HK1079521B - 4-anilino quinazoline derivatives as antiproliferative agents - Google Patents

Description

4-anilinoquinazoline derivatives as antiproliferative agents

The present invention relates to certain novel quinazoline derivatives, or pharmaceutically acceptable salts thereof, which possess anti-tumour activity and are accordingly useful in methods of treatment of the human or animal body. The invention also relates to processes for the preparation of said quinazoline derivatives, to pharmaceutical compositions containing them and to their use in therapeutic methods, such as in the manufacture of medicaments for use in the prevention or treatment of solid tumour diseases in warm-blooded animals such as humans.

Many current treatment regimens for diseases caused by abnormal regulation of cell proliferation (e.g., psoriasis and cancer) employ compounds that inhibit DNA synthesis and cell proliferation. To date, the compounds employed in these treatments are generally toxic to cells, but their enhanced toxic effects on rapidly differentiating cells (e.g., tumor cells) may be beneficial. Other pathways for these cytotoxic antineoplastic agents are currently being developed, such as selective inhibitors of cellular signaling pathways. These types of inhibitors may exhibit the potential for selective enhancement of the effects on tumor cells, and thus may reduce the likelihood of unwanted side effects with the therapy.

Eukaryotic cells respond continuously to a variety of different extracellular signals that enable intra-organ cell communication. These signals regulate a variety of cellular physiological responses, including proliferation, differentiation, apoptosis, and motility. These extracellular signals take the form of a variety of different lytic factors, including growth factors and paracrine and endocrine factors. These ligands integrate these extracellular signals into intracellular signaling pathways by binding to specific transmembrane receptors, thus, conducting the signal through the plasma membrane and allowing the individual cell to respond to its extracellular signal. Many of these signaling processes utilize reversible processes involving protein phosphorylation that promote these diverse cellular responses. The phosphorylation status of targeted proteins is regulated by specific kinases and phosphatases responsible for the regulation of about one third of all proteins encoded by the mammalian genome. Since phosphorylation is an important regulatory mechanism in the signal transduction process, it is not surprising that abnormalities in these intracellular transduction pathways can lead to abnormalities in cell growth and differentiation, thereby promoting cell transformation (see Cohen et al,Curr Opin Chem Biol1999, review of 3, 459-.

It has been widely shown that many of these tyrosine kinases can mutate to produce structurally active forms and/or that overexpression can lead to transformation of a variety of human cells. These mutant and overexpressed forms of the kinase are present in most human tumors (see Kolibaba et al, Biochimica et biophysica Acta, 1997,133review of F217-F248). Since tyrosine kinases play a fundamental role in the proliferation and differentiation of various tissues, much attention has been focused on these enzymes in the development of new anti-cancer therapies. The family of enzymes can be divided into two classes-receptor and non-receptor tyrosine kinases, for example the EGF receptor and SRC families, respectively. As can be seen from the results of a number of studies, including the human gene project, about 90 tyrosine kinases have been identified in the human genome, of which 58 are receptor types and 32 are non-receptor types. They can be divided into 20 receptor tyrosine kinases and 10 non-receptor tyrosine kinase subfamilies (Robinson et al,Oncogene，2000，19，5548-5557)。

the receptor tyrosine kinases are of particular importance in the transduction of mitogenic signals that trigger cell replication. These large glycoproteins that span the plasma membrane of cells have an extracellular binding domain for their specific ligands, such as Endothelial Growth Factor (EGF) for the EGF receptor. Binding of the ligand results in activation of the receptor kinase enzyme activity, which is encoded by the intracellular portion of the receptor. This activity phosphorylates key tyrosine amino acids within the target protein, thereby transducing proliferation signals through the plasma membrane of the cell.

The erbB family of receptor tyrosine kinases are known to include EGFR, erbB2, erbB3, and erbB4, which are generally involved in driving the proliferation and survival of tumor cells (Olayioye et al,EMBO J.，2000，19review of 3159). One mechanism that can be achieved is by over-expressing the receptor at the protein level, which is generally due to amplification of the gene. It has been observed in many common human cancers (see klaper et al,Adv.Cancer Res.，2000，77reviewed in 25), such as breast cancer (Sainsbury et al,Brit.J.Cancer，1988，58458; guerin et al, in the case of a pharmaceutical composition,Oncogene Res，1988，321, 21; slamon et al, to which reference is made,Science，1989，244707; klijin et al, and the like,Breast Cancer Res.Treat.，1994，2973; and Salomon et al,Crit.Rev.Oncol.Hematol，1995，19183), non-small cell lung cancer (NSCLCs), including adenocarcinoma (Cerny et al,Brit.J.Cancer，1986，54265, respectively; reubi et al, supra,Int.J. Cancer，1990，45269; the Rusch et al, in the name of Rusch,Cancer Research，1993，532379; the Brabender et al,Clin.Cancer Res.，2001，71850) and other lung cancers (Hendler et al,Cancer Cells，1989，7347, of; the results of the Ohsaki et al,Oncol Rep.，2000，7603), bladder cancer (Neal et al,Lancet1985, 366; chow, and the like,Clin.Cancer Res.，2001，71957, ZHau et al,Mol Carcinog.，3254), esophageal cancer (Mukaida et al,Cancer，1991，68142), gastrointestinal cancers such as colon, rectal or gastric cancer (Bolen et al,Oncogene Res，1987，1149; kapitanovic et al, and the like,Gastroenterology，2000，1121103; ross, etc., and the like,Cancer Invest，2001，19554), prostate cancer (Visakorpi et al,Histochem J.，1992，24481; the results of Kumar et al, 2000,3273; the Scher et al, supra,J.Natl.Cancer Inst，2000，921866), leukemia (Konaka et al, Cell，1984，371035; Martin-Subero et al,Cancer Genet Cytogenet，2001，127174), ovarian cancer (Hellstrom et al,Cancer Res，2001，612420), head and neck cancer (Shiga et al,HeadNeck，2000，22599) or pancreatic cancer (Ovotny et al,Neoplasma，2001，48,188). With the detection of the expression of the erbB family of receptor tyrosine kinases in more human tumour tissue, the understanding of their wide prevalence and importance is expected to be further enhanced in the future.

As a result of the mismodulation of one or more of these receptors, it is now widely believed that many tumors become clinically more aggressive and poorly diagnostically relevant to patients (Brabender et al,Clin.Cancer Res.，2001，71850; ross, etc., and the like,Cancer Investigation，2001，19554; yu and the like,Bioessays，2000，22.7,673). In addition to these clinical findings, a wealth of preclinical information suggests that the erbB family of receptor tyrosine kinases are involved in cellular transformation. This includes the observation that many tumor cell lines overexpress one or more erbB receptors and that when EGFR or erbB2 is transfected into non-tumor cells, they have the ability to transform these cells. This tumorigenic potential has been demonstrated because transgenic mice overexpressing erbB2 can spontaneously develop tumors in mammalian glands. In addition, a number of preclinical studies have shown that antiproliferative effects can be induced by blocking one or more erbB activities by small molecule inhibitors, dominant negatives or inhibitory antibodies (see Mendelsohn et al, Oncogene，2000，19Review of 6550). It has therefore been recognized that inhibitors of these receptor tyrosine kinases should be of value as selective inhibitors of the proliferative effects of mammalian cancer cells (Yaish et al,Science，1988，242933; kolibaba et al, Biochimica Biophysica Acta, 1997,133F217-F248; Al-Obeidi et Al, 2000,Oncogene，195690-; mendelsohn et al, 2000,Oncogene,19, 6550-6565). In addition to these preclinical data, results using antibodies that inhibit EGFR and/or erbB2 (c-225 and tratsuzumab, respectively) have demonstrated clinical benefit in the treatment of selected solid tumors (see Mendelsohn et al, 2000,Oncogene19, 6550 and 6565).

The amplification and/or activity of members of the erbB-type receptor tyrosine kinases has been detected and has thus been implicated in a number of non-malignant proliferative disorders, such as psoriasis (Ben-Bassat,Curr.Pharm.Des.2000，6933; elder et al, Science, 1989,243811), Benign Prostatic Hypertrophy (BPH) (Kumar et al,Int.Urol.Nephrol.，2000，3273), atherosclerosis and restenosis (Bokemeyer et al, Kidney int, 2000,58,549). It is therefore desirable for erbB type receptor tyrosine kinasesInhibitors would be useful in the treatment of these or other non-malignant hyperproliferative diseases.

European patent application EP 566266 discloses certain 4-anilinoquinazolines as inhibitors of receptor tyrosine kinases.

International patent applications WO 96/33977, WO 96/33978, WO 96/33979, WO96/33980, WO 96/33981, WO 97/30034, WO 97/38994 disclose certain quinazoline derivatives having receptor tyrosine kinase inhibitory activity which bear an anilino substituent at the 4-position and a substituent at the 6-and/or 7-position.

European patent application EP 837063 discloses aryl substituted 4-aminoquinazoline derivatives bearing a moiety comprising an aryl or heteroaryl group at the 6-or 7-position of the quinazoline ring. The compounds are believed to be useful in the treatment of hyperproliferative diseases.

International patent applications WO 97/30035 and WO 98/13354 disclose that 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 characterized in that the substituent in the 6-and/or 7-position carries an ester linkage moiety (RO-CO).

WO 00/56720 discloses 6, 7-dialkoxy-4-anilinoquinazoline compounds for use in the treatment of cancer or allergic reactions.

WO 02/41882 discloses pyrrolidinyl-alkoxy or piperidinyl-alkoxy substituted 4-anilinoquinazoline compounds substituted in the 6-and/or 7-position.

The prior art does not disclose 4- (2, 3-dihaloanilino) quinazoline compounds.

We have now surprisingly found that certain 4- (2, 3-dihaloanilino) quinazoline derivatives have potent anti-tumour activity. Although not wishing to imply that the compounds disclosed herein act pharmacologically by only a single biological process, it is believed that the compounds provide anti-tumour effects by inhibiting the erbB family of one or more receptor tyrosine kinases which are involved in the signalling steps leading to the proliferation of tumour cells. In particular, the compounds of the invention are believed to provide anti-tumour effects by inhibiting EGFR and/or erbB2 receptor tyrosine kinases.

Generally, although the compounds of the invention have less inhibitory activity against other tyrosine kinases, they have potent inhibitory activity against the erbB receptor tyrosine kinase family, for example by inhibiting EGFR and/or erbB2 and/or erbB4 receptor tyrosine kinases. In addition, certain compounds of the invention show significantly better inhibitory potency against EGFR relative to the inhibitory potency against erbB2 tyrosine kinase. The invention also includes compounds which are active against all EGFR, erbB2 and erbB4 receptor tyrosine kinases, or combinations thereof, and which therefore provide effective treatment of diseases mediated by one or more of these receptor tyrosine kinases.

In general, the compounds of the present invention exhibit advantageous physical properties (e.g., high solubility) while retaining high antiproliferative activity. In addition, many compounds of the invention exhibit no or only weak activity in hERG assays.

A first aspect of the invention provides a quinazoline derivative of the formula I:

wherein:

G¹and G²Each independently is halo;

X¹is a direct bond or O;

R¹selected from hydrogen and (1-6C) alkyl, wherein said (1-6C) alkyl is optionally substitutedOne or more substituents which may be the same or different selected from: hydroxy and halo and/or a substituent selected from: amino, nitro, carboxyl, cyano, halo, (1-6C) alkoxy, hydroxy (1-6C) alkoxy, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, carbamoyl, amino-and amino-substituted amino acids,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino, (1-6C) alkoxycarbonyl, sulfamoyl, N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino andN- (1-6C) alkyl- (1-6C) alkylsulfonylamino;

X²is a direct bond or [ CR²R³]_mWherein m is an integer of 1 to 6,

and R is²And R³Each independently selected from hydrogen, hydroxy, (1-4C) alkyl and hydroxy (1-4C) alkyl;

Q¹is (3-7C) cycloalkyl or heterocyclyl, wherein Q¹Optionally carrying 1, 2 or 3 substituents which may be the same or different selected from: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, acryloyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (2-6C) alkenyloxy, (2-6C) alkynyloxy, (1-6C) alkylthio, (2-6C) alkenylthio, (2-6C) alkynylthio, (1-6C) alkylsulfinyl, (2-6C) alkenylsulfinyl, (2-6C) alkynylsulfinyl, (1-6C) alkylsulfonyl, (2-6C) alkenylsulfonyl, (2-6C) alkynylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl.]Amino, (1-6C) alkoxycarbonyl,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino, N- (1-6C) alkyl- (2-6C) alkanoylamino, sulfamoyl,N-(1-6C)An alkylsulfamoyl group,N，NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino, carbamoyl (1-6C) alkyl,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, sulfamoyl (1-6C) alkyl,N- (1-6C) alkylsulfamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl (1-6C) alkyl, (2-6C) alkanoyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl,N- (1-6C) alkyl- (2-6C) alkanoylamino (1-6C) alkyl and (1-6C) alkoxycarbonyl (1-6C) alkyl or a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Is a heterocyclic group, and is a heterocyclic group,

wherein Q²Optionally bearing 1 or 2 substituents which may be the same or different selected from: halo, hydroxy, (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl,

wherein Q¹Any of (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkanoyl groups in (a) optionally bears one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from: halo, hydroxy and (1-6C) alkyl and/or optionally bearing substituents selected from: cyano, nitro, carboxyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, hydroxy (1-6C) alkoxy, (1-4C) alkoxy (1-6C) alkoxy, (2-6C) alkanoyl, (2-6C) alkanoyloxy and NR ^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl, and wherein R^aOr R^bAny (1-4C) alkyl group in (a) optionally bears one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo and hydroxy and/or optionally bears a substituent selected from: cyano, nitro, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy, hydroxy (1-4C) alkoxy and (1-2C) alkoxy (1-4C) alkoxy,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached, form a 4-, 5-or 6-membered ring which optionally bears on available ring carbon atoms 1 or 2 substituents which may be the same or different selected from halo, hydroxy, (1-4C) alkyl and (1-3C) alkylenedioxy, and which optionally bears on any available ring nitrogen atom a substituent selected from (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl (provided that the ring is not therefore quaternized),

wherein as a substituent is present in^aAnd R^bAny (1-4C) alkyl or (2-4C) alkanoyl group on the ring formed together with the nitrogen atom to which they are attached optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo and hydroxy and/or optionally bearing substituents selected from (1-4C) alkyl and (1-4C) alkoxy,

Wherein Q¹-X²Any heterocyclic group in the-group optionally bears 1 or 2 oxo (═ O) or thioxo (═ S) substituents.

In another aspect of the invention there is provided a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein each R¹、G¹、G²、X¹And X²Having any of the meanings defined above; and Q¹Is (3-7C) cycloalkyl or heterocyclyl, wherein Q¹Optionally carrying 1, 2 or 3 substituents which may be the same or different selected from: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (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, (2-6C) alkenylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl sulfonyl]Amino, (1-6C) alkoxycarbonyl,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino, sulfamoyl,N-(1-6C) An alkylsulfamoyl group,N，NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino, carbamoyl (1-6C) alkyl, N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, (2-6C) alkanoyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl,N- (1-6C) alkyl- (2-6C) alkanoylamino (1-6C) alkyl and (1-6C) alkoxycarbonyl (1-6C) alkyl or a group of the formula:

Q²X³-

wherein X³Is CO, Q²Is a heterocyclic group, and is a heterocyclic group,

wherein Q²Optionally bearing 1 or 2 substituents which may be the same or different selected from: (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl,

wherein Q¹Any of (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkanoyl groups in (a) optionally bears one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from: halo, hydroxy and (1-6C) alkyl and/or optionally bearing substituents selected from: cyano, nitro, carboxyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, hydroxy (1-6C) alkoxy, (2-6C) alkanoyl, (2-6C) alkanoyloxy and NR^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached, form a 4, 5 or 6 membered ring optionally bearing on available ring carbon atoms 1 or 2 substituents which may be the same or different selected from (1-4C) alkyl, and optionally bearing on any available ring nitrogen atom a substituent selected from (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl (provided that the ring is not therefore quaternized);

Wherein Q¹-X²Any heterocyclic radical of the groupThe group optionally bears 1 or 2 oxo (═ O) or thio (═ S) substituents.

In another aspect of the invention there is provided a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein each R¹、G¹、G²、X¹And X²Having any of the meanings defined above; and

Q¹is (3-7C) cycloalkyl or heterocyclyl, wherein Q¹Optionally carrying 1, 2 or 3 substituents which may be the same or different selected from: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (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，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino, sulfamoyl,N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino, carbamoyl (1-6C) alkyl, N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, (2-6C) alkanoyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl,N- (1-6C) alkyl- (2-6C) alkanoylamino (1-6C) alkyl and (1-6C) alkoxycarbonyl (1-6C) alkyl,

wherein Q¹Any of (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkanoyl groups in (a) optionally bears one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from: halo, hydroxy and (1-6C) alkyl and/or optionally bearing substituents selected from: cyano, nitro, carboxyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, hydroxy (1-6C) alkoxy and NR^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached form a 4, 5 or 6 membered ring;

wherein Q¹-X²Any heterocyclic group in the-group optionally bears 1 or 2 oxo (═ O) or thioxo (═ S) substituents.

In another aspect of the invention there is provided a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein each R¹、G¹、G²、X¹And X²Having any of the meanings defined above; and Q ¹Is a non-aromatic, saturated or partially saturated 3-to 7-membered, e.g. 4-, 5-or 6-membered, monocyclic heterocyclic ring which carries one ring nitrogen heteroatom and optionally 1 or 2 heteroatoms selected from nitrogen and sulphur, the ring being linked to the group X via a ring carbon atom²-O-is linked, and wherein Q¹Optionally carrying 1, 2 or 3 substituents which may be the same or different selected from: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carbamoyl, acryloyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (2-6C) alkenyloxy, (2-6C) alkynyloxy, (1-6C) alkylthio, (2-6C) alkenylthio, (2-6C) alkynylthio, (1-6C) alkylsulfinyl, (2-6C) alkenylsulfinyl, (2-6C) alkynylsulfinyl, (1-6C) alkylsulfonyl, (2-6C) alkenylsulfonyl, (2-6C) alkynylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl.]Amino group,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino, sulfamoyl,N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino, N- (1-6C) alkyl- (1-6C) alkylsulfonylamino, carbamoyl (1-6C) alkyl,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, sulfamoyl (C1-6C)1-6C) alkyl,N- (1-6C) alkylsulfamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl (1-6C) alkyl, (2-6C) alkanoyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl and N- (1-6C) alkyl- (2-6C) alkanoylamino (1-6C) alkyl or a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Is a heterocyclic radical selected from morpholino (morpholino) and 4, 5 or 6 membered monocyclic heterocyclic radicals containing one nitrogen heteroatom and optionally 1 or 2 heteroatoms selected from sulphur and nitrogen,

wherein Q²Optionally bearing 1 or 2 substituents which may be the same or different selected from: halo, hydroxy, (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl,

wherein Q¹Any of (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkanoyl groups of (a) optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo, hydroxy and (1-6C) alkyl and/or optionally bearing a substituent selected from: cyano, nitro, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, hydroxy (1-6C) alkoxy, (1-4C) alkoxy (1-6C) alkoxy, (2-6C) alkanoyl, (2-6C) alkanoyloxy and NR ^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl, and wherein R^aOr R^bAny (1-4C) alkyl group in (a) optionally bears one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo and hydroxy and/or optionally bears a substituent selected from: cyano, nitro, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy, hydroxy (1-4C) alkoxy and (1-2C) alkoxy (1-4C) alkoxy,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached form a 4-, 5-or 6-membered ring optionally bearing 1 or 2 substituents which may be the same or different selected from halo, hydroxy, (1-4C) Alkyl and (1-3C) alkylenedioxy, and may optionally bear substituents selected from (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl on any available ring nitrogen atom (provided that the ring is not thereby quaternized),

wherein as a substituent is present in^aAnd R^bAny (1-4C) alkyl or (2-4C) alkanoyl group on the ring formed together with the nitrogen atom to which they are attached optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo and hydroxy and/or optionally bearing substituents selected from (1-4C) alkyl and (1-4C) alkoxy,

Wherein Q¹-X²Any heterocyclic group in the group optionally bears 1 or 2 oxo (═ O) or thioxo (═ S) substituents;

provided that when X is²Is [ CH ]₂]_mM is an integer of 1 to 6, Q¹In the case of pyrrolidinyl or piperidinyl substituted in the 1-position by (2-4C) alkyl or (2-5C) alkanoyl, then Q¹The (2-4C) alkyl or (2-5C) alkanoyl group at the 1-position of (a) is not substituted with 2-oxomorpholino.

In this specification, the generic term "alkyl" includes both straight-chain and branched alkyl groups, such as propyl, isopropyl and tert-butyl, and (3-7C) cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. However, reference to an individual alkyl group such as "propyl" is intended to refer only to the straight chain variant, reference to an individual branched alkyl group such as "isopropyl" is intended to refer only to the branched chain variant, and reference to an individual cycloalkyl group such as "cyclopentyl" is intended to refer only to the 5-membered ring. Similar conventions apply to other general terms, such as (1-6C) alkoxy including methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy, (1-6C) alkylamino including methylamino, ethylamino, cyclobutylamino and cyclohexylamino, and di- [ (1-6C alkyl) ] amino including dimethylamino, diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl-N-ethylamino.

It will be appreciated that certain compounds of formula I as defined above may exist in optically active or racemic forms due to the presence of one or more asymmetrically substituted carbon and/or sulfur atoms, and may therefore exist or be isolated as pure enantiomers, diastereomeric mixtures or racemates. The present invention includes within its definition any racemic, optically active, pure enantiomeric, diastereomeric mixture, stereoisomeric form, or mixture thereof, of a compound of formula I, which possesses the above-mentioned activity. The synthesis of the optically active form can be carried out by standard organic chemical techniques well known in the art, for example by spinning photoactive starting material synthesis or by resolution of the racemic form. Similarly, the above-mentioned activities can be evaluated using standard laboratory techniques referred to below.

The present invention relates to all tautomeric forms of the compounds of formula I having antiproliferative activity.

It will also be appreciated that certain compounds of formula I may exist in solvated as well as unsolvated forms such as hydrated forms. It is to be understood that the invention encompasses all such solvate forms having antiproliferative activity.

It will also be appreciated that certain compounds of formula I may exist in polymorphic forms, the polymorphic forms of the present invention including all such forms having antiproliferative activity.

Suitable values for the above mentioned general groups include those listed below.

When Q is¹When it is (3-7C) cycloalkyl, suitable values are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo [2.2.1 ]]A heptyl group.

When Q is¹Or Q²In the case of a heterocyclyl group, it is a 3-to 10-membered monocyclic ring which is non-aromatic saturated (i.e. has maximum saturation) or partially saturated (i.e. the ring system retains some but not all of the unsaturation), which ring has up to 5 heteroatoms selected from oxygen, sulphur and nitrogen (but does not contain any O-O, O-S or S-S bonds), and which is attached via a ring carbon atom or a ring nitrogen atom (provided that the ring is not therefore quaternised). Q¹Or Q²Suitable values include, for example, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydropyranyl, oxepanyl (oxapanyl), oxazepanyl (oxazepanyl), pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-1, 4-thiazinyl, 1-dioxotetrahydro-1, 4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidyl, tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, thiomorpholinyl, and more particularly, for example, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl, tetrahydropyran-4-yl, tetrahydrothiophen-3-yl, tetrahydrothiopyran-4-yl, pyrrolin-3-yl, tetrahydrothiopyranyl-4-yl, Pyrrolin-2-yl, 3-pyrrolin-3-yl, morpholino, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl, piperidino, piperidin-4-yl, piperidin-3-yl, piperidin-2-yl, homopiperidin-3-yl, homopiperidin-4-yl, piperazin-1-yl, 1, 4-oxazepanyl, or 1, 2, 3, 6-tetrahydropyridin-4-yl.

The nitrogen or sulfur atom within the heterocyclic group may be oxidized to give the corresponding N or S oxide, for example, 1-dioxotetrahydrothienyl, 1-oxotetrahydrothienyl, 1-dioxotetrahydrothiopyranyl or 1-oxotetrahydrothiopyranyl. Suitable meanings of such radicals having 1 or 2 oxo-or thio-substituents are, for example, 2-oxopyrrolidinyl, 2-oxopiperazinyl, 2-thiopyrrolidinyl, 2-oxopiperidinyl, 2, 5-dioxopyrrolidinyl or 2, 6-dioxopiperidinyl.

Q¹And Q²Preferred meanings include, for example, non-aromatic saturated or partially saturated 3-7 membered monocyclic heterocyclyl groups bearing one ring nitrogen or sulfur heteroatom and optionally 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of such rings include azetidinyl, oxazepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-1, 4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, or thiomorpholinyl.

Q¹More preferred letterMeans include, for example, a non-aromatic saturated or partially saturated 3-7 membered monocyclic heterocyclic group which carries one ring nitrogen heteroatom and optionally 1 or 2 heteroatoms selected from nitrogen and sulfur, which ring is linked to the group X via a ring carbon atom ²-an O-linkage, such as azetidinyl, pyrrolinyl, pyrrolidinyl, tetrahydro-1, 4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, tetrahydrothiopyranyl or thiomorpholinyl. Q¹More preferably a non-aromatic saturated or partially saturated 4-, 5-or 6-membered monocyclic heterocycle having 1 or 2 nitrogen heteroatoms, which ring is linked via a carbon atom to the radical X²-an O-linkage, more particularly pyrrolidin-3-yl, pyrrolidin-2-yl, 3-pyrrolin-3-yl, piperidin-4-yl, piperidin-3-yl, piperidin-2-yl, homopiperidin-3-yl, homopiperidin-4-yl, piperazin-2-yl, piperazin-3-yl or 1, 2, 3, 6-tetrahydropyridin-4-yl. The nitrogen atom within the heterocyclic group may be oxidized to give the corresponding N-oxide.

Q²Specific meanings of (a) include, for example, morpholino or a 4, 5 or 6 membered monocyclic heterocyclyl group containing 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from nitrogen and sulphur, such as piperazinyl, pyrrolidinyl, piperidinyl, especially pyrrolidin-1-yl, pyrrolidin-2-yl, piperazin-1-yl or piperidino.

When R is^aOr R^bWhen taken together with the nitrogen atom to which they are attached to form a 4-, 5-or 6-membered ring, the ring is a saturated or partially saturated non-aromatic heterocyclic group, the ring containing 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen (but not containing any O-O, O-S or S-S bonds), and wherein the ring so formed is attached via the ring nitrogen atom to the group to which the ring is attached. The ring optionally bears 1 or 2 substituents as hereinbefore defined on available ring carbon atoms (e.g. selected from (1-4C) alkyl groups) and may optionally bear substituents as hereinbefore defined on any available ring nitrogen atom (provided that the ring is not so quaternised) (e.g. selected from (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl). R ^aOr R^bSuitable values for the 4, 5 or 6 membered ring formed together with the nitrogen atom to which they are attached include, for example2-pyrrolin-1-yl, 3-pyrrolin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, and morpholino.

Any R defined as above or below in the specification¹、R²、R³、R⁴、R⁴、R^a、R^b、G¹、G²Or Q¹Suitable values for each group within include:

for halogenation: fluorine, chlorine, bromine and iodine;

for a (1-6C) alkyl group: is methyl, ethyl, propyl, isopropyl, tert-butyl

Butyl, pentyl and hexyl;

for a (1-4C) alkyl group: is methyl, ethyl, propyl, isopropyl and tert

A butyl group;

for (1-6C) alkoxy: is methoxy, ethoxy, propoxy or isopropyl

Oxy and butoxy groups;

for (2-8C) alkenyl: are vinyl, isopropenyl, allyl and butyl

-2-alkenyl;

for (2-8C) alkynyl: is ethynyl, 2-propynyl or but-2-ynyl;

For (2-6C) alkenyloxy: are vinyloxy and allyloxy;

for (2-6C) alkynyloxy: is ethynyloxy and 2-propynyloxy;

for (1-6C) alkylthio: methylthio, ethylthio and propylthio;

for (2-6C) alkenylthio: are vinylthio and allylthio;

for (2-6C) alkynylthio: is ethynylthio and 2-propynylthio;

for (1-6C) alkylsulfinyl: are methylsulfinyl and ethylsulfinyl;

for (2-6C) alkenylsulfinyl: being vinylsulfinyl and allylsulfinyl

A group;

for (2-6C) alkynylsulfinyl: is ethynylsulfinyl and 2-propynylsulfinyl

An acyl group;

for a (1-6C) alkylsulfonyl group: are methanesulfonyl and ethanesulfonyl;

for (2-6C) alkenylsulfonyl: are vinylsulfonyl and allylsulfonyl;

for (2-6C) alkynylsulfonyl: is ethynylsulfonyl and 2-propynylsulfonyl

A group;

for a (1-6C) alkylamino group: is methylamino, ethylamino, propylamino or isopropyl

Amino and butylamino;

for di- [ (1-6C) alkyl]Amino group: is dimethylamino or diethylamino、N-B

Base-N-methylamino and diisopropylamino;

for (1-6C) alkoxycarbonyl: is methoxycarbonyl, ethoxycarbonyl or propoxy

Alkylcarbonyl and tert-butoxycarbonyl;

for N- (1-6C) alkylcarbamoyl: is composed ofN-methylcarbamoyl group,N-ethylamino group

Formyl, methyl,N-propylcarbamoyl andN-

an isopropyl carbamoyl group;

for N, N-di- [ (1-6C) alkyl]The amino methyl isN，N-dimethylcarbamoyl radical,N-ethyl radical

Acyl group: - N-methylcarbamoyl andN，N-diethyl radical

A carbamoyl group;

for (2-6C) alkanoyl: acetyl, propionyl and isobutyryl;

for (2-6C) alkanoyloxy: is acetoxy and propionyloxy;

for (2-6C) alkanoylamino: is acetylamino and propionylamino;

for N- (1-6C) alkyl- (2-6C) alkanoyl are N-methylacetamido and N-methylpropanoyl

Amino group: an amino group;

for N- (1-6C) alkylsulfamoyl: is composed ofN-methylsulfamoyl,N-Ethylsulfamoyl

A base andN-an isopropyl sulfamoyl group;

for N, N-di- [ (1-6C) alkyl]Sulfonamide isN，N-dimethylsulfamoyl andN-methyl-

Base:N-ethylsulfamoyl

For (1-6C) alkylsulfonylamino: are methylsulfonylamino and ethylsulfonylamino;

For N- (1-6C) alkyl- (1-6C) alkylsulfonyl isN-methylmethanesulfonylamino andN-methyl radical

Amino group: an ethanesulfonylamino group;

for amino- (1-6C) alkyl: is aminomethyl, 2-aminoethyl, 1-aminoethyl

And 3-aminopropyl;

as (1-6C) alkylamino- (1-6C) alkanes there may be mentioned methylaminomethyl, ethylaminomethyl, 1-

Base: methylaminoethyl, 2-ethyl

Aminoethyl and 3-methylaminopropyl;

for di- [ (1-6C) alkyl ] amino- (1-6C) is dimethylaminomethyl, diethylaminomethyl

Alkyl groups: 1-dimethylaminoethyl, 2-dimethylaminoethyl

And 3-dimethylaminopropyl;

for halo- (1-6C) alkyl: is chloromethyl, 2-chloroethyl, 1-chloroethyl and 3-

A chloropropyl group;

for hydroxy- (1-6C) alkyl: is hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and

3-hydroxypropyl group;

for hydroxy- (1-6C) alkoxy: is hydroxy methoxy, 2-hydroxy ethoxy, 1-

Hydroxyethoxy and 3-hydroxypropoxy;

for (1-6C) alkoxy- (1-6C) alkyl: is methoxymethyl, ethoxymethyl, 1-methyl

Oxyethyl, 2-methoxyethyl, 2-ethoxy

Ethyl and 3-methoxypropyl;

for cyano- (1-6C) alkyl: is cyanomethyl, 2-cyanoethyl, 1-cyanoethyl

And 3-cyanopropyl;

for amino (2-6C) alkanoyl: is aminoacetyl and 2-aminopropionyl;

for (1-6C) alkylamino- (2-6C) alkanoyl are methylaminoacetyl and 3- (methylamino) propionyl

Base: a group;

for N, N-di- [ (1-6C) alkyl ] amino-is dimethylaminoacetyl and 3- (dimethylamino)

(2-6C) alkanoyl: propionyl group;

for (2-6C) alkanoylamino- (1-6C) alkane are acetylaminomethyl, propionylaminomethyl and

base: 2-Acetaminoethyl

For N- (1-6C) alkyl- (2-6C) alkanoyl isN-methylacetamidomethyl group,N-methyl propane

Amino- (1-6C) alkyl: acylaminomethyl group, 2-, (N-methylacetamido group)

Ethyl and 2-, (N-methylpropionylamino) ethyl;

for (1-6C) alkoxycarbonylamino- (1-is methoxycarbonylaminomethyl, ethoxycarbonyl)

6C) Alkyl groups: aminomethyl, tert-butoxycarbonylaminomethyl

And 2-methoxycarbonylaminoethyl;

for carbamoyl (1-6C) alkyl: is carbamoylmethyl, 1-carbamoyl

Ethyl, 2-carbamoylethyl and 3-amino

Formylpropyl;

for N- (1-6C) alkylcarbamoyl (1-isN-methylcarbamoylmethyl,N-ethyl radical

6C) Alkyl groups: a carbamoylmethyl group,N-propylcarbamoyl

Ylmethyl, 1-, (N-methylcarbamoyl) ethyl

Base, 2-, (N-methylcarbamoyl) ethyl and

3-(N-methylcarbamoyl) propyl;

for the N, N-di (1-6C) alkylcarbamoyl groupN，N-dimethylcarbamoylmethyl,

Alkyl (1-6C):N，N-diethylcarbamoylmethyl,N-first of all

Base-N-ethylcarbamoylmethyl, 1-, (N，N-

Dimethylcarbamoyl) ethyl, 1-, ( N，N-

Diethylcarbamoyl radical) Ethyl group, 2-, (N，N-

Dimethylcarbamoyl) ethyl group,

2-(N，N-diethylcarbamoyl) ethyl and

3- (N, N-dimethylcarbamoyl) propyl;

for sulfamoyl (1-6C) alkyl: is sulfamoylmethyl, 1-sulfamoylethyl

2-sulfamoylethyl and 3-sulfamoyl

Propyl;

for N- (1-6C) alkylsulfamoyl (1-isN-methylsulfamoylmethyl,N-ethylammonia

6C) Alkyl groups: a sulfonyl methyl group,N-propylsulfamoylmethyl

Base, 1-, (N-methylsulfamoyl) ethyl, 2-, (N-

Methylsulfamoyl) ethyl and 3-, (N-methylammonium

Sulfonyl) propyl;

For the N, N-di (1-6C) alkylsulfamoyl group isN，N-dimethylsulfamoylmethyl,N，N-

(1-6C) alkyl group: diethyl (diethylene)Sulfamoylmethyl group, a salt thereof, and a salt thereof,N-methyl-N-

Ethylsulfamoylmethyl, 1-, (N，N-dimethyl

Sulfamoyl) ethyl, 1-, (N，N-Diethylaminosulfonic acid

Acyl) ethyl, 2-, (N，N-dimethylsulfamoyl

Alkyl) ethyl,

2-(N，N-diethylsulfamoyl) ethyl and 3-

(N，N-dimethylsulfamoyl) propyl;

for (2-6C) alkanoyl (1-6C) alkyl: is acetylmethyl, propionylmethyl, 2-ethyl

Acylethyl and 2-propionylethyl;

for the (2-6C) alkanoyloxy (1-6C) alkyl are acetoxymethyl, propionyloxymethyl,

Base: 2-acetoxyethyl and 3-acetoxypropyl

A group;

For (1-6C) alkoxy (1-6C) alkyl are 2-methoxyethylsulfonyl, 2-methoxyethylethyl

S(O)_q： Sulfinyl and 2-methoxyethylthio;

for amino (1-6C) alkyl S (O)_q: is 2-aminoethanesulfonyl, 2-aminoethanesulfinyl

Acyl and 2-aminoethylthio;

for N- (1-6C) alkylamino (1-6C) alkanes are 2- (methylamino) ethanesulfonyl, 2- (ethylamino)

Radical S (O)_q: ethanesulfinyl and 2- (methylamino) ethanethio;

and

for N, N-di [ (1-6C) alkyl ] amino (1-is 2- (dimethylamino) ethanesulfonyl, 3- (dimethylamino) ethanesulfonyl

6C) Alkyl S (O)_q: amino) propanesulfonyl, 2- (diethylamino) ethane

Sulfinyl and 2- (N-methyl-N-ethylamino) ethyl

A thio group.

(1-3C) alkylenedioxy can be represented by R^aAnd R^bWhen present, the substituents on the ring which are formed together with the nitrogen atom to which they are attached are suitably, for example, methylenedioxy, ethylmethylenedioxy, isopropylidenedioxy or ethylenedioxy, with the oxygen atom occupying the ortho position of the ring. For example, when R is ^aAnd R^bWhen taken together with the nitrogen atom to which they are attached to form a pyrrolidin-1-yl ring, the ring may be substituted with methylenedioxy to provide a 3, 4-methylenedioxypyrrolidin-1-yl group.

As previously described, Q¹(1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl or (2-6C) alkanoyl in (1-6C)The radicals may be substituted, for example, by hydroxy, (2-8C) alkenyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy or NR^aR^bIs substituted in which R^aAnd R^bAs previously defined. For example, when Q¹When substituted by acetyl, the acetyl group itself may be substituted by di [ (1-6C) alkyl]Amino substitution at Q¹For example, dimethylaminoacetyl or N-methyl-N-ethylamino-acetyl, or acetyl can be substituted with (2-8C) alkenyl to give alkenoyl, for example, acetyl is substituted with allyl to give but-3-enoyl. Similarly, when for example Q¹When substituted with a (1-6C) alkylsulfonyl group (e.g., propylsulfonyl), the (1-6C) alkyl group may be substituted with, for example, dimethylamino to provide a dimethylamino- (1-6C) alkylsulfonyl group (e.g., 3- (dimethylamino) propylsulfonyl). For another example, when Q¹When substituted by N-methylcarbamoyl, the methyl group may be substituted by, for example, (2-6C) alkenyl or (2-6C) alkynyl to give, for example, N-allylcarbamoyl or N- (2-propynyl) carbamoyl.

It should be clear that when R is¹When it is (1-6C) alkyl substituted by, for example, amino to give, for example, 2-aminoethyl, then the (1-6C) alkyl is reacted with X¹Is linked (or when X¹A quinazoline ring when the bond is direct). Similar transformations apply to the other groups defined herein. For example, when Q¹With (1-6C) alkyl substituted by (1-6C) alkoxy to give (1-6C) alkoxy (1-6C) alkyl substituent, the (1-6C) alkyl group and Q¹And (4) connecting.

It should be clear that when X is³When it is CO, it is a carbonyl group.

When the term "Q" is used herein¹-X²-when any heterocyclyl group in a group optionally bears 1 or 2 oxo (═ O) or thio (═ S) substituents ", said oxo and/or thio groups may be present including Q¹On any heterocyclic radical of (1), including by Q¹Itself, Q²A heterocyclic group represented by^aAnd R^bTogether with the nitrogen atom to which they are attached form a 4-, 5-or 6-membered heterocyclic group.

When reference is made in this specification to a (1-4C) alkyl group, it will be understood that such group refers to alkyl groups containing up to 4 carbon atoms. The skilled person will appreciate that representative examples of such groups are those listed under (1-6C) alkyl above which contain up to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl. Similarly, (1-3C) alkyl refers to alkyl groups containing up to 3 carbon atoms, such as methyl, ethyl, propyl, and isopropyl. Similar definitions apply to the other groups listed above, such as (1-4C) alkoxy, (2-4C) alkenyl, (2-4C) alkynyl and (2-4C) alkanoyl.

In the compounds of formula I, hydrogen atoms are present at the 2, 5 and 8 positions of the quinazoline ring.

Suitable pharmaceutically acceptable salts of the compounds of formula I are, for example, acid addition salts of the compounds of formula I, for example with inorganic or organic acids, such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric or maleic acid; or, for example, a sufficiently acidic salt of a compound of formula I, such as an alkali or alkaline earth metal salt (e.g. 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.

Specific novel compounds of the invention include, for example, quinazoline derivatives of formula I, or pharmaceutically acceptable salts thereof, wherein m, R, unless otherwise specified¹、R²、R³、Q¹、Q²、X¹、X²、m、G¹And G²Having any of the meanings defined in preceding or following paragraphs (a) to (qqq):

(a)Q¹a 3-7 membered monocyclic non-aromatic saturated or partially saturated heterocycle which carries 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur, which ring is interrupted by a ring carbon atom or a ring nitrogen atom with a group X²-O-linkage (provided that the ring is not quaternized thereby), and wherein Q¹Optionally bearing a substituent selected from (wherein the substitution does not result in quaternization) the group consisting of: trifluoromethyl, cyano, carbamoyl, trifluoromethoxy, (1-6C) alkyl, (2- 8C) Alkenyl, (2-8C) alkynyl, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkoxycarbonyl,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, sulfamoyl,N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl, carbamoyl (1-6C) alkyl, carbamoyl (2-C) alkyl, carbamoyl (6C) alkyl, carbamoyl (meth) aryl, or carbamoyl (meth,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, (2-6C) alkanoyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl,N- (1-6C) alkyl- (2-6C) alkanoylamino (1-6C) alkyl and (1-6C) alkoxycarbonyl (1-6C) alkyl,

wherein any of (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkanoyl optionally substituted on an available nitrogen atom with one or more substituents which may be the same or different selected from: fluoro, chloro, hydroxy and (1-4C) alkyl and/or optionally bearing substituents selected from: cyano, nitro, carboxyl, (1-4C) alkoxy, hydroxy (1-4C) alkoxy and NR^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl,

And Q¹Optionally bearing 1 or 2 (suitably 1) substituents selected from: halo, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (1-4C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-4C) alkoxy, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino, hydroxy (1-6C) alkyl, cyano (1-6C) alkyl, amino (1-6C) alkyl, (1-6C) alkylamino (1-6C) alkyl, di- [ (1-6C) alkyl]Amino (1-6C) alkyl and (1-6C) alkoxy (1-6C) alkyl,

wherein Q¹Optionally bearing 1 or 2 oxo or thioxo substituents;

(b)Q¹is not aromatic and is saturatedOr a partially saturated 3-7 membered monocyclic heterocycle having 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur, which ring is linked to the group X via a carbon atom of the ring²-O-is linked, and wherein Q¹Optionally bearing a substituent selected from (wherein the substitution does not result in quaternization) the group consisting of: trifluoromethyl, cyano, carbamoyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkoxycarbonyl, N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, sulfamoyl,N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl, carbamoyl (1-6C) alkyl, carbamoyl (2-C) alkyl, carbamoyl (6C) alkyl, carbamoyl (meth) aryl, or carbamoyl (meth,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, (2-6C) alkanoyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl,N- (1-6C) alkyl- (2-6C) alkanoylamino (1-6C) alkyl and (1-6C) alkoxycarbonyl (1-6C) alkyl,

wherein any of (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkanoyl optionally substituted on an available nitrogen atom with one or more substituents which may be the same or different selected from: fluoro, chloro, hydroxy and (1-4C) alkyl and/or optionally bearing substituents selected from: cyano, nitro, carboxyl, (1-4C) alkoxy, hydroxy (1-4C) alkoxy and NR^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl,

and Q¹Optionally bearing 1 or 2 (suitably 1) substituents selected from: halo, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (1-4C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-4C) alkoxy, (1-6C) alkylamino, di- [ (1-6C) alkyl ]Amino, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino, hydroxy (1-6C) alkyl, cyano (1-6C)-6C) alkyl, amino (1-6C) alkyl, (1-6C) alkylamino (1-6C) alkyl, di- [ (1-6C) alkyl]Amino (1-6C) alkyl and (1-6C) alkoxy (1-6C) alkyl,

wherein Q¹Optionally bearing 1 or 2 oxo or thioxo substituents;

(c)Q¹a 3-7 membered monocyclic non-aromatic saturated or partially saturated heterocycle having 1 nitrogen heteroatom and optionally 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, which ring is linked to the group X via a carbon atom of the ring²-an O-linkage to the substrate,

and wherein Q¹The nitrogen atom of any NH group in (a) optionally bears a substituent selected from: cyano, carbamoyl, trifluoromethyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkoxycarbonyl,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, sulfamoyl,N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl, hydroxy (1-6C) alkyl, cyano (1-6C) alkyl, amino (1-6C) alkyl, (1-6C) alkylamino (1-6C) alkyl, di- [ (1-6C) alkyl ]Amino (1-6C) alkyl, amino (2-6C) alkanoyl, (1-6C) alkylamino- (2-6C) alkanoyl,N，NDi- [ (1-6C) alkyl]Amino- (2-6C) alkanoyl, (1-6C) alkoxy (1-6C) alkyl, hydroxy (1-6C) alkoxy (1-6C) alkyl, carbamoyl (1-6C) alkyl,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, (2-6C) alkanoyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl,N- (1-6C) alkyl- (2-6C) alkanoylamino (1-6C) alkyl, (1-6C) alkoxycarbonyl (1-6C) alkyl, (1-6C) alkoxy (1-6C) alkyl S (O)_q(wherein q is 0, 1 or 2), amino (1-6C) alkyl S (O)_q(wherein q is 0, 1 or 2),N- (1-6C) alkylamino (1-6C) alkyls (O)_q(wherein q is 0, 1 or 2) andN，Ndi- [ (1-6C) alkyl]Amino (1-6C) alkyl S (O)_q(wherein q is 0, 1 or 2)，

And Q¹Optionally bearing 1 or 2 substituents on any available carbon atom in the ring selected from: cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (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, hydroxy (1-6C) alkyl, cyano (1-6C) alkyl, amino (1-6C) alkyl, (1-6C) alkylamino (1-6C) alkyl, di- [ (1-6C) alkyl]Amino (1-6C) alkyl and (1-6C) alkoxy (1-6C) alkyl, wherein Q¹Any of (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkanoyl optionally bearing 1 or 2 substituents which may be the same or different selected from fluoro and chloro,

wherein Q¹Optionally bearing 1 or 2 oxo substituents;

(d)Q¹a 3-7 membered non-aromatic saturated monocyclic heterocycle having 1 nitrogen heteroatom and optionally 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, which ring is linked to the group X via a carbon atom of the ring²-an O-linkage to the substrate,

and wherein Q¹Optionally carrying a substituent as defined in (c) above on the nitrogen atom of any NH group in (a), and Q¹Any of the ring carbon atoms in (a) is optionally substituted as defined in (c) above,

wherein Q¹Optionally bearing 1 or 2 oxo substituents;

(e)Q¹is a 3-7 membered monocyclic heterocyclic ring saturated with non-aromatic moieties and having 1 single carbon-carbon double bond, 1 nitrogen heteroatom and optionally 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, which ring is linked to the group X via one of the ring carbon atoms bearing said carbon-carbon double bond²-an O-linkage (e.g. 3-pyrrolin-3-yl or 1, 2, 3, 6-tetrahydropyridin-4-yl), and wherein Q ¹Optionally carrying a substituent as defined in (c) above on the nitrogen atom of any NH group in (a), and Q¹Any of the ring carbon atoms in (a) is optionally substituted as defined in (c) above,

wherein Q¹Optionally bearing 1 or 2 oxo substituents;

(f)Q¹selected from cyclobutyl, cyclopentyl and cyclohexyl optionally substituted by 1 or 2 substituents selected from (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (1-6C) alkoxy;

(g)Q¹a non-aromatic saturated 5-or 6-membered monocyclic heterocycle having 1 nitrogen heteroatom and optionally 1 or 2 (suitably 1) heteroatoms selected from oxygen and nitrogen, which ring is linked to the group X via a ring-bound carbon atom²-an O-linkage to the substrate,

and wherein Q¹The nitrogen atom of any NH group in (a) optionally bears a substituent selected from: cyano, carbamoyl, (1-4C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-4C) alkylsulfonyl,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl, (2-4C) alkanoyl, sulfamoyl,N- (1-4C) alkylsulfamoyl,N，NDi- [ (1-4C) alkyl]Sulfamoyl, cyano (1-4C) alkyl, (1-4C) alkoxy (1-4C) alkyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl, sulfamoyl, cyano (1-4C) alkyl, sulfamoyl, amino (1-4C) alkanoyl, sulfamoyl, amino (1-4C) alkyl, amino (1,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, carbamoyl- (1-3C) alkyl, N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, (1-4C) alkoxy (1-3C) alkyl S (O)_q(wherein q is 0, 1 or especially 2), amino (1-3C) alkyl S (O)_q(wherein q is 0, 1 or especially 2),N- (1-4C) alkylamino (1-3C) alkyls (O)_q(wherein q is 0, 1 or especially 2) andN，Ndi- [ (1-4C) alkyl]Amino (1-3C) alkyl S (O)_q(wherein q is 0, 1 or especially 2),

and Q¹Optionally bearing 1 or 2 substituents on any available carbon atom in the ring selected from: cyano, oxo, amino, carboxy, carbamoyl, (1-4C) alkyl, (2-6C) alkenyl and(2-6C) an alkynyl group,

wherein Q¹Any of (1-4C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl or (2-4C) alkanoyl in (a) optionally bears 1 or 2 substituents which may be the same or different selected from fluoro and chloro;

(h)Q¹selected from cyclopropyl, cyclopentyl, cyclohexyl, oxetan-3-yl, tetrahydrofuran-2-yl, 1, 3-dioxolan- (2, 4 or 5-yl), 3-or 4-tetrahydropyranyl, 3-or 4-oxepanyl, 1-, 2-or 3-pyrrolidinyl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-3-yl, morpholino, morpholin-2-yl, morpholin-3-yl, thiomorpholino, thiomorpholin-2-yl, thiomorpholin-3-yl, piperidino, piperidin-2-yl, piperidin-3-yl, piperidin-2-yl, and mixtures thereof, Piperidin-4-yl, 1-, 2-, 3-or 4-homopiperidinyl, piperazin-1-yl, piperazin-2-yl, 1, 2, 3, 6-tetrahydropyridin-4-yl, 1, 2, 3, 6-tetrahydropyridin-5-yl, 1, 2, 3, 4-tetrahydropyridin-5-yl, 1, 2, 3, 6-tetrahydropyridin-6-yl, homopiperazinyl, azetidin-3-yl, tetrahydrothiophen-3-yl, 1-dioxotetrahydrothiophen-3-yl, 1-oxotetrahydrothiophen-3-yl, tetrahydrothiopyran-4-yl, 1-oxotetrahydrothiopyran-3-yl, thiopyran-1-oxotetrahydropyran-3-yl, thiopyran-1-yl, and mixtures thereof, 1, 1-dioxotetrahydrothiopyran-3-yl, 1-oxotetrahydrothiopyran-4-yl and 1, 1-dioxotetrahydrothiopyran-4-yl,

Wherein Q¹The nitrogen atom of any NH group in (a) optionally bears a substituent selected from: cyano, (1-4C) alkyl, cyano (1-4C) alkyl, (1-4C) alkoxy (1-4C) alkyl, (1-4C) alkylsulfonyl, trifluoromethyl, carbamoyl,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl, (2-4C) alkanoyl, sulfamoyl,N- (1-4C) alkylsulfamoyl,N，NDi- [ (1-4C) alkyl]Sulfamoyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, carbamoyl (1-3C) alkyl,N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, (1-4C) alkanesOxy (1-3C) alkylsulfonyl, amino (1-3C) alkylsulfonyl,N- (1-4C) alkylamino (1-3C) alkylsulfonyl andN，Ndi- [ (1-4C) alkyl]Amino (1-3C) alkylsulfonyl, and Q¹Optionally bearing 1 or 2 substituents selected from oxo and (1-4C) alkyl on any available carbon atom of the ring,

and wherein Q¹Any (1-4C) alkyl group in (a) optionally bears 1 or 2 fluoro substituents;

(i)Q¹selected from the group consisting of pyrrolidin-2-yl, pyrrolidin-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-3-yl, morpholin-2-yl, morpholin-3-yl, thiomorpholin-2-yl, thiomorpholin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2-, 3-or 4-homopiperidinyl, piperazin-1-yl, 2-oxopiperazin-1-yl, 3-oxopiperazin-1-yl, piperazin-2-yl, 1, 2, 3, 6-tetrahydropyridin-4-yl, 1, 2, 3, 6-tetrahydropyridin-5-yl, 1, 2, 3, 4-tetrahydropyridin-5-yl, 1, 2, 3, 6-tetrahydropyridin-6-yl, 2, 3, 4, 6 or 7-homopiperazinyl, azetidin-3-yl,

Wherein Q¹The nitrogen atom of any NH group in (a) optionally bears a substituent selected from: cyano, (1-4C) alkyl, cyano (1-4C) alkyl, (1-4C) alkoxy (1-4C) alkyl, (1-4C) alkylsulfonyl, trifluoromethyl, carbamoyl,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl, (2-4C) alkanoyl, sulfamoyl,N- (1-4C) alkylsulfamoyl,N，NDi- [ (1-4C) alkyl]Sulfamoyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, carbamoyl (1-3C) alkyl,N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, (1-4C) alkoxy (1-3C) alkylsulfonyl, amino (1-3C) alkylsulfonyl,N- (1-4C) alkylamino (1-3C) alkylsulfonyl andN，Ndi- [ (1-4C) alkyl]Amino (1-3C) alkylsulfonyl, and Q¹Optionally at any point in the ringWith 1 or 2 substituents selected from (1-4C) alkyl and oxo on the carbon atoms,

and wherein Q¹Any (1-4C) alkyl group in (a) optionally bears 1 or 2 fluoro substituents;

(j)Q¹selected from pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl,

Wherein Q¹The nitrogen atom of any NH group in (a) optionally bears a substituent selected from: cyano, cyanomethyl, methyl, ethyl, carbamoyl, carbamoylmethyl, 2-methoxyethyl, methanesulfonyl and ethanesulfonyl (especially methanesulfonyl and carbamoylmethyl),

and Q¹Optionally bearing 1 or 2 substituents selected from methyl, ethyl and oxo on any available carbon atom in the ring;

(k)X²is a direct bond;

(l)X²is [ CR ]²R³]_mWherein m is 1 or 2, R²And R³Is hydrogen;

(m)X²is a direct bond or CH₂；

(n)Q¹-X²Selected from the group consisting of pyrrolidin-2-yl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, pyrrolidin-3-yl, pyrrolidin-3-ylmethyl, 2-pyrrolidin-3-ylethyl, 3-pyrrolidin-3-ylpropyl, 2-pyrrolin-2-yl, 2-pyrrolin-2-ylmethyl, 2-pyrrolin-3-yl, pyrrolin-3-ylmethyl, 3-pyrrolin-3-yl, morpholin-2-ylmethyl, 2-morpholin-2-ylethyl, and mixtures thereof, Morpholin-3-yl, morpholin-3-ylmethyl, 2-morpholin-3-ylethyl, thiomorpholin-methyl, thiomorpholin-2-yl, thiomorpholin-2-ylmethyl, 2-thiomorpholin-2-ylethyl, thiomorpholin-3-yl, thiomorpholin-3-ylmethyl, 2-thiomorpholin-3-ylethyl, piperidinomethyl, 2-piperidinoethyl, piperidin-2-yl, piperidin-2-ylmethylmethylol A group, 2-piperidin-2-ylethyl group, 3-piperidin-2-ylpropyl group, piperidin-3-yl group, piperidin-3-ylmethyl group, 2-piperidin-3-ylethyl group, 3-piperidin-3-ylpropyl group, piperidin-4-yl group, piperidin-4-ylmethyl group, 2-piperidin-4-ylethyl group, 3-piperidin-4-ylpropyl group, piperazin-1-ylmethyl group, 2-piperazin-1-ylethyl group, 3-piperazin-1-ylpropyl group, 2-oxopiperazin-1-ylmethyl group, 2- (2-oxopiperazin-1-yl) ethyl group, 3- (2-oxopiperazin-1-yl) propyl group, 3-piperidin-3-ylethyl group, 3-piperidin-3-ylpropyl group, piperidin-4-yl group, piperidin-4-ylmethyl group, 2, 3-oxopiperazin-1-ylmethyl, 2- (3-oxopiperazin-1-yl) ethyl, 3- (3-oxopiperazin-1-yl) propyl, piperazin-2-yl, piperazin-2-ylmethyl, 2-piperazin-2-ylethyl and 3-piperazin-2-ylpropyl,

wherein Q¹The nitrogen atom of any NH group in (a) optionally bears a substituent selected from: cyano, cyanomethyl, 2-cyanoethyl, methyl, ethyl, 2-methoxyethyl, 2-ethoxyethyl, methylsulfonyl, trifluoromethyl, carbamoyl, trifluoromethyl, and the like,N-methylcarbamoyl group,N-ethylcarbamoyl radical,N，N-dimethylcarbamoyl radical,N，N-diethylcarbamoyl, acetyl, propionyl, sulfamoyl,N-methylsulfamoyl,N-an ethylsulfamoyl group,N，N-a dimethylsulfamoyl group,N，N-diethylsulfamoyl, 3-aminopropionyl, 3- (methylamino) propionyl, 3- (dimethylamino) propionyl, carbamoylmethyl, 2-carbamoylethyl, N-methylcarbamoylmethyl, 2-, (N-methylcarbamoyl) ethyl,N，N-dimethylcarbamoylmethyl, 2-, (N，N-dimethylcarbamoyl) ethyl, methoxymethylsulfonyl, 2-methoxyethylsulfonyl, 2-aminoethylsulfonyl, 2-, (ii) methylN-methylamino) ethanesulfonyl and 2-, (N，N-dimethylamino) ethanesulfonyl;

(o)Q¹-X²selected from piperidin-4-yl and piperidin-4-ylmethyl, wherein the nitrogen atom on the piperidinyl ring optionally bears a substituent selected from: cyano, cyanomethyl, methyl, ethyl, carbamoyl, carbamoylmethyl, 2-methoxyethyl, methanesulfonyl and ethanesulfonyl;

(p)Q¹-X²selected from 1-carbamoylmethylpiperidin-4-yl and 1-methanesulfonylpiperidin-4-yl; (q) R¹-X¹Selected from hydrogen, (1-4C) alkoxy and (1-4C) alkoxy;

(r)R¹-X¹selected from the group consisting of hydrogen, methoxy, ethoxy and 2-methoxyethoxy;

(s)R¹-X¹is methoxy;

(t)G¹and G²Each independently selected from fluoro and chloro;

(u)G¹is fluoro radical, G²Is chloro;

(v)Q¹a non-aromatic saturated 5-or 6-membered monocyclic heterocycle having 1 nitrogen heteroatom and optionally 1 or 2 further heteroatoms selected from oxygen, nitrogen and sulfur, which ring is bonded to the radical X via a carbon atom in the ring²-O-linkage, wherein Q¹With 1 or 2 substituents which may be the same or different selected from: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (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, (2-6C) alkenylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl sulfonyl ]Amino group,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino, sulfamoyl,N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino, carbamoyl (1-6C) alkyl,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, (2-6C) alkanoyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkaneA base andN- (1-6C) alkyl- (2-6C) alkanoylamino (1-6C) alkyl or a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Is a saturated 5-or 6-membered monocyclic heterocyclic ring which carries 1 nitrogen heteroatom and optionally 1 or 2 further heteroatoms selected from oxygen, nitrogen and sulfur, the ring being bridged via the ring nitrogen atom to the group X³Is connected, wherein Q²Optionally bearing 1 or 2 substituents selected from; (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl,

wherein Q¹Any of (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkanoyl groups of (a) optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo and hydroxy and/or optionally bearing substituents selected from: cyano, nitro, carboxyl, (2-8C) alkenyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy and NR ^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl,

or R^aOr R^bTogether with the nitrogen atom to which they are attached, form a 4, 5 or 6 membered ring optionally bearing on available ring carbon atoms 1 or 2 substituents which may be the same or different selected from (1-4C) alkyl groups and optionally bearing on any available ring nitrogen atom a substituent selected from the group consisting of (provided that the ring is not therefore quaternized): (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl;

wherein Q¹-X²Any heterocyclic group in the group optionally bears 1 or 2 oxo (═ O) or thioxo (═ S) substituents;

(w)Q¹a non-aromatic saturated 5-or 6-membered monocyclic heterocycle having 1 nitrogen heteroatom and optionally 1 or 2 further heteroatoms selected from oxygen, nitrogen and sulfur, which ring is bonded to the radical X via a carbon atom in the ring²-O-linkage, wherein Q¹With 1 or 2 substituents which may be the same or different selected from: halogeno, trifluoromethylA group, trifluoromethoxy group, cyano group, nitro group, hydroxyl group, amino group, carboxyl group, carbamoyl group, (1-6C) alkyl group, (2-8C) alkenyl group, (2-8C) alkynyl group, (1-6C) alkoxy group, (2-6C) alkenyloxy group, (2-6C) alkynyloxy group, (1-6C) alkylthio group, (1-6C) alkylsulfinyl group, (1-6C) alkylsulfonyl group, (2-6C) alkenylsulfonyl group, (1-6C) alkylamino group, di- [ (1-6C) alkyl group ]Amino group,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino, sulfamoyl,N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino, carbamoyl (1-6C) alkyl,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, (2-6C) alkanoyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl andN- (1-6C) alkyl- (2-6C) alkanoylamino (1-6C) alkyl or a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from the group consisting of pyrrolidin-1-yl, piperidino, piperazin-1-yl, and morpholino, wherein Q²Optionally bearing 1 or 2 substituents selected from: (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl,

wherein Q¹Any of (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkanoyl groups of (a) optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo and hydroxy and/or optionally bearing substituents selected from: cyano, nitro, carboxyl, (2-8C) alkenyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy and NR ^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl,

or R^aOr R^bTo nitrogen atoms attached theretoTo form a 4, 5 or 6 membered ring optionally bearing 1 or 2 substituents on available ring carbon atoms which may be the same or different selected from (1-4C) alkyl, and optionally bearing substituents on any available ring nitrogen atoms selected from (provided that the ring is not therefore quaternized): (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl;

wherein Q¹-X²Any heterocyclic group in the group optionally bears 1 or 2 oxo (═ O) or thioxo (═ S) substituents;

(x)Q¹a non-aromatic saturated 5-or 6-membered monocyclic heterocycle having 1 nitrogen heteroatom and optionally 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, which ring is bonded to the radical X via a carbon atom in the ring²-O-linkage, wherein Q¹With 1 or 2 substituents which may be the same or different selected from: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (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, (2-6C) alkenylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl sulfonyl ]Amino group,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino, sulfamoyl,N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino, carbamoyl (1-6C) alkyl,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, (2-6C) alkanoyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl andN- (1-6C) alkyl- (2-6C) alkanoylamino (1-6C) alkyl or a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, morpholino and piperidino,

wherein Q¹Any of (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkanoyl groups of (a) optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo and hydroxy and/or optionally bearing substituents selected from: cyano, nitro, carboxyl, (2-8C) alkenyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy and NR^aR^bWherein R is ^aIs hydrogen or (1-4C) alkyl, R^bIs hydrogen or (1-4C) alkyl,

or R^aOr R^bTogether with the nitrogen atom to which they are attached, form a 4, 5 or 6 membered ring optionally bearing on available ring carbon atoms 1 or 2 substituents which may be the same or different selected from (1-4C) alkyl groups and optionally bearing on any available ring nitrogen atom a substituent selected from the group consisting of (provided that the ring is not therefore quaternized): (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl;

wherein Q¹-X²Any heterocyclic group in the group optionally bears 1 or 2 oxo (═ O) or thioxo (═ S) substituents;

(y)Q¹is a fully saturated 5-or 6-membered monocyclic heterocycle having 1 nitrogen heteroatom and optionally 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, which ring is bonded to the radical X via a carbon atom in the ring²-O-linkage, wherein Q¹With 1 or 2 substituents which may be the same or different selected from: carbamoyl, (1-6C) alkyl, (1-6C) alkoxy, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino group,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, sulfamoyl,N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl ]Sulfamoyl, carbamoyl (1-6C) alkyl, carbamoyl (2-C) alkyl, carbamoyl (6C) alkyl, carbamoyl (meth) aryl, or carbamoyl (meth,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl and (2-6C) alkanoylAlkyl of the group (1-6C) or a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, morpholino and piperidino,

wherein Q¹Any of (1-6C) alkyl or (2-6C) alkanoyl in (a) optionally bears a substituent selected from the group consisting of hydroxy, (2-6C) alkanoyl, (2-6C) alkanoyloxy and NR^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs a (1-4C) alkyl group,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached form a pyrrolidin-1-yl, piperidino, piperazin-1-yl, or morpholino ring optionally bearing 1 or 2 substituents which may be the same or different selected from (1-4C) alkyl;

wherein Q¹-X²Any heterocyclic group in the group optionally bears 1 or 2 oxo (═ O) substituents; and

X²is a direct bond or CH₂；

(z)Q¹Is a fully saturated 5-or 6-membered monocyclic heterocycle which carries 1 nitrogen heteroatom and optionally 1 further heteroatom selected from oxygen, nitrogen and sulfur, the ring being bonded to the radical X via a carbon atom in the ring²-O-linkage, wherein Q¹The nitrogen atom of any NH group in (a) carries a substituent selected from: carbamoyl, (1-4C) alkyl, (1-4C) alkylsulfonyl, (1-4C) alkylamino, di- [ (1-4C) alkyl ]Amino group,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl, (2-4C) alkanoyl, sulfamoyl,N- (1-4C) alkylsulfamoyl,N，NDi- [ (1-4C) alkyl]Sulfamoyl, carbamoyl (1-3C) alkyl, carbamoyl (2-C) alkyl,N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, (2-4C) alkanoyl (1-3C) alkyl, hydroxy (2-4C) alkanoyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl、N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, (2-4C) alkanoyloxy- (2-4C) alkanoyl, amino (1-3C) alkylsulfonyl,N- (1-4C) alkylamino- (1-3C) alkylsulfonyl,N，NDi- [ (1-4C) alkyl]Amino (1-3C) alkylsulfonyl, pyrrolidin-1-yl- (2-4C) alkanoyl, piperidino- (2-4C) alkanoyl, piperazin-1-yl- (2-4C) alkanoyl and morpholino- (2-4C) alkanoyl;

wherein Q¹-X²Any heterocyclic group in the group optionally bears an oxo (═ O) substituent; and

X²is a direct bond or CH₂；

(aa)Q¹Is a fully saturated 5-or 6-membered monocyclic heterocycle which carries 1 nitrogen heteroatom and optionally 1 further heteroatom selected from oxygen, nitrogen and sulfur, the ring being bonded to the radical X via a carbon atom in the ring²-O-linkage, wherein Q ¹With 1 substituent on a ring carbon atom selected from: a carbamoyl group,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl, carbamoyl (1-3C) alkyl,N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, (2-4C) alkanoyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, pyrrolidin-1-yl- (2-4C) alkanoyl, piperidino- (2-4C) alkanoyl, piperazin-1-yl- (2-4C) alkanoyl and morpholino- (2-4C) alkanoyl, or a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, morpholino and piperidino,

wherein Q¹The nitrogen atom of any NH group in (1-4C) optionally bearing a substituent selected from (1-4C) alkyl; and

wherein Q¹-X²Any heterocyclic group in the group optionally carriesAn oxo (═ O) substituent; and

X²is a direct bond or CH₂；

(bb)Q¹Selected from by ring carbon atoms with the group X²-O-linked pyrrolidinyl and piperidinyl, wherein said pyrrolidinyl or piperidinyl is substituted with 1 or 2 substituents selected from: carbamoyl, (1-4C) alkyl, (1-4C) alkylsulfonyl, (1-4C) alkylamino, di- [ (1-4C) alkyl ]Amino group,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl, (2-4C) alkanoyl, sulfamoyl,N- (1-4C) alkylsulfamoyl,N，NDi- [ (1-4C) alkyl]Sulfamoyl, carbamoyl (1-3C) alkyl, carbamoyl (2-C) alkyl,N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, (2-4C) alkanoyl (1-3C) alkyl, hydroxy (2-4C) alkanoyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl, substituted or unsubstituted amino,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, (2-4C) alkanoyloxy- (2-4C) alkanoyl, amino (1-3C) alkylsulfonyl,N- (1-4C) alkylamino- (1-3C) alkylsulfonyl,N，NDi- [ (1-4C) alkyl]Amino (1-3C) alkylsulfonyl, pyrrolidin-1-yl- (2-4C) alkanoyl, piperidino- (2-4C) alkanoyl, piperazin-1-yl- (2-4C) alkanoyl, morpholino- (2-4C) alkanoyl and groups of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, morpholino, and piperidino;

wherein Q¹-X²Any heterocyclic group in the group optionally bears an oxo (═ O) substituent; and

X²is a direct bond or CH₂；

(cc)Q¹-X²Selected from pyrrolidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-2-yl Methyl, piperidin-3-ylmethyl and piperidin-4-ylmethyl, wherein Q¹-X²Wherein pyrrolidinyl or piperidinyl bears 1 or 2 substituents selected from: (1-4C) alkyl, (1-4C) alkylsulfonyl,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl, (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]A sulfamoyl group,N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, hydroxy (2-4C) alkanoyl,N- (1-4C) alkylamino- (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, (2-4C) alkanoyloxy- (2-4C) alkanoyl,N- (1-4C) alkylamino- (1-3C) alkylsulfonyl,N，NDi- [ (1-4C) alkyl]Amino (1-3C) alkylsulfonyl, pyrrolidin-1-yl- (2-4C) alkanoyl, piperidino- (2-4C) alkanoyl, morpholino- (2-4C) alkanoyl and groups of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, morpholino, and piperidino;

(dd)Q¹-X²selected from the group consisting of pyrrolidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl, piperidin-3-ylmethyl and piperidin-4-ylmethyl, wherein Q¹-X²Wherein pyrrolidinyl or piperidinyl bears 1 or 2 substituents selected from: (1-4C) alkyl, (1-4C) alkylsulfonyl, N，NDi- [ (1-4C) alkyl]Carbamoyl, (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]A sulfamoyl group,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, hydroxy (2-4C) alkanoyl,N- (1-4C) alkylamino- (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, (2-4C) alkanoyloxy- (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]Amino (1-3C) alkylsulfonyl, pyrrolidin-1-yl- (2-4C) alkanoyl, piperidino- (2-4C) alkanoyl and morpholino- (2-4C) alkanoyl or a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Is morpholino;

(ee)Q¹-X²selected from the group consisting of pyrrolidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl, piperidin-3-ylmethyl and piperidin-4-ylmethyl, wherein Q¹-X²Wherein pyrrolidinyl or piperidinyl is optionally substituted on the ring nitrogen atom with a substituent selected from: methyl, ethyl, methylsulfonyl, ethylsulfonyl,N，N-dimethylcarbamoyl radical,N，N-a diethylcarbamoyl group,N-methyl-N-ethylcarbamoyl, acetyl, propionyl,N，N-a dimethylsulfamoyl group,N，N-a diethylsulfamoyl group,N-methyl-N-an ethylsulfamoyl group,N，N-dimethylcarbamoylmethyl, 2-, ( N，N-dimethylcarbamoyl) ethyl group,N，N-diethylcarbamoylmethyl, 2-, (N，N-diethylcarbamoyl) ethyl, hydroxyacetyl, 2-hydroxypropionyl, N-methylaminoacetyl, N-ethylaminoacetyl, 2- (N-methylamino) propionyl, 2- (N-ethylamino) propionyl,N，NDimethylaminoacetyl, 2-, (N，N-dimethylamino) propanoyl,N，NDiethylaminoacetyl, 2-, (N，N-diethylamino) propionyl group,N-methyl-N-ethylaminoacetyl, 2-, (N-methyl-N-ethylamino) propionyl group, acetoxyacetyl group, 2- (acetoxy) propionyl group, 2-, (ii) acetyl groupN-methylamino) ethanesulfonyl group, 2-, (N-ethylamino) ethanesulfonyl, 2-, (N，N-dimethylamino-ethanesulfonyl group, 2-, (N，N-diethylamino-ethanesulfonyl group, 3-, (N-methylamino) propanesulfonyl, 3-, (N-ethylamino) propanesulfonyl, 3-, (N，N-dimethylamino-propanesulfonyl group, 3-, (N，N-diethylamino) propanesulfonyl, pyrrolidin-1-ylacetyl, 2- (pyrrolidin-1-yl) propionyl, piperidinoThe group consisting of acetoacetyl, 2-piperidinopropionyl, morpholinoacetyl, 2-morpholinopropionyl, and a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Is morpholino;

(ff)Q¹-X²selected from the group consisting of pyrrolidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl, piperidin-3-ylmethyl and piperidin-4-ylmethyl, wherein Q ¹-X²Wherein pyrrolidinyl or piperidinyl is optionally substituted on the ring nitrogen atom with a substituent selected from: methyl, ethyl, methylsulfonyl,N，N-dimethylcarbamoyl, acetyl, hydroxyacetyl, and,N-methylaminoacetyl group,N，NDimethylaminoacetyl, 3-, (N，N-dimethylamino) propanesulfonyl, pyrrolidin-1-ylacetyl, piperidinoacetyl, 2-piperidinopropionyl and morpholinoacetyl;

(gg)Q¹-X²selected from pyrrolidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl, piperidin-3-ylmethyl and piperidin-4-ylmethyl groups, wherein group Q¹-X²Wherein the pyrrolidinyl or piperidinyl group bears 1 substituent selected from: a carbamoyl group,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl and a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, piperidino, and morpholino;

and wherein Q¹Wherein the ring nitrogen atom on the pyrrolidinyl or piperidinyl group optionally bears a substituent selected from (1-4C) alkyl;

(hh)Q¹-X²selected from pyrrolidin-3-yl, pyrrolidin-2-ylmethyl and pyrrolidin-3-ylmethyl wherein the pyrrolidinyl group bears 1 substituent at the 5-position selected from: N，NDi- [ (1-4C) alkyl]Carbamoyl and a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Is morpholino;

and wherein pyrrolidinyl optionally bears a substituent selected from (1-4C) alkyl at the 1-position (with the understanding that this embodiment encompasses, for example, where Q¹-X²Is a radical of pyrrolidin-3-yl of the formula:

wherein X is a substituent at the 5-position, see this example, e.g. 2-, (R) at the 6-position on the quinazoline ringN，N-dimethylcarbamoyl) pyrrolidin-4-yl is an example of such a group);

(ii)Q¹-X²selected from the group consisting of pyrrolidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl, piperidin-3-ylmethyl and piperidin-4-ylmethyl, wherein Q¹-X²Wherein the pyrrolidinyl or piperidinyl group bears 1 substituent on a ring carbon atom selected from:N，N-dimethylcarbamoyl radical,N，N-a diethylcarbamoyl group,N-methyl-N-ethylcarbamoyl and a group of formula:

Q²-X³-

wherein X³Is CO, Q²Is a morpholino group which is capable of,

and wherein Q¹The ring nitrogen atom on the pyrrolidinyl or piperidinyl group in (a) optionally bears a substituent selected from methyl and ethyl;

(jj)Q¹-X²selected from the group consisting of pyrrolidin-3-yl, pyrrolidin-2-ylmethyl and pyrrolidin-3-ylmethyl wherein said pyrrolidinyl bears at the 5-position N，N-a dimethylcarbamoyl substituent;

(kk)X²is CH₂；

(ll)Q¹Is a non-aromatic, saturated or partially saturated, 4-, 5-or 6-membered monocyclic heterocycle having 1 or 2 ring nitrogen heteroatoms, which ring is bound via a ring carbon atom to the radical X²-O-is linked, and wherein Q¹Optionally bearing 1 or 2 substituents which may be the same or different selected from: halo, cyano, nitro, hydroxy, carbamoyl, acryloyl, (1-6C) alkyl, (1-6C) alkylthio, (2-6C) alkenylthio, (2-6C) alkynylthio, (1-6C) alkylsulfinyl, (2-6C) alkenylsulfinyl, (2-6C) alkynylsulfinyl, (1-6C) alkylsulfonyl, (2-6C) alkenylsulfonyl, (2-6C) alkynylsulfonyl,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, sulfamoyl,N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl, carbamoyl (1-6C) alkyl, carbamoyl (2-C) alkyl, carbamoyl (6C) alkyl, carbamoyl (meth) aryl, or carbamoyl (meth,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, sulfamoyl (1-6C) alkyl,N- (1-6C) alkylsulfamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl (1-6C) alkyl, (2-6C) alkanoyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl and N- (1-6C) alkyl- (2-6C) alkanoylamino (1-6C) alkyl or a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Is a heterocyclic group selected from morpholino, piperidinyl, piperazinyl and pyrrolidinyl (wherein piperidinyl, piperazinyl or pyrrolidinyl can be attached to X through a ring carbon or ring nitrogen atom³Connected),

wherein Q²Optionally bearing 1 or 2 substituents which may be the same or different selected from: halo, hydroxy, (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl,

wherein Q¹Any of (1-6C) alkyl or (2-6C) alkanoyl in (a) optionally bearing 1 or 2 substituents which may be the same or different selected from halo, hydroxy and (1-6C) alkyl and/or optionally bearing substituents selected from: cyano, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (2-6C) alkanoyl, (2-6C) alkanoyloxy and NR^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl, and wherein R^aOr R^bAny (1-4C) alkyl group in (a) optionally bears one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo and hydroxy and/or optionally bears one substituent selected from cyano and (1-4C) alkoxy,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached, form a 4-, 5-or 6-membered ring which is free of oxygen atoms, optionally bears on available ring carbon atoms 1 or 2 substituents which may be the same or different selected from halo, hydroxy, (1-4C) alkyl and (1-3C) alkylenedioxy, and optionally bears on any available ring nitrogen atoms substituents selected from (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl (provided that the ring is not therefore quaternized),

Wherein as a substituent is present in^aAnd R^bAny (1-4C) alkyl or (2-4C) alkanoyl group on the ring formed together with the nitrogen atom to which they are attached optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo and hydroxy and/or optionally bearing substituents selected from (1-4C) alkyl and (1-4C) alkoxy,

wherein Q¹-X²Any heterocyclic group in the group optionally bears 1 or 2 oxo (═ O) or thioxo (═ S) substituents;

(mm)Q¹selected from through ring carbonsAtom and group X²-O-linked pyrrolidinyl and piperidinyl, wherein said pyrrolidinyl or piperidinyl is optionally substituted with 1 or 2 groups selected from: halo, cyano, hydroxy, carbamoyl, (1-6C) alkyl, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, sulfamoyl,N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl, carbamoyl (1-6C) alkyl, carbamoyl (2-C) alkyl, carbamoyl (6C) alkyl, carbamoyl (meth) aryl, or carbamoyl (meth,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, sulfamoyl (1-6C) alkyl,N- (1-6C) alkylsulfamoyl (1-6C) alkyl, N，NDi- [ (1-6C) alkyl]Sulfamoyl (1-6C) alkyl and (2-6C) alkanoyl (1-6C) alkyl or a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Is a heterocyclic group selected from morpholino, piperidino, piperazin-1-yl, pyrrolidin-1-yl and pyrrolidin-2-yl,

wherein Q²Optionally bearing 1 or 2 substituents which may be the same or different selected from: halo, hydroxy, (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl,

wherein Q¹Any of (1-6C) alkyl or (2-6C) alkanoyl in (a) optionally bearing 1 or 2 substituents which may be the same or different selected from halo, hydroxy and (1-6C) alkyl and/or optionally bearing substituents selected from: cyano, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (2-6C) alkanoyl, (2-6C) alkanoyloxy and NR^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, R^bIs hydrogen or (1-4C) alkyl, and wherein R^aOr R^bAny (1-4C) alkyl group in (a) optionally bears one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo and hydroxy and/or optionally bears one substituent selected from cyano and (1-4C) alkoxyThe base group is a group of a compound,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached form a ring selected from pyrrolidin-1-yl, piperidino and piperazin-1-yl, which optionally bears on available ring carbon atoms 1 or 2 substituents which may be the same or different selected from halo, hydroxy, (1-4C) alkyl and methylenedioxy, and which optionally bears on any available ring nitrogen atom a substituent selected from (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl (provided that the ring is not therefore quaternised),

Wherein as a substituent is present in^aAnd R^bAny (1-4C) alkyl or (2-4C) alkanoyl group on the ring formed together with the nitrogen atom to which they are attached optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo and hydroxy and/or optionally bearing substituents selected from (1-4C) alkyl and (1-4C) alkoxy,

wherein as a substituent is present in^aAnd R^bAny (1-4C) alkyl or (2-4C) alkanoyl group on the ring formed together with the nitrogen atom to which they are attached optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo and hydroxy and/or optionally bearing substituents selected from (1-4C) alkyl and (1-4C) alkoxy,

wherein Q¹-X²Any heterocyclic group in the group optionally bears 1 or 2 oxo (═ O) substituents;

(nn)Q¹selected from by ring carbon atoms with the group X²-O-linked pyrrolidinyl and piperidinyl, wherein said pyrrolidinyl or piperidinyl is substituted with 1 or 2 groups selected from: carbamoyl, (1-4C) alkyl, (1-4C) alkylsulfonyl,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl, (2-4C) alkanoyl, sulfamoyl,N- (1-4C) alkylsulfamoyl, N，NDi- [ (1-4C) alkyl]Sulfamoyl, carbamoyl (1-3C) alkyl, carbamoyl (2-C) alkyl,N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, (2-4C) alkanoyl (1-3C) alkyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, (2-4C) alkanoyloxy- (2-4C) alkanoyl, amino (1-3C) alkylsulfonyl,N- (1-4C) alkylamino- (1-3C) alkylsulfonyl,N，NDi- [ (1-4C) alkyl]Amino (1-3C) alkylsulfonyl, pyrrolidin-1-yl- (2-4C) alkanoyl, 3, 4-methylenedioxypyrrolidin-1-yl- (2-4C) alkanoyl, piperidino- (2-4C) alkanoyl, piperazin-1-yl- (2-4C) alkanoyl, morpholino- (2-4C) alkanoyl and groups of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino and piperidino,

wherein Q¹In the substituent(s) or by Q²Any of the pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino or piperazin-1-yl groups represented optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, (1-4C) alkyl, (2-4C) alkanoyl and halo (especially chloro, more preferably fluoro),

Wherein Q¹Any of the (2-4C) alkanoyl groups in the substituents optionally bears 1 or 2 substituents which may be the same or different and are selected from hydroxy and (1-3C) alkyl,

wherein Q¹Any of the (1-4C) alkyl groups in the substituents above optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, (1-4C) alkoxy and halo (especially chloro, more preferably fluoro),

wherein Q¹-X²Any heterocyclic group in the group optionally bears an oxo (═ O) substituent; and

X²is a direct bond;

(oo)Q¹selected from by ring carbon atoms with the group X²-O-is(ii) a vicinal pyrrolidinyl group and piperidinyl group, wherein the pyrrolidinyl or piperidinyl group is substituted with 1 or 2 groups which may be the same or different selected from: carbamoyl, (1-4C) alkyl, (1-4C) alkylsulfonyl,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl, (2-4C) alkanoyl, sulfamoyl,N- (1-4C) alkylsulfamoyl,N，NDi- [ (1-4C) alkyl]Sulfamoyl, carbamoyl (1-3C) alkyl, carbamoyl (2-C) alkyl,N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, (2-4C) alkanoyl (1-3C) alkyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl, N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, (2-4C) alkanoyloxy- (2-4C) alkanoyl, amino (1-3C) alkylsulfonyl,N- (1-4C) alkylamino- (1-3C) alkylsulfonyl,N，NDi- [ (1-4C) alkyl]Amino (1-3C) alkylsulfonyl, pyrrolidin-1-yl- (2-4C) alkanoyl, 3, 4-methylenedioxypyrrolidin-1-yl- (2-4C) alkanoyl, piperidino- (2-4C) alkanoyl, piperazin-1-yl- (2-4C) alkanoyl and groups of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, pyrrolidin-2-yl and piperidino,

wherein Q¹In the substituent(s) or by Q²Any of the pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino or piperazin-1-yl groups represented optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, (1-4C) alkyl, (2-4C) alkanoyl and halo (especially chloro, more preferably fluoro),

wherein Q¹Any of the (2-4C) alkanoyl groups in the substituents optionally bears 1 or 2 substituents which may be the same or different and are selected from hydroxy and (1-3C) alkyl,

wherein Q¹Any (1-4C) alkyl group in the substituents optionally has 1 or 2 substituents which may be the same or different and are selected from hydroxy, (1-4C) alkoxyAnd a substituent of a halogeno group (particularly a chloro group, more preferably a fluoro group),

Wherein Q¹-X²Any heterocyclic group in the group optionally bears an oxo (═ O) substituent; and

X²is CH₂；

(pp)Q¹Selected from by ring carbon atoms with the group X²-O-linked pyrrolidinyl and piperidinyl, wherein said pyrrolidinyl or piperidinyl is substituted with 1 or 2 groups which may be the same or different selected from: carbamoyl, (1-4C) alkyl, (1-4C) alkylsulfonyl,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl, (2-4C) alkanoyl, sulfamoyl,N- (1-4C) alkylsulfamoyl,N，NDi- [ (1-4C) alkyl]Sulfamoyl, carbamoyl (1-3C) alkyl, carbamoyl (2-C) alkyl,N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, (2-4C) alkanoyl (1-3C) alkyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, (2-4C) alkanoyloxy- (2-4C) alkanoyl, amino (1-3C) alkylsulfonyl,N- (1-4C) alkylamino- (1-3C) alkylsulfonyl,N，NDi- [ (1-4C) alkyl]Amino (1-3C) alkylsulfonyl,

wherein Q¹Any of the (2-4C) alkanoyl groups in the substituents optionally bears 1 or 2 substituents which may be the same or different and are selected from hydroxy and (1-3C) alkyl,

Wherein Q¹Any of the (1-4C) alkyl groups in the substituents above optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, (1-4C) alkoxy and halo (especially chloro, more preferably fluoro),

X²is a direct bond or CH₂；

(qq)Q¹-X²Selected from pyrrolidin-2-ylmethyl, (2R) -pyrrolidin-2-ylmethyl(ii) yl, (2S) -pyrrolidin-2-ylmethyl, pyrrolidin-3-yl, (3R) -pyrrolidin-3-yl, (3S) -pyrrolidin-3-yl, pyrrolidin-3-ylmethyl, (3R) -pyrrolidin-3-ylmethyl, (3S) -pyrrolidin-3-ylmethyl, piperidin-4-yl, piperidin-4-ylmethyl, piperidin-3-yl, (3R) -piperidin-3-yl and (3S) -piperidin-3-yl, wherein Q is¹Substituted with 1 or 2 substituents which may be the same or different selected from: carbamoyl, (1-4C) alkyl, (1-4C) alkylsulfonyl,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl, (2-4C) alkanoyl, sulfamoyl,N- (1-4C) alkylsulfamoyl,N，NDi- [ (1-4C) alkyl]Sulfamoyl, carbamoyl (1-3C) alkyl, carbamoyl (2-C) alkyl,N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, (2-4C) alkanoyl (1-3C) alkyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl, N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, (2-4C) alkanoyloxy- (2-4C) alkanoyl, amino (1-3C) alkylsulfonyl,N- (1-4C) alkylamino- (1-3C) alkylsulfonyl,N，NDi- [ (1-4C) alkyl]Amino (1-3C) alkylsulfonyl, pyrrolidin-1-yl- (2-4C) alkanoyl, 3, 4-methylenedioxypyrrolidin-1-yl- (2-4C) alkanoyl, piperidino- (2-4C) alkanoyl, piperazin-1-yl- (2-4C) alkanoyl, morpholino- (2-4C) alkanoyl and groups of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino and piperidino,

wherein Q¹In the substituent(s) or by Q²Any of the pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino or piperazin-1-yl groups represented optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, (1-4C) alkyl, (2-4C) alkanoyl and halo (especially chloro, more preferably fluoro),

wherein Q¹Any (2-4C) alkanoyl group of the substituentsOptionally carrying 1 or 2 substituents which may be the same or different selected from hydroxy and (1-3C) alkyl,

wherein Q¹Any of the (1-4C) alkyl groups in the substituents above optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, (1-4C) alkoxy and halo (especially chloro, more preferably fluoro),

Wherein Q¹-X²Any heterocyclic group in the group optionally bears an oxo (═ O) substituent;

(rr)Q¹-X²selected from the group consisting of pyrrolidin-2-ylmethyl, (2R) -pyrrolidin-2-ylmethyl, (2S) -pyrrolidin-2-ylmethyl, pyrrolidin-3-yl, (3R) -pyrrolidin-3-yl, (3S) -pyrrolidin-3-yl, pyrrolidin-3-ylmethyl, (3R) -pyrrolidin-3-ylmethyl, (3S) -pyrrolidin-3-ylmethyl, piperidin-4-yl, piperidin-3-yl, (3R) -piperidin-3-yl and (3S) -piperidin-3-yl, wherein Q is Q¹Wherein pyrrolidinyl or piperidinyl is substituted at the 1-position with a substituent selected from: (1-4C) alkyl, (1-4C) alkylsulfonyl, (2-4C) alkanoyl (1-3C) alkyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, (2-4C) alkanoyloxy- (2-4C) alkanoyl, amino (1-3C) alkylsulfonyl,N- (1-4C) alkylamino- (1-3C) alkylsulfonyl,N，NDi- [ (1-4C) alkyl]Amino (1-3C) alkylsulfonyl, pyrrolidin-1-yl- (2-4C) alkanoyl, 3, 4-methylenedioxypyrrolidin-1-yl- (2-4C) alkanoyl, piperidino- (2-4C) alkanoyl, piperazin-1-yl- (2-4C) alkanoyl and groups of the formula:

Q²-X³-

wherein X³Is CO, Q²Is a pyrrolidine-2-yl group, and the compound is a substituted or unsubstituted pyrrolidine group,

Wherein Q¹In the substituent(s) or by Q²Any of the pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino or piperazin-1-yl groups represented optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, oxo, (1-4C) alkyl, (2-4C) alkaneAcyl and halo (especially chloro, more preferably fluoro) substituents,

wherein Q¹Any of the (2-4C) alkanoyl groups in the substituents optionally bears 1 or 2 substituents which may be the same or different and are selected from hydroxy and (1-3C) alkyl,

wherein Q¹Any of the (1-4C) alkyl groups in the substituents above optionally bears 1 or 2 substituents which may be the same or different, selected from hydroxy, (1-4C) alkoxy and halo (especially chloro, more preferably fluoro);

(ss)Q¹-X²selected from the group consisting of pyrrolidin-3-yl, (3R) -pyrrolidin-3-yl, (3S) -pyrrolidin-3-yl, piperidin-4-yl, piperidin-3-yl, (3R) -piperidin-3-yl, and (3S) -piperidin-3-yl, wherein Q¹Substituted at the 1-position with a substituent selected from: (1-4C) alkyl, (1-4C) alkylsulfonyl, (2-4C) alkanoyl (1-3C) alkyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, (2-4C) alkanoyloxy- (2-4C) alkanoyl, amino (1-3C) alkylsulfonyl, N- (1-4C) alkylamino- (1-3C) alkylsulfonyl,N，NDi- [ (1-4C) alkyl]Amino (1-3C) alkylsulfonyl, pyrrolidin-1-yl- (2-4C) alkanoyl, 3, 4-methylenedioxypyrrolidin-1-yl- (2-4C) alkanoyl, piperidino- (2-4C) alkanoyl, piperazin-1-yl- (2-4C) alkanoyl, morpholino- (2-4C) alkanoyl and groups of the formula:

Q²-X³-

wherein X³Is CO, Q²Is a pyrrolidine-2-yl group, and the compound is a substituted or unsubstituted pyrrolidine group,

wherein Q¹In the substituent(s) or by Q²Any of the pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino or piperazin-1-yl groups represented optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, (1-4C) alkyl, (2-4C) alkanoyl and halo (especially chloro, more preferably fluoro),

wherein Q¹Any of the (2-4C) alkanoyl groups in the substituents optionally bears 1 or 2 substituents which may be the same or different and are selected from hydroxy and (1-3C) alkyl,

wherein Q¹Any of the (1-4C) alkyl groups in the substituents above optionally bears 1 or 2 substituents which may be the same or different, selected from hydroxy, (1-4C) alkoxy and halo (especially chloro, more preferably fluoro);

wherein Q¹-X²Any heterocyclic group in the group optionally bears an oxo (═ O) substituent;

(tt)Q¹-X²selected from: pyrrolidin-3-yl, (3R) -pyrrolidin-3-yl, (3S) -pyrrolidin-3-yl, piperidin-3-yl, (3R) -piperidin-3-yl, (3S) -piperidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl, (2R) -pyrrolidin-2-ylmethyl, (2S) -pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, (3R) -pyrrolidin-3-ylmethyl, (3S) -pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl, (2R) -piperidin-2-ylmethyl, (2S) -piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-2-ylmethyl, di-tert-butylamino-ylmethyl, di-tert-butylamino-ylmethyl, and their use, Piperidin-3-ylmethyl, (3R) -piperidin-3-ylmethyl, (3S) -piperidin-3-ylmethyl and piperidin-4-ylmethyl, wherein Q ¹-X²Wherein pyrrolidinyl or piperidinyl is optionally substituted on the ring nitrogen atom with a substituent selected from: methyl, ethyl, isopropyl, isobutyl, cyclopropylmethyl, methylsulfonyl, ethylsulfonyl,N-methylcarbamoyl group,N-ethylcarbamoyl radical,N-isopropylcarbamoyl group,N-cyclopropylmethylcarbamoyl group,N，N-dimethylcarbamoyl radical,N，N-a diethylcarbamoyl group,N-methyl-N-ethylcarbamoyl, acetyl, propionyl, isobutyryl,N-methylsulfamoyl,N-an ethylsulfamoyl group,N-an isopropylaminosulfonyl group,N-cyclopropylmethylsulfamoyl,N，N-a dimethylsulfamoyl group,N，N-a diethylsulfamoyl group,N-methyl-N-ethylsulfamoyl, carbamoylmethyl,N-methylcarbamoylmethyl, 2-, (N-methylcarbamoyl) ethyl,N-ethylamino groupFormylmethyl group, 2-, (N-ethylcarbamoyl) ethyl,N，N-dimethylcarbamoylmethyl, 2-, (N，N-dimethylcarbamoyl) ethyl group,N，N-diethylcarbamoylmethyl, 2-, (N，N-diethylcarbamoyl) ethyl, hydroxyacetyl, 2-hydroxypropionyl, N-methylaminoacetyl, N-ethylaminoacetyl, 2- (N-methylamino) propionyl, 2- (N-ethylamino) propionyl, N，NDimethylaminoacetyl, 2-, (N，N-dimethylamino) propanoyl,N，NDiethylaminoacetyl, 2-, (N，N-diethylamino) propionyl group,N-methyl-N-ethylaminoacetyl, 2-, (N-methyl-N-ethylamino) propionyl group, acetoxyacetyl group, 2- (acetoxy) propionyl group, 2-, (ii) acetyl groupN-methylamino) ethanesulfonyl group, 2-, (N-ethylamino) ethanesulfonyl, 2-, (N，N-dimethylamino-ethanesulfonyl group, 2-, (N，N-diethylamino-ethanesulfonyl group, 3-, (N-methylamino) propanesulfonyl, 3-, (N-ethylamino) propanesulfonyl, 3-, (N，N-dimethylamino-propanesulfonyl group, 3-, (N，N-diethylamino) propanesulfonyl, pyrrolidin-1-ylacetyl, 2- (pyrrolidin-1-yl) propionyl, 3, 4-methylenedioxypyrrolidin-1-ylacetyl, 2- (3, 4-methylenedioxypyrrolidin-1-yl) propionyl, piperidinoacetyl, 2-piperidinopropionyl, piperazin-1-ylacetyl, 2-piperazin-1-ylpropionyl and groups of the formula:

Q²-X³

wherein X³Is CO, Q²Selected from morpholino, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino and piperazin-1-yl,

wherein Q¹In the substituent(s) or by Q²Any of the pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino or piperazin-1-yl groups represented optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, oxo, methyl, ethyl, acetyl and fluoro,

Wherein Q¹Any of the acetyl, propionyl or isobutyryl groups on the substituents optionally bear 1 or 2 substituents which may be the same or different and are selected from hydroxy and methyl,

wherein Q¹Any (1-4C) alkyl group in the substituents optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, methoxy, fluoro, chloro;

(uu)Q¹-X²selected from: pyrrolidin-3-yl, (3R) -pyrrolidin-3-yl, (3S) -pyrrolidin-3-yl, piperidin-3-yl, (3R) -piperidin-3-yl, (3S) -piperidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl, (2R) -pyrrolidin-2-ylmethyl, (2S) -pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, (3R) -pyrrolidin-3-ylmethyl, (3S) -pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl, (2R) -piperidin-2-ylmethyl, (2S) -piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-2-ylmethyl, di-tert-butylamino-ylmethyl, di-tert-butylamino-ylmethyl, and their use, Piperidin-3-ylmethyl, (3R) -piperidin-3-ylmethyl, (3S) -piperidin-3-ylmethyl and piperidin-4-ylmethyl, wherein Q¹-X²Wherein pyrrolidinyl or piperidinyl is optionally substituted on the ring nitrogen atom with a substituent selected from: acetyl, propionyl, isobutyryl, N-methylaminoacetyl, N-ethylaminoacetyl, 2- (N-methylamino) propionyl, 2- (N-ethylamino) propionyl,N，NDimethylaminoacetyl, 2-, ( N，N-dimethylamino) propanoyl,N，NDiethylaminoacetyl, 2-, (N，N-diethylamino) propionyl group,N-methyl-N-ethylaminoacetyl, 2-, (N-methyl-N-ethylamino) propionyl, acetoxyacetyl, 2- (acetoxy) propionyl, pyrrolidin-1-ylacetyl, 2- (pyrrolidin-1-yl) propionyl, 3, 4-methylenedioxypyrrolidin-1-ylacetyl, 2- (3, 4-methylenedioxypyrrolidin-1-yl) propionyl, piperidinoacetyl, 2-piperidinopropionyl, piperazin-1-ylacetyl and 2-piperazin-1-ylpropionyl,

wherein Q¹In the substituent(s) or by Q²Any of the pyrrolidin-1-yl, piperidino or piperazin-1-yl groups represented optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, oxoSubstituents for radicals, methyl, ethyl, acetyl and fluoro,

wherein Q¹Any of the acetyl, propionyl or isobutyryl groups on the substituents optionally bear 1 or 2 substituents which may be the same or different and are selected from hydroxy and methyl,

wherein Q¹Any (1-4C) alkyl group in the substituents optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, methoxy, fluoro, chloro;

(vv)Q¹-X²selected from: pyrrolidin-2-ylmethyl, (2R) -pyrrolidin-2-ylmethyl, (2S) -pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, (3R) -pyrrolidin-3-ylmethyl, (3S) -pyrrolidin-3-ylmethyl, wherein Q ¹-X²The pyrrolidinyl group in (a) is substituted on the ring nitrogen atom with a substituent selected from the group consisting of: methyl, ethyl, isopropyl, isobutyl, cyclopropylmethyl, methylsulfonyl, ethylsulfonyl,N-methylcarbamoyl group,N-ethylcarbamoyl radical,N-isopropylcarbamoyl group,N-cyclopropylmethylcarbamoyl group,N，N-dimethylcarbamoyl radical,N，N-a diethylcarbamoyl group,N-methyl-N-ethylcarbamoyl, acetyl, propionyl, isobutyryl,N-methylsulfamoyl,N-an ethylsulfamoyl group,N-an isopropylaminosulfonyl group,N-cyclopropylmethylsulfamoyl,N，N-a dimethylsulfamoyl group,N，N-a diethylsulfamoyl group,N-methyl-N-ethylsulfamoyl, carbamoylmethyl,N-methylcarbamoylmethyl, 2-, (N-methylcarbamoyl) ethyl,N-ethylcarbamoylmethyl, 2-, (N-ethylcarbamoyl) ethyl,N，N-dimethylcarbamoylmethyl, 2-, (N，N-dimethylcarbamoyl) ethyl group,N，N-diethylcarbamoylmethyl, 2-, (N，N-diethylcarbamoyl) ethyl, N-methylaminoacetyl, N-ethylaminoacetyl, 2- (N-methylamino) propionyl, 2- (N-ethylamino) propionyl、N，NDimethylaminoacetyl, 2-, ( N，N-dimethylamino) propanoyl,N，NDiethylaminoacetyl, 2-, (N，N-diethylamino) propionyl group,N-methyl-N-ethylaminoacetyl, 2-, (N-methyl-N-ethylamino) propionyl group, acetoxyacetyl group, 2- (acetoxy) propionyl group, 2-, (ii) acetyl groupN-methylamino) ethanesulfonyl group, 2-, (N-ethylamino) ethanesulfonyl, 2-, (N，N-dimethylamino-ethanesulfonyl group, 2-, (N，N-diethylamino-ethanesulfonyl group, 3-, (N-methylamino) propanesulfonyl, 3-, (N-ethylamino) propanesulfonyl, 3-, (N，N-dimethylamino-propanesulfonyl group, 3-, (N，N-diethylamino) propanesulfonyl, pyrrolidin-1-ylacetyl, 2- (pyrrolidin-1-yl) propionyl, 3, 4-methylenedioxypyrrolidin-1-ylacetyl, 2- (3, 4-methylenedioxypyrrolidin-1-yl) propionyl, piperidinoacetyl, 2-piperidinopropionyl, piperazin-1-ylacetyl, 2-piperazin-1-ylpropionyl and groups of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from morpholino, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino and piperazin-1-yl,

wherein Q¹In the substituent(s) or by Q²Any of the pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino or piperazin-1-yl groups represented optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, oxo, methyl, ethyl, acetyl and fluoro,

Wherein Q¹Any of the acetyl, propionyl or isobutyryl groups on the substituents optionally bear 1 or 2 substituents which may be the same or different and are selected from hydroxy and methyl,

wherein Q¹Any (1-4C) alkyl group in the substituents optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, methoxy, fluoro, chloro;

(ww)Q¹-X²selected from: pyrrolidin-2-ylmethyl, (2R) -pyrrolidin-2-ylmethyl, (2S) -pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, (3R) -pyrrolidin-3-ylmethyl, (3S) -pyrrolidin-3-ylmethyl, wherein Q¹-X²The pyrrolidinyl group in (a) is substituted on the ring nitrogen atom with a substituent selected from the group consisting of: methyl, ethyl, isopropyl, isobutyl, cyclopropylmethyl, methylsulfonyl, ethylsulfonyl,N-methylcarbamoyl group,N-ethylcarbamoyl radical,N-isopropylcarbamoyl group,N-cyclopropylmethylcarbamoyl group,N，N-dimethylcarbamoyl radical,N，N-a diethylcarbamoyl group,N-methyl-N-ethylcarbamoyl, acetyl, propionyl, isobutyryl,N-methylsulfamoyl,N-an ethylsulfamoyl group,N-an isopropylaminosulfonyl group,N-cyclopropylmethylsulfamoyl,N，N-a dimethylsulfamoyl group, N，N-a diethylsulfamoyl group,N-methyl-N-ethylsulfamoyl, carbamoylmethyl,N-methylcarbamoylmethyl, 2-, (N-methylcarbamoyl) ethyl,N-ethylcarbamoylmethyl, 2-, (N-ethylcarbamoyl) ethyl,N，N-dimethylcarbamoylmethyl, 2-, (N，N-dimethylcarbamoyl) ethyl group,N，N-diethylcarbamoylmethyl, 2-, (N，N-diethylcarbamoyl) ethyl, N-methylaminoacetyl, N-ethylaminoacetyl, 2- (N-amino) propionyl, 2- (N-ethylamino) propionyl,N，NDimethylaminoacetyl, 2-, (N，N-dimethylamino) propanoyl,N，NDiethylaminoacetyl, 2-, (N，N-diethylamino) propionyl group,N-methyl-N-ethylaminoacetyl, 2-, (N-methyl-N-ethylamino) propionyl group, acetoxyacetyl group, 2- (acetoxy) propionyl group, 2-, (ii) acetyl groupN-methylamino) ethanesulfonyl group, 2-, (N-ethylamino) ethanesulfonyl, 2-, (N，N-dimethylamino-ethanesulfonyl group, 2-, (N，N-diethylamino) ethanesulfonyl group,3-(N-methylamino) propanesulfonyl, 3-, (N-ethylamino) propanesulfonyl, 3-, (N，N-dimethylamino-propanesulfonyl group, 3-, (N，N-diethylamino) propanesulfonyl, pyrrolidin-1-ylacetyl, 2- (pyrrolidin-1-yl) propionyl, 3, 4-methylenedioxypyrrolidin-1-ylacetyl, 2- (3, 4-methylenedioxypyrrolidin-1-yl) propionyl, piperidinoacetyl, 2-piperidinopropionyl, piperazin-1-ylacetyl, 2-piperazin-1-ylpropionyl and groups of the formula:

Q²-X³-

Wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino and piperazin-1-yl,

wherein Q¹In the substituent(s) or by Q²Any of the pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino or piperazin-1-yl groups represented optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, oxo, methyl, ethyl, acetyl and fluoro,

wherein Q¹Any of the acetyl, propionyl or isobutyryl groups on the substituents optionally bear 1 or 2 substituents which may be the same or different and are selected from hydroxy and methyl,

wherein Q¹Any (1-4C) alkyl group in the substituents optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, methoxy, fluoro, chloro;

(xx)Q¹-X²selected from: pyrrolidin-2-ylmethyl, (2R) -pyrrolidin-2-ylmethyl, (2S) -pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, (3R) -pyrrolidin-3-ylmethyl, (3S) -pyrrolidin-3-ylmethyl, wherein Q¹-X²Wherein pyrrolidinyl is substituted on the ring nitrogen with a substituent selected from morpholinoacetyl and 2-morpholinopropionyl, optionally bearing 1 or 2 substituents which may be the same or different selected from hydroxy, oxo, methyl, ethyl and fluoro;

(yy)Q¹-X²Selected from: pyrrolidin-3-yl, (3R) -pyrrolidin-3-yl, (3S) -pyrrolidin-3-yl, piperidin-3-yl, (3R) -piperidin-3-yl, (3S) -piperidin-3-yl, and piperidin-4-yl, wherein Q¹-X²Wherein pyrrolidinyl or piperidinyl is optionally substituted on the ring nitrogen atom with a substituent selected from: methyl, ethyl, isopropyl, isobutyl, cyclopropylmethyl, methylsulfonyl, ethylsulfonyl, acetyl, propionyl, isobutyryl, carbamoylmethyl,N-methylcarbamoylmethyl, 2-, (N-methylcarbamoyl) ethyl,N-ethylcarbamoylmethyl, 2-, (N-ethylcarbamoyl) ethyl,N，N-dimethylcarbamoylmethyl, 2-, (N，N-dimethylcarbamoyl) ethyl group,N，N-diethylcarbamoylmethyl, 2-, (N，N-diethylcarbamoyl) ethyl, N-methylaminoacetyl, N-ethylaminoacetyl, 2- (N-methylamino) propionyl, 2- (N-ethylamino) propionyl,N，NDimethylaminoacetyl, 2-, (N，N-dimethylamino) propanoyl,N，NDiethylaminoacetyl, 2-, (N，N-diethylamino) propionyl group,N-methyl-N-ethylaminoacetyl, 2-, (N-methyl-N-ethylamino) propionyl group, acetoxyacetyl group, 2- (acetoxy) propionyl group, 2-, (ii) acetyl groupN-methylamino) ethanesulfonyl group, 2-, ( N-ethylamino) ethanesulfonyl, 2-, (N，N-dimethylamino-ethanesulfonyl group, 2-, (N，N-diethylamino-ethanesulfonyl group, 3-, (N-methylamino) propanesulfonyl, 3-, (N-ethylamino) propanesulfonyl, 3-, (N，N-dimethylamino-propanesulfonyl group, 3-, (N，N-diethylamino) propanesulfonyl, pyrrolidin-1-ylacetyl, 2- (pyrrolidin-1-yl) propionyl, 3, 4-methylenedioxypyrrolidin-1-ylacetyl, 2- (3, 4-methylenedioxypyrrolidin-1-yl) propionyl, piperidinoacetyl, 2-piperidinopropionyl, morpholinoacetyl, 2-morpholinopropionyl, piperazin-1-ylacetyl, 2-piperazin-1-ylpropionyl and a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from morpholino, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino and piperazin-1-yl,

wherein Q¹In the substituent(s) or by Q²Any of the pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino or piperazin-1-yl groups represented optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, oxo, methyl, ethyl, acetyl and fluoro,

wherein Q¹Any of the acetyl, propionyl or isobutyryl groups on the substituents optionally bear 1 or 2 substituents which may be the same or different and are selected from hydroxy and methyl,

Wherein Q¹Any (1-4C) alkyl group in the substituents optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, methoxy, fluoro, chloro;

(zz)Q¹-X²selected from: pyrrolidin-3-yl, (3R) -pyrrolidin-3-yl, (3S) -pyrrolidin-3-yl, wherein Q¹-X²The pyrrolidinyl group in (a) is substituted on the ring nitrogen atom with a substituent selected from the group consisting of: methyl, ethyl, isopropyl, isobutyl, cyclopropylmethyl, methylsulfonyl, ethylsulfonyl, acetyl, propionyl, isobutyryl, carbamoylmethyl,N-methylcarbamoylmethyl, 2-, (N-methylcarbamoyl) ethyl,N-ethylcarbamoylmethyl, 2-, (N-ethylcarbamoyl) ethyl,N，N-dimethylcarbamoylmethyl, 2-, (N，N-dimethylcarbamoyl) ethyl, N-diethylcarbamoylmethyl, 2- (d-ethylcarbamoylmethyl) ethylN，N-diethylcarbamoyl) ethyl, N-methylaminoacetyl, N-ethylaminoacetyl, 2- (N-methylamino) propionyl, 2- (N-ethylamino) propionyl,N，NDimethylaminoacetyl, 2-, (N，N-dimethylamino) propanoyl,N，NDiethylaminoacetyl, 2-, (N，N-diethylamino) propionyl group,N-methyl-N-ethylaminoacetyl, 2-, (N-methyl-N-ethylamino) propionyl group, acetoxyacetyl group, 2- (acetoxy) propionyl group, 2-, (ii) acetyl group N-methylamino) ethanesulfonyl group, 2-, (N-ethylamino) ethanesulfonyl, 2-, (N，N-dimethylamino-ethanesulfonyl group, 2-, (N，N-diethylamino-ethanesulfonyl group, 3-, (N-methylamino) propanesulfonyl, 3-, (N-ethylamino) propanesulfonyl, 3-, (N，N-dimethylamino-propanesulfonyl group, 3-, (N，N-diethylamino) propanesulfonyl, pyrrolidin-1-ylacetyl, 2- (pyrrolidin-1-yl) propionyl, 3, 4-methylenedioxypyrrolidin-1-ylacetyl, 2- (3, 4-methylenedioxypyrrolidin-1-yl) propionyl, piperidinoacetyl, 2-piperidinopropionyl, morpholinoacetyl, 2-morpholinopropionyl, piperazin-1-ylacetyl, 2-piperazin-1-ylpropionyl and a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from morpholino, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino and piperazin-1-yl,

wherein Q¹In the substituent(s) or by Q²Any of the pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino or piperazin-1-yl groups represented optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, oxo, methyl, ethyl, acetyl and fluoro,

wherein Q¹Any of the acetyl, propionyl or isobutyryl groups on the substituents optionally bear 1 or 2 substituents which may be the same or different and are selected from hydroxy and methyl,

Wherein Q¹Any (1-4C) alkyl group in the substituents optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, methoxy, fluoro, chloro;

(aaa)Q¹-X²selected from: piperidin-3-yl, (3R) -piperidin-3-yl, (3S) -piperidin-3-yl, and piperidin-4-yl, wherein Q¹-X²The piperidinyl group in (a) is substituted on the ring nitrogen atom with a substituent selected from: methyl, ethyl, isopropyl, isobutyl, cyclopropylmethyl, methylsulfonyl, ethylsulfonyl, acetyl, propionyl, isobutyryl, carbamoylmethyl,N-methylcarbamoylmethyl, 2-, (N-methylcarbamoyl) ethyl,N-ethylcarbamoylmethyl, 2-, (N-ethylcarbamoyl) ethyl,N，N-dimethylcarbamoylmethyl, 2-, (N，N-dimethylcarbamoyl) ethyl group,N，N-diethylcarbamoylmethyl, 2-, (N，N-diethylcarbamoyl) ethyl, N-methylaminoacetyl, N-ethylaminoacetyl, 2- (N-methylamino) propionyl, 2- (N-ethylamino) propionyl,N，NDimethylaminoacetyl, 2-, (N，N-dimethylamino) propanoyl,N，NDiethylaminoacetyl, 2-, (N，N-diethylamino) propionyl group,N-methyl-N-ethylaminoacetyl, 2-, (N-methyl-N-ethylamino) propionyl group, acetoxyacetyl group, 2- (acetoxy) propionyl group, 2-, (ii) acetyl group N-methylamino) ethanesulfonyl group, 2-, (N-ethylamino) ethanesulfonyl, 2-, (N，N-dimethylamino-ethanesulfonyl group, 2-, (N，N-diethylamino-ethanesulfonyl group, 3-, (N-methylamino) propanesulfonyl, 3-, (N-ethylamino) propanesulfonyl, 3-, (N，N-dimethylamino-propanesulfonyl group, 3-, (N，N-diethylamino) propanesulfonyl, pyrrolidin-1-ylacetyl, 2- (pyrrolidin-1-yl) propionyl, 3, 4-methylenedioxypyrrolidin-1-ylacetyl, 2- (3, 4-methylenedioxypyrrolidin-1-yl) propionyl, piperidinoacetyl, 2-piperidinopropionyl, morpholinoacetyl, 2-morpholinopropionyl, piperazin-1-ylacetyl, 2-piperazin-1-ylpropionyl and a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from morpholino, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino and piperazin-1-yl,

wherein Q¹In the substituent(s) or by Q²Any of the pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino or piperazin-1-yl groups represented optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, oxo, methyl, ethyl, acetyl, fluoro and chloro,

wherein Q¹Any of the acetyl, propionyl or isobutyryl groups on the substituents optionally bear 1 or 2 substituents which may be the same or different and are selected from hydroxy and methyl,

Wherein Q¹Any (1-4C) alkyl group in the substituents optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, methoxy, fluoro, chloro;

(bbb)Q¹-X²selected from: pyrrolidin-3-yl, (3R) -pyrrolidin-3-yl, (3S) -pyrrolidin-3-yl, piperidin-3-yl, (3R) -piperidin-3-yl, (3S) -piperidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl, (2R) -pyrrolidin-2-ylmethyl, (2S) -pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, (3R) -pyrrolidin-3-ylmethyl, (3S) -pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl, (2R) -piperidin-2-ylmethyl, (2S) -piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-2-ylmethyl, di-tert-butylamino-ylmethyl, di-tert-butylamino-ylmethyl, and their use, Piperidin-3-ylmethyl, (3R) -piperidin-3-ylmethyl, (3S) -piperidin-3-ylmethyl, and piperidin-4-ylmethyl;

(ccc)Q¹-X²selected from: pyrrolidin-3-yl, (3R) -pyrrolidin-3-yl, and (3S) -pyrrolidin-3-yl;

(ddd)Q¹-X²selected from: piperidin-3-yl, (3R) -piperidin-3-yl, (3S) -piperidin-3-yl, and piperidin-4-yl;

(eee)Q¹-X²selected from: pyrrolidin-3-yl, (3R) -pyrrolidin-3-yl, (3S) -pyrrolidin-3-yl, piperidin-3-yl, (3R) -piperidin-3-yl, (3S) -piperidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl, (2R) -pyrrolidin-2-ylmethyl, (2S) -pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, (3R) -pyrrolidin-3-ylmethyl, (3S) -pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl, (2R) -piperidin-2-ylmethyl -ylmethyl, (2S) -piperidin-2-ylmethyl, piperidin-3-ylmethyl, (3R) -piperidin-3-ylmethyl, (3S) -piperidin-3-ylmethyl and piperidin-4-ylmethyl,

wherein Q¹-X²Wherein pyrrolidinyl or piperidinyl is optionally substituted on the ring nitrogen atom with a substituent selected from:N-methylcarbamoyl group,N-ethylcarbamoyl radical,N-isopropylcarbamoyl group,N-cyclopropylmethylcarbamoyl group,N，N-dimethylcarbamoyl radical,N，N-a diethylcarbamoyl group,N-methyl-N-ethylcarbamoyl radical,N-methylsulfamoyl,N-an ethylsulfamoyl group,N-an isopropylaminosulfonyl group,N-cyclopropylmethylsulfamoyl,N，N-a dimethylsulfamoyl group,N，N-a diethylsulfamoyl group,N-methyl-N-ethylsulfamoyl, carbamoylmethyl,N-methylcarbamoylmethyl, 2-, (N-methylcarbamoyl) ethyl,N-ethylcarbamoylmethyl, 2-, (N-ethylcarbamoyl) ethyl,N，N-dimethylcarbamoylmethyl, 2-, (N，N-dimethylcarbamoyl) ethyl group,N，N-diethylcarbamoylmethyl, 2-, (N，N-diethylcarbamoyl) ethyl, N-methylaminoacetyl, N-ethylaminoacetyl, 2- (N-methylamino) propionyl, 2- (N-ethylamino) propionyl, N，NDimethylaminoacetyl, 2-, (N，N-dimethylamino) propanoyl,N，NDiethylaminoacetyl, 2-, (N，N-diethylamino) propionyl group,N-methyl-N-ethylaminoacetyl, 2-, (N-methyl-N-ethylamino) propionyl group, acetoxyacetyl group, 2- (acetoxy) propionyl group, 2-, (ii) acetyl groupN-methylamino) ethanesulfonyl group, 2-, (N-ethylamino) ethanesulfonyl, 2-, (N，N-dimethylamino-ethanesulfonyl group, 2-, (N，N-diethylamino-ethanesulfonyl group, 3-, (N-methylamino) propanesulfonyl, 3-, (N-ethylamino) propanesulfonyl, 3-, (N，N-dimethylamino-propanesulfonyl group, 3-, (N，N-diethyl radicalAmino) propanesulfonyl, pyrrolidin-1-ylacetyl, 2- (pyrrolidin-1-yl) propionyl, 3, 4-methylenedioxypyrrolidin-1-ylacetyl, 2- (3, 4-methylenedioxypyrrolidin-1-yl) propionyl, piperidinoacetyl, 2-piperidinopropionyl, piperazin-1-ylacetyl, 2-piperazin-1-ylpropionyl and groups of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino and piperazin-1-yl,

wherein Q¹In the substituent(s) or by Q²Any of the pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino or piperazin-1-yl groups represented optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, oxo, methyl, ethyl, acetyl, fluoro and chloro,

Wherein Q¹Any (1-4C) alkyl group in the substituents optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, methoxy, fluoro, chloro;

(fff)Q¹-X²selected from: pyrrolidin-3-yl, (3R) -pyrrolidin-3-yl, (3S) -pyrrolidin-3-yl, piperidin-3-yl, (3R) -piperidin-3-yl, (3S) -piperidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl, (2R) -pyrrolidin-2-ylmethyl, (2S) -pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, (3R) -pyrrolidin-3-ylmethyl, (3S) -pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl, (2R) -piperidin-2-ylmethyl, (2S) -piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-2-ylmethyl, di-tert-butylamino-ylmethyl, di-tert-butylamino-ylmethyl, and their use, Piperidin-3-ylmethyl, (3R) -piperidin-3-ylmethyl, (3S) -piperidin-3-ylmethyl and piperidin-4-ylmethyl,

wherein Q¹-X²Wherein pyrrolidinyl or piperidinyl is optionally substituted on the ring nitrogen atom with a substituent selected from: pyrrolidin-1-ylacetyl, 2- (pyrrolidin-1-yl) propionyl, 3, 4-methylenedioxypyrrolidin-1-ylacetyl, 2- (3, 4-methylenedioxypyrrolidin-1-yl) propionyl, piperidinoacetyl, 2-piperidinopropionyl, piperidinopropio,Piperazin-1-ylacetyl and 2-piperazin-1-ylpropanoyl,

wherein Q¹Any of the pyrrolidin-1-yl, piperidino or piperazin-1-yl groups on which optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, oxo, methyl, ethyl, acetyl and fluoro,

Wherein Q¹Any of the acetyl, propionyl or isobutyryl groups on the substituents optionally bear 1 or 2 substituents which may be the same or different and are selected from hydroxy and methyl,

wherein Q¹Any (1-4C) alkyl group in the substituents optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, methoxy, fluoro, chloro;

(ggg)Q¹-X²selected from: pyrrolidin-3-yl, (3R) -pyrrolidin-3-yl, (3S) -pyrrolidin-3-yl, piperidin-3-yl, (3R) -piperidin-3-yl, (3S) -piperidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl, (2R) -pyrrolidin-2-ylmethyl, (2S) -pyrrolidin-2-ylmethyl and piperidin-4-ylmethyl, wherein Q¹-X²Wherein pyrrolidinyl or piperidinyl is optionally substituted on the ring nitrogen atom with a substituent selected from: methyl, acetyl, carbamoylmethyl,N-methylaminoacetyl group,N，NDimethylaminoacetyl, 3-, (N，N-dimethylamino) propanesulfonyl and pyrrolidin-1-ylacetyl,

wherein Q¹Any of the pyrrolidin-1-yl groups on (a) optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, oxo, methyl, ethyl, acetyl and fluoro,

wherein Q¹Any (1-4C) alkyl group in the substituents optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, methoxy, fluoro, chloro,

Wherein Q¹Any acetyl group in the substituents above optionally bears a hydroxyl substituent;

(hhh)Q¹-X²selected from: pyrrolidin-3-yl, (3R) -pyrrolidin-3-yl, (3S) -pyrrolidin-3-yl, piperidin-3-yl, (3R) -piperidin-3-yl, (3S) -piperidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl, (2R) -pyrrolidin-2-ylmethyl, (2S) -pyrrolidin-2-ylmethyl and piperidin-4-ylmethyl, wherein Q¹-X²Wherein pyrrolidinyl or piperidinyl is optionally substituted on the ring nitrogen atom with a substituent selected from: methyl, acetyl, hydroxyacetyl, carbamoylmethyl,N-methylaminoacetyl group,N，N-dimethylaminoacetyl and pyrrolidin-1-ylacetyl;

(iii)Q¹-X²selected from: piperidin-4-yl, pyrrolidin-2-ylmethyl, (2R) -pyrrolidin-2-ylmethyl and (2S) -pyrrolidin-2-ylmethyl, wherein Q¹-X²Wherein pyrrolidinyl or piperidinyl is optionally substituted on the ring nitrogen atom with a substituent selected from: acetyl, hydroxyacetyl, and,N，N-dimethylaminoacetyl and pyrrolidin-1-ylacetyl;

(jjj)Q¹-X²selected from: pyrrolidin-2-ylmethyl, (2R) -pyrrolidin-2-ylmethyl and (2S) -pyrrolidin-2-ylmethyl, wherein Q¹-X²The pyrrolidinyl group in (a) is substituted on the ring nitrogen atom with a substituent selected from the group consisting of:N-methylaminoacetyl group, N，N-dimethylaminoacetyl and pyrrolidin-1-ylacetyl;

(kkk)Q¹-X²is a group of formula A:

wherein:

R⁴selected from the group consisting of carbamoyl,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl and a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Is a heterocyclic group selected from 4-, 5-or 6-membered monocyclic heterocyclic group containing 1 nitrogen heteroatom and optionally containing 1 or 2 heteroatoms selected from sulfur, oxygen and nitrogen,

wherein Q²Through the ring nitrogen atom with X³The connection is carried out by connecting the two parts,

wherein Q²Optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from: halo, hydroxy, (1-4C) alkyl and (2-4C) alkanoyl,

wherein R is⁴Any (1-6C) alkyl or (2-6C) alkanoyl group in (a) optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo, hydroxy and (1-6C) alkyl and/or optionally bearing a substituent selected from: cyano, nitro, (2-8C) alkenyl, (2-8C) alkynyl and (1-6C) alkoxy,

R⁵selected from hydrogen, (1-6C) alkyl, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (2-6C) alkanoyl, carbamoyl (1-6C) alkyl,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl ]Carbamoyl (1-6C) alkyl, sulfamoyl (1-6C) alkyl,N- (1-6C) alkylsulfamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl (1-6C) alkyl and (2-6C) alkanoyl (1-6C) alkyl,

wherein R is⁵Any (1-6C) alkyl or (2-6C) alkanoyl group in (a) optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo, hydroxy and (1-6C) alkyl and/or optionally bearing a substituent selected from: cyano, nitro, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy and NR^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl, and wherein R^aOr R^bAny (1-4C) alkyl group in (b) optionally carries one or more (e.g., 1,2 or 3) may be the same or different and are selected from the group consisting of halogeno and hydroxy and/or optionally bear substituents selected from the group consisting of cyano, nitro and (1-4C) alkoxy,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached, form a 4-, 5-or 6-membered ring which optionally bears on available ring carbon atoms 1 or 2 substituents which may be the same or different selected from halo, hydroxy, (1-4C) alkyl and (1-3C) alkylenedioxy, and which optionally bears on any available ring nitrogen atom a substituent selected from (1-4C) alkyl and (2-4C) alkanoyl (provided that the ring is not therefore quaternized),

Wherein as a substituent is present in^aAnd R^bAny (1-4C) alkyl or (2-4C) alkanoyl group on the ring formed together with the nitrogen atom to which they are attached optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo and hydroxy and/or optionally bearing substituents selected from (1-4C) alkyl and (1-4C) alkoxy,

and wherein Q¹-X²Any heterocyclyl group in (a) optionally bearing 1 or 2 substituents of oxo (═ O) or thioxo (═ S);

(lll)Q¹-X²is a group of formula a as defined above in (kkk), wherein:

R⁴selected from the group consisting of carbamoyl,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl and a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, morpholino, piperidino and piperazin-1-yl,

wherein Q²Optionally bearing 1 or 2 substituents which may be the same or different selected from: halo, hydroxy, (1-4C) alkyl, oxo, and (2-4C) alkanoyl,

wherein R is⁴Any (1-6C) alkyl or (2-6C) alkanoyl group in (a) optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo, hydroxy and (1-6C) alkyl and/or optionally bearing a substituent selected from: cyano, nitro, (2-8C) alkenyl, (2-8C) alkynyl and (1-6C) alkoxy,

R⁵Selected from hydrogen, (1-6C) alkyl, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (2-6C) alkanoyl, carbamoyl (1-6C) alkyl,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, sulfamoyl (1-6C) alkyl,N- (1-6C) alkylsulfamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl (1-6C) alkyl and (2-6C) alkanoyl (1-6C) alkyl,

wherein R is⁵Any (1-6C) alkyl or (2-6C) alkanoyl group in (a) optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo, hydroxy and (1-6C) alkyl and/or optionally bearing a substituent selected from: cyano, nitro, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy and NR^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl, and wherein R^aOr R^bAny (1-4C) alkyl group in (b) optionally bears one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo and hydroxy and/or optionally bears substituents selected from cyano, nitro and (1-4C) alkoxy,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached form a ring selected from: pyrrolidin-1-yl, piperidino, morpholino, and piperazin-1-yl, which rings optionally bear 1 or 2 substituents, which may be the same or different, on available ring carbon atoms selected from halo, hydroxy, (1-4C) alkyl, and oxo, and optionally bear substituents selected from (1-4C) alkyl and (2-4C) alkanoyl on any available ring nitrogen atom (provided that the ring is not therefore quaternised),

Wherein doIs a substituent present in the group R^aAnd R^bAny (1-4C) alkyl or (2-4C) alkanoyl group on the ring formed together with the nitrogen atom to which they are attached optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo and hydroxy and/or optionally bearing substituents selected from (1-4C) alkyl and (1-4C) alkoxy;

(mmm)Q¹-X²is a group of formula a as defined above (kkk), wherein:

R⁴selected from the group consisting of carbamoyl,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl and a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, morpholino, piperidino and piperazin-1-yl,

wherein Q²Optionally bearing 1 or 2 substituents which may be the same or different selected from: fluoro, chloro, hydroxy, methyl, oxo and acetyl,

wherein R is⁴Any (1-6C) alkyl group(s) in (a) optionally bears one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from fluoro, chloro and hydroxy and/or optionally bears one substituent selected from: cyano, nitro, vinyl, ethynyl and methoxy,

R⁵selected from hydrogen, (1-4C) alkyl, (1-4C) alkylthio, (1-4C) alkylsulfinyl, (1-4C) alkylsulfonyl, (2-4C) alkanoyl, carbamoyl (1-4C) alkyl, N- (1-4C) alkylcarbamoyl (1-4C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-4C) alkyl, sulfamoyl (1-4C) alkyl,N- (1-4C) alkylsulfamoyl (1-4C) alkyl,N，NDi- [ (1-4C) alkyl]Sulfamoyl (1-4C) alkyl and (2-4C) alkanoyl (1-4C) alkyl,

wherein R is⁵Any of (1-4C) alkyl or (2-4C) alkane of (1-4C)The acyl group optionally bears one or more (e.g. 1, 2 or 3) substituents which may be the same or different, selected from fluorine, chlorine, hydroxy, methyl and ethyl and/or optionally bears one substituent selected from: cyano, nitro, ethenyl, ethynyl, methoxy and NR^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl, and wherein R^aOr R^bAny (1-4C) alkyl group in (b) optionally bears one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from fluoro, chloro and hydroxy and/or optionally bears one substituent selected from cyano, nitro and methoxy,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached form a ring selected from: pyrrolidin-1-yl, piperidino, morpholino, and piperazin-1-yl, the rings optionally bearing 1 or 2 substituents, which may be the same or different, on available ring carbon atoms selected from halo, hydroxy, methyl, ethyl, and oxo, and optionally bearing substituents on any available ring nitrogen atoms selected from methyl, ethyl, and acetyl (provided that the ring is not therefore quaternized);

(nnn)Q¹-X²Is a group of formula a as defined above (kkk), wherein:

R⁴selected from the group consisting of carbamoyl,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl and a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, morpholino, piperidino and piperazin-1-yl,

wherein Q²Optionally bearing 1 or 2 substituents which may be the same or different selected from: fluoro, chloro, hydroxy, methyl, oxo and acetyl,

wherein R is⁴Any (1-4C) alkyl group in (A) optionally has 1 or 2 groups which may be the same or differentAnd/or optionally bears a substituent selected from the group consisting of fluoro, chloro and hydroxy: cyano, nitro, vinyl, ethynyl and methoxy,

R⁵selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, isobutyl, cyclopropylmethyl, methylsulfonyl, ethylsulfonyl, acetyl, propionyl, isobutyryl, carbamoylmethyl,N- (1-4C) alkylcarbamoylmethyl,N，NDi- [ (1-4C) alkyl]Carbamoylmethyl, sulfamoylmethyl,N- (1-4C) alkylsulfamoylmethyl andN，Ndi- [ (1-4C) alkyl]A sulfamoyl methyl group, a salt thereof,

wherein R is⁵Any of (1-4C) alkyl, acetyl, propionyl or isobutyryl optionally bears 1 or 2 substituents which may be the same or different selected from fluoro, chloro and hydroxy, methyl and ethyl and/or optionally bears one substituent selected from: cyano, nitro, ethenyl, ethynyl, methoxy and NR ^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, R^bIs hydrogen or (1-4C) alkyl, and wherein R^aOr R^bAny of the (1-4C) alkyl groups in (A) optionally bears 1 or 2 substituents which may be the same or different, selected from fluoro, chloro and hydroxy and/or optionally bears one substituent selected from cyano, nitro and methoxy,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached form a ring selected from: pyrrolidin-1-yl, piperidino, morpholino, and piperazin-1-yl, the rings optionally bearing 1 or 2 substituents, which may be the same or different, on available ring carbon atoms selected from halo, hydroxy, methyl, and oxo, and optionally bearing substituents on any available ring nitrogen atoms selected from methyl and acetyl (provided that the ring is not therefore quaternized);

(ooo)Q¹-X²is a group of formula a as defined above (kkk), wherein:

R⁴is selected fromN，N-bis- [ (1-4C)) Alkyl radical]Carbamoyl and a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, morpholino and piperidino,

wherein Q²Optionally bearing 1 or 2 substituents which may be the same or different selected from: fluoro, chloro, hydroxy, methyl and oxo,

wherein R is⁴Any of the (1-4C) alkyl groups in (A) optionally bears 1 or 2 substituents which may be the same or different selected from fluoro, chloro and hydroxy and/or optionally bears a substituent selected from methoxy,

R⁵Selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, isobutyl and cyclopropylmethyl,

wherein R is⁵Any (1-4C) alkyl group in (A) optionally bears 1 or 2 substituents which may be the same or different selected from fluoro, chloro and hydroxy and/or optionally bears a substituent selected from methoxy;

(ppp)Q¹-X²is a group of formula a as defined above (kkk), wherein:

R⁴is selected fromN，N-dimethylcarbamoyl radical,N，N-a diethylcarbamoyl group,N-methyl-N-ethylcarbamoyl and a group of formula:

Q²-X³-

wherein X³Is CO, Q²Is morpholino (preferably R)⁴Is thatN，N-dimethylcarbamoyl group),

R⁵selected from hydrogen, methyl and ethyl (preferably R)⁵Hydrogen or methyl, more preferably methyl);

(qqq)R¹-X¹selected from hydrogen, (1-6C) alkoxy and (1-4C) alkoxy (1-6C) alkoxy,wherein R is¹X¹Any (1-6C) alkoxy group in (A) optionally bears 1, 2 or 3 substituents which may be the same or different, selected from hydroxy, fluoro and chloro, e.g. R¹-X¹Selected from methoxy, ethoxy, isopropoxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2, 2-difluoroethoxy, 2, 2, 2-trifluoroethoxy or 3-hydroxy-3-methylbutoxy.

It is understood that the group represented by formula A in the above paragraphs (kkk) - (ppp) contains 2 chiral centers on the pyrrolidinyl ring. As mentioned above, the present invention encompasses all stereoisomers of the group of formula A, such as the (2R, 4R), (2S, 4S), (2R, 4S) and (2S, 4R) isomers.

Another embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹-X¹selected from the group consisting of hydrogen, (1-6C) alkoxy and (1-6C) alkoxy, wherein R¹X¹Any (1-6C) alkoxy group in (a) optionally bears one or more hydroxyl substituents (suitably one or more) and/or substituents selected from: amino, (1-4C) alkylamino, di- [ (1-4C) alkyl]Amino, carbamoyl, amino-and amino-substituted amino acids,N- (1-4C) alkylcarbamoyl andN，Ndi- [ (1-4C) alkyl]Carbamoyl, sulfamoyl, amino-sulfonyl,N- (1-4C) alkylsulfamoyl andN，Ndi- [ (1-4C) alkyl]A sulfamoyl group;

X²is a direct bond or [ CR²R³]_mWherein m is 1, 2 or 3 (especially 1 or 2, more preferably 1), R²And R³Each independently hydrogen, methyl, ethyl or hydroxy (preferably hydrogen);

Q¹a 3-7 membered monocyclic non-aromatic saturated or partially saturated heterocycle containing one nitrogen heteroatom and optionally containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, which ring is linked to the group X via a carbon atom of the ring²-an O-linkage to the substrate,

wherein Q¹The nitrogen atom of any NH group in (a) optionally bears a substituent selected from: cyano, carbamoyl, trifluoromethyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkoxycarbonyl, N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, sulfamoyl,N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl, hydroxy (1-6C) alkyl, cyano (1-6C) alkyl, amino (1-6C) alkyl, (1-6C) alkylamino (1-6C) alkyl, di- [ (1-6C) alkyl]Amino (1-6C) alkyl, amino (2-6C) alkanoyl, (1-6C) alkylamino- (2-6C) alkanoyl,N，NDi- [ (1-6C) alkyl]Amino- (2-6C) alkanoyl, (1-6C) alkoxy (1-6C) alkyl, hydroxy (1-6C) alkoxy (1-6C) alkyl, sulfamoyl (1-6C) alkyl,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, (2-6C) alkanoyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl,N- (1-6C) alkyl- (2-6C) alkanoylamino (1-6C) alkyl, (1-6C) alkoxycarbonyl (1-6C) alkyl, (1-6C) alkoxy (1-6C) alkyl S (O)_q(wherein q is 0, 1 or 2), amino (1-6C) alkyl S (O)_q(wherein q is 0, 1 or 2),N- (1-6C) alkylamino (1-6C) alkyls (O)_q(wherein q is 0, 1 or 2) andN，Ndi- [ (1-6C) alkyl]Amino (1-6C) alkyl S (O)_q(wherein q is 0, 1 or 2),

Q¹optionally bearing 1 or 2 substituents on any available carbon atom of the ring selected from: (1-4C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl and oxo,

And wherein Q¹Any of (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkanoyl in (a) optionally bears 1 or 2 substituents which may be the same or different selected from fluoro and chloro;

G¹and G²Each independently selected from fluoro, chloro and bromo (preferably G)¹Is fluoro and G²Is a chloro group).

Another embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹-X¹selected from the group consisting of hydrogen, methoxy, ethoxy and 2-methoxyethoxy;

X²is a direct bond or [ CH₂]_mWherein m is 1 or 2 (suitably 1);

Q¹a non-aromatic saturated 5-or 6-membered monocyclic heterocyclic ring containing one nitrogen heteroatom and optionally containing 1 or 2 (suitably 1) heteroatoms selected from oxygen and nitrogen, which ring is linked to the group X via a ring-bound carbon atom²-an O-linkage to the substrate,

wherein Q¹The nitrogen atom of any NH group in (a) optionally bears a substituent selected from: cyano, carbamoyl, (1-4C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-4C) alkylsulfonyl,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl, (2-4C) alkanoyl, sulfamoyl,N- (1-4C) alkylsulfamoyl,N，NDi- [ (1-4C) alkyl]Sulfamoyl, cyano (1-4C) alkyl, (1-4C) alkoxy (1-4C) alkyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl, sulfamoyl, cyano (1-4C) alkyl, sulfamoyl, amino (1-4C) alkanoyl, sulfamoyl, amino (1-4C) alkyl, amino (1, N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, carbamoyl (1-3C) alkyl,N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, (1-4C) alkoxy (1-3C) alkyl S (O)_q(wherein q is 0, 1 or suitably 2), amino (1-3C) alkyl S (O)_q(wherein q is 0, 1 or suitably 2),N- (1-4C) alkylamino (1-3C) alkyls (O)_q(wherein q is 0, 1 or suitably 2) andN，Ndi- [ (1-4C) alkyl]Amino (1-3C) alkyl S (O)_q(wherein q is 0, 1 or suitably 2),

Q¹optionally with 1 or 2 substitutions selected fromBase: oxo, (1-4C) alkyl, (2-6C) alkenyl, and (2-6C) alkynyl,

and wherein Q¹Any of (1-4C) alkyl, (2-6C) alkenyl or (2-6C) alkynyl optionally bearing 1 or 2 substituents which may be the same or different selected from fluoro and chloro; and

G¹and G²Each independently selected from fluoro, chloro and bromo (preferably G)¹Is fluoro and G²Is a chloro group).

Another embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹-X¹selected from the group consisting of hydrogen, methoxy, ethoxy and 2-methoxyethoxy;

X²is a direct bond or CH ²；

Q¹Selected from the group consisting of pyrrolidin-2-yl, pyrrolidin-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-3-yl, morpholin-2-yl, morpholin-3-yl, thiomorpholin-2-yl, thiomorpholin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2-, 3-or 4-homopiperidinyl, piperazin-1-yl, 2-oxopiperazin-1-yl, 3-oxopiperazin-1-yl, piperazin-2-yl, 1, 2, 3, 6-tetrahydropyridin-4-yl, 1, 2, 3, 6-tetrahydropyridin-5-yl, 1, 2, 3, 4-tetrahydropyridin-5-yl, 1, 2, 3, 6-tetrahydropyridin-6-yl, 2, 3, 4, 6 or 7-homopiperazinyl and azetidin-3-yl,

wherein Q¹The nitrogen atom of any NH group in (a) optionally bears a substituent selected from: cyano, (1-4C) alkyl, cyano (1-4C) alkyl, (1-4C) alkoxy (1-4C) alkyl, (1-4C) alkylsulfonyl, trifluoromethyl, carbamoyl,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl, (2-4C) alkanoyl, sulfamoyl,N- (1-4C) alkylsulfamoyl,N，NDi- [ (1-4C) alkyl]Sulfamoyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, carbamoyl (1-3C) alkyl, N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, (1-4C) alkoxy (1-3C) alkylsulfonyl, amino (1-3C) alkylsulfonyl,N- (1-4C) alkylamino (1-3C) alkylsulfonyl andN，Ndi- [ (1-4C) alkyl]Amino (1-3C) alkylsulfonyl, and Q¹Optionally bearing 1 or 2 substituents selected from (1-4C) alkyl and oxo on any available carbon atom of the ring,

and wherein Q¹Any (1-4C) alkyl group in (a) optionally bears 1 or 2 fluoro substituents (examples are given such as 2-fluoroethyl or 2, 2-difluoroethyl); and

G¹and G²Each independently selected from fluoro and chloro (preferably G)¹Is fluoro and G²Is a chloro group).

In this embodiment Q¹X²Suitable values of (D) include, for example, 1-methylpyrrolidin-3-yl, piperidin-4-ylmethyl, 1-methylpiperidin-4-yl, 1-methylpiperidin-4-ylmethyl, 1- (2-methoxyethyl) piperidin-4-yl, 1- (2-methoxyethyl) piperidin-4-ylmethyl, 1-methanesulfonylpiperidin-4-yl, 1-methanesulfonylpiperidin-4-ylmethyl, 1-cyanopiperidin-4-yl, 1-cyanopiperidin-4-ylmethyl, 1-cyanomethylpiperidin-4-yl, 1-cyanomethylpiperidin-4-ylmethyl, 1-carbamoylmethylpiperidin-4-yl, 1-carbamoylmethylpiperidin-4-ylmethyl.

Another embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹-X¹selected from hydrogen and methoxy;

X²is a direct bond;

Q¹selected from pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl,

wherein Q¹The nitrogen atom of any NH group in (a) optionally bears a substituent selected from: cyano, cyanomethyl, methyl, ethyl, carbamoyl, carbamoylmethyl, 2-methoxyethyl, methanesulfonyl and ethanesulfonyl (suitably methanesulfonyl and carbamoylmethyl),

and Q¹Optionally bearing 1 or 2 substituents selected from methyl, ethyl and oxo on any available carbon atom of the ring; and is

G¹And G²Each independently selected from fluoro, chloro and bromo (preferably G)¹Is fluoro and G²Is a chloro group).

In this embodiment Q¹X²Suitable values of (D) include, for example, piperidin-4-yl, 1-methylpiperidin-4-yl, 1- (2-methoxyethyl) piperidin-4-yl, 1-methanesulfonylpiperidin-4-yl, 1-cyanopiperidin-4-yl, 1-cyanomethylpiperidin-4-yl and 1-carbamoylmethylpiperidin-4-yl.

Another embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹-X¹Selected from hydrogen, (1-4C) alkoxy and (1-4C) alkoxy (especially hydrogen and methoxy);

X²is a direct bond or CH₂；

Q¹Is a fully saturated 5-or 6-membered monocyclic heterocyclic ring containing one nitrogen heteroatom and optionally one further heteroatom selected from oxygen, nitrogen and sulfur, which ring is bound via a carbon atom to the ring via the group X²-an O-linkage to the substrate,

wherein Q¹With 1 substituent on a ring carbon atom selected from: a carbamoyl group,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl, carbamoyl (1-3C) alkyl,N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，N-two-[ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, (2-4C) alkanoyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, pyrrolidin-1-yl- (2-4C) alkanoyl, piperidino- (2-4C) alkanoyl, piperazin-1-yl- (2-4C) alkanoyl and morpholino- (2-4C) alkanoyl or a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, morpholino and piperidino,

wherein Q¹The nitrogen atom of any NH group in (a) optionally bears a substituent selected from (1-4C) alkyl,

and wherein Q¹-X²Any heterocyclic group in the group optionally bears an oxo (═ O) substituent; and

G¹And G²Each independently selected from fluoro and chloro (preferably G)¹Is fluoro and G²Is a chloro group).

Another embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹-X¹selected from hydrogen and (1-4C) alkoxy (especially hydrogen and methoxy);

Q¹-X²selected from the group consisting of pyrrolidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl, piperidin-3-ylmethyl and piperidin-4-ylmethyl, wherein Q¹-X²Wherein pyrrolidinyl or piperidinyl bears 1 or 2 substituents selected from: (1-4C) alkyl, (1-4C) alkylsulfonyl,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl, (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]Sulfonyl, alpha-amino acid or alpha-amino acid,N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, hydroxy (2-4C)) Alkanoyl, (2-4C) alkanoyloxy- (2-4C) alkanoyl,N- (1-4C) alkylamino- (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl,N- (1-4C) alkylamino- (1-3C) alkylsulfonyl,N，NDi- [ (1-4C) alkyl]Amino (1-3C) alkylsulfonyl, pyrrolidin-1-yl- (2-4C) alkanoyl, piperidino- (2-4C) alkanoyl, morpholino- (2-4C) alkanoyl or a group of the formula:

Q²-X³-

Wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, morpholino, and piperidino; and is

G¹And G²Each independently selected from fluoro and chloro (preferably G)¹Is fluoro and G²Is a chloro group).

Another embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹-X¹selected from hydrogen and (1-4C) alkoxy (especially methoxy);

Q¹-X²selected from pyrrolidin-3-yl, pyrrolidin-2-ylmethyl and pyrrolidin-3-ylmethyl wherein the pyrrolidinyl group bears 1 substituent at the 5-position selected from the group consisting of:N，Ndi- [ (1-4C) alkyl]Carbamoyl and a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Is morpholino, and

wherein pyrrolidinyl bears 1 substituent selected from (1-4C) alkyl at the 1-position;

G¹is fluoro group; and

G²is a chloro group.

Another embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹-X¹selected from hydrogen and (1-4C) alkoxy (especially methoxy);

Q¹-X²selected from the group consisting of pyrrolidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl, piperidin-3-ylmethyl and piperidin-4-ylmethyl, wherein Q¹-X²Wherein the pyrrolidinyl or piperidinyl group bears a substituent at the 1-position selected from: (1-4C) alkyl, (1-4C) alkylsulfonyl, (2-4C) alkanoyl, hydroxy (2-4C) alkanoyl, N- (1-4C) alkylamino- (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, (2-4C) alkanoyloxy- (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]Amino (1-3C) alkylsulfonyl, pyrrolidin-1-yl- (2-4C) alkanoyl, piperidino- (2-4C) alkanoyl and morpholino- (2-4C) alkanoyl or a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Is morpholino;

G¹is fluoro group; and

G²is a chloro group.

Another embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹-X¹selected from hydrogen, (1-6C) alkoxy and (1-4C) alkoxy (1-6C) alkoxy, wherein R¹X¹Any (1-6C) alkoxy group in (a) optionally bears 1, 2 or 3 substituents which may be the same or different selected from hydroxy, fluoro, chloro (e.g. R)¹-X¹Selected from the group consisting of hydrogen, methoxy, ethoxy, isopropoxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2, 2-difluoroethoxy, 2, 2, 2-trifluoroethoxy or 3-hydroxy-3-methylbutoxy, R¹-X¹Are particularly defined as hydrogen or (1-4C) alkoxyMore particularly (1-4C) alkoxy, such as methoxy); q¹-X²Selected from pyrrolidin-3-yl, (3R) -pyrrolidin-3-yl, (3S) -pyrrolidin-3-yl, piperidin-3-yl, (3R) -piperidin-3-yl, (3S) -piperidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl, (2R) -pyrrolidin-2-ylmethyl, (2S) -pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, (3R) -pyrrolidin-3-ylmethyl, (3S) -pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl, (2R) -piperidin-2-ylmethyl, (2S) -piperidin-2-ylmethyl, piperidin-3-ylmethyl, and combinations thereof, Piperidin-3-ylmethyl, (3R) -piperidin-3-ylmethyl, (3S) -piperidin-3-ylmethyl and piperidin-4-ylmethyl, wherein Q ¹-X²Wherein the pyrrolidinyl or piperidinyl group bears a substituent at the 1-position selected from: (1-4C) alkyl, (1-4C) alkylsulfonyl, (2-4C) alkanoyl, carbamoyl (1-3C) alkyl,N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, hydroxy (2-4C) alkanoyl,N- (1-4C) alkylamino- (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, (2-4C) alkanoyloxy- (2-4C) alkanoyl,N- (1-4C) alkylamino (1-3C) alkylsulfonyl,N，NDi- [ (1-4C) alkyl]Amino (1-3C) alkylsulfonyl, pyrrolidin-1-yl- (2-4C) alkanoyl, 3, 4-methylenedioxypyrrolidin-1-yl- (2-4C) alkanoyl, piperidino- (2-4C) alkanoyl, piperazin-1-yl- (2-4C) alkanoyl or a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from pyrrolidin-2-yl;

wherein Q¹Any of the pyrrolidinyl, piperidino or piperazin-1-yl groups on the substituents optionally bearing 1 or 2 substituents selected from fluoro, chloro, hydroxy, oxo, methyl and acetyl groups,

G¹is fluoro group; and

G²is a chloro group.

Another embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹-X¹selected from hydrogen, (1-6C) alkoxy and (1-4C) alkoxy (1-6C) alkoxy, wherein R ¹X¹Any (1-6C) alkoxy group in (a) optionally bears 1, 2 or 3 substituents which may be the same or different selected from hydroxy, fluoro, chloro (e.g. R)¹-X¹Selected from the group consisting of hydrogen, methoxy, ethoxy, isopropoxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2, 2-difluoroethoxy, 2, 2, 2-trifluoroethoxy or 3-hydroxy-3-methylbutoxy, R¹-X¹Specific meanings of (a) are hydrogen or (1-4C) alkoxy, more especially (1-4C) alkoxy, such as methoxy); q¹-X²Selected from pyrrolidin-3-yl, (3R) -pyrrolidin-3-yl, (3S) -pyrrolidin-3-yl, piperidin-3-yl, (3R) -piperidin-3-yl, (3S) -piperidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl, (2R) -pyrrolidin-2-ylmethyl, (2S) -pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, (3R) -pyrrolidin-3-ylmethyl, (3S) -pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl, (2R) -piperidin-2-ylmethyl, (2S) -piperidin-2-ylmethyl, piperidin-3-ylmethyl, and combinations thereof, Piperidin-3-ylmethyl, (3R) -piperidin-3-ylmethyl, (3S) -piperidin-3-ylmethyl and piperidin-4-ylmethyl, wherein Q¹-X²Wherein the pyrrolidinyl or piperidinyl group bears a substituent selected from morpholino (2-4C) alkanoyl at the 1-position;

G¹is fluoro group; and

G²Is a chloro group.

Another embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹-X¹selected from hydrogen, (1-6C) alkoxy and (1-4C) alkoxy (1-6C) alkoxy, wherein R¹X¹Any (1-6C) alkoxy group in (a) optionally bears 1, 2 or 3 substituents which may be the same or different selected from hydroxy, fluoro, chloro (e.g. R)¹-X¹Selected from hydrogen, methoxy, ethoxy, isopropylOxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2, 2-difluoroethoxy, 2, 2, 2-trifluoroethoxy or 3-hydroxy-3-methylbutoxy, R¹-X¹Specific meanings of (a) are hydrogen or (1-4C) alkoxy, more especially (1-4C) alkoxy, such as methoxy); q¹-X²Is a group of formula A:

wherein:

R⁴selected from the group consisting of carbamoyl,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl and a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Is a heterocyclic group selected from 4-, 5-or 6-membered monocyclic heterocyclic group containing 1 nitrogen heteroatom and optionally containing 1 or 2 heteroatoms selected from sulfur, oxygen and nitrogen,

wherein Q²Through the ring nitrogen atom with X³The connection is carried out by connecting the two parts,

wherein Q²Optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from: halo, hydroxy, (1-4C) alkyl, oxo, and (2-4C) alkanoyl,

Wherein R is⁴Any (1-6C) alkyl or (2-6C) alkanoyl group in (a) optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo, hydroxy and (1-6C) alkyl and/or optionally bearing a substituent selected from: cyano, nitro, (2-8C) alkenyl, (2-8C) alkynyl and (1-6C) alkoxy,

R⁵selected from hydrogen, (1-6C) alkyl, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (2-6C) alkanoyl, ammoniaCarbamoyl (1-6C) alkyl,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, sulfamoyl (1-6C) alkyl,N- (1-6C) alkylsulfamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl (1-6C) alkyl and (2-6C) alkanoyl (1-6C) alkyl,

wherein R is⁵Any (1-6C) alkyl or (2-6C) alkanoyl group in (a) optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo, hydroxy and (1-6C) alkyl and/or optionally bearing a substituent selected from: cyano, nitro, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy and NR^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, R^bIs hydrogen or (1-4C) alkyl, and wherein R ^aOr R^bAny (1-4C) alkyl group in (b) optionally bears one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo and hydroxy and/or optionally bears substituents selected from cyano, nitro and (1-4C) alkoxy,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached, form a 4-, 5-or 6-membered ring which optionally bears on available ring carbon atoms 1 or 2 substituents which may be the same or different selected from halo, hydroxy, (1-4C) alkyl and (1-3C) alkylenedioxy and oxo, and which optionally bears on any available ring nitrogen atom a substituent selected from (1-4C) alkyl and (2-4C) alkanoyl (provided that the ring is not therefore quaternized),

wherein as a substituent is present in^aAnd R^bAny (1-4C) alkyl or (2-4C) alkanoyl group on the ring formed together with the nitrogen atom to which they are attached optionally bearing one or more (e.g. 1, 2 or 3) substituents which may be the same or different selected from halo and hydroxy and/or optionally bearing substituents selected from (1-4C) alkyl and (1-4C) alkoxy,

G¹is fluoro group; and

G²is a chloro group.

Another embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹-X¹Selected from hydrogen, (1-6C) alkoxy and (1-4C) alkoxy (1-6C) alkoxy, wherein R¹X¹Any (1-6C) alkoxy group in (a) optionally bears 1, 2 or 3 substituents which may be the same or different selected from hydroxy, fluoro, chloro (e.g. R)¹-X¹Selected from the group consisting of hydrogen, methoxy, ethoxy, isopropoxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2, 2-difluoroethoxy, 2, 2, 2-trifluoroethoxy or 3-hydroxy-3-methylbutoxy, R¹-X¹Specific meanings of (a) are hydrogen or (1-4C) alkoxy, more especially (1-4C) alkoxy, such as methoxy);

Q¹-X²is a group of formula A:

wherein:

R⁴is selected fromN，NDi- [ (1-4C) alkyl]Carbamoyl and a group of the formula:

Q²-X³-

wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, morpholino and piperidino (e.g. R)⁴Is N, N-dimethylcarbamoyl or morpholinocarbonyl, preferably R⁴Is an N, N-dimethylcarbamoyl group),

wherein Q²Optionally bearing 1 or 2 substituents which may be the same or different selected from: fluoro, chloro, hydroxy, methyl and oxo,

wherein R is⁴Any (1-4C) alkyl group in (1) optionally has 1 or 2 groups which may beIdentical or different substituents from the group consisting of fluoro, chloro and hydroxy and/or optionally bearing substituents from the group consisting of methoxy,

R⁵Selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, isobutyl and cyclopropylmethyl, wherein R is⁵Any of the (1-4C) alkyl groups in (A) optionally bears 1 or 2 substituents which may be the same or different selected from fluoro, chloro and hydroxy and/or optionally bears a substituent selected from methoxy,

G¹is fluoro group; and

G²is a chloro group.

Another embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹-X¹selected from hydrogen, (1-6C) alkoxy and (1-4C) alkoxy (1-6C) alkoxy, wherein R¹X¹Any (1-6C) alkoxy group in (A) optionally bears 1, 2 or 3 substituents which may be the same or different selected from: hydroxy, fluoro, chloro (e.g. R)¹-X¹Selected from the group consisting of hydrogen, methoxy, ethoxy, isopropoxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2, 2-difluoroethoxy, 2, 2, 2-trifluoroethoxy or 3-hydroxy-3-methylbutoxy, R¹-X¹Suitable values of (A) are hydrogen or (1-4C) alkoxy, more especially (1-4C) alkoxy, such as methoxy); q¹-X²Selected from (2S, 4R) -2- (N, N-dimethylcarbamoyl) -1-methylpyrrolidin-4-yl,

(2R, 4S) -2- (N, N-dimethylcarbamoyl) -1-methylpyrrolidin-4-yl,

(2R, 4R) -2- (N, N-dimethylcarbamoyl) -1-methylpyrrolidin-4-yl,

(2S, 4S) -2- (N, N-dimethylcarbamoyl) -1-methylpyrrolidin-4-yl,

(2S, 4R) -2- (N, N-dimethylcarbamoyl) pyrrolidin-4-yl,

(2R, 4S) -2- (N, N-dimethylcarbamoyl) pyrrolidin-4-yl,

(2R, 4R) -2- (N, N-dimethylcarbamoyl) pyrrolidin-4-yl and

(2S, 4S) -2- (N, N-dimethylcarbamoyl) pyrrolidin-4-yl;

G¹is fluoro group; and

G²is a chloro group.

Preferred compounds of the invention are, for example, quinazoline derivatives of the formula I, or pharmaceutically acceptable acid addition salts thereof, selected from:

(1)4- (3-chloro-2-fluoroanilino) -6- { [1- (methylsulfonyl) piperidin-4-yl ] oxy } -7-methoxyquinazoline; and

(2)6- { [1- (carbamoylmethyl) piperidin-4-yl ] oxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline.

Another preferred compound of the invention is, for example, a quinazoline derivative of the formula I, or a pharmaceutically-acceptable acid addition salt thereof, selected from:

(1)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (1-methylpyrrolidin-3-yl) oxy ] quinazoline;

(2)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (piperidin-4-yl) oxy ] quinazoline;

(3)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (piperidin-4-yl) methoxy ] quinazoline;

(4)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (1-methylpiperidin-4-yl) oxy ] quinazoline;

(5)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (1-methylpiperidin-4-yl) methoxy ] quinazoline;

(6)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [2- (1-methylpiperidin-4-yl) ethoxy ] quinazoline;

(7)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (2-methoxyethyl) piperidin-4-yl ] oxy } quinazoline;

(8)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (2-methoxyethyl) piperidin-4-yl ] methoxy } quinazoline;

(9)4- (3-chloro-2-fluoroanilino) -6- { [1- (methylsulfonyl) piperidin-4-yl ] methoxy } -7-methoxyquinazoline;

(10)6- { [1- (carbamoylmethyl) piperidin-4-yl ] methoxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline;

(11)4- (3-chloro-2-fluoroanilino) -6- { [1- (cyanomethyl) piperidin-4-yl ] oxy } -7-methoxyquinazoline;

(12)4- (3-chloro-2-fluoroanilino) -6- { [1- (cyanomethyl) piperidin-4-yl ] methoxy } -7-methoxyquinazoline; and

(13)4- (3-chloro-2-fluoroanilino) -6- [ (1-cyanopiperidin-4-yl) methoxy ] -7-methoxyquinazoline.

Yet another preferred compound of the invention is, for example, a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, selected from:

(1)6- (1-acetylpiperidin-4-yloxy) -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline;

(2)4- (3-chloro-2-fluoroanilino) -6- [1- (N, N-dimethylaminoacetyl) piperidin-4-yloxy ] -7-methoxyquinazoline;

(3)6- [1- (N, N-dimethylsulfamoyl) piperidin-4-yloxy ] -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline;

(4)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [1- (morpholinoacetyl) piperidin-4-yloxy ] quinazoline;

(5)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [1- (pyrrolidin-1-ylacetyl) piperidin-4-yloxy ] quinazoline;

(6)4- (3-chloro-2-fluoroanilino) -6- {1- [3- (dimethylamino) propanesulfonyl ] piperidin-4-yloxy } -7-methoxyquinazoline;

(7)4- (3-chloro-2-fluoroanilino) -6- [1- (methylsulfonyl) piperidin-3-yl ] oxy } -7-methoxyquinazoline;

(8)4- (3-chloro-2-fluoroanilino) -6- [ (3R) -1- (methylsulfonyl) piperidin-3-yloxy ] -7-methoxyquinazoline;

(9)4- (3-chloro-2-fluoroanilino) -6- [ (3S) -1- (methylsulfonyl) piperidin-3-yloxy ] -7-methoxyquinazoline;

(10)6- (1-acetylpiperidin-3-yloxy) -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline;

(11)4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4S) -2- (N, N-dimethylcarbamoyl) pyrrolidin-4-yloxy ] -7-methoxyquinazoline;

(12)4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4S) -2- (N, N-dimethylcarbamoyl) -1-methylpyrrolidin-4-yloxy ] -7-methoxyquinazoline;

(13)4- (3-chloro-2-fluoroanilino) -6- [1- (N, N-dimethylaminoacetyl) piperidin-3-yloxy ] -7-methoxyquinazoline;

(14)4- (3-chloro-2-fluoroanilino) -6- [ (3R) -1- (N, N-dimethylaminoacetyl) piperidin-3-yloxy ] -7-methoxyquinazoline;

(15)4- (3-chloro-2-fluoroanilino) -6- [ (3S) -1- (N, N-dimethylaminoacetyl) piperidin-3-yloxy ] -7-methoxyquinazoline;

(16)4- (3-chloro-2-fluoroanilino) -6- [1- (hydroxyacetyl) piperidin-3-yloxy ] -7-methoxyquinazoline;

(17)6- [1- (acetoxyacetyl) piperidin-3-yloxy ] -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline;

(18)4- (3-chloro-2-fluoroanilino) -6- [ (3R) -1- (methylsulfonyl) pyrrolidin-3-yloxy ] -7-methoxyquinazoline;

(19)4- (3-chloro-2-fluoroanilino) -6- [ (3S) -1- (methylsulfonyl) pyrrolidin-3-yloxy ] -7-methoxyquinazoline;

(20)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1-methanesulfonyl pyrrolidin-2-yl ] methoxy } quinazoline;

(21)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2R) -1-methanesulfonyl pyrrolidin-2-yl ] methoxy } quinazoline;

(22)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (methylsulfonyl) pyrrolidin-3-yl ] methoxy } quinazoline;

(23)4- (3-chloro-2-fluoroanilino) -6- [ (3R) -1-methylpyrrolidin-3-yloxy ] -7-methoxyquinazoline;

(24)4- (3-chloro-2-fluoroanilino) -6- [ (3S) -1-methylpyrrolidin-3-yloxy ] -7-methoxyquinazoline;

(25)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazoline;

(26)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (1-methylpyrrolidin-3-yl) methoxy ] quinazoline;

(27)6- [ (3R) -1-acetylpyrrolidin-3-yloxy ] -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline;

(28)6- { [ (2S) -1-acetylpyrrolidin-2-yl ] methoxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline;

(29)6- { [ (2R) -1-acetylpyrrolidin-2-yl ] methoxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline;

(30)6- [ (1-acetylpyrrolidin-3-yl) methoxy ] -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline;

(31)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (3S) -1- (N, N-dimethylsulfamoyl) pyrrolidin-3-yloxy ] quinazoline;

(32)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (morpholinoacetyl) pyrrolidin-2-yl ] methoxy } quinazoline;

(33)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (hydroxyacetyl) pyrrolidin-2-yl ] methoxy } quinazoline;

(34)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (piperidin-3-yloxy) quinazoline;

(35)4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4R) -2- (N, N-dimethylcarbamoyl) -1-methylpyrrolidin-4-yloxy ] -7-methoxyquinazoline;

(36)4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4R) -2- (N, N-dimethylcarbamoyl) -1-methylpyrrolidin-2-yloxy ] -7-methoxyquinazoline;

(37)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (N-methylaminoacetyl) pyrrolidin-2-yl ] methoxy } quinazoline;

(38)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (N, N-dimethylaminoacetyl) pyrrolidin-2-yl ] methoxy } quinazoline;

(39)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (pyrrolidin-1-ylacetyl) pyrrolidin-2-yl ] methoxy } quinazoline;

(40)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (2RS, 4R) -1-methyl-2- (morpholinocarbonyl) pyrrolidin-4-yloxy ] quinazoline;

(41)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (3S) -piperidin-3-yloxy ] quinazoline;

(42)6- [ (3S) -1-acetylpiperidin-3-yloxy ] -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline;

(43)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (3S) -1- (methylsulfonyl) piperidin-3-yloxy ] quinazoline;

(44)4- (3-chloro-2-fluoroanilino) -6- { (3S) -1- [ (dimethylamino) acetyl ] piperidin-3-yloxy } -7-methoxyquinazoline;

(45)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [1- (pyrrolidin-1-ylacetyl) piperidin-3-yloxy ] quinazoline;

(46)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (3S) -1- (pyrrolidin-1-ylacetyl) piperidin-3-yloxy ] quinazoline;

(47)4- (3-chloro-2-fluoroanilino) -6- { [ (2S) -1- (3, 4-methylenedioxypyrrolidin-1-ylacetyl) pyrrolidin-2-yl ] methoxy } -7-methoxyquinazoline;

(48)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (1-methylpiperazin-4-ylacetyl) pyrrolidin-2-yl ] methoxy } quinazoline;

(49)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2R) -1- (1-methylpiperazin-4-ylacetyl) pyrrolidin-2-yl ] methoxy } quinazoline;

(50)4- (3-chloro-2-fluoroanilino) -6- [ (3R) -1- (hydroxyacetyl) pyrrolidin-3-yloxy ] -7-methoxyquinazoline;

(51)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (2-hydroxyisobutyryl) pyrrolidin-2-yl ] methoxy } quinazoline;

(52)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- {1- [ (2S) -1-methylpyrrolidin-2-ylcarbonyl ] piperidin-3-yloxy } quinazoline;

(53)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [1- (N, N-dimethylcarbamoylmethyl) piperidin-3-yloxy ] quinazoline;

(54)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [1- (3, 3-difluoropyrrolidin-1-ylacetyl) piperidin-3-yloxy ] quinazoline;

(55)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- {1- [ [ (3R) -3-hydroxypyrrolidin-1-yl ] acetyl ] piperidin-3-yloxy } quinazoline;

(56)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (4-methyl-3-oxopiperazin-1-yl) acetyl ] piperidin-3-yloxy } quinazoline;

(57)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- {1- [ (4-acetylpiperazin-1-yl) acetyl ] piperidin-3-yloxy } quinazoline; and

(58)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2R) -1-methylpyrrolidin-2-yl ] methoxy } quinazoline.

Synthesis of quinazoline derivatives of formula I

In another aspect, the invention provides a process for the preparation of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof. It will be appreciated that in some of the following processes, certain substituents may require protection from unwanted reactions. The skilled chemist will be aware of how to introduce these protecting groups at the appropriate positions when such protection is required, and how to subsequently remove these protecting groups.

Examples of protecting Groups are found in many common textbooks on this matter, for example 'Protective Groups in Organic Synthesis' by Theodora Green (John Wiley & Sons). Removal of the protecting group may be carried out by any conventional method described in the literature or by methods known to the skilled chemist as being suitable for removal of the protecting group in question, such methods being selected so as to remove the protecting group while minimising interference with other groups of the molecule.

Thus, if a reactant includes a group such as an amino, carboxyl or hydroxyl group, it may be desirable to protect the group in some of the reactions mentioned above.

Suitable protecting groups for amino or alkylamino are, for example, acyl groups, such as alkanoyl (e.g. acetyl), alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), arylmethoxycarbonyl (e.g. benzyloxycarbonyl) or aroyl (e.g. benzoyl). The deprotection conditions for the above protecting groups must vary depending on the protecting group selected. Thus, acyl groups such as alkanoyl or alkoxycarbonyl or aroyl groups may for example be removed by hydrolysis with a suitable base such as an alkali metal hydroxide (e.g. lithium or sodium hydroxide). Alternatively, an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with an appropriate acid (e.g. hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid), and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst (e.g. palladium on carbon) or by treatment with a Lewis acid (e.g. boron tris (trifluoroacetate)). Other suitable protecting groups for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with alkylamines, such as dimethylaminopropylamine, or with hydrazine.

Suitable protecting groups for hydroxyl groups are, for example, acyl groups, such as alkanoyl (e.g. acetyl), aroyl (e.g. benzoyl) or arylmethyl (e.g. benzyl). The deprotection conditions for the above protecting groups must vary depending on the protecting group selected. Thus, acyl groups such as alkanoyl or aroyl groups may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide (e.g. lithium or sodium hydroxide) or ammonia. Alternatively, arylmethyl groups such as benzyl groups can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

Suitable protecting groups for the carboxyl group are, for example, ester-forming groups, such as methyl or ethyl, which can be removed by hydrolysis with a base, such as sodium hydroxide, or, for example, tert-butyl, which can be removed by treatment with an acid, such as an organic acid (e.g. trifluoroacetic acid), or, for example, benzyl, which can be removed by hydrogenation over a catalyst, such as palladium on carbon.

Resins may also be used as protecting groups.

Protecting groups may be removed at any convenient step of the synthesis using conventional techniques well known in the chemical arts.

The quinazoline derivatives of the formula I, or pharmaceutically acceptable salts thereof, may be prepared by any method known to be suitable for the preparation of chemically related compounds. These processes for preparing quinazoline derivatives of the formula I, or pharmaceutically-acceptable salts thereof, which are illustrated by the following representative examples, provide another feature of the present invention. The necessary starting materials are obtainable by standard methods of Organic Chemistry (see, for example, Advanced Organic Chemistry (Wiley-Interscience), Jerry March). The preparation of these starting materials is described in the accompanying non-limiting examples. In addition, the necessary starting materials can be obtained by methods analogous to those described, which are within the ordinary skill of the organic chemist. Information regarding the preparation of necessary starting materials or related compounds which may be employed to form the necessary starting materials may also be found in the following patents and application publications, the contents of which are incorporated herein by reference in their entirety: WO 94/27965, WO95/03283, WO 96/33977, WO 96/33978, WO 96/33979, WO 96/33980, WO 96/33981, WO 97/30034, WO 97/38994, WO 01/66099, US5252586, EP 520722, EP 566266, EP 602851 and EP 635507.

The invention also provides a process by which a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, may be prepared by the following processes (a) to (h) (wherein the variables are as defined above, unless otherwise specified).

Process (a) reacting a compound of formula II:

wherein R is¹、X¹、G¹And G²Having any of the meanings defined above, but where necessary protecting any functional group,

with a compound of formula III:

Q¹-X²-Lg

formula III

Wherein Q¹And X²Having any of the meanings defined above, but where necessary protected against any functional group, Lg being a displaceable group, wherein the reaction is suitably carried out in the presence of a suitable base,

any protecting groups present are thereafter removed by conventional means.

Conventional displaceable groups Lg are, for example, halo, alkylsulfonyloxy or arylsulfonyloxy, such as chloro, bromo, methylsulfonyloxy, 4-nitrophenylsulfonyloxy or toluene-4-sulfonyloxy (suitably methanesulfonyloxy, 4-nitrophenylsulfonyloxy or toluene-4-sulfonyloxy).

The reaction is advantageously carried out in the presence of a base. Suitable bases are organic amine bases, such as pyridine, 2, 6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine or diazabicyclo [5.4.0 ] ]Undec-7-ene; or as carbonates or hydroxides of alkali metals or alkaline earth metals, such as sodium carbonate, potassium carbonate, caesium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide. Other such bases are, for example, alkali metal hydrides, such as sodium hydride; amides of alkali metals or alkaline earth metals, such as sodium amide or sodium bis (trimethylsilyl) amide; or a sufficiently basic alkali metal halide such as cesium fluoride or sodium iodide. The reaction is suitably carried out in the presence of an inert solvent or diluent, such as an alcohol or ester, such as methanol, ethanol, 2-propanol or ethyl acetate; halogenated solvents such as dichloromethane, chloroform or carbon tetrachloride; ethers, such as tetrahydrofuran or 1, 4-dioxane; aromatic hydrocarbon solvents such as toluene; or (suitably) dipolar aprotic solvents, e.g.N，N-dimethylformamide,N，N-dimethylacetamide,N-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a temperature, for example, in the range 10 to 150 ℃ (or the boiling point of the solvent), preferably in the range 20 to 90 ℃.

When X is present²A particularly suitable base when it is a direct bond is cesium fluoride. The reaction is suitably carried out in an inert dipolar aprotic solvent, such as N, N-dimethylacetamide or N, N-dimethylformamide. The reaction is suitably carried out at a temperature of from 25 to 85 ℃.

Method (b) modifying the substituent or introducing the substituent to convert it to another quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined above, but where necessary protecting any functional group, and thereafter removing any protecting group present by conventional means.

Methods for converting substituents to other substituents are well known in the art. For example, an alkylthio group can be oxidized to an alkylsulfinyl or alkylsulfonyl group, a cyano group reduced to an amino group, a nitro group reduced to an amino group, a hydroxyl group alkylated to a methoxy group, a carbonyl group converted to a thiocarbonyl group (e.g., using Lawsson's reagent), a bromo group converted to an alkylthio group, an amino group acylated to an alkanoylamino group (e.g., by reaction with a suitable acid chloride and anhydride) or an alkanoyloxy group hydrolyzed to a hydroxyl group (e.g., an acetoxyacetyl group can be converted to a hydroxyacetyl group). Thus, in the final step of the preparation of the compounds of formula I, one R may be added¹Conversion of a group to another R¹A group. Substituents may also be introduced into Q in the final step of the preparation of the compounds of formula I¹On the radical. For example, when the compounds of formula I contain primary or secondary amino groups, e.g. ring Q¹(iii) NH groups in (1), a substituent may be added to the nitrogen atom of a primary or secondary amino group by reacting a compound of formula I containing said primary or secondary amino group with a compound of formula R-Lg wherein Lg is a substitutable group (e.g. halo, such as chloro or bromo), R is the desired substituent (e.g. (1-6C) alkyl, (2-6C) alkanoyl, cyano (1-6C) alkyl, (1-6C) alkylsulfonyl, carbamoyl, N-substituted aryl radicals, N-substituted, N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, carbamoyl (1-6C) alkyl,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, sulfamoyl,N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl groups or radicals Q²-X³-, wherein Q²-X³-as defined above, which groups may be optionally substituted as defined above). The above reaction may conveniently be carried out in the presence of a suitable base (such as a base as described in process (a) above, e.g. potassium carbonate, sodium iodide or diisopropylethylamine) and conveniently in an inert solvent or diluent (such as that described in process (a), e.g.N，N-dimethylacetamide, methanol, ethanol or dichloromethane). When Q is¹With a group NR which may be as defined above^aR^bSubstituted (2-6C) alkanoyl or (1-6C) alkylsulfonyl, the NR^aR^bThe radicals can be prepared by reacting in which Q¹Compounds of formula I bearing Lg- (2-6C) alkanoyl or Lg- (1-6C) alkylsulfonyl groups in which Lg is a suitable displaceable group, e.g. chloro, with NHR^aR^bThe compound is conveniently introduced by reaction; wherein the reaction is conveniently carried out in the presence of a suitable base and optionally in the presence of a suitable inert solvent or diluent. For example, Q ¹The pyrrolidin-1-ylacetyl group on (a) may be prepared by reacting a compound of formula (I) wherein Q¹Preparation of compounds of formula I substituted by chloroacetyl with pyrrolidine and analogous methods for preparing Q¹And substituents thereon, such as morpholinoacetyl, N-methylaminoacetyl, N-dimethylaminoacetyl. Similarly, Q¹The 3- (N, N-dimethylamino) propanesulfonyl substituent on (A) may be substituted by reacting a compound wherein Q is¹A compound of formula I bearing a 3-chloropropanesulfonyl substituent is reacted with dimethylamine. Other examples of modifying substituents or converting substituents to other substituents are well known to those skilled in the art and other methods are included in the non-limiting examples that follow.

Method (c) removing the protecting group from the quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof.

Suitable methods for removing protecting groups are well known and are discussed herein. For example, to prepare compounds in which Q¹Or R¹Compounds of formula I containing primary or secondary amino groups, requiring cleavage of Q therein¹Or R¹Corresponding compounds of the formula I which contain protected primary or secondary amino groups.

Suitable protecting groups for amino groups are, for example, any of the protecting groups for amino groups disclosed hereinbefore. Suitable methods for cleaving these amino protecting groups are also disclosed herein before. More particularly, a suitable protecting group is a lower alkoxycarbonyl group, such as a tert-butoxycarbonyl group, which may be cleaved under conventional reaction conditions, such as under acid-catalyzed hydrolysis, for example in the presence of trifluoroacetic acid.

Method (d) reacting a compound of formula II as defined hereinbefore with a compound of formula III as defined hereinbefore under Mitsunobu conditions, except that Lg is OH, under Mitsunobu conditions, after which any protecting groups present are removed by conventional means.

Suitable Mitsunobu conditions include, for example, reaction in the presence of a suitable tertiary phosphine and a dialkyl carboxyazo dicarboxylate in an organic solvent such as THF or a suitable dichloromethane at a temperature in the range of 0 ℃ to 60 ℃, but suitably at room temperature. Suitable tertiary phosphines include, for example, tributylphosphine or suitable triphenylphosphine. Suitable dialkyl azodicarboxylates include, for example, diethyl azodicarboxylate (DEAD) or suitable di-tert-butyl azodicarboxylate. Details of the Mitsunobu reaction are included in tet.letters, 31, 699, (1990); the Mitsunobu Reaction, D.L. Hughes, Organic Reactions, 1992, Vol.42, 335. quadrature. 656 and Progress inter Mitsunobu Reaction, D.L. Hughes, Organic Preparations and Progress International, 1996, Vol.28, 127. quadrature. 164.

Process (e) preparation of wherein R¹-X¹Those compounds of formula I which are hydroxy, by reacting R therein¹-X¹Quinazoline derivatives of the formula I which are (1-6C) alkoxy groups.

The cleavage reaction may be conveniently carried out by any of a variety of methods known for such conversion. Wherein R is¹The cleavage reaction of a compound of formula I which is a (1-6C) alkoxy group may be carried out, for example, by treating the quinazoline derivative with an alkali metal (1-6C) alkylthiolate, such as sodium ethylthiolate, or, for example, by treating with an alkali metal diaryl phosphide, such as lithium diphenylphosphate. Alternatively, the cleavage reaction may conveniently be carried out, for example, by treating the quinazoline derivative with a boron trihalide or aluminium (e.g. boron tribromide) or by reaction with an organic or inorganic acid (e.g. trifluoroacetic acid). These reactions are suitably carried out in the presence of a suitable inert solvent or diluent as hereinbefore defined. The preferred cleavage reaction is to use pyridine as the quinazoline derivative of formula IAnd (4) treating hydrochloride. The cleavage reaction is suitably carried out at a temperature in the range, such as 10-150 deg.C (e.g. 25-80 deg.C).

Process (f) preparation of wherein X¹Those of formula I which are O, by reacting a compound of formula IV (a compound of formula I wherein R is¹-X¹Is OH):

wherein Q¹、X²、G¹And G²Having any of the meanings defined above, but where necessary protected by functional groups, with the formula R¹-Lg of a compound reaction in which R ¹Having any of the meanings defined above, but requiring protection of any functional group if necessary, Lg being a displaceable group, wherein the reaction is conveniently carried out in the presence of a suitable base;

any protecting groups present are thereafter removed by conventional means. Suitable substitutable groups Lg are as defined in the preceding method (a), such as chloro-or bromo-groups. The reaction is suitably carried out in the presence of a suitable base. Suitable solvents, diluents and bases include, for example, those described in connection with process (a) above.

Process (g) preparation of wherein Q¹Or R¹Those compounds of formula I which contain a (1-6C) alkoxy or substituted (1-6C) alkoxy or (1-6C) alkylamino or substituted (1-6C) alkylamino group, in which Q is present in the general presence of a suitable base as defined in process (a) above¹Or R¹Quinazoline derivatives of the formula I containing appropriate hydroxyl or primary or secondary amino groups.

Suitable alkylating agents are, for example, any agent known in the art for alkylating a hydroxy group to an alkoxy or substituted alkoxy group, or an amino group to an alkylamino or substituted alkylamino group, for example alkyl or substituted alkyl halides, such as (1-6C) alkyl chlorides, bromides The compound or iodide or substituted (1-6C) alkyl chloride, bromide or iodide is conveniently carried out in the presence of a suitable base as defined above, in a suitable inert solvent or diluent as defined above, at a temperature in the range, for example 10 to 140℃, conveniently at or near room temperature. The optionally substituted (2-6C) alkanoyloxy, (2-6C) alkanoylamino and (1-6C) alkylsulfonylamino group may be introduced into Q in a similar manner¹Or R¹In (1).

To conveniently prepare the compound in which Q¹Or R¹Compounds of formula I containing a (1-6C) alkylamino or substituted (1-6C) alkylamino group can be prepared using a reductive amination reaction with formaldehyde or a (2-6C) alkylaldehyde (e.g., acetaldehyde or propionaldehyde). For example, to prepare compounds in which Q¹Or R¹ComprisesN-methyl groups, by reacting the corresponding compounds of formula I containing N-H groups with formaldehyde in the presence of a suitable reducing agent. Suitable reducing agents are, for example, hydride reducing agents such as formic acid, alkali metal aluminum hydrides such as lithium aluminum hydride or suitable alkali metal borohydrides such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydride and sodium triacetoxyborohydride. The reaction is conveniently carried out in a suitable inert solvent or diluent, for example tetrahydrofuran and diethyl ether for the more strongly acting reducing agent (e.g. lithium aluminium hydride), dichloromethane or an protic solvent (e.g. methanol and ethanol) for the less strongly acting reducing agent (e.g. sodium triacetoxyborohydride and sodium cyanoborohydride). When the reducing agent is formic acid, the reaction is conveniently carried out using an aqueous solution of formic acid. The reaction is carried out at a temperature in the range of from 10 to 100 deg.C, for example from 70 to 90 deg.C or conveniently at or near room temperature. When the reducing agent is formic acid, the protecting group on the NH group to be alkylated (e.g. the protecting group present in the synthesis of the starting material, such as tert-butoxycarbonyl) may conveniently be removed in situ during the reaction.

Process (h) preparation of wherein R¹Those compounds of formula I substituted by a group T, wherein T is selected from (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (2-6C) alkanoylamino(1-6C) alkylthio, (1-6C) alkylsulfinyl and (1-6C) alkylsulfonyl, reacting a compound of the formula V:

wherein Q¹、X¹、X²、R¹、G¹And G²Having any of the meanings defined above, but where desired protecting any functional group, Lg is a displaceable group (e.g. chloro or bromo) which is reacted with a compound of formula TH, wherein T is as defined above, but where desired protecting the functional group.

Any protecting groups present are thereafter removed by conventional means. The reaction is conveniently carried out in the presence of a suitable base. The reaction may conveniently be carried out in a suitable inert solvent or diluent. Suitable bases, solvents and diluents are, for example, those described in process (a). The reaction is suitably carried out at a temperature within, for example, 10-150 c (e.g. 30-60 c).

It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or may be generated by conventional functional group modifications, either immediately prior to or subsequent to the respective methods mentioned above, which are included in the process aspects of the present invention. These reactions and modification methods include, for example, the introduction of substituents by aromatic substitution reactions, substituent reduction, substituent alkylation, and substituent oxidation. The reagents and reaction conditions for these processes are well known in the chemical arts. Specific examples of aromatic substitution reactions include introduction of nitro groups using concentrated nitric acid, introduction of acyl groups under Friedel Crafts conditions using, for example, acid halides and Lewis acids (e.g., aluminum trichloride); introduction of alkyl groups under Friedel Crafts conditions using, for example, alkyl halides and Lewis acids (e.g., aluminum trichloride); and introducing a halo group.

Process (i) by reacting a compound of formula VI:

wherein R is¹、X¹、X²、Q¹Having any of the meanings defined above, but where necessary protecting the functional groups, Lg being a displaceable group as defined above,

with an aniline of formula VII:

wherein G is¹And G²Having any of the meanings defined above, but where necessary protecting the functional group, and wherein the reaction is conveniently carried out in the presence of a suitable acid,

any protecting groups present are thereafter removed by conventional means.

Suitable substitutable groups represented by Lg are as previously defined, especially halo groups such as chloro groups.

The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester (such as methanol, ethanol, isopropanol or ethyl acetate), a halogenated solvent (such as dichloromethane, chloroform or carbon tetrachloride), an ether (such as tetrahydrofuran or 1, 4-dioxane), an aromatic solvent (such as toluene) or a dipolar aprotic solvent (such as methanol, ethanol, isopropanol or ethyl acetate)N，N-dimethylformamide,N，N-dimethylacetamide, N-methylpyrrolidin-2-one, acetonitrile or dimethylsulfoxide). The reaction is conveniently carried out in the range of, for example, 10 to 250 c, preferably 40 to 120 c, or at reflux temperature where a solvent or diluent is used. Conventionally, hydrogen chloride in an acid (e.g. diethyl ether or dioxane) may conveniently be present under the above conditions in the presence of a protic solvent (e.g. isopropanol) Gas or hydrochloric acid, e.g. 4M hydrogen chloride in dioxane) with a compound of formula VI. Alternatively, the reaction may be carried out in an aprotic solvent (e.g., dioxane) or a dipolar aprotic solvent (e.g., dioxane)N，NDimethylacetamide or acetonitrile) in the presence of an acid, for example diethyl ether or hydrogen chloride gas in dioxane or hydrochloric acid. A compound of formula VI wherein Lg is halo can be reacted with a compound of formula VII in the absence of an acid. In this reaction, displacement of the halogenated leaving group Lg may form acid HLg in situ in the reaction and autocatalytic the reaction. The reaction is conveniently carried out in a suitable inert organic solvent (e.g. isopropanol, dioxane or ethanol)N，N-dimethylacetamide). Suitable conditions for this reaction are as described above.

Alternatively, a compound of formula VI may be reacted with a compound of formula VII in the presence of a suitable base. Suitable bases for this reaction are the bases defined above in connection with process (a). The reaction is conveniently carried out in an inert solvent or diluent such as described above in connection with process (i).

Process (j) preparation of wherein Q¹With substituted carbamoyl radicals (e.g.N，NDi [ (1-6C) alkyl)]Carbamoyl) or a group Q²X³-those of formula I, wherein Q ²Through a ring nitrogen atom with X³Attached nitrogen-containing heterocyclic group, X³Is CO; is as defined above and wherein Q¹Compounds of the formula I which carry a carboxyl group (but where appropriate protected by functional groups) with primary or secondary amines or of the formula Q²H radical is coupled, in which Q²H is a heterocyclic group containing an NH group; any protecting groups present are thereafter removed by conventional means.

The coupling reaction is conveniently carried out in a suitable coupling agent such as a carbodiimide (e.g. 1- [3- (dimethylamino) propyl)]-3-ethylcarbodiimide) or a suitable peptide coupling reagent (e.g. O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium Hexafluorophosphate (HATU)). The coupling reaction is conveniently carried out in an inert solvent, such as a halogenated solvent (e.g. dichloromethane) or a dipolar aprotic solvent(e.g. usingN，N-dimethylformamide,N，NDimethylacetamide, 1-methyl-2-pyrrolidone). The coupling reaction is suitably carried out in the presence of a suitable base such as an organic amine (diisopropylethylamine or 4-dimethylaminopyridine). The coupling reaction is suitably carried out at a temperature of-25 to 150 c, conveniently at room temperature.

It will be appreciated by those of skill in the art that in other instances and where it is more convenient to obtain a compound of the invention, the various process steps set forth above may be performed in a different order and/or the various reactions may be performed in different stages throughout the route (i.e., the various chemical transformations may be performed using intermediates associated with reactions other than those specifically described).

When a pharmaceutically acceptable salt (e.g. an acid addition salt) of a quinazoline derivative of the formula I is required, it may be obtained by conventional means, for example by reacting the quinazoline derivative with an appropriate acid. The compounds may be prepared in the form of non-pharmaceutically acceptable salts for ease of isolation of the compounds during the preparation process. The resulting salt is then modified by conventional techniques to produce a pharmaceutically acceptable salt of the compound. These techniques include, for example, ion exchange techniques or techniques in which the compound is reprecipitated in the presence of a pharmaceutically acceptable counterion. For example, reprecipitation in the presence of a suitable acid (e.g., HCl) yields a hydrochloric acid addition salt.

As mentioned above, certain compounds of the invention may contain one of more chiral centers and thus may exist as stereoisomers (e.g., when Q is¹When pyrrolidin-3-yl is included). The individual stereoisomers may be separated using conventional techniques (e.g. chromatography or fractional crystallisation). Enantiomers may be separated by separation (e.g. by fractional crystallisation, resolution or HPLC) to separate the racemates. Diastereomers may be separated by separation using different physical properties of the diastereomers (e.g., by fractional crystallization, HPLC, or flash chromatography). Alternatively, each specific stereoisomer can be prepared by chiral synthesis from chiral starting materials under conditions which do not cause racemization or epimerization, or by derivatization with a chiral reagent And (4) chemical preparation. Examples of suitable chiral syntheses and isomer separations are described in the examples. When a particular stereoisomer is isolated, it is suitable to isolate it substantially free of the other stereoisomer, e.g., containing less than 20%, particularly less than 10%, and more particularly less than 5%, by weight of the other stereoisomer.

In the above section, the term "inert solvent" refers to a solvent that reacts with a starting material, reagent, intermediate, or product in a manner that does not adversely affect the yield of the desired product.

Preparation of the starting Material

The compounds of formula II are commercially available or can be prepared using conventional techniques or by methods analogous to those described in the prior art. In particular those listed above, such as WO96/15118, WO 01/66099 and EP 566226. For example, the compound of formula II can be prepared according to reaction scheme 1.

Wherein R is¹、X¹、Lg、G¹And G²As defined above, Pg is a hydroxyl protecting group.

(i) The reaction is suitably carried out in an inert protic solvent (e.g. an alkanol, e.g. isopropanol), an aprotic solvent (e.g. dioxane) or a dipolar aprotic solvent (e.g. dioxane)N，NDimethylacetamide) in the presence of an acid such as hydrogen chloride gas in diethyl ether or dioxane or hydrochloric acid under similar conditions as described in process (i) above.

Alternatively, the reaction may be conveniently carried out in one of the above inert solvents in the presence of a base such as potassium carbonate. The above reaction is conveniently carried out in the range of, for example, 0 to 150 c, suitably at or near the reflux temperature of the reaction solvent.

(ii) Pg of these reactions can be cleaved under standard conditions. For example, when Pg is an alkanoyl group (e.g., acetyl), it can be cleaved by heating in the presence of methanolic ammonia solution.

The compounds of formula VIII are known compounds or can be prepared using known methods for preparing analogous compounds. If not available commercially, the compounds of formula VIII may be prepared by a method selected from standard chemical techniques, techniques analogous to the synthesis of known structurally similar compounds, or procedures analogous to those described in the examples. For example, standard chemical techniques described in Houben Weyl. For example, the compound of formula VIII, wherein R is¹-X¹-is methoxy, Lg is chloro, Pg is acetyl.

The skilled person can generalize scheme 2 to compounds in this specification not specifically described (e.g. to introduce a substituent other than methoxy at the 7-position of the quinazoline ring).

The compounds of formula III are commercially available or may be prepared using standard techniques (e.g. as described in US 5252586 and WO 94/27965).

The compound of formula IV can be prepared using the above process (e), starting from, for example, the compound prepared by using process (a).

Compounds of formula V may be prepared, for example, by process (a) or process (d), wherein R¹The groups represented are suitably functionalized with suitable substitutable groups Lg, such as chloro or bromo.

The compounds of formula VI may be prepared by conventional methods well known in the art. For example, the hydroxyl protecting group Pg in the compound of formula VIII described in scheme 1 above can be removed to provide a compound of formula X:

the protecting group Pg may be removed from the compound of formula X using conventional techniques.

The compound of formula X is then coupled with a compound of formula III as defined above using conditions analogous to those described in method (a) or method (d).

Certain novel intermediates utilized in the above-described processes, together with processes for their preparation, constitute another feature of the present invention.

The present invention further features compounds of formulae II and IX as defined above and salts thereof (including pharmaceutically acceptable salts thereof). In particular wherein R¹-X¹Compounds of formulae II and IX which are hydrogen or (1-4C) alkoxy. More particularly wherein R¹-X¹Is hydrogen or (1-4C) alkoxy and G¹And G²Selected from fluoro or chloro compounds of formulae II and IX.

Biological assay

The following assay methods can be used to test the efficacy of the compounds of the invention as erb-tyrosine kinase inhibitors, as inhibitors of proliferation of KB cells (human nasopharyngeal carcinoma cells) in vitro, and as inhibitors of growth of xenografts of Lo Vo tumor cells (rectal carcinoma) in nude mice in vivo.

a) Protein tyrosine kinase phosphorylation assay

This assay measures the ability of a test compound to inhibit phosphorylation of a tyrosine-containing polypeptide substrate by EGFR tyrosine kinase.

The recombinant intracellular fragments EGFR, erbB2 and erbB4 (catalog numbers X00588, X03363 and L07868, respectively) were cloned and expressed in a baculovirus/Sf 21 system. The cells were lysed by ice-cooling the cells with ice-cold lysis buffer (20mM N-2-hydroxyethylpiperazine-N' -2-ethanesulfonic acid (HEPES) pH7.5, 150mM NaCl, 10% glycerol, 1% Triton X-100, 1.5mM MgCl₂、1mMEthylene glycol-bis (beta-aminoethylether) N ', N' -tetraacetic acid (EGTA)) plus protease inhibitor treatment followed by clarification by centrifugation to prepare the lysate.

The constitutive kinase activity of the recombinant protein was determined by its ability to phosphorylate a synthetic peptide consisting of a random copolymer of glutamic acid, alanine and tyrosine in a ratio of 6: 3: 1. Specifically, Maxisorb is prepared by mixing Maxisorb ^TMA96-well immunoassay plate was coated with synthetic peptide (0.2. mu.g peptide in 100. mu.l Phosphate Buffered Saline (PBS)) and then incubated overnight at 4 ℃. Plates were washed sequentially with PBS-T (phosphate buffered saline with 0.5% Tween 20) and 50mM HEPES (pH7.4) at room temperature to remove any excess unbound synthetic peptide. Adenosine Triphosphate (ATP), 10mM MnCl at 100mM HEPES pH7.4, Km concentration for each enzyme at 22 deg.C₂、0.1mM Na₃VO₄0.2mM DL-Dithiothreitol (DTT), 0.1% Triton X-100, and the tyrosine kinase activity of EGFR, ErbB2, or ErbB4 was determined by incubating the peptide coated assay plates with a DMSO solution of the test compound (final concentration 2.5%) for 20 minutes. The reaction was stopped by removing the liquid component from the assay solution and then washing each plate with PBS-T.

The immobilized phospho-peptide (phospho-peptide) product of the reaction is assayed by immunological methods. First, each plate was incubated with an anti-phosphotyrosine primary antibody (4G 10 from Upstate Biotechnology) cultured in mice for 90 minutes at room temperature. After washing well, each plate was treated with horseradish peroxidase (HRP) conjugated to goat anti-mouse secondary antibody (NXA 931 from Amersham) for 60 minutes at room temperature. After further washing, 2' -azino-bis- [ 3-ethylbenzothiazolinesulfonic acid (6) was used as a substrate ]Crystals of diammonium salts (ABTS)^TMPurchased from Roche) colorimetrically determine the HRP activity per well in the plate.

The enzyme activity was determined by quantifying the color development by measuring the absorbance at 405nm with a Molecular Devices ThermoMax microplate reader. Kinase inhibition by given Compounds₅₀The values are represented. By calculating at thatDetermination of the concentration of the Compound required to give 50% inhibition of Phosphorylylation in the assay IC₅₀The value is obtained. The phosphorylation range was calculated from positive (vehicle plus ATP) and negative (vehicle minus ATP) control values.

b) EGFR-driven KB cell proliferation assay

This assay measures the ability of test compounds to inhibit proliferation of KB cells (human nasopharyngeal carcinoma cells, obtained from American Type Culture Collection (ATCC)).

At 7.5% CO₂KB cells (human nasopharyngeal carcinoma cells, supplied by ATCC) were cultured in Dulbecco's Modified Eagle's Medium (DMEM) containing 10% fetal bovine serum, 2mM glutamine and non-essential amino acids at 37 ℃ in an air incubator. Cells were harvested from the stock bottles using trypsin/ethylenediaminetetraacetic acid (EDTA). Cell density was determined using a hemocytometer and then measured at 1.25X 10 per well³Density of individual cells, seeded in 7.5% CO₂DMEM containing 2.5% charcoal-destained plasma (stripeped serum), 1mM glutamine and non-essential amino acids in 96-well plates at 37 ℃, fixed for 4 hours, and then viability was calculated using trypan blue solution.

After the cells were attached to the plate, the cells were treated with (or without) EGF (final concentration of 1ng/ml) and with (or without) Dimethylsulfoxide (DMSO) of a compound in a range of concentrations (final concentration of 0.1%), followed by incubation for 4 days. After the incubation was completed, the number of cells was measured for 2 hours by adding 50. mu.l of 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT) (stock solution 5 mg/ml). The MTT solution was then decanted, the plates were gently tapped dry, and 100 μ l DMSO was added to dissolve the cells.

The absorbance of the lysed cells was read at 540nm by using a Molecular Devices ThermoMax microplate reader. IC for inhibiting proliferation₅₀The values are represented. Determination of IC by calculating the concentration of compound required to produce a 50% inhibition of proliferation₅₀The value is obtained. Proliferation ranges were calculated from positive (vehicle plus EGF) and negative (vehicle minus EGF) control values.

c) H16N-2 cell proliferation assay

This assay measures the ability of a test compound to inhibit heregulin beta or EGF driven H16N-2 cell proliferation. These non-Neoplastic epithelial cells respond in a proliferative manner to stimulation by EGF or heregulin beta (Ram, G.R. and Ethier, S.P. (1996) Cell Growth and Differentiation, 7, 551. 561), which are isolated from human breast tissue (Band, V and Sager, R.Tumour promotion in Breast Cancer. in: J.S.Rhim and A.Dritschilo (eds.), Neoplastic Transformation in human Cell Culture, pp 169-178.Clifton, NJ: Humana Press, 1991), obtained from Dana-Farber Cancer Institute, 44Binney Street, Boston, Massachusetts 02115.

At 7.5% CO₂H16N-2 cells were cultured routinely in air incubators at 37 ℃ in a medium (1: 1GibcoF12 and Ham's α MEM medium mixture containing 1% fetal bovine serum, 10mM HEPES, 1 μ g/ml insulin, 12.5ng/ml EGF, 2.8 μ M hydrocortisone, 2nM estradiol, 5 μ M ascorbic acid, 10 μ g/ml transferrin, 0.1mM phosphoethanolamine, 15nM sodium selenite, 2mM glutamine, 10nM triiodothyronine (tri-iodo-thrynone), 35 μ g/ml bovine pituitary extract and 0.1mM ethanolamine). Cells were harvested from the stock bottles using trypsin/ethylenediaminetetraacetic acid (EDTA). Cell density was determined using a hemocytometer and then measured at 1.0X 10 per well³Density of individual cells, seeded in 7.5% CO₂After fixing for 72 hours in the above medium in a 96-well plate at 37 ℃, the activity was calculated using trypan blue solution.

Then, at 7.5% CO₂Starvation medium (1: 1Gibco F12 and Ham's alpha MEM medium mixture containing 10mM HEPES, 2nM estradiol, 5. mu.M ascorbic acid, 10. mu.g/ml transferrin, 0.1mM ethanolamine phosphate, 15nM sodium selenite, 2mM glutamine and 0.1mM ethanolamine) was added at 37 ℃ and the cells were serum depleted and cultured for 24 hours. The cells were then treated with (or without) dimethyl sulfoxide (DMSO) of compound at a range of concentrations (0.1% final concentration) for 2 hours, Then exogenous ligand (heregulin beta at 100ng/ml final concentration or EGF at 5 ng/ml) was added at 7.5% CO₂Incubate with ligand and compound for 4 days at 37 ℃. After the incubation period, the medium was removed by aspiration and incubated with 50. mu.l of 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT) (stock 5mg/ml) for 2 hours to determine the cell number. The MTT solution was then aspirated off, air dried, and 100. mu.l DMSO was added to dissolve the cells.

The cell biomass was quantified by reading the absorbance of the lysed cells at 540 nm. IC for inhibiting proliferation₅₀The values are represented. Determination of IC by calculating the concentration of compound required to produce 50% inhibition of proliferation₅₀The value is obtained. Proliferation ranges were calculated from positive (vehicle plus ligand) and negative (vehicle minus ligand) control values.

d) In vivo xenograft assay

This assay measures the ability of test compounds to inhibit the growth of LoVo tumors (rectal cancer, from ATCC) in female Swiss athymic mice (Alderley Park, nu/nu strain).

Female Swiss athymic nude mice (nu/nu strain) were reared and then kept in Alderley Park (PFI Systems Ltd.) in negative pressure Isolate (isolator). Mice were housed in a barrier device with 12 hours light/dark cycle, with free access to sterile food and water. All steps were performed with mice at least 8 weeks old. Each mouse was injected subcutaneously with freshly cultured 1X 10 cells in 100. mu.l serum-free medium ⁷Individual cells, xenografts of LoVo tumor cells (colorectal adenocarcinoma, from ATCC) were established in the posterior flank of donor mice. On the 5 th day after transplantation, the mice were randomly divided into 7 groups, and then treated with compound or control medium in an amount of 0.1ml/10g body weight 1 time per day. Tumor volume was measured 2 times per week by double sided vernier caliper and calculated using the following formula: (length x width) × (pi/6), where length is the longest diameter through the tumor and width is the corresponding perpendicular. Mean change in tumor volume by comparing control and treated groupsStatistical significance between the two groups was assessed using Students t-test, counting growth inhibition from the start of the study.

e) hERG-encoded potassium channel inhibition assay

This assay measures the ability of test compounds to inhibit tail current flow through the human ether-a-go-go-related gene (hERG) -encoded potassium channel.

Human Embryonic Kidney (HEK) cells expressing the hERG-encoding channel were grown in Eagle minimal essential medium (EMEM; Sigma-Aldrich; catalog number M2279) supplemented with 10% fetal bovine serum (Labtech International; product number 4-101-500), 10% M1 serum-free supplement (Egg Technologies; product number 70916), and 0.4mg/ml Geneticin G418 (Sigma-Aldrich; catalog number G7034). Cells were isolated from tissue culture flasks using accutase (tcs biologicals) using standard tissue culture methods 1 or 2 days prior to the start of each experiment. They were then placed on glass coverslips in wells of a 12-well plate and covered with 2ml of growth medium.

To record cells per well, glass coverslips containing the cells were placed in the bottom of a Perspex chamber containing a bath (see below) at room temperature (. about.20 ℃). The chamber was mounted on the stage of an inverted phase contrast microscope. The coverslip was placed in the chamber and the chamber was immediately perfused with the bath at a rate of about 2ml/min from a gravity-fed reservoir (gradient-fed resusvorair) for 2 minutes. The perfusion was then stopped.

A film pipette made from a borosilicate glass tube (GC120F, Harvard Apparatus) using a P-97 micropipette puller (Sun Instrument Co.) was filled with pipette solution (see below). The pipette was attached to the tip of a patch clamp amplifier (Axopatch200B, Axon Instruments) via a silver/silver chloride wire. The top and bottom are connected to the ground. It consists of silver/silver chloride wires inserted in 3% agar consisting of 0.85% sodium chloride.

Cells were recorded in a whole cell configuration using patch clamp technique. After "break in" at a holding potential of-80 mV (set by the amplifier) and appropriate tuning of the series of resistance and capacitance controls, the holding potential of (-80mV) was set using electrophysiological software (claudex, Axon Instruments), followed by the transmission of a protocol voltage (voltage protocol). The protocol was applied every 15 seconds, consisting of a 1 second to +40mV step followed by a 1s to-50 mV step. At 1kHz, the current response to each application protocol voltage was low-pass filtered by the amplifier. The filtered signal is then obtained on-line by digitizing a similar signal in the amplifier with a similar digitizer. The digitized signal was then captured on a computer running a claudex software (Axon Instruments). During the sustain voltage and up to +40mV step, the check current was sampled at 1 kHz. The sample rate for the remaining voltage protocol was then set to 5 kHz.

The compositions, pH and penetration of the bath and straw solutions are listed in the table below.

Salt (salt)	Siphon (mM)	Bath lotion (mM)
			NaCl	-	137
KCl	130	4
			MgCl	1	1
CaCl	-	1.8
			HEPES	10	10
Glucose	-	10
			NaATP	5	-
EGTA	5	-

Parameter(s)	Suction tube	Bath lotion
			PH	7.18-7.22	7.40
PH regulator	1M KOH	1M NaOH
			Penetration degree (mOsm)	275-285	285-295

The amplitude of the hERG-encoded potassium channel tail current after the voltage step from +40mV to-50 mV was recorded on-line by Clampex software (Axon Instruments). After the amplitude of the tail current has stabilized, a bath containing a medium containing the test substance is added to the cells. The addition of the medium had no significant effect on the amplitude of the tail current, and then a cumulative concentration response curve for the compound was established.

The effect of each concentration of test compound was quantified by expressing the amplitude of the tail current at a given concentration of test compound (the percentage concentration present in the medium).

The potency (IC) of the test compounds was determined by fitting the percent inhibition values consisting of concentration-effect to the Hill equation for the quaternary parameters using a standard data fitting software package₅₀). If the level of inhibition seen at the highest concentration tested does not exceed 50%, no potency value is produced and the percent inhibition at that concentration is quoted.

Although the pharmacological properties of the compounds of formula I vary as expected with structural changes, in general, the compounds of formula I may be demonstrated to be active in one or more of the above tests (a), (b) and (c) at the following concentrations or dosages:

Test (a): -IC₅₀In the range of, for example, 0.001 to 10. mu.M

Test (b): -IC₅₀In the range of, for example, 0.001 to 10. mu.M

Test (c): -IC₅₀In the range of, for example, 0.001 to 10. mu.M

Test (d): active in a dosage range of, for example, 1-200 mg/kg/day

At an effective dose of the test compound of the present invention, no physiologically unacceptable toxicity is observed in test (c). Thus, when a compound of formula I or a pharmaceutically acceptable salt as defined hereinbefore is administered in the dosage range defined hereinafter, no troublesome toxicological effects are expected.

Another aspect of the invention provides a pharmaceutical composition which comprises a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined above in association with a pharmaceutically-acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use (e.g., tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (e.g., creams, ointments, gelling agents, aqueous or oily solutions or suspensions), for administration by inhalation (e.g., finely divided powders or liquid aerosols), for administration by insufflation (e.g., finely divided powders), or for parenteral administration (e.g., sterile aqueous or oily solutions, which may be for intravenous, subcutaneous, intramuscular, or for rectal administration).

The compositions of the present invention may be prepared by conventional methods using a variety of conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral administration may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, formulations intended for oral administration to humans are generally adapted to contain, for example, from 0.5mg to 0.5g (more suitably from 0.5 to 100mg, e.g. from 1 to 30mg) of the active agent, and the formulation may also contain suitable amounts of excipients which may be present in an amount of from about 5% to 98% by weight of the total composition.

Of course, when the compounds of formula I are used for therapeutic or prophylactic purposes, the size of the dose will vary with the nature and severity of the disease in the animal (i.e., patient), the age and sex of the patient and the route of administration, according to well-known principles of medicine.

In the case of the use of the compounds of the formula I for therapeutic or prophylactic purposes, they are generally administered, for example, in a daily dose in the range from 0.1mg/kg to 75mg/kg of body weight, if appropriate in divided doses. Generally, when the parenteral route is used, lower doses should be administered. Thus, for example, when administered intravenously, a dosage range of, for example, 0.1mg/kg to 30mg/kg of body weight is generally employed. Similarly, when administered by inhalation, dosages in the range of, for example, 0.05mg/kg to 25mg/kg body weight are generally employed. However, oral administration is preferred, particularly in the form of tablets. Generally, unit dosage forms contain from about 0.5mg to about 0.5g of a compound of the present invention.

We have found that the compounds of the invention possess antiproliferative properties (e.g. anti-cancer properties) which are believed to be caused by the inhibitory activity of receptor tyrosine kinases of the erbB family, particularly EGF receptor (erbB1) tyrosine kinase. In addition, certain compounds of the invention have substantially greater effects on EGF receptor tyrosine kinase than other tyrosine kinases, such as erbB 2. These compounds have a sufficiently potent effect on EGF receptor tyrosine kinase and may therefore be used in sufficient amounts to inhibit EGF receptor tyrosine kinase whilst exhibiting little or significantly lower activity on other tyrosine kinases such as erbB 2. These compounds may be useful for the selective inhibition of EGF receptor tyrosine kinase and may be useful for the effective treatment of tumors such as EGF-induced tumors.

Accordingly, it is expected that the compounds of the present invention will be useful in the treatment of diseases or conditions mediated alone or in part by erbB receptor tyrosine kinases, particularly EGF receptor tyrosine kinase, i.e. the compounds will be useful in the production of erbB receptor tyrosine kinase inhibitory effects in a warm-blooded animal in need of such treatment. Accordingly, the compounds of the present invention provide a method of treating malignant cells characterised by inhibiting one or more erbB families of receptor tyrosine kinases. In particular, the compounds of the invention may be used to produce an anti-proliferative and/or pro-apoptotic and/or anti-erosive effect mediated alone or in part by inhibition of erbB receptor tyrosine kinases. In particular, it is expected that the compounds of the invention will be useful in the prevention or treatment of those tumours which are sensitive to inhibition of one or more erbB receptor tyrosine kinases, such as EGF and/or erbB2 and/or erbB4 receptor tyrosine kinases (especially EGF receptor tyrosine kinase) which are involved in the signalling steps which drive proliferation and survival of these tumour cells. Accordingly, it is expected that the compounds of the present invention may be useful in the treatment of psoriasis, Benign Prostatic Hypertrophy (BPH), atherosclerosis and restenosis and/or cancer, particularly in the treatment of erbB receptor tyrosine kinase sensitive cancers, by providing an antiproliferative effect. These benign or malignant tumors can affect any tissue, including non-solid tumors such as leukemia, multiple myeloma or lymphoma, as well as solid tumors such as bile duct, bone, bladder, brain/CNS, breast, colorectal, endometrial, gastric, head and neck, liver, lung, neuronal, esophageal, ovarian, pancreatic, prostate, kidney, skin, testicular, thyroid, uterine and vulvar cancers.

In one aspect the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use as a medicament.

In a further aspect the invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the production of an anti-proliferative effect in a warm-blooded animal such as man.

Accordingly, in one aspect the present invention provides the use of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.

According to a further feature of this aspect of the invention there is provided a method of producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

A further aspect of the invention provides the use of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of erbB receptor tyrosine kinases, such as EGFR and/or erbB2 and/or erbB4 (especially EGFR), which receptor tyrosine kinases are involved in the signalling steps which lead to tumour cell proliferation.

A further feature of this aspect of the invention provides a method of prophylaxis or treatment of those tumours which are sensitive to inhibition of the erbB family of one or more receptor tyrosine kinases, such as EGFR and/or erbB2 and/or erbB4 (particularly EGFR), which are associated with signalling steps which lead to the proliferation and/or survival of tumour cells, which method comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

According to a further feature of this aspect of the invention there is provided the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the prevention or treatment of those tumours which are sensitive to inhibition of erbB receptor tyrosine kinases, such as EGFR and/or erbB2 and/or erbB4 (especially EGFR), which are involved in signalling steps leading to tumour cell proliferation.

According to a further aspect of the invention there is provided the use of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing EGFR and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinase inhibition.

According to a further feature of this aspect of the invention there is provided a method of providing tyrosine kinase inhibition of EGFR and/or erbB2 and/or erbB4 (especially EGFR) which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

According to a further feature of this aspect of the invention there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in providing EGFR and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinase inhibition.

According to another feature of the invention, there is provided the use of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing selective EGFR tyrosine kinase inhibition.

According to a further feature of this aspect of the invention there is provided a method of providing selective EGFR tyrosine kinase inhibition which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

According to another feature of this aspect of the invention there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in providing selective EGFR tyrosine kinase inhibition.

By "selective EGFR kinase inhibition" is meant that the quinazoline derivatives of formula I have a stronger effect on EGF receptor tyrosine kinase than on other kinases. In particular, certain compounds of the invention have a greater effect on EGF receptor kinase than on other tyrosine kinases, such as other erbB receptor tyrosine kinases (e.g. erbB 2). E.g., based on relative IC determined in a suitable assay (e.g., the H116N-2 assay as previously described)₅₀It can be seen that the selective EGFR kinase inhibitors of the present invention have at least a 5-fold, preferably at least a 10-fold, increase in erbB2 receptor tyrosine kinase driven proliferation over EGFR tyrosine kinase driven proliferation.

According to a further feature of this aspect of the invention there is provided the use of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for the treatment of cancer, for example a cancer selected from leukaemia, multiple myeloma, lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectal, endometrial, gastric, head and neck, hepatic, pulmonary, neuronal, oesophageal, ovarian, pancreatic, prostate, renal, skin, testicular, thyroid, uterine and vulval cancers.

According to a further feature of this aspect of the invention there is provided a method of treating cancer (for example a cancer selected from leukaemia, multiple myeloma, lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectal, endometrial, gastric, head and neck, liver, lung, neuronal, oesophageal, ovarian, pancreatic, prostate, renal, skin, testicular, thyroid, uterine and vulval cancers) in a warm-blooded animal (such as a human) in need of such treatment which comprises administering to the animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

According to another feature of this aspect of the invention there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer (e.g. a cancer selected from leukaemia, multiple myeloma, lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectal, endometrial, gastric, head and neck, liver, lung, neuronal, oesophageal, ovarian, pancreatic, prostate, renal, skin, testicular, thyroid, uterine and vulval cancers).

As noted above, the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily vary depending upon other factors, the host treated, the route of administration, and the severity of the disease state being treated.

The anti-proliferative treatment defined above may be used alone as a monotherapy or in combination with conventional surgical, radiation or chemotherapy methods in addition to the quinazoline derivatives of the present invention. Such chemotherapeutic methods may include one or more of the following classes of antineoplastic agents:

(i) antiproliferative/antineoplastic agents employed in medical oncology, such as alkylating agents (e.g., cisplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan, and nitrosoureas); antimetabolites (such as antifolates, e.g. fluoropyrimidines like 5-fluorouracil and tegafur), raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea, antitumor antibiotics (such as anthracyclines like doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, actinomycin and chlortetracycline), antimitotics (such as vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine, and taxols (taxoids like taxol and taxotere), and topoisomerase inhibitors (such as epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);

(ii) Cytostatics, such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), estrogen receptor lowering modulators (e.g., fulvestrant), antiandrogens (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, fluorochlorazole (ravozole) and exemestane) and 5 α -reductase inhibitors such as finasteride;

(iii) agents that inhibit cancer cell invasion (e.g., metalloproteinase inhibitors (e.g., marimastat) and inhibitors of avian kinase plasminogen activator receptor function);

(iv) inhibitors of growth factor function, such inhibitors including growth factor antibodies, growth factor receptor antibodies (e.g., anti-erbb 2 antibody trastuzumab [ Herceptin ]^TM]And the anti-erbbl antibody cetuximab [ C225]) Farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, e.g. inhibitors of the epidermal growth factor family (e.g. EGFR family tyrosine kinase inhibitors)N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD 1839), N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet-type growth factor family and inhibitors of the hepatocyte growth factor family;

(v) anti-angiogenic agents, such as those that inhibit vascular endothelial growth factor (e.g., anti-vascular endothelial growth factor antibody bevacizumab [ Avastin ]^TM]The compounds disclosed in international patent applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) as well as those that act through other mechanisms (such as linoamine, inhibitors of integrin α v β 3 function and angiostatin);

(vi) vascular disrupting agents such as Combretastatin a4 and compounds disclosed in international patent applications WO99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapeutics, e.g., drugs directed to the above-listed targets (e.g., ISIS 2503, an anti-ras antisense);

(viii) gene therapy pathways, including, for example, replacement of aberrant gene pathways, such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (therapy involving enzyme prodrugs of genes) pathways, such as those employing cytosine deaminase, thymidine kinase, or bacterial nitroreductase, and pathways that enhance patient resistance to chemotherapy or radiation therapy, such as multiple drug resistance gene therapy; and

(ix) Immunotherapeutic approaches, including, e.g., in vitro and in vivo approaches to enhance the immunogenicity of patient tumor cells, such as transfection with cytokines (e.g., interleukin 2, interleukin 4, or granulocyte macrophage colony stimulating factor), approaches to reduce T-cell anergy, approaches employing transfected immune cells (e.g., cytokine-transfected dendritic cells), approaches employing cytokine-transfected tumor cell lines, and approaches employing anti-atopic antibodies.

Such combination therapy may be performed by administering the individual components of the therapy simultaneously, sequentially or separately. Such combination products may employ the compounds of the present invention within the dosage ranges previously described, as well as other pharmaceutically active agents within their approved dosage ranges.

According to one aspect of the present invention there is provided a pharmaceutical product comprising a quinazoline derivative of the formula I as defined hereinbefore and a further anti-tumour agent as defined hereinbefore for use in combination therapy for cancer.

Although the compounds of formula I are primarily useful as therapeutic agents in warm-blooded animals including humans, they may also be used to inhibit the action of erbB receptor tyrosine protein kinases when required. Therefore, these compounds can also be used as pharmaceutical standards in new biological test development and new pharmacological drug research.

The invention will now be further illustrated by the following non-limiting examples in which, unless otherwise stated:

(i) temperatures are both degrees Celsius (. degree. C.); all operations are carried out at room or ambient temperature, i.e. in the temperature range of 18-25 ℃;

(ii) drying the organic solvent by anhydrous magnesium sulfate; evaporating the solvent by a rotary evaporator at a bath temperature of not higher than 60 ℃ under reduced pressure (600-;

(iii) chromatography refers to silica gel rapid chromatography; thin Layer Chromatography (TLC) was performed on silica gel plates;

(iv) usually the reaction process is followed by TLC and/or analytical LCMS, the reaction times given are for illustration only;

(v) the final products all have satisfactory proton Nuclear Magnetic Resonance (NMR) spectra and/or mass spectral data;

(vi) the yields given are for illustration only and are not necessarily yields obtained by careful study procedures; if more product is desired, the preparation can be repeated;

(vii) when NMR data are given, unless otherwise statedIt is clear that the NMR data are given as delta values for the main diagnostic protons, expressed in parts per million (ppm) relative to Tetramethylsilane (TMS) as internal standard, using deuterated dimethyl sulfoxide (DMSO-d) ₆) Is a solvent, measured at 300 MHz; the following abbreviations are used: s, singlet; d, double peak; t, triplet; q, quartet; m, multimodal; b, broad peak;

(viii) chemical symbols have the usual meaning; SI units and symbols are used;

(ix) the solvent ratios given are volume to volume (v/v); and

(x) Mass Spectrometry (MS) employs a direct exposure probe for detection using 70 electron volt electron energy in a Chemical Ionization (CI) mode, ionization being by electrospray; giving the m/z value; only protons representing the parent mass are reported; unless otherwise stated, the mass ion is represented as (MH)⁺；

(xi) Unless otherwise indicated, compounds containing asymmetrically substituted carbon and/or sulfur atoms are not resolved;

(xii) When a synthesis is described similar to that described in the previous examples, the millimolar ratio of the amounts used is equivalent to that used in the previous examples;

(xvi) The following abbreviations are used:

DCM dichloromethane;

DMF N, N-dimethylformamide;

DMA N, N-dimethylacetamide;

THF tetrahydrofuran;

HATU hexafluorophosphate O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea

Onium salts

(xvii) When describing a synthetically obtained acid addition salt (e.g., the HCl salt), the specific stoichiometry of the salt is not confirmed;

(xviii) Unless otherwise indicated, all NMR data reported in examples 1-15 and the reference examples are free base species which were converted from the isolated salt to the free base form prior to identification.

Example 1

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (1-methylpyrrolidin-3-yl) oxy ] quinazoline

To a suspension of 4- (3-chloro-2-fluoroanilino) -6-hydroxy-7-methoxyquinazoline (reference example 2; 639mg, 2.0mmol) in DCM (30ml) were added 1-methyl-3-pyrrolidinol (658. mu.l, 6.0mmol) and triphenylphosphine (1572mg, 6.0 mmol). The suspension was cooled to 0 ℃ under a nitrogen atmosphere. A solution of di-tert-butyl azodicarboxylate (1380mg, 6mmol) in DCM (20ml) was added dropwise over 15 min. The resulting light brown solution was allowed to warm to room temperature and stirred overnight. The solution was evaporated and the residue was purified by chromatography eluting with 0-5% methanol in DCM. The appropriate fractions were combined, evaporated and the crude product (230mg) redissolved in 1: 1 methanol/DCM (5 ml). Etherified HCl (1M, 1.14ml) was added and the mixture was evaporated. Crystallization from methanol/diethyl ether gave the title product as the hydrochloride salt as a white crystalline solid (154mg, 16%); ¹ H NMR(hydrochloride salt):

2.30(m，1H)，2.65-2.75(m，1H)，2.88(s，3H)，3.30-3.80(m，3H)，3.85-4.05(m，1H)，4.00(s，3H)，5.46(m，1H)，7.35(dd，1H)，7.45(s，1H)，7.51(dd，1H)，7.62(dd，1H)，8.53(s，1H)，8.72(s，1H)，8.81(s，1H)；

mass spectrometry ：403.3，405.3。

Example 2

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (piperidin-4-yl) oxy ] quinazoline

Coupling 6- { [ (1-tert-Butoxycarbonyl) piperidin-4-yl]Oxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline (reference example 3; 350mg, 0.70mmol) was dissolved in trifluoroacetic acid (5ml), and the solution was left to stand for 2 hours. The excess trifluoroacetic acid was evaporated and the residue azeotroped 2 times with DCM. The residue was purified by chromatography using 0-4% (7: 1 MeOH/concentrated NH)₄Aqueous OH) in DCM. Evaporation of the appropriate fractions afforded the product as an off-white solid (270mg, 96%);

¹ H NMR：1.53-1.64(m，2H)，2.00-2.05(m，2H)，2.64-2.72(m，2H)，3.00-3.07(m，2H)，3.92(s，3H)，4.60(m，1H)，7.20(s，1H)，7.26(ddd，1H)，7.47(dd，1H)，7.50(dd，1H)，7.82(s，1H)，8.34(s，1H)，9.56(s，1H)；

mass spectrometry：403.2，405.2。

Example 3

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (piperidin-4-yl) methoxy ] quinazoline

The procedure described in example 2 was repeated using 6- { [ (1-tert-butoxycarbonyl) piperidin-4-yl ] methoxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline (reference example 4). The title compound was obtained in 91% yield;

¹ H NMR：1.45-1.61(m，2H)，1.95-2.00(m，2H)，2.18(m，1H)，2.92(m，2H)，3.25-3.35(m，2H)，3.93(s，3H)，4.03(d，2H)，7.20(s，1H)，7.26(dd，1H)，7.46(dd，1H)，7.50(dd，1H)，7.89(s，1H)，8.36(s，1H)，8.72(br.s，1H)，9.74(s，1H)；

mass spectrometry：417.4，419。

Example 4

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (1-methylpiperidin-4-yl) oxy ] quinazoline

Coupling 6- { [ (1-tert-Butoxycarbonyl) piperidin-4-yl]Oxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline (reference example 3; 300mg, 0.66mmol) was dissolved in formic acid (10 ml). Aqueous formaldehyde (40%, 1ml) was added and the mixture was heated to 90C for 3 hours. The mixture was evaporated and the residue was dissolved in water (30 ml). The solution was adjusted to pH 8-9 by adding sodium hydroxide solution (1M) resulting in a white precipitate; collected by filtration and washed with water (20 ml). The crude product was purified by chromatography using 0-2.5% (7: 1 MeOH/concentrated NH) ₄Aqueous OH) in DCM. The appropriate fractions were evaporated and the residue was crystallized from acetonitrile to give the title product as a white crystalline solid (55mg, 20%);

¹ H NMR：1.66-1.76(m，2H)，1.95-2.05(m，2H)，2.14-2.22(m，2H)，2.18(s，3H)，2.65-2.70(m，2H)，3.92(s，3H)，4.51(m，1H)，7.19(s，1H)，7.26(dd，1H)，7.47(dd，1H)，7.51(dd，1H)，7.78(s，1H)，8.34(s，1H)，9.53(s，1H)；

mass spectrometry：417.2，419.3。

Example 5

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (1-methylpiperidin-4-yl) methoxy ] quinazoline

The procedure described in example 4 was repeated using 6- { [ (1-tert-butoxycarbonyl) piperidin-4-yl ] methoxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline (reference example 4). After crystallization from methyl tert-butyl ether, the title compound was obtained in 42% yield;

¹ H NMR：1.28-1.42(m，2H)，1.79-1.95(m，5H)，2.17(s，3H)，2.80(m，2H)，3.95(s，3H)，3.98(d，2H)，7.20(s，1H)，7.28(dd，1H)，7.48(dd，1H)，7.52(dd，1H)，7.77(s，1H)，8.37(s，1H)，9.59(s，1H)；

mass spectrometry：431.1，430.0。

Example 6

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [2- (1-methylpiperidin-4-yl) ethoxy ] quinazoline

The procedure described in example 4 was repeated using 6- { [2- (1-tert-butoxycarbonyl) piperidin-4-yl ] ethoxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline (reference example 5). After crystallization from methyl tert-butyl ether, the title compound is obtained in a yield of 60%;

¹ H NMR：1.17-1.30(m，2H)，1.43(m，1H)，1.65-1.85(m，6H)，2.11(s，3H)，2.73(m，2H)，3.92(s，3H)，4.14(t，2H)，7.18(s，1H)，7.26(ddd，1H)，7.46(dd，1H)，7.51(dd，1H)，7.76(s，1H)，835(s，1H)，9.53(s，1H)；

mass spectrometry：445.5，447。

Example 7

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (2-methoxyethyl) piperidin-4-yl ] oxy } quinazoline

Coupling 6- { [ (1-tert-Butoxycarbonyl) piperidin-4-yl]Oxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline (reference example 3; 485mg, 1.07mmol) was dissolved in trifluoroacetic acid (10ml), and the solution was stirred at room temperature for 2 hours. The excess trifluoroacetic acid was evaporated and the residue azeotroped 2 times with DCM. The residue was dissolved in DMA (25 ml); potassium carbonate (887mg, 6.42mmol) and 1-bromo-2-methoxyethane (100. mu.l, 1.07mmol) were added. The mixture was stirred at room temperature for 16 hours. Potassium carbonate (444mg, 3.21mmol) and 1-bromo-2-methoxyethane (100. mu.l, 1.07mmol) were then added and the mixture was heated at 60 ℃ for 4 hours. The solvent was evaporated and the residue partitioned between DCM (50ml) and water (50 ml). The aqueous layer was extracted with DCM (2X 30ml) and the extracts were combined with DCM layers. The combined DCM fractions were filtered through silicone treated filter paper and evaporated. The residue was purified by chromatography using 0-2% (7: 1 MeOH/concentrated NH) ₄Aqueous OH) in DCM. The appropriate fractions were evaporated and the residue was crystallized from acetonitrile to give the title product as a white crystalline solid (153mg, 38%);

¹ H NMR：1.60-1.75(m，2H)，1.95-2.05(m，2H)，2.30(m，2H)，2.49(t，2H)，2.75-2.82(m，2H)，3.22(s，3H)，3.43(t，2H)，3.92(s，3H)，4.51(m，1H)，7.19(s，1H)，7.26(ddd，1H)，7.47(dd，1H)，7.51(dd，1H)，7.78(s，1H)，834(s，1H)，9.53(s，1H)；

mass spectrometry：461.2，463.2。

Example 8

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (2-methoxyethyl) piperidin-4-yl ] methoxy } quinazoline

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (piperidin-4-yl) methoxy]Quinazoline (example 3, 104mg, 0.25mmol) was dissolved in DMA (5 ml). Potassium carbonate (138mg, 1.00mmol) and 1-bromo-2-methoxyethane (24. mu.l, 0.25mmol) were added. The mixture was stirred at 60C for 4 hours. Potassium carbonate (138mg, 1.00mmol) and 1-bromo-2-methoxyethane (24. mu.l, 025mmol) were added and heating at 60 ℃ was continued for 4 hours. The solvent was evaporated and the residue partitioned between DCM (20ml) and water (20 ml). The aqueous layer was extracted with DCM (2X 10ml) and the extracts were combined with DCM layers. The combined DCM fractions were filtered through silicone treated filter paper and evaporated. The residue was purified by chromatography using 0-2.5% (7: 1 MeOH/concentrated NH)₄Aqueous OH) in DCM. The appropriate fractions were combined, evaporated and the crude product (40mg) redissolved in 1: 1 methanol/DCM (5 ml). Ethereal HCl (1M, 0.5ml) was added and the mixture was evaporated. Crystallization from isopropanol/diethyl ether gave the title product as the hydrochloride salt as a yellow solid (28mg, 20%); ¹ H NMR (hydrochloride salt)：

1.60-1.75(m，2H)，2.00-2.05(m，2H)，2.16(m，1H)，2.95-3.10(m，2H)，3.22(t，2H)，3.29(s，3H)，3.50-3.57(m，2H)，3.70(t，2H)，3.99(s，3H)，4.12(d，2H)，7.34(dd，1H)，7.39(s，1H)，7.51(dd，1H)，7.61(dd，1H)，8.46(s，1H)，8.78(s，1H)，10.08(br.s，1H)；

Mass spectrometry：475.5，477。

Example 9

4- (3-chloro-2-fluoroanilino) -6- { [1- (methylsulfonyl) piperidin-4-yl ] oxy } -7-methoxyquinazoline

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (piperidin-4-yl) oxy]The quinazoline (example 2, 1360mg, 3.38mmol) was dissolved in DMA (40ml) and diisopropylethylamine (882. mu.l, 5.07mmol) was added. Methanesulfonyl chloride (392. mu.l, 5.07mmol) was added and the solution was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was purified by chromatography with 0-2% (7: 1 MeOH/concentrated NH)₄Aqueous OH) in DCM. The appropriate fractions were combined, evaporated and the residue crystallized from ethyl acetate/hexanes to give the product as a white crystalline solid (650mg, 40%);

¹ H NMR：1.80-1.90(m，2H)，2.04-2.13(m，2H)，2.91(s，3H)，3.10-3.20(m，2H)，3.34-3.44(m，2H)，3.93(s，3H)，4.67(m，1H)，7.22(s，1H)，7.27(dd，1H)，7.47(dd，1H)，7.51(dd，1H)，7.86(s，1H)，8.37(s，1H)，9.55(s，1H)；

mass spectrometry：481.2，483.1。

Example 10

4- (3-chloro-2-fluoroanilino) -6- { [1- (methylsulfonyl) piperidin-4-yl ] methoxy } -7-methoxyquinazoline

The procedure described in example 9 was repeated using 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (piperidin-4-yl) methoxy ] quinazoline (example 3). After trituration with ether, the following compound was obtained in 71% yield;

¹ H NMR：1.31-1.47(m，2H)，1.90-2.07(m，3H)，2.76(m，2H)，2.85(s，3H)，3.56-3.67(m，2H)，3.93(s，3H)，4.01(d，2H)，7.19(s，1H)，7.26(dd，1H)，7.46(dd，1H)，7.50(dd，1H)，7.78(s，1H)，8.36(s，1H)，9.61，(s，1H)；

mass spectrometry：495.4，497.4。

Example 11

6- { [1- (carbamoylmethyl) piperidin-4-yl ] oxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (piperidin-4-yl) oxy]The quinazoline (example 2, 70mg, 0.17mmol) was dissolved in DMA (10ml) and diisopropylethylamine (45. mu.l, 0.26mmol) was added. 2-Bromoacetamide (36mg, 0.26mmol) was added and the solution was stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by chromatography with 0-3% (7: 1 MeOH/concentrated NH)₄Aqueous OH) in DCM. The appropriate fractions were combined, evaporated and the residue crystallized from acetonitrile to give the product as a white crystalline solid (48mg, 60%);

¹ H NMR：1.70-1.84(m，2H)，1.98-2.09(m，2H)，2.38(m，2H)，2.70-2.80(m，2H)，2.89(s，2H)，3.92(s，3H)，4.54(m，1H)，7.08(br.s，2H)，7.20(s，1H)，7.26(ddd，1H)，7.47(ddd，1H)，7.51(ddd，1H)，7.80(s，1H)，8.35(s，1H)，9.53(s，1H)；

mass spectrometry：460.5，462.4。

Example 12

6- { [1- (carbamoylmethyl) piperidin-4-yl ] methoxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline

The procedure described in example 11 was repeated using 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (piperidin-4-yl) methoxy ] quinazoline (example 3). After crystallization from acetonitrile, the title compound was obtained in 44% yield;

¹ H NMR：1.34-1.50(m，2H)，1.77-1.90(m，3H)，2.05-2.20(m，2H)，2.80-2.95(m，4H)，3.93(s，3H)，3.97(d，2H)，7.04-7.16(m，2H)，7.19(s，1H)，7.26(ddd，1H)，7.46(ddd，1H)，7.50(ddd，1H)，7.76(s，1H)，8.35(s，1H)，9.58(s，1H)；

mass spectrometry：474.4，476.4。

Example 13

4- (3-chloro-2-fluoroanilino) -6- { [1- (cyanomethyl) piperidin-4-yl ] oxy } -7-methoxyquinazoline

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (piperidin-4-yl) oxy]Quinazoline (example 2, 70mg, 0.17mmol) was dissolved in DMA (5 ml). Potassium carbonate (96mg, 0.70mmol) and chloroacetonitrile (17. mu.l, 0.25mmol) were added. The mixture was stirred at 60 ℃ for 4 hours. The solvent was evaporated and the residue partitioned between DCM (20ml) and water (20 ml). The aqueous layer was extracted with DCM (2X 10ml) and the extracts were combined with DCM layers. The combined DCM fractions were filtered through silicone treated filter paper and evaporated. The residue was purified by chromatography using 0-2% (7: 1 MeOH/concentrated NH) ₄Aqueous OH) in DCM. The appropriate fractions were combined, evaporated and the residue triturated with ether to give the product as a white solid (28mg, 36%);

¹ H NMR：1.67-1.80(m，2H)，2.03-2.13(m，2H)，2.46(m，2H)，2.77-2.85(m，2H)，3.76(s，2H)，3.92(s，3H)，4.55(m，1H)，7.20(s，1H)，7.27(dd，1H)，7.47(dd，1H)，7.52(dd，1H)，7.80(s，1H)，8.35(s，1H)，9.54(s，1H)；

mass spectrometry：442.4，444.4。

Example 14

4- (3-chloro-2-fluoroanilino) -6- { [1- (cyanomethyl) piperidin-4-yl ] methoxy } -7-methoxyquinazoline

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (piperidin-4-yl) methoxy]Quinazoline (example 3, 104mg, 0.25mmol) was dissolved in DMA (5 ml). Potassium carbonate (138mg, 1.00mmol) andchloroacetonitrile (17. mu.l, 0.25 mmol). The mixture was stirred at 60 ℃ for 4 hours. Potassium carbonate (138mg, 1.00mmol) and chloroacetonitrile (17. mu.l, 0.25mmol) were added thereto, and heating at 60 ℃ was continued for 4 hours. The solvent was evaporated and the residue partitioned between DCM (20ml) and water (20 ml). The aqueous layer was extracted with DCM (2X 10ml) and the extracts were combined with DCM layers. The combined DCM fractions were filtered through silicone treated filter paper and evaporated. The residue was purified by chromatography using 0-2% (7: 1 MeOH/concentrated NH)₄Aqueous OH) in DCM. The appropriate fractions were combined, evaporated and the residue purified by reverse phase HPLC eluting with 5-95% acetonitrile in 0.2% trifluoroacetic acid in water. Combining the appropriate fractions; acetonitrile was evaporated from the solution and the resulting aqueous solution was adjusted to pH 8 with concentrated ammonia. The resulting suspension was extracted 2 times with DCM, the extracts were combined, filtered through a silicone treated filter paper and evaporated. The residue was triturated with ether to give the product as a white solid (10mg, 9%);

¹ H NMR：1.32-1.46(m，2H)，1.75-1.92(m，3H)，2.20(m，2H)，2.84(m，2H)，3.72(s，2H)，3.93(s，3H)，3.98(d，2H)，7.20(s，1H)，7.26(dd，1H)，7.47(dd，1H)，7.50(dd，1H) 7.76(s，1H)，8.36(s，1H)，9.59(s，1H)；

Mass spectrometry：456.4，458.4。

Example 15

4- (3-chloro-2-fluoroanilino) -6- [ (1-cyanopiperidin-4-yl) methoxy ] -7-methoxyquinazoline

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (piperidin-4-yl) methoxy]The quinazoline (as shown in example 3,104mg, 0.25mmol) was dissolved in DCM (10ml) and diisopropylethylamine (48. mu.l, 0.28mmol) was added. Cyanogen bromide solution (3M in DCM, 92. mu.l, 0.28mmol) was added and the solution was stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by chromatography with 0-2% (7: 1 MeOH/concentrated NH)₄Aqueous OH) in DCM. The appropriate fractions were combined, evaporated and the residue triturated with ether to give the product as a white solid (75mg, 68%);

¹ H NMR：1.34-1.50(m，2H)，1.80-1.90(m，2H)，2.02(m，1H)，3.10(m，2H)，3.37-3.46(m，2H)，3.93(s，3H)，3.99(d，2H)，7.19(s，1H)，7.26(dd，1H)，7.46(dd，1H)，7.46(dd，1H)，7.50(dd，1H)，7.77(s，1H)，836(s，1H)，9.57(s，1H)；

mass spectrometry：442.4，444.4。

Example 16

6- (1-acetylpiperidin-4-yloxy) -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline

Acetyl chloride (179mg) was added to a solution of 6- (piperidin-4-yloxy) -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline dihydrochloride (1g) and diisopropylethylamine (735mg) in dichloromethane which had been cooled to 0 ℃, and the mixture was stirred for 2 hours and then warmed to room temperature. The reaction mixture is absorbed into silica gel and the residue is purified by column chromatography, eluting with a dichloromethane/methanol mixture of increasing polarity (100/0-90/10). The fractions containing the desired product were combined and evaporated in vacuo to give the title product as a colourless foam (0.655 g). ¹ H NMR light Spectrum：

(DMSO d₆)1.54-1.78(m，2H)，1.91-2.10(m，5H)，3.29-3.41(m，2H)，3.66-3.76(m，1H)，3.78-3.88(m，1H)，3.93(s，3H)，4.74(m，1H)，7.20(s，1H)，7.27(t，1H)，7.44-7.55(m，2H)，7.87(s，1H)，8.36(s，1H)，9.54(s，1H)；

Mass spectrometry：(M+H)⁺445。

The starting 6- (piperidin-4-yloxy) -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline dihydrochloride was prepared as follows:

6-acetoxy-4-chloro-7-methoxyquinazoline (example 25-5; 10.0g, 39.6mmol in WO 01/66099) was added in portions to 7N methanolic ammonia solution (220ml) which had been cooled to 10 ℃ in an ice/water bath. After stirring for 1 hour, the precipitate was filtered, washed with ether and dried thoroughly under high vacuum to give 4-chloro-6-hydroxy-7-methoxyquinazoline (5.65g, 67.8%); ¹ H NMR optical spectrum：

(DMSO d₆)3.96(s，3H)；7.25(s，1H)；7.31(s，1H)；8.68(s，1H)；

Mass spectrometry：(M+H)⁺211。

A solution of di-tert-butyl azodicarboxylate (9.22g) in dichloromethane (20ml) was slowly added to a stirred solution of 4-chloro-6-hydroxy-7-methoxyquinazoline (5.63g), 4-hydroxy-1-tert-butoxycarbonylpiperidine (8.06g) and triphenylphosphine (10.5g) in dichloromethane (100ml) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was warmed to room temperature for 16 hours. The reaction mixture was then evaporated in vacuo, taken up in silica gel and the product was eluted with isohexane/ethyl acetate/triethylamine (75/24/1, then 70/29/1). The fractions containing the desired product were combined and evaporated in vacuo to give 4- [ (4-chloro-7-methoxyquinazolin-6-yl) oxy]Piperidine-1-carboxylic acid tert-butyl ester as a white solid (10.3 g); ¹ H NMR spectra：

(DMSO d₆)1.40(s，9H)，1.56-1.69(m，2H)，1.93-2.04(m，2H)，3.20-331(m，2H)，3.60-3.70(m，2H)，4.00(s，3H)，4.89(m，1H)；7.45(s，1H)，7.50(s，1H)，8.86(s，1H)；

Mass spectrometry：(M+H)⁺394。

4.0M HCl in dioxane (4.0ml) was added to 4- [ (4-chloro-7-methoxyquinazolin-6-yl) oxy]Piperidine-1-carboxylic acid tert-butyl ester (2.62g) and 3-chloro-2-fluoroaniline (1.08g) in isopropanol (50 ml). The reaction mixture was stirred and heated to 100 ℃ for 2 hours. The yellow precipitate was filtered hot, washed sequentially with isopropanol and diethyl ether and dried under vacuum to give 6- (piperidin-4-yloxy) -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline as the dihydrochloride salt (2.38 g); ¹ H NMR spectra：

(DMSO d₆)1.84-1.99(m，2H)，2.22-2.33(m，2H)，3.12-3.33(m，4H)，4.00(s，3H)，5.08(m，1H)，734(t，1H)，7.40(s，1H)，7.50(t，1H)，7.62(t，1H)，8.80(s，1H)，8.84-8.94(m，2H)，8.99-9.11(m，1H)；

Mass spectrometry：(M+H)⁺403。

Example 17

4- (3-chloro-2-fluoroanilino) -6- [1- (N, N-dimethylaminoacetyl) piperidin-4-yloxy ] -7-methoxyquinazoline

4- (3-chloro-2-fluoroanilino) -6- [1- (chloroacetyl) piperidin-4-yloxy) at room temperature]A suspension of-7-methoxyquinazoline (0.14g) and sodium iodide (0.1g) in an ethanolic solution of dimethylamine (33%) (10ml) was stirred for 2 hours. The mixture was evaporated in vacuo and the residue was dissolved in dichloromethane and purified by silica gel column chromatography eluting with a dichloromethane/methanol mixture of increasing polarity (saturated with ammonia) (100/0-85/15). MergingFractions containing the title product were evaporated in vacuo and the residue triturated with ether and filtered to give the title product as a crystalline solid (0.085 g); ¹ H NMRSpectrum:

(DMSO d₆)1.56-1.78(m，2H)，1.92-2.08(m，2H)，2.20(s，6H)，3.05-3.18(m，2H)，3.30-3.48(m，2H)，3.79-3.90(m，2H)，3.94(s，3H)，4.75(m，1H)，7.21(s，1H)，7.28(t，1H)，7.44-7.56(m，2H)，7.86(s，1H)，8.37(s，1H)，9.53(s，1H)；

mass spectrometry：(M+H)⁺488。

The starting 4- (3-chloro-2-fluoroanilino) -6- [1- (chloroacetyl) piperidin-4-yloxy ] -7-methoxyquinazoline was prepared as follows:

chloroacetyl chloride (135mg) was added to a solution of 4- (3-chloro-2-fluoroanilino) -6- (piperidin-4-yloxy) -7-methoxyquinazoline dihydrochloride (500mg) (the starting material for example 16) and diisopropylethylamine (368mg) in dichloromethane (15ml) which had been cooled to 0 ℃, and the mixture was stirred for 2 hours and then warmed to room temperature. The reaction mixture was absorbed into silica gel and the residue was purified by column chromatography on silica gel eluting with a dichloromethane/methanol mixture of increasing polarity (100/0-94/6). The fractions containing the desired product were combined and the residue was purified by column chromatography over silica gel eluting with a dichloromethane/methanol mixture of increasing polarity (100/0-96/4). The fractions containing the desired product were combined and evaporated in vacuo to give 4- (3-chloro-2-fluoroanilino) -6- [1- (chloroacetyl) piperidin-4-yloxy)]7-Methoxyquinazoline as a crystalline solid (0.33 g). ¹ H NMRSpectrum:

(DMSO d₆)1.60-1.83(m，2H)，1.94-2.10(m，H)，3.36-3.46(m，2H)，3.67-3.86(m，2H)，3.94(s，3H)，4.40(s，2H)，4.77(m，1H)，7.22(s，1H)，7.27(t，1H)，7.46-7.55(m，2H)，7.89(s，1H)，8.38(s，1H)，9.60(s，1H)；

mass spectrometry：(M+H)⁺479。

Example 18

6- [1- (N, N-dimethylsulfamoyl) piperidin-4-yloxy ] -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline

Dimethylsulfonyl chloride (90mg) was added to a solution of 6- (piperidin-4-yloxy) -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline dihydrochloride (250mg) (starting material from example 16) and diisopropylethylamine (184mg) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was absorbed into silica gel and the residue was purified by column chromatography over silica gel eluting with a dichloromethane/methanol (100/0-95/5) mixture of increasing polarity. The fractions containing the desired product were combined, evaporated in vacuo and the residue triturated with ether to give the title product as a white solid (0.23 g); ¹ H NMRSpectrum:

(DMSO d₆)1.72-1.86(m，2H)，2.00-2.12(m，2H)，2.76(s，6H)；3.12-3.23(m，2H)，3.40-3.51(m，2H)，3.94(s，3H)，4.68(m，1H)，7.19-7.30(m，2H)，7.43-7.54(m，2H)，7.85(s，1H)，8.37(s，1H)，9.52(s，1H)；

mass spectrometry：(M+H)⁺510。

Example 19

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [1- (morpholinoacetyl) piperidin-4-yloxy ] quinazoline

Reacting 4- (3-chloro-2-fluorobenzeneAmino) -6- [1- (chloroacetyl) piperidin-4-yloxy]A suspension of (E) -7-methoxyquinazoline (0.15g) (the starting material used in example 17) and sodium iodide (0.02g) in morpholine (5ml) was stirred at room temperature for 16 hours. The mixture was evaporated in vacuo and the residue was dissolved in dichloromethane/methanol. It was then absorbed into silica gel and purified by column chromatography on silica gel eluting with a dichloromethane/methanol mixture of increasing polarity (100/0-90/10). The fractions containing the title product were combined and evaporated in vacuo. The residue was triturated with ether, filtered and dried in vacuo to give the title product as an off-white crystalline solid (0.105 g); ¹ H NMRspectrum: (DMSO-d)₆And

CD₃COOD)1.57-1.80(m，2H)，1.91-2.12(m，2H)，2.40-2.51(m，4H)，3.14-3.48(m，4H)，3.52-3.61(m，4H)，3.81-3.90(m，2H)，3.94(s，3H)，4.76(m，1H)，7.20-7.30(m，2H)，7.42-7.54(m，2H)，7.85(s，1H)，8.36(s，1H)；

mass spectrometry：(M+H)⁺530。

Example 20

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [1- (pyrrolidin-1-ylacetyl) piperidin-4-yloxy ] quinazoline

4- (3-chloro-2-fluoroanilino) -6- [1- (chloroacetyl) piperidin-4-yloxy)]A suspension of (E) -7-methoxyquinazoline (0.15g) (the starting material used in example 17) and sodium iodide (0.02g) in pyrrolidine (5ml) was stirred at room temperature for 16 hours. The mixture was evaporated in vacuo and the residue was dissolved in dichloromethane/methanol. It is then absorbed into silica gel and purified by column chromatography, eluting with a dichloromethane/methanol mixture of increasing polarity (100/0-92/8). The fractions containing the title product were combined and evaporated in vacuo The residue was triturated with ether, filtered and evaporated in vacuo to give the title product as a white crystalline solid (0.085 g); ¹ H NMRspectrum:

(DMSO d₆)1.57-1.77(m，6H)，1.92-2.09(m，2H)，3.20-3.48(m，8H)，3.80-3.90(m，2H)，3.94(s，3H)，4.75(m，1H)，7.2-7.31(m，2H)，7.45-7.55(m，2H)，7.86(s，1H)，8.37(s，1H)，9.53(s，1H)；

mass spectrometry：(M+H)⁺514。

Example 21

4- (3-chloro-2-fluoroanilino) -6- {1- [3- (dimethylamino) propylsulfonyl ] piperidin-4-yloxy } -7-methoxyquinazoline

4- (3-chloro-2-fluoroanilino) -6- {1- [ 3-chloropropylsulfonyl ] at room temperature]A suspension of piperidin-4-yloxy } -7-methoxyquinazoline (0.15g) and sodium iodide (0.03g) in an ethanol solution of dimethylamine (33%) (15ml) was stirred for 16 hours. The reaction mixture was absorbed into silica gel and purified by column chromatography on silica gel eluting with a dichloromethane/methanol mixture of increasing polarity (saturated with ammonia) (100/0-88/12). The fractions containing the title product were combined and evaporated in vacuo to give the title product (0.105 g); ¹ H NMRspectrum:

(DMSO d₆)1.75-1.87(m，4H)，2.0-2.11(m，2H)，2.12(s，6H)，2.30(t，2H)，3.05-3.14(m，2H)，3.17-3.29(m，2H)，3.40-3.50(m，2H)，3.93(s，3H)，4.69(m，1H)，7.22(s，1H)，7.28(t，1R)，7.44-7.55(m，2H)，7.86(s，1H)，8.37(s，1H)，9.53(s，1H)；

mass spectrometry：(M+H)⁺552。

Starting material 4- (3-chloro-2-fluoroanilino) -6- {1- [ 3-chloropropylsulfonyl ] piperidin-4-yloxy } -7-methoxyquinazoline was prepared as follows:

3-Chloropropylsulfonyl chloride (174mg) was added to a solution of 6- (piperidin-4-yloxy) -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline dihydrochloride (190 mg; the starting material from example 16) and diisopropylethylamine (140mg) in methylene chloride (5ml) at room temperature, and the reaction mixture was stirred for 16 hours. The reaction mixture was absorbed into silica gel and the residue was purified by column chromatography on silica gel eluting with a dichloromethane/methanol mixture of increasing polarity (100/0-94/6). The fractions containing the desired product were combined and evaporated in vacuo to give 4- (3-chloro-2-fluoroanilino) -6- {1- [ 3-chloropropylsulfonyl ]Piperidin-4-yloxy } -7-methoxyquinazoline, a brown gum (0.15 g).Quality of food Spectrum：(M+H)⁺543。

Example 22

4- (3-chloro-2-fluoroanilino) -6- [1- (methylsulfonyl) piperidin-3-yloxy ] -7-methoxyquinazoline

Methanesulfonyl chloride (42mg) was added to a solution of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (piperidin-3-yloxy) quinazoline (134mg) and diisopropylethylamine (65mg) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was absorbed into silica gel and the residue was purified by column chromatography eluting with a dichloromethane/methanol (100/0-95/5) mixture of increasing polarity. The fractions containing the title product were combined, evaporated in vacuo, the residue triturated with ether, filtered and dried in vacuo to give the title product as a mixture of 3R and 3S isomers (0.10 g); ¹ H NMRspectrum: (DMSO d)₆And CD₃COOD)

1.54-2.07(m，4H)，2.95(s，3H)，3.10-3.20(m，1H)，3.21-3.37(m，2H)，3.50-3.59(m，1H)，3.93(s，3H)，4.70(m，1H)，7.20-7.29(m，2H)，7.40-7.55(m，2H)，7.89(s，1H)，8.37(s，1H)；

Mass spectrometry：(M+H)⁺481。

The starting 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (piperidin-3-yloxy) quinazoline was prepared as follows:

4-Nitrobenzenesulfonyl chloride (4.4g) was added to a stirred solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (4.0g) and pyridine (2.25ml) in dichloromethane (80ml), and stirred at room temperature for 16 hours. The reaction mixture was poured into saturated sodium bicarbonate solution. The organic layer was separated, washed with brine and dried over sodium sulfate. The solution was evaporated in vacuo, triturated with ether and filtered to remove unwanted solids. The ether solution was evaporated in vacuo and then dissolved in dichloromethane and purified by column chromatography on silica gel eluting with ethyl acetate/isohexane (20/80). The fractions containing the desired product were combined and evaporated in vacuo to give 3- [ (4-nitrophenyl) sulfonyloxy ]Tert-butyl piperidine-1-carboxylate as a yellow crystalline solid (6.77 g); ¹ H NMRspectrum:

(CDCl₃)1.43(s，9H)，1.40-1.54(m，1H)，1.70-1.94(m，3H)，3.22-3.60(m，4H)，4.67(m，1H)，8.11(s，2H)，8.40(s，2H).

dimethylformamide (23ml) was added to 4- (3-chloro-2-fluoroanilino) -6-hydroxy-7-methoxyquinazoline, 3- [ (4-nitrophenyl) sulfonyloxy]Piperidine-1-carboxylic acid tert-butyl ester (1.93g) and cesium fluoride (2.28 g). The reaction mixture was then stirred at room temperature for 4 days. The reaction mixture was evaporated in vacuo and then partitioned between dichloromethane and water. The solution was filtered to remove insoluble solids, and the dichloromethane solution was washed with water and saturated brine, followed by absorption into silica gel. Purifying the product by silica gel column chromatography with a gradually increasing polarity of the diAnd eluting with a methyl chloride/methanol mixture (100/0-94/6). The fractions containing the desired product were combined and evaporated in vacuo to give 4- (3-chloro-2-fluoroanilino) -6- (1-tert-butoxycarbonylpiperidin-3-yloxy) -7-methoxyquinazoline as a yellow gum (0.67 g);mass spectrometry：(M+H)⁺503。

Trifluoroacetic acid (5ml) was added to a solution of 4- (3-chloro-2-fluoroanilino) -6- (1-tert-butoxycarbonylpiperidin-3-yloxy) -7-methoxyquinazoline (0.67g) in dichloromethane (15ml), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated in vacuo and the residue was dissolved in dichloromethane. The dichloromethane solution was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated to give 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (piperidin-3-yloxy) quinazoline (0.28 g); Mass spectrometry：(M+H)⁺403。

The 4- (3-chloro-2-fluoroanilino) -6-hydroxy-7-methoxyquinazoline starting material used above was prepared as follows:

6-acetoxy-4-chloro-7-methoxyquinazoline (example 25-5; 10.0g, 39.6mmol in WO 01/66099) was suspended in acetonitrile (400ml) and 3-chloro-2-fluoroaniline (6.05g, 41.6mmol) and hydrogen chloride (4.0M in 1, 4-dioxane) (10.4ml, 41.6mmol) were added. The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The resulting precipitate was filtered and washed with acetonitrile and diethyl ether to give a white solid. The solid was added portionwise to a stirred 7N solution of ammonia in methanol (400 ml). The mixture was stirred for 2 hours, the precipitate filtered, washed sequentially with acetonitrile and ether and dried in vacuo to give 4- (3-chloro-2-fluoroanilino) -6-hydroxy-7-methoxyquinazoline as a white solid (12.1g, 95%); ¹ H NMRspectrum:

(DMSO d₆)3.95(s，3H)；7.18(s，1H)；7.20-7.25(m，1H)；7.39-7.44(m，1H)；7.47-7.52(m，1H)；7.65(s，1H)；8.31(s，1H)；9.45(br.s，1H)；

mass spectrometry：(M+H)⁺320。

Example 22.1

Resolution of 4- (3-chloro-2-fluoroanilino) -6- [ (3R) -1- (methylsulfonyl) piperidin-3-yloxy ] -7-methoxyquinazoline and

4- (3-chloro-2-fluoroanilino) -6- [ (3S) -1- (methylsulfonyl) piperidin-3-yloxy ] -7-methoxyquinazoline

The racemic mixture obtained in example 22 (36mg) was resolved into the 3R and 3S enantiomers by chiral HPLC using the following conditions:

Chromatographic column 10 μm ChiralpakAS (20 mm. times.250 mm) No. AS00CJ-

IB004

Eluent isohexane/EtOH (80/20)

Column box temperature room temperature

Flow rate 10ml/min

Detection wavelength 254nm

Ethanol solution with sample concentration of 0.9mg/ml

Elution time 110 minutes

The first eluted enantiomer (10.1 mg); ¹ H NMRspectrum:

(DMSO d₆)1.60-1.80(m，1H)，1.80-1.95(m，1H)，1.95-2.08(m，1H)，2.08-2.22(m，1H)，3.08(s，3H)，3.20-3.45(m，1H)，3.45-3.50(m，2H)，3.70(dd，1H)，4.05(s，3H)，4.70-4.90(m，1H)，7.30-7.50(m，2H)，7.50-7.70(m，2H)，8.02(s，1H)，8.50(s，1H)，9.50(s，1H)；

mass spectrometry：(M+H)⁺481。

The enantiomer eluted later (18.7 mg); ¹ H NMRspectrum:

(DMSO d₆)1.60-1.80(m，1H)，1.80-1.95(m，1H)，1.95-2.08(m，1H)，2.08-2.22(m，1H)，3.08(s，3H)，32.20-3.45(m，1H)，3.45-3.50(m，2H)，3.70(dd，1H)，4.05(s，3H)，4.70-4.90(m，1H)，7.30-7.50(m，2H)，7.50-7.70(m，2H)，8.02(s，1H)，8.50(s，1H)，9.50(s，1H)；

mass spectrometry：(M+H)⁺481。

Example 23

6- (1-acetylpiperidin-3-yloxy) -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline

Acetyl chloride (27mg) was added to a solution of 4- (3-chloro-2-fluoroanilino) -6- (piperidin-3-yloxy) -7-methoxyquinazoline (the starting material described in example 22; 134mg) and diisopropylethylamine (65mg) in dichloromethane (5ml), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was absorbed into silica gel and purified by column chromatography eluting with a mixture of dichloromethane/methanol (100/0-95/5) of increasing polarity. The fractions containing the desired product were combined and evaporated to give the title product (0.07 g); ¹ H NMRspectrum: (DMSO-d)₆，@373K)

1.52-1.62(m，1H)，1.80-1.94(m，2H)，2.00(s，3H)，2.06-2.15(m，1H)，3.43-3.64(m，3H)，3.82-4.04(m，4H)，4.58(m，1H)，7.20-7.29(m，2H)，7.42(t，1H)，7.59(t，1H)，7.93(s，1H)，8.40(s，1H)，9.30(s，1H)；

Mass spectrometry：(M+H)⁺445。

Example 24

4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4S) -2- (N, N-dimethylcarbamoyl) pyrrolidin-4-yloxy ] -7-methoxyquinazoline

Trifluoroacetic acid (5ml) was added to 4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4S) -1- (tert-butoxycarbonyl) -2- (N, N-dimethylcarbamoyl) pyrrolidin-4-yloxy]7-Methoxyquinazoline (0.17g) in dichloromethane (10ml) the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in methanol (saturated with ammonia)/dichloromethane and then taken up in silica gel and purified by column chromatography eluting with a mixture of dichloromethane/methanol (saturated with ammonia) (100/0-85/15) of increasing polarity. The fractions containing the desired product were combined and evaporated in vacuo to give the title product as a colourless gum which crystallised on standing (0.13 g); ¹ H NMRspectrum: (DMSO d)₆And CD₃COOD)

1.85-1.96(m，1H)，2.84-2.95(m，4H)，3.00(s，3H)，3.24-3.32(m，1H)，3.40-3.48(m，1H)，3.95(s，3H)，4.31(m，1H)，5.21(m，1H)，7.20-7.30(m，2H)，7.47-7.55(m，2H)，7.76(s，1H)，8.37(s，1H)；

Mass spectrometry：(M+H)⁺460。

The starting 4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4S) -1- (tert-butoxycarbonyl) -2- (N, N-dimethylcarbamoyl) pyrrolidin-4-yloxy ] -7-methoxyquinazoline was prepared as follows:

1- [3- (dimethylamino) propyl]-3-Ethylcarbodiimide hydrochloride (2.48g) was added to a stirred suspension of N-tert-butoxycarbonyl-L-hydroxyproline (2.0g), 4- (dimethylamino) pyridine (5.28g) and dimethylamine hydrochloride (1.4g) in dichloromethane (100ml), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with citric acid (1.0M), saturated sodium bicarbonate and saturated brine, and then dried over magnesium sulfate. The product was then purified by column chromatography on silica gel eluting with a dichloromethane/methanol mixture of increasing polarity (100/0-90/10). The fractions containing the desired product were combined and evaporated in vacuo to give (2S, 4R) -1- (tert-butoxycarbonyl) -4-hydroxy-2- (N, N-dimethylcarbamoyl) pyrrolidine as a colourless gum (1.01 g); ¹ H NMRSpectrum:

(DMSO d₆)1.29-1.40(m，9H)，1.74-1.83(m，1H)，2.04-2.15(m，1H)，2.80-2.87(m，3H)，3.03(s，3H)，3.26(m，1H)，3.40(m，1H)，4.28(m，1H)，4.64(m，1H)，4.95(d，1H).

4-Nitrobenzenesulfonyl chloride (0.895g) was added to a stirred solution of (2S, 4R) -1- (tert-butoxycarbonyl) -4-hydroxy-2- (N, N-dimethylcarbamoyl) pyrrolidine (0.993g) and pyridine (0.6g) in dichloromethane (10ml), and stirred under nitrogen at 4 ℃ for 16 hours. The reaction mixture was washed with citric acid (1.0M), saturated sodium bicarbonate and dried over magnesium sulfate. The product was then purified by column chromatography on silica gel eluting with a dichloromethane/methanol mixture of increasing polarity (100/0-95/5). The fractions containing the desired product were combined and evaporated in vacuo to give (2S, 4R) -1- (tert-butoxycarbonyl) -2- (N, N-dimethylcarbamoyl) -4- [ (4-nitrophenyl) sulfonyloxy)]Pyrrolidine as a yellow gum (0.685 g); ¹ H NMRspectrum:

(DMSO d₆)1.30-1.36(s，9H)，1.98-2.07(m，1H)；2.37-2.48(m，1H)；2.83(s，3H)，3.00(s，3H)，3.45-3.55(m，2H)，4.70(m，1H)，5.23(m，1H)，8.21(d，2H)，8.47(d，2H).

will twoMethylcarboxamide (8ml) was added to 4- (3-chloro-2-fluoroanilino) -6-hydroxy-7-methoxyquinazoline (0.489 g; prepared as described in the preparation of the starting material in example 22), (2S, 4R) -1- (tert-butoxycarbonyl) -2- (N, N-dimethylcarbamoyl) -4- [ (4-nitrophenyl) sulfonyloxy group]Pyrrolidine (0.678g) and cesium fluoride (0.697 g). The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in dichloromethane/methanol and subsequently taken up in silica gel. The product is then purified by column chromatography, eluting with a dichloromethane/methanol mixture of increasing polarity (100/0-90/10). The fractions containing the desired product were combined and evaporated. The residue was purified by column chromatography eluting with a mixture of ethyl acetate/methanol (100/0-92/8) of increasing polarity. The fractions containing the desired product were combined and evaporated in vacuo. To give 4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4S) -1- (tert-butoxycarbonyl) -2- (N, N-dimethylcarbamoyl) pyrrolidin-4-yloxy ]7-Methoxyquinazoline as a colourless gum, left to crystallize (0.36 g); ¹ H NMRspectrum:

(DMSO d₆@373K)1.41(s，9H)，1.99(m，1H)，2.92-3.03(m，7H)；3.44(m，1H)，3.96(s 3H)，4.14(m，1H)，4.70(t，1H)，5.10(m，1H)，7.22-7.30(m，2H)，7.44(t，1H)，7.62(t，1H)，7.84(s，1H)，8.40(s，1H)，9.30(s，1H)；

mass spectrometry：(M+H)⁺560。

Example 25

4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4S) -2- (N, N-dimethylcarbamoyl) -1-methylpyrrolidin-4-yloxy ] -7-methoxyquinazoline

4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4S) -1- (tert-Butoxycarbonyl) -2- (N, N-dimethylcarbamoyl) pyrrolidin-4-yloxy]7-Methoxyquinazoline (prepared as described in example 24; 0.18g), formic acid (0.31ml) and formaldehyde (0.51ml) were heated at 85 ℃ for 6 hours. The reaction was cooled and evaporated in vacuo. The resulting residue was partitioned between dichloromethane/n-propanol and saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, then absorbed into silica gel and purified by column chromatography, eluting with a dichloromethane/methanol (100/0-90/10) mixture of increasing polarity. The fractions containing the desired product were combined and evaporated in vacuo to afford a white crystalline solid. The solid was washed with water, dissolved in dichloromethane and dried over magnesium sulfate. The solvent was removed in vacuo to give the title product (0.11 g); ¹ H NMRspectrum:

(DMSO d₆)1.87(t，1H)，2.24(s，3H)，2.61-2.68(m，1H)，2.83(s，3H)，2.85-2.94(m，1H)，3.10(s，3H)，3.22-3.31(m，2H)，3.92(s，3H)，5.04(m，1H)，7.22(s，1H)，7.29(t，1H)，7.45-7.56(m，2H)，7.64(s，1H)，8.35(s，H)，9.56(s，1H)；

mass spectrometry：(M+H)⁺474。

Example 26

4- (3-chloro-2-fluoroanilino) -6- [1- (N, N-dimethylaminoacetyl) piperidin-3-yloxy ] -7-methoxyquinazoline

Reacting 6- [1- (chloroacetyl) piperidin-3-yloxy]-4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline (470mg, 0.98mmol) was treated with a solution of 33% dimethylamine in ethanol (20ml) and stirred at room temperature for 3 hours. The solvent was evaporated in vacuo and the residue was purified by column chromatography eluting with dichloromethane/methanol (9/1). The fractions containing the desired product were combined and evaporated in vacuo. Purifying the residue by column chromatography with dichloro-benzeneMethane/methanol (saturated with ammonia) (92/8). The fractions containing the desired product were combined and evaporated to give the title product (185mg, 39%); ¹ H NMRspectrum: (DMSO-d)₆，100℃)

1.40-1.65(m，1H)；1.75-1.95(m，2H)；2.00-2.30(m，7H)；3.05(dd，2H)；3.40-3.62(m，2H)；3.62-3.75(m，1H)；3.88(dd，1H)；3.95(s，3H)；4.45-4.65(m，1H)；7.15-7.30(m，2H)；7.30-7.47(m，1H)；7.50-7.7(m，1H)；7.88(s，1H)；8.40(s，1H)；9.25(s，1H)；

Mass spectrometry：(M+H)⁺488。

The starting 6- [1- (chloroacetyl) piperidin-3-yloxy ] -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline was prepared as follows:

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (piperidin-3-yloxy) quinazoline (430mg, 1.07mmol) (prepared as described in the preparation of the starting material in example 22), chloroacetyl chloride (126mg, 1.12mmol) and N, N-diisopropylethylamine (519mg, 4.02mmol) were stirred in dichloromethane (15ml) at room temperature for 2 hours. The solvent was evaporated in vacuo and the residue was purified by column chromatography eluting with dichloromethane/methanol saturated with ammonia (92/8) solvent. The solvent was removed in vacuo to give 6- [1- (chloroacetyl) piperidin-3-yloxy ]-4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline as a yellow gum (470 mg). This material was used without any further purification.Mass spectrometry：(M+H)⁺479。

Example 26.1

Resolution of 4- (3-chloro-2-fluoroanilino) -6- [ (3R) -1- (N, N-dimethylaminoacetyl) piperidin-3-yloxy ] -7-methoxyquinazoline and

4- (3-chloro-2-fluoroanilino) -6- [ (3S) -1- (N, N-dimethylaminoacetyl) piperidin-3-yloxy ] -7-methoxyquinazoline

The racemic mixture obtained in example 26 (320mg) was resolved into the 3R and 3S enantiomers by chiral HPLC using the following conditions:

chromatographic column Merck 50mm 20 μm Chiralpak AS VCSP No. AS00SC-

JG001

Eluent isohexane/EtOH 80/20

Column box temperature room temperature

Flow rate 40ml/min

Detection wavelength 254nm

EtOH/acetonitrile (80/20) solution with sample concentration of 10mg/ml

Elution time 110 minutes

The first eluted enantiomer (103 mg);mass spectrometry：(M+H)⁺488。

The enantiomer eluted later (97 mg);mass spectrometry：(M+H)⁺488。

Example 27

6- [1- (Acetoxyacetyl) piperidin-3-yloxy ] -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline

A suspension of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (piperidin-3-yloxy) quinazoline dihydrochloride (1.0g, 2.28 mmol; prepared as described in example 45) in dichloromethane (30ml) was treated with N, N-diisopropylethylamine (1.21g, 9.33mmol) and stirred at room temperature for 30 min. Under nitrogen atmosphere The resulting solution was cooled to 0 ℃, acetoxyacetyl chloride (354mg, 2.60mmol) was added, and the mixture was slowly warmed to room temperature with stirring. The solvent was evaporated in vacuo and the residue was purified by column chromatography eluting with dichloromethane/methanol saturated with ammonia (98/2) solvent. The fractions containing the desired product were combined and evaporated in vacuo to afford the title product (1.0g, 87%); ¹ H NMRspectrum: (DMSO-d)₆，100℃)

1.50-1.60(m，1H)，1.80-1.93(m，2H)，2.03(s，3H)；2.04-2.10(m，1H)；3.40-3.60(m，3H)；3.78-3.8(m，1H)；3.97(s，3H)；4.52-4.60(m，1H)；4.75(d，2H)；7.20-7.28(m，2H)；7.38-7.44(m，1H)；7.54-7.64(m，1H)；7.88(s，1H)；8.40(s，1H)；9.22(bs，1H)；

Mass spectrometry：(M+H)⁺503。

Example 28

4- (3-chloro-2-fluoroanilino) -6- [1- (hydroxyacetyl) piperidin-3-yloxy ] -7-methoxyquinazoline

Reacting 6- [1- (acetoxyacetyl) piperidin-3-yloxy)]A solution of (3-chloro-2-fluoroanilino) -7-methoxyquinazoline (930mg, 1.85mmol), (prepared as described in example 27), and potassium carbonate (385mg, 2.79mmol) in methanol (50ml) was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo and the residue was purified by column chromatography eluting with dichloromethane/methanol saturated with ammonia (92/8). The fractions containing the desired product were combined and evaporated. The residue was triturated with acetone, filtered and dried to give the title product (574mg, 67%); ¹ H NMRspectrum: (DMSO-d)₆，100℃)

1.50-1.60(m，1H)；1.80-1.92(m，2H)；2.04-2.13(m，1H)；3.44-3.56(m，3H)；3.77-3.88(m，1H)；3.97(s，3H)；4.10(d，2H)；4.50-4.60(m，1H)；7.20-7.27(m，2H)；7.38-7.42(m，1H)；7.55-7.60(m，1H)；7.88(s，1H)；8.38(s，1H)；9.25(bs，1H)；

Mass spectrometry：(M+H)⁺461。

Example 29

4- (3-chloro-2-fluoroanilino) -6- [ (3R) -1- (methylsulfonyl) pyrrolidin-3-yloxy ] -7-methoxyquinazoline

Under nitrogen atmosphere, 4- (3-chloro-2-fluoroanilino) -6- [ (3R) -pyrrolidin-3-yloxy]-7-Methoxyquinazoline hydrochloride (0.21g, 0.49mmol) was dissolved in a mixture of dichloromethane (4ml), pyridine (1ml) and diisopropylethylamine (0.17 ml). To the stirred solution was added methanesulfonyl chloride (0.06ml, 0.07 mmol). After stirring at room temperature for 2 hours, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtering and evaporating. The residue was purified by column chromatography eluting with dichloromethane/methanol (saturated with ammonia) (94/6). The fractions containing the desired product were combined, evaporated in vacuo, and the residual gum triturated with ether, filtered, and dried in vacuo to give the title product as a white solid (0.17g, 74%). ¹ H NMRSpectrum:

(DMSO d₆)2.18-2.37(m，2H)；2.93(s，3H)；3.33-3.45(m，2H)；3.5(d，1H)；3.69(dd，1H)；3.92(s，3H)；5.17(m，1H)；7.15-7.35(m，2H)；7.40-7.60(m，2H)；7.5(m，2H)；7.80(s，1H)；8.37(s，1H)；9.6(s，1H)；

mass spectrometry：(M+H)⁺467。

Starting 4- (3-chloro-2-fluoroanilino) -6- [ (3R) -pyrrolidin-3-yloxy ] -7-methoxyquinazoline hydrochloride was prepared as follows:

preparation of 3- [ (4-Nitrophenyl) sulfonyloxy group using example 22]In the same manner as described for tert-butyl piperidine-1-carboxylate, (3S) -1-tert-butoxycarbonyl-3-hydroxypyrrolidine (3.75g, 20mmol) was reacted with 4-nitrobenzenesulfonyl chloride to give (3S) -3- [ (4-nitrophenyl) sulfonyloxy group ]Pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown crystalline solid (5.0g, 67%). ¹ H NMRSpectrum:

(CDCl₃)1.44(s，9H)；2.05-2.2(m，2H)；3.37-3.59(m，4H)；5.16-5.23(m，1H)；8.12(d，2H)；8.41(d，2H).

4- (3-chloro-2-fluoroanilino) -6-hydroxy-7-methoxyquinazoline (prepared as described in the preparation of the starting material used in example 22; 4.0g, 12.5mmol) and (3S) -3- [ (4-nitrophenyl) sulfonyloxy]Pyrrolidine-1-carboxylic acid tert-butyl ester (4.7g, 12.6mmol) and cesium fluoride (5.7g, 7.5mmol) were combined. Then, anhydrous N, N-dimethylformamide (60ml) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water, 50% brine, then brine in sequence, over Na₂SO₄Drying, filtering and evaporating. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (98/2). The fractions containing the desired product were combined and evaporated to give 4- (3-chloro-2-fluoroanilino) -6- [ (3R) - (1-tert-butoxycarbonyl) pyrrolidin-3-yloxy]7-methoxyquinazoline as a dry foam (2.35g, 38%); ¹ H NMRspectrum:

(DMSO d₆)1.39(s，9H)；2.10-2.30(m，2H)；3.35-3.50(m，3H)；3.64-3.71(m，1H)；3.92(s，3H)；5.12(m，1H)；7.21(s，1H)；7.23-7.27(m，1H)；7.44-7.55(m，2H)；7.80(s，1H)；8.37(s，1H)；9.61(s，1H)；

mass spectrometry：(M+H)⁺489。

Reacting 4- (3-chloro-2-fluoroanilino) -6- [ (3R) - (1-tert-butoxycarbonyl) pyrrolidin-3-yloxy]-7-Methoxyquinazoline (2.3g, 4.7mmol) was dissolved in acetonitrile (35ml) and hydrogen chloride (4.0M in 1, 4-dioxane) (4.7ml, 18.8mmol) was added. The mixture was heated to reflux for 1 hour. After cooling to room temperature, the solid was filtered, washed with acetonitrile and diethyl ether and dried in vacuo to give 4- (3-chloro-2-fluoroanilino) -6- [ (3R) -pyrrolidin-3-yloxy) as a white solid ]-7-methoxyquinazoline hydrochloride (1.9g, 95%); ¹ H NMRspectrum:

(DMSO d₆)2.17-2.29(m，1H)；2.34-2.44(m，1H)；3.1-3.3(m，3H)；3.72-3.84(m，1H)；4.00(s，3H)；5.44(m，1H)；7.31-7.38(m，1H)；7.45(s，1H)；7.49-7.55(m，1H)；7.59-7.65(m，1H)；8.67(s，1H)；8.80(s，1H)；9.43(br.s 1H)；9.62(br.s，1H)；12.25(br.s，1H)；

mass spectrometry：(M-H)^-387。

Example 30

4- (3-chloro-2-fluoroanilino) -6- [ (3S) -1- (methylsulfonyl) pyrrolidin-3-yloxy ] -7-methoxyquinazoline

Using a similar method to that described in example 29, 4- (3-chloro-2-fluoroanilino) -6- [ (3S) -pyrrolidin-3-yloxy) was reacted]Reaction of-7-methoxyquinazoline hydrochloride (210mg) with methanesulfonyl chloride gave the title product (100mg, 43%). ¹ H NMRSpectrum:

(DMSO d₆)2.18-2.37(m，2H)；2.93(s，3H)；3.38-3.52(m，3H)；3.69(dd，1H)；3.92(s，3H)；5.17(m，1H)；7.15-7.35(m，2H)；7.40-7.60(m，2H)；7.80(s，1H)；8.38(s，1H)；9.58(s，1H)；

mass spectrometry：(M+H)⁺467。

The starting 4- (3-chloro-2-fluoroanilino) -6- [ (3S) -pyrrolidin-3-yloxy ] -7-methoxyquinazoline hydrochloride was prepared in a similar manner to that described for the preparation of the starting material in example 29 as follows:

(R) -1-tert-Butoxycarbonyl-3-hydroxypyrrolidine (3.75g, 20mmol) was converted into (3R) -3- [ (4-nitrophenyl) sulfonyloxy]Pyrrolidine-1-carboxylic acid tert-butyl ester (2.21g, 59%). ¹ H NMRSpectrum:

(DMSO d₆)1.44(s，9H)；2.05-2.25(m，2H)；3.37-3.59(m，4H)；5.20(s，1H)；8.11(d，2H)；8.41(d，2H).

reacting 4- (3-chloro-2-fluoroanilino) -6-hydroxy-7-methoxyquinazoline with (3R) -3- [ (4-nitrophenyl) sulfonyloxy]Pyrrolidine-1-carboxylic acid tert-butyl ester reaction to give 4- (3-chloro-2-fluoroanilino) -6- [ (3S) - (1-tert-butoxycarbonyl) pyrrolidin-3-yloxy]7-methoxyquinazoline as a dry foam (2.9g, 95%); ¹ H NMRspectrum:

(DMSO d₆)1.40(s，9H)；2.07-2.29(m，2H)；3.32-3.50(m，3H)；3.64-3.70(dd，1H)；3.92(s，3H)；5.08-5.18(m，1H)；7.21(s，1H)；7.23-7.30(m，1H)；7.43-7.55(m，2H)；7.79(s，1H)；8.36(s，1H)；9.6(s，1H)；

mass spectrometry：(M+H)⁺489。

Reacting 4- (3-chloro-2-fluoroanilino) -6- [ (3S) - (1-tert-butoxycarbonyl) pyrrolidin-3-yloxy ]The (E) -7-methoxyquinazoline reacted with hydrogen chloride (4.0M in 1, 4-dioxane) to give 4- (3-chloro-2-fluoroanilino) -6- [ (3S) -pyrrolidin-3-yloxy)]-7-methoxyquinazoline hydrochloride (1.94g, 93%); ¹ H NMRspectrum:

(DMSO d₆)2.18-2.28(m，1H)；2.35-2.45(m，1H)；3.27-3.46(m，3H)；3.73-3.82(m，1H)；3.99(s，3H)；5.41-5.47(m，1H)；7.31-7.37(m，1H)；7.44(s，1H)；7.47-7.54(m，1H)；7.58-7.64(m，1H)；8.66(s，1H)；8.80(s，1H)；9.42(bs，1H)；9.61(bs，1H)；12.24(bs，1H)；

mass spectrometry：(M+H)⁺389。

Example 31

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1-methanesulfonyl-pyrrolidin-2-yl ] methoxy } quinazoline

Using a similar procedure to that described in example 29, 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -pyrrolidin-2-yl]Methoxy } quinazoline hydrochloride (300mg) was reacted with methanesulfonyl chloride to give the title product (200mg, 61%). ¹ H NMRSpectrum:

(DMSO d₆)1.88-2.17(m，4H)；2.98(s，3H)；3.38(m，2H)；3.93(s，3H)；4.02(m，1H)；4.15(m，2H)；7.20(s，1H)；7.20-7.30(m，1H)；7.42-7.53(m，2H)；7.81(s，1H)；8.37(s.1H)；9.62(s，1H)；

mass spectrometry：(M+H)⁺481。

Starting material 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -pyrrolidin-2-yl ] methoxy } quinazoline hydrochloride was prepared as follows:

4-chloro-6-hydroxy-7-methoxyquinazoline (prepared as described in the preparation of the starting material in example 16; 2.75g, 13mmol) was combined with triphenylphosphine (5.13g, 19.6mmol) and (2S) -1- (tert-butoxycarbonyl) -2- (hydroxymethyl) pyrrolidine (3.94g, 19.6 mmol). Dichloromethane (85ml) was added and the mixture was cooled under nitrogen in an ice/water bath. Di-tert-butyl azodicarboxylate (4.51g, 19.6mmol) was dissolved in dichloro chlorideMethane (35ml) was added dropwise at such a rate that the internal temperature was kept at less than 10 ℃. After the addition was complete, the cold bath was immediately removed and the reaction mixture was stirred for 3 hours. The solvent was removed in vacuo and the residue was purified by column chromatography eluting with methylene chloride/ethyl acetate (saturated with ammonia) (70/30) to give 4-chloro-7-methoxy-6- { [ (2S) -1-tert-butoxycarbonylpyrrolidin-2-yl ]Methoxy } quinazoline as gum (6.15 g).Mass spectrometry：(M+H)⁺394。

To 4-chloro-7-methoxy-6- { [ (2S) -1-tert-butoxycarbonylpyrrolidin-2-yl]To a solution of methoxy quinazoline in acetonitrile (120ml) was added 3-chloro-2-fluoroaniline (1.4ml, 12.7mmol) and hydrogen chloride (4.0M in 1, 4-dioxane) (13ml, 52 mmol). The mixture was heated to reflux for 1 hour. After cooling to room temperature, the precipitate was filtered off, washed successively with acetonitrile and diethyl ether and dried in vacuo to give 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -pyrrolidin-2-yl-amine as a yellow solid]Methoxy } quinazoline hydrochloride (5.73g, 100%); ¹ H NMRspectrum:

(DMSO d₆)1.70-2.10(m，3H)；2.10-2.30(m，1H)；3.00-3.80(m，2H)；3.97-4.10(m，4H)；4.45-4.57(m，2H)；7.32-7.38(m，1H)；7.46(s，1H)；7.49-7.55(m，1H)；7.59-7.65(m，1H)；8.65(s，1H)；8.81(s，1H)；9.31(bs，1H)；9.67(bs，1H)；12.09(bs，1H)；

mass spectrometry：(M+H)⁺403。

Example 32

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2R) -1-methanesulfonyl-pyrrolidin-2-yl ] methoxy } quinazoline

Using a similar procedure as described in example 29The process of (1), reacting 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (2R) -pyrrolidin-2-ylmethoxy]Quinazoline hydrochloride (300mg) was reacted with methanesulfonyl chloride to give the title product (250mg, 76%). ¹ H NMRSpectrum:

(DMSO d₆)1.88-2.12(m，4H)；2.99(s，3H)；3.30-3.34(m，2H)；3.94(s，3H)；4.02(m，1H)；4.15(m，2H)；7.15-7.30(m，2H)；7.40-7.55(m，2H)；7.81(s，1H)；8.36(s，1H)；9.62(s，1H)；

mass spectrometry：(M+H)⁺481。

Using a similar procedure to that described for the preparation of the starting materials in example 31, the starting material, 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (2R) -pyrrolidin-2-ylmethoxy ] quinazoline hydrochloride, was prepared:

Reaction of 4-chloro-7-methoxy-6-hydroxyquinazoline (2.78g) with (2R) -1- (tert-butoxycarbonyl) -2- (hydroxymethyl) pyrrolidine (3.98g) gave 4-chloro-7-methoxy-6- { [ (2R) -1- (tert-butoxycarbonyl) pyrrolidin-2-yl]Methoxy quinazoline (5.0g, 100%) ¹ H NMRSpectrum:

(DMSO d₆)1.37(s，9H)；1.66-1.88(m，2H)；1.90-2.07(m，2H)；3.15-3.24(m，1H)；3.41-3.49(m，1H)；4.00(s，3H)；4.10-4.25(m，3H)；7.44(d，2H)；8.85(s，1H)；

mass spectrometry：(M+H)⁺394。

Reacting 4-chloro-7-methoxy-6- { [ (2R) -1- (tert-butoxycarbonyl) pyrrolidin-2-yl]Reaction of the methoxy } quinazoline with 3-chloro-2-fluoroaniline to give 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2R) -pyrrolidin-2-yl]Methoxy } quinazoline hydrochloride (5.3g, 100%); ¹ H NMRspectrum:

(DMSO d₆)1.70-1.84(m，1H)；1.87-1.97(m，1H)；1.99-2.08(m，1H)；2.17-2.28(m，1H)；3.18-3.27(m，2H)；3.98-4.10(m，4H)；4.45-4.57(m，2H)；7.32-7.38(m，1H)；7.47(s，1H)；7.49-7.55(m，1H)；7.59-7.65(m，1H)；8.66(s，1H)；8.81(s，1H)；9.30(bs，1H)；9.67(bs，1H)；12.09(bs，1H)；

mass spectrometry：(M-H)^-401。

Example 33

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (methylsulfonyl) pyrrolidin-3-yl ] methoxy } quinazoline

Using a similar method to that described in example 29, 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (pyrrolidin-3-ylmethoxy) quinazoline hydrochloride (300mg) was reacted with methanesulfonyl chloride to give the title product (200mg, 67%). ¹ H NMRSpectrum:

(DMSO d₆+CD3COOD)1.75-1.89(m，1H)；2.08-2.18(m，1H)；2.77-2.86(m，1H)；2.91(s，3H)；3.12-3.18(m，1H)；3.25-3.43(m，2H)；3.47-3.52(m，1H)；3.94(s，3H)；4.06-4.09(m，2H)；7.15-7.30(m，2H)；7.43-7.53(m，2H)：7.81(s，1H)；8.38(s，1H)；

mass spectrometry：(M+H)⁺481。

A similar procedure to that described for the preparation of the starting material, 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (pyrrolidin-3-ylmethoxy) quinazoline hydrochloride, was prepared as follows in example 31:

reaction of 4-chloro-7-methoxy-6-hydroxyquinazoline (2.5g) with 1- (tert-butoxycarbonyl) -3- (hydroxymethyl) pyrrolidine (3.58g) gave 4-chloro-7-methoxy-6- { [1- (tert-butoxycarbonyl) pyrrolidin-3-yl ]Methoxy } quinazoline (5.36g, 100%). ¹ H NMRSpectrum:

(DMSO d₆)1.39(s，9H)；1.45-1.79(m，2H)；1.97-2.08(m，1H)；2.65-2.74(m，1H)；2.91-3.17(m，2H)；3.40-3.52(m，1H)；4.01(s，3H)；4.15-4.22(m，2H)；7.42(s，1H)；7.45(s，1H)；8.86(s，1H)；

mass spectrometry：(M+H)⁺394。

Reacting 4-chloro-7-methoxy-6- { [1- (tert-butoxycarbonyl) pyrrolidin-3-yl]Methoxy } quinazoline (4.5g) was reacted with 3-chloro-2-fluoroaniline to give 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (pyrrolidin-3-ylmethoxy) quinazoline hydrochloride (5.45g, 100%); ¹ H NMRspectrum:

(DMSO d₆)1.71-1.85(m，1H)；2.10-2.22(m，1H)；2.81-2.91(m，1H)；2.97-3.07(m，1H)；3.11-3.22(m，1H)；3.24-3.33(m，1H)；3.35-3.46(m，1H)；4.00(s，3H)；4.28-4.34(m，2H)；7.31-7.37(m，1H)；7.43(s，1H)；7.49-7.54(m，1H)；7.59-7.64(m，1H)；8.60(s，1H)；8.80(s，1H)；9.32(bs，2H)；12.05(bs，1H)；

mass spectrometry：(M-H)^-401。

Example 34

4- (3-chloro-2-fluoroanilino) -6- [ (3R) -1-methylpyrrolidin-3-yloxy ] -7-methoxyquinazoline

4- (3-chloro-2-fluoroanilino) -6- [ (3R) -pyrrolidin-3-yloxy]-7-Methoxyquinazoline hydrochloride (0.24g, 0.56mmol, prepared as described in example 29-preparation of the starting material) was dissolved in formic acid (4ml) and formaldehyde (37% w/v in water) (2ml) was added. The mixture was heated to 85 ℃ for 1 hour and then evaporated under vacuum and azeotroped with toluene. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with brine and washed with Na₂SO₄Drying, filtering and evaporating. The residue was purified by column chromatography eluting with dichloromethane/methanol (saturated with ammonia) (94/6). The fractions containing the desired product were combined, evaporated, and the residue triturated with isohexane/ether, filtered, and dried in vacuo to give the title product as a white solid (0.13 g; 59%). ¹ H NMRSpectrum:

(DMSO d₆)1.70-1.9(m，1H)；2.27(s，3H)；2.30-2.50(m，2H)；2.55-2.75(m，2)；2.91-3.00(m，1H)；3.91(s，3H)；4.90-5.10(m，1H)；7.18(s，1H)；7.20-7.35(m，1H)；7.40-7.58(m，2H)；7.64(s，1H)；8.35(s，1H)；9.57(s，1H)；

mass spectrometry：(M-H)^-401。

Example 35

4- (3-chloro-2-fluoroanilino) -6- [ (3S) -1-methylpyrrolidin-3-yloxy ] -7-methoxyquinazoline

4- (3-chloro-2-fluoroanilino) -6- [ (3S) -1-tert-butoxycarbonylpyrrolidin-3-yloxy]7-Methoxyquinazoline (0.30g) was dissolved in formic acid (5ml) and formaldehyde (37% w/v in water) (2.5ml) was added. The mixture was heated to 85 ℃ for 1 hour and then evaporated under vacuum and azeotroped with methanol. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with brine and Na₂SO₄Drying, filtering and evaporating. The residue was purified by column chromatography eluting with dichloromethane/methanol (saturated with ammonia) (100/0-94/6) of increasing polarity. The fractions containing the desired product were combined, evaporated, and the residue triturated with ether, filtered, and dried in vacuo to give the title product as a white solid (0.133 g; 35%). ¹ H NMRSpectrum:

(DMSO d₆)1.70-1.90(m，1H)，2.28(s，3H)，2.32-2.50(m，2H)，2.55-2.75(m，2H)，2.80-3.00(m，1H)，3.91(s，3H)，4.93-5.10(m，1H)，7.18(s，1H)，7.20-7.35(m，1H)，7.40-7.55(m，2H)，7.65(s，1H)，8.35(s，1H)，9.55(s，1H)；

mass spectrometry：(M+H)⁺403。

The starting 4- (3-chloro-2-fluoroanilino) -6- [ (3S) -1-tert-butoxycarbonylpyrrolidin-3-yloxy ] -7-methoxyquinazoline was prepared as follows:

a solution of 4-nitrobenzenesulfonyl chloride (4.44g) in dichloromethane (50ml) was added to a stirred solution of tert-butyl 3- (R) -hydroxy-pyrrolidine-1-carboxylate (3.75g) and pyridine (2.5ml) in dichloromethane (30ml) at 10 ℃ and the mixture was warmed to room temperature with stirring. The reaction mixture was poured into a saturated sodium bicarbonate solution. The organic layer was separated, washed with brine and Na ₂SO₄And (5) drying. The solution was evaporated in vacuo to give 3- (R) - [ (4-nitrophenyl) sulfonyloxy]Pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow crystalline solid (4.37 g; 59%). ¹ H NMRSpectrum:

(CDCl₃)1.43(s，9H)，1.80-2.40(m，2H)，3.30-3.65(m，4H)，5.20(bs，1H)，8.10(d，2H)，8.42(d，2H).

4- (3-chloro-2-fluoroanilino) -6-hydroxy-7-methoxyquinazoline (2.0 g; prepared as described in the preparation of the starting material in example 22), 3- (R) - [ (4-nitrophenyl) sulfonyloxy ] was added at room temperature]A mixture of pyrrolidine-1-carboxylic acid tert-butyl ester (2.4g) and cesium fluoride (2.9g) in dimethylformamide (30ml) was stirred for 18 hours. The reaction mixture was evaporated in vacuo and then partitioned between dichloromethane and water. The solution was filtered to remove insoluble solids, and the dichloromethane layer was washed with water and saturated brine, and then absorbed into silica gel. The product was then purified by column chromatography on silica gel eluting with a dichloromethane/methanol mixture of increasing polarity (saturated with ammonia) (100/0-96/4). Combining fractions containing the desired product and evaporating in vacuo to giveTo 4- (3-chloro-2-fluoroanilino) -6- [ (3S) -1-tert-butoxycarbonylpyrrolidin-3-yloxy]7-methoxyquinazoline as a yellow foam (2.9g, 95%); ¹ H NMRspectrum:

(DMSO-d₆)1.40(s，9H)，2.00-2.32(m，2H)，3.20-3.55(m，3H)，3.69(dd，1H)，3.92(s，3H)，5.00-5.20(m，1H)，7.20(s，1H)，7.20-732(m，1H)，7.40-7.57(m，2H)，7.80(s，1H)，8.37(s，1H)，9.60(s，1H)；

mass spectrometry：(M+H)⁺489。

Example 36

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazoline

Using a method analogous to that described in example 34, 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1-pyrrolidin-2-yl]Methoxy } quinazoline hydrochloride (300 mg; prepared as described in the preparation of the starting material for example 31) was reacted with formaldehyde (2.5ml) to give the title product (220mg, 77%); ¹ H NMRspectrum:

(DMSOd₆)1.57-1.76(m，3H)；1.96-2.08(m，1H)；2.24(q，1H)；2.42(s，3H)；2.71(m，1H)；2.97(m，1H)；3.92(s，3H)；3.95-4.09(m，2H)；7.19(s，1H)；7.20-7.30(m，1H)；7.42-7.54(m，2H)；7.81(s，1H)；8.36(s，1H)；9.56(s，1H)；

mass spectrometry：(M+H)⁺417。

Example 37

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (methylpyrrolidine) -3-yl ] methoxy } quinazoline

Using a method similar to that described in Synthesis example 34, 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (pyrrolidin-3-ylmethoxy) quinazoline hydrochloride (250 mg; prepared as described in the preparation of the starting material for example 33) was reacted with formaldehyde (2.5ml) to give the title product (125mg, 52%); ¹ H NMRspectrum:

(CDCl₃)1.61-1.72(m，1H)；2.08-2.20(m，1H)；2.38(s，3H)；2.47(q，1H)；2.65(m，2H)；2.69-2.77(m，1H)；2.81-2.88(m，1H)；4.01(s，3H)；4.06-4.13(m，2H)；7.05-7.23(m，3H)；7.26(s，1H)；7.45(s，1H)；8.41-8.47(m，1H)；8.68(s，1H)；

mass spectrometry：(M+H)⁺415。

Example 38

4- (3-chloro-2-fluoroanilino) -6- [ (3R) -1-acetylpyrrolidin-3-yloxy ] -7-methoxyquinazoline

Under nitrogen atmosphere, 4- (3-chloro-2-fluoroanilino) -6- [ (3R) -pyrrolidin-3-yloxy]7-Methoxyquinazoline (0.22g, 0.51 mmol; prepared as described in example 29-preparation of the starting material) was dissolved in a mixture of dichloromethane (4ml), pyridine (1ml) and diisopropylethylamine (0.17 ml). Acetic anhydride (0.1ml, 1.0mmol) was added and the reaction mixture was cooled at room temperature The mixture was stirred for 3 hours. The mixture was then partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated, washed with brine and Na₂SO₄Drying, filtering and evaporating. The residue was purified by column chromatography eluting with dichloromethane/methanol saturated with ammonia (96/4). The fractions containing the desired product were evaporated and triturated with ether. The solid was filtered and dried in vacuo to give the title product as a white solid (0.12 g; 55%). ¹ H NMRSpectrum:

(DMSO d₆)1.95-1.98(m，3H)；2.14-2.40(m，2H)；3.53-3.70(m，3H)；3.91(m，4H)；5.12-5.21(m，1H)；7.15-7.30(m，2H)；7.4-7.60(m，2H)；7.70-7.90(m，1H)；8.36-8.37(d，1H)；9.60-9.62(m，1H)；

mass spectrometry：(M+H)⁺431。

Example 39

6- { [ (2S) -1-Acetylpyrrolidin-2-yl ] methoxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline

Using a method similar to that described in example 38, 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (2S) -pyrrolidin-2-ylmethoxy]Quinazoline hydrochloride (300 mg; prepared as described in example 31) was reacted with acetic anhydride to give the title product (280mg, 92%); ¹ H NMRspectrum:

(DMSO d₆)1.89-2.05(m，6H)；2.15(m，1H)；3.43-3.56(m，2H)；3.93(s，3H)；4.00-4.11(m，1H)；4.17-4.21(m，1H)；4.32-4.42(m，1H)；7.19-7.29(m，2H)；7.41-7.54(m，2H)；7.79-7.82(m，1H)；8.36-8.37(m，1H)；9.52-9.55(m，1H)；

mass spectrometry：(M+H)⁺445。

Example 40

6- { [ (2R) -1-Acetylpyrrolidin-2-yl ] methoxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline

Using a method similar to that described in example 38, 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (2R) -pyrrolidin-2-ylmethoxy]Quinazoline hydrochloride (300 mg; prepared as described in the preparation of the starting material for example 32) was reacted with acetic anhydride to give the title product (203mg, 66%); ¹ H NMRSpectrum:

(DMSO d₆)1.89-2.05(m，6H)；2.11-2.21(m，1H)；3.43-3.56(m，2H)；3.94(s，3H)；4.00-4.11(m，1H)；4.17-4.21(m，1H)；4.30-4.37(m，1H)；7.19-7.29(m，2H)；7.42-7.53(m，2H)；7.79-7.82(m，1H)；8.37(s，1H)；9.54-9.57(m，1H)；

mass spectrometry：(M+H)⁺445。

EXAMPLE 41

6- [ (1-acetylpyrrolidin-3-yl) methoxy ] -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline

Using a method similar to that described in example 38, 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (pyrrolidin-3-ylmethoxy) quinazoline hydrochloride (300 mg; prepared as described in the example 33-preparation of the starting material) was reacted with acetic anhydride to give the title product (194mg, 63%); ¹ H NMRspectrum:

(DMSO d₆+CD3COOD)1.71-1.90(m，1H)；1.93-1.94(m，3H)；2.00-2.20(m，1H)；2.66-2.86(m，1H)；3.18-3.31(m，1H)；3.43-3.72(m，3H)；3.93(m，3H)；4.04-4.18(m，2H)；7.15-7.32(m，2H)；7.42-7.53(m，2H)；7.78-7.80(m，1H)；8.35-8.37(m，1H)；

mass spectrometry：(M+H)⁺445。

Example 42

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (3S) -1- (N, N-dimethylsulfamoyl) pyrrolidin-3-yloxy ] quinazoline

Under nitrogen atmosphere, 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (3S) -pyrrolidin-3-yloxy]Quinazoline hydrochloride (0.21g, 0.49 mmol; prepared as described in the preparation of the starting material for example 30) was dissolved in a mixture of dichloromethane (4ml), pyridine (1ml) and diisopropylethylamine (0.17 ml). To the stirred solution was added dimethylsulfonyl chloride (0.08ml, 0.75 mmol). After stirring overnight at room temperature, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, over Na₂SO₄Drying, filtering and evaporating. The residue was purified by column chromatography eluting with dichloromethane/methanol saturated with ammonia (98/2). The fractions containing the desired product were combined, evaporated in vacuo, the residual gum triturated with ether and evaporated to give the title product as a dry foam (0.13 g; 53%). ¹ H NMRSpectrum:

(DMSO d₆)2.16-2.21(m，1H)；2.25-2.38(m，1H)；2.76(s，6H)；3.41-3.50(m，3H)；3.71(dd，1H)；3.93(m，3H)；5.18(m，1H)；7.15-7.35(m，2H)；7.44-7.55(m，2H)；7.78(s，1H)；8.37(s，1H)；9.59(s，1H)；

mass spectrometry：(M+H)⁺496。

Example 43

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (morpholinoacetyl) pyrrolidin-2-yl ] methoxy } quinazoline

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (chloroacetyl) pyrrolidin-2-yl]Methoxy } quinazoline (0.45g, 0.94mmol) was dissolved in morpholine (7.5ml) and then stirred at room temperature in the presence of potassium iodide (10mg) overnight. The solvent was evaporated and the residue was purified by column chromatography eluting with dichloromethane/methanol saturated with ammonia (98/2). The fractions containing the desired product were combined and evaporated in vacuo to give the title product as a foam (0.22 g; 44%). ¹ H NMRSpectrum:

(CDCl3)1.91-2.01(m，1H)；2.06-2.14(m，2H)；2.19-2.27(m，1H)；2.48-2.53(m，2H)；2.62-2.68(m，2H)；3.18(q，2H)；3.41-3.52(m，1H)；3.56-3.72(m，5H)；4.01-4.08(m，4H)；4.53(d，1H)；4.72(t，1H)；7.11-7.28(m，3H)；7.96(m，1H)；8.36(s，1H)；8.60(s，1H)；8.63(s，1H)；

mass spectrometry：(M-H)^-528。

The starting 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (chloroacetyl) pyrrolidin-2-yl ] methoxy } quinazoline was prepared as follows:

under nitrogen atmosphere, 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (2S) -pyrrolidin-2-ylmethoxy]Quinazoline hydrochloride (1.1g, 2.5 mmol; prepared as described in example 31-preparation of starting material) was dissolved in dichloromethane (20 ml)) And diisopropylethylamine (1.0 ml). The solution was cooled to 4 ℃ in an ice/water bath and chloroacetyl chloride (0.21ml, 2.63mmol) was added. The reaction mixture was stirred for 2 hours with cooling and then partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with brine and Na ₂SO₄Drying, filtration and evaporation gave 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (chloroacetyl) pyrrolidin-2-yl]Methoxy quinazoline (1.14 g; 94.9%).Mass spectrometry：(M+H)⁺479。

Example 44

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (hydroxyacetyl) pyrrolidin-2-yl ] methoxy } quinazoline

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (2S) -pyrrolidin-2-ylmethoxy]Quinazoline hydrochloride (0.25g, 0.57 mmol; prepared as described in the preparation of the starting material for example 31) was dissolved in a mixture of dichloromethane (5ml) and diisopropylethylamine (0.3 ml). The solution was cooled to 4 ℃ in an ice/water bath and acetoxyacetyl chloride (0.064ml, 0.6mmol) was added. The reaction mixture was stirred for 2 hours with cooling and then partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with brine and Na₂SO₄Drying, filtering and evaporating. The residue was dissolved in methanol (5ml) containing anhydrous powdered potassium carbonate (0.2 g). After stirring overnight, the solvent was evaporated and the residue was purified by column chromatography eluting with dichloromethane/isopropanol (96/4) (containing 0.5% triethylamine). Fractions containing the desired product were evaporated and the residue triturated with ether to give the title product as a white solid (0.1 g; 38%). ¹ H NMRSpectrum:

(CDCl₃)1.95-2.29(m，4H)；3.29(m，1H)；3.46(m，2H)；4.03(s，3H)；4.07-4.18(m，3H)；4.55(d，1H)；4.69(t，1H)；7.13-7.16(m，2H)；7.26(s，1H)；8.26(m，1H)；8.35(s，1H)；8.48(s，1H)；8.66(s，1H)；

mass spectrometry：(M+H)⁺461。

Example 45

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (piperidin-3-yloxy) quinazoline

HCl (4.63ml, 4M in dichloromethane) was added to 4-chloro-7-methoxy-6- [1- (tert-butoxycarbonyl) piperidin-3-yloxy]Quinazoline (2.47g) and 3-chloro-2-fluoroaniline (1.01g) in a mixture of acetonitrile (40 ml). The mixture was heated under reflux for 1 hour, cooled and the precipitate collected to give the title product as dihydrochloride as a white solid (2.51 g; 91%). ¹ H NMRSpectrum:

(DMSOd₆)1.9(m，2H)；2.0(m，1H)；2.2(m，1H)；3.0(m，1H)；3.2(m，2H)；3.5(m，1H)；4.0(s，3H)；5.0(m，1H)；7.4(m，1H)；7.5(m，1H)；7.6(s，1H)；7.6(m，1H)；8.8(s，1H)；8.9(s，1H)；9.2(br s，2H)；12.3(br s，1H)；

mass spectrometry：(M+H)403。

Starting 4-chloro-7-methoxy-6- [1- (tert-butoxycarbonyl) piperidin-3-yloxy ] quinazoline was prepared as follows:

diethyl azodicarboxylate (9.41ml, 40% in toluene) was added to a mixture of 4-chloro-6-hydroxy-7-methoxyquinazoline (2.90 g; prepared as described in example 16-preparation of the starting material), triethylamine (5.43g) and tert-butoxycarbonyl-3-hydroxypiperidine (4.15g) in dichloromethane (75 ml). The resulting solution was heated to 40 ℃ for 6 hoursAnd then left overnight at room temperature. Purifying by flash column chromatography, eluting with isohexane (79%), acetone (20%) and triethylamine (1%), to obtain 4-chloro-7-methoxy-6- [1- (tert-butoxycarbonyl) piperidin-3-yloxy]Quinazoline as a white solid (2.47g, 53%); ¹ H NMRSpectrum:

(CDCl₃)1.5(m，9H)；1.6(m，1H)；1.9(m，2H)；2.1(m，1H)；3.5(m，1H)；3.6(m，1H)；4.0(s，3H)；4.2-3.9(m，2H)；4.5(m，1H)；7.3(s，1H)；7.4(s，1H)；8.9(s，1H)；

mass spectrometry：(M+H)394。

Example 46

4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4R) -2- (N, N-dimethylcarbamoyl) -1-methylpyrrolidin-4-yloxy ] -7-methoxyquinazoline and

4- (3-chloro-2-fluoroanilino) -6- [ (2R, 4R) -2- (N, N-dimethylcarbamoyl) -1-methylpyrrolidin-4-yloxy ] -7-methoxyquinazoline

O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (192mg, 0.5mmol) was added to a stirred solution of 4- (3-chloro-2-fluoroanilino) -6- [ (2RS, 4R) -1-methyl-2-carboxypyrrolidin-4-yloxy)]-7-Methoxyquinazoline (150mg, 0.336mmol), dimethylamine hydrochloride (41mg, 0.5mmol) and diisopropylethylamine (175. mu.l, 1.0mmol) in DMF (5 ml). After 18 hours, the reaction mixture was evaporated to dryness. The residue was dissolved in dichloromethane (50ml), washed with water (50ml) and dried (MgSO)₄) Filtered and concentrated to an orange gum. Then purifying by flash chromatography on silica gel eluting with a mixture of dichloromethane/methanol (100/0-90/10) of increasing polarityThe following diastereomers were obtained.

The product fractions eluted first were combined and evaporated to give a colorless gum which was triturated with diethyl ether to give 4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4R) -2- (N, N-dimethylcarbamoyl) -1-methylpyrrolidin-4-yloxy ]7-Methoxyquinazoline as a white powder (56.1 mg). ¹ H NMRSpectrum: (benzene-d)₆)

2.10(s，3H)，2.1-2.28(m，1H)，2.28-2.45(m，6H)，2.65-2.80(m，1H)，2.80-2.90(m，1H)，3.20(t，1H)，3.45(s，3H)，3.60-3.75(m，1H)，5.70-5.80(m，1H)，6.65-6,75(m，1H)，6.85-7.00(m，1H)，7.55(s，1H)，7.93(t，1H)，8.05(s，1H)，8.93(s，1H)，9.08(s，1H)；

Mass spectrometry：(M+H)⁺474。

The product fractions from the second elution were combined and evaporated to give 4- (3-chloro-2-fluoroanilino) -6- [ (2R, 4R) -2- (N, N-dimethylcarbamoyl) -1-methylpyrrolidin-4-yloxy]7-Methoxyquinazoline as a white foam (37.8 mg). ¹ H NMRSpectrum: (benzene-d)₆+DMSO-d₆+ acetic acid-d₄)

2.10-2.25(m，1H)，2.60(s，3H)，2.68(s，3H)，2.83(s，3H)，3.40-3.60(m，1H)，3.83(s，3H)，3.90(dd，1H)，4.03(d，1H)，4.90-5.05(m，1H)，5.40-5.55(m，1H)，6.89(t，1H)，7.10(t，1H)，7.65(t，1H)，7.92(s，1H)，7.95(s，1H)，8.80(s，1H)；

Mass spectrometry：(M+H)⁺474。

Starting material 4- (3-chloro-2-fluoroanilino) -6- [ (2RS, 4R) -1-methyl-2-carboxypyrrolidin-4-yloxy ] -7-methoxyquinazoline was prepared as follows:

4-Nitrobenzenesulfonyl chloride (1.89g) was added to a stirred solution of 1-tert-butyl 2-methyl (2S, 4S) -4-hydroxypyrrolidine-1, 2-dicarboxylate (2.0g) and pyridine (1.29g)A solution of dichloromethane (30ml) was stirred under nitrogen at 4 ℃ for 16 hours. The reaction mixture was washed with citric acid (1.0M), saturated sodium bicarbonate and dried over magnesium sulfate. The product was then purified by column chromatography on silica gel eluting with methylene chloride/methanol (100/0-92/8) of increasing polarity. The fractions containing the desired product were combined and evaporated in vacuo to give (2S, 4S) -4- [ (4-nitrophenyl) sulfonyloxy]Pyrrolidine-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a yellow gum (0.89 g); ¹ H NMRSpectrum:

(DMSO d₆)1.31-1.42(m，9H)，2.12-2.21(m，1H)，2.53-2.67(m，1H)，3.40-3.50(m，1H)，3.58-3.69(m，4H)，4.36(m，1H)，5.25(m，1H)，8.14(d，2H)，8.46(d，2H).

dimethylformamide (15ml) was added to 4- (3-chloro-2-fluoroanilino) -7-methoxy-6-hydroxyquinazoline (0.66 g; prepared as described in the preparation of the starting material in example 22), (2S, 4S) -4- [ (4-nitrophenyl) sulfonyloxy group]Pyrrolidine-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.889g) and cesium fluoride (0.941 g). The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The organics were washed with water and saturated brine, over MgSO₄And (5) drying. The product was then purified by column chromatography eluting with methylene chloride/methanol (100/0-95/5) of increasing polarity. The fractions containing the desired product were combined and evaporated in vacuo to give 4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4R) -1- (tert-butoxycarbonyl) -2- (methoxycarbonyl) pyrrolidin-4-yloxy]7-methoxyquinazoline as a colourless gum (0.36 g);mass spectrometry：(M+H)⁺547。

Reacting 4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4R) -1- (tert-butoxycarbonyl) -2- (methoxycarbonyl) pyrrolidin-4-yloxy]A solution of-7-methoxyquinazoline (480mg, 0.88mmol) in formic acid (50ml) was reacted with paraformaldehyde (29mg, 0.97mmol), and the resulting mixture was heated at 85 ℃ for 6 hours. Evaporating the reaction mixture and dissolving the residue in saturated carbonic acid Aqueous sodium hydrogen (50ml) and ethyl acetate (100ml) were partitioned. The organic layer was MgSO₄Drying, filtering and evaporating. The residue was purified by flash chromatography on silica gel eluting with a dichloromethane/methanol (100/0-90/10) mixture of increasing polarity. The fractions containing the desired product were combined and evaporated to give 4- (3-chloro-2-fluoroanilino) -6- [ (2RS, 4R) -1-methyl-2- (methoxycarbonyl) pyrrolidin-4-yloxy]-7-methoxyquinazoline as a white foam (265 mg);mass spectrometry：(M+H)⁺461。

2M sodium hydroxide (1ml, 2mmol) was added to a stirred solution of 4- (3-chloro-2-fluoroanilino) -6- [ (2RS, 4R) -1-methyl-2- (methoxycarbonyl) pyrrolidin-4-yloxy]-7-Methoxyquinazoline (250mg, 0.54mmol) in methanol (5ml) and the mixture was stirred at room temperature for 18 h. The reaction mixture was evaporated and the residue was redissolved in water (50 ml). Then washed with ethyl acetate (25ml) and the aqueous layer evaporated to dryness, azeotroped with toluene. The residue was triturated with dichloromethane/methanol (9/1) (25ml), filtered and the liquid evaporated to give 4- (3-chloro-2-fluoroanilino) -6- [ (2RS, 4R) -1-methyl-2-carboxypyrrolidin-4-yloxy)]-7-methoxyquinazoline as a white foam (155 mg); Mass spectrometry：(M+H)⁺447。

Example 47

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (2RS, 4R) -1-methyl-2- (morpholinocarbonyl) pyrrolidin-4-yloxy ] quinazoline

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (2S, 4R) -1- (tert-butoxycarbonyl) -2- (morpholinocarbonyl) pyrrolidin-4-yloxy) was reacted at 80 deg.C]A solution of quinazoline (0.3g), formic acid (3.0ml) and paraformaldehyde (0.047mg) was stirred for 8 hours. The reaction was cooled, concentrated in vacuo, and then taken up in silica gel. The product was washed with increasing polarity dichloromethane/methanol (100/0-90/10)And (4) eluting. The fractions containing the desired product were combined and evaporated in vacuo. The product was then repurified by preparative HPLC on a reverse phase Hi-Chrom HIRPB column. The product was eluted with a mixture of acetonitrile/water (0.1% trifluoroacetic acid) (20/80-50/50) of decreasing polarity. The fractions containing the desired product were combined, evaporated in vacuo and the residue dissolved in dichloromethane/methanol (saturated with ammonia) and then taken up in silica gel. The product was eluted with a mixture of dichloromethane/methanol (saturated with ammonia) of increasing polarity (100/0-90/10). The fractions containing the desired product were combined and evaporated in vacuo to give the title product as a colourless foam (0.058 g); ¹ H NMRSpectrum:

(DMSO d₆)2.10-2.18(m，1H)，2.31(s，3H)，2.53-2.60(m，1H)，3.44-3.67(m，10H)，3.72(t，1H)，3.92(s，3H)，5.10(m，1H)，7.21(s，1H)，7.28(t，1H)，7.467.56(m，2H)，7.71(s，1H)，8.36(s，1H)，9.64(s，1H)；

mass spectrometry：(M+H)⁺516。

The starting 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (2S, 4R) -1- (tert-butoxycarbonyl) -2- (morpholinocarbonyl) pyrrolidin-4-yloxy ] quinazoline was prepared as follows:

aqueous sodium hydroxide (2M, 1.0ml) was added to a stirred solution of 4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4R) -1- (tert-butoxycarbonyl) -2- (methoxycarbonyl) pyrrolidin-4-yloxy]-7-Methoxyquinazoline (prepared as described in the preparation of the starting material in example 46) in methanol (8ml) and THF (3ml) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated in vacuo and the residue was dissolved in water and adjusted to pH6 by the addition of hydrochloric acid (2N). The product was extracted with ethyl acetate/n-propanol and the organic layer was washed with brine, over MgSO₄Drying and removing the solvent in vacuo to give 4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4R) -1- (tert-butoxycarbonyl) -2-carboxypyrrolidin-4-yloxy) as a white powdery solid]-7-methoxyquinazoline (0.42g)；Mass spectrometry：(M+H)⁺532.98。

HATU (214mg) was added to a stirred solution of 4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4R) -1- (tert-butoxycarbonyl) -2-carboxypyrrolidin-4-yloxy)]-7-Methoxyquinazoline (215mg), morpholine (50mg) and diisopropylethylamine (200. mu.l) in DMA (5 ml). After stirring at room temperature for 18 hours, the reaction mixture was evaporated to dryness. The residue was dissolved in dichloromethane (50ml), washed with water (50ml), brine (50ml), dried (MgSO) ₄) Filtration and evaporation of the solvent in vacuo afforded 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (2S, 4R) -1- (tert-butoxycarbonyl) -2- (morpholinocarbonyl) pyrrolidin-4-yloxy]Quinazoline, as a pale yellow gum (300 mg). The residue was used without further purification;mass spectrometry：(M+H)⁺602.08。

Example 48

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [1- (pyrrolidin-1-ylacetyl) piperidin-3-yloxy ] quinazoline

Chloroacetyl chloride (89 μ l) was added to a solution of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (piperidin-3-yloxy) quinazoline dihydrochloride (469 mg; prepared as described in example 45) and diisopropylethylamine (700 μ l) in dichloromethane (15ml) cooled to 0 ℃. The mixture was stirred at room temperature for 2 hours to give 6- [1- (chloroacetyl) piperidin-3-yloxy group]-4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline;mass spectrometry：(M+H)⁺479。

Pyrrolidine (0.5ml) was then added and the solution stirred for an additional 1 h and purified by flash chromatography eluting with dichloromethane/methanol (containing ammonia 7N) (97/3). The fractions containing the desired product were combined and evaporated in vacuo to give the title compound as a colourless foam (0.327 g); ¹ H NMRspectrum: (DMS)O d₆，100℃)

1.50-1.72(m，5H)，1.83-1.95(m，2H)，2.08-2.18(m，1H)，2.40-2.58(m，4H)，3.18(d，1H)，3.37(d，1H)，3.48-3.56(m，1H)，3.58-3.64(m，1H)，3.68-3.77(m，1H)，3.89-3.93(m，1H)，3.95(s，3H)，4.51-4.59(m，1H)，7.23-7.31(m，2H)，7.40-7.48(m，1H)，7.57-7.64(m，1H)，7.90(s，1H)，8.41(s，1H)，9.25(br s，1H)；

Mass spectrometry：(M+H)⁺514。

Example 49

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (3S) -piperidin-3-yloxy ] quinazoline

HCl (1.0ml, 4M dioxane solution) was added to 4-chloro-7-methoxy-6- [ (3S) -1- (tert-butoxycarbonyl) piperidin-3-yloxy) dissolved in acetonitrile (25ml)]Quinazoline (0.786g) and 3-chloro-2-fluoroaniline (0.304 g). Heating the mixture to 60 deg.C for 2 hr, cooling, collecting precipitate to obtain 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (3S) -piperidin-3-yloxy)]Quinazoline hydrochloride as a white solid (0.577g, 66%); ¹ H NMRspectrum:

(DMSOd₆)1.70-1.95(m，2H)，1.95-2.10(m，1H)；2.10-2.25(m，1H)，2.95-3.10(m，1H)，3.10-3.30(m，2H)，3.45-3.65(m，1H)；4.03(s，3H)；4.95-5.10(m，1H)；7.30-7.45(m，1H)；7.45-7.60(m，2H)；7.60-7.73(m，1H)，8.85(s，1H)；8.90(s，1H)；9.15(bs，2H)；12.3(bs，1H)；

mass spectrometry：(M+H)403。

The starting 4-chloro-7-methoxy-6- [ (3S) -1- (tert-butoxycarbonyl) piperidin-3-yloxy ] quinazoline was prepared as follows:

diethyl azodicarboxylate (2.76ml, 40% in toluene) was added to a solution of 4-chloro-6-hydroxy-7-methoxyquinazoline (0.89 g; prepared as described in example 16), triphenylphosphine (1.66g) and (3R) -1- (tert-butoxycarbonyl) -3-hydroxypiperidine (CAS registry number 143900-43-0) (1.28g) in dichloromethane (25 ml). The resulting solution was stirred at room temperature overnight. Purifying by flash column chromatography, eluting with acetonitrile/isohexane/triethylamine (79/20/1-64/35/1) mixture with increasing polarity to obtain 4-chloro-7-methoxy-6- [ (3S) -1- (tert-butoxycarbonyl) piperidin-3-yloxy]Quinazoline as a white solid (0.794g, 48%); Mass spectrometry：(M+H)⁺394。

Example 50

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (3S) -1- (pyrrolidin-1-ylacetyl) piperidin-3-yloxy ] quinazoline

Chloroacetyl chloride (66 μ l) was added to 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (3S) -piperidin-3-yloxy) cooled to 0 deg.C]Quinazoline hydrochloride (350 mg; prepared as described in example 49) and diisopropylethylamine (522. mu.l) in dichloromethane (10ml) and the mixture was stirred at room temperature for 30 minutes. Pyrrolidine (0.37ml) was added and the solution stirred for 1 hour and then purified by flash column chromatography eluting with dichloromethane/methanol (containing ammonia 7N) (97/3). The fractions containing the desired product were combined and evaporated to give a foam. The foam was dissolved in dichloromethane (5ml) and crystallized by addition of isohexane (50ml) to give the title product (0.206 g); ¹ H NMRspectrum:

(DMSO d₆，100℃)1.50-1.72(m，5H)，1.83-1.95(m，2H)，2.08-2.18(m，1H)，2.40-2.58(m，4H)，3.18(d，1H)，3.37(d，1H)，3.48-3.56(m，1H)，3.58-3.64(m，1H)，3.68-3.77(m，1H)，3.89-3.93(m，1H)，3.95(s，3H)，4.51-4.59(m，1H)，7.23-7.31(m，2H)，7.40-7.48(m，1H)，7.57-7.64(m，1H)，7.90(s，1H)，8.41(br s，1H)，9.25(br s，1H)；

mass spectrometry：(M+H)⁺514。

Example 51

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (N-methylaminoacetyl) pyrrolidin-2-yl ] methoxy } quinazoline

Using a method similar to that described in Synthesis example 43, 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (chloroacetyl) pyrrolidin-2-yl]Methoxy } quinazoline (0.28 g; prepared as described in the preparation of the starting material for example 43) was reacted with 33% methylamine in ethanol (5ml) to give the title product as a foam (0.131g, 47%); ¹ H NMRSpectrum:

(CDCl₃)1.91-2.22(m，4H)，2.22(s，3H)，2.70-2.90(m，1H)，3.28-3.40(m，2H)，3.44-3.54(m，2H)，3.97-4.09(m，4H)，4.47-4.51(d，1H)，4.60-4.66(t，1H)，7.06-7.20(m，2H)，7.24(s，1H)，8.07-8.13(m，1H)，8.57-8.70(m，3H)；

mass spectrometry：(M-H)^-472。

Example 52

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (N, N-dimethylaminoacetyl) pyrrolidin-2-yl ] methoxy } quinazoline

Using a method similar to that described in Synthesis example 43, 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (chloroacetyl) pyrrolidin-2-yl]Methoxy } quinazoline (0.28g) was reacted with 33% dimethylamine in ethanol (5ml) to give the title product as a foam (0.165g, 58%); ¹ H NMRspectrum:

(CDCl₃)1.91-2.01(m，1H)，2.04-2.11(m，2H)，2.14-2.22(m，1H)，2.33(s，6H)，3.02-3.22(dd，2H)，3.40-3.50(m，1H)，3.59-3.66(m，1H)，4.02(s，3H)，4.05-4.09(m，1H)，4.51-4.55(d，1H)，4.66-4.72(m，1H)，7.09-7.21(m，2H)，7.23(s，1H)，8.00-8.06(m，1H)，8.47(bs，1H)，8.62(s，1H)，8.68(s，1H)；

mass spectrometry：(M-H)^-486。

Example 53

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (pyrrolidin-1-ylacetyl) pyrrolidin-2-yl ] methoxy } quinazoline

Using a method similar to that described in Synthesis example 43, 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (chloroacetyl) pyrrolidin-2-yl]Methoxy } quinazoline (0.28g) was reacted with pyrrolidine (2.5ml) to give the title product as a foam (0.151g, 50%); ¹ H NMRspectrum:

(CDCl₃)1.68-1.75(m，4H)，1.90-2.01(m，1H)，2.04-2.14(m，2H)，2.15-2.23(m，1H)，2.51-2.61(m，2H)，2.66-2.74(m，2H)，3.15-3.21(d，1H)，3.38-3.48(m，2H)，3.55-3.62(m，1H)，4.00-4.08(m，4H)，4.52-4.55(d，1H)，4.68-4.74(t，1H)，7.06-7.27(m，3H)，7.90-7.96(m，1H)，8.43(s，1H)，8.60(s，1H)，8.69(s，1H)；

mass spectrometry：(M-H)^-512。

Example 54

4- (3-chloro-2-fluoroanilino) -6- { [ (2S) -1- (3, 4-methylenedioxypyrrolidin-1-ylacetyl) pyrrolidin-2-yl ] methoxy } -7-methoxyquinazoline

3, 4-Methylenedioxypyrrolidine hydrochloride (87mg) was added to a stirred solution of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (chloroacetyl) pyrrolidin-2-yl ]Methoxy } quinazoline (0.25 g; prepared as described in example 43) and diisopropylethylamine (0.2ml) in acetonitrile (10ml) and the mixture was heated at reflux for 2 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, over Na₂SO₄Drying, filtering and evaporating. The residue was purified by column chromatography eluting with dichloromethane/isopropanol/triethylamine (97/2/1 to 95/4/1) of increasing polarity. The fractions containing the desired product were evaporated in vacuo to afford the title product as a yellow solid (0.203g, 70%); ¹ H NMRspectrum:

(CDCl₃)1.92-2.22(m，4H)，2.54-2.61(m，2H)，3.05-3.15(m，2H)，3.26-3.38(q，2H)，3.42-3.47(m，1H)，3.58-3.65(m，1H)，4.00-4.10(m，4H)，4.47-4.55(m，3H)，4.65-4.72(m，1H)，4.84(s，1H)，5.02(s，1H)，7.11-7.22(m，2H)，7.24(s，1H)，7.96-8.02(m，1H)，8.38(s，1H)，8.61(s，1H)，8.63(s，1H)；

mass spectrometry：(M+H)⁺558。

The starting 3, 4-methylenedioxypyrrolidine hydrochloride was prepared as follows:

di-tert-butyl dicarbonate (Boc)₂O, 78.95h) was added dropwise to a stirred solution of 3-pyrroline (25 g; 65% pure, containing pyrrolidine) and ethyl acetate (125 ml). During the dropwise addition, the reaction temperature is kept between 5 and 10 ℃. The resulting reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was washed successively with water, 0.1N aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. To give 2: 1 tert-butyl 3-pyrroline-1-carboxylate (62g) as a colorless oil (2 g) NMR：(CDCl₃)1.45(s，9H)，4.1(d，4H)，6.75(m，2H)]And pyrrolidine-1-carboxylic acid tert-butyl esterNMR：(CDCl₃)1.5(s，9H)，1.8(br s，4H)，3.3(br s，4H)]A mixture of (a).

An acetone (500ml) solution of the mixture obtained above was added dropwise toN-methylmorpholine-N-oxide (28.45g), osmium tetroxide (1g) and water (500ml of a mixture during which the reaction temperature is kept below 25 ℃ then at room temperature, the reaction mixture is stirred for 5 hours the solvent is evaporated, the residue is partitioned between ethyl acetate and water the organic phase is washed with brine, dried over magnesium sulphate and evaporated the residue is purified by silica gel column chromatography using a mixture of petroleum ether (b.p.40-60 ℃) and ethyl acetate of increasing polarity as eluent and further by silica gel column chromatography using a mixture of dichloromethane and methanol of increasing polarity as eluent to give tert-butyl 3, 4-dihydroxypyrrolidine-1-carboxylate as an oil (34.6 g);NMRspectrum: (CDCl)₃)1.45(s，9H)，2.65(m，2H)，3.35(m，2H)，3.6(m，2H)，4.25(m，2H)。

A solution of tert-butyl 3, 4-dihydroxypyrrolidine-1-carboxylate (34.6g) in DMF (400ml) was cooled to 0-5 ℃ and fractionatedSodium hydride (60% dispersion in mineral oil, 0.375mol) was added. The reaction mixture was stirred at 5 ℃ for 1 hour. Dibromomethane (15.6ml) was added and the reaction mixture was stirred at 5 ℃ for 30 minutes. The reaction mixture was warmed to room temperature and stirred for 16 hours. The DMF was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel using petroleum ether (b.p.40-60 ℃ C.) of increasing polarity and ethyl acetate as eluent. 3, 4-methylenedioxypyrrolidine-1-carboxylic acid tert-butyl ester was obtained as a colorless oil (19.77 g); NMRSpectrum: (CDCl)₃)1.45(s，9H)，3.35(m，2H)，3.75(br s，2H)，4.65(m，2H)，4.9(s，1H)，5.1(s，1H)。

A cooled 5M solution of hydrogen chloride in isopropanol (150ml) was added to an ice bath cooled solution of tert-butyl 3, 4-methylenedioxypyrrolidine-1-carboxylate (19.7g) in dichloromethane (500 ml). The reaction mixture was warmed to room temperature and stirred for 4 hours. The solvent was evaporated and the residue was triturated in ether. The precipitate was collected by filtration, washed with diethyl ether and dried. 3, 4-Methylenedioxypyrrolidine hydrochloride was obtained as a beige solid (13.18 g);NMRspectrum: (DMSOd)₆)3.15(m，2H)，3.35(m，2H)，4.65(s，1H)，4.8(m，2H)，5.1(s，1H)。

Example 55

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (1-methylpiperazin-4-ylacetyl) pyrrolidin-2-yl ] methoxy } quinazoline

Using a method analogous to that described in example 43, 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (chloroacetyl) pyrrolidin-2-yl]Methoxy } quinazoline (0.14g) was reacted with 1-methylpiperazine (5ml) to give the title product as a white foam (0.122 g); ¹ H NMRspectrum:

(CDCl3)1.91-2.01(m，1H)，2.04-2.12(m，2H)，2.17-2.23(m，1H)，2.25(s，3H)，2.34-2.45(m，3H)，2.49-2.59(m，2H)，2.62-2.72(m，2H)，3.08-3.26(q，2H)，3.40-3.51(m，2H)，3.54-3.61(m，1H)，4.00-4.08(m，4H)，4.50-4.56(m，1H)，4.67-4.74(m，1H)，7.10-7.24(m，2H)，7.23(s，1H)，7.91-7.97(m，1H)，8.38(s，1H)，8.60(s，1H)，8.66(s，1H)；

mass spectrometry：(M-H)^-541。

Example 56

4- (3-chloro-2-fluoroanilino) -6- [ (3R) -1- (hydroxyacetyl) pyrrolidin-3-yloxy ] -7-methoxyquinazoline

4- (3-chloro-2-fluoroanilino) -6- [ (3R) -pyrrolidin-3-yloxy]7-Methoxyquinazoline hydrochloride (0.25 g; prepared as described in example 29) was dissolved in a mixture of dichloromethane (10ml) and diisopropylethylamine (0.3 ml). The solution was cooled to 4 ℃ in an ice bath and acetoxyacetyl chloride (0.069ml) was added. The reaction mixture was stirred for 2 hours with cooling and then partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with brine and then Na ₂SO₄Drying, filtering and evaporating. The residue was dissolved in 7M methanolic ammonia (10ml), and the resulting solution was stirred overnight. The solvent was evaporated and the residue was purified by column chromatography eluting with a mixture of dichloromethane/methanol (saturated with ammonia) (98/2 to 92/8) of increasing polarity. The fractions containing the desired product were evaporated and the residue triturated with ether to give the title product as a pale yellow solid (0.161g, 61%); ¹ H NMRspectrum:

(DMSO-d₆@393K，500MHz)2.10-2.40(m，2H)，3.50-3.70(m，3H)，3.70-3.85(m，1H)，3.95(s，3H)，4.05(s，2H)，5.15(s，1H)，7.15-7.30(m，2H)，7.30-7.45(m，1H)，7.50-7.70(m，1H)，7.85(s，1H)，8.40(s，1H)，9.20(bs，1H)；

mass spectrometry：(M+H)⁺447。

Example 57

6- [ (3S) -1-acetylpiperidin-3-yloxy ] -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline

Acetic anhydride (42. mu.l) in dichloromethane (5ml) was added dropwise to a stirred solution of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (3S) -piperidin-3-yloxy) at 0 ℃]Quinazoline hydrochloride (0.175g, 0.4 mmol; prepared as described in example 49) and diisopropylethylamine (208 μ l) in dichloromethane (20ml) the mixture was stirred for 2 hours and then allowed to warm to room temperature. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution and dried (MgSO)₄) Filtered and evaporated to give a white foam. It is purified by column chromatography, eluting with a mixture of dichloromethane/methanol (100/0 to 95/5) of increasing polarity. The fractions containing the desired product were combined and evaporated in vacuo to give the title product as a colourless foam (0.117g, 66%); ¹ H NMRSpectrum: (DMSO d)₆，@373K)

1.40-1.65(m，1H)，1.70-1.94(m，2H)，2.00(s，3H)，1.95-2.20(m，1H)，3.20-3.70(m，3H)，3.70-4.10(m，1H)，3.95(s，3H)，4.40-4.70(m，1H)，7.15-7.33(m，2H)，7.33-7.50(m，1H)，7.50-7.70(m，1H)，7.90(s，1H)，8.40(s，1H)，9.25(s，1H)；

Mass spectrometry：(M+H)⁺445。

Example 58

4- (3-chloro-2-fluoroanilino) -6- [ (3S) -1- (methylsulfonyl) piperidin-3-yloxy ] -7-methoxyquinazoline

A solution of methanesulfonyl chloride (34. mu.l) in dichloromethane (5ml) was added dropwise to a stirred solution of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (3S) -piperidin-3-yloxy) at 0 DEG C]Quinazoline hydrochloride (175 mg; prepared as described in example 49) and diisopropylethylamine (208 μ l) in dichloromethane (20 ml). The reaction mixture was stirred for 2 hours to room temperature. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution and dried (MgSO)₄) Filtered and evaporated to give a foam. It is purified by column chromatography, eluting with dichloromethane/methanol mixtures (100/0 to 97/3) of increasing polarity. The fractions containing the desired product were combined and evaporated in vacuo to give the title product as a white foam (0.164g, 85%); ¹ H NMRspectrum:

(DMSO d₆)1.5-1.67(m，1H)，1.67-1.83(m，1H)，1.83-1.95(m，1H)，1.95-2.12(m，1H)，2.95(s，3H)，3.1-3.23(m，1H)，3.23-3.45(m，2H+H₂O)，3.5-3.65(m，1H)，3.95(s，3H)，4.70(m，1H)，7.18-7.35(m，2H)，7.40-7.60(m，2H)，7.90(s，1H)，8.38(s，1H)，9.58(s，1H)；

mass spectrometry：(M+H)⁺481。

Example 59

4- (3-chloro-2-fluoroanilino) -6- [ (3S) -1- (N, N-dimethylaminoacetyl) piperidin-3-yloxy ] -7-methoxyquinazoline

N, N-dimethylaminoacetyl chloride hydrochloride (69mg) was added portionwise to a stirred solution of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (3S) -piperidin-3-yloxy) at 0 deg.C ]Quinazoline hydrochloride (175 mg; prepared as described in example 49) and diisopropylethylamine (210 μ l) in dichloromethane (25 ml). The reaction mixture was stirred for 2 hours to room temperature. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution and dried (MgSO)₄) Filtered and evaporated to give a foam. It was purified by column chromatography eluting with a mixture of dichloromethane/methanol (saturated with ammonia) (100/0 to 90/10) of increasing polarity. Fractions containing the desired product were evaporated in vacuo to afford the title product as a white foam (0.152g, 78%); ¹ H NMRspectrum: (DMSO)_d6@100℃)

1.40-1.65(m，1H)；1.75-1.95(m，2H)；2.00-2.30(m，7H)；3.05(dd，2H)；3.40-3.62(m，2H)；3.62-3.75(m，1H)；3.88(dd，1H)；3.95(s，3H)；4.45-4.65(m，1H)；7.15-7.30(m，2H)；7.30-7.47(m，1H)；7.50-7.7(m，1H)；7.88(s，1H)；8.40(s，1H)；9.25(s，1H)；

Mass spectrometry：(M+H)⁺488。

Example 60

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2S) -1- (2-hydroxyisobutyryl) pyrrolidin-2-yl ] methoxy } quinazoline

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (2S) -pyrrolidin-2-ylmethoxy]Quinazoline hydrochloride (0.25 g; prepared as described in example 31) was dissolved in a mixture of dichloromethane (5ml) and diisopropylethylamine (0.3 ml). The solution was cooled to 4 ℃ in an ice/water bath and 2-acetoxybutyryl chloride (0.085ml) was added. The reaction mixture was stirred for 1 hour with cooling and then partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with brine and then Na ₂SO₄Drying, filtering and evaporating. The residue was dissolved in 7M methanolic ammonia (10ml), and the resulting solution was stirred overnight. The solvent is evaporated and the residue is purified by column chromatography, eluting with a dichloromethane/isopropanol/triethylamine mixture (97/2/1 to 95/4/1) of increasing polarity. The fractions containing the desired product were evaporated and the residue triturated with ether to give the title product as a white solid (0.210 g); ¹ H NMRspectrum:

(CDCl₃)1.57(s，6H)，1.85-2.30(m，4H)，3.55-3.75(m，1H)，3.75-3.90(m，1H)，3.90-4.20(m，5H)，4.53(d，1H)，4.7-4.85(m，1H)，7.05-7.20(m，2H)，7.25(s，1H)，8.15-8.35(m，2H)，8.50(s，1H)，8.67(s，1H)；

mass spectrometry：(M+H)⁺489。

Example 61

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- {1- [ (2S) -1-methylpyrrolidin-2-ylcarbonyl ] piperidin-3-yloxy } quinazoline

HATU (0.26g) was added to 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (piperidin-3-yl)Oxy) quinazoline dihydrochloride (250 mg; prepared as described in example 45), diisopropylethylamine (210 μ L) and N-methyl-L-proline (0.120g) in DMF (7.5ml) and the mixture was stirred at rt for 2.5 h. DMF was removed under reduced pressure and the residue was dissolved in dichloromethane (50ml) and washed with saturated sodium bicarbonate (50ml) and water (50 ml). Purification was by flash column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4). The fractions containing the desired product were evaporated to give a foam. The foam was dissolved in dichloromethane (5ml) and crystallized by addition of isohexane (50ml) to give the title product as a mixture of two diastereomers (0.130 g); ¹ H NMRSpectrum:

(DMSO d₆)1.43-1.62(m，2H)，1.66-1.95(m，4H)，1.96-2.18(m，4H)，2.20-2.29(m，2H)，2.67-2.80(m，1H)，2.96(m，1H)，3.03-3.20(m，1H)，3.51-3.80(m，2H)，3.80-4.05(m，4H)，4.51-4.68(m，1H)，7.22-7.31(m，2H)，7.47-7.59(m，2H)，7.89(m，1H)，8.39(s，1H)，9.55(m，1H)；

mass spectrometry：(M+H)⁺514。

Example 62

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [1- [ (N, N-dimethylcarbamoylmethyl) piperidin-3-yloxy ] quinazoline

2-chloro-N, N-dimethylacetamide (105mg) was added to a solution of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (piperidin-3-yloxy) quinazoline dihydrochloride (250mg) and potassium carbonate (1.19g) in DMF (5 ml). The reaction mixture was stirred at room temperature for 30 minutes, filtered and the solvent was evaporated. Purification by flash column chromatography eluting with methylene chloride/methanol (96/4) gave a foam. Mixing the bubblesThe foam was triturated with ether and isohexane to give the title product as a white solid (105 mg); ¹ H NMRspectrum:

(DMSO d₆)1.45(m，1H)，1.61(m，1H)，1.78(m，1H)，2.10(m，1H)，2.26(m，1H)，2.38(m，1H)，2.65-2.77(m，1H)，2.75(s，3H)，2.99(s，3H)，3.04(m，1H)，3.22(s，2H)，3.94(s，3H)，4.62(m，1H)，7.21(s，1H)，7.29(m，1H)，7.47-7.55(m，2H)，7.88(s，1H)，8.38(s，1H)，9.59(s，1H)；mass spectrometry：(M+H)⁺488。

Example 63

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [1- (3, 3-difluoropyrrolidin-1-ylacetyl) piperidin-3-yloxy ] quinazoline

Chloroacetyl chloride (47. mu.l) was added to a solution of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (piperidin-3-yloxy) quinazoline dihydrochloride (250mg) and diisopropylethylamine (373. mu.l) in dichloromethane (10ml), and the reaction mixture was stirred at room temperature for 1 hour. 3, 3-difluoropyrrolidine hydrochloride (Synthetic Letters, 1995; 1, 55-57; 328mg) was added and the solution stirred for 1 hour and then washed with saturated aqueous sodium bicarbonate (10ml) and purified by flash column chromatography eluting with dichloromethane/methanol (100/0 to 95/5) of increasing polarity to give a foam. The foam was dissolved in dichloromethane (5ml) and crystallized by addition of isohexane (50ml) to give the title product (102 mg); ¹ H NMRSpectrum:

(DMSO d₆)1.45-1.57(m，1H)，1.73-1.95(m，2H)，1.98-2.18(m，2H)，2.18-2.33(m，1H)，2.63-2.75(m，1H)，2.77-2.85(m，1H)，2.85-2.99(m，1H)，3.04-3.19(m，1H)，3.21-3.29(m，1H)，3.37-3.50(m，2H)，3.52-3.70(m，2H)，3.77-3.99(m，4H)，4.63(m，1H)，7.21-7.29(m，2H)，7.47-7.57(m，2H)，7.87(d，1H)，8.39(s，1H)，9.55(d，1H)；

mass spectrometry：(M+H)⁺550。

Example 64

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- {1- [ [ (3R) -3-hydroxypyrrolidin-1-yl ] acetyl ] piperidin-3-yloxy } quinazoline

Chloroacetyl chloride (47. mu.l) was added to a solution of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (piperidin-3-yloxy) quinazoline dihydrochloride (250mg) and diisopropylethylamine (373. mu.l) in dichloromethane (10ml), and the mixture was stirred at room temperature for 1 hour. (R) - (+) -3-pyrrolidinol (202mg) was added and the solution stirred for 1 hour then washed with saturated aqueous sodium bicarbonate (10ml), purified by flash column chromatography eluting with a mixture of dichloromethane/methanol (saturated with ammonia) of increasing polarity (100/0 to 95/5) to give a foam. The foam was dissolved in dichloromethane (5ml) and crystallized by addition of isohexane (50ml) to give the title product as a mixture of two diastereomers (68 mg); ¹ H NMRspectrum:

(DMSO d₆，100℃)1.52(m，2H)，1.87(m，3H)，2.09(m，1H)，2.38(m，1H)，2.61(m，1H)，2.77(m，1H)，3.18(m，1H)，3.36(d，1H)，3.53(m，2H，)，3.68(m，1H)，3.89(m，1H)，3.94(s，3H)，4.15(m，1H)，4.23(m，1H)，4.53(m，1H)，7.27(m，2H)，7.41(m，1H)，7.59(m，1H)，7.89(s，1H)，8.38(s，1H)，9.24(br s，1H)；

mass spectrometry：(M+H)⁺530。

Example 65

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (4-methyl-3-oxopiperazin-1-yl) acetyl ] piperidin-3-yloxy } quinazoline

Chloroacetyl chloride (47. mu.l) was added to a solution of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (piperidin-3-yloxy) quinazoline dihydrochloride (250mg) and diisopropylethylamine (373. mu.l) in dichloromethane (10ml), and the mixture was stirred at room temperature for 1 hour. 1-methylpiperazin-2-one (195mg) was added, the solution was stirred for 1 hour, then washed with saturated aqueous sodium bicarbonate solution (10ml), purified by flash column chromatography eluting with dichloromethane/methanol (100/0 to 95/5) of increasing polarity to give a foam. The foam was dissolved in dichloromethane (5ml) and crystallized by addition of isohexane (50ml) to give the title product (177 mg); ¹ H NMRSpectrum:

(DMSO d₆，100℃)1.57(m，1H)，1.91(m，2H)，2.08(m，1H)，2.67-2.85(m，5H)，3.08(s，2H)，3.18(m，3H)，3.32(d，J＝15Hz，1H)，3.47-3.60(m，2H)，3.71-3.83(m，2H，)，3.95(s，3H)，4.57(m，1H)，7.27(m，2H)，7.42(m，1H)，7.60(m，1H)，7.89(s，1H)，8.40(s，1H)，9.23(br s，1H)；

mass spectrometry：(M+H)⁺557。

Example 66

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- {1- [ (4-acetylpiperazin-1-yl) acetyl ] piperidin-3-yloxy } quinazoline

Chloroacetyl chloride (47. mu.l) was added to a solution of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (piperidin-3-yloxy) quinazoline dihydrochloride (250mg) and diisopropylethylamine (373. mu.l) in dichloromethane (10ml), and the mixture was stirred at room temperature for 1 hour. 1-acetylpiperazine (292mg) was added and the solution was stirred for 1 hour, then washed with saturated aqueous sodium bicarbonate (10ml), purified by flash column chromatography eluting with dichloromethane/methanol mixtures of increasing polarity (100/0 to 95/5) to give a foam. This foam was dissolved in methylene chloride (5ml), and isohexane (50ml) was added to crystallize to give the title compound (73 mg); ¹ H NMRspectrum:

(DMSO d₆，100℃)1.55(m，1H)，1.88(m，2H)，1.92(s，3H)，2.11(m，1H)，2.30-2.48(m，4H)，3.10(d，1H)，3.28(d，1H)，3.34(m，4H)，3.56(m，2H)，3.73(m，1H)，3.88(m，1H)，3.94(s，3H)，4.56(m，1H)，7.27(m，2H)，7.41(m，1H)，7.60(m，1H)，7.90(s，1H)，8.38(s，1H)，9.27(m，1H)；

mass spectrometry：(M+H)⁺571。

Example 67

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [ (2R) -1-methylpyrrolidin-2-yl ] methoxy } quinazoline

4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (2R) -pyrrolidin-2-ylmethoxy]A mixture of quinazoline hydrochloride (250 mg; prepared as described in example 32), formic acid (5ml) and formaldehyde (37% w/v in water) (2.5ml) was heated to 85 ℃ for 1 hour. The reaction mixture was then evaporated in vacuo and azeotroped with toluene, then Then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was then purified by flash chromatography eluting with a dichloromethane/methanol (saturated with ammonia) (98/2-94/6) mixture of increasing polarity. The fractions containing the desired product were combined and evaporated to give a colourless gum, triturated with ether, filtered and dried in vacuo to give the title product as a white solid (0.15 g); ¹ H NMRspectrum:

(DMSO d₆)1.55-1.83(m，3H)；1.95-2.10(m，1H)；2.20-2.35(m，1H)；2.45(s，3H)；2.68-2.85(m，1H)；2.93-3.10(m，1H)；3.92(s，3H)；3.92-4.15(m，2H)；7.19(s，1H)；7.20-7.30(m，1H)；7.40-7.55(m，2H)；7.81(s，1H)；8.36(s，1H)；9.57(s，1H)；

mass spectrometry：(M+H)⁺417。

Example 68

Pharmaceutical composition

Representative pharmaceutical dosage forms of the invention for use in the treatment or prophylaxis of humans are illustrated below, these dosage forms being defined herein (the active ingredient being referred to as "compound X"):

(a) the

A

A

.

.

A

(b) The injection I.A.

A

.

0.1M hydrochloric acid (pH 7.6)

A

The water for injection is 100 percent

The above-mentioned preparation can be prepared by a conventional method well known in the pharmaceutical field. For example, the tablets may be prepared by mixing the components and subsequently compressing the mixture into tablets.

Reference example 1

6-acetoxy-4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline hydrochloride

6-acetoxy-4-chloro-7-methoxyquinazoline (prepared as described in examples 25-5 in WO 01/66099, 6.00g, 23.8mmol) and 3-chloro-2-fluoroaniline (3.46g, 23.8mmol) were suspended in isopropanol (200 ml). The mixture was heated to reflux at 80 ℃ for 3 hours. The solvent was evaporated and the residue crystallized from acetonitrile to give the hydrochloride salt of the product as pale pink crystals (8.16g, 92%);

¹ H NMR：2.37(s，3H)，4.00(s，3H)，7.34(ddd，1H)，7.48(s，1H)，7.52(ddd，1H)，7.61(ddd，1H)，8.62(s，1H)，8.86(s，1H)；

mass spectrometry：362.4，364.4。

Reference example 2

4- (3-chloro-2-fluoroanilino) -6-hydroxy-7-methoxyquinazoline

6-acetoxy-4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline hydrochloride (reference example 1, 8.72g, 21.9mmol) was dissolved in methanol (200 ml). Concentrated ammonia (15ml) was added and the solution was heated to 50 ℃ with stirring for 2 hours to give a cream solid precipitate. The solid was collected by filtration, washed with diethyl ether (3X 200ml) and dried at 60 ℃ under vacuum over phosphorus pentoxide to give the product as an off-white solid (5.40g, 77%);

¹ H NMR：3.95(s，3H)，7.19(s，1H)，7.23(dd，1H)，7.42(dd，1H)，7.50(dd，1H)，7.64(s，1H)，8.32(s，1H)，9.43(s，1H)，9.67(br.s，1H)；

mass spectrometry：320.4，322.4。

Reference example 3

6- { [ (1-tert-Butoxycarbonyl) piperidin-4-yl ] oxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline

4- (3-chloro-2-fluoroanilino) -6-hydroxy-7-methoxyquinazoline (reference example 2, 1870mg, 5.85mmol) was dissolved in DMA (50 ml). (4-Methanesulfonyloxy) piperidine-1-carboxylic acid tert-butyl ester (according to Chemical) was added& Pharmaceutical Bulletin 2001，49(7)，822-829；490mg，1.76mmol) And cesium fluoride (890mg, prepared by 5.85mmol), the mixture was heated to 85 ℃ with stirring. The above amounts of tert-butyl 4-methanesulfonyloxypiperidine-1-carboxylate and cesium fluoride were added to the reaction mixture at intervals of 2 hours, 4 hours and 6 hours. After the last addition, heating was continued at 85 ℃ for 6 hours. The solvent was evaporated and the residue partitioned between DCM (150ml) and water (150 ml). The aqueous layer was extracted with DCM (4X 100ml) and the extracts were combined with DCM layers. The combined DCM fractions were dried over magnesium sulfate and evaporated. The residue was purified by chromatography using 0-2.5% (7: 1 MeOH/concentrated NH) ₄Aqueous OH) in DCM. The appropriate fractions were combined and evaporated to give the product as a light brown foam (2.40g, 58%, allowing 2.3 equivalents of residual DMA);

¹ H NMR：1.40(s，9H)，1.60-1.65(m，2H)，1.95-2.00(m，2H)，3.20-3.25(m，2H)，3.65-3.70(m，2H)，3.92(s，3H)，4.68(m，1H)，7.21(s，1H)，7.27(dd，1H)，7.47(ddd，1H)，7.51(dd，1H)，7.85(s，1H)，8.36(s，1H)，9.53(s，1H)；

mass spectrometry：503.5，505.5。

Reference example 4

6- { [ (1-tert-Butoxycarbonyl) piperidin-4-yl ] methoxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline

4- (3-chloro-2-fluoroanilino) -6-hydroxy-7-methoxyquinazoline (reference example 2, 700mg, 2.19mmol) was dissolved in DMA (35 ml). Potassium carbonate (1209mg, 8.76mmol) and tert-butyl 4- (toluene-4-sulfonyloxymethyl) piperidine-1-carboxylate (prepared as described in example 1 in WO 9427965; 808mg, 2.19mmol) were added and the mixture was stirred at 80 ℃ for 4 h. The solvent was evaporated and the residue partitioned between water (100ml) and DCM (100 ml). The aqueous layer was extracted with DCM (3X 100ml) and the extracts were combined with DCM layers. The combined DCM fractions were filtered through silicone treated filter paper and evaporated to give the product as a brown solid (1290mg, 98%);

¹ H NMR：1.20(m，2H)，1.39(s，9H)，1.82(m，2H)，2.03(br.m，1H)，2.70-2.85(br.m，2H)，3.93(s，3H)，3.95-4.05(br.m，2H)，3.98(d，2H)，7.19(s，1H)，7.26(dd，1H)，7.46(dd，1H)，7.50(dd，1H)，7.76(s，1H)，8.35(s，1H)，9.57(s，1H)；

mass spectrometry：517.3，519.3。

Reference example 5

6- { [2- (1-tert-Butoxycarbonyl) piperidin-4-yl ] ethoxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline

4- (3-chloro-2-fluoroanilino) -6-hydroxy-7-methoxyquinazoline (reference example 2, 500mg, 1.56mmol) was dissolved in DMA (25 ml). Potassium carbonate (864mg, 6.26mmol) and tert-butyl 4- [2- (methylsulfonyloxy) ethyl ] piperidine-1-carboxylate (prepared as described in example 20 in US 5252586; 504mg, 1.64mmol) were added and the mixture was stirred at 60 ℃ for 16 h. The solvent was evaporated and the residue partitioned between water (100ml) and DCM (100 ml). The aqueous layer was extracted with DCM (3X 100ml) and the extracts were combined with DCM layers. The combined DCM fractions were filtered through silicone treated filter paper and evaporated to give the product as a brown foam (830mg, 100%);

¹ H NMR：1.00-1.18(m，2H)，1.38(s，9H)，1.65-1.80(m，5H)，2.65-2.75(m，2H)，3.92(s，3H)，3.93(m，2H)，4.15(t，2H)，7.18(s，1H)，7.26(dd，1H)，7.46(dd，1H)，7.51(dd，1H)，7.77(s，1H)，8.36(s，1H)，9.54(s，1H)；

Mass spectrometry：531.6，533.6。

Claims (24)

1. A quinazoline derivative of the formula I:

wherein:

G¹and G²Each independently is halo;

R¹-X¹selected from hydrogen, (1-6C) alkoxy and (1-4C) alkoxy (1-6C) alkoxy, wherein R¹-X¹Any of the (1-6C) alkoxy groups optionally bears 1, 2 or 3 substituents which may be the same or different, selected from hydroxy, fluoro and chloro;

X²is a direct bond;

Q¹is (3-7C) cycloalkyl or a non-aromatic saturated or partially saturated 3-7 membered monocyclic heterocyclic group, said heterocyclic group carrying one ring nitrogen or sulfur heteroatom and optionally 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, wherein Q¹Optionally carrying 1, 2 or 3 substituents which may be the same or different selected from: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, carbamoyl, acryloyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (2-6C) alkenyloxy, (2-6C) alkynyloxy, (1-6C) alkylthio, (2-6C) alkenylthio, (2-6C) alkynylthio, (1-6C) alkylsulfinyl, (2-6C) alkenylsulfinyl, (2-6C) alkynylsulfinyl, (1-6C) alkylsulfonyl, (2-6C) alkenylsulfonyl, (2-6C) alkynylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl. ]Amino group,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino, sulfamoyl,N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino, carbamoyl (1-6C) alkyl,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, sulfamoyl (1-6C) alkyl,N- (1-6C) alkylsulfamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl (1-6C) alkyl, (2-6C) alkanoyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl andN- (1-6C) alkyl- (2-6C) alkanoylamino (1-6C) alkyl, or a group of the formula:

Q²-X³-

wherein X³Is CO and Q²Is a heterocyclic group, and is a heterocyclic group,

and wherein Q²Optionally with 1 or 2Substituents which may be the same or different are selected from: halo, hydroxy, (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl,

and wherein Q¹Any of (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkanoyl optionally bearing one or more substituents which may be the same or different selected from: halo, hydroxy and (1-6C) alkyl and/or optionally bearing substituents selected from: cyano, nitro, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, hydroxy (1-6C) alkoxy, (1-4C) alkoxy (1-6C) alkoxy, (2-6C) alkanoyl, (2-6C) alkanoyloxy and NR ^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl, and wherein R^aOr R^bAny (1-4C) alkyl group in (A) optionally bears one or more substituents which may be the same or different selected from halo and hydroxy and/or optionally bears a substituent selected from: cyano, nitro, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy, hydroxy (1-4C) alkoxy and (1-2C) alkoxy (1-4C) alkoxy,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached, form a 4-, 5-or 6-membered ring which optionally bears on available ring carbon atoms 1 or 2 substituents which may be the same or different selected from halo, (1-4C) alkyl and (1-3C) alkylenedioxy, and which optionally bears on any available ring nitrogen atom a substituent selected from (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl, with the proviso that the ring is not therefore quaternized,

and wherein as a substituent is present in^aAnd R^bAny (1-4C) alkyl or (2-4C) alkanoyl group on the ring together with the nitrogen atom to which they are attached optionally bears one or more substituents, which may be the same or different, selected from halo and hydroxy and/or optionally bears substituents selected from (1-4C) alkyl and (1-4C) alkoxy.

2. A quinazoline derivative of the formula I according to claim 1, wherein each R¹、G¹、G²、X¹And X²Has any of the meanings defined in claim 1; and

Q¹is a non-aromatic, saturated or partially saturated, 3-to 7-membered monocyclic heterocyclic ring which carries a ring nitrogen heteroatom and optionally 1 or 2 heteroatoms selected from nitrogen and sulfur, the ring being linked to the group X via a ring carbon atom²-O-is linked, and wherein Q¹Optionally carrying 1, 2 or 3 substituents which may be the same or different selected from: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, carbamoyl, acryloyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (2-6C) alkenyloxy, (2-6C) alkynyloxy, (1-6C) alkylthio, (2-6C) alkenylthio, (2-6C) alkynylthio, (1-6C) alkylsulfinyl, (2-6C) alkenylsulfinyl, (2-6C) alkynylsulfinyl, (1-6C) alkylsulfonyl, (2-6C) alkenylsulfonyl, (2-6C) alkynylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl.]Amino group,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino, sulfamoyl, N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino, carbamoyl (1-6C) alkyl,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, sulfamoyl (1-6C) alkyl,N- (1-6C) alkylsulfamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl (1-6C) alkyl, (2-6C) alkanoyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl andN- (1-6C) alkyl- (2-6C) alkanoylamino (1-6C) alkyl, or a group of the formula:

Q²-X³-

wherein X³Is CO and Q²Is a heterocyclic group selected from morpholino and 4, 5 or 6 membered monocyclic heterocyclic group containing one nitrogen heteroatom and optionally 1 or 2 heteroatoms selected from sulphur and nitrogen,

and wherein Q²Optionally with 1 or 2Substituents which may be the same or different are selected from: halo, (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl,

and wherein Q¹Any of (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkanoyl of (a) optionally bearing one or more substituents which may be the same or different selected from halo, hydroxy and (1-6C) alkyl and/or optionally bearing substituents selected from: cyano, nitro, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, hydroxy (1-6C) alkoxy, (1-4C) alkoxy (1-6C) alkoxy, (2-6C) alkanoyl, (2-6C) alkanoyloxy and NR ^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl, and wherein R^aOr R^bAny (1-4C) alkyl group in (A) optionally bears one or more substituents which may be the same or different selected from halo and hydroxy and/or optionally bears a substituent selected from: cyano, nitro, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy, hydroxy (1-4C) alkoxy and (1-2C) alkoxy (1-4C) alkoxy,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached, form a 4-, 5-or 6-membered ring which optionally bears on available ring carbon atoms 1 or 2 substituents which may be the same or different selected from halo, (1-4C) alkyl and (1-3C) alkylenedioxy, and which optionally bears on any available ring nitrogen atom a substituent selected from (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl, with the proviso that the ring is not therefore quaternized,

and wherein as a substituent is present in^aAnd R^bAny (1-4C) alkyl or (2-4C) alkanoyl group on the ring together with the nitrogen atom to which they are attached optionally bears one or more substituents, which may be the same or different, selected from halo and hydroxy and/or optionally bears substituents selected from (1-4C) alkyl and (1-4C) alkoxy.

3. A quinazoline derivative of the formula I according to claim 1, wherein each R¹、G¹、G²、X¹And X²Has any of the meanings defined in claim 1; and

Q¹is (3-7C) cycloalkyl or a non-aromatic saturated or partially saturated 3-7 membered monocyclic heterocyclic group, said heterocyclic group carrying one ring nitrogen or sulfur heteroatom and optionally 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, wherein Q¹Optionally carrying 1, 2 or 3 substituents which may be the same or different selected from: halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, carbamoyl, (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 group,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino, sulfamoyl,N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino, carbamoyl (1-6C) alkyl, N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, (2-6C) alkanoyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl andN- (1-6C) alkyl- (2-6C) alkanoylamino (1-6C) alkyl,

wherein Q¹Any of (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkanoyl of (a) optionally bearing one or more substituents which may be the same or different selected from halo, hydroxy and (1-6C) alkyl and/or optionally bearing substituents selected from: cyano, nitro, carboxyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, hydroxy (1-6C) alkoxy and NR^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached form a 4, 5 or 6 membered ring.

4. A quinazoline derivative of the formula I according to claim 1, wherein each R¹、G¹、G²、X¹And X²Has any of the meanings defined in claim 1; and

Q¹is a non-aromatic, saturated or partially saturated, 4-, 5-or 6-membered monocyclic heterocyclic ring having 1 or 2 ring nitrogen heteroatoms, which ring is linked to the radical X via a ring-forming carbon atom²-O-is linked, and wherein Q¹Optionally bearing 1 or 2 substituents which may be the same or different selected from: halo, cyano, nitro, carbamoyl, acryloyl, (1-6C) alkyl, (1-6C) alkylthio, (2-6C) alkenylthio, (2-6C) alkynylthio, (1-6C) alkylsulfinyl, (2-6C) alkenylsulfinyl, (2-6C) alkynylsulfinyl, (1-6C) alkylsulfonyl, (2-6C) alkenylsulfonyl, (2-6C) alkynylsulfonyl, N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, sulfamoyl,N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl, carbamoyl (1-6C) alkyl, carbamoyl (2-C) alkyl, carbamoyl (6C) alkyl, carbamoyl (meth) aryl, or carbamoyl (meth,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, sulfamoyl (1-6C) alkyl,N- (1-6C) alkylsulfamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl (1-6C) alkyl, (2-6C) alkanoyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl andN- (1-6C) alkyl- (2-6C) alkanoylamino (1-6C) alkyl, or a group of the formula:

Q²-X³-

wherein X³Is CO, and Q²Is a heterocyclic group selected from morpholino, piperidinyl, piperazinyl and pyrrolidinyl,

and wherein Q²Optionally bearing 1 or 2 substituents which may be the same or different selected from: halo, (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl,

and wherein Q¹Any of (1-6C) alkyl or (2-6C) alkanoyl in (a) optionally has 1 or 2 substituents which may be the same or different selected from halo, hydroxyAnd (1-6C) alkyl and/or optionally bearing a substituent selected from: cyano, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (2-6C) alkanoyl, (2-6C) alkanoyloxy and NR ^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl, and wherein R^aOr R^bAny of the (1-4C) alkyl groups in (A) optionally bears one or more substituents, which may be the same or different, selected from halo and hydroxy substituents and/or optionally bears one substituent selected from cyano and (1-4C) alkoxy,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached, form a 4-, 5-or 6-membered ring which is free of oxygen atoms and which optionally bears, on available ring carbon atoms, 1 or 2 substituents which may be the same or different, selected from halo, (1-4C) alkyl and (1-3C) alkylenedioxy groups and which optionally bears, on any available ring nitrogen atom, a substituent selected from (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl groups, with the proviso that the ring is not therefore quaternized,

and wherein as a substituent is present in^aAnd R^bAny (1-4C) alkyl or (2-4C) alkanoyl group on the ring together with the nitrogen atom to which they are attached optionally bears one or more substituents which may be the same or different selected from halo and hydroxy and/or optionally bears substituents selected from (1-4C) alkyl and (1-4C) alkoxy.

5. A quinazoline derivative of the formula I according to claim 1, wherein each R ¹、G¹、G²、X¹And X²Has any of the meanings defined in claim 1; and

Q¹selected from the group consisting of through a ring carbon atom with the group X²-O-linked pyrrolidinyl and piperidinyl, and wherein said pyrrolidinyl or piperidinyl is optionally substituted with 1 or 2 substituents selected from: halo, cyano, carbamoyl, (1-6C) alkyl, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkaneBase of]Carbamoyl, (2-6C) alkanoyl, sulfamoyl,N- (1-6C) alkylsulfamoyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl, carbamoyl (1-6C) alkyl, carbamoyl (2-C) alkyl, carbamoyl (6C) alkyl, carbamoyl (meth) aryl, or carbamoyl (meth,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, sulfamoyl (1-6C) alkyl,N- (1-6C) alkylsulfamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl (1-6C) alkyl and (2-6C) alkanoyl (1-6C) alkyl, or a group of the formula:

Q²-X³-

wherein X³Is CO, and Q²Is a heterocyclic group selected from morpholino, piperidino, piperazin-1-yl, pyrrolidin-1-yl and pyrrolidin-2-yl,

and wherein Q²Optionally bearing 1 or 2 substituents which may be the same or different selected from: halo, (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl,

And wherein Q¹Any of (1-6C) alkyl or (2-6C) alkanoyl in (a) optionally bearing 1 or 2 substituents which may be the same or different selected from halo, hydroxy and (1-6C) alkyl and/or optionally bearing substituents selected from: cyano, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (2-6C) alkanoyl, (2-6C) alkanoyloxy and NR^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl, and wherein R^aOr R^bAny (1-4C) alkyl group in (b) optionally bears one or more substituents which may be the same or different selected from halo and hydroxy and/or optionally bears one substituent selected from cyano and (1-4C) alkoxy,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached form a ring selected from pyrrolidin-1-yl, piperidino and piperazin-1-yl, which optionally bears on available ring carbon atoms 1 or 2 substituents which may be the same or different selected from halo, (1-4C) alkyl and methylenedioxy, and which optionally bears on any available ring nitrogen atom a substituent selected from (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkylsulfonyl, provided that the ring is not therefore substituted with a quaternary ammoniumThe chemical combination is carried out by dissolving,

and wherein as a substituent is present in ^aAnd R^bAny (1-4C) alkyl or (2-4C) alkanoyl group on the ring together with the nitrogen atom to which they are attached optionally bears one or more substituents which may be the same or different selected from halo and hydroxy and/or optionally bears substituents selected from (1-4C) alkyl and (1-4C) alkoxy.

6. A quinazoline derivative of the formula I according to claim 1, wherein each R¹、G¹、G²And X¹Has any of the meanings defined in claim 1; and

Q¹-X²selected from the group consisting of pyrrolidin-3-yl, piperidin-4-yl and piperidin-3-yl, wherein Q¹Substituted at the 1-position with a group selected from: (1-4C) alkyl, (1-4C) alkylsulfonyl, (2-4C) alkanoyl (1-3C) alkyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, (2-4C) alkanoyloxy- (2-4C) alkanoyl, amino (1-3C) alkylsulfonyl,N- (1-4C) alkylamino- (1-3C) alkylsulfonyl,N，NDi [ (1-4C) alkyl)]Amino (1-3C) alkylsulfonyl, pyrrolidin-1-yl- (2-4C) alkanoyl, 3, 4-methylenedioxypyrrolidin-1-yl- (2-4C) alkanoyl, piperidino- (2-4C) alkanoyl, piperazin-1-yl- (2-4C) alkanoyl, morpholino- (2-4C) alkanoyl and groups of the formula:

Q²-X³-

Wherein X³Is CO and Q²Is a pyrrolidin-2-yl group which,

and wherein Q¹In the substituent(s) or by Q²Any of the pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino or piperazin-1-yl groups represented optionally bears 1 or 2 substituents which may be the same or different selected from (1-4C) alkyl, (2-4C) alkanoyl and halo,

and wherein Q¹Any of the (2-4C) alkanoyl groups in the substituents optionally bears 1 or 2 substituents which may be the same or different and are selected from hydroxy and (1-3C) alkyl,

and whereinQ¹Any (1-4C) alkyl group in the substituents optionally bears 1 or 2 substituents which may be the same or different selected from hydroxy, (1-4C) alkoxy and halo.

7. A quinazoline derivative of the formula I according to claim 1, wherein each R¹、G¹、G²And X¹Has any of the meanings defined in claim 1; and

Q¹-X²selected from: piperidin-3-yl, (3R) -piperidin-3-yl, (3S) -piperidin-3-yl, and piperidin-4-yl, wherein Q¹-X²The piperidinyl group in (a) is substituted on the ring nitrogen atom with a substituent selected from: methyl, ethyl, isopropyl, isobutyl, methylsulfonyl, ethylsulfonyl, acetyl, propionyl, isobutyryl, carbamoylmethyl,N-methylcarbamoylmethyl, 2-, (N-methylcarbamoyl) ethyl, N-ethylcarbamoylmethyl, 2-, (N-ethylcarbamoyl) ethyl,N，N-dimethylcarbamoylmethyl, 2-, (N，N-dimethylcarbamoyl) ethyl group,N，N-diethylcarbamoylmethyl, 2-, (N，N-diethylcarbamoyl) ethyl, N-methylaminoacetyl, N-ethylaminoacetyl, 2- (N-methylamino) propionyl, 2- (N-ethylamino) propionyl,N，NDimethylaminoacetyl, 2-, (N，N-dimethylamino) propanoyl,N，NDiethylaminoacetyl, 2-, (N，N-diethylamino) propionyl group,N-methyl-N-ethylaminoacetyl, 2-, (N-methyl-N-ethylamino) propionyl group, acetoxyacetyl group, 2- (acetoxy) propionyl group, 2-, (ii) acetyl groupN-methylamino) ethanesulfonyl group, 2-, (N-ethylamino) ethanesulfonyl, 2-, (N，N-dimethylamino-ethanesulfonyl group, 2-, (N，N-diethylamino-ethanesulfonyl group, 3-, (N-methylamino) propanesulfonyl, 3-, (N-ethylamino) propanesulfonyl, 3-, (N，N-dimethylamino-propanesulfonyl group, 3-, (N，N-diethylamino) propanesulfonyl, pyrrolidin-1-ylacetyl, 2- (pyrrolidin-1-yl) propionyl, 3, 4-methylenedioxypyrrolidin-1-ylacetyl, 2- (3, 4-methylenedioxypyrrolidin-1-yl-Yl) propionyl, piperidinoacetyl, 2-piperidinopropionyl, morpholinoacetyl, 2-morpholinopropionyl, piperazin-1-ylacetyl, 2-piperazin-1-ylpropionyl, and a group of the formula:

Q²-X³-

Wherein X³Is CO, Q²Selected from morpholino, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino and piperazin-1-yl,

wherein Q¹In the substituent(s) or by Q²Any of the pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino or piperazin-1-yl groups represented optionally bears 1 or 2 substituents which may be the same or different selected from methyl, ethyl, acetyl, fluoro and chloro,

wherein Q¹Any of the acetyl, propionyl or isobutyryl groups on the substituents optionally bear 1 or 2 substituents which may be the same or different and are selected from hydroxy and methyl,

wherein Q¹Any (1-4C) alkyl group in the above substituents optionally bears 1 or 2 substituents which may be the same or different and are selected from hydroxy, methoxy, fluoro, chloro.

8. A quinazoline derivative of the formula I according to claim 1, wherein each R¹、G¹、G²And X¹Has any of the meanings defined in claim 1; and

Q¹-X²is a group of formula A:

wherein:

R⁴selected from the group consisting of carbamoyl,N- (1-6C) alkylcarbamoyl,N，NDi- [ (1-6C) alkyl]Carbamoyl and a group of the formula:

Q²-X³-

and wherein X³Is CO, and Q²Is a heterocyclic group selected from 4-, 5-or 6-membered monocyclic heterocyclic groupsContaining 1 nitrogen heteroatom and optionally containing 1 or 2 heteroatoms selected from sulfur, oxygen and nitrogen,

And wherein Q²Through the ring nitrogen atom with X³The connection is carried out by connecting the two parts,

and wherein Q²Optionally bearing one or more substituents which may be the same or different selected from: halo, (1-4C) alkyl and (2-4C) alkanoyl,

and wherein R⁴Any of (1-6C) alkyl or (2-6C) alkanoyl in (a) optionally bearing one or more substituents which may be the same or different selected from halo, hydroxy and (1-6C) alkyl and/or optionally bearing a substituent selected from: cyano, nitro, (2-8C) alkenyl, (2-8C) alkynyl and (1-6C) alkoxy,

R⁵selected from hydrogen, (1-6C) alkyl, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (2-6C) alkanoyl, carbamoyl (1-6C) alkyl,N- (1-6C) alkylcarbamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Carbamoyl (1-6C) alkyl, sulfamoyl (1-6C) alkyl,N- (1-6C) alkylsulfamoyl (1-6C) alkyl,N，NDi- [ (1-6C) alkyl]Sulfamoyl (1-6C) alkyl and (2-6C) alkanoyl (1-6C) alkyl,

and wherein R⁵Any of (1-6C) alkyl or (2-6C) alkanoyl in (a) optionally bearing one or more substituents which may be the same or different selected from halo, hydroxy and (1-6C) alkyl and/or optionally bearing a substituent selected from: cyano, nitro, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy and NR ^aR^bWherein R is^aIs hydrogen or (1-4C) alkyl, and R^bIs hydrogen or (1-4C) alkyl, and wherein R^aOr R^bAny of the (1-4C) alkyl groups in (A) optionally bears one or more substituents which may be the same or different, selected from halo and hydroxy and/or optionally bears substituents selected from cyano, nitro and (1-4C) alkoxy,

or R^aAnd R^bTogether with the nitrogen atom to which they are attached form a 4, 5 or 6-membered ring optionally bearing, on available ring carbon atoms, 1 or 2 substituents which may be the same or different, selected from halo, (1-4C) alkyl and (1-3C) alkylenedioxyAnd may optionally bear substituents selected from (1-4C) alkyl and (2-4C) alkanoyl on any available ring nitrogen atom, provided that the ring is not so quaternized,

and wherein as a substituent is present in^aAnd R^bAny (1-4C) alkyl or (2-4C) alkanoyl group on the ring together with the nitrogen atom to which they are attached optionally bears one or more substituents which may be the same or different selected from halo and hydroxy and/or optionally bears substituents selected from (1-4C) alkyl and (1-4C) alkoxy.

9. A quinazoline derivative of the formula I according to claim 1, wherein each R¹、G¹、G²And X¹Has any of the meanings defined in claim 1; and

Q¹-X²Is a group of formula A:

wherein:

R⁴is selected fromN，NDi- [ (1-4C) alkyl]Carbamoyl and a group of the formula:

Q²-X³-

and wherein X³Is CO, and Q²Selected from pyrrolidin-1-yl, morpholino and piperidino,

and wherein Q²Optionally bearing 1 or 2 substituents which may be the same or different selected from: fluoro, chloro and methyl groups,

and wherein R⁴Any of the (1-4C) alkyl groups in (A) optionally bears 1 or 2 substituents which may be the same or different selected from fluoro, chloro and hydroxy and/or optionally bears a substituent selected from methoxy,

R⁵selected from the group consisting of hydrogen, methyl, ethyl, isopropyl and isobutyl,

and wherein R⁵Any of the (1-4C) alkyl groups in (A) optionally bears 1 or 2 substituents which may be the same or different and are selected from fluoro, chloro and hydroxyAnd/or optionally bearing a substituent selected from methoxy.

10. A quinazoline derivative of the formula I according to any one of the preceding claims, wherein G¹Is fluorine and G²Is chlorine.

11. A quinazoline derivative of the formula I according to any one of claims 1 to 9, wherein R¹-X¹Selected from hydrogen and (1-4C) alkoxy.

12. A quinazoline derivative of the formula I according to any one of claims 1 to 9, wherein R¹-X¹Is methoxy.

13. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, according to claim 1,

Wherein:

R¹-X¹is (1-4C) alkoxy;

Q¹-X²is a group of formula a:

wherein:

R⁴is N, N-dimethylcarbamoyl or morpholinocarbonyl;

R⁵is hydrogen or methyl;

G¹is fluorine; and

G²is chlorine.

14. A quinazoline derivative of the formula I according to claim 1, wherein

R¹-X¹Selected from hydrogen, (1-4C) alkoxy and (1-4C) alkoxy;

X²is a direct bond;

Q¹is a fully saturated 5-or 6-membered monocyclic heterocyclic ring containing one nitrogen heteroatom and optionally one further heteroatom selected from oxygen, nitrogen and sulfur, which ring is bound via a carbon atom to the ring via the group X²-an O-linkage to the substrate,

wherein Q¹With 1 substituent on a ring carbon atom selected from: a carbamoyl group,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl, carbamoyl (1-3C) alkyl,N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, (2-4C) alkanoyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, pyrrolidin-1-yl- (2-4C) alkanoyl, piperidino- (2-4C) alkanoyl, piperazin-1-yl- (2-4C) alkanoyl and morpholino- (2-4C) alkanoyl or a group of the formula:

Q²-X³-

Wherein X³Is CO, Q²Selected from pyrrolidin-1-yl, morpholino and piperidino,

wherein Q¹The nitrogen atom of any NH group in (a) optionally bears a substituent selected from (1-4C) alkyl, and

G¹is fluoro radical, G²Is a chloro group.

15. A quinazoline derivative of the formula I according to claim 1, wherein

R¹-X¹Selected from the group consisting of hydrogen, methoxy, ethoxy and 2-methoxyethoxy;

X²is a direct bond;

Q¹a non-aromatic saturated 5-or 6-membered monocyclic heterocyclic ring containing one nitrogen heteroatom and optionally 1 heteroatom selected from oxygen and nitrogen, the ring being bridged via a carbon atom of the ring and a group X²-an O-linkage to the substrate,

wherein Q¹The nitrogen atom of any NH group in (a) optionally bears a substituent selected from: cyano, carbamoyl, (1-4C) alkyl2-6C) alkenyl, (2-6C) alkynyl, (1-4C) alkylsulfonyl,N- (1-4C) alkylcarbamoyl,N，NDi- [ (1-4C) alkyl]Carbamoyl, (2-4C) alkanoyl, sulfamoyl,N- (1-4C) alkylsulfamoyl,N，NDi- [ (1-4C) alkyl]Sulfamoyl, cyano (1-4C) alkyl, (1-4C) alkoxy (1-4C) alkyl, amino (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl, sulfamoyl, cyano (1-4C) alkyl, sulfamoyl, amino (1-4C) alkanoyl, sulfamoyl, amino (1-4C) alkyl, amino (1,N，NDi- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl, carbamoyl (1-3C) alkyl, N- (1-4C) alkylcarbamoyl (1-3C) alkyl,N，NDi- [ (1-4C) alkyl]Carbamoyl (1-3C) alkyl, (1-4C) alkoxy (1-3C) alkyl S (O)_q(wherein q is 0, 1 or 2), amino (1-3C) alkyl S (O)_q(wherein q is 0, 1 or 2),N- (1-4C) alkylamino (1-3C) alkyls (O)_q(wherein q is 0, 1 or 2) andN，Ndi- [ (1-4C) alkyl]Amino (1-3C) alkyl S (O)_q(wherein q is 0, 1 or 2),

Q¹optionally bearing 1 or 2 substituents on any available carbon atom of the ring selected from: (1-4C) alkyl, (2-6C) alkenyl, and (2-6C) alkynyl,

and wherein Q¹Any of (1-4C) alkyl, (2-6C) alkenyl or (2-6C) alkynyl optionally bearing 1 or 2 substituents which may be the same or different selected from fluoro and chloro; and

G¹and G²Each independently selected from fluoro, chloro and bromo.

16. A quinazoline derivative of the formula I, or a pharmaceutically acceptable acid addition salt thereof, according to claim 1, which is selected from:

4- (3-chloro-2-fluoroanilino) -6- { [1- (methylsulfonyl) piperidin-4-yl ] oxy } -7-methoxyquinazoline; and

6- { [1- (carbamoylmethyl) piperidin-4-yl ] oxy } -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline.

17. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, according to claim 1 which is selected from:

(1)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (1-methylpyrrolidin-3-yl) oxy ] quinazoline;

(2)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (piperidin-4-yl) oxy ] quinazoline;

(4)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (1-methylpiperidin-4-yl) oxy ] quinazoline;

(7)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (2-methoxyethyl) piperidin-4-yl ] oxy } quinazoline;

(11)4- (3-chloro-2-fluoroanilino) -6- { [1- (cyanomethyl) piperidin-4-yl ] oxy } -7-methoxyquinazoline;

(14)6- (1-acetylpiperidin-4-yloxy) -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline;

(15)4- (3-chloro-2-fluoroanilino) -6- [1- (N, N-dimethylaminoacetyl) piperidin-4-yloxy ] -7-methoxyquinazoline;

(16)6- [1- (N, N-dimethylsulfamoyl) piperidin-4-yloxy ] -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline;

(17)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [1- (morpholinoacetyl) piperidin-4-yloxy ] quinazoline;

(18)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [1- (pyrrolidin-1-ylacetyl) piperidin-4-yloxy ] quinazoline;

(19)4- (3-chloro-2-fluoroanilino) -6- {1- [3- (dimethylamino) propanesulfonyl ] piperidin-4-yloxy } -7-methoxyquinazoline;

(20)4- (3-chloro-2-fluoroanilino) -6- [1- (methylsulfonyl) piperidin-3-yl ] oxy } -7-methoxyquinazoline;

(21)4- (3-chloro-2-fluoroanilino) -6- [ (3R) -1- (methylsulfonyl) piperidin-3-yloxy ] -7-methoxyquinazoline;

(22)4- (3-chloro-2-fluoroanilino) -6- [ (3S) -1- (methylsulfonyl) piperidin-3-yloxy ] -7-methoxyquinazoline;

(23)6- (1-acetylpiperidin-3-yloxy) -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline;

(24)4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4S) -2- (N, N-dimethylcarbamoyl) pyrrolidin-4-yloxy ] -7-methoxyquinazoline;

(25)4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4S) -2- (N, N-dimethylcarbamoyl) -1-methylpyrrolidin-4-yloxy ] -7-methoxyquinazoline;

(26)4- (3-chloro-2-fluoroanilino) -6- [1- (N, N-dimethylaminoacetyl) piperidin-3-yloxy ] -7-methoxyquinazoline;

(27)4- (3-chloro-2-fluoroanilino) -6- [ (3R) -1- (N, N-dimethylaminoacetyl) piperidin-3-yloxy ] -7-methoxyquinazoline;

(28)4- (3-chloro-2-fluoroanilino) -6- [ (3S) -1- (N, N-dimethylaminoacetyl) piperidin-3-yloxy ] -7-methoxyquinazoline;

(29)4- (3-chloro-2-fluoroanilino) -6- [1- (hydroxyacetyl) piperidin-3-yloxy ] -7-methoxyquinazoline;

(30)6- [1- (acetoxyacetyl) piperidin-3-yloxy ] -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline;

(31)4- (3-chloro-2-fluoroanilino) -6- [ (3R) -1- (methylsulfonyl) pyrrolidin-3-yloxy ] -7-methoxyquinazoline;

(32)4- (3-chloro-2-fluoroanilino) -6- [ (3S) -1- (methylsulfonyl) pyrrolidin-3-yloxy ] -7-methoxyquinazoline;

(36)4- (3-chloro-2-fluoroanilino) -6- [ (3R) -1-methylpyrrolidin-3-yloxy ] -7-methoxyquinazoline;

(37)4- (3-chloro-2-fluoroanilino) -6- [ (3S) -1-methylpyrrolidin-3-yloxy ] -7-methoxyquinazoline;

(40)6- [ (3R) -1-acetylpyrrolidin-3-yloxy ] -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline;

(44)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (3S) -1- (N, N-dimethylsulfamoyl) pyrrolidin-3-yloxy ] quinazoline;

(47)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- (piperidin-3-yloxy) quinazoline;

(48)4- (3-chloro-2-fluoroanilino) -6- [ (2S, 4R) -2- (N, N-dimethylcarbamoyl) -1-methylpyrrolidin-4-yloxy ] -7-methoxyquinazoline;

(49)4- (3-chloro-2-fluoroanilino) -6- [ (2R, 4R) -2- (N, N-dimethylcarbamoyl) -1-methylpyrrolidin-2-yloxy ] -7-methoxyquinazoline;

(53)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (2RS, 4R) -1-methyl-2- (morpholinocarbonyl) pyrrolidin-4-yloxy ] quinazoline;

(54)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (3S) -piperidin-3-yloxy ] quinazoline;

(55)6- [ (3S) -1-acetylpiperidin-3-yloxy ] -4- (3-chloro-2-fluoroanilino) -7-methoxyquinazoline;

(56)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (3S) -1- (methylsulfonyl) piperidin-3-yloxy ] quinazoline;

(57)4- (3-chloro-2-fluoroanilino) -6- { (3S) -1- [ (dimethylamino) acetyl ] piperidin-3-yloxy } -7-methoxyquinazoline;

(58)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [1- (pyrrolidin-1-ylacetyl) piperidin-3-yloxy ] quinazoline;

(59)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [ (3S) -1- (pyrrolidin-1-ylacetyl) piperidin-3-yloxy ] quinazoline;

(63)4- (3-chloro-2-fluoroanilino) -6- [ (3R) -1- (hydroxyacetyl) pyrrolidin-3-yloxy ] -7-methoxyquinazoline;

(65)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- {1- [ (2S) -1-methylpyrrolidin-2-ylcarbonyl ] piperidin-3-yloxy } quinazoline;

(66)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [1- (N, N-dimethylcarbamoylmethyl) piperidin-3-yloxy ] quinazoline;

(67)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- [1- (3, 3-difluoropyrrolidin-1-ylacetyl) piperidin-3-yloxy ] quinazoline;

(68)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- {1- [ [ (3R) -3-hydroxypyrrolidin-1-yl ] acetyl ] piperidin-3-yloxy } quinazoline;

(69)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (4-methyl-3-oxopiperazin-1-yl) acetyl ] piperidin-3-yloxy } quinazoline; and

(70)4- (3-chloro-2-fluoroanilino) -7-methoxy-6- {1- [ (4-acetylpiperazin-1-yl) acetyl ] piperidin-3-yloxy } quinazoline.

18. A process for the preparation of a quinazoline derivative of the formula I as defined in claim 1 which comprises:

process (a) reacting a compound of formula II:

formula II

Wherein R is¹、X¹、G¹And G²Having any of the meanings defined in claim 1, but having any functional group protected if necessary, with a compound of formula III:

Q¹-X²-Lg

formula III

Wherein Q¹And X²Having any of the meanings defined in claim 1, but where necessary protected against any functional group, and Lg is a displaceable group,

thereafter removing any protecting groups present by conventional means; or

Method (b) modifying or introducing substituents into another quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined in claim 1, except that any functional groups need to be protected if necessary,

Thereafter removing any protecting groups present by conventional means; or

Process (c) reacting a compound of formula II as defined in process (a) with a compound of formula Q under mitsunobu reaction conditions¹-X²Reaction of a compound of-OH, wherein Q¹And X²Having any of the meanings defined in claim 1, but where necessary protecting any functional group,

thereafter removing any protecting groups present by conventional means; or

Process (d) wherein R is¹-X¹Cleavage of quinazoline derivatives of formula I which are (1-6C) alkoxy groups to prepare compounds in which R is¹-X¹A compound of formula I which is hydroxy; or

Process (e) for the preparation of wherein X¹A compound of formula I which is OReacting a compound of formula I, wherein R¹-X¹Is OH and Q¹、X²、G¹And G²Having any of the meanings defined in claim 1, but optionally protected from any functional group, with the formula R¹-Lg of a compound reaction in which R¹Having any of the meanings defined in claim 1, but where necessary protected against any functional group, and Lg is a displaceable group,

thereafter removing any protecting groups present by conventional means; or

Method (f) for preparing wherein Q¹Or R¹(ii) Compounds of formula I containing a (1-6C) alkoxy or substituted (1-6C) alkoxy or (1-6C) alkylamino or substituted (1-6C) alkylamino group, in which Q ¹Or R¹Alkylation of quinazoline derivatives of formula I containing appropriate hydroxyl or primary or secondary amino groups;

or

Process (g) for the preparation of¹A compound of formula I substituted by a group T, wherein T is selected from (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (2-6C) alkanoylamino, (1-6C) alkylthio, (1-6C) alkylsulfinyl and (1-6C) alkylsulfonyl, reacting a compound of the formula V:

formula V

Wherein Q¹、X¹、X²、R¹、G¹And G²Having any of the meanings defined in claim 1, but where necessary protecting any functional group, and Lg is a displaceable group, with a compound of formula TH, T is as defined above, but where necessary protecting any functional group, after which any protecting group present is removed by conventional means; or

Process (h) is prepared by reacting a compound of formula VI:

formula VI

Wherein R is¹、X¹、X²、Q¹Having any of the meanings defined in claim 1, but protecting any functional group if desired, and Lg being a displaceable group,

with an aniline of formula VII:

formula VII

Wherein G is¹And G²Having any of the meanings defined in claim 1, but protecting any functional group if desired,

thereafter removing any protecting groups present by conventional means; or

Method (i) for preparing wherein Q ¹With substituted carbamoyl radicals or radicals Q²-X³A compound of formula I wherein Q²Through a ring nitrogen atom with X³Attached nitrogen-containing heterocyclic group, and X³Is CO, such that Q is as defined in claim 1 and wherein¹Compounds of the formula I which carry carboxyl groups, but where appropriate with protection of any functional groups, with primary or secondary amines or of the formula Q²H radical is coupled, in which Q²H is a heterocyclic group containing an NH group; thereafter removing any protecting groups present by conventional means;

and may be obtained by conventional methods when a pharmaceutically acceptable salt of a quinazoline derivative of the formula I is required.

19. A pharmaceutical composition which comprises a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined in claim 1 in association with a pharmaceutically-acceptable diluent or carrier.

20. The use of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 9 or 13 to 17 in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal.

21. Use of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 9 or 13 to 17 in the manufacture of a medicament for the treatment of cancer.

22. A compound of formula B:

wherein Y is hydrogen or a hydroxy protecting group; and

R¹、X¹、G¹and G²As defined in claim 1.

23. A compound according to claim 22, wherein R¹-X¹Is hydrogen or (1-4C) alkoxy, and G¹And G²Selected from fluorine and chlorine.

24. A compound or salt thereof according to claim 22 which is 4- (3-chloro-2-fluoroanilino) -6-hydroxy-7-methoxyquinazoline.