Indian Patents
Title of Invention

"A SUBSTITUTED QUINAZOLINE COMPOUNDS"
Abstract The present invention relates to a substituted quinazoline compound of the formula IId: wherein: M, R2a, R2b, R2c, R2d and Q1, Q2 are such as herein described in the specification.
Full Text The present invention relates to a substituted quinazoline compound
The present invention relates to quinazoline derivatives, processes for their preparation, pharmaceutical compositions containing them as active ingredient, methods for the treatment of disease states associated with angiogenesis and/or increased vascular permeability, to their use as medicaments and to their use in the manufacture of medicaments for use in the production of antiangiogenie and/or vascular permeability reducing effects in warm-blooded animals such as humans.
Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function. Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et a], 1995, Treads PharmacoL Sci. 16: 57-66; Folkman, 1995, Nature Medicine 1: 27-31). Alteration of vascular permeability is thought to play a role in both normal and pathological physiological processes (Cullinan-Bove et al, 1993, Endocrinology 133: 829-837; Senger et al, 1993, Cancer and Metastasis Reviews, 12: 303-324). Several polypeptides with in vitro endothelial cell growth promoting activity have been identified including, acidic and basic fibroblast growth factors (aFGF & bFGF) and vascular endothelial growth factor (VEGF). By virtue of the restricted expression of its receptors, the growth factor activity of VEGF, in contrast to that of the FGFs, is relatively specific towards endothelial cells. Recent evidence indicates that VEGF is an important stimulator of both normal and pathological angiogenesis (Jakeman et al, 1993, Endocrinology, 133: 848-859; Kolch et al, 1995, Breast Cancer Research and Treatment, 36:139-155) and vascular permeability (Connolly et al, 1989, J. Biol. Chem. 264: 20017-20024). Antagonism of VEGF
action by sequestration of VEGF with antibody can result in inhibition of tumour growth (Kim efal, 1993, Nature 362: 841-844). -Basic FGF (bFGF) is a potent stimulator of augiogenesis (e.g. Hayek et al, 1987, Biochem. Biophys. Res. Commun. 147: 876-880) and raised levels of FGFs have been found in the serum (Fujimoto et al, 1991, Biochem. Biophys. Res. Commun. 180: 386-392) and urine (Nguyen et al, 1993, J. Natl. Cancer. lost. 85: 241-242) of patients with cancer.
Receptor tyrosiue kinases (RTKs) are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules

characteristically consist of an extracellular ligand-binding domain connected through a
segment in the plasma membrane to an intracellular tyrosine kinase domain. Binding of ligand
to the receptor results in stimulation of the receptor-associated tyrosine kinase activity which
leads to phosphorylation of tyrosine residues on both the receptor and other intracellular
molecules. These changes in tyrosiue phosphorylation initiate a signalling cascade leading to a
variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by
amino acid sequence homo logy, have been identified. One of these subfamilies is presently
comprised by the fins-like tyrosine kinase receptor, Flt-1, the kinase insert domain-containing
receptor, KDR (also referred to as FTk-1), and another fins-like tyrosine kinase receptor, Flt-4.
Two of these related RTKs, Flt-1 and KDR, have been shown to bind VEGF with high affinity
(De Vries et al, 1992, Science 255: 989-991; Terman et al, 1992, Biochem. Biophys. Res.
Comra 1992, 187: 1579-1586). Binding of VEGF to these receptors expressed in
heterologous cells has been associated with changes in the tyrosine phosphorylation status of
cellular proteins and calcium fluxes.
The present invention is based on the discovery of compounds that surprisingly inhibit
the effects of VEGF, a property of value in the treatment of disease states associated with
angiogeiiesis and/or increased vascular permeability such as cancer, diabetes, psoriasis,
rheumatoid arthritis, Kaposi's sarcoma, haemangioma, lymphoedema, acute and chronic
nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation,
excessive scar formation and adhesions, endometriosis, dysfunctional uterine bleeding and
ocular diseases with retinal vessel proliferation including macular degeneration.
VEGF is a key stimulus for vasculogenesis and angiogenesis. This cytokine induces a
vascular sprouting phenotype by inducing endothelial cell proliferation, protease expression
and migration, and subsequent organisation of cells to form a capillary tube (Keck, P.J.,
Hauser, S.D., Krivi, G., Sanzo, K., Warren, T., Feder, J., and Connolly, D.T., Science
(Washington DC), 246: 1309-1312, 1989; Lamoreaux, W.J., Fitzgerald, ME., Reiner, A.,
Hasty, K.A., and Charles, S.T., Microvasc. Res., 55: 29-42, 1998; Pepper, M.S., Montesano,
R., Mandroita, S.J., Orci, L. and Vassalli, J.D., Enzyme Protein, 49: 138-162, 1996.). In
addition, VEGF induces significant vascular permeability (Dvorak, H.F., Detmar, M., Claffey,
K.P., Nagy, J.A., van de Water, L., and Senger, D.R., (Int. Arch, Allergy ImmunoL, 107: 233-
235, 1995; Bates, D.O., Heald, R.I., Curry, F.E. and Williams, B. J. Physiol. (Lond.), 533:
263-272, 2001), promoting formation of a hyper-permeable, immature vascular network which
is characteristic of pathological angiogenesis.
It has been shown that activation of KDR alone is sufficient to promote all of the major
phenotypic responses to VEGF, including endothelial cell proliferation, migration, and survival,
and the induction of vascular permeability (Meyer, M., Clauss, M., Lepple-Wienhues, A.,
Waltenberger, J., Augustin, H.G., Ziche, M., Lanz, C, Biittner, M., Rziha, H-J., and Dehio,
C., EMBO J., 18: 363-374, 1999; Zeng, H., Sanyal, S. and Mukhopadhyay, D., J. Biol. Chem,
276: 32714-32719, 2001; Gille, H., Kowalski, J., Li, B., LeCouter, J., Moffat, B, Zioncheck,
T.R, Pelletier, N. and Ferrara, N., J. Biol. Chera, 276: 3222-3230, 2001).
mtemational patent application publication number WO 00/47212 describes VEGF
receptor tyrosine kinase inhibitors. Compounds of WO 00/47212 possess activity against
VEGF receptor tyrosine kinase (RTK) such that they may be used in an amount sufficient to
inhibit VEGF RTK whilst demonstrating no significant activity against EGF RTK. Their
VEGF RTK inhibitory activity is due both to activity against KDR and against Flt-1, but
generally they are more potent against KDR. Generally they have extended plasma
pharmacokinetics. Some VEGF RTK inhibitors have been found to act as potassium channel
blockers and are positive in a hERG assay; such activity may give rise to ECG
(electrocardiogram) changes in vivo. Compounds of WO 00/47212 have predominantly basic
side chains.
Surprisingly we have now found compounds of the present invention to be very potent
KDR inhibitors but to have less activity against Flt-1 than compounds of WO 00/47212, to
have less extended plasma pharmacokinetics than compounds of WO 00/47212 and to be
inactive or only weakly active in a hERG assay. Compounds of the present invention have
predominantly neutral side chains. Compounds of the present invention have a beneficial
toxicological profile compared to compounds of WO 00/47212.
According to one aspect of the present invention there is provided the use of a
compound of the formula I:
(Figure Remove) wherein:
ring C is an 8, 9, 10, 12 or 13-membered bicyclic or tricyclic moiety which moiety may be
saturated or unsaturated, which roay be aromatic or non-aromatic, and which optionally may
contain 1-3 hetero atoms selected independently from 0, N and S;
Z is -O-, -NH- or -S-;
nisO, 1,2,3, 4 or 5;
misO, 1,2 or 3;
R2 represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, d.3alkyl, Ci.3alkoxy,
Ci-salkylsulphanyl, -NR3R4 (wherein R3 and R4, which may be the same or different, each
represents hydrogen or Ci_3alkyl), or R5X'- (wherein X1 represents a direct bond, -O-, -CH2-, -
OC(O)-, -C(0)-, -S-, -SO-, -SO2-, -NR6C(0)-, -C(O)NR7-, -SO2NR8-, -NR9S02- or -NR10-
(wherein R6, R7, R8, R9 and R10 each independently represents hydrogen, Ci_3alkyl or Ci.
salkoxyC^alkyl), and R5 is selected from one of the following twenty-two groups:
1) hydrogen, oxiranylCi^alkyl or Ci-salkyl which may be unsubstituted or which may be
substituted with one or more groups selected from hydroxy, fluoro, chloro, bromo and amino;
2) Ci.5alkylX2C(O)Rn (wherein X2 represents -0- or -NR12- (in which R12 represents
hydrogen, C,.3alkyl or Ci.3alkoxyC2.3alkyl) and R11 represents Ci-3alkyl, -NR13R14 or -OR^
(wherein R13, R14 and R15 which may be the same or different each represents hydrogen, Ci.
5alkyl or Ci-3alkoxyC2.3alkyl));
3) C,.5alkylX3R16 (wherein X3 represents -0-, -S-, -SO-, -SOr, -OC(0)-, -NR17C(O)-, -
C(O)NR18-, -S02NR19-, -NR20SO2- or -NR21- (wherein R17, R18, R19, R20 and R21 each
independently represents hydrogen, C].3alkyl or Ci-3alkoxyC2.3a3kyl) and R16 represents
hydrogen, Ci-3alkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which Ci-3alkyl group may
bear 1 or 2 substitueuts selected from oxo, hydroxy, halogeno and Ci^alkoxy and which cych'c
group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C\.
4cyanoalkyl, d-»aJkyI, CMhydroxyalkyl, CMalkoxy, CMalkoxyC^alkyl,
4alkyl, d-4alkoxycarbonyl, d^arninoalkyl, CMalkylamino, di(CMalkyl)amino,
4aDcylafflinod-4a]kyl, di(Ci-ialkyl)aminoCMalkyl, CiwialkylamkioQ^alkox
4alkyl)arninod-4alkoxy and a group -(-O-)((CMaIkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and
ring D is a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which cyclic group may bear one or more substitueuts selected
from Chalky!));
4) Ci.5alkylX4Ci.5alkyLX5R22 (wherein X4 and X5 which may be the same or different are each -
O-, -S-, -SO-, -SO2-, -NR23C(O)-, -QOJNR24-, -SO2NR25-, -NR26SO2- or -NR27- (wherein
R23, R24, R25, R26 and R27 each independently represents hydrogen, Ci.3alkyl or d-salkoxyd.
3alkyl) and R22 represents hydrogen, Ci-salkyl or Ci^alkoxyCi-salkyl);
5) R28 (wherein R28 is a 5-6-membered saturated heterocyclic group (linked via carbon or
nitrogen) with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic
group may bear 1 or 2 substitueuts selected from oxo, hydroxy, halogeno, cyano, Ci.
4cyauoalkyl, Ci^alkyl, Ci^hydroxyalkyl, Ciwjalkoxy, d^alkoxyCi^alkyl, Ci^alkylsulphonylCi.
4alkyl, Ci^alkoxycarbonyl, CMaminoalkyl, CMalkylamino, di(Ci^alkyl)amino, Ci.
4alkylainiuoCMalkyl, di(Cj^alkyl)aininoCi.4alkyl, Ci-ialkylaminoCi^alkoxy, di(Ci-
4alkyl)aininoCMa]koxy and a group -(-0-) ring D is a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which cyclic group may bear one or more substituents selected
fromCialkyl));
6) Ci-salkylR28 (wherein R28 is as defined hereinbefore);
7) Cz.jaJkeuylR28 (wherein R28 is as defined hereinbefore);
8) Cz-salkynylR28 (wherein R28 is as defined hereinbefore);
9) R29 (wherein R29 represents a pyridone group, a phenyl group or a 5-6-membered aromatic
heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N
and S, which pyridone, phenyl or aromatic heterocyclic group may carry up to 5 substituents
selected from oxo, hydroxy, halogeuo, amiuo, Ci^alkyl, CMalkoxy, d-Jiydroxyalkyl, d.
4aminoalkyl, d^alkylamino, d^hydroxyalkoxy, carboxy, trifluoromethyl, cyano, -
C(0)NR30R31, -NR32C(O)R" (wherein R30, R31, R32 and R33, which may be the same or
different, each represents hydrogen, Chalky! or Ci.3alkoxyC2.3alkyl) and a group -(-0-XQ.
4a]kyl)£ringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independently from 0, S and N, which
cyclic group may bear one or more substituents selected from Chalky!));
10) Q.salkylR29 (wherein R29 is as defined hereinbefore);
11) C2.sallcenylR29 (wherein R29 is as defined hereinbefore);
12) Q-salkynylR29 (wherein R29 is as defined hereinbefore);
13) d.jalkylX'R29 (wherein X* represents -O-, -S-, -SO-, -SO2-, -NR34C(O)-, -C(0)NR33-, -
SO2NR36-, -NR37SOr or -NR38- (wherein R34, R35, R36, R37 and R38 each independently
represents hydrogen, Ci.jalkyl or C]-3alkoxyd-3alkyl) and R29 is as defined hereinbefore);
14) C2.3alkenylX7R29 (wherein X7 represents -0-, -S-, -SO-, -SO2-, -NR39C(O)-, -C(O)NR40-, -
SO2NR41-, -NR42SO2- or -NR43- (wherein R39, R40, R41, R42 and R43 each independently
represents hydrogen, d-3alkyl or djalkoxyC^alkyl) and R29 is as defined hereinbefore);
15) C2.5alkynylX8R29 (wherein X8 represents -O-, -S-, -SO-, -SO2-, -NR^QO)-, -C(O)NR45-, -
SO2NR46-, -NR47SO2- or -NR48- (wherein R44, R43, R46, R47 and R48 each independently
represents hydrogen, d-3alkyl or C].3alkoxyC2_3alkyl) and R29 is as defined hereinbefore);
16) CMaLkylX9CMalkylR29 (wherein X9 represents -0-, -S-, -SO-, -SO2-, -NR49C(O)-, -
C(O)NR50-, -SO2NR51-, -NR5ZSO2- or -NR53- (wherein R49, R50, R51, R52 and R53 each
independently represents hydrogen, Chalky! or Ci.3alkoxyC2.3alkyl) and R29 is as defined
hereinbefore);
17) C].4alkylX9CMalkylR28 (wherein X9 and R28 are as defined hereinbefore);
18) C2.5a]kenyl which may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, d^alkylamino, N,N-di(d^alkyl)amino,
aminosulphonyl, N-CMalkylaminosulphonyl and N,N-di(CMalkyl)arninosulphonyl;
19) C2-5alkynyl which may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, d^alkylaiuino, N,N-di(CMalkyl)amino,
aminosulphouyl, N-CMalkylaminosulphonyl and N,N-di(dw»alkyl)aniiuosulphouyl;
20) C2.5alkenylX!>CMalkyIR28 (wherein X9 and R28 are as defined hereinbefore);
21) C2.3alkyny]X9CMalkylR28 (wherein X9 and R28 are as defined hereinbefore); and
22) CMalkylR54(CMalkyl)q(X9)rR" (wherein X9 is as denned hereinbefore, q is 0 or 1, r is 0 or
1, and R54 and R55 are each independently selected from hydrogen, Ci.3alkyl, cyclopentyl,
cyclohexyl and a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected
independently from 0, S and N, which d.3alkyl group may bear 1 or 2 substituents selected
fromoxo, hydroxy, halogeno and Ci^alkoxy and which cyclic group may bear 1 or 2
substitueuts selected from oxo, hydroxy, halogeno, cyano, CMcyanoalkyl, Chalky!, Ci.
dhydroxyalkyl, Cwalkoxy, Ci^alkoxyCMalkyl, CMalkylsulphouylCMalkyI, Ci^alkoxycarbonyl,
Ci^arninoalkyl, CMalkylamino, di(Ci.4alkyl) amino, CMalkylaminoCi^alkyl, di(C|.
4alkyl)aminoCi.4a]kyl, Ci^alkylarninoCi-aalkoxy, di(Cwalkyl)aminoCi-4alkoxy and a group -(-
O-)f(Ci.4alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from Chalky!), with the proviso that
R54 cannot be hydrogen);
and additionally wherein any Ci.jalkyl, Cz-salkenyl or C2.jalkynyl group in R5X!- which is
linked to X1 may bear one or more substitueuts selected from hydroxy, halogeno and amino);
R1 represents hydrogen, oxo, halogeno, hydroxy, Ci^alkoxy, Chalky!, Ci-aalkoxymethyl, Ciaalkanoyl,
CiJialoalkyl, cyano, amino, Ca-salkenyl, Cz-salkynyl, d-3alkanoyloxy, nitro, Ci.
4alkanoylamino, Ci^alkoxycarbonyl, C^alkylsulphanyl, Ci^alkylsulphinyl, Ci^alkylsulphonyl,
carbamoyl, N-Ci^alkylcarbamoyl, N,N-di(Ci-4a]kyl)carbamoyl, aminosulphouyl, N-Ci.
4alkylsulphonyl)-N-(C]^alkyl)amiuo, N,N-di(CMalkylsulphonyl)amino, a Cs^alkylene chain
joined to two ring C carbon atoms, Ci^alkanoylamiuoCi^alkyl, carboxy or a group R56X10
(wherein X10 represents a direct bond, -O-, -CH2-, -OC(O)-, -C(O)-, -S-, -SO-, -SOr, -
NR57C(O)-, -C(O)NR58-, -SO2NR'9-, -NR60SO2- or -NR61- (wherein R37, R58, R59, R60 and R61
each independently represents hydrogen, Ci.3alkyl or Ci-3alkoxyC2-3alkyl), and R56 is selected
from one of the following twenty-two groups:
1) hydrogen, oxirauylCi^alkyl or Ci.jalkyl which may be unsubstituted or which may be
substituted with one or more groups selected from hydroxy, fluoro, chloro, bromo and amino;
2) C,.5alkylXuC(O)R" (wherein X11 represents -O- or -NR63- (in which R63 represents
hydrogen, C,.3alkyl or C,.3alkoxyC2.3aIkyl) and R62 represents C^alkyl, -NR64R65 or -OR66
(wherein R64, R65 and R66 which may be the same or different each represents hydrogen, d.
5alkyl or Ci.3alkoxyC2.3alkyl));
3) Ci.5alkylX12R67 (wherein X12 represents -O-, -S-, -SO-, -SO2-, -OC(0)-, -NR68C(O)-, -
C(0)NR69-, -S02NR™-, -NR7IS02- or -NR72- (wherein R68, R69, R70, R71 and R72 each
independently represents hydrogen, Ci.3a]kyl or Ci.3alkoxyC2.3alkyl) and R67 represents
hydrogen, d-salkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which Ci-3alkyl group may
bear 1 or 2 substituents selected from oxo, hydroxy, halogeuo and Ci^alkoxy and which cyclic
group may bear 1 or 2 substitueuts selected from oxo, hydroxy, halogeno, cyano, Ci.
4cyanoalkyl, CMalkyl, Ci Jiydroxyalkyl, CMalkoxy, CMalkoxyC^alkyl, Cj^alkylsulphonylCi-
4alkyl, Ci^alkoxycarbonyl, CMaminoalkyl, Chalky larnino, di(CMalky])amino, C\.
4alkylaiBinoCi^alkyl, di(CMalkyl)aminoCi^alkyl, CMalkylaminoCi^alkoxy, di(Ci.
4alkyl)aminoCMalkoxy and a group -(-O-)r(Ci^alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and
ring D is a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected
independently from 0, S and N, which cyclic group may bear one or more substituents selected
from CMalkyl));
4) Ci.5alkylX13Ci.salkylX14R73 (wherein X13 and X14 which may be the same or different are
each-0-, -S-, -SO-, -SO2-, -NR74C(O)-, -C(O)NR75-, -SO2NR76-, -NR77SO2- or -NR78-
(wherein R7a, R7S, R76, R77 and R78 each independently represents hydrogen, Ci.3alkyl or Ci.
salkoxyCwalkyl) and R73 represents hydrogen, Chalky! or Ci-jalkoxyCz-salkyl);
5) R79 (wherein R79 is a 5-6-membered saturated heterocyclic group (linked via carbon or
nitrogen) with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic
group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C\.
4cyanoalkyl, Chalky!, Ci^thydroxyalkyl, Ci^alkoxy, Ci-4a]koxyCi-4alkyl,
4alkyl, Ci_4alkoxycarbonyl, Ci-aaminoalkyl, Ci^alkylamuio, di(CMalkyl)amino,
4alkylaminoCMalkyl, d^Ci^alky^amiuoCMalkyl, Ci^alkylaminoCMalkox
4alkyl)aminoCMalkoxy and a group -(-O-)j(CMalkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and
ring D is a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected
independently from 0, S and N, wliich cyclic group may bear one or more substituents selected
from CMalkyl));
6) Ci-salkylR79 (wherein R79 is as defined hereinbefore);
7) C2-5alkenylR79 (wherein R79 is as defined hereinbefore);
8) Cz-salkynylR79 (wherein R79 is as defined hereinbefore);
9) R (wherein R80 represents a pyridone group, a phenyl group or a 5-6-membered aromatic
heterocyclic group (IhJced via carbon or nitrogen) with 1-3 heteroatoms selected from O, N
and S, which pyridone, phenyl or aromatic heterocyclic group may carry up to 5 substitueuts
selected from oxo, hydroxy, halogeno, arnino, Chalky!, CMalkoxy, d Jiydroxyalkyl, Q.
4aminoalkyl, Ci^alkylamino, Ci-^hydroxyalkoxy, carboxy, trifluoromethyl, cyano, -
C(O)NR81R82, -NR83C(O)R84 (wherein R81, R82, R83 and R84, which may be the same or
different, each represents hydrogen, Chalky! or Ci.3alkoxyC2.3alkyl) and a group -(-O-)f(Ci.
4alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independently from 0, S and N, which
cyclic group may bear one or more substituents selected from Chalky!));
10) Ci.jalkylR80 (wherein R80 is as defined hereinbefore);
11) C2.5alkenylR80 (wherein R80 is as defined hereinbefore);
12) C2.5alkynylR80 (wherein R80 is as defined hereinbefore);
13) Ci.jalkylX15R80 (wherein X15 represents -O-, -S-, -SO-, -SOr> -NR85C(O)-, -C(O)NR86-, -
SO2NR87-, -NR88SOr or -NR89- (wherein R85, R86, R87, R88 and R89 each independently '
represents hydrogen, Cijalkyl or Ci-salkoxyC^alkyl) and R80 is as defined hereinbefore);
14) C2.5alkenylX16R80 (wherein X16 represents -O-, -S-, -SO-, -SO2-, -NR90C(O)-, -C(O)NR91-,
-SO2NR92-, -NR93S02- or -NR94- (wherein R90, R91, R92, R93 and R94 each independently
represents hydrogen, Ci.3alkyl or Ci-3alkoxyC2.3alkyl) and R80 is as defined hereinbefore);
15) C2.5alkynylX17R80 (wherein X17 represents -O-, -S-, -SO-, -SO2-, -NR95C(O)-, -C(O)NR96-,
-SO2NR97-, -NR98SO2- or -NR99- (wherein R95, R96, R97, R98 and R99 each independently
represents hydrogen, C^alkyl or CualkoxyCa-salkyl) and R80 is as defined hereinbefore);
16) CMalkylX18CMalkylR80 (wherein X18 represents -0-, -S-, -SO-, -SO2-, -NR100C(0)-, -
C(0)NR101-, -S02NR102-, -NR103S02- or -NR104- (wherein R100, R101, R102, R103 and R104 each
independently represents hydrogen, Ci-salkyl or Ci-3alkoxyC2-3alkyl) and R80 is as defined
hereinbefore);
17) CMalkylX18CMalkylR79 (wherein X18 and R79 are as defined hereinbefore);
18) C2.3alkenyl which may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, CMalkylamiuo, N,N-di(Ci-»alkyl)amino,
aminosulphouyl, N-CMalkylaminosulphouyl and N,N-di(CMalkyl)aminosulphonyl;
19) C2_5alkynyl which may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, Ci^alkylainino, N,N-di(Ci^aIkyl)amiuo,
aminosulphouyl, N-CMalkylaminosulphonyl and N,N-di(Ci^alkyl)aminosulphonyl;
20) C2.5alkenylX18CMalkylR79 (wherein X18 and R79 are as defined hereinbefore);
21) C2.5alkynylX18CMalky]R79 (wherein X18 and R79 are as defined hereinbefore); and
22) CMalkylR105(CMalkyl)x(X18)yR106 (wherein X18 is as defined hereinbefore, x is 0 or 1, y is 0
or 1, and R105 and R106 are each independently selected from hydrogen, Chalky], cyclopentyl,
cyclohexyl and a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which Ci_3alkyl group may bear 1 or 2 substitueuts selected
from oxo, hydroxy, halogeno and CMalkoxy and which cyclic group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno, cyano, Ci-4cyanoalkyl, Chalky!, Ci.
4hydroxyalkyl, CMalkoxy, CMalkoxyCMalkyl, d^a]kylsulphonyld-4alkyl, CMalkoxycarbonyl,
Ci^aminoalkyl, d-4alkylamino, di(CMalkyl)amino, Ci^aHcylaminoCMalkyl, di(d-
4alkyl)aminod^alkyl, Ci^alkylaminoC]w»alkoxy, di(d^alkyl)aminod-4alkoxy and a group -(-
O-Xd-^alkyOgriugD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from Chalky!) with the proviso that
R105 cannot be hydrogen);
and additionally wherein any Ci.5a]kyl, Cj-salkenyl or C^alkynyl group in R56X10- which is
linked to X10 may bear one or more substituents selected from hydroxy, halogeno and amino);
with the proviso that one or more R1 and/or one or more R2 are selected from one of the
following five groups:
wherein X1 is as defined hereinbefore and Q1 is selected from one of the following ten groups:
1) Q2 (wherein Q2 is a 5-6-membered saturated or partially unsaturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group bears
at least one substituent selected from Cj^alkenyl, Ca-salkynyl, Ci-gfluoroalkyl, d-ealkanoyl,
amiuoCi-salkanoyl, d-4alkylaminod-6alkanoyl, di(d^alkyl)arninod-oalkanoyl, d-
6fluoroalkauoyl, carbamoyl, d^alkylcarbamoyl, di(d-4alkyl)carbamoyl, carbamoyld-fialkyl, Ci.
4alkylcarbamoylCi.6alkyl, di(CMa]kyl)carbamoylCi-6alkyl, C^alkylsulphonyl and Ci.
6fluoroalkylsulphouyl and which heterocyclic group may optionally bear a further 1 or 2
substituents selected from Cz-salkenyl, C2.salkynyl, Ci.6fiuoroalkyl, Ci-ealkanoyl, aminoCi.
6alkanoyl, CMalkylaminoCi-fialkanoyl, di(CMalky])amiuoCi-6alkanoyl, d.6fluoroalkanoyl,
carbamoyl, Ci^alkylcarbamoyl, di(CMa]kyl)carbamoyl, carbamoylCi-ealkyl, d.
4alkylcarbamoylCi-6alkyl, di(Ci^alkyl)carbamoylCi-6alkyl, Ci.6alkylsulphonyl, Ci.
sfluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano, CMcyanoalkyl, Ci^alkyl, d.
4hydroxyalkyl, CMalkoxy, CMalkoxyCMalkyl, CMalkylsulphonylCMalkyl, CMalkoxycarbonyl,
d-»aminoalkyl, Chalkylamino, di(d^alkyl)amino, d.4alkylaminod-4alkyl, di(C|.
4alkyl)aminoCMalkyl, Ci-4alkylaminoCMalkoxy, di(CMalkyl)aminoCMaIkoxy and a group -(-
O-Xd-4alkyl)EringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 5-6-membered saturated or
partially unsaturated heterocyclic group with 1-2 heteroatoms, selected independently from 0,
S and N, which cyclic group may bear one or more substituents selected from Chalky!));
2) d-salkylW'Q2 (wherein W1 represents -O-, -S-, -SO-, -SO2-, -OC(O)-, -NQ3C(0)-, -
C(O)NQ4-, -SO2NQ5-, -NQ6SO2- or -NQ7- (wherein Q3, Q4, Q5, Q6 and Q7 each independently
represents hydrogen, Cualkyl, doalkoxyC^alkyl, C2.5alkenyl, C2.5alkynyl or d-jhaloalkyl)
and Q2 is as defined hereinbefore;
3) Ci.jalkylQ2 (wherein Q2 is as defined hereinbefore);
4) C2-salkenylQ2 (wherein Q2 is as defined hereinbefore);
5) C2-5alkynylQ2 (wherein Q2 is as denned hereinbefore);
6) Ci^alkylW2CMalkylQ2 (wherein W2 represents -O-, -S-, -SO-, -SO2-, -NQ8C(O)-, -
C(O)NQ9-, -S02NQ10-, -NQJ'SO2- or -NQ12- (wherein Q8, Q9, Q10, Q" and Q12 each
independently represents hydrogen, Ci^alkyl, Ci.3alkoxyC2.3alkyl, C2_5alkenyl, d-salkynyl or
CiJtialoalkyl) and Q2 is as defined hereinbefore);
7) C2.5alkeuylW2CMalkylQ2 (wherein W2 and Q2 are as defined hereinbefore);
8) C2.5alkyiiylW2Ci^alkylQ2 (wherein W2 and Q2 are as defined hereinbefore);
9) CMalkylQ13(CMalkyl)j(W2)kQ14 (wherein W2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q13 and Q14 are each independently selected from hydrogen, Ci-aalkyl, cyclopentyl,
cyclohexyl and a 5-6-membered saturated or partially unsaturated heterocyclic group with 1-2
heteroatoms, selected independently from 0, S and N, which Chalky] group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno and Ci^alkoxy and which cyclic group may
bear 1, 2 or 3 substitueuts selected from C2.5alkenyl, C2.3alkynyl, Cufiuoroalkyl, Ci.6alkanoyl,
amiuoCi-ealkanoyl, CMalkylaminoCi^alkanoyl, di(CMalkyl)amiuoCi-6a]kanoyl, d.
gfluoroalkanoyl, carbamoyl, Ci^alkylcarbamoyl, di(CMalkyl)carbamoyl, carbamoyld-ealkyl, d.
4alkylcarbamoylCi^alkyl, di(Ci^alkyl)carbamoylCi.6alkyl, Ci^alkylsulphonyl, d-
6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyauo, d^cyanoalkyl, Cwalkyl, Ci.
4hydroxyalkyl, Ci^alkoxy, d-4alkoxyd-«a]kyl, d-4alkylsulphonylCMalkyl, CMalkoxycarbonyl,
d^aininoalkyl, CMalkylamino, di(Cualkyl)amino, CMalkylaminoCi-4alkyl, di(d.
4alkyl)aminoCMalkyl, Ci^alkylaminoCi^alkoxy, di(CMaIkyl)aminoCi^alkoxy and a group -(-
O-Xd-4alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 5-6-membered saturated or
partially unsaturated heterocyclic group with 1-2 heteroatoms, selected independently from 0,
S and N, which heterocyclic group may bear one or more substituents selected from Chalky!),
with the provisos that Q13 cannot be hydrogen and one or both of Q13 and Q14 must be a 5-6-
membered saturated or partially unsaturated heterocyclic group as defined hereinbefore which
heterocyclic group bears at least one substituent selected from Cz-jalkeuyl, Cz-salkynyl, C\.
sfluoroalkyl, Ci.6alkanoyl, aminoCi^aLcanoyl, Ci^alkylamiiioCi-fialkanoyl, di(CMalkyl)aminoCi.
ealkanoyl, Ci-6fluoroalkanoyl, carbamoyl, Ci-4alkylcarbamoyl, di(CMalkyl)carbamoyl,
carbamoylCi^alkyl, CMalkylcarbamoylCi.6alkyl, d^CiuialkytycarbamoylCi-calkyl, Cigalkylsulphonyl
and Ci-efluoroalkylsulphonyl and which heterocyclic group optionally bears 1
or 2 further substituents selected from those defined hereinbefore);
10) CMalkylQ13Ci^alkanoylQ14n wherein Q13 is as defined hereinbefore and is not hydrogen
and Q14" is a 5-6-membered saturated or partially unsaturated heterocyclic group containing at
least one nitrogen atom and optionally containing a further nitrogen atom wherein Ql4n is
linked to Ci.«alkanoyl through a nitrogen atom and wherein Q14" optionally bears 1, 2 or 3
substituents selected from Cz-salkenyl, Cz-salkynyl, d-efluoroalkyl, Ci^alkanoyl, aminoCi.
6alkanoyl, CMalkylaminoCi^alkanoyl, di(CMalkyl)amiuoCi-6alkanoyl, Ci^fluoroalkanoyl,
carbamoyl, CMalkylcarbainoyl, di(Ci_4£ilkyl)carbainoyl, carbamoylCi-ealkyl, Q.
4alkylcarbamoylCi-6alkyl, di(Ci^alkyl)carbamoylCi.6a]kyl, Ci-ealkylsulphonyl, Ci.
fifluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano, Cwcyauoalkyl, Chalky!, c\.
4hydroxyalkyl, Ci^alkoxy, Ci^alkoxyCMalkyl, Ci-aalkylsulphonylCi-aalkyl, CMalkoxycarbouyl,
CMaminoalkyl, CMalkylamiuo, di(CMalkyl)amino, CMalkylaminoCMalkyl, di(Ci-
4alkyl)aminoCMalkyl, Ci^alkylarninoCMalkoxy, di(Ci^alkyl)aminoCMalkoxy and a group -(-
O-)KCMaJkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 5-6-membered saturated or
partially unsaturated heterocyclic group with 1 -2 heteroatoms, selected independently from O,
S and N, which heterocyclic group may bear one or more substituents selected from C^aUcyl);
and additionally wherein any Chalky!, C2.5alkenyl or Cz^alkynyl group in C^X1- which is
linked to X1 may bear one or more substituents selected from hydroxy, halogeno and amino);
(ii) Q15W3-
wherein W3 represents -NQ16C(O)-, -C(O)NQ17-, -S02NQ18-, -NQ19S02- or-NQ20- (wherein
Q16, Q17, QIS, Q19 and Q20 each independently represents C^alkenyl, C2.5alkynyl, Cj.
4haloalkyl), and Q15 is Ci^haloalkyl, C2-5alkenyl or C^alkynyl;
(iii) Q'-'W^alkylX'- wherein W* represents -NQ22C(O)-, -C(O)NQ23-, -SO2NQ24-, -
NQ25S02- or -NQ26- (wherein Q22, Q23, Q24, Q25 and Q26 each independently represents
hydrogen, C|.3alkyl, d.3alkoxyC2.3a]kyl, C2.5alkenyl, C2.5alkynyl or d^haloalkyl), and Q21
represents C^haloalkyl, d-salkenyl or d-salkynyl, and X1 is as defined hereinbefore;
I (iv) Q^d-jalkylX1-, Q28C2.3alkenylX1- or Q28d-5alkynylX'- wherein X1 is as defined
hereinbefore and Q28 is an imidazolidinyl group which bears two oxo substituents and one C|.
6alkyl or C3-i0cycloalkyl group which Q.«alkyl or d-iocycloalkyl group may bear a hydroxy
substituent on the carbon atom which is linked to the imidazolidinyl group, and wherein the Q.
salkyl, d-salkenyl or d-salkyuyl linked to X1 may bear one or more substituents selected from
l hydroxy, halogeno and amino; and
(v) (fd-salkylX1-, Q29C2.5alkenylX!- or Q29C2.5alkynylX1- wherein X1 is as defined
hereinbefore, the d-salkyl, Cj.salkeuyl or d.salkynyl linked to X1 may bear one or more
substituents selected from hydroxy, halogeno and amino and Q29 is a group l,4-dioxa-8-
azaspiro[4.5]dec-8-yl, which may be represented:
o..
or R1 may be selected from any of the groups defined hereinbefore and R2 is 6,7-
methylenedioxy or 6,7-ethylenedioxy;
or a salt thereof, or a prodrug thereof for example an ester or an amide, in the manufacture of a
medicament for use in the production of an antiaugiogenic and/or vascular permeability
reducing effect in warm-blooded animals such as humans.
According to one aspect of the present invention there is provided the use of a
compound of the formula I:
(Figure Remove)wherein:
ring C is an 8, 9, 10, 12 or 13-membered bicyclic or tricyclic moiety which moiety may be
saturated or unsaturated, which may be aromatic or non-aromatic, and which optionally may
contain 1-3 heteroatoms selected independently from O, N and S;
Z is -O-, -NH- or -S-;
nisO, 1,2, 3, 4 or 5;
m is 0, 1, 2 or 3;
R2 represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, Ci_3a]kyl, Ci-3alkoxy,
d-3alkylsulphanyl, -NR3R4 (wherein R3 and R4, which may be the same or different, each
represents hydrogen or d.salkyl), or R5X'- (wherein X1 represents a direct bond, -O-, -CH2-, -
OC(O)-, -C(O)-, -S-, -SO-, -SOz-, -NR6C(0)-, -C(O)NR7-, -SO2NR8-, -NR9S02- or -NR10-
(wherein R6, R7, R8, R9 and R'° each independently represents hydrogen, Ci.3alkyl or Cj.
3alkoxyd-3alkyl), and R5 is selected from one of the following twenty-two groups:
1) hydrogen, oxiranylCi^alkyl or d-salkyl which may be unsubstituted or which may be
substituted with one or more groups selected from hydroxy, fluoro, chloro, bromo and amino;
2) Ci.5alkylX2C(O)R" (wherein X2 represents -0- or -NR12- (in which R12 represents
hydrogen, d-3alkyl or Ci.3alkoxyC2.3alkyl) and R11 represents Ci.3alkyl, -NR13R14 or -OR15
(wherein R13, R14 and R15 which may be the same or different each represents hydrogen, d-
5alkyl or d.3alkoxyd.3alkyl));
3) d-salkylXV6 (wherein X3 represents -O-, -S-, -SO-, -SOz-, -OC(O)-, -NR17C(0)-, -
C(0)NR18-, -S02NR19-, -NR20SO2- or -NR21- (wherein R17, R18, R19, R20 and R21 each
independently represents hydrogen, d.3alkyl or d_3alkoxyd_3alkyl) and R16 represents
hydrogen, d.3alkyl, cyclopeatyl, cyclohexyl or a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from 0, S and N, which d.3alkyl group may
bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and d^alkoxy and which cyclic
group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, d-
4cyanoalkyl, CMalkyl, dJiydroxyalkyl, d^alkoxy, d^alkoxyd-talkyl, d-^alkylsulphonyld.
4alkyl, d^alkoxycarbonyl, d-4aminoalkyl, d^alkylamino, di(Cwalkyl)amino, Ci.
4alkylaminoCMalkyl, di(CMalkyl)aminoCMalkyl, CMalkylaminoCMalkoxy, di(d-
4alkyl)aminoCMa]koxy and a group -(-O-)t(d^a]kyl)gringD (wherein f is 0 or 1, g is 0 or 1 and
ring D is a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which cyclic group may bear one or more substituents selected
fromC]-4a]kyl));
4) Ci-5alkylX4Ci.5alkylX5R22 (wherein X4 and Xs which may be the same or different are each -
O-, -S-, -SO-, -SO2-, -NR23C(O)-, -C(0)NR24-, -SOzNR25-, -NR26S02- or -NR27- (wherein
R23, R24, R25, R26 and R27 each independently represents hydrogen, Ci.3alkyl or C|.3alkoxyC2.
salkyl) and R22 represents hydrogen, Ci.salkyi or Ci.3alkoxyC2-3alkyl);
5) R28 (wherein R28 is a 5-6-membered saturated heterocyclic group (linked via carbon or
nitrogen) with 1-2 heteroatoms, selected independently from 0, S and N, which heterocyclic
group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cj.
4cyanoalkyl, Ci^alkyl, CMhydroxyalkyl, Ci^alkoxy, CMalkoxyCi^alkyl, C[.4alkylsulphonylCi.
4alkyl, Ci-4alkoxycarbonyl, Ci^aminoalkyl, CMalkylamino, di(Ci^alkyl)amiuo, Ci.
4alkylaminoCi^alkyl, di(Ci^alky])aminoCi.4alkyl, CMalkylaminoCi-4alkoxy, di(Ci.
4a]kyl)aminoC]Jlalkoxy and a group -(-O-)({C]^alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and
ring D is a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which cyclic group may bear one or more substituents selected
from Chalky!));
6) Cj.jalkylR28 (wherein R28 is as defined hereinbefore);
7) Cz-^alkenylR28 (wherein R28 is as defined hereinbefore);
8) C2.5aIkynylR28 (wherein R28 is as defined hereinbefore);
9) R29 (wherein R29 represents a pyridone group, a phenyl group or a 5-6-membered aromatic
heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N
and S, which pyridone, pheiiyl or aromatic heterocyclic group may carry up to 5 substituents
selected from oxo, hydroxy, halogeno, amiuo, Chalky!, Ci^alkoxy, QJiydroxyalkyl, Ci.
aaminoalkyl, Cwalkylamino, CMhydroxyalkoxy, carboxy, trifluoromethyl, cyano, -
C(O)NR30R31, -NR32C(O)R33 (wherein R30, R31, R32 and R33, which may be the same or
different, each represents hydrogen, Chalky! or Ci-salkoxyC^alkyl) and a group -(-O-)KCi.
4alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independently from 0, S and N, which
cyclic group may bear one or more substituents selected from Chalky!));
10) Ci.jalkylR29 (wherein R29 is as defined hereinbefore);
11) Ci-salkeuylR29 (wherein R29 is as defined hereinbefore);
12) C2-5alkynyIR29 (wherein R29 is as defined hereinbefore);
13) d.5alkylX6R29 (wherein X6 represents -O-, -S-, -SO-, -SO;-, -NR34C(O)-, -C(O)NR35-, -
SO2NR36-, -NR37SO2- or -NR38- (wherein R34, R35, R36, R37 and R38 each independently
represents hydrogen, Ci.3alkyl or Ci.3alkoxyC2.3alkyl) and R29 is as defined hereinbefore);
14) C2.5alkeuylX7R29 (wherein X7 represents -0-, -S-, -SO-, -SO2-, -NR39C(O)-, -C(0)NR40-, -
SO2NR41-, -NR42SO2- or -NR43- (wherein R39, R40, R41, R42 and R43 each independently
represents hydrogen, d.3alkyl or Ci.3alkoxyC2.3alkyl) and R29 is as defined hereinbefore);
15) C2.3alkyuylX8R29 (wherein X8 represents -O-, -S-, -SO-, -SO2-, -NR44C(O)-, -C(O)NR45-, -
S02NR46-, -NR47SO2- or -MR48- (wherein R44, R45, R46, R47 and R48 each independently
represents hydrogen, Ci.3alkyl or Ci.3alkoxyC2.3alkyl) and R29 is as defined hereinbefore);
16) CMalkylX9C^alkylR29 (wherein X9 represents -O-, -S-, -SO-, -SO2-, -NR49C(O)-, -
C(O)NR50-, -SO2NR51-, -NR52SO2- or -NR53- (wherein R49, R50, R51, R52 and R53 each
independently represents hydrogen, C|.3alkyl or Ci.3alkoxyC2.3alkyl) and R29 is as defined
hereinbefore);
17) CMalkylX9CMa1kylR28 (wherein X9 and R28 are as defined hereinbefore);
18) C2.5alkenyl which may be unsubstituted or which may be substituted with one or more
groups selected fromhydroxy, fluoro, amino, CMalkylamino, N,N-di(Ci^alkyl)arnino,
aminosulphonyl, N-Ciwtalkylaminosulphonyl and N,N-di(Ci^alkyl)arnino sulphonyl;
19) C2_5alkynyl which may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, CMalkylamino, N,N-di(CMalkyl)amino,
aminosulphonyl, N-CMalkylaminosulphoiiyl and N,N-di(Ci_4alkyl) amino sulphonyl;
20) C2.5alkeny]X9CMalkylR28 (wherein X9 and R28 are as defined hereinbefore);
21) C2.5alkynylX9CMalkylR28 (wherein X9 and R28 are as defined hereinbefore); and
22) CwalkylR54(Cwalkyl)q(X9)rR55 (wherein X9 is as defined hereinbefore, q is 0 or 1, r is 0 or
1, and R54 and R55 are each independently selected from hydrogen, Ci.3alkyl, cyclopentyl,
cyclohexyl and a 5-6-membered saturated heterocycljc group with 1-2 heteroatoms, selected
independently from O, S and N, which Ci_3alkyl group may bear 1 or 2 substituents selected
from oxo, hydroxy, halogeno and CMalkoxy and which cyclic group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno, cyano, Ci^cyanoalkyl, Ci-aalkyl, Cj.
4hydroxyalkyl, Ci^alkoxy, CMalkoxyCMa]kyl, Cj^alkylsulphonylCMalkyl, Ci^alkoxycarbonyl,
CMamiuoalkyl, Ci^alkylamino, di(CMalkyl)amiuo, Ci^alkylaminoCi^alkyl, di(d.
4alkyl)aminoCMalkyl, CMalkylaminoCi^alkoxy, di(Ci^alkyl)aminoCi^a]koxy and a group -(-
O-MCi-4alkyl)£ringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from CMalkyl), with the proviso that
R54 cannot be hydrogen);
and additionally wherein any C^alkyl, C^alkenyl or d-salkyuyl group in R5X'- which is
linked to X1 may bear one or more substituents selected from hydro xy, halogeno and amino);
R1 represents hydrogen, oxo, halogeno, hydroxy, Ci^alkoxy, Ci^alkyl, d-»alkoxymethyl, d-
4alkauoyl, CiJialoalkyl, cyano, amino, Ci-salkenyl, d-salkynyl, Ci.3alkauoyloxy, nitro, d-
4alkauoylamino, CMalkoxycarbonyl, Ci^alkylsulphanyl, d^aBcylsulphinyl, C]-4alkylsulphonyl,
carbamoyl, N-CMalkylcarbamoyl, N,N-di(Ci-4alkyl)carbamoyl, aminosulphonyl, N-d-
4alky]aminosulphonyl, N,N-di(d^alkyl)aminosulphony], N-(CMalkylsulphonyl)amino, N-(d-
4alkylsulphonyl)-N-(d-4alkyl)arnino, N,N-di(d-aalkylsulphonyl)arnino, a Ca^alkylene chain
joined to two ring C carbon atoms, CwaIkanoylaminoCMalkyl, carboxy or a group R36X10
(wherein X10 represents a direct bond, -O-, -CH2-, -OC(O)-, -C(O)-, -S-, -SO-, -SO2-, -
NR57C(O)-, -C(O)NR58-, -SO2NR59-, -NR60SO2- or -NR61- (wherein R57, R58, R59, R60 and R61
each independently represents hydrogen, Ci-salkyl or Ci-aalkoxyCz-aalkyl), and R56 is selected
from one of the following twenty-two groups:
1) hydrogen, oxiranylCi^alkyl or Ci-salkyl which may be unsubstituted or which may be
substituted with one or more groups selected from hydroxy, fluoro, chloro, bromo and amino;
2) Ci.5alkylXuC(O)R62 (wherein X11 represents -O- or -NR63- (in which R63 represents
hydrogen, Chalky! or doalkoxyCa-salkyl) and R62 represents djalkyl, -NR^R65 or -OR66
(wherein R64, R65 and R66 which may be the same or different each represents hydrogen, Ci.
jalkyl or Ci.3alkoxyC2-3alkyl));
3) Ci-5alkylX12R67 (wherein X12 represents -O-, -S-, -SO-, -SO2-, -OC(O)-, -NR68C(O)-, -
C(O)NR69-, -SO2NR70-, -NR71SO2- or -NR72- (wherein R68, R69, R70, R71 and R72 each
independently represents hydrogen, Ci.3alkyl or Ci.3alkoxyC2.3alkyl) and R67 represents
hydrogen, djalkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which d.3alkyl group may
bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and d^alkoxy and which cyclic
group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, d-
4cyanoalkyl, CMalkyl, CMhydroxyalkyl, Ci^alkoxy, CMalkoxyCi^alkyl, d^alkylsulphonyld.
4alkyl, Ci^alkoxycarbonyl, Ci^aminoalkyl, CMalkylamino, di(CMalkyl)amiuo, d-
4alkylamiriod^alkyl, di(CMalkyl)aminoCMalkyl, CMalkylaminoCi^alkoxy, di(d.
4a]kyl)arninoCi-alkoxy and a group -(-O-)f(Ci.4alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and
ring D is a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected
independently from 0, S and N, which cyclic group may bear one or more substituents selected
from Chalky!));
4) Ci.5alkylX13Ci.5alkylX14R73 (wherein X13 and X14 which may be the same or different are
each -0-, -S-, -SO-, -SO2-, -NR74C(O)-, -C(O)NR75-, -SO2NR76-, -NR77SO2- or -NR78-
(whereiu R74, R75, R76, R77 and R78 each independently represents hydrogen, d-salkyl or Ci.
3alkoxyC2-3alkyl) and R73 represents hydrogen, Ci-3alkyl or Ci.3alkoxyC2-3alkyl);
5) R79 (wherein R79 is a 5-6-membered saturated heterocyclic group (linked via carbon or
nitrogen) with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic
group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Ci.
4cyanoalkyl, Ci^alkyl, CiJiydroxyalkyl, Ci^alkoxy, Ci^alkoxyCi^alkyl,
4aJkyl, CMalkoxycarbonyl, Ci^aminoalkyl, CMalkylamino, di(CMalkyl)amino,
4alkylaminoCi-4alkyl, di(Ci-4alkyl)aminoCMalkyl, Ci^alkylaminoCi^alkox
4alkyl)aminoCi-4alkoxy and a group -(-O-XCMalkyQgringD (wherein f is 0 or 1, g is 0 or 1 and
ring D is a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected
independently from 0, S and N, which cyclic group may bear one or more substituents selected
from Chalky!));
6) Ci.salkylR79 (wherein R79 is as defined hereinbefore);
7) C2-5alkenylR79 (wherein R79 is as defined hereinbefore);
8) C2.5alkynylR79 (wherein R79 is as defined hereinbefore);
9) R80 (wherein R8n represents a pyridone group, a phenyl group or a 5-6-membered aromatic
heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N
and S, which pyridone, phenyl or aromatic heterocyclic group may carry up to 5 substitueuts
selected from oxo, hydroxy, halogeuo, amino, Ci^alkyl, Ci^alkoxy, Ci^Jiydroxyalkyl, Ci.
4aminoalkyl, Ci^alkylamino, Ci^hydroxyalkoxy, carboxy, trifluoromethyl, cyano, -
C(O)NR81R82, -NR83C(O)R84 (wherein R81, R82, R83 and R84, which may be the same or
different, each represents hydrogen, Chalky! or Ci.3alkoxyC2.3alkyl) and a group -(-O-XCi.
4alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independeutly from O, S and N, which
cyclic group may bear one or more substituents selected from Chalky!));
10) CalkylR80 (wherein R80 is as defined hereinbefore);
11) C2.5alkenylR80 (wherein R80 is as defined hereinbefore);
12) C2.5alkynylR80 (wherein R80 is as defined hereinbefore);
13) C,.salkylX15R80 (wherein X13 represents -0-, -S-, -SO-, -SOa-, -NR85C(O)-, -C(O)NR86-, -
SO2NR87-, -NR88SO2- or -NR89- (wherein R85, R86, R87, R88 and R89 each independently
represents hydrogen, Ci.3alkyl or Ci.3alkoxyC2.3alkyl) and R80 is as defined hereinbefore);
14) C2.5alkenylX16R80 (wherein X16 represents -O-, -S-, -SO-, -SO2-, -NR90C(0)-, -C(O)NR91-,
-S02NR92-, -NR93S02- or -NR94- (wherein R90, R91, R92, R93 and R94 each independently
represents hydrogen, Ci.3alkyl or Ci.3alkoxyC2_3alkyl) and R8U is as defined hereinbefore);
15) C2.5alkyny]X17R80 (wherein X17 represents -O-, -S-, -SO-, -SO2-, -NR95C(O)-, -C(O)NR96-,
-SO2NR97-, -NR98SO2- or -NR99- (wherein R95, R96, R97, R98 and R99 each independently
represents hydrogen, Chalky! or Ci-3alkoxyC2-3a]kyl) and R80 is as defined hereinbefore);
16) CMalkylX18Ci^alkylR80 (wherein X18 represents -O-, -S-, -SO-, -SO2-, -NR100C(O)-, -
C(0)NR101-, -S02NR102-, -NRI(13S02- or -NR1M- (wherein R100, R101, R102, R103 and R104 each
independently represents hydrogen, Ci-3alkyl or Ci-3alkoxyC2.3alkyl) and R80 is as defined
hereinbefore);
17) C,alkylX18Ci^alkylR79 (wherein X18 and R79 are as defined hereinbefore);
18) Cz-jalkenyl which may be unsubstituted or which may be substituted with one or more
groups selected fromhydroxy, fluoro, amino, Ci^alkylamino, N,N-di(Ci_4alkyl)amino,
aminosulphonyl, N-CMalkylaminosulphonyl and N,N-di(Cj_4alkyl)aminosulphonyl;
19) C2-5alkynyl which may be unsubstituted or which may be substituted with one or more
groups selected fromhydroxy, fluoro, amiuo, Ci-4alkylarnino, N,N-di(Ci-4alkyl)amino,
aminosulphonyl, N-Ci^alkylaminosulphonyl and N,N-di(Ci_4alkyl)aminosulphonyl;
20) C2.5a]kenylX18C,.4alkylR79 (wherein X18 and R79 are as defined hereinbefore);
21) C2.5alkyuylX18CMalkylR79 (wherein X18 and R79 are as defined hereinbefore); and
22) CMalkylR105(Cwalky])x(XI8)yR106 (wherein X18 is as defined hereinbefore, x is 0 or 1, y is 0
or 1, and R105 and R106 are each independently selected from hydrogen, Ci-3alkyl, cyclopentyl,
cyclohexyl and a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which Ci.3alkyl group may bear 1 or 2 substitueuts selected
from oxo, hydroxy, halogeno and Ci^alkoxy and which cyclic group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno, cyano, Ci^cyanoalkyl, Chalky!, d.
Jiydroxyalkyl, Ci^alkoxy, CMalkoxyCiwtalkyl, Ci-4alkylsulphonylCMaIkyl, CMalkoxycarbonyl,
l, CMalkylaiTuno, di(CMa]kyl)amino, Ci^alkylaminoCMalkyl, di
4alkyl)amiuoCMalkyl, Ci^alkylaminoCMalkoxy, di(Ci^alkyl)amkioCMalkoxy and a group -(-
O-Xd-4alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 5-6-membered saturated
heterocyclic group with 1-2 heteroatorns, selected independently from 0, S and N, which
cyclic group may bear one or more substituents selected from d-aalkyl) with the proviso that
R105 cannot be hydrogen);
arid additionally wherein any d.5alkyl, C2_5alkenyl or C2.5alkynyl group in R56X10- which is
linked to X10 may bear one or more substituents selected from hydroxy, halogeno and amino);
with the proviso that one or more R1 and/or one or more R2 are selected from one of the
following three groups:
(Figure Remove)wherein X1 is as defined hereinbefore and Q1 is selected from one of the following nine groups:
1) Q2 (wherein Q2 is a 5-6-membered saturated or partially unsaturated heterocyclic group
with 1-2 heteroatorns, selected independently from O, S and N, which heterocyclic group bears
at least one substituent selected from C^-jalkenyl, C2.5alkynyl, d-efluoroalkyl, Cj^alkanoyl, Ci.
fifluoroalkanoyl, d^alkylsulphonyl and Cj^fluoroalkylsulphonyl and which heterocyclic group
may optionally bear a further 1 or 2 substituents selected from d-salkenyl, C^alkynyl, defluoroalkyl,
d-ealkanoyl, d-sfluoroalkanoyl, Ci^alkylsulphonyl, d^fluoroalkylsulphouyl,
oxo, hydroxy, halogeno, cyano, Ci^cyanoalkyl, d^alkyl, Ci Jiydroxyalkyl, Ci^alkoxy, Cj.
4alkoxyd-4alkyl, d-oalkylsulphouyld^alkyl, d^alkoxycarbonyl, Ci^aminoalkyl, Ci.
4alkylamino, di(d-aalkyl)amino, CMalkylatninoCi^alkyl, d^Ci^alkyOaminoCMalkyl, Ci.
4alkylaminod^alkoxy, di(Ci-4a]kyl)aminoCMalkoxy and a group -(-O-Xd-4alkyl)gruigD
(wherein f is 0 or 1, g is 0 or 1 and ring D is a 5-6-membered saturated or partially unsaturated
heterocyclic group with 1-2 heteroatorns, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from d^alkyl));
2) d.salkylW'Q2 (wherein W1 represents -0-, -S-, -SO-, -SO2-, -OC(0)-, -NQ3C(O)-, -
C(O)NQ represents hydrogen, d_3alkyl, d.3alkoxyCwaIkyl, C2.5alkenyl, C2-5alkynyl or
and Q2 is as defined hereinbefore;
3) d.5a]kylQ2 (wherein Q2 is as defined hereinbefore);
4) d-jalkeuylQ2 (wherein Q2 is as defined hereinbefore);
5) C2.5alkynylQ2 (wherein Q2 is as defined hereinbefore);
6) CMalkylW2CMalkylQ2 (wherein W2 represents -O-, -S-, -SO-, -S02-, -NQ8C(0)-, -
C(O)NQ9-, -S02NQ10-, -NQUSO2- or -NQ12- (wherein Q8, Q9, Q10, Q11 and Q12 each
independently represents hydrogen, d-aalkyl, d-aalkoxyd-aalkyl, d-salkenyl, d-salkynyl or
d-ahaloalkyl) and Q2 is as defined hereinbefore);
7) C2.jalkenylW2CMalkylQ2 (wherein W2 and Q2 are as defined hereinbefore);
8) d-salkynyiW2d-4alkylQ2 (wherein W2 and Q2 are as defined hereinbefore); and
9) CMalkylQ13(CMalkyl)j(W2)kQM (wherein W2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q13 and Q14 are each independently selected from hydrogen, d-aalkyl, cyclopeuty],
cyclohexyl and a 5-6-membered saturated or partially uiisaturated heterocyclic group with 1-2
heteroatoms, selected independently from O, S and N, which d.3alkyl group may bear 1 or 2
substituents selected fromoxo, hydroxy, halogeno and Ci^alkoxy and which cyclic group may
bear 1, 2 or 3 substituents selected from d-salkenyl, d-salkynyl, d-efluoroalkyl, d-ealkanoyl,
Ci-fifluoroalkanoyl, C^alkylsulphonyl, d-cfluoroalkylsulphonyl, oxo, hydroxy, halogeno,
cyano, Ci^cyanoalkyl, Ci^alkyl, d^hydroxyalky], Ci^alkoxy,
4alkylsulphonylCi^alkyl, d-aalkoxycarbonyl, Ci_4aminoalkyl, C
4alkyl)amino, d-aalkylaminod-ialkyl, di(Cj^alkyl)aminoC
di(d-4alkyl)aminod-4alkoxy and a group -(-O-XCi.4alkyl)gringD (wherein f is 0 or 1, g is 0 or
1 and ring D is a 5-6-membered saturated or partially unsaturated heterocyclic group with 1-2
heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one
or more substituents selected from Chalky]), with the provisos that Q13 cannot be hydrogen
and one or both of Q13 and Q14 must be a 5-6-membered saturated or partially unsaturated
heterocyclic group as defined hereinbefore which heterocyclic group bears at least one
substituent selected from C2.5alkenyl, C2.5alkynyl, d-efluoroalkyl, Ci^alkanoyl, dsfluoroalkauoyl,
Ci^alkylsulphonyl and d^fluoroalkylsulphonyl and which heterocyclic group
optionally bears 1 or 2 further substitueuts selected from those denned hereinbefore);
and additionally wherein any d-jalkyl, d-salkenyl or d.jalkynyl group in QJX!- which is
linked to X1 may bear one or more substituents selected from hydroxy, halogeno and amino);
wherein W3 represents -NQI6C(O)-, -C(O)NQ17-, -S02NQ18-, -NQI9SO2- or -NQ20- (wherein
Q16, Q17, Q18, Q" and Q20 each independently represents C2.5alkenyl, d.5alkynyl, d-
4haloalkyl), and Q15 is d-ehaloalkyl, d-salkenyl or djalkynyl; and
(iii) Q^WCi.jalkylX1- wherein W4 represents -NQ22C(0)-, -C(O)NQ23-, -SC^NQ24-, -
NQ25SO2- or -NQ26- (wherein Q22, Q23, Q24, Q25 and Q26 each independently represents
hydrogen, Ci.3alkyl, Ci.3alkoxyC2.3a]kyl, C^alkenyl, C2-salkynyl or CMhaloalkyl), and Q21
represents Ci^haloalkyl, C2-jalkenyl or C2-salkynyl, and X1 is as denned hereinbefore;
or a salt thereof, or a prodrug thereof for example an ester or an amide, in the manufacture of a
medicament for use in the production of an antiangiogenie and/or vascular permeability
reducing effect in warm-blooded animals such as humans.
According to one aspect of the present invention ring C is a 9-10-membered aromatic
bicyclic moiety which may optionally contain 1-3 heteroatoms selected independently from 0,
NaudS.
According to one aspect of the present invention ring C is a 9-10-membered
heteroaromatic bicyclic moiety which contains 1-3 heteroatoms selected independently fromO,
NandS.
According to one aspect of the present invention ring C is a 9-10-membered
heteroaromatic bicyclic moiety which contains 1 or 2 nitrogen atoms.
According to one aspect of the present invention ring C is indolyl, quinolinyl, iudazolyl
or azaindolyl.
According to one aspect of the present invention ring C is iudolyl, indazolyl or
azaiudolyl.
According to one aspect of the present invention ring C is indolyl or azaindolyl.
According to one aspect of the present invention ring C is azaindolyl.
According to one aspect of the present invention ring C is indolyl.
According to one aspect of the present invention ring C is indazolyl.
According to one aspect of the present invention ring Z is -0- or -S-.
According to one aspect of the present invention ring Z is -O-.
In one embodiment of the present invention X1 represents a direct bond, -O-, -S-, -
NR6C(0)-, -NR9SO2- or -NR10- (wherein R6, R9 and R10 each independently represents
hydrogen, Ci-2a]kyl or d-zalkoxyethyl).
In one embodiment of the present invention X1 represents a direct bond, -O-, -S-, -
NR6C(O)-, -NR9SO2- (wherein R6 and R9 each independently represents hydrogen or Ci.2alkyl)
orNH.
In one embodiment of the present invention X1 represents -O-, -S-, -NR C(O)-
(wherein R6 represents hydrogen or Ci-zalkyl) or NH.
In one embodiment of the present invention X1 represents -0- or -NR6C(0)-
(wherein R6 represents hydrogen or Ci-zalkyl).
In one embodiment of the present invention X1 represents -O- or -NHC(O)-.
In one embodiment of the present invention X1 represents -O-.
According to another aspect of die present invention X1 represents -0- or a direct
bond.
In one embodiment of the present invention R1 is selected from one of the three groups:
(i) Q'X1 wherein Q1 and X1 are as defined hereinbefore;
(ii) Q15 W3 wherein Q15 and W3 are as defined hereinbefore; and
(iii) Q^WC^alkylX1- wherein Q21, W4 and X1 are as defined hereinbefore;
and/or R1 represents oxo, hydroxy, Ci^alkoxymethyl, amino, halogeno, Ci.zalkyi, d-jalkoxy,
trifluoromethyl, cyano, nitro, C2-3alkanoyl.
According to one aspect of the present invention R1 represents methyl, ethyl,
trifluoromethyl or halogeno.
According to another aspect of the present invention R1 represents methyl, fluoro,
chloro or bromo.
According to another aspect of the present invention R1 represents methyl or fluoro.
In one embodiment of the present invention n is 3.
In one embodiment of the present invention n is 2.
In one embodiment of the present invention n is 1.
In one embodiment of the present invention n is 0.
In one embodiment of the present invention n is 0, 1 or 2.
ha one embodiment of the present invention m is 1 or 2.
In one embodiment of the present invention m is 1.
In one embodiment of the present invention m is 2.
hi one embodiment of the present invention X3 represents -O-, -S-, -SO-, -S02-, -
SOzNR19- or -NR21- (wherein R19 and R21 each independently represents hydrogen, Ci^alkyl or
d^alkoxyethyl).
hi one embodiment of the present invention X3 represents -O- or -NR21- (wherein R21
represents hydrogen or C
In one embodiment of the present invention X3 represents -0-.
In one embodiment of the present invention X4 and X5 which may be the same or
different each represents -O-, -S- or -NR27- (wherein R27 represents hydrogen, Ci.2alkyl or Ci-
2alkoxyethyl).
In one embodiment of the present invention X4 and X5 which may be the same or
different each represents -O- or -NH-.
In one embodiment of the present invention X4 and X3 each represents -0-.
r "j n
In one embodiment of the present invention X represents -O-, -S- or -NR - (wherein
R38 represents hydrogen, Chalky! or Ci.2alkoxyethyl).
In one embodiment of the present invention X6 represents -O- or -NR38- (wherein R38
represents hydrogen or Ci.2alkyl).
In one embodiment of the present invention X6 represents -O-.
In one embodiment of the present invention X7 represents -O-, -S- or -NR43- (wherein
R43 represents hydrogen, Ci_2alkyl or Ci.2alkoxyethy]).
In one embodiment of the present invention X7 represents -O- or -NR43- (wherein R43
represents hydrogen or Ci.2alkyl).
In one embodiment of the present invention X represents -0-.
In one embodiment of the present invention X8 represents -0-, -S- or -NR48- (wherein
R48 represents hydrogen, Q.2alkyl or Ci.2alkoxyethyl).
hi one embodiment of the present invention X8 represents -O- or -NR48- (wherein R48
represents hydrogen or C].2alkyl).
hi one embodiment of the present invention X8 represents -0-.
In one embodiment of the present invention X9 represents -O-, -S- or -NR53- (wherein
Rf3 represents hydrogen, Chalky! or Ci.2alkoxyethyl).
hi one embodiment of the present invention X9 represents -O- or -NR53- (wherein R53
represents hydrogen or Ci.2alkyl).
In one embodiment of the present invention X9 represents -O-.
In one embodiment of the present invention R28 is pyrrolidinyl, piperazinyl, piperidinyl,
imidazolidinyl, l,3-dioxolan-2-yl, morpholino or thiomorpholiuo which group may bear 1 or 2
substituents selected frornoxo, hydroxy, halogeno, cyano, Ci^cyanoalkyl, Ci-3alkyl, Cj.
3hydroxyalkyl, d.3alkoxy, Ci.2alkoxyCi-3a]kyl, Ci.2alkylsulphonylCi-3alkyl, C].3alkoxycarbonyl,
C 1.3alkylamiuo, di(Ci-3a]kyl)amino, CijalkylaminoCijalkyl, di(Ci-3aJkyl)aminoCi-3alkyl, C|.
3a]kylaminoCi-3alkoxy, di(Ci.3alkyl)aminoCi.3alkoxy and a group -(-O-)t{Ci.3alkyl)griugD
(wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl,
piperazinyl, piperidinyl, irnidazolidinyl, morpholino and thiomorpholino, which eye lie group
may bear one or more substitueuts selected from Ci.3alkyl).
In one embodiment of the present invention R28 is pyrrolidinyl, piperazinyl, piperidinyl,
1,3-dioxolan-2-yl, morpholino or thiomorpholino which group may bear 1 or 2 substiruents
selected fromoxo, hydroxy, halogeno, cyauo, Ci.3cyanoalkyl, Ci.3alkyl, C].3hydroxyalkyl, Q.
3alkoxy, Ci-2alkoxyCi.3alkyl and Ci.2alkylsulphonylCi.3alkyL
In one embodiment of the present invention R29 is phenyl, pyridyl, imidazolyl, tliiazolyl
or triazolyl group which group may bear 1 or 2 substitueuts selected from oxo, hydroxy,
halogeno, CMalkyl, d^alkoxy, cyano and -NR32C(O)R33 (wherein R32 and R33 are each
independently selected from hydrogen and CMalkyl).
In one embodiment of the present invention R54 and R55 are each selected from
pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, morpholino and thiomorpholino which
group may bear 1 or 2 substiruents selected fromoxo, hydroxy, halogeno, cyano, Q.
3cyanoalkyl, Ci.3alkyl, Ci_3hydroxyalkyl, Ci-3alkoxy, Ci.2alkoxyCi.3alkyl, Ci-2alkylsulphouylCi.
3alkyl, Ci.3alkoxycarbonyl and a group -(-O-)f(Ci-3alkyl)griugD (wherein f is 0 or 1, g is 0 or 1
and ring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl, piperidinyl,
imidazolidinyl, morpholino and thiomorpholino, which cyclic group may bear one or more
substitueuts selected from Ci.3alkyl).
In one embodiment of the present invention R2 is selected from oue of the five groups:
(i) Q'X1 wherein Q1 and X1 are as defined hereinbefore;
(ii) Q15W3 wherein Q15 and W3 are as defined hereinbefore;
(iii) Q^W^alkylX1- wherein Q21, W4 and X1 are as defined hereinbefore;
(iv) qPd.salkylX1-, Q28C2.5alkeny]X'- or Q28C2-5alkynylX'- wherein Q28 and X1 are as defined
hereinbefore; and
(v) Qd.salkylX1-, Q29C2.5alkenylX'- or Q29C2.5aIk}'nylX1- wherein Q29 andX1 are as denned
hereinbefore;
and/or R2 represents 6,7-methylenedioxy, 6,7-ethylenedioxy, hydroxy, Ci-3alkyl, amino or
R5X'- [wherein X1 is as hereinbefore defined and R5 represents methyl, ethyl, benzyl,
trifluoromethyl, 2,2,2-trifIuoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-
methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(ethylsulphinyl)ethyl, 2-
(ethylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-
sulphamoylethyl, 2-(inethylamino)ethyl, 2-(ethylamino)ethyl, 2-(N,N-dimethylamino)ethyl, 2-
(N,N-diethylamiiio)ethyl, 2-(N-methyl-N-methylsulphonylainmo)ethyl, 3-(N-methyl-Nmethylsulphonylamino)
propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 2-
(methylpiperidino)ediyl, 2-(ediylpiperidiuo)ethyl, 2-((2-medioxyediyl)piperidino)etiiyL, 2-((2-
methylsulphonyl)ethylpiperidino)ethyl, 3-((2-methylsulphonyl)ethylpiperidino)propyl, (1 -
cyanomethylpiperidin-3-yl)methyl, (1 -cyauomethylpiperidin-4-yl)methyl, 2-( 1 -
cyauomethylpiperidiri-S-y^ediyl, 2-( 1 -cyanomethylpiperidin-4-yl)ethyl, 3-( 1 -
cyanomethylpiperidin-3-yl)propyl, 3-( 1 -cyanomethylpiperidin-4-yl)propyl, ((2-
methoxyethyl)piperidin-3-yl)methyl, ((2-methoxyethyl)piperidin-4-yl)mediyl, (l-(2-
methylsulphonylethyl)piperidin-3-yl)methyl, (l-(2-rnethylsulphonylethyl)piperidin-4-yl)methyl,
2-((2-methylsulphonylethyl)piperidia-3-yI)ethyl, 2-((2-metliylsulphonylethyl)piperidin-4-
yl)ethyl, 3-((2-methylsulphonylethyl)piperidin-3-yl)propyl, 3-((2-
methylsulphonylethyl)piperidin-4-yl)propyl, 2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-
yloxy)propyl, 2-(l-(cyanomethy])piperidiu-4-yloxy)ethyl, 3-(l-(cyanomethyl)piperidin-4-
yloxy)propyl, 2-(l-(2-cyanoethyl)piperidin-4-yloxy)ediyl, 3-(l-(2-cyanoethyl)piperidin-4-
yloxy)propyl, 2-(piperazin-l-yl)ethyl, (pyrrolidin-2-yl)rnethyl, (2-oxo-teU-ahydro-2flrpyrrolidin-
5-yl)methyl, 5(/?)-(2-oxo-tetraliydro-2/:/-pyrrolidin-5-yl)methyl, (5S)-(2-oxotetraliydro-
2W-pyrrolidin-5-yl)iBethyl, (l,3-dioxolan-2-yl)mediyl, 2-(l,3-dioxolan-2-yl)ethyl, 2-
(2-medioxyethylamino)ethyl, 2-(N-(2-methoxyethyl)-N-methylamino)ethyl, 2-(2-
hydroxyethylamino)ethyl, 3-(2-methoxyediylamino)propyI, 3-(N-(2-medioxyethyl)-Nmethylaraiiio)
propyl, 3-(2-hydroxyediylamino)propyl, 2-methyldiiazol-4-ylmethyl, 2-
acetamidotliiazol-4-yknethyl, l-inethylimidazol-2-ylniethyl, 2-(imidazol-l-yl)ethyl, 2-(2-
methylimidazol-l-yl)ethyl, 2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl, 3-
(2-ethylimidazol-l-yl)propyl, 2-(l,2,3-triazol-l-yl)ethyl, 2-(l,2,3-triazol-2-yl)ethyl, 2-(l,2,4-
triazol-l-yl)ethyl, 2-(l,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-
pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamiuo)ethyl, 2-(4-oxo-1,4-dihydro-1 -
pyridyl)ethyl, 2-(2-oxo-imidazolidin-l-yl)ethyl, 3-(2-oxo-imidazolidin-l-yl)propyl, 2-
thiomorpholinoethyl, 3-thiomorpholinopropyl, 2-(l,l-dioxothiomorpholino)ethyl, 3-(l,ldioxodiiomorpholino)
propyl, 2-(2-metfaoxyethoxy)ethyl, 2-(4-methylpiperazin-l-yl)ethyl, 3-
(methylsalpliinyl)propyl, 3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl, 3-
(ethylsulphonyl)propyl, 2-(5-methyl-l,2,4-triazol-l-yl)ediyl, morpholino, 2-((N-(l-
methyIimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl, 2-((N-(3-morpholinopropylsulphonyl)-
N-methyl)ainino)ethyl, 3-(4-oxidomorpholino)propyl, 2-(2-(4-methylpiperazin-1 -
yl)ethoxy)ethyl, 3-(2-(4-methylpiperaziu-l-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl, 3-
(2-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl, 3-(tetrahydropyran-4-
yloxy)propyl, 2-((2-(pyrrolidin- l-yl)ethyl)carbamoyl)vinyl, 3-((2-(pyrrolidin-1-
yl)ethyl)carbarnoyl)prop-2-en-1 -yl, l-(2-morpholinoethyl)piperidin-4-y]rnethyl, l-(2-
thiomorpholinoethyl)piperidin-4-ylmethyl, 3-morphoIino-2-hydroxypropyl, (2/?)-3-morpholiiio-
2-hydroxypropyl, (25)-3-morpholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl, (2£)-3-
piperidino-2-hydroxypropyl, (25)-3-piperidino -2-hydroxypropyl, 3-( 1 -methylpiperazin-4-yl)-2-
hydroxypropyl, (2/?)-3-(l-rnethylpiperazin-4-yl)-2-hydroxypropyl or (2S)-3-(lmethylpiperazin-
4-yl)-2-hydroxypropyl].
In one embodiment of the present invention R2 is selected from one of the three groups:
(i) Q:X' wherein Q1 and X1 are as defined hereinbefore;
(ii) Q15W3 wherein Q15 and W3 are as defined hereinbefore; and
(iii) Q^V/ti.jalkylX1- wherein Q21, W4 and X1 are as defined hereinbefore;
and/or R2 represents hydroxy, Ci^alkyl, amino or R3X!- [wherein X1 is as hereinbefore defined
and R5 represents methyl, ethyl, benzyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-bydroxyethyl,
3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-
(methylsulphonyl)ethyl, 2-(ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl, 2-(N,Ndimethylsulphamoyl)
ethyl, 2-(N-methylsu]phamoyl)ethyl, 2-sulphamoylethyl, 2-
(methylamino)ethyl, 2-(ethylamino)ethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,Ndiethylamino)
ethyl, 2-(N-methyl-N-methylsulphonylamino)ethyl, 3-(N-methyl-Nmethylsulphonylamino)
propyl, 2-rnorpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 2-
(methylpiperidino)ethyl, 2-(ethylpiperidino)ethyl, 2-((2-methoxyethyl)piperidino)etliyl, 2-((2-
rnethylsulphouyl)ethylpiperidino)ethyl, 3-((2-methylsu]phonyl)ethylpiperidino)propyl, (1-
cyanomethylpiperidin-3-yl)methyl, (l-cyanomethylpiperidin-4-yl)methyl, 2-(lcyanomethylpiperidin-
3-yl)ethyl, 2-(l-cyanomethylpiperidin-4-yl)ethyl, 3-(lcyanomethylpiperidin-
3-yl)propyl, 3-( 1 -cyanomethylpiperidiii-4-yl)propyl, ((2-
methoxyeth}'l)piperidiu-3-yl)methyl, ((2-methoxyethyl)piperidin-4-yl)methyl, (l-(2-
methylsulphonylethyl)piperidin-3-yl)methyl, (l-(2-methylsulphonylethyl)piperidin-4-yl)methyl,
2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl, 2-((2-methylsulphonylethyl)piperidin-4-
yl)ethyl, 3-((2-methylsulphonylethyl)piperidin-3-yl)propyl, 3-((2-
methylsulphouyletJiyl)piperidin-4-yl)propyl, 2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-
yloxy)propyl, 2-( 1 -(cyanomethyl)piperidin-4-yloxy)ethyl, 3-( 1 -(cyanornethyl)piperidin-4-
yloxy)propyl, 2-( 1-(2-cyanoethyl)piperidin-4-yloxy)ethyl, 3-(l-(2-cyanoethyl)piperidin-4-
yloxy)propyl, 2-(piperazin-l-yl)ethyl, (pyrrolidin-2-yl)methyl, (2-oxo-tetrahydro-2//-
pyrrolidiu-5-yl)methyl, 5(/?)-(2-oxo-tetrahydro-2//-pyrrolidin-5-yl)methyl, (5S)-(2-oxotetrahydro-
2//-pyrrolidin-5-yl)methyl, (l,3-dioxolan-2-yl)methyl, 2-( 1,3-dioxolan-2-yl)ethyl, 2-
(2-methoxyethylamiao)ethyl, 2-(N-(2-inethoxyethyl)-N-methylamino)et±iyl, 2-(2-
hydroxyethylamino)ethyl, 3-(2-methoxyethylaTnino)propyl, 3-(N-(2-methoxyethyl)-Nmethy]
amino)propyl, 3-(2-liydroxyethylarnino)propyl, 2-methylthiazol-4-ylmethyl, 2-
acetamidothiazol-4-yknethyl, l-methylimidazol-2-ylmethyl, 2-(imidazol-l-yl)ethyl, 2-(2-
methylimidazol-1-yl)ethyl, 2-(2-ethylimidazol-l-yl)ethyl, 3-(2-methyIimidazol-l-yl)propyl, 3-
(2-ethylknidazol-l-yl)propyl, 2-(l,2,3-triazol-l-yl)ethyl, 2-(l,2,3-triazol-2-yl)ethyl, 2-(l,2,4-
triazol-l-yl)ethyl, 2-(l,2,4-triazoI-4-yl)ethyl, 4-pyridykoethyl, 2-(4-pyridyl)ethyl, 3-(4-
pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl, 2-(4-oxo-l,4-diliydro-lpyridyl)
ethyl, 2-(2-oxo-imidazolidin-l-yl)ethyl, 3-(2-oxo-imidazolidiii-l-yl)propyl, 2-
tliiomorpholinoethyl, 3-tliiomorpholinopropyl, 2-(l,l-dioxothiomoiphobno)etliyl, 3-(l,ldioxothiomorpholino)
propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-l-yl)ethyl, 3-
(methylsulphinyl)propyl, 3-(methylsulphoiiyl)propyl, 3-(ethylsulphiriyl)propyl, 3-
(ethylsulphonyl)propyl, 2-(5-methyl-l,2,4-triazol-l-yl)ethyl, morpholino, 2-((N-(linethylimidazol-
4-ylsulphonyl)-N-methyl)amino)ethyl, 2-((N-(3-morpholinopropylsulpliouyl)-
N-methyl)ami]]o)ethyl, 3-(4-oxidoraorpholino)propyl, 2-(2-(4-methylpiperazia-1 -
yl)ethoxy)ethyl, 3-(2-(4-methylpiperazin-l-yl)etlioxy)propyl, 2-(2-morpholinoethoxy)ethyl, 3-
(2-morpholiuoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl, 3-(tetrahydropyran-4-
yloxy)propyl, 2-((2-(pyrrolidin-l-yl)ethyl)carbanioyl)vinyl, 3-((2-(pyirolidin-lyl)
ethyl)carbamoyl)prop-2-eu-1 -yl, 1 -(2-morpholiDoetliyl)piperidin-4-ylmethyl, 1 -(2-
thiomoipholinoethyl)piperidin-4-ylmethyl, 3-morpholino-2-hydroxypropyl, (2/?)-3-morpholino-
2-hydroxypropyl, (2lS)-3-morpholino-2-hydroxypropyl, 3-piperidiuo-2-hydroxypropyl, (2R)-3~
piperidino-2-hydroxypropyl, (25)-3-piperidino-2-hydroxypropyl, 3-(l-methylpiperazin-4-yl)-2-
hydroxypropyl, (2/?)-3-(l-methylpiperazin-4-yl)-2-hydroxypropyl or (25)-3-(lmethylpiperazin-
4-yl)-2-hydroxypropyl).
In one embodiment of the present invention R2 is selected from one of the five groups:
(i) Q'X1 wherein Q1 and X1 are as defined hereinbefore;
(ii) Q15W3 wherein Q15 and W3 are as defined hereinbefore;
(iii) Q21W4Ci-5alkylX1- wherein Q21, W4 and X1 are as defined hereinbefore;
(iv) Q^d.salkylX1-, Q2SC2.5alkeuylX1- or Q^.jalkynylX1- wherein Q2S and X1 are as defined
hereinbefore; and
(v) qfd.salkylX1-, Q29C2.5alkenylX'- or Q29C2.5alkynylX'- wherein Q29 and X1 are as defined
hereinbefore;
and/or R2 represents 6,7-methylenedioxy, 6,7-ethylenedioxy, hydroxy, Ci.salkyi, amino or
R5X'- [wherein X1 is -O- and R5 represents methyl, ethyl, benzyl, trifluoromethyl, 2,2,2-
trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-
(methylsulpliinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(ethylsulpliinyl)ethyl, 2-
(etliylsulphouyl)ethyl, 2-(N,N-dirnethylsulpharnoyl)ethyl, 2-(N-uaethylsulphamoyl)ethyl, 2-
sulphamoylethyl, 2-(methylamino)ethyl, 2-(ethylamino)ethyl, 2-(N.,N-dimethylamino)ethyl, 2-
(N,N-diethylamino)ethyl, 2-(N-methyl-N-methyJsulphouylamino)ethyl, 3-(N-rnethyl-Nmethylsulphonylamino)
propyl, 2-iTwrpholiuoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 2-
(methylpiperidino)ethyl, 2-(ethylpiperidino)ethyl, 2-((2-methoxyethyl)piperidino)ethyl, 2-((2-
methylsulphonyl)ethylpiperidino)ethyl, 3-((2-methylsulphonyl)ethylpiperidino)propyl, (1-
cyauoinethylpiperidin-3-yl)methyl, (1 -cyanomethylpiperidin-4-yl)methyl, 2-( 1 -
cyauomethylpiperidin-3-yl)ethyl, 2-( 1 -cyanomethylpiperidin-4-yl)ethyl, 3-( 1 -
cyanomethylpiperidin-3-yl)propy], 3-( 1 -cyanomethylpiperidin-4-yl)propyl, ((2-
methoxyethyl)piperidin-3-yl)methyl, ((2-methoxyethyl)piperidin-4-yl)methyl, (l-(2-
methylsu]phonylethyl)piperidin-3-yl)methyl, (l-(2-methylsulphonylethyl)piperidiu-4-yl)metliyl,
2-((2-raethylsulphonylethyl)piperidin-3-yl)ethyl, 2-((2-methylsulphonylethyl)piperidin-4-
yl)ethyl, 3-((2-methylsuiphouylethyl)piperidin-3-yl)propyl, 3-((2-
methylsulphouylethyl)piperidin-4-yl)propyl, 2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-
yloxy)propyl, 2-( 1 -(cyanomethyl)piperidiu-4-yloxy)etliyl, 3-( 1 -(cyanomethyl)piperidin-4-
yloxy)propyl, 2-( l-(2-cyauoethyl)piperidin-4-yloxy)ethyl, 3-(l-(2-cyanoethyl)piperidiu-4-
yloxy)propyl, 2-(piperaziu-l-yl)ethyl, (pyrrolidin-2-yl)metliyl, (2-oxo-tetraliydro-2//-
pyrrolidin-5-yl)methyl, 5(^)-(2-oxo-tetraliydro-2/:/-pyrrolidin-5-yl)methyl, (55)-(2-oxotetrahydro-
2/^-pyrrolidin-5-yl)methyl, (l,3-dioxolan-2-yl)methyl, 2-(l,3-dioxolan-2-yl)ethyl, 2-
I
(2-methoxyethylamino)ethyl, 2-(|s[-(2-methoxyethyl)-N-methylamino)ethyl, 2-(2-
hydroxyethylainino)ethyl, 3-(2-methoxyethylamino)propyl, 3-(N-(2-methoxyethyl)-Nmethylamino)
propyl, 3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylrnethyl, 2-
acetamidothiazol-4-yhnethyl, l-methylimidazol-2-yknethyl, 2-(imidazol-l-yl)ethyl, 2-(2-
methylirnidazol-l-yl)ethyl, 2-(2-ethylimidazol-l-yl)ethyl, 3-(2-methylimidazol-l-yl)propyl, 3-
(2-ethylimidazol-l-yl)propyl, 2-(l,2,3-triazol-l-yl)ethyl, 2-(l,2,3-triazol-2-yl)ethyl, 2-(l,2,4-
triazol-l-yl)ethyl, 2-(l,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-
pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamiuo)ethyl, 2-(4-oxo-l,4-dihydro-lpyridyl)
ethyl, 2-(2-oxo-imidazoIidin-l-yl)ethyl, 3-(2-oxo-irnidazolidin-l-yl)propyl, 2-
tliiomorpholinoethyl, 3-thiomorpholiuopropyl, 2-(l,l-dioxothiomorpholino)ethyl, 3-(l,ldioxotbiomorpholino)
propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperaziu-l-yl)ethyl, 3-
(methylsulphiuyl)propyl, 3-(metbylsulphonyl)propy], 3-(ethylsulphinyl)propyl, 3-
(etliylsulphonyl)propyl, 2-(5-methyl-l,2,4-triazol-l-yl)ethyl, morpholino, 2-((N-(lmethylimidazol-
4-ylsulphonyl)-N-methyl)amino)ethyl, 2-((N-(3-morpholinopropylsulphonyl)-
N-methyl)amino)e±yl, 3-(4-oxidomorpholino)propyl, 2-(2-(4-methylpiperazin-1-
yl)ethoxy)ethyl, 3-(2-(4-methylpiperazin-l-yl)ethoxy)propyl, 2-(2-morpholiuoethoxy)ethyl, 3-
(2-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl, 3-(tetraliydropyran-4-
yloxy)propyl, 2-((2-(pyrrolidin-l-yl)ethyl)carbamoyl)vinyl, 3-((2-(pyrrolidin-lyl)
ethyl)carbamoyl)prop-2-en-1 -yl, 1 -(2-morpholinoethyl)piperidin-4-ylinethyl, 1 -(2-
tliiomorpholiuoetliyl)piperidin-4-yknethyl, 3-morpholino-2-hydrox)'propyl, (2^?)-3-morpholino-
2-hydroxypropyl, (25)-3-morpholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl, (2/?)-3-
piperidino-2-hydroxypropyl, (25)-3-piperidino-2-hydroxypropyl, 3-(l-methylpiperazin-4-yl)-2-
hydroxypropyl, (2^)-3-(l-methylpiperazin-4-yl)-2-hydroxypropyl or (25)-3-(lmethylpiperazin-
4-yl)-2-hydroxypropyl].
In one embodiment of the present invention R2 is selected from one of the three groups:
(i) Q'X1 wherein Q1 and X1 are as defined hereinbefore;
(ii) Q15W3 wherein Q15 and W3 are as defined hereinbefore; and
(iii) Q^V/Ci.jalkylX1- wherein Q21, W4 and X1 are as defined hereinbefore;
and/or R2 represents hydroxy, Ci-salkyl, amino or R5X!- [wherein X1 is -0- and R5 represents
methyl, ethyl, benzyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-
methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphouyl)ethyl, 2-
(ethylsulphiuyl)ethyl, 2-(ethylsulphouyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(Nmethylsulphamoyl)
ethyl, 2-sulpharnoylethyl, 2-(methylamino)ethyl, 2-(ethylamino)ethyl, 2-
(N,N-dimethylarnino)ethyl, 2-(N,N-diethylamino)ethyl, 2-(N-methyl-Nmethylsulphonylamiuo)
ethyl, 3-(N-methyl-N-methylsulphonylarnino)propyl, 2-
morpholiaoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 2-(inethylpiperidino)ethyl, 2-
(ethylpiperidino)ethyl, 2-((2-methoxyethyl)piperidino)ethyl, 2-((2-
methylsulphonyl)ethylpiperidino)ethyl, 3-((2-methylsulphonyl)ethylpiperidino)propyl, (1 -
cyauomethylpiperidin-3-yl)methyl, (1 -cyanomethylpiperidin-4-yl)rnethyl, 2-( 1 -
cyanomethylpiperidin-3-yl)ethyl, 2-( l-cyanomethylpiperidin-4-yl)ethyl, 3-(lcyanomethylpiperidin-
3-yl)propyl, 3-(l-cyaiiomethylpiperidiu-4-yl)propyl, ((2-
methoxyethyl)piperidiu-3-yl)rnethyl, ((2-methoxyethyl)piperidin-4-yl)methyl, (1 -(2-
methylsulphonyletliyl)piperidm-3-yl)methyl, (l-(2-rnethylsulphonyletl]yl)piperidin-4-yl)methyl,
2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl, 2-((2-methylsulphonylethyI)piperidin-4-
yl)ethyl, 3-((2-methylsulphonylethyl)piperidin-3-yl)propyl, 3-((2-
methylsulphonylethyl)piperidin-4-yl)propyl, 2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-
yloxy)propyl, 2-(l-(cyauomethyl)piperidin-4-yloxy)ethyl, 3-(l-(cyanomethyl)piperidin-4-
yloxy)propyl, 2-(l-(2-cyanoethyl)piperidin-4-yloxy)ethyl, 3-(l-(2-cyanoethyl)piperidin-4-
yloxy)propyl, 2-(piperazin-l-yl)ethyl, (pyrrolidin-2-yl)methyl, (2-oxo-tetrahydro-2//-
pyrrolidin-5-yl)methyl, 5(^?)-(2-oxo-tetrahydro-2//-pyrrolidin-5-yl)inethyl, (55)-(2-oxotetraliydro-
2//-pyrrolidiji-5-yl)methyl, (l^-dioxolau^-y^methyl, 2-(l,3-dioxolau-2-yl)ethyl, 2-
(2-methoxyethylarniuo)ethyl, 2-(N-(2-methoxyethyl)-N-methylaniiuo)ethyl, 2-(2-
hydroxyethylamiuo)ethyl, 3-(2-methoxyethylan]iao)propyl, 3-(N-(2-methoxyethyl)-Nmethylamino)
propyl, 3-(2-hydroxyethylamiuo)propyl, 2-methylthiazol-4-ylmethyl, 2-
acetamidothiazol-4-yknethyl, l-methylimidazol-2-yknethyl, 2-(imidazol-l-yl)ethyl, 2-(2-
methylimidazol-l-yl)ethyl, 2-(2-ethyliniidazol-l-yl)ethyl, 3-(2-methylimidazol-l-yl)propyl, 3-
(2-ethylimidazol-l-yl)propyl, 2-(l,2,3-triazol-l-yl)ethyl, 2-(l,2,3-triazol-2-yl)ethyl, 2-(l,2,4-
triazol-l-yl)ethyl, 2-(l,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-
pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl, 2-(4-oxo-l,4-dihydro-lpyridyl)
ethyl, 2-(2-oxo-imidazolidin-l-yl)ethyl, 3-(2-oxo-imidazolidin-1 -yl)propyl, 2-
thiomorpholinoethyl, 3-tliiomorpholinopropyl, 2-(l,l-dioxothiomorpholino)ethy], 3-(l,ldioxotliiomorpholino)
propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-l-yl)ethyl, 3-
(methylsulphiuyl)propyl, 3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl, 3-
(ethylsulphonyl)propyl, 2-(5-methyl-l,2,4-triazol-l-yl)ethyl, morpholiuo, 2-((N-(lmethylimidazol-
4-ylsulphonyl)-N-methyl)amino)ethyl, 2-((N-(3-morpholinopropylsulphonyl)-
N-methyl)arnino)ethyl, 3-(4-oxidomorpholino)propyl, 2-(2-(4-methylpiperazin-1 -
yl)ethoxy)ethyl, 3-(2-(4-rnethylpiperaziD-l-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl, 3-
(2-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl, 3-(tetrahydropyran-4-
yloxy)propyl, 2-((2-(pyrrolidin- l-yl)ethyl)carbamoy])viuyl, 3-((2-(pyrrolidin-1-
y])ethyl)carbamoyl)prop-2-en- 1-yl, l-(2-morpholinoethyl)piperidin-4-ylmethyl, l-(2-
thiomorpholinoet±iyl)piperidin-4-ylmethyl, 3-morpholino-2-hydroxypropyl, (2R~)-3 -morpholino-
2-hydroxypropyl, (25)-3-morpholino-2-hydroxypropyl, 3-piperidkio-2-hydroxypropyl, (2/?)-3-
piperidhio-2-hydroxypropyl, (25)-3-piperidino-2-hydroxypropyl, 3-(l-methylpiperaziu-4-yl)-2-
hydroxypropyl, (2/J)-3-(l-methylpiperazin-4-yl)-2-hydroxypropyl or (25)-3-(linethylpiperazin-
4-yl)-2-hydroxypropyl].
In one embodiment of the present invention R2 substituents are at the 6- and/or 7-
positions of the quinazoline ring.
In one embodiment of the present invention R2 is selected from one of the five groups:
(i) Q'X1 wherein Q1 and X1 are as defined hereinbefore;
(ii) Q15W3 wherein Q15 and W3 are as defined hereinbefore;
(iii) Q21W4Ci.5alkyLXI- wherein Q21, W4 and X1 are as defined hereinbefore;
(iv) Q^Ci.salkylX1-, Q28C2-5alkeuylX'- or Q28C2-5aIkynylX'- wherein Q28 and X1 are as defined
hereinbefore; and
(v) Q29C1.5alkylX1-, Q29C2-5alkenylX1- or Q^Cj-salkynylX1- wherein Q29 and X1 are as defined
hereinbefore;
and/or R2 represents methoxy, or R2 represents 6,7-methyleuedioxy or 6,7-ethylenedioxy.
In one embodiment of the present invention R2 is selected from one of the five groups:
(i) Q'X1 wherein Q1 and X1 are as defined hereinbefore;
(ii) Q15W3 wherein Q15 and W3 are as defined hereinbefore;
(iii) Q21W4Ci.3alkylX1- wherein Q21, W4 and X1 are as defined hereinbefore;
(iv) Q^C^alkylX1-, Q^CwalkenylX1- or Q^Cz-jaJkynylX1- wherein Q28 and X1 are as defined
hereinbefore; and
(v) Q29C,.5a]kylX'-, CfCz.salkenylX1- or Q29C2-5alkynylX1- wherein Q29 and X1 are as defined
hereinbefore;
and/or R2 represents methoxy.
In one embodiment of the present invention R2 is selected from one of the three
groups:
(i) Q'X1 wherein Q1 and X1 are as defined hereinbefore;
(ii) Q15W3 wherein Q15 and W3 are as defined hereinbefore; and
(iii) Q21 WCi.salkylX1- wherein Q21, W and X1 are as defined hereinbefore;
and/or R2 represents methoxy.
In one embodiment of the present invention R2 is Q!X' wherein Q1 and X1 are as
defined hereinbefore and/or R2 represents methoxy.
In one embodiment of the present invention R2 is Q15W3 wherein Q13 and W3 are as
defined hereinbefore and/or R2 represents methoxy.
hi one embodiment of the present invention R2 is Q21W4Ci.5aIkylX1- wherein Q21, W4
and X1 are as defined hereinbefore and/or R2 represents methoxy.
hi one embodiment of the present invention R2 is Q^Ci.salkylX1-, Q28C2-5alkenylX'-
or Q^Cz-jalkynylX1- wherein Q28 and X1 are as defined hereinbefore and/or R2 represents
methoxy.
hi one embodiment of the present invention R2 is Q29C|.5alkylX!-, Q^Cz-saBcenylX1-
or Q29C2-5alkynylXL- wherein Q29 and X1 are as defined hereinbefore and/or R2 represents
methoxy.
hi one embodiment of die present invention R2 is 6,7-methylenedioxy or 6,7-
ethyleuedioxy.
According to another aspect of the present invention there are provided compounds of
the formula I.
According to another aspect of the present invention there are provided compounds of
the formula la:
(la)
[wherein:
ring C" is indolyl, indazolyl or azaindolyl;
Ru is selected from oxo, hydroxy, Ci-zalkoxymethyl, amino, halogeno, Cualkyl, C|.3alkoxy,
trifluoromethyl, cyano, nitro, Ci.3alkanoyl,
(i) Q'X1 wherein Q1 and X1 are as defined hereinbefore,
(ii) Q15W3 wherein Q13 and W3 are as defined hereinbefore,
(iii) Q^V/Ci.salkylX1- wherein Q21, W4 and X1 are as defined hereinbefore;
R2 is as defined hereinbefore;
ma is 0, 1, 2 or 3;
Z' is -0- or -S-;
and na is 0, 1 or 2;
with the proviso that at least one R2 is selected from (i), (ii), (iii), (iv) or (v) as defined
hereinbefore in the definitions of R2, and/or Rla is selected from (i), (ii) and (iii) as defined
hereinbefore,
or R2 is 6,7-methylenedioxy or 6,7-ethylenedioxy;
and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably
esters and amides.
According to another aspect of the present invention there are provided compounds of
the formula II:
(Figure Remove) [wherein:
ring C" is indolyl, indazolyl or azaindolyl;
Rla is selected fromoxo, hydroxy, Ci.jalkoxymethyl, amino, halogeno, Ci.s
trifluoromethyl, cyano, nitro, Ci^alkanoyL,
(i) Q'X1 wherein Q1 and X1 are as defined hereinbefore;
(ii) Q15W3 wherein Q15 and W3 are as defined hereinbefore; and
(iii) Q21W4Ci.5alkylX1- wherein Q21, W4 and X1 are as defined hereinbefore;
-35-
R2" and R2b, are each independently selected from hydrogen, hydroxy, halogeuo, cyauo, nitro,
trifluoromethyl, Ci.3alkyl, Ci.3alkoxy, Cijalkylsulphanyl, -NR3'R4' (wherein R3' and R4", which
may be the same or different, each represents hydrogen or Chalky!),
(i) Q'X1 wherein Q1 and X1 are as defined hereinbefore,
(ii) Q15W3 wherein Q15 and W3 are as defined hereinbefore,
(iii) Q^W^d-salkylX1- wherein Q21, W4 and X1 are as defined hereinbefore,
(iv) QPCi.jalkylX1-, Q^C^alkenylX1- or Q^Cz-salkyuylX1- wherein Q28 and X1 are as defined
herein before or
(v) Q^CualkylX1-, Q^C^alkenylX1- or Q^C^alkynylX1- wherein Q29 and X1 are as defined
herein before,
or R2a and R2b together form 6,7-methylenedioxy or 6,7-ethylenedioxy;
and na is 0, 1 or 2;
with the proviso that at least one of R2" and R2b is selected from (i), (ii), (iii), (iv) or (v) as
defined hereinbefore and/or Ru is selected from (i), (ii) and (iii) as defined hereinbefore, or R20
and R2b together form 6,7-methylenedioxy or 6,7-ethylenedioxy;
and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably
esters and amides.
According to another aspect of the present invention there are provided compounds of
the formula Ila:
R
(Ila)
[wherein:
ring C is indolyl, indazolyl or azaindolyl;
Rl° is selected from oxo, hydroxy, Ci.jalkoxymethyl, amino, halogeno, Chalky!,
trifluoromethyl, cyano, nitro, Ci-aalkanoyl,
(i) Q'X1 wherein Q1 and X1 are as defined hereinbefore;
(ii) QI5W3 wherein Q15 and W3 are as defined hereinbefore; and
(iii) Q^V/Ci.jalkylX1- wherein Q21, W4 and X1 are as defmed-hereinbefore;
R2* and R2b, are each independently selected frorn hydrogen, hydroxy, halogeno, cyano, nitro,
trifluoromethyl, Ci.3a]kyl, d.3alkoxy, d.3alkylsulphanyl, -NR3°R4a (wherein R3' and R4°, which
may be the same or different, each represents hydrogen or Chalky!),
(i) Q'X1 wherein Q1 and X1 are as defined hereinbefore;
(ii) Q15W3 wherein Q15 and W3 are as defined hereinbefore; and
(iii) Q21W4Ci.5alkylX1- wherein Q21, W4 and X1 are as defined hereinbefore;
Z" is -O- or -S-;
and na is 0, 1 or 2;
with the proviso that at least one of R2* and R2b is selected from (i), (ii) and (iii) as defined
hereinbefore and/or R1" is selected from (i), (ii) and (iii) as defined hereinbefore;
and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably
esters and amides.
According to another aspect of the present invention there are provided compounds of
the formula Ila as defined hereinbefore wherein at least one of R2" and R2b is selected from (i),
(ii) and (iii) as defined hereinbefore.
In one embodiment of the present invention Z" is -O-.
hi one embodiment of the present invention C" is indol-5-yl, indol-6-yl, 7-azaindol-5-yl,
indazol-5-yl, indazol-6-yl.
ha one embodiment of the present invention C" is indol-5-yl, 7-azaindol-5-yl or indazol-
5-yl.
In one embodiment of the present invention C is indol-5-yl.
In one embodiment of the present invention C" is 7-azaindol-5-yl.
In one embodiment of the present invention R1 is halogeno or Ci-salkyl.
In one embodiment of the present invention R1' is fluoro or methyl.
In one embodiment of the present invention R2a is methoxy and R2b is selected from one
of the five following groups:
(i) Q'X1 wherein Q1 and X1 are as defined hereinbefore;
(ii) Q15W3 wherein Q15 and W3 are as defined hereinbefore;
(iii) Q2IW4Ci.5aIkylX1- wherein Q21, W4 and X1 are as defined hereinbefore;
(iv) Q28Ci.falkylX'-, Q28C2.5alkenylX'- or Q^C^alkynylX1- wherein Q28 and X1 are as defined'
hereinbefore; and
(v) Qd.jalkylX1-, Q^CwalkeuylX1- or Q29C2.5alkynylX'- wherein Q29 and X1 are as defined
herein before.
In one embodiment of the present invention R2" is methoxy and R2b is selected from one
of the three following groups:
(i) Q'X1 wherein Q1 and X1 are as defined hereinbefore;
(ii) QJ5W3 wherein Q13 and W3 are as defined hereinbefore; and
(iii) Q21W4C1.5alkylX1- wherein Q21, W4 and X1 are as defined hereinbefore.
In another embodiment of the present invention R2b is methoxy and R2a is selected from
one of the five following groups:
(i) Q'X1 wherein Q1 and X1 are as defined hereinbefore;
(ii) QI5W3 wherein Q15 and W3 are as defined hereinbefore;
(iii) Q21W4Ci.5alkylX1- wherein Q21, W4 and X1 are as defined hereinbefore;
(iv) Q28C1.5alkylX1-, Q^C^alkenylX1- or Q28C2.5alkynylX'- wherein Q28 and X1 are as defined
hereinbefore; and
(v) QCi jaDcylX1-, Q29C2-5alkenylX'- or Q^C^alkynylX1- wherein Q29 and X1 are as defined
hereinbefore.
In another embodiment of the present invention R2b is methoxy and R2a is selected from
one of the three following groups:
(i) Q'X1 wherein Q1 and X1 are as defined hereinbefore;
(ii) Q15W3 wherein Q15 and W3 are as defined hereinbefore; and
(iii) Q21W4Ci.5alkylX1- wherein Q21, W4 and X1 are as defined hereinbefore.
According to another aspect of the present invention there are provided compounds of
the formula lib:
(Figure Remove) wherein:
M is -CH- or -N-;
R2c is linked to a carbon atom of the 5-membered ring and is selected from hydrogen and
methyl;
R2d is linked to a carbon atom of the 6-membered ring and is selected from hydrogen and
fluoro;
Z°, R2" and R2b, are as defined hereinbefore;
with the proviso that at least one of R2* and R2b is selected from (i), (ii), (iii), (iv) and (v) as
defined hereinbefore;
and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably
esters and amides.
According to another aspect of the present invention there are provided compounds of
the formula He:
(Figure Remove) wherein:
M is -CH- or -N-;
R2t is linked to a carbon atom of the 5-membered ring and is selected from hydrogen and
methyl;
R2d is linked to a carbon atom of the 6-membered ring and is selected from hydrogen and
fluoro;
Z", R2" and R2b, are as defined hereinbefore;
with the proviso that at least one of R2n and R2b is selected from (i), (ii) and (iii) as defined
hereinbefore;
-39-
and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably
esters and amides.
According to another aspect of the present invention there are provided compounds of
the formula lid:
(Figure Remove)R2c is linked to a carbon atom of the 5-membered ring and is selected from hydrogen and
methyl;
R2d is linked to a carbon atom of the 6-membered ring and is selected from hydrogen and
fluoro;
one of R2" and R2b is rnethoxy and the other is Q!X' wherein X1 is as defined hereinbefore and
Q1 is selected from one of the following ten groups:
1) Qz (wherein Q2 is a heterocyclic group selected from pyrrolidinyl, piperidinyl, piperazinyl,
which heterocyclic group bears at least one substitueut selected from Ci-jalkenyL, C
CMfluoroalkyl, Ci-aalkanoyl, aminoCi^alkauoyl, Ci^alkylaminoCi^alkanoyl, di(Ci.
4alkyl)arninoCi-6alkanoyl, Ci^fluoroalkanoyl, carbamoyl, Ci^alkylcarbamoyl, di(Ci.
4alkyl)carbamoyl, carbamoylQ-eaDcyl, Ci^alkylcarbamoylCi^alkyl, di(CMalkyl)carbarnoylCi.
6alkyl, Ci^alkylsulphonyl and CMfluoroalkylsulphonyl and which heterocyclic group may
optionally bear a further 1 or 2 substituents selected from Cz^alkenyl, C^alkynyl, Ci.
4fluoroalkyl, CMalkanoyI, aminoCualkanoyl, Ci^alkylamiuoCi^alkanoyl, di(Cua]kyl)aminoCi.
6alkanoyl, CMfluoroalkanoyl, carbamoyl, CMalkylcarbamoyl, di(CMalkyl)carbamoyl,
-40-
carbam0ylC[. 4alkylsulphonyl, Ci^fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano, C«cyanoalkyl, C\.
4alkyl, Ci-ohydroxyalkyl, Ci^alkoxy, Ci^alkoxyCMaJkyl, CMalkylsulphonylCMalkyl, Ci.
dalkoxycarbonyl, Cuaminoalkyl, Ci-4alkylarnino, di(CMalkyl)amino, CMalkylaminoCi^alkyl,
di(CMalkyl)aininoCMa]kyl, Ci^aIkylaminoCMalkoxy, di(CMalkyl)aminoCi.4a]koxy and a
group -(-O-XCMalkyOgringD (wherein f is 0 or 1, g is 0 or 1 and ring D is selected from from
pyrrolidinyl, piperidiiiyl, piperazinyl,
and _/
which heterocyclic group may bear one or more substituents selected from Chalky!));
2) Ci.ialkylW'Q2 (wherein W1 represents -O-, -S-, -SO-, -SOr, -OC(O)-, -NQ3C(O)-, -
C(O)NQ4-, -SOzNQ3-, -NQ6SOr or -NQ7- (wherein Q3, Q4, Q5, Q6 and Q7 each independently
represents hydrogen, Ci^aBcyl, Ci.2alkoxyC2.3alkyl, C2-5alkenyl, Cj-jalkynyl or Clujialoalkyi)
and Q2 is as defined hereinbefore;
3) Ci.salkylQ2 (wherein Q2 is as denned hereinbefore);
4) C2-5alkenylQ2 (wherein Q2 is as defined hereinbefore);
5) Ca-salkynylQ2 (wherein Q2 is as defined hereinbefore);
6) CMalkylW2CMalkylQ2 (wherein W2 represents -O-, -S-, -SO-, -S02-, -NQ8C(0)-, -
C(O)NQ9-, -S02NQ10-, -NQ"SO2- or -NQ12- (wherein Q8, Q9, Q10, Qn and Q12 each
independently represents hydrogen, Ci.3a]kyl, Ci-3alkoxyC2.3a]kyl, C2.jalkenyl, C2_5alkynyl or
Ci-jhaloalkyl) and Q2 is as defined hereinbefore);
7) C2.5alkenylW2CMalkylQ2 (wherein W2 and Q2 are as defined hereinbefore);
8) C2.jalkyuylW2C^alkylQ2 (wherein W2 and Q2 are as defined hereinbefore);
9) CMalky]Q13(CMalkyl)j(W2)k-Q14 (wherein W2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q13 and Q14 are each independently selected from pyrrolidinyl, piperidinyl, piperazinyl,
and
which heterocych'c group may bear 1, 2 or 3 substituents selected from C2_5alkenyl, Ci-
Ci-dfluoroalkyl, Cualkanoyl, aminoCi-ealkanoyl, CMalkylaminoCi-ealkanoyl, di(Ci.
4alkyl)amiuoCi.6alkauoyl, Ci^fluoroalkanoyl, carbamoyl, CMalkylcarbarnoyl, di(d.
4alkyl)carbamoyl, carbamoylCi.6alkyl, Ci^alkylcarbamoylCi-aalkyl, di(Ci^alkyl)carbamoylCi.
-41-
6alkyl, CMalkylsulphonyl, CMfluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyauo, Ct.
4cyanoalkyl, CMalkyl, Ci^hydroxyalkyl, Ci^alkoxy, CMalkoxyCi^allcyl, CMalkylsulphonylCi.
4alkyl, Ci_»alkoxycarbonyl, Ci^aminoalkyl, CMalkylarniuo, di(Ci-4alkyl)amino, d.
4alkylaininoCMalkyl, d^CMalky^aminoCi^alkyl, Ci^alkylarninoCMalkoxy, di(Ci_
4alkyl)airtiuoCMalkoxy and a group -(-O-)f(CMalkyl)griugD (wherein f is 0 or 1, g is 0 or 1 and
ring D is selected from pyrrolidinyl, piperidinyl, piperazinyl,
and _
which heterocyclic group may bear one or more substituents selected from Chalky!), with the
proviso that at least one of Q13 and Q14 bears at least one substituent selected from C2-salkenyl,
Cz-salkyuyl, CMfluoroalkyl, CMalkauoyl, aminoCi^alkanoyl, CMalkylaminoCi^alkanoyl, di(Ci.
4a]kyl)atninoCi.6a]kanoyl, Ci-afluoroalkanoyl, carbamoyl, CMalkylcarbamoyl, di(Ci.
4alkyl)carbamoyl, carbamoylCi-salkyl, CMalkylcarbamoyl, di(CMalkyl)carbamoyl, Ci_
4alkylsulphouyl and Ci^fluoroalkylsulphonyl); and
10) C1^alkylQ13CiJialkanoylQMn wherein Q13 is as defined hereinbefore and is not hydrogen
and QMn is selected from pyrrolidinyl, piperidinyl, piperazinyl,
and
wherein Q14" is linked to Ci-ealkanoyl through a nitrogen atom;
and additionally wherein any Ci.jalkyl, Cz-salkeriyl or Ca.jalkynyl group in Q'X1- which is
linked to X1 may bear one or more substituents selected from hydroxy, halogeno and amino);
and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably
esters and amides.
According to another aspect of the present invention there are provided compounds of
the formula He:
(Figure Remove)wherein:
M is -CH- or -N-;
R2c is linked to a carbon atom of the 5-inembered ring and is selected from hydrogen and
methyl;
R2d is linked to a carbon atom of the 6-membered ring and is selected from hydrogen and
fluoro;
one of R2u and R2b is methoxy and the other is Q'X1 wherein X1 is as defined hereinbefore and
Q1 is selected from one of the following nine groups:
1) Q2 (wherein Q2 is a heterocyclic group selected from pyrrolidinyl, piperidinyl, piperaziuyl,
and j
which heterocyclic group bears at least one substituent selected from Cz^alkenyl, i
Ci-4fluoroalkyl, C^alkanoyl, CMfluoroalkanoyl, Ci^alkylsulphonyl and Ci.
4fluoroalkylsulphonyl and wliich heterocyclic group may optionally bear a further 1 or 2
substituents selected from C2-5alkenyl, C2-5alkynyl, CMfluoroalkyl, Ci-aalkanoyl, Cj.
4fluoroalkauoyl, CMalkylsulphonyl, CMfluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
Ci^cyanoalky], Ci^alkyl, CMhydroxyalkyl, Ci^alkoxy,
4alkylsulphonylC i^alky 1, Ci^alkoxycarbonyl,
4alkyl)amino, CMalkylamiuoCi.
di(CMalkyl)ainiuoCMalkoxy and a group -(-O-Xd^alkyOgringD (wherein f is 0 or 1, g is 0 or
1 and ring D is selected from from pyrrolidinyl, piperidiuyl, piperazinyl,
(Figure Remove)which heterocyclic group may bear one or more substituents selected from C\.
2) d.jalkylW'Q2 (wherein W1 represents -O-, -S-, -SO-, -SO2-, -OC(O)-, -NQ3C(0)-, -
C(O)NQ4-, -SO2NQ5-, -NQ6SO2- or -NQ7- (wherein Q3, Q4, Q5, Q6 and Q7 each independently
represents hydrogen, Ci^alkyl, Ci-2alkoxyC2-3alkyl, C2-5alkeuyl, C2-5alkynyl or Ci^haloalkyl)
and Q2 is as defined hereinbefore;
3) d.5alky!Q2 (wherein Q2 is as defined hereinbefore);
4) Ca-jalkenylQ2 (wherein Q2 is as defined hereinbefore);
5) C2.5a]kynylQ2 (wherein Q2 is as defined hereinbefore);
6) CMa]kylW2Cwa]kylQ2 (wherein W2 represents -O-, -S-, -SO-, -SO2-, -NQ8C(O)-, -
C(O)NQ9-, -S02NQ10-, -NQUSO2- or-NQ12- (wherein Q8, Q9, Q10, Q11 and Q12 each
independently represents hydrogen, Cj^alkyl, Ci-3alkoxyC2-3alkyl, Cz.jalkenyl, Cz-jalkynyl or
CiJialoalkyl) and Q2 is as defined hereinbefore);
7) C2.5alkenylW2CMalky]Q2 (wherein W2 and Q2 are as defined hereinbefore);
8) C2_5a]kynylW2Ci.4alkylQ2 (wherein W2 and Q2 are as defined hereinbefore); and
9) CMalkylQ13(CMalkyl)j(W2)kQM (wherein W2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q13 and Q14 are each independently selected from pyrrolidinyl, piperidinyl, piperazinyl,
and
which heterocyclic group may bear 1, 2 or 3 substitueuts selected from Cz-salkenyl, C2-5alkynyl,
d-itfluoroalkyl, CMalkanoyl, Ci^fluoroaBcanoyl, CMalkylsulphonyl, d.4fluoroalkylsulphonyl,
oxo, hydroxy, halogeno, cyano, duicyanoalkyl, Ci^alkyl, CiJiydroxyalkyl, CMalkoxy, Ci.
4alkoxyCMa]kyl, Ci^alkylsulphonylCi^^lkyl. Ci^alkoxycarbonyl, Ci^aminoalkyl, Cj.
4alkylamino, di(Ci_4alkyl)amiuo, CMalkylaminoCj^alkyl, di(CMalkyl)airanoCMa]ky], Ci.
4alkylamiuoCMalkoxy, di(CMa]kyl)aminoCi^alkoxy and a group -(-O-)r(CMalkyl)gringD
(wherein f is 0 or 1, g is 0 or 1 and ring D is selected from pyrrolidinyl, piperidiuyl, piperazinyl,
which heterocyclic group may bear one or more substituents selected from d-aalkyl), with the
proviso that at least one of Q13 and Q14 bears at least one substituent selected from Cz-jalkenyl,
Cijalkynyl, d^fluoroalkyl, d^alkanoyl, Cufluoroalkanoyl, d-4a3kylsulphonyl and C|.
4fluoroalkylsulphonyl) ;
and additionally wherein any d-salkyl, C2-5alkenyl or d-salkynyl group in Q'X1- which is
Unked to X1 may bear one or more substitueuts selected fromhydroxy, halogeuo and amino);
and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably
esters and amides.
In one embodiment of the present invention one of R2" and R2b is methoxy and the
other is Q'X1 wherein X1 is -0- and Q1 is selected from one of the following four groups:
1) Q2 (wherein Q2 is a heterocyclic group selected from pyrrolidinyl, piperidinyl, piperazinyl,
and
which heterocyclic group bears one substituent selected from C2-5alkenyl, d-salkyuyl, Ci.
4fluoroalkyl, d^alkanoyl, aminod-salkanoyl, d^alkylaniinod-ealkanoy], di(d-4alkyl)aminodealkauoyl,
d-efluoroalkanoyl, carbamoyl, d^alkylcarbamoyl, di(CMa!kyl)carbamoyl,
carbamoylCi-fialkyl, CMalkylcarbamoylCi^alkyl, di(CMalkyl)carbanaoylCi-6alkyl, Ci_
4alkylsulphonyl and Ci^fluoroalkylsulphonyl;
2) Ci-salkylQ2 (wherein Q2 is as defined hereinbefore);
3) CMalkylW2CMalkylQ2 (wherein W2 and Q2 are as defined hereinbefore);
4) CMalkylQ13(CMalkyl)j(W2)kQu (wherein W2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q13 and Q14 are each independently selected from pyrrolidinyl, piperidinyl, piperazinyl,
which heterocyclic group may bear 1, 2 or 3 substituents selected from C^alkenyl, Cj.salkynyl,
CMfluoroalkyl, Ci^alkanoyl, aminoCi^alkanoyl, Ci^alkylaminoCi-6alkanoyl, di(d.
4alkyl)aminoCi.6alkauoyl, Ci^fluoroalkanoyl, carbamoyl, Ci^alkylcarbamoyl, di(d.
4alkyl)carbamoyl, carbamoylCi^alkyl, CMalkylcarbamoylCi^alkyl, di(Ci-4alkyl)carbarnoylCi.
6alkyl, Ciwjalkylsulphouyl, Ci^fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano, d.
4cyanoalkyl, CMalkyl, Ci-Jiydroxyalkyl,
with the proviso that at least one of Q13 and Qu bears at least one substituent selected frorn C2.
5alkenyl, Cz-jalkynyl, Ci^fluoroalkyl, Ci^alkanoyl, aminoCi^alkauoyl, CMalkylaminoCi.
6alkanoyl, di(Ci-4alkyl)aminoCi^a]kanoyl, C^fluoroalkanoyl, carbamoyl, Ci.4alky]carbamoy1,
di(Ci-4alkyl)carbamoyl, carbamoylCi-ealkyl, Ci^alkylcarbamoylCi-ealkyl, di(Ci.
4alkyl)carbamoylC|.6alkyl, CMalkylsulphonyl and Ci^fluoroalkylsulphonyl);
and additionally wherein any Ci.3alkyl, group in Q'X1- which is linked to X1 may bear one or
more substituents selected from hydroxy, halogeno and amino).
In one embodiment of the present invention one of R2" and R2b is methoxy and the
other is Q!X] wherein X1 is -0- and Q1 is selected from, one of the following four groups:
1) Q2 (wherein Q2 is a heterocyclic group selected from pyrrolidinyl, piperidinyl, piperazinyl,
and j
which heterocyclic group bears one substituent selected from Cz-salkenyl, C2.salkynyl, Ci.
4fluoroalkyl, Q^alkanoyl, CMfluoroalkanoyl, Ci^alkylsulphonyl and CMfluoroalkylsulphonyl;
2) Ci-salkylQ2 (wherein Q2 is as defined hereinbefore);
3) CMalkylW2C,w»alkylQ2 (wherein W2 and Q2 are as defined hereinbefore);
4) CMalkylQ13(CMalkyl)j(W2)kQ14 (wherein W2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q13 and Q14 are each independently selected from pyrrolidinyl, piperidiuyl, piperazinyl,
and
which heterocyclic group may bear 1, 2 or 3 substituents selected from Cz-salkenyl,
Ci-4fluoroalkyl, Cwalkanoyl, CMfluoroalkauoyl, CMalkylsulphonyl, Ci^fluoroalkylsulphonyl,
oxo, hydroxy, halogeuo, cyano, Ci-acyanoalkyl, Chalky!, dwihydroxyalkyl, Ci^alkoxy, C|.
4a!koxyCi^alkyl;
with the proviso that at least one of Q13 and Q14 bears at least one substitueut selected from Ci.
5alkenyl, Cz-jalkynyl, CMfluoroalkyl, CMalkanoyl, Ci^fluoroalkauoyl, CM^ylsulphonyl and
C i fluoro alkylsulphouy 1);
and additionally wherein any Cualkyl, group in Q'X1- which is linked to X1 may bear one or
more substituents selected from hydroxy, halogeuo and amino).
In one embodiment of the present invention one of R2" and R2b is methoxy and the
other is Q'X1 wherein X1 is -0- and Q1 is selected from one of the following four groups:
1) Q2 (wherein Q2 is a heterocyclic group selected from pyrrolidinyl, piperidinyl, piperazinyl,
and 5
which heterocyclic group bears one substituent selected from C2-5alkenyl, C^-salkyuyl, Ci.
4alkanoyl, aminoCuealkanoyl, CMalkylaminoCi-ealkanoyl, di(CMaIkyl)aminoCi^alkanoyl, Ci_
afluoroalkanoyl, carbamoyl, Ci-4alkylcarbamoyl, di(Ci-aalkyl)carbamoyl, carbamoylCj-ealkyl, Ci
4alkylcarbamoylCi^alkyl, di(CMalkyl)carbamoylCi-6alkyl, Ci-4alkylsulphonyl and Q.
4fluoroalkylsulphonyl;
2) Ci-salkylQ2 (wherein Q2 is as defined hereinbefore);
3) CMalkylW2CMalkylQ2 (wherein W2 and Q2 are as defined hereinbefore);
4) CMalkylQ13(CMalkyl)j(W2)kQ14 (wherein W2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q13 and Q14 are each independently selected from pyrrolidinyl, piperidinyl, piperazinyl,
which heterocyclic group may bear 1, 2 or 3 substituents selected from Cz-salkenyl, C2-5alkynyl,
Ci^alkauoyl, aminoQ-ealkanoyl, Ci^alkylaminoCi-ealkanoyl, di(CMalkyl)aminoCi^alkanoyl,
Ci-efluoroalkanoy], carbamoyl, Ci-jalkylcarbamoyl, di(CMa]kyl)carbamoyl, carbamoylCi-ealkyl,
CMalkylcarbamoylCi,6alkyl, di(Cwalkyl)carbamoylCi-6alkyl, Ci^alkylsulphonyl, CL.
4fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano, Ci^cyauoalkyl, Ci^alkyl, Ci-
4hydroxyalkyl, Ci^alkoxy, CMalkoxyCi^alkyl;
with the proviso that at least one of Q13 and Q14 bears at least one substituent selected from C2.
5alkenyl, Cz.jalkyuyl, Ci^alkauoyl, aminoCi-ealkanoyl, Ci^alkylaminoCi^alkanoyl, di(Ci.
4alkyl)aminoCi.6alkauoyl, Ci^fluoroalkanoyl, carbamoyl, CMalkylcarbamoyl, di(Ci.
4alkyl)carbamoyl, carbamoylCi-galkyl, Ci_4alkylcarbamoylCi-6alkyl, di(CMa]kyl)cai'bainoylCi.
6alkyl, CMalkylsulphonyl and CMfluoroalkylsulphouyl);
and additionally wherein any Ci-salkyl, group in Q^1- which is linked to X1 may bear one or
more substitueuts selected from hydroxy, halogeno and amiuo).
In one embodiment of the present invention one of R2° and R2b is methoxy and the
other is Q'X1 wherein X1 is -0- and Q1 is selected from one of the following four groups:
1) Q2 (wherein Q2 is a heterocyclic group selected from pyrrolidinyl, piperidinyl, piperazinyl,
which heterocyclic group bears one substituent selected from Cz-salkenyl, Cz-jalkynyl, Cj.
4a]kauoyl, CMfluoroalkanoyl, C^alkylsulphonyl and Ci^fluoroalkylsulphonyl;
2) Ci-jalkylQ2 (wherein Q2 is as defined hereinbefore);
3) CMa]kylW2CMalkylQ2 (wherein W2 and Q2 are as defined hereinbefore);
4) CMalkylQ13(Cwa]kyl)j(W2)kQ14 (wherein W2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q13 and Q14 are each independently selected from pyrrolidinyl, piperidinyl, piperazinyl,
and
which heterocyclic group may bear 1, 2 or 3 substiruents selected from Cz-jalkenyl,
CMalkanoyl, Ciwjfluoroalkanoyi, CMalkylsulphouyl, Ci-4fluoroalkylsulphonyl, oxo, hydroxy,
halogeno, cyano, CMcyauoalkyl, Ci^alkyl, CiJiydroxyalkyl, Ci^alkoxy, Q^alkoxyCMalkyl;
with the proviso that at least one of Q13 and Q14 bears at least one substituent selected from C-i.
5alkenyl, Cz-salkynyl, CMalkanoyl, Ci-4fluoroalkanoyl, Q^alkylsulphonyl and Ci-
4fluoroa]kylsu]phouyl);
and additionally wherein any Ci.5alkyl, group in Q'X1- wliich is linked to X1 may bear one or
more substiruents selected from, hydroxy, halogeno and amino).
According to another aspect of the present invention there are provided compounds of
the formula Ilf:
(Figure Remove)
wherein:
Mis-CH-or-N-;
R2c is linked to a carbon atom of the 5-membered ring and is selected from hydrogen and
methyl;
R2d is linked to a carbon atom of the 6-membered ring and is selected from hydrogen and
fluoro;
R2a and R2b are each independently selected from methoxy, Q15W3 (wherein Q15 and W3 are as
defined hereinbefore) and Q21W4Ci.5alkylX1- (wherein Q21, W4 and X1 are as defined
hereinbefore);
with the proviso that R2" and R2b cannot both be methoxy;
and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably
esters and amides.
According to another aspect of the present invention there are provided compounds of
the formula Ilg:
(Figure Remove)R2c is linked to a carbon atom of the 5-membered ring and is selected from hydrogen and
methyl;
R2d is linked to a carbon atom of the 6-membered ring and is selected from hydrogen and
fluoro;
R2a and R2b are each independently selected from methoxy,
Q15W3 (wherein W3 represents -NQ16C(O)-, -C(0)NQ17-, -SO2NQ18-, -NQ19S02- or-NQ20-
(wherein Q16, Q17, Q18, Q19 and Q20 each independently represents C^aDtenyl or Cz-salkynyl),
and Q15 is Cz-falkenyl or C^alkynyl), and
Q^Vd.salkylX1- (wherein W4 represents -NQ22C(0)-, -C(O)NQ23-, -SO^NQ24-, -NQ25SO2-
or -NQ26- (wherein Q22, Q23, Q24, Q25 and Q26 each independently represents hydrogen, d.
3alkyl, d-salkoxyd-salkyl, d-salkenyl, Cwalkynyl or Ci -Jialoalkyl), and Q21 represents Cz.
salkenyl or C2-5aLkynyl, and X1 is as defined hereinbefore);
with the proviso that R2a and R2b cannot both be methoxy;
and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably
esters and amides.
According to another aspect of the present invention there are provided compounds of
the formula Hh:
(Figure Remove)M and T each independently represents a carbon atom or a nitrogen atom with the proviso that
M and T cannot both be nitrogen atoms;
R2t is linked to a carbon atom of the 5-membered ring and is selected from hydrogen and
methyl;
R2d is linked to a carbon atom of the 6-membered ring and is selected from hydrogen and
fluoro;
either R2° and R28 form 6,7-methylenedioxy or
one of R2" and R2b is methoxy and the other is selected from one of the following four groups:
(a) Q'X1-
wherein X1 is -0- and Q1 is selected from one of the following three groups:
1) Q2 (wherein Q2 is a heterocyclic group selected from pyrrolidiuyl, piperidinyl and
piperazinyl, which heterocyclic group bears one substitueut selected from Ci-salkeuyl, Cj.
salkynyl, Ci.6fluoroalkyl, Ci^alkanoyl, aminoCi.«aIkauoyl, Ci-4alkylarniuoCi.6alkanoyl, di(Ci_
4alkyl)aminoCi-6alkanoyl, carbamoyl, CMalkylcarbamoyl, di(Ci_4alkyi)carbamoyl, carbamoylCi.
ealkyl, Ci.4alkylcarbamoylC|.6alkyl, di(CMalkyl)carbarnoylCi-6alkyl and Ci^alkylsulphouyl;
2) Ci-salkylQ2 (wherein Q2 is as defined hereinbefore); and
3) Ci-4alkyr\V2C[^alkylQ2 (wherein W2 represents -O- and Q2 is as defined hereinbefore);
and additionally wherein any Ci_5alkyl group in Q'X1- which is linked to X1 may bear one or
more substituents selected from hydroxy);
(b) Q21W4Ci.5alkylX1- (wherein X1 is -0-, W* is NQ26 (wherein Q26 is hydrogen or C^akyl)
and Q21 is Cz.5alkynyl);
(c) Q28Ci-5alkylXI- wherein X1 is -0- and Q28 is an imidazolidinyl group which bears two oxo
substitueuts and one Chalky! group which Ci^alkyl group bears a hydroxy substituent on the
carbon atom which is linked to the imidazolidinyl group; and
(d) CfCi.salkylX1- wherein X1 is -O- and Q29 is a group l,4-dioxa-8-azaspiro[4.5]dec-8-yl;
and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably
esters and amides.
According to another aspect of the present invention there are provided compounds of
the formula Hi:
x/rM-
R2c is linked to a carbon atom of the 5-rnembered ring and is selected from hydrogen and
methyl;
R2d is linked to a carbon atom of the 6-membered ring and is selected from hydrogen and
fluoro;
one of R2a and R2b is methoxy and the other is selected from Q'X1- (wherein X1 is -0- and Q1
is Ci.5alkylQ2 (wherein Q2 is a heterocyclic group selected from pyrrolidinyl, piperidinyl and
piperazinyl, which heterocyclic group bears one substitueut selected from Cz^alkenyl, Cj-
3alkyuyl, Ci^fluoroalkyl, Ci^alkanoyl and CMalkylsulphonyl)) and Q21W4Ci.5alkylX1- (wherein
X1 is -0-, W4 is NQ26 (wherein Q26 is hydrogen or C|.3alkyl) and Q21 is C2-5alkyuyl);
and salts thereof, and prodrugs thereof for example esters, amides and sulpllides, preferably
esters and amides.
In one embodiment of the present invention R2' is rnethoxy.
In one embodiment of the present invention R2b is selected from is selected from one of the
following four groups:
(a) Q'X1-
wherein X1 is -O- and Q1 is selected from one of the following three groups:
1) Q2 (wherein Q2 is a heterocyclic group selected from pyrrolidinyl, piperidinyl and
piperazinyl, which heterocyclic group bears one substitueut selected from Cz-salkenyl, Cosalkynyl,
Ci.6fluoroalkyl, Ci-salkanoyl, aminoCi. 4alkyl)aminoCi-6alkanoyl, carbamoyl, d^alkylcarbaiiioyl, di(CMalkyl)carbamoyl, carbamoylCi.
6alkyl, Q.4a]kylcarbamoy]Ci-6alkyl, di(Ci.4alkyl)carbamoylCi. 2) C^alkylQ2 (wherein Q2 is as denned hereinbefore); and
3) CMalkylW2Ci-4alkylQ2 (wherein W2 represents -O- and Q2 is as defined hereinbefore);
and additionally wherein any d.salkyl group in Q'X1- which is linked to X1 may bear one or
more substitueuts selected from hydroxy);
(b) Q21W4Ci.5alkylX1- (wherein X1 is -O-, W4 is NQ26 (wherein Q26 is hydrogen or C,.3alkyl)
and Q21 is Cz-jalkynyl);
(c) Q28C].5alkylX1- wherein X1 is -O- and Q28 is an imidazolidinyl group which bears two oxo
substituents and one Ci^alkyl group which C^alkyl group bears a hydroxy substituent on the
carbon atom which is linked to the imidazolidinyl group; and
(d) QfCi-salkylX1- wherein X1 is -0- and Q29 is a group l,4-dioxa-8-azaspiro[4.5]dec-8-yl.
In one embodiment of the present invention R2b is selected from Q'X1- (wherein X1 is -O- and
Q is Ci^alkylQ" (wherein Q is a heterocyclic group selected from pyrrolidinyl, piperidinyl and
piperazinyl, which heterocyclic group bears one substituent selected from C2.jalkenyl, Cz-
5alkynyl, C^alkanoyl and CMalkylsulphonyl)) and Q21W4Ci.5alkylX1- (wherein X1 is -O-, W4 is
NQ26 (wherein Q26 is hydrogen or C^alkyl) and Q21 is C2-5alkenyl).
Preferred compounds of the present invention include:
4-(7-azaindol-5-yloxy)-7-methoxy-6-(3-(4-methylsulphonylpiperazin-lyl)
propoxy)quinazoline,
6-(3-(4-acetylpiperazin-l-yl)propoxy)-4-(7-azaindol-5-yloxy)-7-methoxyquinazoUne,
4-[(4-fiuoro-2-methyl- l#-indol-5-yl)oxy]-7- {[(25)- l-isobutyrylpyrrolidin-2-yl]metlioxy} -6-
metho xyquinazo line,
4-(7-azaindol-5-yloxy)-6-methoxy-7-[3-(4-carbamoylpiperazin-l-yl)propoxy]quinazoline,
6-[2-(4-acetylpiperazin-l-yl)ethoxy]-4-[(4-fluoro-l//-iudol-5-yl)oxy]-7-methoxyquinazoline,
6-[(l-acetylpiperidin-4-yl)iBethoxy]-4-[(4-fluoro-l^-indol-5-yl)oxy]-7-methoxyquinazoline,
7-[2-(4-acetylpiperazin-l-yl)ethoxy]-4-(7-azaindol-5-yloxy)-6-rnethoxyquinazoline,
4-(7-azaindol-5-yloxy)-7-[3-(4-carbamoylmethyl)piperazin-l-yl)propoxy]-6-
methoxyquinazoline,
4-(7-azaindol-5-yloxy)-7T {2-[4-(2-fluoroethyl)piperazin-1 -yljethoxy }-6-metho xyquinazo line,
4-(7-azaindol-5-yloxy)-6-methoxy-7-[3-(4-prop-2-yn-l-ylpiperazin-l-yl)propoxy]quinazoline,
7-[l-(A',Af-diiiiethylarninoacetyl)piperidin-4-yhriethoxy]-4-[(4-fluoro-2-rnethyl-l//-indol)-5-
yloxy]-6-uiethoxyquinazoline,
and salts thereof.
More preferred compounds of the present invention include:
6-(3-(4-acetylpiperazin-l-yl)propoxy)-4-(4-fluoro-2-methynndol-5-yloxy)-7-
metho xyquinazo line,
7-(3-(4-acetylpiperazin-l-yl)propoxy)-4-(7-azaindol-5-yloxy)-6-methoxyquinazoline,
4-(7-azaindol-5-yloxy)-6-medioxy-7-(3-(4-methylsulphonylpiperazin-lyl)
propoxy)quinazoline,
4-(7-azaindol-5-yloxy)-6-methoxy-7-[2-(N-rnethyl-A/-prop-2-yn-l-ylarnino)ethoxy]quinazoline)
4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxy-6-(3-(4-methylsulphonylpiperaziu-lyl)
propoxy)quinazoUne,
4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylsulphonylpiperazin-lyl)
propoxy)quinazoline,
6-(3-(4-acetylpiperazin-l-yl)propoxy)-4-(4-fluoroindol-5-yloxy)-7-methoxyquiuazoline,
7-[(l-acetylpiperidin-4-yl)methoxy]-4-[(4-fluoro-2-methyl-17:/-indol-5-yl)oxy]-6-
methoxyquinazoline,
7-[(25)-l-acetylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-methyl-l/T-indol-5-yl)oxy]-6-
metho xyquiuazo line,
7-[(27?)-l-acetylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-methyl-l^-indol-5-yl)oxy]-6-
methoxyquiiiazoline,
4-[(4-fluoro-2-methyl-l//-indol-5-yl)oxy]-6-methoxy-7-[l-(2,2,2-trifluoroethyl)piperidin-4-
ylmetho xy] quinazo line,
4-[(4-fluoro-2-methyl- l#-indol-5-yl)oxy]-6-methoxy-7- {3-[4-(2,2,2-trifluoroethyl)pipera2inl-
yl]propoxy)quinazoline,
4-[(4-fluoro-2-methyl-lW-indol-5-yl)oxy]-6-methoxy-7-{3-[4-(2,2,2-trifluoroethyl)piperazin-
1 -yl]ethoxy }quinazoline,
7-{2-[4-(2-fluoroethyl)piperazin-l-yl]ethoxy}-4-[(4-fluoro-2-methyl-l^-indol-5-yl)oxy]-6-
metho xyquinazo line,
7-{ 2-[2-(4-acetylpiperazin- l-y])ethoxy]ethoxy }-4-[(4-fluoro-2-methyl- lf/-indol-5-yl)oxy]-6-
inethoxyquinazoline,
4-[(4-fluoro-2-methyl-l//-indol-5-yl)oxy]-7-[(l-isobutyrylpiperidin-4-yl)inethoxy]-6-
metho xyquinazo line,
4-[(4-fluoro-2-rnethyl-lJ?7-indo]-5-yl)oxy]-7-{[(2^)-l-isobutyrylpyiTolidin-2-yl]methoxy}-6-
metho xyquinazo line,
4-[(4-fluoro-2-methyl-1 J7-iudol-5-yl)oxy]-6-methoxy-7-{ [ l-(methylsulfonyl)piperidin-4-
yl]methoxy}quina2oline,
4-[(4-fluoro-2-methyl- l//-indol-5-yl)oxy]-6-methoxy-7-{ [(2S)- l-(methylsulfonyl)pyrrobdin-2-
yljmethoxy} quinazoline,
4-[(4-fluoro-2-methyl-l/:/-indol-5-yl)oxy]-6-methoxy-7-{[(2^?)-l-(methylsulfonyl)pyrrolidin-2-
yljmetho xy} quinazoline,
7-[3-(4-allylpiperaziu-l-yl)propoxy]-4-(7-azaindo]-5-yloxy)-6-methoxyquinazoline,
4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxy-7-{3-[4-(2-propynyl)piperaziu-lyl]
propoxy}quinazoline,
7- {3-[4-(2-fluoroethyl)piperazin-1 -yl]propoxy }-4-[(4-fluoro-2-methyl- lH-indol-5-yl)oxy]-6-
methoxyquinazo line,
7- [3-(4-acetylpiperazin-1 -yl)propoxy]-4-( 1 /7-iadol-5-yloxy)-6-methoxyquinazoline,
7-[(2S)-l-carbamoylpyrrolidin-2-yImethoxy]-4-[(4-fluoro-2-meth.yl-l//-mdol-5-yl)oxy]-6-
methoxyquinazoline,
7- {3-[4-carbamoylpiperazin-l-yl]propoxy}-4-[(4-fluoro-2 -methyl- 177-indol-5-yl)oxy]-6-
methoxyquinazoline,
7-{3-[2,5-dioxo-4-(l-hydroxy-l-methylethyl)imidazolidin-l-yl]propoxy}-4-[(4-fluoro-2-
methyl-l#-indol-5-yloxy]-6-methoxyquinazoline,
6-[(l-acetylpiperidin-4-yl)oxy]-4-[(4-fluoro-l//-indol-5-yl)oxy]-7-raethoxyquinazolineJ
4-[(4-f]uoro-l//-iiidol-5-yl)oxy]-7-methoxy-6-{[l-(methylsulphonyl)piperidin-4-
yl]oxy}quinazoline,
4-[(4-fluoro-2-methyl-lflr-indol-5-yl)oxy]-6-methoxy-7-{2-[A^-methyl-//-(2-
propynyl)amino]ethoxy}quinazoline,
7-[3-(4-acetylpiperazin-l-yl)propoxy]-6-methoxy-4-[(2-methyl-l/:/-indol-5-yl)oxy]quinazoline,
7-[3-(4-acetylpiperazin-l-yl)propoxy]-4-[(4-fluoro-l/f-indol-5-yl)oxy]-6-methoxyquinazoline,
7-[3-(4-carbamoyhBethylpiperazin-l-yl)propoxy]-4-[(4-fluoro-2-inetliyl-l/f-indol-5-yl)oxy]-6-
methoxyquiuazoline,
7-{3-[4-(2-fluoroethyl)piperazin-l-yl]propoxy}-6-methoxy-4-[(2-rnediyl-lff-mdol-5-
yl)oxy]quinazoline,
4-[(4-fluoro-2-methyl- l/7-indol-5-yl)oxy] -7- {(27?)-2-hydroxy-3-[4-prop-2-yn-l -ylpiperazin-1 -
y]]propoxy}-6-methoxyquinazoline,
7-{(2JR)-3-[(l,4-dioxa-8-azaspiro[4.5]dec-8-yl)]-2-hydroxypropoxy}-4-[(4-fluoro-2-methyllflr-
indol-5-yl)oxy]-6-methoxyquinazoline,
7- {(2/?)-3-[4-acetylpiperazin- l-yl]-2-hydroxypropoxy }-4-[(4-fluoro-2-methyl- l//-indol-5-
yl)oxy] -6-methoxyquinazoline,
and salts thereof.
A particular compound of the present invention is 7-(3-(4-acetylpiperazin-ly])
propoxy)-4-(4-fluoro-2-methyUndol-5-yloxy)-6-methoxyquinazouue and salts thereof.
A particular compound of the present invention is 7-[2-(4-acetylpiperazin- l-yl)ethoxy]-4-[(4-
fluoro-2-methyl-lH-iiidol-5-yl)oxy]-6-inethoxyquinazoliue and salts thereof.
Compounds of the present invention include
6-(3-(4-acetylpiperazin-l-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-7-
methoxyquinazoline,
4-(7-azaindol-5-yloxy)-7-niethoxy-6-(3-(4-methylsulphonylpiperazin-lyl)
propoxy)quinazoliue,
6-(3-(4-acetylpiperazin-l-yl)propoxy)-4-(7-azaindol-5-yloxy)-7-methoxyquinazoline,
4-(7-azabdol-5-yloxy)-6-memoxy-7-(3-(4-methylsulphonylpiperazin-1 -
yl)propoxy)quinazoline,
4-(7-azaindol-5-yloxy)-6-methoxy-7-[2-(A'-methyl-A?-prop-2-yn-l-ylamino)ethoxy]quiriazoluie,
4-(4-fluoro-2-methyliudol-5-yloxy)-7-methoxy-6-(3-(4-methylsulphonylpiperazin-lyl)
propoxy)quinazoline,
4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylsulphonylpiperazin-lyl)
propoxy)quinazoline, and
6-(3-(4-acetylpiperazin-l-yl)propoxy)-4-(4-fluoroindol-5-yloxy)-7-methoxyquiuazoIine
and salts thereof.
Compounds of the present invention include
7-(3-(4-acetylpiperazin-l-yl)propoxy)-4-(7-azaindo]-5-yloxy)-6-methoxyquinazoline, and
7-(3-(4-acetylpiperazin-l-yl)propoxy)-4-(4-fluoro-2-methyUndol-5-yloxy)-6-
metho xyquiuazoline
and salts thereof.
Another compound of the present invention is 4-(7-azaindol-5-yloxy)-7-(3-(4-(2-
fluoroethyl)piperazin-1 -yl)propoxy)-6-methoxyquinazoline
and salts thereof.
For the avoidance of doubt it is to be understood that where in this specification a
group is qualified by 'hereinbefore defined' or 'defined hereinbefore' the said group
encompasses the first occurring and broadest definition as well as each and all of the preferred
definitions for that group.
In this specification unless stated otherwise the term "alky!" includes both straight
and branched chain alkyl groups but references to individual alkyi groups such as "propyl" are
specific for the straight chain version only. An analogous convention applies to other generic
terms. Unless otherwise stated the term "alkyl" advantageously refers to chains with 1-6
carbon atoms, preferably 1-4 carbon atoms. The term "alkoxy" as used herein, unless stated
otherwise includes "alkyl"-O- groups in which "alkyl" is as hereinbefore defined. The term
"aryl" as used herein unless stated otherwise includes reference to a C(,.\0 aryl group wliich
may, if desired, carry one or more substkuents selected fromhalogeno, alkyl, alkoxy, nitro,
trifluoromethyl and cyano, (wherein alkyl and aikoxy are as hereinbefore defined). The term
"aryloxy" as used herein unless otherwise stated includes "aryl"-0-groups in which "aryl" is as
hereinbefore defined. The term "sulphonyloxy" as used herein refers to alkylsulphonyloxy and
arylsulphouyloxy groups in which "alkyl" and "aryl" are as hereinbefore defined. The term,
"alkanoyl" as used herein unless otherwise stated includes forniyl and alkylC=0 groups in
which "alkyl" is as defined hereinbefore, for example Cjalkanoyl is ethaaoyl and refers to
CH3C=O, Cialkanoyl is formyl and refers to CHO. Butanoyl refers to CH3-CH2-CH2-C(O),
isobutyryl refers to (CH3)2.CH-C(O). In this specification unless stated otherwise the term
"alkenyl" includes both straight and branched chain alkenyl groups but references to individual
alkenyl groups such as 2-buteuyl are specific for the straight chain version only. Unless
otherwise stated the term "alkenyl" advantageously refers to chains with 2-5 carbon atoms,
preferably 3-4 carbon atoms. In this specification unless stated otherwise the term "alkynyl"
includes both straight and branched chain alkyuyl groups but references to individual alkynyl
groups such as 2-butynyl are specific for the straight chain version only. Unless otherwise
stated the term "alkynyl" advantageously refers to chains with 2-5 carbon atoms, preferably 3-
4 carbon atoms. Unless stated otherwise the term "haloalkyl" refers to an alkyl group as
defined hereinbefore which bears one or more halogeno groups, such as for example
trifluoro methyl.
In this specification the term azaindolyl refers to the moiety (17/-pyrrolo[2,3-
pyridinyl) and an analogous convention applies to similar groups. For example 7-azaindol-5-
yl is (l//-pyrrolo[2,3-fc]pyridin-5-yl) and is the group:
Within the present invention it is to be understood that a compound of the formula I or
a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings
within this specification can represent only one of the possible tautomeric forms. It is to be
understood that the invention encompasses any tautomeric form which inhibits VEGF receptor
tyrosine kinase activity and is not to be limited merely to any one tautomeric form utilised
within the formulae drawings. The formulae drawings within this specification can represent
only one of the possible tautomeric forms and it is to be understood that the specification
encompasses all possible tautomeric forms of the compounds drawn not just those forms which
it has been possible to show graphically herein.
-57-
It will be appreciated that compounds of the formula I or a salt thereof may possess an
asymmetric carbon atom. Such an asymmetric carbon atom is also involved in the tautomerism
described above, and it is to be understood that the present invention encompasses any chiral
form (including both pure enautiomers, scalemic and racemic mixtures) as well as any
tautomeric form which inhibits VEGF receptor tyro sine kinase activity, and is not to be limited
merely to any one tautomeric form or chiral form utilised within the formulae drawings. It is to
be understood that the invention encompasses all optical and diastereomers which inhibit
VEGF receptor tyrosine kinase activity. It is further to be understood that in the names of
chiral compounds (R,S) denotes any scalemic or racemic mixture while (^?) and (,$") denote the
enautiomers. hi the absence of (R,S), (R) or (S) in the name it is to be understood that the
name refers to any scalemic or racemic mixture, wherein a scalemic mixture contains R and S
enautiomers in any relative proportions and a racemic mixture contains R and 5" enantiomers in
the ration 50:50.
It is also to be understood that certain compounds of the formula I and salts thereof can
exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be
understood that the invention encompasses all such solvated forms which inhibit VEGF
receptor tyrosine kinase activity.
For the avoidance of any doubt, it is to be understood that when X1 is, for example, a
group of formula -NRSC(O)-, it is the nitrogen atom bearing the R6 group which is attached to
the quinazoline ring and the carbonyl (C(0)) group is attached to R5, whereas when X1 is, for
example, a group of formula -C(O)NR7-, it is the carbonyl group which is attached to the
quinazoline ring and the nitrogen atom bearing the R7 group is attached to R5. A similar
convention applies to the other two atomX1 linking groups such as -NR9SOj- and -SC^NR8-.
When X1 is -MR10- it is the nitrogen atom bearing the R10 group which is linked to the
quinazoline ring and to R5. An analogous convention applies to other groups. It is further to
be understood that when X1 represents -NR10- and R10 is CioalkoxyCz^alkyl it is the C2-3alkyl
moiety which is linked to the nitrogen atom of X1 and an analogous convention applies to
other groups.
For the avoidance of any doubt, it is to be understood that in a compound of the
formula I when R5 is, for example, a group of formula Ci.3alkylX9Ci.3alkylR29, it is the terminal
yi moiety which is linked to X1, similarly when R3 is, for example, a group of formula
it is the Cz-jalkenyl moiety which is linked to X1 and an analogous convention
applies to other groups. When R5 is a group l-R29prop-l-en-3-yl it is the first carbon to which
the group R29 is attached and it is the third carbon which is linked to X1 and an analogous
convention applies to other groups.
For the avoidance of any doubt, it is to be understood that in a compound of the
formula 1 when R5 is, for example, R28 and R28 is a pyrrolidinyl ring which bears a group -(-OXCMalkyl)
gringD, it is the -O- or Ci^alkyl which is linked to the pyrrolidinyl ring, unless f and
g are both 0 when it is ring D which is linked to the pyrrolidinyl ring and an analogous
convention applies to other groups.
For the avoidance of any doubt, it is to be understood that when R29 carries a Cj.
4aminoalkyl substituent it is the Ci^alkyl moiety which is attached to R29 whereas when R29
carries a Chalkylamino substituent it is the ainiuo moiety which is attached to R29 and an
analogous convention applies to other groups.
For the avoidance of any doubt, it is to be understood that when R28 carries a C|.
4alkoxyCi.4alkyl substituent it is the Cwalkyl moiety which is attached to R28 and an analogous
convention applies to other groups.
For the avoidance of any doubt, it is to be understood that when Q1 is a group Ci_
jalkylW^Q2 it is the C^alkyl group which is linked to X1 which is in turn linked to the
quinazoline ring. Similarly when Q1 is a group Cj.salkenylQ2 it is the Cz-salkenyl group which
is linked to X1 which is in turn linked to the quinazoline ring. An analogous convention applies
to similar groups.
For the avoidance of any doubt, it is to be understood that when R2 is a group Q15 W3 it
is the W3 group which is linked to the quiuazoline ring.
For the avoidance of any doubt, it is to be understood that when R2 is a group
Q21W4Ci-5alkylX1 it is the X1 group which is linked to the quinazoline ring.
For the avoidance of any doubt, it is to be understood that when R2 is a group
Q28Ci.5alkylX' it is the X1 group which is linked to the quinazoline ring and an analogous
convention applies to similar groups.
The present invention relates to the compounds of formula I as hereinbefore defined as
well as to the salts thereof. Salts for use hi pharmaceutical compositions will be
pharmaceutically acceptable salts, but other salts may be useful in die production of the
compounds of formula I and their pharmaceutically acceptable salts. Pharmaceutically
acceptable salts of the invention may, for example, include acid addition salts of the
compounds of fonnula I as hereinbefore defined which are sufficiently basic to form such salts.
Such acid addition salts include for example salts with inorganic or organic acids affording
pharrnaceutically acceptable anious such as with hydrogen halides (especially hydrochloric or
hydrobromic acid of which hydrochloric acid is particularly preferred) or with sulphuric or
phosphoric acid, or with trifluoroacetic, citric or maleic acid. In addition where the
compounds of formula I are sufficiently acidic, pharmaceutically acceptable salts may be
formed with an inorganic or organic base which affords a pharmaceutically acceptable cation.
Such salts with inorganic or organic bases include for example an alkali metal salt, such as a
sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an
ammonium salt or for example a salt with methylamine, dimethylamine, trirnethylamine,
piperidine, morpholine or tris-(2-hydroxyethyl)amine.
A compound of the fonnula I, or salt thereof, and other compounds of the invention
(as herein defined) may be prepared by any process known to be applicable to the preparation
of chemically-related compounds. Such processes include, for example, those illustrated in
International Patent Application Number WO 00/47212 and in European Patent Applications
Publication Nos. 0520722, 0566226, 0602851 and 0635498. Such processes also include, for
example, solid phase synthesis. Such processes, are provided as a further feature of the
invention and are as described hereinafter. Necessary starting materials may be obtained by
standard procedures of organic chemistry. The preparation of such starting materials is
described within the accompanying non-limiting Examples. Alternatively necessary starting
materials are obtainable by analogous procedures to those illustrated which are within the
ordinary skill of an organic chemist.
Thus, the following processes (a) to (f) and (i) to (vi) constitute further features of
the present invention.
Synthesis of Compounds of Formula I
(a) Compounds of the formula I and salts thereof may be prepared by the reaction of a
compound of the formula III:
(Figure Remove) (wherein R2 and m are as defined hereinbefore and LL is a displaceable moiety), with a
compound of the formula IV:
ZH
(IV)
(wherein ring C, R1, Z and n are as defined hereinbefore) to obtain compounds of the formula I
and salts thereof. A convenient displaceable moiety L1 is, for example, a halogeno, alkoxy
(preferably Ci^alkoxy), aryloxy, alkylsulphanyl, arylsulphanyl, alkoxyalkylsulphanyl or
sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, methylsulphauyl, 2-
methoxyethylsulphanyl, methanesulphouyloxy or toluene-4-sulphonyloxy group.
The reaction is advantageously effected in the presence of a base. Such a base is, for
example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine,
4-dimethylaminopyridine, triethylarnine, morpholine, N-methylmorpholine or
diazabicyclo[5.4.0]undec-7-ene, tetramethylguanidine or for example, an alkali metal or
alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium
carbonate, calcium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide.
Alternatively such a base is, for example, an alkali metal hydride, for example sodium hydride,
or an alkali metal or alkaline earth metal amide, for example sodium amide, sodium
bis(trimethylsilyl)amide, potassium amide or potassium bis(trimethylsUyl)amide. The reaction
is preferably effected in the presence of an inert solvent or diluent, for example an ether such as
tetrahydrofuran or 1,4-dioxan, an aromatic hydrocarbon solvent such as toluene, or a dipolar
aprotic solvent such as N,N-dimethylformarnide, N,N-dimethylacetamide,
N-methylpyrrolidin-2-one or dimethyl sulphoxide. The reaction is conveniently effected at a
temperature in the range, for example, 10 to 150°C, preferably in the range 20 to 90°C.
Where R1 or R2 contains a heterocyclic ring with a substituent it is possible to add
the substituent after process (a) above using standard procedures of organic chemistry. Thus
for example a compound of formula III as defined hereinbefore but wherein R2 contains an
unsubstituted heterocyclic ring may be reacted with a compound of formula IV as defined
hereinbefore to give an intermediate compound in which R2 contains an unsubstituted
heterocyclic ring. The intermediate compound can then be substituted on the heterocyclic ring
in R2 using standard organic chemistry techniques to give a final compound of formula I.
When it is desired to obtain the acid salt, the free base may be treated with an acid
such as a hydrogen halide, for example hydrogen cllloride, sulphuric acid, a sulphonic acid, for
example methane sulphonic acid, or a carboxylic acid, for example acetic or citric acid, using a
conventional procedure.
(b) Production of those compounds of formula I and salts thereof wherein at least one
R2 is R5X', Q'X1, Q15W3 or Q21W4C1.5alkylX1, wherein R5, Q1, Q15, W3, Q21 and W4 are as
defined hereinbefore, and X1 is -O-, -S-, -OC(O)- or -NR10- (wherein R10 independently
represents hydrogen, Ci-salkyl or d.3alkoxyC2-3alkyl) can be achieved by the reaction,
conveniently in the presence of a base (as defined hereinbefore in process (a)) of a compound
of the formula V:
HWorHX1
(V)
(wherein ring C, Z, W3, R1, R2 and n are as hereinbefore defined and X1 is as hereinbefore
defined in this section and s is an integer from 0 to 2) with one of the compounds of the
formulae Vla-d:
R5-L' (Via)
Q'-L' (VIb)
Q^-L1 (Vic)
Q21-W4-C,.sa]kyl-LI (VId)
(whereiu R5, Q1, Q15, Q21 and W4 and L1 are as hereinbefore defined), L1 is a displaceable
rnoiety for example a halogeuo or sulphonyloxy group such as a bromo, methauesulphonyloxy
or toluene-4-sulphonyloxy group, or L1 may be generated in situ from an alcohol under
standard Mitsunobu conditions ("Organic Reactions", John Wiley & Sons Inc, 1992, vol 42,
chapter 2, David L Hughes). The reaction is preferably effected in the presence of a base (as
defined hereinbefore in process (a)) and advantageously in the presence of an inert solvent or
diluent (as defined hereinbefore in process (a)), advantageously at a temperature in the range,
for example 10 to 150°C, conveniently at about 50°C.
(c) Compounds of the formula I and salts thereof wherein at least one R2 is R5X\ Q'X1,
Q15W3 or Q21W4CwalkylX1, wherein R5, Q1, Q15, W3, Q21 and W4 are as defined hereinbefore,
and X1 is -O-, -S-, -OC(O)- or -NR10- (wherein R10 represents hydrogen, Chalky! or Ci_
may be prepared by the reaction of a compound of the formula VII:
N H
with one of the compounds of the formulae Vllla-d:
(Figure Remove) (wherein L1, R1, R2, R5, Q1, Q15, W3, Q21, W4, ring C, Z, n and s are all as hereinbefore defined
aud X1 is as hereinbefore defined in this section). The reaction may conveniently be effected in
the presence of a base (as defined hereinbefore in process (a)) and advantageously in the
presence of an inert solvent or diluent (as defined hereinbefore in process (a)), advantageously
at a temperature in the range, for example 10 to 150°C, conveniently at about 100°C.
(d) Compounds of the formula I and salts thereof wherein at least one R2 is R5X\ Q'X1,
Q2IW4Ci.5alkylX1, QMC,.5a]kylXl or Q29C,.5aUcyrX' wherein X1 is as defined hereinbefore, R5 is
Ci.jalkylR113, wherein R113 is selected from one of the following nine groups:
1) X19C,.3alkyl (wherein X19 represents -0-, -S-, -S0r, -NR114C(O)- or -NR113SOr (wherein
R1M and R113 which may be the same or different are each hydrogen, d.3alkyl or Ci.3a]koxyC2-
3aDcyl);
2) NR116R'17 (wherein R116 and R117 which may be the same or different are each hydrogen, d.
3alkyl or CijalkoxyCa-salkyl);
3) X20Ci.5alkylX5R22 (wherein X20 represents -O-, -S-, -S02-, -NR118C(O)-, -NR119SO2- or -
NRJ2°- (wherein R118, R119, and R120 which may be the same or different are each hydrogen, Ci.
3alkyl or Ci.3alkoxyC2-3aIkyl) and X5 and R22 are as defined hereinbefore);
4) R28 (wherein R28 is as defined hereinbefore);
5) X21R29 (wherein X21 represents -O-, -S-, -SO2-, -NR121C(O)-, -NR122SO2-, or-NR123-
(wherein R121, R122, and R123 which may be the same or different are each hydrogen, Ci.3alkyl
or C|.3alkoxyC2-3alkyl) and R29 is as defined hereinbefore); and
6) X22Ci.3alkylR29 (wherein X22 represents -O-, -S-, -SQr, -NR124C(0)-, -NRI23S02- or -
NR126- (wherein R124, R125 and R126 each independently represents hydrogen, Ci_3alkyl or
Ci-3alkoxyC2.3alkyl) and R29 is as denned hereinbefore);
7) R29 (wherein R29 is as defined hereinbefore);
8) X"CMalkylR28 (wherein X22 and R28 are as defined hereinbefore); and
9) R34(CMalkyl)q(X9)rR35 (wherein q, r, X9, R54 and R35 are as defined hereinbefore);
Q1 is Ci-salkylQ27 wherein Q27 is selected from:
10) W'Q2 (wherein W1 and Q2 are as defined hereinbefore);
11) Q2 (wherein Q2 is as defined hereinbefore);
12) W2Ci^alkylQ2 (wherein W2 and Q2 are as defined hereinbefore);
13) Q13(CMalkyl)j(W2),:Q14 (wherein W2, j, k, Q13 and Q14 are as denned hereinbefore); and
14) Ql3(CMalkanoyl)Q14" (wherein Q13 and Q14'1 are as defined hereinbefore), and
Q21, W4, Q28 and Q29 are as defined hereinbefore,
may be prepared by reacting a compound of the formula IX:
(wherein L1, X1, R1, R2, ring C, Z, n and s are as hereinbefore defined) with one of the
compounds of the formulae Xa-e:
(Figure Remove) wherein R113, Q27, Q28, Q29, Q21 and W4 are as defined hereinbefore) to give a compound of
the formula I or salt thereof. The reaction may conveniently be effected in the presence of" a
base (as defined hereinbefore in process (a)) and advantageously in the presence of an inert
solvent or diluent (as defined hereinbefore in process (a)), and at a temperature in the range,
for example 0 to 150°C, conveniently at about 50°C.
Processes (a), (b) and (d) are preferred over process (c).
Processes (a) and (b) are the more preferred.
(e) The production of those compounds of the formula I and salts thereof wherein one
or more of the substituents (R2)m is represented by -NR127R128, where one (and the other is
hydrogen) or both of R127 and R128 are Ci^alkyl, may be effected by the reaction of compounds
of formula I wherein the substitueut (R2)ra is an amino group and an alkylating agent,
preferably in the presence of a base as defined hereinbefore. Such alkylating agents are
Chalky! moieties bearing a displaceable moiety as defined hereinbefore such as Ci^alkyl
halides for example Ci-3alkyl chloride, bromide or iodide. The reaction is preferably effected in
the presence of an inert solvent or diluent (as defined hereinbefore in process (a)) and at a
temperature in the range, for example, 10 to 100°C, conveniently at about ambient
temperature. The production of compounds of formula I and salts thereof wherein one or
more of the substituents R2 is an amiuo group may be effected by the reduction of a
corresponding compound of formula I wherein the substituent(s) at the corresponding
position(s) of the quinazoline group is/are a nitro group(s). The reduction may conveniently be
effected as described in process (i) hereinafter. The production of a compound of formula I
and salts thereof wherein the substitueut(s) at the corresponding position(s) of the quinazoline
group is/are a nitro group(s) may be effected by the processes described hereinbefore and
hereinafter in processes (a-d) and (i-v) using a compound selected from the compounds of the
formulae (I-XXII) in which the substituent(s) at the corresponding positiou(s) of the
quinazoline group is/are a nitro group(s).
(f) Compounds of the formula I and salts thereof wherein X1 is -SO- or -SOz- may be
prepared by oxidation from the corresponding compound in which X1 is -S- or -SO- (when X1
is -S02- is required in the final product). Conventional oxidation conditions and reagents for
such reactions are well known to the skilled chemist.
Synthesis of Intermediates
(i) The compounds of formula III and salts thereof in wliich L1 is halogeno may for
example be prepared by halogenatiug a compound of the formula XI:
(Figure Remove)wherein R2 and m are as hereinbefore defined).
Convenient halogenating agents include inorganic acid halides, for example thionyl
chloride, phosphorus(ni)chloride, phosphorus(V)oxychloride and pbosphorus(V)chloride.
The halogenation reaction may be effected in the presence of an inert solvent or diluent such as
for example a halogeuated solvent such as methylene chloride, trichloromethane or carbon
tetrachloride, or an aromatic hydrocarbon solvent such as benzene or toluene, or the reaction
may be effected without the presence of a solvent. The reaction is conveniently effected at a
temperature in the range, for example 10 to 150°C, preferably in the range 40 to 100°C.
The compounds of formula XI and salts thereof may, for example, be prepared by
reacting a compound of the formula XII:
(Figure Remove) wherein R2, s and L1 are as hereinbefore defined) with one of the compounds of formulae
Vllla-d as hereinbefore defined. The reaction may conveniently be effected in the presence of
a base as defined hereinbefore in process (a)) and advantageously in the presence of an inert
solvent or diluent (as defined hereinbefore in process (a)), advantageously at a temperature in
the range, for example 10 to 150°C, conveniently at about 100°C.
Compounds of formula XI and salts thereof wherein at least one R2 is R5X', Q'X1,
Q15W3 or Q21 VA^alkylX1, wherein R5, Q1, Q15, W3, Q21 and W4 are as defined hereinbefore,
and wherein X1 is -0-, -S-, -SO-, -SO2-, -C(0)-, -C(O)NR7-, -SO2NR8- or -NR10- (wherein R7,
R8 and R10 each independently represents hydrogen, Cj.ialkyl or Ci.jalkoxyCi-salkyD, may for
example also be prepared by the reaction of a compound of the formula XIII:
HW3 or HX1
(XIII)
(wherein R2, W3 and s are as hereinbefore defined and X1 is as hereinbefore defined in this
section) with one of the compounds of formulae Vla-d as hereinbefore defined. The reaction
may for example be effected as described for process (b) hereinbefore. The pivaloyloxymethyl
group can then be cleaved by reacting the product with a base such as, for example, aqueous
ammonia, triethylamine in water, an alkali metal or alkaline earth metal hydroxide or alkoxide,
preferably aqueous ammonia, aqueous sodium hydroxide or aqueous potassium hydroxide, in a
polar protic solvent such as an alcohol, for example methanol or ethanol. The reaction is
conveniently effected at a temperature in the range 20 to 100°C, preferably in the range 20 to
50°C.
The compounds of formula XI and salts thereof may also be prepared by cyclising a
compound of the formula XIV:
(Figure Remove) (wherein R2 and m, are as hereinbefore defined, and A1 is an hydroxy, alkoxy (preferably Ci_
4alkoxy) or amino group) whereby to form a compound of formula XI or salt thereof. The
cyclisation may be effected by reacting a compound of the formula XIV, where A1 is an
hydroxy or alkoxy group, with fonnamide or an equivalent thereof effective to cause
cyclisation whereby a compound of formula XI or salt thereof is obtained, such as [3-
(dimethylamino)-2-azaprop-2-enylidene]dirnethylammonium chloride. The cyclisation is
conveniently effected in the presence of fonnamide as solvent or in the presence of an inert
solvent or diluent such as an ether for'example 1,4-dioxan, The cyclisation is conveniently
effected at an elevated temperature, preferably in the range 80 to 200°C. The compounds of
formula XI may also be prepared by cyclising a compound of the formula XIV, where A1 is an
amino group, with formic acid or an equivalent thereof effective to cause cyclisation whereby a
compound of formula XI or salt thereof is obtained. Equivalents of formic acid effective to
cause cyclisatiou include for example a tri-CMalkoxymetliane, for example triethoxymethane
and trimethoxymethane. The cyclisation is conveniently effected in the presence of a catalytic
amount of an anhydrous acid, such as a sulphonic acid for example p-toluenesulphonic acid,
and in the presence of an inert solvent or diluent such as for example a halogenated solvent
such as methylene chloride, trichlorornethane or carbon tetrachloride, an ether such as diethyl
ether or tetrahydrofuran, or an aromatic hydrocarbon solvent such as toluene. The cyclisation
is conveniently effected at a temperature in the range, for example 10 to 100°C, preferably in
the range 20 to 50°C.
Compounds of formula XIV and salts thereof may for example be prepared by the
reduction of the nitro group in a compound of the formula XV:
(wherein R2, m and A1 are as hereinbefore defined) to yield a compound of formula XIV as
hereinbefore defined. The reduction of the nitro group may conveniently be effected by any of
the procedures known for such a transformation. The reduction may be carried out, for
example, by stirring a solution of the nitro compound under hydrogen at 1 to 4 atmospheres
pressure in the presence of an inert solvent or diluent as defined hereinbefore in the presence of
a metal effective to catalyse hydrogenation reactions such as palladium or platinum. A further
reducing agent is, for example, an activated metal such as activated iron (produced for example
by washing iron powder with a dilute solution of an acid such as hydrochloric acid). Thus, for
example, the reduction may be effected by heating the nitro compound under hydrogen at 2
atmospheres pressure in the presence of the activated metal and a solvent or diluent such as a
mixture of water and alcohol, for example methanol or ethauol, at a temperature in the range,
for example 50 to 150°C, conveniently at about 70°C.
Compounds of the formula XV and salts thereof may for example be prepared by the
reaction of a compound of the formula XVI:
(wherein R2, s, L1 and A1 are as hereinbefore defined) with one of the compounds of formulae
VIIIa-d as hereinbefore defined to give a compound of the formula XV. The reaction of the
compounds of formulae XVI and VIIIa-d is conveniently effected under conditions as
described for process (c) hereinbefore.
Compounds of formula XV and salts thereof wherein at least one R2 is R5X\ Q'X1,
Q13W3 or Q21W4Cl.JalkylX1, wherein R5, Q1, Q13, W3, Q21 and W4 are as defined hereinbefore,
and wherein X1 is -0-, -S-, -SOr, -C(0)-, -C(O)NR7-, -SO2NR8- or -NR10- (wherein R7, Rs
and R!0 each independently represents hydrogen., Ci_3a]kyl or CijalkoxyCi^alkyl), may for
example also be prepared by the reaction of a compound of the formula XVII:
HW3 or HX1
(XVH)
(wherein R2, s and A1 are as hereinbefore defined and X1 is as hereinbefore defined in this
section) with one of the compounds of formulae Vla-d as hereinbefore defined to yield a
compound of formula XV as hereinbefore defined. The reaction of the compounds of formulae
XVII and Vla-d is conveniently effected under conditions as described for process (b)
hereinbefore.
The compounds of formula III and salts thereof wherein at least one R2 is R5X* and
wherein X1 is -CH2- may be prepared for example as described above from a compound of the
formula XV (in which R2 is -CH3) or XIII (in which HX1- is -CH3), by radical bromination or
chlorinatiou to give a -CH^Br or -CHiCl group which may then be reacted with a compound of
the formula R5-H under standard conditions for such substitution reactions.
The compounds of formula III and salts thereof wherein at least one R2 is R5X' and
wherein X1 is a direct bond may be prepared for example as described above from a compound
of the formula XI, wherein the R5 group is already present in the intermediate compounds (for
example in a compound of the formula XV) used to prepare the compound of formula XI.
The compounds of formula III and salts thereof wherein at least one R2 is R5X' and
wherein X1 is -NR6C(O)- or -NR9SC>2- may be prepared for example from a compound of the
formula XIII in which HX1- is an -NHR6- or -NHR9- group (prepared for example from an
amiuo group (later fuuctioualised if necessary) by reduction of a nitro group) which is reacted
with an acid chloride or sulfonyl chloride compound of the formula R5COC1 or R5SO2d
The compounds of formula III and salts thereof wherein at least one R2 is R5X', Q'X1,
QI5W3 or Q2IW4Ci.5alkylX1, wherein R5, Q1, Q15, W3, Q21 and W4 are as defined hereinbefore,
aud wherein X1 is -0-, -S-, -SO2-, -OC(0)-, -C(0)NR7-, -S02NR8- or -NR10- (wherein R7, R8
and R10 each independently represents hydrogen, Ci.3alkyl or Ci^alkoxyCz-salkyl), may also be
prepared for example by reacting a compound of the formula XVIII:
(wherein R2, W3 and s are as hereinbefore defined, X1 is as hereinbefore defined in this section
and L2 represents a displaceable protecting moiety) with one of the compounds of formulae
Vla-d as hereinbefore defined, whereby to obtain a compound of formula HI in which L1 is
represented by L2.
A compound of formula XVIII is conveniently used in which L2 represents a
phenoxy group which may if desired carry up to 5 substituents, preferably up to 2 substituents,
selected from. halo geno, nitro and cyano. The reaction may be conveniently effected under
conditions as described for process (b) hereinbefore.
The compounds of formula XVIII and salts thereof may for example be prepared by
deprotecting a compound of the formula XIX:
(wherein R2, W3, s and L2 are as hereinbefore defined, P1 is a protecting group and X1 is as
hereinbefore defined in die section describing compounds of the formula XVIII). The choice
of protecting group P1 is within the standard knowledge of an organic chemist, for example
those included in standard texts such as "Protective Groups in Organic Synthesis" T.W. Greene
and R.G.M.Wuts, 2nd Ed. Wiley 1991, including N-sulphonyl derivatives (for example, ptoluenesulphonyl),
carbamates (for example, t-butyl carbonyl), N-alkyl derivatives (for
example, 2-chloroethyl, benzyl) and amino acetal derivatives (for example benzyloxymethyl).
The removal of such a protecting group may be effected by any of the procedures known for
such a transformation, including those reaction conditions indicated in standard texts such as
that indicated hereinbefore, or by a related procedure. Deprotection may be effected by
techniques well known in the literature, for example where P1 represents a benzyl group
deprotection may be effected by hydrogenolysis or by treatment with trifluoroacetic acid.
One compound of formula III may if desired be converted into another compound of
formula III in which the moiety L1 is different. Thus for example a compound of formula III in
which L1 is other than halogeno, for example optionally substituted phenoxy, may be converted
to a compound of formula III in which L1 is halogeno by hydrolysis of a compound of formula
III (in which L1 is other than halogeno) to yield a compound of formula XI as hereinbefore
defined, followed by introduction of halide to the compound of formula XI, thus obtained as
hereinbefore defined, to yield a compound of formula III in which L1 represents halogen,
(ii) Compounds of formula IV and salts thereof in which ring C is indolyl may be
prepared by any of the methods known in the art, such as for example those described in
"Indoles Part I", "Indoles Part IT, 1972 John Wiley & Sons Ltd and "Indoles Part III" 1979,
John Wiley & Sons Ltd, edited by W. J. Houlihan.
Examples of the preparation of indoles are given in Examples 1 and 10 hereinafter.
Compounds of formula IV and salts thereof in which ring C is quiuolinyl may be
prepared by any of the methods known in the art, such as for example those described in "The
Chemistry of Heterocycb'c Compounds: Quinolines Parts I, II and III", 1982 (Interscience
publications) John Wiley & Sous Ltd, edited by G. Jones, and in "Comprehensive Heterocyclic
Chemistry Vol II by A. R. Katritzky", 1984 Pergamon Press, edited by A. J. Boulton and A
McKillop.
Compounds of formula IV and salts thereof in which ring C is indazolyl may be
prepared by any of the methods known in the art, such as for example those described in
Petitcoles, Bull. Soc. Chiiu Fr. 1950, 466 and Davies, J. Chem. Soc. 1955, 2412.
Compounds of formula IV and salts thereof in which ring C is azaindolyl may be
prepared by any of the methods known in the art, such as for example those described in
Heterocycles 50, (2), 1065-1080, 1999. They may also be made according to the process in
Example 2 heren after.
In Heterocycles 50, (2), 1065-1080, 1999 a process is described, shown in Scheme
1 hereinafter, wherein 7-azaindole is halogenated to give 3,3,5-tribromo-2-oxo-l,3-
dihydropyrrolo[2,3-b]pyridine (12). 12 is then treated with zinc in acetic acid to give 5-
bromo-2-oxo-l,3-dihydropyrrolo[2,3-b]pyridiiie (13) and 13 is then treated via two steps to
give 5-bromo-7-azaindole (14). This synthesis is shown in Scheme 1:
Scheme 1
(Figure Remove)1
Surprisingly we have found that it is better to synthesise the 5-bromo-7-azaindole by
three steps outlined in Scheme 2:
Scheme 2
(Figure Remove)is surprisingly better than Scheme 1. Scheme 2 requires smaller quantities of
reagent aud is more adaptable for large scale manufacture because it is cheaper, more efficient
and more environmentally friendly than Scheme 1.
Step 1:
The reduction may be carried out by any of the procedures known for such a
transformation. The reduction may be carried out, for example, by treating a solution of 7-
azaindole in an alcohol, for example ethanol, or another solvent for example
decahydronaphthalene, with wet Raney Nickel and then stirring the mixture in a hydrogen
atmosphere under pressure, for example at 5 atmospheres pressure, at 50 to 150°C, preferably
at about 95°C, over a period of time, for example 2 days, to give, after purification, 7-
azaiudoline.
The bromination may be carried out by any of the procedures Icnown for such a
reaction. The bromination may be carried out, for example, by mixing 7-azaiudoline, p-toluene
sulphonic acid monohydrate and l,3-dibromo-5,5-dimethylhydantoin in methylene chloride and
stirring the mixture at for example ambient temperature for a period of time, for example 3
hours. Extraction and purification gives 5-bromo-7-azaindoline.
Step 3:
The oxidation may be carried out by any of the procedures known for such a
transformation. The oxidation may be carried out, for example, by mixing 5-bromo-7-
azaiudoline and precipitated, active manganese (IV) oxide in toluene, then heating the mixture
at 50 to 150°C, preferably at about 90°C to give 5-bromo-7-azaindole.
In Heterocycles 50, (2), 1065-1080, 1999 the 5-bromo-7-azaindole (986rog, S.Ommol)
is dissolved, under an inert atmosphere, in a mixture of DMF (32ml) and methanol (20ml). To
this solution is added successively sodium methoxide (14.3g, 265mmol) and copper(I)bromide
(1.43g, lO.Ommol) at ambient temperature. The mixture is heated at reflux for 2.5 hours to
give, after extraction and purification, 5-methoxy-7-azaindole (530mg, 72%).
We have found that the yield for this reaction is surprisingly and significantly increased
from 72% to 97% if the reagents are used in proportionately smaller quantities including for
example a different solvent mixture. Thus in Example 2 hereinafter:
"A solution of 5-bromo-7-azaindole (8.6 g, 44 mmol), copper (I) bromide (12.6 g, 88
mmol) and sodium methoxide (100 g, 1.85 mol) in a mixture of "degassed" DMF (260 mis)
and methanol (175 mis) was stirred at ambient temperature in a nitrogen atmosphere, and then
heated at reflux for 3.5 hours."
After extraction and partial purification this gave crude solid, 5-methoxy-7-azaiudole
(6.3 g, 97%), which was taken through the next step without further purification.
The 5-hydroxy-7-azaindole may be generated from the 5-methoxy-7-azaiudole by the
following process.
Adding boron tribromide in methylene chloride to a solution of 5-methoxy-7-
azaindole in methyleue chloride cooled at about -30°C. Leaving the mixture to warm up to
ambient temperature and stirring it for a period of time, for example overnight. Pouring the
mixture onto ice and water and adjusting the pH of the aqueous phase to about 6. Separating
the organic phase and further extracting the aqueous phase with ethyl acetate. Combining the
organic phases washing them with brine, drying them, for example over magnesium sulphate,
and then evaporating them. The residue may then be purified, for example by column
chromatography eluting with increasingly polar mixtures of methylene chloride and methanol
to give 5-hydroxy-7-azaindole.
Alternatively the 5-methoxy-7-azaindole may be suspended in methyleue chloride,
stirred in a nitrogen atmosphere, cooled in a cold water bath and a 1.0 M solution of boron
tribromide in methylene chloride added dropwise over a period of time, for example 30
minutes. The mixture is then allowed to stir at ambient temperature for a period of time, for
example 4 hours, before being quenched by taking the solution to about pH7, for example by
the dropwise addition of 5N sodium hydroxide. The resulting 2 phase mixture is allowed to
separate and the organic phase collected and evaporated in vacuo. The residue may be treated
with the aqueous phase from above, the mixture adjusted to about pH7 once more and
subjected to a continuous ethyl acetate extraction over a period of time for example 18 hours.
The resulting ethyl acetate suspension is then evaporated in vacuo to give a product which may
be purified, for example by column chromatography using Kieselgel 60 silica and methylene
chloride/methanol/SSO ammonium hydroxide (100/8/1) solvent to give 5-hydroxyazaiudole.
(iii) Compounds of formula V as hereinbefore defined and salts thereof may be made by
deprotectiug the compound of formula XX:
(Figure Remove) wherein ring C, Z, R1, R2, P!, W3, n and s are as hereinbefore defined and X1 is as
hereinbefore defined in the section describing compounds of the formula V) by a process for
example as described in (i) above.
Compounds of the formula XX and salts thereof may be made by reacting
compounds of the formulae XIX and IV as hereinbefore defined, under the conditions
described in (a) hereinbefore, to give a compound of the formula XX or salt thereof.
(iv) Compounds of the formula VII and salts thereof may be made by reacting a
compound of the formula XXI:
(Figure Remove) wherein R2, s and each L1 are as hereinbefore defined and the L1 in the 4-position and the
other L1 in a further position on the quinazoline ring may be the same or different) with a
compound of the formula IV as hereinbefore defined, the reaction for example being effected
by a process as described in (a) above.
(v) Compounds of formula IX as defined hereinbefore and salts thereof may for example
be made by the reaction of compounds of formula V as defined hereinbefore with compounds
of the formula XXII:
wherein L1 is as hereinbefore defined) to give compounds of formula IX or salts thereof. The
reaction may be effected for example by a process as described in (b) above,
(vi) Intermediate compounds wherein X1 is -SO- or -S02- may be prepared by oxidation
from the corresponding compound in which X1 is -S- or -SO- (when X1 is -SO:- is required in
the final product). Conventional oxidation conditions and reagents for such reactions are well
known to the skilled chemist.
When a pharmaceutically acceptable salt of a compound of the formula I is required,
it may be obtained, for example, by reaction of said compound with, for example, an acid using
a conventional procedure, the acid having a pharmaceutically acceptable anion.
Many of the intermediates defined herein are novel and these are provided as a
further feature of the invention. The preparation of these compounds is as described herein
and/or is by methods well known to persons skilled in the art of organic chemistry.
For example the intermediates 7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-
methoxyquinazoline and 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquiuazoline,
which are both described in Example 7, are novel and each may be used in the manufacture of
compounds of the present invention and of compounds of WO 00/47212. 7-Benzyloxy-4-(4-
fluoro-2-methylindol-5-y]oxy)-6-rnethoxyquinazoline and4-(4-fluoro-2-methylindol-5-yloxy)-
7-hydroxy-6-methoxyquinazoline may each be used in the manufacture of compounds which
inhibit angiogenesis and/or increased vascular permeability.
According to one embodiment of the present invention there is provided 7-benzyloxy-
4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoune or a salt thereof.
According to one embodiment of the present invention there is provided 4-(4-fluoro-2-
methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline or a salt thereof.
According to one embodiment of the present invention there is provided the use of 7-
benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquiuazoline or a salt thereof in the
manufacture of a compound of the present invention or a compound of WO 00/47212.
According to one embodiment of the present invention there is provided the use of 4-
(4-fiuoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoUne or a salt thereof in the
manufacture of a compound of the present invention or a compound of WO 00/47212.
The identification of compounds which inhibit angiogenesis and/or increased vascular
permeability, which potently inhibit the tyrosine kiuase activity associated with the VEGF
receptor KDR and are selective for KDR over Flt-1, which have less extended plasma
pharmacokinetics and which are inactive or only weakly active in the liERG assay, is desirable
and is the subject of the present invention.
These properties may be assessed, for example, using one or more of the procedures set out
below:
fa) In Vitro Receptor Tvrosine Kinase Inhibition Test
This assay determines the ability of a test compound to inhibit tyrosine kinase
activity. DNA encoding VEGF, FGF or EGF receptor cytoplasmic domains may be obtained
by total gene synthesis (Edwards M, International Biotechnology Lab 5(3), 19-25, 1987) or by
cloning. These may then be expressed in a suitable expression system to obtain polypeptide
with tyrosine kinase activity. For example VEGF, FGF and EGF receptor cytoplasmic
domains, which were obtained by expression of recombinaut protein in insect cells, were found
to display intrinsic tyrosine kinase activity. In the case of the VEGF receptor Flt-1 (Genbank
accession number X51602), a 1.7kb DNA fragment encoding most of the cytoplasmic domain,
commencing with methiouine 783 and including the termination codon, described by Shibuya
et al (Oticogeue, 1990, 5: 519-524), was isolated from cDNA and cloned into a baculovirus
transplacement vector (for example pAcYMl (see The Baculovirus Expression System: A
Laboratory Guide, L.A. King and R. D. Possee, Chapman and Hall, 1992) or pAc360 or
pBlueBacHis (available from Invitrogen Corporation)). This recombinant construct was cotrausfected
into insect cells (for example Spodoptera frugiperda 2 l(Sf21)) with vkal DNA (eg
Pharmingen BaculoGold) to prepare recombinant baculovirus. (Details of the methods for the
assembly of recombinant DNA molecules and the preparation and use of recombinant
baculovirus can be found in standard texts for example Sambrook et al, 1989, Molecular
cloning - A Laboratory Manual, 2nd edition, Cold Spring Harbour Laboratory Press and
O'Reilly et al, 1992, Baculovirus Expression Vectors - A Laboratory Manual, W. H. Freeman
and Co, New York). For other tyrosine kinases for use in assays, cytoplasmic fragments
starting from methionine 806 (KDR, Genbank accession number L04947), methionine 668
(EGF receptor, Genbank accession number X00588) and methioniue 399 (FGF Rl receptor,
Genbank accession number X51803) may be cloned and expressed in a similar manner.
For expression of cFlt-1 tyrosine kinase activity, Sf21 cells were infected with
plaque-pure cFlt-1 recombinant virus at a multiplicity of infection of 3 and harvested 48 hours
later. Harvested cells were washed with ice cold phosphate buffered saline solution (PBS)
(lOmM sodium phosphate pH7.4, 138mM sodium chloride, 2.7mM potassium chloride) then
resuspended in ice cold HNTG/PMSF (20mM Hepes pH7.5, 150mM sodium chloride, 10%
v/v glycerol, 1% v/v Triton X100, 1.5mM magnesium chloride, ImM ethylene glycolbis(
paminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA), ImM PMSF
(phenylmethylsulphonyl fluoride); the PMSF is added just before use from a freshly-prepared
lOOmM solution in methanol) using 1ml HNTG/PMSF per 10 million cells. The suspension
was centrifuged for 10 minutes at 13,000 rpm at 4°C, the supernatant (enzyme stock) was
removed and stored in aliquots at -70°C. Each new batch of stock enzyme was titrated in the
assay by dilution with enzyme diluent (lOOmM Hepes pH 7.4, 0.2mM sodium orthovanadate,
0.1% v/v Triton X100, 0.2mM dithiothreitol). For a typical batch, stock enzyme is diluted 1 in
2000 with enzyme diluent and 50jal of dilute enzyme is used for each assay well.
A stock of substrate solution was prepared from a random copolymer containing
tyrosine, for example Poly (Glu, Ala, Tyr) 6:3:1 (Sigma P3899), stored as 1 mg/ml stock in
PBS at -20°C and diluted 1 in 500 with PBS for plate coating.
Oa the day before the assay lOOfxl of diluted substrate solution was dispensed into
all wells of assay plates (Nunc maxisorp 96-well immunoplates) which were sealed and left
overnight at 4°C.
On the day of the assay the substrate solution was discarded and the assay plate
wells were washed once withPBST (PBS containing 0.05% v/v Tween 20) and once with
50mM Hepes pH7.4.
Test compounds were diluted with 10% dimethylsulphoxide (DMSO) and 25JJ.1 of
diluted compound was transferred to wells in die washed assay plates. "Total" control wells
contained 10% DMSO instead of compound. Twenty five microlitres of 40rnM
mangauese(n)chloride containing 8|aM adenosine-5'-triphosphate (ATP) was added to all test
wells except "blank" control wells which contained maugauese(II)chloride without ATP. To
start the reactions 50fJ,l of freshly diluted enzyme was added to each well and the plates were
incubated at ambient temperature for 20 minutes. The liquid was then discarded and the wells
were washed twice with PBST. One hundred microlitres of mouse IgG anti-phospho tyro sine
antibody (Upstate Biotechnology Inc. product 05-321), diluted 1 in 6000 withPBST
containing 0.5% w/v bovine serum albumin (BSA), was added to each well and the plates were
incubated for 1 hour at ambient temperature before discarding the liquid and washing the wells
twice with PBST. One hundred micro litres of horse radish peroxidase (HRP)-linked sheep
anti-mouse Ig antibody (Amersham product NXA 931), diluted 1 in 500 with PBST containing
0.5% w/v BSA, was added and the plates were incubated for 1 hour at ambient temperature
before discarding the liquid and washing the wells twice with PBST. One hundred microlitres
of 2,2'-azino-bis(3-ethylbenzmiazoline-6-sulphonic acid) (ABTS) solution, freshly prepared
using one 50mg ABTS tablet (Boehringer 1204 521) in 50ml freshly prepared 50mM
phosphate-citrate buffer pH5.0 + 0.03% sodium perborate (made with 1 phosphate citrate
buffer with sodium perborate (PCSB) capsule (Sigma P4922) per 100ml distilled water), was
added to each well. Plates were then incubated for 20-60 minutes at ambient temperature until
the optical density value of the "total" control wells, measured at 405nm using a plate reading
spectrophotometer, was approximately 1.0. "Blank" (no ATP) and "total" (no compound)
control values were used to determine the dilution range of test compound which gave 50%
inhibtion of enzyme activity.
rb\In Vitro HUVEC Proliferation Assay
This assay detennines the ability of a test compound to inhibit the growth factorstimulated
proliferation of human umbilical vein endothelial cells (HUVEC).
HUVEC cells were isolated in MCDB 131 (Gibco BRL) + 7.5% v/v foetal calf
serum (PCS) and were plated out (at passage 2 to 8), in MCDB 131 + 2% v/v PCS + 3M.g/ml
hepariu + l|o,g/ml hydrocortisone, at a concentration of 1000 cells/well in 96 well plates. After
a minimum of 4 hours they were dosed with the appropriate growth factor (i.e. VEGF 3ng/ml,
EGF 3ng/ml or b-FGF 0.3ng/ml) and compound. The cultures were then incubated for 4 days
at 37°C with 7.5% CO2. On day 4 the cultures were pulsed with luCi/well of tritiatedthymidine
(Amersham product TRA 61) and incubated for 4 hours. The cells were harvested
using a 96-wel] plate harvester (Tomtek) and then assayed for incorporation of tritium with a
Beta plate counter. Incorporation of radioactivity into cells, expressed as cpm, was used to
measure inhibition of growth factor-stimulated cell proliferation by compounds.
fc) hi Vivo Solid Tumour Disease Model
This test measures the capacity of compounds to inhibit solid tumour growth.
CaLu-6 tumour xeuografts were established in the flank of female athymic Swiss
nu/nu mice, by subcutaneous injection of IxlO6 CaLu-6 cells/mouse in 100/zl of a 50% (v/v)
solution of Matrigel in serum free culture medium. Ten days after cellular implant, mice were
allocated to groups of 8-10, so as to achieve comparable group mean volumes. Tumours were
measured using vernier calipers and volumes were calculated as: (/ x w) x V(Z x w) x (u/6) ,
where / is the longest diameter and w the diameter perpendicular to the longest. Test
compounds were administered orally once daily for a minimum of 21 days, and control animals
received compound diluent. Tumours were measured twice weekly. The level of growth
inhibition was calculated by comparison of the mean tumour volume of the control group
versus the treatment group using a Student T test and/or a Mann-Whitney Rank Sum Test.
The inhibitory effect of compound treatment was considered significant when p (d) hERG-encoded Potassium Channel Inhibition Test
This assay determines the ability of a test compound to inhibit the tail current flowing
through the human ether-a-go-go-related-gene (hERG)-encoded potassium channel.
Human embryonic kidney (HEK) cells expressing the hERG-encoded channel were
grown in Minimum Essential Medium Eagle (EMEM; Sigma-Aldrich catalogue number
M2279), supplemented with 10% Foetal Calf Serum (Labtech International; product number
4-101-500), 10% Ml serum-free supplement (Egg Technologies; product number 70916) and
0.4 mg/ml Geneticin G418 (Sigma-Aldrich; catalogue number G7034). One or two days
before each experiment, the cells were detached from the tissue culture flasks with Accutase
(TCS Biologicals) using standard tissue culture methods. They were then put onto glass
coverslips resting in wells of a 12 well plate and covered with 2 ml of the growing media.
For each cell recorded, a glass coverslip containing the cells was placed at the bottom
of a Perspex chamber containing bath solution (see below) at ambient temperature (-20 °C).
This chamber was fixed to the stage of an inverted, phase-contrast microscope. Immediately
after placing the coverslip in the chamber, bath solution was perfused into the chamber from a
gravity-fed reservoir for 2 minutes at a rate of - 2 ml/ruin. After this time, perfusion was
stopped.
A patch pipette made from borosilicate glass tubing (GC120F, Harvard Apparatus)
using a P-97 micropipette puller (Sutter Instrument Co.) was filled with pipette solution (see
hereinafter). The pipette was connected to the headstage of die patch clamp amplifier
(Axopatch 200B, Axon Instruments) via a silver/silver chloride wire. The headstage ground
was connected to the earth electrode. This consisted of a silver/silver chloride wire embedded
in 3% agar made up with 0.85% sodium chloride.
The cell was recorded in the whole cell configuration of the patch clamp technique.
Following "break-in", which was done at a holding potential of-80 mV (set by the amplifier),
and appropriate adjustment of series resistance and capacitance controls, electrophysiology
software (Clampex, Axon Instruments) was used to set a holding potential (-80 mV) and to
deliver a voltage protocol. This protocol was applied every 15 seconds and consisted of a 1 s
step to +40 mV followed by a 1 s step to -50 mV. The current response to each imposed
voltage protocol was low pass filtered by the amplifier at 1 kHz. The filtered signal was then
acquired, on line, by digitising this analogue signal from the amplifier with an analogue to
digital converter. The digitised signal was then captured on a computer running Clampex
software (Axou Instruments). During the holding potential and the step to + 40 mV the
current was sampled at 1 kHz. The sampling rate was then set to 5 kHz for the remainder of
the voltage protocol.
The compositions, pH and osmolarity of the bath and pipette solution are tabulated
below.
(Figure Remove)The amplitude of die hERG-encoded potassium channel tail current following the
step from +40 mV to -50 mV was recorded on-line by Clampex software (Axon Instruments).
Following stabilisation of the tail current amplitude, bath solution containing the vehicle for the
test substance was appb'ed to the cell. Providing die vehicle application had no significant
effect on tail current amplitude, a cumulative concentration effect curve to the compound was
then constructed.
The effect of each concentration of test compound was quantified by expressing the
tail current amplitude in the presence of a given concentration of test compound as a
percentage of that in the presence of vehicle.
Test compound potency (ICso) was determined by fitting the percentage inhibition
values making up the concentration-effect to a four parameter Hill equation using a standard
data-fitting package. If the level of inhibition seen at the highest test concentration did not
exceed 50%, no potency value was produced and a percentage inhibition value at that
concentration was quoted.
Plasma pharmacokinetics may be assessed by measuring plasma half-life in vivo. The
longer the plasma half-life in vivo the more extended are the plasma pharmacokiuetics.
-83-
Compoiuids of the present invention have less extended plasma pharmacokinetics than
compounds of WO 00/47212. Compounds of the present invention have shorter half-lives in
vivo than compounds of WO 00/47212.
Plasma half-life in vivo may be determined by standard methods which are wellknown
in the art of plasma pharmacokinetics. Any species may be used and the plasma halflife
determined by standard methodology, for example plasma half-life may be measured in rat,
dog, monkey or human.
According to a further aspect of the invention there is provided a pharmaceutical
composition which comprises a compound of the formula I as defined hereinbefore or a
pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable
excipieut or carrier.
The composition may be in a form suitable for oral administration, for example as a
tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular,
intravascular or infusion) for example as a sterile solution, suspension or emulsion, for topical
administration for example as an ointment or cream or for rectal administration for example as
a suppository. In general the above compositions may be prepared in a conventional manner
using conventional excipieuts.
The compositions of the present invention are advantageously presented in unit
dosage form The compound will normally be administered to a warm-blooded animal at a unit
dose within the range 5-5000mg per square metre body area of the animal, i.e. approximately
0. l-100mg/kg. A unit dose in the range, for example, l-100mg/kg, preferably l-50mg/kg is
envisaged and this normally provides a therapeutically-effective dose. A unit dose form such
as a tablet or capsule will usually contain, for example l-250mg of active ingredient.
According to a further aspect of the present invention there is provided a compound
of the formula I or a pharmaceutically acceptable salt thereof as defined hereinbefore for use in
a method of treatment of the human or animal body by therapy.
We have found that compounds of the present invention inhibit VEGF receptor
tyro sine kinase activity and are therefore of interest for their autiangio genie effects and/or their
ability to cause a reduction in vascular permeability.
A further feature of the present invention is a compound of formula I, or a
pharmaceutically acceptable salt thereof, for use as a medicament, conveniently a compound of
formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament for producing
an autiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such
as a human being.
Thus according to a further aspect of the invention there is provided the use of a
compound of the formula I, or a pharmaceutically acceptable salt thereof in the manufacture of
a medicament for use in the production of an antiaugiogenic and/or vascular permeability
reducing effect in a warm-blooded animal such as a human being.
According to a further feature of the invention there is provided a method for
producing an antiangiogenic and/or vascular permeahility reducing effect in a warm-blooded
animal, such as a human being, in need of such treatment which comprises administering to
said animal an effective amount of a compound of formula I or a pharmaceutically acceptable
salt thereof as defined hereinbefore.
As stated above the size of the dose required for the therapeutic or prophylactic
treatment of a particular disease state will necessarily be varied depending on the host treated,
the route of administration and the severity of the illness being treated. Preferably a daily dose
in the range of 0.1 -50mg/kg is employed. However the daily dose will necessarily be varied
depending upon the host treated, the particular route of administration, and the severity of the
illness being treated. Accordingly the optimum dosage may be determined, by the practitioner
who is treating any particular patient.
The antiangiogenic and/or vascular permeability reducing treatment defined
hereinbefore may be applied as a sole therapy or may involve, in addition to a compound of the
invention, one or more other substances and/or treatments. Such conjoint treatment may be
achieved by way of the simultaneous, sequential or separate administration of die individual
components of the treatment. In the field of medical oncology it is normal practice to use a
combination of different forms of treatment to treat each patient with cancer. In medical
oncology the other component(s) of such conjoint treatment in addition to the antiangiogenic
and/or vascular permeability reducing treatment defined hereinbefore may be: surgery,
radiotherapy or chemotherapy. Such chemotherapy may cover three main categories of
therapeutic agent:
(i) other autiangiogenic agents such as those which inhibit the effects of vascular eudothelial
growth factor, (for example the anti-vascular endothelial cell growth factor antibody
bevacizumab [Avastiu™], and those that work by different mechanisms from those defined
hereinbefore (for example linornide, inhibitors of integrin av(33 function, angiostatin, razoxiu,
thalidomide), and including vascular targeting agents (for example combretastatin phosphate
and compounds disclosed in International Patent Applications WOOO/40529, WO 00/41669,
W001/92224, WO02/04434 and WO02/08213 and the vascular damaging agents described in
International Patent Application Publication No. WO 99/02166 the entire disclosure of which
document is incorporated herein by reference, (for example N-acetylcolchinol-0-phosphate));
(ii) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene,
droloxifeue, iodoxyfeue), oestrogen receptor down regulators (for example fulvestrant),
progestogens (for example megestrol acetate), aromatase inhibitors (for example auastrozole,
letrazole, vorazole, exemestane), antiprogestogens, antiandrogens (for example flutamide,
rjilutamide, bicalutamide, cyproteroue acetate), LHRH agonists and antagonists (for example
goserelin acetate, luprolide, buserelin), inhibitors of 5a-reductase (for example finasteride),
anti-invasion agents (for example metalloproteinase inhibitors like marimastat and inhibitors of
urokinase plasminogen activator receptor function) and inhibitors of growth factor function,
(such growth factors include for example platelet derived growth factor and hepatocyte growth
factor), such inhibitors include growth factor antibodies, growth factor receptor antibodies,
(for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody
cetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinase inhibitors for example
inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase
inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-
morphoUnopropoxy)quioazolin-4-ainine (gefitinib, AZD1839), N-(3-ethyuylphenyl)-6,7-bis(2-
methoxyethoxy)quinazoliu-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-
fluorophenyl)-7-(3-inorpholiuopropoxy)quinazolin-4-amine (CI1033)) and serine/tlireouine
kinase inhibitors); and
(iii) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical
oncology, such as antimetabolites (for example antifolates like methotrexate, fiuoropyrimidines
like 5-fluorouracil, tegafur, purine and adenosiue analogues, cytosine arabinoside); antitumour
antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,
epirubiciu and idarubicin, initomycin-C, dactinomycin, mithramycin); platinum derivatives (for
example cisplatin, carboplatiu); alkylatiug agents (for example nitrogen mustard, melphalan,
cbJorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic
agents (for example vinca alkaloids like vincristine, viublastine, vindesine, vinorelbine, and
taxoids like taxol, taxotere); topoisomerase inhibitors (for example epipodophyllotoxins like
etoposide and teniposide, amsacriue, topotecan, camptothecin and also irinotecau); also
enzymes (for example asparaginase); and thymidylate synthase inhibitors (for example
raltitrexed);
and additional types of chemotherapeutic agent include:
(iv) biological response modifiers (for example interferoii);
(v) antibodies (for example edrecolomab);
(vi) antisense therapies, for example those which are directed to the targets listed above, such
as ISIS 2503, an anti-ras antisense;
(vii) gene therapy approaches, including for example approaches to replace aberrant genes
such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug
therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial
nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or
radiotherapy such as multi-drug resistance gene therapy; and
(viii) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to
increase the immunogenicity of patient rumour cells, such as transfection with cytokines such
as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor,
approaches to decrease T-cell anergy, approaches using transfected immune cells such as
cytokine-trausfected dendritic cells, approaches using cytokiue-trausfected tumour cell lines
and approaches using anti-idiotypic antibodies.
For example such conjoint treatment may be achieved by way of the simultaneous,
sequential or separate administration of a compound of formula I as defined hereinbefore, and
a vascular targeting agent described in WO 99/02166 such as N-acerylcolchinol-O-phosphate
(Example 1 of WO 99/02166).
It is known from WO 01/74360 that antiangiogeiiics can be combined with
antihypertensives. A compound of the present invention can also be administered in
combination with an antihypertensive. An antihypertensive is an agent which lowers blood
pressure, see WO 01/74360 which is incorporated herein by reference.
Thus according to the present invention there is provided a method of treatment of a
disease state associated with angiogenesis which comprises the administration of an effective
amount of a combination of a compound of the present invention or a pharmaceutically
acceptable salt thereof and an anti-hypertensive agent to a warm-blooded animal, such as a
human being.
According to a further feature of the present invention there is provided the use of a
combination of a compound of the present invention or a pharmaceutically acceptable salt
thereof and an anti-hypertensive agent for use in the manufacture of a medicament for die
treatment of a disease state associated with angiogenesis in a warm-blooded mammal, such as
a human being.
According to a further feature of the present invention there is provided a
pharmaceutical composition comprising a compound of the present invention or a
pharmaceutically acceptable salt thereof and an anti-hypertensive agent for the treatment of a
disease state associated with angiogenesis in a warm-blooded mammal, such as a human being.
According to a further aspect of the present invention there is provided a method for
producing an anti-angiogeuic and/or vascular permeability reducing effect in a warm-blooded
animal, such as a human being, which comprises administering to said animal an effective
amount of a combination of a compound of the present invention or a pharmaceutically
acceptable salt thereof and an anti-hypertensive agent.
According to a further aspect of the present invention there is provided the use of a
combination of a compound of the present invention or a pharmaceutically acceptable salt
thereof and an anti-hypertensive agent for the manufacture of a medicament for producing an
anti-angiogenic and/or vascular permeability reducing effect in a warm-blooded mammal, such
as a human being.
Preferred antihypertensive agents are calcium channel blockers, angiotensiu converting
enzyme inhibitors (ACE inhibitors), angiotensin n receptor antagonists (A-II antagonists),
diuretics, beta-adrenergic receptor blockers ((3-blockers), vasodilators and alpha-adrenergic
receptor blockers (a-blockers). Particular antihypertensive agents are calcium channel
blockers, angiotensin converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor
antagonists (A-II antagonists) and beta-adrenergic receptor blockers ((3-blockers), especially
calcium channel blockers.
As stated above the compounds defined in the present invention are of interest for their
antiaugiogenie and/or vascular permeability reducing effects. Such compounds of the
invention are expected to be useful in a wide range of disease states including cancer, diabetes,
psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, lymphoedema, acute and
chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation,
excessive scar formation and adhesions, eiidometric sis, dysfunctional uterine bleeding and
ocular diseases with retinal vessel proliferation including age-related macular degeneration.
Cancer may affect any tissue and includes leukaemia, multiple myeloma and lymphoma. In
particular such compounds of the invention are expected to slow advantageously the growth of
primary and recurrent solid tumours of, for example, the colon, breast, prostate, lungs and
skin. More particularly such compounds of the invention are expected to inhibit any form of
cancer associated with VEGF including leukaemia, mulitple myeloma and lymphoma and also,
for example, the growth of those primary and recurrent solid tumours which are associated
with VEGF, especially those tumours which are significantly dependent on VEGF for their
growth and spread, including for example, certain tumours of the colon, breast, prostate, lung,
vulva and skin.
hi addition to their use in therapeutic medicine, the compounds of formula I and their
pharmaceutically acceptable salts are also useful as pharmacological tools in the development
and standardisation of in vitro and in vivo test systems for the evaluation of the effects of
inhibitors of VEGF receptor tyrosiue kinase activity in laboratory animals such as cats, dogs,
rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
It is to be understood that where the term "ether" is used anywhere in this
specification it refers to diethyl ether.
The invention will now be illustrated in the following non-limiting Examples in
which, unless otherwise stated: -
(i) evaporations were carried out by rotary evaporation in vacuo and work-up
procedures were carried out after removal of residual solids such as drying agents by filtration;
(ii) operations were carried out at ambient temperature, that is in the range 18-25°C
and under an atmosphere of an inert gas such as argon;
(iii) column chromatography (by the flash procedure) and medium pressure liquid
chroma to graphy (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck
Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained fromE. Merck, Darmstadt,
Gennany;
(iv) yields are given for illustration only and are not necessarily the maximum
attainable;
(v) melting points are uncorrected and were determined using a Mettler SP62
automatic melting point apparatus, an oil-bath apparatus or a Koffler hot plate apparatus.
(vi) the structures of the end-products of the formula I were confirmed by nuclear
(generally proton) magnetic resonance (NMR) and mass spectral techniques; proton magnetic
resonance chemical shift values were measured on the delta scale and peak multiplicities are
shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q, quartet, quin,
quintet;
(vii) intermediates were not generally fully characterised and purity was assessed by
tliin layer chromatography (TLC), high-perfonnance liquid chromatography (HPLC), infra-red
(IR) or NMR analysis;
(viii) HPLC were run under 2 different conditions:
1) on a TSK Gel super ODS 2/zM 4.6mm x 5cm column, eluting with a gradient of methanol
in water (containing 1% acetic acid) 20 to 100% in 5 minutes. Flow rate 1.4 ml/minute.
Detection: U.V. at 254 nm and light scattering detections;
2) on a TSK Gel super ODS 2/iM 4.6mm x 5cm column, eluting with a gradient of methanol
in water (containing 1% acetic acid) 0 to 100% in 7 minutes. Flow rate 1.4 ml/minute.
Detection: U.V. at 254 nm and light scattering detections.
(ix) petroleum ether refers to that fraction boiling between 40-60°C
(x) the following abbreviations have been used:-
DMF N,N-dimethylformamide
DMSO dimethylsulphoxide
TFA trifluoro acetic acid
THF tetrahydrofuran
DEAD diethyl azodicarboxylate
DMA dimethylacetamide
DMAP 4-dimethylamiuopyridine
LC/MS HPLC coupled to mass spectrometry
Example 1
Diethyl azodicarboxylate (0.178 g, 1.02 mrnol) was added to a solution of 4-(4-fluoro-
2-metliylii]do]-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.267g, 0.787 mmol),
triphenylphosphine (0.31g, l.lSmmol) and 3-(4-acetylpiperazin-lyl)propan-l-ol (0.176g,
0.945 mmol) in methylene chloride (10 ml). After stirring for 15 minutes at ambient
temperature, further triphenylphosphine (0.062mg, 0.236 mmol) and diethyl azodicarboxylate
(0.041mg, O.Smmol) were added. After stirring for 1 hour at ambient temperature, the mixture
was poured onto a column of silica and eluted with increasingly polar mixtures of ethyl acetate
and methylene chloride followed by methylene chloride and methanol. The fractions
containing the expected product were combined and evaporated. The residue was triturated
under diethyl ether and the solid was filtered, washed with ether and dried under vacuum to
give6-(3-(4-acetylpiperazin-l-yl)propoxy)-4-(4-fluoro-2-inethylindol-5-yloxy)-7-
methoxyquinazoline 0.2 lOg, 60%).
'H NMR Spectrum: (DMSOd6, CF3COOD) 2.1 (s, 3H), 2.35 (m, 2H), 2.45 (s, 3H), 3.0 (m,
2H), 3.2 (m, 1H), 3.4 (dd, 2H), 3.5 (m, 1H), 3.65 (d, 2H), 4.1 (m, 1H), 4.15 (s, 3H), 4.45 (dd,
2H), 4.55 (d, 1H), 6.3 (s, 0.3 H, partly exchanged), 7.05 (dd, 1H), 7.28 (d, 1H), 7.6 (s, 1H),
7.9 (s, lH),9.2(s, 1H)
MS-ESI: 508.5 [M+H]+
The starting material was prepared as follows:
A suspension of 1-acetylpiperazine (3.85g, 30 mmol), potassium carbonate (8.3g, 60
mmol) and 3-bromo-l-propanol (4ml, 45 mmol) in acetorutrile (30ml) was heated and stirred
at 80°C for 5 hours. After cooling, the mixture was filtered and the filtrate was evaporated.
The residue was purified by column chromatography, eluting with increasingly polar mixtures
of methylene chloride and ethauoL The fractions containing the expected product were
combined and evaporated to give 3-(4-acetylpiperazin-l-yl)propau-l-ol (3.15g, 56%).
'H NMR Spectrum (CDC13): 1.7 (m, 2H), 2.08 (s, 3H), 2.45 (m, 4H), 2.6 (dd, 2H), 3.45 (dd,
2H), 3.6 (dd, 2H), 3.78 (dd, 2H), 4.6 (br s, 1H)
MS-ESI: 187 [M+HJ+
A solution of 6-benzyloxy-4-cWoro-7-methoxyquinazoline (0.39g, 1.3mrnol),
(EP1153920 production examples 28-30), 4-fluoro-5-hydroxy-2-methylindole (0.24g,
1.43inmol) and cesium carbonate (1.2g, 4mmol) in DMF (4ml) was stirred at 95°C for 45
minutes. After cooling, the mixture was filtered and the filtrate was evaporated under vacuum.
The residue was purified by column chromatography eluting with increasingly polar mixtures
of methylene chloride and ethyl acetate to give 6-benzyloxy-4-(4-fluoro-2-methylindol-5-
yloxy)-7-methoxyquinazoline (0.213g, 37%).
'H NMR Spectrum: (DMSO do) 2.42 (s, 3H), 4.05 (s, 3H), 5.3 (s, 2H), 6.25 (s, 1H), 7.0 (dd,
1H), 7.18 (d, 1H), 7.35-7.6 (m, 6H), 7.8 (s, 1H), 8.55 (s, 1H)
MS-ESI: 430 [M+H]+
A solution of 6-beuzyloxy-4-(4-fluoro-2-memylindol-5-yloxy)-7-methoxyquinazoline
(1.32g, 3mmol), ammonium formate (1.94g, 30mmol) and 10% palladium on carbon (0.2g) in
DMF (15ml) containing water (2ml) was stirred at ambient temperature for 1 hour. The
mixture was filtered and the filtrate was evaporated. The residue was triturated under diethyl
ether, filtered, washed with diethyl ether followed by water and dried under vacuum over P2Os
overnight to give 4-(4-fluoro-2-inethyliudol-5-yloxy)-6-hydroxy-7-methoxyquiriazoune (Ig,
100%).
'H NMR Spectrum (DMSOd6) 2.35 (s, 3H), 4.0 (s, 3H), 6.25 (s, 1H), 7.0 (m, 1H), 7.15 (d,
1H), 7.4 (s, 1H), 7.6 (s, 1H), 8.0 (s, 1H), 8.55 (s, 1H)
MS-ESI: 340 [M+H]+
To a solution of 2-fluoro-4-nitroanisole (9.9 g, 58 mmol) and 4-
chlorophenoxyacetonitrile (10.7 g, 64 mmol) in DMF (50 ml) cooled at -15°C was added
potassium fert-butoxide (14.3 g, 127 mmol) in DMF (124 ml). After stirring for 30 minutes at
-15°C, the mixture was poured onto cooled IN hydrochloric acid. The mixture was extracted
with ethyl acetate. The organic layer was washed with IN sodium hydroxide, brine, dried
(MgSO4) and evaporated. The residue was purified by column chromatography eluting with
methylene chloride. The fractions containing the expected product were combined and
evaporated. The residue was dissolved in ethauol (180 ml) and acetic acid (24 ml) containing
10 % palladium on charcoal (600 mg) and the mixture was hydrogenated under 3 atmospheres
pressure for 2 hours. The mixture was filtered, and the volatiles were removed under vacuum.
The residue was partitioned between ethyl acetate and water. The organic layer was separated,
aud washed with saturated sodium hydrogen carbonate followed by brine, dried (MgS04) and
evaporated. The residue was purified by column chromatography eluting with methylene
chloride to give a mixture of 4-fluoro-5-methoxyindole aud 6-fluoro-5-metlioxyindole (5.64 g,
59 %) in a ratio 1/2.
'H NMR Spectrum: (DMSOde) 3.85 (s, 3H) ; 6.38 (s, 1H, 6-Fluoro) ; 6.45 (s, 1H ; 4-Fluoro) ;
6.9-7.4 (m, 3H)
A solution of 4-fluoro-5-methoxyindo]e and 6-fluoro-5-methoxyindole in a ratio 1/2
(496 mg, 3 mmol), di-te/tbutyl dicarbonate (720 mg, 3.3 mmol) in acetonitrile (12 ml)
contaiuiug DMAP (18 mg, 0.15 mmol) was stirred at ambient temperature for 24 hours. The
volatiles were removed under vacuum. The residue was dissolved in ethyl acetate, washed
with IN hydrochloric acid, followed by water, brine, dried (MgSO4) aud evaporated to give a
mixture of 4-fluoro-5-methoxy-l-te/t-butoxycarbonylindole and 6-fluoro-5-methoxy-l-tertbutoxycarbonyliudole
in a ratio 1/2 (702 mg, 88 %).
'H NMR Spectrum: (DMSOd6) 1.65 (s, 9H) ; 3.9 (s, 3H) ; 6.6 (d, 1H, 6-fluoro) ; 6.72 (d, 1H,
4-fluoro) ; 7.2 (t, 1H, 6-fluoro) ; 7.4 (d, 1H, 4-fluoro) ; 7.62 (d, 1H, 6-fluoro) ; 7.68 (d, 1H, 4-
fluoro); 7.78 (s, 1H, 4-fluoro) ; 7.85 (s, 1H, 6-fluoro)
To a solution of 4-fluoro-5-methoxy-l-/m-butoxycarbonylindole and 6-fluoro-5-
methoxy-1-fert-butoxycarbonylindole in a ratio 1/2 (8.1 g, 30.5 mmol) in THF (100 ml) cooled
at -65°C was added Cert-butyUitliium (1.7 M) (23 ml, 35.7 mmol). After stirring for 4 hours at
-70°C, methyl iodide (8.66 g, 61 mmol) was added and the mixture was left to warm-up to
ambient temperature. Water was added and the mixture was extracted with ether. The
organic layer was washed with water, brine, dried (MgSO4) and evaporated and was used
directly in the next step.
The crude product was dissolved in methylene chloride (100 ml) and TFA (25 ml) was
added. After stirring for 1 hour at ambient temperature, the volatiles were removed under
vacuum. The residue was dissolved in ethyl acetate and the organic layer was washed with IN
sodium hydroxide, followed by water, brine, dried (MgSC>4) and evaporated. The residue was
purified by column chromatography, eluting with ethyl acetate/petroleum ether (3/7) to give 6-
fluoro-5-methoxy-2-methylindole (1.6 g) and 4-fluoro-5-methoxy-2-methylindole (0.8 g, 48
6-fluoro-5-rnethoxy-2-methylindole:
MS-ESI: 180[MH]+
'H NMR Spectrum: (DMSOd6) 2.35 (s, 3H) ; 3.8 (s, 3H) ; 6.05 (s, 1H) ; 7.1 (s, 1H) ; 7.12 (s,
1H) ; 10.8 (s, 1H)
4-fluoro-5-methoxy-2-methylindole:
MS-ESI: 180[MHf
'H NMR Spectrum: (DMSOd6) 2.35 (s, 3H) ; 3.8 (s, 3H) ; 6.15 (s, 1H) ; 6.9 (t, 1H) ; 7.05 (d,
To a solution of 4-fluoro-5-methoxy-2-methytindole (709 mg, 3.95 mmol) in methylene
i chloride (9 ml) cooled at -30°C was added a solution of boron tribromide (2. 18 g, 8.7 mmol)
in methylene chloride (1 ml). After stirring for 1 hour at ambient temperature, the mixture was
poured onto water and was diluted with methylene chloride. The pH of the aqueous layer was
adjusted to 6. The organic layer was separated, washed with water, brine, dried (MgS04) and
evaporated. The residue was purified by column chromatography, eluting with ethyl
acetate/petroleum ether (3/7) to give 4-fluoro-5-hydroxy-2-methyliudole (461 mg, 70 %).
MS-ESI : 166 [MH]+
'H NMR Spectrum: (DMSOd6) 2.35 (s, 3H) ; 6.05 (s, 1H) ; 6.65 (dd, 1H) ; 6.9 (d, 1H) ; 8.75
(s, 1H) ; 10.9 (s, 1H)
13C NMR Spectrum: (DMSOd6) 13.5 ; 94,0 ; 106,0 ; 112 ; 118.5; 132; 136; 136.5 ; 142.5
Alternatively the 4-fluoro-5-hydroxy-2-methylindole may be prepared as follows:
To a suspension of sodium hydride (5.42 g, 226 mmol) (prewashed with pentane) in
THF (100 ml) cooled at 10°C was added ethyl acetoacetate (29.4 g, 226 mmol) while keeping
the temperature below 15°C. After completion of addition, the mixture was further stirred for
15 minutes and cooled to 5°C. A solution of l,2,3-trifluoro-4-nitrobenzene (20 g, 1 13 mmol)
in THF (150 ml) was added while keeping the temperature below 5°C. The mixture was then
left to warm up to ambient temperature and stirred for 24 hours. The voladles were removed
under vacuum and the residue was partitioned between ethyl acetate and 2N aqueous
hydrochloric acid. The organic layer was washed with water, brine, dried (MgSCU) and
evaporated. The residue was dissolved in concentrated hydrochloric acid (650 ml) and acetic
acid (600 ml) and the mixture was refluxed for 15 hours. After cooling, the volatiles were
removed under vacuum and the residue was partitioned between aqueous sodium hydrogen
carbonate (5 %) and ethyl acetate. The organic layer was washed with sodium hydrogen
carbonate, water, brine, dried (MgS04) and evaporated. The residue was purified by column
chromatography eluting with ethyl acetate/petroleum ether (75/25) to give 3-acetylmethyl-l,2-
difluoro-4-nitrobenzene (17.5 g, 72 %).
'H NMR Spectrum (CDCfe) 2.4 (s, 3H) ; 4.25 (s, 2H) ; 7.25 (dd, 1H) ; 8.0 (dd, 1H)
A solution of 3-acetylmethyl-l,2-difluoro-4-nitrobenzene (500 mg, 2.3 mmol) in
methylene chloride (5 ml) containing montmorillonite K10 (1 g) and trimethyl orthoformate (5
ml) was stirred for 24 hours at ambient temperature. The solid was filtered, washed with
methylene chloride and the filtrate was evaporated to give l,2-difluoro-3-(2,2-
dimethoxypropyl)-4-nitrobenzene (534 mg, 88 %).
'H NMR Spectrum (CDC13) 1.2 (s, 3H) ; 3.2 (s, 6H) ; 3.52 (s, 2H) ; 7.18 (dd, 1H) ; 7.6 (m,
1H)
To a solution of benzyl alcohol (221 mg, 2.05 mmol) in DMA (1.5 ml) was added 60%
sodium hydride (82 mg, 2.05 mmol). The mixture was stirred for 1 hour at ambient
temperature. A solution of l,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (534 mg,
2.05 mmol) in DMA (1.5 ml) was added and the mixture was stirred for 3 hours at ambient
temperature. The mixture was diluted with IN hydrochloric acid (10 ml) and extracted with
ethyl acetate. The organic layer was evaporated and the residue was dissolved in THF (2 ml)
and 6N hydrochloric acid (0.3 ml) was added. The mixture was stirred for 1 hour at ambient
temperature and the solvents were removed under vacuum. The residue was partitioned
between ethyl acetate and water. The organic layer was separated, washed with brine, dried
(MgS04) and evaporated. The solid was triturated with ether, filtered, washed with ether and
dried under vacuum to give 3-acetylmethyl-l-benzyloxy-2-fluoro-4-nitrobenzene (350 mg, 56
%).
'H NMR Spectrum (CDC13) 2.35 (s, 3H) ; 4.25 (s, 2H) ; 5.25 (s, 2H) ; 7.0 (dd, 1H) ; 7.32-7.5
(m, 5H) ; 8.0 (dd, 1H)
A solution of 3-acetyknethyl-l-benzyloxy-2-fluoro-4-nitrobenzene (300 mg, 0.99
mmol) in ethanol (10 ml) and acetic acid (1 ml) containing 10 % palladium on charcoal (30
mg) was hydrogenated at 2 atmospheres pressure for 2 hours. The mixture was filtered and
the filtrate was evaporated. The residue was dissolved in ethyl acetate and the organic layer
was washed with aqueous sodium hydrogen carbonate, brine and evaporated to give 4-fluoro-
5-hydroxy-2-methylindole. The residue was purified by column chromatography elutiug with
ethyl acetate/petroleum ether (3/7) to give 4-fluoro-5-hydroxy-2-methyliudole (63 mg, 30%).
Analytical data as above.
Alternatively the 4-fluoro-5-methoxy-2-methyliadole can be prepared as follows:
A solution of sodium methoxide (freshly prepared from sodium (l.Vlg) and methanol
(35ml)) was added to a solution of l,2-difluoro-3-(2,2-dimetlioxypropyl)-4-nitrobenzene (16.2
g, 62 mmol), (prepared as described above), in methanol (200ml) cooled at 5°C. The mixture
was left to warm to ambient temperature and was stirred for 3 days. The volatiles were
removed under vacuum and the residue was partitioned between ethyl acetate and 2N
hydrochloric acid (1ml). The organic layer was concentrated to a total volume of 100ml and
THF (100ml) and 6N hydrochloric acid (25ml) were added. The mixture was stirred for 1
hour at ambient temperature. The volatiles were removed under vacuum and the residue was
partitioned between ethyl acetate and water. The organic layer was separated, washed with
water, brine, dried (MgSCU) and evaporated. The residue was purified by column
chromatography eluting with ethyl acetate/petroleum ether (3/7) to give 3-acetyImethyl-2-
fluoro-l-methoxy-4-nitrobenzeiie (12.7 g, 90%).
MS-ESI: 250 [MNa]+
'H NMR Spectrum: (CDC13) 2.38 (s, 3H); 4.0 (s, 3H); 4.25 (s, 2H) ; 7.0 (dd, 1H) ; 8.05 (d,
1H)
To a solution of 3-acetylmethyl-2-fluoro-l-methoxy-4-nitrobenzene (11.36g, 50 mmol)
in acetone (200ml) was added 4M aqueous ammonium acetate (700ml) followed by a solution
of titanium trichloride (15% in water, 340ml) dropwise. The mixture was stirred for 10
minutes at ambient temperature and the mixture was extracted with ether. The organic layer
was washed with 0.5N aqueous sodium hydroxide followed by water, brine, dried (MgSO4)
and the volatiles were removed under vacuum. The residue was purified by column
chromatography eluting with methylene chloride to give 4-fluoro-5-methoxy-2-methylindole
(8.15g, 90%).
1H NMR Spectrum: (DMSO) 2.35 (s, 3H); 3.8 (s, 3H) ; 6.1 (s, 1H) ; 6.85 (dd, 1H) ; 7.02 (d,
1H)
Cleavage of 4-fluoro-5-methoxy-2-methyUudole with boron tribromide to give 4-
fluoro-5-hydroxy-2-methylindole is described above.
Exaniple 2
O MeSO2"
Diethyl azodicarboxylate (0.09g, 0.518mmoi) was added dropwise to a solution of 4-
(7-azaindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.133g, 0.432mmol),
triphenylphosphine (0.17g, 0.647mmol) and 3-(4-inethylsulphonylpiperazin-l-yl)propau-l-ol
(0.115g, 0.519mmol) in DMF (4ml) and the mixture was stirred at ambient temperature for 1
hour. The volatiles were removed under vacuum and the residue was purified by column
chrornatography using increasingly polar mixtures of ethyl acetate and methylene chloride
foDowed by methylene chloride and methanol. The fractions containing the expected product
were combined and evaporated. The solid was then repurified by preparative LC/MS eluting
with acetonitrOe/water (containing 1% acetic acid). The fractions containing the expected
product were combined and evaporated. The residue was dissolved in aqueous sodium
hydrogen carbonate and methylene chloride. The organic phase was separated and dried over
magnesium sulphate and evaporated. The residue was triturated under diethyl ether, filtered,
washed with ether and dried under vacuum over PiQs to give 4-(7-azaindol-5-yloxy)-7-
methoxy-6-(3-(4-methylsulphonylpipera2in-l-yl)propoxy)quinazoline (0.09, 40%).
'H NMR Spectrum (DMSOd6, CF3COOD) 2.3 (m, 2H), 3.05 (s, 3H), 3.1-3.3 (m, 4H), 3.4
(dd, 2H), 3.7 (d, 2H), 3.8 (d, 2H), 4.1 (s, 3H), 4.4 (dd, 2H), 6.6 (d, 1H), 7.55 (s, 1H), 7.65 (d,
1H), 7.8 (s, 1H), 8.1 (s, 1H), 8.3 (s, 1H), 9.0 (s, 1H)
MS-ESI: 513 [M+H]+
The starting material was prepared as follows:
Methanesulphonyl chloride (2.28ml) was added dropwise to a solution of \-(tertbutoxycarbonyl)
piperazine (5g) in methylene chloride (90ml) containing triethylamine (4.5ml).
The solution was stirred at ambient temperature for 24 hours. The solution was poured onto
cooled water and extracted with methylene chloride. The organic phase was separated,
washed with brine and dried over magnesium sulphate and evaporated to give ferf-butyl 4-
(methylsulphonyl)piperazine- 1-carboxylate (7g).
'H NMR Spectrum: (CDC13) 1.45 (s, 9H), 2.75 (s, 3H), 3.15 (m, 4H), 3.5 (m, 4H)
A solution of terr-butyl 4-(metliy1sulphonyl)piperazine-l-carboxylate (7g) in methylene
chloride (150ml) containing TFA (35ml) was stirred for 2 hours at ambient temperature. The
volatiles were removed under vacuum and the resultant residue was partitioned between
methylene chloride arid 2N aqueous sodium hydroxide. The organic phase was separated and
washed with brine, dried over magnesium sulphate and evaporated to give 1-
(methylsulphonyl)piperazine (2.18g).
>H NMR Spectrum : (CDC13) 2.9 (s, 3H), 3.0 (m, 4H), 3.2 (m, 2H)
A suspension of l-(methylsulphonyl)piperazine (3g, 18.3mmol), 3-bromopropan-l-ol
(3.3g, 23.8mmol) and potassium carbonate (3.28g, 23.8mmol) in acetonitrile (20ml) was
stirred at 70°C for 4 hours. After cooling, the mixture was filtered and the filtrate was
evaporated. The residue was purified by column chromatography eluting with increasingly
polar mixtures of methanol and methylene chloride to give 3-(4-methylsulphonylpiperazin-lyl)
propan-l-ol(2.93g, 72%).
JH NMR Spectrum: (CDC13) 1.72 (m, 2H), 2.55-2.7 (m, 6H), 2.75 (s, 3H), 3.25 (m, 4H), 3.75
(dd, 2H)
MS-ESI:223 [M+H]+
A solution of 7-azaindole (20.0g, 169mmol) in ethanol (200ml) was treated with wet
Rauey Nickel (4g, 50% water) and stirred in a hydrogen atmosphere at 5 atmospheres pressure
at 95°C over 2 days. The reaction mixture was filtered through diatomaceous earth and the
filtrate evaporated under vacuum The residue was purified by column chromatography eluting
with ethyl acetate followed by increasingly polar mixtures of methylene chloride and methanol
(saturated with ammonia) to give 7-azaindoliiie (12.1 g, 79%).
]H NMR Spectrum : (CDC13) 3.06 (t, 2H), 3.61 (t, 2H), 4.48 (br s, 1H), 6.50 (in, 1H), 7.25
(m, 1H), 7.8 l(d, 1H)
A solution of 7-azaindoline (22.7 g, 189 mmol), p-toluene sulphonic acid monohydrate
(2.95 g, 15 mmol) and l,3-dibromo-5,5-dknethylhydantoin (27.4 g, 96 mrnol) in methylene
chloride (1500 ml) was stirred at ambient temperature for 3 hours. The reaction solution was
then decanted from a black polymeric material; washed with 0.2 M sodium thiosulphate (4 x
250 mis) followed by brine and dried over magnesium sulphate. The filtrate was evaporated
under vacuum to give a black solid which was extracted with boiling ethyl acetate (2 x 800 mis
and 2 x 500 mis). The combined extracts were heated at reflux for a few minutes with
decolourising charcoal, filtered and evaporated under vacuum to give 5-bromo-7-azaindoline
(16.6 g, 44%).
'H NMR Spectrum : (CDCfe) 3.07 (t, 2H), 3.64 (t, 2H), 4.52 (s, 1H), 7.31 (d, 1H), 7.84 (d,
1H)
A mixture of 5-bromo-7-azaindoline (15.6g, 78 rnmol) aud precipitated, active
manganese (IV) oxide (21.9 g, 252 rnmol) in toluene (300 mis) was heated at 90°C for 1 hour
and the hot solution filtered through a pad of diatomaceous earth. The diatomaceous earth and
manganese residues were washed with acetone and these washings added to the toluene
filtrate. Evaporation of the filtrate under vacuum gave 5-bromo-7-azaindole (12.1 g, 78%).
'H NMR spectrum: (CDC13) 6.47 (m, 1H), 7.36 (m, 1H), 8.08 (d, 1H), 8.35 (d, 1H), 9.89 (s,
1H)
A solution of 5-bromo-7-azaindole (8.6 g, 44 mmol), copper (I) bromide (12.6 g, 88
mmol) and sodium methoxide (100 g, 1.85 mol) in a mixture of "degassed" DMF (260 mis)
and methanol (175 mis) was stirred at ambient temperature in a nitrogen atmosphere, and then
heated at reflux for 3.5 hours. The mixture was concentrated to about half its original volume,
cooled in a cold water bath and treated dropwise with water causing an exotherm. The
resulting suspension was evaporated under vacuum to give a brown solid which was then
treated with water followed by ammonium hydroxide. The aqueous phase was extracted with
ethyl acetate and the combined extracts were washed with dilute ammonium hydroxide until no
blue colour was seen in the aqueous washings. The ethyl acetate solution was washed with
brine, dried over MgSCU, filtered and evaporated under vacuum. This crude solid, 5-methoxy-
7-azaindole (6.3 g, 97%), was taken through the next step without further purification.
Boron tribromide (0.506/xl, 5.35mmol) in methylene chloride (1ml) was added to a
solution of 5-methoxy-7-azaindole (0.36g, 2.43mmol) in methylene chloride (25ml) cooled at
-30°C. The mixture was left to warm up to ambient temperature and was stirred overnight.
The mixture was poured onto ice and water aud the pH of the aqueous phase was adjusted to
6. The organic phase was separated and the aqueous phase was further extracted with ethyl
acetate. The organic phases were combined, washed with brine, dried over magnesium
sulphate and evaporated. The residue was purified by column chromatography eluting with
increasingly polar mixtures of methylene chloride and methanol to give 5-hydroxy-7-azaindole
(0.23g,71%).
'H NMR Spectrum: (DMSOd^) 6.25 (s, 1H), 7.25 (s, 1H), 7.35 (s, 1H), 7.85 (s, 1H), 9.05 (br
sH)
MS-ESI: 135 [M+H]+
A solution of 6-benzyloxy-4-chloro-7-methoxyquinazoline (0.449g, 1.49 mmol),
(EP1153920 production examples 28-30), 5-hydroxy-7-azaindole (0.22g, 1.64rnmol) and
potassium carbonate (0.28g, 2.02 mmol) in DMF (5ml) was stirred at 95°C for 3 hours. The
mixture was filtered and the filtrate was evaporated and dried overnight under vacuum. The
residue was triturated under methylene chloride and ethyl acetate and the solid was filtered and
dried under vacuum to give 4-(7-azaindol-5-yloxy)-6-benzyloxy-7-methoxyquinazoline (0.36g,
60%).
'H NMR spectrum (DMSOd6) : 4.05 (s, 3H), 5.35 (s, 2H), 6.5 (s, 1H), 7.35-7.5 (m, 4H), 7.5-
7.6 (m, 3H), 7.8 (s, 1H), 7.95 (s, 1H), 8.2 (s, 1H), 8.55 (s, 1H)
MS-ESI: 399 [M+H]+
A solution of 4-(7-azaindol-5-yloxy)-6-benzyloxy-7-rnethoxyquinazoline (0.36g, 0.873
mmol), ammonium formate (0.55g, 8.73 mmol) and 10% palladium on carbon (0.05g) in DMF
(7 ml) containing water (0.3ml) was stirred at ambient temperature for 1 hour. The mixture
was filtered and the filtrate was evaporated. The residue was triturated under diethyl ether and
the solid was filtered, washed with ether and dried under vacuum. The solid was triturated
under water, filtered, washed with water and dried under vacuum over PzOs to give 4-(7-
azaindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.26g, 85%).
'H NMR Spectrum: (DMSOd^) 4.05 (s, 3H), 6.5 (d, 1H), 7.4 (s, 1H),7.6 (m, 2H), 7.95 (s,
1H), 8.2 (s, 1H), 8.5 (s, 1H)
MS-ESI: 307 [M-H]-
Example 3
Using an analogous procedure to that described for the preparation of Example 2, 4-(7-
azaindo]-5-yloxy)-6-hydroxy-7-methoxyquinazoline(0.133g, 0.432mmol), (prepared as
described for the stalling material in Example 2), was reacted with 3-(4-acetylpiperazin-lyl)
propan-l-ol (0.097, 0.51mmol), (prepared as described for the starting material in Example
1 or Example 7), to give 6-(3-(4-acetylpiperazin-l-yl)propoxy)-4-(7-azaindol-5-yloxy)-7-
methoxyquinazoline (0.1 Ig, 53%).
'H NMR Spectrum: (DMSOd6, CF3 GOOD) 2.08 (s, 3H), 2.3 (m, 2H), 2.9-3.1 (m, 2H), 3.1-
3.25 (in, 1H), 3.35 (dd, 2H), 3.45 (m, 1H), 3.6 (d, 2H), 4.0-4.05 (m, 1H), 4.1 (s, 3H), 4.4 (dd,
2H), 4.5 (d, 1H), 6.6 (d, 1H), 7.6 (s, 1H), 7.68 (d, 1H), 7.85 (s, 1H), 8.1 (s, 1H), 8.38 (s, 1H),
9.1(8, 1H)
MS-ESI: 477 [M+H]+
Example 4
A solution of 7-(3-(4-acetylpiperazin-l-yl)propoxy)-4-chloro-6-methoxyquinazoline
(0.285g, 0.753mmol), 5-hydroxy-7-azaindole (O.lllg, 0.828mmol), (prepared as described for
the starting material in Example 2), and potassium carbonate (0.114g, 0.828rnniol) in DMF
(1.6ml) was stirred and heated at 95°C under nitrogen for 3 hours. The mixture was cooled
and filtered and the filtrate was evaporated. The residue was purified by column
chromatography eluting with increasingly polar mixtures of methylene chloride and methanol
(saturated with ammonia). The fractions containing the expected product were combined and
evaporated and the residue was triturated under diethyl ether, filtered and dried under vacuum
to give 7-(3-(4-acetylpiperazin-l-yi)propoxy)-4-(7-azaind.oI-5-yloxy)-6-
methoxyquinazoline (0.225g, 62%).
'H NMR Spectrum: (DMSOd6) 1.98 (s, 3H), 1.98 (m, 2H), 2.35 (dd, 2H), 2.4 (dd, 2H), 2.5
(m, 2H), 3.41 (m, 4H), 4.0 (s, 3H), 4.25 (dd, 2H), 6.47 (d, 1H), 7.38 (s, 1H), 7.55 (dd, 1H),
7.6 (s, 1H), 7.9 (d, 1H), 8.18 (d, 1H), 8.5 (s, 1H)
MS-ESI: 477.6 [M+H]+
The starting material was prepared as follows :
A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (lOg, 0.04mol), (J. Med.
Chem. 1977, vol 20, 146-149), and Gold's reagent (7.4g, O.OSmol) in dioxane (100ml) was
stirred and heated at reflux for 24 hours. Sodium acetate (3.02g, 0.037mol) and acetic acid
(1.65ml, 0.029mol) were added to the reaction mixture and it was heated for a further 3 hours.
The mixture was evaporated, water was added to the residue, the solid was filtered off, washed
with water and dried (MgSCH). Recrystallisation from acetic acid gave
7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7g, 84%).
10% Palladium on carbon (8.3g) was added to a suspension of
7-benzyloxy-6-fflethoxy-3,4-dihydroquinazolin-4-one (50 g, 0.177 mol) in dimethylfonnamide
(800 ml) under nitrogen. Ammonium formate (111.8 g, 1.77 mol) was then added in portions
over 5 minutes. The reaction mixture was stirred for one hour at ambient temperature then
heated to 80°C for a further hour. The reaction mixture was filtered hot through diatomaceous
earth and the residues washed with dimethylformamide. The filtrate was then concentrated and
the residue suspended in water. The pH was adjusted to 7.0 using 2M sodium hydroxide and
the resulting mixture was stirred at ambient temperature for one hour. The solid was filtered,
washed with water and dried over phosphorus pentoxide yielding 7-hydroxy-6-methoxy-3,4-
dihydroquinazolin-4-one as a white solid (20.52 g, 60%).
:H NMR Spectrum: (DMSOd6) 3.85 (s, 3H), 6.95 (s, 1H), 7.40 (s, 1H), 7.85 (s, 1H)
MS-ESI: 193 [M+H]+
Pyridine (20 ml) was added to a suspension of 7-hydroxy-6-rnethoxy-3,4-
dihydroquinazolin-4-one (20.5 g, 107 rmnol) in acetic anhydride (150 ml, 1.6 mol). The
reaction mixture was heated to 120°C for three hours, during which time the solid dissolved.
The reaction mixture was allowed to cool then poured into ice-water (900 ml). The reaction
mixture was stirred lor one hour then the solid was removed by filtration and dried over
phosphorus pentoxide yielding 7-acetoxy-6-methoxy-3,4-dihydroquinazolin-4-one as a white
solid (20.98 g, 84%).
'H NMR Spectrum: (DMSOd6) 2.25 (s, 3H), 3.85 (s, 3H), 7.40 (s, 1H), 7.60 (s, 1H), 8.00 (s,
1H)
MS-ESI: 235 [M+H]+
7-Acetoxy-6-methoxy-3,4-dihydroquinazolin-4-one (1 g, 4.3 mmol) was suspended in
thionyl chloride (10.5 ml). One drop of dimethylformamide was added and the reaction was
heated to 80°C for two hours, during which time the solid dissolved. The reaction mixture
was cooled and the thionyl chloride was removed in vacua. The residue was azeotroped with
toluene before being suspended in methylene chloride. A solution of 10% ammonia in
methanol (40 ml) was added and the reaction mixture was heated to 80°C for 15 minutes.
After cooling the solvents were removed in vacua and the residue redissolved in water (10 ml)
and the pH adjusted to 7.0 with 2M hydrochloric acid. The resulting solid was filtered, washed
with water and dried over phosphorus pentoxide yielding 4-chloro-7-hydroxy-6-
methoxyquinazoline as a white solid (680 mg, 75%).
!H NMR Spectrum: (DMSOd6) 4.00 (s, 3H), 7.25 (s, 1H), 7.35 (s, 1H), 8.75 (s, 1H)
MS-ESI: 211-213 [M+H]+
Diethyl azodicarboxylate (0.243g, 1.396roniol) was added dropwise to a solution of 4-
chloro-7-hydroxy-6-rnethoxyquinazoline(0.245g, 1.16mmol), triphenylphosphine (0.396g,
l.Slmmol) and 3-(4-acetylpiperazin-l-yl)propan-l-ol (0.238g, 1.28rmuol), (prepared as
described for the starting material in Example 1 or Example 7). After stirring at ambient
temperature for 1 hour, the mixture was poured onto silica and eluted with increasingly polar
mixtures of rnethylene chloride and methanol to give 7-(3-(4-acetylpiperazin-l-yl)propoxy)-4-
chloro-6-methoxyquinazoline (0.29g, 66%).
'H NMR Spectrum: (DMSOd6) 2.0 (s, 3H), 2.0 (in, 2H), 2.35 (dd, 2H), 2.4 (dd, 2H), 2.5 (dd,
2H), 3.45 (in, 4H), 4.02 (s, 3H), 4.3 (dd, 2H), 7.4 (s,lH), 7.5 (s, 1H), 8.9 (s, 1H)
MS-ESI: 379-381 [M+H]+
Example 5
MeSO.,- MeSO.
A suspension of 4-chloro-6-methoxy-7-(3-(4-methylsulphonylpiperazin-lyl)
propoxy)quinazoline (0.25g, 0.6rnniol), 5-hydroxy-7-azaindole (0.089g, 0.663mmol),
(prepared as described for the starting material in Example 2), and potassium carbonate
(0.091g, 0.66mmol) in DMF (3ml) was stirred at 85°C for 3 hours. The mixture was filtered
and the filtrate was purified by preparative LC/MS eluting with acetonitrile/water (containing
1% acetic acid). The fractions containing the expected product were combined and
evaporated. The residue was dissolved in methylene chloride and washed with 0.5N aqueous
ammonia followed by brine, dried (MgS04) and evaporated. The residue was triturated under
diethyl ether, filtered and dried under vacuum to give 4-(7-azaindol-5-yloxy)-6-methoxy-7-
(3-(4-methylsulphonylpiperazin-l-yl)propoxy)qumazoline (0.138g, 45%).
-103-
!H NMR Spectrum: (DMSOd6) 2.02 (m, 2H), 2.52 (m, 6H), 2.9 (s, 3H), 3.15 (m, 4H), 4.02 (s,
3H), 4.3 (dd, 2H), 6.5 (d, 1H), 7.4 (s, 1H), 7.6 (d, 1H), 7.65 (s, 1H), 7.95 (d, 1H), 8.2 (s, 1H),
8.52 (s, 1H)
MS-ESI: 513.5 [M+H]+
The starting material was prepared as follows :
Using an analogous procedure to that described for the preparation of the starting
material in Example 4, 4-cMoro-7-hydroxy-6-rnethoxyquinazoline (0.25g, 1.19mmol),
(prepared as described for the starting material in Example 4), was reacted with 3-(4-
methylsulphonylpiperazin-l-yl)propan-l-ol (0.29g, 1.3 mmol), (prepared as described in
Example 2), to give 4-ch1oro-6-methoxy-7-(3-(4-methylsulphonylpiperazin-lyl)
propoxy)quinazoline (0.339g, 69%).
'H NMR Spectrum: (DMSOdfi) 2.0 (m, 2H), 2.5 (m, 6H), 2.85 (s, 3H), 3.1 (m4H), 4.0 (s,
3H), 4.3 (dd, 2H), 7.4 (s, 1H), 7.42 (s, 1H), 8.85 (s, 1H)
MS-ESI: 415-417 [M+H]+
Example 6
Using an analogous procedure to that described for the preparation of Example 5, 4-
chloro-6-methoxy-7-[2-(A^-methy]-A^-prop-2-yn-l-ylamiQo)ethoxy]quinazoline (0.25g,
0.817mmol) was reacted with 5-hydroxy-7-azaindole (0.12g, 0.899mmol), (prepared as
described for the starting material in Example 2), to give 4-(7-azaindoI-5-yloxy)-6-methoxy-
7-[2-(N-methyl-W-prop-2-yn-l-ylaniino)ethoxy]quinazoline (0.156g, 47%).
'H NMR Spectrum: (DMSOd6) 2.35 (s, 3H), 2.9 (dd, 2H), 3.2 (dd, 1H), 3.45 (d, 2H), 4.02 (s,
3H), 4.31 (dd, 2H), 6.5 (d, 1H), 7.45 (s, 1H), 7.6 (dd, 1H), 7.65 (s, 1H), 7.95 (d, 1H), 8.2 (d,
1H), 8.52 (s, 1H)
MS-ESI: 404 [M-fH]+
The starting material was prepared as follows:
6N Aqueous sodium hydroxide (4.2mJ) was added to a solution of 2-
(methylaniino)ethanol (1.42g, 18.9mmol), propargyl bromide in toluene (1.5g, 12.6mmol;
1.6ml) in dioxane (8ral). After stirring overnight at ambient temperature, the mixture was
partitioned between water and ethyl acetate. The organic phase was separated, washed with
brine, dried with magnesium sulphate and evaporated. The residue was purified by column
chroinatography eluting with increasingly polar mixtures of methylene chloride and methanol
to give 2-(Af-methyl-N-prop-2-yn-l-ylamino)ethanol (0.794g, 56%).
'H NMR Spectrum: (CDC13) 2.2 (dd, 1H), 2.3 (s, 3H), 2.58 (dd, 2H), 3.35 (d, 2H), 3.6 (dd,
2H)
Diethyl azodicarboxylate (0.297g, l.Vlmmol) was added to a solution of 4-chloro-7-
hydroxy-6-methoxyquinazoline (0.3g, 1.42mmol), (prepared as described for the starting
material in Example 4), triphenylphospbine (0.485g, 1.85mmol) and 2-(Ar-rnethyl-./V-prop-2-ynl-
ylamino)ethanol (0.177g, 1.56mmol) in methylene chloride (8ml). The mixture was stirred
for 2 hours at ambient temperature and poured onto a column of silica and eluted with
increasingly polar mixtures of methylene chloride and ethyl acetate followed by ethyl acetate to
give 4-chloro-6-methoxy-7-[2-(Af-methyl-A^-prop-2-yn-l-ylamino)ethoxy]quinazohne (0.341g,
78%).
'H NMR Spectrum: (DMSOd6) 2.33 (s, 3H), 2.87 (t, 2H), 3.17 (t, 1H), 3.44 (d, 2H), 4.02 (s,
3H), 4.33 (t, 2H), 7.41 (s, 1H), 7.51 (s, 1H), 8.89 (s, 1H)
Example 7
A solution of 7-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-
rnethoxyquinazoline (0.25g, 0.543mmol) and 1-acetylpiperazine (0.208g, 1.63mmol) in DMF
(4ml) was stirred at 80°C for 2.5 hours. The volatiles were removed under vacuum and the
residue was purified by colum chromatography eluting with increasingly polar mixtures of
methylene chloride and methanol. The fractions containing the expected product were
combined and evaporated. The residue was triturated under diethyl ether and the resulting
solid was filtered, washed with diethyl ether and dried under vacuum to give 7-(3-(4-
acety!piperazin-l-yI)propoxy)-4-(4-fluoro-2-niethylindol-5-yloxy)-6-methoxyquinazoline
(0.25g, 0.543mmol).
LH NMR Spectrum: (DMSOd6) 1.98 (s, 3H), 2.0 (m, 2H), 2.4 (s, 3H), 2.4 (m, 4H), 2.55 (t,
2H), 3.45 (dd, 4H), 4.0 (s, 3H), 4.3 (t, 2H), 6.22 (s, 1H), 6.98 (dd, 1H), 7.15 (d, 1H), 7.4 (s,
1H), 7.62 (s, 1H), 8.48 (s, 1H), 10.98 (br s, 1H)
MS-ESI: 508 [M+H]+
The starting material was prepared as follows:
A mixture of 7-benzyloxy-6-niethoxy-3,4-dihydroquinazolin-4-one (2.82g, O.Olmol),
(prepared as described for the starting material in Example 4), thionyl chloride (40ml) and
DMF (0.28ml) was stirred and heated at reflux for 1 hour. The mixture was evaporated, the
residue was taken up in toluene and evaporated to dryness to give
7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (3.45g).
7-Benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (3.35g) was dissolved in
methylene chloride (250ml) and washed with aqueous sodium hydrogen carbonate until the pH
of the aqueous solution was adjusted to pH8. The organic layer was washed with brine, dried
(MgSOii) and evaporated to give 7-benzyloxy-4-chloro-6-methoxyquinazoline free base (2.9g,
96%).
A suspension of 7-benzyloxy-4-chloro-6-methoxyquinazoline free base (lOg, 33.2
mmol), 4-fiuoro-5-hydroxy-2-inethylindole (5.9g, 35.7 mmol), (prepared as described for the
starting material in Example 1), and potassium carbonate (9.2g, 66.6 mmol) in NMP (100ml)
was stirred at 95 C for 1 hour. After cooling, the mixture was partitioned between ethyl
acetate and aqueous sodium hydrogen carbonate. The organic layer was separated, washed
with brine and dried over magnesium sulphate and evaporated under vacuum. The residue was
triturated under acetonitrile and the suspension was cooled. The precipitate was filtered and
dried under vacuum to give 7-benzyloxy-4-(4-fluoro-2-niethylindol-5-yloxy)-6-
methoxyquinazoline (8.2g, 57%).
'H NMR Spectrum: (DMSOd6) : 2.4 (s, 3H), 4.0 (s, 3H), 5.35 (s, 2H), 6.22 (s, 1H), 6.95 (dd,
1H), 7.15 (d, 1H), 7.3-7.55 (m, 6H), 7.51 (s, 1H), 8.5 (s, 1H)
A suspension of 7-benzyloxy-4-(4-fluoro-2-methyundol-5-yloxy)-6-
methoxyquinazoline (8.2g, 19.1 mmol), ammonium formate (12g, 190 mmol) in DMF (50 ml)

containing 10% palladium on carbon (2g) was stirred at ambient temperature for 1.5 hours.
The mixture was diluted with ethyl acetate and filtered over diatornaceous earth. A solid
precipitated out of the filtrate. The solid was filtered off. The filtrate was washed with
aqueous sodium hydrogen carbonate, followed by brine and dried over magnesium sulphate.
The volatiles were removed under vacuum. The residual solid was combined with the solid
previously isolated from the filtrate and was then triturated with acetonitrile under cooling.
The precipitate was filtered, washed with acetonitrile followed by diethyl ether and dried under
vacuum to give 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoune (6.48g,
quant.).
'H NMR Spectrum: (DMSOd6) 2.4 (s, 3H), 3.98 (s, 3H), 6.22 (s, 1H), 6.95 (dd, 1H), 7.15 (d,
1H), 7.2 (s, 1H), 7.58 (s, 1H), 8.38 (s, 1H)
Diethyl azodicarboxylate (557/il, 3.53 minoi) was added to a solution of 4-(4-tluoro-2-
methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (Ig, 2.95mmol), triphenylphosphine
(1.15g, 4.42mmol) and 3-bromo-l-propanol (293/il, 3.24rumol) in methylene chloride (25ml).
The mixture was stirred at ambient temperature for 1 hour and the residue was purified by
column chromatography eluting with increasingly polar mixtures of methylene chloride and
rnethanol. The fractions containing the expected product were combined and evaporated. The
residue was triturated under diethyl ether and the solid was filtered, washed with diethyl ether
and evaporated to give 7-(3-bromopropoxy)-4-(4-fluoro-2-rnethylindol-5-yloxy)-6-
methoxyquinazoUne (1.35g, 100%).
'H NMR Spectrum: (DMSOd6) 2.4 (m, 2H), 2.45 (s, 3H), 3.75 (dd, 2H), 4.05 (s, 3H), 4.35
(dd, 2H), 6.25 (s, 1H), 7.0 (dd, 1H), 7.2 (d, 1H), 7.45 (s, 1H), 7.65 (s, 1H), 8.55 (s, 1H), 9.0
(br s, 1H)
MS-ESI: 460-462 [M+H]+
Alternatively 7-[3-(4-acetylpiperazin-l-yl)propoxy]-4-[(4-fluoro-2-methyl-l//-indol-5-
yl)oxy]-6-naethoxyquinazoline maybe prepared as follows:
4-[(4-Fluoro-2-methyl-l^-indol-5-yl)oxy]-7-hydroxy-6-meth.oxyquinazoline (14g,
41.3mmol), (prepared as described for the starting material in this example hereinbefore), 3-(4-
acetylpiperazin-l-yl)propan-l-ol (9.2g, 49.5mmol) and triphenylphosphine (12.9g, 49.5mmol)
were stirred together in methylene chloride (210ml). Diisopropyl azodicarboxylate (9.75ml,
49.5mmol) was added dropwise and an ice/water bath was used to keep the temperature of the
reaction mixture between 15 and 18°C. After the end of addition the reaction mixture was
allowed to warm to ambient temperature and stirred for 3 hours. The mixture was filtered and
concentrated under reduced pressure and the resulting viscous oil dissolved in acetone (280ml)
and stirred for 45 minutes. The solid that formed was filtered off and dried under vacuum.
The solid was purified by chromatography eluting with methylene chloride/methanol (saturated
with ammonia) (96/4) to give 7-[3-(4-acetylpiperazin-l-yl)propoxy]-4-[(4-fluoro-2-niethyl-
Lff-indol-5-yI)oxy]-6-methoxyquinazoline (12.5g, 60%) as a white solid.
MS and NMR details are given hereinbefore.
The starting material was prepared as follows:
1 -Acetylpiperazine (15.Og, 117mmol) was dissolved in acetonitrile (200ml) and
potassium carbonate (40.4g, 293mmol) was added followed by 3-bromo-l-propanol (10.6ml,
117mmol). The mixture was heated at reflux for 2.5 hours, cooled, filtered and concentrated
under reduced pressure. The resulting viscous oil was cooled in ice for 3 hours and the
crystalline product that formed was suspended in diethyl ether and filtered off. The
hydroscopic solid was dried under vacuum (P^Oj) overnight to give 3-(4-acetylpiperazin-lyl)
propan-l-ol (17.3g, 90%) as a pale yellow solid.
'H NMR Spectrum: (CDC13) 1.75 (m, 2H); 2.08 (s, 3H); 2.51 (m, 4H); 2.65 (t, 2H); 3.47 (br t,
2H); 3.64 (br t, 2H); 3.82 (t, 2H)
MS-ESI: 187 [M+H]+
Altematively 7-[3-(4-acetylpiperazin-l-yl)propoxy]-4-[(4-fluoro-2-methyl-l/7-indol-5-
yl)oxy]-6-methoxyquinazoline may be prepared as follows:
A mixture of 7-[3-(4-acetylpiperazin-l-yl)propoxy]-4-cliloro-6-niethoxyquinazoline
(20.Og, 52.3mmol), 4-f]uoro-5-hydroxy-2-niethylindole (10.5g, 63.3mmol), (prepared as
described for the starting material in Example 1), and cesium carbonate (34.4g, 106mmol) in
acetone (500ml) was heated at reflux for 4 hours. The mixture was cooled and allowed to
stand overnight. The mixture was filtered and the solid suspended in water and re-filtered and
dried under vacuum. The solid was purified by column chromatography eluting with
methylene chloride/methanol (saturated with ammonia) (95/5) to give 7-[3-(4-
acetylpiperazin-l-yl)propoxy]-4-[(4-fluoro-2-methyl-lH-indol-5-yl)oxy]-6-
methoxyquinazoline (20.4g, 77%) as a white solid.
MS and NMR details are given hereinbefore.
The starting material was prepared as follows:
4-Chloro-7-hydroxy-6-methoxyquinazoline (3g, 14.2mmol), (prepared as described for
the starting material in Example 4), 3-(4-acetylpiperazin-l-yl)propan-l-ol (3.2g, 17.1mmol),
(prepared as described for the starting material in this example hereinbefore), and
triphenylphosphine (4.5g, 17.1mmol) were stirred together in dichloromethajie (140ml).
Diisopropyl azodicarboxylate (3.4ml, 17.1mmol) was added dropwise and an ice/water bath
used to keep the temperature of the reaction mixture below 10°C. After the addition, the
reaction mixture was allowed to warm to ambient temperature and stirred overnight. The
mixture was concentrated under reduced pressure. Column chromatography of the residue
(2:1 iso-hexane:ethyl acetate then 3% - 5% methanol/dichloromethane) gave 7-[3-(4-
acetylpiperazin-l-yl)propoxy]-4-chloro-6-methoxyquinazoune (3.96g, 74%) as a white solid.
'H NMR Spectrum: (DMSOd6) 1.98 (in, 5H); 2.34 (m, 2H); 2.40 (m, 2H); 2.46 (t, 2H); 3.43
(m, 4H); 4.01 (s, 3H); 4.29 (t, 2H); 7.40 (s, 1H); 7.46 (s, 1H); 8.87 (s, 1H)
MS-ESI 379.1 and 381.1 [MHf
Alternatively 7-[3-(4-acetylpiperazin-l-yl)propoxy]-4-[(4-fluoro-2-methyl-l//-indol-5-
yl)oxy]-6-methoxyquinazoline may be prepared as follows:
4-[(4-Huoro-2-methyM#-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline (250mg,
0.74mmol), (prepared as described for the starting material in this example hereinbefore), and
potassium carbonate (112mg, O.Slmmol) were stirred together in N-methylpyrrolidinone (3ml).
l-Acetyl-4-(3-chloropropoxy)piperazine (166mg, O.Slmmol) in N-methylpyrrolidinone (1ml)
was added and the mixture heated at 90°C for 3 hours. The mixture was cooled, filtered and
concentrated under reduced pressure. The residue was purified by column chromatography
.eluting with inethylene chloride/methanol (saturated with ammonia) (97/3) to give 7-[3-(4-
acetylpiperazin-l-yI)propoxy]-4-[(4-nuoro-2-methyl-lflr-indol-5-yl)oxy]-6-
oiethoxyquinazoline (268mg, 71%) as a white solid.
MS and NMR details are given hereinbefore.
The starting material was prepared as follows:
A mixture of 1-acetylpiperazine (l.Og, 7.8mmol), l-bromo-3-chloropropane (772|U.l,
7.8mruol) and potassium carbonate (2.7g, 19.5rnrnol) in acetonitrile (150ml) was heated at
reflux for 2 hours. The mixture was cooled, filtered and concentrated under reduced pressure.
The residue was purified by column chrornatography eluting with methylene chJoride/niethanol
(98/2) to give l-acetyl-4-(3-chloropropoxy)piperazine (656mg, 41%) as a colourless oil.
'H NMR Spectrum: (CDC13) 1.95 (m. 2H); 2.08 (s, 3H); 2.42 (m, 4H), 2.51 (t, 2H); 3.46 (t,
2H); 3.61 (t, 4H)
Example 8
A solution of 6-(3-brornopropoxy)-4-(4-fluoro-2-methyUndol-5-yloxy)-7-
methoxyquinazoline (0.3g, 0.652mmol) and l-(methylsulphonyl)piperazine (0.322g,
1.95mmol), (prepared as described for the starting material in Example 2), in DMF (4ml) was
stirred at 80 C for 2.5 hours. The volatiles were removed under vacuum and the residue was
purified by column chromatography eluting with increasingly polar mixtures of methylene
chloride and methanol. The fractions containing the expected product were combined and
evaporated. The residue was triturated under diethyl ether and the resulting solid was filtered,
washed with diethyl ether and dried under vacuum to give 4-(4-fluoro-2-methyIindol-5-
yloxy)-7-methoxy-6-(3-(4-methyIsulphoDylpiperazin-l-yl)propoxy)quinazoline(0.08g,
23%).
'H NMR Spectrum: (DMSOd6 and CF3COOD) 2.3 (m, 2H), 2.4 (s, 3H), 3.0 (s, 3H), 3.1-3.3
(m, 4H), 3.4 (dd, 2H), 3.7 (d, 2H), 3.8 (d, 2H), 4.1 (s, 3H), 4.4 (dd, 2H), 6.25 (s, 0.2H, partly
exchanged), 7.0 (dd, 1H), 7.2 (d, 1H), 7.55 (s, 1H), 7.82 (s, 1H), 9.1 (s, 1H)
MS-ESI: 544 [M+H]+
The starting material was prepared as follows :
Diethyl azodicarboxylate (0.847g, 4.86mmol) was added to a solution of 4-(4-fluoro-2-
methylmdol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (1.5g, 4.42mmol), (prepared as
described for the starting material in Example 1), triphenylphosphine (1.74g, 6.63mmol) and 3-
bromo-1-propanol (0.923g, 6.63mmol) in methylene chloride. After stirring for 1 hour at
ambient temperature, triphenylphosphine (I.l6g) and DEAD (0.770g) was added. After
stirring for 30 minutes, the volatiles were removed under vacuum and the residue was purified
by column chromatograhy eluting with increasingly polar mixtures of methylene chloride and
ethyl acetate to give 6-(3-bromopropoxy)-4-(4-fluoro-2-niethylindol-5-yloxy)-7-
niethoxyquinazoline (1.5g, 73%).
'H NMR Spectrum: (DMSOd6) 2.4 (m, 2H), 2.45 (s, 3H), 3.75 (dd, 2H), 4.05 (s, 3H), 4.32
(dd, 2H), 6.25 (s, 1H), 7.02 (dd, 2H), 7.18 (d, 1H), 7.42 (s, 1H), 7.7 (s, 1H)8.55 (s, 1H)
MS-ESI: 460-462 [M+H]+
Example 9
Using an analogous procedure to that described for the preparation of Example 8, 7-(3-
bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquina2,ohne (0.25g, 0.54mmol),
(prepared as described for the starting material in Example 7), was reacted with 1-
methylsulphonylpiperazine (0.268g, 163mrao]), (prepared as described for the starting material
Example 2), in DMF to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-
methylsulphonylpiperazin-l-yl)propoxy)quinazoline (0.14g, 47%).
'H NMR Spectrum: (DMSOd6, CF3COOD) 2.35 (m, 2H), 2.4 (s, 3H), 3.02 (s, 3H), 3.1-3.3
(m, 4H), 3.4 (dd, 2H), 3.7 (d, 2H), 3.8 (d, 2H), 4.08 (s, 3H), 4.4 (dd, 2H), 6.25 (s, 0.2H,
partly exchanged), 7.0 (dd, 1H), 7.2 (d, 1H), 7.58 (s, 1H), 7.82 (s, 1H), 9.1 (s, 1H)
MS-ESI: 544 [M+H]+
Example 10
Diethyl azodicarboxylate (117/d, 0.738nnnol) was added dropwise to a solution of 4-
(4-fiuoroindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.2g, 0.615rnmo]),
triphenylphosphine (0.242g, 0.92mrnol) and 3-(4-acetylpiperazin-l-yl)propan-l-ol (0.137g,
0.738mmol), (prepared as described for the starting material in Example 1 or Example 7), in
methylene chloride (5ml). After stirring at ambient temperature for 1 hour, triphenylphosphine
(0.032g), 3-(4-acetylpiperazin-l-yl)propan-l-ol(0.022g) and diethyl azodicarboxylate (20/il)
were added. The mixture was stirred for 1 hour at ambient temperature and evaporated under
vacuum. The residue was purified by column chromatography, eluting with increasingly polar
mixtures of methylene chloride and ethyl acetate followed by methylene chloride and methanol.
The fractions containing the expected product were combined and evaporated. The residue
was repurified by preparative LC/MS eluting with increasingly polar mixtures of acetom'trile
and water (containing 1% acetic acid). The fractions containing the expected product were
combined and evaporated. The residue was triturated under diethy] ether and pentane and the
residue was filtered, washed with diethyl ether and dried under vacuum to give 6-(3-(4-
acetylpiperazin-l-yl)propoxy)-4-(4-fluoroindol-5-yloxy)-7-niethoxyquiiiazoliiie(0.057g,
19%).
'H NMR Spectrum: (DMSOd6, CF3COOD) 2.05 (s, 3H), 2.3 (m, 2H), 2.9-3.1 (m, 2H), 3.15
(m, 1H), 3.35 (dd, 2H), 3.45 (m, 1H), 3.6 (d, 2H), 4.05 (m, 1H), 4.1 (s, 3H), 4.4 (dd, 2H), 4.5
(d, 1H), 6.55 (d, 1H), 7.15 (dd, 1H), 7.38 (d, 1H), 7.5 (d, 1H), 7.58 (s, 1H), 7.85 (s, 1H), 9.12
(s, 1H)
MS-ESI: 494 [M+H]+
The starting material was prepared as follows :
A mixture of 6-benzyloxy-4-chloro-7-methoxyquinazoline (0.88g, 2.9mmol),
(EP1153920 production examples 28-30), 4-fluoro-5-hydroxyindole (0.53g, 3.5mmol) and
potassium carbonate (0.607g, 4.39muiol) in DMF (18ml) was stirred at 95°C for 2 hours.
After cooling, the mixture was filtered and the volatiles were removed under vacuum. The
residue was purified by column chromatography eluting with increasingly polar mixtures of
methylene chloride and ethyl acetate to give 6-benzyloxy-4-(4-fluoroindol-5-yloxy)-7-
methoxyquinazoune (0.8g, 67%).
:H NMR Spectrum: (DMSOd6) 4.05 (s, 3H), 5.35 (s, 2H), 6.6 (s, 1H), 7.1 (dd, 1H), 7.35 (d,
1H), 7.35-7.5 (m, 5H), 7.55 (d, 2H), 7.8 (s, 1H), 8.55 (s, 1H), 11.5 (br s, 1H)
MS-ESI: [M+HJ+416
6-Benzyloxy-4-(4-fluoroindol-5-yloxy)-7-rnethoxyquinazoline (0.75g, l.Smmol),
ammonium formate (1.14g, ISmmol) and 10% palladium on carbon (115mg) in DMF (8ml)
containing water (1.5ml) was stirred at ambient temperature for 2.5 hours. The mixture was
filtered over diatomaceous earth and the filtrate was evaporated. The residue was triturated
under diethyl ether, filtered, washed with water, followed by diethyl ether and dried overnight
overPaOj to give 4-(4-fluoroindol-5-yloxy)-6-hydroxy-7-methoxyquiaazohne (0.471g, 80%).
'H NMR Spectrum: (DMSOd6)4.02 (s, 3H), 6.55 (s, 1H), 7.1 (dd, 1H), 7.3 (d, 1H), 7.4 (s,
1H), 7.5 (dd, 1H), 7.6 (s, 1H), 8.48 (s, 1H)
MS-ESI: 326 [M+H]+
A mixture of 2-fluoro-4-nitrophenol (15gr, 95.5 mmol) and benzyl bromide
(I8g, 105 mmol) in acetone (125 ml) containing potassium carbonate (26.5 gr, 190 mmol) was
heated at reflux for 2 hours. The volatiles were removed and the residue was partitioned
between 2N hydrochloric acid and ethyl acetate. The organic layer was separated, washed
with water, brine, dried (MgSO4) and the volatiles were removed under vacuum. The solid
was triturated with petroleum ether to give 2-fluoro-4-nitro-benzyloxybenzene (23g, 97%).
'H NMR Spectrum: (CDC13) 5.3 (s, 2H) ; 7.1 (t, 1H); 7.35-7.55 (m, 5H) ; 8.0( m, 2H)
To a solution of potassium te/t-butoxide (1.72g, 15.4 mmol) in DMF (15 ml) cooled at
-30°C, was added dropwise a solution of 2-fluoro-4-nitro-benzyloxybenzene (1.73g, 7 mmol)
and 4-chlorophenoxyacetonitrile (1.29 g, 7.7 mmol) while maintaining the temperature below -
25°C. After completion of addition, the mixture was stirred for 30 minutes at -20°C and then
poured onto a mixture of cold IN hydrochloric acid and ether. The organic layer was
separated, washed with IN sodium hydroxide, followed by water, brine, dried (MgSCXt). The
volatiles were removed under vacuum and the residue was purified by column chromatography
eluting with methylene chloride/petroleum ether (3/1) to give a mixture of 3-cyanornethyl-2-
fluoro-4-nitrobenzyloxybenzene and 5-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene ( 1.2 g,
60%).
]H NMR Spectrum: (DMSOd6) 4.22 (s, 2H, 3-cyanomethyl isomer) ; 4.3 (s, 2H, 5-
cyanomethyl isomer); 5.32 (s, 2H, 5-cyanoinethyl isomer) ; 5.36 (s, 2H, 3-cyanomethyl
isomer); 7.3-7.7 (m, 6H); 8.1 (d, 1H, 3-cyanomethyl isomer); 8.2 (d, 1H, 5-cyanomethyl
isomer)
A solution of a mixture of 3-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene and 5-
cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene (23g, 80.4 mmol) in ethanol (220ml) and
acetic acid (30ml) containing 10% palladium on charcoal (600mg) was hydrogenated under 3
atmospheres pressure until hydrogen uptake ceased. The mixture was filtered and the filtrate
was evaporated under vacuum. The residue was purified on column chromatography using a
Prochrom® equipment eluting with methylene chloride/petroleum ether (20/80) to give 4-
fluoro-5-hydroxyindole (2.48g) and 6-fluoro-5-hydroxyindole (3.5 g).
4-flLioro-5-hydroxyindole:
'H NMR Spectrum: (DMSOd6) 6.32 (s, 1H) ; 6.75 (dd, 1H) ; 7.0 (d, 1H) ; 7.28 (dd, 1H) ; 8.8
(bis, lH);11.05(brs, 1H)
6-fluoro-5-hydroxyindole:
'H NMR Spectrum: (DMSOd6) 6.25 (s, 1H) ; 7.0 (d, 1H) ; 7.12 (d, 1H) ; 7.2 (dd, 1H) ; 9.0 (br
s, 1H)
(Figure Remove)ExamplgJ.1
4-[(4-Huoro-2-methyl-l#-mdol-5-yl)oxy]-6-methoxy-7-(piperidin-4-
ylmethoxy)quinazoline (150mg, 0.34mmol) was suspended in methylene chloride (5ml), and
dusopropylethylamine (72^.1, 0.41minol) and acetyl chloride (29/il, 0.41mmol) were added.
The mixture was stirred for half an hour at ambient temperature, washed with saturated sodium
hydrogen carbonate solution, dried (MgSC>4) and concentrated under reduced pressure. The
solid was suspended in methanol and filtered off to give 7-[(l-acetylpiperidin-4-yl)methoxy]-
4-[(4-fluoro-2-methyl-Lff-indol-5-yl)oxy]-6-methoxyquinazoIine (117mg, 71%).
MS-ESI: 479.5 [MH]+
1H NMR Spectrum: (DMSOd6) 1.22 (m, 2H); 1.83 (m, 2H); 1.99 (s, 3H); 2.13 (m, 1H); 2.40
(s, 3H); 2.58 (m, 1H); 3.06 (m, 1H), 3.85 (m, 1H); 3.98 (s, 3H); 4.08 (d, 2H); 4.40 (m, 1H);
6.22 (s, 1H); 6.96 (t, 1H); 7.14 (d, 1H); 7.38 (s, 1H); 7.59 (s, 1H); 8.48 (s, 1H); 11.29 (br s,
1H) -
The starting material was prepared as follows:
While maintaining the temperature in the range 0-5°C, a solution of di-fe/t-butyl
dicarbonate (41.7g, 0.19mol) in ethyl acetate (75ml) was added in portions to a solution of
ethyl 4-piperidinecarboxylate (30g, 0.19mol) in ethyl acetate (150ml) cooled at 5°C. After
stirring for 48 hours at ambient temperature, the mixture was poured onto water (300ml). The
organic layer was separated, washed successively with water (200ml), 0.1N aqueous
hydrochloric acid (200uil), saturated sodium hydrogen carbonate (200ml) and brine (200ml),
dried (MgSCU) and evaporated to give ethyl 4-(l-(fert-butoxycarbonyl)piperidine)carboxylate
(48g, 98%).
'HNMR Spectrum: (CDC13) 1.25(t, 3H); 1.45(s, 9H); 1.55-1.70(m, 2H); 1.8-2.0(d, 2H); 2.35-
2.5(m, 1H); 2.7-2.95(t, 2H); 3.9-4.l(br s, 2H); 4.15 (q, 2H)
A solution of 1M lithium aluminium hydride in THF (133ml, 0.133mol) was added in
portions to a solution of ethyl 4-(l-(fer/-butoxycarbonyl)piperidine)carboxylate (48g, 0.19mol)
in dry THF (180ml) cooled at 0°C. After stirring at 0°C for 2 hours, water (30ml) was added
followed by 2N sodium hydroxide (10ml). The precipitate was removed by filtration through
diatomaceous earth and washed with ethyl acetate. The filtrate was washed with water, brine,
dried (MgSOu) and evaporated to give l-(rerr-butoxycarbonyl)-4-hydroxyrnethylpiperidine
(36.3g, 89%).
MS (El): 215 [M.]+
'H NMR Spectrum: (CDC13) 1.05-1.2(m, 2H); 1.35-1.55(m, 10H); 1.6-1.8(m, 2H); 2.6-2.8(t,
2H); 3.4-3.6(t, 2H); 4.0-4.2(br s, 2H)
Diisopropyl azodicarboxylate (139/il, 0.71mmol) was added to a mixture of 4-(4-
fluoro-2-methyandol-5-yloxy)-7-hydroxy-6-methoxyquinazohne (200mg, 0.59mmol),
(prepared as described for the starting material in Example 7), triphenylphosphine (186mg,
0.71mmol) and l-(terr-butoxycarbonyl)-4-hydroxymethylpiperidine, (also known as terf-butyl
4-(hydroxymethyl)piperidine-l-carbbxylate), (152mg, 0.71mmol) in methylene chloride (3ml),
cooled in an ice/water bath. The mixture was allowed to warm to ambient temperature and
was stirred overnight. The mixture was concentrated under reduced pressure and the residue
purified by column chromatography, eluting with 1% methanol/methylene chloride and 0.1%
triethylamine to give tert-baiyl 4-[(4-[(4-flu.oro-2-inethyl-l#-indol-5-yl)oxy]-6-
methoxyquinazolin-7-yloxy)methyl]piperidine-l-carboxylate (293mg containing 13.5rnol%
triphenylphospine oxide, 86%).
MS-ESI: 537.6 [MH]+
1H NMR Spectrum: (DMSOd6) 1.22 (in, 2H); 1.39 (s, 9H); 1.78 (m, 2H); 2.04 (m, IH); 2.40
(s, 3H); 2.76 (m, 2H); 3.97 (m, 5H); 4.07 (d, 2H); 6.22 (s, IH); 6.96 (t, IH); 7.14 (d, 2H);
7.37 (s, IH); 7.69 [m, 3.3H (IH + Ph3PO)]; 8.47 (s, IH); 11.29 (br s, IH)
rer/-Butyl4-[(4-[(4-fluoro-2-methyl-l//-indol-5-yl)oxy]-6-methoxyquinazolin-7-
yloxy)methyl]piperidine-l-carboxylate [285mg (containing 13.5% triphenylphospine oxide),
0.49rnmol] was dissolved in 4M hydrogen chloride in dioxane (5ml) and stirred at ambient
temperature for 3 hours. The solvent was removed under reduced pressure and the solid
suspended in methylene chloride and filtered off. The solid was dissolved in methanol and
absorbed onto an Isolute SCX column which was washed through with methanol and then the
product eluted with 7N ammonia in methanol. Concentration of the fractions gave 4-[(4-
fluoro-2-methyl-lflr-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-ylmethoxy)quinazolnie (185mg,
86%).
MS-ESI: 437.5 [MH]+
'H NMR Spectrum: (CDC13) 1.34 (m, 2H); 1.85-2.20 (m, 3H); 2.45 (s, 3H); 2.68 (m, 2H);
3.15 (m, 2H); 4.05 (m, 5H); 6.32 (s, IH); 6.97 (t, IH); 7.11 (d, IH); 7.30 (s, IH) 7.63 (s, IH);
8.58 (s, IH); 9.08 (br s, IH)
Example 12
DIPEA, Ao-CI
Using an analogous procedure to that described for the preparation of Example 11,4-
[(4-fluoro-2-methyl-l//-indol-5-yl)oxy]-6-methoxy-7-[(25)-pyrrolidin-2-
ylmethoxy]quinazoliue (120mg, 0.28mmol) was reacted with acetyl chloride (24/d, 0.34
mmol). The crude product was purified by column chromatography eluting with
methanol/methylene chloride (2/98) to give 7-[(2S)-l-acetylpyrrolidin-2-ylmethoxy]-4-[(4-
fluoro-2-methyl-l/Z-indol-5-yl)oxy]-6-methoxyquinazoline (76mg, 58%).
MS-ESI: 465.6 [MH]+
'H NMR Spectrum: (100°C, DMSOd6) 2.02 (m, 7H); 2.41 (s, 3H); 3.50 (m, 2H); 4.00 (s, 3H),
4.29 (m, 3H); 6.22 (s, IH); 6.95 (t, IH); 7.14 (d, IH); 7.43 (s, IH); 7.63 (s, IH); 8.47 (s, IH);
11.02(brs, IH)
The starting material was prepared as follows:
Using an analogous procedure to that described for the preparation of the starting
material in Example 11, rert-butyl (25)-2-(hydroxyniethyl)pyrroh'dine-l-carboxylate (142mg,
0.71mmol) was reacted with 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-
methoxyquinazoline (200mg, 0.59mmol), (prepared as described for the starting material in
Example 7), and the product purified by column chromatography, eluting with
niethanol/rnethylene chloride (1/9) containing 0.1% triethylamine to give rert-butyl (25")-2-[(4-
[(4-fluoro-2-methyl-l/7-iadol-5-yl)oxy]-6-methoxyquinazohn-7-yloxy)methyl]pyrrolidine-lcarboxylate
(178mg, 58%).
MS-ESI: 523.3 [MH
'H NMR Spectrum: (DMSOd6) 1.40 (s, 9H); 1.80 (m, IH); 1.98 (m, 3H); 2.40 (s, 3H); 3.98
(s, 3H); 4.19 (m, 3H); 6.22 (s, IH); 6.97 (t, IH); 7.14 (d, IH); 7.43 (br s, IH); 7.59 (s, IH);
8.48 (s, IH); 11.29 (br s, IH)
Using an analogous procedure to that described for the preparation of the starting
material in Example 11, rerr-butyl (2S)-2-[(4-[(4-fluoro-2-methyl-l#-indol-5-yl)oxy]-6-
methoxyquinazolk-7-yloxy)iriethyl]pyrrolidine-l-carboxylate (170mg, 0.33mmol) was reacted
with hydrogen chloride in dioxane. The solid was dissolved in methanol and absorbed onto an
Isolute SCX column which was washed through with methanol and then the product was
eluted with 7N ammonia in methanol to give 4-[(4-fluoro-2-methyl-l#-indol-5-yl)oxy]-6-
rnethoxy-7-[(23>pyrrolidrn-2-ylmethoxy]qumazoline (128mg, 93%).
MS-ESI: 423.5 [MH]+
'H NMR Spectrum: (DMSOd6) 1.53 (m, IH); 1.71 (m, 2H); 1.88 (m, IH); 2.40 (s, 3H); 2.84
(m, 2H); 3.52 (m, IH); 3.98 (s, 3H); 4.04 (d, 2H); 6.22 (s, IH); 6.97 (t, IH); 7.14 (d, IH);
7.37 (s, IH); 7.59 (s, IH); 8.47 (s, IH); 11.30 (br s, IH)
Example 13
Using an analogous procedure to that described for the preparation of Example 11, 4-
[(4-fluoro-2-methyl-l/7-indol-5-yl)oxy]-6-methoxy-7-t(2J?)-pyrrolidin-2-
ylmethoxy]quinazoline (160mg, 0.38mmol) was reacted with acetyl chloride (32 jil,
0.46mmol). The crude product was purified by column chromatography eluting with
methanol/methylene chloride (2/98) to give 7-[(2J?)-l-acetylpyrrolidin-2-ylmethoxy]-4-[(4-
fluoro-2-methyl-l.£Mndol-5-yl)oxy]-6-methoxyqiiinazoIine (82mg, 46%).
MS-ESI: 465.6 [MH]+
'H NMR Spectrum: (100°C, DMSOd6) 2.02 (m, 7H); 2.41 (s, 3H); 3.50 (m, 2H); 4.00 (s, 3H),
4.29 (m, 3H); 6.22 (s, IH); 6.95 (t, IH); 7.14 (d, IH); 7.43 (s, IH); 7.63 (s, IH); 8.47 (s, IH);
11.02(brs, IH)
The starting material was prepared as follows:
Using an analogous procedure to that described for tlie preparation of the starting
material in Example 11, terr-butyl (2£)-2-(hydroxymethyl)pyrrolidine-l-carboxylate (1.48g,
7.37 mmol) was reacted with 4-(4-fiuoro-2-methylindol-5-yloxy)-7-hydroxy-6-
methoxyquinazoline (l.Og, 2.95mmol), (prepared as described for the starting material in
Example 7), and the product purified by column chromatography, eluting with
methanol/methylene'chloride (1/9) containing 0.1% triethylainine to give terf-butyl (2i?)-2-[(4-
[(4-fluoro-2-methyl-l^-indol-5-yl)oxy]-6-methoxyquinazolin-7-yloxy)methyl]pyrrolidine-lcarboxylate
(970mg, 62%).
MS-ESI: 523.3 [MH]+
'H NMR Spectrum: (DMSOd6) 1.40 (s, 9H); 1.80 (m, 1H); 1.98 (m, 3H); 2.40 (s, 3H); 3.98
(s, 3H); 4.19 (in, 3H); 6.22 (s, 1H); 6.97 (t, 1H); 7.14 (d, 1H); 7.43 (br s, 1H); 7.59 (s, 1H);
8.48 (s,lH); 11.29 (brs, 1H)
Using an analogous procedure to that described for the preparation of the starting
material in Example 11, te/t-butyl (2fl)-2-[(4-[(4-fluoro-2-methyl-l#-indol-5-yl)oxy]-6-
methoxyquinazoHn-7-yloxy)methyl]pyrrolidine-l-carboxylate (960mg, 1.84mmol) was reacted
with hydrogen chloride in dioxane. The solid was dissolved in methanol and absorbed onto an
Isolute SCX column which was washed through with methanol and then the product was
eluted with 7N ammonia in methanol to give 4-[(4-fluoro-2-methyl-l/?-indol-5-yl)oxy]-6-
methoxy-7-[(2jR)-pyrrolidin-2-ylmethoxy]quinazoHne (480mg, 62%).
MS-ESI: 423.5 [MH]+
'H NMR Spectrum: (DMSOd6) 1.53 (m, 1H); 1.71 (m, 2H); 1.88 (m, 1H); 2.40 (s, 3H); 2.84
(m, 2H); 3.52 (m, 1H); 3.98 (s, 3H); 4.04 (d, 2H); 6.22 (s, 1H); 6.97 (t, 1H); 7.14 (d, 1H);
7.37 (s, 1H); 7.59 (s, 1H); 8.47 (s, 1H); 11.30 (br s, 1H)
Example 14
4-[(4-Fluoro-2-methyl-l/7-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-
y]methoxy)quinazoline (180mg, 0.41mmol), (prepared as described for the starting material in
Example 11), was suspended in tetrahydrofuran (15ml), and diisopropylethylamine (108/il,
0.45mmol) and 2,2,2-trifluoroethyl trifluoromethanesulphonate (98mg, 0.62mmol) were
added. The mixture was heated at reflux for 1.5 hours. Diisopropylethylamine (36^1,
0.21mmol) and 2,2,2-trifiuoroethyl trifluoromethanesulphonate (45mg, 0.21mmol) were added
and the mixture was heated at reflux for a further 2 hours. The mixture was concentrated
under reduced pressure and column chromatography of the residue, eluting with 1 %
methanol/methylene chloride gave a sticky solid. This was triturated with diethyl ether and
filtered to give 4-[(4-fluoro-2-methyl-l.Hr-indol-5-yl)oxy]-6-inethoxy-7-[l-(2,2,2-
trifluoroethyl)piperidin-4-yImethoxy]quinazoIine (93mg, 44%).
MS-ESI.-519.1 [MH]+
'H NMR Spectrum: (DMSOd6) 1.40 (m, 2H); 1.80 (m, 3H); 2.36 (m, 5H); 2.95 (br d, 2H);
3.14 (m, 2H); 3.98 (s, 3H); 4.06 (d, 2H); 6.22 (s, IH); 6.96 (t, IH); 7.14 (d, IH); 7.36 (s, IH);
7.58 (s, IH); 8.48 (s, IH); 11.29 (brs, IH)
Example 15
Using an analogous procedure to that described for the preparation of Example 14, 4-
[(4-fluoro-2-methyl-l^T-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-l-ylpropoxy)quinazoune
(250mg, 0.54mmol) was reacted with 2,2,2-trifluoroetbyl trifluoromethanesulphonate (128mg,
0.59mmol) and purified by column chromatography, eluting with 5% methanol/methylene
chloride to give a sticky solid. The sticky solid was dissolved hi methanol and absorbed onto
an Isolute SCX column. The column was washed with methanol and eluted with 7N ammonia
in methanol. The product was triturated in ether/isohexane and filtered to give 4-t(4-fluoro-2-
methyl-lfir-indol-5-yl)oxy]-6-methoxy-7-{3-[4-(2,2,2-trifluoroethyl)piperazin-lyl]
propoxy}quinazoline (130mg, 44%).
MS-ESI: 548.6 [MH]+
-120-
'H NMR Spectrum: (DMSOd6) 1.95 (m, 2H); 2.40 (rn, 9H); 2.62 (m, 4H); 3.12 (q, 2H); 3.97
(s, 3H); 4.22 (t, 2H); 6.22 (s, IH); 6.96 (t, IH); 7.14 (d, IH); 7.36 (s, IH); 7.58 (s, IH); 8.47
(s, IH); 11.29 (brs, IH)
The starting material was prepared as follows:
A mixture of 1-terr-butoxycarbonylpiperazine (l.Og, 5.37mmol), 3-bromo-l-propanol
(0.49ml, 5.37mmol) and potassium carbonate (1.86g, 13.4mmol) was heated at reflux in
acetonitrile (10ml) for 1.5 hours. The mixture was concentrated under reduced pressure and
column chromatography of the residue, eluting with 2% methanol/methylene chloride, gave 1-
terZ-butoxycarbonyl-4-(3-hydroxypropyl)piperazine (1.2g, 91%).
!H NMR Spectrum: (CDC13) 1.46 (s, 9H); 1.74 (m, 2H); 2.46 (m, 4H); 2.61 (t, 2H); 3.43 (m,
4H); 3.80 (t, 2H)
Using an analogous procedure to that described for the preparation of the starting
material in Example 11, l-/err-butoxycarbonyl-4-(3-hydroxypropyl)piperazine (432rng,
1.77mmol) was reacted with 4-[(4-fluoro-2-methyl-l//-indol-5-yl)oxy]-7-hydroxy-6-
methoxyquinazoline (500rng, 1.47mmol), (prepared as described for the starting material in
Example 7). The product was purified by column chromatography, eluting with 2%-5%
methanol/methylene chloride to give tert-butyl 4-[3-(4-[(4-fluoro-2-methyl-l/7-indol-5-
yl)oxy]-6-methoxyquinazoun-7-yloxy)propyl]piperazine-l-carboxylate (582mg, 70%).
LC-MS (ESI) 1.67mm, 100%, 566.7 [MH]+
1H NMR Spectrum: (DMSOd6) 1.38 (s, 9H); 1.97 (m, 2H); 2.24-2.35 (rn, 6H); 2.46 (s, 3H);
3.31 (m, 4H); 3.97 (s, 3H); 4.24 (t, 2H); 6.22 (s, IH); 6.96 (t, IH); 7.14 (d, IH); 7.37 (s, IH);
7.58 (s, IH); 8.48 (s, IH); 11.29 (brs, IH)
Using an analogous procedure to that described for the preparation of the starting
material in Example 11, /erf-butyl 4-[3-(4-[(4-fluoro-2-methyl-l#-indol-5-yl)oxy]-6-
methoxyquinazoun-7-yloxy)propyl]piperazine-l-carboxylate was reacted with hydrogen
chloride in dioxane. The crude product was absorbed onto an Isolute SCX column, washing
with methanol and eluting with 7N ammonia in methanol to give 4-[(4-fluoro-2-methyl-1#-
indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-l-ylpropoxy)quinazoUne (96%) as a pale orange
foam.
MS-ESI 466.5 [MHf
JH NMR Spectrum: (DMSOd6) 1.96 (m, 2H); 2.30 (m, 4H); 2.40 (m, 5H); 2.69 (m, 4H), 3.97
(s, 3H); 4.23 (t, 2H); 6.22 (s, IH); 6.96 (t, IH); 7.13 (d, IH); 7.37 (IH, s); 7.58 (s, IH); 8.49
(s, lH);11.32(brs, IH)
Example 16
Using an analogous procedure to that described for the preparation of Example 14,
2,2,2-trifluoroethyl trifluoromethanesulphonate was reacted with 4-[(4-fluoro-2-methyl-l//-
indol-5-yl)oxy]-6-methoxy-7-(2-piperazin-l-ylethoxy)quinazoline. The product was purified
by column chromatography, eluting with 5% inethanol/methylene chloride to give a sticky
solid. The sticky solid was dissolved in methanol and absorbed onto an Isolute SCX column,
washed with methanol and eluted with 7N ammonia in methanol. The product was
concentrated from ether to give 4-[(4-fluoro-2-methyl-lff-indol-5-yl)oxy]-6-methoxy-7-{3-
[4-(2,2,2-trifluoroethyI)piperazin-l-yl]ethoxy}quinazoIine.
MS-ESI: 534.2 [MH]+
'H NMR Spectrum: (DMSOd6) 2.40 (s, 3H); 2.55 (m, 4H); 2.63 (m, 4H); 2.79 (t, 2H); 3.13
(q, 2H); 3.97 (s, 3H); 4.29 (t, 2H); 6.22 (s, IH); 6.97 (t, IH); 7.14 (d, IH); 7.41 (s, IH); 7.58
(s, IH); 8.48 (s, IH); 11.29 (br s, IH)
Example 17
A mixture of 7-(2-bromoethoxy)-4-[(4-fluoro-2-methyl-l#-indol-5-yl)oxy]-6-
methoxyquinazoline (150mg, 0.36mmol), l-(2-fluoroethyl)piperazine di-trifluoroacetic acid
salt (240mg, 0.67mmol) and diisopropylethylamine (293/il, 1.68mmol) in N,Ndimethylfonnamide
(3ml) was stirred overnight at ambient temperature. The mixture was
-122-
dUuted with ethyl acetate, washed with brine (x2), dried (MgSO4) and concentrated under
reduced pressure. Column chromatography of the residue, eluting with 4%
methanol/inethylene chloride gave 7-{2-[4-(2-fluoroethyl)piperazin-l-yl]ethoxy}-4-[(4-
fluoro-2-methyl-lJf7-indol-5-yl)oxy]-6-rnethoxyquinazoIine (50mg, 30%),
MS-ESI: 498.6 [MH]+
1H NMR Spectrum: (DMSOd6) 2.42 (s, 3H); 2.64 (t, 1H); 2.81 (t, 2H); 4.00 (s, 3H); 4.32 (t,
2H); 4.47 (t, 1H); 4.59 (t, 1H); 6.25 (s, 1H); 6.99 (t, 1H); 7.17 (d, 1H); 7.44 (s, 1H); 7.61 (s,
1H); 8.50 (s, 1H); 11.32 (br s, 1H)
The starting material was prepared as follows:
A suspension of 4-[(4-fluoro-2-methyl-l#-indol-5-yl)oxy]-7-hydroxy-6-
methoxyquinazoline (530 mg, 1.56 mmol), (prepared as described for the starting material in
Example 7), in methylene chloride (15 ml) was treated with triphenylphosphine (570 mg, 2.18
mmol), 2-bromoethanol (300 mg, 2.40 mmol) and diisopropyl azodicarboxylate (380 mg, 1.88
mmol) and the mixture stirred at ambient temperature for 2 hours. The crude reaction mixture
was loaded onto a silica column and eluted using ethyl acetate as solvent. The relevant
fractions were combined and evaporated under vacuum to give a residue, which was triturated
with ether, filtered and dried. This gave 7-(2-bromoethoxy)-4-[(4-iluoro-2-methyl-l#-indol-
5-yl)oxy]-6-methoxyquinazoline as a white solid (546 mg, 78%).
XH NMR Spectrum: (DMSOd6) 2.40 (s, 3H), 3.90 (t, 2H), 3.99 (s, 3H), 4.56 (t, 2H), 6.21 (s,
1H), 6.97 (t, 1H), 7.16 (d, 1H), 7.42 (s, 1H), 7.62 (s, 1H), 8.49 (s, 1H) and 11.29 (s, 1H)
MS (ESI) : 446 and 448 (MH)+
A mixture of l-(/erf-butoxycarbony])piperazine (5g), l-bromo-2-fluoroethane (S.llg),
potassium carbonate (9.26 g) and acetonitrile (60 ml) was stirred and heated tq 60°C for 4
hours. The reaction mixture was cooled to ambient temperature and filtered and the filtrate
was evaporated. The residue was purified by column chomatography on silica using
increasingly polar mixtures of isohexane and ethyl acetate as eluent. There was thus obtained
4-(fm-butoxycarbonyl)-l-(2-fiuoroethyl)piperazine as a solid (3.7 g).
'H NMR Spectrum: (DMSOd6 and CD3C02D) 1.37 (s, 9H), 2.34-2.4 (m, 4H), 2.56 (t, 1H),
2.67 (t, 1H), 3.25-3.34 (m, 4H), 4.42 (t, 1H), 4.58 (t, 1H)
Trifiuoroacetic acid (20 ml) was added to a mixture of 4-(£ert-butoxycarbonyl)-l-(2-
fluoroethyl)piperazine (3.7 g), triethylsilane (8 ml) and methylene chloride (100 ml) and the
resultant mixture was stirred at ambient temperature for 1.5 hours. The mixture was
evaporated and the residue was triturated under diethyl ether. The solid so obtained was
isolated, washed with diethyl ether and dried to give l-(2-fluoroethyl)piperazine trifluoroacetic
acid salt (6.0 g) as a solid.
'H NMR Spectrum: (DMSOd* and CD3CO2D) 3.0-3.31 (m, 10H), 4.59 (in, IH), 4.75 (in, IH)
Example 18
A mixture of 7-[2-(2-bromoethoxy)ethoxy]-6-methoxy-4-(4-fluoro-2-methylindol-5-
yloxy)quinazoline (165mg, 0.38mmol) and 1-acetylpiperazine (129mg, l.Olmmol) inN.Ndimethylformamide
(4ml) was stirred overnight at ambient temperature. The mixture was
diluted with ethyl acetate, washed with brine (x2), dried (MgS04) and concentrated under
reduced pressure. Column chromatography of the residue, eluting with 5% 7N ammonia in
methanol/methylene chloride gave 7-{2-[2-(4-acetylpiperazin-l-yl)ethoxy]ethoxy}-4-[(4-
fluoro-2-methyl-l/T-indol-5-yl)oxy]-6-methoxyquina2:oline (130rng, 72%).
MS-ESI: 538.6 [MH]+
'H NMR Spectrum: (DMSOd6) 1.94 (s; 3H); 2.38 (m, 7H); 3.37 (m, 4H); 3.63 (t, 2H); 3.82
(br t, 2H); 3.98 (s, 3H); 4.33 (br t; 2H); 6.22 (s, IH); 6.97 (t, IH); 7.14 (d, IH); 7.41 (s, IH);
7.60 (s, IH); 8.48 (s, IH); 11.29 (brs, IH)
The starting material was prepared as follows :
Using an analogous procedure to that described for the preparation of the starting
material in Example 11, 2-(2-bromoethoxy)ethanol, (600mg, 3.54 mmol) (J. Org. Chern.,
7697, 58, 1993), was reacted with 4-[(4-fluoro-2-methyl-l#-mdol-5-yl)oxy]-7-hydroxy-6-
rnethoxyquinazoline (l.Og, 2.95mmol), (prepared as described for the starting material in
Example 7). The crude product was purified by column chromatography, eluting with
methanol/methylene chloride (1/98 followed by 2/98) to give the expected product
contaminated by triphenylphosphine oxide. This was crystallised from methanol to give 7-[2-
(2-bromoethoxy)ethoxy]-6-methoxy-4-(4-fluoro-2-methyhndol-5-yloxy)quinazoune (675mg,
47%).
MS-ESI: 492.4 [Miff
H NMR Spectrum: (DMSOd6) 2.40 (s, 3H); 3.63 (t, 2H); 3.85 (t, 2H); 3.90 (br t, 2H), 3.98
(s, 3H); 4.34 (br t, 2H); 6.22 (s, IH); 6.97 (t, IH); 7.14 (d, IH); 7.41 (s, IH); 7.60 (s, IH);
8.48 (s, lH);11.29(brs, IH)
Example 19
DIPEA, 'PrC(O)CI
Diisopropylethylamine (72/il, 0.41mrnol) and isobutyryl chloride (44mg, 0.41mmol), in
methylene chloride (0.5ml) were added to a suspension of 4-[(4-fluoro-2-methyl-l#-indol-5-
yl)oxy]-6-methoxy-7-(piperidin-4-yknethoxy)quinazoline (150mg, 0.34mmol), (prepared as
described for the starting material in Example 11), in methylene chloride (4ml). After a few
minutes all the material had gone into solution. The mixture was stirred for 3 hours at ambient
temperature, washed with saturated sodium hydrogen carbonate solution, dried (MgSO,)) and
concentrated under reduced pressure. Column chromatography of the residue, eluting with 2%
rnethanol/methylene chloride gave 4-[(4-fluoro-2-methyl-lHr-indol-5-yl)oxy]-7-[(lisobutyrylpiperidin-
4-yl)methoxy]-6-rnethoxyquinazoline (90mg, 52%).
MS-ESI: 507.5 [MH]+
'H NMR Spectrum: (DMSOd6) 0.99 (d, 6H); 1.20 (m, 2H); 1.85 (br t, 2H); 2.13 (m, IH); 2.40
(s, 3H); 2.58 (br t, IH); 2.87 (m, IH); 3.07 (br t, IH); 3.98 (m, 4H); 4.08 (br d, 2H); 4.44 (br
d, IH); 6.22 (s, IH); 6.96 (t, IH); 7.14 (d, IH); 7.37 (s, IH); 7.58 (s, IH); 8.48 (s, IH); 11.29
(br s, IH)
Example 20
Using an analogous procedure to that described for the preparation of Example 19, 4-
[(4-fluoro-2-methyl-l^-indol-5-yl)oxy]-6-methoxy-7-[(25)-pyrrolidin-2-
y]methoxy]quinazo]ine (150mg, 0.36mmol), (prepared as described for the starting material in
Example 12), was reacted with isobutyryl chloride (45 /il, 0.43mmol). The product was
purified by column chromatography, eluting with methanol/methylene chloride (2/98) to give
4-[(4-fluoro-2-methyl-Lff-indol-5-yl)oxy]-7-{[(25)-l-isobutyrylpyrroHdin-2-yI]methoxy}-
6-methoxyquinazoline (95mg, 54%).
MS-ESI: 493.2 [MH]+
'H NMR Spectrum: (100°C, DMSOd6) 1.03 (m, 6H); 2.02 (m, 4H); 2.41 (s, 3H); 2.72 (m,
IH); 3.54 (in, 2H); 3.99 (s, 3H); 4.26 (m, 2H); 4.39 (m, IH); 6.22 (s, IH); 6.95 (t, IH); 7.14
(d, IH), 7.44 (s, IH); 7.62 (s, IH); 8.46 (s, IH); 11.02 (br s, IH)
Example 21
DIPEA, 'PrC(O)CI
Using an analogous procedure to that described for the preparation of Example 19, 4-
[(4-fluoro-2-rnethyl-lfl'-indol-5-yl)oxy]-6-met]ioxy-7-[(27?)-pyiTolidin-2-
ylrnethoxy]quinazoline (160mg, 0.38mmol), (prepared as described for the starting material in
Example 13), was reacted with isobutyryl chloride (48 /il, 0.45mmol). The product was
purified by column chromatography, eluting with niethanol/niethylene chloride (2/98) to give
4-[(4-fluoro-2-methyl-l//-indol-5-yl)oxy]-7-{[(2fi)-l-isobutyr)7JpyiToIidin-2-yl]methoxy}-
6-methoxyquinazoline (120mg, 64%).
MS-ESI: 493.2 [MH]+
-126-
JH NMR Spectrum: (100°C, DMSOd6) 1.03 (m, 6H); 2.02 (m, 4H); 2.41 (s, 3H); 2.72 (m,
1H); 3.54 (m, 2H); 3.99 (s, 3H); 4.26 (m, 2H); 4.39 (m, 1H); 6.22 (s, 1H); 6.95 (t, 1H); 7.14
(d, 1H), 7.44 (s, 1H); 7.62 (s, 1H); 8.46 (s, 1H); 11.02 (br s, 1H)
Example 22
Diisopropylethylamine (72/xl, 0.41mmol) and rnethanesulphonyl chloride (32/il,
0.41mmol) were added to a suspension of 4-[(4-fluoro-2-methyl-l#-indol-5-y])oxy]-6-
methoxy-7-(piperidin-4-ylmethoxy)quinazoline (150mg, 0.34mmol), (prepared as described for
the starting material in Example 11), in methylene chloride (4ml). After a few minutes all the
material had gone into solution. The mixture was stirred for 3 hours at ambient temperature,
washed with saturated sodium hydrogen carbonate solution, dried (MgSCU) and concentrated
under reduced pressure. The solid was suspended in methanol and filtered to give 4-[(4-
fluoro-2-methyl-lH-indoI-5-yl)oxy]-6-methoxy-7-{[l-(methylsulfonyI)piperidin-4-
y]]methoxy}quinazoline (83mg, 47%).
MS-ESI: 515.5 [MH]+
'H NMR Spectrum: (DMSOd6) 1.41 (m, 2H); 1.95 (m, 3H); 2.40 (s, 3H); 2.77 (br t, 2H); 2.85
(s, 3H); 3.60 (br t, 2H); 3.98 (s, 3H); 4.12 (br d, 2H); 6.22 (s, 1H); 6.97 (t, 1H); 7.14 (d, 1H);
7.39 (s, 1H); 5.59 (s, 1H); 8.48 (s, 1H); 11.29 (br s, 1H)
Example 23
Using an analogous procedure to that described for the preparation of Example 22, 4-
[(4-fluoro-2-niethyl-l^r-indol-5-yl)oxy]-6-methoxy-7-[(25)-pyrrou'din-2-
ylmethoxyjquinazoline (150mg, 0.36mmol), (prepared as described for the starting material in
Example 12), was reacted with methanesulphonyl chloride (33 /d, 0.43 mmol). The product
was purified by column chromatography, eluting with methanol/methylene chloride (2/98) to
give4-[(4-fluoro-2-methyl-l/:r-indoI-5-yl)oxy]-6-methoxy-7-{[(25)-l-
(methylsulfonyl)pyrrolidin-2-yl]meth.oxy}quinazoline (105 mg, 59%).
MS-ESI: 501.6 [MH]+
'H NMR Spectrum: (100°C, DMSOd6) 2.02 (m, 4H); 2.41 (s, 3H); 3.38 (br t, 2H); 4.00 (s,
3H); 4.19 (m, 2H); 4.30 (dd, IH); 6.22 (s, IH); 6.96 (t, IH); 7.14 (d, IH); 7.40 (s, IH); 7.64
(s, IH); 8.47 (s, IH); 11.02 (br s, IH)
Example 24
DIPEA, MeSCLCI
0'Using an analogous procedure to that described for the preparation of Example 22, 4-
[(4-fluoro-2-methyl-l//-indol-5-yl)oxy]-6-methoxy-7-[(2J?)-pyrrolidin-2-
ylmethoxyjquinazoline (160mg, 0.38 mmol), (prepared as described for the starting material in
Example 13), was reacted with methanesulphonyl chloride (35 fJ.1, 0.45 mmol). The product
was purified by column chromatography, eluting with methanol/methylene chloride (2/98) to
give4-[(4-fluoro-2-methyl-lH-indol-5-yl)oxy]-6-methoxy-7-{[(2J?)-l-
(tnethylsulfonyl)pyrrolidin-2-yI]methoxy}quinazoline (108mg, 57%).
MS-ESI: 501.6 [MH]+
]H NMR Spectrum: (100°C, DMSOd6) 2.02 (m, 4H); 2.41 (s, 3H); 3.38 (br t, 2H); 4.00 (s,
3H); 4.19 (m, 2H); 4.30 (dd, IH); 6.22 (s, IH); 6.96 (t, IH); 7.14 (d, IH); 7.40 (s, IH); 7.64
(s, IH); 8.47 (s, IH); 11.02 (br s, IH)
Example 25
A mixture of 7-[3-(4-allylpiperazin-l-yl)propoxy]-4-cnloro-6-methoxyquinazoline (288
nig, 0.76 mmol), 5-hydroxy-7-azaindole (113 mg, 0.84 mmol), (prepared as described for the
starting material in Example 2), and potassium carbonate (116 mg, 0.84 mmol) in DMA (8 ml)
was stirred at 85°C for 3 hours and allowed to cool to ambient temperature. The mixture was
filtered, the filtrate evaporated under vacuum and the residue purified by column
chromatography eluting with methylene chloride/methanol (saturated with ammonia)
(100/8/1). The volatiles were removed under vacuum to give a white solid which was
triturated with diethyl ether, filtered and dried to give 7-[3-(4-aUylpiperazm-l-yl)propoxy]-4-
(7-azaindol-5-yloxy)-6-rnethoxyquinazoline (280 mg, 77%).
MS-ESI: 475 [MHf
'H NMR Spectrum: (CDC13) 2.14 (m, 2H); 2.53 (m, 8H); 2.59 (t, 2H), 3.03 (d, 2H); 4.07 (s,
3H); 4.29 (t, 2H); 5.20 (m, 2H); 5.89 (m, IH); 6.55 (m, IH); 7.35 (s, IH); 7.40 (m, IH); 7.61
(s, IH); 7.86 (d, IH); 8.30 (d, IH); 8.60(s, IH); 9.68 (s, IH).
The starting material was prepared as follows:
To a suspension of 4-chloro-7-hydroxy-6-methoxyquinazoune (300 mg, 1.43 mmol),
(prepared as described for the starting material in Example 4), in methylene chloride (15 ml)
was added triphenylphosphine (522 mg, 2.0 mmol), 3-(4-allylpiperazin-l-yl)propan-l-ol (288
mg, 1.57 mmol), (DE 2755707), and dusopropyl azodicarboxylate (336 ul, 1.71 mmol) and the
mixture stirred at ambient temperature for 2 hours. The crude reaction mixture was loaded
directly onto a silica chromatography column and eluted with methylene chloride/methanol
(95/5). The volatile solvents were removed under vacuum to give 7-[3-(4-allylpiperazin-lyl)
propoxy]-4-chloro-6-methoxyquinazoline as an oil which crystallised on standing (480 mg,
89%).
MS-ESI: 377-379 [MHf
'H NMR Spectrum: (CDC13) 2.12 (m, 2H); 2.51 (m, 8H); 2.57 (t, 2H); 3.01 (d, 2H); 4.05 (s,
3H); 4.27 (t, 2H); 5.16 (m, 2H); 5.87 (m, IH); 7.34 (s, IH); 7.38 (s, IH); 8.85 (s, IH)
(Figure Remove)l-Prop-2-ynylpiperaziae diTFA salt (329 mg, 0.94 mmol) and potassium carbonate
(258 mg, 1.87 mmol) were added to a solution of 7-(3-bromopropoxy)-4-[(4-fluoro-2-
methyh'ndol-5-y])oxy]-6-methoxyquinazoline (144 mg, 0.31 mmol), (prepared as described for
the starting material in Example 7), in DMA (3.6 ml). The reaction mixture was stirred at
-130-
85°C ovemiglit before being filtered. The filtrate was concentrated under vacuum and the
crude product was purified by column chroinatography eluting with increasingly polar mixtures
of ammonia/methanol in methylene chloride (1 to 7%). A second purification by column
chromatography eluting with a mixture of methanol in methylene chloride (1/9) gave 4-[(4-
fluoro-2-methylindol-5-yl)oxy]-6-methoxy-7-{3-[4-(2-propynyl)piperazin-lyl]
propoxy}quinazoline as a white solid (115 mg, 73%).
MS-ESI : 504 [MH]+
*H NMR Spectrum: (DMSOd6) 1.96 (m, 2H); 2.39 (s, 3H); 2.42 (m, 2H); 2.45 (m, 4H); 3.09
(t, 1H); 3.22 (d, 2H);'3,28 (m, 4H); 3.97 (s, 3H); 4.22 (t, 2H); 6.22 (s, 1H); 6.96 (t, 1H); 7.14
(d, 1H); 7.36 (s, 1H); 7.58 (s, 1H); 8.47 (s, 1H); 11.29 (br s, 1H)
The starting material was prepared as follows :
Potassium carbonate (1.04 g, 7.5 mmol) and propargyl bromide (654 mg, 5.5 mmol)
were added to a. solution of tot-butyl-1-piperazinecarboxylate (931 mg, 5.0 mmol) in acetone
(5 ml). The reaction mixture was heated at 60°C for 1 hour, and then filtered to remove the
inorganics. The solvent was removed under vacuum to give a crude product which was
purified by column chromatography (10-30% ethyl acetate/hexane) yielding
4-propargylpiperazine-l-carboxylic acid /erf-butyl ester (894 mg, 80%).
'H NMR Spectrum: (CDC13) 1.46 (s, 9H); 2.25 (t, 1H); 2.51 (t, 4H); 3.31 (d, 2H); 3.47 (t, 4H)
Trifluoroacetic acid (5 ml, mmol) was added to a solution of 4-propargylpiperazine-lcarboxylic
acid te/t-butyl ester (559 mg, 2.5 mmol) in methylene chloride (2 ml). The reaction
mixture was stirred at ambient temperature for 40 minutes before the solvent was removed
under high vacuum. The residue was azeotroped with ethanol yielding l-prop-2-yn-lylpiperazine
di-trifluoroacetic salt ( 865 mg, 98%) as a white solid.
MS-EI 125 [MH]+
'H NMR Spectrum: (DMSOd6) 2.91 (t, 4H); 3.20 (t, 4H); 3.45 (t, 1H); 3.64 (d, 2H); 8.88 (br
s,lH)
Example 27
Diisopropyl azadicarboxylate (230 ul, 1.17 rmnol) was added drop wise to a solution, of
3-[4-(2-fluoroethyl)piperazin-l-yI]propan-l-ol (203 mg, 1.07 mmol), triphenylpliosphine (357
mg, 1.36 rmnol) and 4-[(4-f]uoro-2-niethyl-l#-indol-5-yl)oxy]-7-hydroxy-6-
methoxyquinazoline (330 mg, 0.97 rnniol), (prepared as described for the starting material in
Example 7), in dichloromethane (8.5 ml). The reaction mixture was stirred at ambient
temperature for 1.5 hours and then loaded directly onto a silica column, eluting with a mixture
of methanol in methylene chloride (11/89) to give 7-{3-[4-(2-fluoroethyI)piperazin-lyl]
propoxy}-4-[(4-fluoro-2-methyl-lflr-indol-5-yI)oxy]-6-methoxyquinazoline(413 mg,
83%) as a white solid.
MS-ESI: 512 [MEf
'H NMR Spectrum: (DMSOd6) 1.96 (m, 2H); 2.40 (s, 3H); 2.43 (m, 4H); 2.45 (m, 4H); 2.48
(m, 2H); 2.58 (dt, 2H); 3.97 (s, 3H); 4.23 (t, 2H); 4.50 (dt, 2H); 6.22 (s, 1H); 6.97 (t, 1H);
7.14 (d, 1H); 7.36 (s, 1H);7.58 (s, 1H); 8.48 (s, 1H); 11.29 (brs, 1H)
The starting material was prepared as follows:
Potassium carbonate (1.85 g, 13.4 mmol) and l-bromo-2-fluoroethane (440 ul, 5.9
mmol) were added to a solution of /er/-butyl-l-piperazinecarboxylate (1 g, 5.4 mmol) in
acetonitrile (12 ml). The reaction mixture was stirred at 65°C for 3.5 hours after which time
more l-bromo-2-fluoroethane (160 pi, 2.1 mmol) was added. The reaction was heated for a
further 3 hours then filtered to remove the inorganic solids. The filtrate was concentrated and
the crude product was purified using column chromatography eluting with ethyl acetate to give
4-(2-fluoroethyl)-piperazine-l-carboxylic acid tert-butyl ester (714 mg, 57%).
MS-ESI: 233 [MH]+
'H NMR Spectrum: (CDC13) 1.46 (s, 9H); 2.50 (t, 4H); 2.70 (dt, 2H); 3.45 (t, 4H); 4.57 (dt,
2H)
Trifluoroacetic acid (3ml, 17.5rnrnol) was added to a solution of 4-(2-fluoroethyl)-
piperazine-1-carboxylic acid re/f-butyl ester (350 mg, 1.5 mmol) in methylene chloride (12 ml).
The reaction mixture was stirred at ambient temperature for 40 minutes, before the solvent was
evaporated under high vacuum. The residue was azeotroped with toluene to give l-(2-
fluoroethyl)-piperazine diTFA salt (377 mg, 96%).
MS-EI: 133 [MH]+ '
JH NMR Spectrum: (DMSOd6) 3.06 (s, 4H); 3.17 (in, 2H); 3.25 (m, 4H); 4.67 (dt, 2H); 9.03
(br s, 1H)
3-Bromopropan-l-ol (581 mg, 4.18 mmol) and potassium carbonate (2.88 g, 20.9
rnniol) were added to a solution of l-(2-fluoroethyl)-piperazine diTFA salt (1.5 g, 4.18 mmol)
in acetonitrile (11 ml). The reaction mixture was stirred at 85°C for 4 hours and then loaded
directly onto a column and eluted with a mixture of methanol in rnethylene chloride (7/93) to
give 3-[4-(2-fluoroethyl)piperazin-l-yl]propan-l-ol (721 mg, 91%).
MS-EI: 191 [MH]+
'H NMR Spectrum: (CDC13) 1.72 (m, 2H); 2.58 (m, 8H) 2.62 (m, 2H); 2.73 (t, 2H); 3.79 (t,
2H); 4.55 (dt, 2H)
Example 28
A mixture of 7-[2-(4-acetylpiperazin-l-yl)ethoxy]-4-chloro-6-methoxyquinazoline
(12.24g, 33.5mmol), 4-fluoro-5-hydroxy-2-methylindole (5.54g, 33.5mmol), (prepared as
described for the starting material in Example 1), and potassium carbonate (4.64g, 33.5mmol)
was heated in N, N-dimethylacetamide (150ml) at 85°C for 4 hours. 4-Fluoro-5-hydroxy-2-
methylindole (33mg, 0.2mmol) and potassium carbonate (108mg, 57%) were added and the
mixture heated for a further 1 hour at 85°C and then stirred at ambient temperature overnight.
The mixture was filtered and concentrated under reduced pressure. The residue was purified
by column chromatography eluting with methylene chloride/methanol (95/5) to give a white
solid which was suspended in acetone (150ml) and heated at reflux for 1 hour. After cooling
the mixture was filtered and the solid dried in air to give 7-[2-(4-acetylpiperazin-lyl)
ethoxy]-4-[(4-fluoro-2-methyl-lJ?-indol-5-yl)oxy]-6-methoxyquinazoIine (lOg, 60%) as
a white solid.
'H NMR Spectrum: (DMSOd6) 2.00 (s, 3H); 2.42 (s, 3H); 2.52 (t, 2H); 2.56 (br t, 2H); 2.85
(t, 2H); 3.45 (m, 4H); 4.00 (s, 3H); 4.35 (t, 2H); 6.25 (s, 1H), 6.99 (t, 1H); 7.17 (d, 1H); 7.45
(s, 1H); 7.62 (s, 1H); 8.51 (s, 1H); 11.32 (br s, 1H)
MS-ESI: 494.3 [M+H]+
The starting material was prepared as follows :
A suspension of 4-chloro-7-hydroxy-6-methoxyquinazoline (222 mg, 1.05 mmol),
(prepared as described for the starting material in Example 4), in methylene chloride (12 ml)
was treated with triphenylphosphine (389 mg, 1.48 mmol), 2-(4-acety]piperazin-l-yl)ethanol
(200 mg, 1.16 mmol) and diisopropyl azodicarboxylate (255 mg, 1.26 mmol) and the mixture
stirred at ambient temperature for 2.5 hours. The crude reaction mixture was loaded onto a
silica column and eluted using-methylene chloride/methanol (saturated with ammonia) (92/8).
The relevant fractions were combined and evaporated under vacuum to give a residue, which
was triturated with acetone, filtered and dried. This gave 7-[2-(4-acetylpiperazin-l-yl)ethoxy]-
4-chloro-6-methoxyquinazoline as a white solid (240 mg, 62%).
1U NMR Spectrum: (DMSOd6) 1.97 (s, 3H), 2.50 (m, 4H), 2.82 (t, 2H), 3.41 (m, 4H), 3.98
(s, 3H), 4.32 (t, 2H), 7.38 (s, 1H), 7.48 (s, 1H), 8.85 (s, 1H)
MS-ESI: 365 (MH)+
Alternatively 7-[2-(4-acetylpiperazia-l-yl)ethoxy]-4-[(4-fluoro-2-methyl-l//-indol-5-
yl)oxy]-6-methoxyquinazoline may be prepared as follows:
A mixture of 7-(2-bromoethoxy)-4-[(4-fluoro-2-methyl-l#-indol-5-yl)oxy]-6-
methoxyquinazoline (310mg of a sample containing triphenylphosphine oxide (approx. 12%
w/w), 0.61mmol) and 1-acetylpiperazine (258mg, 2.02mmol) in A^N-dimethylformamide (5ml)
was stirred at ambient temperature overnight and then concentrated under reduced pressure.
The residue was purified by column chromatography eluting with methylene chloride/methanol
(95/5) to give 7-[2-(4-acetylpiperaan-l-yl)ethoxy]-4-[(4-fluoro-2-inethyl-lflr-ind.ol-5-
yl)oxy]-6-methoxyquinazoline (202mg, 67%) as a white solid.
MS and NMR details are given hereinbefore.
The starting material was prepared as follows:
A suspension of 4-[(4-fluoro-2-methyl-l#-indol-5-yl)oxy]-7-hydroxy-6-
methoxyquiaazoline (530 mg, 1.56 mmol), (prepared as described for the starting material in
Example 7), in methylene chloride (15 ml) was treated with triphenylphosphine (570 mg, 2.18
mmol), 2-bromoethanol (300 mg, 2.40 mmol) and diisopropyl azodicarboxylate (380 mg, 1.88
mmol) and the mixture stirred at ambient temperature for 2 hours. The crude reaction mixture
was loaded onto a silica column and eluted using ethyl acetate as solvent. The relevant
fractions were combined and evaporated under vacuum to give a residue, which was triturated
with ether, filtered and dried. This gave 7-(2-bromoethoxy)-4-[(4-fluoro-2-methy]-lH'-indol-
5-yl)oxy]-6-methoxyquinazoline as a white solid (546 mg, 78%).
'H NMR Spectrum: (DMSOd6) 2.40 (s, 3H), 3.90 (t, 2H), 3.99 (s, 3H), 4.56 (t, 2H), 6.21 (s,
1H), 6.97 (t, 1H), 7.16 (d, 1H), 7.42 (s, 1H), 7.62 (s, 1H), 8.49 (s, 1H), 11.29 (s, 1H)
MS (ESI) : 446 and 448 (MH)+
Alternatively 7-[2-(4-acetylpiperazin-l-yl)ethoxy]-4-[(4-fluoro-2-methyl-lW-indol-5-
yl)oxy]-6-methoxyquinazoline may be prepared as follows:
4-[(4-Huoro-2-methyH#-radol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline (300mg,
O.SSmmol), (prepared as described for the starting material in Example 7), 2-(4-
acetylpiperazin-l-yl)ethanol (183mg, 1.06mmol) and triphenylphosphine (278mg, 1.06mmol)
were stirred together in dichloromethane (10ml) and the mixture cooled in an ice/water bath.
Diisopropyl azodicarboxylate (209)il, 1.06mmol) was added and the mixture stirred for 1.5
hours. A further one mole equivalent of 2-(4-acetylpiperazin-l-yl)ethanol (172mg, 1 mmol),
triphenylphosphine (262mg, 1 mmol) and diisopropyl azodicarboxylate (197 [il, 1 mmol) were
added and the mixture stirred for a further 1 hour. The volatiles were removed under vacuum
and the residue was purified by colum chromatography eluting with methylene
chloride/methanol (95/5) to give a crude solid that was further purified by preparative HPLC
to give7-[2-(4-acetylpiperazin-l-yI)ethoxy]-4-[(4-fluoro-2-methyl-lH-indol-5-yI)oxy]-6-
methoxyquinazoline (75mg, 17%).
MS and NMR details are given hereinbefore.
The starting material was prepared as follows:
A mixture of 1-acetylpiperazine (2.5g, 19.5mmol), 2-bromoethanol (1.38ml,
19.5mmol) and potassium carbonate (6.7g, 48.8mm.ol) in acetonitrile (30ml) was heated at
reflux for 3 hours. The mixture was cooled, filtered and concentrated under reduced pressure.
The residue was purified by column chromatography eluting with methylene chloride/methanol
(9/1) to give 2-(4-acetylpiperazin-l-yl)ethanol (1.89g, 56%) as a colourless oil.
]H NMR Spectrum: (CDC13) 2.09 (s, 3H); 2.50 (m, 4H); 2.57 (t, 2H); 3.48 (t, 2H); 3.63 (m,
4H)
Alternatively 7-[2-(4-acetylpiperazin-l-yl)ethoxy]-4-[(4-fluoro-2-methyl-l//-indol-5-
yl)oxy]-6-methoxyquiuazoline maybe prepared as follows:
A mixture of 4-[(4-fluoro-2-methyl-l/7-indol-5-yl)oxy]-7-hydroxy-6-
methoxyquinazoline (250mg, 0.74mmol), l-acetyl-4-(2-chloroethyl)piperazine (144mg,
0.81mmol) and potassium carbonate (112mg, O.Slmmol) in Af-methylpyrrolidinone (6ml) was
heated at 90°C for 2 hours. The mixture was cooled and water added. After 30 minutes the
solid was filtered off and dried under vacuum. The residue was purified by column
chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4) to
give7-[2-(4-acetylpiperazin-l-yl)ethoxy]-4-[(4-fluoro-2-methyl-l/ir-indol-5-yl)oxy]-6-
metrioxyquinazotine (310mg, 58%) as a white solid.
MS and NMR details are given hereinbefore.
The starting material was prepared as follows:
2-(4-Acetylpiperazin-l-yl)ethanol (SOOmg, 2.90mmol), (prepared as described for the
starting material in this example hereinbefore), was dissolved in methylene chloride (10ml) and
triethylamine (445^,1, 3.19mmol) and 4-toluenesulphonyl chloride (609mg, 3.19mmol) were
added and the mixture was stirred at ambient temperature overnight. The mixture was washed
with brine, dried (MgSCU) and concentrated under reduced pressure. The residue was purified
by column chromatography eluting with methylene chloride/methanol (98/2) to give 1-acetyl-
4-(2-chloroethyl)piperazine (300mg, 54%) as an oil.
'H NMR Spectrum: (CDC13) 2.08 (s, 3H); 2.48 (br t, 2H); 2.52 (br t, 2H); 2.75 (t, 2H); 3.48
(br t, 2H); 3.59 (t, 2H); 3.63 (br t, 2H)
Example 29
Cs,C03, acetone
A mixture of 7-[3-(4-acetylpiperazin-l-yl)propoxy]-4-chloro-6-methoxyquinazoHne
(235mg, 0.62rnniol), (prepared as described for the starting material in Example 7), 5-
hydroxyindazole (lOOmg, 0.75mmol) and cesium carbonate (303mg, 0.93mmol) in acetone
(15ml) was heated at reflux for 1.25 hours. The mixture was cooled, filtered and the filtrate
concentrated under reduced pressure. The residue was purified by column chromatography
eluting with methylene chloride/methanol (saturated with ammonia) (96/4). The residue was
further purified by preparative HPLC to give 7-[3-(4-acetylpiperazm-l-yl)propoxy]-4-(LHindazol-
5-yloxy)-6-methoxyquinazoline (127mg, 43%) as a white foam.
'H NMR Spectrum: (DMSOd6) 1.98 (m, 5H); 2.33 (m, 2H); 2.39 (m, 2H); 2.48 (t, 2H); 3.42
(m, 4H); 3.97 (s, 3H); 4.24 (t, 2H); 7.26 (dd, 1H); 7.36 (s, 1H); 7.60 (m, 2H); 7.65 (d, 1H);
8.07 (s, 1H); 8.48 (s, 1H); 13.15 (br s, 1H)
MS -ESI: 477.6 [M+H]+
The starting material was prepared as follows:
5-Methoxyindazole (1.7g, ll.Smmol), (Tetrahedron, 1994, 50, 3529), was dissolved in
methylene chloride (35ml) and cooled in an ice/water bath. Boron tribromide (57.4ml of a 1M
solution in methylene chloride, 57.4mmol) was added over 10 minutes and then the mixture
allowed to warm to ambient temperature. The mixture was stirred for 2 hours and then recooled
in an ice/water bath. 2N Sodium hydroxide was slowly added until pH8. The
precipitated solid was filtered off and dried under vacuum at 60°C overnight. The residue was
purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 5-
hydroxyindazole (l.Og, 65%) as a brown solid.
'H NMR Spectrum: (DMSOd6) 6.87 (dd, IH); 6.95 (d, IH); 7.32 (d, IH); 7.81 (s, IH); 8.99
(s, IH); 12.69 (s, IH)
MS-ESI: 135 [M+H]+
Example 30
DMF
A mixture of 7-(3-bromopropoxy)-4-(l#-indol-5-yloxy)-6-methoxyquinazoline
(200mg, 0.47mmol), (WO 00/47212 Al, Example 314), and 1-acetylpiperazine (180mg,
1.40mmol) in A^jV-dimethylformamide (4ml) was stirred at ambient temperature for 3 hours.
The mixture was diluted with ethyl acetate and washed with brine (x2), dried (MgSOt) and
concentrated under reduced pressure. Column chromatography of the residue (5%
methanol/dichlorotnethane) gave 7-[3-(4-acetylpiperazm-l-yl)propoxy]-4-(l£T-indol-5-
yloxy)-6-methoxyquinazoline (109mg, 49%) as a white solid.
'H NMR Spectrum: (DMSOd6) 1.97 (m, 5H); 2.32 (m, 2H); 2.39 (m, 2H); 2.48 (t, 2H); 3.42
(m/4H); 3.97 (s, 3H); 4.24 (t, 2H); 6.43 (s, IH); 6.96 (dd, IH); 7.35 (s, IH); 7.42 (m, 3H);
7.58 (s, IH); 8.46 (s, IH); 11.17 (br s, IH)
MS-ESI: 476.6 [MHf
4-[(4-Ruoro-2-methyl-l//-indol-5-yl)oxy]-6-meth.oxy-7-[(25)-pyrrolidin-2-
ylmethoxyjquinazoline (60mg, 0.14mmol), (prepared as described for the starting material in
Example 12), was dissolved in pyridine (3ml) and cooled to 0°C. Trichloroacetyl isocyanate
(17^1, 0.14mmol) was added and the mixture stirred for 2 hours. The solvent was removed
under reduced pressure and the residue dissolved in 7N ammonia in methanol and stirred at
ambient temperature overnight and then at 50°C for 2 hours. The solvent was removed under
reduced pressure. Column chromatography of the residue (2% to 5%
methanol/dichloromethane) gave 7-[(25)-l-carbanioylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-
2-methyl-lH-indol-5-yl)oxy]-6-methoxyquinazoline (40mg, 69%) as a yellow solid.
'H NMR Spectrum: (DMSOd6) 1.80-2.50 (m, 4H); 2.40 (s, 3H); 3.25 (m, 2H); 3.99 (s, 3H);
4.17 (m, 3H); 5.85 (s, 2H); 6.22 (s, IH); 6.97 (t, IH); 7.14 (d, IH); 7.44 (s, IH); 7.59 (s, IH);
8.47 (s, IH); 11.29 (brs, IH)
MS-ESI: 466.5 [MHf
Example 32
1 . CI,C(0)NCO
2. NHj/MeOH
4-[(4-Fluoro-2 -methyl- 17T-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-lylpropoxy)
quinazoUne (240mg, 0.52mmol), (prepared as described for the starting material in
Example 15), was dissolved in pyridine (5ml) and cooled to 0°C. Trichloroacetyl isocyanate
(61j-il, 0.52mmol) was added and the mixture stirred at ambient temperature for 1 hour. The
mixture was concentrated under reduced pressure and the residue dissolved in 7N ammonia in
methanol and stirred at 45°C for 2.5 hours. Aqueous ammonia (1ml) was added and the
-139-
mixture was stirred at 60°C for 1.5 hours and then at ambient temperature overnight. The
solvent was removed under reduced pressure. Column chromatography of the residue using
methylne chloride/methanol (90/10) followed by methylene chloride/methanol (saturated with
ammonia) (90/10) gave a solid which was suspended in methanol and filtered to give 7-{3-[4-
carbamoylpiperazin-l-yl]propoxy}-4-[(4-fluoro-2-methyl-li?-indol-5-yl)oxy]-6-
methoxyquinazoline (120mg, 46%) as a pale yellow solid.
1H NMR Spectrum: (DMSOd6) 1.98 (in, 2H); 2.32 (m, 4H); 2.40 (s, 3H); 2.48 (t, 2H); 3.28
(m, 4H); 3.97 (s, 3H); 4.24 (t, 2H); 5.88 (s, 2H); 6.22 (s, IH); 6.97 (t, IH); 7.14 (d, IH); 7.37
(s, IH); 7.58 (s, IH); 8.48 (s, IH); 11.29 (br s, IH)
MS-ESI: 509.6 [MH]+
A mixture of 6-[3-(4-acetylpiperazin-l-yl)propoxy]-4-chloro-7-methoxyquina2oHne
(235mg, 0.62mniol), 5-hydroxyindazole (lOOmg, 0.75mrnol), (prepared as described for the
starting material in Example 29), and cesium carbonate (303mg, 0.93mmol) in acetone (20ml)
was heated at reflux for 2 hours. The mixture was filtered and the filtrate concentrated under
reduced pressure. The residue was purified by column chromatography eluting with methylene
chloride/methanol (95/5) to give 6-[3-(4-acetylpiperazin-l-yl)propoxy]-4-(lfl-indazol-5-
yloxy)-7-methoxyquinazoline (200mg, 68%) as a pale green solid.
'H NMR Spectrum: (DMSOd6) 1.95 (s, 3H); 2.00 (m, 2H); 2.34 (br t, 2H); 2.41 (br t, 2H); 2.4
(t, 2H); 2.5 (m, 2H); 3.42 (m, 4H); 4.01 (s, 3H); 4.25 (t, 2H); 7.29 (dd, IH); 7.39 (s, IH); 7.63
(m, 2H); 7.68 (d, IH); 8.09 (s, IH); 8.51 (s, IH); 13.18 (br s, IH)
MS-ESI: 477.6 [MHf
The starting material was prepared as follows:
6-Acetoxy-4-chloro-7-methoxyquinazoline (10.Og, 39.6mmol), (WO 01/04102, Table
VI examples), was added in portions to a stirred 7N niethanolic ammonia solution (220 ml)
and the mixture cooled to 10°C in an ice/water bath. Initially the solid dissolved to give a
yellow solution which then deposited a yellow precipitate. After stirring for one hour the
precipitate was filtered off, washed with diethyl ether and dried thoroughly under high vacuum
to give 4-chloro-6-hydroxy-7-methoxyquinazoline (5.65g, 67.8%).
'H NMR Spectrum: (DMSOd6) 3.96 (s, 3H); 7.25 (s, 1H); 7.31 (s, 1H); 8.68 (s, 1H)
MS-ESI:211 [M+H]+
Diethyl azodiearboxylate (991 mg, 5.7mmol) was added dropwise to a solution of 4-
chloro-6-hydroxy-7-methoxyquinazoHne (Ig, 4.75 mmol), 3-(4-acetylpiperazin-l-yl)propan-lol
(972mg, 5.22 mmol), (prepared as described for the starting material in Example 1 or
Example 7), and triphenylphosphine (1.74g, 6.65 mmol) in rnethyleue chloride (25ml). The
mixture was stirred at ambient temperature for 2 hours. The solution was poured onto silica
and eluted with methylene chloride, followed by methylene chloride/methanol (97/3 followed
by 92/8). The fractions containing the expected product were combined and evaporated to
give 6-[3-(4-acetylpiperazin-l-yl)propoxy]-4-chloro-7-methoxyquinazoUne (1.3g, 72%).
NMR Spectrum: (DMSOd6) 2.0 (s, 3H), 2.05 (m, 2H), 2.35 (m, 2H), 2.4 (m, 2H), 2.5 (m,
2H),2.45 (m, 4H), 4.02 (s, 3H), 4.2 (m, 2H), 7.4 (s, 1H), 7.5 (s, 1H), 8.9 (s, 1H)
MS-ESI: 379 [M+H]+
Example 34
4-(7-Azamdol-5-yloxy)-6-methoxy-7-(3-piperazin-l-ylpropoxy)quinazoline (200mg,
0.46mmol) was dissolved in pyridine (5ml) and cooled to 0°C. Trichloroacetyl isocyanate
(55|il, 0.46mmol) was added and the mixture stirred at ambient temperature for 3 hours. The
mixture was concentrated under reduced pressure and the residue dissolved in 7N ammonia in
methanol and stirred at ambient temperature for 20 hours. The solvent was removed under
reduced pressure and the residue was purified by column chromatography eluting with
methylene chloride/methanol (90/10) to give 4-(7-azaindoI-5-yloxy)-6-methoxy-7-[3-(4-
carbamoylpiperazi7i-l-yl)propoxy]quinazoline (95mg, 43%) as a white solid.
'H NMR Spectrum: (DMSOd6) 2.01 (m, 2H); 2.35 (br t, 4H); 2.48 (t, 2H); 3.3 (m, 4H); 4.01
(s, 3H); 4.27 (t, 2H); 5.91 (s, 2H); 6.50 (dd, 1H); 7.40 (s, 1H); 7.57 (t, 1H); 7.64 (s, 1H); 7.93
(d, 1H); 8.20 (d, 1H); 8.51 (s, 1H); 11.78 (brs, 1H)
MS-ESI: 478.6 [MH]+
The starting material was prepared as follows :
4-Chloro-7-hydroxy-6-rnethoxyquinazoline (1.7g, O.OSmmol), (prepared as described
for the starting material in Example 4), te/t-butyl 4-(3-hydroxypropyl)piperazine-l-carboxylate
(2.17g, 8.89mmol), (prepared as described for the starting material in Example 15), and
triphenylphosphine (2.97g, ll.Smmol) were added to dichloromethane (42.5ml). Diisopropyl
azodicarboxylate (1.91ml, 9.70mmol) was added and the reaction mixture stirred at ambient
temperature for 1.5 hours and then concentrated under reduced pressure. The residue was
purified by column chromatography eluting with methylene chloride/iaethaaol (95/5 followed
by 92/8) to give the product containing a single impurity. A second column chromatography
elating with methylene chloride/methanol (saturated with ammonia) (96/4) gave ten-butyl 4-
{3-[(4-chloro-6-methoxyquinazoEn-7-yl)oxy]propyl}piperazine-l-carboxylate (3.0g, 99%) as a
white solid.
'H NMR Spectrum: (CDC13) 1.46 (s, 9H); 2.12 (m, 2H); 2.42 (t, 4H); 2.57 (t, 2H); 3.44 (t,
4H); 4.05 (s, 3H); 4.29 (t, 2H); 7.35 (s, 1H); 7.38 (s, 1H); 8.85 (s, 1H)
MS-ESI: 437.1, 439.0 [MH]+
tert-Butyl4-{3-[(4-chloro-6-methoxyquinazohn-7-yl)oxy]propyl}piperazine-lcarboxylate
(2.0g, 4.42mmol) was dissolved in N, N-diinethylacetainide (60ml) and 5-hydroxy-
7-azaindole (651mg, 4.86muiol), (prepared as described for the starting material in Example
2), and potassium carbonate (671mg, 4.86mmol) added. The reaction mixture was heated at
85°C for 3 hours. The mixture was cooled, filtered and concentrated under reduced pressure.
Column chromatography of the residue (8-10% methanol/dichloromethane) gave 4-(7-
azaindol-5-yloxy)-7- {3-[4-(fert-butoxycarbonyl)piperazia-1 -yljpropoxy) -6-
methoxyquinazoline (2.0g, 85%) as a white solid.
'H NMR Spectrum: (CDC13) 1.47 (s, 9H); 2.14 (m, 2H); 2.44 (t, 4H); 2.59 (t, 2H); 3.45 (t,
4H); 4.07 (s, 3H); 4.29 (t, 2H); 6.55 (rn, 1H); 7.36 (s, 1H); 7.41 (m, 1H); 7.61 (s, 1H); 7.86
(d, 1H); 8.30 (d, 1H); 8.61 (s, 1H); 9.80 (br s, 1H)
MS-ESI: 535.0 [MH]+
4-(7-Azaindol-5-yloxy)-7-{3-[4-(ferr-butoxycarbonyl)piperazin-l-yl]propoxy}-6-
methoxyquinazoline (1.9g, 3.55mmol) was suspended in dichloromethane (60ml) and
trifluoroacetic acid (2rnl) added dropwise. All solid dissolved at this point giving an orange
solution which was stirred for 3 hours at ambient temperature. More trifluoroacetic acid (4ml)
was added and the mixture stirred overnight. The mixture was concentrated under reduced
pressure and the residue concentrated from dichloromethane (x3) and toluene to remove
trifluoro acetic acid. The residue was dissolved in methanol, placed on an Isolute SCX column,
washed with methanol and then eluted with 7N ammonia in methanol. The product was then
purified by column chromatography eluting with methylene chloride/rnethanol (saturated with
ammonia) (95/5 followed by 93/7) to give 4-(7-azaindol-5-yloxy)-6-methoxy-7-(3-piperazin-lylpropoxy)
quinazoline (660mg, 43%) as a white foam.
'H NMR Spectrum: (DMSOd6) 1.95 (m, 2H); 2.30 (m, 4H); 2.41 (t, 2H); 2.68 (t, 4H); 3.97 (s,
3H), 4.22 (t, 2H); 6.46 (d, 2H); 7.36 (s, IH); 7.55 (d, IH); 7.60 (s, IH); 7.90 (d, IH); 8.17 (d,
IH); 8.48 (s, IH); 11.76 (br s, IH)
MS-ESI: 435.6 [MH]+
Example 35
A mature of 4-chloro-7-[3-(2,5-dioxoimidazolidin-l-yl)propoxy]-6-
methoxyquinazoline (200mg, 0.57rnmol), 4-fluoro-5-hydroxy-2-methylindole (113mg,
0.68mmol), (prepared as described for the starting material in Example 1), and caesium
carbonate (279mg, 0.86mmol) in acetone (15ml) was heated at reflux for 4 hours. The mixture
was cooled, filtered and the filtrate concentrated under reduced pressure. The residue was
purified by column chromatography eluting with methylene chloride/methanol (97/3 followed
by 95/5) to give 7-{3-[2,5-dioxo-4-(l-hydroxy-l-methylethyl)imidazolidin-l-yl]propoxy}-
4-[(4-fluoro-2-methyl-l#-indol-5-yloxy]-6-methoxyquinazoline (87mg, 28%) as a brown
foam.
'H NMR Spectrum: (DMSOd6) 1.17 (s, 3H); 1.22 (s, 3H); 2.06 (m, 2H); 2.42 (s, 3H); 3.57 (t,
2H); 3.84 (d, IH); 4.01 (s, 3H); 4.21 (t, 2H); 4.78 (s, IH); 6.25 (s, IH); 6.99 (t, IH); 7.16 (d,
IH); 7.33 (s, IH); 7.62 (s, lH);8.19(s, IH); 8.50 (s, IH); 11.32 (br s, IH)
MS-ESI: 538.6 [M+H]+
-143-
The starting material was prepared as follows:
ImidazolidiDe-2,4-dione (l.Og, 9.99mmol), 3-benzyloxypropan-l-ol (1.9ml, 12.0mniol)
and triphenylphosphine (3.1g, 12.0mmol) were stirred in methylene chloride (20mJ) and cooled
to 0°C. Diisopropyl azodicarboxylate (2.36jJ,l, 12.0mmo]) in dichloromethane (5ml) was
• slowly added and the mixture stirred at ambient temperature overnight. The mixture was
washed with water, dried (MgSdj) and concentrated under reduced pressure. The residue was
purified by column chromatography eluting with methylene chloride/methanol (98/2) to give 3-
(3-benzyloxypropyl)imidazolidine-2,4-dione (1.3g, 53%, containing 7% w/w
triphenylphosphine oxide) as a pale yellow solid.
1H NMR Spectrum: (DMSOd6) 1.76 (m, 2H); 3.40 (m, 4H); 3.83 (d, 2H); 4.41 (s, 2H); 7.31
(m, 5H);7.94(brs, 1H)
3-(3-Benzyloxypropyl)imidazolidine-2,4-dione (1.3g, 5.26mmol) was dissolved in
methanol (15inl) and the system purged with nitrogen. 10% Palladium on carbon (130mg,
10% by mass) and a few drops of glacial acetic acid were added and the mixture stirred under
a hydrogen atmosphere (1 atmosphere) for 3 days. The mixture was filtered and concentrated
under reduced pressure. The residue was purified by column chromatography eluting with
methylene chloride/methanol (98/2 to 95/5) to give 3-(3-hydroxypropyl)iniidazolidine-2,4-
dione (606mg, 73%) as a viscous oil which crystallised on standing.
'H NMR Spectrum: (DMSOd6) 1.65 (m, 2H); 3.39 (m, 4H); 3.88 (s, 2H); 4.44 (t, 1H), 7.96
(br s, 1H)
A mixture of 4-chloro-7-hydroxy-6-methoxyquinazoline (665mg, 3.16mmol),
(prepared as described for the starting material in Example 4), 3-(3-
hydroxypropyl)knidazoIidine-2,4-dione (600mg, 3.79mmol) and triphenylphosphine in
dichloromethane (15ml) was stirred and cooled to 0°C. Diisopropyl azodicarboxylate (747ul,
3.79mmol) in dichloromethane (5ml) was added and the mixture stirred at ambient temperature
for 3 hours. Initially all material went into solution but later a precipitate formed. The mixture
was concentrated and the solid residue suspended in methanol, filtered and dried in air to give
4-chloro-7-[3-(2,5-dioxoimidazolidin-l-yl)propoxy]-6-methoxyquinazoline (765mg, 69%) as a
pale yellow solid.
'H NMR Spectrum: (DMSOd,;) 2.09 (m, 2H); 3.58 (t, 2H); 3.88 (d, 2H); 4.02 (s, 3H); 4.25 (t,
2H); 7.39 (s, 1H), 7.41 (s, 1H); 7.99 (br s, 1H); 8.87 (s, 1H)
MS-ESI: 351.5 and 353.5 [MH]+
A mixture of 4-[(4-fluoro-l^-indol-5-yl)oxy]-6-hydroxy-7-methoxyquinazoune
(260mg, O.SOmmol), (prepared as described for the starting material in Example 10), 2-(4-
acetylpiperazin-l-yl)ethanol (165mg, 0.96mmol), (prepared as described for the starting
material in Example 28), and triphenylphosphine (252mg, 0.96mmol) in dichloromethane
(15ml) was stirred and cooled in an ice/water bath. Diisopropyl azodicarboxylate (189(0.1,
0.96mmol) was added. The mixture was stirred for 3 hours and then a further 0.5 mole
equivalent of 2-(4-acetylpiperazin-l-yl)ethanol, triphenylphosphine and diisopropyl
azodicarboxylate were added. The mixture was stirred for a further 1 hour and then
concentrated under reduced pressure. The residue was purified by column chromatography
eluting with rnethylene chloride/methanol (95/5) to give 6-[2-(4-acetylpiperazin-lyI)
ethoxy]-4-[(4-fluoro-lH-indol-5-yl)oxy]-7-methoxyquinazoline (260mg, 68%) as a white
solid.
'H NMR Spectrum: (DMSOd6) 1.98 (s, 3H); 2.45 (m, 2H); 2.55 (m, 2H); 2.83 (t, 2H); 3.43
(m, 4H); 4.00 (s, 3H); 4.33 (t, 2H); 6.55 (s, IH); 7.09 (t, IH); 7.30 (d, IH); 7.41 (s, IH); 7.48
(t, IH); 7.70 (s, IH); 8.51 (s, IH); 11.52 (br s, IH)
MS-ESI: 480.1 [MHf
Example 37
AcCl, DIPEA, dichloromethane
4-[(4-Fluoro-l/:/-radol-5-yl)oxy]-7-inethoxy-6-(piperidin-4-ylniethoxy)quinazohiie
(210mg, O.SOmmol) was suspended in dichloromethane (7ml) and diisopropyleth)'lamiae
(104)0,1, 0.60mniol) and acetyl chloride (42ul, 0.60mmol) were added. All solid material went
into solution. The mixture was stirred at ambient temperature overnight. The mixture was
washed witb brine, followed by saturated aqueous sodium hydrogen carbonate, dried (MgSO,))
and concentrated under reduced pressure. The residue was purified by column
chromatography eluting with methylene cliloride/rnethanol (98/2) to give 6-[(lacetylpiperidin-
4-yl)methoxy]-4-[(4-fluoro-lfiT-indol-5-yL)oxy]-7-methoxyquinazoIine
(146mg, 63%) as a white foam.
1H NMR Spectrum: (DMSOd6) 1.14-1.36 (m, 2H); 1.85 (m, 2H); 2.01 (s, 3H); 2.12 (m, 1H);
2.61 (br t, 1H); 3.09 (br t, 1H); 3.87 (br d, 1H); 4.01 (s, 3H); 4.09 (d, 2H); 4.41 (br d, 1H);
6.55 (s, 1H); 7.09 (t, 1H); 7.30 (d, 1H); 7.41 (s, 1H); 7.47 (t, 1H); 7.63 (s, 1H); 8.51 (s, 1H);
11.49(brs, 1H)
MS-ESI: 465.1 [MH]+
The starting material was prepared as follows:
A mixture of 4-[(4-fluoro-l#-indol-5-yl)oxy]-6-hydroxy-7-methoxyquinazoline
(250mg, 0.77mmol), (prepared as described for the starting material in Example 10), tert-butyl
4-(hydroxymethyl)piperidine-l-carboxylate (199rug, 0.92mmol), (prepared as described for the
starting material in Example 11), and triphenylphosphine (242ing, 0.92nunol) in
dichloromethane (15ml) was stirred and cooled to 0°C. Diisopropyl azodicarboxylate (182^1,
0.92mmol) in dichlorornethane (2ml) was added. The mixture was stirred for 3 hours and then
a further 0.5 mole equivalent of tert-butyl 4-(hydroxymethyl)piperidine-l-carboxylate,
triphenylphosphine and diisopropyl azodicarboxylate added. The mixture was stirred for 1
hour and then concentrated under reduced pressure. The residue was purified by column
chromatography eluting with ethyl acetate/hexane (1/1) followed by methylene'
chloride/methanol (99/1) to give 6-[l-(te^butoxycarbonyl)piperidin-4-y]]methoxy-4-[(4-
fluoro-l//-indol-5-yI)oxy]-7-methoxyquinazoline (306mg containing 10% w/w
triphenylphosphine oxide) which was used without further purification in the next step.
MS-ESI: 523.1 [MH]+
6-[l-(^ert-Butoxycarbonyl)piperidin-4-yl]methoxy-4-[(4-fluoro-l//-indol-5-yl)oxy]-7-
niethoxyquinazoline (306mg containing 10% w/w triphenylpbosphine oxide) was dissolved in
1,4-dioxane (5ml) and 4M hydrogen chloride in 1,4-dioxane (5ml) was added. The mixture
was stirred at ambient temperature for 2.5 hours and then concentrated under reduced
pressure. The residue was dissolved in methanol and adsorbed onto an Isolute SCX column,
washed with methanol and then eluted with 7N ammonia in methanol to give 4-[(4-fluoro-lW-
ffldol-5-yl)oxy]-7-methoxy-6-(piperidin-4-y]methoxy)quinazoline (215mg, 66% over two
steps).
1H NMR Spectrum: (DMSOd*) 1.24 (m, 2H); 1.75 (br d, 2H); 1.93 (m, IH); 2.98 (br d, 2H);
4.01 (m, 5H); 6.55 (s, IH); 7.09 (t, IH), 7.30 (d, IH); 7.40 (s, IH); 7.47 (t, IH), 7.61 (s, IH);
8.50 (s, IH); 11.50 (s, IH)
MS-ESI: 423.1 [MH]+
4-[(4-Huoro-l/7-indol-5-yl)oxy]-7-nietboxy-6-(piperidin-4-yloxy)quinazoIine (215mg,
0.53mniol) was suspended in dichlororaethane (10ml) and diisopropylethylamine (llOjil,
0.63nnnol) and acetyl chloride (45(J,I, 0.63mmol) were added. The mixture was stirred at
ambient temperature for 3 hours. The mixture was washed with brine, followed by aqueous
sodium hydrogen carbonate, dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by column chromatograpby eluting with methylene chloride/methanol
(98/2) to give 6-[(l-acetylpiperidin-4-yl)oxy]-4-t(4-fluoro-lflr-indol-5-yl)oxy]-7-
methoxyquinazoline (128rng, 54%) as a white foam.
1H NMR Spectrum: (DMSOd*) 1.67 (m, IH); 1.79 (m, IH), 2.09 (m, 5H); 3.35 (m, IH); 3.47
(m, IH); 3.76 (m, IH); 3.93 (m, IH); 4.06 (s, 3H); 5.00 (m, IH); 6.61 (s, IH); 7.16 (t, IH);
7.63 (d, IH); 7.49 (s, IH); 7.53 (t, 1H);7.82 (s, IH); 8.57 (s, IH); 11.55 (br s, IH)
MS-ESI: 451.1 [MH]+
The starting material was prepared as follows:
4-[(4-Ruoro-l#-indo]-5-yl)oxy]-6-hydroxy-7-methoxyquinazoline (700ing,
2.15mmol), (prepared as described for the starting material in Example 10), rert-butyl 4-
hydroxypiperidine-1-carboxylate (520ing, 2.58nimol) and triphenylphosphine (677mg,
2.58mniol) were stirred in dichloromethane (20ml) and cooled to 0°C. Diisopropyl
azodicarboxylate (508p,l, 2.58mmol) in dichloromethane (3ml) was added and the mixture
stirred at ambient temperature overnight. The mixture was filtered and concentrated under
reduced pressure. The residue was purified by column chromatography eluting with ethyl
acetate/isohexane (1/1) followed by methylene cbJoride/methanol (99/1) to give 6-[(l-?e/tbutoxycarbonyl)
piperidin-4-yloxy]-4-[(4-fluoro-lflr-indol-5-yl)oxy]-7-methoxyquinazoline
(933mg containing 35% w/w triphenylphosphine oxide) which was used directly in the next
step without further purification.
MS-ESI: 509.2 [MH]+
6- [(1 -rert-Butoxycarbonyl)piperidin-4-yloxy] -4-[(4-fluoro- l/f-indol-5-yl)oxy]-7-
methoxyquinazoline (933mg containing 35% w/w triphenylphosphine oxide) was dissolved in
1,4-dioxane (5ml) and 4M hydrogen chloride in 1,4-dioxane (lOrnl) was added. The mixture
was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure.
The residue was dissolved in methanol and adsorbed onto an Isolute SCX column, washed
with methanol and then eluted with 7N ammonia in methanol to give 4-[(4-fluoro-l/f-indol-5-
yl)oxy]-7-methoxy-6-(piperidin-4-yloxy)quinazo]ine (430mg, 49% over two steps),
approximately 86% pure. Used without further purification.
MS-ESI: 409.1 [MH]+
Example 39

4-[(4-Fluoro-l//-iudol-5-yl)oxy]-7-methoxy-6-(piperidin-4-yloxy)quinazoune (215mg,
0.53mmol), (prepared as described for the starting material in Example 38), was suspended in
dichloromethane (10ml) and diisopropylethylamine (llOp.1, 0.63mmol) and methane sulphoayl
chloride (49|il, 0.63mmol) were added. All solid material went into solution. The mixture was
stirred at ambient temperature for 3 hours. The mixture was washed with brine, followed by
aqueous sodium hydrogen carbonate, dried (MgS04) and concentrated under reduced
pressure. The residue was purified by column chromatography eluting with metbylene
chloride/methanol (98/2) to give 4-[(4-fluoro-l#-indol-5-yl)oxy]-7-methoxy-6-{[l-
(methylsulphonyl)piperidin-4-yl]oxy}quinazoline (168mg, 66%) as a white foam.
1H NMR Spectrum: (DMSOd6) 1.85 (m, 2H); 2.12 (m, 2H); 2.91 (s, 3H); 3.19 (m, 2H); 3.43
(in, 2H); 4.02 (s, 3H); 4.87 (m, 1H); 6.55 (s, 1H); 7.10 (t, 1H); 7.30 (d, 1H); 7.44 (s, 1H);
7.47 (t, 1H); 7.76 (s, 1H); 8.52 (s, 1H); 11.49 (s, 1H)
-148-
MS-ESI:487.1[MH]+
Example 40
A stirred solution of 7-(2-bromoethoxy)-4-[(4-fluoro-2-methyl-l//-indol-5-yl)oxy]-6-
methoxyquinazoUne (250 mg, 0.56 mmol), (prepared as described for the starting material in
Example 17), inDMF (2.5 ml) was treated withW-methylpropargylamine (116 mg, 1.68 mmol)
and stirred at ambient temperature overnight. The solvent was evaporated under vacuum and
the residue purified by column chromatography eluting with methylene chloride/methanol
(saturated with ammonia) (92/8). The relevant fractions were combined and evaporated under
vacuum to give 4-[(4-fluoro-2-methyl-lH-indol-5-yl)oxy]-6-methoxy-7-{2-[A^-methyl-A?-(2-
propynyl)amino]ethoxy}quinazoline as a white solid. (165 mg, 68%).
:H NMR Spectrum: (DMSOd6) : 2.32 (s, 3H), 2.40 (s, 3H), 2.86 (t, 2H), 3.14 (s, 1H), 3.42 (d,
2H), 3.98 (s, 3H), 4.30 (t, 2H), 6.21 (s, 1H), 6.96 (t, 1H), 7.14 (d, 1H), 7.40 (s, 1H), 7.60 (s,
1H), 8.50 (s, 1H), and 11.29 (s, 1H)
MS-ESI: 435 [M+H)+
Example 41
A mixture of 7:[2-(4-acetylpiperazin-l-yl)etboxy]-4-chloro-6-methoxyquinazoane (224
mg, 0.61 mmol), (prepared as described for the starting material in Example 28), 5-hydroxy-7-
azaindole (91 mg, 0.68 mmol), (prepared as described for the starting material in Example 2),
and potassium carbonate (94 mg, 0.68 mmol) in DMA (5 ml) was stirred at 85°C for 2 hours,
allowed to cool to ambient temperature and the solvent evaporated under vacuum. The
residue was purified by column chromatography eluting with methylene chloride/methanol
(saturated with ammonia) (95/5) to give a white solid. This was triturated with acetone,
filtered and dried to give 7-[2-(4-acetylpipera2in-l-yl)ethoxy]-4-(7-azaindol-5-yloxy)-6-
methoxyquinazoline (227 mg, 80%)
'H NMR Spectrum: (CDC13) 2.03 (s, 3H), 2.57 (m, 4H), 2.91 (t, 2H), 3.43 (t, 2H), 3.59 (t,
2H), 3.99 (s, 3H), 4.29 (t, 2H), 6.48'(m, IH), 7.27 (s, IH), 7.33 (t, IH), 7.55 (s, IH), 7.78 (d,
IH), 8.22 (d, IH), 8.54 (s, IH) and 9.59 (s, IH)
MS -ESI: 463 [M+Hf
Example 42
A mixture of 7-[3-(4-acetylpiperazin-l-yl)propoxy]-4-chloro-6-methoxyquinazo]ine
(190 mg, 0.50 mrnol), (prepared as described for the starting material in Example 4), 5-
hydroxy-2-methylindole (81 mg, 0.55 mmol), (WO 00/47212, Example48), and potassium
carbonate (76 mg, 0.55 mmol) in DMA (6 ml) was stirred at 85°C for 3 hours, allowed to cool
to ambient temperature and the solvent evaporated under vacuum. The residue was purified by
column chromatography eluting with methylene chloride/rnethanol (saturated with ammonia)
(92/8) to give a white solid. This was triturated with a mixture of ether and acetone, filtered
and dried to give 7-[3-(4-acetylpiperazin-l-yl)propoxy]-6-methoxy-4-[(2-methyl-12?-indol-
5-yl)oxy]quinazoline (130 mg, 53%).
'H NMR Spectrum:. (CDC13) 2.02 (s, 3H), 2.09 (m, 2H), 2.39 (s, 3H), 2.41 (m, 4H), 2.54 (t,
2H), 3.40 (m, 2H), 3.57 (m, 2H), 3.98 (s, 3H), 4.22 (t, 2H), 6.17 (s, IH), 6.90 (dd, IH), 7.24
(m, 3H), 7.56 (s, IH), 8.00 (br s, IH) and 8.52 (s, IH)
MS-ESI: 490 [M+H]+
Example 43
A mixture of 7-[3-(4-acetylpiperazin-l-yl)propoxy]-4-cMoro-6-methoxyquinazoline
(190 mg, 0.50 mmol), (prepared as described for the starting material in Example 4), 4-fluoro-
5-hydroxyindole (83 mg, 0.55 mmol), (WO 00/47212, Example 242), and potassium carbonate
(76 mg, 0.55 mmol) in DMA (6 ml) was stirred at 85°C for 3 hours, allowed to cool to
ambient temperature and the solvent evaporated under vacuum. The residue was purified by
column chromatography elating with methylene chloride/methanol (saturated with ammonia)
(92/8) to give a white solid. This was triturated with acetone, filtered and dried to give 7-[3-
(4-acetylpiperarin-l-yl)propoxy]-4-[(4-fluoro-lH-indol-5-yI)oxy]-6-methoxyquina2oline
(75 mg, 30%).
'H NMR Spectrum: (CDC13) 2.03 (s, 3H), 2.06 (m, 2H), 2.40 (m, 4H), 2.53 (t, 2H), 3.40 (m,
2H), 3.58 (m, 2H), 4.00 (s, 3H), 4.22 (t, 2H), 6.60 (rn, IH), 7.05 (m, IH), 7.17 (m, 2H), 7.30
(s, IH), 7.58 (s, IH), 8.44 (br s, IH) and 8.56 (s, IH)
MS-ESI: 494 [M4-H]+
Example 44
A mixture of 4-(7-azaindol-5-yloxy)-6-methoxy-7-(3-piperazin-lylpropoxy)
quinazoline (87 mg, 0.2 mmol), (prepared as described for the starting material in
Example 34). iodoacetamide (41 mg, 0.22 mmol) and N.A'-diisopropylethylarnine (26 mg, 0.22
mrnol) in acetonitrile (5 ml) was stirred at reflux for 1 hour and allowed to cool to ambient
temperature. The crude reaction mixture was loaded onto a silica column and eluted using
methylene chloride/methanol (saturated with ammonia) (92/8) solvent. The relevant fractions
were combined and evaporated under vacuum to give a residue which was triturated with
acetone, filtered and dried to give 4-(7-azaindol-5-yloxy)-7-[3-(4-
carbamoylmethyl)piperazin-l-yl)propoxy]-6-methoxyquina2oIine (62 mg, 63%).
'H NMR Spectrum: (CDCfe) 2.07 (m, 2H), 2.51 (m, 10H), 2.96 (s, 2H), 4.00 (s, 3H), 4.22 (t,
2H), 5.57 (br s, 1H), 6.48 (m, 1H), 6.96 (br s, 1H), 7.28 (s, 1H), 7.33 (m, 1H), 7.54 (s, 1H),
7.78 (d, 1H); 8.21 (d, 1H); 8.53 (s, 1H) and 9.37 (s, 1H)
MS-ESI: 492 [M+Hf
Example 45
N O
A mixture of 4-[(4-fluoro-2-methyl-l/7-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-lylpropoxy)
quinazoline (370 mg, 0.8 mniol), (prepared as described for the starting material in
Example 15), iodoacetamide (162 mg, 0.88 mmol) and AfW-diisopropylethylamine (230 mg,
1.80 mmol) in acetonitrile (10 ml) was stirred at reflux for 1 hour and allowed to cool to
ambient temperature. The solvent was removed under vacuum and the residue purified by
column chromatography eluting with inethylene chloride/methanol (saturated with ammonia)
(92/8) solvent. The relevant fractions were combined and evaporated under vacuum to give a
solid which was triturated with acetone, filtered and dried to give 7-[3-(4-
carbamoylniethylpiperazia-l-yl)propoxy]-4-t(4-fluoro-2-inethyl-lfir-indol-5-yI)oxy]-6-
methoxyquinazoline (132 mg, 32%).
'H NMR Spectrum: (CDC13) 2.06 (m, 2H), 2.39 (s, 3H), 2.51 (m, 10H), 2.95 (s, 2H), 3.99 (s,
3H), 4.21 (t, 2H), 5.33 (br s,' 1H), 6.28 (m, 1H), 6.93 (m, 2H), 7.03 (d, 1H), 7.27 (s, 1H), 7.56
(s, 1H), 8.05 (br s, 1H), 8.53 (s, 1H)
MS-ESI: 523 [M+H]+
Example 46
A solution of 4-chloro-7-{3-[4-(2-fluoroethyl)piperazin-l-yl]propoxy}-6-
methoxyquinazoline (240 nig, 0.63 mmol) in DMA (5 ml) was treated with potassium
carbonate (96 mg, 0.69 mmol) and 5-hydroxy-2-methylindole (102 nig, 0.69 mmol), (WO
00/47212, Example48), and stirred at 85°C for 4 hours. The mixture was cooled and the
solvent evaporated under vacuum to give a residue which was purified by column
chromatography eluting with methylene cnloride/methanol (saturated with ammonia) (92/8).
Evaporation of the relevant fractions gave an oil which crystallised on trituration with ether to
give 7-{3-[4-(2-fluoroethyI)piperazin-l-yl]propoxy}-6-methoxy-4-[(2-methyl-l£r-indol-5-
yl)oxy]quinazoline (150 mg, 48%).
'H NMR Spectrum: (CDC13) 2.06 (m, 2H), 2.39 (s, 3H), 2.51 (m, 10H), 2.60 (t, 1H), 2.67 (t,
1H), 3.97 (s, 3H), 4.20 (t, 2H), 4.44 (t, 1H), 4.56 (t, 1H), 6.17 (s, 1H), 6.90 (m, 1H), 7.26
(m, 3H), 7.54 (s, 1H), 7.92 (br s, 1H), 8.53 (s, 1H)
MS-ESI: 494 [M+H]+
The starting material was prepared as follows:-
A suspension of 4-chloro-7-hydroxy-6-methoxyquinazoline (202 mg, 0.96 mmol),
(prepared as described for the starting material in Example 4), in methylene chloride (10 ml)
was treated with triphenylphosphine (352 mg, 1.35 mmol), 3-[4-(2-fluoroethyl)piperazin-lyl)
propan-l-ol (200 mg, 1.06 mmol), (prepared as described for the starting material in
Example 27), and diisopropyl azodicarboxylate (226 mg, 1.15 mmol) and the mixture stirred at
ambient temperature for 2 hours. The crude reaction mixture was loaded onto a silica column
and eluted using methylene chloride/methanol (95/5). The relevant fractions were combined
and evaporated under vacuum to give 4-chloro-7-{3-[4-(2-fluoroethyl)piperazin-lyl]
propoxy)-6-methoxyquinazoline (208 mg, 57%) as a white solid.
1H NMR Spectrum: (CDC13) 2.12 (t, 2H), 2.57 (in, 10H), 2.66 (t, 1H), 2.75 (t, 1H), 4.05 (s,
3H), 4.28 (t, 2H), 4.49 (t, 1H), 4.65 (t, 1H), 7.35 (s, 1H), 7.38 (s, 1H), 8.85 (s, 1H)
MS-ESI: 383 [M+H]+
Example 47
8-CMoro[l,3]dioxolo[4,5-£]quinazotine (100 mg, 0.48 mmol), (WO 9749688), was
dissolved in dimethylacetamide (2.5 ml). 5-Hydroxy-7-azaindole (71 mg, 0.53 mmol),
(prepared as described for the starting material in Example 2), and potassium carbonate (73
mg, 0.53 mmol) were added and the mixture heated to 85 °C for 3 hours. The reaction
mixture was cooled, filtered and concentrated. The resulting residue was purified by column
chromatography eluting with inethylene chloride/methanol (91/9) to yield 4-(7-azaindol-5-
yloxy)-6,7-niethylenedioxyquinazoline (92 mg, 63%).
]H NMR Spectrum: (DMSOd6) 6.30 (s, 2H), 6.45 (d, 1H), 7.35 (s, 1H), 7.55 (t, 1H), 7.65 (s,
1H), 7.90 (d, 1H), 8.15 (d, 1H), 8.45 (s, 1H), 11.75 (br s, 1H)
MS-ESI: 307 [M+H]+
Example 48
4-[(4-Huoro-2-methyl-l#-mdol-5-yl)oxy]-6-methoxy-7-[(2JR)-oxiran-2-
ylmethoxyjquinazoline (200 mg, 0.5 mmol) was dissolved in dimethylformamide (2 ml) and
added to a solution of l-prop-2-yn-l-ylpiperazine di-trifluoracetic acid salt (535 mg, 1.5
mmol), (prepared as described for the starting material in Example 26), and potassium
carbonate (414 mg, 3 mrnol) in dimethylfonnamide (3 ml). The reaction was heated to 60°C
and left overnight. The reaction mixture was cooled, filtered and concentrated. The resulting
residue was purified by column chromatography eluting with methylene chloride/methanol
(saturated with ammonia) (94/6) to give 4-[(4-fluoro-2-methyl-LF?-mdol-5-yl)oxy]-7-{(2/?)-
2-hydroxy-3-[4-prop-2-yn-l-ylpiperaziii-l-yl]propoxy}-6-methoxyquinazoline (200 mg,
76%).
'H NMR Spectrum: (DMSOd6) 2.35 (s, 3H), 2.40 (m, 10H), 3.05 (t, 1H), 3.20 (d, 2H), 4.00
(s, 3H), 4.05 (m, 2H), 4.20 (m, 1H), 4.90 (d, 1H), 6.20 (s, 1H), 6.95 (dd, 1H), 7.15 (d, IK),
7.40 (s, 1H), 7.60 (s, 1H), 8.45 (s, 1H), 11.30 (br s, 1H)
MS-ESI: 520 [M+H]+
The starting material was prepared as follows:
4-(4-Fluoro-2-methyHndol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (339 mg, 1
mmol), (prepared as described for the starting material in Example 7), was dissolved in
dimethylacetamide (5 ml) under nitrogen. (2R) Glycidyl tosylate (285 mg, 1.25 mmol) and
potassium carbonate (345 mg, 2.5 mmol) were added and the reaction stirred at ambient
temperature for 2.5 hours, then warmed to 40°C and left overnight. The solvent was removed
under vacuum and the residue partitioned between water and dichloromethane. The organic
phase was washed with brine and dried (Na2SO4). The residue was purified by column
chromatography, eluting with methylene chloride/methanol (97/3) to give 4-[(4-Fluoro-2-
methyl-l//-indol-5-yl)oxy]-6-methoxy-7-[(2^)-oxiran-2-y]methoxy]quinazoline (339 mg,
85%).
'H NMR Spectrum: (DMSOd6) 2.40 (s, 3H), 2.75 (m, 1H), 2.90 (m, 1H), 3.40 (m, 1H), 4.00
(s, 3H), 4.05 (m, 1H), 4.60 (m, 1H), 6.20 (s, 1H), 6.95 (dd, 1H), 7.15 (d, 1H), 7.40 (s, 1H),
7.60 (s, 1H), 8.45 (s, 1H), 11.30 (br s, 1H)
MS-ESI: 396 [M+H]-K
-155-
Example 49
4-Chloro-7-{2-[4-(2-fluoroetbyl)piperazin-l-yl]ethoxy}-6-inetlioxyquiiiazoline (172
mg, 0.47 mmol) was dissolved in dimethylacetamide (5 ml). 5-Hydroxy-7-azaindole (69 tag,
0.51 mmol), (prepared as described for the starting material in Example 2), and potassium
carbonate (71 mg, 0.51 mmol) were added and the mixture heated to 85 °C for 4 hours. Tbe
reaction mixture was cooled, filtered and concentrated. The resulting residue was purified by
column chrornatography eluting with methylene chloride/methanol (saturated with ammonia)
(94/6). The fractions containing the expected product were evaporated under vacuum and the
residue was suspended in acetone, filtered and dried under vacuum to give 4-(7-azaindol-5-
yloxy)-7-{2-[4-(2-fluoroethyl)piperazin-l-yI]ethoxy}-6-ruethoxyquinazoline (123 mg,
56%).
'H NMR Spectrum: (CDC13) 2.60 (m, 4H), 2.65 (m, 4H), 2.75 (t, 2H), 3.00 (t, 2H), 4.05 (s,
3H), 4.35 (t, 2H), 4.50 (t, 1H), 4.65 (t, 1H), 6.55 (d, 1H), 7.35 (s, 1H), 7.40 (t, 1H), 7.60 (s,
1H), 7.85 (d, 1H), 8.30 (d, 1H), 8.60 (s, 1H), 9.70 (br s, 1H)
MS-ESI: 467 [M+H]+
The starting material was prepared as follows:
l-(2-Fluoroethyl)piperazine diTFA salt (464 mg, 1.29 mmol), (prepared as described
for the starting material in Example 27), was dissolved in acetonitrile (3.5 ml). Potassium
carbonate (889 mg, 6.44 mmol) and 2-bromoethanol (95 fil, 1.34 mmol) were added and the
mixture heated to 85°C and left overnight. More bromoethanol (95 J^L, 1.34 mmol) was added
and the reaction mixture heated at 85°C for a farther 2 hours. The reaction mixture was
cooled, filtered and concentrated. The residue was purified by column chrornatography eluting
with methyleiie chloride/niethanol (saturated with ammonia) (92/8) to give 2-[4~(2-
fluoroethyl)piperazin-l-yl]ethanol (151 mg, 66%).
1H NMR Spectmni: (CDC13) 2.60 (m, 10H), 2.65 (t, 1H), 2.75 (t, 1H), 3.60 (t, 2H), 4.45 (t,
1H), 4.65 (t, 1H)
MS-ESI: 177 [M+H]+
4-Chloro-7-hydroxy-6-methoxyquinazoline (146 mg, 0.69 mmol), (prepared as
described for the starting material in Example 4), was suspended in dichloromethane (7.5 ml).
Triphenylphosphine (254 mg, 0.97 nunol) and 2-[4-(2-fluoroethyl)piperazin-l-yl]ethanol (134
mg, 0.76 mmol) were added. Diisopropyl azadicarboxylate (165 p.1, 0.83 mmol) was then
added dropwise. The reaction mixture was stirred for 2.25 hours at ambient temperature and
then loaded directly onto a silica column and eluted with methylene chloride/methanol (92/8)
to give 4-chloro-7-{2-[4-(2-fluoroethyl)piperazin-l-yl]ethoxy}-6-methoxyquinazoUne (172
rug, 67%).
'H NMR Spectrum: (CDC13) 2.65 (10H, in), 2.95 (2H, t), 4.05 (3H, s), 4.30 (2H, t), 4.50 (1H,
t), 4.65 (1H, t), 7.30 (1H, s), 7.40 (1H, s), 8.85 (1H, s)
MS-ESI: 369 and 371 [M+H]+
Example 50
4-Chloro-6-methoxy-7-[3-(4-prop-2-yn-l-ylpiperazin-l-yl)propoxy]quinazoHne (300
mg, 0.8 mmol) was dissolved in dkuethylacetamide (10 ml). 5-Hydroxy-7-azaindole (118 mg,
0.88 mmol), (prepared as described for the starting material in Example 2), and potassium
carbonate (122 mg, 0.88 mmol) were added and the mixture heated to 85°C for 1.5 hours.
The reaction mixture was cooled, filtered and concentrated. The resulting residue was
preabsorbed on silica and eluted with methylene chloride/methanol (saturated with ammonia)
(90/10) to give 4-(7-azaindol-5-yloxy)-6-methoxy-7-[3-(4-prop-2-yn-l-ylpiperazin-lyl)
propoxy]quinazoline (288 mg, 76%).
JH NMR Spectrum: (DMSO-dfi) 1.95 (m, 2H), 2.45 (m, 10H), 3.10 (t, 1H), 3.25 (d, 2H),
4.00 (s, 3H), 4.20 (t, 2H), 6.45 (d, 1H), 7.35 (s, 1H), 7.55 (t, 1H), 7.60 (s, 1H), 7.90 (d, 1H),
8.20 (d, 1H), 8.50 (s, 1H), 11.75 (br s, 1H)
MS-ES: 473 (IVTHH
The starting material was prepared as follows:
l-Prop-2-yn-l-ylpiperazine diTFA salt (704 mg, 2 minol), (prepared as described for
the starting material in Example 26), was dissolved in acetonitrile (5 ml). Potassium carbonate
v
(1.38 g, 10 mmol) and 3-bromopropan-l-ol (180 |J-L, 2 mmol) were added and the mixture
heated to 85°C for 6.5 hours. The reaction mixture was cooled, filtered and concentrated to
give an oil. This was triturated with diethyl ether to give a white solid, which was partitioned
between dichloromethane and water. The organic phase was then dried (MgSO/t) and
concentrated to give 3-(4-prop-2-yn-l-ylpiperazin-l-yl)propan-l-ol (286 mg, 79%).
'H NMR Spectrum (CDC13) 1.70 (m, 2H), 2.25 (t, 1H), 2.60 (m, 10H), 3.25 (d, 2H), 3.80 (t,
2H)
MS-ESI: 183 [M+H]+
4-Ch]oro-7-hydroxy-6-methoxyquinazoline (300 mg, 1.42 mmol), (prepared as
described for the starting material in Example 4), was suspended in dichloromethane (15 ml).
Triphenylphosphine (523 mg, 2 mmo]) and 3-(4-prop-2-yn-l-ylpiperazin-l-yl)propan-l-ol (267
mg, 1.46 mmol) were added. Diisopropyl azadicarboxylate (340 fil, 1.71 mmol) was then
added dropwise. The reaction mixture was stirred for 1.25 hours at ambient temperature and
then loaded directly onto a silica column, and eluted with methylene chloride/methanol-(90/8
followed by 90/10) to give 4-chloro-6-methoxy-7-[3-(4-prop-2-yn-l-ylpiperazin-lyl)
propoxy]quinazoline (409 mg, 77%).
1H NMR Spectrum: (DMSO-d6) 1.95 (m, 2H), 2.45 (m, 10H), 3.10 (t, 1H), 3.20 (d, 2H),
4.00 (s, 3H), 4.25 (t, 2H), 7.35 (s, 1H), 7.40 (s, 1H), 8.80 (s, 1H)
MS-ESI: 375 and 3'77 [M+H]+
Exaniple 51
A mixture of 4-[(4-fluoro-2-methyl-l#-mdol-5-yl)oxy]-6-methoxy-7-[(2#)-oxiran-2-
ylmethoxy]quinazoline (200mg, 0.506 mmol), (prepared as described for the starting material
in Example 48), and l,4-dioxa-8-azaspiro[4.5]decane (195 /il, 1.52 mmol) in DMF (3 ml) was
stirred at 70°C urder argon for 3 hours. The volatiles were removed under vacuum and the
residue was purified by column chromatography eluting with methylene chloride/methanol
(95/5 followed by 90/10). The fractions containing the expected product were combined and
evaporated to dryness. The residue was triturated with diethyl ether, filtered and dried under
vacuum to give 7-{(2/J)-3-[(l,4-dioxa-8-azaspiro[4.5]dec-8-yl)]-2-hydroxypropoxy}-4-[(4-
fluoro-2-niethyl-l#-indol-5-yl)oxy]-6-methoxyquinazoline (190mg, 70%).
1HNMR Spectrum: (DMSOd6) 1.65 (t, 4H); 2.43 (s, 3H); 2.49-2.64 (m, 6H); 3.87 (s, 4H);
4.01 (s, 3H); 4.05 (br s; 1H); 4.13 (dd,lH); 4.26 (dd, 1H); 4.97 (d, 1H); 6.26 (s, 1H); 7.01
(dd, 1H); 7.18 (d, 1H); 7.44 (s, 1H); 7.63 (s,!H ); 8.52 (s,lH); 11.31 (s,lH)
MS-ESI: 539.5 [M+H]+
Example 52
Using an analogous procedure to that described for the preparation of Example 51, 4-
[(4-fluoro-2-methyl-l/7-indol-5-yl)oxy]-6-methoxy-7-[(2/?)-oxiran-2-y]methoxy]quinazoune
(200mg, 0.506 mmol), (prepared as described for the starting material in Example 48), was
reacted with l-acety]piperazine (195mg, 1.51 mmol) to give 7-{(2fi)-3-[4-acetylpiperazin-lyl]-
2-hydroxypropoxy}-4-[(4-fluoro-2-methyl-l/?-mdoI-5-yl)oxy]-6-methoxyquinazoline
(175mg, 66%).
JH NMR Spectrum: (DMSOd6) 2.00 (s, 3H); 2.43 (s, 3H); 2.35-2.60 (m, 6H); 3.40-3.52 ( m,
4H); 4.02 (s, 3H); 4.11 (br s, 1H); 4.15 (dd, 1H); 4.27 (dd, 1H); 5.05 (d, 1H); 6.26 (s, 1H);
7.01 (dd, 1H); 7.18 (d, 1H); 7.46 (s, 1H); 7.63 (s, 1H); 8.52 (s, 1H); 11.36 (s, 1H)
MS-ESI: 524.5 [M+H]+
-159-
Example 53
(Me)2NCH2CO2H, HATU,
DIPEA, DMF
4-[(4-Fluoro-2-methyl-l#-indol)-5-yloxy]-6-methoxy-7-(piperidin-4-
ylmethoxy)quinazo]ine (SOOmg, 1.15 mmol), (prepared as described for the starting material in
Example 11), N,N-dimethylglycine (142mg, 1.37mmo!) and O-(7-azabenzotriazol-l-yl)-
AWAW'-tetramethyluronium hexafluorophosphate (HATU) (523mg, 1.37mmol) were stirred
in AfAf-dimethylformamide (4ml) and A^A^-diisopropylethylamine (399 Dl, 2.29mmol) was
added. The mixture was stirred for 1 hour, diluted with ethyl acetate, washed with brine
followed by 2N aqueous sodium hydroxide. The organic layer was dried (MgSOii) and
concentrated under reduced pressure. The residue was purified by column chromatography
eluting with methylene chloride/methane! (saturated with ammonia) (98/2) to give 7-[l-(A^^Vdbnethylaniinoacetyl)
piperidin-4-ylniethoxy]-4-[(4-fluoro-2-niethyl-l/r-indol)-5-yloxy]-
6-methoxyquinazoIine (455mg, 76%) as a white foam.
MS-ESI: 522.1 [MH]+
'H NMR Spectrum: (DMSOd6) 1.33 (m, 2H); 1.87 (br d, 2H); 2.22 (m, 7H); 2.44 (s, 3H);
2.65 (br t, 1H); 3.10 (m, 3H); 4.02 (s, 3H); 4.12 (m, 3H); 4.43 (br d, 1H); 6.27 (s, 1H); 7.01
(t, 1H); 7.18 (d, 1H); 7.42 (s, 1H); 7.63 (s, 1H); 8.52 (s, 1H); 11.34 (br s, 1H)
Example 54
The foDowing illustrate representative pharmaceutical dosage forms containing the
compound of formula I, or a pharmaceutically acceptable salt thereof (hereafter compound X),
for therapeutic or prophylactic use in humans:
(a) Tablet I
Compound X
Lactose Ph.Eur
rug/tablet
100
182.75
Croscarmellose sodium
Maize starch paste (5% w/v paste)
Magnesium stearate
12.0
2.25
3.0
(b) Tablet II mg/tablet
Compound X 50
Lactose Ph.Eur 223.75
Croscannellose sodium 6.0
Maize starch 15.0
Polyvinylpyrrolidone (5% w/v paste) 2.25
Magnesium stearate 3.0
(c) Tablet III
Compound X
Lactose Ph.Eur
Croscarmellose sodium
Maize starch paste (5% w/v paste)
Magnesium stearate
mg/tablet
1.0
93.25
4.0
0.75
1.0
(d) Capsule
Compound X
Lactose Ph.Eur
Magnesium stearate
mg/capsule
10
488.5
1.5
(e) Injection I
Compound X
1M Sodium hydroxide solution
0.1M Hydrochloric acid
(to adjust pH to 7.6)
Polyethylene glycol 400
Water for injection to 100%
(50 mg/ml)
5.0% w/v
15.0% v/v
4.5% w/v
(f) Injection II 10 me/ml')
Compound X 1.0% w/v
Sodium phosphate BP 3.6% w/v
0.1M Sodium hydroxide solution 15.0% v/v
Water for injection to 100%
(g) Injection III f Img/ml.buffered to pH6')
Compound X 0.1% w/v
Sodium phosphate BP 2.26% w/v
Citric acid 0.38% w/v "
Polyethylene glycol 400 3.5% w/v
Water for injection to 100%
Note
The above formulations may be obtained by conventional procedures well known in the
pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for
example to provide a coating of cellulose acetate phthalate.





We Claim:
1. A substituted quinazoline compound of the formula lid:
(Formula Removed)
wherein: M is -CH- or -N-;
R2c is linked to a carbon atom of the 5-membered ring and is selected from hydrogen and methyl;
R2d is linked to a carbon atom of the 6-membered ring and is selected from hydrogen and fluoro;
one of R2a and R2b is methoxy and the other is Q1X1 wherein X1 is -O- and Q1 is selected from one of the following four groups:
1) Q2 (wherein Q2 is a heterocyclic group selected from pyrrolidinyl,
piperidinyl, piperazinyl,
(Formula Removed)
which heterocyclic group bears one substituent selected from C2-5alkenyl, C2-5alkynyl, C1-4alkanoyl, aminoC1-6alkanoyl, C1-4alkylaminoC1-6alkanoyl, di(C1-4alkyl)aminoC1-6alkanoyl, C1-6fluoroalkanoyl, carbamoyl, C1-4alkylcarbamoyl, di(C1-4alkyl)carbamoyl, carbamoylC1-6alkyl, C1-4alkylcarbamoylC1-6alkyl, di(C1-4alkyl)carbamoylC1-6alkyl, C1-4alkylsulphonyl and C1-4fluoroalkylsulphonyl;
2) C1-5alkylQ2 (wherein Q2 is as defined herein);
3) C1-4alkylW2C1-4alkylQ2 (wherein W2 represents -O-, -S-, -SO-, -
SO2-, -NQ8C(O)-, -C(O)NQ9-, -SO2NQ10-, -NQnSO2- or -NQ12-
(wherein Q8, Q9, Q10, Q11 and Q12 each independently represents
hydrogen, C1-salkyl, C1-3alkoxyC2-3alkyl, Ca-salkenyl, C2-5alkynyl
or C1-4haloalkyl) and Q2 is as defined herein);
4) C1-4alkylQ13(C1-4alkyl)j(W2)kQ14 (wherein W2 is as defined herein,
j is 0 or 1, k is 0 or 1, and Q13 and Q14 are each independently
selected from pyrrolidinyl, piperidinyl, piperazinyl,
(Formula Removed)
which heterocyclic group may bear 1, 2 or 3 substituents
selected from C2-5alkenyl, C2-5alkynyl, C1-4alkanoyl, aminoC1-
6alkanoyl, C1-4alkylaminoC1-6alkanoyl, di(C1-4alkyl)aminoC1-
6alkanoyl, C1-6fiuoroalkanoyl, carbamoyl, C1-4alkylcarbamoyl,
di(C1-4alkyl)carbamoyl, carbamoylC1-6alkyl, C1-
4alkylcarbamoylC1-6alkyl, di(C1-4alkyl)carbamoylC1-6alkyl, C1-4alkylsulphonyl, C1-4fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano, C1-4cyanoalkyl, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, C1-4alkoxyC1-4alkyl;
with the proviso that at least one of Q13 and Q14 bears at least one substituent selected from C2-5alkenyl, C2-5alkynyl, C1-4alkanoyl, aminoC1-6alkanoyl, C1-4alkylaminoC1-6alkanoyl, di(C1-4alkyl)aminoC1-6alkanoyl, C1-6fluoroalkanoyl, carbamoyl, C1-4alkylcarbamoyl, di(C1-4alkyl)carbamoyl, carbamoylC1-6alkyl, C1-4alkylcarbamoylC1-6alkyl, di(C1-4alkyl)carbamoylC1-6alkyl, C1-4alkylsulphonyl and C1-4fluoroalkylsulphonyl); and additionally wherein any C1-salkyl, group in Q1X1- which is linked to X1 may bear one or more substituents selected from hydroxy, halogeno and amino.
2. A compound as claimed in claim 1 selected from:
4-(7-azaindol-5-yloxy)-7-rnethoxy-6-(3-(4-
methylsulphonylpiperazin-1 -yl)propoxy)quinazoline,
6-(3-(4-acetylpiperazin-1 -yl)propoxy)-4-(7-azaindol-5-yloxy)-7-
methoxyquinazoline,
4-[(4-fluoro-2-methyl-lH-indol-5-yl)oxy]-7-{[(2S)-l-isobutyrylpyrrolidin-2-yl]methoxy}-6-methoxyquinazoline, 4-(7-azamdol-5-yloxy)-6-methoxy-7-[3-(4-carbamoylpiperazin-l-y 1) propoxy ] quinazoline,
6-[2-(4-acetylpiperazin-l-yl)ethoxy]-4-[(4-fluoro-lH-indol-5-yl)oxy]-7-methoxyquinazoline, 6-[(l-acetylpiperidin-4-yl)methoxy]-4-[(4-fluoro-lH-indol-5-
yl) oxy] - 7-methoxyquinazoline,
7-[2-(4-acetylpiperazin-l-yl)ethoxy]-4-(7-azaindol-5-yloxy)-6-methoxyquinazoline,
4-(7-azaindol-5-yloxy)-7-[3-(4-carbamoylmethyl)piperazin-l-y 1) propoxy] - 6 - methoxy quinazoline,
4-(7-azaindol-5-yloxy)-6-methoxy-7-[3-(4-prop-2-yn-l-ylpiperazin-1 -yl)propoxy]quinazoline,
7-[l-(N,N-dimethylaminoacetyl)piperidin-4-ylmethoxy]-4-[(4-fluoro-2-methyl-1 H-indol)- 5-yloxy]-6-methoxyquinazoline, and salts thereof.
3. A compound as claimed in claim 1 selected from:
6-(3-(4-acetylpiperazin-l-yl)propoxy)-4-(4-fluoro-2-methylindol-
5-yloxy)-7-methoxyquinazoline,
7-(3-(4-acetylpiperazin-1 -yl)propoxy)-4-(7-azaindol-5-yloxy)-6-methoxyquinazoline,
4-(7-azaindol-5-yloxy)-6-rnethoxy-7-(3-(4-methylsulphonylpiperazin-1 -yl) propoxy) quinazoline, 4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxy-6-(3-(4-methylsulphonylpiperazin-1 -yl) propoxy) quinazoline,
4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-
methylsulphonylpiperazin-1 -yl)propoxy)quinazoline,
6-(3-(4-acetylpiperazin-l-yl)propoxy)-4-(4-fluoroindol-5-yloxy)-7-
methoxyquinazoline,
7-[(l-acetylpiperidin-4-yl)methoxy]-4-[(4-fluoro-2-methyl-lH-
indol-5-yl)oxy]-6-methoxyquinazoline,
7-[(2S)-l-acetylpyrrolidin-2-ylmethoxy]-4-[(4-nuoro-2-methyl-
lH-indol-5-yl)oxy]-6-methoxyquinazoline,
7-[(2R)-l-acetylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-methyl-
lH-indol-5-yl)oxy]-6-methoxyquinazoline,
7-{2-[2-(4-acetylpiperazin-l-yl)ethoxy]ethoxy}-4-[(4-fluoro-2-
methyl-lH-indol-5-yl)oxy]-6-methoxyquinazoline,
4-[(4-fluoro-2-methyl-lH-indol-5-yl)oxy]-7-[(l-
isobutyrylpiperidin-4-yl)methoxy]-6-methoxyquinazoline,
4-[(4-fluoro-2-methyl-lH-indol-5-yl)oxy]-7-{[(2R)-l-
isobutyrylpyrrolidin-2-yl]methoxy}-6-methoxyquinazoline,
4- [(4-fluoro-2-methyl-1 H-indol-5-yl)oxy]-6-methoxy-7-{[ 1 -
(methyl sulfonyl) piperidin-4 -yl] methoxy}quinazoline,
4-[(4-fluoro-2-methyl-lH-indol-5-yl)oxy]-6-methoxy-7-{[(2S)-l-
(methylsulfonyl) pyrrolidin- 2 -yl] me thoxyjquinazoline,
4-[(4-fluoro-2-methyl-lH-indol-5-yl)oxy]-6-methoxy-7-{[(2R)-l-
(methylsulfonyl)pyrrolidin-2-yl]methoxy}quinazoline,
7-[3-(4-allylpiperazin-l-yl)propoxy]-4-(7-azaindol-5-yloxy)-6-
methoxyquinazoline,
4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxy-7-{3-[4-(2-
propynyl)piperazin-1 -yl]propoxy}quinazoline,
7-[3-(4-acetylpiperazin-l-yl)propoxy]-4-(lH-indol-5-yloxy)-6-
methoxyquinazoline,
7-[(2S)-l-carbamoylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-
methyl-lH-indol-5-yl)oxy]-6-methoxyquinazoline,
7-{3-[4-carbamoylpiperazin-l-yl]propoxy}-4-[(4-fluoro-2-methyl-
lH-indol-5-yl)oxy]-6-methoxyquinazoline,
6-[(l-acetylpiperidin-4-yl)oxy]-4-[(4-fluoro-lH-indol-5-yl)oxy]-7-
methoxyquinazoline,
4-[(4-fluoro-lH-indol-5-yl)oxy]-7-methoxy-6-{[l-
(methylsulphonyl)piperidin-4-yl]oxy}quinazolme,
7-[3-(4-acetylpiperazin-l-yl)propoxy]-6-methoxy-4-[(2-methyl-
lH-indol-5-yl)oxy]quinazoline,
7-[3-(4-acetylpiperazin-l-yl)propoxy]-4-[(4-fluoro-lH-indol-5-
yl)oxy]-6-methoxyquinazoline,
7-[3-(4-carbamoylmethylpiperazin-1 -yl)propoxy]-4-[(4-fluoro-2-
methyl-lH-indol-5-yl)oxy]-6-methoxyquinazoline,
4-[(4-fluoro-2-methyl-lH-indol-5-yl)oxy]-7-{(2R)-2-hydroxy-3-[4-
prop-2-yn-1-ylpiperazin-1 -yl]propoxy}-6-methoxyquinazoline,
7-{(2R)-3-[4-acetylpiperazin-1-yl]-2-hydroxypropoxy}-4-[(4-
fluoro-2-methyl- lH-indol-5-yl)oxy]-6-methoxyquinazoline,
and salts thereof.
4. A compound as claimed in claim 1 which is 7-(3-(4-
acetylpiperazin-l-yl)propoxy)-4-(4-fluoro-2-niethylindol-5-yloxy)-
6-methoxyquinazoline and salts thereof.
5. A compound as claimed in claim 1 which is 7-[2-(4-
acetylpiperazin-1 -yl)ethoxy]-4-[(4-fluoro-2-methyl- lH-indol-5-
yl)oxy]-6-methoxyquinazoline and salts thereof.
6. A compound as claimed in claim 1 in the form of a
pharmaceutically acceptable salt.
7. A process for the preparation of a compound as claimed in claim
1 of the formula lid or salt thereof which comprises:
(a) the reaction of a compound of the formula III:
(Formula Removed)
(wherein R2 is R2a and R2b as defined in claim 1, m is 2 and L1 is a displaceable moiety), with a compound of the formula IV:
(Formula Removed)
(wherein ring C is the bicyclic heteroaromatic ring containing M as defined in claim 1, R1 is R2c and R2d as defined in claim 1, Z is -O- and n is 2);
and when a salt of a compound of formula lid is required, reaction of the compound obtained with an acid or base whereby to obtain the desired salt.

Documents:

2016-DELNP-2004-Abstract-(21-11-2008).pdf

2016-delnp-2004-abstract.pdf

2016-DELNP-2004-Claims-(21-11-2008).pdf

2016-delnp-2004-claims.pdf

2016-DELNP-2004-Correspondence-Others-(21-11-2008).pdf

2016-delnp-2004-correspondence-others.pdf

2016-DELNP-2004-Description (Complete)-(21-11-2008).pdf

2016-delnp-2004-description (complete).pdf

2016-DELNP-2004-Form-1-(21-11-2008).pdf

2016-delnp-2004-form-1.pdf

2016-delnp-2004-form-18.pdf

2016-DELNP-2004-Form-2-(21-11-2008).pdf

2016-delnp-2004-form-2.pdf

2016-DELNP-2004-Form-3-(21-11-2008).pdf

2016-delnp-2004-form-3.pdf

2016-delnp-2004-form-5.pdf

2016-DELNP-2004-GPA-(21-11-2008).pdf

2016-delnp-2004-gpa.pdf

2016-delnp-2004-pct-210.pdf

2016-delnp-2004-pct-220.pdf

2016-delnp-2004-pct-304.pdf

2016-delnp-2004-pct-306.pdf

2016-delnp-2004-pct-409.pdf

2016-delnp-2004-pct-416.pdf

2016-DELNP-2004-Petition-137-(21-11-2008).pdf

2016-DELNP-2004-Petition-138-(21-11-2008).pdf


« Previous Patent
Next Patent »
Patent Number 232952
Indian Patent Application Number 2016/DELNP/2004
PG Journal Number 13/2009
Publication Date 27-Mar-2009
Grant Date 24-Mar-2009
Date of Filing 14-Jul-2004
Name of Patentee ASTRAZENECA AB
Applicant Address S-151 85 SöDERTäLJE, SWEDEN.
Inventors:
# Inventor's Name Inventor's Address
1 LAURENT FRANCOIS ANDRE HENNEQUIN C/O ASTRAZENECA R & D ALDERLEY, ALDERLEY PARK, MACCLESFIELD, CHESHIRE SK10 4TG, ENGLAND.
PCT International Classification Number C07D 403/12
PCT International Application Number PCT/GB03/00343
PCT International Filing date 2003-01-28
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 02290242.3 2002-02-01 EUROPEAN UNION