U.S. patent application number 10/115452 was filed with the patent office on 2002-08-29 for pyrimidinone compounds and pharmaceutical compositions containing them.
Invention is credited to Hickey, Deirdre Mary Bernadette, Ife, Robert John, Leach, Colin Andrew, Pinto, Ivan Leo, Porter, Roderick Alan, Smith, Stephen Allan.
Application Number | 20020120139 10/115452 |
Document ID | / |
Family ID | 26312554 |
Filed Date | 2002-08-29 |
United States Patent
Application |
20020120139 |
Kind Code |
A1 |
Hickey, Deirdre Mary Bernadette ;
et al. |
August 29, 2002 |
Pyrimidinone compounds and pharmaceutical compositions containing
them
Abstract
A group of novel pyrimidone compounds are inhibitors of the
enzyme LDL PLA2 and therefore of use in treating
atherosclerosis.
Inventors: |
Hickey, Deirdre Mary
Bernadette; (Saffron Walden, GB) ; Ife, Robert
John; (Stevenage, GB) ; Leach, Colin Andrew;
(Stevenage, GB) ; Pinto, Ivan Leo; (Sutton,
GB) ; Porter, Roderick Alan; (Ashwell, GB) ;
Smith, Stephen Allan; (Bishops Stortford, GB) |
Correspondence
Address: |
GLAXOSMITHKLINE
Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Family ID: |
26312554 |
Appl. No.: |
10/115452 |
Filed: |
April 2, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10115452 |
Apr 2, 2002 |
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09530713 |
Jun 28, 2000 |
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09530713 |
Jun 28, 2000 |
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PCT/EP98/06988 |
Oct 23, 1998 |
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Current U.S.
Class: |
544/309 ;
544/123; 544/295; 544/60 |
Current CPC
Class: |
C07D 249/08 20130101;
A61P 29/00 20180101; C07D 239/56 20130101; C07D 233/56 20130101;
A61P 25/18 20180101; C07D 401/06 20130101; C07D 409/14 20130101;
C07D 239/52 20130101; C07D 405/06 20130101; A61P 9/10 20180101;
A61P 9/12 20180101; C07D 407/14 20130101; C07D 403/06 20130101;
C07D 417/06 20130101; C07D 401/14 20130101; A61P 43/00 20180101;
A61P 3/10 20180101; C07D 417/14 20130101; A61P 19/02 20180101; C07D
231/12 20130101; A61P 25/28 20180101; A61P 9/02 20180101 |
Class at
Publication: |
544/309 ; 544/60;
544/295; 544/123 |
International
Class: |
C07D 417/02; C07D
413/02; C07D 43/02; C07D 239/46 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 6, 1997 |
GB |
9723352.2 |
Nov 6, 1997 |
GB |
9723358.9 |
Claims
1. A compounds of formula (I): 608in which: Z is a bond and R.sup.1
is halogen; or Z is CR.sup.3R.sup.4, where R.sup.3 and R.sup.4 are
each hydrogen or C.sub.(1-4)alkyl, or R.sup.3 and R.sup.4 together
with the intervening carbon atom form a C.sub.(3-6)cycloalkyl ring;
and R.sup.1 is an aryl or heteroaryl group, optionally substituted
by 1, 2, 3 or 4 substituents selected from C.sub.(1-18)alkyl,
C.sub.(1-18)alkoxy, C.sub.(1-18)alkylthio, arylC.sub.(1-18)alkoxy,
oxo, hydroxy, halogen, CN, COR.sup.5, COOR.sup.5,
CONR.sup.5R.sup.6, NR.sup.5COR.sup.6, SO.sub.2NR.sup.5R.sup.6,
NR.sup.5SO.sub.2R.sup.6, NR.sup.5R.sup.6, mono to
perfluoro-C.sub.(1-4)alkyl and mono to perfluoro-C.sub.(1-4)alkoxy;
X is O or S; Y is a group of formula -A.sup.1-A.sup.2-A.sup.3- in
which A.sup.1 and A.sup.3 each represent a bond or a straight chain
or branched C.sub.(1-10)alkylene group and A.sup.2 represents a
bond or O, S, SO, SO.sub.2, CO, C.dbd.CH.sub.2, C.dbd.CH,
C.ident.C, CONH, NHCO, or CR.sup.5R.sup.6, providing that when
A.sup.2 is O, S, SO, SO.sub.2 or CONH, A.sup.3 contains at least
two carbon atoms linking the A.sup.2 group and the CH.sub.2 group
in formula (I); R.sup.2 is an aryl or heteroaryl group, optionally
substituted by 1, 2, 3 or 4 substituents selected from the
substituents hereinbefore defined for R.sup.1, as well as aryl and
arylC.sub.(1-4)alkyl; W is a bond and R.sup.7 is hydrogen; or W is
SO.sub.2 or a bond; and R.sup.7 is R.sup.1 or a hydrocarbyl group
which hydrocarbyl group may be optionally interupted within the
carbon chain by a group selected from O, COO, OCO, CO, CONR.sup.8,
NR.sup.8CO, NR.sup.8CONR.sup.9, NR.sup.8COO, OCONR.sup.8, and
NR.sup.8, and which hydrocarbyl group may also be optionally
substituted by 1 or 2 substituents selected from mono to
perfluoro-C.sub.(1-4)alkyl, OR.sup.8, COOR.sup.8,
CONR.sup.8R.sup.9, NR.sup.8COR.sup.9, NR.sup.8CONR.sup.9R.sup- .10,
NR.sup.8COOR.sup.9, OCONR.sup.8R.sup.9, NR.sup.11R.sup.12 and
R.sup.1; R.sup.5 and R.sup.6 are independently hydrogen or
C.sub.(1-20)alkyl, for instance C.sub.(1-4)alkyl (e.g. methyl or
ethyl); R.sup.8, R.sup.9 and R.sup.10 are independently selected
from hydrogen, C.sub.(1-20)alkyl (for instance C.sub.(1-15)alkyl),
(which may optionally be fluorinated, including up to
perfluorinated on the terminal 1 to 3 carbon atoms),
C.sub.(1-20)alkenyl (preferably C.sub.(12-18)alkenyl), aryl,
arylC.sub.(1-10)alkyl, C.sub.(1-10)alkoxyC.sub.(1-10)alkyl, or
aryloxyC.sub.(1-10)alkyl and in which an aryl group may have one or
two substituents selected from halogen, C.sub.(1-20)alkyl,
C.sub.(1-20)alkoxy, aryloxy and COOC.sub.(1-20)alkyl; and R.sup.11
and R.sup.12 are independently selected from one of the values
hereinbefore defined for R.sup.8 and R.sup.9 or R.sup.11 and
R.sup.12 together with the nitrogen atom to which they are attached
form a 5- to 7 membered ring optionally containing one or two
further heteroatoms selected from oxygen, nitrogen and sulphur, and
optionally substituted by one or two substituents selected from
hydroxy, oxo, C.sub.(1-4)alkyl, phenyl, or benzyl.
2. A compound as claimed in claim 1 in which Z is CH.sub.2.
3. A compound as claimed in claim 1 or 2 in which R.sup.1 is an
aryl group selected from phenyl, naphthyl, or a 5- or 6-membered,
monocyclic heteroaryl group containing 1 or 2 nitrogen
heteroatoms.
4. A compound as claimed in claim 3 in which R.sup.1 is selected
from pyridyl, pyrimidyl or pyrazolyl.
5. A compound as claimed in any one of claims 1 to 4 in which X is
S.
6. A compound as claimed in any one of claims 1 to 5 in which
A.sup.1, A.sup.2 and A.sup.3 each represent a bond or A.sup.1 and
A.sup.3 are straight chain C.sub.(1-10)alkylene groups and A.sup.2
is selected from CO, C.dbd.CH.sub.2 and O.
7. A compound as claimed in any one of claims 1 to 6 in which
R.sup.2 is phenyl optionally substituted by 1, 2 or 3 substituents
selected from halogen, C.sub.(1-4)alkyl, C.sub.(1-4)alkoxy, phenyl
and benzyl.
8. A compound as claimed in any one of claims 1 to 7 in which
R.sup.2YCH.sub.2X is a 4-fluorobenzylthio group.
9. A compound as claimed in any one of claims 1 to 8 in which W is
a bond.
10. A compound as claimed in any one of claims 1 to 9 in which
R.sup.7 when a hydrocarbyl group is selected from
C.sub.(1-20)alkyl, C.sub.(2-20)alkenyl, C.sub.(2-20)alkynyl,
C.sub.(3-6)cycloalkyl, C.sub.(3-6)cycloalkylC.sub.(1-5)alkyl, or
C.sub.(1-15)alkoxyC.sub.(1-10)a- lkyl each of which may be
optionally substituted by 1 or 2 substituents selected from mono to
perfluoro-C.sub.(1-4)alkyl, OR.sup.8, COOR.sup.8,
CONR.sup.8R.sup.9, NR.sup.8COR.sup.9, NR.sup.8CONR.sup.9R.sup.10,
NR.sup.8COOR.sup.9, OCONR.sup.8R.sup.9, NR.sup.11R.sup.12 and
R.sup.1.
11. A compound as claimed in any one of claims 1 to 10 in which W
is a bond and R.sup.7 is: (a) C.sub.(1-10)alkyl which is
substituted by one or two substituents selected from hydroxy,
C.sub.(1-10)alkoxy, COOC.sub.(1-10)alkyl, CONR.sup.8R.sup.9,
NR.sup.8CONR.sup.9R.sup.10, NHCOR.sup.8 (in which R.sup.8, R.sup.9
and R.sup.10 is each independently C.sub.(1-20)alkyl),
NR.sup.11R.sup.12, phenyl which may be optionally substituted by
COOC.sub.(1-6)alkyl and heteroaryl; (b) R.sup.7 is a phenyl or a
phenylC.sub.(1-8)alkyl group substituted in the phenyl ring by 1 or
2 substituents selected from C.sub.(6-12)alkyl, C.sub.(6-12)alkoxy,
COOH, COOC.sub.(6-12)alkyl and CONHC.sub.(6-12)alkyl; or (c)
R.sup.7 is heteroarylC.sub.(1-8)alkyl in which the heteroaryl ring
is monocyclic with 5 to 6 members and one or two heteroatoms
selected from nitrogen, oxygen and sulphur.
12. A compound as claimed in any one of claims 1 to 11 in which W
is a bond and R.sup.7 is a group of the formula
(CH.sub.2).sub.nBR.sup.13 where n is an integer from 1 to 6, B is
selected from NR.sup.14CO, CONR.sup.14, NR.sup.14CONR.sup.15,
NR.sup.15COO (in which R.sup.14 and R.sup.15 are independently
selected from hydrogen or C.sub.(1-6)alkyl) and R.sup.13 is
C.sub.(8-18)alkyl (which may optionally be fluorinated, including
up to perfluorinated on the terminal 1 to 3 carbon atoms),
C.sub.(8-18)alkenyl, phenyl C.sub.(1-6)alkyl and
phenylC.sub.(1-8)alkoxyC- .sub.(1-6)alkyl in which phenyl may be
optionally substituted by halogen or C.sub.(1-6)alkyl.
13. A compound selected from:
2-(8-Phenyloct-1-yl)thio-5-((1-benzyl-2-oxo--
pyrid-4-yl)methyl)pyrimidin-4-one;
2-(8-(4-Fluorophenyl)oct-1-yl)thio-5-((-
1-benzyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;hyl)pyrimidin-4-one;
2-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio-5-((1-benzyl-2-oxo-pyrid-4-yl)me-
thyl)pyrimidin-4-one;
2-(8-(4-Fluorophenyl)-8-oxooct-1-yl)thio-5-((1-benzy-
l-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;
2-(9-Phenylnon-1-yl)thio-5-((1--
benzyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;
2-(6-Phenylhex-1-yl)thio-5-
-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;
2-(7-Phenylhept-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin--
4-one
2-(8-Phenyloct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimi-
din-4-one;
2-(9-Phenylnon-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)p-
yrimidin-4-one;
2-(6-Benzyloxyhex-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)-
methyl)pyrimidin-4-one;
2-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio-5-((1-met-
hyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;
2-(8-Phenyloct-1-yl)thio-5-((-
1-butyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;
2-(8-Phenyloct-1-yl)thio--
5-((2,3-dimethylpyrid-5-yl)methyl)pyrimidin-4-one;
2-(6-Benzyloxyhex-1-yl)-
thio-5-((2,3-dimethylpyrid-5-yl)methyl)pyrimidin-4-one;
2-(8-Phenyloct-1-yl)thio-5-((2,4-dimethylpyrid-5-yl)methyl)pyrimidin-4-on-
e;
2-(5-Phenylpent-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one-
;
2-(N-(6-(4-Fluorophenyl)hexyl)carboxamidomethyl)thio-5-((2-methylpyrid-5-
-yl)methyl)pyrimidin-4-one;
2-(6-Benzyloxyhex-1-yl)thio-5-((2-methylpyrid--
5-yl)methyl)pyrimidin-4-one;
2-(8-Phenyloct-1-yl)thio-5-((2-methylpyrid-5--
yl)methyl)pyrimidin-4-one;
2-(7-Phenylhept-1-yl)thio-5-((2-methylpyrid-5-y-
l)methyl)pyrimidin-4-one;
2-(6-Phenylhex-1-yl)thio-5-((2-methylpyrid-5-yl)-
methyl)pyrimidin-4-one;
2-(9-Phenylnon-1-yl)thio-5-((2-methylpyrid-5-yl)me-
thyl)pyrimidin-4-one;
2-(6-(4-Chlorobenzyloxy)hex-1-yl)thio-5-((2-methylpy-
rid-5-yl)methyl)pyrimidin-4-one;
2-(6-(4-Fluorobenzyloxy)hex-1-yl)thio-5-(-
(2-methylpyrid-5-yl)methyl)pyrimidin-4-one;
2-(8-(4-Methoxyphenyl)-8-oxooc-
t-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one;
2-(8-(Methoxyphenyl)oct-1-yl)thio-5-((2-methyl
pyrid-5-yl)methyl)pyrimidi- n-4-one;
2-(8-(4-Fluorophenyl)oct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)-
pyrimidin-4-one;
2-(8-(4-Fluorophenyl)-8-oxooct-1-yl)thio-5-((2-methylpyri-
d-5-yl)methyl)pyrimidin-4-one;
2-(8-(4-Chlorophenyl)oct-1-y)thio-5-((2-met-
hylpyrid-5-yl)methyl)pyrimidin-4-one;
2-(8-(4-Chlorophenyl)-8-oxooct-1-yl)-
thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one;
2-(8-Phenyl-8-oxooct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4--
one;
2-(8-(4-Chlorophenyl)-8-hydroxyoct-1-yl)thio-5-((2-methylpyrid-5-yl)m-
ethyl)pyrimidin-4-one;
2-(8-(4-Methylphenyl)-8-oxooct-1-yl)thio-5-(((2-met-
hylpyrid-5-yl)methyl)pyrimidin-4-one;
2-(4-Phenylbut-1-yl)thio-5-((2-methy-
lpyrid-5-yl)methyl)pyrimidin-4-one;
2-(8-Phenyloct-1-yl)thio-5-((1-oxo-2-m-
ethylpyrid-5-yl)methyl)pyrimidin-4-one;
2-(8-Phenyloct-1-yl)thio-5-((2-met-
hoxypyrid-4-yl)methyl)pyrimidin-4-one,
2-(8-(4-Chlorophenyl)-8-oxooct-1-yl-
)thio-5-(pyrazin-2-ylmethyl)pyrimidin-4-one;
2-(8-Phenyloct-1-yl)thio-5-(p- yrid-2-ylmethyl)pyrimidin-4-one;
2-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio--
5-(thiazol-2-ylmethyl)pyrimidin-4-one;
2-(6-Phenylhex-1-yl)thio-5-(pyrid-3- -ylmethyl)pyrimidin-4-one;
2-(7-Phenylhept-1-yl)thio-5-(pyrid-3-ylmethyl)p- yrimidin-4-one;
2-(8-Phenyloct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-o- ne;
2-(9-Phenylnon-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one;
2-(6-Benzyloxyhex-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one;
2-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4--
one;
2-(8-(4-Fluorophenyl)non-8-en-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-
-4-one;
2-(6-(4-Chlorobenzoylamino)hex-1-yl)thio-5-(pyrid-3-ylmethyl)pyrim-
idin-4-one;
2-(8-(4-Bromophenyl)-8-oxooct-1-yl)thio-5-(pyrid-3-ylmethyl)py-
rimidin-4-one;
2-(7-(4-Chlorophenoxy)hept-1-yl)thio-5-(pyrid-3-ylmethyl)py-
rimidin-4-one;
2-(7-Phenoxyhept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-- one;
2-(7-Phenylthiohept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one;
2-(7-(4-Chlorophenylthio)hept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-o-
ne;
2-(6-(3-Chlorophenyl)hex-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one-
;
2-(7-Phenylsulfinylhept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one;
2-(7-(4-Chlorophenylsulfinyl)hept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-
-4-one;
2-(7-Phenylsulfonylhept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4--
one;
2-(7-(4-Chlorophenylsulfonyl)hept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrim-
idin-4-one;
2-(8-(3-Chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimid-
in-4-one;
2-(8-(3,4-Dichlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrim-
idin-4-one;
2-(8-(2-Thienyl)-8-oxooct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimi-
din-4-one;
2-(8-(2-Furyl)-8-oxooct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-
-4-one;
2-(8-(2-Pyridyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one;
2-(9-(4-Chlorophenyl)-9-oxonon-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4--
one;
2-(8-(3,4-Dichlorophenyl)oct-7-yn-1-yl)thio-5-(pyrid-3-ylmethyl)pyrim-
idin-4-one;
2-(8-(4-Acetylphenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimid-
in-4-one;
2-(8-(4-Methylnaphth-1-yl)-8-oxooct-1-yl)thio-5-(pyrid-3-ylmethy-
l)pyrimidin-4one;
2-(8-(4-Pyridyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimi-
din-4-one;
2-(8-(4-Chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidi-
n-4-one;
2-(4-(3-Phenylprop-1-yloxy)but-1-yl)thio-5-(pyrid-3-ylmethyl)pyri-
midin-4-one;
2-(6-Benzyloxyhex-1-yl)thio-5-(quinolin-3-ylmethyl)pyrimidin--
4-one;
2-(8-Phenyloct-1-yl)thio-5-(quinolin-3-ylmethyl)pyrimidin-4-one;
2-(8-Phenyloct-1-yl)thio-5-((4-methoxypyrid-2-yl)methyl)pyrimidin-4-one;
2-(8-Phenyloct-1-yl)thio-5-(2-oxopyrid-4-ylmethyl)pyrimidin-4-one;
2-(8-Phenyloct-1-yl)thio-5-(pyrid-4-ylmethyl)pyrimidin-4-one;
2-(6-Benzyloxyhex-1-yl)thio-5-(pyrid-4-ylmethyl)pyrimidin-4one;
2-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin--
4-one; 2-(8-Phenyloct-1-yl)thio-5-(fur-2-ylmethyl)pyrimidin-4-one;
2-(6-Benzyloxyhex-1-y;)thio-5-(fur-2-ylmethyl)pyrimidin-4-one;
2-(6-Benzyloxyhex-1-yl)thio-5-(fur-3-ylmethyl)pyrimidin-4-one;
2-(8-Phenyloct-1-yl) thio-5-(fur-3-ylmethyl)pyrimidin-4-one;
2-Benzylthio-5-((1-methyl-2-oxo-pyrid-4yl)methyl)pyrimidin-4one;
2-Benzylthio-5-(fur-2-ylmethyl)pyrimidin-4-one;
2-(3-Chlorobenzyl)thio-5-- (fur-2-ylmethyl)pyrimidin-4-one;
2-(4-Chlorobenzyl)thio-5-(fur-2-ylmethyl)- pyrimidin-4-one;
2-Benzylthio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-on- e;
2-Benzylthio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin-4-one;
2-Benzyl thio-5-(pyrazin-2-ylmethyl)pyrimidin-4-one;
2-Benzylthio-5-(thiazol-2-ylm- ethyl)pyrimidin-4-one;
2-(4-Chlorobenzyl)thio-5-(pyrid-3-ylmethyl)pyrimidi- n-4-one;
2-Benzylthio-5-(pyrid-3-ylmethyl)pyrimidin-4-one;
2-(3,4-Dichlorobenzyl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one;
2-Benzylthio-5-(pyrid-4-ylmethyl)pyrimidin-4-one;
2-(4-Chlorobenzyl)thio-- 5-(pyrid-4-ylmethyl)pyrimidin-4-one;
2-(3,4-Dichlorobenzyl)thio-5-(pyrid-4- -ylmethyl)pyrimidin-4-one;
2-Benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-- one;
2-Benzylthio-5-(2-(pyrid-4-yl)ethyl)pyrimidin-4-one,
2-Benzylthio-5-benzylpyrimidin-4-one;
2-(8-Phenyloct-1-yl)oxy-5-(pyrid-3-- ylmethyl)pyrimidin-4-one;
2-(8-(4-Chlorophenyl)-8-oxooct-1-yl)oxy-5-(pyrid-
-3-ylmethyl)pyrimidin-4-one;
2-(4-Phenylbut-1-yl)oxy-5-((2-methylpyrid-5-y-
l)methyl)pyrimidin-4-one;
2-(2-Phenylethyl)thio-5-((2-methylpyrid-5-yl)met-
hyl)pyrimidin-4-one;
2-(2-Phenylethyl)thio-5-((2-methoxypyrid-4-yl)methyl)-
pyrimidin-4-one;
2-Benzylthio-5-((1-methylpyrazol-4-yl)methyl)pyrimidin-4-- one;
2-(4-Fluorobenzylthio)-5-((pyrimid-5-yl)methyl)pyrimidin-4-one;
2-(3,4-Difluorobenzylthio)-5-((2-methoxypyrimid-5-yl)methyl)pyrimidin-4-o-
ne;
2-(4-Fluorobenzylthio)-5-((2-methoxypyrimid-5-yl)methyl)pyrimidin-4-on-
e;
2-(4-Fluorobenzylthio)-5-((2-benzyloxypyrimid-5-yl)methyl)pyrimidin-4-o-
ne;
1-(4-Hydroxycyclohexyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(py-
rimid-5-yl-methyl)pyrimidin-4-one;
1-(2-Methoxyethyl)-2-(8-(4-chlorophenyl-
)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)-pyrimidin-4-one;
1-(3-(1-Imidazolyl)prop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5--
(pyrimid-5-yl-methyl)pyrimidin-4-one;
1-(3-(1-Morpholino)prop-1-yl)-2-(8-(-
4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-(2-Oxo-1-pyrrolidino)prop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)-
thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-Dimethylaminoprop-1-yl)-2-
-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4--
one.
1-(3-Hydroxyprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(py-
rimid-5-ylmethyl)pyrimidin-4-one;
1-(3-Hydroxyprop-1-yl)-2-(8-(4-chlorophe-
nyl)oct-1-yl)thio-5-benzylpyrimidin-4-one;
1-(3-Methoxyprop-1-yl)-2-(8-(4--
chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-Phenylprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-
-5-ylmethyl)pyrimidin-4-one;
1-(5-Hydroxypent-1-yl)-2-(8-(4-chlorophenyl)--
8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Pyrid-2-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid--
5-ylmethyl)pyrimidin-4-one;
1-(Pyrid-2-ylmethyl)-2-(8-(4-chlorophenyl)oct--
1-yl)thio-5-benzylpyrimidin-4-one;
1-(Pyrid-3-ylmethyl)-2-(8-(4-chlorophen-
yl)-8-oxooct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-on-
e;
1-(Pyrid-3-ylmethyl)-2-(8-(4-chlorophenyl)-g-oxooct-1-yl)thio-5-(pyrimi-
d-5-ylmethyl)pyrimidin-4-one;
1-(Pyrid-3-ylmethyl)-2-(8-(4-chlorophenyl)oc-
t-1-yl)thio-5-benzylpyrimidin-4-one;
1-(Pyrid-4-ylmethyl)-2-(8-(4-chloroph-
enyl)oct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;
1-(Pyrid-4-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-((1-methy-
l-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;
1-(Pyrid-4-ylmethyl)-2-(8-(4-ch-
lorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Pyrid-4-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin-
-4-one;
1-(Pyrid-4-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thiopyrimidin-4-
-one;
1-(2-(Pyrid-2-yl)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(-
pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-(Pyrid-3-yl)ethyl)-2-(8-(4-chloro-
phenyl)-8-oxooct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin--
4-one;
1-(2-(Pyrid-3-yl)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5--
(pyrimid-5-ylmethyl)pyrimidin-4one;
1-(2-(Pyrid-4-yl)ethyl)-2-(8-(4-chloro-
phenyl)-8-oxooct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin--
4-one;
1-(2-(Pyrid-4-yl)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5--
(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-Phenylethyl)-2-(8-(4-chloropheny-
l)oct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;
1-(2-Phenylethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)-
pyrimidin-4-one;
1-(2-Methylprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl-
)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-Phenylsulfonyl-2-(8-(4-chlo-
rophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one;
1-Benzyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl-
)methyl)pyrimidin-4-one;
1-Benzyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-
-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;
1-Benzyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl-
)pyrimidin-4-one;
1-Benzyl-2-(8-phenyloct-1-yl)thio-5-((2-methylpyrid-5-yl-
)methyl)pyrimidin-4-one;
1-Benzyl-2-(8-phenyloct-1-yl)thio-5-((2-methoxypy-
rid-4-yl)methyl)pyrimidin-4-one;
1-Benzyl-2-(8-(4-chlorophenyl)-8-oxooct-1-
-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one;
1-(2-Thienylmethyl)-2-(8-(4--
chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2,2-Dimethylprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyr-
imid-5-ylmethyl)pyrimidin-4-one;
1-(2-(1-Piperidino)ethyl)-2-(8-(4-chlorop-
henyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-Hydroxyethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5--
ylmethyl)pyrimidin-4-one;
1-(2-Hydroxyethyl)-2-(8-(4chlorophenyl)oct-1-yl)-
thio-5-benzylpyrimidin-4-one;
1-Ethyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)-
thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Fur-2-ylmethyl)-2-(8-(4-chl-
orophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Fur-2-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin-4-
-one;
1-Methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-bromopyrimidin-4-
-one;
1-Methyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-
-4-yl)methyl)pyrimidin-4-one;
1-Methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl-
)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;
1-Methyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-
-4-one
1-Methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylme-
thyl)pyrimidin-4-one;
1-Methyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzyl-
pyrimidin-4-one;
1-Phenyl-2-(8-(4chlorophenyl)oct-1-yl)thio-5-((1-methyl-2-
-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;
1-Methylsulfonyl-2-(8-(4-chlorophe-
nyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one;
1-Benzyl-2-(8-phenyloct-1-yl)oxy-5-(pyrid-3-ylmethyl)pyrimidin-4-one;
1-(2-Methoxyethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-Phenylprop-1-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(5-Hydroxypent-1-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one-
;
1-(pyrid-2-ylmethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Pyrid-3-ylmethyl)-2-benzylthio-5-((-methyl-2-oxo-pyrid-4-yl)methyl)pyr-
imidin-4-one;
1-(Pyrid-4-ylmethyl)-2-benzylthio-5-benzylpyrimidin-4-one;
1-(2-(Pyrid-2-yl)ethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-on-
e;
1-(2-(Pyrid-3-yl)ethyl)-2-benzylthio-S-(pyrimid-5-ylmethyl)pyrimidin-4--
one;
1-(2-(Pyrid-4-yl)ethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin--
4-one;
1-(2-(Pyrid-4-yl)ethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidi-
n-4-one;
1-(2-Phenylethyl)-2-benzylthio-5-((2-methoxypyrid-4-yl)methyl)pyr-
imidin-4-one;
1-Benzyl-2-benzylthio-5-((2-methoxypyrid-4-yl)methyl)pyrimid-
in-4-one;
1-(2-Thienylmethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-
-4-one;
1-(2,2-Dimethylprop-1-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrim-
idin-4-one;
1-(Fur-2-ylmethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidi-
n-4-one;
1-Methyl-2-benzylthio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin-4o-
ne;
1-Benzyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyri-
midin-4-one;
1-(2-Phenylethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrim-
id-5-ylmethyl)pyrimidin-4-one;
1-Methyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-
-5-(pyrimid-5-ylmethyl)pyrimidin-4-one; 1
Benzyl-2-(8-(4-chlorophenyl)oct--
1-yl)thio-5-(pyrid-4-yl)pyrimidin-4-one;
1-Benzyl-2-(8-(4-chlorophenyl)-8--
oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-Phenylethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-y-
lmethyl)pyrimidin-4-one;
1-(Fur-2-ylmethyl)-2-(2-phenylethyl)thio-5-(pyrim-
id-5-ylmethyl)pyrimidin-4-one;
1-(2-Fluorobenzyl)-2-benzylthio-5-(pyrimid--
5-ylmethyl)pyrimidin-4-one;
1-(8-Phenyloctyl)-2-benzylthio-5-(pyrid-5-ylme-
thyl)pyrimidin-4-one;
1-(9-Phenylnonyl)-2-benzylthio-5-(pyrimid-5-ylmethyl-
)pyrimidin-4-one;
1-Benzyl-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-- one;
1-Benzyl-2-benzylthio-5-((1-methylpyrazol-4-yl)methyl)pyrimidin-4-one-
;
1-Benzyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2,2-Dimethylprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)py-
rimidin-4-one;
1-(2-Phenylethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimi-
din-4-one;
1-(Fur-2-ylmethyl)-2-(4-methylbenzyl)thio-5-(pyrimid-5-ylmethyl-
)pyrimidin-4-one;
1-(Fur-2-ylmethyl)-2-(2-fluorobenzyl)thio-5-(pyrimid-5-y-
lmethyl)pyrimidin-4one;
1-(Fur-2-ylmethyl)-2-(4-chlorobenzyl)thio-5-(pyrim-
id-5-ylmethyl)pyrimidin-4-one;
1-(Fur-2-ylmethyl)-2-(3-fluorobenzyl)thio-5-
-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Fur-2-ylmethyl)-2-(3-chlorobenzyl-
)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-Methyl-2-benzylthio-5-(pyri- mid-5-ylmethyl)pyrimidin-4-one;
1-((R)-Tetrahydofuran-2-ylmethyl)-2-benzyl-
thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-((S)-Tetrahydofuran-2-ylmeth-
yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(4-Fluorobenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-
-4-one;
1-(4-Bromobenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyr-
imidin-4-one;
1-(2-(6-(4-Fluorophenyl)hex-1-yloxy)ethyl)-2-(4-fluorobenzyl-
)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-Phenoxyethyl)-2-(3,4-dif-
luorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-(5-Phenylpent-1-yloxy)prop-1-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)-
pyrimidin-4-one;
1-(9-Phenylnonyl)-2-furfurylthio-5-(pyrimid-5-ylmethyl)py-
rimidin-4-one;
1-(9-Phenylnonyl)-2-(thiazol-2-ylmethyl)thio-5-(pyrimid-5-y-
lmethyl)pyrimidin-4-one;
1-(9-Phenylnonyl)-2-(thien-2-ylmethyl)thio-5-(pyr-
imid-5-ylmethyl)pyrimidin-4-one;
1-(9-Phenylnonyl)-2-(3,4-difluorobenzyl)t-
hio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-(2-Pent-1-ylphenyl)ethyl)--
2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-(3-Pent-1-ylphenyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmeth-
yl)pyrimidin-4-one;
1-(2-(4-Bromophenyl)ethyl)-2-(4-fluorobenzyl)thio-5-(p-
yrimid-5-ylmethyl)pyrimidin-4-one;
1-(5-Methylfuran-2-ylmethyl)-2-(4-fluor-
obenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-(2-Chlorophenyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-
pyrimidin-4-one;
1-(2-(Thien-2-yl)ethyl)-2-(3,4-difluorobenzyl)thio-5-(pyr-
imid-5-ylmethyl)pyrimidin-4-one;
1-(2-Phenylethyl)-2-(2,3,4-trifluorobenzy-
l)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-Phenylethyl)-2-(2,3,5-t-
rifluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-Phenylethyl)-2-(2,4,6-trifluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyr-
imidin-4-one;
1-(2-Phenylethyl)-2-(2,4-difluorobenzyl)thio-5-(pyrimid-5-yl-
methyl)pyrimidin-4-one;,
1-(2-Phenylethyl)-2-(2-fluorobenzyl)thio-5-(pyrim-
id-5-ylmethyl)pyrimidin-4-one;
1-(2-Phenylethyl)-2-furfurylthio-5-(pyrimid-
-5-ylmethyl)pyrimidin-4-one;
1-(2-Phenylethyl)-2-(thien-2-ylmethyl)thio-5--
(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-Phenylethyl)-2-(3,4,5-trifluorob-
enzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-Phenylethyl)-2-(3,4-
-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-Phenylethyl)-2-(3,5-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimi-
din-4-one;
1-(2-Phenylethyl)-2-(3-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-
pyrimidin-4-one;
1-(2-Phenylethyl)-2-(4-fluorobenzylithio-5-(pyrimid-5-ylm-
ethyl)pyrimidin-4-one;
1-(2-Phenylethyl)-2-(1-phenylethyl)thio-5-(pyrimid--
5-ylmethyl)pyrimidin-4-one;
1-(2-(4-Methoxyphenyl)ethyl)-2-(3,4-difluorobe-
nzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-(4-Pent-1-ylphenyl)e-
thyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Cycloprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-
-4-one;
1-(Dodec-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)py-
rimidin-4-one;
1-Ethyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimi-
din-4-one;
1-(-Methylethyl)-2-(4-fluorobenzylthio-5-(pyrimid-5-ylmethyl)py-
rimidin-4-one;
1-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl-
)pyrimidin-4-one;
1-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(2-oxopyrimid-5--
ylmethyl)pyrimidin-4-one;
1-Benzyl-2-benzylthio-5-(2-methoxypyrimid-5-ylme-
thyl)pyrimidin-4-one;
1-(2-Phenylethyl)-2-(3,4-difluorobenzyl)thio-5-(2-me-
thoxypyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Furan-2-ylmethyl)-2-(3,4-diflu-
orobenzyl)thio-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(2-methoxypyrimid-5-ylmethyl)pyri-
midin-4-one;
1-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(2-ethoxypyrimid-5-yl-
methyl)pyrimidin-4-one;
1-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(2-methylp-
yrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-Phenylethyl)-2-(4-fluorobenzyl)thi-
o-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;
1-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methy-
l)pyrimidin-4-one;
1-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(1-methyl-2-oxo-
pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Undec-1-yl)-2-(4-fluorobenzyl)thio--
5-(1-benzyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Undec-1-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-Methyl-2-(4-fluorobenzyl)thio-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin--
4-one;
1-Methyl-2-(4-fluorobenzyl)thio-5-(2-oxopyrimid-5-ylmethyl)pyrimidi-
n-4-one;
1-(4-Acetylphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)p-
yrimidin-4-one;
1-(3-(Non-1-yloxy)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimi-
d-5-ylmethyl)pyrimidin-4-one;
1-(3-(Dec-1-yl)phenyl)-2-(4-fluorobenzyl)thi-
o-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-Methyl-2-(4-fluorobenzyl)thio-5-
-(1-undecyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one;
1-Phenyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-Phenyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)p-
yrimidin-4-one;
1-(4-(Non-1-yloxyphenyl))-2-(4-fluorobenzyl)thio-5-(pyrimi-
d-5-ylmethyl)pyrimidin-4-one;
1-(4-Iodophenyl)-2-(4-fluorobenzyl)thio-5-(p-
yrimid-5-ylmethyl)pyrimidin-4-one;
1-(4-(Hex-1-yl)phenyl)-2-(4-fluorobenzy-
l)thio--(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(4-(Dec-1-yl)phenyl)-2-(4-f-
luorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-Ethoxycarbonylmethyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimi-
d-5-ylmethyl)pyrimidin-4-one;
1-(3-Ethoxycarbonylprop-1-yl)-2-(8-(4-chloro-
phenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-Ethoxycarbonylprop-1-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidi-
n-4-one;
1-(3-Ethoxycarbonylprop-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrim-
id-5-ylmethyl)pyrimidin-4-one;
1-(3-Ethoxycarbonylprop-1-yl)-2-(4-fluorobe-
nzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(5-Ethoxycarbonylpent-1-
-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(1-(Ethoxycarbonyl)cycloprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5--
ylmethyl)pyrimidin-4-one;
1-(4-Fluorobenzyloxycarbonylmethyl)-2-(4-fluorob-
enzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-Ethoxycarbonylmethyl-2-
-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(1-(Methoxycarbonyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl-
)pyrimidin-4-one
1-(trans-4-(Methoxycarbonyl)cyclohex-1-ylmethyl)-2-(4-flu-
orobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(trans-4-(Methoxycarbonyl)cyclohex-1-yl)-2-(4-fluorobenzyl)thio-5-(pyri-
mid-5-ylmethyl)pyrimidin-4one;
1-(3-Ethoxycarbonylprop-1-yl)-2-(4-fluorobe-
nzyl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;
1-(Ethoxycarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxypyrimid-5-ylm-
ethyl)pyrimidin-4-one;
1-(4-(Ethoxycarbonyl)benzyl)-2-(4-fluorobenzyl)thio-
-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(4-Methoxycarbonylbenzyl)-2-(8-(-
4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)-pyrimidin-4-one;
1-(3-Carboxyprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrim-
idin-4-one;
1-Carboxymethyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)p-
yrimidin-4-one;
1-(3-Carboxyprop-1-yl)-2-(4-fluorobenzyl)thio-5-((1-methyl-
-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;
1-(3-Carboxyprop-1-yl)-2-(3,4-di-
fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(5-Carboxypent-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)p-
yrimidin-4-one;
1-(4-Carboxybenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-yl-
methyl)-2-thiouracil;
1-(4-Carboxycyclohex-1-yl)-2-(4-fluorobenzyl)thio-5--
(pyrimid-5-ylmethyl)-2-thiouracil;
1-(3-Ethoxycarbonylphenyl)-2-(4-fluorob-
enzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-Ethoxycarbonylpheny-
l)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidi-
n-4-one;
1-(3-Carboxyphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-
pyrimidin-4-one;
1-(3-Carboxyphenyl)2-(8-(4-chlorophenyl)-8-oxooct-1-yl)th-
io-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(4-Ethoxycarbonylphenyl)-2-(4--
fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4 one;
1-(4-Ethoxycarbonylphenyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(py-
rimid-5-ylmethyl)pyrimidin-4-one;
1-(4-Carboxyphenyl)-2-(4-fluorobenzyl)th-
io-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(4-Carboxyphenyl)-2-(8-(4-chlo-
rophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(5-(Ethoxycarbonyl)fur-2-yl)-2-4fluorobenzyl)thio-5-(pyrimid-5-ylmethyl-
)pyrimidin-4-one;
1-(3-Ethoxycarbonyl-4-iodobenzyl)-2-(4-fluorobenzyl)thio-
-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-(Hept-1-yloxy)-4-methoxycarbo-
nylbenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-(Hept-1-yloxy)-4-methoxycarbonylbenzyl)-2-(4-fluorobenzyl)thio-5-(py-
rimid-5-ylmethyl)pyrimidin-4-one;
1-(3-Carboxy-4-(hept-1-yloxy)benzyl)-2-(-
4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-(Hept-1-yloxy)4-carboxybenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-y-
lmethyl)pyrimidin-4-one;
1-(3-Methoxycarbonyl-4-hydroxybenzyl)-2-(4-fluoro-
benzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-Methoxycarbonylben-
zyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-Carboxybenzyl)-2-(4-fluorobenzylithio-5-(pyrimid-5-ylmethyl)pyrimidi-
n-4-one;
1-(3,4-Di-(methoxycarbonyl)benzyl)-2-(4-fluorobenzyl)thio-5-(pyri-
mid-5-ylmethyl)pyrimidin-4-one;
1-Carboxamidomethyl-2-(8-(4-chlorophenyl)o-
ct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one;
1-Dimethylaminocarbonylm-
ethyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrim-
idin-4-one;
1-Carboxamidomethyl-2-benzylthio-5-((2-methoxypyrid-4-yl)methy-
l)pyrimidin-4-one;
1-(3-(Octadec-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobe-
nzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-(Octadec-9-(Z)-en-1y-
laminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyr-
imidin-4-one;
1-(3-(Octadec-9-(E)-en-1ylaminocarbonyl)prop-1-yl)-2-(4-fluo-
robenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-(N-Dodec-1yl-N-methylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-
-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-(N-Non-1-yl-N-methylaminocarb-
onyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-o-
ne;
1-(4-(Pent-1-ylaminocarbonyl)benzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-
-5-ylmethyl)pyrimidin-4-one;
1-(1-(6-(4-Fluorophenyl)hex-1-ylaminocarbonyl-
)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-(11-Dimethylaminoundec-1-ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzy-
l)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-(3-Ethoxyprop-1ylaminoc-
arbonyl)prop-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimi-
din-4-one;
1-(3-(5-(Methoxycarbonyl)-5-(benzykloxycarbonylamino)pent-1ylam-
inocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimi-
din-4-one;
1-(3-(5-(Methoxycarbonyl)pent-1ylaminocarbonyl)prop-1-yl)-2-(4--
fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-(Hex-1ylaminocarbonyl)prop-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrim-
id-5-ylmethyl)pyrimidin-4-one;
1-(3-(5-(t-Butoxycarbonylamino)pent-1ylamin-
ocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidi-
n-4-one;
1-(3-(6-(t-Butoxycarbonylamino)hex-1ylaminocarbonyl)prop-1-yl)-2--
(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-(Dec-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-
-ylmethyl)pyrimidin-4-one; 1-(3-(Dec-1
ylaminocarbonyl)prop-1-yl)-2-(4-flu-
orobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-(Hept-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid--
5-ylmethyl)pyrimidin-4-one;
1-(3-(Hex-1ylaminocarbonyl)prop-1-yl)-2-(4-flu-
orobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one; 1-(3-(Non-1
ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)p-
yrimidin-4-one;
1-(3-(Oct-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)th-
io-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-(Pent-1ylaminocarbonyl)prop-
-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-(N-Hex-1yl-N-methylaminocarbonyl)prop-1-yl)-2-(3,4-difluorobenzyl)th-
io-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(5-(2-methoxyethylaminocarbony-
l)pent-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4--
one;
1-(5-(2-Phenylethylaminocarbonyl)pent-1-yl)-2-(3,4-difluorobenzyl)thi-
o-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(5-(But-1-ylaminocarbonyl)pent--
1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(5-(N-(2-Phenylethyl)-N-methylaminocarbonyl)pent-1-yl)-2-(3,4-difluorob-
enzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(5-(N-But-1-yl-N-methy-
laminocarbonyl)pent-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl-
)pyrimidin-4-one;
1-((R)-1-(Hex-1-ylaminocarbonyl)ethylaminocarbonylmethyl-
)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-((S)-1-(Hex-1-ylaminocarbonyl)ethylaminocarbonylmethyl)-2-(4-fluorobenz-
yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-((S)-2-(Hex-1-ylaminocarb-
onyl)pyrrolidin-1-ylcarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-yl-
methyl)pyrimidin-4-one;
1-(1-Pyrrolidinocarbonylmethyl)-2-(4-fluorobenzyl)-
thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-Butoxyprop-1-ylaminocarbo-
nylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(6-Hydroxyhex-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimi-
d-5-ylmethyl)pyrimidin-4-one;
1-(6-(4-Fluorophenyl)hex-1-ylaminocarbonylme-
thyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Tridec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-yl-
methyl)pyrimidin-4-one;
1-(Tetradec-1-ylaminocarbonylmethyl)-2-(4-fluorobe-
nzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Octadec-1-ylaminocarbo-
nylmethyl)-2-(4-fluorobenzyl)thio-S-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Octadec-9-(Z)-en-1--ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(p-
yrimid-5-ylmethyl)pyrimidin-4-one;
1-(Octadec-9-(E)-en-1ylaminocarbonylmet-
hyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Dec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmet-
hyl)pyrimidin-4-one;
1-(Dodec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)t-
hio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
1-(Hept-1-ylaminocarbonylmethyl)-
-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Oct-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmet-
hyl)pyrimidin-4-one;
1-(Undec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)t-
hio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-Hydroxyethylaminocarbonylm-
ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-Methoxyethylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-
-ylmethyl)pyrimidin-4-one;
1-(2-Phenylethylaminocarbonylmethyl)-2-(4-fluor-
obenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-(4-Pent-1-ylphenyl)ethylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio--
5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Hex-1-ylaminocarbonylmethylamino-
carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-o-
ne;
1-(N-(Dodec-1-yl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio--
5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(N-(2-Phenylethyl)-N-methylaminoc-
arbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-on-
e;
1-(4-(But-1-ylaminocarbonyl)cyclohex-1-yl)-2-(4-fluorobenzyl)thio-5-(py-
rimid-5-ylmethyl)pyrimidin-4-one;
1-(4-(Hex-1-ylaminocarbonyl)cyclohex-1-y-
l)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(4-(2-Methoxyethylaminocarbonyl)cyclohex-1-yl)-2-(4-fluorobenzyl)thio-5-
-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(1-(6-(4-Fluorophenyl)hex-1-yl)ami-
nocarbonyl)cycloprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)py-
rimidin-4-one;
1-(1-(Non-1-ylaminocarbonyl)cycloprop-1-yl)-2-(4-fluorobenz-
yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-((R)-1-(Non-1-ylaminocarb-
onyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(1-(Dimethylamino)undec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-
-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-(6-(4-Fluorophenyl)hex-1-ylox-
y)ethylaminocabonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)py-
rimidin-4-one;
1-(5-(Methoxycarbonyl)-5-(benzyloxycarbonylamino)pent-1-yla-
minocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-
-4-one;
1-(5-(Methoxycarbonyl)pent-1-ylaminocarbonylmethyl)-2-(4-fluoroben-
zyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Non-1-ylaminocarbonylme-
thyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-Dimethylaminocarbonylmethyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethy-
l)pyrimidin-4-one;
1-(N-(2-Hydroxyethyl)-N-methylaminocabonylmethyl)-2-(4--
fluorobenzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(trans-4-(4-Fluorobenzylaminocarbonyl)cyclohex-1-ylmethyl)-2-(4-fluorob-
enzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(trans-4-(Pent-1-ylami-
nocarbonyl)cyclohex-1-ylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmeth-
yl)pyrimidin-4one;
1-(3-(Hex-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl-
)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;
1-(N-(N'-Hex-1-yl-N'-methylaminocarbonylmethyl)-N-methylaminocarbonylmeth-
yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(N-(N'-Hex-1-ylaminocarbonylmethyl)-N-methylaminocarbonylmethyl)-2-(4-f-
luorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(N-(N'-Hex-1-yl-N'-methylaminocarbonylmethyl)aminocarbonylmethyl)-2-(4--
fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-Phenylaminocarbonylmethyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-
pyrimidin-4one;
1-(4-Methoxycarbonylbenzylaminocarbonylmethyl)-2-(4-fluoro-
benzyl)thio-S-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(N-Benzylaminocarbony-
lmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one,
1-(N,N-Di-(but-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimr-
id-5-ylmethyl)pyrimidin-4-one;
1-(N-Methyl-N-(dodec-1-yl)aminocarbonylmeth-
yl)-2-(4-fluorobenzyl)thio-5-(2methoxypyrimid-5-ylmethyl)pyrimidin-4-one;
1-(N-Methyl-N-(oct-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2--
methoxypyrimid-5-ylmethyl)pyrimidin-4-one;
1-(N-Methyl-N-(oct-1-yl)aminoca-
rbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxypyrimid-5-ylmethyl)pyrimi-
din-4-one;
1-(N-Methyl-N-(oct-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)-
thio-5-(2-benzyloxypyrimid-5-ylmethyl)pyrimidin-4-one;
1-(N-Methyl-N-(dodec-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(-
2-oxopyrimid-5-ylmethyl)pyrimidin-4-one;
1-(N-Methyl-N-(oct-1-yl)aminocarb-
onylmethyl)-2-(4-fluorobenzyl)thio-5-(2-oxopyrimid-5-ylmethyl)pyrimidin-4--
one;
1-(3-(N-(Hept-1-yl)-N-methylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)t-
hio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-(N-Ethyl-N-methylaminocarb-
onyl)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(4-(Prop-1-ylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5--
ylmethyl)pyrimidin-4-one,
1-(4-(But-1-ylaminocarbonyl)phenyl)-2-(8-(4-chlo-
rophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(4-(Hex-1-yloxycarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylm-
ethyl)pyrimidin-4-one,
1-(4-Methylaminocarbonylbenzyl)-2-(4-fluorobenzyl)t-
hio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-Methylaminocarbonyl-4-(hep-
t-1-yloxy)benzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-
-one;
1-(2-(t-Butoxycarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-
-5-ylmethyl)pyrimidin-4-one,
1-(2-(Trifluoroacetylamino)ethyl)-2-(4-fluoro-
benzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-(Benzoylamino)ethy-
l)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-(Hex-1-ylcarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-yl-
methyl)pyrimidin-4-one;
1-(2-(5-Phenylpent-1-ylcarbonylamino)ethyl)-2-(4-f-
luorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-(Hept-1-ylcarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-y-
lmethyl)pyrimidin-4-one;
1-(2-Acetylaminoethyl)-2-(8-(4-chlorophenyl)-8-ox-
ooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(4-(tert-Butoxycarbonylamnino)but-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrim-
id-5-ylmethyl)pyrimidin-4-one;
1-(3-(Ethoxycarbonylamino)prop-1-yl)-2-(4-f-
luorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(3-(Benzylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-
-ylmethyl)pyrimidin-4-one;
1-(2-(Dodec-1-ylaminocarbonylamino)ethyl)-2-(4--
fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-(Hept-1-ylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimi-
d-5-ylmethyl)pyrimidin-4-one;
1-(2-(Oct-1-ylaminocarbonylamino)ethyl)-2-(4-
-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-(2-Thien-2-ylethylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-
-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-(1,1,3,3-Tetramethylbut-1-ylami-
nocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimi-
din-4-one;
1-(2-(4-(butoxycarbonyl)phenylaminocarbonylamino)ethyl)-2-(4-fl-
uorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-(4-(1-Methylethyl)phenylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)-
thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(2-(4-Methylphenylaminocarbo-
nylamino)ethyl)-2-(4-fluorobenzyl)thio-5-pyrimid-5-ylmethyl)pyrimidin-4-on-
e;
1-(2-(4-Ethoxyphenylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5--
(pyrimid-5-ylmethyl)pyrimidin-4-one; and
1-(2-(4-Phenoxyphenylaminocarbony-
lamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one-
.
14. A compound selected from:
2-(4-Fluorobenzylthio)-5-((pyrimid-5-yl)meth- yl)pyrimidin-4-one;
1-Methyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-
pyrimidin-4-one;
1-(Tetradec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)th-
io-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(N-(Dodec-1-yl)-N-methylaminoc-
arbonylmethyl)-2-(4-fluorobenzyl)thio-(pyrimid-5-ylmethyl)pyrimidin-4-one;
and
1-(N-Methyl-N-(dodec-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-
-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-one.
15. A pharmaceutical composition comprising a compound of formula
(I) as claimed in claim 1 and a pharmaceutically acceptable
carrier.
16. A compound of formula (I) as claimed in claim 1 for use in
therapy.
17. A compound of formula (I) as claimed in claim 1 for use in the
treatment of atherosclerosis.
18. A method of treating a disease state associated with activity
of the enzyme Lp-PLA.sub.2 which method involves treating a patient
in need thereof with a therapeutically effective amount of a
compound of formula (I) as claimed in claim 1.
19. A process for preparing a compound of formula (I) which process
comprises: (a) treating a compound of formula (IIA): 609 in which
R.sup.1 and Z are as hereinbefore defined; with a compound of
formula (III): R.sup.2YCH.sub.2L.sup.1 (III) in which Y and R.sup.2
are as hereinbefore defined and L.sup.1 is a leaving group e.g.
bromine or iodine: to give a compound of formula (IA): 610 in which
Z, Y, R.sup.1 and R.sup.2 are as hereinbefore defined and X is S;
or (b) treating a compound of formula (IV): 611 in which Z and
R.sup.1 are as hereinbefore defined and L.sup.2 is a leaving group,
e.g. halogen such as chlorine or bromine, alkylthio such as
methylthio, or --NHNO.sub.2, with a compound of formula (V):
R.sup.2YCH.sub.2XH (V) in which X, Y and R.sup.2 are as
hereinbefore defined: advantageously at an elevated temperature, in
a solvent such as pyridine, to give a compound of formula (IA); and
thereafter, and if so desired: treating a compound of formula (IA)
form (a) or (b) above with a compound of formula (VI):
R.sup.7WL.sup.1 (VI) in which L.sup.1, W and R.sup.7 are as
hereinbefore defined; to give a compound of formula (1B): 612 in
which X, Y, Z, R.sup.1 and R.sup.2 are as hereinbefore defined and
WR.sup.7 is as hereinbefore defined, other than --H; (c) treating a
compound of formula (IIB): 613 in which W is a bond, Z and R.sup.1
are as hereinbefore defined and R.sup.7 are as hereinbefore
defined, other then H, with a compound of formula (Ill) as
hereinbefore defined, to obtain a compound of formula (IB); and,
thereafter and if so desired; treating a compound of formula (IA)
or (IB) in which X is S with a compound of formula (V):
R.sup.2YCH.sub.2OH (VII) in which Y and R.sup.2 are as hereinbefore
defined; to give a corresponding compound of formula (I) in which X
is O; or (d) for a compound of formula (I) in which Z is a bond and
R.sup.1 represents halogen, treating a compound of formula (VIII):
614 in which W, Y, R.sup.2, and R.sup.7 are as hereinbefore
defined; with a halogenating agent, preferably with bromine to form
a compound of formula (I) in which Z is a bond and R.sup.1 is
bromine, the reaction being advantageously effected in a solvent
such as dichloromethane.
Description
[0001] The present invention relates to certain novel pyrimidinone
compounds, processes for their preparation, intermediates useful in
their preparation, pharmaceutical compositions containing them and
their use in therapy, in particular in the treatment of
atherosclerosis.
[0002] WO 95/00649 (SmithKline Beecham plc) describe the
phospholipase A2 enzyme Lipoprotein Associated Phospholipase
A.sub.2 (Lp-PLA.sub.2), the sequence, isolation and purification
thereof, isolated nucleic acids encoding the enzyme, and
recombinant host cells transformed with DNA encoding the enzyme.
Suggested therapeutic uses for inhibitors of the enzyme included
atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial
infarction, reperfusion injury and acute and chronic inflammation.
A subsequent publication from the same group further describes this
enzyme (Tew D et al, Arterioscler Thromb Vas Biol 1996:16;591-9)
wherein it is referred to as LDL-PLA.sub.2. A later patent
application (WO 95109921, Icos Corporation) and a related
publication in Nature (Tjoelker et al, vol 374, Apr 6, 1995, 549)
describe the enzyme PAF-AH which has essentially the same sequence
as Lp-PLA.sub.2 and suggest that it may have potential as a
therapeutic protein for regulating pathological inflammatory
events.
[0003] It has been shown that Lp-PLA.sub.2 is responsible for the
conversion of phosphatidylcholine to lysophosphatidylcholine,
during the conversion of low density lipoprotein (LDL) to its
oxidised form. The enzyme is known to hydrolyse the sn-2 ester of
the oxidised phosphatidylcholine to give lysophosphatidylcholine
and an oxidatively modified fatty acid. Both products of
Lp-PLA.sub.2 action are biologically active with
lysophosphatidylcholine, a component of oxidised LDL, known to be a
potent chemoattractant for circulating monocytes. As such,
lysophosphatidylcholine is thought play a significant role in
atherosclerosis by being responsible for the accumulation of cells
loaded with cholesterol ester in the arteries. Inhibition of the
Lp-PLA.sub.2 enzyme would therefore be expected to stop the build
up of these macrophage enriched lesions (by inhibition of the
formation of lysophosphatidylcholine and oxidised free fatty acids)
and so be useful in the treatment of atherosclerosis.
[0004] The increased lysophosphatidylcholine content of oxidatively
modified LDL is also thought to be responsible for the endothelial
dysfunction observed in patients with atherosclerosis. Inhibitors
of Lp-PLA.sub.2 could therefore prove beneficial in the treatment
of this phenomenon. An Lp-PLA.sub.2 inhibitor could also find
utility in other disease states that exhibit endothelial
dysfunction including diabetes, hypertension, angina pectoris and
after ischaemia and reperfusion.
[0005] In addition, Lp-PLA.sub.2 inhibitors may also have a general
application in any disorder that involves activated monocytes,
macrophages or lymphocytes, as all of these cell types express
Lp-PLA.sub.2. Examples of such disorders include psoriasis.
[0006] Furthermore, Lp-PLA.sub.2 inhibitors may also have a general
application in any disorder that involves lipid peroxidation in
conjunction with Lp-PLA.sub.2 activity to produce the two injurious
products, lysophosphatidylcholine and oxidatively modified fatty
acids. Such conditions include the aforementioned conditions
atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial
infarction, reperfusion injury and acute and chronic inflammation.
Further such conditions include various neuropsychiatric disorders
such as schizophrenia (see Psychopharmacology Bulletin, 31,
159-165, 1995).
[0007] Patent applications WO 96/12963, WO 96/13484, WO96/19451, WO
97/02242, W097/217675, W0971217676, WO 96/41098, and WO97/41099
(SmithKline Beecham plc) disclose inter alia various series of
4-thionyl/sulfinyl/sulfonyl azetidinone compounds which are
inhibitors of the enzyme Lp-PLA.sub.2. These are irreversible,
acylating inhibitors (Tew et al, Biochemistry, 37, 10087,
1998).
[0008] GB 1 582 527 describes, as compounds of formula (7), a group
of pyrimidone compounds of the formula (A): 1
[0009] in which Alk is lower alkyl, Het is selected from 2- or
4-imidazolyl, 2-pyridyl, 2-thiazolyl, 3-isothiazolyl,
1.2.5-thiadiazolyl and n is from 1 to 4. These compounds are said
to be useful as intermediates in the preparation of further
compounds which are H2 antagonists.
[0010] A new class of pyrimidone compounds has now been identified
which are inhibitors of the enzyme Lp-PLA.sub.2.
[0011] Accordingly, the present invention provides compounds of
formula (I): 2
[0012] in which:
[0013] Z is a bond and R.sup.1 is halogen; or
[0014] Z is CR.sup.3R.sup.4, where R.sup.3 and R.sup.4 are each
hydrogen or C.sub.(1-4)alkyl, or R.sup.3 and R.sup.4 together with
the intervening carbon atom form a C.sub.(3-6)cycloalkyl ring;
and
[0015] R.sup.1 is an aryl or heteroaryl group, optionally
substituted by 1, 2, 3 or 4 substituents selected from
C.sub.(1-18)alkyl, C.sub.(1-18)alkoxy, C.sub.(1-18)alkylthio,
arylC.sub.(1-18)alkoxy, oxo, hydroxy, halogen, CN, COR.sup.5,
COOR.sup.5, CONR.sup.5R.sup.6, NR.sup.5COR.sup.6,
SO.sub.2NR.sup.5R.sup.6, NR.sup.5SO.sub.2R.sup.6, NR.sup.5R.sup.6,
mono to perfluoro-C.sub.(1-4)alkyl and mono to
perfluoro-C.sub.(1-4)alkoxy;
[0016] X is O or S;
[0017] Y is a group of formula -A.sup.1-A.sup.2-A.sup.3- in which
A.sup.1 and A.sup.3 each represent a bond or a straight chain or
branched C.sub.(1-10)alkylene group and A.sup.2 represents a bond
or O, S, SO, SO.sub.2, CO, C.dbd.CH.sub.2, C.dbd.CH, C.ident.C,
CONH, NHCO, or CR.sup.5R.sup.6, providing that when A.sup.2 is O,
S, SO, SO.sub.2 or CONH, A.sup.3 contains at least two carbon atoms
linking the A.sup.2 group and the CH.sub.2 group in formula
(I);
[0018] R.sup.2 is an aryl or heteroaryl group, optionally
substituted by 1, 2, 3 or 4 substituents selected from the
substituents hereinbefore defined for R.sup.1, as well as aryl and
arylC.sub.(1-4)alkyl;
[0019] W is a bond and R.sup.7 is hydrogen; or
[0020] W is SO.sub.2 or a bond; and
[0021] R.sup.7 is R.sup.1 or a hydrocarbyl group which hydrocarbyl
group may be optionally interupted within the carbon chain by a
group selected from O, COO, OCO, CO, CONR.sup.8, NR.sup.8CO.
NR.sup.8CONR.sup.9, NR.sup.8COO, OCONR.sup.8, and NR.sup.8, and
which hydrocarbyl group may also be optionally substituted by 1 or
2 substituents selected from mono to perfluoro-C.sub.(1-4)alkyl,
OR.sup.8, COOR.sup.8, CONR.sup.8R.sup.9, NR.sup.8COR.sup.9,
NR.sup.8CONR.sup.9R.sup.10, NR.sup.8COOR.sup.9, OCONR.sup.8R.sup.9,
NR.sup.11R.sup.12 and R.sup.1;
[0022] R.sup.5 and R.sup.6 are independently hydrogen or
C.sub.(1-20)alkyl, for instance C.sub.(1-4)alkyl (e.g. methyl or
ethyl);
[0023] R.sup.8, R.sup.9 and R.sup.10 are independently selected
from hydrogen, C.sub.(1-20)alkyl (for instance C.sub.(1-15)alkyl),
(which may optionally be fluorinated, including up to
perfluorinated on the terminal 1 to 3 carbon atoms),
C.sub.(1-20)alkenyl (preferably C.sub.(12-18)alkenyl), aryl,
arylC.sub.(1-10)alkyl, C.sub.(1-10)alkoxyC.sub.(1-10)alkyl, or
aryloxyC.sub.(1-10)alkyl and in which an aryl group may have one or
two substituents selected from halogen, C.sub.(1-20)alkyl,
C.sub.(1-20)alkoxy, aryloxy and COOC.sub.(1-20)alkyl; and
[0024] R.sup.11 and R.sup.12 are independently selected from one of
the values hereinbefore defined for R.sup.8 and R.sup.9 or R.sup.11
and R.sup.12 together with the nitrogen atom to which they are
attached form a 5- to 7 membered ring optionally containing one or
two further heteroatoms selected from oxygen, nitrogen and sulphur,
and optionally substituted by one or two substituents selected from
hydroxy, oxo, C.sub.(1-4)alkyl, phenyl, or benzyl.
[0025] Preferably, Z is CH.sub.2.
[0026] Representative examples of R.sup.1 when an aryl group
include phenyl and naphthyl. Representative examples of R.sup.1
when a heteroaryl group include pyridyl, pyrimidyl, pyrazolyl,
furyl, thienyl, thiazolyl, quinolyl, benzothiazolyl, pyridazolyl
and pyrazinyl.
[0027] Preferably R.sup.1 is a 5- or 6-membered, monocyclic
heteroaryl group containing 1 or 2 nitrogen heteroatoms, preferably
pyridyl, pyrimidyl or pyrazolyl, more preferably, pyrid-4-yl or
pyrimid-5-yl and optionally substituted by 1 or 2 substituents
preferably selected from arylC.sub.(1-4)alkyl (e.g. benzyl),
C.sub.(1-18)alkyl (e.g. methyl or ethyl), halogen (e.g. chlorine),
oxo, hydroxy, C.sub.(1-4)alkoxy (e.g. methoxy) and
arylC.sub.(1-4)alkoxy (e.g. benzyloxy). More preferably, R.sup.1 is
pyrimid-5-yl or a 2-oxo-pyrimid-5-yl group, optionally substituted
at N-1 by C.sub.(1-18)alkyl (e.g. undecyl, methyl or ethyl), or a
2-C.sub.(1-4)-alkoxy- or arylC.sub.(1-4)alkoxy-pyrimid-5-yl
group.
[0028] Preferably, ZR.sup.1 is 2-oxo-pyrid-4-ylmethyl,
pyrimid-5-ylmethyl or 2-oxo-pyrimid-5-ylmethyl in which the
2-oxo-pyrimid-5-yl moiety is as hereinbefore defined.
[0029] Preferably X is S.
[0030] Preferred compounds of formula (I) include those in which Y
is a bond, i.e. A.sup.1, A.sup.2 and A.sup.3 each represent a bond.
Other preferred examples of the groups A.sup.1 and A.sup.3 are
straight chain C.sub.(1-10)alkylene groups. When A.sup.2 is other
than a bond, A.sup.1 is preferably a bond. Preferred examples of
A.sup.2 when other than a bond include CO, C.dbd.CH.sub.2 and O,
the CO group being especially preferred. Other preferred examples
of Y are (CH.sub.2).sub.7 and CO(CH.sub.2).sub.6.
[0031] Representative examples of R.sup.2 when an aryl group
include phenyl and naphthyl. Representative examples of R.sup.2
when a heteroaryl group include pyridyl, pyrimidinyl, pyrazolyl,
furanyl, thienyl, thiazolyl, quinolyl, benzothiazolyl, pyridazolyl
and pyrazinyl Preferrably, R.sup.2 is phenyl optionally substituted
by 1, 2 or 3 substituents selected from halogen (e.g. chlorine or
fluorine), C.sub.(1-4)alkyl (e.g. methyl or ethyl) or
C.sub.(1-4)alkoxy (e.g. methoxy). Further optional substituents
include phenyl and benzyl.
[0032] Representative examples of R.sup.2YCH.sub.2X include
4-fluorobenzylthiogroup, 4-chlorophenylheptylthio and
4-chlorophenyl-1-oxaheptylthio. Preferably, R.sup.2YCH.sub.2X is
4-fluorobenzylthio group.
[0033] Preferably W is a bond.
[0034] Representative examples of R.sup.7 when a hydrocarbyl group
include C.sub.(1-20)alkyl. C.sub.(2-20)alkenyl,
C.sub.(2-20)alkynyl, C.sub.(3-6)cycloalkyl,
C.sub.(3-6)cycloalkylC.sub.(1-5)alkyl, or
C.sub.(1-15)alkoxyC.sub.(1-10)alkyl each of which may be optionally
substituted by 1 or 2 substituents as hereinbefore defined.
[0035] Preferably, W is a bond and R.sup.7 is C.sub.(1-20)alkyl,
especially C.sub.(10-20)alkyl. Preferably, R.sup.7 is also
C.sub.(1-10)alkyl, more preferably a C.sub.(1-6)alkyl which is
substituted by one or two substituents selected from hydroxy,
C.sub.(1-10)alkoxy (e.g. methoxy), COOC.sub.(1-10)alkyl (e.g.
COOCH.sub.3, COOC.sub.2H.sub.5), CONR.sup.8R.sup.9,
NR.sup.8CONR.sup.9R.sup.10, NHCOR.sup.8 (in which R.sup.8, R.sup.9
and R.sup.10 is each independently C.sub.(1-20)alkyl e.g. methyl).
Further optional substituents include aryl, preferably phenyl which
may be optionally substituted by COOC.sub.(1-6)alkyl (e.g. methyl)
and heteroaryl (for instance pyridyl, imidazolyl, furanyl, thienyl
and 2-oxo pyrrolidinyl). Preferred examples of the substituent
NR.sup.11R.sup.12 include morpholino, piperidino or
2-oxo-pyrrolidino group.
[0036] A preferred sub-group of compounds of formula (I) are those
in which W is a bond and R.sup.7 is a phenyl or a
phenylC.sub.(1-8)alkyl group, for instance benzyl or phenethyl,
substituted in the phenyl ring by 1 or 2 substituents selected from
C.sub.(6-12)alkyl (for instance hexyl and decyl),
C.sub.(6-12)alkoxy, COOH, COOC.sub.(6-12)alkyl and
CONHC.sub.(6-12)alkyl. Alternatively, R.sup.7 maybe
heteroarylC.sub.(1-8)alkyl, preferably heteroarylC.sub.(1-3)alkyl
in which the heteroaryl ring is monocyclic with 5 to 6 members and
one or two heteroatoms selected from nitrogen, oxygen and sulphur,
such as pyridyl, furanyl, thienyl and imidazolyl.
[0037] A further preferred subgroup of compounds of formula (I) are
those in which W is a bond and R.sup.7 is a group of the formula
(CH.sub.2).sub.nBR.sup.13 where n is an integer from 1 to 6,
preferably 1 to 4, B is selected from NR.sup.14CO, CONR.sup.14,
NR.sup.14CONR.sup.15, NR.sup.15COO (in which R.sup.14 and R.sup.15
are independently selected from hydrogen or C.sub.(1-6)alkyl,
preferably hydrogen) and R.sup.13 is C.sub.(8-18)alkyl (which may
optionally be fluorinated, including up to perfluorinated on the
terminal 1 to 3 carbon atoms), C.sub.(8-18)alkenyl, phenyl
C.sub.(1-6)alkyl and phenylC.sub.(1-8)alkoxyC.sub.(1-6)alkyl in
which phenyl may be optionally substituted by halogen or
C.sub.(1-6)alkyl. Prefered examples of C.sub.(8-18)alkyl are
straight chains and include octyl, dodecyl and fatty alkyl groups
such as lauryl and stearyl. Preferred values of C.sub.(8-18)alkenyl
include octadec-9-(Z)-en-lyl. Preferred examples of optionally
substituted phenylC.sub.(1-6)alkyl and
phenylC.sub.(1-8)alkoxyC.sub.(1-6)alkyl include
4-fluorophenylhexyl, 4-pentylphenylethyl and
4-fluorophenylhexoxyethyl. Particularly preferred compounds of
formula (I) are those in which R.sup.12 is C.sub.(12-18)alkyl or
C.sub.(12-18)alkenyl. Such a long, lipophilic substituent is found
to be especially beneficial for enzyme inhibition.
[0038] When used herein, the term `alkyl` and similar terms such as
`alkoxy` includes all straight chain and branched isomers.
Representative examples thereof include methyl, ethyl, n-propyl,
iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, n-pentyl and
n-hexyl.
[0039] When used herein, the term "hydrocarbyl" refers to a group
having from 1 to 20 carbon atoms which may be in a straight chain
or a branched chain and include a saturated carbocyclic ring having
from 3 to 6 carbon atoms and which chain may contain unsaturation
(double and/or triple carbon-carbon bonds).
[0040] When used herein, the term `aryl` refers to, unless
otherwise defined, a mono- or bicyclic aromatic ring system
containing up to 10 carbon atoms in the ring system, for instance
phenyl or naphthyl.
[0041] When used herein, the term `heteroaryl` refers to a mono- or
bicyclic heteroaromatic ring system comprising up to four,
preferably 1 or 2, heteroatoms each selected from oxygen, nitrogen
and sulphur. Each ring may have from 4 to 7, preferably 5 or 6,
ring atoms. A bicyclic heteroaromatic ring system may include a
carbocyclic ring. Representative examples include pyridyl, pyridyl
N-oxide, pyrimidyl, pyrazolyl, furyl, thienyl, thiazolyl,
pyridazolyl and pyrazinyl, quinolyl and benzothiazolyl.
[0042] When used herein, the terms `halogen` and `halo` include
fluorine, chlorine, bromine and iodine and fluoro, chloro, bromo
and iodo, respectively.
[0043] Compounds of formula (I) are inhibitors of Lp-PLA.sub.2 and
as such are expected to be of use in treating atherosclerosis and
the other disease conditions noted elsewhere. Such compounds are
found to act as inhibitors of Lp-PLA.sub.2 in in vitro assays.
[0044] Particularly preferred compounds of formula (I) are
[0045]
2-(4-Fluorobenzylthio)-5-((pyrimid-5-yl)methyl)pyrimidin-4-one;
[0046]
1-Methyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-o-
ne;
[0047]
1-(Tetradec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyri-
mid-5-ylmethyl)pyrimidin-4-one;
[0048]
1-(N-(Dodec-1-yl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)th-
io-5-(pyrimid-5-ylmethyl)pyrimidin-4-one; and
[0049]
1-(N-Methyl-N-(dodec-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)th-
io-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-one.
[0050] Since the compounds of the present invention, in particular
compounds of formula (I), are intended for use in pharmaceutical
compositions, it will be understood that they are each provided in
substantially pure form, for example at least 50% pure, more
suitably at least 75% pure and preferably at least 95% pure (% are
on a wt/wt basis). Impure preparations of the compounds of formula
(I) may be used for preparing the more pure forms used in the
pharmaceutical compositions. Although the purity of intermediate
compounds of the present invention is less critical, it will be
readily understood that the substantially pure form is Preferred as
for the compounds of formula (I). Preferably, whenever possible,
the compounds of the present invention are obtained in crystalline
form.
[0051] When some of the compounds of this invention are allowed to
crystallise or are recrystallised from organic solvents, solvent of
crystallisation may be present in the crystalline product. This
invention includes within its scope such solvates. Similarly, some
of the compounds of this invention may be crystallised or
recrystallised from solvents containing water. In such cases water
of hydration may be formed. This invention includes within its
scope stoichiometric hydrates as well as compounds containing
variable amounts of water that may be produced by processes such as
lyophilisation. In addition, different crystallisation conditions
may lead to the formation of different polymorphic forms of
crystalline products. This invention includes within its scope all
polymorphic forms of the compounds of formula (I).
[0052] Compounds of the present invention are inhibitors of the
enzyme lipoprotein associated phospholipase A.sub.2 (Lp-PLA.sub.2)
and as such are expected to be of use in therapy, in particular in
the treatment of atherosclerosis. In a further aspect therefore the
present invention provides a compound of formula (I) for use in
therapy. The compounds of formula (I) are inhibitors of
lysophosphatidylcholine production by Lp-PLA.sub.2 and may
therefore also have a general application in any disorder that
involves endothelial dysfunction, for example atherosclerosis,
diabetes, hypertension, angina pectoris and after ischaemia and
reperfusion. In addition, compounds of formula (I) may have a
general application in any disorder that involves lipid
peroxidation in conjunction with enzyme activity, for example in
addition to conditions such as atherosclerosis and diabetes, other
conditions such as rheumatoid arthritis, stroke, inflammatory
conditions of the brain such as Alzheimer's Disease, myocardial
infarction, reperfusion injury, sepsis, and acute and chronic
inflammation. Further such conditions include various
neuropsychiatric disorders such as schizophrenia (see
Psychopharmacology Bulletin, 31, 159-165, 1995).
[0053] Further applications include any disorder that involves
activated monocytes, macrophages or lymphocytes, as all of these
cell types express Lp-PLA.sub.2. Examples of such disorders include
psoriasis.
[0054] Accordingly, in a further aspect, the present invention
provides for a method of treating a disease state associated with
activity of the enzyme Lp-PLA.sub.2 which method involves treating
a patient in need thereof with a therapeutically effective amount
of an inhibitor of the enzyme. The disease state may be associated
with the increased involvement of monocytes, macrophages or
lymphocytes: with the formation of lysophosphatidylcholine and
oxidised free fatty acids: with lipid peroxidation in conjunction
with Lp PLA2 activity; or with endothelial dysfunction.
[0055] Compounds of the present invention may also be of use in
treating the above mentioned disease states in combination with
anti-hyperlipidaemic or anti-atherosclerotic or anti-diabetic or
anti-anginal or anti-inflammatory or anti-hypertension agents.
Examples of the above include cholesterol synthesis inhibitors such
as statins, anti-oxidants such as probucol, insulin sensitisers,
calcium channel antagonists, and anti-inflammatory drugs such as
NSAIDs.
[0056] In therapeutic use, the compounds of the present invention
are usually administered in a standard pharmaceutical composition.
The present invention therefore provides, in a further aspect, a
pharmaceutical composition comprising a compound of formula (I) and
a pharmaceutically acceptable carrier.
[0057] Suitable pharmaceutical compositions include those which are
adapted for oral or parenteral administration or as a
suppository.
[0058] Suitable pharmaceutical compositions include those which are
adapted for oral or parenteral administration or as a suppository.
Compounds of formula (I) which are active when given orally can be
formulated as liquids, for example syrups, suspensions or
emulsions, tablets, capsules and lozenges. A liquid formulation
will generally consist of a suspension or solution of the compound
or pharmaceutically acceptable salt in a suitable liquid carrier(s)
for example, ethanol, glycerine, non-aqueous solvent, for example
polyethylene glycol, oils, or water with a suspending agent,
preservative, flavouring or colouring agent. A composition in the
form of a tablet can be prepared using any suitable pharmaceutical
carrier(s) routinely used for preparing solid formulations.
Examples of such carriers include magnesium stearate, starch,
lactose, sucrose and cellulose. A composition in the form of a
capsule can be prepared using routine encapsulation procedures. For
example, pellets containing the active ingredient can be prepared
using standard carriers and then filled into a hard gelatin
capsule; alternatively, a dispersion or suspension can be prepared
using any suitable pharmaceutical carrier(s), for example aqueous
gums, celluloses, silicates or oils and the dispersion or
suspension then filled into a soft gelatin capsule. Typical
parenteral compositions consist of a solution or suspension of the
compound of formula (I) in a sterile aqueous carrier or
parenterally acceptable oil, for example polyethylene glycol,
polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
Alternatively, the solution can be lyophilised and then
reconstituted with a suitable solvent just prior to administration.
A typical suppository formulation comprises a compound of formula
(I) which is active when administered in this way, with a binding
and/or lubricating agent such as polymeric glycols, gelatins or
cocoa butter or other low melting vegetable or synthetic waxes or
fats.
[0059] Preferably the composition is in unit dose form such as a
tablet or capsule. Each dosage unit for oral administration
contains preferably from 1 to 500 mg (and for parenteral
administration contains preferably from 0.1 to 25 mg) of a compound
of the formula (I). The daily dosage regimen for an adult patient
may be, for example, an oral dose of between 1 mg and 1000 mg
preferably between 1 mg and 500 mg, or an intravenous,
subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg,
preferably between 0.1 mg and 25 mg, of the compound of the formula
(I), the compound being administered 1 to 4 times per day. Suitably
the compounds will be administered for a period of continuous
therapy, for example for a week or more.
[0060] Compounds of formula (I) may be conveniently prepared from
readily available starting materials by adapting synthetic
methodology well known in the art for the preparation and
derivatisation of pyrimidones by a process.
[0061] Accordingly, in a first aspect, the present invention
provides a process for preparing a compound of formula (I) which
process comprises:
[0062] (a) treating a compound of formula (IIA): 3
[0063] in which R.sup.1 and Z are as hereinbefore defined;
[0064] with a compound of formula (III):
R.sup.2YCH.sub.2L.sup.1 (III)
[0065] in which Y and R.sup.2 are as hereinbefore defined and
L.sup.1 is a leaving group e.g. bromine or iodine; to give a
compound of formula (IA): 4
[0066] in which Z, Y, R.sup.1 and R.sup.2 are as hereinbefore
defined and X is S; or
[0067] (b) treating a compound of formula (IV): 5
[0068] in which Z and R.sup.1 are as hereinbefore defined and
L.sup.2 is a leaving group, e.g. halogen such as chlorine or
bromine, alkylthio such as methylthio, or --NHNO.sub.2, with a
compound of formula (V):
R.sup.2YCH.sub.2XH (V)
[0069] in which X, Y and R.sup.2 are as hereinbefore defined;
advantageously at an elevated temperature, in a solvent such as
pyridine, to give a compound of formula (IA); and thereafter, and
if so desired;
[0070] treating a compound of formula (IA) form (a) or (b) above
with a compound of formula (VI):
R.sup.7WL.sup.1 (VI)
[0071] in which L.sup.1, W and R.sup.7 are as hereinbefore defined;
to give a compound of formula (1B): 6
[0072] in which X, Y, Z, R.sup.1 and R.sup.2 are as hereinbefore
defined and WR.sup.7 is as hereinbefore defined, other than --H;
or
[0073] (c) treating a compound of formula (IIB): 7
[0074] in which W is a bond, Z and R.sup.1 are as hereinbefore
defined and R.sup.7 are as hereinbefore defined, other then H,
[0075] with a compound of formula (III) as hereinbefore defined, to
obtain a compound of formula (IB); and, thereafter and if so
desired;
[0076] treating a compound of formula (IA) or (IB) in which X is S
with a compound of formula (V):
R.sup.2YCH.sub.2OH (VII)
[0077] in which Y and R.sup.2 are as hereinbefore defined;
[0078] to give a corresponding compound of formula (I) in which X
is O.
[0079] In the above process, the reaction of the compounds of
formulae (IIA/B) and (III) is advantageously effected in the
presence of a base such as sodium ethoxide, potassium carbonate,
preferably in a solvent such as ethanol or dimethylformamide, or a
base such as di-isopropyl ethylamine, preferably in a solvent such
as dichloromethane.
[0080] In the above process, the reaction of the compounds of
formulae (IA) and (VI) is advantageously effected at a temperature
of 20-100 degrees C, in the presence of sodium hydride in a solvent
such as dimethylformamide; or by the compound of formula (IA) being
pre-treated with tributyl tin chloride in the presence of
di-isopropylethylamine, for example in a dichloromethane solvent at
reflux temperature, followed by addition of (VI) Alternatively, the
compound of formula (IA) may be treated directly with a compound of
formula (VI) and di-isopropylethylamine in a dichloromethane
solvent at room temperature.
[0081] In the above processes, the reaction of the compounds of
formulae (IAIIB) and (VII) is conveniently effected in the presence
of pyridine at an elevated temperature, containing a catalytic
amount of 4-dimethylaminopyridine.
[0082] A compound of formula (I) in which Z is a bond and R.sup.1
represents halogen may be obtained by treating a compound of
formula (VIII): 8
[0083] in which W, Y, R.sup.2, and R.sup.7 are as hereinbefore
defined; with a halogenating agent, preferably with bromine to form
a compound of formula (I) in which Z is a bond and R.sup.1 is
bromine, the reaction being advantageously effected in a solvent
such as dichloromethane.
[0084] A compound of formula (IIA) may be obtained from a compound
of formula (IX):
L.sup.3OCOCH.sub.2ZR.sup.1 (IX)
[0085] in which L.sup.3 is C.sub.(1-6)alkyl, for instance methyl,
and Z and R.sup.1 are as hereinbefore defined;
[0086] by the initial treatment thereof with a formylating agent
such ethyl formate in the presence of a strong base such as
potassium t-butoxide or sodium hydride, to give an enolate metal
salt compound of formula (X): 9
[0087] in which L.sup.3, Z and R.sup.1 are as hereinbefore defined
and M is a metal cation, for instance sodium or potassium. Further
treatment of a compound of formula (X) or a salt thereof with
thiourea leads to a compound of formula (IIA). The two steps,
starting form the compound of formula (IX) may conveniently be
carried out as a "one-pot" process.
[0088] A compound of formula (IIB) may be obtained from a compound
of formula (X), in a series of steps. In a first step, a compound
of formula (X) is converted into the corresponding methyl enol
ether by treatment with a methylating agent such as dimethyl
sulphate in the presence of a base such as potassium carbonate. The
corresponding carboxylic acid may then be obtained by conventional
hydrolysis, for instance basic hydrolysis, using, for instance
aqueous sodium hydroxide. The acid may then be converted into the
corresponding acyl chloride, by treatment with oxalyl chloride, and
the acyl chloride treated with potassium thiocyanate in a solvent
such as acetonitrile, to give an intermediate of the formula (XI):
10
[0089] in which R.sup.1 and Z are as hereinbefore defined.
Treatment of a compound of formula (XI) with a compound of formula
(XII):
R.sup.7WNH.sub.2 (XII)
[0090] in which R.sup.7 is as hereinbefore defined and W is a bond,
followed by the addition of an organic base such as sodium
ethoxide, leads to a compound of formula (IIB).
[0091] A compound of formula (IV) in which L.sup.2 is N(H)NO.sub.2
can be conveniently prepared by reacting a compound of formula (X)
above with a compound of formula (XIII): 11
[0092] in which the reaction is carried out in a conventional
manner.
[0093] A compound of formula (VIII) may be obtained by treating a
3,3-dialkoxypropionic ester of the formula (XIV):
(L.sup.3)O.sub.2CCH.sub.2CH(OL.sup.3).sub.2 (XIV)
[0094] in which L.sup.3 is as hereinbefore defined;
[0095] with a thiourea of the formula (XV):
R.sup.7NHCSNH.sub.2 (XV)
[0096] in which R.sup.7 is as hereinbefore defined;
[0097] in the presence of sodium hydride followed by aqueous acetic
acid.
[0098] Compounds of formula (I) in which R.sup.7 comprises an amide
moiety can be prepared from a precursor comprising an ester, for
instance a methyl or ethyl ester, by first converting the ester to
an acid, by hydrolysis and then treating the acid with an
appropriate amine, under amide bond forming conditions. The acid
may preferably be converted into an activated derivative, prior to
amide bond formation.
[0099] Compounds of formula (I) in which R.sup.7 comprises a urea
moiety can be prepared from a precursor comprising an amine moiety,
by treating the amine with an isocyanate, under urea forming
conditions, well known in the art.
[0100] The present invention will now be illustrated by the
following examples.
[0101] Intermediate A1--8-Bromo-1-(4-chlorophenyl)octan-1-one
12
[0102] To a stirring suspension of aluminium chloride (33.6 g) in
dry dichloromethane (474 ml) was added 8-bromo-n-octanoyl chloride
(67.8 g) over 10 min. Chlorobenzene (123 ml) was then added over 10
min and the mixture allowed to stir at 25.degree. C. for 74 h and
stood for 64 . The mixture was poured into ice/water (540 ml) and
diethyl ether (1.3L). The organic layer was removed and was washed
with water (540 ml), saturated sodium hydrogen carbonate (540 ml),
water (400 ml) and brine (400 ml) and dried over magnesium sulfate.
Removal of the organic layer under reduced pressure and
chromatography of the residue on silica gel using 5% ethyl acetate
in hexane gave 8-bromo-l-(4-chlorophenyl)octan-1-one (35.5 g).
.sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.6 (6H,m), 1.6-1.95 (4H,m),
2.95 (2H,t), 3.42 (2H,t), 7.43 (2H,m) and 7.90 (2H,m).
[0103] Intermediate A2--8-Hydroxy-1-(4-chlorophenyl)octan-1-one
13
[0104] To 8-bromo-1-(4-chlorophenyl)octan-1-one (4.0 g) in ethanol
(170 ml) was added 3% aqueous sodium hydroxide (70 ml). The mixture
was heated at reflux for 3 h, cooled and evaporated to one third
volume. Water (50 ml) and dichloromethane (100 ml) were added. The
organic layer was separated and the aqueous layer was re-extracted
with dichloromethane (2.times.50 ml). The combined extracts were
washed with water (30 ml) and dried over magnesium sulphate. The
solvent was removed under reduced pressure and the residue was
crystallised from 40-60.degree. C. petroleum ether to give
8-hydroxy-1-(4-chlorophenyl)octan-1-one (1.0 g). .sup.1H-NMR
(CDCl.sub.3) .delta. 1.25-1.9 (10H,m), 2.94 (2H,t), 3.64 (2H,t),
7.43 (2H,m) and 7.89 (2H,m). (EI) Found M.sup.+=254.
C.sub.14H.sub.19ClO.sub.2 requires 254.
[0105] Intermediate A3--8-Bromo-1-(4-methoxyphenyl)octan-1-one
14
[0106] Prepared analogously to intermediate Al. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.3-1.95 (10H,m), 2.91 (2H,t). 3.41 (2H,t),
3.87 (3H,s), 6.93 (2H,m) and 7.94 (2H,m).
[0107] Intermediate A4--8-Bromo-1-(4-bromophenyl)octan-1-one 15
[0108] Prepared analogously to intermediate Al. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.25-1.55 (6H,m), 1.65-1.95 (4H,m), 2.93
(2H,t), 3.41 (2H,t), 7.60 (2H,m) and 7.83 (2H,t).
[0109] Intermediate A5--8-Bromo-1-(2-thienyl)octan-1-one 16
[0110] Prepared analogously to intermediate A1, except using
SnCl.sub.4 as catalyst in place of AlCl.sub.3. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.3-1.55 (6H,m), 1.65-1.95 (4H,m), 2.90
(2H,t), 3.41 (2H,t), 7.13 (1H,dd), 7.63 (1H,dd) and 7.70
(1H,dd).
[0111] Intermediate A6--8-Bromo-1-(2-furyl)octan-1-one 17
[0112] Prepared analogously to intermediate A1, except using
SnCl.sub.4 as catalyst in place of AlCl.sub.3. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.3-1.55 (6H,m), 1.6-1.95 (4H,m), 2.82 (2H,t),
3.41 (2H,t), 6.53 (1H,m), 7.18 (1H,m) and 7.58 (1H,m).
[0113] Intermediate A7--8-Bromo-1-(4-methylphenyl)octan-1-one
18
[0114] Prepared analogously to intermediate Al. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.3-1.55 (6H,m), 1.65-1.95 (4H,m), 2.41
(3H,s), 2.94 (2H,t), 3.41 (2H,t), 7.25 (2H,m) and 7.86 (2H,m).
[0115] Intermediate A8--8-Bromo-1-(4-fluorophenyl)octan-1-one
19
[0116] Prepared analogously to intermediate Al. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.3-1.6 (6H,m), 1.6-1.95 (4H,m), 2.94 (2H,t).
3.41 (2H,t), 7.13 (2H,m) and 7.98 (2H,m).
[0117] Intermediate A9--8-Bromo-1-(4-methyl-1-naphthyl)octan-1-one
20
[0118] Prepared analogously to intermediate Al. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.3-1.55 (6H,m), 1.7-1.95 (4H,m), 2.74 (3H,s),
3.03 (2H,t), 3.41 (2H,t), 7.32 (1H,m), 7.5-7.65 (2H,m), 7.76
(1H,d), 8.0-8.1 (1H,m) and 8.55-8.7 (1H,m).
[0119] Intermediate A10--1-Bromo-8-(2-thiazolinyl)octane 21
[0120] To a solution of 2-methyl-2-thiazoline (1.01 g in dry
tetrahydrofuran at -70.degree. C. was added a solution of n-butyl
lithium in hexanes (2.5M, 4.0 ml) dropwise over 10 min. After
stirring at -70.degree. C. for 2 h, 1,7-dibromoheptane (12.9 g) was
added in one portion (temperature increased to -45.degree. C.). The
mixture was cooled again to -70.degree. C. for 1 h and then allowed
to warm to room temperature over 1 h. The mixture was cooled to
0.degree. C. and water (10 ml) added, followed by dilute
hydrochloric acid (to pH 2). The organic layer was separated and
the aqueous layer extracted with diethyl ethyl (2.times.20 ml). The
organic layers were combined and washed with water and brine and
dried over magnesium sulfate. Evaporation under reduced pressure
gave an oil that was chromatographed on silica gel using
40-60.degree. C. petroleum ether:ethyl acetate 5:1 to give
1-bromo-8-(2-thiazolinyl)octane (1.06 g). .sup.1H-NMR (CDCl.sub.3)
.delta. 1.2-1.5 (6H,m), 1.5-1.75 (4H,m), 1.75-1.95 (2H,m), 2.50
(2H,t), 3.28 (2H,t), 3.40 (2H,t) and 4.21 (2H,dt).
[0121] Intermediate A11--1-Bromo-8-(2-pyridyl)octane 22
[0122] Prepared analogously to intermediate A10. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-1.55 (8H,m), 1.6-1.95 (4H,m). 2.76 (2H,t),
3.41 (2H,t), 7.05-7.2 (2H,m), 7.5-7.65 (1H,m) and 8.52 (1H,m).
[0123] Intermediate A12--8-(3,4-Dichlorophenyl)oct-7-yn-1-ol 23
[0124] A mixture of 3.4-dichloroiodobenzene (2.16 g), oct-7-yn-1-ol
(1.20 g), tetrakis (triphenylphosphine)palladium (0) (0.185 g),
copper (I) iodide (0.046 g) and triethylamine (15 ml) was stirred
at room temperature for 16 h. The solid was filtered off and the
filtrate evaporated under reduced pressure. The residual oil was
dissolved in ethyl acetate (15 ml) and washed with water (10 ml),
2M hydrochloric acid (2.times.10 ml) and brine (10 ml). Drying over
magnesium sulfate and removal of the solvent under reduced pressure
gave an oil that was purified by flash chromatography on silica gel
using dichloromethane as eluent. This gave
8-(3,4-dichlorophenyl)oct-7-yn-1-ol (1.89 g). .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-1.75 (8H,m), 2.40 (2H,t), 3.66 (2H,t),7.19
(1H,dd), 7.35 (1H,d) and 7.47 (1H,dd)
[0125] Intermediate A13--8-(3,4-Dichlorophenyl)octan-1-ol 24
[0126] To a solution of 8-(3.4-dichlorophenyl)-oct-7-yn-1-ol (0.70
g) in methanol (20 ml) was added platinum dioxide (0.05 g) and the
mixture reacted under an atmosphere of hydrogen (initial pressure
50 psi). After 1 h. the catalyst was filtered through Hyflo and
washed with methanol. The combined methanol layers were evaporated
under reduced pressure to give 8-(3,4-dichlorophenyl)octan-1-ol
(0.69 g). .sup.1H-NMR (CDCl.sub.3) .delta. 1.1-1.8 (12H,m), 2.55
(2H,t), 3.64 (2H,m), 6.99 (1H,dd) and 7.2-7.4 (2H,m)
[0127] Intermediate A14--8-Bromo-1-(3,4-dichlorophenyl)-1-octyne
25
[0128] A solution of 8-(3,4-dichlorophenyl)-oct-7-yn-1-ol (0.52 g)
in diethyl ether (2.5 ml) was treated with phosphorous tribromide
(0.23 g) at 0.degree. C. (ice/salt bath). The solution was stirred
at 0-5.degree. C. for 2 h and allowed to warm to room temperature.
Aqueous sodium hydrogen carbonate solution was added. The aqueous
layer was extracted with further diethyl ether (2.times.5 ml) and
the combined organic layers were washed with brine (5 ml) and dried
over magnesium sulfate. Removal of the solvent under reduced
pressure gave an oil that was chromatographed on silica gel using
dichloromethane as eluent. This gave
8-bromo-1-(3,4-dichlorophenyl)-1-octyne (0.25 g). .sup.1H-NMR
(CDCl.sub.3) .delta. 1.35-1.7 (6H,m), 1.75-1.95 (2H,m), 2.33
(2H,t), 3.35 (2H,t), 7.13 (1H,dd), 7.27 (1H,d) and 7.40 (1H,d).
[0129] Intermediate A15--1-Bromo-8-(3,4-dichlorophenyl)octane
26
[0130] A solution of 8-(3,4-dichlorophenyl)octan-1-ol (0.66 g) in
48% hydrobromic acid (7 ml) was stirred under reflux for 2 h. Water
(20 ml) and diethyl ether (20 ml) were added. The organic layer was
separated and the aqueous layer reextracted with diethyl ether (10
ml). The combined organic extracts were washed with water (10 mn),
sodium hydrogen carbonate solution (10 ml) and brine (10 ml) and
dried over magnesium sulfate. The solution was treated with
charcoal, filtered and evaporated under reduced pressure to give
1-bromo-8-(3,4-dichlorophenyl)octane (0.74 g). .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-1.8 (12H,m), 2.55 (2H,t), 3.41 (2H,t),
7.00 (1H,dd), 7.25 (1H,dd) and 7.33 (1H,d).
[0131] Intermediate A16--8-(3-Chlorophenyl)oct-7-yn-1-ol 27
[0132] Prepared analogously to intermediate A12. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.25 (8H,m), 2.41 (2H,t), 3.66 (2H,t),
7.13-7.33 (3H,m) and 7.37 (1H,m)
[0133] Intermediate A17--8-(3-Chlorophenyl)octan-1-ol 28
[0134] Prepared analogously to intermediate A13. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.1-1.8 (12H,m), 2.57 (2H,t), 3.64 (2H,t),
7.0-7.4 (4H,m)
[0135] Intermediate A18--1-Bromo-8-(3-chlorophenyl)octane 29
[0136] Prepared analogously to intermediate A15. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.05-1.9 (12H,m), 2.50 (2H,t), 3.33 (2H,t) and
6.9-7.25 (4H,m).
[0137] Intermediate A19--8-(4-Acetylphenyl)octan-1-ol 30
[0138] Prepared analogously to intermediate A13. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-1.8 (12H,m), 2.59 (3H,s). 2.68 (2H,t),
3.63 (2H,t)7.25 (2H,m) and 7.88 (2H,m).
[0139] Intermediate A20--1-Bromo-8-(4-acetylphenyl)octane 31
[0140] Prepared analogously to intermediate A15. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-1.75 (10H,m), 1.85 (2H,m), 2.59 (3H,s),
2.67 (2H,m), 3.40 (2H,t), 7.2-7.3 (2H,m) and 7.88 (2H,m).
[0141] Intermediate A21--1-Bromo-8-(4-fluorophenyl)octane 32
[0142] Triethylsilane (30.5 g, 260 mmol) was added dropwise to
8-bromo-1-(4-fluorophenyl)octan-1-one (230 ml, 105 mmol) over 20
min, with cooling to keep the temperature at ca 30.degree. C. After
2 hours stirring, a further 3.1 g (27 mmol) triethylsilane was
added, and reaction continued for an additional 2 hours. The
mixture was poured into ice-water (200 ml) and ether (300 ml), then
the organic layer was washed with aqueous sodium hydroxide, dried
and evaporated, finally at 65.degree. C./0.01 mm. The residue was
filtered through silica gel, eluting with petroleum ether, then
distilled, collecting the fraction at 122-140.degree. C./0.5 mm
(24.2 g). .sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.7 (10H,m), 1.85
(2H,m), 2.57 (2H,t), 3.40 (2H,t), 6.9-7.05 (2H,m) and 7.05-7.2
(2H,m).
[0143] Intermediate A22--1-Bromo-8-(4-methoxyphenyl)octane 33
[0144] Prepared as in reference 1
[0145] Intermediate A23--1-Bromo-8-(4-pyridyl)octane 34
[0146] Prepared analogously to intermediate A10. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-1.95 (12H,m), 2.48 (2H,t), 3.42 (2H,t),
7.11 (2H,d) and 8.47 (2H,m).
[0147] Intermediate A24--1-Bromo-8-(4-chlorophenyl)octane 35
[0148] Prepared analogously to intermediate A21. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-1.5 (8H,m), 1.5-1.7 (2H,m), 1.75-1.95
(2H,m), 2.56 (2H,t), 3.40 (2H,t), 7.08 (2H,m) and 7.23 (2H,m).
[0149] Intermediate A25--1-Bromo-6-(4-chlorobenzyloxy)hexane 36
[0150] Sodium hydride (60%, 0.39 g) was added to a mixture of
6-bromohexanol (1.78 g) and 4-chlorobenzyl bromide (2.02 g) in dry
tetrahydrofuran (150 ml). The mixture was stirred at 25.degree. C.
for 5 h and poured into 1M hydrochloric acid. Extraction with
diethyl ether (3.times.), and washing the combined extracts with
water and brine gave a solution that was dried over magnesium
sulfate and evaporated under reduced pressure. The residue so
obtained was chromatographed on silica gel using 40-60.degree. C.
petroleum ether to 10% diethyl ether in 40-60.degree. C. petroleum
ether as eluents. This gave 1-bromo-6-(4-chlorobenzyloxy)hexane
(1.7 g). .sup.1H-NMR (CDCl.sub.3) .delta. 1.3-1.55 (4H,m), 1.55-1.7
(2H,m), 1.75-1.95 (2H,m), 3.35-3.55 (4H,m), 4.46 (2H,s) and 7.2-7.4
(4H,m).
[0151] Intermediate A26--1-Bromo-6-(4-fluorobenzyloxy)hexane 37
[0152] Prepared analogously to intermediate A25. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.3-1.5 (4H,m), 1.6 (2H,m), 1.9 (2H,m), 3.39
(2H,t), 3.45 (2H,t), 4.44 (2H,s), 7.0-7.1 (2H,m), 7.2-7.4
(2H,m).
[0153] Intermediate A27--1-Bromo-6-benzyloxyhexane 38
[0154] Prepared as in reference 14.
[0155] Intermediate A28--1-Bromo-7-phenoxyheptane 39
[0156] To a mixture of phenol (0.58 g) and 1,7-dibromoheptane (4.76
g) in dimethylformamide (5 ml) was added potassium carbonate (4.3
g) and the mixture was heated at 80.degree. C. for 6 h. The mixture
was cooled and the solvent was removed under reduced pressure.
Toluene (10 ml) was added and removed under reduced pressure. The
residue was chromatographed on silica gel using hexane as eluent.
This gave 1-bromo-7-phenoxyheptane (1.15 g). .sup.1H-NMR
(CDCl.sub.3) .delta. 1.3-1.7 (6H,m), 1.7-2.1 (4H,m), 3.41 (2H,t).
3.95 (2H,t), 6.8-7.0 (3H,m) and 7.2-7.4 (2H,m).
[0157] Intermediate A29--1-Bromo-7-(4-chlorophenoxy)heptane 40
[0158] Prepared analogously to intermediate A28. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.3-1.6 (6H,m), 1.7-2.0 (4H,m), 3.41 (2H,t).
3.91 (2H,t), 6.75-6.9 (2H,m) and 7.15-7.3 (2H,m).
[0159] Intermediate A30--1-Bromo-7-(4-chlorophenylthio)heptane
41
[0160] To 1,7-dibromoheptane (23 g) and potassium carbonate (10 g)
in dry dimethylformamide (100 ml) was added 4-chlorothiophenol (4.3
g) dropwise with stirring at 25.degree. C. After 6 h, the mixture
was filtered and the solvent removed under reduced pressure.
Chromatography of the residue on silica gel using hexane as eluent
gave 1-bromo-7-(4-chlorophenylthio)h- eptane (9.6 g). .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-1.55 (6H,m), 1.55-1.75 (2H,m), 1.8-2.0
(2H,m), 2.89 (2H,t), 3.40 (2H,t) and 7.2-7.4 (4H,m).
[0161] Intermediate A31--1-Bromo-7-(4-chlorophenylsulfinyl)heptane
42
[0162] A solution of 1-bromo-7-(4-chlorophenylthio)heptane (0.80 g)
in dichloromethane (10 ml) was cooled to -78.degree. C.
(cardice/acetone) and a slurry of metachloroperbenzoic acid (60%,
0.72 g) in dichloromethane (5 ml) was added over 20 min. After 40
min, the reaction was allowed to warm to room temperature and
shaken with aqueous sodium sulfite/sodium hydrogen carbonate
solution. The organic layer was dried over magnesium sulfate and
evaporated under reduced pressure. The residue was chromatographed
on silica gel using dichloromethane to 4% methanol in
dichloromethane as eluents to give
1-bromo-7-(4-chlorophenylsulfinyl)hept- ane (0.43 g). .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-2.0 (10H,m), 2.77 (2H,t), 3.39 (2H,t) and
7.4-7.7 (4H,m).
[0163] Intermediate A32--1-Bromo-7-(4-chlorophenylsulfonyl)heptane
43
[0164] To a solution of l-bromo-7-(4-chlorophenylthio)heptane (1.19
g) in dichloromethane (20ml) at -20.degree. C. was added
metachloroperbenzoic acid (60%, 2.23 g) portionwise over 15 min.
The mixture was allowed to warm to room temperature over 1 h and
was shaken with aqueous sodium sulfite/sodium hydrogen carbonate
solution. The organic layer was dried over magnesium sulfate and
evaporated under reduced pressure. The residue was chromatographed
on silica gel using 50:50 hexane:dichloromethane as eluent to give
1-bromo-7-(4-chlorophenylsulfonyl)heptane (1.17 g). .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-2.0 (10H,m), 3.07 (2H,m), 3.38 (2H,t),
7.5-7.6 (2H,m) and 7.8-7.9 (2H,m).
[0165] Intermediate A33--1-Bromo-7-phenylthioheptane 44
[0166] Prepared analogously to intermediate A30. .sup.1H-NMR
(CDCl.sub.3) 5 1.2-1.55 (6H,m), 1.6-1.75 (2H,m). 1.75-1.95 (2H,m),
2.91 (2Ht), 3.40 (2H,t) and 7.1-7.4 (5H,m).
[0167] Intermediate A34--1-Bromo-7-phenylsulfinylheptane 45
[0168] Prepared analogously to intermediate A31. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-1.95 (10H,m), 2.91 (2H,t), 3.40 (2H,m) and
7.1-7.4 (5H,m).
[0169] Intermediate A35--1-Bromo-7-phenylsulfonylheptane 46
[0170] Prepared analogously to intermediate A32. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-2.0 (1H,m), 3.09 (2H,m), 3.38 (2H,t),
7.5-7.8 (3H,m) and 7.85-8.0 (2H,m).
[0171] Intermediate A36--8-Bromo-1-(4-chlorophenyl)-1-hydroxyoctane
47
[0172] To a solution of 8-bromo-1-(4-chlorophenyl)octan-1-one (0.95
g) in industrial methylated spirit (10 ml) was added sodium
borohydride (0.115 g) at -10C. After stirring for 1 h, glacial
acetic acid (0.2 g) was added and the mixture was poured into water
(60 ml) and extracted with diethyl ether. The diethyl ether layer
was washed with brine and dried over magnesium sulfate. Removal of
the solvent under reduced pressure gave an oil that was
chromatographed on silica gel using dichloromethane as eluent. This
gave 8-bromo-1-(4-chlorophenyl)-1-hydroxyoctane (0.70 g).
.sup.1H-NMR (CDCl.sub.3) .delta. 1.15-1.95 (12H,m), 3.40 (2H,t),
4.65 (1H,t) and 7.2-7.4 (4H,m).
[0173] Intermediate A37--9-Bromo-2-(4-fluorophenyl)-1-nonene 48
[0174] To a solution of butyl lithium (2.5M, 3.2 ml) in anhydrous
tetrahydrofuran (75 ml) was added triphenylmethylphosphonium
bromide (2.86 g) in portions over 10 min. The mixture was stirred
at 25.degree. C. for 3 h and a solution of
8-bromo-1-(4-fluorophenyl)octan-1one (1.20 g) in dry
tetrahydrofuran (15 ml) added dropwise over 5 min. After stirring
at 25.degree. C. for 1 h, the mixture was heated at reflux for 24
h. The mixture was evaporated under reduced pressure and
partitioned between diethyl ether (70 ml) and water (4.times.30ml).
The organic layer was washed with brine and dried over magnesium
sulfate. Removal of the solvent under reduced pressure gave an oil
that was chromatographed on silica gel using 5% diethyl ether in
hexane. This gave 9-bromo-2-(4-fluorophenyl)-l-nonene (0.75 g).
.sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.55 (8H,m), 1.80 (2H,m). 2.46
(2H,t), 3.39 (2H,t), 5.03 (1H,bs), 5.20 (1H,bs), 7.03 (2H,m) and
7.3-7.45 (2H,m).
[0175] Intermediate A38--1-(3-Chlorophenyl)hex-1-yn-.DELTA.ol
49
[0176] Prepared analogously to intermediate A12. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.6-1.85 (4H,m), 2.45 (2H,bt), 3.71 (2H,t),
7.15-7.33 (3H,m) and 7.37 (1H,m).
[0177] Intermediate A39--6-(3-Chlorophenyl)hexan-1-ol 50
[0178] Prepared analogously to intermediate A13. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-1.8 (gH,m), 2.58 (2H,t), 3.64 (2H,t) and
7.0-7.3 (4H,m).
[0179] Intermediate A40--1-Bromo-6-(3-chlorophenyl)hexane 51
[0180] Prepared analogously to intermediate A15. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-1.95 (8H,m), 2.59 (2H,t), 3.40 (2H,t) and
7.0-7.3 (4H,m).
[0181] Intermediate A41--9-Bromo-1-(4-chlorophenyl)nonan-1-one
52
[0182] 9-Bromononanoyl chloride was obtained from the carboxylic
acid (reference 12) by treatment with thionyl chloride.
9-Bromo-1-(4-chlorophenyl)nonan-1-one was prepared analogously to
intermediate A1. .sup.1H-NMR (CDCl.sub.3) .delta. 1.2-2.0 (12H,m),
2.95 (2H,t), 3.41 (2H,t), 7.44 (2H,m) and 7.90 (2H,m).
[0183] Intermediate
A42--N-(6-(4-Fluorophenyl)hexyl)-2-bromoacetamide 53
[0184] To a solution of 6-(4-fluorophenyl)-1-hexylamine (21.8 g) in
dry dichloromethane (200 ml) at 0.degree. C. under an argon
atmosphere was added duisopropylethylamine (14.4 g) followed by
bromoacetyl bromide (22.5 g) over 30 min whilst maintaining the
temperature between 0-5.degree. C. The resulting orange solution
was stirred at 0-5.degree. C. for 45 min and evaporated to dryness.
The residue was mixed with diethyl ether and the hydrobromide salt
filtered off. The filtrate was evaporated under reduced pressure
and the residue was chromatographed on silica gel using 5:1 to 3:2
40-60.degree. C. petroleum ether:ethyl acetate as eluents. This
gave a yellow oil that was triturated with 40-60.degree. C.
petroleum ether filtered and dried to give
N-(1-(4-fluorophenyl)-hexyl) bromoacetamide (24.8 g). .sup.1H-NMR
(CDCl.sub.3) .delta. 1.25-1.45 (4H,m), 1.45-1.75 (4H,m), 2.57
(2H,t), 3.28 (2H,q), 3.88 (2H,s), 6.5 (1H,bs), 6.85-7.05 (2H,m) and
7.05-7.2 (2H,m).
[0185] Intermediate A43--1-Bromo-4-(3-phenylpropyloxy)butane 54
[0186] Prepared as in reference 13.
[0187] Intermediate A44--6-(4-Chlorobenzoylamino)hexan-1-ol 55
[0188] To a solution of 6-amino-1-hexanol (12.9 g) and
diisopropylethylamine (11.9 g,) in dry dichloromethane (100 ml) at
5.degree. C. was added 4-chlorobenzoyl chloride (16.1 g) in dry
dichloromethane at such a rate to maintain the temperature below
10.degree. C. After stirring for 16 h, the mixture was poured into
water and filtered. The solid was washed with water, 2M
hydrochloric acid (150 ml), water, dichloromethane and was dried
under reduced pressure to give 6-(4-chlorobenzoylamino) hexan-1-ol
(19.2 g). .sup.1H-NMR (d.sub.6-DMSO) .delta. 1.25-1.65 (8H,m), 3.24
(2H,q), 3.38 (2H,t), 7.52 (2H,m), 7.84 (2H,m) and 8.54 (1H,bt).
[0189] Intermediate A45--1-Bromo-6-(4-chlorobenzoylamino)hexane
56
[0190] 6-(4-Chlorobenzoylamino)hexan-1-ol (17.0 g) was refluxed in
48% hydrobromic acid (260 ml) for 2.5 h. The mixture was cooled and
added to water (450 ml) and diethyl ether (450 ml). The organic
layer was washed with saturated sodium bicarbonate (450 ml) and
brine (450 ml) and was dried over magnesium sulfate. Evaporation
followed by recrystallisation from diethyl ether gave
1-bromo-6-(4-chlorobenzoylamino)hexane (8.6 g). .sup.1H-NMR
(CDCl.sub.3) .delta. 1.3-2.0 (8H,m), 3.35-3.55 (4H,m), 6.15
(1H,bs), 7.40 (2H,m) and 7.70 (2H,m).
[0191] Intermediate B1--Ethyl 3-(5-pyrimidinyl)acrylate 57
[0192] A mixture of 5-bromopyrimidine (5.93 g), ethyl acrylate
(5.08 g), palladium acetate (0.112 g), triphenyl phosphine (0.23 g)
and triethylamine (4.5 g) was stirred at 150.degree. C. in a
pressure vessel for 6 hours. After cooling overnight, water (50 ml)
was added to the dark residue, and the product was extracted into
toluene. Drying, charcoaling and evaporation gave a pale oil, which
was triturated with pet, ether to obtain ethyl
3-(5-pyrimidyl)acrylate (4.78 g). .sup.1H-NMR (CDCl.sub.3) .delta.
1.36 (3H,t), 4.27 (2H,q), 6.59 (1H,d), 7.62 (1H,d). 8.88 (2H,s),
9.20 (1H,s).
[0193] Intermediate B2--Ethyl 3-(5-pyrimidyl)propionate 58
[0194] To a solution of ethyl 3-(5-pyrimidyl)acrylate (4.75 g) in
ethanol (90 ml) was added 5% palladium on charcoal (0.2 g). The
mixture was hydrogenated at an initial pressure of 50 psi, then
filtered to remove catalyst and the solvent evaporated. Water was
added, and the product extracted into ether. Drying, charcoaling
and evaporation gave ethyl 3-(5-pyrimidyl)propionate (2.3 g) as a
yellow oil. .sup.1H-NMR (CDCl.sub.3) .delta. 1.23 (3H,t), 2.69
(2H,t), 2.96 (2H,t), 4.14 (2H,q), 8.635 (2H,s) and 9.09 (1H,s).
[0195] Intermediate B3--Ethyl 2-formyl-3-(5-pyrimidyl)propionate
59
[0196] A mixture of ethyl 3-(5-pyrimidyl)propionate (2.28 g) and
ethyl formate (1.41 ml) dissolved in dry dimethoxyethane (5 ml) was
added dropwise over 30 min to a suspension of sodium hydride (60%,
4.0 g) in DME (5 ml) under nitrogen, keeping the temperature below
0.degree. C. Stirring was continued for a further 24 h, then the
mixture was poured onto ice and washed with ether. The aqueous
layer was adjusted to pH 7, then evaporated and the residue
extracted with acetone. Filtration and evaporation gave crude
product, which was taken up in ethyl acetate, charcoaled, dried and
evaporated to give ethyl 2-formyl-3-(5-pyrimidyl)pr- opionate. Like
other compounds of this type, this proved difficult to characterise
and was used without further purification.
[0197] Intermediate B4--3-(5-Pyrimidyl)acrylic acid 60
[0198] A mixture of 5-bromopyrimidine (10 g), acrylic acid (48 g),
triphenylphosphine (2.5 g) and palladium II acetate (0.1 g) was
refluxed in tri-n-butylamine (260 ml) with overhead stirring for
4.5 h at 145-160.degree. C. The mixture was cooled and a 10%
solution of potassium carbonate (2L) added followed by
dichloromethane (500 mL). The organic layer was separated and the
aqueous phase extracted with diethyl ether (3.times.300ml). The
aqueous layer was brought to pH 3 with concentrated hydrochloric
acid (ice-cooling) and the solid so formed was filtered and dried
in vactio to give 3-(5-pyrimidyl)acrylic acid (35g). .sup.1H-NMR
(d.sub.6-DMSO) .delta. 6.82(1H,d), 7.60(1H,d) and 9.15(3H,
2.times.s)
[0199] Intermediate B5--Methyl 3-(5-pyrimidinyl)acrylate 61
[0200] 3-(5-Pyrimidyl)acrylic acid (100 g) was added to a mixture
of dry methanol (2L) and 4M hydrogen chloride in dioxan (445 ml)
and allowed to stir at 60.degree. C. under argon for 18 h. The
mixture was cooled, and the solvent removed under reduced pressure.
The residue was partitioned between dichloromethane (500 ml) and
was washed with saturated sodium bicarbonate (300 ml). The aqueous
layer was extracted with dichloromethane and the combined
dichloromethane layers were dried over magnesium sulfate and
evaporated in vacuo to give methyl 3-(5-pyrimidinyl)acrylate (85
g). .sup.1H-NMR (d.sub.6-DMSO) .delta. 3.82(3H,s), 7.03(1H,d),
7.75(1H,d) and 9.28(3H,s)
[0201] Intermediate B6--Methyl 3-(5-pyrimidyl)propionate 62
[0202] To a solution of methyl 3-(5-pyrimidyl)acrylate (85 g) in
glacial acetic acid was added 10% palladium on charcoal (11.3 g)
and ammonium formate (74.2 g) under argon. The mixture was heated
at 110.degree. C. for 20 min, cooled and the solvent removed in
vacuo. The resulting oil was dissolved in dichloromethane (1.5L)
and washed with saturated sodium bicarbonate (750 ml). The aqueous
layer was extracted with further dichloromethane (200 ml), the
organic layers were combined and dried over magnesium sulfate.
Removal of the solvent under reduced pressure gave an oil. This was
distilled under reduced pressure to give methyl
3-(5-pyrimidyl)propionate (26 g). .sup.1H-NMR (CDCl.sub.3) .delta.
2.69(2H,t), 2.97(2H,t), 3.70(3H,s), 8.65(2H,s) and 9.12(1H,s).
[0203] Intermediate B7--Methyl
2-(5-pyrimidyl)methyl)-3-methoxyacrylate 63
[0204] A mixture of methyl 3-(5-pyrimidyl)propionate (13.1 g) and
methyl formate (7.1 ml) dissolved in dry dimethoxyethane (20 ml)
was added portionwise to a suspension of sodium hydride (60%, 4.0
g) in DME (10 ml) under argon. Reaction initiated rapidly and was
stirred for a further 2 h, diluted with dry diethyl ether (50 ml)
and filtered. The solid so separated was washed with further
diethyl ether (50 ml) and was dried in vacuo to give a solid that
was dissolved in dry dimethyl formamide (50 ml) and potassium
carbonate (11.3 g) added under argon. A solution of dimethyl
sulfate (7.0 ml) was then added over 1 hour. The mixture was
stirred for 18 h and the solvent removed in vacuo. The residue was
partitioned between ethyl acetate (200 ml) and water (100 ml). The
aqueous layer was re-extracted with ethyl acetate (2.times.100 ml)
and the combined ethyl acetate layers washed with brine (50 ml) and
dried over sodium sulfate. The solvent was removed in vacuo to give
methyl 2((5-pyrimidyl)methyl)-3-methoxyacrylate (9.1 g).
[0205] Intermediate B8--2-(5-Pyrimidyl)methyl)-3-methoxyacrylic
acid 64
[0206] To methyl 2-((5-pyrimidyl)methyl)-3-methoxyacrylate (9.0 g)
was added, with stirring, a solution of sodium hydroxide (3.5 g) in
water (43 ml) at RT under argon. After 20 h, the pH of the solution
was brought to 3.5 with concentrated hydrochloric acid. Sonication
of the oil so formed gave 2-((5-pyrimidyl)methyl)-3-methoxyacrylic
acid (5.4 g) as a pale yellow solid.
[0207] Intermediate B9--5-(Pyrimid-5-ylmethyl)-2-thiouracil 65
[0208] Sodium (0.25 g) was dissolved in ethanol (5 ml), thiourea
(0.77 g) added, and the mixture stirred under reflux for 1 hour. A
solution of ethyl 2-formyl-3-(5-pyrimidyl)propionate (1.99 g) in
ethanol (5 ml) was added slowly, and reflux continued for 18 hours.
The solvent was evaporated, and the residue taken up in water and
washed with dichloromethane. The aqueous solution was acidified to
pH 5, and the precipitate filtered off, washed with water and dried
to obtain 5-(pyrimid-5-ylmethyl)-2-thiouracil (0.71 g). .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.58 (2H,s), 7.54 (1H,s), 8.70 (2H,s) and
9.02 (1H,s). MPt 265-6.degree. C.
[0209] Intermediate
B10--5-((1-Benzyl-2-oxo-pyrid-4-yl)methyl)-2-thiouraci- l 66
[0210] Prepared from methyl
2-(1-benzyl-2-oxo-pyrid-4-yl)methyl)-3-hydroxy- acrylate (reference
7) analogously to intermediate B9. .sup.1H-NMR (d.sub.6-DMSO)
.delta. 5.04 (2H,s), 6.15 (1H,dd), 6.21 (1H,bs), 7.2-7.4 (5H,m),
7.45 (1H,s) and 7.67 (1H,d); (EI) M=325. C.sub.17H.sub.15N.sub.3O-
.sub.2S requires 325.
[0211] Intermediate
B11--5-((1-Methyl-2-oxo-pyrid-4-yl)methyl)-2-thiouraci- l 67
[0212] Prepared from methyl
2-(1-methyl-2-oxo-pyrid-4-yl)methyl)-3-hydroxy- acrylate (reference
7) analogously to intermediate B9. .sup.1H-NMR (CD.sub.3OD) .delta.
3.50,3.51 (5H,2.times.s), 6.32 (1H,dd), 6.40 (1H,bs), 7.35 (1H,s)
and 7.54 (1H,d).
[0213] Intermediate
B12--5-((2,3-Dimethylpyrid-5-yl)methyl)-2-thiouracil 68
[0214] Prepared analogously to intermediate B9. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 2.19 (3H,s), 2.35 (3H,s), 7.36 (2H,m) and
8.13 (1H,bs)
[0215] Intermediate B13--5-(Fur-2-ylmethyl)-2-thiouracil 69
[0216] Prepared analogously to intermediate B9. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.58 (2H, s), 6.11 (1H, m), 6.35 (1H, m),
7.27 (1H, s), 7.52 (1H, m), 12 41 (2H, br,m). Mpt 205-7.degree. C.
(dec).
[0217] Intermediate B14--5-(Pyrazin-2-ylmethyl)-2-thiouracil 70
[0218] Prepared from methyl 3-(2-pyrazinyl)propionate (reference
10) analogously to intermediate B9. .sup.1H-NMR (d.sub.6-DMSO)
.delta. 3.77 (2H,s), 7.48 (1H,s), 8.46 (1H,d), 8.51 (1H,t) and 8.59
(1H,d). Mpt 265-7.degree. C. (dec).
[0219] Intermediate B15--5-(Fur-3-ylmethyl)-2-thiouracil 71
[0220] Prepared from methyl 3-(3-furyl)propionate (reference 9)
analogously to intermediate B9. .sup.1H-NMR (d.sub.6-DMSO) .delta.
3.33 (2H, s), 6.38 (1H, m). 7.19 (1H, s), 7.47 (1H, m), 7.56 (1H,
m). Mot 197-9.degree. C. (dec).
[0221] Intermediate B16--5-(Quinolin-3-ylmethyl)-2-thiouracil
72
[0222] Prepared analogously to intermediate B9. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.77 (2H, s), 7.54 (2H, m), 7.2 0 (7H,m)
and(2H, m), 8.84 (1H, m) Mpt 274-9.degree. C.
[0223] Intermediate B17--5-(2-(Pyrid-4-yl)ethyl)-2-thiouracil
73
[0224] Prepared analogously to intermediate B9. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 2.53 (2H,t), 2.77 (2H,t), 7.20 (3H,m) and
8.45 (2H,m). MPt 265-7.degree. C. (dec).
[0225] Intermediate B18--5-(Pyrid-2-ylmethyl)-2-thiouracil 74
[0226] Prepared as in reference 2.
[0227] Intermediate B19--5-(Pyrid-3-ylmethyl)-2-thiouracil 75
[0228] Prepared as in reference 11.
[0229] Intermediate B20--5-(Pyrid-4-ylmethyl)-2-thiouracil 76
[0230] Prepared analogously to intermediate B9. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.57 (2H, s), 7.25 (2H, m), 7.47 (1H, s),
8.44 (2H, m), 12.43 (2H, br,m) Mpt>250.degree. C.
[0231] Intermediate
B21--5-((2-Methylpyrid-5-yl)methyl)-2-thiouracil 77
[0232] Prepared as in reference 5.
[0233] Intermediate B22--5-(Thiazol-2-ylmethyl)-2-thiouracil 78
[0234] Prepared as in reference 2.
[0235] Intermediate B23--5-Benzyl-2-thiouracil 79
[0236] Prepared as in reference 6.
[0237] Intermediate
B24--5-(Pyrid-3-ylmethyl)-2-(nitroamino)pyrimidin-4-on- e 80
[0238] Prepared as in reference 4.
[0239] Intermediate
B25--5-(2-Methoxypyrid-4-ylmethyl)-2-(nitroamino)pyrim- idin-4-one
81
[0240] Prepared as in reference 3.
[0241] Intermediate B26
--5-(4-Methoxypyrid-2-ylmethyl)-2-(nitroamino)pyri- midin-4-one
82
[0242] Prepared as in reference 4.
[0243] Intermediate
B27--5-((1-Butyl-2-oxo-pyrid-4-yl)methyl)-2-(nitroamin-
o)pyrimidin-4-one 83
[0244] Prepared as in reference 7.
[0245] Intermediate
B28--5-((1-Oxo-2-methylpyrid-5-yl)methyl)-2-(nitroamin-
o)pyrimidin-4-one 84
[0246] Prepared as in reference 3.
[0247] Intermediate
B29--5-((2,4-Dimethylpyrid-5-yl)methyl)-2-(nitroamino)-
pyrimidin-4-one 85
[0248] Prepared as in reference 8.
[0249] Intermediate B30--3-(1-Methylpyrazol-4-yl)acrylic acid
86
[0250] A mixture of 1-methylpyrazole-4-carboxaldehyde (made as in
reference 15) (18.1 g), malonic acid (17.1 g), pyridine (15 ml) and
piperidine (0.2 ml) was heated to 100.degree. C. for 1 hour. After
cooling, water was added, followed by aqueous ammonia to obtain a
clear solution, which was acidified to pH5 with hydrochloric acid.
The resulting solid was filtered off, washed with water and dried
to obtain 3-(1-methylpyrazol-4-yl)acrylic acid (18.9 g).
.sup.1H-NMR (d.sub.6-DMSO) .delta. 3.83 (3H,s), 6.18 (1H,d), 7.44
(1H,d), 7.83 (1H,s), 8.07 (1H,s). (APCI) M+H=153.
C.sub.7H.sub.8N.sub.2O.sub.2 requires 152.
[0251] Intermediate B31--Methyl 3-(1-methylpyrazol-4-yl)acrylate
87
[0252] 3-(1-Methylpyrazol-4-yl)acrylic acid (18.86 g) was added to
a solution of sulphuric acid (15 ml) in methanol (150 ml), and the
mixture refluxed for 2 hours, cooled, and poured onto ice. The acid
was neutralised with solid sodium carbonate and the product
extracted into dichloromethane, which was dried and evaporated.
Crystallisation from ether/petrol gave methyl
3-(1-methylpyrazol-4-yl)acrylate (16.0 g). .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.77, (3H,s), 3.91 (3H,s), 6.16 (1H,d), 7.54
(1H,s), 7.56 (1H,d), 7.69 (1H,s). (APCI) M+H=167.
C.sub.8H.sub.10N.sub.2O.sub.2 requires 166.
[0253] Intermediate B32--Methyl 3-(1-methylpyrazol-4-yl)propionate
88
[0254] Prepared analogously to intermediate B6. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 2.56 (2H,t), 2.79 (2H,t), 3.67 (3H,s), 3.85
(3H,s), 7.17 (1H,s), 7.31 (3H,s). (APCI) M+H=169.
C.sub.8H.sub.12N.sub.2O.sub.2 requires 168.
[0255] Intermediate B33--Methyl
2-formyl-3-(1-methylpyrazol-4-yl)propionat- e, sodium salt 89
[0256] Sodium hydride (2.62 g, 60% in oil) was washed with petrol
and suspended in dry dimethoxyethane (20 ml). Methyl
3-(1-methylpyrazol-4-yl)- propionate (8.8 g) and methyl formate
(4.87 ml) were dissolved in DME (20 ml), and a few drops of the
mixture added to the sodium hydride suspension, which was warmed
briefly to initiate the reaction before continuing dropwise
addition at a rate which sustained controlled evolution of
hydrogen. The mixture was stirred for a further 16 hours at room
temperature, then diluted with ether. The solid was filtered off,
washed with ether and immediately dried, and was used promptly
without further purification.
[0257] Intermediate
B34--5-((1-Methylpyrazol-4-yl)methyl)-2-thiouracil 90
[0258] Prepared analogously to intermediate B9, except using the
preformed sodium salt instead of adding sodium ethoxide.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 3.33 (3H,s), 3.75 (3H,s), 7.15
(1H,s), 7.23 (1H,s), 7.46 (1H,s), 12.2 (1H,br s), 12.4 (1H,br s).
(APCI) M+H=223. C.sub.9H.sub.10N.sub.4OS requires 222.
[0259] Intermediate B35--Ethyl 3-(2-methoxypyrimidin-5-yl)acrylate
91
[0260] A mixture of 2-methoxy-5-bromopyrimidine (75.43 g, 0.399
mol), ethyl acrylate (47.5 ml. 0.439 mol), palladium (II) acetate
(1.07 g, 0.0048 mol), tri-o-tolylphosphine (2.92 g, 0.0096 mol) and
triethylamine (84 ml) were heated at 135.degree. C. with stirring
under argon for 12 h. After allowing to cool the solid mass was
dissolved in water and ethyl acetate, filtered, and the aqueous
phase separated and further extracted with ethyl acetate. The
combined extracts were washed with saturated aqueous ammonium
chloride, dried (MgSO.sub.4) and evaporated. The solid thus
obtained was triturated with ether/light petrol (1:3, 350 ml),
filtered, washed and dried, yield 52.41 g (63%). .sup.1H-NMR
(CDCl.sub.3) .delta. 1.33 (3H, t), 4.06 (3H, s), 4.28 (2H, q), 6.45
(1H, d), 7.58 (1H, d), 8.67 (2H, s); MS (APCI+) found (M+H)=209;
C.sub.10H.sub.12N.sub.2O.su- b.3 requires 208.
[0261] Intermediate B36--Ethyl
3-(2-methoxypyrimidin-5-yl)propionate 92
[0262] A suspension of ethyl 3-(2-methoxypyrimidin-5-yl)acrylate
(52.4 g, 0.252 mol) in ethanol (400 ml) and triethylamine (50 ml)
was treated with 10% palladium on carbon (3 ) and hydrogenated at
50 psi for 1.75 h. The catalyst was filtered off through hyflo and
the filtrate evaporated. The residue was dissolved in
dichloromethane, washed twice with saturated aqueous ammonium
chloride, dried (MgSO.sub.4) and evaporated to an oil, yield 41.2 g
(78%). .sup.1H-NMR (CDCl.sub.3) .delta. 1.23 (3H, t), 2.61 (2H, t),
2.87 (2H, t), 3.99 (3H, s), 4.13 (2H, q), 8.39 (2H, s); MS (APCI+)
found (M+H)=211; C.sub.10H.sub.14N.sub.2O.sub.3 requires 210.
[0263] Intermediate
B37--2-(Methoxymethylene)-3-(2,methoxypyrimidin-5-yl)p- ropionic
acid, mixed methylethyl esters 93
[0264] To a stirring suspension of sodium hydride (0.83 g of a 60%
dispersion in oil) in anhydrous 1,2-dimethoxyethane (6 ml) was
added dropwise a solution of methyl formate (1.54 ml) and ethyl
3-(2-methoxypyrimid-5-yl)propionate (3.5 g) in anhydrous
1,2-dimethoxyethane (6 ml) at such a rate as to maintain the
reaction temperature at 25-30.degree. C. After 1 h, ether was added
and the precipitated oil allowed to settle. The solution was
decanted off and replaced with fresh ether, and the oil slowly
solidified. The solid 2-(hydroxymethylene) derivative was filtered,
washed and dried, yield 3.8 g. A 1.33 g portion was suspended in
dimethyl formamide (10 ml) together with anhydrous potassium
carbonate (1.15 g), and a solution of dimethyl sulphate (0.48 ml)
in dimethylformamide (10 ml) was added dropwise with stirring over
30 min. After 16 h the solvent was evaporated and the residue
treated with water and extracted with ethyl acetate. The extracts
were washed with water, dried (MgSO.sub.4) and evaporated to give
the product as an oil, yield 0.91 g. .sup.1H-NMR (CDCl.sub.3)
.delta. 1.23 (3H, t), 3.46 (2H, s), 3.69 (3H, s, methyl ester),
3.88 (3H, s), 3.97 (3H, s), 4.16 (21H, q), 7.39 (1H, s), 8.40 (2H,
s). 3:2 ratio of methyl:ethyl esters. MS (APCI+) found (M+1)=253,
239 (ethyl and methyl esters): C.sub.12H.sub.16N.sub.2O.sub.4
requires 252. C, H.sub.14N.sub.2O.sub.4 requires 238.
[0265] Intermediate
B38--2-(Methoxymethylene)-3-(2-methoxypyrimidin-5-yl)p- ropionic
acid 94
[0266] A suspension of the mixed esters of intermediate 5 (0.9 g)
in 2M aqueous sodium hydroxide (3.6 ml) was stirred at ambient
temperature for 16 h to give a clear solution. This was diluted
with water, extracted with dichloromethane and evaporated to about
half volume, then acidified to pH 3-4 (2M hydrochloric acid) when
the product crystallised out. The white solid was filtered, washed
with ice-cold water and dried, yield 0.46 g. .sup.1H-NMR
(CDCl.sub.3) .delta. 3.43 (2H, s), 3.91 (3H, s), 3.99 (3H, s,),
7.49 (1H, s), 8.42 (2H, s); MS (APCI+) found (M+1)=225,
C.sub.10H.sub.12N.sub.2O.sub.4 requires 224.
[0267] Intermediate
B39--5-(2-Methoxypyrimidin-5-ylmethyl)-2-thiouracil 95
[0268] To an ice cooled solution of potassium t-butoxide (7.83 g,
0.07 mol) in anhydrous THF (60 ml) was added dropwise with stirring
under argon over 1 hour to a solution of ethyl
3-(2-methoxypyrimidin-5-yl) propionate (5.87 g, 0.028 mol) and
methyl formate (3.6 ml, 0.059 mol) in anhydrous ether (70 ml).
After stirring for 16 h, the solvents were evaporated, thiourea
(4.25 g, 0.056 mol) and propan-2-ol (80 Ml) added and the mixture
refluxed for 5 h. The solvent was evaporated and the residue
dissolved in water, extracted twice with ether and acidified to pH
4.5 with acetic acid. The solid which precipitated was filtered,
washed well with water and dried, yield 5.57 g (80%). .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.47 (2H, s), 3.85 (3H, s), 7.43 (1H, s),
8.48 (2H, s), 12.25 (1H, br s), 12.46 (1H, br s); MS (APCI+) found
(M+H)=251; C.sub.10H.sub.10N.sub.4O.sub.2S requires 250.
[0269] Intermediate
B40--5-(2-Benzyloxypyrimid-5-ylmethyl)-2-thiouracil 96
[0270] To a solution of benzyl alcohol (20 ml) in dry
dimethylformamide (20 ml) was added sodium hydride ((60% in oil)
2.3 g) over 0.5 h under argon. A slurry of 2-methoxypyrimidyl
thiouracil (3.6 g) in dry dimethylformamide (10 ml) was added in
one portion and the solution heated to 80.degree. C. for 2.5 h.
After cooling, the solvent was removed under reduced pressure and
the residue partitioned between diethyl ether and water. The
aqueous layer was washed with further diethyl ether and then
acidified to pH4 with glacial acetic acid. The solid so formed was
filtered, washed with water and diethyl ether and dried in vacuo to
give the desired material. .sup.1H-NMR (d.sub.6-DMSO) .delta. 3.49
(2H,s), 5.36 (2H,s), 7.2-7.5 (6H,m), 8.50 (2H,s); MS (APCI+) found
(M+1)=327; C.sub.16H.sub.14N.sub.4O.sub.2S requires 326.
[0271] Intermediate B41--Methyl 2-benzyl-3-methoxyacrylate 97
[0272] Prepared analogously to intermediate B7.
[0273] Intermediate B42--2-Benzyl-3-methoxyacrylic acid 98
[0274] Prepared analogously to intermediate B8.
[0275] Intermediate B43--Methyl
2-(1-methyl-2-oxo-pyrid-4-yl)methyl)-3-met- hoxyacrylate 99
[0276] Prepared from methyl 3-(1-methyl-2-oxo-pyrid-4-yl)propionate
(reference 7) analogously to intermediate B7.
[0277] Intermediate
B44--2-((1-Methyl-2-oxo-pyrid-4-yl)methyl)-3-methoxyac- rylic acid
100
[0278] Prepared analogously to intermediate B8.
[0279] Intermediate
B45--1-(Pyrid-2-ylmethyl)-5-(pyrimid-5-ylmethyl)-2-thi- ouracil
101
[0280] 2-((5-pyrimidyl)methyl)-3-methoxyacrylic acid (5.5 g) was
slurried in dry dichloromethane (100 ml) and oxalyl chloride (4.3
ml) added over 5 min. After stirring at RT for 3 h. the solvent was
removed in vacuo and the residue triturated with toluene. The
solvent was removed in vacuo to give a solid that was slurried in
dry acetonitrile (100 ml) under Ar. Dried powdered potassium
thiocyanate (3.25 g) was added in one portion at RT and the mixture
was stirred for 15 h. Removal of the solvent in vacuo gave a solid
that was slurried with dry dimethylformamide (90 ml). One ninth of
the slurry was added to triethylamine (0.42 ml) and
2-pyridylmethylamine (0.49 g). The mixture was stirred for 19 h
under argon and a solution of sodium ethoxide (3M) in ethanol (1.5
ml) was added in one portion. The mixture was heated on an oil bath
(bath temp 101.degree. C.) for 2 h, cooled and the solvent removed
under reduced pressure. The residue was dissolved in water (12 ml)
and brought to pH 4 with glacial acetic acid. The solid so formed
was filtered and dried in vacuo to give
1-(pyrid-2-ylmethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil (0.69 g).
.sup.1H-NMR (d.sub.6-DMSO) .delta. 3.63(2H,s), 5.47(2H,s),
7.2-7.4(2H,m), 7.7-7.85(1H,m), 8.04(1H,s), 8.5(1H,m), 8.7(2H,s) and
9.04(1H,s): (APCI) M+H=312. C.sub.15H.sub.13N.sub.5OS requires
311.
[0281] Intermediate
B46--1-(4-Hydroxycyclohexyl)-5-(pyrimid-5-ylmethyl)-2-- thiouracil
102
[0282] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.0-2.0(8H,m), 3.63(2H,s), 8.10(1H,s),
8.72(2H,s) and 9.02(1H,s); (ES-) Found (M-1)=317.
C.sub.15H.sub.18N.sub.4O.sub.2S requires 318.
[0283] Intermediate
B47--1-(3-(1-Imidazolyl)prop-1-yl)-5-(pyrimid-5-ylmeth-
yl)-2-thiouracil 103
[0284] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 2.22 (2H, m), 3.58 (2H, s), 4.13 (4H, m),
7.12 (1H, m), 7.36 (1H, m), 7.88 (1H, s), 8.08 (1H, s), 8.73 (2H,
s), 9.05 (1H, s), 12.68 (1H, br s); (APCI+) Found (M+1)=329.
C.sub.15H.sub.16N.sub.6OS requires 328.
[0285] Intermediate
B48--1-(3-(1-Morpholino)prop-1-yl)-5-(pyrimid-5-ylmeth-
yl)-2-thiouracil 104
[0286] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 2.35-2.6(6H+d5-DMSO,m), 3.4-3.8(6H+HOD,m),
4.19(2H,t), 7.96(1H,s), 8.74(2H,s) and 9.04); (APCI+) Found
(M+1)=348. C.sub.16H.sub.21N.sub.5O.sub.2S requires 347.
[0287] Intermediate
B49--1-(3-(2-Oxo-1-pyrrolidino)prop-1-yl)-5-(pyrimid-5-
-ylmethyl)-2-thiouracil 105
[0288] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.91 (4H, m) 2.20 (2H, t), 3.24 (2H, t),
3.37 (2H, t), 3.58 (2H, t), 4.09 (2H, t), 7.97 (2H, s), 8.74 (2H
s). 9.04 (1H, s)=(APCI+) Found (M+1)=346.
C.sub.16H.sub.19N.sub.5O.sub.2S requires 345.
[0289] Intermediate
B50--1-(3-Ethoxycarbonylprop-1-yl)-5-(pyrimid-5-ylmeth-
yl)-2-thiouracil 106
[0290] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.17(1H,t), 1.98(2H,m), 2.34(2H,t),
3.59(2H,s), 4.04(2H,q), 4.16(2H,t), 7.90(1H,s), 8.75(2H,s) and
9.03(1H,s); (ES+) Found (M+1)=335. C.sub.15H.sub.18N.sub.4O.sub.3S
requires 334.
[0291] Intermediate
B51--1-(3-Dimethylaminoprop-1-yl)-5-(pyrimid-5-ylmethy-
l)-2-thiouracil 107
[0292] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 2.21(6H,s), 3.60(2H,s), 4.15(2H,t),
7.91(1H,s), 8.72(2H,s), 9.03(1H,s); (APCI+) Found (M+I)=306.
C.sub.14H.sub.19N.sub.5O- .sub.2S requires 305.
[0293] Intermediate
B52--1-(3-Hydroxyprop-1-yl)-5-(pyrid-5-ylmethyl)-2-thi- ouracil
108
[0294] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.85(2H,m), 3.45(2H,b), 3.61(2H,s),
4.19(2H,t), 4.65(1H,bs), 7.85-8.0(2H,m), 8.71(2H,s) and 9.04(1H,s);
(APCI) M+H=279. C.sub.11H.sub.14N.sub.4O.sub.2S requires 278.
[0295] Intermediate
B53--1-(3-Hydroxyprop-1-yl)-5-benzyl-2-thiouracil 109
[0296] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.85(2H,m), 3.46(2H,m), 3.56(2H,s),
4.19(2H,t), 4.65(1H,t), 7.1-7.4(5H,m) and 7.81(1H,s); (FAB)
M+H=277. C.sub.14H.sub.16N.sub.2O.sub.2S requires 276.
[0297] Intermediate
B54--1-(3-Methoxyprop-1-yl)-5-(pyrimid-5-ylmethyl)-2-t- hiouracil
110
[0298] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.94(2H,m), 3.21(3H,s), 8.55(2H,s),
4.20(2H,t), 7.88(1H,s), 8.72(2H,s) and 9.03(1H,s); (ES-) Found
(M-1)=291. C.sub.19H.sub.22BrClN.sub.2O,S requires 292.
[0299] Intermediate
B55--1-(3-Phenylprop-1-yl)-5-(pyrimid-5-ylmethyl)-2-th- iouracil
111
[0300] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 2.04(2H,m), 2.63(2H,t), 3.58(2H,s),
4.18(2H,t), 7.1-7.35(5H,m), 7.92(1H,s), 8.72(2H,s) and 9.03(1H,s);
(APCI+) Found (M+1)=339. C.sub.18H.sub.18N.sub.4OS requires
338.
[0301] Intermediate
B56--1-(5-Hydroxypent-1-yl)-5-(pyrimid-5-ylmethyl)-2-t- hiouracil
112
[0302] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. (HOAc salt) 1.79(3H,s), 3.59(2H,s),
4.13(2H,t), 7.96(1H,s), 8.72(2H,s) and 9.02(1H,s); (APCI+) Found
(M+1)=307. C.sub.14H.sub.18N.sub.4O.sub.2S requires 306.
[0303] Intermediate B57--1-(Pyrid-2-ylmethyl)-5-benzyl-2-thiouracil
113
[0304] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.59(2H,s), 5.49(2H,s), 7.1-7.45(7H,m),
7.79(1H,m), 7.95(1H,s) and 8.51 (1H,m); MPt 171-4.degree. C.; (EI)
M=309. C.sub.17H.sub.15N.sub.3OS requires 309.
[0305] Intermediate
B58--1-(Pyrid-3-ylmethyl)-5-((1-methyl-2-oxo-pyrid-4-y-
l)methyl)-2-thiouracil 114
[0306] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.11 (3H, s), 3.15 (2H, s), 5.21 (2H, s),
5.86 (1H, m), 5.95 (1H, m), 7.15 (1H, m), 7.34 (1H, m), 7.52 (1H,
m), 7.80 (1H, s), 8.26 (1H, m), 8.34 (1H, m), 12.55 (1H, br s);
(APCI+) Found (M+1)=341. C.sub.17H.sub.16N.sub.4OS requires
340.
[0307] Intermediate
B59--1-(Pyrid-3-ylmethyl)-5-(pyrimid-5-ylmethyl)-2-thi- ouracil
115
[0308] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.49 (2H, s), 5.33 (2H, s), 7.28 (1H, m),
7.64 (1H, m), 7.97 (1H, s), 8.42 (2H, m), 8.59 (2H, s), 8.88 (1H,
m) 12.70 (1H, br s) Mpt>250.degree. C.
[0309] Intermediate B60--1-(Pyrid-3-ylmethyl)-5-benzyl-2-thiouracil
116
[0310] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.57(2H,s), 5.46(2H,s), 7.1-7.35(5H,m),
7.40(1H,m), 7.75(1H,s), 8.02(1H,s), 8.5 1(1H,m) and 8.59(1H,m). MPt
236-8.degree. C.; (EI) M=309. C.sub.17H.sub.15N.sub.3OS requires
309.
[0311] Intermediate
B61--1-(Pyrid-4-ylmethyl)-5-((1-methyl-2-oxo-pyrid-4-y-
l)methyl)-2-thiouracil 117
[0312] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.39(3H,s), 5.45(2H,s), 6.11(1H,dd), 6.21
(1H,m), 7.25(2H,m), 7.58(1H,d), 7.96(1H,s) and 8.54(2H,m). MPt
181-3.degree. C.; (EI) M=340. C.sub.17H.sub.16N.sub.4OS requires
340.
[0313] Intermediate
B62--1-(Pyrid-4-ylmethyl)-5-(pyrimid-5-ylmethyl)-2-thi- ouracil
118
[0314] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.64 (2H, s), 5.45 (2H, s), 7.28 (2H, m),
8.00 (1H, s), 8.55 (2H, m), 8.73 (2H, m), 9.05 (1H, m), 12.85 (1H,
br s) Mpt>250.degree. C.
[0315] Intermediate B63--1-(Pyrid-4-ylmethyl)-5-benzyl-2-thiouracil
119
[0316] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.58(2H,s), 5.46(2Hs), 7.1-7.4(7H,m),
7.93(1H,s) and 8.54(2H,m); MPt 174-6.degree. C.; (EI) M=309.
C.sub.17H.sub.15N.sub.3- OS requires 309.
[0317] Intermediate B64--1-(Pyrid-4-ylmethyl)-2-thiouracil 120
[0318] Prepared from 3-methoxyacrylic acid, analogously to
intermediate B45. .sup.1H-NMR (d.sub.6-DMSO) .delta. 5.45(2H,s),
6.03(2H,d), 7.23(2H,m), 7.94(2H,d) and 8.54(2H,m); MPt
267-70.degree. C.; (EI) M=219. C.sub.10H.sub.9N.sub.3OS requires
219.
[0319] Intermediate
B65--1-(2-(Pyrid-2-yl)ethyl)-5-(pyrimid-5-ylmethyl)-2-- thiouracil
121
[0320] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.12(2H,t), 3.51(2H,s), 4.51(2H,t),
7.25(2H,m), 7.7(2H,m), 8.47(1H,m), 8.61(2H,s) and 9.03(1H,s);
(APCI+) Found (M+1)=326. C.sub.16H.sub.15N.sub.5OS requires
325.
[0321] Intermediate
B66--1-(2-(Pyrid-3-yl)ethyl)-5-((1-methyl-2-oxo-pyrid--
4-yl)methyl)-2-thiouracil 122
[0322] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.08 (2H, t), 3.29 (2H, s), 3.37 (3H, s),
4.38 (2H, t), 5.96 (1H, m), 6.13 (1H, m), 7.34 (1H, m), 7.60 (1H,
m), 7.67 (1H, m), 7.71 (1H, s), 8.46 (2H, m), 12.73 (1H, br s);
(APCI+) Found (M+1)=355. C.sub.18H.sub.19N.sub.4O.sub.2S requires
354.
[0323] Intermediate
B67--1-(2-(Pyrid-3-yl)ethyl)-5-(pyrimid-5-ylmethyl)-2-- thiouracil
123
[0324] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.08(2H,t), 3.53(2H,s), 4.36(2H,t),
7.3(1H,m), 7.65(1H,m), 7.78(1H,s), 8.45(2H,bs), 8.65(2H,s) and
9.05(1H,s); (APCI+) Found (M+1)=326. C.sub.16H.sub.15N.sub.5OS
requires 325.
[0325] Intermediate
B68--1-(2-(Pyrid-4-yl)ethyl)-5-((1-methyl-2-oxo-pyrid--
4-yl)methyl)-2-thiouracil 124
[0326] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.07 (2H, t), 3.30 (2H, s), 3.37 (3H, s),
4.39 (2H, t), 5.94 (1H, m), 6.15 (1H, m), 7.27 (2H, m), 7.56 (1H,
m), 7.72 (1H, s), 8.48 (2H, m), 12.72 (1H, br s); (APCI+) Found
(M+1)=355. C.sub.18H.sub.18N.sub.4O.sub.2S requires 354.
[0327] Intermediate
B69--1-(2-(Pyrid-4-yl)ethyl)-5-(pyrimid-5-ylmethyl)-2-- thiouracil
125
[0328] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.16(2H,t), 3.54(2H,s), 4.45(2H,t),
7.48(2H,d), 7.82(1H,s), 8.60(2H,d), 8.67(2H,s) and 9.05(1H,s);
(ES+) Found (M+1)=326. C.sub.16H.sub.15N.sub.5OS requires 325.
[0329] Intermediate
B70--1-(2-Phenylethyl)-5-((1-methyl-2-oxo-pyrid-4-yl)m-
ethyl)-2-thiouracil 126
[0330] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.04(2H,t), 3.27(3H,s), 4.35(2H,t),
5.93(1H,m), 6.12(1H,bs), 7.1-7.45(5H,m), 7.56(1H,d) and 7.67(1H,s);
MPt 230-3.degree. C.; (APCI) M+H=354.
C.sub.19H.sub.19N.sub.3O.sub.2S requires 353.
[0331] Intermediate
B71--Benzyl-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)-2-th- iouracil
127
[0332] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.38(s), 5.44(2H,s), 6.07(1H,m), 6.18(1H,m),
7.1-7.5(5H,m), 7.57(1H,d) and 7.96(1H,s). (EI) M=339.
C.sub.18H.sub.17N.sub.3O.sub.2S requires 339.
[0333] Intermediate B72--1,5-Dibenzyl-2-thiouracil 128
[0334] Prepared analogously to intermediate B45. .sup.1H-NMR
(CDCl.sub.3) .delta. 3.63(2H,s), 5.35(2H,s), 6.84(1H,s) and
7.05-7.45(10H,m). MPt 15i-2.degree. C.; (EI) M=308.
C.sub.18H.sub.16N.sub.2OS requires 308.
[0335] Intermediate
B73--1-(2-Thienylmethyl)-5-(pyrimid-5-ylmethyl)-2-thio- uracil
129
[0336] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.60 (2H,s)), 5.58 (2H, s), 7.03 (1H, m),
7.26 (1H, m), 7.50 (1H, m), 8.08 (1H, s), 8.69 (2H, s), 9.04 (1H,
s), 12.18 (1H, br s) (APCI+) Found (M+1)=317.
C.sub.14H.sub.12N.sub.4OS.sub.2 requires 316.
[0337] Intermediate B74--1-(2,2-Dimethyl
prop-1-yl)-5-(pyrimid-5-ylmethyl)- -2-thiouracil 130
[0338] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 0.96(9H,s), 3.62(2H,s), 4.17(2H,s),
7.77(1H,s), 8.73(2H,s) and 9.04((H,s); (APCs+) Found (M+1)=291.
C.sub.14H.sub.18N.sub.4OS requires 290.
[0339] Intermediate
B75--1-(2-(1-Piperidino)ethyl)-5-(pyrimid-5-ylmethyl)--
2-thiouracil 131
[0340] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.28-1.72 (6H, m), 2.50 (4H, m), 2.73 (2H,
t), 3.61 (2H, s), 4.29(2H, t), 7.80 (1H, s), 8.73 (2H, s), 9.05
(1H, s), 12.71 (1H, br s); (APCI+) Found (M+1)=332.
C.sub.16H.sub.21N.sub.5OS requires 331.
[0341] Intermediate
B76--1-(2-Acetylaminoethyl)-5-(pyrimid-5-ylmethyl)-2-t- hiouracil
132
[0342] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.75(3H,s), 3.43(2H,m), 3.61(2H,s),
4.18(2H,t), 7.78(1H,s), 8.03(1H,bt), 8.73(2H,s) and 9.03(1H,s);
(ES+) Found (M+1)=306. C.sub.13H.sub.15N.sub.5O.sub.2S requires
305.
[0343] Intermediate
B77--1-(2-Hydroxyethyl)-5-(pyrimid-5-ylmethyl)-2-thiou- racil
133
[0344] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.60(2H,s), 3.72(2H,bq), 4.21(2H,t),
4.99(1H,t), 7.83(1H,s), 8.73(2H,s) and 9.03(1H,s); (ES+) Found
(M+1)=265. C.sub.11H.sub.12N.sub.4O.sub.2S requires 264.
[0345] Intermediate B78--1-(2-Hydroxyethyl)-5-benzyl-2-thiouracil
134
[0346] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.55(2H,s), 3.71(2H,bm), 4.20(2H,t),
4.99(1H,bs), 7.1-7.45(5H,m) and 7.70(1H,s); MPt 171-3.degree. C.;
(FAB) M+H=263. C.sub.13H.sub.14N.sub.2O.sub.2S requires 262.
[0347] Intermediate
B79--1-Dimethylaminocarbonylmethyl-5-(pyrimid-5-ylmeth-
yl)-2-thiouracil 135
[0348] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 2.86 (3H, s), 3.02 (3H, s), 3.61 (2H, s),
5.09 (2H, s), 7.76 (1H, s), 8.71 (2H, s), 9.05 (1H, s); (APCI+)
Found (M+1)=306. C.sub.13H.sub.15N.sub.5O.sub.2S requires 305.
[0349] Intermediate
B80--1-Ethoxycarbonylmethyl-5-(pyrimid-5-ylmethyl)-2-t- hiouracil
136
[0350] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.19 (3H, t), 3.62 (2H, s), 4.16 (2H, q),
4.94 (2H, s), 7.88 (1H, s), 8.73 (2H, s), 9.06 (1H, s); (APCI+)
Found (M+1)=307. C.sub.13H.sub.14N.sub.4O.sub.3S requires 306.
[0351] Intermediate
B81--1-(Fur-2-ylmethyl)-5-(pyrimid-5-ylmethyl)-2-thiou- racil
137
[0352] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.62 (2H, s), 5.43 (2H, s), 6.47 (2H, m),
7.66 (1H, m), 7.98 (1H, s), 8.70 (2H, s), 9.04 (1H, s), 12.75 (1H,
br s); (APCI+) Found (M+1)=301. C.sub.14H.sub.12N.sub.4O.sub.2S
requires 300.
[0353] Intermediate B82--1-(Fur-2-ylmethyl)-S-benzyl-2-thiouracil
138
[0354] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.57(2H,s), 5.43(2H,s), 6.45(2H,s),
7.1-7.4(5H,m), 7.66(1H,m) and 7.85(1H,s); MPt 153-5.degree. C.;
(FAB) M+H=299. C.sub.16H.sub.14N.sub.2O.sub.2S requires 298.
[0355] Intermediate
B83--1-Methyl-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)-2-- thiouracil
139
[0356] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.57(3H,s), 6.12(1H,m), 6.20(1H,bs),
7.57(1H,d) and 7.87(1H,s); (EI) M=263.
C.sub.12H.sub.13N.sub.3O.sub.2S requires 263.
[0357] Intermediate
B84--1-Methyl-5-(pyrimid-5-ylmethyl)-2-thiouracil 140
[0358] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.33(3H,s), 7.93(1H,s) 8.73(2H,s) and
9.02(1H,s); (APCI) M+H=235. C.sub.10H.sub.10N.sub.4OS requires
234.
[0359] Intermediate B85--1-Methyl-5-benzyl-2-thiouracil 141
[0360] Prepared analogously to intermediate B45. .sup.1H-NMR
(CDCl.sub.3) .delta. 3.55(2H,s), 3.57(3H,s), 7.1-7.4(5H,m) and
7.84(1H,s); MPt 143-6.degree. C.; (EI) M=232.
C.sub.12H.sub.12N.sub.2OS requires 232.
[0361] Intermediate
B86--1-Phenyl-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)-2-- thiouracil
142
[0362] Prepared analogously to intermediate B45. .sup.1H-NMR
(CDCl.sub.3) .delta. 3.51(3H+MeOH,s), 6.16(1H,m), 6.48(1H,m),
7.1-7.45(4H,m) and 7.45-7.65(3H,m); (EI) M=325;
C.sub.17H.sub.15N.sub.3O.sub.2S requires 325.
[0363] Intermediate
B87--5-(2-Methoxyethyl)-5-(pyrimid-5-ylmethyl)-2-thiou- racil
143
[0364] Prepared analogously to intermediate B45. .sup.1H-NMR
(CDCl.sub.3) .delta. 3.26 (3H,s), 3.60 (2H,s), 3.65 (2H,t), 4.33
(2H,t), 7.83 (1H,s), 8.70 (2Hs), 9.04 (1Hs); (ES+) M+H=279;
C.sub.12H.sub.14N.sub.4O.sub.2S requires 278.
[0365] Intermediate
B88--1-(2-Methylprop-1-yl)-5-(pyrimid-5-ylmethyl)-2-th- iouracil
144
[0366] Prepared analogously to intermediate B45. (APCI) M-H=275.
C.sub.13H.sub.16N.sub.4OS requires 276.
[0367] Intermediate
B89--1-Ethyl-5-(pyrimid-5-ylmethyl)-2-thiouracil 145
[0368] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.23 (3H,t), 3.60 (2H,s), 4.19 (2H,q),
7.95(1H,s) 8.73(2H,s) and 9.04(1H,s); (APCI) M-H=247.
C.sub.11H.sub.12N.sub.4OS requires 248.
[0369] Intermediate
B90-1-(8-Phenyloctyl)-5-(pyrimid-5-ylmethyl)-2-thioura- cil 146
[0370] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.15-1.4(8H,m), 1.45-1.8(4H,m), 2.56(2H,t),
3.6 (2H,s), 4.11(2H,t), 7.1-7.35(5H,m), 7.94(1H,s), 8.73(2H,s) and
9.02(1H,s). (APCI) M+H=409. C.sub.23H.sub.28N.sub.4OS requires
408.
[0371] Intermediate
B91--1-(9-Phenylnonyl)-5-(pyrimid-5-ylmethyl)-2-thiour- acil
147
[0372] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.15-1.4(8H,m), 1.45-1.8(4H,m), 2.55(2H,t),
3.58 (2H,s), 4.12(2H,t), 7.1-7.35(5H,m), 7.95(1H,s), 8.72(2H,s) and
9.02(1H,s). (APCI) M+H=421. C.sub.24H.sub.30N.sub.4OS requires
422.
[0373] Intermediate
B92--1-Undecyl-5-(2-ethoxypyrimid-5-ylmethyl)-2-thiour- acil
148
[0374] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6 DMSO) .delta. 0.8-0.95 (3H,m), 1.05-1.5 (19H,m), 1.6-1.8
(2H,m), 3.49 (2H,s), 4.11 (2H,t), 4.31 (2H,q), 8.48 (2H,s); MS
(APCI+) found (M+1)=418; C.sub.12H.sub.34N.sub.4O.sub.2S requires
417.
[0375] Intermediate
B93--1-(2-Phenylethyl)-5-(pyrimid-5-ylmethyl)-2-thiour- acil
149
[0376] Prepared analogously to intermediate B45. Solid. .sup.1H-NMR
(DMSO) .delta. 3.00-3.10 (2H, t), 3.50 (2H, s), 4.29-4.40 (2H, t),
7.10-7.33 (5H, m), 7.71 (1H, s), 8.68 (2H, s), 9.00 (1H, s),
12.62-12.75 (1H, br,s); MS (APCI-) found (M-1)=323;
C.sub.17H.sub.16N.sub.4OS requires 324.
[0377] Intermediate
B94--1-Benzyl-5-(pyrimid-5-ylmethyl)-2-thiouracil 150
[0378] Prepared analogously to intermediate B45. Solid. .sup.1H-NMR
(DMSO) .delta. 3.57 (2H, s), 4.46 (2H, s), 7.10-7.44 (6H, m), 7.91
(1H, s), 8.69 (2H, s), 9.01 (1H, s); MS (APCI+) found (M+1)=311;
C.sub.16H.sub.14N40S requires 310.
[0379] Intermediate
B95--1-Undecyl-5-(pyrimid-5-ylmethyl)-2-thiouracil 151
[0380] Prepared analogously to intermediate B45. Solid. .sup.1H-NMR
(DMSO) .delta. 0.79-0.93 (3H, t), 1.12-1.44 (16H, m), 1.60-1.79
(2H, t), 3.59 (2H, s), 4.05-4.20 (2H, t), 7.96 (1H, s), 8.70 (2H,
s), 9.01 (1H, s), 12.61 (1H, s): MS (APCI-) found (M-1)=373;
C.sub.20H.sub.30N.sub.4OS requires 374.
[0381] Intermediate
B96--1-Dodecyl-5-(pyrimid-5-ylmethyl)-2-thiouracil 152
[0382] Prepared analogously to intermediate B45. Solid. .sup.1H-NMR
(DMSO) .delta. 0.79-0.94 (3H, t), 1.13-1.47 (18H, s), 1.60-1.80
(2H, br,t), 3.59 (2H, s),4.06-4.20 (2H, t), 7.96 (1H, s), 8.71 (2H,
s), 9.03 (1H, s); MS (ES-) found (M-1)=387:
C.sub.21H.sub.32N.sub.4OS requires 388.
[0383] Intermediate
B97--1-(2-(Thien-2-yl)ethyl)-5-(pyrimid-5-ylmethyl)-2-- thiouracil
153
[0384] Prepared analogously to intermediate B45. Solid. .sup.1H-NMR
(DMSO) .delta. 3.17-3.47 (2H, t), 3.52 (2H, s), 4.30-4.43 (2H, t),
6.80-7.04 (2H, m), 7.27-7.40 (1H, m), 7.73 (1H, s), 8.62 (2H, s),
9.03 (1H, s) 11.97-12.5 (1H, br,s); MS (APCI-) found (M-1)=329;
C.sub.15H.sub.14N.sub.4OS.sub.2 requires 330.
[0385] Intermediate
B98--1-(5-Methylfuran-2-ylmethyl)-5-(pyrimid-5-ylmethy-
l)-2-thiouracil 154
[0386] Prepared analogously to intermediate B45. Solid. .sup.1H-NMR
(DMSO) .delta. 2.24 (3H, s), 3.63 (2H, s), 5.37 (2H, s), 6.01-6.08
(1H, d), 6.30-6.38 (1H, d), 7.92 (1H, s), 8.72 (2H, s), 9.04 (1H,
s) 12.73 (1H, s), MS (ES-) found (M-1)=313;
C.sub.15H.sub.14N.sub.4O.sub.2S requires 314.
[0387] Intermediate
B99--1-(4-Fluorobenzyl)-5-(pyrimid-5-ylmethyl)-2-thiou- racil
155
[0388] Prepared analogously to intermediate B45. Solid. .sup.1H-NMR
(DMSO) .delta. 3.60 (2H, s), 5.41 (2H, s), 7.13-7.25 (2H, m),
7.35-7.47 (2H, m), 8.02 (1H, s), 8.70 (2H, s), 9.03 (1H, s), 12.78
(1H,s); MS found (M-1)=327; C.sub.16H.sub.13FN.sub.4OS requires
328.
[0389] Intermediate
B100--1-(2-(2-Chlorophenyl)ethyl)-5-(Pyrimid-5-ylmethy-
l)-2-thiouracil 156
[0390] Prepared analogously to intermediate B45. Solid. .sup.1H-NMR
(DMSO) .delta. 3.12-3.22 (2H, t), 3.49 (2H, s), 4.34-4.46 (2H, t),
7.14-7.43 (4H, m), 7.52 (1H, s), 8.57 (2H, s), 9.04 (1H, s),
11.40-11.85 (1H, br,s); MS (APCI-) found (M-1)=357;
C.sub.17H.sub.15ClN.sub.4OS requires 358.
[0391] Intermediate
B101--1-(2-Phenoxyethyl)-5-(Pyrimid-5-ylmethyl)-2-thio- uracil
157
[0392] Prepared analogously to intermediate B45. Solid. .sup.1H-NMR
(DMSO) .delta. 3.63 (2H, s), 4.25-4.37 (2H, t), 4.50-4.60 (2H, t),
6.84-7.00 (3H, m), 7.20-7.33 (2H, t), 7.94 (1H, s), 8.71 (2H, s),
9.06 (1H, s), 12.78 (1H, s); MS (ES+) found (M+1)=341;
C.sub.17H.sub.16N.sub.4O.sub.2S requires 340.
[0393] Intermediate
B102--1-(5-Ethoxycarbonylpent-1-yl)-5-(Pyrimid-5-ylmet-
hyl)-2-thiouracil 158
[0394] Prepared analogously to intermediate B45. Solid. .sup.1H-NMR
(DMSO) .delta. 1.10-1.20 (3H, t), 1.21-1.39 (2H, m), 1.45-1.80 (4H,
m), 2.22-2.38 (2H, m), 3.59 (2H, s), 3.96-4.19 (4H, m), 7.94 (1H,
s), 8.70 (2H, s), 9.03 (1H, s), 12.12-12.35 (1H, br,s); MS (ES-)
found (M-1) 361; C.sub.17H.sub.22N.sub.4O.sub.3S requires 362.
[0395] Intermediate
B103--1-(1-Ethoxycarbonylethyl)-5-(pyrimid-5-ylmethyl)-
-2-thiouracil 159
[0396] Prepared analogously to intermediate B45. Solid. .sup.1H-NMR
(DMSO) .delta. 1.06-1.30 (3H, t), 1.58-1.70 (3H, d), 3.67 (2H, d),
4.02-4.27 (2H, m), 6.02-6.19 (1H, q), 8.05 (1H, s), 8.70 (2H, s),
9.03 (1H, s), 12.80 (1H, s); MS (APCI+) found (M+1)=321;
C.sub.14H.sub.16N.sub.4O.sub.3- S requires 320.
[0397] Intermediate
B104--1-(1-Methylethyl)-5-(pyrimid-5-ylmethyl)-2-thiou- racil
160
[0398] Prepared analogously to intermediate B45. Solid. .sup.1H-NMR
(DMSO) .delta. 1.26-1.45 (6H, d), 3.65 (2H, s), 5.53-5.74 (1H, m),
8.10 (1H, s), 8.72 (2H, s), 9.02 (1H, s), 12.60 (1H, s); MS (APCI-)
found (M+1)=261; C.sub.12H.sub.14N.sub.4OS requires 262.
[0399] Intermediate
B105--1-Cyclopropyl-5-(pyrimid-5-ylmethyl)-2-thiouraci- l 161
[0400] Prepared analogously to intermediate B45. Solid. .sup.1H-NMR
(DMSO) .delta. 0.92-1.10 (4H, m), 3.37-3.43 (1H, m), 3.60 (2H, s),
7.89 (1H, s), 8.71 (2H, s), 9.02 (1H, s), 12.60 (1H, s); MS (APCI-)
found (M-1)=259; C.sub.12H.sub.12N.sub.4OS requires 260.
[0401] Intermediate
B106--1-(1-Ethoxycarbonylcycloprop-1-yl)-5-(pyrimid-5--
ylmethyl)-2-thiouracil 162
[0402] Prepared analogously to intermediate B45. Solid. .sup.1H-NMR
(DMSO) .delta. 1.05-1.20 (3H, t), 1.40-1.95 (4H, m), 3.61 (2H, s),
4.02-4.18 (2H, q), 7.98 (1H, s), 8.72 (2H, s), 9.04 (1H, s), 12.04
(1H, s); MS (APCI+) found (M+1)=333; C.sub.15H.sub.16N.sub.4OS
requires 332.
[0403] Intermediate
B107--1-(4-Ethoxycarbonylbenzyl)-5-(pyrimid-5-ylmethyl-
)-2-thiouracil 163
[0404] Prepared analogously to intermediate B45. Solid. .sup.1H-NMR
(DMSO) .delta. 1.23-1.38 (3H, t), 3.60 (2H, s), 4.24-4.40 (2H, q),
5.50 (2H, s), 7.35-7.47 (2H, m), 7.86-8.00 (2H, m), 8.04 (1H, s),
8.70 (2H, s), 9.03 (1H, s), 12.07-12.40 (1H, br,s); MS (APCI-)
found (M-1)=381; C.sub.19H.sub.18N.sub.4O.sub.3S requires 382.
[0405] Intermediate
B108--1-(4-Methoxycarbonylcyclohex-1-yl)-5-(pyrimid-5--
ylmethyl)-2-thiouracil 164
[0406] Prepared analogously to intermediate B45. Solid. .sup.1H-NMR
(DMSO) .delta. 1.32-1.92 (6H, m), 2.10-2.30 (2H, m), 2.67-2.80 (1H,
m), 3.64 (3H, s), 3.69 (2H, s), 5.17-5.34 (1H, br,s), 7.87 (1H, s),
8.70 (2H, s), 9.01 (1H, s), 12.63 (1H, s): MS (APCI-) found
(M-1)=359; C.sub.17H.sub.20N.sub.4O.sub.3S requires 360.
[0407] Intermediate
B109--1-(2-(6-(4-Fluorophenyl)hex-1-yloxy)ethyl)-5-(py- rimid-5
ylmethyl)-2-thiouracil 165
[0408] Prepared analogously to intermediate B45. Solid. .sup.1H-NMR
(DMSO) .delta. 1.14-1.60 (12H, m), 3.60 (2H, s), 3.62-3.70 (2H, t),
4.26-4.35 (2H, t), 7.00-7.12 (2H, t), 7.14-7.24 (2H, m), 7.80 (1H,
s), 8.70 (2H, s), 9.00 (1H, s), 12.64-12.77 (1H, br,s); MS (APCI-)
found (M-1)=441; C.sub.23H.sub.27FN.sub.4O.sub.2S requires 442.
[0409] Intermediate
B100--1-Undecyl-5-(1-methyl-2-oxopyrid-4-ylmethyl)-2-t- hiouracil
166
[0410] Prepared analogously to intermediate B45. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.88 (3H, t), 1.26 (14H, m), 1.32 (2H, t),
1.75 (2H, m), 3.48 (2H, s), 3.52 (3H, s), 4.11 (2H, t), 6.10 (1H,
m), 6.40 (1H, s), 7.08 (1H, s), 7.22 (1H, d), 9.56 (1H, bs); MS
(APCI+) M+1=404, C.sub.22H.sub.33N.sub.3O.sub.2S requires 403. MPt
137-140.degree. C. (cream solid).
[0411] Intermediate
B111--1-(3-Ethoxycarbonylpropyl)-5-(1-methyl-2-oxopyri-
d-4-ylmethyl)-2-thiouracil 167
[0412] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.17 (3H, t), 1.95 (2H, m), 2.35 (2H, m),
3.34 (5H, m), 4.03 (2H, q), 4.17 (2H, m), 6.11 (1H, m), 6.20 (1H,
s), 7.57 (1H, d), 7.83 (1H, s), 12.63 (1H, bs); MS (APCI+)
M+1=3642, C.sub.17H.sub.21N.sub.3O.sub.4S requires 363. MPt
168-170.degree. C. (cream solid).
[0413] Intermediate
B112--1-(2-(4-Pent-1-ylphenyl)ethyl)-5-(pyrimid-5-ylme-
thyl)-2-thiouracil 168
[0414] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 0.85 (3H, m), 1.25 (4H, m), 1.53 (2H, m),
2.52 (2H, m), 2.99 (2H, m), 3.49 (2H, s), 4.33 (2H, m), 7.03-7.24
(4H, m),7.71 (1H, s), 8.59 (2H, s), 9.03 (1H, s), 12.70 (1H, bs);
MS (APCI+) M+1=395, C.sub.22H.sub.26N.sub.4OS requires 394. (light
brown solid).
[0415] Intermediate
B113--1-(2-(4-Pent-2-en-1-ylphenyl)ethyl)-5-(pyrimid-5-
-ylmethyl)-2-thiouracil 169
[0416] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 0.89 (3H, m), 1.30-1.60 (2H, m), 2.24 (2H,
m), 3.03 (2H, m), 3.51 (2H, s), 4.35 (2H, m), 5.63 (1H, m), 6.33
(1H, s), 7.10-7.33 (4H, m),7.76 (1H, s), 8.61 (2H, s), 9.03 (1H,
s), 12.70 (1H, bs); MS (APCI+) M+1=393, C.sub.22H.sub.24N.sub.4OS
requires 392. (light brown solid).
[0417] Intermediate
B114--1-(2-(4-Bromophenyl)ethyl)-5-(pyrimid-5-ylmethyl-
)-2-thiouracil 170
[0418] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.02 (211,t), 3.53 (211, s), 4.33 (211, t),
7.22 (2H, m), 7.49 (2H, m), 7.77 (111, s), 8.60 (2H, s), 9.02 (1H,
s), 12.7 (1H, bs), MS (APCI+) M+1=403, C.sub.17H.sub.15BrN.sub.4OS
requires 402.
[0419] Intermediate
B115--1-(4-Bromobenzyl)-5-(pyrimid-5-ylmethyl)-2-thiou- racil
SB-296961- 171
[0420] Prepared analogously to intermediate B45. .sup.1H1-NMR
(d.sub.6-DMSO) .delta. 3.60 (211,s), 5.39 (211, s), 7.29 (211, d),
7.57 (211, d), 8.01 (1H, s), 8.70 (211, s), 9.03 (1H, s), 12.75
(1H, bs), MS (APCI+) M+1=389, C.sub.16H .sub.13BrN.sub.4S requires
388
[0421] Intermediate
B116--1-(2-(3-Pent-1-ylphenyl)ethyl)-5-(pyrimid-5-ylme-
thyl)-2-thiouracil 172
[0422] Prepared analogously to intermediate B45. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.89 (3H, m), 1.30 (4H, m), 1.55 (2H, m), 2.53
(2H, t), 3.10 (2H, t), 3.42 (2H, s), 4.35 (2H, t), 6.49 (1H, s),
6.91-7.22 (4H, m), 8.44 (2H, s), 9.11 (1H, s), 9.60 (1H, bs)
MS(APCI+) M+1=395, C.sub.22H.sub.26N.sub.4OS requires 394. MPt
137.5.degree. C. (colourless solid).
[0423] Intermediate
B117--1-(2-(2-Pent-1-ylphenyl)ethyl)-5-(pyrimid-5-ylme-
thyl)-2-thiouracil 173
[0424] Prepared analogously to intermediate B45. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.88 (3H, t), 1.28 (4H, m), 1.49 (2H, m), 2.50
(2H, t), 3.15 (2H, t), 3.42 (2H, s), 4.34 (2H, t), 6.41 (1H, s),
7.03-7.21 (4H, m), 8.50 (2H, s), 9.12 (1H, s), 9.70 (1H, bs);
MS(APCI+) M+1=395, C.sub.22H.sub.26N.sub.4OS requires 394. MPt
181.6.degree. C. (pale orange solid)
[0425] Intermediate
B118--1-(3-Ethoxycarbonylphenyl)-5-(pyrimid-5-ylmethyl-
)-2-thiouracil 174
[0426] Prepared analogously to intermediate B45. .sup.1H NMR
(CDCl.sub.3) .delta. 1.41 (t, 3H), 3.70 (s, 2H), 4.41 (q, 2H), 7.30
(s, 1H), 7.35 (m, 1H), 7.60 (m. 2H), 7.98 (m, 1H), 8.15 (d, 1H),
8.71 (s, 2H), 9.10 (s, 1H), MS (ES+) Found (M+1)=369;
C.sub.18H.sub.16N.sub.4O.sub.3S requires 368.
[0427] Intermediate
B119--1-(4-Ethoxycarbonylphenyl)-2-(4-fluorobenzyl)thi-
o-5-(pyrimid-5-ylmethyl)-2-thiouracil 175
[0428] Prepared analogously to intermediate B45. .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.41 (t, 3H), 3.69 (s, 2H), 4.39 (q, 2H),
7.30 (s, 1H), 7.46 (d, 2H), 8.21 (d, 2H), 8.72 (s, 2H), 9.10 (s,
1H). MS (ES+) Found (M+1)=369; C.sub.18H.sub.16N.sub.4O.sub.3S
requires 368.
[0429] Intermediate
B120--1-(5-(Ethoxycarbonyl)fur-2-yl)-2-(4-fluorobenzyl-
)thio-5-(pyrimid-5-ylmethyl)-2-thiouracil 176
[0430] Prepared analogously to intermediate B45. .sup.1H NMR
(CDCl.sub.3) .delta.: 1.39 (t, 3H), 3.69 (s, 2H), 4.39 (q, 2H),
6.69 (d, 1H), 7.28 (d, 1H), 7.41 (s, 1H), 8.72 (s, 2H), 9.12 (s,
1H). MS (APCI+) Found (M+1)=359; C.sub.16H.sub.14N.sub.4O.sub.4S
requires 358.
[0431] Intermediate
B121--1-Phenyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylm-
ethyl)-2-thiouracil 177
[0432] Prepared analogously to intermediate B45. .sup.1H NMR
(CDCl.sub.3) .delta.: 3.69 (s, 2H),7.30 (m, 3H), 7.50 (m, 3H), 8.72
(s, 2H), 9.10 (s, 1H). MS (ES+) Found (M+1)=297;
C.sub.15H.sub.2N.sub.4OS requires 296.
[0433] Intermediate
B122--1-(4-(tert-Butoxycarbonylamino)but-1-yl)-2-(4-fl-
uorobenzyl)thio-5-(pyrimid-5-ylmethyl)-2-thiouracil 178
[0434] Prepared analogously to intermediate B45. .sup.1H NMR
(DMSO-d.sub.6) .delta.: 1.37 (s, 9H), 1.4 (m, 2H), 1.65 (m, 2h),
2.93 (m, 2H), 3.59 (s, 2H), 4.13 (t, 2H), 6.81 (br s, 1H), 7.94 (s,
1H), 8.70 (s, 2H), 9.04 (s, 1H), 13.45 (br s, 1H), MS (ES+) Found
(M+1)=392; C.sub.18H.sub.25N.sub.5O.sub.3S requires 391.
[0435] Intermediate
B123--1-(3-(Ethoxycarbonylamino)prop-1-yl)-2-(4-fluoro-
benzyl)thio-5-(pyrimid-5-ylmethyl)-2-thiouracil 179
[0436] Prepared analogously to intermediate B45 as a pale buff
solid. .sup.1H NMR (DMSO-d.sub.6) .delta.: 1.15 (t, 3H), 1.85 (m,
2H), 3.02 (m, 2H), 3.59 (s, 2H), 4.01 (q, 2H), 4.14 (t, 2H), 7.12
(br s, 1H), 7.93 (s, 1H), 8.69 (s, 2H), 9.00 (s, 1H), 13.55 (br s,
1H). MS (APCI+) Found (M+1)=350; C.sub.15H.sub.19N.sub.5O.sub.3S
requires 349.
[0437] Intermediate
B124--1-(1-Undecyl)-5-(2-methoxypyrimid-5-ylmethyl)-2-- thiouracil
180
[0438] Prepared analogously to intermediate B45, except using
sodium methoxide in place of ethoxide. .sup.1H-NMR (CDCl.sub.3)
.delta. 0.8-0.95 (3H,t), 1.1-1.85 (18H,m), 3.59 (2H, s), 4.01
(3H,s), 4.11 (2H,t), 7.04 (1H,s), 8.43 (2H, s); MS (APCI+) found
(M+1)=405; C.sub.21H.sub.32N.sub.4- O.sub.2S requires 404.
[0439] Intermediate
B125--1-(4-(Dec-1-yl)phenyl)-5-(pyrimid-5-ylmethyl)-2-- thiouracil
181
[0440] Prepared analogously to intermediate B45. The ethoxide
cyclisation step failed to go to completion, but the crude
thiouracil was used in the next step without purification.
[0441] Intermediate
B126--1-(4-(Non-1-yloxyphenyl))-5-(pyrimid-5-ylmethyl)-
-2-thiouracil 182
[0442] Prepared analogously to intermediate B125.
[0443] Intermediate
B127--1-(4-(Hex-1-yl)phenyl)-5-(pyrimid-5-ylmethyl)-2-- thiouracil
183
[0444] Prepared analogously to intermediate B125.
[0445] Intermediate
B128--1-(3-(Non-1-yloxy)phenyl)-5-(pyrimid-5-ylmethyl)-
-2-thiouracil 184
[0446] Prepared analogously to intermediate B125.
[0447] Intermediate
B129--1-(3-(Dec-1-yl)phenyl)-5-(pyrimid-ylmethyl)-2-th- iouracil
185
[0448] Prepared analogously to intermediate B125.
[0449] Intermediate B130
--1-(4-Iodophenyl)-5-(pyrimid-5-ylmethyl)-2-thiou- racil 186
[0450] Prepared analogously to intermediate B125.
[0451] Intermediate
B131--1-(2-Fluorobenzyl)-5(pyrimid-5-ylmethyl)-2-thiou- racil
187
[0452] Prepared analogously to intermediate B45. .sup.1H NMR
(d.sub.6-DMSO) .delta. 3.62 (2H,s), 5.45 (2H, s), 7.1-7.4 (4H, m),
7.98 (1H, s), 8.70 (2H, s), 9.04 (1H, s), 12.8 (1H, bs), MS (APCI-)
M-1=327. C.sub.16H.sub.13FN.sub.4OS requires 328.
[0453] Intermediate
B132--(S)-1-(Tetrahydrofur-2-ylmethyl)-5-(pyrimid-5-yl-
methyl)-2-thiouracil 188
[0454] Prepared analogously to intermediate B45. .sup.1H NMR
(d.sub.6-DMSO) .delta. 1.5-1.65 (1H,m), 1.75-2.05 (3H,m), 3.62
(2H,s), 3.65 (1H,m), 3.79 (1H,m), 3.95 (1H,m), 4.24 (1H, m), 4.47
(1H,dd), 7.83 (1H, s), 8.70 (2H, s), 9.04 (1H, s), 12.7 (1H, bs),
MS (APCI-) M-1=303, C.sub.14H.sub.16N.sub.4O.sub.2S requires
304.
[0455] Intermediate
B133--(R)-1-(Tetrahydrofur-2-ylmethyl)-5-(pyrimid-5-yl-
methyl)-2-thiouracil 189
[0456] Prepared analogously to intermediate B45. .sup.1H NMR
(d.sub.6-DMSO) .delta. 1.5-1.65 (1H,m), 1.75-2.05 (3H,m), 3.62
(2H,s), 3.65 (1H,m), 3.79 (1H,m), 3.95 (1H,m), 4.24 (1H, m), 4.47
(1H,dd), 7.83 (1H, s), 8.70 (2H, s), 9.04 (1H, s), 12.7 (1H, bs),
MS (APCI-) M-1=303, C.sub.14H.sub.16N.sub.4O.sub.2S requires
304.
[0457] Intermediate
B134--1-(2-(4-Methoxyphenyl)ethyl)-5-(pyrimid-5-ylmeth-
yl)-2-thiouracil 190
[0458] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 2.97 (2H,t), 3.51 (2H, s), 3,74 (3H,s), 4.31
(2H, t), 6.85 (2H, m), 7.49 (2H, m), 7.14 (1H, s), 8.59 (2H, s),
9.03 (1H, s), 12.7 (1H, bs), MS (APCI+) M+1=355,
C.sub.18H.sub.18N.sub.4O.sub.2S requires 354
[0459] Intermediate B
135--1-(Undec-1-yl)-5-(2-methylpyrimid-5-ylmethyl)-2- -thiouracil
191
[0460] Prepared analogously to intermediate B45, except using
sodium methoxide in place of ethoxide. .sup.1H-NMR (CDCl.sub.3)
.delta. 0.8-0.9 (3H,t), 1.2-1.35 (16H,m), 1.75 (2H,m), 2.73 (3H,s),
3.62 (2H, s), 4.11 (2H,t), 7.05 (1H,s), 8.57 (2H, s), 9.7-9.8
(1H,br s); MS (APCI+) found (M+1)=389; C.sub.21 H.sub.32N.sub.4OS
requires 388.
[0461] Intermediate
B136--1-(4-Acetylphenyl)-5-(pyrimid-5-ylmethyl)-2-thio- uracil
192
[0462] Prepared analogously to intermediate B125.
[0463] Intermediate
B137--1-(trans-4-(Methoxycarbonyl)cyclohex-1-ylmethyl)-
-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-2-thiouracil 193
[0464] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.0-1.4 (4H, m), 1.65 (2H, m), 1.92 (2H,m),
2.15-2.35 (1H, m), 3.58 (3H, s), 3.60 (2H, s), 4.01 (2H,m), 7.88
(1H, s), 8.70 (2H, s), 9.06 (1H, s), 12.6 (1H, br s);, MS (APCI-)
found (M-1)=373; C.sub.18H.sub.22N.sub.4O.sub.3S requires 374.
[0465] Intermediate
B138--1-(2-(t-Butoxycarbonylamino)ethyl)-5-(pyrimid-5--
ylmethyl)-2-thiouracil 194
[0466] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.34 (9H, s), 3.32 (2H,m), 3.58 (2H,s), 4.19
(2H,m), 6.99 (1H,t), 7.69 (1H, s), 8.71 (2H, s), 9.03 (1H, s), 12.6
(1H, br s); MS (APCI-) found (M-1)=362;
C.sub.16H.sub.21N.sub.5O.sub.3S requires 363.
[0467] Intermediate
B139--1-(3-(5-Phenylpent-1-yloxy)prop-1-yl)-5-(pyrimid-
-5-ylmethyl)-2-thiouracil 195
[0468] Prepared analogously to intermediate B45. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.33 (2H, m), 1.4-1.7 (4H, m), 1.95 (2H, m),
2.55 (2H, t), 3.2-3.5 (4H, m), 3.60 (2H, s), 4.18 (2H, t), 7.1-7.3
(5H,m), 7.86 (1H, s), 8.71 (2H, s), 9.03 (1H, s), 12.6 (1H, br s);
MS (APCI+) found (M+1)=425; C.sub.23H.sub.28N.sub.4O.sub.2S
requires 424.
[0469] General Method A: S-Alkylation of thiouracils
[0470] A1 (N1-unsubstituted thiouracils). Sodium (2.2 equiv) was
dissolved in ethanol to give a ca. 0.5M solution of sodium
ethoxide. The appropriate thiouracil (1 equiv) was added, usually
giving a clear solution, then the appropriate alkyating agent was
added (1.0-1.25 equiv were used in various preparations, but no
consistent advantage was seen with higher amounts) and the mixture
was stirred at room temperature overnight. The ethanol was removed
by evaporation, the residue was taken up in water, and the solution
adjusted to pH 5 with acetic acid. In many cases the product
precipitated, and was filtered off, washed with water and dried.
When necessary, the aqueous solution was extracted with ethyl
acetate, the organic layers dried and evaporated, and the residue
triturated with ether or pet, ether to obtain the product.
[0471] A2. A mixture of thiouracil (1 equiv), the appropriate
alkylating agent (1-1.1 equiv) and diisopropylethylamine (1-1.1
equiv) was stirred overnight at room temperature in dichloromethane
(12 ml/mmol). The solution was diluted with dichloromethane and
washed with saturated sodium bicarbonate solution. The organic
layer was added directly to a silica gel column. Elution (ethyl
acetate to methanol:ethyl acetate) gave the desired product.
[0472] A3. A mixture of thiouracil (1 equiv), the appropriate
alkylating agent (1-1.1 equiv) and diisopropylethylamine (1-1.1
equiv) was stirred for 1 h at between 64 and 72.degree. C. in
1,2-dichloroethane (12 ml/mmol). The solution was diluted with
dichloromethane and washed with saturated sodium bicarbonate
solution. The organic layer was added directly to a silica gel
column. Elution (ethyl acetate to methanol:ethyl acetate) gave the
desired product.l
[0473] A4. A mixture of the appropriate thiouracil (1 equiv), the
appropriate alkylating agent (1.1 equiv) and potassium carbonate
(2-3 equiv) in dry dimethylformamide (ca 4 ml/mmol) was heated at
65.degree. C. for 2.5 h. The mixture was cooled, the solvent was
removed under reduced pressure and the residue partitioned between
dichloromethane (50 ml) and 3% aqueous potassium carbonate
solution. The organic layer was applied directly to a SepPak
cartridge (10 g, Silica) and elution was continued with 2% to 8%
methanol in ethyl acetate as eluent. This gave
1-(4-hydroxycyclohexyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrim-
id-5-ylmethyl)pyrimidin-4-one (0.1 8 g)
[0474] A5. Array synthesis. This proceeded essentially as in method
A1, except that parallel reactions were carried out in screw-capped
polypropylene tubes. The appropriate thiouracil (1 equiv) was
weighed into each tube, then 0.5M ethanolic sodium ethoxide (2
equiv) and the appropriate alkyl halide (1 equiv) as an 0.5M
ethanol solution were dispensed in by pipette and the tubes capped
and vortexed at room temperature overnight on an orbital shaker.
After removal of solvent in a vacuum centrifuge, individual
products were worked up in the usual way.
[0475] General Method B: Displacement of 2-(nitroamino)pyrimidones
with Thiols
[0476] The appropriate 2-(nitroamino)pyrimidone (1 equiv) and thiol
(2 equiv) in pyridine (ca 2ml per mmol) were stirred at reflux for
2 days, then the pyridine was evaporated. Trituration with an
appropriate solvent, as described in the individual examples, gave
the desired product.
[0477] General method C: N1-Alkylation of pyrimidin-4-ones
[0478] C1. To a stirred solution of the pyrimidinone (1 equiv) in
dry DMF (20 ml) was added sodium hydride (1 equiv). The mixture was
stirred at room temperature for 30 min, then the appropriate
alkylating agent (1-1.1 equiv) was added in portions over 15 min,
and the mixture was stirred overnight. Ethyl acetate and dilute
hydrochloric acid were added, the organic layer was separated and
washed with water and brine, dried and evaporated. Flash
chromatography (silica, 1-10% methanol in dichloromethane) gave
first a mixture of the 3-alkyl and 4-alkoxypyrimidine byproducts,
then the desired 1-alkylpyrimidin-4-one.
[0479] C2. A mixture of pyrimidinone (1 equiv), the appropriate
alkylating agent (1-1.1 equiv) and diisopropylethylamine (1-1.5
equiv, usually 1.25-1.3 equiv) was stirred for between 20-72 h at
room temperature in dichloromethane (12 ml/mmol) (if the
pyrimidinone was only partially soluble in dichloromethane,
dimethylformamide (2 ml/mmol) was also added). The solution was
diluted with dichloromethane containing up to 2% methanol (if
dimethylformamide was used, the solvent was first removed under
reduced pressure) and washed with saturated ammonium chloride
solution and sodium bicarbonate solution. The organic layer was
separated and added directly to a silica gel column. Elution (ethyl
acetate to methanol:dichloromethane:ethyl acetate) gave the desired
product.
[0480] C3. Similar to method C2. except that the solvent was
1,2-dichloroethane in place of dichloromethane, and the pyrimidone
was treated with tributyltin chloride (1 equiv) and stirred
overnight to form the silyl ether before addition of the alkylating
agent.
[0481] General Method D: Ester Hydrolysis
[0482] To a solution of the ester (1 equiv) in 1,4 dioxane (9
ml/mmol) under argon was added a solution of sodium hydroxide
(0.95-1 equiv) in water (2-4.5ml/mmol) whilst keeping the
temperature below 25.degree. C. After stirring for between 2-20 h
at room temperature (the reaction was checked for completion), 75%
of the solvent was removed under reduced pressure at <25.degree.
C. The residue was diluted with water and brought to pH3 with 5%
aqueous sodium bisulphate. The solid so formed was filtered and
dried in vacuo to give the desired material.
[0483] General Method E: Amide Coupling
[0484] To a slurry/solution of the carboxylic acid (1 equiv) in
dichloromethane (or dimethylformamide) (12 ml/mmol) was added
hydroxybenzotriazole (0.1 equiv), the amine (1equiv) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.05
eq). After stirring under argon for 24 h, (the solvent removed
under reduced pressure if dimethylformamide) the mixture was
diluted with dichloromethane and washed with saturated sodium
bicarbonate. Addition of the organic layer directly to a silica gel
column and elution (ethyl acetate to methanol:ethyl acetate) gave
the desired product. Alternatively, the crude product could be
purified by solid phase extraction on a BondElut SCX cartridge,
eluted with dichloromethane/methanol.
[0485] General Method F: Urea Synthesis
[0486] The appropriate BOC-protected amine was dissolved in neat
TFA (ca 5 ml/g) at room temperature. After 5 min the solution was
concentrated to a brown gum and re-evaporated from ethyl acetate.
The crude amine salt in dichloromethane (ca 15 ml/g) was treated
with the isocyanate (1.1 equiv.) in dichloromethane, followed by
the addition of triethylamine and the reaction mixture shaken
overnight. The reaction mixture was centrifuged to remove any solid
material and the supernatent washed with water. The organic layer
was dried over anhydrous magnesium sulfate and the solution
concentrated. The crude material was then purified by silica gel
chromatography.
EXAMPLE 1
2-(8-Phenyloct-1-yl)thio-5-((1-benzyl-2oxo-pyrid-4-yl)methyl)pyrimidin-4-o-
ne
[0487] 196
[0488] Prepared from intermediate B10 by general method A1 as a
white solid. MPt 124-129.degree. C.; .sup.1H-NMR (d.sub.6 DMSO)
.delta. 1.2-1.5 (8H,m), 1.5-1.8 (4H,m), 2.59 (2H,t), 3.13 (2H,t),
3.54 (2H,s), 5.10 (2H,s), 6.14 (1H,dd), 6.50 (1H,bs), 7.15-7.4
(11H,m) and 7.68 (1H,s).
EXAMPLE 2
2-(8-(4-Fluorophenyl)oct-1-yl)thio-5-((1-benzyl-2-oxo-pyrid-4-yl)methyl)py-
rimidin-4-one
[0489] 197
[0490] Prepared from intermediate B10 and A21 by general method A5
as a white solid. MPt 147-15 1.degree. C.; .sup.1H-NMR (CDCl.sub.3)
.delta. 1.2-1.5 (8H,m), 1.5-1.8 (4H,m), 2.58 (2H,t), 3.15 (2H,t),
3.55 (2H,s), 5.10 (2H,s), 6.15 (1H,dd), 6.47 (1H,m), 6.95 (2H,t),
7.05-7.2 (3H,m), 7.25-7.45 (5H,m) and 7.67 (1H,s); MS (EI) M=531;
C.sub.31H.sub.34FN.sub.3- O.sub.2S requires 531.
Example 3
2-(8-(4-Chlorophenyl)oct-1-yl)thio-5-((1-benzyl-2-oxo-pyrid-4-yl)methyl)py-
rimidin-4-one
[0491] 198
[0492] Prepared from intermediates B10 and A24 by general method A5
as a white solid. MPL 160-164.degree. C.; .sup.1H-NMR (CDCl.sub.3)
.delta. 1.2-1.8 (12H,m), 2.56 (2H,t), 3.13 (2H,t), 3.55 (2H,s),
5.10 (2H,s), 6.15 (1H, m), 6.48 (1H,bs), 7.0-7.45 (10H,m) and 7.67
(1H,s); MS (EI) M=547; C31H34ClN302S requires 547.
EXAMPLE 4
2-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio-5-((1-benzyl-2-oxo-pyrid-4-yl)met-
hyl)pyrimidin-4-one
[0493] 199
[0494] Prepared from intermediates B10 and A1 by general method A5
as a white solid. MPt 147-151.degree. C.; .sup.1H-NMR (CDCl.sub.3)
.delta. 1.2-1.8 (10H,m), 2.93 (2H,t), 3.13 (2H,t), 3.55 (2H,s),
5.10 (2H,s), 6.15 (1H,dd), 6.49 (1H,bs), 7.05-7.5 (8H,m), 7.68
(1H,s) and 7.89 (2H,d); MS (EI) M=561;
C.sub.31H.sub.32ClN.sub.3O.sub.3S requires 561.
EXAMPLE 5
2-(8-(4-Fluorophenyl)-8-oxooct-1-yl)thio-5-((1-benzyl-2-oxo-pyrid-4-yl)met-
hyl)pyrimidin-4-one
[0495] 200
[0496] Prepared from intermediates B 10 and A8 by general method A5
as a white solid. MPt 125-133.degree. C.; .sup.1H-NMR (CDCl.sub.3)
.delta. 1.2-1.8 (10H), 2.93 (2H,t), 3.13 (2H,t), 3.55 (2H,s), 5.10
(2H,s), 6.15 (1H,m), 6.48 (1H,bs), 7.05-7.45 (8H,m), 7.68 (1H,s)
and 7.97 (2H,m); MS (EI) M=545; C.sub.31H.sub.32FN.sub.3O.sub.3S
requires 545.
EXAMPLE 6
2-(9-Phenylnon-1-yl)thio-5-((1-benzyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4--
one
[0497] 201
[0498] Prepared from intermediate B10 by general method A5 as a
white solid. MPt 127-132.degree. C.; .sup.1H-NMR (CDCl.sub.3)
.delta. 1.2-1.9 (14H,m), 2.58 (2H,t), 3.14 (2H,t), 3.55 (2H,s),
5.10 (2H,s), 6.15 (1H,dd), 6.48 (1H,bd), 7.05-7.4 (10H,m) and 7.67
(1H,s); MS (EI) M=527; C.sub.32H.sub.37N.sub.3O.sub.2S requires
527.
EXAMPLE 7
2-(6-Phenylhex-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4--
one
[0499] 202
[0500] Prepared from intermediate B11 by general method A5.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 1.3 (4H,m), 1.6 (4H,m), 2.55
(2H,t), 3.08 (2H,t), 3.35 (3H,s), 3.41 (2H,s), 6.10 (1H,dd), 6.16
(1H,d), 7.1-7.3 (5H,m), 7.55 (1H,d), 7.78 (1H,s).
EXAMPLE 8
2-(7-Phenylhept-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-
-one
[0501] 203
[0502] Prepared from intermediate B11 by general method A5.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 1.3 (6H,m), 1.6 (4H,m), 2.55
(2H,t), 3.07 (2H,t), 3.35 (3H,s), 3.41 (2H,s), 6.10 (1H,dd), 6.15
(1H,d), 7.1-7.3 (5H,m), 7.55 (1H,d), 7.77 (1H,s).
EXAMPLE 9
2-(8-Phenyloct-1-yl)thio-5-((l-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4--
one
[0503] 204
[0504] Prepared from intermediate B11 by general method A5.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 1.3 (8H,m), 1.6 (4H,m), 2.55
(2H,t), 2.97 (2H,t), 3.40 (3H,s), 3.42 (2H,s), 6.25 (1H,dd), 6.29
(1H,d), 7.1-7.3 (5H,m), 7.52 (1H,d), 7.58 (1H,s).
EXAMPLE 10
2-(9-Phenylnon-1-yl)thio-5-((I-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin
4-one
[0505] 205
[0506] Prepared from intermediate B11 by general method A5.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 1.3 (10H,m), 1.6 (4H,m), 2.55
(2H,t), 3.06 (2H,t), 3.34 (3H,s), 6.10 (1H,dd), 6.15 (1H,d),
7.1-7.3 (5H,m), 7.55 (1H,d), 7.75 (1H,s).
EXAMPLE 11
2-(6-Benzyloxyhex-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-
-4-one
[0507] 206
[0508] Prepared from intermediates B11 and A27 by general method
AS. .sup.1H-NMR (d.sub.6-DMSO) .delta. 1.3 (4H,m), 1.5 (2H,m), 1.6
(2H,m), 3.08 (2H,t), 3.40 (2H,t), 3.64 (2H,s), 4.43 (2H,s), 6.09
(1H,dd), 6.15 (1H,d), 7.1-7.3 (5H,m), 7.55 (1H,d), 7.75 (1H,s).
EXAMPLE 12
2-(8-(4-Chlorophenyl)-8-oxooct-l-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)met-
hyl)pyrimidin-4-one
[0509] 207
[0510] Prepared from intermediates B11 and A1 by general method A5
as a white solid. MPt 125-127.degree. C.; .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.3 (6H,m), 1.6 (4H,m), 3.00 (2H,t), 3.08
(2H,t), 3.35 (3H,s), 3.41 (2H,s), 6.10 (1H,m), 6.15 (1H,s), 7.57
(3H,m), 7.79 (1H,s), 7.97 (2H,d).
EXAMPLE 13
2-(8-Phenyloct-1-yl)thio-5-((1-butyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-o-
ne
[0511] 208
[0512] Prepared from intermediate B27 by general method B as a
white solid from pet, ether. .sup.1H-NMR (d.sub.6-DMSO) .delta.
0.87 (3H,t), 1.26 (10H,m), 1.5-1.7 (6H,m), 2.55 (2H,t), 3.08
(2H,t), 3.42 (2H,s), 3.79 (2H,t), 6.1 (2H,m), 7.2 (3H,m), 7.3
(2H,m), 7.54 (1H,d), 7.81 (1H,s), 12.8 (1H,br s).
Example 14
2-(8-Phenyloct-1-yl)thio-5-((2,3-dimethylpyrid-5-yl)methyl)pyrimidin-4-one
[0513] 209
[0514] Prepared from intermediate B 12 by general method A1 as a
light brown solid. MPt 111-113.degree. C.; .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.3 (8H,m), 1.6 (4H,m), 2.18 (3H,s), 2.35
(3H,s), 2.51 (2H,t), 3.05 (2H,t), 3.52 (2H,s), 7.1=7.3 (5H,m), 7.34
(1H,d), 7.74 (1H,s), 8.14 (1H,d).
EXAMPLE 15
2-(6-Benzyloxyhex-1-yl)thio-5-((2,3-dimethylpyrid-5-yl)methyl)pyrimidin-4--
one
[0515] 210
[0516] Prepared from intermediates B12 and A27 by general method A1
as a light brown solid. MPt 100-102.degree. C.; .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.3 (4H,m), 1.5 (2H,m), 1.6 (2H,m), 2.18
(3H,s), 2.35 (3H,s), 3.06 (2H,t), 3.36 (2H,t), 3.52 (2H,s), 4.43
(2H,s), 7.3 (6H,m), 7.74 (1H,s), 8.14 (1H,d).
EXAMPLE 16
2-(8-Phenyloct-1-yl)thio-5-((2,4-dimethylpyrid-5-yl)methyl)pyrimidin-4-one
[0517] 211
[0518] Prepared from intermediate B29 by general method B as a
beige solid from ether/pet. ether. MPt 73-75.degree. C.;
.sup.1H-NMR (d.sub.6-DMSO) .delta. 1.2 (8H,m), 1.6 (4H,m), 2.21
(3H,s), 2.37 (3H,s), 2.57 (2H,t), 3.06 (2H,t), 3.57 (2H,s), 6.83
(1H,s), 7.1-7.3 (5H,m), 7.51 (1H,s), 8.15 (1H,s), 12.8
(1H,brs).
Example 17
2-(5-Phenylpent-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one
[0519] 212
[0520] Prepared from intermediate B21 by general method A1 as a
white solid. MPt 113-117.degree. C.; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 1.35 (2H,m), 1.6 (4H,m), 2.40 (3H,s), 2.55 (2H,t), 3.07
(2H,t), 3.57 (2H,s), 7.1-7.3 (6H,m), 7.52 (1H,dd), 7.78 (1H,s),
8.33 (1H,d).
EXAMPLE 18
2-(N-(6-(4-Fluorophenyl)hexyl)carboxamidomethyl)thio-5-((2
methylpyrid-5-yl)methyl)pyrimidin 4-one
[0521] 213
[0522] Prepared from intermediates B21 and A42 by general method
A1. MPt 159-161.degree. C.; .sup.1H-NMR (d.sub.6-DMSO) .delta. 1.2
(4H,m), 1.4 (2H,m), 1.5 (2H,m), 2.40 (3H,s), 2.52 (2H,t), 3.04
(2H,m), 3.57 (2H,s), 3.81 (2H,s), 7.0-7.2 (5H,m), 7.49 (1H,dd),
7.75 (1H,s), 8.15 (1H,t), 8.33 (1H,dd).
EXAMPLE 19
2-(6-Benzyloxyhex-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one
[0523] 214
[0524] Prepared from intermediates B21 and A27 by general method
A1. MPt 93-95.degree. C.; .sup.1H-NMR (d.sub.6-DMSO) .delta. 1.3
(4H,m), 1.5 (2H,m), 1.6 (2H,m), 2.40 (3H,s), 3.07 (2H,t), 3.40
(2H,t), 3.57 (2H,s), 4.43 (2H,s), 7.13 (1H,d), 7.3 (5H,m), 7.51
(1H,dd), 7.80 (1H,s), 8.34 (1H,d).
EXAMPLE 20
2-methylpyrid-S-yl)methyl)pyrimidin-4-one
[0525] 215
[0526] Prepared from intermediate B21 by general method A5 as a
white solid. MPt 92-94.degree. C.; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 1.3 (8H,m), 1.6 (4H,m), 2.40 (3H,s), 2.55 (2H,t), 3.02
(2H,t), 3.54 (2H,s), 7.11 (1H,d), 7.16 (3H,m), 7.25 (2H,m), 7.50
(1H,m), 7.69 (1H,s), 8.33 (1H,d).
EXAMPLE 21
2-(7-Phenylhept-1-yl)thio-5-((2-methylpyrid-S-yl)methyl)pyrimidin-4-one
[0527] 216
[0528] Prepared from intermediate B21 by general method A5 as a
white solid. MPt 101 -103.degree. C.; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 1.3 (6H,m), 1.6 (4H,m), 2.40 (3H,s), 2.55 (2H,t), 3.02
(2H,t), 3.54 (2H,s), 7.11 (1H,d), 7.16 (3H,m), 7.25 (2H,m), 7.50
(1H,m), 7.68 (1H,s), 8.33 (1H,d).
EXAMPLE 22
2-(6-Phenylhex-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one
[0529] 217
[0530] Prepared from intermediate B21 by general method A1 as a
white solid. MPt 104-106.degree. C.; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 1.3 (4H,m), 1.6 (4H,m), 2.40 (3H,s), 2.55 (2H,t), 3.05
(2H,t), 3.57 (2H,s), 7.1-7.3 (6H,m), 7.50 (1H,m), 7.78 (1H,s), 8.33
(1H,d).
EXAMPLE 23
2-(9-Phenylnon-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one
[0531] 218
[0532] Prepared from intermediate B21 by general method A1 as a
white solid. MPt 112-114.degree. C.; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 1.3 (10H,m), 1.6 (4H,m), 2.40 (3H,s), 2.54 (2H,t), 3.05
(2H,t), 3.55 (2H,s), 7.1-7.3 (6H,m), 7.50 (1H,m), 7.88 (1H,s), 8.33
(1H,d).
EXAMPLE 24
2-(6-(4-Chlorobenzyloxy)hex-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimi-
din-4-one
[0533] 219
[0534] Prepared from intermediates B21 and A25 by general method A1
as a white solid. MPt 93--95.degree. C.: .sup.1H-NMR (d.sub.6-DMSO)
.delta. 1.3 (4H,m), 1.5 (2H,m), 1.6 (2H,m), 2.51 (3H,s), 3.13
(2H,t), 3.44 (2H,t), 3.70 (2H,s), 4.45 (2H,s), 7.06 (1H,d), 7.3
(3H,m), 7.53 (1H,dd), 7.64 (1H,s), 8.43 (1H,d).
EXAMPLE 25
2-(6-(4-Fluorobenzyloxy)hex-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimi-
din-4-one
[0535] 220
[0536] Prepared from intermediates B21 and A26 by general method A1
as a white solid. MPt 90--92.degree. C.; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 1.3 (4H,m), 1.5 (2H,m), 1.6 (2H,m), 2.51 (3H,s), 3.13
(2H,t), 3.45 (2H,t), 3.70 (2H,s), 4.44 (2H,s), 7.0 (3H,m), 7.3
(2H,m), 7.53 (1H,dd), 7.64 (1 H,s), 8.43 (1H,d).
EXAMPLE 26
2-(8-(4-Methoxyphenyl)-8-oxooct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)py-
rimidin-4-one
[0537] 221
[0538] Prepared from intermediates B21 and A3 by general method A1
as a white solid. MPt 114--116.degree. C.; .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.3 (6H,m), 1.6 (4H,m), 2.40 (3H,s), 2.93
(2H,t), 3.08 (2H,t), 3.57 (2H,s), 3.83 (3H,s), 7.02 (2H,d), 7.13
(1H,d), 7.51 (1H,dd), 7.79 (1H,s), 7.93 (2H,d), 8.34 (1H,d), 12.7
(1H,br s).
EXAMPLE 27
2-(8-(4-Methoxyphenyl)oct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidi-
n-4-one
[0539] 222
[0540] Prepared from intermediates B21 and A22 by general method A1
as a white solid. MPt 103-105.degree. C.; .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.3 (8H,m), 1.4-1.7 (4H,m), 2.40 (3H,s),
2.48 (2H,t), 3.07 (2H,t), 3.57 (2H,s), 3.84 (3H,s), 6.82 (2H,d),
7.07 (2H,d), 7.12 (1H,d), 7.51 (1H,dd), 7.78 (1H,s), 8.34 (1H,d),
12.7 (1H,br s).
EXAMPLE 28
2-(8-(4-Fluorophenyl)oct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-
-4-one
[0541] 223
[0542] Prepared from intermediates B21 and A21 by general method
A1. .sup.1H-NMR (d.sub.6-DMSO) 1.3 (8H,m), 1.6 (4H,m), 2.40 (3H,s),
2.53 (2H,t), 3.06 (2H,t), 3.56 (2H,s), 7.0-7.2 (5H,m), 7.5 (1H,m),
7.77 (1H,s), 8.33 (1H,m).
EXAMPLE 29
2-(8-(4-Fluorophenyl)-8-oxooct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyr-
imidin-4-one
[0543] 224
[0544] Prepared from intermediates B21 and A8 by general method A1.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 1.3 (6H,m), 1.6 (4H,m), 2.40
(3H,s), 3.00 (2H,t), 3.08 (2H,t), 3.57 (2H,s), 7.13 (1H,d),
7.34(2H,m), 7.51 (1H,dd), 7.80 (1H,s), 8.04 (2H,m), 8.34 (1H,d),
12.7 (1H,brs).
EXAMPLE 30
2-(8-(4-Chlorophenyl)oct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-
-4-one
[0545] 225
[0546] Prepared from intermediates B21 and A24 by general method A1
as a white solid. MPt 100-102.degree. C.; .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.3 (8H,m), 1.6 (4H,m), 2.40 (3H,s), 2.57
(2H,t), 3.06 (2H,t), 3.56 (2H,s), 7.12 (1H,d), 7.20 (2H,d), 7.31
(2H,d), 7.50 (1H,dd), 7.76 (1H,s), 8.33 (1H,d).
EXAMPLE 31
2-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyr-
imidin-4-one
[0547] 226
[0548] Prepared from intermediates B21 and A1 by general method A1
as a white solid. MPt 90-92.degree. C.; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 1.3 (6H,m), 1.6 (4H,m), 2.40 (3H,s), 3.00 (2H,t), 3.07
(2H,t), 3.56 (2H,s), 7.12 (1H,d), 7.51 (1H,dd), 7.58 (2H,d), 7.86
(1H,s), 7.97 (2H,d), 8.34 (1H,d).
EXAMPLE 32
2-(8-Phenyl-8-oxooct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-o-
ne
[0549] 227
[0550] Prepared from intermediate B21 by general method A1 as a
white solid. MPt 72-74.degree. C.; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 1.3 (6H,m), 1.6 (4H,m), 2.40 (3H,s), 3.00 (2H,t), 3.08
(2H,t), 3.57 (2H,s), 7.13 (1H,m), 7.5 (3H,m), 7.6 (1H,m), 7.80
(1H,s), 7.94 (1H,m), 8.33 (1H,d), 12.6 (1H,br s).
EXAMPLE 33
2-(8-(4-Chlorophenyt)-8-hydroxyoct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl-
)pyrimidin-4-one
[0551] 228
[0552] Prepared from intermediates B21 and A36 by general method
A1. .sup.1H-NMR (d.sub.6-DMSO) .delta. 1.3 (8H,m), 1.6 (4H,m), 2.40
(3H,s), 3.08 (2H,t), 3.58 (2H,s), 4.5 (1H,br t), 4.9 (1H,br s),
7.10 (1H,m), 7.31 (4H,m), 7.48 (1H,m), 7.71 (1H,s), 8.32 (1H,m),
12.4 (1H,br s).
EXAMPLE 34
2-(8-(4-Methylphenyl)-8-oxooct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyr-
imidin-4-one
[0553] 229
[0554] Prepared from intermediates B21 and A7 by general method A1
as a white solid. MPt 115--116.degree. C.; .sup.1H-NMR (CDCl.sub.3)
.delta. 1.2-1.8 (10H,m), 2.41 (3H,s), 2.51 (3H,s), 2.93 (2H,t),
3.13 (2H,t), 7.06 (1H,m), 7.25 (2H,m), 7.26 (1H,s), 7.54 (1H,m),
7.85 (2H,m) and 8.43 (1H,d); MS (EI) M=449;
C.sub.26H.sub.31N.sub.3O.sub.2S requires 449.
EXAMPLE 35
2-(4-Phenylbut-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one
[0555] 230
[0556] Prepared from intermediate B21 by general method A1. Mpt
129-30.degree. C.; .sup.1H-NMR (d.sub.6-DMSO) .delta. 1.6 (4H,m),
2.40 (3H,s), 2.58 (2H,m), 3.11 (2H,m), 3.57 (2H,s), 7.1-7.3 (6H,m),
7.52 (1H,dd), 7.80 (1H,s), 8.33 (1H,d).
EXAMPLE 36
2-(8-Phenyloct-1-yl)thio-5-((1-oxo-2-methylpyrid-5-yl)methyl)pyrimidin-4-o-
ne
[0557] 231
[0558] Prepared from intermediate B28 by general method B.
Trituration with ether and recrystallisation from ethyl acetate
gave the product as an off-white solid. MPt 93-95.degree. C.;
.sup.1H-NMR (d.sub.6-DMSO) .delta. 1.3 (8H,m), 1.6 (4H,m), 2.55
(2H,t), 3.07 (2H,t), 3.56 (2H,s), 7.1-7.3 (6H,m), 7.52 (1H,dd),
7.78 (1H,s), 8.33 (1H,d).
EXAMPLE 37
2-(8-Phenyloct-l-yl)thio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin-4-one
[0559] 232
[0560] Prepared from intermediate B25 by general method B as a
beige solid from ethanol. MPt 70-72.degree. C.: .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.3 (8H,m), 1.6 (4H,m), 2.55 (2H,t), 3.08
(2H,t), 3.58 (2H,s), 3.80 (3H,s), 6.64 (1H,s), 6.84 (1H,d), 7.1-7.3
(5H,m), 7.80 (1H,s), 8.02 (1H,d).
EXAMPLE 38
2-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrazin-2-ylmethyl)pyrimidin-4-
-one
[0561] 233
[0562] Prepared from intermediates B14 and A1 by general method A1
as a white solid. MPt 122.5-124.degree. C.; .sup.1H-NMR (d.sub.6
DMSO) .delta. 1.2-1.5 (6H,m), 1.5-1.8 (4H,m), 3.00 (2H,t), 3.10
(2H,t), 3.81 (2H,s), 7.59 (2H,d), 7.8 (1H,bs), 7.97 (2H,d), 8.46
(1H,m), 8.50 (1H,m) and 8.58 (1H,m); MS (FAB) M+1=457;
C23H25ClN4O2S requires 456.
EXAMPLE 39
2-(8-Phenyloct-1-yl)thio-5-(pyrid-2-ylmethyl)pyrimidin-4-one
[0563] 234
[0564] Prepared from intermediate B18 by general method A1.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 1.3 (8H,m), 1.6 (4H,m), 2.55
(2H,t), 3.09 (2H,t), 3.76 (2H,s), 7.1-7.3 (7H,m), 7.67 (1H,m), 7.74
(1H,s), 8.44 (1H,m), 12.7 (1H,br s).
EXAMPLE 40
2-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio-5-(thiazol-2-ylmethyl)pyrimidin-4-
-one
[0565] 235
[0566] Prepared from intermediates B22 and AI by general method A1
as a pale buff solid. MPt 112-114.degree. C.; .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-1.85 (10H,m), 2.92 (2H,t), 3.15 (2H,t),
4.17 (2H,s), 7.22 (1H,d), 7.42 (2H,m), 7.69 (1H,d) and 7.8-8.0
(3H,m); MS (EI) M=461; CH.sub.22H.sub.24ClN.sub.3O.sub.2S.sub.2
requires 461.
EXAMPLE 42
2-(6-Phenylhex-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0567] 236
[0568] Prepared from intermediate B19 by general method A5.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 1.3 (4H,m), 1.6 (4H,m), 2.55
(2Ht), 3.07 (2H,t), 3.62 (2H,s), 7.1-7.3 (5H,m), 7.63 (1H,m), 7.81
(1H,s), 8.39 (1H,m), 8.48 (1H,d).
EXAMPLE 43
2-(7-Phenylhept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0569] 237
[0570] Prepared from intermediate B19 by general method A5.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 1.3 (6H,m), 1.6 (4H,m), 2.55
(2H,t), 3.07 (2H,t), 3.62 (2H,s), 7.1-7.3 (5H,m), 7.63 (1H,m), 7.82
(1H,s), 8.39 (1H,m), 8.48 (1H,d).
EXAMPLE 44
2-(8-Phenyloct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0571] 238
[0572] Prepared from intermediate B19 by general method A5.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 1.3 (8H,m), 1.6 (4H,m), 2.55
(2H,t), 2.97 (2H,t), 3.62 (2H,s), 7.1-7.3 (5H,m), 7.63 (1H,m), 7.82
(1H,s), 8.39 (1H,m), 8.48 (1H,d).
EXAMPLE 45
2-(9-Phenylnon-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0573] 239
[0574] Prepared from intermediate B19 by general method A5.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 1.3 (10H,m), 1.6 (4H,m), 2.55
(2H,t), 3.07 (2H,t), 3.62 (2H,s), 7.1-7.3 (5H,m), 7.63 (1H,m), 7.81
(1H,s), 8.39 (1H,m), 8.48 (1H,d).
EXAMPLE 46
2-(6-Benzyloxyhex-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0575] 240
[0576] Prepared from intermediates B19 and A27 by general method
A5. .sup.1H-NMR (d.sub.6-DMSO) .delta. 1.3 (4H,m), 1.5 (2H,m), 1.6
(2H,m), 3.08 (2H,t), 3.40 (2H,t), 3.62 (2H,s), 4.43 (2H,s), 7.1-7.3
(5H,m), 7.64 (6H,m), 7.82 (I H,s), 8.39 (1H,m), 8.49 (1H,d).
EXAMPLE 47
2-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrid-3-ylmethyl)-pyrimidin-4--
one
[0577] 241
[0578] Prepared from intermediates B19 and A1 by general method A1
as a white solid. MPt 105-107.degree. C.; .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.3 (6H,m), 1.6 (4H,m), 3.00 (2H,t), 3.08
(2H,t), 3.62 (2H,s), 7.3 (1H,m), 7.58 (2H,d), 7.6 (1H,m), 7.82
(1H,s), 7.97 (2H,d), 8.39 (1H,m), 8.48 (1H,m).
EXAMPLE 48
2-(8-(4-Fluorophenyl)non-8-en-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-on-
e
[0579] 242
[0580] Prepared from intermediates B19 and A37 by general method A1
as a white powder. MPt 70-75.degree. C.; .sup.1H-NMR (d.sub.6 DMSO)
.delta. 1.2-1.8 (10H,m), 2.45 (2H,t), 3.06 (2H,m), 3.62 (2H,s),
5.04 (1H,s), 5.26 (1H,s), 7.16 (2H,t), 7.29 (1H,d.times.d),
7.4-7.55 (2H,m), 7.81 (1H,s), 8.38 (1H,m) and 8.48 (1H,d); MS (EI)
Found M=437; C.sub.25H.sub.28FN.sub.- 3OS requires 437.
EXAMPLE 49
2-(6-(4-Chlorobenzoylamino)hex-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-o-
ne
[0581] 243
[0582] Prepared from intermediate B19 and A45 by general method A1
as a white solid. MPt 135--139.degree. C.; .sup.1H-NMR (d.sub.6
DMSO) .delta. 1.2-1.8 (8H,m), 3.09 (2H,t), 3.23 (2H,q), 3.61
(2H,s), 7.28 (1H,s), 7.51 (2H,m), 7.62 (1H,m), 7.84 (3H,m), 8.38
(1H,m), 8.48 (1H,bs) and 8.53 (1H,bt).
EXAMPLE 50
2-(8-(4-Bromophenyl)-8-oxooct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-on-
e
[0583] 244
[0584] Prepared from intermediate B19 and A4 by general method A1
as a white solid. MPt 132-137.degree. C.; .sup.1H-NMR (d.sub.6
DMSO) .delta. 1.2-1.5 (6H,m), 1.5-1.8 (4H,m), 2.98 (2H,t), 3.08
(2H,t), 3.62 (2H,t), 7.28 (1H,m), 7.5-7.95 (6H,m), 8.38 (1H,m) and
8.48 (1H,bd).
EXAMPLE 51
2-(7-(4-Chlorophenoxy)hept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0585] 245
[0586] Prepared from intermediate B19 and A29 by general method A1.
.sup.1H-NMR (d.sub.6 DMSO) .delta. 1.2-1.5 (6H,m), 1.5-1.8 (4H,m),
3.09 (2H,t), 3.62 (2H,s), 3.93 (2H,t), 6.94 (2H,m), 7.29 (2H,m),
7.63 (1H, m), 7.83 (1H,bs), 8.38 (1H,m) and 8.48 (1H,bd).
EXAMPLE 52
2-(7-Phenoxyhept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0587] 246
[0588] Prepared from intermediate B19 and A28 by general method A1.
.sup.1H-NMR (d.sub.6 DMSO) .delta. 1.2-1.5 (6H,m), 1.5-1.8 (4H,m),
3.09 (2H,t), 3.62 (2H,s), 3.93 (2H,t), 6.90 (3H,m), 7.27 (3H,m),
7.63 (1H,m), 7.82 (1H,s), 8.39 (1H,m) and 8.48 (1H,m).
EXAMPLE 53
2-(7-Phenylthiohept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0589] 247
[0590] Prepared from intermediate B19 and A33 by general method A1.
.sup.1H-NMR (d.sub.6 DMSO) .delta. 1.2-1.5 (6H,m), 1.5-1.8 (4H,m),
2.94 (2H,t), 3.06 (2H,t), 3.62 (2H,s), 7.16 (1H,m), 7.20-7.35
(5H,m), 7.62 (1H,m), 7.81 (1H,s), 8.38 (1H,m) and 8.48 (1H,bs).
EXAMPLE 54
2-(7-(4-Chlorophenylthio)hept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-on-
e
[0591] 248
[0592] Prepared from intermediate B19 and A30 by general method A1.
.sup.1H-NMR (d.sub.6 DMSO) .delta. 1.2-1.5 (6H,m), 1.5-1.8 (4H,m),
2.94 (2H,t), 3.07 (2H,t), 3.62 (2H,s), 7.2-7.5 (5H,m), 7.62 (1H,m),
7.82 (1H,s), 8.38 (1H,m) and 8.48 (1H,bs).
EXAMPLE 55
2-(6-(3-Chlorophenyl)hex-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0593] 249
[0594] Prepared from intermediate B19 and A40 by general method A1
as a white solid. MPt 84-85.degree. C.; .sup.1H-NMR (CDCl.sub.3)
.delta. 1.2-1.8 (8H,m), 2.57 (2H,t), 3.13 (2H,t), 3.74 (2H,s), 7.03
(1H,m), 7.15-7.25 (4H,m), 7.65 (2H,m), 8.47 (1H,m),and 8.56 (1H,d);
MS (EI) M=413, C.sub.22H.sub.24ClN.sub.3OS requires 413.
EXAMPLE 56
2-(7-Phenylsulfinylhept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0595] 250
[0596] Prepared from intermediate B19 and A34 by general method A1.
.sup.1H-NMR (d.sub.6 DMSO) .delta. 1.2-1.5 (6H,m), 1.5-1.8 (4H,m),
2.6-3.0 (4H,m), 3.55 (2H,s), 7.25 (1H,m), 7.45-7.7 (7H,m), 8.35
(1H,m) and 8.46 (1H,m).
EXAMPLE 57
2-(7-(4-Chlorophenyisuflfnyl)hept-1-yl)thio-5-(pyrid-3-ylmethyl)-pyrimidin-
-4-one
[0597] 251
[0598] Prepared from intermediate B19 and A31 by general method A1.
.sup.1H-NMR (d.sub.6 DMSO) .delta. 1.2-1.5 (6H,m), 1.5-1.8 (4H,m),
2.7-3.2 (4H,m), 3.61 (2H,s), 7.28 (1H,m), 7.55-7.75 (5H,m), 7.80
(1H,s), 8.38 (1H,m) and 8.47 (1H,bs).
EXAMPLE 58
2-(7-Phenylsulfonylhept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0599] 252
[0600] Prepared from intermediate B19 and A35 by general method A1.
.sup.1H-NMR (d.sub.6 DMSO) .delta.1.2-1.5 (6H,m), 1.5-1.8 (4H,m),
3.05 (2H,t), 3.29 (2H,t), 3.62 (2H,s), 7.29 (1H,m), 7.6-8.0 (7H,m),
8.44 (1H,m) and 8.49 (1H,m).
EXAMPLE 59
2-(7-(4-Chlorophenylsulfonyl)hept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin--
4-one
[0601] 253
[0602] Prepared from intermediate B19 and A32 by general method A1.
.sup.1H-NMR (d.sub.6 DMSO) .delta.0 1.2-1.5 (6H,m), 1.5-1.8 (4H,m),
3.05 (2H,t), 3.62 (2H,s), 7.28 (1H,m), 7.6-80 (6H,m). 8.44 (1H,m)
and 8.48 (1H,m).
EXAMPLE 60
2-(8-(3-Chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0603] 254
[0604] Prepared from intermediate B19 and A18 by general method A1
as a white solid. MPt 68-70.degree. C.; .sup.1H-NMR (CDCl.sub.3)
.delta. 1.2-1.5 (8H,m), 1.5-1.8 (4H,m), 2.56 (2H,t), 3.13 (2H,t),
3.74 (2H,t), 7.05 (1H,m), 7.15-7.25 (4H,m), 7.65 (2H,m), 8.46
(1H,m) and 8.57 (1H,m): MS (EI) M=441 C.sub.24H.sub.28ClN.sub.3OS
requires 441.
EXAMPLE 61
2-(8-(3,4-Dichlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0605] 255
[0606] Prepared from intermediate B19 and A15 by general method A1
as a white solid. MPt 96-99.degree. C.; .sup.1H-NMR (CDCl.sub.3)
.delta. 1.2-1.5 (8H,m), 1.5-1.8 (4H,m), 2.54 (2H,t), 3.13 (2H,t),
3.74 (2H,s), 7.0 (1H,m), 7.2-7.35 (3H,m), 7.65 (2H,m), 8.46 (1H,m)
and 8.56 (1H,d); MS (EI) M=475; C.sub.24H.sub.27C.sub.12N.sub.3O
requires 475.
EXAMPLE 62
2-(8-(2-Thienyl)-8-oxooct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0607] 256
[0608] Prepared from intermediate B19 and A5 by general method A1
as a light brown solid. MPt 101-102.degree. C.; .sup.1H-NMR
(d.sub.6 DMSO) .delta. 1.2-1.45 (6H,m), 1.5-1.75 (4H,m), 2.79
(2H,t), 3.07 (2H,t), 3.61 (2H,s), 6.69 (1H,dd), 7.2-7.3 (1H,m),
7.45 (1H,d), 7.6-7.7 (1H,m), 7.81 (1H,s), 7.97 (1H,s), 8.3-8.4
(1H,m) and 8.47 (1H,d).
EXAMPLE 63
2-(8-(2-Furyl)-8-oxooct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0609] 257
[0610] Prepared from intermediate B19 and A6 by general method A1
as a light brown solid. MPt 104-107.degree. C.; .sup.1H-NMR
(d.sub.6 DMSO) .delta. 1.2-1.45 (6H,m) 1.5-1.8 (4H,m), 2.79 (2H,t),
3.07 (2H,t), 3.61 (2H,s), 6.69 (1H,m), 7.28 (1H,m), 7.45 (1H,m),
7.63 (1H,m), 7.81 (1H,m), 7.97 (1H,m),8.38 (1H,m) and 8.48
(1H,m).
EXAMPLE 64
2-(8-(2-Pyridyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0611] 258
[0612] Prepared from intermediate B19 and A11 by general method A1
as a light brown solid. MPt 76-79.degree. C.; .sup.1H-NMR (d.sub.6
DMSO) .delta. 1.2-1.5 (8H,m), 1.55-1.8 (4H,m), 2.69 (2H,t), 3.07
(2H,t), 3.62 (2H,s), 7.05-7.4 (3H,m), 7.55-7.75 (2H,m), 7.82 (1H,s)
and 8.35-8.55 (3H,m).
EXAMPLE 65
2-(9-(4-Chlorophenyl)-9-oxonon-1-yl)thio-5-(pyrid-3-ylmethyl)-pyrimidin-4--
one
[0613] 259
[0614] Prepared from intermediate B19 and A1 by general method A1
as a white solid. MPt 112-114.degree. C.; .sup.1H-NMR (CDCl.sub.3)
.delta. 1.2-1.8 (14H), 2.92 (2H,t), 3.11 (2H,t), 3.74 (2H,s), 7.2
(1H,m), 7.42 (2H,d), 7.6-7.75 (2H,m), 7.88 (2H,m), 8.45 (1H,m) and
8.55 (1H,m); MS (EI) M=469; C.sub.25H.sub.28ClN.sub.3O.sub.2S
requires 469.
EXAMPLE 66
2-(8-(3,4-Dichlorophenyl)oct-7-yn-1-yl)thio-5-(pyrid-3-ylmethyl)-pyrimidin-
-4-one
[0615] 260
[0616] Prepared from intermediate B19 and A14 by general method A1
as a white solid. MPt 92-94.degree. C.; .sup.1H-NMR (CDCl.sub.3)
.delta. 1.4-1.9 (8H,m), 2.39 (2H,t), 3.15 (2H,t), 3.74 (2H,s),
7.1-7.4 (5H,m), 7.6-7.75 (2H,m), 8.45 (1H,m) and 8.57 (1H,m); MS
(EI) M=471; C.sub.24H.sub.23Cl.sub.2N.sub.3OS requires 471.
EXAMPLE 67
2-(8-(4-Acetylphenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0617] 261
[0618] Prepared from intermediate B19 and A20 by general method A1
as a white solid. MPt 81-84.degree. C.; .sup.1H-NMR (CDCl.sub.3)
.delta. 1.2-1.8 (12H,m), 2.58 (3H,s), 2.65 (2H,t), 3.13 (2H,t),
3.74 (2H,s), 7.1-7.35 (3H,m), 7.6-7.75 (2H,m), 7.87 (2H,d) and
8.3-8.7 (2H,bd); MS (EI) M=449; C.sub.26H.sub.31N.sub.3O.sub.2S
requires 449.
EXAMPLE 68
2-(8-(4-Methylnaphth-1-yl)-8-oxooct-1-yl)thio-5-(pyrid-3-ylmethyl)-pyrimid-
in-4-one
[0619] 262
[0620] Prepared from intermediate B19 and A9 by general method A1
as a white solid. MPt 102-104.degree. C.; .sup.1H-NMR (CDCl.sub.3)
.delta. 1.2-1.5 (6H,m), 1.5-1.8 (4H,m), 2.73 (3H,s), 3.02 (2H,t),
3.13 (2H,t), 3.73 (2H,s), 7.25 (1H,m), 7.28 (1H,d), 7.45-7.75
(4H,m), 7.75 (1H,d), 8.02 (1H,m), 8.45 (l H,m) and 8.5-8.7 (2H,m);
MS (EI) M=485; C.sub.29H.sub.31N.sub.3O.sub.2S requires 485.
EXAMPLE 69
2-(8-(4-Pyridyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0621] 263
[0622] Prepared from intermediate B19 and A23 by general method A1
as a white solid. MPt 86-88.degree. C.; .sup.1H-NMR (d.sub.6 DMSO)
.delta. 1.2-1.5 (8H,m), 1.5-1.8 (4H,m), 2.57 (2H,t), 3.07 (2H,t),
3.62 (2H,s), 7.21 (2H,d), 7.25 (1H,m), 7.81 (1H,s) and 8.3-8.6
(4H,m).
EXAMPLE 70
2-(8-(4-Chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0623] 264
[0624] Prepared from intermediate B19 and A24 by general method A1.
.sup.1H-NMR (d.sub.6 DMSO) .delta. 1.2-1.5 (6H,m), 1.5-1.8 (4H,m),
2.54 (2H,t), 3.07 (2H,t), 3.61 (2H,s), 7.1-7.4 (5H,m), 7.63 (1H,m),
7.80 (1H,s), 8.38 (1H,m) and 8.47 (1H,bs).
EXAMPLE 71
2-(4-(3-Phenylprop-1-yloxy)but-1-yl)thio-5-(pyrid-3-ylmethyl)
pyrimidin-4-one
[0625] 265
[0626] Prepared from intermediate B19 and A43 by general method A1.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 1.5-1.9 (6H,m), 2.59 (2H,t),
3.12 (2H,t), 3.3 (4H,m), 3.61 (2H,s), 7.1-7.3 (6H,m), 7.6 (1H,m),
7.81 (1H,s), 8.38 (1H,m), 8.48 (1H,d).
EXAMPLE 72
2-(6-Benzyloxyhex-1-yl)thio-5-(quinolin-3-ylmethyl)pyrimidin-4-one
[0627] 266
[0628] Prepared from intermediate B19 and A27 by general method A11
as a light brown solid. MPt 120-122.degree. C.; .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.3 (4H,m), 1.5 (2H,m), 1.6 (2H,m), 3.08
(2H,t), 3.39 (2H,t), 3.82 (2H,s), 4.42 (2H,s), 7.3 (5H,m), 7.56
(1H,m), 7.70 (1H,m), 7.9-8.0 (3H,m), 8.13 (1H,d), 8.85 (1H,d), 12.7
(1H,br s).
EXAMPLE 73
2-(8-Phenyloct-1-yl)thio-5-(quinolin-3-ylmethyl)pyrimidin-4-one
[0629] 267
[0630] Prepared from intermediate B16 by general method A1 as a
light brown solid. MPt 124-126.degree. C.; .sup.1H-NMR
(d.sub.6-DMSO) .delta. 7.1-7.3 (5H,m), 7.56 (1H,m), 7.68 (1H,m),
7.9-8.0 (3H,m), 8.12 (1H,d), 8.85 (1H,d).
EXAMPLE 74
2-(8-Phenyloct-1-yl)thio-5-((4-methoxypyrid-2-yl)methyl)pyrimidin-4-one
[0631] 268
[0632] Prepared from intermediate B26 by general method B as a
brown solid after trituration with ether and recrystallisation from
ethyl acetate. M Pt 58-60.degree. C; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 1.3 (8H,m), 1.6 (4H,m), 2.55 (2H,t), 3.07 (2H,t), 3.69
(2H,s), 3.78 (3H,s), 6.8 (2H,m), 7.1-7.3 (5H,m), 7.70 (1H,s), 8.25
(1H,d).
EXAMPLE 75
2-(8-Phenyloct-1-yl)thio-5-(2-oxopyrid-4-ylmethyl)pyrimidin-4-one
[0633] 269
[0634] A mixture of
2-(8-phenyloct-1-yl)thio-5-(2-methoxypyrid-4-ylmethyl)-
pyrimidin-4-one (0.40 g, 0.9 mmol), chlorotrimethylsilane (0.23 ml,
1.8 mmol) and sodium iodide (0.27 g, 1.8 mmol) in acetonitrile (30
ml) was heated at reflux for 6 hours. The solvent was evaporated,
the residue taken up in dichloromethane, and washed with water and
aqueous sodium thiosulphate. Evaporation of the solvent and
trituration with ether gave
2-(8-phenyloct-1-yl)thio-5-(2-oxopyrid-4-ylmethyl)pyrimidin-4-one
as a white solid (0.03 g). .sup.1H-NMR (d.sub.6-DMSO) .delta. 1.3
(8H,m), 1.6 (4H,m), 2.55 (2H,t), 3.07 (2H,t), 6.07 (2H,m), 7.1-7.3
(6H,m), 7.77 (1H,s); MPt indeterminate.
EXAMPLE 76
2-(8-Phenyloct-1-yl)thio-5-(pyrid-4-ylmethyl)pyrimidin-4-one
[0635] 270
[0636] Prepared from intermediate B20 by general method A1 as a
beige solid. MPt 124-125.degree. C.: .sup.1H-NMR (d.sub.6-DMSO)
.delta. 1.3 (8H,m), 1.6 (4H,m), 2.55 (2H,t), 3.08 (2H,t), 3.63
(2Hs), 7.1-7.3 (7H,m), 7.83 (1H,s), 8.42 (2H,d).
EXAMPLE 77
2-(6-Benzyloxyhex-1-yl)thio-5-(pyrid-4-ylmethyl)pyrimidin-4-one
[0637] 271
[0638] Prepared from intermediate B20 and A27 by general method A1
as a white solid. MPt 111-113.degree. C.; .sup.1H-NMR
(d.sub.6-DMSO) .delta. 7.23 (2H,d), 7.3 (5H,m), 7.83 (1H,s), 8.43
(2H,d), 1.28 (1H,br s).
EXAMPLE 78
2-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)-pyrimidin--
4-one
[0639] 272
[0640] Prepared from intermediate B9 and A1 by general method A1 as
a white solid. MPt 129-130.degree. C., .sup.1H-NMR (CDCl.sub.3)
.delta. 1.2-1.5 (6H,m), 1.5-1.8 (4H,m), 2.93 (2H,t), 3.15 (2H,t),
3.71 (2H,s), 7.43 (2HH d), 7.78 (1H,s), 7.89 (2H,d), 8.72 (2H,s)
and 9.07 (2H,s); MS (EI) M=456; C.sub.23H.sub.25ClN.sub.4O.sub.2S
requires 456.
EXAMPLE 79
2-(8-Phenyloct-1-yl)thio-5-(fur-2-ylmethyl)pyrimidin-4-one
[0641] 273
[0642] Prepared from intermediate B13 by general method A1 as a
light brown solid. MPt 79-81.degree. C.; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 1.3 (8H,m), 1.6 (4H,m), 2.55 (2H,t), 3.07 (2H,t), 3.64
(2H,s), 6.08 (1H,m), 6.34 (1H,m), 7.1-7.3 (5H,m), 7.51 (1H,m), 7.67
(1H,s).
EXAMPLE 80
2-(6-Benzyloxyhex-1-yl)thio-5-(fur-2-ylmethyl)pyrimidin-4-one
[0643] 274
[0644] Prepared from intermediate B13 and A27 by general method A1
as a brown solid. MPt 63--65.degree. C. .sup.1H-NMR (d.sub.6-DMSO)
.delta. 1.3 (4H,m), 1.5 (2H,m), 1.6 (2H,m), 3.08 (2H,t), 3.40
(2H,t), 3.64 (2H,s), 4.43 (2H,s), 6.08 (1H,m), 6.34 (1H,m), 7.3
(5H,m), 7.51 (1H,m), 7.68 (1H,s).
EXAMPLE 81
2-(6-Benzyloxyhex-1-yl)thio-5-(fur-3-ylmethyl)pyrimidin-4-one
[0645] 275
[0646] Prepared from intermediate B15 and A27 by general method A1
as a white solid. MPt 58-60.degree. C.; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 1.3 (4H,m), 1.5 (2H,m), 1.6 (2H,m), 3.08 (2H,t), 3.4
(4H,m), 4.43 (2H,s), 6.37 (1H, m), 7.3 (5H,m), 7.44 (1H,m), 7.55
(1H,m), 7.68 (1H,s).
EXAMPLE 82
2-(8-Phenyloct-1-yl)thio-5-(fur-3-ylmethyl)pyrimidin-4-one
[0647] 276
[0648] Prepared from intermediate B15 by general method A1 as a
white solid. MPt 78-80.degree. C.; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 6.37 (1H,s), 7.1-7.3 (5H,m), 7.44 (1H,m), 7.55 (1H,m), 7.65
(1H,s).
EXAMPLE 83
2-Benzylthio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one
[0649] 277
[0650] Prepared from intermediate B11 by general method A1 as a
white solid. MPt 194-196.degree. C.; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 3.35 (3H,s), 3.44 (2H,s), 4.39 (2H,s), 6.10 (1H,m), 6.16
(1H,s), 7.56 (1H,d), 7.86 (1H,s), 12.8 (1H,br s).
EXAMPLE 84
2-Benzylthio-5-(fur-2-ylmethyl)pyrimidin-4-one
[0651] 278
[0652] Prepared from intermediate B13 by general method AS.
.sup.1H-NMR (d.sub.6-DMSO) .delta. .366 (2H,s), 4.38 (2H,s), 6.09
(1H,m), 6.35 (1H,m), 7.2-7.4 (5H,m), 7.52 (1H,m), 7.74 (1H,s).
EXAMPLE 85
2-(3-Chlorobenzyl)thio-5-(fur-2-ylmethyl)pyrimidin-4-one
[0653] 279
[0654] Prepared from intermediate B13 by general method A5.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 3.66 (2H,s), 4.39 (2H,s), 6.09
(1H,m), 6.35 (1H,m), 7.3-7.4 (5H,m), 7.50 (1H,m), 7.74 (1H,s).
EXAMPLE 86
2-(4-Chlorobenzyl)thio-5-(fur-2-ylmethyl)pyrimidin-4-one
[0655] 280
[0656] Prepared from intermediate B13 by general method A5.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 3.63 (2H,s), 4.33 (2H,s), 6.07
(1H,m), 6.34 (1H,m), 7.35 (2H,d), 7.42 (2H,d), 7.50 (1H,m), 7.64
(1H,s).
EXAMPLE 87
2-Benzylthio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one
[0657] 281
[0658] Prepared from intermediate B21 by general method A1 as a
white solid. MPt 226-228.degree. C.; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 2.40 (3H,s), 3.59 (2H,s), 4.38 (2H,s), 7.14 (1H,d), 7.2-7.5
(5H,m), 7.52 (1H,dd), 7.84 (1H,s), 8.34 (1H,d).
EXAMPLE 88
2-Benzylthio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin-4-one
[0659] 282
[0660] Prepared from intermediate B25 by general method B as a
white solid. MPt 193-5.degree. C.; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 3.60 (2H, s), 3.81 (3H, s), 4.39 (2H, s), 6.65 (1H, s),
6.85 (1H, m), 7.25-7.42 (5H, m), 7.87 (1H, s), 8.03 (1H, m).
EXAMPLE 89
2-Benzylthio-5-(pyrazin-2-ylmethyl)pyrimidin-4-one
[0661] 283
[0662] Prepared from intermediate B14 by general method A1 as a
white solid. MPt 174-175.degree. C.; .sup.1H-NMR (d.sub.6 DMSO)
.delta. 3.84 (2H,s), 4.40 (2H,s), 7.1-7.5 (5H,m), 7.89 (1H,bs),
8.47 (1H,d), 8.51 (1H,t) and 8.59 (1H,d); MS (FAB) M+1=311;
C.sub.16H.sub.14N.sub.4OS requires 310.
EXAMPLE 90
2-Benzylthio-5-(thiazol-2-ylmethyl)pyrimidin-4-one
[0663] 284
[0664] Prepared from intermediate B22 by general method A1 as light
brown crystals; .sup.1H-NMR (d.sub.6 DMSO) 4.02 (2H,s), 4.41
(2H,s), 7.2-7.45 (6H,m), 7.55 (1H,d), 7.67 (1H,d) and 7.95 (1H,bs);
MS (EI) M=315; C.sub.15H.sub.13N.sub.3OS.sub.2 requires 315.
EXAMPLE 91
2-(4-Chlorobenzyl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0665] 285
[0666] Prepared from intermediate B19 by general method A5.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 3.59 (2H,s), 4.30 (2H,s), 7.26
(1H,m), 7.31 (2Hd), 7.41 (2H,d), 7.63 (1H,m), 7.72 (1H,s), 8.37
(1H,m), 8.47 (1H,m).
EXAMPLE 92
2-Benzylthio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0667] 286
[0668] Prepared from intermediate B19 by general method A5.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 3.61 (2H,s), 4.33 (2H,s),
7.2-7.4 (5H,m), 7.64 (1H,m), 7.78 (1H,s), 8.38 (1H,m), 8.49
(1H,m).
EXAMPLE 93
2-(3,4-Dichlorobenzyl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0669] 287
[0670] Prepared from intermediate B19 by general method A5.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 3.60 (2H,s), 4.31 (2H,s), 7.26
(1H,m), 7.39 (1H,m) 7.53 (1H,d), 7.65 (1H,m), 7.75 (1H,s), 8.37
(1H,m), 8.48 (1H,m).
EXAMPLE 94
2-Benzylthio-5-(pyrid-4-ylmethyl)pyrimidin-4-one
[0671] 288
[0672] Prepared from intermediate B20 by general method A1 as a
white solid. MPt 183-185.degree. C.; .sup.1H-NMR (DC-DMSO) .delta.
3.64 (2H,s), 4.39 (2H,s), 7.24 (2H,d), 7.3-7.4 (5H,m), 7.89 (1H,s),
8.43 (2H,d).
EXAMPLE 95
2-(4-Chlorobenzyl)thio-5-(pyrid-4-ylmethyl)pyrimidin-4-one
[0673] 289
[0674] Prepared from intermediate B20 by general method A5.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 3.65 (2H,s), 4.38 (2H,s), 7.24
(2H,d), 7.37 (2H,d), 7.44 (2H,d), 7.88 (1H,s), 8.43 (2H,d).
EXAMPLE 96
2-(3,4-Dichlorobenzyl)thio-5-(pyrid-4-ylmethyl)pyrimidin-4-one
[0675] 290
[0676] Prepared from intermediate B20 by general method A5.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 3.66 (2H,s), 4.39 (2H,s), 7.25
(2H,dd) 7.57 (1H,d), 7.69 (1H,d), 7.89 (1H,s), 8.44 (2H,d).
EXAMPLE 97
2-Benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0677] 291
[0678] Prepared from intermediate B9 by general method A1 as a
white solid. MPt 239-241.degree. C.; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 3.65 (2H,s), 4.39 (2H,s), 7.1-7.5 (5H,m), 7.95 (1H,bs),
8.71 (2H,s) and 9.02 (1H,s); MS (EI) M=310;
C.sub.16H.sub.14N.sub.4OS requires 310.
EXAMPLE 98
2-Benzylthio-5-(2-(pyrid-4-yl)ethyl)pyrimidin-4-one
[0679] 292
[0680] Prepared from intermediate B17 by general method A1 as a
white solid. MPt 209-2105.degree. C.; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 2.61 (2H,t), 2.81 (2H,t), 4.36 (2H,s), 7.1-7.5 (7H,m), 7.69
(1H,s) and 8.45 (2H,d); MS (FAB) M+1=324; C.sub.18H.sub.17N.sub.3OS
requires 323.
EXAMPLE 99
2-Benzylthio-5-benzylpyrimidin-4-one
[0681] 293
[0682] Prepared from intermediate B23 by general method A1 as a
brown solid. MPt 156-158.degree. C.; .sup.1H-NMR (d.sub.6-DMSO)
.delta. 3.62 (2H,s), 4.38 (2H,s), 7.1-7.5 (1OH,m), 7.8 (1H,s), 12.8
(1H,brs).
EXAMPLE 100
2-(8-Phenyloct-1-yl)oxy-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0683] 294
[0684] A mixture of 8-phenyl-1-octanol (1.5 g),
.sup.2-nitroamino-5-(pyrid- -3-ylmethyl)pyrimidin-4-one (1.0 g) and
pyridine (5 ml) was stirred at reflux for 24 hours, then the
pyridine was removed by evaporation. Water was added, and the
product extracted into dichloromethane, which was dried and
evaporated. The residue was purified by chromatography (silica,
0-5% methanol in dichloromethane) and recrystallisation from ether
to give 2-(8-phenyloct-1-yl)oxy-5-(pyrid-3-ylmethyl)pyrimidin-4-one
as a pale buff solid (0.1 g). MPt 53-55.degree. C; .sup.1H-NMR
(CDCl.sub.3) .delta. 1.32 (8H,m), 1.60 (2H,m), 1.74 (2H,m), 2.58
(2H,t), 3.72 (2H,t), 4.31 (2H,t), 7.1-7.3 (6H,m), 7.54 (1H,m), 7.63
(1H,m), 8.45 (1H,m) and 8.55 (1H,d); MS (EI) Found M=391;
C.sub.24H.sub.29N.sub.3O.sub.2 requires 391.
EXAMPLE 101
2-(8-(4-Chlorophenyl)-8-oxooct-1-yl)oxy-5-(pyrid-3-ylmethyl)-pyrimidin-4-o-
ne
[0685] 295
[0686] Prepared from intermediates B24 and A2 analogously to
example 100. Recrystallisation from acetonitrile/ether gave the
product as an off-white solid. MPt 116-7.degree. C.; .sup.1H-NMR
(CDCl.sub.3) .delta. 1.39 (6H,m), 1.74 (4H,m), 2.93 (2H,t), 3.72
(2H,t), 4.31 (2H,t), 7.2 (1H,m), 7.42 (2H,d), 7.55 (1H,s), 7.62
(1H,d), 7.88 (2H,d), 8.45 (1H,m) and 8.54 (1H,d); MS (FAB) M+1=440;
C.sub.24H.sub.26ClN.sub.3O.sub.2 requires 439.
EXAMPLE 102
2-(4-Phenylbut-1-yl)oxy-S-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one
[0687] 296
[0688] Finely ground cyanamide (1.68 g, 0.04 mol) and cyanamide
dihydrochloride (2.26 g, 0.02 mol) were treated with
4-phenyl-1-butanol (3.24 g, 0.02 mol), occasionally stirring with a
glass rod over a 20 day period. The white paste was dissolved in
water, extracted with chloroform and the aqueous layer adjusted to
pH 13 (conc. sodium hydroxide) with ice cooling. The oil which
precipitated was extracted into ethyl acetate, dried (MgSO.sub.4)
and the solvent evaporated to give the isourea as a clear oil (3.88
g). A portion of this material (2.44 g) was converted to the
hydrochloride salt by treatment with HCl/ethanol/ether, the
solvents evaporated and the residue washed several times with ether
and dried under high vacuum to yield 1.47 g.
[0689] This material (1.47 g, 0.00646 mol) was dissolved in ethanol
(40 ml) together with ethyl
2-formyl-3-(6-methylpyrid-3-yl)propionate (0.95 g, 0.00431 mol) and
triethylamine and heated under reflux for 6 h. The solvent was
evaporated and the residue treated with water and extracted with
ethyl acetate, dried (MgSO.sub.4) and evaporated to an oil.
Purification by chromatography (silica, methanol/chloroform)
followed by crystallisation from ethyl acetate-petrol gave
2-(4-phenylbut-1-yl)thio-5-
-((2-methylpyrid-5-yl)methyl)-pyrimidin-4-one, yield 0.09 g (6%).
MPt 88-90.degree. C.; .sup.1H-NMR (CDCl.sub.3) .delta. 1.75 (4H,
m), 2.49 (3H, s), 2.65 (2H, t), 3.64 (2H,s), 4.32 (2H, t),
6.90-7.60 (8H, m), 8.38 (1H, m).
EXAMPLE 103
2-(2-Phenylethyl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one
[0690] 297
[0691] Prepared from intermediate B21 by general method B as white
crystals; MPt 158-160.degree. C. .sup.1H-NMR (d.sub.6-DMSO) .delta.
2.41 (3H,s), 2.93 (2H,t), 3.3 (2H+H.sub.2O, t), 3.58 (2H,s), 7.14
(1H,d), 7.2-7.3 (5H,m), 7.52 (1H,dd), 7.83 (1H,s), 8.34 (1H,d),
12.7 (1H,br s).
EXAMPLE 104
2-(2-Phenylethyl)thio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin-4-one
[0692] 298
[0693] Prepared from intermediate B25 by general method B as white
crystals; MPt 139-140.degree. C. .sup.1H-NMR (d.sub.6-DMSO) .delta.
2.94 (2H,t), 3.3 (2H+H,O, t), 3.59 (2H,s), 3.81 (3H,s), 6.65
(1H,s), 6.86 (1H,dd), 7.2-7.3 (5H,m), 7.85 (1H,br s), 8.03
(1H,d)
EXAMPLE 105
2-Benzylthio-5-((1-methylpyrazol-4-yl)methyl)pyrimidin-4-one
[0694] 299
[0695] Prepared from intermediate B34 by general method A1 as a
white crystalline solid. .sup.1H-NMR (d.sub.6-DMSO) .delta. 3.37
(2H,s), 3.71 (3H,s), 4.33 (2H,s), 7.2-7.4 (6H,m), 7.41 (1H,s), 7.67
(1H,br s), 12.7 (1H,br s); (APCI) M+H=313.
C.sub.16H.sub.16N.sub.4OS requires 312.
EXAMPLE 106
2-(4-Fluorobenzylthio)-5-((pyrimid-5-yl)methyl)pyrimidin-4-one
[0696] 300
[0697] Prepared from intermediate B9 by general method A4.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 3.65 (2H,s), 4.38 (2H,s),
7.05-7.2 (2H,m), 7.35-7.5 (2H,m), 7.94 (1H,bs), 8.71 (2H,s), 9.06
(1H,s); MS (APCI-) found (M-1 )=327; C.sub.16H.sub.13FN.sub.4OS
requires 328.
EXAMPLE 107
2-(3,4-Difluorobenzylthio)-5-((2-methoxypyrimid-5-yl)methyl)pyrimidin-4-on-
e
[0698] 301
[0699] Prepared from intermediate B39 by general method A4.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 3.57 (2H, s), 3.87 (3H, s), 4.37
(2H, s), 7.24-7.53 (3H, m), 7.88 (1H, br,s), 8.49 (2H, s), 12.88
(1H, brs); MS (APCI+) found (M+t)=377;
C.sub.17H.sub.20F.sub.2N.sub.4O.sub.2S requires 376.
EXAMPLE 108
2-(4-Fluorobenzylthio)-5-((2-methoxypyrimid-5-yl)methyl)pyrimidin-4-one
[0700] 302
[0701] Prepared from intermediate B39 by general method A4.
.sup.1H-NMR (d.sub.6 DMSO) .delta. 3.55 (2H,s), 3.85 (3H,s), 4.36
(2H,s), 7.0-7.2 (2H,m), 7.35-7.5 (2H,m), 7.86 (1H,bs), 8.48 (2H,s)
12.81 (1H,b); MS (APCI+) found (M+1)=359;
C.sub.17H.sub.15FN.sub.4O.sub.2S requires 358.
EXAMPLE 109
2-(4-Fluorobenzylthio)-5-((2-benzyloxypyrimid-5-yl)methyl)pyrimidin-4-one
[0702] 303
[0703] Prepared from intermediate B40 by general method A4.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 3.57 (2H,s), 4.38 (2H,s), 5.35
(2H,s), 7.0-7.2 (2H,m), 7.25-7.5 (7H,m), 7.87 (1H,bs), 8.51 (2H,s);
MS (APCI+) found (M+1 )=435; C.sub.23H.sub.19FN.sub.4O.sub.2S
requires 434.
EXAMPLE 110
1-(4-Hydroxycyclohexyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimi-
d-5-ylmethyl)pyrimidin-4-one
[0704] 304
[0705] Prepared from intermediates B46 and A1 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.1-2.3(18H,m), 2.94(2H,t),
3.24(2H,t), 3.6-3.8(3H,m), 4.2(1 H,m), 7.12(1H,s), 7.45(2H,m),
7.90(2H,m), 8.71(2H,s) and 9.09(1H,s); MS (APCI+) found (M+1)=555;
C.sub.29H.sub.35ClN.sub.4O.su- b.3S requires 554.
EXAMPLE 111
1-(2-Methoxyethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-(pyrimid-5-ylm-
ethyl)pyrimidin-4-one
[0706] 305
[0707] Prepared from intermediate B87 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.25-1.85(10H,m), 2.93(2H,t),
3.26(2H,t), 3.32(3H,s), 3.62(2H,t), 3.69(2H,s), 3.98(2H,t),
7.08(1H,s), 7.43(2H,m), 7.90(2H,m), 8.70(2H,s) and 9.09(1H,s); MS
(APCI+) found (M+1)=515; C.sub.26H.sub.31ClN.sub.4O.sub.3S requires
514.
EXAMPLE 112
1-(3-(1-Imidazolyl)prop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(-
pyrimid-5-ylmethyl)pyrimidin-4-one
[0708] 306
[0709] Prepared from intermediate B47 and A1 by general method A4,
as a yellow oil. .sup.1H-NMR (CDCl.sub.3) .delta. 1.38 (6H, m),
1.70 (4H, m), 2.25 (2H, m), 2.91 (2H, t), 3.25 (2H, t), 3.69 (2H,
s), 3.77 (2H, t), 4.07 (2H, t), 6.81 (1H, s), 6.92 (1H, s), 7 13
(1H, s), 7.43 (2H, d), 7.50 (1H, s), 7.89 (2H, d), 8.70 (2H, s),
9.10 (1H, s); MS APCI+) found (M+1)=565; C, H.sub.33ClN.sub.6OS
requires 564.
EXAMPLE 113
1-(3-(1-Morpholino)prop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(-
pyrimid-5-ylmethyl)pyrimidin-4-one
[0710] 307
[0711] Prepared from intermediate B48 and A1 by general method A4,
as a thick gum. .sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.8(10H,m),
1.93(2H,m), 2.25-2.5(6H,m), 2.93(2H,t), 3.25(2H,t), 3.55-3.8(6H,m),
3.90(2H,t), 7.07(1H,s), 7.45(2H,m), 7.90(2H,m), 8.72(2H,s) and
9.12(1H,s); MS (APCI+) found (M+1)=584;
C.sub.30H.sub.38ClN.sub.5O.sub.3S requires 583.
EXAMPLE 114
1-(3-(2-Oxo-1-pyrrolidino)prop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)t-
hio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0712] 308
[0713] Prepared from intermediate B49 and A1 by general method A4,
as a yellow oil. .sup.1H-NMR (CDCl.sub.3) .delta. 1.38 (6H, m),
1.74 (4H, m), 1.98 (2H, m), 2.10 (2H, m), 2.43 (2H, t), 2.93 (2H,
m), 3.25 (2H, t), 3.34 (2H, t), 3.41 (2H, t), 3.70 (2H, s), 3.82
(2H, t), 7.43 (2H, m), 7.54 (1H, s), 7.89 (2H, m), 8.74 (2H, s),
9.07 (1H, s); MS APCI+) found (M+1)=582;
C.sub.30H.sub.36ClN.sub.5O.sub.3S requires 581.
EXAMPLE 115
1-(3-Dimethylaminoprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(p-
yrimid-5-ylmethyl)pyrimidin-4one
[0714] 309
[0715] Prepared from intermediate B51 and A1 by general method A4.
as a thick gum. .sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.8(10H,m),
1.8-2.05(4H,m), 2.14(3H,s), 2.19(3H,s), 2.93(2H,t), 3.24(2H,t),
3.70(2H,s), 7.42(2H,m), 7.88(2H,m) 8.72(2H,s) and 9.09(1H,s); MS
(APCI+) found (M+1)=542. C.sub.28H.sub.36ClN.sub.5O.sub.2S requires
541.
EXAMPLE 116
1-(3-Hydroxyprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-
-5-ylmethyl)pyrimidin-4-one
[0716] 310
[0717] Prepared from intermediate B52 and A1 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.3-1.55 (6H,m), 1.6-1.85 (4H),
1.95-2.1(2H,m), 2.93(2H,t), 3.25(2H,t), 3.6-3.8 (4H,m), 4.01(2H,t),
7.11(1H,s) 7.45(2H,d), 7.89(2H,d), 8.70(2H,m) and 9.08(1H,s); MS
(APCI+) found (M+1)=515: C.sub.26H.sub.31ClN.sub.4O.sub.3S requires
514.
EXAMPLE 117
1-(3-Hydroxyprop-1-yl)-2-(5-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidi-
n-4-one
[0718] 311
[0719] Prepared from intermediate B52and A24 by general method A4,
as a colourless powder. MPt 76-77.degree. C.; .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-2.0(14H,m), 2.56(2H,t), 3.25(2H,t),
3.61(2H,t), 3.73(2H,s), 3.88(2H,t), 6.76(1H,s), 7.09(1H,d) and
7.15-7.4(7H,m); MS (FAB) found M+H=499;
C.sub.32H.sub.35ClN.sub.2O.sub.2S requires 498.
EXAMPLE 118
1-(3-Methoxyprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-
-5-ylmethyl)pyrimidin-4-one
[0720] 312
[0721] Prepared from intermediate B54 and A1 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.85(10H,m), 2.00(2H,m),
2.94(2H,t), 3.2-3.4(7H,m), 3.70(2H,s), 3.92(2H,t), 6.99(1H,s),
7.44(2H,m), 7.90(2H,m), 8.71(2H,s) and 9.10(1H,s); MS (APCI+) found
(M+1)=529; C.sub.27H.sub.33ClN.sub.4O.sub.3S requires 528.
EXAMPLE 119
1-(3-Phenylprop-1-y;)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid--
5-ylmethyl)pyrimidin-4-one
[0722] 313
[0723] Prepared from intermediate B55 and A1 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.85(1OH,m), 2.11(2H,quintet),
2.69(2H,t), 2.93(2H,t), 3.24(2H,t), 3.67(2H,s), 3.78(2H,t),
6.84(1H,s), 7.1-7.5(7H,m), 7.90(2H,m), 8.70(2H,s) and 9.10(1H,s);
MS (APCI+) found (M+1)=575. C.sub.32H.sub.35ClN.sub.4O.sub.2S
requires 574.
EXAMPLE 120
1-(5-Hydroxypent-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-ylthio-5-(pyrimid--
5-ylmethyl)pyrimidin-4-one
[0724] 314
[0725] Prepared from intermediate B56 and A1 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.3-1.9(16H,m), 2.94(2H,t),
3.25(2H,t), 3.6-3.75(4H,m), 3.80(2H,t), 6.96(1Hem), 7.44(2H,m),
7.90(2H,m), 8.71(2H,s) and 9.09(1H,s): MS (APCI+) found (M+1)=543:
C.sub.2,H.sub.35ClN.sub.4O.sub.3S requires 542.
EXAMPLE 121
1-(Pyrid-2-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-
-ylmethyl)pyrimidin-4-one
[0726] 315
[0727] Prepared from intermediate B45 and A1 by general method A4,
as a white solid. .sup.1H-NMR (CDCl.sub.3) .delta. 1.3-1.5 (6H,m),
1.6-1.8(4H,m), 2.92(2H,t), 3.25(2H,t), 3.71(2H,s), 5.06(2H,s),
7.2-7.35(3H,m), 7.6-7.8(1H,m), 8.5-8.6(1H,m), 8.70(2H,s) and
9.10(1H,s); MS (APCI+) found (M+1)=548;
C.sub.29H.sub.30ClN.sub.5O.sub.2S requires 547.
EXAMPLE 122
1-(Pyrid-2-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin--
4-one
[0728] 316
[0729] Prepared from intermediate B57 and A24 by general method A4,
as a pale brown oil. .sup.1H-NMR (CDCl.sub.3) .delta.
1.2-1.5(8H,m), 1.5-1.85(4H,m), 2.55(2H,t), 3.24(2H,t), 3.77(2H,s),
5.00(2H,s), 6.88(1H,s), 7.09(2H,d), 7.25-7.4(9H,m), 7.68(1H,m) and
8.57(1H,m), MS (EI) found M=531; C.sub.31H.sub.34ClN.sub.3OS
requires 531.
EXAMPLE
123--1-(Pyrid-3-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-
-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one
[0730] 317
[0731] Prepared from intermediate B58 and A1 by general method A4.
as a buff coloured solid. MPt 105-106.degree. C.; .sup.1H-NMR
(CDCl.sub.3) .delta. 1.36 (6H, m), 1.71 (4H, m), 2.96 (2H, t), 3.26
(2H, t), 3.49 (3H, s), 3.53 (2H, s), 5.02 (2H, s), 6.14 (1H, m),
6.34 (1H, s), 6.99 (1H, s), 7.17 (1H, m), 7.25-7.55 (4H, m), 7.91
(2H, d), 8.52 (1H, s), 8.64 (1H, m); MS (APCI+) found (M+1)=577,
C.sub.31H.sub.33ClN.sub.4O.sub.3S requires 576.
EXAMPLE 124
1-(Pyrid-3-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-
-ylmethyl)pyrimidin-4-one
[0732] 318
[0733] Prepared from intermediate B59 and A1 by general method A4,
as a white solid. MPt 80-83.degree. C.; .sup.1H-NMR (CDCl.sub.3)
.delta. 1.40 (6H, m), 1.69 (4H, m), 2.93 (2H, t), 3.26 (2H, t),
3.69 (2H, s), 5.04 (2H, s), 7.04 (1H, s), 7.30-7.56 (4H, m), 7.91
(2H, d), 8.55 (1H, m), 8.68 (3H, m), 9.10 (1H, s); MS (APCI+) found
(M+1)=548; C.sub.29H.sub.30ClN.sub.5O.sub.2S requires 547.
EXAMPLE 125
1-(Pyrid-3-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin--
4-one
[0734] 319
[0735] Prepared from intermediate B60 and A24 by general method A4,
as a pale brown oil. .sup.1H-NMR (CDCl.sub.3) .delta.
1.2-1.5(8H,m), 1.5-1.85(4H,m), 2.56(2H,t), 3.26(2H,t), 3.75(2H,s),
4.92(2H,s), 6.66(1H,s), 7.09(1H,d), 7.15-7.5(9H,m), 8.45(1H,m) and
8.59(1H,m); MS (EI) found 531; C.sub.31H.sub.34ClN.sub.3OS requires
531.
EXAMPLE 126
1-(Pyrid-4-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-((1-methyl-2-oxo-
-pyrid-4-yl)methyl)pyrimidin-4-one
[0736] 320
[0737] Prepared from intermediate B61 and A24 by general method A4,
as an orange gum. .sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.5(8H,m),
1.5-1.75(4H,m), 2.55(2H,t), 3.24(2H,t), 3.49(3H,s), 3.55(2H,s),
5.01(2H,s), 6.16(1H,m), 6.35(1H,bs), 6.9-7.35(8H,m) and 8.63(2H,m);
MS (FAB) M+1=563; C.sub.31H.sub.35ClN.sub.4OS requires 562.
EXAMPLE 127
1-(Pyrid-4-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-((1-methyl-
-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one
[0738] 321
[0739] Prepared from intermediate B61 and A1 by general method A4,
as an off-white solid. MPt 113-114.degree. C.; .sup.1H-NMR
(CDCl.sub.3) .delta. 1.29 (6H, m), 1.63 (4H, m), 2.86 (2H, t), 3.19
(2H, t), 3.43 (3H, s), 3.49 (2H, s), 4.95 (2H, s), 6.09 (1H, m),
6.29 (1H, m), 6.89 (1H, s), 6.99 (2H, m), 7.12 (1H, d), 7.36 (2H,
d), 7.83 (2H, d), 8.58 (2H, m).
EXAMPLE 128
1-(Pyrid-4-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-
-ylmethyl)pyrimidin-4-one
[0740] 322
[0741] Prepared from intermediate B62 and A1 by general method A4,
as a buff coloured solid. MPt 75-77.degree. C.; .sup.1H-NMR
(CDCl.sub.3) .delta. 1.35 (6H, m), 1.67 (4H, m), 2.92 (2H, t), 3.27
(2H, t), 3.72 (2H, s), 5.02 (2H, s), 6.99 (1H, s), 7.05 (2H, m),
7.43 (2H, d), 7.89 (2H, d), 8.64 (4H, m), 9.09 (1 H, s); MS (APCI+)
found (M+1)=548; C.sub.29H.sub.30ClN.sub.5OS requires 547.
EXAMPLE 129
1-(Pyrid-4-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin--
4one
[0742] 323
[0743] Prepared from intermediate B63 and A24 by general method A4,
as a buff powder. MPt 108-110.degree. C.; .sup.1H-NMR (CDCl.sub.3)
.delta. 1.2-1.8(12H,m), 2.55(2H,t), 3.25(2H,t), 3.77(2H,s),
4.91(2H,s), 6.62(1H,s), 6.68(2H,d), 7.08(2H,d), 7.15-7.4(7H,m) and
8.5-8.7(2H,m); MS (EI) found M=531; C.sub.31H.sub.34ClN.sub.3OS
requires 531.
EXAMPLE 130
1-(Pyrid-4-ylmethyl)-2-(8-(4-chlorophenyl)oct-1yl)thiopyrimidin-4-one
[0744] 324
[0745] Prepared from intermediate B64 and A24 by general method A4,
as a brown gum. .sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.5(4H,m),
1.5-1.8(4H,m), 2.55(2H,t), 3.24(2H,t), 5.04(2H,s), 6.11(1H,d),
7.0-7.4(7H,m) and 8.65(2H,m); MS (EI) M=441;
C.sub.24H.sub.28ClN.sub.3OS requires 441.
EXAMPLE 131
1-(2-(Pyrid-2-yl)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimi-
d-5-ylmethyl)pyrimidin-4-one
[0746] 325
[0747] Prepared from intermediate B65 and A1 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.8(10H,m), 2.94(2H,t),
3.2-3.35(4H,m), 3.53(2H,s), 4.32(2H,t), 6.74(1H,s), 7.04(1H,m),
7.20(1H,m), 7.43(2H,m), 7.57(1H,m), 7.88(2H,m), 8.4-8.55(3H,m) and
9.09(1H,s); MS (APCI+) found (M+1)=562;
C.sub.30H.sub.32ClN.sub.5O.sub.2S requires 561.
EXAMPLE 132
1-(2-(Pyrid-3-yl)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-((1-met-
hyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one
[0748] 326
[0749] Prepared from intermediate B66 and A1 by general method A4,
as a cream coloured crystalline solid. MPt 121-123.degree. C.;
.sup.1H-NMR (CDCl.sub.3) .delta. 1.42 (6H, m), 1.7 (4H, m), 2.94
(2H, t), 3.07 (2H, t), 3.29 (2H, t), 3.45 (2H, s), 3.51 (3H, s),
4.01 (2H, t), 6.05 (1H, m), 6.28 (1H, m), 6.64 (1H, s), 7.16 (1H,
d), 7.26 (1H, m), 7.45 (3H, m), 7.89 (2H, d), 8.45 (1H, m), 8.54
(1H, m); MS (APCI+) found (M+1)=591;
C.sub.32H.sub.35ClN.sub.4O.sub.3S requires 590.
EXAMPLE 133
1-(2-(Pyrid-3-yl)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimi-
d-5-ylmethyl)pyrimidin-4-one
[0750] 327
[0751] Prepared from intermediate B67 and A1 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.3-1.9 (10H,m), 2.94 (2H,t), 3.08
(2H,t), 3.58(2H,s), 4.03(2H,t), 6.57 (1H,s), 7.43 (2H,m), 7.90
(2H,m), 8.44 (1H,m), 8.55 (3H,m) and 9.09 (1H,m); MS (APCI+) found
(M+1)=562: C.sub.30H.sub.32ClN.sub.5O.sub.2S requires 561.
EXAMPLE 134
1-(2-(Pyrid-4-yl)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-((1-met-
hyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one
[0752] 328
[0753] Prepared from intermediate B68 and A1 by general method A4,
as a cream coloured crystalline solid. MPt 129-130.degree. C.;
.sup.1H-NMR (CDCl.sub.3) .delta. 1.40 (6H, m), 1.70 (4H, m), 2.95
(2H,t), 3.06 (2H, t), 3.30 (2H, t), 3.44 (2H, s), 3.51 (3H, s),
4.04 (2H, t), 5.95 (1H, m), 6.29 (1H, m), 6.56 (1H, s), 7.08 (2H,
m), 7.17 (1H, d), 7.44 (2H,d), 7.90 (2H, d), 8.53 (2H, m); MS
(APCI+) found (M+1)=591; C.sub.32H.sub.35ClN.sub.4O.sub.3S requires
590.
EXAMPLE 135
1-(2-Pyrid-4-yl)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-
-5-ylmethyl)pyrimidin-4-one
[0754] 329
[0755] Prepared from intermediates B69 and A1 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.25-1.9(10H,m), 2.91(2H,t),
3.06(2H,t), 3.29(2H,t), 3.59(2H,s), 4.04(2H,t), 6.62(1H,s),
7.07(2H,m), 7.43(2H,m), 7.90(2H,m), 8.45-8.7(4H,m) and 9.10(1H,s);
MS (APCI+) found (M+1)=562: C.sub.30H.sub.32ClN.sub.5O.sub.2S
requires 561.
EXAMPLE 136
1-(2-Phenylethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-((1-methyl-2-oxo-py-
rid-4-yl)methyl)pyrimidin-4-one
[0756] 330
[0757] Prepared from intermediate B70 and A24 by general method A4,
as a pale brown gum. .sup.1H-NMR (d.sub.6-DMSO) .delta.
1.2-1.5(8H,m), 1.5-1.8(4H,m), 2.54(2H,t), 3.01(2H,t), 3.11(2H,t),
3.26(2H,s), 3.35(3H+HOD), 4.09(2H,t), 5.94(1H,dd), 6.10(1H,d),
7.1-7.4(9H,m) and 7.54(2H,m).
EXAMPLE 137
1-(2-Phenylethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)p-
yrimidin-4-one
[0758] 331
[0759] Prepared from Example 70 by general method C1, as a
brown/green gum. .sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.8(12H,m),
2.56(2H,t), 3.01(2H,t), 3.26(2H,t), 3.51(2H,t), 3.97(2H,t),
6.27(1H,s), 7.0-7.5(11H,m), 8.30(1H,m) and 8.46(1H,m); MS (FAB)
M+1=546; C.sub.32H.sub.36ClN.sub.3OS requires 545.
EXAMPLE 138
1-(2-Methylprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid--
5-ylmethyl)pyrimidin-4-one
[0760] 332
[0761] Prepared from intermediate B88 and A1 by general method A4.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 0.88 (6H,d), 1.2-1.4 (6H,m),
2.5-2.7 (4H,m), 2.08 (1H,m), 3.00 (2H,t), 3.11 (2H,t), 3.57 (2H,s),
3.69 (2H,d), 7.58 (2H,d), 7.82 (1H,s), 7.97 (2H,d), 8.70 (2H,s),
9.01 (1H,s); MS (APCI) M=513; C.sub.27H.sub.33ClN.sub.4O.sub.2S
requires 513.
EXAMPLE 139
1-Phenylsulfonyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)py-
rimidin-4-one
[0762] 333
[0763] Benzenesulfonyl chloride (41 mg) was added to a solution of
2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one
(103mg) in pyridine (0.5 ml), and the mixture stirred overnight.
Evaporation of the pyridine followed by chromatography (silica,
0-2% methanol in dichloromethane) gave
1-phenylsulfonyl-2-(8-(4-chlorophenyl)o-
ct-1-yl)thio-5-(pyrid-3-ylmethyl pyrimidin-4-or (25 mg).
.sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.5(8H,m), 1.5-1.8(4H,m),
2.56(2H,t), 2.92(2H,t), 3.87(2H,s), 7.08(2H,d), 7.15-7.8(7H,m),
7.95(2H,m), 8.29(1H,s) and 8.35-8.7(2H,bm).
EXAMPLE 140
Benzyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-((-methyl-2-oxo-pyrid-4-yl)met-
hyl)pyrimidin-4-one
[0764] 334
[0765] Prepared from intermediate B71 and A24 by general method A4,
as a yellow/orange gum. .sup.1H-NMR (CDCl.sub.3) .delta.
1.2-1.5(8H,m), 1.5-1.8(4H,m), 2,56(2H,t), 3.25(2H,t), 3.49(3H,s),
3.52(2H,s), 4.99(2H,s), 6.16(1H,dd), 6.34(1H,m), 6.95(1H,s) and
7.0-7.5(10H,m); MS (EI) M=561; C.sub.32H.sub.36ClN.sub.3O.sub.2S
requires 561.
EXAMPLE 141
1-Benzyl-2-(8-{4-chlorophenyl)-8-oxooct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-
-4-yl)methyl)pyrimidin-4-one
[0766] 335
[0767] Prepared from intermediate B71 and A1 by general method A4,
as a pale brown solid. .sup.1H-NMR (CDCl.sub.3) .delta. 1.38 (6H,
m), 1.73 (4H, m), 2.93 (2H, t), 3.26 (2H, t), 3.49 (3H, s), 3.52
(2H, s), 4.99 (2H, s), 6.16 (1H, m), 6.33 (1H, m), 6.96 (1H, s),
7.16 (3H, m), 7.27-7.45 (5H, m), 7.90 (2H, d).
EXAMPLE 142
1-Benzyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)-
pyrimidin-4-one
[0768] 336
[0769] Prepared from Example 30 by general method C1, as a pale
yellow gum. .sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.8(12H,m),
2.5-2.65(5H,m), 3.25(2H,t), 3.68(2H,s), 4.95(2H,s), 6.78(1 H,s),
7.0-7.6(11H,m) and 8.31 (1H,d); MS (EI) found M=546;
C.sub.32H.sub.36ClN.sub.3OS requires 546.
EXAMPLE 143
1-Benzyl-2-(8-phenyloct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin--
4-one
[0770] 337
[0771] Prepared from Example 21 by general method C1, as a pale
yellow oil. .sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.5(8H,m),
1.5-1.8(4H,m), 2.53(3H,s), 2.59(2H,t), 3.24(2H,t), 3.68(2H,s),
4.95(2H,s), 6.78(1H,s), 7.0-7.5(11H,m), 7.52(1H,m) and 8.31(1H,bs);
MS (FAB) M+1=512; C.sub.32H.sub.37N.sub.3OS requires 511.
EXAMPLE 144
1-Benzyl-2-(8-phenyloct-1-yl)thio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin-
-4-one
[0772] 338
[0773] Prepared from Example 37 by general method C1, as a thick
gum. .sup.1H-NMR (CDCl.sub.3) .delta.0 1.2-1.8(10H,m), 2.59(2H,t),
3.26(2H,t), 3.66(2H,s), 3.91(3H,s), 4.95(2H,s), 6.56(1H,bs),
6.73(1H,m), 6.78(1H,s), 7.05-7.45(10H,m) and 8.03(1H,m); MS (APCI+)
Found (M+1)=528. C.sub.32H.sub.37N.sub.3O.sub.2S requires 527.
EXAMPLE 145
1-Benzyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrid-3-ylmethyl)pyri-
midin-4-one
[0774] 339
[0775] Prepared from Example 47 by general method C1, as a
colourless oil. .sup.1H-NMR (CDCl.sub.3) .delta. 1.25-1.5(6H,m),
1.5-1.85(4H,m), 2.93(2H,t), 3.25(2H,t), 3.71(2H,s), 4.96(2H,s),
6.83(1H,s), 7.05-7.5(8H,m), 7.60(1H,txd), 7.88(2H,d) and
8.4-8.55(2H,m); MS (EI) found M=545;
C.sub.31H.sub.37ClN.sub.3O.sub.2S requires 545.
EXAMPLE 147
1-(2-Thienylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5--
ylmethyl)pyrimidin-4-one
[0776] 340
[0777] Prepared from intermediates B73 and A1 by general method A4,
as a white crystalline solid. MPt 68--70.degree. C.; .sup.1H-NMR
(CDCl.sub.3) .delta. 1.38 (6H, m), 1.69 (4H, m), 2.93 (2H, t), 3.29
(2H, t), 3.67 (2H, s), 5.14 (2H, s), 7.04 (3H, m), 7.37 (1H, m),
7.43 (2H, m), 7.90 (2H, m), 8.67 (2H, s), 9.01 (1H, s); MS APCI+)
found (M+1)=553; C.sub.28H.sub.29ClN.sub.4O.sub.2S.sub.2 requires
552.
EXAMPLE 148
1-(2,2-Dimethylprop-1-yl)-2-(8-(4chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrim-
id-5-ylmethyl)pyrimidin-4-one
[0778] 341
[0779] Prepared from intermediates B74 and A1 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 0.98(9H,s), 1.2-1.85(10H,m),
2.93(2H,t), 3.24(2H,t), 3.65(2H,s), 3.70(2H,s), 6.89(1H,s),
7.43(2H,m), 7.90(2H,m), 8.69(2H,s) and 9.09(l H,s): MS (APCI+)
found (M+1)=527; C.sub.28H.sub.35ClN.sub.4O.sub.2S requires
526.
EXAMPLE 149
1-(2-(1-Piperidino)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyri-
mid-5-ylmethyl)pyrimidin-4-one
[0780] 342
[0781] Prepared from intermediates B75 and A1 by general method A4,
as a yellow oil. .sup.1H-NMR (CDCl.sub.3) .delta. 1.34-1.90 (16H,
m), 2.30-2.55 (6H, m), 2.93 (2H, t), 3.25 (2H, t), 3.71 (2H, s),
4.40 (2H, m), 7.02 (1H, s), 7.42 (2H, m), 7.89 (2H, m), 8.70 (2H,
s), 9.09 (1H, s); MS APCI+) found (M+1)=568;
C.sub.30H.sub.38ClN.sub.5O.sub.2S requires 567.
EXAMPLE 150
1-(2-Hydroxyethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-y-
lmethyl)pyrimidin-4-one
[0782] 343
[0783] Prepared from intermediates B77 and A1 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.3-1.8(10H,m), 2.93(2H,t),
3.25(2H,t), 3.66(2H,s), 3.99(4H,m), 7.20(1H,s), 7.43(2H,m),
7.89(2H,m), 8.68(2H,s) and 9.05(1H,s), MS (APCI+) found (M+1)=501;
C.sub.25H.sub.29ClN.sub.4O.su- b.3S requires 500.
EXAMPLE 151
1-(2-Hydroxyethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin-4--
one
[0784] 344
[0785] Prepared from intermediates B78 and A24 by general method
A4, as a colourless gum. .sup.1H-NMR (CDCl.sub.3) .delta.
1.2-1.5(8H,m), 1.5-1.8(4H,m), 2.54(2H,t), 3.21(2H,t), 3.64(2H,s),
3.8-4.15(4H,m), 5.23(1H,bs), 6.97(1H,s), 7.08(2H,d) and
7.1-7.45(7H,m).
EXAMPLE 152
1-Ethyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyr-
imidin-4-one
[0786] 345
[0787] Prepared from intermediates B89 and A1 by general method A4.
.sup.1H-NMR (d.sub.6-DMSO) .delta. 1.2-1.4 (9H,m), 2.5-2.7 (4H,m),
2.84 (2H,t), 3.11 (2H,t), 3.56 (2H,s), 3.89 (2H,q), 7.58 (2H,d),
7.85 (1H,s), 7.97 (2H,d), 8.70 (2H,s), 9.01 (1H,s); MS (APCI)
M=485; C.sub.25H.sub.29ClN.sub.4O.sub.2S requires 485.
EXAMPLE 153
1-(Fur-2-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-y-
lmethyl)pyrimidin-4-one
[0788] 346
[0789] Prepared from intermediates B81 and A1 by general method A4,
as a light brown oil. .sup.1H-NMR (CDCl.sub.3) .delta. 1.38 (6H,
m), 1.70 (4H, m), 2.93 (2H, t), 3.27 (2H, t), 3.69 (2H, s), 4.94
(2H, s), 6.40 (2H, m), 7.06 (1H, s), 7.44 (3H, m), 7.90 (2H, m),
8.68 (2H, s), 9.09 (1H, s); MS APCI+) found (M+1)=537;
C.sub.28H.sub.29ClN.sub.4O.sub.3S requires 536.
EXAMPLE 154
1-(Fur-2-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin-4--
one
[0790] 347
[0791] Prepared from intermediates B82 and A24 by general method
A4, as a pale brown gum. .sup.1H-NMR (CDCl.sub.3) .delta.
1.2-1.5(8H,m), 1.5-1.8(4H,m), 2.56(2H,t), 3.27(2H,t), 3.73(2H,s),
4.85(2H,s), 6.33(2H,s), 6.73(1H,s), 7.09(2H,d) and 7.2-7.5(8H,m);
MS (FAB) M+1=521; C.sub.30H.sub.33ClN.sub.2O.sub.2S requires
520.
EXAMPLE 155
1-Methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-bromopyrimidin-4-one
[0792] 348
[0793]
1-Methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thiopyrimidin-4-one
was prepared from 1-methyl-2-thiouracil by general method A4. A
solution of bromine (0.05 ml) in dichloromethane (1 ml) was added
to a slurry of
1-methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thiopyrimidin-4-one
(0.38 g) in dichloromethane (20 ml), and the mixture was stirred
for 24 hours. The solution was washed with aqueous sodium
carbonate, dried and evaporated. Chromatography (silica, 1-4%
methanol in dichloromethane) gave
1-methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-bromopyrimidin-4-one
(0.18 g), as a white solid. .sup.1H-NMR (CDCl.sub.3) .delta.
1.3-1.5 (6H,m), 1.65-1.8 (4H,m), 2.94 (2H,t), 3.26(2H, t),
3.56(3H,s), 7.45(2H,d), 7.56(1H,s) and 7.90(2H,d); MS (APCI+) found
(M+1)=459; C.sub.19H.sub.22BrClN.sub.2O.sub.2S requires 458.
EXAMPLE 156
1-Methyl-2-(8-(4-chlorophenyl)oct-1yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)m-
ethyl)pyrimidin-4-one
[0794] 349
[0795] Prepared from intermediates B83 and A24 by general method
A4, as a colourless solid. .sup.1H-NMR (CDCl.sub.3) .delta.
1.2-1.5(8H,m), 1.5-1.8(4H,m), 2.56(2H,t), 3.25(2H,t), 3.49(3H,s),
3.51(3H,s), 3.54(2H,s), 6.19(1H,m), 6.38(1H,m), 6.93(1H,s) and
7.0-7.35(5H,m); MS (EI) M=485: C.sub.26H.sub.32ClN.sub.3O.sub.2S
requires 485.
EXAMPLE 157
1-Methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-
-4-yl)methyl)pyrimidin-4-one
[0796] 350
[0797] Prepared from intermediates B83 and A1 by general method A4,
as a cream coloured crystalline solid. MPt 90-5.degree. C.;
.sup.1H-NMR (CDCl.sub.3) .delta. 1.38 (6H, m), 1.72 (4H, m), 2.91
(2H, t), 3.26 (2H,t), 3.49 (3H, s), 3.51 (3H, s), 3.54 (2H, s),
6.19 (1H, m), 6.38 (1H, s), 6.93 (1H, s), 7.19 (1H, m), 7.43 (2H,
d), 7.90 (2H, d); MS (APCI+) Found (M+1)=500;
C.sub.26H.sub.30N.sub.3O.sub.3S requires 499.
EXAMPLE 158
1-Methyl-2-(5-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin--
4-one
[0798] 351
[0799] Prepared from Example 70 by general method C1. as a pale
yellow oil. .sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.8(12H,m),
2.56(2H,t), 3.22(2H,t), 3.46(3H,s), 3.74(2H,s), 6.77(1H,s),
7.08(2H,d), 7.15-7.35(4H,m), 7.66(1H,txd) and 8.49(2H,bs); MS (EI)
found M=455; C25H.sub.30ClN.sub.3OS requires 455.
EXAMPLE 159
1-Methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)py-
rimidin-4-one
[0800] 352
[0801] Prepared from intermediates B84 and A1 by general method A4,
as a white solid. .sup.1H-NMR (CDCl.sub.3) .delta. 1.3-1.55(6H,m),
1.6-1.85(4H,m), 2.93(2H,t), 3.26(2H,t), 3.51(3H,s), 3.70(2H,s),
6.94(1H,s), 7.45(2H,d), 7.89(2H,d), 8.70(2H,s) and 9.1(1H,s); MS
(APCI+) found (M+I)=471; C.sub.24H.sub.27ClN.sub.4O.sub.2S requires
470.
EXAMPLE 160
1-Methyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin-4-one
[0802] 353
[0803] Prepared from intermediates B85 and A24 by general method
A4, as a colourless powder. MPt 92-93.degree. C.; .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-1.8(12H,m), 2.56(2H,t), 3.26(2H,t),
3.40(3H,s), 3.76(2H,s), 6.59(1H,s), 7.09(2H,d) and 7.15-7.45(7H,m);
MS (EI) found M=454; C.sub.26H.sub.3,ClN.sub.2OS requires 454.
EXAMPLE 161
1-Phenyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)-
methyl)pyrimidin-4-one
[0804] 354
[0805] Prepared from intermediates B86 and A24 by general method
A4, as a yellow/orange solid. .sup.1H-NMR (CDCl.sub.3) .delta.
1.2-1.5(5H,m), 1.5-1.8(4H,m), 2.54(2H,t), 3.14(2H,t), 3.49(3H,s),
3.57(2H,s), 6.22(1H,m), 6.38(1H,m), 7.00(1H,s), 7.08(2H,d),
7.15-7.4(5H,m) and 7.5-7.6(3H,m); MS (EI) M=547;
C.sub.31H.sub.34ClN.sub.3O.sub.2S requires 547.
EXAMPLE 162
1-Methylsulfonyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)py-
rimidin-4-one
[0806] 355
[0807] Prepared from Example 70, analogously to example 139.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.8(12H,m), 2.56(2H,t),
3.10(2H,t) 3.55(3H,s), 4.03(2H,s), 7.09(2H,m), 7.15-7.3(2H,m),
7.61(1H,m), 7.96(1H,m), 8.45(1H,s) and 8.60(2H,m).
EXAMPLE 163
1-Benzyl-2-(8-phenyloct-1-yl)oxy-5-(pyrid-3-ylmethyl)pyrimidin-4-one
[0808] 356
[0809] Prepared from Example 100 by general method C1, as a pale
buff solid. MPt 74-78.degree. C.; .sup.1H-NMR (CDCl.sub.3) .delta.
1.2-1.5(8H,m), 1.5-1.85(4H,m), 2.58(2H,t), 3.72(2H,s), 4.40(2H,t),
4.83(2H,s), 6.76(1H,s), 7.0-7.4(11H,m), 7.6-7.7(1H,m) and
8.46(2H,m); IR 1655, 1621 cm-1.
EXAMPLE 164
1-(2-Methoxyethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0810] 357
[0811] Prepared from intermediate B87 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 3.31(3H,s), 3.59(2H,t),
3.71(2H,s), 4.51(2H,s), 7.10(1H,s), 7.2-7.45(5H,m), 8.72(2H,s) and
9.10(1H,s); MS (APCI+) found (M+1)=369;
C.sub.19H.sub.20N.sub.4O.sub.2S requires 368.
EXAMPLE 165
1-(3-Phenylprop-1-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0812] 358
[0813] Prepared from intermediate B55 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 2.08(2H,quintet), 2.65(2H,t),
3.68(2H,s), 3.75(2H,t), 4.49(2H,s), 5.30(2H,s), 6.84(1H,s),
7.10(2H,m), 7.15-7.5(8H,m), 8.69(2H,s) and 9.10(1H,s); MS (APCI+)
found (M+1)=429, C.sub.25H.sub.24N.sub.4OS requires 428.
EXAMPLE 166
1-(5-Hydroxypent-1-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0814] 359
[0815] Prepared from intermediate B56 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.3-1.9(6H,m), 3.64(2H,t),
3.7-3.9(4H,m), 4.50(2H,s), 6.98(1H,m), 7.2-7.5(5H,m), 8.72(2H,s)
and 9.10(1 H,s); MS (APCI+) found (M+1 )=397;
C.sub.21H.sub.24N.sub.4O.sub.2S requires 396.
EXAMPLE 167
1-(Pyrid-2-ylmethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0816] 360
[0817] Prepared from intermediate B45 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 3.73(2H,s), 4.49(2H,s),
5.03(2H,s), 7.1-7.4(8H,m), 7.69(1H,m), 8.57(1H,m), 8.71(2H,s) and
9.09(1H,s); MS (APCI+) found (M+1)=402: C.sub.22H.sub.19N.sub.5OS
requires 401.
EXAMPLE 168
1-(Pyrid-3-ylmethyl)-2-benzylthio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyr-
imidin-4-one
[0818] 361
[0819] Prepared from intermediate B58 by general method A4, as a
buff coloured solid. .sup.1H-NMR (CDCl.sub.3) .delta. 3.5 (3H, s),
3.55 (2H, s), 4.51 (2H, s), 4.99 (2H, s), 6.27 (1H, m), 6.26 (1H,
s), 7.01 (1H, s), 7.15-7.50 (8H, m),8.50 (1H, s), 8.62 (1H, m); MS
(APCI+) found (M+1)=431; C.sub.24H.sub.22N.sub.4O.sub.2S requires
430.
EXAMPLE 169
1-(Pyrid-4-ylmethyl)-2-benzylthio-5-benzylpyrimidin-4-one
[0820] 362
[0821] Prepared from intermediate B63 by general method A4, as a
brown gum. .sup.1H-NMR (CDCl.sub.3) .delta. 3.78(2H,s), 4.50(2H,s),
4.89(2H,s), 6.64(1H,s), 6.94(2H,d), 7.1-7.5(10H,m) and 8.58(2H,d);
MS (EI) found M=399; C.sub.24H.sub.21N.sub.3OS requires 399.
EXAMPLE 170
1-(2-(Pyrid-2-yl)ethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0822] 363
[0823] Prepared from intermediate B65 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 3.20(2H,t), 3.55(2H,s),
4.30(2H,t), 4.53(2H,s), 6.75(11H,s), 6.96(1H,m), 7.17(11H,m),
7.25-7.5(5H,m), 7.56(1H,m), 8.4-8-55(3H,m) and 9.10(1H,s),; MS
(APCI+) found (M+1)=416; C.sub.23H.sub.21N.sub.5OS requires
415.
EXAMPLE 171
1-(2-(Pyrid-3-yl)ethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0824] 364
[0825] Prepared from intermediate B67 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 3.05(2H,t), 3.60(2H,s),
4.00(2H,t), 4.54(2H,s), 6.57(1H,s), 7.1-7.5(6H,m), 8.43(1H,m),
8.5-8.65(3H,m) and 9.10(1H,s); MS (APCI+) found (M+1)=416;
C.sub.23H.sub.21N.sub.5OS requires 415.
EXAMPLE 172
1-(2-(Pyrid-4-yl)ethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0826] 365
[0827] Prepared from intermediate B68 by general method A4, as a
buff coloured solid. .sup.1H-NMR (CDCl.sub.3) .delta. 3.02 (2H, t),
3.45 (2H, s), 3.52 (3H, s), 4.00 (2H, t), 4.55 (2H, s), 5.95 (1H,
m), 6.30 (1H, s), 6.57 (1H, s), 7.02 (2H, m), 7.18 (1H, m),
7.19-7.44 (5H, m), 8.50 (2H, m); MS (APCI+) Found (M+1)=445;
C.sub.25H.sub.24N.sub.4O.sub.2S requires 444.
EXAMPLE 173
1-(2-(Pyrid-4-yl)ethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0828] 366
[0829] Prepared from intermediate B69 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 3.03(2H,t), 3.60(2H,s),
4.01(2H,t), 4.54(2H,s), 6.61(1H,s), 7.01(2H,m), 7.25-7.5(5H,m),
8.45-8.65(4H,m) and 9.1 I(1H,s); MS (APCI+) found (M+1)=416;
C23H21N5OS requires 415.
EXAMPLE 174
1-(2-Phenylethyl)-2-benzylthio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin-4--
one
[0830] 367
[0831] Prepared from Example 88 by general method C1. .sup.1H-NMR
(CDCl.sub.3) .delta. 3.01(2H,t), 3.57(2H,s), 3.95(5H,m),
4.53(2H,m), 6.27(1H,s), 6.45(1H,s), 6.55(1H,m), 7.0(2H,m),
7.1-7.5(8H,m) and 8.02(1H,d); MS (APCI+) found M+H=444;
C.sub.26H.sub.25N.sub.3O.sub.2S requires 443.
EXAMPLE 175
1-Benzyl-2-benzylthio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin-4-one
[0832] 368
[0833] Prepared from intermediate Example 88 by general method C1,
as a colourless stiff gum. .sup.1H-NMR (CDCl.sub.3) .delta.
3.67(2H,s), 3.90(3H,s), 4.51(2H,s), 4.93(2H,s), 6.57(1H,s),
6.73(1H,m), 6.81(1H,s), 7.10(1H,m), 7.25-7.45(9H,m) and 8.04(1H,d);
MS (EI) M=429; C.sub.25H.sub.23N.sub.3O.sub.2S requires 429.
EXAMPLE 176
1-(2-Thienylmethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin
4-one
[0834] 369
[0835] Prepared from intermediate B73 by general method A4, as a
pale yellow crystalline solid. MPt 110-112.degree. C.; .sup.1H-NMR
(CDCl.sub.3) .delta. 3.69 (2H, s), 4.54 (2H, s), 5.11 (2H, s), 7.02
(3H, m), 7.30-7.42 (6H, m), 8.65 (2H, s), 9.09 (1 H, s); MS APCI+)
found (M+1)=407; C.sub.21H.sub.18N.sub.4OS.sub.2 requires 406.
EXAMPLE 177
1-(2,2-Dimethylprop-l-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-o-
ne
[0836] 370
[0837] Prepared from intermediate B74 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 0.96(9H,s), 3.62(2H,s),
3.72(2H,s), 4.49(2H,s), 6.91(1H,s), 7.25-7.45(5H,m), 8.70(2H,s) and
9.11(1H,s); MS (APCI+) found (M+1)=381; C.sub.21H.sub.24N.sub.4OS
requires 380.
EXAMPLE 178
1-(Fur-2-ylmethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0838] 371
[0839] Prepared from intermediate B81 by general method A4, as a
brown oil. .sup.1H-NMR (CDCl.sub.3) .delta. 3.70 (2H, s), 4.52 (2H,
s), 4.91 (2H, s), 6.40 (2H, m), 7.06 (1H, S), 7.26-7.42 (6H, m),
8.70 (2H, s), 9.10 (1H, s); MS APCI+) found (M+1)=391;
C.sub.21H.sub.18N.sub.4O.sub.2S requires 390.
EXAMPLE 179
1-Methyl-2-benzylthio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin-4-one
[0840] 372
[0841] Prepared from Example 88 by general method C1, as a pale
cream powder. MPt 119-120.degree. C.; .sup.1H-NMR (CDCl.sub.3)
.delta. 3.44(3H,s), 3.69(2H,s), 3.93(3H,s), 4.52(2H,s),
6.62(1H,bs), 6.78(2H,m), 7.2-7.5(5H,m) and 8.10(1H,m); MS (EI)
M=353; C.sub.19H.sub.19N.sub.3O.sub- .2S requires 353.
EXAMPLE 180
1-Benzyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidi-
n-4-one
[0842] 373
[0843] Prepared from intermediate B94 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.8 (12H,m), 2.55(2H,t), 3.25
(2H,t), 3.67 (2H,s), 5.00 (2H,s), 6.8-7.4 (10H,m), 8.7 (2H,s), 9.07
(1H,s); (APCI) M+H=533. C.sub.30H.sub.33ClN.sub.4OS requires
532.
EXAMPLE 181
1-(2-Phenylethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrimid-5-ylmethyl-
)pyrimidin-4-one
[0844] 374
[0845] Prepared from intermediate B93 by general method A4, as a
white crystalline solid. .sup.1H-NMR (CDCl.sub.3) .delta.
1.2-1.5(8H,m), 1.5-1.8(4H,m), 2.56(2H,t), 3.05 (2H,t), 3.29 (2H,t),
3.50(2H,s), 4.02 (2H,t), 6.36(1H,s), 7.0-7.1 (4H,m), 7.2-7.3
(5H,m), 8.47(2H,s) and 9.07(1H,s): (APCI) M+H=547.
C.sub.31H.sub.35ClN.sub.4OS requires 546.
EXAMPLE 182
1-Methyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidi-
n-4-one
[0846] 375
[0847] Prepared from intermediate B84 by general method A4 as a
white crystalline solid. .sup.1H-NMR (CDCl.sub.3) .delta.
1.2-1.5(8H,m), 1.5-1.8(4H,m), 2.56(2H,t), 3.25 (2H,t), 3.50
(3H,st), 3.70(2H,s), 6.94(1H,s), 7.09 (2H,m), 7.23 (2H,m),
8.69(2H,s) and 9.09(1H,s); (APCI) M+H=457.
C.sub.24H.sub.29ClN.sub.4OS requires 456.
EXAMPLE 183
1-Benzyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrid-4-yl)pyrimidin--
4-one
[0848] 376
[0849]
1-Benzyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-pyrimidin-4-one
was prepared from 1-benzyl-2-thiouracil and intermediate AI by
general method A4, then iodinated with iodine (1.2 equiv) and
silver trifluoromethanesulfonate (1 equiv) in chloroform at room
temperature overnight, giving
1-benzyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-iod-
opyrimidin-4-one in 27% yield after chromatography. This compound
(1 equiv) and 4-pyridylboronic acid (2 equiv) were suspended in
dimethoxyethane, 2M aqueous sodium carbonate added, followed by
tetrakis(triphenylphosphine)palladium (0.05 equiv). The mixture was
refluxed for 16 hours, then the solvent evaporated. Aqueous workup,
chromatography and crystallisation from ether gave the title
compound as a white crystalline solid. .sup.1H-NMR (CDCl.sub.3)
.delta. 1.3-1.5 (6H,m), 1.6-1.8 (4H,m), 2.94 (2H,t), 3.32 (2H,t),
5.13 (2H,s), 7.27 (2H,d), 7.4 (6H,m), 7.55 (2H,d), 7.90 (2H,d);
(APCI) M+H=532. C.sub.30H.sub.30ClN.sub.3OS requires 531.
EXAMPLE 184
1-Benzyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)py-
rimidin-4-one
[0850] 377
[0851] Prepared from intermediate B94 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.3-1.5 (4H,m), 1.6-1.8 (4H,m)2.93
(2H,t), 3.26 (2H,t), 3.67 (2H,s), 5.01 (2H,s), 6.98 (1H,s), 7.1-7.2
(2H,m), 7.4-7.5 (5H,m), 7.90 (2H,d), 8.7 (2H,s), 9.07 (1H,s);
(APCI) M+H-547. C.sub.30H.sub.31ClN.sub.4O.sub.2S requires 546.
EXAMPLE 185
1-(2-Phenylethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-yl-
methyl)pyrimidin-4-one
[0852] 378
[0853] Prepared from intermediate B93 by general method A4 as a
cream coloured crystalline solid. .sup.1H-NMR (CDCl.sub.3) .delta.
1.3-1.5(6H,m), 1.6-1.8(4H,m), 2.94(2H,t), 3.05 (2H,t), 3.30 (2H,t),
3.50(2H,s), 4.03 (2H,t), 6.37(1H,s), 7.05 (2H,m), 7.3 (3H,m), 7.43
(2H,d), 7.89 (2H,d), 8.47 (2H,s), 9.08 (1H,s); (APCI) M+H=561.
C.sub.31H.sub.33ClN.sub.4O.sub.2S requires 560.
EXAMPLE 186
1-(Fur-2-ylmethyl)-2-(2-phenylethyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-
-one
[0854] 379
[0855] Prepared from intermediate B81 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 3.02 (2H,t), 3.54 (2H,t), 3.69
(2H,s), 4.91 (2H,s), 6.38 (2H,m), 7.06 (1H,s), 7.2-7.35 (5H,m), 7.4
(1H,m), 8.7 (2H,s), 9.09 (1H,s); (APCI) M+H=405.
C.sub.22H.sub.20N.sub.4O.sub.2S requires 404.
EXAMPLE 187
1-(2-Fluorobenzyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0856] 380
[0857] Prepared from intermediate B131 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 3.70 (2H,s), 4.51 (2H,s), 5.01
(2H,s), 7.08 (11H,s), 7.1-7.2 (3H1,m), 7.2-7.4 (6H,m), 8.7 (2H,s),
9.09 (1H,s); (APCI) M+H=419. C.sub.23H.sub.19FN.sub.4OS requires
418.
EXAMPLE 188
1-(8-Phenyloctyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0858] 381
[0859] Prepared from intermediate B90 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.2-4(8H,m), 1.5-1.8(4H,m),
2.59(2H,t), 3.6-3.8(4H,m), 4.50(2H,s), 6.93(1H,s), 7.1-7.5(10H,m),
8.70(2H,s) and 9.10(1H,s); (APCI) M+H=499.
C.sub.30H.sub.34N.sub.4OS requires 498.
EXAMPLE 189
1-(9-Phenylnonyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0860] 382
[0861] Prepared from intermediate B91 by general method A4 as a
thick oil. .sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.4(10H,m),
1.5-1.85(4H,m), 2.59(2H,t), 3.6-3.8(4H,m), 4.50(2H,s), 6.94(1H,s),
7.1-7.45(1H,m), 8.69(2H,s) and 9.10(1H,s); (APCI) M+H=513.
C.sub.31H.sub.36N.sub.4OS requires 512.
EXAMPLE 190
1-Benzyl-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0862] 383
[0863] Prepared from intermediate B94 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 3.68 (2H,s), 4.51 (2H,s), 4.97
(2H,s), 7.00 (1H,s), 7.1 (2H,m), 7.2-7.4 (2H,m), 8.7(2H,s) and
9.08(1 H,s); (APCI) M+H=401. C.sub.23H.sub.20N.sub.4OS requires
400.
EXAMPLE 191
1-Benzyl-2-benzylthio-5-((1-methylpyrazol-4-yl)methyl)pyrimidin-4-one
[0864] 384
[0865] Prepared from Example 105 by general method C3, as a pale
brown oil. .sup.1H-NMR (CDCl.sub.3) .delta. 3.57 (2H,s), 3.84
(3H,s), 4.52 (2H,s), 4.93 (2H,s), 6.90 (1H,s), 7.1 (2H,s), 7.2-7.4
(10H,m); (APCI) M+H=403. C.sub.23H.sub.22N.sub.4OS requires
402.
EXAMPLE 192
1-Benzyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0866] 385
[0867] Prepared from intermediate B94 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 3.68 (2H,s), 4.48 (2H,s), 4.97
(2H,s), 7.0 (3H,m), 7.1 (2H,m), 7.3-7.4 (5H,m), 8.7 (2H,s), 9.08 (1
H,s); (APCI) M+H=419. C.sub.23H.sub.19FN.sub.4OS requires 418.
EXAMPLE 193
1-(2,2-Dimethylprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyr-
imidin-4-one
[0868] 386
[0869] Prepared from intermediate B74 by general method A4 as a
oil. .sup.1H-NMR (CDCl.sub.3) .delta. 0,96(9H,s), 3.61(2H,s),
3.72(2H,s), 4.46(2H,s), 6.85-7.1(3H,m), 7.3-7.45(2H,m), 8.70(2H,s)
and 9.1 1(1H,s); (APCI) M+H=399. C.sub.21H.sub.23FN.sub.4OS
requires 398.
EXAMPLE 194
1-(2-Phenylethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0870] 387
[0871] Prepared from intermediate B93, by general method A4, as a
cream coloured crystalline solid. .sup.1H-NMR (CDCl.sub.3) .delta.
3.02 (2H,t), 3.51 (2H,s), 4.00 (2H,t), 4.55 (2H,s), 6.37 (1H,s),
7.0 (2H,m), 7.2-7.4 (8H,m), 8.47 (2H,s), 9.09 (1H,s); (APCI)
M+H=415. C.sub.24H.sub.22N.sub.4- OS requires 414.
EXAMPLE 195
1-(Fur-2-ylmethyl)-2-(4-methylbenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin--
4-one
[0872] 388
[0873] Prepared from intermediate B81 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 2.33 (3H,s), 3.70 (2H,s), 4.49
(2H,s), 4.90 (2H,s), 6.3-6.4 (2H,m), 6.84 (1H,s), 7.08 (2H,d), 7.33
(2H,d), 7.41 (1H,m), 8.7 (2H,s), 9.10 (1H,s); (APCI) M+H=405.
C.sub.22H.sub.20N.sub.4O.sub.2S requires 404.
EXAMPLE 196
1-(Fur-2-ylmethyl)-2-(2-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin--
4-one
[0874] 389
[0875] Prepared from intermediate B93 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 3.70 (2H,s), 4.56 (2H,s), 4.90
(2H,s), 6.37 (1H,m), 6.41 (1H,m), 7.1 (3H,m), 7.3 (1H,m), 7.41
(1H,m), 7.55 (1H,m), 8.7 (2H,s), 9.10 (1H,s), (APCI) M+H=409.
C.sub.21H.sub.17FN.sub.4O.sub.2S requires 408.
EXAMPLE 197
1-(Fur-2-ylmethyl)-2-(4-chlorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin--
4-one
[0876] 390
[0877] Prepared from intermediate B81 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 3.69 (2H,s), 4.48 (2H,s), 4.90
(2H,s), 6.38 (2H,m), 7.06 (1H,m), 7.28 (2H,d), 7.35 (2H,d), 7.42
(1H,m), 8.7 (2H,s), 9.10 (1H,s); (APCI) M+H=425, 2M+H=849.
C.sub.21H.sub.17ClN.sub.4O.sub.2S requires 424.
EXAMPLE 198
1-(Fur-2-ylmethyl)-2-(3-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin--
4-one
[0878] 391
[0879] Prepared from intermediate B81 by general method A4. H-NMR
(CDCl.sub.3) .delta. 3.70 (2H,s), 4.51 (2H,s), 4.90 (2H,s), 6.38
(1H,m), 6.41 (1H,m), 7.0 (1H,m), 7.1-7.3 (5H,m), 7.42 (1H,m), 8.7
(2H,s), 9.10 (1H,s); (APCI) M+H=409.
C.sub.21H.sub.17FN.sub.4O.sub.2S requires 408.
EXAMPLE 199
1-(Fur-2-ylmethyl)-2-(3-chlorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin--
4-one
[0880] 392
[0881] Prepared from intermediate B81 by general method A4, as an
orange oil. .sup.1H-NMR (CDCl.sub.3) .delta. 3.69 (2H,s),
4.47(2H,s), 4.93 (2H,s), 6.38 (1H,m), 6.41 (1H,m), 7.12 (1H,s),
7.2-7.4 (5H,m), 8.7 (2H,s), 9.08 (1H,s); (APCI) M+H=425.
C.sub.21H.sub.17ClN.sub.4O.sub.2S requires 424.
EXAMPLE 200
1-Methyl-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0882] 393
[0883] Prepared from intermediate B84 by general method A4, as an
off-white crystalline solid. .sup.1H-NMR (CDCl.sub.3) .delta. 3.49
(3H,s), 3.71 (2H,s), 4.51 (2H,s), 6.96 (1H,s), 7.2-7.5 (5H,m), 8.70
(2H,s), 9.10 (1H,s), (APCI) M+H=325. C.sub.17H.sub.16N.sub.4OS
requires 324.
EXAMPLE 201
1-((R)-Tetrahydofuran-2-ylmethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrim-
idin-4-one
[0884] 394
[0885] Prepared from intermediate B133 by general method A4. White
solid. .sup.1H-NMR (CDCl.sub.3) .delta. 1.37-1.60 (1H, m),
1.81-2.14 (3H, m), 3.53-3.87 (5H, m), 3.99-4.18 (2H, m), 4.50 (1H,
s), 7.18(1H, s), 7.28-7.44 (5H, m), 8.72 (2H, s), 9.09 (11H, s); MS
(APCI+) found (M+1)=395 C.sub.21H.sub.22N.sub.4O.sub.2S requires
394.
EXAMPLE 202
1-((S)-Tetrahydofuran-2-ylmethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrim-
idin-4-one
[0886] 395
[0887] Prepared from intermediate B132 by general method A4, as a
white solid. .sup.1H-NMR (CDCl.sub.3) .delta. 1.37-1.58 (1H, m),
1.8-2.12 (3H, m), 3.55-3.88 (5H, m), 3.98-4.19 (2H, m), 4.5 (2H,
s), 7.17 (11H, s), 7.29-7.44 (5H, m), 8.70 (2H, s), 9.02(11H, s);
MS (APCI+) found (M+1)=395; C.sub.21H.sub.22N.sub.4O.sub.2S
requires 394.
EXAMPLE 203
1-(4-Fluorobenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin--
4-one
[0888] 396
[0889] Prepared from intermediate B99 by general method A2. as an
orange solid. .sup.1H-NMR (CDCl.sub.3) .delta. 3.68 (2H, s), 4.47
(2H, s), 4.94 (2H, s), 6.92-7.20 (7H, m), 7.28-7.41 (2H, m), 8.66
(2H, s), 9.08 (1H, s); MS (APCI+) found (M+1)=437;
C.sub.23H.sub.18F.sub.2N.sub.4OS requires 436.
EXAMPLE 204
1-(4-Bromobenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-
-one
[0890] 397
[0891] Prepared from intermediate B115 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 3.68 (2H, s), 4.46 (2H, s), 4.91
(2H, s), 7.01 (5H, m), 7.35 (2H, m), 7.50 (2H, m), 8.70 (2H, s),
9.09 (1H, s), MS(APCI+) M+1=497, C.sub.23H.sub.18BrFN.sub.4OS
requires 496. MPt 162.2.degree. C. (cream solid). MPt, 162.2.
EXAMPLE 205
1-(2-(6-(4-Fluorophenyl)hex-1-yloxy)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrim-
id-5-ylmethyl)pyrimidin-4-one
[0892] 398
[0893] Prepared from intermediate B109 by general method A2 as an
oil. .sup.1H-NMR (CDCl.sub.3) .delta. 1.15-1.72 (8H, m), 2.50-2.63
(2H, t), 3.28-3.30 (2H, t), 3.55-3.64 (2H, t), 3.69 (2H, s),
3.89-3.98 (2H, t), 4.47(2H, s), 6.88-7.43 (9H, m), 8.69 (2H, s),
9.08 (1H, s); MS (APCI+) found (M+1)=551;
C.sub.30H.sub.32F.sub.2N.sub.4O.sub.2S requires 550.
EXAMPLE 206
1-(2-Phenoxyethyl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimi-
din-4-one
[0894] 399
[0895] Prepared from intermediate B101 by general method A2 as a
solid. .sup.1H-NMR (CDCl.sub.3) .delta. 3.72 (2H, s), 4.10-4.29
(4H, m), 4.47 (2H, s), 6.70-6.80 (2H, d), 6.95-7.39 (7H, m), 8.70
(2H, s), 9.12 (1H,s); MS (ES+) found (M+1)=467;
C.sub.24H.sub.20F.sub.2N.sub.4O.sub.2S requires 466.
EXAMPLE 207
1-(3-(5-Phenylpent-1-yloxy)prop-1-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)p-
yrimidin-4-one
[0896] 400
[0897] Prepared from intermediate B139 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.35 (2H, m), 1.59 (4H, m), 1.95
(2H, m), 2.60 (2H, t), 3.32 (4H, m), 3.68 (2H, s), 3.87 (2H, t),
4.50 (2H, s), 7.01 (1H, s), 7.14-7.38 (1OH, m), 8.68(2H, s) 9.08
(1H, s); MS (APCI+) found (M+1)=515;
C.sub.30H.sub.34N.sub.4O.sub.2S requires 514.
EXAMPLE 208
1-(9-Phenylnonyl)-2-furfurylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0898] 401
[0899] Prepared from intermediate B91 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.28 (10H, m), 1.65 (4H, m), 2.60
(2H, t), 3.69 (4H, m), 4.56 (2H, s), 6.30 (1H, m), 6.40 (1H, m),
6.98 (1H, s), 7.14-7.36 (6H, m), 8.69 (2H, s), 9.10 (1H, s); MS
(APCI+) found (M+1)=503; C.sub.29H.sub.34N.sub.4O.sub.2S requires
502.
EXAMPLE 209
1-(9-Phenylnonyl)-2-(thiazol-2-ylmethyl)thio-5-(pyrimid-5-ylmethyl)pyrimid-
in-4-one
[0900] 402
[0901] Prepared from intermediate B91 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.28 (10H, m), 1.65 (4H, m), 2.60
(2H, t), 3.72 (2H, s), 3.75 (2H, t), 4.85 (2H, s), 6.97 (1H, s),
7.14-7.30 (6H, m), 7.71 (1H, d), 8.71 (2H, s), 9.11 (1H, s); MS
(APCI+) found (M+1)=520; C28H33N5S2 requires 519.
EXAMPLE 210
1-(9-Phenylnonyl)-2-(thien-2-ylmethyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-
-4-one
[0902] 403
[0903] Prepared from intermediate B91 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.28 (10H, m), 1.64 (4H, m), 2.60
(2H, t), 3.75 (4H, m), 4.73 (2H, s), 6.94 (2H, m), 7.09 (1H, m),
7.15-7.27 (6H, m), 8.73 (2H, s), 9.10 (1H, s); MS (APCI+) found
(M+1)=519; C.sub.29H.sub.34N.sub.4OS.sub.2 requires 518.
EXAMPLE 211
1-(9-Phenylnonyl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimid-
in-4-one
[0904] 404
[0905] Prepared from intermediate B91 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.28 (10H, m), 1.60 (4H, m), 2.59
(2H, t), 3.71 (4H, m), 4.44 (2H, s), 6.95 (1H,s), 7.10-7.27 (8H,m),
8.70 (2H, s), 9.10 (1H, s); MS (APCI+) found (M+1)=549;
C.sub.31H.sub.34F.sub.2N.sub.4OS requires 548.
EXAMPLE 212
1-(2-(2-Pent-1-ylphenyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethy-
l)pyrimidin-4-one
[0906] 405
[0907] Prepared from intermediate B117 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 0.87 (3H, t), 1.25 (4H, m), 1.45
(2H, m), 2.39 (2H, t), 3.04 (2H, t), 3.50 (2H, s), 3.97 (2H, t),
4.52 (2H, s), 6.31 (1H, s), 6.94-7.21 (8H, m), 7.40 (2H, m), 8.50
(2H, s), 9.09 (1H, s), MS(APCI+) M+1=503,
C.sub.29H.sub.31FN.sub.4OS requires 502. MPt 112.3.degree. C.
(colourless solid).
EXAMPLE 213
1-(2-(3-Pent-1-ylphenyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethy-
l)pyrimidin-4-one
[0908] 406
[0909] Prepared from intermediate B116 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 0.89 (3H, m), 1.30 (4H, m), 1.50
(2H, m), 2.52 (2H, t), 2.98 (2H, t), 3.51 (2H, s), 3.98 (2H, t),
4.51 (2H, s), 6.41 (11H, s), 6.80-7.16 (6H, m), 7.41 (2H, m), 8.49
(2H, s), 9.08 (11H, s), MS(APCI+) M+1=503,
C.sub.29H.sub.31FN.sub.4OS requires 502. MPt 93.2.degree. C.
(colourless solid).
EXAMPLE 214
1-(2-(4-Bromophenyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)py-
rimidin-4-one
[0910] 407
[0911] Prepared from intermediate B114 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 2.97 (2H, t), 3.59 (2H, s), 3.95
(2H, t), 4.49 (2H, s), 6.50 (1H, s), 6.89-7.05 (4H, m), 7.35-7.44
(4H, m), 8.58 (2H, s), 9.11 (1H, s), MS(APCI+) M+1=511,
C.sub.24H.sub.20BrFN.sub.4OS requires 510. MPt 151.6.degree. C.
(cream solid).
EXAMPLE 215
1-(5-Methylfuran-2-ylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-
pyrimidin-4-one
[0912] 408
[0913] Prepared from intermediate B98 by general method A2 as a
pale yellow solid. .sup.1H-NMR (CDCl.sub.3) .delta. 1.64 (3H, s),
3.70 (2H, s), 4.49 (2H, s), 4.83 (2H, s), 5.95 (1H, d), 6.28 (1H,
d), 6.94-7.09 (3H, m), 7.33-7.45 (2H, m), 8.69 (2H, s), 9.09 (1H,
s), MS (APCI+) found (M+1)=423; C.sub.22H.sub.19FN.sub.4O.sub.2S
requires 422.
EXAMPLE 216
1-(2-(2-Chlorophenyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)p-
yrimidin-4-one
[0914] 409
[0915] Prepared from intermediate B100 by general method A2 as a
pale yellow solid. .sup.1H-NMR (CDCl.sub.3) .delta. 3.10-3.23 (2H,
t), 3.51 (2H, s), 4.00-4.12 (2H, t), 4.51 (2H, t), 6.42 (1H, s),
6.90-7.48 (8H, m), 8.48 (2H, s), 9.09 (1H, s); MS (APCI+) found
(M+1)=467; C.sub.24H.sub.20ClFN.sub.4OS requires 466.
EXAMPLE 217
1-(2-(Thien-2-yl)ethyl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)p-
yrimidin-4-one
[0916] 410
[0917] Prepared from intermediate B97 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 3.26 (2H, t), 3.55 (2H, s), 4.02
(2H, t), 4.48 (2H, s), 6.51 (1H, s), 6.67 (1H, m), 6.91 (1H, m),
7.05-7.27 (4H, m), 8.53(2H, s) 9.09 (1H, s); MS (APCI+) found
(M+I)=457; C.sub.22H.sub.18F.sub.2N.sub- .4OS.sub.2 requires
456.
EXAMPLE 218
1-(2-Phenylethyl)-2-(2,3,4-trifluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyri-
midin-4-one
[0918] 411
[0919] Prepared from intermediate B93 by general method A3 as a
pale yellow foam .sup.1H-NMR (CDCl.sub.3) .delta. 3.02 (2H, t),
3.51 (2H,s), 3.99 (2H,t), 4.55 (2H,s), 6.42 (1H,s), 6.8-7.1 (3H,m),
7.2-7.45 (4H,m), 8.48 (2H,s), 9.09 (1H,s); MS (APCI+) found
(M+1)=469; C.sub.24H.sub.19F.sub.3N.sub.4OS requires 468.
EXAMPLE 219
1-(2-Phenylethyl)-2-(2,3,5-trifluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyri-
midin-4one
[0920] 412
[0921] Prepared from intermediate B93 by general method A3 as a
white solid .sup.1H-NMR (CDCl.sub.3) .delta. 3.02 (2H, t), 3.52
(2H,s), 3.99 (2H,t), 4.51 (2H,s), 6.40 (1H,s), 6.85-7.1 (3H,m),
7.2-7.35 (3H,m), 7.4-7.55 (1H,m), 8.5 (2H,s), 9.09 (1H,s); MS
(APCI+) found (M+1)=469; C.sub.24H.sub.19F.sub.3N.sub.4OS requires
468.
EXAMPLE 220
1-(2-Phenylethyl)-2-(2,4,6-trifluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyri-
midin-4-one
[0922] 413
[0923] Prepared from intermediate B93 by general method A3 as a
white solid .sup.1H-NMR (CDCl.sub.3) .delta. 3.02 (2H, t), 3.51
(2H,s), 3.99 (2H,t), 4.60 (2H,s), 6.38 (1H,s), 6.6-6.8 (2H,m),
7.0-7.1 (2H,m), 7.2-7.3 (3H,m), 8.48 (2H,s), 9.09 (1H,s); MS
(APCI+) found (M+1)=469; C.sub.24H.sub.19F.sub.3N.sub.4OS requires
468.
EXAMPLE 221
1-(2-Phenylethyl)-2-(2,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimid-
in-4one
[0924] 414
[0925] Prepared from intermediate B93 by general method A2 as a
pale yellow solid. .sup.1H-NMR (CDCl.sub.3) .delta. 2.95-3.08 (2H,
t), 3.51 (2H, s), 3.94-4.05 (2H, t), 4.54 (2H, s), 6.39 (1H, s),
6.74-6.91 (2H, m), 6.95-7.06 (2H, m), 7.18-7.34 (3H, m), 7.52-7.67
(1H, m), 8.48 (2H, s), 9.09 (I H, s); MS (APCI+) found (M+1)=451;
C.sub.24H.sub.20F.sub.2N.s- ub.4OS requires 450.
EXAMPLE 222
1-(2-Phenylethyl)-2-(2-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-
-one
[0926] 415
[0927] Prepared from intermediate B93 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 2.95-3.09 (2H, t), 3.49 (2H, s),
3.92-4.06 (2H, t), 4.59 (2H, s), 6.38 (1H, s), 6.94-7.37 (8H, m),
7.50-7.63 (1H, t), 8.49 (2H, s), 9.08 (1H, s): MS (APCI+) found
(M+1)=433; C.sub.24H.sub.21FN.sub.4OS requires 432.
EXAMPLE 223
1(2Phenylethyl)-1-furfurylthio-5(pyrimid-5ylmethyl)pyrimidin-4-one
[0928] 416
[0929] Prepared from intermediate B93 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 3.03 (2H, t), 3.51 (2H, s), 4.00
(2H, t), 4.62 (2H, s), 6.41 (3H, m), 7.03 (2H, m), 7.27 (3H, m),
7.38 (1H, m), 8.46 (2H, s), 9.09 (1H, s); MS (APCI+) found
(M+1)=405; C.sub.22H.sub.20N.sub.4O.sub.2S requires 404.
EXAMPLE 224
1-(2-Phenylethyl)-2-(thien-2-ylmethyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-
-4-one
[0930] 417
[0931] Prepared from intermediate B93 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 3.03 (2H, t), 3.51 (2H, s), 3.99
(2H, t), 4.78 (2H, s), 6.36 (1H, s), 6.93-7.02 (3H, m), 7.12 (1H,
m), 7.22-7.28 (4H, m), 8.48 (2H, s), 9.09 (1H, s); MS (APCI+) found
(M+1)=421; C.sub.22H.sub.20N.sub.4OS.sub.2 requires 420.
EXAMPLE 225
1-(2-Phenylethyl)-2-(3,4,5-trifluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyri-
midin-4-one
[0932] 418
[0933] Prepared from intermediate B93 by general method A3 as a
pale yellow foam. .sup.1H-NMR (CDCl.sub.3) .delta. 3.03 (2H, t),
3.52 (2H,s), 4.02 (2H,t), 4.45 (2H,s), 6.46 (1H,s), 6.95-7.2
(4H,m), 7.2-7.4 (3H,m), 8.49 (2H,s), 9.09 (1H,s); MS (APCI+) found
(M+1)=469; C.sub.24H.sub.19F.sub.3N.sub.4OS requires 468.
EXAMPLE 226
1-(2-Phenylethyl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimid-
in-4-one
[0934] 419
[0935] Prepared from intermediate B93 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 2.95-3.10 (2H, t), 3.52 (2H, s),
3.95-4.07 (2H, t), 4.49 (2H, s), 6.39 (1H, s), 6.96-7.36 (8H, m),
8.48 (2H, s), 9.09 (1H, s); MS (APCI+) found (M+1)=451,
C.sub.24H.sub.20F.sub.2N.sub.4OS requires 450.
EXAMPLE 227
1-(2-Phenylethyl)-2-(3,5-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimid-
in-4-one
[0936] 420
[0937] Prepared from intermediate B93 by general method A2 as a
pale yellow solid. .sup.1H-NMR (CDCl.sub.3) .delta. 2.97-3.10 (2H,
t), 3.52 (2H, s), 3.95-4.16 (2H, t), 4.51 (2H, s), 6.40 (1H, s),
6.66-6.80 (1H, m), 6.89-7.08 (4H, m),:7.18-7.37 (3H, m), 8.49 (2H,
s), 9.09 (1H, s); MS (APCI+) found (M+1)=451;
C.sub.24H.sub.20F.sub.2N.sub.4OS requires 450.
EXAMPLE 228
1-(2-Phenylethyl)-2-(3-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-
-one
[0938] 421
[0939] Prepared from intermediate B93 by general method A2 as a
pale yellow solid. .sup.1H-NMR (CDCl.sub.3) .delta. 2.95-3.09 (2H,
s), 3.52 (2H, s), 3.94-4.07 (2H, t), 4.53 (2H, s), 6.39 (1H, s),
6.90-7.38 (9H, m), 8.48 (2H, s), 9.09 (1H, s); MS (APCI+) found
(M+1)=433; C.sub.24H.sub.21FN.sub.4OS, requires 432.
EXAMPLE 229
1-(2-Phenylethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-
-one
[0940] 422
[0941] Prepared from intermediate B93 by general method A2 as a
pale yellow solid. .sup.1H-NMR (CDCl.sub.3) .delta. 2.98-3.10 (2H,
t), 3.49 (2H, s), 3.94-4.06 (2H, s), 4.51 (2H, s), 6.39 (1H, s),
6.94-7.08 (4H, m), 7.20-7.33 (3H, m), 7.36-7.48 (2H, m), 8.48 (2H,
s), 9.09 (1H, s); MS (APCI+) found (M+1)=433;
C.sub.24H.sub.21FN.sub.4OS requires 432.
EXAMPLE 230
1-(2-Phenylethyl)-2-(1-phenylethyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4--
one
[0942] 423
[0943] Prepared from intermediate B93 by general method A2 as a
pale yellow solid. .sup.1H-NMR (CDCl.sub.3) .delta. 1.82 (2H, t),
2.99 (2H,t), 3.50 (2H,s), 3.85-4.1 (2H,m), 5.35 (1H,q), 6.34
(1H,s), 6.9-7.05 (2H,m), 7.15-7.5 (8H,m), 8.49 (2H,s), 9.09 (1H,s);
MS (APCI+) found (M+1)=429; C.sub.25H.sub.24N.sub.4OS requires
428.
EXAMPLE 231
1-(2-(4-Methoxyphenyl)ethyl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmet-
hyl)pyrimidin-4-one
[0944] 424
[0945] Prepared from intermediate B134 by general method A2 as a
white solid. .sup.1H-NMR (CDCl.sub.3) .delta. 2.91-3.02 (2H, t),
3.59 (2H, s), 3.84 (3H, s), 3.90-4.02 (2H, t), 4.48 (2H, s), 6.42
(1H, s), 6.73-7.31 (7H, m), 8.51 (2H, s), 9.10 (1H, s); MS (APCI+)
found (M+1)=481; C.sub.25H.sub.22F.sub.2N.sub.4O.sub.2S requires
480.
EXAMPLE 232
1-(2-(4-Pent-1-ylphenyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethy-
l)pyrimidin-4-one
[0946] 425
[0947] Prepared from intermediate B112 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 0.88 (3H, t), 1.32 (4H, m), 1.60
(2H, m), 2.60 (2H, m), 2.97 (2H, m), 3.52 (2H, s), 3.97 (2H, t),
4.51 (2H, s),6.46 (1H, s), 6.84-7.11 (6H, m), 7.40 (2H, m), 8.50
(2H, s), 9.08 (1H, s); MS(APCI+) M+1=503,
C.sub.29H.sub.31FN.sub.4OS requires 502. MPt 98.7.degree. C.
(colourless solid).
EXAMPLE 233
1-(Cycloprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-pyrimidin-
-4-one
[0948] 426
[0949] Prepared from intermediate B105 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 0.94-1.32 (4H, m), 3.03-3.18 (1H,
m), 3.69 (2H, s), 4.42 (2H, s), 6.93-7.07 (2H, t), 7.14 (1H, s),
7.31-7.45 (2H, m), 8.70 (2H, s), 9.10 (1H, s); MS (APCI+) found
(M+1)=369; C.sub.19H.sub.17FN.sub.4OS requires 368.
EXAMPLE 234
1-(Dodec-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin--
4-one
[0950] 427
[0951] Prepared from intermediate B96 by general method A2 as an
oil. .sup.1H-NMR (CDCl.sub.3) 30.78-0.85 (3H, t), 1.13-1.70 (20H,
m), 3.65-3.80 (4H, m), 4.45 (2H, s), 6.92-7.27 (4H, s), 8.70 (2H,
s), 9.11 (1H, s); MS (APCI+) found (M+1)=515;
C.sub.28H.sub.36F.sub.2N.sub.4OS requires 514.
EXAMPLE 235
1-Ethyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0952] 428
[0953] Prepared from intermediate B89 by general method A2 as a
solid. .sup.1H-NMR (CDCl.sub.3) .delta. 1.30-1.44 (3H, t), 3.72
(2H, s), 3.75-3.90 (2H, q), 4.47 (2H, s), 6.94-7.17 (3H, m),
7.33-7.45 (2H, m), 8.70 (2H, S), 9.10 (1H, s); MS (APCI+) found
(M+1)=357; C.sub.18H.sub.17FN.sub.4OS requires 356.
EXAMPLE 236
1-(1-Methylethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-
-one
[0954] 429
[0955] Prepared from intermediate B104 by general method A2 as a
solid. .sup.1H-NMR (CDCl.sub.3) .delta. 1.32-1.45 (6H, d), 3.73
(2H, s), 4.46 (2H, s), 4.49-4.65 (1H, m), 6.94-7.05 (2H, t), 7.17
(1H, s), 7.33-7.45 (2H, m), 8.72 (2H, s), 9.10 (1H, s); MS (APCI+)
found (M+1)=371; C.sub.19H.sub.19FN.sub.4OS requires 370.
EXAMPLE 237
1-Methyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0956] 430
[0957] Prepared from intermediate B84 by general method A2 as a
solid. .sup.1H-NMR (CDCl.sub.3) .delta. 3.49 (3H, s), 3.71 (2H, s),
4.48 (2H, s),6.93-7.07 (3H, m), 7.32-7.44 (2H, m), 8.70 (2H, s),
9.10 (1H, s); MS (APCI+) found (M+1)=343;
C.sub.17H.sub.15FN.sub.4OS requires 342.
EXAMPLE 238
1-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-on-
e
[0958] 431
[0959] Prepared from intermediate B95 by general method A2 as an
oil. .sup.1H-NMR (CDCl.sub.3) .delta. 0.82-0.98 (3H, t), 1.13-1.80
(18H, m), 3.65-3.79 (4H, m), 4.47 (2H, s), 6.90-7.07 (3H, m),
7.31-7.43 (2H, m), 8.70 (2H, s)9.10 (1H, s); MS (APCI+) found
(M+1)=483; C.sub.27H.sub.35FN.sub.4OS requires 482.
EXAMPLE 239
1-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(2-oxopyrimid-5-ylmethyl)pyrimidin-
-4-one
[0960] 432
[0961] To a solution of either Example 243 or 244 (0.2 g) in dry
methylene chloride (4 ml) at 4.degree. C. was added boron
tribromide (1M in methylene chloride, 2 ml). The mixture was
stirred under argon for 24 h and poured into a: mixture of ice (50
ml) and 0.880 ammonia (15 ml) with stirring. Extraction with 5%
methanol:methylene chloride was followed by filtration through
kieselguhr and drying the organic layer over sodium sulphate.
Removal of the solvent in vacuo gave the desired material as a grey
solid (0.15 g). .sup.1H-NMR (CDCl.sub.3) .delta. 0.8-0.95 (3H,m),
1.1-1.4 (16H,m), 1.6-1.85 (2H,m), 3.49 (2H,s), 3.79 (2H,t), 4.45
(2H,s), 6.9-7.1 (2H,m), 7.2-7.45 (3H,m), 8.32 (2H,s); MS (APCI+)
found (M+1)=499; C.sub.27H.sub.35FN.sub.4O.sub.2S requires 498.
EXAMPLE 240
1-Benzyl-2-benzylthio-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-one
[0962] 433
[0963] Prepared from Example B39 by alkylation with benzyl bromide
using general method A4, followed by N-alkylation using general
method C2. .sup.1H-NMR (CDCl.sub.3) .delta. 3.62 (2H, s), 3.98 (3H,
s), 4.51 (2H, s), 4.96 (2H, s), 6.92 (1H, s), 7.10 (1H, m),
7.23-7.40 (9H,m), 8.41 (2H, s); MS (APCI+) found (M+1)=431;
C.sub.24H.sub.22N.sub.4O.sub.2S requires 430.
EXAMPLE 241
1-(2-Phenylethyl)-2-(3,4-difluorobenzyl)thio-5-(2-methoxypyrimid-5-ylmethy-
l)pyrimidin-4-one
[0964] 434
[0965] Prepared from Example 107 by general method C3. .sup.1H-NMR
(CDCl.sub.3) .delta. 3.01 (2H, t), 3.46 (2H, s), 3.99 (2H, t), 4.01
(3H, s), 4.49 (2H, s), 6.33 (1H, s), 6.99-7.29 (8H, m), 8.22 (2H,
s): MS (APCI+) found (M+1)=481;
C.sub.25H.sub.22F.sub.2N.sub.4O.sub.2S requires 480.
EXAMPLE 242
1-(Furan-2-ylmethyl)-2-(3,4-difluorobenzyl)thio-5-(2-methoxypyrimid-5-ylme-
thyl)pyrimidin-4-one
[0966] 435
[0967] Prepared from Example 107 by general method C3. .sup.1H-NMR
(CDCl.sub.3) .delta. 3.63 (2H, s), 4.00 (3H, s), 4.46 (2H, s), 4.90
(2H, s), 6.38 (2H, m), 7.01 (1H, s), 7.07-7.26 (3H, m), 7.42 (1H,
m), 8.44 (2H, s); MS (APCI+) found (M+1) 457;
C.sub.22H.sub.18F.sub.2N.sub.4O.sub.- 3S requires 456.
EXAMPLE 243
1-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(2-methoxypyrimid-5-ylmethyl)pyrim-
idin-4-One
[0968] 436
[0969] Prepared from intermediate B124 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 0.88 (3H, t), 1.25 (16H, m), 1.68
(2H, m), 3.64 (2H, s), 3.71 (2H, t), 4.00 (3H, s), 4.47 (2H, s),
6.87 (1H, s), 7.00 (2H, m), 7.36(2H, m), 8.46(2H, s); MS (APCI+)
found (M+1)=513; C.sub.23H.sub.37N.sub.4O.sub.1S requires 512.
EXAMPLE 244
1-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(2-ethoxypyrimid-5-ylmethyl)pyrimi-
din-4-one
[0970] 437
[0971] Prepared from intermediate B92 by general method A3 as an
off-white solid. .sup.1H-NMR (CDCl.sub.3) .delta. 0.8-0.95 (3H,m),
1.15-1.4 (16H,m), 1.43 (3H,t), 1.55-1.8 (2H,m), 3.68 (2H,s), 3.71
(2H,t), 4.41 (2H,q), 4.47 (2H,s), 6.86 (1H,s), 6.9-7.1 (2H,m),
7.3-7.45 (2H,m), 8.45 (2H,d): MS (APCI+) found (M+1)=527;
C.sub.19H.sub.39FN.sub.4O.sub.2S requires 526.
EXAMPLE 245
1-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(2-methylpyrimid-5-ylmethyl)pyrimi-
din-4-one
[0972] 438
[0973] Prepared from intermediate B135 by general method A2. H-NMR
(CDCl.sub.3) .delta. 0.88 (3H, t), 1.25 (16H, m), 1.68 (2H, m),
2.72 (3H, s), 3.68 (2H, s), 3.72 (2H, t), 4.47 (2H, s), 6.89 (1H,
s), 6.97 (2H, m), 7.38 (2H, m), 8.58(2H, s); MS (APCI+) found
(M+1)=497; C.sub.28H.sub.37N.sub.4OS requires 496.
EXAMPLE 246
1-(2-Phenylethyl)-2-(4-fluorobenzyl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)met-
hyl)pyrimidin-4-one
[0974] 439
[0975] Prepared from intermediate B70 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 3.01 (2H, t), 3.40 (2H, s), 3.51
(3H, s), 3.97 (2H, t), 4.51 (2H, s), 6.02 (1H, m), 6.24 (1H, s),
6.49 (1H, s), 6.98-7.43 (1OH, m); MS (APCI+) M+1=462;
C.sub.26H.sub.24FN.sub.3O.sub.2S requires 461. MPt 69-75.degree. C.
(cream solid).
EXAMPLE 247
1-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl-
)pyrimidin-4-one
[0976] 440
[0977] Prepared from intermediate B110 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 0.88 (3H, t), 1.25 (16H, m), 1.69
(2H, m), 3.50 (3H, s), 3.55 (2H, s), 3.71 (2H, t), 4.78 (2H, s),
6.17 (1H, m), 6.38 (1H, d), 6.84 (1H, s), 6.96 (2H, m), 7.19 (1H,
m), 7.39 (2H, m); MS (APCI+) M+1=512,
C.sub.29H.sub.38FN.sub.3O.sub.2S requires 511. MPt 78-79.degree. C.
(colourless solid).
EXAMPLE 248
1-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(1-methyl-2-oxopyrimid-5-ylmethyl)-
pyrimidin-4-one
[0978] 441
[0979] Prepared from Example 239 by treatment with methyl iodide (1
equiv) and potassium carbonate (2 equiv) in DMF. The misture was
stirred at room temperature for 16 hours, then at 50.degree. C. for
1 hour. Evaporation of the solvent, aqueous workup and
chromatography gave the title compound in 72% yield. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.8-0.95 (3H,m), 1.15-1.4 (16H,m), 1.6-1.85
(2H,m), 3.43 (2H,bs), 3.54 (3H,s), 3.78 (2H,t), 4.46 (2H,s),
6.9-7.1 (2H,m), 7.1.sup.9 (1H,s), 7.25-7.45 (2H,m), 8.01 (1H,bd),
8.46 (1H,m).
EXAMPLE 249
1-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(1-benzyl-2-oxopyrimid-5-ylmethyl)-
pyrimidin-4-one
[0980] 442
[0981] Prepared from Example 239 analogously to Example 248, using
benzyl bromide in place of methyl iodide. .sup.1H-NMR (CDCl.sub.3)
.delta. 0.8-0.95 (3H,m), 1.15-1.4 (16H,m), 1.6-1.85 (2H,m), 3.39
(2H,s), 3.74 (2H,t), 4.46 (2H,s), 5.08 (2H,s), 6.9-7.1 (3H,m),
7.25-7.45 (7H,m), 7.94 (1H,d), 8.43 (1H,d); MS (APCI+) found
(M+1)=589; C.sub.34H.sub.41FN.sub.4- O.sub.2S requires 588.
EXAMPLE 250
1-(Undec-1-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0982] 443
[0983] Prepared from intermediate B95 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 0.88 (3H,t), 1.25 (16H,brs), 1.71
(2H,m), 3.71 (2H,s), 3.74 (2H,m),-4.49 (2H,s), 7.04 (1H,s),
7.26-7.41 (5H,m), 8.69 (2H,s), 9.09 (1H,s); MS (APCI) found
(M+H)=465; C.sub.27H.sub.36N.sub.4OS requires 464.
EXAMPLE 251
1-Methyl-2-(4-fluorobenzyl)thio-5-(2-methoxypyrimid-5-ylmethyl)
pyrimidin-4-one
[0984] 444
[0985] Prepared from Example 108 by general method C2. .sup.1H-NMR
(CDCl.sub.3) .delta. 3.47 (3H,s), 3.64 (2H,t), 3.99 (3H,s), 4.47
(2H,s), 6.88 (1H,s), 6.9-7.1 (2H,m), 7.3-7.5 (2H,m), 8.44 ,-(2H,s);
MS (APCI+) found (M+1) 373; C.sub.18H.sub.17FN.sub.4O.sub.2S
requires 372.
EXAMPLE 252
1-Methyl-2-(4-fluorobenzyl)thio-5-(2-oxopyrimid-5-ylmethyl)pyrimidin-4-one
[0986] 445
[0987] To a solution of Example 251 (5 g) in dry methylene chloride
was added a solution of boron tribromide 1M in dichloromethane (50
ml) at 5.degree. C. under argon with stirring. After 0.5 h, the
mixture was allowed to warm to room temperature and was allowed to
stir at room temperature for 72 h. The mixture was decanted into a
mixture of ice (50 ml) and 0.880 ammonia (50 ml). The solid
remaining in the flask was treated with some of the aqueous mixture
and 10% methanol in methylene chloride. The entire mixture was
filtered through kieselguhr and the organic layer was separated.
The aqueous layer was reduced to one quarter volume in vacuo and
the solid formed filtered off, washed with water and dried in vacuo
to give the desired product (2.2g). .sup.1H-NMR (d.sub.6 DMSO)
.delta. 3.30 (2H,s), 3.47 (3H,s), 4.41 (2H,s), 7.05-7.25 (2H,m),
7.4-7.55 (2H,m), 7.65 (1H,s), 7.85-8.3 (2H,b): MS (APCI+) found
(M+1)=359; C.sub.17H.sub.15FN.sub.4O.sub.2S requires 358.
EXAMPLE 253
1-(4-Acetylphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-pyrimidin-
-4-one
[0988] 446
[0989] Prepared from intermediate B136 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 2.64(3H,s), 3.79(2H,s),
4.39(2H,s), 6.95(2H,m), 7.05(1H,s), 7.29(2H,m), 7.43(2H,d,j=8.5
Hz), 8.08(2H,dj=8.5), 8.75(2H,s), 9.09(1H,s): MS (APCI) found
(M+H)=447; C.sub.24H.sub.19FN.sub.4O.sub.2S requires 446.
EXAMPLE 254
1-(3-(Non-1-yloxy)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyr-
imidin-4-one
[0990] 447
[0991] Prepared from intermediate B128 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 9.08 (1H, s), 8.73 (2H, s),
7.41-7.28 (3H, m), 7.09 (1H, s), 7.03-6.78 (5H, m), 4.36 (2H, s),
3.95 (2H, t), 3.73 (2H, s), 1.78 (2H, quintet), 1.47-1.23 (12H, m),
0.88 (3H, t); MS (APCI+) found (M+1)=547,
C.sub.31H.sub.35FN.sub.4O.sub.2S requires 546.
EXAMPLE 255
1-(3-(Dec-1-y;)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimi-
din-4-one
[0992] 448
[0993] Prepared from intermediate B129 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 9.08 (1H, s), 8.73 (2H, s),
7.40-7.27 (4H, m), 7.11-7.08 (3H, m), 6.94 (2H, t), 4.35 (2H, s),
3.73 (2H, s), 2.65 (2H, t), 1.67-1.56 (2H, m), 1.30-1.22 (14H, m),
0.88 (3H, t); MS (APCI+) found (M+1)=545,
C.sub.32H.sub.37FN.sub.4OS requires 544.
EXAMPLE 256
1-Methyl-2-(4-fluorobenzyl)thio-5-(1-undecyl-2-oxopyrimid-5-ylmethyl)pyrim-
idin-4-one
[0994] 449
[0995] Prepared from Example 252 and undecyl iodide by the method
of Example 248. .sup.1H-NMR (CDCl.sub.3) .delta. 0.88 (3H,s),
1.2-1.4 (16H,m), 1.77 (2H,m), 3.43 (2H,s), 3.53 (3H,s), 3.86
(2H,t), 4.47 (2H,s), 6.9-7.1 (2H,m), 7.20 (1H,s), 7.3-7.45 (2H,m),
7.96 (1H,d), 8.44 (1H,d); MS (APCI+) found (M+1)=513;
C.sub.28H.sub.37FN.sub.4O.sub.2S requires 512.
EXAMPLE 257
1-Phenyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[0996] 450
[0997] Prepared from intermediate B121 by general method A2.
.sup.1H NMR (CDCl.sub.3) .delta. 3.74 (s, 2H), 4.36 (s, 2H), 6.95
(t, 2H), 7.06 (s, 1H), 7.30 (m, 4H), 7.55 (m, 3H), 8.72 (s, 2H),
9.10 (s, 1H). MS (APCI+) Found (M+1)=405;
C.sub.22H.sub.17FN.sub.4OS requires 404.
EXAMPLE 258
1-Phenyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)py-
rimidin-4-one
[0998] 451
[0999] Prepared from intermediate B121 by general method A2.
.sup.1H NMR (CDCl.sub.3) .delta. 1.35 (m, 6H), 1.65 (m, 4H), 2.91
(t, 2H), 3.14 (t, 2H), 3.76 (s, 2H), 7.04 (s, 1H), 7.3 (m, 2H),
7.43 (d, 2H), 7.55 (m, 3H), 7.89 (d, 2H), 8.72 (s, 2H), 9.10 (s,
1H). MS (APCI+) Found (M+1)=533/535;
C.sub.29H.sub.29ClN.sub.4O.sub.2S requires 533.
EXAMPLE 259
1-(4-(Non-1-yloxyphenyl))-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyr-
imidin-4-one
[1000] 452
[1001] Prepared from intermediate B126 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 9.07 (1H, s), 8.73 (2H, s), 7.30
(2H, dd), 7.21 (2H, d), 7.13 (1H, s), 6.95 (2H, d), 6.94 (2H, t),
4.33 (2H, s), 3.97 (2H, t), 3.73 (2H, s), 1.79 (2H, quintet),
1.47-1.23 (12H, m), 0.88 (3H, t); MS (APCI+) found (M+1)=547,
C.sub.31H.sub.35FN.sub.4O.sub.2S requires 546.
EXAMPLE 260
1-(4-Iodophenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4--
one
[1002] 453
[1003] Prepared from intermediate B130 by general method A2.
.sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) .delta. 9.08 (1H, s), 8.72 (2H,
s), 7.85 (2H, d), 7.33-7.26 (2H, m), 7.07 (1H, s), 7.05 (2H, d),
6.98 (2H, t), 4.35 (2H, s), 3.73 (2H, s); MS (APCI+) found
(M+1)=531, C.sub.22H.sub.16F.sub.4OS requires 530.
EXAMPLE 261
1-(4-(Hex-1-yl)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimi-
din-4-one
[1004] 454
[1005] Prepared from intermediate B127 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 9.08 (1H, s), 8.73 (2H, s),
7.33-7.27 (4H, m), 7.19 (2H, d), 7.09 (1H, s), 6.94 (2H, t), 4.35
(2H, s), 3.73 (2H, s), 2.66 (2H, t), 1.62 (2H, quintet), 1.39-1.27
(6H, m), 0.87 (3H, t); MS (APCI+) found (M+1)=489,
C.sub.28H.sub.29FN.sub.4OS requires 488.
EXAMPLE 262
1-(4-(Dec-1-yl)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimi-
din-4-one
[1006] 455
[1007] Prepared from intermediate B125 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 9.08 (1H, s), 8.73 (2H, s),
7.33-7.27 (4H, m), 7.19 (2H, d), 7.10 (1H, s), 6.94 (2H, t), 4.35
(2H, s), 3.73 (2H, s), 2.65 (2H, t), 1.67-1.56 (2H, m), 1.34-1.22
(14H, m), 0.88 (3H, t); MS (APCI+) found (M+1)=545,
C.sub.32H.sub.37FN.sub.4OS requires 544.
EXAMPLE 263
1-Ethoxycarbonylmethyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-
-5-ylmethyl)pyrimidin-4-one
[1008] 456
[1009] Prepared from intermediates B80 and A1 by general method A4,
as a light brown crystalline solid. MPt 100-102.degree. C.;
.sup.1H-NMR (CDCl.sub.3) .delta. 1.30 (3H, t), 1.37 (6H, m), 1.70
(4H, m), 2.93 (2H, t), 3.26 (2H, t), 3.71 (2H, s), 4.28 (2H, q),
4.50 (2H, s), 6.90 (1H, s), 7.44 (2H, m), 7.90 (2H, m), 8.71 (2H,
s), 9.10 (1H, s); MS APCI+) found (M+1)=543;
C.sub.27H.sub.31ClN.sub.4O.sub.4S requires 542.
EXAMPLE 264
1-(3-Ethoxycarbonylprop-1-yl)-2-(8
(4-chlorophenyl)-B-oxooct-1-yl)thio-5-(-
pyrimid-5-ylmethyl)pyrimidin-4-one
[1010] 457
[1011] Prepared from intermediates B50 and A1 by general method A4,
as a brown oil. .sup.1H-NMR (CDCl.sub.3) .delta. 1.27 (3H, t), 1.38
(6H, m), 1.69 (4H, m), 2.05 (2H, m), 2.38 (2H, t), 2.93 (2H, t),
3.25 (2H, t), 3.70 (2H, s), 3.88 (2H, t), 4.12 (2H, q), 7.05 (1H,
s), 7.42 (2H, d), 7.91 (2H, d), 8.72 (2H, s), 9.09 (1H, s); MS
(APCI+) found (M+1)=571; C.sub.29H.sub.35ClN.sub.4O.sub.4S requires
570.
EXAMPLE 265
1-(3-Ethoxycarbonylprop-1-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-
-4-one
[1012] 458
[1013] Prepared from intermediate B50 by general method A4, as a
brown oil. .sup.1H-NMR (CDCl.sub.3) .delta. 1.24 (3H, t), 2.01 (2H,
m), 2.35 (2H, m), 3.71 (2H, s), 3.86 (2H, t), 4.12 (2H, q), 4.50
(2H, s), 7.07 (1H, s), 7.27-7.41 (5H, m), 8.72 (2H, s), 9.12 (1H,
s); MS (APCI+) found (M+1)=425; C.sub.22H.sub.24N.sub.4O.sub.3S
requires 424.
EXAMPLE 266
1-(3-Ethoxycarbonylprop-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylme-
thyl)pyrimidin-4-one
[1014] 459
[1015] Prepared from intermediate B50 by general method A2 as an
oil. .sup.1H-NMR (CDCl.sub.3) .delta. 1.17-1.30 (3H, m), 1.96-2.12
(2H, m), 2.30-2.41 (2H, t), 3.70 (2H, s), 3.80-3.90 (2H, t),
4.06-4.20 (2H, q), 4.49 (2H, s), 7.01-7.26 (4H, m), 8.72 (2H, s),
9.10 (1H, s); MS (ES+) found (M+)=461;
C.sub.22H.sub.22F.sub.2N.sub.4O.sub.3S requires 460.
EXAMPLE 267
1-(3-Ethoxycarbonylprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl-
)pyrimidin 4-one
[1016] 460
[1017] Prepared from intermediate B50 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.26 (3H, t), 2.03 (2H, m), 2.35
(2H, t), 3.70 (2H, s), 3.85 (2H, t), 4.12 (2H, m), 4.47 (2H, s),
6.71-7.07 (3H, m), 7.35-7.41 (2H, m), 8.70 (2H, s), 9.10 (1H, s);
MS (APCI+) M+1=443, C.sub.22H.sub.23FN.sub.4O.sub.3S requires 442
(orange oil).
EXAMPLE 268
1-(5-Ethoxycarbonylpent-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylme-
thyl)pyrimidin-4-one
[1018] 461
[1019] Prepared from intermediate B102 by general method A2 as an
oil. .sup.1H-NMR (CDCl.sub.3) 1.14-1.87 (9H, m), 2.25-2.37 (2H, m),
3.63-3.82 (4H, m), 4.04-4.19 (2H, q), 4.45 (2H, s), 6.97-7.30 (4H,
m), 8.70 (2H, s), 9.10 (1H, s); MS (ES+) found (M+1)=489;
C.sub.24H.sub.26F.sub.2N.sub.- 4O.sub.3S requires 488.
EXAMPLE 269
1-(1-(Ethoxycarbonyl)cycloprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-y-
lmethyl)pyrimidin-4-one
[1020] 462
[1021] Prepared from intermediate B106 by general method A2 as a
foam. .sup.1H-NMR (CDCl.sub.3) .delta. 1.08-1.20 (3H, t), 1.38-1.54
(1H, m), 1.58-1.85 (2H, m), 1.94-2.10 (1H, m), 3.71 (2H, s),
4.04-4.28 (2H, m), 4.35-4.52 (2H, q), 6.90-7.05 (2H, t), 7.08 (1H,
S), 7.29-7.42 (2H, m), 8.70 (2H, s), 9.10 (1H, s); MS (APCI+) found
(M+1)=441; C.sub.22H.sub.21FN.sub.4O.sub.3S requires 440.
EXAMPLE 270
1-(4-Fluorobenzyloxycarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-yl-
methyl)pyrimidin-4-one
[1022] 463
[1023] Prepared from intermediate B80 by alkaline hydrolysis as in
general method D, followed by alkylation with 4-fluorobenzyl
bromide by general method A2. .sup.1H-NMR (CDCl.sub.3) .delta. 3.71
(2H, s), 4.46 (4H, m), 5.16 (2H, s), 6.87 (1H, s), 6.94-7.06 (4H,
m), 7.25-7.35 (4H, m), 8.68 (2H, s), 9.10 (1H, s); MS(APCI+)
M+1=495, C25H.sub.20F.sub.2N.sub.4O.sub.- 3S requires 494. MPt
184-186.degree. C. (colourless solid). MPt. 184-186.
EXAMPLE 271
1-Ethoxycarbonylmethyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimi-
din-4-one
[1024] 464
[1025] Prepared from intermediate B80 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.26 (3H, t), 3.71 (2H, s), 4.26
(2H, q), 4.46 (2H, s), 4.48 (2H, s), 6.91 (1H, s), 6.98 (2H, m),
7.35 (2H, m), 8.70 (2H, s), 9.09 (1H, s); MS(APCI+) M+1=415,
C.sub.20H.sub.19FN.sub.4O.sub.3S requires 414. MPt 145.1.degree. C.
(yellow solid).
EXAMPLE 272
1-(1(Methoxycarbonyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)p-
yrimidin-4-one
[1026] 465
[1027] Prepared from intermediate B103 by general method A2 as a
solid. .sup.1H-NMR (CDCl.sub.3) .delta. 1.68 (3H, d), 3.70 (2H, s),
3.78 (3H, s), 4.38-4.58 (2H, br,q), 4.98-5.10 (1H, q), 6.95-7.07
(2H, t), 7.19 (1H, s), 7.30-7.42 (2H, m), 8.72 (2H, s), 9.10 (1H,
s); MS (APCI+) found (M+1)=429. C.sub.20H.sub.19FN.sub.4O.sub.3S
requires 428.
EXAMPLE 273
1-(trans-4-(Methoxycarbonyl)cyclohex-1-ylmethyl)-2-(4-fluorobenzyl)thio-5--
(pyrimid-5-ylmethyl)pyrimidin-4-one
[1028] 466
[1029] Prepared from intermediate B137 by general method A2 as a
solid. 1H-NMR (CDCl.sub.3) .delta. 0.88-1.11 (2H, m), 1.30-1.54
(2H, m), 1.60-1.82 (4H, m), 1.94-2.13 (1H, m), 2.14-2.34 (1H, m),
3.53-3.74 (7H, m), 4.46 (2H, s), 6.90 (1H, s), 6.94-7.08 (2H, t),
7.30-7.44 (2H, m), 8.70 (2H, s), 9.11 (1H, s); MS (APCI+) found
(M+1)=483; C.sub.25H.sub.27FN.sub.4O.sub.3S requires 482.
EXAMPLE 274
1-(trans-4(Methoxycarbonyl)cyclohex-1-yl)-2-(4-fuorobenzyl)thio-5-(pyrimid-
-5-ylmethyl)pyrimidin-4-one
[1030] 467
[1031] Prepared from intermediate B108 by general method A2 as a
solid. .sup.1H-NMR (CDCl.sub.3) .delta. 1.54-1.97 (6H, m),
2.22-2.39 (2H, d), 2.68-2.79 (1H, br,s), 3.70 (2H, s), 3.73 (3H,
s), 4.03-4.25 (1H, m), 4.45 (2H, s), 6.93-7.08 (2H, m), 7.21 (1H,
s), 7.30-7.43 (2H, m), 8.71 (2H, s), 9.08 (1H, s); MS (APCI+) found
(M+1)=469; C.sub.24H.sub.25FN.sub.4O.s- ub.3S requires 468.
EXAMPLE 275
1-(3-Ethoxycarbonylprop-l-yl),2-(4
fuorobenzyl)thio-5-((1-methyl-2-oxo-pyr- id-4-yl)methyl)pyrimidin
4-one
[1032] 468
[1033] Prepared from intermediate B111 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.25 (3H, t), 2.02 (2H, m), 2.35
(2H, t), 3.50 (3H, s), 3.54 (2H, s), 3.83 (2H, t), 4.12 (2H, q),
4.47 (2H, s), 6.19 (1H, m), 6.37 (1H, s), 6.84-7.41 (6H, m); MS
(APCI+) M+1=472, C.sub.24H.sub.26FN.sub.3O.sub.4S requires 471. MPt
109-111.degree. C. (colourless solid). MPt. 109-111.
EXAMPLE 276
1-(Ethoxycarbonylmethyl)-2-(4-uorobenzyl)thio-5-(2-methoxypyrimid-5-ylmeth-
yl)pyrimidin-4-one
[1034] 469
[1035] Prepared from Example 108 by general method C2. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.26 (3H, t), 3.66 (2H, s), 3.99 (3H, s), 4.23
(2H, q), 4.47 (2H, s), 4.48 (2H, s), 6.84 (1H, s), 6.98 (2H, m),
7.34 (2H, m), 8.44 (2H, s); MS (APCI+) found (M+1)=445;
C.sub.21H.sub.21FN.sub.4O.sub.4- S requires 444.
EXAMPLE 277
1-(4-(Ethoxycarbonyl)benzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-
pyrimidin-4-one
[1036] 470
[1037] Prepared from intermediate B107 by general method A2 as a
solid. .sup.1H-NMR (CDCl.sub.3) .delta. 1.35-1.47 (3H, t), 3.70
(2H, s), 3.93 (1H, s), 4.32-4.52 (3H, m), 5.02 (2H, s), 6.90-7.06
(3H, m), 7.13-7.40 (4H, m), 7.98-8.10-(2H, d), 8.67 (2H, s), 9.09
(1H, s); MS (APCI+) found (M+1)=491;
C.sub.26H.sub.23FN.sub.4O.sub.3S requires 490.
EXAMPLE 278
1-(4-Methoxycarbonylbenzyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3--
ylmethyl)pyrimidin-4-one
[1038] 471
[1039] Prepared from Example 70 by general method C1. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-1.45(8H,m), 1.45-1.75(4H,m), 2.55(2H,t),
3.24(2H,t), 3.73(2H,s), 3.92(3H,s), 5.01(2H,s), 6.81(1H,s),
7.05-7.3(7H,m), 7.61(1H,txd), 8.03(2H,d) and 8.46(2H,bs); MS (EI)
found M=589; C.sub.33H.sub.36ClN.sub.3O.sub.3S requires 589.
EXAMPLE 279
1-(3-Carboxyprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimi-
din-4-one
[1040] 472
[1041] Prepared from Example 267 by general method D. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.93 (2H, m), 2.29 (2H, t), 3.58 (2H, s),
3.87 (2H, t), 4.40 (2H, s), 7.14 (2H, m), 7.48 (2H, m), 7.81 (1H,
s), 8.70 (2H, s), 9.02 (1H, s); MS (APCI-) M-1=413,
C.sub.20H.sub.19FN.sub.4O.sub.- 3S requires 414. MPt
188-190.degree. C. (colourless solid).
EXAMPLE 280
1-Carboxymethyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-o-
ne
[1042] 473
[1043] Prepared from Example 271 by general method D. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.59 (2H, s), 4.41 (2H, s), 4.67 (2H, s),
7.11 (2H, m), 7.45 (2H, m), 7.72 (1H, s), 8.70 (2H, s), 9.03 (1H,
s), 13.55 (1H, bs); MS (APCI-) M-1=385,
C.sub.18H.sub.15FN.sub.4O.sub.3S requires 386. MPt 206-207.degree.
C. (colourless solid).
EXAMPLE 281
1-(3-Carboxyprop-1-yl)-2-(4-fluorobenzyl)thio-5-((1-methyl-2-oxo-pyrid-4-y-
l)methyl)pyrimidin-4-one
[1044] 474
[1045] Prepared from Example 275 by general method D. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.90 (2H, m), 2.28 (2H, t), 3.37 (5H, m),
3.86 (2H, t), 4.41 (2H, s), 6.12 (1H, m), 6.18 (1H, s), 7.14 (2H,
m), 7.50 (3H, m), 7.73 (1H, s), 12.2 (1H, bm): MS (APCI+) M+1=444,
C.sub.22H.sub.22FN.sub.3O.sub.4S requires 443. MPt 245-249.degree.
C. (colourless solid).
EXAMPLE 282
1-(3-Carboxyprop-1-yl)-2-(3,4-difluorobenzylithio-5-(pyrimid-5-ylmethyl)py-
rimidin-4-one
[1046] 475
[1047] Prepared from Example 266 by general method D as a white
solid. .sup.1H-NMR (DMSO) .delta. 1.83-2.03 (2H, m), 2.24-2.37 (2H,
t), 3.58 (2H, s), 3.81-3.93 (2H, t), 4.41 (2H, s), 7.23-7.59 (3H,
m), 7.81 (1H, s), 8.71 (2H, s), 9.02 (1H, s), 12.13-12.20 (1H, s);
MS (APCI-) found (M-1)=431; C.sub.20H.sub.18F.sub.2N.sub.4O.sub.3S
requires 432.
EXAMPLE 283
1-(5-Carboxypent-1-yl)-2-(3,4-difluorobenzyl)thio-(pyrimid-5-ylmethyl)pyri-
midin-4-one
[1048] 476
[1049] Prepared from Example 268 by general method D as a white
solid. .sup.1H-NMR (DMSO) .delta. 1.18-1.81 (6H, m), 2.14-2.29 (2H,
t), 3.59 (2H, s), 3.76-3.90 (2H, t), 4.41 (2H, s), 7.23-7.60 (3H,
m), 7.85 (1H, s), 8.70 (2H, s), 9.02 (1H, s), 11.92-12.10 (1H, s);
MS (APCI-) found (M-1)=459; C.sub.22H.sub.22F.sub.2N.sub.4O.sub.3S
requires 460.
EXAMPLE 284
1-(4-Carboxybenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-2-thiour-
acil
[1050] 477
[1051] Prepared from Example 277 by general method D. .sup.1H-NMR
(DMSO) .delta. 3.60 (2H, s), 4.39 (2H, s), 5.21 (2H, s), 7.03-7.19
(2H, t), 7.26-7.49 (4H, m), 7.38-8.02 (3H, m), 8.72 (2H, s), 9.03
(1H, s), 12.92-13.10 (1H, br,s); MS (APCI+) found (M+1)=463;
C.sub.24H.sub.19FN.sub.4O.sub.3S requires 462.
EXAMPLE 285
1-(4-Carboxycyclohex-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-2-
-thiouracil
[1052] 478
[1053] Prepared from Example 274 by general method D. .sup.1H-NMR
(DMSO) .delta. 1.57-1.88 (6H, m), 2.13-2.26 (2H, d), 2.60 (1H, s),
3.62 (2H, s), 3.98-4.10 (1H, m), 4.40 (2H, s), 7.09-7.19 (2H, t),
7.44-7.53 (2H, m), 8.00 (1H, s), 8.72 (2H, s), 9.00 (1H, s), 12.27
(1H, s); MS (APCI+) found (M+1)=455;
C.sub.23H.sub.23FN.sub.4O.sub.3S requires 454.
EXAMPLE 286
1-(3-Ethoxycarbonylphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)py-
rimidin 4-one
[1054] 479
[1055] Prepared from intermediate B118 by general method A2.
.sup.1H NMR (CDCl.sub.3) .delta. 1.41 (t, 3H), 3.75 (s, 2H), 4.37
(s, 2H), 4.41 (q, 2H), 6.95 (t, 2H), 7.05 (s, 1H), 7.30 (m, 2H),
7.50 (m. 1H), 7.60 (t, 1H), 7.97 (m, 1H), 8.21 (d, 1H), 8.72 (s,
2H), 9.10 (s, 1H). MS (APCI+) Found (M+1)=477;
C.sub.25H.sub.21FN.sub.4O.sub.3S requires 476.
EXAMPLE 287
1-(3-Ethoxycarbonylphenyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyr-
imid-5-ylmethyl)pyrimidin-4-one
[1056] 480
[1057] Prepared from intermediate B118 by general method A4.
.sup.1H NMR (CDCl.sub.3) .delta. 1.3 (m, 6H), 1.42 (t, 3H), 1.65
(m, 4H), 2.91 (t, 2H), 3.15 (t, 2H), 3.73 (s, 2H), 4.42 (q, 2H),
7.03 (s, 1H), 7.42 (d, 2H), 7.5 (m, 1H), 7.62 (t, 1H), 7.88 (d,
2H), 7.98 (s, 1H), 8.22 (d, 1H), 8.72 (s, 2H), 9.09 (s, 1H), MS
(APCI+) Found (M+1)=605/607; C.sub.32H.sub.33ClN.sub.4O.sub.4S
requires 605.
EXAMPLE 288
1-(3-Carboxyphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-
-4-one
[1058] 481
[1059] Prepared from Example 286 by general method D as a white
solid, m.p. 157-1600. .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.62 (s,
2H), 4.31 (s, 2H), 7.10 (t, 2H), 7.40 (m, 2H), 7.70 (t, 1H), 7.87
(d, 1H), 7.94 (s, 1H), 8.10 (m, 2H), 8.77 (s, 2H), 9.01 (s, 1H),
13.4 (br s, 1H). MS (APCI+) Found (M+1)=449;
C.sub.23H.sub.17FN.sub.4O.sub.3S requires 448.
EXAMPLE 289
1-(3-Carboxyphenyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5--
ylmethyl)pyrimidin-4-one
[1060] 482
[1061] Prepared from Example 287 by general method D as a white
solid, m.p. 109-1120. .sup.1H NMR (DMSO-d.sub.6) .delta. 1.3 (m,
6H), 1.65 (m, 4H), 2.9-3.1 (m, 4H), 3.60 (s, 2H), 7.57 (d, 2H),
7.71 (t, 1H), 7.8-8.0 (m, 4H), 8.13 (m, 2H), 8.75 (s, 2H), 9.02 (s,
1H) 13.35 (br s, 1H). MS (APCI+) Found (M+1)=577/579:
C.sub.30H.sub.29ClN.sub.4O.sub.4S requires 577.
EXAMPLE 290
1-(4-Ethoxycarbonylphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)py-
rimidin-4-one
[1062] 483
[1063] Prepared from intermediate B119 by general method A2.
.sup.1H NMR (CDCl.sub.3) .delta. 1.40 (t, 3H), 3.74 (s, 2H), 4.37
(s, 2H), 4.41 (q, 2H), 6.95 (t, 2H), 7.05 (s, 1H), 7.30 (m, 2H),
7.40 (d, 2H), 8.20 (d, 2H), 8.72 (s, 2H), 9.11 (s, 11H). MS (APCI+)
Found (M+1)=477. C.sub.25H.sub.21FN.sub.4O.sub.3S requires 476.
EXAMPLE 291
1-(4-Ethoxycarbonylphenyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyr-
imid-5-ylmethyl)pyrimidin-4-one
[1064] 484
[1065] Prepared from intermediate B119 by general method A4.
.sup.1H NMR (CDCl.sub.3) .delta. 1.3 (m, 6H), 1.42 (t, 3H), 1.65
(m, 4H), 2.91 (t, 2H), 3.15 (t, 2H), 3.73 (s, 2H), 4.44 (q, 2H),
7.03 (s, 1H), 7.4 (m, 4H), 7.88 (d, 2H), 8.20 (d, 2H), 8.71 (s,
2H), 9.10 (s, 1H). MS (APCI+) Found (M+1)=605/607;
C.sub.32H.sub.33ClN.sub.4O.sub.4S requires 605.
EXAMPLE 292
1-(4-Carboxyphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-
-4-one
[1066] 485
[1067] Prepared from Example 290 by general method D as a white
solid, m.p. 258-262.degree. dec. .sup.1H-NMR (DMSO-d.sub.6)
.delta.:3.63 (s, 2H), 4.31 (s, 2H), 7.10 (t, 2H), 7.40 (m, 2H),
7.74 (d, 2H), 7.95 (s, 1H), 8.10 (d, 2H), 8.77 (s, 2H), 9.01 (s,
1H), 13.3 (br s, 1H). MS (APCI+) Found (M+1)=449;
C.sub.23H.sub.27FN.sub.4O.sub.3S requires 448.
EXAMPLE 293
1-(4-Carboxyphenyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5--
ylmethyl)pyrimidin-4-one
[1068] 486
[1069] Prepared from Example 291 by general method D as a white
solid, m.p. 92-96. .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.3 (m, 6H),
1.6 (m, 4H), 2.9-3.1 (m, 4H), 3.61 (s, 2H), 7.57 (d, 2H), 7.74 (d,
2H), 7.95 (m, 3H), 8.10 (d, 2H), 8.75 (s, 2H), 9.02 (s, 1H) 13.35
(br S, 1H). MS (APCI+) Found (M+1)=577/579;
C.sub.30H.sub.29ClN.sub.4O.sub.4S requires 577.
EXAMPLE 294
1-(5-(Ethoxycarbonyl)fur-2-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethy-
l)pyrimidin-4-one
[1070] 487
[1071] Prepared from intermediate B120 by general method A2.
.sup.1H NMR (CDCl.sub.3) .delta. 1.38 (t, 3H), 3.72 (s, 2H), 4.38
(s, 2H), 4.39 (q, 2H), 6.60 (d, 1H), 6.97 (t, 2H), 7.08 (s, 1H),
7.20 (d, 1H), 7.3 (m, 2H), 8.71 (s, 2H), 9.11 (s, 1H). MS (APCI+)
Found (M+1)=467; C.sub.23H19FN.sub.4O.sub.4S requires 466.
EXAMPLE 295
1-(3-Ethoxycarbonyl-4-iodobenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylme-
thyl)pyrimidin-4-one
[1072] 488
[1073] Prepared from Example 106 by general method C2 as a yellow
solid. .sup.1H-NMR (250 MHz, DMSO) 9.03 (s, 1H), 8.82 (s, 2H), 8.00
(m, 2H), 7.57 (s, 1H), 7.42 (m, 2H), 7.11 (m, 3H), 5.14 (s, 2H),
4.39 (s, 2H), 3.87 (s, 3H), 3.62 (s, 2H). MS (AP+) 603 (M+H.sup.+,
100%).
EXAMPLE 296
1-(3-(Hept-1-yloxy)4-methoxycarbonylbenzyl)-2-(4-fluorobenzyl)thio-5-(pyri-
mid-5-ylmethyl)pyrimidin-4-one
[1074] 489
[1075] Prepared from Example 106 by general method C2 as a yellow
solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) 9.00 (s, 1H), 8.61 (s,
2H), 7.53 (d, 1H), 7.30 (d, 1H), 7.28 (d, 1H), 7.15 (dd, 1H), 6.90
(m, 4H), 4.82 (s, 2H), 4.40 (s, 2H), 3.96 (t, 2H), 3.82 (s, 3H),
3.60 (s, 2H), 1.73 (m, 2H), 1.42 (m, 2H), 1.29 (m, 6H), 0.83 (t,
3H). MS (AP+) 591 (M+H.sup.+, 100%).
EXAMPLE 297
1-(3-(Hept-1-yloxy)-4-methoxycarbonylbenzyl)-2-(4-fluorobenzyl)thio-5-(pyr-
imid-5-ylmethyl)pyrimidin-4-one
[1076] 490
[1077] Prepared from Example 106 by general method C2 as a yellow
solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) 9.00 (s, 1H), 8.59 (s,
2H), 7.68 (d, 1H), 7.29 (d, 1H), 7.28 (d, 1H), 6.91 (m, 3H), 6.59
(s, 2H), 4.88 (s, 2H), 4.40 (s, 2H), 3.81 (m, 5H), 3.62 (s, 2H),
1.72 (m, 2H), 1.40 (m, 2H), 1.28 (6H) 0.83 (t, 3H), MS (AP+) 591
(M+H.sup.+, 100%).
EXAMPLE 298
1-(3-Carboxy-4-(hept-1-yloxy)benzyl)-2-(4-fluorobenzyl)thio-5
(pyrimid-5-ylmethyl)pyrimidin-4-one
[1078] 491
[1079] Prepared from Example 296 by general method D as a
colourless solid. .sup.1H-NMR (250 MHz, CDCl.sub.3) 9.05 (s, 1H),
8.75 (s, 2H), 8.65 (br s, 1H), 8.02 (d, 1H), 7.32 (m, 4H), 6.98 (m,
3H), 4.99 (s, 2H), 4.40 (s, 2H), 4.21 (t, 2H), 3.70 (s, 2H), 1.88
(m, 2H), 1.50-1.20 (m, 8H), 0.87 (t, 3H). MS (AP+) 577 (M+H.sup.+,
100%).
EXAMPLE 299
1-(3-(Hept-1-yloxy)-4-carboxybenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-y-
lmethyl)pyrimidin-4-one
[1080] 492
[1081] Prepared from Example 297 by general method D as a
colourless solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) 9.04 (s, 1H),
8.67 (s, 2H), 8.11 (d, 1H), 7.33 (d, 1H), 7.31 (d, 1H), 7.05 (s,
1H), 6.95 (t, 2H), 6.82 (d, 1H), 6.68 (s, 1H), 4.99 (s, 2H), 4.44
(s, 2H), 4.05 (t, 2H), 3.69 (s, 2H), 1.87 (m, 2H), 1.50-1.25 (m,
8H), 0.87 (t, 3H). MS (AP+) 577 (M+H.sup.+, 55%).
EXAMPLE 300
1-(3-Methoxycarbonyl-4-hydroxybenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5--
ylmethyl)pyrimidin-4-one
[1082] 493
[1083] Prepared from Example 106 by general method C2 as a yellow
solid. 1H-NMR (250 MHz, CDCl.sub.3) 10.82 (s, 1H) 9.03 (s, 1H),
8.64 (s, 2H), 7.77 (d, 1H), 7.30 (m, 2H), 6.93 (m, 3H), 6.68 (d,
1H), 6.53 (dd, 1H), 4.88 (s, 2H), 4.41 (s, 2H), 3.91 (s, 3H), 3.64
(s, 2H).
EXAMPLE 301
1-(3-Methoxycarbonylbenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)p-
yrimidin-4-one
[1084] 494
[1085] Prepared from Example 106 by general method C2 as a yellow
solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) 9.10 (s, 1H), 8.71 (s,
2H), 8.07 (d, 1H), 7.86 (s, 1H), 7.50 (t, 1H), 7.30 (m, 3H), 7.07
(s, 1H), 7.01 (t, 2H), 5.05 (s, 2H), 4.50 (s, 2H), 3.97 (s, 3H),
3.72 (s, 2H). MS (AP+) 477 (M+H.sup.+, 25%).
EXAMPLE 302
1-(3-Carboxybenzyl)-2-(4-fluorobenzyl)thio-5(pyrimid-5-ylmethyl)-pyrimidin-
-4-one
[1086] 495
[1087] Prepared from Example 301 by general method D as colourless
crystals. .sup.1H-NMR (400 MHz. DMSO) 13.20 (br s, 1H), 9.07 (s,
1H), 8.78 (s, 2H), 8.06 (s, 1H), 7.95 (d, 1H), 7.85 (s, 1H), 7.50
(m, 4H), 7.16 (t, 2H), 5.26 (s, 2H), 4.44 (s, 2H), 3.68 (s,
2H).
EXAMPLE 303
1-(3,4-Di-(methoxycarbonyl)benzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylm-
ethyl)pyrimidin-4-one
[1088] 496
[1089] Prepared from Example 106 by general method C2 as a yellow
solid. .sup.1H-NMR (250 MHz, CDCl.sub.3) 9.05 (s, 1H), 8.65 (s,
2H), 7.69 (m, 1H), 7.44 (s, 1H), 7.27 (m, 3H), 6.96 (m, 3H), 4.99
(s, 2H), 4.62 (s, 2H), 4.09 (s, 6H), 3.87 (s, 2H), MS (AP+) 535
(M+H.sup.+, 100%).
EXAMPLE 304
1-Carboxamidomethyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl-
)pyrimidin-4-one
[1090] 497
[1091] Prepared from Example 70 by general method C1, as a buff
powder. MPt 147-152.degree. C.; .sup.1H-NMR (d.sub.6 DMSO) .delta.
1.2-1.5(8H,m), 1.5-1.8(4H,m), 2.54(2H,t), 3.08(2H,t), 3.56(2H,s),
4.53(2H,s),7.1-7.9(9H,m), 8.38(1H,m) and 8.48(1H,bs); MS (EI)
M=498; C.sub.26H.sub.31ClN.sub.4O.sub.2S requires 498.
EXAMPLE 305
1-Dimethylaminocarbonylmethyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(-
pyrimid-5-ylmethyl)pyrimidin-4-one
[1092] 498
[1093] Prepared from intermediates B79 and A1 by general method A4,
as a light brown crystalline solid. MPt 57-59.degree. C.;
.sup.1H-NMR (CDCl.sub.3) .delta. 1.37 (6H, m), 1.69 (4H, m), 2.92
(2H, t), 3.01 (3H, s), 3.16 (3H, s), 3.68 (2H, s), 4.43 (2H, m),
5.06 (2H, s), 7.11 (1H, s), 7.42 (2H, m), 7.89 (2H, m), 8.71 (2H,
s), 9.1 1(1H, s).
EXAMPLE 306
1-Carboxamidomethyl-2-benzylthio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin--
4-one
[1094] 499
[1095] Prepared from Example 88 by general method C1, as a cream
solid. MPt 126-132.degree. C.; .sup.1H-NMR (d.sub.6 DMSO) .delta.
3.53(2H,s), 3.81(3H,s), 4.40(2H,s), 4.53), 6.66(1H,s), 6.85(1H,dd),
7.2-7.5(6H,m), 7.63(1H,s), 7.75(1H,bs) and 8.03(1H,d); MS (EI)
found M=396; C.sub.20H.sub.20N.sub.4O.sub.3S requires 396.
EXAMPLE 307
1-(3-(Octadec-1ylaminocarbonyl)prop-1
yl)-2-(4-fluorobenzyl)thio-5-(pyrimi-
d-5-ylmethyl)pyrimidin-4-one
[1096] 500
[1097] Prepared from Example 279 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.88 (3H, m), 1.25 (30H, m), 1.47 (2H, m),
2.05 (2H, m), 2.18 (2H, m), 3.21 (2H, m), 3.69 (2H, s), 3.92 (2H,
m), 4.46 (2H, s), 5.42 (1H, m), 6.98 (2H, m), 7.27 (}H, m), 7.37
(2H, m), 8.71 (2H, s), 9.09 (1H, s), MS(APCI+) M+1=666,
C.sub.38H.sub.56FN.sub.5O.sub.2S requires 665. MPt 115.1.degree. C.
(colourless solid).
EXAMPLE 308
1-(3-(Octadec-9-(Z)-en-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio--
5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1098] 501
[1099] Prepared from Example 279 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.88 (3H, m), 1.27 (22H, m), 1.47 (2H, m),
1.99-2.20 (8H, m), 3.20 (2H, m), 3.69 (2H, s), 3.92 (2H, m), 4.46
(2H, s), 5.32 (2H, m), 5.42 (1H, m), 6.99 (2H, m), 7.26 (1H, s),
7.37 (2H, m), 8.71 (2H, s), 9.08 (1H, s), MS(APCI+) M+1=664,
C.sub.38H54FN.sub.5O.sub.2S requires 663 (waxy solid).
EXAMPLE 309
1-(3-(Octadec-9-(E)-en-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio--
5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1100] 502
[1101] Prepared from Example 279 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.88 (3H, t), 1.27 (22H, m), 1.47 (2H, m),
1.99-2.20 (8H, m), 3.20 (2H, m), 3.69 (2H, s), 3.92 (2H, m), 4.46
(2H, s), 5.37 (2H, m), 5.44 (1H, m), 6.99 (2H, m), 7.26 (1H, s),
7.37 (2H, m), 8.71 (2H, s), 9.08 (1H, s), MS(APCI+) M+1=664,
C.sub.38H.sub.54FN.sub.5O.sub.2- S requires 663. MPt 108.4.degree.
C. (colourless solid).
EXAMPLE 310
1-(3-(N-Dodec-1yl-N-methylaminocarbonyl)prop-1yl)-2-(4-fluorobenzyl)thio-5-
-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1102] 503
[1103] Prepared from Example 279 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.88 (3H, m), 1.26 (18H, m), 1.49 (2H, m),
2.02 (2H, m), 2.30 (2H, m), 2.90 (3H, s), 3.17, 3.32 (each 1H, m),
3.69 (2H, s), 3.92 (2H, t), 4.46 (2H, s), 6.98 (2H, m), 7.24 (1H,
m), 7.35 (2H, m), 8.70 (2H, s), 9.08 (1H, s), MS(APCI+) M+1=596,
C.sub.33H.sub.46FN.sub.5O.- sub.2S requires 595. MPt 76.9.degree.
C. (colourless solid).
EXAMPLE 311
1-(3-(N-Non-1-yl-N-methylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-
-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1104] 504
[1105] Prepared from Example 279 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.88 (3H, m), 1.26 (8H, m), 1.48 (2H, m), 2.05
(2H, m), 2.30 (2H, m), 2.90 (3H, s), 3.18, 3.32 (each 1H, m), 3.69
(2H, s), 3.91 (2H, t), 4.46 (2H, s), 6.99 (2H, m), 7.25 (1H, m),
7.35 (2H, m), 8.71 (2H, s), 9.08 (1H, s), MS(APCI.sup.+) M+1=526,
C.sub.28H.sub.36FN.sub.5OS requires 525. (coloured oil).
EXAMPLE 312
1-(4-(Pent-1-ylaminocarbonyl)benzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-y-
lmethyl)pyrimidin-4-one
[1106] 505
[1107] Prepared from Example 284 by general method E as a solid.
.sup.1H-NMR (CDCl.sub.3) .delta. 0.82-1.05 (3H, t), 1.21-1.48 (3H,
m), 1.52-1.77 (3H, 3 ), 3.38-3.54 (2H, q), 3.69 (2H, s), 4.49 (2H,
s), 5.01 (2H, 3), 6.14-6.27 (1H, br,t), 6.90-7.05 (3H, 7m),
7.10-7.21 (2H, d), 7.28-7.39 (2H, s), 7.70-7.80 (2H, d), 8.65 (2H,
s), 9.07 (1H, s); MS (APCI.sup.+) found (M+1)=532;
C.sub.29H.sub.30FN.sub.5O.sub.2S requires 531.
EXAMPLE 315
1-(1-(6-(4-Fluorophenyl)hex-1-ylaminocarbonyl)ethyl)-2-(4-fluorobenzyl)thi-
o-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1108] 506
[1109] Prepared from Example 272 by hydrolysis using general method
D, followed by amide coupling using general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.15-1.72 (11H, m), 2.47-2.60 (2H, t),
3.17-3.35 (2H, m), 3.52-3.70 (2H, m), 4.25-4.49 (2H, br,q),
4.74-4.89 (1H, q), 6.53-6.66 (1H, br,t), 6.87-7.16 (6H, m),
7.21-7.40 (2H, m), 7.53 (1H, s), 8.69 (2H, s), 9.08 (1H, s); MS
(APCI+) found (M+1)=578; C.sub.31H.sub.33F.sub.2N.sub.5O.sub.2S
requires 577.
EXAMPLE 316
1-(3-(11-Dimethylaminoundec-1-ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl-
)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1110] 507
[1111] Prepared from Example 279 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.27 (10H, m), 1.47 (4H, m), 1.99-2.20 (4H,
m), 2.30 (6H, m),3.20 (2H, m), 3.69 (2H, s), 3.92 (2H, m), 4.46
(2H, s), 5.49 (1 H, bm), 6.99 (2H, m), 7.26 (11H, s), 7.37 (2H, m),
8.71 (2H, s), 9.08 (1H, s), MS (APCI.sup.+) M+1=611,
C.sub.33H.sub.47FN.sub.6O.sub.2S requires 610 (gum).
EXAMPLE 317
1-(3-(3-Ethoxyprop-1ylaminocarbonyl)prop-1-yl)-2-(3,4-difluorobenzyl)thio--
5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1112] 508
[1113] Prepared from Example 282 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.14-1.35 (5H, m), 1.70-1.88 (2H, m),
2.11-2.23 (2, t), 3.70-3.43 (2H, q), 3.435-3.60 (41, m), 3.70 (2H,
s), 3.87-4.01 (2H, t), 4.44 (2H, s), 6.23-6.38 (1H, br,t),
7.01-7.33 (4H, m), 8.71 (2H), s), 9.09 (1H,s); MS (APCI.sup.+)
found (M+1)=518; C.sub.25H.sub.29F.sub.2N.su- b.5O.sub.3S requires
517.
EXAMPLE 318
1-(3-(5-(Methoxycarbonyl)-5-(benzykloxycarbonylamino)pent-1ylaminocarbonyl-
)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1114] 509
[1115] Prepared from Example 279 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-2.2 (10H, m), 3.19 (2H, m), 3.67 (2H, s),
3.74 (3H, s), 3.85 (2H, t), 4.35 (1H, m), 4.45 (2H, s), 5.09 (2H,
s), 5.55 (2H, m), 6.99 (2H, m), 7.22-7.37 (8H, m), 8.71 (2H, s),
9.08 (1H, s), MS(APCI+) M+1=691, C35H39FN6O6S requires 690
(colourless foam).
EXAMPLE 319
1-(3-(5-(Methoxycarbonyl)pent-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzy-
l)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1116] 510
[1117] Prepared from Example 279 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.2-1.7 (6H, m), 1.98-2.21 (4H, m), 2.31 (2H,
t), 3.22 (2H,m), 3.66 (3H, s), 3.70 (2H, s), 3.92 (2H, t), 4.45
(2H, s), 5.57 (1H, bm), 6.99 (2H, m), 7.26 (1H, s), 7.36 (2H, m),
8.71 (2H, s), 9.08 (1H, s); MS(APCI+) M+1=542,
C.sub.27H.sub.32FN.sub.5O.sub.4S requires 541. (oil).
EXAMPLE 320
1-(3-(Hex-1ylaminocarbonyl)prop-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimi-
d-5-ylmethyl)pyrimidin-4-one
[1118] 511
[1119] Prepared from Example 279 by general method E as a solid.
.sup.1H-NMR (CDCl.sub.3) .delta. 0.83-0.98 (3H, t), 1.20-1.59 (8H,
m), 1.97-2.28 (4H, n), 3.15-3.29 (2H, q), 3.69 (2H, s), 3.87-4.01
(2H, t), 4.43 (2H, s), 5.49-5.64 (1H, br,t), 6.99-7.32 (4H, m),
8.71 (2H, s), 9.08 (1H, s); MS (APCI+) found (M+1)=516;
C.sub.26H.sub.30F.sub.2N.sub.5O.sub.- 2S requires 515.
EXAMPLE 321
1-(3-(5-(t-Butoxycarbonylamino)pent-1ylaminocarbonyl)prop-1-yl)-2-(4-fluor-
obenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1120] 512
[1121] Prepared from Example 279 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.18-1.5 (15H, m), 2.05 (2H, m), 2.19 (2H, m),
3.16 (4H, m), 3.70 (2H, s), 3.92 (2H, t), 4.52 (2H, s), 4.64
(1H,bm), 5.71 (1H, bm), 6.99 (2H, m), 7.28 (1H, s), 7.37 (2H, m),
8.72 (2H, s), 9.08 (1H, s); MS(APCI.sup.+) M+1=599,
C.sub.30H.sub.39FN.sub.6O.sub.4S requires 598. (colourless
foam).
EXAMPLE 322
1-(3-(6-(t-Butoxycarbonylamino)hex-1ylaminocarbonyl)prop-1-yl)-2-(4-fluoro-
benzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1122] 513
[1123] Prepared from Example 279 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.18-1.5 (17H, m), 2.04 (2H, m), 2.20 (2H, m),
3.15 (4H, m), 3.69 (2H, s), 3.92 (2H, t), 4.45 (2H, s), 4.59 (1H,
bm), 5.80 (1H, bm), 6.96 (2H, s), 7.28 (1H, s), 7.36 (2H, m), 8.71
(2H, s), 9.08 (1H, s); MS(APCI.sup.+) NM+1=613,
C.sub.31H.sub.41FN.sub.6O.sub.4S requires 612. MPt 90-98.degree. C.
(colourless foam).
EXAMPLE 323
1-(3-(Dec-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5--
ylmethyl)pyrimidin-4-one
[1124] 514
[1125] Prepared from Example 279 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.88 (3H, t), 1.26 (14H, m), 1.47 (2H, m),
1.98-2.20 (4H, m), 3.20 (2H, m), 3.69 (2H, s), 3.92 (2H, t), 4.46
(2H, s), 5.39 (1H, bm), 6.98 (2H, m), 7.24 (1H, s), 7.37 (2H, m),
8.70 (2H, s), 9.08 (1H, s); s); MS(APCI.sup.+) M+1=554,
C.sub.30H.sub.40FN.sub.5O.sub.2S requires 553. MPt 90-98.degree. C.
(colourless solid).
EXAMPLE 324
1-(3-(Dec-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5--
ylmethyl)pyrimidin-4-one
[1126] 515
[1127] Prepared from Example 279 by general method E. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 0.85 (3H, m), 1.22 (14H, m), 1.31 (2H, m),
1.87 (2H, m), 2.12 (2H, m), 2.98 (2H, m), 3.35 (3H, s), 3.37 (2H,
s), 3.84 (2H, m), 4.41 (2H, s), 6.13 (2H, m), 7.13 (2H, m), 7.51
(3H, m), 7.77 (2H, m); MS (APCI+) M+1=583,
C.sub.32H.sub.43FN.sub.4O.sub.3S requires 582. MPt 133.3.degree. C.
(colourless solid).
EXAMPLE 325
1-(3-(Hept-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-
-ylmethyl)pyrimidin-4-one
[1128] 516
[1129] Prepared from Example 279 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta.0.88 (3H, t), 1.27 (8H,m), 1.47 (2H,m),
1.98-2.25 (4H, m), 3.20 (2H, m), 3.69 (2H, s), 3.92 (2H, t), 4.52
(2H, s), 5.42 (1H, bm), 6.98 (2H, m), 7.25 (1H, s), 7.37 (2H, m),
8.68 (2H, s), 9.08 (1H, s); MS(APCI.sup.+) M+1=512, C27H34FN5O2S
requires 511. MPt 84-89.degree. C. (colourless solid). MPt.
84-89.
EXAMPLE 326
1-(3-(Hex-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5--
ylmethyl)pyrimidin-4-one
[1130] 517
[1131] Prepared from Example 279 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.89 (3H, m), 1.20-1.55 (8H, m), 1.98-2.20
(4H, m), 3.19 (2H, m), 3.69 (2H, s), 3.92 (2H, t), 4.45 (2H, s),
5.44 (1H, bm), 6.96 (2H, m), 7.25 (1H, s), 7.37 (2H, m), 8.68 (2H,
s), 9.08 (1H, s); MS(APCI=)M+1=498,
C.sub.26H.sub.32FN.sub.5O.sub.2S requires 497. MPt 106-109.degree.
C. (colourless solid).
EXAMPLE 327
1-(3-(Non-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-pyrimid-5-y-
lmethyl)pyrimidin-4-one
[1132] 518
[1133] Prepared from Example 279 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.87 (3H, t), 1.26 (12H, m), 1.47 (2H, m),
1.98-2.25 (4H, m), 3.20 (2H, m), 3.69 (2H, s), 3.91 (2H, t), 4.46
(2H, s), 5.39 (1H, bm), 6.98 (2H, m), 7.24 (1H, s), 7.37 (2H, m),
8.70 (2H, s), 9.08 (1H, s); MS(APCI.sup.+) M+1=540,
C.sub.29H.sub.38FN.sub.5O.sub.2S requires 539. MPt 92-97.degree. C.
(colourless solid).
EXAMPLE 328
1-(3-(Oct-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5--
ylmethyl)pyrimidin-4-one
[1134] 519
[1135] Prepared from Example 279 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.88 (3H, t), 1.27 (IOH, m), 1.47 (2H, m),
1.98-2.20 (4H, m), 3.22 (2H, m), 3.69 (2H, s), 3.92 (2H, t), 4.45
(2H, s), 5.43 (1H, bm), 6.98 (2H, m), 7.25 (1H, s), 7.37 (2H, m),
8.70 (2H, s), 9.08 (1H, S); MS(APCI.sup.+) M+1=526,
C.sub.28H.sub.36FN.sub.5OS requires 525. MPt 72-83.degree. C.
(colourless solid).
EXAMPLE 329
1-(3-(Pent-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-
-ylmethyl)pyrimidin-4-one
[1136] 520
[1137] Prepared from Example 279 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.90 (3H, m), 1.17-1.61 (6H, m), 1.98-2.26
(4H, m), 3.20 (2H, m), 3.69 (2H, s), 3.92 (2H, t), 4.45 (2H, s),
5.44 (1H, bm), 6.97 (2H, m), 7.25 (1H, s), 7.38 (2H, m), 8.68 (2H,
s), 9.08 (1H, s); MS(APCI.sup.+) M+1=484,
C.sub.25H.sub.30FN.sub.5O.sub.2S requires 483. MPt 64-69.degree. C.
(colourless solid).
EXAMPLE 330
1-(3-(N-Hex-1yl-N-methylaminocarbonyl)prop-1-yl)-2-(3,4-difluorobenzyl)thi-
o-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1138] 521
[1139] Prepared from Example 282 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.78-0.99 (3H, m), 1.19-1.77 (8H, m),
1.95-2.14 (2H, m), 2.25-2.44 (2H, q), 2.92 (3H, d), 3.12-3.27 (1H,
t), 3.29-3.42 (1H, t), 3.70 (2H, s), 3.84-4.00 (2H, t), 4.44 (2H,
t), 7.01-7.31 (4H, m), 8.71 (2H,s), 9.10 (1H, s); MS (APCI.sup.+)
found (M+1)=530; C.sub.27H.sub.33F.sub.2N.sub.5O.sub.2S requires
529.
EXAMPLE 331
1-(5-(2-methoxyethylaminocarbonyl)pent-1-yl)-2-(3,4-difluorobenzyl)thio-5--
(pyrimid-5-ylmethyl)pyrimidin-4-one
[1140] 522
[1141] Prepared from Example 283 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.22-1.85 (6H, m), 2.13-2.25 (2H, t),
3.29-3.38 (3H, s), 3.39-3.53 (4H, s), 3.68-3.85 (4H, m), 4.44 (2H,
s), 5.09-6.04 (1H, br,s), 7.01-7.29 (4H, m), 8.72 (2H, s), 9.09
(1H, s); MS (APCI.sup.+) found 1)=518;
C.sub.25H.sub.29F.sub.2N.sub.5O.sub.3S requires 517.
EXAMPLE 332
1-(5-(2-Phenylethylaminocarbonyl)pent-1-yl)-2-(3,4-difluorobenzyl)thio-5-(-
pyrimid-5-ylmethyl)pyrimidin-4-one
[1142] 523
[1143] Prepared from Example 283 by general method E as a foam.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.17-1.38 (2H, m), 1.56-1.84 (4H,
m), 2.04-2.19 (2H, t), 2.77-2.89 (2H, t), 3.41-3.60 (2H, m),
3.64-3.86 (4H, m), 4.43 (2H, s), 5.68-5.85 (1H, m), 7.00-7.38 (9H,
m), 8.67 (2H, s), 9.06 (1H, s); MS (APCI+) found (M+1)=564;C30H31
F2N5O2S requires 563.
EXAMPLE 333
1-(5-(But-1-ylaminocarbonyl)pent-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrim-
id-5-ylmethyl)pyrimidin-4-one
[1144] 524
[1145] Prepared from Example 283 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.88-1.00 (3H, t), 1.17-1.76 (10H, m),
2.11-2.22 (2H, t), 3.18-3.30 (2H, q), 3.67-3.88 (4H, m), 4.43 (2H,
s), 5.52-5.70 (1H, br,t), 7.00-7.30 (4H, m), 8.71 (2H, s), 9.09
(1H, s); MS (APCI.sup.+) found M+1)=516;
C.sub.26H.sub.31F.sub.2N.sub.5O.sub.2S requires 515.
EXAMPLE 334
1-(5-(N-(2-Phenylethyl)-N-methylaminocarbonyl)pent-1-yl)-2-(3,4-difluorobe-
nzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1146] 525
[1147] Prepared from Example 283 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.01-1.86 (6H, m), 1.98-2.09 (1H, t),
2.21-2.35 (1H, t), 2.76-2.99 (5H, m), 3.44-3.87 (6H, m), 4.44 (2H,
s), 7.00-7.35 (9H, m), 8.71 (2H, d), 9.09 (1H, s); MS (APCI.sup.+)
found (M+1)=578; C31H33F2N5O2S requires 577.
EXAMPLE 335
1-(5-(N-But-1-yl-N-methylaminocarbonyl)pent-1-yl)-2-(3,4-difluorobenzyl)th-
io-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1148] 526
[1149] Prepared from Example 283 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.20-1.87 (13H, m), 2.24-2.39 (2H, q),
2.88-2.99 (3H, d), 3.18-3.42 (2H, m), 3.68-3.88 (4H, m), 4.44 (2H,
s), 7.00-7.29 (4H, m), 8.72 (2H, s), 9.09 (1H, s);MS (APCI.sup.+)
found (M+1)=530; C.sub.27H.sub.33F.sub.2N.sub.5O.sub.2S requires
529.
EXAMPLE 336
1-((R)-1-(Hex-1-ylaminocarbonyl)ethylaminocarbonylmethyl)-2-(4-fluorobenzy-
l)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1150] 527
[1151] Prepared from Example 280 by general method E. .sup.1H-NMR
(d.sub.6 DMSO) .delta. 0.8-0.95 (3H, m), 1.15-1.5 (11H,m), 2.95-3.2
(2H,m), 3.64 (2H,s), 4.34.5 (3H,m), 4.64 (2H,s), 6.95-7.1 (2H,m),
7.3-7.5 (2H,m), 7.71 (1H,d), 8.47 (1H,bd), 8.7 (2H,s), 8.97 (1H,s);
MS (APCI.sup.+) found (M+1)=541; C.sub.27H.sub.33FN.sub.6O.sub.3S
requires 540.
EXAMPLE 337
1-((S)-1-(Hex-1-ylaminocarbonyl)ethylaminocarbonylmethyl)-2-(4-fluorobenzy-
l)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1152] 528
[1153] Prepared from Example 280 by general method E. .sup.1H-NMR
(d.sub.6 DMSO) .delta. 0.8-0.95 (3H, m), 1.2-1.55 (11H,m), 3.0-3.25
(2H,m), 3.64 (2H,s), 4.35-4.5 (3H,m), 4.60 (2H,s), 6.90-7.05
(2H,m), 7.25-7.45 (4H,m), 8.3 (1H,bd), 8.71 (2H,s), 9.01 (1H,s); MS
(APCI.sup.+) found (M+1)=541; C.sub.27H.sub.33FN.sub.6O.sub.3S
requires 540.
EXAMPLE 338
1-((S)-2-(Hex-1-ylaminocarbonyl)pyrrolidin-1-ylcarbonylmethyl)-2-(4-fluoro-
benzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1154] 529
[1155] Prepared from Example 280 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.8-0.95 (3H, m), 1.15-1.55 (8H,m), 1.75-2.45
(4H,m), 3.0-3.8 (6H,m), 3.72 (2H,bd), 4.35-4.60 (5H,m), 6.43
(1H,m), 6.90-7.05 (2H,m), 7.26 (1H,s), 7.27-7.45 (2H,m), 8.71
(2H,s), 9.09 (1H,s); MS (APCI.sup.+) found (M+1)=567;
C.sub.29H.sub.35FN.sub.6O.sub.3S requires 566.
EXAMPLE 339
1-(1-Pyrrolidinocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmeth-
yl)pyrimidin-4-one
[1156] 530
[1157] Prepared from Example 280 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.87-2.08 (4H, m), 3.44-3.52H (4H, m), 3.72
(2H, s) 4.46 (2H, s), 4.49 (2H, s), 6.95 (3H, m), 7.34 (2H, m),
8.73 (2H, s), 9.10 (1H, s); MS (APCI.sup.+) found (M+1)=440;
C.sub.22H.sub.22FN.sub.5O.- sub.2S requires 439.
EXAMPLE 340
1-(3-Butoxyprop-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-
-5-ylmethyl)pyrimidin-4-one
[1158] 531
[1159] Prepared from Example 280 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.89 (3H, t), 1.32 (2H, m), 1.47 (2H, m), 1.75
(2H, m), 3.32-3.44 (4H, m), 3.51 (2H, t), 3.71 (2H, s), 4.31 (2H,
s), 4.47 (2H, s), 6.73 (1H, br, t), 6.98(3H, m), 7,32 (2H, m), 8.71
(2H, s), 9.11 (1H, s); MS (APCI.sup.+) found (M+1)=500;
C.sub.25H.sub.30FN.sub.5.sub.3S requires 499.
EXAMPLE 341
1-(6-Hydroxyhex-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio
5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1160] 532
[1161] Prepared from Example 280 by general method E. .sup.1H-NMR
(CDCl.sub.3/d.sub.6 DMSO) .delta. 1.2-1.6 (8H, m), 3.14 (2H,q), 3.5
(2H,q), 3.67 (2H,s), 3.95 (1H,t) 4.44 (2H,s), 4.52 (2H,s), 6.9-7.1
(2H,m), 7.3-7.5 (2H,m), 7.51(1H,s), 8.04 (1H,bt), 8.73 (2H,s), 9.01
(1H,s); MS (APCI.sup.+) found (M+1)=486;
C.sub.24H.sub.28FN.sub.5O.sub.3S requires 485.
EXAMPLE 342
1-(6-(4-Fluorophenyl)hex-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-
-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1162] 533
[1163] Prepared from Example 280 by general method E. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.20-1.55 (8H, m), 2.51 (2H, m), 3.05 (2H,
m), 3.59 (2H, s), 4.38 (2H, s), 4.53 (2H, s), 7.03-7.22 (6H, m),
7.43 (2H, m), 7.69 (1H, s), 8.21 (1H, m), 8.71 (2H, s), 9.02 (1H,
s); MS (APCI.sup.+) M+1=564, C.sub.30H.sub.31F.sub.2N.sub.5O.sub.2S
requires 563. MPt 170.8.degree. C. (cream solid). MPt. 170.8.
EXAMPLE 343
1-(Tridec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylm-
ethyl)pyrimidin-4-one
[1164] 534
[1165] Prepared from Example 280 by general method E. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 0.85 (3H, m), 1.20 (20H, m), 1.37 (2H, m),
3.06 (2H, m), 3.59 (2H, s), 4.39 (2H, s), 4.53 (2H, s), 7.12 2H,
m), 7.44 (2H, m), 7.69 (1H, s), 8.21 (1H, m), 8.70 (2H, s), 9.05
(1H, s); MS APCI.sup.+) M+1=568, C.sub.31H.sub.42FN.sub.5O.sub.2S
requires 567. MPt 191.5.degree. C. (colourless solid).
EXAMPLE 344
1-(Tetradec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-y-
lmethyl)pyrimidin-4-one
[1166] 535
[1167] Prepared from Example 280 by general method E. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 0.85 (3H, m), 1.23 (22H, m), 1.36 (2H, m),
3.05 (2H, m), 3.59 (2H, s), 4.38 (2H, s), 4.53 (2H, s), 7.12 (2H,
m), 7.44 (2H, m), 7.69 (1H, s), 8.25 (1H, m), 8.70 (2H, s), 9.02
(1H, s); MS (APCI.sup.+) M+1=582, C.sub.32H44FN.sub.5O.sub.2S
requires 581. MPt 191.7.degree. C. (colourless solid).
EXAMPLE 345
1-(Octadec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-yl-
methyl)pyrimidin-4-one
[1168] 536
[1169] Prepared from Example 280 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.87 (3H, m), 1.25 (30H, m), 1.47 (2H, m),
3.26 (2H, m), 3.70 (2H, s), 4.37 (2H, s), 4.45 (2H, s), 5.95 (1H,
m), 6.99 (3H, m), 7.32 (2H, m), 8.70 (2H, s), 9.09 (1H, s),
MS(APCI.sup.+) M+1=638, C.sub.36H.sub.52FN.sub.5O.sub.2S requires
637. MPt 189.8.degree. C. (pale yellow solid).
EXAMPLE 346
1-(Octadec-9-(Z)-en-1ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyri-
mid-5-ylmethyl)pyrimidin-4-one
[1170] 537
[1171] Prepared from Example 280 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.88 (3H, s), 1.26 (22H, m), 1.47 (2H, m),
2.01 (4H, m), 3.26 (2H, m), 3.71 (2H, s), 4.35 (2H, s),4.46 (2H,
s), 5.33 (2H, m), 5.73 (1H, m), 6.98 (3H, m), 7.34 (2H, m), 8.70
(2H, s), 9.09 (1H, s), MS(APCI+) M+1=636,
C.sub.36H.sub.50FN.sub.5O.sub.2S requires 635. MPt 179.7.degree. C.
(cream solid).
EXAMPLE 347
1-(Octadec-9-(E)-en-1ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyri-
mid-5-ylmethyl)pyrimidin-4-one
[1172] 538
[1173] Prepared from Example 280 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.88 (3H, s), 1.26 (22H, m), 1.47 (2H, m),
1.95 (4H, m), 3.26 (2H, m), 3.70 (2H, s), 4.36 (2H, s), 4.45 (2H,
s), 5.38 (2H, m), 5.87 (1H, m), 6.98 (3H, m), 7.32 (2H, m), 8.70
(2H, s), 9.08 (1H, s), MS(APCI.sup.+) M+1=636,
C.sub.36H.sub.50FN.sub.5O.sub.2S requires 635. MPt 184.6.degree. C.
(yellow solid). MPt. 184.6.
EXAMPLE 348
1-(Dec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmeth-
yl)pyrimidin-4-one
[1174] 539
[1175] Prepared from Example 280 by general method E. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 0.85 (3H, m), 1.21 (14H, m.), 1.37 (2H, m),
3.06 (2H, m), 3.59 (2H, s), 4.39 (2H, 5), 4.53 (2H, s), 7.12 (2H,
m), 7.42 (2H, m), 7.69 (1H, S), 8.26 (1H, m), 8.70 (2H, s), 9.03
(1H, s); MS (APCI+) M+1=526, C.sub.29H.sub.36FN.sub.5O.sub.2S
requires 525. MPt 187.7.degree. C. (colourless solid). MPt.
187.7.
EXAMPLE 350
1-(Hept-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmet-
hyl)pyrimidin-4-one
[1176] 540
[1177] Prepared from Example 280 by general method E. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 0.85 (3H, m), 1.23 (18H, m), 1.35 (2H, m),
3.05 (2H, m), 3.59 (2H, S), 4.39 (2H, S), 4.53 (2H, S), 7.12 (2H,
m), 7.43 (2H, m), 7.69 (I H, s), 8.20 (I H, m), 8.71 (2H, s), 9.03
(1 H, S); MS (APCI.sup.+) M+1=554, C.sub.30H.sub.40FN.sub.5O.sub.2S
requires 553. MPt 191.1.degree. C. (colourless solid).
EXAMPLE 350
1-(Hept-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmet-
hyl)pyrimidin-4-one
[1178] 541
[1179] Prepared from Example 280 by general method E. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 0.84 (3H, m), 1.20 (8H, m), 1.37 (2H, m),
3.06 (2H, m), 3.59 (2H, s), 4.38 (2H, s), 4.54 (2H, s), 7.13 2H,
m), 7.42 (2H, m), 7.70 (1H, s), 8.26 (1H, m), 8.70 (2H, s), 9.03
(1H, s); MS (APCI.sup.+) M+1=484, C.sub.25H.sub.30FN.sub.5O.sub.2S
requires 483. MPt 189.1.degree. C. (colourless solid). MPt.
189.1.
EXAMPLE 351
1-(Oct-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmeth-
yl)pyrimidin-4-one
[1180] 542
[1181] Prepared from Example 280 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.88 (3H, t), 1.25 (10H, m), 1.48 (2H, m),
3.26 (2H, m), 3.70 (2H, s), 4.35 (2H, s), 4.46 (2H, s), 5.81 (1H,
m), 6.93-7.03 (3H, m), 7.34 (2H, m), 8.71 (2H, s), 9.08 (1H, s);
MS(APCI.sup.+) M+1=498, C.sub.26H.sub.32FN.sub.5O.sub.2S requires
497. MPt 191-192.degree. C. (colourless solid). MPt. 190-192.
EXAMPLE 352
1-(Undec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylme-
thyl)pyrimidin-4-one
[1182] 543
[1183] Prepared from Example 280 by general method E. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 0.85 (3H, m), 1.20 (16H, m), 1.37 (2H, m),
3.06 (2H, m), 3.59 (2H, s), 4.39 (2H, s), 4.53 (2H, s), 7.12 (2H,
m), 7.42 (2H, m), 7.69 (1H, s), 8.26 (1H, m), 8.70 (2H, s), 9.03
(1H, s); MS (APCI.sup.+) M+1=540. C29H38FN5O2S requires 539. MPt
190.1.degree. C. (colourless solid). MPt. 190.1.
EXAMPLE 353
1-(2-Hydroxyethylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5--
ylmethyl)pyrimidin-4-one
[1184] 544
[1185] Prepared from Example 280 by general method E as a white
solid .sup.1H-NMR (d.sub.6 DMSO) .delta. 3.15 (2H,q), 3.4 (2H,q),
3.58 (2H,s), 4.37 (2H,s), 4.57 (2H,s), 4.68 (1H,t), 7.05-7.2
(2H,m), 7.4-7.55 (2H,m), 7.70 (1H,s), 8.33 (1H,bt), 8.70 (2H,s),
9.03 (1H,s); MS (APCI.sup.+) found (M+1)=430;
C.sub.20H.sub.20FN.sub.5O.sub.3S requires 429.
EXAMPLE 354
1-(2-Methoxyethylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5--
ylmethyl)pyrimidin-4-one
[1186] 545
[1187] Prepared from Example 280 by general method E as a white
solid .sup.1H-NMR (CDCl.sub.3/d6 DMSO) .delta. 3.2-3.45 (7H,m),
3.63 (2H,s), 4.41 (2H,s), 4.59 (2H,s), 6.95-7.1 (2H,m), 7.35-7.5
(2H,m), 7.69 (1H,s), 8.37 (1H,bt), 8.70 (2H,s), 9.06 (1H,s); MS
(APCI.sup.+) found (M+1)=444; C.sub.21H.sub.22FN.sub.5O.sub.3S
requires 443.
EXAMPLE 355
1-(2-Phenylethylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-y-
lmethyl)pyrimidin-4-one
[1188] 546
[1189] Prepared from Example 280 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 2.80 (2H, t), 3.55 (2H,q), 3.66 (2H,s), 4.32
(2H,s), 4.41 (2H,s), 6.08 (1H,bt), 6.9-7.4 (10H,m), 8.66 (2H,s),
9.05 (1H,s); MS (APCI.sup.+) found (M+1)=490;
C.sub.26H.sub.24FN.sub.5O.sub.2S requires 489.
EXAMPLE 356
1-(2-(4-Pent-1-ylphenyl)ethylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-
-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1190] 547
[1191] Prepared from Example 280 by general method E. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 0.86 (3H, m), 1.25 (4H, m), 1.51 (2H, m),
2.46 (2H, m), 2.66 (2H, m), 3.24 (2H, m), 3.59 (2H, s), 4.39 (2H,
s), 4.53 (2H, s), 7.0-7.17 (6H, m), 7.46 (2H, m), 7.69 (1H, s),
8.32 (1H, m), 8.71 (2H, s), 9.02 (1H, s); MS (APCI.sup.+) M+1=560,
C.sub.31H.sub.34FN.sub.5O- .sub.2S requires 559. MPt 170.6.degree.
C. (colourless solid).
EXAMPLE 357
1-(Hex-1-ylaminocarbonylmethylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio--
5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1192] 548
[1193] Prepared from Example 280 by general method E, white solid
.sup.1H-NMR (d6 DMSO) .delta. 0.8-0.95 (3H, m), 1.2-1.45 (8H,m),
2.95-3.10 (2H,m), 3.58 (2H,s), 3.72 (2H,bd), 4.38 (2H,m), 4.64
(2H,s), 7.05-7.2 (2H,m), 7.40-7.55 (2H,m), 7.70 (1H,s), 7.75-7.9
(1H,m), 8.5-8.6 (1H,m), 8.70 (2H,s), 9.01 (1H,s); MS (APCI.sup.+)
found (M+1)=527; C.sub.26H.sub.31FN.sub.6O.sub.3S requires 526.
EXAMPLE 358
1-(N-(Dodec-1-yl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(p-
yrimid-5-ylmethyl)pyrimidin-4-one
[1194] 549
[1195] Prepared from Example 280 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.88 (3H, m), 1.25 (18H, m), 1.50 (2H, m),
2.98 (3H, d), 3.21, 3.37 each (1H, m), 3.73 (2H, s), 4.52 (4H, m),
6.88 (1H, s), 6.99 (2H, m), 7.33 (2H, m), 8.71 (2H, s), 9.10 (1H,
s), MS(APCI.sup.+) M+1=568, C.sub.31H.sub.42FN.sub.5O.sub.2S
requires 567. MPt 145.3.degree. C. (cream solid).
EXAMPLE 359
1-(N-(2-Phenylethyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-
-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1196] 550
[1197] Prepared from Example 280 by general method E as a solid.
.sup.1H-NMR (CDCl.sub.3) .delta. 2.78-2.97 (3H, m), 3.05 (2H, s),
3.42-3.57 (1H, m), 3.58-3.69 (2H, m), 3.73 (2H, s), 4.35-4.53 (3H,
m), 6.12 (1H, s), 6.90-7.43 (9H, m), 8.62-8.75 (2H, d), 9.06-9.18
(1H, d); MS (APCI.sup.+) found (M+1)=504;
C.sub.27H.sub.26FN.sub.5O.sub.2S requires 503.
EXAMPLE 360
1-(4-(But-1-ylaminocarbonyl)cyclohex-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrim-
id-5-ylmethyl)pyrimidin-4-one
[1198] 551
[1199] Prepared from Example 285 by general method E as a solid.
.sup.1H-NMR (CDCl.sub.3) .delta. 0.85-1.04 (3H, t), 1.20-2.50 (13H,
m), 3.18-3.33 (2H, q), 3.70 (2H, s), 4.01-4.20 (1H, m), 4.44 (2H,
s), 5.47-5.63 (11H, br,t), 6.93-7.07 (2H, t), 7.32-7.43 (2H, m),
7.44 (11H, s), 8.72 (2H, s), 9.08 (11H, s); MS (APCI.sup.+) found
(M+1)=510; C27H.sub.32FN.sub.5O.sub.2S requires 509.
EXAMPLE 361
1-(4-(Hex-1-ylaminocarbonyl)cyclohex-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrim-
id-5-ylmethyl)pyrimidin-4-one
[1200] 552
[1201] Prepared from Example 285 by general method E as a solid.
.sup.1H-NMR (CDCl.sub.3) .delta. 0.78-0.97 (3H, t), 1.20-2.50 (17H,
m), 3.17-3.32 (2H, q), 3.70 (2H, s), 4.03-4.20 (1H, m), 4.44 (2H,
s), 5.47-5.60 (1H, br,t), 6.92-7.06 (2H, t), 7.30-7.40 (2H, m),
7.44 (1H, s), 8.71 (2H, s), 9.09 (1H, s); MS (APCI.sup.+) found
(M+1)=538; C.sub.29H.sub.36FN.sub.5O.sub.2S requires 537.
EXAMPLE 362
1-(4-(2-Methoxyethylaminocarbonyl)cyclohex-1-yl)-2-(4-fluorobenzyl)thio-5--
(pyrimid-5-ylmethyl)pyrimidin-4-one
[1202] 553
[1203] Prepared from Example 285 by general method E as a solid.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.58-1.90 (4H, m), 2.02-2.30 (4H,
m), 2.48 (11H, br,s), 3.36 (3H, s), 3.47 (4H, s), 3.64 (2H, s),
4.03-4.20 (1H, m), 4.44 (2H, s), 5.91 (1H, br,s), 6.92-7.06 (2H,
t), 7.31-7.45 (3H, m), 8.72 (2H, s), 9.06 (1H, s); MS (APCI.sup.+)
found (M+1)=512; C.sub.26H.sub.30FN.sub.5O.sub.3S requires 511.
EXAMPLE 363
1-(1-(6-(4-Fluorophenyl)hex-1-yl)aminocarbonyl)cycloprop-1-yl)-2-(4-fluoro-
benzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1204] 554
[1205] Prepared from Example 269, analogously to Example 315.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.15-1.71 (10H, m), 1.73-1.89 (1H,
m), 1.94-2.01 (1H, m), 2.47-2.52 (2H, t), 2.98-3.18 (1H, m),
3.20-3.39 (1H, m), 3.60-3.69 (2H, d), 4.38 (2H, s), 5.64-5.78 (1H,
br,t), 6.88-7.01 (4H, m), 7.03-7.20 (3H, m), 7.28-7.40 (2H, m),
8.68 (2H, s), 9.07 (1H, s); MS (APCI.sup.+) found (M+1)=590;
C.sub.32H.sub.33F.sub.2N.sub.5O.sub.2S requires 589.
EXAMPLE 364
1-(1-(Non-1-ylaminocarbonyl)cycloprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyri-
mid-5-ylmethyl)pyrimidin-4-one
[1206] 555
[1207] Prepared from Example 269, analogously to Example 315.
.sup.1H-NMR (CDCl.sub.3) .delta. 0.78-0.98 (3H, t), 1.11-1.69 (16H,
m), 1.73-1.89 (1H, m), 1.95-2.11 (1H, m), 3.00-3.19 (1H, m),
3.22-3.41 (1H, m), 3.55-3.78 (2H, br,q), 4.40 (2H, s), 5.52-5.65
(1H, br,t), 6.92-7.07 (2H, t), 7.26 (1H, s), 7.29-7.40 (2H, m),
8.69 (2H, s), 9.09 (1H,s); MS (APCI.sup.+) found (M+1)=538;
C.sub.29H.sub.36FN.sub.5O.sub.2S requires 537.
EXAMPLE 365
1-((R)-1-(Non-1-ylaminocarbonyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-
-ylmethyl)pyrimidin-4-one
[1208] 556
[1209] Prepared from Example 272. analogously to Example 315.
.sup.1H-NMR (CDCl.sub.3) .delta. 0.80-0.94 (3H, t), 1.15-1.37 (12H,
m), 1.38-1.54 (2H, m), 1.55-1.66 (3H, d), 3.10-3.36 (2H, m),
3.58-3.80 (2H, br,q), 4.32-4.55 (2H, br,q), 4.72-4.88 (1H, q),
6.08-6.20 (1H, br,t), 6.41-7.06 (2H, t), 7.29-7.39 (2H, m), 7.50
(1H, s), 8.70 (2H, s), 9.07 (11H, s); MS (APCI.sup.+) found
(M+1)=526; C.sub.28H.sub.36FN.sub.5O.sub.2S requires 525.
EXAMPLE 366
1-(11-(Dimethylamino)undec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-
-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1210] 557
[1211] Prepared from Example 280 by general method E. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.20 (16H, m), 1.37 (2H, m), 2.15 (6H, s),
2.22 (2H, m), 3.07 (2H, m), 3.59 (2H, s), 4.38 (2H, s), 4.5 4 (2H,
s), 7.13 (2H, m), 7.43 (2H, m), 7.70 (2H, s), 8.26 (1H, m), 8.70
(2H, A), 9.03 (1H, s); MS (APCI.sup.+) M+1=583,
C.sub.31H.sub.43FN.sub.6O.sub.2S requires 582. MPt 152-1552C
(colourless solid). MPt. 152-155.
EXAMPLE 367
1-(2-(6-(4-Fluorophenyl)hex-1-yloxy)ethylaminocabonylmethyl)-2-(4-fluorobe-
nzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1212] 558
[1213] Prepared from Example 280 by general method E. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.26 (4H, m), 1.47 (4H, m), 2.56 (2H, m),
3.23 (2H, m), 3.40 (4H, m), 3.59 (2H, s), 4.38 (2H, s), 4.56 (2H,
s), 7.03-7.21 (6H, m), 7.43 (2H, m), 7.69 (1H, s), 8.26 (1H, m),
8.70 (2H, s), 9.03 (1H, s); MS (APCI.sup.+) M+1=608,
C.sub.32H.sub.35F.sub.2N.sub.5- O.sub.3S requires 607. MPt
155-159.degree. C. (colourless solid). MPt. 155-159.
EXAMPLE 368
1-(5-(Methoxycarbonyl)-5-(benzyloxycarbonylamino)pent-1-ylaminocarbonylmet-
hyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1214] 559
[1215] Prepared from Example 280 by general method E. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.35 (4H, m), 1.61 (2H, m), 3.05 (2H, m),
3.61 (5H, m), 3.99 (1H, m), 4.38 (2H, s), 4.52 (2H, s), 5.03 (2H,
s), 7.11 (2H, m), 7.34 (5H, m), 7.44 (2H, m), 7.69 (2H, m), 8.24
(1H, m), 8.71 (2H, s), 9.02 (1H, s); MS (APCI+) M+1=663,
C.sub.33H.sub.35FN.sub.6O.sub.- 6S requires 662. (colourless
solid).
EXAMPLE 369
1-(5-(Methoxycarbonyl)pent-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-
-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1216] 560
[1217] Prepared from Example 280 by general method E. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 1.19-1.55 (6H, m), 2.24 (2H, m), 3.06 (2H,
m), 3.58 (3H, s), 3.60 (2H, s), 4.39 (2H, s), 4.53 (2H, s), 7.12
(2H, m), 7.44 (2H, m), 7.69 (1H, s), 8.26 (1H, m), 8.70 (2H, s),
9.03 (1H, s); MS (APCI.sup.+) M+1=514,
C.sub.25H.sub.28FN.sub.5O.sub.4S requires 513. MPt 166.8.degree. C.
(colourless solid). MPt. 166-172.
EXAMPLE 370
1-(Non-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmeth-
yl)pyrimidin-4-one
[1218] 561
[1219] Prepared from Example 280 by general method E. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 0.85 (3H, m), 1.21 (12H, bs), 1.35 (2H, m),
3.07 (2H, m), 3.60 (2H, s), 4.39 (2H, s), 4.53 (2H, s), 7.14 (2H,
m), 7.45 (2H, m), 7.69 (1H, s), 8.22 (1H, m), 8.68 (2H, s), 9.06
(1H, s); MS (APCI.sup.+) M+1=512, C.sub.27H.sub.34FN.sub.5O.sub.2S
requires 511. MPt 200-202.degree. C. (colourless solid).
EXAMPLE 371
1-Dimethylaminocarbonylmethyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl-
)pyrimidin-4-one
[1220] 562
[1221] Prepared from Example 280 by general method E as a solid.
.sup.1H-NMR (DMSO) .delta. 2.86 (3H, s), 2.97 (3H, s), 3.59 (2H,
s), 4.39 (2H, s), 4.86 (2H, s), 7.06-7.20 (2H, t), 7.49-7.52 (2H,
m), 7.59 (1H, s), 8.70 (2H, s), 9.04 (1H, s); MS (APCI.sup.+) found
(M+1)=414; C.sub.20H.sub.20FN.sub.5O.sub.2S requires 413.
EXAMPLE 372
1-(N-(2-Hydroxyethyl)-N-methylaminocabonylmethyl)-2-(4-fluorobenzyl)thio-5-
-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1222] 563
[1223] Prepared from Example 280 by general method E, pale yellow
solid .sup.1H-NMR (d6 DMSO) .delta. 2.86+3.02 (2H,2.times.s),
3.2-3.65 (6H,m), 4.39 (2H,s), 4.6-5.05 (3H,m), 7.05-7.2 (2H,m),
7.35-7.55 (2H,m), 8.70 (2H,s), 9.03 (1H,s); MS (APCI.sup.+) found
(M+1)=444; C.sub.21H.sub.22FN.sub.5O.sub.3S requires 443.
EXAMPLE 373
1-(trans-(4-Fluorobenzylaminocarbonyl)cyclohex-1-ylmethyl)-2-(4-fluorobenz-
yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1224] 564
[1225] Prepared from Example 273, analogously to Example 315.
.sup.1H-NMR (CDCl.sub.3) .delta. 0.80-2.15 (10H, m), 3.51-3.65 (2H,
d), 3.71 (2H, s), 4.33-4.43 (2H, d), 4.47 (2H, s), 5.64-5.78 (1H,
br,t), 6.89 (1H, s), 6.92-7.08 (4H, t), 7.15-7.44 (4H, m), 8.69
(2H, s), 9.10 (1H, s); MS (APCI.sup.+) found (M+1)=576;
C.sub.31H.sub.31F.sub.2N.sub.5O.sub.2S requires 575.
EXAMPLE 374
1-(trans-4-(Pent-1-ylaminocarbonyl)cyclohex-1-ylmethyl)-2-(4-fluorobenzyl)-
thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1226] 565
[1227] Prepared from Example 273, analogously to Example 315.
.sup.1H-NMR (CDCl.sub.3) .delta. 0.81-2.09 (19H, m), 3.16-3.40 (2H,
q), 3.52-3.65 (2H, d), 3.71 (2H, s), 4.46 (2H, s), 5.32-5.45 (1H,
br,t), 6.89 (1H, s), 6.95-7.08 (2H, t, 7.30-7.45 (2H, m), 8.70 (2H,
s), 9.11 (1H, s); MS (APCI.sup.+) found (M+1)=538;
C.sub.29H.sub.36FN.sub.5O.sub.2S requires 537.
EXAMPLE 375
1-(3-(Hex-l
ylaminocarbonyl)prop-1-yl)-2-(4-fuorobenzyl)thio-5-((1-methyl--
2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one
[1228] 566
[1229] Prepared from Example 281 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.88 (3H, t), 1.28 (6H, m), 1.45 (2H, m), 2.04
(2H, m), 2.20 (2H, m), 3.19 (2H, m), 3.50 (3H, s), 3.54 (2H, s),
3.86 (2H, t), 4.47 (2H, s), 5.69 (1h, bm), 6.21 (1H, m), 6.34 (1H,
s), 7.01 (2H, m), 7.09 (1H, s), 7.19 (1H, d), 7.39 (2H, m): MS
(APCI.sup.+) M+1=527, C.sub.28H.sub.35FN.sub.4O.sub.3S requires
526. MPt 134-136.degree. C. (colourless solid). MPt. 134-136.
EXAMPLE 376
1-(N-(N'-Hex-1-yl-N'-methylaminocarbonylmethyl)-N-methyl-aminocarbonylmeth-
yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1230] 567
[1231] Prepared from Example 280 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.88 (3H, m), 1.28 (6H, m), 1.4-1.65 (2H, m),
2.92-3.09 (6H, m), 3.17-3.36 (2H, m), 3.70 (2H,s), 4.05-4.19 (2H,
m), 4.48-4.67 (4H, m), 6.97 (2H, m) 7.07 (1H, s), 7.35 (2H, m),
8.71 (2H, s), 9.08 (1H, s); MS (APCI+) found (M+1)=555;
C.sub.28H.sub.35FN.sub.6O.sub.3- S requires 554.
EXAMPLE 377
1-(N-(N'-Hex-1-ylaminocarbonylmethyl)-N-methylaminocarbonyl-methyl)-2-(4-f-
luorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1232] 568
[1233] Prepared from Example 280 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.87 (3H, m), 1.26 (6H, m), 1.44 (2H, m), 2.98
and 3.14 (3H,2.times.s), 3.19 (2H, m), 3.70 (2H, s), 3.87 and 3.97
(2H, 2.times.s), 4.46 (2H, m), 4.64 (2H, m), 5.98 and 6.16 (1H,
2.times.t), 6.98 (3H, m), 7.33 (2H, m), 8.70 (2H, s), 9.08 (1H, s);
MS (APCI.sup.+) found (M+1)=541; C.sub.27H.sub.33FN.sub.6O.sub.3S
requires 540.
EXAMPLE 378
1-(N-(N'-Hex-1-yl-N'-methylaminocarbonylmethyl)aminocarbonyl-methyl)-2-(4--
fluorobenzyl)thio-5-ylmethyl)pyrimidin-4-one
[1234] 569
[1235] Prepared from Example 280 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.88 (3H, m), 1.28 (6H, m), 1.52 (2H, m), 2.94
(3H, m), 3.18 and 3.38 (2H, 2.times.t), 3.72 (2H, s), 4.03 (2H, m),
4.47 (4H, m), 6.98 (3H, m), 7.34 (2H, m), 8.71 (2H, s), 9.09 (1H,
s); MS (APCI.sup.+) found (M+1)=541;
C.sub.27H.sub.33FN.sub.6O.sub.3S requires 540.
EXAMPLE 379
1-Phenylaminocarbonylmethyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)p-
yrimidin-4-one
[1236] 570
[1237] Prepared from Example 280 by general method E. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.62 (2H,s), 4.41 (2H,s), 4.79 (2H,s),
7.0-7.2 (3H,m), 7.25-7.4 (2H,m), 7.4-7.6 (4H,m), 7.76 (2H,bs), 8.72
(2H,s), 9.04 (1H,s); MS (APCI.sup.+) found (M+1)=462;
C.sub.24H.sub.20FN.sub.5O.sub.2S requires 461.
EXAMPLE 380
1-(4-Methoxycarbonylbenzylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(p-
yrimid-5-ylmethyl)pyrimidin-4-one
[1238] 571
[1239] Prepared from Example 280 by general method E. .sup.1H-NMR
(d.sub.6-DMSO) .delta. 3.60 (2H,s), 3.86 (3H,s), 4.38 (2H,s), 4.40
(2H,s), 4.67 (2H,s), 7.05-7.25 (2H,m), 7.3-7.55 (4H,m), 7.74
(1H,s), 7.84 (2H,d), 8.70 (2H,s), 8.93 (1H,t), 9.03 (1H,s); MS
(APCI.sup.+) found (M+1)=532; C.sub.17H.sub.24FN.sub.5O.sub.4S
requires 533.
EXAMPLE 381
1-(N-Benzylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmeth-
yl)pyrimidin-4-one
[1240] 572
[1241] Prepared from Example 280 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 3.66(2H,s), 4.41(4H,s), 4.45(2H,d,j=5.7 Hz),
6.40(1H,brs), 6.94(1H,t,j=8.6 Hz), 7.03(1H,s), 7.23(8H,m),
8.66(2H,s), 9.06(1H,s): MS (APCI) found (M+H)=476;
C.sub.25H.sub.22FN.sub.5O.sub.2S requires 475.
EXAMPLE 382
1-(N,N-Di-(but-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-
-5-ylmethyl)pyrimidin-4-one
[1242] 573
[1243] Prepared from Example 280 by general method E. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.8-1.05 (6H,m), 1.1-1.75 (8H,m), 3.19 (2H,t),
3.33 (2H,t), 3.72 (2H,s), 4.49 (2H,s), 4.52 (2H,s), 6.85-7.1
(3H,m), 7.3-7.45 (2H,m), 8.70 (1H,s), 9.09 (1H,s); MS (APCI+) found
(M+1 )=498, C.sub.28H.sub.32FN.sub.5O.sub.2S requires 497
EXAMPLE 383
1-(N-Methyl-N-(dodec-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-
-methoxypyrimid-5-ylmethyl)pyrimidin-4-one
[1244] 574
[1245] Prepared from Example 108 by general method C2. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.85 (3H,t), 1.2 (18H,m), 1.5 (2H,m,), 2.92
and 2.95 (3H,2.times.s), 3.17 and 3.33 (2H,2.times.m), 3.63 (2H,s),
3.96 (3H,s), 4.45 (2H,s), 4.49 and 4.52 (2H,2.times.s), 6.79
(1H,s), 6.95 (2H,m), 7.30 (2H,m), 8.42 (2H,s); MS (APCI+) found
(M+1)=598, C.sub.32H.sub.44FN.sub.5- O.sub.3S requires 597.
EXAMPLE 384
1-(N-Methyl-N-(oct-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-m-
ethoxypyrimid-5-ylmethyl)pyrimidin-4-one
[1246] 575
[1247] Prepared from Example 108 by general method C2. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.8-0.95 (3H,m), 1.1-1.7 (12H,m), 2.95 and
2.99 (3H,2.times.s), 3.21 and 3.36 (2H, 2.times.t), 3.66 (2H,s),
3.99 (3H,s), 4.48 (2H,s), 4.51 and 4.55 (2H,d), 6.80 (1H,s),
6.9-7.1 (2H,m), 7.3-7.45 (2H,m), 8.45 (2H,s); MS (APCI+) found
(M+1)=542; C.sub.28H.sub.36FN.sub.5- O.sub.3S requires 541.
EXAMPLE 385
1-(N-Methyl-N-(oct-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-e-
thoxypyrimid-5-ylmethyl)pyrimidin-4-one
[1248] 576
[1249] Isolated as an impurity from one of the batches of Example
384, which had in turn been made from an impure batch of Example
108. .sup.1H-NMR (CDCl.sub.3) .delta. 0.8-0.95 (3H,t), 1.1-1.7
(12H,m), 1.42 (3H,t), 2.95 and 2.99 (3H,2.times.s), 3.23 and 3.36
(2H, 2.times.t), 3.65 (2H,s), 4.39 (2H,q), 4.49 (2H,s), 4.50 and
4.54 (2H,d), 6.77 (1H,s), 6.9-7.1 (2H,m), 7.3-7.4 (2H,m), 8.43
(2H,s): MS (APCI+) found (M+1)=556;
C.sub.29H.sub.39FN.sub.5O.sub.3S requires 555.
EXAMPLE 386
1-(N-Methyl-N-(oct-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-b-
enzyloxypyrimid-5-ylmethyl)pyrimidin-4-one
[1250] 577
[1251] Prepared from Example 109 by general method C2. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.75-1.0 (3H,t), 1.05-1.75 (12H,m), 2.95 and
2.98 (3H, 2.times.s), 3.20 and 3.36 (2H, 2.times.s), 3.65 (2H,s),
4.4-4.6 (4H,m), 5.42 (2H,s), 6.80 (1H,s), 6.9-7.1 (2H,m), 7.05-7.2
(2H,m), 7.15-7.55 (7H,m), 8.45 (2H,s); MS (APCI-) found (M+1)=618;
C.sub.34H.sub.40FN.sub.5O.sub.3S requires 617.
EXAMPLE 387
1-(N-Methyl-N-(dodec-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-
-oxopyrimid-5-ylmethyl)pyrimidin-4-one
[1252] 578
[1253] To a stirring solution of Example 383 (7.05 g) in
dichloromethane (200 ml) was added in one portion
B-bromocatecholborane (10 g). After stirring for 16 h at room
temperature, the mixture was poured into water with stirring,
diluted with more dichloromethane, shaken, and the phases allowed
to separate slowly. The organic layer was purified by flash
chromatography (silica, methanol-dichloromethane) and trituration
with pet, ether. .sup.1H-NMR (CDCl.sub.3) .delta. 0.87 (3H,m),
1.2-1.4 (20,m), 2.88 and 2.96 (3H,2.times.s), 3.15-3.4 (4H,m), 3.43
(2H,s), 4.41 (2H,m), 4.88 (2H,m), 6.9-7.0 (2H,m), 7.25-7.4 (2H,m),
7.50 (1H,m), 8.15 (2H,b); MS (APCI+) found (M+1)=584;
C.sub.31H.sub.42FN.sub.5O.sub.3S requires 583.
EXAMPLE 388
1-(N-Methyl-N-(oct-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-o-
xopyrimid-5-ylmethyl)pyrimidin-4-one
[1254] 579
[1255] Prepared analogously to Example 387, from Example 384.
.sup.1H-NMR (d.sub.6 DMSO) .delta. 0.8-0.95 (3H,m), 1.05-1.65
(12,m), 2.81 and 2.94 (3H,2.times.s), 3.15-3.4 (4H,m), 4.39 (2H,s),
4.83 and 4.85 (2H,2.times.d), 7.05-7.2 (2H,m), 7.35-7.55 (3H,m),
7.95-8.35 (2H,b); MS (APCI+) found (M+1)=526.
C.sub.27H.sub.35FN.sub.5O.sub.3S requires 525.
EXAMPLE 389
1-(3-(N-(Hept-1-yl)-N-methylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5-
-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1256] 580
[1257] Prepared from Example 288 by general method E. .sup.1H NMR
(DMSO-d.sub.6) .delta. 0.7-1.05 (m, 6H), 1.3 (m, 5H), 1.41 (m, 1H),
1.56 (br s, 1H), 2.9 (d, 3H), 3.15 (m, 1H), 3.4 (m, 1H), 3.63 (s,
2H), 4.30 (s, 2H), 7.10 (t, 2H), 7.41 (m, 2H), 7.55 (m, 1H),
7.60-7.85 (m, 3H), 7.95 (m, 1H), 8.78 (s, 2H), 9.02 (s, 1H). MS
(APCI+) Found (M+1)=560; C.sub.31H.sub.34FN.sub.5O.sub.2S requires
559.
EXAMPLE 390
1-(3-(N-Ethyl-N-methylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5-(pyri-
mid-5-ylmethyl)pyrimidin-4-one
[1258] 581
[1259] Prepared from Example 288 by general method E. .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.0-1.2 (m, 3H), 2.9 (d, 3H), 3.18 (m, 1H),
3.45 (m, 1H), 3.62 (s, 2H), 4.31 (s, 2H), 7.10 (t, 2H), 7.40 (m,
2H), 7.60-7.85 (m, 4H), 7.96 (s, 1H), 8.78 (s, 2H), 9.01 (s, 1H).
MS (APCI+) Found (M+1)=490; C.sub.26H.sub.24FN.sub.5O.sub.2S
requires 489.
EXAMPLE 391
1-(4-(Prop-1-ylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-y-
lmethyl)pyrimidin-4-one
[1260] 582
[1261] Prepared from Example 292 by general method E. .sup.1H NMR
(CDCl.sub.3) .delta. 1.00 (t, 3H), 1.65 ((m, 2H), 3.44 (q, 2H),
3.81 (s, 2H), 4.35 (s, 2H), 6.15 (t, 1H), 6.95 (t, 2H), 7.20 (s,
1H), 7.25 (m, 2H), 7.41 (d, 2H), 7.89 (d, 2H), 8.95 (s, 2H), 9.20
(s, 1H), MS (APCI+) Found (M+1)=490;
C.sub.26H.sub.24FN.sub.5O.sub.2S requires 489.
EXAMPLE 392
1-(4-(But-1-ylaminocarbonyl)phenyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)th-
io-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1262] 583
[1263] Prepared from Example 293 by general method E. .sup.1H NMR
(CDCl.sub.3) .delta. 1.01 (t, 3H), 1.21 (m, 2H), 1.3 (m, 6H), 1.7
(m, 4H), 2.91 (t, 2H), 3.15 (t, 2H), 3.46 (m, 2H), 3.73 (s, 2H),
6.29 (t, 1H), 7.03 (s, 1H), 7.4 (m, 4H), 7.95 (m, 4H), 8.71 (s,
2H), 9.08 (s, 1H), MS (APCI+) Found (M+1)=618/620;
C.sub.33H.sub.36ClN.sub.5O.sub.3S requires 618.
EXAMPLE 393
1-(4-(Hex-1-yloxycarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5-pyrimid-5-ylmet-
hyl)pyrimidin-4-one
[1264] 584
[1265] Prepared from Example 292 by general method E as a white
solid, m.p. 121-123.degree.. .sup.1H-NMR (CDCl.sub.3) .delta. 0.89
(t, 3H), 1.35 (m, 4H), 1.65 (m, 4H), 3.46 (q, 2H), 3.74 (s, 2H),
4.36 (s, 2H), 6.11 (t, 1H), 6.95 (t, 2H), 7.04 (s, 1H), 7.30 (m,
2H), 7.39 (d, 2H), 7.90 (d, 2H), 8.72 (s, 2H), 9.10 (s, 1H). MS
(APCI+) Found (M+1)=532; C.sub.29H.sub.30FN.sub.5O.sub.2S requires
531.
EXAMPLE 394
1-(4-Methylaminocarbonylbenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmeth-
yl)pyrimidin-4-one
[1266] 585
[1267] Carbonyl diimidazole (105 mg, 0.65 mmol) was added to a
suspension of Example 284 (150 mg, 0.32 mmol) in dichloromethane
(10 ml) under an atmosphere of argon and the reaction stirred for 1
h. Methylamine (1.62 ml, 2M solution in THF) was added and stirring
continued for 2 h. The solvent was removed under reduced pressure
and the residue partitioned between ethyl acetate and water. The
aqueous phase was extracted with ethyl acetate and the combined
organic phase dried (MgSO.sub.4) and the the solvent removed under
reduced pressure. The residue was purified by flash chromatography
(10% methanol/ethyl acetate) to afford the desired compound as an
off white solid (77 mg, 50%).
[1268] .sup.1H-NMR (CDCl.sub.3) 8.90 (s, 1H), 8.47 (s, 2H), 7.60
(m, 2H), 7.25-6.65 (m, 6H), 6.28 (s, 1H), 4.85 (s, 2H), 4.27 (s,
2H), 3.51 (s, 2H), 2.85 (s, 3H). MS (AP+) 476 (M+H.sup.+,
100%).
EXAMPLE 395
1-(3-Methylaminocarbonyl-4-(hept-1-yloxy)benzyl)-2-(4-fluorobenzyl)thio-5--
(pyrimid-5-ylmethyl)pyrimidin-4-one
[1269] 586
[1270] Prepared analogously to Example 394, from Example 298, as an
off white solid. 1H-NMR (CDCl.sub.3) 8.98 (s, 1H), 8.67 (s, 2H),
8.58 (s, 1H), 8.06 (m, 1H), 7.28 (m, 2H), 7.06 (m, 2H), 6.89 (m,
2H), 4.87 (s, 2H), 4.38 (s, 2H), 4.05 (t, 2H), 3.58 (s, 2H), 2.93
(s, 3H), 1.81 (m, 2H), 1.45-1.15 (m, 8H), 0.82 (m, 3H). MS (AP+)
590 (M+H.sup.+, 100%).
EXAMPLE 396
1-(2-(t-Butoxycarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylm-
ethyl)pyrimidin-4-one
[1271] 587
[1272] Prepared from intermediate B138 by general method A2.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.41 (9H, s), 3.43 (2H, q, J 6.0
Hz), 3.67 (2H, s), 3.97 (2H, s), 4.46 (2H, s), 4.88 (1H, s), 6.99
(2H, m), 7.07 (1H, s), 7.36 (2H, m), 8.70 (2H, s) and 9.09 (1H, s).
(APCI+) Found (M+1)=472. C.sub.23H.sub.26FN.sub.5O.sub.3S requires
471.
EXAMPLE 397
1-(2-(Trifluoroacetylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylme-
thyl)pyrimidin-4-one
[1273] 588
[1274] The compound of Example 396 (200 mg) was dissolved in neat
TFA (1 ml) at room temperature. After 5 min, the solution was
concentrated to a brown gum and re-evaporated from ethyl acetate.
The crude amine salt in ethyl acetate (5 ml) was treated with
diisopropylethylamine (81 mg) and acetyl chloride (50 mg) for 24 h.
The crude reaction mixture was purified by silica gel
chromatography to give the title compound as a colourless solid.
(72 mg, 37%), .sup.1H-NMR (CDCl.sub.3) .delta. 3.58 (2H, s), 3.77
(2H, m), 4.11 (2H, t, J 4.7 Hz), 4.37 (2H, s), 6.92-7.02 (3H, m),
7.24-7.31 (2H, m), 8.63 (2H, s), 9.04 (1H, s) and 9.13 (1H, t, J
5.5 Hz). (APCI-) Found (M-1)=466.
C.sub.20H.sub.17F.sub.4N.sub.5O.sub.2S requires 467.
EXAMPLE 398
1-(2-(Benzoylamino)ethyl)-2-(4-fuorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyri-
midin-4-one
[1275] 589
[1276] The compound of Example 396 was treated with trifluoroacetic
acid as described in the previous example. A solution of the salt
in ethyl acetate was treated with excess 1M hydrochloric acid in
ether. The corresponding dihydrochloride salt was precipitated,
filtered, washed with ether and dried in vacuo to give the crude
salt as a white solid.
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72
mg), 1-hydroxy-benzotriazole benzotriazole hydrate (52 mg) and
benzoic acid (42 mg) in dichloromethane (5 ml) at room temperature
was treated with the above dihydrochloride (150 mg).
Diisopropylethylamine (88 mg) in DMF (1 ml) was added and the
solution stirred for 48h. The reaction mixture was diluted with
dichloromethane washed with water, brine, dried over anhydrous
magnesium sulfate and concentrated. The crude product was purified
by silica gel chromatography to give the title compound as a white
solid, (84 mg, 52%), .sup.1H-NMR (CDCl.sub.3) 3.52 (2H, s), 3.60
(2H, m), 4.04 (2H, t, J 5.5 Hz), 4.36 (2H, s), 7.09 (2H, m),
7.35-7.53 (5H, m), 7.71-7.75 (3H, m), 8.63 (3H, m and s) and 9.02
(1H, s), (APCI.sup.+) Found (M+1)=476.
C.sub.25H.sub.22FN.sub.5O.sub.2S requires 475.
EXAMPLE 399
1-(2-(Hex-1-ylcarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylm-
ethyl)pyrimidin-4-one
[1277] 590
[1278] Prepared analogously to Example 398, using heptanoic acid.
1H-NMR (CDCl.sub.3) .delta. 0.87 (3H, t, J 6.8 Hz), 1.26 (6H, br,
s), 1.56 (2H, m), 2.14 (2H, t, 3 7.9 Hz), 3.54 (2H, dd, J 5.8,5.9
Hz), 3.66 (2H, s), 4.00 (2H, t, J 5.9 Hz), 4.43 (2H, s), 6.19 (1H,
t, J 5.8 Hz) 7.02 (2H, m), 7.06 (1H, s), 8.70 (2H, s) and 9.08 (1H,
s). (APCI.sup.+) Found (M+1)=484. C25H.sub.30FN.sub.5O.sub.2S
requires 483.
EXAMPLE 400
1-(2-(5-Phenylpent-1-ylcarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyri-
mid-5-ylmethyl)pyrimidin-4-one
[1279] 591
[1280] a) Prepared analogously to Example 398, using
6-phenylhexanoic acid. 1H-NMR (CDCl.sub.3) .delta. 1.33 (2H, m),
1.61 (4H, m), 2.13 (2H, t, J 7.7 Hz), 2.59 (2H, t, J 7.7 Hz), 3.52
(2H, m), 3.60 (2H, s), 3.97 (2H, t, J 5.8 Hz), 4.40 (2H, s), 6.44
(1H, t, J 5.2 Hz), 6.99 (2H, t, J 8.6 Hz), 7.04 (1H, s), 7.12-8.57
(7H, m), 8.67 (2H, s) and 9.05 (1H, s). (APCI+) Found (M+1)=546.
C.sub.30H.sub.32FN.sub.5O.sub.2S requires 545.
[1281] b) Also prepared by reaction of the amine dihydrochloride
with 6-phenylhexanoyl chloride in the presence of diisopropylamine.
After work up and purification by silica gel chromatography, the
title compound was obtained as a colourless solid in 49% yield.
EXAMPLE 401
1-(2-(Hept-1-ylcarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-yl-
methyl)pyrimidin-4-one
[1282] 592
[1283] Prepared analogously to Example 398, using octanoic acid.
1H-NMR (CDCl.sub.3) .delta. 0.86 (3H, t, J 6.8 Hz), 1.25 (8H, br,
s), 1.58 (2H, m), 2.16 (2H, t, J 7.8 Hz), 3.55 (2H, m), 3.63 (2H,
s), 4.01 (2H, t, J 5.7 Hz), 4.40 (2H, s), 6.69 (1H, br, t, J 5.4
Hz), 6.98 (2H, t, J 8.5 Hz), 7.09 (1H, s), 7.31 (2H, m), 8.69 (2H,
s) and 9.07 (1H, s). (APCI.sup.+) Found (M+1)=498.
C.sub.26H.sub.32FN.sub.5O.sub.2S requires 497.
EXAMPLE 402
1-(2-Acetylaminoethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-
-5-ylmethyl)pyrimidin-4-one
[1284] 593
[1285] Prepared from intermediate B76 by general method A4.
.sup.1H-NMR (CDCl.sub.3) .delta. 1.2-1.9(10H,m), 2.02(3H,s),
2.92(2H,t), 3.20(2H,t), 3.5-3.8(4H,m), 4.04(2H,m), 7.04(1H,s),
7.43(2H,m), 7.88(2H,m), 8.71(2H,s) and 9.06(1H,s); MS (APCI.sup.+)
found (M+1)=542; C.sub.27H.sub.32ClN.sub.- 5O.sub.3S requires
541.
EXAMPLE 403
1-(4-(tert-Butoxycarbonylamino)but-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-
-5-ylmethyl)pyrimidin-4-one
[1286] 594
[1287] Prepared from intermediate B122 by general method A2.
.sup.1H NMR (CDCl.sub.3) .delta. 1.43 (s, 9H), 1.5 (m, 2H), 1.75
(m, 2H), 3.15 (m, 2H), 3.70 (s, 2H), 3.83 (t, 2H), 4.46 (s, 2H),
4.65 (br s, 1H), 7.00 (t, 2H), 7.20 (s, 1H), 7.37 (m, 2H), 8.70 (s,
2H), 9.08 (s, 1H), MS (APCI+) Found (M+1)=500;
C.sub.25H.sub.30FN.sub.5O.sub.3S requires 499.
EXAMPLE 404
1-(3-(Ethoxycarbonylamino)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-y-
lmethyl)pyrimidin-4-one
[1288] 595
[1289] Prepared from intermediate B123 by general method A2.
.sup.1H NMR (CDCl.sub.3) .delta. 1.23 (t, 3H), 1.93 (m, 2H), 3.20
(q, 2H), 3.71 (s, 2H), 3.86 (t, 2H), 4.10 (m, 2H), 4.46 (s, 2H),
5.25 (br s, 1H), 7.00 (t, 2H), 7.30 (s, 1H), 7.40 (m, 2H), 8.72 (s,
2H), 9.06 (s, 1H). MS (APCI+) Found (M+1)=458;
C.sub.22H.sub.24FN.sub.5O.sub.3S requires 457.
EXAMPLE 405
1-(2-(Benzylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5--
ylmethyl)pyrimidin-4-one
[1290] 596
[1291] Prepared from Example 396 by general method F. 1H-NMR
(CDCl.sub.3) .delta. 3.39 (2H, s), 3.58 (2H, m), 4.03 (2H, t, J 5.7
Hz), 4.31 (2H, s), 4.30 (2H, d, J 5.0 Hz), 5.97 (1H, t, J 5.9 Hz),
6.26 (1H, t, J 5.6 Hz), 6.91-6.99 (3H, m), 7.20-8.58 (7H, m), 8.58
(2H, s) and 9.05 (1H, s). (APCI.sup.+) Found (M+1)=505.
C.sub.26H.sub.25FN.sub.6O.sub.2S requires 504.
EXAMPLE 406
1-(2-(Dodec-1-ylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimi-
d-5-ylmethyl)pyrimidin-4-one
[1292] 597
[1293] Prepared from Example 396 by general method F. 1H-NMR
(CDCl.sub.3) .delta. 0.87 (3H, t, J 6.8 Hz), 1.27 (18H, v,br s),
1.48 (2H, m), 3.17 (2H, dd, J 6.5,13.0 Hz), 3.52 (2H, m), 3.58 (2H,
s), 4.03 (2H, t, J 5.0 Hz), 4.40 (2H, s), 5.21 (1H, m), 5.70 (1H,
m), 6.95 (2H, m), 7.10 (1H, s), 7.30 (2H, m), 8.66 (2H, s) and 9.08
(1H, s). (APCI.sup.+) Found (M+1)=583.
C.sub.31H.sub.43FN.sub.6O.sub.2S requires 582.
EXAMPLE 407
1-(2-(Hept-1-ylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-
-5-ylmethyl)pyrimidin-4-one
[1294] 598
[1295] Prepared from Example 396 by general method F. .sup.1H-NMR
(CDCl.sub.3) .delta. 0.85 (3H, m), 1.26 (8H, m), 1.49 (2H, m), 3.16
(2H, m), 3.51-3.60 (4H, s and m), 4.04 (2H, t, J 5.8 Hz), 4.39 (2H,
s), 5.30 (1H, m), 5.83 (1H, m), 6.94-7.02 (2H, m), 7.07 (1H, s),
7.28-8.60 (2H, m), 8.67 (2H, s) and 9.08 (1H, s). (APCI.sup.+)
Found (M+1)=513. C.sub.26H.sub.33FN.sub.6O.sub.2S requires 512.
EXAMPLE 408
1-(2-(Oct-1-ylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid--
5-ylmethyl)pyrimidin-4-one
[1296] 599
[1297] Prepared from Example 396 by general method F. 1H-NMR
(CDCl.sub.3) .delta. 0.86 (3H, m), 1.24 (10H, m), 1.50 (2H, m),
3.17 (2H, dd, J 6.8,13.0 Hz), 3.52 (2H, m), 3.57 (2H, s), 4.04 (2H,
t, J 5.5 Hz), 4.39 (2H, s), 5.31 (1H, m), 5.85 (1H, m), 7.01 (2H,
m), 7.07 (1H, s), 7.30 (2H, m), 7.68 (2H, s) and 9.08 (1H, s).
(APCI.sup.+) Found (M+1)=527. C.sub.27H.sub.35FN.sub.6O.sub.2S
requires 526.
EXAMPLE 409
1-(2-(2-Thien-2-ylethylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5--
(pyrimid-5-ylmethyl)pyrimidin-4-one
[1298] 600
[1299] Prepared from Example 396 by general method F. 1H-NMR
(CDCl.sub.3) .delta. 3.06 (2H, t, J 6.8 Hz), 3.52 (6H, m), 4.01
(2H, t, J 5.6 Hz), 4.37 (2H, s), 5.47 (1H, t, J 5.7 Hz), 5.97 (1H,
t, J 5.3 Hz), 6.85-7.31 (8H, m), 8.65 (2H, s) and 9.07 (1H, s).
(APCI.sup.+) Found (M+1)=525.
C.sub.25H.sub.25FN.sub.6O.sub.2S.sub.2 requires 524.
EXAMPLE 410
1-(2-(1,1,3,3-Tetramethylbut-1-ylaminocarbonylamino)ethyl)-2-(4-fluorobenz-
yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1300] 601
[1301] Prepared from Example 396 by general method F. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.01 (9H, s), 1.39 (6H, s), 1.75 (2H, s), 3.51
(2H, m), 3.59 (2H, s), 4.02 (2H, t, 35.5 Hz), 4.39 (2H, s), 5.25
(1H, s), 5.78 (1H, t, J 5.6 Hz), 6.98 (2H, m), 7.13 (1H, s), 7.31
(2H, m), 8.67 (2H, s) and 9.08 (1H, s), (APCI.sup.+) Found
(M+1)=527. C.sub.27H.sub.35FN.sub.6O- .sub.2S requires 526.
EXAMPLE 411
1-(2-(4-(Butoxycarbonyl)phenylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)-
thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1302] 602
[1303] Prepared from Example 396 by general method F. 1H-NMR
(CDCl.sub.3) .delta.0 0.97 (3H, t, J 7.4 Hz), 1.44 (2H, m), 1.73
(2H, m), 3.54 (2H, s), 3.67 (2H, m), 4.13 (2H, m), 4.28 (4H, m),
6.92 (3H, m), 7.18 (2H, m), 7.55 (2H, d, J 8.8 Hz), 7.93 (2H, d, J
8.8 Hz), 8.62 (2H, s), 8.82 (1H, s) and 9.10 (1H, s). (APCI.sup.+)
Found (M+1)=591. C.sub.30H.sub.31FN.sub.6O.sub.4S requires 590.
EXAMPLE 412
1-(2-(4-(1-Methylethyl)phenylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)t-
hio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one
[1304] 603
[1305] Prepared from Example 396 by general method F. 1H-NMR
(CDCl.sub.3) .delta. 1.20 (6H, d, J 6.9 Hz), 2.84 (1H, m), 3.55
(2H, s), 3.60 (2H, m), 4.12 (2H, t, J 4.8 Hz), 4.33 (2H, s), 6.48
(1H, m), 6.92 (2H, m), 7.11-7.34 (7H, m), 8.00 (1H, s), 8.63 (2H,
s) and 9.10 (1H, s), (APCI.sup.+) Found (M+1)=533.
C.sub.28H.sub.29FN.sub.6O.sub.2S requires 532.
EXAMPLE 413
1-(2-(4-Methylphenylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(py-
rimid-5-ylmethyl)pyrimidin-4-one
[1306] 604
[1307] Prepared from Example 396 by general method F. 1H-NMR
(CDCl.sub.3) .delta. 2.29 (3H, s), 3.54 (2H, s), 3.60 (2H, m), 4.11
(2H, t J 5.5 Hz), 4.32 (2H, s), 6.50 (1H, m), 6.90-7.08 (4H, m),
7.18-7.30 (5H, m), 8.03 (1H, br,s), 8.64 (2H, s) and 9.09 (1H, s).
(APCI.sup.+) Found (M+1)=505. C26H25FN6O2S requires 504.
EXAMPLE 414
1-(2-(4-Ethoxyphenylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(py-
rimid-5-ylmethyl)pyrimidin-4-one
[1308] 605
[1309] Prepared from Example 396 by general method F. .sup.1H-NMR
(CDCl.sub.3) .delta. 1.40 (3H, t, J 4.2 Hz), 3.57 (4H, v,br,s),
3.97 (2H, q, J 4.2 Hz), 4.08 (2H, t, J 5.4 Hz), 4.34 (2H, s), 6.13
(1H, br,s), 6.79-6.98 (4H, m), 7.17 (1H, s), 7.23 (4H, m), 7.63
(1H, br,s), 8.66 (2H, s) and 9.09 (1H, s). (APCI.sup.+) Found
(M+1)=535. C.sub.27H.sub.27FN.sub.6O.sub.3S requires 534.
EXAMPLE 415
1-(2-(4-Phenoxyphenylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(p-
yrimid-5-ylmethyl)pyrimidin-4-one
[1310] 606
[1311] Prepared from Example 396 by general method F. 1H-NMR
(CDCl.sub.3) .delta. 3.56 (2H, s), 3.63 (2H, m), 4.13 (2H, m), 6.57
(1H, m), 6.57-8.22 (14H, m), 8.23 (1H, s), 8.65 (2H, s) and 9.05
(1H, s). (APCI.sup.+) Found (M+1)=583.
C.sub.31H.sub.27FN.sub.6O.sub.3S requires 582.
REFERENCES
[1312] 1. EP 645370 (1995)
[1313] 2. Eur J Med Chem 1989, 24 (1), 65
[1314] 3. Eur J Med Chem 1990, 25 (3), 217
[1315] 4. Eur J Med Chem 1993, 28 (7-8), 601
[1316] 5. J Labelled Comp Radiopharm 1987, 24 (4), 431
[1317] 6. J Med Chem 1995, 38, 3850
[1318] 7. EP 117345 (1984)
[1319] 8. EP 68833 (1982)
[1320] 9. Liebigs Ann Chem 1994, 1849
[1321] 10. J Amer Chem Soc 1950, 72, 3539
[1322] 11. GB 1 582 527
[1323] 12. Bull. Soc. Chi. Fr. 1263 (1956); ibid. 1466 (1957)
[1324] 13. DE 84-3414752A1 1984
[1325] 14. Tet Lett 1983, 24 (48), 5309-5312
[1326] 15. J. Chem. Soc. 1957, 3314.
[1327] Biological Data
[1328] 1. Screen for Lp-PLA.sub.2 Inhibition.
[1329] Enzyme activity was determined by measuring the rate of
turnover of the artificial substrate (A) at 37 C in 50 mM HEPES
(N-2-hydroxyethylpiperazine-N'-2-ethanesulphonic acid) buffer
containing 150 mM NaCl, pH 7.4. 607
[1330] Assays were performed in 96 well titre plates.
[1331] Recombinant LpPLA.sub.2 was purified to homogeneity from
baculovirus infected Sf9 cells, using a zinc chelating column, blue
sepharose affinity chromatography and an anion exchange column.
Following purification and ultrafiltration, the enzyme was stored
at 6 mg/ml at 4.degree. C. Assay plates of compound or vehicle plus
buffer were set up using automated robotics to a volume of 170
.mu.l. The reaction was initiated by the addition of 201 .mu.l of
10.times. substrate (A) to give a final substrate concentration of
20 .mu.M and 10 .mu.l of diluted enzyme to a final 0.2 nM
LpPLA.sub.2.
[1332] The reaction was followed at 405 nm and 37.degree. C. for 20
minutes using a plate reader with automatic mixing. The rate of
reaction was measured as the rate of change of absorbance.
[1333] Results
[1334] The compounds described in the above Examples were tested as
hereinbefore described and were found to have IC.sub.50 values in
the range 0.000 1 to 60 uM.
* * * * *