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ZA200602191B - Quinazoline derivatives as tyrosine kinase inhibitors - Google Patents

Quinazoline derivatives as tyrosine kinase inhibitors Download PDF

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ZA200602191B
ZA200602191B ZA200602191A ZA200602191A ZA200602191B ZA 200602191 B ZA200602191 B ZA 200602191B ZA 200602191 A ZA200602191 A ZA 200602191A ZA 200602191 A ZA200602191 A ZA 200602191A ZA 200602191 B ZA200602191 B ZA 200602191B
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alkyl
group
alkoxy
formula
hydroxy
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ZA200602191A
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Hennequin Laurent Franco Andre
Halsall Christopher Thomas
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Astrazeneca Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

QUINAZOLINE DERIVATIVES AS TYROSINE KINASE INHIBITORS
The invention concerns certain novel quinazoline derivatives, or pharmaceutically acceptable salts, or pharmaceutically acceptable esters thereof, which possess anti-tumour activity and are accordingly useful in methods of treatment of the human or animal body. The invention also concems processes for the manufacture of said quinazoline derivatives, 10 pharmaceutical compositions containing them and to their use in therapeutic methods, for example in the manufacture of medicaments for use in the prevention or treatment of solid tumour disease in a warm-blooded animal such as man.
Many of the current treatment regimes for diseases resulting from the abnormal regulation of cellular proliferation such as psoriasis and cancer, utilise compounds that inhibit
DNA synthesis and cellular proliferation. To date, compounds used in such treatments are generally toxic to cells however their enhanced effects on rapidly dividing cells such as tumour cells can be beneficial. Alternative approaches to these cytotoxic anti-tumour agents are currently being developed, for example selective inhibitors of cell signalling pathways.
These types of inhibitors are likely to have the potential to display an enhanced selectivity of action against tumour cells and so are likely to reduce the probability of the therapy possessing unwanted side effects.
Eukaryotic cells are continually responding to many diverse extracellular signals that enable communication between cells within an organism. These signals regulate a wide variety of physical responses in the cell including proliferation, differentiation, apoptosis and motility. The extracellular signals take the form of a diverse variety of soluble factors including growth factors as well as paracrine and endocrine factors. By binding to specific transmembrane receptors, these ligands integrate the extracellular signal to the intracellular signalling pathways, therefore transducing the signal across the plasma membrane and allowing the individual cell to respond to its extracellular signals. Many of these signal transduction processes utilise the reversible process of the phosphorylation of proteins that are involved in the promotion of these diverse cellular responses. The phosphorylation status of target proteins is regulated by specific kinases and phosphatases that are responsible for the regulation of about one third of all proteins encoded by the mammalian genome. As phosphorylation is such an important regulatory mechanism in the signal transduction process, it is therefore not surprising that aberrations in these intracellular pathways result in abnormal cell growth and differentiation and so promote cellular transformation (reviewed in
Cohen ez al, Curr Opin Chem Biol, 1999, 3, 459-465).
It has been widely shown that a number of these tyrosine kinases are mutated to constitutively active forms and/or when over-expressed result in the transformation ofa
S variety of human cells. These mutated and over-expressed forms of the kinase are present ina large proportion of human tumours (reviewed in Kolibaba et al, Biochimica et Biophysica
Acta, 1997, 133, F217-F248). As tyrosine kinases play fundamental roles in the proliferation and differentiation of a variety of tissues, much focus has centred on these enzymes in the development of novel anti-cancer therapies. This family of enzymes is divided into two groups - receptor and non-receptor tyrosine kinases €.g. EGF Receptors and the SRC family respectively. From the results of a large number of studies including the Human Genome
Project, about 90 tyrosine kinase have been identified in the human genome, of this 58 are of the receptor type and 32 are of the non-receptor type. These can be compartmentalised in to 20 receptor tyrosine kinase and 10 non-receptor tyrosine kinase sub-families (Robinson et al,
Oncogene, 2000, 19, 5548-5557).
The receptor tyrosine kinases are of particular importance in the transmission of mitogenic signals that initiate cellular replication. These large glycoproteins, which span the plasma membrane of the cell possess an extracellular binding domain for their specific ligands (such as Epidermal Growth Factor (EGF) for the EGF Receptor). Binding of ligand results in the activation of the receptor’s kinase enzymatic activity that is encoded by the intracellular portion of the receptor. This activity phosphorylates key tyrosine amino acids in target proteins, resulting in the transduction of proliferative signals across the plasma membrane of the cell.
It is known that the erbB family of receptor tyrosine kinases, which include EGFR, erbB2, erbB3 and erbB4, are frequently involved in driving the proliferation and survival of tumour cells (reviewed in Olayioye et al., EMBO I., 2000, 19, 3159). One mechanism in which this can be accomplished is by overexpression of the receptor at the protein level, generally as a result of gene amplification. This has been observed in many common human cancers (reviewed in Klapper et al., Adv. Cancer Res., 2000, 77, 25) such as breast cancer (Sainsbury et al., Brit. J. Cancer, 1988, 58, 458; Guerin et al., Oncogene Res., 1988, 3, 21;
Slamon et al., Science, 1989, 244, 707; Klijn et al., Breast Cancer Res. Treat., 1994, 29, 73 and reviewed in Salomon et al., Crit. Rev. Oncol. Hematol., 1995, 19, 183), non-small cell jung cancers (NSCLC) including adenocarcinomas (Cerny et al., Brit. J. Cancer, 1986, 54,
265; Reubi et al., Int. J. Cancer, 1990, 45, 269; Rusch et al., Cancer Research, 1993, 53,2379;
Brabender et al, Clin. Cancer Res., 2001, 7, 1850) as well as other cancers of the lung (Hendler et al., Cancer Cells, 1989, 7, 347; Ohsaki et al., Oncol. Rep., 2000, 7, 603), bladder cancer (Neal et al., Lancet, 1985, 366; Chow et al., Clin. Cancer Res., 2001, 7, 1957, Zhau et
S al., Mol Carcinog., 3, 254), oesophageal cancer (Mukaida et al., Cancer, 1991, 68, 142), gastrointestinal cancer such as colon, rectal or stomach cancer (Bolen et al., Oncogene Res., 1987, 1, 149; Kapitanovic et al., Gastroenterology, 2000, 112, 1103; Ross et al., Cancer
Invest., 2001, 19, 554), cancer of the prostate (Visakorpi et al., Histochem. J., 1992, 24, 481,
Kumar et al., 2000, 32, 73; Scher et al, J. Natl. Cancer Inst., 2000, 92, 1866), leukaemia (Konaka et al., Cell, 1984, 37, 1035, Martin-Subero et al., Cancer Genet Cytogenet, 2001, 127, 174), ovarian (Hellstrom et al., Cancer Res., 2001, 61, 2420), head and neck (Shiga ef al., Head Neck, 2000, 22, 599) or pancreatic cancer (Ovotny et al., Neoplasma, 2001, 48, 188). As more human tumour tissues are tested for expression of the erbB family of receptor tyrosine kinases it is expected that their widespread prevalence and importance will be further enhanced in the future.
As a consequence of the mis-regulation of one or more of these receptors, it is widely believed that many tumours become clinically more aggressive and so correlate with a poorer prognosis for the patient (Brabender et al, Clin. Cancer Res., 2001, 7, 1850; Ross et al, Cancer
Investigation, 2001, 19, 554, Yu et al., Bioessays, 2000, 22.7, 673). In addition to these clinical findings, a wealth of pre-clinical information suggests that the erbB family of receptor tyrosine kinases are involved in cellular transformation. This includes the observations that many tumour cell lines overexpress one or more of the erbB receptors and that EGFR or erbB2 when transfected into non-tumour cells have the ability to transform these cells. This tumourigenic potential has been further verified as transgenic mice that overexpress erbB2 spontaneously develop tumours in the mammary gland. In addition to this, a number of pre-clinical studies have demonstrated that anti-proliferative effects can be induced by knocking out one or more erbB activities by small molecule inhibitors, dominant negatives or inhibitory antibodies (reviewed in Mendelsohn et al., Oncogene, 2000, 19, 6550). Thus it has been recognised that inhibitors of these receptor tyrosine kinases should be of value as a selective inhibitor of the proliferation of mammalian cancer cells (Yaish et al. Science, 1988, 242, 933, Kolibaba et al, Biochimica et Biophysica Acta, 1997, 133, F217-F248; Al-Obeidi er al, 2000, Oncogene, 19, 5690-5701; Mendelsohn et al, 2000, Oncogene, 19, 6550-6565).
Recently the small molecule EGFR tyrosine kinase inhibitor, Iressa (also known as gefitinib, and ZD 1834) has been approved for use in the treatment of advanced non-small cell lung cancer. Furthermore, findings using inhibitory antibodies against EGFR and erbB2 (c-225 and trastuzumab respectively) have proven to be beneficial in the clinic for the treatment of selected solid tumours (reviewed in Mendelsohn et al, 2000, Oncogene, 19, 6550-6565).
Amplification and/or activity of members of the erbB receptor tyrosine kinases have been detected and so have been implicated to play a role in a number of non-malignant proliferative disorders such as psoriasis (Ben-Bassat, Curr. Pharm. Des., 2000, 6, 933; Elder et al., Science, 1989, 243, 811), benign prostatic hyperplasia (BPH) (Kumar gt al., Int. Urol.
Nephrol., 2000, 32,73), atherosclerosis and restenosis (Bokemeyer et al., Kidney Int., 2000, 58, 549). It is therefore expected that inhibitors of erbB receptor tyrosine kinases will be useful in the treatment of these and other non-malignant disorders of excessive cellular proliferation.
European patent application EP 566 226 discloses certain 4-anilinoquinazolines that are receptor tyrosine kinase inhibitors.
International patent applications WO 96/33977, WO 96/33978, WO 96/33979, WO 96/33980, WO 96/33981, WO 97/30034, WO 97/38994 disclose that certain quinazoline derivatives which bear an anilino substituent at the 4-position and a substituent at the 6- and/or 7- position possess receptor tyrosine kinase inhibitory activity.
European patent application EP 837 063 discloses aryl substituted 4-aminoquinazoline derivatives carrying moiety containing an aryl or heteroaryl group at the 6-or 7- position on the quinazoline ring. The compounds are stated to be useful for treating hyperproliferative disorders.
International patent applications WO 97/30035 and WO 98/13354 disclose certain 4-anilinoquinazolines substituted at the 7-position are vascular endothelial growth factor receptor tyrosine kinase inhibitors.
WO 00/55141 discloses 6,7-substituted 4-anilinoquinazoline compounds characterised in that the substituents at the 6-and/or 7-position carry certain ester groups.
WO 00/56720 discloses 6,7-dialkoxy-4-anilinoquinazoline compounds for the treatment of cancer or allergic reactions.
WO001/21596 discloses the use of certain 4-anilinoquinazoline derivatives as aurora 2 kinase inhibitors.
substituted at the 6- and/or 7- position which are stated to have an inhibitory effect upon signal transduction mediated by tyrosine kinases.
WO 02/41882 discloses 4-anilinoguinazoline compounds substituted at the 6- and/or 7- position by a substituted pyrrolidinyl-alkoxy or piperidinyl-alkoxy group.
We have now found that surprisingly certain quinazoline derivatives substituted at the 7-position with a substituent containing certain substituted alkanoyl groups possess potent anti-tumour activity. The compounds of the present invention also generally possess high cellular potency, and favourable physical properties, particularly solubility, which may provide advantages in the formulation and delivery of the compound to patients. Many of the compounds of the invention posses favourable DMPK properties, for example high bioavailability and/or high free-plasma levels and/or advantageous half life and/or advantageous volume of distribution and such properties are expected to provide improved in- vivo efficacy and may reduce inter-patient variability in exposure to the compound compared to other EGER tyrosine kinase inhibitors such as gefitinib.
Furthermore, many of the compounds according to the present invention are inactive or only weakly active in a hERG assay.
Without wishing to imply that the compounds disclosed in the present invention possess pharmacological activity only by virtue of an effect on a single biological process, it is believed that the compounds provide an anti-tumour effect by way of inhibition of one or more of the erbB family of receptor tyrosine kinases that are involved in the signal transduction steps which lead to the proliferation of tumour cells. In particular, it is believed that the compounds of the present invention provide an anti-tumour effect by way of inhibition of EGFR tyrosine kinase.
Generally the compounds of the present invention possess potent inhibitory activity against the erbB receptor tyrosine kinase family, for example by inhibition of EGF and/or erbB2 and/or erbB4 receptor tyrosine kinases, whilst possessing less potent inhibitory activity against other kinases, such as VEGF and KDR receptor tyrosine kinases. Furthermore, the compounds of the present invention possess substantially better potency against the EGFR tyrosine kinase over that of the erbB2 tyrosine kinase. Accordingly, it may be possible to administer a compound according to the present invention at a dose that is sufficient to inhibit
EGFR tyrosine kinase whilst having no significant effect upon erbB2 (or other) tyrosine kinases. The selective inhibition provided by the compounds according to the present invention may provide treatments for conditions mediated by EGFR tyrosine kinase, whilst reducing undesirable side effects that may be associated with the inhibition of other tyrosine kinases.
According to a first aspect of the invention there is provided a quinazoline derivative of the Formula I: [Fen ” HN : Ww), Dee,
Coe x wherein:
R! is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula :
Q-X- wherein X’ is a direct bond or is O, and Q? is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R' substituent are optionally separated by the insertion into the chain of a group selected from O,
S, SO, SO,, N(R?), CO, CH(OR®), CON(R?), N(R*)CO, SO,NR?), NR*)SO;, CH=CH and
C=C wherein R® is hydrogen or (1-6C)alkyl, and wherein any CH,=CH- or HC=C- group within a R! substituent optionally bears at the terminal CH,= or HC= position a substituent selected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N.N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkylJamino-(1-6C)alkyl or from a group of the formula :
Q*-X*- wherein X’is a direct bond or is selected from CO and N®R*CO, wherein R* is hydrogen or (1-6C)alkyl, and Q* is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any CH; or CH; group within a R! substituent, other than a CH, group within a heterocyclyl ring, optionally bears on each said CH; or CH; group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, oxo, thioxo, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, : (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl,
N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and
N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the formula: -x*-Q* wherein X° is a direct bond or is selected from O, S, SO, SO2, N(R®), CO, CH(OR),
CON(R®), N(R®)CO, SON(R®), N(R*)SOz, C(R®);0, CR®),S and CR®);N(R?), wherein Ris hydrogen or (1-6C)alkyl, and Q* is (3-7C)cycloalkyl, (3-7C)cycloalkyi- (1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R! optionally bears one or more (for example 1, 2 or 3) substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, formyl, mercapto, sulfamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1 -6C)alkylamino, di-[(1-6C)alkyl]Jamino, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, N-(1-6C)alkylsulfamoyl,
N,N-di-[(1-6C)alkyl]sulfamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl,
N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino, and
N-(1-6C)alkyl-(1-6C)alkanesuifonylamino, or from a group of the formula: -X8-R® wherein X%is a direct bond or is selected from O, N(R’) and C(O), wherein R” is hydrogen or (1-6C)alkyl, and RCis halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl, (1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,
N,N-di-[(1-6C)alkyl}carbamoyl-(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl or (1-6C)alkoxycarbonyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R! optionally bears 1 or 2 oxo or thioxo substituents; b isl, 2,3,40r5; each R?, which may be the same or different, is selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, trifluoromethyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2- 6C)alkanoy!, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino, N-(1- 6C)alkyl- (1-6C)alkanesulfonylamino and a group of the formula: -X"-R® wherein X” is a direct bond or is selected from O and N(R®), wherein R” is hydrogen or (1- 6C)alkyl, and R® is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1- 6C)alkyl}Jamino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl or (1- 6C)alkoxycarbonylamino-(1-6C)alkyl;
Q! is piperidinyl; ais0,1,2,30r4; each W, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, oxo, amino, formyl, mercapto, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyllamino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -x8-RY wherein X® is a direct bond or is selected from O, CO, SO; and N(R"), wherein R'! is hydrogen or (1-6C)alkyl, and R'? is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,
N-(1-6C)alkylamino-(1-6C)alky! or N,N-di-[(1-6C)alkylJamino-(1-6C)alkyl;
X! is selected from CO and SO»;
X? is a group of the formula:
(CR™R®),-(Q*)u-(CR¥R™)q- wherein misOor1,pis0,1,2,30r4andqis0, 1, 2,3o0r4, each of R'?, R'3, R™ and R', which may be the same or different, is selected from hydrogen, (1-6C)alkyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl]Jamino, and Q’ is selected from (3-7C)cycloalkylene and (3-7C)cycloalkenylene, and wherein any CH, or CH; group within an X? group, optionally bears on each said
CH, or CH; group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]Jamino;
Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl}amino, (1- 6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula:
Q-X°- wherein X’ is a direct bond or is selected from O, NR'®), SO; and SO,N(R'®), wherein R'¢ is hydrogen or (1-6C)alkyl, and Q°% is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4Calkyl; provided that when X? is a direct bond, Q° is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO,
SO,, N(R"), CO, -C=C- and -C=C- wherein R"" is hydrogen or (1-6C)alkyl, and wherein and wherein any CH, or CH3 group within any Z group, other than a CH; group within a heterocyclyl ring, optionally bears on each said CH; or CHj group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]Jamino,
N-(1-6C)alkylcarbamoyl, N .N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,
N-(1-6C)alkylsulfamoyi, N,N-di-[(1-6C)alkyl}sulfamoyl, (1-6C)alkanesulfonylamino and
N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl,
(2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsuifonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: _ x10- Rr! 8 wherein X'0 is a direct bond or is selected from O, CO, SO; and N(R"), wherein RY is hydrogen or (1-4C)alkyl, and R'® is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl,
N-(1-4C)alkylamino-(1-4C)alkyl and N N-di-[(1-4C)alkyl]amino-(1-4C)alkyl; provided that: when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or 4-chloro-2- fluoroanilino and R' is hydrogen or (1-3C)alkoxy, then ais 0 and Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkylJamino, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alky!-(1-6C)alkanesulfonylamino, and a group of the formula Q4-x°-; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof.
In a particular embodiment of the invention there is provided a quinazoline derivative of the Formula I as defined above, or a pharmaceutically acceptable salt thereof.
In this specification the generic term “alkyl” includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and (3-7C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. However references to individual alkyl groups such as “propyl” are specific for the straight-chain version only, references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only and references to individual cycloalkyl groups such as “cyclopentyl” are specific for that 5-membered ring only. An analogous convention applies to other generic terms, for example (1-6C)alkoxy includes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy, (1-6C)alkylamino includes methylamino, ethylamino, cyclobutylamino and cyclohexylamino, and di-{( 1-6Calkyljamino includes dimethylamino, diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl-N-ethylamino.
It is to be understood that, insofar as certain of the compounds of Formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity. It is further to be understood that in the names of chiral compounds (R,S) denotes any scalemic or racemic mixture while (R) and (5)
denote the enantiomers. In 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 enantiomers in any relative proportions and a racemic mixture contains R and § enantiomers in the ratio 50:50. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
Suitable values for the generic radicals referred to above include those set out below.
A suitable value for any one of the ‘Q’ groups (for example Q%4 Q%or Q%) when it is (3-7C)cycloalky! or for the (3-7C)cycloalkyl group within a ‘Q’ or R group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1}heptyl and a suitable value for any one of the ‘Q’ groups (for example Q? Q‘or Q%) when itis (3-7C)cycloalkenyl or for the (3-7C)cycloalkeny! group within a *Q’ group is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. It is to be understood that reference to (3-7C)cycloalkylene used herein for Q’refersto a divalent (3-7C)cycloalkane linking group, which group may be linked via different carbon atoms in the (3- 7C)cycloalkylene ring, or which may be linked via a single carbon atom in the (3- 7C)cycloalkylene ring. Accordingly, reference to, for example, a “cyclopropylene” group includes cycloprop-1,2-ylene and a cyclopropylidene group of the formula:
However references to an individual (3-7C)cycloalklene group such as cyclopropylidene are specific for that group only. A silmilar convention is adopted for the (3-7C)cycloalkenylene groups represented by Q’. :
A suitable value for the ‘Q’ groups, other than Q' (for example Q% Q’, Q*or Q% when it is heterocyclyl or for the heterocyclyl group within a ‘Q’ group is a non-aromatic saturated (i.e. ring systems with the maximum degree of saturation) or partially saturated (i.e. ring systems retaining some, but not the full, degree of unsaturation) 3 to 10 membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulfur, which, unless specified otherwise, may be carbon or nitrogen linked, for example oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4- dioxanyl, oxepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl,
1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, decahydroisoquinolinyl or decahydroquinolinyl, particularly tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1,4-oxazepanyl, thiamorpholinyl 1,1-dioxotetrahydro-4H- 1 4-thiazinyl, piperidinyl or piperazinyl, more particularly tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydrothien -3-yl, tetrahydrothiopyran-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, morpholino, morpholin-2-yl, piperidino, piperidin-4-yl, piperidin-3-yl, piperidin-2-yl or piperazin-1-yl. A nitrogen or sulfur atom within a heterocyclyl group may be oxidized to give the corresponding N or S oxide, for example 1,1-dioxotetrahydrothienyl, 1-oxotetrahydrothienyl, 1,1-dioxotetrahydrothiopyranyl or 1-oxotetrahydrothiopyranyl. A suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.
Q! is piperidinyl, which group is linked to the oxygen in Formula I by a ring carbon atom.
A suitable value for a ‘Q’ group when itis heterocyclyl-(1-6C)alkyl is, for example, heterocyclylmethyl, 2-heterocyclylethyl and 3-heterocyclylpropyl. The invention comprises corresponding suitable values for ‘Q’ groups when, for example, rather than a heterocyclyl-(1-6C)alkyl group, an (3-7C)cycloalkyl-(1-6C)alkyl or (3-7C)cycloalkenyl-(1-6C)alkyl is present.
Suitable values for any of the ‘R’ groups R' to R"), W, or for various groups within a
X', X? or Z group include:- for halogeno fluoro, chloro, bromo and iodo; for (1-6C)alkyl: methyl, ethyl, propyl, isopropyl! and tert-butyl; for (2-8C)alkenyl: vinyl, isopropenyl, allyl and but-2-enyl; for (2-8C)alkynyl: ethynyl, 2-propynyl and but-2-ynyl; for (1-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (2-6C)alkenyloxy: vinyloxy and allyloxy; for (2-6C)alkynyloxy: ethynyloxy and 2-propynyloxy; for (1-6C)alkylthio: methylthio, ethylthio and propylthio; for (1-6C)alkylsulfinyl: methylsulfinyl and ethylsulfinyl; for (1-6C)alkylsulfonyl: methylsulfony! and ethylsulfonyl;
for (1-6C)alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; for di-[(1-6C)alkyl}amino: dimethylamino, diethylamino, N-ethyl- _ N-methylamino and diisopropylamino; for (1-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for N-(1-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and
N-propylcarbamoyl; for N,N -di-[(1-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl, N-ethyl-
N-methylcarbamoyl and N,N-diethylcarbamoyl; for (2-6C)alkanoyl: acetyl, propionyl, butyryl and isobuyryl; for (2-6C)alkanoyloxy: acetoxy and propionyloxy; for (2-6C)alkanoylamino: acetamido and propionamido; for N-(1-6C)alkyl-(2-6C)alkanoylamino: N-methylacetamido and N-methylpropionamido; for N-(1-6C)alkylsulfamoyl: N-methylsulfamoyl and N-ethylsulfamoyl; for N,N-di-[(1-6C)alkyl]sulfamoyl: N,N-dimethylsulfamoy}; for (1-6C)alkanesulfonylamino: methanesulfonylamino and ethanesulfonylamino; for N-(1-6C)alkyl-(1-6C)alkanesulfonylamino: N-methylmethanesulfonylamino and
N-methylethanesulfonylamino; for (3-6C)alkenoylamino: acrylamido, methacrylamido and crotonamido; for N-(1-6C)alkyl-(3-6C)alkenoylamino: N-methylacrylamido and N-methylcrotonamido; for (3-6C)alkynoylamino: propiolamido; for N-(1-6C)alkyl-(3-6C)alkynoylamino: N-methylpropiolamido; for amino-(1-6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethy! and 3-aminopropyl; for (1-6C)alkylamino-(1-6C)alkyl: methylaminomethyl, ethylaminomethyl, 1-methylaminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl and 3-methylaminopropyl, for di-[(1-6C)alkyllamino-(1-6C)alkyl: dimethylaminomethyl, diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and 3-dimethylaminopropyl; for halogeno-(1-6C)alkyl: chloromethyl, 2-chloroethyl, 1-chloroethyl and 3-chloropropyl;
for hydroxy-(1-6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl; for (1-6C)alkoxy-(1-6C)alkyl: methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl; for cyano-(1-6C)alkyl: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and 3-cyanopropyl; for (1-6C)alkylthio-(1-6C)alkyl: methylthiomethyl, ethylthiomethyl, 2-methylthioethyl, 1-methylthioethyl and 3-methylthiopropyl; for (1-6C)alkylsulfinyl-(1-6C)alkyl: methylsulfinylmethyl, ethylsulfinylmethyl, 2-methylsulfinylethyl, 1-methylsulfinylethyl and 3-methylsulfinylpropyl; for (1-6C)alkylsulfonyl-(1-6C)alkyl: methylsulfonylmethyl, ethylsulfon yimethyl, 2-methylsulfonylethyl, 1-methylsulfonylethyl and 3-methylsulfonylpropyl; for (2-6C)alkanoylamino-(1-6C)alkyl: acetamidomethyl, propionamidomethyl and 2-acetamidoethyl; for N-(1-6C)alkyl-(2-6C)alkanoylamino-(1-6C)alkyl: N-methylacetamidomethyl, 2- (N-methylacetamido)ethyl and 2- (N-methylpropionamido)ethyl; for (1-6C)alkoxycarbonylamino-(1-6C)alkyl: methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl, tert-butoxycarbonylaminomethy! and 2-methoxycarbonylaminoethyl; (2-6C)alkanoyloxy-(1-6C)alkyl: acetoxymethyl, 2-acetoxyethyl and 2- propionyloxyethyl; for carbamoyl-(1-6C)alkyl: carbamoylmethyl, l1-carbamoylethyl, 2-carbamoylethyl and 3-carbamoylpropyl; for (2-6C)alkanoy!l-(1-6C)alkyl: acetylmethyl and 2-acetylethyl; for N-(1-6C)alkylcarbamoyl-(1-6C)alky!: N-methylcarbamoyimethyl,
N-ethylcarbamoylmethyl,
N-propylcarbamoylmethyl,
1-(N-methylcarbamoyl)ethyl, 1-(N-ethylcarbamoyl)ethyl, 2-(N-methylcarbamoyl)ethyl, 2-(N-ethylcarbamoyl)ethyl and 3-(N-methylcarbamoyl)propyl; for N,N-di[(1-6C)alkyl]carbamoyl-(1-6C)alkyl: N.N-dimethylcarbamoylmethyl,
N,N-diethylcarbamoylmethyl, 2-(N,N-dimethylcarbamoyl)ethyl, and 3.(N,N-dimethylcarbamoyl)propyl; for sulfamoyl(1-6C)alkyl: sulfamoylmethyl, 1-sulfamoylethyl, 2-sulfamoylethyl and 3-sulfamoylpropyl; for N-(1-6C)alkylsulfamoyl(1-6C)alkyl: N-methylsulfamoylmethyl,
N-ethylsulfamoylmethyl, N-propylsulfamoylmethyl, 1-(N-methylsulfamoyl)ethyl, 2-(N-methylsulfamoyl)ethyl and 3-(N-methylsulfamoyl)propyl; and for N.N di-(1-6C)alkylsulfamoyl(1-6C)alkyl: N,N-dimethylsulfamoyimethyl,
N,N-diethylsulfamoyimethyl, N methyl, N-ethylsulfamoylmethyl, 1-(
N,N-dimethylsulfamoyl)ethyl, 1-(N,N-diethylsulfamoyl)ethyl, 2-(N,N-dimethylsulfamoyl)ethyl, 2-(N,N-diethylsulfamoyl)ethyl and 3-(N,N-dimethylsulfamoyl)propyl.
When, as defined hereinbefore Z in Formula I is a group of the formula Q%-X’-, and x2 is SO,N(R'®), the SO; group is attached to Q° and the nitrogen atom is attached to X%in
Formula I. The same convention is applied to other groups defined herein. For example when X? is a group of the formula Q*-(CR'*R"),, the Q’ group is attached to the group Z in
Formula I and the (CR'R"), group is attached to the X! group in Formula lL.
As defined hereinbefore, adjacent carbon atoms in any (2-6C)alkylene chain within, for example, a R' substituent may be optionally separated by the insertion into the chain of a group such as 0, CON(R®), N(R?) or C=C. For example, insertion of a C=C group into the ethylene chain within a 2-morpholinoethoxy group gives rise to a 4-morpholinobut-2-ynyloxy group and, for example, insertion of a CONH group into the ethylene chain within a 3-methox ypropoxy group gives rise to, for example, a 2-(2-methoxyacetamido)ethoxy group-
It is to be understood that the term (2-6C)alkylene chain refers to any CH,CH; group (for example within RY) and includes, for example alkylene chains within a (1-6C)alkyl, (1- 6C)alkoxy, (2-8C)alkenyl, (2-8C)alkenyloxy, (2-8C)alkynyl and (2-8C)alkynyloxy group-
For example the insertion of a N(CH3) group between the third and fourth carbon atoms in a hex-5-enyloxy group in R! gives rise to a 3-(N-methyl-N-allylamino)propoxy group.
When, as defined hereinbefore, any CH;=CH- or HC=C- group within a R' substituent optionally bears at the terminal CH,= or HC= position a substituent such as a group of the formula Q*- X*- wherein X* is, for example, NHCO and Q’ is a heterocyclyl-(1-6C)alkyl group, suitable R! substituents so formed include, for example,
N-[heterocyclyl-(1-6C)alkyl]carbamoylvinyl groups such as
N-(2-pyrrolidin-1-ylethyl)carbamoylvinyl or
N-[heterocyclyl-(1-6C)alkyl]carbamoylethynyl groups such as N-(2-pyrrolidin- 1-ylethyl)carbamoylethynyl.
When reference is made herein to a CH; or CH; group optionally bearing on each said
CH; or CH; group one or more halogeno or (1-6C)alkyl substituents, there are suitably 1 or 2 halogeno or (1-6C)alkyl substituents present on each said CH, group and there are suitably 1, 2 or 3 such substituents present on each said CHs group.
Where reference is made herein to any CH; or CH; group optionally bearing on each said CH, or CH3 group a substituent as defined herein, suitable substituents so formed include, for example, hydroxy-substituted heterocyclyl-(1-6C)alkoxy groups such as 2-hydroxy-3-piperidinopropoxy and 2-hydroxy-3-morpholinopropoxy, hydroxy-substituted heterocyclyl-(1-6C)alkylamino groups such as 2-hydroxy-3-piperidinopropylamino and 2-hydroxy-3-morpholinopropylamino, and hydroxy-substituted (2-6)alkanoyl groups such as hydroxyacetyl, 2-hydroxypropionyl and 2-hydroxybutyryl.
Where reference is made herein to “any CH; or CH3 group, other than a CH, group within a heterocyclyl group, optionally bearing a substituent”, it is to be understood that such a statement is present only to distinguish between optional substituents that may be present on, for example, a CH; group in an alkyl group from substituents that may be present on carbon atoms of a heterocyclyl group. Accordingly, it is to be understood, that this statement does not exclude other substituents being present on ring carbon atoms in a heterocyclyl group when it is stated herein that said heterocyclyl group may also optionally bear one or more substituents. For example, if R! is 3-(pyrrolidin-1-yl)propoxy and herein it is stated that a CH, or CH; group within, for example, a R! substituent, other than a CH; group within a heterocyclyl group, optionally bears a hydroxy substituent, and that any heterocyclyl group within R! optionally bears an alkyl substituent, then the optional hydroxy substituent may be present on a CH; of the propoxy group to give for example a 2-hydroxy-3-(pyrrolidin-1- yl)propoxy group. Similarly an alkyl group such as methyl may be present on the pyrrolidinyl ring to give, for example, a 3-(3-methylpyrrolidin-1-yl)propoxy group. Equally, the propoxy group may be substituted by a hydroxy group and the pyrrolidinyl ring may be substituted by a methyl group to give, for example, a 2-hydroxy-3-(3-methylpyrrolidin-1-yl)propoxy group.
For the avoidance of doubt, when W is oxo, a CH; in Q' is substituted by O to give a
C(O) group.
It is to be understood that reference herein to Q' being, for example piperidin-4-yl refers to the attachment of the piperidine ring to the oxygen in Formula I. The piperidine ring is further substituted at the 1-position by the group Z-X2-X'- and optionally bears one or more
W substituents on one or more of the available piperidinyl ring carbon atoms.
It is to be understood that certain compounds of the Formula I may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. Itis to be understood that the invention encompasses all such solvated forms which exhibit an inhibitory effect on an erbB receptor tyrosine Kinase.
Tt is also to be understood that certain compounds of the Formula I may exhibit polymorphism, and that the invention encompasses all such forms which exhibit an inhibitory effect on an erbB receptor tyrosine kinase.
It is also to be understood that the invention relates to all tautomeric forms of the compounds of the Formula I forms which exhibit an inhibitory effect on an erbB receptor tyrosine kinase.
A suitable pharmaceutically acceptable salt of a compound of the Formula I is, for example, an acid-addition salt of a compound of the Formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
The term "pharmaceutically acceptable ester” used herein refers to an ester of a quinazoline derivative of the Formula I which hydrolyses in vivo to leave the parent compound or a pharmaceutically acceptable salt thereof. An in-vivo hydrolysable ester of a quinazoline of Formula I may be used to alter or improve the physical and/or pharmacokinetic profile of the parent compound, for example the solubility. Suitable ester groups that may be used in the formation of pharmaceutically acceptable ester prodrugs are well known, for example as discussed in for example:
Pro-drugs as Novel Delivery Systems, T. Higuchi and V. Stella, Vol. 14 of the ACS
Symposium Series, and in Edward B. Roche, ed;
Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon
Press, 1987;
Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology,
Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);
A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.
Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991);
H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);
H. Bundgaard, et al., Jounal of Pharmaceutical Sciences, 77, 285 (1988); and
N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).
A particular pharmaceutically acceptable ester of a quinazoline derivative of the
Formula I or a pharmaceutically acceptable salt thereof is, an ester formed with a carboxy or, particularly, a hydroxy group (for example when Z is hydroxy) in Formula I, which ester is hydrolysed in the human or animal body to produce the parent quinazoline of Formula I when administered to a warm blooded animal such as a human.
Suitable pharmaceutically acceptable esters for a carboxy group in Formula I include
C,.salkoxymethyl esters for example methoxymethyl, Cy salkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, Cs.scycloalkoxycarbonyloxyCi.salkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and C 1 salkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
Suitable pharmaceutically acceptable esters for a hydroxy group in Formula Iora pharmaceutically acceptable salt thereof include inorganic esters such as phosphate esters, 0 acyloxyalkyl ethers and related compounds, and esters derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms, and may be formed at any hydroxy group in the compounds of this invention, for example when Z is hydroxy or contains a hydroxy group. Following administration, the pharmaceutically acceptable ester undergoes in-vivo hydrolysis breakdown to give the parent carboxy/hydroxy group in the quinazoline derivative of Formula 1.
Examples of a-acyloxyalkyl ethers that may be used to form a pharmaceutically acceptable ester include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of pharmaceutically acceptable ester forming groups for a hydroxy group in Formula I (for example when Z is hydroxy) include (1-6C)alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, (1-6C)alkoxycarbonyl (to give alkyl carbonate esters), di-(1- 4C)alkylcarbamoyl and N-(di-(1-4C)alkylaminoethyl)-N-(1-4C)alkylcarbamoyl (to give carbamates), di-(1-4C)alkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include chloromethyl or aminomethyl, (1-4C)alkylaminomethyl and di-((1- 4C)alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom viaa methylene linking group to the 3- or 4-position of the benzoyl ring.
Particular pharmaceutically acceptable esters are phosphate esters formed with a hydroxy group in the quinazoline derivative for the Formula I (for example when Z is hydroxy or contains a hydroxy group), or a pharmaceutically acceptable salt thereof. More particularly, pharmaceutically acceptable esters include quinazoline derivatives of the
Formula I in which a hydroxy group in Formula I forms a phosphoryl (npd is 1) or phosphiryl (npd is 0) ester of the formula (PD1), or a pharmaceutically acceptable salt thereof:
Nie
HO ~F ~0~
HO
(PD1)
Another particular pharmaceutically acceptable ester is a quinazoline derivative of the
Formula I in which a hydroxy in Formula I (for example when Z is hydroxy) forms a phosphoryl to give a group of the formula (PD1) wherein npd is 1.
Useful intermediates for the preparation of such esters include compounds containing a group of formula (PD1) in which either or both of the -OH groups in (PD1) is independently protected by (1-4C)alkyl (such compounds also being interesting compounds in their own right), phenyl or phenyl-(1-4C)alkyl (such phenyl groups being optionally substituted by 1 or 2 groups independently selected from (1-4C)alkyl, nitro, halo and (1-4C)alkoxy).
Pharmaceutically acceptable esters of a quinazoline derivative of Formula I containing a group such as (PD1), may be prepared by reaction of a quinazoline derivative Formula I with a suitably protected phosphorylating agent (for example, containing a chloro or dialkylamino leaving group), followed by oxidation (if necessary) and deprotection. Suitable phosphorylating agents are well known and include, for example protected phosphoramidite compounds such as a N,N-di-[(1-6C)alkyl]- phosphoramidite, for example di-tert-butyl N,N- diethylphosphoramidite.
It is to be understood that an ester group in the quinazoline derivative of the Formula may form a pharmaceutically acceptable salt of the ester group and that such salts form part of the present invention. Where pharmaceutically acceptable salts of a pharmaceutically acceptable ester is required this is achieved by conventional techniques well known to those of ordinary skill in the art. Thus, for example, compounds containing a group of formula (PD1), may ionise (partially or fully) to form salts with an appropriate number of counter- ions. By way of example, if a pharmaceutically acceptable ester pro-drug of a quinazoline derivative Formula I contains a (PD1) group, there are two HO-P- functionalities present, each of which may form an appropriate salt with a suitable counter-ion. Suitable salts of a group of the formula (PD1) are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium or an organic amine salt for example triethylamine, or tris-(2-hydroxyethyl)amine. Thus for example the group (PD1) may form, a mono- or di-sodium salt).
Particular novel compounds of the invention include, for example, quinazoline derivatives of the Formula I, or pharmaceutically acceptable salts, or pharmaceutically acceptable esters thereof, wherein, unless otherwise stated, each of RL R%,W,Q, X', X?% ab and Z has any of the meanings defined hereinbefore or in paragraphs (a) to (nnnn) hereinafter:- (a) R! is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula :
Q*-X*-
wherein X3 is a direct bond or is O, and Q? is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R' substituent are optionally separated by the insertion into the chain of a group selected from O,
N(R%), CONR?Y), N(R*)CO, CH=CH and C=C wherein R? is hydrogen or (1-6C)alkyl, and wherein any CH,=CH- or HC=C- group within a R' substituent optionally bears at the terminal CH,= or HC= position a substituent selected from carbamoyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkylJcarbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl}amino-(1-6C)alkyl or from a group of the formula:
Q*-x*- wherein X's a direct bond or is selected from CO and N(R*)CO, wherein R* is hydrogen or (1-6C)alkyl, and Q’ is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any CH, or CH; group within a R! substituent, other than a CH; group within a heterocyclyl ring, optionally bears on each said CH, or CHj3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, amino, cyano, carbamoyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl}amino, N-(1 -6C)alkylcarbamoy! and N,N-di-[(1-6C)alkyl]carbamoyl, or from a group of the formula : -x5-Q* wherein X is a direct bond or is selected from O, N(R®), CON(R?), NR*)CO and C(R’),0, wherein R® is hydrogen or (1-6C)alkyl, and Q* is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R' optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (1 -6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, or from a group of the formula: -x6-R® wherein X% is a direct bond or is selected from O and N(R"), wherein R” is hydrogen or (1-6C)alkyl, and R® is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl}amino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,
N-(1-6C)alkylcarbamoy}-(1-6C)alkyl and N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl,
and wherein any heterocyclyl group within a substituent on R' optionally bears 1 or 2 oxo substituents; (b) R'is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula :
Q*-Xx3- wherein X° is a direct bond or is O, and Q? is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R' substituent are optionally separated by the insertion into the chain of a group selected from 0,
N(R?), CON(R®), N(R*)CO, CH=CH and C=C wherein R’ is hydrogen or (1-6C)alkyl, and wherein any CH,=CH- or HC=C- group within a R! substituent optionally bears at the terminal CH,= or HC= position a substituent selected from carbamoyl,
N-(1-6C)alkylcarbamoyl, N.N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alky!l and di-[(1-6C)alkyl]amino-(1-6C)alkyl and wherein any CH; or CH; group within a R! substituent, other than a CH; group within a heterocyclyl ring, optionally bears on each said CH; or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, amino, cyano, carbamoyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl and N,N-di-[(1-6C)alkyllcarbamoy], or from a group of the formula : -X5-Q* wherein X° is a direct bond or is selected from O, N(R®), CON(R®), N®R®)CO and C(R’);0, wherein R® is hydrogen or (1-6C)alkyl, and Q* is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R' optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, or from a group of the formula: -x¢-R® wherein Xs a direct bond or is selected from O and NR’), wherein Ris hydrogen or (1-6C)alkyl, and Réis halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alky! and di-[(1-6C)alkyl]amino-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R! optionally bears 1 or 2 oxo substituents;
(© R! is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy and (2-6C)alkynyloxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R! substituent are optionally separated by the insertion into the chain of a group selected from 0,
N(R®), CON(R®), N(R*)CO, CH=CH and C=C wherein R? is hydrogen or (1-6C)alkyl, and wherein any CH; or CH; group within a R! substituent, other than a CH; group within a heterocyclyl ring, optionally bears on each said CH; or CH; group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, amino, cyano, carbamoyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[( 1-6C)alkyl}amino, N-(1 -6C)alkylcarbamoyl and N,N-di-[(1-6C)alkyl]carbamoyl; (d R'is selected from hydrogen, hydroxy, (1-6C)alkoxy, or from a group of the formula:
Q*-X3- wherein X? is O, and Q? is (3-TC)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, heterocyclyl of heterocyclyl-(1-6C)alkyi, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R' substituent are optionally separated by the insertion into the chain of a group selected from O and N(R?), wherein R® is hydrogen or (1-4C)alkyl, and wherein any CH; or CH; group within a R! substituent, other than a CH; group within a heterocyclyl ring, optionally bears on each said CH, or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, amino, cyano, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and wherein any heterocyclyl group within a substituent on R' optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alky!]Jamino,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoy! and (2-6C)alkanoyl, and wherein any heterocyclyl group within a substituent on R! optionally bears 1 or 2 oxo substituents; (e) R! is selected from hydrogen, hydroxy, (1-6C)alkoxy, or from a group of the formula:
Q-X*- wherein X° is O, and Q” is azetidin-3-yl-(1-4C)alkyl, azetidin-1-yl-(2-4C)alkyl, pyrrolidin-2- yl-(1-4C)alkyl, pyrrolidin-3-yl-(1-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidin-2-yl-(1-
4C)alkyl, piperidin-3-yl-(1-4C)alkyl, piperidin-4-yl-(1-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R' substituent are optionally separated by the insertion into the chain of a group selected from O and N(R®), wherein R? is hydrogen or (1-4C)alkyl, and wherein any CH; or CH; group within a R! substituent, other than a CH; group within a heterocyclyl ring, optionally bears on each said CH; or CH; group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, (1-4C)alkoxy, amino, (1-4C)alkylamino and di-[(1-4C)alkyl]amino, and wherein any heterocyclyl group within a substituent on R' optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, carbamoyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C)alkyljamino, N-(1-4C)alkylcarbamoyl,
N,N-di-(1-4C)alkylJcarbamoy! and (2-4C)alkanoyl, and wherein any heterocyclyl group within a substituent on R' optionally bears 1 oxo substituent (preferably any oxo group on a morpholino group in R' is located at the 3 or 5 position on the morpholino ring); ¢9) R! is selected from hydrogen, hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1- 3C)alkoxy-(2-4C)alkoxy or from a group of the formula :
Q*-X3- wherein X2 is O, and Q? is azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino- (2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein any heterocyclyl group within a substituent on R' optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C)alkyl}amino, and (2-4C)alkanoyl, and wherein any heterocyclyl group within a substituent on R' optionally bears 1 oxo substituent; ®) R' is selected from hydrogen, hydroxy, methoxy, ethoxy, propoxy, isopropyloxy, 2-hydroxyethoxy, 2-fluoroethoxy, cyclopropylmethoxy, 2-cyclopropylethoxy, vinyloxy, allyloxy, ethynyloxy, 2-propynyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofurfuryloxy, tetrahydrofuran-3-ylmethoxy, 2-(tetrahydrofuran-2-yl)ethoxy, 3-( tetrahydrofuran-2-yl)propoxy,
2-(tetrahydrofuran-3-yl)ethoxy, 3-( tetrahydrofuran-3-yl)propoxy, tetrahydropyranylmethoxy, 2-tetrahydropyranylethoxy, 3-tetrahydropyranylpropoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(1,1 -dioxotetrahydro-4H-1,4-thiazin-4-ylethoxy, 3-(1,1-dioxotetrahydro-4H-1 /A-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy, 2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy, 3-homopiperazin-1-ylpropoxy, pyrrolidin-1-yl, morpholino, piperidino and piperazin-1-y}, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R' substituent are optionally separated by the insertion into the chain of a group selected from O,
NH, N(CH;),CH=CH and C=C, and when R! is a vinyloxy, allyloxy, ethynyloxy or 2-propynyloxy group, the R! substituent optionally bears at the terminal CH= or HC= position a substituent selected from
N-(2-dimethylaminoethyl)carbamoyl, N-(3-dimethylaminopropyl)carbamoyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl and 4-dimethylaminobutyl, or from a group of the formula:
Q*-x*- wherein X* is a direct bond or is NHCO or N(CH3)CO and Q} is pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl or 4-piperazin-1-ylbutyl, and wherein any CH; group which is attached to 2 carbon atoms (other than a CH, group within a heterocyclyl ring) or any CH3 group which is attached to a carbon atom within aR! substituent optionally bears on each said CH, or CHj group a substituent selected from hydroxy, amino, methoxy, ethoxy, methylsulfonyl, methylamino and dimethylamino,
and wherein any heterocyclyl group within a substituent on R' optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, carbamoyl, methyl, ethyl, n-propyl, isopropyl and methoxy, and any piperidin-3-ylmethyl, piperidin-4-ylmethyl or piperazin-1-yl group within a R! substituent is optionally
N-substituted with 2-methoxyethyl, 3-methoxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropy!, acetyl or propionyl, and wherein any heterocyclyl group within a substituent on R' optionally bears 1 or 2 oxo substituents; h) R! is selected from hydrogen, hydroxy, (1-6C)alkoxy, (3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy, and wherein any CH; or CH; group within a R! substituent optionally bears on each said CH, or CH; group one or more halogeno or (1-6C)alkyl substituents, or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, oxo, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)aikylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyljamino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoy],
N-(1-6C)alkylsulfamoyl and N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and
N-(1-6C)alkyl-(1-6C)alkanesulfonylamino; (1) R! is selected from hydrogen, hydroxy, (1-6C)alkoxy, (3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy, and wherein any CH, or CH; group within a R! substituent optionally bears on each said CH, or CH; group one or more fluoro or chloro substituents, or a substituent selected from hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino; () R! is selected from hydrogen, hydroxy, (1-6C)alkoxy, (3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR! substituent are optionally separated by the insertion into the chain of an O atom, and wherein any CH; or CHj group within a R! substituent optionally bears on each said CH; or CH; group one or more fluoro or chloro substituents, or a substituent selected from hydroxy and (1-4C)alkoxy;
(k) R'is selected from hydrogen, (1-6C)alkoxy, cyclopropyl-(1-4Cjalkoxy, cyclobutyl-(1-4C)alkoxy, cyclopentyl-(1-4C)alkoxy, cyclohexyl-(1-6C)alkoxy, tetrahydrofuranyl-(1-4C)alkoxy and tetrahydropyranyl-(1-4C)alkoxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR substituent are optionally separated by the insertion into the chain of an O atom, and wherein any CH; or CH; group within a R! substituent optionally bears on each said CH, or CHs group one or more fluoro or chloro substituents, or a substituent selected from hydroxy and (1-3C)alkoxy; (4) R! is selected from hydrogen, (1-6C)alkoxy, cyclopropylmethoxy and 2- cyclopropylethoxy, and wherein any CH, or CH; group within a R! substituent optionally bears on each said CH, or CHj group one or more fluoro or chloro substituents, or a substituent selected from hydroxy, methoxy and ethoxy; (m) R'is selected from methoxy, ethoxy, propyloxy, isopropyloxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2,2-difluoroethoxy 2,2,2-trifluoroethoxy, 2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy, 2- piperidinoethoxy, 3-piperidinopropyl, 2-piperazinoethoxy, 3-piperazinopropoxy, 2- morpholinoethoxy and 3-morpholinopropoxy; (n) R! is selected from hydrogen methoxy, ethoxy, propyloxy, isopropyloxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy; (0) R! is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-3C)alkoxy-(2- 3C)alkoxy; (@) R'is selected from hydrogen and (1-3C)alkoxy (particularly R' is (1-3C)alkoxy such as methoxy, ethoxy and isopropyloxy); (@ R'is hydrogen; ( R'is methoxy; (s) each R?, which may be the same or different, is selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy, and a group of the formula : -X’-R® wherein X’ is a direct bond or is selected from O and N(R®), wherein R? is hydrogen or (1- 6C)alkyl, and R® is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1- 6C)alkyllamino-(1-6C)alkyl; 50 each R?, which may be the same or different, is selected from halogeno, hydroxy, amino, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl}Jamino; (u) each R?, which may be the same or different, is selected from fluoro, chloro, bromo, iodo, cyano, hydroxy, trifluoromethyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (1-4C)alkoxy;
Ww) each R?, which may be the same or different, is selected from fluoro, chloro, bromo, (1-4C)alkyl, (2-4C)alkenyl and (2-4C)alkynyl; (w) each R?, which may be the same or different, is selected from fluoro, chloro, bromo, iodo, cyano, carbamoyl, hydroxy, trifluoromethyl, methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, allyl, ethynyl, 1-propynyl, 2-propyny}, N-methylcarbamoyl, N-ethylcarbamoyl and
N.N-dimethylcarbamoyl; (x) each RZ, which may be the same or different, is selected from fluoro, chloro, bromo, iodo, cyano, hydroxy, trifluoromethyl, methyl, cthyl, isopropyl, methoxy, ethoxy, vinyl, allyl, ethynyl, 1-propynyl, and 2-propynyl; (y) each RZ, which may be the same or different, is selected from fluoro, chloro, bromo, cyano, hydroxy, trifluoromethyl, methyl, ethyl, methoxy, ethoxy and ethynyl; (2) each R?, which may be the same or different, is selected from fluoro, chloro, bromo and ethynyl; (aa) each R?, which may be the same or different, is selected from halogeno (particularly fluoro, chloro and bromo), (bb) bis 1,2 or3andone R? is at the meta (3-) position on the anilino group in Formula 1; (cc) bis1,2or3andeach R?, which may be the same or different, is as defined in any of (s) to (aa) above; (dd) bisl,2or3, one R? is at the meta (3-) position on the anilino group in Formula land is halogeno, and when b is 2 or 3 the other R? group(s), which may be the same or different, are as defined in any of any of (s) to (aa) above; (ee) bis 1,2or3, each R?, which may be the same or different, is halogeno, and wherein one R? is at the meta (3-) position on the anilino group;
(ff) bis 1or2, each R?, which may be the same or different, is halogeno (particularly fluoro, chloro or bromo) and wherein one RZ is at the meta (3-) position and the other R? is at the ortho (2-) or para (4-) position on the anilino group; (gg) bis1or2,one RZ is at the meta (3-) position on the anilino group and is chloro or bromo (particularly chloro), and when b is 2 the other R? group is selected from fluoro, chloro and bromo;
(hh) the anilino group at the 4-position on the quinazoline ring in Formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5- chloroanilino, 3-bromoanilino and 3-ethynylanilino;
(ii) the anilino group at the 4-position on the quinazoline ring in Formula Lis selected from 3-chloro-4-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3- bromoanilino, 3-methylanilino and 3-ethynylanilino;
(jj) the anilino group at the 4-position on the quinazoline ring in Formula I is 3-chloro-4- fluoroanilino;
(kk) the anilino group at the 4-position on the quinazoline ring in Formula I is 3-chloro-2- fluoroanilino or 3-bromo-2-fluoroanilino (more particularly the anilino is 3-chloro-2- fluoroanilino);
an Q! is selected from piperidin-3-yl and piperidin-4-yl; (mm) Q! is piperidin-4-yl; (nn) each W, which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, oxo, (1-6C)alkyl, (1-6C)alkoxy, and from a group of the formula: -x8-R!® wherein X® is a direct bond or is O, and R'is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl or (1-6C)alkoxy-(1-6C)alkyl;
(00) each W, which may be the same or different, is selected from halogeno, hydroxy, oxo,
(1-6C)alky] and (1-6C)alkoxy;
(pp) each W, which may be the same or different, is selected from halogeno (particularly fluoro), hydroxy, (1-3C)alkyl and (1-3C)alkoxy;
(qq) ais 0, 1, or 2 and each W, which may be the same or different, is as defined in any of (nn) to (pp);
(r) aisOorland Wisas defined in any of (nn) to (pp);
(ss) aisO;
(t) Q'ispiperidin-4-yl, ais 0 or 1 and W is as defined in any of (nn) to (pp);
(uw) X'isCO; (vw) X'isSOy; (ww) X2is a group of the formula:
A(CRR"),-(Q*)n-(CR"R*)- wherein mis Qor 1, pis 0,1,2,30or4andqis0,1,2,3 ord, each of R'2, R'3, R' and R'"*, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl}amino, and Qs selected from (3-7C)cycloalkylene and (3-7C)cycloalkenylene, and wherein any CH, or CH3 group within an X? group, optionally bears on each said
CH, or CH; group one or more halogeno or (1-6C)alkyl substituents, and wherein any CH, group which is attached to 2 carbon atoms or any CH; group which is attached to a carbon atom within a X? substituent optionally bears on each said CH, or CH; group a substituent selected from hydroxy, cyano, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; (xx) XZis selected from a group of the formula «(Q)m-(CR™R")q- and a group of the formula -(CR'2R'*)q-(Q®)m-, wherein mis O or 1, qis 1,2, 3 or 4, and Q°,R'2Z, RP, R"and RY are as hereinbefore defined; (yy) Xis a group of the formula ~Q*-, for example (3-7C)cycloalkylene such as cyclopropylidene; (zz) X:is selected from cyclopropylene, cyclopbutylene, cyclopentylene, cyclohexylene, methylene-(3-6C)cycloalkylene, (3-6C)cycloalkylene-methylene-, ethylene-(3- 6C)cycloalkylene and (3-6C)cycloalkylene-ethylene-, and wherein and wherein any CH; or CHj group within X2, optionally bears on each said CH, or CHj group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]Jamino; (aaa) Xis a group of the formula (CR"R")q-, qis 1, 2, 3 or 4 (particularly 1 or 2), each of R'2 and R'?, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, and wherein and wherein any CH; or CH; group within X?, optionally bears on each said CH; or CH; group one or more halogeno substituents, and wherein any CH, group which is attached to 2 carbon atoms or any CHj group which is attached to a carbon atom within a X? substituent optionally bears on each said CH,
or CH; group a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; (bbb) X?2is a group of the formula —(CR'"RY),, qis1,2o0r3, each of R'2 and R'?, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, - and wherein any CH; or CH; group within an X? group, optionally bears on each said
CH, or CH3 group one or more halogeno substituents, and wherein any CH; group which is attached to 2 carbon atoms or any CH; group which is attached to a carbon atom within a X? substituent optionally bears on each said CH; or CH; group a substituent selected from hydroxy, and (1-6C)alkoxy; (ccc) X2 is a group of the formula ~(CR’R")~(CR'*™R"™)., qis 1, 2 or 3 (particularly 1 or 2, more particularly 1), each of R'2, R'® and R'3*, which may be the same or different, is selected from hydrogen and (1-6C)alkyl,
R'%4 is selected from amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and wherein any CH; or CHj group within an X? group, optionally bears on each said
CH, or CH; group one or more halogeno substituents, and wherein any CH; group which is attached to 2 carbon atoms or any CH; group which is attached to a carbon atom within a X? substituent optionally bears on each said CH; or CH group a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkylJamino; (ddd) X?isa group of the formula ~CR"RY),-, gis 1, 2, 3 or 4 (particularly 1 or 2, more particularly 1), each of R'? and R', which may be the same or different, is selected from hydrogen and (1-6C)alkyl, provided that at least one of the R'? or R'> groups in X2is (1-6C)alkyl, and wherein any CH, or CH3 group within an X? group, optionally bears on each said
CH, or CH; group one or more halogeno substituents, and wherein any CH, group which is attached to 2 carbon atoms or any CHj group which is attached to a carbon atom within a X? substituent optionally bears on each said CH, or CH; group a substituent selected from hydroxy, and (1-6C)alkoxy; (eee) Xis selected from a group of the formula ~(CR'"’R")-, ~(CR'R'*CH,)-, - (CR'2RVCH;CHy)-, -(CH,CR'’R")- and -(CH,CH,CR'’R")-,
each of R'? and R'?, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, and wherein any CH; or CH; group within X?, optionally bears on each said CH,or
CH; group one or more halogeno substituents, and wherein any CH; group which is attached to 2 carbon atoms or any CHj group which is attached to a carbon atom within a X? substituent optionally bears on each said CH; or CH; group a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl}amino; (fff) X? is selected from a group of the formula —(CR"R")-, (CRR"’CHy)-, - (CR"RVCH;CH;)-, (CH,CR'’R")- and (CH,CH,CR""R")-, each of R'? and R'?, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, provided that at least one of R'? or R® is a branched (1-6C)alky! group, and wherein any CH; or CHj group within X?, optionally bears on each said CH; or
CH; group one or more halogeno substituents, and wherein any CH; group which is attached to 2 carbon atoms or any CH; group which is attached to a carbon atom within a X? substituent optionally bears on each said CH, or CH; group a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alky!Jamino; (egg) X’ is selected from a group of the formula (CR "’R")-, (CR"’R"*CHo)-, ~ (CR"R'CH;CH,)-, -(CH,CR"’R")- and -(CH,CH,CR"’R")-, each of R'2 and R'?, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, provided that at least one of R'> or R" in X? is a branched alkyl group, which branched alkyl group is preferably selected from iso-propyl, iso-butyl, sec-butyl and tert-butyl, and wherein any CH; or CH3 group within X?, optionally bears on each said CH, or
CH; group one or more fluoro or chloro substituents, and wherein any CH, group which is attached to 2 carbon atoms or any CHj; group which is attached to a carbon atom within a X? substituent optionally bears on each said CH, or CH; group a substituent selected from hydroxy and (1-3C)alkoxy; (hhh) X? is selected from a group of the formula ~CH,-, —CH,CH;-, -CH,CH,CH;- —- (CR'R")-, CR'?R*CH)- and -(CH,CR""R")-
wherein each of R'? and R'?, which may be the same or different, is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl and (1-4C)alkoxy-(1-4C)alkyl, provided that R'" and R'* are not both hydrogen; (ii) X?is selected from a group of the formula ~CHz-, -CHCHy-, —(CHR'®)-, - (CHR'"CHy)-, «CR *):CHy)-, -(CH:CR ))- and -(CH:CHR ®), wherein each R'?, which may be the same or different, is selected from (1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino- (1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl, and wherein R'2 is selected from hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]-amino, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl])-amino-(1-4C)alkyl;
Gi) X2is selected from a group of the formula ~CH;-, -CH2CHy-, ~(CHR'?)., - (CHR '2CHy,)- and -(CH,CHR '*)- wherein R'Z is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl and di- [(1-4C)alkyl]-amino-(1-4C)alkyl, and wherein R'? is selected from hydrogen, hydroxy, amino, (1-4C)alkyl, (1- 4C)alkoxy, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl; (kkk) X? is selected from a group of the formula -CHa-, ~CH,CH;-, ~CHR'®)-, - (CHR'*CHy)-, (C(R"*);,CHy)-, (CHC(R'™),)- and -(CH,CHR'®)-, wherein each R'?, which may be the same or different, is (1-4C)alkyl, and wherein R'2 is selected from amino, (1-4C)alkylamino and di-[(1-4C)alkyl}- amino; (I) X?is selected from a group of the formula —(CHR'%)-, (CHR'*CH))-, - (CR'™),CHy)-, (CH,CR ®)y)- and -(CH.CHR'®)-, wherein each R'%, which may be the same or different, is (1-4C)alkyl (particularly (1- 3C)alkyl), and wherein R'? is selected from amino, (1-4C)alkylamino and di-[(1-4C)atkyl]- amino (particularly R'? is selected from (1-4C)alkylamino and di-[(1-4C)alkyl]-amino, more particularly di-[(1-3C)alkyl]-amino); (mmm) X2 is selected from a group of the formula -CH,-, -CH,CHz-, —~(CHR')., - (CHR'’CH,)- and -(CH,CHR %)-
wherein R'2 is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl and di- [(1-4C)alkyl]-amino-(1-4C)alkyl; (nnn) X? is selected from a group of the formula ~CH,-, —CH,CH,-,—(CHR'®)-, - (CHR'%CHy)-, C(R"™),CHy)-, (CH:C(R™)2)- and -(CH,CHR'*)-, wherein each R!?, which may be the same or different, is (1-4C)alkyl; (000) X? is selected from a group of the formula —(CHR'®)-, —(CHR'#CH,)-, - (C(R'#),CH,)-, -(CH,C(R'*),)- and -(CH,CHR'*)- (particularly, X? is (CHR '%)-), wherein each R'®, which may be the same or different, is (1-4C)alkyl; (ppp) X? is selected from a group of the formula (CHz)g-, wherein q is 1, 2 or 3, particularly qis 1 or 2, more particularly 1; (qqq) Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1- 6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino and
N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula:
Q5-x°- wherein X is a direct bond or is selected from O, N(R), SO, and SO;N(R"), wherein R' is hydrogen or (1-6C)alkyl, and Q° is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, provided that when X? is a direct bond, Q° is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl, and wherein any heterocyclyl group in Z is a monocyclic fully saturated 4, 5,6 or 7- membered heterocyclyl group containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, and wherein and wherein any CH; or CH; group within a Z group, other than a CH, group within a heterocyclyl ring, optionally bears on each said CH, or CHj3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkyisulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]Jamino,
N-(1-6C)alkylcarbamoyl, N.N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,
N-(1-6C)alkylsulfamoyl, N.N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and
N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,
and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkylJamino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -x10-R!8 wherein X'0 is a direct bond or is selected from 0, CO, SO; and NR'), wherein RY is hydrogen or (1-4C)alkyl, and R'? is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (14C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl,
N-(1-4C)alkylamino-(1-4C)alkyl and N,N-di-[(1-4C)alkyl]amino-(1-4C)alky}; (rrr) Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1- 6C)alkoxy and a group of the formula:
QS-X°- wherein X’ is a direct bond or is selected from O and NR'®), wherein R'®is hydrogen or (1-6C)alkyl, and QC is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)al kyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, provided that when X? is a direct bond, Q® is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl, and wherein any heterocyclyl group in Z is a monocyclic non-aromatic fully saturated or partially saturated 4, 5, 6 or 7-membered heterocyclyl group containing 1 heteroatom selected from oxygen and nitrogen and optionally a further heteroatom selected from oxygen, nitrogen and sulfur, and wherein and wherein any CH, or CH; group within a Z group, other than a CH, group within a heterocyclyl ring, optionally bears on each said CH; or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
N-(1-6C)alkylcarbamoyl, N.,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)atkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl}sulfamoyl, (1-6C)alkanesulfonylamino and
N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,
and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-{(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -xl0-g!® wherein X'? is a direct bond or is selected from O, CO, SO; and N(R'®), wherein R" is hydrogen or (1-4C)alkyl, and R'is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl,
N-(1-4C)alkylamino-(1-4C)alkyl and N,N-di-[(1 -4C)alkyl]amino-(1-4C)alkyl; (sss) Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkylJamino, (1- 6C)alkoxy and a group of the formula:
Q°-X’- wherein X° is a direct bond or is selected from O and N(R'®), wherein R'®is hydrogen or (1-6C)alkyl, and Q° is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4Calkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, provided that when X? is a direct bond, Q° is heterocyclyl, and provided that when m, p and q are ali 0, then Z is heterocyclyl, and wherein any heterocyclyl group in Z is selected from tetrahydrofuranyl, 1,3- dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, which heterocyclyl group may be carbon or nitrogen linked to the group to which it is attached, and wherein and wherein any CH; or CH; group within a Z group, other than a CH, group within a heterocyclyl ring, optionally bears on each said CH; or CHj3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,
N-(1-6C)alkylsuifamoyl, N.N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and
N-(1-6C)alkyl-(1-6C)alkanesuifonylamino,
and wherein any heterocyclyl group within aZ substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: — x!0- R! 8 wherein X'? is a direct bond or is selected from O, CO, SO and NR"), wherein R" is hydrogen or (1-4C)alkyl, and R'® is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl,
N-(1-4C)alkylamino-(1-4C)alkyl and N,N-di-[(1-4C)alkylJamino-(1-4C)alkyl; (ttt) Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1- 6C)alkoxy and a group of the formula:
Q-X°- wherein X° is a direct bond and Q° is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl (preferably carbon linked to X), and wherein any heterocyclyl group in Z is selected from azetidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, and wherein and wherein any CH; or CH; group within a Z group optionally bears on each said CH, or CH; group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy and (1-6C)alkoxy, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and (2-6C)alkanoyl; (uuu) Z is selected from hydroxy, amino, (1-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]amino, N-[hydroxy-(2-6C)alkyl}-N- (1-6C)alkylamino, N-[(1-4C)alkoxy-(2-6C)aikyl]-N-(1-6C)alkylamino, di-[hydroxy- (2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkylJamino, N-[( 1-4C)alkoxy-(2-6C)alkyl]-N- [hydroxy-(2-6C)alkyl]-amino, ( 1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-
6C)alkoxy, azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl homopiperazin-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3- dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl and a group of the formula:
Q5-X°- wherein X is selected from O and N(R'®), wherein R'S is hydrogen or (1-4C)alkyl, and Q° is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, and wherein any heterocyclyl group in Q’ is selected from tetrahydrofuranyl, 1,3- dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, which heterocyclyl group may be carbon or nitrogen linked to the group to which it is attached, and provided that when m, p and q are all 0, then Z is heterocyclyl, preferably one of the above mentioned heterocyclyl groups that may be represented by QS, (which heterocyclyl group is preferably carbon linked to X'), and wherein and wherein any CH; or CH; group within a Z group, other than a CH, group within a heterocyclyl ring, optionally bears on each said CH, or CHj group one or more halogeno or (1-6C)alky! substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,
N-(1-6C)alkylsulfamoyl, N,N-di-[{(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and
N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1,2 or 3) substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -x0-R® wherein X'? is a direct bond or is selected from O, CO, SO; and N(R'), wherein R" is hydrogen or (1-4C)alkyl, and R'8 is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl,
(1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl,
N-(1-4C)alkylamino-(1-4C)alkyl and N,N-di-[(1-4C)alkylJamino-(1-4C)alky}; (vwv) Z is selected from amino, (1-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1- 4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]amino, N-[hydroxy-(2-6C)alkyl}-N- (1-6C)alkylamino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino, di-[hydroxy- (2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N- [hydroxy-(2-6C)alkyl}-amino, azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl and homopiperazin-1-yl, : and wherein and wherein any CH; or CH; group within a Z group, optionally bears on each said CH; or CH; group one or more fluoro substituents or a substituent selected from hydroxy, cyano, amino, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and wherein any heterocyclyl group within aZ substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, cyano, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkanoyl, (14C)alkylamino and di-[(1-4C)alkyl]amino, and provided that when m, p and q are all 0, then Z is one of the above mentioned heterocyclyl groups that may be represented by Z, such as pyrrolidin-1-yl or piperidino (preferably the sum of m +p+q is at least 1); (www)Z is selected from hydroxy, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2- 6C)alkoxy, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydropyranyl and a group of the formula:
QE-X°- wherein X° is O, and Q° is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, wherein any heterocyclyl group represented by Q° is preferably selected from tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, 1,4-dioxanyl and tetrahydropyranyl, and provided that when m, p and q are all 0, then Z is selected from tetrahydrofuran-2- yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydropyranyl and oxepanyl, and wherein any CH; or CHj group within a Z group, optionally bears on each said
CH, or CH; group one or more fluoro substituents or a substituent selected from hydroxy,
cyano, amino, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, cyano, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl}amino; (xxx) Z is selected from hydroxy, amino, (1-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1- 4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl}amino, N-[hydroxy-(2-6C)alkyl]-N- (1-6C)alkylamino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino, di-[hydroxy- (2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyljamino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N- [hydroxy-(2-6C)alkyl]-amino, (1-6C)alkoxy, hydroxy-(2-6C)atkoxy and (1-4C)alkoxy-(2- 6C)alkoxy, and wherein the sum of m +p+q is at least 1; (yyy) Zis selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1- 6C)alkoxy, hydroxy-(2-6C)alkoxy and (1-4C)alkoxy-(2-6C)alkoxy, and the sum of m +p+q is at least 1; (zzz) Zis selected from hydroxy, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy and (1-4C)alkoxy- (2-4C)alkoxy), and the sum of m +p+q is at least 1; (aaaa) Z is selected from hydroxy, methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, amino, methylamino, ethylamino, N-(2-hydroxyethyl)amino, N-(2-methoxyethyl)amino, dimethylamino, N-methyl-N-ethylamino, di-ethylamino, N-(2-hydroxyethyl)-N-methylamino,
N-(2-hydroxyethyl)-N-ethylamino, N,N-di-(2-hydroxyethyl)amino, N-(2-methoxyethyl)-N- methylamino, N-(2-methoxyethyl)-N-ethylamino, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, tetrahydrofuranyl and tetrahydropyranyl, and wherein any heterocyclyl group within Z optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (2- 4C)alkanoyl and (1-4C)alkoxy, and provided that when m, p and q are all 0, then Z is one of the above mentioned heterocyclyl groups that may be represented by Z, such as pyrrolidin-1-yl, tetrahydrofuranyl or piperidino (preferably the sum of m +p+q is at least 1); (bbbb) Z is selected from pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl, homopiperazin-1-yl, (particularly Z is selected from pyrrolidin-1-yl, piperidino, piperazin-1-yl and morpholino),
and wherein the heterocyclyl group within Z optionally bears one or more (for example 1, 2 or 3) substituents, which may be the same or different selected from fluoro, chloro, cyano, hydroxy, amino, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyllcarbamoyl, acetyl, propionyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, cyanomethyl, hydroxyacetyl, aminoacetyl, methylaminoacetyl, ethylaminoacetyl, dimethylaminoacetyl and N-methyl-N- ethylaminoacetyl (preferably the sum of m +p+q is at least 1); (cece) Z is selected from hydroxy, (1-4C)alkoxy, tetrahydrofuranyl and tetrahydropyranyl and wherein any tetrahydrofuranyl or tetrahydropyranyl group within Z optionally bears one or two substituents, which may be the same or different selected from fluoro, chloro, hydroxy, (1-4C)alkyl and (1-4C)alkoxy, and provided that when m, p and q are all 0, then Z is selected from tetrahydrofuranyl and tetrahydropyranyl (preferably the sum of m +p+q is at least 1); (dddd) Z is hydroxy or (1-4C)alkoxy (particularly Z is hydroxy), and the sum of m +p+q is at least 1; (eeee) Z is as defined in any of (4qq) to (dddd) above, and wherein X? is selected from ~CHg-, —CH,CH,-, «CR "R®)-, (CR "RCH,)-- (CH,CR'’R")- and (3-6C)cycloalkenylene (for example cyclopropylene such as cyclopropylidene), wherein each of R'? and RB, which may be the same or different, is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl, provided that R" and R'3 are not both hydrogen, and wherein X' is CO; (fff) Z is as defined in any of (qqq) to (dddd) above;
X2 is selected from a group of the formula -CH;-, -CH,CHz-, —(CHR'®)-, - (CHR'#CHy)-, (C(R'*),CH,)- , -(CH:C(R'*)z)- and (CH;CHR'®)- (particularly, X* is — (CHR'™)-), wherein each R'?*, which may be the same or different, is selected from (1-4C)alkyl, hydroxy-(1-4C)alkyl and (1-3C)alkoxy-(1-4C)alkyl, and wherein R'? is selected from hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]-amino, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl}-amino-(1-4C)alkyl; and wherein X' is CO;
(ggge) Z is selected from hydroxy and (1-4C)alkoxy,
X2 is selected from a group of the formula —CH,-, -CH,CH-, —(CHR'®)-, - (CHR '*CH,)-, (C(R"*);CHy)- , -(CH,C(R'™),)- and -(CH;CHR'®).- (particularly, X* is (CHR'®).), wherein each R'%, which may be the same or different, is (1-4C)alkyl, and wherein R'? is selected from hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]-amino, and wherein X' is CO; (hhhh) Z-X?-X! is hydroxy-(2-4C)alkanoyl, for example hydroxyacetyl, 2-hydroxypropionyl or 3-hydroxypropionyl, particularly Z-X2.X' is 2-hydroxypropionyl); (iif) 7-X2-X' is (1-4C)alkoxy-(2-4C)alkanoyl, for example methoxyacetyl, 2- methoxypropionyl or 3-methoxypropionyl);
Gili) Z-X>-X'is selected from amino-(2-4C)alkanoyl, (1-4C)alkylamino-(2-4C)alkanoyl and di-[(1-4C)alkyl]amino-(2-4C)alkanoyl (for example Z-X2-X! is di-[(1-4C)alkyl]amino- acetyl such as dimethylaminoacetyl); (kkkk) 7.X2- is selected from tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4- dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, which heterocyclyl is linked to the carbonyl group in Formula I, by a ring carbon, and wherein the heterocyclyl group within Z-X? optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl; (1) Z-X2- is selected from tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4- dioxanyl, oxepanyl (for example Z-X2 is selected tetrahydrofuran-2-yl or tetrahydropyran-2- yb (mmmm) Z-X2- is selected from pyrrolidiny!, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, which heterocyclyl is linked to X' in Formula I, by aring carbon, and wherein the heterocyclyl group within Z-X? optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl; and (nnnn) Z-X? is selected from pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, homopiperidin-1-yl and homopiperazin-1-yl,
and wherein the heterocyclyl group within Z-X? optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl.
A particular embodiment of the present invention is a quinazoline derivative of the
Formula I wherein:
R! is selected from hydrogen, (1-6C)alkoxy, cyclopropyl-(1-4C)alkoxy, cyclobutyl-(1-4C)alkoxy, cyclopentyl-(1-4C)alkoxy, cyclohexyl-(1-6C)alkoxy, tetrahydrofuranyl-(1-4C)alkoxy and tetrahydropyranyl-(1-4Cjalkoxy, and wherein any CH, or CH; group within a R' substituent optionally bears on each said CH, or CHs group one or more halogeno substituents, or a substituent selected from hydroxy and (1-4C)alkoxy; bis1,2o0r3; each R%, which may be the same or different, is selected from halogeno (particularly fluoro, chloro or bromo), cyano, hydroxy, trifluoromethyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (1-4C)alkoxy;
Q! is piperidin-4-yl; ais0,1or2; each W, which may be the same or different, is selected from halogeno (particularly fluoro), trifluoromethyl, hydroxy, oxo, (1-6C)alkyl, (1-6C)alkoxy, and from a group of the formula: _x&-R© wherein X? is a direct bond or is O, and R'is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl or (1-6C)alkoxy-(1-6C)alkyl;
X! is CO; and
Z and X* have any of the values hereinbefore defined; provided that: when the 4-anilino group in Formula 1 is 4-bromo-2-fluoroanilino or 4-chloro-2- fluoroanilino, R' is hydrogen or (1-3C)alkoxy, and X' is CO, then ais 0 and Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1- 6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and a group of the formula Q%-X%-, wherein QS5-X°- is as hereinbefore defined; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof.
In this embodiment, a particular value for X%isa group selected from 3- 6C)cycloalkylene (such as cyclopropylidene), -CHa-, —-CH,CH,-, -CH,CH,;CH>- —~(CR'R")-, ~(CR"R"CH,)- and (CH,CR"’R")- wherein each of R'? and R'?, which may be the same or different, is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl, provided that R"? and R'3 are not both hydrogen, and wherein any CH, group within a (3-6C)cycloalkylene group in X?, optionally bears on each said CH, or group one or more (1-4C)alkyl substituents or a substituent selected from hydroxy, (1-4C)alkoxy, hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl.
In this embodiment, a particular value for Z is a group selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy and a group of the formula:
Q%-X°- wherein X° is a direct bond or is selected from O and NR'®), wherein R'is hydrogen or (1-6C)alkyl, and Q° is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, provided that when X? is a direct bond, Q° is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl, and wherein any heterocyclyl group in Z is selected from tetrahydrofuranyl, 1,3- dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, which heterocyclyl group may be carbon or nitrogen linked to the group to which it is attached, and wherein and wherein any CH, or CH; group within a Z group, other than a CH; group within a heterocyclyl ring, optionally bears on each said CH; or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, suifamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
N-(1-6C)alkylcarbamoyl, N.N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,
N-(1-6C)alkylsulfamoyl, N.N-di-[(1-6C)alkyl]sulfamoyl, (1 -6C)alkanesulfonylamino and
N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,
and wherein any heterocyclyl group withinaZ substituent optionally bears one or more (for example 1,2 or 3) substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -xI0-R® wherein X'? is a direct bond or is selected from 0, CO, SO, and NR), wherein Ris hydrogen or (1-4C)alkyl, and R'® is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl,
N-(1-4C)alkylamino-(1-4C)alkyl and N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl.
Another particular value for Z in this embodiment is a group selected from hydroxy, amino, (1-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]amino, N-[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino, N-[(1-4C)alkoxy- (2-6C)alkyl}-N-(1-6C)alkylamino, di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy- (2-6C)alkyl]amino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino, (1- 6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy, azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl homopiperazin-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl and 1,4- dioxanyl, and provided that when m, p and q are all 0, then Z is one of the heterocyclyl groups mentioned above, and wherein any heterocyclyl group in Z optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl and (1- 4C)alkoxy.
Another particular value for Z in this embodiment is a group selected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-4C)alkoxy-(2-4C)alkoxy more particularly Z is hydroxy or(1-4C)alkoxy.
In this embodiment a particular value for each R?, which may be the same or different, is a group selected from fluoro, chloro or bromo and (2-4C)alkynyl;
In this embodiment a particular 4-anilino group in Formula I is selected from 3- chloro-4-fluoroaniline, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-
chloroanilino, 3-bromoanilino and 3-ethynylanilino. Still more particularly the anilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino.
Another particular embodiment of the present invention is a quinazoline derivative of the Formula I wherein:
S R! is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula:
Q*-X°- wherein X° is O, and Q? is azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2-4C)aikyl or morpholino-(2-4C)alkyl, and wherein any heterocyclyl group within a substituent on R! optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, and (2-4C)alkanoyl, and wherein any heterocyclyl group within a substituent on R' optionally bears 1 oxo substituent; bis 1,2 or 3; each R?, which may be the same or different, is selected from fluoro, chloro, bromo and (2-4C)alkynyl;
Q! is piperidin-4-yl; ais 0 or 1 (preferably 0); each W, which may be the same or different is selected from halogeno (particularly fluoro), hydroxy, (1-3C)alky! and (1-3C)alkoxy;
X'is CO;
X? is selected from a group of the formula -CHz-, -CH,CHy-, —(CHR'®)-, — (CHR'®CH,)-, (C(R'*),CHy)- , (CH,CR'*)y)- and -(CH,CHR'®)-, wherein each R'?, which may be the same or different, is selected from (1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino- (1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl (particularly R'% is (1-4C)alky), and wherein R'? is selected from hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]-amino, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl (particularly R'® selected from amino, (1-4C)alkylamino and di-[(1-4C)alkyl}-amino);
7 is selected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-4C)alkoxy- (2-4C)alkoxy, or 7-X? is selected from tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl, wherein Z-X? is linked to X' by a ring carbon atom, and wherein any heterocyclyl group within Z optionally bears one or two substituents, which may be the same or different selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl; provided that: when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or 4-chloro-2- fluoroanilino and R! is (1-3C)alkoxy, then a is 0; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof.
In this embodiment a particular value for Z is a group selected from hydroxy, and (1- 4C)alkoxy (for example Z is hydroxy, methoxy or ethoxy).
In this embodiment a particular 4-anilino group in Formula I is selected from 3- chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5- chloroanilino, 3-bromoanilino and 3-ethynylanilino. Still more particularly the anilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino.
Another particular embodiment of the present invention is a quinazoline derivative of the Formula I wherein:
R! is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula:
Q*-X:3- wherein X° is O, and Q? is azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4Cjalkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein any heterocyclyl group within a substituent on R' optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl, ( 1-4C)alkylamino, di-[(1-4C)alkyl]amino, and (2-4C)alkanoyl, and wherein any heterocyclyl group within a substituent on R! optionally bears 1 oxo substituent (particularly R' is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1- 3C)alkoxy-(2-4C)alkoxy, more particularly R! is (1-4C)alkoxy; bis 1, 2 or 3 (particularly b is 1, more particularly b is 2);
each R2, which may be the same or different, is selected from fluoro, chloro, bromo and (2-4C)alkynyl;
Q! is piperidin-4-yl; ais 0 or 1 (preferably 0); each W, which may be the same or different is selected from halogeno (particularly fluoro), hydroxy, (1-3C)alkyl and (1-3C)alkoxy; x! is CO;
X2 is a group of the formula —(CRRP)HCR'*R"*)., qis 1, 2 or 3 (particularly 1 or 2, more particularly 1), each of R'2, R'? and R'**, which may be the same or different, is selected from hydrogen and (1-6C)alkyl,
R'2% is selected from amino, (1-4C)alkylamino and di-{(1-4C)alkyl]amino;
Z is selected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-4C)alkoxy- (2-4C)alkoxy, or
Z-X? is Z is selected from tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl, wherein Z-X? is linked to X' by a ring carbon atom, and wherein any heterocyclyl group within Z optionally bears one or two substituents, which may be the same or different selected from fluoro, chloro, hydroxy, (14C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl; provided that: when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or 4-chloro-2- fluoroanilino and R' is (1-3C)alkoxy, then a is 0; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof.
In this embodiment a particular value for Z is a group selected from hydroxy, and (1- 4C)alkoxy (for example Z is hydroxy, methoxy or ethoxy).
In this embodiment a particular 4-anilino group in Formula I is selected from 3- chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino 3-bromoanilino and 3-ethynylanilino. More particularly in this embodiment the 4-anilino group in Formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino and 3-bromoanilino. Still more particularly the anilino group is 3-chloro-2-fluoroanilino or 3- bromo-2-fluoroanilino. Preferably the anilino group is 3-chloro-2-fluoroanilino.
Another particular embodiment of the present invention is a quinazoline derivative of the Formula I wherein:
R' is selected from (14C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula:
Q*-X*- wherein X is O, and Q? is azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein any heterocyclyl group within a substituent on R' optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino (particularly R'is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-3C)alkoxy-(2-4C)alkoxy, more particularly R' is (1-4C)alkoxy, for example methoxy, ethoxy, isopropyloxy, still more particularly R! is methoxy); the 4-anilino group in Formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo- 2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino and 3- ethynylanilino; bis lor 2; each R?, which may be the same or different, is selected from fluoro, chloro, bromo and ethynyl;
Q! is piperidin-4-yl; ais 0 or 1 (preferably 0); each W, which may be the same or different is selected from halogeno (particularly fluoro), hydroxy, (1-3C)alkyl and (1-3C)alkoxy;
Xx! is CO;
X? is selected from a group of the formula (CHR '%*)-, (CHR '*’CHy)-, - (CR'%),CHy)-, -(CH,CR'?);)- and -(CH.CHR *), wherein each R'%, which may be the same or different, is (1-4C)alkyl (particularly (1- 3C)alkyl), and wherein R'? is selected from amino, (1-4C)alkylamino and di-[(1-4C)alkyl]- amino (particularly R'? is selected from (1-4C)alkylamino and di-[(1-4C)alkyl]-amino, more particularly di-[(1-3C)alkyl]-amino);
Z is selected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-4C)alkoxy- (2-4C)alkoxy, or
7X2 is selected from tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl, which is linked to X' by a ring carbon atom, and wherein any heterocyclyl group within Z optionally bears one or two substituents, which may be the same or different selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof.
In this embodiment a particular value for Z is a group selected from hydroxy, and (1- 4C)alkoxy (for example Z is hydroxy, methoxy or ethoxy).
In this embodiment a particular 4-anilino group in Formula I is selected from 3- bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilino and 3-ethynylanilino. Still more particularly the anilino group is 3.chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino.
Another particular embodiment of the present invention is a quinazoline derivative of the Formula I wherein:
R!is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula:
Q*-X3- wherein X° is O, and Q? is azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein any heterocyclyl group within a substituent on R! optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyllamino (particularly R'is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-3C)alkoxy-(2-4C)alkoxy, more particularly R! is (1-4C)alkoxy, for example methoxy, ethoxy, isopropyloxy, still more particularly R'is methoxy); the 4-anilino group in Formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo- 2_fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino and 3- ethynylanilino;
Z is hydroxy or (1-4C)alkoxy, (particularly Z is hydroxy, methoxy or ethoxy, more particularly Z is hydroxy or methoxy, especially Z is hydroxy);
Q! is piperidin-4-yl; ais 0 or 1 (preferably 0); each W, which may be the same or different is selected from hydroxy, (1-3C)alkyl and (1-3C)alkoxy;
X! is CO; xX? is selected from a group of the formula (CHR '**)- and -(CH,CHR'™)-, wherein R'is (1-4C)alkyl (particularly (1-3C)alkyl, more particularly methyl), and wherein R'2 is selected from amino, (1-4C)alkylamino and di-[(1-4C)alkyl]- amino (particularly R'™ is selected from (1-3C)alkylamino and di-[(1-3C)alkyl]-amino, more particularly di-[(1-3C)alkyl]-amino, still more particularly R'? is methylamino and especially dimethylamino); or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof.
In this embodiment a particular 4-anilino group in Formula I is selected from 3- bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilino and 3-ethynylanilino. Still more particularly the anilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino.
Another particular embodiment of the present invention is a quinazoline derivative of the Formula I wherein:
R! is (1-4C)alkoxy (for example methoxy, ethoxy, isopropyloxy, particularly methoxy); the 4-anilino group in Formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo- 2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-S-chloroanilino, 3-bromoanilino and 3- ethynylanilino;
Q! is piperidin-4-yl; ais 0 or | (preferably 0); each W, which may be the same or different is selected from hydroxy, (1-3C)alkyl and (1-3C)alkoxy;
X' is CO;
Z-X? is selected from tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl (particularly Z-X? is tetrahydrofuranyl or pyrrolidinyl), wherein
Z-X? is linked to X' by a ring carbon atom, and wherein any heterocyclyl group within Z optionally bears one or two substituents, which may be the same or different selected from fluoro, chloro, hydroxy, methyl, methoxy and acetyl; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof.
In this embodiment a particular 4-anilino group in Formula I is selected from 3- bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilino and 3-ethynylanilino, more particularly the anilino group is selected from 3-bromo-2-fluoroanilino and 3-chloro-2- fluoroanilino.
Another embodiment of the compounds of Formula 1 is a quinazoline derivative of the
Formula Ia: (Rs
Bul
A! 0 W)q SN 1A —X o) N
Ia wherein:
R! is selected from hydrogen, (1-6C)alkoxy, cyclopropyl-(1-4Calkoxy, cyclobutyl-(1-4C)alkoxy, cyclopentyl-(1-4C)alkoxy, cyclohexyl-(1-6C)alkoxy, tetrahydrofuranyl-(1-4C)alkoxy and tetrahydropyranyl-(1-4C)alkoxy, and wherein any CH, or CHj group within a R! substituent optionally bears on each said CH, or CH; group one or more halogeno substituents, or a substituent selected from hydroxy and (1-4C)alkoxy; byis 0, 1 or 2; each R?, which may be the same or different, is selected from halogeno (particularly fluoro, chloro or bromo), cyano, hydroxy, trifluoromethyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (1-4C)alkoxy (particularly RZ is selected from fluoro, chloro, bromo or ethynyl, more particularly R? is selected from fluoro, chloro and bromo);
R*is halogeno (particularly fluoro, chloro or bromo, more particularly fluoro or chloro, still more particularly chloro or bromo, and especially R* is chloro); ais0,1or2; each W, which may be the same or different, is selected from halogeno (particularly fluoro), hydroxy, (1-4C)alkyl and (1-4C)alkoxy;
X? is a group of the formula: {(CR'R"™),(Q*)m-(CR™R")q- whereinmisOorl,pis0,1,2,30r4andqis0,1,2,3 or 4,
each of R'2, R, R" and R", which may be the same or different, is selected from hydrogen, (1-6C)alkyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and Q° is selected from (3-7C)cycloalkylene and (3-7C)cycloalkenylene, and wherein any CH; or CH; group within an X? group, optionally bears on each said
CH, or CH; group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino;
Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1- 6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and a group of the formula:
Q5-X°- wherein X° is a direct bond or is selected from O, N(R'®), SO; and SO,N(R'®), wherein R'S is hydrogen or (1-6C)alkyl, and Q° is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, provided that when X? is a direct bond, Q° is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO,
SO,, N(R"), CO, -C=C- and -C=C- wherein R"” is hydrogen or (1-6C)alkyl, and wherein and wherein any CH; or CH; group within any Z group, other than a CH, group within a heterocyclyl ring, optionally bears on each said CH, or CH; group one or more halogeno or (1-6C)alky substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and
N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,
(1-6C)alkylsuifonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]lamino, (2-6C)alkanoy!, (2-6C)alkanoyloxy and from a group of the formula: -xI0-R!8 wherein X'? is a direct bond or is selected from O, CO, SO; and NR"), wherein R'is hydrogen or (1-4C)alkyl, and R'is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl,
N-(1-4C)alkylamino-(1-4C)alkyl and N,N-di-[(1-4C)alkyl}amino-(1-4C)alkyl; provided that: when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or 4-chloro-2- fluoroanilino and R' is (1-3C)alkoxy, then a is 0; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof.
Another embodiment of the present invention is a quinazoline derivative of the
Formula Ia as hereinbefore defined, wherein X? is a group selected from (3-6C)cycloalkylene (such as cyclopropylidene), -CH,-, ~CH,CH-, -CH;CH2CH;- HCR'’R'®)-, «(CR'’R’CHa)- and -(CH,CR'’R")- wherein each of R'2 and R'?, which may be the same or different, is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl, provided that R" and R'? are not both hydrogen, and wherein any CH; group within a (3-6C)cycloalkylene group in X?, optionally bears on each said CH; or group one or more (1-4C)alkyl substituents or a substituent selected from hydroxy, (1-4C)alkoxy, hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl.
Another embodiment of the present invention is a quinazoline derivative of the
Formula 1a as hereinbefore defined, wherein X” is a group selected from cyclopropylidene, —
CHy-, ~CH,CH,-, (CR'’R®)-, (CR"?R'"*CHy)- and -(CH,CR"*R}-, wherein each of R'? and RY, which may be the same or different, is selected from hydrogen and (1-4C)alkyl.
Another embodiment of the present invention is a quinazoline derivative of the
Formula la as hereinbefore defined, wherein Z is selected from hydroxy, amino, (1-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]lamino, N-[hydroxy-(2-6C)alkyl}-N-(1-6C)alkylamino, N-[(1-4C)alkoxy- (2-6C)alkyl]-N-(1-6C)alkylamino, di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy- (2-6C)alkyl]amino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino, (1- 6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy, azetidin-1-yl, pymrolidin-1-yl,
piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl homopiperazin-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl and 1,4- dioxanyl; or the group Z-X? is selected from is selected from tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, which heterocyclyl represented by Z-X*is linked to the carbonyl group in Formula Ia, by a ring carbon, and wherein any heterocyclyl group within Z-X? optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl.
More particularly, in Formula 1a, Z is selected from hydroxy, methoxy, ethoxy, 2- hydroxyethoxy, 2-methoxyethoxy, amino, methylamino, ethylamino, N-(2- hydroxyethyl)amino, N-(2-methoxyethyl)amino, dimethylamino, N-methyl-N-ethylamino, di- ethylamino, N-(2-hydroxyethyl)-N-methylamino, N-(2-hydroxyethyl!)-N-ethylamino, N,N-di- (2-hydroxyethyl)amino, N -(2-methoxyethyl)-N-methylamino, N-(2-methoxyethyl)-N- ethylamino, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, tetrahydrofuranyl and tetrahydropyranyl; or the group Z-X? is selected from is selected from tetrahydrofuranyl and tetrahydropyranyl, and wherein any heterocyclyl group within Z optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl and (1-4C)alkoxy. More particularly Z is selected from hydroxy, (1-4C)alkoxy, hydroxy-(2- 4C)alkoxy and (1-4C)alkoxy-(2-4C)alkoxy, still more particularly Z is selected from hydroxy and (1-4C)alkoxy (for example Z is hydroxy or methoxy). Preferably Z is hydroxy.
Another embodiment of the present invention is a quinazoline derivative of the
Formula 1a as hereinbefore defined, wherein:
R? is bromo or chloro (particularly chioro); and bis 0 or 1 and R? is at the ortho (2-) position and is halogeno (particularly R? is fluoro); or bis 0 or 1 and R? is at the para (4-) position and is halogeno (particularly Ris fluoro) and wherein R', W, a, X? and Z have any of the meanings defined hereinabove in relation to the quinazoline derivative of Formula la.
Another particular embodiment of the invention is a quinazoline derivative of the
Formula 1a as hereinbefore defined wherein the anilino group at the 4-position on the quinazoline ring is selected from 3-bromo-2-fluoroanilino, 3-bromoanilino, 3-chloro-4- fluoroanilino and 3-chloro-2-fluoroanilino. Particularly the anilino group is selected from 3- chloro-4-fluoroanilino and 3-chloro-2-fluoroanilino. More particularly the anilino group is 3- chloro-4-fluoroanilino. It is preferred that the anilino group is 3-chloro-2-fluoroanilino.
Wherein in this embodiment R,W,a, X? and Z have any of the meanings defined hereinabove in relation to the quinazoline derivative of Formula 1a.
Another embodiment of the compounds of Formula I is a quinazoline derivative of the
Formula Ib:
Real
Ww), : xn apes x o N
Ib wherein:
R! is selected from hydrogen, (1-6C)alkoxy, cyclopropyl-(1-4C)alkoxy, cyclobutyl-(1-4C)alkoxy, cyclopentyl-(1-4C)alkoxy, cyclohexyl-(1-6C)alkoxy, tetrahydrofuranyl-(1-4C)alkoxy and tetrahydropyranyl-(1-4C)aikoxy, and wherein any CH, or CH; group within a R! substituent optionally bears on each said CH, or CH; group one or more halogeno substituents, or a substituent selected from hydroxy and (1-4C)alkoxy;
R?® is bromo or chloro (particularly chloro); a is 0, | or 2 (particularly a is 0); each W, which may be the same or different, is selected from hydroxy, halogeno (particularly fluoro), (1-4C)alky! and (1-4C)alkoxy;
X? is selected from a group of the formula -CHy-, <CH;CH,-, -CH.CH,CH,- - (CR'R")-, (CR'?R"’CH,)- and -(CH,CR"R")-
wherein each of R'2 and R'3, which may be the same or different, is selected from hydrogen and (1-4C)alkyl (particularly xX? is CH,, more particularly X* is(CHR'®)-, wherein
R'2 is (1-4C)alkyl);
Z is selected from hydroxy, amino, (1-6C)alkylamino, hydroxy-(2-6C)alkylamino, (- 4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]jamino, N-[hydroxy-(2-6C)alkyl]-N- (1-6C)alkylamino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1 -6C)alkylamino, di-{hydroxy- (2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino, N-[(1-4C)alkoxy-(2-6C)alkyl])-N- [hydroxy-(2-6C)alkyi]-amino, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2- 6C)alkoxy, azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl homopiperazin-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3 dioxolanyl, tetrahydropyranyl and 1,4-dioxanyl; or the group Z-X2 is selected from is selected from tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, which heterocyclyl represented by z-Xlis linked to the carbonyl group in Formula Ib, by a ring carbon, and wherein any heterocyclyl group within Z-X? optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof.
In an embodiment in Formula Ib, Z is selected from hydroxy, methoxy, ethoxy, 2- hydroxyethoxy, 2-methoxyethoxy, amino, methylamino, ethylamino, N-(2- hydroxyethyl)amino, N-(2-methoxyethyl)amino, dimethylamino, N-methyl-N-ethylamino, di- ethylamino, N-(2-hydroxyethyl)-N-methylamino, N-(2-hydroxyethyl)-N-ethylamino, N,N-di- (2-hydroxyethyl)amino, N-(2-methoxyethyl)-N-methylamino, N-(2-methoxyethyl)-N- ethylamino, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, tetrahydrofuranyl and tetrahydropyranyl; or the group Z-X? is selected from is selected from tetrahydrofuranyl and tetrahydropyranyl, and wherein any heterocyclyl group within Z optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl and (1-4C)alkoxy.
In another embodiment in formula Ib, R' is selected from hydrogen methoxy, ethoxy, propyloxy, isopropyloxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy,
2-methoxyethoxy, 2-ethoxyethoxy, 2.2-difluoroethoxy and 2,2,2-trifluoroethoxy (Particularly
R! is selected from hydrogen and (1-3C)alkoxy, more particularly R! is (1-3C)alkoxy such as methoxy).
In another embodiment in Formula Ib, R! is selected from (1-4C)alkoxy, hydrox y-(2- 4C)alkoxy and (1-3C)alkoxy-(2-4C)alkoxy; a is 0; Z is selected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-4C)alkoxy-(2-4C)alkoxy, more particularly Z is selected from hydroxy and (1-4C)alkoxy, particularly Z is hydroxy or methoxy (especially hydroxy), and X* has any of the meanings defined hereinabove in relation to the quinazoline of the Formula 1b.
Another embodiment of the compounds of Formula Lis a quinazoline derivative of the
Formula Ic:
A o § S'S
OC
2 (Or "
Ic wherein:
R™ is selected from (1-3C)alkoxy, hydroxy-(2-3C)alkoxy and (1-3C)alkoxy-(2- 3C)alkoxy (particulary R' is methoxy);
X28 is selected from a group of the formula —(CHR'®)- and -(CH,CHR'®)-, wherein R'? is (1-4C)alkyl (particularly (1-3C)alkyl, more particularly methyl), and wherein R'? is selected from amino, (1-4C)alkylamino and di-[(1-4C)alkyl}- amino (particularly R'? is selected from (1-3C)alkylamino and di-{(1-3C)alkyl]-amino, more particularly di-[(1-3C)alkyl]-amino, still more particularly R'? is methylamino and especially dimethylamino);
Z! is selected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-4C)alkoxy- (2-4C)alkoxy (particularly Z! is hydroxy or (1-4C)alkoxy, for example hydroxy or methoxy), or the group Z'X% is selected from tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and piperidinyl, wherein Z'-X* is linked to the carbonyl group by a ring carbon atom, and wherein any heterocyclyl group within Z! optionally bears one or two substituents, which may be the same or different selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl;
or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof.
In this embodiment, preferably 7! is selected from hydroxy and (1-4C)alkoxy (particularly Z'is hydroxy or methoxy, still more particularly Z' is hydroxy).
In this embodiment, preferably X? is a group of the formula ~(CHR'®)-, wherein R'2 is (1-4C)alkyl (particularly (1-3C)alkyl, more particularly methyl),
Another embodiment of the compounds of Formula I'is a quinazoline derivative of the
Formula Id: © A (o]
NS San
Id wherein:
R™ is (1-4C)alkoxy, and wherein any CH, or CH3 group within a R'® substituent optionally bears on each said CH, or CH; group one or more halogeno substituents, or any CH, or CHj group within a
R! which is not attached to an oxygen atom optionally bears on each said CH; or CH; group a substituent selected from hydroxy and (1-3C)alkoxy;
X?® is selected from a group of the formula —CH,-, -CH2CH,-, (CHR"?)-, - (CHR'’CH,)- and -(CH,CHR'?)- wherein R'? is selected from (1-3C)alkyl, hydroxy-(1-3C)alkyl and (1-3C)atkoxy- (1-3C)alkyl; and 7% is selected from hydroxy, (1-3C)alkoxy, hydroxy-(2-3C)alkoxy, (1-3C)alkoxy-(2- 3C)alkoxy, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl and 1,4-dioxanyl; and wherein any heterocyclyl group within Z2-X" optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-3C)alkyl, (1-3C)alkoxy and (2-3C)alkanoyl; or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof.
In an embodiment in formula Id, R" is selected from methoxy, ethoxy, 2-hydroxyethoxy, 2-fluorcethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy (Particularly R'® is (1-3C)alkoxy such as methoxy).
In another embodiment in formula Id, Xx? is selected from a group of the formula -
CHj-, -CH,CH,- and ~(CHR'?)-, wherein R'? is selected from (1-3C)alkyl, hydroxy-(1- 3C)alkyl and (1-3C)alkoxy-(1-3C)alkyl (for example R'? is methyl).
In another embodiment in formula Id, X? is selected from a group of the formula -
CH,- and (CHR '?)-, wherein R!'Zis (1-3C)alkyl (for example methyl). For example X® is selected from —CH,- and -CH(CH3)-, particularly X? is -CH(CH3)-.
In another embodiment in formula Id, 72 is selected from hydroxy and (1-3C)alkoxy (especially hydroxy).
In another embodiment in formula Id, the group Z2-X”- is selected from hydroxymethyl, methoxymethyl, (S)-1-hydroxyethyl, (R)-1-hydroxyethyl, (S)-1- methoxyethyl, (R)-1-methoxyethyl. Particularly the group Z2-X®- is 1-hydroxyethyl, more particularly (S)-1-hydroxyethyl or (R)-1-hydroxyethyl.
In another embodiment in formula Id R" is (1-3C)alkoxy such as methoxy; and the group 72.X?_ is selected from hydroxymethyl, methoxymethyl, (S)-1-hydroxyethyl, (R)-1- hydroxyethyl, (S)-1-methoxyethyl, (R)-1-methoxyethyl. Particularly in this embodiment zx
X? is 1-hydroxyethyl, more particularly (S)-1-hydroxyethyl or (R)-1-hydroxyethyl.
A particular compound of the invention is, for example, a quinazoline derivative of the Formula I selected from:
N-(3-chloro-2-fluorophenyl)-7-({ 1-[(dimethylamino)acetyl]piperidin-4-yl} 0Xy)-6- methoxyquinazolin-4-amine;
N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({ 1-[(2-methoxyethoxy)acetyl]piperidin-4- yl}oxy)quinazolin-4-amine;
N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(methox yacetyl)piperidin-4- ylJoxy }quinazolin-4-amine; 2-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl Joxy)piperidin-1-yl}-2- oxoethanol;
N-(3-chloro-2-fluorophenyl)-7-{{ 1-(ethoxyacetyl)piperidin-4-ylJoxy }-6-methox yquinazolin- 4-amine;
N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{ [1-(3-methoxypropanoyl)piperidin-4- ylloxy}quinazolin-4-amine; 3-[4-({4-[3-chloro-2-fluoroanilino] -6-methoxyquinazolin-7-yl Joxy)piperidin-1-yl}-3- oxopropan-1-ol;

Claims (35)

1. A quinazoline derivative of the Formula I: Ge HN R! (W), SN Poy JS Q' +O N x 2X -N z 5S wherein: R! is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula : Q*-X3- wherein X’ is a direct bond or is O, and Q? is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R! substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, 80, N(R®), CO, CH(OR?), CON(R?), N(R*)CO, SO:N(R), N(R*)SO;, CH=CH and C=C wherein R? is hydrogen or (1-6C)alkyl, and wherein any CH,=CH- or HC=C- group within a R! substituent optionally bears at the terminal CH,= or HC= position a substituent selected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl}carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula : Q’-x*- wherein X*is a direct bond or is selected from CO and N(R*)CO, wherein R* is hydrogen or (1-6C)alkyl, and Q’ is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any CH; or CH; group within a R! substituent, other than a CH; group within a heterocyclyl ring, optionally bears on each said CH, or CH; group one or more halogeno or (1-6C)alky! substituents or a substituent selected from hydroxy, cyano, amino,
carboxy, carbamoyl, sulfamoyl, oxo, thioxo, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl}amino, (1-6C)alkoxycarbonyl, N-( 1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the formula:
ox wherein X® is a direct bond or is selected from O, S, SO, S02, NR®), CO, CH(OR), CONR®), NR®)CO, SO;N(R®), N(R®)SO;, C(R®):0, C(R*):S and C(R*);N(R’), wherein Ris hydrogen or (1-6C)alkyl, and Q* is (3-7C)cycloalkyl, (3-7C)cycloalkyl- (1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R! optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, formyl, mercapto, sulfamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl}amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]Jcarbamoyl, N-(1-6C)alkylsulfamoyl,
N,N-di-[(1-6C)alkyl]sulfamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino, and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the formula:
-X%-R® wherein X%is a direct bond or is selected from O, NR") and C(O), wherein Ris hydrogen or (1-6C)alkyl, and RC is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, carboxy-(1-6C)alkyl,
(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,
(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyljamino-(1-6C)alkyl,
(2-6C)alkanoylamino-(1-6C)alkyl, (1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl, N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl or (1-6C)alkoxycarbonyl-(1-6C)alkyl,
and wherein any heterocyclyl group within a substituent on R! optionally bears 1 or 2 oxo or thioxo substituents; bisl,2,3,40r5; each R2, which may be the same or different, is selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, trifluoromethyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2- 6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N -(1-6C)alkyl-(2-6C)alkanoylamino,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino, N-(1-
6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula : -X'-R® wherein X is a direct bond or is selected from O and N(R®), wherein R’ is hydrogen or (1- 6C)alkyl, and R® is halogeno-(1-6C)alkyl, hydroxy-(1-6C)atkyl, (1-6C)alkoxy-(1-6C)alkyl,
cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1- 6C)alkyl}amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl or (1-
" 6C)alkox ycarbonylamino-(1-6C)alkyl; Q! is piperidinyl; ais0,1,2,30r4;
each W, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, oxo, amino, formyl, mercapto, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
-x8-R© wherein X% is a direct bond or is selected from O, CO, SO and NR, wherein R'! is hydrogen or (1-6C)alkyl, and R'®is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, N-(1-6C)alkylamino-(1-6C)alkyl or N,N-di-[(1-6C)alkyl]Jamino-(1-6C)alkyl;
X! is selected from CO and SO»;
X? is a group of the formula:
{CR"R"),-(Q")m-(CR“R")- wherein misQorl,pis0,1,2,30r4andqis0,1,2,3 or4,
each of R'2, R', R' and R', which may be the same or different, is selected from hydrogen, (1-6C)alkyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl}amino, and Q is selected from (3-7C)cycloalkylene and (3-7C)cycloalkenylene,
and wherein any CH; or CH; group within an X? group, optionally bears on each said
CH, or CH; group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkylJamino;
Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1- 6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula:
Q5-X°-
wherein X’ is a direct bond or is selected from O, N(R'®), SO; and SO,NR'®), wherein R'® is hydrogen or (1-6C)alkyl, and Q° is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl;
provided that when X’ is a direct bond, Qt is heterocyclyl,
and provided that when m, p and q are all 0, then Z is heterocyclyl,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain withina Z substituent are optionally separated by the insertion into the chain of a group selected from 0, 8S, 80, SO,, N(R"), CO, -C=C- and -C=C- wherein R'” is hydrogen or (1-6C)alkyl,
and wherein and wherein any CH, or CH; group within any Z group, other than a CH; group within a heterocyclyl ring, optionally bears on each said CH, or CHj group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,
di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)aikyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,
and wherein any heterocyclyl group within a Z substituent optionally bears one or more substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl}amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -X'0-R!® wherein X'? is a direct bond or is selected from O, CO, SOz and N(R'®), wherein RY is hydrogen or (1-4C)alkyl, and R'3 is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl and N,N -di-[(1-4C)alkyl]amino-(1-4C)alkyl; provided that: when the 4-anilino group in Formula Lis 4-bromo-2-fluoroanilino or 4-chloro-2- fluoroanilino and R' is hydrogen or (1-3C)alkoxy, then ais 0 and Zis selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl}amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and a group of the formula Q%-X°-; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof.
2. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to claim 1 wherein: R! is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula : Q*-X*- wherein X? is a direct bond or is O, and Q is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R' substituent are optionally separated by the insertion into the chain of a group selected from O, N(R?), CON(R?), N(R*)CO, CH=CH and C=C wherein R’ is hydrogen or (1-6C)alkyl, and wherein any CH,=CH- or HC=C- group within a R' substituent optionally bears at the terminal CH,= or HC= position a substituent selected from carbamoyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]Jamino-(1-6C)atkyl and wherein any CH; or CH; group within a R! substituent, other than a CH; group within a heterocyclyl ring, optionally bears on each said CH, or CH; group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, amino, cyano, carbamoyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl and N,N-di-[(1-6C)alkyl]Jcarbamoyl, or from a group of the formula :
-X5-Q wherein X° is a direct bond or is selected from O, NR®), CONR®), NR*)CO and CR10, wherein R® is hydrogen or (1-6C)alkyl, and Q* is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R! optionally bears 1, 20r 13 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyljcarbamoyl, (2-6C)alkanoyl, or from a group of the formula: -X5-RS wherein X°is a direct bond or is selected from O and N(R"), wherein R'is hydrogen or (1-6C)alkyl, and RS is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R! optionally bears 1 or 2 oxo substituents.
3. A quinazoline derivative of the Formula I, ora pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to claim 1 wherein: R! is selected from hydrogen, hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1- 3C)alkoxy-(2-4C)alkoxy or from a group of the formula : Q*-X3- wherein X is O, and Q’ is azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino- (2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein any heterocyclyl group within a substituent on R' optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkylamino, di-{(1-4C)al kyl}amino, and (2-4C)alkanoyl, and wherein any heterocyclyl group within a substituent on R' optionally bears 1 oxo substituent.
4. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to claim 1 wherein R'is (1-3C)alkoxy.
3. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims wherein: bis 1,2or3; and each R?, which may be the same or different, is selected from fluoro, chloro, bromo, (1-4C)alkyl, (2-4C)alkenyl and (2-4C)alkynyl.
6. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable sait, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims wherein: bis 1, 2 or 3 and one R? is at the meta (3-) position on the anilino group in Formula 1 and is halogeno.
71. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of claims 1 to 4 wherein the anilino group at the 4-position on the quinazoline ring in the compound of Formula I is selected from 3-chloro-2-bromoanilino, 3-chloro-2-fluoroanilino, 3-ethynylanilino and 3- bromoanilino.
8. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims wherein: X?2 is a group of the formula -(CR'’R'*)~(CR'**R"***)-, wherein qis1,2o0r3, each of R'?, R'" and R'®, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, R'? is selected from amino, (1-6C)alkylamino and di-{(1-6C)alkyl}amino, and wherein any CH; or CH; group within an X? group, optionally bears on each said CH, or CHj3 group one or more halogeno substituents, and wherein any CH; group which is attached to 2 carbon atoms or any CHj group which is attached to a carbon atom within a X° substituent optionally bears on each said CH; or CH; group a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino.
9. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of claims 1 to 7 wherein: X2 is a group of the formula —(CR'R"),-, wherein . qis1,2,30r4, each of R'2 and R'?, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, provided that at least one of the RZ or R" groups in X? is (1-6C)alkyl, and wherein any CH; or CH; group within an X? group, optionally bears on each said CH, or CH; group one or more halogeno substituents, and wherein any CH, group which is attached to 2 carbon atoms or any CH; group which is attached to a carbon atom within a X?2 substituent optionally bears on each said CH; or CH; group a substituent selected from hydroxy, and (1-6C)alkoxy.
10. A quinazoline derivative of the Formula, or a pharmaceutically acceptable sait, or a pharmaceutically acceptable ester thereof, according to any one of claims 1 to 7 wherein: X2 is selected from a group of the formula -CHp-, -CH,CH;-,~(CHR'®)-, - (CHR'%CH;)-, «(CR );CHz)-, (CH;CR'**),)- and -(CH,CHR"™)-, wherein each R'?, which may be the same or different, is (1-4C)alkyl.
11. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims wherein: Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl}amino, (1- 6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy and a group of the formula: QS-x°- wherein X° is a direct bond and Q° is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl linked to X' by a ring carbon atom, and wherein any heterocyclyl group in Z is selected from azetidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, and wherein and wherein any CH; or CH; group within a Z group, other than a CH; group within a heterocyclyl ring, optionally bears on each said CH; or CH; group one or more halogeno or (1-4C)alkyl substituents or a substituent selected from hydroxy and (14C)alkoxy, and wherein any heterocyclyl group within a Z substituent optionally bears one Or more substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino and (2-4C)alkanoyl.
12. A quinazoline derivative of the Formula I, ora pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims wherein: Z is hydroxy or (1-4C)alkoxy; and the sum of m +p4q is at least 1.
13. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable sait, or a pharmaceutically acceptable ester thereof, according to any one of claims 1 to 7 wherein: X? is selected from a group of the formula -CH;-, -CH,CH-, —(CHR'%)-, - (CHR '2CH)-, {C(R"#),CH,)-, (CH,CR *");)- and -(CH.CHR'*)-, wherein each R'%, which may be the same or different, is (1-4C)alkyl; and Z is hydroxy or (1-4C)alkoxy.
14. A quinazoline derivative of the Formula, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims wherein: Q} is piperidin-4-yl; aisOorl;and W is selected from halogeno, hydroxy, (1-3C)alkyl and (1-3C)alkoxy.
15. A quinazoline derivative of the Formula, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims wherein X! is CO.
16. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to claim 1 wherein:
R! is selected from hydrogen, (1-6C)alkoxy, cyclopropyl-(1-4C)alkoxy, cyclobutyl-(1-4C)alkoxy, cyclopentyl-(1-4C)alkoxy, cyclohexyl-(1-6C)alkoxy, tetrahydrofuranyl-(1-4C)alkoxy and tetrahydropyranyl-(1-4C)alkoxy, and wherein any CH; or CH; group within a R! substituent optionally bears on each said CH; or CH; group one or more halogeno substituents, or a substituent selected from hydroxy and (1-4C)alkoxy; bis1,2o0r3; each R?, which may be the same or different, is selected from halogeno, cyano, hydroxy, trifluoromethyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (1-4C)alkoxy; Q! is piperidin-4-yl; ais0,1lor2; each W, which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, oxo, (1-6C)alkyl, (1-6C)alkoxy, and from a group of the formula: -x8&-RY wherein X® is a direct bond or is O, and R' is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl or (1-6C)alkoxy-(1-6C)alkyl; X' is CO; X2 is a group selected from (3-6C)cycloalkylene, —CH,-, -CH,CHa-, -CH,CH,CH,-, —(CR"R")-, (CR7R"CH)- and -(CH,CR'R")-, wherein each of R'? and R"?, which may be the same or different, is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl, provided that 1:30 and R'? are not both hydrogen, and wherein any CH, group within a (3-6C)cycloalkylene group in X2, optionally bears on each said CH; or group one or more (1-4C)alkyl substituents or a substituent selected from hydroxy, (1-4C)alkoxy, hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl; and Z is selected from hydroxy and (1-4C)alkoxy; provided that: when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or 4-chloro-2- fluoroanilino, R' is hydrogen or (1-3C)alkoxy, and X' is CO, then a is 0.
17. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to claim 1 wherein:
the 4-anilino group on the quinazoline ring in Formula I is selected from 3-chloro-4- fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilino and 3- ethynylanilino; R!is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula: Q?-X- wherein X® is O, and Q? is azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein any heterocyclyl group within a substituent on R! optionally bears 1,2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino; Z is hydroxy or (1-4C)alkoxy; Q! is piperidin-4-yl; aisOorl; each W, which may be the same or different is selected from hydroxy, (1-3C)alkyl and (1-3C)alkoxy; x! is CO; X? is selected from a group of the formula (CHR '%)- and -(CH,CHR'®)-, wherein R'2 is (1-4C)alkyl, and wherein R'? is selected from amino, (1-4C)alkylamino and di-[(1-4C)alkyl]- amino.
18. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to claim 1 of the Formula Id: ® pes AOA 2” Id wherein: R™ js (1-4C)alkoxy,
and wherein any CH; or CH3 group within a R'® substituent optionally bears on each said CH, or CH; group one or more halogeno substituents, or any CH; or CH; group within a R' which is not attached to an oxygen atom optionally bears on each said CH; or CH; group a substituent selected from hydroxy and (1-3C)alkoxy; X? is selected from a group of the formula —CH;-, -CH;CHa-, (CHR '?)-, — (CHR "’CH,)- and (CH,CHR'?)- wherein Ris selected from (1-3C)alkyl, hydroxy-(1-3C)alkyl and (1-3C)alkoxy- (1-3C)alkyl; and 72 is selected from hydroxy, (1-3C)alkoxy, hydroxy-(2-3C)alkoxy, (1-3C)alkoxy-(2- 3C)alkoxy, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl and 1,4-dioxanyl; and wherein any heterocyclyl group within Z2-X® optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-3C)alkyl, (1-3C)alkoxy and (2-3C)alkanoyl; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof.
19. A quinazoline derivative according to claim 18, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, wherein 7? is hydroxy and R'?is (1-3C)alkyl;
20. A quinazoline derivative according to claim 18, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, wherein: R'™ is (1-3C)alkoxy; and the group Z2-X. is selected from hydroxymethyl, methoxymethyl, (S)-1-hydroxyethyl, (R)- 1-hydroxyethyl, (S)-1-methoxyethyl and (R)-1-methoxyethyl.
21. A quinazoline derivative of the Formula I according to claim 1 selected from: N-(3-chloro-2-fluorophenyl)-7-({ 1-[(dimethylamino)acetyl]piperidin-4-yl } oxy)-6- methoxyquinazolin-4-amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({ 1-[(2-methoxyethoxy)acetyl]piperidin-4- yl}oxy)quinazolin-4-amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{ [1-(methoxyacetyl)piperidin-4- ylJoxy}quinazolin-4-amine;
2-[4-({4-[3-chloro-2-fluoroanilino]-6-methox yquinazolin-7-yl Joxy)piperidin-1 -yl]-2- oxoethanol; N-(3-chloro-2-fluorophenyl)-7-{ [1-(ethoxyacetyl)piperidin-4-yljoxy} -6-methoxyquinazolin- 4-amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(3-methoxypropanoyl)piperidin-4- ylloxy}quinazolin-4-amine; 3-[4-({4-[3-chloro-2-fluoroanilino]-6-methox yquinazolin-7-yl }oxy)piperidin-1-yl]-3- oxopropan-1-ol; (28)-1-[4-({4-[3-chloro-2-fluoroanilino}-6-methoxyquinazolin-7-yl }oxy)piperidin-1-yi]-1- oxopropan-2-ol; (25,3S5)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methox yquinazolin-7-yl Joxy)piperidin-1-yl]-3- methyl-1-oxopentan-2-ol; 4-[4-({4-[3-chloro-2-fluoroanilino}-6-methox yquinazolin-7-yl }oxy)piperidin-1-yl]-2-methyl- 4-oxobutan-2-ol; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{ [1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4- ylloxy }quinazolin-4-amine; 3-[4-({4-[3-chloro-2-fluoroanilino]-6-methox yquinazolin-7-yl }oxy)piperidin-1-y1]-2,2- dimethyl-3-oxopropan-1-ol; (3R,55)-1-acetyl-5-{ [4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7- yl}oxy)piperidin-1-yljcarbonyl}pyrrolidin-3-ol; and N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({ 1-[(4-methylpiperazin-1-yl)acetyl]piperidin-4- yl }oxy)quinazolin-4-amine; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof.
22. A quinazoline derivative of the Formula I selected from: N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-{[1-(methoxyacetyl)pipendin-4- ylJoxy }quinazolin-4-amine; 2-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl ox y)piperidin-1-yl]-2- oxoethanol; N-(3-chloro-2-fluorophenyl)-7-{[1-(ethoxyacetyl)piperidin-4-ylJoxy}-6-methoxyquinazolin- 4-amine; (25)-1-[4-({4-[3-chloro-2-fluoroanilino}-6-methoxyquinazolin-7-yl Joxy)piperidin-1-yl]-1- oxopropan-2-ol;
3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl Joxy)piperidin-1-yl]-2,2- dimethyl-3-oxopropan-1-ol; (25)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methox yquinazolin-7-yl Joxy)piperidin-1-yl]-3,3- dimethyl-1-oxobutan-2-ol; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(1-methyl-L-prolyl)piperidin-4- yljoxy}quinazolin-4-amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({ 1-[(2S)-tetrahydrofuran-2-ylcarbonyl|piperidin- 4-yl}oxy)quinazolin-4-amine; (2R)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methox yquinazolin-7-yl }oxy)piperidin-1-yi}-1- oxopropan-2-ol; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({ 1-[(2S)-2-methoxypropanoyl]piperidin-4- yl}oxy)quinazolin-4-amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({ 1-[(2R)-2-methox ypropanoyl]piperidin-4- yl }oxy)quinazolin-4-amine; (2R)-3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl Joxy)piperidin-1-yli]-2- (dimethylamino)-3-oxopropan-1-ol; (25)-1-[4-({ 4-[(3-chloro-4-fluoroanilino]-6-methoxyquinazolin-7-yl }oxy)piperidin-1-yl]-1- oxopropan-2-ol; (25)-1-[4-({4-[3-bromoanilino]-6-methoxyquinazolin-7-yl }oxy)piperidin-1-yl]-1-oxopropan- 2-0; (25)-1-[4-({4-[3-bromo-2-fluoroanilino]-6-methoxyquinazolin-7-yl Jox y)piperidin-1-yl]-1- oxopropan-2-ol; (2R)-1-[4-({4-[3-bromo-2-fluoroanilino]-6-methox yquinazolin-7-yl Jox y)piperidin-1-yl]-1- oxopropan-2-0l; and (2R)-1-[4-({4-[3-bromoanilino]}-6-methoxyquinazolin-7-yl Joxy)piperidin-1-yl]-1-oxopropan- 2-0l; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof.
23. A quinazoline derivative of the Formula I according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.
24. A pharmaceutical composition which comprises a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester
PCT/GB2004/003923 thereof, according to any one of the preceding claims, in association with a pharmaceutically acceptable diluent or carrier.
25. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a S pharmaceutically acceptable ester thereof, according to any one of claims 1 to 23,foruseasa medicament.
26. Use of a quinazoline derivative of the Formula I, a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 23 in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as a human.
27. Use of a quinazoline derivative of the Formula I, a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 23 in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of EGFR tyrosine kinases, that are involved in the signal transduction steps which lead to the proliferation of tumour cells.
28. Use of a quinazoline derivative of the Formula], or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 23 in the manufacture of a medicament for use in providing a selective EGFR tyrosine kinase inhibitory effect in a warm-blooded animal such as a human.
29. Use of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, © 25 or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 23 in the manufacture of a medicament for use in the treatment of a cancer in a warm-blooded animal such as a human.
30. A process for the preparation of a quinazoline derivative of the Formula I as defined in Claim 1 which comprises: Process (a): for the preparation of compounds of the Formula I wherein X' is CO, the coupling of a quinazoline of the formula IT or a salt thereof: ARSERCDED CLEAT
PCT/GB2004/003923 ; HN R > a 0 N HN II
10 . wherein R', R%, W, a, b and Q' are as defined in claim 1,except that any functional group is protected if necessary, with an acid of the formula III, or a reactive denvative ’ thereof: Z-X*- COOH HI wherein Z and X? are as defined in claim 1, except that any functional group is protected if necessary; or Process (b) the reaction of a quinazoline of the formula II or a salt thereof, as defined in relation to Process (a), with a compound of the formula IV: z-x>-x'-L' IV wherein L' is a displaceable group and Z, X' and X? are as defined in claim 1, except that any functional group is protected if necessary; or Process (c) for the preparation of those quinazoline derivatives of the Formula I wherein Z is linked to X? by nitrogen, the reaction of a compound of the formula V: 2 HN R! (W), XN p Q' 0 N 12—xz-x'-N Vv AMENDED SHEET
PCT/GB2004/003923 wherein L? is a displaceable group and R!, R%, W, X', X? a, b and Q' are as defined in claim 1, except that any functional group is protected if necessary, with a compound of the formula ZH, wherein Z is as hereinbefore defined, except that any functional group is protected if necessary; or Process (d) for the preparation of those quinazoline derivatives which carry a mono- or di-(1- 6C)alkylamino group, the reductive amination of the corresponding quinazoline derivative of the Formula I which contains an N-H group using formaldehyde or a (2-6C)alkanolaldehyde; or Process (e) for the preparation of those quinazoline derivatives of the Formula [ wherein R'is is hydroxy, the cleavage of a quinazoline derivative of the Formula I wherein R'isa(l- 6C)alkoxy group; or Process (f) for the preparation of those quinazoline derivatives of the Formula I wherein R'is linked to the quinazoline ring by an oxygen atom, by coupling a compound of the Formula VI:
fe HN HO J (oy o Ni 2X! -N 7% \%! wherein R%, W, X', X3, Z, a, b and are as defined in claim 1 except that any functional group is protected if necessary, with a compound of the formula ROH, wherein the group R"O is one of the oxygen linked groups as defined for R' in claim 1, except that any functional group is protected if necessary; and thereafter, if necessary (in any order): AMENDED SHEET
PCT/GB2004/003923 (i) converting a quinazoline derivative of the Formula I into another quinazoline derivative of the Formula I; ‘ (ii) removing any protecting group that is present by conventional means; and S (iii) forming a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester of the quinazoline derivative of the Formula L
31. A quinazoline derivative of the Formula II: : HN” g “Rr R 2d (Ww), SV J Qt? e) N HN II 30 wherein: R', W, Q' and a are as defined in claim 1; and RZ and R¥, which may be the same or different are halogeno; or a salt thereof.
32. A derivative according to any one of claims 1 to 23, 25 or 31, substantially as herein described with reference to any of the examples and as illustrated.
33. A composition according to claim 24, substantially as herein described with reference to any of the examples and as illustrated.
34. Use according to any one of claims 26 to 29, substantially as herein described with reference to any of the examples and as illustrated. AMENDED SHEET
PCT/GB2004/003923
35. A process according to claim 30, substantially as herein described with reference to any of the examples and as illustrated. AMENDED SHEET
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