U.S. patent application number 12/128479 was filed with the patent office on 2009-08-27 for substituted quinazoline derivatives as inhibitors of aurora kinases.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Frederic Henri Jung, Georges Rene Pasquet.
Application Number | 20090215770 12/128479 |
Document ID | / |
Family ID | 8183051 |
Filed Date | 2009-08-27 |
United States Patent
Application |
20090215770 |
Kind Code |
A1 |
Jung; Frederic Henri ; et
al. |
August 27, 2009 |
Substituted Quinazoline Derivatives as Inhibitors of Aurora
Kinases
Abstract
The invention provides quinazoline derivatives of formula (I):
##STR00001## in the preparation of a medicament for use in the
inhibition of Aurora kinase and also novel quinazoline derivatives,
processes for their preparation, pharmaceutical compositions
containing them and their use in therapy.
Inventors: |
Jung; Frederic Henri; (Reims
Cedex, FR) ; Pasquet; Georges Rene; (Reims Cedex,
FR) |
Correspondence
Address: |
ASTRAZENECA R&D BOSTON
35 GATEHOUSE DRIVE
WALTHAM
MA
02451-1215
US
|
Assignee: |
AstraZeneca AB
Sodertalje
SE
|
Family ID: |
8183051 |
Appl. No.: |
12/128479 |
Filed: |
May 28, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10499684 |
Nov 17, 2004 |
7402585 |
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PCT/GB02/05845 |
Dec 20, 2002 |
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12128479 |
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Current U.S.
Class: |
514/234.5 ;
514/266.22; 514/266.23; 544/119; 544/284 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 31/517 20130101; C07D 401/14 20130101; C07D 403/14 20130101;
A61P 35/00 20180101; C07D 403/12 20130101 |
Class at
Publication: |
514/234.5 ;
544/119; 544/284; 514/266.23; 514/266.22 |
International
Class: |
A61K 31/517 20060101
A61K031/517; C07D 413/14 20060101 C07D413/14; C07D 403/12 20060101
C07D403/12; C07D 403/14 20060101 C07D403/14; C07D 401/14 20060101
C07D401/14; A61K 31/5377 20060101 A61K031/5377 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 24, 2001 |
EP |
01403357.5 |
Claims
1. Use of a compound of formula (I): ##STR00035## or a salt, ester
or amide thereof, where: X is O or S, S(O) or S(O).sub.2, or
NR.sup.6 where R.sup.6 is hydrogen or C.sub.1-6alkyl; R.sup.5 is a
group of formula (a) or (b): ##STR00036## where * indicates the
point of attachment to the group X in formula (I); R.sup.1,
R.sup.2, R.sup.3, R.sup.4 are independently selected from hydrogen,
halo, cyano, nitro, trifluoromethyl, C.sub.1-3alkyl,
--NR.sup.7R.sup.8 or --X.sup.1R.sup.9; R.sup.7 and R.sup.8 are
independently hydrogen or C.sub.1-3alkyl; X.sup.1 is a direct bond,
--O--, --CH.sub.2--, --OCO--, carbonyl, --S--, --SO--,
--SO.sub.2--, --NR.sup.10CO--, --CONR.sup.11--,
--SO.sub.2NR.sup.12--, --NR.sup.13SO.sub.2-- or --NR.sup.14--;
R.sup.10, R.sup.11, R.sup.12, R.sup.13 and R.sup.14 are
independently hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl; R.sup.9 is selected from one of the
following groups: 1) hydrogen or C.sub.1-5alkyl which may be
unsubstituted or which may be substituted with one or more groups
selected from hydroxy, fluoro or amino; 2)
C.sub.1-5alkylX.sup.2COR.sup.15 (wherein X.sup.2 represents --O--
or --NR.sup.16-- (in which R.sup.15 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.16
represents C.sub.1-3alkyl, --NR.sup.17R.sup.18 or --OR.sup.19
(wherein R.sup.17, R.sup.18 and R.sup.19 which may be the same or
different each represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); 3) C.sub.1-5alkylX.sup.3R.sup.20
(wherein X.sup.3 represents --O--, --S--, --SO--, --SO.sub.2--,
--OCO--, --NR.sup.21CO--, --CONR.sup.22--, --SO.sub.2NR.sup.23--,
--NR.sup.24SO.sub.2-- or --NR.sup.25-- (wherein R.sup.21, R.sup.22,
R.sup.23, R.sup.24 and R.sup.25 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.20 represents hydrogen, C.sub.1-3alkyl, cyclopentyl,
cyclohexyl or a 5- or 6-membered saturated heterocyclic group with
1 or 2 heteroatoms, selected independently from O, S and N, which
C.sub.1-3alkyl group may bear 1 or 2 substituents selected from
oxo, hydroxy, halo and C.sub.1-4alkoxy and which cyclic group may
bear 1 or 2 substituents selected from oxo, hydroxy, halo,
C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl and C.sub.1-4alkoxy); 4)
C.sub.1-5alkylX.sup.4C.sub.1-5alkylX.sup.5R.sup.26 (wherein X.sup.4
and X.sup.5 which may be the same or different are each --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.27CO--, --CONR.sup.28--,
--SO.sub.2NR.sup.29--, --NR.sup.30SO.sub.2-- or --NR.sup.31--
(wherein R.sup.27, R.sup.28, R.sup.29, R.sup.30 and R.sup.31 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.26 represents hydrogen or
C.sub.1-13alkyl); 5) R.sup.32 (wherein R.sup.2 is a 5- or
6-membered saturated heterocyclic group (linked via carbon or
nitrogen) with 1 or 2 heteroatoms, selected independently from O, S
and N, which heterocyclic group may bear 1 or 2 substituents
selected from oxo, hydroxy, halo, C.sub.1-4alkyl,
C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl and
C.sub.1-4alkylsulphonylC.sub.1-4alkyl); 6) C.sub.1-5alkylR.sup.32
(wherein R.sup.32 is as defined hereinbefore); 7)
C.sub.2-5alkenylR.sup.32 (wherein R.sup.32 is as defined
hereinbefore); 8) C.sub.2-5alkynylR.sup.32 (wherein R.sup.32 is as
defined hereinbefore); 9) R.sup.33 (wherein R.sup.33 represents a
pyridone group, a phenyl group or a 5- or 6-membered aromatic
heterocyclic group (linked via carbon or nitrogen) with 1, 2 or 3
heteroatoms selected from O, N and S, which pyridone, phenyl or
aromatic heterocyclic group may carry up to 5 substituents on
available carbon atoms selected from hydroxy, halo, amino,
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4hydroxyalkyl,
C.sub.1-4-aminoalkyl, C.sub.1-4alkylamino, C.sub.1-4hydroxyalkoxy,
carboxy, trifluoromethyl, cyano, --CONR.sup.34R.sup.35 and
--NR.sup.36COR.sup.37 (wherein R.sup.34, R.sup.35, R.sup.36 and
R.sup.37, which may be the same or different, each represents
hydrogen, C.sub.1-4alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl)); 10)
C.sub.1-5alkylR.sup.33 (wherein R.sup.33 is as defined
hereinbefore); 11) C.sub.2-5alkenylR.sup.33 (wherein R.sup.33 is as
defined hereinbefore); 12) C.sub.2-5alkynylR.sup.33 (wherein
R.sup.33 is as defined hereinbefore); 13)
C.sub.1-5alkylX.sup.6R.sup.33 (wherein X.sup.6 represents --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.38CO--, --CONR.sup.39--,
--SO.sub.2NR.sup.40--, --NR.sup.41SO.sub.2-- or --NR.sup.42--
(wherein R.sup.38, R.sup.39, R.sup.40, R.sup.41 and R.sup.42 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.33 is as defined
hereinbefore); 14) C.sub.2-5alkenylX.sup.7R.sup.33 (wherein X.sup.7
represents --O--, --S--, --SO--, --SO.sub.2--, --NR.sup.43CO--,
--CONR.sup.44--, --SO.sub.2NR.sup.45--, --NR.sup.46SO.sub.2-- or
--NR.sup.47-- (wherein R.sup.43, R.sup.44, R.sup.45, R.sup.46 and
R.sup.47 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.33 is as defined
hereinbefore); 15) C.sub.2-5alkynylX.sup.8R.sup.33 (wherein X.sup.8
represents --O--, --S--, --SO--, --SO.sub.2--, --NR.sup.48CO--,
--CONR.sup.49--, --SO.sub.2NR.sup.50--, --NR.sup.51SO.sub.2-- or
--NR.sup.52 (wherein R.sup.48, R.sup.49, R.sup.50, R.sup.51 and
R.sup.52 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.33 is as defined
hereinbefore); 16) C.sub.1-3alkylX.sup.9C.sub.1-3alkylR.sup.33
(wherein X.sup.9 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.53CO--, --CONR.sup.54--SO.sub.2NR.sup.55,
--NR.sup.56SO.sub.2-- or --NR.sup.5-- (wherein R.sup.57, R.sup.53,
R.sup.54, R.sup.55 and R.sup.56 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.33 is as defined hereinbefore); 17)
C.sub.1-3alkylX.sup.9C.sub.1-3alkylR.sup.32 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); 18) C.sub.1-5alkyl
optionally substituted by 1, 2 or 3 halo; 19)
C.sub.1-5alkylX.sup.10C.sub.1-5alkylX.sup.11R.sup.90 (wherein
X.sup.10 and X.sup.11, which may be the same or different, are each
--O--, --S--, --SO--, --SO.sub.2--, --NR.sup.91CO--,
--CONR.sup.92--, --SO.sub.2NR.sup.93--, --NR.sup.94SO.sub.2-- or
--NR.sup.95-- (wherein R.sup.91, R.sup.92, R.sup.93, R.sup.94 and
R.sup.95 each independently represents C.sub.1-5alkyl,
C.sub.1-3alkyl (substituted by 1, 2 or 3 halo, C.sub.1-4alkyl or
C.sub.1-4alkoxy groups (and where there are 2 C.sub.1-4alkoxy
groups the C.sub.1-4alkyl groups of alkoxy may together form a 5-
or 6-membered saturated heterocyclic group having 2 oxygen atoms)),
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.3-6cycloalkyl (optionally
substituted by halo, hydroxy, C.sub.1-3alkyl or
C.sub.1-4hydroxyalkyl), C.sub.3-6cycloalkylC.sub.1-3alkyl
(optionally substituted by halo, hydroxy, C.sub.1-3alkyl or
C.sub.1-4hydroxyalkyl) or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.90 represents hydrogen or C.sub.1-3alkyl); 20)
C.sub.3-6cycloalkyl; 21) R.sup.96 (wherein R.sup.96 is a 5- or
6-membered heterocyclic group which may be saturated or unsaturated
(linked via carbon or nitrogen) with 1 or 2 heteroatoms, selected
independently from O, S and N which heterocyclic group may bear 1
or 2 substitutents selected from C.sub.1-4hydroxyalkyl,
C.sub.1-4alkyl, hydroxy and C.sub.1-4alkoxyC.sub.1-4alkyl; 22)
C.sub.1-5alkylR.sup.96 (wherein R.sup.96 is defined hereinbefore);
and where: R.sup.60, R.sup.61 and R.sup.62 are independently
hydrogen, nitro, cyano, halo, oxo, amino, trifluoromethyl,
C.sub.1-4alkoxymethyl, di(C.sub.1-4alkoxy)methyl or
C.sub.1-6alkanoyl or a group selected from C.sub.1-10alkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl, C.sub.1-10alkoxy, arylC.sub.1-10alkyl,
aryl, C.sub.3-10cycloalkyl, C.sub.3-10cycloalkenyl and
C.sub.3-10cycloalkynyl (which group is optionally substituted by 1,
2 or 3 substituents independently selected from halo,
C.sub.1-4alkyl (optionally substituted by 1, 2 or 3 halo),
mercapto, hydroxy, carboxy, C.sub.1-10alkoxy, nitro, cyano, aryl,
heteroaryl, heteroaryloxy, C.sub.2-10alkenyloxy,
C.sub.2-10alkynyloxy, C.sub.1-4alkoxyC.sub.1-4alkoxy, aryloxy
(where the aryl group may be substituted by halo, nitro, or
hydroxy), amino, cyano, nitro, mono- or di(C.sub.1-6alkyl)amino,
oximino or S(O).sub.y where y is 0, 1, 2 or 3), or a group selected
from .dbd.CR.sup.78R.sup.79, C(O).sub.xR.sup.77, OR.sup.77,
S(O).sub.yR.sup.77, NR.sup.78R.sup.79, C(O)NR.sup.78R.sup.79,
OC(O)NR.sup.78R.sup.79, .dbd.NOR.sup.77,
--NR.sup.77C(O).sub.xR.sup.78, --NR.sup.77CONR.sup.78R.sup.79,
--N.dbd.CR.sup.78R.sup.79, S(O).sub.yNR.sup.78R.sup.79 or
--NR.sup.77S(O).sub.yR.sup.78 or a group selected from phenyl,
benzyl or a 5- to 6-membered heterocyclic group with 1, 2 or 3
heteroatoms, selected independently from O, S and N, which
heterocyclic group may be aromatic or non-aromatic and may be
saturated (linked via a ring carbon or nitrogen atom) or
unsaturated (linked via a ring carbon atom), which phenyl, benzyl
or heterocyclic group may bear on one or more carbon ring atoms up
to 5 substituents selected from hydroxy, halo, C.sub.1-3alkyl,
C.sub.1-3alkoxy, C.sub.1-3alkanoyloxy, trifluoromethyl, cyano,
amino, nitro, C.sub.2-4alkanoyl, C.sub.1-4alkanoylamino,
C.sub.1-4alkoxycarbonyl, C.sub.1-4alkylsulphanyl,
C.sub.1-4alkylsulphinyl, C.sub.1-4alkylsulphonyl, carbamoyl,
N--C.sub.1-4alkylcarbamoyl, N,N-di(C.sub.1-4alkyl)carbamoyl,
aminosulphonyl, N--C.sub.1-4alkylaminosulphonyl,
N,N-di(C.sub.1-4alkyl)aminosulphonyl, C.sub.1-4alkylsulphonylamino,
and a saturated heterocyclic group selected from morpholino,
thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl,
imidazolidinyl and pyrazolidinyl, which saturated heterocyclic
group may bear 1 or 2 substituents selected from oxo, hydroxy,
halo, C.sub.1-3alkyl, C.sub.1-3alkoxy, C.sub.1-3alkanoyloxy,
trifluoromethyl, cyano, amino, nitro and C.sub.1-4alkoxycarbonyl,
or a group of sub-formula (k): ##STR00037## or a group of
sub-formula (II): ##STR00038## or a group of sub-formula (VI):
##STR00039## where: p and q are independently 0 or 1; r is 0, 1, 2,
3 or 4; R.sub.1' and R.sub.1'' are independently hydrogen, hydroxy,
halo, cyano, C.sub.1-10alkyl, C.sub.3-10cycloalkyl,
C.sub.2-10alkenyl or C.sub.2-10alkynyl (wherein C.sub.1-10alkyl,
C.sub.3-10cycloalkyl, C.sub.2-10alkenyl and C.sub.2-10alkynyl are
optionally substituted by halo, nitro, cyano, hydroxy,
trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C.sub.1-14alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl,
C.sub.3-6cycloalkyl, C.sub.3-6cycloalkenyl, C.sub.1-4alkoxy,
C.sub.1-4alkanoyl, C.sub.1-4alkanoyloxy, C.sub.1-4alkanoylamino,
N,N-di(C.sub.1-4alkanoyl)amino, N--(C.sub.1-14alkyl)carbamoyl,
N,N-di(C.sub.1-4alkyl)carbamoyl, C.sub.1-14alkylS,
C.sub.1-4alkylS(O), C.sub.1-4alkylS(O).sub.2,
C.sub.1-4alkoxycarbonyl, N--(C.sub.1-4 alkyl)sulphamoyl,
N,N-di(C.sub.1-4alkyl)sulphamoyl, C.sub.1-14alkylsulphonylamino or
heterocyclyl); or R.sub.1' and R.sub.1'' can together form a 3- to
6-membered ring which may be saturated or unsaturated; T is
C.dbd.O, SO.sub.n (where n is 0, 1 or 2), C(.dbd.NOR)CO, C(O)C(O),
C.dbd.NCN or CV.dbd.NO; V is independently R.sup.63 or
N(R.sup.63)R.sup.64; R.sup.63 and R.sup.64 are independently
selected from hydrogen, --(CH.sub.2).sub.q'R.sup.70 (q' is 0 or 1),
aryl (optionally substituted by 1, 2 or 3 C.sub.1-6alkyl
(optionally substituted by 1, 2 or 3 hydroxy groups)),
C.sub.1-10alkyl (optionally substituted by 1, 2 or 3 groups
independently selected from aryl or heterocyclic group where aryl
and heterocyclic group are optionally substituted by 1, 2, or 3
groups independently selected from C.sub.1-6alkyl, nitro, cyano,
halo, oxo, .dbd.CR.sup.78R.sup.79, C(O).sub.xR.sup.77, OR.sup.77,
S(O).sub.yR.sup.77, NR.sup.78R.sup.79, C(O)NR.sup.78R.sup.79,
OC(O)NR.sup.78R.sup.79, .dbd.NOR.sup.77,
--NR.sup.77C(O).sub.xR.sup.78, --NR.sup.77CONR.sup.78R.sup.79,
--N.dbd.CR.sup.78R.sup.79, S(O).sub.yNR.sup.78R.sup.79,
--NR.sup.77S(O).sub.yR.sup.78) or a group selected from
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
heterocyclyl, C.sub.1-10alkoxy, C.sub.1-10alkyl, aryl,
C.sub.3-10cycloalkyl, C.sub.3-10cycloalkenyl and
C.sub.3-10cycloalkynyl (which group is optionally substituted by 1,
2 or 3 groups independently selected from C.sub.1-6alkyl,
C.sub.1-4alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl,
difluoromethoxy, nitro, cyano, halo, oxo, .dbd.CR.sup.78R.sup.79,
C(O).sub.xR.sup.77, OR.sup.77, S(O).sub.yR.sup.77,
NR.sup.78R.sup.79, C(O)NR.sup.78R.sup.79, OC(O)NR.sup.78R.sup.79,
.dbd.NOR.sup.77, --NR.sup.77C(O).sub.xR.sup.78,
--NR.sup.77CONR.sup.78R.sup.79, --N.dbd.CR.sup.78R.sup.79,
S(O).sub.yNR.sup.78R.sup.79, --NR.sup.77S(O).sub.yR.sup.71); or
R.sup.63 and R.sup.64 together with the nitrogen atom to which they
are attached form a heterocyclic ring which ring is aromatic or
non-aromatic and which is optionally substituted by hydroxy,
C.sub.1-6alkoxy or C.sub.1-6alkyl (optionally substituted by
hydroxy); R.sup.70 is hydrogen, hydroxy (other than when q is 0),
C.sub.1-6alkyl, C.sub.1-6alkoxy, amino, N--C.sub.1-6alkylamino,
N,N-di(C.sub.1-6alkyl)amino, C.sub.2-6hydroxyalkoxy,
C.sub.1-6alkoxyC.sub.2-6alkoxy, aminoC.sub.2-6alkoxy,
N--C.sub.1-6alkylaminoC.sub.2-6alkoxy,
N,N-di(C.sub.1-6alkyl)aminoC.sub.2-6alkoxy, C.sub.3-7cycloalkyl
(optionally substituted by 1 or 2 oxo or thioxo substitutents) or
of formula (III): --K-J (III) K is a bond, oxy, imino,
N--(C.sub.1-6alkyl)imino, oxyC.sub.1-6alkylene,
iminoC.sub.1-6alkylene, N--(C.sub.1-6alkyl)iminoC.sub.1-6alkylene,
--NHC(O)--, --SO.sub.2NH--, --NHSO.sub.2--,
--NHC(O)--C.sub.1-6alkylene-, --OCO-- or C.sub.2-4alkenylene; J is
aryl, heteroaryl or heterocyclyl (where hetrocyclyl is optionally
substituents by 1 or 2 oxo or thioxo substituents); and wherein any
aryl, heteroaryl or heterocyclyl group in a R.sup.70 group is
optionally substituted by 1, 2, 3 or 4 groups selected from
hydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino,
carboxy, carbamoyl, formyl, aminosulphonyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
--O--(C.sub.1-3alkyl)-O--, C.sub.1-6alkylS(O).sub.n-- (where n is
0, 1 or 2), N--C.sub.1-6alkylamino, N,N-di(C.sub.1-6alkyl)amino,
C.sub.1-6alkoxycarbonyl, N--C.sub.1-6alkylcarbamoyl,
N,N-di(C.sub.1-6alkyl)carbamoyl, C.sub.2-6alkanoyl,
C.sub.1-6alkanoyloxy, C.sub.1-6alkanoylamino,
N--C.sub.1-6alkylaminosulphonyl,
N,N-di(C.sub.1-6alkyl)aminosulphonyl, C.sub.1-6alkylsulphonylamino
and C.sub.1-6alkylsulphonyl-N--(C.sub.1-6alkyl)amino or by 1, 2, 3
or 4 groups selected from: a group of formula (IV) ##STR00040##
(wherein A.sup.1 is halo, hydroxy, C.sub.1-6alkoxy, cyano, amino,
C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino, carboxy,
C.sub.1-6alkoxycarbonyl, carbamoyl, N--C.sub.1-6alkylcarbamoyl or
N,N-di(C.sub.1-6alkyl)carbamoyl; p' is 1, 2, 3, 4, 5 or 6; and
B.sup.1 is a bond, oxy, imino, N--(C.sub.1-6alkyl)imino or
--NHC(O)--; with the proviso that p is 2 or more unless B.sup.1 is
a bond or --NHC(O)--); and a group of formula (V) ##STR00041##
(wherein D.sup.1 is aryl, heteroaryl or heterocyclyl (where
heterocyclyl is optionally substituted by 1 or 2 oxo or thioxo
substituents) and E.sup.1 is a bond, C.sub.1-6alkylene,
oxyC.sub.1-6alkylene, oxy, imino, N--(C.sub.1-6alkyl)imino,
iminoC.sub.1-6alkylene, N--(C.sub.1-6alkyl)iminoC.sub.1-6alkylene,
C.sub.1-6alkylene-oxyC.sub.1-6alkylene,
C.sub.1-6alkylene-iminoC.sub.1-16alkylene,
C.sub.1-16alkylene-N--(C.sub.1-16alkyl)-iminoC.sub.1-6alkylene,
--NHC(O)--, --NHSO.sub.2--, --SO.sub.2NH-- or
--NHC(O)--C.sub.1-6alkylene-, and any aryl, heteroaryl or
heterocyclyl group in a substituent on D.sup.1 is optionally
substituted with 1, 2, 3 or 4 groups selected from hydroxy, halo,
C.sub.1-6alkyl, C.sub.1-6alkoxy, carboxy, C.sub.1-6alkoxycarbonyl,
carbamoyl, N--C.sub.1-6alkylcarbamoyl,
N,N-di(C.sub.1-16alkyl)carbamoyl, C.sub.2-6alkanoyl, amino,
C.sub.1-16alkylamino and di(C.sub.1-6alkyl)amino); and any of the
R.sup.70 groups defined hereinbefore which comprises a CH.sub.2
group which is attached to 2 carbon atoms or a CH.sub.3 group which
is attached to a carbon atom optionally bears on each said CH.sub.2
or CH.sub.3 group a substituent selected from hydroxy, amino,
C.sub.1-6alkoxy, C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino and
heterocyclyl; R.sup.71 and R.sup.72 are independently selected from
hydrogen or C.sub.1-4alkyl or R.sup.71 and R.sup.72 together form a
bond; R.sup.73 is OR.sup.74 or NR.sup.71R.sup.76; R.sup.74,
R.sup.75 and R.sup.76 are independently C.sub.1-10alkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, aryl, heterocyclyl,
C.sub.1-10alkoxy, arylC.sub.1-10alkyl, C.sub.3-10cycloalkyl,
C.sub.3-10cycloalkenyl, C.sub.3-10cycloalkynyl, each of which is
optionally substituted by 1, 2, 3 or 4 groups selected from nitro,
cyano, halo, oxo, .dbd.CR.sup.78R.sup.79, C(O).sub.xR.sup.77,
OR.sup.77, S(O).sub.yR.sup.77, NR.sup.78R.sup.79,
C(O)NR.sup.78R.sup.79, OC(O)NR.sup.78R.sup.79, .dbd.NOR.sup.77,
--NR.sup.77C(O).sub.xR.sup.78, --NR.sup.77CONR.sup.78R.sup.79,
--N.dbd.CR.sup.78R.sup.79, S(O).sub.yNR.sup.78R.sup.79 or
--NR.sup.77S(O).sub.yR.sup.78 where y is 0, 1, 2 or 3; or R.sup.74,
R.sup.75 and R.sup.76 are independently heterocyclyl optionally
substituted by C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl
and C.sub.3-6cycloalkyl; or R.sup.75 and R.sup.76 together with the
nitrogen to which they are attached form an aromatic or
non-aromatic ring which optionally contains 1, 2 or 3 further
heteroatoms independently selected from N, O and S; R.sup.77,
R.sup.78 and R.sup.79 are independently selected from hydrogen or a
group selected from C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, aryl, heterocyclyl, C.sub.1-10alkoxy,
arylC.sub.1-10alkyl, C.sub.3-10cycloalkyl, C.sub.3-10cycloalkenyl,
C.sub.3-10cycloalkynyl where the group is optionally substituted by
halo, C.sub.1-4 perhaloalkyl, mercapto, hydroxy, carboxy,
C.sub.1-10alkoxy, aryl, heteroaryl, heteroaryloxy,
C.sub.2-10alkenyloxy, C.sub.2-10alkynyloxy,
C.sub.1-6alkoxyC.sub.1-6alkoxy, aryloxy (where the aryl group may
be substituted by halo, nitro, or hydroxy), cyano, nitro, amino,
mono- or di(C.sub.1-6alkyl)amino, oximino or S(O).sub.y where y is
0, 1, 2 or 3; or R.sup.78 and R.sup.79 together form a ring which
optionally contains further heteroatoms such as S(O).sub.y oxygen
and nitrogen, x is an integer of 1 or 2, y is 0, 1, 2 or 3 which
ring is optionally substituted by 1, 2 or 3 groups independently
selected from halo, C.sub.1-4 perhaloalkyl, mercapto, hydroxy,
carboxy, C.sub.1-10alkoxy, aryl, heteroaryl, heteroaryloxy,
C.sub.2-10alkenyloxy, C.sub.2-10alkynyloxy,
C.sub.1-6alkoxyC.sub.1-6alkoxy, aryloxy (where the aryl group may
be substituted by halo, nitro, or hydroxy), cyano, nitro, amino,
mono- or di(C.sub.1-6alkyl)amino, oximino or S(O).sub.y where y is
0, 1, 2 or 3; in the preparation of a medicament for use in the
inhibition of Aurora kinase.
2. Use according to claim 1 wherein Aurora kinase is Aurora-A
kinase.
3. Use according to claim 1 or 2 wherein R.sup.9 is hydrogen,
C.sub.3-6cycloalkyl, --C.sub.1-5alkyl-O--C.sub.1-3alkyl or a 5- to
6-membered saturated heterocyclic group (linked via carbon or
nitrogen) with 1 or 2 heteroatoms selected independently from O, S
or N which heterocyclic group is optionally substituted by
C.sub.1-4alkyl or R.sup.9 is a 5- or 6-membered aromatic
heterocyclic group (linked via carbon or nitrogen) with 1, 2 or 3
heteroatoms or R.sup.9 is --C.sub.1-5alkylR.sup.32,
--C.sub.1-5alkylR.sup.96, C.sub.1-5alkyl (optionally substituted by
halo), --C.sub.1-5alkyl-OR.sup.20, --C.sub.1-5alkyl-NHR.sup.20,
--C.sub.1-5alkyl-N(C.sub.1-3alkyl)-R.sup.20,
--C.sub.1-5alkyl-NH--C.sub.1-5alkyl-OH,
--C.sub.1-5alkyl-N(C.sub.1-3alkyl)-C.sub.1-5alkyl-OH and
--C.sub.1-5alkyl-NR.sup.95--C.sub.1-5alkyl-OH and wherein R.sup.32,
R.sup.96, R.sup.20 and R.sup.95 are as defined in claim 1.
4. Use according to any one of the preceding claims wherein X.sup.1
is --O--.
5. Use according to any one of the preceding claims wherein R.sup.1
is hydrogen, methoxy, N--(C.sub.1-5alkyl)piperidin-4-yloxy,
prop-2-yloxy or methoxyethoxy; R.sup.2 is hydrogen or methoxy; and
R.sup.4 is hydrogen.
6. A method for inhibiting Aurora kinase in a warm blooded animal,
such as man, in need of such treatment, which comprises
administering to said animal an effective amount of a compound as
defined in claim 1, or a pharmaceutically acceptable salt or an in
vivo hydrolysable ester thereof.
7. A compound of formula (IA): ##STR00042## or a salt, ester or
amide thereof, wherein X is as defined in claim 1; R.sup.1',
R.sup.2', R.sup.3', R.sup.4' are equivalent to R.sup.1, R.sup.2,
R.sup.3, R.sup.4 as defined in claim 1; and R.sup.5a is equivalent
to R.sup.5 as defined in claim 1; provided that one of R.sup.60,
R.sup.61 and R.sup.62 of R.sup.5a is other than hydrogen and that
if R.sup.61 is other than hydrogen, it is not a group selected
from: phenylC.sub.1-3alkyl, heteroaryl or optionally substituted
phenyl; and C.sub.3-5cycloalkyl, C.sub.3-5cycloalkylC.sub.1-3alkyl,
C.sub.2-5alkenyl or optionally substituted C.sub.1-4alkyl; where
optional substitutents for phenyl and C.sub.1-4alkyl are
C.sub.1-4alkyl, halo, methoxy, nitro or trifluoromethyl.
8. A compound according to claim 7 wherein R.sup.60 and R.sup.62
are both hydrogen and R.sup.61 is a group of sub-formula (k):
##STR00043## wherein R.sub.1' and R.sub.1'' are independently
hydrogen or C.sub.1-3alkyl; T is C.dbd.O; q is 1; and V is
N(R.sup.63)R.sup.64.
9. A compound according to claim 8 wherein R.sup.64 is hydrogen or
C.sub.1-3alkyl and R.sup.63 is aryl optionally substituted by 1 or
2 substituents independently selected from halo, C.sub.1-4alkyl,
C.sub.1-4alkoxy, trifluoromethyl, trifluoromethoxy, hydroxy, nitro,
difluoromethyl, difluoromethoxy and cyano.
10. A compound according to claim 9 wherein R.sup.61 is
--CH.sub.2--COR.sup.64-J and wherein J is phenyl optionally
substituted by 1 or 2 halo.
11. A compound according to any one of claims 8 to 10 wherein
R.sup.9 is hydrogen, C.sub.3-6cycloalkyl,
--C.sub.1-5alkyl-O--C.sub.1-3alkyl or a 5- to 6-membered saturated
heterocyclic group (linked via carbon or nitrogen) with 1 or 2
heteroatoms selected independently from O, S or N which
heterocyclic group is optionally substituted by C.sub.1-14alkyl or
R.sup.9 is a 5- or 6-membered aromatic heterocyclic group (linked
via carbon or nitrogen) with 1, 2 or 3 heteroatoms or R.sup.9 is
--C.sub.1-5alkylR.sup.32, --C.sub.1-5alkylR.sup.96, C.sub.1-5alkyl
(optionally substituted by halo), --C.sub.1-15alkyl-OR.sup.20,
--C.sub.1-5alkyl-NHR.sup.20,
--C.sub.1-5alkyl-N(C.sub.1-3alkyl)-R.sup.20,
--C.sub.1-5alkyl-NH--C.sub.1-5alkyl-OH,
--C.sub.1-5alkyl-N(C.sub.1-3alkyl)-C.sub.1-5alkyl-OH and
--C.sub.1-5alkyl-NR.sup.95--C.sub.1-5alkyl-OH and wherein R.sup.32,
R.sup.96, R.sup.20 and R.sup.95 are as defined in claim 1.
12. A compound according to any one of claims 8 to 11 wherein
R.sup.1 is hydrogen, methoxy,
N--(C.sub.1-15alkyl)piperidin-4-yloxy, prop-2-yloxy or
methoxyethoxy; R.sup.2 is hydrogen or methoxy; and R.sup.4 is
hydrogen.
13. Use of a compound as defined in any one of claims 7 to 12 as a
medicament.
14. Use of a compound as defined in any one of claims 8 to 12 in
the preparation of a medicament for use in the inhibition of Aurora
kinase.
15. Use according to claim 14 wherein Aurora kinase is Aurora-A
kinase.
16. A pharmaceutical composition comprising a compound according to
any one of claims 7 to 12, or a pharmaceutically acceptable salt
thereof in combination with a pharmaceutically acceptable
carrier.
17. A process for the preparation of a compound according to claim
7 comprising the step of: a) when X is NH, reacting a compound of
formula (VII) ##STR00044## where R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are R.sup.1', R.sup.2', R.sup.3', and R.sup.4' as defined
in claim 7 and R.sup.85 is a group NR.sup.86R.sup.87 where R.sup.86
and R.sup.87 are independently selected from C.sub.1-4alkyl, with a
compound of formula (VIII) H.sub.2N--R.sup.5' (VIII) where R.sup.5'
is a group R.sup.5a as defined in claim 7 or a precursor group
thereof, and thereafter if desired or necessary, converting a
precursor group R.sup.5' to a group R.sup.5 or R.sup.5a and/or
modifying substituents on the group R.sup.5 or R.sup.5a; or b) when
X is as defined in claim 6, reacting a compound of formula (X)
##STR00045## where R.sup.1', R.sup.2'', R.sup.3'', and R.sup.4' are
equivalent to a group R.sup.1', R.sup.2', R.sup.3' and R.sup.4' as
defined in claim 6 or a precursor thereof, and R.sup.85 is a
leaving group, with a compound of formula (XI) H--X--R.sup.5 (XI)
and R.sup.5 is R.sup.5a as defined in claim 6: and thereafter if
desired or necessary converting a group R.sup.1', R.sup.2'',
R.sup.3'' or R.sup.4' to a group R.sup.1', R.sup.2', R.sup.3' and
R.sup.4' respectively or to a different such group.
Description
[0001] The present invention relates to certain quinazoline
derivatives for use in the treatment of certain diseases in
particular to proliferative disease such as cancer and in the
preparation of medicaments for use in the treatment of
proliferative disease, to novel quinazoline compounds and to
processes for their preparation, as well as pharmaceutical
compositions containing them as active ingredient.
[0002] Cancer (and other hyperproliferative disease) is
characterised by uncontrolled cellular proliferation. This loss of
the normal regulation of cell proliferation often appears to occur
as the result of genetic damage to cellular pathways that control
progress through the cell cycle.
[0003] In eukaryotes, an ordered cascade of protein phosphorylation
is thought to control the cell cycle. Several families of protein
kinases that play critical roles in this cascade have now been
identified. The activity of many of these kinases is increased in
human tumours when compared to normal tissue. This can occur by
either increased levels of expression of the protein (as a result
of gene amplification for example), or by changes in expression of
co activators or inhibitory proteins.
[0004] The first identified, and most widely studied of these cell
cycle regulators have been the cyclin dependent kinases (or CDKs).
Activity of specific CDKs at specific times is essential for both
initiation and coordinated progress through the cell cycle. For
example, the CDK4 protein appears to control entry into the cell
cycle (the G0-G1-S transition) by phosphorylating the
retinoblastoma gene product pRb. This stimulates the release of the
transcription factor E2F from pRb, which then acts to increase the
transcription of genes necessary for entry into S phase. The
catalytic activity of CDK4 is stimulated by binding to a partner
protein, Cyclin D. One of the first demonstrations of a direct link
between cancer and the cell cycle was made with the observation
that the Cyclin D1 gene was amplified and cyclin D protein levels
increased (and hence the activity of CDK4 increased) in many human
tumours (Reviewed in Sherr, 1996, Science 274: 1672-1677; Pines,
1995, Seminars in Cancer Biology 6: 63-72). Other studies (Loda et
al., 1997, Nature Medicine 3(2): 231-234; Gemma et al., 1996,
International Journal of Cancer 68(5): 605-11; Elledge et al. 1996,
Trends in Cell Biology 6; 388-392) have shown that negative
regulators of CDK function are frequently down regulated or deleted
in human tumours again leading to inappropriate activation of these
kinases.
[0005] More recently, protein kinases that are structurally
distinct from the CDK family have been identified which play
critical roles in regulating the cell cycle and which also appear
to be important in oncogenesis. These include the newly identified
human homologues of the Drosophila aurora and S. cerevisiae Ipl1
proteins. The three human homologues of these genes Aurora-A,
Aurora-B and Aurora-C (also known as aurora2, aurora1 and aurora3
respectively) encode cell cycle regulated serine-threonine protein
kinases (summarised in Adams et al., 2001, Trends in Cell Biology.
11(2): 49-54). These show a peak of expression and kinase activity
through G2 and mitosis. Several observations implicate the
involvement of human aurora proteins in cancer. This evidence is
particularly strong for Aurora-A. The Aurora-A gene maps to
chromosome 20q13, a region that is frequently amplified in human
tumours including both breast and colon tumours. Aurora-A may be
the major target gene of this amplicon, since Aurora-A DNA is
amplified and mRNA overexpressed in greater than 50% of primary
human colorectal cancers. In these tumours Aurora-A protein levels
appear greatly elevated compared to adjacent normal tissue. In
addition, transfection of rodent fibroblasts with human Aurora-A
leads to transformation, conferring the ability to grow in soft
agar and form tumours in nude mice (Bischoff et al., 1998, The EMBO
Journal. 17(11): 3052-3065). Other work (Zhou et al., 1998, Nature
Genetics. 20(2): 189-93) has shown that artificial overexpression
of Aurora-A leads to an increase in centrosome number and an
increase in aneuploidy, a known event in the development of cancer.
Other work has shown an increase in expression of Aurora-B (Adams
et al., 2001, Chromsoma. 110(2):65-74) and Aurora-C (Kimura et al.,
1999, Journal of Biological Chemistry, 274(11): 7334-40) in tumour
cells when compared to normal cells.
[0006] Importantly, it has also been demonstrated that abrogation
of Aurora-A expression and function by antisense oligonucleotide
treatment of human tumour cell lines (WO 97/22702 and WO 99/37788)
leads to cell cycle arrest and exerts an antiproliferative effect
in these tumour cell lines. Additionally, small molecule inhibitors
of Aurora-A and Aurora-B have been demonstrated to have an
antiproliferative effect in human tumour cells (Keen et al. 2001,
Poster #2455, American Association of Cancer research annual
meeting). This indicates that inhibition of the function of
Aurora-A (and possibly Aurora-B) will have an antiproliferative
effect that may be useful in the treatment of human tumours and
other hyperproliferative diseases. Further, inhibition of Aurora
kinases as a therapeutic approach to these diseases may have
significant advantages over targeting signalling pathways upstream
of the cell cycle (e.g. those activated by growth factor receptor
tyrosine kinases such as epidermal growth factor receptor (EGFR) or
other receptors). Since the cell cycle is ultimately downstream of
all of these diverse signalling events, cell cycle directed
therapies such as inhibition of Aurora kinases would be predicted
to be active across all proliferating tumour cells, whilst
approaches directed at specific signalling molecules (e.g. EGFR)
would be predicted to be active only in the subset of tumour cells
which express those receptors. It is also believed that significant
"cross talk" exists between these signalling pathways meaning that
inhibition of one component may be compensated for by another.
[0007] A number of quinazoline derivatives have been proposed
hitherto for use in the inhibition of various kinases. For example,
WO 96/09294, WO 96/15118 and WO 99/06378 describe the use of
certain quinazoline compounds as receptor tyrosine kinase
inhibitors, which may be useful in the treatment of proliferative
disease and WO 00/21955 discloses certain quinazoline derivatives
as inhibitors of the effects of VEGF.
[0008] Quinazoline derivatives have also been disclosed for use in
the inhibition of Aurora-A kinase. WO 02/00649 discloses
quinazoline derivative bearing a 5-membered heteroaromatic ring
where the ring is, in particular, substituted thiazole or
substituted thiophene. However despite the compounds of WO 02/00649
there still exists the need for further compounds having Aurora
kinase inhibitory properties.
[0009] The applicants have been successful in finding a novel
series of compounds which inhibit the effects of the Aurora kinases
and in particular Aurora-A kinase and which are thus of use in the
treatment of proliferative disease such as cancer, in particular in
such diseases such as colorectal or breast cancer where Aurora
kinases are known to be active.
[0010] According to one aspect of the present invention there is
provided the use of a compound of formula (I)
##STR00002##
or a salt, ester or amide thereof; where: X is O or S, S(O) or
S(O).sub.2, or NR.sup.6 where R.sup.6 is hydrogen or
C.sub.1-6alkyl; R.sup.5 is a group of formula (a) or (b):
##STR00003##
where * indicates the point of attachment to the group X in formula
(I); R.sup.1, R.sup.2, R.sup.3, R.sup.4 are independently selected
from hydrogen, halo, cyano, nitro, trifluoromethyl, C.sub.1-3alkyl,
--NR.sup.7R.sup.8 or --X.sup.1R.sup.9; R.sup.7 and R.sup.8 are
independently hydrogen or C.sub.1-3alkyl; X.sup.1 is a direct bond,
--O--, --CH.sub.2--, --OCO--, carbonyl, --S--, --SO--,
--SO.sub.2--, --NR.sup.10CO--, --CONR.sup.11--,
--SO.sub.2NR.sup.12--, --NR.sup.13SO.sub.2-- or --NR.sup.14--;
R.sup.10, R.sup.11, R.sup.12, R.sup.13 and R.sup.14 are
independently hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl; R.sup.9 is selected from one of the
following groups: 1) hydrogen or C.sub.1-5alkyl which may be
unsubstituted or which may be substituted with one or more groups
selected from hydroxy, fluoro or amino; 2)
C.sub.1-5alkylX.sup.2COR.sup.15 (wherein X.sup.2 represents --O--
or --NR.sup.16-- (in which R.sup.15 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.16
represents C.sub.1-3alkyl, --NR.sup.17R.sup.18 or --OR.sup.19
(wherein R.sup.17, R.sup.18 and R.sup.19 which may be the same or
different each represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); 3) C.sub.1-5alkylX.sup.3R.sup.20
(wherein X.sup.3 represents --O--, --S--, --SO--, --SO.sub.2--,
--OCO--, --NR.sup.2CO--, --CONR.sup.22--, --SO.sub.2NR.sup.23--,
--NR.sup.24SO.sub.2-- or --NR.sup.25-- (wherein R.sup.21, R.sup.22,
R.sup.23, R.sup.24 and R.sup.25 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.20 represents hydrogen, C.sub.1-3alkyl, cyclopentyl,
cyclohexyl or a 5- or 6-membered saturated heterocyclic group with
1 or 2 heteroatoms, selected independently from O, S and N, which
C.sub.1-3alkyl group may bear 1 or 2 substituents selected from
oxo, hydroxy, halo and C.sub.1-4alkoxy and which cyclic group may
bear 1 or 2 substituents selected from oxo, hydroxy, halo,
C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl and C.sub.1-4alkoxy); 4)
C.sub.1-5alkylX.sup.4C.sub.1-5alkylX.sup.5R.sup.26 (wherein X.sup.4
and X.sup.5 which may be the same or different are each --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.27CO--, --CONR.sup.28--,
--SO.sub.2NR.sup.29--, --NR.sup.3SO.sub.2-- or --NR.sup.31--
(wherein R.sup.27, --R.sup.28, R.sup.29, R.sup.30 and R.sup.31 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.26 represents hydrogen or
C.sub.1-13alkyl); 5) R.sup.32 (wherein R.sup.32 is a 5- or
6-membered saturated heterocyclic group (linked via carbon or
nitrogen) with 1 or 2 heteroatoms, selected independently from O, S
and N, which heterocyclic group may bear 1 or 2 substituents
selected from oxo, hydroxy, halo, C.sub.1-4alkyl,
C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl and
C.sub.1-4alkylsulphonylC.sub.1-4alkyl); 6) C.sub.1-5alkylR.sup.32
(wherein R.sup.32 is as defined hereinbefore); 7)
C.sub.2-5alkenylR.sup.32 (wherein R.sup.32 is as defined
hereinbefore); 8) C.sub.2-5alkynylR.sup.32 (wherein R.sup.2 is as
defined hereinbefore); 9) R.sup.33 (wherein R.sup.33 represents a
pyridone group, a phenyl group or a 5- or 6-membered aromatic
heterocyclic group (linked via carbon or nitrogen) with 1, 2 or 3
heteroatoms selected from O, N and S, which pyridone, phenyl or
aromatic heterocyclic group may carry up to 5 substituents on
available carbon atoms selected from hydroxy, halo, amino,
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4hydroxyalkyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, C.sub.1-4hydroxyalkoxy,
carboxy, trifluoromethyl, cyano, --CONR.sup.34R.sup.35 and
--NR.sup.36COR.sup.37 (wherein R.sup.34, R.sup.35, R.sup.36 and
R.sup.37, which may be the same or different, each represents
hydrogen, C.sub.1-4alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl)); 10)
C.sub.1-5alkylR.sup.33 (wherein R.sup.33 is as defined
hereinbefore); 11) C.sub.2-5alkenylR.sup.33 (wherein R.sup.33 is as
defined hereinbefore); 12) C.sub.2-5alkynylR.sup.33 (wherein
R.sup.33 is as defined hereinbefore); 13)
C.sub.1-5alkylX.sup.6R.sup.33 (wherein X.sup.6 represents --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.38CO--, --CONR.sup.39--,
--SO.sub.2NR.sup.40--, --NR.sup.41SO.sub.2-- or --NR.sup.42--
(wherein R.sup.38, R.sup.39, R.sup.40, R.sup.41 and R.sup.42 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.33 is as defined
hereinbefore); 14) C.sub.2-5alkenylX.sup.7R.sup.33 (wherein X.sup.7
represents --O--, --S--, --SO--, --SO.sub.2--, --NR.sup.43CO--,
--CONR.sup.44--, --SO.sub.2NR.sup.45--, --NR.sup.46SO.sub.2-- or
--NR.sup.47-- (wherein R.sup.43, R.sup.44, R.sup.45, R.sup.46 and
R.sup.47 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.33 is as defined
hereinbefore); 15) C.sub.2-5alkynylX.sup.8R.sup.33 (wherein X.sup.8
represents --O--, --S--, --SO--, --SO.sub.2--, --NR.sup.48CO--,
--CONR.sup.49--, --SO.sub.2NR.sup.50--, --NR.sup.51SO.sub.2-- or
--NR.sup.52-- (wherein R.sup.48, R.sup.49, R.sup.50, R.sup.51 and
R.sup.52 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.33 is as defined
hereinbefore); 16) C.sub.1-3alkylX.sup.9C.sub.1-3alkylR.sup.33
(wherein X.sup.9 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.53CO--, --CONR.sup.54--, --SO.sub.2NR.sup.55--,
--NR.sup.56SO.sub.2-- or --NR.sup.57-- (wherein R.sup.53, R.sup.54,
R.sup.55, R.sup.56 and R.sup.57 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.33 is as defined hereinbefore); 17)
C.sub.1-3alkylX.sup.9C.sub.1-3alkylR.sup.32 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); 18) C.sub.1-5alkyl
optionally substituted by 1, 2 or 3 halo; 19)
C.sub.1-5alkylX.sup.10C.sub.1-5alkylX.sup.11R.sup.90 (wherein
X.sup.10 and X.sup.11, which may be the same or different, are each
--O--, --S--, --SO--, --SO.sub.2--, --NR.sup.91CO--,
--CONR.sup.92--, --SO.sub.2NR.sup.93--, --NR.sup.94SO.sub.2-- or
--NR.sup.95-- (wherein R.sup.91, R.sup.92, R.sup.93, R.sup.94 and
R.sup.95 each independently represents C.sub.1-5alkyl,
C.sub.1-3alkyl (substituted by 1, 2 or 3 halo, C.sub.1-4alkyl or
C.sub.1-4alkoxy groups (and where there are 2 C.sub.1-4alkoxy
groups the C.sub.1-4alkyl groups of alkoxy may together form a 5-
or 6-membered saturated heterocyclic group having 2 oxygen atoms)),
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.3-6cycloalkyl (optionally
substituted by halo, hydroxy, C.sub.1-3alkyl or
C.sub.1-4hydroxyalkyl), C.sub.3-6cycloalkylC.sub.1-3alkyl
(optionally substituted by halo, hydroxy, C.sub.1-3alkyl or
C.sub.1-4hydroxyalkyl) or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.90 represents hydrogen or C.sub.1-3alkyl); 20)
C.sub.3-6cycloalkyl; 21) R.sup.96 (wherein R.sup.96 is a 5- or
6-membered heterocyclic group which may be saturated or unsaturated
(linked via carbon or nitrogen) with 1 or 2 heteroatoms, selected
independently from O, S and N which heterocyclic group may bear 1
or 2 substitutents selected from C.sub.1-4hydroxyalkyl,
C.sub.1-4alkyl, hydroxy and C.sub.1-4alkoxyC.sub.1-4alkyl; 22)
C.sub.1-5alkylR.sup.96 (wherein R.sup.96 is defined hereinbefore);
and where: R.sup.60, R.sup.61 and R.sup.62 are independently
hydrogen, nitro, cyano, halo, oxo, amino, trifluoromethyl,
C.sub.1-4alkoxymethyl, di(C.sub.1-4alkoxy)methyl or
C.sub.1-6alkanoyl or a group selected from C.sub.1-10alkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl, C.sub.1-10alkoxy, arylC.sub.1-10alkyl,
aryl, C.sub.3-10cycloalkyl, C.sub.3-10cycloalkenyl and
C.sub.3-10cycloalkynyl (which group is optionally substituted by 1,
2 or 3 substituents independently selected from halo,
C.sub.1-4alkyl (optionally substituted by 1, 2 or 3 halo),
mercapto, hydroxy, carboxy, C.sub.1-10alkoxy, nitro, cyano, aryl,
heteroaryl, heteroaryloxy, C.sub.2-10alkenyloxy,
C.sub.2-10alkynyloxy, C.sub.1-4alkoxyC.sub.1-4alkoxy, aryloxy
(where the aryl group may be substituted by halo, nitro, or
hydroxy), amino, cyano, nitro, mono- or di(C.sub.1-6alkyl)amino,
oximino or S(O).sub.y where y is 0, 1, 2 or 3), or a group selected
from .dbd.CR.sup.78R.sup.79, C(O).sub.xR.sup.77, OR.sup.77,
S(O).sub.yR.sup.77, NR.sup.78R.sup.79, C(O)NR.sup.78R.sup.79,
OC(O)NR.sup.78R.sup.79, .dbd.NOR.sup.77,
--NR.sup.77C(O).sub.xR.sup.78, --NR.sup.77CONR.sup.78R.sup.79,
--N.dbd.CR.sup.78R.sup.79, S(O).sub.yNR.sup.78R.sup.79 or
--NR.sup.77S(O).sub.yR.sup.78 or a group selected from phenyl,
benzyl or a 5- to 6-membered heterocyclic group with 1, 2 or 3
heteroatoms, selected independently from O, S and N, which
heterocyclic group may be aromatic or non-aromatic and may be
saturated (linked via a ring carbon or nitrogen atom) or
unsaturated (linked via a ring carbon atom), which phenyl, benzyl
or heterocyclic group may bear on one or more carbon ring atoms up
to 5 substituents selected from hydroxy, halo, C.sub.1-3alkyl,
C.sub.1-3alkoxy, C.sub.1-3alkanoyloxy, trifluoromethyl, cyano,
amino, nitro, C.sub.2-4alkanoyl, C.sub.1-4alkanoylamino,
C.sub.1-4alkoxycarbonyl, C.sub.1-4alkylsulphanyl,
C.sub.1-4alkylsulphinyl, C.sub.1-4alkylsulphonyl, carbamoyl,
N--C.sub.1-4alkylcarbamoyl, N,N-di(C.sub.1-4alkyl)carbamoyl,
aminosulphonyl, N--C.sub.1-4alkylaminosulphonyl,
N,N-di(C.sub.1-4alkyl)aminosulphonyl, C.sub.1-4alkylsulphonylamino,
and a saturated heterocyclic group selected from morpholino,
thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl,
imidazolidinyl and pyrazolidinyl, which saturated heterocyclic
group may bear 1 or 2 substituents selected from oxo, hydroxy,
halo, C.sub.1-3alkyl, C.sub.1-3alkoxy, C.sub.1-3alkanoyloxy,
trifluoromethyl, cyano, amino, nitro and C.sub.1-4alkoxycarbonyl,
or a group of sub-formula (k):
##STR00004##
or a group of sub-formula (II):
##STR00005##
or a group of sub-formula (VI):
##STR00006##
where: p and q are independently 0 or 1; r is 0, 1, 2, 3 or 4;
R.sub.1' and R.sub.1'' are independently hydrogen, hydroxy, halo,
cyano, C.sub.1-10alkyl, C.sub.3-10cycloalkyl, C.sub.2-10alkenyl or
C.sub.2-10alkynyl (wherein C.sub.1-10alkyl, C.sub.3-10cycloalkyl,
C.sub.2-10alkenyl and C.sub.2-10alkynyl are optionally substituted
by halo, nitro, cyano, hydroxy, trifluoromethyl, amino, carboxy,
carbamoyl, mercapto, sulphamoyl, C.sub.1-4alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl, C.sub.3-6cycloalkyl, C.sub.3-6cycloalkenyl,
C.sub.1-4alkoxy, C.sub.1-4alkanoyl, C.sub.1-4alkanoyloxy,
C.sub.1-4alkanoylamino, N,N-di(C.sub.1-4alkanoyl)amino,
N--(C.sub.1-4alkyl)carbamoyl, N,N-di(C.sub.1-4alkyl)carbamoyl,
C.sub.1-4alkylS, C.sub.1-4alkylS(O), C.sub.1-4alkylS(O).sub.2,
C.sub.1-4alkoxycarbonyl, N--(C.sub.1-4 alkyl)sulphamoyl,
N,N-di(C.sub.1-4alkyl)sulphamoyl, C.sub.1-4alkylsulphonylamino or
heterocyclyl); or R.sub.1' and R.sub.1'' can together form a 3- to
6-membered ring which may be saturated or unsaturated; T is
C.dbd.O, SO.sub.4, (where n is 0, 1 or 2), C(.dbd.NOR)CO, C(O)C(O),
C.dbd.NCN or CV.dbd.NO; V is independently R.sup.63 or
N(R.sup.63)R.sup.64; R.sup.63 and R.sup.64 are independently
selected from hydrogen, --(CH.sub.2).sub.q'R.sup.70 (q' is 0 or 1),
aryl (optionally substituted by 1, 2 or 3 C.sub.1-6alkyl
(optionally substituted by 1, 2 or 3 hydroxy groups)),
C.sub.1-10alkyl (optionally substituted by 1, 2 or 3 groups
independently selected from aryl or heterocyclic group where aryl
and heterocyclic group are optionally substituted by 1, 2, or 3
groups independently selected from C.sub.1-6alkyl, nitro, cyano,
halo, oxo, .dbd.CR.sup.78R.sup.79, C(O).sub.xR.sup.77, OR.sup.77,
S(O).sub.yR.sup.77, NR.sup.78R.sup.79, C(O)NR.sup.78R.sup.79,
OC(O)NR.sup.78R.sup.79, .dbd.NOR.sup.77,
--NR.sup.77C(O).sub.xR.sup.78, --NR.sup.77CONR.sup.78R.sup.79,
--N.dbd.CR.sup.78R.sup.79, S(O).sub.yNR.sup.78R.sup.79,
--NR.sup.77S(O).sub.yR.sup.78) or a group selected from
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
heterocyclyl, C.sub.1-10alkoxy, C.sub.1-10alkyl, aryl,
C.sub.3-10cycloalkyl, C.sub.3-10cycloalkenyl and
C.sub.3-10cycloalkynyl (which group is optionally substituted by 1,
2 or 3 groups independently selected from C.sub.1-6alkyl,
C.sub.1-4alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl,
difluoromethoxy, nitro, cyano, halo, oxo, .dbd.CR.sup.78R.sup.79,
C(O).sub.xR.sup.77, OR.sup.77, S(O).sub.yR.sup.77,
NR.sup.78R.sup.79, C(O)NR.sup.78R.sup.79, OC(O)NR.sup.78R.sup.79,
.dbd.NOR.sup.77, --NR.sup.77C(O).sub.xR.sup.78,
--NR.sup.77CONR.sup.78R.sup.79, --N.dbd.CR.sup.78R.sup.79,
S(O).sub.yNR.sup.78R.sup.79, --NR.sup.77S(O).sub.yR.sup.78); or
R.sup.63 and R.sup.64 together with the nitrogen atom to which they
are attached form a heterocyclic ring which ring is aromatic or
non-aromatic and which is optionally substituted by hydroxy,
C.sub.1-6alkoxy or C.sub.1-6alkyl (optionally substituted by
hydroxy); R.sup.70 is hydrogen, hydroxy (other than when q is 0),
C.sub.1-6alkyl, C.sub.1-6alkoxy, amino, N--C.sub.1-6alkylamino,
N,N-di(C.sub.1-6alkyl)amino, C.sub.2-6hydroxyalkoxy,
C.sub.1-6alkoxyC.sub.2-6alkoxy, aminoC.sub.2-6alkoxy,
N--C.sub.1-6alkylaminoC.sub.2-6alkoxy,
N,N-di(C.sub.1-6alkyl)aminoC.sub.2-6alkoxy, C.sub.3-7cycloalkyl
(optionally substituted by 1 or 2 oxo or thioxo substitutents) or
of formula (III):
--K-J (III)
K is a bond, oxy, imino, N--(C.sub.1-6alkyl)imino,
oxyC.sub.1-6alkylene, iminoC.sub.1-6alkylene,
N--(C.sub.1-6alkyl)iminoC.sub.1-6alkylene, --NHC(O)--,
--SO.sub.2NH--, --NHSO.sub.2--, --NHC(O)--C.sub.1-6alkylene-,
--OCO-- or C.sub.2-4alkenylene; J is aryl, heteroaryl or
heterocyclyl (where hetrocyclyl is optionally substituents by 1 or
2 oxo or thioxo substituents); and wherein any aryl, heteroaryl or
heterocyclyl group in a R.sup.70 group is optionally substituted by
1, 2, 3 or 4 groups selected from hydroxy, halo, trifluoromethyl,
cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl,
aminosulphonyl, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, --O--(C.sub.1-3alkyl)-O--,
C.sub.1-6alkylS(O).sub.n-- (where n is 0, 1 or 2),
N--C.sub.1-6alkylamino, N,N-di(C.sub.1-6alkyl)amino,
C.sub.1-6alkoxycarbonyl, N--C.sub.1-6alkylcarbamoyl,
N,N-di(C.sub.1-6alkyl)carbamoyl, C.sub.2-6alkanoyl,
C.sub.1-6alkanoyloxy, C.sub.1-6alkanoylamino,
N--C.sub.1-6alkylaminosulphonyl,
N,N-di(C.sub.1-6alkyl)aminosulphonyl, C.sub.1-6alkylsulphonylamino
and C.sub.1-6alkylsulphonyl-N--(C.sub.1-6alkyl)amino or by 1, 2, 3
or 4 groups selected from: a group of formula (IV)
##STR00007##
(wherein A.sup.1 is halo, hydroxy, C.sub.1-6alkoxy, cyano, amino,
C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino, carboxy,
C.sub.1-6alkoxycarbonyl, carbamoyl, N--C.sub.1-6alkylcarbamoyl or
N,N-di(C.sub.1-6alkyl)carbamoyl; p' is 1, 2, 3, 4, 5 or 6; and
B.sup.1 is a bond, oxy, imino, N--(C.sub.1-6alkyl)imino or
--NHC(O)--; with the proviso that p is 2 or more unless B.sup.1 is
a bond or --NHC(O)--); and a group of formula (V)
##STR00008##
(wherein D.sup.1 is aryl, heteroaryl or heterocyclyl (where
heterocyclyl is optionally substituted by 1 or 2 oxo or thioxo
substituents) and E.sup.1 is a bond, C.sub.1-6alkylene,
oxyC.sub.1-6alkylene, oxy, imino, N--(C.sub.1-6alkyl)imino,
iminoC.sub.1-6alkylene, N--(C.sub.1-6alkyl)iminoC.sub.1-6alkylene,
C.sub.1-6alkylene-oxyC.sub.1-6alkylene,
C.sub.1-6alkylene-iminoC.sub.1-6alkylene,
C.sub.1-6alkylene-N--(C.sub.1-6alkyl)-iminoC.sub.1-6alkylene,
--NHC(O)--, --NHSO.sub.2--, --SO.sub.2NH-- or
--NHC(O)--C.sub.1-6alkylene-, and any aryl, heteroaryl or
heterocyclyl group in a substituent on D.sup.1 is optionally
substituted with 1, 2, 3 or 4 groups selected from hydroxy, halo,
C.sub.1-6alkyl, C.sub.1-6alkoxy, carboxy, C.sub.1-6alkoxycarbonyl,
carbamoyl, N--C.sub.1-6alkylcarbamoyl,
N,N-di(C.sub.1-6alkyl)carbamoyl, C.sub.2-6alkanoyl, amino,
C.sub.1-6alkylamino and di(C.sub.1-6alkyl)amino); and any of the
R.sup.70 groups defined hereinbefore which comprises a CH.sub.2
group which is attached to 2 carbon atoms or a CH.sub.3 group which
is attached to a carbon atom optionally bears on each said CH.sub.2
or CH.sub.3 group a substituent selected from hydroxy, amino,
C.sub.1-6alkoxy, C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino and
heterocyclyl; R.sup.71 and R.sup.72 are independently selected from
hydrogen or C.sub.1-4alkyl or R.sup.71 and R.sup.72 together form a
bond;
R.sup.73 is OR.sup.74 or NR.sup.75R.sup.76;
[0011] R.sup.74, R.sup.75 and R.sup.76 are independently
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, aryl,
heterocyclyl, C.sub.1-10alkoxy, arylC.sub.1-10alkyl,
C.sub.3-10cycloalkyl, C.sub.3-10cycloalkenyl,
C.sub.3-10cycloalkynyl, each of which is optionally substituted by
1, 2, 3 or 4 groups selected from nitro, cyano, halo, oxo,
.dbd.CR.sup.78R.sup.79, C(O).sub.xR.sup.77, OR.sup.77,
S(O).sub.yR.sup.77, NR.sup.78R.sup.79, C(O)NR.sup.78R.sup.79,
OC(O)NR.sup.78R.sup.79, .dbd.NOR.sup.77,
--NR.sup.77C(O).sub.xR.sup.78, --NR.sup.77CONR.sup.78R.sup.79,
--N.dbd.CR.sup.78R.sup.79, S(O).sub.yNR.sup.78R.sup.79 or
--NR.sup.77S(O).sub.yR.sup.78 where y is 0, 1, 2 or 3; or R.sup.74,
R.sup.75 and R.sup.76 are independently heterocyclyl optionally
substituted by C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl
and C.sub.3-6cycloalkyl; or R.sup.75 and R.sup.76 together with the
nitrogen to which they are attached form an aromatic or
non-aromatic ring which optionally contains 1, 2 or 3 further
heteroatoms independently selected from N, O and S; R.sup.77,
R.sup.78 and R.sup.79 are independently selected from hydrogen or a
group selected from C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, aryl, heterocyclyl, C.sub.1-10alkoxy,
arylC.sub.1-10alkyl, C.sub.3-10cycloalkyl, C.sub.3-10cycloalkenyl,
C.sub.3-10cycloalkynyl where the group is optionally substituted by
halo, C.sub.1-4 perhaloalkyl such as trifluoromethyl, mercapto,
hydroxy, carboxy, C.sub.1-10alkoxy, aryl, heteroaryl,
heteroaryloxy, C.sub.2-10alkenyloxy, C.sub.2-10alkynyloxy,
C.sub.1-6alkoxyC.sub.1-6alkoxy, aryloxy (where the aryl group may
be substituted by halo, nitro, or hydroxy), cyano, nitro, amino,
mono- or di(C.sub.1-6alkyl)amino, oximino or S(O).sub.y where y is
0, 1, 2 or 3; or R.sup.78 and R.sup.79 together form a ring which
optionally contains further heteroatoms such as S(O).sub.y oxygen
and nitrogen, x is an integer of 1 or 2, y is 0, 1, 2 or 3 which
ring is optionally substituted by 1, 2 or 3 groups independently
selected from halo, C.sub.1-4 perhaloalkyl such as trifluoromethyl,
mercapto, hydroxy, carboxy, C.sub.1-10alkoxy, aryl, heteroaryl,
heteroaryloxy, C.sub.2-10alkenyloxy, C.sub.2-10alkynyloxy,
C.sub.1-6alkoxyC.sub.1-6alkoxy, aryloxy (where the aryl group may
be substituted by halo, nitro, or hydroxy), cyano, nitro, amino,
mono- or di(C.sub.1-6alkyl)amino, oximino or S(O).sub.y where y is
0, 1, 2 or 3; in the preparation of a medicament for use in the
inhibition of Aurora kinase.
[0012] Also provided is the use of a compound of formula (I) in the
preparation of a medicament for use in the inhibition of Aurora-A
kinase.
[0013] Also provided is the use of a compound of formula (I) in the
preparation of a medicament for use in the inhibition of Aurora-B
kinase.
[0014] In particular, medicaments containing compounds of the
present invention are useful in the treatment of proliferative
disease such as cancer, and in particular cancers where Aurora-A is
upregulated such as colon or breast cancers.
[0015] In a further aspect the present invention provides the use
of a compound of formula (I)
##STR00009##
or a salt, ester or amide thereof; where X is O, or S, S(O) or
S(O).sub.2, or NR.sup.6 where R.sup.6 is hydrogen or
C.sub.1-6alkyl; R.sup.5 is a group of formula (a) or (b):
##STR00010##
R.sup.60, R.sup.61 and R.sup.62 are independently selected from
hydrogen or a substituent group and * indicates the point of
attachment to the group X in formula (I); R.sup.1R.sup.2, R.sup.3,
R.sup.4 are independently selected from, halo, cyano, nitro,
trifluoromethyl, C.sub.1-3alkyl, --NR.sup.7R.sup.8 (wherein R.sup.7
and R.sup.8, which may be the same or different, each represents
hydrogen or C.sub.1-3alkyl), or --X.sup.1R.sup.9 (wherein X.sup.1
represents a direct bond, --O--, --CH.sub.2--, --OCO--, carbonyl,
--S--, --SO--, --SO.sub.2--, --NR.sup.10CO--, --CONR.sup.11--,
--SO.sub.2NR.sup.12--, --NR.sup.13SO.sub.2-- or --NR.sup.14--
(wherein R.sup.10, R.sup.11, R.sup.12, R.sup.13 and R.sup.14 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl), and R.sup.9 is selected from one of
the following groups: 1) hydrogen or C.sub.1-5alkyl which may be
unsubstituted or which may be substituted with one or more groups
selected from hydroxy, fluoro or amino, 2)
C.sub.1-5alkylX.sup.2COR.sup.15 (wherein X.sup.2 represents --O--
or --NR.sup.16-- (in which R.sup.15 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.16
represents C.sub.1-3alkyl, --NR.sup.17R.sup.18 or --OR.sup.19
(wherein R.sup.17, R.sup.18 and R.sup.19 which may be the same or
different each represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); 3) C.sub.1-5alkylX.sup.3R.sup.20
(wherein X.sup.3 represents --O--, --S--, --SO--, --SO.sub.2--,
--OCO--, --NR.sup.21CO--, --CONR.sup.22--, --SO.sub.2NR.sup.23--,
--NR.sup.24SO.sub.2-- or --NR.sup.25-- (wherein R.sup.21, R.sup.22,
R.sup.23, R.sup.24 and R.sup.25 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.20 represents hydrogen, C.sub.1-3alkyl, cyclopentyl,
cyclohexyl or a 5-6-membered saturated heterocyclic group with 1-2
heteroatoms, selected independently from O, S and N, which
C.sub.1-3alkyl group may bear 1 or 2 substituents selected from
oxo, hydroxy, halogeno and C.sub.1-4alkoxy and which cyclic group
may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno,
C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl and C.sub.1-4alkoxy); 4)
C.sub.1-5alkylX.sup.4C.sub.1-5alkylX.sup.5R.sup.26 (wherein X.sup.4
and X.sup.5 which may be the same or different are each --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.27CO--, --CONR.sup.28--,
--SO.sub.2NR.sup.29--, --NR.sup.3SO.sub.2-- or --NR.sup.31--
(wherein R.sup.27, R.sup.28, R.sup.29, R.sup.30 and R.sup.31 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.26 represents hydrogen or
C.sub.1-3alkyl); 5) R.sup.32 (wherein R.sup.2 is a 5-6-membered
saturated heterocyclic group (linked via carbon or nitrogen) with
1-2 heteroatoms, selected independently from O, S and N, which
heterocyclic group may bear 1 or 2 substituents selected from oxo,
hydroxy, halogeno, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl and
C.sub.1-4alkylsulphonylC.sub.1-4alkyl); 6) C.sub.1-5alkylR.sup.32
(wherein R.sup.32 is as defined hereinbefore); 7)
C.sub.2-5alkenylR.sup.32 (wherein R.sup.32 is as defined
hereinbefore); 8) C.sub.2-5alkynylR.sup.32 (wherein R.sup.32 is as
defined hereinbefore); 9) R.sup.33 (wherein R.sup.33 represents a
pyridone group, a phenyl group or a 5-6-membered aromatic
heterocyclic group (linked via carbon or nitrogen) with 1-3
heteroatoms selected from O, N and S, which pyridone, phenyl or
aromatic heterocyclic group may carry up to 5 substituents on an
available carbon atom selected from hydroxy, halogeno, amino,
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4hydroxyalkyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, C.sub.1-4hydroxyalkoxy,
carboxy, trifluoromethyl, cyano, --CONR.sup.34R.sup.35 and
--NR.sup.36COR.sup.37 (wherein R.sup.34, R.sup.35, R.sup.36 and
R.sup.37, which may be the same or different, each represents
hydrogen, C.sub.1-4alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl)); 10)
C.sub.1-5alkylR.sup.33 (wherein R.sup.33 is as defined
hereinbefore); 11) C.sub.2-5alkenylR.sup.33 (wherein R.sup.33 is as
defined hereinbefore); 12) C.sub.2-5alkynylR.sup.33 (wherein
R.sup.33 is as defined hereinbefore); 13)
C.sub.1-5alkylX.sup.6R.sup.33 (wherein X.sup.6 represents --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.38CO--, --CONR.sup.39--,
--SO.sub.2NR.sup.40--, --NR.sup.41SO.sub.2-- or --NR.sup.42--
(wherein R.sup.38, R.sup.39, R.sup.40, R.sup.41 and R.sup.42 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.33 is as defined
hereinbefore); 14) C.sub.2-5alkenylX.sup.7R.sup.33 (wherein X.sup.7
represents --O--, --S--, --SO--, --SO.sub.2--, --NR.sup.43CO--,
--CONR.sup.44--, --SO.sub.2NR.sup.45--, --NR.sup.46SO.sub.2-- or
--NR.sup.47-- (wherein R.sup.43, R.sup.44, R.sup.45, R.sup.46 and
R.sup.47 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.33 is as defined
hereinbefore); 15) C.sub.2-5alkynylX.sup.8R.sup.33 (wherein X.sup.8
represents --O--, --S--, --SO--, --SO.sub.2--, --NR.sup.48CO--,
--CONR.sup.49--, --SO.sub.2NR.sup.50--, --NR.sup.51SO.sub.2-- or
--NR.sup.52-- (wherein R.sup.48, R.sup.49, R.sup.50, R.sup.51 and
R.sup.52 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.33 is as defined
hereinbefore); 16) C.sub.1-3alkylX.sup.9C.sub.1-3alkylR.sup.33
(wherein X.sup.9 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.53CO--, --CONR.sup.54--SO.sub.2NR.sup.55,
--NR.sup.56SO.sub.2-- or --NR.sup.57-- (wherein R.sup.53, R.sup.54,
R.sup.55, R.sup.56 and R.sup.57 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.33 is as defined hereinbefore); and 17)
C.sub.1-3alkylX.sup.9C.sub.1-3alkylR.sup.32 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore):
[0016] in the preparation of a medicament for use in the inhibition
of aurora 2 kinase.
[0017] In this specification the term alkyl when used either alone
or as a suffix or prefix includes straight-chain and branched-chain
saturated structures comprising carbon and hydrogen atoms. Unless
otherwise stated, these groups may contain up to 10 carbon atoms
(C.sub.1-10alkyl), preferably up to 6 carbon atoms (C.sub.1-6alkyl)
and more preferably up to 4 carbon atoms (C.sub.1-4alkyl).
References to individual alkyl groups are specific for the
straight-chain version only and references to individual
branched-chain alkyl groups such as t-butyl are specific for the
branched chain version only. For example C.sub.1-4alkyl includes
the examples of methyl, ethyl, propyl, butyl and tert-butyl where
the ethyl, propyl and butyl groups may be bonded at the 1 or 2
position (e.g. prop-1-yl and prop-2-yl). A similar analysis of
alkyl groups having different ranges of carbon atoms can be
performed.
[0018] Similarly the terms alkenyl and alkynyl refer to unsaturated
straight-chain or branched-chain structures containing for example
from 2 to 10 carbon atoms (C.sub.2-10alkenyl and C.sub.2-10alkynyl)
and preferably from 2 to 6 carbon atoms (C.sub.2-6alkenyl and
C.sub.2-6alkynyl) and more preferably 2 to 4 carbon atoms
(C.sub.2-4alkenyl and C.sub.2-4alkynyl). Again references to
individual groups are specific for the straight-chain version only
and references to individual branched-chain groups are specific for
the branched chain version only. The above comment concerning the
bonding position of alkyl is applicable to alkenyl and alkynyl
groups.
[0019] Cyclic moieties such as cycloalkyl, cycloalkenyl and
cycloalkynyl are similar in nature but have at least 3 carbon
atoms, the following terms thus being used in the specification to
indicate the minimum and maximum number of carbon atoms in the
rings: C.sub.3-10cycloalkyl, C.sub.3-10cycloalkenyl and
C.sub.3-10cycloalkynyl and preferably C.sub.3-6cycloalkyl,
C.sub.3-6cycloalkenyl and C.sub.3-6cycloalkynyl and most preferably
C.sub.3-4cycloalkyl.
[0020] Terms such as alkoxy comprise alkyl groups as is understood
in the art and thus contain up to 10 carbon atoms
(C.sub.1-10alkoxy), preferably up to 6 carbon atoms
(C.sub.1-6alkoxy) and more preferably up to 4 carbon atoms
(C.sub.1-4alkoxy).
[0021] The term halo includes fluoro, chloro, bromo and iodo.
[0022] References to aryl groups include aromatic carbocyclic
groups such as phenyl and naphthyl.
[0023] The terms heterocyclyl and heterocyclic group include
(unless specifically stated) aromatic or non-aromatic rings and may
comprise more than one ring (e.g. they are monocyclic, bicyclic or
tricyclic and preferably they are monocyclic and bicyclic), for
example containing from 4 to 20, suitably from 5 to 8 ring atoms,
at least one of which is a heteroatom such as oxygen, sulphur or
nitrogen. Examples of such groups include furyl, thienyl, pyrrolyl,
pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl,
oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl,
benzothiazolyl, benzoxazolyl, benzothienyl or benzofuryl.
[0024] Heteroaryl refers to those heterocyclyl groups described
above which have an aromatic character.
[0025] The term aralkyl refers to aryl substituted alkyl groups
such as benzyl.
[0026] Other expressions used in the specification include
hydrocarbyl which refers to any structure comprising carbon and
hydrogen atoms. For example, these may be alkyl, alkenyl, alkynyl,
aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl or
cycloalkynyl.
[0027] The term functional group refers to reactive substituents
such as nitro, cyano, halo, oxo, .dbd.CR.sup.78R.sup.79,
C(O).sub.xR.sup.77, OR.sup.77, S(O).sub.yR.sup.77,
NR.sup.78R.sup.79, C(O)NR.sup.78R.sup.79, OC(O)NR.sup.78R.sup.79,
.dbd.NOR.sup.77, --NR.sup.77C(O).sub.xR.sup.78,
--NR.sup.77CONR.sup.78R.sup.79, --N.dbd.CR.sup.78R.sup.79,
S(O).sub.yNR.sup.78R.sup.79 or --NR.sup.77S(O).sub.yR.sup.78 where
R.sup.77, R.sup.78 and R.sup.79 are independently selected from
hydrogen or optionally substituted hydrocarbyl, or R.sup.78 and
R.sup.79 together form an optionally substituted ring which
optionally contains further heteroatoms such as S(O).sub.y oxygen
and nitrogen, x is an integer of 1 or 2, y is 0, 1, 2 or 3.
[0028] Suitable optional substituents for hydrocarbyl groups
R.sup.77, R.sup.78 and R.sup.79 include halo, perhaloalkyl such as
trifluoromethyl, mercapto, hydroxy, carboxy, alkoxy, aryl,
heteroaryl, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyalkoxy,
aryloxy (where the aryl group may be substituted by halo, nitro, or
hydroxy), cyano, nitro, amino, mono- or di-alkyl amino, oximino or
S(O).sub.y where y is as defined above.
[0029] Suitable optional substituents for any hydrocarbyl group,
heterocyclyl group or C.sub.1-10alkoxy group (unless specifically
stated) include halo, perhaloalkyl such as trifluoromethyl,
mercapto, hydroxy, carboxy, alkoxy, aryl, heteroaryl,
heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyalkoxy, aryloxy (where
the aryl group may be substituted by halo, nitro, or hydroxy),
cyano, nitro, amino, mono- or di-alkyl amino, oximino or S(O).sub.y
where y is as defined above.
[0030] Where optional substituents are chosen from one of more
groups or substituents it is to be understood that this definition
includes all substituents being chosen from one of the specified
groups i.e. all substitutents being the same, or the substituents
being chosen from two or more of the specified groups i.e. the
substituents not being the same. Preferably one or more means 1, 2,
3 or 4 but one or more may also means 1, 2 or 3 or 1 or 2.
[0031] Where a compound of formula (I), formula (IA) or formula
(IB) contains more than one specific R group it is to be understood
that each selection made for such a group is independent from any
other selection made for that same group, for example when a
compound of formula (I) contains more than one R.sup.77 group, each
R.sup.77 group can the same as the other R.sup.77 groups or
different.
Within this specification composite terms are used to describe
group comprising more than one functionality such as
C.sub.1-3alkoxyC.sub.2-3alkyl. Such terms are to be interpreted as
is understood in the art. Unless specifically stated the bonding
atom of a group may be any atom of that group so for example propyl
includes prop-1-yl and prop-2-yl.
[0032] Suitable values for any of the R groups (R.sup.1 to
R.sup.96) or any part or substitutents for such groups include:--
[0033] for C.sub.1-3alkyl: methyl, ethyl and propyl [0034] for
C.sub.1-4alkyl: C.sub.1-3alkyl, butyl and tert-butyl [0035] for
C.sub.1-5alkyl: C.sub.1-4alkyl, pentyl and 2,2-dimethylpropyl
[0036] for C.sub.1-6alkyl: C.sub.1-5alkyl, hexyl and
2,3-dimethylbutyl [0037] for C.sub.1-10alkyl: C.sub.1-6alkyl,
octanyl and decanyl [0038] for C.sub.2-4alkenyl: vinyl, allyl and
but-2-enyl [0039] for C.sub.2-4alkenylene --CH.dbd.CH--,
--CH.sub.2--CH.dbd.CH--, --CH.dbd.CH--CH.sub.2-- and
--CH.sub.2--CH.dbd.CH--CH.sub.2-- [0040] for C.sub.2-5alkenyl:
C.sub.2-4alkenyl and 3-methylbut-2-enyl [0041] for
C.sub.2-6alkenyl: C.sub.2-5alkenyl and 3-methylpent-2-enyl [0042]
for C.sub.2-10alkenyl: C.sub.2-6alkenyl and octenyl [0043] for
C.sub.2-4alkynyl: ethynyl, propargyl and prop-1-ynyl [0044] for
C.sub.2-5alkynyl: C.sub.2-4alkynyl and pent-4-ynyl [0045] for
C.sub.2-6alkynyl: C.sub.2-5alkynyl and 2-methylpent-4-ynyl [0046]
for C.sub.2-10alkynyl: C.sub.2-6alkynyl and oct-4-ynyl [0047] for
C.sub.3-6cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl [0048] for C.sub.3-7cycloalkyl: C.sub.3-6cycloalkyl and
cyclopentyl [0049] for C.sub.3-10cycloalkyl: C.sub.3-7cycloalkyl
and cyclononyl [0050] for C.sub.3-6cycloalkenyl: cyclobutenyl,
cyclopentenyl, cyclohexenyl and cyclohex-1,4-dienyl [0051] for
C.sub.3-10cycloalkenyl: C.sub.3-6cycloalkenyl, cycloheptenyl and
cyclooctenyl [0052] for C.sub.3-10cycloalkynyl: cyclodecynyl [0053]
for C.sub.3-6cycloalkylC.sub.1-3alkyl: cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl and
cyclobutylethyl [0054] for C.sub.1-3alkoxy: methoxy, ethoxy and
propoxy [0055] for C.sub.1-4alkoxy: C.sub.1-3alkoxy, butoxy and
tert-butoxy [0056] for C.sub.1-6alkoxy: C.sub.1-4alkoxy,
3,3-dimethylpentoxy and hexyloxy [0057] for C.sub.1-10alkoxy:
C.sub.1-6alkoxy, 2,2,4,4-tetramethylpentoxy [0058] for
C.sub.2-10alkenyloxy: allyloxy, but-2-enyloxy,
3-methylbut-2-enyloxy, 3-methylpent-2-enyloxy and octenyloxy [0059]
for C.sub.2-10alkynyloxy: propargyloxy, pent-4-ynyloxy and
oct-4-ynyloxy [0060] for aryl: phenyl and naphthyl [0061] for
arylC.sub.1-10alkyl: benzyl, phenethyl, naphylmethyl and
naphthylethyl [0062] for arylC.sub.1-6alkyl: benzyl, phenethyl,
naphylmethyl and naphthylethyl [0063] for aryloxy: phenoxy and
naphthyloxy [0064] for heteroaryl: furyl, thienyl, pyrrolyl,
pyrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and
quinolinyl [0065] for heteroaryloxy: pyridyloxy and quinolinyloxy
[0066] for heterocyclyl: furyl, thienyl, pyrrolyl, pyrrolidinyl,
imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl,
pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,
quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl,
benzoxazolyl, benzothienyl or benzofuryl [0067] for
heterocyclylC.sub.1-6alkyl: furylmethyl, thienylethyl,
pyrrolylethyl, pyridlymethyl and pyrimidinylethyl [0068] for
C.sub.1-4hydroxyalkyl: hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, 3-hydroxypropyl, 1-hydroxyprop-2-yl and
1-hydroxy-2-methylprop-2-yl [0069] for
C.sub.1-3alkoxyC.sub.2-3alkyl: methoxyethyl, ethoxyethyl and
methoxypropyl [0070] for C.sub.1-4alkoxyC.sub.1-4alkyl:
methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl,
methoxypropyl and ethoxybutyl [0071] for C.sub.1-4alkoxymethyl:
methoxymethyl, ethoxymethyl, propoxymethyl and prop-2-oxymethyl
[0072] for di(C.sub.1-4alkoxy)methyl: dimethoxymethyl and
diethoxymethyl [0073] for C.sub.1-4hydroxyalkoxy: 2-hydroxyethoxy,
3-hydroxypropoxy and 2-hydroxypropoxy [0074] for
C.sub.2-6hydroxyalkoxy: 2-hydroxyethoxy, 3-hydroxypropoxy and
4-hydroxybutoxy [0075] for C.sub.1-4alkoxyC.sub.1-4alkoxy:
methoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxymethoxy and
propoxyethoxy [0076] for C.sub.1-6alkoxyC.sub.2-6alkoxy:
methoxyethoxy and ethoxybutoxy [0077] for C.sub.1-4aminoalkyl:
aminomethyl, aminoethyl, 3-aminopropyl and 2-aminopropyl [0078] for
C.sub.1-4alkylamino: methylamino, ethylamino and propylamino [0079]
for C.sub.1-6alkylamino: C.sub.1-4alkylamino and 2-methylbutyl
amino [0080] for di(C.sub.1-4alkyl)amino: dimethylamino,
N-methyl-N-ethylamino and diethylamino [0081] for
di(C.sub.1-6alkyl)amino: N-methyl-N-pentylamino [0082] for
aminoC.sub.2-6alkoxy: aminoethoxy and 3-aminopropoxy [0083] for
N--C.sub.1-6alkylaminoC.sub.2-6alkoxy: N-ethylaminoethoxy [0084]
for N,N-di(C.sub.1-6alkyl)aminoC.sub.2-6alkoxy:
N,N-dimethylaminoethoxy [0085] for C.sub.2-4alkanoyl: acetyl and
propionyl [0086] for C.sub.1-4alkanoyl: acetyl and propionyl [0087]
for C.sub.2-6alkanoyl: C.sub.2-4alkanoyl and pentanoyl [0088] for
C.sub.1-6alkanoyl: C.sub.1-4alkanoyl and hexanoyl [0089] for
C.sub.1-3alkanoyloxy: acetyloxy and propionyloxy [0090] for
C.sub.1-4alkanoyloxy: C.sub.1-3alkanoyloxy and butanoyloxy [0091]
for C.sub.1-6alkanoyloxy: C.sub.1-4alkanoyloxy and hexanoyloxy
[0092] for C.sub.1-4alkanoylamino: acetylamino and propionylamino
[0093] for C.sub.1-6alkanoylamino: C.sub.1-4alkanoylamino and
pentanoylamino [0094] for N,N-di(C.sub.1-4alkanoyl)amino:
N,N-diacetylamino [0095] for C.sub.1-4alkoxycarbonyl:
methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl [0096] for
C.sub.1-6alkoxycarbonyl: C.sub.1-4alkoxycarbonyl and
pentoxycarbonyl [0097] for N--C.sub.1-6alkylcarbamoyl:
N-methylcarbamoyl and N-ethylcarbamoyl [0098] for
N,N-di(C.sub.1-6alkyl)carbamoyl: N,N-dimethylcarbamoyl and
N,N-diethylcarbamoyl [0099] for
C.sub.1-4alkylsulphonylC.sub.1-4alkyl: methylsulphonylmethyl and
methylsulphonylethyl [0100] for C.sub.1-4alkylsulphanyl:
methylsulphanyl and ethylsulphanyl [0101] for
C.sub.1-4alkylsulphinyl: methylsulphinyl and ethylsulphinyl [0102]
for C.sub.1-4alkylsulphonyl: methylsulphonyl and ethylsulphonyl
[0103] for N--C.sub.1-4alkylcarbamoyl: N-methylcarbamoyl and
N-ethylcarbamoyl [0104] for N,N-di(C.sub.1-4alkyl)carbamoyl:
N,N-dimethylcarbamoyl and N-ethyl-N-methylcarbamoyl [0105] for
N--(C.sub.1-4alkyl)aminosulphonyl: N-methylaminosulphonyl and
N-ethylaminosulphonyl [0106] for N--(C.sub.1-6alkyl)aminosulphonyl:
N--(C.sub.1-4alkyl)aminosulphonyl and N-hexylaminosulphonyl [0107]
for N,N-di(C.sub.1-4alkyl)aminosulphonyl:
N,N-dimethylaminosulphonyl [0108] for
N,N-di(C.sub.1-6alkyl)aminosulphonyl:
N,N-di(C.sub.1-4alkyl)aminosulphonyl and
N-hexyl-N-methylaminosulphonyl [0109] for
C.sub.1-4alkylsulphonylamino: methylsulphonylamino and
ethylsulphonylamino [0110] for C.sub.1-6alkylsulphonylamino:
C.sub.1-4alkylsulphonylamino and hexylsulphonylamino [0111] for
C.sub.1-6alkylsulphonyl-N--(C.sub.1-6alkyl)amino:
methylsulphonyl-N-ethylamino [0112] for N--(C.sub.1-6alkyl)imino:
N-methylimino and N-ethylimino [0113] for iminoC.sub.1-6alkylene:
iminomethylene and iminoethylene [0114] for
C.sub.1-6alkylene-iminoC.sub.1-6alkylene: methyleneiminomethylene
[0115] for N--(C.sub.1-6alkyl)iminoC.sub.1-16alkylene:
N-ethyliminomethylene [0116] for
C.sub.1-6alkylene-N--(C.sub.1-6alkyl)iminoC.sub.1-6alkylene:
ethylene-N-methyliminomethylene [0117] for C.sub.1-6alkylene:
methylene, ethylene and propylene [0118] for oxyC.sub.1-6alkylene:
oxymethylene, oxyethylene and oxypropylene [0119] for
C.sub.1-6alkylene oxyC.sub.1-6alkylene: methyleneoxyethylene.
[0120] Within the present invention it is to be understood that a
compound of the formula (I), formula (IA) or formula (IB) or a
salt, ester or amide thereof may exhibit the phenomenon of
tautomerism and that the formulae drawings within this
specification can represent only one of the possible tautomeric
forms. It is to be understood that the invention encompasses any
tautomeric form which has Aurora kinase inhibition activity and in
particular Aurora-A kinase or Aurora-B kinase inhibition activity
and is not to be limited merely to any one tautomeric form utilized
within the formulae drawings. The formulae drawings within this
specification can represent only one of the possible tautomeric
forms and it is to be understood that the specification encompasses
all possible tautomeric forms of the compounds drawn not just those
forms which it has been possible to show graphically herein. The
possibility of tautomeric forms is particular pertinent for R.sup.5
when R.sup.62 is hydrogen.
[0121] It is also to be understood that, insofar as certain
compounds of the invention may exist in optically active or racemic
forms by virtue of one of more racemic carbon or sulphur atom, the
invention includes in its definition any such optically active or
racemic form which possesses Aurora kinase inhibitory activity and
in particular Aurora-A kinase inhibitory activity. The synthesis of
optically active forms may be carrier out by standard techniques of
organic chemistry well known in the art, for example by synthesis
from optically active starting materials or by resolution of a
racemic form.
[0122] It is also to be understood that certain compounds of the
formula (I), formula (IA) or formula (IB) and salts thereof can
exist in solvated as well as unsolvated forms such as, for example,
hydrated forms. It is to be understood that the invention
encompasses all such solvated forms which have Aurora kinase
inhibition activity and in particular Aurora-A kinase inhibition
activity.
Compounds of the present invention have been named using computer
software (ACD/Name version 6.6 or ACD/Name batch version 6.0).
[0123] Preferred values of X, R.sup.1, R.sup.2, R.sup.3, R.sup.4
and R.sup.5 are as follows. Such values may be used where
appropriate with any of the definitions, claims or embodiments
defined hereinbefore or hereinafter.
[0124] In one aspect of the invention X is NR.sup.6 or O. In
another aspect X is NH.
[0125] In one aspect of the invention R.sup.6 is hydrogen or
C.sub.1-3alkyl. In another aspect R.sup.6 is hydrogen.
[0126] In one aspect of the invention R.sup.1 is hydrogen or
--X.sup.1R.sup.9. In another aspect R.sup.1 is hydrogen or
--X.sup.1R.sup.9 where X.sup.1 is a direct bond, --O--, --NH-- or
--NMe- and R.sup.9 is selected from a group 1), 3), 5), 9) or 20)
as defined above. In a yet another aspect R.sup.1 is hydrogen or
--X.sup.1R.sup.9 where X.sup.1 is a direct bond, --O-- or --NH--
and R.sup.9 is hydrogen, C.sub.1-5alkyl, C.sub.3-6cycloalkyl,
--C.sub.1-5alkyl-O--C.sub.1-3alkyl or a 5- to 6-membered saturated
heterocyclic group (linked via carbon or nitrogen) with 1 or 2
heteroatoms selected independently from O, S or N which
heterocyclic groups is optionally substituted by C.sub.1-4alkyl or
a 5- or 6-membered aromatic heterocyclic group (linked via carbon
or nitrogen with 1, 2 or 3 heteroatoms. In a further aspect R.sup.1
is hydrogen, methoxy, N--(C.sub.1-5alkyl)piperidin-4-yloxy,
prop-2-yloxy or methoxyethoxy. In an even further aspect R.sup.1 is
hydrogen.
[0127] In one aspect of the invention R.sup.2 is hydrogen, halo or
--X.sup.1R.sup.9. In a further aspect of the invention R.sup.2 is
hydrogen, halo or --X.sup.1R.sup.9 where X.sup.1 is a direct bond
or --O-- and R.sup.9 is a group 1) as defined above. In yet another
aspect R.sup.2 is hydrogen, halo, hydroxy, methoxy or
--OC.sub.1-3alkyl (optionally substituted by 1 or 2 hydroxy or
halo). In a further aspect R.sup.2 is hydrogen or methoxy.
[0128] In one aspect R.sup.3 is --X.sup.1R.sup.9. In another aspect
R.sup.3 is --X.sup.1R.sup.9 where X.sup.1 is --O-- and R.sup.9 is
selected from a group 3), 4), 6), 18), 19) or 22) as defined above.
In yet another aspect R.sup.3 is --X.sup.1R.sup.9 where X.sup.1 is
--O-- and R.sup.9 is --C.sub.1-5alkylR.sup.2,
--C.sub.1-5alkylR.sup.96, C.sub.1-5alkyl (optionally substituted by
halo), --C.sub.1-5alkyl-OR.sup.20, --C.sub.1-5alkyl-NHR.sup.20,
--C.sub.1-5alkyl-N(C.sub.1-3alkyl)-R.sup.20,
--C.sub.1-5alkyl-NH--C.sub.1-5alkyl-OH,
--C.sub.1-5alkyl-N(C.sub.1-3alkyl)-C.sub.1-5alkyl-OH and
--C.sub.1-5alkyl-NR.sup.95--C.sub.1-5alkyl-OH. In yet another
aspect R.sup.3 is --X.sup.1R.sup.9 where X.sup.1 is --O-- and
R.sup.9 is --C.sub.1-5alkylR.sup.32 (where R.sup.32 is
pyrrolidinyl, piperidinyl or piperazinyl each being optionally
substituted by hydroxy, hydroxymethyl, 2-hydroxyethyl, methyl or
2-(tert-butoxy)ethyl), --C.sub.1-5alkyl-NHR.sup.20,
--C.sub.1-5alkyl-NH--C.sub.1-5alkyl-OH,
--C.sub.1-5alkyl-N(C.sub.1-3alkyl)-C.sub.1-5alkyl-OH and
--C.sub.1-5alkyl-NR.sup.95--C.sub.1-5alkyl-OH. In a further aspect
R.sup.3 is 3-morpholinopropoxy, 3-chloropropoxy,
3-[N-ethyl-N-(2-hydroxyethyl)amino]propoxy,
3-(2-hydroxymethylpyrrolidin-1-yl)propoxy,
3-(piperidin-1-yl)propoxy, 3-(pyrrolidin-1-yl)propoxy,
3-(N-(2-hydroxyethyl)amino]propoxy,
3-[N-(2-hydroxy-1,1-dimethylethyl)amino}propoxy,
3-[N-methyl-N-(2-hydroxyethyl)amino]propoxy,
3-[N-(1-hydroxymethyl-2-methylpropyl)amino]propoxy,
3-(4-methylpiperazin-1-yl)propoxy,
3-[N-(2-hydroxy-1-methylethyl)amino]propoxy,
3-[N-(4-hydroxybutyl)amino]propoxy,
3-(4-hydroxypiperidin-1-yl)propoxy,
3-[2-(2-hydroxyethyl)piperidin-1-yl]propoxy,
3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy,
3-[4-(2-hydroxyethyl)piperidin-1-yl]propoxy,
3-(3-hydroxypiperidin-1-yl)propoxy,
3-[N-2-(hydroxybutyl)amino]propoxy,
3-(4-hydroxymethylpiperidin-1-yl)propoxy,
3-[N-(3-hydroxy-2,2-dimethylpropyl)amino]propoxy,
3-[N-(1-hydroxymethylcyclopent-1-yl)amino]propoxy,
3-[N-(2-hydroxypropyl)amino]propoxy,
3-(3-hydroxypyrrolidin-1-yl)propoxy,
3-[N-(2-fluoroethyl)N-(2-hydroxyethyl)amino]propoxy,
2-[1-(2-hydroxyethyl)piperidin-4-yl]ethoxy,
3-[N-(2-hydroxyethyl)-N-propylamino]propoxy,
3-[N-(2-hydroxyethyl)-N-(prop-2-yl)amino]propoxy,
3-[N-(2-hydroxyethyl)-N-isobutylamino]propoxy,
3-[N-(2-hydroxyethyl)-N-neopentylamino]propoxy,
3-[N-allyl-N-(2-hydroxyethyl)amino]propoxy,
3-[N-(2-hydroxyethyl)-N-(prop-2-yn-1-yl)amino]propoxy,
3-[N-cyclopropyl-N-(2-hydroxyethyl)amino]propoxy,
3-[N-cyclopropylmethyl-N-(2-hydroxyethyl)amino]propoxy,
3-[N-cyclobutyl-N-(2-hydroxyethyl)amino]propoxy,
3-[N-cyclopentyl-N-(2-hydroxyethyl)amino]propoxy,
3-[N-(2,2-dimethoxyethyl)-N-(2-hydroxyethyl)amino]propoxy,
3-[N-(2,2-difluoroethyl)-N-(2-hydroxyethyl)amino]propoxy,
3-[N-(2-hydroxyethyl)-N-(3,3,3-trifluoropropyl)amino]propoxy,
3-[N-cyclobutylmethyl-N-(2-hydroxyethyl)amino]propoxy,
3-[N-(2-hydroxyethyl)-N-(2-methoxyethyl)amino]propoxy,
3-[N-(1,3-dioxolan-2-ylmethyl)-N-(2-hydroxyethyl)amino]propoxy,
4-chlorobutoxy, 4-[(2-hydroxymethyl)pyrrolidin-1-yl]butoxy,
4-[N-(2-hydroxyethyl)-N-isobutylamino]butoxy,
1-(2-tert-butoxyethyl)pyrrolidin-2-ylmethoxy,
1-(2-hydroxyethyl)pyrrolidin-2-ylmethoxy,
3-[N-2-(hydroxyethyl)-N-(isobutyl)amino]propoxy,
3-[N-2-(hydroxyethyl)-N-(neopentyl)amino]propoxy,
3-[N-2-(hydroxyethyl)-N-(tert-butyl)amino]propoxy, methoxy and
methoxyethoxy.
[0129] In one aspect of the invention R.sup.32 is a 5- or
6-membered saturated heterocyclic group (linked via carbon or
nitrogen) with 1 or 2 heteroatoms selected independently from O, S,
and N which group is optionally substituted by 1 or 2 substituents
selected from C.sub.1-4hydroxyalkyl, C.sub.1-4alkyl, hydroxy and
C.sub.1-4alkoxyC.sub.1-4alkyl. In another aspect R.sup.32 is
morpholino, pyrrolidinyl, piperidinyl or piperazinyl each being
optionally substituted by hydroxy, hydroxymethyl, 2-hydroxyethyl,
methyl or 2-(tert-butoxy)ethyl. In a further aspect R.sup.32 is
2-hydroxymethylpyrrolidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl,
4-methylpiperazin-1-yl, 4-hydroxypiperidin-1-yl,
2-(2-hydroxyethyl)piperidin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl,
4-(2-hydroxyethyl)piperidin-1-yl, 4-hydroxymethylpiperidin-1-yl,
3-hydroxypyrrolidin-1-yl, 1-(2-hydroxyethyl)piperidin-4-yl,
1-(2-tert-butoxyethyl)pyrrolidin-2-yl and
1-(2-hydroxyethyl)pyrrolidin-2-yl.
[0130] In one aspect of the invention R.sup.20 is C.sub.1-3alkyl
(optionally substituted by hydroxy) or cyclopentyl (optionally
substituted by C.sub.1-4hydroxyalkyl). In a further aspect R.sup.20
is 2-hydroxyethyl, 1-hydroxyprop-2-yl, 2-hydroxyprop-1-yl and
1-hydroxymethylcyclopentyl
[0131] In one aspect of the invention R.sup.95 is methyl, ethyl,
2-fluoroethyl, prop-1-yl, prop-2-yl, isobutyl, neopentyl, allyl,
propargyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl, cyclobutylmethyl,
methoxyethyl, 1,3-dioxolan-2-ylmethyl and 2,2-dimethoxyethyl.
[0132] In one aspect of the invention R.sup.96 is
4,5-dihydro-1H-imidazoyl optionally substituted by hydroxy or
C.sub.1-4hydroxyalkyl.
[0133] In one aspect of the invention R.sup.4 is hydrogen.
[0134] In one aspect of the invention X.sup.1 is a direct bond,
--O-- or --N(C.sub.1-3alkyl)-. In another aspect X.sup.1 is
--O--.
[0135] In one aspect of the invention R.sup.9 is a group selected
from group 1), 3), 4), 5), 6), 9), 18), 19), 20) and 22). In
another aspect R.sup.9 is hydrogen, C.sub.3-6cycloalkyl,
--C.sub.1-5alkyl-O--C.sub.1-3alkyl or a 5- to 6-membered saturated
heterocyclic group (linked via carbon or nitrogen) with 1 or 2
heteroatoms selected independently from O, S or N which
heterocyclic group is optionally substituted by C.sub.1-4alkyl or
R.sup.9 is a 5- or 6-membered aromatic heterocyclic group (linked
via carbon or nitrogen) with 1, 2 or 3 heteroatoms or R.sup.9 is
--C.sub.1-5alkylR.sup.32, --C.sub.1-5alkylR.sup.96, C.sub.1-5alkyl
(optionally substituted by halo), --C.sub.1-5alkyl-OR.sup.20,
--C.sub.1-5alkyl-NHR.sup.20,
--C.sub.1-5alkyl-N(C.sub.1-3alkyl)-R.sup.20,
--C.sub.1-5alkyl-NH--C.sub.1-5alkyl-OH,
--C.sub.1-5alkyl-N(C.sub.1-3alkyl)-C.sub.1-5alkyl-OH and
--C.sub.1-5alkyl-NR.sup.95--C.sub.1-5alkyl-OH.
[0136] In one aspect of the invention R.sup.60 is hydrogen, nitro,
halo, cyano, oxo or C.sub.1-3alkyl. In another aspect R.sup.60 is a
group of sub-formula (k) as defined above. In a further aspect
R.sup.60 is hydrogen.
[0137] In one aspect of the invention R.sup.61 is a group selected
from hydrogen, cyano, nitro halo, C.sub.1-6alkyl, aryl,
arylC.sub.1-6alkyl, heterocyclyl, heterocyclylC.sub.1-6alkyl (where
aryl and heterocyclyl of the latter four groups are optionally
substituted by 1, 2 or 3 substitutents independently selected from
halo, hydroxy, mercapto, carboxy, C.sub.1-4alkyl (optionally
substituted by 1, 2 or 3 halo), aryl, heteroaryl, amino, cyano,
nitro, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino and S(O).sub.y
where y is 0, 1 or 2), a group of sub-formula (k) as defined above,
a group of sub-formula (II) as defined above and a group of formula
(VI) as defined above. In another aspect R.sup.61 is a group of
sub-formula (k) as defined above. In yet a further aspect of the
invention R.sup.61 is J, --(CH.sub.2)-J, --(CH.sub.2).sub.2-J,
--O-J, --(CH.sub.2)--O-J, --O--(CH.sub.2)-J,
--(CH.sub.2)--O--(CH.sub.2)-J, --CO-J, --(CH.sub.2)--CO-J,
--CO--(CH.sub.2)-J, --(CH.sub.2)--CO--(CH.sub.2)-J, --S-J,
--(CH.sub.2)--S-J, --S--(CH.sub.2)-J,
--(CH.sub.2)--S--(CH.sub.2)-J, --SO-J, --(CH.sub.2)--SO-J,
--SO--(CH.sub.2)-J, --(CH.sub.2)--SO--(CH.sub.2)-J, --SO.sub.2-J,
--(CH.sub.2)--SO.sub.2-J, --SO.sub.2--(CH.sub.2)-J,
--(CH.sub.2)--SO.sub.2--(CH.sub.2)-J, --(NR.sub.1')CO-J,
--(CH.sub.2)--(NR.sub.1')CO-J, --(NR.sub.1')CO--(CH.sub.2)-J,
--(CH.sub.2)--(NR.sub.1')CO--(CH.sub.2)-J, --(NR.sub.1')SO.sub.2-J,
--(CH.sub.2)--(NR.sub.1')SO.sub.2-J,
--(NR.sub.1')SO.sub.2--(CH.sub.2)-J,
--(CH.sub.2)--(NR.sub.1')SO.sub.2--(CH.sub.2)-J, --NR.sup.64-J,
--(CH.sub.2)--NR.sup.64-J, --NR.sup.64--(CH.sub.2)-J,
--(CH.sub.2)--NR.sup.64--(CH.sub.2)-J, --CONR.sup.64-J,
--(CH.sub.2)--CONR.sup.64-J, --CONR.sup.64--(CH.sub.2)-- J,
--(CH.sub.2)--CONR.sup.64--(CH.sub.2)-J, --SO.sub.2NR.sup.64-J,
--(CH.sub.2)--SO.sub.2NR.sup.64-J,
--SO.sub.2NR.sup.64--(CH.sub.2)-J,
--(CH.sub.2)--SO.sub.2NR.sup.64--(CH.sub.2)-J, --NR.sub.1'CO--NH-J,
--(CH.sub.2)--NR.sub.1'CO--NH-J, --NR.sub.1'CO--NH--(CH.sub.2)-J,
--(CH.sub.2)--NR.sub.1'CO--NH--(CH.sub.2)-J,
--NR.sub.1'CO--N(C.sub.1-4alkyl)-J,
--(CH.sub.2)--NR.sub.1'CO--N(C.sub.1-4alkyl)-J,
--NR.sub.1'CO--N(C.sub.1-4alkyl)-(CH.sub.2)-J,
--(CH.sub.2)--NR.sub.1'CO--N(C.sub.1-4alkyl)-(CH.sub.2)-J,
--NR.sub.1'CO--O-J, --(CH.sub.2)--NR.sub.1'CO--O-J,
--NR.sub.1'CO--O--(CH.sub.2)-J,
--(CH.sub.2)--NR.sub.1'CO--O--(CH.sub.2)-J, --OCO-J,
--CH.sub.2--OCO-J, --CH.dbd.CH-J, --CH.sub.2--CH.dbd.CH-J,
--CH.dbd.CH--CH.sub.2-J and --CH.sub.2--CH.dbd.CH--CH.sub.2-J. In
yet a further aspect R.sup.61 is --CONR.sup.64-J or
--(CH.sub.2)--CONR.sup.64-J. In another aspect R.sup.61 is
--(CH.sub.2)--CONR.sup.64-J.
[0138] In one aspect of the invention R.sup.62 is a group selected
from hydrogen, cyano, nitro halo, C.sub.1-6alkyl, aryl,
arylC.sub.1-6alkyl, heterocyclyl, heterocyclylC.sub.1-6alkyl (where
aryl and heterocyclyl of the latter four groups are optionally
substituted by 1, 2 or 3 substitutents independently selected from
halo, hydroxy, mercapto, carboxy, C.sub.1-4alkyl (optionally
substituted by 1, 2 or 3 halo), aryl, heteroaryl, amino, cyano,
nitro, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino and S(O).sub.y
where y is 0, 1 or 2), a group of sub-formula (K) as defined above,
a group of sub-formula (II) as defined above and a group of formula
(VI) as defined above. In another aspect R.sup.62 is a group of
sub-formula (k) as defined above. In yet another aspect of the
invention R.sup.62 is hydrogen, halo or C.sub.1-3alkyl. In a
further aspect R.sup.62 is hydrogen.
[0139] Preferred values of R.sub.1', R.sub.1'', p, T, V, r and
R.sup.70 are as follows. Such values may be used where appropriate
with any of the definitions, claims or embodiments defined
hereinbefore or hereinafter.
[0140] In one aspect of the invention R.sub.1' is hydrogen or
C.sub.1-3alkyl.
[0141] In one aspect of the invention R.sub.1'' is hydrogen or
C.sub.1-3alkyl.
[0142] In one aspect of the invention p is 1.
[0143] In one aspect of the invention T is C.dbd.O, SO.sub.4,
(where n is 0, 1 or 2), C(.dbd.NOR)CO, C(O)C(O) or C.dbd.NCN. In
another aspect T is C.dbd.O.
[0144] In one aspect of the invention q is 1.
[0145] In one aspect of the invention V is N(R.sup.63)R.sup.64.
[0146] In one aspect of the invention R.sup.63 is
--(CH.sub.2).sub.q'R.sup.70 or aryl or heteroaryl where the latter
two groups are optionally substituted by 1 or 2 substituents
independently selected from halo, C.sub.1-4alkyl, C.sub.1-4alkoxy,
trifluoromethyl, trifluoromethoxy, hydroxy, nitro, difluoromethyl,
difluoromethoxy and cyano. In another aspect R.sup.63 is aryl
optionally substituted by 1 or 2 substituents independently
selected from halo, C.sub.1-4alkyl, C.sub.1-4alkoxy,
trifluoromethyl, trifluoromethoxy, hydroxy, nitro, difluoromethyl,
difluoromethoxy and cyano.
[0147] In one aspect of the invention R.sup.64 is hydrogen or
C.sub.1-3alkyl. In another aspect R.sup.64 is hydrogen.
[0148] In one aspect of the invention R.sup.70 is a group of
formula (III) --K-J.
[0149] In one aspect of the invention K is a bond, oxy, imino,
N--(C.sub.1-4alkyl)imino, oxyC.sub.1-4alkylene,
iminoC.sub.1-4alkylene and
N--(C.sub.1-4alkyl)iminoC.sub.1-4alkylene. In another aspect K is a
bond.
[0150] In one aspect of the invention J is aryl or heteroaryl which
are both optionally substituted by 1, 2 or 3 substitutents selected
from halo, C.sub.1-3alkyl, C.sub.3-4cycloalkyl,
C.sub.3-4cycloalkylC.sub.1-3alkyl, cyano and C.sub.1-3alkoxy. In
another aspect J is a group select from phenyl, pyridyl,
pyrimidinyl, furyl, thienyl and pyrrolyl which group is optionally
substituent by 1 or 2 substituents selected from halo, methyl,
ethyl, methoxy, cyano, cyclopropyl and cyclopropylmethyl. In yet
another aspect J is phenyl optionally substituted by 1 or 2 halo.
In a further aspect of the invention J is 3-fluorophenyl,
2,3-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl,
3-methoxyphenyl, phenyl, 4-fluorophenyl, 3,5-dichlorophenyl,
5-chloro-2-methoxyphenyl, 3-trifluoromethylphenyl, 3-hydroxyphenyl,
3-nitrophenyl, 4-bromo-2-fluorophenyl, 3,5-dimethoxyphenyl,
3-chloro-2-fluorophenyl, 2-fluoro-3-trifluormethylphenyl,
3,4-difluorophenyl, 2,4-difluorophenyl, 3-chloro-4-fluorophenyl,
2-difluoromethoxyphenyl, 3-cyanophenyl, 3-bromophenyl, 5-indanzolyl
and 5-methylpyridin-2-yl.
[0151] Preferably R.sup.4 is hydrogen.
[0152] Suitably R.sup.1 is hydrogen or a group set out for R.sup.2
or R.sup.3 below. Frequently, R.sup.1 is hydrogen.
[0153] In a preferred embodiment, at least one group R.sup.1,
R.sup.2 or R.sup.3, preferably R.sup.3, comprises a chain of at
least 3 and preferably at least 4 optionally substituted carbon
atoms or heteroatoms such as oxygen, nitrogen or sulphur. Most
preferably the chain is substituted by a polar group which assists
in solubility.
[0154] Suitably R.sup.3 is a group X.sup.1R.sup.9. Preferably in
this case, X.sup.1 is oxygen and R.sup.9 is selected from a group
of formula (1) or (10) above. Particular groups R.sup.9 are those
in group (1) above, especially alkyl such as methyl or halo
substituted alkyl, or those in group (10) above. In one preferred
embodiment, at least one of R.sup.2 or R.sup.3 is a group
--OC.sub.1-5alkylR.sup.33 and R.sup.33 is a heterocyclic ring such
as an N-linked morpholine ring such as 3-morpholinopropoxy.
[0155] Suitably R.sup.2 is selected from, halo, cyano, nitro,
trifluoromethyl, C.sub.1-3alkyl, --NR.sup.9R.sup.10 (wherein
R.sup.9 and R.sup.10, which may be the same or different, each
represents hydrogen or C.sub.1-3alkyl), or a group
--X.sup.1R.sup.11. Preferred examples of --X.sup.1R.sup.11 for
R.sup.2 include those listed above in relation to R.sup.3.
[0156] Other examples for R.sup.2 and R.sup.3 include methoxy or
3,3,3-trifluoroethoxy.
[0157] Preferably X is NH or O and is most preferably NH.
[0158] In one aspect of the invention, one of R.sup.60, R.sup.61 or
R.sup.62 is a substituent group and the others are either hydrogen
or a small substituent such as C.sub.1-3 alkyl, for instance
methyl. Suitably R.sup.62 is hydrogen. Preferably R.sup.61 is other
than hydrogen,
[0159] Suitable substituents for groups R.sup.5 include optionally
substituted hydrocarbyl, optionally substituted heterocylyl or a
functional group as defined above.
[0160] In particular, R.sup.60, R.sup.61 or R.sup.62 is a group of
sub-formula (k)
##STR00011##
[0161] where p and q are independently 0 or 1 and wherein R.sub.1'
and R.sub.1'' are independently hydrogen, hydroxy, optionally
substituted alkyl, optionally substituted cycloalkyl, halogen,
cyano, optionally substituted alkyl, optionally substituted
alkyenyl. The optionally substituted alkyl or alkynyl may be
substituted with halo, nitro, cyano, hydroxy, trifluoromethyl,
amino, carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-4 alkyl,
C.sub.2-4alkenyl, C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl,
C.sub.3-6 cycloalkenyl, C.sub.1-4 alkoxy, C.sub.1-4 alkanoyl,
C.sub.1-4 alkanoyloxy, N--(C.sub.1-4 alkyl), N(C.sub.1-4
alkyl).sub.2, C.sub.1-4 alkanoylamino, (C.sub.1-4
alkanoyl).sub.2-amino, N--(C.sub.1-4alkyl)carbamoyl,
N,N--(C.sub.1-4).sub.2-carbamoyl, C.sub.1-4)S, C.sub.1-4S(O),
(C.sub.1-4alkyl)S(O).sub.2, (C.sub.1-4) alkoxycarbonyl,
N--(C.sub.1-4 alkyl)sulphamoyl, N,N--C.sub.1-4 alkyl)sulphamoyl,
C.sub.1-4 alkylsulphonylamino, or heterocyclyl. R is preferably
C.sub.1-4 alkyl, C.sub.2-4alkenyl, or C.sub.2-4 alkynyl, and
R.sub.1' can form with R.sub.11'' a 3 to 6 membered ring.
[0162] T is C.dbd.O, SO.sub.n, C(.dbd.NOR)CO, C(O)C(O), C.dbd.NCN,
CV.dbd.NO or wherein n=0, 1 or 2 and V is independently R.sup.63 or
N(R.sup.63)R.sup.64 wherein R.sup.63 and R.sup.64 are independently
selected from hydrogen, optionally substituted hydrocarbyl or
optionally substituted heterocyclyl, or R.sup.63 and R.sup.64
together with the nitrogen atom to which they are attached form an
optionally substituted heterocyclic ring.
[0163] Examples of groups for R.sup.63 and R.sup.64 include the
group --(CH.sub.2).sub.qR.sup.70 where q and R.sup.70 are as
defined below in relation to formula (II).
[0164] Suitably one of R.sup.63 or R.sup.64 is hydrogen, or methyl,
ethyl or propyl optionally substituted with hydroxy and preferably
one of R.sup.63 or R.sup.64 is hydrogen. In this case, the other is
suitably a larger substituent for example of at least 4 carbon or
heteroatoms, and is optionally substituted hydrocarbyl or
optionally substituted heterocyclyl. Particular optionally
substituted hydrocarbyl groups for R.sup.63 or R.sup.64 include
alkyl, cycloalkyl, alkenyl, or aryl any of which is optionally
substituted with a functional group as defined above, or in the
case of aryl groups, with an alkyl group and in the case of alkyl
group, with an aryl or heterocyclic group either of which may
themselves be optionally substituted with alkyl or a functional
group. Examples of optionally substituted aryl groups R.sup.63 or
R.sup.64 include phenyl optionally substituted with one or more
groups selected from C.sub.1-6 alkyl group such as methyl or ethyl
(either of which may be optionally substituted with a functional
group such as hydroxy), or a functional group as defined above
(such as halo like fluoro, chloro or bromo, hydroxy, alkoxy such as
methoxy, trifluoromethyl, nitro, cyano, trifluoromethoxy,
CONH.sub.2, C(O)CH.sub.3, amino, or dimethylamino).
[0165] When R.sup.63 or R.sup.64 is an optionally substituted alkyl
group, it is suitably a C.sub.1-6alkyl group, optionally
substituted with one or more functional groups (such as cyano,
hydroxy, alkoxy, in particular methoxy, COOalkyl such as
COOCH.sub.3), or aryl optionally substituted with a functional
group as defined above (in particular in relation to R.sup.63 or
R.sup.64 themselves, or an optionally substituted heterocyclic
group such as N-methylpyrrole.
[0166] When R.sup.63 and R.sup.64 is optionally substituted
cycloalkyl, it is suitable cyclohexyl optionally substituted with a
functional group such as hydroxy.
[0167] When R.sup.63 and R.sup.64 is optionally substituted
alkenyl, it is suitably prop-2-enyl.
[0168] When R.sup.63 or R.sup.64 is optionally substituted
heterocyclyl, or R.sup.63 and R.sup.64 together form a heterocyclic
group, then this may be aromatic or non-aromatic and includes in
particular, piperidine, piperazine, morpholino, pyrrolidine or
pyridine any of which may be optionally substituted with a
functional group such as hydroxy, alkoxy such as methoxy, or alkyl
such as methyl which may itself be substituted with for instance a
hydroxy group.
[0169] Alternatively at least one of R.sup.60, R.sup.61 or R.sup.62
is a functional group, and in particular, one of R.sup.60, R.sup.61
or R.sup.62 is a functional group a group of formula
(CR.sub.2).sub.pC(O).sub.xR.sup.77 where R, p, x and R.sup.77 are
as defined above, and in particular x is 2 and R.sup.77 is hydrogen
or alkyl such as methyl.
[0170] Alternatively, R.sup.5 is substituted by one or more groups
selected from nitro, halo, C.sub.1-6alkyl, optionally substituted
C.sub.1-6 alkoxy, C.sub.1-4alkoxymethyl, di(C.sub.1-4alkoxy)methyl,
C.sub.1-6alkanoyl, trifluoromethyl, cyano, amino, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, a phenyl group, a benzyl group or a 5-6-membered
heterocyclic group with 1-3 heteroatoms, selected independently
from O, S and N, which heterocyclic group may be aromatic or
non-aromatic and may be saturated (linked via a ring carbon or
nitrogen atom) or unsaturated (linked via a ring carbon atom), and
which phenyl, benzyl or heterocyclic group may bear on one or more
ring carbon atoms up to 5 substituents selected from hydroxy,
halogeno, C.sub.1-3alkyl, C.sub.1-3alkoxy, C.sub.1-3alkanoyloxy,
trifluoromethyl, cyano, amino, nitro, C.sub.2-4alkanoyl,
C.sub.1-4alkanoylamino, C.sub.1-4alkoxycarbonyl,
C.sub.1-4alkylsulphanyl, C.sub.1-4alkylsulphinyl,
C.sub.1-4alkylsulphonyl, carbamoyl, N--C.sub.1-4alkylcarbamoyl,
N,N-di(C.sub.1-4alkyl)carbamoyl, aminosulphonyl,
N--C.sub.1-4alkylaminosulphonyl,
N,N-di(C.sub.1-4alkyl)aminosulphonyl, C.sub.1-4alkylsulphonylamino,
and a saturated heterocyclic group selected from morpholino,
thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl
imidazolidinyl and pyrazolidinyl, which saturated heterocyclic
group may bear 1 or 2 substituents selected from oxo, hydroxy,
halogeno, C.sub.1-3alkyl, C.sub.1-3alkoxy, C.sub.1-3alkanoyloxy,
trifluoromethyl, cyano, amino, nitro and C.sub.1-4alkoxycarbonyl.
Suitably R.sup.5 is substituted with at least one group which has
at least 4 atoms which may be carbon or heteroatoms forming a
chain. A particular example of such a substituent is optionally
substituted alkoxy or alkoxy methyl. Suitable substituents for the
alkoxy group include those listed above in relation to R.sup.77,
R.sup.78 and R.sup.79.
A further particular substituent group for R.sup.5 is a group of
sub-formula (II)
##STR00012##
where p and q are independently 0 or 1, and r is 0, 1, 2, 3 or 4
and, R1', R1'' and T are as previously defined above; R.sup.70 is
hydrogen, hydroxy (other than where q is 0), C.sub.1-6alkyl,
C.sub.1-6alkoxy, amino, N--C.sub.1-6alkylamino,
N,N--(C.sub.1-6alkyl).sub.2-amino, hydroxyC.sub.2-6alkoxy,
C.sub.1-6alkoxyC.sub.2-6alkoxy, aminoC.sub.2-6alkoxy,
N--C.sub.1-6alkylaminoC.sub.2-6alkoxy,
N,N--(C.sub.1-6alkyl).sub.2-aminoC.sub.2-6alkoxy or
C.sub.3-7cycloalkyl,
or R.sup.70 is of the Formula (III):
[0171] --K-J (III)
wherein J is aryl, heteroaryl or heterocyclyl and K is a bond, oxy,
imino, N--(C.sub.1-6alkyl)imino, oxyC.sub.1-16alkylene,
iminoC.sub.1-16alkylene,
N--(C.sub.1-16alkyl)iminoC.sub.1-16alkylene, --NHC(O)--,
--SO.sub.2NH--, --NHSO.sub.2-- or --NHC(O)--C.sub.1-6alkylene-, and
any aryl, heteroaryl or heterocyclyl group in a R.sup.70 group may
be optionally substituted by one or more groups selected from
hydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino,
carboxy, carbamoyl, formyl, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
--O--(C.sub.1-3alkyl)-O--, C.sub.1-6alkylS(O).sub.n-- (wherein n is
0-2), N--C.sub.1-6alkylamino, N,N--(C.sub.1-6alkyl).sub.2-amino,
C.sub.1-16alkoxycarbonyl, N--C.sub.1-6alkylcarbamoyl,
N,N--(C.sub.1-6alkyl).sub.2-carbamoyl, C.sub.2-6alkanoyl,
C.sub.1-6alkanoyloxy, C.sub.1-6alkanoylamino,
N--C.sub.1-6alkylsulphamoyl, N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-16alkylsulphonylamino and
C.sub.1-6alkylsulphonyl-N--(C.sub.1-6alkyl)amino, or any aryl,
heteroaryl or heterocyclyl group in a R.sup.70 group may be
optionally substituted with one or more groups of the Formula
(IV):
##STR00013##
wherein A.sup.1 is halo, hydroxy, C.sub.1-6alkoxy, cyano, amino,
N--C.sub.1-6alkylamino, N,N--(C.sub.1-6alkyl).sub.2-amino, carboxy,
C.sub.1-6alkoxycarbonyl, carbamoyl, N--C.sub.1-6alkylcarbamoyl or
N,N--(C.sub.1-6alkyl).sub.2-carbamoyl, p is 1-6, and B.sup.1 is a
bond, oxy, imino, N--(C.sub.1-6alkyl)imino or --NHC(O)--, with the
proviso that p is 2 or more unless B.sup.1 is a bond or --NHC(O)--;
or any aryl, heteroaryl or heterocyclyl group in a R.sup.70 group
may be optionally substituted with one or more groups of the
Formula (V):
##STR00014##
wherein D.sup.1 is aryl, heteroaryl or heterocyclyl and E.sup.1 is
a bond, C.sub.1-6alkylene, oxyC.sub.1-6alkylene, oxy, imino,
N--(C.sub.1-6alkyl)imino, iminoC.sub.1-6alkylene,
N--(C.sub.1-6alkyl)-iminoC.sub.1-6alkylene,
C.sub.1-6alkylene-oxyC.sub.1-6alkylene,
C.sub.1-6alkylene-iminoC.sub.1-6alkylene,
C.sub.1-6alkylene-N--(C.sub.1-6alkyl)iminoC.sub.1-6alkylene,
--NHC(O)--, --NHSO.sub.2--, --SO.sub.2NH-- or
--NHC(O)--C.sub.1-6alkylene-, and any aryl, heteroaryl or
heterocyclyl group in a substituent on D.sup.1 may be optionally
substituted with one or more groups selected from hydroxy, halo,
C.sub.1-6alkyl, C.sub.1-6alkoxy, carboxy, C.sub.1-6alkoxycarbonyl,
carbamoyl, N--C.sub.1-6alkylcarbamoyl,
N--(C.sub.1-6alkyl).sub.2-carbamoyl,
[0172] C.sub.2-6alkanoyl, amino, N--C.sub.1-6alkylamino and
N,N--(C.sub.1-6alkyl).sub.2-amino,
and any C.sub.3-7cycloalkyl or heterocyclyl group in a R.sup.70
group may be optionally substituted with one or two oxo or thioxo
substituents, and any of the R.sup.70 groups defined hereinbefore
which comprises a CH.sub.2 group which is attached to 2 carbon
atoms or a CH.sub.3 group which is attached to a carbon atom may
optionally bear on each said CH.sub.2 or CH.sub.3 group a
substituent selected from hydroxy, amino, C.sub.1-6alkoxy,
N--C.sub.1-6alkylamino, N,N--(C.sub.1-6alkyl).sub.2-amino and
heterocyclyl. A preferred example of a substituent of formula (TI)
is a group where q is 0. A particular example of a group R.sup.70
in formula (TI) is phenyl. Another preferred substituent group for
R.sup.5 is a group of formula (VI)
##STR00015##
where R.sup.71 and R.sup.72 are independently selected from
hydrogen or C.sub.1-4alkyl, or R.sup.71 and R.sup.72 together form
a bond, and R.sup.73 is a group OR.sup.74, NR.sup.75R.sup.76 where
R.sup.74, R.sup.75 and R.sup.76 are independently selected from
optionally substituted hydrocarbyl or optionally substituted
heterocyclic groups, and R.sup.75 and R.sup.76 may additionally
form together with the nitrogen atom to which they are attached, an
aromatic or non-aromatic heterocyclic ring which may contain
further heteroatoms.
[0173] Suitable optional substituents for hydrocarbyl or
heterocyclic groups R.sup.74, R.sup.75 and R.sup.76 include
functional groups as defined above. Heterocyclic groups R.sup.74,
R.sup.75 and R.sup.76 may further be substituted by hydrocarbyl
groups.
In particular, R.sup.71 and R.sup.72 in sub-formula (VI) are
hydrogen. Particular examples of R.sup.73 are groups OR.sup.74
where R.sup.74 is C.sub.1-4alkyl. Further examples of R.sup.73 are
groups of formula NR.sup.75R.sup.76 where one of R.sup.75 or
R.sup.76 is hydrogen and the other is optionally substituted
C.sub.1-6alkyl, optionally substituted aryl or optionally
substituted heterocyclyl. In particular, one of R.sup.75 or
R.sup.76 is hydrogen and the other is C.sub.1-6alkyl optionally
substituted with trifluoromethyl, C.sub.1-3 alkoxy such as methoxy,
cyano, thioC.sub.1-4alkyl such as methylthio, or heterocyclyl
optionally substituted with hydrocarbyl, such as indane, furan
optionally substituted with C.sub.1-4 alkyl such as methyl. In
another embodiment, one of R.sup.75 or R.sup.76 is hydrogen and the
other is an optionally substituted heterocyclic group such as
pyridine, or a phenyl group optionally substituted with for example
one or more groups selected from halo, nitro, alkyl such as methyl,
or alkoxy such as methoxy.
[0174] A preferred class of compounds is of formula (I)
wherein:
X is NH;
[0175] R.sup.1 is hydrogen, methoxy,
N--(C.sub.1-5alkyl)piperidin-4-yloxy, prop-2-yloxy or
methoxyethoxy; R.sup.2 is hydrogen or methoxy; R.sup.3 is
3-morpholinopropoxy, 3-chloropropoxy,
3-[N-ethyl-N-(2-hydroxyethyl)amino]propoxy,
3-(2-hydroxymethylpyrrolidin-1-yl)propoxy,
3-(piperidin-1-yl)propoxy, 3-(pyrrolidin-1-yl)propoxy,
3-(N-(2-hydroxyethyl)amino]propoxy,
3-[N-(2-hydroxy-1,1-dimethylethyl)amino}propoxy,
3-[N-methyl-N-(2-hydroxyethyl)amino]propoxy,
3-[N-(1-hydroxymethyl-2-methylpropyl)amino]propoxy,
3-(4-methylpiperazin-1-yl)propoxy,
3-[N-(2-hydroxy-1-methylethyl)amino]propoxy,
3-[N-(4-hydroxybutyl)amino]propoxy,
3-(4-hydroxypiperidin-1-yl)propoxy,
3-[2-(2-hydroxyethyl)piperidin-1-yl]propoxy,
3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy,
3-[4-(2-hydroxyethyl)piperidin-1-yl]propoxy,
3-(3-hydroxypiperidin-1-yl)propoxy,
3-[N-2-(hydroxybutyl)amino]propoxy,
3-(4-hydroxymethylpiperidin-1-yl)propoxy,
3-[N-(3-hydroxy-2,2-dimethylpropyl)amino]propoxy,
3-[N-(1-hydroxymethylcyclopent-1-yl)amino]propoxy,
3-[N-(2-hydroxypropyl)amino]propoxy,
3-(3-hydroxypyrrolidin-1-yl)propoxy,
3-[N-(2-fluoroethyl)N-(2-hydroxyethyl)amino]propoxy,
2-[1-(2-hydroxyethyl)piperidin-4-yl]ethoxy,
3-[N-(2-hydroxyethyl)-N-propylamino]propoxy,
3-[N-(2-hydroxyethyl)-N-(prop-2-yl)amino]propoxy,
3-[N-(2-hydroxyethyl)-N-isobutylamino]propoxy,
3-[N-(2-hydroxyethyl)-N-neopentylamino]propoxy,
3-[N-allyl-N-(2-hydroxyethyl)amino]propoxy,
3-[N-(2-hydroxyethyl)-N-(prop-2-yn-1-yl)amino]propoxy,
3-[N-cyclopropyl-N-(2-hydroxyethyl)amino]propoxy,
3-[N-cyclopropylmethyl-N-(2-hydroxyethyl)amino]propoxy,
3-[N-cyclobutyl-N-(2-hydroxyethyl)amino]propoxy,
3-[N-cyclopentyl-N-(2-hydroxyethyl)amino]propoxy,
3-[N-(2,2-dimethoxyethyl)-N-(2-hydroxyethyl)amino]propoxy,
3-[N-(2,2-difluoroethyl)-N-(2-hydroxyethyl)amino]propoxy,
3-[N-(2-hydroxyethyl)-N-(3,3,3-trifluoropropyl)amino]propoxy,
3-[N-cyclobutylmethyl-N-(2-hydroxyethyl)amino]propoxy,
3-[N-(2-hydroxyethyl)-N-(2-methoxyethyl)amino]propoxy,
3-[N-(1,3-dioxolan-2-ylmethyl)-N-(2-hydroxyethyl)amino]propoxy,
4-chlorobutoxy, 4-[(2-hydroxymethyl)pyrrolidin-1-yl]butoxy,
4-[N-(2-hydroxyethyl)-N-isobutylamino]butoxy,
1-(2-tert-butoxyethyl)pyrrolidin-2-ylmethoxy,
1-(2-hydroxyethyl)pyrrolidin-2-ylmethoxy,
3-[N-2-(hydroxyethyl)-N-(isobutyl)amino]propoxy,
3-[N-2-(hydroxyethyl)-N-(neopentyl)amino]propoxy,
3-[N-2-(hydroxyethyl)-N-(tert-butyl)amino]propoxy, methoxy and
methoxyethoxy; R.sup.4 is hydrogen; R.sup.60 is hydrogen; R.sup.61
is a group of sub-formula (k) as defined above; R.sup.62 is
hydrogen; R.sub.1' is hydrogen or C.sub.1-3alkyl; R.sub.1'' is
hydrogen or C.sub.1-3alkyl; p is 1;
T is C.dbd.O;
[0176] q is 1;
V is N(R.sup.63)R.sup.64;
[0177] R.sup.63 is --(CH.sub.2).sub.q'R.sup.70 or aryl or
heteroaryl where the latter two groups are optionally substituted
by 1 or 2 substituents independently selected from halo,
C.sub.1-4alkyl, C.sub.1-4alkoxy, trifluoromethyl, trifluoromethoxy,
hydroxy, nitro, difluoromethyl, difluoromethoxy and cyano; R.sup.64
is hydrogen; R.sup.70 is a group of formula (III) --K-J; K is a
bond; and J is 3-fluorophenyl, 2,3-difluorophenyl,
3,5-difluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, phenyl,
4-fluorophenyl, 3,5-dichlorophenyl, 5-chloro-2-methoxyphenyl,
3-trifluoromethylphenyl, 3-hydroxyphenyl, 3-nitrophenyl,
4-bromo-2-fluorophenyl, 3,5-dimethoxyphenyl,
3-chloro-2-fluorophenyl, 2-fluoro-3-trifluormethylphenyl,
3,4-difluorophenyl, 2,4-difluorophenyl, 3-chloro-4-fluorophenyl,
2-difluoromethoxyphenyl, 3-cyanophenyl, 3-bromophenyl, 5-indanzolyl
and 5-methylpyridin-2-yl.
[0178] A further preferred class of compounds is of formula (I)
wherein:
[0179] X is NR.sup.6 or 0;
[0180] R.sup.6 is hydrogen or C.sub.1-3alkyl;
[0181] R.sup.1 is hydrogen or --X.sup.1R.sup.9 where X.sup.1 is a
direct bond, --O-- or --NH-- and R.sup.9 is hydrogen,
C.sub.1-5alkyl, C.sub.3-6cycloalkyl,
--C.sub.1-5alkyl-O--C.sub.1-3alkyl or a 5- to 6-membered saturated
heterocyclic group (linked via carbon or nitrogen) with 1 or 2
heteroatoms selected independently from O, S or N which
heterocyclic groups is optionally substituted by C.sub.1-4alkyl or
a 5- or 6-membered aromatic heterocyclic group (linked via carbon
or nitrogen with 1, 2 or 3 heteroatoms;
[0182] R.sup.2 is hydrogen, hydroxy, halo, methoxy or
--OC.sub.1-3alkyl (optionally substituted by 1 or 2 hydroxy or
halo);
[0183] R.sup.3 is --X.sup.1R.sup.9 where X.sup.1 is --O-- and
R.sup.9 is --C.sub.1-5alkylR.sup.32, --C.sub.1-5alkylR.sup.96,
C.sub.1-5alkyl (optionally substituted by halo),
--C.sub.1-5alkyl-OR.sup.20, --C.sub.1-5alkyl-NHR.sup.20,
--C.sub.1-5alkyl-N(C.sub.1-3alkyl)-R.sup.20,
--C.sub.1-5alkyl-NH--C.sub.1-5alkyl-OH,
--C.sub.1-5alkyl-N(C.sub.1-3alkyl)-C.sub.1-5alkyl-OH and
--C.sub.1-5alkyl-NR.sup.95--C.sub.1-5alkyl-OH;
[0184] R.sup.32 is morpholino, pyrrolidinyl, piperidinyl or
piperazinyl optionally substituted by hydroxymethyl,
2-hydroxyethyl, methyl, hydroxy or 2-(tert-butoxy)ethyl;
[0185] R.sup.20 is C.sub.1-3alkyl optionally substituted by
hydroxy) or cyclopentyl (optionally substituted by
C.sub.1-4hydroxyalkyl);
[0186] R.sup.95 is methyl, ethyl, 2-fluoroethyl, prop-1-yl,
prop-2-yl, isobutyl, neopentyl, allyl, propargyl, cyclopropyl,
cyclopropylmethyl, cyclobutyl, cyclopentyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, cyclobutylmethyl, methoxyethyl,
1,3-dioxolan-2-ylmethyl and 2,2-dimethoxyethyl;
[0187] R.sup.96 is 4,5-dihydro-1H-imidazoyl optionally substituted
by C.sub.1-4hydroxyalkyl;
[0188] R.sup.4 is hydrogen;
[0189] R.sup.60 is hydrogen;
[0190] R.sup.61 is J, --(CH.sub.2)-J, --(CH.sub.2).sub.2-J, --O-J,
--(CH.sub.2)--O-J, --O--(CH.sub.2)-J,
--(CH.sub.2)--O--(CH.sub.2)-J, --CO-J, --(CH.sub.2)--CO-J,
--CO--(CH.sub.2)-J, --(CH.sub.2)--CO--(CH.sub.2)-J, --S-J,
--(CH.sub.2)--S-J, --S--(CH.sub.2)-J,
--(CH.sub.2)--S--(CH.sub.2)-J, --SO-J, --(CH.sub.2)--SO-J,
--SO--(CH.sub.2)-J, --(CH.sub.2)--SO--(CH.sub.2)-J, --SO.sub.2-J,
--(CH.sub.2)--SO.sub.2-J, --SO.sub.2--(CH.sub.2)-J,
--(CH.sub.2)--SO.sub.2--(CH.sub.2)-J, --(NR.sub.1')CO-J,
--(CH.sub.2)--(NR.sub.1')CO-J,
--(NR.sub.1')CO--(CH.sub.2)-J-(CH.sub.2)--(NR.sub.1')CO--(CH.sub.2)-J,
--(NR.sub.1')SO.sub.2-J, --(CH.sub.2)--(NR.sub.1')SO.sub.2-J,
--(NR.sub.1')SO.sub.2--(CH.sub.2)-J,
--(CH.sub.2)--(NR.sub.1')SO.sub.2--(CH.sub.2)-J, --NR.sup.64-J,
--(CH.sub.2)--NR.sup.64-J, --NR.sup.64--(CH.sub.2)-J,
--(CH.sub.2)--NR.sup.64--(CH.sub.2)-J, --CONR.sup.64-J,
--(CH.sub.2)--CONR.sup.64-J, --CONR.sup.64--(CH.sub.2)-J,
--(CH.sub.2)--CONR.sup.64--(CH.sub.2)-J, --SO.sub.2NR.sup.64-J,
--(CH.sub.2)--SO.sub.2NR.sup.64-J,
--SO.sub.2NR.sup.64--(CH.sub.2)-J,
--(CH.sub.2)--SO.sub.2NR.sup.64--(CH.sub.2)-J, --NR.sub.1'CO--NH-J,
--(CH.sub.2)--NR.sub.1'CO--NH-J, --NR.sub.1'CO--NH--(CH.sub.2)-J,
--(CH.sub.2)--NR.sub.1'CO--NH--(CH.sub.2)-J,
--NR.sub.1'CO--N(C.sub.1-4alkyl)-J,
--(CH.sub.2)--NR.sub.1'CO--N(C.sub.1-4alkyl)-J,
--NR.sub.1'CO--N(C.sub.1-4alkyl)-(CH.sub.2)-J,
--(CH.sub.2)--NR.sub.1'CO--N(C.sub.1-4alkyl)-(CH.sub.2)-J,
--NR.sub.1'CO--O-J, --(CH.sub.2)--NR.sub.1'CO--O-J,
--NR.sub.1'CO--O--(CH.sub.2)-J,
--(CH.sub.2)--NR.sub.1'CO--O--(CH.sub.2)-J, --OCO-J,
--CH.sub.2--OCO-J, --CH.dbd.CH-J, --CH.sub.2--CH.dbd.CH-J,
--CH.dbd.CH--CH.sub.2-J and --CH.sub.2--CH.dbd.CH--CH.sub.2-J;
[0191] R.sup.62 is hydrogen, halo or C.sub.1-3alkyl;
[0192] R.sub.1' is hydrogen or C.sub.1-3alkyl;
[0193] R.sup.64 is hydrogen or C.sub.1-3alkyl; and
[0194] J is a group select from phenyl, pyridyl, pyrimidinyl,
furyl, thienyl and pyrrolyl which group is optionally substituent
by 1 or 2 substituents selected from halo, methyl, ethyl, methoxy,
cyano, cyclopropyl and cyclopropylmethyl.
[0195] In another aspect of the invention, preferred compounds are
any one of: [0196]
2-(3-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino}-1H-pyr-
azol-5-yl)-N-phenylacetamide; [0197]
N-(3-fluorophenyl)-2-(3-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-
-4-yl]amino}-1H-pyrazol-5-yl)acetamide; [0198]
2-(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-y-
l)-N-(3-fluorophenyl)acetamide; [0199]
2-(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-y-
l)-N-(3,5-difluorophenyl)acetamide; [0200]
2-(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-y-
l)-N-(2,3-difluorophenyl)acetamide; [0201]
N-(3-chlorophenyl)-2-(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]am-
ino}-1H-pyrazol-5-yl)acetamide; [0202]
2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl-
)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide; [0203]
N-(3-fluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pro-
poxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0204]
N-(3-fluorophenyl)-2-(3-{[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazolin-
-4-yl]amino}-1H-pyrazol-5-yl)acetamide; [0205]
N-(3-fluorophenyl)-2-(3-{[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoli-
n-4-yl]amino}-1H-pyrazol-5-yl)acetamide; [0206]
N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)amino]propoxy}-6-methoxyq-
uinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0207]
N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxy-1,1-dimethylethyl)amino]propox-
y}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0208]
N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(methyl)amino]propoxy}-6--
methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0209]
N-(3-fluorophenyl)-2-(3-{[7-(3-{[1-(hydroxymethyl)-2-methylpropyl]amino}p-
ropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetamide;
[0210]
N-(3-fluorophenyl)-2-[3-({6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]-
quinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetamide; [0211]
N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxy-1-methylethyl)amino]propoxy}-6-
-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0212]
N-(3-fluorophenyl)-2-{3-[(7-{3-[(4-hydroxybutyl)amino]propoxy}-6-methoxyq-
uinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0213]
N-(3-fluorophenyl)-2-[3-({7-[3-(4-hydroxypiperidin-1-yl)propoxy]-6-methox-
yquinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetamide; [0214]
N-(3-fluorophenyl)-2-{3-[(7-{3-[2-(2-hydroxyethyl)piperidin-1-yl]propoxy}-
-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0215]
N-(3-fluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy}-
-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0216]
N-(3-fluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperidin-1-yl]propoxy}-
-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0217]
N-(3-fluorophenyl)-2-[3-({7-[3-(3-hydroxypiperidin-1-yl)propoxy]-6-methox-
yquinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetamide; [0218]
N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxybutyl)amino]propoxy}-6-methoxyq-
uinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0219]
N-(3-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}--
6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0220]
N-(3-fluorophenyl)-2-{3-[(7-{3-[(3-hydroxy-2,2-dimethylpropyl)amino]propo-
xy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0221]
N-(3-fluorophenyl)-2-(3-{[7-(3-{[1-(hydroxymethyl)cyclopentyl]amino}propo-
xy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetamide;
[0222]
N-(3-fluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]pro-
poxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0223]
N-(3-fluorophenyl)-2-(3-{[7-(3-{[(2S)-2-hydroxypropyl]amino}propoxy)-6-me-
thoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetamide; [0224]
N-(3-fluorophenyl)-2-(3-{[7-(3-{[(2R)-2-hydroxypropyl]amino}propoxy)-6-me-
thoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetamide; [0225]
N-(3-fluorophenyl)-2-{3-[(7-{3-[(3S)-3-hydroxypyrrolidin-1-yl]propoxy}-6--
methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0226]
N-(3-fluorophenyl)-2-{3-[(7-{3-[(3R)-3-hydroxypyrrolidin-1-yl]propoxy}-6--
methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0227]
2-{3-[(7-{3-[(2-fluoroethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyquina-
zolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide;
[0228]
N-(3-fluorophenyl)-2-{3-[(7-{2-[1-(2-hydroxyethyl)piperidin-4-yl]ethoxy}--
6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0229]
N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy}-6--
methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0230]
N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isopropyl)amino]propoxy}-
-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0231]
N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propoxy}--
6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0232]
2-{3-[(7-{3-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]propoxy}-6-methoxy-
quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide;
[0233]
2-{3-[(7-{3-[allyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazol-
in-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide; [0234]
N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-1-yl)amino]pro-
poxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0235]
2-{3-[(7-{3-[cyclopropyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazoli-
n-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide; [0236]
2-{3-[(7-{3-[(cyclopropylmethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyq-
uinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide;
[0237]
2-{3-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-
-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide; [0238]
2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazoli-
n-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide; [0239]
2-{3-[(7-{3-[(2,2-dimethoxyethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxy-
quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide;
[0240]
2-{3-[(7-{3-[(2,2-difluoroethyl)(2-hydroxyethyl)amino]propoxy}-6-m-
ethoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide;
[0241]
N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(3,3,3-trifluoropr-
opyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetam-
ide; [0242]
2-{3-[(7-{3-[(cyclobutylmethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyqu-
inazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide;
[0243]
N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(2-methoxyethyl)amino]pro-
poxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0244]
2-{3-[(7-{3-[(1,3-dioxolan-2-ylmethyl)(2-hydroxyethyl)amino]propoxy}-6-me-
thoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide;
[0245]
2-(3-{[7-(4-chlorobutoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyraz-
ol-5-yl)-N-(3-fluorophenyl)acetamide; [0246]
N-(3-fluorophenyl)-2-{3-[(7-{4-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]but-
oxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0247]
N-(3-fluorophenyl)-2-{3-[(7-{4-[(2-hydroxyethyl)(isobutyl)amino]butoxy}-6-
-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0248]
2-{3-[(7-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-6-methoxyq-
uinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide;
[0249]
N-(3-fluorophenyl)-2-{3-[(7-{[(2R)-1-(2-hydroxyethyl)pyrrolidin-2-yl]meth-
oxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0250]
N-(3,5-difluorophenyl)-2-(3-{[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quina-
zolin-4-yl]amino}-1H-pyrazol-5-yl)acetamide; [0251]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)amino]propoxy}-6-meth-
oxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0252]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxy-1,1-dimethylethyl)amino]pr-
opoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0253]
N-(3,5-difluorophenyl)-2-[3-({6-methoxy-7-[3-(4-methylpiperazin-1-yl)prop-
oxy]quinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetamide; [0254]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6-
-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0255]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[2-(2-hydroxyethyl)piperidin-1-yl]prop-
oxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0256]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperazin-1-yl]prop-
oxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0257]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperidin-1-yl]prop-
oxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0258]
N-(3,5-difluorophenyl)-2-[3-({7-[3-(3-hydroxypiperidin-1-yl)propoxy]-6-me-
thoxyquinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetamide; [0259]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxybutyl)amino]propoxy}-6-meth-
oxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0260]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propo-
xy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0261]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(3-hydroxy-2,2-dimethylpropyl)amino]p-
ropoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0262]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl-
]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0263]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolid-
in-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide-
; [0264]
N-(3,5-difluorophenyl)-2-(3-{[7-(3-{[(2S)-2-hydroxypropyl]amino}p-
ropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetamide;
[0265]
N-(3,5-difluorophenyl)-2-(3-{[7-(3-{[(2R)-2-hydroxypropyl]amino}propoxy)--
6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetamide; [0266]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(3S)-3-hydroxypyrrolidin-1-yl]propoxy-
}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0267]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(3R)-3-hydroxypyrrolidin-1-yl]propoxy-
}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0268]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propo-
xy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0269]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy-
}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0270]
2-{3-[(7-{3-[allyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl-
)amino]-1H-pyrazol-5-yl}-N-(3,5-difluorophenyl)acetamide; [0271]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-1-yl)amino-
]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0272]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isopropyl)ami-
no]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0273]
N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2,2-dimethylpropyl)(2-hydroxy-
ethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}aceta-
mide; [0274]
2-{3-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-
-4-yl)amino]-1H-pyrazol-5-yl}-N-(3,5-difluorophenyl)acetamide;
[0275]
2-{3-[(7-{3-[(cyclopropylmethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyq-
uinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3,5-difluorophenyl)acetamide;
[0276]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolid-
in-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide-
; [0277]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2,2-dimethylpropyl)(2-hydrox-
yethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acet-
amide; [0278]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy-
}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0279]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propo-
xy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0280]
2-{3-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-
-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide;
[0281]
2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazoli-
n-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide;
[0282]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl-
]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0283]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-1-y-
l)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide-
; [0284]
2-{3-[(7-{3-[(cyclopropylmethyl)(2-hydroxyethyl)amino]propoxy}-6--
methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)aceta-
mide; [0285]
2-{3-[(7-{3-[(cyclobutylmethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyqu-
inazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide;
[0286]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2,2-dimethoxyethyl)(2-hydroxy-
ethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}aceta-
mide; [0287]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperidin-1-yl]prop-
oxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0288]
N-(2,3-difluorophenyl)-2-[3-({7-[3-(4-hydroxypiperidin-1-yl)propoxy]-6-me-
thoxyquinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetamide; [0289]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperazin-1-yl]prop-
oxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0290]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(2-methoxyethyl)amino-
]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0291]
2-{3-[(7-{3-[allyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazol-
in-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide;
[0292]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(1,3-dioxolan-2-ylmethyl)(2-hydroxyet-
hyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetami-
de; [0293]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]-
propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0294]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isopropyl)amino]prop-
oxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0295]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxy-1,1-dimethylethyl)amino]pr-
opoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0296]
N-(2,3-difluorophenyl)-2-{3-[(7-{[(2R)-1-(2-hydroxyethyl)pyrrolidin-2-yl]-
methoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0297]
N-(3-chlorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pro-
poxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0298]
N-(3-chlorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]pro-
poxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0299]
N-(3-chlorophenyl)-2-[3-({7-[3-(3-hydroxypiperidin-1-yl)propoxy]-6-methox-
yquinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetamide; [0300]
N-(3-chlorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6-met-
hoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0301]
2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-
-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-methoxyphenyl)acetamide; [0302]
2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-
-4-yl)amino]-1H-pyrazol-5-yl}-N-phenylacetamide;
[0303]
N-(4-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]pr-
opoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0304]
N-(3,5-dichlorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propo-
xy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0305]
N-(5-chloro-2-methoxyphenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl-
]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0306]
2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyqui-
nazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-[3-(trifluoromethyl)phenyl]acetamid-
e; [0307]
2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyq-
uinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-hydroxyphenyl)acetamide;
[0308]
2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyqui-
nazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-nitrophenyl)acetamide;
[0309]
2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-
-4-yl)amino]-1H-pyrazol-5-yl}-N-- 1H-indazol-5-ylacetamide; [0310]
N-(4-bromo-2-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]p-
ropoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0311]
N-(3-chlorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}--
6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0312]
N-(2-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}--
6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0313]
N-(3,5-dimethoxyphenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]prop-
oxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0314]
2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-
-4-yl)amino]-1H-pyrazol-5-yl}-N-(5-methylpyridin-2-yl)acetamide;
[0315]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propo-
xy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0316]
N-(3-chloro-2-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]-
propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0317]
N-(2,5-difluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propo-
xy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0318]
N-[2-fluoro-5-(trifluoromethyl)phenyl]-2-{3-[(7-{3-[4-(hydroxymethyl)pipe-
ridin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetam-
ide; [0319]
N-(3,4-difluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propo-
xy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0320]
N-(2,4-difluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propo-
xy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0321]
N-(3-chloro-4-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]-
propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0322]
N-[2-(difluoromethoxy)phenyl]-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-y-
l]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0323]
N-(3-cyanophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]pro-
poxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0324]
N-(3-bromophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-
-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0325]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}qu-
inazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0326]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isopropyl)amino]prop-
oxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0327]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl-
]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0328]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy-
}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0329]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-1-yl)amino-
]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0330]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propo-
xy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0331]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2,2-dimethylpropyl)(2-hydroxyethyl)a-
mino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0332]
N-(3-fluorophenyl)-2-[3-({5-{[1-(2-hydroxyethyl)piperidin-4-yl]oxy}-7-[3--
(4-methylpiperazin-1-yl)propoxy]quinazolin-4-yl}amino)-1H-pyrazol-5-yl]ace-
tamide; [0333]
N-(3-fluorophenyl)-2-[5-({7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinaz-
olin-4-yl}amino)-1H-pyrazol-3-yl]acetamide; [0334]
N-(2,3-difluorophenyl)-2-{3-[(5,7-dimethoxyquinazolin-4-yl)amino]-1H-pyra-
zol-5-yl}acetamide; [0335]
2-(3-{[5,7-bis(2-methoxyethoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N--
(2,3-difluorophenyl)acetamide; [0336]
N-(2,3-difluorophenyl)-2-(3-{[5-isopropoxy-7-(2-methoxyethoxy)quinazolin--
4-yl]amino}-1H-pyrazol-5-yl)acetamide; [0337]
N-(3-fluorophenyl)-2-(3-{[5-isopropoxy-7-(2-methoxyethoxy)quinazolin-4-yl-
]amino}-1H-pyrazol-5-yl)acetamide; [0338]
N-(3-fluorophenyl)-2-{3-[(5-{[1-(2-hydroxyethyl)piperidin-4-yl]oxy}-7-met-
hoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0339]
2-{3-[(5,7-dimethoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluoroph-
enyl)acetamide; [0340]
2-(3-{[5,7-bis(2-methoxyethoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N--
(3-fluorophenyl)acetamide; [0341]
N-(3-fluorophenyl)-3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propoxy}-6-m-
ethoxyquinazolin-4-yl)amino]-1H-pyrazole-5-carboxamide; and [0342]
N-(2,3-difluorophenyl)-3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propoxy}-
-6-methoxyquinazolin-4-yl)amino]-1H-pyrazole-5-carboxamide. In a
further aspect of the invention, even more preferred compounds are
any one of: [0343]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolid-
in-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide-
; [0344]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2,2-dimethylpropyl)(2-hydrox-
yethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acet-
amide; [0345]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy-
}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; [0346]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propo-
xy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0347]
2-{3-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-
-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide;
[0348]
2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazoli-
n-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide;
[0349]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl-
]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0350]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-1-y-
l)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide-
; [0351]
2-{3-[(7-{3-[(cyclopropylmethyl)(2-hydroxyethyl)amino]propoxy}-6--
methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)aceta-
mide; [0352]
2-{3-[(7-{3-[(cyclobutylmethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyqu-
inazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide;
[0353]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2,2-dimethoxyethyl)(2-hydroxy-
ethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}aceta-
mide; [0354]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperidin-1-yl]prop-
oxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0355]
N-(2,3-difluorophenyl)-2-[3-({7-[3-(4-hydroxypiperidin-1-yl)propoxy]-6-me-
thoxyquinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetamide; [0356]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperazin-1-yl]prop-
oxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0357]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(2-methoxyethyl)amino-
]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0358]
2-{3-[(7-{3-[allyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazol-
in-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide;
[0359]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(1,3-dioxolan-2-ylmethyl)(2-hydroxyet-
hyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetami-
de; [0360]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]-
propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0361]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isopropyl)amino]prop-
oxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
[0362]
N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxy-1,1-dimethylethyl)amino]pr-
opoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;
and [0363]
N-(2,3-difluorophenyl)-2-{3-[(7-{[(2R)-1-(2-hydroxyethyl)pyrrolidi-
n-2-yl]methoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide.
[0364] The present invention relates to the compounds of formula
(I), formula (IA) or formula (IB) as defined herein as well as to
the salts thereof. Salts for use in pharmaceutical compositions
will be pharmaceutically acceptable salts, but other salts may be
useful in the production of compounds of formula (I), formula (IA)
or formula (IB) and their pharmaceutically acceptable salts.
Suitable pharmaceutically acceptable salts of compounds of formula
(I), formula (IA) or formula (IB) include acid addition salts such
as methanesulphonate, fumarate, hydrochloride, hydrobromide,
citrate, maleate and salts formed with phosphoric and sulphuric
acid. There may be more than one cation or anion depending on the
number of charged functions and the valency of the cations or
anions. Where the compound of formula (I), formula (IA) or formula
(IB) includes an acid functionality, salts may be base salts such
as an alkali metal salt for example sodium, an alkaline earth metal
salt for example calcium or magnesium, an organic amine salt for
example triethylamine, morpholine, N-methylpiperidine,
N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine,
ethanolamine, diethanolamine or amino acids for example lysine. A
preferred pharmaceutically acceptable salt is a sodium salt.
[0365] The invention also provides for an in vivo hydrolysable
ester of a compound of formula (T), formula (IA) or formula (IB)
containing carboxy or hydroxy group. Such an ester is, for example,
a pharmaceutically acceptable ester which is hydrolysed in the
human or animal body to produce the parent acid or alcohol.
[0366] Suitable pharmaceutically acceptable esters for carboxy
include C.sub.1-6alkyl esters such as methyl or ethyl esters,
C.sub.1-6alkoxymethyl esters for example methoxymethyl,
C.sub.1-6alkanoyloxymethyl esters for example pivaloyloxymethyl,
phthalidyl esters, C.sub.3-8cycloalkoxy-carbonyloxyC.sub.1-6alkyl
esters for example 1-cyclohexylcarbonyloxyethyl;
1,3-dioxolen-2-onylmethyl esters for example
5-methyl-1,3-dioxolen-2-onylmethyl; and
C.sub.1-6alkoxycarbonyloxyethyl esters for example
1-methoxycarbonyloxyethyl and may be formed at any carboxy group in
the compounds of this invention.
[0367] An in vivo hydrolysable ester of a compound of formula (T),
formula (IA) or formula (IB) containing a hydroxy group includes
inorganic esters such as phosphate esters and .alpha.-acyloxyalkyl
ethers and related compounds which as a result of the in vivo
hydrolysis of the ester breakdown to give the parent hydroxy group.
Examples of .alpha.-acyloxyalkyl ethers include acetoxymethoxy and
2,2-dimethylpropionyloxymethoxy. A selection of in vivo
hydrolysable ester forming groups for hydroxy include alkanoyl,
benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl,
alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl
and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),
dialkylaminoacetyl and carboxyacetyl.
[0368] Suitable amides are derived from compounds of formula (I),
formula (IA) or formula (IB) which have a carboxy group which is
derivatised into an amide such as a N--C.sub.1-6alkyl and
N,N-di-(C.sub.1-6alkyl)amide such as N-methyl, N-ethyl, N-propyl,
N,N-dimethyl, N-ethyl-N-methyl or N,N-diethylamide.
Preferred compounds of formula (I), formula (IA) or formula (IB)
are those that are stable in mouse, rat, or human serum, preferably
those that are stable in human serum.
[0369] Esters which are not in vivo hydrolysable may be useful as
intermediates in the production of the compounds of formula (I),
formula (IA) or formula (IB).
[0370] Compounds of formula (I), formula (IA) or formula (IB) may
be prepared by various methods which would be apparent from the
literature. For example compounds of formula (I), formula (IA) or
formula (IB) where X is NH may be prepared by reacting a compound
of formula (VII)
##STR00016##
[0371] where R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 as defined in relation to formula (T)
or formula (IB) or R.sup.1', R.sup.2', R.sup.3', and R.sup.4' as
defined in relation to formula (IA) and R.sup.85 is a group
NR.sup.86R.sup.87 where R.sup.86 and R.sup.87 are independently
selected from alkyl such as methyl, with a compound of formula
(VIII)
H.sub.2N--R.sup.5' (VIII)
where R.sup.5' is a group R.sup.5 as defined in relation to formula
(T) or a group R.sup.5a as defined in relation to formula (IA) or a
precursor group thereof, and thereafter if desired or necessary,
converting a precursor group R.sup.5' to a group R.sup.5 or
R.sup.5a and/or modifying substituents on the group R.sup.5 or
R.sup.5a. The reaction is suitably effected in an organic solvent
such as an acetic acid at elevated temperatures, conveniently at
the reflux temperature of the solvent. Examples of reactions in
which a precursor group R.sup.5 is converted to a group R.sup.5 or
R.sup.5a and/or substituents on the group R.sup.5 or R.sup.5a are
modified are standard chemical reactions, such as conversion of
esters to acids, and thereafter, if required to the preferred
amides. Examples of such reactions are provided hereinafter.
[0372] Compounds of formula (VII) are suitably prepared by reacting
a compound of formula (IX)
##STR00017##
with an appropriate acetal such as N,N-dimethylformamide dimethyl
acetal. The reaction is suitably effected in an organic solvent
such as benzene, at elevated temperature, conveniently at the
reflux temperature of the solvent.
[0373] Alternatively compounds of formula (I), formula (IA) or
formula (IB) may be prepared by reacting a compound of formula
(X)
##STR00018##
where R.sup.1', R.sup.2'', R.sup.3'', and R.sup.4' are equivalent
to a group R.sup.1, R.sup.2, R.sup.3 and R.sup.4 as defined in
relation to formula (I) or formula (IB) or R.sup.1', R.sup.2',
R.sup.3' and R.sup.4' as defined in relation formula (IA) or a
precursor thereof, and R.sup.85 is a leaving group, with a compound
of formula (XI)
H--X--R.sup.5 (XI)
where X as defined in relation to formula (I) or formula (IA) and
R.sup.5 is R.sup.5 as defined in relation to formula (I) or
R.sup.5a as defined in relation to formula (IA): and thereafter if
desired or necessary converting a group R.sup.1', R.sup.2'',
R.sup.3'' or R.sup.4' to a group R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 respectively or a group R.sup.1', R.sup.2', R.sup.3' and
R.sup.4' respectively or to a different such group.
[0374] Suitable leaving groups for R.sup.85 include halo such as
chloro, mesylate and tosylate. The reaction is suitably effected in
an organic solvent such as an alcohol like isopropanol, at elevated
temperatures, conveniently at the reflux temperature of the
solvent.
[0375] The conversion of a group R.sup.1', R.sup.2'', R.sup.3'' or
R.sup.4' to a group R.sup.1, R.sup.2, R.sup.3 and R.sup.4
respectively or to a group R.sup.1', R.sup.2', R.sup.3' and
R.sup.4' respectively or to a different such group, may be
particularly useful in connection with the preparation of compounds
of formula (I), formula (IA) or formula (IB) where these groups are
complex in nature and examples of these preparations are provided
hereinafter.
[0376] In a particular embodiment, R.sup.1', R.sup.2'', R.sup.3''
or R.sup.4' are groups R.sup.1, R.sup.2, R.sup.3 and R.sup.4
respectively.
[0377] Compounds of formula (X) and (XI) are either known compounds
or they can be derived from known compounds by conventional methods
which would be apparent from the literature.
[0378] Alternatively, compounds of formula (I), formula (IA) or
formula (IB) where X is NH may be prepared by rearranging a
compound of formula (XII)
##STR00019##
where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 as defined in relation to formula (I) or
formula (IB) or R.sup.1', R.sup.2', R.sup.3' and R.sup.4' as
defined in relation to formula (IA) and R.sup.5' is as defined in
relation to formula (VIII) above, and thereafter if desired or
necessary, converting a precursor group R.sup.5' to a group R.sup.5
or R.sup.5a and/or modifying substituents on the group R.sup.5 or
R.sup.5a, for example as described generally above.
[0379] The rearrangement reaction is suitably effected in an
organic solvent such as an alkyl alcohol, in particular methanol,
ethanol or cyclohexanol, acetic acid, or dimethylformamide, using a
strong base such as sodium hydride, sodium hydroxide, sodium
acetate, sodium methylate, or dimethylamine. Elevated temperatures,
for example of from 20.degree.-120.degree. C. and preferably at
about 75.degree. C. are employed.
[0380] Compounds of formula (XII) are suitably obtained by reacting
a compound of formula (XIII)
##STR00020##
where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 as defined in relation to formula (I) or
formula (IB) or R.sup.1', R.sup.2', R.sup.3' and R.sup.4' as
defined in relation to formula (IA) and R.sup.86 is an alkyl group
such as methyl; with a compound of formula (XIV)
H.sub.2N--R.sup.5' (XIV)
where R.sup.5' is as defined in relation to formula (VIII). The
reaction is suitably effected in an organic solvent such as
methylene chloride, in the presence of a salt such as pyridinium
hydrochloride. Moderate temperatures for example of from
0.degree.-50.degree. C. and conveniently ambient temperature are
employed.
[0381] Compounds of formula (XIII) are suitably prepared by
reacting a compound of formula (IX) as defined above, with a
trialkylorthoformate such as trimethylorthoformate. The reaction is
suitably effected at elevated temperature, for example of from
50.degree. C. to 120.degree. C., and preferably at about
100.degree. C., in the presence of a catalytic amount of an acid
such as p-toluene sulphonic acid.
[0382] Compounds of formula (IX) are either known compounds or they
can be prepared by conventional methods. In particular, compounds
of formula (IX) may be prepared by reduction of the corresponding
nitro compound of formula (XV)
##STR00021##
where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 as defined in relation to formula (I) or
formula (IB) or R.sup.1', R.sup.2', R.sup.3' and R.sup.4' as
defined in relation to formula (IA). Suitable reaction conditions
are illustrated hereinafter.
[0383] Compounds of formula (XV) may be obtained by nitration of a
compound of formula (XVI)
##STR00022##
for example, using nitric acid as the nitrating agent. Again,
suitable reaction conditions are illustrated hereinafter.
[0384] The nitrile of formula (XVI) may be derived by reaction of
the corresponding formamide with hydroxylamine as illustrated
hereinafter.
[0385] It will be appreciated that certain of the various ring
substituents in the compounds of the present invention may be
introduced by standard aromatic substitution reactions or generated
by conventional functional group modifications either prior to or
immediately following the processes mentioned above, and as such
are included in the process aspect of the invention. Such reactions
and modifications include, for example, introduction of a
substituent by means of an aromatic substitution reaction,
reduction of substituents, alkylation of substituents and oxidation
of substituents. The reagents and reaction conditions for such
procedures are well known in the chemical art. Particular examples
of aromatic substitution reactions include the introduction of a
nitro group using concentrated nitric acid, the introduction of an
acyl group using, for example, an acyl halide and Lewis acid (such
as aluminium trichloride) under Friedel Crafts conditions; the
introduction of an alkyl group using an alkyl halide and Lewis acid
(such as aluminium trichloride) under Friedel Crafts conditions;
and the introduction of a halogen group. Particular examples of
modifications include the reduction of a nitro group to an amino
group by for example, catalytic hydrogenation with a nickel
catalyst or treatment with iron in the presence of hydrochloric
acid with heating; oxidation of alkylthio to alkylsulphinyl or
alkylsulphonyl. It will also be appreciated that in some of the
reactions mentioned herein it may be necessary/desirable to protect
any sensitive groups in the compounds. The instances where
protection is necessary or desirable and suitable methods for
protection are known to those skilled in the art. Conventional
protecting groups may be used in accordance with standard practice
(for illustration see T. W. Green, Protective Groups in Organic
Synthesis, John Wiley and Sons, 1991). Thus, if reactants include
groups such as amino, carboxy or hydroxy it may be desirable to
protect the group in some of the reactions mentioned herein.
[0386] A suitable protecting group for an amino or alkylamino group
is, for example, an acyl group, for example an alkanoyl group such
as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl,
ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl
group, for example benzyloxycarbonyl, or an aroyl group, for
example benzoyl. The deprotection conditions for the above
protecting groups necessarily vary with the choice of protecting
group. Thus, for example, an acyl group such as an alkanoyl or
alkoxycarbonyl group or an aroyl group may be removed for example,
by hydrolysis with a suitable base such as an alkali metal
hydroxide, for example lithium or sodium hydroxide. Alternatively
an acyl group such as a t-butoxycarbonyl group may be removed, for
example, by treatment with a suitable acid as hydrochloric,
sulphuric or phosphoric acid or trifluoroacetic acid and an
arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be
removed, for example, by hydrogenation over a catalyst such as
palladium-on-carbon, or by treatment with a Lewis acid for example
boron tris(trifluoroacetate). A suitable alternative protecting
group for a primary amino group is, for example, a phthaloyl group
which may be removed by treatment with an alkylamine, for example
dimethylaminopropylamine, or with hydrazine.
[0387] A suitable protecting group for a hydroxy group is, for
example, an acyl group, for example an alkanoyl group such as
acetyl, an aroyl group, for example benzoyl, or an arylmethyl
group, for example benzyl. The deprotection conditions for the
above protecting groups will necessarily vary with the choice of
protecting group. Thus, for example, an acyl group such as an
alkanoyl or an aroyl group may be removed, for example, by
hydrolysis with a suitable base such as an alkali metal hydroxide,
for example lithium or sodium hydroxide. Alternatively an
arylmethyl group such as a benzyl group may be removed, for
example, by hydrogenation over a catalyst such as
palladium-on-carbon.
[0388] A suitable protecting group for a carboxy group is, for
example, an esterifying group, for example a methyl or an ethyl
group which may be removed, for example, by hydrolysis with a base
such as sodium hydroxide, or for example a t-butyl group which may
be removed, for example, by treatment with an acid, for example an
organic acid such as trifluoroacetic acid, or for example a benzyl
group which may be removed, for example, by hydrogenation over a
catalyst such as palladium-on-carbon.
[0389] The protecting groups may be removed at any convenient stage
in the synthesis using conventional techniques well known in the
chemical art.
[0390] Compounds of formula (I) and formula (IA) are inhibitors of
Aurora kinase and in particular Aurora A kinase. As a result, these
compounds can be used to treat disease mediated by these agents, in
particular proliferative disease.
[0391] According to a further aspect of the present invention there
is provided a method for inhibiting Aurora kinase in a warm blooded
animal, such as man, in need of such treatment, which comprises
administering to said animal an effective amount of a compound of
formula (I), formula (IA) or formula (IB), or a pharmaceutically
acceptable salt, or an in vivo hydrolysable ester thereof. There is
further provided a method of inhibiting Aurora-A kinase as
described above and a method of inhibiting Aurora-B kinase as
described above.
[0392] A further aspect of the invention relates to a method of
treating a human suffering from a disease in which inhibition of
Aurora kinase is beneficial, comprising the steps of administering
to a person in need thereof a therapeutically effective amount of a
compound of formula (I), formula (IA) or formula (IB). In
particular it is envisaged that inhibition of Aurora-A kinase will
be beneficial although inhibition of Aurora-B kinase may also be
beneficial.
[0393] Certain compounds of formula (I) are novel and these form a
further aspect of the invention. Thus the invention further
comprises a compound of formula (IA)
##STR00023##
or a salt, ester or amide thereof; where X is as defined in
relation to formula (I); R.sup.1', R.sup.2', R.sup.3', R.sup.4' are
equivalent to R.sup.1, R.sup.2, R.sup.3, R.sup.4 as defined in
relation to formula (I) and R.sup.5a is equivalent to R.sup.5
defined in relation to formula (I). Also provided is a compound of
formula (IA) or a salt, ester or amide thereof; where X is as
defined in relation to formula (I); R.sup.1', R.sup.2', R.sup.3',
R.sup.4' are equivalent to R.sup.1, R.sup.2, R.sup.3, R.sup.4 as
defined in relation to formula (I); and R.sup.5a is equivalent to
R.sup.5 as defined in relation to formula (I); provided that one of
R.sup.60, R.sup.61 and R.sup.62 of R.sup.5a is other than hydrogen
and that if R.sup.61 is other than hydrogen, it is not a group
selected from: [0394] phenylC.sub.1-3alkyl, heteroaryl or
optionally substituted phenyl; and [0395] C.sub.3-5cycloalkyl,
C.sub.3-5cycloalkylC.sub.1-3alkyl, C.sub.2-5alkenyl or optionally
substituted C.sub.1-4alkyl; where optional substitutents for phenyl
and C.sub.1-4alkyl are C.sub.1-4alkyl, halo, methoxy, nitro or
trifluoromethyl.
[0396] In a particular aspect of the invention R.sup.61 of a
compound of formula (IA) is --O-J, --(CH.sub.2)--O-J,
--O--(CH.sub.2)-J, --(CH.sub.2)--O--(CH.sub.2)-J, --CO-J,
--(CH.sub.2)--CO-J, --CO--(CH.sub.2)-J,
--(CH.sub.2)--CO--(CH.sub.2)-J, --S-J, --(CH.sub.2)--S-J,
--S--(CH.sub.2)-J, --(CH.sub.2)--S--(CH.sub.2)-J, --SO-J,
--(CH.sub.2)--SO-J, --SO--(CH.sub.2)-J,
--(CH.sub.2)--SO--(CH.sub.2)-J, --SO.sub.2-J,
--(CH.sub.2)--SO.sub.2-J, --SO.sub.2--(CH.sub.2)-J,
--(CH.sub.2)--SO.sub.2--(CH.sub.2)-J, --(NR.sub.1')CO-J,
--(CH.sub.2)--(NR.sub.1')CO-J,
--(NR.sub.1')CO--(CH.sub.2)-J-(CH.sub.2)--(NR.sub.1')CO--(CH.sub.2)-J,
--(NR.sub.1')SO.sub.2-J, --(CH.sub.2)--(NR.sub.1')SO.sub.2-J,
--(NR.sub.1')SO.sub.2--(CH.sub.2)-J,
--(CH.sub.2)--(NR.sub.1')SO.sub.2--(CH.sub.2)-J, --NR.sup.64-J,
--(CH.sub.2)NR.sup.64-J, --NR.sup.64--(CH.sub.2)-J,
--(CH.sub.2)--NR.sup.64--(CH.sub.2)-J, --CONR.sup.64-J,
--(CH.sub.2)--CONR.sup.64-J, --CONR.sup.64--(CH.sub.2)-J,
--(CH.sub.2)--CONR.sup.64--(CH.sub.2)-J, --SO.sub.2NR.sup.64-J,
--(CH.sub.2)--SO.sub.2NR.sup.64-J,
--SO.sub.2NR.sup.64--(CH.sub.2)-J,
--(CH.sub.2)--SO.sub.2NR.sup.64--(CH.sub.2)-J, --NR.sub.1'CO--NH-J,
--(CH.sub.2)--NR.sub.1'CO--NH-J, --NR.sub.1'CO--NH--(CH.sub.2)-J,
--(CH.sub.2)--NR.sub.1'CO--NH--(CH.sub.2)-J,
--NR.sub.1'CO--N(C.sub.1-4alkyl)-J,
--(CH.sub.2)--NR.sub.1'CO--N(C.sub.1-4alkyl)-J,
--NR.sub.1'CO--N(C.sub.1-4alkyl)-(CH.sub.2)-J,
--(CH.sub.2)--NR.sub.1'CO--N(C.sub.1-4alkyl)-(CH.sub.2)-J,
--NR.sub.1'CO--O-J, --(CH.sub.2)--NR.sub.1'CO--O-J,
--NR.sub.1'CO--O--(CH.sub.2)-J,
--(CH.sub.2)--NR.sub.1'CO--O--(CH.sub.2)-J, --OCO-J,
--CH.sub.2--OCO-J, --CH.dbd.CH-J, --CH.sub.2--CH.dbd.CH-J,
--CH.dbd.CH--CH.sub.2-J and --CH.sub.2--CH.dbd.CH--CH.sub.2-J.
Other aspects of the invention relating to a compound of formula
(IA) are the preferred values of X, R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 as described above.
[0397] Where R.sup.5a is a pyrazole group, it carries a
substitutent of formula (k), (II) of (VI) above,
(ii) that where x is NH and R.sup.5a is a substituted pyrazolone or
tetrazolyl group, at least one of R.sup.1', R.sup.2', R.sup.3' and
R.sup.4' is other than hydrogen; or (iii) that where X is O and
R.sup.5a is 1-methyl-4-nitro-1H-imidazol-5-yl, at least one of
R.sup.1', R.sup.2', R.sup.3' and R.sup.4' is other than hydrogen.]
Preferably at least one of R.sup.1', R.sup.2', R.sup.3' and
R.sup.4' is other than hydrogen. In particular, R.sup.5a is
substituted by at least one group of formula (k), (II) of (VI)
above. Other preferred or particular groups and substitutents in
formula (IA) are as set out for the equivalent groups in formula
(I) above.
[0398] Additionally a compound of formula (IB) is provided:
##STR00024##
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined in
relation to formula (I); and Ar is indazole or pyridine (optionally
substituted by methyl) or aryl (optionally substituted by 1 or 2
substitutents independently selected from halo, methoxy,
trifluoromethyl, hydroxy, nitro, cyano and difluoromethoxy).
[0399] Preferred values of R.sup.1, R.sup.2, R.sup.3 and R.sup.4
are as described above.
[0400] Also provided is a compound of Formula (XVa):
##STR00025##
wherein R is phenyl, 3 fluorophenyl, 3,5-difluorophenyl, or
3-chlorophenyl; and R' is morpholin-4-yl, ethyl
(2-hydroxyethyl)amino, (2S)-2(hydroxymethyl)pyrrolidin-1-yl,
piperidin-1-yl, pyrrolidin-1-yl, (2-hydroxyethyl)amino,
(2-hydroxy-1,1-dimethylethyl)amino, methyl(2-hydroxyethyl)amino,
(1-(hydroxymethyl)-2-methylpropyl)amino, 4-methylpiperazin-1-yl,
(2-hydroxy-1-methylethyl)amino, (4-hydroxybutyl)amino,
4-hydroxypiperidin-1-yl 2-(2-hydroxyethyl)piperidin-1-yl,
4-(2-hydroxyethyl)piperazin-1-yl, 4-(2-hydroxyethyl)piperidin-1-yl,
3-hydroxypiperidin-1-yl, (2-hydroxybutyl)amino
4-(hydroxymethyl)piperidin-1-yl,
(3-hydroxy-2,2-dimethylpropyl)amino
(1-(hydroxymethyl)cyclopentyl)amino,
(2R)-2-(hydroxymethyl)pyrrolidin-1-yl ((2R)-2-hydroxypropyl)amino,
((2S)-2-hydroxypropyl)amino, (3R)-3-hydroxypyrrolidin-1-yl
(3S)-3-hydroxypyrrolidin-1-yl, pyrrolidin-1-yl,
(2-hydroxyethyl)amino, (2-hydroxy-1,1-dimethylethyl)amino,
4-methylpiperazin-1-yl, ethyl(2-hydroxyethyl)amino,
4-(2-hydroxyethyl)piperidin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl,
4-(2-hydroxyethyl)piperidin-1-yl, 3-hydroxypiperidin-1-yl,
(2-hydroxybutyl)amino, 4-(hydroxymethyl)piperidin-1-yl,
(3-hydroxy-2,2-dimethylpropyl)amino,
(2R)-2-(hydroxymethyl)pyrrolidin-1-yl,
(2S)-2-(hydroxymethyl)pyrrolidin-1-yl, ((2R)-2-hydroxypropyl)amino,
((2S)-2-hydroxypropyl)amino (3R)-3-hydroxypyrrolidin-1-yl,
(3S)-3-hydroxypyrrolidin-1-yl,
(2S)-2-(hydroxymethyl)pyrrolidin-1-yl, 3-hydroxypiperidin-1-yl,
(2R)-2-(hydroxymethyl)pyrrolidin-1-yl, or
ethyl(2-hydroxyethyl)amino; or a pharmaceutically acceptable salt,
ester or amide thereof.
[0401] Further provided is a compound of formula (IA) as defined
herein for use as a medicament.
[0402] According to yet a further aspect of the invention there is
provided a compound of the formula (IA) as defined herein, or a
pharmaceutically acceptable salt or an in vivo hydrolysable ester
thereof, for use in a method of treatment of the human or animal
body by therapy. In particular, the compounds are used in methods
of treatment of proliferative disease such as cancer and in
particular cancers such as colorectal or breast cancer where
Aurora-A is upregulated. The compounds are also useful in the
treatment of disease where Aurora-B kinase inhibition is
beneficial.
[0403] A compound of formula (IA) also has use in the preparation
of a medicament for use in the inhibition of Aurora kinase and in
particular a medicament for the treatment of disease where Aurora
kinase inhibition is beneficial. Preferably Aurora-A kinase is
inhibited but the invention also provides for such use where
Aurora-B kinase is inhibited.
[0404] The invention also provides a pharmaceutical composition
comprising a compound of formula (IA) as defined herein, or a
pharmaceutically acceptable salt, or an in vivo hydrolysable ester
thereof, in combination with a pharmaceutically acceptable carrier.
Preferred or particular compounds of formula (IA) for use in the
compositions of the invention are as described above in relation to
preferred compounds of formula (I).
[0405] A compound of formula (IB) also has use as a medicament, use
in a method of treatment of proliferative diseases and use in the
preparation of a medicament for use in the inhibition of Aurora
kinase whereby each use is distinct and is as described above for a
compound of formula (IA).
[0406] The compositions of the invention may be in a form suitable
for oral use (for example as tablets, lozenges, hard or soft
capsules, aqueous or oily suspensions, emulsions, dispersible
powders or granules, syrups or elixirs), for topical use (for
example as creams, ointments, gels, or aqueous or oily solutions or
suspensions), for administration by inhalation (for example as a
finely divided powder or a liquid aerosol), for administration by
insufflation (for example as a finely divided powder) or for
parenteral administration (for example as a sterile aqueous or oily
solution for intravenous, subcutaneous, intramuscular or
intramuscular dosing or as a suppository for rectal dosing or as a
dispersed dosage form).
[0407] The compositions of the invention may be obtained by
conventional procedures using conventional pharmaceutical
excipients, well known in the art. Thus, compositions intended for
oral use may contain, for example, one or more colouring,
sweetening, flavouring and/or preservative agents.
[0408] Suitable pharmaceutically acceptable excipients for a tablet
formulation include, for example, inert diluents such as lactose,
sodium carbonate, calcium phosphate or calcium carbonate,
granulating and disintegrating agents such as corn starch or
algenic acid; binding agents such as starch; lubricating agents
such as magnesium stearate, stearic acid or talc; preservative
agents such as ethyl or propyl p-hydroxybenzoate, and
anti-oxidants, such as ascorbic acid. Tablet formulations may be
uncoated or coated either to modify their disintegration and the
subsequent absorption of the active ingredient within the
gastrointestinal track, or to improve their stability and/or
appearance, in either case, using conventional coating agents and
procedures well known in the art.
[0409] Compositions for oral use may be in the form of hard gelatin
capsules in which the active ingredient is mixed with an inert
solid diluent, for example, calcium carbonate, calcium phosphate or
kaolin, or as soft gelatin capsules in which the active ingredient
is mixed with water or an oil such as peanut oil, liquid paraffin,
soya bean oil, coconut oil, or preferably olive oil, or any other
acceptable vehicle
[0410] Aqueous suspensions generally contain the active ingredient
in finely powdered form together with one or more suspending
agents, such as sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents such as 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 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 polyethylene sorbitan
monooleate. The aqueous suspensions may also contain one or more
preservatives (such as ethyl or propyl p-hydroxybenzoate,
anti-oxidants (such as ascorbic acid), colouring agents, flavouring
agents, and/or sweetening agents (such as sucrose, saccharine or
aspartame).
[0411] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil (such as arachis oil, olive oil,
sesame oil or coconut oil) or in a mineral oil (such as liquid
paraffin). The oily suspensions may also contain a thickening agent
such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set out above, and flavouring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0412] Dispersible or lyophilised powders and granules suitable for
preparation of an aqueous suspension or solution by the addition of
water generally contain the active ingredient together with a
dispersing or wetting agent, suspending agent and one or more
preservatives. Suitable dispersing or wetting agents and suspending
agents are exemplified by those already mentioned above. Additional
excipients such as sweetening, flavouring and colouring agents, may
also be present.
[0413] 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, such as olive oil or arachis oil, or a mineral oil,
such as for example liquid paraffin or a mixture of any of these.
Suitable emulsifying agents may be, for example,
naturally-occurring gums such as gum acacia or gum tragacanth,
naturally-occurring phosphatides such as soya bean, lecithin, an
esters or partial esters derived from fatty acids and hexitol
anhydrides (for example sorbitan monooleate) and condensation
products of the said partial esters with ethylene oxide such as
polyoxyethylene sorbitan monooleate. The emulsions may also contain
sweetening, flavouring and preservative agents.
[0414] Syrups and elixirs may be formulated with sweetening agents
such as glycerol, propylene glycol, sorbitol, aspartame or sucrose,
and may also contain a demulcent, preservative, flavouring and/or
colouring agent.
[0415] The pharmaceutical compositions may also be in the form of a
sterile injectable aqueous or oily suspension, solutions, emulsions
or particular systems, which may be formulated according to known
procedures using one or more of the appropriate dispersing or
wetting agents and suspending agents, which have been mentioned
above. A sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic
parenterally-acceptable diluent or solvent, for example a solution
in polyethylene glycol.
[0416] Suppository formulations may be prepared by mixing the
active ingredient with a suitable non-irritating excipient which is
solid at ordinary temperatures but liquid at the rectal temperature
and will therefore melt in the rectum to release the drug. Suitable
excipients include, for example, cocoa butter and polyethylene
glycols.
[0417] Topical formulations, such as creams, ointments, gels and
aqueous or oily solutions or suspensions, may generally be obtained
by formulating an active ingredient with a conventional, topically
acceptable, vehicle or diluent using conventional procedure well
known in the art.
[0418] Compositions for administration by insufflation may be in
the form of a finely divided powder containing particles of average
diameter of, for example, 30 .mu.m or much less preferably 5 .mu.m
or less and more preferably between 5 .mu.m and 1 .mu.m, the powder
itself comprising either active ingredient alone or diluted with
one or more physiologically acceptable carriers such as lactose.
The powder for insufflation is then conveniently retained in a
capsule containing, for example, 1 to 50 mg of active ingredient
for use with a turbo-inhaler device, such as is used for
insufflation of the known agent sodium cromoglycate.
[0419] Compositions for administration by inhalation may be in the
form of a conventional pressurised aerosol arranged to dispense the
active ingredient either as an aerosol containing finely divided
solid or liquid droplets. Conventional aerosol propellants such as
volatile fluorinated hydrocarbons or hydrocarbons may be used and
the aerosol device is conveniently arranged to dispense a metered
quantity of active ingredient.
[0420] For further information on Formulation the reader is
referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal
Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon
Press 1990.
[0421] The amount of active ingredient that is combined with one or
more excipients to produce a single dosage form will necessarily
vary depending upon the host treated and the particular route of
administration. For example, a formulation intended for oral
administration to humans will generally contain, for example, from
0.5 mg to 2 g of active agent compounded with an appropriate and
convenient amount of excipients which may vary from about 5 to
about 98 percent by weight of the total composition. Dosage unit
forms will generally contain about 1 mg to about 500 mg of an
active ingredient. For further information on Routes of
Administration and Dosage Regimes the reader is referred to Chapter
25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin
Hansch; Chairman of Editorial Board), Pergamon Press 1990.
[0422] The size of the dose for therapeutic or prophylactic
purposes of a compound of the formula (I), formula (IA) or formula
(IB) will naturally vary according to the nature and severity of
the conditions, the age and sex of the animal or patient and the
route of administration, according to well known principles of
medicine. As mentioned above, compounds of the formula (I), formula
(IB) or formula (IA) are useful in treating diseases or medical
conditions which are due alone or in part to the effects of
Aurora-A kinase and also due alone or in part to the effects of
Aurora-B kinase.
[0423] In using a compound of the formula (I), formula (IA) or
formula (IB) for therapeutic or prophylactic purposes it will
generally be administered so that a daily dose in the range, for
example, 0.5 mg to 75 mg per kg body weight is received and but a
range of 0.1 mg to 75 mg may also be required, given if required in
divided doses. In general lower doses will be administered when a
parenteral route is employed. Thus, for example, for intravenous
administration, a dose in the range, for example, 0.5 mg to 30 mg
per kg body weight will generally be used but a range of 0.1 mg to
25 mg may be required. Similarly, for administration by inhalation,
a dose in the range, for example, 0.5 mg to 25 mg per kg body
weight will be used.
[0424] A further aspect of the invention comprises a compound of
formula (I), formula (IA) or formula (IB) as defined above, or a
pharmaceutically acceptable salt or in vivo hydrolysable ester
thereof, for use in the preparation of a medicament for the
treatment of proliferative disease. Preferred compounds of formula
(I), formula (IA) or formula (IB) for this purpose are as described
above.
[0425] In addition to their use in therapeutic medicine, a compound
of formula (I) or formula (IA) and the pharmaceutically acceptable
salt is also useful as pharmacological tool in the development and
standardisation of in vitro and in vivo test systems for the
evaluation of the effects of inhibitors of cell cycle activity in
laboratory animals such as cats, dogs, rabbits, monkeys, rats and
mice, as part of the search for new therapeutic agents.
[0426] The treatment defined hereinbefore may be applied as a sole
therapy or may involve, in addition to the compound of the
invention, conventional surgery or radiotherapy or chemotherapy.
Such chemotherapy may include one or more of the following
categories of anti-tumour agents:--
(i) antiproliferative/antineoplastic drugs and combinations
thereof, as used in medical oncology, such as alkylating agents
(for example cis-platin, carboplatin, cyclophosphamide, nitrogen
mustard, melphalan, chlorambucil, busulphan and nitrosoureas);
antimetabolites (for example antifolates such as fluoropyrimidines
like 5-fluorouracil and tegafur, raltitrexed, methotrexate,
cytosine arabinoside and hydroxyurea; antitumour antibiotics (for
example anthracyclines like adriamycin, bleomycin, doxorubicin,
daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and
mithramycin); antimitotic agents (for example vinca alkaloids like
vincristine, vinblastine, vindesine and vinorelbine and taxoids
like taxol and taxotere); and topoisomerase inhibitors (for example
epipodophyllotoxins like etoposide and teniposide, amsacrine,
topotecan and camptothecin); (ii) cytostatic agents such as
antioestrogens (for example tamoxifen, toremifene, raloxifene,
droloxifene and iodoxyfene), antiandrogens (for example
bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH
antagonists or LHRH agonists (for example goserelin, leuprorelin
and buserelin), progestogens (for example megestrol acetate),
aromatase inhibitors (for example as anastrozole, letrozole,
vorazole and exemestane) and inhibitors of 5.alpha.-reductase such
as finasteride; (iii) Agents which inhibit cancer cell invasion
(for example metalloproteinase inhibitors like marimastat and
inhibitors of urokinase plasminogen activator receptor function);
(iv) inhibitors of growth factor function, for example such
inhibitors include growth factor antibodies, growth factor receptor
antibodies (for example the anti-erbb2 antibody trastuzumab
[Herceptin.TM.] and the anti-erbb1 antibody cetuximab [C225]),
farnesyl transferase inhibitors, tyrosine kinase inhibitors and
serine-threonine kinase inhibitors, for example inhibitors of the
epidermal growth factor family (for example EGFR family tyrosine
kinase inhibitors such as
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-
-amine (gefitinib, AZD1839),
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
(erlotinib, OSI-774) and
6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoli-
n-4-amine (CI 1033)), for example inhibitors of the
platelet-derived growth factor family and for example inhibitors of
the hepatocyte growth factor family; (v) antiangiogenic agents such
as those which inhibit the effects of vascular endothelial growth
factor, (for example the anti-vascular endothelial cell growth
factor antibody bevacizumab [Avastin.TM.], compounds such as those
disclosed in International Patent Applications WO 97/22596, WO
97/30035, WO 97/32856 and WO 98/13354) and compounds that work by
other mechanisms (for example linomide, inhibitors of integrin
.alpha.v.beta.3 function and angiostatin); (vi) vascular damaging
agents such as Combretastatin A4 and compounds disclosed in
International Patent Applications WO 99/02166, WO00/40529, WO
00/41669, WO01/92224, WO02/04434 and WO02/08213; (vii) antisense
therapies, for example those which are directed to the targets
listed above, such as ISIS 2503, an anti-ras antisense; (viii) gene
therapy approaches, including for example approaches to replace
aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,
GDEPT (gene-directed enzyme pro-drug therapy) approaches such as
those using cytosine deaminase, thymidine kinase or a bacterial
nitroreductase enzyme and approaches to increase patient tolerance
to chemotherapy or radiotherapy such as multi-drug resistance gene
therapy; and (ix) immunotherapy approaches, including for example
ex-vivo and in-vivo approaches to increase the immunogenicity of
patient tumour cells, such as transfection with cytokines such as
interleukin 2, interleukin 4 or granulocyte-macrophage colony
stimulating factor, approaches to decrease T-cell energy,
approaches using transfected immune cells such as
cytokine-transfected dendritic cells, approaches using
cytokine-transfected tumour cell lines and approaches using
anti-idiotypic antibodies.
[0427] Such conjoint treatment may be achieved by way of the
simultaneous, sequential or separate dosing of the individual
components of the treatment. Such combination products employ the
compounds of this invention within the dosage range described
hereinbefore and the other pharmaceutically-active agent within its
approved dosage range.
[0428] As stated hereinbefore the compounds of the invention
inhibit the serine-threonine kinase activity of Aurora kinase and
in particular of Aurora-A kinase and/or Aurora-B kinase and thus
inhibit the cell cycle and cell proliferation. These properties may
be assessed, for example, using one or more of the procedures set
out below:
(a) In Vitro Aurora-A Kinase Inhibition Test
[0429] This assay determines the ability of a test compound to
inhibit serine-threonine kinase activity. DNA encoding Aurora-A may
be obtained by total gene synthesis or by cloning. This DNA may
then be expressed in a suitable expression system to obtain
polypeptide with serine-threonine kinase activity. In the case of
Aurora-A, the coding sequence was isolated from cDNA by polymerase
chain reaction (PCR) and cloned into the BamH1 and Not1 restriction
endonuclease sites of the baculovirus expression vector pFastBac
HTc (GibcoBRL/Life technologies). The 5' PCR primer contained a
recognition sequence for the restriction endonuclease BamH1 5' to
the Aurora-A coding sequence. This allowed the insertion of the
Aurora-A gene in frame with the 6 histidine residues, spacer region
and rTEV protease cleavage site encoded by the pFastBac HTc vector.
The 3' PCR primer replaced the Aurora-A stop codon with additional
coding sequence followed by a stop codon and a recognition sequence
for the restriction endonuclease Not1. This additional coding
sequence (5' TAC CCA TAC GAT GTT CCA GAT TAC GCT TCT TAA 3')
encoded for the polypeptide sequence YPYDVPDYAS. This sequence,
derived from the influenza hemagglutin protein, is frequently used
as a tag epitope sequence that can be identified using specific
monoclonal antibodies. The recombinant pFastBac vector therefore
encoded for an N-terminally 6 his tagged, C terminally influenza
hemagglutin epitope tagged Aurora-A protein. Details of the methods
for the assembly of recombinant DNA molecules can be found in
standard texts, for example Sambrook et al. 1989, Molecular
Cloning--A Laboratory Manual, 2.sup.nd Edition, Cold Spring Harbor
Laboratory press and Ausubel et al. 1999, Current Protocols in
Molecular Biology, John Wiley and Sons Inc.
[0430] Production of recombinant virus can be performed following
manufacturer's protocol from GibcoBRL. Briefly, the pFastBac-1
vector carrying the Aurora-A gene was transformed into E. coli
DH10Bac cells containing the baculovirus genome (bacmid DNA) and
via a transposition event in the cells, a region of the pFastBac
vector containing gentamycin resistance gene and the Aurora-A gene
including the baculovirus polyhedrin promoter was transposed
directly into the bacmid DNA. By selection on gentamycin,
kanamycin, tetracycline and X-gal, resultant white colonies should
contain recombinant bacmid DNA encoding Aurora-A. Bacmid DNA was
extracted from a small scale culture of several BH10Bac white
colonies and transfected into Spodoptera frugiperda Sf21 cells
grown in TC100 medium (GibcoBRL) containing 10% serum using
CellFECTIN reagent (GibcoBRL) following manufacturer's
instructions. Virus particles were harvested by collecting cell
culture medium 72 hrs post transfection. 0.5 mls of medium was used
to infect 100 ml suspension culture of Sf21s containing
1.times.10.sup.7 cells/ml. Cell culture medium was harvested 48 hrs
post infection and virus titre determined using a standard plaque
assay procedure. Virus stocks were used to infect Sf9 and "High 5"
cells at a multiplicity of infection (MOI) of 3 to ascertain
expression of recombinant Aurora-A protein.
[0431] For the large scale expression of Aurora-A kinase activity,
Sf21 insect cells were grown at 28.degree. C. in TC100 medium
supplemented with 10% foetal calf serum (Viralex) and 0.2% F68
Pluronic (Sigma) on a Wheaton roller rig at 3 r.p.m. When the cell
density reached 1.2.times.10.sup.6 cells ml.sup.-1 they were
infected with plaque-pure Aurora-A recombinant virus at a
multiplicity of infection of 1 and harvested 48 hours later. All
subsequent purification steps were performed at 4.degree. C. Frozen
insect cell pellets containing a total of 2.0.times.10.sup.8 cells
were thawed and diluted with lysis buffer (25 mM HEPES
(N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulphonic acid]) pH7.4 at
4.degree. C., 100 mM KCl, 25 mM NaF, 1 mM Na.sub.3VO.sub.4, 1 mM
PMSF (phenylmethylsulphonyl fluoride), 2 mM 2-mercaptoethanol, 2 mM
imidazole, 1 .mu.g/ml aprotinin, 1 .mu.g/ml pepstatin, 1 .mu.g/ml
leupeptin), using 1.0 ml per 3.times.10.sup.7 cells. Lysis was
achieved using a dounce homogeniser, following which the lysate was
centrifuged at 41,000 g for 35 minutes. Aspirated supernatant was
pumped onto a 5 mm diameter chromatography column containing 500
.mu.l Ni NTA (nitrilo-tri-acetic acid) agarose (Qiagen, product no.
30250) which had been equilibrated in lysis buffer. A baseline
level of UV absorbance for the eluent was reached after washing the
column with 12 ml of lysis buffer followed by 7 ml of wash buffer
(25 mM HEPES pH7.4 at 4.degree. C., 100 mM KCl, 20 mM imidazole, 2
mM 2-mercaptoethanol). Bound Aurora-A protein was eluted from the
column using elution buffer (25 mM HEPES pH7.4 at 4.degree. C., 100
mM KCl, 400 mM imidazole, 2 mM 2-mercaptoethanol). An elution
fraction (2.5 ml) corresponding to the peak in UV absorbance was
collected. The elution fraction, containing active Aurora-A kinase,
was dialysed exhaustively against dialysis buffer (25 mM HEPES
pH7.4 at 4.degree. C., 45% glycerol (v/v), 100 mM KCl, 0.25%
Nonidet P40 (v/v), 1 mM dithiothreitol).
[0432] Each new batch of Aurora-A enzyme was titrated in the assay
by dilution with enzyme diluent (25 mM Tris-HCl pH7.5, 12.5 mM KCl,
0.6 mM DTT). For a typical batch, stock enzyme is diluted 1 in 666
with enzyme diluent & 20 .mu.l of dilute enzyme is used for
each assay well. Test compounds (at 10 mM in dimethylsulphoxide
(DMSO) were diluted with water & 10 .mu.l of diluted compound
was transferred to wells in the assay plates. "Total" & "blank"
control wells contained 2.5% DMSO instead of compound. Twenty
microlitres of freshly diluted enzyme was added to all wells, apart
from "blank" wells. Twenty microlitres of enzyme diluent was added
to "blank" wells. Twenty microlitres of reaction mix (25 mM
Tris-HCl, 78.4 mM KCl, 2.5 mM NaF, 0.6 mM dithiothreitol, 6.25 mM
MnCl.sub.2, 6.25 mM ATP, 7.5 .mu.M peptide substrate
[biotin-LRRWSLGLRRWSLGLRRWSLGLRRWSLG]) containing 0.2 .mu.Ci
[.gamma..sup.33P]ATP (Amersham Pharmacia, specific
activity.gtoreq.2500 Ci/mmol) was then added to all test wells to
start the reaction. The plates were incubated at room temperature
for 60 minutes. To stop the reaction 100 .mu.l 20% v/v
orthophosphoric acid was added to all wells. The peptide substrate
was captured on positively-charged nitrocellulose P30 filtermat
(Whatman) using a 96-well plate harvester (TomTek) & then
assayed for incorporation of .sup.33P with a Beta plate counter.
"Blank" (no enzyme) and "total" (no compound) control values were
used to determine the dilution range of test compound which gave
50% inhibition of enzyme activity.
[0433] In this test, the compounds of the invention give 50%
inhibition of enzyme activity at concentrations of 0.0001 .mu.M to
1.5 .mu.M and in particular compound 8 in Table 3 gave 50%
inhibition of enzyme activity at a concentration of 0.01 .mu.M and
compound 13 in Table 3 gave 50% inhibition of enzyme activity at a
concentration of 0.001 .mu.M.
(b) In Vitro Aurora-B Kinase Inhibition Test
[0434] This assay determines the ability of a test compound to
inhibit serine-threonine kinase activity. DNA encoding Aurora-B may
be obtained by total gene synthesis or by cloning. This DNA may
then be expressed in a suitable expression system to obtain
polypeptide with serine-threonine kinase activity. In the case of
Aurora-B, the coding sequence was isolated from cDNA by polymerase
chain reaction (PCR) and cloned into the pFastBac system in a
manner similar to that described above for Aurora-A (i.e. to direct
expression of a 6-histidine tagged Aurora-B protein).
[0435] For the large scale expression of Aurora-B kinase activity,
Sf21 insect cells were grown at 28.degree. C. in TC100 medium
supplemented with 10% foetal calf serum (Viralex) and 0.2% F68
Pluronic (Sigma) on a Wheaton roller rig at 3 r.p.m. When the cell
density reached 1.2.times.10.sup.6 cells ml.sup.-1 they were
infected with plaque-pure Aurora-B recombinant virus at a
multiplicity of infection of 1 and harvested 48 hours later. All
subsequent purification steps were performed at 4.degree. C. Frozen
insect cell pellets containing a total of 2.0.times.10.sup.8 cells
were thawed and diluted with lysis buffer (50 mM HEPES
(N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulphonic acid]) pH7.5 at
4.degree. C., 1 mM Na.sub.3VO.sub.4, 1 mM PMSF
(phenylmethylsulphonyl fluoride), 1 mM dithiothreitol, 1 .mu.g/ml
aprotinin, 1 .mu.g/ml pepstatin, 1 .mu.g/ml leupeptin), using 1.0
ml per 2.times.10.sup.7 cells. Lysis was achieved using a
sonication homogeniser, following which the lysate was centrifuged
at 41,000 g for 35 minutes. Aspirated supernatant was pumped onto a
5 mm diameter chromatography column containing 1.0 ml CM sepharose
Fast Flow (Amersham Pharmacia Biotech) which had been equilibrated
in lysis buffer. A baseline level of UV absorbance for the eluent
was reached after washing the column with 12 ml of lysis buffer
followed by 7 ml of wash buffer (50 mM HEPES pH7.4 at 4.degree. C.,
1 mM dithiothreitol). Bound Aurora-B B protein was eluted from the
column using a gradient of elution buffer (50 mM HEPES pH7.4 at
4.degree. C., 0.6 M NaCl, 1 mM dithiothreitol, running from 0%
elution buffer to 100% elution buffer over 15 minutes at a flowrate
of 0.5 ml/min). Elution fractions (1.0 ml) corresponding to the
peak in UV absorbance was collected. Elution fractions were
dialysed exhaustively against dialysis buffer (25 mM HEPES pH7.4 at
4.degree. C., 45% glycerol (v/v), 100 mM KCl, 0.05% (v/v) IGEPAL
CA630 (Sigma Aldrich), 1 mM dithiothreitol). Dialysed fractions
were assayed for Aurora-B kinase activity.
[0436] Each new batch of Aurora-B enzyme was titrated in the assay
by dilution with enzyme diluent (25 mM Tris-HCl pH7.5, 12.5 mM KCl,
0.6 mM DTT). For a typical batch, stock enzyme is diluted 1 in 40
with enzyme diluent & 20 .mu.l of dilute enzyme is used for
each assay well. Test compounds (at 10 mM in dimethylsulphoxide
(DMSO) were diluted with water & 10 .mu.l of diluted compound
was transferred to wells in the assay plates. "Total" & "blank"
control wells contained 2.5% DMSO instead of compound. Twenty
microlitres of freshly diluted enzyme was added to all wells, apart
from "blank" wells. Twenty microlitres of enzyme diluent was added
to "blank" wells. Twenty microlitres of reaction mix (25 mM
Tris-HCl, 78.4 mM KCl, 2.5 mM NaF, 0.6 mM dithiothreitol, 6.25 mM
MnCl.sub.2, 37.5 mM ATP, 25 .mu.M peptide substrate
[biotin-LRRWSLGLRRWSLGLRRWSLGLRRWSLG]) containing 0.2 .mu.Ci
[.gamma..sup.33P]ATP (Amersham Pharmacia, specific
activity.gtoreq.2500 Ci/mmol) was then added to all test wells to
start the reaction. The plates were incubated at room temperature
for 60 minutes. To stop the reaction 100 .mu.l 20% v/v
orthophosphoric acid was added to all wells. The peptide substrate
was captured on positively-charged nitrocellulose P30 filtermat
(Whatman) using a 96-well plate harvester (TomTek) & then
assayed for incorporation of .sup.33P with a Beta plate counter.
"Blank" (no enzyme) and "total" (no compound) control values were
used to determine the dilution range of test compound which gave
50% inhibition of enzyme activity.
(c) In Vitro Cell Proliferation Assay
[0437] This and other assays can be used to determine the ability
of a test compound to inhibit the growth of adherent mammalian cell
lines, for example the human tumour cell line SW620 (ATCC CCL-227).
This assay determines the ability of at test compound to inhibit
the incorporation of the thymidine analogue,
5'-bromo-2'-deoxy-uridine (BrdU) into cellular DNA. SW620 or other
adherent cells were typically seeded at 1.times.10.sup.5 cells per
well in L-15 media (GIBCO) plus 5% foetal calf serum, 1%
L-glutamine (100 l/well) in 96 well tissue culture treated 96 well
plates (Costar) and allowed to adhere overnight. The following day
the cells were dosed with compound (diluted from 10 mM stock in
DMSO using L-15 (with 5% FCS, 1% L-glutamine). Untreated control
wells and wells containing a compound known to give 100% inhibition
of BrdU incorporation were included on each plate. After 48 hours
in the presence/absence of test compound the ability of the cells
to incorporate BrdU over a 2 hour labelling period was determined
using a Boehringer (Roche) Cell Proliferation BrdU ELISA kit (cat.
No. 1 647 229) according to manufacturers directions. Briefly, 15
.mu.l of BrdU labelling reagent (diluted 1:100 in media--L-15, 5%
FCS, 1% L-glutamine) was added to each well and the plate returned
to a humidified (+5% CO.sub.2) 37.degree. C. incubator for 2 hours.
After 2 hours the labelling reagent was removed by decanting and
tapping the plate on a paper towel. FixDenat solution (50 .mu.l per
well) was added and the plates incubated at room temperature for 45
mins with shaking. The FixDenat solution was removed by decanting
and tapping the inverted plate on a paper towel. The plate was then
washed once with phosphate buffered saline (PBS) and 100 .mu.l/well
of Anti-BrdU-POD antibody solution (diluted 1:100 in antibody
dilution buffer) added. The plate was then incubated at room
temperature with shaking for 90 min. Unbound Anti-BrdU-POD antibody
was removed by decanting and washing the plate 4 times with PBS
before being blotted dry. TMB substrate solution was added (100
.mu.l/well) and incubated for approximately 10 minutes at room
temperature with shaking until a colour change was apparent. The
optical density of the wells was then determined at 690 nm
wavelength using a Titertek Multiscan plate reader. The values from
compound treated, untreated and 100% inhibition controls were used
to determine the dilution range of a test compound that gave 50%
inhibition of BrdU incorporation. The compounds of the invention
are active at 0.001 .mu.M to 101M in this test and in particular
compound 8 in table 3 was active at 0.086 .mu.M and compound 13 in
table 3 was active at 0.079 .mu.M.
(d) In Vitro Cell Cycle Analysis Assay
[0438] This assay determines the ability of a test compound to
arrest cells in specific phases of the cell cycle. Many different
mammalian cell lines could be used in this assay and SW620 cells
are included here as an example. SW620 cells were seeded at
7.times.10.sup.5 cells per T25 flask (Costar) in 5 ml L-15 (5% FCS,
1% L-glutamine). Flasks were then incubated overnight in a
humidified 37.degree. C. incubator with 5% CO.sub.2. The following
day, 5 .mu.l of L-15 (5% FCS, 1% L-glutamine) carrying the
appropriate concentration of test compound solubilised in DMSO was
added to the flask. A no compound control treatments was also
included (0.5% DMSO). The cells were then incubated for a defined
time (24 hours) with compound. After this time the media was
aspirated from the cells and they were washed with 5 ml of
prewarmed (37.degree. C.) sterile PBSA, then detached from the
flask by brief incubation with trypsin and followed by resuspension
in 5 ml of 1% Bovine Serum Albumin (BSA, Sigma-Aldrich Co.) in
sterile PBSA. The samples were then centrifuged at 2200 rpm for 10
min. The supernatant was aspirated to leave 200 .mu.l of the
PBS/BSA solution. The pellet was resuspended in this 200 .mu.l of
solution by pipetting 10 times to create a single cell suspension.
One ml of ice-cold 80% ethanol was slowly added to each cell
suspension and the samples stored at -20.degree. C. overnight or
until required for staining. Cells were pelleted by centrifugation,
ethanol aspirated off and pellets resuspended in 200 .mu.l PBS
containing 100 .mu.g/ml RNAse (Sigma Aldrich) & 10 .mu.g/ml
Propidium Iodide (Sigma Aldrich). Cell suspensions were incubated
at 37.degree. C. for 30 min, a further 200 .mu.l PBS added and
samples stored in the dark at 4.degree. C. overnight.
[0439] Each sample was then syringed 10 times using 21-gauge
needle. The samples were then transferred to LPS tubes and DNA
content per cell analysed by Fluorescence activated cell sorting
(FACS) using a FACScan flow cytometer (Becton Dickinson). Typically
30,000 events were counted and recorded using CellQuest v1.1
software (Verity Software). Cell cycle distribution of the
population was calculated using Modfit software (Verity Software)
and expressed as percentage of cells with 2N (G0/G1), 2N-4N(S
phase) and with 4N (G2/M) DNA content.
[0440] The following Scheme illustrates the general method for
making compounds of the present invention.
##STR00026##
##STR00027##
[0441] The invention will now be illustrated in the following non
limiting examples, in which standard techniques known to the
skilled chemist and techniques analogous to those described in
these examples may be used where appropriate, and in which, unless
otherwise stated:
(i) evaporations were carried out by rotary evaporation in vacuo
and work up procedures were carried out after removal of residual
solids such as drying agents by filtration; (ii) operations were
carried out at ambient temperature, typically in the range
18-25.degree. C. and in air unless stated, or unless the skilled
person would otherwise operate under an atmosphere of an inert gas
such as argon; (iii) column chromatography (by the flash procedure)
and medium pressure liquid chromatography (MPLC) were performed on
Merck Kieselgel silica (Art. 9385); (iv) yields are given for
illustration only and are not necessarily the maximum attainable;
(v) the structures of the end products of the formula (I) were
generally confirmed by nuclear (generally proton) magnetic
resonance (NMR) and mass spectral techniques; proton magnetic
resonance chemical shift values were measured in deuterated
dimethyl sulphoxide (DMSO d.sub.6) (unless otherwise stated) on the
delta scale (ppm downfield from tetramethylsilane) using one of the
following four instruments
[0442] Varian Gemini 2000 spectrometer operating at a field
strength of 300 MHz
[0443] Bruker DPX300 spectrometer operating at a field strength of
300 MHz
[0444] JEOL EX 400 spectrometer operating at a field strength of
400 MHz
[0445] Bruker Avance 500 spectrometer operating at a field strength
of 500 MHz
Peak multiplicities are shown as follows: s, singlet; d, doublet;
dd, double doublet; t, triplet; q, quartet; qu, quintet; m,
multiplet; br s, broad singlet; (vi) robotic synthesis was carried
out using a Zymate XP robot, with solution additions via a Zymate
Master Laboratory Station and stirred via a Stem RS5000
Reacto-Station at 25.degree. C.; (vii) work up and purification of
reaction mixtures from robotic synthesis was carried out as
follows: evaporations were carried out in vacuo using a Genevac HT
4; column chromatography was performed using either an Anachem
Sympur MPLC system on silica using 27 mm diameter columns filled
with Merck silica (60 .mu.m, 25 g); the structures of the final
products were confirmed by LCMS on a Waters 2890/ZMD micromass
system using the following and are quoted as retention time (RT) in
minutes: [0446] Column: waters symmetry C18 3.5 .mu.m 4.6.times.50
mm [0447] Solvent A: H.sub.2O [0448] Solvent B: CH.sub.3CN [0449]
Solvent C: MeOH+5% HCOOH [0450] Flow rate: 2.5 ml/min [0451] Run
time: 5 minutes with a 4.5 minute gradient from 0-100% C [0452]
Wavelength: 254 nm, bandwidth 10 nm [0453] Mass detector: ZMD
micromass [0454] Injection volume 0.005 ml (viii) Analytical LCMS
for compounds which had not been prepared by robotic synthesis was
performed on a Waters Alliance HT system using the following and
are quoted as retention time (RT) in minutes: [0455] Column: 2.0
mm.times.5 cm Phenomenex Max-RP 80A [0456] Solvent A: Water [0457]
Solvent B: Acetonitrile [0458] Solvent C: Methanol/1% formic acid
or Water/1% formic acid [0459] Flow rate: 1.1 ml/min [0460] Run
time: 5 minutes with a 4.5 minute gradient from 0-95% B+constant 5%
solvent C [0461] Wavelength: 254 nm, bandwidth 10 nm [0462]
Injection volume 0.005 ml [0463] Mass detector: Micromass ZMD (ix)
Preparative high performance liquid chromatography (HPLC) was
performed on either
[0464] Waters preparative LCMS instrument, with retention time (RT)
measured in minutes: [0465] Column: .beta.-basic Hypercil
(21.times.100 mm) 5 .mu.m [0466] Solvent A: Water/0.1% Ammonium
carbonate [0467] Solvent B: Acetonitrile [0468] Flow rate: 25
ml/min [0469] Run time: 10 minutes with a 7.5 minute gradient from
0-100% B [0470] Wavelength: 254 nm, bandwidth 10 nm [0471]
Injection volume 1-1.5 ml [0472] Mass detector: Micromass ZMD
[0473] Gilson preparative HPLC instrument, with retention time (RT)
measured in minutes: [0474] Column: 21 mm.times.15 cm Phenomenex
Luna2 C18 [0475] Solvent A: Water+0.1% trifluoracetic acid, [0476]
Solvent B: Acetonitrile+0.1% trifluoracetic acid [0477] Flow rate:
21 ml/min [0478] Run time: 20 minutes with various 10 minute
gradients from 5-100% B [0479] Wavelength: 254 nm, bandwidth 10 nm
[0480] Injection volume 0.1-4.0 ml (x) intermediates were not
generally fully characterised and purity was assessed by thin layer
chromatography (TLC), HPLC, infra-red (IR), MS or NMR analysis.
TABLE-US-00001 [0480] TABLE 1 (xvii) ##STR00028## Compound X 1
phenyl 2 3-fluorophenyl
TABLE-US-00002 TABLE 2 (xviii) ##STR00029## Compound X 3
3-fluorophenyl 4 3,5-difluorophenyl 5 2,3-difluorophenyl 6
3-chlorophenyl
TABLE-US-00003 TABLE 3 (xix) ##STR00030## Compound X Y 7
3-fluorophenyl 3-[ethyl(2-hydroxyethyl)amino]propoxy 8
3-fluorophenyl 3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy 9
3-fluorophenyl 3-piperidin-1-ylpropoxy 10 3-fluorophenyl
3-pyrrolidin-1-ylpropoxy 11 3-fluorophenyl
3-[(2-hydroxyethyl)amino]propoxy 12 3-fluorophenyl
3-[(2-hydroxy-1,1-dimethylethyl)amino]propoxy 13 3-fluorophenyl
3-[(2-hydroxyethyl)(methyl)amino]propoxy 14 3-fluorophenyl
3-{[1-(hydroxymethyl)-2- methylpropyl]amino}propoxy 15
3-fluorophenyl 3-(4-methylpiperazin-1-yl) propoxy 16 3-fluorophenyl
3-[(2-hydroxy-1-methylethyl)amino]propoxy 17 3-fluorophenyl
3-[(4-hydroxybutyl)amino]propoxy 18 3-fluorophenyl
3-(4-hydroxypiperidin-1-yl)propoxy 19 3-fluorophenyl
3-[2-(2-hydroxyethyl)piperidin-1-yl]propoxy 20 3-fluorophenyl
3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy 21 3-fluorophenyl
3-[4-(2-hydroxyethyl)piperidin-1-yl]propoxy} 22 3-fluorophenyl
3-(3-hydroxypiperidin-1-yl)propoxy] 23 3-fluorophenyl
3-[(2-hydroxybutyl)amino]propoxy 24 3-fluorophenyl
3-[4-(hydroxymethyl)piperidin-1-yl]propoxy 25 3-fluorophenyl
3-[(3-hydroxy-2,2-dimethylpropyl)amino]propoxy 26 3-fluorophenyl
3-{[1-(hydroxymethyl)cyclopentyl]amino}propoxy 27 3-fluorophenyl
3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy 28 3-fluorophenyl
3-{[(2S)-2-hydroxypropyl]amino}propoxy 29 3-fluorophenyl
3-{[(2R)-2-hydroxypropyl]amino}propoxy 30 3-fluorophenyl
3-[(3S)-3-hydroxypyrrolidin-1-yl]propoxy 31 3-fluorophenyl
3-[(3R)-3-hydroxypyrrolidin-1-yl]propoxy 32 3-fluorophenyl
3-[(2-fluoroethyl)(2-hydroxyethyl)amino]propoxy 33 3-fluorophenyl
2-[1-(2-hydroxyethyl)piperidin-4-yl]ethoxy 34 3-fluorophenyl
3-[(2-hydroxyethyl)(propyl)amino]propoxy 35 3-fluorophenyl
3-[(2-hydroxyethyl)(isopropyl)amino]propoxy 36 3-fluorophenyl
3-[(2-hydroxyethyl)(isobutyl)amino]propoxy 37 3-fluorophenyl
3-[(2,2-dimethylpropyl)(2-hydroxyethyl) amino]propoxy 38
3-fluorophenyl 3-[allyl(2-hydroxyethyl)amino]propoxy 39
3-fluorophenyl 3-[(2-hydroxyethyl)(prop-2-yn-1-yl)amino]propoxy 40
3-fluorophenyl 3-[cyclopropyl(2-hydroxyethyl)amino]propoxy 41
3-fluorophenyl 3-[(cyclopropylmethyl)(2- hydroxyethyl)amino]propoxy
42 3-fluorophenyl 3-[cyclobutyl(2-hydroxyethyl)amino]propoxy 43
3-fluorophenyl 3-[cyclopentyl(2-hydroxyethyl)amino]propoxy 44
3-fluorophenyl 3-[(2,2-dimethoxyethyl)(2-
hydroxyethyl)amino]propoxy 45 3-fluorophenyl
3-[(2,2-difluoroethyl)(2- hydroxyethyl)amino]propoxy 46
3-fluorophenyl 3-[(2-hydroxyethyl)(3,3,3-trifluoropropyl)amino]
propoxy 47 3-fluorophenyl 3-[(cyclobutylmethyl)(2-
hydroxyethyl)amino]propoxy 48 3-fluorophenyl
3-[(2-hydroxyethyl)(2-methoxyethyl)amino]propoxy 49 3-fluorophenyl
3-[(1,3-dioxolan-2-ylmethyl)(2- hydroxyethyl)amino]propoxy 50
3-fluorophenyl 4-chlorobutoxy 51 3-fluorophenyl
4-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]butoxy 52 3-fluorophenyl
4-[(2-hydroxyethyl)(isobutyl)amino]butoxy 53 3-fluorophenyl
(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy 54
3-fluorophenyl (2R)-1-(2-hydroxyethyl)pyrrolidin-2-yl]methoxy 55
3,5-difluorophenyl 3-pyrrolidin-1-ylpropoxy 56 3,5-difluorophenyl
3-[(2-hydroxyethyl)amino]propoxy 57 3,5-difluorophenyl
3-[(2-hydroxy-1,1-dimethylethyl)amino]propoxy 58 3,5-difluorophenyl
3-(4-methylpiperazin-1-yl)propoxy 59 3,5-difluorophenyl
3-[ethyl(2-hydroxyethyl)amino]propoxy 60 3,5-difluorophenyl
3-[2-(2-hydroxyethyl)piperidin-1-yl]propoxy 61 3,5-difluorophenyl
3-[4-(2-hydroxyethyl) piperazin-1-yl]propoxy 62 3,5-difluorophenyl
3-[4-(2-hydroxyethyl)piperidin-1-yl]propoxy 63 3,5-difluorophenyl
3-(3-hydroxypiperidin-1-yl)propoxy 64 3,5-difluorophenyl
3-[(2-hydroxybutyl) amino]propoxy 65 3,5-difluorophenyl
3-[4-(hydroxymethyl)piperidin-1-yl]propoxy 66 3,5-difluorophenyl
3-[(3-hydroxy-2,2-dimethylpropyl)amino]propoxy 67
3,5-difluorophenyl 3-[(2R)-2-(hydroxymethyl)
pyrrolidin-1-yl]propoxy 68 3,5-difluorophenyl
3-[(2S)-2-(hydroxymethyl) pyrrolidin-1-yl]propoxy 69
3,5-difluorophenyl 3-{[(2S)-2-hydroxypropyl]amino}propoxy 70
3,5-difluorophenyl 3-{[(2R)-2-hydroxypropyl]amino}propoxy 71
3,5-difluorophenyl 3-[(3S)-3-hydroxypyrrolidin-1-yl]propoxy 72
3,5-difluorophenyl 3-[(3R)-3-hydroxypyrrolidin-1-yl]propoxy 73
3,5-difluorophenyl 3-[(2-hydroxyethyl)(isobutyl)amino]propoxy 74
3,5-difluorophenyl 3-[(2-hydroxyethyl)(propyl)amino]propoxy 75
3,5-difluorophenyl 3-[allyl(2-hydroxyethyl)amino]propoxy 76
3,5-difluorophenyl 3-[(2-hydroxyethyl)(prop-2-yn-1-yl)amino]propoxy
77 3,5-difluorophenyl 3-[(2-hydroxyethyl)(isopropyl)amino]propoxy
78 3,5-difluorophenyl 3-[(2,2-dimethylpropyl)(2-
hydroxyethyl)amino]propoxy 79 3,5-difluorophenyl
3-[cyclobutyl(2-hydroxyethyl)amino]propoxy 80 3,5-difluorophenyl
3-[(cyclopropylmethyl)(2- hydroxyethyl)amino]propoxy 81
2,3-difluorophenyl 3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy
82 2,3-difluorophenyl 3-[(2,2-dimethylpropyl)(2-
hydroxyethyl)amino]propoxy 83 2,3-difluorophenyl
3-[(2-hydroxyethyl)(propyl)amino]propoxy 84 2,3-difluorophenyl
3-[(2-hydroxyethyl)(isobutyl)amino]propoxy 85 2,3-difluorophenyl
3-[cyclobutyl(2-hydroxyethyl)amino]propoxy 86 2,3-difluorophenyl
3-[cyclopentyl(2-hydroxyethyl)amino]propoxy 87 2,3-difluorophenyl
3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy 88
2,3-difluorophenyl 3-[(2-hydroxyethyl)(prop-2-yn-1-yl)amino]propoxy
89 2,3-difluorophenyl 3-[(cyclopropylmethyl)(2-
hydroxyethyl)amino]propoxy 90 2,3-difluorophenyl
3-[(cyclobutylmethyl)(2- hydroxyethyl)amino]propoxy 91
2,3-difluorophenyl 3-[(2,2-dimethoxyethyl)(2-
hydroxyethyl)amino]propoxy 92 2,3-difluorophenyl
3-[4-(2-hydroxyethyl)piperidin-1-yl]propoxy 93 2,3-difluorophenyl
3-(4-hydroxypiperidin-1-yl)propoxy 94 2,3-difluorophenyl
3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy 95 2,3-difluorophenyl
3-[(2-hydroxyethyl)(2-methoxyethyl)amino]propoxy 96
2,3-difluorophenyl 3-[allyl(2-hydroxyethyl)amino]propoxy 97
2,3-difluorophenyl 3-[(1,3-dioxolan-2-ylmethyl)(2-
hydroxyethyl)amino]propoxy 98 2,3-difluorophenyl
3-[ethyl(2-hydroxyethyl)amino]propoxy 99 2,3-difluorophenyl
3-[(2-hydroxyethyl)(isopropyl)amino]propoxy 100 2,3-difluorophenyl
3-[(2-hydroxy-1,1-dimethylethyl)amino]propoxy 101
2,3-difluorophenyl (2R)-1-(2-hydroxyethyl)pyrrolidin-2-yl]methoxy
102 3-chlorophenyl 3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy
103 3-chlorophenyl 3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy
104 3-chlorophenyl 3-(3-hydroxypiperidin-1-yl)propoxy 105
3-chlorophenyl 3-[ethyl(2-hydroxyethyl)amino]propoxy
TABLE-US-00004 TABLE 4 (xx) ##STR00031## Compound X 106
3-methoxyphenyl 107 phenyl 108 4-fluorophenyl 109
3,5-dichlorophenyl 110 2-methoxy-5-chlorophenyl 111
3-(trifluoromethyl)phenyl 112 3-hydroxyphenyl 113 3-nitrophenyl 114
5-indazolyl 115 2-fluoro-4-bromophenyl 116 3-chlorophenyl 117
2-fluorophenyl 118 3,5-dimethoxyphenyl 119 6-(3-picolinyl) 120
2,3-difluorophenyl 121 2-fluoro-3-chlorophenyl 122
2,5-difluorophenyl 123 2-fluoro-5- (trifluoromethyl)phenyl 124
3,4-difluorophenyl 125 2,4-difluorophenyl 126
3-chloro-4-fluorophenyl 127 2-(difluoromethoxy)phenyl 128
3-cyanophenyl 129 3-bromophenyl
TABLE-US-00005 TABLE 5 (xxi) ##STR00032## Com- pound R Y 130 2,3-
3-[ethyl(2-hydroxyethyl)amino]propoxy difluorophenyl 131 2,3-
3-[isopropyl(2-hydroxyethyl)amino]propoxy difluorophenyl 132 2,3-
3-[(2R)-2-(hydroxymethyl)pyrrolidin-1- difluorophenyl yl]propoxy
133 2,3- 3-[propyl(2-hydroxyethyl)amino]propoxy difluorophenyl 134
2,3- 3-[propargyl(2-hydroxyethyl)amino]propoxy difluorophenyl 135
2,3- 3-[isobutyl(2-hydroxyethyl)amino]propoxy difluorophenyl 136
2,3- 3-[neopentyl(2-hydroxyethyl)amino]propoxy difluorophenyl
TABLE-US-00006 TABLE 6 (xxii) ##STR00033## Com- pound R Y Z 137
3-fluorophenyl 3-(4-methylpiperazin- (1-(2-hydroxyethyl)-
1-yl)propoxy piperidin-4-yl)oxy 138 3-fluorophenyl methoxy
(1-methyl-piperidin-4- yl)oxy 139 2,3- methoxy methoxy
difluorophenyl 140 2,3- 2-methoxyethoxy 2-methoxyethoxy
difluorophenyl 141 2,3- 2-methoxyethoxy isopropoxy difluorophenyl
142 3-fluorophenyl 2-methoxyethoxy isopropoxy 143 3-fluorophenyl
methoxy (1-methyl-piperidin-4- yl)oxy 144 3-fluorophenyl methoxy
methoxy 145 3-fluorophenyl 2-methoxyethoxy 2-methoxyethoxy
TABLE-US-00007 TABLE 7 (xxiii) ##STR00034## Com- pound X Y 146
3-fluorophenyl 3-[(2-hydroxyethyl)(isobutyl)amino]propoxy 147 2,3-
3-[(2-hydroxyethyl)(isobutyl)amino]propoxy difluorophenyl
EXAMPLE 1
Preparation of Compound 1 in Table
1--2-(3-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino}-1H--
pyrazol-5-yl)-N-phenylacetamide
[0481]
(5-((6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl)amino)-1H-
-pyrazol-3-yl)acetic acid (300 mg, 0.68 mmol) in dimethylformamide
(5 ml) was reacted with aniline (62 .mu.l, 0.68 mmol) in the
presence of O-(7-azabenzotriazol-1-yl) N,N,N',N'-tetramethyluronium
hexafluorophosphate (260 mg, 0.68 mmol) and diisopropylethylamine
(420 .mu.l, 2.38 mmol) at 40.degree. C. for 36 h. The solvent was
evaporated in vacuo, water was added to the residue and the mixture
was acidified (with 6.0 N hydrochloric acid) to pH 3-4. The water
was evaporated and the residue was dissolved in methanol, adsorbed
on silica gel, and purified by chromatography on silica gel.
Elution with methanol:ammonia:dichloromethane (9:1:90) to yield
compound 1 in table 1 (216 mg, 62% yield):
[0482] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.92 (s, 1H), 8.26 (s, 1H),
7.55-7.62 (m, 2H), 7.20-7.25 (m, 3H), 7.03 (m, 1H), 6.80 (s, 1H),
4.28 (m, 2H), 3.95-4.05 (m, 2H), 3.97 (m, 3H), 3.79 (s, 2H), 3.65
(m, 2H), 3.45-3.55 (m, 2H), 3.30 (m, 2H), 3.12 (m, 2H), 2.20-2.30
(m, 2H):
[0483] MS (+ve ESI): 518.6 (M+H).sup.+.
[0484]
(5-((6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl)amino)-1H-
-pyrazol-3-yl)acetic acid, used as the starting material, was
obtained as follows:
[0485] a) 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline
(227 mg, 0.64 mmol) in pentan-2-ol (12 ml) and 6.0 N hydrochloric
acid (0.25 ml, 1.5 mmol) was heated at 120.degree. C. for 2 hours
in the presence of methyl (5-amino-1H-pyrazol-3-yl)acetate (100 mg,
0.64 mmol). The reaction mixture was cooled, the solid was
collected by filtration, dried and purified by chromatography on
silica gel, eluting with methanol:ammonia:dichloromethane (9:1:90)
to yield methyl
(5-((6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl)amino)-1H-pyraz-
ol-3-yl)acetate (251 mg, 85% yield):
[0486] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.37 (s, 1H), 6.82 (s, 1H), 4.32 (m, 2H), 4.01-4.10 (m, 2H), 4.01
(s, 3H), 3.86 (s, 2H), 3.70-3.80 (m, 2H), 3.69 (s, 3H), 3.50-3.60
(m, 2H), 3.35 (m, 2H), 3.18 (m, 2H), 2.28-2.40 (m, 2H)
[0487] MS (+ve ESI): 457.6 (M+H).sup.+.
[0488] b) Methyl
(5-((6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl)amino)-1H-pyraz-
ol-3-yl)acetate (2.44 g, 5.35 mmol) in methanol (61 ml) and 2.0 N
aqueous sodium hydroxide solution (61 ml, 122 mmol) was heated at
80.degree. C. for 4 hours. The reaction mixture was cooled, the
methanol was evaporated in vacuo and 6.0 N hydrochloric acid was
added (to acidify the mixture to pH 3-4). The residual methanol was
evaporated in vacuo, and the solid was purified by chromatography
over an Oasis copolymer (Waters) to yield
5-((6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl)amino)-1H-pyrazo-
l-3-yl)acetic acid (1.64 g, 36% yield):
[0489] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.97 (s, 1H), 8.30 (s, 1H),
7.33 (s, 1H), 6.80 (s, 1H), 4.31 (m, 2H), 4.09 (m, 2H), 4.08 (s,
3H), 3.75 (s, 2H), 3.68 (m, 2H), 3.50-3.60 (m, 2H), 3.35 (m, 2H),
3.15 (m, 2H), 2.20-2.38 (m, 2H):
[0490] MS (+ve ESI): 443.6 (M+H).sup.+.
EXAMPLE 2
Preparation of Compound 2 in Table
1--N-(3-fluorophenyl)-2-(3-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazo-
lin-4-yl]amino}-1H-pyrazol-5-yl)acetamide
[0491] An analogous reaction to that described in example 1, but
starting with 3-fluoroaniline (37 .mu.l, 0.41 mmol) yielded
compound 2 in table 1 (34 mg, 19% yield):
[0492] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.60-7.70 (m, 1H), 7.32-7.42 (m, 2H), 7.32 (s, 1H), 6.85-6.92 (m,
1H), 6.83 (s, 1H), 4.30 (m, 2H), 4.00-4.10 (m, 2H), 4.01 (s, 3H),
3.85 (s, 2H), 3.69 (m, 2H), 3.50-3.60 (m, 2H), 3.35 (m, 2H), 3.16
(m, 2H), 2.25-2.40 (m, 2H):
[0493] MS (+ve ESI): 536.6 (M+H).sup.+.
EXAMPLE 3
Preparation of Compound 3 in Table
2--2-(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol--
5-yl)-N-(3-fluorophenyl)acetamide
[0494]
(5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-
-3-yl)acetic acid (7.83 g, 20 mmol) in dimethylformamide (78 ml)
was reacted with 3-fluoroaniline (2.44 g, 22 mmol) in the presence
of 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride
(4.2 g, 22 mmol), 2-hydroxypyridin-1-oxide (2.22 g, 20 mmol) and
diisopropylethylamine (2.8 g, 22 mmol) at 50.degree. C. for 1.7
hours. The solvent was removed by evaporation in vacuo, the residue
was triturated with water (twice), and purified by chromatography
on silica gel, eluting with dichloromethane:methanol (95:3 to
85:15) to give compound 3 in table 2 (4.5 g, 46% yield) as a beige
solid:
[0495] .sup.1H-NMR (DMSO d.sub.6): 8.47 (s, 1H), 8.02 (s, 1H),
7.60-7.68 (m, 1H), 7.40 (m, 2H), 7.20-7.30 (s, 1H), 6.88 (m, 1H),
6.84 (s, 1H), 4.27 (m, 2H), 3.96 (s, 3H), 3.84 (m, 2H), 3.78 (s,
2H), 2.26 (m, 2H):
[0496] MS (+ve ESI): 485.6 (M+H).sup.+.
[0497]
(5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-
-3-yl)acetic acid, used as the starting material, was obtained as
follows:
[0498] a) A mixture of 4-benzyloxy-3-methoxybenzaldehyde (157 g,
649 mmol), sodium acetate (106 g, 1.29 mol), hydroxylamine
hydrochloride (90 g, 1.29 mol) and acetic acid (500 ml) was heated
at reflux for 21 hours. The solvent was evaporated and ice/water
(1000 ml) was added to the residue forming a sticky solid. The
mixture was neutralised with aqueous sodium hydroxide solution then
extracted with dichloromethane (2.times.500 ml). The organic
solution was washed with 1.0 N sodium hydroxide (100 ml), brine
(100 ml) and then dried over magnesium sulphate. Solvent
evaporation in vacuo, trituration of the residue with hexane:ethyl
acetate (3:1) and collection of the solid by suction filtration
yielded 4-benzyloxy-3-methoxybenzonitrile (123 g, 80% yield) as a
brown solid:
[0499] .sup.1H-NMR (DMSO d.sub.6): 7.38 (m, 7H), 7.19 (m, 1H), 5.18
(s, 2H), 3.80 (s, 3H)
[0500] MS (-ve ESI): 238 (M-H).sup.-.
[0501] b) Acetic acid (17 ml) was added slowly to nitric acid (40
ml, 440 mmol) at 5.degree. C. Powdered
4-benzyloxy-3-methoxybenzonitrile (10 g, 42 mmol) was added and the
mixture warmed to 23.degree. C. over 10 minutes. An exotherm
occurred and the temperature was controlled at <30.degree. C.
using an ice bath. The mixture was stirred at 23.degree. C. for 20
hours then poured into ice/water (1000 ml). After stirring for two
hours the yellow solid was collected by suction filtration, washed
with water and dried to yield
4-benzyloxy-3-methoxy-6-nitrobenzonitrile (10.1 g, 85% yield) as a
yellow solid:
[0502] .sup.1H-NMR (DMSO d.sub.6): 7.95 (s, 1H), 7.70 (s, 1H), 7.40
(m, 5H), 5.30 (s, 2H), 3.95 (s, 3H)
[0503] MS (-ve ESI): 283 (M-H).sup.-.
[0504] c) A mixture of 4-benzyloxy-3-methoxy-6-nitrobenzonitrile
(46 g, 162 mmol), sodium bicarbonate (95 g, 1.13 mol), water (750
ml), dichloromethane (550 ml) and tetrabutylammonium chloride (30
g, 108 mmol) was rapidly stirred at 20.degree. C. and treated
portionwise with sodium dithionite (66 g, 379 mmol) over 2 hours.
The mixture was stirred for a further 1 hour then the phases
separated. The aqueous phase was extracted with dichloromethane
(2.times.200 ml) and the combined organic solution washed with
water (300 ml) and dried over magnesium sulphate. The solution was
concentrated to 250 ml and 4.0 N hydrochloric acid in 1,4-dioxane
(150 ml, 0.6 mol) added. The reaction was then diluted with diethyl
ether (1000 ml) and cooled on ice. The resulting solid was
collected by suction filtration and washed with diethyl ether. The
solid was stirred in methanol (1000 ml) and sodium bicarbonate
solution (800 ml) added (pH 8) and the mixture stirred for 1 hour.
The solid was collected by suction filtration, washed with water,
methanol and dried in vacuo to yield
2-amino-4-(benzyloxy)-5-methoxybenzonitrile (34 g, 82% yield) as
light brown solid:
[0505] .sup.1H-NMR (DMSO d.sub.6): 7.40 (m, 5H), 6.90 (s, 1H), 6.50
(s, 1H), 5.60 (br s, 2H), 5.02 (s, 2H), 3.65 (s, 3H):
[0506] MS (+ve ESI): 254 (M+H).sup.+.
[0507] d) 2-amino-4-(benzyloxy)-5-methoxybenzonitrile (100 g, 394
mmol) in toluene (1400 ml) was treated with dimethylformamide
dimethylacetal (100 ml, 940 mmol) at reflux with slow distillation
of solvent to maintain the internal temperature at 105.degree. C.
After 3 hours the solution was cooled and filtered to remove a
small amount of solid. The filtrate was evaporated in vacuo, the
residue triturated with diethyl ether, the solid collected by
suction filtration and dried in vacuo to yield
N'-(5-(benzyloxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide
(110 g, 90% yield) as a brown solid:
[0508] .sup.1H-NMR (DMSO d.sub.6): 7.90 (s, 1H), 7.40 (m, 5H), 7.10
(s, 1H), 6.88 (s, 1H), 5.15 (s, 2H), 3.70 (s, 3H), 3.02 (s, 3H),
2.95 (s, 3H)
[0509] MS (+ve ESI): 310 (M+H)+
[0510] MS (-ve ESI): 308 (M-H).sup.-.
[0511] e)
N'-(5-(benzyloxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoform-
amide (110 g, 356 mmol) and trifluoroacetic acid (600 ml) were
heated at reflux for 15 minutes. The reaction was evaporated in
vacuo and then azeotroped with toluene. The residue was triturated
with diethyl ether and the solid collected by suction filtration.
The solid was dried in vacuo to yield
N'-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamide
(112 g, 95% yield) as a light brown trifluoroacetate salt:
[0512] .sup.1H-NMR (DMSO d.sub.6): 8.39 (s, 1H), 7.38 (s, 1H), 6.90
(s, 1H), 3.80 (s, 3H), 3.25 (s, 3H), 3.17 (s, 3H):
[0513] MS (+ve ESI): 220 (M+H)+
[0514] MS (-ve ESI): 218 (M-H).sup.-.
[0515] f) A mixture of
N'-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamide
(21.9 g, 66 mmol), caesium carbonate (998 g, 300 mmol) and
1-bromo-3-chloropropane (11 ml, 110 mmol) in acetonitrile (300 ml)
was heated at reflux for 1 hour. The reaction mixture was cooled
and the solvent evaporated in vacuo. Water (200 ml) was added and
this was extracted with dichloromethane (2.times.150 ml). The
organic solution was washed with brine (50 ml) and dried over
magnesium sulphate. The solvent was evaporated in vacuo and the
residue triturated with diethyl ether. The solid was collected by
suction filtration and dried in vacuo to yield
N'-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformami-
de (17.7 g, 91% yield) as a white solid:
[0516] .sup.1H-NMR (DMSO d.sub.6): 8.89 (s, 1H), 7.07 (s, 1H), 6.75
(s, 1H), 4.15 (t, 2H), 3.77 (t, 2H), 3.70 (s, 3H), 3.05 (s, 3H),
2.95 (s, 3H), 2.18 (m, 2H)
[0517] MS (+ve ESI): 296.4 (M+H).sup.+.
[0518] g)
N'-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimi-
doformamide (230 mg, 0.78 mmol) in acetic acid (0.7 ml) was heated
with methyl (5-amino-1H-pyrazol-3-yl)acetate (110 mg, 0.74 mmol) at
reflux for 1 hour. The mixture was cooled, the acetic acid was
evaporated in vacuo, and the residue purified by chromatography on
silica gel, eluting with methanol:ammonia:dichloromethane (9:1:90),
to yield methyl
(5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-3-yl)-
acetate (219 mg, 69% yield) as a cream solid:
[0519] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.93 (s, 1H), 8.28 (s, 1H),
7.32 (s, 1H), 6.80 (s, 1H), 4.02 (m, 2H), 4.00 (s, 3H), 3.75-3.85
(m, s, 4H), 3.65 (s, 3H), 2.30 (m, 2H), 1.90 (s, 3H):
[0520] MS (+ve ESI): 406.5 (M+H).sup.+.
[0521] h) Methyl
(5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-3-yl)-
acetate (100 mg, 0.247 mmol) in tetrahydrofuran (1.2 ml)/water (0.6
ml), was stirred with lithium hydroxide (21 mg, 0.493 mmol) at
ambient temperature for 18 hours. The mixture was acidified with
6.0 N hydrochloric acid to pH 4 and the solid was recovered by
filtration, washed with water and dried to yield
(5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-3-yl)-
acetic acid (72 mg, 75% yield) as a beige solid:
[0522] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.28 (s, 1H),
7.32 (s, 1H), 6.80 (s, 1H), 4.33 (m, 2H), 4.00 (s, 3H), 3.83 (m,
2H), 3.74 (s, 2H), 2.40-2.50 (m, 2H):
[0523] MS (+ve ESI): 392.5, 394.5 (M+H).sup.+.
[0524] Alternatively,
N'-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformami-
de (14.78 g, 50 mmol) in acetic acid (40 ml) was heated at reflux
with (5-amino-1H-pyrazol-3-yl)acetic acid (8.1 g, 57.5 mmol) for
1.5 h. The reaction mixture was cooled to ambient temperature,
water (250 ml) was added to the mixture and the solid was recovered
by suction filtration. The solid was washed with 1) water, ii)
ethyl acetate and iii) diethyl ether and dried in vacuo at
50.degree. C. to yield
(5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-3-yl)-
acetic acid as a yellow solid (13.6 g, 69% yield)
[0525] i) (5-amino-1H-pyrazol-3-yl)acetic acid (3.02 g, 0.022 mmol)
in methanol (32 ml) was added to a mixture of methanol (32 ml) and
thionyl chloride (3.15 ml) at 0.degree. C. The resulting mixture
was stirred for 18 hours, evaporated and the residue purified by
chromatography on silica gel, eluting with
methanol:ammonia:dichloromethane (9:1:90), to yield methyl
(5-amino-1H-pyrazol-3-yl)acetate (1.58 g, 48% yield):
[0526] .sup.1H-NMR (CDCl.sub.3): 5.52 (s, 1H), 3.70 (s, 3H), 3.61
(s, 2H).
EXAMPLE 4
Preparation of Compound 4 in Table
2--2-(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol--
5-yl)-N-(3,5-difluorophenyl)acetamide
[0527] A suspension of
3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)a-
cetic acid (3.91 g, 10 mmol) in dimethylformamide (20 ml) was
reacted with 3,5-difluoroaniline (1.42 g, 11 mmol) in the presence
of 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (2.01
g, 10.5 mmol) and 2-hydroxypyridine-1-oxide (1.11 g, 10 mmol) at
60.degree. C. for 1.75 hours. The solvent was evaporated in vacuo
and the residue was triturated twice with water. The resulting wet
paste was dissolved in a mixture of dichloromethane:methanol
(80:20), adsorbed onto silica gel and purified by chromatography on
silica gel, eluting with dichloromethane:methanol (95:5 to 85:15)
to yield compound 4 in table 2 (2.45 g, 49% yield) as a beige
solid:
[0528] .sup.1H-NMR (DMSO d.sub.6): 8.47 (s, 1H), 8.02 (s, 1H), 7.36
(m, 2H), 7.20 (s, 1H), 6.94 (t, 1H), 6.84 (s, 1H), 4.27 (m, 2H),
3.96 (s, 3H), 3.83 (m, 2H), 3.79 (s, 2H), 2.27 (m, 2H)
[0529] MS (+ve ESI): 503.5, 505.5 (M+H).sup.+.
EXAMPLE 5
Preparation of compound 5 in table
2--2-(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol--
5-yl)-N-(2,3-difluorophenyl)acetamide
[0530]
3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol--
5-yl)acetic acid (3.91 g, 10 mmol) was suspended in pyridine (20
ml) in the presence of 2,3-difluoroaniline (1.55 g, 12 mmol) under
argon at 0.degree. C. Phosphorus oxychloride (1.53 g, 10 mmol) in
ethyl acetate (2 ml) was slowly added at 0.degree. C. and the
resulting mixture was allowed to warm to ambient temperature over
1.5 hours. The reaction mixture was diluted with ethyl acetate (150
ml) and diethyl ether (50 ml) resulting in the precipitation of a
red solid. The solid was recovered by suction filtration, dried and
re-suspended in water (100 ml). The mixture was cooled to 0.degree.
C. and the pH adjusted to 7 by addition of 1.5 N aqueous ammonium
hydroxide solution. After 15 minutes stirring, the solid was
recovered, dried, and purified by chromatography on silica gel.
Elution with dichloromethane:methanol (95/5) and increased polarity
to dichloromethane:methanolic ammonia (95:2) yielded compound 5 in
table 2 as a pink solid (2.55 g, 50% yield):
[0531] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 8.28 (s, 1H),
7.73 (m, 1H), 7.33 (s, 1H), 7.15-7.22 (m, 1H), 6.84 (s, 1H), 4.30
(m, 2H), 4.00 (s, 3H), 3.94 (s, 2H), 3.84 (m, 2H), 2.30 (m,
2H):
[0532] MS (+ve ESI): 503.9 (M+H).sup.+.
EXAMPLE 6
Preparation of Compound 6 in Table
2--N-(3-chlorophenyl)-2-(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-
]amino}-1H-pyrazol-5-yl)acetamide
[0533]
3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol--
5-yl)acetic acid (1.3 g, 3 mmol) vas dissolved in dimethylformamide
(13 ml) and reacted with 3-chloroaniline (536 mg, 4.2 mmol) in the
presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodimide
hydrochloride (919 mg, 3.9 mmol) and 2-hydroxypyridine-1-oxide (433
mg, 3.9 mmol) at 50.degree. C. for 1.5 hours. The solvent was
evaporated in vacuo and the residue purified by chromatography on
silica gel. Elution with dichloromethane:methanol (95:5) and
increased polarity to dichloromethane:methanol (9:1) yielded
compound 6 in table 2 (710 mg, 47% yield):
[0534] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 8.28 (s, 1H),
7.85 (s, 1H), 7.48 (d, 1H), 7.35 (dd, 1H), 7.31 (s, 1H), 7.13 (dd,
1H), 6.83 (s, 1H), 4.32 (m, 2H), 4.00 (s, 3H), 3.84 (m, 2H), 3.83
(s, 2H), 2.30 (m, 2H):
[0535] MS (+ve ESI): 501.44 (M+H).sup.+.
EXAMPLE 7
Preparation of Compound 7 in Table
3--2-[3-[(7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]-6-methoxyquinazolin-4-
-yl)amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide
[0536] 2-(5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)
1H-pyrazol-3-yl)-N-(3-fluorophenyl)acetamide (97 mg, 0.2 mmol) in
dimethylacetamide (1 ml) was reacted with 2-(ethylamino)ethanol (53
mg, 0.6 mmol) at 90.degree. C. for 8 hours. The mixture was cooled
and purified by preparative LCMS to yield compound 7 in table 3 (36
mg, 33% yield):
[0537] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.62-7.65 (m, 1H), 7.25-7.40 (m, 3H), 6.83-6.90 (m, 1H), 6.83 (s,
1H), 4.30 (m, 2H), 4.00 (s, 3H), 3.84 (s, 2H), 3.77 (m, 2H),
3.20-3.40 (m, 6H), 2.25 (m, 2H), 1.26 (t, 3H):
[0538] MS (+ve ESI): 538.6 (M+H).sup.+.
EXAMPLE 8
Preparation of Compound 8 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-
propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0539] An analogous reaction to that described in example 7, but
starting with L-prolinol (121 mg, 0.25 mmol) yielded compound 8 in
table 3 (86 mg, 62% yield) as an off-white solid:
[0540] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.60-7.70 (m, 1H), 7.28-7.40 (m, 3H), 6.85-6.92 (m, 1H), 6.82 (s,
1H), 4.31 (m, 2H), 4.00 (s, 3H), 3.84 (s, 2H), 3.70-3.80 (m, 1H),
3.50-3.70 (m, 4H), 3.10-3.30 (m, 2H), 2.20-2.40 (m, 2H), 2.05-2.20
(m, 1H), 1.95-2.10 (m, 1H), 1.85-1.95 (m, 1H), 1.70-1.85 (m,
1H):
[0541] MS (+ve ESI): 550.6 (M+H).sup.+.
EXAMPLE 9
Preparation of Compound 9 in Table
3--N-(3-fluorophenyl)-2-(3-{[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazo-
lin-4-yl]amino}-1H-pyrazol-5-yl)acetamide
[0542] An analogous reaction to that described in example 7, but
starting with piperidine (85 mg, 1 mmol) yielded compound 9 in
table 3 (31 mg, 23% yield):
[0543] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.65 (d, 1H), 7.34 (m, 2H), 7.32 (s, 1H), 6.90 (m, 1H), 6.83 (s,
1H), 4.30 (m, 2H), 4.00 (s, 3H), 3.85 (s, 2H), 3.54 (d, 2H), 3.27
(m, 2H), 2.96 (m, 2H), 2.90 (m, 2H), 1.84 (m, 2H), 1.60-1.80 (m,
3H), 1.42 (m, 1H):
[0544] MS (+ve ESI): 534.6 (M+H).sup.+.
EXAMPLE 10
Preparation of Compound 10 in Table
3--N-(3-fluorophenyl)-2-(3-{[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinaz-
olin-4-yl]amino}-1H-pyrazol-5-yl)acetamide
[0545] An analogous reaction to that described in example 7, but
starting with pyrrolidine (71 mg, 1 mmol) yielded compound 10 in
table 3 (58 mg, 45% yield):
[0546] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.64 (d, 1H), 7.35 (m, 2H), 7.33 (s, 1H), 6.90 (m, 1H), 6.84 (s,
1H), 4.30 (m, 2H), 4.00 (s, 3H), 3.85 (s, 2H), 3.68 (m, 2H), 3.31
(m, 2H), 3.10 (m, 2H), 2.28 (m, 2H), 1.91 (m, 2H):
[0547] MS (+ve ESI): 520.6 (M+H).sup.+.
EXAMPLE 11
Preparation of Compound 11 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)amino]propoxy}-6-metho-
xy(quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0548] An analogous reaction to that described in example 7, but
starting with ethanolamine (61 mg, 1 mmol) yielded compound 11 in
table 3 (80 mg, 77% yield):
[0549] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.37 (d, 1H), 7.34 (m, 2H), 7.31 (s, 1H), 6.95 (m, 1H), 6.83 (s,
1H), 4.30 (m, 2H), 4.00 (s, 3H), 3.85 (s, 2H), 3.68 (m, 2H), 3.16
(m, 2H), 3.09 (m, 2H), 2.21 (m, 2H):
[0550] MS (+ve ESI): 509.5 (M+H).sup.+.
EXAMPLE 12
Preparation of Compound 12 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxy-1,1-dimethylethyl)amino]pro-
poxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0551] An analogous reaction to that described in example 7, but
starting with 2-amino-2-methyl-1-propanol (89 mg, 1 mmol) yielded
compound 12 in table 3 (47 mg, 35% yield):
[0552] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.62 (m, 1H), 7.34 (m, 2H), 7.32 (s, 1H), 6.88 (m, 1H), 6.84 (s,
1H), 4.32 (m, 2H), 4.00 (s, 3H), 3.85 (s, 2H), 3.46 (s, 2H), 3.10
(m, 2H), 2.10 (m, 2H), 1.24 (s, 6H)
[0553] MS (+ve ESI): 538.6 (M+H).sup.+.
EXAMPLE 13
Preparation of Compound 13 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(methyl)amino]propoxy}-
-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0554] An analogous reaction to that described in example 7, but
starting with 2-(methylamino)ethanol (75 mg, 1 mmol) yielded
compound 13 in table 3 (88 mg, 67% yield):
[0555] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.3 (s, 1H),
7.64 (d, 1H), 7.35 (m, 2H), 7.33 (s, 1H), 6.90 (m, 1H), 6.84 (s,
1H), 4.30 (m, 2H), 4.01 (s, 3H), 3.85 (s, 2H), 3.77 (t, 2H),
3.15-3.45 (m, 4H), 2.38 (s, 3H), 2.30 (m, 2H):
[0556] MS (+ve ESI): 524.6 (M+H).sup.+.
EXAMPLE 14
Preparation of Compound 14 in Table
3--N-(3-fluorophenyl)-2-(3-{[7-(3-{[1-(hydroxymethyl)-2-methylpropyl]amin-
o}propoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetamide
[0557] An analogous reaction to that described in example 7, but
starting with 2-amino-3-methylbutan-1-ol (103 mg, 1 mmol) yielded
compound 14 in table 3 (40 mg, 29% yield):
[0558] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.63 (d, 1H), 7.65 (m, 2H), 7.62 (s, 1H), 6.90 (m, 1H), 6.83 (s,
1H), 4.32 (m, 2H), 4.00 (s, 3H), 3.85 (s, 2H), 3.75 (dd, 1H), 3.66
dd, 1H), 3.23 (m, 2H), 3.03 (m, 2H), 2.27 (m, 2H), 2.08 (m, 1H),
1.02 (d, 3H), 0.97 (d, 3H):
[0559] MS (+ve ESI): 552.6 (M+H).sup.+.
EXAMPLE 15
Preparation of Compound 15 in Table
3--N-(3-fluorophenyl)-2-[3-({6-methoxy-7-[3-(4-methylpiperazin-1-yl)propo-
xy]quinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetamide
[0560] An analogous reaction to that described in example 7, but
starting with 1-methylpiperazine (100 mg, 1 mmol) yielded compound
15 in table 3 (51 mg, 37% yield)
[0561] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.65 (d, 1H), 7.38 (m, 2H), 7.35 (s, 1H), 6.88 (m, 1H), 6.84 (s,
1H), 4.31 (m, 2H), 3.20-4.10 (m, 8H), 4.01 (s, 3H), 3.85 (s, 2H),
3.40 (m, 2H), 2.95 (s, 3H), 2.30 (m, 2H)
[0562] MS (+ve ESI): 549.6 (M+H).sup.+.
EXAMPLE 16
Preparation of Compound 16 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxy-1-methylethyl)amino]propoxy-
}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0563] An analogous reaction to that described in example 7, but
starting with 2-amino-1-propanol (75.1 mg, 1 mmol) yielded compound
16 in table 3 (80 mg, 61% yield):
[0564] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.64 (d, 1H), 7.36 (m, 2H), 7.34 (s, 1H), 6.88 (m, 1H), 6.84 (s,
1H), 4.32 (m, 2H), 4.01 (s, 3H), 3.85 (s, 2H), 3.69 (dd, 1H), 3.50
(dd, 1H), 3.33 (m, 1H), 3.18 (m, 2H), 2.23 (m, 2H), 1.23 (d,
3H):
[0565] MS (+ve ESI): 524.6 (M+H).sup.+.
EXAMPLE 17
Preparation of Compound 17 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[(4-hydroxybutyl)amino]propoxy}-6-metho-
xyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0566] An analogous reaction to that described in example 7, but
starting with 4-aminobutan-1-ol (89 mg, 1 mmol) yielded compound 17
in table 3 (56 mg, 42% yield):
[0567] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.64 (d, 1H), 7.34 (m, 2H), 7.32 (s, 1H), 6.90 (m, 1H), 6.84 (s,
1H), 4.30 (m, 2H), 4.01 (s, 3H), 3.85 (s, 2H), 3.45 (t, 2H), 3.14
(m, 2H), 2.98 (m, 2H), 2.20 (m, 2H), 1.67 (m, 2H), 1.50 (m,
2H):
[0568] MS (+ve ESI): 538.6 (M+H).sup.+.
EXAMPLE 18
Preparation of Compound 18 in Table
3--N-(3-fluorophenyl)-2-[3-({7-[3-(4-hydroxypiperidin-1-yl)propoxy]-6-met-
hoxyquinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetamide
[0569] An analogous reaction to that described in example 7, but
starting with piperidin-4-ol (101 mg, 1 mmol) yielded compound 18
in table 3 (75 mg, 57% yield):
[0570] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.29 (s, 1H),
7.64 (m, 1H), 7.36 (m, 2H), 7.34 (s, 1H), 6.90 (m, 1H), 6.83 (s,
1H), 4.29 (t, 2H), 4.00 (s, 3H), 3.85 (s, 2H), 3.66 (m, 1H), 3.55
(d, 1H), 3.40 (m, 1H), 3.12-3.35 (m, 3H), 3.00 (t, 1H), 2.80 (m,
2H), 2.00 (m, 1H), 1.75-1.95 (m, 2H), 1.60 (m, 1H):
[0571] MS (+ve ESI): 550.6 (M+H).sup.+.
EXAMPLE 19
Preparation of Compound 19 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[2-(2-hydroxyethyl)piperidin-1-yl]propo-
xy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0572] An analogous reaction to that described in example 7, but
starting with 2-(2-hydroxyethyl)piperidine (129 mg, 1 mmol) yielded
compound 19 in table 3 (63 mg, 44% yield):
[0573] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.63 (d, 1H), 7.34 (m, 2H), 7.32 (s, 1H), 6.90 (m, 1H), 6.83 (s,
1H), 4.30 (m, 2H), 4.00 (s, 3H), 3.85 (s, 2H), 3.10-3.70 (m, 7H),
2.20-2.30 (m, 2H), 2.00-2.20 (m, 1H), 1.60-1.90 (m, 6H), 1.50 (m,
1H):
[0574] MS (+ve ESI): 578.7 (M+H).sup.+.
EXAMPLE 20
Preparation of Compound 20 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperazin-1-yl]propo-
xy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0575] An analogous reaction to that described in example 7, but
starting with 2-piperazin-1-ylethanol (130 mg, 1 mmol) yielded
compound 20 in table 3 (69 mg, 48% yield):
[0576] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.63 (d, 1H), 7.36 (s, 1H), 7.34 (m, 2H), 6.90 (m, 1H), 6.84 (s,
1H), 4.31 (m, 2H), 2.70-4.10 (m, 8H), 4.01 (s, 3H), 3.85 (s, 2H),
3.79 (m, 2H), 3.40 (m, 2H), 3.35 (m, 2H), 2.29 (m, 2H):
[0577] MS (+ve ESI): 579.6 (M+H).sup.+.
EXAMPLE 21
Preparation of Compound 21 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperidin-1-yl]propo-
xy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0578] Analogous reaction to that described in example 7, but
starting with 4-(2-hydroxyethyl)piperidine (129 mg, 1 mmol) yielded
compound 21 in table 3 (91 mg, 63% yield):
[0579] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.64 (d, 1H), 7.35 (m, 2H), 7.33 (s, 1H), 6.88 (m, 1H), 6.84 (s,
1H), 4.30 (m, 2H), 4.00 (s, 3H), 3.85 (s, 2H), 3.55 (m, 2H), 3.48
(m, 2H), 3.25 (m, 2H), 2.98 (m, 2H), 2.28 (m, 2H), 1.90 (m, 2H),
1.70 (m, 1H), 1.40 (m, 4H)
[0580] MS (+ve ESI): 578.7 (M+H).sup.+.
EXAMPLE 22
Preparation of Compound 22 in Table
3--N-(3-fluorophenyl)-2-[3-({7-[3-(3-hydroxypiperidin-1-yl)propoxy]-6-met-
hoxyquinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetamide
[0581] An analogous reaction to that described in example 7, but
starting with piperidin-3-ol (101 mg, 1 mmol) yielded compound 22
in table 3 (65 mg, 47% yield):
[0582] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.29 (s, 1H),
7.62 (d, 1H), 7.38 (m, 2H), 7.34 (m, 2H), 7.34 (s, 1H), 6.90 (m,
1H), 6.84 (s, 1H), 4.28 (m, 2H), 4.10 (m, 1H), 4.00 (s, 3H), 3.85
(s, 2H), 2.80-3.50 (m, 6H), 1.30-2.40 (m, 6H):
[0583] MS (+ve ESI): 550.6 (M+H).sup.+.
EXAMPLE 23
Preparation of Compound 23 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxybutyl)amino]propoxy}-6-metho-
xyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0584] An analogous reaction to that described in example 7, but
starting with 1-aminobutan-2-ol (89 mg, 1 mmol) yielded compound 23
in table 3 (79 mg, 59% yield):
[0585] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.29 (s, 1H),
7.64 (d, 1H), 7.32-7.41 (m, 2H), 7.32 (s, 1H), 6.90 (t, 1H), 6.83
(s, 1H), 4.30 (t, 2H), 4.01 (s, 3H), 3.85 (s, 2H), 3.68 (m, 1H),
3.16 (t, 2H), 3.09 (d, 1H), 2.83 (t, 1H), 2.25 (m, 2H), 1.45 (m,
2H), 0.92 (t, 3H):
[0586] MS (+ve ESI): 538.6 (M+H).sup.+.
EXAMPLE 24
Preparation of Compound 24 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propox-
y}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0587] An analogous reaction to that described in example 7, but
starting with 4-(hydroxymethyl)piperidine (115 mg, 1 mmol) yielded
compound 24 in table 3 (80 mg, 57% yield):
[0588] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.63 (m, 1H), 7.36 (m, 3H), 6.90 (m, 1H), 6.84 (s, 1H), 4.30 (t,
2H), 4.01 (s, 3H), 3.85 (s, 2H), 3.62 (d, 2H), 3.32 (d, 2H), 3.27
(m, 2H), 2.98 (t, 2H), 2.29 (m, 2H), 1.90 (d, 2H), 1.67 (m, 1H),
1.42 (m, 2H):
[0589] MS (+ve ESI): 564.6 (M+H).sup.+.
EXAMPLE 25
Preparation of Compound 25 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[(3-hydroxy-2,2-dimethylpropyl)amino]pr-
opoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0590] An analogous reaction to that described in example 7, but
starting with 3-amino-2,2-dimethylpropan-1-ol (103 mg, 1 mmol)
yielded compound 25 in table 3 (63 mg, 46% yield):
[0591] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.29 (s, 1H),
7.64 (d, 1H), 7.31-7.41 (m, 2H), 7.35 (s, 1H), 6.90 (t, 1H), 6.83
(s, 1H), 4.30 (t, 2H), 4.01 (s, 3H), 3.85 (s, 2H), 3.29 (s, 2H),
3.16 (t, 2H), 2.92 (t, 2H), 2.28 (m, 2H), 0.95 (s, 6H):
[0592] MS (+ve ESI): 552.7 (M+H).sup.+.
EXAMPLE 26
Preparation of Compound 26 in Table
3--N-(3-fluorophenyl)-2-(3-{[7-(3-{[1-(hydroxymethyl)cyclopentyl]amino}pr-
opoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetamide
[0593] An analogous reaction to that described in example 7, but
starting with (1-amino-cyclopentyl)methanol (115 mg, 1 mmol)
yielded compound 26 in table 3 (69 mg, 49% yield)
[0594] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.64 (d, 1H), 7.32-7.41 (m, 3H), 6.90 (t, 1H), 6.83 (s, 1H), 4.32
(t, 2H), 4.01 (s, 3H), 3.85 (s, 2H), 3.48 (s, 2H), 3.12 (m, 2H),
2.23 (m, 2H), 1.68-1.83 (m, 6H), 1.59 (m, 2H):
[0595] MS (+ve ESI): 564.6 (M+H).sup.+.
EXAMPLE 27
Preparation of Compound 27 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]-
propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0596] An analogous reaction to that described in example 7, but
starting with D-prolinol (101 mg, 1 mmol) yielded compound 27 in
table 3 (61 mg, 44% yield):
[0597] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.65 (d, 1H), 7.31-7.41 (m, 2H), 7.34 (s, 1H), 6.90 (t, 1H), 6.84
(s, 1H), 4.31 (t, 2H), 4.01 (s, 3H), 3.85 (s, 2H), 3.77 (m, 1H),
3.53-3.68 (m, 4H), 3.15-3.30 (m, 2H), 2.30 (m, 2H), 2.13 (m, 1H),
2.02 (m, 1H), 1.90 (m, 1H), 1.78 (m, 1H):
[0598] MS (+ve ESI): 550.6 (M+H).sup.+.
EXAMPLE 28
Preparation of Compound 28 in Table
3--N-(3-fluorophenyl)-2-(3-{[7-(3-{[(2S)-2-hydroxypropyl]amino}propoxy)-6-
-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetamide
[0599] An analogous reaction to that described in example 7, but
starting with (S)-(+)-1-aminopropan-2-ol (75 mg, 1 mmol) yielded
compound 28 in table 3 (70 mg, 53% yield)
[0600] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.64 (d, 1H), 7.31-7.40 (m, 2H), 7.32 (s, 1H), 6.90 (t, 1H), 6.83
(s, 1H), 4.30 (t, 2H), 4.01 (s, 3H), 3.95 (m, 1H), 3.85 (s, 2H),
3.15 (t, 2H), 3.05 (dd, 1H), 2.83 (dd, 1H), 2.23 (m, 2H), 1.15 (d,
3H)
[0601] MS (+ve ESI): 524.6 (M+H).sup.+.
EXAMPLE 29
Preparation of Compound 29 in Table
3--N-(3-fluorophenyl)-2-(3-{[7-(3-{[(2R)-2-hydroxypropyl]amino}propoxy)-6-
-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetamide
[0602] An analogous reaction to that described in example 7, but
starting with (R)-(-)-1-aminopropan-2-ol (75 mg, 1 mmol) yielded
compound 29 in table 3 (80 mg, 61% yield)
[0603] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.64 (d, 1H), 7.31-7.40 (m, 2H), 7.31 (s, 1H), 6.90 (t, 1H), 6.83
(s, 1H), 4.30 (t, 2H), 4.01 (s, 3H), 3.95 (m, 1H), 3.85 (s, 2H),
3.15 (m, 2H), 3.06 (d, 1H), 2.83 (dd, 1H), 2.24 (m, 2H), 1.14 (d,
3H):
[0604] MS (+ve ESI): 524.6 (M+H).sup.+.
EXAMPLE 30
Preparation of Compound 30 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[(3S)-3-hydroxypyrrolidin-1-yl]propoxy}-
-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0605] An analogous reaction to that described in example 7, but
starting with (S)-(-)-3-hydroxypyrrolidine (87 mg, 1 mmol) yielded
compound 30 in table 3 (84 mg, 63% yield)
[0606] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.65 (d, 1H), 7.30-7.40 (m, 3H), 6.88 (t, 1H), 6.84 (s, 1H),
4.43-4.51 (m, 1H), 4.29 (m, 2H), 4.02 (s, 3H), 3.86 (s, 2H), 3.73
(m, 2H), 3.02-3.53 (m, 4H), 2.27 (m, 3H), 1.85-2.04 (m, 1H)
[0607] MS (+ve ESI): 536.6 (M+H).sup.+.
EXAMPLE 31
Preparation of Compound 31 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[(3R)-3-hydroxypyrrolidin-1-yl]propoxy}-
-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0608] An analogous reaction to that described in example 7, but
starting with (R)-(+)-3-hydroxypyrrolidine (87 mg, 1 mmol) yielded
compound 31 in table 3 (70 mg, 52% yield)
[0609] .sup.1H-NMR (DMSO d.sub.6, TFA): 10.45 (s, 1H), 10.18 (s,
1H), 8.46 (s, 1H), 7.98 (br s, 1H), 7.63 (d, 1H), 7.32-7.41 (m,
2H), 7.34 (s, 1H), 7.15 (s, 1H), 6.91 (t, 1H), 6.83 (br s, 1H),
4.69 (s, 1H), 4.15-4.24 (m, 3H), 3.94 (s, 3H), 3.76 (s, 2H), 2.72
(dd, 1H), 2.41-2.64 (m, 4H), 2.34 (dd, 1H), 1.91-2.04 (m, 3H), 1.55
(m, 1H)
[0610] MS (+ve ESI): 536.6 (M+H).sup.+.
EXAMPLE 32
Preparation of Compound 32 in Table
3--2-{3-[(7-{3-[(2-fluoroethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxy(q-
uinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide
[0611] An analogous reaction to that described in example 7, but
starting with 2-((2-fluoroethyl)amino)ethanol (180 mg, 1.68 mmol)
and carrying out the reaction in N-methyl pyrrolidinone at
100.degree. C. for 8 hours yielded compound 32 in table 3 (12 mg,
5% yield):
[0612] .sup.1H-NMR (DMSO d.sub.6): 10.45 (s, 1H), 10.18 (s, 1H),
8.47 (s, 1H), 8.00 (s, 1H), 7.63 (d, 1H), 7.37 (m, 1H), 7.35 (s,
1H), 7.15 (s, 1H), 6.91 (t, 1H), 6.83 (s, 1H), 4.54 (t, 1H), 4.43
(t, 1H), 4.37 (t, 1H), 4.18 (t, 2H), 3.95 (s, 3H), 3.77 (s, 2H),
3.46 (dd, 2H), 2.78 (t, 1H), 2.70 (t, 1H), 2.60 (t, 2H), 2.52 (t,
2H), 1.92 (m, 2H)
[0613] MS (+ve ESI): 556.4 (M+H).sup.+.
[0614] 2-((2-fluoroethyl)amino)ethanol used as starting material
was obtained as follows:
[0615] Potassium carbonate (22 g, 159 mmol) was added to a solution
of ethanolamine (4.75 ml, 78.7 mmol) and 1-bromo-2-fluoroethane
(10.0 g, 78.7 mmol) in dioxane (100 ml) and the reaction mixture
was heated at 80.degree. C. for 10 hours. The reaction was
concentrated and purified by chromatography on silica gel. Elution
with dichloromethane:methanol (95:5) and increased polarity to
dichloromethane:methanol:ammonia (90:5:5) yielded
2-((2-fluoroethyl)amino)ethanol (7.94 g, 74% yield). This compound
was further purified by distillation under reduced pressure to give
2-((2-fluoroethyl)amino)ethanol (3.44 g, 32% yield):
[0616] .sup.1H-NMR (DMSO d.sub.6, TFA): 9.94 (br s, 1H), 4.79 (t,
1H), 4.68 (t, 1H), 3.67 (t, 2H), 3.37 (d, 1H), 3.30 (d, 1H), 3.07
(d, 2H).
EXAMPLE 33
Preparation of Compound 33 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{2-[1-(2-hydroxyethyl)piperidin-4-yl]ethox-
y}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0617]
2-{3-[(7-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-6-methoxy-
quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide
(160 mg, 0.25 mmol) was reacted with trifluoroacetic acid (3 ml) in
dichloromethane (3 ml) at 40.degree. C. for 1 hour. The solvent was
evaporated, the residue dissolved in a mixture of
dichloromethane:methanol. Hydrogen chloride (2.0 N in ether, 0.4
ml) was added resulting in the precipitation of a beige solid which
was isolated and purified by preparative LCMS to yield compound 33
in table 3 as a beige solid (95 mg, 58% yield):
[0618] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 8.29 (s, 1H),
7.63 (m, 1H), 7.35 (m, 3H), 6.89 (m, 1H), 6.83 (s, 1H), 4.24 (m,
2H), 3.99 (s, 3H), 3.85 (s, 2H), 3.76 (m, 2H), 3.52 (d, 2H), 3.26
(m, 1H), 3.14 (m, 2H), 2.98 (t, 2H), 1.94 (d, 2H), 1.81 (m, 2H),
1.57 (m, 2H):
[0619] MS (+ve ESI): 564.2 (M+H).sup.+.
[0620]
2-{3-[(7-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-6-methoxy-
quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide
used as starting material was obtained as follows.
[0621] a) 4-(2-hydroxyethyl)piperidine (1.94 g, 15 mmol) in
dimethylformamide (20 ml) was reacted with
2-(2-bromoethoxy)-2-methylpropane (3.13 g, 17.3 mmol) at 50.degree.
C. for 15 hours. The mixture was cooled and the solid removed by
filtration. The solid was washed with ethyl acetate and the
organics were washed with water, dried (magnesium sulphate) and
concentrated to give 2-(1-(2-tert-butoxy
ethyl)piperidin-4-yl)ethanol as a yellow oil (2.35 g, 100%
yield):
[0622] .sup.1H-NMR (DMSO d.sub.6, TFA): 3.63 (m, 2H), 3.40-3.50 (m,
4H), 3.20 (m, 2H), 2.93 (t, 2H), 1.84 (d, 2H), 1.50-1.70 (m, 1H),
1.30-1.45 (4H), 1.18 (s, 9H).
[0623] b)
N'-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamid- e
(876 mg, 4 mmol) in dichloromethane (2 ml) was reacted with
2-(1-(2-tert-butoxyethyl)piperidin-4-yl)ethanol (916 mg, 4.4 mmol)
in the presence of triphenylphosphine (1.2 g, 4.6 mmol) by slow
addition of a solution of di-tert-butyl azodicarboxylate (1.058 g,
4.6 mmol) in dichloromethane (5 ml). The mixture was stirred for 2
hours at ambient temperature and purified by chromatography.
Elution with dichloromethane:ethyl acetate:methanol (5:4:1) yielded
N'-(5-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-2-cyano-4-methoxyp-
henyl)-N,N-dimethylimidoformamide (720 mg, 42% yield):
[0624] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.54 (s, 1H), 7.50 (s, 1H),
7.29 (s, 1H), 4.14 (m, 2H), 3.85 (s, 3H), 3.64 (m, 2H), 3.53 (d,
2H), 3.37 (s, 3H), 3.33 (m, 1H), 3.27 (s, 3H), 3.21 (m, 2H), 2.98
(t, 2H), 1.80-2.00 (m, 2H), 1.60-1.80 (m, 2H), 1.30-1.60 (m, 2H),
1.18 (s, 9H):
[0625] MS (+ve ESI): 431.28 (M+H).sup.+.
[0626] c)
N'-(5-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-2-cyano-4-
-methoxyphenyl)-N,N-dimethylimidoformamide (654 mg, 1.5 mmol) in
acetic acid (1.35 ml) was heated with
(3-amino-1H-pyrazol-5-yl)acetic acid (214 mg, 1.52 mmol) at reflux
for 45 minutes. Acetic acid was evaporated and the residue taken up
in a mixture of dichloromethane:methanol. Excess
diisopropylethylamine was added, and the solvent evaporated in
vacuo. Dichloromethane was added to the solid, which was filtered
and dried to yield
{3-[(7-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-6-methoxyqu-
inazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic acid as a white powder
(530 mg, 66% yield):
[0627] .sup.1H-NMR (DMSO d.sub.6): 8.94 (s, 1H), 8.27 (s, 1H), 7.33
(s, 1H), 6.80 (s, 1H), 4.27 (m, 2H), 3.99 (s, 3H), 3.74 (s, 2H),
3.65 (m, 2H), 3.52 (d, 2H), 3.20-3.30 (m, 3H), 2.99 (t, 2H), 1.98
(d, 2H), 1.9-1.7 (m, 2H), 1.5 (m, 2H), 1.82 (s, 9H)
[0628] MS (+ve ESI): 527.2 (M+H).sup.+.
[0629] d)
{3-[(7-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-6-methox-
yquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic acid (210 mg, 0.4
mmol) in dimethylformamide (2.1 ml) was reacted with
3-fluoroaniline (58 mg, 0.52 mmol) in the presence of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107
mg, 0.56 mmol) and 2-hydroxypyridine-1-oxide (53 mg, 0.48 mmol) at
55.degree. C. for 1.5 hours. The reaction mixture was cooled,
diluted with dichloromethane (7 ml) and purified by chromatography
on silica gel. Elution with dichloromethane:methanol (9:1) and
increased polarity to dichloromethane:methanol:ammonia (9:1:0.1)
yielded
2-{3-[(7-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-6-metho-
xyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide
(162 mg, 65% yield) as a light pink solid:
[0630] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 8.27 (s, 1H),
7.63 (m, 1H), 7.32-7.40 (m, 3H), 6.89 (m, 1H), 6.82 (s, 1H), 4.25
(m, 2H), 3.99 (s, 3H), 3.84 (s, 2H), 3.64 (m, 2H), 3.51 (d, 2H),
3.10-3.30 (m, 3H), 2.99 (t, 2H), 1.97 (d, 2H), 1.60-1.95 (m, 2H),
1.78 (s, 9H); 1.51 (m, 2H):
[0631] MS (+ve ESI): 620.3 (M+H).sup.+.
EXAMPLE 34
Preparation of Compound 34 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy}-
-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0632] An analogous reaction to that described in example 7, but
starting with 2-(propylamino)ethanol (160 mg, 1.55 mmol) and
carrying out the reaction in N-methyl pyrrolidinone (2.5 ml) in the
presence of potassium iodide (103 mg, 0.62 mmol) at 60.degree. C.
for 8 hours yielded compound 34 in table 3 (21 mg, 12% yield):
[0633] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.98 (s, 1H), 8.32 (s, 1H),
7.66 (d, 1H), 7.35-7.41 (m, 2H), 7.36 (s, 1H), 6.91 (t, 1H), 6.85
(s, 1H), 4.32 (t, 2H), 4.02 (s, 3H), 3.86 (s, 2H), 3.78 (t, 2H),
3.35 (m, 2H), 3.28 (m, 2H), 3.17 (m, 2H), 2.29 (m, 2H), 1.73 (m,
2H):
[0634] MS (+ve ESI): 552.2 (M+H).sup.+.
EXAMPLE 35
Preparation of Compound 35 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isopropyl)amino]propo-
xy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0635] An analogous reaction to that described in example 34, but
starting with 2-(isopropyl amino)ethanol (160 mg, 1.55 mmol)
yielded compound 35 in table 3 (98 mg, 57% yield):
[0636] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.98 (s, 1H), 8.31 (s, 1H),
7.66 (d, 1H), 7.32-7.41 (m, 2H), 7.37 (s, 1H), 6.92 (t, 1H), 6.85
(s, 1H), 4.33 (t, 2H), 4.02 (s, 3H), 3.86 (s, 2H), 3.79 (m, 2H),
3.33 (m, 4H), 3.17 (m, 1H), 2.33 (m, 2H), 1.31 (t, 6H)
[0637] MS (+ve ESI): 552.2 (M+H).sup.+.
EXAMPLE 36
Preparation of Compound 36 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propox-
y}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0638] An analogous reaction to that described in example 34, but
starting with 2-(isobutyl amino)ethanol (181 mg, 1.55 mmol) yielded
compound 36 in table 3 (101 mg, 57% yield):
[0639] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.63 (d, 1H), 7.32-7.41 (m, 2H), 7.34 (s, 1H), 6.90 (t, 1H), 6.83
(s, 1H), 4.30 (t, 2H), 4.00 (s, 3H), 3.84 (s, 2H), 3.80 (t, 2H),
3.37 (t, 2H), 3.28 (t, 2H), 3.00-3.15 (m, 2H), 2.29 (m, 2H), 2.12
(m, 2H), 1.00 (d, 6H)
[0640] MS (+ve ESI): 566.3 (M+H).sup.+.
[0641] 2-(isobutylamino)ethanol used as starting material was
obtained as follows
[0642] Ethylene oxide (5.28 g, 120 mmol) in methanol (14 ml),
cooled to -60.degree. C., was slowly added to a solution of
isobutylamine (30.7 g, 420 mmol) in methanol (100 ml) at
-65.degree. C. under argon. The mixture was allowed to stir at
ambient temperature for 14 hours, concentrated and the residual oil
was purified by distillation (130.degree. C. (0.5 mm Hg) to yield
2-(isobutylamino)ethanol (11 g, 78% yield):
[0643] .sup.1H-NMR (DMSO d.sub.6): 4.40 (m, 1H), 3.42 (m, 2H), 2.50
(m, 2H), 2.30 (d, 2H), 1.63 (m, 1H), 0.85 (d, 6H).
EXAMPLE 37
Preparation of Compound 37 in Table
3--2-{3-[(7-{3-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]propoxy}-6-meth-
oxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide
[0644] An analogous reaction to that described in example 34, but
starting with 2-(2,2-dimethylpropyl)amino)ethanol (203 mg, 1.55
mmol) yielded compound 37 in table 3 (111 mg, 61% yield):
[0645] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.64 (d, 1H), 7.32-7.41 (m, 2H), 7.34 (s, 1H), 6.90 (t, 1H), 6.83
(s, 1H), 4.31 (t, 2H), 3.99 (s, 3H), 3.84 (s, 2H), 3.83 (t, 2H),
3.42 (t, 2H), 3.32 (t, 2H), 3.20 (dd, 2H), 2.35 (m, 2H), 1.07 (s,
9H)
[0646] MS (+ve ESI): 580.3 (M+H).sup.+.
[0647] 2-((2,2-dimethylpropyl)amino)ethanol used as starting
material was obtained as follows
[0648] Ethylene oxide (2.5 ml, 5.0 mmol) cooled to -20.degree. C.
was slowly added to a solution of (2,2-dimethylpropyl)amine (13 g,
150 mmol) in methanol (15 ml) at -30.degree. C. under argon. The
mixture was stirred at ambient temperature for 16 hours. The
solvent was evaporated, and the residue purified by distillation
(b.p. 132.degree. C. @ 9 mmHg) to yield
2-((2,2-dimethylpropyl)amino)ethanol (6.4 g, 97% yield):
[0649] .sup.1H-NMR (DMSO d.sub.6, TFA): 3.70 (m, 2H), 3.02 (m, 2H),
2.81 (m, 2H), 0.98 (s, 9H).
EXAMPLE 38
Preparation of Compound 38 in Table
3--2-{3-[(7-{3-[allyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-
-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide
[0650] An analogous reaction to that described in example 34, but
starting with 2-(allylamino)ethanol (156 mg, 1.55 mmol) yielded
compound 38 in table 3 (33 mg, 19% yield):
[0651] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.98 (s, 1H), 8.31 (s, 1H),
7.65 (d, 1H), 7.34-7.43 (m, 2H), 7.34 (s, 1H), 6.92 (t, 1H), 6.85
(s, 1H), 6.01 (m, 1H), 5.64 (d, 1H), 5.58 (d, 1H), 4.31 (t, 2H),
4.02 (s, 3H), 3.92 (t, 2H), 3.86 (s, 2H), 3.81 (t, 2H), 3.20-3.40
(m, 4H), 2.31 (m, 2H)
[0652] MS (+ve ESI): 550.2 (M+H).sup.+.
[0653] 2-(allylamino)ethanol used as starting material was obtained
as follows:
[0654] Ethylene oxide (2.5 ml, 50 mmol) cooled to -20.degree. C.
was added to a solution of allylamine (14 g, 250 mmol) in methanol
(20 ml) at -20.degree. C. The mixture was stirred at ambient
temperature for 14 hours, the solvent was evaporated, and the
residual oil purified by distillation (b.p. 140.degree. C. @ 14
mmHg) to yield 2-(allylamino)ethanol (4.2 g, 84% yield):
[0655] .sup.1H-NMR (DMSO d.sub.6): 5.80-5.86 (m, 1H), 5.14 (m, 1H),
5.02 (m, 1H), 3.43 (m, 2H), 3.14 (m, 2H), 2.50 (m, 2H).
EXAMPLE 39
Preparation of Compound 39 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-1-yl)amino]-
propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0656] An analogous reaction to that described in example 34, but
starting with 2-(prop-2-yn-1-ylamino)ethanol (153 mg, 1.55 mmol)
yielded compound 39 in table 3 (48 mg, 28% yield):
[0657] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.29 (s, 1H),
7.64 (d, 1H), 7.32-7.41 (m, 2H), 7.32 (s, 1H), 6.90 (t, 1H), 6.90
(s, 1H), 4.31 (t, 2H), 4.29 (s, 2H), 4.00 (s, 3H), 3.90 (s, 1H),
3.84 (s, 2H), 3.79 (t, 2H), 3.43 (m, 2H), 3.34 (m, 2H), 2.30 (m,
2H)
[0658] MS (+ve ESI): 548.2 (M+H).sup.+.
[0659] 2-(prop-2-yn-1-ylamino)ethanol used as starting material was
obtained as follows:
[0660] Ethylene oxide (3.3 g, 75 mmol) in methanol (10 ml) cooled
to -40.degree. C. was slowly added to a solution of propargylamine
(16.5 g, 300 mmol) in methanol (60 ml) cooled to -65.degree. C.
under argon. The mixture was stirred at ambient temperature for 16
hours, the solvent was evaporated, and the residue purified by
distillation to yield 2-(prop-2-yn-1-ylamino)ethanol (5 g, 67%
yield):
[0661] .sup.1H-NMR (DMSO d.sub.6, TFA): 3.91 (m, 2H), 3.65 (m, 3H),
3.06 (m, 2H).
EXAMPLE 40
Preparation of Compound 40 in Table
3--2-{3-[(7-{3-[cyclopropyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinaz-
olin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide
[0662] An analogous reaction to that described in example 34, but
starting with 2-(cyclopropylamino)ethanol (156 mg, 1.55 mmol,
obtained as described by Morrow, D, F et al in J. Med. Chem. 1973,
16, 736-9) yielded compound 40 in table 3 (22 mg, 13% yield):
[0663] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.97 (s, 1H), 8.31 (s, 1H),
7.65 (d, 1H), 7.33-7.42 (m, 2H), 7.37 (s, 1H), 6.92 (t, 1H), 6.85
(s, 1H), 4.33 (m, 2H), 4.02 (s, 3H), 3.86 (s, 2H), 3.79 (t, 2H),
3.48 (m, 2H), 3.42 (t, 2H), 2.97 (m, 1H), 2.36 (m, 2H), 1.04 (m,
2H), 0.94 (m, 2H):
[0664] MS (+ve ESI): 550.2 (M+H).sup.+.
EXAMPLE 41
Preparation of Compound 41 in Table
3--2-{3-[(7-{3-[(cyclopropylmethyl)(2-hydroxyethyl)amino]propoxy}-6-metho-
xyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide
[0665] An analogous reaction to that described in example 34, but
starting with 2-((cyclopropylmethyl)amino)ethanol (178 mg, 1.55
mmol) yielded compound 41 in table 3 (19 mg, 11% yield):
[0666] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.97 (s, 1H), 8.31 (s, 1H),
7.66 (d, 1H), 7.33-7.42 (m, 2H), 7.34 (s, 1H), 6.91 (t, 1H), 6.85
(s, 1H), 4.32 (t, 2H), 4.01 (s, 3H), 3.86 (s, 2H), 3.81 (t, 2H),
3.44 (m, 2H), 3.35 (m, 2H), 3.18 (t, 2H), 2.30 (m, 2H), 1.16 (m,
1H), 0.61 (m, 2H), 0.46 (m, 2H):
[0667] MS (+ve ESI): 564.2 (M+H).sup.+.
[0668] 2-((cyclopropylmethyl)amino)ethanol used as starting
material was obtained as follows
[0669] a) A solution of ethyl oxalyl chloride (4.2 ml, 37.6 mmol)
in dichloromethane (35 ml) was added over 30 minutes to a solution
of cyclopropylmethylamine (3 ml, 34.6 mmol) and triethylamine (7
ml) in dichloromethane (35 ml) at 0.degree. C. The mixture was
stirred at ambient temperature for 2 hours. Water (20 ml) was added
and the pH adjusted to 3 using 2.0 N hydrochloric acid. The organic
phase was separated, dried (magnesium sulphate) and concentrated to
yield ethyl [(cyclopropylmethyl)amino](oxo)acetate (5.9 g, 100%
yield):
[0670] .sup.1H-NMR (CDCl.sub.3): 7.24 (br s, 1H), 3.24 (m, 2H),
1.43 (t, 3H), 1.04 (m, 1H), 0.59 (m, 2H), 0.29 (m, 2H):
[0671] MS (+ve ESI): 172 (M+H).sup.+.
[0672] b) A solution of ethyl
[(cyclopropylmethyl)amino](oxo)acetate (5.9 g, 34.6 mmol) in
tetrahydrofuran (30 ml) was added at ambient temperature to a
mixture of borane-tetrahydrofuran complex (130 ml of a 1.0 N
solution in THF, 130 mmol) and chlorotrimethylsilane (34 ml, 268
mmol). The reaction mixture was stirred at ambient temperature for
48 hours. Methanol (20 ml) was added and the reaction stirred for a
further 30 minutes before dilution with dichloromethane followed by
addition of a concentrated solution of hydrochloric acid (4 ml).
The mixture was stirred for 30 minutes, basified with methanolic
ammonia (7 N) and the resultant solid filtered and washed with
dichloromethane. The organic phases were recovered, concentrated
and purified by chromatography on silica gel. Elution with
dichloromethane followed by increased polarity to
dichloromethane:methanol (95:5), dichloromethane:methanolic ammonia
(9:1) yielded 2-((cyclopropylmethyl)amino)ethanol as a pale yellow
liquid (2.99 g, 75% yield):
[0673] .sup.1H-NMR (DMSO d.sub.6, TFA): 3.66 (t, 2H), 3.02 (t, 2H),
2.84 (d, 2H), 1.06 (m, 1H), 0.58 (m, 2H), 0.35 (m, 2H).
EXAMPLE 42
Preparation of Compound 42 in Table
3--2-{3-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazo-
lin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide
[0674] An analogous reaction to that described in example 34, but
starting with 2-(cyclobutylamino)ethanol (178 mg, 1.55
mmol--obtained as described by D. F. Morrow et al, J. Med. Chem.
1973, 16, 736-9) yielded compound 42 in table 3 (42 mg, 24%
yield):
[0675] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.29 (s, 1H),
7.64 (d, 1H), 7.36 (m, 2H), 7.34 (s, 1H), 6.90 (t, 1H), 6.83 (s,
1H), 4.29 (t, 2H), 4.00 (s, 3H), 3.94 (m, 1H), 3.85 (s, 2H), 3.75
(m, 2H), 3.25 (m, 2H), 3.17 (m, 2H), 2.08-2.39 (m, 6H), 1.76 (m,
1H), 1.69 (m, 1H):
[0676] MS (+ve ESI): 564.2 (M+H).sup.+.
EXAMPLE 43
Preparation of Compound 43 in Table
3--2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinaz-
olin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide
[0677] An analogous reaction to that described in example 34, but
starting with 2-(cyclopentylamino)ethanol (200 mg, 1.55
mmol--obtained as described by D. F. Morrow et al J. Med. Chem.
1973, 16, 736-9) yielded compound 43 in table 3 (30 mg, 17%
yield):
[0678] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.64 (d, 1H), 7.34-7.42 (m, 2H), 7.33 (s, 1H), 6.90 (t, 1H), 6.84
(s, 1H), 4.31 (t, 2H), 4.00 (s, 3H), 3.85 (s, 2H), 3.65 (t, 2H),
3.48 (m, 1H), 3.37 (m, 2H), 3.28 (m, 2H), 2.30 (m, 2H), 2.08 (m,
2H), 1.72 (m, 3H), 1.58 (m, 3H)
[0679] MS (+ve ESI): 578.3 (M+H).sup.+.
EXAMPLE 44
Preparation of Compound 44 in Table
3--2-{3-[(7-{3-[(2,2-dimethoxyethyl)(2-hydroxyethyl)amino]propoxy}-6-meth-
oxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide
[0680] An analogous reaction to that described in example 34, but
starting with 2-((2,2-dimethoxyethyl)amino)ethanol (231 mg, 1.55
mmol) yielded compound 44 in table 3 (89 mg, 48% yield):
[0681] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.63 (d, 1H), 7.31-7.40 (m, 2H), 7.33 (s, 1H), 6.89 (t, 1H), 6.83
(s, 1H), 4.85 (t, 1H), 4.28 (t, 2H), 4.00 (s, 3H), 3.84 (s, 2H),
3.80 (t, 2H), 3.41 (s, 6H), 3.37 (m, 6H), 2.29 (m, 2H):
[0682] MS (+ve ESI): 598.2 (M+H).sup.+.
[0683] 2-((2,2-dimethoxyethyl)amino)ethanol used as starting
material was obtained as follows.
[0684] Ethanolamine (4 ml, 66.3 mmol) in dioxane (50 ml) in the
presence of potassium carbonate (6.9 g, 50 mmol) was reacted with
2-bromo-1,1-dimethoxyethane (5 ml, 42.3 mmol) at 75.degree. C. for
6 hours. The solid was filtered and washed with dioxane. The
recovered organic phase was concentrated and purified by
chromatography on silica gel. Elution with dichloromethane followed
by increased polarity to dichloromethane:methanol (97:3),
dichloromethane:methanolic ammonia (94:6) yielded
2-((2,2-dimethoxyethyl)amino)ethanol (2.4 g, 38% yield) as a pale
yellow liquid:
[0685] .sup.1H-NMR (DMSO d.sub.6, AcOD): 4.64 (t, 1H), 3.61 (t,
2H), 3.34 (s, 6H), 2.99 (m, 2H), 2.93 (m, 2H).
EXAMPLE 45
Preparation of Compound 45 in Table
3--2-{3-[(7-{3-[(2,2-difluoroethyl)(2-hydroxyethyl)amino]propoxy}-6-metho-
xyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide
[0686] An analogous reaction to that described in example 34, but
starting with 2-((2,2-difluoroethyl)amino)ethanol (194 mg, 1.55
mmol) yielded compound 45 in table 3 (27 mg, 15% yield):
[0687] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.64 (d, 1H), 7.33-7.40 (m, 2H), 7.33 (s, 1H), 6.89 (t, 1H), 6.84
(s, 1H), 6.61 (t, 1H), 4.30 (t, 2H), 4.01 (s, 3H), 3.90 (t, 2H),
3.85 (m, 4H), 3.48 (m, 2H), 3.42 (m, 2H), 2.34 (m, 2H):
[0688] MS (+ve ESI): 574.3 (M+H).sup.+,
[0689] 2-((2,2-difluoroethyl)amino)ethanol used as starting
material was obtained as follows:
[0690] a) Methyl difluoroacetate (5 g, 45 mmol) in acetonitrile (50
ml) was reacted with ethanolamine (2.66 ml, 45.4 mmol) at ambient
temperature for 24 hours. The solvent was evaporated and the
residual oil was purified by chromatography on silica gel, eluting
with dichloromethane:methanol (96:4) then
dichloromethane:methanolic ammonia (94:6) to yield
2,2-difluoro-N-(2-hydroxyethyl)acetamide (6.18 g, 98% yield):
[0691] .sup.1H-NMR (DMSO d.sub.6): 8.76 (br s, 1H), 6.21 (t, 1H),
4.78 (t, 1H), 3.46 (t, 2H), 3.22 (t, 2H)
[0692] MS (+ve ESI): 140 (M+H).sup.+.
[0693] b) Borane-tetrahydrofuran complex (40 ml of a 1.0 N solution
in THF, 40 mmol) was added dropwise at 0.degree. C. to a solution
of 2,2-difluoro-N-(2-hydroxyethyl)acetamide (2.78 g, 20 mmol) in
tetrahydrofuran (30 ml). The mixture was warmed to ambient
temperature and then heated at reflux for 18 hours. The reaction
mixture was cooled to ambient temperature and concentrated
hydrochloric acid (6 ml) was added dropwise. The solvent was
evaporated and the crude product was purified by chromatography on
silica gel. Elution with dichloromethane:methanolic ammonia (96:4)
then dichloromethane:methanolic ammonia (94:6) yielded
2-((2,2-difluoroethyl)amino)ethanol (0.97 g, 39% yield):
[0694] .sup.1H-NMR (DMSO d.sub.6, TFA): 6.40 (m, 1H), 3.69 (t, 2H),
3.56 (m, 2H), 3.11 (t, 2H).
EXAMPLE 46
Preparation of compound 46 in table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(3,3,3-trifluoropropyl-
)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0695] An analogous reaction to that described in example 34, but
starting with 2-((3,3,3-trifluoropropyl)amino)ethanol (221 mg, 1.55
mmol) yielded compound 46 in table 3 (77 mg, 41% yield):
[0696] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.29 (s, 1H),
7.63 (d, 1H), 7.31-7.40 (m, 2H), 7.33 (s, 1H), 6.89 (t, 1H), 6.83
(s, 1H), 4.29 (t, 2H), 3.99 (s, 3H), 3.84 (s, 2H), 3.79 (t, 2H),
3.51 (m, 2H), 3.38 (m, 2H), 2.91 (m, 2H), 2.29 (m, 2H):
[0697] MS (+ve ESI): 606.2 (M+H).sup.+.
[0698] 2-((3,3,3-trifluoropropyl)amino)ethanol used as starting
material was obtained as follows
[0699] 3-bromo-1,1,1-trifluoropropane (5.5 ml, 51.65 mmol) in
dioxane (50 ml) in the presence of potassium carbonate (14.15 g,
102.5 mmol) was reacted with ethanolamine (3.0 ml, 51 mmol) at
60.degree. C. for 36 hours. The solvent was evaporated and the
residue purified by chromatography on silica gel. Elution with
dichloromethane:methanol (95:5) then increased polarity to
dichloromethane:methanolic ammonia (95:5) yielded
2-((3,3,3-trifluoropropyl)amino)ethanol (4.47 g, 55% yield):
[0700] .sup.1H-NMR (DMSO d.sub.6, TFA): 3.56 (t, 2H), 2.97 (t, 2H),
2.82 (t, 2H), 2.57 (m, 2H).
EXAMPLE 47
Preparation of Compound 47 in Table
3--2-{3-[(7-{3-[(cyclobutylmethyl)(2-hydroxyethyl)amino]propoxy}-6-methox-
yquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide
[0701] An analogous reaction to that described in example 34, but
starting with 2-((cyclobutylmethyl)amino)ethanol (200 mg, 1.55
mmol) yielded compound 47 in table 3 (87 mg, 49% yield):
[0702] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.64 (d, 1H), 7.32-7.43 (m, 2H), 7.32 (s, 1H), 6.89 (t, 1H), 6.83
(s, 1H), 4.29 (t, 2H), 4.00 (s, 3H), 3.85 (s, 2H), 3.77 (t, 2H),
3.19-3.34 (m, 6H), 2.75-3.03 (m, 1H), 2.27 (m, 2H), 2.11 (m, 2H),
1.85 (m, 6H):
[0703] MS (+ve ESI): 578.3 (M+H).sup.+.
[0704] 2-((cyclobutylmethyl)amino)ethanol used as starting material
was obtained as follows:
[0705] a) Cyclobutane carbonyl chloride (5 ml, 43.8 mmol) was
slowly added to a solution of ethyl glycinate (5.86 g, 42 mmol) in
dichloromethane (100 ml) and triethylamine (14.6 ml, 105 mmol) at
0.degree. C. The mixture was then stirred at ambient temperature
for 14 hours. The reaction mixture was washed with 1.0 N
hydrochloric acid and the organic phase separated, dried (magnesium
sulphate) and evaporated in vacuo to yield a yellow solid.
Recrystallisation from dichloromethane:petroleum ether, yielded
ethyl N-(cyclobutylcarbonyl)glycinate as a white solid (7.78 g,
100% yield):
[0706] .sup.1H-NMR (DMSO d.sub.6): 8.08 (t, 1H), 4.09 (q, 2H), 3.79
(s, 2H), 3.07 (m, 1H), 2.00-2.18 (m, 4H), 1.89 (m, 1H), 1.78 (m,
1H), 1.20 (t, 3H).
[0707] b) Ethyl N-(cyclobutylcarbonyl)glycinate (7.6 g, 41 mmol) in
tetrahydrofuran (40 ml) was added to borane-tetrahydrofuran complex
(100 ml of a 1.0 N solution in tetrahydrofuran, 100 mol) and heated
at 60.degree. C. for 24 hours. Additional borane-tetrahydrofuran
complex (20 ml) was added to the mixture and heating continued for
a further 8 hours. The reaction mixture was then diluted slowly
with methanol (20 ml) and stirred at ambient temperature for 0.5
hour. A concentrated solution of hydrochloric acid (6 ml) was
slowly added following dilution with dichloromethane. The solid
which precipitated was removed by filtration and washed with
dichloromethane. The organic phase was dried (magnesium sulphate),
concentrated and purified by chromatography on silica gel. Elution
with dichloromethane:methanol (96:4) then
dichloromethane:methanolic ammonia (94:6) yielded
2-((cyclobutylmethyl)amino)ethanol (4.16 g, 78% yield):
[0708] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.38 (br s, 1H), 3.65 (t,
2H), 2.98 (m, 4H), 2.62 (m, 2H), 2.06 (m, 2H), 1.72-1.94 (m,
4H).
EXAMPLE 48
Preparation of Compound 48 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(2-methoxyethyl)amino]-
propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0709] An analogous reaction to that described in example 34, but
starting with 2-((2-methoxy ethyl)amino)ethanol (184 mg, 1.55
mmol--obtained according to A. A. Santilli at al, J. Heterocycl.
Chem. 1972, 9, 309-13) yielded compound 48 in table 3 (37 mg, 21%
yield):
[0710] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.64 (d, 1H), 7.31-7.42 (m, 2H), 7.32 (s, 1H), 6.89 (t, 1H), 6.83
(s, 1H), 4.29 (t, 2H), 4.00 (s, 3H), 3.84 (s, 2H), 3.78 (t, 1H),
3.71 (t, 1H), 3.65 (t, 1H), 3.59 (t, 1H), 3.35-3.53 (m, 4H), 3.14
(t, 1H), 3.02 (t, 1H), 2.29 (m, 2H)
[0711] MS (+ve ESI): 568.2 (M+H).sup.+.
EXAMPLE 49
Preparation of Compound 49 in Table
3--2-{3-[(7-{3-[(1,3-dioxolan-2-ylmethyl)(2-hydroxyethyl)amino]propoxy}-6-
-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamid-
e
[0712] An analogous reaction to that described in example 34, but
starting with 2-((1,3-dioxolan-2-ylmethyl)amino)ethanol (227 mg,
1.55 mmol) yielded compound 49 in table 3 (105 mg, 57% yield):
[0713] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.64 (d, 1H), 7.31-7.41 (m, 2H), 6.88 (t, 1H), 6.83 (s, 1H), 5.31
(t, 1H), 4.29 (t, 2H), 4.00 (s, 3H), 4.00 (t, 2H), 3.89 (t, 2H),
3.84 (s, 2H), 3.81 (t, 2H), 3.34-3.55 (m, 6H), 2.31 (m, 2H):
[0714] MS (+ve ESI): 596.3 (M+H).sup.+.
[0715] 2-((1,3-dioxolan-2-ylmethyl)amino)ethanol used as starting
material was obtained as follows
[0716] 2-(bromomethyl)-1,3-dioxolane (4.4 ml, 42.5 mmol) in dioxane
(60 ml) was reacted with ethanolamine (4 ml, 66.3 mmol) in the
presence of potassium carbonate (6.9 g, 50 mmol) at 75.degree. C.
for 7 hours. The mixture was concentrated and purified by
chromatography on silica gel, eluting with dichloromethane:methanol
(97:3) then dichloromethane:methanolic ammonia (94:6), to yield
2-((1,3-dioxolan-2-ylmethyl)amino)ethanol (1.90 g, 24% yield)
[0717] .sup.1H-NMR (DMSO d.sub.6, TFA): 5.17 (t, 1H), 3.86-4.04 (m,
4H), 3.67 (t, 2H), 3.20 (m, 2H), 3.06 (m, 2H).
EXAMPLE 50
Preparation of Compound 50 in Table
3--2-(3-{[7-(4-chlorobutoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-
-yl)-N-(3-fluorophenyl)acetamide
[0718] An analogous reaction to that described in example 3, but
starting with
(3-{[7-(4-chlorobutoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-
-yl)acetic acid (2.05 g, 5 mmol) yielded compound 50 in table 3 as
an off-white solid (1.45 g, 58% yield):
[0719] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 8.27 (s, 1H),
7.64 (m, 1H), 7.33-7.40 (m, 2H), 7.29 (s, 1H), 6.72-6.88 (m, 1H),
6.83 (s, 1H), 4.27 (m, 2H), 4.01 (s, 3H), 3.85 (s, 2H), 3.76 (m,
2H), 1.92-1.99 (m, 4H):
[0720] MS (+ve ESI): 499.1 (M+H).sup.+.
[0721]
(3-{[7-(4-chlorobutoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol--
5-yl)acetic acid used as starting material was obtained as
follows:
[0722] a) A solution of
N'-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamide
(3.29 g, 1.5 mmol) in dimethylformamide (33 ml) and potassium
carbonate (4.14 g, 30 mmol) was reacted with 1-bromo-4-chlorobutane
(3.86 g, 2.5 mmol) at 60.degree. C. for 2 hours. Water was added to
the reaction mixture which was then extracted with ethyl acetate.
The organic phase was dried (magnesium sulphate), concentrated and
the residue was purified by chromatography on silica gel. Elution
with dichloromethane:ethyl acetate (8:2) then increased polarity to
(6:4) yielded
N'-[5-(4-chlorobutoxy)-2-cyano-4-methoxyphenyl]-N,N-dimethylimidoformamid-
e as a white solid (3.7 g, 80% yield):
[0723] .sup.1H-NMR (DMSO d.sub.6): 7.97 (s, 1H), 7.09 (s, 1H), 6.74
(s, 1H), 4.07 (m, 2H), 3.73 (m, 5H), 3.06 (s, 3H), 2.96 (s, 3H),
1.87 (m, 4H).
[0724] b)
N'-[5-(4-chlorobutoxy)-2-cyano-4-methoxyphenyl]-N,N-dimethylimid-
oformamide (464 g, 15 mmol) in acetic acid (13.5 ml, 225 mmol) was
reacted with (3-amino-1H-pyrazol-5-yl)acetic acid (2.22 g, 15.8
mmol) at reflux for 1 hour. The mixture was cooled, diluted with
ethanol (25 ml) and the resultant precipitate recovered by suction
filtration. The solid was stirred in water for 1 hour, collected by
suction filtration and dried to yield
(3-{[7-(4-chlorobutoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol--
5-yl)acetic acid (4.5 g, 74% yield):
[0725] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.47 (s, 1H), 7.97 (s, 1H),
7.15 (s, 1H), 6.69 (s, 1H), 4.18 (m, 2H), 3.94 (s, 3H), 3.76 (m,
2H), 3.65 (s, 2H), 1.93 (m, 4H):
[0726] MS (+ve ESI): 406.14 (M+H).sup.+.
EXAMPLE 51
Preparation of Compound 51 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{4-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]-
butoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0727] An analogous reaction to that described in example 7, but
starting with
2-(3-{[7-(4-chlorobutoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-
-5-yl)-N-(3-fluorophenyl)acetamide (125 mg, 0.25 mmol) and
D-prolinol (76 mg, 0.75 mmol) in the presence of potassium iodide
(83 mg, 0.5 mmol) and heating for 3 hours, yielded compound 51 in
table 3 as a pale yellow solid (68 mg, 48% yield):
[0728] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.29 (s, 1H),
7.64 (m, 1H), 7.34-7.40 (m, 2H), 7.33 (s, 1H), 6.90 (m, 1H), 6.84
(s, 1H), 4.25 (m, 2H), 4.01 (s, 3H), 3.79 (s, 2H), 3.77 (m, 1H),
3.58-3.65 (m, 3H), 3.40-3.50 (m, 1H), 3.14 (m, 2H), 2.10 (m, 1H),
2.00 (m, 1H), 1.80-1.95 (m, 5H), 1.75 (m, 1H):
[0729] MS (+ve ESI): 564.3 (M+H).sup.+.
EXAMPLE 52
Preparation of Compound 52 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{4-[(2-hydroxyethyl)(isobutyl)amino]butoxy-
}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0730] An analogous reaction to that described in example 51, but
starting with 2-(isobutyl amino)ethanol (117 mg, 0.75 mmol) yielded
compound 52 in table 3 as a yellow solid (88 mg, 60% yield):
[0731] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.65 (m, 1H), 7.33-7.38 (m, 3H), 6.89 (m, 1H), 6.85 (s, 1H), 4.26
(m, 2H), 4.01 (s, 3H), 3.86 (s, 2H), 3.79 (m, 2H), 3.23-3.29 (m,
2H), 3.09 (m, 1H), 2.98 (m, 1H), 2.10 (m, 1H), 1.91 (m, 4H), 0.99
(d, 6H):
[0732] MS (+ve ESI): 580.2 (M+H).sup.+.
EXAMPLE 53
Preparation of Compound 53 in Table
3--2-{3-[(7-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-6-metho-
xyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide
[0733] An analogous reaction to that described in example 3, but
starting with
3-[(7-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-6-methox-
yquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic acid (450 mg, 0.9
mmol) yielded compound 53 in table 3 (130 mg, 24% yield)
[0734] .sup.1H-NMR (DMSO d.sub.6): 10.45 (s, 1H), 10.18 (s, 1H),
8.45 (s, 1H), 7.95 (s, 1H), 7.62 (d, 1H), 7.36 (m, 2H), 7.14 (s,
1H), 6.90 (m, 1H), 6.73 (s, 1H), 4.06 (m, 1H), 3.93 (m, 4H), 3.73
(s, 2H), 3.40 (m, 2H), 3.00 (m, 4H), 2.36 (m, 2H), 1.75 (m, 3H),
1.11 (s, 9H)
[0735] MS (+ve ESI): 592.2 (M+H).sup.+.
[0736]
3-[(7-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-6-metho-
xyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic acid used as
starting material was obtained as follows
[0737] a) A solution of
N'-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamide
(3.00 g, 13.7 mmol) in dichloromethane (30 ml) was reacted with
tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (3.03 g,
15 mmol) in the presence of triphenylphosphine (5.38 g, 20.5 mmol)
and diethyl azodicarboxylate (3.23 ml, 20.5 mmol). The mixture was
stirred at ambient temperature for 2 hours, the solvent was
evaporated, and the residue purified by chromatography on silica
gel. Elution with ethyl acetate:petroleum ether (2:8) then (1:1)
yielded tert-butyl
(2R)-2-[(4-cyano-5-{[(1E)(dimethylamino)methylene]amino}-2-methoxyphenoxy-
)methyl]pyrrolidine-1-carboxylate (5.4 g, 99% yield):
[0738] .sup.1H-NMR (DMSO d.sub.6): 7.88-8.00 (m, 1H), 6.92-7.10 (m,
1H), 6.73 (s, 1H), 4.08 (m, 2H), 3.98 (m, 1H), 3.73 (s, 3H), 3.26
(m, 2H), 3.05 (s, 3H), 2.95 (s, 3H), 1.99 (m, 2H), 1.96 (m, 2H),
1.41 (s, 9H):
[0739] MS (+ve ESI): 403.3 (M+H).sup.+.
[0740] b) tert-butyl
(2R)-2-[(4-cyano-5-{[(1E)-(dimethylamino)methylene]amino}-2-methoxyphenox-
y)methyl]pyrrolidine-1-carboxylate (5.4 g, 13 mmol) was reacted
with a mixture of dichloromethane/trifluoroacetic acid (5:1) at
ambient temperature for 14 hours. The solvent was evaporated, and
the residue purified by chromatography on silica gel, eluting with
dichloromethane:methanol (9:1) then dichloromethane:methanolic
ammonia (9:1), to yield
N'-{2-cyano-4-methoxy-5-[(2R)-pyrrolidin-2-ylmethoxy]phenyl}-N,N-dimethyl-
imidoformamide (1.5 g, 35% yield):
[0741] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.56 (s, 1H), 7.57 (s, 1H),
7.36 (s, 1H), 4.40 (m, 1H), 4.21 (m, 1H), 4.05 (m, 1H), 3.90 (s,
3H), 3.27 (m, 2H), 3.39 (s, 3H), 3.29 (s, 3H), 2.20 (m, 1H), 2.02
(m, 1H), 1.95 (m, 1H), 1.75 (m, 1H)
[0742] MS (+ve ESI): 330.2 (M+H).sup.+.
[0743] c)
N'-{2-cyano-4-methoxy-5-[(2R)-pyrrolidin-2-ylmethoxy]phenyl}-N,N-
-dimethylimidoformamide (1.23 g, 4.06 mmol) in dimethylformamide
(13 ml) was reacted with 2-(2-bromoethoxy)-2-methylpropane (809 mg,
4.47 mmol) in the presence of potassium carbonate (842 mg, 6.1
mmol) at 50.degree. C. for 5 hours. The solvent was then
evaporated, and the residue purified by chromatography on silica
gel, eluting with dichloromethane:methanol (98:2) then (95:5), to
yield
N'-(5-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-2-cyano-4-met-
hoxyphenyl)-N,N-dimethylimidoformamide (908 mg, 56% yield):
[0744] .sup.1H-NMR (DMSO d.sub.6): 7.91 (s, 1H), 7.07 (s, 1H), 6.74
(s, 1H), 3.97 (m, 1H), 3.84 (m, 1H), 3.72 (s, 3H), 3.39 (m, 2H),
2.92 (m, 2H), 2.50 (m, 1H), 2.31 (m, 1H), 1.91 (m, 1H), 1.68 (m,
2H), 1.57 (m, 1H), 1.11 (s, 9H)
[0745] MS (+ve ESI): 403.25 (M+H).sup.+.
[0746] d)
N'-(5-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-2-cy-
ano-4-methoxyphenyl)-N,N-dimethylimidoformamide (300 mg, 0.74 mmol)
in acetic acid (0.64 ml) was reacted with
(3-amino-1H-pyrazol-5-yl)acetic acid (110 mg, 0.78 mmol) at
120.degree. C. for 20 minutes. The solvent was evaporated, and the
residue triturated with dichloromethane to yield
{3-[(7-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-6-methoxyqui-
nazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic acid (183 mg, 47%
yield):
[0747] .sup.1H-NMR (DMSO d.sub.6): 10.25 (s, 1H), 8.44 (s, 1H),
7.97 (s, 1H), 7.13 (s, 1H), 6.65 (s, 1H), 4.06 (m, 1H), 3.93 (m,
4H), 3.64 (s, 2H), 3.40 (m, 2H), 3.05 (m, 4H), 2.36 (m, 2H), 1.75
(m, 3H), 1.11 (s, 9H):
[0748] MS (+ve ESI): 499.17 (M+H).sup.+.
EXAMPLE 54
Preparation of Compound 54 in Table
3--N-(3-fluorophenyl)-2-{3-[(7-{[(2R)-1-(2-hydroxyethyl)pyrrolidin-2-yl]m-
ethoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0749]
2-{3-[(7-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-6-me-
thoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide
(120 mg, 0.2 mmol) was reacted with a mixture of
dichloromethane/trifluoroacetic acid (5:2) at ambient temperature
for 18 hours. The solvent was evaporated in vacuo and the residue
purified by chromatography on silica gel, eluting with
dichloromethane:methanol (9:1) then dichloromethane:methanolic
ammonia (95:5), to yield compound 54 in table 3 (40 mg, 37%
yield):
[0750] .sup.1H-NMR (DMSO d.sub.6): 11.00 (s, 1H), 10.33 (s, 1H),
8.45 (s, 1H), 7.99 (s, 1H), 7.62 (d, 1H), 7.34 (m, 2H), 7.15 (s,
1H), 6.89 (t, 1H), 6.83 (s, 1H), 4.40 (s, 1H), 4.07 (s, 1H), 3.93
(m, 4H), 3.76 (s, 2H), 3.50 (s, 2H), 3.09 (m, 1H), 2.97 (m, 2H),
2.31 (m, 1H), 1.94 (m, 1H), 1.73 (m, 2H), 1.65 (m, 1H):
[0751] MS (+ve ESI): 536.2 (M+H).sup.+.
EXAMPLE 55
Preparation of Compound 55 in Table
3--N-(3,5-difluorophenyl)-2-(3-{[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)qu-
inazolin-4-yl]amino}-1H-pyrazol-5-yl)acetamide
[0752] An analogous reaction to that described in example 7, but
starting with
2-(5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazo-
l-3-yl)-N-(3,5-difluorophenyl)acetamide (130 mg, 0.26 mmol) and
pyrrolidine (71 mg, 1 mmol) yielded compound 55 in table 3 (24 mg,
17% yield):
[0753] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.25-7.45 (m, 3H), 6.91 (m, 1H), 6.84 (s, 1H), 4.30 (m, 2H), 4.01
(s, 3H), 3.86 (s, 2H), 3.60-3.75 (m, 2H), 3.30-3.45 (m, 2H),
3.00-3.15 (m, 2H), 2.20-2.32 (m, 2H), 2.00-2.15 (m, 2H), 1.80-2.00
(m, 2H):
[0754] MS (+ve ESI): 538.5 (M+H).sup.+.
EXAMPLE 56
Preparation of Compound 56 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)amino]propoxy}-6-m-
ethoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0755] An analogous reaction to that described in example 55 but
starting with ethanolamine (61 mg, 1 mmol) yielded compound 56 in
table 3 (50 mg, 36% yield):
[0756] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.36 (d, 1H), 7.35 (d, 1H), 7.31 (s, 1H), 6.92 (t, 1H), 6.83 (s,
1H), 4.30 (t, 2H), 4.01 (s, 3H), 3.86 (s, 2H), 3.69 (t, 2H), 3.16
(m, 2H), 3.09 (m, 2H), 2.23 (m, 2H):
[0757] MS (+ve ESI): 528.5 (M+H).sup.+.
EXAMPLE 57
Preparation of Compound 57 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxy-1,1-dimethylethyl)amino-
]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0758] An analogous reaction to that described in example 55, but
starting with 2-amino-2-methyl-1-propanol (89 mg, 1 mmol) yielded
compound 57 in table 3 (50 mg, 35% yield):
[0759] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.37 (d, 1H), 7.35 (d, 1H), 7.33 (s, 1H), 6.91 (t, 1H), 6.84 (s,
1H), 4.32 (t, 2H), 4.01 (s, 3H), 3.86 (s, 2H), 3.46 (s, 2H), 3.10
(m, 2H), 2.22 (m, 2H), 1.25 (s, 6H):
[0760] MS (+ve ESI): 556.5 (M+H).sup.+.
EXAMPLE 58
Preparation of Compound 58 in Table
3--N-(3,5-difluorophenyl)-2-[3-({6-methoxy-7-[3-(4-methylpiperazin-1-yl)p-
ropoxy]quinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetamide
[0761] An analogous reaction to that described in example 55, but
starting with 1-methylpiperazine (100 mg, 1 mmol) yielded compound
58 in table 3 (60 mg, 41% yield)
[0762] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.37 (d, 1H), 7.35 (s, 1H), 7.34 (d, 1H), 6.91 (t, 1H), 6.84 (s,
1H), 4.31 (t, 1H), 4.01 (s, 3H), 3.86 (s, 2H), 3.20-3.95 (m, 8H),
3.44 (t, 2H), 2.95 (s, 3H), 2.30 (m, 2H)
[0763] MS (+ve ESI): 567.5 (M+H).sup.+.
EXAMPLE 59
Preparation of Compound 59 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy-
}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0764] An analogous reaction to that described in example 55, but
starting with 2-(ethylamino)ethanol (89 mg, 1 mmol) yielded
compound 59 in table 3 (124 mg, 86% yield):
[0765] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.35 (m, 2H), 7.33 (s, 1H), 6.90 (m, 1H), 6.84 (s, 1H), 4.30 (m,
2H), 4.01 (s, 3H), 3.86 (s, 2H), 3.78 (t, 2H), 3.30 (m, 6H), 2.29
(m, 2H), 1.27 (t, 3H):
[0766] MS (+ve ESI): 556.5 (M+H).sup.+.
EXAMPLE 60
Preparation of Compound 60 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[2-(2-hydroxyethyl)piperidin-1-yl]p-
ropoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0767] An analogous reaction to that described in example 55, but
starting with 2-(2-hydroxyethyl)piperidine (129 mg, 1 mmol) yielded
compound 60 in table 3 (58 mg, 37% yield):
[0768] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.36 (m, 3H), 6.95 (t, 1H), 6.90 (s, 1H), 4.30 (m, 2H), 4.00 (s,
3H), 3.85 (s, 2H), 3.10-3.70 (m, 7H), 2.25 (m, 2H), 1.80 (m, 6H),
1.50 (m, 2H):
[0769] MS (+ve ESI): 596.6 (M+H).sup.+.
EXAMPLE 61
Preparation of Compound 61 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperazin-1-yl]p-
ropoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0770] An analogous reaction to that described in example 55, but
starting with 2-piperazin-1-ylethanol (130 mg, 1 mmol) yielded
compound 61 in table 3 (80 mg, 52% yield):
[0771] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.36 (m, 3H), 6.95 (t, 1H), 6.83 (s, 1H), 4.31 (m, 2H), 4.00 (s,
3H), 3.86 (s, 2H), 3.30-3.90 (m, 14H), 2.30 (m, 2H):
[0772] MS (+ve ESI): 597.5 (M+H).sup.+.
EXAMPLE 62
Preparation of Compound 62 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperidin-1-yl]p-
ropoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0773] An analogous reaction to that described in example 55, but
starting with 4-(2-hydroxyethyl)piperidine (129 mg, 1 mmol) yielded
compound 62 in table 3 (67 mg, 43% yield):
[0774] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.45 (s, 1H), 8.00 (s, 1H),
7.37 (m, 2H), 7.14 (s, 1H), 6.95 (m, 1H), 6.84 (s, 1H), 4.34 (t,
1H), 4.17 (m, 2H), 3.94 (s, 3H), 3.79 (s, 2H), 3.45 (m, 2H), 2.88
(m, 2H), 2.40 (t, 2H), 1.90 (m, 4H), 1.62 (d, 2H), 1.36 (m, 3H),
1.15 (m, 2H):
[0775] MS (+ve ESI): 596.6 (M+H).sup.+.
EXAMPLE 63
Preparation of Compound 63 in Table
3--N-(3,5-difluorophenyl)-2-[3-({7-[3-(3-hydroxypiperidin-1-yl)propoxy]-6-
-methoxyquinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetamide
[0776] An analogous reaction to that described in example 55, but
starting with piperidin-3-ol (101 mg, 1 mmol) yielded compound 63
in table 3 (105 mg, 71% yield):
[0777] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.29 (s, 1H),
7.97 (m, 3H), 6.92 (t, 1H), 6.86 (s, 1H), 4.30 (m, 2H), 4.00 (s,
3H), 3.86 (s, 2H), 2.80-3.60 (m, 6H), 1.70-2.30 (m, 2H):
[0778] MS (+ve ESI): 568.5 (M+H).sup.+.
EXAMPLE 64
Preparation of Compound 64 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxybutyl)amino]propoxy}-6-m-
ethoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0779] An analogous reaction to that described in example 55, but
starting with 1-aminobutan-2-ol (89 mg, 1 mmol) yielded compound 64
in table 3 (80 mg, 55% yield):
[0780] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.29 (s, 1H),
7.37 (m, 3H), 6.90 (t, 1H), 6.83 (s, 1H), 4.30 (m, 2H), 4.00 (s,
3H), 3.85 (s, 2H), 3.70 (m, 1H), 2.80-3.20 (m, 4H), 2.25 (m, 2H),
1.45 (m, 2H), 0.90 (t, 3H):
[0781] MS (+ve ESI): 556.5 (M+H).sup.+.
EXAMPLE 65
Preparation of Compound 65 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]pr-
opoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0782] An analogous reaction to that described in example 55, but
starting with 4-(hydroxymethyl)piperidine (115 mg, 1 mmol) yielded
compound 65 in table 3 (54 mg, 35% yield):
[0783] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.29 (s, 1H),
7.37 (m, 3H), 6.92 (t, 1H), 6.83 (s, 1H), 4.30 (t, 2H), 4.00 (s,
3H), 3.86 (s, 2H), 3.61 (d, 2H), 3.30 (m, 4H), 3.00 (t, 2H), 2.30
(m, 2H), 1.90 (d, 2H), 1.65 (m, 1H), 1.40 (m, 2H)
[0784] MS (+ve ESI): 582.6 (M+H).sup.+.
EXAMPLE 66
Preparation of Compound 66 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(3-hydroxy-2,2-dimethylpropyl)amin-
o]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0785] An analogous reaction to that described in example 55, but
starting with 3-amino-2,2-dimethylpropan-1-ol (103 mg, 1 mmol)
yielded compound 66 in table 3 (53 mg, 36% yield):
[0786] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.29 (s, 1H),
7.36 (m, 3H), 6.92 (t, 1H), 6.83 (s, 1H), 4.30 (t, 2H), 4.00 (s,
3H), 3.85 (s, 2H), 3.28 (s, 2H), 3.16 (m, 2H), 2.91 (s, 2H), 2.26
(m, 2H), 0.94 (s, 6H):
[0787] MS (+ve ESI): 570.6 (M+H).sup.+.
EXAMPLE 67
Preparation of Compound 67 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-
-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0788] An analogous reaction to that described in example 55, but
starting with D-prolinol (101 mg, 1 mmol) yielded compound 67 in
table 3 (83 mg, 56% yield):
[0789] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.30-7.40 (m, 3H), 6.85-6.95 (m, 1H), 6.84 (s, 1H), 4.30 (m, 2H),
4.01 (s, 3H), 3.86 (s, 2H), 3.72-3.82 (m, 1H), 3.50-3.70 (m, 4H),
3.15-3.30 (m, 2H), 2.25-2.40 (m, 2H), 1.95-2.20 (m, 2H), 1.85-1.95
(m, 1H), 1.70-1.85 (m, 1H):
[0790] MS (+ve ESI): 568.5 (M+H).sup.+.
EXAMPLE 68
Preparation of Compound 68 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-
-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0791] An analogous reaction to that described in example 55, but
starting with L-prolinol (101 mg, 1 mmol) yielded compound 68 in
table 3 (85 mg, 57% yield):
[0792] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.30-7.40 (m, 3H), 6.85-6.95 (m, 1H), 6.84 (s, 1H), 4.30 (m, 2H),
4.01 (s, 3H), 3.86 (s, 2H), 3.72-3.82 (m, 1H), 3.50-3.70 (m, 4H),
3.15-3.30 (m, 2H), 2.25-2.40 (m, 2H), 1.95-2.20 (m, 2H), 1.85-1.95
(m, 1H), 1.70-1.85 (m, 1H):
[0793] MS (+ve ESI): 568.5 (M+H).sup.+.
EXAMPLE 69
Preparation of Compound 69 in Table
3--N-(3,5-difluorophenyl)-2-(3-{[7-(3-{[(2S)-2-hydroxypropyl]amino}propox-
y)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetamide
[0794] An analogous reaction to that described in example 55, but
starting with (S)-(+)-1-aminopropan-2-ol (75 mg, 1 mmol) yielded
compound 69 in table 3 (67 mg, 48% yield):
[0795] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.29 (s, 1H),
7.36 (m, 3H), 6.90 (t, 1H), 6.84 (s, 1H), 4.31 (t, 2H), 4.01 (s,
3H), 3.95 (m, 1H), 3.86 (s, 2H), 3.16 (m, 2H), 3.07 (m, 1H), 2.85
(m, 1H), 2.25 (m, 2H), 1.15 (d, 3H):
[0796] MS (+ve ESI): 542.5 (M+H).sup.+.
EXAMPLE 70
Preparation of Compound 70 in Table
3--N-(3,5-difluorophenyl)-2-(3-{[7-(3-{[(2R)-2-hydroxypropyl]amino}propox-
y)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetamide
[0797] An analogous reaction to that described in example 55, but
starting with (R)-(-)-1-aminopropan-2-ol (75 mg, 1 mmol) yielded
compound 70 in table 3 (52 mg, 37% yield):
[0798] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.29 (s, 1H),
7.36 (m, 3H), 6.91 (t, 1H), 6.83 (s, 1H), 4.29 (t, 2H), 4.00 (s,
3H), 3.95 (m, 1H), 3.85 (s, 2H), 3.15 (m, 2H), 3.07 (m, 1H), 2.85
(m, 1H), 2.25 (m, 2H), 1.15 (d, 3H):
[0799] MS (+ve ESI): 542.5 (M+H).sup.+.
EXAMPLE 71
Preparation of Compound 71 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(3S)-3-hydroxypyrrolidin-1-yl]prop-
oxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0800] An analogous reaction to that described in example 55, but
starting with (S)-(-)-3-hydroxypyrrolidine (87 mg, 1 mmol) yielded
compound 71 in table 3 (76 mg, 53% yield)
[0801] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.29 (s, 1H),
7.34 (m, 3H), 6.91 (t, 1H), 6.83 (s, 1H), 4.45 (m, 1H), 4.30 (m,
2H), 4.00 (s, 3H), 3.86 (s, 2H), 3.00-3.80 (m, 6H), 2.25 (m, 2H),
1.95 (m, 2H):
[0802] MS (+ve ESI): 554.5 (M+H).sup.+.
EXAMPLE 72
Preparation of Compound 72 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(3R)-3-hydroxypyrrolidin-1-yl]prop-
oxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0803] An analogous reaction to that described in example 55, but
starting with (R)-(+)-3-hydroxypyrrolidine (87 mg, 1 mmol) yielded
compound 72 in table 3 (76 mg, 53% yield):
[0804] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.29 (s, 1H),
7.35 (m, 3H), 6.90 (t, 1H), 6.84 (s, 1H), 4.45 (m, 1H), 4.30 (m,
2H), 4.01 (s, 3H), 3.86 (s, 2H), 3.00-3.80 (m, 6H), 2.25 (m, 2H),
1.95 (m, 2H):
[0805] MS (+ve ESI): 554.5 (M+H).sup.+.
EXAMPLE 73
Preparation of Compound 73 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]pr-
opoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0806]
2-(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyraz-
ol-5-yl)-N-(3,5-difluorophenyl)acetamide (2 g, 4 mmol) in
1-methyl-2-pyrrolidinone (20 ml) was reacted with potassium iodide
(1.33 g, 8 mmol) and 2-(isobutylamino)ethanol (1.88 g, 16 mmol)
under argon, at 60.degree. C. for 8 hours. The solvent was
evaporated, and the residue purified by chromatography on silica
gel, eluting with dichloromethane:methanol (95:5) then
dichloromethane:methanolic ammonia (95:5), to yield compound 73 in
table 3 (1.05 g, 45% yield):
[0807] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.35 (d, 2H), 7.34 (s, 1H), 6.92 (t, 1H), 6.83 (s, 1H), 4.30 (m,
2H), 4.00 (s, 3H), 3.86 (s, 2H), 3.82 (t, 2H), 3.89 (m, 2H), 3.29
(m, 2H), 2.17-2.98 (m, 2H), 2.30 (m, 2H), 2.13 (m, 1H), 1.01 (d,
6H):
[0808] MS (+ve ESI): 584.3 (M+H).sup.+.
EXAMPLE 74
Preparation of Compound 74 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]prop-
oxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0809] An analogous reaction to that described in example 73, but
starting with 2-(propylamino)ethanol (1.83 ml, 16 mmol) yielded
compound 74 in table 3 (900 mg, 39% yield):
[0810] .sup.1H-NMR (DMSO d.sub.6): 10.63 (s, 1H), 10.17 (s, 1H),
8.46 (s, 1H), 8.00 (s, 1H), 7.36 (d, 2H), 7.14 (s, 1H), 6.94 (t,
1H), 6.85 (s, 1H), 4.35 (br s, 1H), 4.20 (t, 2H), 3.95 (s, 3H),
3.79 (s, 2H), 3.46 (m, 2H), 2.63 (m, 2H), 2.52 (m, 2H), 2.42 (m,
2H), 1.92 (m, 2H), 1.42 (m, 2H), 0.83 (t, 3H):
[0811] MS (+ve ESI): 570.3 (M+H).sup.+.
EXAMPLE 75
Preparation of Compound 75 in Table
3--2-{3-[(7-{3-[allyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-
-yl)amino]-1H-pyrazol-5-yl}-N-(3,5-difluorophenyl)acetamide
[0812] An analogous reaction to that described in example 73, but
starting with 2-(allylamino)ethanol (101 mg, 1 mmol) in
dimethylacetamide (1.4 ml) at 110.degree. C. for 2.5 hours yielded
compound 75 in table 3 (52 mg, 33% yield):
[0813] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.35 (m, 2H), 7.32 (s, 1H), 6.91 (m, 1H), 6.84 (s, 1H), 5.90-6.10
(m, 1H), 5.50-5.75 (m, 2H), 4.30 (m, 2H), 4.00 (s, 3H), 3.86-4.00
(m, 2H), 3.86 (s, 2H), 3.79 (m, 2H), 3.20-3.40 (m, 4H), 2.20-2.40
(m, 2H):
[0814] MS (+ve ESI): 568.2 (M+H).sup.+.
EXAMPLE 76
Preparation of Compound 76 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-1-yl)am-
ino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0815] An analogous reaction to that described in example 73, but
starting with 2-(prop-2-yn-1-ylamino)ethanol (99 mg, 1 mmol) and
heating at 105.degree. C. for 12 hours yielded compound 76 in table
3 (50 mg, 31% yield):
[0816] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.34 (m, 2H), 7.31 (s, 1H), 6.91 (m, 1H), 6.83 (s, 1H), 4.29 (m,
4H), 4.00 (s, 3H), 3.89 (m, 1H), 3.86 (s, 2H), 3.80 (m, 2H), 3.43
(m, 2H), 3.36 (m, 2H), 2.30 (m, 2H):
[0817] MS (+ve ESI): 566.2 (M+H).sup.+.
EXAMPLE 77
Preparation of Compound 77 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isopropyl)amino]p-
ropoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0818] An analogous reaction to that described in example 73, but
starting with 2-(isopropylamino)ethanol (130 mg, 1 mmol) and
heating at 105.degree. C. for 12 hours and 125.degree. C. for 8
hours, yielded compound 77 in table 3 (40 mg, 25% yield):
[0819] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.30-7.40 (m, 3H), 6.89 (m, 1H), 6.84 (s, 1H), 4.30 (m, 2H), 4.00
(s, 3H), 3.86 (s, 2H), 3.76 (m, 2H), 3.35 (m, 4H), 3.18 (m, 1H),
2.30 (m, 2H), 1.30 (m, 6H):
[0820] MS (+ve ESI): 570.3 (M+H).sup.+.
EXAMPLE 78
Preparation of Compound 78 in Table
3--N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2,2-dimethylpropyl)(2-hydroxyethy-
l)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0821] An analogous reaction to that described in example 73, but
starting with 2-((2,2-dimethylpropyl)amino)ethanol (131 mg, 1 mmol)
and heating at 130.degree. C. for 2 hours, yielded compound 78 in
table 3 (42 mg, 25% yield):
[0822] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.30-7.40 (m, 3H), 6.88 (m, 1H), 6.83 (s, 1H), 4.30 (m, 2H), 3.99
(s, 3H), 3.85 (s, 2H), 3.78-3.85 (m, 2H), 3.40 (m, 2H), 3.30 (m,
2H), 3.22 (m, 1H), 3.12 (m, 1H), 2.30 (m, 2H):
[0823] MS (+ve ESI): 598.2 (M+H).sup.+.
EXAMPLE 79
Preparation of Compound 79 in Table
3--2-{3-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazo-
lin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3,5-difluorophenyl)acetamide
[0824] An analogous reaction to that described in example 73, but
starting with 2-(cyclobutylamino)ethanol (115 mg, 1 mmol) and
heating at 80.degree. C. for 6 hours in the presence of potassium
iodide (93 mg, 0.56 mmol), yielded compound 79 in table 3 (33 mg,
20% yield):
[0825] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.35 (m, 2H), 7.32 (s, 1H), 6.88 (m, 1H), 6.83 (s, 1H), 4.29 (m,
2H), 4.00 (s, 3H), 3.87-3.99 (m, 1H), 3.86 (s, 2H), 3.72 (m, 2H),
3.35 (m, 2H), 3.15 (m, 2H), 2.30 (m, 2H), 2.20 (m, 4H), 1.85 (m,
2H):
[0826] MS (+ve ESI): 582.3 (M+H).sup.+.
EXAMPLE 80
Preparation of Compound 80 in Table
3--2-{3-[(7-{3-[(cyclopropylmethyl)(2-hydroxyethyl)amino]propoxy}-6-metho-
xyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3,5-difluorophenyl)acetamide
[0827] An analogous reaction to that described in example 79, but
starting with 2-((cyclopropylmethyl)amino)ethanol (115 mg, 1 mmol)
yielded compound 80 in table 3 (33 mg, 20% yield):
[0828] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.30 (s, 1H),
7.35 (m, 2H), 7.33 (s, 1H), 6.88 (m, 1H), 6.84 (s, 1H), 4.30 (m,
2H), 4.00 (s, 3H), 3.86 (s, 2H), 3.80 (s, 2H), 3.20-3.45 (m, 4H),
3.15 (m, 2H), 2.30 (m, 2H), 1.12 (m, 1H), 0.68 (m, 2H), 0.42 (m,
2H):
[0829] MS (+ve ESI): 582.3 (M+H).sup.+.
EXAMPLE 81
Preparation of Compound 81 in Table
3--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-
-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0830] An analogous reaction to that described in example 73, but
starting with L-prolinol (1.3 ml, 13.17 mmol) and
2-(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-y-
l)-N-(2,3-difluorophenyl)acetamide (1.63 g, 3.24 mmol) yielded
compound 81 in table 3 (1.64 g, 89% yield):
[0831] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.74 (m, 1H), 7.33 (s, 1H), 7.19 (t, 2H), 6.84 (s, 1H), 4.31 (t,
2H), 4.01 (s, 3H), 3.94 (s, 2H), 3.77 (q, 1H), 3.64 (m, 4H), 3.22
(m, 2H), 2.30 (m, 2H), 2.14 (m, 1H), 2.03 (m, 1H), 1.90 (m, 1H),
1.78 (m, 1H):
[0832] MS (+ve ESI): 568.3 (M+H).sup.+.
EXAMPLE 82
Preparation of Compound 82 in Table
3--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2,2-dimethylpropyl)(2-hydroxyethy-
l)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0833] An analogous reaction to that described in example 81, but
starting with 2-((2,2-dimethylpropyl)amino)ethanol (131 mg, 1 mmol)
in dimethylacetamide at 70.degree. C. for 10 hours yielded compound
82 in table 3 (64 mg, 33% yield):
[0834] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.74 (m, 1H), 7.35 (s, 1H), 7.19 (m, 2H), 6.84 (s, 1H), 4.31 (m,
2H), 3.99 (s, 3H), 3.94 (s, 2H), 3.84 (m, 2H), 3.42 (m, 2H), 3.3
(m, 2H), 3.22 (d, 1H), 3.15 (d, 1H), 3.13 (m, 2H), 2.35 (m, 2H),
1.09 (s, 9H):
[0835] MS (+ve ESI): 598.3 (M+H).sup.+.
EXAMPLE 83
Preparation of Compound 83 in Table
3--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]prop-
oxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0836] An analogous reaction to that described in example 81, but
starting with 2-(propylamino)ethanol (700 mg, 68 mmol) and heating
at 85.degree. C. for 5 hours, yielded compound 83 in table 3 as an
off-white solid (650 mg, 67% yield):
[0837] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.75 (m, 1H), 7.33 (s, 1H), 7.18-7.22 (m, 2H), 6.84 (s, 1H), 4.30
(m, 2H), 4.00 (s, 3H), 3.94 (s, 2H), 3.78 (m, 2H), 3.30-3.45 (m,
2H), 3.28 (m, 2H), 3.15-3.20 (m, 2H), 2.28 (m, 2H), 1.73 (m, 2H),
0.95 (t, 3H)
[0838] MS (+ve ESI): 570.3 (M+H).sup.+.
EXAMPLE 84
Preparation of Compound 84 in Table
3--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]pr-
opoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0839] An analogous reaction to that described in example 81, but
starting with 2-(isobutylamino)ethanol (936 mg, 80 mmol) and
heating at 90.degree. C. for 3.5 hours, yielded compound 84 in
table 3 as an off-white solid (810 mg, 69% yield):
[0840] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.45 (m, 1H), 7.34 (s, 1H), 7.21 (m, 2H), 6.84 (s, 1H), 4.31 (m,
2H), 4.00 (s, 3H), 3.95 (s, 2H), 3.81 (m, 2H), 3.36 (m, 2H), 3.30
(m, 2H), 3.12 (m, 1H), 3.06 (m, 1H), 2.31 (m, 2H), 2.13 (m, 1H),
1.01 (d, 6H):
[0841] MS (+ve ESI): 584.3 (M+H).sup.+.
EXAMPLE 85
Preparation of Compound 85 in Table
3--2-{3-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazo-
lin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide
[0842] An analogous reaction to that described in example 81, but
starting with 2-(cyclobutylamino)ethanol (117 mg, 1 mmol) and
potassium iodide (103 mg, 0.62 mmol) in dimethylacetamide (2 ml) at
95.degree. C. for 4 hours under argon yielded compound 85 in table
3 (97 mg, 56% yield):
[0843] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.92 (s, 1H), 8.27 (s, 1H),
7.74 (m, 1H), 7.29 (s, 1H), 7.15-7.20 (m, 2H), 6.83 (s, 1H), 4.30
(m, 2H), 3.98 (s, 3H), 3.98 (m, 3H), 3.68-3.80 (m, 2H), 3.20-3.30
(m, 2H), 3.15 (m, 2H), 2.30 (m, 2H), 2.22 (m, 4H), 1.65-1.82 (m,
2H):
[0844] MS (+ve ESI): 582.2 (M+H).sup.+.
EXAMPLE 86
Preparation of Compound 86 in Table
3--2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinaz-
olin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide
[0845] An analogous reaction to that described in example 85, but
starting with 2-(cyclopentylamino)ethanol (129 mg, 1 mmol) yielded
compound 86 in table 3 (86 mg, 48% yield):
[0846] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.93 (s, 1H), 8.28 (s, 1H),
7.73 (m, 1H), 7.30 (s, 1H), 7.14 (m, 2H), 6.83 (s, 1H), 4.29 (m,
2H), 3.98 (s, 3H), 3.93 (s, 2H), 3.78 (m, 3H), 3.37 (m, 2H), 3.26
(m, 2H), 2.30 (m, 2H), 2.09 (m, 2H), 1.74 (m, 4H), 1.72 (m,
2H):
[0847] MS (+ve ESI): 596.2 (M+H).sup.+.
EXAMPLE 87
Preparation of Compound 87 in Table
3--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-
-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0848] An analogous reaction to that described in example 81, but
starting with (2R)-pyrrolidin-2-ylmethanol (101 mg, 1 mmol) yielded
compound 87 in table 3 (134 mg, 79% yield):
[0849] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.75 (m, 1H), 7.32 (s, 1H), 7.16 (m, 2H), 6.84 (s, 1H), 4.30 (m,
2H), 4.00 (s, 3H), 3.94 (s, 2H), 3.70-3.85 (m, 1H), 3.52-3.70 (m,
4H), 3.15-3.30 (m, 2H), 2.25 (m, 2H), 1.75-2.20 (m, 4H):
[0850] MS (+ve ESI): 568.2 (M+H).sup.+.
EXAMPLE 88
Preparation of Compound 88 in Table
3--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-1-yl)am-
ino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0851] An analogous reaction to that described in example 81, but
starting with 2-(prop-2-yn-1-ylamino)ethanol (99 mg, 1 mmol)
yielded compound 88 in table 3 (128 mg, 75% yield):
[0852] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.74 (m, 1H), 7.31 (s, 1H), 7.18 (m, 2H), 6.83 (s, 1H), 4.30 (m,
4H), 4.00 (s, 3H), 3.94 (s, 2H), 3.87 (m, 1H), 3.80 (m, 2H), 3.44
(m, 2H), 3.35 (m, 2H), 2.30 (m, 2H)
[0853] MS (+ve ESI): 566.2 (M+H).sup.+.
EXAMPLE 89
Preparation of Compound 89 in Table
3--2-{3-[(7-{3-[(cyclopropylmethyl)(2-hydroxyethyl)amino]propoxy}-6-metho-
xyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide
[0854] An analogous reaction to that described in example 81, but
starting with 2-(cyclopropylmethyl)amino)ethanol (115 mg, 1 mmol)
yielded compound 89 in table 3 (6 mg, 3% yield):
[0855] .sup.1H-NMR (DMSO d.sub.6): 10.23 (s, 1H), 10.16 (s, 1H),
8.44 (s, 1H), 7.98 (s, 1H), 7.72 (m, 1H), 7.18 (m, 2H), 7.14 (s,
1H), 6.84 (s, 1H), 4.32 (s, 1H), 4.18 (t, 2H), 3.93 (s, 3H), 3.85
(s, 2H), 3.45 (m, 2H), 2.69 (t, 2H), 2.58 (t, 2H), 2.35 (d, 2H),
1.90 (m, 2H), 0.83 (m, 1H), 0.41 (m, 2H), 0.08 (m, 2H):
[0856] MS (+ve ESI): 582.2 (M+H).sup.+.
EXAMPLE 90
Preparation of Compound 90 in Table
3--2-{3-[(7-{3-[(cyclobutylmethyl)(2-hydroxyethyl)amino]propoxy}-6-methox-
yquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide
[0857] An analogous reaction to that described in example 81, but
starting with 2-((cyclobutylmethyl)amino)ethanol (129 mg, 1 mmol)
yielded compound 90 in table 3 (134 mg, 75% yield):
[0858] .sup.1H-NMR (DMSO d.sub.6): 8.49 (s, 1H), 8.00 (s, 1H),
7.70-7.78 (m, 1H), 7.15-7.30 (m, 3H), 6.75 (m, 1H), 4.25 (m, 2H),
3.96 (s, 3H), 3.86 (s, 2H), 3.60-3.80 (m, 2H), 3.00-3.40 (m, 4H),
2.50-2.80 (m, 4H), 1.61-2.40 (m, 7H):
[0859] MS (+ve ESI): 596.2 (M+H).sup.+.
EXAMPLE 91
Preparation of Compound 91 in Table
3--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2,2-dimethoxyethyl)(2-hydroxyethy-
l)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0860] An analogous reaction to that described in example 81, but
starting with 2-((2,2-dimethoxyethyl)amino)ethanol (149 mg, 1 mmol)
yielded compound 91 in table 3 (94 mg, 51% yield):
[0861] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.70-7.80 (m, 1H), 7.32 (s, 1H), 7.17 (m, 2H), 6.84 (s, 1H), 4.85
(t, 1H), 4.30 (m, 2H), 4.00 (s, 3H), 3.94 (s, 2H), 3.81 (m, 2H),
3.30-3.55 (m, 10H), 2.30 (m, 2H):
[0862] MS (+ve ESI): 616.2 (M+H).sup.+.
EXAMPLE 92
Preparation of Compound 92 in Table
3--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperidin-1-yl]p-
ropoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0863] An analogous reaction to that described in example 81, but
starting with 4-(2-hydroxyethyl)piperidine (129 mg, 1 mmol) yielded
compound 92 in table 3 (113 mg, 63% yield):
[0864] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 8.28 (s, 1H),
7.73 (m, 1H), 7.31 (s, 1H), 7.10-7.20 (m, 2H), 6.83 (s, 1H), 4.30
(m, 2H), 3.99 (s, 3H), 3.93 (s, 2H), 3.56 (d, 2H), 3.47 (m, 2H),
3.26 (m, 2H), 2.96 (m, 2H), 2.30 (m, 2H), 1.75-1.95 (m, 2H),
1.60-1.75 (m, 1H), 1.30-1.45 (m, 4H):
[0865] MS (+ve ESI): 596.2 (M+H).sup.+.
EXAMPLE 93
Preparation of Compound 93 in Table
3--N-(2,3-difluorophenyl)-2-[3-({7-[3-(4-hydroxypiperidin-1-yl)propoxy]-6-
-methoxyquinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetamide
[0866] An analogous reaction to that described in example 81, but
starting with piperidin-4-ol (101 mg, 1 mmol) yielded compound 93
in table 3 (146 mg, 86% yield):
[0867] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.73 (m, 1H), 7.32 (s, 1H), 7.19 (m, 2H), 6.84 (s, 1H), 4.30 (m,
2H), 4.00 (s, 3H), 3.94 (s, 2H), 3.70-3.80 (m, 1H), 3.55-3.70 (m,
2H), 3.35-3.45 (m, 1H), 3.25-3.35 (m, 2H), 2.95-3.10 (m, 1H), 2.30
(m, 2H), 1.95-2.05 (m, 1H), 1.75-1.95 (m, 2H), 1.55-1.70 (m,
1H):
[0868] MS (+ve ESI): 568.2 (M+H).sup.+.
EXAMPLE 94
Preparation of Compound 94 in Table
3--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperazin-1-yl]p-
ropoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0869] An analogous reaction to that described in example 81, but
starting with 2-piperazin-1-ylethanol (130 mg, 1 mmol) yielded
compound 94 in table 3 (52 mg, 29% yield):
[0870] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.30 (s, 1H),
7.72 (m, 2H), 7.32 (s, 1H), 7.17 (m, 2H), 6.84 (s, 1H), 4.33 (m,
2H), 4.00 (s, 3H), 3.94 (s, 2H), 3.78 (m, 2H), 3.45-3.78 (m, 8H),
3.44 (m, 2H), 3.37 (m, 2H), 2.30 (m, 2H):
[0871] MS (+ve ESI): 597.2 (M+H).sup.+.
EXAMPLE 95
Preparation of Compound 95 in Table
3--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(2-methoxyethyl)am-
ino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0872] An analogous reaction to that described in example 81, but
starting with 2-((2-methoxyethyl)amino)ethanol (119 mg, 1 mmol)
yielded compound 95 in table 3 (124 mg, 71% yield):
[0873] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.97 (s, 1H), 8.31 (s, 1H),
7.76 (m, 1H), 7.33 (s, 1H), 7.19 (m, 2H), 6.85 (s, 1H), 4.31 (t,
2H), 4.02 (s, 3H), 3.95 (s, 2H), 3.80 (t, 2H), 3.73 (t, 2H), 3.45
(m, 4H), 3.36 (m, 5H), 2.31 (m, 2H):
[0874] MS (+ve ESI): 586.2 (M+H).sup.+.
EXAMPLE 96
Preparation of Compound 96 in Table
3--2-{3-[(7-{3-[allyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-
-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide
[0875] An analogous reaction to that described in example 81, but
starting with 2-(allylamino)ethanol (101 mg, 1 mmol) yielded
compound 96 in table 3 (99 mg, 58% yield):
[0876] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.97 (s, 1H), 8.32 (s, 1H),
7.77 (m, 1H), 7.33 (s, 1H), 7.18 (m, 2H), 6.87 (s, 1H), 6.01 (m,
1H), 5.60 (m, 2H), 4.31 (t, 2H), 4.02 (s, 3H), 3.94 (m, 4H), 3.82
(t, 2H), 3.35 (m, 4H), 2.34 (m, 2H):
[0877] MS (+ve ESI): 568.2 (M+H).sup.+.
EXAMPLE 97
Preparation of Compound 97 in Table
3--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(1,3-dioxolan-2-ylmethyl)(2-hydrox-
yethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acet-
amide
[0878] An analogous reaction to that described in example 81, but
starting with 2-((1,3-dioxolan-2-ylmethyl)amino)ethanol (147 mg, 1
mmol) yielded compound 97 in table 3 (126 mg, 68% yield):
[0879] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 8.29 (s, 1H),
7.75 (m, 1H), 7.31 (s, 1H), 7.16 (m, 2H), 6.83 (s, 1H), 5.30 (m,
1H), 4.30 (m, 2H), 4.01 (m, 5H), 3.99 (s, 2H), 3.93 (m, 2H), 3.89
(m, 2H), 3.45 (m, 6H), 2.30 (m, 2H):
[0880] MS (+ve ESI): 614.2 (M+H).sup.+.
EXAMPLE 98
Preparation of Compound 98 in Table
3--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy-
}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0881] An analogous reaction to that described in example 81, but
starting with 2-(ethylamino)ethanol (89 mg, 1 mmol) yielded
compound 98 in table 3 (94 mg, 56% yield):
[0882] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 8.29 (s, 1H),
7.75 (m, 1H), 7.31 (s, 1H), 7.15 (m, 2H), 6.83 (s, 1H), 4.31 (m,
2H), 3.99 (s, 3H), 3.93 (s, 2H), 3.76 (m, 2H), 3.30 (m, 6H), 2.26
(m, 2H), 1.25 (t, 3H):
[0883] MS (+ve ESI): 556.2 (M+H).sup.+.
EXAMPLE 99
Preparation of Compound 99 in Table
3--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isopropyl)amino]p-
ropoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0884] An analogous reaction to that described in example 81, but
starting with 2-(isopropylamino)ethanol (103 mg, 1 mmol) yielded
compound 99 in table 3 (84 mg, 49% yield):
[0885] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.97 (s, 1H), 8.33 (s, 1H),
7.79 (m, 1H), 7.35 (s, 1H), 7.18 (m, 2H), 6.88 (s, 1H), 4.34 (t,
2H), 4.03 (s, 3H), 3.98 (s, 2H), 3.81 (m, 3H), 3.40 (m, 3H), 3.20
(m, 1H), 2.35 (m, 2H), 1.33 (m, 6H)
[0886] MS (+ve ESI): 570.2 (M+H).sup.+.
EXAMPLE 100
Preparation of Compound 100 in Table
3--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxy-1,1-dimethylethyl)amino-
]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0887] An analogous reaction to that described in example 81, but
starting with 2-amino-2-methylpropan-1-ol (101 mg, 1 mmol) yielded
compound 100 in table 3 (165 mg, 99% yield):
[0888] .sup.1H-NMR (DMSO d.sub.6): 8.48 (s, 1H), 7.99 (s, 1H), 7.72
(m, 1H), 7.22 (m, 4H), 4.25 (t, 2H), 3.95 (s, 3H), 3.85 (s, 2H),
3.35 (m, 2H), 2.95 (m, 2H), 2.10 (m, 2H), 1.16 (s, 6H):
[0889] MS (+ve ESI): 556.2 (M+H).sup.+.
EXAMPLE 101
Preparation of Compound 101 in Table
3--N-(2,3-difluorophenyl)-2-{3-[(7-{[(2R)-1-(2-hydroxyethyl)pyrrolidin-2--
yl]methoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0890] An analogous reaction to that described in example 54, but
starting with
2-{3-[(7-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-6-met-
hoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamid-
e (67 mg, 0.11 mmol) yielded compound 101 in table 3 (36 mg, 59%
yield):
[0891] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.98 (s, 1H), 8.35 (s, 1H),
7.76 (m, 1H), 7.36 (s, 1H), 7.19 (m, 2H), 6.87 (s, 1H), 4.62 (m,
1H), 4.50 (m, 1H), 4.20 (m, 1H), 4.04 (s, 3H), 3.96 (s, 2H), 3.81
(m, 2H), 3.73 (m, 2H), 3.33 (m, 2H), 2.34 (m, 1H), 2.11 (m, 2H),
1.91 (m, 1H):
[0892] MS (+ve ESI): 554.1 (M+H).sup.+.
[0893]
2-{3-[(7-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-6-me-
thoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetami-
de use as starting material was obtained as follows:
[0894] An analogous reaction to that described in example 5, but
starting with
{3-[(7-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-6-metho-
xyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic acid (240 mg, 0.48
mmol) yielded
2-{3-[(7-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-6--
methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)aceta-
mide (72 mg, 25% yield):
[0895] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.98 (s, 1H), 8.34 (s, 1H),
7.75 (m, 1H), 7.35 (s, 1H), 7.19 (m, 2H), 6.85 (s, 1H), 4.62 (m,
1H), 4.50 (m, 1H), 4.20 (m, 1H), 4.03 (s, 3H), 3.95 (s, 2H), 3.72
(m, 4H), 3.40 (m, 2H), 2.34 (m, 1H), 2.11 (m, 2H), 1.91 (m, 1H),
1.20 (s, 9H):
[0896] MS (+ve ESI): 610.2 (M+H).sup.+.
EXAMPLE 102
Preparation of Compound 102 in Table
3--N-(3-chlorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-
propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0897] An analogous reaction to that described in example 7, but
starting with
2-(5-((7-(3-chloropropoxy)-6-methoxy-quinazolin-4-yl)amino)-1H-pyraz-
ol-3-yl)-N-(3-chlorophenyl)acetamide (100 mg, 0.2 mmol) and
L-prolinol (71 mg, 0.7 mmol) yielded compound 102 in table 3 (73
mg, 64% yield):
[0898] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.86 (m, 1H), 7.40-7.50 (m, 1H), 7.30-7.40 (m, 2H), 7.10-7.15 (m,
1H), 6.83 (s, 1H), 4.30 (m, 2H), 4.00 (s, 3H), 3.84 (s, 2H),
3.70-3.80 (m, 1H), 3.47-3.70 (m, 4H), 3.12-3.35 (m, 2H), 2.20-2.40
(m, 2H), 1.97-2.20 (m, 2H), 1.85-1.97 (m, 1H), 1.70-1.85 (m,
1H):
[0899] MS (+ve ESI): 566.5 (M+H).sup.+.
EXAMPLE 103
Preparation of Compound 103 in Table
3--N-(3-chlorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]-
propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0900] An analogous reaction to that described in example 102, but
starting with D-prolinol (71 mg, 0.7 mmol) yielded compound 103 in
table 3 (75 mg, 66% yield):
[0901] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 8.29 (s, 1H),
7.86 (s, 1H), 7.48 (m, 1H), 7.34 (m, 2H), 7.12 (m, 1H), 6.82 (s,
1H), 4.30 (m, 2H), 3.99 (s, 3H), 3.83 (s, 2H), 3.76 (m, 1H), 3.60
(m, 4H), 3.20 (m, 2H), 2.30 (m, 2H), 1.95 (m, 4H):
[0902] MS (+ve ESI): 566.5 (M+H).sup.+.
EXAMPLE 104
Preparation of Compound 104 in Table
3--N-(3-chlorophenyl)-2-[3-({7-[3-(3-hydroxypiperidin-1-yl)propoxy]-6-met-
hoxyquinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetamide
[0903] An analogous reaction to that described in example 102, but
starting with piperidin-3-ol (71 mg, 0.7 mmol) yielded compound 104
in table 3 (82 mg, 72% yield):
[0904] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 8.29 (s, 1H),
7.86 (s, 1H), 7.47 (m, 1H), 7.34 (m, 2H), 7.12 (m, 1H), 6.82 (s,
1H), 4.28 (m, 2H), 4.09 (m, 0.5H), 3.99 (s, 3H), 3.83 (s, 2H), 3.70
(m, 0.5H), 2.60-3.55 (m, 6H), 1.15-3.40 (m, 6H):
[0905] MS (+ve ESI): 566.5 (M+H).sup.+.
EXAMPLE 105
Preparation of Compound 105 in Table
3--N-(3-chlorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6--
methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0906] An analogous reaction to that described in example 102, but
starting with 2-(ethylamino)ethanol (78 mg, 0.87 mmol) yielded
compound 105 in table 3 (72 mg, 52% yield):
[0907] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.86 (m, 1H), 7.45-7.52 (m, 1H), 7.25-7.30 (m, 2H), 7.08-7.15 (m,
1H), 6.83 (s, 1H), 4.29 (m, 2H), 4.00 (s, 3H), 3.84 (s, 2H),
3.70-3.82 (m, 2H), 3.20-3.45 (m, 6H), 2.20-2.35 (m, 2H), 1.26 (t,
3H)
[0908] MS (+ve ESI): 554.5 (M+H).sup.+.
EXAMPLE 106
Preparation of Compound 106 in Table
4--2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazo-
lin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-methoxyphenyl)acetamide
[0909]
{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinaz-
olin-4-yl)amino]-1H-pyrazol-5-yl}acetic acid (118 mg, 0.25 mmol) in
dimethylformamide (1.2 ml) was reacted with 3-methoxyaniline (46
mg, 0.37 mmol) in the presence of
1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (81
mg, 0.42 mmol), 2-hydroxypyridin-1-oxide (42 mg, 0.37 mmol) at
55.degree. C. for 2 hours. The solvent was evaporated, and the
residue purified by preparative LCMS to yield compound 106 in table
4 (50 mg, 35% yield):
[0910] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.35 (m, 2H), 7.23 (t, 1H), 7.16 (d, 1H), 6.83 (s, 1H), 6.66 (m,
1H), 4.30 (t, 2H), 4.01 (s, 3H), 3.82 (s, 2H), 3.74 (s, 3H), 3.60
(d, 2H), 3.30 (m, 4H), 2.98 (t, 2H), 2.28 (m, 2H), 1.87 (d, 2H),
1.65 (m, 1H), 1.44 (m, 2H):
[0911] MS (+ve ESI): 576.6 (M+H).sup.+.
[0912]
{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinaz-
olin-4-yl)amino]-1H-pyrazol-5-yl}acetic acid used as starting
material was obtained as follows:
[0913]
(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-
-5-yl)acetic acid (7.83 g, 20 mmol) in dimethylacetamide (30 ml)
was reacted with 4-(hydroxymethyl)piperidine (8.05 g, 70 mmol) at
100.degree. C. for 2 hours. The solvent was evaporated, and the
residue triturated with a mixture of dichloromethane: ethyl acetate
(1:1). The paste was recovered, and dissolved in a mixture of
dichloromethane: methanol. Ethanolic HCl (7.0 N) (10 ml, 70 mmol)
was added to the mixture and the solvents were evaporated. Methanol
(200 ml) was added to the solid and the mixture was stirred for 0.5
hour. The reaction mixture was reduced in volume and
dichloromethane added. The resultant solid was recovered by
filtration and dried to yield
{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-4-
-yl)amino]-1H-pyrazol-5-yl}acetic acid (6.5 g, 60% yield) as a
yellow solid:
[0914] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.31 (s, 1H),
7.37 (s, 1H), 6.80 (s, 1H), 4.31 (m, 2H), 4.00 (s, 3H), 3.75 (s,
2H), 3.59 (d, 2H), 3.24-3.30 (m, 4H), 2.97 (t, 2H), 2.35 (m, 2H),
1.86-1.91 (m, 2H), 1.68 (m, 1H), 1.47 (m, 2H).
EXAMPLE 107
Preparation of Compound 107 in Table
4--2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazo-
lin-4-yl)amino]-1H-pyrazol-5-yl}-N-phenylacetamide
[0915] An analogous reaction to that described in example 106, but
starting with aniline (35 mg, 0.37 mmol) yielded compound 107 in
table 4 (106 mg, 75% yield):
[0916] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 8.29 (s, 1H),
7.63 (d, 2H), 7.31 (t, 3H), 7.05 (t, 1H), 6.83 (s, 1H), 4.27 (t,
2H), 3.99 (s, 3H), 3.82 (s, 2H), 3.60 (d, 2H), 3.30 (m, 4H), 2.97
(t, 2H), 2.27 (m, 2H), 1.89 (d, 2H), 1.65 (m, 1H), 1.44 (m,
2H):
[0917] MS (+ve ESI): 546.5 (M+H).sup.+.
EXAMPLE 108
Preparation of Compound 108 in Table
4--N-(4-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propox-
y}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0918] An analogous reaction to that described in example 106, but
starting with 4-fluoroaniline (42 mg, 0.37 mmol) yielded compound
108 in table 4 (127 mg, 88% yield)
[0919] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 8.29 (s, 1H),
7.65 (m, 2H), 7.31 (s, 1H), 7.14 (t, 2H), 6.82 (s, 1H), 4.27 (t,
2H), 3.99 (s, 3H), 3.82 (s, 2H), 3.60 (d, 2H), 3.30 (m, 4H), 2.97
(t, 2H), 2.27 (m, 2H), 1.89 (d, 2H), 1.65 (m, 1H), 1.44 (m, 2H)
[0920] MS (+ve ESI): 564.5 (M+H).sup.+.
EXAMPLE 109
Preparation of Compound 109 in Table
4--N-(3,5-dichlorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]pr-
opoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0921] An analogous reaction to that described in example 106, but
starting with 3,5-dichloroaniline (62 mg, 0.37 mmol) yielded
compound 109 in table 4 (46 mg, 28% yield):
[0922] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.30 (s, 1H),
7.70 (m, 2H), 7.33 (s, 1H), 7.27 (s, 1H), 6.84 (s, 1H), 4.27 (t,
2H), 3.99 (s, 3H), 3.82 (s, 2H), 3.60 (d, 2H), 3.30 (m, 4H), 2.97
(t, 2H), 2.27 (m, 2H), 1.89 (d, 2H), 1.65 (m, 1H), 1.44 (m, 2H)
[0923] MS (+ve ESI): 614.4 (M+H).sup.+.
EXAMPLE 110
Preparation of Compound 110 in Table
4--N-(5-chloro-2-methoxyphenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-
-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0924] An analogous reaction to that described in example 106, but
starting with 5-chloro-2-methoxyaniline (60 mg, 0.37 mmol) yielded
compound 110 in table 4 (65 mg, 41% yield)
[0925] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
8.15 (s, 1H), 7.32 (s, 1H), 7.08 (m, 2H), 6.81 (s, 1H), 4.27 (t,
2H), 3.99 (s, 3H), 3.82 (s, 2H), 3.60 (d, 2H), 3.30 (m, 4H), 2.97
(t, 2H), 2.27 (m, 2H), 1.69 (d, 2H), 1.65 (m, 1H), 1.44 (m, 2H)
[0926] MS (+ve ESI): 610.5 (M+H).sup.+.
EXAMPLE 111
Preparation of Compound III in Table
4--2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazo-
lin-4-yl)amino]-1H-pyrazol-5-yl}-N-[3-(trifluoromethyl)phenyl]acetamide
[0927] An analogous reaction to that described in example 106, but
starting with 3-trifluoromethylaniline (61 mg, 0.37 mmol) yielded
compound III in table 4 (75 mg, 47% yield):
[0928] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
8.14 (s, 1H), 7.80 (d, 1H), 7.52 (t, 1H), 7.40 (d, 1H), 7.31 (s,
1H), 6.85 (s, 1H), 4.29 (t, 2H), 4.00 (s, 3H), 3.87 (s, 2H), 3.60
(d, 2H), 3.30 (m, 4H), 2.97 (t, 2H), 2.27 (m, 2H), 1.89 (d, 2H),
1.65 (m, 1H), 1.44 (m, 2H):
[0929] MS (+ve ESI): 614.5 (M+H).sup.+.
EXAMPLE 112
Preparation of Compound 112 in Table
4--2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazo-
lin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-hydroxyphenyl)acetamide
[0930] An analogous reaction to that described in example 106, but
starting with 3-hydroxyaniline (41 mg, 0.37 mmol) yielded compound
112 in table 4 (118 mg, 82% yield):
[0931] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.31 (s, 1H), 7.21 (s, 1H), 7.07 (t, 1H), 7.01 (d, 1H), 6.81 (s,
1H), 6.45 (d, 1H), 4.28 (t, 2H), 3.99 (s, 3H), 3.79 (s, 2H), 3.58
(d, 2H), 3.30 (m, 4H), 2.97 (t, 2H), 2.27 (m, 2H), 1.89 (d, 2H),
1.65 (m, 1H), 1.44 (m, 2H):
[0932] MS (+ve ESI): 562.5 (M+H).sup.+.
EXAMPLE 113
Preparation of Compound 113 in Table
4--2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazo-
lin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-nitrophenyl)acetamide
[0933] An analogous reaction to that described in example 106, but
starting with 3-nitroaniline (52 mg, 0.37 mmol) yielded compound
113 in table 4 (62 mg, 40% yield):
[0934] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.70 (s, 1H),
8.30 (s, 1H), 7.94 (d, 2H), 7.62 (t, 1H), 7.32 (s, 1H), 6.86 (s,
1H), 4.29 (t, 2H), 4.00 (s, 3H), 3.79 (s, 2H), 3.58 (d, 2H), 3.30
(d, 2H), 2.97 (t, 2H), 2.27 (m, 2H), 1.89 (d, 2H), 1.65 (m, 1H),
1.44 (m, 2H):
[0935] MS (+ve ESI): 591.5 (M+H).sup.+.
EXAMPLE 114
Preparation of Compound 114 in Table
4--2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazo-
lin-4-yl)amino]-1H-pyrazol-5-yl}-N-1H-indazol-5-ylacetamide
[0936] An analogous reaction to that described in example 106, but
starting with 1H-indazol-5-amine (51 mg, 0.37 mmol) yielded
compound 114 in table 4 (95 mg, 63% yield):
[0937] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 8.29 (s, 1H),
8.18 (s, 1H), 8.03 (s, 1H), 7.50 (m, 2H), 7.35 (s, 1H), 6.84 (s,
1H), 4.28 (t, 2H), 3.99 (s, 3H), 3.83 (s, 2H), 3.60 (d, 2H), 3.30
(m, 4H), 2.97 (t, 2H), 2.27 (m, 2H), 1.89 (d, 2H), 1.65 (m, 1H),
1.44 (m, 2H):
[0938] MS (+ve ESI): 586.5 (M+H).sup.+.
EXAMPLE 115
Preparation of Compound 115 in Table
4--N-(4-bromo-2-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-y-
l]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0939] An analogous reaction to that described in example 106, but
starting with 4-bromo-2-fluoroaniline (72 mg, 0.37 mmol) yielded
compound 115 in table 4 (28 mg, 16% yield):
[0940] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 8.28 (s, 1H),
7.95 (t, 1H), 7.53 (m, 1H), 7.35 (d, 1H), 7.31 (s, 1H), 6.82 (s,
1H), 4.28 (t, 2H), 3.99 (s, 3H), 3.92 (s, 2H), 3.60 (d, 2H), 3.30
(m, 4H), 2.97 (t, 2H), 2.27 (m, 2H), 1.89 (d, 2H), 1.65 (m, 1H),
1.44 (m, 2H):
[0941] MS (+ve ESI): 644.4 (M+H).sup.+.
EXAMPLE 116
Preparation of compound 116 in table
4--N-(3-chlorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propox-
y}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0942] An analogous reaction to that described in example 106, but
starting with 3-chloroaniline (48 mg, 0.37 mmol) yielded compound
116 in table 4 (96 mg, 64% yield):
[0943] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.30 (s, 1H),
7.86 (s, 1H), 7.48 (d, 1H), 7.34 (m, 2H), 7.13 (d, 1H), 6.84 (s,
1H), 4.28 (t, 2H), 4.00 (s, 3H), 3.84 (s, 2H), 3.60 (d, 2H), 3.30
(m, 4H), 2.97 (t, 2H), 2.27 (m, 2H), 1.89 (d, 2H), 1.65 (m, 1H),
1.44 (m, 2H):
[0944] MS (+ve ESI): 580.5 (M+H).sup.+.
EXAMPLE 117
Preparation of Compound 117 in Table
4--N-(2-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propox-
y}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0945] An analogous reaction to that described in example 106, but
starting with 2-fluoroaniline (42 mg, 0.37 mmol) yielded compound
117 in table 4 (74 mg, 50% yield):
[0946] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.94 (m, 1H), 7.33 (s, 1H), 7.26 (m, 1H), 7.16 (m, 2H), 6.83 (s,
1H), 4.28 (t, 2H), 4.00 (s, 3H), 3.92 (s, 2H), 3.60 (d, 2H), 3.30
(m, 4H), 2.97 (t, 2H), 2.27 (m, 2H), 1.89 (d, 2H), 1.65 (m, 1H),
1.44 (m, 2H):
[0947] MS (+ve ESI): 564.5 (M+H).sup.+.
EXAMPLE 118
Preparation of compound 118 in table
4--N-(3,5-dimethoxyphenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]p-
ropoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0948] An analogous reaction to that described in example 106, but
starting with 3,5-dimethoxyaniline (58 mg, 0.37 mmol) yielded
compound 118 in table 4 (89 mg, 57% yield):
[0949] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.31 (s, 1H), 6.89 (m, 2H), 6.82 (s, 1H), 6.24 (m, 1H), 4.29 (t,
2H), 4.00 (s, 3H), 3.80 (s, 2H), 3.71 (s, 6H), 3.60 (m, 2H), 3.30
(m, 4H), 3.00 (t, 2H), 2.30 (m, 2H), 1.90 (m, 2H), 1.65 (m, 1H),
1.40 (m, 2H):
[0950] MS (+ve ESI): 606.5 (M+H).sup.+.
EXAMPLE 119
Preparation of Compound 119 in Table
4--2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazo-
lin-4-yl)amino]-1H-pyrazol-5-yl}-N-(5-methylpyridin-2-yl)acetamide
[0951] An analogous reaction to that described in example 106, but
starting with 2-amino-5-picoline (41 mg, 0.37 mmol) yielded
compound 119 in table 4 (89 mg, 62% yield):
[0952] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 8.29 (s, 1H),
8.26 (s, 1H), 8.05 (m, 1H), 7.75 (m, 1H), 7.35 (s, 1H), 6.87 (s,
1H), 4.29 (t, 2H), 4.00 (m, 5H), 3.60 (d, 2H), 3.30 (m, 4H), 3.00
(t, 2H), 2.34 (s, 3H), 2.30 (m, 2H), 1.90 (m, 2H), 1.65 (m, 1H),
1.40 (m, 2H):
[0953] MS (+ve ESI): 561.6 (M+H).sup.+.
EXAMPLE 120
Preparation of Compound 120 in Table
4--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]pr-
opoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0954] An analogous reaction to that described in example 81, but
starting with 4-(hydroxymethyl)piperidine (115 mg, 1 mmol) yielded
compound 120 in table 4 (138 mg, 79% yield):
[0955] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.75 (m, 1H), 7.32 (s, 1H), 7.17 (m, 2H), 6.83 (s, 1H), 4.29 (m,
2H), 4.00 (s, 3H), 3.93 (s, 2H), 3.60 (d, 2H), 3.30 (m, 4H), 3.00
(t, 2H), 2.30 (m, 2H), 1.90 (m, 2H), 1.70 (m, 1H), 1.40 (m,
2H):
[0956] MS (+ve ESI): 582.2 (M+H).sup.+.
EXAMPLE 121
Preparation of Compound 121 in Table
4--N-(3-chloro-2-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1--
yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0957] An analogous reaction to that described in example 106, but
starting with 3-chloro-2-fluoroaniline (55 mg, 0.37 mmol) yielded
compound 121 in table 4 (16 mg, 9% yield):
[0958] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.29 (s, 1H),
7.89 (m, 1H), 7.32 (m, 2H), 7.21 (m, 1H), 6.83 (s, 1H), 4.29 (m,
2H), 4.00 (s, 3H), 3.93 (s, 2H), 3.59 (d, 2H), 3.30 (m, 4H), 2.97
(m, 2H), 2.30 (m, 2H), 1.86 (m, 2H), 1.68 (m, 1H), 1.40 (m,
2H):
[0959] MS (+ve ESI): 598.5 (M+H).sup.+.
EXAMPLE 122
Preparation of Compound 122 in Table
4--N-(2,5-difluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]pr-
opoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0960] An analogous reaction to that described in example 106, but
starting with 2,5-difluoroaniline (49 mg, 0.37 mmol) yielded
compound 122 in table 4 (15 mg, 8% yield):
[0961] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 8.29 (s, 1H),
7.95 (m, 1H), 7.25-7.40 (m, 1H), 7.32 (s, 1H), 6.95 (m, 1H), 4.31
(m, 2H), 4.00 (s, 3H), 3.93 (s, 2H), 3.59 (d, 2H), 3.30 (m, 4H),
2.97 (t, 2H), 2.30 (m, 2H), 1.86 (m, 2H), 1.65 (m, 1H), 1.43 (m,
2H):
[0962] MS (+ve ESI): 582.5 (M+H).sup.+.
EXAMPLE 123
Preparation of Compound 123 in Table
4--N-[2-fluoro-5-(trifluoromethyl)phenyl]-2-{3-[(7-{3-[4-(hydroxymethyl)p-
iperidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}ace-
tamide
[0963] An analogous reaction to that described in example 106, but
starting with 2-fluoro-5-trifluoromethylaniline (68 mg, 0.37 mmol)
yielded compound 123 in table 4 (6 mg, 1% yield):
[0964] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 8.48 (d, 1H),
8.30 (s, 1H), 7.52 (s, 1H), 7.50 (m, 1H), 7.31 (s, 1H), 6.84 (s,
1H), 4.30 (m, 2H), 3.99 (s, 3H), 3.98 (s, 2H), 3.60 (m, 2H),
3.20-3.35 (m, 4H), 2.98 (m, 2H), 2.30 (m, 2H), 1.88 (m, 2H), 1.67
(m, 1H), 1.42 (m, 2H):
[0965] MS (+ve ESI): 632.5 (M+H).sup.+.
EXAMPLE 124
Preparation of Compound 124 in Table
4--N-(3,4-difluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]pr-
opoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0966] An analogous reaction to that described in example 106, but
starting with 3,4-difluoroaniline (49 mg, 0.37 mmol) yielded
compound 124 in table 4 (85 mg, 56% yield):
[0967] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.30 (s, 1H),
7.83 (m, 1H), 7.35 (m, 2H), 7.33 (s, 1H), 6.84 (s, 1H), 4.30 (m,
2H), 4.00 (s, 3H), 3.84 (s, 2H), 3.60 (d, 2H), 3.30 (m, 4H), 2.98
(t, 2H), 2.31 (m, 2H), 1.87 (m, 2H), 1.68 (m, 1H), 1.44 (m,
2H):
[0968] MS (+ve ESI): 582.5 (M+H).sup.+.
EXAMPLE 125
Preparation of Compound 125 in Table
4--N-(2,4-difluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]pr-
opoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0969] An analogous reaction to that described in example 106, but
starting with 2,4-difluoroaniline (49 mg, 0.37 mmol) yielded
compound 125 in table 4 (62 mg, 41% yield):
[0970] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.96 (s, 1H), 8.30 (s, 1H),
7.88 (m, 1H), 7.33 (s, 1H), 7.29 (m, 1H), 7.06 (m, 1H), 6.84 (s,
1H), 4.30 (m, 2H), 4.00 (s, 3H), 3.90 (s, 2H), 3.61 (d, 2H), 3.31
(m, 2H), 3.28 (m, 2H), 3.00 (t, 2H), 2.31 (m, 2H), 1.87 (m, 2H),
1.65 (m, 1H), 1.42 (m, 2H)
[0971] MS (+ve ESI): 582.5 (M+H).sup.+.
EXAMPLE 126
Preparation of Compound 126 in Table
4--N-(3-chloro-4-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1--
yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0972] An analogous reaction to that described in example 106, but
starting with 3-chloro-4-fluoroaniline (55 mg, 0.37 mmol) yielded
compound 126 in table 4 (84 mg, 54% yield):
[0973] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.30 (s, 1H),
7.97 (m, 1H), 7.49 (m, 1H), 7.35 (t, 1H), 7.32 (s, 1H), 6.84 (s,
1H), 4.30 (m, 2H), 4.00 (s, 3H), 3.84 (s, 2H), 3.61 (d, 2H), 3.30
(m, 2H), 3.27 (m, 2H), 2.98 (t, 2H), 2.30 (m, 2H), 1.87 (m, 2H),
1.68 (m, 1H), 1.45 (m, 2H):
[0974] MS (+ve ESI): 598.5 (M+H).sup.+.
EXAMPLE 127
Preparation of Compound 127 in Table
4--N-[2-(difluoromethoxy)phenyl]-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin--
1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0975] An analogous reaction to that described in example 106, but
starting with 2-difluoro-methoxyaniline (60 mg, 0.37 mmol) yielded
compound 127 in table 4 (49 mg, 30% yield):
[0976] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.93 (s, 1H), 8.29 (s, 1H),
7.95 (m, 1H), 7.31 (s, 1H), 7.10-7.30 (m, 3H), 6.84 (s, 1H), 4.3
(m, 2H), 3.99 (s, 3H), 3.92 (s, 2H), 3.59 (d, 2H), 3.20-3.30 (m,
4H), 2.97 (t, 2H), 2.26 (m, 2H), 1.86 (m, 2H), 1.65 (m, 1H), 1.42
(m, 2H):
[0977] MS (+ve ESI): 612.5 (M+H).sup.+.
EXAMPLE 128
Preparation of Compound 128 in Table
4--N-(3-cyanophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy-
}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0978] An analogous reaction to that described in example 106, but
starting with 3-cyanoaniline (45 mg, 0.37 mmol) yielded compound
128 in table 4 (65 mg, 43% yield):
[0979] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.93 (s, 1H), 8.28 (s, 1H),
8.14 (s, 1H), 7.81 (d, 1H), 7.51 (m, 2H), 7.30 (s, 1H), 6.84 (s,
1H), 4.28 (m, 2H), 3.99 (s, 3H), 3.86 (s, 2H), 3.59 (d, 2H),
3.20-3.35 (m, 4H), 2.96 (t, 2H), 2.30 (m, 2H), 1.88 (m, 2H), 1.68
(m, 1H), 1.44 (m, 2H):
[0980] MS (+ve ESI): 571.6 (M+H).sup.+.
EXAMPLE 129
Preparation of Compound 129 in Table
4--N-(3-bromophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy-
}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0981] An analogous reaction to that described in example 106, but
starting with 3-bromoaniline (65 mg, 0.37 mmol) yielded compound
129 in table 4 (62 mg, 32% yield):
[0982] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.95 (s, 1H), 8.30 (s, 1H),
8.00 (s, 1H), 7.52 (d, 1H), 7.32 (s, 1H), 7.26-7.31 (m, 2H), 6.84
(s, 1H), 4.29 (m, 2H), 4.00 (s, 3H), 3.84 (s, 2H), 3.60 (m, 2H),
3.20-3.35 (m, 4H), 2.98 (t, 2H), 2.30 (m, 2H), 1.87 (m, 2H), 1.65
(m, 1H), 1.44 (m, 2H):
[0983] MS (+ve ESI): 626.4 (M+H).sup.+.
EXAMPLE 130
Preparation of Compound 130 in Table
5--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy-
}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[0984]
2-(3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-
-(2,3-difluorophenyl)acetamide (300 mg, 0.634 mmol), potassium
iodide (210 mg, 1.27 mmol), dimethylamine (2 ml) and
2-(ethylamino)ethanol (226 mg, 2.54 mmol) were combined and heated
to 50.degree. C. for 72 hours. The reaction was diluted with
dichloromethane (20 ml) and loaded onto a 40S silica biotage
column. Elution with dichloromethane followed by increased polarity
to dichloromethane:methanol (9:1), then
dichloromethane:methanol:ammonia (9:1:0.8) yielded compound 130 in
table 5 as a pale pink solid (181 mg, 54% yield):
[0985] .sup.1H-NMR (DMSO d.sub.6): 12.35 (s, 1H), 10.25 (s, 2H),
8.52 (s, 2H), 7.71 (m, 1H), 7.16 (m, 4H), 6.78 (s, 1H), 4.33 (t,
1H), 4.17 (t, 2H), 3.84 (s, 2H), 3.43 (m, 2H), 2.60 (t, 2H), 2.49
(m, 4H), 1.88 (m, 2H), 0.96 (t, 3H):
[0986] MS (-ve ESI): 524 (M-H).sup.-,
[0987] MS (+ve ESI): 526 (M+H).sup.+.
[0988]
2-(3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-
-(2,3-difluorophenyl)acetamide, used as the starting material was
obtained as follows:
[0989] a) 2-Amino-4-fluorobenzoic acid (15 g, 96 mmol) was
dissolved in 2-methoxyethanol (97 ml). Formamidine acetate (20.13
g, 193.4 mmol) was added and the mixture heated to reflux for 18
hours. The reaction was cooled, concentrated and the residue
stirred in aqueous ammonium hydroxide (0.01 N, 250 ml) for 1 hour.
The suspension was filtered, washed with water and dried over
phosphorus pentoxide to yield 7-fluoroquinazolin-4(3H)-one as an
off-white solid (10.35 g, 65% yield):
[0990] .sup.1H-NMR (DMSO d.sub.6): 12.32 (br s, 1H), 8.19 (dd, 1H),
8.14 (s, 1H), 7.45 (dd, 1H), 7.39 (m, 1H):
[0991] MS (-ve ESI): 163 (M-H).sup.-,
[0992] MS (+ve ESI): 165 (M+H).sup.+.
[0993] b) Sodium hydride (14.6 g, 365 mmol) was added at 0.degree.
C. to a solution of 1,3-propanediol (27.8 g, 365 mmol) in
dimethylformamide (70 ml). 7-Fluoroquinazolin-4(3H)-one (10 g, 60.9
mmol) was added portionwise and the reaction mixture heated at
60.degree. C., then at 110.degree. C. for 3 hours. The reaction was
cooled to 0.degree. C., quenched with water (280 ml) and adjusted
to pH 5.9. The resulting suspension was filtered, washed with water
then ether and dried over phosphorus pentoxide to afford
7-(3-hydroxypropoxy)quinazolin-4(3H)-one as a white powder (12.41
g, 92% yield):
[0994] .sup.1H-NMR (DMSO d.sub.6): 11.90 (br s, 1H), 8.04 (s, 1H),
8.00 (d, 1H), 7.10 (m, 2H), 4.17 (t, 2H), 3.58 (t, 2H), 1.92 (m,
2H):
[0995] MS (+ve ESI): 221 (M+H).sup.+.
[0996] c) 7-(3-hydroxypropoxy)quinazolin-4(3H)-one (10.5 g, 47.7
mmol) and thionyl chloride (100 ml, 137 mmol) were combined.
Dimethylformamide (1 ml) was added and the reaction mixture heated
to 85.degree. C. for 1 hour. The mixture was cooled to room
temperature, diluted with toluene and evaporated to dryness. This
was repeated until all thionyl chloride was removed. The residue
was dissolved in dichloromethane and washed with a saturated sodium
bicarbonate solution. The aqueous layer was extracted with
dichloromethane. The organics were combined, dried (magnesium
sulphate) and concentrated to leave a yellow solid. Trituration
with ether removed a less soluble impurity and the ether filtrate
was concentrated to leave 4-chloro-7-(3-chloropropoxy)quinazoline
as an off-white solid (8.5 g, 70% yield):
[0997] .sup.1H-NMR (DMSO d.sub.6): 13.25 (br s, 1H), 8.34 (s, 1H),
8.06 (d, 1H), 7.17 (m, 2H), 4.21 (t, 2H), 3.83 (t, 2H), 2.23 (m,
2H):
[0998] MS (+ve ESI): 257, 259 (M+H).sup.+.
[0999] d) 4-chloro-7-(3-chloropropoxy)quinazoline (2.5 g, 9.72
mmol) and (3-amino-1H-pyrazol-5-yl)acetic acid (1.37 g, 9.72 mmol)
were combined in dimethylformamide (25 ml). A solution of 4M HCl in
dioxane (1.25 ml, 4.8 mmol) was added and the reaction heated to
90.degree. C. for 40 minutes. The solution was cooled to room
temperature, diluted with water (250 ml) and filtered through
celite. The acidic solution was basified to pH 4.9 and the yellow
powder filtered. (At pH 3, a red solid precipitated which was
isolated, suspended in water and basified to pH 12. Careful
adjustment back to pH 4.8 resulted in the precipitation of a yellow
powder, which was combined with the first crop). The solid was
washed with diethyl ether and dried over phosphorus pentoxide to
yield
(3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetic
acid as a pale orange solid (2.88 g, 82% yield):
[1000] .sup.1H-NMR (DMSO d.sub.6): 12.60 (br s, 2H), 10.78 (br s,
1H), 8.65 (s, 1H), 8.60 (d, 1H), 7.26 (d, 1H), 7.22 (s, 1H), 6.67
(s, 1H), 4.28 (t, 2H), 3.83 (t, 2H), 3.67 (s, 2H), 2.24 (m,
2H):
[1001] MS (-ve ESI): 360, 362 (M-H).sup.-,
[1002] MS (+ve ESI): 362, 364 (M+H).sup.+.
[1003] e) 2,3-difluoroaniline (1.15 g, 8.95 mmol) was added to a
suspension of
(3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetic
acid (2.70 g, 7.46 mmol) in pyridine (30 ml) and the reaction
cooled to 0.degree. C. Phosphorous oxychloride (1.14 g, 7.46 mmol)
was added dropwise and the reaction stirred at 0.degree. C. for 1
hour. The reaction was warmed to ambient temperature and more
phosphorous oxychloride (0.5 ml) added. The reaction was stirred
for 4.5 hours. The reaction mixture was diluted with ethyl
acetate:ether (100 ml:37 ml) and stirred for 18 hours. The
precipitate was filtered, suspended in water and neutralised with
ammonium hydroxide (7%, 15 ml). The resultant yellow suspension was
filtered, washed with water and dried (phosphorous pentoxide) to
yield
2-(3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(2,3--
difluorophenyl)acetamide as an orange powder (3.15 g, 89%
yield):
[1004] .sup.1H-NMR (DMSO d.sub.6): 10.64 (br s, 1H), 10.27 (s, 1H),
8.60 (s, 1H), 8.55 (d, 1H), 7.70 (m, 1H), 7.20 (m, 6H), 6.68 (s,
1H), 4.27 (t, 2H), 3.83 (m, 4H), 2.25 (m, 2H):
[1005] MS (-ve ESI): 471, 473 (M-H).sup.-,
[1006] MS (+ve ESI): 473, 475 (M+H).sup.+.
EXAMPLE 131
Preparation of Compound 131 in Table
5--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isopropyl)amino]p-
ropoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[1007] An analogous reaction to that described in example 130, but
starting with 2-(isopropylamino)ethanol (262 mg, 2.54 mmol) yielded
compound 131 in table 5 as a pink solid (182 mg, 53% yield):
[1008] .sup.1H-NMR (DMSO d.sub.6): 12.35 (s, 1H), 10.20 (s, 1H),
8.50 (s, 2H), 7.71 (m, 1H), 7.20 (m, 4H), 6.78 (s, 1H), 4.29 (br s,
1H), 4.19 (t, 2H), 3.85 (s, 2H), 3.38 (dt, 2H), 2.88 (m, 1H), 2.55
(t, 2H), 2.45 (t, 2H), 1.82 (m, 2H), 0.93 (d, 6H):
[1009] MS (-ve ESI): 538 (M-H).sup.-,
[1010] MS (+ve ESI): 540 (M+H).sup.+.
EXAMPLE 132
Preparation of Compound 132 in Table
5--N-(2,3-difluorophenyl)-2-[3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-
-yl]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl]acetamide
[1011] An analogous reaction to that described in example 130, but
starting with D-prolinol (257 mg, 2.54 mmol) yielded compound 132
in table 5 as a pink solid (206 mg, 60% yield):
[1012] .sup.1H-NMR (DMSO d.sub.6, AcOD): 11.60 (br s, 7H), 10.25
(s, 1H), 8.52 (m, 2H), 7.75 (m, 1H), 7.16 (m, 4H), 6.67 (s, 1H),
4.22 (t, 2H), 3.84 (s, 2H), 3.50 (d, 2H), 3.35 (m, 1H), 3.28 (m,
1H), 3.07 (m, 1H), 2.86 (m, 1H), 2.72 (m, 1H), 2.05 (m, 2H), 1.95
(m, 1H), 1.60-1.90 (m, 4H):
[1013] MS (-ve ESI): 536 (M-H).sup.-,
[1014] MS (+ve ESI): 538 (M+H).sup.+.
EXAMPLE 133
Preparation of Compound 133 in Table
5--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]prop-
oxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[1015] An analogous reaction to that described in example 130, but
starting with 2-(n-propylamino)ethanol (262 mg, 2.54 mmol) yielded
compound 133 in table 5 as a pink solid (168 mg, 49% yield):
[1016] .sup.1H-NMR (DMSO d.sub.6): 12.35 (s, 1H), 10.22 (s, 2H),
8.51 (s, 2H), 7.71 (m, 1H), 7.20 (m, 4H), 6.78 (s, 1H), 4.30 (t,
1H), 4.17 (t, 2H), 3.85 (s, 2H), 3.43 (m, 2H), 2.59 (t, 2H), 2.49
(m, 2H), 2.39 (t, 2H), 1.87 (m, 2H), 1.39 (m, 2H), 0.82 (t,
3H):
[1017] MS (-ve ESI): 538 (M-H).sup.-,
[1018] MS (+ve ESI): 540 (M+H).sup.+.
EXAMPLE 134
Preparation of Compound 134 in Table
5--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-1-yl)am-
ino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[1019] An analogous reaction to that described in example 130, but
starting with 2-(prop-2-yn-1-ylamino)ethanol (220 mg, 2.22 mmol)
yielded compound 134 in table 5 as a beige solid (162 mg, 48%
yield):
[1020] .sup.1H-NMR (DMSO d.sub.6): 12.40 (s, 1H), 10.22 (br s, 1H),
8.50 (s, 2H), 7.73 (m, 1H), 7.17 (m, 4H), 6.78 (br s, 1H), 4.52 (br
s, 1H), 4.17 (t, 2H), 3.84 (s, 2H), 3.49 (s, 4H), 3.17 (s, 1H),
2.70 (s, 2H), 2.60 (s, 2H), 1.93 (m, 2H):
[1021] MS (-ve ESI): 534 (M-H).sup.-,
[1022] MS (+ve ESI): 536 (M+H).sup.+.
EXAMPLE 135
Preparation of Compound 135 in Table
5--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]pr-
opoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[1023] An analogous reaction to that described in example 130, but
starting with 2-(isobutylamino)ethanol (260 mg, 2.22 mmol) yielded
compound 135 in table 5 as a beige solid (168 mg, 48% yield):
[1024] .sup.1H-NMR (DMSO d.sub.6): 12.35 (s, 1H), 10.28 (br s, 2H),
8.50 (s, 2H), 7.72 (m, 1H), 7.16 (m, 4H), 6.78 (s, 1H), 4.32 (s,
1H), 4.20 (t, 2H), 3.85 (s, 2H), 3.45 (m, 2H), 2.57 (br s, 2H),
2.48 (m, 2H), 2.16 (d, 2H), 1.89 (m, 2H), 1.66 (m, 1H), 0.83 (d,
6H):
[1025] MS (-ve ESI): 552 (M-H).sup.-,
[1026] MS (+ve ESI): 554 (M+H).sup.+.
EXAMPLE 136
Preparation of Compound 136 in Table
5--N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2,2-dimethylpropyl)(2-hydroxyethy-
l)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[1027] An analogous reaction to that described in example 130, but
starting with 2-[(2,2-dimethylpropyl)amino]ethanol (291 mg, 2.22
mmol) yielded compound 136 in table 5 as a beige solid (93 mg, 26%
yield):
[1028] .sup.1H-NMR (DMSO d.sub.6): 12.36 (s, 1H), 10.22 (s, 1H),
8.52 (s, 2H), 7.72 (m, 1H), 7.19 (m, 4H), 6.77 (s, 1H), 4.34 (s,
1H), 4.19 (m, 2H), 3.83 (s, 2H), 3.45 (m, 2H), 2.64 (m, 2H), 2.54
(m, 2H), 2.21 (s, 2H), 1.89 (m, 2H), 0.83 (s, 9H):
[1029] MS (-ve ESI): 566 (M-H).sup.-,
[1030] MS (+ve ESI): 568 (M+H).sup.+.
EXAMPLE 137
Preparation of Compound 137 in Table
6--N-(3-fluorophenyl)-2-[3-({5-{[1-(2-hydroxyethyl)piperidin-4-yl]oxy}-7--
[3-(4-methylpiperazin-1-yl)propoxy]quinazolin-4-yl}amino)-1H-pyrazol-5-yl]-
acetamide
[1031]
2-[3-({5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-[3-(4-methyl-
piperazin-1-yl)propoxy]quinazolin-4-yl}amino)-1H-pyrazol-5-yl]-N-(3-fluoro-
phenyl)acetamide (102 mg, 0; 117 mmol) was treated with a mixture
of dichloromethane:trifluoroacetic acid (5:1) at ambient
temperature for 16 hours. The solvent was evaporated, and the
residue purified by preparative LCMS to yield compound 137 in table
6 (55 mg, 71% yield):
[1032] .sup.1H-NMR (DMSO d.sub.6): 10.44 (s, 1H), 10.28 (s, 1H),
8.44 (s, 1H), 7.61 (d, 1H), 7.31-7.39 (m, 1H), 7.33 (s, 1H), 6.91
(t, 1H), 6.87 (s, 1H), 6.77 (s, 1H), 6.75 (s, 1H), 4.87 (br s, 1H),
4.40 (t, 1H), 4.13 (t, 2H), 3.76 (s, 2H), 3.50 (s, 2H), 2.78 (m,
2H), 2.19-2.47 (m, 14H), 2.14 (s, 3H), 2.09 (m, 2H), 1.91 (m, 2H),
1.84 (m, 2H):
[1033] MS (+ve ESI): 662.3 (M+H).sup.+.
[1034]
2-[3-({5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-[3-(4-methyl-
piperazin-1-yl)propoxy]quinazolin-4-yl}amino)-1H-pyrazol-5-yl]-N-(3-fluoro-
phenyl)acetamide used as starting material was obtained as
follows:
[1035] a) A solution of 5,7-difluoroquinazolin-4(3H)-one (1.82 g,
10 mmol) and 1-(2-tert-butoxyethyl)piperidin-4-ol (1.91 g, 9.5
mmol) in tetrahydrofuran (40 ml) was treated with potassium
tert-butoxide (3.36 g, 30 mmol). The mixture was heated at
70.degree. C. for 5 hours. The solvent was evaporated and the
residue purified by chromatography on silica gel. Elution with
dichloromethane:methanolic ammonia (95:5) yielded
5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-fluoroquinazolin--
4(3H)-one (2.88 g, 83% yield):
[1036] .sup.1H-NMR (DMSO d.sub.6): 7.98 (s, 1H), 7.01 (d, 1H), 6.90
(d, 1H), 4.58 (br s, 1H), 3.43 (t, 2H), 2.74 (m, 2H), 2.43 (t, 2H),
2.34 (m, 2H), 1.90 (m, 2H), 1.71 (m, 2H), 1.13 (s, 9H):
[1037] MS (+ve ESI): 364.3 (M+H).sup.+.
[1038] b)
5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-fluoroquinazolin-
-4(3H)-one (5.45 mg, 1.5 mmol) in anhydrous diglyme (15 ml) was
reacted with 3-(4-methylpiperazin-1-yl)propan-1-ol (474 mg, 3 mmol)
in the presence of potassium tert-butoxide (11.77 g, 10 mmol) at
100.degree. C. for 4 hours. The reaction mixture was diluted with
dichloromethane (10 ml) and water (10 ml) and the pH adjusted to
7.7. The mixture was extracted several times with dichloromethane
and the organic phase dried (magnesium sulphate), evaporated and
the residue purified by chromatography on silica gel. Elution with
dichloromethane:methanolic ammonia (9:1) yielded
5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-[3-(4-methylpiperazin-1-y-
l)propoxy]quinazolin-4(3H)-one (411 mg, 55% yield):
[1039] .sup.1H-NMR (DMSO d.sub.6): 7.89 (s, 1H), 6.63 (s, 1H), 6.55
(s, 1H), 4.49 (br s, 1H), 4.09 (t, 2H), 3.40 (t, 2H), 2.75 (m, 2H),
2.52 (m, 2H), 2.22-2.43 (m, 12H), 2.14 (s, 3H), 1.88 (m, 4H), 1.69
(m, 2H), 1.12 (s, 9H):
[1040] MS (+ve ESI): 502.4 (M+H).sup.+.
[1041] c)
5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-[3-(4-methylpipe-
razin-1-yl)propoxy]quinazolin-4(3H)-one (400 mg, 0.8 mmol) in
dichloroethane (8 ml) was reacted with triphenylphosphine (420 mg,
1.6 mmol) and carbon tetrachloride (0.78 ml, 8 mmol) at 70.degree.
C. for 1.5 hours. The solvent was evaporated, the residue dissolved
in isopropanol (8 ml) and reacted with
(3-amino-1H-pyrazol-5-yl)acetic acid (124 mg, 0.88 mmol) at
80.degree. C. under argon for 2 hours. The solvent was evaporated,
and the residue purified by preparative LCMS to yield
[3-({5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-[3-(4-methylpiperazi-
n-1-yl)propoxy]quinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetic acid
(270 mg, 54% yield):
[1042] .sup.1H-NMR (DMSO d.sub.6): 8.99 (s, 1H), 7.09-7.15 (m, 1H),
6.96 (m, 1H), 6.88 (m, 1H), 5.08-5.38 (m, 1H), 4.30 (t, 2H),
3.29-3.95 (m, 21H), 3.22 (t, 1H), 2.74 (s, 3H), 2.08-2.39 (m, 6H),
1.20 (m, 9H):
[1043] MS (+ve ESI): 625.3 (M+H).sup.+.
[1044] d)
[3-({5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-[3-(4-methy-
lpiperazin-1-yl)propoxy]quinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetic
acid (140 mg, 0.22 mmol) in dimethylformamide (1 ml) was reacted
with 3-fluoroaniline (24 .mu.l, 0.25 mmol) in the presence of
1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (48
mg, 0.25 mmol) and 2-hydroxypyridin-1-oxide (27 mg, 0.24 mmol) at
50.degree. C. for 45 minutes. The solvent was evaporated and the
residue purified by chromatography on silica gel. Elution with
dichloromethane:methanol (97:3) then dichloromethane:methanolic
ammonia (95:5) yielded
2-[3-({5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-[3-(4-methylpipera-
zin-1-yl)propoxy]quinazolin-4-yl}amino)-1H-pyrazol-5-yl]-N-(3-fluorophenyl-
)acetamide (109 mg, 58% yield):
[1045] .sup.1H-NMR (DMSO d.sub.6): 10.44 (s, 1H), 10.27 (s, 1H),
8.44 (s, 1H), 7.61 (d, 1H), 7.30-7.38 (m, 1H), 7.33 (s, 1H), 6.88
(t, 1H), 6.87 (s, 1H), 6.76 (s, 1H), 6.75 (s, 1H), 4.86 (br s, 1H),
4.13 (t, 2H), 3.75 (s, 2H), 3.41 (t, 2H), 2.78 (m, 2H), 2.20-2.48
(m, 12H), 2.17 (t, 2H), 2.14 (s, 3H), 2.07 (m, 2H), 1.90 (t, 2H),
1.82 (m, 2H), 1.11 (s, 9H):
[1046] MS (+ve ESI): 718.1 (M+H).sup.+.
EXAMPLE 138
Preparation of Compound 138 in Table
6--N-(3-fluorophenyl)-2-[5-({7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]qui-
nazolin-4-yl}amino)-1H-pyrazol-3-yl]acetamide
[1047]
[5-({7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinazolin-4-yl}amino-
)-1H-pyrazol-3-yl]acetic acid (95 mg, 0.2 mmol) in
dimethylformamide (1 ml) was reacted with 3-fluoroaniline (21
.mu.l, 0.22 mmol) in the presence of
1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (46
mg, 0.24 mmol) and 2-hydroxypyridin-1-oxide (24 mg, 0.22 mmol) at
60.degree. C. for 2.5 hours. The solvent was evaporated, and the
residue purified by chromatography on silica gel. Elution with
dichloromethane then increased polarity to
dichloromethane:methanolic ammonia (9:1) yielded compound 138 in
table 6 (30 mg, 30% yield):
[1048] .sup.1H-NMR (DMSO d.sub.6): 8.47 (s, 1H), 7.63 (d, 1H), 7.35
(m, 2H), 6.90 (m, 2H), 6.80 (m, 2H), 4.88 (m, 1H), 3.90 (s, 3H),
3.77 (s, 2H), 2.68 (m, 2H), 2.39 (m, 2H), 2.23 (s, 3H), 2.12 (m,
2H), 1.90 (m, 2H):
[1049] MS (+ve ESI): 506.2 (M+H).sup.+.
[1050]
[5-({7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinazolin-4-yl}amino-
)-1H-pyrazol-3-yl]acetic acid used as starting material was
obtained as follows:
[1051] a) 3,5-Dimethoxyaniline hydrochloride (80.21 g, 0.424 mol)
was added cautiously to oxalyl chloride (136 ml, 1.56 mol) and the
solution heated at reflux for 3 hours. The solution was cooled and
concentrated in vacuo. Methanol (300 ml) was added to the residue
and the mixture heated at reflux for 1 hour. The reaction was
allowed to cool, and the resulting precipitate filtered and washed
with methanol to yield 4,6-dimethoxyisatin (40.4 g, 46%) as a
yellow solid:
[1052] .sup.1H-NMR (DMSO d.sub.6): 10.86 (br s, 1H), 6.17 (d, 1H),
6.00 (d, 1H), 3.86 (s, 3H), 3.83 (s, 3H).
[1053] b) 4,6-Dimethoxyisatin (5.00 g, 24.0 mmol) was dissolved in
33% (w/v) aqueous sodium hydroxide solution (42 ml) at 75.degree.
C. To this solution was added hydrogen peroxide (30%, 8 ml)
dropwise over 30 minutes. The reaction was stirred for an hour at
75.degree. C. and then cooled to room temperature. Ice was added,
and the reaction mixture acidified to pH 1 with concentrated
hydrochloric acid. The resulting precipitate was filtered, washed
with water and dried in vacuo to yield 2-amino-4,6-dimethoxybenzoic
acid hydrochloride salt (3.3 g, 59% yield) acid as a pale yellow
solid:
[1054] .sup.1H-NMR (DMSO d.sub.6): 5.92 (d, 1H), 5.77 (d, 1H), 3.75
(s, 3H), 3.69 (s, 3H)
[1055] MS (+ve ESI): 198 (M+H).sup.+.
[1056] c) Dimethyl sulfate (1.04 ml, 11.0 mmol) was added dropwise
to a mixture of potassium carbonate (3.34 g, 24.2 mmol) and
2-amino-4,6-dimethoxybenzoic acid (2.56 g, 11.0 mmol) in
dimethylformamide (70 ml) at 0.degree. C. The reaction was stirred
for 1 hour, then poured into water. The resulting precipitate was
filtered, washed with water and dried in vacuo. The filtrate was
extracted with ethyl acetate, and the combined organic extracts
were dried (magnesium sulphate) and concentrated in vacuo. The
combined solids were dried in vacuo to yield methyl
2-amino-4,6-dimethoxybenzoate (1.8 g, 77% yield) as a yellow
crystalline solid:
[1057] .sup.1H-NMR (DMSO d.sub.6): 6.13 (s, 2H), 5.90 (d, 1H), 5.75
(d, 1H), 3.68 (s, 3H), 3.67 (s, 3H), 3.66 (s, 3H).
[1058] d) A solution of methyl 2-amino-4,6-dimethoxybenzoate (600
mg, 2.8 mmol) and formamidine acetate (650 mg, 6.3 mmol) in
2-methoxyethanol (7 ml) was heated at 120.degree. C. for 16 hours.
The reaction was cooled, concentrated in vacuo, and the residue
triturated with methanol to give
5,7-dimethoxy-3,4-dihydroquinazolin-4(3H)-one as a beige solid (290
mg, 58% yield):
[1059] .sup.1H-NMR (DMSO d.sub.6): 11.62 (br s, 1H), 7.88 (s, 1H),
6.63 (d, 1H), 6.51 (d, 1H), 3.84 (s, 3H), 3.80 (s, 3H):
[1060] MS (+ve ESI): 207 (M+H).sup.+.
[1061] e) Magnesium bromide (3.83 g, 20.8 mmol) was added
cautiously to 5,7-dimethoxy-3,4-dihydroquinazolin-4(3H)-one (4.29
g, 20.8 mmol) in pyridine (60 ml) and the solution heated at reflux
for 1 hour. The reaction mixture was cooled, concentrated in vacuo
and the residue triturated with water and filtered to yield
7-methoxyquinazoline-4,5-diol (3.72 g, 93% yield) as an off-white
solid:
[1062] MS (+ve ESI): 193 (M+H).sup.+.
[1063] f) Sodium hydride (60 mg, 1.49 mmol) was added portionwise
over 5 minutes to 7-methoxyquinazoline-4,5-diol (260 mg, 1.35 mmol)
in dimethylformamide (2 ml) at 0.degree. C. Chloromethyl pivalate
(200 .mu.l, 1.36 mmol) was added dropwise over 15 minutes to give a
clear orange solution. The reaction mixture was allowed to warm to
ambient temperature and stirred for a further 18 hours. Incomplete
reaction was seen by tlc, therefore the reaction was cooled to
0.degree. C. and sodium hydride (10 mg, 0.25 mmol) was added
followed by chloromethyl pivalate (26 .mu.l, 0.18 mmol). The
reaction was complete after stirring for 1 hour at ambient
temperature. The reaction mixture was concentrated in vacuo and
purified by chromatography on silica gel, eluting with 2-10%
methanol in dichloromethane, to yield
(5-hydroxy-7-methoxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate (170
mg, 41% yield) as a cream solid
[1064] .sup.1H-NMR (DMSO d.sub.6): 11.42 (s, 1H), 8.37 (s, 1H),
6.66 (d, 1H), 6.51 (d, 1H), 5.86 (s, 2H), 3.85 (s, 3H), 1.11 (s,
9H):
[1065] MS (+ve ESI): 305 (M+H).sup.+.
[1066] g) (5-hydroxy-7-methoxy-4-oxoquinazolin-3(4H)-yl)methyl
pivalate (500 mg, 1.63 mmol), 4-hydroxy-N-methylpiperidine (280 mg,
2.45 mmol) and triphenylphosphine (640 mg, 2.45 mmol) were
dissolved in anhydrous dichloromethane (8 ml), under a nitrogen
atmosphere at 0.degree. C. A solution of di-tert-butyl
azodicarboxylate (560 mg, 2.45 mmol) in dichloromethane (1 ml) was
added dropwise over 5 minutes and the resulting yellow solution was
allowed to warm to ambient temperature and stirred for 18 hours. A
further 1 equivalent of all reagents was added in the same sequence
as above under the same reaction conditions and was left to stir
for a further 12 hours at ambient temperature. The reaction mixture
was concentrated in vacuo and the residue purified by
chromatography on silica gel, eluting with 2-8% methanol in
dichloromethane, to yield
(7-methoxy-5-((1-methylpiperidin-4-yl)oxy)-4-oxoquinazolin-3(4H)-yl)methy-
l pivalate (370 mg, 56% yield) as a cream solid:
[1067] .sup.1H-NMR (DMSO d.sub.6): 8.16 (s, 1H), 6.67 (d, 1H), 6.61
(d, 1H), 5.79 (s, 2H), 4.52 (m, 1H), 3.84 (s, 3H), 2.57 (m, 2H),
2.18 (m, 2H), 2.13 (s, 3H), 1.87 (m, 2H), 1.71 (m, 2H), 1.11 (s,
9H):
[1068] MS (+ve ESI): 405 (M+H).sup.+.
[1069] h) 7.0 N ammonia in methanol (25 ml) was added to
(7-methoxy-5-((1-methylpiperidin-4-yl)oxy)-4-oxoquinazolin-3(4H)-yl)methy-
l pivalate (370 mg, 0.92 mmol) and the solution stirred at ambient
temperature for 18 hours. The reaction mixture was concentrated in
vacuo to give an oil which was triturated with diethyl ether to
give an orange solid which was collected by suction filtration and
dried in vacuo to yield
7-methoxy-5-((1-methylpiperidin-4-yl)oxy)quinazolin-4(3H)-one (200
mg, 75% yield):
[1070] .sup.1H-NMR (DMSO d.sub.6): 11.60 (br s, 1H), 7.86 (s, 1H),
6.64 (d, 2H), 6.53 (d, 2H), 4.45 (m, 1H), 3.82 (s, 3H), 2.61 (m,
2H), 2.18 (m, 2H), 2.11 (s, 3H), 1.84 (m, 2H), 1.68 (m, 2H):
[1071] MS (+ve ESI): 290 (M+H).sup.+.
[1072] i) A solution of
7-methoxy-5-((1-methylpiperidin-4-yl)oxy)quinazolin-4(3H)-one (3.00
g, 10.4 mmol) and diisopropyl ethylamine (5 ml) in dichloromethane
(300 ml) was stirred at ambient temperature under an atmosphere of
nitrogen. Phosphoryl chloride (10 ml) was added, and the resultant
orange solution was heated at reflux for 20 hours. The reaction
mixture was then cooled to ambient temperature and concentrated in
vacuo. Residual phosphoryl chloride was then removed by azeotrope
with toluene to give the crude product as an orange oil.
Purification by chromatography on silica gel, eluting with 5%
triethylamine in dichloromethane, gave an orange solid, which was
further purified by trituration under acetonitrile, and then dried
in vacuo to yield
4-chloro-5-(N-methylpiperidin-4-yloxy)-7-methoxyquinazoline (2.4 g,
75% yield) as a pale yellow amorphous solid:
[1073] .sup.1H-NMR (CDCl.sub.3) 8.80 (s, 1H), 6.94 (d, 1H), 6.60
(d, 1H), 4.58 (s, 1H), 3.95 (s, 3H), 2.74 (m, 2H), 2.44 (m, 2H),
2.35 (s, 3H), 2.10 (m, 4H):
[1074] MS (+ve ESI): 308, 310 (M+H).sup.+.
[1075] j)
4-chloro-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinazoline (307
mg, 0.85 mmol) was condensed with (3-amino-1H-pyrazol-5-yl)acetic
acid (132 mg, 0.93 mmol) in dimethylacetamide (3 ml) and
hydrochloric acid in dioxane (4.0 N solution, 467 .mu.l) at
90.degree. C. for 1 hour. The solvent was evaporated, and the
residual oil was triturated with ethanol diethyl ether to yield
[5-({7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinazolin-4-yl}amino)-1H-p-
yrazol-3-yl]acetic acid as a beige solid (320 mg, 78% yield):
[1076] .sup.1H-NMR (DMSO d.sub.6): 8.88 (m, 1H), 7.12 (m, 1H), 6.88
(m, 1H), 6.82 (m, 1H), 5.05-5.45 (m, 1H), 3.96 (m, 3H), 3.73 (s,
2H), 3.10-3.60 (m, 4H), 2.80 (m, 3H), 2.00-2.50 (m, 4H):
[1077] MS (+ve ESI): 413.2 (M+H).sup.+.
EXAMPLE 139
Preparation of Compound 139 in Table
6--N-(2,3-difluorophenyl)-2-{3-[(5,7-dimethoxyquinazolin-4-yl)amino]-1H-p-
yrazol-5-yl}acetamide
[1078] An analogous reaction to that described in example 137d but
starting with
{3-[(5,7-dimethoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic
acid (165 mg, 0.5 mmol) and 2,3-difluoroaniline (70 .mu.l, 0.6
mmol) at 50.degree. C. for 10 hours yielded compound 139 in table 6
(30 mg, 14% yield):
[1079] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.82 (s, 1H), 7.65 (m, 1H),
7.09-7.16 (m, 1H), 7.12 (s, 1H), 6.92 (s, 1H), 6.79 (d, 1H), 6.66
(d, 1H), 4.10 (s, 3H), 3.92 (s, 3H), 3.85 (s, 2H):
[1080] MS (+ve ESI): 441.0 (M+H).sup.+.
[1081]
{3-[(5,7-dimethoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic
acid used as starting material was obtained as follows:
[1082] a) An analogous reaction to that described in example 137c,
but starting with 5,7-dimethoxyquinazolin-4(3H)-one (618 mg, 3
mmol--see patent WO 0194341) yielded
{3-[(5,7-dimethoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic
acid (913 mg, 92% yield):
[1083] .sup.1H-NMR (DMSO d.sub.6): 10.72 (s, 1H), 8.85 (s, 1H),
7.00 (s, 1H), 6.96 (s, 1H), 6.67 (s, 1H), 4.16 (s, 3H), 3.97 (s,
3H), 3.72 (s, 2H):
[1084] MS (+ve ESI): 330.1 (M+H).sup.+.
EXAMPLE 140
Preparation of Compound 140 in Table
6--2-(3-{[5,7-bis(2-methoxyethoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-
-N-(2,3-difluorophenyl)acetamide
[1085] A solution of phosphoryl chloride (51 .mu.l, 0.55 mmol) in
dichloromethane (0.5 ml) was added slowly at 0.degree. C. to a
solution of
(3-{[5,7-bis(2-methoxyethoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)ac-
etic acid (209 mg, 0.5 mmol) and 2,3-difluoroaniline (61 .mu.l, 0.6
mmol) in pyridine (2 ml. The mixture was stirred at ambient
temperature for 6 hours. Ice was then added to the reaction mixture
at 0.degree. C., and the solvent was evaporated. The crude product
was purified by preparative LCMS to yield compound 140 in table 6
(26 mg, 10% yield):
[1086] .sup.1H-NMR (DMSO d.sub.6): 10.22 (s, 1H), 10.15 (s, 1H),
8.45 (s, 1H), 7.71 (t, 1H), 7.14-7.23 (m, 1H), 7.18 (s, 1H), 6.86
(s, 1H), 6.79 (s, 1H), 6.74 (s, 1H), 4.40 (s, 2H), 4.24 (t, 2H),
3.84 (s, 4H), 3.71 (t, 2H), 3.42 (s, 3H), 3.33 (s, 3H):
[1087] MS (+ve ESI): 529.1 (M+H).sup.+.
[1088]
(3-{[5,7-bis(2-methoxyethoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl-
)acetic acid used as starting material was obtained as follows
[1089] a) 5,7-difluoroquinazolin-4(3H)one (728 mg, 4 mmol) in
diglyme (15 ml) and potassium tert-butoxide (4.48 g, 32 mmol) were
reacted with 2-methoxyethanol (2.52 ml, 32 mmol) at 110.degree. C.
for 1 hour. The mixture was cooled and purified by chromatography
on silica gel. Elution with dichloromethane:methanol (96:4) then
increased polarity to dichloromethane:methanolic ammonia (95:5)
yielded 5,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (982 mg, 99%
yield):
[1090] .sup.1H-NMR (DMSO d.sub.6): 11.71 (br s, 1H), 7.90 (s, 1H),
6.66 (d, 1H), 6.56 (d, 1H), 4.20 (t, 2H), 4.15 (t, 2H), 3.69 (m,
4H), 3.36 (s, 3H), 3.32 (s, 3H):
[1091] MS (+ve ESI): 295.1 (M+H).sup.+.
[1092] b) An analogous reaction to that described in example 137c,
but starting with 5,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (648
mg, 2.2 mmol) yielded
(3-{[5,7-bis(2-methoxyethoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)aceti-
c acid (632 mg, 68% yield) as a beige solid:
[1093] .sup.1H-NMR (DMSO d.sub.6): 10.90 (s, 1H), 8.86 (s, 1H),
7.02 (s, 1H), 6.96 (s, 1H), 6.78 (s, 1H), 4.52 (t, 2H), 4.31 (t,
2H), 3.85 (t, 2H), 3.74 (t, 2H), 3.71 (s, 2H), 3.42 (s, 3H), 3.33
(s, 3H):
[1094] MS (+ve ESI): 418.1 (M+H).sup.+.
EXAMPLE 141
Preparation of Compound 141 in Table
6--N-(2,3-difluorophenyl)-2-(3-{[5-isopropoxy-7-(2-methoxyethoxy)quinazol-
in-4-yl]amino}-1H-pyrazol-5-yl)acetamide
[1095] An analogous reaction to that described in example 140, but
starting with
(3-{[5-isopropoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino}-1H-pyrazol-5--
yl)acetic acid (230 mg, 0.5 mmol) yielded compound 141 in table 6
(68 mg, 31% yield) as a beige solid:
[1096] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.92 (s, 1H), 7.73 (m, 1H),
7.17-7.23 (m, 2H), 7.07 (s, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 5.19
(m, 1H), 4.33 (t, 2H), 3.93 (s, 2H), 3.75 (t, 2H), 3.54 (s, 3H),
1.52 (s, 3H), 1.51 (s, 3H):
[1097] MS (+ve ESI): 513.16 (M+H).sup.+.
[1098]
(3-{[5-isopropoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino}-1H-pyra-
zol-5-yl)acetic acid used as starting material was obtained as
follows.
[1099] a) 5,7-Difluoroquinazolin-4(3H)one (2.73 g, 15 mmol) in
dimethylformamide (20 ml) was reacted with isopropanol (1.26 ml,
16.4 mmol) and sodium hydride (1.8 g, 45 mmol) at 0.degree. C.
under argon. The mixture was stirred at ambient temperature for 14
hours, acidified with acetic acid and concentrated. The residue was
washed with water and dried to yield
7-fluoro-5-isopropoxyquinazolin-4(3H)-one (3.17 g, 95% yield) as a
beige solid:
[1100] .sup.1H-NMR (DMSO d.sub.6): 11.92 (br s, 1H), 7.97 (s, 1H),
6.95 (dd, 1H), 6.89 (dd, 1H), 4.73 (m, 1H), 1.32 (s, 3H), 1.31 (s,
3H):
[1101] MS (+ve ESI): 223.1 (M+H).sup.+.
[1102] b) An analogous reaction to that described in example 137b,
but starting with 7-fluoro-5-isopropoxyquinazolin-4(3H)-one (444
mg, 2 mmol) and 2-methoxyethanol (0.32 ml, 4.06 mmol) and heating
at 120.degree. C. for 1.5 hours yielded
5-isopropoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one (155 mg, 28%
yield) as a beige solid:
[1103] .sup.1H-NMR (DMSO d.sub.6): 11.62 (m, 1H), 7.88 (s, 1H),
6.64 (d, 1H), 6.54 (d, 1H), 4.66 (m, 1H), 4.66 (m, 2H), 4.20 (m,
2H), 1.30 (s, 3H), 1.29 (s, 3H):
[1104] MS (+ve ESI): 279.2 (M+H).sup.+.
[1105] c) An analogous reaction to that described in example 137c,
but starting with
5-isopropoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one (935 mg, 3.36
mmol) yielded
(3-{[5-isopropoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino}-H-pyrazol-5-y-
l)acetic acid as a beige solid (1.0 g, 74% yield):
[1106] .sup.1H-NMR (DMSO d.sub.6): 11.06 (s, 1H), 8.87 (s, 1H),
7.03 (s, 1H), 6.94 (s, 1H), 6.82 (s, 1H), 5.17 (m, 1H), 4.31 (t,
2H), 3.74 (t, 2H), 3.72 (s, 2H), 3.34 (s, 3H), 1.51 (s, 3H), 1.49
(s, 3H):
[1107] MS (+ve ESI): 402.1 (M+H).sup.+.
EXAMPLE 142
Preparation of Compound 142 in Table
6--N-(3-fluorophenyl)-2-(3-{[5-isopropoxy-7-(2-methoxyethoxy)quinazolin-4-
-yl]amino}-1H-pyrazol-5-yl)acetamide
[1108] An analogous reaction to that described in example 140, but
starting with
(3-{[5-isopropoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino}-1H-pyrazol-5--
yl)acetic acid (308 mg, 0.7 mmol) and 3-fluoroaniline (81 .mu.l,
0.84 mmol) yielded compound 142 in table 6 as a white solid (62 mg,
18% yield):
[1109] .sup.1H-NMR (DMSO d.sub.6): 10.44 (s, 1H), 10.33 (s, 1H),
8.44 (s, 1H), 7.61 (d, 1H), 7.30-7.39 (m, 1H), 7.32 (s, 1H), 6.89
(t, 1H), 6.85 (s, 1H), 6.77 (s, 1H), 6.76 (s, 1H), 5.01 (m, 1H),
4.24 (t, 2H), 3.75 (s, 2H), 3.71 (t, 2H), 3.33 (s, 3H), 1.47 (s,
3H), 1.46 (s, 3H):
[1110] MS (+ve ESI): 495.1 (M+H).sup.+.
EXAMPLE 143
Preparation of Compound 143 in Table
6--N-(3-fluorophenyl)-2-{3-[(5-{[1-(2-hydroxyethyl)piperidin-4-yl]oxy}-7--
methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide
[1111] An analogous reaction to that described in example 137, but
starting with
2-{3-[(5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-methoxyquinazolin--
4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide (39 mg,
0.066 mmol) yielded compound 143 in table 6 as a beige solid (26
mg, 74% yield):
[1112] .sup.1H-NMR (DMSO d.sub.6, TFA): 8.94 (s, 1H), 7.61 (d, 1H),
7.29-7.37 (m, 2H), 7.12-7.18 (m, 1H), 6.91-6.85 (m, 3H), 5.10-5.35
(s, 0.5H), 3.97 (s, 3H), 3.83 (s, 2H), 3.79 (t, 1H), 3.76 (t, 1H),
3.71 (d, 1H), 3.60 (d, 1H), 3.41 (t, 1H), 3.32 (s, 1H), 3.23 (m,
1H), 3.19 (t, 1H), 2.52 (m, 1H), 2.30 (m, 2H), 2.14 (m, 1H):
[1113] MS (+ve ESI): 536.1 (M+H).sup.+.
[1114]
2-{3-[(5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-methoxyquina-
zolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide used
as starting material was obtained as follows.
[1115] a) An analogous reaction to that described in example 137b,
but starting with
5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-fluoroquinazolin-4(3H)-on-
e (363 mg, 1 mmol) and methanol (162 .mu.l, 4 mmol) at 110.degree.
C. for 2 hours yielded
5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-methoxyquinazolin-4(3H)-o-
ne (237 mg, 63% yield):
[1116] .sup.1H-NMR (DMSO d.sub.6): 11.64 (br s, 1H), 7.91 (s, 1H),
6.65 (d, 1H), 6.56 (d, 1H), 4.48 (m, 1H), 3.84 (s, 3H), 3.40 (t,
2H), 2.74 (m, 2H), 2.41 (t, 2H), 2.29 (m, 2H), 1.87 (m, 2H), 1.69
(m, 2H), 1.12 (s, 9H):
[1117] MS (+ve ESI): 376.2 (M+H).sup.+.
[1118] b) An analogous reaction to that described in example 137c,
but starting with
5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-methoxyquinazolin-4(3H)-o-
ne (458 mg, 1.22 mmol) and heating for 4 hours yielded
{3-[(5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-methoxyquinazolin-4--
yl)amino]-1H-pyrazol-5-yl}acetic acid as a beige solid (386 mg, 63%
yield):
[1119] .sup.1H-NMR (DMSO d.sub.6): 8.97 (s, 1H), 7.14-7.20 (m, 1H),
6.98 (s, 1H), 6.86 (m, 1H), 5.10-5.35 (m, 1H), 3.99 (s, 3H),
3.67-3.80 (m, 3H), 3.75 (s, 2H), 3.60 (m, 1H), 3.27-3.46 (m, 3H),
3.22 (t, 1H), 2.52 (m, 1H), 2.34 (br s, 2H), 2.15 (m, 1H), 1.21 (s,
3H), 1.16 (s, 3H)
[1120] MS (+ve ESI): 499.1 (M+H).sup.+.
[1121] c) An analogous reaction to that described in example 137d,
but starting with
{3-[(5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-methoxyquinazolin-4--
yl)amino]-1H-pyrazol-5-yl}acetic acid (250 mg, 0.5 mmol) and
heating for 4 hours yielded
2-{3-[(5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-methoxyquinazolin--
4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide as a
yellow solid (44 mg, 15% yield):
[1122] .sup.1H-NMR (DMSO d.sub.6): 12.36 (s, 1H), 10.44 (s, 1H),
10.28 (s, 1H), 8.45 (s, 1H), 7.61 (d, 1H), 7.31-7.37 (m, 2H), 6.89
(t, 1H), 6.87 (s, 1H), 6.79 (s, 1H), 6.78 (s, 1H), 4.85 (br s, 1H),
3.89 (s, 3H), 3.75 (s, 2H), 3.41 (t, 2H), 2.79 (m, 2H), 2.46 (m,
4H), 2.07 (m, 2H), 1.83 (m, 2H), 1.11 (s, 9H):
[1123] MS (+ve ESI): 592.2 (M+H).sup.+.
EXAMPLE 144
Preparation of Compound 144 in Table
6--2-{3-[(5,7-dimethoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluor-
ophenyl)acetamide
[1124] An analogous reaction to that described in example 140, but
starting with
{3-[(5,7-dimethoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic
acid (230 mg, 0.70 mmol) and 3-fluoroaniline (81 .mu.l, 0.84 mmol)
yielded compound 144 in table 6 as a pale orange solid (43 mg, 15%
yield):
[1125] .sup.1H-NMR (DMSO d.sub.6): 12.39 (s, 1H), 10.44 (s, 1H),
9.88 (s, 1H), 8.45 (s, 1H), 7.61 (d, 1H), 7.30-7.39 (m, 1H), 7.33
(s, 1H), 6.89 (t, 1H), 6.82 (s, 1H), 6.80 (s, 1H), 6.72 (s, 1H),
4.08 (s, 3H), 3.90 (s, 3H), 3.76 (s, 2H):
[1126] MS (+ve ESI): 423 (M+H).sup.+.
EXAMPLE 145
Preparation of Compound 145 in Table
6--2-(3-{[5,7-bis(2-methoxyethoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-
-N-(3-fluorophenyl)acetamide
[1127] An analogous reaction to that described in example 140, but
starting with
(3-{[5,7-bis(2-methoxyethoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)aceti-
c acid (222 mg, 0.70 mmol) and 3-fluoroaniline (81 .mu.l, 0.84
mmol) yielded compound 145 in table 6 as a beige solid (108 mg, 30%
yield):
[1128] .sup.1H-NMR (DMSO d.sub.6): 8.90 (s, 1H), 7.61 (d, 1H),
7.30-7.38 (m, 2H), 7.32 (s, 1H), 7.05 (s, 1H), 6.88 (t, 1H), 6.85
(s, 1H), 6.82 (s, 1H), 4.53 (t, 2H), 4.32 (t, 2H), 3.85 (t, 2H),
3.81 (s, 2H), 3.73 (t, 2H), 3.42 (s, 3H), 3.33 (s, 3H):
[1129] MS (+ve ESI): 511.1 (M+H).sup.+.
EXAMPLE 146
Preparation of Compound 146 in Table
7--N-(3-fluorophenyl)-3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propoxy}--
6-methoxyquinazolin-4-yl)amino]-1H-pyrazole-5-carboxamide
[1130] An analogous reaction to that described in example 7, but
starting with 2-(isobutylamino)ethanol (110 mg, 0.94 mmol) and
3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-N-(3-fluorophenyl-
)-1H-pyrazole-5-carboxamide (120 mg, 0.23 mmol) in the presence of
potassium iodide (78 mg, 0.47 mmol) and heating for 3 hours yielded
compound 146 in table 7 (96 mg, 73% yield):
[1131] .sup.1H-NMR (DMSO d.sub.6, TFA): 9.04 (s, 1H), 8.34 (s, 1H),
7.81 (m, 1H), 7.74 (s, 1H), 7.62 (m, 1H), 7.43 (m, 2H), 6.96 (m,
1H), 4.34 (s, 2H), 4.04 (s, 3H), 3.84 (t, 2H), 3.38 (m, 2H), 3.32
(m, 2H), 3.11 (m, 2H), 2.36 (m, 2H), 2.16 (m, 1H), 1.04 (d,
6H):
[1132] MS (+ve ESI): 552.2 (M+H).sup.+.
[1133]
3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-N-(3-fluoro-
phenyl)-1H-pyrazole-5-carboxamide used as starting material was
obtained as follows:
[1134] a) 3-nitro-1H-pyrazole-5-carboxylic acid (1 g, 6.36 mmol) in
dimethylformamide (10 ml) was reacted with 3-fluoroaniline (673
.mu.l, 7 mmol) in the presence of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.34
g, 7 mmol) and 2-hydroxy-pyridin-1-oxide (778 mg, 7 mmol) at
40.degree. C. for 1.5 hour. The solvent was evaporated, and the
residue purified by chromatography on silica gel. Elution with
dichloromethane:methanol (99:1) then (97:3) yielded
N-(3-fluorophenyl)-3-nitro-1H-pyrazole-5-carboxamide (668 mg, 42%
yield):
[1135] .sup.1H-NMR (DMSO d.sub.6): 7.86 (s, 1H), 7.71 (m, 1H), 7.51
(m, 1H), 7.44 (m, 1H), 7.01 (m, 1H).
[1136] b) N-(3-fluorophenyl)-3-nitro-1H-pyrazole-5-carboxamide (100
mg, 0.4 mmol) in ethyl acetate:ethanol (10:4) was stirred with
platinum dioxide (10 mg) under an atmosphere of hydrogen (70 psi)
for 3 hours. The catalyst was filtered off and the solvent was
evaporated in vacuo to yield
3-amino-N-(3-fluorophenyl)-1H-pyrazole-5-carboxamide (65 mg, 73%
yield):
[1137] .sup.1H-NMR (DMSO d.sub.6): 7.76 (m, 1H), 7.60 (s, 1H), 7.33
(m, 1H), 6.86 (s, 1H), 5.71 (s, 1H), 5.22 (s, 2H):
[1138] MS (+ve ESI): 221.2 (M+H).sup.+.
[1139] c) 3-Amino-N-(3-fluorophenyl)-1H-pyrazole-5-carboxamide (153
mg, 0.69 mmol) in dimethylacetamide (1.8 ml) and HCl in dioxane (4
M solution in dioxane, 174 .mu.l, 0.69 mmol) was reacted with
4-chloro-7-(3-chloropropoxy)-6-methoxyquinazoline (200 mg, 0.69
mmol) at 90.degree. C. for 1.5 hour. Dichloromethane (35 ml) was
added to the cooled reaction mixture, and the solid recovered by
filtration, washed with dichloromethane and dried to yield
3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-N-(3-fluorophenyl-
)-1H-pyrazole-5-carboxamide (286 mg, 81% yield):
[1140] .sup.1H-NMR (DMSO d.sub.6, TFA): 9.03 (s, 1H), 8.33 (s, 1H),
7.80 (m, 1H), 7.73 (s, 1H), 7.62 (m, 1H), 7.44 (m, 2H), 6.96 (m,
1H), 4.36 (t, 2H), 4.04 (s, 3H), 3.85 (t, 2H), 2.33 (t, 2H):
[1141] MS (+ve ESI): 471.0 (M+H).sup.+.
[1142] 4-chloro-7-(3-chloropropoxy)-6-methoxyquinazoline was itself
made as follows:
[1143] d) A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (10
g, 0.04 mol), (prepared according to J. Med. Chem. 1977, 20,
146-149), and Gold's reagent (7.4 g, 0.05 mol) in dioxane (100 ml)
was stirred and heated at reflux for 24 hours. Sodium acetate (3.02
g, 0.037 mol) and acetic acid (1.65 ml, 0.029 mol) were added to
the reaction mixture and it was heated for a further 3 hours. The
volatiles were removed by evaporation, water was added to the
residue, the solid was collected by filtration, washed with water
and dried. Recrystallisation from acetic acid yielded
7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 84%
yield) as a white solid.
[1144] e) Chloromethyl pivalate (225 ml, 1.56 mol) was added
dropwise to a stirred mixture of
6-methoxy-7-benzyloxyquinazol-4-one (400 g, 1.42 mol) and potassium
carbonate (783 g, 5.67 mol) in dimethylacetamide (5500 ml). The
reaction was heated to 90.degree. C. for 4 hours. The reaction was
cooled and filtered to remove inorganic salts. The filtrate was
concentrated in vacuo to yield, crude tert-butyl
2-[7-(benzyloxy)-6-methoxy-4-oxo-3(4H)-quinazolinyl]acetate (562 g,
100% yield):
[1145] .sup.1H-NMR (DMSO d.sub.6): 8.33 (s, 1H), 7.30-7.50 (m, 6H),
7.25 (s, 1H), 5.90 (s, 2H), 5.25 (s, 2H), 3.88 (s, 3H), 1.10 (s,
9H):
[1146] MS (+ve ESI): 397 (M+H).sup.+.
[1147] f) 10% palladium on carbon (56 g, 53 mmol) was added to a
solution of tert-butyl
2-[7-(benzyloxy)-6-methoxy-4-oxo-3(4H)-quinazolinyl]acetate (562 g,
1.42 mmol) in dimethylacetamide (3500 ml) at ambient temperature
and stirred for 3 hours under an atmosphere of hydrogen (1 bar).
The reaction was filtered through a pad of celite and the solvent
evaporated in vacuo. The residual solid was dissolved in 20%
methanol in dichloromethane and passed through a pad of silica gel.
Evaporation of the solvent in vacuo followed by trituration with
methanol yielded, tert-butyl
2-[7-hydroxy-6-methoxy-4-oxo-3(4H)-quinazolinyl]acetate (188 g, 43%
yield):
[1148] .sup.1H-NMR (DMSO d.sub.6): 8.25 (s, 1H), 7.45 (s, 1H), 6.97
(s, 1H), 5.85 (s, 2H), 4.04 (s, 1H), 3.87 (s, 3H), 1.10 (s,
9H):
[1149] MS (+ve ESI): 307 (M+H).sup.+.
[1150] g) A mixture of tert-butyl
2-[7-hydroxy-6-methoxy-4-oxo-3(4H)-quinazolinyl]-acetate (10 g,
0.327 mol), 3-bromopropanol (49.3 g, 0.355 mol) and potassium
carbonate (133 g, 0.967 mol) in dimethylformamide (500 ml) was
stirred at 80.degree. C. for 20 hours. The reaction was cooled and
concentrated to quarter volume in vacuo. The residue was poured
into ice/water (1500 ml) and the resulting solid collected by
suction filtration. Purification by crystallisation from ethanol,
yielded crude tert-butyl
2-[7-(3-hydroxypropoxy)-6-methoxy-4-oxo-3(4H)-quinazolinyl]acetate
(33.8 g, 41% yield) as a beige solid:
[1151] .sup.1H-NMR (DMSO d.sub.6): 7.95 (s, 1H), 7.43 (s, 1H), 7.10
(s, 1H), 4.16 (t, 2H), 3.86 (m, 5H), 2.08 (t, 2H), 1.12 (s,
9H):
[1152] MS (+ve ESI): 365 (M+H).sup.+.
[1153] h) Aqueous sodium hydroxide solution (100 ml, 0.2 mol) was
added to a solution of tert-butyl
2-[7-(3-hydroxypropoxy)-6-methoxy-4-oxo-3(4H)-quinazolinyl]acetate
(33.8 g, 93 mmol) in methanol (300 ml) and the solution heated to
reflux for 1 hour. The methanol was evaporated in vacuo, the
residue was acidified with aqueous hydrochloric acid, sodium
bicarbonate was added and the solid was collected by suction
filtration. Washing with water and drying yielded
7-(3-hydroxypropoxy)-6-methoxy-4-quinazolone (26 g, 95% yield):
[1154] .sup.1H-NMR (DMSO d.sub.6): 7.96 (s, 1H), 7.41 (s, 1H), 7.07
(s, 1H), 4.14 (t, 2H), 3.84 (s, 3H), 3.55 (t, 2H), 1.90 (t,
2H):
[1155] MS (+ve ESI): 251 (M+H).sup.+.
[1156] i) 7-(3-hydroxypropoxy)-6-methoxy-4-quinazolone (25 g, 100
mmol) was added slowly to a solution of dimethylforamide (1 ml) in
thionyl chloride (250 ml). The mixture was heated to reflux for 4
hours then cooled and the solvents evaporated in vacuo. The residue
was dissolved in dichloromethane and washed with aqueous sodium
bicarbonate, brine, dried over magnesium sulphate and evaporated.
Trituration and collection of the solid by suction filtration
yielded, 4-chloro-6-methoxy-7-(3-chloroxypropoxy)quinazoline (19.5
g, 68% yield) as a yellow solid:
[1157] .sup.1H-NMR (CDCl.sub.3): 8.85 (s, 1H), 7.40 (s, 1H), 7.38
(s, 1H), 4.38 (t, 2H), 4.03 (s, 3H), 3.80 (t, 2H), 2.40 (m,
2H):
[1158] MS (+ve ESI): 287 (M+H).sup.+.
EXAMPLE 147
Preparation of Compound 147 in Table
7--N-(2,3-difluorophenyl)-3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propo-
xy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazole-5-carboxamide
[1159] An analogous reaction to that described in example 146, but
starting with
3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-N-(2,3-difluoroph-
enyl)-1H-pyrazole-5-carboxamide (120 mg, 0.23 mmol) yielded
compound 147 in table 7 (59 mg, 45% yield):
[1160] .sup.1H-NMR (DMSO d.sub.6, TFA): 9.03 (s, 1H), 8.32 (s, 1H),
7.69 (s, 1H), 7.50 (m, 1H), 7.41 (s, 1H), 7.30 (m, 3H), 4.33 (m,
2H), 4.03 (s, 3H), 3.82 (m, 2H), 3.40 (m, 2H), 3.31 (m, 2H), 3.13
(m, 2H), 2.33 (m, 2H), 2.15 (m, 1H), 1.03 (d, 6H):
[1161] MS (+ve ESI): 570.2 (M+H).sup.+.
[1162]
3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-N-(2,3-difl-
uorophenyl)-1H-pyrazole-5-carboxamide used as starting material was
obtained as follows:
[1163] a) An analogous reaction to that described in 146a, but
starting with 2,3-difluoroaniline (212 .mu.l, 2.1 mmol) yielded
N-(2,3-difluorophenyl)-3-nitro-1H-pyrazole-5-carboxamide (200 mg,
0.74 mmol) (230 mg, 45% yield):
[1164] .sup.1H-NMR (DMSO d.sub.6): 7.86 (s, 1H), 7.43 (m, 1H), 7.37
(m, 1H), 7.29 (m, 1H).
[1165] b) An analogous reaction to that described in 146b, but
starting with
N-(2,3-difluorophenyl)-3-nitro-1H-pyrazole-5-carboxamide (200 mg,
0.74 mmol) yielded
3-amino-N-(2,3-difluorophenyl)-1H-pyrazole-5-carboxamide (161 mg,
91% yield):
[1166] .sup.1H-NMR (DMSO d.sub.6): 9.50 (s, 1H), 7.72 (s, 1H), 7.20
(m, 2H), 5.72 (s, 1H), 5.28 (s, 2H).
[1167] c) An analogous reaction to that described in 146c, but
starting with
3-amino-N-(2,3-difluorophenyl)-1H-pyrazole-5-carboxamide (124 mg,
0.52 mmol) yielded
3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-N-(2,3-difluoroph-
enyl)-1H-pyrazole-5-carboxamide (246 mg, 89% yield):
[1168] .sup.1H-NMR (DMSO d.sub.6, TFA): 9.02 (s, 1H), 8.32 (s, 1H),
7.69 (s, 1H), 7.52 (m, 1H), 7.43 (s, 1H), 7.27 (m, 2H), 4.36 (t,
2H), 4.04 (s, 3H), 3.85 (t, 2H), 2.33 (m, 2H):
[1169] MS (+ve ESI): 489.0 (M+H).sup.+.
Sequence CWU 1
1
4133DNAArtificial SequenceSynthetic 1tacccatacg atgttccaga
ttacgcttct taa 33210PRTArtificial SequenceSynthetic 2Tyr Pro Tyr
Asp Val Pro Asp Tyr Ala Ser1 5 10328PRTArtificial SequenceSynthetic
3Leu Arg Arg Trp Ser Leu Gly Leu Arg Arg Trp Ser Leu Gly Leu Arg1 5
10 15Arg Trp Ser Leu Gly Leu Arg Arg Trp Ser Leu Gly 20
25428PRTArtificial SequenceSynthetic 4Leu Arg Arg Trp Ser Leu Gly
Leu Arg Arg Trp Ser Leu Gly Leu Arg1 5 10 15Arg Trp Ser Leu Gly Leu
Arg Arg Trp Ser Leu Gly 20 25
* * * * *