U.S. patent application number 12/902543 was filed with the patent office on 2011-09-29 for quinazoline derivatives as antiproliferative agents.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Bernard Christophe Barlaam, Christopher Thomas Halsall, Laurent Francois Andre Hennequin.
Application Number | 20110237610 12/902543 |
Document ID | / |
Family ID | 29286773 |
Filed Date | 2011-09-29 |
United States Patent
Application |
20110237610 |
Kind Code |
A1 |
Barlaam; Bernard Christophe ;
et al. |
September 29, 2011 |
Quinazoline Derivatives as Antiproliferative Agents
Abstract
The invention concerns quinazoline derivatives of Formula I
##STR00001## wherein each of R.sup.1a, R.sup.1b, R.sup.2, R.sup.3
and a have any of the meanings defined in the description;
processes for their preparation, pharmaceutical compositions
containing them and their use in the manufacture of a medicament
for use as an antiproliferative agent in the prevention or
treatment of tumours which are sensitive to inhibition of erbB
receptor tyrosine kinases.
Inventors: |
Barlaam; Bernard Christophe;
(Reims, FR) ; Hennequin; Laurent Francois Andre;
(Reims, FR) ; Halsall; Christopher Thomas;
(Macclesfield, GB) |
Assignee: |
AstraZeneca AB
Sodertalje
SE
|
Family ID: |
29286773 |
Appl. No.: |
12/902543 |
Filed: |
October 12, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10572794 |
Mar 21, 2006 |
7838530 |
|
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PCT/GB2004/004137 |
Sep 22, 2004 |
|
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12902543 |
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Current U.S.
Class: |
514/266.22 ;
544/284; 544/293 |
Current CPC
Class: |
C07D 405/14 20130101;
C07D 413/14 20130101; A61P 17/06 20180101; C07D 401/12 20130101;
A61P 35/02 20180101; C07D 409/14 20130101; A61P 13/08 20180101;
A61P 43/00 20180101; C07D 401/14 20130101; A61P 35/00 20180101;
A61P 9/10 20180101 |
Class at
Publication: |
514/266.22 ;
544/293; 544/284 |
International
Class: |
A61K 31/517 20060101
A61K031/517; C07D 409/14 20060101 C07D409/14; C07D 413/14 20060101
C07D413/14; C07D 401/12 20060101 C07D401/12; C07D 401/14 20060101
C07D401/14; A61P 35/00 20060101 A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 25, 2003 |
GB |
0322409.4 |
Claims
1: A quinazoline derivative of the Formula I: ##STR00220## wherein:
one of R.sup.1a or R.sup.1b is a group of sub-formula (i)
Q.sup.2-X.sup.1--Z-Q.sup.1-X.sup.2--O-- (i) wherein: X.sup.1 is a
direct bond or a methylene or ethylene group; X.sup.2 is a direct
bond; Z is --C(O)--, --NR.sup.10--C(O)-- (wherein R.sup.10 is H or
(1-6C)alkyl), or --O--C(O)--; Q.sup.1 is piperidin-4-yl or
piperidin-3-yl; Q.sup.2 is selected from furyl, thienyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl,
pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, oxadiazolyl, furazanyl, thiadiazolyl, tetrazolyl,
quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, phthalazinyl,
quinoxalinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,
benzimidazolyl, benzothiazolyl, purinyl, phenyl and naphthyl; and
is optionally substituted by 1 or 2 substituents, which may be the
same or different, selected from halogeno, hydroxy, nitro, amino,
cyano, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkanoyl and
(1-4C)alkylsulfonyl, (1-4C)alkylamino, di[(1-4C)alkyl]amino,
N-[(1-4C)alkyl]carbamoyl, and N,N-di[(1-4C)alkyl]carbamoyl; and the
other of R.sup.1a or R.sup.1b is a group R.sup.1 which is methoxy;
R.sup.2 is hydrogen; and the group of sub-formula (ii) ##STR00221##
in formula (I) is 3-chloro-2-fluorophenyl; or a pharmaceutically
acceptable salt thereof; subject to the following proviso; when
Q.sup.2 is phenyl or naphthyl, then R.sup.1a is a group of
sub-formula (i) defined above and R.sup.1b is the group R.sup.1
defined above.
2. (canceled)
3. The quinazoline derivative according to claim 1, wherein
R.sup.1a is a group of sub-formula (i), and R.sup.1b is a group
R.sup.1 as defined in claim 1.
4. The quinazoline derivative according to claim 1, wherein
R.sup.1a is a group R.sup.1, and R.sup.1b is a group of sub-formula
(i) as defined in claim 1.
5-11. (canceled)
12. The quinazoline derivative according to claim 1, wherein Z is
--C(O)--.
13. The quinazoline derivative according to claim 1, wherein Z is
selected from --NH--C(O)-- and --O--C(O)--.
14-18. (canceled)
19. The quinazoline derivative according to claim 1 wherein Q.sup.2
is selected from furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,
oxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, oxadiazolyl, furazanyl, thiadiazolyl or
tetrazolyl.
20. (canceled)
21. The quinazoline derivative according to claim 1, wherein
Q.sup.2 is selected from quinolinyl, isoquinolinyl, cinnolinyl,
quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, isoindolyl,
benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl or
purinyl.
22. The quinazoline derivative according to claim 1, wherein
Q.sup.2 is selected from phenyl and naphthyl.
23-30. (canceled)
31. A compound as claimed in claim 1 selected from (1)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[1-(pyridin-3-ylcarbonyl)piperid-
in-4-yl]oxy}quinazolin-4-amine; (2)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[1-(pyridin-2-ylcarbonyl)piperid-
in-4-yl]oxy}quinazolin-4-amine; (3)
N-(3-chloro-2-fluorophenyl)-6-{[1-(2-furoyl)piperidin-4-yl]oxy}-7-methoxy-
quinazolin-4-amine; (4)
N-(3-chloro-2-fluorophenyl)-7-{[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]ox-
y}-6-methoxyquinazolin-4-amine; (5)
N-(3-chloro-2-fluorophenyl)-7-{[1-(2-furoyl)piperidin-4-yl]oxy}-6-methoxy-
quinazolin-4-amine; (6)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(2-thienylacetyl)piperid-
in-3-yl]oxy}quinazolin-4-amine; (7)
N-(3-chloro-2-fluorophenyl)-6-{[(3R)-1-isonicotinoylpiperidin-3-yl]oxy}-7-
-methoxyquinazolin-4-amine; (8)
6-({(3R)-1-[(2-aminopyridin-3-yl)carbonyl]piperidin-3-yl}oxy)-N-(3-chloro-
-2-fluorophenyl)-7-methoxyquinazolin-4-amine; (9)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(1H-pyrrol-2-ylcarbonyl)-
piperidin-3-yl]oxy}quinazolin-4-amine; (10)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(2-thienylcarbonyl)piper-
idin-3-yl]oxy}quinazolin-4-amine; (11)
N-(3-chloro-2-fluorophenyl)-6-{[(3R)-1-(2-furoyl)piperidin-3-yl]oxy}-7-me-
thoxyquinazolin-4-amine; (12)
N-(3-chloro-2-fluorophenyl)-6-{[(3R)-1-(3-furoyl)piperidin-3-yl]oxy}-7-me-
thoxyquinazolin-4-amine; (13)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(3-thienylcarbonyl)piper-
idin-3-yl]oxy}quinazolin-4-amine; (14)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(3-thienylacetyl)piperid-
in-3-yl]oxy}quinazolin-4-amine; (15)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({(3R)-1-[(1-methyl-1H-pyrrol-2-y-
l)carbonyl]piperidin-3-yl}oxy)quinazolin-4-amine; (16)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({(3R)-1-[(4-nitro-1H-pyrazol-1-y-
l)acetyl]piperidin-3-yl}oxy)quinazolin-4-amine; (17)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(4-{N,N-dimethylcarbamoy-
l}-1H-pyrazol-1-ylacetyl)piperidin-3-yl]oxy}quinazolin-4-amine;
(18)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(4-cyano-1H-pyrazol-1-yl-
acetyl)piperidin-3-yl]oxy}quinazolin-4-amine; (19)
4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-ph-
enylpiperidine-1-carboxamide; (20)
N-Benzyl-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-
oxy)piperidine-1-carboxamide; (21)
4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-[4-
-(dimethylamino)phenyl]piperidine-1-carboxamide; (22)
4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-(2-
-phenylethyl)piperidine-1-carboxamide; (23)
4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-(3-
,4-dimethoxyphenyl)piperidine-1-carboxamide; (24)
4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-(3-
-fluorophenyl)piperidine-1-carboxamide; (25)
4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-2--
thienylpiperidine-1-carboxamide; and (26)
4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-3--
thienylpiperidine-1-carboxamide.
32-33. (canceled)
34. A pharmaceutical composition which comprises a quinazoline
derivative of the Formula I, or a pharmaceutically-acceptable salt
thereof, as defined in any one of claims 1, 3, 4, 12, 13, 19, 21,
22 and 31 in association with a pharmaceutically-acceptable diluent
or carrier.
35-36. (canceled)
37. A method for producing an anti-proliferative effect in
warm-blooded animal in need of such treatment which comprises
administering to said animal a quinazoline derivative of the
Formula I, or a pharmaceutically acceptable salt thereof; as
defined in claim 1.
Description
[0001] The invention concerns certain novel quinazoline
derivatives, or pharmaceutically-acceptable salts thereof, which
possess anti-tumour activity and are accordingly useful in methods
of treatment of the human or animal body. The invention also
concerns processes for the manufacture of said quinazoline
derivatives, to pharmaceutical compositions containing them and to
their use in therapeutic methods, for example in the manufacture of
medicaments for use in the prevention or treatment of solid tumour
disease in a warm-blooded animal such as man.
[0002] Many of the current treatment regimes for diseases resulting
from the abnormal regulation of cellular proliferation such as
psoriasis and cancer, utilise compounds that inhibit DNA synthesis
and cellular proliferation. To date, compounds used in such
treatments are generally toxic to cells however their enhanced
effects on rapidly dividing cells such as tumour cells can be
beneficial. Alternative approaches to these cytotoxic anti-tumour
agents are currently being developed, for example selective
inhibitors of cell signalling pathways. These types of inhibitors
are likely to have the potential to display an enhanced selectivity
of action against tumour cells and so are likely to reduce the
probability of the therapy possessing unwanted side effects.
[0003] Eukaryotic cells are continually responding to many diverse
extracellular signals that enable communication between cells
within an organism. These signals regulate a wide variety of
physical responses in the cell including proliferation,
differentiation, apoptosis and motility. The extracellular signals
take the form of a diverse variety of soluble factors including
growth factors as well as paracrine and endocrine factors. By
binding to specific transmembrane receptors, these ligands
integrate the extracellular signal to the intracellular signalling
pathways, therefore transducing the signal across the plasma
membrane and allowing the individual cell to respond to its
extracellular signals. Many of these signal transduction processes
utilise the reversible process of the phosphorylation of proteins
that are involved in the promotion of these diverse cellular
responses. The phosphorylation status of target proteins is
regulated by specific kinases and phosphatases that are responsible
for the regulation of about one third of all proteins encoded by
the mammalian genome. As phosphorylation is such an important
regulatory mechanism in the signal transduction process, it is
therefore not surprising that aberrations in these intracellular
pathways result in abnormal cell growth and differentiation and so
promote cellular transformation (reviewed in Cohen et al, Curr Opin
Chem Biol, 1999, 3, 459-465).
[0004] It has been widely shown that a number of these tyrosine
kinases are mutated to constitutively active forms and/or when
over-expressed result in the transformation of a variety of human
cells. These mutated and over-expressed forms of the kinase are
present in a large proportion of human tumours (reviewed in
Kolibaba et al, Biochimica et Biophysica Acta, 1997, 133,
F217-F248). As tyrosine kinases play fundamental roles in the
proliferation and differentiation of a variety of tissues, much
focus has centred on these enzymes in the development of novel
anti-cancer therapies. This family of enzymes is divided into two
groups--receptor and non-receptor tyrosine kinases e.g. EGF
Receptors and the SRC family respectively. From the results of a
large number of studies including the Human Genome Project, about
90 tyrosine kinase have been identified in the human genome, of
this 58 are of the receptor type and 32 are of the non-receptor
type. These can be compartmentalised in to 20 receptor tyrosine
kinase and 10 non-receptor tyrosine kinase sub-families (Robinson
et al, Oncogene, 2000, 19, 5548-5557).
[0005] The receptor tyrosine kinases are of particular importance
in the transmission of mitogenic signals that initiate cellular
replication. These large glycoproteins, which span the plasma
membrane of the cell, possess an extracellular binding domain for
their specific ligands (such as Epidermal Growth Factor (EGF) for
the EGF Receptor). Binding of a ligand results in the activation of
the receptor's kinase enzymatic activity that is encoded by the
intracellular portion of the receptor. This activity phosphorylates
key tyrosine amino acids in target proteins, resulting in the
transduction of proliferative signals across the plasma membrane of
the cell.
[0006] It is known that the erbB family of receptor tyrosine
kinases, which include EGFR, erbB2, erbB3 and erbB4, are frequently
involved in driving the proliferation and survival of tumour cells
(reviewed in Olayioye et al., EMBO J., 2000, 19, 3159). One
mechanism in which this can be accomplished is by over expression
of the receptor at the protein level, generally as a result of gene
amplification. This has been observed in many common human cancers
(reviewed in Klapper et al., Adv. Cancer Res., 2000, 77, 25) such
as breast cancer (Sainsbury et al., Brit. J. Cancer, 1988, 58, 458;
Guerin et al., Oncogene Res., 1988, 3, 21; Slamon et al., Science,
1989, 244, 707; Klijn et al., Breast Cancer Res. Treat., 1994, 29,
73 and reviewed in Salomon et al., Crit. Rev. Oncol. Hematol.,
1995, 19, 183), non-small cell lung cancers (NSCLCs) including
adenocarcinomas (Cerny et al., Brit. J. Cancer, 1986, 54, 265;
Reubi et al., Int. J. Cancer, 1990, 45, 269; Rusch et al., Cancer
Research, 1993, 53, 2379; Brabender et al, Clin. Cancer Res., 2001,
7, 1850) as well as other cancers of the lung (Hendler et al.,
Cancer Cells, 1989, 7, 347; Ohsaki et al., Oncol. Rep., 2000, 7,
603), bladder cancer (Neal et al., Lancet, 1985, 366; Chow et al.,
Clin. Cancer Res., 2001, 7, 1957, Zhau et al., Mol. Carcinog., 3,
254), oesophageal cancer (Mukaida et al., Cancer, 1991, 68, 142),
gastrointestinal cancer such as colon, rectal or stomach cancer
(Bolen et al., Oncogene Res., 1987, 1, 149; Kapitanovic et al.,
Gastroenterology, 2000, 112, 1103; Ross et al., Cancer Invest.,
2001, 19, 554), cancer of the prostate (Visakorpi et al.,
Histochem. J., 1992, 24, 481; Kumar et al., 2000, 32, 73; Scher et
al., J. Natl. Cancer Inst., 2000, 92, 1866), leukaemia (Konaka et
al., Cell, 1984, 37, 1035, Martin-Subero et al., Cancer Genet
Cytogenet., 2001, 127, 174), ovarian (Hellstrom et al., Cancer
Res., 2001, 61, 2420), head and neck (Shiga et al., Head Neck,
2000, 22, 599) or pancreatic cancer (Ovotny et al., Neoplasma,
2001, 48, 188). As more human tumour tissues are tested for
expression of the erbB family of receptor tyrosine kinases it is
expected that their widespread prevalence and importance will be
further enhanced in the future.
[0007] As a consequence of the mis-regulation of one or more of
these receptors, it is widely believed that many tumours become
clinically more aggressive and so correlate with a poorer prognosis
for the patient (Brabender et al, Clin. Cancer Res., 2001, 7, 1850;
Ross et al, Cancer Investigation, 2001, 19, 554, Yu et al.,
Bioassays, 2000, 22.7, 673). In addition to these clinical
findings, a wealth of pre-clinical information suggests that the
erbB family of receptor tyrosine kinases are involved in cellular
transformation. This includes the observations that many tumour
cell lines over express one or more of the erbB receptors and that
EGFR or erbB2 when transfected into non-tumour cells have the
ability to transform these cells. This tumourigenic potential has
been further verified as transgenic mice that over express erbB2
spontaneously develop tumours in the mammary gland. In addition to
this, a number of pre-clinical studies have demonstrated that
anti-proliferative effects can be induced by knocking out one or
more erbB activities by small molecule inhibitors, dominant
negatives or inhibitory antibodies (reviewed in Mendelsohn et al.,
Oncogene, 2000, 19, 6550). Thus it has been recognised that
inhibitors of these receptor tyrosine kinases should be of value as
a selective inhibitor of the proliferation of mammalian cancer
cells (Yaish et al. Science, 1988, 242, 933, Kolibaba et al,
Biochimica et Biophysica Acta, 1997, 133, F217-F248; Al-Obeidi et
al, 2000, Oncogene, 19, 5690-5701; Mendelsohn et al, 2000,
Oncogene, 19, 6550-6565). In addition to this pre-clinical data,
findings using inhibitory antibodies against EGFR and erbB2 (c-225
and trastuzumab respectively) have proven to be beneficial in the
clinic for the treatment of selected solid tumours (reviewed in
Mendelsohn et al, 2000, Oncogene, 19, 6550-6565).
[0008] Amplification and/or activity of members of the erbB type
receptor tyrosine kinases have been detected and so have been
implicated to play a role in a number of non-malignant
proliferative disorders such as psoriasis (Ben-Bassat, Curr. Pharm.
Des., 2000, 6, 933; Elder et al., Science, 1989, 243, 811), benign
prostatic hyperplasia (BPH) (Kumar et al., Int. Urol. Nephrol.,
2000, 32, 73), atherosclerosis and restenosis (Bokemeyer et al.,
Kidney Int., 2000, 58, 549). It is therefore expected that
inhibitors of erbB type receptor tyrosine kinases will be useful in
the treatment of these and other non-malignant disorders of
excessive cellular proliferation.
[0009] European patent application publication number EP 566 226
discloses certain 4-anilinoquinazolines that are receptor tyrosine
kinase inhibitors.
[0010] International patent application publication numbers WO
96/33977, WO 96/33978, WO 96/33979, WO 96/33980, WO 96/33981, WO
97/30034, WO 97/38994 disclose that certain quinazoline
derivatives, which bear an anilino substituent at the 4-position
and a substituent at the 6- and/or 7-position, possess receptor
tyrosine kinase inhibitory activity.
[0011] European patent application publication number EP 837 063
discloses aryl substituted 4-aminoquinazoline derivatives carrying
moiety containing an aryl or heteroaryl group at the 6- or
7-position on the quinazoline ring. The compounds are stated to be
useful for treating hyperproliferative disorders.
[0012] International patent application publication numbers WO
97/30035 and WO 98/13354 disclose certain 4-anilinoquinazolines
substituted at the 7-position are vascular endothelial growth
factor receptor tyrosine kinase inhibitors.
[0013] WO 00/55141 discloses 6,7-substituted 4-anilinoquinazoline
compounds characterised in that the substituents at the 6- and/or
7-position carry an ester-linked moiety (RO--CO).
[0014] WO 00/56720 discloses 6,7-dialkoxy-4-anilinoquinazoline
compounds for the treatment of cancer or allergic reactions.
[0015] WO 02/41882 discloses 4-anilinoquinazoline compounds
substituted at the 6- and/or 7-positions by a substituted
pyrrolidinyl-alkoxy or piperidinyl-alkoxy group.
[0016] International patent application publication number WO
2004/006846 discloses that certain quinazoline derivatives, which
bear an anilino substituent at the 4-position and a substituent at
the 6- and 7-positions, are capable of modulating tyrosine kinase
activity, particularly ephrin and EGFR. Particular compounds
disclosed in WO 2004/006846 are:
N-(3,4-dichlorophenyl)-7-[({4-[(3,5-dimethylisoxazol-4-yl)carbonyl]morpho-
lin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine;
N-(3,4-dichlorophenyl)-7-({[4-(furan-3-ylcarbonyl)morpholin-2-yl]methyl}o-
xy)-6-(methyloxy)quinazolin-4-amine;
7-[({4-[(2-chloropyridin-3-yl)carbonyl]morpholin-2-yl}methyl)oxy]-N-(3,4--
dichlorophenyl)-6-(methyloxy)quinazolin-4-amine; and
7-[({4-[(6-chloropyridin-3-yl)carbonyl]morpholin-2-yl}methyl)oxy]-N-(3,4--
dichlorophenyl)-6-(methyloxy)quinazolin-4-amine.
[0017] We have now surprisingly found that other
4-(anilino)quinazoline derivatives possess potent anti-tumour
activity. Without wishing to imply that the compounds disclosed in
the present invention possess pharmacological activity only by
virtue of an effect on a single biological process, it is believed
that the compounds provide an anti-tumour effect by way of
inhibition of one or more of the erbB family of receptor tyrosine
kinases that are involved in the signal transduction steps which
lead to the proliferation of tumour cells. In particular, it is
believed that the compounds of the present invention provide an
anti-tumour effect by way of inhibition of EGFR and/or erbB2
receptor tyrosine kinases.
[0018] Generally the compounds of the present invention possess
potent inhibitory activity against the erbB receptor tyrosine
kinase family, for example by inhibition of EGFR and/or erbB2
and/or erbB4 receptor tyrosine kinases, whilst possessing less
potent inhibitory activity against other kinases. Furthermore,
certain compounds of the present invention possess substantially
better potency against the EGFR over that of the erbB2 tyrosine
kinase. The invention also includes compounds that are active
against all or a combination of EGFR, erbB2 and erbB4 receptor
tyrosine kinases, thus potentially providing treatments for
conditions mediated by one or more of these receptor tyrosine
kinases.
[0019] Generally the compounds of the present invention exhibit
favourable physical properties such as a high solubility whilst
retaining high antiproliferative activity. Furthermore, many of the
compounds according to the present invention are inactive or only
weakly active in a hERG assay.
[0020] According to a first aspect of the invention there is
provided a quinazoline derivative of the Formula I:
##STR00002##
wherein: one of R.sup.1a or R.sup.1b is a group of sub-formula
(i)
Q.sup.2-X.sup.1--Z-Q.sup.1-X.sup.2--O-- (i)
where X.sup.2 and X.sup.1 are independently selected from a direct
bond or a group --[CR.sup.4R.sup.5].sub.m--, wherein m is an
integer from 1 to 6, Z is C(O), SO.sub.2, --C(O)NR.sup.10--,
--N(R.sup.10)C(O)--, --C(O)O-- or --OC(O)-- where R.sup.10 is
hydrogen or (1-6C)alkyl, and each of R.sup.4 and R.sup.3 is
independently selected from hydrogen, hydroxy, (1-4C)alkyl,
halo(1-4C)alkyl, hydroxy (1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, or
R.sup.4 and R.sup.5 together with the carbon atom(s) to which they
are attached form a (3-7)cycloalkyl ring, provided that when a
group R.sup.4 or R.sup.5 is hydroxy, m is at least 2 and the carbon
atom to which the hydroxy group is attached is not also attached to
another oxygen or a nitrogen atom; Q.sup.1 is (3-7C)cycloalkylene
or heterocyclyl group, which is optionally substituted by one or
two substituents selected from halogeno, trifluoromethyl,
trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl,
acryloyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,
(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,
(2-6C)alkenylthio, (2-6C)alkynylthio, (1-6C)alkylsulfinyl,
(2-6C)alkenylsulfinyl, (2-6C)alkynylsulfinyl, (1-6C)alkylsulfonyl,
(2-6C)alkenylsulfonyl, (2-6C)alkynylsulfonyl, (1-6C)alkylamino,
di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, sulfamoyl,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,
(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,
carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl, sulfamoyl(1-6C)alkyl,
N-(1-6C)alkylsulfamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]sulfamoyl(1-6C)alkyl,
(2-6C)alkanoyl(1-6C)alkyl, (2-6C)alkanoyloxy(1-6C)alkyl,
(2-6C)alkanoylamino(1-6C)alkyl,
N-(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl and
(1-6C)alkoxycarbonyl(1-6C)alkyl; Q.sup.2 is an aryl or heteroaryl
group, said aryl or heteroaryl group being optionally substituted
by one of more substituents selected from halogeno,
trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino,
carboxy, carbamoyl, acryloyl, (1-6C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,
(1-6C)alkylthio, (2-6C)alkenylthio, (2-6C)alkynylthio,
(1-6C)alkylsulfinyl, (2-6C)alkenylsulfinyl, (2-6C)alkynylsulfinyl,
(1-6C)alkylsulfonyl, (2-6C)alkenylsulfonyl, (2-6C)alkynylsulfonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, sulfamoyl,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,
(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,
carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl, sulfamoyl(1-6C)alkyl,
N-(1-6C)alkylsulfamoyl(1-6C)alkyl, N,N-di-[(1-6C)alkyl]sulfamoyl
(1-6C)alkyl, (2-6C)alkanoyl(1-6C)alkyl,
(2-6C)alkanoyloxy(1-6C)alkyl, (2-6C)alkanoylamino (1-6C)alkyl,
N-(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl and
(1-6C)alkoxycarbonyl(1-6C)alkyl,
[0021] and wherein any (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl
and (2-6C)alkanoyl substituent on Q.sup.1 or Q.sup.2 optionally
bears one or more substituents (for example 1, 2 or 3) which may be
the same or different selected from halogeno, hydroxy and
(1-6C)alkyl and/or optionally a substituent selected from cyano,
nitro, carboxy, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,
hydroxy(1-6C)alkoxy, (1-4C)alkoxy(1-6C)alkoxy, (2-6C)alkanoyl,
(2-6C)alkanoyloxy and NR.sup.aR.sup.b, wherein R.sup.a is hydrogen
or (1-4C)alkyl and R.sup.b is hydrogen or (1-4C)alkyl, and wherein
any (1-4C)alkyl in R.sup.a or R.sup.b optionally bears one or more
substituents (for example 1, 2 or 3) which may be the same or
different selected from halogeno and hydroxy and/or optionally a
substituent selected from cyano, nitro, (2-4C)alkenyl,
(2-4C)alkynyl, (1-4C)alkoxy, hydroxy(1-4C)alkoxy and
(1-2C)alkoxy(1-4C)alkoxy,
[0022] or R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a 4, 5 or 6 membered ring, which
optionally bears 1 or 2 substituents, which may be the same or
different, on an available ring carbon atom selected from halogeno,
hydroxy, (1-4C)alkyl and (1-3C)alkylenedioxy, and may optionally
bear on any available ring nitrogen a substituent (provided the
ring is not thereby quaternised) selected from (1-4C)alkyl,
(2-4C)alkanoyl and (1-4C)alkylsulfonyl,
[0023] and wherein any (1-4C)alkyl or (2-4C)alkanoyl group present
as a substituent on the ring formed by R.sup.a and R.sup.b together
with the nitrogen atom to which they are attached, optionally bears
one or more substituents (for example 1, 2 or 3) which may be the
same or different selected from halogeno and hydroxy and/or
optionally a substituent selected from (1-4C)alkyl and
(1-4C)alkoxy;
[0024] and wherein any heterocyclyl group Q.sup.1--group optionally
bears 1 or 2 oxo (.dbd.O) or thioxo (.dbd.S) substituents;
[0025] and the other of R.sup.1a or R.sup.1b is a group R.sup.1
which is selected from hydrogen, hydroxy, (1-6C)alkoxy,
(2-6C)alkenyloxy, (2-6C)alkynyloxy, or a group of the formula:
Q.sup.4-X.sup.3--
wherein X.sup.3 is a direct bond or is selected from O or S, and
Q.sup.4 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl,
(3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or
heterocyclyl-(1-6C)alkyl,
[0026] and wherein adjacent carbon atoms in any (2-6C)alkylene
chain within a R.sup.1 substituent are optionally separated by the
insertion into the chain of a group selected from O, S, SO,
SO.sub.2, N(R.sup.4), CO, CH(OR.sup.4), CON(R.sup.4), N(R.sup.4)CO,
SO.sub.2N(R.sup.4), N(R.sup.4)SO.sub.2, CH.dbd.CH and C.ident.C
wherein R.sup.4 is hydrogen or (1-6C)alkyl,
[0027] and wherein any CH.sub.2.dbd.CH-- or HC.ident.C-- group
within a R.sup.1 substituent optionally bears at the terminal
CH.sub.2.dbd. or HC.ident. position a substituent selected from
halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and
di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the
formula:
Q.sup.5-X.sup.4--
wherein X.sup.4 is a direct bond or is selected from CO and
N(R.sup.5)CO, wherein R.sup.5 is hydrogen or (1-6C)alkyl, and
Q.sup.5 is heterocyclyl or heterocyclyl-(1-6C)alkyl,
[0028] and wherein any alkyl or alkylene group within a R.sup.1
substituent optionally bears one or more halogeno, (1-6C)alkyl,
hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (1-6C)alkoxy,
(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl,
N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and
N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the
formula:
--X.sup.5-Q.sup.6
wherein X.sup.5 is a direct bond or is selected from O, S, SO,
SO.sub.2, N(R.sup.6), CO, CH(OR.sup.6), CON(R.sup.6), N(R.sup.6)CO,
SO.sub.2N(R.sup.6), N(R.sup.6)SO.sub.2, C(R.sup.6).sub.2O,
C(R.sup.6).sub.2S and C(R.sup.6).sub.2N(R.sup.6), wherein R.sup.6
is hydrogen or (1-6C)alkyl, and Q.sup.6 is (3-7C)cycloalkyl,
(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,
(3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or
heterocyclyl-(1-6C)alkyl,
[0029] and wherein any heterocyclyl group within a substituent on
R.sup.1 optionally bears 1, 2 or 3 substituents, which may be the
same or different, selected from halogeno, trifluoromethyl, cyano,
nitro, hydroxy, amino, carboxy, carbamoyl, formyl, mercapto,
(1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,
(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,
(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,
di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl,
N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino, and
N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the
formula:
--X.sup.6--R.sup.7
wherein X.sup.6 is a direct bond or is selected from O, N(R.sup.8)
and C(O), wherein R.sup.8 is hydrogen or (1-6C)alkyl, and R.sup.7
is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, carboxy-(1-6C)alkyl,
(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,
(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,
(2-6C)alkanoylamino-(1-6C)alkyl,
(1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,
N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl,
(2-6C)alkanoyl-(1-6C)alkyl or (1-6C)alkoxycarbonyl-(1-6C)alkyl,
[0030] and wherein any heterocyclyl group within a substituent on
R.sup.1 optionally bears 1 or 2 oxo or thioxo substituents;
[0031] R.sup.2 is selected from hydrogen and (1-6C)alkyl;
[0032] each R.sup.3, which may be the same or different, is
selected from halogeno, cyano, nitro, hydroxy, amino, carboxy,
carbamoyl, sulfamoyl, trifluoromethyl, (1-6C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,
(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
N-(1-6C)alkylsulfamoyl, and N,N-di-[(1-6C)alkyl]sulfamoyl
a is 1, 2, 3, 4 or 5; or a pharmaceutically acceptable salt
thereof; subject to the following provisos:
[0033] (i) when Q.sup.2 is aryl, then R.sup.1a is a group of
sub-formula (i) defined above and R.sup.1b is the group R.sup.1
defined above; and
[0034] (ii) the compound of formula I is not one of the following:
[0035]
N-(3,4-dichlorophenyl)-7-[({4-[(3,5-dimethylisoxazol-4-yl)carbonyl]morpho-
lin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine; [0036]
N-(3,4-dichlorophenyl)-7-({[4-(furan-3-ylcarbonyl)morpholin-2-yl]methyl}o-
xy)-6-(methyloxy)quinazolin-4-amine; [0037]
7-[({4-[(2-chloropyridin-3-yl)carbonyl]morpholin-2-yl}methyl)oxy]-N-(3,4--
dichlorophenyl)-6-(methyloxy)quinazolin-4-amine; or [0038]
7-[({4-[(6-chloropyridin-3-yl)carbonyl]morpholin-2-yl}methyl)oxy]-N-(3,4--
dichlorophenyl)-6-(methyloxy)quinazolin-4-amine.
[0039] In this specification the generic term "alkyl" includes both
straight-chain and branched-chain alkyl groups such as propyl,
isopropyl and tert-butyl, and (3-8C)cycloalkyl groups such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
However references to individual alkyl groups such as "propyl" are
specific for the straight-chain version only, references to
individual branched-chain alkyl groups such as "isopropyl" are
specific for the branched-chain version only and references to
individual cycloalkyl groups such as "cyclopentyl" are specific for
that 5-membered ring only. An analogous convention applies to other
generic terms, for example (1-6C)alkoxy includes methoxy, ethoxy,
cyclopropyloxy and cyclopentyloxy, (1-6C)alkylamino includes
methylamino, ethylamino, cyclobutylamino and cyclohexylamino, and
di-[(1-6Calkyl]amino includes dimethylamino, diethylamino,
N-cyclobutyl-N-methylamino and N-cyclohexyl-N-ethylamino.
[0040] The term "aryl" refers to aromatic hydrocarbon ring systems
and includes, for example, phenyl, indenyl, indanyl, naphthyl and
fluorenyl. Particular values of aryl are phenyl and naphthyl,
preferably phenyl.
[0041] The terms "heterocyclic" or "heterocyclyl" include ring
structures that may be mono- or bicyclic and contain from 3 to 15
atoms, at least one of which, and suitably from 1 to 4 of which, is
a heteroatom such as oxygen, sulphur or nitrogen. Rings may be
aromatic, non-aromatic or partially aromatic in the sense that one
ring of a fused ring system may be aromatic and the other
non-aromatic. Particular examples of such ring systems include
furyl, benzofuranyl, tetrahydrofuryl, chromanyl, thienyl,
benzothienyl, pyridyl, piperidinyl, quinolyl,
1,2,3,4-tetrahydroquinolinyl, isoquinolyl,
1,2,3,4-tetrahydroisoquinolinyl, pyrazinyl, piperazinyl,
pyrimidinyl, pyridazinyl, isoquinolinyl, phthalazinyl, purinyl,
quinoxalinyl, quinazolinyl, cinnolinyl, pyrrolyl, pyrrolidinyl,
indolyl, indolinyl, isoindolyl, imidazolyl, benzimidazolyl,
pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl,
thiazolyl, benzothiazolyl, isothiazolyl, morpholinyl,
4H-1,4-benzoxazinyl, 4H-1,4-benzothiazinyl, 1,2,3-triazolyl,
1,2,4-triazolyl, oxadiazolyl, furazanyl, thiadiazolyl, tetrazolyl,
dibenzofuranyl, dibenzothienyl oxiranyl, oxetanyl, azetidinyl,
tetrahydropyranyl, oxepanyl, oxazepanyl, tetrahydro-1,4-thiazinyl,
1,1-dioxotetrahydro-1,4-thiazinyl, homopiperidinyl,
homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl,
dihydropyrimidinyl, tetrahydropyrimidinyl, tetrahydrothienyl,
tetrahydrothiopyranyl or thiomorpholinyl.
[0042] Where rings include nitrogen atoms, these may carry a
hydrogen atom or a substituent group such as an (C1-6)alkyl group
if required to fulfil the bonding requirements of nitrogen, or they
may be linked to the rest of the structure by way of the nitrogen
atom. A nitrogen atom within a heterocyclyl group may be oxidized
to give the corresponding N oxide.
[0043] The term "heteroaryl" however refers to heterocyclic groups
which are completely aromatic in nature. Particular examples of
such ring systems include furyl, benzofuranyl, thienyl,
benzothienyl, pyridyl, quinolyl, isoquinolyl, phthalazinyl,
purinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinoxalinyl,
quinazolinyl, cinnolinyl, pyrrolyl, indolyl, indolinyl, isoindolyl,
imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, oxazolyl,
benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, furazanyl,
thiadiazolyl, tetrazolyl, dibenzofuranyl or dibenzothienyl.
[0044] In an embodiment of the invention, R.sup.1a is a group of
sub-formula (i) and R.sup.1b is a group R.sup.1.
[0045] In a further embodiment, R.sup.1a is a group R.sup.1 and
R.sup.1b is a group of sub-formula (i).
[0046] Particular examples of groups R.sup.1 are hydrogen, hydroxy,
(1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or a group of the
formula:
Q.sup.4-X.sup.3--
wherein X.sup.3 is a direct bond or is O or S (particularly a
direct bond or O), and Q.sup.4 is (3-7C)cycloalkyl,
(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,
(3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or
heterocyclyl-(1-6C)alkyl, and wherein any alkyl or alkylene group
within a R.sup.1 substituent optionally bears one or more halogeno,
(1-6C)alkyl, hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl,
(1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,
(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,
(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,
(1-6C)alkanesulfonylamino and
N-(1-6C)alkyl-(1-6C)alkanesulfonylamino.
[0047] In particular R.sup.1-- is selected from hydrogen,
(1-6C)alkoxy and (1-6C)alkoxy(1-6C)alkoxy, wherein any (1-6C)alkoxy
group in R.sup.1 optionally bears one or more hydroxy substituents
(suitably 1 or 2) and/or a substituent selected from amino,
(1-4C)alkylamino, di-[(1-4C)alkyl]amino, carbamoyl,
N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl,
sulfamoyl, N-(1-4C)alkylsulfamoyl and
N,N-di-[(1-4C)alkyl]sulfamoyl.
[0048] For instance, R.sup.1 is selected from hydrogen,
(1-6C)alkoxy and (1-4C)alkoxy(1-6C)alkoxy, and wherein any
(1-6C)alkoxy group within R.sup.1 optionally bears 1, 2 or 3
substituents, which may be the same or different, selected from
hydroxy, fluoro and chloro, for example R.sup.1 is selected from
methoxy, ethoxy, isopropyloxy, cyclopropylmethoxy, 2-hydroxyethoxy,
2-fluoroethoxy, 2-methoxyethoxy, 2,2-difluoroethoxy,
2,2,2-trifluoroethoxy or 3-hydroxy-3-methylbutoxy.
[0049] In particular R.sup.1 is selected from hydrogen,
(1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkoxy. For instance, R.sup.1 is
selected from hydrogen, methoxy, ethoxy and 2-methoxyethoxy and
2-hydroxyethoxy. A particular example of a group R.sup.1 is
methoxy.
[0050] In a particular embodiment, X.sup.2 or X.sup.1 is a group
C(R.sup.4R.sup.5).sub.m, wherein R.sup.4 and R.sup.5, which may be
the same or different, are selected from hydrogen, (1-4C)alkyl,
hydroxymethyl, hydroxyethyl or halo(C1-2)alkyl, such as
CH.sub.2CH.sub.2F, CH.sub.2CHF.sub.2 or CH.sub.2CF.sub.3. Where
R.sup.4 and R.sup.5 together with the carbon atom(s) to which they
are attached form a (3-7C) cycloalkyl ring, it is preferably that
both R.sup.4 and R.sup.5 groups are on the same carbon atom. Thus a
particular example of such a group is a cyclopropyl group.
[0051] In particular, R.sup.4 and R.sup.5 are hydrogen. The value
of m is suitably 0, 1 or 2. In particular, m is 1 or 0.
[0052] In a particular embodiment, X.sup.2 is a direct bond.
[0053] X.sup.1 is suitably a direct bond or an (1-6C) alkylene
group such as methyl or ethyl, and in particular is a direct
bond.
[0054] Z is suitably selected from C(O), SO.sub.2,
--C(O)NR.sup.10--, --NR.sup.10--C(O)--, --O--C(O)-- or --C(O)O--,
where R.sup.10 is hydrogen or (1-3C)alkyl such as methyl.
[0055] Preferably any R.sup.10 group is hydrogen.
[0056] In particular compounds of Formula (I), Z is selected from
C(O), --NR.sup.10--C(O)--, and --O--C(O)--.
[0057] In an embodiment, Z is --NR.sup.10--C(O)--, wherein R.sup.10
is H.
[0058] In a further embodiment, Z is --O--C(O)--.
[0059] Preferably, Z is C(O).
[0060] A suitable value for Q.sup.1 when it is (3-7C)cycloalkyl is,
for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl or bicyclo[2.2.1]heptyl.
[0061] When Q.sup.1 is heterocyclyl it is suitably a non-aromatic
saturated (i.e. with the maximum degree of saturation) or partially
saturated (i.e. ring systems retaining some, but not the full,
degree of unsaturation) 3 to 10 membered monocyclic ring with up to
five heteroatoms selected from oxygen, nitrogen and sulfur (but not
containing any O--O, O--S or S--S bonds), and linked via a ring
carbon atom, or a ring nitrogen atom (provided the ring is not
thereby quaternised). Suitable values for Q.sup.1 include for
example, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl,
tetrahydropyranyl, oxepanyl, oxazepanyl, pyrrolinyl, pyrrolidinyl,
morpholinyl, tetrahydro-1,4-thiazinyl,
1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl,
piperazinyl, homopiperazinyl, dihydropyridinyl,
tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl,
tetrahydrothienyl, tetrahydrothiopyranyl, thiomorpholinyl, more
specifically including for example, tetrahydrofuran-3-yl,
tetrahydrofuran-2-yl-, tetrahydropyran-4-yl, tetrahydrothien-3-yl,
tetrahydrothiopyran-4-yl, pyrrolidin-3-yl, pyrrolidin-2-yl,
3-pyrrolin-3-yl-, morpholino,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino,
piperidin-4-yl, piperidin-3-yl, piperidin-2-yl, homopiperidin-3-yl,
homopiperidin-4-yl, piperazin-1-yl, 1,4-oxazepanyl, or
1,2,3,6-tetrahydropyridin-4-yl. A nitrogen or sulfur atom within a
heterocyclyl group may be oxidized to give the corresponding N or S
oxide(s), for example 1,1-dioxotetrahydrothienyl,
1-oxotetrahydrothienyl, 1,1-dioxotetrahydrothiopyranyl or
1-oxotetrahydrothiopyranyl. A suitable value for such a group which
bears 1 or 2 oxo or thioxo substituents is, for example,
2-oxopyrrolidinyl, 2-oxopiperazinyl, 2-thioxopyrrolidinyl,
2-oxopiperidinyl, 2,5-dioxopyrrolidinyl or
2,6-dioxopiperidinyl.
[0062] Particular values for Q.sup.1 include, for example,
non-aromatic saturated or partially saturated 3 to 7 membered
monocyclic heterocyclyl rings with 1 ring nitrogen or sulfur
heteroatom and optionally 1 or 2 heteroatoms selected from
nitrogen, oxygen and sulfur. Examples of such rings include
azetidinyl, oxazepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl,
tetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl,
piperazinyl, homopiperazinyl, dihydropyridinyl,
tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl,
tetrahydrothienyl, tetrahydrothiopyranyl or thiomorpholinyl.
[0063] Further particular values for Q.sup.1 include, for example,
non-aromatic saturated or partially saturated 3 to 7 membered
monocyclic heterocyclyl rings with 1 ring nitrogen heteroatom and
optionally 1 or 2 heteroatoms selected from nitrogen and sulfur,
which rings are linked to X.sup.2--O by a ring carbon atom, such
as, for example, azetidinyl, pyrrolinyl, pyrrolidinyl,
tetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl,
piperazinyl, homopiperazinyl, dihydropyridinyl,
tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl,
tetrahydrothiopyranyl or thiomorpholinyl. More particularly Q.sup.1
is a non-aromatic saturated or partially saturated 4, 5 or 6
membered monocyclic heterocyclyl ring with 1 or 2 ring nitrogen
heteroatom(s), which ring is linked to the group X.sup.2--O-- by a
ring carbon atom, more particularly pyrrolidin-3-yl,
pyrrolidin-2-yl, 3-pyrrolin-3-yl-, piperidin-4-yl, piperidin-3-yl,
piperidin-2-yl, homopiperidin-3-yl, homopiperidin-4-yl,
piperazin-2-yl, piperazin-3-yl, or 1,2,3,6-tetrahydropyridin-4-yl.
A nitrogen atom within a heterocyclyl group may be oxidized to give
the corresponding N oxide.
[0064] In a particular embodiment, Q.sup.1 is piperidin-4-yl.
[0065] In a further embodiment, Q.sup.1 is piperidin-3-yl.
[0066] Suitably, the group Q.sup.2-X.sup.1--Z-- is linked to a
nitrogen atom on a heterocyclic Q.sup.1, in particular when the
group Z is a carbonyl group C(O).
[0067] The group Q.sup.1 optionally carries further
substituents.
[0068] In one embodiment, any available nitrogen in a heterocyclic
Q.sup.1 optionally bears a substituent (where such substitution
does not result in quaternization) selected from trifluoromethyl,
cyano, carbamoyl, trifluoromethyl, (1-6C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl, (1-6C)alkylthio, (1-6C)alkylsulfinyl,
(1-6C)alkylsulfonyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, sulfamoyl,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,
carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl,
(2-6C)alkanoyl(1-6C)alkyl, (2-6C)alkanoyloxy(1-6C)alkyl,
(2-6C)alkanoylamino(1-6C)alkyl,
N-(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl and
(1-6C)alkoxycarbonyl(1-6C)alkyl,
[0069] wherein any (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and
(2-6C)alkanoyl group within an optional substituent on an available
nitrogen is optionally substituted by one or more substituents,
which maybe the same or different, selected from fluoro, chloro,
hydroxy and (1-4C)alkyl, and/or optionally a substituent selected
from cyano, nitro, carboxy, (1-4C)alkoxy, hydroxy(1-4C)alkoxy and
NR.sup.aR.sup.b, wherein R.sup.a is hydrogen or (1-4C)alkyl and
R.sup.b is hydrogen or (1-4C)alkyl.
[0070] Q.sup.1 optionally bears on any available carbon atom in the
ring 1 or 2 (suitably 1) substituents selected from halogeno,
trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl,
(1-4C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-4C)alkoxy,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, hydroxy(1-6C)alkyl,
cyano(1-6C)alkyl, amino(1-6C)alkyl, (1-6C)alkylamino(1-6C)alkyl,
di-[(1-6C)alkyl]amino(1-6C)alkyl and (1-6C)alkoxy(1-6C)alkyl.
[0071] Q.sup.1 optionally also bears 1 or 2 oxo or thioxo
substituents.
[0072] In particular however, Q.sup.1 carries no substituents other
than the group Q.sup.2-X.sup.1--Z--.
[0073] Where Q.sup.2 is heteroaryl, it is suitably a 5 or
6-membered heteroaryl ring which optionally contains one or more
heteroatoms selected from oxygen, nitrogen or sulphur. In
particular, Q.sup.2 is selected from furyl, thienyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl,
pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, furazanyl,
thiadiazolyl, tetrazolyl, or a 9 or 10 membered bicyclic heteroaryl
ring system such as quinolinyl, isoquinolinyl, cinnolinyl,
quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, isoindolyl,
benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl or
purinyl.
[0074] Particular examples include 5-membered rings such as furyl,
thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
oxadiazolyl, furazanyl, thiadiazolyl or tetrazolyl.
[0075] Further examples include 9- or 10-membered bicyclic ring
systems such as indolyl, quinolinyl, benzofuranyl, or
benzothienyl.
[0076] More particularly, Q.sup.2 is selected from isoxazolyl,
furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, indolyl, quinolinyl,
benzofuranyl, or benzothienyl.
[0077] Where Q.sup.2 is aryl, it is suitably selected from phenyl
and naphthyl, particularly phenyl.
[0078] Suitable substituents for group Q.sup.2 include Q.sup.2
optionally bearing 1 or 2 substituents, which may be the same or
different, selected from halogeno, hydroxy, nitro, amino, cyano,
carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkanoyl and
(1-4C)alkylsulfonyl, (1-4C)alkylamino, di[(1-4C)alkyl]amino,
N-[(1-4C)alkyl]carbamoyl, and N,N-di[(1-4C)alkyl]carbamoyl.
[0079] and wherein any (1-4C)alkyl, or (2-4C)alkanoyl group within
Q.sup.2 optionally bears 1 or 2 substituents, which may be the same
or different, selected from halogeno, hydroxy and (1-6C)alkyl
and/or optionally a substituent selected from cyano, (2-8C)alkenyl,
(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkanoyl, (2-6C)alkanoyloxy and
NR.sup.aR.sup.b, wherein R.sup.a is hydrogen or (1-4C)alkyl and
R.sup.b is hydrogen or (1-4C)alkyl, and wherein any (1-4C)alkyl in
R.sup.a or R.sup.b optionally bears one or more substituents (for
example 1, 2 or 3) which may be the same or different selected from
halogeno and hydroxy and/or optionally a substituent selected from
cyano, and (1-4C)alkoxy,
[0080] or R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a 4, 5 or 6 membered ring which does
not contain oxygen, which ring optionally bears 1 or 2
substituents, which may be the same or different, on an available
ring carbon atom selected from halogeno, hydroxy, (1-4C)alkyl and
(1-3C)alkylenedioxy, and may optionally bear on any available ring
nitrogen a substituent (provided the ring is not thereby
quaternised) selected from (1-4C)alkyl, (2-4C)alkanoyl and
(1-4C)alkylsulfonyl,
[0081] and wherein any (1-4C)alkyl or (2-4C)alkanoyl group present
as a substituent on the ring formed by R.sup.a and R.sup.b together
with the nitrogen atom to which they are attached optionally bears
one or more substituents (for example 1, 2 or 3), which may be the
same or different, selected from halogeno and hydroxy and/or
optionally a substituent selected from (1-4C)alkyl and
(1-4C)alkoxy.
[0082] Particular examples of substituents for Q.sup.2 include one
or two groups, which may be the same or different, selected from
halogeno (particularly chloro and bromo and fluoro), hydroxy,
nitro, amino, cyano, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy,
(2-4C)alkanoyl and (1-4C)alkylsulfonyl, [(1-4C)alkyl]amino,
di[(1-4C)alkyl]amino, N-[(1-4C)alkyl]carbamoyl, and
N,N-di[(1-4C)alkyl]carbamoyl.
[0083] and wherein any (2-4C)alkanoyl group in a substituent on
Q.sup.2 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy and (1-3C)alkyl,
[0084] and wherein any (1-4C)alkyl group in a substituent on
Q.sup.2 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy, (1-4C)alkoxy and halogeno
(particularly chloro and more particularly fluoro).
[0085] Suitably Q.sup.2 is unsubstituted or substituted by a
(1-4C)alkyl group such as methyl, a (1-4C)alkoxy group such as
methoxy, halogeno (particularly bromo, chloro or fluoro), amino,
nitro, cyano, carbamoyl, di-[(1-4C)alkyl]amino such as
dimethylamino, and N,N-di[(1-4C)alkyl]carbamoyl such as
N,N-dimethylcarbamoyl.
[0086] Suitably Q.sup.2 is a heteroaryl group optionally
substituted by a (1-4C)alkyl group such as methyl, halogeno
(particularly bromo, chloro or fluoro), amino, nitro, cyano,
[(1-4C)alkyl]amino, di-[(1-4C)alkyl]amino such as dimethylamino,
N-[(1-4C)alkyl]carbamoyl, and N,N-di[(1-4C)alkyl]carbamoyl such as
N,N-dimethylcarbamoyl.
[0087] Suitably Q.sup.2 is an aryl group optionally substituted by
a (1-4C)alkyl group such as methyl, halogeno (particularly bromo,
chloro or fluoro), amino, nitro, [(1-4C)alkyl]amino,
di-[(1-4C)alkyl]amino such as dimethylamino,
N-[(1-4C)alkyl]carbamoyl, and N,N-di[(1-4C)alkyl]carbamoyl such as
N,N-dimethylcarbamoyl.
[0088] R.sup.2 is suitably hydrogen or (1-3C)alkyl such as methyl,
but in particular is hydrogen.
[0089] In an embodiment of the invention, a is 1, 2 or 3.
[0090] Examples of suitable R.sup.3 substituents are halogeno,
carbamoyl, trifluoromethyl, (1-6C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl, N-(1-6C)alkylcarbamoyl, or
N,N-di-[(1-6C)alkyl]carbamoyl.
[0091] In a particular embodiment, when R.sup.3 is in the para
position on the anilino ring it is selected from halogeno, cyano,
nitro, hydroxy, amino, trifluoromethyl, (1-6C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,
(1-6C)alkylthio, (1-6C)alkylamino and di-[(1-6C)alkyl]amino.
[0092] In a particular embodiment at least one R.sup.3, and
suitable all R.sup.3 groups are halogeno, such as chloro or
fluoro.
[0093] Particular examples of the group of sub-formula (ii)
##STR00003##
[0094] in formula (I) are groups of sub-formula in formula (I) are
groups of sub-formula (iii)
##STR00004##
where one of R.sup.15 or R.sup.17 is hydrogen and the other is
halogeno, such as chloro or fluoro, and preferably fluoro, and
R.sup.16 is halogeno such as chloro or fluoro and particularly
chloro.
[0095] Particular examples of such groups are
3-chloro-2-fluorophenyl, or 3-chloro-4-fluorophenyl, especially
3-chloro-2-fluorophenyl.
[0096] In a preferred embodiment of the invention, the compounds
have the general structural formula (A) shown below:
##STR00005##
wherein
[0097] R.sup.15, R.sup.16, and R.sup.17 are as hereinbefore
defined;
[0098] R.sup.1 is (1-4C)alkyl;
[0099] p is 0, 1 or 2; and
[0100] Q.sup.2 is aryl or heteroaryl as hereinbefore defined, which
may be optionally substituted as hereinbefore defined;
[0101] or a pharmaceutically acceptable salt thereof.
[0102] In the compounds of formula (A), or a pharmaceutically
acceptable salt thereof, R.sup.1, R.sup.15, R.sup.16, R.sup.17, p
and Q.sup.2 may have any of the meanings hereinbefore defined, or
as defined in any one of paragraphs (a) to (n) hereinafter: [0103]
(a) R.sup.1 is methyl; [0104] (b) R.sup.15 is hydrogen, fluoro or
chloro; [0105] (c) R.sup.15 is fluoro; [0106] (d) R.sup.16 is
fluoro or chloro; [0107] (e) R.sup.16 is fluoro; [0108] (f)
R.sup.17 is hydrogen, fluoro or chloro; [0109] (g) R.sup.17 is
hydrogen; [0110] (h) p is 0 or 1; [0111] (i) p is 0; [0112] (j) p
is 1; [0113] (k) Q.sup.2 is an optionally substituted 5- or
6-membered or 9- or 10-membered heteraryl ring (as hereinbefore
defined); [0114] (l) Q.sup.2 is a heteroaryl ring selected from the
group consisting of isoxazolyl, furyl, thienyl, pyridyl, pyrazolyl,
pyrrolyl, indolyl, quinolinyl, benzofuranyl, and benzothienyl, and
wherein said ring may be optionally substituted by halogeno
(particularly bromo, chloro or fluoro), amino, nitro, cyano, (1-4C)
alkyl, [(1-4C)alkyl]amino, di-[(1-4C)alkyl]amino such as
dimethylamino, N-[(1-4C)alkyl]carbamoyl and
N,N-di[(1-4C)alkyl]carbamoyl such as N,N-dimethylcarbamoyl; [0115]
(m) Q.sup.2 is phenyl optionally substituted by halogeno
(particularly bromo, chloro or fluoro), amino, nitro, cyano, (1-4C)
alkyl, [(1-4C)alkyl]amino, di-[(1-4C)alkyl]amino such as
dimethylamino, N-[(1-4C)alkyl]carbamoyl and
N,N-di[(1-4C)alkyl]carbamoyl such as N,N-dimethylcarbamoyl; [0116]
(n) Q.sup.2 is phenyl.
[0117] In particular compounds of formula (A) above, R.sup.1 is
methyl, R.sup.15 is fluoro, R.sup.16 is chloro, R.sup.17 is
hydrogen, p is 0 or 1, and Q.sup.2 is aryl or heteroaryl as
hereinbefore defined or as defined in any one of paragraphs (k) to
(n) above.
[0118] In a further preferred embodiment of the invention, the
compounds have the general structural formula (B) shown below:
##STR00006##
wherein
[0119] R.sup.15, R.sup.16, and R.sup.17 are as hereinbefore
defined;
[0120] R.sup.1 is (1-4C)alkyl;
[0121] p is 0, 1 or 2; and
[0122] Q.sup.2 is heteroaryl as hereinbefore defined, which may be
optionally substituted as hereinbefore defined;
[0123] or a pharmaceutically acceptable salt thereof.
[0124] In the compounds of formula (B), or a pharmaceutically
acceptable salt thereof, R.sup.1, R.sup.15, R.sup.16, R.sup.17, p
and Q.sup.2 may have any of the meanings hereinbefore defined, or
as defined in any one of paragraphs (a) to (l) hereinafter: [0125]
(a) R.sup.1 is methyl; [0126] (b) R.sup.15 is hydrogen, fluoro or
chloro; [0127] (c) R.sup.15 is fluoro; [0128] (d) R.sup.16 is
fluoro or chloro; [0129] (e) R.sup.16 is fluoro; [0130] R.sup.17 is
hydrogen, fluoro or chloro; [0131] (g) R.sup.17 is hydrogen; [0132]
(h) p is 0 or 1; [0133] (i) p is 0; [0134] (j) p is 1; [0135] (k)
Q.sup.2 is an optionally substituted 5- or 6-membered or 9- or
10-membered heteraryl ring (as hereinbefore defined); [0136] (l)
Q.sup.2 is a heteroaryl ring selected from the group consisting of
isoxazolyl, furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, indolyl,
quinolinyl, benzofuranyl, and benzothienyl, and wherein said ring
may be optionally substituted by halogeno (particularly bromo,
chloro or fluoro), amino, nitro, cyano, (1-4C) alkyl,
[(1-4C)alkyl]amino, di-[(1-4C)alkyl]amino such as dimethylamino,
N-[(1-4C)alkyl]carbamoyl and N,N-di[(1-4C)alkyl]carbamoyl such as
N,N-dimethylcarbamoyl.
[0137] In particular compounds of formula (B) above, R.sup.1 is
methyl, R.sup.15 is fluoro, R.sup.16 is chloro, R.sup.17 is
hydrogen, p is 0 or 1, and Q.sup.2 is heteroaryl as hereinbefore
defined or as defined in either paragraphs (k) and (l) above.
[0138] In a further preferred embodiment of the invention, the
compounds have the general structural formula (C) shown below:
##STR00007##
wherein
[0139] R.sup.15, R'6,
[0140] and R.sup.17 are as hereinbefore defined;
[0141] R.sup.1 is (1-4C)alkyl;
[0142] p is 0, 1 or 2; and
[0143] Q.sup.2 is aryl or heteroaryl as hereinbefore defined, which
may be optionally substituted as hereinbefore defined;
[0144] or a pharmaceutically acceptable salt thereof.
[0145] In the compounds of formula (C), or a pharmaceutically
acceptable salt thereof, R.sup.1, R.sup.15, R.sup.16, R.sup.17, p
and Q.sup.2 may have any of the meanings hereinbefore defined, or
as defined in any one of paragraphs (a) to (n) hereinafter: [0146]
(a) R.sup.1 is methyl; [0147] (b) R.sup.15 is hydrogen, fluoro or
chloro; [0148] (c) R.sup.15 is fluoro; [0149] (d) R.sup.16 is
fluoro or chloro; [0150] (e) R.sup.16 is fluoro; [0151] (f)
R.sup.17 is hydrogen, fluoro or chloro; [0152] (g) R.sup.17 is
hydrogen; [0153] (h) p is 0 or 1; [0154] (i) p is 0; [0155] (j) p
is 1; [0156] (k) Q.sup.2 is an optionally substituted 5- or
6-membered or 9- or 10-membered heteraryl ring (as hereinbefore
defined); [0157] (l) Q.sup.2 is a heteroaryl ring selected from the
group consisting of isoxazolyl, furyl, thienyl, pyridyl, pyrazolyl,
pyrrolyl, indolyl, quinolinyl, benzofuranyl, and benzothienyl, and
wherein said ring may be optionally substituted by halogeno
(particularly bromo, chloro or fluoro), amino, nitro, cyano, (1-4C)
alkyl, [(1-4C)alkyl]amino, di-[(1-4C)alkyl]amino such as
dimethylamino, N-[(1-4C)alkyl]carbamoyl and
N,N-di[(1-4C)alkyl]carbamoyl such as N,N-dimethylcarbamoyl; [0158]
(m) Q.sup.2 is phenyl optionally substituted by halogeno
(particularly bromo, chloro or fluoro), amino, nitro, cyano, (1-4C)
alkyl, [(1-4C)alkyl]amino, di-[(1-4C)alkyl]amino such as
dimethylamino, N-[(1-4C)alkyl]carbamoyl and
N,N-di[(1-4C)alkyl]carbamoyl such as N,N-dimethylcarbamoyl; [0159]
(n) Q.sup.2 is phenyl.
[0160] In particular compounds of formula (C) above, R.sup.1 is
methyl, R.sup.15 is fluoro, R.sup.16 is chloro, R.sup.17 is
hydrogen, p is 0 or 1, and Q.sup.2 is aryl or heteroaryl as
hereinbefore defined or as defined in any one of paragraphs (k) to
(n) above.
[0161] In a further preferred embodiment of the invention, the
compounds have the general structural formula (D) shown below:
##STR00008##
wherein
[0162] R.sup.15, R.sup.16, and R.sup.17 are as hereinbefore
defined;
[0163] R.sup.1 is (1-4C)alkyl;
[0164] p is 0, 1 or 2; and
[0165] Q.sup.2 is aryl or heteroaryl as hereinbefore defined, which
may be optionally substituted as hereinbefore defined;
[0166] or a pharmaceutically acceptable salt thereof.
[0167] In the compounds of formula (D), or a pharmaceutically
acceptable salt thereof, R.sup.1, R.sup.15, R.sup.16, R.sup.17, p
and Q.sup.2 may have any of the meanings hereinbefore defined, or
as defined in any one of paragraphs (a) to (o) hereinafter: [0168]
(a) R.sup.1 is methyl; [0169] (b) R.sup.15 is hydrogen, fluoro or
chloro; [0170] (c) R.sup.15 is fluoro; [0171] (d) R.sup.16 is
fluoro or chloro; [0172] (e) R.sup.16 is fluoro; [0173] (f)
R.sup.17 is hydrogen, fluoro or chloro; [0174] (g) R.sup.17 is
hydrogen; [0175] (h) p is 0, 1 or 2; [0176] (i) p is 0; [0177] (j)
p is 1; [0178] (k) p is 2; [0179] (l) Q.sup.2 is an optionally
substituted 5- or 6-membered or 9- or 10-membered heteraryl ring
(as hereinbefore defined); [0180] (m) Q.sup.2 is a heteroaryl ring
selected from the group consisting of isoxazolyl, furyl, thienyl,
pyridyl, pyrazolyl, pyrrolyl, indolyl, quinolinyl, benzofuranyl,
and benzothienyl, and wherein said ring may be optionally
substituted by halogeno (particularly bromo, chloro or fluoro),
amino, nitro, cyano, (1-4C) alkyl, [(1-4C)alkyl]amino,
di-[(1-4C)alkyl]amino such as dimethylamino,
N-[(1-4C)alkyl]carbamoyl and N,N-di[(1-4C)alkyl]carbamoyl such as
N,N-dimethylcarbamoyl; [0181] (n) Q.sup.2 is phenyl optionally
substituted by halogeno (particularly bromo, chloro or fluoro),
amino, nitro, cyano, (1-4C) alkyl, [(1-4C)alkyl]amino,
di-[(1-4C)alkyl]amino such as dimethylamino,
N-[(1-4C)alkyl]carbamoyl and N,N-di[(1-4C)alkyl]carbamoyl such as
N,N-dimethylcarbamoyl; [0182] (o) Q.sup.2 is phenyl.
[0183] In particular compounds of formula (D) above, R.sup.1 is
methyl, R.sup.15 is fluoro, R.sup.16 is chloro, R.sup.17 is
hydrogen, p is 0, 1 or 2, and Q.sup.2 is aryl or heteroaryl as
hereinbefore defined or as defined in any one of paragraphs (l) to
(o) above.
[0184] Suitable values for any of the various groups within formula
(I) as defined hereinbefore or hereafter in this specification
include:-- [0185] for halogeno fluoro, chloro, bromo and iodo;
[0186] for (1-6C)alkyl: methyl, ethyl, propyl, isopropyl,
tert-butyl, pentyl and hexyl; [0187] for (1-4C)alkyl: methyl,
ethyl, propyl, isopropyl and tert-butyl; [0188] for (1-6C)alkoxy:
methoxy, ethoxy, propoxy, isopropoxy and butoxy; [0189] for
(2-8C)alkenyl: vinyl, isopropenyl, allyl and but-2-enyl; [0190] for
(2-8C)alkynyl: ethynyl, 2-propynyl and but-2-ynyl; [0191] for
(2-6C)alkenyloxy: vinyloxy and allyloxy; [0192] for
(2-6C)alkynyloxy: ethynyloxy and 2-propynyloxy; [0193] for
(1-6C)alkylthio: methylthio, ethylthio and propylthio; [0194] for
(2-6C)alkenylthio: vinylthio and allylthio; [0195] for
(2-6C)alkynylthio: ethynlythio and 2-propynylthio [0196] for
(1-6C)alkylsulfinyl: methylsulfinyl and ethylsulfinyl; [0197] for
(2-6C)alkenylsulfinyl: vinylsulfinyl and allylsulfinyl; [0198] for
(2-6C)alkynylsulfinyl: ethynylsulfinyl and 2-propynylsulfinyl
[0199] for (1-6C)alkylsulfonyl: methylsulfonyl and ethylsulfonyl;
[0200] for (2-6C)alkenylsulfonyl: vinylsulfonyl and allylsulfonyl;
[0201] for (2-6C)alkynylsulfonyl: ethynylsulfonyl and
2-propynylsulfonyl; [0202] for (1-6C)alkylamino: methylamino,
ethylamino, propylamino, isopropylamino and butylamino; [0203] for
di-[(1-6C)alkyl]amino: dimethylamino, diethylamino,
N-ethyl-N-methylamino and diisopropylamino; [0204] for
(1-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl and tert-butoxycarbonyl; [0205] for
N-(1-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl,
N-propylcarbamoyl and N-isopropylcarbamoyl; [0206] for
N,N-di-[(1-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl,
N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl; [0207] for
(2-6C)alkanoyl: acetyl, propionyl and isobutyryl; [0208] for
(2-6C)alkanoyloxy: acetoxy and propionyloxy; [0209] for
(2-6C)alkanoylamino: acetamido and propionamido; [0210] for
N-(1-6C)alkyl-(2-6C)alkanoylamino: N-methylacetamido and
N-methylpropionamido; [0211] for N-(1-6C)alkylsulfamoyl:
N-methylsulfamoyl, N-ethylsulfamoyl and N-isopropylsulfamoyl;
[0212] for N,N-di-[(1-6C)alkyl]sulfamoyl: N,N-dimethylsulfamoyl and
N-methyl-N-ethylsulfamoyl; [0213] for (1-6C)alkanesulfonylamino:
methanesulfonylamino and ethanesulfonylamino; [0214] for
N-(1-6C)alkyl-(1-6C)alkanesulfonylamino:
N-methylmethanesulfonylamino and N-methylethanesulfonylamino;
[0215] for amino-(1-6C)alkyl: aminomethyl, 2-aminoethyl,
1-aminoethyl and 3-aminopropyl; [0216] for
(1-6C)alkylamino-(1-6C)alkyl: methylaminomethyl, ethylaminomethyl,
1-methylaminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl and
3-methylaminopropyl; [0217] for di-[(1-6C)alkyl]amino-(1-6C)alkyl:
dimethylaminomethyl, diethylaminomethyl, 1-dimethylaminoethyl,
2-dimethylaminoethyl and 3-dimethylaminopropyl; [0218] for
halogeno-(1-6C)alkyl: chloromethyl, 2-chloroethyl, 1-chloroethyl
and 3-chloropropyl; [0219] for hydroxy-(1-6C)alkyl: hydroxymethyl,
2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl; [0220] for
hydroxy-(1-6C)alkoxy: hydroxymethoxy, 2-hydroxyethoxy,
1-hydroxyethoxy and 3-hydroxypropoxy; [0221] for
(1-6C)alkoxy-(1-6C)alkyl: methoxymethyl, ethoxymethyl,
1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl;
[0222] for cyano-(1-6C)alkyl: cyanomethyl, 2-cyanoethyl,
1-cyanoethyl and 3-cyanopropyl; [0223] for amino(2-6C)alkanoyl:
aminoacetyl and 2-aminopropionyl; [0224] for
(1-6C)alkylamino-(2-6C)alkanoyl: methylaminoacetyl and
3-(methylamino)propionyl; [0225] for
N,N-di-[(1-6C)alkyl]amino-(2-6C)alkanoyl: di-methylaminoacetyl and
3-(di-methylamino)propionyl; [0226] for
(2-6C)alkanoylamino-(1-6C)alkyl: acetamidomethyl,
propionamidomethyl and 2-acetamidoethyl; [0227] for
N-(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl:
N-methylacetamidomethyl, N-methylpropionamidomethyl,
2-(N-methylacetamido)ethyl and 2-(N-methylpropionamido)ethyl;
[0228] for (1-6C)alkoxycarbonylamino-(1-6C)alkyl:
methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl,
tert-butoxycarbonylaminomethyl and 2-methoxycarbonylaminoethyl;
[0229] for carbamoyl(1-6C)alkyl: carbamoylmethyl, 1-carbamoylethyl,
2-carbamoylethyl and 3-carbamoylpropyl; [0230] for
N-(1-6C)alkylcarbamoyl(1-6C)alkyl: N-methylcarbamoylmethyl,
N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl,
1-(N-methylcarbamoypethyl, 2-(N-methylcarbamoyl)ethyl and
3-(N-methylcarbamoyl)propyl; [0231] for N,N
di-(1-6C)alkylcarbamoyl(1-6C)alkyl: N,N-dimethylcarbamoylmethyl,
N,N-diethylcarbamoylmethyl, N methyl, N-ethylcarbamoylmethyl,
1-(N,N-dimethylcarbamoyl)ethyl, 1-(N,N-diethylcarbamoypethyl,
2-(N,N-dimethylcarbamoyl)ethyl, 2-(N,N-diethylcarbamoypethyl and
3-(N,N-dimethylcarbamoyl)propyl; [0232] for sulfamoyl(1-6C)alkyl:
sulfamoylmethyl, 1-sulfamoylethyl, 2-sulfamoylethyl and
3-sulfamoylpropyl; [0233] for N-(1-6C)alkylsulfamoyl(1-6C)alkyl:
N-methylsulfamoylmethyl, N-ethylsulfamoylmethyl,
N-propylsulfamoylmethyl, 1-(N-methylsulfamoypethyl,
2-(N-methylsulfamoyl)ethyl and 3-(N-methylsulfamoyl)propyl; [0234]
for N,N di-(1-6C)alkylsulfamoyl(1-6C)alkyl:
N,N-dimethylsulfamoylmethyl, N,N-diethylsulfamoylmethyl, N methyl,
N-ethylsulfamoylmethyl, 1-(N,N-dimethylsulfamoyl)ethyl,
1-(N,N-diethylsulfamoypethyl, 2-(N,N-dimethylsulfamoypethyl,
2-(N,N-diethylsulfamoypethyl and 3-(N,N-dimethylsulfamoyl)propyl;
[0235] for (2-6C)alkanoyl(1-6C)alkyl: acetylmethyl,
propionylmethyl, 2-acetylethyl and 2-propionylethyl; [0236] for
(2-6C)alkanoyloxy(1-6C)alkyl: acetoxymethyl, propionyloxymethyl,
2-acetoxyethyl and 3-acetoxypropyl; [0237] for
(1-6C)alkoxy(1-6C)alkylS(O).sub.q: 2-methoxyethylsulfonyl,
2-methoxyethylsulpinyl and 2-methoxyethylthio; [0238] for
amino(1-6C)alkylS(O).sub.q: 2-aminoethylsulfonyl,
2-aminoethylsulfinyl and 2-aminoethylthio; [0239] for
N-(1-6C)alkylamino(1-6C)alkylS(O).sub.q:
2-(methylamino)ethylsulfonyl, 2-(ethylamino)ethylsulfinyl and
2-(methylamino)ethylthio; and [0240] for
N,N-di[(1-6C)alkyl]amino(1-6C)alkylS(O).sub.q:
2-(dimethylamino)ethylsulfonyl, 3-(dimethlyamino)propylsulfonyl,
2-(di-ethylamino)ethylsulfinyl and
2-(N-methyl-N-ethylamino)ethylthio.
[0241] It is to be understood that when, R.sup.1 is a group
(1-6C)alkoxy substituted by, for example amino to give for example
a 2-aminoethoxy group, it is the (1-6C)alkoxy group that is
attached to the quinazoline ring. An analogous convention applies
to the other groups defined herein.
[0242] When in this specification reference is made to a
(1-4C)alkyl group it is to be understood that such groups refer to
alkyl groups containing up to 4 carbon atoms. A skilled person will
realise that representative examples of such groups are those
listed above under (1-6C)alkyl that contain up to 4 carbon atoms,
such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.
Similarly, reference to a (1-3C)alkyl group refers to alkyl groups
containing up to 3 carbon atoms such as methyl, ethyl, propyl and
isopropyl. A similar convention is adopted for the other groups
listed above such as (1-4C)alkoxy, (2-4C)alkenyl, (2-4C)alkynyl and
(2-4C)alkanoyl.
[0243] In the compound of Formula I hydrogen atoms are present at
the 2, 5 and 8 positions on the quinazoline ring.
[0244] It is to be understood that, insofar as certain of the
compounds of Formula I defined above may exist in optically active
or racemic forms by virtue of one or more asymmetrically
substituted carbon and/or sulfur atoms, and accordingly may exist
in, and be isolated as enantiomerically pure, a mixture of
diastereoisomers or as a racemate. The present invention includes
in its definition any racemic, optically-active, enantiomerically
pure, mixture of diastereoisomers, stereoisomeric form of the
compound of Formula (I), or mixtures thereof, which possesses the
above-mentioned activity. The synthesis of optically active forms
may be carried 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. Similarly,
the above-mentioned activity may be evaluated using the standard
laboratory techniques referred to hereinafter.
[0245] The invention relates to all tautomeric forms of the
compounds of the Formula I that possess antiproliferative
activity.
[0246] It is also to be understood that certain compounds of the
Formula I may 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 possess
antiproliferative activity.
[0247] It is also to be understood that certain compounds of the
Formula I may exhibit polymorphism, and that the invention
encompasses all such forms which possess antiproliferative
activity.
[0248] A suitable pharmaceutically-acceptable salt of a compound of
the Formula I is, for example, an acid-addition salt of a compound
of the Formula I, for example an acid-addition salt with an
inorganic or organic acid such as hydrochloric, hydrobromic,
sulfuric, trifluoroacetic, citric or maleic acid; or, for example,
a salt of a compound of the Formula I which is sufficiently acidic,
for example an alkali or alkaline earth metal salt such as a
calcium or magnesium salt, or an ammonium salt, or a salt with an
organic base such as methylamine, dimethylamine, trimethylamine,
piperidine, morpholine or tris-(2-hydroxyethyl)amine.
[0249] A preferred compound of the invention is, for example, a
quinazoline derivative of the Formula I selected from the compounds
illustrated in Tables I to V below.
TABLE-US-00001 TABLE I ##STR00009## Compound No Q.sup.2 p 1
##STR00010## 0 2 ##STR00011## 1 3 ##STR00012## 0 4 ##STR00013## 0 5
##STR00014## 0 6 ##STR00015## 0 7 ##STR00016## 0 8 ##STR00017## 0 9
##STR00018## 1 10 ##STR00019## 0 11 ##STR00020## 0 12 ##STR00021##
0 13 ##STR00022## 0 14 ##STR00023## 0 15 ##STR00024## 0 16
##STR00025## 0 17 ##STR00026## 0 18 ##STR00027## 0 19 ##STR00028##
0 20 ##STR00029## 0 21 ##STR00030## 0 22 ##STR00031## 0 23
##STR00032## 1 24 ##STR00033## 0 25 ##STR00034## 0 26 ##STR00035##
0 27 ##STR00036## 0 28 ##STR00037## 0 29 ##STR00038## 0 30
##STR00039## 1 31 ##STR00040## 0
TABLE-US-00002 TABLE II ##STR00041## Compound No. Q.sup.2 p 32
##STR00042## 0 33 ##STR00043## 1 34 ##STR00044## 0 35 ##STR00045##
1 36 ##STR00046## 0 37 ##STR00047## 0 38 ##STR00048## 0 39
##STR00049## 0 40 ##STR00050## 0 41 ##STR00051## 0 42 ##STR00052##
0 43 ##STR00053## 0 44 ##STR00054## 0 45 ##STR00055## 0 46
##STR00056## 0 47 ##STR00057## 0 48 ##STR00058## 1 49 ##STR00059##
0 50 ##STR00060## 0 51 ##STR00061## 0 52 ##STR00062## 0 53
##STR00063## 0 54 ##STR00064## 0 55 ##STR00065## 0 56 ##STR00066##
0 57 ##STR00067## 1 58 ##STR00068## 0
TABLE-US-00003 TABLE III ##STR00069## Compound No. Q.sup.2 p 59
##STR00070## 0 60 ##STR00071## 1 61 ##STR00072## 0 62 ##STR00073##
0 63 ##STR00074## 0 64 ##STR00075## 0 65 ##STR00076## 0 66
##STR00077## 0 67 ##STR00078## 0 68 ##STR00079## 0 69 ##STR00080##
0 70 ##STR00081## 0 71 ##STR00082## 0 72 ##STR00083## 0 73
##STR00084## 0 74 ##STR00085## 1 75 ##STR00086## 0 76 ##STR00087##
0 77 ##STR00088## 0 78 ##STR00089## 0 79 ##STR00090## 0 80
##STR00091## 0 81 ##STR00092## 0 82 ##STR00093## 0 83 ##STR00094##
1 84 ##STR00095## 1 85 ##STR00096## 0 86 ##STR00097## 1 87
##STR00098## 1 88 ##STR00099## 1
TABLE-US-00004 TABLE IV Compound No. Q.sup.2 p 89 ##STR00100##
0
TABLE-US-00005 TABLE V ##STR00101## Compound No. Q.sup.2 p 90
##STR00102## 0 91 ##STR00103## 1 92 ##STR00104## 0 93 ##STR00105##
2 94 ##STR00106## 0 95 ##STR00107## 0 96 ##STR00108## 0 97
##STR00109## 0 98 ##STR00110## 0
[0250] In a further aspect, the present invention provides a
compound selected from one of the following: [0251] (1)
N-(3-chloro-2-fluorophenyl)-6-{[1-(isoxazol-5-ylcarbonyl)piperidin-4-yl]o-
xy}-7-methoxyquinazolin-4-amine; [0252] (2)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(3-methylisoxazol-5-yl)acety-
l]piperidin-4-yl}oxy)quinazolin-4-amine; [0253] (3)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(3-methylisoxazol-5-yl)carbo-
nyl]piperidin-4-yl}oxy)quinazolin-4-amine; [0254] (4)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(5-methylisoxazol-3-yl)carbo-
nyl]piperidin-4-yl}oxy)quinazolin-4-amine; [0255] (5)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(5-methylisoxazol-4-yl)carbo-
nyl]piperidin-4-yl}oxy)quinazolin-4-amine; [0256] (6)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(3-methylisoxazol-4-yl)carbo-
nyl]piperidin-4-yl}oxy)quinazolin-4-amine; [0257] (7)
N-(3-chloro-2-fluorophenyl)-6-({1-[(3,5-dimethylisoxazol-4-yl)carbonyl]pi-
peridin-4-yl}oxy)-7-methoxyquinazolin-4-amine; [0258] (8)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[1-(pyridin-3-ylcarbonyl)piperid-
in-4-yl]oxy}quinazolin-4-amine; [0259] (9)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[1-(pyridin-2-ylcarbonyl)piperid-
in-4-yl]oxy}quinazolin-4-amine; [0260] (10)
N-(3-chloro-2-fluorophenyl)-6-{[1-(2-furoyl)piperidin-4-yl]oxy}-7-methoxy-
quinazolin-4-amine; [0261] (11)
N-(3-chloro-2-fluorophenyl)-7-{[1-(isoxazol-5-ylcarbonyl)piperidin-4-yl]o-
xy}-6-methoxyquinazolin-4-amine; [0262] (12)
N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(3-methylisoxazol-5-acetyl]p-
iperidin-4-yl}oxy)quinazolin-4-amine; [0263] (13)
N-(3-chloro-2-fluorophenyl)-7-{[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]ox-
y}-6-methoxyquinazolin-4-amine; [0264] (14)
N-(3-chloro-2-fluorophenyl)-7-{[1-(2-furoyl)piperidin-4-yl]oxy}-6-methoxy-
quinazolin-4-amine; [0265] (15)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(2-thienylacetyl)piperid-
in-3-yl]oxy}quinazolin-4-amine; [0266] (16)
N-(3-chloro-2-fluorophenyl)-6-{[(3R)-1-isonicotinoylpiperidin-3-yl]oxy}-7-
-methoxyquinazolin-4-amine; [0267] (17)
6-({3R)-1-[(2-aminopyridin-3-yl)carbonyl]piperidin-3-yl}oxy)-N-(3-chloro--
2-fluorophenyl)-7-methoxyquinazolin-4-amine; [0268] (18)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(1H-pyrrol-2-ylcarbonyl)-
piperidin-3-yl]oxy}quinazolin-4-amine; [0269] (19)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(2-thienylcarbonyl)piper-
idin-3-yl]oxy}quinazolin-4-amine; [0270] (20)
N-(3-chloro-2-fluorophenyl)-6-{[(3R)-1-(2-furoyl)piperidin-3-yl]oxy}-7-me-
thoxyquinazolin-4-amine; [0271] (21)
N-(3-chloro-2-fluorophenyl)-6-{[(3R)-1-(3-furoyl)piperidin-3-yl]oxy}-7-me-
thoxyquinazolin-4-amine; [0272] (22)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(3-thienylcarbonyl)piper-
idin-3-yl]oxy}quinazolin-4-amine; [0273] (23)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(3-thienylacetyl)piperid-
in-3-yl]oxy}quinazolin-4-amine; [0274] (24)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({(3R)-1-[(1-methyl-1H-pyrrol-2-y-
l)carbonyl]piperidin-3-yl}oxy)quinazolin-4-amine; [0275] (25)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({(3R)-1-[(4-nitro-1H-pyrazol-1-y-
l)acetyl]piperidin-3-yl}oxy)quinazolin-4-amine; [0276] (26)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({(3R)-1-[(3-methylisoxazol-5-yl)-
acetyl]piperidin-3-yl}oxy)quinazolin-4-amine; [0277] (27)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(4-{N,N-dimethylcarbamoy-
l}-1H-pyrazol-1-ylacetyl)piperidin-3-yl]oxy}quinazolin-4-amine;
[0278] (28)
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(4-cyano-1H-pyrazol-
-1-ylacetyl)piperidin-3-yl]oxy}quinazolin-4-amine; [0279] (29)
4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-ph-
enylpiperidine-1-carboxamide; [0280] (30)
N-Benzyl-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-
oxy)piperidine-1-carb oxamide; [0281] (31)
4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-[4-
-(dimethylamino)phenyl]piperidine-1-carboxamide; [0282] (32)
4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-(2-
-phenylethyl)piperidine-1-carboxamide; [0283] (33)
4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-(3-
,4-dimethoxyphenyl)piperidine-1-carboxamide; [0284] (34)
4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-(3-
-fluorophenyl)piperidine-1-carboxamide; [0285] (35)
4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-(3-
,5-dimethylisoxazol-4-yl)piperidine-1-carboxamide; [0286] (36)
4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-2--
thienylpiperidine-1-carboxamide; [0287] (37)
4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-3--
thienylpiperidine-1-carboxamide.
[0288] A further aspect the present invention provides a process
for preparing a quinazoline derivative of Formula I or a
pharmaceutically-acceptable salt thereof. It will be appreciated
that during certain of the following processes certain substituents
may require protection to prevent their undesired reaction. The
skilled chemist will appreciate when such protection is required,
and how such protecting groups may be put in place, and later
removed.
[0289] For examples of protecting groups see one of the many
general texts on the subject, for example, `Protective Groups in
Organic Synthesis` by Theodora Green (publisher: John Wiley &
Sons). Protecting groups may be removed by any convenient method as
described in the literature or known to the skilled chemist as
appropriate for the removal of the protecting group in question,
such methods being chosen so as to effect removal of the protecting
group with minimum disturbance of groups elsewhere in the
molecule.
[0290] Thus, if reactants include, for example, groups such as
amino, carboxy or hydroxy it may be desirable to protect the group
in some of the reactions mentioned herein.
[0291] 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,
sulfuric 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.
[0292] 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, sodium hydroxide or ammonia. Alternatively an
arylmethyl group such as a benzyl group may be removed, for
example, by hydrogenation over a catalyst such as
palladium-on-carbon.
[0293] 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.
Resins may also be used as a protecting group.
[0294] The protecting groups may be removed at any convenient stage
in the synthesis using conventional techniques well known in the
chemical art.
[0295] A quinazoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, may be prepared by any
process known to be applicable to the preparation of
chemically-related compounds. Such processes, when used to prepare
a quinazoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, are provided as a further
feature of the invention and are illustrated by the following
representative examples. Necessary starting materials may be
obtained by standard procedures of organic chemistry (see, for
example, Advanced Organic Chemistry (Wiley-Interscience), Jerry
March). The preparation of such starting materials is described
within the accompanying non-limiting Examples. Alternatively,
necessary starting materials are obtainable by analogous procedures
to those illustrated which are within the ordinary skill of an
organic chemist. Information on the preparation of necessary
starting materials or related compounds (which may be adapted to
form necessary starting materials) may also be found in the
following patent and application Publications, the contents of the
relevant process sections of which are hereby incorporated herein
by reference: WO94/27965, WO 95/03283, WO 96/33977, WO 96/33978, WO
96/33979, WO 96/33980, WO 96/33981, WO 97/30034, WO 97/38994, WO
01/66099, U.S. Pat. No. 5,252,586, EP 520 722, EP 566 226, EP 602
851 and EP 635 507.
[0296] The present invention also provides that quinazoline
derivatives of the Formula I, or pharmaceutically acceptable salts
thereof, can be prepared by a process (a) to (i) as follows
(wherein the variables are as defined above unless otherwise
stated):
Process (a)
[0297] By reacting a compound of the Formula II:
##STR00111##
wherein R.sup.3 and a are as defined in relation to formula (I),
one of R.sup.1a' or R.sup.1b' is hydroxy and the other is a group
R.sup.1 as defined in relation to formula (I), except that any
functional group is protected if necessary, with a compound of the
Formula III:
Q.sup.2-X.sup.1--Z-Q.sup.1-X.sup.2-Lg Formula III
wherein Q.sup.1, Q.sup.2, Z, X.sup.2 and X.sup.1 have any of the
meanings defined hereinbefore except that any functional group is
protected if necessary and Lg is a displaceable group, wherein the
reaction is conveniently performed in the presence of a suitable
base,
[0298] and whereafter any protecting group that is present is
removed by conventional means.
[0299] A convenient displaceable group Lg is, for example, a
halogeno, alkanesulfonyloxy or arylsulfonyloxy group, for example a
chloro, bromo, methanesulfonyloxy, 4-nitrobenzenesulfonyloxy or
toluene-4-sulfonyloxy group (suitably a methanesulfonyloxy,
4-nitrobenzenesulfonyloxy or toluene-4-sulfonyloxy group).
[0300] The reaction is advantageously carried out in the presence
of base. A suitable base is, for example, an organic amine base
such as, for example, pyridine, 2,6-lutidine, collidine,
4-dimethylaminopyridine, triethylamine, N-methylmorpholine or
diazabicyclo[5.4.0]undec-7-ene, or for example, an alkali metal or
alkaline earth metal carbonate or hydroxide, for example sodium
carbonate, potassium carbonate, cesium carbonate, calcium
carbonate, sodium hydroxide or potassium hydroxide. Alternatively
such a base is, for example, an alkali metal hydride, for example
sodium hydride, an alkali metal or alkaline earth metal amide, for
example sodium amide or sodium bis(trimethylsilyl)amide, or a
sufficiently basic alkali metal halide, for example cesium fluoride
or sodium iodide. The reaction is suitably effected in the presence
of an inert solvent or diluent, for example an alkanol or ester
such as methanol, ethanol, 2-propanol or ethyl acetate, a
halogenated solvent such as methylene chloride, trichloromethane or
carbon tetrachloride, an ether such as tetrahydrofuran or
1,4-dioxan, an aromatic hydrocarbon solvent such as toluene, or
(suitably) a dipolar aprotic solvent such as N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidin-2-one or
dimethylsulfoxide. The reaction is conveniently effected at a
temperature in the range, for example, 10 to 150.degree. C. (or the
boiling point of the solvent), suitably in the range 20 to
90.degree. C.
[0301] When X.sup.2 is a direct bond a particularly suitable base
is cesium fluoride. This reaction is suitably performed in an inert
dipolar aprotic solvent such as N,N-dimethylacetamide or
N,N-dimethylformamide. The reaction is suitably carried out at a
temperature of from 25 to 85.degree. C.
Process (b)
[0302] By modifying a substituent in or introducing a substituent
into another quinazoline derivative of Formula I or a
pharmaceutically acceptable salt thereof, as hereinbefore defined
except that any functional group is protected if necessary, and
whereafter any protecting group that is present is removed by
conventional means.
[0303] Methods for converting substituents into other substituents
are known in the art. For example an alkylthio group may be
oxidised to an alkylsulfinyl or alkylsulfonyl group, a carbamoyl
group may be converted to cyano group (for example by reacting the
carbamoyl substituent with trifluoroacetic anhydride in the
presence of a suitable base, such as triethylamine), a cyano group
reduced to an amino group, a nitro group reduced to an amino group,
a hydroxy group alkylated to a methoxy group, a carbonyl group
converted to a thiocarbonyl group (eg. using Lawsson's reagent), a
bromo group converted to an alkylthio group, an amino group may be
acylated to give an alkanoylamino group (for example by reaction
with a suitable acid chloride or acid anhydride) or an alkanoyloxy
group may be hydrolysed to a hydroxy group (for example an
acetyloxyacetyl group may be converted to a hydroxyacetyl group)
Conveniently, one R.sup.1 group may be converted into another
R.sup.1 group as a final step in the preparation of a compound of
the Formula I. It is also possible to introduce a substituent onto
the group Q.sup.1 as a final step in the preparation of a compound
of the Formula I. For example when the compound of Formula I
contains primary or secondary amino group, for example an NH group
in the ring Q.sup.1, a substituent may be added to the nitrogen
atom of the primary or secondary amino group by reacting the
compound of the Formula I containing a primary or secondary amino
group with a compound of the formula R-Lg, wherein Lg is a
displaceable group (for example halogeno such as chloro or bromo)
and R is the required substituent (for example (1-6C)alkyl,
(2-6C)alkanoyl, cyano, cyano(1-6C)alkyl, (1-6C)alkylsulfonyl,
carbamoyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl sulfamoyl,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl or a group
Q.sup.2-X.sup.3--, wherein Q.sup.2-X.sup.3-- are as hereinbefore
defined, which groups may be optionally substituted as hereinbefore
defined). The reactions described above are conveniently performed
in the presence of a suitable base (such as those described above
in process (a), for example potassium carbonate, sodium iodide or
di-isopropylethylamine) and conveniently in the presence of an
inert solvent or diluent (for example the inert solvents and
diluents described in process (a) such as N,N-dimethylacetamide,
methanol, ethanol or methylene chloride). Conveniently, when
Q.sup.1 or Q.sup.2 carries, for example an (2-6C)alkanoyl or
(1-6C)alkylsulfonyl group, which is substituted by a group
NR.sup.aR.sup.b, as hereinbefore defined, the NR.sup.aR.sup.b group
may be introduced by reaction of a compound of the Formula I
wherein Q.sup.1 or Q.sup.2 carries a group of the formula
Lg-(2-6C)alkanoyl or Lg-(1-6C)alkylsulfonyl, wherein Lg is a
suitable displaceable group such as chloro, with a compound of the
formula NHR.sup.aR.sup.b; wherein the reaction is conveniently
performed in the presence of a suitable base and optionally in a
suitable inert solvent or diluent. For example a
pyrrolidin-1-ylacetyl group on Q.sup.1 or Q.sup.2 may be prepared
by reacting a compound of the Formula I wherein Q.sup.1 or Q.sup.2
is substituted by a chloroacetyl group with pyrrolidine, analogous
procedures may be used to prepare substituents on Q.sup.1 or
Q.sup.2 such as morpholinoacetyl, N-methylaminoacetyl,
N,N-dimethylaminoacetyl. Similarly, for example a
3-(N,N-dimethylamino)propylsulfonyl substituent on Q.sup.1 or
Q.sup.2 may be prepared by reacting a compound of the Formula I
wherein Q.sup.1 or Q.sup.2 carries a 3-chloropropylsulfonyl
substituent with di-methylamine. Further examples of modifying or
converting substituents into other substituents are well known to
those skilled in the art and further methods are contained in the
accompanying non-limiting Examples.
Process (c)
[0304] By reacting a compound of the Formula II as hereinbefore
defined with a compound of the Formula III as defined hereinbefore
except Lg is OH under Mitsunobu conditions, and whereafter any
protecting group that is present is removed by conventional
means.
[0305] Suitable Mitsunobu conditions include, for example, reaction
in the presence of a suitable tertiary phosphine and a
di-alkylazodicarboxylate in an organic solvent such as TEM, or
suitably dichloromethane and in the temperature range 0.degree.
C.-60.degree. C., but suitably at ambient temperature. A suitable
tertiary phosphine includes for example tri-n-butylphosphine or
suitably tri-phenylphosphine. A suitable di-alkylazodicarboxylate
includes for example diethyl azodicarboxylate (DEAD) or suitably
di-tert-butyl azodicarboxylate. Details of Mitsunobu reactions are
contained in Tet. Letts., 31, 699, (1990); The Mitsunobu Reaction,
D. L. Hughes, Organic Reactions, 1992, Vol. 42, 335-656 and
Progress in the Mitsunobu Reaction, D. L. Hughes, Organic
Preparations and Procedures International, 1996, Vol. 28,
127-164.
Process (d)
[0306] For the preparation of those compounds of the Formula I
wherein the group R.sup.1 is a hydroxy group formed by the cleavage
of a quinazoline derivative of the Formula I wherein R.sup.1 is a
(1-6C)alkoxy group.
[0307] The cleavage reaction may conveniently be carried out by any
of the many procedures known for such a transformation. The
cleavage reaction of a compound of the Formula I wherein R.sup.1 is
a (1-6C)alkoxy group may be carried out, for example, by treatment
of the quinazoline derivative with an alkali metal
(1-6C)alkylsulfide such as sodium ethanethiolate or, for example,
by treatment with an alkali metal diarylphosphide such as lithium
diphenylphosphide. Alternatively the cleavage reaction may
conveniently be carried out, for example, by treatment of the
quinazoline derivative with a boron or aluminium trihalide such as
boron tribromide, or by reaction with an organic or inorganic acid,
for example trifluoroacetic acid. Such reactions are suitably
carried out in the presence of a suitable inert solvent or diluent
as defined hereinbefore. A preferred cleavage reaction is the
treatment of a quinazoline derivative of the Formula I with
pyridine hydrochloride. The cleavage reactions are suitably carried
out at a temperature in the range, for example, of from 10 to
150.degree. C., for example from 25 to 80.degree. C.
Process (e)
[0308] For the preparation of those compounds of the Formula I
wherein R.sup.1 is a (1-6C)alkoxy, (2-6C)alkenyloxy,
(2-6C)alkynyloxy, or a group of the formula:
Q.sup.4-X.sup.3--
wherein X.sup.3 is O and Q.sup.4 is as defined above, by the
reaction of a compound of the Formula I wherein R.sup.1 is OH,
except that any functional group is protected if necessary, with a
compound of the formula R.sup.1'-Lg, wherein R.sup.1' is a
(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, or a group Q.sup.4 where
Q.sup.4 is as defined above, and Lg is a displaceable group,
wherein the reaction is conveniently performed in the presence of a
suitable base;
[0309] and whereafter any protecting group that is present is
removed by conventional means. Suitable displaceable groups, Lg,
are as hereinbefore defined for process a, for example chloro or
bromo. The reaction is suitably performed in the presence of a
suitable base. Suitable solvents, diluents and bases include, for
example those hereinbefore described in relation to process
(a).
Process (f)
[0310] For the preparation of those compounds of the Formula I
wherein Q.sup.1, Q.sup.2 or R.sup.1 contains a (1-6C)alkoxy or
substituted (1-6C)alkoxy group or a (1-6C)alkylamino or substituted
(1-6C)alkylamino group, the alkylation, conveniently in the
presence of a suitable base as defined hereinbefore for process a,
of a quinazoline derivative of the Formula I wherein Q.sup.1,
Q.sup.2 or R.sup.1 contains a hydroxy group or a primary or
secondary amino group as appropriate.
[0311] A suitable alkylating agent is, for example, any agent known
in the art for the alkylation of hydroxy to alkoxy or substituted
alkoxy, or for the alkylation of amino to alkylamino or substituted
alkylamino, for example an alkyl or substituted alkyl halide, for
example a (1-6C)alkyl chloride, bromide or iodide or a substituted
(1-6C)alkyl chloride, bromide or iodide, conveniently in the
presence of a suitable base as defined hereinbefore, in a suitable
inert solvent or diluent as defined hereinbefore and at a
temperature in the range, for example, 10 to 140.degree. C.,
conveniently at or near ambient temperature. An analogous procedure
may be used to introduce optionally substituted (2-6C)alkanoyloxy,
(2-6C)alkanoylamino and (1-6C)alkanesulfonylamino groups into
Q.sup.1, Q.sup.2 or R.sup.1.
[0312] Conveniently for the production of those compounds of the
Formula I wherein Q', Q.sup.2 or R.sup.1 contains a
(1-6C)alkylamino or substituted (1-6C)alkylamino group, a reductive
amination reaction may be employed using formaldehyde or a
(2-6C)alkanolaldehyde (for example acetaldehyde or
propionaldehyde). For example, for the production of those
compounds of the Formula I wherein Q.sup.1, Q.sup.2 or R.sup.1
contains an N-methyl group, the corresponding compound containing a
N--H group may be reacted with formaldehyde in the presence of a
suitable reducing agent. A suitable reducing agent is, for example,
a hydride reducing agent, for example formic acid, an alkali metal
aluminium hydride such as lithium aluminium hydride, or, suitably,
an alkali metal borohydride such as sodium borohydride, sodium
cyanoborohydride, sodium triethylborohydride, sodium
trimethoxyborohydride and sodium triacetoxyborohydride. The
reaction is conveniently performed in a suitable inert solvent or
diluent, for example tetrahydrofuran and diethyl ether for the more
powerful reducing agents such as lithium aluminium hydride, and,
for example, methylene chloride or a protic solvent such as
methanol and ethanol for the less powerful reducing agents such as
sodium triacetoxyborohydride and sodium cyanoborohydride. When the
reducing agent is formic acid the reaction is conveniently carried
out using an aqueous solution of the formic acid. The reaction is
performed at a temperature in the range, for example, 10 to
100.degree. C., such as 70 to 90.degree. C. or, conveniently, at or
near ambient temperature. Conveniently, when the reducing agent is
formic acid, protecting groups such as tert-butoxycarbonyl on the
NH group to be alkylated (for example present from the synthesis of
the starting material) may be removed in-situ during the
reaction.
Process (g)
[0313] For the preparation of those compounds of the Formula I
wherein R.sup.1 is substituted by a group T, wherein T is selected
from (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoylamino,
(1-6C)alkylthio, (1-6C)alkylsulfinyl and (1-6C)alkylsulfonyl, the
reaction of a compound which is of formula (I) except that the
group R.sup.1 is replaced with a group R.sup.1''-Lg wherein Lg is a
displaceable group (for example chloro or bromo), and R.sup.1'' is
a group R.sup.1 except that it has Lg in place of the group T, and
further that any functional group is protected if necessary, with a
compound of the formula TH, wherein T is as defined above except
that any functional group is protected if necessary;
[0314] and whereafter any protecting group that is present is
removed by conventional means. The reaction is conveniently carried
out in the presence of a suitable base. The reaction may
conveniently be performed in a suitable inert solvent of diluent.
Suitable bases, solvents and diluents are for example those
described under process (a). The reaction is suitable performed at
a temperature of for example, from 10 to 150.degree. C., for
example 30 to 60.degree. C.
[0315] 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 halogeno group.
Process (h)
[0316] By reacting a compound of the formula VI:
##STR00112##
wherein R.sup.1a and R.sup.1b have any of the meanings defined
hereinbefore except that any functional group is protected if
necessary and Lg is a displaceable group as hereinbefore defined,
with an aniline of the formula VII:
##STR00113##
wherein R.sup.3 and a have any of the meanings defined hereinbefore
except that any functional group is protected if necessary, and
wherein the reaction is conveniently performed in the presence of a
suitable acid,
[0317] and whereafter any protecting group that is present is
removed by conventional means.
[0318] Suitable displaceable groups represented by Lg are as
hereinbefore defined, in particular halogeno such as chloro.
[0319] The reaction is conveniently carried out in the presence of
a suitable inert solvent or diluent, for example an alcohol or
ester such as methanol, ethanol, isopropanol or ethyl acetate, a
halogenated solvent such as methylene chloride, chloroform or
carbon tetrachloride, an ether such as tetrahydrofuran or
1,4-dioxane, an aromatic solvent such as toluene, or a dipolar
aprotic solvent such as N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidin-2-one acetonitrile or
dimethylsulfoxide. The reaction is conveniently carried out at a
temperature in the range, for example, 10 to 250.degree. C.,
conveniently in the range 40 to 120.degree. C. or where a solvent
or diluent is used at the reflux temperature. Conveniently, the
compound of formula VI may be reacted with a compound of the
formula VII in the presence of a protic solvent such as
isopropanol, conveniently in the presence of an acid, for example
hydrogen chloride gas in diethyl ether or dioxane, or hydrochloric
acid, for example a 4M solution of hydrogen chloride in dioxane,
under the conditions described above. Alternatively, this reaction
may be conveniently carried out in an aprotic solvent, such as
dioxane or a dipolar aprotic solvent such as N,N-dimethylacetamide
or acetonitrile in the presence of an acid, for example hydrogen
chloride gas in diethyl ether or dioxane, or hydrochloric acid. The
compound of the formula VI, wherein Lg is halogeno, may be reacted
with a compound of the formula VII in the absence of an acid. In
this reaction displacement of the halogeno leaving group Lg results
in the formation of the acid HLg in-situ and auto-catalysis of the
reaction. Conveniently the reaction is carried out in a suitable
inert organic solvent, for example isopropanol, dioxane or
N,N-dimethylacetamide. Suitable conditions for this reaction are as
described above.
[0320] Alternatively, the compound of formula VI may be reacted
with a compound of the formula VII in the presence of a suitable
base. Suitable bases for this reaction are as hereinbefore defined
under Process (a). This reaction is conveniently performed in an
inert solvent or diluent, for example those mentioned above in
relation to this process (i);
Process (i)
[0321] For the preparation of those compounds of the Formula I
wherein Q.sup.1 is a nitrogen containing heterocyclyl group linked
to the --Z-- group by a ring nitrogen, the coupling of a compound
of the Formula I, as hereinbefore defined, except that the group of
sub-formula (i) is a group of sub-formula (x)
H-Q.sup.1-X.sup.2--O--, and any functional group is protected if
necessary, with a compound of formula Q.sup.2-X.sup.1--Z-Lg,
wherein Z, Q.sup.2 and X.sup.1 are as defined above and Lg is a
leaving group as hereinbefore defined (such as --OH or halogeno
such as chloro); and whereafter any protecting group that is
present is removed by conventional means.
[0322] This reaction is particularly suitable when Z is C(O) and Lg
is --OH, so the compound of formula Q.sup.2-X.sup.1--Z-Lg is a
carboxylic acid of the formula Q.sup.2-X.sup.1--C(O)--OH.
[0323] The coupling reaction is conveniently carried out in the
presence of a suitable coupling agent, such as a carbodiimide (for
example 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide), or a
suitable peptide coupling agent, for example
O-(7-azabenzotriazol-1-yl)-N,N,N,N'-tetramethyluronium
hexafluoro-phosphate (HATU). The coupling reaction is conveniently
carried out in an inert solvent such as, for example, a halogenated
solvent such as methylene chloride, or a dipolar aprotic solvent
such as N,N-dimethylformamide, N,N-dimethylacetamide,
1-methyl-2-pyrrolidinone. Suitably the coupling reaction is carried
out in the presence of a suitable base, such as an organic amine,
for example di-isopropylethylamine or 4-dimethylaminopyridine. The
coupling reaction is suitably performed at -25.degree. C. to
150.degree. C., conveniently at ambient temperature.
[0324] This reaction is also particularly suitable when Z is
--O--C(O)-- and Lg is chloro, so the compound of formula
Q.sup.2-X.sup.1--Z-Lg is a chloroformate of the formula
Q.sup.2-X.sup.1--O--C(O)--Cl.
Process (j)
[0325] For the preparation of those compounds of the Formula I
wherein Q.sup.1 is a nitrogen containing heterocyclyl group linked
to the --Z-- group by a ring nitrogen, and Z is a group of formula
--NR.sup.10--C(O)-- (where R.sup.10 is preferably H); said process
comprising the coupling of a compound of the Formula I, as
hereinbefore defined, except that the group of sub-formula (i) is a
group of sub-formula (x) H-Q.sup.1-X.sup.2--O--, and any functional
group is protected if necessary, with a compound of formula
Q.sup.2-X.sup.1--N.dbd.C.dbd.O, wherein Q.sup.2 and X.sup.1 are as
defined above; and whereafter any protecting group that is present
is removed by conventional means.
[0326] The coupling reaction is conveniently carried out in an
inert solvent such as, for example, a halogenated solvent such as
methylene chloride. The coupling reaction is suitably performed at
-25.degree. C. to 150.degree. C., conveniently at ambient
temperature.
[0327] Suitably, after any of these processes, any protecting
groups are removed to produce a quinazoline derivative of Formula
I, or a pharmaceutically acceptable salt thereof.
[0328] Suitable methods for removal of protecting groups are well
known and are discussed herein. For example for the production of
those compounds of the Formula I wherein R.sup.1a or R.sup.1b
contains a primary or secondary amino group, the cleavage of the
corresponding compound of Formula I wherein R.sup.1a or R.sup.1b
contains a protected primary or secondary amino group.
[0329] Suitable protecting groups for an amino group are, for
example, any of the protecting groups disclosed hereinbefore for an
amino group. Suitable methods for the cleavage of such amino
protecting groups are also disclosed hereinbefore. In particular, a
suitable protecting group is a lower alkoxycarbonyl group such as a
tert-butoxycarbonyl group which may be cleaved under conventional
reaction conditions such as under acid-catalysed hydrolysis, for
example in the presence of trifluoroacetic acid.
[0330] Persons skilled in the art will appreciate that, in order to
obtain compounds of the invention in an alternative and in some
occasions, more convenient manner, the individual process steps
mentioned hereinbefore may be performed in different order, and/or
the individual reactions may be performed at different stage in the
overall route (i.e. chemical transformations may be performed upon
different intermediates to those associated hereinbefore with a
particular reaction).
[0331] When a pharmaceutically-acceptable salt of a quinazoline
derivative of the Formula I is required, for example an
acid-addition salt, it may be obtained by, for example, reaction of
said quinazoline derivative with a suitable acid using a
conventional procedure. To facilitate isolation of the compound
during preparation, the compound may be prepared in the form of a
salt that is not a pharmaceutically acceptable salt. The resulting
salt can then be modified by conventional techniques to give a
pharmaceutically acceptable salt of the compound. Such techniques
include, for example ion exchange techniques or re-precipitation of
the compound in the presence of a pharmaceutically acceptable
counter ion. For example re-precipitation in the presence of a
suitable acid such as HCl to give a hydrochloride acid addition
salt.
[0332] As mentioned hereinbefore some of the compounds according to
the present invention may contain one of more chiral centers and
may therefore exist as stereoisomers (for example when Q.sup.1
contains a pyrrolidin-3-yl group). Stereoisomers may be separated
using conventional techniques, e.g. chromatography or fractional
crystallisation. The enantiomers may be isolated by separation of a
racemate for example by fractional crystallisation, resolution or
HPLC. The diastereomers may be isolated by separation by virtue of
the different physical properties of the diastereoisomers, for
example, by fractional crystallisation, HPLC or flash
chromatography. Alternatively particular stereoisomers may be made
by chiral synthesis from chiral starting materials under conditions
which will not cause racemisation or epimerisation, or by
derivatisation, with a chiral reagent. Examples of suitable chiral
synthesis and separation of isomers are described in the Examples.
When a specific stereoisomer is isolated it is suitably isolated
substantially free for other stereoisomers, for example containing
less than 20%, particularly less than 10% and more particularly
less than 5% by weight of other stereoisomers.
[0333] In the section above the expression "inert solvent" refers
to a solvent which does not react with the starting materials,
reagents, intermediates or products in a manner which adversely
affects the yield of the desired product.
[0334] Preparation of Starting Materials
[0335] Compounds of Formula II are commercially available or may be
prepared using conventional techniques or analogous processes to
those described in the prior art. In particular those patents and
applications listed hereinbefore, such as WO96/15118, WO 01/66099
and EP 566 226. For example, the compounds of Formula II may be
prepared in accordance with Reaction Scheme 1:
##STR00114##
wherein R.sup.3, and a are as hereinbefore defined, one of
R.sup.1a''' or R.sup.1b''' is a group O-Pg where Pg is a hydroxy
protecting group, and the other is a group R.sup.1 is as defined
herein before, except that any functional groups are protected if
necessary, and R.sup.1a' and R.sup.1b' are as defined above in
relation to formula (II), except that any functional groups are
protected if necessary. (i) Reaction is suitably carried out in an
inert protic solvent (such as an alkanol for example iso-propanol),
an aprotic solvent (such as dioxane) or a dipolar aprotic solvent
(such as N,N-dimethylacetamide) in the presence of an acid, for
example hydrogen chloride gas in diethyl ether or dioxane, or
hydrochloric acid, under analogous conditions to those described
above under process (i).
[0336] Alternatively the reaction may be carried out in one of the
above inert solvents conveniently in the presence of a base, for
example potassium carbonate. The above reactions are conveniently
carried out at a temperature in the range, for example, 0 to
150.degree. C., suitably at or near the reflux temperature of the
reaction solvent.
(ii) Cleavage of Pg may be performed under standard conditions for
such reactions. For example when Pg is an alkanoyl group such as
acetyl, it may be cleaved by heating in the presence of a
methanolic ammonia solution.
[0337] Compounds of formula VIII are known or can be prepared using
known processes for the preparation of analogous compounds. If not
commercially available, compounds of the formula (VIII) may be
prepared by procedures which are selected from standard chemical
techniques, techniques which are analogous to the synthesis of
known, structurally similar compounds, or techniques which are
analogous to the procedures described in the Examples. For example,
standard chemical techniques are as described in Houben Weyl. By
way of example the compound of the formula VIII in which the group
R.sup.1b is a group R.sup.1, and this is methoxy, Lg is chloro and
Pg is acetyl may be prepared using the process illustrated in
Reaction Scheme 2:
##STR00115##
[0338] Reaction Scheme 2 may be generalised by the skilled man to
apply to compounds within the present specification which are not
specifically illustrated (for example to introduce a substituent
other than methoxy at the 7-position in the quinazoline ring).
[0339] Compounds of the Formula III are commercially available or
may be prepared using standard techniques.
[0340] Compounds of the Formula IV may be prepared using process
(e) above, starting with a compound prepared, for example using
Process (a).
[0341] Compounds of the formula V may be prepared using, for
example process (a) or process (d) in which the group represented
by R.sup.1 is appropriately functionalised with a suitable
displaceable group Lg such as chloro or bromo.
[0342] Compounds of the formula VI may be prepared using
conventional methods well known in the art. For example the hydroxy
protecting group, Pg, in a compound of the formula VIII as
hereinbefore described in Reaction Scheme 1 is removed to give the
compound of the formula X:
##STR00116##
wherein R.sup.1a' and R.sup.1b' are as defined above in relation to
formula (II). The protecting group Pg may be removed from the
compound of formula X using conventional techniques.
[0343] The compound of the formula X may then be coupled with a
compound of the Formula III as hereinbefore defined using analogous
conditions to those described in Process (a) or Process (d).
[0344] Certain novel intermediates utilised in the above processes
are provided as a further feature of the present invention together
with the process for their preparation. In particular, any
intermediates which include a complete sub-group (i) are novel.
Biological Assays
[0345] The following assays may be used to measure the effects of
the compounds of the present invention as inhibitors of the
erb-tyrosine kinases, as inhibitors in-vitro of the proliferation
of KB cells (human naso-pharangeal carcinoma cells) and as
inhibitors in vivo on the growth in nude mice of xenografts of LoVo
tumour cells (colorectal adenocarcinoma).
a) Protein Tyrosine Kinase Phosphorylation Assays
[0346] This test measures the ability of a test compound to inhibit
the phosphorylation of a tyrosine containing polypeptide substrate
by EGFR tyrosine kinase enzyme.
[0347] Recombinant intracellular fragments of EGFR, erbB2 and erbB4
(accession numbers X00588, X03363 and L07868 respectively) were
cloned and expressed in the baculovirus/Sf21 system. Lysates were
prepared from these cells by treatment with ice-cold lysis buffer
(20 mM N'-2-hydroxyethylpiperizine-N'-2-ethanesulfonic acid (HEPES)
pH7.5, 150 mM NaCl, 10% glycerol, 1% Triton X-100, 1.5 mM
MgCl.sub.2, 1 mM ethylene glycol-bis(.beta.-aminoethyl ether)
N',N',N',N'-tetraacetic acid (EGTA), plus protease inhibitors and
then cleared by centrifugation.
[0348] Constitutive kinase activity of the recombinant protein was
determined by its ability to phosphorylate a synthetic peptide
(made up of a random co-polymer of Glutamic Acid, Alanine and
Tyrosine in the ratio of 6:3:1). Specifically, Maxisorb.TM. 96-well
immunoplates were coated with synthetic peptide (0.2 .mu.g of
peptide in a 100 .mu.l phosphate buffered saline (PBS) solution and
incubated at 4.degree. C. overnight). Plates were washed in PBS-T
(phosphate buffered saline with 0.5% Tween 20) then in 50 mM HEPES
pH 7.4 at room temperature to remove any excess unbound synthetic
peptide. EGFR, ErbB2 or ErbB4 tyrosine kinase activity was assessed
by incubation in peptide coated plates for 20 minutes at 22.degree.
C. in 100 mM HEPES pH 7.4, adenosine trisphosphate (ATP) at Km
concentration for the respective enzyme, 10 mM MnCl.sub.2, 0.1 mM
Na.sub.3VO.sub.4, 0.2 mM DL-dithiothreitol (DTT), 0.1% Triton X-100
with test compound in DMSO (final concentration of 2.5%). Reactions
were terminated by the removal of the liquid components of the
assay followed by washing of the plates with PBS-T.
[0349] The immobilised phospho-peptide product of the reaction was
detected by immunological methods. Firstly, plates were incubated
for 90 minutes at room temperature with anti-phosphotyrosine
primary antibodies that were raised in the mouse (4G10 from Upstate
Biotechnology). Following extensive washing, plates were treated
with Horseradish Peroxidase (HRP) conjugated sheep anti-mouse
secondary antibody (NXA931 from Amersham) for 60 minutes at room
temperature. After further washing, HRP activity in each well of
the plate was measured colorimetrically using
22'-Azino-di-[3-ethylbenzthiazoline sulfonate (6)] diammonium salt
crystals (ABTS.TM. from Roche) as a substrate.
[0350] Quantification of colour development and thus enzyme
activity was achieved by the measurement of absorbance at 405 nm on
a Molecular Devices ThermoMax microplate reader. Kinase inhibition
for a given compound was expressed as an IC.sub.50 value. This was
determined by calculation of the concentration of compound that was
required to give 50% inhibition of phosphorylation in this assay.
The range of phosphorylation was calculated from the positive
(vehicle plus ATP) and negative (vehicle minus ATP) control
values.
b) EGFR Driven KB Cell Proliferation Assay
[0351] This assay measures the ability of a test compound to
inhibit the proliferation of KB cells (human naso-pharangeal
carcinoma obtained from the American Type Culture Collection
(ATCC).
[0352] KB cells (human naso-pharangeal carcinoma obtained from the
ATCC were cultured in Dulbecco's modified Eagle's medium (DMEM)
containing 10% foetal calf serum, 2 mM glutamine and non-essential
amino acids at 37.degree. C. in a 7.5% CO.sub.2 air incubator.
Cells were harvested from the stock flasks using
Trypsin/ethylaminediaminetetraacetic acid (EDTA). Cell density was
measured using a haemocytometer and viability was calculated using
trypan blue solution before being seeded at a density of
1.25.times.10.sup.3 cells per well of a 96 well plate in DMEM
containing 2.5% charcoal stripped serum, 1 mM glutamine and
non-essential amino acids at 37.degree. C. in 7.5% CO.sub.2 and
allowed to settle for 4 hours.
[0353] Following adhesion to the plate, the cells are treated with
or without EGF (final concentration of 1 ng/ml) and with or without
compound at a range of concentrations in dimethylsulfoxide (DMSO)
(0.1% final) before incubation for 4 days. Following the incubation
period, cell numbers were determined by addition of 50 .mu.l of
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
(stock 5 mg/ml) for 2 hours. MTT solution was then tipped off, the
plate gently tapped dry and the cells dissolved upon the addition
of 100 .mu.l of DMSO.
[0354] Absorbance of the solubilised cells was read at 540 nm using
a Molecular Devices ThermoMax microplate reader. Inhibition of
proliferation was expressed as an IC.sub.50 value. This was
determined by calculation of the concentration of compound that was
required to give 50% inhibition of proliferation. The range of
proliferation was calculated from the positive (vehicle plus EGF)
and negative (vehicle minus EGF) control values.
c) Clone 24 phospho-erbB2 Cell Assay
[0355] This immunofluorescence end point assay measures the ability
of a test compound to inhibit the phosphorylation of erbB2 in a
MCF7 (breast carcinoma) derived cell line which was generated by
transfecting MCF7 cells with the full length erbB2 gene using
standard methods to give a cell line that overexpresses full length
wild type erbB2 protein (hereinafter `Clone 24` cells).
[0356] Clone 24 cells were cultured in Growth Medium (phenol red
free Dulbecco's modified Eagle's medium (DMEM) containing 10%
foetal bovine serum, 2 mM glutamine and 1.2 mg/ml G418) in a 7.5%
CO.sub.2 air incubator at 37.degree. C. Cells were harvested from
T75 stock flasks by washing once in PBS (phosphate buffered saline,
pH7.4, Gibco No. 10010-015) and harvested using 2 mls of Trypsin
(1.25 mg/ml)/ethylaminediaminetetraacetic acid (EDTA) (0.8 mg/ml)
solution. The cells were resuspended in Growth Medium Cell density
was measured using a haemocytometer and viability was calculated
using Trypan Blue solution before being further diluted in Growth
Medium and seeded at a density of 1.times.10.sup.4 cells per well
(in 100 ul) into clear bottomed 96 well plates (Packard, No.
6005182).
[0357] 3 days later, Growth Medium was removed from the wells and
replaced with 100 ul Assay Medium (phenol red free DMEM, 2 mM
glutamine, 1.2 mg/ml G418) either with or without erbB inhibitor
compound. Plates were returned to the incubator for 4 hrs and then
20 .mu.l of 20% formaldehyde solution in PBS was added to each well
and the plate was left at room temperature for 30 minutes. This
fixative solution was removed with a multichannel pipette, 100
.mu.l of PBS was added to each well and then removed with a
multichannel pipette and then 50 .mu.l PBS was added to each well.
Plates were then sealed and stored for up to 2 weeks at 4.degree.
C.
[0358] Immunostaining was performed at room temperature. Wells were
washed once with 200 .mu.l PBS/Tween 20 (made by adding 1 sachet of
PBS/Tween dry powder (Sigma, No. P3563) to 1 L of double distilled
H.sub.2O) using a plate washer then 200 .mu.l Blocking Solution (5%
Marvel dried skimmed milk (Nestle) in PBS/Tween 20) was added and
incubated for 10 minutes. Blocking Solution was removed using a
plate washer and 200 .mu.l of 0.5% Triton X-100/PBS was added to
permeabalise the cells. After 10 minutes, the plate was washed with
200 .mu.l PBS/Tween 20 and then 200 .mu.l Blocking Solution was
added once again and incubated for 15 minutes. Following removal of
the Blocking Solution with a plate washer, 30 .mu.l of rabbit
polyclonal anti-phospho ErbB2 IgG antibody (epitope phospho-Tyr
1248, SantaCruz, No. SC-12352-R), diluted 1:250 in Blocking
Solution, was added to each well and incubated for 2 hours. Then
this primary antibody solution was removed from the wells using a
plate washer followed by two 200 .mu.l PBS/Tween 20 washes using a
plate washer. Then 30 .mu.l of Alexa-Fluor 488 goat anti-rabbit IgG
secondary antibody (Molecular Probes, No. A-11008), diluted 1:750
in Blocking Solution, was added to each well. From now onwards,
wherever possible, plates were protected from light exposure, at
this stage by sealing with black backing tape. The plates were
incubated for 45 minutes and then the secondary antibody solution
was removed from the wells followed by two 200 .mu.l PBS/Tween 20
washes using a plate washer. Then 100 .mu.l PBS was added to each
plate, incubated for 10 minutes and then removed using a plate
washer. Then a further 100 .mu.l PBS was added to each plate and
then, without prolonged incubation, removed using a plate washer.
Then 50 .mu.l of PBS was added to each well and plates were
resealed with black backing tape and stored for up to 2 days at
4.degree. C. before analysis.
[0359] The Fluorescence signal is each well was measured using an
Acumen Explorer Instrument (Acumen Bioscience Ltd.), a plate reader
that can be used to rapidly quantitate features of images generated
by laser-scanning. The instrument was set to measure the number of
fluorescent objects above a pre-set threshold value and this
provided a measure of the phosphorylation status of erbB2 protein.
Fluorescence dose response data obtained with each compound was
exported into a suitable software package (such as Origin) to
perform curve fitting analysis. Inhibition of erbB2 phosphorylation
was expressed as an IC.sub.50 value. This was determined by
calculation of the concentration of compound that was required to
give 50% inhibition of erbB2 phosphorylation signal.
d) In Vivo Xenograft Assay
[0360] This assay measures the ability of a test compound to
inhibit the growth of a LoVo tumour (colorectal adenocarcinoma
obtained from the ATCC) in Female Swiss athymic mice (Alderley
Park, nu/nu genotype).
[0361] Female Swiss athymic (nu/nu genotype) mice were bred and
maintained in Alderley Park in negative pressure Isolators (PFI
Systems Ltd.). Mice were housed in a barrier facility with 12 hr
light/dark cycles and provided with sterilised food and water ad
libitum. All procedures were performed on mice of at least 8 weeks
of age. LoVo tumour cell (colorectal adenocarcinoma obtained from
the ATCC) xenografts were established in the hind flank of donor
mice by sub cutaneous injections of 1.times.10.sup.7 freshly
cultured cells in 100 .mu.l of serum free media per animal. On day
5 post-implant, mice were randomised into groups of 7 prior to the
treatment with compound or vehicle control that was administered
once daily at 0.1 ml/10 g body weight. Tumour volume was assessed
twice weekly by bilateral Vernier calliper measurement, using the
formula (length.times.width).times.
(length.times.width).times.(.pi./6), where length was the longest
diameter across the tumour, and width was the corresponding
perpendicular. Growth inhibition from start of study was calculated
by comparison of the mean changes in tumour volume for the control
and treated groups, and statistical significance between the two
groups was evaluated using a Students t test.
e) hERG-Encoded Potassium Channel Inhibition Assay
[0362] This assay determines the ability of a test compound to
inhibit the tail current flowing through the human
ether-a-go-go-related-gene (hERG)-encoded potassium channel.
[0363] Human embryonic kidney (HEK) cells expressing the
hERG-encoded channel were grown in Minimum Essential Medium Eagle
(EMEM; Sigma-Aldrich catalogue number M2279), supplemented with 10%
Foetal Calf Serum (Labtech International; product number
4-101-500), 10% M1 serum-free supplement (Egg Technologies; product
number 70916) and 0.4 mg/ml Geneticin G418 (Sigma-Aldrich;
catalogue number G7034). One or two days before each experiment,
the cells were detached from the tissue culture flasks with
Accutase (TCS Biologicals) using standard tissue culture methods.
They were then put onto glass coverslips resting in wells of a 12
well plate and covered with 2 ml of the growing media.
[0364] For each cell recorded, a glass coverslip containing the
cells was placed at the bottom of a Perspex chamber containing bath
solution (see below) at room temperature (.about.20.degree. C.).
This chamber was fixed to the stage of an inverted, phase-contrast
microscope. Immediately after placing the coverslip in the chamber,
bath solution was perfused into the chamber from a gravity-fed
reservoir for 2 minutes at a rate of .about.2 ml/min. After this
time, perfusion was stopped.
[0365] A patch pipette made from borosilicate glass tubing (GC120F,
Harvard Apparatus) using a P-97 micropipette puller (Sutter
Instrument Co.) was filled with pipette solution (see hereinafter).
The pipette was connected to the headstage of the patch clamp
amplifier (Axopatch 200B, Axon Instruments) via a silver/silver
chloride wire. The headstage ground was connected to the earth
electrode. This consisted of a silver/silver chloride wire embedded
in 3% agar made up with 0.85% sodium chloride.
[0366] The cell was recorded in the whole cell configuration of the
patch clamp technique. Following "break-in", which was done at a
holding potential of -80 mV (set by the amplifier), and appropriate
adjustment of series resistance and capacitance controls,
electrophysiology software (Clampex, Axon Instruments) was used to
set a holding potential (-80 mV) and to deliver a voltage protocol.
This protocol was applied every 15 seconds and consisted of a 1 s
step to +40 mV followed by a 1 s step to -50 mV. The current
response to each imposed voltage protocol was low pass filtered by
the amplifier at 1 kHz. The filtered signal was then acquired, on
line, by digitising this analogue signal from the amplifier with an
analogue to digital converter. The digitised signal was then
captured on a computer running Clampex software (Axon Instruments).
During the holding potential and the step to +40 mV the current was
sampled at 1 kHz. The sampling rate was then set to 5 kHz for the
remainder of the voltage protocol.
[0367] The compositions, pH and osmolarity of the bath and pipette
solution are tabulated below.
TABLE-US-00006 Salt Pipette (mM) Bath (mM) NaCl -- 137 KCl 130 4
MgCl.sub.2 1 1 CaCl.sub.2 -- 1.8 HEPES 10 10 glucose -- 10
Na.sub.2ATP 5 -- EGTA 5 --
TABLE-US-00007 Parameter Pipette Bath pH 7.18-7.22 7.40 pH
adjustment with 1M KOH 1M NaOH Osmolarity (mOsm) 275-285
285-295
[0368] The amplitude of the hERG-encoded potassium channel tail
current following the step from +40 mV to -50 mV was recorded
on-line by Clampex software (Axon Instruments). Following
stabilisation of the tail current amplitude, bath solution
containing the vehicle for the test substance was applied to the
cell. Providing the vehicle application had no significant effect
on tail current amplitude, a cumulative concentration effect curve
to the compound was then constructed.
[0369] The effect of each concentration of test compound was
quantified by expressing the tail current amplitude in the presence
of a given concentration of test compound as a percentage of that
in the presence of vehicle.
[0370] Test compound potency (IC.sub.50) was determined by fitting
the percentage inhibition values making up the concentration-effect
to a four parameter Hill equation using a standard data-fitting
package. If the level of inhibition seen at the highest test
concentration did not exceed 50%, no potency value was produced and
a percentage inhibition value at that concentration was quoted.
[0371] Although the pharmacological properties of the compounds of
the Formula I vary with structural change as expected, in general
activity possessed by compounds of the Formula I, may be
demonstrated at the following concentrations or doses in one or
more of the above tests (a), (b) and (c):--
[0372] Test (a):--IC.sub.50 in the range, for example, 0.001-10
.mu.M;
[0373] Test (b):--IC.sub.50 in the range, for example, 0.001-10
.mu.M;
[0374] Test (c):--IC.sub.50 in the range, for example, 0.01-10
.mu.M;
[0375] Test (d):--activity in the range, for example, 1-200
mg/kg/day;
[0376] By way of example, using Test (a) (for the inhibition of
tyrosine kinase protein phosphorylation) and Test (b) described
above, representative compounds described in the Examples herein
gave the IC.sub.50 results shown below in Table VI.
TABLE-US-00008 TABLE VI IC.sub.50 (nM) Test (a) IC.sub.50 (nM)
(inhibition of tyrosine Test (b) (EGFR Compound kinase protein
driven KB cell Example Number phosphorylation) proliferation assay)
1 1 (Table 1) <1 17 10 10 (Table 1) 14 16 33 33 (Table 2) 15 47
34 34 (Table 2) 43 87 60 60 (Table 3) <1 30 96 96 (Table 5)
<1 17
[0377] According to a further aspect of the invention there is
provided a pharmaceutical composition which comprises a quinazoline
derivative of the Formula I, or a pharmaceutically-acceptable
thereof, as defined hereinbefore in association with a
pharmaceutically-acceptable diluent or carrier.
[0378] 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).
[0379] 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.
[0380] 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 0.5 g of active agent (more suitably from 0.5 to 100 mg,
for example from 1 to 30 mg) 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.
[0381] The size of the dose for therapeutic or prophylactic
purposes of a compound of the Formula I 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.
[0382] In using a compound of the Formula I for therapeutic or
prophylactic purposes it will generally be administered so that a
daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body
weight is received, 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, 0.1 mg/kg to 30 mg/kg body weight will
generally be used. Similarly, for administration by inhalation, a
dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight
will be used. Oral administration is however preferred,
particularly in tablet form. Typically, unit dosage forms will
contain about 0.5 mg to 0.5 g of a compound of this invention.
[0383] We have found that the compounds of the present invention
possess anti-proliferative properties such as anti-cancer
properties that are believed to arise from their erbB family
receptor tyrosine kinase inhibitory activity, particularly
inhibition of the EGF receptor (erbB1) tyrosine kinase.
Furthermore, certain of the compounds according to the present
invention possess substantially better potency against the EGF
receptor tyrosine kinase, than against other tyrosine kinase
enzymes, for example erbB2. Such compounds possess sufficient
potency against the EGF receptor tyrosine kinase that they may be
used in an amount sufficient to inhibit EGF receptor tyrosine
kinase whilst demonstrating little, or significantly lower,
activity against other tyrosine kinase enzymes such as erbB2. Such
compounds are likely to be useful for the selective inhibition of
EGF receptor tyrosine kinase and are likely to be useful for the
effective treatment of, for example EGF driven tumours.
[0384] Accordingly, the compounds of the present invention are
expected to be useful in the treatment of diseases or medical
conditions mediated alone or in part by erbB receptor tyrosine
kinases (especially EGF receptor tyrosine kinase), i.e. the
compounds may be used to produce an erbB receptor tyrosine kinase
inhibitory effect in a warm-blooded animal in need of such
treatment. Thus the compounds of the present invention provide a
method for the treatment of malignant cells characterised by
inhibition of one or more of the erbB family of receptor tyrosine
kinases. Particularly the compounds of the invention may be used to
produce an anti-proliferative and/or pro-apoptotic and/or
anti-invasive effect mediated alone or in part by the inhibition of
erbB receptor tyrosine kinases. Particularly, the compounds of the
present invention are expected to be useful in the prevention or
treatment of those tumours that are sensitive to inhibition of one
or more of the erbB receptor tyrosine kinases, such as EGF and/or
erbB2 and/or erbB4 receptor tyrosine kinases (especially EGF
receptor tyrosine kinase) that are involved in the signal
transduction steps which drive proliferation and survival of these
tumour cells. Accordingly the compounds of the present invention
are expected to be useful in the treatment of psoriasis, benign
prostatic hyperplasia (BPH), atherosclerosis and restenosis and/or
cancer by providing an anti-proliferative effect, particularly in
the treatment of erbB receptor tyrosine kinase sensitive cancers.
Such benign or malignant tumours may affect any tissue and include
non-solid tumours such as leukaemia, multiple myeloma or lymphoma,
and also solid tumours, for example bile duct, bone, bladder,
brain/CNS, breast, colorectal, endometrial, gastric, head and neck,
hepatic, lung, neuronal, oesophageal, ovarian, pancreatic,
prostate, renal, skin, testicular, thyroid, uterine and vulval
cancers.
[0385] According to this aspect of the invention there is provided
a compound of the Formula I, or a pharmaceutically acceptable salt
thereof, for use as a medicament.
[0386] According to a further aspect of the invention there is
provided a compound of the Formula I, or a pharmaceutically
acceptable salt thereof, for use in the production of an
anti-proliferative effect in a warm-blooded animal such as man.
[0387] Thus according to this aspect of the invention there is
provided the use of a quinazoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined hereinbefore
in the manufacture of a medicament for use in the production of an
anti-proliferative effect in a warm-blooded animal such as man.
[0388] According to a further feature of this aspect of the
invention there is provided a method for producing an
anti-proliferative effect in a warm-blooded animal, such as man, in
need of such treatment which comprises administering to said animal
an effective amount of a quinazoline derivative of the Formula I,
or a pharmaceutically acceptable salt thereof, as hereinbefore
defined.
[0389] According to a further aspect of the invention there is
provided the use of a quinazoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined hereinbefore
in the manufacture of a medicament for use in the prevention or
treatment of those tumours which are sensitive to inhibition of
erbB receptor tyrosine kinases, such as EGFR and/or erbB2 and/or
erbB4 (especially EGFR), that are involved in the signal
transduction steps which lead to the proliferation of tumour
cells.
[0390] According to a further feature of this aspect of the
invention there is provided a method for the prevention or
treatment of those tumours which are sensitive to inhibition of one
or more of the erbB family of receptor tyrosine kinases, such as
EGFR and/or erbB2 and/or erbB4 (especially EGFR), that are involved
in the signal transduction steps which lead to the proliferation
and/or survival of tumour cells which comprises administering to
said animal an effective amount of a quinazoline derivative of the
Formula I, or a pharmaceutically-acceptable salt thereof, as
defined hereinbefore.
[0391] According to a further feature of this aspect of the
invention there is provided a compound of the Formula I, or a
pharmaceutically acceptable salt thereof, for use in the prevention
or treatment of those tumours which are sensitive to inhibition of
erbB receptor tyrosine kinases, such as EGFR and/or erbB2 and/or
erbB4 (especially EGFR), that are involved in the signal
transduction steps which lead to the proliferation of tumour
cells.
[0392] According to a further aspect of the invention there is
provided the use of a quinazoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined hereinbefore
in the manufacture of a medicament for use in providing a EGFR
and/or erbB2 and/or erbB4 (especially an EGFR) tyrosine kinase
inhibitory effect.
[0393] According to a further feature of this aspect of the
invention there is provided a method for providing a EGFR and/or an
erbB2 and or an erbB4 (especially an EGFR) tyrosine kinase
inhibitory effect which comprises administering to said animal an
effective amount of a quinazoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined
hereinbefore.
[0394] According to a further feature of this aspect of the
invention there is provided a compound of the Formula I, or a
pharmaceutically acceptable salt thereof, for use in providing a
EGFR and/or erbB2 and/or erbB4 (especially an EGFR) tyrosine kinase
inhibitory effect.
[0395] According to a further feature of the present invention
there is provided the use of a quinazoline derivative of the
Formula I, or a pharmaceutically-acceptable salt thereof, as
defined hereinbefore in the manufacture of a medicament for use in
providing a selective EFGR tyrosine kinase inhibitory effect.
[0396] According to a further feature of this aspect of the
invention there is provided a method for providing a selective EGFR
tyrosine kinase inhibitory effect which comprises administering to
said animal an effective amount of a quinazoline derivative of the
Formula I, or a pharmaceutically-acceptable salt thereof, as
defined hereinbefore.
[0397] According to a further feature of this aspect of the
invention there is provided a compound of the Formula I, or a
pharmaceutically acceptable salt thereof, for use in providing a
selective EGFR kinase inhibitory effect.
[0398] By "a selective EGFR kinase inhibitory effect" is meant that
the quinazoline derivative of Formula I is more potent against EGFR
tyrosine kinase than it is against other kinases. In particular
some of the compounds according to the invention are more potent
against EGFR receptor tyrosine kinase than it is against other
tyrosine kinases such as other erb-B receptor tyrosine kinases,
particularly erbB2 receptor tyrosine kinase. For example a
selective EGFR kinase inhibitor according to the invention is at
least 5 times, preferably at least 10 times more potent against
EGFR tyrosine kinase than it is against erbB2 receptor tyrosine
kinase, as determined from the relative IC.sub.50 values in
suitable assays (for example the by comparing the IC.sub.50 value
from the Clone 24 phospho-erbB2 cell assay (a measure of the erb-B2
tyrosine kinase inhibitory activity in cells) with the IC.sub.50
from the KB cell assay (a measure of the EGFR tyrosine kinase
inhibitory activity in cells) for a given test compound as
described above).
[0399] According to a further aspect of the present invention there
is provided the use of a quinazoline derivative of the Formula I,
or a pharmaceutically-acceptable salt thereof, as defined
hereinbefore in the manufacture of a medicament for use in the
treatment of a cancer (for example a cancer selected from
leukaemia, multiple myeloma, lymphoma, bile duct, bone, bladder,
brain/CNS, breast, colorectal, endometrial, gastric, head and neck,
hepatic, lung, neuronal, oesophageal, ovarian, pancreatic,
prostate, renal, skin, testicular, thyroid, uterine and vulval
cancer).
[0400] According to a further feature of this aspect of the
invention there is provided a method for treating a cancer (for
example a cancer selected from leukaemia, multiple myeloma,
lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectal,
endometrial, gastric, head and neck, hepatic, lung, neuronal,
oesophageal, ovarian, pancreatic, prostate, renal, skin,
testicular, thyroid, uterine and vulval cancer) in a warm-blooded
animal, such as man, in need of such treatment, which comprises
administering to said animal an effective amount of a quinazoline
derivative of the Formula I, or a pharmaceutically-acceptable salt
thereof, as defined hereinbefore.
[0401] According to a further aspect of the invention there is
provided a compound of the Formula I, or a pharmaceutically
acceptable salt thereof, for use in the treatment of a cancer (for
example selected from leukaemia, multiple myeloma, lymphoma, bile
duct, bone, bladder, brain/CNS, breast, colorectal, endometrial,
gastric, head and neck, hepatic, lung, neuronal, oesophageal,
ovarian, pancreatic, prostate, renal, skin, testicular, thyroid,
uterine and vulval cancer).
[0402] As mentioned above the size of the dose required for the
therapeutic or prophlyactic treatment of a particular disease will
necessarily be varied depending upon, amongst other things, the
host treated, the route of administration and the severity of the
illness being treated.
[0403] The anti-proliferative treatment defined hereinbefore may be
applied as a sole therapy or may involve, in addition to the
quinazoline derivative 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), oestrogen receptor down regulators
(for example fulvestrant), 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 other 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 anergy,
approaches using transfected immune cells such as
cytokine-transfected dendritic cells, approaches using
cytokine-transfected tumour cell lines and approaches using
anti-idiotypic antibodies.
[0404] 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.
[0405] According to this aspect of the invention there is provided
a pharmaceutical product comprising a quinazoline derivative of the
Formula I as defined hereinbefore and an additional anti-tumour
agent as defined hereinbefore for the conjoint treatment of
cancer.
[0406] Although the compounds of the Formula I are primarily of
value as therapeutic agents for use in warm-blooded animals
(including man), they are also useful whenever it is required to
inhibit the effects of the erbB receptor tyrosine protein kinases.
Thus, they are useful as pharmacological standards for use in the
development of new biological tests and in the search for new
pharmacological agents.
[0407] The invention will now be illustrated by the following non
limiting examples in which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (.degree. C.);
operations were carried out at room or ambient temperature, that
is, at a temperature in the range of 18-25.degree. C.; (ii) organic
solutions were dried over anhydrous magnesium sulfate; evaporation
of solvent was carried out using a rotary evaporator under reduced
pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath temperature of
up to 60.degree. C.; (iii) chromatography means flash
chromatography on silica gel; thin layer chromatography (TLC) was
carried out on silica gel plates; (iv) in general, the course of
reactions was followed by TLC and/or analytical LCMS, and reaction
times are given for illustration only; (v) final products had
satisfactory proton nuclear magnetic resonance (NMR) spectra and/or
mass spectral data; (vi) yields are given for illustration only and
are not necessarily those which can be obtained by diligent process
development; preparations were repeated if more material was
required; (vii) when given, NMR data is in the form of delta values
for major diagnostic protons, given in parts per million (ppm)
relative to tetramethylsilane (TMS) as an internal standard,
determined at 300 or 400 MHz using perdeuterio dimethyl sulfoxide
(DMSO-d.sub.6) as solvent unless otherwise indicated; the following
abbreviations have been used: s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; b, broad; (viii) chemical symbols have
their usual meanings; SI units and symbols are used; (ix) solvent
ratios are given in volume:volume (v/v) terms; and (x) mass spectra
(MS) were run with an electron energy of 70 electron volts in the
chemical ionization (CI) mode using a direct exposure probe and
ionization was effected by electrospray; values for m/z are given;
generally, only ions which indicate the parent mass are reported;
and unless otherwise stated, the mass ion quoted is (MH).sup.+;
alternatively, mass spectra (MS) were run using a Waters or
Micromass electrospray LC-MS (where stated) in positive or negative
ion mode; values for m/z are again given; generally, only ions
which indicate the parent mass are reported; and unless otherwise
stated, the mass ion quoted is again (MH).sup.+; (xi) unless stated
otherwise compounds containing an asymmetrically substituted carbon
and/or sulfur atom have not been resolved; (xii) where a synthesis
is described as being analogous to that described in a previous
example the amounts used are the millimolar ratio equivalents to
those used in the previous example; (xvi) the following
abbreviations have been used: DMSO dimethylsulphoxide;
THF Tetrahydrofuran;
[0408] HATU
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluorophosphat-
e DIPEA di-isopropylethylamine
DMA N,N-dimethylacetamide
[0409] DCM dichloromethane MeOH methanol AcOH acetic acid TBTU
O-(1H-Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate EDCI
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide LCMS liquid
chromatography mass spectrometer xvii) where a synthesis is
described as leading to an acid addition salt (e.g. HCl salt), the
specific stoichiometry of the salt was not confirmed.
EXAMPLE 1
Preparation of Compound No 1 in Table 1
##STR00117##
[0410] HATU (0.31 g) was added to a solution of
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-a-
mine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and
isoxazole-5-carboxylic acid (0.110 g) in methylene chloride (9 ml).
The resulting mixture was stirred at room temperature for 2.5 hrs.
Methylene chloride (20 ml) was added and the organics washed with
aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes
were then purified by flash column chromatography eluting with
methanol/methylene chloride (2.5/97.5). Fractions containing the
desired product were evaporated to a white foam which was
triturated with diethyl ether (20 ml) to give
N-(3-chloro-2-fluorophenyl)-6-{[1-(isoxazol-5-ylcarbonyl)piperidin-4-yl]o-
xy}-7-methoxyquinazolin-4-amine as a white solid (0.110 g). .sup.1H
NMR Spectrum: (DMSO d.sub.6 373K) 1.88 (m, 2H), 2.09 (m, 2H), 3.61
(m, 2H), 3.84 (m, 2H), 3.96 (s, 3H), 4.78 (m, 1H), 6.87 (s, 1H),
7.29 (m, 1H), 7.29 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.93 (s,
1H), 8.39 (s, 1H), 8.64 (s, 1H), 9.28 (br s, 1H); Mass Spectrum:
(M+H).sup.+ 498.
Preparation of Starting Material
[0411] The
6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyqui-
nazoline dihydrochloride starting material was prepared as
follows:
[0412] 6-Acetoxy-4-chloro-7-methoxyquinazoline, (Example 25-5 of in
WO01/66099; 10.0 g, 39.6 mmole) was added in portions to a stirred
7N methanolic ammonia solution (220 ml) cooled to 10.degree. C. in
an ice/water bath. After stirring for one hour the precipitate was
filtered, washed with diethylether and dried thoroughly under high
vacuum to give 4-chloro-6-hydroxy-7-methoxyquinazoline (5.65 g,
67.8%); .sup.1H NMR Spectrum: (DMSO d.sub.6) 3.96 (s, 3H); 7.25 (s,
1H); 7.31 (s, 1H); 8.68 (s, 1H); Mass Spectrum: (M+H).sup.+ 211
[0413] Di-tert-butylazodicarboxylate (9.22 g) in methylene chloride
(20 ml) was added slowly to a stirred suspension of
4-chloro-6-hydroxy-7-methoxyquinazoline (5.63 g),
4-hydroxy-1-tert-butoxycarbonylpiperidine (8.06 g) and
triphenylphosphine (10.5 g) in methylene chloride (100 ml) at
5.degree. C. under an atmosphere of nitrogen. The reaction mixture
was allowed to warm to room temperature for 16 hours. The reaction
mixture was then evaporated under vacuum and adsorbed onto silica
and the product was eluted with isohexane/ethyl
acetate/triethylamine (75/24/1 followed by 70/29/1). The fractions
containing the desired product were combined and evaporated under
vacuum to give tert-butyl
4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1-carboxylate
as a white solid (10.3 g); .sup.1H NMR Spectrum: (DMSO d.sub.6)
1.40 (s, 9H), 1.56-1.69 (m, 2H), 1.93-2.04 (m, 2H), 3.20-3.31 (m,
2H), 3.60-3.70 (m, 2H), 4.00 (s, 3H), 4.89 (m, 1H), 7.45 (s, 1H),
7.50 (s, 1H), 8.86 (s, 1H); Mass Spectrum: (M+H).sup.+ 394.
[0414] 4.0M HCl in Dioxane (4.0 ml) was added to a suspension of
tert-butyl
4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1-carboxylate
(2.62 g) and 3-chloro-2-fluoroaniline (1.08 g) in iso-propanol (50
ml). The reaction mixture was stirred and heated at 100.degree. C.
for 2 hours. The yellow precipitate was filtered hot and washed
with iso-propanol followed by diethylether and dried under vacuum
to give
6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline
as a di-hydrochloride salt (2.38 g); .sup.1H NMR Spectrum: (DMSO
d.sub.6) 1.84-1.99 (m, 2H), 2.22-2.33 (m, 2H), 3.12-3.33 (m, 4H),
4.00 (s, 3H), 5.08 (m, 1H), 7.34 (t, 1H), 7.40 (s, 1H), 7.50 (t,
1H), 7.62 (t, 1H), 8.80 (s, 1H), 8.84-8.94 (m, 2H), 8.99-9.11 (m,
1H); Mass Spectrum: (M+H).sup.+ 403.
EXAMPLE 2
Preparation of Compound No 3 in Table 1
##STR00118##
[0415] HATU (0.31 g) was added to a solution of
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-a-
mine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and
3-methyl-5-isoxazolecarboxylic acid (0.126 g) in methylene chloride
(9 ml). The resulting mixture was stirred at room temperature for
2.5 hrs. Methylene chloride (20 ml) was added and the organics
washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml).
The crudes were then purified by flash column chromatography
eluting with methanol/methylene chloride (2.5/97.5). Fractions
containing the desired product were evaporated to a white foam
which was triturated with diethyl ether (20 ml) to give
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(3-methylisoxazol-5-yl)carbo-
nyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.145
g). .sup.1H NMR Spectrum: (DMSO d.sub.6 373K) 1.89 (m, 2H), 2.10
(m, 2H), 2.35 (s, 3H), 3.64 (m, 2H), 3.88 (m, 2H), 3.99 (s, 3H),
4.82 (m, 1H), 6.73 (s, 1H), 7.29 (m, 1H), 7.29 (s, 1H), 7.42 (m,
1H), 7.59 (m, 1H), 7.93 (s, 1H), 8.39 (s, 1H), 9.28 (br s, 1H);
Mass Spectrum: (M+H).sup.+ 512.
[0416] The staring material was prepared in the manner described in
Example 1 above.
EXAMPLE 3
Preparation of Compound No 4 in Table 1
##STR00119##
[0417] HATU (0.31 g) was added to a solution of
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-a-
mine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and
5-methyl-3-isoxazolecarboxylic acid (0.127 g) in methylene chloride
(9 ml). The resulting mixture was stirred at room temperature for
2.5 hrs. Methylene chloride (20 ml) was added and the organics
washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml).
The crudes were then purified by flash column chromatography
eluting with methanol/methylene chloride (2.5/97.5). Fractions
containing the desired product were evaporated to a white foam
which was triturated with diethyl ether (20 ml) to give
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(5-methylisoxazol-3-yl)carbo-
nyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.115
g). .sup.1H NMR Spectrum: (DMSO d.sub.6 373K) 1.87 (m, 2H), 2.08
(m, 2H), 2.48 (s, 3H), 3.61 (m, 2H), 3.89 (m, 2H), 3.96 (s, 3H),
4.80 (m, 1H), 6.40 (s, 1H), 7.22 (m, 1H), 7.22 (s, 1H), 7.42 (m,
1H), 7.59 (m, 1H), 7.90 (s, 1H), 8.39 (s, 1H), 9.26 (br s, 1H);
Mass Spectrum: (M+H).sup.+ 512.
[0418] The staring material was prepared in the manner described in
Example 1 above.
EXAMPLE 4
Preparation of Compound No 5 in Table 1
##STR00120##
[0419] HATU (0.31 g) was added to a solution of
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-a-
mine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and
5-methyl-4-isoxazolecarboxylic acid (0.127 g) in methylene chloride
(9 ml). The resulting mixture was stirred at room temperature for
2.5 hrs. Methylene chloride (20 ml) was added and the organics
washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml).
The crudes were then purified by flash column chromatography
eluting with methanol/methylene chloride (2.5/97.5). Fractions
containing the desired product were evaporated to a white foam
which was triturated with diethyl ether (20 ml) to give
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(5-methylisoxazol-4-yl)carbo-
nyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.138
g). .sup.1H NMR Spectrum: (DMSO d.sub.6 373K) 1.83 (m, 2H), 2.08
(m, 2H), 2.40 (s, 3H), 3.52 (m, 2H), 3.80 (m, 2H), 3.97 (s, 3H),
4.79 (m, 1H), 7.24 (m, 1H), 7.24 (s, 1H), 7.42 (m, 1H), 7.59 (m,
1H), 7.89 (s, 1H), 8.39 (s, 1H), 8.59 (s, 1H), 9.27 (br s, 1H);
Mass Spectrum: (M+H).sup.+ 512.
[0420] The staring material was prepared in the manner described in
Example 1 above.
EXAMPLE 5
Preparation of Compound No 6 in Table 1
##STR00121##
[0421] HATU (0.31 g) was added to a solution of
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-a-
mine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and
3-methyl-4-isoxazolecarboxylic acid (0.128 g) in methylene chloride
(9 ml). The resulting mixture was stirred at room temperature for
2.5 hrs. Methylene chloride (20 ml) was added and the organics
washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml).
The crudes were then purified by flash column chromatography
eluting with methanol/methylene chloride (2.5/97.5). Fractions
containing the desired product were evaporated to a white foam
which was triturated with diethyl ether (20 ml) to give
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(3-methylisoxazol-4-yl)carbo-
nyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.068
g). .sup.1H NMR Spectrum: (DMSO d.sub.6 373K) 1.86 (m, 2H), 2.02
(m, 2H), 2.30 (s, 3H), 3.52 (m, 2H), 3.82 (m, 2H), 3.96 (s, 3H),
4.79 (m, 1H), 7.22 (m, 1H), 7.22 (s, 1H), 7.40 (m, 1H), 7.58 (m,
1H), 7.89 (s, 1H), 8.39 (s, 1H), 9.00 (s, 1H), 9.25 (br s, 1H);
Mass Spectrum: (M+H).sup.+ 512
[0422] The staring material was prepared in the manner described in
Example 1 above.
EXAMPLE 6
Preparation of Compound No. 7 in Table 1
##STR00122##
[0423] HATU (0.31 g) was added to a solution of
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-a-
mine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and
3,5-dimethyl-4-isoxazolecarboxylic acid (0.141 g) in methylene
chloride (9 ml). The resulting mixture was stirred at room
temperature for 2.5 hrs. Methylene chloride (20 ml) was added and
the organics washed with aqueous sodium hydroxide (2M, 30 ml) and
water (30 ml). The crudes were then purified by flash column
chromatography eluting with methanol/methylene chloride (2.5/97.5).
Fractions containing the desired product were evaporated to a white
foam which was triturated with diethyl ether (20 ml) to give
N-(3-chloro-2-fluorophenyl)-6-({1-[(3,5-dimethylisoxazol-4-yl)carbonyl]pi-
peridin-4-yl}oxy)-7-methoxyquinazolin-4-amine as a white solid
(0.107 g). .sup.1H NMR Spectrum: (DMSO d.sub.6 373K) 1.80 (m, 2H),
2.01 (m, 2H), 2.20 (s, 3H), 2.40 (s, 3H), 3.47 (m, 2H), 3.75 (m,
2H), 3.96 (s, 3H), 4.76 (m, 1H), 7.23 (m, 1H), 7.23 (s, 1H), 7.40
(m, 1H), 7.58 (m, 1H), 7.89 (s, 1H), 8.39 (s, 1H), 9.25 (br s, 1H);
Mass Spectrum: (M+H).sup.+ 526.
[0424] The staring material was prepared in the manner described in
Example 1 above.
EXAMPLE 7
Preparation of Compound No 2 in Table 1
##STR00123##
[0425] HATU (0.31 g) was added to a solution of
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-a-
mine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and
3-methyl-5-isoxazoleacetic Acid (0.135 g) in methylene chloride (9
ml). The resulting mixture was stirred at room temperature for 2.5
hrs. Methylene chloride (20 ml) was added and the organics washed
with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The
crudes were then purified by flash column chromatography eluting
with methanol/methylene chloride (2.5/97.5). Fractions containing
the desired product were evaporated to a white foam which was
triturated with diethyl ether (20 ml) to give
N-(3-chloro-2-fluorophenyl)-7-methoxy-6({1-[(3-methylisoxazol-5-yl)acetyl-
]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.269 g).
.sup.1H NMR Spectrum: (DMSO d.sub.6 373K) 1.79 (m, 2H), 1.98 (m,
2H), 2.23 (s, 3H), 3.50 (m, 2H), 3.79 (m, 2H), 3.92 (s, 2H), 3.97
(s, 3H), 4.77 (m, 1H), 6.18 (s, 1H), 7.24 (m, 2H), 7.42 (m, 1H),
7.59 (m, 1H), 7.89 (s, 1H), 8.39 (s, 1H), 9.28 (br s, 1H); Mass
Spectrum: (M+H).sup.+ 526.
[0426] The staring material was prepared in the manner described in
Example 1 above.
EXAMPLES 8 TO 31
Preparation of Compound No.s 8 to 31 in Table 1
Generic Process
##STR00124##
[0427] Solid HATU (119 mg, 0.815 mmol) and DIPEA (0.171 ml, 0.96
mmol) were dissolved in anhydrous DMA (0.5 ml) were added to a
solution of
(3-chloro-2-fluorophenyl)-[7-methoxy-6-(piperidin-4-yloxy)-quinazolin-4-y-
l]-amine.dihydrochloride (100 mg, 0.24 mmol), and the carboxylic
acid (0.36 mmol) in DMA (0.5 ml) at room temperature. The resulting
solution was allowed to stir at room temperature overnight. The
crude reaction mixtures were purified using mass-triggered
preparative LCMS.
[0428] The fractions containing the desired compound were
evaporated in a Genevac and the residue taken up in 10% (v/v) MeOH
in DCM (0.4 ml), diluted with 6 ml of 15% (v/v) Et.sub.2O in
pentane and left at 4.degree. C. overnight. The resulting
precipitates were collected by filtration and dried to a constant
weight to afford the desired amides as amorphous or crystalline
solids.
Standard Conditions for Purification by Mass-Triggered Preparative
LCMS
[0429] Column: ThermoHypersil Keystone B-Basic 5.mu. 21
mm.times.100 mm
[0430] Eluant: 7.5 minutes Gradient from 20% to 95% of acetonitrile
in water (buffer 2 g/l of (NH.sub.4).sub.2CO.sub.3, pH 8.9).
[0431] Flow rate: 25 ml/min.
[0432] The staring material was prepared in the manner described in
Example 1 above.
TABLE-US-00009 Example/ Compound NMR .delta. en ppm No. R MH+ (DMSO
+ TFAd) Yield 8 ##STR00125## 508.2 1.82-2.01 (m, 2H); 2.04- 2.28
(m, 2H); 3.35-3.46 (m, 1H); 3.58-3.75 (m, 2H); 3.96-4.10 (m, 1H);
4.05 (s, 3H); 4.95 (M, 1H); 7.39 (s, 1H); 7.41 (dd, 1H); 7.58(dd,
1H); 7.69 (dd, 1H); 8.15 (dd, 1H); 8.17 (s, 1H); 8.69 (d, 1H); 8.93
(s, 1H); 9.02 (d, 1H); 9.14 (s, 1H). 30 9 ##STR00126## 527.1
1.64-1.74 (m, 2H); 1.98- 2.09 (m, 2H); 3.37-3.57 (m, 2H); 3.80-3.94
(m, 2H); 4.02 (dd, 2H); 4.04 (s, 3H); 4.85 (bs, 1H); 6.97 (s, 1H);
6.98 (dd, 1H); 7.37 (s, 1H); 7.37-7.44 (m, 2H); 7.59 (dd, 1H); 7.68
(dd, 1H); 8.12 (s, 1H); 8.92 (s, 1H). 35 10 ##STR00127## 508.1
1.80-1.95 (m, 2H); 2.05- 2.25 (m, 2H); 3.38-3.47 (m, 1H); 3.62-3.75
(m, 2H); 3.94-4.04 (m, 1H); 4.06 (s, 3H); 4.94 (bs, 1H); 7.39 (s,
1H); 7.41 (dd, 1H); 7.59 (ddd, 1H); 7.75- 7.71 (m, 2H); 7.80 (d,
1H); 8.15 (ddd, 1H); 8.17 (s, 1H); 8.73 (d, 1H); 8.92 (s, 1H). 30
11 ##STR00128## 508.2 1.81-1.90 (m, 1H); 1.90- 1.99 (m, 1H);
2.03-2.13 (m, 1H); 2.18-2.26 (m, 1H); 3.26-3.34 (m, 1H); 3.47-3.56
(m, 1H); 3.65- 3.74 (m, 1H); 3.94-4.03 (m, 1H); 4.05 (s, 3H); 4.94
(bs, 1H); 7.37 (s, 1H); 7.41 (dd, 1H); 7.58 (ddd, 1H); 7.69 (ddd,
1H); 8.16 (s, 1H); 8.19 (d, 2H); 8.92 (s, 1H); 9.08 (d, 2H). 31 12
##STR00129## 523.2 1.71-2.01 (m, 2H): 2.01- 2.33 (m, 2H); 3.27-3.46
(m, 1H); 3.48-3.72 (m, 2H); 3.88-4.03 (m, 1H); 4.05 (s, 3H); 4.92
(bs, 1H); 6.99 (dd, 1H); 7.38 (s, 1H); 7.41 (dd, 1H); 7.58 (ddd,
1H); 7.69 (ddd, 1H); 8.03-8.10 (m, 2H); 8.15 (s, 1H); 8.92 (s, 1H).
19 13 ##STR00130## 497.2 1.79-1.92 (m, 2H); 2.10- 2.23 (m, 2H);
3.58-3.77 (m, 2H); 3.91-4.09 (m, 2H); 4.06 (s, 3H); 4.93 (bs, 1H);
6.63 (dd, 1H); 7.03 (d, 1H); 7.38 (s, 1H); 7.41 (dd, 1H); 7.59
(ddd, 1H); 7.69 (ddd, 1H); 7.83 (dd, 1H); 8.17 (s, 1H); 8.92 (s,
1H). 28 14 ##STR00131## 497.1 1.77-1.88 (m, 2H); 2.09- 2.18 (m,
2H); 3.54-3.63 (m, 2H); 3.86-3.98 (m, 2H); 4.05 (s, 3H); 4.92 (bs,
1H); 6.70 (dd, 1H); 7.38 (s, 1H); 7.41 (ddd, 1H); 7.59 (ddd, 1H);
7.68 (ddd, 1H); 7.73 (dd, 1H); 8.06 (s, 1H); 8.16 (s, 1H); 8.92 (s,
1H). 33 15 ##STR00132## 575.1 1.79-1.90 (m, 2H); 2.11- 2.21 (m,
2H); 3.59-3.74 (m, 2H); 3.91-4.02 (m, 2H); 4.05 (s, 3H); 4.92 (bs,
1H); 6.76 (d, 1H); 7.07 (d, 1H); 7.37 (s, 1H); 7.41 (dd, 1H); 7.59
(dd, 1H); 7.69 (dd, 1H); 8.16 (s, 1H); 8.92 (s, 1H). 41 16
##STR00133## 513.1 1.77-1.90 (m, 2H); 2.06- 2.21 (m, 2H); 3.44-3.64
(3, 2H); 3.65-4.11 (m, 2H); 4.06 (s, 3H); 4.92 (bs, 1H); 7.27 (dd,
1H); 7.37 (s, 1H); 7.41 (dd, 1H); 7.59 (ddd, 1H); 7.62 (dd, 1H);
7.69 (ddd, 1H); 7.83 (dd, lH); 8.16 (s, 1H); 8.92 (s, 1H). 37 17
##STR00134## 512.2 1.82-1.94 (m, 2H); 2.11- 2.23 (m, 2H); 3.56-3.68
(m, 2H); 3.92-4.02 (m, 2H); 4.06 (s, 3H); 4.95 (bs, 1H); 7.39 (s,
1H); 7.41 (dd, 1H); 7.59 (ddd, 1H); 7.68 (ddd, 1H); 8.19 (s, 1H);
8.33 (s, 1H); 8.93 (s, 1H). 37 18 ##STR00135## 558.2 1.81-1.97 (m,
2H); 2.10- 2.18 (m, 1H); 2.19-2.29 (m, 1H); 3.44-3.55 (m, 1H);
3.70-3.80 (m, 2H); 4.02-4.11 (m, 1H); 4.06 (s, 3H); 4.96 (bs, 1H);
7.38 (s, 1H); 7.41 (dd, 1H); 7.59 (ddd, 1H); 7.68 (dd, 1H); 7.72
(ddd, 1H); 7.78 (d, 1H); 7.88 (ddd, 1H); 8.08 (d, 1H); 8.10 (d,
1H); 8.17 (s, 1H); 8.59 (d, 1H); 8.92 (s, 1H). 22 19 ##STR00136##
547.2 1.84-1.95 (m, 2H); 2.16- 2.26 (m, 2H); 3.64-3.84 (m, 2H);
3.96-4.10 (m, 2H); 4.06 (s, 3H); 4.96 (bs, 1H); 7.35 (dd, 1H); 7.38
(s, 1H); 7.42 (ddd, 1H); 7.45 (s, 1H); 7.46 (ddd, 1H); 7.59 (ddd,
1H); 7.67 (d, 1H); 7.69 (ddd, 1H); 7.76 (d, 1H); 8.18 (s, 1H); 8.92
(s, 1H). 31 20 ##STR00137## 563.2 1.84-1.97 (m, 2H); 2.15- 2.26 (m,
2H); 3.65-3.80 (m, 2H); 3.97-4.05 (m, 2H); 4.06 (s, 3H); 4.96 (bs,
1H); 7.38 (s, 1H); 7.41 (ddd, 1H); 7.44-7.50 (m, 2H); 7.59 (ddd,
1H); 7.69 (ddd, 1H); 7.79 (s, 1H); 7.94 (dd, 1H); 8.03 (dd, 1H);
8.18 (s, 1H); 8.93 (s, 1H). 43 21 ##STR00138## 558.2 1.89-2.02 (m,
2H); 2.07- 2.19 (m, 1H); 2.20-231(m, 1H); 3.47-3.60(m, 1H);
3.67-3.86 (m, 2H); 4.01- 4.14 (m, 1H); 4.07 (s, 3H); 4.98 (bs, 1H);
7.40 (s, 1H); 7.41 (dd, 1H); 7.58 (dd, 1H); 7.68 (dd, 1H); 7.99
(dd, 1H); 8.18 (s, 1H); 8.19 (s, 1H); 8.31 (d, 1H); 8.40 (d, 1H);
8.93 (s, 1H); 9.26 (s, 1H); 9.49 (d, 1H). 28 22 ##STR00139## 546.2
1.79-1.89 (m, 2H); 2.13- 2.22 (m, 2H); 3.55-3.66 (m, 2H); 3.98-4.09
(m, 2H); 4.06 (s, 3H); 4.92 (bs, 1H); 713 (dd, 1H); 7.18 (dd, 1H);
7.38 (s, 1H); 7.41 (dd, 1H); 7.47 (d, 1H); 7.59 (ddd, 1H); 7.69
(ddd, 1H); 7.73 (d, 1H); 7.75 (s, 1H); 8.16 (s, 1H); 8.92 (s, 1H).
36 23 ##STR00140## 527.2 1.57-1.74 (m, 2H); 1.91- 2.00 (m, 1H);
2.00-2.08 (m, 1H); 3.37-3.57 (m, 2H); 3.74-3.86 (m, 1H); 3.76 (d,
1H); 3.81 (d, 1H); 3.85-3.95 (m, 1H); 4.04 (s, 3H); 4.82 (bs, 1H);
7.03 (dd, 1H); 7.30 (d, 1H); 7.36 (s, 1H); 7.41 (ddd, 1H); 7.49
(dd, 1H); 7.58 (ddd, 1H); 7.68 (ddd, 1H); 8.11 (s, 1H); 8.91 (s,
1H). 39 24 ##STR00141## 591.1 1.81-1.93 (m, 2H); 2.11- 2.22 (m,
2H); 3.61-3.74 (m, 2H); 3.89-3.98 (m, 2H); 4.05 (s, 3H); 4.93 (bs,
1H); 7.26 (bs, 1H); 7.33 (bs, 1H); 7.37 (s, 1H); 7.41 (dd, 1H);
7.59 (dd, 1H); 7.69 (bs, 1H); 8.16 (s, 1H); 8.92 (s, 1H). 43 25
##STR00142## 578.2 1.80-1.95(m, 2H); 2.03- 2.12 (m, 1H); 2.13-2.22
(m, 1H); 3.26-3.36 (m, 1H); 3.48-3.58 (m, 1H): 3.60-3.70 (m, 1H);
3.87- 3.98 (m, 1H); 4.05 (s, 3H); 4.91 (bs, 1H); 7.38 (s, 1H); 7.42
(dd, 1H); 7.58 (dd, 1H); 7.69 (dd, 1H); 7.72 (s, 2H); 8.14 (s, 1H);
8.92 (s, 1H). 39 26 ##STR00143## 527.2 1.79-1.91 (m, 2H); 2.10-
2.21 (m, 2H); 2.49 (s, 3H); 3.19-3.72 (m, 2H); 3.91- 4.02 (m, 2H);
4.06 (s, 3H); 4.93 (bs, 1H); 6.83 (dd, 1H); 7.27 (d, 1H); 7.38 (s,
1H); 7.41 (ddd, 1H); 7.59 (ddd, 1H); 7.68 (ddd, 1H); 8.17 (s, 1H);
8.93 (s, 1H). 18 27 ##STR00144## 510.2 1.76-1.87 (m, 2H); 2.09-
2.20 (m, 2H); 3.53-3.66 (m, 2H); 3.71 (s, 3H); 3.49-4.06 (m, 2H);
4.06 (s, 3H); 4.91 (bs, 1H); 6.05 (dd, 1H); 6.38 (dd, 1H); 6.90
(dd, 1H); 7.38 (s, 1H); 7.42 (ddd, 1H); 7.59 (ddd, 1H); 7.69 (ddd,
1H); 8.16 (s, 1H); 8.92 (s, 1H). 35 28 ##STR00145## 560.3 1.83-1.95
(m, 2H); 2.12- 2.26 (m, 2H); 3.64-3.75 (m, 2H); 3.82 (s, 3H);
3.95-4.10 (m, 2H); 4.07 (s, 3H); 4.96 (bs, 1H); 6.74 (s, 1H); 7.12
(dd, 1H); 7.27 (dd, 1H); 7.39 (s, 1H); 7.41 (dd, 1H); 7.52 (d, 1H);
7.59 (ddd, 1H); 7.63 (d, 1H); 7.69 (ddd, 1H); 8.19 (s, 1H); 8.93
(s, 1H). 33 29 ##STR00146## 542.2 1.78-1.94 (m, 2H); 2.02- 2.13 (m,
1H); 2.13-2.23 (m, 1H); 3.25-3.38 (m, 1H); 3.47-3.57 (m, 1H);
3.61-3.71 (m, 1H); 3.88- 4.00 (m, 1H); 4.05 (s, 3H); 4.91 (bs, 1H);
7.37 (s, 1H); 7.41 (dd, 1H); 7.50 (d, 1H); 7.58 (dd, 1H); 7.65 (s,
1H); 7.69 (dd, 1H); 8.15 (s, 1H); 8.53 (d, 1H); 8.92 (s, 1H). 14 30
##STR00147## 556.2 1.71-1.81 (m, 1H); 1.85- 1.96 (m, 1H); 2.04-2.13
(m, 1H); 2.14-2.23 (m, 1H); 3.42-3.56 (m, 2H); 3.75-3.91 (m, 2H);
4.06 (s, 3H); 4.91 (bs, 1H); 5.36 (s, 2H); 7.38 (s, 1H); 7.42 (ddd,
1H); 7.59 (ddd, 1H); 7.69 (ddd, 1H); 8.16 (s, 1H); 8.27 (s, 1H);
8.81 (s, 1H); 8.93 (s, 1H). 30 31 ##STR00148## 542.2 1.82-1.98 (m,
2H); 2.11- 2.23 (m, 2H); 3.64-3.74 (m, 2H); 3.85-3.99 (m, 2H); 4.05
(s, 3H); 3.94 (bs, 1H); 7.38 (s, 1H); 7.41 (dd, 1H); 7.42 (s, 1H);
7.59 (ddd, 1H); 7.69 (ddd, 1H); 8.17 (s, 1H); 8.93 (s, 1H). 54
EXAMPLE 32
Preparation of Compound No 32 in Table II
##STR00149##
[0433] HATU (0.31 g) was added to a solution of
N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-a-
mine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and
isoxazole-5-carboxylic acid (0.110 g) in methylene chloride (9 ml).
The resulting mixture was stirred at room temperature for 2.5 hrs.
Methylene chloride (20 ml) was added and the organics washed with
aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes
were then purified by flash column chromatography eluting with
methanol/methylene chloride (2.5/97.5). Fractions containing the
desired product were evaporated to a white foam which was
triturated with diethyl ether (20 ml) to give
N-(3-chloro-2-fluorophenyl)-7-{[1-(isoxazol-5-ylcarbonyl)piperidin-4-yl]o-
xy}-6-methoxyquinazolin-4-amine as a white solid (0.045 g). .sup.1H
NMR Spectrum: (DMSO d.sub.6 373K) 1.86 (m, 2H), 2.10 (m, 2H), 3.59
(m, 2H), 3.88 (m, 2H), 3.98 (s, 3H), 4.92 (m, 1H), 6.87 (s, 1H),
7.26 (m, 1H), 7.38 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.83 (s,
1H), 8.39 (s, 1H), 8.62 (s, 1H), 9.30 (br s, 1H); Mass Spectrum:
(M+H).sup.+ 498.
Preparation of the Starting Material
Step 1
7-(benzyloxy)-N-(3-chloro-2-fluorophenyl)-6-methoxyquinazolin-4-amine
hydrochloride
[0434] 4.0M HCl in Dioxane (4.0 ml) was added to a stirred
suspension of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline (60 g,
0.2 mol) [prepared as described in WO98/13354, Example 1] and
3-chloro-2-fluoroaniline (31.96 g, 0.22 mol) in acetonitrile (1200
mL). The reaction mixture was heated at 80.degree. C. for 1 hour
then left to stand O/N. Acetonitrile (500 mL) was added and the
resulting precipitate filtered, washed with Acetonitrile
(3.times.500 mL) and dried under vacuum to give
7-(benzyloxy)-N-(3-chloro-2-fluorophenyl)-6-methoxyquinazolin-4-amine
hydrochloride 2 as a beige solid (85.45 g, 96%); .sup.1H NMR
Spectrum: (DMSO d.sub.6) 4.02 (s, 3H), 5.35 (s, 2H), 7.30-7.60 (m,
9H), 7.65 (m, 1H), 8.38 (s, 1H), 8.85 (s, 1H), 11.8 (s, 1H); Mass
Spectrum: (M+H).sup.+ 410.27.
Step 2
4-[(3-chloro-2-fluorophenyl)amino]-6-methoxyquinazolin-7-ol
[0435] A solution of
7-(benzyloxy)-N-(3-chloro-2-fluorophenyl)-6-methoxyquinazolin-4-amine
hydrochloride 2 (85.45 g, 0.192 mol) in trifluoroacetic acid (300
mL) was heated at 80.degree. C. for 1 hour. The reaction mixture
was the evaporated to dryness and the residues re-dissolved in
methanol (200 mL). This solution was then added dropwise to a
stirred aqueous solution of saturated sodium bicarbonate (500 mL).
The resulting precipitate was collected by filtration, washed with
acetonitrile and dried under vacuum. The crude solids were then
purified by hot (100.degree. C.) trituration with a mixture of
butanone (500 mL) and MeOH (100 mL), filtered and dried to
4-[(3-chloro-2-fluorophenyl)amino]-6-methoxyquinazolin-7-ol 3 as a
cream solid (45 g, 73%); .sup.1H NMR Spectrum: (DMSO d.sub.6): 3.98
(s, 3H), 7.10 (s, 1H), 7.25-7.30 (m, 1H), 7.40-7.50 (m, 1H),
7.50-7.60 (m, 1H), 7.80 (s, 1H), 8.30 (s, 1H), 9.55 (s, 1H), 10.32
(s, 1H); Mass Spectrum: (M+H).sup.+ 319.98
Step 3
tert-butyl
4-({4-[(3-chloro-2-fluorophenyl)amino]-6-methoxyquinazolin-7-yl-
}oxy)piperidine-1-carboxylate
[0436] 4-[(3-chloro-2-fluorophenyl)amino]-6-methoxyquinazolin-7-ol
(3, 500 mg, 1.565 mmol) was dissolved in DMA (20 ml). tert-Butyl
(4-methanesulfonyloxy)piperidine-1-carboxylate (436.6 mg, 1.565
mmol) and cesium fluoride (236.3 mg, 1.565 mmol) were added, and
the mixture was heated to 60.degree. C. with stirring. After 18
hours, tert-butyl 4-methanesulfonyloxypiperidine-1-carboxylate and
cesium fluoride were again added in the same quantities to the
reaction mixture and heating was continued at 60.degree. C. for a
further 18 hours. The solvent was evaporated, and the residue was
partitioned between saturated aqueous sodium bicarbonate solution
(50 mL) and EtOAc (2.times.50 mL). The organics were combined,
dried over MgSO.sub.4 and evaporated. The crudes were then purified
by column chromatography eluting with increasingly polar mixtures
of methylene chloride/EtOAc (100/0 to 0/100). The fractions
containing the desired product were combined and evaporated under
vacuum to give tert-butyl
4-({.sup.4-[(3-chloro-2-fluorophenyl)amino]-6-methoxyquinazolin-7-yl}oxy)-
piperidine-1-carboxylate as a colourless foam (757 mg, 96%);
.sup.1H NMR Spectrum: (DMSO-d.sub.6): 1.52 (s, 9H), 1.60-1.80 (m,
2H), 2.02-2.20 (m, 2H), 3.20-3.45 (m, 2H), 3.75-3.92 (m, 2H), 4.05
(s, 3H), 4.95 (m, 1H), 7.32-7.45 (m, 2H), 7.55-7.70 (m, 2H), 7.92
(s, 1H), 8.50 (s, 1H), 9.73 (s, 1H); Mass Spectrum: (M+H).sup.+
503.08.
Step 5
N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-am-
ine dihydrochloride
##STR00150##
[0438] Trifluoroacetic acid (50 mL) was added to a solution of
tert-butyl
4-({4-[(3-chloro-2-fluorophenyl)amino]-6-methoxyquinazolin-7-yl}oxy)piper-
idine-1-carboxylate (750 mg, 1.49 mmol) in methylene chloride (1
mL) and Triethylsilane (1 mL) and the solution stirred for 1 hour.
The reaction mixture was then evaporated under reduced pressure and
the residues re-dissolved in EtOAc (5 mL). This solution was then
treated with 1M HCl/Diethylether (1 mL) followed by more
Diethylether (50 mL) to give a heavy white precipitation. The
resulting solids were collected following centrifugation and dried
under vacuum to give
N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-a-
mine dihydrochloride 5 as an white solid (750 mg); .sup.1H NMR
Spectrum: (DMSO-d.sub.6): 2.00-2.20 (m, 2H), 2.25-2.45 (m, 2H),
3.15-3.50 (m, 4H), 4.15 (s, 3H), 5.02 (m, 1H), 7.48 (m, 1H),
7.60-7.85 m, 3H), 8.35 (s, 1H), 8.85 (s, 1H), 9.56 (bs, 2H); Mass
Spectrum: (M+H).sup.+ 403.08.
EXAMPLE 33
Preparation of Compound No 33 in Table II
##STR00151##
[0439] HATU (0.31 g) was added to a solution of
N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-a-
mine dihydrochloride 5 (300 mg), diisopropylethylamine (0.45 ml)
and 3-methyl-5-isoxazoleacetic acid (0.135 g) in methylene chloride
(9 ml). The resulting mixture was stirred at room temperature for
2.5 hrs. Methylene chloride (20 ml) was added and the organics
washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml).
The crudes were then purified by flash column chromatography
eluting with methanol/methylene chloride (4/96). Fractions
containing the desired product were evaporated to a white foam
which was triturated with diethyl ether (20 ml) to give
N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(3-methylisoxazol-5-yl)carbo-
nyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.224
g). .sup.1H NMR Spectrum: (DMSO d.sub.6) 1.54-1.76 (m, 2H), 2.05
(m, 2H), 2.22 (s, 3H), 3.32 (m, 1H), 3.47 (m, 1H), 3.82 (m, 1H),
3.93 (m, 1H), 3.96 (s, 3H), 4.00 (s, 2H), 4.92 (m, 1H), 6.23 (s,
1H), 7.29 (m, 1H), 7.36 (s, 1H), 7.48 (m, 1H), 7.53 (m, 1H), 7.83
(s, 1H), 8.39 (s, 1H), 9.63 (br s, 1H); Mass Spectrum: (M+H).sup.+
526.
[0440] The staring material was prepared in the manner described in
Example 32 above.
EXAMPLES 34 TO 58
Preparation of Compound Numbers 34 to 58 of Table II
Generic Process
##STR00152##
[0442] Solid HATU (119 mg, 0.815 mmol) and DIPEA (0.171 ml, 0.96
mmol) were dissolved in anhydrous DMA (0.5 ml) were added to a
solution of
(3-chloro-2-fluorophenyl)-[6-methoxy-7-(piperidin-4-yloxy)-quinazolin-4-y-
l]-amine.dihydrochloride (100 mg, 0.24 mmol), and the carboxylic
acid (0.36 mmol) in DMA (0.5 ml) at room temperature. The resulting
solution was allowed to stir at room temperature overnight. The
crude reaction mixtures were purified using mass-triggered
preparative LCMS.
[0443] The fractions containing the desired compound were
evaporated in a Genevac and the residue taken up in 10% (v/v) MeOH
in DCM (0.4 ml), diluted with 6 ml of 15% (v/v) Et.sub.2O in
pentane and left at 4.degree. C. overnight. The resulting
precipitates were collected by filtration and dried to a constant
weight to afford the desired amides as amorphous or crystalline
solids.
[0444] The staring material was prepared in the manner described in
Example 32 above.
Standard Conditions for Purification by Mass-Triggered Preparative
LCMS
[0445] Column: ThermoHypersil Keystone B-Basic 5 .mu.l 21
mm.times.100 mm
[0446] Eluant: 7.5 minutes Gradient from 20% to 95% of acetonitrile
in water (buffer 2 g/l of (NH.sub.4).sub.2CO.sub.3, pH 8.9).
[0447] Flow rate: 25 ml/min.
TABLE-US-00010 Example/ NMR .delta. en ppm Compound No. R MH+ (DMSO
+ TFAd) Yield 34 ##STR00153## 508.1 1.84-2.01 (m, 2H); 2.04- 2.29
(m, 2H); 3.35-3.48 (m, 1H); 3.56-3.71 (m, 2H); 3.99-4.12 (m, 1H);
4.04 (s, 3H); 5.02 (bs, 3H); 7.40 (ddd, 1H); 7.55 (s, 1H); 7.58
(ddd, 1H); 7.67 (ddd, 1H); 8.14 (s, 1H); 8.17 (dd, 1H); 8.71 (s,
1H); 8.92 (d, 1H); 9.04 (d, 1H); 9.16 (s, 1H). 67 35 ##STR00154##
527.1 1.64-1.75 (m, 2H); 2.00- 2.11 (m, 2H); 3.36-3.44 (m, 1H);
3.49-3.56 (m, 1H); 3.83-3.90 (m, 1H); 3.91-3.99 (m, 1H); 5.02 (bs,
5H); 4.91 (bs, 1H); 6.95-7.01 (m, 2H); 3.36- 3.43 (m, 2H); 7.46 (s,
1H); 7.57 (dd, 1H); 7.66 (dd, 1H); 8.11 (s, 1H); 8.90 (s, 1H). 15
36 ##STR00155## 508.1 1.80-1.95 (m, 2H); 2.06- 2.16 (m, 1H);
2.17-2.27 (m, 1H); 3.39-3.49 (m, 1H); 3.62-3.73 (m, 2H); 3.99-4.11
(m, 1H); 4.04 (s, 3H); 5.02 (bs, 1H); 7.40 (dd, 1H); 7.51 (s, 1H);
7.58 (dd, 1H); 7.64-7.74 (m, 2H); 7.82-7.87 (m, 1H); 8.13 (s, 1H);
8.16-8.23 (m, 1H); 8.73-8.78 (m, 1H); 8.98 (s, 1H). 37 37
##STR00156## 523.1 1.76-2.31 (m, 4H); 3.30- 3.46 (m, 1H); 3.47-3.68
(m, 2H); 3.94-4.11 (m, 1H); 4.03 (m, 3H); 4.99 (bs, 1H); 6.99 (dd,
1H); 7.41 (dd, 1H); 7.54 (s, 1H); 7.58 (ddd, 1H); 7.67 (ddd, 1H);
8.05 (dd, 1H); 8.09 (dd, 1H); 8.13 (s, 1H); 8.92 (s, 1H). 9 38
##STR00157## 496.1 1.77-1.87(m, 2H); 2.12- 2.22 (m, 2H); 3.59-3.70
(m, 2H); 4.04 (s, 3H); 4.06- 4.16 (m, 2H); 4.95-5.02 (m, 1H) 6.14
(dd, 1H); 6.54 (d, 1H); 6.92 (bs, 1H); 7.41 (dd, 1H); 7.50 (s, 1H);
7.58 (ddd, 1H); 7.67 (ddd, 1H); 8.12 (s, 1H); 8.93(s, 1H). 20 39
##STR00158## 513.1 1.79-1.91 (m, 2H); 2.12- 2.23 (m, 2H); 3.57-3.69
(m, 2H); 3.95-4.07 (m, 2H); 4.04 (s, 3H); 4.99 (bs, 1H); 7.14 (dd,
1H); 7.41 (ddd, 1H); 7.47 (dd, 1H); 7.50 (s, 1H); 7.58 (ddd, 1H);
7.68 (ddd, 1H); 7.76 (dd, 1H); 8.12 (s, 1H); 8.92 (s, 1H). 11 40
##STR00159## 497.1 1.77-1.90 (m, 2H); 2.11- 2.21 (m, 2H); 3.54-3.74
(m, 2H); 3.94-4.08 (m, 2H); 4.03 (s, 3H); 4.99 (bs, 1H); 6.64 (dd,
1H); 7.04 (d, 1H); 7.41 (dd, 1H); 7.49 (s, 1H); 7.58 (ddd, 1H);
7.68 (ddd, 1H); 7.84 (s, 1H); 8.11 (s, 1H); 8.92 (s, 1H). 5 41
##STR00160## 558.2 1.59-1.70 (m, 0.5H); 1.81- 1.97 (m, 1H);
1.98-2.13 (m, 1.5H); 2.28-2.40 9m, 1H); 3.20-3.34 (m, 1H);
3.37-3.48 (m, 1H); 3.68- 3.76 (m, 0.5H); 3.77-3.85 (m, 0.5H);4.01
(s, 1.5H); 4.04 (1.5H); 4.14-4.22 (m, 0.5H); 4.23-4.32 (m, 0.5);
5.01 (bs, 1H); 7.40 (dd, 1H); 7.50-7.61 (m, 2H); 7.64-7.70 (dd,
1H); 7.99- 8.06 (m, 1H); 8.10-8.26 (m, 4H); 8.36 (d, 1H); 8.91 (s,
1H); 8.45 (s, 0.5H); 8.46 (s, 0.5H). 43 42 ##STR00161## 497.1
1.74-1.88 (m, 2H); 2.08- 2.20 (m, 2H); 3.48-3.59 (m, 2H); 3.84-4.06
(m, 2H); 4.03 (s, 3H); 4.97 (bs, 1H); 6.71 (s, 1H); 7.41 (dd, 1H);
7.51 (s, 1H); 7.58 (ddd, 1H); 7.67 (ddd, 1H); 7.74 (s, 1H); 8.07
(s, 1H); 8.17 (s, 1H);8.91 (s, 1H). 89 43 ##STR00162## 577.1
1.79-1.91 (m, 2H); 2.12- 2.22 (m, 2H); 3.53-3.74 (m, 2H); 3.95-4.05
(m, 2H); 4.03 (m, 3H); 4.99 (bs, 1H); 6.77 (d, 1H); 7.08 (d, 1H);
7.41 (dd, 1H); 7.50 (s, 1H); 7.58 (ddd, 1H); 7.68 (ddd, 1H); 8.12
(s, 1H): 8.92 (s, 1H). 48 44 ##STR00163## 513.1 1.77-1.90 (m, 2H);
2.06- 2.21 (m, 2H); 3.44-3.64 (3, 2H); 3.65-4.11 (m, 2H); 4.06 (s,
3H); 4.92 (bs, 1H); 7.27 (dd, 1H); 7.37 (s, 1H); 7.41 (dd, 1H);
7.59 (ddd, 1H); 7.62 (dd, 1H); 7.69 (ddd, 1H); 7.83 (dd, 47 45
##STR00164## 547.1 1.80-1.93 (m, 2H); 2.14- 2.24 (m, 2H); 3.54-3.84
(m, 2H); 3.97-4.10 (m, 2H); 4.01 (s, 3H); 5.00 (bs, 1H); 7.32 (dd,
1H); 7.37 (dd, 1H); 7.41 (s, 1H); 7.43 (dd, 1H); 7.48 (s, 1H); 7.55
(ddd, 1H); 7.61-7.66 (m, 2H); 7.73 (d, 1H); 8.09 (s, 1H); 8.89 (s,
1H). 53 46 ##STR00165## 558.2 1.88-2.01 (m, 2H); 2.06- 2.33 (m,
2H); 3.46 (3.85 (m, 3H); 4.04 (s, 3H); 4.09- 4.22 (m, 1H); 5.05
(bs, 1H); 7.41 (dd, 1H); 7.56 (s, 1H); 7.58 (dd, 1H); 7.68 (ddd,
1H); 7.97 (s, 1H); 8.14 (s, 1H); 8.16 (dd, 1H); 8.30 (d, 1H); 8.37
(d, 1H); 8.92 (s, 1H); 9.20 (s, 1H); 9.44 (d, 1H). 42 47
##STR00166## 546.2 1.80-1.89 (m, 2H); 2.14- 2.22 (m, 2H); 3.54-3.63
(m, 2H); 4.02-4.11 (m, 2H); 4.04 (s, 3H); 4.98 (bs, 1H); 7.14 (dd,
1H); 7.19 (dd, 1H); 7.40 (dd, 1H); 7.48 (d, 1H); 7.50 (s, 1H); 7.58
(dd, 1H); 7.67 (ddd, 1H); 7.73 (d, 1H); 7.76 (s, 1H); 8.13 (s, 1H);
8.92 (s, 1H). 15 48 ##STR00167## 527.1 1.55-1.71 (m, 2H); 1.93-
2.09 (m, 2H); 3.29-3.40 (m, 1H); 3.41-3.50 (m, 1H); 3.73-3.85 (m,
1H): 3.75 (d, 1H); 3.80 (d, 1H); 3.89-3.99 (m, 1H); 4.00 (s, 3H);
4.88 (bs, 1H); 7.02 (d, 1H); 7.28 (d, 1H); 7.39 (dd, 1H); 7.44 (s,
1H); 7.48 (dd, 1H); 7.52-7.59 (m, 2H); 7.60-7.68 (m, 2H); 8.09 (s,
1H); 8.90 (s, 1H). 43 49 ##STR00168## 597.1 1.80-1.94 (m, 2H);
2.08- 2.30 9m, 2H); 3.34-3.58 (m, 1H); 3.60-3.79 (m, 2H); 3.99-4.13
(m, 1H); 4.03 (s, 3H); 5.01 (bs, 1H); 7.40 (dd, 1H); 7.49 (s, 1H);
7.55-7.63 (m, 3H); 7.67 (dd, 1H); 7.89 (dd, 1H); 8.12 (s, 1H); 8.13
(d, 1H); 8.81 (s, 1H). 27 50 ##STR00169## 580.2 1.82-1.95 (m, 2H);
2.16- 2.26 (m, 2H): 3.63-3.83 (m, 2H); 4.04 (s, 3H); 4.08- 4.19 (m,
2H); 5.03 (bs, 1H); 6.94 (s, 1H); 7.21 (dd, 1H); 7.41 (dd, 1H);
7.47 (d, 1H); 7.51 (s, 1H); 7.58 (ddd, 1H); 7.65-7.70 (m, 2H);8.13
(s, 1H); 8.92 (s, 1H). 31 51 ##STR00170## 593.1 1.81-1.92 (m, 2H);
2.11- 2.22 (m, 2H); 3.57-3.69 (m, 2H); 3.93-4.04 (m, 2H); 4.03 (s,
3H); 4.99 (bs, 1H); 7.26 (d, 1H); 7.33 (d, 1H); 7.41 (dd, 1H); 7.50
(s, 1H); 7.58 (dd, 1H); 7.68 (ddd, 1H); 8.12 (s, 1H); 8.92 (s, 1H).
35 52 ##STR00171## 578.1 1.80-1.94 (m, 2H); 2.03- 2.12 (m, 1H);
2.13-2.22 (m, 1H); 3.28-3.38 (m, 1H); 3.45-3.65 (m, 2H); 3.96-4.03
(m, 1H); 4.03 (s, 311); 4.98 (bs, 1H); 7.41 (dd, 1H); 7.50 (s, 1H);
7.58 (ddd, 1H); 7368 (ddd, 1H); 7.72 (s, 2H); 8.11 (s, 1H); 8.91
(s, 1H). 41 53 ##STR00172## 527.2 1.78-1.88 (m, 2H); 2.11- 2.21 (m,
2H); 2.48 (s, 3H); 3.56-3.67 (m, 2H); 3.96- 4.06 (m, 2H); 4.03 (s,
3H); 4.98 (bs, 1H); 6.84 (d, 1H); 7.27 (d, 1H); 7.40 (dd, 1H); 7.49
(s, 1H); 7.58 (dd, 1H); 7.68 (ddd, 1H); 7.12 (s, 1H); 7.92 (s, 1H).
21 54 ##STR00173## 510.2 1.77-1.88 (m, 2H); 2.11- 2.21 (m, 2H);
3.51-3.62 (m, 2H); 3.71 (s, 3H); 3.99- 4.09 (m, 2H); 4.03 (s, 3H);
4.97 (bs, 1H); 6.06 (dd, 1H); 6.38 (dd, 1H); 6.90 (bs, 1H); 7.41
(dds, 1H); 7.50 (s, 1H); 7.58 (ddd, 1H); 7.67 (ddd, 1H); 8.12 (s,
1H); 8.92 (s, 1H). 34 55 ##STR00174## 560.2 1.82-1.93 (m, 2H);
2.11- 2.27 (m, 2H); 3.58-3.69 (m, 2H); 3.81 (s, 3H); 3.93- 4.16 (m,
2H); 4.04 (s, 3H); 5.02 (bs, 1H); 6.74 (s, 1H); 7.12 (dd, 1H); 7.27
(dd, lH); 7.41 (dd, 1H); 7.51 (s, 1H); 7.53 (d, 1H); 7.58 (dd, 1H);
7.63 (d, 1H); 7.67 (dd, 1H); 8.12 (s, 1H); 8.92 (s, 1H). 34 56
##STR00175## 542.1 1.80-1.95 (m, 2H); 2.03- 2.13 (m, 1H); 2.14-2.25
(m, 1H); 3.29-3.39 (m, 1H); 3.48-3.65 (m, 2H): 3.97-4.07 (m, 1H);
4.03 (s, 3H); 4.99 (bs, 1H); 7.41 (dd, 1H); 7.50 (bs, 2H); 7.58
(ddd, 1H); 7.64 (s, 1H); 7.67 (dd, 1H); 8.12 (s, 1H); 8.53 (d, 1H);
8.92 (s, 1H). 20 57 ##STR00176## 556.2 1.69-1.79 (m, 1H); 1.85-
1.95 (m, 1H); 2.06-2.24 (m, 2H); 3.37-3.46 (m, 1H); 3.46-3.56 (m,
1H); 3.76-3.85 (m, 1H); 3.86- 3.95 (m, 1H); 4.03 (s, 3H); 4.98 (bs,
1H); 5.36 (s, 2H); 7.41 (ddd, 1H); 7.52 (s, 1H); 7.58 (ddd, 1H);
7.68 (ddd, 1H); 8.12 (s, 1H); 8.27 (s, 1H); 8.80 (s, 1H); 8.92 (s,
1H). 10 58 ##STR00177## 542.1 1.83-1.99 (m, 2H); 2.15- 2.24 (m,
2H); 3.61-3.75 (m, 2H); 3.98-4.07 (m, 2H); 4.04 (s, 3H); 5.03 (bs,
1H); 7.40 (dd, 1H); 7.42 (s, 1H); 7.52 (s, 1H); 7.58 (dd, 1H); 7.67
(dd, 1H); 8.14 (s, 1H); 8.93 (s, 1H). 21
EXAMPLES 59 TO 85
Preparation of Compound Numbers 59 to 85 of Table III
Generic Process
##STR00178##
[0448] Solid HATU (119 mg, 0.815 mmol) and DIPEA (0.171 ml, 0.96
mmol) were dissolved in anhydrous DMA (0.5 ml) were added to a
solution of
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-[(3R)-piperidin-3-yloxy]-quinazol-
in-4-yl-amine dihydrochloride (100 mg, 0.24 mmol), and the
carboxylic acid (0.36 mmol) in DMA (0.5 ml) at room temperature.
The resulting solution was allowed to stir at room temperature
overnight. The crude reaction mixtures were purified using
mass-triggered preparative LCMS.
[0449] The fractions containing the desired compound were
evaporated in a Genevac and the residue taken up in 10% (v/v) MeOH
in DCM (0.4 ml), diluted with 6 ml of 15% (v/v) Et.sub.2O in
pentane and left at 4.degree. C. overnight. The resulting
precipitates were collected by filtration and dried to a constant
weight to afford the desired amides as amorphous or crystalline
solids.
Standard Conditions for purification by Mass-Triggered Preparative
LCMS
[0450] Column: ThermoHypersil Keystone B-Basic 5.mu. 21
mm.times.100 mm
[0451] Eluant: 7.5 minutes Gradient from 20% to 95% of acetonitrile
in water (buffer 2 g/l of (NH.sub.4).sub.2CO.sub.3, pH 8.9).
[0452] Flow rate: 25 ml/min.
Preparation of Starting Material
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-[(3R)-piperidin-3-yloxy]quinazolin-
e hydrochloride
##STR00179##
[0453] HCl (1.77 ml, 4M solution in dioxane) was added to
4-chloro-7-methoxy-6-[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yloxy]quina-
zoline (1.77 g) and 3-chloro-2-fluoroaniline (0.69 g) dissolved in
acetonitrile (70 ml). The mixture was heated to 70.degree. C.
overnight. HCl (1.77 ml, 4M solution in dioxane) was then added and
the mixture heated a further 1.5 hours. The reaction mixture was
cooled and the resulting precipitate collected by filtration to
give
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3R)-piperidin-3-yloxy]quinazol-
ine hydrochloride as a white solid (1.814 g, 92%); .sup.1H NMR
Spectrum: (DMSOd.sub.6) 1.70-1.95 (m, 2H), 1.95-2.10 (m, 1H);
2.10-2.25 (m, 1H), 2.95-3.10 (m, 1H), 3.10-3.65 (m, 3H+H.sub.2O);
4.03 (s, 3H); 4.95-5.10 (m, 1H); 7.35 (m, 1H); 7.47 (s, 1H); 7.53
(m, 1H); 7.64 (m, 1H), 8.84 (s, 2H); 9.10 (bs, 2H); 12.10 (bs, 1H);
Mass Spectrum: (M+H): 403.
[0454] The
4-chloro-7-methoxy-6-[(3R)-1-(tert-butoxycarbonyl)piperidin-3-y-
loxy]quinazoline starting material was prepared as follows:
[0455] Diethyl azodicarboxylate (5.7 ml) was added to
4-chloro-6-hydroxy-7-methoxyquinazoline (4.39 g; prepared as
described in Example 1 (Preparation of starting materials)),
triphenylphosphine (8.2 g) and
(3S)-1-(tert-butoxycarbonyl)-3-hydroxypiperidine (Commercially
Available--CAS Registry No 143900-44-1) (6.29 g) in dichloromethane
(130 ml) and the reaction mixture was stirred at 40.degree. C. for
6 hours. This was allowed to stand overnight at -18.degree. C. then
filtered. The filtrates were purified by flash column
chromatography eluting with acetone/isohexane/triethylamine
(17/82/1) to give
4-chloro-7-methoxy-6-[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yloxy)]quin-
azoline as a white solid (0.794 g, 48%); Mass Spectrum: (M+H)+
394.
TABLE-US-00011 Example/ Compound NMR .delta. en ppm No. R MH+ (DMSO
+ TFAd) Yield 59 ##STR00180## 508.1 1.53-1.72 (m, 1H); 1.76- 1.96
(m, 1H); 1.97-2.09 (m, 1H); 2.11-2.23 (m, 1H); 3.18-3.29 (m, 0.7H);
3.38- 3.53 (m, 0.6H); 3.65-3.73 (m, 0.7H); 3.74-3.81 (m, 0.3H);
3.84-3.93 (m, 0.7H); 4.06 (s, 2.1H); 3.12 (s, 0.9H); 4.23-4.32 (m,
0.3H); 4.33-4.42 (m, 0.7H); 4.75 (bs, 7H); 4.91 (bs, 0.3H);
7.37-7.45 (m, 2H); 7.56 (dd. 0.7H); 7.61 (dd, 0.3H); 7.94 (s,
0.7H); 8.01 (dd, 0.7H); 8.1 dd, 0.3H); 8.26 (s, 0.3H); 8.53 (d,
0.7H); 8.61 (d, 0.7H); 8.88-8.96 (m, 1.6H); 8.99 (s, 0.3H); 9.04
(bs, 1H) 48 60 ##STR00181## 527.1 1.50-1.62 (m, 1H); 1.73- 2.03 (m,
2H); 2.07-2.19 (m, 1H); 3.43-4.08 (m, 6H); 4.03 (s, 3H); 4.72 (bs,
1H); 6.81 (d, 0.5H); 6.88 (dd, 0.5H); 6.95-7.01 (m, 1H); 7.30 (d,
0.5H); 7.33-2.46 (m, 2.5H); 7.54-7.60 (m, 1H); 7.64-7.71 (m, 1H);
8.13 (s, 0.5H); 8.17 (s, 0.5H); 8.92 (s, 0.5H); 8.93 (s, 0.5H). 33
61 ##STR00182## 508.1 43 62 ##STR00183## 508.1 1.50-1.60 (m, 0.4H);
1.63- 1.72 (m, 0.6H); 1.74-1.94 (m, 1H); 1.97-2.23 (m, 2H);
3.17-3.28 (m, 0.6H); 3.30- 3.39 (m, 1H); 3.61-3.78 (m, 1.4H); 4.08
(s, 1.2 H); 4.14 (s, 1.8H); 4.38 (d, 1H); 4.75 (bs, 0.6H); 4.95
(bs, 0.4H); 7.35-7.46 (m, 2H); 7.56 (dd, 0.6H); 7.62 (dd, 0.4H);
7.68 (dd, 1H); 7.96 (s, 0.6H); 8.03 (d, 0.8H); 8.11 (d, 1.2H); 8.26
(s, 0.4H); 8.93 (s, 0.6H); 8.94 (s, 0.4H); 8.98 (d, 1.2H); 8.10 (d,
0.8H). 48 63 ##STR00184## 523.2 1.52-1.72(m, 1H); 1.78-1.92 (m,
1H): 1.97-2.24 (m, 2H); 3.12-4.01 (m, 3H); 4.08 (s, 3H); 4.18-4.39
(m, 1H); 4.72 (m, 0.6H); 4.92 (m, 0.4H); 6.71 (bs, 0.6H); 7.05 (bs,
0.4H); 7.37 (bs, 1H); 7.41 (dd, 1H); 7.57 (bs, 1H); 7.68 (ddd, 1H);
7.83-7.97 (m, 2H); 8.12 (bs, 0.6H); 8.24 (bs, 0.4H); 8.92 (s, 1H).
57 64 ##STR00185## 496.1 1.59-1.70 (m, 1H); 1.88- 2.00 (m, 2H);
2.14-2.24 (m, 1H); 3.65-3.85 (m, 2H); 4.00 (s, 3H); 4.02-4.09 (m,
2H); 4.74 (bs, 1H); 6.04 (bs, 1H); 6.49 (bs, 1H); 6.82 (bs, 1H);
7.32 (s, 1H); 7.41 (ddd, 1H); 7.58 (ddd, 1H); 7.68 (ddd, 1H); 8.14
(s, 1H); 8.91 (s, 1H). 31 65 ##STR00186## 513.1 1.58-1.69 (m, 1H);
1.86- 2.21 (m, 3H); 3.42-3.71 (m, 1H); 3.80-4.01 (m, 2H); 4.02 (s,
3H); 4.02-4.25 (m, 1H); 4.78 (bs, 1H); 7.04 (bs, 1H); 7.33 (s, 1H);
7.37-7.45 (m, 2H); 7.58 (dd, 1H); 7.64 (bs, 1H); 7.68 (ddd, 1H);
8.09 (bs, 1H); 8.91 (s, 1H). 46 66 ##STR00187## 497.1 1.59-1.70 (m,
1H); 1.87- 2.05 (m, 2H); 2.10-2.23 (m, 1H); 3.37-3.62 (m, 1H);
3.77-3.72 (m, 1H); 3.96 (d, 1H); 3.99 (s, 3H); 4.05-4.35 (m, 1H);
4.77 (bs, 1H); 6.31-6.75 (bs, 1H); 6.93 (bs, 1H); 7.32 (s, 1H);
7.41 (dd, m); 7.44-7.82 (bs, 1H); 7.58 (dd, 1H); 7.68 (ddd, 1H);
8.10 (bs, 1H); 8.92 (s, 1H). 48 67 ##STR00188## 497.1 1.55-1.66 (m,
1H); 1.73- 2.28 (m, 3H); 3.23-3.43 (m, 1H); 3.51-4.17 (m, 3H); 4.03
(s, 3H); 4.75 (bs, 1H); 6.63 (s, 1H); 7.35 (s, 1H); 7.41 (ddd, 1H);
6.46-6.83 (m, 1H); 7.58 (dd, 1H); 7.68 (ddd, 1H); 7.86-8.31 (m,
2H); 8.92 (s, 1H). 45 68 ##STR00189## 577.1 1.58-1.70 (m, 1H);
1.88- 2.22 (m, 3H); 3.16-3.45 (m, 1H); 3.88 (dd, 1H); 3.92- 4.11
(m, 1H); 3.98 (s, 3H); 4.29-4.54 (m, 1H); 4.78 (bs, 1H); 6.38-6.61
(bs, 1H); 6.95 (bs, 1H); 7.29 (bs, 1H); 7.41 (dd, 1H); 7.58 (dd,
1H); 7.68 (dd, 1H); 8.08 (bs, 1H); 8.91 (s, 1H). 55 69 ##STR00190##
513.1 1.55-1.68 (m, 1H); 1.82- 2.22 (m, 3H); 3.18-4.25 (m, 4H);
4.05 (s, 3H); 4.65-4.87 (m, 1H); 7.05-7.25 (bs, 1H); 7.34 (bs, 2H);
7.41 (dd, 1H); 7.58 (bs, 1H); 7.62-7.77 (bs, 1H); 7.68 (dd, 1H);
7.81 (bs, 0.6H); 8.23 (bs, 0.4H); 8.92 (s, 1H). 20 70 ##STR00191##
547.2 1.62-1.72 (m, 1H); 1.95- 2.18 (m, 3H); 3.12-3.25 (m, 1H);
3.73-3.87 (m, 1H); 4.01 (s, 3H): 4.28-4.40 (m, 1H); 4.74 (bs, 1H);
4.83- 4.95 (m, 1H); 6.95-7.82 (m, 10H); 8.71 (bs, 1H). 52 71
##STR00192## 563.1 1.63-1.73 (m, 1H): 1.90- 2.29 (m, 3H); 3.15-3.42
(m, 0.6H); 3.70-3.90 (m, 1.4H); 4.00-4.10 (m, 1H); 4.02 (s, 3H);
4.22 -4.44 (m, 0.6): 4.53-4.93 (m, 1.4H); 7.08- 8.03 (m, 10H);
8.66-8.96 (bs, 1H). 52 72 ##STR00193## 558.2 1.54-1.77 (m, 1H);
1.89- 2.24 (m, 3H); 3.17-.30 (m, 0.7H); 3.47-3.57 (m, 0.3H);
3.57-3.63 (m, 0.3H); 3.71 (d, 0.7H); 3.86 (d, 0.3H); 4.05-4.13 (m,
0.7H); 4.16 (s, 3H); 4.24 (4.33 (m, 0.3H); 4.45-4.55 (m, 0.7H);
4.67 (m, 0.7H); 4.92 (0.3H); 7.28-8.42 (m, 9H); 8.78 (bs, 1.4H);
8.95 (bs, 0.6H); 8.22 (s, 0.7H); 8.25 (s, 0.3H). 53 73 ##STR00194##
546.2 1.59-1.68 (m, 1H); 1.91- 2.04 (m, 2H); 2.11-2.20 (m, 1H);
3.47-3.58 (m, 1H); 3.84-3.97 (m, 2H); 4.02 (s, 3H); 4.15-4.26 (m,
1H); 4.73 (bs, 1H); 7.06-7.15 (m, 2H); 7.23 (bs, 1H): 7.33 (d, 1H);
7.41 (dd, 1H); 7.58 (dd, 1H); 7.61 (s, 1H); 7.64- 7.70 (m, 2H);
7.94-8.04 (m, 1H); 8.89 (s, 1H). 35 74 ##STR00195## 527.2 1.42-1.58
(m, 1H); 1.68- 1.82 (m, 1H); 1.85-1.97 (m, 1H); 2.02-2.15 (m, 1H);
3.42-3.52 (m, 1H); 3.54- 3.71 (m, 2.5H); 3.71-3.89 (m, 1.9H); 4.04
(s, 1.2H); 4.06 (s, 1.8H); 4.10 (dd, 0.6H); 4.64 (bs, 0.4 H); 4.73
(bs, 0.6H); 6.93 (d, 0.4H); 7.02 (d, 0.6H); 7.15 (d, 0.4H); 7.30
(d, 0.6H); 7.35 (s, 0.4H); 7.36 (s, 0.6H); 7.37-7.44 (m, 1.4H);
7.50 (dd, 0.6H); 7.56-7.63 (m, 1H); 7.66-7.72 (m, 1H); 8.10 (s,
0.4H); 8.14 (s, 06H); 8.91 (s, 06H); 8.92 (s, 0.4H). 17 75
##STR00196## 597.2 1.52-1.75 (m, 1H); 1.88- 2.19 (m, 3H); 3.20-3.32
(m, 0.6H); 3.39-3.50 (m, 0.4H); 3.51-3.62 (m, 0.4H); 3.67- 3.79 (m,
1H); 4.08 (s, 3H); 4.17-4.25 (m, 0.6H); 4.32- 4.43 (m, 1H); 4.64
(bs, 0.6H); 4.91 (bs, 0.4H); 7.22- 7.46 (m, 4H); 7.54-7.73 (m,
3.2H); 7.72-7.81 (bs, 0.6H); 7.81-7.84 (bs, 0.4H); 8.09- 8.16 (bs,
0.4H); 8.20-8.26 (bs, 0.4H); 8.75 (bs, 0.6H); 8.92 (bs, 0.4H). 13
76 ##STR00197## 580.2 162-1.72 (m, 1H); 1.94-2.22 (m, 3H);
3.02-5.04 (m, 5H); 4.01 (s, 3H); 6.29-7.90 (m, 9H); 8.80 (s, 1H).
33 77 ##STR00198## 593.1 1.58-1.69 (m, 1H); 1.85- 1.97 (m, 1H);
(1.98-2.18 (m, 2H); 3.22-3.61 (bs, 1H); 3.81 (d, 1H); 3.96-4.14
(bs, 1H); 4.02 (s, 3H); 4.14-4.39 (m, 1H); 4.76 (bs, 1H); 7.02-7.20
(bs, 1H); 7.24 (d, 1H); 7.33 (s, 1H); 7.41 (dd, 1H); 7.58 (dd, 1H);
7.69 (dd, 1H); 7.92-8.13 (bs, 1H); 8.92 (s, 1H). 43 78 ##STR00199##
576.1 1.50-1.58 (m, 0.3H); 1.62- 1.70 (m, 0.7H); 1.75-1.90 (m, 1H);
1.92-2.23 (m, 2H); 3.08 (dd, 0.7H); 3.29-3.36 (m, 0.3H); 3.37-3.44
(m, 0.3H); 3.54-3.64 (m, 1H); 3.90 (d, 0.7H); 4.09 (s, 2.1H); 4.14
(s, 0.9H); 4.35 (dd, 0.3H); 4.43 (d, 0.7H); 4.75 (bs, 0.7H); 4.92
(bs, 0.3H); 7.37-7.45 (m, 2H); 7.50-7.58 (m, 2.7H); 7.61 (dd,
0.3H); 7.68 (ddd, 1H); 7.87 (s, 0.7H); 8.23 (s, 0.3H); 8.93 (s,
1H). 37 79 ##STR00200## 527.2 1.56-1.67 (m, 1H); 1.85- 2.05 (m,
2H); 2.07-2.20 (m, 1H): 2.37 (bs, 3H); 3.40- 3.70 (m, 1H);
3.81-3.96 (m, 2H); 4.01 (s, 3H); 4.03-4.23 (m, 1H); 4.75 (bs, 1H);
6.61-6.77 (bs, 1H); 7.19 (bs, 1H); 7.32 (bs, 1H); 7.41 (dd, 1H);
7.58 (dd, 1H); 7.69 (ddd, 1H); 8.07 (bs, 1H): 8.91 (s, 1H). 35 80
##STR00201## 510.1 1.56-1.66 (m, 1H); 1.83- 1.94 (m, 1H); 1.95-2.05
(m, 1H); 2.06-2.17 (m, 1H); 3.43-3.56 (m, 1H); 3.62 (s, 3H); 3.79
3.86(m, 1H); 3.85-3.95 (m, 1H); 4.01(s, 3H); 4.13-4.24 (m, 1H);
4.76 (bs, 1H); 5.96 (bs, 1H); 6.34 (dd, 1H); 6.78 (bs, 1H); 7.34
(s, 1H); 7.41 (dd, 1H); 7.58 (dd, 1H); 7.68 (ddd, 1H); 8.10 (bs,
1H); 8.91 (s, 1H). 59 81 ##STR00202## 560.1 1.58-1.69 (m, 1H);
1.86- 1.98 (m, 1H); 2.00-2.13 (m, 2H); 3.17-3.40 (m, 1H); 3.57-3.74
(m, 4H); 4.03 (s, 3H); 4.15-4.39 (m, 1H); 4.40-4.51 (m, 1H); 4.59-
4.85 (m, 1H): 6.53 (bs, 1H); 6.76-7.76 (m, 9H); 8.79 (bs, 1H). 52
82 ##STR00203## 542.1 1.49-1.58 (0.3H); 1.61-1.71 (m, 0.7H);
1.78-1.91 (m, 1H); 1.94-2.21 (m, 2H); 3.06-3.15 (m, 0.7H); 3.28-
3.42 (m, 0.6H); 3.53-3.66 (m, 1H); 3.84-3.93 (m, 0.7H); 4.08 (s,
0.9H); 4.13 (s, 2.1H); 4.31-4.44 (m, 1H); 4.73 (bs, 0.7H); 4.91
(bs, 0.3H); 7.34-7.45 (m, 3.7H); 7.48 (s, 0.3H); 7.54 (dd, 0.7H);
7.61 (dd, 0.3H); 7.68 (ddd, 1H); 7.85 (s, 0.7H); 8.23 (s, 0.3H);
8.33 (d, 0.7H); 8.56 (d, 0.3H); 8.92 (s, 1H). 23 83 ##STR00204##
556.1 1.49-1.81 (1.6H); 1.84-2.23 (m, 2.4H); 3.35-3.44 (m, 0.6H);
3.54-3.52 (m, 1H); 3.75-3.90 (m, 2.4H); 4.03 (s, 1.2H); 4.09 (s,
1.8H); 4.71 (bs, 0.4H); 4.81 (bs, 0.4H); 5.19-5.47 (m, 2H); 7.33
(s, 0.4H); 7.39 (0.6H); 7.41 (dd, 1H); 7.55-7.62 (m, 1H); 7.65-7.72
(m, 1H); 8.16 (s, 1H); 8.24 (s, 0.4H); 8.26 (s, 0.6H); 8.71 (s,
0.4H); 8.76 (s, 0.6H); 8.91 (s, 0.4H); 8.92 (s, 0.6H). 51 84
##STR00205## 526.1 1.49-2.17 (m, 4H); 2.19 (s, 1.5H); 2.22 (s,
1.5H); 3.37- 3.46 (m, 0.5H); 3.54-3.61 (m, 1H); 3.71-3.78 (m, 1H);
3.82-3.86 (m, 1H); 3.86- 3.99 (m, 1.5H); 4.00-4.08 (m, 1H); 4.03
(s, 1.5H); 4.05 (s, 1.5H); 4.71 (bs, 0.5H); 4.76 (bs, 0.5H); 6.17
(s, 0.5H); 6.20 (s, 0.5H); 7.34 (s, 0.5H); 7.37 (s, 0.5H);
7.38-7.45 (m, 1H); 7.54- 7.62 (m, 1H); 7.66-7.72 (m, 1H); 8.13 (s,
0.5H); 8.15 (s, 0.5H); 8.91 (s, 0.5H); 8.92 (s, 0.5H). 28 85
##STR00206## 542.1 1.64-1.73 (m, 1H); 1.83- 2.23 (m, 3H); 3.18-3.28
(m, 0.7H); 3.66-3.92 (m, 1.6H); 4.01 (bs, 3H); 4.08-4.18 (m, 0.3H);
4.27-4.36 (m, 0.7H); 4.37-4.45 (m, 0.7H); 4.81 (bs, 1H); 7.20 (s,
0.7H); 7.26 (s, 0.7H); 7.32-7.40 (m, 0.6H); 7.42 (dd, 1H); 7.55
(dd, 0.7H); 7.56-7.63 (m, 0.3H); 7.68 (dd, 1H); 7.98 (bs, 0.7H);
8.23 (bs, 0.3H); 8.92 (s, 1H). 57
EXAMPLES 86 AND 87
Preparation of Compounds 86 and 87 of Table III
[0456] Compounds 86 and 88 were prepared as follows:
##STR00207##
To a stirred solution of 15 (0.20 g, 0.28 mmol) in DMF (1 ml) at
0.degree. C. was added concentrated aqueous ammonia (1 ml). The
reaction mixture was stirred for 10 minutes, concentrated and
purified by flash chromatography (elution with a gradient from 100%
DCM to 5% 7N NH.sub.3-MeOH in DCM) to afford Compound 86 (0.12 g,
77%) as a white solid; .sup.1H NMR Spectrum: (DMSO-d.sub.6):
.delta. en ppm 1.47-1.82 (m, 2H), 1.91-2.18 (m, 2H), 3.43-3.84 (m,
4H), 3.99 (s, 3H), 4.55 and 4.73 (m, 1H), 5.11-5.33 (m, 2H), 6.99
(br s, 1H), 7.25-7.30 (m, 2H), 7.48-7.56 (m, 2H), 7.79 (s, 1H),
7.91 (m, 1H), 8.01 (s, 1H), 8.39 (s, 1H), 9.63 (s, 1H); Mass
Spectrum: (M+H).sup.+ 554.13.
[0457] To a stirred solution of 15 (0.20 g, 0.28 mmol) in DMF (1
ml) at 0.degree. C. was added a 2.0 M solution of dimethylamine in
tetrahydrofuran (1.4 ml). The reaction mixture was stirred for 1
hour, concentrated and purified by flash chromatography (elution
with a gradient from 100% DCM to 5% 7N NH.sub.3-MeOH in DCM) to
afford Compound 87 (0.042 g, 26%) as a white solid; .sup.1H NMR
Spectrum: (DMSO-d.sub.6): .delta. en ppm 1.46-1.78 (m, 2H),
1.91-2.21 (m, 2H), 2.89-3.16 (m, 6H), 3.56-3.86 (m, 4H), 3.98 (s,
3H), 4.47 and 4.71 (m, 1H), 5.11-5.32 (m, 2H), 7.27-7.30 (m, 2H),
7.49 (m, 2H), 7.68 (s, 1H), 7.90-7.99 (m, 2H), 8.39 (s, 1H), 9.61
(s, 1H); Mass Spectrum: (M+H).sup.+ 582.20.
[0458] Intermediate 15 was prepared as follows:
##STR00208##
[0459] To a stirred suspension of ethyl-1H-pyrazole carboxylate
(540 mg, 3.85 mmol) and potassium carbonate (800 mg, 5.78 mmol) in
DMF (5 ml) at 0.degree. C., was added tert-butyl bromoacetate (0.63
ml, 4.24 mmol) over a period of 5 minutes. The resulting suspension
was stirred for 2 hours at room temperature. The reaction mixture
was diluted with diethyl ether (100 ml), washed with water
(3.times.20 ml), dried (MgSO.sub.4) and concentrated to afford a
beige oil which was purified by flash chromatography on silica gel
(elution with pentane-DCM 50/50) to afford 16 (950 mg, 97%) as a
colourless oil; .sup.1H NMR Spectrum: (CDCl.sub.3): .delta. en ppm
1.35 (t, 3H), 1.47 (s, 9H), 4.30 (q, 2H), 4.81 (s, 2H), 7.95 (s,
1H), 7.97 (s, 1H).
[0460] At 0.degree. C., 16 (950 mg, 3.7 mmol) was added to
trifluoroacetic acid (10 ml) containing 1 ml of thioanisole. The
reaction mixture was allowed to warm to room temperature and
stirred for 4 hours, evaporated to dryness and the residue was
triturated with pentane (50 ml) and the solid collected by
filtration, washed with pentane (2.times.50 ml) and dried to a
constant weight at 40.degree. C. to afford 17 (736 mg, 100%);
.sup.1H NMR Spectrum: (CDCl.sub.3): 5 en ppm 1.34 (t, 3H), 4.31 (q,
2H), 4.81 (s, 2H), 5.01 (s, 2H), 7.99 (s, 1H), 8.02 (s, 1H).
[0461] To a stirred solution of 17 (950 mg, 3.7 mmol), DTPEA (1.43
g, 11.1 mmol) and
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-[(3R)-piperidin-3-yloxy-
]quinazoline (1.50 g, 3.70 mmol) [prepared as described for
examples 59 to 85] in DCM (5 ml) at 0.degree. C., was added solid
TBTU (1.78 g, 5.55 mmol) over a period of 5 minutes. The reaction
mixture was allowed to warm to room temperature and stirred for 2
hours. The resulting yellow solution was diluted with DCM (50 ml)
and washed with 2N NaOH (2.times.10 ml), dried (MgSO.sub.4) and
evaporated to dryness to afford 18 (2.1 g, 100%) as a beige foam
which was used without further purification; Mass Spectrum:
(M+H).sup.+ 583.13.
[0462] To a stirred solution of 18 (2 g, 3.45 mmol) in ethanol (5
ml) was added a 1N solution of NaOH (5.6 ml, 5.6 mmol). The
reaction mixture was allowed to warm to room temperature and
stirred for 16 hours. The ethanol was removed by evaporation and
the pH of aqueous solution decreased to 2 with a 10% w/v solution
of potassium hydrogensulfate. The resulting precipitate was taken
up in DCM (2 ml) and purified by flash chromatography on silica gel
(elution with DCM-MeOH-AcOH 90/9/1) to afford 19 (0.761 g, 40%) as
a yellow foam; .sup.1H NMR Spectrum: (DMSO-d.sub.6): .delta. en ppm
1.45-1.82 (m, 2H), 1.86-2.19 (m, 2H), 3.56-3.86 (m, 4H), 4.01 (s,
3H), 4.56 and 4.71 (m, 1H), 5.10-5.33 (m, 2H), 7.21-7.29 (m, 2H),
7.48-7.53 (m, 2H), 7.70 (s, 1H), 7.93 (s, 1H), 7.98-8.01 (m, 1H),
8.38 (s, 1H); Mass Spectrum: (M+H).sup.+ 555.12.
[0463] To a stirred solution of 19 (0.7 g, 1.26 mmol) and
pentafluorophenol (0.30 g, 1.64 mol) in DMF (5 ml) at 0.degree. C.,
was added solid EDCI (0.265 g, 1.39 mmol). The reaction mixture was
allowed to warm to room temperature and stirred for 16 hours. The
resulting solution was purified by flash chromatography on silica
gel (elution with a gradient from 100% pentane to 100% DCM) to
afford 15 (0.592 g, 65%) as a white foam, which was used without
further purification; Mass Spectrum: (M+H).sup.+ 721.18.
EXAMPLE 88
Preparation of Compound No. 88 of Table III
##STR00209##
[0465] To a stirred solution of Compound 86 (0.08 g, 0.145
mmol--prepared as described above in Example 86) in triethylamine
(0.146 g, 1.45 mmol) at 0.degree. C. was added trifluoroacetic
anhydride (0.152 g, 0.725 mmol) over 5 minutes. The resulting
solution was allowed to warm to room temperature and stirred for 2
hours. The solution was concentrated and the residue purified by
mass-triggered preparative LCMS to afford Compound 87 (0.04 g, 53%)
as a white solid; .sup.1HNMR Spectrum: (DMSO-d.sub.6): .delta. en
ppm 1.53-1.99 (m, 4H), 2.08-2.15 (m, 214), 3.56-3.96 (m, 2H), 4.01
(s, 3H), 4.47 and 4.74 (m, 1H), 5.20-5.44 (m, 2H), 7.24 (s, 1H),
7.27 (s, 1H), 7.34 (m, 1H), 7.54-7.57 (m, 2H), 7.98 (s, 1H), 8.04
(s, 1H), 8.41 (m, 1H), 8.57 (s, 1H); Mass Spectrum: (M+H).sup.+
534.15.
EXAMPLE 89
Preparation of Compound No. 89 shown in Table IV (phenyl
4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piper-
idine-1-carboxylate)
##STR00210##
[0466] Phenyl chloroformate (43 mg, 0.25 mmol) was added dropwise
to a mixture of
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-a-
mine (100 mg, 0.25 mmol) [prepared as described in Example 1] and
diisopropylethylamine (50 .mu.l, 0.30 mmol) in dichloromethane (2
ml). The mixture was stirred at room temperature for 18 hours.
After evaporation of the solvents under vacuum, the residue was
diluted in DMF (1 ml) and purified on an HPLC column (C18, 5
microns, 19 mm diameter, 100 mm length) of a preparative HPLC-MS
system eluting with a mixture of water and acetonitrile containing
2 g/l of ammonium formate (gradient) to give the title compound as
a solid (76 mg, 57%).
[0467] NMR spectrum (DMSO-d.sub.6) 1.81 (m, 2H), 2.11 (m, 2H), 3.39
(m, 1H), 3.58 (m, 1H), 3.79 (m, 1H), 3.90 (m, 1H), 3.96 (s, 3H),
4.78 (m, 1H), 7.15 (d, 2H), 7.23 (m, 2H), 7.30 (m, 1H), 7.39 (m,
2H), 7.50 (m, 2H), 7.91 (s, 1H), 8.38 (s, 1H); Mass spectrum:
MH.sup.+ 523.
EXAMPLES 90 TO 98
Preparation of Compound Numbers 90 to 98 Shown in Table V
General Procedure:
[0468] The corresponding isocyanate (0.3 mmol) was added dropwise
to a mixture of
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-a-
mine (100 mg, 0.25 mmol) [prepared as described in Example 1] in
dichloromethane (2 ml). The mixture was stirred at room temperature
for 18 hours. After evaporation of the solvents under vacuum, the
residue was diluted in DMF (1 ml) and purified on an HPLC column
(C18, 5 microns, 19 mm diameter, 100 mm length) of a preparative
HPLC-MS system eluting with a mixture of water and acetonitrile
containing 2 g/l of ammonium formate (gradient) to give the
following compounds:
Compound 90
(4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-ph-
enylpiperidine-1-carboxamide)
##STR00211##
[0469] 90 mg, 70%; starting isocyanate: phenyl isocyanate.
[0470] NMR spectrum (DMSO-d.sub.6) 1.72 (m, 2H), 2.06 (m, 2H), 3.39
(m, 2H), 3.86 (m, 2H), 3.95 (s, 3H), 4.75 (m, 1H), 6.93 (m, 1H);
7.30-7.20 (m, 4H), 7.55-7.45 (m, 4H), 7.89 (s, 1H), 7.38 (s, 1H),
8.57 (s, 1H), 9.60 (m, 1H); Mass spectrum: MH.sup.+ 522.
Compound 91
(N-Benzyl-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-
oxy)piperidine-1-carboxamide)
##STR00212##
[0471] 26 mg, 19%; starting isocyanate: benzyl isocyanate.
[0472] NMR spectrum (DMSO-d.sub.6) 1.63 (m, 2H), 2.01 (m, 2H), 3.22
(m, 2H), 3.78 (m, 2H), 3.94 (s, 3H), 4.26 (d, 2H), 4.72 (m, 1H),
7.30-7.10 (m, 8H), 7.51 (m, 2H), 7.86 (s, 1H), 8.37 (s, 1H); Mass
spectrum: MH.sup.+ 536
Compound 92
(4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-[4-
-(dimethylamino)phenyl]piperidine-1-carboxamide)
##STR00213##
[0473] 68 mg, 49%; starting isocyanate: 4-dimethylaminophenyl
isocyanate.
[0474] NMR spectrum (DMSO-d.sub.6) 1.70 (m, 2H), 2.06 (m, 2H), 2.82
(s, 6H), 3.30 (m, 2H), 3.85 (m, 2H), 3.95 (s, 3H), 4.75 (m, 1H),
6.66 (d, 2H); 7.24 (m, 3H), 7.30 (m, 1H), 7.52 (m, 2H), 7.89 (s,
8.27 (s, 1H), 8.38 (s, 1H), 9.60 (s, 1H); Mass spectrum: MH.sup.+
565
[0475] Compound
93--(4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-
-N-(2-phenylethyl)piperidine-1-carboxamide)
##STR00214##
57 mg, 42%; starting isocyanate: phenethyl isocyanate.
[0476] NMR spectrum (DMSO-d.sub.6) 1.60 (m, 2H), 1.98 (m, 2H), 2.73
(t, 2H), 3.14 (m, 2H), 3.25 (m, 2H), 3.72 (m, 2H), 3.95 (s, 3H),
4.69 (m, 1H), 6.67 (m, 1H), 7.20 (m, 4H), 7.29 (m, 3H), 7.50 (m,
2H), 7.85 (s, 1H), 8.37 (m, 1H), 9.60 (s, 1H); Mass spectrum:
MH.sup.+ 550.
Compound 94
(4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-(3-
,4-dimethoxyphenyl)piperidine-1-carboxamide)
##STR00215##
[0477] 45 mg, 31%; starting isocyanate: 3,4-dimethoxyphenyl
isocyanate.
[0478] NMR spectrum (DMSO-d.sub.6) 1.70 (m, 2H), 2.05 (m, 2H), 3.35
(m, 2H), 3.70 (s, 3H), 3.71 (s, 3H), 3.85 (m, 2H), 3.95 (s, 3H),
4.75 (m, 1H). 6.83 (d, 1H), 6.98 (d, 1H), 7.17 (s, 1H), 7.24 (s,
1H), 7.30 (m, 1H), 7.51 (m, 2H), 7.89 (s, 1H), 8.38 (s, 1H), 8.41
(s, 1H), 9.60 (m, 1H); Mass spectrum: MH.sup.+ 582
Compound 95
(4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-(3-
-fluorophenyl)piperidine-1-carboxamide)
##STR00216##
[0479] 108 mg, 81%; starting isocyanate: 3-fluorophenyl
isocyanate.
[0480] NMR spectrum (DMSO-d.sub.6) 1.72 (m, 2H), 2.07 (m, 2H), 3.35
(m, 2H), 3.85 (m, 2H), 3.95 (s, 3H), 4.77 (m, 1H), 6.74 (m, 1H),
7.31-7.24 (m, 4H), 7.55-7.44 (m, 3H), 7.90 (s, 1H), 8.38 (s, 1H),
8.79 (s, 1H), 9.60 (m, 1H); Mass spectrum: MH.sup.+ 540
Compound 96
(4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-(3-
,5-dimethylisoxazol-4-yl)piperidine-1-carboxamide)
##STR00217##
[0481] 106 mg, 79%; starting isocyanate: 3,5-dimethylisoxazol-4-yl
isocyanate.
[0482] NMR spectrum (DMSO-d.sub.6) 1.70 (m, 2H), 2.07 (s, 3H), 2.08
(m, 2H), 2.23 (s, 3H), 3.35 (m, 2H), 3.83 (m, 2H), 3.95 (s, 3H),
4.76 (m, 1H), 7.24 (s, 1H), 7.30 (m, 1H), 7.52 (m, 2H), 7.88 (s,
1H), 7.99 (s, 1H), 8.38 (s, 1H), 9.60 (m, 1H); Mass spectrum:
MH.sup.+ 541
Compound 97
(4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-2--
thienylpiperidine-1-carboxamide)
##STR00218##
[0483] 81 mg, 62%; starting isocyanate: 2-thienyl isocyanate.
[0484] NMR spectrum (DMSO-d.sub.6) 1.70 (m, 2H), 2.06 (m, 2H), 3.37
(m, 2H), 3.85 (m, 2H), 3.95 (s, 3H), 4.76 (m, 1H), 6.61 (m, 1H),
6.79 (m, 2H), 7.24 (s, 1H), 7.29 (m, 1H), 7.52 (m, 2H), 7.89 (s,
1H), 8.38 (s, 1H), 9.60 (m, 1H); 9.73 (m, 1H); Mass spectrum:
MH.sup.+ 528
Compound 98
(4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-3--
thienylpiperidine-1-carboxamide)
##STR00219##
[0485] 61 mg, 47%; starting isocyanate: 3-thienyl isocyanate.
[0486] NMR spectrum (DMSO-d.sub.6) 1.70 (m, 2H), 2.06 (m, 2H), 3.37
(m, 2H), 3.85 (m, 2H), 3.95 (s, 3H), 4.75 (m, 1H), 7.13 (m, 1H),
7.24 (s, 1H), 7.31-7.26 (m, 2H), 7.36 (m, 1H), 7.52 (m, 2H), 7.89
(s, 1H), 8.38 (s, 1H), 8.98 (s, 1H); Mass spectrum: MH.sup.+
528
* * * * *