U.S. patent application number 14/316166 was filed with the patent office on 2016-06-02 for pharmaceutical compounds.
The applicant listed for this patent is F.HOFFMANN-LA ROCHE AG, GENENTECH, INC.. Invention is credited to Georgette Castanedo, Irina Chuckowree, Adrian Folkes, Richard Goldsmith, Janet Gunzer-Toste, Tim Heffron, Simon Mathieu, Alan Olivero, Sally Oxenford, Stephen Shuttleworth, Daniel P. Sutherlin, Nan Chi Wan, Bing-Yan Zhu.
Application Number | 20160152632 14/316166 |
Document ID | / |
Family ID | 38606432 |
Filed Date | 2016-06-02 |
United States Patent
Application |
20160152632 |
Kind Code |
A9 |
Folkes; Adrian ; et
al. |
June 2, 2016 |
PHARMACEUTICAL COMPOUNDS
Abstract
Compounds of Formulae Ia, and stereoisomers, geometric isomers,
tautomers, solvates, metabolites and pharmaceutically acceptable
salts thereof, are useful for inhibiting lipid kinases including
PI3K, and for treating disorders such as cancer mediated by lipid
kinases. Methods of using compounds of Formula Ia for in vitro, in
situ, and in vivo diagnosis, prevention or treatment of such
disorders in mammalian cells, or associated pathological
conditions, are disclosed. ##STR00001##
Inventors: |
Folkes; Adrian; (Basel,
CH) ; Shuttleworth; Stephen; (Basel, CH) ;
Chuckowree; Irina; (Basel, CH) ; Oxenford; Sally;
(Basel, CH) ; Wan; Nan Chi; (Basel, CH) ;
Castanedo; Georgette; (South San Francisco, CA) ;
Goldsmith; Richard; (South San Francisco, CA) ;
Gunzer-Toste; Janet; (South San Francisco, CA) ;
Heffron; Tim; (South San Francisco, CA) ; Mathieu;
Simon; (South San Francisco, CA) ; Olivero; Alan;
(South San Francisco, CA) ; Sutherlin; Daniel P.;
(South San Francisco, CA) ; Zhu; Bing-Yan; (South
San Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
F.HOFFMANN-LA ROCHE AG
GENENTECH, INC. |
Basel
South San Francisco |
CA |
CH
US |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20140309216 A1 |
October 16, 2014 |
|
|
Family ID: |
38606432 |
Appl. No.: |
14/316166 |
Filed: |
June 26, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11789468 |
Apr 24, 2007 |
8802670 |
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14316166 |
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60795048 |
Apr 26, 2006 |
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Current U.S.
Class: |
514/218 ;
514/232.5; 514/234.2; 540/575; 544/117; 544/82 |
Current CPC
Class: |
C07D 495/04 20130101;
A61P 25/28 20180101; C07D 491/048 20130101; A61P 35/00 20180101;
A61P 35/02 20180101; A61P 29/00 20180101; A61P 31/12 20180101; A61P
3/00 20180101; A61P 31/00 20180101; C07D 491/04 20130101; A61P 9/00
20180101; A61P 37/02 20180101; A61K 45/06 20130101; A61P 25/00
20180101; A61P 5/00 20180101; A61K 31/551 20130101; A61P 37/00
20180101; A61P 43/00 20180101; A61K 31/5377 20130101; A61P 37/04
20180101 |
International
Class: |
C07D 495/04 20060101
C07D495/04; A61K 45/06 20060101 A61K045/06; A61K 31/551 20060101
A61K031/551; A61K 31/5377 20060101 A61K031/5377; C07D 491/048
20060101 C07D491/048 |
Claims
1. A compound which is a fused pyrimidine of formula (Ia):
##STR00233## wherein X is O or S; R.sup.1 is a group of formula:
##STR00234## R.sup.2 is H, halo or C.sub.1-C.sub.6 alkyl R.sup.4
and R.sup.5 form, together with the N atom to which they are
attached, a group selected from piperazine, piperidine,
pyrrolidine, oxazolidinone, diazepan and
2,5-diaza-bicyclo[2,2,1]-heptane, which group is unsubstituted or
substituted by -[(alk).sub.q-NR].sub.r--S(O).sub.2-(alk).sub.q-Z or
--C(O)-(alk).sub.q-S(O).sub.2Z wherein Z is R.sup.10 or
--NR.sup.11R.sup.12, or by unsubstituted C.sub.1-C.sub.6 alkyl,
hydroxyl-C.sub.1-C.sub.6 alkyl, oxo (.dbd.O), -(alk).sub.q-OR,
--C(O)--C(R').sub.2--N(R).sub.2, --C(R).sub.2--C(O)--N(R).sub.2,
--C(O)--(NR).sub.q-(alk).sub.q-OR, --C(O)-cyclyl, --C(O)R,
--C(O)OR, --C(O)-Tet or --NR.sup.13R.sup.14; or one of R.sup.4 and
R.sup.5 is C.sub.1-C.sub.6 alkyl, -(alk).sub.q-Heterocyclyl or
-(alk).sub.q-OR and the other is a piperazine, piperidine,
pyrrolidine, sulphonylpyran or -(alk).sub.q-Heterocyclyl group,
wherein said piperazine, piperidine, pyrrolidine, sulphonylpyran or
Heterocyclyl is unsubstituted or substituted by C.sub.1-C.sub.6
alkyl, -(alk).sub.q-OR or --S(O).sub.2R.sup.10; R is H or
C.sub.1-C.sub.6 alkyl which is unsubstituted; each R' is,
independently, H or C.sub.1-C.sub.6 alkyl which is unsubstituted,
or the two groups R' form, together with the C atom to which they
are attached, a cyclyl group; R.sup.10 is H, cyclyl,
C.sub.1-C.sub.6 alkyl which is unsubstituted or CF.sub.3; R.sup.11
and R.sup.12 are each independently selected from H,
C.sub.1-C.sub.6 alkyl which is unsubstituted and -(alk).sub.q--OR,
or R.sup.11 and R.sup.12 together form, with the N atom to which
they are attached, a 5- or 6-membered saturated N-containing
heterocyclic group containing 0 or 1 additional heteroatoms
selected from O, N and S; R.sup.13 and R.sup.14 are each
independently selected from C.sub.1-C.sub.6 alkyl,
--S(O).sub.2R.sup.10, and -(alk).sub.q-OR; Tet is a
tetrahydrofuranyl or tetrahydropyranyl group, which group is
unsubstituted or substituted; Heterocyclyl is a 5- or 6-membered
saturated N-containing heterocyclic group containing 0 or 1
additional heteroatoms selected from O, N and S; Cyclyl is a
C.sub.3-C.sub.6 cycloalkyl group; each q is independently 0 or 1; r
is 0 or 1; alk is C.sub.1-C.sub.6 alkylene; and R.sup.3 is selected
from: (a) a group of the following formula: ##STR00235## wherein B
is a phenyl ring which is unsubstituted or substituted, and Z is
selected from H, --OR, --SR, CH.sub.2OR, --CO.sub.2R, CF.sub.2OH,
CH(CF.sub.3)OH, C(CF.sub.3).sub.2OH, --(CH.sub.2).sub.qOR,
--(CH.sub.2).sub.qNR.sub.2--C(O)N(R).sub.2, --NR.sub.2, --NRC(O)R,
--S(O).sub.mN(R).sub.2, --OC(O)R, OC(O)N(R).sub.2, --NRS(O).sub.mR,
--NRC(O)N(R).sub.2, CN, halogen and --NO.sub.2, wherein each R is
independently selected from H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.10 cycloalkyl and a 5- to 12-membered aryl or
heteroaryl group, the group being unsubstituted or substituted, m
is 1 or 2 and q is 0, 1 or 2; (b) a heteroaryl group which contains
1, 2, 3 or 4 ring nitrogen atoms and 0, 1 or 2 additional
heteroatoms selected from O and S, which group is monocyclic or
bicyclic and which is unsubstituted or substituted; and (c) a
benzene ring which is unsubstituted or substituted and which is
fused to a heteroaryl group as defined above; or a pharmaceutically
acceptable salt thereof; with the provisos that: (i) when X in
formula (Ia) is S, then R.sup.3 is other than an indole or
3-hydroxyphenyl group; (ii) when X in formula (Ib) is S, then
R.sup.3 is other than an indole group; (iii) in formula (Ia) only,
when X is S and R.sup.2 is H and R.sup.3 is indazol-4-yl, then
R.sup.4 and R.sup.5 do not form: (i) piperazine which is
unsubstituted or substituted by a group selected from methyl,
--S(O).sub.2Me, --S(O).sub.2NMe.sub.2, -alk-OH, -alk-OMe,
--S(O).sub.2-alk-NMe.sub.2, and --S(O).sub.2-alk-morpholino; or
(ii) piperidine which is substituted by a group selected from
--S(O).sub.2Me, --C(O)--NR-(alk).sub.q-OR, --NMe-S(O).sub.2-Me,
methyl, piperidine and --NR.sup.13R.sup.14 wherein one of R.sup.13
and R.sup.14 is -(alk).sub.q-OR.
2. A compound which is a fused pyrimidine of formula (Ia')
##STR00236## wherein X is O or S; Y is N or --CH--; R is H or
C.sub.1-C.sub.6 alkyl which is unsubstituted; R.sup.2 is H, halo or
C.sub.1-C.sub.6 alkyl; each R' is, independently, H,
C.sub.1-C.sub.6 alkyl or hydroxyl-C.sub.1-C.sub.6 alkyl, or two
groups R' on the same carbon atom form an oxo (.dbd.O) group; or
when Y is N, two groups R' on different carbon atoms together form
a --CH.sub.2-- bridgehead; each R'' is, independently, H or
C.sub.1-C.sub.6 alkyl, or two groups R'' on the same carbon atom
form an oxo (.dbd.O) group; Z is R.sup.10 or
-(alk).sub.q-NR.sup.11R.sup.12; R.sup.10 is H, a C.sub.3-C.sub.6
cycloalkyl group, C.sub.1-C.sub.6 alkyl which is unsubstituted, or
CF.sub.3; R.sup.11 and R.sup.12 are each independently selected
from H, C.sub.1-C.sub.6 alkyl which is unsubstituted and
-(alk).sub.q-OR, or R.sup.11 and R.sup.12 together form, with the N
atom to which they are attached, a 5- or 6-membered saturated
N-containing heterocyclic group containing 0 or 1 additional
heteroatoms selected from O, N and S; q is 0 or 1; r is 0 or 1; alk
is C.sub.1-C.sub.6 alkylene; and and R.sup.3 is selected from: (a)
a group of the following formula: ##STR00237## wherein B is a
phenyl ring which is unsubstituted or substituted and Z is selected
from H, --OR, --SR, CH.sub.2OR, --CO.sub.2R, CF.sub.2OH,
CH(CF.sub.3)OH, C(CF.sub.3).sub.2OH, --(CH.sub.2).sub.qOR,
--(CH.sub.2).sub.qNR.sub.2, --C(O)N(R).sub.2, --NR.sub.2,
--NRC(O)R, --S(O).sub.mN(R).sub.2, --OC(O)R, OC(O)N(R).sub.2,
--NRS(O).sub.mR, --NRC(O)N(R).sub.2, CN, halogen and --NO.sub.2,
wherein each R is independently selected from H, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.10 cycloalkyl and a 5- to 12-membered aryl or
heteroaryl group, the group being unsubstituted or substituted, m
is 1 or 2 and q is 0, 1 or 2; (b) a heteroaryl group which contains
1, 2, 3 or 4 ring nitrogen atoms and 0, 1 or 2 additional
heteroatoms selected from O and S, which group is monocyclic or
bicyclic and which is unsubstituted or substituted; and (c) a
benzene ring which is unsubstituted or substituted and which is
fused to a heteroaryl group as defined above; or a pharmaceutically
acceptable salt thereof; with the provisos that: (ii) R.sup.3 is
other than an indole or 3-hydroxyphenyl group when X is S; (ii) Z
is other than a group selected from Me, -(alk).sub.q-NMe.sub.2 and
-alk-morpholino when the following are satisfied: Y is N, each of
R' and R'' is H, R.sup.2 is H and R.sup.3 is indazol-4-yl; (iii) Z
is other than Me when the following are satisfied: Y is --CH--,
each of R' and R'' is H, R.sup.2 is H and R.sup.3 is
indazol-4-yl.
3. A compound which is a fused pyrimidine of formula (Ia''):
##STR00238## wherein X is O or S; R.sup.2 is H, halo or
C.sub.1-C.sub.6 alkyl; R.sup.4' is C.sub.1-C.sub.6 alkyl,
-(alk).sub.q-Heterocyclyl, or -(alk).sub.q-OR; R.sup.5' is a
piperazine, piperidine, pyrrolidine, sulphonylpyran or
-(alk).sub.q-Heterocyclyl group, wherein said piperazine,
piperidine, pyrrolidine, sulphonylpyran or Heterocyclyl group is
unsubstituted or substituted by C.sub.1-C.sub.6 alkyl,
-(alk).sub.q-OR or --S(O).sub.2R.sup.10; R is H, C.sub.1-C.sub.6
alkyl which is unsubstituted; R.sup.10 is H, a C.sub.3-C.sub.6
cycloalkyl group, C.sub.1-C.sub.6 alkyl which is unsubstituted, or
CF.sub.3; Heterocyclyl is a 5- or 6-membered saturated N-containing
heterocyclic group containing 0 or 1 additional heteroatoms
selected from O, N and S; q is 0 or 1; alk is C.sub.1-C.sub.6
alkylene; and and R.sup.3 is selected from: (a) a group of the
following formula: ##STR00239## wherein B is a phenyl ring which is
unsubstituted or substituted and Z is selected from H, --OR, --SR,
CH.sub.2OR, --CO.sub.2R, CF.sub.2OH, CH(CF.sub.3)OH,
C(CF.sub.3).sub.2OH, --(CH.sub.2).sub.qOR,
--(CH.sub.2).sub.qNR.sub.2, --C(O)N(R).sub.2, --NR.sub.2,
--NRC(O)R, --S(O).sub.mN(R).sub.2, --OC(O)R, OC(O)N(R).sub.2,
--NRS(O).sub.mR, --NRC(O)N(R).sub.2, CN, halogen and --NO.sub.2,
wherein each R is independently selected from H, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.10 cycloalkyl and a 5- to 12-membered aryl or
heteroaryl group, the group being unsubstituted or substituted, m
is 1 or 2 and q is 0, 1 or 2; (b) a heteroaryl group which contains
1, 2, 3 or 4 ring nitrogen atoms and 0, 1 or 2 additional
heteroatoms selected from O and S, which group is monocyclic or
bicyclic and which is unsubstituted or substituted; and (c) a
benzene ring which is unsubstituted or substituted and which is
fused to a heteroaryl group as defined above; or a pharmaceutically
acceptable salt thereof; with the provisos that: (i) when X in
formula (Ia'') is S, then R.sup.3 is other than an indole or
3-hydroxyphenyl group; and (ii) when X in formula (Ib'') is S, then
R.sup.3 is other than an indole group.
4. A compound according to claim 1 wherein R.sup.1 is
(4-methylsulfonylpiperazin-1-yl)methyl.
5. A compound according to claim 1 wherein R.sup.2 is H.
6. A compound according to claim 1 wherein R.sup.3 is selected
from: ##STR00240## where W is CR.sup.10 or N; each R.sup.10 is
independently selected from H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 acyl, --C(O)NR'R'',
--S(O).sub.tNR'R'', aryl, heteroaryl, sulphonyl and halogen; R' and
R'' are each independently H or C.sub.1-C.sub.6 alkyl; and t is 1
or 2.
7. A compound according to claim 1 wherein R.sup.3 is
1H-indazol-4-yl.
8. A compound selected from:
(1S,4S)-2-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)m-
ethyl)-5-methylsulfonyl-2,5-diaza-bicyclo[2.2.1]heptane;
2-(1H-indazol-4-yl)-6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholi-
nofuro[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-(N-morpholino)sulfonylpiperazin-1-yl)methyl)-4--
morpholinothieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-(((3S,5R)-3-methyl-4-methylsulfonylpiperazin-1-yl)m-
ethyl)-4-morpholinothieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-(((3S,5R)-3,5-dimethyl-4-methylsulfonylpiperazin-1--
yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine;
6-(((2R,6S)-4-methylsulfonyl-2,6-dimethylpiperazin-1-yl)methyl)-2-(1H-ind-
azol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine;
6-(((2R,6S)-4-isopropylsulfonyl-2,6-dimethylpiperazin-1-yl)methyl)-2-(1H--
indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine;
6-(((2R,6S)-4-trifluoromethylsulfonyl-2,6-dimethylpiperazin-1-yl)methyl)--
2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine;
6-(((R)-4-methylsulfonyl-3-methylpiperazin-1-yl)methyl)-2-(1H-indazol-4-y-
l)-4-morpholinothieno[3,2-d]pyrimidine;
3-(6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]py-
rimidin-2-yl)benzenesulfonamide;
(4-(6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]p-
yrimidin-2-yl)phenyl)methanol;
3-(6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]py-
rimidin-2-yl)benzamide;
1-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-
-methylsulfonylpiperazin-2-one;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl-
)piperazin-1-yl)-2-amino-2-methylpropan-1-one;
2-(1H-indazol-4-yl)-6-((4-N-methyl-N-methoxyethylaminosulfonylpiperidin-1-
-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-(4-N,N-dimethylaminosulfonylpiperidin-1-yl)methyl)--
7-methyl-4-morpholinothieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-N-methylaminosulfonylpiperidin-1-yl)methyl)-4-m-
orpholinothieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-7-methyl-6-((4-(methylsulfonylpiperidin-1-yl)methyl)--
4-morpholinothieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-N-4-methylpiperazinosulfonylpiperidin-1-yl)meth-
yl)-4-morpholinothieno[3,2-d]pyrimidine;
2-(1H-imidazol-1-yl)-6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morphol-
inothieno[3,2-d]pyrimidine;
2-(1H-benzo[d]imidazol-1-yl)-6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-
-morpholinothieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-N,N-dimethylaminosulfonylpiperidin-1-yl)methyl)-
-4-morpholinothieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-N-morpholinosulfonylpiperazin-1-yl)methyl)-4-mo-
rpholinothieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-7-methyl-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-
-4-morpholinothieno[3,2-d]pyrimidine;
N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-
-methylsulfonyl-N-(2-morpholinoethyl)piperidin-4-amine;
(1-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)p-
yrrolidin-2-yl)-N-methylsulfonylmethanamine;
2-chloro-5-(6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]p-
yrimidin-2-yl)phenol;
N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-
-(2-methoxyethyl)-1-methylsulfonylpiperidin-4-amine;
4-fluoro-3-(6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]p-
yrimidin-2-yl)phenol;
2,3-difluoro-5-(6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-
-d]pyrimidin-2-yl)phenol;
5-(6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin--
2-yl)pyridin-3-ol;
2-(1H-indazol-4-yl)-6-((1-methylpiperidin-4-yl)methyl)-4-morpholinothieno-
[3,2-d]pyrimidine;
6-((4-methylpiperazin-1-yl)methyl)-4-morpholino-2-(1H-pyrazol-4-yl)thieno-
[3,2-d]pyrimidine;
(3-(6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-
-2-yl)phenyl)methanol;
N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-t-
etrahydro-N-methyl-2H-sulfonylpyran-4-amine;
2-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl-
)piperazin-1-yl)-2-methylpropanamide;
N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-
-(2-methoxyethyl)-N-methylpiperidin-4-amine;
N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-
,1-dimethylpiperidin-4-amine;
1-(2-hydroxyethyl)-4-((2-(3-hydroxyphenyl)-4-morpholinothieno[3,2-d]pyrim-
idin-6-yl)methyl)piperazin-2-one;
4-((2-(3-hydroxyphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-
-(2-methoxyethyl)-N-methylpiperazine-1-carboxamide;
(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)p-
iperazin-1-yl)(cyclopropyl)methanone;
2-(1H-indazol-4-yl)-6-((3-(methylsulfonyl)pyrrolidin-1-yl)methyl)-4-morph-
olinothieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-(((S)-2-methyl-4-methylsulfonylpiperazin-1-yl)methy-
l)-4-morpholinothieno[3,2-d]pyrimidine;
(3-(6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]p-
yrimidin-2-yl)phenyl)methanol;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl-
)piperazin-1-yl)-2,2-dimethylpropan-1-one;
4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)pi-
perazine-1-carbaldehyde;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl-
)piperazin-1-yl)ethanone; ethyl
4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)pi-
perazine-1-carboxylate; methyl
4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)pi-
perazine-1-carboxylate;
1-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-
-methyl-N-methylsulfonylpyrrolidin-3-amine;
N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-
-methyl(1-methylsulfonylpyrrolidin-2-yl)methanamine;
N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-
-methyl-(1-methylsulfonylpyrrolidin)-3-amine;
1-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)pi-
peridin-4-ol;
1-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)py-
rrolidin-3-ol;
1-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)pi-
peridin-3-ol;
(S)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)me-
thyl)piperazin-1-yl)-2-hydroxypropan-1-one;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl-
)piperazin-1-yl)-2-(dimethylamino)ethanone;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl-
)piperazin-1-yl)-2-aminoethanone;
2-(1H-indazol-6-yl)-6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothieno-
[3,2-d]pyrimidine;
N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-
-(2-methoxyethyl)-1-methylpiperidin-4-amine;
(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)--
1-methylsulfonylpiperazin-2-yl)-N,N-dimethylmethanamine;
N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-
,1-dimethylpiperidin-4-amine;
3-(6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]py-
rimidin-2-yl)benzenemethylsulfonylamine;
6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholino-2-(pyrimidin-5-yl-
)thieno[3,2-d]pyrimidine;
2-(6-fluoropyridin-3-yl)-6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-mor-
pholinothieno[3,2-d]pyrimidine;
N-methyl-3-(6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinothieno-
[3,2-d]pyrimidin-2-yl)benzamide;
2-(3-fluorophenyl)-6-(4-methylpiperazin-1-yl)methyl)-4-morpholinothieno[3-
,2-d]pyrimidine;
2-(2-fluoropyridin-3-yl)-6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-mor-
pholinothieno[3,2-d]pyrimidine;
6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-2-pyridin-3-y-
l-thieno[3,2-d]pyrimidine;
N-{4-[6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[-
3,2-d]pyrimidin-2-yl]-phenyl}-methanesulfonamide;
N-{4-[6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[-
3,2-d]pyrimidin-2-yl]-phenyl}-acetamide;
6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-2-(2-methyl-imidazol-1-yl)-4-m-
orpholin-4-yl-thieno[3,2-d]pyrimidine;
3-[6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-
-d]pyrimidin-2-yl]-quinoline;
4-[6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-
-d]pyrimidin-2-yl]-isoquinoline;
2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-2,2-dimethyl-piperazin-1-ylmethy-
l)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine;
2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-3,3-dimethyl-piperazin-1-ylmethy-
l)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine;
6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-2-(2-methyl-benzoimidazol-1-yl-
)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine;
(R)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)me-
thyl)piperazin-1-yl)-2-hydroxypropan-1-one;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl-
)piperazin-1-yl)-2-hydroxy-2-methylpropan-1-one;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl-
)piperazin-1-yl)-2-hydroxyethanone;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl-
)piperazin-1-yl)-2-methoxyethanone;
(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)p-
iperazin-1-yl)(tetrahydrofuran-2-yl)methanone;
(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)p-
iperazin-1-yl)(1-aminocyclopropyl)methanone;
(S)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)me-
thyl)piperazin-1-yl)-2-aminopropan-1-one;
(R)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)me-
thyl)piperazin-1-yl)-2-aminopropan-1-one;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl-
)piperazin-1-yl)-2-(methylsulfonyl)ethanone;
2-(1H-indol-4-yl)-6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholino-
furo[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholi-
nothieno[3,2-d]pyrimidine;
N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-
-methylpiperidin-4-amine;
(S)-1-(4-((2-(1H-indazol-4-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidi-
n-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one;
N-((2-(1H-indazol-4-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-
methyl)-N,1-dimethylpiperidin-4-amine;
6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholino-2-(1H-pyrrolo[2,3-
-b]pyridin-5-yl)thieno[3,2-d]pyrimidine;
(S)-1-((S)-4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-y-
l)methyl)-3-methylpiperazin-1-yl)-2-hydroxypropan-1-one;
2-(1H-benzo[d]imidazol-5-yl)-6-((4-methylpiperazin-1-yl)methyl)-4-morphol-
inothieno[3,2-d]pyrimidine;
2-(2-methyl-1H-benzo[d]imidazol-5-yl)-6-((4-methylsulfonylpiperazin-1-yl)-
methyl)-4-morpholinothieno[3,2-d]pyrimidine;
2-(1H-indazol-5-yl)-6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholi-
nothieno[3,2-d]pyrimidine;
5-(6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]py-
rimidin-2-yl)-1H-benzo[d]imidazol-2(3H)-one;
2-(1H-benzo[d]imidazol-4-yl)-6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-
-morpholinothieno[3,2-d]pyrimidine;
6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholino-2-(1H-pyrrolo[2,3-
-b]pyridine-5-yl)furo [3,2-d]pyrimidine;
N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-
-isopropyl-N-methylpiperidin-4-amine;
6-(6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]py-
rimidin-2-yl)-3H-imidazo[4,5-b]pyridine;
(S)-2-hydroxy-1-(4-((7-methyl-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5--
yl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propan-1-one;
(S)-2-hydroxy-1-(4-((7-methyl-4-morpholino-2-(quinolin-3-yl)thieno[3,2-d]-
pyrimidin-6-yl)methyl)piperazin-1-yl)propan-1-one;
2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morp-
holin-4-yl-thieno[3,2-d]pyrimidine;
6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-2-(2-methyl-1H-benzoimidazol-5-
-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine;
2-(1H-Indazol-5-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholi-
n-4-yl-thieno[3,2-d]pyrimidine;
5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]-
pyrimidin-2-yl)-1H-indazol-3-amine;
6-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]-
pyrimidin-2-yl)-1H-indazol-3-amine; and
(S)-2-hydroxy-1-(4-((7-methyl-2-(2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)--
4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propan-1-one-
. and the pharmaceutically acceptable salts thereof.
9. A process for producing a compound as defined in claim 1, which
process comprises treating a compound of formula (Ma): ##STR00241##
wherein X, R.sup.2 and R.sup.3 are as defined in claim 1, with an
amine of formula NHR.sup.4R.sup.5 in which R.sup.4 and R.sup.5 are
as defined in claim 1, in the presence of a suitable reducing
agent.
10. A process according to claim 9 which further comprises
producing the compound of formula (IIIa) by treating a compound of
formula (IIa): ##STR00242## wherein X and R.sup.2 are as defined in
claim 1, with a boronic acid or ester thereof of formula
R.sup.3B(OR.sup.15).sub.2, in which R.sup.3 is as defined in claim
1 and each R.sup.15 is H or C.sub.1-C.sub.6 alkyl or the two groups
OR.sup.15 form, together with the boron atom to which they are
attached, a pinacolato boronate ester group, in the presence of a
Pd catalyst.
11. A process for producing a compound as defined in claim 1, which
process comprises treating a compound of formula (IVa):
##STR00243## wherein X, R.sup.2, R.sup.4 and R.sup.5 are as defined
in claim 1, with a boronic acid or ester thereof of formula
R.sup.3B(OR.sup.15).sub.2 in which R.sup.3 is as defined in claim 1
and each R.sup.15 is H or C.sub.1-C.sub.6 alkyl or the two groups
OR.sup.15 form, together with the boron atom to which they are
attached, a pinacolato boronate ester group, in the presence of a
Pd catalyst.
12. A process according to claim 11 which further comprises
producing the compound of formula (IVa) by treating a compound of
formula (IIa): ##STR00244## wherein X and R.sup.2 are as defined
above, with an amine of formula NHR.sup.4R.sup.5 in which R.sup.4
and R.sup.5 are as defined above, in the presence of a suitable
reducing agent.
13. A process for producing a pharmaceutically acceptable salt as
defined in claim 1, which process comprises treating a fused
pyrimidine of formula (Ia): ##STR00245## wherein R.sup.1, R.sup.2,
R.sup.3 and X are as defined in claim 1, with a suitable acid in a
suitable solvent.
14. A process according to claim 13, wherein the acid is selected
from hydrochloric acid, hydrobromic acid, hydroiodic acid,
sulphuric acid, nitric acid, phosphoric acid, methanesulfonic acid,
benzenesulphonic acid, formic acid, acetic acid, trifluoroacetic
acid, propionic acid, oxalic acid, malonic acid, succinic acid,
fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid,
citric acid, ethanesulfonic acid, aspartic acid and glutamic
acid.
15. A process according to claim 13, wherein the acid is selected
from methane sulphonic acid, benzenesulphonic acid, hydrochloric
acid, phosphoric acid and sulphuric acid.
16. A pharmaceutical composition which comprises a pharmaceutically
acceptable carrier or diluent and, as an active ingredient, a
compound as claimed in claim 1.
17. A composition according to claim 16, further comprising a
chemotherapeutic agent.
18. A composition according to claim 16, which is formulated for
oral administration.
19. A method of treating cancer, which method comprises
administering to a patient in need thereof a compound as defined in
claim 1.
20. A method according to claim 19, wherein the cancer is selected
from glioblastoma, melanoma, prostate, endometrial, ovarian,
breast, lung, head and neck, hepatocellular, and thyroid
cancers.
21. A kit, comprising: (a) a first pharmaceutical composition
comprising a compound as defined in claim 1; and (b) instructions
for use in treating a PI3K-mediated condition.
Description
PRIORITY OF INVENTION
[0001] This application is a divisional application of U.S. patent
application Ser. No. 11/789,468 that was filed on 24 Apr. 2007,
which claims priority to U.S. Provisional Application No.
60/795,048 that was filed on 26 Apr. 2006. The entire content of
the applications are hereby incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to pyrimidine derivatives and
their use as inhibitors of phosphatidylinositol 3-kinase
(PI3K).
BACKGROUND TO THE INVENTION
[0003] Phosphatidylinositol (hereinafter abbreviated as "PI") is
one of a number of phospholipids found in cell membranes. In recent
years it has become clear that PI plays an important role in
intracellular signal transduction. In the late 1980s, a PI3 kinase
(PI3K) was found to be an enzyme which phosphorylates the
3-position of the inositol ring of phosphatidylinositol (D. Whitman
et al, 1988, Nature, 332, 664).
[0004] PI3K was originally considered to be a single enzyme, but it
has now been clarified that a plurality of subtypes are present in
PI3K. Each subtype has its own mechanism for regulating activity.
Three major classes of PI3Ks have been identified on the basis of
their in vitro substrate specificity (B. Vanhaesebroeck, 1997,
Trend in Biol. Sci, 22, 267). Substrates for class I PI3Ks are PI,
PI 4-phosphate (PI4P) and PI 4,5-biphosphate (PI(4,5)P2). Class I
PI3Ks are further divided into two groups, class Ia and class Ib,
in terms of their activation mechanism. Class Ia PI3Ks include PI3K
p110.alpha., p110.beta. and p110.delta. subtypes, which transmit
signals from tyrosine kinase-coupled receptors. Class Ib PI3K
includes a p110.gamma. subtype activated by a G protein-coupled
receptor. PI and PI(4)P are known as substrates for class II PI3Ks.
Class II PI3Ks include PI3K C2.alpha., C2.beta. and C2.gamma.
subtypes, which are characterized by containing C2 domains at the C
terminus. The substrate for class III PI3Ks is PI only.
[0005] In the PI3K subtypes, the class Ia subtype has been most
extensively investigated to date. The three subtypes of class Ia
are heterodimers of a catalytic 110 kDa subunit and regulatory
subunits of 85 kDa or 55 kDa. The regulatory subunits contain SH12
domains and bind to tyrosine residues phosphorylated by growth
factor receptors with a tyrosine kinase activity or oncogene
products, thereby inducing the PI3K activity of the p110 catalytic
subunit which phosphorylates its lipid substrate. Thus, the class
Ia subtypes are considered to be associated with cell proliferation
and carcinogenesis.
[0006] There continues to be a need for class I PI3 kinase
inhibitors with improved pharmacokinetic and pharmacodynamic
properties. The PI3 kinase/Akt/PTEN pathway is thus an attractive
target for cancer drug development since such agents would be
expected to inhibit proliferation, reverse the repression of
apoptosis and surmount resistance to cytotoxic agents in cancer
cells. PI3 kinase inhibitors have been reported (Yaguchi et al
(2006) Jour. of the Nat. Cancer Inst. 98(8):545-556; U.S. Pat. No.
6,608,056; U.S. Pat. No. 6,608,053; U.S. Pat. No. 6,838,457; U.S.
Pat. No. 6,770,641; U.S. Pat. No. 6,653,320; U.S. Pat. No.
6,403,588; WO 2004017950; US 2004092561; WO 2004007491; WO
2004006916; WO 2003037886; US 2003149074; WO 2003035618; WO
2003034997; US 2003158212; EP 1417976; US 2004053946; JP
2001247477; JP 08175990; JP 08176070). Wortmannin analogs have PI3
kinase activity in mammals (U.S. Pat. No. 6,703,414; WO
97/15658).
SUMMARY OF THE INVENTION
[0007] It has now been found that a novel class of fused pyrimidine
compounds are effective inhibitors of PI3K with drug-like
physicochemical and pharmacokinetic properties. The compounds
exhibit selectivity for class Ia PI3Ks over class Ib, in particular
for the p110.alpha. subtype.
[0008] Accordingly, the present invention provides a compound which
is a fused pyrimidine of formula (Ia) or (Ib):
##STR00002##
and stereoisomers, geometric isomers, tautomers, solvates,
metabolites, and pharmaceutically acceptable salts thereof, wherein
X is O or S. Groups R.sup.1, R.sup.2 and R.sup.3 are as defined
herein.
[0009] Another aspect of the invention provides a pharmaceutical
composition comprising a thienopyrimidine or furanopyrimidine
compound of Formulas Ia or Ib and a pharmaceutically acceptable
carrier. The pharmaceutical composition may further comprise one or
more additional therapeutic agents selected from anti-proliferative
agents, anti-inflammatory agents, immunomodulatory agents,
neurotropic factors, agents for treating cardiovascular disease,
agents for treating liver disease, anti-viral agents, agents for
treating blood disorders, agents for treating diabetes, and agents
for treating immunodeficiency disorders.
[0010] Another aspect of the invention provides methods of
inhibiting PI3 kinase activity, comprising contacting a PI3 kinase
with an effective inhibitory amount of a compound of Formula Ia or
Ib, or a stereoisomer, geometric isomer, tautomer, solvate,
metabolite, or pharmaceutically acceptable salt or prodrug
thereof.
[0011] Another aspect of the invention provides methods of
preventing or treating a disease or disorder modulated by PI3
kinases, comprising administering to a mammal in need of such
treatment an effective amount of a compound of Formula Ia or Ib, or
a stereoisomer, geometric isomer, tautomer, solvate, metabolite, or
pharmaceutically acceptable salt or prodrug thereof. Examples of
such diseases, conditions and disorders include, but are not
limited to, hyperproliferative disorders (e.g., cancer, including
melanoma and other cancers of the skin), neurodegeneration, cardiac
hypertrophy, pain, migraine, neurotraumatic diseases, stroke,
diabetes, hepatomegaly, cardiovascular disease, Alzheimer's
disease, cystic fibrosis, viral diseases, autoimmune diseases,
atherosclerosis, restenosis, psoriasis, allergic disorders,
inflammation, neurological disorders, hormone-related diseases,
conditions associated with organ transplantation, immunodeficiency
disorders, destructive bone disorders, proliferative disorders,
infectious diseases, conditions associated with cell death,
thrombin-induced platelet aggregation, chronic myelogenous leukemia
(CML), liver disease, pathologic immune conditions involving T cell
activation, and CNS disorders.
[0012] Another aspect of the invention provides methods of
preventing or treating a hyperproliferative disorder, comprising
administering to a mammal in need of such treatment an effective
amount of a compound of Formula Ia or Ib, or a stereoisomer,
geometric isomer, tautomer, solvate, metabolite, or
pharmaceutically acceptable salt or prodrug thereof, alone or in
combination with one or more additional compounds having
anti-hyperproliferative properties.
[0013] In a further aspect the present invention provides a method
of using a compound of this invention to treat a disease or
condition modulated by PI3 kinase in a mammal. An additional aspect
of the invention is the use of a compound of this invention in the
preparation of a medicament for the treatment or prevention of a
disease or condition modulated by PI3 kinase in a mammal.
[0014] Another aspect of the invention includes kits comprising a
compound of Formula Ia or Ib, or a stereoisomer, geometric isomer,
tautomer, solvate, metabolite, or pharmaceutically acceptable salt
or prodrug thereof, a container, and optionally a package insert or
label indicating a treatment.
DETAILED DESCRIPTION OF THE INVENTION
[0015] Compounds of formulae Ia and Ib are regioisomers, i.e. they
differ by the placement of atom X in the thienopyrimidine
(X=sulphur) or furanopyrimidine (X=oxygen) fused ring system. The
four possible regioisomeric forms of the ring systems encompassed
by formulae Ia and Ib are:
##STR00003##
[0016] Compounds of the invention thus include both regioisomers of
each of the 4-morpholino thienopyrimidine and 4-morpholino
furanopyrimidine compounds of formulae (Ia), (Ia'), (Ia'') and
(Ia'''), and (Ib), (Ib'), (Ib'') and (Ib''').
DEFINITIONS
[0017] As used herein, the terms "treat" and "treatment" refer to
both therapeutic treatment and prophylactic or preventative
measures, wherein the object is to prevent or slow down (lessen) an
undesired physiological change or disorder, such as the development
or spread of cancer. For purposes of this invention, beneficial or
desired clinical results include, but are not limited to,
alleviation of symptoms, diminishment of extent of disease,
stabilized (i.e., not worsening) state of disease, delay or slowing
of disease progression, amelioration or palliation of the disease
state, and remission (whether partial or total), whether detectable
or undetectable. "Treatment" can also mean prolonging survival as
compared to expected survival if not receiving treatment. Those in
need of treatment include those already with the condition or
disorder as well as those prone to have the condition or disorder
or those in which the condition or disorder is to be prevented.
[0018] The phrase "therapeutically effective amount" means an
amount of a compound of the present invention that (i) treats or
prevents the particular disease, condition, or disorder, (ii)
attenuates, ameliorates, or eliminates one or more symptoms of the
particular disease, condition, or disorder, or (iii) prevents or
delays the onset of one or more symptoms of the particular disease,
condition, or disorder described herein. In the case of cancer, the
therapeutically effective amount of the drug may reduce the number
of cancer cells; reduce the tumor size; inhibit (i.e., slow to some
extent and preferably stop) cancer cell infiltration into
peripheral organs; inhibit (i.e., slow to some extent and
preferably stop) tumor metastasis; inhibit, to some extent, tumor
growth; and/or relieve to some extent one or more of the symptoms
associated with the cancer. To the extent the drug may prevent
growth and/or kill existing cancer cells, it may be cytostatic
and/or cytotoxic. For cancer therapy, efficacy can be measured, for
example, by assessing the time to disease progression (TTP) and/or
determining the response rate (RR).
[0019] The phrase "pharmaceutically acceptable" indicates that the
substance or composition must be compatible chemically and/or
toxicologically, with the other ingredients comprising a
formulation, and/or the mammal being treated therewith.
[0020] The terms "cancer" and "cancerous" refer to or describe the
physiological condition in mammals that is typically characterized
by unregulated cell growth. A "tumor" comprises one or more
cancerous cells. Examples of cancer include, but are not limited
to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or
lymphoid malignancies. More particular examples of such cancers
include squamous cell cancer (e.g., epithelial squamous cell
cancer), lung cancer including small-cell lung cancer, non-small
cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous
carcinoma of the lung, cancer of the peritoneum, hepatocellular
cancer, gastric or stomach cancer including gastrointestinal
cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian
cancer, liver cancer, bladder cancer, hepatoma, breast cancer,
colon cancer, rectal cancer, colorectal cancer, endometrial or
uterine carcinoma, salivary gland carcinoma, kidney or renal
cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic
carcinoma, anal carcinoma, penile carcinoma, as well as head and
neck cancer.
[0021] A "chemotherapeutic agent" is a chemical compound useful in
the treatment of cancer. Examples of chemotherapeutic agents
include Erlotinib (TARCEVA.RTM., Genentech/OSI Pharm.), Bortezomib
(VELCADE.RTM., Millennium Pharm.), Fulvestrant (FASLODEX.RTM.,
AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA.RTM.,
Novartis), Imatinib mesylate (GLEEVEC.RTM., Novartis), PTK787/ZK
222584 (Novartis), Oxaliplatin (Eloxatin.RTM., Sanofi), 5-FU
(5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE.RTM.,
Wyeth), Lapatinib (TYKERB.RTM., GSK572016, Glaxo Smith Kline),
Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), and
Gefitinib (IRESSA.RTM., AstraZeneca), AG1478, AG1571 (SU 5271;
Sugen), alkylating agents such as thiotepa and CYTOXAN.RTM.
cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan
and piposulfan; aziridines such as benzodopa, carboquone,
meturedopa, and uredopa; ethylenimines and methylamelamines
including altretamine, triethylenemelamine,
triethylenephosphoramide, triethylenethiophosphoramide and
trimethylomelamine; acetogenins (especially bullatacin and
bullatacinone); a camptothecin (including the synthetic analog
topotecan); bryostatin; callystatin; CC-1065 (including its
adozelesin, carzelesin and bizelesin synthetic analogs);
cryptophycins (particularly cryptophycin 1 and cryptophycin 8);
dolastatin; duocarmycin (including the synthetic analogs, KW-2189
and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin;
spongistatin; nitrogen mustards such as chlorambucil,
chlornaphazine, chlorophosphamide, estramustine, ifosfamide,
mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,
novembichin, phenesterine, prednimustine, trofosfamide, uracil
mustard; nitrosureas such as carmustine, chlorozotocin,
fotemustine, lomustine, nimustine, and ranimnustine; antibiotics
such as the enediyne antibiotics (e.g., calicheamicin, especially
calicheamicin gamma1I and calicheamicin omegall (Angew Chem. Intl.
Ed. Engl. (1994) 33:183-186); dynemicin, including dynemicin A;
bisphosphonates, such as clodronate; an esperamicin; as well as
neocarzinostatin chromophore and related chromoprotein enediyne
antibiotic chromophores), aclacinomysins, actinomycin, authramycin,
azaserine, bleomycins, cactinomycin, carabicin, caminomycin,
carzinophilin, chromomycinis, dactinomycin, daunorubicin,
detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN.RTM.
(doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin,
2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin,
esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin
C, mycophenolic acid, nogalamycin, olivomycins, peplomycin,
porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin,
streptozocin, tubercidin, ubenimex, zinostatin, zorubicin;
anti-metabolites such as methotrexate and 5-fluorouracil (5-FU);
folic acid analogs such as denopterin, methotrexate, pteropterin,
trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine,
thiamiprine, thioguanine; pyrimidine analogs such as ancitabine,
azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine,
doxifluridine, enocitabine, floxuridine; androgens such as
calusterone, dromostanolone propionate, epitiostanol, mepitiostane,
testolactone; anti-adrenals such as aminoglutethimide, mitotane,
trilostane; folic acid replenisher such as frolinic acid;
aceglatone; aldophosphamide glycoside; aminolevulinic acid;
eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate;
defofamine; demecolcine; diaziquone; elfornithine; elliptinium
acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea;
lentinan; lonidainine; maytansinoids such as maytansine and
ansamitocins; mitogliazone; mitoxantrone; mopidanmol; nitraerine;
pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic
acid; 2-ethylhydrazide; procarbazine; PSK.RTM. polysaccharide
complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;
sizofuran; spirogermanium; tennazonic acid; triaziquone;
2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2
toxin, verracurin A, roridin A and anguidine); urethan; vindesine;
dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman;
gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa;
taxoids, e.g., TAXOL.RTM.) (paclitaxel; Bristol-Myers Squibb
Oncology, Princeton, N.J.), ABRAXANE.TM. (Cremophor-free),
albumin-engineered nanoparticle formulations of paclitaxel
(American Pharmaceutical Partners, Schaumberg, Ill.), and
TAXOTERE.RTM. (doxetaxel; Rhone-Poulenc Rorer, Antony, France);
chloranmbucil; GEMZAR.RTM. (gemcitabine); 6-thioguanine;
mercaptopurine; methotrexate; platinum analogs such as cisplatin
and carboplatin; vinblastine; etoposide (VP-16); ifosfamide;
mitoxantrone; vincristine; NAVELBINE.RTM. (vinorelbine);
novantrone; teniposide; edatrexate; daunomycin; aminopterin;
capecitabine (XELODA.RTM.); ibandronate; CPT-11; topoisomerase
inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such
as retinoic acid; and pharmaceutically acceptable salts, acids and
derivatives of any of the above.
[0022] Also included in the definition of "chemotherapeutic agent"
are: (i) anti-hormonal agents that act to regulate or inhibit
hormone action on tumors such as anti-estrogens and selective
estrogen receptor modulators (SERMs), including, for example,
tamoxifen (including NOLVADEX.RTM.; tamoxifen citrate), raloxifene,
droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018,
onapristone, and FARESTON.RTM. (toremifine citrate); (ii) aromatase
inhibitors that inhibit the enzyme aromatase, which regulates
estrogen production in the adrenal glands, such as, for example,
4(5)-imidazoles, aminoglutethimide, MEGASE.RTM. (megestrol
acetate), AROMASIN.RTM. (exemestane; Pfizer), formestanie,
fadrozole, RIVISOR.RTM. (vorozole), FEMARA.RTM. (letrozole;
Novartis), and ARIMIDEX.RTM. (anastrozole; AstraZeneca); (iii)
anti-androgens such as flutamide, nilutamide, bicalutamide,
leuprolide, and goserelin; as well as troxacitabine (a
1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase
inhibitors; (v) lipid kinase inhibitors; (vi) antisense
oligonucleotides, particularly those which inhibit expression of
genes in signaling pathways implicated in aberrant cell
proliferation, such as, for example, PKC-alpha, Ralf and H-Ras;
(vii) ribozymes such as VEGF expression inhibitors (e.g.,
ANGIOZYME.RTM.) and HER2 expression inhibitors; (viii) vaccines
such as gene therapy vaccines, for example, ALLOVECTIN.RTM.,
LEUVECTIN.RTM., and VAXID.RTM.; PROLEUKIN.RTM. rIL-2; a
topoisomerase 1 inhibitor such as LURTOTECAN.RTM.; ABARELIX.RTM.
rmRH; (ix) anti-angiogenic agents such as bevacizumab
(AVASTIN.RTM., Genentech); and (x) pharmaceutically acceptable
salts, acids and derivatives of any of the above.
[0023] The term "prodrug" as used in this application refers to a
precursor or derivative form of a compound of the invention that is
less cytotoxic to cells compared to the parent compound or drug and
is capable of being enzymatically or hydrolytically activated or
converted into the more active parent form. See, e.g., Wilman,
"Prodrugs in Cancer Chemotherapy" Biochemical Society Transactions,
14, pp. 375-382, 615th Meeting Belfast (1986) and Stella et al.,
"Prodrugs: A Chemical Approach to Targeted Drug Delivery," Directed
Drug Delivery, Borchardt et al., (ed.), pp. 247-267, Humana Press
(1985). The prodrugs of this invention include, but are not limited
to, phosphate-containing prodrugs, thiophosphate-containing
prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs,
D-amino acid-modified prodrugs, glycosylated prodrugs,
.beta.-lactam-containing prodrugs, optionally substituted
phenoxyacetamide-containing prodrugs, optionally substituted
phenylacetamide-containing prodrugs, 5-fluorocytosine and other
5-fluorouridine prodrugs which can be converted into the more
active cytotoxic free drug. Examples of cytotoxic drugs that can be
derivatized into a prodrug form for use in this invention include,
but are not limited to, compounds of the invention and
chemotherapeutic agents such as described above.
[0024] A "metabolite" is a product produced through metabolism in
the body of a specified compound or salt thereof. Metabolites of a
compound may be identified using routine techniques known in the
art and their activities determined using tests such as those
described herein. Such products may result for example from the
oxidation, reduction, hydrolysis, amidation, deamidation,
esterification, deesterification, enzymatic cleavage, and the like,
of the administered compound. Accordingly, the invention includes
metabolites of compounds of the invention, including compounds
produced by a process comprising contacting a compound of this
invention with a mammal for a period of time sufficient to yield a
metabolic product thereof.
[0025] A "liposome" is a small vesicle composed of various types of
lipids, phospholipids and/or surfactant which is useful for
delivery of a drug (such as the PI3 kinase inhibitors disclosed
herein and, optionally, a chemotherapeutic agent) to a mammal. The
components of the liposome are commonly arranged in a bilayer
formation, similar to the lipid arrangement of biological
membranes.
[0026] The term "chiral" refers to molecules which have the
property of non-superimposability of the mirror image partner,
while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
[0027] The term "stereoisomers" refers to compounds which have
identical chemical constitution, but differ with regard to the
arrangement of the atoms or groups in space.
[0028] "Diastereomer" refers to a stereoisomer with two or more
centers of chirality and whose molecules are not mirror images of
one another. Diastereomers have different physical properties, e.g.
melting points, boiling points, spectral properties, and
reactivities. Mixtures of diastereomers may separate under high
resolution analytical procedures such as electrophoresis and
chromatography.
[0029] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0030] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds",
John Wiley & Sons, Inc., New York, 1994. The compounds of the
invention may contain asymmetric or chiral centers, and therefore
exist in different stereoisomeric forms. It is intended that all
stereoisomeric forms of the compounds of the invention, including
but not limited to, diastereomers, enantiomers and atropisomers, as
well as mixtures thereof such as racemic mixtures, form part of the
present invention. Many organic compounds exist in optically active
forms, i.e., they have the ability to rotate the plane of
plane-polarized light. In describing an optically active compound,
the prefixes D and L, or R and S, are used to denote the absolute
configuration of the molecule about its chiral center(s). The
prefixes d and 1 or (+) and (-) are employed to designate the sign
of rotation of plane-polarized light by the compound, with (-) or 1
meaning that the compound is levorotatory. A compound prefixed with
(+) or d is dextrorotatory. For a given chemical structure, these
stereoisomers are identical except that they are mirror images of
one another. A specific stereoisomer may also be referred to as an
enantiomer, and a mixture of such isomers is often called an
enantiomeric mixture. A 50:50 mixture of enantiomers is referred to
as a racemic mixture or a racemate, which may occur where there has
been no stereoselection or stereospecificity in a chemical reaction
or process. The terms "racemic mixture" and "racemate" refer to an
equimolar mixture of two enantiomeric species, devoid of optical
activity.
[0031] The term "tautomer" or "tautomeric form" refers to
structural isomers of different energies which are interconvertible
via a low energy barrier. For example, proton tautomers (also known
as prototropic tautomers) include interconversions via migration of
a proton, such as keto-enol and imine-enamine isomerizations.
Valence tautomers include interconversions by reorganization of
some of the bonding electrons.
[0032] An alkyl group is a straight or branched chain saturated
hydrocarbon radical which is unsubstituted or substituted.
Typically it is C.sub.1-C.sub.20 alkyl, for instance
C.sub.1-C.sub.10 alkyl, such as C.sub.1-C.sub.6 alkyl.
C.sub.1-C.sub.6 alkyl is typically C.sub.1-C.sub.4 alkyl. It may
be, for example, methyl (Me, --CH.sub.3), ethyl (Et,
--CH.sub.2CH.sub.3), 1-propyl (n-Pr, n-propyl,
--CH.sub.2CH.sub.2CH.sub.3), 2-propyl (i-Pr, i-propyl,
--CH(CH.sub.3).sub.2), 1-butyl (n-Bu, n-butyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-methyl-1-propyl (i-Bu,
i-butyl, --CH.sub.2CH(CH.sub.3).sub.2), 2-butyl (s-Bu, s-butyl,
--CH(CH.sub.3)CH.sub.2CH.sub.3), 2-methyl-2-propyl (t-Bu, t-butyl,
--C(CH.sub.3).sub.3), 1-pentyl (n-pentyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.3), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 3-methyl-1-butyl
(--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-1-butyl
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), 1-hexyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-hexyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)),
2-methyl-2-pentyl (--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3),
3-methyl-2-pentyl (--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3),
4-methyl-2-pentyl (--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2),
3-methyl-3-pentyl (--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2),
2-methyl-3-pentyl (--CH(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2),
2,3-dimethyl-2-butyl (--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2), or
3,3-dimethyl-2-butyl (--CH(CH.sub.3)C(CH.sub.3).sub.3.
[0033] When an alkyl group is substituted it typically bears one or
more substituents R.sup.20 selected from halogen, alkoxy,
carbocyclyl, a 5- or 6-membered saturated N-containing heterocyclic
group as defined above, OH, SR, CN, nitro, NR.sub.2, --COOR,
--C(O)R, S(O).sub.mR and --CONR.sub.2, wherein each R is H,
unsubstituted alkyl or C.sub.3-C.sub.10 cycloalkyl and m is 1 or 2.
It is, for instance, a hydroxyalkyl group, a haloalkyl group or a
group -alk-N(R.sup.4)(R.sup.5) wherein alk is an alkylene chain and
R.sup.4 and R.sup.5 form, together with the N atom to which they
are attached, a 5- or 6-membered saturated N-containing
heterocyclic group which includes 0 or 1 additional heteroatoms
selected from N, S and O, which may be fused to a benzene ring and
which is unsubstituted or substituted.
[0034] Typically R.sup.20 is selected from halogen, alkoxy,
carbocyclyl, a 5- or 6-membered saturated N-containing heterocyclic
group as defined above, OH, CN, NR.sub.2, --COOR and --CONR.sub.2,
wherein each R is H or unsubstituted alkyl as defined above. It is,
for instance, a haloalkyl group or a group -alk-N(R.sup.6)(R.sup.5)
wherein alk is an alkylene chain and R.sup.4 and R.sup.5 form,
together with the N atom to which they are attached, a 5- or
6-membered saturated N-containing heterocyclic group as defined
above.
[0035] An alkylene group is unsubstituted or substituted, straight
or branched chain saturated divalent hydrocarbon group. Typically
it is C.sub.1-C.sub.8 alkylene, for instance C.sub.1-C.sub.6
alkylene. Preferably it is C.sub.1-C.sub.4 alkylene, for example
C.sub.2-C.sub.4 alkylene, such as methylene, ethylene, i-propylene,
n-propylene, t-butylene, s-butylene or n-butylene. It may also be
pentylene, hexylene, heptylene, octylene and the various branched
chain isomers thereof. When the alkylene group is substituted it is
typically substituted by a group R.sup.20 as defined above.
[0036] An alkenyl group is an unsubstituted or substituted,
straight or branched chain hydrocarbon radical having one or more
double bonds. Typically it is C.sub.2-C.sub.8 alkenyl, for instance
C.sub.2-C.sub.6 alkenyl, such as allyl, butenyl, butadienyl,
pentenyl or hexenyl. When the alkenyl group is substituted it is
typically substituted by a group R.sup.20 as defined above or by
alkyl which is unsubstituted or substituted by a group R.sup.20 as
defined above.
[0037] An alkynyl group is an unsubstituted or substituted,
straight or branched chain hydrocarbon radical having one or more
triple bonds. Typically it is C.sub.2-C.sub.8 alkynyl, for instance
C.sub.2-C.sub.6 alkynyl, such as ethynyl, propynyl or butynyl. When
the alkynyl group is substituted it is typically substituted by a
group R.sup.20 as defined above or by alkyl which is unsubstituted
or substituted by a group R.sup.20 as defined above.
[0038] A haloalkyl group is an alkyl group as defined above,
substituted by one or more halogen atoms. It can be a perhaloalkyl
group, for instance trifluoromethyl or perfluorohexyl.
[0039] A halogen is chlorine, fluorine, bromine or iodine. It is
typically bromine or iodine.
[0040] An alkoxy group is typically C.sub.1-C.sub.6 alkoxy, for
instance C.sub.1-C.sub.4 alkoxy, such as methoxy, ethoxy,
i-propoxy, n-propoxy, t-butoxy, n-butoxy or s-butoxy. It is
unsubstituted or substituted, for instance by a group R.sup.20 as
defined above or by alkyl which is unsubstituted or substituted by
a group R.sup.20 as defined above or by alkyl which is
unsubstituted or substituted by a group R.sup.20 as defined above.
Typically it is substituted by carbocyclyl, morpholino, OH, CN,
NR.sub.2, --COOR or --CONR.sub.2, wherein each R is H or
unsubstituted alkyl as defined above.
[0041] A carbocyclyl group is a non-aromatic saturated monocyclic
hydrocarbon ring, typically having from 3 to 10 carbon atoms. It
may be a C.sub.3-C.sub.8 cycloalkyl group, or C.sub.5-C.sub.10
cycloalkyl group, for instance cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. A carbocyclyl
group may be unsubstituted or substituted, for instance by a group
R.sup.20 as defined above or by alkyl which is unsubstituted or
substituted by a group R.sup.20 as defined above. Typically it is
substituted by alkoxy, morpholino, OH, CN, NR.sub.2, --COOR and
--CONR.sub.2, wherein each R is H or unsubstituted alkyl as defined
above.
[0042] The term "cyclyl" as used herein denotes a C.sub.3-C.sub.6
cycloalkyl group, for instance cyclopropyl, cyclobutyl, cyclopentyl
or cyclohexyl. In particular, cyclyl is a cyclopropyl group.
[0043] A 5- or 6-membered saturated N-containing heterocyclic group
which includes 0 or 1 additional heteroatoms selected from N, S and
O is unsubstituted or substituted and is typically selected from
morpholine, piperidine, piperazine, pyrrolidine and
thiomorpholine.
[0044] When a 5- or 6-membered saturated N-containing heterocyclic
group as defined above is substituted it is typically substituted
by one or more substituents, for instance 1, 2 or 3 substituents,
typically by 1 or 2 substituents. Typically the substituents are
selected from alkyl which is unsubstituted or substituted, alkoxy
which is unsubstituted or substituted, --NR.sub.2,
--N(R''')-alk-OR, -alk-OR, --O-alk-OR, -alk-C(O)NR.sub.2,
--C(O)NR.sub.2, -alk-Het, --N(R)-Het, --O-Het, --N(R)--C(O)-alk-OR,
--C(O)--N(R)-alk-OR, -alk-S(O).sub.2R, --N(R)-alk-OR, -alk-NR'R'',
--N(R''')--S(O).sub.2R, S(O).sub.2R''', -alk-N(R)-alk-OR,
--S(O).sub.2-alk-OR, a second 5- or 6-membered saturated
N-containing heterocyclic group as defined above, a 5- or
6-membered N-containing heteroaryl group which is unsubstituted or
substituted and which may be fused to a benzene ring, --COOR,
--CONR.sub.2, oxo (.dbd.O), --SO.sub.2NR.sub.2,
--SO.sub.2-alk-NR.sub.2 and --CO-alk-OR, wherein: alk is an
alkylene chain as defined above; Het is a 5- or 6-membered
N-containing heteroaryl group as defined herein which is
unsubstituted or substituted; R is H or alkyl, or when two groups R
are bonded to N they may form, together with the N atom, a
saturated 5- or 6-membered N-containing heterocyclic group as
defined herein which is unsubstituted or substituted; each of R'
and R'' is independently H, alkyl or alkoxy; and R''' is alkyl
which is unsubstituted or substituted, for instance by CF.sub.3,
NR.sub.2, OR, a 5- or 6-membered saturated N-containing
heterocyclic group as defined herein or a 5- or 6-membered
N-containing heteroaryl group as defined herein, the said
heterocyclic and heteroaryl groups being unsubstituted or
substituted. It may be substituted by a group R.sup.20 as defined
above or by alkyl which is unsubstituted or substituted by a group
R.sup.20 as defined above.
[0045] Typically a 5- or 6-membered saturated N-containing
heterocyclic group as defined above is substituted by a group
selected from alkyl which is unsubstituted or substituted, alkoxy
which is unsubstituted or substituted, a second 5- or 6-membered
saturated N-containing heterocyclic group as defined above, a 5- or
6-membered N-containing heteroaryl group which is unsubstituted or
substituted and which may be fused to a benzene ring, --COOR,
--CONR.sub.2, --CONR, oxo (.dbd.O), OH, --NSO.sub.2R,
--SO.sub.2NR.sub.2 or --CO(CH.sub.2).sub.nOR wherein R is H or
alkyl, --NR'R'' wherein each of R' and R'' is independently H,
alkyl or alkoxy, and --SO.sub.2R''' wherein R''' is alkyl which is
unsubstituted or substituted, for instance by NR.sub.2 or a 5- or
6-membered saturated N-containing heterocyclic group as defined
above.
[0046] More typically a 5- or 6-membered saturated N-containing
heterocyclic group is substituted by one or more substituents
selected from alkyl as defined above which is unsubstituted or
substituted (for instance by R.sup.20 as defined above), haloalkyl
as defined above, alkoxy as defined above which is unsubstituted or
substituted, halogen, hydroxy, CN, nitro, amino, oxo (.dbd.O), and
-NR'R'' wherein each of R' and R'' is independently H or alkyl.
[0047] A heteroaryl group is a heteroaryl group which contains 1, 2
3 or 4 ring nitrogen atoms and 0, 1 or 2 additional heteroatoms
selected from O, N and S, which group is monocyclic or bicyclic and
which is unsubstituted or substituted. It is typically a 5- to
12-membered ring. Examples of a heteroaryl group include pyrrole,
pyrazole, triazole, tetrazole, indazole, thiazole, isothiazole,
oxazole, isooxazole, indole, isoindole, 1,3-dihydro-indol-2-one,
pyridine-2-one, pyridine, pyridin-3-ol, imidazole,
1,3-dihydro-benzimidazolone, benzimidazole, benzothiazole,
benzothiadiazole, quinoline, isoquinoline, quinoxaline,
pyrazolopyridine, aminopyrazolinone, imidazopyridine, pyrimidine,
pyridazine, pyrazine and isatin groups. Preferred examples include
indazole, indole, pyrazole and tetrazole groups. These groups may
be unsubstituted or substituted, for instance by a group R.sup.20
as specified above or by alkyl which is unsubstituted or
substituted by a group R.sup.20 as defined above.
[0048] A 5- or 6-membered N containing heteroaryl group which may
be fused to a benzene ring is typically selected from pyrrole,
pyrazole, triazole, tetrazole, indazole, thiazole, isothiazole,
oxazole, isooxazole, indole, isoindole, 1,3-dihydro-indol-2-one,
pyridine-2-one, pyridine, pyridin-3-ol, imidazole,
1,3-dihydro-benzimidazolone, benzimidazole, benzothiazole,
benzothiadiazole, quinoline, isoquinoline, quinoxaline,
pyrazolopyridine, aminopyrazolinone, imidazopyridine, pyrimidine,
pyridazine and pyrazine. When such a heteroaryl group is
substituted it may be substituted by a group R.sup.20 as defined
above or by alkyl which is unsubstituted or substituted by a group
R.sup.20 as defined above.
PI3 Kinase Inhibitor Compounds
[0049] The present invention provides fused pyrimidines which are
4-morpholino thienopyrimidine and furanopyrimidine compounds, and
pharmaceutically acceptable salts thereof, that are potentially
useful in the treatment of diseases, conditions and/or disorders
modulated by PI3 kinases. The compounds may inhibit p110 isoforms
including alpha, beta, gamma, and delta as pan inhibitors. The
compounds may be p110 isoform selective inhibitors by selective
inhibition of one of the p110 isoforms.
[0050] More specifically, the present invention provides a compound
which is a fused pyrimidine of formula Ia or Ib:
##STR00004##
X is O or S;
[0051] R.sup.1 is a group of formula:
##STR00005##
[0052] R.sup.2 is H, halo or C.sub.1-C.sub.6 alkyl
R.sup.4 and R.sup.5 form, together with the N atom to which they
are attached, a group selected from piperazine, piperidine,
pyrrolidine, oxazolidinone, diazepan and
2,5-diaza-bicyclo[2,2,1]-heptane, which group is unsubstituted or
substituted by -[(alk).sub.q-NR].sub.r--S(O).sub.2-(alk).sub.q-Z or
--C(O)-(alk).sub.q-S(O).sub.2Z wherein Z is R.sup.10 or
--NR.sup.11R.sup.12, or by unsubstituted C.sub.1-C.sub.6 alkyl,
hydroxyl-C.sub.1-C.sub.6 alkyl, oxo (.dbd.O), -(alk).sub.q-OR,
--C(O)--C(R').sub.2--N(R).sub.2, --C(R).sub.2--C(O)--N(R).sub.2,
--C(O)--(NR).sub.q-(alk).sub.q-OR, --C(O)-cyclyl, --C(O)R,
--C(O)OR, --C(O)-Tet or --NR.sup.13R.sup.14; or one of R.sup.4 and
R.sup.5 is C.sub.1-C.sub.6 alkyl, -(alk).sub.q-Heterocyclyl or
-(alk).sub.q-OR and the other is a piperazine, piperidine,
pyrrolidine, sulphonylpyran or -(alk).sub.q-Heterocyclyl group,
wherein said piperazine, piperidine, pyrrolidine, sulphonylpyran or
Heterocyclyl is unsubstituted or substituted by C.sub.1-C.sub.6
alkyl, -(alk).sub.q-OR or --S(O).sub.2R.sup.10; R is H or
C.sub.1-C.sub.6 alkyl which is unsubstituted; each R' is,
independently, H or C.sub.1-C.sub.6 alkyl which is unsubstituted,
or the two groups R' form, together with the C atom to which they
are attached, a cyclyl group; R.sup.10 is H, cyclyl,
C.sub.1-C.sub.6 alkyl which is unsubstituted or CF.sub.3; R.sup.11
and R.sup.12 are each independently selected from H,
C.sub.1-C.sub.6 alkyl which is unsubstituted and -(alk).sub.q-OR,
or R.sup.11 and R.sup.12 together form, with the N atom to which
they are attached, a 5- or 6-membered saturated N-containing
heterocyclic group containing 0 or 1 additional heteroatoms
selected from O, N and S; R.sup.13 and R.sup.14 are each
independently selected from C.sub.1-C.sub.6 alkyl,
--S(O).sub.2R.sup.10, and -(alk).sub.q-OR; Tet is a
tetrahydrofuranyl or tetrahydropyranyl group, which group is
unsubstituted or substituted; Heterocyclyl is a 5- or 6-membered
saturated N-containing heterocyclic group containing 0 or 1
additional heteroatoms selected from O, N and S; Cyclyl is a
C.sub.3-C.sub.6 cycloalkyl group; each q is independently 0 or 1; r
is 0 or 1; alk is C.sub.1-C.sub.6 alkylene; and R.sup.3 is selected
from:
[0053] (a) a group of the following formula:
##STR00006##
[0054] wherein B is a phenyl ring which is unsubstituted or
substituted, and Z is selected from H, --OR, --SR, CH.sub.2OR,
--CO.sub.2R, CF.sub.2OH, CH(CF.sub.3)OH, C(CF.sub.3).sub.2OH,
--(CH.sub.2).sub.qOR, --(CH.sub.2).sub.qNR.sub.2, --C(O)N(R).sub.2,
--NR.sub.2, --NRC(O)R, --S(O).sub.mN(R).sub.2, --OC(O)R,
OC(O)N(R).sub.2, --NRS(O).sub.mR, --NRC(O)N(R).sub.2, CN, halogen
and --NO.sub.2, wherein each R is independently selected from H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10 cycloalkyl and a 5- to
12-membered aryl or heteroaryl group, the group being unsubstituted
or substituted, m is 1 or 2 and q is 0, 1 or 2;
[0055] (b) a heteroaryl group which contains 1, 2, 3 or 4 ring
nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from O
and S, which group is monocyclic or bicyclic and which is
unsubstituted or substituted; and
[0056] (c) a group comprising a benzene ring which is unsubstituted
or substituted and which is fused to a heteroaryl group as defined
above;
or a pharmaceutically acceptable salt thereof; with the provisos
that: [0057] (i) when X in formula (Ia) is S, then R.sup.3 is other
than an indole or 3-hydroxyphenyl group; [0058] (ii) when X in
formula (Ib) is S, then R.sup.3 is other than an indole group;
[0059] (iii) in formula (Ia) only, when X is S and R.sup.2 is H and
R.sup.3 is indazol-4-yl, then R.sup.4 and R.sup.5 do not form: (i)
piperazine which is unsubstituted or substituted by a group
selected from methyl, --S(O).sub.2Me, --S(O).sub.2NMe.sub.2,
-alk-OH, -alk-OMe, --S(O).sub.2-alk-NMe.sub.2, and
--S(O).sub.2-alk-morpholino; or (ii) piperidine which is
substituted by a group selected from --S(O).sub.2Me,
--C(O)--NR-(alk).sub.q-OR, --NMe-S(O).sub.2-Me, methyl, piperidine
and --NR.sup.13R.sup.14 wherein one of R.sup.13 and R.sup.14 is
-(alk).sub.q-OR.
[0060] In one embodiment the invention provides a compound which is
a fused pyrimidine of formula (Ia'):
##STR00007##
wherein
X is O or S;
Y is N or --CH--;
[0061] R.sup.2 is H, halo or C.sub.1-C.sub.6 alkyl; each R' is,
independently, H, C.sub.1-C.sub.6 alkyl or hydroxyl-C.sub.1-C.sub.6
alkyl, or two groups R' on the same carbon atom form an oxo
(.dbd.O) group; or when Y is N, two groups R' on different carbon
atoms together form a --CH.sub.2-- bridgehead; each R'' is,
independently, H or C.sub.1-C.sub.6 alkyl, or two groups R'' on the
same carbon atom form an oxo (.dbd.O) group; Z is R.sup.10 or
-(alk).sub.q-NR.sup.11R.sup.12; R.sup.10 is H, a C.sub.3-C.sub.6
cycloalkyl group, C.sub.1-C.sub.6 alkyl which is unsubstituted, or
CF.sub.3; R.sup.11 and R.sup.12 are each independently selected
from H, C.sub.1-C.sub.6 alkyl which is unsubstituted and
-(alk).sub.q-OR, or R.sup.11 and R.sup.12 together form, with the N
atom to which they are attached, a 5- or 6-membered saturated
N-containing heterocyclic group containing 0 or 1 additional
heteroatoms selected from O, N and S; q is 0 or 1; r is 0 or 1; alk
is C.sub.1-C.sub.6 alkylene; and R.sup.3 is selected from:
[0062] (a) a group of the following formula:
##STR00008##
wherein B is a phenyl ring which is unsubstituted or substituted
and Z is selected from H, --OR, --SR, CH.sub.2OR, --CO.sub.2R,
CF.sub.2OH, CH(CF.sub.3)OH, C(CF.sub.3).sub.2OH,
--(CH.sub.2).sub.qOR, --(CH.sub.2).sub.qNR.sub.2, --C(O)N(R).sub.2,
--NR.sub.2, --NRC(O)R, --S(O).sub.mN(R).sub.2, --OC(O)R,
OC(O)N(R).sub.2, --NRS(O).sub.mR, --RC(O)N(R).sub.2, CN, halogen
and --NO.sub.2, wherein each R is independently selected from H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10 cycloalkyl and a 5- to
12-membered aryl or heteroaryl group, the group being unsubstituted
or substituted, m is 1 or 2 and q is 0, 1 or 2;
[0063] (b) a heteroaryl group which contains 1, 2, 3 or 4 ring
nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from O
and S, which group is monocyclic or bicyclic and which is
unsubstituted or substituted; and
[0064] (c) a group comprising a benzene ring which is unsubstituted
or substituted and which is fused to a heteroaryl group as defined
above;
or a pharmaceutically acceptable salt thereof; with the provisos
that: [0065] (i) R.sup.3 is other than an indole or 3-hydroxyphenyl
group when X is S; [0066] (ii) Z is other than a group selected
from Me, -(alk).sub.q-NMe.sub.2 and -alk-morpholino when the
following are satisfied: Y is N, each of R' and R'' is H, R.sup.2
is H and R.sup.3 is indazol-4-yl; [0067] (iii) Z is other than Me
when the following are satisfied: Y is --CH--, each of R' and R''
is H, R.sup.2 is H and R.sup.3 is indazol-4-yl.
[0068] In another embodiment the invention provides a compound
which is fused pyrimidine of formula (Ib'):
##STR00009##
wherein
X is O or S;
Y is N or --CH--;
[0069] R.sup.2 is H, halo or C.sub.1-C.sub.6 alkyl; each R' is,
independently, H, C.sub.1-C.sub.6 alkyl or hydroxy-C.sub.1-C.sub.6
alkyl, or two groups R' on the same carbon atom form an oxo
(.dbd.O) group; or when Y is N, two groups R' on different carbon
atoms together form a --CH.sub.2-- bridgehead; each R'' is,
independently, H or C.sub.1-C.sub.6 alkyl, or two groups R'' on the
same carbon atom form an oxo (.dbd.O) group; Z is R.sup.10 or
-(alk).sub.q-NR.sup.11R.sup.12; R.sup.10 is H, a C.sub.3-C.sub.6
cycloalkyl group, C.sub.1-C.sub.6 alkyl which is unsubstituted, or
CF.sub.3; R.sup.11 and R.sup.12 are each independently selected
from H, C.sub.1-C.sub.6 alkyl which is unsubstituted and
-(alk).sub.g-OR, or R.sup.11 and R.sup.12 together form, with the N
atom to which they are attached, a 5- or 6-membered saturated
N-containing heterocyclic group containing 0 or 1 additional
heteroatoms selected from O, N and S; q is 0 or 1; r is 0 or 1; alk
is C.sub.1-C.sub.6 alkylene; and R.sup.3 is selected from:
[0070] (a) a group of the following formula:
##STR00010##
wherein B is a phenyl ring which is unsubstituted or substituted
and Z is selected from H, --OR, --SR, CH.sub.2OR, --CO.sub.2R,
CF.sub.2OH, CH(CF.sub.3)OH, C(CF.sub.3).sub.2OH,
--(CH.sub.2).sub.qOR, --(CH.sub.2).sub.qNR.sub.2, --C(O)N(R).sub.2,
--NR.sub.2, --NRC(O)R, --S(O).sub.mN(R).sub.2, --OC(O)R,
OC(O)N(R).sub.2, --NRS(O).sub.mR, --RC(O)N(R).sub.2, CN, halogen
and --NO.sub.2, wherein each R is independently selected from H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10 cycloalkyl and a 5- to
12-membered aryl or heteroaryl group, the group being unsubstituted
or substituted, m is 1 or 2 and q is 0, 1 or 2;
[0071] (b) a heteroaryl group which contains 1, 2, 3 or 4 ring
nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from O
and S, which group is monocyclic or bicyclic and which is
unsubstituted or substituted; and
[0072] (c) a group comprising a benzene ring which is unsubstituted
or substituted and which is fused to a heteroaryl group as defined
above;
or a pharmaceutically acceptable salt thereof.
[0073] In a yet further embodiment the invention provides a
compound which is a fused pyrimidine of formula (Ia'') or
(Ib''):
##STR00011##
wherein
X is O or S;
[0074] R.sup.2 is H, halo or C.sub.1-C.sub.6 alkyl; R.sup.4 is
C.sub.1-C.sub.6 alkyl, -(alk).sub.q-Heterocyclyl, or
-(alk).sub.q-OR; R.sup.5 is a piperazine, piperidine, pyrrolidine,
sulphonylpyran or -(alk).sub.q-Heterocyclyl group, wherein said
piperazine, piperidine, pyrrolidine, sulphonylpyran or Heterocyclyl
is unsubstituted or substituted by C.sub.1-C.sub.6 alkyl,
-(alk).sub.q-OR or --S(O).sub.2R.sup.10; R is H, C.sub.1-C.sub.6
alkyl which is unsubstituted; R.sup.10 is H, a C.sub.3-C.sub.6
cycloalkyl group, C.sub.1-C.sub.6 alkyl which is unsubstituted, or
CF.sub.3; Heterocyclyl is a 5- or 6-membered saturated N-containing
heterocyclic group containing 0 or 1 additional heteroatoms
selected from O, N and S; q is 0 or 1; alk is C.sub.1-C.sub.6
alkylene; and R.sup.3 is selected from:
[0075] (a) a group of the following formula:
##STR00012##
wherein B is a phenyl ring which is unsubstituted or substituted
and Z is selected from H, --OR, --SR, CH.sub.2OR, --CO.sub.2R,
CF.sub.2OH, CH(CF.sub.3)OH, C(CF.sub.3).sub.2OH,
--(CH.sub.2).sub.qOR, --(CH.sub.2).sub.qNR.sub.2, --C(O)N(R).sub.2,
--NR.sub.2, --NRC(O)R, --S(O).sub.mN(R).sub.2, --OC(O)R,
OC(O)N(R).sub.2, --NRS(O).sub.mR, --RC(O)N(R).sub.2, CN, halogen
and --NO.sub.2, wherein each R is independently selected from H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10 cycloalkyl and a 5- to
12-membered aryl or heteroaryl group, the group being unsubstituted
or substituted, m is 1 or 2 and q is 0, 1 or 2;
[0076] (b) a heteroaryl group which contains 1, 2, 3 or 4 ring
nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from O
and S, which group is monocyclic or bicyclic and which is
unsubstituted or substituted; and
[0077] (c) a group comprising a benzene ring which is unsubstituted
or substituted and which is fused to a heteroaryl group as defined
above;
or a pharmaceutically acceptable salt thereof; with the provisos
that: [0078] (i) when X in formula (Ia) is S, then R.sup.3 is other
than an indole or 3-hydroxyphenyl group; and [0079] (ii) when X in
formula (Ib) is S, then R.sup.3 is other than an indole group.
[0080] In R.sup.1, the groups R.sup.4 and R.sup.5 typically form,
together with the N atom to which they are attached, a group
selected from piperidine, piperazine, pyrrolidine, oxazolidinone,
diazepan and 2,5-diaza-bicyclo[2,2,1]-heptane. Typically the group
formed by R.sup.4 and R.sup.5 is piperidine, piperazine or
pyrrolidine.
[0081] The group formed by R.sup.4 and R.sup.5 with the N atom is
unsubstituted or substituted by
-[(alk).sub.q-NR].sub.r--S(O).sub.2-(alk).sub.q-Z or by
unsubstituted C.sub.1-C.sub.6 alkyl, oxo (.dbd.O), -(alk).sub.q-OR,
--C(O)--C(R).sub.2--N(R).sub.2, --C(R).sub.2--C(O)--N(R).sub.2,
--C(O)--(NR).sub.q-(alk).sub.q-OR, --C(O)-cyclyl --C(O)R, --C(O)OR,
or --NR.sup.13R.sup.14.
[0082] Alternatively, one of R.sup.4 and R.sup.5 is C.sub.1-C.sub.6
alkyl, -(alk).sub.q-Heterocyclyl or -(alk).sub.q-OR and the other
is a piperazine, piperidine, pyrrolidine, sylphonylpyran or
-(alk).sub.q-Heterocyclyl group, wherein said piperazine,
piperidine, pyrrolidine, sulphonylpyran or Heterocyclyl group is
unsubstituted or substituted by C.sub.1-C.sub.6 alkyl,
-(alk).sub.q-OR or --S(O).sub.2R.sup.10.
[0083] Examples of Heterocyclyl include piperidine, for instance
piperidin-1-yl, piperidin-2-yl, piperidin-3-yl or piperidin-4-yl,
in particular piperidin-4-yl; morpholine; and pyrrolidine, for
instance pyrrolidin-2-yl or pyrrolidin-3-yl, groups.
[0084] Examples of
-[(alk).sub.q-NR].sub.r--S(O).sub.2-(alk).sub.q-Z include
--S(O).sub.2R.sup.10, --S(O).sub.2-(alk).sub.q-NR.sup.11R.sup.12
and -(alk).sub.q-NR--S(O).sub.2R.sup.10. Examples of
--S(O).sub.2R.sup.10 include --S(O).sub.2Me and
--S(O).sub.2-cyclopropyl.
[0085] Examples of --C(O)-(alk).sub.q-S(O).sub.2Z include
--C(O)--CH.sub.2--S(O).sub.2Me, --C(O)--CHMe-S(O).sub.2Me and
--C(O)--C(Me).sub.2-S(O).sub.2Me.
[0086] R.sup.10 is typically H, methyl, propyl (either n-propyl or
i-propyl), or CF.sub.3.
[0087] Examples of --S(O).sub.2-(alk).sub.q-NR.sup.11R.sup.12
include --S(O).sub.2--N(Me).sub.2, --S(O).sub.2--NHMe,
--S(O).sub.2--N(Me)(CH.sub.2CH.sub.2OMe),
--S(O).sub.2--N(Me)(CH.sub.2CH.sub.2OH),
##STR00013##
[0088] Examples of -(alk).sub.q-NR--S(O).sub.2R.sup.10 include
--CH.sub.2NH(SO.sub.2Me), --CH.sub.2N(Me)(SO.sub.2Me),
--NH--SO.sub.2Me and --N(Me)(SO.sub.2Me).
[0089] Examples of -(alk).sub.q-OR include --OH, --OMe,
--CH.sub.2OH, --CH.sub.2OMe, --CH.sub.2CH.sub.2OMe,
--CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2CH.sub.2OMe and
--CH.sub.2CH.sub.2CH.sub.2OH.
[0090] Examples of --C(O)--C(R').sub.2--N(R).sub.2 include
--C(O)--CH.sub.2--N(Me).sub.2, --C(O)--CH.sub.2--NHMe,
--C(O)--CH.sub.2--NH.sub.2, --C(O)--CHMe-N(Me).sub.2,
--C(O)--CHMe-NHMe, --C(O)--CHMe-NH.sub.2,
--C(O)--C(Me).sub.2-N(Me).sub.2, --C(O)--C(Me).sub.2-NHMe,
--C(O)--C(Me).sub.2-NH.sub.2, --C(O)--C(Me).sub.2-NH.sub.2,
##STR00014##
[0091] Examples of --C(R).sub.2--C(O)--N(R).sub.2 include
--C(Me).sub.2-C(O)--NH.sub.2, --CH.sub.2--C(O)--NH.sub.2,
--CHMe-C(O)--NH.sub.2, --C(Me).sub.2-C(O)--NHMe,
--CH.sub.2--C(O)--NHMe, --CHMe-C(O)--NHMe,
--C(Me).sub.2-C(O)--N(Me).sub.2, --CH.sub.2--C(O)--N(Me), and
--CHMe-C(O)--N(Me).sub.2.
[0092] Examples of --C(O)--(NR).sub.q-(alk).sub.q-OR when each q is
1 include --C(O)--N(Me)--CH.sub.2--OMe,
--C(O)--N(Me)--CH.sub.2--OH, --C(O)--NH--CH.sub.2--OH, and
--C(O)--NH--CH.sub.2--OMe.
[0093] Examples of --C(O)--(NR).sub.q-(alk).sub.q-OR when one q is
0 and the other q is 1 include --C(O)--CH.sub.2--OMe,
--C(O)--CH(Me)-OMe, --C(O)--C(Me).sub.2-OMe, --C(O)--CH.sub.2--OH,
--C(O)--CH(Me)--OH,
--C(O)--C(Me).sub.2-OH and --C(O)--CH(Me)-OMe.
[0094] Examples of --C(O)-cyclyl include --C(O)-(cyclopropyl).
[0095] Examples of --C(O)R include --C(O)H, --C(O)Me, --C(O)Et, and
--C(O)--C(CH.sub.3).sub.3
[0096] Examples of --C(O)OR include --C(O)OH, --C(O)OMe, --C(O)OEt,
and --C(O)OC(CH.sub.3).sub.3
[0097] In the definition (a) for R.sup.3 the phenyl ring B is
unsubstituted (apart from group Z) or substituted. When it is
unsubstituted the group Z is the sole substituent. Z may be at the
2-, 3-, 4-, 5- or 6-position on the phenyl ring. Typically it is at
the 2-, 3- or 4-position, more typically at the 3- or 4-position. Z
is most typically other than H, such that moiety -BZ is a
substituted phenyl ring. Specific examples of the group Z include
--OH, --CH.sub.2OH, F, Cl, 1-hydroxyethyl, --NHS(O).sub.2Me,
--NC(O)Me,
--S(O).sub.2NH.sub.2Me and --C(O)Me.
[0098] When the phenyl ring B is substituted it typically
comprises, in addition to group Z, one or more substituents
selected from halo, alkyl, alkenyl, alkynyl, CN, NO.sub.2, OR',
SR', NR'.sub.2, C(O)R', SOR', SO.sub.2R', SO.sub.2NR'.sub.2,
NC(O)R' and CO.sub.2R', wherein each R' is independently H or
C.sub.1-C.sub.6 alkyl.
[0099] In definition (b) for R.sup.3 the heteroaryl group is
unsubstituted or substituted. It is typically selected from
indazole, indole, pyridine, pyrimidine, benzimidazole, quinoline,
isoquinoline, imidazole and pyrazole, each of which is linked via
any available ring C or N atom. For instance, an indazole group may
be linked as indazol-4-yl, indazol-5-yl or indazol-6-yl. Pyrimidine
may be linked as pyrimidin-1-yl, pyrimidine-2-yl, pyrimidin-3-yl or
pyrimidin-4-yl. Pyridine may be linked as pyridin-1-yl,
pyridine-2-yl, pyridine-3-yl or pyridine-4-yl. Benzimidazole may be
linked via N as benzimidazol-1-yl. Quinoline may be linked as
quinolin-3-yl or quinolin-4-yl. Isoquinoline may be linked as
isoquinolin-3-yl or isoquinolin-4-yl. Imidazole may be linked via N
as imidazol-1-yl
[0100] If the heteroaryl group is substituted it may be substituted
by one or more substituents selected from a group Z, R.sup.20 as
defined above, alkyl which is unsubstituted or substituted by a
R.sup.20 as defined above, any group specified above as an
additional substituent on the phenyl ring B, and an oxo group
(.dbd.O). Typically, if substituted, the heteroaryl group is
substituted by OH, OMe, NH.sub.2, NMe.sub.2, F or Cl. In one
embodiment the heteroaryl group is unsubstituted.
[0101] In definition (c) for R.sup.3 the benzene ring is
unsubstituted or substituted. If it is substituted it may be
substituted by one or more substituents selected from a group Z,
R.sup.20 as defined above, alkyl which is unsubstituted or
substituted by R.sup.20 as defined above, and any of the groups
specified above as an additional substituent on the phenyl ring B.
The heteroaryl group to which the benzene ring is fused is itself
unsubstituted or substituted, for instance by a group Z, R.sup.20
or alkyl which is unsubstituted or substituted by a group R.sup.20
as defined above; by any group specified above as an option for an
additional substituent on the phenyl ring B; or by an oxo group
(.dbd.O). In one embodiment both the benzene ring and the
heteroaryl group are unsubstituted.
[0102] Groups included in definitions (b) and (c) for R.sup.3 as
defined above include the following structures:
##STR00015## ##STR00016## ##STR00017## ##STR00018##
wherein each R.sup.10 is independently selected from H,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
acyl, --C(O)NR'R'', --S(O).sub.tNR'R'', aryl, heteroaryl, sulphonyl
and halogen, wherein R' and R'' are each independently H or
C.sub.1-C.sub.6 alkyl and t is 1 or 2; each R.sup.H is
independently selected from --OR.sup.10 and --N(R.sup.10).sub.2,
wherein R.sup.10 is as defined above; each R.sup.12 is
independently H, F or CF.sub.3; each W is independently selected
from CR.sup.10 and N, wherein R.sup.10 is as defined above; and W'
is selected from O, S and NR.sup.12 wherein R.sup.12 is as defined
above.
[0103] Typical examples of R.sup.3 include
##STR00019##
wherein P is selected from H, --OR, --NR.sub.2, --CN, halo and
C.sub.1-C.sub.6 alkyl.
[0104] Typically in compounds of the invention, R.sup.3 takes
definition (a) or (b) as defined above.
[0105] In one aspect the invention provides a compound which is a
fused pyrimidine of formula (Ia''') or (Ib'''):
##STR00020##
wherein R.sup.2, R.sup.3, X, Y, Z, R' and R'' are as defined above
for formulae (Ia') and (Ib'); or a pharmaceutically acceptable salt
thereof; with the provisos that, in formula (Ia''') only: [0106]
(i) R.sup.3 is other than an indole or 3-hydroxyphenyl group when X
is S; [0107] (ii) Z is other than a group selected from Me,
-(alk).sub.q-NMe.sub.2 and -alk-morpholino when the following are
satisfied: Y is N, each of R' and R'' is H, R.sup.2 is H and
R.sup.3 is indazol-4-yl; and [0108] (iii) Z is other than Me when
the following are satisfied: Y is --CH--, each of R' and R'' is H,
R.sup.2 is H and R.sup.3 is indazol-4-yl.
[0109] In one aspect the invention provides a compound which is a
fused pyrimidine of formula (Ia) or (Ib):
##STR00021##
wherein
X is O or S;
[0110] R.sup.1 is a group of formula:
##STR00022##
R.sup.2 is H, halo or C.sub.1-C.sub.6 alkyl R.sup.4 and R.sup.5
form, together with the N atom to which they are attached, a group
selected from piperazine, piperidine, pyrrolidine, oxazolidinone,
diazepan and 2,5-diaza-bicyclo[2,2,1]-heptane, which group is
unsubstituted or substituted by
-[(alk).sub.q-NR].sub.r--S(O).sub.2-(alk).sub.q-Z or
--C(O)-(alk).sub.q-S(O).sub.2Z wherein Z is R.sup.10 or
--NR.sup.11R.sup.12, or by unsubstituted C.sub.1-C.sub.6 alkyl,
hydroxyl-C.sub.1-C.sub.6 alkyl, oxo (.dbd.O), -(alk).sub.q-OR,
--C(O)--C(R').sub.2--N(R).sub.2, --C(R).sub.2--C(O)--N(R).sub.2,
--C(O)--(NR).sub.q-(alk).sub.q-OR, --C(O)-cyclyl, --C(O)R,
--C(O)OR, --C(O)-Tet or --NR.sup.13R.sup.14, with the proviso that,
in formula (Ia) only, when X is S and R.sup.2 is H and R.sup.3 is
indazol-4-yl, said group is other than (i) piperazine which is
unsubstituted or substituted by a group selected from methyl,
--S(O).sub.2Me, --S(O).sub.2NMe.sub.2, -alk-OH, -alk-OMe,
--S(O).sub.2-alk-NMe.sub.2, and --S(O).sub.2-alk-morpholino; and
(ii) piperidine which is substituted by a group selected from
--S(O).sub.2Me, --C(O)--NR-(alk).sub.q-OR, --NMe-S(O).sub.2-Me,
methyl, piperidine and --NR.sup.13R.sup.14 wherein one of R.sup.13
and R.sup.14 is -(alk).sub.q-OR; or one of R.sup.4 and R.sup.5 is
C.sub.1-C.sub.6 alkyl, -(alk).sub.q-Heterocyclyl or -(alk).sub.q-OR
and the other is a piperazine, piperidine, pyrrolidine,
sulphonylpyran or -(alk).sub.q-Heterocyclyl group, wherein said
piperazine, piperidine, pyrrolidine, sulphonylpyran or Heterocyclyl
is unsubstituted or substituted by C.sub.1-C.sub.6 alkyl,
-(alk).sub.q-OR or --S(O).sub.2R.sup.10; R is H or C.sub.1-C.sub.6
alkyl which is unsubstituted; each R' is, independently, H or
C.sub.1-C.sub.6 alkyl which is unsubstituted, or the two groups R'
form, together with the C atom to which they are attached, a cyclyl
group; R.sup.10 is H, C.sub.1-C.sub.6 alkyl which is unsubstituted
or CF.sub.3; R.sup.11 and R.sup.12 are each independently selected
from H, C.sub.1-C.sub.6 alkyl which is unsubstituted and
-(alk).sub.q-OR, or R.sup.11 and R.sup.12 together form, with the N
atom to which they are attached, a 5- or 6-membered saturated
N-containing heterocyclic group containing 0 or 1 additional
heteroatoms selected from O, N and S; R.sup.13 and R.sup.14 are
each independently selected from C.sub.1-C.sub.6 alkyl,
--S(O).sub.2R.sup.10, and -(alk).sub.q-OR; Tet is a
tetrahydrofuranyl or tetrahydropyranyl group, which group is
unsubstituted or substituted; Heterocyclyl is a 5- or 6-membered
saturated N-containing heterocyclic group containing 0 or 1
additional heteroatoms selected from O, N and S; Cyclyl is a
C.sub.3-C.sub.6 cycloalkyl group; each q is independently 0 or 1; r
is 0 or 1; alk is C.sub.1-C.sub.6 alkylene; and R.sup.3 is selected
from:
[0111] (a) a group of the following formula:
##STR00023##
[0112] wherein B is a phenyl ring which is unsubstituted or
substituted and Z is selected from H, --OR, --SR, CH.sub.2OR,
--CO.sub.2R, CF.sub.2OH, CH(CF.sub.3)OH, C(CF.sub.3).sub.2OH,
--(CH.sub.2).sub.qOR, --(CH.sub.2).sub.qNR.sub.2, --C(O)N(R).sub.2,
--NR.sub.2, --NRC(O)R, --S(O).sub.mN(R).sub.2, --OC(O)R,
OC(O)N(R).sub.2, --NRS(O).sub.mR, --NRC(O)N(R).sub.2, CN, halogen
and --NO.sub.2, wherein each R is independently selected from H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10 cycloalkyl and a 5- to
12-membered aryl or heteroaryl group, the group being unsubstituted
or substituted, m is 1 or 2 and q is 0, 1 or 2;
[0113] (b) a heteroaryl group which contains 1, 2, 3 or 4 ring
nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from O
and S, which group is monocyclic or bicyclic and which is
unsubstituted or substituted; and
[0114] (c) a group comprising a benzene ring which is unsubstituted
or substituted and which is fused to a heteroaryl group as defined
above;
or a pharmaceutically acceptable salt thereof; with the provisos
that: [0115] (i) when X in formula (Ia) is S, then R.sup.3 is other
than an indole or 3-hydroxyphenyl group; and [0116] (ii) when X in
formula (Ib) is S, then R.sup.3 is other than an indole group.
[0117] In one aspect the invention provides a compound which is a
fused pyrimidine of formula (Ia')
##STR00024##
wherein
X is O or S;
Y is N or --CH--;
[0118] R.sup.2 is H, halo or C.sub.1-C.sub.6 alkyl; each R' is,
independently, H, C.sub.1-C.sub.6 alkyl or hydroxyl-C.sub.1-C.sub.6
alkyl, or two groups R' on the same carbon atom form an oxo
(.dbd.O) group; or when Y is N, two groups R' on different carbon
atoms together form a --CH.sub.2-- bridgehead; each R'' is,
independently, H or C.sub.1-C.sub.6 alkyl, or two groups R'' on the
same carbon atom form an oxo (.dbd.O) group; Z is R.sup.10 or
-(alk).sub.q-NR.sup.11R.sup.12; R.sup.10 is H, C.sub.1-C.sub.6
alkyl which is unsubstituted, or CF.sub.3; R.sup.11 and R.sup.12
are each independently selected from H, C.sub.1-C.sub.6 alkyl which
is unsubstituted and -(alk).sub.q-OR, or R.sup.11 and R.sup.12
together form, with the N atom to which they are attached, a 5- or
6-membered saturated N-containing heterocyclic group containing 0
or 1 additional heteroatoms selected from O, N and S; q is 0 or 1;
alk is C.sub.1-C.sub.6 alkylene; and and R.sup.3 is selected
from:
[0119] (a) a group of the following formula:
##STR00025##
[0120] wherein B is a phenyl ring which is unsubstituted or
substituted and Z is selected from H, --OR, --SR, CH.sub.2OR,
--CO.sub.2R, CF.sub.2OH, CH(CF.sub.3)OH, C(CF.sub.3).sub.2OH,
--(CH.sub.2).sub.qOR, --(CH.sub.2).sub.qNR.sub.2, --C(O)N(R).sub.2,
--NR.sub.2, --NRC(O)R, --S(O).sub.mN(R).sub.2, --OC(O)R,
OC(O)N(R).sub.2, --NRS(O).sub.mR, --NRC(O)N(R).sub.2, CN, halogen
and --NO.sub.2, wherein each R is independently selected from H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10 cycloalkyl and a 5- to
12-membered aryl or heteroaryl group, the group being unsubstituted
or substituted, m is 1 or 2 and q is 0, 1 or 2;
[0121] (b) a heteroaryl group which contains 1, 2, 3 or 4 ring
nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from O
and S, which group is monocyclic or bicyclic and which is
unsubstituted or substituted; and
[0122] (c) a group comprising a benzene ring which is unsubstituted
or substituted and which is fused to a heteroaryl group as defined
above;
or a pharmaceutically acceptable salt thereof; with the provisos
that: [0123] (i) R.sup.3 is other than an indole or 3-hydroxyphenyl
group when X is S; [0124] (ii) Z is other than a group selected
from Me, -(alk).sub.q-NMe.sub.2 and -alk-morpholino when the
following are satisfied: Y is N, each of R' and R'' is H, R.sup.2
is H and R.sup.3 is indazol-4-yl; [0125] (iii) Z is other than Me
when the following are satisfied: Y is --CH--, each of R' and R''
is H, R.sup.2 is H and R.sup.3 is indazol-4-yl.
[0126] In one aspect the invention provides a compound which is
fused pyrimidine of formula (Ib'):
##STR00026##
wherein
X is O or S;
Y is N or --CH--;
[0127] R.sup.2 is H, halo or C.sub.1-C.sub.6 alkyl; each R' is,
independently, H, C.sub.1-C.sub.6 alkyl or hydroxy-C.sub.1-C.sub.6
alkyl, or two groups R' on the same carbon atom form an oxo
(.dbd.O) group; or when Y is N, two groups R' on different carbon
atoms together form a --CH.sub.2-- bridgehead; each R'' is,
independently, H or C.sub.1-C.sub.6 alkyl, or two groups R'' on the
same carbon atom form an oxo (.dbd.O) group; Z is R.sup.10 or
-(alk).sub.q-NR.sup.11R.sup.12; R.sup.10 is H, C.sub.1-C.sub.6
alkyl which is unsubstituted, or CF.sub.3; R.sup.11 and R.sup.12
are each independently selected from H, C.sub.1-C.sub.6 alkyl which
is unsubstituted and -(alk).sub.q-OR, or R.sup.11 and R.sup.12
together form, with the N atom to which they are attached, a 5- or
6-membered saturated N-containing heterocyclic group containing 0
or 1 additional heteroatoms selected from O, N and S; q is 0 or 1;
alk is C.sub.1-C.sub.6 alkylene; and and R.sup.3 is selected
from:
[0128] (a) a group of the following formula:
##STR00027##
[0129] wherein B is a phenyl ring which is unsubstituted or
substituted and Z is selected from H, --OR, --SR, CH.sub.2OR,
--CO.sub.2R, CF.sub.2OH, CH(CF.sub.3)OH, C(CF.sub.3).sub.2OH,
--(CH.sub.2).sub.qOR, --(CH.sub.2).sub.qNR.sub.2, --C(O)N(R).sub.2,
--NR.sub.2, --NRC(O)R, --S(O).sub.mN(R).sub.2, --OC(O)R,
OC(O)N(R).sub.2, --NRS(O).sub.mR, --NRC(O)N(R).sub.2, CN, halogen
and --NO.sub.2, wherein each R is independently selected from H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10 cycloalkyl and a 5- to
12-membered aryl or heteroaryl group, the group being unsubstituted
or substituted, m is 1 or 2 and q is 0, 1 or 2;
[0130] (b) a heteroaryl group which contains 1, 2, 3 or 4 ring
nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from O
and S, which group is monocyclic or bicyclic and which is
unsubstituted or substituted; and
[0131] (c) a group comprising a benzene ring which is unsubstituted
or substituted and which is fused to a heteroaryl group as defined
above;
or a pharmaceutically acceptable salt thereof.
[0132] In one aspect the invention provides a compound which is a
fused pyrimidine of formula (Ia'') or (Ib''):
##STR00028##
wherein
X is O or S;
[0133] R.sup.2 is H, halo or C.sub.1-C.sub.6 alkyl; R.sup.4 is
C.sub.1-C.sub.6 alkyl, -(alk).sub.q-Heterocyclyl, or
-(alk).sub.q-OR; R.sup.5 is a piperazine, piperidine, pyrrolidine,
sulphonylpyran or -(alk).sub.q-Heterocyclyl group, wherein said
piperazine, piperidine, pyrrolidine, sulphonylpyran or Heterocyclyl
group is unsubstituted or substituted by C.sub.1-C.sub.6 alkyl,
-(alk).sub.q-OR or --S(O).sub.2R.sup.10; R is H, C.sub.1-C.sub.6
alkyl which is unsubstituted; R.sup.10 is H, C.sub.1-C.sub.6 alkyl
which is unsubstituted, or CF.sub.3; Heterocyclyl is a 5- or
6-membered saturated N-containing heterocyclic group containing 0
or 1 additional heteroatoms selected from O, N and S; q is 0 or 1;
alk is C.sub.1-C.sub.6 alkylene; and and R.sup.3 is selected
from:
[0134] (a) a group of the following formula:
##STR00029##
[0135] wherein B is a phenyl ring which is unsubstituted or
substituted and Z is selected from H, --OR, --SR, CH.sub.2OR,
--CO.sub.2R, CF.sub.2OH, CH(CF.sub.3)OH, C(CF.sub.3).sub.2OH,
--(CH.sub.2).sub.qOR, --(CH.sub.2).sub.mNR.sub.2, --C(O)N(R).sub.2,
--NR.sub.2, --NRC(O)R, --S(O).sub.mN(R).sub.2, --OC(O)R,
OC(O)N(R).sub.2, --NRS(O).sub.mR, --NRC(O)N(R).sub.2, CN, halogen
and --NO.sub.2, wherein each R is independently selected from H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10 cycloalkyl and a 5- to
12-membered aryl or heteroaryl group, the group being unsubstituted
or substituted, m is 1 or 2 and q is 0, 1 or 2;
[0136] (b) a heteroaryl group which contains 1, 2, 3 or 4 ring
nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from O
and S, which group is monocyclic or bicyclic and which is
unsubstituted or substituted; and
[0137] (c) a group comprising a benzene ring which is unsubstituted
or substituted and which is fused to a heteroaryl group as defined
above;
or a pharmaceutically acceptable salt thereof; with the provisos
that: [0138] (i) when X in formula (Ia'') is S, then R.sup.3 is
other than an indole or 3-hydroxyphenyl group; and [0139] (ii) when
X in formula (Ib'') is S, then R.sup.3 is other than an indole
group.
[0140] Specific examples of compounds of the invention include:
TABLE-US-00001 TABLE 1a Compound No. Structure Name 1 ##STR00030##
(1S,4S)-2-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)-5-methylsulfonyl-2,5- diaza-bicyclo[2.2.1]heptane 2
##STR00031## 2-(1H-indazol-4-yl)-6-((4- methylsulfonylpiperazin-1-
yl)methyl)-4-morpholinofuro[3,2- d]pyrimidine 3 ##STR00032##
2-(1H-indazol-4-yl)-6-((4-(N- morpholino)sulfonylpiperazin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidine 4. ##STR00033##
2-(1H-indazol-4-yl)-6-(((3S,5R)-3-
methyl-4-methylsulfonylpiperazin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidine 5. ##STR00034##
6-((4-methylsulfonylpiperazin-1- yl)methyl)-4-morpholino-2-
(pyrimidin-5-yl)thieno[2,3- d]pyrimidine 6. ##STR00035##
2-(1H-indazol-4-yl)-6-(((3S,5R)-3,5-
dimethyl-4-methylsulfonylpiperazin- 1-yl)methyl)-4-
morpholinothieno[3,2-d]pyrimidine 7. ##STR00036##
6-(((2R,6S)-4-methylsulfonyl-2,6- dimethylpiperazin-1-yl)methyl)-2-
(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidine 8.
##STR00037## 6-(((2R,6S)-4-isopropylsulfonyl-2,6-
dimethylpiperazin-1-yl)methyl)-2- (1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidine 9. ##STR00038## 6-(((2R,6S)-4-
trifluoromethylsulfonyl-2,6- dimethylpiperazin-1-yl)methyl)-2-
(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidine 10.
##STR00039## 6-(((R)-4-methylsulfonyl-3-
methylpiperazin-1-yl)methyl)-2-(1H- indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidine 11. ##STR00040##
3-(6-((4-methylsulfonylpiperazin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidin-2-
yl)benzenesulfonamide 12. ##STR00041##
(4-(6-((4-methylsulfonylpiperazin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidin-2-yl)phenyl)methanol
13. ##STR00042## 3-(6-((4-methylsulfonylpiperazin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidin-2-yl)benzamide 14.
##STR00043## 1-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)-4-
methylsulfonylpiperazin-2-one 15. ##STR00044##
1-(4-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-amino-2- methylpropan-1-one 16.
##STR00045## 2-(2-methyl-1H-benzo[d]imidazol-1-
yl)-6-((4-methylsulfonylpiperazin-1-
yl)methyl)-4-morpholinothieno[2,3- d]pyrimidine 17. ##STR00046##
(3-(6-((4-methylpiperazin-1- yl)methyl)-4-morpholinothieno[2,3-
d]pyrimidin-2-yl)phenyl)methanol 18. ##STR00047##
2-(1H-indazol-4-yl)-6-((4-N-methyl- N-
methoxyethylaminosulfonylpiperidin- 1-yl)methyl)-4-
morpholinothieno[3,2-d]pyrimidine 19. ##STR00048##
2-(1H-indazol-4-yl)-6-((4-N,N- dimethylaminosulfonylpiperidin-1-
yl)methyl)-4-morpholinothieno[2,3- d]pyrimidine 20. ##STR00049##
2-(1H-indazol-4-yl)-6-((4-N,N- dimethylaminosulfonylpiperidin-1-
yl)methyl)-7-methyl-4- morpholinothieno[3,2-d]pyrimidine 21.
##STR00050## 2-(1H-indazol-4-yl)-6-((4- methylsulfonylpiperidin-1-
yl)methyl)-4-morpholinothieno[2,3- d]pyrimidine 22. ##STR00051##
2-(1H-indazol-4-yl)-6-((4-N- methylaminosulfonylpiperidin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidine 23. ##STR00052##
2-(1H-indazol-4-yl)-7-methyl-6-((4- (methylsulfonyl)piperidin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidine 24. ##STR00053##
2-(1H-indazol-4-yl)-6-((4-N-4- methylpiperazinosulfonylpiperidin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidine 25. ##STR00054##
2-(1H-imidazol-1-yl)-6-((4- methylsulfonylpiperazin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidine 26. ##STR00055##
2-(1H-benzo[d]imidazol-1-yl)-6-((4- methylsulfonylpiperazin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidine 27. ##STR00056##
2-(1H-indazol-4-yl)-6-((4-N,N- dimethylaminosulfonylpiperidin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidine 28. ##STR00057##
2-(1H-indazol-4-yl)-6-((4-N- morpholinosulfonylpiperazin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidine 29. ##STR00058##
2-(1H-indazol-4-yl)-7-methyl-6-((4- (methylsulfonyl)piperazin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidine 30. ##STR00059##
N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)-1-methylsulfonyl-N-(2- morpholinoethyl)piperidin-4-amine
31. ##STR00060## 2-(1H-indazol-4-yl)-6-((4-
methylpiperazin-1-yl)methyl)-4- morpholinothieno[2,3-d]pyrimidine
32. ##STR00061## (1-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)pyrrolidin-2-yl)-N-
methylsulfonylmethanamine 33. ##STR00062##
2-chloro-5-(6-((4-methylpiperazin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidin-2-yl)phenol 34.
##STR00063## N-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)-N-(2-methoxyethyl)-1- methylsulfonylpiperidin-4-amine
35. ##STR00064## 4-fluoro-3-(6-((4-methylpiperazin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidin-2-yl)phenol 36.
##STR00065## 2,3-difluoro-5-(6-((4- methylpiperazin-1-yl)methyl)-4-
morpholinothieno[3,2-d]pyrimidin-2- yl)phenol 37. ##STR00066##
5-(6-((4-methylpiperazin-1- yl)methyl)-4-morpholinothieno[3,2-
d]pyrimidin-2-yl)pyridin-3-ol 38. ##STR00067##
2-(1H-indazol-4-yl)-6-((1- methylpiperidin-4-yl)methyl)-4-
morpholinothieno[3,2-d]pyrimidine 39. ##STR00068##
6-((4-methylpiperazin-1-yl)methyl)- 4-morpholino-2-(1H-pyrazol-4-
yl)thieno[3,2-d]pyrimidine 40. ##STR00069##
1-(3-(6-((4-methylpiperazin-1- yl)methyl)-4-morpholinothieno[3,2-
d]pyrimidin-2-yl)phenyl)ethanol 41. ##STR00070##
(3-(6-((4-methylpiperazin-1- yl)methyl)-4-morpholinothieno[3,2-
d]pyrimidin-2-yl)phenyl)methanol 42. ##STR00071##
N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)-tetrahydro-N-methyl-2H- sulfonylpyran-4-amine 43.
##STR00072## 2-(4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)piperazin-1-yl)-2-
methylpropanamide 44. ##STR00073## N-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)-1-(2-methoxyethyl)-N- methylpiperidin-4-amine 45.
##STR00074## N-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)-N,1-dimethylpiperidin-4- amine 46. ##STR00075##
1-(2-hydroxyethyl)-4-((2-(3- hydroxyphenyl)-4-
morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)piperazin-2-one 47.
##STR00076## 4-((2-(3-hydroxyphenyl)-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)-N-(2-methoxyethyl)-N- methylpiperazine-1-carboxamide 48.
##STR00077## (4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)piperazin-1-
yl)(cyclopropyl)methanone 49. ##STR00078##
2-(1H-indazol-4-yl)-6-((3- (methylsulfonyl)pyrrolidin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidine 50. ##STR00079##
2-(1H-indazol-4-yl)-6-(((S)-2- methyl-4-methylsulfonylpiperazin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidine 51. ##STR00080##
(3-(6-((4-methylsulfonylpiperazin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidin-2-yl)phenyl)methanol
52. ##STR00081## 1-(4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)piperazin-1-yl)-2,2-
dimethylpropan-1-one 53. ##STR00082## 4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazine-1-carbaldehyde 54. ##STR00083##
1-(4-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)ethanone 55. ##STR00084## ethyl
4-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazine-1-carboxylate 56. ##STR00085## methyl
4-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazine-1-carboxylate 57. ##STR00086##
2-(1H-indazol-4-yl)-6-((4- methylsulfonylpiperazin-1-yl)methyl)-4-
morpholinothieno[2,3-d]pyrimidine 58. ##STR00087##
1-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)-N-methyl-N- methylsulfonylpyrrolidin-3-amine 59.
##STR00088## N-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)-N-methyl(1-
methylsulfonylpyrrolidin-2-yl)methanamine 60. ##STR00089##
N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)-N-methyl-(1- methylsulfonylpyrrolidin)-3-amine 61.
##STR00090## 1-((1-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperidin-4-yl)methyl)pyrrolidin-2- one 62. ##STR00091##
6-((4-((1H-pyrazol-1-yl)methyl)piperidin-1-
yl)methyl)-2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidine
63. ##STR00092## 1-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)piperidin-4-ol 64.
##STR00093## 1-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)pyrrolidin-3-ol 65.
##STR00094## 1-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)piperidin-3-ol 66.
##STR00095## (S)-1-(4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-hydroxypropan-1- one 67. ##STR00096##
1-(4-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2- (dimethylamino)ethanone 68.
##STR00097## 1-(4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-aminoethanone
69. ##STR00098## 6-((4-methylsulfonylpiperazin-1-yl)methyl)-2-
(4-(methylsulfonyl)phenyl)-4- morpholinothieno[3,2-d]pyrimidine 70.
##STR00099## 2-(1H-indazol-6-yl)-6-((4-methylpiperazin-1-
yl)methyl)-4-morpholmothieno[3,2- d]pyrimidine 71. ##STR00100##
N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)-N-(2-methoxyethyl)-1- methylpiperidin-4-amine 72.
##STR00101## (4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)-1-methylsulfonylpiperazin-2-yl)- N,N-dimethylmethanamine
73. ##STR00102## 1-(2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6- yl)pyrrolidin-2-one 74.
##STR00103## N-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)-N,1-dimethylpiperidin-4-amine 75. ##STR00104##
3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-
yl)oxazolidin-2-one 76. ##STR00105##
3-(6-((4-methylsulfonylpiperazin-1-yl)methyl)-
4-morpholinothieno[3,2-d]pyrimidin-2- yl)benzenemethylsulfonylamine
77. ##STR00106## 6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-
morpholino-2-(pyrimidin-5-yl)thieno[3,2- d]pyrimidine 78.
##STR00107## 2-(6-fluoropyridin-3-yl)-6-((4-
methylsulfonylpiperazin-1-yl)methyl)-4-
morpholinothieno[3,2-d]pyrimidine 79. ##STR00108##
N-methyl-3-(6-((4-melhylsulfonylpiperazin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidin-2-yl)benzamide 80.
##STR00109## 2-(3-fluorophenyl)-6-((4-methylpiperazin-1-
yl)methyl)-4-morpholinothieno[3,2- d]pyrimidme 81. ##STR00110##
2-(2-fluoropyridin-3-yl)-6-((4-
methylsulfonylpiperazin-1-yl)methyl)-4-
morpholinothieno[3,2-d]pyrimidine 82. ##STR00111##
6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-2-
(2-methoxy-pyrimidin-5-yl)-4-morpholin-4-yl-
thieno[2,3-d]pyrimidine 83. ##STR00112##
{5-[6-(4-Methanesulfonyl-piperazin-1-
ylmethyl)-4-morpholin-4-yl-thieno[2,3-
d]pyrimidin-2-yl]-pyrimidin-2-yl}-dimethyl- amine 84. ##STR00113##
6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-
morpholin-4-yl-2-pyridin-3-yl-thieno[3,2- d]pyrimidine 85.
##STR00114## N-{4-[6-(4-Methanesulfonyl-piperazin-1-
ylmethyl)-4-morpholin-4-yl-thieno[3,2-
d]pyrimidin-2-yl]-phenyl}-methanesulfonamide 86. ##STR00115##
N-4-[6-(4-Methanesulfonyl-piperazin-1-
ylmethyl)-4-morpholin-4-yl-thieno[3,2-
d]pyrimidin-2-yl]-phenyl}-acetamide 87. ##STR00116##
6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-
morpholin-4-yl-2-pyridin-3-yl-thieno[2,3- d]pyrimidine 88.
##STR00117## 6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-2-
(2-methyl-imidazol-1-yl)-4-morpholin-4-yl- thieno[3,2-d]pyrimidine
89. ##STR00118## 3-[6-(4-Methanesulfonyl-piperazin-1-
ylmethyl)-4-morpholin-yl-thieno[3,2- d]pyrimidin-2-yl]-quinoline
90. ##STR00119## 4-[6-(4-Methanesulfonyl-piperazin-1-
ylmethyl)-4-morpholin-4-yl-thieno[3,2-
d]pyrimidin-2-yl]-isoquinoline 91. ##STR00120##
1-{3-[6-(4-Methanesulfonyl-piperazin-1-
ylmethyl)-4-morpholin-4-yl-thieno[2,3-
d]pyrimidin-2-yl]-phenyl}-ethanone 92. ##STR00121##
2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-
[1,4]diazepan-1-ylmethyl)-4-morpholin-4-yl- thieno[3,2-d]pyrimidine
93. ##STR00122## 1-{3-[6-(4-Methanesulfonyl-piperazin-1-
ylmethyl)-4-morpholin-4-yl-thieno[2,3-
d]pyrimidin-2-yl]-phenyl}-ethanol 94. ##STR00123##
4-[6-(4-Methanesulfonyl-piperazin-1-
ylmethyl)-4-morpholin-4-yl-thieno[2,3-
d]pyrimidin-2-yl]-isoquinoline 95. ##STR00124##
3-[6-(4-Methanesulfonyl-piperazin-1-
ylmethyl)-4-morpholin-4-yl-thieno[2,3- d]pyrimidin-2-yl]-quinoline
96. ##STR00125## 2-(1H-lndazol-4-yl)-6-((S)-4-methanesulfonyl-
3-methyl-piperazin-1-ylmethyl)-4-morpholin-4-
yl-thieno[2,3-d]pyrimidine 97. ##STR00126##
2-(1H-Indazol-4-yl)-4-morpholin-4-yl-6-[4-
(propane-2-sulfonyl)-piperazin-1-ylmethyl]- thieno[2,3-d]pyrimidine
98. ##STR00127## 2-(1H-Indazol-4-yl)-6-((R)-4-methanesulfonyl-
3-methyl-piperazin-1-ylmethyl)-4-morpholin-4-
yl-thieno[2,3-d]pyrimidine 99. ##STR00128##
2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-2,2-
dimethyl-piperazin-1-ylmethyl)-4-morpholin-4-
yl-thieno[3,2-d]pyrimidine 100. ##STR00129##
2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-3,3-
dimethyl-piperazin-1-ylmethyl)-4-morpholin-4-
yl-thieno[3,2-d]pyrimidine 101. ##STR00130##
6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-2-
(2-methyl-benzoimidazol-1-yl)-4-morpholin-4-
yl-thieno[3,2-d]pyrimidine 102. ##STR00131##
2-(1H-Indazol-4-yl)-6-((2S,6R)-4-
methanesulfonyl-2,6-dimethyl-piperazin-1-
ylmethyl)-4-morpholin-4-yl-thieno[2,3- d]pyrimidine 103
##STR00132## [2-(1H-Indazol-4-yl)-4-morpholin-4-yl-
thieno[2,3-d]pyrimidin-6-ylmethyl]-
methyl-(1-methyl-piperidin-4-yl)-amine 104 ##STR00133##
2-{4-[2-(1H-Indazol-4-yl)-4-morpholin-4-yl-
thieno[2,3-d]pyrimidin-6-ylmethyl]-piperazin-
1-yl}-N,N-dimethyl-acetamide 105 ##STR00134##
2-{4-[2-(1H-Indazol-4-yl)-4-morpholin-4-yl-
thieno[2,3-d]pyrimidin-6-ylmethyl]-piperazin-
1-yl}-N-methyl-isobutyramide 106 ##STR00135##
2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-
piperazin-1-ylmethyl)-5-methyl-4-morpholin-
4-yl-thieno[2,3-d]pyrimidine 107 ##STR00136##
(R)-1-(4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-hydroxypropan-1- one 108 ##STR00137##
1-(4-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-hydroxy-2- methylpropan-1-one 109
##STR00138## 1-(4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-hydroxyethanone 110 ##STR00139##
1-(4-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-methoxyethanone 111 ##STR00140##
(4-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)(tetrahydrofuran-2- yl)methanone 112
##STR00141## (4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)piperazin-1-yl)(1-
aminocyclopropyl)methanone 113 ##STR00142##
(S)-1-(4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-aminopropan-1-one 114 ##STR00143##
(R)-1-(4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-aminopropan-1-one 115 ##STR00144##
1-(4-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2- (methylsulfonyl)ethanone 116
##STR00145## (S)-1-(4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[2,3-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-hydroxypropan-1- one 117 ##STR00146##
(R)-1-(4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)
piperazin-1-yl)-2-hydroxypropan-1-one 118 ##STR00147##
1-(4-((2-(1H-indazol-4-yl)-4- morpholinothieno[2,3-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-hydroxy-2- methylpropan-1-one 119
##STR00148## 1-(4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[2,3-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-hydroxyethanone 120 ##STR00149##
1-(4-((2-(1H-indazol-4-yl)-4- morpholinothieno[2,3-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-methoxyethanone 121 ##STR00150##
(4-((2-(1H-indazol-4-yl)-4- morpholinothieno[2,3-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)(tetrahydrofuran-2- yl)methanone 122
##STR00151## 1-(4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[2,3-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-amino-2- methylpropan-1-one 123
##STR00152## (4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[2,3-d]pyrimidin-6- yl)methyl)piperazin-1-yl)(1-
aminocyclopropyl)methanone 124 ##STR00153##
1-(4-((2-(1H-indazol-4-yl)-4- morpholinothieno[2,3-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-aminoethanone 125 ##STR00154##
(S)-1-(4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[2,3-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-aminopropan-1-one 126 ##STR00155##
(R)-1-(4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[2,3-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-aminopropan-1-one 127 ##STR00156##
1-(4-((2-(1H-indazol-4-yl)-4- morpholinothieno[2,3-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2- (methylsulfonyl)ethanone
TABLE-US-00002 TABLE 1b Compound No. Structure Name 128
##STR00157## 2-(1H-indol-4-yl)-6-((4-
methylsulfonylpiperazin-1-yl)methyl)-4-
morpholinofuro[3,2-d]pyrimidine 129 ##STR00158##
2-(1H-indazol-4-yl)-6-((4- methylsulfonylpiperazin-1-yl)methyl)-4-
morpholinothieno[3,2-d]pyrimidine 130 ##STR00159##
N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)-N-methylpiperidin-4-amine 131 ##STR00160##
(S)-1-(4-((2-(1H-indazol-4-yl)-7-methyl-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)-2-hydroxyl)ropan-1- one 132 ##STR00161##
N-((2-(1H-indazol-4-yl)-7-methyl-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)-N,1-dimethylpiperidin-4-amine 133 ##STR00162##
6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-
morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-
yl)thieno[3,2-d]pyrimidine 134 ##STR00163##
(S)-1-((S)-4-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)-3-methylpiperazin-1-yl)-2- hydroxypropan-1-one 135
##STR00164## 2-(1H-benzo[d]imidazol-5-yl)-6-((4-
methylpiperazin-1-yl)methyl)-4- morpholinothieno[3,2-d]pyrimidine
136 ##STR00165## 2-(2-methyl-1H-benzo[d]imidazol-5-yl)-6-((4-
methylsulfonylpiperazin-1-yl)methyl)-4-
morpholinothieno[3,2-d]pyrimidine 137 ##STR00166##
2-(1H-indazol-5-yl)-6-((4- methylsulfonylpiperazin-1-yl)methyl)-4-
morpholinothieno[3,2-d]pyrimidine 138 ##STR00167##
5-(6-((4-methylsulfonylpiperazin)1-yl)methyl)-
4-morpholinothieno[3,2-d]pyrimidin-2-yl)-1H-
benzo[d]imidazol-2(3H)-one 139 ##STR00168##
2-(1H-benzo[d]imidazol-4-yl)-6-((4-
methylsulfonylpiperazin)1-yl)methyl)-4-
morpholinothieno[3,2-d]pyrimidine 140 ##STR00169##
6-((4-methylsulfonylpiperazin)1-yl)methyl)-4-
morpholino-2-(1H-pyrrolo[2,3-b]pyridin)5-
yl)thieno[2,3-d]pyrimidine 141 ##STR00170##
2-(1H-indazol-4-yl)-6-((4- methylsulfonylpiperazin-1-yl)methyl)-4-
morpholinofuro[2,3-d]pyrimidine 142
6-((4-methylsulfonylpiperazin)1-yl)methyl)-4-
morpholino-2-(1H-pyrrolo[2,3-b]pyridin)5- yl)furo[3,2-d]pyrimidine
143 ##STR00171## N-((2-(1H-indazol-4-yl)-4-
morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)-1-isopropyl-N-methylpiperidin-4- amine 144
6-(6-((4-methylsulfonylpiperazin)1-yl)methyl)-
4-morpholinothieno[3,2-d]pyrimidin-2-yl)-3H- imidazo[4,5-b]pyridine
145 ##STR00172## 6((4-isopropylsulfonylpiperazin-1-yl)methyl)-
4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-
yl)thieno[2,3-d]pyrimidine 146 ##STR00173##
6-((4-(2-thiophen)sulfonylpiperazin-1-
yl)methyl)-4-morpholino-2-(1H-pyrrolo[2,3-
b]pyridin-5-yl)thieno[2,3-d]pyrimidine 147 ##STR00174##
6-(6-((4-methylsulfonylpiperazin)1-yl)methyl)-
4-morpholinothieno[2,3-d]pyrimidin-2-yl)-3H- imidazo[4,5-b]pyridine
148 ##STR00175## (S)-2-hydroxy-1-(4-((7-methyl-4-morpholino-2-
(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-
d]pyrimidin-6-yl)methyl)piperazin-1-yl)propan- 1-one 149
##STR00176## (S)-2-hydroxy-1-(4-((4-morpholino-2-(1H-
pyrrolo[2,3-b]pyridin-5-yl)thieno[2,3-
d]pyrimidin-6-yl)methyl)piperazin-1-yl)propan- 1-one 150
##STR00177## (S)-2-hydroxy-1-(4-((7-methyl-4-morpholino-2-
(quinolin-3-yl)thieno[3,2-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)propan-1-one 151 ##STR00178##
(S)-2-hydroxy-1-(4-((4-morpholino-2-(quinolin-
3-yl)thieno[2,3-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)propan-1-one 152 ##STR00179##
2-methyl-6-(6-((4-methylsulfonylpiperazin-1-
yl)methyl)-4-morpholinothieno[2,3-
d]pyrimidin-2-yl)-3H-imidazo[4,5-b]pyridine 153 ##STR00180##
(S)-2-hydroxy-1-(4-((2-(2-methyl-3H- imidazo[4,5-b]pyridin-6-yl)-4-
morpholinothieno[2,3-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)propan-1-one 154 ##STR00181##
6-(6-((4-methylsulfonylpiperazin-1-yl)methyl)-
4-morpholinothieno[2,3-d]pyrimidin-2- yl)imidazo[1,2-a]pyrimidine
155 ##STR00182## 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-
[1,4]diazepan-1-ylmethyl)-4-morpholin-4-yl- thieno[2,3-d]pyrimidine
156 ##STR00183## 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-
1,4]diazepan-1-ylmethyl)-4-morpholin-4-yl- thieno[3,2-d]pyrimidine
157 ##STR00184## 6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-2-
(2-methyl-1H-benzoimidazol-5-yl)-4-
morpholin-4-yl-thieno[3,2-d]pyrimidine 158 ##STR00185##
2-(1H-Indazol-5-yl)-6-(4-methanesulfonyl-
piperazin-1-ylmethyl)-4-morpholin-4-yl- thieno[3,2-d]pyrimidine 159
##STR00186## 2-(1H-benzo[d]imidazol-5-yl)-6-((4-
(methylsulfonyl)piperazin-1-yl)methyl)-4-
morpholinothieno[2,3-d]pyrimidine 160 ##STR00187##
2-(2-methyl-1H-benzo[d]imidazol-5-yl)-6-((4-
(methylsulfonyl)piperazin-1-yl)methyl)-4-
morpholinothieno[2,3-d]pyrimidine 161 ##STR00188##
4-(6-((4-(methylsulfonyl)piperazin-1-
yl)methyl)-4-morpholinothieno[2,3-
d]pyrimidin-2-yl)benzene-1,2-diamine 162 ##STR00189##
4-(6-((4-(methylsulfonyl)piperazin-1-
yl)methyl)-2-(pyrido[2,3-b]pyrazin-7-
yl)thieno[2,3-d]pyrimidin-4-yl)morpholine 163 ##STR00190##
5-(6-((4-(methylsulfonyl)piperazin-1-
yl)methyl)-4-morpholinothieno[3,2-
d]pyrimidin-2-yl)-1H-indazol-3-amine 164 ##STR00191##
6-(6-((4-(methylsulfonyl)piperazin-1-
yl)methyl)-4-morpholinothieno[3,2-
d]pyrimidin-2-yl)-1H-indazol-3-amine 165 ##STR00192##
4-(6-((4-(methylsulfonyl)piperazin-1-
yl)methyl)-2-(1H-pyrazolo[3,4-b]pyridin-5-
yl)thieno[2,3-d]pyrimidin-4-yl)morpholine 166 ##STR00193##
4-(6-((4-(methylsulfonyl)piperazin-1-
yl)methyl)-2-(1H-pyrazolo[3,4-c]pyridin-4-
yl)thieno[2,3-d]pyrimidin-4-yl)morpholine 167 ##STR00194##
4-(6-((4-(methylsulfonyl)piperazin-1-
yl)methyl)-2-(5,6,7,8-tetrahydroquinolin-3-
yl)thieno[2,3-d]pyrimidin-4-yl)morpholine 168 ##STR00195##
N,1-dimethyl-N-((4-morpholino-2-(quinolin-3-
yl)thieno[2,3-d]pyrimidin-6- yl)methyl)piperidin-4-amine 169
##STR00196## (S)-2-hydroxy-1-(4-((7-methyl-2-(2-methyl-1H-
imidazo[4,5-b]pyridin-6-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-
yl)methyl)piperazin-1-yl)propan-1-one
and the pharmaceutically acceptable salts thereof.
[0141] The Formula Ia and Ib compounds of the invention may contain
asymmetric or chiral centers, and therefore exist in different
stereoisomeric forms. It is intended that all stereoisomeric forms
of the compounds of the invention, including but not limited to,
diastereomers, enantiomers and atropisomers, as well as mixtures
thereof such as racemic mixtures, form part of the present
invention.
[0142] In addition, the present invention embraces all geometric
and positional isomers. For example, if a Formula Ia and Ib
compound incorporates a double bond or a fused ring, the cis- and
trans-forms, as well as mixtures thereof, are embraced within the
scope of the invention. Both the single positional isomers and
mixture of positional isomers are also within the scope of the
present invention.
[0143] In the structures shown herein, where the stereochemistry of
any particular chiral atom is not specified, then all stereoisomers
are contemplated and included as the compounds of the invention.
Where stereochemistry is specified by a solid wedge or dashed line
representing a particular configuration, then that stereoisomer is
so specified and defined. The compounds of the present invention
may exist in unsolvated as well as solvated forms with
pharmaceutically acceptable solvents such as water, ethanol, and
the like, and it is intended that the invention embrace both
solvated and unsolvated forms.
[0144] The compounds of the present invention may also exist in
different tautomeric forms, and all such forms are embraced within
the scope of the invention. The term "tautomer" or "tautomeric
form" refers to structural isomers of different energies which are
interconvertible via a low energy barrier. For example, proton
tautomers (also known as prototropic tautomers) include
interconversions via migration of a proton, such as keto-enol and
imine-enamine isomerizations. Valence tautomers include
interconversions by reorganization of some of the bonding
electrons.
[0145] The present invention also embraces isotopically-labeled
compounds of the present invention which are identical to those
recited herein, but for the fact that one or more atoms are
replaced by an atom having an atomic mass or mass number different
from the atomic mass or mass number usually found in nature. All
isotopes of any particular atom or element as specified are
contemplated within the scope of the compounds of the invention,
and their uses. Exemplary isotopes that can be incorporated into
compounds of the invention include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and
iodine, such as .sup.2H, .sup.3H, .sup.11C, .sup.13C, .sup.14C,
.sup.13N, .sup.15N, .sup.15O, .sup.17O, .sup.18O, .sup.32P,
.sup.33P, .sup.35S, .sup.18F, .sup.36Cl, .sup.123I and .sup.125I.
Certain isotopically-labeled compounds of the present invention
(e.g., those labeled with .sup.3H and .sup.14C) are useful in
compound and/or substrate tissue distribution assays. Tritiated
(.sup.3H) and carbon-14 (.sup.14C) isotopes are useful for their
ease of preparation and detectability. Further, substitution with
heavier isotopes such as deuterium (i.e., .sup.2H) may afford
certain therapeutic advantages resulting from greater metabolic
stability (e.g., increased in vivo half-life or reduced dosage
requirements) and hence may be preferred in some circumstances.
Positron emitting isotopes such as .sup.15O, .sup.13N, .sup.11C and
.sup.18F are useful for positron emission tomography (PET) studies
to examine substrate receptor occupancy. Isotopically labeled
compounds of the present invention can generally be prepared by
following procedures analogous to those disclosed in the Schemes
and/or in the Examples herein below, by substituting an
isotopically labeled reagent for a non-isotopically labeled
reagent.
[0146] The compounds of the invention may exist in the form of
geometrical isomers or tautomers depending on the kinds of
substituent groups, and these isomers in separated forms or
mixtures thereof may be used in the present invention. Where the
compounds have asymmetric carbon atoms, optical isomer forms may
exist based on such carbon atoms. All of the mixtures and the
isolated forms of these optical isomers may be used in the present
invention.
[0147] A suitable synthetic strategy for producing compounds of the
invention as defined above employs the precursor carboxaldehyde of
formula (IIa) or (IIb):
##STR00197##
wherein X and R.sup.2 are as defined above. Starting from this
precursor the synthesis comprises performing, in either order, a
palladium-mediated (Suzuki-type) cross-coupling reaction and a
reductive amination. The process comprises:
[0148] (a) treating a compound of formula (IIa) or (IIb):
##STR00198##
wherein X and R.sup.2 are as defined above, with a boronic acid or
ester thereof of formula R.sup.3B(OR.sup.15).sub.2, in which
R.sup.3 is as defined above and each R.sup.15 is H or
C.sub.1-C.sub.6 alkyl or the two groups OR.sup.15 form, together
with the boron atom to which they are attached, a pinacolato
boronate ester group, in the presence of a Pd catalyst; and
treating the resulting compound of formula (IIIa or (IIIb):
##STR00199##
wherein X, R.sup.2 and R.sup.3 are as defined above, with an amine
of formula NHR.sup.4R.sup.5 in which R.sup.4 and R.sup.5 are as
defined above, in the presence of a suitable reducing agent; or
[0149] (b) treating a compound of formula (IIIa) or (IIIb) as
defined above with an amine of formula NHR.sup.4R.sup.5 wherein
R.sup.4 and R.sup.5 are as defined above, in the presence of a
suitable reducing agent; and treating the resulting compound of
formula (IVa) or (IVb):
##STR00200##
wherein X, R.sup.2, R.sup.4 and R.sup.5 are as defined above, with
a boronic acid or ester thereof of formula
R.sup.3B(OR.sup.15).sub.2, in which R.sup.3 is as defined above and
each R.sup.15 is H or C.sub.1-C.sub.6 alkyl or the two groups
OR.sup.15 form, together with the boron atom to which they are
attached, a pinacolato boronate ester group, in the presence of a
Pd catalyst.
[0150] Accordingly, the present invention provides a process for
producing a compound of the invention as defined above, which
process comprises treating a compound of formula (IIIa or
(IIIb):
##STR00201##
wherein X, R.sup.2 and R.sup.3 are as defined above, with an amine
of formula NHR.sup.4R.sup.5 in which R.sup.4 and R.sup.5 are as
defined above, in the presence of a suitable reducing agent.
[0151] The process may further comprise producing the compound of
formula (IIIa) or (IIIb) by treating a compound of formula (IIa) or
(IIb):
##STR00202##
wherein X and R.sup.2 are as defined above, ith a boronic acid or
ester thereof of formula R.sup.3B(OR.sup.15).sub.2, in which
R.sup.3 is as defined above and each R.sup.15 is H or
C.sub.1-C.sub.6 alkyl or the two groups OR.sup.15 form, together
with the boron atom to which they are attached, a pinacolato
boronate ester group, in the presence of a Pd catalyst.
[0152] The invention further provides a process for producing a
compound of the invention as defined above, which process comprises
treating a compound of formula (IVa) or (IVb):
##STR00203##
wherein X, R.sup.2, R.sup.4 and R.sup.5 are as defined above, with
a boronic acid or ester thereof of formula
R.sup.3B(OR.sup.15).sub.2 in which R.sup.3 is as defined above and
each R.sup.15 is H or C.sub.1-C.sub.6 alkyl or the two groups
OR.sup.15 form, together with the boron atom to which they are
attached, a pinacolato boronate ester group, in the presence of a
Pd catalyst.
[0153] The process may further comprise producing the compound of
formula (IVa) or (IVb) by treating a compound of formula (IIa or
(IIb):
##STR00204##
wherein X and R.sup.2 are as defined above, with an amine of
formula NHR.sup.4R.sup.5 in which R.sup.4 and R.sup.5 are as
defined above, in the presence of a suitable reducing agent.
[0154] Both the amination step and the Pd-mediated cross-coupling
step take place under conventional conditions. The palladium
catalyst may be any that is typically used for Suzuki-type
cross-couplings, such as PdCl.sub.2(PPh.sub.3).sub.2. The reducing
agent is typically a borohydride, for instance NaBH(OAc).sub.3,
NaBH.sub.4 or NaCNBH.sub.4, in particular NaBH(OAc).sub.3.
[0155] Compounds of formula (Ia) or (Ib) in which R.sup.3 is a 3-
or 4-hydroxyphenyl group may be produced by a process which
comprises:
[0156] (a) treating a compound of formula (Va) or (Vb):
##STR00205##
wherein OR' is bonded at position 3 or 4 of the phenyl ring to
which it is attached, R' is a hydroxy protecting group and X and
R.sup.2 are as defined above, with an amine of formula
NHR.sup.4R.sup.5 wherein R.sup.4 and R.sup.5 are as defined above,
in the presence of a suitable reducing agent; and
[0157] (b) removing the hydroxy protecting group.
[0158] The reducing agent is typically a borohydride, for instance
as specified above.
[0159] Examples of hydroxy protecting groups are known in the art,
for instance as described in "Protective Groups for Organic
Chemistry", Third Edition, T. W. Greene and P. G. M. Wuts, John
Wiley & Sons, 1999. For instance, a hydroxy group can be
protected as an acetal, a substituted acetal, an ester, a xanthate,
an ether or a silyl ether. The acetal is preferably
tetrahydropyran. The silyl ether is preferably trimethylsilyl
ether, t-butyl dimethylsilyl ether, triiso-propylsilyl ether or
t-butyldiphenyl-silyl ether. These protecting groups are removed by
conventional techniques.
[0160] A compound of formula (Va) or (Vb) as defined above may be
produced by a process which comprises treating a compound of
formula (VIa) or (VIb):
##STR00206##
wherein X, R.sup.2 and R' are as defined above, with a lithiating
agent followed by N,N'-dimethylformamide (DMF). The reaction is
typically conducted by adding a solution of the lithiating agent in
a non-polar organic solvent, for instance a hydrocarbon solvent
such as hexane, to a suspension of the compound of formula (VI) in
an organic solvent such as tetrahydrofuran (THF). If THF is used
the addition takes place at a low temperature, of about -78.degree.
C. The lithiating agent is typically an alkyllithium, for instance
n-butyllithium.
[0161] A compound of formula (VIa) or (VIb) as defined above may be
produced by a process which comprises treating a compound of
formula (VIIa) or (VIIb):
##STR00207##
wherein X and R.sup.2 are as defined above, with a boronic acid of
formula (VIII):
##STR00208##
wherein R' and R.sup.15 are as defined above, in the presence of a
palladium catalyst. The reaction is conducted under conventional
conditions for a Suzuki-type cross-coupling reaction, for instance
as described above.
[0162] A fused pyrmidine of the invention may be converted into a
pharmaceutically acceptable salt, and a salt may be converted into
the free compound, by conventional methods. The phrase
"pharmaceutically acceptable salt" as used herein, refers to
pharmaceutically acceptable organic or inorganic salts of a
compound of the invention.
[0163] Examples of pharmaceutically acceptable salts include salts
with inorganic acids such as hydrochloric acid, hydrobromic acid,
hydroiodic acid, sulphuric acid, nitric acid and phosphoric acid;
and organic acids such as methanesulfonic acid, benzenesulphonic
acid, formic acid, acetic acid, trifluoroacetic acid, propionic
acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
maleic acid, lactic acid, malic acid, tartaric acid, citric acid,
ethanesulfonic acid, aspartic acid and glutamic acid.
[0164] Exemplary salts include, but are not limited, to sulfate,
citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,
bisulfate, phosphate, acid phosphate, isonicotinate, lactate,
salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,
bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,
gluconate, glucuronate, saccharate, formate, benzoate, glutamate,
methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate,
p-toluenesulfonate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. A
pharmaceutically acceptable salt may involve the inclusion of
another molecule such as an acetate ion, a succinate ion or other
counter ion. The counter ion may be any organic or inorganic moiety
that stabilizes the charge on the parent compound. Furthermore, a
pharmaceutically acceptable salt may have more than one charged
atom in its structure. Instances where multiple charged atoms are
part of the pharmaceutically acceptable salt can have multiple
counter ions. Hence, a pharmaceutically acceptable salt can have
one or more charged atoms and/or one or more counter ion.
[0165] If the compound of the invention is a base, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method available in the art, for example, treatment of the free
base with an inorganic acid, such as hydrochloric acid, hydrobromic
acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric
acid and the like, or with an organic acid, such as acetic acid,
maleic acid, succinic acid, mandelic acid, fumaric acid, malonic
acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a
pyranosidyl acid, such as glucuronic acid or galacturonic acid, an
alpha hydroxy acid, such as citric acid or tartaric acid, an amino
acid, such as aspartic acid or glutamic acid, an aromatic acid,
such as benzoic acid or cinnamic acid, a sulfonic acid, such as
p-toluenesulfonic acid or ethanesulfonic acid, or the like.
[0166] If the compound of the invention is an acid, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method, for example, treatment of the free acid with an inorganic
or organic base, such as an amine (primary, secondary or tertiary),
an alkali metal hydroxide or alkaline earth metal hydroxide, or the
like. Illustrative examples of suitable salts include, but are not
limited to, organic salts derived from amino acids, such as glycine
and arginine, ammonia, primary, secondary, and tertiary amines, and
cyclic amines, such as piperidine, morpholine and piperazine, and
inorganic salts derived from sodium, calcium, potassium, magnesium,
manganese, iron, copper, zinc, aluminum and lithium. Typically the
salt is a mesylate, a hydrochloride, a phosphate, a
benzenesulphonate or a sulphate. Most typically the salt is a
mesylate or a hydrochloride.
[0167] The salts, for instance salts with any of the inorganic or
organic acids mentioned above, may be mono-salts or bis-salts.
Thus, for example, the mesylate salt may be the mono-mesylate or
the bis-mesylate.
[0168] A fused pyrimidine of the invention and its salts may exist
as a solvate or a hydrate. A "solvate" refers to an association or
complex of one or more solvent molecules and a compound of the
invention. Examples of solvents that form solvates include, but are
not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl
acetate, acetic acid, and ethanolamine. The term "hydrate" refers
to the complex where the solvent molecule is water.
Biological Activity
[0169] Compounds of the present invention have been found in
biological tests to be inhibitors of PI3 kinase. Determination of
the activity of PI3 kinase activity of a compound of the present
invention is possible by a number of direct and indirect detection
methods. Certain exemplary compounds described herein were
prepared, characterized, and assayed for their PI3K binding
activity (Example 7). Certain exemplary compounds of the invention
had PI3K binding activity IC.sub.50 values less than 50 uM.
[0170] The compounds of the present invention may inhibit p110
catalytic subunit isoforms including alpha, beta, gamma, and delta
as pan inhibitors. Certain compounds of the invention may be p110
isoform selective inhibitors by selectively inhibiting one of one
of the p110 isoforms; alpha, beta, gamma, or delta. A p110
selective inhibitor may mitigate the risk of toxicity due to
potential toxicities associated with inhibiting the other p110
isoforms. Certain compounds of the invention may be p110 isoform
pan inhibitors by possessing significant binding to two or more of
the p110 isoforms.
[0171] Binding of compounds of the invention from above Tables 1a
and 1b to purified preparations of p110 isoforms alpha, beta,
delta, and gamma was measured by a Scintillation Proximity Assay
(SPA) to determine binding activity (IC.sub.50 .mu.Mol) and
selectivity of binding of beta, delta, and gamma isoforms relative
to alpha (Example 8). These values are expressed in Table 2.
[0172] A compound of the present invention may be used as an
inhibitor of PI3 kinase, in particular of a class Ia PI3 kinase.
The compounds are typically selective for class Ia kinases over
class Ib and typically exhibit a 20-fold selectivity for class Ia
over class Ib PI3 kinases. In particular the compounds ae selective
for the p110alpa isoform.
[0173] Accordingly, a compound of the present invention can be used
to treat a disease or disorder arising from abnormal cell growth,
function or behaviour. Such abnormal cell growth, function or
behaviour is typically associated with PI3 kinase. Examples of such
diseases and disorders are discussed by Drees et al in Expert Opin.
Ther. Patents (2004) 14(5):703-732. These include cancer, immune
disorders, cardiovascular disease, viral infection, inflammation,
metabolism/endocrine disorders and neurological disorders. Examples
of metabolism/endocrine disorders include diabetes and obesity.
[0174] Examples of cancers which the present compounds can be used
to treat include leukaemia, brain tumours, renal cancer, gastric
cancer and cancer of the skin, bladder, breast, uterus, lung,
colon, prostate, ovary and pancreas. A human or animal patient
suffering from an immune disorder, cancer, cardiovascular disease,
viral infection, inflammation, a metabolism/endocrine disorder or a
neurological disorders may thus be treated by a method comprising
the administration thereto of a compound of the present invention
as defined above. The condition of the patient may thereby be
improved or ameliorated.
[0175] Diseases and conditions treatable according to the methods
of this invention include, but are not limited to, cancer, stroke,
diabetes, hepatomegaly, cardiovascular disease, Alzheimer's
disease, cystic fibrosis, viral disease, autoimmune diseases,
atherosclerosis, restenosis, psoriasis, allergic disorders,
inflammation, neurological disorders, a hormone-related disease,
conditions associated with organ transplantation, immunodeficiency
disorders, destructive bone disorders, proliferative disorders,
infectious diseases, conditions associated with cell death,
thrombin-induced platelet aggregation, chronic myelogenous leukemia
(CML), liver disease, pathologic immune conditions involving T cell
activation, and CNS disorders in a patient. In one embodiment, a
human patient is treated with a compound of Formula Ia or Ib and a
pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein
said compound of Formula Ia or Ib is present in an amount to
detectably inhibit PI3 kinase activity.
[0176] Cancers which can be treated according to the methods of
this invention include, but are not limited to, breast, ovary,
cervix, prostate, testis, genitourinary tract, esophagus, larynx,
glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung,
epidermoid carcinoma, large cell carcinoma, non-small cell lung
carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone,
colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular
carcinoma, undifferentiated carcinoma, papillary carcinoma,
seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and
biliary passages, kidney carcinoma, myeloid disorders, lymphoid
disorders, hairy cells, buccal cavity and pharynx (oral), lip,
tongue, mouth, pharynx, small intestine, colon-rectum, large
intestine, rectum, brain and central nervous system, Hodgkin's and
leukemia.
[0177] Cardiovascular diseases which can be treated according to
the methods of this invention include, but are not limited to,
restenosis, cardiomegaly, atherosclerosis, myocardial infarction,
and congestive heart failure.
[0178] Neurodegenerative disease which can be treated according to
the methods of this invention include, but are not limited to,
Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis, Huntington's disease, and cerebral ischemia, and
neurodegenerative disease caused by traumatic injury, glutamate
neurotoxicity and hypoxia.
[0179] Inflammatory diseases which can be treated according to the
methods of this invention include, but are not limited to,
rheumatoid arthritis, psoriasis, contact dermatitis, and delayed
hypersensitivity reactions.
[0180] In addition to possessing biochemical potency a compound of
the invention exhibits physicochemical and pharmacokinetic
properties which makes it particularly well adapted for drug use.
This is shown for instance in the results of the biological assays
described in Example 5 which follows. In particular the compound
possesses high aqueous solubility at physiological pH; the
solubility is greater than 100 .mu.M. High solubility at
physiological pH is desirable since it promotes
bioavailability.
[0181] The compound also possesses high metabolic stability, as
shown in particular by the hepatocyte clearance assay described in
Example 2 in which the compound was shown to have low hepatocyte
clearance. Low hepatocyte clearance correlates with a low rate of
liver metabolism. It can therefore be seen that the compound of the
present invention possess improved physicochemical and
pharmacokinetic properties whilst retaining biochemical potency as
an inhibitor of PI3 kinase.
[0182] A compound of the present invention can be administered in a
variety of dosage forms, for example orally such as in the form of
tablets, capsules, sugar- or film-coated tablets, liquid solutions
or suspensions or parenterally, for example intramuscularly,
intravenously or subcutaneously. The compound may therefore be
given by injection or infusion.
[0183] The dosage depends on a variety of factors including the
age, weight and condition of the patient and the route of
administration. Daily dosages can vary within wide limits and will
be adjusted to the individual requirements in each particular case.
Typically, however, the dosage adopted for each route of
administration when a compound is administered alone to adult
humans is 0.0001 to 50 mg/kg, most commonly in the range of 0.001
to 10 mg/kg, body weight, for instance 0.01 to 1 mg/kg. Such a
dosage may be given, for example, from 1 to 5 times daily. For
intravenous injection a suitable daily dose is from 0.0001 to 1
mg/kg body weight, preferably from 0.0001 to 0.1 mg/kg body weight.
A daily dosage can be administered as a single dosage or according
to a divided dose schedule.
[0184] Typically a dose to treat human patients may range from
about 10 mg to about 1000 mg of a compound of the invention. A
typical dose may be about 100 mg to about 300 mg of the compound. A
dose may be administered once a day (QID), twice per day (BID), or
more frequently, depending on the pharmacokinetic and
pharmacodynamic properties, including absorption, distribution,
metabolism, and excretion of the particular compound. In addition,
toxicity factors may influence the dosage and administration
regimen. When administered orally, the pill, capsule, or tablet may
be ingested daily or less frequently for a specified period of
time. The regimen may be repeated for a number of cycles of
therapy.
[0185] A compound is formulated for use as a pharmaceutical or
veterinary composition also comprising a pharmaceutically or
veterinarily acceptable carrier or diluent. The compositions are
typically prepared following conventional methods and are
administered in a pharmaceutically or veterinarily suitable form.
The compound may be administered in any conventional form, for
instance as follows:
[0186] A) Orally, for example, as tablets, coated tablets, dragees,
troches, lozenges, aqueous or oily suspensions, liquid solutions,
dispersible powders or granules, emulsions, hard or soft capsules,
or syrups or elixirs. Compositions intended for oral use may be
prepared according to any method known in the art for the
manufacture of pharmaceutical compositions and such compositions
may contain one or more agents selected from the group consisting
of sweetening agents, flavouring agents, colouring agents and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations.
[0187] Tablets contain the active ingredient in admixture with
non-toxic pharmaceutically acceptable excipients which are suitable
for the manufacture of tablets. These excipients may be for
example, inert diluents, such as calcium carbonate, sodium
carbonate, lactose, dextrose, saccharose, cellulose, corn starch,
potato starch, calcium phosphate or sodium phosphate; granulating
and disintegrating agents, for example, maize starch, alginic acid,
alginates or sodium starch glycolate; binding agents, for example
starch, gelatin or acacia; lubricating agents, for example silica,
magnesium or calcium stearate, stearic acid or talc; effervescing
mixtures; dyestuffs, sweeteners, wetting agents such as lecithin,
polysorbates or lauryl sulphate. The tablets may be uncoated or
they may be coated by known techniques to delay disintegration and
adsorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a time delay
material such as glyceryl monostearate or glyceryl distearate may
be employed. Such preparations may be manufactured in a known
manner, for example by means of mixing, granulating, tableting,
sugar coating or film coating processes.
[0188] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is present as such, or mixed with water or an oil
medium, for example, peanut oil, liquid paraffin, or olive oil.
[0189] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example,
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethyl-cellulose, sodium alginate,
polyvinylpyrrolidone gum tragacanth and gum acacia; dispersing or
wetting agents may be naturally-occurring phosphatides, for example
lecithin, or condensation products of an alkylene oxide with fatty
acids, for example polyoxyethylene stearate, or condensation
products of ethylene oxide with long chain aliphatic alcohols, for
example heptadecaethyleneoxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids and a
hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides for example polyoxyethylene
sorbitan monooleate.
[0190] The said aqueous suspensions may also contain one or more
preservatives, for example, ethyl or n-propyl p-hydroxybenzoate,
one or more colouring agents, such as sucrose or saccharin.
[0191] Oily suspension may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol.
[0192] Sweetening agents, such as those set forth above, and
flavouring agents may be added to provide a palatable oral
preparation. These compositions may be preserved by this addition
of an antioxidant such as ascorbic acid. Dispersible powders and
granules suitable for preparation of an aqueous suspension by the
addition of water provide the active ingredient in admixture with a
dispersing or wetting agent, a suspending agent and one or more
preservatives. Suitable dispersing or wetting agents and suspending
agents are exemplified by those already mentioned above. Additional
excipients, for example sweetening, flavouring and colouring
agents, may also be present.
[0193] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oils, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally occurring phosphatides, for
example soy bean lecithin, and esters or partial esters derived
from fatty acids an hexitol anhydrides, for example sorbitan
mono-oleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsion may also contain sweetening and flavouring
agents. Syrups and elixirs may be formulated with sweetening
agents, for example glycerol, sorbitol or sucrose. In particular a
syrup for diabetic patients can contain as carriers only products,
for example sorbitol, which do not metabolise to glucose or which
only metabolise a very small amount to glucose.
[0194] Such formulations may also contain a demulcent, a
preservative and flavouring and coloring agents; [0195] B)
Parenterally, either subcutaneously, or intravenously, or
intramuscularly, or intrasternally, or by infusion techniques, in
the form of sterile injectable aqueous or oleaginous suspensions.
This suspension may be formulated according to the known art using
those suitable dispersing of wetting agents and suspending agents
which have been mentioned above. The sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic paternally-acceptable diluent or solvent, for example as
a solution in 1,3-butane diol.
[0196] Among the acceptable vehicles and solvents that may be
employed are water, Ringer's solution and isotonic sodium chloride
solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or suspending medium. For this purpose any
bland fixed oil may be employed including synthetic mono- or
diglycerides. In addition fatty acids such as oleic acid find use
in the preparation of injectables; [0197] C) By inhalation, in the
form of aerosols or solutions for nebulizers; [0198] D) Rectally,
in the form of suppositories prepared by mixing the drug with a
suitable non-irritating excipient which is solid at ordinary
temperature but liquid at the rectal temperature and will therefore
melt in the rectum to release the drug. Such materials are cocoa
butter and poly-ethylene glycols; [0199] E) Topically, in the form
of creams, ointments, jellies, collyriums, solutions or
suspensions. [0200] F) Vaginally, in the form of pessaries,
tampons, creams, gels, pastes, foams or spray formulations
containing in addition to the active ingredient such carriers as
are known in the art to be appropriate.
[0201] Sustained-release preparations of a compound of the
invention may be prepared. Suitable examples of sustained-release
preparations include semipermeable matrices of solid hydrophobic
polymers containing a compound of Formula Ia or Ib, which matrices
are in the form of shaped articles, e.g., films, or microcapsules.
Examples of sustained-release matrices include polyesters,
hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or
poly(vinyl alcohol)), polylactides (U.S. Pat. No. 3,773,919),
copolymers of L-glutamic acid and gamma-ethyl-L-glutamate,
non-degradable ethylene-vinyl acetate, degradable lactic
acid-glycolic acid copolymers such as the LUPRON DEPOT.TM.
(injectable microspheres composed of lactic acid-glycolic acid
copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric
acid.
[0202] A compound of the invention may be employed alone or in
combination with other therapeutic agents for the treatment of a
disease or disorder described herein, such as a hyperproliferative
disorder (e.g., cancer). In certain embodiments, a compound of the
invention is combined in a pharmaceutical combination formulation,
or dosing regimen as combination therapy, with a second compound
that has anti-hyperproliferative properties or that is useful for
treating a hyperproliferative disorder (e.g., cancer). The second
compound of the pharmaceutical combination formulation or dosing
regimen preferably has complementary activities to the compound of
the invention such that they do not adversely affect each other.
Such compounds are suitably present in combination in amounts that
are effective for the purpose intended. In one embodiment, a
composition of this invention comprises a compound of the
invention, in combination with a chemotherapeutic agent such as
described herein.
[0203] The combination therapy may be administered as a
simultaneous or sequential regimen. When administered sequentially,
the combination may be administered in two or more administrations.
The combined administration includes coadministration, using
separate formulations or a single pharmaceutical formulation, and
consecutive administration in either order, wherein preferably
there is a time period while both (or all) active agents
simultaneously exert their biological activities.
[0204] Suitable dosages for any of the above coadministered agents
are those presently used and may be lowered due to the combined
action (synergy) of the newly identified agent and other
chemotherapeutic agents or treatments.
[0205] The invention will be further described in the Examples
which follow:
Example 1
A General Synthetic Procedures
[0206] The following general procedures A, B and C are referred to
in the subsequent Examples and Reference Examples:
A) Suzuki Coupling:
##STR00209##
[0208] Substituted 2-chloro-4-morpholinothieno[3,2-c]pyrimidine or
2-chloro-4-morpholinothieno[2,3-d]pyrimidine was combined with 1.5
equivalents of
4-(4,4,5,5-tertamethyl-1,3,2-dioxaborolan-2-yl)1H-indazole
(alternatively, a variety of boronic acids or boronic esters can be
used in place of the indazole boronic ester indicated) and
dissolved in 3.0 equivalents of sodium carbonate as a 1 molar
solution in water and an equal volume of acetonitrile. In some
cases potassium acetate was used in place of sodium carbonate to
adjust the pH of the aqueous layer. The reaction was then heated to
between 140-150.degree. C. under pressure in a Biotage Optimizer
microwave reactor (Biotage, Inc.) for 10 to 30 minutes. The
contents were extracted with ethyl acetate. After evaporation of
the organic layer the product was purified on silica or by reverse
phase HPLC.
B) Amide Coupling:
##STR00210##
[0210]
2-Chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimi-
dine or
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrim-
idine is treated with 1.5 eq HATU, 3 eq of amine and 3 eq of DIPEA
in DMF to approximately 0.1 M concentration. The reaction is
stirred until complete and extracted in Ethyl Acetate with
Saturated Bicarbonate Solution one time. The organic layer is
dried, filtered and concentrated to yield the crude
intermediate.
C) Reductive Amination:
##STR00211##
[0212] 2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde
or 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde was
dissolved to a 0.2 M concentration in dichloroethane. To this
solution was added 1.5 to 2.0 equivalents of an amine, 10
equivalents of trimethylorthoformate, and 1 equivalent of acetic
acid. The mixture was allowed to stir for 2-6 hours prior to adding
1.5 equivalents of sodium triacetoxyborohydride. Following 12 to 16
hours of stirring the reaction was poured into saturated sodium
bicarbonate and extracted several times with ethyl acetate. This
intermediate was either purified on silica gel or used crude in the
next reaction.
Example 1B
Further General Synthetic Procedures
[0213] D) Removal of t-butoxylcarbonyl (BOC) Group:
##STR00212##
[0214] Ten or more equivalents of 4N HCl in Dioxane, with or
without dichloromethane as a co-solvent, are added to the starting
material (general scheme shown above but similar scaffolds also
used). Heating up to 40.degree. C. for several hours is
occasionally required to remove the boc group. The reaction is
concentrated to dryness and used crude in subsequent reaction.
E) Suzuki Coupling Reactions:
##STR00213##
[0216] Generally, substituted
2-chloro-4-morpholinofuro[3,2-d]pyrimidine 14 (1 eq),
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine
(1.7 eq) (or other boronic acid/ester) and
bis(triphenylphosphine)palladium(II) dichloride (0.1 eq) in 1M KOAc
aqueous solution (3 eq) and an equal volume of acetonitrile (3 eq)
was heated to 100.degree. C. in a sealed microwave reactor for
10-15 min. Upon completion, the contents are extracted with ethyl
acetate, or another organic solvent. After evaporation of the
organic layer the product 15, may be purified on silica or by
reverse phase HPLC.
Reference Example 1
2,4-Dichloro-thieno[3,2-d]pyrimidine
##STR00214##
[0218] A mixture of methyl 3-amino-2-thiophenecarboxylate (13.48 g,
85.85 mmol) and urea (29.75 g, Seq.) was heated at 190.degree. C.
for 2 hours. The hot reaction mixture was then poured onto sodium
hydroxide solution and any insoluble material removed by
filtration. The mixture was then acidified (HCl, 2N) to yield
1H-thieno[3,2-d]pyrimidine-2,4-dione) as a white precipitate, which
was collected by filtration and air dried (9.49 g, 66%).
[0219] .sup.1H NMR (400 MHz, d.sub.6-DMSO) 6.90 (1H, d, J=5.2 Hz),
8.10 (1H, d, J=5.2 Hz), 11.60-11.10 (2H, br, s).
[0220] A mixture of 1H-thieno[3,2-d]pyrimidine-2,4-dione (9.49 g,
56.49 mmol) and phosphorous oxychloride (150 mL) was heated at
reflux for 6 hours. The reaction mixture was then cooled and poured
onto ice/water with vigorous stirring yielding a precipitate. The
mixture was then filtered to yield
2,4-dichloro-thieno[3,2-d]pyrimidine as a white solid (8.68 g,
75%).
[0221] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.56 (1H, d, J=5.5 Hz).
8.13 (1H, d, J=5.5 Hz).
Reference Example 2
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine
##STR00215##
[0223] A mixture of 2,4-dichloro-thieno[3,2-d]pyrimidine (8.68 g,
42.34 mmol), morpholine (8.11 mL, 2.2 eq.) and methanol (150 mL)
was stirred at room temperature for 1 hour. The reaction mixture
was then filtered, washed with water and methanol, to yield the
title compound as a white solid (11.04 g, 100%).
[0224] .sup.1H NMR (400 MHz, d.sub.6-DMSO) 3.74 (4H, t, J=4.9 Hz),
3.90 (4H, t, J=4.9 Hz), 7.40 (1H, d, J=5.6 Hz), 8.30 (1H, d, J=5.6
Hz).
Reference Example 3
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
[0225] To a suspension of
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (65) (1.75 g,
6.85 mmol) in dry THF (40 mL) at -78.degree. C. was added a 2.5M
solution of nBuLi in hexane (3.3 mL, 1.2 eq.). After stirring for 1
hour, dry N,N-dimethylformamide (7964, 1.5 eq.) was added. The
reaction mixture was stirred for 1 hour at -78.degree. C. and then
warmed slowly to room temperature. After a further 2 hours at room
temperature the reaction mixture poured onto ice/water yielding a
yellow precipitate. This was collected by filtration and air-dried
to yield the title compound (1.50 g, 77%).
[0226] .sup.1H NMR (400 MHz, d.sub.6-DMSO) 3.76 (4H, t, J=4.9 Hz),
3.95 (4H, t, J=4.9 Hz), 8.28 (1H, s), 10.20 (1H, s).
[0227]
2-Chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde
was prepared in an analogous manner by commencing with
methyl-2-aminothiophen-3-carboxylate.
[0228]
2-Chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbal-
dehyde was also prepared in analogous manner by commencing with
3-amino-4-methyl-thiophene-2-carboxylic acid ethyl ester.
Reference Example 4
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole
##STR00216##
[0230] To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91
mmol) in acetic acid (60 mL) was added a solution of sodium nitrite
(1.13 g, 1.1 eq.) in water (5 mL). After 2 hours, the deep red
solution was poured onto ice/water and the precipitate collected by
filtration to yield 4-nitro-1H-indazole (1.98 g, 81%).
[0231] A mixture of 4-nitro-1H-indazole (760 mg, 4.68 mmol),
palladium on charcoal (10%, cat.) and ethanol (30 mL) was stirred
under a balloon of hydrogen for 4 hours. The reaction mixture was
then filtered through celite, and the solvent removed in vacuo to
yield 1H-indazol-4-ylamine (631 mg, 100%).
[0232] An aqueous solution of sodium nitrite (337 mg, 4.89 mmol) in
water (2 mL) was added dropwise to a suspension of
1H-indazol-4-ylamine (631 mg, 4.74 mmol) in 6M hydrochloric acid
(7.2 mL) at below 0.degree. C. After stirring for 30 minutes sodium
tetrafluorobrate (724 mg) was added. The reaction mixture became
very thick and was filtered and washed briefly with water to yield
1H-indazole-4-diazonium, tetrafluoroborate salt (218 mg, 20%) as a
deep red solid.
[0233] Dry methanol (4 mL) was purged with argon for 5 minutes. To
this was added 1H-indazole-4-diazonium, tetrafluoroborate salt (218
mg, 0.94 mmol), bis-pinacolato diboron (239 mg, 1.0 eq.) and
[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) chloride (20
mg). The reaction mixture was stirred for 5 hours and then filtered
through celite. The residue was purified using flash chromatography
to yield the desired title compound (117 mg).
##STR00217##
[0234] To a solution of 3-bromo-2-methyl aniline (5.0 g, 26.9 mmol)
in chloroform (50 mL) was added potassium acetate (1.05 eq., 28.2
mmol, 2.77 g). Acetic anhydride (2.0 eq., 53.7 mmol, 5.07 mL) was
added with concurrent cooling in ice-water. The mixture was then
stirred at room temperature for 10 minutes after which time a white
gelatinous solid formed. 18-Crown-6 (0.2 eq., 5.37 mmol, 1.42 g)
was then added followed by iso-amyl nitrite (2.2 eq., 59.1 mmol,
7.94 mL) and the mixture was heated under reflux for 18 h. The
reaction mixture was allowed to cool, and was partitioned between
chloroform (3.times.100 mL) and saturated aqueous sodium hydrogen
carbonate (100 mL). The combined organic extracts were washed with
brine (100 mL), separated and dried (MgSO.sub.4).
[0235] The crude product was evaporated onto silica and purified by
chromatography eluting with 20%.fwdarw.40% EtOAc-petrol to give
1-(4-bromo-indazol-1-yl)-ethanone (A) (3.14 g, 49%) as an orange
solid, and 4-bromo-1H-indazole (B)(2.13 g, 40%) as a pale orange
solid.
A .sup..quadrature.H NMR .quadrature.(400 MHz, CDCl.sub.3) 2.80
(3H, s), 7.41 (1H, t, J=7.8 Hz), 7.50 (1H, d, J=7.8 Hz), 8.15 (1H,
s), 8.40 (1H, d, J=7.8 Hz).
[0236] B: .sup..quadrature.H NMR (400 MHz, CDCl.sub.3) 7.25 (1H, t,
J=7.3 Hz), 7.33 (1H, d, J=7.3 Hz), 7.46 (1H, d, J=7.3 Hz), 8.11
(1H, s), 10.20 (1H, br s),
[0237] To a solution of the 1-(4-bromo-indazol-1-yl)-ethanone (3.09
g, 12.9 mmol) in MeOH (50 mL) was added 6N aqueous HCl (30 mL) and
the mixture was stirred at room temperature for 7 h. The MeOH was
evaporated and the mixture partitioned between EtOAc (2.times.50
mL) and water (50 mL). The combined organic layers were washed with
brine (50 mL), separated and dried (MgSO.sub.4). The solvent was
removed by evaporation under reduced pressure to give
4-bromo-1H-indazole (2.36 g, 93%).
[0238] To a solution of the 4-bromo-1H-indazole (500 mg, 2.54 mmol)
and bis(pinacolato)diboron (1.5 eq., 3.81 mmol) in DMSO (20 mL) was
added potassium acetate (3.0 eq., 7.61 mmol, 747 mg; dried in
drying pistol) and PdCl.sub.2(dppf).sub.2 (3 mol %, 0.076 mmol, 62
mg). The mixture was degassed with argon and heated at 80.degree.
C. for 40 h. The reaction mixture was allowed to cool and
partitioned between water (50 mL) and ether (3.times.50 mL). The
combined organic layers were washed with brine (50 mL), separated
and dried (MgSO.sub.4). The crude material was purified by
chromatography eluting with 30%-->/40% EtOAc-petrol to give an
inseparable 3:1 mixture of the
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (369
mg, 60%) and indazole (60 mg, 20%); this was isolated as a yellow
gum which solidified upon standing to furnish as an off-white
solid.
[0239] .sup..quadrature.H NMR (400 MHz, d.sub.6-DMSO) 1.41 (12H,
s), 7.40 (1H, dd, J=8.4 Hz, 6.9 Hz), 7.59 (1H, d, J=8.4 Hz), 7.67
(1H, d, J=6.9 Hz), 10.00 (1H, br s), 8.45 (1H, s), and indazole:
7.40 (1H, t), 7.18 (1H, t, J=7.9 Hz), 7.50 (1H, d, J=9.1 Hz), 7.77
(1H, d, J=7.9 Hz), 8.09 (1H, s). Impurity at 1.25.
Reference Example 5
2-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyd-
e
[0240] A mixture of
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
(100 mg, 0.35 mmol),
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (95
mg, 0.39 mmol) and sodium carbonate (112 mg) were suspended in
toluene (2.5 mL), ethanol (1.5 mL) and water (0.7 mL). To this was
added bis(triphenylphosphine)palladium(II) chloride (13.5 mg) and
the reaction vessel was flushed with argon. The reaction mixture
was microwaved at 120.degree. C. for 1 hour and then partitioned
between dichloromethane and water, the organic layer was washed
with brine, dried over magnesium sulfate, filtered and evaporated
in vacuo. The resulting residue was purified using flash
chromatography to yield the title compound (97 mg).
Reference Example 6
Preparation of
2-(1H-Indazol-4-yl)-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-th-
ieno[3,2-d]pyrimidine
[0241] To a mixture of
2-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehy-
de (91 mg, 0.26 mmol), 1-methylpiperazine (34 mg, 0.36 mmol) and
acetic acid (15 uL) in 1,2-dichloroethane (2 mL) was added sodium
triacetoxyborohydride (60 mg, 0.28 mmol). The reaction mixture was
stirred at room temperature overnight and then basified
(NaHCO.sub.3, saturated), diluted with dichloromethane, washed with
brine. Organic layer was separated, dried (MgSO.sub.4), filtered
and evaporated in vacuo. The residue was purified using flash
chromatography to give the title compound (33 mg).
Reference Example 7
2-chloro-6-(4-methyl-piperazin-1-yl
methyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine
##STR00218##
[0243] To a mixture of
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
(66) (147 mg, 0.52 mmol), 1-methyl-piperazine (1.5 eq., 87 .mu.L)
and acetic acid (1.05 eq., 32 .mu.L) in 1,2-dichloroethane (3 mL)
was added sodium triacetoxyborohydride (1.1 eq., 121 mg) and then
stirred at room temperature overnight. The reaction mixture was
diluted with dichloromethane, washed with a saturated solution of
sodium hydrogen carbonate, brine, separated and dried (MgSO.sub.4).
The crude product was evaporated in vacuo and purified by
chromatography to give the title compound 72 as an off-white
crystalline solid (51 mg, 45%).
Reference Example 8
(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanol
##STR00219##
[0245] A solution of
2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (1.0 g,
3.5 mmol) in MeOH (30 mL) at 0.degree. C. was treated with
NaBH.sub.4 (0.1 g, 3.5 mmol). The solution was allowed to warm to
room temperature and stirred 15 min. The reaction mixture was
quenched with a mixture of a saturated solution of sodium
bicarbonate and water (1:1, v/v). The aqueous solution was
extracted with EtOAc. The combined organic layers were dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material
required no further purification (0.9 g, 90%). MS (Q1) 286 (M)+
Reference Example 9
6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine
##STR00220##
[0247] To a solution of
(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanol (100 mg,
0.4 mmol) in benzene (3.0 mL) at 0.degree. C. was added PBr.sub.3
(30 .mu.L, 0.4 mmol). The reaction was heated at reflux for 1 hour.
After cooling to room temperature the reaction was quenched by the
addition of water. The aqueous layer was extracted with EtOAc. The
combined organics were dried over Na.sub.2SO.sub.4 and concentrated
in vacuo. The crude material did not require further purification
(115 mg, 94%). MS (Q1) 350 (M)+
Reference Example 10
1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-4-methanes-
ulfonyl-piperazin-2-one
##STR00221##
[0249] To a solution of 4-BOC-piperazinone (0.3 g, 1.6 mmol) in DMF
(3 mL) at 0.degree. C. was added NaH (60% in mineral oil, 1.9
mmol). Next,
6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine (0.6
g, 2 mmol) was added and the reaction stirred for 15 min. The
reaction was quenched with saturated NH.sub.4Cl and the aqueous
layer was extracted with EtOAc. The combined organics were dried
over Na.sub.2SO.sub.4 and concentrated in vacuo. This intermediate
was dissolved in CH.sub.2Cl.sub.2 (40 mL) and MeOH (40 mL) and
Et.sub.2O (10 mL) and cooled to 0.degree. C. To this solution was
added 4 M HCl in dioxane (20 mL). The reaction was warmed to room
temperature, stirred 18 h, then was concentrated in vacuo. To the
residue was added CH.sub.2Cl.sub.2 (50 mL), Et.sub.3N (1.5 mL, 11
mmol), and MeSO.sub.2Cl (0.6 mL, 8 mmol). The reaction mixture
stirred 42 h at room temperature. The reaction was quenched with
water and extracted with EtOAc. The combined organics were dried
over Na.sub.2SO.sub.4 and concentrated in vacuo (0.25 g, 28% over 3
steps). MS (Q1) 446 (M)+
Reference Example 11
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thien-
o[3,2-d]pyrimidine
##STR00222##
[0251] Reaction between N-BOC-piperazine and methane sulfonyl
chloride in dichloromethane and triethylamine yielded
4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester.
Cleavage of the BOC protecting group using HCl (2M) in
dichloromethane yielded 1-methanesulfonyl-piperazine. HCl salt.
[0252] Reaction between 1-methanesulfonyl-piperazine. HCl salt and
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
using procedure C yielded the title compound.
Reference Example 12
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thien-
o[2,3-d]pyrimidine
##STR00223##
[0254] Reaction between 1-methanesulfonyl-piperazine. HCL salt and
2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde
using procedure C yielded the title compound
Reference Example 13
Tert-butyl furan-3-ylcarbamate
##STR00224##
[0256] 3-Furoic acid (5.60 g, 1.0 eq) was dissolved in tert-butanol
(200 ml) and treated with triethylamine (10 ml, 1.4 eq) and
diphenyl phosphoryl azide (12 ml, 1.1 eq). Mixture was heated at
reflux for 18 h. Reaction mixture was cooled to room temperature,
then concentrated to 50 ml and poured into saturated aq.
NaHCO.sub.3. Mixture was stirred at 0.degree. C. for 2 h. Solid was
collected by filtration and dried under high vacuum. The crude
reaction mixture was purified by flash chromatography to yield
tert-butyl furan-3-ylcarbamate (6.95 g, 76%): .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 7.71 (bs, 1H), 7.27 (m, 1H), 6.27
(bs, 1H), 6.20 (bs, 1H), 1.50 (s, 9H); MS (Q1) 184 (M).sup.+.
Reference Example 14
Tert-butyl 2-(methoxycarbonyl)furan-3-ylcarbamate
##STR00225##
[0258] To a solution of tert-butyl furan-3-ylcarbamate (1.7 g, 1.0
eq) in THF (50 ml) at -30.degree. C. was added TMEDA (1.75 ml, 1.3
eq) followed by 1.6M solution of n-butyllithium (8.4 ml, 2.25 eq,
1.6M in hexanes). Reaction mixture was allowed to warm up to
0.degree. C. and stirred for 1 h, before being cooled back to
-30.degree. C. Dimethyl carbonate (2.4 ml, 3.0 eq) was quickly
added, before the reaction mixture was allowed to warm up to room
temperature for 1 hr. Reaction mixture was quenched with 2M HCl,
followed by addition of saturated aq. NaCl. Mixture was extracted
with ethyl acetate. The combined organic extracts were dried with
Na.sub.2SO.sub.4 and concentrated. The crude reaction mixture was
purified by flash chromatography to yield tert-butyl
2-(methoxycarbonyl)furan-3-ylcarbamate (1.14 g, 51%): MS (Q1)
242
Reference Example 15
Methyl 3-aminofuran-2-carboxylate
##STR00226##
[0260] Tert-butyl 2-(methoxycarbonyl)furan-3-ylcarbamate (1.14 g,
1.0 eq) was dissolved in dichloromethane (8 ml) and treated with
trifluoroacetic acid (5 ml). Reaction mixture was stirred at room
temperature for 3 h, and was then concentrated. Residue was
dissolved in dichloromethane and washed with saturated aq.
NaHCO.sub.3. The organic layer was dried (Na.sub.2SO.sub.4) and
concentrated Mixture was extracted with ethyl acetate. The combined
organic extracts were dried with Na.sub.2SO.sub.4 and concentrated.
The crude reaction mixture was purified by flash chromatography to
yield methyl 3-aminofuran-2-carboxylate (574 mg, 86%): MS (Q1) 142
(M).sup.+.
Reference Example 16
Ethyl 3-ureidofuran-2-carboxylate
##STR00227##
[0262] To a solution of methyl 3-aminofuran-2-carboxylate (100 mg,
1.0 eq) in dichloromethane (3 ml) at -78.degree. C. was added
chlorosulfonyl isocyanate (0.09 ml, 1.4 eq) dropwise. The reaction
was slowly warmed to room temperature and stirred for 40 minutes.
Reaction was concentrated. To the residue was added 6N HCl (3.5 ml)
and mixture was heated to 100.degree. C. for 20 minutes. Reaction
mixture was allowed to cool down to room temperature, and was
neutralized with saturated aq. NaHCO.sub.3. Solid was collected by
filtration to yield ethyl 3-ureidofuran-2-carboxylate (120 mg, 92%)
as a beige solid which was used in the next reaction without
further purification.
Reference Example 17
Furo[3,2-d]pyrimidine-2,4-diol
##STR00228##
[0264] Ethyl 3-ureidofuran-2-carboxylate (120 mg, 1.0 eq) was
suspended in methanol (6 ml) and treated with 1.5 M NaOH (1.5 ml).
Reaction mixture was heated to reflux for 90 minutes. Reaction
mixture was allowed to cool down to room temperature, and was
acidified with 6N HCl up to pH 3. Mixture was concentrated.
Methanol was added to residue and solid was filtered and dried at
95.degree. C. under high vacuum for 24 h to yield
furo[3,2-d]pyrimidine-2,4-diol (90 mg, 91%) which was used in the
next reaction without further purification.
Reference Example 18
2,4-Dichlorofuro[3,2-d]pyrimidine
##STR00229##
[0266] Furo[3,2-d]pyrimidine-2,4-diol (39 mg, 1.0 eq) was dissolved
in POCl.sub.3 (1.8 ml). Mixture was cooled to -40.degree. C. and
N,N-diisopropylethylamine (0.45 ml) wad slowly added. Reaction
mixture was then heated to reflux for 48 h, then cooled to room
temperature Reaction mixture was poured into ice/water. Mixture was
extracted with ethyl acetate. The combined organic layers were
washed with saturated aq. NaHCO.sub.3, dried (Na.sub.2SO.sub.4) and
concentrated to yield 2,4-dichlorofuro[3,2-d]pyrimidine (23 mg,
48%) which was used in the next reaction without further
purification.
Reference Example 19
2-Chloro-4-morpholinofuro[3,2-d]pyrimidine
##STR00230##
[0268] 2,4-Dichlorofuro[3,2-d]pyrimidine (23 mg, 1.0 eq) was
suspended in methanol (1.7 ml) and treated with morpholine (0.09
ml, 4.0 eq). Reaction mixture was stirred at room temperature for 2
h, before being quenched with saturated aq. NaHCO.sub.3. Mixture
was extracted with dichloromethane. The combined organic layers
were dried (Na.sub.2SO.sub.4) and concentrated to yield
2-chloro-4-morpholinofuro[3,2-d]pyrimidine (14 mg, 48%) which was
used in the next reaction without further purification.
Reference Example 20
2-Chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carbaldehyde
##STR00231##
[0270] To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine
(40 mg, 1.0 eq) dissolved in THF (1.7 ml) at -78.degree. C. was
added 1.6M solution of n-butyllithium (0.14 ml, 1.3 eq, 1.6M in
hexanes). Reaction mixture was stirred at -78.degree. C. for 30
minutes. DMF (0.05 ml, 4.0 eq) was added and reaction mixture was
allowed to slowly warm up to room temperature and stirred for 90
minutes. Reaction mixture was quenched with water, and extracted
with dichloromethane. The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated. The crude reaction mixture was
purified by flash chromatography to yield
2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carbaldehyde (22 mg,
50%): .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.92 (s, 1H), 7.48
(s, 1H), 4.12 (m, 4H), 3.86 (dd, 4H); MS (Q1) 268 (M).sup.+.
Reference Example 21
2-Chloro-64(4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,2--
d]pyrimidine
##STR00232##
[0272] 2-Chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carbaldehyde
(65 mg, 1.0 eq) was dissolved in 1,2-dichloroethane (9.7 ml) and
treated with hydrochloride salt of 1-methanesulfonylpiperazine (69
mg, 1.4 eq), sodium acetate (28 mg, 1.4 eq) and trimethyl
orthoformate (0.27 ml, 10 eq). Reaction mixture was stirred at room
temperature for 12 h. Sodium triacetoxyborohydride (62 mg, 1.2 eq)
was added and reaction mixture was stirred at room temperature for
8 h. Reaction mixture was quenched with saturated aq. NaHCO.sub.3
and extracted with dichloromethane. The combined organic layers
were dried (Na.sub.2SO.sub.4) and concentrated. The crude reaction
mixture was purified by flash chromatography to yield
2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,-
2-d]pyrimidine (70 mg, 68%): MS (Q1) 416 (M).sup.+.
Example 2
Compounds of the Invention--Series A
[0273] The following compounds of the invention were prepared. The
compound numbering corresponds to that used in Table 1A above.
[0274] 14:
1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-
-4-methanesulfonyl-piperazin-2-one (100 mg, 0.2 mmol) was converted
to 14 using General Procedure A (10 mg, 10%). MS (Q1) 528 (M)+
[0275] 68: To 1 g of
2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde was
added 855 mg 1-BOC-piperazine via Procedure C to give 1.59 g of
2-chloro-4-morpholino-6-((Boc-piperazin-1-yl)methyl)thieno[3,2-d]pyrimidi-
ne. The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
was then formed by treatment with 5 eq 4N HCl in dioxane in a
solution of DCM and subsequent evaporation to dryness.
[0276] 100 mg of crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
was treated with 135 mg of Boc-Glycine via Procedure B. This crude
intermediate was then subjected to Procedure A to give 31.5 mg of
68. MS (Q1) 493.2 (M)+.
[0277] 67: 25 mg of crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
was treated with 135 mg of N,N-Dimethylglycine via Procedure B.
This crude intermediate was then subjected to Procedure A to give
7.4 mg of 67. MS (Q1) 521.2 (M)+.
[0278] 66: 400 mg of crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
was treated with 175 mg of L-Lactic Acid via Procedure B. This
crude intermediate was then subjected to Procedure A to give 212 mg
of 66. MS (Q1) 508.2 (M)+.
[0279] 56: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
(50 mg) was treated with 5 eq methyl chloroformate and 6 eq DIPEA
in 1 mL of DMF. The reaction mixture was concentrated and extracted
into Ethyl Acetate with Saturated Ammonium Chloride. The aqueous
layer was back-extracted once with DCM. The organics were combined
and concentrated to dryness. This crude intermediate was then
subjected to Procedure A to give 3.7 mg of 56. MS (Q1) 494.2
(M)+.
[0280] 55: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
(50 mg) was treated with 5 eq ethyl chloroformate and 6 eq DIPEA in
1 mL of DMF. The reaction mixture was concentrated and extracted
into Ethyl Acetate with Saturated Ammonium Chloride. The aqueous
layer was back-extracted once with DCM. The organics were combined
and concentrated to dryness. This crude intermediate was then
subjected to Procedure A to give 35.4 mg of 55. MS (Q1) 508.2
(M)+.
[0281] 54: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
(50 mg) was treated with 3 eq Acetic Anhydride and 5 eq DIPEA in 1
mL of DCM. The reaction mixture was concentrated and extracted into
Ethyl Acetate with Saturated Ammonium Chloride. The aqueous layer
was back-extracted once with DCM. The organics were combined and
concentrated to dryness. This crude intermediate was then subjected
to Procedure A to give 20.2 mg of 54. MS (Q1) 478.2 (M)+.
[0282] 53: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
(50 mg) was treated with 5 eq of Formic Acid, 5 eq EDC and 5 eq
DIPEA in 1 mL of DMF. This crude intermediate was then subjected to
Procedure A to give 5.1 mg of 53. MS (Q1) 464.2 (M)+.
[0283] 52: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
(50 mg) was treated with 2.5 eq of pivaloyl chloride and 3 eq DIPEA
in 1 mL of DCM. This crude intermediate was then subjected to
Procedure A to give 36.7 mg of 52. MS (Q1) 520.3 (M)+.
[0284] 48: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
(50 mg) was treated with 2.5 eq of cyclopropanecarbonyl chloride
and 3 eq DIPEA in 1 mL of DCM. This crude intermediate was then
subjected to Procedure A to give 27.2 mg of 48. MS (Q1) 504.2
(M)+.
[0285] 107: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
(100 mg) was treated with 70 mg of D-Lactic Acid via Procedure B.
This crude intermediate was then subjected to Procedure A to give
(R)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)me-
thyl)piperazin-1-yl)-2-hydroxypropan-1-one. MS (Q1) 508.2 (M)+.
[0286] 108: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
(100 mg) was treated with 75 mg of 2-Hydroxyisobutyric Acid via
Procedure B. This crude intermediate was then subjected to
Procedure A to give
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl-
)piperazin-1-yl)-2-hydroxy-2-methylpropan-1-one. MS (Q1) 522.2
(M)+.
[0287] 109: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
(100 mg) was treated with 55 mg of Glycolic Acid via Procedure B.
This crude intermediate was then subjected to Procedure A to give
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl-
)piperazin-1-yl)-2-hydroxyethanone. MS (Q1) 494.4 (M)+.
[0288] 110: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
(100 mg) was treated with 55 mg of Methoxyacetic Acid via Procedure
B. This crude intermediate was then subjected to Procedure A to
give
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl-
)piperazin-1-yl)-2-methoxyethanone. MS (Q1) 508 (M)+.
[0289] 111: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
(100 mg) was treated with 70 .mu.L of tetrahydro-2-furoic acid via
Procedure B. This crude intermediate was then subjected to
Procedure A to give
(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)met-
hyl)piperazin-1-yl)(tetrahydrofuran-2-yl)methanone. MS (Q1) 534.3
(M)+.
[0290] 112: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
(100 mg) was treated with 100 mg of
Boc-amino-cyclopropanecarboxylic acid via Procedure B. This crude
intermediate was then subjected to Procedure A to give
(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-y-
l)methyl)piperazin-1-yl)(1-aminocyclopropyl)methanone. MS (Q1)
519.3 (M)+.
[0291] 113: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
(100 mg) was treated with 140 mg of Boc-Alanine via Procedure B.
This crude intermediate was then subjected to Procedure A to give
(S)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)me-
thyl)piperazin-1-yl)-2-aminopropan-1-one. MS (Q1) 507.3 (M)+.
[0292] 114: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
(100 mg) was treated with 140 mg of Boc-D-Alanine via Procedure B.
This crude intermediate was then subjected to Procedure A to give
(R)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)me-
thyl)piperazin-1-yl)-2-aminopropan-1-one. MS (Q1) 507.3 (M)+.
[0293] 115: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine
(100 mg) was treated with 100 mg of methanesulphonylacetic acid via
Procedure B. This crude intermediate was then subjected to
Procedure A to give
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)m-
ethyl)piperazin-1-yl)-2-(methylsulfonyl)ethanone. MS (Q1) 556.3
(M)+.
[0294] 116: To 700 mg of
2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde was
added 645 mg 1-BOC-piperazine via Procedure C to give 1.12 g of
2-chloro-4-morpholino-6-((Boc-piperazin-1-yl)methyl)thieno[2,3-d]pyrimidi-
ne. The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidine
was then formed by treatment with 5 eq 4N HCl in dioxane in a
solution of DCM and subsequent evaporation to dryness.
[0295] The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidine
(100 mg) was treated with 65 mg of L-Lactic Acid via Procedure B.
This crude intermediate was then subjected to Procedure A to give
(S)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)me-
thyl)piperazin-1-yl)-2-hydroxypropan-1-one. MS (Q1) 508.2 (M)+.
[0296] 117: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidine
(75 mg) was treated with 51 mg of D-Lactic Acid via Procedure B.
This crude intermediate was then subjected to Procedure A to give
(R)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)me-
thyl)piperazin-1-yl)-2-hydroxypropan-1-one. MS (Q1) 508.2 (M)+.
[0297] 118: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidine
(75 mg) was treated with 55 mg of 2-Hydroxyisobutyric Acid via
Procedure B. This crude intermediate was then subjected to
Procedure A to give
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl-
)piperazin-1-yl)-2-hydroxy-2-methylpropan-1-one. MS (Q1) 522.2
(M)+.
[0298] 119: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidine
(75 mg) was treated with 40 mg of Glycolic Acid via Procedure B.
This crude intermediate was then subjected to Procedure A to give
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl-
)piperazin-1-yl)-2-hydroxyethanone. MS (Q1) 494.4 (M)+.
[0299] 120: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidine
(75 mg) was treated with 41 .mu.L of methoxylacetic acid via
Procedure B. This crude intermediate was then subjected to
Procedure A to give
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl-
)piperazin-1-yl)-2-methoxyethanone. MS (Q1) 508 (M)+.
[0300] 121: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidine
(75 mg) was treated with 50 .mu.L of Tetrahydro-2-furoic Acid via
Procedure B. This crude intermediate was then subjected to
Procedure A to give
(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)met-
hyl)piperazin-1-yl)(tetrahydrofuran-2-yl)methanone. MS (Q1) 534.3
(M)+.
[0301] 122: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidine
(75 mg) was treated with 100 mg of Boc-2-Aminoisobutyric Acid via
Procedure B. This crude intermediate was then subjected to
Procedure A to give
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)m-
ethyl)piperazin-1-yl)-2-amino-2-methylpropan-1-one. MS (Q1) 521.5
(M)+.
[0302] 123: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidine
(75 mg) was treated with 100 mg of Boc-amino-cyclopropanecarboxylic
acid via Procedure B. This crude intermediate was then subjected to
Procedure A to give
(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-y-
l)methyl)piperazin-1-yl)(1-aminocyclopropyl)methanone. MS (Q1)
519.3 (M)+.
[0303] 124: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidine
(75 mg) was treated with 93 mg of Boc-Glycine Acid via Procedure B.
This crude intermediate was then subjected to Procedure A to give
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl-
)piperazin-1-yl)-2-aminoethanone. MS (Q1) 493.3 (M)+.
[0304] 125: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidine
(75 mg) was treated with 100 mg of Boc-Alanine Acid via Procedure
B. This crude intermediate was then subjected to Procedure A to
give
(S)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)me-
thyl)piperazin-1-yl)-2-aminopropan-1-one. MS (Q1) 507.3 (M)+.
[0305] 126: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidine
(75 mg) was treated with 100 mg of N-Boc-D-alanine via Procedure B.
This crude intermediate was then subjected to Procedure A to give
(R)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)me-
thyl)piperazin-1-yl)-2-aminopropan-1-one. MS (Q1) 507.3 (M)+.
[0306] 127: The crude HCl salt of
2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidine
(75 mg) was treated with 100 mg of methanesulphonylacetic acid via
Procedure B. This crude intermediate was then subjected to
Procedure A to give
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)m-
ethyl)piperazin-1-yl)-2-(methylsulfonyl)ethanone. MS (Q1) 556.3
(M)+.
[0307] 63:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (50 mg)
was reacted with 4-hydroxypiperidine following the protocol in
general procedure C. The crude material was then used in general
procedure A to give 3 mg of 63 following reversed phase HPLC
purification. MS (Q1) 451 (M)+
[0308] 64:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (50 mg)
was reacted with 3-hydroxypyrrolidine following the protocol in
general procedure C. The crude material was then used following
general procedure A to give 7 mg of 64 following reversed phase
HPLC purification. MS (Q1) 437 (M)+
[0309] 65:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (50 mg)
was dissolved in 2 mL dimethylformamide. To this solution was added
2.6 equivalents of 3-hydroxypiperidine, 3 equivalents of magnesium
sulfate, and 0.04 mL of acetic acid. The mixture was allowed to
stir for 6 hours prior to adding 2.5 equivalents of sodium
triacetoxyborohydride. Following 12 to 16 hours of stirring the
reaction was poured into saturated sodium bicarbonate and extracted
several times with ethylacetate. This chloro intermediate used
crude following the protocol for general procedure A to give 6 mg
of 65 after reversed phase HPLC purification. MS (Q1) 451 (M)+
[0310] 49:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (175
mg) was reacted with 3-(methanesulfonyl)pyrrolidine following the
protocol in general procedure C. The crude material was then used
in general procedure A to give 177 mg of G-34670 following
purification on silica (0 to 15% MeOH gradient in dichloromethane
over 40 min, 40 g column). MS (Q1) 499.2 (M)+
[0311] 50:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (200
mg) was reacted according to procedure C with
(S)-4-N-trityl-2-methyl-piperazine. The crude material was then
dissolved in 10 mL of methanol and treated with 0.5 mL of
concentrated HCl for several hours before basifying with NaOH and
extracting into EtOAc. After evaporation the crude reaction mixture
containing
2-chloro-6-(((S)-2-methylpiperazin-1-yl)methyl-4-morpholinothieno[3,2-d]p-
yrimidine was dissolved in 10 mL of dichloromethane and treated
with 0.3 mL of diisopropylethylamine and 54 .mu.L of
methanesulfonyl chloride. After overnight stirring an additional 20
.mu.L of methanesulfonyl chloride was added to convert remaining
starting material to product. Upon completion the reaction was
extracted with dichloromethane and water and then purified on
silica gel using a MeOH gradient in dichloromethane to give 186 mg
of
2-chloro-6-(((S)-4-N-sulfonyl-2-methylpiperazin-1-yl)methyl-4-morpholinot-
hieno[3,2-d]pyrimidine. 160 mg of this material was used following
general procedure SUZUKI and purified with reversed phase HPLC to
give compound 50. MS (Q1) 528 (M)+
[0312] 1:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (100
mg) was reacted according to procedure C with
(1S,4S)--N-Boc-2,5-diaza-bicyclo[2.2.1]heptane to give 140 mg of
the Boc protected piperazine following silica gel purification (25%
to 100% EtOAc gradient in hexanes, 12 g column). The Boc group was
removed by treating the compound with 1.5 mmol of HCl in dioxane.
After evaporation the free amine was sulfonylated in 3 mL of
dichloromethane using 100 .mu.L of triethylamine as a base and 35
.mu.L of methanesulfonylchloride. After two hours the reaction was
complete and extracted with dichloromethane and saturated NaCl. The
crude material from this reaction was used following general
procedure SUZUKI and purified with reversed phase HPLC to give 61
mg of compound 1. MS (Q1) 526 (M)+
[0313] 75: N-Butyllithium (9.4 mL, 22.48 mmol, 2.5 M in hexane
solution) was added to a mixture of
2-chloro-4-morpholinothieno[3,2-d]pyrimidine (3.0 g, 11.74 mmol) in
60 mL of THF at -78.degree. C. The reaction mixture was allowed to
warm to -40.degree. C. and stirred for 30 min. A solution of iodine
(6.0 g, 23.48 mmol) in 10 mL of THF was added dropwise. After the
addition was completed. The reaction mixture was brought to room
temperature and stirred for 2 h. The mixture was quenched by
diluting with dichloromethane (300 mL) and extracting with H.sub.2O
(2.times.100 mL). The organic layer was washed with
Na.sub.2S.sub.2O.sub.3 (2.times.100 mL), H.sub.2O (2.times.100 mL),
dried over MgSO.sub.4, filtered and evaporated to afford
2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine (3.4 g,
75%).
[0314] 2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine (150
mg), 2-oxazolidinone (103 mg), potassium phosphate tribasic (250
mg), copper iodide (7 mg), 4 .mu.L of N,N-dimethylethylenediamine
in 2 mL of 1,4-dioxane was heated to 100.degree. C. for 15 hr. The
reaction mixture was evaporated and the residue was diluted with
ethyl acetate (50 mL), washed with brine (30 mL), dried over
MgSO.sub.4, filtered and evaporated. The crude product was purified
on reverse phase HPLC to give 46 mg of
3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)oxazolidin-2-
-one.
[0315]
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)oxazolidin-2-on-
e (46 mg) was coupled to
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole via
Procedure A. The product was purified by reverse phase HPLC to
yield 8.6 mg of
3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)oxazolidin-
-2-one. MS (Q1) 423 (M).sup.+
[0316] 73: 2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine (150
mg), 90 .mu.L of 2-pyrrolidinone, potassium phosphate tribasic (250
mg), copper iodide (7 mg), 4 .mu.L of N,N-dimethylethylenediamine
in 2 mL of 1,4-dioxane was heated to 100.degree. C. for 16 h. The
reaction mixture was evaporated and the residue was diluted with
ethyl acetate (60 mL), washed with brine (30 mL), dried over
MgSO.sub.4, filtered and evaporated. The crude product was purified
on reverse phase HPLC to give 53 mg of
1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyrrolidin-2-
-one.
[0317]
1-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyrrolidin-2-on-
e (35 mg) was coupled to
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole via
Procedure A. The product was purified by reverse phase HPLC to
yield 19.5 mg of
1-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyrrolidin-2--
one. MS (Q1) 421 (M).sup.+
[0318] 81:
2-Chloro-6-(4-methylsulfonyl-piperazin-1-yl-methyl)-4-morpholin-
-4-yl-thieno[3,2-d]pyrimidine was reacted with
2-fluoropyridine-5-boronic acid in General Procedure A on a 18.5
mmol scale to give 34.2 mg. of the desired product after RP-HPLC
purification. MS (Q1) 493.1 (M)+.
[0319] 80:
2-Chloro-6-(4-methylsulfonyl-piperazin-1-yl-methyl)-4-morpholin-
-4-yl-thieno[3.2-d]pyrimidine was reacted with 3-fluorophenyl
boronic acid in General Procedure A on a 18.5 mmol scale to give
20.8 mg. of the desired product after RP-HPLC purification. MS (Q1)
492.3 (M)+.
[0320] 79:
2-Chloro-6-(4-methylsulfonyl-piperazin-1-yl-methyl)-4-morpholin-
-4-yl-thieno[3.2-d]pyrimidine was reacted with
3-(N-methylaminocarbonyl)phenyl boronic acid in General Procedure A
on a 18.5 mmol scale to give 7.4 mg. of the desired product after
RP-HPLC purification. MS (Q1) 531.3 (M)+.
[0321] 78:
2-Chloro-6-(4-methylsulfonyl-piperazin-1-yl-methyl)-4-morpholin-
-4-yl-thieno[3.2-d]pyrimidine was reacted with
2-fluoropyridine-3-boronic acid in General Procedure A on a 18.5
mmol scale to give 23.5 mg. of the desired product after RP-HPLC
purification. MS (Q1) 493.4 (M)+.
[0322] 77:
2-Chloro-6-(4-methylsulfonyl-piperazin-1-yl-methyl)-4-morpholin-
-4-yl-thieno[3.2-d]pyrimidine was reacted with pyrimidine-5-boronic
acid in General Procedure A on a 18.5 mmol scale to give 8.1 mg. of
the desired product after RP-HPLC purification. MS (Q1) 476.3
(M)+.
[0323] 76:
2-Chloro-6-(4-methylsulfonyl-piperazin-1-yl-methyl)-4-morpholin-
-4-yl-thieno[3.2-d]pyrimidine was reacted with
3-methylsulfonylaminophenyl boronic acid in General Procedure A on
a 18.5 mmol scale to give 76 mg. of the desired product after
RP-HPLC purification. MS (Q1) 567.2 (M)+.
[0324] 2:
2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholi-
nofuro[3,2-d]pyrimidine (40 mg, 1.0 eq) was dissolved in
toluene/ethanol/water (4:2:1, 1.6 ml) and treated with
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (59 mg,
2.5 eq), PdCl.sub.2(PPh.sub.3).sub.2 (6.8 mg, 0.10 eq) and sodium
carbonate (36 mg, 3.5 eq). The vial was sealed and heated with
stirring in the microwave to 150.degree. C. for 15 minutes. The
crude reaction mixture was concentrated and purified by reverse
phase HPLC to afford
2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpho-
linofuro[3,2-d]pyrimidine: MS (Q1) 498 (M).sup.+.
Example 3
Further Compounds of the Invention--Series B
[0325] The following compounds of the invention were prepared. The
compound numbering corresponds to that used in Table 1A above.
[0326] 5:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin--
4-yl-thieno[2,3-d]pyrimidine was reacted with pyrimidine-5-boronic
acid in General Procedure A. Purification on silica yielded the
desired compound.
[0327] MS (Q1) 476.3 (M)+.
[0328] NMR (400 MHz CDCl3): 2.67 (4H, t (J 4.79), CH2), 2.81 (3H,
s, CH3), 3.29 (4H, m, CH2), 3.83 (2H, s, CH2), 3.89-4.01 (8H, m,
CH2), 7.18 (1H, s, ar), 9.28 (1H, s, ar), 9.67 (2H, s, ar)
[0329] 11:
2-Chloro-6-(4-methylsulfonyl-piperazin-1-yl-methyl)-4-morpholin-
-4-yl-thieno[3.2-d]pyrimidine was reacted with
benzenesulfonamide-3-boronic acid pinacol ester in General
Procedure A. Purification on silica yielded the desired
compound.
[0330] NMR: (CDCl3): 2.68-2.72 (4H, m), 2.82 (3H, s), 3.29-3.33
(4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.05-4.10 (4H, m), 4.81
(211, br. s), 7.33 (1H, s), 7.62-7.66 (1H, m), 8.00 (1H, d, J=8.0),
8.68 (1H, d, J=8.0), 9.02 (1H, s) (ESI+): MH+ 553.18
[0331] 12:
2-Chloro-6-(4-methylsulfonyl-piperazin-1-yl-methyl)-4-morpholin-
-4-yl-thieno[3.2-d]pyrimidine was reacted with
4-(hydroxymethyl)phenyl boronic acid in General Procedure A.
Purification on silica yielded the desired compound
[0332] NMR: (DMSO-d6): 2.58-2.62 (4H, m), 2.89 (3H, s), 3.13-3.18
(4H, m), 3.78-3.81 (4H, m), 3.92 (2H, s), 3.95-4.00 (4H, m), 4.56
(2H, d, J=5.7), 5.23 (1H, t, J=5.7), 7.40 (1H, s), 7.44 (2H, d,
J=8.2), 8.38 (2H, d, J=8.2) (ESI+): MH+ 504.18
[0333] 13:
2-Chloro-6-(4-methylsulfonyl-piperazin-1-yl-methyl)-4-morpholin-
-4-yl-thieno[3,2-d]pyrimidine was reacted with 3-carbamoylphenyl
boronic acid in General Procedure A. Purification on silica yielded
the desired compound (DMSO-d6): 2.58-2.62 (4H, m), 2.89 (3H, s),
3.13-3.18 (4H, m), 3.78-3.81 (4H, m), 3.92 (2H, s), 3.95-4.00 (4H,
m), 7.40 (1H, br), 7.42 (1H, s), 7.53-7.58 (1H, m), 7.94 (1H, d,
J=7.7), 8.09 (1H, br), 8.51 (1H, d, J=7.7), 8.38 (1H, s) (ESI+):
MH+ 517.24
[0334] 84:
2-Chloro-6-(4-methylsulfonyl-piperazin-1-yl-methyl)-4-morpholin-
-4-yl-thieno[3,2-d]pyrimidine was reacted with pyridine-3-boronic
acid in General Procedure A. Purification on silica yielded the
desired compound.
[0335] NMR: (CDCl3): 2.68-2.72 (4H, m), 2.82 (3H, s), 3.29-3.33
(4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.05-4.10 (4H, m), 7.33
(1H, s), 7.34-7.38 (1H, m), 8.68 (2H, d, J=5.6), 9.64 (1H, s)
(ESI+): MH+ 475.11
[0336] 47:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-
-4-yl-thieno[2,3-d]pyrimidine was reacted with
3-formylphenylboronic acid in General Procedure A to yield
3-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-
-d]pyrimidin-2-yl]-benzaldehyde. Treatment of this aldehyde with
sodium borohydride (2.5 equivalents) in ethanol yielded the desired
compound.
[0337] 1H NMR CDCL3
[0338] NMR: 1.67 (t, H, OH, J=6.08 Hz), 2.64-2.67 (m, 4H,
2.times.Ch2), 2.80 (s, 3H, Ch3), 3.27-3.29 (m, 4H, 2.times.CH2),
3.89-3.90 (m, 4H, 2.times.CH2), 3.96-3.98 (m, 4H, 2.times.Ch2),
4.80 (d, 2H, CH2, J=6.06 Hz), 7.14 (s, H, ArH), 7.46 (m, 2H,
2.times.ArH), 8.38 (m, H, ArH), 8.43 (s, H, ArH).
[0339] MH+=504.15
[0340] 85:
2-Chloro-6-(4-methylsulfonyl-piperazine-1-yl-methyl)-4-morpholi-
n-4-yl-thieno[3.2-d}pyrimidine was reacted with
N-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylmethanesulfonamide
in General Procedure A. Purification on silica yielded the desired
compound.
[0341] NMR: (CDCl3): 2.68-2.72 (4H, m), 2.82 (3H, s), 3.06 (3H, s),
3.29-3.33 (4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.05-4.10 (4H,
m), 6.45 (1H, br. s), 7.27 (2H, d, J=8.8), 7.32 (1H, s), 8.44 (2H,
d, J=8.8)
[0342] MS: (ESI+): MH+ 567.20
[0343] 86:
2-Chloro-6-(4-methylsulfonyl-piperazine-1-yl-methyl)-4-morpholi-
n-4-yl-thieno[3.2-d}pyrimidine was reacted with
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in General
Procedure A. Purification on silica yielded
4-[6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-
-d]pyrimidin-2-yl]aniline. This was then reacted with acetic
anhydride in dichloromethane and triethylamine to give the desired
compound.
[0344] NMR: (CDCl3): 2.20 (3H, s), 2.68-2.72 (4H, m), 2.82 (3H, s),
3.29-3.33 (4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.05-4.10 (4H,
m), 7.22 (1H, br. s), 7.32 (1H, s), 7.62 (2H, d, J=8.5), 8.42 (2H,
d, J=8.5)
[0345] NMR: (ESI+): MH+ 531.19
[0346] 89:
2-Chloro-6-(4-methylsulfonyl-piperazine-1-yl-methyl)-4-morpholi-
n-4-yl-thieno[3.2-d}pyrimidine was reacted with
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline in General
Procedure A. Purification on silica yielded the desired
compound.
[0347] NMR: (CDCl3): 2.68-2.72 (4H, m), 2.82 (3H, s), 3.29-3.33
(4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.05-4.10 (4H, m), 7.49
(1H, s), 7.58 (1H, t, J=7.0), 7.75 (1H, t, J=7.0), 7.97 (1H, d,
J=7.6), 8.29 (1H, d, J=8.4), 9.17 (1H, d, J=1.9), 9.96 (1H, d,
J=2.1)
[0348] MS: (ESI+): MH+ 525.24
[0349] 90:
2-Chloro-6-(4-methylsulfonyl-piperazine-1-yl-methyl)-4-morpholi-
n-4-yl-thieno[3,2-d}pyrimidine was reacted with
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline in
General Procedure A. Purification on silica yielded the desired
compound.
[0350] NMR: (CDCl3): 2.68-2.72 (4H, m), 2.82 (3H, s), 3.29-3.33
(4H, m), 3.90-3.94 (4H, m), 3.96 (2H, s), 4.05-4.10 (4H, m), 7.42
(1H, s), 7.64 (1H, t, J=7.0), 7.75 (1H, t, J=7.0), 8.06 (1H, d,
J=8.0), 8.83 (1H, d, J=8.6), 9.13 (1H, s), 9.32 (1H, s)
[0351] MS: (ESI+): MH+ 525.23
[0352] 87:
2-chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-
-4-yl-thieno[2,3-d]pyrimidine was reacted with pyridine-3-boronic
acid in General Procedure A. Purification on silica yielded the
desired compound.
[0353] NMR: (CDCl.sub.3): 2.65-2.67 (m, 4H, 2.times.CH2), 2.87 (s,
3H, CH3), 3.27-3.30 (m, 4H, 2.times.CH2), 3.82 (s, 2H, CH2),
3.88-3.90 (m, 4H, 2.times.CH2), 3.97-3.99 (m, 4H, 2.times.CH2),
7.16 (s, H, ArH), 7.36-7.39 (m, H, ArH), 8.66-8.69 (m, 2H,
2.times.ArH), 9.62 (d, H, ArH, J=1.28 Hz).
[0354] MS: (ESI+): MH+=475.18
[0355] 91:
2-chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-
-4-yl-thieno[2,3-d]pyrimidine was reacted 3-acetylphenylboronic
acid in General Procedure A. Purification on silica yielded the
desired compound.
[0356] NMR: (CDCl.sub.3): 2.65-2.67 (m, 4H, 2.times.CH2), 2.70 (s,
3H, CH3), 2.80 (s, 3H, CH3), 3.27-3.30 (m, 4H, 2.times.CH2), 3.82
(s, 2H, CH2), 3.89-3.92 (m, 4H, 2.times.CH2), 3.98-4.00 (m, 4H,
2.times.CH2), 7.16 (s, H, ArH), 7.55 (t, H, ArH, J=7.75 Hz), 8.03
(d, H, ArH, J=7.73 Hz), 8.64 (d, H, ArH, J=7.78 Hz), 9.01 (s, H,
ArH).
[0357] MS: (ESI+): MH+=516.19
[0358] 93:
1-{3-[6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4--
yl-thieno[2,3-d]pyrimidin-2-yl]-phenyl}-ethanone was treated with
sodium borohydride (2.8 eq.) in ethanol. Purification on silica
yielded the desired compound.
[0359] NMR: (CDCl.sub.3): 1.57 (d, 3H, CH3), 1.85 (d, H, OH),
2.64-2.67 (m, 4H, 2.times.CH2), 2.80 (s, 3H, CH3), 3.27-3.28 (m,
4H, 2.times.CH2), 3.81 (s, 2H, CH2), 3.88-3.91 (m, 4H, 2.times.CH2)
3.96-3.98 (m, 4H, 2.times.CH2), 5.00-5.03 (m, H, CH), 7.14 (s, H,
ArH), 7.42-7.49 (m, 2H, 2.times.ArH), 8.35 (d, H, ArH, J=7.27 Hz),
8.43 (s, H, ArH).
[0360] MS: (ESI+): MH+=518.27
[0361] 94:
2-chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-
-4-yl-thieno[2,3-d]pyrimidine was reacted with
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline in
General Procedure A. Purification on silica yielded the desired
compound.
[0362] NMR: (CDCl.sub.3): 2.67-2.69 (m, 4H, 2.times.CH2), 2.80 (s,
3H, CH3), 3.29-3.31 (m, 4H, 2.times.CH2), 3.85 (s, 2H, CH2),
3.88-3.90 (m, 4H, 2.times.CH2), 3.99-4.01 (m, 4H, 2.times.CH2),
7.22 (s, H, ArH), 7.63 (t, ArH, J=7.53 Hz), 7.75 (t, H, ArH, J=8.31
Hz), 8.03 (d, H, ArH, J=8.1 Hz), 8.88 (d, H, ArH, J=8.61 Hz), 9.16
(s, H, ArH), 9.30 (s, H, ArH).
[0363] MS: (ESI+): MH+=525.23
[0364] 95:
2-chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-
-4-yl-thieno[2,3-d]pyrimidine was reacted with
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline in General
Procedure A. Purification on silica yielded the desired
compound.
[0365] NMR: (CDCl.sub.3): 2.66-2.69 (m, 4H, 2.times.CH2), 2.80 (s,
3H, CH3), 3.28-3.31 (m, 4H, 2.times.CH2), 3.83 (s, 2H, CH2),
3.91-3.91 (m, 4H, 2.times.CH2), 4.01-4.04 (m, 4H, 2.times.CH2),
7.18 (s, H, ArH), 7.57 (t, H, ArH, J=7.27 Hz), 7.74 (t, H, ArH,
J=7.14 Hz), 7.96 (d, H, ArH, J=8.47 Hz), 9.15 (d, H, ArH, J=2.0
Hz), 9.94 (d, H, ArH, J=2.0 Hz).
[0366] MS: (ESI+): MH+=525.28
[0367] 37: To a solution of 4-methoxybenzyl alcohol (1.73 g) in
DMSO (10 mL) at room temperature was added sodium hydride (500 mg).
The reaction mixture was stirred for 75 min and then a solution of
3,5-dibromopyridine (3.0 g) in DMSO (15 mL) was added. The reaction
mixture was then heated at 90.degree. C. for 2.5 h and then allowed
to cool to room temperature, quenched with water (60 mL) and
extracted into diethyl ether (3.times.60 mL). The combined organics
were washed with brine (100 mL), dried (MgSO.sub.4), reduced in
vacuo and purified by column chromatography to give
3-bromo-5-(4-methoxy-benzyloxy)-pyridine as a white solid (1.76
g).
[0368] To a solution of 3-bromo-5-(4-methoxy-benzyloxy)-pyridine
(300 mg) in THF (10 mL) was added triiospropyl borate (0.28 mL) and
the mixture cooled to -78.degree. C. Then n-butyllithium (0.49 mL
of a 2.5 M solution in hexanes) was added maintaining the
temperature below -65.degree. C. The reaction mixture was then
allowed to warm to -20.degree. C. over 1 h and then quenched with 2
M aqueous hydrochloric acid (2 mL). The mixture was allowed to warm
to room temperature over 1 h and then diluted with water (25 mL),
the pH was adjusted to 7 and then extracted into ethyl acetate
(3.times.25 mL). The combined organics were washed with brine (20
mL), dried (MgSO.sub.4) and reduced in vacuo. A mixture of the
crude product and pinacol (236 mg) in toluene (15 mL) was then
heated at reflux for 4 h. The mixture was then reduced in vacuo,
dissolved in ethyl acetate (30 mL) and washed with water
(2.times.30 mL) and brine (30 mL). The combined organics were dried
(MgSO.sub.4) and reduced in vacuo to give
3-(4-methoxy-benzyloxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-pyridine as an off-white solid (162 mg).
[0369]
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[-
3,2-d]pyrimidine was reacted with
3-(4-methoxy-benzyloxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)--
pyridine in General Procedure A. Purification on silica yielded
2-[5-(4-methoxy-benzyloxy)-pyridin-3-yl]-6-(4-methyl-piperazin-1-ylmethyl-
)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This was then reacted
with trifluoroacetic acid in dichloromethane to give the desired
compound.
[0370] NMR: (CDCl3): 2.31 (3H, s, Me), 2.46-2.68 (8H, m, CH2), 3.73
(2H, s, CH2), 3.74-3.82 (4H, m, CH2), 3.94-3.99 (4H, m, CH2), 7.20
(1H, s, Ar), 8.12 (1H, s, Ar), 8.22 (1H, s, Ar) and 9.07 (1H, s,
Ar).
[0371] MS: (ESI+): MH+ 427.15
[0372] 39:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thi-
eno[3,2-d]pyrimidine was reacted with
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic
acid tert-butyl ester in General Procedure A. The BOC group was
cleaved under the conditions of the Suzuki reaction. Purification
on silica yielded the desired compound.
[0373] NMR: (DMSO): 13.05 (bs, 1H); 8.31 (bs, 2H); 7.26 (s, 1H);
3.92 (m, 4H); 3.85 (s, 2H); 3.77 (m, 4H); 2.41 (m, 8H); 2.15 (s,
3H).
[0374] MS: (ESI+): MH+ 400.21
[0375] 40:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thi-
eno[3,2-d]pyrimidine was reacted with 3-formyl phenyl boronic acid
in General Procedure A. Purification on silica yielded
3-[6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimi-
din-2-yl]-benzaldehyde. This was then treated with methylmagnesium
bromide in THF to give the desired compound.
[0376] NMR: (CDCl3): 1.49 (d, J=6.5, 3H), 2.10 (d, J=1.7, 1H), 2.25
(s, 3H), 2.46 (s, br, 4H), 2.54 (s, br, 4H), 3.74 (s, 2H), 3.82 (t,
J=4.8, 4H), 3.98 (t, J=4.8, 4H), 4.94 (q, J=6.4, 1H), 7.23 (s, 1H),
7.35-7.42 (m, 2H), 8.27 (m, 1H), 8.35 (s, 1H).
[0377] MS: (ESI+): MH+ 454.27
[0378] 41:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thi-
eno[3,2-d]pyrimidine was reacted with 3-formyl phenyl boronic acid
in General Procedure A. Purification on silica yielded
3-[6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimi-
din-2-yl]-benzaldehyde. This was then treated with sodium
borohydride in methanol to give the desired compound.
[0379] NMR: (CDCl3): 2.25 (s, 3H), 2.47 (s, 4H), 2.54 (s, 4H), 3.75
(s, 2H), 3.80 (t, J=4.8, 4H), 3.98 (t, J=4.8, 4H), 4.71 (s, 2H),
7.23 (m, 1H), 7.38 (m, 2H), 8.28 (m, 1H), 8.34 (s, 1H).
[0380] MS: (ESI+): MH+ 440.23
[0381] 35: A solution of 4-methoxybenzylalcohol (10 g) in ether
(300 ml) was shaken with hydrobromic acid, 48%, (150 ml). The
organic phase was washed with saturated sodium bromide, dried
(K.sub.2CO.sub.3) and the solvents removed in vacuo to give
4-methoxybenzylbromide (13.17 g).
[0382] To a solution of 3-bromo-4-fluorophenol (0.59 g) in
tetrahydrofuran (7 ml) under nitrogen was added sodium hydride, 60%
dispersion in mineral oil (0.13 g). The solution was stirred at
room temperature. After 30 minutes a solution of
4-methoxybenzylbromide (0.62 g) was added in tetrahydrofuran (5
ml). The reaction mixture was stirred at 50.degree. C. overnight.
The reaction mixture was partitioned between dichloromethane and
brine, then dried (MgSO.sub.4), the solvents were removed in vacuo
to give a crude residue. This crude residue was purified using
flash chromatography to give
2-bromo-1fluoro-4-(4-methoxy-benzyloxy)-benzene (0.71 g). To a
solution of 2-bromo-1fluoro-4-(4-methoxy-benzyloxy)-benzene (0.33
g) in tetrahydrofuran (10 ml) under nitrogen was added
triiopropylborate (0.29 ml). The mixture was cooled to -78.degree.
C. and 2.5M n-butyllithium solution in hexanes was added. The
reaction mixture was stirred at -40.degree. C. for 1 hour, then
warmed to 20.degree. C. and quenched with 2M hydrochloric acid (aq)
(2 ml). The reaction mixture was warmed to room temperature and
stirred for 1 hour. The reaction mixture was adjusted to pH 7 using
saturated sodium bicarbonate solution, then partitioned between
ethyl acetate and water, dried (MgSO.sub.4) and the solvents
removed in vacuo to yield a crude residue (0.31 g). A mixture of
this crude residue and pinacol (0.25 g) in toluene (10 ml) were
stirred under reflux overnight in a Dean-Stark apparatus. The
solvents were removed in vacuo, the residue was then partitioned
between ethyl acetate and water, the combined organics were washed
with water then brine and dried (MgSO.sub.4), the solvents were
removed in vacuo to yield
2-[2-fluoro-5-(4-methoxy-benzyloxy-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dio-
xyborolane (0.28 g)
[0383]
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[-
3,2-d]pyrimidine was reacted with
2-[2-fluoro-5-(4-methoxy-benzyloxy-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dio-
xyborolane in general procedure A. Purification on silica yielded
2-[2-fluoro-5-(4-methoxy-benzyloxy)-phenyl]-6-(4-methyl-piperazin-1-ylmet-
hyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This was then
reacted with trifluoroacetic acid in dichloromethane to yield the
desired compound.
[0384] NMR: 400 MHz; CDCl3: 2.34(3H, s); 2.58 (8H, m); 3.84 (2H,
s); 3.90 (4H, t, J=4.8 Hz); 4.04 (4H, t, J=4.8 Hz); 6.84 (1H, m);
7.02 (1H, t, J=9.6 Hz); 7.30 (1H, s); 7.57 (1H, m).
[0385] MS: (ESI+): MH+ 444
[0386] 36: A solution of 4-methoxybenzylalcohol (10 g) in ether
(300 ml) was shaken with hydrobromic acid, 48%, (150 ml). The
organic phase was washed with saturated sodium bromide, dried
(K.sub.2CO.sub.3) and the solvents removed in vacuo to give
4-methoxybenzylbromide (13.17 g).
[0387] To a solution of 5-bromo-2,3-difluorophenol (1.0 g) in
tetrahydrofuran (10 ml) under nitrogen was added sodium hydride,
60% dispersion in mineral oil (0.20 g). The solution was stirred at
room temperature. After 30 minutes a solution of
4-methoxybenzylbromide (0.96 g) was added in tetrahydrofuran (7
ml). The reaction mixture was stirred at 50.degree. C. overnight.
The reaction mixture was partitioned between dichloromethane and
brine, then dried (MgSO.sub.4), the solvents were removed in vacuo
to give a crude residue. This crude residue was purified using
flash chromatography to give
5-bromo-1,2-difluoro-3-(4-methoxy-benzyloxy)-benzene (0.76 g).
[0388] To a solution of
5-bromo-1,2-difluoro-3-(4-methoxy-benzyloxy)-benzene (0.35 g) in
tetrahydrofuran (10 ml) under nitrogen was added triiopropylborate
(0.29 ml). The mixture was cooled to -78.degree. C. and 2.5M
n-butyllithium solution in hexanes was added. The reaction mixture
was stirred at -40.degree. C. for 1 hour, then warmed to 20.degree.
C. and quenched with 2M hydrochloric acid (aq) (2 ml). The reaction
mixture was warmed to room temperature and stirred for 1 hour. The
reaction mixture was adjusted to pH 7 using saturated sodium
bicarbonate solution, then partitioned between ethyl acetate and
water, dried (MgSO.sub.4) and the solvents removed in vacuo to
yield a crude residue (0.31 g). A mixture of this crude residue and
pinacol (0.25 g) in toluene (10 ml) were stirred under reflux
overnight in a Dean-Stark apparatus. The solvents were removed in
vacuo, the residue was then partitioned between ethyl acetate and
water, the combined organics were washed with water then brine and
dried (MgSO.sub.4), the solvents were removed in vacuo to yield
2-[3,4-difluoro-5-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,-
2]dioxaborolane (0.28 g)
[0389]
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[-
3,2-d]pyrimidine was reacted with yield
2-[3,4-difluoro-5-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,-
2]dioxaborolane in general procedure A. Purification on silica
yielded
2-[3,4-difluoro-5-(4-methoxy-benzyloxy)-phenyl]-6-(4-methyl-piperazin-1-y-
lmethyl)-4-morpholin-yl-thieno[3,2-d]pyrimidine. This was then
reacted with trifluoroacetic acid in dichloromethane to yield the
desired compound.
[0390] NMR: 400 MHz; CDCl3: 2.36(3H, s); 2.67 (8H, m); 3.84 (2H,
s); 3.90 (4H, t, J=4.7 Hz); 4.00 (4H, t, J=4.7 Hz); 7.24 (1H, s);
7.80 (1H, m); 7.90 (1H, d, J=7.6 Hz).
[0391] MS: (ESI+): MH+ 462
[0392] 33: A solution of 4-methoxybenzylalcohol (10 g) in ether
(300 ml) was shaken with hydrobromic acid, 48%, (150 ml). The
organic phase was washed with saturated sodium bromide, dried
(K.sub.2CO.sub.3) and the solvents removed in vacuo to give
4-methoxybenzylbromide (13.17 g).
[0393] To a solution of 5-bromo-2-chlorophenol (1.0 g) in
tetrahydrofuran (10 ml) under nitrogen was added sodium hydride,
60% dispersion in mineral oil (0.20 g). The solution was stirred at
room temperature. After 30 minutes a solution of
4-methoxybenzylbromide (0.97 g) was added in tetrahydrofuran (7
ml). The reaction mixture was stirred at 50.degree. C. overnight.
The reaction mixture was partitioned between dichloromethane and
brine, then dried (MgSO.sub.4), the solvents were removed in vacuo
to give a crude residue. This crude residue was purified using
flash chromatography to give
4-bromo-1-chloro-2-(4-methoxy-benzyloxy)-benzene (0.96 g).
[0394] To a solution of
4-bromo-1-chloro-2-(4-methoxy-benzyloxy)-benzene (0.35 g) in
tetrahydrofuran (10 ml) under nitrogen was added triiopropylborate
(0.29 ml). The mixture was cooled to -78.degree. C. and 2.5M
n-butyllithium solution in hexanes was added. The reaction mixture
was stirred at -40.degree. C. for 1 hour, then warmed to 20.degree.
C. and quenched with 2M hydrochloric acid (aq) (2 ml). The reaction
mixture was warmed to room temperature and stirred for 1 hour. The
reaction mixture was adjusted to pH 7 using saturated sodium
bicarbonate solution, then partitioned between ethyl acetate and
water, dried (MgSO.sub.4) and the solvents removed in vacuo to
yield a crude residue (0.31 g). A mixture of this crude residue and
pinacol (0.25 g) in toluene (10 ml) were stirred under reflux
overnight in a Dean-Stark apparatus. The solvents were removed in
vacuo, the residue was then partitioned between ethyl acetate and
water, the combined organics were washed with water then brine and
dried (MgSO.sub.4), the solvents were removed in vacuo to yield
2-[4-chloro-3-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,-
3,2]dioxaborolane (0.28 g).
[0395]
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[-
3,2-d]pyrimidine was reacted with
2-[4-chloro-3-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]di-
oxaborolane in general procedure A. Purification on silica yielded
2-[4-chloro-3-(4-methoxy-benzyloxy)-phenyl]-6-(4-methyl-piperazin-1-ylmet-
hyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This was then
reacted with trifluoroacetic acid in dichloromethane to yield the
desired compound.
[0396] NMR: 400 MHz; CDCl3: 2.25(3H, s); 2.50 (8H, m); 3.77 (2H,
s); 3.82 (4H, t, J=4.9 Hz); 3.98 (4H, t, J=5.0 Hz); 7.23 (1H, s);
7.32 (1H, d, J=8.4 Hz); 7.93 (1H, d, J=8.4 Hz); 8.04 (1H, s).
[0397] MS: (ESI+): MH+ 460
[0398] 16: To 2-methylbenzimidazole (75 mg) in
N,N-dimethylformamide (3 mL) was added sodium hydride (60%
dispersion, 23 mg). After stirring for 30 mins,
2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin--
4-yl-thieno[2,3-d]pyrimidine (242 mg) was added and the reaction
mixture was heated to 90.degree. C. After 16 hours the reaction
mixture was cooled, diluted with ethyl acetate and washed with
brine. The organic fraction was concentrated in vacuo and purified
using flash chromatography to yield the title compound [M+H]+
528.21
[0399] (400 MHz CDCl3): 2.68 (4H, t (J 4.80), CH2), 2.81 (3H, s,
CH3), 2.94 (3H, s, CH3), 3.30 (4H, t (J 4.61), CH2), 3.83 (2H, s,
CH2), 3.88-4.00 (8H, m, CH2), 7.19 (1H, s, ar), 7.31 (1H, m, ar),
7.70-7.73 (1H, m, ar), 8.10-8.12 (1H, m, ar)
[0400] 88:
6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-2-(2-methyl-imidazol-
-1-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was made in a
similar manner to the compound above using 2-methylimidazole and
2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thie-
no[3,2-d]pyrimidine.
[0401] (CDCl3): 2.68-2.72 (4H, m), 2.82 (3H, s), 2.85 (3H, s),
3.29-3.33 (4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.05-4.10 (4H,
m), 6.93 (1H, d, J=1.6), 7.25 (1H, s), 7.82 (1H, d, J=1.6)
[0402] (ESI+): MH+ 478.17
[0403] 101:
6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-2-(2-methyl-benzoimidazol-1-yl-
)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was made in a similar
manner to the compound above using 2-methylbenzimidazole and
2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thie-
no[3,2-d]pyrimidine.
[0404] (ESI+): MH+
[0405] (CDCl3): 2.68-2.72 (4H, m), 2.82 (3H, s), 2.92 (3H, s),
3.29-3.33 (4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.05-4.10 (4H,
m), 7.27-7.30 (2H, m), 7.32 (1H, s), 7.71-7.75 (1H, m), 8.09-8.12
(1H, m)
Example 4
Compounds of the Invention--Series C
[0406] The following compounds of the invention were prepared. The
compound numbering corresponds to that used in Table 1A above.
[0407] 3: To 1-Boc-4-piperidone (10 g) in ethanol stirring at
0.degree. C. was added sodium borohydride (9.45 g) portionwise. The
reaction mixture was stirred at 0.degree. C. for 1 hour. The
reaction mixture was then quenched with water and extracted with
chloroform. The combined organic were washed with brine and dried
(MgSO.sub.4). The solvent was removed in vacuo to yield 9.2 g of
4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
[0408] To 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester
(9.2 g) in dichloromethane (170 ml), stirring at 0.degree. C. was
added methane sulphoyl chloride (5.33 ml) and triethylamine (10.24
ml). The reaction mixture was slowly warmed to room temperature and
stirred overnight. The reaction mixture was partitioned between
chloroform and water. The combined organics were washed with brine
and dried (MgSO.sub.4). The solvent was removed in vacuo to yield
14 g of 4-methanesulfonyl-piperidine-carboxylic acid tert-butyl
ester.
[0409] A mixture of 4-methanesulfonyl-piperidine-carboxylic acid
tert-butyl ester (2.82 g) thioacetate (2.31 g) and DMF (40 ml) was
stirred at 60.degree. C. After 4 hours the reaction mixture was
cooled and partitioned between ethyl acetate and brine. The
combined organics were dried (MgSO.sub.4) and the solvents removed
in vacuo. The resulting crude mixture was purified by flash
chromatography to yield 4-acetylsulfanyl-piperidine-1-carboxylic
acid tert-butyl ester (1.8 g).
4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (400
mg) was stirred in acetic acid (3 ml) and water (3 ml) at 0.degree.
C. Chlorine gas was bubbled through the reaction mixture. The
reaction mixture was stirred for 1.5 hours. The reaction mixture
was then diluted with water to yield a precipitate which was
collected by filtration to yield
4-chlorosulfonyl-piperidine-1-carboxylic acid tert-butyl ester (295
mg).
[0410] To a solution of 4-chlorosulfonyl-piperidine-1-carboxylic
acid tert-butyl ester (295 mg) in dichloromethane stirring at
0.degree. C. was added triethylamine (96 .mu.L) and morpholine (55
.mu.L). The reaction mixture was stirred overnight then quenched
with water and extracted into dichloromethane. The combined
organics were washed with brine and dried (MgSO4). The solvent was
removed in vacuo to yield
4-(morpholine-4-sulfonyl)-piperidine-1-carboxylic acid tert-butyl
ester (120 mg).
[0411] To a solution of
4-(morpholine-4-sulfonyl)-piperidine-1-carboxylic acid tert-butyl
ester in dichloromethane (10 ml) and methanol (10 ml) was added 2M
hydrogen chloride in ether (2 .mu.L). The reaction mixture was
stirred overnight. The solvents were removed in vacuo to yield
4-(piperidine-4-sulfonyl)-morpholine hydrochloride salt.
[0412] Reaction with
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
using procedure C yielded
1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-
e-4-sulfonic acid dimethylamide. This compound was subjected to
procedure A to yield the desired final compound which was purified
using flash chromatography.
[0413] (M+H)+ 542.28
[0414] (400 MHz CDCl3): 1.95-2.04 (4H, m, CH2), 2.14 (2H, td (J
11.36, 2.99), CH2), 2.94 (6H, s, CH3), 2.99 (1H, m, CH), 3.13 (2H,
d (J 11.59), CH2), 3.85 (2H, s, CH2), 3.92-3.95 (4H, m, CH2),
4.08-4.15 (4H, m, CH2), 7.36 (1H, s, ar), 7.50 (1H, t (J 7.73),
ar), 7.58 (1H, d (J 8.34), ar), 8.27 (1H, d (J 7.52), 9.02 (1H, s,
ar), 10.25 (1H, b, NH)
[0415] The following compounds were prepared in an analogous manner
using the appropriate amine.
[0416] 27:
1-[2-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin--
6-ylmethyl]-piperidine-4-sulfonic acid dimethylamide was prepared
as above using piperidine-4-sulfonic acid dimethyl amide
hydrochloride salt.
[0417] (M+H)+ 542.28
[0418] (400 MHz CDCl3): 1.95-2.04 (4H, m, CH2), 2.14 (2H, td (J
11.36, 2.99), CH2), 2.94 (6H, s, CH3), 2.99 (1H, m, CH), 3.13 (2H,
d (J 11.59), CH2), 3.85 (2H, s, CH2), 3.92-3.95 (4H, m, CH2),
4.08-4.15 (4H, m, CH2), 7.36 (1H, s, ar), 7.50 (1H, t (J 7.73),
ar), 7.58 (1H, d (J 8.34), ar), 8.27 (1H, d (J 7.52), 9.02 (1H, s,
ar), 10.25 (1H, b, NH)
[0419] 22:
1-[2-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin--
6-ylmethyl]-piperidine-4-sulfonic acid methylamide was prepared as
above using piperidine-4-sulfonic acid methylamine hydrochloride
salt.
[0420] MH+=528.24
[0421] 400 MHz 1H NMR CDCl3
[0422] 1.60-1.70 (m, 2H, CH2), 1.90-2.0 (m, 2H, CH2), 2.1-2.2 (m,
2H, CH2), 2.58 (d, 3H, CH3, J=4.76 Hz), 2.95-3.05 (m, 2H, CH2),
3.80-3.85 (m, 4H, 2.times.CH2), 3.88 (s, 2H, CH2), 3.95-4.05 (m,
4H, 2.times.CH2), 6.90 (m, H, ArH), 7.45 (m, H, ArH), 7.64 (d, H,
ArH, J=8.21 Hz), 8.2 (d, H, ArH, J=7.2 Hz), 8.86 (s, H, ArH), 13.15
(sbr, H, NH).
[0423] 24:
2-(1H-Indazol-4-yl)-6-[4-(4-methyl-piperazine-1-sulfonyl)-piper-
idin-1-ylmethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was
prepared as above using
1-methyl-4-(piperidine-4-sulphonyl)-piperizine hydrochloride
salt.
[0424] 400 MHz 1H NMR CDCl3
[0425] 1.90-2.0 (m, 2H, CH2), 2.05-2.15 (m, 2H, CH2), 2.32 (s, 3H,
CH3), 2.45-2.55 (m, 4H, 2.times.CH2), 2.90-3.09 (m, H, CH),
3.05-3.15 (m, 2H, CH2), 3.38-3.43 (m, 4H, 2.times.CH2), 7.35 (s, H,
ArH), 7.49 (t, H, ArH, J=7.6 Hz), 7.58 (d, H, ArH, J=8.33 Hz), 8.27
(d, H, ArH, J=7.53 Hz), 9.00 (s, H, ArH, 10.15 (sbr, H, NH).
[0426] MH+=597.25
[0427] 18:
1-[2-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin--
6-ylmethyl]-piperidine-4-sulfonic acid
(2-methoxy-ethyl)-methyl-amide was prepared as above using
piperidine-4-sulfonic acid (2-methoxy-ethyl)-methyl-amide
hydrochloride salt.
[0428] (CDCl3): 1.98-2.10 (4H, m), 2.11-2.19 (2H, m), 2.99 (3H, s),
3.00-3.10 (1H, m), 3.12-3.18 (2H, m), 3.37 (3H, s), 3.41-3.45 (2H,
m), 3.53-3.58 (2H, m), 3.84 (2H, s), 3.90-3.94 (4H, m), 4.10-4.14
(4H, m), 7.38 (1H, s), 7.48-7.52 (1H, m), 7.58 (1H, d, J=8.3), 8.38
(1H, d, J=7.6), 9.20 (1H, s), 10.10 (1H, br)
[0429] (ESI+): MH+ 586
[0430] 19:
1-[2-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidin--
6-ylmethyl]-piperidine-4-sulfonic acid dimethylamide was prepared
as above using piperidine-4-sulfonic acid dimethyl amide
hydrochloride salt.
[0431] NMR: 1.9-2.0 (m, 2H, CH2), 2.0-2.2 (m, 4h, 2.times.CH2),
2.94 (s, 6H, 2.times.CH3), 2.95-3.0 (m, H, CH), 3.05-3.10 (m, 2H,
CH2), 3.79 (s, 2H, CH2), 3.92-3.94 (m, 4H, 2.times.CH2), 7.15 (s,
H, ArH), 7.50 (t, H, ArH, J=7.79 Hz), 7.59 (d, H, ArH, J=8.23 Hz),
8.32 (d, H, ArH, J=7.34 Hz), 9.02 (s, H, ArH), 10.1 (sbr, H,
NH).
[0432] MH+=542.19
[0433]
20:1-[2-(1H-Indazol-4-yl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]py-
rimidin-6-ylmethyl]piperidine-4-sulfonic acid dimethylamide was
prepared as above using piperidine-4-sulfonic acid dimethyl amide
hydrochloride salt.
[0434] NMR: 1.98-2.08 (4H, m), 2.12-2.18 (2H, m), 2.54 (3H, s),
2.94 (6H, s), 2.98-3.06 (1H, m), 3.12-3.18 (2H, m), 3.84 (2H, s),
3.90-3.94 (4H, m), 4.10-4.14 (4H, m), 7.48-7.52 (1H, m), 7.58 (1H,
d, J=8.3), 8.38 (1H, d, J=7.6), 9.20 (1H, s), 10.10 (1H, br)
[0435] (ESI+): MH+ 556
[0436] 21: A mixture of
4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester
(1.015 g) and sodium thiomethoxide (635 mg) was heated to
80.degree. C. in dimethylformamide (10 mL). After 4h, the reaction
mixture was diluted with water, extracted with ethyl acetate, dried
(MgSO.sub.4), filtered and concentrated in vacuo and then purified
by flash chromatography to give
4-methylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (600
mg). To a solution of 4-methylsulfanyl-piperidine-1-carboxylic acid
tert-butyl ester (600 mg) in chloroform (15 mL) was added mCPBA
(1.46 g). After stirring for 2 days, the reaction mixture was
diluted with dichloromethane, washed with sodium bicarbonate
solution, dried (MgSO.sub.4) and the solvent removed in vacuo to
yield 4-methanesulfonyl-piperidine-1-carboxylic acid tert-butyl
ester (505 mg) as a white solid.
[0437] Treatment of this compound with HCl in
dichloromethane/methanol yielded 4-methanesulfonyl-piperidine,
which was isolated as the hydrochloride salt.
[0438] Reaction with
2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehydeusing
procedure C yielded
2-chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thie-
no[2,3-d]pyrimidine. This compound was subjected to procedure A to
yield the desired final compound which was purified using flash
chromatography.
[0439] 1H NMR CDCL3
[0440] 1.9-2.0 (m, 2H, Ch2), 2.1-2.2 (m, 4H, 2.times.CH2), 2.84 (m,
4H, 2.times.CH2), 3.15-3.20 (m, 2H, CH2), 3.90-3.95 (m, 4H,
2.times.CH2), 4.0-4.05 (m, 4H, 2.times.CH2), 7.15 (s, H, ArH), 7.50
(t, H, ArH, J=7.78), 7.59 (d, H, ArH, J=8.32 Hz), 8.32 (d, H, ArH,
J=7.21 Hz), 9.02 (s, H, ArH), 10.1 (sbr, H, NH).
[0441] MH+=513.19
[0442] The following compound was prepared in an analogous
manner:
[0443] 23: (ESI+): MH+ 527
[0444] (CDCl3): 1.94-2.03 (2H, m), 2.12-2.24 (4H, m), 2.55 (3H, s),
2.88 (3H, s), 2.88-2.95 (1H, m), 3.21-3.25 (2H, m), 3.84 (2H, s),
3.90-3.94 (4H, m), 4.10-4.14 (4H, m), 7.48-7.52 (1H, m), 7.58 (1H,
d, J=8.3), 8.38 (1H, d, J=7.6), 9.20 (1H, s), 10.10 (1H, br)
[0445] 45: Reaction between
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
and 1-methyl-4-(methylamino)piperidine using procedure C yielded
(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-(1-m-
ethyl-piperidin-4-yl)-amine. This compound was subjected to
procedure A to yield the desired final compound which was purified
using flash chromatography.
[0446] 1H NMR 400 MHz DMSO
[0447] 13.2 (bs, 1H); 8.87 (s, 1H); 8.21 (d, 1H); 7.65 (d, 1H,
J=7.3 Hz); 7.46 (t, 2H, J=7.7 Hz); 3.90 (m, CH2.times.4); 3.93 (s,
2H); 2.79 (d, 2H, J=11.2); 2.40 (m, 1H); 2.25 (s, 3H); 2.12 (s,
3H); 1.68 (m, CH2.times.3).
[0448] M/S (m+1)=478.3; LC>/95% purity
[0449] 9: To a solution of piperazine (1 g) and triethylamine (1.78
mL) in dichloromethane (20 mL) at 0.degree. C. was added dropwise
trifluoromethanesulfonyl chloride (1.24 mL). The reaction mixture
was stirred at room temperature for 16 h and then quenched with
water (20 mL) and extracted into dichloromethane (2.times.40 mL).
The combined organic layers were washed with saturated aqueous
brine solution (2.times.40 mL), dried (MgSO.sub.4) and concentrated
to afford 1-trifluoromethanesulfonyl-piperazine as a pale yellow
solid (1.92 g, 76%). Reaction between
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
and 1-trifluoromethanesulfonyl-piperazine using procedure C yielded
2-chloro-4-morpholin-4-yl-6-(4-trifluoromethanesulfonyl-piperazin-1-ylmet-
hyl)-thieno[3,2-d]pyrimidine. This compound was subjected to
procedure A to yield the desired final compound which was purified
using flash chromatography
[0450] [M+H]+ 568.23
[0451] NMR: (400 MHz, CDCl3): 2.67-2.72 (4H, m, CH2), 3.53-3.64
(4H, m, CH2), 3.90-3.98 (6H, m, CH2), 4.08-4.14 (4H, m, CH2), 7.40
(1H, s, Ar), 7.48 (1H, t, J 8.23, Ar), 7.53 (1H, d, J 8.28, Ar),
8.27 (1H, d, J 7.33, Ar), 9.02 (1H, s, Ar) and 10.11 (1H, s,
NH).
[0452] 4: To a solution of (S)-methylpiperazine (400 mg) in
dichloromethane (20 mL) at 0.degree. C. was added di-tert-butyl
dicarbonate (871 mg). The reaction was stirred at room temperature
for 4 h and then quenched with water (20 mL) and extracted into
dichloromethane (2.times.40 mL). The combined organics were washed
with saturated aqueous brine solution (40 mL), dried (MgSO.sub.4)
and concentrated to give (S)-3-methyl-piperazine-1-carboxylic acid
tert-butyl ester as a white solid (669 mg, 84%).
[0453] To a solution of (S)-3-methyl-piperazine-1-carboxylic acid
(669 mg) and triethylamine (0.56 mL) in dichloromethane (10 mL) at
0.degree. C. was added dropwise methanesulfonyl chloride (0.28 mL).
The reaction mixture was stirred at room temperature for 16 h and
then quenched with water (10 mL) and extracted into dichloromethane
(2.times.20 mL). The combined organic layers were washed with
saturated aqueous brine solution (2.times.20 mL), dried
(MgSO.sub.4) and concentrated to give
(S)-4-methanesulfonyl-3-methyl-piperazine-1-carboxylic acid
tert-butyl ester as a pale yellow solid (924 mg, 99%).
[0454] To a solution of
(S)-4-methanesulfonyl-3-methyl-piperazine-1-carboxylic acid
tert-butyl ester (924 mg) in dichloromethane (20 mL) at 0.degree.
C. was added dropwise HCl (6.65 mL of a 2 M solution in diethyl
ether). The reaction mixture was stirred at room temperature for 2
h. The precipitate formed was then collected by filtration and
dried to afford (S)-1-methanesulfonyl-2-methyl-piperazine
hydrochloride salt as a white solid (583 mg, 82%).
[0455] Reaction between
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
and (S)-1-methanesulfonyl-2-methyl-piperazine hydrochloride salt
using procedure C yielded
2-chloro-6-((S)-4-methanesulfonyl-3-methyl-piperazin-1-ylmethyl)-4-morpho-
lin-4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to
procedure A to yield the desired final compound which was purified
using flash chromatography.
[0456] NMR: (400 MHz, CDCl3): 1.42 (3H, d, J 6.75, Me), 2.33 (1H,
td, J 11.42 and 3.45), 2.43 (1H, dd, J 3.62 and 11.23), 2.76 (1H,
d, J 11.17), 2.88 (3H, s, Me), 2.91 (1H, d, J 11.54), 3.34 (1H, td,
J 12.01 and 3.04), 3.59 (1H, d, J 12.81), 3.72-3.94 (6H, m, CH2),
4.08-4.12 (6H, m, CH2), 7.39 (1H, s, Ar), 7.51 (1H, t, J 8.19, Ar),
7.60 (1H, t, J 8.29, Ar), 8.25 (1H, d, J 6.96, Ar), 9.01 (1H, s,
Ar) and 10.12 (1H, s, NH).
[0457] [M+H]+ 528.26
[0458] The following compound was prepared in an analogous manner
using
2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde.
[0459] 96: (400 MHz, CDCl3): 1.34 (3H, d (J 6.77), CH3), 2.25-2.35
(2H, m, CH2), 2.70 (1H, d, CH), 2.80 (3H, s, CH3), 2.90 (1H, d,
CH), 3.25-3.30 (1H, m, CH), 3.42 (1H, d, CH), 3.55 (1H, m, CH),
3.67 (1H, d, CH), 3.76 (1H, d, CH), 3.86-3.93 (8H, m, CH2), 7.09
(1H, s, ar), 7.44-7.46 (1H, m, ar), 7.52 (1H, d, ar), 8.25 (1H, d
(J 7.56) ar), 8.96 (1H, s, ar), 10.00 (1H, b, NH)
[0460] (M+H)+ 528.24
[0461] 10: This compound was prepared in an analogous manner to the
compound above using (R)-methylpiperazine as the starting
material.
[0462] NMR: (400 MHz, CDCl3): 1.42 (3H, d, J 6.75, Me), 2.33 (1H,
td, J 11.42 and 3.45), 2.43 (1H, dd, J 3.62 and 11.23), 2.76 (1H,
d, J 11.17), 2.88 (3H, s, Me), 2.91 (1H, d, J 11.54), 3.34 (1H, td,
J 12.01 and 3.04), 3.59 (1H, d, J 12.81), 3.72-3.94 (6H, m, CH2),
4.08-4.12 (6H, m, CH2), 7.40 (1H, s, Ar), 7.51 (1H, t, J 8.22, Ar),
7.60 (1H, t, J 8.31, Ar), 8.27 (1H, d, J 6.79, Ar), 9.01 (1H, s,
Ar) and 10.20(1H, s, NH).
[0463] [M+H]+ 528.27
[0464] The following compound was prepared in an analogous manner
using
2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde.
[0465] 98: (M+H)+ 528.23
[0466] NMR: (400 MHz CDCl3): 1.25-1.28 (1H, m, CH), 1.42 (3H, d (J
6.71), CH3), 1.54 (1H, s, CH), 2.29-2.40 (2H, m, CH), 2.77 (1H, d
(J 11.1), CH), 2.87 (3H, s, CH3), 2.95 (1H, d (J 11.25), CH),
3.30-3.36 (1H, m, CH), 3.60 (1H, d, (J 12.75), CH), 3.72 (1H, d (J
14.18), CH), 3.85 (2H, d (J 14.13), CH2), 3.92-4.01 (8H, m, CH2),
4.12-4.13 (1H, m, CH), 7.16 (1H, s, ar), 7.51 (1H, t (J 7.75, ar),
7.60 (1H, d (J 8.29), ar), 8.32 (1H, d (J 7.29), ar), 9.04 (1H, s,
ar), 10.10 (1H, b, NH)
[0467] 8: To a solution of piperazine (1 g) and triethylamine (1.78
mL) in dichloromethane (20 mL) at 0.degree. C. was added dropwise
2-propanesulfonyl chloride (1.30 mL). The reaction mixture was
stirred at room temperature for 16 h and then quenched with water
(20 mL) and extracted into dichloromethane (2.times.40 mL). The
combined organic layers were washed with saturated aqueous brine
solution (2.times.40 mL), dried (MgSO.sub.4) and concentrated to
afford 1-(propane-2-sulfonyl)-piperazine as a white solid (1.87 g,
84%).
[0468] Reaction between
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
and 1-(propane-2-sulfonyl)-piperazine using procedure C yielded
2-chloro-4-morpholin-4-yl-6-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-
-thieno[3,2-d]pyrimidine. This compound was subjected to procedure
A to yield the desired final compound which was purified using
flash chromatography.
[0469] [M+H]+ 542.22
[0470] NMR: (400 MHz, CDCl3): 1.28 (6H, d, J 6.84, Me), 2.51-2.61
(4H, m, CH2), 3.13 (1H, septet, J 6.93, CH), 3.35-3.60 (4H, m,
CH2), 3.81 (2H, s, CH2), 3.83-3.90 (4H, m, CH2), 3.96-4.04 (4H, m,
CH2), 7.32 (1H, s, Ar), 7.40 (1H, t, J 8.20, Ar), 7.48 (1H, d, J
8.22, Ar), 8.20 (1H, d, J 7.32, Ar), 8.92 (1H, s, Ar) and 10.26
(1H, s, Ar).
[0471] The following compound was prepared in an analogous manner
using
2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde.
[0472] 97: NMR: (400 MHz, CDCl3): 1.24 (1H, m, CH), 1.36 (6H, d (J
6.84), CH3), 2.62 (4H, m, CH2), 3.44-3.49 (4H, m, CH2), 3.82 (2H,
s, CH2), 3.93-4.00 (8H, m, CH2), 7.17 (1H, s, ar), 7.51-7.53 (1H,
m, ar), 7.59 (1H, m, ar), 8.32 (1H, d (J 6.69), ar), 9.04 (1H, s,
ar), 10.05 (1H, b, NH)
[0473] (M+H)+ 542.24
[0474] 7: To a solution of cis-2,6-dimethyl-piperazine (600 mg) and
triethylamine (0.80 mL) in dichloromethane (10 mL) at 0.degree. C.
was added dropwise methanesulfonyl chloride (0.43 mL). The reaction
mixture was stirred at room temperature for 16 h and then quenched
with water (10 mL) and extracted into dichloromethane (2.times.20
mL). The combined organic layers were washed with saturated aqueous
brine solution (2.times.20 mL), dried (MgSO.sub.4) and concentrated
to afford (3S,5R)-1-methanesulfonyl-3,5-dimethyl-piperazine as a
white solid (817 mg, 81%).
[0475] Reaction between
6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine and
(3S,5R)-1-methanesulfonyl-3,5-dimethyl-piperazine using potassium
carbonate and acetonitrile yielded
2-chloro-6-((2S,6R)-4-methanesulfonyl-2,6-dimethyl-piperazin-1-ylmethyl)--
4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This compound was
subjected to procedure A to yield the desired final compound which
was purified using flash chromatography.
[0476] [M+H]+ 542.24
[0477] NMR: (400 MHz, CDCl3): 1.18 (6H, d, J 6.90, Me), 2.48-2.52
(2H, m, CH2), 2.72 (3H, s, SO2Me), 2.78-2.88 (2H, m, CH2),
3.51-3.56 (2H, m, CH2), 3.81-3.88 (4H, m, CH2), 3.96-4.02 (4H, m,
CH2), 4.12 (2H, s, CH2), 7.28 (1H, s, Ar), 7.42 (1H, t, J 8.22,
Ar), 7.49 (1H, d, J 8.31, Ar), 8.20 (1H, d, J 7.26, Ar) 8.94 (1H,
s, Ar) and 10.08 (1H, s, NH).
[0478] The following compound was prepared in an analogous manner
using
2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde.
[0479] 102: NMR: (400 Mhz, CDCl3): 1.19-1.24 (6H, m, CH3), 2.61
(2H, t (J 10.72), CH2), 2.80 (3H, s, CH3), 2.88-2.90 (2H, m, CH2),
3.59 (2H, d (J 10.46), CH2), 3.93-4.00 (8H, m, CH2) 4.14 (2H, s,
CH2), 7.12 (1H, s, ar), 7.51 (1H, t (J 7.80), ar), 7.60 (1H, d (J
8.29), ar), 8.32 (1H, d (J 6.73), ar), 9.04 (1H, s, ar), 10.10 (1H,
b, NH)
[0480] 6: Reaction between
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
and cis-2,6-dimethyl-piperazine using procedure C yielded
2-chloro-6-((3R,5S)-3,5-dimethyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-t-
hieno[3,2-d]pyrimidine. This compound treated with methane
sulphonyl chloride using standard conditions to yield
2-chloro-6-((3R,5S)-4-methanesulfonyl-3,5-dimethyl-piperazin-1-ylmethyl)--
4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This compound was
subjected to procedure A to yield the desired final compound which
was purified using flash chromatography.
[0481] [M+H]+ 542.25
[0482] (400 MHz, CDCl3): 1.52 (6H, d, J 6.93, Me), 2.33 (2H, dd, J
11.37 and 4.34, CH2), 2.81 (2H, d, J 11.15, CH2), 2.89 (3H, s,
SO2Me), 3.86 (2H, s, CH2), 3.88-3.94 (4H, m, CH2), 4.05-4.13 (6H,
m, CH2), 7.40 (1H, s, Ar), 7.51 (1H, t, J 8.20, Ar), 7.58 (1H, d, J
8.29, Ar), 8.27 (1H, d, J 7.32, Ar), 9.02 (1H, s, Ar) and 10.14
(1H, s, Ar).
[0483] 92: To 1-BOC-homopiperizine (0.8 ml) was added methane
sulphonyl chloride (0.34 ml) and triethylamine (0.68 ml). The
reaction mixture was stirred at room temperature for 4 hours. The
reaction mixture was then partitioned between dichloromethane and
water. The combined organic extracts were then washed with brine
and dried (MgSO.sub.4). The solvent was removed in vacuo to yield
1.23 g crude 4-methanesulfonyl-[1,4]diazepane-1-carboxylic acid
tert-butyl ester.
[0484] Crude 4-Methanesulfonyl-[1,4]diazepane-1-carboxylic acid
tert-butyl ester (1.23 g) was stirred in anhydrous methanol (10
ml). 2M hydrogen chloride in ether (22 ml) was added. The reaction
mixture was stirred at room temperature. After 5 minutes a
precipitate formed, addition of anhydrous methanol (5 ml) caused
this to dissolve. The reaction mixture was stirred overnight at
room temperature. The solvents were removed in vacuo to yield 1.06
g of 1-methanesulfonyl-[1,4]diazepane hydrochloride salt.
[0485] Reaction between
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
and 1-methanesulfonyl-[1,4]diazepane hydrochloride salt using
procedure C yielded
2-chloro-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morphol-
in-4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to
procedure A to yield the desired final compound which was purified
using flash chromatography.
[0486] NMR: (400 MHz, CDCl3): 1.26 (3H, s, CH3), 1.96 (2H, m, CH2),
2.86-2.88 (4H, m, CH2), 3.49-3.52 (4H, m, CH2), 3.92-3.94 (4H, m,
CH2), 4.03 (2H, s, CH2), 4.08-4.11 (4H, m, CH2), 7.38 (1H, s, ar),
7.51-7.53 (1H, m, ar), 7.58 (1H, d, ar), 8.28 (1H, d, J (7.41),
ar), 9.02 s, ar), 10.05 (1H, b, NH) (M+H)+ 528.23
[0487] 94: To a mixture of isobutyraldehyde (9.5 mL) and dioxane
(0.38 mL) in diethyl ether (40 mL) at room temperature was added
bromine (0.11 mL). The reaction mixture was cooled to 0.degree. C.
and bromine (5.1 mL) was added dropwise. The reaction mixture was
stirred for 10 min and then poured into ice water (250 mL). Sodium
carbonate (6 g) was added gradually to the mixture with vigorous
stirring. Then, the organic phase was separated, dried (MgSO.sub.4)
and distilled using Kugelrohr apparatus to give
2-bromo-2-methyl-propionaldehyde as a colourless oil (3.794 g).
[0488] To a solution of ethylene diamine (8.40 mL) in toluene (20
mL) at 0.degree. C. was added 2-bromo-2-methyl-propionaldehyde
(3.794 g). The reaction mixture was stirred vigorously at room
temperature for 1 h and then at reflux for 30 min. After cooling to
room temperature the two phases were separated and the lower phase
was extracted with toluene (2.times.30 mL). The toluene phase was
then concentrated and distilled using Kugelrhor apparatus to give
6,6-dimethyl-1,2,3,6-tetrahydro-pyrazine (1.56 g).
[0489] To a solution of 6,6-dimethyl-1,2,3,6-tetrahydro-pyrazine
(1.56 g) in ethanol (100 mL) was added Pd/C (300 mg). The reaction
mixture was stirred for 16 h with a hydrogen balloon. The mixture
was then filtered through Celite and the filtrate concentrated and
distilled using kugelrohr apparatus to afford
2,2-dimethyl-piperazine as a colourless oil which solidified on
standing (1.23 g).
[0490] To a solution of 2,2-dimethypiperazine (400 mg) and
triethylamine (0.59 mL) in dichloromethane (10 mL) at 0.degree. C.
was added dropwise methanesulfonyl chloride (0.30 mL). The reaction
mixture was stirred at room temperature for 16 h and then quenched
with water (10 mL) and extracted into dichloromethane (2.times.20
mL). The combined organic layers were washed with saturated aqueous
brine solution (2.times.20 mL), dried (MgSO.sub.4) and concentrated
to afford 1-methanesulfonyl-3,3-dimethyl-piperazine as a white
solid (412 mg, 61%).
[0491] Reaction between
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
and 1-methanesulfonyl-3,3-dimethyl-piperazine using procedure C
yielded
2-chloro-6-(4-methanesulfonyl-2,2-dimethyl-piperazin-1-ylmethyl)-4-morpho-
lin-4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to
procedure A to yield the desired final compound which was purified
using flash chromatography.
[0492] (400 MHz, CDCl3): 1.15 (6H, s, Me), 2.62-2.68 (2H, m, CH2),
2.72 (3H, s, Me), 2.95 (2H, s, CH2), 3.12-3.18 (2H, m, CH2),
3.81-3.90 (6H, m, CH2), 3.98-4.04 (4H, m, CH2), 7.32 (1H, s, Ar),
7.42 (1H, t, J 8.22, Ar), 7.50 (1H, d, J 8.23, Ar), 8.20 (1H, d, J
7.18, Ar), 8.92 (1H, s, Ar) and 9.98 (1H, s, NH).
[0493] [M+H]+ 542.25
[0494] 100: To a solution of 2,2-dimethypiperazine (400 mg) in
dichloromethane (20 mL) at 0.degree. C. was added di-tert-butyl
dicarbonate (766 mg). The reaction was stirred at room temperature
for 4 h and then quenched with water (20 mL) and extracted into
dichloromethane (2.times.40 mL). The combined organics were washed
with saturated aqueous brine solution (40 mL), dried (MgSO.sub.4)
and concentrated to give 3,3-diemethyl-piperazine-1-carboxylic acid
tert-butyl ester as a white solid (720 mg, 96%).
[0495] To a solution of 3,3-diemethyl-piperazine-1-carboxylic acid
tert-butyl ester (720 mg) and triethylamine (0.59 mL) in
dichloromethane (10 mL) at 0.degree. C. was added dropwise
methanesulfonyl chloride (0.30 mL). The reaction mixture was
stirred at room temperature for 16 h and then quenched with water
(10 mL) and extracted into dichloromethane (2.times.20 mL). The
combined organic layers were washed with saturated aqueous brine
solution (2.times.20 mL), dried (MgSO.sub.4) and concentrated to
give 4-methanesulfonyl-3,3-dimethyl-piperazine-1-carboxylic acid
tert-butyl ester as a white solid (914 mg, 93%).
[0496] To a solution of
4-methanesulfonyl-3,3-dimethyl-piperazine-1-carboxylic acid
tert-butyl ester (914 mg) in dichloromethane (20 mL) at 0.degree.
C. was added dropwise HCl (6.65 mL of a 2 M solution in diethyl
ether). The reaction mixture was stirred at room temperature for 2
h. The precipitate formed was then collected by filtration and
dried to afford 1-methanesulfonyl-2,2-dimethyl-piperazine
hydrochloride salt as a white solid (540 mg, 75%).
[0497] Reaction between
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
and 1-methanesulfonyl-2,2-dimethyl-piperazine hydrochloride salt
using procedure C yielded
2-chloro-6-(4-methanesulfonyl-3,3-dimethyl-piperazin-1-ylmethyl)-4-morpho-
lin-4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to
procedure A to yield the desired final compound which was purified
using flash chromatography.
[0498] (400 MHz, CDCl3): 1.49 (6H, s, Me), 2.28 (2H, s, CH2),
2.55-2.58 (2H, m, CH2), 2.88 (3H, s, Me), 3.44-3.48 (2H, m, CH2),
3.76 (2H, s, CH2), 3.82-3.89 (4H, m, CH2), 4.01-4.08 (4H, m, CH2),
7.29 (1H, s, Ar), 7.41 (1H, t, J 8.22, Ar), 7.52 (1H, d, J 8.24,
Ar), 8.20 (1H, d, J 7.21, Ar), 8.96 (1H, s, Ar) and 10.02 (1H, s,
NH).
[0499] [M+H]+ 542.27
[0500] 29: Reaction between N-BOC-piperazine and methane sulfonyl
chloride in dichloromethane and triethylamine yielded
4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester.
Cleavage of the BOC protecting group using HCl (2M) in
dichloromethane yielded 1-methanesulfonyl-piperazine. HCl salt.
[0501] Reaction between 1-methanesulfonyl-piperazine. HCL salt and
2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
using procedure C yielded
2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-7-methyl-4-morpholin--
4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to
procedure A to yield the desired final compound which was purified
using flash chromatography.
[0502] NMR: (CDCl3): 2.55 (3H, s), 2.71-2.75 (4H, m), 2.82 (3H, s),
3.30-3.33 (4H, m), 3.89 (2H, s), 3.90-3.93 (4H, m), 4.06-4.10 (4H,
m), 7.51-7.54 (1H, m), 7.60 (1H, d, J=8.3), 8.37 (1H, d, J=6.8),
9.18 (1H, s), 10.05 (1H, br)
[0503] (ESI+): MH+ 528 (100%)
[0504] 31: Reaction between 1-methylpiperazine and
2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde
using Procedure C yielded
2-chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]-
pyrimidine. This compound was subjected to procedure A to yield the
desired final compound which was purified using flash
chromatography.
[0505] 400 MHz 1H NMR CDCl3
[0506] 2.31 (s, 3H, CH3), 2.50 (m, 4H, 2.times.CH2), 2.60 (m, 4H,
2.times.CH2), 3.78 (s, 2H, CH2), 3.91-3.94 (m, 4H, 2.times.CH2),
3.98-4.00 (m, 4H, 2.times.CH2), 7.16 (s, H, ArH), 7.50 (t, H, ArH,
J=7.39 Hz), 7.58 (d, H, ArH, J=8.29 Hz), 8.32 (d, H, ArH, J=7.37
Hz), 9.03 (s, H, ArH), 10.15 (sbr, H, NH).
[0507] MH+=450.18
[0508] 57:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-
-4-yl-thieno[2,3-d]pyrimidine (see intermediates) was subjected to
procedure A. The final compound was purified using flash
chromatography.
[0509] 400 MHz 1H NMR CDCl3
[0510] 2.67 (m, 4H, 2.times.CH2), 2.81 (s, 3H, CH3), 3.30 (m, 4H,
2.times.CH2), 3.83 (s, 2H, CH2), 3.92-3.94 (m, 4H, 2.times.CH2),
3.98-4.00 (m, 4H, 2.times.CH2), 7.17 (s, H, ArH), 7.50 (t, H, ArH,
J=7.81 Hz), 7.59 (d, H, ArH, J=8.31 Hz), 8.31 (d, H, ArH, J=6.98
Hz), 10.12 (sbr, H, NH). MH+=514.10
[0511] 43: To a solution of N-BOC-piperazine (1.06 g) in
CH.sub.2Cl.sub.2/MeOH (20 mL) at 0.degree. C. was added 2M HCl in
ether (3.14 mL). After 1 h the solvent was removed in vacuo to give
a white solid. This was dissolved in water and NaCN was added (280
mg). To this mixture was added a solution of acetone (4204) in
water (2 mL). The resultant was stirred at room temperature for 72
h then diluted with water and extracted with ethyl acetate.
Combined extracts were dried (Na.sub.2SO.sub.4), filtered and
concentrated to give
4-(cyano-dimethyl-methyl)-piperazine-1-carboxylic acid tert-butyl
ester (77%).
[0512] To a solution of
4-(cyano-dimethyl-methyl)-piperazine-1-carboxylic acid tert-butyl
ester (1 g) and K.sub.2CO.sub.3 (100 mg) in dry DMSO (20 mL) at
0.degree. C. was added a 27.5% hydrogen peroxide (2 mL) dropwise.
The resulting mixture was heated at 40.degree. C. overnight then
diluted with water give a solid. This was collected, washed and
dried to give
4-(1-carbamoyl-1-methyl-ethyl)-piperazine-1-carboxylic acid
tert-butyl ester (806 mg). Subsequent treatment with 2M HCl in
ether gave 2-piperazin-1-yl-isobutyramide dihydrochloride
(100%).
[0513] Reductive amination of
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
with 2-piperazin-1-yl-isobutyramide dihydrochloride according
General Procedure C gave
2-[4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-pipera-
zin-1-yl]isobutyramideafter purification on silica.
[0514]
2-[4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)--
piperazin-1-yl]-isobutyramide was reacted with
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in
General Procedure A. Purification on silica yielded the desired
compound.
[0515] NMR: (CDCl.sub.3): 1.24 (s, 6H, 2.times.CH2), 2.55-2.65 (m,
8H, 4.times.CH2), 3.85 (s, 2H, CH2), 3.90-3.92 (m, 4H,
2.times.CH2), 4.07-4.09 (m, 4H, 2.times.CH2), 5.35 (m, H, NH), 7.09
(m, H, NH), 7.37 (s, H, ArH), 7.48 (t. H, ArH, J=7.72 Hz), 7.57 (d,
H, ArH, J=8.22 Hz), 8.26 (d, H, ArH, J=7.14 Hz), 9.0 (s, H, ArH0,
10.4 (sbr, H, NH).
[0516] MS: (ESI+): MH+=521.27
[0517] 44: To a solution of piperidone (317 mg) and potassium
carbonate (530 mg) in acetonitrile at room temperature (20 mL) was
added 2-bromoethyl methyl ether (0.48 mL). The reaction mixture was
heated at reflux for 16 h, allowed to cool to room temperature and
then reduced in vacuo. The residue was then redissolved in
dichloromethane (20 mL) and washed with water (20 mL) and brine (20
mL), dried (MgSO.sub.4) and reduced in vacuo to give
1-(2-methoxy-ethyl)-piperidin-4-one as colourless oil (171 mg).
[0518] To a suspension of
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
(1.0 g) and molecular sieves in methanol (20 mL) at room
temperature was added acetic acid (0.1 mL) and a solution of
methylamine (219 mg) in methanol (1 ml). The reaction mixture was
stirred at room temperature for 24 h. Then sodium borohydride (542
mg) was added portionwise and the reaction stirred at room
temperature for a further 30 min. The reaction was then quenched
with saturated aqueous sodium hydrogen carbonate solution (10 mL)
and extracted into dichloromethane (2.times.10 mL). The combined
organics were washed with brine (20 mL), dried (MgSO4) and reduced
in vacuo to give
(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amin-
e as a white solid (0.95 g).
[0519]
(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methy-
l-amine was then reacted with 1-(2-methoxy-ethyl)-piperidin-4-one
in general procedure C. Purification on silica yielded
(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-[1-(2-metho-
xy-ethyl)-piperidin-4-yl]-methyl-amine.
[0520]
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-[1-(2-
-methoxy-ethyl)-piperidin-4-yl]-methyl-amine was then reacted with
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in
general procedure A. Purification on silica yielded the title
compound.
[0521] NMR: DMSO: 13.15 (bs, 1H); 8.86 (s, 1H); 8.21 (d, 1H, J=7.3
Hz); 7.65 (d, 1H, J=8.2 Hz); 7.45 (m, 2H); 3.99 (m, 4H); 3.94 (s,
2H); 3.82 (m, 4H); 3.38 (m, 2H); 3.22 (s, 3H); 2.94 (m, 2H); 2.49
(m, 2H); 2.48 (m, 1H); 2.22 (s, 3H); 1.94 (m, 2H); 1.74 (m, 2H);
1.35 (m, 2H).
[0522] 32: Hydrogen chloride gas (4 g) was bubbled through methanol
(120 mL) at 0.degree. C. Proline (3.80 g) was then added and the
mixture was stirred at room temperature for 4.5 h and then reduced
in vacuo to give pyrrolidine-2-carboxylic acid methyl ester
hydrochloride salt as a white solid (5.5 g).
[0523] To a suspension of pyrrolidine-2-carboxylic acid methyl
ester hydrochloride salt (5.5 g) in acetonitrile (90 mL) was added
triethylamine (10.2 mL) and di-tert-butyldicarbonate (8.0 g). The
reaction mixture was stirred at room temperature for 16 h and then
reduced in vacuo. The residue was redissolved in dichloromethane
(40 mL) and washed with brine (40 mL), dried (MgSO4), reduced in
vacuo and purified by column chromatography to give
pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
as a yellow oil (6.33 g).
[0524] To a solution of pyrrolidine-1,2-dicarboxylic acid
1-tert-butyl ester 2-methyl ester (3.5 g) in toluene (40 mL) at
-78.degree. C. was added dropwise diisobutylaluminium hydride (20
mL of a 1.5 M solution in toluene) maintaining the temperature
below -65.degree. C. The reaction mixture was stirred at
-78.degree. C. for 2 h and then quenched with methanol (10 mL). The
mixture was then diluted with diethyl ether (50 mL), potassium
sodium tartrate tetrahydrate was added and the mixture stirred
vigorously for 20 min at room temperature. The two phases were then
separated and the aqueous layer extracted with dichloromethane
(2.times.50 mL). The combined organics were then washed with brine
(100 mL), dried (MgSO.sub.4), reduced in vacuo and purified by
column chromatography to give 2-formyl-pyrrolidine-1-carboxylic
acid tert-butyl ester as a pale yellow oil (2.687 g).
[0525] To a suspension of 2-formyl-pyrrolidine-1-carboxylic acid
tert-butyl ester (2.68 g) in methanol (30 mL) at room temperature
was added a solution of methylamine (831 mg) in methanol (3 mL).
The reaction mixture was stirred at room temperature for 72 h and
then sodium borohydride (760 mg) and molecular sieves were added.
After stirring at room temperature for 2 h, the reaction mixture
was filtered and the filtrate reduced in vacuo. The residue was
redissolved in dichloromethane (30 mL) and washed with saturated
sodium bicarbonate solution (30 mL). The combined organics were
washed with brine (30 mL), dried (MgSO.sub.4) and reduced in vacuo
to give 2-methylaminomethyl-pyrrolidine-1-carboxylic acid
tert-butyl ester as a pale yellow oil (2.56 g).
[0526] To a solution of
2-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(500 mg) in dichloromethane (10 mL) at room temperature was added
triethylamine (0.36 mL) and methanesulphonyl chloride (0.20 mL).
The reaction mixture was stirred at room temperature for 4 h and
then partitioned between dichloromethane (20 mL) and saturated
aqueous sodium bicarbonate solution (30 mL). The combined organics
were washed with brine (30 mL), dried (MgSO.sub.4), reduced in
vacuo and purified by column chromatography to give
2-[(methanesulfonyl-methyl-amino)-methyl]-pyrrolidine-1-carboxylic
acid tert-butyl ester as a white solid (0.63 g).
[0527] To a solution of
2-[(methanesulfonyl-methyl-amino)-methyl]-pyrrolidine-1-carboxylic
acid tert-butyl ester (0.63 g) in dichloromethane (10 mL) at room
temperature was added hydrogen chloride (3.0 mL of a 2 M solution
in diethyl ether). The reaction mixture was stirred at room
temperature for 72 h and then reduced in vacuo to give
N-methyl-N-pyrrolidin-2-ylmethyl-methanesulfonamide as a
crystalline solid (0.49 g).
[0528] To a mixture of
6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine
(0.50 g) and N-methyl-N-pyrrolidin-2-ylmethyl-methanesulfonamide
(390 mg) in acetonitrile (10 mL) was added potassium carbonate (490
mg). The reaction mixture was heated at 80.degree. C. for 16 h and
then allowed to cool to room temperature. The reaction mixture was
then partitioned between dichloromethane (20 mL) and saturated
aqueous sodium bicarbonate solution (20 mL). The combined organics
were washed with brine (30 mL), dried (MgSO.sub.4), reduced in
vacuo and purified by column chromatography to give
N-[1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-p-
yrrolidin-2-ylmethyl]-N-methyl-methanesulfonamide as a pale yellow
solid (580 mg).
[0529]
N-[1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)--
pyrrolidin-2-ylmethyl]-N-methyl-methanesulfonamide was reacted with
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in
general procedure A. Purification on silica yielded the title
compound.
[0530] NMR: CDCl.sub.3: 1.80 (3H, m); 2.02 (1H, m); 2.40 (1H, m);
2.80 (3H, s); 2.97 (4H, m); 3.18 (3H, m); 3.90 (4H, m); 4.10 (4H,
t, J=4.7 Hz); 4.30 (1H, d, J=14.6 Hz); 7.37 (1H, s); 7.50 1H, t,
J=7.7 Hz); 7.58 (1H, d, J=8.2 Hz); 8.28 (1H, d, J=7.1 Hz); 9.02
(1H, s); 10.00 (1H, br s).
[0531] MS: (ESI+): MH+ 542
[0532] 42: To a solution of tetrahydrothiopyran-4-one (400 mg)
stirring in acetonitrile (5 ml) and Na2.EDTA (0.0004 M aq, 3 ml)
was added potassium peroxymonosulphate (Oxone.TM., 6.34 g) and
NaHCO3 (2.69 g) in several aliquots over 30 minutes. The reaction
mixture was stirred at room temperature for a further 2 hours, then
diluted with water (40 ml), extracted into dichloromethane, and
dried (MgSO4) to give 1,1-dioxo-tetrahydro-thiopyran-4-one (330 mg)
as a white solid. To this compound (75 mg) stirring in anhydrous
1,2-dichloroethane (6 ml) was added
2-chloro-4-morpholin-4-yl-thienopyrimidine-6-yl methyl methylamine
(150 mg, as previously prepared from
2-chloro-4-morpholin-4-yl-thienopyrimidine-6-carbaldehyde and
methylamine under reductive amination conditions), followed by
glacial acetic acid (31 .mu.l) and sodium triacetoxy borohydride
(138 mg). The reaction mixture was stirred for 24 hours at room
temperature, and the product isolated by extraction into
dichloromethane, followed by purification by flash chromatography
to give
(2-chloro-4-morpholin-4-yl-thienopyrimidine-6-ylmethyl)-(1,1-dioxo-hexahy-
dro-thiopyran-4-yl)-methyl-amine (115 mg) as a yellow solid, which
was used in a Suzuki coupling with
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole, to
give, after flash silica purification the title compound (38 mg) as
a white solid.
[0533] 1H NMR 400 MHz DMSO
[0534] 13.18 (bs, 1H); 8.87 (s, 1H); 8.21 (d, 1H, J=7.2 Hz); 7.65
(d, 1H, J=8.2 Hz) 7.45 (m, 2H); 3.98 (m, 6H) 3.82 (m, 4H);
3.26-3.06 (m, CH2.times.2)
[0535] 2.91 (m, 1H); 2.28 (s, 3H); 2.04 (m, CH2.times.2)
[0536] M/S ESI (m+1)=513.1
[0537] LC>/95% purity
[0538] 34: To a solution of 1-methanesulphonyl-piperidine-4-one
(182 mg; prepared from N-BOC-piperidone by reaction of
piperidone-4-one TFA salt with methane sulphonyl chloride),
stirring in anhydrous 1,2-dichloroethane (6 ml) was added
2-methoxyethylamine (90 .mu.l) followed by glacial acetic acid (62
.mu.l). Sodium triacetoxy borohydride (284 mg), was added in
aliquots over 30 minutes and the reaction mixture stirred for 12
hours at room temperature, then diluted with dichloromethane (40
ml), washed with 50% NaHCO3 solution and dried (MgSO4). The
solvents were removed in vacuo to give a residue which was purified
by silica flash chromatography to give
1-methanesulphonyl-piperidin-4-yl-2-methoxy-ethylamine (148 mg), as
a white solid.
[0539] To a solution of
1-methanesulphonyl-piperidin-4-yl-2-methoxy-ethylamine (146 mg),
stirring in 1,2-dichloroethane (10 ml), was added
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
(176 mg), followed by glacial acetic acid (38 .mu.l), and sodium
triacetoxy borohydride (171 mg). The reaction mixture was stirred
for 12 hours at room temperature. The product was isolated by
extraction into dichloromethane, followed by purification by flash
silica chromatography, to give
(2-chloro-4-morpholino-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-
-methanesulphonyl-piperidin-4-yl)-(2-methoxyethylamine), (103 mg)
as a white solid, which was used in a Suzuki coupling with
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole, to
give, after flash silica purification the title compound (72 mg) as
a white solid.
[0540] 1H NMR 400 MHz d6 DMSO
[0541] 13.15 (bs, 1H); 8.87 (s, 1H); 8.21 (d, 1H, J=8.3 Hz)
[0542] 7.65 (d, 1H, J=8.3 Hz); 7.46 (t, 1H); 4.08 (s, 2H)
[0543] 4.01 (m, 4H+CH2); 3.83 (m, 4H); 3.60 (m, 2H); 3.22 (s,
3H);
[0544] 2.81 (s, 3H); 2.75 (m, CH2.times.2); 2.67 (m, CH); 1.86 (m,
CH2)
[0545] LC-MS
[0546] (m+1) 586.2
[0547] Purity>/95%
[0548] 30: To a solution of 4-(2-aminoethyl)-morpholine (600 mg)
stirring in anhydrous 1,2-dichloroethane (40 ml), was added
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
(1.31 g), followed by glacial acetic acid (277 .mu.l) and sodium
triacetoxy borohydride (1.27 g) added in several aliquots over 30
minutes. The reaction mixture was stirred for 12 hours at room
temperature, then diluted with chloroform (50 ml), washed with 50%
NaHCO3 solution and dried (MgSO4). The solvents were removed in
vacuo to give a residue which was purified by flash silica
chromatography to give
(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-ylmethyl)-(2-morphol-
in-4-yl-ethyl)-amine (398 mg), as a white solid.
[0549] To this compound (172 mg), stirring in anhydrous
1,2-dichloroethane (8 ml), was added
1-methanesulphonyl-piperidine-4-one, (77 mg; prepared from
N-BOC-piperidone by reaction of piperidone-4-one TFA salt with
methane sulphonyl chloride), followed by glacial acetic acid (26
.mu.l), and sodium triacetoxy borohydride (129 mg). The reaction
mixture was stirred for 12 hours at room temperature and then
diluted with chloroform (30 ml), washed with 50% NaHCO3 solution
and dried (MgSO4). The solvents were removed in vacuo to give a
residue which was purified by silica flash chromatography to give
(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-methanes-
ulphonyl-piperidine-4-yl)-(2-morpholin-4-yl-ethyl)-amine, (123 mg)
as an off-white solid, which was used in a Suzuki coupling with
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole, to
give, after flash silica purification the title compound (6 mg) as
a white solid.
[0550] 1H NMR 400 MHz DMSO
[0551] 13.15 (bs, 1H); 8.87 (s, 1H); 8.30 (s, 1H); 8.21 (d, 1H,
J=6.9 Hz);
[0552] 7.65 (d, 1H, J=8.2 Hz); 7.46 (m, 1H); 4.02 (m, 4H+CH2), 3.83
(m, 4H);
[0553] 3.61 (m, CH2.times.2); 3.53 (m, CH2.times.2); 2.81 (s, 3H);
2.68 (m, CH2.times.2);
[0554] 2.40 (m, CH+CH2.times.2); 1.86 (m, CH2); 1.56 (m, CH2).
[0555] 71: To a solution of 1-methyl-piperidone (1.00 g) in
1,2-dichloroethane (20 ml) was added 2-methoxyethylamine (0.77 ml),
followed by sodium triacetoxyborohydride (2.62 g) and acetic acid
(0.53 g). The reaction mixture was stirred at room temperature
overnight. Dichloromethane/aqueous sodium hydrogen carbonate
extraction and purification on silica gave
(2-methoxy-ethyl)-(1-methyl-piperidin-4-yl)-amine (1.52 g).
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
(150 mg) and (2-methoxy-ethyl)-(1-methyl-piperidin-4-yl)-amine (128
mg) were stirred together in 1,2-dichloroethane (8 ml) and acetic
acid (32 mg) with sodium triacetoxyborohydride (146 mg) at room
temperature overnight. Dichloromethane/aqueous sodium hydrogen
carbonate extraction and purification on silica yielded
(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(2-methoxy--
ethyl)-(1-methyl-piperidin-4-yl)-amine (97 mg).
(96 mg), 4-indazole-boronate ester (107 mg), sodium carbonate (70
mg) and PdCl.sub.2(PPh.sub.3).sub.2 (8 mg) in toluene (2 ml),
ethanol (1 ml) and water (0.5 ml) were heated in a microwave at
120.degree. C. for 60 min. Dichloromethane/water extraction and
purification on silica gave the title compound (64 mg).
[0556] NMR: (DMSO) 13.15 (bs, 1H); 8.86 (s, 1H); 8.21 (d, 1H, J=7.0
Hz); 7.65 (d, 1H, J=8.0 Hz); 7.45 (t, 2H, J=7.7 Hz); 4.05 (s, 2H);
3.99 (m, CH2.times.2); 3.82 (m, CH2.times.2); 3.39 (m, 2H); 3.21
(s, 3H); 2.79 (m, 2H); 2.73 (m, 2H); 2.49 (m, 1H); 2.12 (s, 3H);
1.89-1.49 (m, CH2.times.3)
[0557] MS: MH+=522.31
[0558] 59: Hydrogen chloride gas (4 g) was bubbled through methanol
(120 mL) at 0.degree. C. Proline (3.80 g) was then added and the
mixture was stirred at room temperature for 4.5 h and then reduced
in vacuo to give pyrrolidine-2-carboxylic acid methyl ester
hydrochloride salt as a white solid (5.5 g).
[0559] To a suspension of pyrrolidine-2-carboxylic acid methyl
ester hydrochloride salt (5.5 g) in acetonitrile (90 mL) was added
triethylamine (10.2 mL) and di-tert-butyldicarbonate (8.0 g). The
reaction mixture was stirred at room temperature for 16 h and then
reduced in vacuo. The residue was redissolved in dichloromethane
(40 mL) and washed with brine (40 mL), dried (MgSO.sub.4), reduced
in vacuo and purified by column chromatography to give
pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
as a yellow oil (6.33 g).
[0560] To a solution of pyrrolidine-1,2-dicarboxylic acid
1-tert-butyl ester 2-methyl ester (3.5 g) in toluene (40 mL) at
-78.degree. C. was added dropwise diisobutylaluminium hydride (20
mL of a 1.5 M solution in toluene) maintaining the temperature
below -65.degree. C. The reaction mixture was stirred at
-78.degree. C. for 2 h and then quenched with methanol (10 mL). The
mixture was then diluted with diethyl ether (50 mL), potassium
sodium tartrate tetrahydrate was added and the mixture stirred
vigorously for 20 min at room temperature. The two phases were then
separated and the aqueous layer extracted with dichloromethane
(2.times.50 mL). The combined organics were then washed with brine
(100 mL), dried (MgSO.sub.4), reduced in vacuo and purified by
column chromatography to give 2-formyl-pyrrolidine-1-carboxylic
acid tert-butyl ester as a pale yellow oil (2.687 g).
[0561] To a suspension of 2-formyl-pyrrolidine-1-carboxylic acid
tert-butyl ester (2.68 g) in methanol (30 mL) at room temperature
was added a solution of methylamine (831 mg) in methanol (3 mL).
The reaction mixture was stirred at room temperature for 72 h and
then sodium borohydride (760 mg) and molecular sieves were added.
After stirring at room temperature for 2 h, the reaction mixture
was filtered and the filtrate reduced in vacuo. The residue was
redissolved in dichloromethane (30 mL) and washed with saturated
sodium bicarbonate solution (30 mL). The combined organics were
washed with brine (30 mL), dried (MgSO.sub.4) and reduced in vacuo
to give 2-methylaminomethyl-pyrrolidine-1-carboxylic acid
tert-butyl ester as a pale yellow oil (2.56 g).
To a solution of
6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine
(420 mg) and 2-methylaminomethyl-pyrrolidine-1-carboxylic acid
tert-butyl ester (310 mg) in acetonitrile (10 mL) was added
potassium carbonate (250 mg). The reaction mixture was heated at
80.degree. C. for 4 h and then allowed to cool to room temperature.
The mixture was then partitioned between dichloromethane (20 mL)
and saturated aqueous sodium bicarbonate solution (20 mL) and the
organic layer washed with brine (20 mL), dried (MgSO4), reduced in
vacuo and purified on column chromatography to give
2-{[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl--
amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester as a
white solid (487 mg).
[0562] To a solution of
2-{[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl--
amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (480
mg) in dichloromethane (10 mL) was added hydrogen chloride (3 mL of
a 2.0 M solution in diethyl ether). The mixture was stirred at room
temperature for 16 h and then reduced in vacuo to give
(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-pyrr-
olidin-2-ylmethyl-amine hydrochloride salt as a yellow solid (380
mg).
To a stirring solution of
(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-pyrr-
olidin-2-ylmethyl-amine hydrochloride salt (380 mg) in
dichloromethane (10 mL) was added triethylamine (0.30 mL) and
methane sulfonyl chloride (71 .mu.L). The mixture was stirred at
room temperature for 2 h and then partitioned between
dichloromethane (20 mL) and saturated aqueous sodium bicarbonate
solution (20 mL). The organics were washed with brine (20 mL),
dried, reduced in vacuo and purified by column chromatography to
give
(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-met-
hanesulfonyl-pyrrolidin-2-ylmethyl)-methyl-amine as an off-white
solid (124 mg).
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(-
1-methanesulfonyl-pyrrolidin-2-ylmethyl)-methyl-amine was reacted
with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole
in general procedure A. Purification on silica yielded the title
compound.
[0563] NMR: CDCl.sub.3: 1.88-1.96 (2H, m); 1.99-2.03 (1H, m);
2.04-2.12 (1H, m); 2.40 (3H, s); 2.52 (1H, dd, J=12.50 and 9.21);
2.72 (1H, dd, J=12.52 and 4.55); 2.88 (3H, s); 3.28-3.41 (2H, m);
3.84-3.92 (7H, m); 4.02-4.10 (4H, m); 7.46 (1H, s); 7.49 (1H, t,
J=8.14); 7.62 (1H, d, J=8.28); 8.28 (1H, d, J=7.26); 9.01 (1H, s);
10.10 (1H, s).
[0564] MS: ESI+: MH+ 542
[0565] 58: To a solution of 1-N-BOC-3-pyrrolidinone (3.0 g) in
methanol (30 ml) was added a solution of freshly prepared
methylamine (0.75 g) in methanol (3.1 ml). The reaction mixture was
stirred for 1 hour and then sodium borohydride (0.61 g) was added.
After stirring for 4 hours the reaction mixture was then diluted
with dichloromethane, washed with sodium bicarbonate solution,
dried (Mg.sub.2SO.sub.4) and the solvent removed in vacuo to give
3-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (3.18
g).
[0566] To a solution of 3-methylamino-pyrrolidine-1-carboxylic acid
tert-butyl ester (0.50 g) in dichloromethane (10 ml) was added
triethylamine (0.38 ml) followed by methanesulfonic acid (0.21 ml).
After stirring for 24 hours, the reaction mixture was diluted with
dichloromethane, washed with sodium bicarbonate solution, dried
(MgSO.sub.4) and the solvent removed in vacuo. The residue was
purified by flash chromatography to yield
3-(methanesulfonyl-methyl-amino)-pyrrolidine-1-carboxylic acid
tert-butyl ester (0.52 g). Treatment of this compound with HCl in
dichloromethane/methanol yielded
N-Methyl-N-pyrrolidin-3-yl-methanesulfonamide hydrochloride salt
(0.41 g).
[0567] To a solution of
6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine
(500 mg) and N-Methyl-N-pyrrolidin-3-yl-methanesulfonamide
hydrochloride salt (370 mg) in acetonitrile (10 mL) was added
potassium carbonate (490 mg). The reaction mixture was heated at
80.degree. C. for 16 h and then allowed to cool to room
temperature. The mixture was then partitioned between
dichloromethane (20 mL) and saturated aqueous sodium bicarbonate
solution (20 mL) and the organic layer washed with brine (20 mL),
dried (MgSO.sub.4), reduced in vacuo and purified on column
chromatography to give
N-methyl-N-[1-(2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl-
methyl)-pyrrolidin-3-yl]-methanesulfonamide as a pale yellow solid
(395 mg).
[0568]
N-methyl-N-[1-(2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-y-
lmethyl)-pyrrolidin-3-yl]-methanesulfonamide was reacted with
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in
general procedure A. Purification on silica yielded the title
compound.
[0569] NMR: CDCl.sub.3: 1.88-1.98 (1H, m); 2.12-2.26 (1H, m); 2.44
(1H, q, J=8.28); 2.62-2.70 (1H, m); 2.89 (3H, s); 2.86 (1H, dd,
J=10.24 and 3.98); 2.92 (3H, s); 2.96-3.01 (1H, m); 3.84-3.98 (6H,
m); 4.02-4.10 (4H, m); 4.52-4.63 (1H, m); 7.34 (1H, s); 7.50 (1H,
t, J=8.20); 7.61 (1H, d, J=8.21); 8.26 (1H, d, J=7.23); 9.01 (1H,
s); 10.11 (1H, s).
[0570] MS: ESI+: MH+ 528
[0571] 60: To a solution of 1-N-BOC-3-pyrrolidinone (3.0 g) in
methanol (30 ml) was added a solution of freshly prepared
methylamine (0.75 g) in methanol (3.1 ml). The reaction mixture was
stirred for 1 hour and then sodium borohydride (0.61 g) was added.
After stirring for 4 hours the reaction mixture was then diluted
with dichloromethane, washed with sodium bicarbonate solution,
dried (Mg.sub.2SO.sub.4) and the solvent removed in vacuo to give
3-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (3.18
g).
[0572] To a mixture of
6-bromomethyl-2-chloro-4-morpholino-4-yl-thieno[3,2,-d]pyrimidine
(0.50 g) and 3-methylamino-pyrrolidine-1-carboxylic acid tert-butyl
ester (0.34 g) in acetonitrile (10 ml) was added potassium
carbonate (0.30 g) and heated to 80.degree. C. for 3 hours. The
reaction mixture was then diluted with dichloromethane, washed with
sodium bicarbonate solution, dried (Mg.sub.2SO.sub.4) and the
solvent removed in vacuo. The residue was purified by flash
chromatography to yield
3-[(2-Chloro-4-morpholin-4-yl-thieno[3,2,-d]pyrimidin-6-ylmethyl)-amino]--
pyrrolidine-1-carboxylic acid tert-butyl ester (0.65 g). Treatment
of this compound with HCl in dichloromethane/methanol yielded
(2-chloro-4-morpholin-4-yl-thieno[3,2,-d]pyrimidin-6-ylmethyl)-amino-pyrr-
olidin-3-amine hydrochloride salt (0.56 g).
[0573] To a suspension of
(2-chloro-4-morpholin-4-yl-thieno[3,2,-d]pyrimidin-6-ylmethyl)-amino-pyrr-
olidin-3-amine hydrochloride salt (0.56 g) in dichloromethane (10
ml) was added triethylamine (0.42 ml) followed by methanesulfonyl
chloride (0.12 ml). After stirring for 3 hours the reaction mixture
was diluted with dichloromethane, washed with sodium bicarbonate
solution, dried (Mg.sub.2SO.sub.4) and the solvent removed in
vacuo. The residue was purified by flash chromatography to yield
(2-chloro-4-morpholin-4-yl-thieno[3,2,-d]pyrimidin-6-ylmethyl)-(1-methane-
sulfonyl-pyrrolidin-3-yl)-methyl-amine (0.25 g).
(2-Chloro-4-morpholin-4-yl-thieno[3,2,-d]pyrimidin-6-ylmethyl)-(1-methane-
sulfonyl-pyrrolidin-3-yl)-methyl-amine was reacted with
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in
general procedure A. Purification on silica yielded the title
compound.
[0574] NMR: CDCl.sub.3: 1.94-2.01 (1H, m); 2.20-2.28 (1H, m); 2.36
(3H, s); 2.85 (3H, s); 3.20-3.38 (3H, m); 3.52-3.65 (2H, m);
3.72-3.95 (6H, m); 4.02-4.07 (4H, m); 7.33 (1H, s); 7.49 (1H, t,
J=8.21); 7.60 (1H, d, J=8.22); 8.24 (1H, d, J=7.20); 9.01 (1H, s);
10.12 (1H, s).
[0575] MS: ESI+: MH+ 528
[0576] 74: Reductive amination of 1-Methanesulfonyl-piperidin-4-one
(150 mg) with
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-me-
thyl-amine (250 mg) under standard conditions followed by aqueous
work-up and purification on silica gave
(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-methanes-
ulfonyl-piperidin-4-yl)-methyl-amine (279 mg).
[0577]
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-me-
thanesulfonyl-piperidin-4-yl)-methyl-amine was reacted with
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in
General Procedure A. Purification on silica yielded the desired
compound.
[0578] NMR: (DMSO): 13.16 (bs, 1H); 8.87 (s, 1H); 8.21 (d, 1H,
J=7.3 Hz); 7.65 (d, 1H, J=8.3 Hz); 7.46 (m, 2H); 3.99 (m, 4H); 3.95
(s, 2H); 3.82 (m, 4H); 3.61 (m, 2H); 2.84 (s, 3H); 2.72 (m, 2H);
2.62 (m, 1H); 2.29 (s, 3H); 1.87 (m, 2H); 1.58 (m, 2H)
[0579] MS: (ESI+): MH+=542.3
[0580] 72: To a suspension of piperazine-2-carboxylic acid
dihydrochloride (10 g) in 1,4-dioxane (100 mL) and water (50 mL) at
0.degree. C. was added 17M NaOH solution in portions followed by
di-tert-butyldicarbonate (11.8 g). The resulting mixture was warmed
to R.T. and stirred for 5 h. Triethylamine (13.7 mL) and
methanesulfonyl chloride (3.8 mL) were added this mixture was
stirred overnight at R.T. The reaction mixture was concentrated in
vacuo, diluted with 2M HCl and extracted with EtOAC. Combined
extracts were dried (MgSO4), filtered and concentrated to give
4-methanesulfonyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl
ester (8.46 g).
[0581] To a solution of
4-methanesulfonyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl
ester (8.4 g, crude) in DMF (50 mL) was added K.sub.2CO.sub.3 (7.5
g) and iodomethane (8.5 mL) The mixture was stirred overnight at
R.T. An aqueous work-up followed by purification on silica gave
4-methanesulfonyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl
ester 3-methyl ester (3.267 g). A solution of
4-methanesulfonyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl
ester 3-methyl ester (3.2 g) in dry THF (20 mL) was added via
cannular to a mixture of lithium aluminium hydride (0.75 g) in THF
(30 mL0 at 0.degree. C. and under N.sub.2 atmosphere. The resultant
mixture was then warmed to R.T. and stirred for 2.5 h. The reaction
was carefully quenched with aqueous ammonium chloride (5 mL) then
filtered over Celite. An aqueous work-up followed by purification
on silica gave
3-hydroxymethyl-4-methanesulfonyl-piperazine-1-carboxylic acid
tert-butyl ester (1.13 g).
[0582] 3-Formyl-4-methanesulfonyl-piperazine-1-carboxylic acid
tert-butyl ester was prepared from
3-hydroxymethyl-4-methanesulfonyl-piperazine-1-carboxylic acid
tert-butyl ester following a procedure in J. Med. Chem. 2005,
48(2), pp 4009-4024.
[0583] Reductive amination of
3-formyl-4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl
ester (160 mg) with dimethylamine hydrochloride (67 mg) according
to General Procedure C followed by an aqueous work-up and
purification on silica gave
3-dimethylaminomethyl-4-methanesulfonyl-piperazine-1-carboxylic
acid tert-butyl ester (160 mg). This was treated with 2M HCl to
give desired
(1-methanesulfonyl-piperazin-2-ylmethyl)-dimethyl-amine
dihydrochloride (140 mg).
[0584] To a mixture of
6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine
(140 mg) and
(1-methanesulfonyl-piperazin-2-ylmethyl)-dimethyl-amine
dihydrochloride (140 mg) in dry MeCN (6 mL) was added
K.sub.2CO.sub.3 (190 mg). The mixture was stirred at 80.degree. C.
for 4 h. An aqueous work-up followed by purification on silica gave
[4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1-methan-
esulfonyl-piperazin-2-ylmethyl]-dimethyl-amine (115 mg).
[0585]
[4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1--
methanesulfonyl-piperazin-2-ylmethyl]dimethyl-amine was reacted
with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole
in General Procedure A. Purification on silica yielded the desired
compound.
[0586] 400 MHz; CDCl3
[0587] 2.30(7H, m); 2.37 (2H, m); 2.53 (1H, m); 2.83-3.07 (6H, m);
3.27 (1H, m); 3.68 (1H, d, J=12.6 Hz); 3.84 (3.84(2H, m); 3.94 (4H,
t, J=4.7 Hz); 4.10 (4H, t, J=4.7 Hz); 7.40 (1H, s); 7.52 (1H, t,
J=7.7 Hz); 7.60 (1H, d, J=8.3 Hz); 8.28 (1H, d, J=7.4 Hz); 9.02
(1H, s); 10.15 (1H, br s).
[0588] MS: (ESI+) M+H (571)
[0589] 70:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thi-
eno[3,2-d]pyrimidine was reacted with
3-amino-4-methylbenzeneboronic acid in general procedure A.
Purification by flash chromatography on silica yielded
2-Methyl-5-[6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-th-
ieno[3,2-d]pyrimidin-2-yl]-phenylamine. To a solution of
2-Methyl-5-[6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-
-d]pyrimidin-2-yl]-phenylamine (154 mg) in chloroform (10 ml) and
acetic acid (2 ml) was added isoamyl nitrite (55 .mu.L). The
reaction mixture was stirred at room temperature for 3 days. The
reaction mixture was diluted with chloroform and washed with a
50/50 mixture of saturated sodium bicarbonate solution and brine,
dried (MgSO.sub.4) and the solvents were removed in vacuo to give a
crude residue. This was purified by flash chromatography to yield
the desired product.
[0590] NMR: 400 MHz 1H NMR DMSO: 13.15 (bs, 1H); 8.57 (s, 1H); 8.20
(d, 1H); 8.10 (s, 1H) 7.81 (d, 1H); 7.40 (s, 1H); 3.99 (m, 4H);
3.82 (m, 4H+CH2); 2.35 (m, 8H), 2.16 (s, 3H)
[0591] MS: (ESI+): 450.2
[0592] 62: To a solution of 4-hydroxymethyl-piperidine-1-carboxylic
acid tert-butyl ester (2.0 g) in anhydrous tetrahyrofuran (50 ml)
was added carbon tetrabromide (6.2 g) and triphenylphosphine (4.88
g). the reaction mixture was stirred at room temperature for 3
dayss. The reaction mixture was filtered through celite. The
filtrate was taken up in ethyl actetate, washed with water then
brine, dried (MgSO4) and the solvent removed in vacuo give a crude
product. This was purified using flash chromatography which yielded
Bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.287
g).
[0593] To a solution of pyrazole (68 mgs) in anhydrous
dimethylformamide was added sodium hydride (44 mgs). The reaction
mixture was stirred at 50.degree. C. for 25 minutes.
4-Bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (280
mgs) in anhydrous dimethylformamide was added. The reaction mixture
was stirred at 70.degree. C. under argon for 2.5 hours. The
reaction mixture was quenched with water (1 ml) and the solvents
were removed in vacuo. The crude residue was partitioned between
dichloromethane and water, dried (MgSO.sub.4) and the solvents
removed in vacuo to give a crude product. This was purified using
flash chromatography to yield
4-Pyrazol-1-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester
(148 mg).
[0594] To a solution of
4-Pyrazol-1-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester
(215 mg) in anhydrous dichloromethane (5 ml) was added 2M hydrogen
chloride in ether (4.1 ml). The reaction mixture was stirred at
room temperature for 6 hours. The solvents were removed in vacuo to
yield 4-Pyrazol-1-ylmethyl-piperidine hydrochloride salt.
[0595] To a solution of 4-Pyrazol-1-ylmethyl-piperidine
hydrochloride salt in 1,2-dichloroethane (5 ml) was added
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
(230 mg) and glacial acetic acid (50 .mu.L). The reaction mixture
was stirred at room temperature for 6 hours. Sodium
triacetoxyborohydride (224 mg) and triethylamine (113 .mu.L) were
added. The reaction mixture was stirred at room temperature
overnight. The reaction mixture was diluted with dichloromethane,
washed with a 50/50 mixture of saturated sodium bicarbonate
solution and brine, dried (MgSO.sub.4) and the solvents removed in
vacuo to give a crude product. This was purified by flash
chromatography to yield
2-Chloro-4-morpholin-4-yl-6-(4-pyrazol-1-ylmethyl-piperidin-1-ylmethyl)-t-
hieno[3,2-d]pyrimidine (154 mg).
[0596]
2-Chloro-4-morpholin-4-yl-6-(4-pyrazol-1-ylmethyl-piperidin-1-ylmet-
hyl)-thieno[3,2-d]pyrimidine was reacted with
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in
general procedure A. Purification by flash chromatography on silica
yielded the desired product.
[0597] NMR: 400 MHz 1H NMR in DMSO: 13.15 (bs, 1H); 8.87 (s, 1H);
8.21 (d, 1H, J=6.7 HZ); 7.67 (d, 1H, J=6.2 Hz); 7.64 (s, 1H); 7.44
(m, 3H); 6.20 (t, 1H); 4.01 (m, 4H+CH2); 3.83 (m, 4H+CH2); 2.91 (m,
2H); 2.04 (m, 2H); 1.98 (m, 2H); 1.45 (m, 2H); 1.25 (m, 2H)
[0598] MS: (ESI+): 512.2
[0599] 61: To a solution of 4-hydroxymethyl-piperidine-1-carboxylic
acid tert-butyl ester (2.0 g) in anhydrous tetrahyrofuran (50 ml)
was added carbon tetrabromide (6.2 g) and triphenylphosphine (4.88
g). the reaction mixture was stirred at room temperature for 3
days. The reaction mixture was filtered through celite. The
filtrate was taken up in ethyl actetate, washed with water then
brine, dried (MgSO4) and the solvent removed in vacuo give a crude
product. This was purified using flash chromatography which yielded
Bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.287
g).
[0600] To a solution of 2-pyrrolidone (86 mg) in anhydrous
dimethylormamide (5 ml) was added sodium hydride (45 mg). the
reaction mixture was stirred under nitrogen at 50.degree. C. for 35
minutes. 4-Bromomethyl-piperidine-1-carboxylic acid tert-butyl
ester (86 mg) in anhydrous dimethylformamide (5 ml) was added. The
reaction mixture was stirred at 70.degree. C. overnight. The
solvents were removed in vacuo and the crude residue was
partitioned between dichloromethane and water, the combined organic
extracts were washed with brine, dried (MgSO4) and the solvents
removed in vacuo to give a crude product. This was purified using
flash chromatography to yield
4-(2-Oxo-pyrrolidin-1-ylmethyl)-piperidine-1-carboxylic acid
tert-butyl ester (99 mg).
[0601] To a solution of
4-(2-Oxo-pyrrolidin-1-ylmethyl)-piperidine-1-carboxylic acid
tert-butyl ester in dichloromethane was added 2M hydrogen chloride
in ether (1.78 ml). The reaction mixture was stirred at room
temperature for 6 hours. The solvents were removed in vacuo to
yield 1-Piperidin-4-ylmethyl-pyrrolidin-2-one hydrochloride
salt.
[0602] To a solution of 1-Piperidin-4-ylmethyl-pyrrolidin-2-one
hydrochloride salt in anhydrous 1,2-dichloroethane was added
triethyamine (47 .mu.L), the reaction mixture was stirred at room
temperature for 2 hours.
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
(99 mg) and glacial acetic acid were added, the reaction mixture
was stirred at room temperature for 4 hours. Sodium
triacetoxyborohydride (96 mg) was added. The reaction mixture was
stirred at room temperature overnight. The reaction mixture was
diluted with dichloromethane, washed with a 50/50 mixture of
saturated sodium bicarbonate solution and brine, dried (MgSO4) and
the solvents removed in vacuo to give a crude residue. This was
purified using column chromatography to give
2-[1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperi-
din-4-ylmethyl]-cyclopentanone (73 mg).
[0603]
2-[1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)--
piperidin-4-ylmethyl]-cyclopentanone was reacted with
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxa borolan-2-yl)-1H-indazole in
procedure A. Purification by flash chromatography on silica yielded
the desired product.
[0604] NMR: 1H NMR 400 MHz, d6 DMSO: 13.15 (bs, 1H); 8.87 (s, 1H);
8.21 (d, 1H, J=7.4 Hz); 7.65 (d, 1H, J=8.3 Hz); 7.46 (t, 1H, J=8.3
Hz); 4.01 (m, 4H); 3.83 (m, 4H+CH2); 3.06 (m, 2H); 2.91 (m, 2H);
2.20 (t, 1H, J=7.8 Hz); 2.06 (t, 1H, J=11.2 Hz); 1.90 (m, 2H); 1.56
(m, 3H); 1.19 (m, 2H).
[0605] MS: (ESI+): 532.3
[0606] 82:
2-chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-
-4-yl-thieno[2,3-d]pyrimidine was reacted with
2-methoxy-5-pyrimidine-boronic acid in General Procedure A.
Purification on silica yielded the desired compound.
[0607] NMR: (CDCl.sub.3): 2.64-2.67 (m, 4H, 2.times.CH2), 2.80 (s,
3H, CH3), 3.27-3.30 (m, 4H, 2.times.CH2), 3.81 (s, 2H, CH2),
3.87-3.89 (m, 4H, 2.times.CH2), 3.95-3.97 (m, 4H, 2.times.CH2),
4.09 (s, 3H, CH3), 7.14 (s, H, ArH), 9.45 (s, 2H, 2.times.ArH).
[0608] MS: (ESI+): MH+=506.16
[0609] 83:
2-chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-
-4-yl-thieno[2,3-d]pyrimidine was reacted with
2-dimethylamino-pyrimidine-5-boronic acid in General Procedure A.
Purification on silica yielded the desired compound.
[0610] NMR: (CDCl.sub.3): 2.63-2.66 (m, 4H, 2.times.CH2), 2.79 (s,
3H, CH3), 3.25-3.28 (m, 10H, 2.times.CH2+2.times.CH3), 3.79 (s, 2H,
CH2), 3.84-3.87 (m, 4H, 2.times.CH2), 3.91-3.94 (m, 4H,
2.times.CH2), 7.101 (s, H, ArH), 9.28 (s, 2H, 2.times.ArH).
[0611] MS: (ESI+): MH+=519.27
Example 5
Further Compounds of the Invention
[0612] The following further compounds of the invention were
prepared. The compound numbering corresponds to that used in Table
1B.
[0613] 140: To 190 mg of
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thie-
no[2,3-d]pyrimidine in 1 mL 1M KOAc and 2 mL acetonitrile was added
109.8 mg (1.02 eq) of 7-azaindole-5-boronic acid pinacol ester and
50.8 mg (0.1 eq) of Pd(PPh.sub.3).sub.4 as per General Procedure A
to give 170.7 mg of the desired product after RP-HPLC purification
(75% yield). MS (Q1) 514.2 (M)+.
[0614] 152: To 200 mg of
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thie-
no[2,3-d]pyrimidine in 2 mL 1M Sodium carbonate in water and 2 mL
acetonitrile was added 270 mg (1.5 eq) of
3-((2-(trimethylsilyl)ethoxy)methyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,-
2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]Pyridine and 54 mg (0.05 eq)
of Pd (PPh.sub.3).sub.4 as per General Procedure A. This insoluble
intermediate was filtered off, washed with water, concentrated in
vacuo and dissolved in 20 mL THF followed by the addition of 2.8 mL
(6.0 eq) of 1.0 M Tetra-n-butylammonium fluoride in THF. After
heating the reaction to 80.degree. C. with a reflux condenser
attached overnight, complete reaction was confirmed by LCMS. The
reaction was diluted with water, extracted with EtOAc, concentrated
in vacuo and gave 55.2 mg of the desired product after RP-HPLC
purification (21% yield). MS (Q1) 529.2 (M)+.
[0615] 132: To 96 mg (0.23 mM) of
2-chloro-6-(4-methyl-piperazin-1-yl
methyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine in 1 mL 1M KOAc
and 1.5 mL acetonitrile was added 73.2 mg (1.3 eq) of
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole and
26.6 mg (0.1 mM) of Pd (PPh.sub.3).sub.4 as per General Procedure A
to Give 23.4 mg of the desired product after RP-HPLC purification
(17% yield). MS (Q1) 492.4 (M)+.
[0616] 131: 590 mg of crude HCl salt of
2-chloro-7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyr-
imidine was treated with 430 mg of L-Lactic Acid via Procedure B.
60 mg of this crude intermediate was reacted with
4-(4,4,5,5-tertamethyl-1,3,2-dioxaborolan-2-yl)1H-indazole via
Procedure A to give 32.5 mg of the desired product after reverse
phase HPLC purification. MS (Q1) 522.3 (M)+.
[0617] 134: 200 mg of
2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde was
used according to procedure C with
(S)-4-N-trityl-2-methyl-piperazine. The crude material was then
dissolved in 10 mL of methanol and reacted with 0.5 mL of
concentrated HCl for several hours before basifying with NaOH and
extracting into EtOAc. After evaporation the crude reaction mixture
containing 200 mg of
2-chloro-6-(((S)-2-methylpiperazin-1-yl)methyl-4-morpholinothieno[3,2-d]p-
yrimidine was reacted with lactic acid via Procedure B. 120 mg of
(S)-1-((S)-4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3-
-methylpiperazin-1-yl)-2-hydroxypropan-1-one was reacted with
4-(4,4,5,5-tertamethyl-1,3,2-dioxaborolan-2-yl)1H-indazole via
Procedure A to give 47.5 mg of the desired product after reverse
phase HPLC purification. MS (Q1) 522.3 (M)+.
[0618] 148: 250 mg of tert-butyl
4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)pipe-
razine-1-carboxylate was reacted with
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine
via Procedure A. This crude intermediate was subjected to Procedure
D.
[0619] The crude HCl salt of
7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)-2-(1H-pyrrolo[2,3-b]pyri-
din-5-yl)thieno[3,2-d]pyrimidine was reacted with L-Lactic acid via
Procedure B to give 86.7 mg of the desired product after reverse
phase HPLC purification. MS (Q1) 522.2 (M)+.
[0620] 150: 100 mg of tert-butyl
4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)pipe-
razine-1-carboxylate was reacted with quinolin-3-yl-3-boronic ester
via Procedure A. This crude intermediate was subjected to Procedure
D.
[0621] The crude HCl salt of
3-(7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-
-2-yl)quinoline was reacted with L-Lactic acid via Procedure B to
give 21.6 mg of the desired product after reverse phase HPLC
purification.
[0622] MS (Q1) 533.2 (M)+.
[0623] 149: 250 mg of tert-butyl
4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazine-1--
carboxylate was reacted with
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine
via Procedure A. This crude intermediate was subjected to Procedure
D.
[0624] The crude HCl salt of
4-morpholino-6-((piperazin-1-yl)methyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-
thieno[2,3-d]pyrimidine was reacted with L-Lactic acid via
Procedure B to give 58.5 mg of the desired product after reverse
phase HPLC purification. MS (Q1) 508.2 (M)+.
[0625] 151: 100 mg of tert-butyl
4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazine-1--
carboxylate was reacted with quinolin-3-yl-3-boronic ester via
Procedure A. This crude intermediate was subjected to Procedure
D.
[0626] The crude HCl salt of
3-(4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-2-yl)qui-
noline reacted with L-Lactic acid via Procedure B to give 68 mg of
the desired product after reverse phase HPLC purification. MS (Q1)
519.2 (M)+.
[0627] 153: 100 mg of tert-butyl
4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazine-1--
carboxylate was reacted with
3-((2(trimethylsilyl)ethoxy)methyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-
-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine via Procedure A.
Crude intermediate tert-butyl
4-((2-(1-((2-(trimethylsilyl)ethoxy)methyl)-2-methyl-1H-benzo[d]imidazol--
6-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazine-1-carboxyl-
ate was then refluxed overnight with 2 equivalents of
tetrabutylammoniumfloride in THF to remove the SEM protecting
group. The crude material was then extracted with water and ethyl
acetate. The organic layer was concentrated to dryness and then
subjected to Procedure D.
[0628] The crude HCl salt of
2-(2-methyl-1H-benzo[d]imidazol-5-yl)-4-morpholino-6-((piperazin-1-yl)met-
hyl)thieno[2,3-d]pyrimidine was reacted with L-Lactic Acid via
Procedure B to give 14.1 mg of the desired product after reverse
phase HPLC purification. MS (Q1) 523.2 (M)+.
[0629] 142:
2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,-
2-d]pyrimidine (1 eq), azaindole boronic ester (1.7 eq) and
bis(triphenylphosphine)palladium(II) dichloride (0.1 eq) in 1M
Na.sub.2CO.sub.3 aqueous solution (3 eq) and an equal volume of
acetonitrile (3 eq) was heated to 130.degree. C. in a sealed
microwave reactor for 10 min. Upon completion, the reaction mixture
was concentrated and crude mixture was purified by reverse phase
HPLC to yield 12 mg of
5-(4-morpholinofuro[2,3-d]pyrimidin-2-yl)pyrimidin-2-amine. MS (Q1)
498 (M).sup.+.
[0630] 141:
2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[2,-
3-d]pyrimidine (1 eq),
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.7
eq) and bis(triphenylphosphine)palladium(II) dichloride (0.1 eq) in
1M KOAc aqueous solution (3 eq) and an equal volume of acetonitrile
(3 eq) was heated to 140.degree. C. in a sealed microwave reactor
for 10 min. Upon completion, the reaction mixture was concentrated
and crude mixture was purified by reverse phase HPLC to yield 16 mg
of
2-(1H-indazol-4-yl)-6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholi-
nofuro[2,3-d]pyrimidine. MS (Q1) 498 (M).sup.+.
[0631] 128:
2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,-
2-d]pyrimidine (1 eq), indole boronic ester (1.7 eq) and
bis(triphenylphosphine)palladium(II) dichloride (0.1 eq) in 1M
Na.sub.2CO.sub.3 aqueous solution (3 eq) and an equal volume of
acetonitrile (3 eq) was heated to 140.degree. C. in a sealed
microwave reactor for 10 min. Upon completion, the reaction mixture
was concentrated and crude mixture was purified by reverse phase
HPLC to yield 12 mg of
5-(4-morpholinofuro[2,3-d]pyrimidin-2-yl)pyrimidin-2-amine. MS (Q1)
497 (M).sup.+.
[0632] 133: Prepared from the appropriate intermediate according to
General Procedure A using
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-
. The compound is obtained after reverse phase HPLC purification
(49 mg). MS (Q1) 514 (M)+130: To
2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (100
mg, 0.35 mmol) in 1,2-dichloroethane (2 mL) was added AcOH (20 pt,
0.35 mmol) and 4-Amino-1-BOC-piperidine (210 mg, 1.05 mmol). The
resulting solution stirred overnight at room temperature then
Na(OAc).sub.3BH (90 mg, 0.42 mmol) was added and the reaction
stirred 4 h at room temperature. The reaction was quenched with
water and extracted with DCM then EtOAc. The combined organics were
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo.
The crude product was dissolved in MeOH (5 mL) and AcOH (80 .mu.L),
then formaldehyde (37%, 31 .mu.L) and NaCNBH.sub.3 (26 mg, 0.42
mmol) were added. The reaction mixture was allowed to stir
overnight then additional formaldehyde (37%, 56 .mu.l) was added to
drive the reaction to completion.
[0633] After 1 h at room temperature the reaction was complete and
quenched with saturated aqueous K.sub.2CO.sub.3 and diluted with
EtOAc. The aqueous layer was extracted with EtOAc and the combined
organics were dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The crude product was dissolved in
CH.sub.2Cl.sub.2 (10 mL), MeOH (10 mL), and Et.sub.2O (5 mL) and 4
M HCl in dioxane (10 mL) was added. The resulting mixture stirred
at room temperature for 3 days then was concentrated in vacuo. The
residue was dissolved in CH.sub.2Cl.sub.2 (20 mL) and Et.sub.3N (5
mL) was added. Excess water was added to the solution. The organic
phase was separated and the aqueous layer was extracted with EtOAc.
The combined organics were dried over Na.sub.2SO.sub.4, filtered,
and concentrated in vacuo. The crude material was carried onto the
next step without purification. Compound 130 was produced by Suzuki
coupling with
4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole
according to General Procedure A (6 mg).
MS (Q1) 464 (M)+
Example 6
Additional Compounds of the Invention
[0634] The following additional compounds of the invention were
prepared. The compound numbering corresponds to that used in Table
1B above.
[0635] 129: To N-BOC-piperazine (1.3 g) in dry DCM (10 ml) was
added triethylamine (1.2 mL) and cyclopropanesulphonyl chloride
(1.04 g) and the reaction mixture was stirred at room temperature
for 16 hours. The reaction mixture was then diluted with DCM,
washed with water, dried (MgSO.sub.4) and reduced in vacuo. The
residue was dissolved in methanol (10 mL) and 4M HCL in dioxane was
added (20 mL). After stirring overnight the solvent was reduced in
vacuo to yield 1-cyclopropanesulfonyl-piperazine hydrochloride.
[0636]
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
was treated with 1-cyclopropanesulfonyl-piperazine hydrochloride
using General Procedure C (reductive amination) to yield
2-chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-
-thieno[3,2-d]pyrimidine.
[0637]
2-chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-4-morpholi-
n-4-yl-thieno[3,2-d]pyrimidine was reacted with
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in
general procedure A. Purification by column chromatography yielded
the title compound.
[0638] (400 Mhz, CDCl3): 1.00-1.02 (2H, m, CH2), 1.19-1.23 (2H, m,
CH2), 2.29 (1H, m, CH), 2.69 (4H, m, CH2), 3.40 (4H, m, CH2),
3.91-3.94 (6H, m, CH2), 4.08-4.11 (4H, m, CH2), 7.41 (1H, s, ar),
7.49-7.53 (1H, m, ar), 7.60 (1H, d (J8.30), ar), 8.29 (1H, d J
(7.05), ar), 9.02 (1H, s, ar), 10.10 (1H, b, NH)
[0639] (M+H)+ 540.34
[0640] 137:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thie-
no[3,2-d]pyrimidine was reacted with
5-(4,4,5,5-tetramethyl-[1.3.2]dioxaborolan-2-yl)-1H-indazole
(commercially available) in general procedure A. Purification by
column chromatography yielded the title compound.
[0641] NMR: CDCl.sub.3: 2.58-2.62 (4H, m, CH.sub.2), 2.74 (1H, s,
Me), 3.22-3.25 (4H, m, CH.sub.2), 3.82 (2H, s, CH.sub.2), 3.82-3.86
(4H, m, CH.sub.2), 4.00-4.02 (4H, m, CH.sub.2), 7.28 (1H, s, Ar),
7.48 (1H, d, J 8.2, Ar), 8.09 (1H, s, Ar), 8.48 (1H, d, J 8.2, Ar),
8.82 (1H, d, J 7.5, Ar) and 10.01 (1H, s, NH).
[0642] MS: (ESI+): MH+ 514.17
[0643] 143:
(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amin-
e was made by treating
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
(intermediate 10) and 40% methylamine in water according to General
Procedure C (reductive amination).
[0644]
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-is-
opropyl-piperidin-4-yl)-methyl-amine was made by treating
(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amin-
e and 1-isopropyl-4-piperidone according to the General Procedure C
(reductive amination).
[0645] A suspension of
(2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethyl)-(1-isopropyl-
-piperidin-4-yl)-methyl-amine (63 mg, 0.149 mmol),
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (44
mg, 0.179 mmol), 1M Na.sub.2CO.sub.3 (0.5 ml, 0.5 mmol) and
Pd(PPh.sub.3).sub.2Cl.sub.2 (11 mg, 0.015 mmol) in acetonitrile (3
ml) was heated in a microwave at 140.degree. C. for 25 mins. The
reaction was then acidified with 2N HCl (aq) extracted with ethyl
acetate, the water layer separated and basified with
K.sub.2CO.sub.3 (sat. aq) resulting in an impure precipitate. This
was purified on alumina using 5% methanol in dichloromethane as the
eluent, (11 mg, 15%).
[0646] NMR (CDCl3, 400 MHz), 0.96 (6H, d, J=6.4), 1.54-1.60 (2H,
m), 1.77-1.80 (2H, m), 2.04-2.09 (2H, m), 2.30 (3H, s), 2.40-2.46
(1H, m), 2.62-2.68 (1H, m), 2.88-2.92 (2H, m), 3.84 (4H, t, J=4.4),
3.87 (2H, s), 4.02 (4H, t, J=4.8), 7.19 (1H, s), 7.43 (1H, t,
J=7.6), 7.50 (1H, d, J=8.4), 8.20 (1H, dd, J=7.2, 0.8), 8.95 (1H,
d, J=0.8), 10.2 (1H, br s).
[0647] MS: (ESI+): MH+=506.
[0648] 145: Intermediate F (1.00 g) was reacted with
tert-butyl-1-piperazine carboxylate (0.85 g) in General Procedure
Z. Aqueous work-up and purification on silica gave
4-(2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-ylmethyl0-piperazi-
ne-1-carboxylic acid tert-butyl ester (1.61 g).
[0649]
4-(2-Chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-ylmethyl0-pi-
perazine-1-carboxylic acid tert-butyl ester (1.61 g) was treated
with an excess of hydrogen chloride in diethyl ether at room
temperature overnight. Removal of volatiles and basification with
aqueous sodium hydrogen chloride afforded
2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[2,3-d]pyrimidine
(0.90 g).
[0650] To
2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[2,3-d]py-
rimidine (187 mg) in anhydrous DCM (5 ml) and triethylamine (111
ul) was added cyclopropanesulfonyl chloride (65 ul) at 0.degree. C.
The reaction mixture was allowed to warm up to room temperature
over 4 hours. Aqueous work-up and purification on silica gave
2-chloro-4-morpholin-4-yl-6-[4-(cyclopropane-2-sulfonyl)-piperazin-1-ylme-
thyl]-thieno[2,3-d]pyrimidine (159 mg).
2-Chloro-4-morpholin-4-yl-6-[4-(cyclopropane-2-sulfonyl)-piperazin-1-ylme-
thyl]thieno[2,3-d]pyrimidine was reacted with 7-azaindole-5-boronic
acid pinacol ester in General Procedure A. Purification on silica
yielded the desired compound.
[0651] NMR (CDCl3): 1.00-1.05 (2H, m), 1.18-1.22 (2H, m), 2.28-2.32
(1H, m), 2.65-2.69 (4H, m), 3.37-3.41 (4H, m), 3.83 (2H, s),
3.92-3.96 (4H, m), 4.00-4.04 (4H, m), 6.62-6.64 (1H, m), 7.18 (1H,
s), 7.37-7.39 (1H, m), 9.02 (1H, d), 9.37 (1H, br), 9.46 (1H,
d)
[0652] MS (ESI+): MH+ 540.21 (15%)
[0653] 146: To
2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[2,3-d]pyrimidine
(150 mg) in anhydrous DCM (4 ml) and triethylamine (90 ul) was
added 2-thiophenesulfonyl chloride (101 ul) at 0.degree. C. The
reaction mixture was allowed to warm up to room temperature over 4
hours. Aqueous work-up and purification on silica gave
2-chloro-4-morpholin-4-yl-6-[4-(thiophene-2-sulfonyl)-piperazin-1-ylmethy-
l]-thieno[2,3-d]pyrimidine (208 mg).
2-Chloro-4-morpholin-4-yl-6-[4-(thiophene-2-sulfonyl)-piperazin-1-ylmethy-
l]-thieno[2,3-d]pyrimidine was reacted with 7-azaindole-5-boronic
acid pinacol ester in General Procedure A. Purification on silica
yielded the desired compound.
[0654] NMR (CDCl3): 2.67-2.70 (4H, m), 3.15-3.18 (4H, m), 3.79 (2H,
s), 3.91-3.95 (4H, m), 3.99-4.03 (4H, m), 6.61-6.63 (1H, m), 7.15
(1H, s), 7.18-7.20 (1H, m), 7.33-7.36 (1H, m), 7.54-7.57 (1H, m),
7.66-7.68 (1H, m), 8.91 (1H, br), 8.99 (1H, d), 9.44 (1H, d)
[0655] MS (ESI+): MH+582 (10%)
[0656] 138:
4-[6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-
-d]pyrimidin-2-yl]-benzene-1,2-diamine (150 mg, described above))
was heated in dry THF (4 ml) with CDI (195 mg) at 40.degree. C. for
5 hours and then stirred at room temperature overnight. Added
water, precipitate was filtered, washed with water and dried. The
residue was purified by flash chromatography to give the title
compound (43 mg).
[0657] NMR (DMSO): 2.49-2.52 (4H, m), 2.90 (3H, s), 3.15-3.18 (4H,
m), 3.80-3.83 (4H, m), 3.92 (2H, s), 3.95-3.97 (4H, m), 7.00 (1H,
d, J=8.2), 7.39 (1H, s), 7.99 (1H, s), 8.12 (1H, d, J=8.2), 10.65
(1H, br), 10.80 (1H, br)
[0658] MS (ESI+): MH+ 530.36
[0659] 139: A solution of (3-acetamido-2-nitrophenyl)boronic acid
(300 mg) in 2M aqueous hydrochloric acid solution (4 mL) was heated
at 80.degree. C. for 20 min. After cooling to room temperature, the
solvent was reduced in vacuo to give a brown solid which was
redissolved in 1,4-dioxane (5 mL). Pinacol (316 mg) was added and
the mixture heated at 100.degree. C. for 30 min. After cooling to
room temperature the solvent was reduced in vacuo to give a beige
solid which was dissolved in acetic acid (5 mL). Palladium on
carbon (100 mg) was added and the mixture stirred under an
atmosphere of hydrogen at 40.degree. C. for 1 h. The reaction
mixture was then filtered through Celite and the filtrate reduced
in vacuo. Purification by column chromatography gave
2-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.
[0660]
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-y-
l-thieno[3,2-d]pyrimidine was reacted with
2-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in
general procedure A. Purification by column chromatography yielded
3-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-
-d]pyrimidin-2-yl]-benzene-1,2-diamine which was heated in formic
acid at reflux for 4 h. After cooling to room temperature, the
solution was poured into saturated aqueous sodiumhydrogen carbonate
solution (20 mL) and extracted into dichloromethane (3.times.20
mL). The combined organics were washed with aqueous brine solution
(2.times.20 mL), dried (MgSO.sub.4), reduced in vacuo and purified
by column chromatography to give the title compound.
[0661] NMR: CDCl.sub.3: 2.62-2.65 (4H, m, CH.sub.2), 2.74 (3H, s,
Me), 3.24-3.27 (4H, m, CH.sub.2), 3.84 (2H, s, CH.sub.2), 3.85-3.87
(4H, m, CH.sub.2), 4.01-4.05 (4H, m, CH.sub.2), 7.30-7.32 (2H, m,
Ar), 7.86 (1H, d, J 7.9, Ar), 8.10 (1H, s, Ar) and 8.32 (1H, d, J
7.9, Ar).
[0662] MS: (ESI+): MH+ 514.22
[0663] 144: A solution of 2,3-diamino-5-bromopyridine (1.34 g) in
formic acid (7 mL) was heated at reflux for 3 h. After cooling to
room temperature, the solvent was reduced in vacuo to give an
off-white solid which was recrystallised from methanol-water to
give 6-bromo-3H-imidazo[4,5-b]pyridine as a pale orange solid.
[0664] To a solution of 6-bromo-3H-imidazo[4,5-b]pyridine (1.0 g)
in THF (20 mL) at 0.degree. C. was added sodium hydride (187 mg)
and the reaction stirred at 0.degree. C. for 1 h. Then,
2-(trimethylsilyl)ethoxymethyl chloride (0.94 mL) was added and the
reaction stirred at room temperature for 16 h. The reaction was
quenched with water (20 mL) and extracted into ethyl acetate
(2.times.20 mL). The combined organics were washed with aqueous
brine solution (2.times.20 mL), dried (MgSO.sub.4), reduced in
vacuo and purified by column chromatography to give
6-bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridine.
[0665] To a solution of
6-bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridine
(350 mg) in 1,4-dioxane (10 mL) was added bis(tributyltin) (1.08
mL), tetrakis(triphenylphosphine)palladium (0) (62 mg) and lithium
chloride (136 mg) and the reaction heated at reflux for 16 h. After
cooling to room temperature, the reaction mixture was filtered
through Celite, washing with ethyl acetate. The filtrate was washed
with water (2.times.30 mL), aqueous brine solution (2.times.20 mL),
dried (MgSO.sub.4), reduced in vacuo and purified by column
chromatography to give
6-tributylstannanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4-
,5-b]pyridine as a colourless oil.
[0666] To a solution of
2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thie-
no[3,2-d]pyrimidine (450 mg) in DMF (6 mL) was added sodium
thiomethoxide (183 mg) and the reaction heated at 100.degree. C.
for 16 h. After cooling to room temperature the reaction mixture
was poured into ice water and the resulting precipitate filtered
and air dried to give
6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-
-yl-thieno[3,2-d]pyrimidine as a white solid.
[0667] To a solution of
6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-
-yl-thieno[3,2-d]pyrimidine (90 mg) in 1,2-dimethoxyethane (10 mL)
was added
6-tributylstannanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[-
4,5-]pyridine (219 mg) and copper(I)bromide-dimethylsulfide (84 mg)
and the reaction stirred at room temperature for 10 min. Then,
tetrakis(triphenylphosphine)palladium (0) (12 mg) was added and the
reaction heated at reflux for 16 h. After cooling to room
temperature, the reaction mixture was diluted with ethyl acetate
(20 mL) and washed with water (2.times.30 mL), aqueous brine
solution (2.times.20 mL), dried (MgSO.sub.4), reduced in vacuo and
purified by column chromatography to give
6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-2-[3-(2--
trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-thieno[3,2-d-
]pyrimidine as a white solid.
[0668] To a solution of
6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-2-[3-(2-trime-
thylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-thieno[3,2-d]pyri-
midine (70 mg) in THF (10 mL) was added tetrabutylammonium fluoride
(0.16 mL of a 1 M solution in THF) and the reaction heated at
reflux for 1 h. After cooling to room temperature, the reaction was
diluted with dichloromethane (20 mL) and washed with water
(2.times.30 mL), aqueous brine solution (2.times.20 mL), dried
(MgSO.sub.4), reduced in vacuo and purified by column
chromatography to give the title compound.
[0669] NMR: CDCl.sub.3: 2.61-2.64 (4H, m, CH.sub.2), 2.76 (3H, s,
Me), 3.22-3.25 (4H, m, CH.sub.2), 3.80 (2H, s, CH.sub.2), 3.81-3.84
(4H, m, CH.sub.2), 4.02-4.05 (4H, m, CH.sub.2), 7.31 (1H, s, Ar),
8.21 (1H, s, Ar), 9.09 (1H, s, Ar) and 9.50 (1H, s, Ar).
[0670] MS: (ESI+): MH+ 515.19
[0671] 147: To a solution
2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thie-
no[2,3-d]pyrimidine (450 mg) in DMF (6 mL) was added sodium
thiomethoxide (183 mg) and the reaction heated at 100.degree. C.
for 16 h. After cooling to room temperature the reaction mixture
was poured into ice water and the resulting precipitate filtered
and air dried to give
6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-
-yl-thieno[2,3-d]pyrimidine as a white solid.
[0672] To a solution of
6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-
-yl-thieno[2,3-d]pyrimidine (90 mg) in 1,2-dimethoxyethane (10 mL)
was added
6-tributylstannanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[-
4,5-]pyridine (219 mg) and copper(I)bromide-dimethylsulfide (84 mg)
and the reaction stirred at room temperature for 10 min. Then,
tetrakis(triphenylphosphine)palladium (0) (12 mg) was added and the
reaction heated at reflux for 16 h. After cooling to room
temperature, the reaction mixture was diluted with ethyl acetate
(20 mL) and washed with water (2.times.30 mL), aqueous brine
solution (2.times.20 mL), dried (MgSO.sub.4), reduced in vacuo and
purified by column chromatography to give
6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-2-[3-(2--
trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-thieno[2,3-d-
]pyrimidine as a white solid.
[0673] To a solution of
6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-2-[3-(2-trime-
thylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-thieno[2,3-d]pyri-
midine (70 mg) in THF (10 mL) was added tetrabutylammonium fluoride
(0.16 mL of a 1 M solution in THF) and the reaction heated at
reflux for 1 h. After cooling to room temperature, the reaction was
diluted with dichloromethane (20 mL) and washed with water
(2.times.30 mL), aqueous brine solution (2.times.20 mL), dried
(MgSO.sub.4), reduced in vacuo and purified by column
chromatography to give the title compound.
[0674] NMR: CDCl.sub.3: 2.58-2.61 (4H, m, CH.sub.2), 2.72 (3H, s,
Me), 3.21-3.23 (4H, m, CH.sub.2), 3.76 (2H, s, CH.sub.2), 3.80-3.82
(4H, m, CH.sub.2), 3.92-3.94 (4H, m, CH.sub.2), 7.10 (1H, s, Ar),
8.15 (1H, s, Ar), 9.09 (1H, s, Ar) and 9.49 (1H, s, Ar).
[0675] MS: (ESI+): MH+ 515.14
[0676] 135: Intermediate G (500 mg) was reacted with
2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (613
mg) in a General Procedure A. Aqueous work-up and purification by
flash chromatography gave
4-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-
-d]pyrimidin-2-yl]-2-nitro-phenylamine (633 mg).
[0677]
4-[6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thie-
no[3,2-d]pyrimidin-2-yl]-2-nitro-phenylamine (200 mg) was stirred
under hydrogen balloon with palladium on carbon (10%, 70 mg) in a
mixture of MeOH and DCM (1:1, 10 ml) at room temperature overnight.
The reaction mixture was then filtered through celite, volatiles
removed in vacuo, and the residue purified by flash chromatography
to give
4-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-
-d]pyrimidin-2-yl]-benzene-1,2-diamine (99 mg).
[0678]
4-[6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thie-
no[3,2-d]pyrimidin-2-yl]-benzene-1,2-diamine (95 mg) was refluxed
in formic acid (1 mL) for 1 hour. The reaction mixture was basified
with aqueous sodium hydrogen carbonate and extracted into DCM.
Flash chromatography and recrystallisation from hot DCM/hexane gave
the title compound (32 mg).
[0679] NMR (CDCl3): 2.67-2.71 (4H, m), 2.81 (3H, s), 3.29-3.33 (4H,
m), 3.89 (2H, s), 3.89-3.93 (4H, m), 4.08-4.12 (4H, m), 7.35 (1H,
s), 7.70-7.80 (1H, br), 8.10 (1H, s), 8.48 (1H, d, J=8.6), 8.80
(1H, br)
[0680] MS (ESI+): MH+ 514.20 (100%)
[0681] 136:
2-Nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(1.00 g) was stirred under hydrogen balloon with palladium on
carbon (10%, 150 mg) in a mixture of MeOH and DCM (1:1, 10 ml) at
room temperature overnight. The reaction mixture was then filtered
through celite, volatiles removed in vacuo, and the residue
purified by flash chromatography to give
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine
(890 mg).
[0682] Intermediate G (750 mg) was reacted with
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine
(815 mg) in a General Procedure A. Purification by flash
chromatography afforded
4-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-t-
hieno[3,2-d]pyrimidin-2-yl]-benzene-1,2-diamine (535 mg).
[0683]
4-[6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thie-
no[3,2-d]pyrimidin-2-yl]-benzene-1,2-diamine (102 mg) was refluxed
in acetic acid (1 mL) for 1 hour. The reaction mixture was basified
with aqueous sodium hydrogen carbonate and extracted into DCM.
Flash chromatography and diethyl ether trituration gave the title
compound (47 mg).
[0684] NMR (CDCl3/MeOD): 2.56 (3H, s), 2.63-2.66 (4H, m), 2.78 (3H,
s), 3.24-3.27 (4H, m), 3.85 (2H, s), 3.85-3.87 (4H, m), 4.02-4.05
(4H, m), 7.29 (1H, s), 7.60 (1H, br), 8.22 (1H, d, J=1.5), 8.30
(1H, br)
[0685] MS (ESI+): MH+ 528.33
[0686] 154:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thie-
no[2,3-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic
acid pinacol ester in general procedure A. Purification by column
chromatography yielded
5-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-
-d]pyrimidin-2-yl]-pyrimidin-2-ylamine.
[0687] To a solution of
5-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-
-d]pyrimidin-2-yl]pyrimidin-2-ylamine (70 mg) in chloroacetaldehyde
(2 mL) was added sodium hydrogen carbonate (300 mg) and the mixture
was stirred at room temperature for 72 h. The mixture was then
diluted with dichloromethane (10 mL) and washed with aqueous brine
solution (2.times.10 mL), dried (MgSO.sub.4), reduced in vacuo and
purified by column chromatography to give the title compound.
[0688] NMR: CDCl.sub.3: 2.60-2.63 (4H, m), 2.54 (3H, s), 3.21-3.24
(4H, m), 3.76 (2H, s), 3.83-3.85 (4H, m), 3.91-3.94 (4H, m), 7.53
(1H, s, Ar), 7.78 (1H, s, Ar), 9.36 (1H, d, J 2.2, Ar) and 9.50
(1H, d, J 2.2, Ar).
[0689] MS: (ESI+): MH+ 515.19
[0690] 155: To 1-BOC-homopiperizine (0.8 ml) was added methane
sulphonyl chloride (0.34 ml) and triethylamine (0.68 ml). The
reaction mixture was stirred at room temperature for 4 hours. The
reaction mixture was then partitioned between dichloromethane and
water. The combined organic extracts were then washed with brine
and dried (MgSO.sub.4). The solvent was removed in vacuo to yield
1.23 g of crude 4-methanesulfonyl-[1,4]diazepane-1-carboxylic acid
tert-butyl ester.
[0691] Crude 4-methanesulfonyl-[1,40diazepane-1-carboxylic acid
tert-butyl ester (1.23 g) was stirred in anhydrous methanol (10
ml). 2M hydrogen chloride in ether (22 ml) was added. The reaction
mixture was stirred at room temperature. After 5 minutes a
precipitate formed, addition of anhydrous methanol (5 ml) caused
this to dissolve. The reaction mixture was stirred overnight at
room temperature. The solvents were removed in vacuo to yield 1.06
g of 1-methanesulfonyl-[1,4]diazepane hydrochloride salt.
[0692] Reaction between
2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde
and 1-methanesulfonyl-[1,4]diazepane hydrochloride salt using
General Procedure C (reductive amination) yielded
2-chloro-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morpholin-4-yl--
thieno[2,3-d]pyrimidine.
[0693]
2-Chloro-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morpholin-
-4-yl-thieno[2,3-d]pyrimidine was reacted with
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in
general procedure A. Purification by column chromatography yielded
the title compound.
[0694] (400 MHz CDCl3): 3.38-3.44 (4H, m, CH2), 3.86-3.92 (10H, m,
CH2), 7.10 (1H, s, ar), 7.42-7.46 (1H, m, ar), 7.53 (1H, d
(J=8.33), ar), 8.25 (1H, d (J=6.65), ar), 8.96 (1H, s, ar), 10.00
(1H, b, NH)
[0695] MH+=528.24
[0696] 156: To 1-BOC-homopiperizine (0.8 ml) was added methane
sulphonyl chloride (0.34 ml) and triethylamine (0.68 ml). The
reaction mixture was stirred at room temperature for 4 hours. The
reaction mixture was then partitioned between dichloromethane and
water. The combined organic extracts were then washed with brine
and dried (MgSO.sub.4). The solvent was removed in vacuo to yield
1.23 g crude 4-methanesulfonyl-[1,4]diazepane-1-carboxylic acid
tert-butyl ester.
[0697] Crude 4-Methanesulfonyl-[1,4]diazepane-1-carboxylic acid
tert-butyl ester (1.23 g) was stirred in anhydrous methanol (10
ml). 2M hydrogen chloride in ether (22 ml) was added. The reaction
mixture was stirred at room temperature. After 5 minutes a
precipitate formed, addition of anhydrous methanol (5 ml) caused
this to dissolve. The reaction mixture was stirred overnight at
room temperature. The solvents were removed in vacuo to yield 1.06
g of 1-methanesulfonyl-[1,4]diazepane hydrochloride salt.
[0698] Reaction between
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde
and 1-methanesulfonyl-[1,4]diazepane hydrochloride salt using
procedure C yielded
2-chloro-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morphol-
in-4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to
procedure A to yield the desired final compound which was purified
using flash chromatography.
[0699] NMR: (400 MHz, CDCl3): 1.26 (3H, s, CH3), 1.96 (2H, m, CH2),
2.86-2.88 (4H, m, CH2), 3.49-3.52 (4H, m, CH2), 3.92-3.94 (4H, m,
CH2), 4.03 (2H, s, CH2), 4.08-4.11 (4H, m, CH2), 7.38 (1H, s, ar),
7.51-7.53 (1H, m, ar), 7.58 (1H, d, ar), 8.28 (1H, d, J (7.41),
ar), 9.02 (1H, s, ar), 10.05 (1H, b, NH)
[0700] (M+H)+ 528.23
[0701] 157:
2-Nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(1.00 g) was stirred under hydrogen balloon with palladium on
carbon (10%, 150 mg) in a mixture of MeOH and DCM (1:1, 10 ml) at
room temperature overnight. The reaction mixture was then filtered
through celite, volatiles removed in vacuo, and the residue
purified by flash chromatography to give
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine
(890 mg).
[0702] Intermediate G (750 mg) was reacted with
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine
(815 mg) in a General Procedure A. Purification by flash
chromatography afforded
4-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-t-
hieno[3,2-d]pyrimidin-2-yl]-benzene-1,2-diamine (535 mg).
[0703]
4-[6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thie-
no[3,2-d]pyrimidin-2-yl]-benzene-1,2-diamine (102 mg) was refluxed
in acetic acid (1 mL) for 1 hour. The reaction mixture was basified
with aqueous sodium hydrogen carbonate and extracted into DCM.
Flash chromatography and diethyl ether trituration gave the title
compound (47 mg).
[0704] NMR (CDCl3/MeOD): 2.56 (3H, s), 2.63-2.66 (4H, m), 2.78 (3H,
s), 3.24-3.27 (4H, m), 3.85 (2H, s), 3.85-3.87 (4H, m), 4.02-4.05
(4H, m), 7.29 (1H, s), 7.60 (1H, br), 8.22 (1H, d, J=1.5), 8.30
(1H, br)
[0705] MS (ESI+): MH+ 528.33
[0706] 158:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thie-
no[3,2-d]pyrimidine was reacted with
5-(4,4,5,5-tetramethyl-[1.3.2]dioxaborolan-2-yl)-1H-indazole
(commercially available) in general procedure A. Purification by
column chromatography yielded the title compound.
[0707] NMR: CDCl3: 2.58-2.62 (4H, m, CH.sub.2), 2.74 (1H, s, Me),
3.22-3.25 (4H, m, CH.sub.2), 3.82 (2H, s, CH.sub.2), 3.82-3.86 (4H,
m, CH.sub.2), 4.00-4.02 (4H, m, CH.sub.2), 7.28 (1H, s, Ar), 7.48
(1H, d, J 8.2, Ar), 8.09 (1H, s, Ar), 8.48 (1H, d, J 8.2, Ar), 8.82
(1H, d, J 7.5, Ar) and 10.01 (1H, s, NH).
[0708] 159: A solution of
4-(6-((4-methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]p-
yrimidin-2-yl)benzene-1,2-diamine (87.5 mg, 0.20 mMol) in 1 mL of
formic acid was refluxed for several hours, then cooled to room
temperature and concentrated in vacuo to give a dark solid. This
residue was taken into DMF at 100 mM, and purified by prep RP-HPLC
to give 36.5 mg of the desired product in a 36.5% yield MS (Q1)
514.0 (M)+
[0709] 160: A solution of
4-(6-((4-methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]p-
yrimidin-2-yl)benzene-1,2-diamine (87.5 mg, 0.20 mMol) in 1 mL of
acetic acid was refluxed for several hours, then cooled to room
temperature and concentrated in vacuo to give a dark solid. This
residue was taken into DMF at 100 mM, and purified by prep RP-HPLC
to give 31.5 mg of the desired product in a 30% yield MS (Q1) 528.5
(M)+
[0710] 161:
12-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno-
[2,3-d]pyrimidine and 3,5-diaminophenyl boronic acid were used in
General procedure A Suzuki Coupling to produce
4-(6-((4-methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]p-
yrimidin-2-yl)benzene-1,2-diamine in 78% yield MS (Q1) 514.2
(M)+
Example 7
Biological Testing
[0711] Compounds of the invention, prepared as described in the
preceding Examples, were submitted to the following series of
biological assays:
(i) PI3K Biochemical Screening
[0712] Compound inhibition of PI3K was determined in a radiometric
assay using purified, recombinant enzyme and ATP at a concentration
of 1 uM. All compounds were serially diluted in 100% DMSO. The
kinase reaction was incubated for 1 hour at room temperature, and
the reaction was terminated by the addition of PBS. IC.sub.50
values were subsequently determined using sigmoidal dose-response
curve fit (variable slope). All of the compounds tested had an
IC.sub.50 against PI3K of 50 uM or less.
(ii) Cellular Proliferation Inhibition
[0713] Cells were seeded at optimal density in a 96 well plate and
incubated for 4 days in the presence of test compound. Alamar
Blue.TM. was subsequently added to the assay medium, and cells were
incubated for 6 hours before reading at 544 nm excitation, 590 nm
emission. EC.sub.50 values were calculated using a sigmoidal dose
response curve fit. All the compounds tested had an EC.sub.50s of
50 uM or less in the range of cell lines utilized.
(iii) Caco-2 Permeability
[0714] Caco-2 cells were seeded onto Millipore Multiscreen plates
at 1.times.10.sup.5 cells/cm.sup.2, and were cultured for 20 days.
Assessment of compound permeability was subsequently conducted. The
compounds were applied to the apical surface (A) of cell monolayers
and compound permeation into the basolateral (B) compartment was
measured. This was performed in the reverse direction (B-A) to
investigate active transport. A permeability coefficient value,
P.sub.app, for each compound, a measure of the rate of permeation
of the compound across the membrane, was calculated. Compounds were
grouped into low (P.sub.app<=1.0.times.10.sup.6 cm/s) or high
(P.sub.app>/=1.0.times.10.sup.6 cm/s) absorption potential based
on comparison with control compounds with established human
absorption.
[0715] For assessment of a compound's ability to undergo active
efflux, the ratio of basolateral (B) to apical (A) transport
compared with A to B was determined. Values of B-A/A-B>/=1.0
indicated the occurrence of active cellular efflux. All of the
compounds tested through the Caco-2 permeability screen had
P.sub.app values 4=1.0.times.10.sup.6 cm/s. One compound assessed
through the bidirectional assay, PI540, had an B-A/A-B asymmetry
index of less than 1.0, indicating that the compound does not
undergo active cellular efflux.
(iv) Hepatocyte Clearance
[0716] Suspensions of cryopreserved human hepatocytes were used.
Incubations were performed at compound concentration of 1 mM or 3
.mu.M at a cell density of 0.5.times.10.sup.6 viable cells/mL. The
final DMSO concentration in the incubation was 0.25%. Control
incubations were also performed in the absence of cells to reveal
any non-enzymatic degradation. Duplicate samples (50 .mu.L) were
removed from the incubation mixture at 0, 5, 10, 20, 40 and 60
minutes (control sample at 60 minutes only) and added to
methanol--containing internal standard (100 .mu.L)--to terminate
the reaction. Tolbutamide, 7-hydroxycoumarin, and testosterone were
used as control compounds. Samples were centrifuged and the
supernatants at each time point pooled for analysis by LC-MSMS.
From a plot of ln peak area ratio (parent compound peak
area/internal standard peak area) against time, intrinsic clearance
(CL.sub.int) was calculated as follows: CL.sub.int
(.mu.l/min/million cells)=V.times.k, where k is the elimination
rate constant, obtained from the gradient of ln concentration
plotted against time; V is a volume term derived from the
incubation volume and is expressed as uL 10.sup.6 cells.sup.-1.
[0717] Compounds were classified with low (CL</=4.64
.mu.L/min/10.sup.6 cells), medium (CL>/=4.6; </=25.2
.mu.l/min/10.sup.6 cells) and high (>/=25.2 .mu.l/min/10.sup.6
cells) clearance. The majority of the tested compounds of the
invention were determined to have low hepatocyte clearance.
(v) Cytochrome P450 Inhibition
[0718] Compounds of the invention were screened against five CYP450
targets (1A2, 2C9, 2C19, 2D6, 3A4) at 10 concentrations in
duplicate, with a top concentration of 100 uM being used. Standard
inhibitors (furafylline, sulfaphenazole, tranylcypromine,
quinidine, ketoconazole) were used as controls. Plates were read
using a BMG LabTechnologies PolarStar in fluorescence mode. The
majority of the tested compounds assessed in this assay displayed
weak activity (IC.sub.50>/=5 uM) against all isoforms of
CYP450.
(vi) Cytochrome P450 Induction
[0719] Freshly isolated human hepatocytes from a single donor were
cultured for 48 hours prior to addition of test compound at three
concentrations and were incubated for 72 hours. Probe substrates
for CYP3A4 and CYP1A2 were added for 30 minutes and 1 hour before
the end of the incubation. At 72 hours, cells and media were
removed and the extent of metabolism of each probe substrate
quantified by LC-MS/MS. The experiment was controlled by using
inducers of the individual P450s incubated at one concentration in
triplicate. The compounds of the invention assessed in this assay
showed negligible effects on induction of cytochrome P450
enzymes.
(vii) Plasma Protein Binding
[0720] Solutions of test compound (5 um, 0.5% final DMSO
concentration) were prepared in buffer and 10% plasma (v/v in
buffer). A 96 well HT dialysis plate was assembled so that each
well was divided in two by a semi-permeable cellulose membrane. The
buffer solution was added to one side of the membrane and the
plasma solution to the other side; incubations were then conducted
at 37.degree. C. over 2 hours in triplicate. The cells were
subsequently emptied, and the solutions for each batch of compounds
were combined into two groups (plasma-free and plasma-containing)
then analysed by LC-MSMS using two sets of calibration standards
for plasma-free (6 points) and plasma-containing solutions (7
points). The fraction unbound value for each compound was
calculated: highly protein bound compounds (>/=90% bound) had an
Fu</=0.1. The compounds of the invention assessed in this assay
had Fu values>/=0.1.
(viii) hERG channel blockage
[0721] Compounds of the invention were evaluated for their ability
to modulate rubidium efflux from HEK-294 cells stably expressing
hERG potassium channels using established flux methodology. Cells
were prepared in medium containing RbCl and were plated into
96-well plates and grown overnight to form monolayers. The efflux
experiment was initiated by aspirating the media and washing each
well with 3.times.100 .mu.L of pre-incubation buffer (containing
low [K.sup.+]) at room temperature. Following the final aspiration,
50 .mu.L of working stock (2.times.) compound was added to each
well and incubated at room temperature for 10 minutes. 50 .mu.L of
stimulation buffer (containing high [K+]) was then added to each
well giving the final test compound concentrations. Cell plates
were then incubated at room temperature for a further 10 minutes.
80 .mu.L of supernatant from each well was then transferred to
equivalent wells of a 96-well plate and analysed via atomic
emission spectroscopy. Compounds were screened as 10 pt duplicate
IC.sub.50 curves, n=2, from a top concentration of 100 .mu.M.
Example 8
p110 Isoform Selectivity Scintillation Proximity Binding Assay
[0722] The ability of representative compounds from Tables 1a and
1b to inhibit the lipid kinase activity of purified preparations of
human PI3K isoforms alpha, beta, delta, and gamma was determined by
a radiometric scintillation proximity assay (SPA, GE Healthcare,
Amersham Biosciences). Concentration dependent inhibition at 50%
(IC.sub.50 .mu.Mol) was determined for all four isoforms (alpha)
and fold potency over beta, delta, and gamma relative to alpha was
calculated for a selection of compounds in Table 2. Each compound
has a p110 alpha IC.sub.50<1 .mu.Mol.
TABLE-US-00003 TABLE 2 Compound alpha/beta alpha/delta alpha/gamma
2 >10 <10 >10 4 >10 <10 >10 7 >10 <10
>10 16 >10 <10 >10 23 >10 <10 >10 24 >10
<10 >10 27 >10 <10 >10 28 >10 <10 >10 29
>10 <10 >10 34 >10 <10 >10 54 <10 <10
>10 57 >10 <10 >10 58 >10 <10 >10 59 >10
<10 >10 60 >10 <10 >10 62 >10 <10 >10 65
<10 <10 >10 66 <10 <10 >10 89 >10 >10
>10 90 >10 <10 >10 94 >10 <10 >10 95 >10
>10 >10 133 >10 <10 >10 139 <10 <10 <10 140
>10 >10 >10 141 <10 <10 >10 142 >10 <10
>10 144 <10 <10 >10 147 >10 >10 >10 157 >10
<10 >10
Example 9
Tablet Composition
[0723] Tablets, each weighing 0.15 g and containing 25 mg of a
compound of the invention are manufactured as follows:
Composition for 10,000 tablets Active compound (250 g)
Lactose (800 g)
[0724] Corn starch (415 g) Talc powder (30 g) Magnesium stearate (5
g)
[0725] The active compound, lactose and half of the corn starch are
mixed. The mixture is then forced through a sieve 0.5 mm mesh size.
Corn starch (10 g) is suspended in warm water (90 ml). The
resulting paste is used to granulate the powder. The granulate is
dried and broken up into small fragments on a sieve of 1.4 mm mesh
size. The remaining quantity of starch, talc and magnesium is
added, carefully mixed and processed into tablets.
Example 10
Injectable Formulation
Formulation A
TABLE-US-00004 [0726] Active compound 200 mg Hydrochloric Acid
Solution 0.1M or 4.0 to 7.0 Sodium Hydroxide Solution 0.1M q.s. to
pH Sterile water q.s. to 10 ml
[0727] The compound of the invention is dissolved in most of the
water (35.degree. 40.degree. C.) and the pH adjusted to between 4.0
and 7.0 with the hydrochloric acid or the sodium hydroxide as
appropriate. The batch is then made up to volume with water and
filtered through a sterile micropore filter into a sterile 10 ml
amber glass vial (type 1) and sealed with sterile closures and
overseals.
Formulation B
TABLE-US-00005 [0728] Active Compound 125 mg Sterile, Pyrogen-free,
pH 7 Phosphate Buffer, q.s. to 25 ml Active compound 200 mg Benzyl
Alcohol 0.10 g Glycofurol 75 1.45 g Water for injection q.s to 3.00
ml
[0729] The active compound is dissolved in the glycofurol. The
benzyl alcohol is then added and dissolved, and water added to 3
ml. The mixture is then filtered through a sterile micropore filter
and sealed in sterile 3 ml glass vials (type 1).
Example 11
Syrup Formulation
TABLE-US-00006 [0730] Active compound 250 mg Sorbitol Solution 1.50
g Glycerol 2.00 g Sodium benzoate 0.005 g Flavour 0.0125 ml
Purified Water q.s. to 5.00 ml
[0731] The compound of the invention is dissolved in a mixture of
the glycerol and most of the purified water. An aqueous solution of
the sodium benzoate is then added to the solution, followed by
addition of the sorbitol solution and finally the flavour. The
volume is made up with purified water and mixed well.
* * * * *