U.S. patent application number 10/342810 was filed with the patent office on 2003-09-18 for heterocyclic compounds.
Invention is credited to Carter, Malcolm Clive, Cockerill, George Stuart, Guntrip, Stephen Barry, Lackey, Karen Elizabeth, Smith, Kathryn Jane.
Application Number | 20030176451 10/342810 |
Document ID | / |
Family ID | 10825153 |
Filed Date | 2003-09-18 |
United States Patent
Application |
20030176451 |
Kind Code |
A1 |
Carter, Malcolm Clive ; et
al. |
September 18, 2003 |
Heterocyclic compounds
Abstract
A process for the preparation of a compound of formula (I) 1
comprising the steps: (a) reacting a compound of formula (II) 2
wherein L and L' are suitable leaving groups, with a compound of
formula (III) UNH.sub.2 (III) to prepare a compound of formula (IV)
3 and subsequently (b) substituting the group R.sup.1 by
replacement of the leaving group L'.
Inventors: |
Carter, Malcolm Clive;
(Ware, GB) ; Cockerill, George Stuart; (Bedford,
GB) ; Guntrip, Stephen Barry; (Hertford, GB) ;
Lackey, Karen Elizabeth; (Hillsborough, NC) ; Smith,
Kathryn Jane; (Bishop's Stortford, GB) |
Correspondence
Address: |
DAVID J LEVY, CORPORATE INTELLECTUAL PROPERTY
GLAXOSMITHKLINE
FIVE MOORE DR., PO BOX 13398
RESEARCH TRIANGLE PARK
NC
27709-3398
US
|
Family ID: |
10825153 |
Appl. No.: |
10/342810 |
Filed: |
January 15, 2003 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10342810 |
Jan 15, 2003 |
|
|
|
09582746 |
Jun 30, 2000 |
|
|
|
09582746 |
Jun 30, 2000 |
|
|
|
PCT/EP99/00048 |
Jan 8, 1999 |
|
|
|
Current U.S.
Class: |
514/264.11 ;
514/266.2; 514/266.21; 544/279; 544/284 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 31/00 20180101; A61P 17/00 20180101; C07D 417/14 20130101;
C07D 411/04 20130101; C07D 239/94 20130101; C07D 405/04 20130101;
A61P 9/00 20180101; C07D 405/14 20130101; C07D 471/04 20130101;
A61P 29/00 20180101; A61P 37/00 20180101; A61P 3/10 20180101; A61K
31/517 20130101; A61P 17/06 20180101; A61P 9/10 20180101; A61P
35/00 20180101; C07D 417/04 20130101 |
Class at
Publication: |
514/264.11 ;
514/266.2; 514/266.21; 544/279; 544/284 |
International
Class: |
A61K 031/519; A61K
031/517; C07D 487/02; C07D 43/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 12, 1998 |
GB |
9800569.7 |
Claims
1. A process for the preparation of a compound of formula (I)
57wherein; Y is CR.sup.1 and V is N; or Y is CR.sup.1 and V is
CR.sup.2; R.sup.1 represents a group
CH.sub.3SO.sub.2CH.sub.2CH.sub.2NHCH.sub.2--Ar--, wherein Ar is
selected from furan or thiazole, each of which may optionally be
substituted by one or two halo, C.sub.1-4 alkyl or C.sub.1-4 alkoxy
groups; R.sup.2 is selected from the group consisting of hydrogen,
halo, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
alkylamino and di(C.sub.1-4 alkyl)amino; U represents a phenyl,
pyridyl, 3H-imidazolyl, indolyl, isoindolyl, indolinyl,
isoindolinyl, 1H-indazolyl, 2,3-dihydro-1H-indazolyl,
1H-benzimidazolyl, 2,3-dihydro-1H-benzimidazolyl or
1H-benzotriazolyl group, substituted by an R.sup.3 group and
optionally substituted by at least one independently selected
R.sup.4 group; R.sup.3 is selected from a group consisting of
benzyl, halo-, dihalo- and trihalobenzyl, benzoyl, pyridylmethyl,
pyridylmethoxy, phenoxy, benzyloxy, halo-, dihalo- and
trihalobenzyloxy and benzenesulphonyl; or R.sup.3 represents a
group of formula 58wherein each R.sup.5 is independently selected
from halogen, C.sub.1-4 alkyl and C.sub.1-4 alkoxy; and n is 0 to
3; each R.sup.4 is independently hydroxy, halogen, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 alkoxy, amino,
C.sub.1-4 alkylamino, di(C.sub.1-4 alkyl)amino, C.sub.1-4
alkylthio, C.sub.1-4 alkylsulphinyl, C.sub.1-4 alkylsulphonyl,
C.sub.1-4 alkylcarbonyl, carboxy, carbamoyl, C.sub.1-4
alkoxycarbonyl, C.sub.1-4 alkanoylamino, N-(C.sub.1-4
alkyl)carbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, cyano, nitro and
trifluoromethyl; comprising the steps: 59wherein Y' is CL' and V'
is N; or Y' is CL' and V' is CR.sup.2; wherein L and L' are
suitable leaving groups, with a compound of formula (III) UNH.sub.2
(III) to prepare a compound of formula (IV) 60and subsequently (b)
substituting the group R.sup.1 by replacement of the leaving group
L'.
2. A process for the preparation of a compound of formula (I) as
defined in claim 1 which comprises the steps: 61wherein U is as
defined in claim 1; Y" is CT and V" is N; or Y" is CT and V" is
CR.sup.2; wherein R is as defined in claim 1 and T is a group Ar
substituted with formyl, CH.sub.3SCH.sub.2CH.sub.2NHCH.sub.2--; or
CH.sub.3SOCH.sub.2CH.sub.2NHCH.- sub.2--; and (b) subsequently
converting the group T into the group R.sup.1.
3. The process of claim 2, wherein the Group T is converted into
the group R.sup.1 by reductive amination.
4. The process of claim 2, wherein the Group T is converted into
the group R.sup.1 by oxidation.
5. The process of claim 1, further comprising converting the
compound of formula (I) thereby obtained into another compound of
formula (I), wherein said conversion is effected by akylthio group
oxidation, nitro group reduction, amino group acylation, or amino
group substitution.
6. The process of claim 2, further comprising converting the
compound of formula (I) thereby obtained into another compound of
formula (I), wherein said conversion is effected by akylthio group
oxidation, nitro group reduction, amino group acylation, or amino
group substitution.
Description
[0001] The present invention relates to a series of substituted
heteroaromatic compounds, methods for their preparation,
pharmaceutical compositions containing them and their use in
medicine. In particular, the invention relates to quinoline,
quinazoline, pyridopyridine and pyridopyrimidine derivatives which
exhibit protein tyrosine kinase inhibition.
[0002] Protein tyrosine kinases catalyse the phosphorylation of
specific tyrosyl residues in various proteins involved in the
regulation of cell growth and differentiation (A. F. Wilks,
Progress in Growth Factor Research, 1990, 2, 97-111; S. A.
Courtneidge, Dev. Supp.I, 1993, 57-64; J. A. Cooper, Semin. Cell
Biol., 1994, 5(6), 377-387; R. F. Paulson, Semin. Immunol., 1995,
7(4), 267-277; A. C. Chan, Curr. Opin. Immunol., 1996, 8(3),
394-401). Protein tyrosine kinases can be broadly classified as
receptor (e.g. EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr) or
non-receptor (e.g. c-src, lck, zap70) kinases. Inappropriate or
uncontrolled activation of many of these kinase, i.e. aberrant
protein tyrosine kinase activity, for example by over-expression or
mutation, has been shown to result in uncontrolled cell growth.
[0003] Aberrant activity of protein tyrosine kinases, such as
c-erbB-2, c-src, c-met, EGFr and PDGFr have been implicated in
human malignancies. Elevated EGFr activity has, for example, been
implicated in non-small cell lung, bladder and head and neck
cancers, and increased c-erbB-2 activity in breast, ovarian,
gastric and pancreatic cancers. Inhibition of protein tyrosine
kinases should therefore provide a treatment for tumours such as
those outlined above.
[0004] Aberrant protein tyrosine kinase activity has also been
implicated in a variety of other disorders: psoriasis, (Dvir et al,
J. Cell. Biol; 1991, 113, 857-865), fibrosis, atherosclerosis,
restenosis, (Buchdunger et al, Proc. Natl. Acad. Sci. USA; 1991,
92, 2258-2262), auto-immune disease, allergy, asthma,
transplantation rejection (Klausner and Samelson, Cell; 1991, 64,
875-878), inflammation (Berkois, Blood; 1992, 79(9), 2446-2454),
thrombosis (Salari et al, FEBS; 1990, 263(1), 104-108) and nervous
system diseases (Ohmichi et al, Biochemistry, 1992, 31, 4034-4039).
Inhibitors of the specific protein tyrosine kinases involved in
these diseases eg PDGF-R in restenosis and EGF-R in psoriasis,
should lead to novel therapies for such disorders. P56lck and zap
70 are indicated in disease conditions in which T cells are
hyperactive e.g. rheumatoid arthritis, autoimmune disease, allergy,
asthma and graft rejection. The process of angiogenesis has been
associated with a number of disease states (e.g. tumourogenesis,
psoriasis, rheumatoid arthritis) and this has been shown to be
controlled through the action of a number of receptor tyrosine
kinases (L. K. Shawver, DDT, 1997, 2(2), 50-63).
[0005] It is therefore a general object of the present invention to
provide compounds suitable for the treatment of disorders mediated
by protein tyrosine kinase activity, and in particular treatment of
the above mentioned disorders.
[0006] In addition to the treatment of tumours, the present
invention envisages that other disorders mediated by protein
tyrosine kinase activity may be treated effectively by inhibition,
including preferential inhibition, of the appropriate protein
tyrosine kinase activity.
[0007] Broad spectrum inhibition of protein tyrosine kinase may not
always provide optimal treatment of, for example tumours, and could
in certain cases even be detrimental to subjects since protein
tyrosine kinases provide an essential role in the normal regulation
of cell growth.
[0008] It is another object of the present invention to provide
compounds which preferentially inhibit protein tyrosine kinases,
such as EGFr, c-erbB-2, c-erbB-4, c-met, tie-2, PDGFr, c-src, lck,
Zap70, and fyn. There is also perceived to be a benefit in the
preferential inhibition involving small groups of protein tyrosine
kinases, for example groups including two or more of c-erbB-2,
c-erbB-4, EGF-R, lck and zap70.
[0009] A further object of the present invention is to provide
compounds useful in the treatment of protein tyrosine kinase
related diseases which minimise undesirable side-effects in the
recipient.
[0010] The present invention relates to heterocyclic compounds
which may be used to treat disorders mediated by protein tyrosine
kinases and in particular have anti-cancer properties. More
particularly, the compounds of the present invention are potent
inhibitors of protein tyrosine kinases such as such as EGFr,
c-erbB-2, c-erbB-4, c-met, tie-2, PDGFr, c-src, lck, Zap70, and
fyn, thereby allowing clinical management of particular diseased
tissues.
[0011] The present invention envisages, in particular, the
treatment of human malignancies, for example breast, non-small cell
lung, ovary, stomach, and pancreatic tumours, especially those
driven by EGF-R or erbB-2, using the compounds of the present
invention. For example, the invention includes compounds which are
highly active against the c-erbB-2 protein tyrosine kinase often in
preference to the EGF receptor kinase hence allowing treatment of
c-erbB-2 driven tumours. However, the invention also includes
compounds which are highly active against both c-erbB-2 and EGF-R
receptor kinases hence allowing treatment of a broader range of
tumours.
[0012] The present invention also includes compounds which are
active against lck and/or zap70 receptor kinases; these may also be
active against c-erbB-2 and/or EGF-R receptor kinases. The
compounds may be selective towards lck and/or zap70 in comparison
to c-erbB-2 and/or EGF-R.
[0013] More particularly, the present invention envisages that
disorders mediated by protein tyrosine kinase activity may be
treated effectively by inhibition of the appropriate protein
tyrosine kinase activity in a relatively selective manner, thereby
minimising potential side effects.
[0014] Accordingly, the present invention provides a compound of
formula (I) 4
[0015] or a salt or solvate thereof;
[0016] wherein X is N or CH;
[0017] Y is CR.sup.1 and V is N;
[0018] or Y is N and V is CR.sup.1;
[0019] or Y is CR.sup.1 and V is CR.sup.2;
[0020] or Y is CR.sup.2 and V is CR.sup.1;
[0021] R.sup.1 represents a group
CH.sub.3SO.sub.2CH.sub.2CH.sub.2NHCH.sub- .2--Ar--, wherein Ar is
selected from phenyl, furan, thiophene, pyrrole and thiazole, each
of which may optionally be substituted by one or two halo,
C.sub.1-4 alkyl or C.sub.1-4 alkoxy groups;
[0022] R.sup.2 is selected from the group comprising hydrogen,
halo, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
alkylamino and di[C.sub.1-4 alkyl]amino;
[0023] U represents a phenyl, pyridyl, 3H-imidazolyl, indolyl,
isoindolyl, indolinyl, isoindolinyl, 1H-indazolyl,
2,3-dihydro-1H-indazolyl, 1H-benzimidazolyl,
2,3-dihydro-1H-benzimidazolyl or 1H-benzotriazolyl group,
substituted by an R.sup.3 group and optionally substituted by at
least one independently selected R.sup.4 group;
[0024] R.sup.3 is selected from a group comprising benzyl, halo-,
dihalo- and trihalobenzyl, benzoyl, pyridylmethyl, pyridylmethoxy,
phenoxy, benzyloxy, halo-, dihalo- and trihalobenzyloxy and
benzenesulphonyl;
[0025] or R.sup.3 represents trihalomethylbenzyl or
trihalomethylbenzyloxy;
[0026] or R.sup.3 represents a group of formula 5
[0027] wherein each R.sup.5 is independently selected from halogen,
C.sub.1-4 alkyl and C.sub.1-4 alkoxy; and n is 0 to 3;
[0028] each R.sup.4 is independently hydroxy, halogen, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 alkoxy,
amino, C.sub.1-4 alkylamino, di[C.sub.1-4 alkyl]amino, C.sub.1-4
alkylthio, C.sub.1-4 alkylsulphinyl, C.sub.1-4 alkylsulphonyl,
C.sub.1-4 alkylcarbonyl, carboxy, carbamoyl, C.sub.1-4
alkoxycarbonyl, C.sub.1-4 alkanoylamino, N-(C.sub.1-4
alkyl)carbamoyl, N,N-di(C.sub.1-4 alkyl)carbamoyl, cyano, nitro and
trifluoromethyl;
[0029] with the proviso that the following compounds are
excluded:
[0030]
(1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)-m-
ethyl)furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl-amine;
[0031]
(4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-
-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl-amine;
[0032]
(1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)-m-
ethyl)furan-2-yl)-quinazolin-4-yl-amine;
[0033]
(1-Benzyl-1H-indazol-5-yl)-(7-(5-((2-methanesulphonyl-ethylamino)-m-
ethyl)furan-2-yl)-quinazolin-4-yl-amine;
[0034]
(1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)-m-
ethyl)-1-methyl-pyrrol-2-yl)-quinazolin-4-yl-amine;
[0035] and their hydrochloride salts.
[0036] Solvates of the compounds of formula (I) are also included
within the scope of the present invention.
[0037] The definitions for X, Y and V thus give rise to a number of
possible basic ring systems for the compounds of formula (I). In
particular the compounds may contain the following basic ring
systems: 6
[0038] It will be seen that for compounds containing the basic ring
system (1) the group R.sup.1 may be at the 6- or 7-position; the
compounds in which R.sup.1 is in the 7-position are of particular
interest in the context of lck and/or zap70 activity.
[0039] It will be seen that for compounds containing the basic ring
system (2) the group R.sup.1 may be at the 6- or 7-position; the
compounds in which R.sup.1 is in the 6-position are of particular
interest in the context of c-erbB-2 activity whereas the compounds
in which R.sup.1 is in the 7-position are of particular interest in
the context of lck and/or zap70 activity.
[0040] Ring systems (1), (2), (5) and (6) are preferred; ring
systems (2) and (6) are more preferred.
[0041] Ring system (1) is also more preferred.
[0042] Alkyl groups containing three or more carbon atoms may be
straight, branched or cyclised; preferably they are straight or
branched. References to a specific alkyl group such as "butyl" is
intended to refer to the straight chain (n-) isomer only.
References to other generic terms such as alkoxy, alkylamino etc.
are to be interpreted analogously.
[0043] Suitable values for the various groups listed above within
the definitions for R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are as
follows:
[0044] halo is, for example, fluoro, chloro, bromo or iodo;
preferably it is fluoro, chloro or bromo, more preferably fluoro or
chloro;
[0045] C.sub.1-4 alkyl is, for example, methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; preferably it
is methyl, ethyl, propyl, isopropyl or butyl, more preferably
methyl;
[0046] C.sub.2-4 alkenyl is, for example, ethenyl, prop-1-enyl or
prop-2-enyl; preferably it is ethenyl;
[0047] C.sub.2-4 alkynyl is, for example, ethynyl, prop-1-ynyl or
prop-2-ynyl; preferably it is ethynyl;
[0048] C.sub.1-4 alkoxy is, for example, methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or
tert-butoxy; preferably it is methoxy, ethoxy, propoxy, isopropoxy
or butoxy; more preferably it is methoxy;
[0049] C.sub.1-14 alkylamino is, for example, methylamino,
ethylamino or propylamino; preferably it is methylamino;
[0050] di[C.sub.1-4 alkyl]amino is, for example, dimethylamino,
diethylamino, N-methyl-N-ethylamino or dipropylamino; preferably it
is dimethylamino;
[0051] C.sub.1-4 alkylthio is, for example, methylthio, ethylthio,
propylthio or isopropylthio, preferably methylthio;
[0052] C.sub.1-4 alkylsulphinyl is, for example, methylsulphinyl,
ethylsulphinyl, propylsulphinyl or isopropylsulphinyl, preferably
methylsulphinyl;
[0053] C.sub.1-4 alkylsulphonyl is, for example, methanesulphonyl,
ethylsulphonyl, propylsulphonyl or isopropylsulphonyl, preferably
methanesulphonyl;
[0054] C.sub.1-4 alkylcarbonyl is, for example methylcarbonyl,
ethylcarbonyl or propylcarbonyl;
[0055] C.sub.1-4 alkoxycarbonyl is, for example, methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or
tert-butoxycarbonyl;
[0056] C.sub.1-4 alkanoylamino (where the number of carbon atoms
includes the CO functionality) is, for example, formamido,
acetamido, propionamido or butyramido;
[0057] N-(C.sub.1-4 alkyl)carbamoyl is, for example,
N-methylcarbamoyl or N-ethylcarbamoyl;
[0058] N,N-di(C.sub.1-4 alkyl)carbamoyl is, for example,
N,N-dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl or
N,N-diethylcarbamoyl.
[0059] In an especially preferred embodiment X is N, Y is CR.sup.1
and V is CR.sup.2 (ring system (2) above).
[0060] In a further especially preferred embodiment X is N, Y is
CR.sup.2 and V is CR.sup.1 (ring system (2) above).
[0061] In a further especially preferred embodiment X is N, Y is
CR.sup.1 and V is N (ring system (6) above).
[0062] In a preferred embodiment R.sup.2 represents hydrogen or
C.sub.1-4 alkoxy.
[0063] In a more preferred embodiment R.sup.2 represents hydrogen
or methoxy.
[0064] In a further preferred embodiment R.sup.2 represents halo;
more preferred R.sup.2 is fluoro.
[0065] In a preferred embodiment the group Ar is substituted by one
halo, C.sub.1-4 alkyl or C.sub.1-4 alkoxy group.
[0066] In a more preferred embodiment the group Ar is substituted
by a C.sub.1-4 alkyl group.
[0067] In a further more preferred embodiment the group Ar does not
carry any optional substituents.
[0068] In a further more preferred embodiment Ar represents furan,
phenyl or thiazole, each of which may optionally be substituted as
indicated above.
[0069] In a further more preferred embodiment Ar represents furan
or thiazole, each of which may optionally be substituted as
indicated above.
[0070] In a most preferred embodiment Ar represents unsubstituted
furan or thiazole.
[0071] The side chain CH.sub.3SO.sub.2CH.sub.2CH.sub.2NHCH.sub.2
may be linked to any suitable position of the group Ar. Similarly,
the group R.sup.1 may be linked to the carbon atom carrying it from
any suitable position of the group Ar.
[0072] In a preferred embodiment, when Ar represents furan the side
chain CH.sub.3SO.sub.2CH.sub.2CH.sub.2NHCH.sub.2 is in the
4-position of the furan ring and the link to the carbon atom
carrying the group R.sup.1 is from the 2-position of the furan
ring.
[0073] In another preferred embodiment, when Ar represents furan
the side chain CH.sub.3SO.sub.2CH.sub.2CH.sub.2NHCH.sub.2 is in the
3-position of the furan ring and the link to the carbon atom
carrying the group R.sup.1 is from the 2-position of the furan
ring.
[0074] In a most preferred embodiment, when Ar represents furan the
side chain CH.sub.3SO.sub.2CH.sub.2CH.sub.2NHCH.sub.2 is in the
5-position of the furan ring and the link to the carbon atom
carrying the group R.sup.1 is from the 2-position of the furan
ring.
[0075] In a further most preferred embodiment, when Ar represents
thiazole the side chain CH.sub.3SO.sub.2CH.sub.2CH.sub.2NHCH.sub.2
is in the 2-position of the thiazole ring and the link to the
carbon atom carrying the group R.sup.1 is from the 4-position of
the thiazole ring.
[0076] The R.sup.3 and R.sup.4 groups may be bound to the ring
system U by either a carbon atom or a heteroatom of the ring
system. The ring system itself may be bound to the bridging NH
group by a carbon atom or a heteroatom but is preferably bound by a
carbon atom. The R.sup.3 and R.sup.4 groups may be bound to either
ring when U represents a bicyclic ring system, but these groups are
preferably bound to the ring which is not bound to the bridging NH
group in such a case.
[0077] In a preferred embodiment U represents a phenyl, indolyl, or
1H-indazolyl group substituted by an R.sup.3 group and optionally
substituted by at least one independently selected R.sup.4
group.
[0078] In a more preferred embodiment U represents a phenyl or
1H-indazolyl group substituted by an R.sup.3 group and optionally
substituted by at least one independently selected R.sup.4
group.
[0079] In a more preferred embodiment, where U represents a phenyl
group the group R.sup.3 is in the para-position relative to the
bond from U to the linking NH group.
[0080] In a further more preferred embodiment, where U represents a
1H-indazolyl group the group R.sup.3 is in the 1-position of the
indazolyl group.
[0081] In a preferred embodiment R.sup.3 represents benzyl,
pyridylmethyl, phenoxy, benzyloxy, halo-, dihalo- and
trihalobenzyloxy and benzenesulphonyl.
[0082] In a further preferred embodiment R.sup.3 represents
trihalomethylbenzyloxy.
[0083] In a further preferred embodiment R.sup.3 represents a group
of formula 7
[0084] wherein Hal is Br or Cl, particularly Cl, more especially
wherein the Hal substituent is in the position marked with a star
in the ring as shown.
[0085] In a more preferred embodiment R.sup.3 represents benzyloxy,
fluorobenzyloxy (especially 3-fluorobenzyloxy), benzyl, phenoxy and
benzenesulphonyl.
[0086] In a further more preferred embodiment R.sup.3 represents
bromobenzyloxy (especially 3-bromobenzyloxy) and
trifluoromethylbenzyloxy- .
[0087] In a further preferred embodiment the ring U is not
substituted by an R.sup.4 group; in an especially preferred
embodiment U is phenyl or indazolyl unsubstituted by an R.sup.4
group.
[0088] In a further preferred embodiment the ring U is substituted
by an R.sup.4 group selected from halo or C.sub.1-4 alkoxy;
especially chloro, fluoro or methoxy.
[0089] In a more preferred embodiment the ring U is substituted by
an R.sup.4 group wherein R.sup.4 represents halo, especially
3-fluoro.
[0090] In an especially preferred embodiment U together with
R.sup.4 represents methoxyphenyl, fluorophenyl,
trifluoromethylphenyl or chlorophenyl.
[0091] In a more especially preferred embodiment U together with
R.sup.4 represents methoxyphenyl or fluorophenyl.
[0092] In an especially preferred embodiment the group U together
with the substituent(s) R.sup.3 and R.sup.4 represents
benzyloxyphenyl, (fluorobenzyloxy)phenyl, (benzenesulphonyl)phenyl,
benzylindazolyl or phenoxyphenyl.
[0093] In a more especially preferred embodiment the group U
together with the substituent(s) R.sup.3 and R.sup.4 represents
benzyloxyphenyl, (3-fluorobenzyloxy)phenyl,
(benzenesulphonyl)phenyl or benzylindazolyl.
[0094] In another more especially preferred embodiment the group U
together with the substituent(s) R.sup.3 and R.sup.4 represents
(3-bromobenzyloxy)phenyl, (3-trifluoromethylbenzyloxy)phenyl, or
(3-fluorobenzyloxy)-3-methoxyphenyl.
[0095] In another more especially preferred embodiment the group U
together with the substituent(s) R.sup.3 and R.sup.4 represents
3-fluorobenzyloxy-3-chlorophenyl, benzyloxy-3-chlorophenyl,
benzyloxy-3-trifluoromethylphenyl, (benzyloxy)-3-fluorophenyl,
(3-fluorobenzyloxy)-3-fluorophenyl or
(3-fluorobenzyl)indazolyl.
[0096] In a most especially preferred embodiment the group U
together with the substituent(s) R.sup.3 and R.sup.4 represents
benzyloxyphenyl or (3-fluorobenzyloxy)phenyl.
[0097] In a preferred embodiment there is provided a compound of
formula (I) or a salt or solvate thereof wherein X is N; V is
CR.sup.2, wherein R.sup.2 is hydrogen, halo (especially fluoro) or
C.sub.1-4 alkoxy (especially methoxy); Y is CR.sup.1 wherein
R.sup.1 is as defined above in which Ar is unsubstituted phenyl,
furan or thiazole; U is phenyl or indazole; R.sup.3 is benzyl,
fluorobenzyl, benzyloxy, fluorobenzyloxy, bromobenzyloxy,
trifluoromethylbenzyloxy, phenoxy or benzenesulphonyl; and R.sup.4
is not present or is halo (especially chloro or fluoro), or
methoxy.
[0098] In a most preferred embodiment there is provided a compound
of formula (I) or a salt or solvate thereof wherein X is N; V is
CR.sup.2, wherein R.sup.2 is hydrogen, halo (especially fluoro) or
C.sub.1-4 alkoxy (especially methoxy); Y is CR.sup.1 wherein
R.sup.1 is as defined above in which Ar is unsubstituted furan or
thiazole; U is phenyl; R.sup.3 is benzyloxy, fluorobenzyloxy or
benzenesulphonyl; and R.sup.4 is not present or is halo (especially
chloro or fluoro), or methoxy.
[0099] In a most preferred embodiment there is provided a compound
of formula (I) or a salt or solvate thereof wherein X is N; V is
CR.sup.2, wherein R.sup.2 is hydrogen, halo (especially fluoro) or
C.sub.1-4 alkoxy (especially methoxy); Y is CR.sup.1 wherein
R.sup.1 is as defined above in which Ar is unsubstituted furan or
thiazole; U is indazole; R.sup.3 is benzyl or fluorobenzyl; and
R.sup.4 is not present.
[0100] In a further more preferred embodiment there is provided a
compound of formula (I) or a salt or solvate thereof wherein X is
N; Y is CR.sup.2, wherein R.sup.2 is hydrogen, halo (especially
fluoro) or C.sub.1-4 alkoxy (especially methoxy); V is CR.sup.1
wherein R.sup.1 is as defined above in which Ar is unsubstituted
phenyl, furan or thiazole; U is phenyl or indazole; R.sup.3 is
benzyl, fluorobenzyl, benzyloxy, fluorobenzyloxy, bromobenzyloxy,
trifluoromethylbenzyloxy, phenoxy or benzenesulphonyl; and R.sup.4
is not present or is halo (especially chloro or fluoro), or
methoxy.
[0101] In a further most preferred embodiment there is provided a
compound of formula (I) or a salt or solvate thereof wherein X is
N; Y is CR.sup.2, wherein R.sup.2 is hydrogen, halo (especially
fluoro) or C.sub.1-4 alkoxy (especially methoxy); V is CR.sup.1
wherein R.sup.1 is as defined above in which Ar is unsubstituted
furan or thiazole; U is phenyl; R.sup.3 is benzyloxy,
fluorobenzyloxy or benzenesulphonyl; and R.sup.4 is not present or
is halo (especially chloro or fluoro), or methoxy.
[0102] In a further most preferred embodiment there is provided a
compound of formula (I) or a salt or solvate thereof wherein X is
N; Y is CR.sup.2, wherein R.sup.2 is hydrogen, halo (especially
fluoro) or C.sub.1-4 alkoxy (especially methoxy); V is CR.sup.1
wherein R.sup.1 is as defined above in which Ar is unsubstituted
furan or thiazole; U is indazole; R.sup.3 is benzyl or
fluorobenzyl; and R.sup.4 is not present.
[0103] In a most especially preferred embodiment there is provided
a compound of formula(1) or a salt or solvate thereof wherein X is
N, Y is CR.sup.2, wherein R.sup.2 is hydrogen, halo (especially
fluoro) or C.sub.1-4 alkoxy (especially methoxy); V is CR.sup.1
wherein R.sup.1 is as defined above in which Ar is unsubstituted
furan or thiazole; U is phenyl; R.sup.3 is phenoxy; and R.sup.4 is
not present.
[0104] In another more preferred embodiment there is provided a
compound of formula (I) or a salt or solvate thereof wherein X is
N; V is N; Y is CR.sup.1 wherein R.sup.1 is as defined above in
which Ar is unsubstituted phenyl, furan or thiazole; U is phenyl or
indazole; R.sup.3 is benzyl, fluorobenzyl, benzyloxy,
fluorobenzyloxy, bromobenzyloxy, trifluoromethylbenzyloxy, phenoxy
or benzenesulphonyl; and R.sup.4 is not present or is halo
(especially chloro or fluoro), or methoxy.
[0105] In another most preferred embodiment there is provided a
compound of formula (I) or a salt or solvate thereof wherein X is
N; V is N, Y is CR.sup.1 wherein R.sup.1 is as defined above in
which Ar is unsubstituted furan or thiazole; U is phenyl; R.sup.3
is benzyloxy, fluorobenzyloxy or benzenesulphonyl; and R.sup.4 is
not present or is halo (especially chloro or fluoro), or
methoxy.
[0106] In another most preferred embodiment there is provided a
compound of formula (I) or a salt or solvate thereof wherein X is
N; V is N, Y is CR.sup.1 wherein R.sup.1 is as defined above in
which Ar is unsubstituted furan or thiazole; U is indazole; R.sup.3
is benzyl or fluorobenzyl; and R.sup.4 is not present.
[0107] In yet another preferred embodiment there is provided a
compound of formula (I) or a salt or solvate thereof wherein X is
CH; Y is CR.sup.2, wherein R.sup.2 is hydrogen, halo (especially
fluoro) or C.sub.1-4 alkoxy (especially methoxy); V is CR.sup.1
wherein R.sup.1 is as defined above in which Ar is unsubstituted
phenyl, furan or thiazole; U is phenyl or indazole; R.sup.3 is
benzyl, fluorobenzyl, benzyloxy, fluorobenzyloxy, bromobenzyloxy,
trifluoromethylbenzyloxy, phenoxy or benzenesulphonyl; and R.sup.4
is not present or is halo (especially chloro or fluoro), or
methoxy.
[0108] In yet another most preferred embodiment there is provided a
compound of formula (I) or a salt or solvate thereof wherein X is
CH; Y is CR.sup.2, wherein R.sup.2 is hydrogen, halo (especially
fluoro) or C.sub.1-4 alkoxy (especially methoxy); V is CR.sup.1
wherein R.sup.1 is as defined above in which Ar is unsubstituted
furan or thiazole; U is phenyl; R.sup.3 is benzyloxy,
fluorobenzyloxy, phenoxy or benzenesulphonyl; and R.sup.4 is not
present or is halo (especially chloro or fluoro), or methoxy.
[0109] In yet another most preferred embodiment there is provided a
compound of formula (I) or a salt or solvate thereof wherein X is
CH; Y is CR.sup.2, wherein R.sup.2 is hydrogen, halo (especially
fluoro) or C.sub.1-4 alkoxy (especially methoxy); V is CR.sup.1
wherein R.sup.1 is as defined above in which Ar is unsubstituted
furan or thiazole; U is indazole; R.sup.3 is benzyl or
fluorobenzyl; and R.sup.4 is not present.
[0110] In a most especially preferred embodiment there is provided
a compound of formula(1) or a salt or solvate thereof wherein X is
CH, Y is CR.sup.2, wherein R.sup.2 is hydrogen, halo (especially
fluoro) or C.sub.1-4 alkoxy (especially methoxy); V is CR.sup.1
wherein R.sup.1 is as defined above in which Ar is unsubstituted
furan or thiazole; U is phenyl; R.sup.3 is phenoxy; and R.sup.4 is
not present.
[0111] Preferred compounds of the present invention include:
[0112]
4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino-
)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0113]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0114]
(4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)m-
ethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0115]
(4-Benzyloxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-
phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0116]
(4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-
-furan-2-yl)-quinazolin-4-yl)-amine;
[0117]
(4-(3-Fluorobenzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino-
)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0118]
(4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-
-thiazol-4-yl)-quinazolin-4-yl)-amine;
[0119]
N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl-
]amino}methyl)-2-furyl]-4-quinazolinamine;
[0120]
N-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenyl}-6-[5-({[2-(methanesulph-
onyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0121]
N-[4-(Benzyloxy)phenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl-
]amino}methyl)-2-furyl]-4-quinazolinamine;
[0122]
N-[4-(Benzyloxy)phenyl]-6-[4-({[2-(methanesulphonyl)ethyl]amino}met-
hyl)-2-furyl]-4-quinazolinamine;
[0123]
N-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenyl}-6-[2-({[2-(methanesulph-
onyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0124]
N-{4-[(3-Bromobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]-
amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0125]
N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl-
]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0126]
N-[4-(Benzyloxy)-3-fluorophenyl]-6-[2-({[2-(methanesulphonyl)ethyl]-
amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0127]
N-(1-Benzyl-1H-indazol-5-yl)-7-methoxy-6-[5-({[2-(methanesulphonyl)-
ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0128]
6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-(4-{[3-(-
trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine;
[0129]
N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulpho-
nyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0130]
N-{4-[(3-Bromobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]-
amino}methyl)-2-furyl]-4-quinazolinamine;
[0131]
N-[4-(Benzyloxy)phenyl]-6-[3-({[2-(methanesulphonyl)ethyl]amino}met-
hyl)-2-furyl]-4-quinazolinamine;
[0132]
N-[1-(3-Fluorobenzyl)-1H-indazol-5-yl]-6-[2-({[2-(methanesulphonyl)-
ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0133]
6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-[4-(benz-
enesulphonyl)phenyl]-4-quinazolinamine;
[0134]
6-[2-({[2-(Methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-N-
-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine;
[0135]
6-[2-({[2-(Methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-N-
-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine
[0136]
N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulpho-
nyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0137]
N-(1-Benzyl-1H-indazol-5-yl)-6-[2-({[2-(methanesulphonyl)ethyl]amin-
o}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0138]
N-(3-Fluoro-4-benzyloxyphenyl)-6-[2-({[2-(methanesulphonyl)ethyl]am-
ino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0139]
N-(3-Chloro-4-benzyloxyphenyl)-6-[2-({[2-(methanesulphonyl)ethyl]am-
ino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0140]
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulpho-
nyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0141]
6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-7-methoxy--
N-(4-benzenesulphonyl)phenyl-4-quinazolinamine;
[0142]
N-[4-(Benzyloxy)phenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]-
amino}methyl)-2-furyl]-4-quinazolinamine;
[0143]
N-(1-Benzyl-1H-indazol-5-yl)-7-fluoro-6-[5-({[2-(methanesulphonyl)e-
thyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0144]
N-[4-(Benzenesulphonyl)phenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl-
)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0145]
N-(3-Trifluoromethyl-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl-
)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine;
[0146] and salts or solvates thereof, particularly pharmaceutically
acceptable salts thereof.
[0147] Other preferred compounds of the present invention
include:
[0148]
(4-Phenoxyphenyl)-(7-(2-(2-methanesulphonyl)ethylaminomethyl)thiazo-
l-4-yl)-quinolin-4-yl)amine;
[0149]
(4-Phenoxyphenyl)-(7-(4-(2-methanesulphonyl)ethylaminomethyl)thiazo-
l-5-yl)-quinolin-4-yl)amine;
[0150]
(4-Phenoxyphenyl)-(7-(5-(2-(methanesulphonyl)ethylaminomethyl)furan-
-2-yl)quinolin-4-yl)amine;
[0151] and salts or solvates thereof, particularly pharmaceutically
acceptable salts thereof.
[0152] Other preferred compounds of the present invention include
the following (in groups denoted hereafter as Lists 1 to 48):
[0153] List 1
[0154]
(4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-fu-
ran-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0155]
(1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)me-
thyl)furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0156]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0157]
(4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)m-
ethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0158]
(4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)--
furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0159]
(4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-fu-
ran-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0160] List 2
[0161]
(1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)me-
thyl)thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0162]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0163]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0164]
(4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)m-
ethyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0165]
(4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0166]
(4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0167] List 3
[0168]
(1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)me-
thyl)thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0169]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0170]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0171]
(4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)m-
ethyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0172]
(4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0173]
(4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0174] List 4
[0175]
(1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)me-
thyl)thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0176]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0177]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0178]
(4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)m-
ethyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0179]
(4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0180]
(4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0181] List 5
[0182]
(1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)me-
thyl)thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0183]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0184]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0185]
(4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)m-
ethyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0186]
(4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0187]
(4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0188] List 6
[0189]
(1-Benzyl-1H-indazol-5-yl)-(6-(3-((2-methanesulphonyl-ethylamino)me-
thyl)phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0190]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0191]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0192]
(4-Benzenesulphonyl-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)m-
ethyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0193]
(4-Phenoxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-p-
henyl)pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0194] List 7
[0195]
(1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)me-
thyl)phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0196]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0197]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0198]
(4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)m-
ethyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0199]
(4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-
phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0200]
(4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-p-
henyl)pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0201] List 8
[0202]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;
[0203]
(4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-fu-
ran-2-yl)-quinazolin-4-yl)-amine;
[0204] List 9
[0205]
(1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)me-
thyl)furan-2-yl)-quinazolin-4-yl)-amine;
[0206]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;
[0207]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;
[0208]
(4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)m-
ethyl)-furan-2-yl)-quinazolin-4-yl)-amine;
[0209]
(4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-fu-
ran-2-yl)-quinazolin-4-yl)-amine;
[0210] List 10
[0211]
(1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)me-
thyl)thiazol-4-yl)-quinazolin-4-yl)-amine;
[0212]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;
[0213]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;
[0214]
(4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-4-yl)-quinazolin-4-yl)-amine;
[0215] List 11
[0216]
(1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)me-
thyl)thiazol-5-yl)-quinazolin-4-yl)-amine;
[0217]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;
[0218]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;
[0219]
(4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)m-
ethyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;
[0220]
(4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-5-yl)-quinazolin-4-yl)-amine;
[0221]
(4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-5-yl)-quinazolin-4-yl)-amine;
[0222] List 12
[0223]
(1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)me-
thyl)thiazol-2-yl)-quinazolin-4-yl)-amine;
[0224]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;
[0225]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;
[0226]
(4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)m-
ethyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;
[0227]
(4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-2-yl)-quinazolin-4-yl)-amine;
[0228]
(4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-quinazolin-4-yl)-amine;
[0229] List 13
[0230]
(1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)me-
thyl)thiazol-2-yl)-quinazolin-4-yl)-amine;
[0231]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;
[0232]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;
[0233]
(4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)m-
ethyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;
[0234]
(4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-2-yl)-quinazolin-4-yl)-amine;
[0235]
(4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-quinazolin-4-yl)-amine;
[0236] List 14
[0237]
(1-Benzyl-1H-indazol-5-yl)-(6-(3-((2-methanesulphonyl-ethylamino)me-
thyl)phenyl)-quinazolin-4-yl)-amine;
[0238]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-quinazolin-4-yl)-amine;
[0239]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-quinazolin-4-yl)-amine;
[0240]
(4-Benzenesulphonyl-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)m-
ethyl)-phenyl)-quinazolin-4-yl)-amine;
[0241]
(4-Benzyloxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-
phenyl)-quinazolin-4-yl)-amine;
[0242]
(4-Phenoxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-p-
henyl)quinazolin-4-yl)-amine;
[0243] List 15
[0244]
(1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)me-
thyl)phenyl)-quinazolin-4-yl)-amine;
[0245]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-quinazolin-4-yl)-amine;
[0246]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-quinazolin-4-yl)-amine;
[0247]
(4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)m-
ethyl)-phenyl)-quinazolin-4-yl)-amine;
[0248]
(4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-
phenyl)-quinazolin-4-yl)-amine;
[0249]
(4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-p-
henyl)quinazolin-4-yl)-amine;
[0250] List 16
[0251]
(4-(4-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;
[0252]
(4-(3-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;
[0253]
(4-Benzenesulphonyl-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)m-
ethyl)-furan-2-yl)-quinazolin-4-yl)-amine;
[0254]
(4-Benzyloxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)--
furan-2-yl)-quinazolin-4-yl)-amine;
[0255]
(4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-fu-
ran-2-yl)-quinazolin-4-yl)-amine;
[0256] List 17
[0257]
(1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)me-
thyl)furan-2-yl)-quinazolin-4-yl)-amine;
[0258]
(4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;
[0259]
(4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;
[0260]
(4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)m-
ethyl)-furan-2-yl)-quinazolin-4-yl)-amine;
[0261] 5
(4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl-
)-furan-2-yl)-quinazolin-4-yl)-amine;
[0262]
(4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-fu-
ran-2-yl)-quinazolin-4-yl)-amine;
[0263] List 18
[0264]
(1-Benzyl-1H-indazol-5-yl)-(7-(2-((2-methanesulphonyl-ethylamino)me-
thyl)thiazol-4-yl)-quinazolin-4-yl)-amine;
[0265]
(4-(4-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;
[0266]
(4-(3-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;
[0267]
(4-Benzenesulphonyl-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)m-
ethyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;
[0268]
(4-Benzyloxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-4-yl)-quinazolin-4-yl)-amine;
[0269]
(4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-4-yl)-quinazolin-4-yl)-amine;
[0270] List 19
[0271]
(1-Benzyl-1H-indazol-5-yl)-(7-(2-((2-methanesulphonyl-ethylamino)me-
thyl)thiazol-5-yl)-quinazolin-4-yl)-amine;
[0272]
(4-(4-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;
[0273]
(4-(3-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;
[0274]
(4-Benzenesulphonyl-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)m-
ethyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;
[0275]
(4-Benzyloxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-5-yl)-quinazolin-4-yl)-amine;
[0276]
(4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-5-yl)-quinazolin-4-yl)-amine;
[0277] List 20
[0278]
(1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)me-
thyl)thiazol-2-yl)-quinazolin-4-yl)-amine;
[0279]
(4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;
[0280]
(4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;
[0281]
(4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)m-
ethyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;
[0282]
(4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-2-yl)-quinazolin-4-yl)-amine;
[0283]
(4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-quinazolin-4-yl)-amine;
[0284] List 21
[0285]
(1-Benzyl-1H-indazol-5-yl)-(7-(5-((2-methanesulphonyl-ethylamino)me-
thyl)thiazol-2-yl)-quinazolin-4-yl)-amine;
[0286]
(4-(4-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;
[0287]
(4-(3-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;
[0288]
(4-Benzenesulphonyl-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)m-
ethyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;
[0289]
(4-Benzyloxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-2-yl)-quinazolin-4-yl)-amine;
[0290]
(4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-quinazolin-4-yl)-amine;
[0291] List 22
[0292]
(1-Benzyl-1H-indazol-5-yl)-(7-(3-((2-methanesulphonyl-ethylamino)me-
thyl)phenyl)-quinazolin-4-yl)-amine;
[0293]
(4-(4-Fluorobenzyloxy)-phenyl)-(7-(3-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-quinazolin-4-yl)-amine;
[0294]
(4-(3-Fluorobenzyloxy)-phenyl)-(7-(3-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-quinazolin-4-yl)-amine;
[0295]
(4-Benzenesulphonyl-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)m-
ethyl)-phenyl)-quinazolin-4-yl)-amine;
[0296]
(4-Benzyloxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-
phenyl)-quinazolin-4-yl)-amine;
[0297]
(4-Phenoxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-p-
henyl)quinazolin-4-yl)-amine;
[0298] List 23
[0299]
(1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)me-
thyl)phenyl)-quinazolin-4-yl)-amine;
[0300]
(4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-quinazolin-4-yl)-amine;
[0301]
(4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-quinazolin-4-yl)-amine;
[0302]
(4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)m-
ethyl)-phenyl)-quinazolin-4-yl)-amine;
[0303]
(4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-
phenyl)-quinazolin-4-yl)-amine;
[0304]
(4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-p-
henyl)quinazolin-4-yl)-amine;
[0305] List 24
[0306]
(1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)me-
thyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0307]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-fu ran-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0308]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-fu ran-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0309]
(4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)--
methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0310]
(4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)--
fu ran-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0311]
(4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-fu-
ran-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0312] List 25
[0313]
(1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)me-
thyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0314]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0315]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-fu ran-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0316]
(4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)--
methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0317]
(4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)--
furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0318]
(4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-fu-
ran-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0319] List 26
[0320]
(1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)me-
thyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0321]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0322]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0323]
(4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)--
methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0324]
(4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0325]
(4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0326] List 27
[0327]
(1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)me-
thyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0328]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0329]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0330]
(4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)--
methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0331]
(4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0332]
(4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0333] List 28
[0334]
(1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)me-
thyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0335]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0336]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0337]
(4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)--
methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0338]
(4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0339]
(4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0340] List 29
[0341]
(1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)me-
thyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0342]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0343]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0344]
(4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)--
methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0345]
(4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0346]
(4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0347] List 30
[0348]
(1-Benzyl-1H-indazol-5-yl)-(6-(3-((2-methanesulphonyl-ethylamino)me-
thyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0349]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0350]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0351]
(4-Benzenesulphonyl-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)--
methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0352]
(4-Benzyloxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-
-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0353]
(4-Phenoxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-p-
henyl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0354] List 31
[0355]
(1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)me-
thyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0356]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0357]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0358]
(4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)--
methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0359]
(4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-
-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0360]
(4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-p-
henyl)-pyrido[3,4-d]pyridin-4-yl)-amine;
[0361] List 32
[0362]
(4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-fu-
ran-2-yl)-quinolin-4-yl)-amine;
[0363]
(4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-fu-
ran-2-yl)-quinolin-4-yl)-amine;
[0364]
(4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-4-yl)-quinolin-4-yl)-amine;
[0365]
(4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-5-yl)-quinolin-4-yl)-amine;
[0366]
(4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-quinolin-4-yl)-amine;
[0367]
(4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-quinolin-4-yl)-amine;
[0368]
(4-Phenoxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-p-
henyl)-quinolin-4-yl)-amine;
[0369]
(4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-p-
henyl)-quinolin-4-yl)-amine;
[0370] List 33
[0371]
(1-Benzyl-1H-indazol-5-yl)-(7-(5-((2-methanesulphonyl-ethylamino)me-
thyl)-furan-2-yl)-quinolin-4-yl)-amine;
[0372]
(4-(4-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-furan-2-yl)-quinolin-4-yl)-amine;
[0373]
(4-(3-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-furan-2-yl)-quinolin-4-yl)-amine;
[0374]
(4-Benzenesulphonyl-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)--
methyl)-furan-2-yl)-quinolin-4-yl)-amine;
[0375]
(4-Benzyloxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)--
furan-2-yl)-quinolin-4-yl)-amine;
[0376]
(4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-fu-
ran-2-yl)-quinolin-4-yl)-amine;
[0377] List 34
[0378]
(1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)me-
thyl)-furan-2-yl)-quinolin-4-yl)-amine;
[0379]
(4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-furan-2-yl)-quinolin-4-yl)-amine;
[0380]
(4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-furan-2-yl)-quinolin-4-yl)-amine;
[0381]
(4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)--
methyl)-furan-2-yl)-quinolin-4-yl)-amine;
[0382]
(4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)--
furan-2-yl)-quinolin-4-yl)-amine;
[0383] (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)
methyl)-furan-2-yl)-quinolin-4-yl)-amine;
[0384] List 35
[0385]
(1-Benzyl-1H-indazol-5-yl)-(7-(2-((2-methanesulphonyl-ethylamino)me-
thyl)-thiazol-4-yl)-quinolin-4-yl)-amine;
[0386]
(4-(4-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;
[0387]
(4-(3-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;
[0388]
(4-Benzenesulphonyl-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)--
methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;
[0389]
(4-Benzyloxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-4-yl)-quinolin-4-yl)-amine;
[0390]
(4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-4-yl)-quinolin-4-yl)-amine;
[0391] List 36
[0392]
(1-Benzyl-1H-indazol-5-yl)-(7-(2-((2-methanesulphonyl-ethylamino)me-
thyl)-thiazol-5-yl)-quinolin-4-yl)-amine;
[0393]
(4-(4-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;
[0394]
(4-(3-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;
[0395]
(4-Benzenesulphonyl-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)--
methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;
[0396]
(4-Benzyloxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-5-yl)-quinolin-4-yl)-amine;
[0397]
(4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-5-yl)-quinolin-4-yl)-amine;
[0398] List 37
[0399]
(1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)me-
thyl)-thiazol-2-yl)-quinolin-4-yl)-amine;
[0400]
(4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;
[0401]
(4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;
[0402]
(4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)--
methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;
[0403]
(4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-2-yl)-quinolin-4-yl)-amine;
[0404]
(4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-quinolin-4-yl)-amine;
[0405] List 38
[0406]
(1-Benzyl-1H-indazol-5-yl)-(7-(5-((2-methanesulphonyl-ethylamino)me-
thyl)-thiazol-2-yl)-quinolin-4-yl)-amine;
[0407]
(4-(4-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;
[0408]
(4-(3-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;
[0409]
(4-Benzenesulphonyl-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)--
methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;
[0410]
(4-Benzyloxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)--
thiazol-2-yl)-quinolin-4-yl)-amine;
[0411]
(4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-quinolin-4-yl)-amine;
[0412] List 39
[0413]
(1-Benzyl-1H-indazol-5-yl)-(7-(3-((2-methanesulphonyl-ethylamino)me-
thyl)-phenyl)-quinolin-4-yl)-amine;
[0414]
(4-(4-Fluorobenzyloxy)-phenyl)-(7-(3-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-quinolin-4-yl)-amine;
[0415]
(4-(3-Fluorobenzyloxy)-phenyl)-(7-(3-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-quinolin-4-yl)-amine;
[0416]
(4-Benzenesulphonyl-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)--
methyl)-phenyl)-quinolin-4-yl)-amine;
[0417]
(4-Benzyloxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-
-phenyl)-quinolin-4-yl)-amine;
[0418]
(4-Phenoxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-p-
henyl)-quinolin-4-yl)-amine;
[0419] List 40
[0420]
(1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)me-
thyl)-phenyl)-quinolin-4-yl)-amine;
[0421]
(4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-quinolin-4-yl)-amine;
[0422]
(4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamin-
o)methyl)-phenyl)-quinolin-4-yl)-amine;
[0423]
(4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)--
methyl)-phenyl)-quinolin-4-yl)-amine;
[0424]
(4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-
-phenyl)-quinolin-4-yl)-amine;
[0425]
(4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-p-
henyl)-quinolin-4-yl)-amine;
[0426] List 41
[0427]
(4-Benzyloxy-3-chlorophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-
methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0428]
(4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(5-((2-methanesulphonyl--
ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0429]
(4-Benzyloxy-3-trifluoromethylphenyl)-(6-(5-((2-methanesulphonyl-et-
hylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0430]
(4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-(6-(5-((2-methanes-
ulphonyl-ethylamino)methyl)-fu
ran-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amin- e;
[0431]
(4-Benzyloxy-3-bromophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)m-
ethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0432]
(4-(3-Fluoro-benzyloxy-3-bromophenyl)-(6-(5-((2-methanesulphonyl-et-
hylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0433]
(4-Benzyloxy-3-iodophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)me-
thyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0434]
(4-(3-Fluoro-benzyloxy-3-iodophenyl)-(6-(5-((2-methanesulphonyl-eth-
ylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0435]
(4-Benzyloxy-3-fluorophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-
methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0436]
(4-(3-Fluoro-benzyloxy-3-fluorophenyl)-(6-(5-((2-methanesulphonyl-e-
thylamino)methyl)-fu
ran-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0437] List 42
[0438]
(4-Benzyloxy-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-
methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0439] 35
(4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(2-((2-methanesulphon-
yl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0440]
(4-Benzyloxy-3-trifluoromethylphenyl)-(6-(2-((2-methanesulphonyl-et-
hylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0441]
(4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-(6-(2-((2-methanes-
ulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-ami-
ne;
[0442]
(4-Benzyloxy-3-bromophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)m-
ethyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0443]
(4-(3-Fluoro-benzyloxy-3-bromophenyl)-(6-(2-((2-methanesulphonyl-et-
hylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0444]
(4-Benzyloxy-3-iodophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)me-
thyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0445]
(4-(3-Fluoro-benzyloxy-3-iodophenyl)-(6-(2-((2-methanesulphonyl-eth-
ylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0446]
(4-Benzyloxy-3-fluorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-
methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0447]
(4-(3-Fluoro-benzyloxy-3-fluorophenyl)-(6-(2-((2-methanesulphonyl-e-
thylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0448] List 43
[0449]
(4-Benzyloxy-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-
methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine
[0450]
(4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(2-((2-methanesulphonyl--
ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;
[0451]
(4-Benzyloxy-3-trifluoromethylphenyl)-(6-(2-((2-methanesulphonyl-et-
hylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;
[0452]
(4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-(6-(2-((2-methanes-
ulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;
[0453]
(4-Benzyloxy-3-bromophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)m-
ethyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;
[0454]
(4-(3-Fluoro-benzyloxy-3-bromophenyl)-(6-(2-((2-methanesulphonyl-et-
hylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;
[0455]
(4-Benzyloxy-3-iodophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)me-
thyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;
[0456]
(4-(3-Fluoro-benzyloxy-3-iodophenyl)-(6-(2-((2-methanesulphonyl-eth-
ylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;
[0457] List 44
[0458]
(4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-(6-(5-((2methanesu-
lphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;
[0459]
(4-Benzyloxy-3-bromophenyl)-(6-(5-((2methanesulphonyl-ethylamino)-m-
ethyl)-furan-2-yl)-quinazolin-4-yl)-amine;
[0460]
(4-(3-Fluoro-benzyloxy-3-bromophenyl)-(6-(5-((2methanesulphonyl-eth-
ylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;
[0461]
(4-Benzyloxy-3-iodophenyl)-(6-(5-((2methanesulphonyl-ethylamino)-me-
thyl)-furan-2-yl)-quinazolin-4-yl)-amine;
[0462]
(4-(3-Fluoro-benzyloxy-3-iodophenyl)-(6-(5-((2methanesulphonyl-ethy-
lamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine.
[0463] List 45
[0464]
N-[4-(Benzyloxy)-3-chlorophenyl]-7-methoxy-6-[5-({[2-(methanesulpho-
nyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0465]
N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-methoxy-6-[5-({[2-(meth-
anesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0466]
N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-methoxy-6-[5-({[2-(methan-
esulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0467]
N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-methoxy-6-[5-(-
{[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0468]
N-[4-Benzyloxy-3-bromophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl-
)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0469]
N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-methoxy-6-[5-({[2-(methan-
esulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0470]
N-[4-Benzyloxy-3-iodophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)-
ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0471]
N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-methoxy-6-[5-({[2-(methane-
sulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0472]
N-[4-Benzyloxy-3-fluorophenyl]-7-methoxy-6-[5-({[2-(methanesulphony-
l)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0473]
N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-methoxy-6-[5-({[2-(metha-
nesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0474]
N-[1-(3-Fluorobenzyl-1H-indazol-5-yl]-7-methoxy-6-[5-({[2-(methanes-
ulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0475] List 46
[0476]
N-[4-(Benzyloxy)-3-chlorophenyl]-7-fluoro-6-[5-({[2-(methanesulphon-
yl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0477]
N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-fluoro-6-[5-({[2-(metha-
nesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine
[0478]
N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-fluoro-6-[5-({[2-(methane-
sulphonyl)ethyl]amino)methyl)-2-furyl]-4-quinazolinamine
[0479]
N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-fluoro-6-[5-({-
[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine
[0480]
N-[4-Benzyloxy-3-bromophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)-
ethyl]amino}methyl)-2-furyl]-4-quinazolinamine
[0481]
N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-fluoro-6-[5-({[2-(methane-
sulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine
[0482]
N-[4-Benzyloxy-3-iodophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)e-
thyl]amino}methyl)-2-furyl]-4-quinazolinamine
[0483]
N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-fluoro-6-[5-({[2-(methanes-
ulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine
[0484]
N-[4-Benzyloxy-3-fluorophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl-
)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine
[0485]
N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-fluoro-6-[5-({[2-(methan-
esulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine
[0486]
N-[1-(3-fluorobenzyl-1H-indazol-5-yl]-7-fluoro-6-[5-({[2-(methanesu-
lphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine
[0487] List 47
[0488]
N-[4-(benzyloxy)-3-chlorophenyl]-7-methoxy-6-[2-({[2-(methanesulpho-
nyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0489]
N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-methoxy-6-[2-({[2-(meth-
anesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0490]
N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-methoxy-6-[2-({[2-(methan-
esulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0491]
N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-methoxy-6-[2-(-
{[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4yl]-4-quinazolinami-
ne;
[0492]
N-[4-Benzyloxy-3-bromophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl-
)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0493]
N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-methoxy-6-[2-({[2-(methan-
esulphonyl)ethyl]amino)methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0494]
N-[4-Benzyloxy-3-iodophenyl]-7-methoxy-6-[2-(([2-(methanesulphonyl)-
ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0495]
N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-methoxy-6-[2-({[2-(methane-
sulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0496]
N-[4-Benzyloxy-3-fluorophenyl]-7-methoxy-6-[2-({[2-(methanesulphony-
l)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0497]
N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-methoxy-6-[2-({[2-(metha-
nesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0498]
N-[1-(3-fluorobenzyl-1H-indazol-5-yl]-7-methoxy-6-[2-({[2-(methanes-
ulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0499] List 48
[0500]
N-[4-(benzyloxy)-3-chlorophenyl]-7-fluoro-6-[2-({[2-(methanesulphon-
yl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0501]
N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-fluoro-6-[2-({[2-(metha-
nesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0502]
N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-fluoro-6-[2-({[2-(methane-
sulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0503]
N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-fluoro-6-[2-({-
[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinami-
ne;
[0504]
N-[4-Benzyloxy-3-bromophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)-
ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0505]
N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-fluoro-6-[2-({[2-(methane-
sulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0506]
N-[4-Benzyloxy-3-iodophenyl]-7-fluoro-6-[2-(([2-(methanesulphonyl)e-
thyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0507]
N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-fluoro-6-[2-({[2-(methanes-
ulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0508]
N-[4-Benzyloxy-3-fluorophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl-
)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0509]
N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-fluoro-6-[2-({[2-(methan-
esulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0510]
N-[1-(3-fluorobenzyl-1H-indazol-5-yl]-7-fluoro-6-[2-({[2-(methanesu-
lphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0511] and salts or solvates thereof, particularly pharmaceutically
acceptable salts or solvates thereof.
[0512] Particularly preferred compounds of the present invention
include:
[0513]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[0514]
(4-Benzyloxyphenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)--
fu ran-2-yl)-quinazolin-4-yl)-amine;
[0515]
N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl-
]amino}methyl)-2-furyl]-4-quinazolinamine;
[0516]
N-[4-(Benzyloxy)phenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl-
]amino}methyl)-2-furyl]-4-quinazolinamine;
[0517]
N-(1-Benzyl-1H-indazol-5-yl)-7-methoxy-6-[5-({[2-(methanesulphonyl)-
ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0518]
N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulpho-
nyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0519]
N-[1-(3-Fluorobenzyl)-1H-indazol-5-yl]-6-[2-({[2-(methanesulphonyl)-
ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0520]
6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-[4-(benz-
enesulphonyl)phenyl]-4-quinazolinamine;
[0521]
N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulpho-
nyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0522]
N-(1-Benzyl-1H-indazol-5-yl)-6-[2-({[2-(methanesulphonyl)ethyl]amin-
o}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;
[0523]
N-(3-Fluoro-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]am-
ino}methyl)-4-furyl]-4-quinazolinamine;
[0524]
N-(3-Chloro-4-benzyloxyphenyl)-6-[2-({[2-(methanesulphonyl)ethyl]am-
ino}methyl)-4-furyl]-4-quinazolinamine;
[0525]
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulpho-
nyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0526]
N-(1-Benzyl-1H-indazol-5-yl)-7-fluoro-6-[5-({[2-(methanesulphonyl)e-
thyl]amino}methyl)-2-furyl]-4-quinazolinamine;
[0527]
N-(3-Trifluoromethyl-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl-
)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine;
[0528] and salts or solvates thereof, particularly pharmaceutically
acceptable salts or solvates thereof.
[0529] Further particularly preferred compounds of the present
invention include:
[0530]
(4-Phenoxyphenyl)-(7-(2-(2-methanesulphonyl)ethylaminomethyl)thiazo-
l-4-yl)-quinolin-4-yl)amine;
[0531]
(4-Phenoxyphenyl)-(7-(4-(2-methanesulphonyl)ethylaminomethyl)thiazo-
l-5-yl)-quinolin-4-yl)amine;
[0532]
(4-Phenoxyphenyl)-(7-(5-(2-(methanesulphonyl)ethylaminomethyl)furan-
-2-yl)-quinolin-4-yl)amine;
[0533] and salts or solvates thereof, particularly pharmaceutically
acceptable salts or solvates thereof.
[0534] Other particularly preferred compounds of the present
invention include:
[0535]
(4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-fu-
ran-2-yl)-quinazolin-4-yl)-amine;
[0536]
(4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-fu-
ran-2-yl)-quinazolin-4-yl)-amine;
[0537]
(4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-4-yl)-quinazolin-4-yl)-amine;
[0538]
(4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-5-yl)-quinazolin-4-yl)-amine;
[0539]
(4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-quinazolin-4-yl)-amine;
[0540]
(4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-quinazolin-4-yl)-amine;
[0541]
(4-Phenoxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-ph-
enyl)-quinazolin-4-yl)-amine;
[0542]
(4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-ph-
enyl)-quinazolin-4-yl)-amine;
[0543]
(4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-fu-
ran-2-yl)-quinolin-4-yl)-amine;
[0544]
(4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-fu-
ran-2-yl)-quinolin-4-yl)-amine;
[0545]
(4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-4-yl)-quinolin-4-yl)-amine;
[0546]
(4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-5-yl)-quinolin-4-yl)-amine;
[0547]
(4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-quinolin-4-yl)-amine;
[0548]
(4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-quinolin-4-yl)-amine;
[0549]
(4-Phenoxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-ph-
enyl)-quinolin-4-yl)-amine;
[0550]
(4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-ph-
enyl)-quinolin-4-yl)-amine;
[0551] and salts or solvates thereof, particularly pharmaceutically
acceptable salts or solvates thereof.
[0552] Other most particularly preferred compounds of the present
invention include:
[0553]
(4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-4-yl)-quinolin-4-yl)-amine;
[0554]
(4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-5-yl)-quinolin-4-yl)-amine;
[0555]
(4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-quinolin-4-yl) amine;
[0556]
(4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-th-
iazol-2-yl)-quinolin-4-yl)-amine;
[0557] and salts or solvates thereof, particularly pharmaceutically
acceptable salts or solvates thereof.
[0558] Certain compounds of formula (I) may exist in stereoisomeric
forms (e.g. they may contain one or more asymmetric carbon atoms or
may exhibit cis-trans isomerism). The individual stereoisomers
(enantiomers and diastereoisomers) and mixtures of these are
included within the scope of the present invention. Likewise, it is
understood that compounds of formula (I) may exist in tautomeric
forms other than that shown in the formula and these are also
included within the scope of the present invention.
[0559] Salts of the compounds of the present invention may comprise
acid addition salts derived from a nitrogen in the compound of
formula (I). The therapeutic activity resides in the moiety derived
from the compound of the invention as defined herein and the
identity of the other component is of less importance although for
therapeutic and prophylactic purposes it is, preferably,
pharmaceutically acceptable to the patient. Examples of
pharmaceutically acceptable acid addition salts include those
derived from mineral acids, such as hydrochloric, hydrobromic,
phosphoric, metaphosphoric, nitric and sulphuric acids, and organic
acids, such as tartaric, acetic, trifluoroacetic, citric, malic,
lactic, fumaric, benzoic, glycolic, gluconic, succinic and
methanesulphonic and arylsulphonic, for example p-toluenesulphonic,
acids.
[0560] According to a further aspect of the present invention there
is provided a process for the preparation of a compound of formula
(I) as defined above which comprises the steps:
[0561] (a) the reaction of a compound of formula (II) 8
[0562] wherein X is as defined above;
[0563] Y' is CL' and V' is N;
[0564] or Y' is N and V' is CL';
[0565] or Y' is CL' and V' is CR.sup.2;
[0566] or Y' is CR.sup.2 and V' is CL';
[0567] wherein R.sup.2 is as defined above, and L and L' are
suitable leaving groups, with a compound of formula (III)
UNH.sub.2 (III)
[0568] wherein U is as defined above, to prepare a compound of
formula (IV) 9
[0569] and subsequently (b) reaction with appropriate reagent(s) to
substitute the group R.sup.1 by replacement of the leaving group
L'; and, if desired, (c) subsequently converting the compound of
formula (I) thereby obtained into another compound of formula (I)
by means of appropriate reagents.
[0570] Alternatively, the compound of formula (II) as defined above
is reacted with the appropriate reagents to substitute the group
R.sup.1 by replacement of the leaving group L' and then the product
thereby obtained (of formula (V) below) is reacted with the
compound of formula (III) as defined above, followed, if desired,
by conversion of the compound of formula (I) thereby obtained into
another compound of formula (I).
[0571] In a variant of this alternative the compound of formula (V)
10
[0572] wherein X, Y, V, U and L are as defined above, may be
prepared by the reaction of a compound of formula (VI) 11
[0573] wherein V' and Y' are as defined above, with appropriate
reagents to substitute the group R.sup.1 for the leaving group L'
to prepare a compound of formula (VII) 12
[0574] and subsequent reaction to incorporate the leaving group L.
For example, a chloro leaving group can be incorporated by reaction
of a corresponding 3,4-dihydropyrimidone with carbon
tetrachloride/triphenylph- osphine in an appropriate solvent.
[0575] The group R.sup.1 may, therefore, be substituted onto the
basic ring system by replacement of a suitable leaving group. This
may, for example, be carried out by reaction of the corresponding
aryl or heteroaryl stannane derivative with the corresponding
compound of formula (IV) carrying the leaving group L' in the
appropriate position on the ring.
[0576] According to a further aspect of the present invention there
is provided a process for the preparation of a compound of formula
(I) as defined above which comprises the steps:
[0577] (a) reacting a compound of formula (IV) as defined above
with appropriate reagent(s) to prepare a compound of formula (VIII)
13
[0578] wherein X and U are as defined above;
[0579] Y" is CT and V" is N;
[0580] or Y" is N and V" is CT;
[0581] or Y" is CT and V" is CR.sup.2;
[0582] or Y" is CR.sup.2 and V" is CT; wherein R.sup.2 is as
defined above and T is an appropriately functionalised group;
[0583] and (b) subsequently converting the group T into the group
R.sup.1 by means of appropriate reagent(s); and, if desired, (c)
subsequently converting the compound of formula (I) thereby
obtained into another compound of formula (I) by means of
appropriate reagents.
[0584] In one alternative, the group T would represent a group Ar
as defined above carrying a formyl group (CHO).
[0585] Where T represents a group Ar carrying a formyl group the
compound (of formula (VIIIa)) may be suitably prepared from the
corresponding dioxolanyl substituted compound (of formula (VIIIb)),
for example by acid hydrolysis. The dioxolanyl substituted compound
may be prepared by reaction of a compound of formula (IV) with an
appropriate reagent to substitute the relevant leaving group with
the substituent carrying the dioxolanyl ring. This reagent could,
for example, be an appropriate heteroaryl stannane derivative.
[0586] Therefore a suitable process may comprise reaction of a
compound of formula (VIIIa) in which T is a group Ar carrying a
formyl substituent (i.e. a --CHO group) with a compound of formula
CH.sub.3SO.sub.2CH.sub.2C- H.sub.2NH.sub.2. The reaction preferably
involves a reductive amination by means of an appropriate reducing
agent, for example sodium triacetoxyborohydride.
[0587] Alternatively, another suitable process may comprise
oxidation of a compound of formula (VIIIc) in which T is a group Ar
carrying a substituent of formula
CH.sub.3SCH.sub.2CH.sub.2NHCH.sub.2 or
CH.sub.3SOCH.sub.2CH.sub.2NHCH.sub.2. Suitable methods for the
oxidation to the desired compound of formula (I) will be well known
to the person skilled in the art but include, for example, reaction
with an organic peroxide, such as peracetic acid or
metachlorobenzoic acid, or reaction with an inorganic oxidising
agent, such as OXONE.RTM.. The compound of formula (VIIIc) in which
T is a group Ar carrying a substituent of formula
CH.sub.3SCH.sub.2CH.sub.2NHCH.sub.2 or CH.sub.3SOCH.sub.2CH.sub.2-
NHCH.sub.2 may be prepared by an analogous reaction to that
described above, namely reaction of a compound of formula (VIIIa)
in which T is a group Ar carrying a formyl substituent (i.e. a
--CHO group) with a compound of formula
CH.sub.3SCH.sub.2CH.sub.2NH.sub.2 or
CH.sub.3SOCH.sub.2CH.sub.2NH.sub.2 respectively.
[0588] Alternatively, an analogous scheme to those described above
could be used wherein the substitution of the group R.sup.1 onto
the basic ring system occurs prior to the coupling reaction with
the compound of formula (III).
[0589] According to a further alternative process the group T is
converted into the group R.sup.1 by a de novo synthesis of a
substituted heterocyclic system using appropriate agents. Such a
process would involve standard synthetic methodology known to the
person skilled in the art for building up the heterocylic ring
system.
[0590] For example, T could represent a haloketone group as shown
in the compound of formula (IX) in scheme 1 below which, when
coupled with an appropriate N-protected thioamide [compound of
formula (XI) in scheme 2], would result in the formation of an
N-protected amino-substituted thiazole system of formula (X).
[0591] Scheme 1 outlines, for example, the synthesis of derivatives
carrying a substituted thiazole ring as an R.sup.1 substituent:
14
[0592] wherein halo is as previously defined (preferably iodo), and
P' in the compound of formula (XI) is a suitable protecting group,
such as trifluorocarbonyl.
[0593] An analogous process may be used to prepare compounds of
formula(I) which carry R.sup.1 in the 7-position of the basic ring
system from a starting compound of formula(IVb) 15
[0594] via intermediates of formulae (Xb) and (XIb) which are
respectively analogous to those of formulae (Xa) and (XIb).
[0595] An appropriately substituted thioamide coupling reagent,
suitable for preparation of a thiazole ring system, may be prepared
according to Scheme 2: 16
[0596] Wherein in scheme 2 the trifluorocarbonyl protecting group
in the compounds of formula (XIV), (XV) and (XVIa) is equivalent to
the group P' in scheme 1.
[0597] Alternatively, an analogous scheme to those described above
could be used wherein the substitution of the group R.sup.1 onto
the basic ring system occurs prior to the coupling reaction with
the compound of formula(III).
[0598] Other substituted thioamides are prepared using analogous
processes to that shown above.
[0599] In general, the group R.sup.2 will be present as a
substituent in the basic ring system prior to the introduction of
the group R.sup.1 or the group NHU. Where R.sup.2 is other than
hydrogen it may in certain circumstances be necessary to protect
the group prior to performing the reaction steps to introduce the
R.sup.1 and NHU substituents. Particular mention should be made of
the situation where R.sup.2 is hydroxy; suitable protecting groups
to ensure non-interference with the subsequent reaction steps
include the 2-methoxyethoxymethyl ether (MEM) group or a bulky
silyl protecting group such as tert-butyldiphenylsilyl (TBDPS).
[0600] Suitable protecting groups, methods for their introduction
and methods for their removal would be well known to the person
skilled in the art. For a description of protecting groups and
their use see T. W. Greene and P. G. M. Wuts, "Protective Groups in
Organic Synthesis", 2nd edn., John Wiley & Sons, New York,
1991.
[0601] Suitable leaving groups for L and L' will be well known to
those skilled in the art and include, for example, halo such as
fluoro, chloro, bromo and iodo; sulphonyloxy groups such as
methanesulphonyloxy and toluene-p-sulphonyloxy; alkoxy groups; and
triflate.
[0602] The coupling reaction referred to above with the compound of
formula (III) is conveniently carried out in the presence of a
suitable inert solvent, for example a C.sub.1-4 alkanol, such as
isopropanol, a halogenated hydrocarbon, an ether, an aromatic
hydrocarbon or a dipolar aprotic solvent such as acetone,
acetonitrile or DMSO at a non-extreme temperature, for example from
0 to 150.degree. C., suitably 10 to 120.degree. C., preferably 50
to 100.degree. C.
[0603] Optionally, the reaction is carried out in the presence of a
base. Examples of suitable bases include an organic amine such as
triethylamine, or an alkaline earth metal carbonate, hydride or
hydroxide, such as sodium or potassium carbonate, hydride or
hydroxide.
[0604] The compound of formula (I) may be obtained from this
process in the form of a salt with the acid HL, wherein L is as
hereinbefore defined, or as the free base by treating the salt with
a base as hereinbefore defined.
[0605] The compounds of formulae (II) and (III) as defined above,
the reagents to substitute the group R.sup.1, and the reagent(s) to
convert the group T into the group R.sup.1 are either readily
available or can be readily synthesised by those skilled in the art
using conventional methods of organic synthesis.
[0606] As indicated above, the compound of formula (I) prepared may
be converted to another compound of formula (I) by chemical
transformation of the appropriate substituent or substituents using
appropriate chemical methods (see for example, J. March "Advanced
Organic Chemistry", Edition III, Wiley Interscience, 1985).
[0607] For example, a compound containing an alkylthio group may be
oxidised to the corresponding sulphinyl or sulphonyl compound by
use of an organic peroxide (e.g. benzoyl peroxide) or suitable
inorganic oxidant (eg OXONE .RTM.).
[0608] A compound containing a nitro substituent may be reduced to
the corresponding amino-compound, e.g. by use of hydrogen and an
appropriate catalyst (if there are no other susceptible groups), by
use of Raney Nickel and hydrazine hydrate or by use of iron/acetic
acid.
[0609] Amino substituents may be acylated by use of an acid
chloride or an anhydride under appropriate conditions. Equally an
amide group may be cleaved to the amino compound by treatment with,
for example, dilute aqueous base.
[0610] An amino substituent may also be converted to a
dimethylamino substituent by reaction with formic acid and sodium
cyanoborohydride. Similarly, reaction of a primary or secondary
amino group with another suitable aldehyde under reducing
conditions will lead to the corresponding substituted amine.
[0611] All of the above-mentioned chemical transformations may also
be used to convert any relevant intermediate compound to another
intermediate compound prior to the final reaction to prepare a
compound of formula (I); this would thus include their use to
convert one compound of formula (III) to a further compound of
formula (III) prior to any subsequent reaction.
[0612] Various intermediate compounds used in the above-mentioned
processes, including but not limited to certain of the compounds of
formulae (II), (III), (IV), (V), (VI), (VII) and (VIII) as
illustrated above, are novel and thus represent a further aspect of
the present invention.
[0613] In particular, a further aspect of the present invention is
intermediate compounds of formulae (VIIIa) and (VIIIb) defined
above, with the exception of the following compounds:
[0614]
(1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-py-
rido[3,4-d]pyrimidin-4-yl)-amine;
[0615]
5-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-f-
uran-2-carbaldehyde;
[0616]
5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-
-carbaldehyde;
[0617] (4-Benzyloxy-phenyl)-(6-(5-[1,3-dioxolan-2-yl]-fu
ran-2-yl)-quinazolin-4-yl)-amine;
[0618]
5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyd-
e;
[0619]
(1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-qu-
inazolin-4-yl)-amine;
[0620] 5-(4-(1-Benzyl-1
H-indazol-5-ylamino)-quinazolin-6-yl)-furan-2-carb- aldehyde;
[0621]
5-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-1-methyl-pyrr-
ole-2-carbaldehyde;
[0622]
(1-Benzyl-1H-indazol-5-yl)-(7-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-qu-
inazolin-4-yl)-amine;
[0623]
5-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl)-furan-2-carba-
ldehyde.
[0624] In particular, a yet further aspect of the present invention
is intermediate compounds of formula (VIIIc) as defined above;
[0625] with the proviso that the following compound is
excluded:
[0626]
(4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphinyl-ethylamino)-methyl)-
-fu ran-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine.
[0627] In particular, another further aspect of the present
invention is intermediate compounds of formulae (X), (XI), (XII),
(XIII), (XIV), (XV) and (XVI) as defined above.
[0628] The compounds of formula (I) and salts thereof have
anticancer activity as demonstrated hereinafter by their inhibition
of the protein tyrosine kinase c-erbB-2, c-erbB-4 and/or EGF-R
enzymes and their effect on selected cell lines whose growth is
dependent on c-erbB-2 or EGF-r tyrosine kinase activity. Certain
compounds of formula (I) are also demonstrated hereinafter to
inhibit lck and/or zap70 protein tyrosine kinase enzymes and are
expected to have activity in disease conditions in which T cells
are hyperactive.
[0629] The present invention thus also provides compounds of
formula (I) and pharmaceutically acceptable salts or solvates
thereof for use in medical therapy, and particularly in the
treatment of disorders mediated by aberrant protein tyrosine kinase
activity such as human malignancies and the other disorders
mentioned above. The compounds of the present invention are
especially useful for the treatment of disorders caused by aberrant
c-erbB-2 and/or EGF-r and/or lck activity such as breast, ovarian,
gastric, pancreatic, non-small cell lung, bladder, head and neck
cancers, psoriasis and rheumatoid arthritis.
[0630] A further aspect of the invention provides a method of
treatment of a human or animal subject suffering from a disorder
mediated by aberrant protein tyrosine kinase activity, including
susceptible malignancies, which comprises administering to said
subject an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt or solvate thereof.
[0631] A further aspect of the present invention provides the use
of a compound of formula (I), or a pharmaceutically acceptable salt
or solvate thereof, in therapy.
[0632] A further aspect of the present invention provides the use
of a compound of formula (I), or a pharmaceutically acceptable salt
or solvate thereof, in the preparation of a medicament for the
treatment of cancer and malignant tumours.
[0633] A further aspect of the present invention provides the use
of a compound of formula (I), or a pharmaceutically acceptable salt
or solvate thereof, in the preparation of a medicament for the
treatment of psoriasis.
[0634] A further aspect of the present invention provides the use
of a compound of formula (I), or a pharmaceutically acceptable salt
or solvate thereof, in the preparation of a medicament for the
treatment of rheumatoid arthritis.
[0635] Whilst it is possible for the compounds, salts or solvates
of the present invention to be administered as the new chemical, it
is preferred to present them in the form of a pharmaceutical
formulation.
[0636] According to a further feature of the present invention
there is provided a pharmaceutical formulation comprising at least
one compound of formula (I), or a pharmaceutically acceptable salt
or solvate thereof, together with one or more pharmaceutically
acceptable carriers, diluents or excipients.
[0637] Pharmaceutical formulations may be presented in unit dose
forms containing a predetermined amount of active ingredient per
unit dose. Such a unit may contain for example 0.5 mg to 1 g,
preferably 70 mg to 700 mg, more preferably 5 mg to 100 mg of a
compound of the formula (I) depending on the condition being
treated, the route of administration and the age, weight and
condition of the patient.
[0638] Pharmaceutical formulations may be adapted for
administration by any appropriate route, for example by the oral
(including buccal or sublingual), rectal, nasal, topical (including
buccal, sublingual or transdermal), vaginal or parenteral
(including subcutaneous, intramuscular, intravenous or intradermal)
route. Such formulations may be prepared by any method known in the
art of pharmacy, for example by bringing into association the
active ingredient with the carrier(s) or excipient(s).
[0639] Pharmaceutical formulations adapted for oral administration
may be presented as discrete units such as capsules or tablets;
powders or granules; solutions or suspensions in aqueous or
non-aqueous liquids; edible foams or whips; or oil-in-water liquid
emulsions or water-in-oil liquid emulsions.
[0640] Pharmaceutical formulations adapted for transdermal
administration may be presented as discrete patches intended to
remain in intimate contact with the epidermis of the recipient for
a prolonged period of time. For example, the active ingredient may
be delivered from the patch by iontophoresis as generally described
in Pharmaceutical Research, 3(6), 318 (1986).
[0641] Pharmaceutical formulations adapted for topical
administration may be formulated as ointments, creams, suspensions,
lotions, powders, solutions, pastes, gels, sprays, aerosols or
oils.
[0642] For treatments of the eye or other external tissues, for
example mouth and skin, the formulations are preferably applied as
a topical ointment or cream. When formulated in an ointment, the
active ingredient may be employed with either a paraffinic or a
water-miscible ointment base. Alternatively, the active ingredient
may be formulated in a cream with an oil-in-water cream base or a
water-in-oil base.
[0643] Pharmaceutical formulations adapted for topical
administrations to the eye include eye drops wherein the active
ingredient is dissolved or suspended in a suitable carrier,
especially an aqueous solvent.
[0644] Pharmaceutical formulations adapted for topical
administration in the mouth include lozenges, pastilles and mouth
washes.
[0645] Pharmaceutical formulations adapted for rectal
administration may be presented as suppositories or as enemas.
[0646] Pharmaceutical formulations adapted for nasal administration
wherein the carrier is a solid include a coarse powder having a
particle size for example in the range 20 to 500 microns which is
administered in the manner in which snuff is taken, i.e. by rapid
inhalation through the nasal passage from a container of the powder
held close up to the nose. Suitable formulations wherein the
carrier is a liquid, for administration as a nasal spray or as
nasal drops, include aqueous or oil solutions of the active
ingredient.
[0647] Pharmaceutical formulations adapted for administration by
inhalation include fine particle dusts or mists which may be
generated by means of various types of metered dose pressurised
aerosols, nebulizers or insufflators.
[0648] Pharmaceutical formulations adapted for vaginal
administration may be presented as pessaries, tampons, creams,
gels, pastes, foams or spray formulations.
[0649] Pharmaceutical formulations adapted for parenteral
administration include aqueous and non-aqueous sterile injection
solutions which may contain anti-oxidants, buffers, bacteriostats
and solutes which render the formulation isotonic with the blood of
the intended recipient; and aqueous and non-aqueous sterile
suspensions which may include suspending agents and thickening
agents. The formulations may be presented in unit-dose or
multi-dose containers, for example sealed ampoules and vials, and
may be stored in a freeze-dried (lyophilized) condition requiring
only the addition of the sterile liquid carrier, for example water
for injections, immediately prior to use. Extemporaneous injection
solutions and suspensions may be prepared from sterile powders,
granules and tablets.
[0650] Preferred unit dosage formulations are those containing a
daily dose or sub-dose, as herein above recited, or an appropriate
fraction thereof, of an active ingredient.
[0651] It should be understood that in addition to the ingredients
particularly mentioned above, the formulations may include other
agents conventional in the art having regard to the type of
formulation in question, for example those suitable for oral
administration may include flavouring agents.
[0652] The animal requiring treatment with a compound, salt or
solvate of the present invention is usually a mammal, such as a
human being.
[0653] A therapeutically effective amount of a compound, salt or
solvate of the present invention will depend upon a number of
factors including, for example, the age and weight of the animal,
the precise condition requiring treatment and its severity, the
nature of the formulation, and the route of administration, and
will ultimately be at the discretion of the attendant physician or
veterinarian However, an effective amount of a compound of the
present invention for the treatment of neoplastic growth, for
example colon or breast carcinoma, will generally be in the range
of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and
more usually in the range of 1 to 10 mg/kg body weight per day.
Thus, for a 70 kg adult mammal, the actual amount per day would
usually be from 70 to 700 mg and this amount may be given in a
single dose per day or more usually in a number (such as two,
three, four, five or six) of sub-doses per day such that the total
daily dose is the same. An effective amount of a salt or solvate of
the present invention may be determined as a proportion of the
effective amount of the compound per se. It is envisaged that
similar dosages would be appropriate for treatment of the other
conditions referred to above.
[0654] The compounds of the present invention and their salts and
solvates may be employed alone or in combination with other
therapeutic agents for the treatment of the above-mentioned
conditions. In particular, in anti-cancer therapy, combination with
other chemotherapeutic, hormonal or antibody agents is envisaged.
Combination therapies according to the present invention thus
comprise the administration of at least one compound of formula (I)
or a pharmaceutically acceptable salt or solvate thereof and at
least one other pharmaceutically active agent. The compound(s) of
formula (I) and the other pharmaceutically active agent(s) may be
administered together or separately and, when administered
separately this may occur simultaneously or sequentially in any
order. The amounts of the compound(s) of formula (I) and the other
pharmaceutically active agent(s) and the relative timings of
administration will be selected in order to achieve the desired
combined therapeutic effect.
[0655] Certain embodiments of the present invention will now be
illustrated by way of example only. The physical data given for the
compounds exemplified is consistent with the assigned structure of
those compounds.
[0656] .sup.1H NMR spectra were obtained at 500 MHz on a Bruker
AMX500 spectrophotometer, on a Bruker spectrophotometer at 300 MHz,
on a Bruker AC250 or Bruker AM250 spectrophotometer at 250 MHz and
on a Varian Unity Plus NMR spectrophotometer at 300 or 400 MHz. J
values are given in Hz. Mass spectra were obtained on one of the
following machines: VG Micromass Platform (electrospray positive or
negative), HP5989A Engine (thermospray positive) or Finnigan-MAT
LCQ (ion trap) mass spectrometer. Analytical thin layer
chromatography (tic) was used to verify the purity of some
intermediates which could not be isolated or which were too
unstable for full characterisation, and to follow the progess of
reactions. Unless otherwise stated, this was done using silica gel
(Merck Silica Gel 60 F254). Unless otherwise stated, column
chromatography for the purification of some compounds used Merck
Silica gel 60 (Art. 1.09385, 230-400 mesh), and the stated solvent
system under pressure.
[0657] Petrol refers to petroleum ether, either the fraction
boiling at 40-60.degree. C., or at 60-80.degree. C.
[0658] Ether refers to diethylether.
[0659] DMSO refers to dimethylsulphoxide.
[0660] THF refers to tetrahydrofuran.
[0661] HPLC refers to high pressure liquid chromatography.
[0662] NMM refers to N-methylmorpholine
[0663] Useful preparative techniques are described in WO96/09294,
WO97/03069, WO97/13771, WO95/19774, WO96/40142 and WO97/30034; also
described in these publications are appropriate intermediate
compounds other than those detailed below.
[0664] Preparation processes specified in the prior art or in the
experimental details below for compounds with a particular basic
ring system (1) to (6) above may be suitably adapted for others of
these basic ring systems.
[0665] General Procedures
[0666] (A) Reaction of an Amine with a Bicyclic Species Containing
a 4-chloropyrimidine or 4-chloropyridine Ring
[0667] The optionally substituted bicyclic species and the
specified amine were mixed in an appropriate solvent (typically
acetonitrile unless otherwise specified, although ethanol,
2-propanol or DMSO may also be used), and heated to reflux. When
the reaction was complete (as judged by tic), the reaction mixture
was allowed to cool. The resulting suspension was diluted, e.g.
with acetone, and the solid collected by filtration, washing e.g.
with excess acetone, and dried at 60.degree. C. in vacuo, giving
the product as the hydrochloride salt. If the free base was
required (e.g. for further reaction), this was obtained by
treatment with a base e.g. triethylamine; purification by
chromatography was then performed if required.
[0668] (B) Reaction of a Product from Procedure (A) with a
Heteroaryl Tin Reagent
[0669] A stirred mixture of the product from Procedure (A),
(containing a suitable leaving group such as chloro, bromo, iodo or
triflate), a heteroaryl stannane and a suitable palladium catalyst,
such as bis(triphenylphosphine)palladium (II) chloride or
1,4-bis(diphenylphosphi- no)butane palladium (II) chloride
(prepared as described in C. E. Housecroft et. al., Inorg. Chem.,
(1991), 30(1), 125-130), together with other appropriate additives
(such as diisopropylethylamine or lithium chloride), were heated at
reflux in dry dioxane or another suitable solvent (e.g. DMF) under
nitrogen until the reaction was complete. The resulting mixture was
generally purified by chromatography on silica.
[0670] (C) Removal of a 1,3-dioxolan-2-yl Protecting Group to
Liberate an Aldehyde
[0671] The compound containing the 1,3-dioxolan-2-yl group was
suspended in an appropriate solvent, e.g. THF and treated with
hydrochloric acid, either as an aqueous solution (e.g. 2N) or as a
solution in dioxane (e.g. 4 molar) and stirred at ambient
temperature until the reaction was judged complete (e.g. by tic or
LC/MS analysis). Generally the mixture was diluted with water, and
the resulting precipitate was collected by filtration, washed with
water and dried to give the aldehyde.
[0672] (D) Reaction of an Aldehyde with an Amine by Reductive
Amination
[0673] An aldehyde (such as the product of General Procedure C) and
the required primary or secondary amine were stirred together in a
suitable solvent (such as dichloromethane) containing glacial
acetic acid (4A molecular sieves may also be present) for ca. 1 h.
A suitable reducing agent, such as sodium (triacetoxy) borohydride
was then added and stirring continued under nitrogen until the
reaction was complete (as judged by hplc or tic). The resulting
mixture was washed with an aqueous basic solution (e.g. sodium or
potassium carbonate) and extracted with a suitable solvent, e.g.
dichloromethane. The dried organic phase was evaporated and the
residue purified either by column chromatography or by Bond
Elut.TM. cartridge. If desired, the isolated material was then
converted into the hydrochloride salt e.g. by treatment with
ethereal hydrogen chloride.
[0674] (E) Reaction Sequence to Prepare Appropriately Substituted
Thioamides E-1 Reaction of an Aminosulfide with
Chloroacetonitrile
[0675] To a stirred mixture of an aminosulfide and a suitable base
such as sodium bicarbonate or sodium carbonate in an appropriate
solvent (typically acetonitrile, although DMF or dioxane can be
used) was added chloroacetonitrile dropwise. The resulting mixture
was heated to reflux until the reaction was complete. The solid was
filtered and the filtrate was concentrated to provide the
corresponding aminonitrile.
[0676] E-2 Trifluoroacetamide Protection of an Aminonitrile
[0677] A solution of the aminonitrile (such as the product of
general procedure A) and an amine base, such as triethylamine or
NMM in a suitable solvent (e.g. dichloromethane), was cooled to
0.degree. C. and trifluoroacetic anhydride was added dropwise. The
resulting mixture was stirred at room temperature until the
reaction was complete. Water was added and the mixture was
extracted with a suitable solvent (e.g. dichloromethane), the
organic layer was dried over anhydrous magnesium sulfate and
concentrated. The crude product was purified by column
chromatography to provide the corresponding trifluoroacetamide.
[0678] E-3 Oxidation of a Cyanosulfide
[0679] To a stirred solution of a sulfide (such as the product of
general procedure El) in a suitable solvent (typically
methanol/water (2:1), although dichloromethane can be used) cooled
to 0.degree. C. was added an oxidizing agent (typically oxone,
although MCPBA can be used). The resulting mixture was stirred at
room temperature until the reaction was complete. The reaction was
concentrated to remove any organic solvents, diluted with water,
and extracted with an appropriate solvent (e.g. dichloromethane).
The organic layer was dried and concentrated to provide the
corresponding cyanosulfone.
[0680] E-4 Preparation of Thioamides
[0681] To a solution of a cyanosulfone (such as the product of
general procedure E-3) and an organic base (e.g. triethylamine) in
THF was added hydrogen sulfide gas. The resulting mixture was
stirred at room temperature until the reaction was complete. The
mixture was concentrated and triturated with hexane to provide
thioamide.
[0682] (F) Reaction Sequence to Prepare an Optionally Substituted
Thiazole
[0683] F-1 Reaction of a Vinyistannane with a Product from
Procedure (A)
[0684] A stirred mixture of the optionally substituted bicyclic
4-anilinopyrimidine species, tributyl(1-ethoxyvinyl)stannane (1 to
5 molar equivalents), and a suitable palladium catalyst (0.03 to
0.1 molar equivalents), such as bis(triphenylphosphine) palladium
(II) chloride or tetrakis(triphenylphosphine) palladium (0) was
heated at reflux in an appropriate solvent (typically acetonitrile,
although DMF or dioxane can be used) until the reaction was
complete. The resulting mixture was concentrated and generally
purified by trituration with diethyl ether to provide the
corresponding bicyclic pyrimidine vinyl ether.
[0685] F-2 Reaction of a Product from Procedure (F-1) with a
Bromination Reagent
[0686] A bicyclic pyrimidine vinyl ether (such as the product of
general procedure F-1) and 1 equivalent of a bromination reagent,
such as N-bromosuccinimide or bromine, were stirred at 0.degree. C.
in a suitable solvent (typically 10% aqueous THF or
dichloromethane) until the reaction was complete. The resulting
mixture was dried over anhydrous magnesium sulfate and
concentrated, or in the case of bromine the solid was filtered, to
provide the corresponding .alpha.-bromoketone.
[0687] F-3 Reaction of a Product from Procedure (F-2) with a
Product from Procedure (E-4)
[0688] A stirred mixture of an .alpha.-bromoketone (such as the
product of general procedure F-2) and thioamide from Procedure E-4
in a 1:1 molar ratio was heated to 70-100.degree. C. in an
appropriate solvent (typically DMF, although acetonitrile and THF
can be used) until the reaction was complete. The resulting mixture
was washed with an aqueous basic solution (e.g. sodium carbonate)
and extracted with a suitable solvent, e.g. ethyl acetate. The
dried organic layer was concentrated and the residue was purified
by column chromatography to provide the corresponding
trifluoroacetamide aminothiazole.
[0689] F-4 Removal of a Trifluoroacetamide Protecting Group to
Liberate an Aminothiazole
[0690] A mixture of a trifluoroacetamide protected aminothiazole
(such as the product of general procedure F-3) in 2M NaOH/methanol
(1:1) was stirred at room temperature until the reaction was
complete. The mixture was concentrated, poured into water and
extracted with an appropriate solvent e.g. 10%
MeOH/dichloromethane. The dried organic layer was concentrated,
then dissolved in ethyl acetate/MeOH (1:1) and treated with 4M
HCl/dioxane. The resulting solid was filtered to provide the
corresponding amine hydrochloride salt.
[0691] Synthesis of Intermediates
[0692] N-5-[N-tert-Butoxycarbonyl)amino]-2-chloropyridine
[0693] A stirred solution of 6-chloronicotinic acid (47.3 g),
diphenylphosphoryl azide (89.6 g) and triethylamine (46 ml) in
t-butanol (240 ml) were heated under reflux under nitrogen for 2.5
hours. The solution was cooled and concentrated in vacuo. The
syrupy residue was poured into 3 litres of a rapidly stirred
solution of 0.33N aqueous sodium carbonate. The precipitate was
stirred for one hour and filtered. The solid was washed with water
and dried in vacuo at 70.degree. C. to give the title compound (62
g) as a pale brown solid; m.p. 144-146.degree. C.; .delta.H
[.sup.2H.sub.6]-DMSO 8.25(1H, d), 7.95 (1H, bd), 7.25 (1H, d),
6.65(1H, bs), 1.51 (9H,s); m/z (M+1).sup.+229.
[0694] This material may subsequently be carried forward to the
appropriately substituted pyridopyrimidine intermediate according
to the procedures as described in WO95/19774, J. Med. Chem., 1996,
39, pp 1823-1835, and J. Chem. Soc., Perkin Trans. 1,1996, pp
2221-2226. Specific compounds made by such procedures include
6-chloro-pyrido[3,4-d]pyrimidin-4-one and
4,6-dichloro-pyrido[3,4-d]pyrim- idine.
[0695] 2-Amino-4-fluoro-5-iodo-benzoic Acid
[0696] To a vigorously stirred solution of dichloromethane (700
ml), methanol (320 ml), and 2-amino-4-fluoro-benzoic acid (33.35
grams, 215 mmoles) was added solid sodium hydrogencarbonate (110
grams, 1.31 moles) followed by portion addition of benzyltrimethyl
ammonium dichloroiodate (82.5 grams, 237 mmoles). The mixture was
allowed to stir for 48 hours. The mixture was filtered to remove
the insolubles. The remaining solid residue was washed with 200 ml
of dichloromethane. The filtrate was concentrated and redissolved
in a one to one mixture of ethyl acetate (1 litre) and a 0.2 N
solution of sodium hydroxide (1 litre), added-to a 2 litre
separatory funnel and extracted. The organic layer was washed with
an additional 200 ml of water. The aqueous layers were combined and
acidified with 2N hydrochloric acid. The resulting precipitate was
collected by suction filtration, washed with water and dried under
vacuum at 60.degree. C. to yield 46.5 grams (77%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.04(d, 1H),
7.1 (s, broad, 2H), 6.63(d, 1H). ESI-MS m/z 280 (M-1).
[0697] 4-Fluoro-5-iodo-isatoic Anhydride
[0698] Anhydrous dioxane (0.5 litres),
2-amino-4-fluoro-5-iodo-benzoic acid (46 grams, 164 mmoles), and
trichloromethylchloroformate (97.4 grams, 492 mmoles) were added to
a one litre one neck flask equipped with a magnetic stir bar and
reflux condenser. The solution was placed under anhydrous nitrogen,
stirred and heated to reflux for 16 hours. The reaction mixture was
allowed to cool and was poured into one litre of hexanes. The solid
was collected by suction filtration, washed with an additional 0.5
litres of hexanes, and dried under vacuum at room temperature to
yield 45.5 grams (90%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 11.86(s, 1H), 8.24(d, 1H), 6.84(d, 1H).
ESI-MS m/z 308 (M+1).
[0699] 4-Chloro-6-bromoquinazoline and 4-Chloro-6-iodoquinazoline
were Prepared as Described in WO 96/09294.
[0700] 4-Hydroxy-6-iodo-7-fluoroquinazoline
[0701] Dimethylformamide (0.5 litres), 4-fluoro-5-iodo-isatoic
anhydride (45 grams, 147 mmoles), and formamidine acetate (45.92
grams, 441 mmoles), were combined in a one litre one-neck flask
fitted with a magnetic stir bar. The mixture was placed under
anhydrous nitrogen and heated at 110.degree. C. for 6 hours. The
mixture was allowed to cool, followed by concentrating the reaction
mixture to one third its original volume on the rotary evaporator.
The resulting mixture was poured onto 3 litres of ice water. The
resulting precipitated solid was collected by suction filtration.
The solid was washed with an additional one litre of distilled
water. The resulting solid was dried under vacuum at 70.degree. C.
to yield 38.9 grams (91%) of the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.: 12.43(s, 1H), 8.46(d, 1H), 8.12(s, 1H),
7.49(d, 1H). ESI-MS m/z 291(M+1).
[0702] 4-Chloro-6-iodo-7-fluoro-quinazoline Hydrochloride
[0703] Thionyl chloride (0.6 litres),
4-hydroxy-6-iodo-7-fluoro-quinazolin- e (36 grams, 124 mmoles), and
dimethylformamide (6 ml) were combined in a one litre one-neck
flask fitted with a magnetic stir bar. The mixture was placed under
anhydrous nitrogen and heated to a gentle reflux for 24 hours. The
mixture was allowed to cool, followed by concentrating the reaction
mixture to a thick yellowish residue. To this residue was added
dichloromethane (0.1 litre) and toluene (0.1 litre). The mixture
was concentrated to dryness. This procedure was repeated two
additional times. To the resulting solid was added 0.5 litres of
dry dichloromethane and the mixture was stirred for one hour. The
mixture was filtered and the remaining solids were washed with
minimal dichloromethane. The dichoromethane filtrates were
combined, concentrated to a solid, and dried under vacuum at room
temperature to yield 28.6 grams (67%) of the title compound.
.sup.1H NMR (400 MHz, CDCl.sub.3-d.sub.1) .delta.: 9.03(s, 1H),
8.76(d, 1H), 7.69(d, 1H). ESI-MS m/z 309(M+1).
[0704] 2-Bromo-4-(1,3-dioxolan-2-yl) Thiazole
[0705] 2-Bromothiazole-4-carbaldehyde (6.56 g, 34.17 mmol) [A. T.
Ung, S. G. Pyne/Tetrahedron: Asymmetry 9 (1998) 1395-1407]and
ethylene glycol (5.72 ml, 102.5 mmol) were heated under reflux in
toluene (50 ml),with a Dean and Stark trap fitted, for 18 hr. The
product was concentrated and purified by column chromatography (15%
ethyl acetate/hexane) to give the product as a yellow solid (6.03
g); m/z 236,238.
[0706] 4-(1,3-Dioxolan-2-yl)-5-(tributylstannyl)Thiazole
[0707] 2-Bromo-4-(1,3-dioxolan-2-yl) thiazole (6.4 g, 27.14 mmol)
was stirred at -780 C in dry THF (38 ml).1.6M n butyl lithium in
hexane (18.6 ml, 29.78 mmol) was added dropwise under nitrogen.
After 30 min at this temperature, tributyl tin chloride (7.35 ml,
27.14 mmol) was added dropwise. The reaction was allowed to warm to
0.degree. and water (20 ml) was added. The product was extracted
into ether (3.times.100 ml). The combined organic extracts were
dried (MgSO.sub.4) and evaporated. The residue was triturated with
isohexane (3.times.100 ml) and the mother liquors were decanted,
combined and concentrated to give a brown oil (11.88 g); m/z
444-450.
[0708] 1-N-Benzyl-5-nitro-1H-indazole and
2-N-Benzyl-5-nitro-1H-indazole
[0709] A stirred mixture of 5-nitroindazole (50 g), potassium
carbonate (46.6 g, 1.1 equiv.) and benzyl bromide (57.6 g, 1.1
equiv) in N,N-dimethylformamide (500 ml) was heated at 75.degree.
C. for a period of 4 hours. The reaction was then cooled and water
(500 ml) was gradually added to precipitate the product which was
filtered off and washed with water (50 ml) and dried in the air at
ambient temperature. The weight of pale yellow solid thus obtained
was 72.3 g (93%), m.p. 95-97.degree. C.; HPLC (Partisil 5,
dichloromethane, 4 ml/min, 250 nm) gave an isomer ratio
(1-N-benzyl: 2-N-benzyl) of 63:37 (RT-1N 3.4 min, RT-2N 6.6 min).
To a filtered solution of the mixed regioisomers (100 g) in acetone
(470 ml) at room temperature was added, gradually with stirring,
water (156 ml) and the mixture was stirred for one hour. The
resultant yellow crystalline solid was filtered off and dried in
the air at ambient temperature to give 36.4 g (34%) of material;
m.p.124-126.degree. C.; HPLC showed an isomer ratio (1-N-benzyl
2-N-benzyl) of 96:4; .quadrature..quadrature. (CDCl.sub.3) 5.58
(2H,s,CH.sub.2), 7.12-7.15(2H) & 7.22-7.29(3H)-(phenyl), 7.33
(1H,dt, J=1 Hz & 9 Hz, H-7), 8.15(1H,dd, J=2 Hz & 9
Hz,H-6), 8.19(1H,d,J=1 Hz,H-3), 8.67 (1H,dd,J=1 Hz & 2 Hz,
H-4).
[0710] Also note the published method in FR 5600, Jan. 8, 1968.
[0711] 5-Amino-1-N-benzyl-1H-indazole
[0712] 1-Benzyl-5-nitroindazole (400 g) was suspended in ethanol (5
litre) and hydrogenated in the presence of 5% platinum on carbon
catalyst (20 g) operating at 1 bar pressure and 50-60.degree. C.
When hydrogen uptake was complete the reactor contents were heated
to 70.degree. C., discharged and filtered while still hot and the
filtrate concentrated to .about.4 litre which caused some
crystallisation. Water (4 litre) was then gradually added with
stirring and the mixture was stirred at 5.degree. C. overnight. The
resultant crystals were filtered off and air-dried at ambient
temperature to give 305 g (86%) of material, m.p.150-152.degree.
C.; HPLC (Supelcosil ABZ+, gradient 0.05% trifluoroacetic acid in
water/0.05% trifluoroacetic acid in acetonitrile, 1.5 ml/min, 220
nm) showed <1% of the corresponding 2-N-isomer (RT-1 N 6.03 min,
RT-2N 5.29 min); .quadrature..quadrature. (CDCl.sub.3)
3.3-3.8(2H,broad s,NH.sub.2), 5.47 (2H,s,CH.sub.2), 6.74 (1H,dd,J=2
Hz & 9 Hz,H-6), 6.87 (1H,dd,J=1 Hz & 2 Hz,H-4),
7.06-7.11(3H) & 7.17-7.25 (3H)-(phenyl & H-7), 7.77
(1H,d,J=1 Hz,H-3).
[0713] Also note the published method in FR 5600, Jan. 8, 1968.
[0714] 1-Benzyl-3-methyl-5-nitro-1H-indazole
[0715] 2-Fluoro-5-nitroacetophenone (H. Sato et al, Bioorganic and
Medicinal Chemistry Letters, 5(3), 233-236,1995) (0.24 g) was
treated with triethylamine (0.73 ml)and benzyl hydrazine
dihydrochloride (0.255 g) in ethanol (20 ml) at reflux under
N.sub.2 for 8 days. The mixture was cooled and the solid
1-benzyl-3-methyl-5-nitroindazole (0.16 g) was collected by
filtration; m/z (M+1).sup.+268.
[0716] 1-Benzyl-3-methyl-1H-indazol-5-ylamine
[0717] 1-Benzyl-3-methyl-5-nitroindazole (0.15 g) in THF (15 ml)
was treated with platinum on carbon (0.05 g, 5%) under an
atmosphere of hydrogen at room temperature. When hydrogen uptake
was complete, the mixture was filtered and concentrated in vacuo to
give the title compound; m/z (M+1).sup.+268.
[0718] Further Amino-Indazole Intermediates
[0719] The relevant nitro-substituted 1H-indazole was treated with
a base such as potassium carbonate or sodium hydroxide in a
suitable solvent, such as acetone or acetonitrile. The appropriate
aryl halide or heteroaryl halide was added and the reaction mixture
heated or stirred at room temperature overnight. Subsequent
concentration in vacuo and chromatography on silica gave the
desired 1-substituted nitro-1H-indazoles. Hydrogenation was carried
out by analogy with the preparation of 5-amino-1-benzyl-1H-indole
described above.
[0720] Amines prepared by such methods include:
[0721] 5-Amino-1-benzyl-1H-indazole; m/z (M+1).sup.+224
[0722] 5-Amino-1-(2-fluorobenzyl)-1H-indazole; m/z
(M+1).sup.+242
[0723] 5-Amino-1-(3-fluorobenzyl)-1H-indazole; m/z
(M+1).sup.+242
[0724] 5-Amino-1-(4-fluorobenzyl)-1H-indazole; m/z
(M+1).sup.+242
[0725] 5-Amino-1-(2-pyridylmethyl)-1H-indazole; m/z
(M+1).sup.+225
[0726] 5-Amino-1-(3-pyridylmethyl)-1H-indazole; m/z
(M+1).sup.+225
[0727] 5-Amino-1-(4-pyridylmethyl)-1H-indazole; m/z
(M+1).sup.+225
[0728] 5-Amino-1-(2,3-difluorobenzyl)-1H-indazole; m/z
(M+1).sup.+260
[0729] 5-Amino-1-(3,5-difluorobenzyl)-1H-indazole; m/z
(M+1).sup.+260.
[0730] 1-Benzenesulphonylindol-5-yl-amine was Prepared According to
the Published Method (J. Org. Chem., 55,1379-90, (1990)).
[0731] 4-Benzyloxyaniline is commercially available as the
hydrochloride salt; this is treated with aqueous sodium carbonate
solution, and the mixture extracted with ethyl acetate; the organic
solution is dried (MgSO.sub.4) and concentrated to give the free
base as a brown solid, used without further purification.
[0732] Other substituted anilines were in general prepared by
analogous methods to those outlined in WO 96/09294 and/or as
follows:
[0733] Step 1: Preparation of the Precursor Nitro-Compounds
[0734] 4-Nitrophenol (or an appropriate substituted analogue, such
as 3-chloro-4-nitrophenol) was treated with a base such as
potassium carbonate or sodium hydroxide in an appropriate solvent,
such as acetone or acetonitrile. The appropriate aryl or heteroaryl
halide was added and the reaction mixture heated or stirred at room
temperature overnight.
[0735] Purification A: Most of the acetonitrile was removed in
vacuo, and the residue was partitioned between water and
dichloromethane. The aqueous layer was extracted with further
dichloromethane (.times.2), and the combined dichloromethane layers
were concentrated in vacuo.
[0736] Purification B: removal of insoluble material by filtration,
followed by concentration of the reaction mixture in vacuo, and
chromatography on silica.
[0737] Step 2: Reduction to the Corresponding Aniline
[0738] The precursor nitro compound was reduced by catalytic
hydrogenation at atmospheric pressure using 5% Pt/carbon, in a
suitable solvent (eg ethanol, THF, or mixtures thereof to promote
solubility). When reduction was complete, the mixture was filtered
through Harborlite.TM., washing with excess solvent, and the
resulting solution concentrated in vacuo to give the desired
aniline. In some cases, the anilines were acidified with HCl (e.g.
in a solution in dioxane) to give the corresponding hydrochloride
salt.
[0739] Anilines prepared by such methods include:
[0740] 4-(2-Fluorobenzyloxy)aniline; m/z (M+1).sup.+218
[0741] 4-(3-Fluorobenzyloxy)aniline; m/z (M+1).sup.+218
[0742] 4-(4-Fluorobenzyloxy)aniline; m/z (M+1).sup.+218
[0743] 3-Chloro-4-(2-fluorobenzyloxy)aniline; m/z
(M+1).sup.+252
[0744] 3-Chloro-4-(3-fluorobenzyloxy)aniline; m/z
(M+1).sup.+252
[0745] 3-Chloro-4-(4-fluorobenzyloxy)aniline; m/z
(M+1).sup.+252
[0746] 4-Benzyloxy-3-chloroaniline; m/z (M+1).sup.+234
[0747] and, in appropriate cases, their hydrochloride salts.
4-Benzenesulphonylaniline was prepared by the published method
(Helv. Chim. Acta., 1983, 66(4), p1046.
[0748] 4-Benzyloxy-3-trifluoromethyl-nitrobenzene
[0749] 60% NaH dispersion (1.4 g, 33.5 mmol) in mineral oil was
washed with hexanes and then suspended in DMF (10 ml). To this NaH
suspension in DMF, added benzyl alcohol (2.8 ml, 26.3 mmol) with
water bath to keep the temperature below 30.degree. C. The reaction
mixture was stirred until the evolution of the hydrogen gas ceased.
To a solution of 2-fluoro-5-nitrobenzotrifluoride (5.0 g, 23.9
mmol) in DMF (20 ml) was added the benzyl alkoxide solution slowly
at 0.degree. C. Upon the completion of the addition, the ice bath
was removed and the reaction mixture was stirred at room
temperature for 2 hours. The reaction mixture was poured into 200
ml ice water, stirred until the yellow solid was formed. Filtered
and the solid was washed with water and then trituated with
pentane. 5.9 g yellow solid was collected (yield: 83%). ESI-MS m/z
298 (M+H).sup.+
[0750] 4-Benzyloxy-3-trifluoromethyl-aniline
[0751] Raney Ni suspension (about 200 mg Ni) was stirred with
methanol. The supernate was decanted. This was repeated twice and
then fresh methanol was added. To this suspension of Ni in
methanol, was added 2-O-benzyl-5-nitrotrifluoride (375 mg, 1.26
mmol). With the water bath to keep the temperature below 30
.degree. C., the hydrazine hydrate (189 mg, 3.79 mmol) was slowly
added. Upon the completion of addition, the reaction mixture was
stirred at room temperature for 10 minutes and then 45.degree. C.
until evolution of nitrogen gas ceased. Filtered through
Celite.RTM. and the filtrate was concentrated under reduced
pressure. 336 mg thick yellow syrup was obtained (yield: 100%).
ESI-MS m/z 268 (M+H).sup.+.
[0752] 4-(Tributylstannyl)thiazole-2-carbaldehyde
[0753] 4-Bromo-2-(tributylstannyl)thiazole (T. R. Kelly and F.
Lang, Tetrahedron Lett., 36, 9293, (1995)) (15.0 g) was dissolved
in THF (150 ml) under a nitrogen atmosphere, cooled to
-85.quadrature.C and treated with t-BuLi (1.7M, in pentane, 43 ml).
The mixture was stirred at -85.quadrature.C for 30 min, and then
N-formylmorpholine (8.4 g) was added by syringe. After further
stirring at -85.quadrature.C for 10 min the mixture was allowed to
warm to room temperature. Water (200 ml) was added and the mixture
was extracted with diethyl ether (4.times.100 ml). The combined
ethereal extracts were washed with water, dried (NaSO.sub.4), and
concentrated in vacuo. Chromatography on silica, eluting with
10%ether/i-hexane, gave the title compound as a yellow oil;
.quadrature..quadrature.[.sup.2H.sub.6]DMSO 10.03 (1H,s), 8.29
(1H,s), 1.55(6H,q), 1.21-1.37 (6H,m), 1.09-1.20 (6H,m), 0.85
(9H,t).
[0754]
(1-Benzyl-1H-indazol-5-yl)-(6-chloropyrido[3,4-d]pyrimidin-4-yl)-am-
ine Hydrochloride
[0755] Prepared according to Procedure A from
1-benzyl-1H-indazol-5-ylamin- e and
4,6-dichloropyrido[3,4-d]pyrimidine; .delta.H [.sup.2H.sub.6]-DMSO
9.08 (1H,s), 8.92 (1H,s), 8.82 (1H,s), 8.23 (1H,d), 8.19 (1H,s),
7.80 (1H,d), 7.70 (1H,dd), 7.38-7.22 (5H,m), 5.69 (2H,s); m/z
(M+1).sup.+387.
[0756]
(1-Benzyl-1H-indazol-5-yl)-(6-(5-[1.3-dioxolan-2-yl]-furan-2-yl)-py-
rido[3,4-d]-pyrimidin-4-yl)-amine
[0757]
(1-Benzyl-1H-indazol-5-yl)-(6-chloropyrido[3,4-d]pyrimidin-4-yl)-am-
ine (4.28 g), 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (J.
Chem Soc., Chem. Commun., (1988), p560) (10 g) and
1,4-bis(diphenylphosphino)b- utane palladium (II) chloride (1 g)
were heated at reflux in dioxane (150 ml) for 24 hr (Procedure B).
The solvent was removed in vacuo and the residue chromatographed on
silica. Subsequent trituration gave the title compound as a yellow
solid; .quadrature..quadrature.[.sup.2H.sub.6]-DMSO 10.46 (1H, s),
9.17 (1H, s), 8.74 (1H, s), 8.52 (1H, s), 8.23 (1H, s), 8.18 (1H,
s), 7.80-7.68 (2H, m), 7.41-7.22 (5H, m), 7.17 (1H, d), 6.80 (1H,
d), 6.06 (1H, s), 5.71 (2H, s), 4.20-3.96 (4H, m).
[0758]
5-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-f-
uran-2-carbaldehyde
[0759]
(1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolanyl]-furan-2-yl)-pyrid-
o[3,4-d]pyrimidin-4-yl)-amine (3.03 g) and 2N HCl (50 ml) were
stirred in THF (50 ml) for 16 hr. The resulting precipitate was
filtered and washed with water to give the hydrochloride salt of
the product; .delta.H [.sup.2H.sub.6]DMSO 11.70 (1H,s), 9.74 (1H,s)
9.30 (1H,s), 9.27 (1H,s), 8.85 (1H,s), 8.23 (1H,s), 8.18 (1H,s),
7.68-7.87 (3H,m), 7.55 (1H,d), 7.22-7.38 (5H,m), 5.71 (2H,s).
Subsequent neutralisation with triethylamine in ethanol/water gave
the title compound; .delta.H [.sup.2H.sub.6]-DMSO 9.64(1H,s), 9.19
(1H,s), 9.09(1H,s), 8.72(1H,s), 8.12(2H,m), 7.71 (2H,m),
7.63(1H,dd), 7.43(1H,d), 7.20(5H,m), 5.62(2H,s).
[0760]
(4-Benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine
[0761] Prepared according to Procedure A from 4-benzyloxyaniline
and 4,6-dichloro-pyrido[3,4-d]pyrimidine; .quadrature..quadrature.
(CDCl.sub.3) 9.11 (1H,s), 8.78 (1H,s), 7.75 (1H,d), 7.56 (2H,dd),
7.40 (5H,m), 7.15 (2H,d), 5.10 (2H,s); m/z (M+1).sup.+409.
[0762]
5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-
-carbaldehyde
[0763]
(4-Benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine
(4.0 g, 11.0 mmol), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan
(J. Chem. Soc., Chem. Commun., (1988), 560) (6.0 g, 14.0 mmol) were
reacted together in a procedure analogous to Procedure B above for
20 hrs. The reaction mixture was allowed to cool, 1N HCl (50 ml)
added and stirred at room temperature for 15 minutes. The reaction
was filtered and the residue washed with dioxane (20 ml) and 2N HCl
(20 ml). The combined filtrate and washings were stirred at room
temperature for a further hour. The dioxane was removed under
vacuum, the reaction diluted with water and the solid which
precipitated was collected by filtration, and washed with water,
iso-hexane and acetone. This precipitate was converted to the free
base by partitioning into a mixture of triethylamine, ethyl acetate
and water. The organic phase was washed with water, dried
(magnesium sulphate) and the solvent removed under vacuum. The
residue was triturated with iso-hexane/ethyl acetate to give the
product (2.41 g, 52%) as a yellow solid; .quadrature..quadrature.
[.sup.2H.sub.6]-DMSO 10.60 (1H, b, NH), 9.83 (1H, s, CHO), 9.30
(1H, s, 2-H), 9.08 (1H, s, 5-H or 8-H), 8.76 (1H, s, 5-H or 8-H),
7.89 (1H, d, furan-H), 7.82 (2H, d, 2'-H, 6'-H), 7.65-7.42 (6H, m,
5.times.Ph-H, furan-H), 7.21 (2H, d, 3'-H, 5'-H), 5.26 (2H, s,
OCH.sub.2); m/z (M+1).sup.+423.
[0764]
(4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-pyrido[3,-
4-d]pyrimidin-4-yl)-amine
[0765] Reaction of
(4-benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-- yl)amine
(5.44 g, 15.0 mmol), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)fur-
an (10.4 g, 24.2 mmol) and bis(triphenylphosphine)palladium (II)
chloride (catalytic amount) in dioxane (150 ml) according to
Procedure B, followed by purification by silica gel chromatography
(eluted with 50-100% EtOAc/i-hexane), allowed the isolation of the
dioxolane product (3.45 g, 7.40 mmol, 49%);
.quadrature..quadrature. [.sup.2H.sub.6]DMSO 10.28 (1H,s), 9.13
(1H,s), 8.69 (1H,s), 8.61 (1H,s), 7.71 (2H,d), 7.31-7.52 (5H,m),
7.14 (1H,d), 7.09 (2H,d), 6.77 (1H,d), 6.03 (1H,s), 5.15 (2H,s),
3.95-4.19 (4H,m).
[0766] This could then be converted to
5-(4-(4-Benzyloxy-phenylamino)-pyri-
do[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde (identical to that
described above) using Procedure C.
[0767] (4-Phenoxyphenyl)-(7-iodoquinolin-4-yl)amine
[0768] 4-Chloro-7-iodoquinoline (10 g, 34 mmol) [Semenov, V. P.;
Studenikov, A. N. Synthesis of 7-iodo-4-aminoquinoline derivatives.
Khim. Geterotsikl. Soedin. (1980), Issue 7, 972-5] and
4-phenoxyaniline (6.38 g, 34 mmol) in butanol (75 ml) were heated
at gentle reflux (120.degree. C.) overnight (18 hrs). On cooling
the resultant precipitate was collected by filtration and washed
with acetonitrile (2.times.50 ml). The resultant solid was
suspended in chloroform (500 ml) and 2N sodium carbonate solution
(300 ml) and heated at 75.degree. C. for 45 mins. On cooling the
resultant precipitate was collected by filtration, washed with
water (2.times.50 ml) and dried to yield the product as a pale
brown solid. (9.95 g, 66%) .delta.H [.sup.2H.sub.6] DMSO
8.35(3H,m), 8.20(1H,s), 8.10(1H,d), 7.85(1H,s), 7.35(4H,m),
7.15(4H,d), 6.75(1H,d).
[0769] (4-Benzyloxyphenyl)-(6-bromoquinazolin-4-yl)-amine
Hydrochloride
[0770] 4-Chloro-6-bromoquinazoline (0.25 g, 1.0 mmol) and
4-benzyloxyaniline (0.25 g, 1.3 mmol) were mixed in 2-propanol (6
ml) and heated at reflux for 10 mins (Procedure A). The solution
was allowed to cool at room temperature and the 2-propanol removed
in vacuo. The resulting solid was triturated with acetone to give
the product as a yellow solid (0.39 g, 88%); .delta.H
[.sup.2H.sub.6]-DMSO 11.60 (1H, b, NH), 9.21 (1H, s, 5-H), 8.86
(1H, s, 2-H), 8.20 (1H, d, 7-H), 7.90 (1H, d, 8-H), 7.65 (2H, d,
2'-H, 6'-H), 7.50-7.25 (5H, m, Ph-H), 7.10 (2H, d, 3'-H, 5'-H),
5.15 (2H, s, CH.sub.2); m/z 405/407 (M+).
[0771] (4-Benzyloxyphenyl)-(6-iodoquinazolin-4-yl)-amine
Hydrochloride
[0772] 4-Chloro-6-iodoquinazoline (8 g) was treated with
4-benzyloxyaniline (5.5 g) in acetonitrile (500 ml) at reflux under
N.sub.2 for 18 hours. Subsequent cooling and filtration gave the
title compound (13.13 g); .delta.H [.sup.2H.sub.6]-DMSO 11.45 (1H,
b, NH), 9.22 (1H, s, 5-H), 8.89 (1H, s, 2-H), 8.36 (1H, d, 7-H),
7.69 (1H, d, 8-H), 7.63 (2H, d, 2'-H, 6'-H), 7.52-7.29 (5H, m,
Ph-H), 7.14 (2H, d, 3'-H, 5'-H), 5.18 (2H, s, CH.sub.2); m/z
(M+1)+454.
[0773] (4-Benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine
Hydrochloride
[0774] Prepared according to Procedure A from
4-chloro-6-iodo-7-fluoro-qui- nazoline hydrochloride (4.02 grams,
11.65 mmoles), anhydrous dioxane (70 ml), dichloromethane (20 ml)
and 4-benzyloxyaniline hydrochloride (2.83 grams, 12 mmoles). The
mixture was stirred and heated to 110.degree. C. (oil bath
temperature) for 16 hours. The mixture was cooled to room
temperature and filtered to remove the precipitated solids. The
solids were washed with cold anhydrous dioxane (100 ml) followed by
cold anhydrous diethyl ether. The yellowish solid was collected and
dried under vacuum at room temperature to yield 4.68 grams (79%) of
the title compound. .delta.H (400 MHz, DMSO-d.sub.6): 11.2(s, 1H),
9.3(d, 1H), 8.79(s, 1H), 7.64(d, 1H), 7.58(d, 2H), 7.44(d, 2H),
7.38(m, 2H), 7.31 (m, 1H), 7.09(d, 2H), 5.14(s, 2H) ESI-MS m/z
472(M+1).
[0775]
(1-Benzyl-1H-indazol-5-yl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine
Hydrochloride
[0776] Prepared according to Procedure A from
1-benzyl-1H-indazol-5-ylamin- e and
4-chloro-6-iodo-7-fluoroquinazoline. .delta.H (400 MHz,
DMSO-d.sub.6): 11.55(s, 1H), 9.41 (d, 1H), 8.8(s, 1H), 8.18(s, 1H),
8.05(d, 1H), 7.78(d, 1H), 7.69(d, 1H), 7.61 (m, 1H), 7.29(m, 2H),
7.23(m, 3H), 5.67(s, 2H). ESI-MS m/z 496(M+1).
[0777]
(4-Benzenesulphonyl)phenyl-(6-iodo-7-fluoro-quinazolin-4-yl)-amine
Hydrochloride
[0778] Prepared according to Procedure A from
4-(benzenesulphonyl)phenylam- ine and
4-chloro-6-iodo-7-fluoroquinazoline. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 10.89(s, 1H), 9.3(d, 1H), 8.79(s, 1H),
8.07(d, 2H), 8.0(d, 2H), 7.94(d, 2H), 7.67(m, 2H), 7.61 (m, 2H).
ESI-MS m/z 504(M-1).
[0779]
6-Iodo-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-quinazolin-4yl)amine
[0780] Prepared according to Procedure A from
(4-(3-fluorobenzyloxy)-3-chl- orophenyl)amine and
4-chloro-6-iodo-quinazoline. .sup.1H NMR (DMSO-d.sub.6) 9.83 (s,
1H); 8.92 (s, 1H); 8.58 (s, 1H); 8.09 (d, 1H); 8.00 (d, 1H); 7.61
(d, 1H); 7.52 (d, 1H); 7.44 (m, 1H); 7.20-7.33 (m, 3H); 7.15 (m,
1H); 5.21 (s, 2H); MS m/z 506 (M+1).
[0781]
6-Iodo-(4-(3-fluorobenzyloxy)-3-fluorophenyl)-quinazolin-4yl)amine
[0782] Prepared according to Procedure A from
(4-(3-fluorobenzyloxy)-3-flu- orophenyl)amine and
4-chloro-6-iodo-quinazoline. .sup.1H NMR (DMSO-d.sub.6) 9.83 (s,
1H); 8.92 (s, 1H); 8.57 (s, 1H); 8.08 (d, 1H); 7.85 (d, 1H); 7.53
(d, 1H); 7.50 (d, 1H); 7.43 (m, 1H); 7.30-7.20 (m, 3H); 7.15 (m,
1H); 5.20 (s, 2H); MS m/z 490 (M+1).
[0783]
6-Iodo-(4-(3-fluorobenzyloxy)-3-methoxyphenyl)-quinazolin-4yl)Amine
[0784] Prepared according to Procedure A from
(4-(3-fluorobenzyloxy)-3-met- hoxyphenyl)amine and
4-chloro-6-iodo-quinazoline. .sup.1H NMR 400 MHz (DMSO-d.sub.6)
11.29 (bs, 1H0; 9.14 (s, 1H); 8.87 (s, 1H); 8.32 (d, 1H); 7.62 (d,
1H); 7.42 (m, 1H); 7.34 (d, 1H); 7.29-7.22 (m, 3H); 7.18-7.08 (m,
2H); 5.15 (s, 2H); 3.80 (s, 3H); MS m/z 502 (M+1)
[0785]
6-Iodo-(4-benzyloxy-3-fluorophenyl)-quinazolin-4-yl)Amine
[0786] Prepared according to Procedure A from
4-benzyloxy)-3-fluorophenyla- mine and 4-chloro-6-iodo-quinazoline.
.sup.1H NMR (DMSO-d.sub.6) 9.82 (s, 1H); 8.93 (s, 1H); 8.57 (s,
1H); 8.09 (d, 1H); 7.84 (d, 1H); 7.51 (m, 2H); 7.44 (d, 2H); 7.37
(m, 2H); 7.33 (m, 1H); 7.24 (m, 1H); 5.18 (s, 2H); MS m/z 472
(M+1)
[0787]
6-Iodo-(4-(3-bromobenzyloxy)-phenyl)-quinazolin-4-yl)Amine
[0788] Prepared according to Procedure A from
(4-(3-bromobenzyloxy)-phenyl- )amine and
4-chloro-6-iodo-quinazoline. .sup.1H NMR (DMSO-d.sub.6) 9.84 (s,
1H); 8.98 (s, 1H); 8.57 (s, 1H); 8.13 (m, 2H); 7.71 (d, 2H); 7.56
(d, 2H); 7.50 (m, 1H); 7.41 (m, 1H); 7.08 (d, 2H); 5.17 (s,
2H).
[0789]
6-Iodo-(4-(3-fluorobenzyloxy)-phenyl)-quinazolin-4-yl)Amine
[0790] Prepared according to Procedure A from
(4-(3-fluorobenzyloxy)-pheny- l)amine and
4-chloro-6-iodo-quinazoline. .sup.1H NMR (DMSO-d.sub.6) 9.77 (s,
1H); 8.92 (s, 1H); 8.50 (s, 1H); 8.06 (d, 1H); 7.66 (d, 2H); 7.50
(d, 1H); 7.42 (m, 1H); 7.30-7.25 (m, 2H); 7.14 (m, 1H); 7.03 (d,
2H); 5.13 (s, 2H); MS m/z 472 (M+1)
[0791]
6-Iodo-(4-(3-trifluoromethylbenzyloxy)-phenyl)-quinazolin-4-yl)Amin-
e
[0792] Prepared according to Procedure A from
(4-(3-trifluoromethylbenzylo- xy)-phenyl)amine and
4-chloro-6-iodo-quinazoline. .sup.1H NMR (DMSO-d.sub.6) 9.2 (bs,
1H); 8.91 (s, 1H); 8.37 (d, 1H); 7.89-7.72 (m, 8H); 7.19 (d, 2H);
5.30 (s, 2H).
[0793]
6-Iodo-(4-benzyloxy-3-trifluoromethyl-phenyl)-quinazolin-4-yl)Amine
[0794] The mixture of 4-chloro-6-iodo-quinazoline (366 mg, 1.26
mmol) and 4-O-benzyl-3-trifluoroaniline (405 mg, 1.26 mmol) in
isopropanol (12 ml) was heated to reflux for 3.5 hours. Filtered,
washed with isopropanol and dried. 535 mg yellow solid was
afforded. (yield: 76%). ESI-MS m/z 522 (M+H).sup.+.
[0795]
(4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro--
quinazolin-4-yl)-amine
[0796] Synthesized according to Procedure B from a solution of
(4-benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine
hydrochloride (508 mg, 1 mmole),
5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (645 mg, 1.5 mmole),
diisopropylethyl amine (650 mg, 5 mmole), and
dichlorobis(triphenylphosphine) palladium (140 mg, 0.2 mmole) in 6
ml of DMF under nitrogen was stirred at 100.degree. C. (oil bath
temperature) for 4 hours. The cooled reaction mixture was extracted
with water (100 ml) and ethyl acetate (100 ml). The organic phase
was washed with brine (100 ml). The aqueous layers were combined
and washed with additional ethyl acetate (100 ml). The organic
layers were combined, dried with MgSO.sub.4, filtered and
concentrated to a residue. The residue was chromatographed on
silica gel with a methanol-chloroform mixture. Fractions were
collected, combined, and concentrated. The resultant solid was
suspended in dichloromethane (10 ml) and diethyl ether was added
facilitate precipitation. The solid was filtered and dried under
vacuum at room temperature to yield a yellowish solid 287 mg (59%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 10.1(s, 1H), 8.85(d,
1H), 8.45(s, 1H), 7.6(m, 3H), 7.44(d, 2H), 7.38(m, 2H), 7.31 (m,
1H), 7.03(m, 2H), 6.94(m, 1H), 6.74(d, 1H), 6.01(s, 1H), 5.1(s,
2H), 4.10(m, 2H), 3.96(m, 2H). ESI-MS m/z 482(M-1).
[0797]
(1-Benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7--
fluoro-quinazolin-4-yl)-amine
[0798] Prepared according to Procedure B from
(1-benzyl-1H-indazol-5-yl)-(-
6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride and
5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan. .delta..sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.27(s, 1H), 8.89(d, 1H), 8.46(s,
1H), 8.1(d, 2H), 7.69(d, 1H), 7.61(m, 2H), 7.26(m, 5H), 6.96(m,
1H), 6.74(d, 1H), 6.01 (s, 1H), 5.65(s, 2H), 4.09(m, 2H), 3.96(m,
2H). ESI-MS m/z 506(M-1).
[0799] (4-Benzenesulphonyl)phenyl-(6-(5-(1,3-dioxolan-2-yl)-fu
ran-2-yl)-7-fluoro-quinazolin-4-yl)-amine
[0800] Prepared according to Procedure B from
(4-benzenesulphonyl)phenyl-(-
6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride and
5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan. .delta..sup.1H NMR
(400 MHz, DMSO-d.sub.6) 10.49(s, 1H), 8.88(d, 1H), 8.63(s, 1H), 8.1
(d, 2H), 7.95(m, 4H), 7.65(m, 4H), 6.97(m, 1H), 6.75(d, 1H), 6.01
(s, 1H), 4.09(m, 2H), 3.97(m, 2H). ESI-MS m/z 516(M-1).
[0801]
(4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazoli-
n-4-yl)-amine
[0802] Prepared according to Procedure B from
(4-benzyloxy-phenyl)-(6-brom- oquinazolin-4-yl)-amine (1.5 g, 3.7
mmol) and 5-(1,3-dioxolan-2-yl)-2-(tri- butylstannyl)-furan (1.9 g,
4.42 mmol) dissolved in dioxan (30 ml) and heated at reflux under
nitrogen for 6 hr. The solvent was removed from the cooled reaction
under vacuum, and the residual oil was triturated with
iso-hexane/ethyl acetate to give the product (1.07 g, 62%) as a
pale yellow solid; .delta.H [.sup.2H.sub.6]-DMSO 9.96 (1H, b, NH),
8.80 (1H, s, 5-H), 8.51 (1H, s, 2-H), 8.18 (1H, d, 7-H), 7.80 (1H,
d, 8-H), 7.70 (2H, d, 2'-H, 6'-H), 7.58-7.30 (5H, m, 5.times.Ph-H),
7.10 (3H, m, 3'-H, 5'-H, furan 3-H), 6.78 (1H, d, furan 4-H), 6.12
(1H, s, CH0.sub.2), 5.18 (2H, s, PhCH.sub.2), 4.22-3.94 (4H, m,
2.times.CH.sub.2); m/z 466 (M+1).sup.+.
[0803]
(4-Benzyloxy-3-trifluoromethylphenyl)-(6-(5-(1,3-dioxolan-2-yl)-fur-
an-2-yl)-quinazolin-4-yl)-amine
[0804] Prepared according to Procedure B using
6-Iodo-(4-benzyloxy-3-trifl-
uoromethyl-phenyl)-quinazolin-4-yl)amine (480 mg, 0.92 mmol), and
5-tributyltin-(1,3-dioxolan-2-yl)-furan (731 mg, 1.38 mmol) in
dioxane (10 ml). The resulting product was a yellow solid (0.47 g,
95.8% yield). ESI-MS m/z 534 (M+H).sup.+.
[0805]
5-(4-(4-Benzyloxy-3-trifluoromethylphenylamino)-quinazolin-6-yl)-fu-
ran-2-carbaldehyde
[0806] Prepared according to Procedure C using
(4-Benzyloxy-3-trifluoromet-
hylphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine
(470 mg, 0.88 mmol) solution in THF (5 ml) followed by the addition
of 2N HCl (20 ml) at room temperature. The resulting mixture was
stirred for 30 minutes. Water was added (15 ml) then filtered. The
yellow solid was washed with water and small amount of ether and
dried in vacuo (0.39 g, 84% yield). ESI-MS m/z 490 (M+H).sup.+.
[0807]
(4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-
-quinazolin-4-yl)-amine
[0808] Prepared according to Procedure B from a solution of
(4-benzyloxyphenyl)-7-methoxy-6-trifluoromethanesulphonyl-quinazolin-4-yl-
)-amine (0.30 g, 0.59 mmol),
5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)fura- n (0.37 g, 0.86
mmol), lithium chloride (78 mg, 1.8 mmol), and
dichloro-bis(triphenylphosphine)palladium (90 mg, 0.13 mmol) in 2
ml of DMF under nitrogen was stirred at 85-90.degree. C. for 50
minutes. The cooled reaction mixture was partitioned between 30 ml
of water and 40 ml of ethyl acetate. The organic solution was
washed with 30 ml of brine, dried with Na.sub.2SO.sub.4 and
concentrated in vacuo. The residue was chromatographed on silica
gel with hexanes/ethyl acetate (1:1 to 0:1). The resulting solution
was concentrated to near dryness and the resulting solid suspended
in ether and filtered to give 0.232 g of product as a pale yellow
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 9.90(s, 1H),
8.71 (s, 1H), 8.40(s, 1H), 7.60(d, 2H), 7.44(d, 2H), 7.37(t, 2H),
7.30(t, 1H), 7.24(s, 1H), 7.00(m, 3H), 6.67(d, 1H), 5.99(s, 1H),
5.09(s, 2H), 4.10(m, 2H), 4.02(s, 3H), 3.95(m, 2H). ESI-MS m/z
496(M+1).
[0809]
(4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro--
quinazolin-4-yl)-amine
[0810] Prepared according to Procedure B from a solution of
(4-benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine
hydrochloride (508 mg, 1 mmole),
5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (645 mg, 1.5 mmole),
diisopropylethyl amine (650 mg, 5 mmole), and
dichlorobis(triphenylphosphine) palladium (140 mg, 0.2 mmole) in 6
ml of DMF under nitrogen was stirred at 100.degree. C. (oil bath
temperature) for 4 hours. The cooled reaction mixture was extracted
with water (100 ml) and ethyl acetate (100 ml). The organic phase
was washed with brine (100 ml). The aqueous layers were combined
and washed with additional ethyl acetate (100 ml). The organic
layers were combined, dried with MgSO.sub.4, filtered and
concentrated to a residue. The residue was chromatographed on
silica gel with a methanol-chloroform mixture. Fractions were
collected, combined, and concentrated. The resultant solid was
suspended in dichloromethane (10 ml) and diethyl ether was added to
facilitate precipitation. The solid was filtered and dried under
vacuum at room temperature to yield a yellow solid 287 mg (59%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 10.1 (s, 1H), 8.85 (d,
1H), 8.45 (s, 1H), 7.6 (m, 3H), 7.44 (d, 2H), 7.38 (m, 2H), 7.31
(m, 1H), 7.03 (m, 2H), 6.94 (m, 1H), 6.74 (d, 1H), 6.01 (s, 1H),
5.1 (s, 2H), 4.10 (m, 2H), 3.96 (m, 2H). ESI-MS m/z 482(M-1).
[0811] (4-Benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine
Hydrochloride
[0812] Prepared according to Procedure A from
4-chloro-6-iodo-7-fluoro-qui- nazoline hydrochloride (4.02 grams,
11.65 mmoles), anhydrous dioxane (70 ml), dichloromethane (20 ml),
and 4-benzyloxyaniline hydrochloride (2.83 grams, 12 mmoles). The
mixture was stirred and heated to 110.degree. C. (oil bath
temperature) for 16 hours, cooled to room temperature and filtered
to remove the precipitated solids. The solids were washed with cold
anhydrous dioxane (100 ml) followed by cold anhydrous diethyl
ether. The yellowish solid was collected and dried under vacuum at
room temperature to yield 4.68 grams (79%) of the title compound.
.delta.H NMR (400 MHz, DMSO-d.sub.6): 11.2(s, 1H), 9.3(d, 1H),
8.79(s, 1H), 7.64(d, 1H), 7.58(d, 2H), 7.44(d, 2H), 7.38(m, 2H),
7.31 (m, 1H), 7.09(d, 2H), 5.14(s, 2H) ESI-MS m/z 472(M+1).
[0813]
(1-Benzyl-1H-indazol-5-yl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine
Hydrochloride
[0814] Prepared according to Procedure A from
1-benzyl-1H-indazol-5-ylamin- e and
4-chloro-6-iodo-7-fluoroquinazoline. 8H NMR (400 MHz,
DMSO-d.sub.6): 11.55(s, 1H), 9.41 (d, 1H), 8.8(s, 1H), 8.18(s, 1H),
8.05(d, 1H), 7.78(d, 1H), 7.69(d, 1H), 7.61 (m, 1H), 7.29(m, 2H),
7.23(m, 3H), 5.67(s, 2H). ESI-MS m/z 496(M+1).
[0815]
(4-Benzenesulphonyl)phenyl-(6-iodo-7-fluoro-quinazolin-4-yl)-amine
Hydrochloride
[0816] Prepared according to Procedure A from
4-benzenesulphonyl)phenylami- ne and
4-chloro-6-iodo-7-fluoroquinazoline. .delta.HNMR (400 MHz,
DMSO-d.sub.6) .delta.: 10.89(s, 1H), 9.3(d, 1H), 8.79(s, 1H),
8.07(d, 2H), 8.0(d, 2H), 7.94(d, 2H), 7.67(m, 2H), 7.61 (m, 2H).
ESI-MS m/z 504(M-1).
[0817]
6-Iodo-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-quinazolin-4yl)Amine
[0818] Prepared according to Procedure A from
4-(3-fluorobenzyloxy)-3-chlo- rophenyl)-amine and
4-chloro-6-iodoquinazoline. .sup.1H NMR (DMSO-d.sub.6) 9.83 (s,
1H); 8.92 (s, 1H); 8.58 (s, 1H); 8.09 (d, 1H); 8.00 (d, 1H); 7.61
(d, 1H); 7.52 (d, 1H); 7.44 (m, 1H); 7.20-7.33 (m, 3H); 7.15 (m,
1H); 5.21 (s, 2H); MS m/z 506 (M+1)
[0819]
6-Iodo-(4-(3-fluorobenzyloxy)-3-fluorophenyl)-quinazolin-4yl)Amine
[0820] Prepared according to Procedure A from
(4-(3-fluorobenzyloxy)-3-flu- orophenyl)-amine and
4-chloro-6-iodoquinazoline. .sup.1H NMR (DMSO-d.sub.6) 9.83 (s,
1H); 8.92 (s, 1H); 8.57 (s, 1H); 8.08 (d, 1H); 7.85 (d, 1H); 7.53
(d, 1H); 7.50 (d, 1H); 7.43 (m, 1H); 7.30-7.20 (m, 3H); 7.15 (m,
1H); 5.20 (s, 2H); MS m/z 490 (M+1)
[0821]
6-Iodo-(4-(3-fluorobenzyloxy)-3-methoxyphenyl)-quinazolin-4yl)Amine
[0822] Prepared according to Procedure A from
(4-(3-fluorobenzyloxy)-3-flu- orophenyl)-amine and
4-chloro-6-iodoquinazoline. .sup.1H NMR 400 MHz (DMSO-d.sub.6)
11.29 (bs, 1H0; 9.14 (s, 1H); 8.87 (s, 1H); 8.32 (d, 1H); 7.62 (d,
1H); 7.42 (m, 1H); 7.34 (d, 1H); 7.29-7.22 (m, 3H); 7.18-7.08 (m,
2H); 5.15 (s, 2H); 3.80 (s, 3H); MS m/z 502 (M+1)
[0823]
6-Iodo-(4-benzyloxy-3-fluorophenyl)-quinazolin-4-yl)Amine
[0824] Prepared according to Procedure A from
(4-benzyloxy-3-fluorophenyl)- -amine and
4-chloro-6-iodoquinazoline. .sup.1H NMR (DMSO-d.sub.6) 9.82 (s,
1H); 8.93 (s, 1H); 8.57 (s, 1H); 8.09 (d, 1H); 7.84 (d, 1H); 7.51
(m, 2H); 7.44 (d, 2H); 7.37 (m, 2H); 7.33 (m, 1H); 7.24 (m, 1H);
5.18 (s, 2H), MS m/z 472 (M+1)
[0825]
6-Iodo-(4-(3-bromobenzyloxy)-phenyl)-quinazolin-4-yl)Amine
[0826] Prepared according to Procedure A from
(4-(3-bromobenzyloxy)-phenyl- )-amine and
4-chloro-6-iodoquinazoline. .sup.1H NMR (DMSO-d.sub.6) 9.84 (s,
1H); 8.98 (s, 1H); 8.57 (s, 1H); 8.13 (m, 2H); 7.71 (d, 2H); 7.56
(d, 2H); 7.50 (m, 1H); 7.41 (m, 1H); 7.08 (d, 2H); 5.17 (s,
2H).
[0827]
6-Iodo-(4-(3-fluorobenzyloxy)-phenyl)-quinazolin-4-yl)Amine
[0828] Prepared according to Procedure A from
(4-(3-fluorobenzyloxy)-pheny- l)-amine and
4-chloro-6-iodoquinazoline. .sup.1H NMR (DMSO-d.sub.6) 9.77 (s,
1H); 8.92 (s, 1H); 8.50 (s, 1H); 8.06 (d, 1H); 7.66 (d, 2H); 7.50
(d, 1H); 7.42 (m, 1H); 7.30-7.25 (m, 2H); 7.14 (m, 1H); 7.03 (d,
2H); 5.13 (s, 2H), MS m/z 472 (M+1)
[0829]
6-Iodo-(4-(3-trifluoromethylbenzyloxy)-phenyl)-quinazolin-4-yl)Amin-
e
[0830] Prepared according to Procedure A from
(4-(3-trifluoromethylbenzylo- xy)-phenyl)-amine and
4-chloro-6-iodoquinazoline. .sup.1H NMR (DMSO-d.sub.6) 9.2 (bs,
1H); 8.91 (s, 1H); 8.37 (d, 1H); 7.89-7.72 (m, 8H); 7.19 (d, 2H);
5.30 (s, 2H).
[0831] 4-(4-(4-Phenoxyphenylamino)-quinolin-7-yl)
Thiazole-2-carbaldehyde
[0832] Prepared according to Procedure B from
(4-phenoxyphenyl)-(7-iodoqui- nolin-4-yl)amine (2 g, 4.56 mmol),
4-(tributylstannyl)thiazole-2-carbaldeh- yde (1.84 g, 4.56 mmol)
and dichlorobis(triphenylphosphine)palladium (II) (0.74 g, 20 mol
%) heated at reflux overnight (18 hrs) in dioxane (50 ml). The
cooled solution was filtered through a plug of Celite.RTM.,
concentrated and triturated with iso-hexane (3.times.20 ml). The
resultant solid was purified via flash column chromatography on
silica gel, eluting with 5% methanol in chloroform. The purified
product was isolated as a yellow solid (0.85 g, 44%). .delta.H
[.sup.2H.sub.6] DMSO 10.10(1H,s), 9.30(1,bs), 8.90(1Hs), 8.50(2H,
s&d), 8.45(1H,d), 8.20(1H,d), 7.40(5H, bm), 7.10(4H, 2d),
6.80(1H,d).
[0833] 5-(4-(4-Phenoxyphenylamino)-quinolin-7-yl)
thiazole-4-carbaldehyde
[0834] Prepared according to Procedure B from
(4-phenoxyphenyl)-(7-iodoqui- nolin-4-yl)amine (0.876 g, 2 mmol),
4-(1,3-dioxolan-2-yl)-5-tributylstanny- lthiazole (2.1 mmol), bis
(triphenylphosphine) palladium (II) chloride (0.105 g, 0.15 mmol,
7.5 mol %) and silver oxide (0.463 g, 2 mmol) heated under reflux
under nitrogen for 18 hr. The reaction mixture was then filtered
through Harborlite.RTM. and the filtrate was concentrated. The
product was purified on Bond Elut.TM. cartridge, eluting
sequentially with dichloromethane, chloroform, diethyl ether and
ethyl acetate. The ketal (0.385 g, 0.824 mmol) was stirred at room
temperature in a mixture of THF (10 ml) and 1N HCl (10 ml) for 2
hr. The suspension was basified with 2N NaOH (5 ml) and the THF was
removed. The aqueous suspension was filtered and washed with water
to give the product as a yellow solid (0.346 g);m/z 424.
[0835]
5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyd-
e
[0836] Prepared according to Procedure C from
4-(4-benzyloxy-phenylamino)--
(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine (1.0
g, 2.1 mmol). The precipitate which formed was collected by
filtration and washed with acetone, then partitioned between ethyl
acetate, triethylamine and water. The organic phase was washed with
water, dried (magnesium sulphate) and the solvent was removed under
vacuum. Trituration with isohexane/ethyl acetate gave the product
as an orange solid (610 mg, 69%); .delta.H [.sup.2H.sub.6]-DMSO
10.05 (1H, b, NH), 9.62 (1H, s, CHO), 8.95 (1H, s, 5-H), 8.48 (1H,
s, 2-H), 8.24 (1H, d, 7-H), 7.80 (1H, d, 8-H), 7.70 (1H, d, furan
4-H), 7.59 (2H, d, 2'-H, 6'-H), 7.48-7.25 (6H, m, 5.times.Ph-H,
furan 3-H), 7.02 (2H, m, 3'-H, 5'-H), 5.09 (2H, s, CH.sub.2); m/z
422 (M+1).sup.+.
[0837] 5-(4-(4-Benzyloxy-phenylamino)-7-methoxy-quinazolin-6-yl)-fu
ran-2-carbaldehyde Hydrochloride
[0838] Prepared according to Procedure C from
(4-benzyloxyphenyl)-(6-(5-(1-
,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-pyrido[3,4-d]pyrimidin-4-yl)-amine-
(0.301 g, 0.60 mmol). After stirring 45 minutes, the resulting
suspension was filtered and washed with ether to give 0.26 g of
product as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 11.67(br s, 1H), 9.68(s, 1H), 9.14(s, 1H), 8.78(s, 1H),
7.73(d, 1H), 7.52(d, 2H), 7.44(m, 3H), 7.39(m, 3H), 7.32(m, 1H),
7.11(d, 2H), 5.14(s, 2H), 4.12(s, 3H). ESI-MS m/z 452(M+1).
[0839]
6-(5-(1,3-Dioxolan-2-yl)-furan-2-yl)-7-methoxy-quinazolin-4-yl-(4-b-
enzenesulphonyl)Phenyl-amine
[0840] Prepared according to Procedure B from
4-(4-benzenesulphonyl)phenyl- -7-methoxy-quinazolin-4-yl-amine and
5-(1,3-dioxolan-2-yl)-2-(tributylstan- nyl)furan. .delta..sup.1H
NMR (400 MHz, DMSO-d.sub.6) 10.36(s, 1H), 8.74(s, 1H), 8.58(s, 1H),
8.10(d, 2H), 7.93(m, 4H), 7.62(m, 3H), 7.32(s, 1H), 7.04(d, 1H),
6.68(d, 1H), 5.99(s, 1H), 4.09(m, 2H), 4.04(s, 3H), 3.95(m, 2H).
ESI-MS m/z 530(M+1).
[0841]
5-(4-(4-Phenoxyphenylamino)-quinolin-7-yl)furan-2-carbaldehyde
[0842]
(4-Phenoxyphenyl)-(7-(5-(1,3-dioxolan-2-yl)furan-2-yl)-quinolin-4-y-
l)amine (1.4 g) was treated with 1 M aqueous hydrochloric
acid-tetrahydrofuran (60 ml, 1:1) in accordance with procedure C.
Addition of 1M aqueous sodium hydroxide solution to pH 10 followed
by extraction with ethyl acetate, drying (magnesium sulfate) and
concentration to dryness afforded a yellow solid (1.2 g); .delta.H
[.sup.2H.sub.6] DMSO 9.70 (1H, s), 9.10 (1H, s), 8.51 (2H, m), 8.35
(1H, s), 8.02 (1H, d), 7.73 (1H, d), 7.57 (1H, d), 7.42 (4H, m),
7.22-7.04 (5H, m), 6.88 (1H, d); m/z 407 (M+1).sup.+.
[0843]
5-(7-Methoxy-4-(4-benzenesulphonyl)phenylamino-quinazolin-6-yl)-fur-
an-2-carbaldehyde Hydrochloride
[0844] Prepared according to Procedure C from
6-(5-(1,3-dioxolan-2-yl)-fur-
an-2-yl)-7-methoxy-quinazolin-4-yl-(4-benzenesulphonyl)phenyl-amine.
61H NMR (400 MHz, DMSO-d.sub.6) 11.54(br s, 1H), 9.68(s, 1H),
9.13(s, 1H), 8.83(s, 1H), 7.95-8.06(m, 6H), 7.72(d, 1H), 7.68(m,
1H), 7.62(m, 2H), 7.46(s, 1H), 7.39(d, 1H), 4.12(s, 3H). ESI-MS m/z
486(M+1).
[0845]
5-(4-(4-Benzyloxy-phenylamino)-7-fluoro-quinazolin-6-yl)-furan-2-ca-
rboxaldehyde Hydrochloride
[0846] Prepared according to Procedure C from a stirred solution of
(4-benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinaz-
olin-4-yl)-amine (0.51 grams, 1.1 mmol) in 20 ml of THF was added 5
ml of 1 N HCl. After stirring for 90 minutes, the resultant
suspension was filtered and washed with diethyl ether (200 ml) to
yield, after drying under vacuum, a yellow solid (0.32 grams, 61%
yield). .delta..sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.52(s, 1H),
9.70(s, 1H), 9.25(d, 1H),8.76(s, 1H), 7.76(m, 2H), 7.55(d, 2H),
7.45(d, 2H), 7.33(m, 4H), 7.11(d, 2H), 5.14(s, 2H). ESI-MS m/z
440(M+1).
[0847]
5-(4-(1-Benzyl-1H-indazol-5-ylamino)-7-fluoro-quinazolin-6-yl)-fura-
n-2-carbaldehyde Hydrochloride
[0848] Prepared according to Procedure C from
(1-benzyl-1H-indazol-5-ylami-
no)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine.
.delta..sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.68(s, 1H),9.71 (s,
1H), 9.28(d, 1H), 8.74(s, 1H), 8.12(s, 1H), 8.02(s, 1H), 7.78(m,
3H), 7.58(m, 2H), 7.3(m, 5H), 5.65(s, 2H). ESI-MS m/z 462(M-1).
[0849]
5-(4-(4-Benzenesulphonylphenylamino)-7-fluoro-quinazolin-6-yl)-fu
ran-2-carbaldehyde Hydrochloride
[0850] Prepared according to Procedure C from
6-(5-(1,3-dioxolan-2-yl)-fur-
an-2-yl)-7-fluoro-quinazolin-4-yl-(4-benzenesulphonyl)phenyl-amine.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 10.96(s, 1H), 9.7(s,
1H), 9.16(d, 1H), 8.72(s, 1H), 8.07(d, 2H), 7.96(m, 4H), 7.75(m,
2H), 7.64(m, 3H), 7.29(m, 1H. ESI-MS m/z 472(M-1).
[0851]
5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyd-
e Hydrochloride
[0852] Prepared according to Procedure C from
4-(4-benzyloxyphenylamino)-(-
6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine (6.70
g, 14.4 mmol). The resulting precipitate was collected by
filtration and washed with water to give the hydrochloride salt as
a yellow solid (6.50 g, 14.1 mmol, 98%); .delta.H
[.sup.2H.sub.6]DMSO 12.15 (1H,s), 9.69 (1H,s) 9.58 (1H,s), 8.88
(1H,s), 8.50 (1H,dd), 8.02 (1H,d), 7.77 (1H,d), 7.62-7.74 (3H,m),
7.31-7.52 (5H,m), 7.15 (2H,d), 5.17 (2H,s).
[0853]
(4-Phenoxyphenyl)-(7-(5-(1,3-dioxolan-2-yl)furan-2-yl)-quinolin-4-y-
l)Amine
[0854] (4-Phenoxyphenyl)-(7-iodo-quinolin-4-yl)amine (2 g) was
treated with 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (2.16
g) and tetrakis (triphenylphosphine) palladium (0) (0.26 g) in
dimethylacetamide (20 ml) in accordance with Procedure B.
Purification via column chromatography, eluting with ethyl acetate,
followed by trituration with diethylether afforded a yellow solid
(1.4 g); .delta.H [.sup.2H.sub.6] DMSO 9.10 (1H, s), 8.45 (2H, m),
8.13 (1H, s), 7.96 (1H, d), 7.41 (4H, m), 7.22 (1H, d), 7.20-7.03
(5H, m), 6.83 (1H, d), 6.75 (1H, d), 6.02 (1H, s), 4.13 (2H, m),
4.01 (2H, m); m/z 451 (M+1).sup.+.
[0855]
(1-Benzyl-1H-indazol-5-yl)-(6-bromoquinazolin-4-yl)-amine
[0856] Prepared according to Procedure A from
6-bromo-4-chloroquinazoline (5.0 g) and
5-amino-1-benzyl-1H-indazole (5.0 g) in acetonitrile (100 ml) at
100.degree. C. The resulting precipitate was treated with
triethylamine in ethyl acetate and water to give the title compound
as a yellow solid, (7.37 g); .delta.H [.sup.2H.sub.6]-DMSO
9.93(1H,s), 8.82 (1H,d), 8.52(1H,s), 8.19(1H,s), 8.09(1H,s),
7.92(1H,dd), 7.65(3H,m), 7.25(5H,m), 5.62(2H,s).
[0857] (1-Benzyl-1H-indazol-5-yl)-(6-iodoquinazolin-4-yl)-amine
Hydrochloride
[0858] Prepared according to Procedure A from
4-chloro-6-iodoquinazoline (5.8 g) was treated with
5-amino-1-benzyl-1H-indazole (3.90 g) in acetonitrile (500 ml) at
reflux under N.sub.2 for 18 hours. Subsequent cooling and
filtration gave the title compound (8.26 g); m/z (M+1)+478.
[0859]
(1-Benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-qu-
inazolin-4-yl)-amine
[0860] Prepared according to Procedure B from
(1-benzyl-1H-indazol-5-yl)-(- 6-bromoquinazolin-4-yl)-amine (4.3
g), 2-(tributylstannyl)-5-(1,3-dioxolan- -2-yl)-furan (J. Chem.
Soc., Chem Commun., (1988), 560) (10 g) and
1,4-bis(diphenylphosphino) palladium (II) chloride (1 g) in
dioxane. The solvent was removed in vacuo and the residue
chromatographed on silica. Subsequent trituration gave the title
compound .delta.H [.sup.2H.sub.6]-DMSO 10.13 (1H, s), 8.85 (1H, s),
8.54 (1H, s), 8.20 (3H, m), 7.80 (3H, m), 7.30 (5H, m), 7.13 (1H,
d), 6.79 (1H, d), 6.04 (1H, s), 5.71 (2H, s), 4.15 (4H, m).
[0861]
(1-Benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7--
methoxy-quinazolin-4-yl)-amine
[0862] Prepared according to Procedure B from
(1-benzyl-1H-indazol-5-yl)-7-
-methoxy-6-trifluoromethanesulphonyl-quinazolin-4-yl)-amine and
2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.: 10.07(s, 1H), 8.75(s, 1H), 8.42(s, 1H),
8.09(s, 2H), 7.64(m, 2H), 7.2-7.3(m, 6H), 7.01 (d, 1H), 6.68(d,
1H), 5.99(s, 1H), 5.64(s, 2H), 4.09(m, 2H), 4.03(s, 3H), 3.94(m,
2H). ESI-MS m/z 520(M+1).
[0863]
5-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-furan-2-carba-
ldehyde Hydrochloride
[0864] Prepared according to Procedure C from
(1-benzyl-1H-indazol-5-yl)-(-
6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine (2.0
g). The resulting precipitate was filtered, washed with water and
dried at 60.degree. C. in vacuo to give the product as a yellow
solid (1.80 g, 3.73 g, 91%); .delta.H [.sup.2H.sub.6]-DMSO 12.30
(1H, s), 9.79 (1H, s), 9.62 (1H, s), 8.85 (1H, s), 8.62 (1H, m),
8.31 (1H, s), 8.19 (1H, m), 8.10 (1H, d), 7.90 (2H, m), 7.78 (2H,
m), 7.40 (5H, m), 5.80 (2H, s).
[0865]
5-(4-(1-Benzyl-1H-indazol-5-yl)-7-methoxy-quinazolin-6-yl)-furan-2--
carbaldehyde Hydrochloride
[0866] Prepared according to Procedure C from
(1-benzyl-1H-indazol-5-yl)-(-
6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-quinazolin-4-yl)-amine.
.delta.H NMR (400 MHz, DMSO-d.sub.6): 11.94(br s, 1H), 9.68(s, 1H),
9.20(s, 1H), 8.79(s, 1H), 8.19(s, 1H), 7.97(d, 1H), 7.81(d, 1H),
7.74(d, 1H), 7.57(m, 1H), 7.44(s, 1H), 7.41(d, 1H), 7.30(m, 2H),
7.24(m, 3H), 5.68(s, 2H), 4.13(s, 3H). ESI-MS m/z 476(M+1).
[0867] 7-Iodoquinazolin-4-one
[0868] 7-Amino-quinazolin-4-one (R. Dempsy and E. Skito,
Biochemistry, 30, 1991, 8480) (1.61 g) was suspended in 6N HCl (20
ml) and cooled in an ice bath. A solution of sodium nitrite (0.75
g) in water (10 ml) was added dropwise over 15 minutes. After a
further 10 minutes, a solution of potassium iodide (1.66 g) in
water (5 ml) was added dropwise. The mixture was warmed to
20.degree. C. and after 3 hours partitioned between ethyl acetate
and sodium thiosulphate. The organic phase was dried and
concentrated in vacuo to give the title compound (0.485 g); m/z
(M+1+) 271.
[0869] 4-Chloro-7-iodoquinazoline
[0870] 7-Iodoquinazolin-4-one (0.46 g) was treated with phosphorous
oxychloride (5 ml) at reflux under nitrogen for 2 hours. The
mixture was cooled, evaporated and partitioned between saturated
aqueous sodium carbonate and ethyl acetate. The organic phase was
dried and concentrated in vacuo to give the title compound (0.43
g); m/z (M+1+) 291.
[0871] (1-Benzyl-1H-indazol-5-yl)-(7-iodoquinazolin-4-yl)-amine
Hydrochloride
[0872] Prepared according to Procedure A from
4-Chloro-7-iodoquinazoline (0.42 g) and
1-benzyl-1H-indazol-5-ylamine (0.323 g) in acetonitrile (20 ml) at
reflux under nitrogen for 18 hours. The mixture was cooled and
filtered to give the title compound (0.57 g); m/z (M+1+) 478.
[0873]
(1-Benzyl-1H-indazol-5-yl)-[7-(5-(1,3-dioxolan-2-yl)-furan-2-yl)qui-
nazolin-4-yl]Amine Hydrochloride
[0874] Prepared according to Procedure B from
(1-benzyl-1H-indazol-5-yl)-(- 7-iodoquinazolin-4-yl)-amine
hydrochloride and 5-(1,3-dioxolan-2-yl)-2-(tr-
i-n-butylstannyl)furan; tlc Rf, 0.25 (100% EtOAc on silica); m/z
(M+1+) 490.
[0875]
5-[4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl]-furan-2-carba-
ldehyde
[0876] Prepared according to Procedure C from
(1-benzyl-1H-indazol-5-yl)-[-
7-(5-(1,3-dioxolan-2-yl)furan-2-yl)quinazolin-4-yl]-amine
hydrochloride (0.27 g) stirred in THF:2N HCl (2:1, 15 ml) at
20.degree. C. for 1 hour. Filtration gave
5-[4-(1-benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl]-fur-
an-2-carbaldehyde, which was not further characterised.
[0877]
(4-Benzyloxy-phenyl)-(6-((5-(2-methylthio-ethylamino)-methyl)-furan-
-2-yl)-quinazolin-4-yl)-amine Dihydrochloride
[0878]
5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyd-
e (100 mg) and (methylthio)ethylamine (80 mg) in dichloromethane (5
ml) were reacted together as in Procedure D. Purification using
column chromatography, followed by conversion to the hydrochloride
salt gave a yellow solid (61 mg). m/z 497 (M+1).sup.+.
[0879]
(6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(4-fluorobenzyloxy)-phenyl-
)-amine
[0880] 4,6-Dichloro-pyrido[3,4-d]pyrimidine (1 g) and
4-(4-fluorobenzyloxy)aniline (1.08 g) in acetonitrile (70 ml) were
reacted together as in Procedure A. The product was collected by
filtration as a yellow solid (1.83 g); m/z 381 (M+1).sup.+.
[0881]
(6-(5-(1,3-Dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)--
(4-(4-fluorobenzyloxy)-phenyl)-amine
[0882]
(6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(4-fluorobenzyloxy)-phenyl-
)-amine (1.82 g) and
5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (3.75 g) in dioxan
(40 ml) were reacted together as in Procedure B. The mixture was
evaporated and the residue suspended in dichloromethane. This was
then filtered through celite and the solvent evaporated. The gummy
residue was then triturated with hexane giving a beige solid (1.21
g); m/z 485 (M+1).sup.+.
[0883]
5-(4-(4-(4-Fluorobenzyloxy)-phenylamino)-pyrido[3,4-d]pyrimidin-6-y-
l)-furan-2-carbaldehyde
[0884]
(6-(5-(1,3-Dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)--
(4-(4-fluorobenzyloxy)-phenyl)-amine (500 mg) was treated with acid
as in Procedure C. The product was collected by filtration as a red
solid (330 mg); m/z 441 (M+1).sup.+.
[0885]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-(2-(methylthio)-ethylaminometh-
yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine
[0886]
5-(4-(4-(4-Fluorobenzyloxy)-phenyl)-pyrido[3,4-d]pyrimidin-6-yl)-fu-
ran-2-carbaldehyde (110 mg) and (methylthio)ethylamine (0.06 ml) in
dichloromethane (5 ml) were reacted together as in Procedure D.
Purification using a Bond Elut.TM. cartridge gave a yellow oil (52
mg); m/z 516 (M+1).sup.+.
[0887]
(6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl-
)-amine
[0888] 4,6-Dichloro-pyrido[3,4-d]pyrimidine (1 g) and
4-(3-fluorobenzyloxy)aniline (1.08 g) in acetonitrile (70 ml) were
reacted together as in Procedure A. The product was collected by
filtration as a yellow solid (1.86 g); m/z 381 (M+1).sup.+.
[0889]
(6-(5-(1,3-Dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)--
(4-(3-fluorobenzyloxy)-phenyl)-amine
[0890]
(6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl-
)-amine (1.85 g) and
5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (3.82 g) in dioxan
(40 ml) were reacted together as in Procedure B. The mixture was
evaporated and the residue suspended in dichloromethane. This was
then filtered through Celite.RTM. and the solvent evaporated. The
gummy residue was then triturated with hexane giving a beige solid
(1.74 g); m/z 485 (M+1).sup.+.
[0891]
5-(4-(4-(3-Fluorobenzyloxy)-phenylamino)-pyrido[3,4-d]pyrimidin-6-y-
l)-furan-3-carbaldehyde
[0892]
(6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl-
)-amine (1 g) and 5-(tributylstannyl)-furan-3-carbaldehyde (J. Org.
Chem. (1992), 57(11), 3126-31) (1.84 g) in dioxan (35 ml) were
reacted together as in Procedure B. The solvent was evaporated and
the residue suspended in dichloromethane. The mixture was filtered
through Celite.RTM. and then evaporated. The residue was triturated
with hexane giving a beige solid (1 g); m/z 441 (M+1).sup.+.
[0893]
5-(4-(4-(3-Fluorobenzyloxy)-phenylamino)-pyrido[3,4-d]pyrimidin-6-y-
l)-furan-2-carbaldehyde
[0894] (6-(5-(1,3-Dioxolan-2-yl)-fu
ran-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-
-(4-(3-fluorobenzyloxy)-phenyl)-amine (500 mg) was treated with
acid as in Procedure C. The product was collected by filtration as
a beige solid (251 mg); m/z 441 (M+1).sup.+.
[0895]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-(2-(methylthio)-ethylaminometh-
yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine
[0896]
(5-(4-(4-(3-Fluorobenzyloxy)-phenyl)-pyrido[3,4-d]pyrimidin-6-yl)-f-
uran-2-carbaldehyde (125 mg) and (methylthio)ethylamine (0.08 ml)
in dichloromethane (5 ml) were reacted together as in Procedure D.
Purification using a Bond Elut.TM. cartridge gave a yellow oil (80
mg); m/z 516 (M+1).sup.+.
[0897]
(4-Benzenesulphonyl-phenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)--
amine
[0898] Prepared according to Procedure A from
4-benzenesulphonylaniline (Helv. Chim. Acta., 1983, 66 (4), 1046)
and 4,6-dichloropyrido[3,4-a]pyri- midine; .quadrature..quadrature.
[.sup.2H.sub.6]-DMSO 9.09 (1H,s), 8.80-8.88 (2H,m), 8.19 (2H,d),
7.94-8.09 (4H,m), 7.53-7.20 (3H,m); m/z (M+1).sup.+397.
[0899]
(4-Benzenesulphonyl-phenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-p-
yrido[3,4-d]pyrimidin-4-yl)-amine
[0900]
(4-Benzenesulphonyl-phenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)--
amine (3.67 g) and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan
(6.9 g) were reacted together in dioxan (100 ml) as in Procedure B.
Purification by column chromatography gave a cream solid (2.59 g);
.quadrature..quadrature. [.sup.2H.sub.6]DMSO 10.6 (1H,s) 9.26
(1H,s) 8.82 (1H,s) 8.78 (1H,s) 8.25 (2H,d) 8.0-8.3 (4H, d+m)
7.65-7.8 (3H,m) 7.21 (1H,d) 6.82 (1H,d) 6.09 (1H,s) 4.0-4.2 (4H,m);
m/z 501 (M+1).sup.+.
[0901]
5-(4-(4-Benzenesulphonyl-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)f-
uran-2-carbaldehyde Hydrochloride
[0902]
(4-Benzenesulphonyl-phenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-p-
yrido[3,4-d]pyrimidin-4-yl)-amine (2.59 g) was treated with acid in
tetrahydrofuran (70 ml) as in Procedure C. The compound was
obtained as a yellow solid after filtration (1.57 g);
.quadrature..quadrature. [.sup.2H.sub.6]DMSO 9.7 (1H,s) 9.26 (1H,s)
9.11 (1H,s) 8.82 (1H,s) 8.19 (1H,s) 8.15 (1H,s) 7.95-8.03 (4H,m)
7.75 (1H,d) 7.58-7.7 (3H,m) 7.49 (1H,s); m/z 457 (M+1).sup.+.
[0903]
(4-Benzenesulphonyl-phenyl)-(6-(5-((2-methylthio-ethylamino)-methyl-
)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine
Dihydrochloride
[0904]
5-(4-((4-Benzenesulphonyl-phenyl)amino)-pyrido[3,4-d]pyrimidin-6-yl-
)-furan-2-carbaldehyde (250 mg) and (methylthio)ethylamine (185
mg)) in dichloromethane (5 ml) were reacted together as in
Procedure D. Purification using a Bond Elut.TM. cartridge, gave a
yellow solid (245 mg), 70 mg of which was converted to the
hydrochloride salt, (yellow solid, 68 mg); m/z 532 (M+1).sup.+.
[0905]
(4-Benzyloxy-phenyl)-(6-(3-(1,3-dioxolan-2-yl)-phenyl)-pyrido[3,4-d-
]pyrimidin-4-yl)-amine
[0906]
(4-Benzyloxy-phenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine
(1.4 g) and 3-(1,3-dioxolan-2-yl)-phenyl-tributylstannane (3.08 g)
[A. Lee and W--C. Dai, Tetrahedron (1997), 53(3), 859-868] in
dioxan (30 ml) were reacted together as in Procedure B. The mixture
was evaporated and the residue suspended in dichloromethane. This
was then filtered through celite and the solvent evaporated. The
gummy residue was then triturated with hexane giving a beige solid.
This material was further purified by column chromatography, giving
a brown foam (252 mg); m/z 477 (M+1).sup.+.
[0907]
3-(4-((4-Benzyloxy-phenyl)-amino)-pyrido[3,4-d]pyrimidin-6-yl)-benz-
aldehyde
[0908]
(4-(4-Benzyloxy-phenyl)-6-(3-(1,3-dioxolan-2-yl)-phenyl)-pyrido[3,4-
-d]pyrimidin-4-yl)-amine (250 mg) was treated with acid as in
Procedure C. The product was isolated by filtration as a brown
solid (115 mg); m/z 433 (M+1).sup.+.
[0909]
4-(4-(4-Benzyloxy-phenyl)-amino)-quinazolin-6-yl)-thiazol-2-carbald-
ehyde
[0910] (4-Benzyloxy-phenyl)-(6-iodo-quinazolin-4-yl)-amine (2 g)
and 4-(tributylstannyl)-thiazol-2-carbaldehyde (3.28 g) in dioxan
(25 m[) were reacted together as in Procedure B. The mixture was
evaporated and the residue purified using column chromatography,
giving a yellow solid (849 mg); m/z 439 (M+1).sup.+.
[0911] Other suitable intermediates prepared by analogous methods
to those described above are:
[0912]
(4-Benzyloxy-3-chlorophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)--
amine;
[0913]
(4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-6-chloro-pyrido[3,4-d]pyrim-
idin-4-yl)-amine;
[0914]
(4-Benzyloxy-3-trifluoromethylphenyl)-6-chloro-pyrido[3,4-d]pyrimid-
in-4-yl)-amine;
[0915]
(4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-6-chloro-pyrido[3,-
4-d]pyrimidin-4-yl)-amine;
[0916]
(4-Benzyloxy-3-bromophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-a-
mine;
[0917]
(4-(3-Fluoro-benzyloxy-3-bromophenyl)-6-chloro-pyrido[3,4-d]pyrimid-
in-4-yl)-amine;
[0918]
(4-Benzyloxy-3-iodophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-am-
ine;
[0919]
(4-(3-Fluoro-benzyloxy-3-iodophenyl)-6-(chloro-pyrido[3,4-d]pyrimid-
in-4-yl)-amine;
[0920]
(4-Benzyloxy-3-fluorophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)--
amine;
[0921]
(4-(3-Fluoro-benzyloxy-3-fluorophenyl)-6-chloro-pyrido[3,4-d]pyrimi-
din-4-yl)-amine;
[0922]
5-((4-Benzyloxy-3-chlorophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-f-
u ran-2-carbaldehyde;
[0923]
5-((4-(3-Fluoro-benzyloxy)-3-chlorophenylamino)-pyrido[3,4-d]pyrimi-
din-6-yl)-furan-2-carbaldehyde;
[0924] 5-((4-Benzyloxy-3-trifluoromethylphenylamino)-pyrido[3,4-d]
6-yl)-furan-2-carbaldehyde;
[0925]
5-((4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenylamino)-pyrido[3,4-
-d]pyrimidin-6-yl)-fu ran-2-carbaldehyde;
[0926]
5-((4-Benzyloxy-3-bromophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-fu
ran-2-carbaldehyde;
[0927]
5-((4-(3-Fluoro-benzyloxy-3-bromophenylamino)-pyrido[3,4-d]6-yl)-fu-
ran-2-carbaldehyde;
[0928]
5-((4-Benzyloxy-3-iodophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-fu
ran-2-carbaldehyde;
[0929] 5-((4-(3-Fluoro-benzyloxy-3-iodophenylamino)-pyrido[3,4-d]
6-yl)-furan-2-carbaldehyde;
[0930]
5-((4-Benzyloxy-3-fluorophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-f-
uran-2-carboxaldehyde;
[0931] 5-((4-(3-Fluoro-benzyloxy-3-fluorophenylamino)-pyrido[3,4-d]
6-yl)-furan-2-carbaldehyde;
[0932]
N-[4-(benzyloxy)-3-chlorophenyl]-7-fluoro-6-chloro-4-quinazolinamin-
e;
[0933]
N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-fluoro-6-chloro-4-quina-
zolinamine
[0934]
N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-fluoro-6-chloro-4-quinazo-
linamine
[0935]
N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-fluoro-6-chlor-
o-4-quinazolinamine;
[0936]
N-[4-Benzyloxy-3-bromophenyl]-7-fluoro-6-chloro-4-quinazolinamine;
[0937]
N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-fluoro-6-chloro-4-quinazo-
linamine;
[0938]
N-[4-Benzyloxy-3-iodophenyl]-7-fluoro-6-chloro-4-quinazolinamine;
[0939]
N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-fluoro-6-chloro-4-quinazol-
inamine;
[0940]
N-[4-Benzyloxy-3-fluorophenyl]-7-fluoro-6-chloro-4-quinazolinamine;
[0941]
N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-fluoro-6-chloro-4-quinaz-
olinamine;
[0942]
N-[1-(3-fluorobenzyl-1H-indazol-5-yl]-7-fluoro-6-chloro-4-quinazoli-
namine;
[0943]
5-(4-[4-(Benzyloxy)-3-chlorophenylamino]-7-fluoro-quinazolin-6-yl)--
furan-2-carbaldehyde;
[0944]
5-(4-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-fluoro-quinazolin-6--
yl)-furan-2-carbaldehyde;
[0945]
5-(4-[4-Benzyloxy-3-trifluoromethylphenyl]-7-fluoro-quinazolin-6-yl-
)-furan-2-carbaldehyde;
[0946]
5-(4-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-fluoro-quin-
azolin-6-yl)-furan-2-carbaldehyde;
[0947]
5-(4-[4-Benzyloxy-3-bromophenyl]-7-fluoro-quinazolin-6-yl)-furan-2--
carbaldehyde;
[0948]
5-(4-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-fluoro-quinazolin-6-yl-
)-furan-2-carbaldehyde;
[0949]
5-(4-[4-Benzyloxy-3-iodophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-c-
arbaldehyde;
[0950]
5-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-fluoro-quinazolin-6-yl)-fu-
ran-2-carbaldehyde;
[0951]
5-[4-Benzyloxy-3-fluorophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-ca-
rbaldehyde
[0952]
5-(4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-fluoro-quinazolin-6-yl)--
furan-2-carbaldehyde;
[0953]
5-(4-[1-(3-Fluorobenzyl-1H-indazol-5-ylamino]-7-fluoro-quinazolin-6-
-yl)-furan-2-carbaldehyde;
EXAMPLES
Example 1
[0954] 17
[0955]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine
Dihydrochloride
[0956]
(4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-(2-(methylthio)-ethylaminometh-
yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine (52 mg) in
methanol (9 ml) and water (3 ml) was treated with Oxone.TM. (99 mg)
at room temperature for 2 days. The mixture was then partitioned
between aqueous sodium carbonate solution and dichloromethane. The
dried organic phase was evaporated and the residue purified by Bond
Elut.TM. cartridge, followed by conversion to the hydrochloride
salt, giving a yellow solid (31 mg); .delta.H [.sup.2H.sub.6]DMSO
9.9 (1H,bs) 9.25 (1H,s) 8.8 (1H,s) 7.9 (2H,d) 7.5-7.6 (2H,m)
7.1-7.3 (5H,m) 6.9 (1H,d) 5.2 (2H,s) 4.5 (2H,s) 3.6-3.8 (4H,m) 3.2
(3H,s);-m/z 548 (M+1).sup.+.
Example 2
[0957] 18
[0958]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamin-
o)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine
Dihydrochloride
[0959]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-(2-(methylthio)-ethylaminometh-
yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine (80 mg) in
methanol (9 ml) and water (3 ml) was treated with Oxone.TM. (153
mg) at room temperature for 2 days. The mixture was then
partitioned between aqueous sodium carbonate solution and
dichloromethane. The dried organic phase was evaporated and the
residue purified by Bond Elut.TM. cartridge, followed by conversion
to the hydrochloride salt, giving a yellow solid (69 mg); .delta.H
[.sup.2H.sub.6]DMSO 9.8 (1H,bs) 9.4 (1H,s) 9.3 (1H,s) 8.7 (1H,s)
7.8 (2H,d) 7.3-7.4 (2H,m) 7.0-7.3 (5H,m) 6.8 (1H,d) 5.3 (2H,s) 4.4
(2H,s) 3.5-3.7 (4H,m) 3.1 (3H,s); m/z 548 (M+1).sup.+.
Example 3
[0960] 19
[0961]
(4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)--
methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine
Dihydrochloride
[0962]
(4-Benzenesulphonyl-phenyl)-(6-(5-((2-methylthio-ethylamino)-methyl-
)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine (162 mg) in
methanol (20 ml) and water (10 ml) was treated with Oxone.TM. (345
mg) at room temperature for 18 h. The mixture was then evaporated
and the residue purified by Bond Elut.TM. cartridge, followed by
conversion to the hydrochloride salt, giving a yellow solid (55
mg); .delta.H [.sup.2H.sub.6]DMSO 9.8 (1H,bs) 9.3 (1H,s) 9.2 (1H,s)
8.8 (1H,s) 8.3 (2H,d) 7.9-8.0 (4H,m) 7.6-7.7 (3H,m) 7.2 (1H,d) 6.8
(1H,d) 4.4 (2H,s) 3.3-3.7 (4H,m) 3.1 (3H,s); m/z 564
(M+1).sup.+.
Example 4
[0963] 20
[0964]
(4-Benzyloxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-
-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine Dihydrochloride.
[0965]
3-((4-(4-Benzyloxy-phenyl)-amino)-pyrido[3,4-d]pyrimidin-6-yl)-benz-
aldehyde (106 mg) and 2-methanesulphonyl-ethylamine (111 mg) in
dichloromethane (5 ml) were reacted together as in Procedure D.
Purification using column chromatography, followed by conversion to
the hydrochloride salt, gave a yellow solid (66 mg); .delta.H
[.sup.2H.sub.6]DMSO 9.6 (2H,bs) 9.3 (1H,s) 9.2 (1H,s) 8.65 (1H,s)
8.55 (1H,s) 8.3 (1H,m) 7.7-7.8 (2H,m) 7.6 (2H,m) 7.25-7.45 (4H,m)
7.0 (2H,d) 5.1 (2H,s) 4.3 (2H,s) 3.2-3.8 (4H,m) 3.1 (3H,s). m/z 540
(M+1).sup.+.
Example 5
[0966] 21
[0967]
(4-Benzyloxyphenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)--
furan-2-yl)-quinazolin-4-yl)-amine Dihydrochloride
[0968]
5-((4-(4-Benzyloxyphenyl)-amino)-quinazolin-6-yl)-furan-2-carbaldeh-
yde (200 mg) and 2-methanesulphonyl-ethylamine (215 mg) in
dichloromethane (10 ml) were reacted together as in Procedure D.
Purification using column chromatography, followed by conversion to
the hydrochloride salt, gave a yellow solid (121 mg); .delta.H
[.sup.2H.sub.6]DMSO 9.7 (1H,s) 8.9 (1H,s) 8.4 (1H,d) 8.0 (1H,d)
7.75 (2H,d) 7.3-7.5 (7H,m) 7.1 (2H,d) 6.85 (1H,d) 5.2 (2H,s) 4.4
(2H,s) 3.2-3.7 (4H,m) 3.1 (3H,s); m/z 529(M+1).sup.+.
Example 6
[0969] 22
[0970]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamin-
o)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine
Dihydrochloride
[0971]
5-(4-(4-(3-Fluorobenzyloxy)-phenyl)-pyrido[3,4-d]pyrimidin-6-yl)-fu-
ran-3-carbaldehyde (300 mg) and 2-methanesulphonyl-ethylamine (335
mg) in dichloromethane (15 ml) were reacted together as in
Procedure D. Purification using a Bond Elut.TM. cartridge, followed
by conversion to the hydrochloride salt, gave a yellow solid (110
mg); .delta.H [.sup.2H.sub.6]DMSO 9.8 (2H,br) 9.3 (1H,s) 9.0 (1H,s)
8.8 (1H,s) 8.2 (1H,s) 8.0 (1H,s) 7.1-7.8 (7H,m) 7.0 (1H,s) 5.2
(2H,s) 4.1-4.3 (4H,brm) 3.3-3.5 (2H,bs) (hidden under H.sub.2O
peak) 3.2 (3H,s); m/z 548(M+1).sup.+.
Example 7
[0972] 23
[0973]
(4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-
-thiazol-4-yl)-quinazolin-4-yl)-amine Dihydrochloride
[0974]
4-(4-(4-Benzyloxy-phenyl)-amino)-quinazolin-6-yl)-thiazol-2-carbald-
ehyde (70 mg) and 2-methanesulphonyl-ethylamine (79 mg) in
dichloromethane (10 ml) were reacted together as in Procedure D.
Purification using a Bond Elut.TM. cartridge, followed by
conversion to the hydrochloride salt, gave a yellow solid (59 mg);
.delta.H [.sup.2H.sub.6]DMSO 12.3 (1H,s) 10.0 (1H,s) 8.95 (1H,s)
8.8 (1H,s) 8.75 (1H,d) 7.4-7.6 (6H,m) 7.2 (2H,d) 5.25 (2H,s) 4.8
(2H,s) 3.6-3.8 (4H,m) 3.2 (3H,s); m/z 546(M+1).sup.+.
Example 8
[0975] 24
[0976]
N-{4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl-
]amino}methyl)-2-furyl]-4-quinazolinamine
[0977] Prepared according to Procedure D from
5-(4-{4-(3-fluorobenzyloxy)a-
nilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and
2-methanesulphonyl-ethylamine (1 equiv). .sup.1H NMR 400 MHz
(DMSO-d.sub.6) 9.40 (s,1H); 8.67 (s,1H);
[0978] 8.30 (d,1H); 7.86 (d,1H); 7.75 (d,2H); 7.43 (m,1H);
7.30-7.21 (m,3H); 7.15 (m,1H); 7.07 (d,2H); 6.80 (d,1H); 5.15
(s,2H); 4.40 (s,2H); 3.65 (m,2H); 3.40 (m,2H); 3.11 (s,3H); MS m/z
547 (M+1).
Example 9
[0979] 25
[0980]
N-{4-[(3-fluorobenzyl)oxy]-3-methoxyphenyl}-6-[5-({[2-(methanesulph-
onyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine
[0981] Prepared according to Procedure D from
5-(4-{3-methoxy-4-(3-fluorob-
enzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv)
and 2-methanesulphonyl-ethylamine (1 equiv). .sup.1H NMR 400 MHz
(DMSO-d.sub.6) 9.22 (s,1H); 8.78 (s,1H); 8.31 (d,1H); 7.88 (d,1H);
7.50-7.08 (m,8H); 6.84 (d,1H); 5.13 (s,2H); 4.42 (s,2H); 3.80
(s,3H); 3.60 (m,2H); 3.40 (m, 2H, obscured by water peak); 3.10
(s,3H); MS m/z 577 (M+1).
Example 10
[0982] 26
[0983]
N-[4-(benzyloxy)phenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl-
]amino}methyl)-2-furyl]-4-quinazolinamine
[0984] Prepared in a similar manner to Procedure D from
5-(4-(4-benzyloxy-phenylamino)-7-methoxy-quinazolin-6-yl)-fu
ran-2-carbaldehyde hydrochloride(78 mg, 0.16 mmol),
2-methanesulphonylethylamine(33 mg, 0.27 mmol), acetic acid(15 mg,
0.25 mmol) and triethylamine(18 mg, 0.18 mmol) in 3 ml of
1,2-dichloroethane added to sodium triacetoxyborohydride(102 mg,
0.48 mmol) portionwise over a two day period. The reaction mixture
was stirred four days and then partitioned between 10 ml of 0.5M
NaHCO.sub.3 solution and 50 ml of ethyl acetate. The organic
solution was dried with Na.sub.2SO.sub.4 and concentrated in vacuo.
The residue was chromatographed on silica gel with
methanol/methylene chloride(1:49 to 2:48). The resulting solid was
crystallized from a small volume of ethyl acetate, suspended in
ether and filtered to give 43 mg of product as a pale yellow solid.
.delta..sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.78(s, 1H), 8.73(s,
1H), 8.42(s, 1H), 6.64(d, 2H), 7.47(m, 2H), 7.40(m, 2H), 7.33(m,
1H), 7.25(s, 1H), 7.04(d, 2H), 6.98(d, 1H), 6.46(d, 1H), 5.12(s,
2H), 4.04(s, 3H), 3.86(s, 2H), 3.28(t, 2H), 3.01 (s, 3H), 2.99(t,
2H). ESI-MS m/z 559(M+1).
Example 11
[0985] 27
[0986]
N-[4-(benzyloxy)phenyl]-6-[4-({[2-methanesulphonyl)ethyl]amino}meth-
yl)-2-furyl]-4-quinazolinamine
[0987] Prepared according to Procedure D from
5-(4-{4-benzyloxyanilino}-6-- quinazolinyl)-furan-3-carbaldehyde
(0.6 equiv) and 2-methanesulphonyl-ethy- lamine (1 equiv).
.sup.1HNMR 400 MHz, d6DMSO 9.51 (bs,2H), 9.11 (s, 1H), 8.79 (s,
1H), 8.29 (d, 1H), 8.06 (s, 1H), 7.90 (d, 1H), 7.60 (d, 2H),
7.5-7.3 (m, 5H), 7.11 (d, 2H), 5.14 (s, 2H), 4.14 (bs, 2H), 3.6-3.5
(m, 3H), 3.12 (s, 3H); MS m/z 529 (M+1).
Example 12
[0988] 28
[0989]
N-{4-[(3-fluorobenzyl)oxy]-3-methoxyphenyl}-6-[2-({[2-(methanesulph-
onyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine
[0990] Prepared according to Procedure F from
6-iodo-(4-(3-fluorobenzyloxy- )-3-methoxypheny)quinazolin-4-ylamine
(1 equiv), 2-ethoxyvinyl-tributylsta- nnane (1 equiv),
N-bromosuccinimide (1 equiv) and N-(trifluoroacetyl)-N-(m-
ethanesulphonylethyl)-aminomethylthioamide (1 equiv). .sup.1H NMR
400 MHz (CD.sub.3OD) 9.40 (s, 1H); 8.79 (s, 1H); 8.76 (d, 1H); 8.38
(s, 1H); 7.89 (d, 1H); 7.50 (s, 1H); 7.40 (t, 1H); 7.34 (m, 1H);
7.27 (d, 1H); 7.22 (d, 1H); 7.08 (d, 1H); 7.03 (t, 1H); 5.19 (s,
2H); 4.81 (s, 2H); 3.85 (m, 2H); 3.75 (m, 2H); 3.10 (s, 3H); MS m/z
594 (M+1).sup.+, 592 (m-1).sup.-.
Example 13
[0991] 29
[0992]
N-{4-[(3-bromobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]-
amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine.
[0993] Prepared according to Procedure F from
6-iodo-(4-(3-bromobenzyloxy)- -phenyl)quinazolin-4-ylamine (1
equiv), 2-ethoxyvinyl-tributylstannane (1 equiv),
N-bromosuccinimide (1 equiv) and N-(trifluoroacetyl)-N-(methanesu-
lphonylethyl)-aminomethylthioamide (1 equiv). .sup.1H NMR 400 MHz
(CD.sub.3OD) 9.40 (s, 1H); 8.78 (d, 1H); 8.74 (d, 1H); 8.34 (s,
1H); 7.88 (d, 1H); 7.65 (d, 2H); 7.62 (s, 1H); 7.48 (d, 1H); 7.30
(d, 1H); 7.30 (m, 1H); 7.12 (d, 2H); 5.16 (s, 2H); 4.80 (s, 2H);
3.85 (m, 2H); 3.75 (m, 2H); 3.10 (s, 3H); MS m/z 624, 626
(M+1).sup.+, 622, 624 (m-1).sup.-.
Example 14
[0994] 30
[0995]
N-{4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl-
]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine
[0996] Prepared according to Procedure F from
6-iodo-(4-(3-fluorobenzyloxy- )-phenyl)-quinazolin-4-ylamine and (1
equiv), 2-ethoxyvinyl-tributylstanna- ne (1 equiv),
N-bromosuccinimide (1 equiv) and N-(trifluoroacetyl)-N-(meth-
anesulphonylethyl)-aminomethylthioamide (1 equiv). .sup.1H NMR 400
MHz (CD.sub.3OD) 9.44 (s, 1H); 8.79 (s, 1H); 8.76 (d, 1H); 8.37 (s,
1H); 7.90 (d, 1H); 7.74 (d, 1H); 7.53 (d, 1H); 7.46 (d, 2H); 7.38
(m, 2H); 7.32 (d, 1H); 7.24 (d, 1H); 5.21 (s, 2H); 4.82 (s, 2H);
3.85 (m, 2H); 3.77 (m, 2H); 3.11 (s, 3H); MS m/z 564 (M+1).sup.+,
562 (m-1).sup.-.
Example 15
[0997] 31
[0998]
N-[4-(benzyloxy)-3-fluorophenyl]-6-[2-({[2-(methanesulphonyl)ethyl]-
amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine
[0999] Prepared according to Procedure F from
6-iodo-(4-benzyloxy)-3-fluor- ophenyl)quinazolin-4-ylamine and
N-(trifluoroacetyl)-N-(methanesulphonylet-
hyl)-aminomethylthioamide (1 equiv), 2-ethoxyvinyl-tributylstannane
(1 equiv), N-bromosuccinimide (1 equiv) and
N-(trifluoroacetyl)-N-(methanesu-
lphonylethyl)-aminomethylthioamide (1 equiv). .sup.1H NMR 400 MHz
(CD.sub.3OD) 9.41 (s, 1H); 8.77 (d, 1H); 8.75 (s, 1H); 8.36 (s,
1H); 7.90 (d, 1H); 7.71 (d, 2H); 7.60 (m, 1H); 7.40 (m, 1H); 7.23
(m, 1H); 7.11 (d, 2H); 7.03 (m, 1H); 5.17 (s, 2H); 4.81 (s, 2H);
3.85 (m, 2H); 3.76 (m, 2H); 3.10 (s, 3H); MS m/z 564 (M+1).sup.+,
562 (m-1).sup.-.
Example 16
[1000] 32
[1001]
N-(1-benzyl-1H-indazol-5-yl)-7-methoxy-6-[5-({[2-(methanesulphonyl)-
ethyl]amino}methyl)-2-furyl]-4-quinazolinamine
[1002] Prepared according to Procedure D from
5-(4-{4-(1-benzyl-1H-indazol-
-5-yl)-7-methoxy-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv)
and 2-methanesulphonyl-ethylamine (1 equiv). .delta. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) 9.94(s, 1H), 8.76(s, 1H), 8.43(s, 1H),
8.13(d, 1H), 8.12(s, 1H), 7.70(d, 1H), 7.66(m, 1H), 7.31 (m, 2H),
7.25(m, 4H), 7.00(d, 1H), 6.46(d, 1H), 5.67(s, 2H), 4.05(s, 3H),
3.85(s, 2H), 3.27(t, 2H), 3.00(s, 3H), 2.98(t, 2H); ESI-MS m/z
583(M+1).
Example 17
[1003] 33
[1004]
6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-(4-{[3-(-
trifluoromethyl) benzyl]oxy}phenyl)-4-quinazolinamine
[1005] Prepared according to Procedure D from
5-(4-{4-(3-trifluoromethylbe-
nzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv)
and 2-methanesulphonyl-ethylamine (1 equiv). .sup.1H NMR 300 MHz
(DMSO-d.sub.6) 11.63 (bs, 1H); 9.88 (bs, 1H); 9.59 (bs, 1H); 8.88
(s, 1H); 8.43 (d, 1H); 7.97 (d, 1H); 7.90-7.67 (m, 6H); 7.34 (d,
1H); 7.19 (d, 2H); 6.89 (d, 1H); 5.30 (s, 2H); 4.45 (s, 2H); 3.78
(m, 2H); 3.45 (m, 2H, obscured by water peak); 3.19 (s, 3H); MS m/z
597 (M+1).
Example 18
[1006] 34
[1007]
N-{3-fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulpho-
nyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine
[1008] Prepared according to Procedure D from
5-(4-{3-fluoro-4-(3-fluorobe- nzyloxy)anilino}-6-quinazolinyl)-fu
ran-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1
equiv). .sup.1H NMR 400 MHz (DMSO-d.sub.6) 9.61 (bs, 2H); 9.28 (bs,
1H); 8.80 (s, 1H); 8.34 (d, 1H); 7.87 (m, 2H); 7.59 (d, 1H); 7.44
(m, 1H); 7.2-7.38 (m, 4H); 7.18 (m, 1H); 6.83 (s, 1H); 5.25 (s,
2H); 4.42 (s, 2H); 3.60 (m, 2H); 3.45 (m, 2H, obscured by water
peak); 3.16 (s, 3H); MS m/z 565 (M+1).
Example 19
[1009] 35
[1010]
N-{4-[(3-bromobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]-
amino}methyl)-2-furyl]-4-quinazolinamine
[1011] Prepared according to Procedure D from
5-(4-{3-bromo-4-benzyloxyani-
lino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and
2-methanesulphonyl-ethylamine (1 equiv). .sup.1H NMR 400 MHz
(DMSO-d.sub.6) 11.78 (bs, 1H); 9.65 (bs, 1H); 9.39 (bs, 1H); 8.78
(s, 1H); 8.37 (d, 1H); 7.90 (d, 1H); 7.66 (m, 3H); 7.53 (d, 1H);
7.42 (d, 1H); 7.38 (m, 1H); 7.22 (s, 1H); 7.18 (d, 2); 6.82 (d,
1H); 5.18 (s, 2H); 4.41 (s, 2H); 3.62 (m, 2H); 3.44 (m, 2H,
obscured by water peak); 3.10 (s, 3H); MS m/z 606, 608 (M+1).
Example 20
[1012] 36
[1013]
N-[4-(benzyloxy)phenyl]-6-[3-({[2-(methanesulphonyl)ethyl]amino}met-
hyl)-2-furyl]-4-quinazolinamine
[1014] Prepared according to Procedure D from
5-(4-(4-benzyloxyanilino)-6-- quinazolinyl)-furan-2-carbaldehyde
(0.6 equiv) and 2-methanesulphonyl-ethy- lamine(1 equiv).
.sup.1HNMR 400 MHz,(d.sub.6DMSO) 9.46(brs,1H), 8.94 (s,1H), 8.7
(s,1H), 8.16 (d,1H), 7.96 (s,1H), 7.88 (d,1H), 7.67 (d,2H), 7.5-7.2
(m,5H), 7.07 (d,2H), 6.93 (s,1H), 5.12 (s, 2H), 4.38 (brs,2H), 3.59
(m,2H), 3.46 (brs,2H), 3.09 (s,3H); MS m/z 529 (M+1)
Example 21
[1015] 37
[1016]
N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]-6-[2-({[2-(methanesulphonyl)-
ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine
[1017] Prepared according to Procedure F from
6-iodo-(4-(3-fluorobenzyl)-1- H-indazol-5-yl)quinazolin-4-ylamine
(1 equiv), 2-ethoxyvinyl-tributylstann- ane (1 equiv),
N-bromosuccinimide (1 equiv) and N-(trifluoroacetyl)-N-(met-
hanesulphonylethyl)-aminomethylthioamide (1 equiv). .sup.1H NMR
(d.sub.4 MeOH) d 9.44 (s, 1H), 8.76 (m, 2H), 8.36 (s, 1H), 8.18 (s,
1H), 8.15, (s, 1H), 7.92 (d, 1H), 7.75 (m, 2H), 7.34 (m, 1H), 7.04
(m, 2H), 6.92 (d, 1H), 5.71 (s, 2H), 4.80 (s, 2H), 3.82 (m, 2H),
3.74 (m, 2H), 3.08 (s, 3H); MS m/z 588 (M+H.sup.+)
Example 22
[1018] 38
[1019]
6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-[4-(benz-
enesulphonyl)phenyl]-4-quinazolinamine
[1020] Prepared according to Procedure D from
5-(4-{4-(benzenesulphonyl)ph-
enyl}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and
2-methanesulphonyl-ethylamine (1 equiv). .sup.1H NMR (DMSO-d.sub.6)
10.27 (s, 1H), 8.78 (s, 1H), 8.65 (s, 1H), 8.18-8.22 (m, 3H),
7.97-8.01 (m, 4H), 7.86 (d, 1H), 7.62-7.72 (m, 3H), 7.10 (d, 1H),
6.51 (d, 1H), 3.84 (s, 1H), 3.28 (t, 2H), 3.03 (s, 3H), 2.99 (t,
2H); m/z (M+1).sup.+563.
Example 23
[1021] 39
[1022]
6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-N-
-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine
[1023] Prepared according to Procedure F from
6-iodo-(4-(benzenesulphonyl)- -phenyl)-quinazolin-4-ylamine (1
equiv), 2-ethoxyvinyl-tributylstannane (1 equiv),
N-bromosuccinimide (1 equiv) and N-(trifluoroacetyl)-N-(methanesu-
lphonylethyl)-aminomethylthioamide (1 equiv). .sup.1H NMR 400 MHz
(DMSO-d.sub.6) 9.80 (s, 1H); 8.87 (s, 1H); 8.65 (s, 1H); 8.64 (s,
1H); 8.17 (s, 1H); 8.03 (s, 1H); 7.98 (m, 2H); 7.66 (m, 5H); 4.73
(s, 2H); 3.68 (m, 2H); 3.55 (m, 2H); 3.12 (s, 3H); MS m/z 580
(M+1).sup.+, 578 (m-1).sup.-.
Example 24
[1024] 40
[1025]
6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-N-
-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine
[1026] Prepared according to Procedure F from
6-iodo-(4-(3-trifluoromethyl-
benzyloxy)-phenyl)quinazolin-4-ylamine (1 equiv),
2-ethoxyvinyl-tributylst- annane (1 equiv), N-bromosuccinimide (1
equiv) and N-(trifluoroacetyl)-N-(-
methanesulphonylethyl)-aminomethylthioamide (1 equiv). .sup.1H NMR
400 MHz (CD.sub.3OD) 9.40 (s, 1H); 8.75 (d, 1H); 8.73 (s, 1H); 8.35
(s, 1H); 7.89 (d, 1H); 7.77 (s, 1H); 7.73 (m, 1H); 7.61 (m, 3H);
7.52 (m, 1H); 7.14 (d, 2H); 5.24 (s, 2H); 4.82 (s, 2H); 3.85 (m,
2H); 3.76 (m, 2H); 3.10 (s, 3H); MS m/z 614 (M+1).sup.+, 612
(m-1).sup.-.
Example 25
[1027] 41
[1028]
N-{3-fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulpho-
nyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine
[1029] Prepared according to Procedure F from
6-iodo-4-(1-benzyl-1H-indazo- l-5-yl)-quinazolin-4-ylamine (1
equiv), 2-ethoxyvinyl-tributylstannane (1 equiv),
N-bromosuccinimide (1 equiv) and N-(trifluoroacetyl)-N-(methanesu-
lphonylethyl)-aminomethylthioamide (1 equiv). .sup.1H NMR 400 MHz
(CD.sub.3OD) 9.28 (s, 1H); 8.78 (s, 1H); 8.74 (d, 1H); 8.31 (s,
1H); 7.90 (d, 1H); 7.74 (d, 1H); 7.63 (m, 1H); 7.54 (m, 1H); 7.49
(m, 1H); 7.37 (m, 1H); 7.25 (m, 2H); 7.05 (m, 1H); 5.24 (s, 2H);
4.77 (s, 2H); 3.81 (m, 2H); 3.72 (m, 2H); 3.10 (s, 3H); MS m/z 582
(M+1).sup.+, 580 (m-1).sup.-
Example 26
[1030] 42
[1031]
N-(1-benzyl-1H-indazol-5-yl)-6-[2-({[2-(methanesulphonyl)ethyl]amin-
o}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine
[1032] Prepared according to Procedure F from
6-iodo-4-(1-benzyl-1H-indazo- l-5-yl)-quinazolin-4-ylamine (1
equiv), 2-ethoxyvinyl-tributylstannane (1 equiv),
N-bromosuccinimide (1 equiv) and N-(trifluoroacetyl)-N-(methanesu-
lphonylethyl)-aminomethylthioamide (1 equiv). .delta..sup.1H NMR
(d.sub.4 MeOH) 9.37 (s, 1H), 8.74 (m, 2H), 8.33 (s, 1H), 8.17 (s,
1H), 8.14, (s, 1H), 7.90 (d, 1H), 7.70 (m, 2H), 7.22 (m, 5H), 5.69
(s, 2H), 4.78 (s, 2H), 3.81 (m, 2H), 3.74 (m, 2H), 3.09 (s, 3H); MS
m/z 570 (M+H.sup.+).
Example 27
[1033] 43
[1034]
N-(3-Fluoro-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]am-
ino}methyl)-4-furyl]-4-quinazolinamine
[1035] Prepared according to Procedure D from
5-(4-{3-fluoro-4-benzyloxyan-
ilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and
2-methanesulphonyl-ethylamine (1 equiv). .sup.1H NMR 400 MHz
(DMSO-d.sub.6) 8.83 (s,1H); 8.35 (d,1H); 7.89 (d,1H); 7.83 (d,1H);
7.59 (d,1H); 7.48-7.31 (m,7H); 7.26 (s,1H); 6.83 (d,1H); 5.21
(s,2H); 4.42 (s,2H); 3.60 (m,2H); 3.44 (m, 2H, obscured by water
peak); 3.12 (s,3H); MS m/z 547 (M+H.sup.+).
Example 28
[1036] 44
[1037]
N-(3-Chloro-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]am-
ino}methyl)-4-furyl]-4-quinazolinamine
[1038] Prepared according to Procedure D from
5-(4-{3-chloro-4-benzyloxyan-
ilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and
2-methanesulphonyl-ethylamine (1 equiv). .sup.1H NMR 400 MHz
(DMSO-d.sub.6) 9.71 (bs, 2H); 9.45 (bs, 1H); 8.86 (s, 1H); 8.36 (d,
1H); 7.98 (d, 1H); 7.90 (d, 1H); 7.74 (d, 1H); 7.49-7.44 (m, 2H);
7.40 (m, 2H); 7.35-7.30 (m, 2H); 7.28 (d, 1H); 6.83 (d, 1H); 5.25
(s, 2H); 4.42 (s, 2H); 3.62 (m, 2H); 3.44 (m, 2H); 3.12 (s, 3H); MS
m/z 563 (M+H.sup.+).
Example 29
[1039] 45
[1040]
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulpho-
nyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine
[1041] Prepared according to Procedure D from
5-(4-{3-chloro-4-(3-fluorobe-
nzyloxy)-anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv)
and 2-methanesulphonyl-ethylamine (1 equiv). .sup.1H NMR 400 MHz
(DMSO-d.sub.6) 9.60 (bs, 1H); 9.32 (bs, 1H); 8.82 (bs, 1H); 8.34
(d, 1H); 8.0 (s, 1H); 7.88 (d, 1H); 7.74 (d, 1H); 7.45 (m, 1H);
7.34-7.23 (m, 4H); 7.17 (m, 1H); 6.83 (d, 1H); 5.27 (s, 2H); 4.42
(s, 2H); 3.59 (m, 2H); 3.40 (m, 2H, obscured by waterpeak); 3.12
(s, 3H); MS m/z 581 (M+H.sup.+).
Example 30
[1042] 46
[1043]
(4-Phenoxyphenyl)-(7-(2-(2-methanesulphonyl)ethylaminomethyl)thiazo-
l-4-yl)-quinolin-4-yl)amine
[1044] A suspension of
(4-(4-(4-phenoxy)anilino)-quinolin-7-yl)thiazole-2-- carbaldehyde
(0.05 g, 0.14 mmol), sodium triacetoxyborohydride (0.12 g, 0.56
mmol), methanesulphonylethylamine (0.15 g, 1.2 mmol) and powdered 3
.ANG. molecular sieves in dichloromethane (6 ml) and glacial acetic
acid (1 ml) was stirred at room temperature (21.degree. C.)
overnight (18 hrs) according to Procedure D. The crude reaction
mixture was filtered through a SPE column (SCX resin, 5 g, 25 ml),
sequentially washed with methanol (2.times.10 ml) and 10% ammonia
in methanol (3.times.10 ml) and the product isolated as a pale
yellow gum. Trituration with water (5 ml) and drying of the
resultant solid over phosphorus pentoxide at 60.degree. C. under
vacuum for 5 hrs yielded the purified product as a pale yellow
solid (0.031 g, 49%); .delta.H [.sup.2H.sub.6] DMSO 8.80(1H,s),
8.25(3H,m), 8.10(1H,s), 7.90(1H,d), 7.20(4H,2d), 6.85(5H,m),
6.60(1H,d), 3.95(2H,d), 2.90(7H,m); m/z 531 (M+1).sup.+.
Example 31
[1045] 47
[1046]
(4-Phenoxyphenyl)-(7-(4-(2-methanesulphonyl)ethylaminomethyl)thiazo-
l-5-yl)-quinolin-4-yl)amine
[1047] 4-(4-Phenoxyanilino) 7-(4-formyl thiazol-5-yl) quinoline(50
mg, 0.118 mmol), methanesulphonylethylamine (50 mg) and molecular
seives (4A, 2 large spatula tips) were stirred in a mixture of
dichloromethane (6 ml) and acetic acid (1 ml) at room temperature
for 2 hr (Procedure D). Sodium triacetoxyborohydride (0.12 g, 0.567
mmol) was then added and the reaction was stirred at room temp for
18 hr. The reaction mixture was added to a 5 g SCX cartridge and
washed with methanol, the product was eluted with 10% methanolic
ammonia. The product was triturated with water to give a beige
solid (39.7 mg); .delta.H [.sup.2H.sub.6] DMSO 9.32 (1H,s), 9.22
(1H,s), 8.64 (2H, m), 8.19 (1H, s), 7.87 (1H,d), 7.56 (4H, m), 7.27
(6H, m), 7.02 (1H, d), 4.07 (2H, s), 3.42 (2H,t), 3.14 (5H,m);m/z
531.
Example 32
[1048] 48
[1049]
(4-Phenoxyphenyl)-(7-(5-(2-(methanesulphonyl)ethylaminomethyl)furan-
-2-yl)-quinolin-4-yl)Amine
[1050]
5-(4-(4-phenoxyphenylamino)-quinolin-7-yl)furan-2-carbaldehyde
(0.05 g) was reacted with 2-(methanesulphonyl)ethylamine (0.075 g)
according to procedure D. Acidification with acetic acid (0.5 ml)
followed by purification using a ion-exchange (SCX) Bond Elut.TM.
cartridge, eluting with methanol-ammonia (9:1), concentration and
trituration with diethylether afforded an off-white solid; .delta.H
[.sup.2H.sub.6] DMSO 8.44 (1H, d), 8.41 (1H, d), 8.11 (1H, s), 7.85
(1H, d), 7.44-7.35 (4H, m), 7.18-7.03 (6H, m), 6.79 (1H, d), 6.47
(1H, d), 3.82 (2H, s), 3.01 (2H, t); m/z 514 (M+1).sup.+.
Example 33
[1051] 49
[1052]
6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-7-methoxy--
N-(4-benzenesulphonyl)phenyl-4-quinazolinamine
[1053] Prepared according to Procedure D from
5-(7-methoxy-4-(4-benzenesul-
phonyl)phenylamino-quinazolin-6-yl)furan-2-carbaldehyde
hydrochloride (0.6 equiv) and 2-methanesulphonyl (1 equiv).
.delta..sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.23 (s, 1H), 8.76(s,
1H), 8.59 (s, 1H), 8.14 (d, 2H), 7.96 (m, 4H), 7.59-7.71 (m, 3H),
7.33 (s, 1H), 7.03 (d, 1H), 6.47 (d, 1H), 4.06 (s, 3H), 3.86 (s,
2H), 3.27 (t, 2H), 3.00 (s, 3H), 2.98 (t, 2H). ESI-MS m/z
593(M+1).
Example 34
[1054] 50
[1055]
N-[4-(Benzyloxy)phenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]-
amino}methyl)-2-furyl]-4-quinazolinamine
[1056] Prepared according to Procedure D from a mixture of
5-(4-(4-benzyloxy-phenylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbalde-
hyde hydrochloride (0.13 grams) in 1,2-dichloroethane (3 ml),
diisopropylethylamine (65 mg), acetic acid (45 mg),
2-methanesulphonylethylamine (0.125 grams), and sodium
triacetoxyborohydride (0.27 grams). The mixture was stirred for 18
hours. The reaction mixture was quenched with methanol (3 ml) and
poured into a separatory funnel containing aqueous saturated sodium
hydrogen carbonate (100 ml) and ethyl acetate (100 ml). The mixture
was extracted. The organic layer was washed with water. The organic
layer was dried over magnesium sulfate, filtered, and concentrated.
The residue was treated with ethyl acetate/hexanes and collected by
filtration (0.083 g, 61% yield). .delta..sup.1H NMR (400 MHz,
DMSO-d.sub.6) 9.98(s, 1H), 8.83(d, 1H), 8.44(s, 1H), 7.58(m, 3H),
7.44(m, 2H), 7.37(m, 2H), 7.31 (m, 1H), 7.03(d, 1H), 6.91(m, 1H),
6.5(d, 1H), 5.1(s, 2H), 3.84(s, 1H), 3.25(m, 2H), 2.99(s, 3H),
2.96(m, 2H). ESI-MS m/z 545(M-1).
Example 35
[1057] 51
[1058]
N-(1-Benzyl-1H-indazol-5-yl)-7-fluoro-6-[5-({[2-(methanesulphonyl)e-
thyl]amino}methyl)-2-furyl]-4-quinazolinamine
[1059] Prepared according to Procedure D from
5-(4-(1-Benzyl-1H-indazol-5--
ylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde (0.6 equiv)
and 2-methanesulphonyl-ethylamine (1 equiv). .delta..sup.1H NMR
(400 MHz, DMSO-d.sub.6) 10.16(s, 1H), 8.91(d, 1H), 8.46(s, 1H),
8.11(s, 2H), 7.65(m, 3H), 7.26(m, 5H), 6.93(m, 1H), 6.54(d, 2H),
5.65(s, 2H), 3.89(s, 2H), 3.28(m, 2H), 2.99(m, 5H). ESI-MS m/z
569(M-1).
Example 36
[1060] 52
[1061]
N-[4-(Phenylsulphonyl)phenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)-
ethyl]amino}methyl)-2-furyl]-4-quinazolinamine
[1062] Prepared according to Procedure D from
5-(4-(4-Phenylsulphonylpheny-
lamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde (0.6 equiv)
and 2-methanesulphonyl-ethylamine (1 equiv). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 10.38(s, 1H), 8.87(d, 1H), 8.62(s, 1H), 8.11
(d, 2H), 7.95(m, 4H), 7.63(m, 4H), 6.94(m, 1H), 6.51 (d, 1H),
3.84(s, 2H), 3.25(m, 2H), 2.98(s, 3H), 2.95(m, 2H). ESI-MS m/z
579(M-1).
Example 37
[1063] 53
[1064]
N-(3-Trifluoromethyl-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl-
)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine
[1065] The mixture of
5-(4-(4-benzyloxy-3-trifluoromethylphenylamino)-quin-
azolin-6-yl)-furan-2-carbaldehyde (211 mg, 0.40 mmol),
2-methanesulphonyl-ethylamine (99 mg, 2.0 mmol), acetic acid (0.5
ml) in dichloromethane (15 ml) was stirred at room temperature for
1.5 hours then was heated to reflux for 1 hour. The mixture was
cooled to 0.degree. C. with ice bath. Sodium cyanoborohydride (50
mg, 0.8 mmol) was added at 0.degree. C. The reaction mixture then
was stirred at room temperature for 1 hour. Diluted with ethyl
acetate (50 ml), then quenched with saturated sodium bicarbonate
solution slowly. Extracted with ethyl acetate and the combined
organic extracts were washed with brine, dried over MgSO.sub.4 and
concentrated in vacuo. Purification of the resulting residue was
accomplished using flash chromatography on silica gel with 2%
methanol in ethyl acetate which afforded a yellow solid (0.10 g,
43% yield). H.sup.1 NMR (400 MHz, DMSO)..delta.10.0 (s, 1H), 8.7
(s, 1H), 8.5 (s,1H), 8.1 (d, 1H), 8.1 (s, 2H), 7.8 (d, 1H), 7.4 (m,
5H), 7.3 (m,1H), 7.0 (d, 1H), 6.5 (d,1H), 5.3 (s,2H), 3.8 (s,2H),
3.2 (m, 2H), 3.0 (s, 3H), 2.9 (m, 2H). ESI-MS m/z 597
(M+H).sup.+.
Further Examples
[1066] The compounds in Lists 1 to 48 above and their hydrochloride
salts, if appropriate, are prepared by analogous techniques using
the appropriate starting materials.
[1067] Biological Data
[1068] Compounds of the present invention were tested for protein
tyrosine kinase inhibitory activity in substrate phosphorylation
assays and cell proliferation assays.
[1069] Substrate Phosphorylation Assay
[1070] The substrate phosphorylation assays use baculovirus
expressed, recombinant constructs of the intracellular domains of
c-erbB-2 and c-erbB-4 that are constitutively active and EGFr
isolated from solubilised A431 cell membranes. The method measures
the ability of the isolated enzymes to catalyse the transfer of the
g-phosphate from ATP onto tyrosine residues in a biotinylated
synthetic peptide (Biotin-GluGluGluGluTyrPheGluLeuVal). Substrate
phosphorylation was detected following either of the following two
procedures: a.) c-ErbB-2, c-ErbB4 or EGFr were incubated for 30
minutes, at room temperature, with 10 mM MnCl.sub.2, 10 mM ATP, 5
mM peptide, and test compound (diluted from a 5 mM stock in DMSO,
final DMSO concentration is 2%) in 40 mM HEPES buffer, pH 7.4. The
reaction was stopped by the addition of EDTA (final concentration
0.15 mM) and a sample was transferred to a streptavidin-coated
96-well plate. The plate was washed and the level of
phosphotyrosine on the peptide was determined using a
Europium-labelled antiphosphotyrosine antibody and quantified with
a time-resolved fluorescence technique. b.) ErbB2 was incubated for
50 minutes at room temperature with 15 mM MnCl2, 2 mM ATP, 0.25 mCi
[.gamma.-.sup.33P] ATP/well, 5 mM peptide substrate, and test
compound (diluted from a 10 mM stock in DMSO, final DMSO
concentration is 2%) in 50 mM MOPS pH 7.2. The reaction was
terminated by the addition of 200 ml of PBS containing 2.5 mg/ml
streptavidin-coated SPA beads (Amersham Inc.), 50 mM ATP, 10 mM
EDTA and 0.1%TX-100. The microtitre plates were sealed and SPA
beads were allowed to settle for at least six hours. The SPA signal
was measured using a Packard Topcount 96-well plate scintillation
counter (Packard Instrument Co., Meriden, Conn.).
[1071] The results are shown in Tables 1 A (examples 1 to 7) and 1
B (examples 8 to 29 and 33 to 37) as the IC.sub.50 values.
1 TABLE 1A Substrate Phosphorylation Example erbB2 - assay (b)
EGF-r - assay (a) 1 +++ +++ 2 +++ +++ 3 +++ +++ 4 ++ +++ 5 +++ +++
6 ++ 7 +++ +++
[1072]
2TABLE 1B Substrate Phosphorylation Example erbB2 - assay (b) 8 +++
9 +++ 10 +++ 11 +++ 12 ++ 13 ++ 14 +++ 15 +++ 16 +++ 17 +++ 18 +++
19 +++ 21 +++ 22 +++ 23 +++ 24 +++ 25 +++ 26 +++ 27 +++ 28 +++ 29
+++ 33 +++ 34 +++ 35 +++ 36 +++ 37 +++ IC.sub.50 values Symbol
<0.10 .mu.M +++ 0.10 -1.0 .mu.M ++ 1.0-10.0 .mu.M + >10.0
.mu.M - Not determined ND
[1073] Cellular Assays: Methylene Blue Growth Inhibition Assay
[1074] Human breast (BT474), head and neck (HN5) and gastric tumor
(N87) cell lines were cultured in low glucose DMEM (Life
Technologies 12320-032) containing 10% fetal bovine serum (FBS) at
37.degree. C. in a humidified 10% CO.sub.2, 90% air incubator. The
SV40 transformed human mammary epithelial cell line HB4a was
transfected with either human H-ras cDNA (HB4a r4.2) or the human
c-erbB2 cDNA (HB4a c5.2). The HB4a clones were cultured in RPMI
containing 10% FBS, insulin (5 .mu.g/ml), hydrocortisone (5
.mu.g/ml), supplemented with the selection agent hygromycin B (50
.mu.g/ml). Cells were harvested using trypsin/EDTA, counted using a
haemocytometer, and plated in 100 ml of the appropriate media, at
the following densities, in a 96-well tissue culture plate (Falcon
3075): BT474 10,000 cells/well, HN5 3,000 cells/well, N87 10,000
cells/well, HB4a c5.2 3,000 cells/well, HB4a r4.2 3,000 cells/well.
The next day, compounds were diluted in DMEM containing 100 mg/ml
gentamicin, at twice the final required concentration, from 10 mM
stock solutions in DMSO. 100 ml/well of these dilutions were added
to the 100 ml of media currently on the cell plates. Medium
containing 0.6% DMSO was added to control wells. Compounds diluted
in DMEM were added to all cell lines, including the HB4a r4.2 and
HB4a c5.2 cell lines. The final concentration of DMSO in all wells
was 0.3%. Cells were incubated at 37.degree. C., 10% CO.sub.2 for 3
days. Medium was removed by aspiration. Cell biomass was estimated
by staining cells with 100 .mu.l per well methylene blue (Sigma
M9140, 0.5% in 50:50 ethanol:water), and incubation at room
temperature for at least 30 minutes. Stain was removed, and the
plates rinsed under a gentle stream of water, and air-dried. To
release stain from the cells 100 .mu.l of solubilization solution
was added (1% N-lauroyl sarcosine, Sodium salt, Sigma L5125, in
PBS), and plates were shaken gently for about 30 minutes. Optical
density at 620 nM was measured on a microplate reader. Percent
inhibition of cell growth was calculated relative to vehicle
treated control wells. Concentration of compound that inhibits 50%
of cell growth (IC.sub.50) was interpolated using nonlinear
regression (Levenberg-Marquardt) and the equation,
y=V.sub.max*(1-(x/(K+x)))+Y2, where "K" was equal to the
IC.sub.50.
[1075] Table 2 illustrates the inhibitory activity of compounds of
the present invention as IC.sub.50 values in .mu.M against a range
of tumor cell lines.
3 TABLE 2 Cell Proliferation HB4a HB4a Example erbB2 ras B1474 HN5
N87 1 +++ + +++ +++ +++ 2 +++ + +++ +++ +++ 3 +++ + +++ +++ +++ 4
+++ - +++ +++ +++ 5 +++ - +++ +++ +++ 6 +++ - +++ +++ +++ 7 +++ ++
+++ +++ +++ 8 +++ ++ +++ +++ +++ 9 +++ ++ +++ +++ +++ 10 +++ ++ +++
+++ +++ 11 +++ - +++ +++ +++ 12 +++ - +++ ++ +++ 13 ++ - ++ + ++ 14
+++ - +++ +++ +++ 15 +++ - +++ +++ +++ 16 +++ ++ +++ +++ +++ 17 ++
++ +++ ++ ++ 18 +++ ++ +++ +++ +++ 19 +++ - +++ +++ +++ 20 +++ -
+++ ++ +++ 21 +++ ++ +++ +++ +++ 22 +++ + +++ +++ +++ 23 +++ + +++
+++ ++ 24 ++ - ++ +++ ++ 25 +++ - +++ +++ +++ 26 +++ ++ +++ +++ +++
27 +++ ++ +++ +++ +++ 28 +++ + +++ +++ +++ 29 +++ - +++ +++ +++ 33
+++ ++ +++ +++ +++ 34 +++ - +++ +++ +++ 35 +++ + +++ +++ +++ 36 ++
- ++ ++ ++ 37 +++ + +++ +++ +++ IC.sub.50 value Symbol <5 .mu.M
+++ 5-25 .mu.M ++ 25-50 .mu.M + >50 .mu.M - Not determined
ND
[1076] Major Metabolites:
[1077] Liver S-9 homogenates (5 mg/mL protein concentration) from
prepared pooled male Sprague Dawley rat livers and pooled human
livers (XenoTech, LLC, Kansas City, Kans.) were incubated in
96-well polypropylene plates with representative examples selected
from examples 1 to 40 (10 .mu.M) in a total volume of 0.5 mL. Stock
solutions of these compounds were prepared in DMSO at a
concentration of 1 mM to maintain a <1% final DMSO concentration
for each reaction. Enzymatic incubations contained cofactors (5.71
mM NADPH, 7.14 mM glucose-6-phosphate, 7.14 mM UDPGA, 47.1 mM
potassium chloride, and 11.4 mM magnesium chloride in 0.1 M
potassium phosphate buffer, pH 7.4). Control samples were aspirated
from the reaction samples at time zero and placed immediately into
2 volumes of ice-chilled acetonitrile. Sample reaction plates were
incubated for 60 min in a shaker incubator maintained at 37.degree.
C. supplied with O.sub.2. Reactions were terminated by addition of
2 volumes of ice-chilled acetonitrile. All samples were vortexed
and centrifuged at 2000.times.g for 10 min. The supernatant was
removed and analyzed by LC-MS. The metabolite identification work
was done by using reversed-phase HPLC coupled with ion-trap mass
spectroscopy.
[1078] For example: 54
[1079]
N-[4-(Benzyloxy)phenyl]-6-[4-(aminomethyl)-2-furyl]-4-quinazolinami-
ne 55
[1080] Prepared according to Procedure D and identified as a major
metabolite of
N-[4-(benzyloxy)phenyl]-6-[4-({[2-(methanesulphonyl)ethyl]a-
mino}methyl)-2-furyl]-4-quinazolinamine in .sup.1HNMR 300 MHz,
CDCl3 8.69(s,1H), 8.11 (s,1H), 8.02 (d,1H), 7.88 (d, 1H), 7.61
(d,2H), 7.5-7.2 (m,7H), 7.05 (d,2H), 6.83 (s,1H), 5.10 (s,2H), 3.82
(s,2H); MS m/z 423 (M+1).
[1081] Thus, particular compounds of interest as metabolites
(either as isolated compounds or compounds in vivo) are compounds
of formula (XVII): 56
[1082] in which Ar, Y, V, X and U are as defined above; all
possible preferments for these groups as defined above are
applicable.
[1083] Compounds of formula (XII) of special interest include:
[1084]
4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-(aminomethyl)-furan-2-yl)-pyrid-
o[3,4-d]pyrimidin-4-yl)-amine;
[1085]
(4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-(aminomethyl)-furan-2-yl)-pyri-
do[3,4-d]pyrimidin-4-yl)-amine;
[1086]
(4-Benzenesulphonyl-phenyl)-(6-(5-(aminomethyl)-furan-2-yl)-pyrido[-
3,4-d]pyrimidin-4-yl)-amine;
[1087]
(4-Benzyloxy-phenyl)-(6-(3-(aminomethyl)phenyl-pyrido[3,4-d]pyrimid-
in-4-yl)-amine;
[1088]
(4-Benzyloxy-phenyl)-(6-(5-(aminomethyl)-furan-2-yl)-quinazolin-4-y-
l)-amine;
[1089] (4-(3-Fluorobenzyloxy-phenyl)-(6-(4-(aminomethyl)-fu
ran-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;
[1090]
(4-Benzyloxy-phenyl)-(6-(2-(aminomethyl)-thiazol-4-yl)-quinazolin-4-
-yl)-amine;
[1091]
N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[5-(aminomethyl)-2-furyl]-4-qui-
nazolinamine;
[1092]
N-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenyl}-6-[5-(aminomethyl)-2-fu-
ryl]-4-quinazolinamine;
[1093]
N-[4-(Benzyloxy)phenyl]-7-methoxy-6-[5-(aminomethyl)-2-furyl]-4-qui-
nazolinamine;
[1094]
N-[4-(Benzyloxy)phenyl]-6-[4-(aminomethyl)-2-furyl]-4-quinazolinami-
ne;
[1095]
N-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenyl}-6-[2-(aminomethyl)-1,3--
thiazol-4-yl]-4-quinazolinamine;
[1096]
N-{4-[(3-Bromobenzyl)oxy]phenyl}-6-[2-(aminomethyl)-1,3-thiazol-4-y-
l]-4-quinazolinamine;
[1097]
N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[2-(aminomethyl)-1,3-thiazol-4--
yl]-4-quinazolinamine;
[1098]
N-[4-(Benzyloxy)-3-fluorophenyl]-6-[2-(aminomethyl)-1,3-thiazol-4-y-
l]-4-quinazolinamine;
[1099]
N-(1-Benzyl-1H-indazol-5-yl)-7-methoxy-6-[5-(aminomethyl)-2-furyl]--
4-quinazolinamine;
[1100]
6-[5-(aminomethyl)-2-furyl]-N-(4-{[3-(trifluoromethyl)benzyl]oxy}ph-
enyl)-4-quinazolinamine;
[1101]
N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-(aminomethyl)-2-fur-
yl]-4-quinazolinamine;
[1102]
N-{4-[(3-Bromobenzyl)oxy]phenyl}-6-[5-(aminomethyl)-2-furyl]-4-quin-
azolinamine;
[1103]
N-[4-(Benzyloxy)phenyl]-6-[3-(aminomethyl)-2-furyl]-4-quinazolinami-
ne;
[1104]
N-[1-(3-Fluorobenzyl)-1H-indazol-5-yl]-6-[2-(aminomethyl)-1,3-thiaz-
ol-4-yl]-4-quinazolinamine;
[1105]
6-[5-(Aminomethyl)-2-furyl]-N-[4-(benzenesulphonyl)phenyl]-4-quinaz-
olinamine;
[1106]
6-[2-(Aminomethyl)-1,3-thiazol-4-yl]-N-[4-(benzenesulphonyl)phenyl]-
-4-quinazolinamine;
[1107]
6-[2-(Aminomethyl)-1,3-thiazol-4-yl]-N-(4-{[3-(trifluoromethyl)benz-
yl]oxy}phenyl)-4-quinazolinamine
[1108]
N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-(aminomethyl)-1,3-t-
hiazol-4-yl]-4-quinazolinamine;
[1109]
N-(1-Benzyl-1H-indazol-5-yl)-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-
-quinazolinamine;
[1110]
N-(3-Fluoro-4-benzyloxyphenyl)-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-
-4-quinazolinamine;
[1111]
N-(3-Chloro-4-benzyloxyphenyl)-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-
-4-quinazolinamine;
[1112]
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-(aminomethyl)-2-fur-
yl]-4-quinazolinamine;
[1113]
(4-Phenoxyphenyl)-(7-(2-(aminomethyl)-thiazol-4-yl)-quinolin-4-yl)a-
mine;
[1114]
(4-Phenoxyphenyl)-(7-(4-(aminomethyl)-thiazol-5-yl)-quinolin-4-yl)a-
mine;
[1115]
(4-Phenoxyphenyl)-(7-(5-(aminomethyl)-furan-2-yl)-quinolin-4-yl)ami-
ne;
[1116]
6-[5-(Aminomethyl)-2-furyl]-7-methoxy-N-(4-phenylsulphonyl)phenyl-4-
-quinazolinamine;
[1117]
N-[4-(Benzyloxy)phenyl]-7-fluoro-6-[5-(aminomethyl)-2-furyl]-4-quin-
azolinamine;
[1118]
N-(1-Benzyl-1H-indazol-5-yl)-7-fluoro-6-[5-(aminomethyl)-2-furyl]-4-
-quinazolinamine;
[1119]
N-[4-(Benzenesulphonyl)phenyl]-7-fluoro-6-[5-(aminomethyl)-2-furyl]-
-4-quinazolinamine;
[1120]
N-(3-Trifluoromethyl-4-benzyloxyphenyl)-6-[5-(aminomethyl)-4-furyl]-
-4-quinazolinamine;
[1121] and salts or solvates thereof, particularly pharmaceutically
acceptable salts thereof.
* * * * *