U.S. patent application number 10/151518 was filed with the patent office on 2002-10-10 for 5-cyano-2-aminopyrimidine derivatives.
Invention is credited to Batchelor, Mark James, Davis, Jeremy Martin, Hutchings, Martin Clive, Moffat, David Festus Charles.
Application Number | 20020147339 10/151518 |
Document ID | / |
Family ID | 10855609 |
Filed Date | 2002-10-10 |
United States Patent
Application |
20020147339 |
Kind Code |
A1 |
Batchelor, Mark James ; et
al. |
October 10, 2002 |
5-cyano-2-aminopyrimidine derivatives
Abstract
Pyrimidines of formula (1) are described 1 wherein Ar is an
optionally substituted aromatic or heteroaromatic group; R.sup.1 is
a hydrogen atom or a straight or branched chain alkyl group;
R.sup.2 is a --X.sup.1--R.sup.3 group where X.sup.1 is a direct
bond or a linker atom or group, and R.sup.3 is an optionally
substituted aliphatic, cycloaliphatic, heteroaliphatic,
heterocycloaliphatic, aromatic or heteroaromatic group; and the
salts, solvates, hydrates and N-oxides thereof. The compounds are
selective KDR Kinase and/or FGFr Kinase inhibitors and are of use
in the prophylaxis and treatment of disease states associated with
angiogenesis.
Inventors: |
Batchelor, Mark James;
(Watlington, GB) ; Moffat, David Festus Charles;
(Maidenhead, GB) ; Davis, Jeremy Martin;
(Wokingham, GB) ; Hutchings, Martin Clive;
(Wokingham, GB) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP
ONE LIBERTY PLACE, 46TH FLOOR
1650 MARKET STREET
PHILADELPHIA
PA
19103
US
|
Family ID: |
10855609 |
Appl. No.: |
10/151518 |
Filed: |
May 20, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10151518 |
May 20, 2002 |
|
|
|
09596952 |
Jun 16, 2000 |
|
|
|
Current U.S.
Class: |
544/330 ;
544/331 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
27/02 20180101; C07D 401/04 20130101; A61P 43/00 20180101; C07D
409/04 20130101; A61P 29/00 20180101; A61P 17/06 20180101; A61P
35/00 20180101; A61P 19/02 20180101; C07D 239/42 20130101; A61P
9/14 20180101; C07D 403/12 20130101 |
Class at
Publication: |
544/330 ;
544/331 |
International
Class: |
C07D 43/02; C07D
49/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 18, 1999 |
GB |
9914258.0 |
Claims
1. A compound of formula (1): 7wherein Ar is an optionally
substituted aromatic or heteroaromatic group; R.sup.1 is a hydrogen
atom or a straight or branched chain alkyl group; R.sup.2 is a
--X.sup.1--R.sup.3 group where X.sup.1 is a direct bond or a linker
atom or group, and R.sup.3 is an optionally substituted aliphatic,
cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or
heteroaromatic group; and the salts, solvates, hydrates and
N-oxides thereof.
2. A compound according to claim 1 wherein R.sup.1 is a hydrogen
atom.
3. A compound according to claim 1 wherein R.sup.2 is a group
--X.sup.1R.sup.3 in which X.sup.1 is a direct bond.
4. A compound according to claim 3 in which R.sup.3 is an
optionally substituted aromatic or heteroaromatic group, said
heteroaromatic group containing one or two ring oxygen, sulphur
and/or nitrogen atoms.
5. A compound according to claim 4 wherein R.sup.3 is a phenyl,
thienyl, thiazolyl, indolyl or pyridyl group optionally substituted
by one, two or three --R.sup.4b or -Alk(R.sup.4b).sub.m
substituents in which R.sup.4b is a halogen atom, or an amino
(--NH.sub.2), substituted amino, nitro, cyano, hydroxyl (--OH),
substituted hydroxyl, formyl, carboxyl (--CO.sub.2H), esterified
carboxyl, thiol (--SH), substituted thiol, --COR.sup.5 [where
R.sup.5 is a -Alk(R.sup.4).sub.m, aryl or heteroaryl group],
--CSR.sup.5, --SO.sub.3H, --SO.sub.2R.sup.5, --SO.sub.2NH.sub.2,
--SO.sub.2NHR.sup.5, --SO.sub.2N[R.sup.5].sub.2, --CONH.sub.2,
--CSNH.sub.2, --CONHR.sup.5, --CSNHR.sup.5, --CON[R.sup.5].sub.2,
--CSN[R.sup.5].sub.2, --NHSO.sub.2H, --NHSO.sub.2R.sup.5,
--N[SO.sub.2R.sup.5].sub.2, --NHSO.sub.2NH.sub.2,
--NHSO.sub.2NHR.sup.5, --NHSO.sub.2N[R.sup.5].sub.2, --NHCOR.sup.5,
--NHCONH.sub.2, --NHCONHR.sup.5, --NHCON[R.sup.5].sub.2,
--NHCSR.sup.5, --NHC(O)OR.sup.5, or optionally substituted
cycloaliphatic, hetero-cycloaliphatic, aryl or heteroaryl group;
Alk is a straight or branched C.sub.1-6 alkylene, C.sub.2-6
alkenylene or C.sub.2-6 alkynylene chain, optionally interrupted by
one, two or three --O-- or --S-- atoms or groups selected from
--S(O)--, --S(O).sub.2-- or --N(R.sup.6) [where R.sup.6 is a
hydrogen atom or a straight or branched chain C alkyl group]; and m
is zero or an integer 1, 2 or 3.
6. A compound according to claim 1 wherein Ar is a phenyl, pyridyl,
indolyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl,
isoquinolyl or benzoxazolyl group each substituted by one, two or
three --R.sup.4 or -Alk(R.sup.4).sub.m substituents in which
R.sup.4 is a halogen atom, or an amino (--NH.sub.2), substituted
amino, nitro, cyano, hydroxyl (--OH), substituted hydroxyl, formyl,
carboxyl (--CO.sub.2H), esterified carboxyl, thiol (--SH),
substituted thiol, --COR.sup.5 [where R.sup.5 is a
-Alk(R.sup.4).sub.m, aryl or heteroaryl group], --CSR.sup.5
--SO.sub.3H, --SO.sub.2R.sup.5, --SO.sub.2NH.sub.2,
--SO.sub.2NHR.sup.5, SO.sub.2N[R.sup.5].sub.2, --CONH.sub.2,
--CSNH.sub.2, --CONHR.sup.5, --CSNHR.sup.5, --CON[R.sup.5].sub.2,
--CSN[R.sup.5].sub.2, --NHSO.sub.2H, --NHSO.sub.2R.sup.5,
--N[SO.sub.2R.sup.5].sub.2, --NHSO.sub.2NH.sub.2,
--NHSO.sub.2NHR.sup.5, --NHSO.sub.2N[R.sup.5].sub.2, --NHCOR.sup.5,
--NHCONH.sub.2, --NHCONHR.sup.5, --NHCON[R.sup.5].sub.2,
--NHCSR.sup.5, --NHC(O)OR.sup.5, or optionally substituted
cycloaliphatic, hetero-cycloaliphatic, aryl or heteroaryl group;
Alk is a straight or branched C.sub.1-6 alkylene, C.sub.2-6
alkenylene or C.sub.2-6 alkynylene chain, optionally interrupted by
one, two or three --O-- or --S-- atoms or groups selected from
--S(O)--, --S(O).sub.2-- or --N(R.sup.6)-- [where R.sup.6 is a
hydrogen atom or a straight or branched chain C.sub.1-6 alkyl
group]; and m is zero or an integer 1, 2 or 3.
7. A compound according to claim 6 wherein Ar is a phenyl group
substituted by one, two or three --R.sup.4 or -Alk(R.sup.4).sub.m
substituents.
8. A compound according to any one of claim 5 to claim 7 wherein at
least one of --R.sup.4, -Alk(R.sup.4).sub.m, R.sup.4b or
-Alk(R.sup.4b).sub.m is a
--X.sup.1a(Alk.sup.a).sub.pNR.sup.7aR.sup.7b) (where X.sup.1a is a
direct bond or a linker atom or group, Alk.sup.a is as defined for
Alk, p is zero or an integer 1 and R.sup.7a and R.sup.7b which may
be the same or different is each a hydrogen atom or a straight or
branched C.sub.1-6alkyl group),
--X.sup.1a(Alk.sup.a).sub.pNHet.sup.1 (where --NHet.sup.1 is an
optionally substituted C.sub.3-7cyclicamino group optionally
containing one or more --O-- or --S-- atoms or --N(R.sup.6) [where
R.sup.6 is a hydrogen atom or a straight or branched chain
C.sub.1-6alkyl group]) or --X.sup.1a(Alk.sup.a).sub.pAr.sup.2 group
(where Ar.sup.2 is a nitrogen containing heteroaromatic group).
9. A compound which is:
5-Cyano-4-phenyl-N-(3,4,5-trimethoxyphenyl)pyrimid- ine-2-amine;
5-Cyano-N-[4-(2-imidazol-1-ylethyl)phenyl]-4-(4-methoxcarbony-
lphenyl)pyrimidine-2-amine;
5-Cyano-4-(4-hydroxymethylphenyl)-N-(3,4,5-tri-
methoxyphenyl)pyrimidine-2-amine;
5-Cyano-4[(4-N,N-diethylaminomethyl)phen-
yl]-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;
5-Cyano-4-[2-(3(R)-dimet-
hylaminopyrrolidin-1-yl)pyridin-5-yl]-N-(indazol-5-yl)pyrimidine-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(indazol-5-yl)pyrimidine-2--
amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3,4,5-trimethoxyphen-
yl)pyrimidine-2-amine;
5-Cyano-N-[4-(2-N,N-diethylaminoethylaminocarboxy)p-
henyl]-4-phenylpyrimidine-2-amine;
5-Cyano-4-phenyl-N-4-[2-(2-ethylimidazo-
l-1-yl)ethyl]phenyl)pyrimidine-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl-
]-5-cyano-N-4(1,2,3-triazol-1-yl)phenyl]pyrimidine-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N[{4-2-(2-ethylimidazol-1-yl)-
ethyl]phenyl}pyrimidine-2-amine;
N-[3-(5-Cyano-4-thiophen-2-ylpyrimidin-2--
ylamino)phenyl]-4-(4-methylpiperazin-1-ylmethyl)benzamide;
4-[3-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-12-(2-methyl-imidazol-1--
yl)ethyl]phenyl}pyrimidine-2-amino;
5-Cyano-4-[4-(imiadzol-1-yl)methyl]phe-
nyl-N-(3,4,5-trimethoxy-phenyl)pyrimidine-2-amino; and the salts,
solvates, hydrates and N-oxides thereof.
10. A compound which is:
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4(-
1,2,4-triazol-1-yl)phenyl]pyrimidine-2-amine;
5-Cyano-N-[4-(1,2,4-triazol--
1-yl)phenyl]-4-[4(1-dimethylamino-1-methyl
ethyl)phenyl]pyrimidine-2-amine- ;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(4-fluorophenyl)pyrimidine-
-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-piperidin-1--
ylethyl]phenyl}pydimidine-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-c-
yano-N-[4-(2-imidazol-1-ylethyl)phenyl]pyrimidine-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-morpholinoethyl)pheny-
l]pyrimidine-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[3-(2--
morpholinoethyl)phenyl]pyrimidine-2-amine;
5-Cyano-4-[4-(1-methyl-1-pyrrol-
idin-1-ylethyl)phenyl]-N-(4-fluorophenyl)pyrimidine-2-amine;
5-Cyano-4-{2-([2-(diethylamino)ethyl]amino)pyridin-5-yl}-N-(4-fluoropheny-
l)pyrimidine-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3-flu-
orophenyl)pyrimidine-2-amine; and the salts, solvates, hydrates and
N-oxides thereof.
11. A pharmaceutical composition comprising a compound according to
claim 1 together with one or more pharmaceutically acceptable
carriers, excipients or diluents
Description
[0001] This invention relates to substituted
5-cyano-2-aminopyrimidines, to processes for their preparation, to
pharmaceutical compositions containing them, and to their use in
medicine.
[0002] Angiogenesis, the growth of capillaries from existing blood
vessels, is an essential process in normal embryonic development,
tissue repair and some aspects of female reproductive function. It
is also associated with the development of several pathological
disorders including solid tumour growth, metastasis, psoriasis and
rheumatoid arthritis, as well as diabetic retinopathy and age
related macular degeneration [Folkman, Nature Medicine, (1995)1,
27-310].
[0003] Several growth factors have been shown to mediate
angiogenesis through alteration of vascular permeability, including
vascular endothelial growth factor [VEGF; G. Breier et al., Trends
in Cell Biology, (1996), 6, 454-6], platelet derived growth factor
(PDGF) and acidic and basic fibroblast growth factors (a & b
FGF).
[0004] VEGF in dimeric form is a ligand that binds to two
transmembrane tyrosine kinase associated receptors, expressed
exclusively on proliferating endothelial cells, KDR (Flk-1 in mice)
also known as VEGFR-2, and Flt-1 also known as VEGFR-1. Binding of
VEGF to KDR/Flk and Flt leads to receptor dimerisation, kinase
activation, autophosphorylation of the receptor and phosphorylation
of intracellular substrates. An analogous series of events ensues
after ligand occupancy of the more widely expressed tyrosine kinase
associated FGFr receptor by aFGF or bFGF. Thus receptor tyrosine
kinase activity initiates a cellular signalling pathway leading to
proliferation.
[0005] Antagonism of VEGF with antibody completely suppresses
neovascularisation and growth of human rhabdomyosarcoma A673
speroids in athymic mice [Borgstrom et al, Cancer Res., (1996), 56
4032-4039]. Suppression of bFGF gene expression by interferons a
and b inhibits capillary density in mice, leading to pancreatic
eyelet tumour suppression [Folkman et al, Proc. Natl. Acad. Sci.
(1996), 93, 2002 and Singh et al Proc. Natl. Acad. Sci. (1995), 92,
10457). Other receptor associated kinases such as PDGF and EGFr may
also have some role in mediating angiogenesis.
[0006] We have now found a series of substituted
5-cyano-2-aminopyrimidine- s which are potent and selective
inhibitors of receptor tyrosine kinases involved in angiogenesis,
especially KDR kinase and/or FGFr kinase. Selective inhibition of
these kinases can be expected to have a beneficial effect and the
compounds are thus of use in the prophylaxis and treatment of
disease states associated with angiogenesis, as described
hereinafter.
[0007] Thus, according to one aspect of the invention, we provide a
compound of formula (1): 2
[0008] wherein Ar is an optionally substituted aromatic or
heteroaromatic group;
[0009] R.sup.1 is a hydrogen atom or a straight or branched chain
alkyl group;
[0010] R.sup.2 is a --X.sup.1--R.sup.3 group where X.sup.1 is a
direct bond or a linker atom or group, and
[0011] R.sup.3 is an optionally substituted aliphatic,
cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or
heteroaromatic group;
[0012] and the salts, solvates, hydrates and N-oxides thereof.
[0013] When Ar in the compounds of formula (1) is an aromatic group
it may be for example an optionally substituted monocyclic or
bicyclic fused ring C.sub.6-12aromatic group, such as an optionally
substituted phenyl, 1- or 2-naphthyl, 1- or 2-tetrahydronaphthyl,
indanyl or indenyl group.
[0014] When the group Ar in compounds of the invention is a
heteroaromatic group it may be an optionally substituted C.sub.1-13
heteroaromatic group, such as a C.sub.1-9 heteroaromatic group,
containing for example one, two, three or four heteroatoms selected
from oxygen, sulphur or nitrogen atoms.
[0015] In general, the heteroaromatic group may be for example an
optionally substituted monocyclic heteroaromatic, or a bicyclic or
tricyclic fused-ring heteroaromatic group. Monocyclic
heteroaromatic groups include for example five- or six-membered
heteroaromatic groups containing one, two, three or four
heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Bicyclic heteroaromatic groups include for example nine- to
thirteen-membered fused-ring heteroaromatic groups containing one,
two or more heteroatoms selected from oxygen, sulphur or nitrogen
atoms. Tricyclic heteroaromatic groups include for example ten- to
fourteen-membered fused-ring heteroaromatic groups containing one,
two or more heteroatoms selected from oxygen, sulphur or nitrogen
atoms. The heteroaromatic group may be attached to the remainder of
the compound of formula (1) through any of its ring carbon
atoms.
[0016] Particular examples of heteroaromatic groups represented by
Ar include optionally substituted pyrrolyl, furyl, thienyl,
imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl,
1,2,5-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl,
pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl,
1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl,
[2,3-dihydrol]benzofuryl, isobenzofuryl, benzothienyl,
benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl,
benzimidazolyl, indazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl,
benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl,
quinoxalinyl, cinnolinyl, naphthyndinyl, pyrido[3,4-b]pyridyl,
pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl,
tetrazolyl, 5,6,7,8-tetrahydro-quinolyl,
5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,
xanthenyl or benzoquinolyl.
[0017] Optional substituents which may be present on the aromatic
or heteroaromatic groups represented by Ar include one, two, three
or more substituents, each represented by an atom or group
--R.sup.4 or -Alk(R.sup.4).sub.m, where R.sup.4 is a halogen atom,
or an amino (--NH.sub.2), substituted amino, nitro, cyano, hydroxyl
(--OH), substituted hydroxyl, formyl, carboxyl (--CO.sub.2H),
esterified carboxyl, thiol (--SH), substituted thiol, --COR.sup.5
[where R.sup.5 is a -Alk(R.sup.4).sub.m, aryl or heteroaryl group],
--CSR.sup.5, --SO.sub.3H, --SO.sub.2R.sup.5, --SO.sub.2NH.sub.2,
--SO.sub.2NHR.sup.5, --SO.sub.2N[R.sup.5].sub.2, --CONH.sub.2,
--CSNH.sub.2, --CONHR.sup.5, --CSNHR.sup.5, --CON[R.sup.5].sub.2,
--CSN[R.sup.5].sub.2, --NHSO.sub.2H, --NHSO.sub.2R.sup.5,
--N[SO.sub.2R.sup.5].sub.2, --NHSO.sub.2NH.sub.2,
--NHSO.sub.2NHR.sup.5,
[0018] --NHSO.sub.2NR.sup.5].sub.2, --NHCOR.sup.5, --NHCONH.sub.2,
--NHCONHR.sup.5, --NHCON[R.sup.5].sub.2, --NHCSR.sup.5,
--NHC(O)OR.sup.5, or optionally substituted cycloaliphatic,
hetero-cycloaliphatic, aryl or heteroaryl group; Alk is a straight
or branched C.sub.1-6 alkylene, C.sub.2-6 alkenylene or C.sub.2-6
alkynylene chain, optionally interrupted by one, two or three --O--
or --S-- atoms or groups selected from --S(O)--, --S(O).sub.2-- or
--N(R.sup.6)-- [where R.sup.6 is a hydrogen atom or a straight or
branched chain C.sub.1-6 alkyl group]; and m is zero or an integer
1, 2 or 3.
[0019] When in the group -Alk(R.sup.4).sub.m m is an integer 1, 2
or 3, it is to be understood that the substituent or substituents
R.sup.4 may be present on any suitable carbon atom in -Alk. Where
more than one R.sup.4 substituent is present these may be the same
or different and may be present on the same or different atom in
-Alk or in R.sup.4 as appropriate. Thus for example,
-Alk(R.sup.4).sub.m may represent a --CH(R.sup.4).sub.2 group, such
as a --CH(OH)Ar.sup.1 group where Ar.sup.1 is an aryl or heteroaryl
group as defined below. Clearly, when m is zero and no substituent
R.sup.4 is present the alkylene, alkenylene or alkynylene chain
represented by Alk becomes an alkyl, alkenyl or alkynyl group.
[0020] When R.sup.4 is a substituted amino group it may be for
example a group --NHR.sup.5 [where R.sup.5 is as defined above] or
a group --N[R.sup.5].sub.2 wherein each R.sup.5 group is the same
or different.
[0021] When R.sup.4 is a halogen atom it may be for example a
fluorine, chlorine, bromine, or iodine atom.
[0022] When R.sup.4 is a substituted hydroxyl or substituted thiol
group it may be for example a group --OR.sup.5 or --SR.sup.5
respectively.
[0023] Esterified carboxyl groups represented by the group R.sup.4
include groups of formula --CO.sub.2Alk.sup.1 wherein Alk.sup.1 is
a straight or branched, optionally substituted C.sub.1-8 alkyl
group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl,
i-butyl, s-butyl or t-butyl group; a C.sub.6-12arylC.sub.1-8alkyl
group such as an optionally substituted benzyl, phenylethyl,
phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; a
C.sub.6-12aryl group such as an optionally substituted phenyl,
1-naphthyl or 2-naphthyl group; a C.sub.6-12aryloxyC.sub.1-8alkyl
group such as an optionally substituted phenyloxymethyl,
phenyloxyethyl, 1-naphthyloxymethyl, or 2-naphthyloxymethyl group;
an optionally substituted C.sub.1-8alkanoyloxyC.sub.1-8alkyl group,
such as a pivaloyloxymethyl, propionyloxyethyl or
propionyloxypropyl group; or a C.sub.6-12aroyloxyC.sub.1-8alkyl
group such as an optionally substituted benzoyloxyethyl or
benzoyl-oxypropyl group. Optional substituents present on the
Alk.sup.1 group include R.sup.4 substituents described above.
[0024] When Alk is present in or as a substituent, it may be for
example a methylene, ethylene, n-propylene, i-propylene,
n-butylene, i-butylene, s-butylene, t-butylene, ethenylene,
2-propenylene, 2-butenylene, 3-butenylene, ethynylene,
2-propynylene, 2-butynylene or 3-butynylene chain, optionally
interrupted by one, two, or three --O-- or --S--, atoms or
--S(O)--, --S(O).sub.2-- or --N(R.sup.6)-- (where R.sup.6 is a
hydrogen atom or a straight or branched C.sub.1-6alkyl group)
groups.
[0025] When R.sup.4 is present in compounds of formula (1) as an
optionally substituted cycloaliphatic group it may be an optionally
substituted C.sub.3-10 cycloaliphatic group. Particular examples
include optionally substituted C.sub.3-10cycloalkyl, e.g.
C.sub.3-10cycloalkyl, or C.sub.3-10cycloalkenyl e.g.
C.sub.3-7cyclo-alkenyl groups.
[0026] Heterocycloaliphatic groups represented by R.sup.4 include
the aliphatic or cycloaliphatic groups just described for R.sup.4
but with each group additionally containing one, two, three or four
heteroatoms or heteroatom-containing groups selected from --O-- or
--S-- atoms or --N(R.sup.6)--, --C(O), --C(S)--, --S(O)-- or
--S(O.sub.2)-- groups.
[0027] Particular examples of R.sup.4 cycloaliphatic and
heterocycloaliphatic groups include optionally substituted
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,
2,4-cyclopentadien-1-yl, 3,5,-cyclohexadien-1-yl,
tetrahydrofuranyl, pyrroline, e.g. 2- or 3-pyrrolinyl,
pyrrolidinyl, dioxolanyl, e.g. 1,3-dioxolanyl, imidazolinyl, e.g.
2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl,
pyrazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl,
1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,
piperazinyl, 1,3,5-trithianyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-,
6H-1,2-, 2H-1,2- or 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl,
isoxazinyl, oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl, or
1,3,5-oxadiazinyl groups.
[0028] Optional substituents which may be present on R.sup.4
cycloaliphatic and heterocycloaliphatic groups include one, two,
three or more substituents selected from halogen atoms, e.g.
fluorine, chlorine, bromine or iodine atoms, or hydroxyl,
C.sub.1-6alkoxy, e.g. methoxy or ethoxy, thiol, C.sub.1-6alkylthio,
e.g. methylthio or ethylthio, hydroxy, C.sub.1-6alkyl, e.g.
hydroxymethyl, hydroxyethyl, --CN, --NO.sub.2, --NHR.sup.5 or
--N(R.sup.5).sub.2 groups.
[0029] Aryl and heteroaryl groups represented by the groups
R.sup.4, R.sup.5 or Ar.sup.1 include for example optionally
substituted monocyclic or bicyclic C.sub.6-12 aromatic groups, e.g.
phenyl groups, or C.sub.1-9 heteroaromatic groups such as those
described above in relation to the group Ar. Optional substituents
which may be present on these groups include one, two or three
R.sup.4a atoms or groups described below.
[0030] Particularly useful atoms or groups represented by R.sup.4,
-Alk(R.sup.4).sub.m or R.sup.4a as appropriate include fluorine,
chlorine, bromine or iodine atoms, or C.sub.1-6alkyl, e.g. methyl
or ethyl, C.sub.1-6alkylamino, e.g. methylamino or ethylamino,
hydroxyC.sub.1-6alkyl, e.g. hydroxymethyl or hydroxyethyl,
hydroxyC.sub.2-6alkoxy, e.g. 2-hydroxyethoxy or 3-hydroxyethoxy,
C.sub.1-6alkylthiol e.g. methylthiol or ethylthiol,
C.sub.1-6alkoxy, e.g. methoxy or ethoxy, C.sub.5-7cycloalkoxy, e.g.
cyclopentyloxy, haloC.sub.1-6alkyl, e.g. trifluoromethyl, amino
(--NH.sub.2), aminoC.sub.1-6alkyl, e.g. aminomethyl or aminoethyl,
C.sub.1-6dialkylamino, e.g. dimethylamino or diethylamino,
aminoC.sub.1-6alkoxy, C.sub.1-6alkylaminoC.sub.1-6alkoxy,
diC.sub.1-6alkylaminoC.sub.1-6alkoxy, imido, such as phthalimido or
naphthalimido, e.g. 1,8-naphthalimido,
1,1,3-trioxobenzo[d]thiazolidino, nitro, cyano, hydroxyl (--OH),
formyl [HC(O)--], carboxyl (--CO.sub.2H), --CO.sub.2Alk.sup.1
[where Alk.sup.1 is as defined above], C.sub.1-6 alkanoyl e.g.
acetyl, thiol (--SH), thioC.sub.1-6alkyl, e.g. thiomethyl or
thioethyl, --SC(NH.sub.2+)NH.sub.2, sulphonyl (--SO.sub.3H),
C.sub.1-6alkyl-sulphonyl, e.g. methylsulphonyl, aminosulphonyl
(--SO.sub.2NH.sub.2), C.sub.1-6alkyl-aminosulphonyl, e.g.
methylaminosulphonyl or ethylaminosulphonyl,
C.sub.1-6dialkylaminosulphon- yl, e.g. dimethylaminosulphonyl or
diethylamino-sulphonyl, phenylaminosulphonyl, carboxamido
(--CONH.sub.2), C.sub.1-6alkylamino-car- bonyl, e.g.
methylaminocarbonyl or ethylaminocarbonyl,
C.sub.1-6dialkyl-aminocarbonyl, e.g. dimethylaminocarbonyl or
diethylaminocarbonyl, sulphonylamino (--NHSO.sub.2H),
C.sub.1-6alkylsulphonylamino, e.g. methylsulphonyl-amino or
ethylsulphonylamino, C.sub.1-6dialkylsulphonylamino, e.g.
dimethyl-sulphonylamino or diethylsulphonylamino, optionally
substituted phenyl-sulphonylamino e.g. 2-, 3- or 4-substituted
phenylsulphonylamino such as 2-nitrophenylsulphonylamino,
aminosulphonylamino (--NHSO.sub.2NH.sub.2),
C.sub.1-6alkylaminosulphonylamino, e.g. methylaminosulphonylamino
or ethyl-aminosulphonylamino, C.sub.1-6dialkylaminosulphonylamino,
e.g. dimethyl-aminosulphonylamino or diethylaminosulphonylamino,
phenylamino-sulphonylamino aminocarbonylamino,
C.sub.1-6alkylaminocarbonylamino e.g. methylaminocarbonylamino or
ethylaminocarbonylamino, C.sub.1-6dialkylamino-carbonylamino, e.g.
dimethylaminocarbonylamino or diethylamino-carbonylamino,
phenylaminocarbonylamino, C.sub.1-6alkanoylamino, e.g. acetylamino,
optionally substituted phenylcarbonylamino,
C.sub.1-6alkanoyl-aminoC.sub.1-6alkyl, e.g. acetylaminomethyl,
C.sub.1-6alkoxycarbonylamino, e.g. methoxycarbonylamino,
ethoxycarbonylamino or t-butoxycarbonylamino, optionally
substituted heteroC.sub.3-6cycloalkyl, e.g. piperidinyl,
piperazinyl, 4-(C.sub.1-6alkyl)piperazinyl, e.g.
4-methylpiperazinyl, homopipeprazinyl, or morpholinyl, optionally
substituted heteroC.sub.3-6cycloalkylC.sub.1-6alkyl, e.g.
piperidinylC.sub.1-6alkyl, piperazinylC.sub.1-6alkyl,
4-(C.sub.1-6alkyl)piperazinylC.sub.1-6alkyl, e.g.
4-methylpiperazinylmethyl, or morpholinylC.sub.1-6alkyl, optionally
substituted heteroC.sub.3-6cycloalkylC.sub.1-6alkoxy, e.g.
morpholinylC.sub.1-6alkoxy, optionally substituted
heteroC.sub.3-6alkylC.sub.1-6alkylamino, optionally substituted
heteroC.sub.3-6cycloalkylamino, tetrazolyl, optionally substituted
imidazolyl, optionally substituted triazolyl, e.g.1,2,4-, 1,2,3-,
1,3,4- or 1,2,5-triazolyl, optionally substituted
imidazolylC.sub.1-6alkyl, optionally substituted
imidazolylC.sub.1-6alkoxy, optionally substituted
triazolylC.sub.1-6alkoxy, optionally substituted
imidazolylaminoC.sub.1-6- alkoxy, optionally substituted
phenylamino, optionally substituted benzylamino, optionally
substituted benzyloxy, or optionally substituted pyridylmethylamino
group.
[0031] Where desired, two R.sup.4 or -Alk(R.sup.4).sub.m
substituents may be linked together to form a cyclic group such as
a cyclic ether, e.g. a C.sub.2-6alkylenedioxy group such as
ethylenedioxy.
[0032] It will be appreciated that where two or more R.sup.4,
-Alk(R.sup.4).sub.m or R.sup.4a substituents are present, these
need not necessarily be the same atoms and/or groups.
[0033] Especially useful R.sup.4, -Alk(R.sup.4).sub.m or R.sup.4a
substituents include for example fluorine, chlorine, bromine or
iodine atoms, or a methylamino, ethylamino, hydroxymethyl,
hydroxyethyl, methylthiol, ethylthiol, methoxy, ethoxy, n-propoxy,
2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy, 2-amino-ethoxy,
3-aminopropoxy, 2-(methylamino)ethoxy, 2-(dimethylamino)ethoxy,
3-(dimethyl-amino)propoxy- , cyclopentyloxy, cyclohexyl,
cyclohexylamino, 2-hydroxycyclohexylamino, trifluoromethyl,
trifluoromethoxy, methylamino, ethylamino, amino (--NH).sub.2,
aminomethyl, aminoethyl, dimethylamino, diethylamino, ethyl(methyl)
amino, propyl(methyl)amino, 2-hydroxyethylamino,
3-hydroxypropylamino, 4-hydroxybutylamino, 2-aminoethylamino,
3-aminopropylamino, 4-aminobutylamino, 2-(methylamino)ethylamino,
2-(ethylamino)ethylamino, 2-(i-propylamino)ethylamino,
3-(i-propylamino)propylamino, 2-(dimethylamino)ethylamino,
3-(dimethylamino)propylamino, 2-(diethylamino)ethylamino,
3-(diethylamino)propylamino, 2-(methylamino)-ethyl(methyl)amino,
3-(methylamino)propyl(methyl)amino,
2-(dimethylamino)ethyl(methyl)amino,
2-(dimethylamino)ethyl(ethyl)amino, dimethylaminoethoxy, nitro,
cyano, hydroxyl (--OH), formyl [HC(O)--], carboxyl (--CO.sub.2H),
--CH.sub.2CO.sub.2H, --OCH.sub.2CO.sub.2H, --CO.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.3, --CH.sub.2CO.sub.2CH.sub.3,
--CH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CO.sub.2CH.sub.2phenyl, t-butoxycarbonylmethoxy, acetyl,
phenacetyl thio (--SH), thiomethyl, thioethyl, --SC(NH)NH.sub.2,
sulphonyl (--SO.sub.2H), methylsulphonyl, methylaminosulphonyl,
ethylaminosulphonyl, dimethylaminosulphonyl, diethylaminosulphonyl,
carboxamido (--CONH.sub.2), methylaminocarbonyl,
ethylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl,
methylaminocarbonylmethyl, --NHC(S)NH.sub.2, sulphonylamino
(--NHSO.sub.2H), methylsulphonylamino ethylsulphonylamino,
dimethylsulphonylamino, diethylsulphonylamino, sulphonylamino
(--NHSO.sub.2NH.sub.2), methylaminosulphonylamino,
ethylaminosulphonylamino, dimethylaminosulphonylamino,
diethylaminosulphonylamino, methylamino-carbonylamino,
ethylaminocarbonylamino, dimethylaminocarbonylamino
diethylaminocarbonylamino, acetylamino, phenylcarbonylamino,
amino-methylcarbonylamino, acetylaminomethyl, methoxycarbonylamino,
ethoxycarbonylamino, t-butoxycarbonylamino, pyrrolidinyl,
piperidinyl, piperazinyl, 4-methylpiperazinyl,
4-methylpiperazinylC.sub.1-6alkylphenyl- carbonylamino,
homopiperazinyl, morpholinyl, pyrrolidinylC.sub.1-6alkyl,
piperidinylC.sub.1-6alkyl, piperazinylC.sub.1-6alkyl,
4-(C.sub.1-6alkyl)piperazinylC.sub.1-6alkyl,
morpholinylC.sub.1-6alkyl, morpholinoethoxy,
2-pyrrolidinylethylamino, 2-(1-methylpyrrolidinyl)ethyl- amino,
1-ethylpyrrolidinylmethylamino, piperidinylamino,
1-benzyl-piperidinylamino, imidazolyl, 1,2,4-triazolyl,
1,2,3-triazolyl, 1,3,4-triazolyl, 1,2,5-triazolyl,
C.sub.1-6alkylimidazolylC.sub.1-6alkyl, imidazolylC.sub.1-6alkoxy,
triazolylC.sub.1-6alkyl, triazolylC.sub.1-6alkoxy,
imidazolylC.sub.1-6alkyl such as imidazlylmethyl or
imidazolylethyl, 4-(methoxy)phenylamino,
4-(3-hydroxypropyl)phenylamino, benzylamino, benzyloxy or
pyridiylmethylamino group.
[0034] In the compounds of formula (1), when the group R.sup.1 or
the group R.sup.6 [when present as --N(R.sup.6)--] is a straight or
branched chain alkyl group it may be for example a C.sub.1-6
straight or branched chain alkyl group such as a methyl, ethyl,
n-propyl or isopropyl group.
[0035] Linker atoms represented by X.sup.1 when present in
compounds of formula (1) include --O-- or --S-- atoms. When X.sup.1
is a linker group it may be for example a --C(O)--, --C(S)--,
--S(O)--, --S(O).sub.2--, --N(R.sup.7)-- [where R.sup.7 is a
hydrogen atom or a C.sub.1-6 alkyl, e.g. methyl or ethyl, group],
--C(R.sup.7).sub.2--, --CON(R.sup.7)--, --OC(O)N(R.sup.7)--,
--CSN(R.sup.7)--, --N(R.sup.7)CO--, --N(R.sup.7)C(O)O--,
--N(R.sup.7)CS--, --SON(R.sup.7), --SO.sub.2N(R.sup.7),
--N(R.sup.7)SO.sub.2--, --N(R.sup.7)CON(R.sup.7)--,
--N(R.sup.7)CSN(R.sup.7)--, --N(R.sup.7)SON(R.sup.7)-- or
--N(R.sup.7)SO.sub.2N(R.sup.7) group.
[0036] In the compounds of formula (1), when R.sup.2 is
--X.sup.1R.sup.3 and R.sup.3 is an optionally substituted aliphatic
group, R.sup.3 may be an optionally substituted C.sub.1-10
aliphatic group for example an optionally substituted straight or
branched chain C.sub.1-6 alkyl, e.g. C.sub.1-3 alkyl, C.sub.2-6
alkenyl, e.g. C.sub.2-4 alkenyl, or C.sub.2-6 alkynyl, e.g.
C.sub.2-4 alkynyl group. Each of said groups may be optionally
interrupted by one or two heteroatoms or heteroatom-containing
groups represented by X.sup.2 [where X.sup.2 is an atom or group as
just described for X.sup.1], to form an optionally substituted
R.sup.3 heteroaliphatic group.
[0037] Particular examples of aliphatic groups represented by
R.sup.3 include optionally substituted --CH.sub.3,
--CH.sub.2CH.sub.3 --(CH.sub.2).sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3,
--(CH.sub.2).sub.3CH.sub.3, --CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3,
--(CH.sub.2).sub.4CH.sub.3, --(CH.sub.2).sub.5CH.sub.3,
--CHCH.sub.2, --CHCHCH.sub.3, --CH.sub.2CHCH.sub.2,
--CHCHCH.sub.2CH.sub.3, --CH.sub.2CHCHCH.sub.3,
--(CH.sub.2).sub.2CHCH.sub.2, --CCH, --CCCH.sub.3, --CH.sub.2CCH,
--CCCH.sub.2CH.sub.3, --CH.sub.2CCCH.sub.3, or
--(CH.sub.2).sub.2CCH groups. Where appropriate each of said groups
may be optionally interrupted by one or two atoms and/or groups
X.sup.2 to form an optionally substituted heteroaliphatic group.
Particular examples include --CH.sub.2X.sup.2CH.sub.3,
--CH.sub.2X.sup.2CH.sub.2CH.s- ub.3,
--(CH.sub.2).sub.2X.sup.2CH.sub.3 and
--(CH.sub.2).sub.2X.sup.2CH.su- b.2CH.sub.3 groups.
[0038] The optional substituents which may be present on these
aliphatic and/or heteroaliphatic groups include one, two, three or
more substituents selected from halogen atoms, e.g. fluorine,
chlorine, bromine or iodine atoms, or hydroxyl, C.sub.1-6 alkoxy,
e.g. methoxy or ethoxy, thiol, C.sub.1-6 alkylthio, e.g. methylthio
or ethylthio, --SC(NH)NH.sub.2, --CH.sub.2C(NH)NH.sub.2, amino,
substituted amino or cyclic amino groups.
[0039] Substituted amino groups include for example groups of
formulae --NR.sup.8R.sup.9 [where R.sup.8 is an optionally
substituted C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl
group optionally interrupted by one or two heteroatoms or
heteroatom-containing groups represented by X.sup.3 (where X.sup.3
is an atom or group as described above for X.sup.1) and R.sup.9 is
a hydrogen atom or is a group as just defined for R.sup.8],
--N(R.sup.9)COR.sup.8, --N(R.sup.9)CSR.sup.8,
--N(R.sup.9)SOR.sup.8, --N(R.sup.9)SO.sub.2R.sup.8,
--N(R.sup.9)CONH.sub.2, --N(R.sup.9)CONR.sup.8R.sup.9,
--N(R.sup.9)C(O)OR.sup.8, --N(R.sup.9)C(NH)NH.sub.2,
--N(R.sup.9)C(NH)NR.sup.8NR.sup.9, --N(R.sup.9)CSNH.sub.2,
--N(R.sup.9)CSNR.sup.8R.sup.9, --N(R.sup.9)SONH.sub.2,
--N(R.sup.9)SONR.sup.8R.sup.9, --N(R.sup.9)SONH.sub.2,
--N(R.sup.9)SO.sub.2NH.sub.2, --N(R.sup.9)SONR.sup.8R.sup.9 or
--N(R.sup.9)Cyc.sup.1 [where Cyc.sup.1 is an optionally substituted
C.sub.3-7 monocyclic carbocyclic group optionally containing one or
more --O-- or --S-- atoms or --N(R.sup.6)--, --C(O)--, --C(S)--,
--S(O)-- or --S(O.sub.2)-- groups].
[0040] Cyclic amino substituents which may be present on R.sup.3
aliphatic or heteroaliphatic groups include groups of formula
--NHet.sup.1, where --NHet.sup.1 is an optionally substituted
C.sub.3-7 cyclic amino group optionally containing one or more
other heteroatoms or heteroatom containing groups selected from
--O-- or --S-- atoms or --N(R.sup.6)--, --C(O), --C(S)--, --S(O)--
or --S(O.sub.2)-- groups.
[0041] Particular examples of amino, substituted amino and cyclic
amino groups include --NH.sub.2, methylamino, ethylamino,
dimethylamino, diethylamino, --NHCyc.sup.1 where Cyc.sup.1 is an
optionally substituted cyclopentyl, cyclohexyl, pyrrolidinyl,
imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl,
piperazinyl or thiomorpholinyl group, or --NHet.sup.1 where
--NHet.sup.1 is an optionally substituted pyrrolidinyl,
imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl,
piperazinyl or thiomorpholinyl group. Optional substituents which
may be present on these groups and substituted and cyclic amino
groups in general include one, two or three halogen atoms, e.g.
fluorine, chlorine, bromine or iodine atoms, or C.sub.1-4alkyl,
e.g. methyl or ethyl, --NH2--, --NHCH3--, --N(CH.sub.3).sub.2,
hydroxyl, or C.sub.1-4alkoxy, e.g. methoxy or ethoxy groups.
[0042] When R.sup.3 is present in compounds of formula (1) as an
optionally substituted cycloaliphatic group it may be an optionally
substituted C.sub.3-10 cycloaliphatic group. Particular examples
include optionally substituted C.sub.3-10cycloalkyl, e.g.
C.sub.3-7cycloalkyl, or C.sub.3-10cycloalkenyl e.g.
C.sub.3-7cycloalkenyl groups.
[0043] Heteroaliphatic or heterocycloaliphatic groups represented
by R.sup.3 include the aliphatic or cycloaliphatic groups just
described for R.sup.3 but with each group additionally containing
one, two, three or four heteroatoms or heteroatom-containing groups
represented by X.sup.2, where X.sup.2 is as described above.
[0044] Particular examples of R.sup.3 cycloaliphatic and
heterocycloaliphatic groups include optionally substituted
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclo-penten-1-yl,
2,4-cyclopentadien-1-yl, 3,5,-cyclohexadien-1-yl,
tetrahydro-furanyl, pyrroline, e.g. 2- or 3-pyrrolinyl,
pyrrolidinyl, dioxolanyl, e.g. 1,3-dioxolanyl, imidazolinyl, e.g.
2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl,
pyrazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl,
1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,
piperazinyl, 1,3,5-trithianyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-,
6H-1,2-, 2H-1,2- or 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl,
isoxazinyl, oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl, or
1,3,5-oxadiazinyl groups.
[0045] Optional substituents which may be present on R.sup.3
cycloaliphatic and heterocycloaliphatic groups include
C.sub.1-6alkyl groups and those optional substituents described
above for R.sup.3 when it is an aliphatic group. The
heterocycloaliphatic groups may be attached to the remainder of the
molecule of formula (1) through any appropriate ring carbon or
heteroatom.
[0046] When R.sup.3 is present as an aromatic or heteroaromatic
group in compounds of formula (1) it may be for example an
optionally substituted aromatic or heteroaromatic group as
described above in relation to the group Ar. Optional substituents
which may be present on these aromatic or heteroaromatic groups
include one, two or three R.sup.4b or -Alk(R.sup.4b).sub.m
substituents where R.sup.4b is an atom or group as described above
for R.sup.4, and Alk and m are as described previously. Particular
substituents include optionally substituted C.sub.1-6alkyl groups
[wherein the optional substituents include one, two or three of
those optional substituents described above for R.sup.3 when it is
an aliphatic group and halogen atoms, e.g. fluorine, chlorine,
bromine or iodine atoms or hydroxyl, C.sub.1-6alkoxy, e.g. methoxy
or ethoxy, thiol, C.sub.1-6alkylthio, e.g. methylthio or ethylthio,
--SC(NH)NH.sub.2, --CH.sub.2C(NH)NH.sub.2, amino, substituted amino
or cyclic amino groups as described above for the optional
substituents on aliphatic R.sub.3 groups.
[0047] The presence of certain substituents in the compounds of
formula (1) may enable salts of the compounds to be formed.
Suitable salts include pharmaceutically acceptable salts, for
example acid addition salts derived from inorganic or organic
acids, and salts derived from inorganic and organic bases.
[0048] Acid addition salts include hydrochlorides, hydrobromides,
hydroiodides, alkylsulphonates, e.g. methanesulphonates,
ethanesulphonates, or isethionates, arylsulphonates, e.g.
p-toluenesulphonates, besylates or napsylates, phosphates,
sulphates, hydrogen sulphates, acetates, trifluoroacetates,
propionates, citrates, maleates, fumarates, malonates, succinates,
lactates, oxalates, tartrates and benzoates.
[0049] Salts derived from inorganic or organic bases include alkali
metal salts such as sodium or potassium salts, alkaline earth metal
salts such as magnesium or calcium salts, and organic amine salts
such as morpholine, piperidine, piperazine, dimethylamine or
diethylamine salts.
[0050] Particularly useful salts of compounds according to the
invention include pharmaceutically acceptable salts, especially
acid addition pharmaceutically acceptable salts.
[0051] It will be appreciated that depending on the nature of the
group Ar and the substituent R.sup.2, the compounds of formula (1)
may exist as tautomers and/or geometrical isomers and/or may have
one or more chiral centres so that enantiomers or diasteromers may
exist. It is to be understood that the invention extends to all
such tautomers and isomers of the compounds of formula (1), and to
mixtures thereof, including racemates.
[0052] In the compounds according to the invention the aromatic
group represented by Ar is preferably a substituted phenyl group.
The heteroaromatic group represented by Ar is preferably a
substituted five- or six-membered monocyclic heteroaromatic group
or a nine- or ten-membered fused-ring heteroaromatic group, each of
said groups containing one or two oxygen, sulphur and/or nitrogen
atoms. Particularly useful groups of these types include
substituted pyridyl, indolyl, benzimidazolyl, indazolyl,
benzothiazolyl, quinolyl, isoquinolyl and benzoxazolyl groups.
Substituted quinolyl, indazolyl or benzothiazolyl groups are
especially useful. The substituent(s) present on any of the
above-mentioned preferred Ar groups may be any of those --R.sup.4
or -Alk(R.sup.4).sub.m atoms or groups, particularly one, two or
three --R.sup.4 and/or -Alk(R.sup.4).sub.m atoms or groups,
generally or particularly described above and hereinafter in the
Examples. Particularly useful substituents are those which contain
one or more basic centres, as described hereinafter. In one
preference, at least one --R.sup.4 or -Alk(R.sup.4).sub.m
substituent will contain a basic centre.
[0053] In general in compounds of the invention R.sup.1 is
preferably a hydrogen atom.
[0054] In one general preference, R.sup.2 in compounds of formula
(1) is a group --X.sup.1R.sup.3 in which X.sup.1 is a direct bond.
In these compounds R.sup.3 is preferably an optionally substituted
aromatic group or an optionally substituted heteroaromatic group
containing one or two ring oxygen, sulphur and/or nitrogen atoms
and is especially a monocyclic heteroaromatic group. Thus in
particular R.sup.3 may be an optionally substituted phenyl,
thienyl, thiazolyl, indolyl or pyridyl group. The pyridyl group may
in general be attached to the remainder of the compound of formula
(1) through any available ring carbon atom and is in relation to
that carbon atom, a 2-, 3- or 4-pyridyl group.
[0055] Substituted 3-pyridyl groups are especially useful.
Substituents which may be present on these R.sup.3 aromatic and
heteroaromatic groups include one, two or three --R.sup.4b or
-Alk(R.sup.4b).sub.m substituents as described in general and in
particular above and hereinafter in the Examples. In one
preference, at least one --R.sup.4b or -Alk(R.sup.4b).sub.m
substituent will contain a basic centre as described
hereinafter.
[0056] A particularly useful group of compounds according to the
invention has the formula (1) wherein Ar is a substituted phenyl,
six-membered monocyclic heteroaromatic group or nine- or
ten-membered fused-ring heteroaromatic group, each of said groups
containing one or two oxygen, sulphur and/or nitrogen atoms;
R.sup.1 is a hydrogen atom and R.sup.2 is an optionally substituted
phenyl, thienyl, thiazolyl or monocyclic or bicyclic heteroaromatic
group containing one or two oxygen, sulphur and/or nitrogen
atoms.
[0057] In compounds of this type, Ar is especially a substituted
phenyl, pyridyl, indolyl, indazolyl, benzimidazolyl,
benzothiazolyl, quinolyl, isoquinolyl or benzoxazolyl group.
Substituted phenyl groups are particularly useful. The group
R.sup.2 is preferably an optionally substituted thienyl, phenyl,
indolyl or pyridyl group.
[0058] The substituents which may be present on Ar or R.sup.2
groups of these types include one, two or three of those --R.sup.4,
-Alk(R.sup.4).sub.m, --R.sup.4b and/or -Alk(R.sup.4b).sub.m
substituents generally and particularly described above in relation
to compounds of formula (1), especially substituents which contain
one or more basic centres. Particularly useful substituents
containing basic centres include nitrogen containing groups such as
amino, substituted amino and cyclic amino groups, as described
above in relation to optional substituents present on R.sup.3
aliphatic groups, optionally substituted and nitrogen-containing
heteroaromatic groups, particularly five- or six-membered
nitrogen-containing monocyclic heteroaromatic groups such as
optionally substituted imidazolyl groups.
[0059] Particular groups containing basic centres include
--X.sup.1a(Alk.sup.a).sub.pNR.sup.7aR.sup.7b (where X.sup.1a is a
direct bond or a linker atom or group as defined above for X.sup.1,
Alk.sup.a is as defined above for Alk, p is zero or an integer 1)
and R.sup.7a and R.sup.7b which may be the same or different is
each a hydrogen atom or a straight or branched C.sub.1-6alkyl
group, --X.sup.1a(Alk.sup.a).sub.pNHe- t.sup.1 (where --NHet.sup.1
is as defined above) and --X.sup.1a (Alk.sup.a).sub.pAr.sup.2
(where Ar.sup.2 is a nitrogen containing heteroaromatic group as
described above for Ar). In these groups, NR.sup.7aR.sup.7b may in
particular be --NHCH.sub.3, --N(CH.sub.3).sub.2,
--NHCH.sub.2CH.sub.3, --N(CH.sub.3)(CH.sub.2CH.sub.3), or
--N(CH.sub.2CH.sub.3).sub.2, --NHet.sup.1 may in particular be
optionally substituted pyrrolidinyl, piperidinyl, imidazolidinyl,
piperazinyl, morpholinyl, thiomorpholinyl or pyrazolidinyl;
Ar.sup.2 may in particular be optionally substituted imidazolyl.
X.sup.1a when present may in particular be an oxygen atom or a
--NH-- group.
[0060] Especially useful --R.sup.4b and -Alk(R.sup.4b ).sub.m
substituents in compounds of the invention include --NH.sub.2,
--(CH.sub.2).sub.2NH.su- b.2, --C(CH.sub.3).sub.2NH.sub.2,
--C(CH.sub.3).sub.2NHCH.sub.3,
--C(CH.sub.3).sub.2N(CH.sub.3).sub.2,
--CH.sub.2N(CH.sub.2CH.sub.3).sub.2-
,--CONH(CH.sub.2).sub.2N(CH.sub.2CH.sub.3).sub.2,
--C(CH.sub.3.sub.2-- pyrrolidinyl, dimethylaminopyrrolidinyl,
imidazolyl, imidazolylmethyl, imidazolylethyl and piperidinylethyl
groups. Particularly useful --R.sup.4 and -Alk(R.sup.4).sub.m
substituents include fluorine and chlorine atoms and methyl, ethyl,
methoxy, --CF.sub.3, --CH.sub.2F.sub.2, --CH.sub.2F, --OH,
--OCF.sub.3, --OCHF.sub.3, --OCHF.sub.2, --OCH.sub.2F, --NO.sub.2,
--CN, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, Ar.sup.2a
where Ar.sup.2a is imidazolyl, C.sub.1-3alkylimidazolyl, triazolyl
or C.sub.1-3alkyl-triazolyl, --C.sub.1-3alkylAr.sup.2a,
--OC.sub.1-3alkylAr.sup.2a, --NHet.sup.1a, where --NHet.sup.1a is
piperidinyl, C.sub.1-3alkylpiperidinyl, morpholinyl,
C.sub.1-3alkylmorpholinyl, pyrrolidinyl,
C.sub.1-3alkylpyrrolidinyl, piperazinyl, C.sub.1-3alkylpiperazinyl,
imidazolidinyl, C.sub.1-3alkylimiazolidinyl, pyrazolidinyl or
C.sub.1-3alkylpyrazolidinyl- , --C.sub.1-3alkylNHet.sup.1a,
--OC.sub.1-3alkylNHet.sup.1a, and --NHCOAr.sup.3 where Ar.sup.3 is
phenyl optionally substituted by Ar.sup.2a,
--C.sub.1-3alkylAr.sup.2a, --OC.sub.1-3alkylAr.sup.2a,
--NHet.sup.1, --C.sub.1-3alkylNHet.sup.1 and
--OC.sub.1-3alkylNHet.sup.1.
[0061] In the above preferred groups the term triazolyl is intended
to mean all possible isomers as described above in relation to the
group Ar and especially includes 1,2,3- and 1,2,4-triazolyl
groups.
[0062] Particularly useful compounds of the invention include:
[0063]
5-Cyano-4-phenyl-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;
[0064]
5-Cyano-N-[4-(2-imidazol-1-ylethyl)phenyl]-4-(4-methoxcarbonylpheny-
l)pyrimidine-2-amine;
[0065]
5-Cyano-4-(4-hydroxymethylphenyl)-N-(3,4,5-trimethoxyphenyl)pyrimid-
ine-2-amine;
[0066]
5-Cyano-4[(4-N,N-diethylaminomethyl)phenyl]-N-(3,4,5-trimethoxyphen-
yl)pyrimidine-2-amine;
[0067]
5-Cyano-4-[2-(3(R)-dimethylaminopyrrolidin-1-yl)pyridin-5-yl]-N-(in-
dazol-5-yl)pyrimidine-2-amine;
[0068]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(indazol-5-yl)pyrimid-
ine-2-amine;
[0069]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3,4,5-trimethoxyphen-
yl)pyrimidine-2-amine;
[0070]
5-Cyano-N-[4-(2-N,N-diethylaminoethylaminocarboxy)phenyl]-4-phenylp-
yrimidine-2-amine;
[0071]
5-Cyano-4-phenyl-N-{4-[2-(2-ethylimidazol-1-yl)ethyl]phenyl}pyrimid-
ine-2-amine;
[0072]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-4(1,2,3-triazol-1-yl)-
-phenyl]pyrimidine-2-amine;
[0073]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-(2-ethylimidazo-
l-1-yl)ethyl]phenyl}pyrimidine-2-amine;
[0074]
N-[3-(5-Cyano-4-thiophen-2-ylpyrimidin-2-ylamino)phenyl]-4-(4-methy-
l piperazin-1-ylmethyl)benzamide;
[0075]
4-[3-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-(2-methylimidaz-
ol-1-yl)ethyl]phenyl}pyrimidine-2-amino;
[0076]
5-Cyano-4-[4-(imiadzol-1-yl)methyl]phenyl-N-(3,4,5-trimethoxyphenyl-
)-pyrimidine-2-amino;
[0077] and the salts, solvates, hydrates and N-oxides thereof.
[0078] Especially useful compounds according to the invention
include:
[0079]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4(1,2,4-triazol-1-yl-
)phenyl]pyrimidine-2-amine;
[0080]
5-Cyano-N-[4-(1,2,4-triazol-1-yl)phenyl]-4-[4-(1-dimethylamino-1-me-
thylethyl)phenyl]pyrimidine-2-amine;
[0081]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(4-fluorophenyl)pyrim-
idine-2-amine;
[0082]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-piperidin-1-yle-
thyl]phenyl}pyrimidine-2-amine;
[0083]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-imidazol-1-ylet-
hyl)phenyl]pyrimidine-2-amine;
[0084]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-morpholino
ethyl)phenyl]pyrimidine-2-amine;
[0085]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[3-(2-morpholino
ethyl)phenyl]pyrimidine-2-amine;
[0086]
5-Cyano-4-[4-(1-methyl-1-pyrrolidin-1-ylethyl)phenyl]-N-(4-fluoroph-
enyl)pyrimidine-2-amine;
[0087]
5-Cyano-4-{2-([2-(diethylamino)ethyl]amino)pyridin-5-yl}-N-(4-fluor-
ophenyl)pyrimidine-2-amine;
[0088]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3-fluorophenyl)pyrim-
idine-2-amine;
[0089] and the salts, solvates, hydrates and N-oxides thereof.
[0090] Compounds according to the invention are potent and
selective inhibitors of KDR and/or FGFr kinases as demonstrated by
differential inhibition of these enzymes when compared to
inhibition of other protein kinases such as EGFr kinase,
p56.sup.lck kinase, ZAP-70 kinase, protein kinase C, Csk kinase and
p59.sup.fyn kinase. The ability of the compounds to act in this way
may be simply determined by employing tests such as those described
in the Examples hereinafter.
[0091] The compounds according to the invention are thus of
particular use in the prophylaxis and treatment of diseases in
which inappropriate KDR kinase action plays a role, for example in
disease states associated with angiogenesis. The compounds are then
of use for example in the prophylaxis and treatment of cancer,
prosiasis, rheumatoid arthritis, Kaposi's Sarcoma, ischemic heart
disease, atherosclerosis and occular diseases, such as diabetic
retinopathy, involving retinal vessl proliferation and the
invention is to be understood to extend to such uses and to the use
of a compound of formula (1) in the preparation of a medicament for
the prophylaxis and treatment of such diseases.
[0092] For the prophylaxis or treatment of disease the compounds
according to the invention may be administered as pharmaceutical
compositions, and according to a further aspect of the invention we
provide a pharmaceutical composition which comprises a compound of
formula (1) together with one or more pharmaceutically acceptable
carriers, excipients or diluents.
[0093] Pharmaceutical compositions according to the invention may
take a form suitable for oral, buccal, parenteral, nasal, topical
or rectal administration, or a form suitable for administration by
inhalation or insulation.
[0094] For oral administration, the pharmaceutical compositions may
take the form of, for example, tablets, lozenges or capsules
prepared by conventional means with pharmaceutically acceptable
excipients such as binding agents (e.g. pregelatinised maize
starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose);
fillers (e.g. lactose, microcrystalline cellulose or calcium
hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or
silica); disintegrants (e.g. potato starch or sodium glycollate);
or wetting agents (e.g. sodium lauryl sulphate). The tablets may be
coated by methods well known in the art. Liquid preparations for
oral administration may take the form of, for example, solutions,
syrups or suspensions, or they may be presented as a dry product
for constitution with water or other suitable vehicle before use.
Such liquid preparations may be prepared by conventional means with
pharmaceutically acceptable additives such as suspending agents,
emulsifying agents, non-aqueous vehicles and preservatives. The
preparations may also contain buffer salts, flavouring, colouring
and sweetening agents as appropriate.
[0095] Preparations for oral administration may be suitably
formulated to give controlled release of the active compound.
[0096] For buccal administration the compositions may take the form
of tablets or lozenges formulated in conventional manner.
[0097] The compounds for formula (1) may be formulated for
parenteral administration by injection, including bolus injection
or infusion or particle mediated injection. Formulations for
injection may be presented in unit dosage form, e.g. in glass
ampoule or multi dose containers, e.g. glass vials or a device
containing a compressed gas such as helium for particle mediated
administration. The compositions for bolus injection or infusion
may take such forms as suspensions, solutions or emulsions in oily
or aqueous vehicles, and may contain formulatory agents such as
suspending, stabilising, preserving and/or dispersing agents.
Alternatively, the active ingredient may be in powder form for
constitution with a suitable vehicle, e.g. sterile pyrogen-free
water, before use. For particle mediated administration the complex
may be coated on particles such as microscopic gold particles.
[0098] In addition to the formulations described above, the
compounds of formula (1) may also be formulated as a depot
preparation. Such long acting formulations may be administered by
implantation or by intramuscular injection. Where desired, the
compounds according to the invention may also be conjugated to a
polymer, e.g. a naturally occuring polymer such as albumin, to
prolong the half life of the compounds when in use. Such conjugates
may be formulated and delivered as described above.
[0099] For nasal administration or administration by inhalation,
the compounds for use according to the present invention are
conveniently delivered in the form of an aerosol spray presentation
for pressurised packs or a nebuliser, with the use of suitable
propellant, e.g. dichlorodifluoromethane, trichloro-fluoromethane,
dichlorotetrafluoroetha- ne, carbon dioxide or other suitable gas
or mixture of gases.
[0100] The compositions may, if desired, be presented in a pack or
dispenser device which may contain one or more unit dosage forms
containing the active ingredient. The pack or dispensing device may
be accompanied by instructions for administration.
[0101] The quantity of a compound of the invention required for the
prophylaxis or treatment of a particular condition will vary
depending on the compound chosen, and the condition of the patient
to be treated. In general, however, daily dosages may range from
around 100 ng/kg to 100 mg/kg e.g. around 0.01 mg/kg to 40 mg/kg
body weight for oral or buccal administration, from around 10 ng/kg
to 50 mg/kg body weight for parenteral administration and around
0.05 mg to around 1000 mg e.g. around 0.5 mg to around 1000 mg for
nasal administration or administration by inhalation or
insufflation.
[0102] The compounds of the invention may be prepared by a number
of processes as generally described below and more specifically in
the Examples hereinafter. In the following process description, the
symbols R.sup.1, R.sup.2, Alk, Alk.sup.1 and Ar when used in the
text or formulae depicted are to be understood to represent those
groups described above in relation to formula (1) unless otherwise
indicated. In the reactions described below, it may be necessary to
protect reactive functional groups, for example hydroxy, amino,
thio or carboxy groups, where these are desired in the final
product, to avoid their unwanted participation in the reactions.
Conventional protecting groups may be used in accordance with
standard practice [see, for example, Green, T. W. in "Protective
Groups in Organic Synthesis", John Wiley and Sons, (1991)]. In some
instances, deprotection may be the final step in the synthesis of a
compound of formula (1) and the processes according to the
invention described hereinafter are to be understood to extend to
such removal of protecting groups.
[0103] Thus according to a further aspect of the invention, a
compound of formula (1) may be prepared by reaction of a guanidine
of formula (2):
Ar--N(R.sup.1)C(.dbd.NH)NH.sub.2 (2)
[0104] or a salt thereof with an enaminone of formula (3):
R.sup.2COC(CN)CHN(R.sup.10)(R.sup.11) (3)
[0105] where R.sup.10 and R.sup.11, which may be the same or
different is each a C.sub.1-6 alkyl group.
[0106] The reaction may be performed in a solvent, for example a
protic solvent such as an alcohol, e.g. ethanol, methoxyethanol or
propan-2-ol, optionally in the presence of a base e.g. an alkali
metal base, such as sodium hydroxide or potassium carbonate, at an
elevated temperature, e.g. the reflux temperature.
[0107] Salts of the compounds of formula (2) include acid salts
such as inorganic acid salts e.g. hydrochlorides or nitrates.
[0108] Intermediate guanidines of formula (2) may be prepared by
reaction of the corresponding amine ArNH.sub.2 with cyanamide at an
elevated temperature. The reaction may be performed in a solvent
such as ethanol at an elevated temperature, e.g. up to the reflux
temperature. Where it is desired to obtain a salt of a guanidine of
formula (2), the reaction may be performed in the presence of a
concentrated acid, e.g. hydrochloric or nitric acid.
[0109] The amines ArNH.sub.2 are either known compounds or may be
obtained by conventional procedures, for example by hydrogenation
of the corresponding nitro derivatives using for example hydrogen
in the presence of a metal catalyst in a suitable solvent, for
example as more particularly described in the interconversion
reactions discussed below. The nitrobenzenes for this particular
reaction are either known compounds or may be prepared using
similar methods to those used for the preparation of the known
compounds.
[0110] Intermediate enaminones of formula (3) are either known
compounds or may be prepared by reaction of an acetyl derivative
R.sup.2COCH.sub.2CN with an acetal
(R.sup.10)(R.sup.11)NCH(OR.sup.12).sub- .2 (where R.sup.12 is a
C.sub.1-6alkyl group such as a methyl or ethyl group) at an
elevated temperature. The starting materials for this reaction are
either known compounds or may be prepared by methods analogous to
those used for the preparation of the known compounds.
[0111] One particularly useful method for the preparation of acetyl
derivatives R.sup.2COCH.sub.2CN involves treating a corresponding
isoxazole of formula (4): 3
[0112] with a base such as an alkoxide, e.g. sodium ethoxide, in a
solvent such as an alcohol, e.g. ethanol, at ambient temperature.
Intermediate isoxazoles of formula (4) may be obtained by reaction
of the corresponding aminopropenone
(R.sup.2COCHCHN(R.sup.10)(R.sup.11) with hydroxyl-amine in a
solvent such as an alcohol, e.g. MeOH at ambient temperature. The
aminopropenone starting material for this rection may be obtained
by reaction of the corresponding methyl ketone R.sup.2COCH.sub.3
with an acetal (R.sup.10)(R.sup.11)NCH(OR.sup.12).sub.2 as
described above.
[0113] In another process according to the invention, a compound of
formula (1) may be prepared by displacement of a chlorine atom in a
pyrimidine of formula (5): 4
[0114] with an amine ArNH.sub.2.
[0115] The reaction may be performed at an elevated temperature,
for example the reflux temperature, where necessary in the presence
of a solvent, for example an alcohol, such as 2-ethoxyethanol or
isopopanol, a cyclic ether, e.g. dioxane or a substituted amide
such as dimethylformamide, optionally in the presence of a base,
for example an organic amine such as pyridine.
[0116] Intermediate pyrimidines of formula (5) may be obtained by
reaction of a corresponding pyrimidine of formula (6): 5
[0117] with phosphorous oxychloride optionally in a solvent such as
a substituted amide e.g. dimethylformamide at an elevated
temperature, for example the reflux temperature.
[0118] Intermediates of formula (6) may be prepared from the
corresponding amine of formula (7): 6
[0119] with sodium nitrite in an aqueous acid, e.g. aqueous
sulphuric acid at around ambient temperature.
[0120] Amines of formula (7) may be prepared by reaction of an
enaminone of formula (3) with a guanidine salt, e.g. guanidine
carbonate, as described above for the preparation of compounds of
formula (1).
[0121] Compounds of formula (1) may also be prepared by
interconversion of other compounds of formula (1) and it is to be
understood that the invention extends to such interconversion
processes. Thus, for example, standard substitution approaches
employing for example alkylation, arylation, heteroarylation,
acylation, thioacylation, sulphonylation, formylation or coupling
reactions may be used to add new substitutents to and/or extend
existing substituents in compounds of formula (1). Alternatively
existing substituents in compounds of formula (1) may be modified
by for example oxidation, reduction or cleavage reactions to yield
other compounds of formula (1).
[0122] The following describes in general terms a number of
approaches which can be employed to modify existing Ar and/or
R.sup.2 groups in compounds of formula (1). It will be appreciated
that each of these reactions will only be possible where an
appropriate functional group exists in a compound of formula
(1).
[0123] Where desired, these reactions may also be performed on
intermediates to compounds of formula (1), for example in the
preparation of intermediate amines, ArNH.sub.2 or acetyl
derivatives R.sup.2COCH.sub.2CN, and the description which follows
is intended to apply to these intermediates even though only a
compound of formula (1) is mentioned.
[0124] Thus, for example alkylation, arylation or heteroarylation
of a compound of formula (1) may be achieved by reaction of the
compound with a reagent AlkL or Ar.sup.3L, where Alk is an alkyl
group and Ar.sup.3 is an aryl or heteroaryl group as defined above
in relation to compounds of formula (1) and L is a leaving atom or
group such as a halogen atom, e.g. a chlorine or bromine atom, or a
sulphonyloxy group, e.g. an arylsulphonyloxy group such as a
p-toluenesulphonyloxy group.
[0125] The alkylation, arylation or heteroarylation reaction may be
carried out in the presence of a base, e.g. an inorganic base such
as a carbonate, e.g. caesium or potassium carbonate, an alkoxide,
e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, in a
dipolar aprotic solvent such as an amide, e.g. a substituted amide
such as dimethylformamide or an ether, e.g. a cyclic ether such as
tetrahydrofuran, at around 0.degree. C. to around 40.degree. C.
[0126] In a variation of this process the leaving group L may be
alternatively part of the compound of formula (1) and the reaction
performed with an appropriate nucleophilic reagent at an elevated
temperature. Particular nucleophilic reagents include cyclic
amines, such as piperazine or imidazole. Where appropriate the
reaction may be performed in a solvent such as an aprotic solvent,
e.g. a substituted amide such as dimethylformamide.
[0127] In another general example of an interconversion process, a
compound of formula (1) may be acylated orthioacylated. The
reaction may be performed for example with an acyl halide or
anhydride in the presence of a base, such as a tertiary amine e.g.
triethylamine in a solvent such as a halogenated hydrocarbon, e.g.
dichloromethane or chloroform at for example ambient temperature,
or by reaction with a thioester in an inert solvent such as
tetrahydrofuran at a low temperature such as around 0.degree. C.
Alternatively, the reaction may be performed with an acid, in the
presence of a condensing agent, for example a diimide such as
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, advantageously in
the presence of a catalyst such as a N-hydroxy compound, e.g. a
N-hydroxytriazole such as 1-hydroxybenzotriazole in the presence of
a base, e.g. a cyclic amine such as N-methylmorpholine. The
reaction is particularly suitable for use with compounds of formula
(1) containing primary or secondary amino groups.
[0128] In a further general example of an interconversion process,
a compound of formula (1) may be formylated, for example by
reaction of the compound with a mixed anhydride HCOOCOCH.sub.3 or
with a mixture of formic acid and acetic anhydride.
[0129] Compounds of formula (1) may be prepared in another general
interconversion reaction by sulphonylation, for example by reaction
of the compound with a reagent AlkS(O).sub.2L, or
Ar.sup.2S(O).sub.2L in the presence of a base, for example an
inorganic base such as sodium hydride in a solvent such as an
amide, e.g. a substituted amide such as dimethylformamide at for
example ambient temperature. The reaction may in particular be
performed with compounds of formula (1) possessing a primary or
secondary amino group.
[0130] In further examples of interconversion reactions according
to the invention compounds of formula (1) may be prepared from
other compounds of formula (1) by modification of existing
functional groups in the latter.
[0131] Thus in one example, ester groups --CO.sub.2Alk.sup.1in
compounds of formula (1) may be converted to the corresponding acid
[--CO.sub.2H] by acid- or base-catalysed hydrolysis or by catalytic
hydrogenation depending on the nature of the group Alk.sup.1. Acid-
or base-catalysed hydrolysis may be achieved for example by
treatment with an organic or inorganic acid, e.g. TFA acid in an
aqueous solvent or a mineral acid such as hydrochloric acid in a
solvent such as dioxan or an alkali metal hydroxide, e.g. lithium
hydroxide in an aqueous alcohol or ether e.g. aqueous MeOH or
tetrahydrofuran,. Catalytic hydrogenation may be carried out using
for example hydrogen in the presence of a metal catalyst, for
example palladium on a support such as carbon in a solvent such as
an ether, e.g. tetrahydrofuran or an alcohol, e.g. MeOH.
[0132] In a second example, --OAlk.sup.2 [where Alk.sup.2
represents an alkyl group such as a methyl group] groups in
compounds of formula (1) may be cleaved to the corresponding
alcohol --OH by reaction with boron tribromide in a solvent such as
a halogenated hydrocarbon, e.g. dichloromethane at a low
temperature, e.g. around -78.degree. C.
[0133] In another example, alcohol --OH groups in compounds of
formula (1) may be converted to a corresponding --OAlk or --OAr
group by coupling with a reagent AlkOH or AROH in a solvent such as
tetrahydrofuran in the presence of a phosphine, e.g.
triphenylphosphine and an activator such as diethyl-, diisopropyl-,
or dimethylazodicarboxylate.
[0134] Aminosulphonylamino [--NHSO.sub.2NH.sub.2] groups in
compounds of formula (1) may be obtained, in another example, by
reaction of a corresponding amine [--NH.sub.2] with sulphamide in
the presence of an organic base such as pyridine at an elevated
temperature, e.g. the reflux temperature.
[0135] In another example of an interconversion process secondary
amine groups in compounds of formula (1) may be alkylated using an
alcohol, e.g. ethanol and catalytic hydrogenation, employing for
example hydrogen in the presence of a metal catalyst such as
palladium on a support such as carbon.
[0136] In a further example, amine [--NH.sub.2] groups in compounds
of formula (1) may be obtained by hydrolysis from a corresponding
imide by reaction with hydrazine in a solvent such as an alcohol,
e.g. ethanol at ambient temperature. In an alternative, amine
groups may also be generated by reduction of the corresponding
nitrile, for example using a reducing agent such as a borohydride,
e.g. sodium borohydride or cerium trichloride. Alternatively, amine
groups may be obtained by Ce.sup.IV oxidation of the corresponding
p-anisyl- or p-anisylmethylamines using for example ceric ammonium
nitrate in a solvent such as acetonitrile.
[0137] In another example cyclic amino groups in compounds of
formula (1) may be prepared by cyclisation of a corresponding
compound containing an amine [--NH.sub.2] group with a reagent
L.sup.1AlkL.sup.2 where L.sup.1 and L.sup.2 which may be the same
or different is each a leaving atom or group as described above L
and may for example each be a halogen atom such as a bromine atom.
The reaction may advantageously be carried out in the presence of a
base e.g. an inorganic base such as potassium carbonate, at an
elevated temperature.
[0138] In another example, a nitro [--NO.sub.2] group may be
reduced to an amine [--NH.sub.2], for example by catalytic
hydrogenation as just described, or by chemical reduction using for
example a metal, e.g. tin or iron, in the presence of an acid such
as hydrochloric acid.
[0139] N-oxides of compounds of formula (1) may be prepared for
example by oxidation of the corresponding nitrogen base using an
oxidising agent such as hydrogen peroxide in the presence of an
acid such as acetic acid, at an elevated temperature, for example
around 70.degree. C. to 80.degree. C., or alternatively by reaction
with a peracid such as peracetic acid in a solvent, e.g.
dichloromethane, at ambient temperature.
[0140] Where salts of compounds of formula (1) are desired, these
may be prepared by conventional means, for example by reaction of a
compound of formula (1) with an appropriate acid or base in a
suitable solvent or mixture of solvents, e.g. an organic solvent
such as an ether, e.g. diethylether, or an alcohol, e.g.
ethanol.
[0141] The following Examples illustrate the invention. In the
Examples all .sup.1Hnmr were run at 300 MHz unless specified
otherwise. All temperatures are in .degree. C.
[0142] The following abbreviations are used:
[0143] THF--tetrahydrofuran; DMF--dimethylformamide;
DMSO--dimethylsulphoxide; TFA--trifluoroacetic acid;
DIBAL-H--diisobutylaluminium hydride; MeOH--methanol.
INTERMEDIATE 1
4-[2-(1,2,3-Triazol-1-yl)ethoxy]phenylguanidinium Nitrate
[0144] The title compound was prepared from
4-[2-(1,2,3-triazol-1-yl)ethox- y]aniline (4.91 g, 24.07 mmol),
cyanamide (1.56 g, 40.97 mmol) and concentrated HNO.sub.3 (1.58 mL,
26.47 mmol) in a manner similar to the guanidine of Example 1 to
give the desired material (4.7 g) as an off-white solid, m.p.
>250.degree.. .delta.H (d.sup.6 DMSO) 9.33 (1H, s), 8.20 (1H,
s), 7.74 (1H, s), 7.17-7.14 (6H, m), 7.00-6.97 (2H, m), 4.79 (2H,t,
J 4.95 Hz) and 4.41 (2H, t, J 4.95 Hz).
[0145] 4-[2-(1,2,3-Triazol-1-yl)ethoxy]aniline was prepared from
4-[2-(1,2,3-triazol-1-yl)ethoxy]nitrobenzene (5.98 g, 25.5 mmol)
and 10% palladium on charcoal (1.5 g) in a manner similar to the
aniline intermediate of Example 12 to give the desired material
(4.91 g) as a yellow solid m.p. 141.degree.. .delta.H (CDCl.sub.3)
7.69 (1 H, d, J 0.5 Hz), 7.62 (1H, d J 0.5 Hz), 6.65 (2H, d, J 5.8
Hz), 6.58 (2H, d, J 5.8Hz), 4.71 (2H, t, J 5.0 Hz), 4.24 (2H, t, J
5.0 Hz) and 3.43 (2H, s).
[0146] 4-[2-(1,2,3-Triazol-1-yl)ethoxy]nitrobenzene was prepared
from 4-[(2-p-toluenesulphonyl oxy)ethoxy]nitrobenzene (10 g, 29.7
mmol) and 1,2,3-triazole, sodium salt (2.46 mmol) in a manner
similar to the analogous reaction of Example 24 to give the desired
material (2.25 g) as yellow solid, m.p. 123.degree.. .delta.H
(d.sup.6 DMSO) 8.21 (1H, s), 8.20 (2H, d, J 2.3 Hz), 7.74 (1H, d, J
0.5 Hz), 7.14 (2H, d, J 2.4 Hz), 4.84 (2H, t, J 4.9 Hz) and 4.57
(2H, t, J 4.9 Hz). The reaction also yielded
4-[2-(1,2,3-triazol-2-yl)ethoxy]nitro-benzene (4.36 g) as a yellow
solid, m.p. 111.degree.. .delta.H (d.sup.6 DMSO) 8.17 (2H, d, J 9.3
Hz), 7.80 (2H, s), 7.11 (2H, d, J 9.3 Hz), 4.86 (2H, t, J 4.8 Hz)
and 4.64 (2H, t, J 4.8 Hz).
INTERMEDIATE 2
4-[2-(1,2,3-Triazol-2-yl)ethoxy]phenylguanidinium Nitrate
[0147] The title compound was prepared from
4-[2-(1,2,3-triazol-2-yl)ethox- y]aniline (8.85 g, 43.4 mmol),
cyanamide (2.82 g, 73.78 mmol) and concentrated HNO3 (1.58 mL,
26.47 mmol) in a manner similar to the guanidine of Example 1 to
give the desired material (7.95 g) as an off-white solid, m.p.
>250.degree.. .delta.H (d.sup.6 DMSO) 9.32 (1H, s), 7.80 (2H,
s), 7.16-7.13 (6H, m), 7.00-6.97 (2H, m), 4.79 (2H, t, J 4.95 mmol)
and 4.41 (2H, t, J 4.95 mmol).
[0148] 4-[2-(1,2,3-Triazol-2-yl)ethoxy]aniline was prepared from
4-[2-(1,2,3-triazol-2-yl)ethoxy]nitrobenzene (10.5 g, 44.8 mmol)
and 10% palladium on charcoal (1.5 g) in a manner similar to the
aniline intermediate of Example 12 to give the desired material
(4.91 g) as a yellow solid m.p. 159.degree.. .delta.H (CDCl.sub.3)
7.62 (2H, s), 6.73-6.58 (4H, m), 4.77 (2H, t, J 5.8 Hz), 4.40 (2H,
t, J 5.8 Hz) 3.43 (2H, s).
INTERMEDIATE 3
4-[1,2,4-Triazol-1-yl)ethoxy]phenylguanidinium Nitrate
[0149] The title compound was prepared from
4-[2-(1,2,4-triazol-1-yl)ethox- y]aniline (5.30 g, 25.9 mmol),
cyanamide (1.86 g, 44.11 mmol) and concentrated HNO.sub.3 (1.88 mL,
28.54 mmol) in a manner similar to the guanidine of Example 1 to
give the desired material (6.62 g) as an off-white solid, m.p.
280-282.degree.. .delta.H (d.sup.6 DMSO) 9.33 (1H, bs), 8.56 (1H,
s), 7.97 (1H, s), 7.17 (4H, bs), 7.16-7.12 (2H, s), 6.98-6.94 (2H,
m), 4.58 (2H, t, J 5.0 Hz) and 4.34 (2H, t, J 2.0 Hz).
[0150] 4-[2-(1,2,4-Triazol-1-yl)ethoxy]aniline was prepared from
4-[2-(1,2,4-triazol-1-yl)ethoxy]nitrobenzene (6.28 g, 26.8 mmol)
and 10% palladium on charcoal (0.5 g) in a manner similar to the
aniline intermediate of Example 12 to give the desired material
(5.31 g) as a yellow solid m.p. 85-86.degree.. .delta.H
(CDCl.sub.3) 8.21 (1H, s), 7.94 (1H, s), 6.69-6.58 (4H, m), 4.51
(2H, t, J 5.0 Hz), 4.24 (2H, t, J 5.2 Hz) and 3.45 (2H, bs).
[0151] 4-[2-(1,2,4-Triazol-1-yl)ethoxy]nitrobenzene was prepared
from 4-[(2-p-toluenesulphonyloxy)ethoxy]nitrobenzene (10 g, 30.7
mmol) and 1,2,4-triazole, sodium salt (3.36 g, 36.8 mmol) in a
manner similar to the analogous reaction of Example 24 to give the
desired material (6.45 g) as yellow solid, m.p. 118-120.degree..
.delta.H (CDCl.sub.3) 8.21-8.17 (3H, m), 7.97 (1H, s), 6.93-6.90
(2H, m), 4.62 (2H, t, J 5.2 Hz) and 4.45 (2H,t, J 5.3 Hz).
INTERMEDIATE 4
2-Cyano-3-dimethylamino-1-pyridin3-ylpropen-1-one
[0152] 2-Hydroxy-2-pyridin-3-ylacrylonitrile, sodium salt (1.0 g,
5.95 mmol) was dissolved in methanol (20 mL) and dimethylformamide
diethylacetal (1.2 mL, 7.0 mmol) followed by 1M hydrochloric acid
in diethyl ether (5.95 mL) were added. The reaction was stirred at
room temperature for 1.5 h and then concentrated under reduced
pressure. The resulting residue was subjected to column
chromatography (silica 3% methanol in dichloromethane) to give the
desired product (560 mg) as yellow solid. .delta.H (CDCl3) 8.98
(1H, dd, J 2.3, 0.8 Hz), 8.69 (1H, dd, 4.8, 1.6 Hz), 8.08 (1H, dt,
J 7.9, 2.2 Hz), 7.98 (1H, s), 7.37-7.33 (1H, m), 3.50 (3H,s) and
(3H, s).
[0153] 2-Hydroxy-2-pyridin-3-ylacrylonitrile was prepared by adding
a solution of ethyl nicotinate (22.67 g, 0.15 mol) and acetonitrile
(15.6 mol, 0.3 mol) in toluene (100 mL) and DMF (25 mL) to a
suspension of sodium ethoxide (9.70 g, 0.143 mol) and the resulting
mixture heated at reflux for 2 h with vigorous stirring. On cooling
the reaction was diluted with ether (400 mL) and the resulting
precipitate collected and washed further with ether to give the
desired material (20.1 g) which was used without purification.
EXAMPLE 1
5-Cyano-4-phenyl-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine
[0154] A mixture of 3,4,5-trimethoxyphenylguanidinium nitrate (1.44
g, 5.0 mmol), 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (1.0 g,
5.0 mmol) and sodium hydroxide (0.22 g, 5.5 mmol) in ethanol (20
ml) was heated at reflux for 18 h. On cooling the resulting
precipitate was collected by filtration, washed with water and
diethyl ether, then dried to give the title compound (895 mg) as a
green solid m.p. 246.degree.. .delta.H (d.sup.6 DMSO) 10.37 (1H, br
s), 8.93 (1H, s), 7.99 (2H, m), 7.60 (3H, m), 7.25 (2H, m), 3.75
(6H, s) and 3.63 (3H, s).
[0155] The propenone used as starting material was prepared by
refluxing benzoylacetonitrile (4.50 g, 31.0 mmol) in
dimethylformamide diethylacetal (20 ml) for 12 h. On cooling the
resulting solid was collected and washed with diethyl ether to give
the desired product (4.50 g) as a beige solid m.p. 98.degree..
[0156] 3,4,5-Trimethoxyphenylguanidinium nitrate was prepared by
heating a solution of 3,4,5-trimethoxyaniline (5.49 g, 30.0 mmol),
cyanamide [Aldrich, 50% solution in water w/v] (3.50 ml, 34.5 mmol)
and concentrated HNO.sub.3 (2.1 ml, 30.0 mmol) in ethanol (30 ml).
The solid which formed on cooling to room temperature was collected
by filtration, washed with ethanol and dried to give the desired
material (4.60 g) as a grey solid m.p. 187.degree..
EXAMPLE 2
5-Cyano-N-[4-(2-hydroxyethyl)phenyl]-4-methoxycarbonylphenylpyrimidine-2-a-
mine
[0157] In a similar manner to the compound of Example 1, from
4-(2-hydroxyethyl)phenylguanidinium nitrate (1.88 g, 7.75 mmol),
1-(4-methoxycarbonylphenyl)-2-cyano-3-dimethylaminopropen-1-one
(2.07 g, 7.75 mmol) and sodium hydroxide (310 mg, 7.75 mmol) to
give the title compound (2.40 g) as a yellow solid m.p.
194-196.degree.. .delta.H (d.sup.6 DMSO) 10.52 (1H, br s), 8.96
(1H, s), 8.15 (2H, d, J 8.2 Hz), 8.04 (2H, d, J 8.2 Hz), 7.63 (2H,
d, J 7.9 Hz), 7.18 (2H, d, J 7.9 Hz), 4.61 (1H, t, J 5.1 Hz), 3.90
(3H, s), 3.57 (2H, m), and 2.68 (2H, d, J 7.0 Hz).
[0158] The propenone used as starting material in the above process
was prepared in a similar manner to the analogous compound of
Example 1, to give a yellow solid m.p. 118.degree..
[0159] 4-(2-Hydroxyethyl)phenylguanidinium nitrate was prepared in
a similar manner to the guanidine of Example 1 as an off-white
solid.
EXAMPLE 3
5-Cyano-4-(4-methoxycarbonyl
phenyl)-N-(3,4,5-trimethoxyphenyl)pyrimidine-- 2-amine
[0160] In a similar manner to the compound of Example 1, from
3,4,5-trimethoxyphenylguanidinium nitrate (1.12 g, 3.88 mmol),
2-cyano-1-(4-methoxy-carbonylphenyl)-3-dimethylaminopropen-1-one
(1.0 g, 3.9 mmol) and sodium hydroxide (258 mg, 3.88 mmol) to give
the title compound (760 mg) as a yellow solid m.p. 206-208.degree..
.delta.H (d.sup.6 DMSO) 10.46 (1H, s), 8.97 (1H, s), 8.15 (4H, m),
7.23 (2H, br s), 3.89 (3H, s), 3.74(6H, s) and 3.62 (3H, s).
EXAMPLE 4
5-Cyano-N-[4-(2-imidazol-1-ylethyl)phenyl]-4-(4-methoxcarbonylphenyl)pyrim-
idine-2-amine
[0161] To a solution of the compound of Example 2 (750 mg, 2.0
mmol) in pyridine (10 ml) was added 4-toluenesulphonyl chloride
(458 mg, 2.0 mmol) and the mixture stirred at ambient temperature
for 2.5 h. The reaction was diluted with dichloromethane (50 ml),
washed with 1M hydrochloric acid (2.times.50 ml) followed by
saturated Na.sub.2CO.sub.3 (1.times.25 ml), dried (MgSO.sub.4) and
then concentrated under reduced pressure. The residue was subjected
to column chromatography (silica gel; 5% methanol-dichloromethane)
to give the desired tosylate (600 mg) as a yellow solid. This
material was dissolved in dry DMF (15 ml) containing imidazole (272
mg, 4.0 mmol) and the resulting mixture was stirred under a
nitrogen atmosphere at 80.degree. for 6 h. To the reaction was
added saturated brine (150 ml) and 2M NaOH (10 ml) and this was
extracted with dichloromethane (1.times.100 ml). The organic phase
was dried (MgSO.sub.4) and concentrated under reduced pressure. The
residue was recrystallised from ethyl acetate/propan-2-ol (10:1) to
give the title compound (185 mg) as a pale yellow solid m.p.
216-218.degree.. .delta.H (d.sup.6 DMSO) 10.55 (1H, br s), 8.97
(1H, s), 8.15 (2H, d, J 8.0 Hz), 8.04 (2H, d, J 8.0 Hz), 7.64 (2H,
d, J 6.9 Hz), 7.48 (1H, s), 7.13 (3H, br s), 6.83 (1H, s), 4.18
(2H, m), 3.90 (3H, s), and 3.30 (2H, m).
EXAMPLE 5
5-Cyano-4-(4-hydroxymethylphenyl)-N-3,4,5-trimethoxyphenyl)pyrimidine-2-am-
ine
[0162] To a solution of the compound of Example 3 (210 mg, 0.5
mmol) in dry THF (20 ml) at 0.degree., under a nitrogen atmosphere,
was added DIBAL-H (1M in THF) (2.5 ml, 2.5 mmol) and the reaction
was allowed to warm to ambient temperature over 4.5 h. The reaction
was quenched with 1M potassium-sodium tartrate (75 ml) and
extracted with ethyl acetate (2.times.75 ml). The organic phase was
dried (MgSO.sub.4), concentrated under reduced pressure and the
residue subjected to column chromatography (silica gel; 3%
methanol-dichloromethane) to give the title compound (150 mg) as a
yellow solid m.p.188-191.degree.. .delta.H (d.sup.6DMSO) 10.46 (1H,
br s), 8.92 (1H, s), 7.99 (2H, br m), 7.54(2H, d, J 8.0 Hz), 7.23
(2H, br s), 5.37 (2H, t, J 4.1 Hz), 4.58 (2H, d, J 4.1 Hz), 3.73
(6H, s) and 3.53 (3H, s).
EXAMPLE 6
5-Cyano-4[(4-N,N-diethylaminomethyl)phenyl]-N-(3,4,5-trimethoxyphenyl)pyri-
midine-2-amine
[0163] The compound of Example 5 was dissolved in chloroform (10
mL), thionyl chloride (37 .mu.l) added and the resulting solution
heated at reflux for 0.1 h. The reaction was concentrated under
reduced pressure and the residue taken up in acetonitrile (6 ml) to
which N,N-diethylamine (150 .mu.l) was added. After heating at
reflux for 5 h the mixture was concentrated under reduced pressure
and the residue was subjected to column chromatography (silica gel;
5% methanol-dichloromethane) to give the title compound as a yellow
solid m.p. 137.degree.. .delta.H (d.sup.6 DMSO) 8.68 (1H, s), 8.05
(2H, d, J 8.0 Hz), 7.55-7.51 (3H, m), 7.00 (2H, br s), 3.88 (6H,s),
3.85 (3H, s), 2.56 (4H, q, J 7.1 Hz) and 1.07 (6H, t, J 7.1
Hz).
EXAMPLE 7
5-Cyano-4-[2-(3-(R)-dimethylaminopyrrolidin-1-yl)pyridin-5-yl]-N-(indazol--
5-yl)pyrimidine-2-amine
[0164]
4-(2-Chloropyridin-5-yl)-5-cyano-N-(indazol-5-yl)pyrimidine-2-amine
(522 mg, 1.5 mmol) and 3-(R)-dimethylaminopyrrolidine were heated
together at 140 .degree. in a sealed flask for 2 h. On cooling the
reaction mixture was triturated with water to give a brown solid
which was collected and subjected to column chromatography (silica
gel; 1% triethylamine-10% methanol-89% dichloromethane) to give the
title compound (417 mg) as a yellow solid m.p.249-250.degree..
.delta.H (d.sup.6 DMSO) 13.00 (1H, br s), 10.32 (1H, s), 8.81 (2H,
d, J 9.2 Hz), 8.15-8.12 (2H, m), 8.04 (1H, s), 7.59 (1H, m), 7.52
(1H, d, J 9.8 Hz 6.63 (1H, d, J 9.0 Hz), 3.77-3.67 (2H, m),
3.41-3.24 (2H, m), 2.82 (1H, br m), 2.22 (6H, s), 2.21 (1H, m) and
1.84 (1H,m).
[0165] The chloropyridine used as starting material was prepared
from indazol-5-ylguanidinium nitrate (1.51 g ,6.36 mmol),
1-(2-chloropyridin-5-yl)-2-cyano-3-dimethylaminopropen-1-one (1.50
g, 6.36 mmol) and sodium hydroxide (254 mg, 6.36 mmol) to give the
desired product (1.49 g) as a white solid m.p. >285.degree.
(decomp).
[0166] The propenone was prepared from
3-(2-chloropyridin-5-yl)-3-oxopropi- o-nitrile (4.2 g, 23.3 mmol)
and dimethylformamide diethylacetal (13 ml) to give the desired
material (5.05 g) as an off-white solid m.p. 130-132.degree..
[0167] 3-(2-Chloropyridin-5-yl)-3-oxopropionitrile was prepared by
treating a solution of cyanoacetic acid (9.10 g, 53.5 mmol) and
2,2'-bipyridyl (5 mg) in dry THF (500 ml), cooled to -70.degree.
under a nitrogen atmosphere, dropwise with n-butyllithium (85.6 ml,
214 mmol of a 2.5M solution in hexane). The reaction was allowed to
warm to 0.degree. over a period of 1 h and then recooled to
-70.degree., at which point a solution of 6-chloronicotinyl
chloride (9.42 g, 53.5 mmol) in THF (75 ml) was added to the
resulting red slurry. The reaction was stirred at -70.degree. for a
further 1 h upon complete addition, and then allowed to reach
0.degree. where upon 2M hydrochloric acid (250 ml) was added. The
reaction was extracted with chloroform (2.times.400 ml) and the
combined organic phases were then washed with saturated aqueous
NaHCO.sub.3 (1.times.250 ml) and saturated brine (1.times.250 ml),
dried (MgSO.sub.4) and concentrated under reduced pressure. The
resulting solid was triturated with diethyl ether/n-hexane (1:5) to
give the desired material (4.20 g) as a pale yellow powder m.p.
122-123.degree..
[0168] Indazol-5-ylguanidinium nitrate was prepared from
5-aminoindazole (4.0 g,mmol), cyanamide (1.89 g, 45.1 mmol) and
concentrated HNO.sub.3 (2.8 ml) to give the desired material as a
solid m.p. 252-254.degree..
EXAMPLE 8
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(indazol-5-yl)pyrimidine-2-a-
mine
[0169] A mixture of indazol-5-ylguanidinium nitrate (524 mg, 2.2
mmol),
1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethyl-
aminopropen-1-one (714 mg, 2.0 mmol) and powdered sodium hydroxide
(96 mg, 2.4 mmol) in propan-2-ol (30 ml) was heated at reflux for 6
h. The reaction was concentrated in vacuo and the residue purified
by column chromatography (silica, 60% ethyl acetate in hexane,
loading the crude material in dichloromethane) to give
4-[4-(1-tert-butoxycarbonylamino-1-m-
ethylethyl)phenyl]-5-cyano-N-(indazol-5-yl)-pyrimidine-2-amine as a
yellow solid (850 mg). .delta.H (CDCl.sub.3) 8.69 (1H, s), 8.18
(1H, s), 8.11 (1H, s), 8.05 (2H, d, J 8.4 Hz), 7.93 (1H, bs), 7.57
(2H, d, J 8.4 Hz), 7.50 (2H, m), 5.10 (1H, bs), 1.66 (6H, s), 1.40
(9H, bs). MS (ESI) 492 (MNa+, 61%), 470 (MH+, 100%), 414 (19%).
This product was dissolved in a mixture of TFA acid (20 ml) and
CH.sub.2Cl.sub.2 (20 ml) and was stirred for 30 mins at room
temperature before concentrating the reaction in vacuo. The residue
was dissolved in 10% MeOH in CH.sub.2Cl.sub.2 (200 ml) and the
organic phase washed with sat. Na.sub.2CO.sub.3 (aq) (50 ml), dried
(MgSO.sub.4) and concentrated in vacuo to give the title compound
as a bright yellow solid (541 mg) m.p. 267-271.degree. (dec.).
.delta.H (d.sup.6 DMSO) 13.03 (1H, bs), 10.46 (1H, s), 8.91 (1H,
s), 8.16 (1H, s), 8.04 (1H, s), 7.94 (2H, d, J 8.4 Hz), 7.74 (2H,
d, J 8.4 Hz), 7.61 (1H, m), 7.52 (1H, d, J 8.9 Hz), 3.44 (2H, bs),
1.48 (6H, s). MS (ESI) 392 (MNa+, 11%), 370 (MH+, 23%), 353
(100%).
[0170] The
1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano--
3-dimethyl-aminopropen-1-one used in the above process was prepared
as follows:
[0171] A mixture of 4-acetylbenzonitrile (51.84 g, 0.357 mol) and
N,N-dimethylformamide dimethyl acetal (142 ml, 1.07 mol) was heated
to reflux for 1.5 h. The reaction was cooled to room temperature
and the resultant crystalline mass collected by filtration and
washed with diethyl ether (4.times.100 ml) to give
1-(4-cyanophenyl)-3-dimethylaminop- ropen-1-one as an orange solid
(44.56 g). An additional crop of this product (11.40 g) could be
obtained by partially concentrating the filtrate. .delta.H (d.sup.6
DMSO) 8.01 (2H, d, J 8.2 Hz), 7.87 (2H, d, J 8.2 Hz), 7.75 (1H, d,
J 12.2 Hz), 5.83 (1H, d, J 12.2 Hz), 3.15 (3H, bs), 2.92 (3H, bs).
MS (ESI) 201 (MH+, 100%).
[0172] Hydroxylamine hydrochloride (21.40 g, 308 mmol) was added to
a suspension of 1-(4-cyanophenyl)-3-dimethylaminopropen-1-one
(55.96 g, 280 mmol) in MeOH (450 ml) and the reaction stirred at
room temperature for 24 h. The reaction was diluted with water (400
ml) and the resultant precipitate collected by filtration, washed
with water (5.times.150 ml) and dried in vacuo to give
4-(5-isoxazolyl)-benzonitrile as a pale yellow solid (42.53 g) m.p.
148-149.degree.. .delta.H (CDCl.sub.3) 8.35 (1H, d, J 1.8 Hz), 7.91
(2H, d, J 8.3 Hz), 7.77, (2H, d, J 8.3 Hz), 6.66 (1H, d, J 1.8
Hz).
[0173] Cerium trichloride heptahydrate (112.6 g, 302 mmol) was
dried under vacuum (0.6 mbar) at 140-150.degree. (oil bath) for 4 h
in a flask fitted with a large magnetic stirring bar. The flask was
refilled with nitrogen, cooled to 0.degree. with an ice bath and
anhydrous THF (500 ml) introduced with stirring. On complete
addition the ice bath was removed and the milky suspension stirred
at room temperature for 16 h. The reaction was cooled to
-78.degree. and methyl lithium (188 ml of a 1.6M solution in
diethyl ether, 300 mmol) added dropwise with stirring. After 45
mins a solution of 4-(5-isoxazolyl)-benzonitrile (17.0 g, 100 mmol)
in anhydrous THF (100 ml) was added and the reaction mixture left
to warm in the cooling bath from -78.degree. to -10.degree. over 3
h. The reaction was quenched with 33% ammonium hydroxide (250 ml)
and filtered through a pad of Celite.RTM. to remove the resultant
solids. The Celite.RTM. pad was washed thoroughly with ethyl
acetate (4.times.100 ml) and the combined filtrates concentrated to
approximately 200 ml. These filtrates were diluted with brine (200
ml) and extracted with ethyl acetate (2.times.150 ml), the organic
extracts were dried (MgSO.sub.4) and concentrated in vacuo to give
1-[4-(5-isoxazolyl)phenyl]-1-methylethylami- ne as a yellow solid
(19.53 g). .delta.H (CDCl.sub.3) 8.27 (1H, d, J 1.9 Hz), 7.76 (2H,
dt, J 8.7, 2.0 Hz), 7.62 (2H, d, dt, J 8.7, 2.0 Hz), 6.49 (1H, d, J
1.9 Hz), 1.94 (2H, bs), 1.53 (6H, s). This compound was used in the
following step without purification. A mixture of
1-[4-(5-isoxazolyl)phenyl]-1-methylethylamine (23.87 g, 118.2 mmol)
and di-tert-butyl dicarbonate (28.37 g, 130 mmol) in toluene (200
ml) was heated to reflux for 1 h before removing solvent in vacuo.
The resultant solid was recrystallised from ethanol to give
tert-butyl N-{1-[4-(5-isoxazolyl)phenyl]-1-methylethyl}carbamate as
bright yellow crystals (24.90 g) m.p. 145-146.degree.. .delta.H
(CDCl.sub.3) 8.27 (1H, d, J 1.8 Hz), 7.75 (2H, d t, J 8.7, 2.1 Hz),
7.50 (2H, d t, J 8.7, 2.1 Hz), 6.49 (1H, d, J 1.8 Hz), 4.97 (1H,
bs), 1.64 (6H, s), 1.37 (9H, bs). MS (ESI) 325 (MNa+,42%), 303
(MH+,56%), 186 (100%).
[0174] A freshly prepared solution of sodium ethoxide (3.77 g, 164
mmol of sodium in 150 ml of ethanol) was added to a suspension of
tert-butyl N-{1-[4-(5-isoxazolyl) phenyl]-1-methylethyl}carbamate
(24.76 g, 82 mmol) in ethanol (150 ml) and the reaction stirred at
room temperature for 1 h. Ethanol was removed in vacuo and the
residue partitioned between ethyl acetate (150 ml) and cold 1M
hydrochloric acid (250 ml). The aqueous layer was re-extracted with
ethyl acetate (2.times.80 ml) and the combined ethyl acetate
extracts washed with brine (100 ml), dried (MgSO.sub.4) and
concentrated in vacuo to give tert-butyl
N-{1-[4-(2-cyanoacetyl)phenyl]-1-methylethyl}carbamate as an
off-white solid m.p.122-123.degree.. This crude product was
dissolved in THF (150 ml), N,N-dimethylformamide diethyl acetal
(14.48 g, 98.4 mmol) added and the mixture heated to 50.degree. for
1 h. Solvent was removed in vacuo and the residue purified by
column chromatography (silica, 2-4% MeOH in CH.sub.2Cl.sub.2) to
give 1-[4-(1-tert-butoxycarbonyl-amino-1-methylethyl-
)phenyl]-2-cyano-3-dimethylaminopropen-1-one as a pale yellow solid
(24.46 g) m.p. 160-162.degree.. .delta.H (CDCl.sub.3) 7.94 (1H, s),
7.77 (2H, dt, J 8.6, 1.9 Hz), 7.45 (2H, dt, J 8.6, 1.9 Hz), 5.08
(1H, bs), 3.48 (3H, s), 3.28 (3H, s), 1.63 (6H, s), 1.32 (9H, bs).
MS (ESI) 380 (MNa+, 63%), 358 (MH+, 32%), 302 (96%), 241
(100%).
EXAMPLE 9
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3,4,5-trimethoxyphenyl)
pyrimidine-2-amine
[0175] The title compound was prepared from
3,4,5-trimethoxyphenylguanidin- ium nitrate (576 mg, 2.0 mmol),
1-[4-(1-tert-butoxycarbonylamino-1-methyle- thyl)
phenyl]-2-cyano-3-dimethylaminopropen-1-one (660 mg, 1.8 mmol) and
powdered sodium hydroxide (89 mg, 2.2 mmol) following the method
described for the compound of Example 8. This gave the intermediate
4-[4-(1-tert-butoxycarbonylamino-1methylethyl)phenyl]-5-cyano-N-(3,4,5-tr-
imethoxyphenyl)pyrimidine-2-amine as a yellow solid (769 mg) after
column chromatography (silica, 40% ethyl acetate in hexane). This
compound was treated with TFA acid in CH.sub.2Cl.sub.2 as described
for the analogous compound of Example 8 to give the title compound
as a pale yellow solid (597 mg) m.p.167-168.degree.. .delta.H
(d.sup.6 DMSO) 10.34 (1H, bs), 8.90 (1H, s), 7.96 (2H, bd, J 7.8
Hz), 7.73 (2H, d, J 8.2 Hz), 7.24 (2H, bs), 3.76 (6H, s), 3.63 (3H,
s), 3.18 (2H, bs), 1.42 (6H, s). MS (ESI) 442 (MNa+, 16%), 420
(MH+, 57%), 403 (100%).
[0176] Except where otherwise indicated, the following compounds of
Examples 10-23 and their respective intermediates were prepared in
a manner to the compound of Example 8 and its intermediates:
EXAMPLE 10
4-[4-(1-Amino-1-methylethyl)phenyl]-5cyano-N-[(4-imidazol-1-yl)phenyl]pyri-
midine-2-amine
[0177] From 4-(imidazol-1-yl)phenylguanidinium nitrate (916 mg, 2.8
mmol),
1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethyl-
aminopropenone (1.0 g, 2.8 mmol) and powdered sodium hydroxide (224
mg, 3.6 mmol) to give
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]--
5-cyano-N[(4-imidazol-1-yl)phenyl]pyrimidine-2-amine as a yellow
solid (675 mg) after column chromatography (silica, 2% MeOH in
dichloromethane). This compound was treated with TFA acid in
CH.sub.2Cl.sub.2 as described for Example 8 to give the title
compound as a pale yellow solid (471 mg) m.p. 232-233.degree..
.delta.H (d.sup.6 DMSO) 10.51 (1H, bs), 8.95 (1H, s), 8.19 (1H, s),
7.93-7.89 (4H, m), 7.76-7.61 (5H, m), 7.08 (1H, s), 2.20 (2H, bs)
and 1.41 (6H, s).
EXAMPLE 11
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(1,2,4-triazol-1-yl)pheny-
l]pyrimidine-2-amine
[0178] From 4-(1,2,4-triazol-1-yl)phenylguanidinium nitrate (750
mg, 2.8 mmol),
1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-d-
imethyl-amino propenone (1.0 g, 2.8 mmol) and powdered sodium
hydroxide (150 mg, 3.75 mmol) to give
4-[4-(1-tert-butoxycarbonylamino-1-methylethy-
l)phenyl]-5-cyano-N[4-(1,2,4-triazol-1-yl)phenyl]pyrimidine-2-amine
as a yellow solid (380 mg) after column chromatography (silica, 2%
MeOH in dichloromethane). This compound was treated with TFA acid
in CH.sub.2Cl.sub.2 as described for Example 8 to give the title
compound as a pale yellow solid (224 mg) m.p. 208-209.degree..
.delta.H (d.sup.6 DMSO) 10.67 (1H, bs), 9.21 (1H, s), 8.97 (1H, s),
8.20 (1H, s), 7.97-7.94 (4H, m), 7.82 (2H, d, J 9.1 Hz), 7.76 (2H,
d,J 8.9 Hz), 2.09 (2H, bs) and 1.41 (6H, s).
[0179] The guanidine used as starting material in the above process
was prepared from 4-(1,2,4-triazol-1yl)aniline (1.60 g, 10.0 mmol),
cyanimide (715 mg, 17 mmol) and concentrated HNO.sub.3 (725 mL, 11
mmol), in a manner similar to the corresponding starting material
of Example 1, as a beige solid (1.50 g) m.p. >310.degree.
(decomp).
[0180] 4-(1,2,4-triazol-1yl)aniline was prepared by suspending
4-(1,2,4-triazol-1-yl)nitobenzene (2.25 g, 11.83 mmol) with 10%
palladium on charcoal in ethanol (125 ml), containing 4M
hydrochloric acid (75 mL). The resulting mixture was stirred under
a hydrogen atmosphere at normal pressure and room temperature for
16 h. The reaction was filtered through a pad of Celite.RTM.
washing thoroughly with ethanol. The filtrate was concentrated to
50 mL in volume and 2M NaOH added until the pH was >10. The
solution was again concentrated to 50 mL and cooled to 0.degree..
The resulting solid was collected by filtration and washed
sparingly with water to give the desired material (1.65 g) as an
off-white solid, m.p. 150-152.degree..
[0181] The nitrobenzene used in the above process was prepared by
heating a mixture of 4-fluornitrobenzene (40 g, 28.3 mmol) and
1,2,4-triazole, sodium salt (28.4 g, 31.2 mmol) in DMF (250 mL) at
80.degree. for 4 h. On cooling the reaction was poured into cooled
saturated brine (600 mL) and 2M NaOH (400 mL). The resulting solid
was collected by filtration, washed with 2M NaOH (2.times.150 mL),
water (3.times.100 mL) then ethanol (2.times.75 mL) and dried under
high vacuum. The product was purified by column chromatography
(silica 3% MeOH in dichloromethane) to give the desired material as
a yellow solid (9.05 g).
EXAMPLE 12
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(1,2,3-triazol-1-yl)pheny-
l]pyrimidine-2-amine
[0182] From 4-(1,2,3-triazol-1-yl)phenylguanidinium nitrate (750
mg, 2.8 mmol),
1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-d-
imethyl aminopropenone (1.0 g, 2.8 mmol) and powdered sodium
hydroxide (150 mg, 3.75 mmol) to give
4-[4-(1-tert-butoxycarbonylamino-1-methylethy-
l)phenyl]-5-cyano-N[4-(1,2,4-triazol-1-yl)phenyl]pyrimidine-2-amine
as a yellow solid (380 mg) after column chromatography (silica, 2%
MeOH in dichloromethane). This compound was treated with TFA acid
in CH.sub.2Cl.sub.2 as described for Example 8 to give the title
compound as a pale yellow solid (224 mg) m.p. 208-209.degree..
.delta.H (d.sup.6 DMSO) 10.67 (1H, bs), 9.21 (1H, s), 8.97 (1H, s),
8.20 (1H, s), 7.97-7.94 (4H, m), 7.82 (2H, d, J 9.1 Hz), 7.76 (2H,
d, J 8.9 Hz), 2.09 (2H, bs) and 1.41 (6H, s).
[0183] 4-(1,2,3-trazol-1-yl)phenylguanidinium nitrate was prepared
from 4-(1,2,3-triazol-1-yl)aniline (1.42 g, 8.87 mmol), cyanamide
(635 mg, 15.1 mmol) and concentrated HNO.sub.3 (645 ml, 9.67 mmol)
in a manner similar to the corresponding starting material of
Example 1, as a white solid (1.0 g), m.p. >320.degree..
[0184] The aniline used in the above process was prepared by
hydrogenation of 4-(1,2,3-trazol-1-yl)nitrobenzene (1.86 g, 9.78
mmol) in ethanol (75 mL) over 10% palladium on charcoal (500 mg) at
atmospheric pressure and room temperature for 20 h. The catalyst
was removed by filtration through Celite.RTM. and the filtrate
concentrated to give the desired product as an off-white solid
(1.43 g), m.p. 139-140.degree..
EXAMPLE 13
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3,5-difluorophenyl)
pyrimidine-2-amine
[0185] From 3,5-difluorophenylguanidinium nitrate (983 mg, 2 mmol),
1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethyl-
aminopropenone (1.5 g, 4.2 mmol) and powdered sodium hydroxide (176
mg, 4.3 mmol) to give
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]--
5-cyano-N-[3,5-difluorophenyl]pyrimidine-2-amine as a yellow solid
(510 mg) after column chromatography (silica, 2% MeOH in
dichloro-methane). This compound was treated with TFA acid in
CH.sub.2Cl.sub.2 as described for Example 8 to give the title
compound as a pale yellow solid (332 mg) m.p. 209.degree.. .delta.H
(d.sup.6 DMSO) 9.06 (1H, s), 8.00 (2H, d, J 8.5 Hz), 7.78 (2H, d, J
8.5 Hz), 7.62-7.54 (2H, m), 6.93-6.86 (1H, m) and 1.60 (6H, s).
EXAMPLE 14
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3-fluoro-4-methyl
phenyl)pyrimidine-2-amine
[0186] From 3-fluoro-4-methylphenylguanidinium nitrate (1.15 g, 5.0
mmol),
1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethyl
aminopropenone (1.78 g, 4.98 mmol) and powdered sodium hydroxide
(176 mg, 4.2 mmol) to give
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]--
5-cyano-N-[3-fluoro-4-methylphenyl]pyrimidine-2-amine as a yellow
solid (1.47 g) after column chromatography (silica, 2% MeOH in
dichloromethane). This compound was treated with TFA acid in
CH.sub.2Cl.sub.2 as described for Example 8 to give the title
compound as a pale yellow solid (1.16) m.p. 209.degree.. .delta.H
(d.sup.6 DMSO) 8.96 (1H, s), 7.91 (2H,d, J 8.5 Hz), 7.76 (2H,d, J
8.5 Hz), 7.70 (1H,m), 7.46-7.43 (1H, m), 7.27-7.21 (1H, m) and 1.60
(6H, s).
EXAMPLE 15
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3,4,5-trifluorophenyl)
pyrimidine-2-amine
[0187] From 3,4,5-trifluorophenylguanidinium nitrate (1.06 g, 4.2
mmol),
1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethyl-
aminopropenone (1.5 g, 4.2 mmol) and powdered sodium hydroxide (176
mg, 4.2 mmol) to give
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]--
5-cyano-N-[3,4,5-trifluoro-phenyl]pyrimidine-2-amine as a yellow
solid (597 mg) after column chromatography (silica, 2% MeOH in
dichloro-methane). This compound was treated with TFA acid in
CH.sub.2Cl.sub.2 as described for Example 8 to give the title
compound as a pale yellow solid (401 mg) m.p. 220.degree.. .delta.H
(d.sup.6 DMSO) 9.01(1H, s), 7.91 (2H, m), 7.78-7.71 (4H, m) and
1.40 (6H, s).
EXAMPLE 16
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-4-fluoro-3-trifluoro
methylphenyl)pyrimidine-2-amine
[0188] From 4-fluoro-3-trifluoromethylphenylguanidinium nitrate
(1.19 g, 4.2 mmol),
1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-
-3-dimethylamino-propenone (1.5 g, 4.2 mmol) and powdered sodium
hydroxide (176 mg, 4.2 mmol) to give
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl-
)phenyl]-5-cyano-N-[4-fluoro-3-trifluoromethylphenyl]pyrimidine
-2-amine as a yellow solid (648 mg) after column chromatography
(silica, 2% MeOH in dichloromethane). This compound (211 mg) was
treated with TFA acid in CH.sub.2Cl.sub.2 as described for Example
8 to give the title compound as a pale yellow solid (157 mg) m.p.
181.degree.. .delta.H (d.sup.6 DMSO) 8.91 (1H, s), 8.32 (1H, dd, J
6.5, 2.6 Hz), 8.06-8.00 (1H, s), 7.99 (2H, d, J 8.8 Hz), 7.77 (2H,
d, J 8.8 Hz), 7.44 (1H, m) and 1.47 (6H, s).
EXAMPLE 17
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(2,4-difluorophenyl)
pyrimidine-2-amine
[0189] From 2,4-difluorophenylguanidinium nitrate (0.98 g, 4.2
mmol),
1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethyl-
amino propenone (1.5 g, 4.2 mmol) and powdered sodium hydroxide
(176 mg, 4.3 mmol) to give
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]--
5-cyano-N-[2,4,-difluoro-phenyl]pyrimidine-2-amine as a yellow
solid (648 mg) after column chromatography (silica, 2% MeOH in
dichloromethane). This compound was treated with TFA acid in
CH.sub.2Cl.sub.2 as described for Example 8 to give the title
compound as a pale yellow solid (460 mg) m.p. 203.degree.. .delta.H
(d.sup.6 DMSO) 8.65 (1H, s), 7.82 (2H, d, J 6.6 Hz), 7.70 (2H, d, J
8.3 Hz), 7.61-7.55 (1H, m), 7.38-7.32 (1H, m), 7.14-7.09 (1H, m)
and 1.39 (6H, s).
EXAMPLE 18
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3,4-difluorophenyl)
pyrimidine-2-amine
[0190] From 3,4-difluorophenylguanidinium nitrate (0.98 g, 4.2
mmol),
1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethyl-
amino propenone (1.5 g, 4.2 mmol) and powdered sodium hydroxide
(176 mg, 4.3 mmol) to give
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]--
5-cyano-N-[3,4-difluorophenyl]pyrimidine-2-amine as a yellow solid
(631 mg) after column chromatography (silica, 2% MeOH in
dichloromethane). This compound was treated with TFA acid in
CH.sub.2Cl.sub.2 as described for Example 8 to give the title
compound as a pale yellow solid (412 mg) m.p. 192.degree.. .delta.H
(d.sup.6 DMSO) 10.66 (1H, bs), 8.97 (1H, s), 7.99-7.92 (1H, m),
7.90 (2H, d, J 8.5 hz), 7.76 (2H, d, J 8.5 hz), 7.53-7.38 (2H, m)
and 1.41 (6H, s).
EXAMPLE 19
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3-chloro-4-fluorophenyl)pyr-
imidine-2-amine
[0191] From 3-chloro-4-fluorophenylguanidinium nitrate (1.05 g, 4.2
mmol),
1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethyl
aminopropenone (1.5 g, 4.2 mmol) and powdered sodium hydroxide (176
mg, 4.3 mmol) to give
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]--
5-cyano-N-[3-chloro-4-fluorophenyl]pyrimidine-2-amine as a yellow
solid (895 mg) after column chromatography (silica, 2% MeOH in
dichloromethane). This compound was treated with TFA acid in
CH.sub.2Cl.sub.2 as described for Example 8 to give the title
compound as a pale yellow solid (501 mg) m.p. 237.degree.. .delta.H
(d.sup.6 DMSO) 10.60 (1H, bs), 8.97 (1H, s), 8.07 (1H, d, J 6.8,
2.5 Hz), 7.91 (2H, dapp, J 8.5 Hz), 7.75 (2H, d, J 8.5 Hz),
7.73-7.69 (1H, m), 7.41 (1H, tapp, J 9.1 Hz) and 1.41 (6H, s).
EXAMPLE 20
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(4-fluorophenyl)
pyrimidine-2-amine
[0192] From 4-fluorophenylguanidinium nitrate (0.91 g, 4.2 mmol),
1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethyl-
amino propenone (1.5 g, 4.2 mmol) and powdered sodium hydroxide
(176 mg, 4.3 mmol) to give
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]--
5-cyano-N-[4-fluorophenyl] pyrimidine-2-amine as a yellow solid
(1.28 g) after column chromatography (silica, 2% MeOH in
dichloromethane). This compound was treated with TFA acid in
CH.sub.2Cl.sub.2 as described for Example 8 to give the title
compound as a pale yellow solid (607 mg) m.p. 228-229.degree..
.delta.H (d.sup.6 DMSO) 10.59 (1H, s), 9.02 (1H, s), 8.00 (2H, d, J
8.4 Hz), 7.86-7.83 (4H, m), 7.32-7.27 (2H, m) and 1.51 (6H, s).
EXAMPLE 21
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3-trifluoromethyl
phenyl)pyrimidine-2-amine
[0193] From 3-trifluoromethylphenylguanidinium nitrate (1.12 g, 4.2
mmol),
1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethyl-
amino propenone (1.5 g, 4.2 mmol) and powdered sodium hydroxide
(176 mg, 4.3 mmol) to give
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]--
5-cyano-N-[3-trifluoromethyl] pyrimidine-2-amine as a yellow solid
(1.32 g) after column chromatography (silica, 2% MeOH in
dichloromethane). This compound was treated with TFA in
CH.sub.2Cl.sub.2 as described for Example 8 to give the title
compound as a pale yellow solid (607 mg) m.p. 192.degree.. .delta.H
(d.sup.6 DMSO) 10.70 (1H, bs), 8.93 (1H, s), 7.92 (1H, d, J 8.3
Hz), 7.87 (2H, d, J 8.3 Hz), 7.68 (2H, d, J 8.3 Hz), 7.51 (1H, t, J
8.0 Hz), 7.33 (1H, d, J 7.7 Hz) and 1.34 (6H, s).
EXAMPLE 22
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3-fluorophenyl)
pyrimidine-2-amine
[0194] From 3-fluorophenylguanidinium nitrate (0.91 g, 4.2 mmol),
1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethyl-
amino propenone (1.5 g, 4.2 mmol) and powdered sodium hydroxide
(176 mg, 4.3 mmol) to give
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]--
5-cyano-N-[3-fluorophenyl] pyrimidine-2-amine as a yellow solid
(381 mg) after column chromatography (silica, 2% MeOH in
dichloromethane). This compound was treated with TFA acid in
CH.sub.2Cl.sub.2 as described for Example 8 to give the title
compound as a pale yellow solid (161 mg) m.p. 209.degree.. .delta.H
(d.sup.6 DMSO) 10.66 (1H, s), 8.98 (1H, s), 7.92 (2H, dapp, J 8.5
Hz), 7.76 (2H, dapp, J 8.5 Hz), 7.74 (1H, m), 7.56-7.54 (1H, m),
7.40-7.34 (1H, m), 6.91-6.86 (1H, m), 2.48 (2H, bs) and 1.41 (6H,
s).
EXAMPLE 23
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(phenyl)pyrimidine-2-amine
[0195] From phenylguanidinium nitrate (0.45 g, 2.8 mmol),
1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethyl-
amino propenone (1.0 g, 2.8 mmol) and powdered sodium hydroxide
(112 mg, 2.8 mmol) to give
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]--
5-cyano-N-[phenyl]pyrimidine-2-amine as a yellow solid (820 mg)
after column chromatography (silica, 2% MeOH in dichloromethane).
This compound was treated with TFA acid in CH.sub.2Cl.sub.2 as
described for Example 8 to give the title compound as a pale yellow
solid (589 mg) m.p. 303-304.degree.. .delta.H (d.sup.6 DMSO) 8.72
(1H, s), 8.09 (2H, d, J 8.0 Hz), 7.69-7.58 (5H, m), 7.43-7.38 (2H,
m), 7.15 (1H, t, J 7.7 Hz), 2.32 (2H, bs) and 1.68 (6H, s).
EXAMPLE 24
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-piperidin-1-ylethyl]ph-
enyl}pyrimidine-2-amine
[0196]
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-
-(2-piperidin-1-ylethyl)phenyl]pyrimidine-2-amine (380 mg) was
stirred in 50% v/v CH.sub.2Cl.sub.2-TFA (5 mL) at room temperature
for 30 min. The solvent was removed under reduced pressure and the
resulting residue was redissolved in CH.sub.2Cl.sub.2, washed with
saturated aqueous NaHCO.sub.3, dried (MgSO.sub.4) and evaporated to
give the title compound (240 mg) as a yellow solid,
m.p.150.degree.. .delta.H (CDCl.sub.3) 8.70 (1H, s), 8.01 (2H, d, J
8.0 Hz), 7.73 (2H, d, J 8.0 Hz), 7.55 (2H, d, J 8.0 Hz), 7.22 (2H,
d, J 8.0Hz), 2.84 (2H, m), 2.63 (2H, m), 2.52 (4H, m) and 1.51 (6H,
s).
[0197] The pyrimidine used in the above process was prepared by
stirring
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-p--
toluenesulphonyloxyethyl)phenyl]pyrimidine-2-amine (500 mg, 0.8
mmol) with piperidine (400 ml, 4 mmol) in DMF (5 mL) at 70.degree.
for 4 h. The solvent was then removed under reduced pressure and
the resulting residue was redissolved in CH.sub.2Cl.sub.2, washed
with saturated aqueous NaHCO.sub.3, saturated brine, dried
(MgSO.sub.4) and concentrated under reduced pressure. The resulting
residue was subjected to column chromatography (silica 7% MeOH in
dichloromethane) to give the desired material (392 mg) as a yellow
solid, m.p. 142.degree.. .delta.H (CDCl.sub.3) 8.67 (1H, s), 8.05
(2H, d, J 8.3 Hz), 7.58-7.55 (4H, m), 7.22 (2H, d, J 8.5 Hz), 5.00
(1H, s), 2.88-2.82 (2H, m), 2.63-2.52 (6H, m), 1.66 (12H, bs) and
1.48-1.39 (9H, m).
[0198] The tosylate used in the above process was prepared by
stirring
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-hy-
droxyethyl)phenyl]pyrimidine-2-amine (4.02 g, 8.5 mmol),
4-toluenesulphonyl chloride (2.43 g, 12.7 mmol) and
4-dimethylaminopyridine (150 mg) in dichloromethane (70 ml) at
ambient temperature for 12 h. The reaction was diluted with
dichloromethane (70 mL) and washed with 2M hydrochloric acid (150
mL). The organic phase was separated and washed with 2M
hydrochloric acid, brine and water, dried (MgSO.sub.4) and
concentrated under reduced pressure. The resulting residue was
subjected to column chromatography (silica 40% ethyl
acetate-hexane) to give the desired material (3.6 g) as a yellow
solid 134.degree.. .delta.H (CDCl.sub.3) 8.68 (1H, s), 8.05 (2H,
m), 7.72 (2H, d, J 8.4 Hz), 7.57 (4H, t, J 8.5 Hz), 7.29 (2H, d, J
8.0Hz), 7.15 (2H, d, J 8.5Hz), 5.00 (1H, s), 4.22 (2H, t, J 7.1
Hz), 2.96 (2H, t, J 7.1 Hz), 2.42 (3H, s), 1.67 (6H, bs) and 1.56
(9H).
[0199] The pyrimidine used in the above process was prepared from
4-(2-hydroxyethyl)phenylguanidinium nitrate (3.73 g, 15.4 mmol),
1-[4-(1-tert-butoxy-carbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethy-
lamino propenone (5.0 g, 14.0 mmol) and powdered sodium hydroxide
(672 mg 16.8 mmol) to give the desired product (7.7 g) as a pale
yellow solid, m.p. 114.degree..
[0200] The following compounds of Examples 25-41 and their
respective intermediates were prepared in an analogous manner to
those in Example 24 except where otherwise indicated:
EXAMPLE 25
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-imidazol-1-ylethyl)phe-
nyl]pyrimidine-2-amine
[0201] From
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-
-N-[4-(2-imidazol-1-ylethyl)phenyl]pyrimidine-2-amine (370 mg, 0.71
mmol) to give the title compound (290 mg) as a pale yellow solid
m.p. 184.degree.. .delta.H (d.sup.6 DMSO) 10.51 (1H, s), 8.90 (1H,
s), 8.02 (2H, d, J 8.0 Hz), 7.73 (2H, d, J 8.0 Hz), 7.62 (2H, d, J
8.0 Hz), 7.41 (1H, s), 7.13 (3H, m), 6.81 (1H, s), 4.22 (2H, t, J
7.0 Hz), 3.0 (2H, t, J 7.0 Hz) and 1.6 (6H, s).
[0202]
4-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-
-(2-imidazol-1-ylethyl)phenyl]pyrimidine-2-amine was prepared from
4-[4-(1-tert-butoxy
carbonyl-amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2--
p-toluenesulphonyloxyethyl)phenylpyrimidine-2-amine (500 mg, 0.8
mmol) and imidazole (272 mg, 4.0 mmol) as a yellow solid (380 mg),
m.p. 124.degree.. .delta.H (CDCl.sub.3) 8.68 (1H, s), 8.04 (2H, m),
7.66-7.56 (4H, m), 7.32 (1H, s), 7.04 (3H, m), 6.85 (1H, t, J 1.3
Hz), 5.03 (1H, s), 4.18 (2H, t, J 7.0 Hz), 3.05 (2H, t, J 7.0 Hz),
1.66 (6H, bs) and 1.39 (9H, bs).
EXAMPLE 26
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-morpholinoethyl)phenyl-
]pyrimidine-2-amine
[0203] From
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-
-N-[4-(2-morpholinoethyl)phenyl]pyrimidine-2-amine (430 mg) to give
the title compound (392 mg) as a pale yellow solid m.p.
156.degree.. .delta.H (d.sup.6 DMSO) 10.40 (1H, s), 8.91 (1H, s),
7.93 (2H, d, J 8.4 Hz), 7.74 (2H, d, J 8.4 Hz), 7.64 (2H, d, J 7.8
Hz), 7.19 (2H, d, J 8.5 Hz), 3.56 (4H, m), 3.36 (8H, bm), 2.70 (2H,
t, J 7.5 Hz), 2.51-2.46 (2H, m) and 1.49 (6H, s).
[0204]
4-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-
-(2-morpholinoethyl)phenyl]pyrimidine-2-amine was prepared from
4-[4-(1-tert-butoxy
carbonyl-amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2--
ptoluene-sulphonyloxyethyl)phenyl]pyrimidine-2-amine (500 mg, 0.80
mmol) and morpholine (350 .mu.L, 4.0 mmol) as a yellow solid (440
mg), m.p. 200.degree.. .delta.H (CDCl.sub.3 ) 8.66 (1H, s), 8.05
(2H, d, J 8.3 Hz), 7.69 (1H, s), 7.58-7.55 (4H, m), 7.21 (2H, d, J
8.5Hz), 5.04 (1H, s), 3.74 (4H, t, J4.7hz), 2.83-2.78 (2H, m),
2.63-2.57 (2H, m), 2.53 (4H, t, J 4.7 Hz), 1.65 (6H, bs) and 1.38
(9H, bs).
EXAMPLE 27
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-ethylimidazol
-1-yl)ethyl]phenyl}pyrimidine-2-amine
[0205] From
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-
-N-{4-[2-(2-ethylimidazol-1-yl)ethyl]phenyl}pyrimidine-2-amine to
give the title compound (310 mg) as a yellow solid m.p.
138.degree.. .delta.H (d.sup.6 DMSO) 10.51 (1H, s), 8.91 (1H, s),
8.00 (2H, d, J 8.0 Hz), 7.71 (2H, d, J 8.0 Hz), 7.62 (2H, d, J 8.0
Hz), 7.11 (2H, d, J8.0 Hz), 7.03 (1H, s), 6.71 (1H, s), 4.12 (2H,
t, J 7.0 Hz), 3.33 (bs), 2.91 (2H, t, J 7.0 Hz), 2.40 (2H, t, J 7.0
Hz), 1.62 (6H, s) and 1.11 (3H, t, J 7.0 Hz).
[0206]
4-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-{4-
-[2-(2-ethyl-imidazol-1-yl)ethyl]phenyl}pyrimidine-2-amine was
prepared from
4-[4-(1-tert-butoxycarbonyl-amino-1-methylethyl)phenyl]-5-cyano-N-[4-
-(2-p[toluene-sulphonyloxyethyl)phenyl]pyrimidine-2-amine (500 mg,
0.80 mmol) and 2-ethylimidazole (383 mg) to give the title compound
(400 mg) as a yellow solid, m.p. 210.degree.. .delta.H (CDCl.sub.3)
8.68 (1H, s), 8.05 (2H, d, J 8.4 Hz), 7.60-7.56 (5H, bm), 7.05 (2H,
d, J 8.4 Hz), 6.94 (1H, d, J 1.3 Hz), 6.76 (1H, d, J 1.3 Hz), 5.00
(1H, s), 4.07 (2H, t, J 7.1 Hz), 3.00 (2H,t, J 7.1 Hz), 2.49 (2H,
q, J 7.5 Hz), 1.67 (6H, bs), 1.39-1.23 (9H,bm) and 0.88 (3H, t, J
7.0 Hz).
EXAMPLE 28
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-4-(2-imidazol-1-ylethoxy)phe-
nylpyrimidine-2-amine
[0207] From
4-(4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-
-N-4-(2-imidazol-1-ylethoxy)phenyl]pyrimidine-2-amine (857 mg, 1.59
mmol) to give the title compound (566 mg) as a yellow solid, m.p.
208-209.degree.. .delta.H (d.sup.6 DMSO) 10.32 (1H,bs), 8.86
(1H,s), 7.89 (2H, d, J 8.5 Hz), 7.73 (2H, d, J 8.5 Hz), 7.67-7.63
(3H, m), 7.23 (1H, s), 6.94-6.88 (3H, m), 4.33 (2H, t, J 5.0 Hz),
4.22 (2H, t, J 5.1 Hz), 2.01 (2H, bs) and 1.40 (6H, s).
[0208]
4-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-
-(2-imidazol-1-yl-ethoxy)phenyl]pyrimidine-2-amine was prepared
from 4-[4-(1-tert-butoxycarbonyl
amino-1-methyl-ethyl)phenyl]-5-cyano-N-{4-[(2-
-p-toluene-sulphonyloxy)ethoxy]phenyl}pyrimidine-2-amine (2.0 g,
3.1 mmol) and imidazole (1.02 g, 15 mmol) as a yellow solid (870
mg). .delta.H (d.sup.6 DMSO) 10.34 (1H, s), 8.88 (1H, s), 7.90 (2H,
d, J 8.5 Hz), 7.68-7.64 (3H, m), 7.53 (2H, d, J 8.5 Hz), 7.31 (1H,
bs), 7.24 (1H, t, J 1.1 Hz), 6.93 (2H, d, J 9.0 Hz), 6.89 (1H, t, J
1.0 Hz), 4.35 (2H, t, J 5.2 Hz), 4.23 (2H, t, J 5.2 Hz), 1.54 (6H,
s) and 1.34 (9H, bs).
[0209]
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-{4-
-[(2-p-toluenesulphonyloxy)ethoxyl]phenyl}pyrimidine-2-amine was
prepared from
4-[4-(1-tert-butoxy-carbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-
-(2-hydroxyethoxy)phenyl]-pyrimidine-2-amine (2.1 g, 4.29 mmol) and
4-toluene sulphonylchloride (1.24 g, 6.5 mmol) as a yellow solid
(2.10 g), m.p. 145-146.degree..
[0210]
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-
-(2-hydroxyethoxy)phenyl]pyrimidine-2-amine was prepared from
1-[4-(1-tert-butoxycarbonyl
amino-1-methylethyl)phenyl]-5-cyano-3-dimethy- laminopropenone
(2.16 g, 8.0 mmol), 4-(2-hydroxyethoxy)phenylguanidinium nitrate
(2.08 g, 8.0 mmol) and sodium hydroxide (320 mg, 8.0 mmol) as a
pale green solid (2.28 g), m.p. 126-127.degree.. .delta.H
(CDCl.sub.3) 8.64 (1H, s), 8.06-8.02 (2H, m), 7.58-7.51 (5H, m),
6.97-6.94 (2H, m), 5.03 (1H, bs), 4.14 (2H,t, J 5.2 Hz), 4.00-3.95
(2H, bm), 2.12 (1H, bs), 1.68 (6H, s) and 1.38 (9H, bs).
[0211] The guanidine used in the above process was prepared by
heating a solution of 4-(2-hydroxyethoxy)aniline (38.0 g, 0.25
mmol), cyanamide (17.67 g, 0.421 g) in 25 mL water, and
concentrated HNO.sub.3 (17.8 mL, 0.27 mmol) in ethanol (350 mL) for
24 h. The reaction was cooled to 0.degree. and diluted with ether
(350 mL). The resulting solid was collected by filtration and dried
to give the desired material as a purple solid (42.45 g). .delta.H
(d.sup.6 DMSO) 9.34 (1H, s), 7.18 (4H, bs), 7.16-7.12 (2H, m),
7.01-6.96 (2H, m), 4.85 (1H, t, J 5.3 Hz), 3.98 (2H, t, J 5.2 Hz)
and 3.70 (2H, t, J 5.0 Hz).
EXAMPLE 29
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[3-(2-morpholinoethyl)phenyl-
]pyrimidine-2-amine
[0212] From
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-
-N-[3-(2-morpholinoethyl)phenyl]pyrimidine-2-amine (400 mg, 0.73
mmol) to give the title compound (250 mg) as a pale yellow solid
m.p. 166-167.degree.. .delta.H (CDCl.sub.3) 8.69 (1H, s), 8.05 (2H,
d, J 8.5 Hz), 7.68 (2H, d, J 8.7 Hz), 7.61 (1H, bs), 7.53-7.48 (2H,
m), 7.30 (1H, t, J 7.8 Hz), 7.00 (1H, d, J 7.5 Hz), 3.76-3.73 (4H,
m), 2.87-2.81 (2H, m), 2.67-2.61 (2H, m), 2.55-2.52 (4H, m), 1.83
(2H, bs) and 1.54 (6H, s).
[0213]
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[3-
-(2-morpholinoethyl)phenyl]pyrimidine-2-amine was prepared from
4-[4-(1-tert-butoxy
carbonyl-amino-1-methylethyl)phenyl]-5-cyano-N-[3-(2--
p-toluene-suphonyloxyethyl)phenyl]pyrimidine-2-amine (500 mg, 0.84
mmol) and morpholine (293 .mu.L, 3.36 mmol) as a yellow solid (413
mg). .delta.H (CDCl.sub.3) 8.68 (1H, s), 8.06 (2H, d, J 8.2 Hz),
7.58-7.51 (5H, m), 7.30 (1H, t, J 7.8 Hz), 7.00 (1H, d, J 7.7 Hz),
5.04 (1H, bs), 3.76-3.73 (4H, m), 2.86-2.81 (2H, m), 2.66-2.61 (2H,
m), 2.55-2.52 (4H, m), 1.65 (6H, s) and 1.39 (9H, bs).
[0214]
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[3-
-(2-p-toluenesuphonyloxyethyl)phenyl]pyrimidine-2-amine was
prepared from
4-[4-(1-tert-butoxy-carbonylamino-1-methylethyl)phenyl]-5-cyano-N-[3-(2-h-
ydroxyethyl phenyl]pyrimidine-2-amine (880 mg) and
4-toluenesulphonyl-chlo- ride (572 mg, 3.0 mmol) as yellow solid
(945 mg). .delta.H (CDCl.sub.3) 8.68 (1H, s), 8.06 (2H, d, J 7.9
Hz), 8.06 (2H, d, J 7.9 Hz), 7.60-7.53 (4H, m), 7.43 (1H, bs),
7.29-7.24 (3H, m), 6.90 (1H, d, J 7.0 Hz), 5.04 (1H, bs), 4.26 (2H,
t, J 6.8 Hz), 2.98 (2H, t, J 7.0 Hz), 2.39 (3H, s), 1.66 (6H, s)
and 1.39 (9H, bs).
[0215]
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[3-
-(2-hydroxyethyl)phenyl]pyrimidine-2-amine was prepared from
4-[4-(1-tert-butoxycarbonyl
amino-1-methyl-ethyl)phenyl]-5-cyano-N-[3-(hy-
droxyethoxy)phenyl]pyrimidine-2-amine (2.0 g, 5.6 mmol),
3-(2-hydroxyethyl)phenylguanidinium nitrate (1.6 g, 5.6 mmol) and
sodium hydroxide (336 mg, 8.4 mmol) as a yellow solid (980 mg),
m.p. 164-164.degree.. .delta.H (CDCl.sub.3) 8.66 (1H, s), 8.05 (2H,
d, J 8.4 Hz), 7.71 (1H, bs), 7.59-7.51 (4H, m), 7.32 (1H, t, J 7.9
Hz), 7.01 (1H, d, J 7.7 Hz), 5.06 (1H, bs), 3.89 (2H, t, J 6.5 Hz),
2.89 (2H, t, J 6.5 Hz), 1.65 (6H, s) and 1.39 (9H, bs).
EXAMPLE 30
5-Cyano-4-phenyl-N-[4-(2-piperidin-1-ylethyl)phenyl]pyrimidine-2-amine
[0216] From
5-cyano-4-phenyl-N-[4-(2-p-toluenesulphonyloxyethyl)phenyl]pyr-
imidine-2-amine (800 mg, 1.70 mmol) and piperidine (0.84 mL, 8.5
mmol) to give the title compound (367 mg) as a pale yellow solid,
m.p. 124-125.degree.. .delta.H (CDCl.sub.3) 8.69 (1H, s), 8.05 (2H,
d, J 6.8 Hz), 7.60-7.51 (6H, m), 7.22 (2H, d, J 8.4 Hz), 2.87-2.83
(2H, m), 2.61-2.50 (6H, m), 1.66 (4H, bs) and 1.48-1.43 (2H,
m).
[0217]
5-Cyano-4-phenyl-N-[4-(2-p-toluenesulphonyloxyethyl)phenyl]pyrimidi-
ne-2-amine was prepared from
5-cyano-4-phenyl-N-[4-(2-hydroxyethyl)-phenyl- ]pyrimidine-2-amine
(3.30 g, 10.43 mmol) and 4-toluenesulphonylchloride (2.19 g, 11.47
mmol) as a pale yellow solid (3.91 g) m.p. 134-135.degree..
.delta.H (d.sup.6 DMSO) 8.69 (1H, s), 8.05 (2H, dd, J 6.0, 2.0 Hz),
7.72 (2H, d, J 8.3 Hz), 7.61-7.51 (6H, m), 7.29 (2H, d, J 8.1 Hz),
7.14 (2H, d, J 8.5 Hz), 4.21(2H, t, J 7.0 Hz), 2.95 (2H, t, J 7.0
Hz) and 2.41 (3H, s).
[0218]
5-Cyano-4-phenyl-N-[4-(2-hydroxyethyl)phenyl]pyrimidine-2-amine was
prepared from 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (4.0 g,
20 mmol), 4-(2-hydroxyethyl)phenyl-guanidinium nitrate (4.24 g, 20
mmol) and sodium hydroxide (800 mg, 20.0 mmol) as a yellow solid
(3.50 g), m.p. 142-143.degree.. .delta.H (CDCl.sub.3) 8.68 (1H, s),
8.03 (2H, dd, J 6.0, 2.0 Hz), 7.66 (1H, bs), 7.59-7.51 (5H, m),
7.23 (2H, m), 3.88 (2H, t, J 6.5 Hz), 2.87 (2H, t, J 6.5 Hz) and
1.62 (2H, bs).
EXAMPLE 31
5-Cyano-4-phenyl-N-[4-(2-imidazol-1-ylethyl)phenyl]pyrimidine-2-amine
[0219] From
5-cyano-4-phenyl-N-[4-(2-p-toluenesulphonyloxyethyl)phenyl]-py-
rimidine-2-amine (800 mg, 1.70 mmol) and imidazole (578 mg, 8.50
mmol) to give the title compound (378 mg) as a yellow solid m.p.
210-211.degree.. .delta.H (CDCl.sub.3/d.sup.6 DMSO) 10.28 (1H, bs),
8.74 (1H, s), 7.99 (1H, s), 7.94 (1H, d, J 6.7 Hz), 7.65 (2H, d, J
8.74 Hz), 7.57-7.49 (2H, d, J 6.7 Hz), 7.03 (2H, d, J 8.4 Hz), 6.98
(1H, s), 6.85 (1H, t, J 0.9 Hz), 4.16 (2H, t, J 7.1 Hz) and 2.97
(2H, t, J 7.1 Hz).
EXAMPLE 32
5-Cyano-4-phenyl-N-{4-[2-(2-ethylimidazol-1-yl)ethyl]phenyl}-pyrimidine-2--
amine
[0220] From
5-cyano-4-phenyl-N-[4-(2-p-toluenesulphonyloxyethyl)phenyl]-py-
rimidine-2-amine (800 mg, 1.70 mmol) and 2-ethylimidazole (817 mg,
8.5 mmol) to give the title compound (480 mg) as a yellow solid,
m.p. 190-192.degree.. .delta.H (CDCl.sub.3) 8.72 (1H, s), 8.07 (2H,
dd, J 5.4, 1.4 Hz), 7.75 (1H, bs), 7.62-7.54 (5H, m), 7.06 (2H, d,
J 8.5 Hz), 6.98 (1H, d, J 1.3 Hz), 6.79 (1H, d, J 1.3 Hz), 4.09
(2H, t, J 7.0 Hz), 3.02 (2H, t, J 7.0 Hz), 2.51 (2H, q, J 7.6 Hz)
and 1.27 (3H, t, J 7.6 Hz).
EXAMPLE 33
5-Cyano-4-phenyl-N-{4-[2-(1,2,4-triazol-1-ylethyl)phenyl}pyrimidine-2-amin-
e
[0221] From
5-cyano-4-phenyl-N-[4-(2-p-toluenesulphonyloxyethyl)phenyl]-py-
rimidine-2-amine (500 mg, 1.12 mmol) and 1,2,4-triazole, sodium
salt (122 mg, 1.35 mmol) to give the title compound (188 mg) as a
yellow solid, m.p. 217-218.degree.. .delta.H (d.sup.6 DMSO) 10.48
(1H, s), 8.94 (1H, s), 8.33 (1H, s), 7.96 (3H, m), 7.68-7.59 (5H,
m), 7.11 (2H, d, J 8.5 Hz), 4.42 (2H, t, J 7.1 Hz) and 3.08 (2H, t,
J 7.1 Hz).
EXAMPLE 34
5-Cyano-4-phenyl-N-[4-(2-imidazol-1-ylethoxy)phenyl]pyrimidine-2-amine
[0222] From
5-cyano-4-phenyl-N-[4-(2-p-toluenesulphonyloxyethoxy)phenyl]-p-
yrimidine-2-amine (1.54 g, 3.17 mmol) and imidazole (1.08 g, 15.8
mmol) to give the title compound (790 mg) as a yellow solid, m.p.
185.degree.. .delta.H (CDCl.sub.3) 8.67 (1H, s), 8.04 (2H, d, J 8.1
Hz), 7.60 (1H, s), 7.58-7.52 (5H, m), 7.45 (1H, s). 7.07 (1H, s),
7.05 (1H, t, J 1.2 Hz), 6.91 (1H, d, J 2.2 Hz), 6.88 (1H, d, J 2.2
Hz), 4.35 (2H, t, J 5.0 Hz) and 4.23 (2H, t, J 5.0 Hz).
[0223]
5-cyanophenyl-N-[4-(2-p-toluenesulphonyloxyethoxy)phenyl]pyrimidine-
-2-amine was prepared from
5-cyano-4-phenyl-N-[4-(2-hydroxy-ethoxy)phenyl]-
-pyrimidine-2-amine (1.42 g, 4.28 mmol) and 4-toluene-sulphonyl
chloride (1.23 g, 6.4 mmol) as a yellow solid, m.p. 147.degree..
.delta.H (CDCl.sub.3) 8.67 (1H, s), 8.05-8.03 (2H, m), 7.83 (2H,
dd, J 6.5, 1.8 Hz), 7.58-7.49 (6H, m), 7.35 (2H, dd, J 8.6, 0.9
Hz), 6.83 (2H, d, J 0.9 Hz), 4.38-4.36 (2H, m), 4.18-4.16 (2H, m)
and 2.45 (3H, s).
[0224]
5-cyano-4-phenyl-N-[4-(2-hydroxyethoxy)phenyl]pyrimidine-2-amine
was prepared from 1-phenyl-2-cyano-3-dimethylaminopropen-1-one
(1.41 g, 7.0 mmol), 4-(2-hydroxy-ethoxy) phenylguanidinium nitrate
(2.0 g, 7.7 mmol) and sodium hydroxide (340 mg, 8.4 mmol) to give a
yellow solid (1.54 g), m.p. 151.degree.. .delta.H (CDCl) 8.67 (1H,
s), 8.04 (2H, d, J 7.7 Hz), 7.58-7.52 (5H, m), 7.45 (1H, s), 6.95
(2H, dd, J 6.7, 2.3 Hz), 4.12-4.09 (2H, m), 4.00-3.97 (2H, m) and
2.05-2.01 (1H, m).
EXAMPLE 35
5-Cyano-N-{4-[2-(2-ethylimidazol-1-yl)ethoxy]phenyl}-4-thien-2-yl
pyrimidine-2-amine
[0225] From
5-cyano-N-[4-(2-p-toluenesulphonyloxyethoxy)phenyl]-4-thien-2-- yl
pyrimidine-2-amine (1.5 g, 3.0 mmol) and 2-ethylimidazole (1.46 g,
15.2 mmol) to give the title compound (0.94 g) as a pale yellow
solid, m.p. 205.degree.. .delta.H (CDCl.sub.3) 8.59 (1H, s), 8.41
(1H, d, J 4.0 Hz), 7.63 (1H, d, J 5.0 Hz), 7.53 (2H, m), 7.37 (1H,
s), 7.22 (1H, m), 6.97 (2H, d, J 6.5 Hz), 6.88 (2H, d, J 9.0 Hz),
4.24 (4H, dd, J 6.8, 4.3 Hz), 2.78 (2H, q, J 7.8 Hz) and 1.39 (3H,
t, J 7.5 Hz).
[0226]
5-cyano-N-[4-(2-p-toluenesulphonyloxyethoxy)phenyl]-4-thien-2-ylpyr-
imidin-2-amine was prepared from
5-cyano-N-[4-(2-hydroxyethoxy)-phenyl]-4--
thien-2-ylpyrimidine-2-amine (8.02 g, 23.7 mmol) and
4-toluene-sulphonylchloride (9.0 g, 47.4 mmol) to give a yellow
solid (4.97 g), m.p. 160.degree.. .delta.H (d.sup.6 DMSO) 10.32
(1H, s), 8.84 (1H, s), 8.26 (1H, d, J 3.9 Hz), 7.99 (1H, d, J 5.0
Hz), 7.80 (2H, d, J 8.3 Hz), 7.64 (2H, m), 7.47 (2H, d, J 8.3 hz),
7.33 (1H, t, J 4.5 Hz), 6.85 (2H, d, J 9.0 Hz), 4.33 (2H, t, J 4.0
Hz), 4.15 (2H, m) and 2.41 (3H, s).
EXAMPLE 36
5-Cyano-N-[4-{2-(2-methylimidazol-1-ylethoxy}phenyl]-4-thien-2-ylpyrimidin-
e-2-amine
[0227] From
5-cyano-N-[4-(2-p-toluenesulphonyloxyethoxy)phenyl]-4-thien-2--
ylpyrimidin-2-amine (2.0 g, 4.07 mmol) and 2-methylimidazole (1.67
g, 5 mmol) to give the title compound (0.87 g) as a yellow solid,
m.p. 190.degree.. .delta.H (d.sup.6 DMSO) 10.30 (1H, bs), 8.83 (1H,
s), 8.25 (1H, d, J 3.8 Hz), 7.97 (1H, d, J 5.0 Hz), 7.65 (1H, bs),
7.32 (1H, t, J 4.0 hz), 7.10 (1H, s), 6.93 (2H, d, J 8.7 Hz), 6.72
(1H, s), 4.23 (4H, m) and 2.32 (3H, s).
EXAMPLE 37
5-Cyano-N-[4-(2-imidazol-1-ylethoxy)phenyl]-4-thien-2-ylpyrimidine-2-amine
[0228] From
5-cyano-N-(4-(2-p-toluenesulphonyloxyethoxy)phenyl]-4-thien-2--
ylpyrimidin-2-amine (2.45 g, 5.0 mmol) and imidazole (1.7 g, 25
mmol) to give the title compound (1.0 g) as a yellow solid, m.p.
199-200.degree.. .delta.H (d.sup.6 DMSO) 9.90 (1H, bm), 8.76 (1H,
d, J 1.0 Hz), 8.26 (1H, m), 7.92 (1H, dd, J 5.0, 1.1 Hz), 7.65 (3H,
m), 7.31 (1H, dd, J 5.0, 3.8 Hz), 7.20 (1H, t, J 1.2 Hz), 6.94 (3H,
m), 4.36 (2H, m) and 4.30 (2H, m).
EXAMPLE 38
5-Cyano-N-[-4-(2-(1,2,4-triazol-yl)ethoxy)phenyl]-4-thien-2-ylpyrimidine-2-
-amine
[0229] From
5-cyano-N-[4-(2-p-toluenesulphonyloxyethoxy)phenyl[-4-thien-2--
ylpyrimidin-2-amine (1.29 g, 3.6 mmol) and 1,2,4-triazole sodium
salt (990 mg, 10.9 mmol) to give the title compound (500 mg) as a
yellow solid, m.p. 180-182.degree.. .delta.H (d.sup.6 DMSO) 8.84
(1H, s), 8.56 (1H, s), 8.24 (1H, d, J 4.0 Hz), 7.98-7.99 (2H, m),
7.63 (2H, bs), 7.32 (1H, dd, J 4.0 Hz), 6.92 (2H, d, J 8.8 Hz),
4.57 (2H, t, J 5.1 Hz) and 4.34 (2H, t, J 5.1 Hz).
EXAMPLE 39
5-Cyano-N-[4-(2-(1,3,4-triazol-1-yl)ethoxy)phenyl]-4-thien-2-ylpyrimidine--
2amine
[0230] From the same reactants in Example 38 and produced as as a
side product the title compound was obtained (100 mg) as a yellow
solid, m.p. 228.degree.. .delta.H (d.sup.6 DMSO) 8.84 (1H, s), 8.56
(2H, s), 8.25 (1H, d, J 3.9 Hz), 7.98 (1H, d, J 4.9 Hz), 7.65 (2H,
bs), 7.33 (1H, t, J 4.5 Hz), 6.95 (2H, d, J 8.9 Hz), 4.44 (2H, t, J
5.0 Hz), and 4.26 (2H, t, J 5.0 Hz).
EXAMPLE 40
5-Cyano-N-{4-[2-(1H-imidazol-2-ylamino)ethoxy]phenyl}-4-thien-2-ylpyrimidi-
ne-2-amine
[0231] From
5-cyano-N-[4-(2-p-toluenesulphonyloxyethoxy)phenyl]-4-thien-2--
ylpyrimidin-2-amine (500 mg, 0.78 mmol), and 2-aminoimidazole
sulphate (500 mg, 3.78 mmol) and potassium carbonate (522 mg, 3.78
mmol) to give the title compound (170 mg) as a yellow solid, m.p.
140.degree.. .delta.H 8.84 (1H, s), 8.25 (1H, d, J 4.0 Hz), 7.98
(1H, d, J 5.0 Hz), 7.76-7.60 (2H, m), 7.35-7.32 (1H, m), 6.93 (2H,
d, J 8.7 Hz), 6.64 (1H, s), 6.36 (1H, s), 5.34 (1H, m) and 4.08
(4H, m).
EXAMPLE 41
5-Cyano-N-[4-(2-imidazol-1-ylethylphenyl]-4-thien-2-ylpyrimidine-2-amine
[0232] From
5-cyano-[4-thien-2-yl-N-[4-(2-p-toluenesulphonyloxyethyl)pheny-
l]pyrimidine-2-amine (550 mg, 1.15 mmol) and imidazole (393 mg,
5.77 mmol) to give the title compound (300 mg) as a yellow solid,
m.p. 187.degree.. .delta.H (CDCl.sub.3) 8.62 (1H, s), 8.43 (1H, dd,
J 3.2, 1.0 Hz), 7.65 (1H, dd, J 5.9, 0.0 Hz), 7.59 (2H, d, J 8.2
Hz), 7.51 (1H, s), 7.35 (1H, s), 7.24 (1H, dd, J 4.0, 1.0 Hz),
7.10-7.05 (3H, m), 6.85 (1H, s), 4.19 (2H, t, J 7.0 Hz) and 3.06
(2H, t, J 7.0 Hz).
[0233]
5-Cyano-4-thien-2-yl-N-[4-(2-p-toluenesulphonyloxyethyl)phenyl]pyri-
midine-2-amine was prepared from
5-cyano-N-[4-(2-hydroxyethyl)-phenyl]-4-t-
hien-2-ylpyrimidine-2-amine (1.39 g, 4.30 mmol) and
4-toluenesulphonylchloride (1.23 g, 6.5 mmol) as a yellow solid
(1.15 g), m.p. 190.degree.. .delta.H (CDCl.sub.3) 8.62 (1H, s),
8.43 (1H, dd, J 3.1, 1.0 Hz), 7.66-7.61 (3H, m), 7.45 (1H, s),
7.28-7.22 (3H, m), 3.73 (2H, t, J 7.3 Hz) and 3.09 (2H, t, J 7.3
Hz).
[0234]
5-cyano-N-[4-(2-hydroxyethyl)phenyl]-4-thien-2-ylpyrimidine-2-amine
was prepared from 1-thien-2-yl-2-cyano-3-dimethylaminopropen-1one
(2.17 g, 10.5 mmol), 4-(2-hydroxy-ethyl)phenylguanidinium nitrate
(2.8 g, 11.6 mmol) and powdered sodium hydroxide (505 mg) as a
yellow solid, m.p. 178.degree.. .delta.H (d.sup.6 DMSO) 10.36 (1H,
s), 8.86 (1H, s), 8.26 (1H, m), 8.00 (1H, d, J 4.1 Hz), 7.64 (2H,
m), 7.33 (1H, dd, J 4.0, 1.0 Hz), 7.20 (2H, d, J 8.4 Hz), 4.60 (1H,
t, J 5.2 Hz), 3.58 (2H, t, J 7.0 Hz) and 2.69 (2H, t, J 7.0
Hz).
[0235] The compounds following Examples 42-71 were prepared in a
similar manner to the compound of Example 1:
EXAMPLE 42
5-Cyano-N-[4-(imidazol-1-yl)phenyl]-4-phenylpyrimidine-2-amine
[0236] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (1.5 g,
7.49 mmol), 4-imidazol-1-ylphenylguanidinium nitrate (2.45 g, 7.40
mmol) and sodium hydroxide (600 mg, 15 mmol) to give the title
compound (1.40 g) as a yellow solid, m.p. 278-280.degree.. .delta.H
10.69 (1H, bs), 9.00 (1H, s), 8.21 (1H, s), 7.98-7.91 (4H, m),
7.70-7.60 (6H, m) and 7.10 (1H, s).
EXAMPLE 43
5-Cyano-N-[4-(2-dimethylaminoethoxy)phenyl]-4-phenyl
pyrimidine-2-amine
[0237] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (250 mg,
1.25 mmol), 4-(2-dimethylaminoethoxy)phenylguanidinium nitrate (523
mg, 1.25 mmol) and sodium hydroxide (108 mg, 2.7 mmol) to give the
title compound (230 mg) as a yellow solid, m.p. 152-153.degree..
.delta.H (d.sup.6 DMSO) 10.37 (1H, s), 8.40 (1H, s), 7.94 (2H, m),
7.62 (5H, m), 6.94 (2H, dt, J 9.0, 2.0 Hz), 4.02 (2H, t, J 5.8 Hz),
2.61 (2H, t, J 5.8 Hz) and 2.21 (6H, s).
EXAMPLE 44
5-Cyano-N-[3,5-dimethyl-4-(2-morpholinoethoxy)phenyl]-4-phenylpyrimidine-2-
-amine
[0238] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (250 mg,
1.25 mmol), 3,5-dimethyl-4-(2-morpholinoethoxy)phenylguanidinium
nitrate (523 mg, 1.25 mmol) and sodium hydroxide (108 mg, 2.7 mmol)
to give the title compound (317 mg) as a yellow solid, m.p.
160-162.degree.. .delta.H (d.sup.6 DMSO) 10.32 (1H, s), 8.92 (1H,
s), 7.96 (2H, m), 7.64-7.59 (3H, m), 7.42 (2H, bs), 3.83 (2H, t, J
5.7 Hz), 3.59 (4H, t, J 4.6 Hz), 2.68 (2H, t, J 5.7 Hz), 2.50 (4H,
m) and 2.23 (6H, s).
EXAMPLE 45
5-Cyano-N-[3,5-dimethoxyphenyl]-4-phenylpyrimidine-2-amine
[0239] From 1-phenyl-2-cyano-3dimethylaminopropen-1-one (250 mg,
1.25 mmol), 3,5-dimethoxyphenylguanidinium nitrate (321 mg, 1.4
mmol) and sodium hydroxide (56 mg, 1.4 mmol) to give the title
compound (280 mg) as a yellow solid m.p. 206-207.degree.. .delta.H
(d.sup.6 DMSO) 10.47 (1H, s), 8.98 (1H, s), 7.99 (2H, m), 7.63 (3H,
m), 7.13 (2H, bs), 6.25 (1H, t, J 2.2 Hz) and 3.78 (3H, s).
EXAMPLE 46
5-Cyano-N-[3,4-dimethoxyphenyl]-4-phenylpyrimidine-2-amine
[0240] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (250 mg,
1.25 mmol), 3,4-dimethoxyphenylguanidinium nitrate (348 mg, 1.25
mmol) and sodium hydroxide (56 mg) to give the title compound (107
mg) as an orange solid, m.p. 155-157.degree.. .delta.H (d.sup.6
DMSO) 9.78 (1H, bs), 8.80 (1H, s), 8.00 (2H, m), 7.63-7.51 (3H, m),
7.25 (1H, dd, J 8.7, 2.5 mmol), 6.94 (1H, d, J 8.7 mmol), 3.79 (3H,
s) and 3.78 (3H, s).
EXAMPLE 47
5-Cyano-4-phenyl-N-[phenyl]pyrimidine-2-amine
[0241] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (1.0 g,
5.0 mmol), phenylguanidinium nitrate (830 mg, 2.5 mmol) and sodium
hydroxide (200 mg, 5.0 mmol) to give the title compound (660 mg) as
a yellow solid, m.p. 160-161.degree.. .delta.H (CDCl.sub.3) 8.71
(1H, s), 8.08-8.05 (2H, m), 7.66-7.51 (6H, m), 7.42-7.36 (2H, m)
and 7.19-7.13 (1H, m).
EXAMPLE 48
5-Cyano-4-indol-3-yl-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine
[0242] From 1-indol-3-yl-2-cyano-3-dimethylaminopropen-1-one (1.0
g, 4.18 mmol), 3,4,5-trimethoxyphenylguanidinium nitrate (1.20 g,
4.18 mmol) and sodium hydroxide (167 mg, 4.18 mmol) to give the
title compound (475 mg) as a yellow solid, m.p. 200-201.degree..
.delta.H (d.sup.6 DMSO) 12.04 (1H, bs), 10.04 (1H, s), 8.77 (1H,
s), 8.52 (1H, s), 8.50 (1H, bs), 7.52 (1H, d, J 8.1 Hz), 7.24 (2H,
t, J 7.4 Hz), 7.12 (2H, bs), 3.70 (6H, s) and 3.66 (3H, s).
[0243] 1-indol-3-yl-2-cyano-3-dimethylaminopropen-1-one was
prepared from 3-(cyanoacetyl) indole (4.0 g, mmol) and
dimethylformamide dimethylacetal (4.1 mL, 23.9 mmol) as a yellow
solid (2.4 g), m.p. 187-188.degree.. .delta.H (d.sup.6 DMSO) 11.73
(1H, bs), 8.26 (1H, s), 8.12 (1H, dd, J 6.8, 1.3 Hz), 7.98 (1H, s),
7.47-7.44 (1H, m), 7.20-7.09 (2H, m), 3.35 (3H, s) and 3.26 (3H,
s).
[0244] 3-(Cyanoacetyl)indole was prepared by suspending indole
(11.71 g, 0.10 mmol) and potassium cyanoacetate (24.6 g, 0.2 mmol)
in acetonitrile (300 mL), and to this methanesulphonylchloride (7.7
mL, 0.1 mmol) was added. The resulting mixture was stirred at
ambient temperature for 1 h, and then sodium carbonate (10 g in 50
mL water) was added. After 5 min, the organic phase was separated,
dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure.
The residue was recrystallised from ethanol (100 mL) to give the
desired material as an orange solid (4.31 g), m.p. 226-227.degree..
.delta.H (d.sup.6 DMSO) 12.20 (1H, bs), 8.38 (1H, d, J 2.8 Hz),
8.14-8.10 (1H, m), 7.53-7.50 (1H, m), 7.25-7.21 (2H, m) and 4.49
(2H, s).
EXAMPLE 49
5-Cyano-4-indol-3-yl-N-[4-(1,2,4-triazol-1-yl)phenyl]pyrimidine-2-amine
[0245] From 1-indol-3-yl-2-cyano-3-dimethylaminopropen-1-one (289
mg, 1.2 mmol), 4-(1,2,4-triazol-1-yl)phenylguanidinium nitrate (320
mg, 1.2 mmol) and sodium hydroxide (48 mg, mmol) to give the title
compound (270 mg) as a yellow solid, m.p. 329-330.degree.. .delta.H
(d.sup.6 DMSO) 12.00 (1H, bs), 10.39 (1H, bs), 9.26 (1H, s), 8.84
(1H, s), 8.55 (2H, bm), 8.28-8.21 (1H, m), 7.96 (2H, d, J 8.8 Hz),
7.86 (2H, d, J 8.8 Hz), 7.56-7.52 (1H, m), 7.28-7.15 (2H, m) and
3.30 (1H, bs).
EXAMPLE 50
5Cyano-4-thiazol-2-yl-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine
[0246] From 2-cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one (300
mg, 13.8 mmol), 3,4,5-trimethoxyphenylguanidinium nitrate (436 mg,
15.2 mmol) and sodium hydroxide (61 mg, 15.2 mmol) to give the
title compound (324 mg) as a yellow solid, m.p. 223.degree..
.delta.H (d.sup.6 DMSO) 10.52 (1H, bs), 9.03 (1H, s), 8.28 (1H, d,
J 3.0 Hz), 8.22 (1H, d, J 3.0 Hz), 7.23 (2H, s), 3.88 (6H, s) and
3.72 (3H, s).
[0247] 2-Cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one was
prepared from 2-cyanoacetyl thiazole (400 mg, 2.94 mmol) and
dimethylformamide dimethylacetal (1.5 mL) as a yellow solid, m.p.
126.degree. .delta.H (CDCl.sub.3) 8.89 (1H, s), 7.96 (1H, d, J 3.3
Hz), 7.60 (1H, d, J 3.1 Hz), 3.54 (3H, s) and 3.35 (3H, s).
[0248] 2-Cyanoacetylthiazole was prepared by heating a solution of
2-ethoxycarbonyl-thiazole (1.08 g, 6.88 mmol), acetonitrile (360
mL, 7.57 mmol) and sodium hydride [60% dispersion in oil] (303 mg,
7.57 mmol) in benzene (20 mL) and DMF (2 mL) at 80.degree. for 90
min. On cooling the resulting precipitate was collected by
filtration and dissolved in water (60 mL). The solution was poured
into cold 2M hydrochloric acid (100 mL) and the resulting
precipitate collected by filtration to give the desired product
(200 mg) as a yellow solid, m.p. 109.degree. .delta.H (CDCl.sub.3)
8.06 (1H, d, J 2.9 Hz), 7.82 (1H, d, J 2.9 Hz) and 4.32 (2H,
s).
EXAMPLE 51
5-Cyano-4thiazol-2-yl-N-[4-(1,2,4-triazol-1-yl)phenyl]pyrimidine-2-amine
[0249] From 2-cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one (300
mg, 1.38 mmol), 4-(1,2,4-triazol-1-yl)phenylguanidinium nitrate
(425 mg, 1.38 mmol) and sodium hydroxide (61 mg, 1.52 mmol) to give
the title compound (381 mg) as a yellow solid, m.p. 331.degree..
.delta.H (d.sup.6 DMSO) 10.86 (1H, bs), 9.30 (1H, s), 9.10 (1H, s),
8.31-8.25 (3H, m), 8.01 (2H, dapp, J 8.6 Hz) and 7.93 (2H, dapp, J
8.6 Hz).
EXAMPLE 52
5-Cyano-N-[3,4-dimethoxyphenyl]-4-thiazol-2-ylpyrimidine-2-amine
[0250] From 2-cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one (500
mg, 2.3 mmol), 3,4-dimethoxyphenylguanidinium nitrate (585 mg, 2.3
mmol) and sodium hydroxide (100 mg, 2.3 mmol) to give the title
compound (721 mg) as yellow solid, m.p. 258.degree.. .delta.H
(d.sup.6 DMSO) 9.98 (1H, bs), 8.66 (1H, s), 7.96 (1H, d, J 3.1 Hz),
7.87 (1H, d, J 3.1 Hz), 7.20 (1H, d, J 1.8 Hz), 6.96-6.93 (1H, m)
and 6.67 (1H, d, J 8.4 Hz) and 5.79 (2H, s).
EXAMPLE 53
5-Cyano-4-thiazol-2-yl-N-{4-[2-(1,2,4triazol-1-yl)ethoxy]phenyl}pyrimidine-
-2-amine
[0251] From 2-cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one (500
mg, 2.3 mmol), 4-[2-(1,2,4-triazol-1-yl)ethoxy]phenylguanidinium
nitrate (714 mg, 2.3 mmol) and sodium hydroxide (100 mg, 2.3 mmol)
to give the title compound (812 mg) as a yellow solid, m.p.
224.degree.. .delta.H (d.sup.6 DMSO) 10.02 (1H, s), 8.70 (1H, s),
8.33 (1H, s), 8.01 (1H, d, J 3.1 Hz), 7.91 (1H, d, J 3.1 Hz), 7.77
(1H, s), 7.47 (2H, d, J 8.8 Hz), 6.79-6.76 (2H, m), 4.41 (2H, t, J
5.2 Hz) and 4.23 (2H, t, J 5.2 Hz).
EXAMPLE 54
5-Cyano-4-thiazol-2-yl-N-{4-[2-(1,2,3-triazol-1-yl)ethoxy]phenyl}pyrimidin-
e-2-amine
[0252] From 2-cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one (700
mg, 3.2 mmol), 4-[2-(1,2,3-triazol-1-yl)ethoxy]phenylguanidinium
nitrate (1.0 g, 3.2 mmol) and sodium hydroxide (136 mg, 3.2 mmol)
to give the title compound (0.98 g) as a yellow solid, m.p.
203.degree.. .delta.H (d.sup.6 DMSO) 10.21 (1H, bs), 8.90 (1H, s),
8.21 (1H, d, J 2.9 Hz), 8.14 (1H, s), 8.11 (1H, d, J 2.9 Hz), 7.73
(1H, s), 7.68-7.66 (2H, m), 6.99-6.95 (2H, m), 4.81 (2H, t, J 5.1
Hz) and 4.47 (2H, t, J 5.1 Hz).
EXAMPLE 55
5-Cyano-4-thiazol-2-yl-N-{4-[2-(1,2,3-triazol-2-yl)ethoxy]phenyl}pyrimidin-
e-2-amine
[0253] From 2-cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one (700
mg, 3.2 mmol), 4-[2-(1,2,3-triazol-2-yl)ethoxy]phenylguanidinium
nitrate (1.0 g, 3.2 mmol) and sodium hydroxide (136 mg, 3.2 mmol)
to give the title compound (1.1 g) as a yellow solid, m.p.
203.degree.. .delta.H (d.sup.6 DMSO) 10.19 (1H, s), 8.87 (1H, s),
8.19 (1H, d, J 3.1 Hz), 8.09 (1H, d, J 3.1 Hz), 7.76 (2H, s),
7.66-7.62 (2H, m), 6.95-6.91 (2H, m), 4.80-4.78 (2H, m) and 4.52
(2H, t, J 5.5 Hz).
EXAMPLE 56
5-Cyano-N-[4-(2-imidazol-1-ylethoxy)phenyl]-4-thiazol-2-ylpyrimidine-2-ami-
ne
[0254] From 2-cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one (700
mg, 3.2 mmol), 4-(2-imidazol-1-ylethoxy)phenylguanidinium nitrate
(1.0 g, 3.2 mmol) and sodium hydroxide (160 mg, 3.8 mmol) to give
the title compound (981 mg) as a yellow solid, m.p. 221.degree..
.delta.H (d.sup.6 DMSO) 9.93 (1H, s), 8.83 (1H, s), 8.16 (1H, d, J
3.12 Hz), 8.03 (1H, d, J 3.1 Hz), 7.67-7.62 (3H, m), 7.18 (1H, d, J
1.0 Hz), 6.99-6.91 (3H, m) and 4.37-4.29 (4H, m).
EXAMPLE 57
5-Cyano-N-[4-fluorophenyl]-4-thiazol-2-ylpyrimidine-2-amine
[0255] From 2-cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one (700
mg, 3.2 mmol), 4-fluorophenylguanidinium nitrate (700 mg, 3.2 mmol)
and sodium hydroxide (160 mg, 3.2 mmol) to give the title compound
(891 mg) as a yellow solid, m.p. 263.degree.. .delta.H (d.sup.6
DMSO) 10.10 (1H, s), 8.88 (1H, s), 8.17 (1H, d, J 3.1 Hz), 8.05
(1H, d, J 3.1 Hz), 7.78-7.75 (2H, m), 7.20-7.15 (2H, m).
EXAMPLE 58
5-Cyano-4-phenyl-N-{4-[2-(1,2,4-triazol-1-yl)ethoxy]phenyl}pyrimidine-2-am-
ine
[0256] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (470 mg,
2.35 mmol), 4-[2-(1,2,4-triazol-1-yl)ethoxy]phenylguanidinium
nitrate (800 mg, 2.6 mmol) and sodium hydroxide (113 mg, 2.8 mmol)
to give the title compound (390 mg) as a yellow solid m.p.
105.degree.. .delta.H (d.sup.6 DMSO) 10.36 (1H, s), 8.89 (1H, s),
7.97 (1H, s), 7.92 (2H, d, J 7.9 Hz), 7.61-7.58 (5H, m), 6.90 (2H,
d, J 9.1 Hz), 4.56 (2H, t, J 5.0 Hz) and 4.32 (2H, t, J 5.0
Hz).
EXAMPLE 59
5-Cyano-4-phenyl-N-{4-[2-(1,2,3-triazol-1-yl)ethoxy]phenyl}pyrimidine-2-am-
ine
[0257] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (412 mg,
2.05 mmol), 4-[2-(1,2,3-triazol-1-yl)ethoxy]phenylguanidinium
nitrate (700 mg, 2.06 mmol) and sodium hydroxide (100 mg, 2.5 mmol)
to give the title compound (300 mg) as a yellow solid m.p.
178.degree.. .delta.H 10.37 (1H, s), 8.90 (1H, s), 7.92 (2H, d, J
7.9 Hz), 7.73 (1H, s), 7.61-7.58 (5H, m), 6.92 (2H, d, J 9.1 Hz),
4.77 (2H, t, J 5.1 Hz) and 4.38 (2H, t, J 5.1 Hz).
EXAMPLE 60
5-Cyano-4-phenyl-N-{4-[2-(1,2,3triazol-2-yl)ethoxy]phenyl}pyrimidine-2-ami-
ne
[0258] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (470 mg,
2.55 mmol), 4-[2-(1,2,3-triazol-1-yl)ethoxy]phenylguanidinium
nitrate (800 mg, 2.56 mmol) and sodium hydroxide (113 mg, 2.8 mmol)
to give the title compound (430 mg) as a yellow solid m.p.
156.degree.. .delta.H (d.sup.6 DMSO) 10.30 (1H, s), 8.89 (1H, s),
7.92 (2H, d, J 7.9 Hz), 7.79 (2H, s), 7.61-7.58 (5H, m), 6.89 (2H,
d, J 9.1 Hz), 4.78 (2H, t, J 5.1 Hz) and 4.46 (2H, t, J 5.1
Hz).
EXAMPLE 61
5-Cyano-N-[4-hydroxyphenyl]-4-phenylpyrimidine-2-amine
[0259] From 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (1.51 g,
7.55 mmol), 4-hydroxyphenylguanidinium nitrate (1.78 g, 8.3 mmol)
and sodium hydroxide (362 mg, 9.06 mg) to give the title compound
(1.23 g) as a yellow solid, m.p. 201.degree.. .delta.H (d.sup.6
DMSO) 10.23 (1H, s), 9.26 (1H, s), 8.85 (1H, d, J 1.0 Hz), 7.92
(2H, dd, J 7.0, 1.0 Hz), 7.59 (3H, m), 7.48 (2H, d, J 8.0 Hz) and
6.73 (2H, d, J 8.0 Hz).
EXAMPLE 62
5-Cyano-N-[4-(2-hydroxyethoxy)phenyl]-4-pyridin-3-ylpyrimidine-2-amine
[0260] From 2-cyano-3-dimethylamino-1-pyridin-3-ylpropen-1-one
(1.20 g, 5.95 mmol), 4-(2-hydroxyethoxy)phenylguanidinium nitrate
(1.54 g, 5.95 mmol) and sodium hydroxide (262 mg, 6.34 mmol) to
give the title compound (1.28 g) as a yellow solid, m.p.
209-210.degree.. .delta.H (d.sup.6 DMSO) 10.43 (1H, bs), 9.07 (1H,
d, J 1.9 Hz), 8.93 (1H, s), 8.77 (1H. dd, J 4.8, 1.6 Hz), 8.31-8.28
(1H, m), 7.65-7.60 (3H, m), 6.92 (2H, d, J 9.0 Hz), 4.82 (1H, t, J
5.6 Hz), 3.96 (2H, t, J 5.0 Hz) and 3.69 (2H, q, 15.1 Hz).
EXAMPLE 63
5-Cyano-4-pyridin-yl-N-[4-(1,2,4-triazol-1-yl)phenyl]pyrimidine-2-amine
[0261] From 2-cyano-3-dimethylamino-1-pyridin-3-ylpropen-1-one (516
mg, 2.56 mmol), 4-(1,2,4-triazol-1-yl)phenylguanidinium nitrate
(679 mg, 2.56 mmol) and sodium hydroxide (113 mg, 2.82 mmol) to
give the title compound (425 mg) as a yellow solid, m.p.
250-251.degree.. .delta.H 10.79 (1H, bs), 9.20 (1H, s), 9.12 (1H,
s), 9.04 (1H, s), 8.81 (1H, bm), 8.35-8.32 (1H, bm), 8.20 (1H, s),
7.93 (2H, d, J 8.6 Hz), 7.82 (2H, d, J 8.6 Hz) and 7.65 (1H,
bs).
EXAMPLE 64
5-Cyano-N-[4-morpholinophenyl]-4-pyridin-3-ylpyrimidine-2-amine
[0262] From 2-cyano-3-dimethylamino-1-pyridin-3-ylpropen-1-one (516
mg, 2.56 mmol), 4-morpholinophenylguanidinium nitrate (725 mg, 2.56
mmol) and sodium hydroxide (113 mg, 2.82 mmol) to give the title
compound (707 mg) as an orange solid, m.p. 199-200.degree..
.delta.H (d.sup.6 DMSO) 10.39 (1H, bs), 9.07 (1H, d, J 1.8 Hz),
8.91 (1H, s), 8.78 (1H, dd, J 4.9,1.6 Hz), 8.31-8.28 (1H, m),
7.65-7.56 (3H, m), 6.93 (2H, d, J 9.1 Hz), 3.74-3.70 (4H, m) and
3.07-3.04 (4H, m).
EXAMPLE 65
5-Cyano-N-[4-fluorophenyl]-4-indol3-ylpyrimidine-2-amine
[0263] From 1-indol-3-yl-2-cyano-3-dimethylaminopropen-1-one (950
mg, 3.97 mmol), 4-fluorophenylguanidinium nitrate (858 mg, 3.97
mmol) and sodium hydroxide (176 mg) to give the title compound (200
mg) as an off-white solid, m.p. 256-257.degree.. .delta.H (d.sup.6
DMSO) 11.83 (1H, bs), 9.91 (1H, s), 8.73 (1H, s), 8.51 (1H, s),
8.50-8.47 (1H, m), 7.78-7.73 (2H, m), 7.53 (1H, dt, J 7.2, 0.8 Hz)
and 7.27-7.13 (4H, m).
EXAMPLE 66
5-Cyano-N-[4-(2-imidazol-1-ylethoxy)phenyl]-4-indol-3-ylpyrimidine-2-amine
[0264] From 1-indol-3-yl-2-cyano-3-dimethylaminopropen-1-one (300
mg, 1.25 mmol), 4-(2-imidazol-1-ylethoxy)phenylguanidinium nitrate
(465 mg, 1.25 mmol) and sodium hydroxide (100 mg, 2.5 mmol) to give
the title compound (150 mg) as a yellow solid, m.p.
238-239.degree.. .delta.H (d.sup.6 DMSO) 12.02 (1H, bs), 10.04 (1H,
s), 8.72 (1H, s), 8.55 (1H, s), 8.33 (1H, bm), 7.68 (1H, s),
7.63-7.55 (3H, m), 7.28-7.23 (2H, m), 7.22-7.05 (2H, bm), 6.98-6.91
(3H, m), 4.52 (2H, t, J 5.0 Hz) and 4.26 (2H, t, J 5.0 Hz).
EXAMPLE 67
5-Cyano-4-pyridin-3-yl-N-{4-[2-(1,2,4-triazol-1-yl)ethoxy]phenyl}pyrimidin-
e-2-amine
[0265] From 2-cyano-3-dimethylamino-1-pyridin-3-ylpropen-1-one (800
mg, 3.97 mmol), 4-[2-(1,2,4-triazol-1-yl)ethoxy]phenylguanidinium
nitrate (1.23 g, 3.97 mmol) and sodium hydroxide (176 mg, 4.4 mmol)
to give the title compound (1.0 g) as a yellow solid, m.p.
180-181.degree.. .delta.H (d.sup.6 DMSO) 10.45 (1H, bs), 9.07 (1H,
d, J 1.8 Hz), 8.93 (1H, s), 8.77 (1H, dd, J 4.8, 1.5 Hz), 8.55 (1H
s), 8.29 (1H, d, J 8.1 Hz), 7.97 (1H, s), 7.64-7.60 (3H, m), 6.91
(2H, d, J 9.0 Hz), 4.56 (2H, t, J 5.0 Hz) and 4.32 (2H, t, J 5.0
Hz).
EXAMPLE 68
5-Cyano-4-pyridin-3-yl-N-{4-[2-(1,2,3-triazol-1-yl)ethoxy]phenyl}pyrimidin-
e-2-amine
[0266] From 2-cyano-3-dimethylamino-1-pyridin-3-ylpropen-1-one (516
mg, 2.56 mmol), 4-[2-(1,2,3-triazol-1-yl)ethoxy]phenylguanidinium
nitrate (800 mg, 2.56 mmol) and sodium hydroxide (113 mg, 2.82
mmol) to give the title compound (531 mg) as a yellow solid, m.p.
177-178.degree.. .delta.H (d.sup.6 DMSO) 10.45 (1H, bs), 9.08 (1H,
s), 8.93 (1H, s), 8.78 (1H, dd, J 4.8,1.5 Hz), 8.31-8.28 (1H, m),
8.17 (1H, s), 7.73 (1H, s), 7.65-7.60 (3H, m), 6.92 (2H, d, J 9.0
Hz), 4.77 (2H, t, J 5.0 Hz).
EXAMPLE 69
5-Cyano-4-pyridin-3-yl-N-{4-[2-(1,2,3-triazol-1-2-yl)ethoxy]phenyl}pyrimid-
ine-2-amine
[0267] From 2-cyano-3-dimethylamino-1-pyridin-3-ylprope-1-one (800
mg, 3.97 mmol), 4-[2-(1,2,3-triazol-2-yl)ethoxy]phenylguanidinium
nitrate (1.23 g, 3.97 mmol) and sodium hydroxide (176 mg, 4.4 mmol)
to give the title compound (970 mg) as a yellow solid, m.p.
179-180.degree.. .delta.H (d.sup.6 DMSO) 10.45 (1H, bs), 9.08 (1H,
d, J 1.6 Hz), 8.93 (1H, s), 8.78 (1H, dd, J 5.0, 1.6 Hz), 8.32-8.27
(1H, m), 7.79 (2H, s), 7.65-7.59 (3H, m), 6.90 (2H, d, J 9.1 Hz),
4.78 (2H, t, J 5.2 Hz) and 4.46 (2H, t, J 5.1 Hz).
EXAMPLE 70
5-Cyano-N-{4-[2-(1,2,3-triazol-1-yl)ethoxy]phenyl}-4-thien-3-ylpyrimidine--
2-amine
[0268] From 2-cyano-3-dimethylamino-1-thien-3-ylpropen-1-one (557
mg, 2.7 mmol), 4-[2-(1,2,3-triazol-1-yl)ethoxy]phenylguanidinium
nitrate (920 mg, 3.0 mmol) and sodium hydroxide (130 mg, 3.2 mmol)
to give the title compound (710 mg) as a yellow solid, m.p.
177.degree.. .delta.H (d.sup.6 DMSO) 10.28 (1H, s), 8.84 (1H,s),
8.48 (1H, s), 8.18 (1H, d, J 0.8 Hz), 7.78-7.73 (3H, m), 7.61 (2H,
d, J 7.6 Hz), 6.91 (2H, d, J 8.9 Hz) and 4.77 (2H, t, J 5.0
Hz).
[0269] 2-Cyano-3-dimethylamino-1-thien-3-ylpropen-1-one was
prepared from 3-cyanoacetyl thiophene (7.64 g, 50.56 mmol) and
dimethylformamide dimethylacetal (20 mL, 152 mmol) as a yellow
solid (6.6 g), m.p. 134.degree.. .delta.H (CDCl.sub.3) 8.27 (1H,
dd, J 3.0, 1.3 Hz), 8.00 (1H, s), 7.61 (1H, dd, J 5.0 Hz), 7.27
(1H, dd, J 5.0,3.0 Hz), 3.48 (3H, s) and 3.29 (3H, s).
[0270] 3-Cyanoacetylthiophene was prepared in a similar manner to
the analogous starting material of Example 8 from
3-isoxazol-5-ylthiophene (8.15 g, 53.9 mmol) and a freshly prepared
solution of sodium ethoxide [1.24 g, 53.9 mmol sodium in ethanol
(100 mL)] to give the desired material (7.76 g) as an orange solid,
.delta.H (CDCl.sub.3) 8.16 (1H, dd, J 5.0, 1.3 Hz), 7.55 (1H, dd,
J5.0,2.3 Hz), 7.40 (1H, dd, J 15.0, 2.3 Hz) and 3.96 (2H, m).
[0271] 3-Isoxazol-5-ylthiophene was prepared in a similar manner to
the analogous starting material of Example 8 from
3-dimethylamino-1-thien-3-y- lpropen-1-one (10 g, 55.2 mmol) and
hydroxylamine hydrochloride (4.2 g, 60.7 mmol) to give the desired
product (8.15 g) as a colourless oil, .delta.H (CDCl.sub.3) 8.18
(1H, d, J 1.9 Hz), 7.72 (1H, t, J 2.1 Hz), 7.34 (2H, d, J 2.1 Hz)
and 6.29 (1H, d, J 1.8 Hz).
[0272] 3-dimethylamino-1-thien-3-ylpropen-1-one was prepared from
3-acetylthiophene (15.0 g) and dimethylformamide dimethylacetal
(47.5 mL, 357 mmol) as a yellow solid (14 g), m.p. 98.degree..
.delta.H (CDCl.sub.3) 7.90 (1H, dd, J 3.0, 1.0 Hz), 7.76 (1H, d, J
12.4 Hz), 7.53 (1H, dd, J 5.9,1.0 Hz), 7.28-7.25 (1H, m), 5.57
(1H,d, J 12.4 Hz) and 3.03 (6H, bs).
EXAMPLE 71
5-Cyano-N-[4-(2-(1,2,4-triazol-1-ylethyl)phenyl]-4-thien-3-ylpyrimidine
-2-amine
[0273] From 2-cyano-3-dimethylamino-1-thien-3-ylpropen-1-one (800
mg, 3.9 mmol), 4-[2-(1,2,4-triazol-1-yl)ethyl]phenylguanidinium
nitrate (1.26 g, 4.3 mmol) and sodium hydroxide (186 mg, 4.7 mmol)
to give the title compound (721 mg) as a light orange solid, m.p.
209.degree.. .delta.H (d.sup.6 DMSO) 10.37 (1H, s), 8.88 (1H, s),
8.49 (1H, s), 8.31 (1H, s), 7.94 (1H, s), 7.80-7.76 (2H, m), 7.63
(2H, d, J 8.5 Hz), 7.10 (2H, d, J 8.5 Hz), 4.41 (2H, t, J 7.0 Hz)
and 3.07 (2H, t, J 7.0 Hz).
[0274] 4-[2-(1,2,4-Triazol-1-yl)ethyl]phenylguanidinium nitrate was
prepared from 4-[2-(1,2,4-triazol-1-yl)ethyl]aniline (5.75 g, 30.4
mmol), cyanamide (2.17 g, 51.7 mmol in water [2 mL]) and
concentrated HNO.sub.3 (2.2 mL, 33.3 mmol) as a pink solid, m.p.
183.degree.. .delta.H (d.sup.6 DMSO) 9.40 (1H, bs), 8.33 (1H, s),
7.94 (1H, s), 7.27-7.19 (4H,m), 7.14-7.11 (2H, m), 4.42 (2H, t ,J
7.2 Hz) and 3.11 (2H, t, J 7.2 Hz).
[0275] 4-[2-(1,2,4-triazol-1-yl)ethyl]aniline was prepared from
4-[2-(1,2,4-triazol-1-yl)ethyl]-nitro benzene (7.0 g, 32.1 mmol) in
a manner similar to the analogous intermediate of Example 12 as an
off white solid (5.8 g), m.p. 79.degree.. .delta.H 7.93 (1H, s),
7.73 (1H, s), 6.79 (2H, d, J 8.5 Hz), 6.58 (2H, d, J 8.5 Hz), 4.31
(2H, t, J 7.0 Hz), 3.30 (2H,bs) and 3.03 (2H ,t, J7.0 Hz).
[0276] 4-[2-(1,2,4-triazol-1-yl)ethyl]nitrobenzene was prepared
from 4-[2-p-toluenesulphonyloxy ethyl]nitrobenzene (2.77 g, 8.6
mmol) and 1,2,4-triazole sodium salt (942 mg, 10.3 mmol) as a pink
solid (2.0 g), m.p. 97.degree.. .delta.H (CDCl.sub.3) 8.12 (2H, d,
J 9.0 Hz), 8.00 (1H, s), 7.80 (1H, s), 7.20 (2H, m), 4.44 (2H, t, J
7.0 Hz) and 3.32 (2H, t, J 7.0 Hz).
[0277] 4-[2-p-toluenesulphonyloxyethyl]nitrobenzene was prepared
from 4-nitrophenethyl alcohol (20.0 g, 120 mmol) and
4-toluenesulphonyl chloride (34.2 g, 180 mmol) as a yellow solid
(3.0 g), m.p. 133.degree.. .delta.H (CDCl.sub.3) 8.10 (2H, d, J 9.0
Hz), 7.66 (2H, d, J 9.0 Hz), 7.26 (4H, m), 4.29 (2H, t, J 6.0 Hz),
3.07 (2H, t, J 6.0 Hz) and 2.43 (3H, s).
EXAMPLE 72
4-(2-Aminopyridin-5-yl)-5-cyano-N-(4-fluorophenyl)pyrimidine-2-amine
[0278] To a suspension of
5-cyano-N-(4-fluorophenyl)-4-[2-(4-methoxybenzyl-
amino)pyridin-5-yl]pyrimidine-2-amine (104 mg, 0.24 mmol) in
acetonitrile (4 mL), MeOH (2 mL) and dichloromethane (2 mL), was
added dropwise a solution of ceric ammonium nitrate (133 mg, 0.24
mmol) in water (1 mL). After 0.5 h the reaction was poured into
saturated NaHCO.sub.3 and extracted with CHCl.sub.2. The organic
phase was dried (MgSO.sub.4) and concentrated under reduced
pressure to give the title compound (42 mg) as a buff solid, m.p.
289.degree.. .delta.H (d.sup.6 DMSO) 9.93 (1H, s), 8.76 (1H, d, J
2.3 Hz), 8.74 (1H, s), 8.09 (1H, dd, J 8.8,2.5 Hz), 7.77-7.73 (2H,
bm), 7.18-7.13 (2H, m), 6.85 (1H, s) and 6.63 (1H, d, J 8.8
Hz).
[0279]
5-cyano-N-(4-fluorophenyl)-4-[2-(4-methoxybenzylamino)pyridin-5-yl]-
-pyrimidine-2-amine was prepared in a similar manner to the title
compound of Example 7 from
4-(2-chloropyridin-5-yl)-5-cyano-N-(4-fluoro-phenyl)pyr-
imidine-2-amine (764 mg, 2.3 mmol) and p-methoxybenzyl-amine (644
mg, 4.6 mmol) as a yellow solid (432 mg). .delta.H (d.sup.6 DMSO)
10.35 (1H, s), 8.82 (1H, s), 8.77 (1H, d, J 2.3 Hz), 8.04 (1H, dd,
J 8.9, 2.3 Hz), 7.84 (1H, t, J 5.6 Hz), 7.77-7.74 (1H, m), 7.28
(2H, d, J 8.6 Hz), 7.21 (2H, t, J 8.9 Hz), 6.90 (2H, d, J 8.6 Hz),
6.66 (1H, d, J 8.9 Hz), 4.51 (2H, s) and 3.73 (3H, s).
[0280]
4-[2-Chloropyridin-5-yl]-5-cyano-N-(4-fluorophenyl)pyrimidine-2-ami-
ne was prepared from
1-(2chloropyridin-5-yl)-2-cyano-3-dimethylamino propen-1-one (8.0
g, 36 mmol), 4-fluorophenylguanidinium nitrate (8.23 g, 37.8 mmol)
and sodium hydroxide (1.49 g, 37.8 mmol) as a yellow solid (7.23
g). .delta.H (d.sup.6DMSO) 10.66 (1H, bs), 9.00 (1H, s), 8.95 (1H,
d, J 2.3 Hz), 8.38 (1H, dd, J 8.4,2.5 Hz), 7.80 (1H, d, J 8.4 Hz),
7.77-7.74 (2H, m) and 7.24-7.20 (2H, m).
EXAMPLE 73
5-Cyano-4-{2-([2-(diethylamino)ethyl]amino)pyridin-5-yl}-N-(4-fluorophenyl-
) pyrimidine-2-amine
[0281] From
4-[2-Chloropyridin-5-yl]-5-cyano-N-(4-fluorophenyl)pyrimidine--
2-amine (600 mg, 1.8 mmol) and N,N-diethylethylenediamine (430 mg)
in a manner analogous to the compound of Example 7, to give the
title compound (197 mg) as a yellow solid, m.p. 166.degree..
.delta.H (d.sup.6 DMSO) 9.79 (1H, bs), 8.83 (1H, d, J 2.3 Hz), 8.72
(1H, s), 8.08 (1H, dd, J 8.9,2.3 Hz), 7.76-7.72 (2H, m), 7.17-7.11
(2H, m), 6.73 (1H, bs), 6.65 (1H, d, J 8.9 Hz), 3.53-3.48 (2H, m),
2.85 (2H, bs), 2.73-2.69 (2H, m), 2.61-2.51 (4H, m) and 1.78-1.70
(4H, m).
EXAMPLE 74
4-[4-(1-Acetamido-1-methylethyl)phenyl]-5-cyano-N-4-fluorophenylpyrimidine-
-2-amine
[0282] To a suspension of the compound of Example 20 (100 mg 0.29
mmol) in CHCl.sub.3 (8 mL) was added pyridine (0.1 mL) and acetic
anhydride (0.1 mL). The reaction was stirred at ambient temperature
for 6 h. The reaction was then washed with 2M HCl and saturated
NaHCO.sub.3, dried (MgSO.sub.4), and concentrated under reduced
pressure to give the title compound (103 mg) as a yellow solid,
m.p. 212-216.degree.. .delta.H 8.69 (1H, s), 8.06 (2H, d, J 8.4
Hz), 7.63-7.60 (2H, m), 7.56 (2H, d, J 8.4 Hz), 7.12-7.08 (2H, m),
5.82 (1H, s), 2.03 (3H, s) and 1.74 (6H, s).
EXAMPLE 75
5-Cyano-4-[4-(1-dimethylamino-1-methylethyl)phenyl]-N-(4-fluoro
phenyl)pyrimidine-2-amine
[0283] The compound of Example 20 (500 mg, 1.44 mmol) was heated at
reflux in formic acid (10 mL) and 37% aqueous formaldehyde (10 mL)
for 4 days. The reaction was diluted in 100 mL dichloromethane and
concentrated under reduced pressure. The resulting residue was
redissolved in dichloromethane (100 mL) and washed with 2M NaOH,
dried (MgSO.sub.4) and again concentrated under reduced pressure.
The residue was subjected to column chromatography (silica 10-15%
MeOH-dichloromethane) to give the title compound (411 mg) as a
yellow solid, m.p. 179.degree.. .delta.H (CDCl.sub.3) 8.61 (1H, s),
7.94 (2H, d, J 8.1 Hz), 7.63 (2H, d, J 8.3 Hz), 7.51-7.48 (2H, s),
7.04-7.01 (2H, m), 2.12 (6H, s) and 1.32 (6H, s).
EXAMPLE 76
5-Cyano-N-[4-(1,2,4-triazol-1-yl)phenyl]-4-[4-(1-dimethylamino-1-methyl
ethyl)phenyl]pyrimidine-2-amine
[0284] In a manner analogous to the compound of Example 75, from
the compound of Example 11 (750 mg, 1,76 mmol) to give the title
compound (687 mg) as a yellow solid, m.p.235-237.degree.. .delta.H
(d.sup.6 DMSO) 10.68 (1H, bs), 9.23 (1H, s), 8.99 (1H, J 1.9 Hz),
8.21 (1H, s), 7.99-7.96 (4H, m), 7.85 (2H, dd, J 7.1, 1.9 Hz), 7.72
(2H, d, J 8.5 Hz), 2.13 (6H, s) and 1.35 (6H, s).
EXAMPLE 77
5-Cyano-4-[4-(1-methyl-1-pyrrolidin-1-ylethyl)phenyl]-N-(4-fluoro
phenyl)pyrimidine-2-amine
[0285] To a solution of the compound (1.0 g, 2.88 mmol) of Example
20 in DMF (20 mL) was added potassium carbonate (786 mg, 5.7 mmol)
and 1,4-dibromobutane (622 mg, 2.88 mmol) and the resulting mixture
stirred at 60.degree.for 12 h. The reaction was partitioned between
brine and ethyl acetate then the organic phase was dried
(MgSO.sub.4) and concentrated under reduced pressure. The residue
was subjected to column chromatography to give the title compound
(591 mg) as a yellow solid, m.p. 124.degree.. .delta.H (d.sup.6
DMSO) 8.58 (1H, s), 7.94 (2H, dapp, J 8.4 Hz), 7.63 (4H, m), 6.96
(2H, tapp, J 8.7 Hz), 3.23 (4H, s), 2.61 (4H, s) and 1.47 (6H,
s).
EXAMPLE 78
5-Cyano-4-{[4-(imidazol-1-yl)methyl]phenyl}-N-(3,4,5-trimethoxyphenyl)
pyrimidine-2-amine
[0286] From
2-cyano-3-dimethylamino-1-[(4-imidazol-1-ylmethyl)phenyl]prope-
n-1-one (260 mg, 0.89 mmol), 3,4,5-trimethoxyphenylguanidinium
nitrate (308 mg, 1.07 mmol) and sodium hydroxide (46 mg, 1.16 mmol)
in a similar manner to the compound of Example 1 to give the title
compound (80 mg) as a yellow solid, m.p. 253.degree.. .delta.H
(d.sup.6 DMSO) 10.07 (1H, bs), 8.86 (1H, s), 7.99 (2H, dt, J 8.4,
1.9 Hz), 7.72 (1H, s), 7.43 (2H, dt, J 8.4,1.9 Hz), 7.21 (2H, s),
7.17 (1H, t, J 1.2 Hz), 6.94 (1H, t, J 2.1 Hz), 5.31 (2H, s), 3.77
(6H, s) and 3.67 (3H, s).
[0287]
2-Cyano-3-dimethylamino-1-[(4-imidazol-1-ylmethyl)phenyl]propen-1-o-
ne was prepared by the addition of
3-hydroxy-3-(4-(imidazol-1-ylmethyl)phe- nyl)acrylonitrile, lithium
salt (2.16 g, 10.0 mmol) to a solution of MeOH-acetyl chloride (15
mL-1 mL) followed by dimethylformamide dimethylacetal (1.3 mL). The
reaction was stirred at room temperature for 1 h, then concentrated
under reduced pressure. The resulting residue was partitioned
between ethyl acetate and saturated Na.sub.2CO.sub.3. The organic
phase was dried (MgSO.sub.4) and concentrated under reduced
pressure. After chromatography (silica, 5-8%
MeOH--CH.sub.2Cl.sub.2) of the residue the desired material was
obtained as a yellow oil (260 mg). .delta.H (300 MHz) 7.94 (1H, s),
7.75 (2H, dt, J 8.3,1.8 Hz), 7.54 (1H, s), 7.16 (2H, d, J 8.5 Hz),
7.08 (1H, t, J 1.0 Hz), 6.89 (1H, t, J 1.3 Hz), 5.14 (2H, s), 3.46
(3H, s) and 3.28 (3H, s).
[0288] 3-Hydroxy-3-(4-(imidazol-1-ylmethyl)phenyl)acrylonitrile,
lithium salt was prepared as follows: -Acetonitrile (1.04 mL, 20.0
mmol) was added to a solution of lithium bistrimethylamide (20 mL
1.0M in THF, 20.0 mmol) at -78.degree. under a nitrogen atmosphere,
and the resulting mixture stirred for 20 min. A solution of methyl
4-(imidazol-1-ylmethyl)b- enzoate (2.16 g, 10 mmol) in THF was
added dropwise and the reaction temperature then allowed to warm to
room temperature over a 3 h period. The reaction was diluted with
diethyl ether (30 mL) and the resulting solid collected by
filtration washing further with ether (3.times.30 mL). The solid
was dried under vacuum to give the desired material as a yellow
solid (2.65 g) and was used without purification. .delta.H (d.sup.6
DMSO) 7.72 (1H, s), 7.59 (2H, d, J 8.1 Hz), 7.15 (1H, s), 7.10 (2H,
d, J 8.2 Hz), 6.88 (1H, s), 5.13 (2H, s) and 3.93 (1H, s).
EXAMPLE 79
5-Cyano-N-[3-fluorophenyl]-4-[4-(imidazol-1-yl)phenyl]pyrimidine-2-amine
[0289] From
2-cyano-3-dimethylamino-1-(4-imidazol-1-ylphenyl)propen-1-one (480
mg, 1.8 mmol), 3-fluorophenylguanidinium nitrate (480 mg, 1.98
mmol) and sodium hydroxide (87 mg) in a similar manner to the
compound of Example 1 to give the title compound (412 mg) as a
yellow solid, m.p. 300.degree.. .delta.H (d.sup.6 DMSO) 10.73 (1H,
s), 9.03 (1H, s), 8.44 (1H, s), 8.12 (2H, d, J 9.0 Hz), 7.96-7.90
(3H, m), 7.80 (1H, d, 1 Hz), 7.55 (1H, d, J 8.0 hz), 7.35 (1H, q, J
9.0 Hz), 7.16 (1H, d, J 1.0 Hz) and 6.90 (1H, m).
[0290]
2-Cyano-3-dimethylamino-1-(4-imidazol-1-ylphenyl)propen-1-one was
prepared in a manner similar to the analogous starting material of
Example 79, as a yellow solid (970 mg), m.p. 165.degree.. .delta.H
(CDCl.sub.3) 8.01 (1H, s), 7.96-7.92 (3H, m), 7.48-7.45 (2H, m),
7.33 (1H, t, J 1.4 hz), 7.23 (1H, d, J 1.0 Hz), 3.52 (3H, s) and
3.34 (3H, s).
[0291] 3-Hydroxy-3-(4-imidazol-1-ylphenyl)acrylonitrile, sodium
salt was prepared from 5-(4-imidazol-1-ylphenyl)isoxazole (1.22 g,
5.78 mmol) and sodium (133 mg, 5.78 mmol) in ethanol (15 mL) in a
manner similar to the analogous starting material of Example 8, as
a beige solid (1.14 g), m.p. 286.degree..
[0292] 5-(4-imidazol-1-ylphenyl)isoxazole was prepared by treating
a solution of
3-dimethylamino-1-[(4-imidazol-1-yl)phenyl]propen-1-one (1.64 g,
6.8 mmol) in MeOH with hydroxylamine-O-sulphonic acid (831 mg, 7.35
mmol) at ambient temperature for 16 h. A further quantity of
hydroxylamine-O-sulphonic acid (831 mg, 7.35 mmol) was added and
stirring continued for 3 h. The reaction was then treated with
saturated NaHCO.sub.3 solution, the resulting solution being
collected by filtration and washed with water and diethyl ether to
give the desired material (1.08 g) as a pink solid, m.p.
168.degree.. _.delta.H (d.sup.6 DMSO) 8.67 (1H, d, J 1.8 Hz), 3.89
(1H, s), 8.03-7.99 (2H, m), 7.86-7.84 (3H, m), 7.14 (1H, s) and
7.10 (1H, d, J 1.9 Hz).
EXAMPLE 80
N-[3-(5-Cyano-4-thiophen-2-ylpyrimidin-2-ylamino)phenyl]-4-(4-methyl
piperazin-1-ylmethyl)benzamide
[0293] A solution of
N-3-aminophenyl-5-cyano-4-thien-2-ylpyrimidine-2-amin- e (300 mg,
1.0 mmol) and 4-(4-methylpiperazin-1-yl)methylbenzoic acid, lithium
salt (300 mg, 1.0 mmol) in DMF (10 mL) was treated with
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (307 mg, 1.6 mmol),
1-hydroxybenzotriazole (216 mg, 1.6 mmol) and N-methylmorpholine
(350 ml, 3.2 .mu.mol) and the resulting mixture was stirred at
ambient temperature for 48 h. The reaction was then concentrated
under reduced pressure and the resulting residue partitioned
between ethyl acetate and saturated brine. The organic phase was
dried (MgSO4), concentrated under reduced pressure and the
resulting residue recrystallised from ethyl acetate-ether-MeOH
(4:4:1) to give the title compound (312 mg) as a colourless solid,
m.p. 208-209.degree.. .delta.H (d.sup.6 DMSO) 10.48 (1H, bs), 10.23
(1H, s), 8.89 (1h,s), 8.28 (1H, d, J 3.5 Hz), 8.13 (1H, m), 7.98
(1H, d, J 4.8 Hz), 7.90 (2H, d, J 8.2 Hz), 7.60 (1H, bs), 7.43 (3H,
d, J 8.2 Hz), 7.36-7.30 (2H, s), 3.52 (2H, s), 2.37 (8H, bs) and
2.15 (3H,s).
[0294] N-3-Aminophenyl-5-cyano-4-thien-2-ylpyrimidine-2-amine was
prepared by heating a solution of
5-cyano-N-3-nitrophenyl-4-thien-2-ylpyrimidine-2- -amine (2.77 g,
8.57 mmol) and tin(II)chloride dihydrate (7.73 g, 34.05 mmol) in
ethanol (160 mL) at reflux for 18 h. On cooling the reaction was
concentrated under reduced pressure and partitioned between
CH.sub.2Cl.sub.2 and 2M NaOH. The organic phase was dried
(MgSO.sub.4) and evaporated to give the desired material (320 mg)
as a yellow solid, m.p. 221-222.degree.. .delta.H (d.sup.6 DMSO)
10.16 (1H, s), 8.83 (1H, s), 8.24 (1H, d, J 3.9 Hz), 7.97 (1H, d, J
5.1 Hz), 7.32 (1H, dd, J 5.0, 4.0 Hz), 6.97 (3H, bm), 6.31 (1H, m)
and 5.04 (2H, bs).
[0295] 5-Cyano-N-3-nitrophenyl-4-thien-2-ylpyrimidine-2-amine was
prepared from 2-cyano-3-dimethylamino-1-thien-2-ylpropen-1-one
(3.20 g, 15.51 mmol), 3-nitrophenylguanidinium nitrate (3.74 g,
15.53 mmol) and sodium hydroxide (652 mg, 7.82 mmol) to give the
desired material (841 mg) as an off-white solid,
m.p.275-277.degree.. .delta.H (d.sup.6 DMSO) 10.87 (1H, bs), 8.98
(1H, s), 8.90 (1H, bs), 8.31-8.29 (1H, m), 8.09-8.05 (2H, m), 7.91
(1H, dd, J 7.7,2.0 Hz), 7.64 (1H, t, J 8.1 Hz) and 7.37-7.35 (1H,
m).
[0296] 4-(4-Methylpiperazin-1-yl)methylbenzoic acid, lithium salt
was prepared by stirring methyl
4-(4-methylpiperazin-1-yl)methylbenzoate (845 mg, 3.41 mmol) and
lithium hydroxide monohydrate (300 mg, 7.15 mmol) in THF-H2O [50%
v/v] (14 mL) at room temperature for 16 h. The solvent was removed
under reduced pressure to give the desired material (799 mg) as a
white solid, m.p. 230.degree.. .delta.H (d.sup.6 DMSO) 7.80 (2H, d,
J 8.1 Hz), 7.16 (2H,d, J 8.1 Hz), 3.41 (2H, s), 2.30 (8H, bs) and
2.12 (3H, s).
[0297] Methyl 4-(4-methylpiperazin-1-yl)methylbenzoate was prepared
by heating methyl (4-bromomethyl)benzoate (2.3 g, 10.0 mmol) and
1-methylpiperazine (1.0 g, 10.0 mmol) in DMF (10 mL) for 3 h. The
reaction was concentrated under reduced pressure and the residue
dried under high vacuum to give the desired product (1.2 g) as a
white solid, m.p. 152.degree.. .delta.H (d.sup.6 DMSO) 7.90 (2H, d,
J 8.2 Hz), 7.43 (2H, d, J 8.2 Hz), 3.83 (3H, s), 2.67 (4H, bs),
2.47 (4H, bs) and 2.40 (3H, s).
EXAMPLES 81 to 104
[0298] The compounds of Examples 81 to 104 were prepared by
solution phase parallel synthesis performed on a Quest 210 Personal
Synthesizer (Argonaut Technologies, San Carlos, Calif., USA)
employing the following intermediate:
2-Chloro-5-cyano-4-phenylpyrimidine
[0299] 5-cyano-4-phenyl-1(H)-pyrimidin-2-one (0.83 g, 4.21 mmol)
was heated in phosphorous oxychloride (20 mL) and DMF (.about.1 ml)
at 115.degree. for 24 h. On cooling, the reaction was concentrated
under reduced pressure and the residue poured into a cooled
saturated NaHCO.sub.3 solution. This was extracted with ethyl
acetate, the combined organic phases dried (MgSO.sub.4) and
evaporated to give the desired material (0.79 g) as a yellow solid
m.p. 79-81.degree..
[0300] The pyrimidin-2-one was prepared by treating a solution of
2-amino-5-cyano-4-phenylpyrimidine (2.0 g, 10.2 mmol) in 50%
concentrated H.sub.2SO.sub.4-water (v/v) at room temperature, with
a solution of sodium nitrite (2.82 g, 40.8 mmol) in water (30 ml)
over 1 h. The reaction was allowed to stir overnight at room
temperature, before additional sodium nitrite (2.82 g, 10.2 mmol)
was added and stirring continued for 3 h. After this time ammonium
hydroxide (33% aqueous) was added to pH9, and the resulting
precipitate collected and dried to give the desired material (2.2
g) as a white solid m.p. 220-222.degree..
[0301] 2-Amino-5-cyano-4-phenylpyrimidine was prepared from
guanidine carbonate (1.57 g, 17.5 mmol),
1-phenyl-2-cyano-3-dimethylaminopropen-1-o- ne (3.5 g, 17.5 mmol)
and sodium hydroxide (720 mg, 19.3 mmol) in a similar method to the
compound of Example 1, as an off-white solid, m.p. 147.degree..
EXAMPLE 81
5-Cyano-4-phenyl-N-quinol-6-ylpyrimidine-2-amine
[0302] To a Quest 5 ml Teflon reaction vessel (RV), was added
6-aminoquinoline (61 .mu.mol) and a solution of
2-chloro-5-cyano-4-phenyl- pyrimidine (10 mg, 47 mmol) in
1,4-dioxan (1.5 mL). The resulting mixture was heated (85.degree.)
with agitation every 10 min. for 48 h. After this time
PS-isocyanate resin (Argonaut Technologies) (100 mg, 150 .mu.mol)
and PS-trisamine (Argonaut Technologies) (50 mg, 150 mmol) were
added to the reaction vessel and the reaction was agitated every 10
min at 55.degree. for 18 h. The reaction was diluted with THF
(.about.3 ml) and then filtered into a pre-weighed vial, the resins
being further washed with dichloromethane. The combined filtrates
were evaporated under reduced pressure overnight and the residue
taken up in DMSO (500 .mu.l). The residue was purified using
semi-preparitive HPLC (System; Waters HPLC Pump Module 600E, Waters
486 detector with semi-prep flow cell and Waters 717 Autosampler
(250 .mu.l). Column; 150.times.10 mm Luna C18 (2) 5 .mu.m.
Conditions; 90% [0.1% TFA-water] 10% [0.1% TFA-acetonitrile] to 10%
[0.1% TFA-water] 90% [0.1% TFA-acetonitrile] at 5.0 mlmin.sup.-1
with a run time of 15 min at ambient temperature) to give the title
compound. HPLC-MS Retention time 4.2 mins (MH)+ 324.
[0303] HPLC-MS Conditions
[0304] HPLC-MS was performed on a Hewlett Packard Binary Pump
1100/MSD ES Single Quadropole using a Luna C18(2), 50.times.4.6 mm
column, running a gradient of 95% [20 mM ammonium formate pH3.5] 5%
[acetonitrile-0.1% TFA] to 5% [20 mM ammonium formate pH3.5] 95%
[acetonitrile-0.1% TFA] at 0.8 mlmin with a run time of 5 min. MS
acquired at 70V in positive ion API-electrospray mode of
ionisation, scanning from 150-750 amu.
EXAMPLE 82
N-(3-Chloro-4-methylphenyl)-5-cyano-4-phenylpyrimidine-2-amine
[0305] 3-Chloro-4-methylaniline gave the title compound HPLC-MS
Retention time 5.13 mins (MH)+ 322
EXAMPLE 83
N-3-Acetyiphenyl)-5-cyano-4-phenylpyrimidine-2-amine
[0306] 3-Aminoacetophenone gave the title compound HPLC-MS
Retention time 4.42 mins (MH)+ 315
EXAMPLE 84
N-(4-Chloro-3-trifluoromethylphenyl)-5-cyano-4-phenylpyrimidine-2-amine
[0307] 4-Chloro-3-trifluoromethylaniline gave the title compound
HPLC-MS Retention time 5.19 mins (MH)+ 376
EXAMPLE 85
5-Cyano-N-(4-methoxycarbonylphenyl)-4-phenylpyrimidine-2-amine
[0308] Methyl 4-aminobenzoate gave the title compound HPLC-MS
Retention time 4.58 mins (MH)+ 331
EXAMPLE 86
N-(4-Carboxymethylphenyl)-5-cyano-4-phenylpyrimidine-2-amine
[0309] 4-Aminophenylacetic acid gave the title compound HPLC-MS
Retention time 4.0 mins (MH)+ 331
EXAMPLE 87
5-Cyano-N-[4-(2-N,N-diethylaminoethylaminocarboxy)phenyl]-4-phenylpyrimidi-
ne-2-amine
[0310] Procainamide hydrochloride gave the title compound HPLC-MS
Retention time 3.33 mins (MH)+ 415.5
EXAMPLE 88
N-(3-Carboxyphenyl)-5-cyano-4-phenylpyrimidine-2-amine
[0311] 3-Aminobenzoic acid gave the title compound HPLC-MS
Retention time 4.03 mins (MH)+ 317
EXAMPLE 89
5-Cyano-4-phenyl-N-[3-(1,1,2,2-tetrafluoroethoxyphenyl)]pyrimidine-2-amine
[0312] 1,1,2,2-Tetrafluoroethoxyaniline gave the title compound
HPLC-MS Retention time 4.77 mins (MH)+ 389
EXAMPLE 90
5-Cyano-N-(3-oxazol-5-ylphenyl)-4-phenylpyrimidine-2-amine
[0313] 3-Oxazol-5-ylaniline gave the title compound HPLC-MS
Retention time 4.4 mins (MH)+ 340
EXAMPLE 91
5-Cyano-N-[2-(4-fluorophenoxy)pyridin-5-yl)-4-phenylpyrimidine-2-amine
[0314] 5-Amino-2-(4-fluorophenoxy)pyridine gave the title compound
HPLC-MS Retention time 4.72 mins (MH)+ 384
EXAMPLE 92
5-Cyano-N-(4-methoxycarbonylthien-3-yl)-4-phenylpyrimidine-2-amine
[0315] Methyl 3-aminothiophene-4-carboxylate gave the title
compound HPLC-MS Retention time 5.09 min (MH)+ 337
EXAMPLE 93
5-Cyano-N-(2-morpholinopyridin-5-yl)-4-phenylpyrimidine-2-amine
[0316] 2-Morphilino-5-aminopyridine gave the title compound HPLC-MS
Retention time 4.1 min (MH)+ 359
EXAMPLE 94
5-Cyano-N
-[4-(6-methylbenzothiazol-2-yl)phenyl]]pyrimidine-2-amine
[0317] 2-Amino-6-methylbenzothiazole gave the title compound
HPLC-MS Retention time 5.7 min (MH)+ 420.5
EXAMPLE 95
5-Cyano-N-(4-isopropyl-2-methylphenyl)-4-phenylpyrimidine-2-amine
[0318] 4-isopropyl-2-methylaniline gave the title compound HPLC-MS
Retention time 5.35 mins (MH)+ 329
EXAMPLE 96
5-Cyano-N-3-methanesulphonyl)phenyl-4-phenylpyrimidine-2-amine
[0319] 3-(Methanesulphonyl)aniline gave the title compound HPLC-MS
Retention time 4.12 mins (MH)+ 351
EXAMPLE 97
5-Cyano-N-[2-(3,5-dimethylpyrazol-1-yl)pyridin-3-yl)-4-phenylpyrimidine-2--
amine
[0320] 3-Amino-2-(3,5-dimethylpyrazol-1-yl)pyridine gave the title
compound HPLC-MS Retention time 5.12 mins (MH)+ 368
EXAMPLE 98
5-Cyano-N-(4-ethylphenyl)-4-phenylpyrimidine-2-amine
[0321] 4-Ethylaniline gave title compound HPLC-MS Retention time
4.99 mins (MH)+ 301
EXAMPLE 99
5-Cyano-N-(8-methoxyquinol-6-yl)-4-phenylpyrimidine-2-amine
[0322] 6-Amino-8-methoxyquinoline sgave the title compound HPLC-MS
Retention time 3.96 mins (MH)+ 354
EXAMPLE 100
N-4-n-Butoxyphenyl)-5-cyano-4-phenylpyrimidine-2-amine
[0323] 4-n-Butoxyaniline gave the title compound HPLC-MS Retention
time 5.19 mins (MH)+ 345.4
EXAMPLE 101
5-Cyano-N-(2-oxo-2-phenylethyl)-4-phenylpyrimidine-2-amine
[0324] 2-Oxo-2-phenethylamine gave the title compound HPLC-MS
Retention time 4.4 mins (MH)+ 315
EXAMPLE 102
5-Cyano-N-[3-n-(4-methylpiperazin-1-yl)propyl]-4-phenylpyrimidine-2-amine
[0325] 3-N-(4-Methylpiperazin-1-yl)propylamine gave the title
compound HPLC-MS Retention time 3.1 mins (MH)+ 337
EXAMPLE 103
N-(Adamant-1-yl)-5-cyano-4-phenylpyrimidine-2-amine
[0326] 1-Adamantanamine gave the title compound HPLC-MS Retention
time 6.0 mins (MH)+ 331
EXAMPLE 104
5-Cyano-N-(2-morpholinoethyl)-4-phenylpyrimidine-2-amine
[0327] 2-Morpholinoethylamine gave the title compound HPLC-MS
Retention time 3.1 mins (MH)+ 310
EXAMPLE 105
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(1,2,4-triazol-1-yl)pheny-
l]pyrimidine-2-amine citrate
[0328] The compound of Example 11 (100 mg, 0.25 mmol) was dissolved
in acetone/methanol (25 mL, 1:1 v/v) and to this citric acid (52.5
mg, 0.25 mmol) was added. The resulting solution was diluted with
diethyl ether (20 ml) to give the title compound (145 mg). .delta.H
(d.sup.6 DMSO) 10.73 (1H, bs), 9.21 (1H, s), 9.01 (1H, s), 8.20
(1H, s), 8.02 (2H, d, J 8.4 Hz), 7.94 (2H, d, J 8.7 Hz), 7.80 (2H,
d, J 7.4 Hz, 7.78 (2H, d, J 8.3 Hz), 2.49 (4H, m) and 1.65 (6H,
s)
[0329] Biological Activity
[0330] The following assays were used to demonstrate the activity
and selectivity of compounds according to the invention:
[0331] The activity of the compounds against KDR kinase and a FGFR
Kinase [FGFR2 kinase] can be determined in the following two
assays:
[0332] KDR Kinase and FGFr2 Kinase
[0333] The activities of recombinant KDR kinase and FGFr2 kinase
were determined by measuring their ability to transfer the
.gamma.-phosphate from [.sup.33P]ATP to polyglutamic acid--tyrosine
(pEY).
[0334] The assay methodology employed for both kinases is identical
except that in the assay of KDR kinase the diluent used throughout
was 20 mM HEPES pH 7.25 containing 2 mM MnCl.sub.2, 2 mM
MnCl.sub.2, 5 mM DTT and 0.05% Brij 35, whereas in the FGFr2 assay
10 mM MnCl.sub.2 is used instead of 2 mM MnCl.sub.2 and 2 mM
MnCl.sub.2.
[0335] The assay was conducted in a total volume of 202 .mu.l
containing 1-10 ng kinase, 5 .mu.g/ml pEY (4:1) (Sigma, UK), 1
.mu.M ATP (containing .about.50,000 cpm [.sup.33P]ATP (Amersham
International, UK) (Sigma, UK) and test inhibitors at the
appropriate concentration. The test inhibitors were dissolved in
DMSO and added such that the final concentration of DMSO in the
assay did not exceed 2% (v/v). The assay was initiated by addition
of kinase and terminated after 10 minutes incubation at room
temperature by addition of 50 .mu.l of 20 mM HEPES pH 7.25
containing 0.125M EDTA and 10 mM ATP. A 200 .mu.l aliquot was
applied to the well of a Millipore (UK) MAFC filter plate
containing 100 .mu.l of 30% (w/v) trichloroacetic acid (TCA). The
plate was then placed on a suitable manifold and connected to a
vacuum. After complete elimination of the liquid each well was
washed under vacuum using five volumes (100 .mu.l per wash) of 10%
(w/v) TCA and finally two volumes (100 .mu.l per wash) of ethanol.
The bottom of the filter plate was then sealed and 100 .mu.l per
well of Ultima Gold (Beckham, UK) scintillant was added to each
well. The readioactivity was measured using an appropiate
scintillation counter such as a Wallac Trilux or Packard TopCount.
The IC.sub.50 value for each inhibitor was obtained from log dose
inhibition curves fitted to the four-parameters logistic
equation.
[0336] In this assay compounds according to the invention have
IC.sub.50 values of around 1 .mu.M and below, the most active
compounds having values of 100 nM and below.
[0337] The selectivity of compounds according to the invention can
be determined in the following assays:
[0338] p56.sup.lck Kinase Assay
[0339] The tyrosine kinase activity of p56.sup.lck was determined
using a RR-src peptide (RRLIEDNEYTARG) and [.gamma.-.sup.33P]ATP as
substrates. Quantitation of the .sup.33P-phosphorylated peptide
formed by the action of p56.sup.lck was achieved using an adaption
of the method of Geissler et al (J. Biol. Chem. (1990) 265,
22255-22261).
[0340] All assays were performed in 20 mM HEPES pH 7.5 containing
10 mM MgCl.sub.2, 10 mM MnCl.sub.2, 0.05% Brij, 1 .mu.M ATP (0.5
.mu.Ci[.gamma.-.sup.33P]ATP) and 0.8 mg/ml RR-src. Inhibitors in
dimethylsulphoxide (DMSO) were added such that the final
concentration of DMSO did not exceed 1%, and enzyme such that the
consumption of ATP was less than 10%. After incubation at
30.degree. C. for 15 min, the reaction was terminated by the
addition of one-third volume of stop reagent (0.25 mM EDTA and 33
mM ATP in dH.sub.2O). A 15 .mu.l aliquot was removed, spotted onto
a P-30 filtermat (Wallac, Milton Keynes, UK), and washed
sequentially with 1% acetic acid and de-ionised water to remove
ATP. The bound .sup.33P-RR-src was quantitated by scintillation
counting of the filtermat in a Betaplate scintillation counter
(Wallac, Milton Keynes, UK) after addition of Meltilex scintillant
(Wallac, Milton Keynes, UK).
[0341] The dpm obtained, being directly proportional to the amount
of .sup.33P-RR-src produced by p56.sup.lck, were used to determine
the IC.sub.50 for each compound. The IC.sub.50 was defined as the
concentration of compound required to reduce the production of
.sup.33P-RR-src by 50%.
[0342] In this test, compounds according to the invention have
IC.sub.50 values of 10 .mu.M and above.
[0343] Zap-70 Kinase Assay
[0344] The tyrosine kinase activity of Zap-70 was determined using
a capture assay based on that employed above for p56.sup.lck. The
RR-src peptide was replaced with polyGlu-Tyr (Sigma; Poole, UK) at
a final concentration of 17 .mu.g/ml. After addition of the stopped
reaction to the filtermat, trichloroacetic acid 10% (w/v) was
employed as the wash reagent instead of acetic acid and a final
wash in absolute ethanol was also performed before scintillation
counting. IC.sub.50 values were determined as described above in
the p.sub.56.sup.lck assay.
[0345] In this test the compounds of the invention have IC.sub.50
values of around 10 .mu.M and above.
[0346] EGFr Kinase Assay
[0347] The tyrosine kinase activity of the EGF receptor (EGFr) was
determined using a similar methodology to the p56.sup.lck kinase
assay, except that the RR-src peptide was replaced by a peptide
substrate for EGFr obtained from Amersham International pic (Little
Chalfont, UK) and used at the manufacturer's recommended
concentration. IC.sub.50 values were determined as described
previously in the p56.sup.lck assay.
[0348] Protein Kinase C Assay
[0349] Inhibitor activity against protein kinase C (PKC) was
determined using PKC obtained from Sigma Chemical Company (Poole,
UK) and a commercially available assay system (Amersham
International pic, Amersham, UK). Briefly, PKC catalyses the
transfer of the y-phosphate (.sup.32p) of ATP to the threonine
group on a peptide specific for PKC. Phosphorylated peptide is
bound to phosphocellulose paper and subsequently quantified by
scintillation counting. The inhibitor potency is expressed as
either (i) the concentration required to inhibit 50% of the enzyme
activity (IC.sub.50) or (ii) the percentage inhibition achieved by
10 .mu.M inhibitor.
[0350] In this test the compounds of the invention have IC.sub.50
values of around 10 .mu.M and above.
* * * * *