. s, 1H, NH).
4-[2-(4-Chloro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrro-
le-2-carbonitrile [39]
M.p. 194.2 197.9.degree. C. MS: [M+H].sup.+=338.0 (C.sub.18H.sub.16ClN.sub.5
requires 337.8). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.27 (s, 3H,
CH.sub.3), 2.31 (s, 3H, CH.sub.3), 2.41 (s, 3H, CH.sub.3), 6.86
(d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.28 (d, 1H, J=8.5 Hz, Ph-H),
7.61 (dd, 1H, J=8.8, 2.4 Hz, Ph-H), 7.73 (d, 1H, J=2.7 Hz, Ph-H),
8.43 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 9.51 (s, 1H, NH), 12.21 (br.
s, 1H, NH).
4-[2-(3-Hydroxy-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrr-
ole-2-carbonitrile [40]
M.p. 221 225.degree. C. MS: [M+H].sup.+=320.9 (C.sub.18H.sub.17N.sub.5O
requires 319.4). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.03 (s, 3H,
CH.sub.3), 2.29 (s, 3H, CH.sub.3), 2.40 (s, 3H, CH.sub.3), 6.78
(d, 1H, J=5.1 Hz, pyrimidinyl-H), 6.89 (d, 1H, J=8.1 Hz, Ph-H),
7.02 (dd, 1H, J=8.3, 1.7 Hz, Ph-H), 7.29 (d, 1H, J=0.7 Hz, Ph-H),
8.37 (d, 1H, J=4.9 Hz, pyrimidinyl-H), 9.08 (s, 1H), 9.20 (s, 1H),
12.17 (br. s, 1H, NH).
4-[2-(4-Fluoro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrro-
le-2-carbonitrile [41]
M.p. 161.3 164.1.degree. C. MS: [M+H].sup.+=321.6 (C.sub.18H.sub.16FN.sub.5
requires 321.4). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.19 (s, 3H,
CH.sub.3), 2.30 (s, 3H, CH.sub.3), 2.42 (s, 3H, CH.sub.3), 6.82
(d, 1H, J=5.1 Hz, pyrimidinyl-H), 7.03 (t, 1H, J=9.3 Hz, Ph-H),
7.53 (m, 1H, Ph-H), 7.61 (dd, 1H, J=7.1, 2.4 Hz, Ph-H), 8.39 (d,
1H, J=5.1 Hz, pyrimidinyl-H), 9.36 (s, 1H, NH), 12.20 (br. s, 1H,
NH).
4-[2-(3-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrro-
le-2-carbonitrile [42]
M.p. 177.7 179.9.degree. C. MS: [M+H].sup.+=322.5 (C.sub.18H.sub.16FN.sub.5
requires 321.3). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.15 (s, 3H,
CH.sub.3), 2.30 (s, 3H, CH.sub.3), 2.43 (s, 3H, CH.sub.3), 6.86
(d, 1H, J=5.1 Hz, pyrimidinyl-H), 7.13 (t, 1H, J=9.0 Hz, Ph-H),
7.36 (dd, 1H, J=8.1, 1.7 Hz, Ph-H), 7.75 (dd, 1H, J=12.9, 1.5 Hz,
Ph-H), 8.43 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.56 (s, 1H, NH),
12.21 (br. s, 1H, NH).
4-[2-(4-Dimethylamino-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-
-2-carbonitrile [43]
M.p. 190.6 193.7.degree. C. MS: [M+H].sup.+=334.7 (C.sub.19H.sub.20N.sub.6
requires 332.4). .sup.1H-NMR (CDCl.sub.3) .delta.: 2.36 (s, 3H,
CH.sub.3), 2.46 (s, 3H, CH.sub.3), 2.94 (br. s, 6H, CH.sub.3), 6.66
(d, 1H, J=5.6 Hz, pyrimidinyl-H), 6.79 6.80 (m, 2H, Ph-H), 7.05
(br. s, 1H, NH), 7.40 7.43 (m, 2H, Ph-H), 8.34 (d, 1H, J=5.1 Hz,
pyrimidinyl-H), 8.52 (br. s, 1H, NH).
Example 5
4-(3-Dimethylamino-acryloyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic
acid amide
##STR00009##
1-(2,4-Dimethyl-1H-pyrrol-3-yl)-ethanone (1.1 g, 10 mmol) was partially
dissolved in 2 M solution of ammonia in MeOH and H.sub.2O.sub.2
(10 mL of a 27% w/w solution in H.sub.2O) was added dropwise over
a period of 40 min at such a rate as to maintain the internal temperature
.ltoreq.30.degree. C. The mixture was stirred for 18 h at room temperature.
The resulting suspended white solid was filtered and recrystallised
from EtOAc to afford 4-acetyl-3,5-dimethyl-1H-pyrrole-2-carboxylic
acid amide (1.06 g). An aliquot (720 mg, 4 mmol) was suspended in
1,1-bis-dimethylamino-3,3-dimethyl-butan-2-one (2 mL, 9.6 mmol)
in a N.sub.2-flushed flask and heated at 75.degree. C. for 48 h.
The crude mixture was cooled and purified by SiO.sub.2 chromatography
(EtOAc/MeOH gradient elution). The title compound (449 mg) was obtained
as a buff solid. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.30 (s, 3H,
CH.sub.3), 2.46 (s, 3H, CH.sub.3), 2.90 (br. s, 2H, NH). 3.09 (s,
3H, CH.sub.3), 3.13 (s, 3H, CH.sub.3), 5.23 (d, 1H, J=12.4 Hz, CH),
7.38 (d, 1H, J=12.7 Hz, CH), 10.97 (br. s, 1H, NH).
Example 6
4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carb-
oxylic acid amide [44]
4-(3-Dimethylamino-acryloyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic
acid amide (100 mg, 0.43 mmol), 4-fluorophenylguanidine nitrate
(139 mg, 0.65 mmol) and K.sub.2CO.sub.3 (94 mg, 0.68 mmol) were
partially dissolved in 2-methoxyethanol (5 mL) and heated at 120.degree.
C. for 18 h. The mixture was concentrated in vacuo and purified
by SiO.sub.2 chromatography (EtOAc/MeOH gradient elution). The crude
product was triturated in iPr.sub.2O to afford the title compound
(31 mg) as a buff solid. M.p. 93.5 96.8.degree. C. MS: [M+H.sup.+]=326.9
(C.sub.17H.sub.16FN.sub.5O requires 325.3). .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 2.36 (s, 3H, CH.sub.3), 2.39 (s, 3H, CH.sub.3), 6.79 (d,
1H, J=5.4 Hz, pyrimidinyl-H), 6.92 (br. s, 2H, NH), 7.07 (t, 2H,
J=8.5 Hz, Ph-H), 7.76 7.78 (m, 2H, Ph-H), 8.36 (d, 1H, J=5.4 Hz,
pyrimidinyl-H), 9.41 (s, 1H, NH), 11.24 (br. s, 1H, NH).
Example 7
3-Dimethylamino-1-(3,5-dimethyl-1H-pyrrol-2-yl)-propenone
##STR00010##
Pentane-2,4-dione (10.3 mL, 0.1 mol) was diluted with AcOH and
cooled to 0.degree. C. NaNO.sub.2 (6.9 g, 0.1 mol) was dissolved
in H.sub.2O (10 mL) and added dropwise, keeping the internal temperature
.ltoreq.10.degree. C. The mixture was stirred for 1 h with cooling
then 3 h at room temperature. Ethyl acetoacetate (14 mL, 0.11 mol)
was dissolved in 1:1 AcOH/H.sub.2O (100 mL) and Zn powder (7.19
g, 0.11 mol) was added. To this the oxime solution was added and
the mixture was heated at 100.degree. C. for 30 min then poured
into H.sub.2O (0.8 L). The aqueous mixture was extracted with EtOAc
(3.times.500 mL). The combined organic extracts were washed (brine),
dried (MgSO.sub.4), filtered, and evaporated in vacuo. The residue
was purified by SiO.sub.2 chromatography (heptane/EtOAc gradient
elution) to afford 5-acetyl-2,4-dimethyl-1H-pyrrole-3-carboxylic
acid ethyl ester (4.32 g). An aliquot (3.5 g, 16.7 mmol) was added
to KOH (4.22 g, 75.3 mmol) dissolved in H.sub.2O (5 mL) and the
mixture was heated at 130.degree. C. for 18 h. It was then cooled,
diluted with H.sub.2O (50 mL) and acidified with 2 M aq HCl. This
mixture was extracted with EtOAc (3.times.50 mL). The combined organic
extracts were washed (brine), dried (MgSO.sub.4), filtered, and
evaporated in vacuo. The residue was purified by SiO.sub.2 chromatography
(EtOAc) to afford 1-(3,5-dimethyl-1H-pyrrol-2-yl)-ethanone (1.05
g). An aliquot (536 mg, 3.9 mmol) was suspended in N,N-dimethylformamide
dimethyl acetal (1.2 mL, 8.8 mmol) in a N.sub.2-flushed flask and
heated at 90.degree. C. for 48 h. The mixture was cooled and triturated
in cold EtOAc. The resulting precipitate was filtered and washed
with EtOAc to afford the title compound (444 mg) as a buff. 1H-NMR
(DMSO-d.sub.6) .delta.: 1.41 (s, 3H, CH.sub.3), 2.23 (s, 3H, CH.sub.3),
2.23 (br. s, 6H, CH.sub.3), 4.77 (d, 1H, J=12.4 Hz, CH), 4.95 (s,
1H, pyrrolyl-H), 6.85 (d, 1H, J=12.4 Hz, CH).
Example 8
[4-(3,5-Dimethyl-1H-pyrrol-2-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine
[45]
3-Dimethylamino-1-(3,5-dimethyl-1H-pyrrol-2-yl)-propenone (125
mg, 0.65 mmol), 4-fluorophenyl guanidine nitrate (211 mg, 0.98 mmol),
and K.sub.2CO.sub.3 (149 mg, 1.08 mmol) were partially dissolved
in 2-methoxyethanol and heated at 120.degree. C. for 18 h. The mixture
was concentrated in vacuo and purified by SiO.sub.2 chromatography
(5-g Isolute SI.TM. cartridge eluted with an heptane/EtOAc gradient).
The crude product was triturated in iPr.sub.2O to afford the title
compound (158 mg) as a buff solid. M.p. 168.4 171.5.degree. C. MS:
[M+H].sup.+=283.9 (C.sub.16H.sub.15FN.sub.4 requires 282.3). .sup.1H-NMR
(CDCl.sub.3) .delta.: 2.30 (s, 3H, CH.sub.3), 2.35 (s, 3H, CH.sub.3),
5.85 (s, 1H, pyrrolyl-H), 6.83 (d, 1H, J=5.6 Hz, pyrimidinyl-H),
6.87 (br. s, 1H, NH), 7.05 (t, 2H, J=8.5 Hz, Ph-H), 7.51 7.54 (m,
2H, Ph-H), 8.26 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.08 (br. s, 1H,
NH).
Example 9
3-Dimethylamino-1-(1,2,4-trimethyl-1H-pyrrol-3-yl)-propenone
##STR00011##
KOH (818 mg, 14.6 mmol) was partially dissolved in DMSO (115 mL)
and stirred for 5 min. 1-(2,4-dimethyl-1H-pyrrol-3-yl)-ethanone
(1 g, 7.3 mmol) was added in small portions and the mixture was
stirred for 45 min. Iodomethane (0.54 mL, 8.75 mmol) was added dropwise
at such a rate as to maintain the internal temperature .ltoreq.30.degree.
C. The mixture was stirred for a further 45 min then poured into
H.sub.2O (50 mL) and extracted with Et.sub.2O (3.times.60 mL). The
combined organic extracts were washed (brine), dried (MgSO.sub.4),
filtered, and evaporated in vacuo to afford 1-(1,2,4-trimethyl-1H-pyrrol-3-yl)-ethanone
(1.06 g) as a pink solid. This was suspended in 1,1-bis-dimethylamino-3,3-dimethyl-butan-2-one
(3.6 mL, 17.5 mmol) in a N.sub.2-flushed flask and heated at 70.degree.
C. for 36 h. The mixture was evaporated in vacuo and the residue
triturated in EtOAc. The titled compound (973 mg) was obtained as
a reddish solid. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.30 (s, 3H,
CH.sub.3), 1.51 (s, 3H, CH.sub.3), 2.20 (br. s, 6H, CH.sub.3), 2.66
(s, 3H, CH.sub.3), 4.57 (d, 1H, J=12.5 Hz, CH), 5.53 (s, 1H, pyrrolyl-H),
6.72 (d, 1H, J=12.7 Hz, CH).
Example 10
(4-Fluoro-phenyl)-[4-(1,2,4-trimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-amin-
e [46]
3-Dimethylamino-1-(1,2,4-trimethyl-1H-pyrrol-3-yl)-propenone (150
mg, 0.73 mmol), 4-fluorophenyl guanidine nitrate (189 mg, 0.87 mmol)
and K.sub.2CO.sub.3 (144 mg, 1.04 mmol) were partially dissolved
in 2-methoxyethanol (3 mL) and heated at 110.degree. C. 36 h. The
mixture was concentrated in vacuo and purified by SiO.sub.2 chromatography
(heptane/EtOAc gradient elution). The title compound (20 mg) was
obtained as a brownish solid after recrystallisation from iPr.sub.2O/heptane.
M.p. 124.2 128.3.degree. C. MS: [M+H].sup.+=298.4 (C.sub.17H.sub.17FN.sub.4
requires 296.3). .sup.1H-NMR (CDCl.sub.3) .delta.: 2.21 (s, 3H,
CH.sub.3), 2.42 (s, 3H, CH.sub.3), 3.51 (s, 3H, CH.sub.3), 6.40
(s, 1H, pyrrolyl-H), 6.76 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.01
(t, 2H, J=8.8 Hz, Ph-H), 7.58 7.61 (m, 2H, Ph-H), 7.70 (br. s, 1H,
NH), 8.28 (d, 1H, J=5.6 Hz, pyrimidinyl-H).
Example 11
3-Dimethylamino-1-(2,4-dimethyl-5-nitro-1H-pyrrol-3-yl)-propenone
##STR00012##
HNO.sub.3 (0.28 mL of a 69% w/v aq solution, 4.37 mmol) was added
dropwise to Ac.sub.2O (5 mL) at room temperature, keeping the internal
temperature .ltoreq.25.degree. C. The nitrating mixture was stirred
at room temperature for 15 min before cooling to -40.degree. C.
1-(2,4-dimethyl-1H-pyrrol-3-yl)-ethanone (500 mg, 3.64 mmol) was
dissolved in Ac.sub.2O (6 mL) and added dropwise, keeping the internal
temperature .ltoreq.-30.degree. C. The mixture was stirred at -40.degree.
C. for 30 min then at -10.degree. C. for a further 30 min. The mixture
was poured into ice-water (50 mL) and was extracted with Et.sub.2O
(3.times.60 mL). The combined organic eztracts were washed (brine),
dried (Na.sub.2SO.sub.4), filtered, and evaporated in vacuo to give
a dark brown solid. This was recrystallised from MeOH to afford
1-(2,4-dimethyl-5-nitro-1H-pyrrol-3-yl)-ethanone (158 mg). An aliquot
(150 mg, 0.82 mmol) was suspended in 1,1-bis-dimethylamino-3,3-dimethyl-butan-2-one
(0.42 mL, 2.02 mmol) in a N.sub.2-flushed flask and was heated at
70.degree. C. for 18 h. The mixture was triturated in EtOAc to afford
the title compound (119 mg) as a brown solid. .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 2.30 (s, 3H, CH.sub.3), 2.40 (s, 3H, CH.sub.3), 2.80 (br.
s, 3H, CH.sub.3), 3.07 (br. s, 3H, CH.sub.3), 5.19 (d, 1H, J=12.7
Hz, CH), 7.45 (d, 1H, J=12.4 Hz, CH), 12.76 (br, 1H, NH).
Example 12
[4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-
-amine [47]
3-Dimethylamino-1-(2,4-dimethyl-5-nitro-1H-pyrrol-3-yl)-propenone
(110 mg, 0.46 mmol), 4-fluorophenyl guanidine nitrate (150 mg, 0.7
mmol), and K.sub.2CO.sub.3 (193 mg, 1.4 mmol) were partially dissolved
in 2-methoxyethanol and heated at 120.degree. C. for 18 h. The mixture
was concentrated in vacuo and purified by SiO.sub.2 chromatography
(heptane/EtOAc gradient elution). The crude product was triturated
in iPr.sub.2O to afford the title compound (22 mg) as a pale orange
solid. M.p. 166.3 170.1.degree. C. MS: [M+H].sup.+=329.3 (C.sub.16H.sub.14FN.sub.5O.sub.2
requires 327.3). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.49 (s, 3H,
CH.sub.3), 2.59 (s, 3H, CH.sub.3), 6.73 (d, 1H, J=5.1 Hz, pyrimidinyl-H),
7.04 (t, 2H, J=8.8 Hz, Ph-H), 7.07 (br. s, 1H, NH), 7.55 7.58 (m,
2H, Ph-H), 8.44 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 9.40 (br. s, 1H,
NH).
The following compound was prepared in analogous manner:
N-[4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-N',N'-dimethyl--
benzene-1,4-diamine [48]
M.p. 265 268.degree. C. MS: [M+H].sup.+=353.0 (C.sub.18H.sub.20N.sub.6O.sub.2
requires 352.4). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.39 (s, 3H,
CH.sub.3), 2.48 (br. s, 6H, CH.sub.3), 2.82 (s, 3H, CH.sub.3), 6.69
(d, 2H, J=9.0 Hz, Ph-H), 6.74 (d, 1H, J=5.1 Hz, pyrimidinyl-H),
7.50 (d, 2H, J=9.0 Hz, Ph-H), 8.38 (d, 1H, J=5.1 Hz, pyrimidinyl-H),
9.18 (s, 1H, NH), 13.00 (br. s, 1H, NH).
Example 13
[4-(5-Amino-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-
-amine [49]
[4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-
-amine (45 mg, 0.14 mmol) was dissolved in EtOH (3 mL) and 10% Pd(C)
catalyst (10 mg) was added, followed by hydrazine hydrate (48 .mu.L
of a 55% w/w aq solution, 0.84 mmol). The mixture was heated at
reflux for 18 h. The cooled mixture was filtered through a pad of
Celite filter aid and the filtrate was evaporated in vacuo. The
residue was purified by SiO.sub.2 chromatography (20:1 EtOAc/2 M
ammonia in MeOH) to afford the title compound (14 mg) as a yellow
solid. M.p. 227 231.degree. C. MS: [M+H].sup.+=397.8 (C.sub.16H.sub.16FN.sub.5
requires 297.3). .sup.1H-NMR (CDCl.sub.3) .delta.: 1.98 (s, 3H,
CH.sub.3), 2.37 (s, 3H, CH.sub.3), 4.86 (br. s, 2H, NH.sub.2), 6.65
(d, 1H, J=4.9 Hz, pyrimidinyl-H), 7.03 (t, 2H, J=8.3 Hz, Ph-H),
7.49 (br. s, 2H, NH), 7.58 7.61 (m, 2H, Ph-H), 8.53 (d, 1H, J=4.9
Hz, pyrimidinyl-H).
Example 14
[4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-
-amine [50]
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine
(80 mg, 0.28 mmol) was dissolved in THF (4 mL) and cooled to -50.degree.
C. N-Bromosuccinimide (55 mg, 0.31 mmol) was dissolved in THF (2
mL) and added dropwise, keeping the internal temperature .ltoreq.-40.degree.
C. The mixture was stirred for 1 h with cooling then evaporated
in vacuo. The residue was treated with H.sub.2O (10 mL) and extracted
with EtOAc (3.times.10 mL). The combined organic extractss were
washed (brine), dried (MgSO.sub.4), filtered, and evaporated in
vacuo. The crude product was purified by SiO.sub.2 chromatography
heptane/EtOAc gradient elution) to afford the title compound (19
mg) as an orange solid after recrystallisation from iPr.sub.2O.
M.p. 181.4 183.3.degree. C. MS: [M+H].sup.+=362.9 (C.sub.16H.sub.14BrFN.sub.4
requires 361.2). .sup.1H-NMR (CDCl.sub.3) .delta.: 2.10 (s, 3H,
CH.sub.3), 2.36 (s, 3H, CH.sub.3) 6.56 (d, 1H, J=5.1 Hz, pyrimidinyl-H),
6.97 (t, 2H, J=8.3 Hz, Ph-H), 7.00 (br. s, 1H, NH), 7.79 7.52 (m,
2H, Ph-H), 8.85 (br. s, 1H, NH), 8.26 (d, 1H, J=5.1 Hz, pyrimidinyl-H).
The following compound was prepared in analogous manner:
[4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)--
amine [51]
M.p. 198.1 203.degree. C. MS: [M+H].sup.+=389.3 (C.sub.16H.sub.14BrN.sub.5O.sub.4
requires 361.2). .sup.1H-NMR (CDCl.sub.3) .delta.: 2.49 (s, 3H,
CH.sub.3), 2.59 (s, 3H, CH.sub.3) 6.73 (d, 1H, J=5.1 Hz, pyrimidinyl-H),
7.04 (t, 2H, J=8.8 Hz, Ph-H), 7.57 (m, 2H, Ph-H), 7.90 (br. s, 1H,
NH), 8.44 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 9.40 (br. s, 1H, NH).
Example 15
[4-(5-Chloro-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl-
)-amine [52]
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine
(80 mg, 0.28 mmol) was dissolved in THF (4 mL) and cooled to -60.degree.
C. N-Chlorosuccinimide (41 mg, 0.31 mmol) was dissolved in THF (2
mL) and added dropwise, keeping the internal temperature .ltoreq.-50.degree.
C. The mixture was stirred for 30 min with cooling then evaporated
in vacuo. The residue was treated with H.sub.2O (10 mL) and extracted
with EtOAc (3.times.10 mL). The combined organic extracts were washed
(brine), dried (MgSO.sub.4), filtered, and evaporated in vacuo.
The crude product was purified by SiO.sub.2 chromatography (heptane/EtOAc
gradient elution) to afford the title compound (37 mg) as an orange
solid after recrystallisation from iPr.sub.2O. M.p. 200 203.degree.
C. MS: [M+H].sup.+=317.7 (C.sub.16H.sub.14ClFN.sub.4 requires 316.8).
.sup.1H-NMR (CDCl.sub.3) .delta.: 2.17 (s, 3H, CH.sub.3), 2.42 (s,
3H, CH.sub.3) 6.77 (d, 1H, J=5.9 Hz, pyrimidinyl-H), 7.02 7.06 (m,
3H, Ph-h, NH), 7.54 7.56 (m, 2H, Ph-H), 7.95 (br. s, 1H, NH), 8.25
(d, 1H, J=5.4 Hz, pyrimidinyl-H).
Example 16
[4-(5-Diethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-f-
luoro-phenyl)-amine [53]
Diethylamine (40 .mu.L, 0.31 mmol) was diluted with methanol (0.5
mL) and formaldehyde (30 .mu.L of a 37% w/w aq solution, 0.37 mmol)
was added. [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine
(87 mg, 0.31 mmol) was added in small portions and the mixture was
heated to reflux. After 1.5 h the mixture was diluted with H.sub.2O
(10 mL). The resulting precipitate was filtered and triturated in
2 M aq HCl. The mixture was filtered and the filtrate was washed
with 2 M aq NaOH. The filtrate was extracted with EtOAc (3.times.15
mL). The combined organic extracts were washed (brine), dried (MgSO.sub.4),
filtered, and evaporated in vacuo. The crude product was purified
by SiO.sub.2 chromatography (heptane/EtOAc gradient elution) to
afford the title compound (36 mg) as an orange solid after recrystallisation
from iPr.sub.2O. M.p. 71.9 74.2.degree. C. MS: [M+H].sup.+=367.7
(C.sub.21H.sub.26FN.sub.5 requires 367.5). .sup.1H-NMR (CD.sub.3OD)
.delta.: 1.10 (t, 6H, J=7.1 Hz, CH.sub.3), 2.19 (s, 3H, CH.sub.3),
2.41 (s, 3H, CH.sub.3), 2.58 (t, 4H, J=7.8 Hz, CH.sub.2), 3.56 (s,
2H, CH.sub.2), 6.78 (d, 1H, J=5.6 Hz, pyrimidinyl-H), 7.00 (t, 2H,
J=8.5 Hz, Ph-H), 7.61 7.63 (m, 2H, Ph-H), 8.22 (d, 1H, J=5.4 Hz,
pyrimidinyl-H).
The following compounds were prepared in analogous manner:
[4-(5-Dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4--
fluoro-phenyl)-amine [54]
M.p. 88.4 91.6.degree. C. MS: [M+H].sup.+=340.6 (C.sub.19H.sub.22FN.sub.5
requires 339.4). .sup.1H-NMR (CDCl.sub.3) .delta.: 2.18 (s, 3H,
CH.sub.3), 2.56 (s, 6H, CH.sub.3), 2.42 (s, 3H, CH.sub.3), 3.38
(s, 2H, CH.sub.2), 6.75 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.00 (t,
2H, J=8.6 Hz, Ph-H), 7.13 (br. s, 1H, NH), 7.56 7.59 (m, 2H, Ph-H),
8.31 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 8.55 (br. s, 1H, NH).
[4-(2,4-Dimethyl-5-morpholin-4-ylmethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-
-fluoro-phenyl)-amine [55]
M.p. 94.7 97.6.degree. C. MS: [M+H].sup.+=382.1 (C.sub.21H.sub.24FN.sub.5O
requires 381.5). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.12 (s, 3H,
CH.sub.3), 2.33 2.35 (m, 7H, CH.sub.3, CH.sub.2), 3.55 (m, 4H, CH.sub.2),
4.03 (s, 2H, CH.sub.2), 6.73 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.08
(t, 2H, J=9.0 Hz, Ph-H), 7.74 7.78 (m, 2H, Ph-H), 8.28 (d, 1H, J=5.4
Hz, pyrimidinyl-H), 9.27 (s, 1H, NH), 10.76 (s, 1H, NH).
{4-[2,4-Dimethyl-5-(4-methyl-piperazin-1-ylmethyl)-1H-pyrrol-3-yl]-pyrimid-
in-2-yl}-(4-fluoro-phenyl)-amine [56]
M.p. 120.4 123.1.degree. C. MS: [M+H].sup.+=396.4 (C.sub.22H.sub.27FN.sub.5
requires 394.5). .sup.1H-NMR (CDCl.sub.3) .delta.: 1.62 (br. s,
4H, CH.sub.2), 2.10 (s, 3H, CH.sub.3), 2.34 (s, 3H, CH.sub.3), 2.37
(s, 3H, CH.sub.3), 2.43 (br. s, 4H, CH.sub.2), 3.42 (s, 2H, CH.sub.2),
6.67 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 6.91 6.96 (m, 3H, Ph-H, NH),
|