UA80302C2 - Quinazoline derivatives as src tyrosine kinase inhibitors, process for their preparation, pharmaceutical compositions containing them and their use - Google Patents

Abstract

The invention concerns quinazoline derivatives of Formula (I): ( , (I) wherein Z is an O, S, SO, SO2, N(R2) or C(R2)2 group wherein each R2 group is hydrogen or (1-8C) alkyl, m is 0, 1, 2 or 3, each R1 group is selected from halogeno, (1-8C) alkyl, (1-6C) alkoxy and any of the other meanings defined in the description, n is 0, 1, 2 or 3, and each R3 group is selected from halogeno, (1-8C) alkyl, (1-6C) alkoxy and any of the other meanings defined in the description, or pharmaceutically-acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.

Description

Description of the invention

The invention relates to certain novel quinazoline derivatives or pharmaceutically acceptable salts thereof, which have antitumor activity and, accordingly, are useful in methods of treating humans or animals. The invention also relates to a method of obtaining the indicated quinazoline derivatives, pharmaceutical compositions containing them, and their use in therapeutic methods, for example, for the preparation of medicinal products for use in the prevention or treatment of solid tumor disease in a warm-blooded animal, such as a human.

Many current approaches to the treatment of cell proliferative diseases, such as psoriasis and 70 malignancies, use compounds that inhibit DNA synthesis. Such compounds are generally toxic to cells, but their toxic effects on rapidly dividing cells, such as tumor cells, may be beneficial. Alternative approaches consider antitumor agents that act by a mechanism other than inhibition of DNA synthesis and potentially have increased selectivity of action.

In recent years, it has been established that a cell can become malignant by transforming 72 parts of its DNA into an oncogene, that is, a gene that, when activated, causes the formation of malignant tumor cells

IVgaaznam, Mshiiadepeziv, 1986, 1, 91). Some such oncogenes cause an increase in the formation of peptides, which are receptors for growth factors. As a result of the activation of the receptor-growth factor complex, cell proliferation increases. It is known, for example, that some oncogenes encode tyrosine kinase enzymes and that certain growth factor receptors are also tyrosine kinase enzymes (Magdep et al., App. Chem, Viospet., 1988, 57, dAZ; |agvep et al., App. Kerogiz ip Med Spet., 1989, chapter 13)|. The first group of identified tyrosine kinases originates from such viral oncogenes, such as rrbO-92 tyrosine kinase (also known as hu-Z5gs), and corresponding tyrosine kinases in normal cells, such as rrbO-92 tyrosine kinase (also known as c-Zgo).

Receptor tyrosine kinases play an important role in the transmission of biochemical signals that cause cell division. They are large enzymes located in the cell membrane that have an extracellular binding domain for growth factors such as epidermal growth factor (EGF) and an intracellular portion, (o) that acts as a kinase by phosphorylating tyrosine amino acid residues in proteins and in this method affects cell proliferation. Different classes of receptor tyrosine kinases are known (MiK5, Admapsez ip Sapseg Kezeagsi. 1993, 60, 43-73) based on families of growth factors that bind to different receptor tyrosine kinases. Receptor tyrosine kinases are distinguished according to this classification class, which includes the ESE family of receptor tyrosine kinases, such as ESE, TORBA, Mey and egoB receptors, II class receptor tyrosine kinases, which includes | "c) a family of insulin receptor tyrosine kinases, such as insulin receptors and IZE1 and insulin-like receptors (IKK), and receptor tyrosine kinases of class III, which includes the family of receptor tyrosine kinases of platelet-derived growth factor (ROSE), such as ROSEA, ROSEV receptors and colony-stimulating factor 1 | "c) from (C5E1). co

It is also known that certain tyrosine kinases belong to the class of non-receptor tyrosine kinases, and they are located intracellularly and participate in the transmission of biochemical signals that affect the mobility, spread and invasiveness of tumor cells, as well as the subsequent metastatic growth of tumors. 1990, 61, 203-212, VoYiep et al., BABEV .u., 1992, 6, 3403-3409, VgisKay et al., Styisa! Kemiemzhv ip Opsodepeviv, « 20 1992, Z, 401-406, Woiiep et al., Opsodepe. 1993, 8, 2025-2031, Sotzshippedde et al., Zetip. Sapseg Vio!., 1994, -o 5, 239-246, Iasheprigdeg et al., Seyi, 1996, 84, 359-369, NapKk5 et al., VioEvzamv, 1996, 19, 137-145, with Ragwope et al. , Sitepi Oripiop ip SeyiYi Vioodu. 1997, 9, 187-192, Vgomup et al., Viospitis ei Viorpuvisa :z» Asia. 1996, 1287, 121-149 and ZspiIaerieg et al., Rgodgez5v ip Viorpuzisv and Moiesshag Vioiodu. 1999, 71, 435-478). Different classes of non-receptor tyrosine kinases are known, including the Zgs family, such as Zgs, up, and Mez 415 tyrosine kinases, the ABI family, such as ABI and Aga, and the Zak family, such as Uak 1 and TukK 2. o The 5gs family of non-receptor tyrosine kinases is known to significantly is regulated in normal cells and in the absence of an extracellular stimulus is maintained in an inactive conformation. Despite this, some members of the 5Zgs family, such as c-5gs tyrosine kinase, are often found in a significantly activated state (compared to its level in normal cells) in common types of human malignancies, such as gastrointestinal cancer , for example, cancer of the colon, rectum and stomach ISagimgidni et al., Rgos. («c) Main. Asad. si. OBA. 1990, 87, 558-562 and Mao et al., Opsodepe. 1997, 15, 3083- 3090, and breast cancer

Kz IMiiyizulatu and others, Opsodepe. 1995, 11, 1801-1810). The Zgs family of non-receptor tyrosine kinases is also found in many other common types of human malignancies, such as non-small cell lung cancer (NSCLC), including adenocarcinomas and squamous cell lung cancer | MaigepKo et al., Eigoreap

U9otsgpai oi Sapseg, 1992, 28, 372-7), bladder cancer |Bappipd et al., Sapseg Kezeagsi. 1992, 52, 1457-62), esophageal cancer (ChapkomuzKi et al., USA, 1992, 33, 1033-8), prostate cancer, ovarian cancer

GF) GM/iepeg, etc., Sipy. Sapseg Kezeagsp. 1999, 5, 2164-70) and pancreatic cancer shi and others, Viospet. Apa, Viorpuz. Kez. Sott.. 1998, 243, 503-8). Because many human tumor tissues are studied relative to the family

Zgs of non-receptor tyrosine kinases, expect that in the future knowledge about their widespread distribution and significance will be more detailed.

It is also known that the dominant effect of c-5gs non-receptor tyrosine kinase is to control the aggregation of focal adhesion complexes by interacting with many cytoplasmic proteins, including, for example, focal adhesion kinase and paxillin. In addition, c-Zgs is involved in signaling pathways that regulate the actin cytoskeleton, which improves cell motility. Non-receptor tyrosine kinases c-Zgs, c-Zhev and c-Rup also play an important role in integrin-mediated signal transmission pathways, as well as in the destruction of cadherin-dependent cell junctions. 2000, 11,

51-64 and Kiipopoieg and others, EMVO doishgpa! 1999, 18, 2459-2471). Cell motility is essential for the progression of a localized tumor through the stages of dissemination through the bloodstream, invasion into other tissues, and the initiation of metastatic tumor growth. For example, the progression of colon tumors from localized to disseminated, invasive growth of metastatic tumors is interrelated with the activity of c-Zgs non-receptor tyrosine kinase

IVhypiop and others, Opsodepe. 1997, 14, 283-293, Ripspat et al., EMVO 3, 1998, 17, 81-92 and Megreek et al., Ehr.

Sow! Kezeagsp. 1999, 248, 531-537).

Thus, it was found that an inhibitor of such non-receptor tyrosine kinases can be effective as a selective inhibitor of tumor cell motility and as a selective inhibitor of the dissemination and invasiveness of 7/0 cells of malignant mammalian tumors, leading to the inhibition of metastatic tumor growth. Preferably, an inhibitor of such non-receptor tyrosine kinases may be effective as an anti-invasive agent for use in controlling the spread and/or treating solid tumor disease.

Now we unexpectedly discovered that certain quinazoline derivatives have significant antitumor activity.

Without being limited to the theory that the compounds disclosed in this invention have a pharmacological effect only 7/5 by influencing a separate biological process, it is believed that the compounds provide an antitumor effect by inhibiting one or more non-receptor tyrosine-specific protein kinases involved in phased transmission of signals leading to invasiveness and the ability to spread metastasizing tumor cells. In particular, it is believed that the compounds according to the present invention provide an antitumor effect by inhibiting Zgs of the family of non-receptor tyrosine kinases, for example, by inhibiting one or more c-Zgs, c-Zhev and c-Rup.

It is also known that c-5Zgs non-receptor tyrosine kinase enzymes are involved in the regulation of bone resorption mediated by osteoclasts | Zogiapo et al., Seiyi, 1991, 64, 693-702; Vouse and others, 9. Siip. Ipmevi.. 1992, 90, 1622-1627; Mopeda, etc., U. SiIipy. Ipmevi 1993, 91, 2791-2795 and Mivzrasp et al., Vope. 1999, 24, 437-49). Thus, c-Zhs non-receptor tyrosine kinase inhibitor is effective in the prevention and treatment of bone diseases such as osteoporosis, deforming osteodystrophy, bone metastases and tumor-induced hypercalcemia.

The compounds of the present invention are also useful for inhibiting uncontrolled cell proliferation resulting from a variety of non-malignant diseases such as inflammatory diseases (e.g. rheumatoid arthritis and inflammatory bowel disease), fibrotic diseases (e.g. liver cirrhosis and pulmonary fibrosis), glomerulonephritis, multiple sclerosis, psoriasis, allergic skin reactions, diseases of blood vessels (for example, atherosclerosis and restenosis), allergic asthma, insulin-dependent diabetes, diabetic retinopathy and o diabetic nephropathy. with

In general, the compounds according to the present invention have a significant inhibitory effect on the Zgs family of non-receptor tyrosine kinases, for example by inhibiting c-5gs and/or c-ZhHez, while they have a less pronounced inhibitory effect on other tyrosine kinase enzymes, such as receptor tyrosine kinases, for example, so

ESE receptor tyrosine kinase and/or MESE receptor tyrosine kinase.

In addition, certain compounds according to the present invention are more effective in relation to non-receptor tyrosine kinases of the Zgs family, for example, c-Zgs and/or c-Zhez, in comparison with activity in relation to the MESE receptor tyrosine kinase. Such compounds show sufficient activity in relation to non-receptor tyrosine kinases of the Zgs family, for example c-Zgs and/or c-ZhMez, accordingly, they can be used in an amount sufficient for inhibition, for example, c-Zgs and/or c-Mez, showing at the same time insignificant activity in relation to MESE receptor tyrosine kinase. It is desirable to minimize the inhibitory effect on the relationship;" to the MESE receptor tyrosine kinase, since some compounds with such activity have been found to act as potassium channel blockers, for example, in the study of the potassium channel encoded by the human eShSheg-a-do-do-linked gene (PECO ). Such an action can cause changes in the electrocardiogram (ECG) in conditions of ip mimo.

The anticancer treatment described below can be used as monotherapy, or, in addition to the quinazoline derivative of the invention, conventional surgical methods or radiotherapy or 2) chemotherapy can also be used. It is well known that almost all drugs are to some extent converted in the human body, usually to such compounds that will be less soluble in lipids, and thus will be more easily excreted by the kidneys. o Many drug-metabolizing enzymes have been found in the endoplasmic reticulum

Ge of hepatocytes (which forms microsomes during homogenization). The liver is the main organ of drug conversion, as liver cells (hepatocytes) contain enzymes that convert drugs, mostly in high concentrations. Cytochrome P450 is a family of isozymes found in liver microsomes. six specific RA5O isoenzymes are responsible for the transformation of the most commonly used drugs, namely P450 1A2, 2029, 23219, 206, 2E1 and ЗА4. With combined chemotherapy may occur

F) difficulties, if one or several components of the medicinal products of the combination are metabolized by cytochrome P450 ka ZA4 (hereinafter SUR ZA4). This component can be a substrate of ZAA4 CUR or it can be an inducer or inhibitor of this isozyme. Such an effect can negatively affect the pharmacokinetics of other components during combined treatment.

We found that certain compounds according to the present invention have superior properties, as they are significantly less subject to transformation under the influence of such P450 isoenzymes, mainly SUR ZA4. Thus, it is possible to more safely introduce these compounds during combined anticancer chemotherapy.

In addition, we have found that certain compounds of the present invention have a dual advantage, since 65 They have little activity towards the MESE receptor tyrosine kinase, and they either show little or no ability to be converted by P4 and 50 isoenzymes such as SUR ZA4 subject to such transformation.

IP international patent application UUO 01/94341) lists a number of quinazoline derivatives that are useful for the treatment of malignant neoplasms. The described compounds have an inhibitory effect on Zgs family of non-receptor tyrosine kinases. This document describes certain 5-substituted quinazoline derivatives, including certain 5-substituted 4-(2,3-methylenedioxyanilino)quinazolines. But this document does not describe any derivatives of 4-(2,3-methylenedioxypyrid-4-ylamino)quinazoline.

IP international patent application Me) 02/163521 lists a number of 4-(2,3-methylenedioxyanilino)quinazoline derivatives that are useful for the treatment of malignant neoplasms. The described compounds /0 show an inhibitory effect in relation to 5gs of the family of non-receptor tyrosine kinases. But this document does not describe any derivatives of 4-(2,3-methylenedioxypyrid-4-ylamino)quinazoline.

According to one embodiment of the invention, a quinazoline derivative of the formula I is provided! (d) p

M y u o, sch o / about them (V) WHAT y

From t a o

M so "c) d) where 7 represents the group 0, 5, 50, 505, MK) or С(К7)", where each BC group, which can be the same or different, represents hydrogen or С.-Св- alkyl; t is 0,1,2 or 3; "each group B", which may be the same or different, is selected from halogen, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, C1-C8-alkyl, C0-C8-alkenyl, Co -C6-alkynyl, C6-C6-alkoxy, Co-C6-alkenyloxy, Co-C6-alkynyloxy, C6-C6-alkylthio, C6-C6-alkylsulfinyl, "» C6-C6-alkylsulfonyl, C.-Cv-alkylamino, di-C4-Cv-alkyl|amino, C.1-Cv-alkoxycarbonyl, M-C4-Cv-alkylcarbamoyl, M,M-di-|C4-Cv-alkyl|carbamoyl, Co -Cv-alkanoyl, Co-Cv-alkanoyloxy,

Co-Cv-alkanoylamino, M-C4-Cv-alkyl-Co-Cv-alkanoylamino, Ca3-Cv-alkenoylamino,

M-C.-Cv-alkyl-Ca-Cv-alkenoylamino, Ca-Cv-alkynoylamino, M-C4-Cv-alkyl-C3-Cv-alkynoylamino, co M-C.4-Cv-alkylsulfamoyl, M, M- di-(C4-Cv-alkyl|sulfamoyl, cSi-Cv-alkanesulfonylamino and o M-C4-Cv-alkyl-C4-Cv-alkanesulfonylamino, or from the group of the formula: oh. o where X" represents a simple bond or chosen from 0, 5, 50, 505, MORE), СО, СН(ОКУ), СОМ), More СО,

Ge Sho 502МЩ(833, Ш80», ОС)», SKZ» and ШЧАС(В7)», where K7 is hydrogen or C 41-Cv-alkyl, and C! represents

With itself oaryl, aryl-Ci-Cv-alkyl, C3-C,-cycloalkyl, Ca-C,-cycloalkyl-Ci-Cv-alkyl, C3-C,-cycloalkenyl,

C3-C,-cycloalkenyl-C,-C6-alkyl, heteroaryl, heteroaryl-C,4-C6-alkyl, heterocyclyl or heterocyclyl-C 1-C6-alkyl, or (K")t represents C,-C3- alkylenedioxy, and where the adjacent carbon atoms in any Co-Cv-alkylene chain within the K" substituent are not necessarily separated by a group inserted into the chain, selected from О, 5, 50, 505, Ш(КУ), СО, СН (OKU), SOM), SHAZSO, 5Oo.M(VU), M(8U)50", SN-SN and С-С, where is B? represents hydrogen or C.-Cv-alkyl or, if the inserted group is M(e), then 2? can also be Co-Cv-alkanoyl, and where any CH.-CH- or HC-C- group within EC! the substituent does not necessarily have a substituent selected from halogen, carboxy, carbamoyl, C.-Cv-alkoxycarbonyl,

M-C4-Cv-alkylcarbamoyl, M,M-di-|C.--Cv-alkylIcarbamoyl, amino-C--Cv-alkyl, C.--Cv-alkylamino-C.i-Cv-alkyl and di- IS--Cv-alkyl|iamino-C.-Cv-alkyl or from the group of the formula:

O2-X2- 65 where X? is a simple bond or selected from CO and M(K 9U)CO, where KU is hydrogen or

C 1 -C 4 -alkyl, and O2 is aryl, aryl-C 4 -C 4 -alkyl, heteroaryl, heteroaryl-C 4 -C 4 -alkyl, heterocyclyl or heterocyclyl-C 4 -C 4 -alkyl, and where any CH or SNu group within KE! the substituent optionally has one or more halogen or C.-Cv-alkyl substituents on each specified CH or CHnu group or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, oxo, thioxo, C.--Svaloxy, C .i-Cv-alkylthio, C.-Cv-alkylsulfinyl,

C.4-Cv-alkylsulfonyl, C.-Cv-alkylamino, di-IS4-Cv-alkyl|amino, C.1-Cv-alkoxycarbonyl,

M-C4-Cv-alkylcarbamoyl, M,M-di-|C4-Cv-alkyl|carbamoyl, Co-Cv-alkanoyl, Co-Cv-alkanoyloxy,

Co-Cv-alkanoylamino, M-C4-Cv-alkyl-Co-Cv-alkanoylamino, M-C4-Cv-alkylsulfamoyl,

M,M-di-IS 4-Cv-alkyl|sulfamoyl, C-Co-alkanesulfonylamino and M-C.4-Cv-alkyl-C4-Cv-alkanesulfonylamino, or from the 70 group of the formula: -X3.Oo3 where XZ represents is a simple connection or selected from О, 5, 50, 505, ШЭ), СО, СН(ОК У), СОМ, Шче ЛсСО, 502МЩ(87, ШЧА 780», С(В 7-0, С(К 55 and ШЧА LS(В 75, where КЕ" represents hydrogen or C 4 -C 4 -alkyl, and 03 represents oaryl, aryl-C 1 -C 2 -alkyl, C 3 -C 1 -cycloalkyl, Ca -C 1 -cycloalkyl- C3-C6-alkyl, C3-C6-cycloalkenyl, 79 C3-C6-cycloalkenyl-C1-C6-alkyl, heteroaryl, heteroaryl-C6-C6-alkyl, heterocyclyl or heterocyclyl-C6-C6-alkyl, and wherein any aryl, heteroaryl, or heterocyclyl group within the KE" substituent optionally has 1, 2, or C substituents, which may be the same or different, selected from halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, C.i-Cv-alkyl, C.i.-Cv-alkenyl, C.i-Cv-alkynyl, C.i.-Cv-alkoxy,

Co-Cv-alkenyloxy, Co-Cv-alkynyloxy, C.-Cv-alkylthio, C.-Cv-alkylsulfinyl, C.-Cv-alkylsulfonyl,

C.4-Cv-alkylamino, di-C.4-Cv-alkyl|amino, C.-Cv-alkoxycarbonyl, M-C.4-Cv-alkylcarbamoyl,

M,M-di-IS 41-Cv-alkyl)carbamoyl, Co-Cv-alkanoyl, Co-Cv-alkanoyloxy, Co-Cv-alkanoylamino,

M-C.4-Cv-alkyl-Co-Cv-alkanoylamino, M-C4-Cv-alkylsulfamoyl, M,M-di-C4-Cv-alkyl|sulfamoyl,

C.i-Cv-alkanesulfonylamino, M-C.-Cv-alkyl-Ci-Cs-alkanesulfonylamino and C.-C3-alkylenedioxy, or from the group of the formula: c -x"v8 Ge) where X" is a simple zv' connection or selected from O and ME U), where E? represents hydrogen or C.-Cv-alkyl, and Gese represents halogen-C 4-Cv-alkyl, hydroxy-Ci-Cv-alkyl, C.i.-Cv-alkyl-C.--Cv-alkyl, cyano- C-Cv-alkyl, amino-C.4-Cv-alkyl, C.-Cv-alkylamino-C.-Cv-alkyl, di-IS4-Cv-alkyl|Iamino-C.4-Cv-alkyl, sch

Co-Cv-alkanoylamino-C.-Ce-alkyl or C.i-C.- alkoxycarbonylamino-C 4-Ce-alkyl, or from the group of the formula: -X5.d44 | "c) where is X? is a simple bond or selected from O, M(B 79) and CO, where CO is hydrogen or CO

C.-C.-alkyl, and OO" is aryl, aryl-C.sub.1 -C.sub.4-alkyl, heteroaryl, heteroaryl-C.sub.1-C.sub.-alkyl, heterocyclyl or heterocyclyl-C.sub.-C.sub.-alkyl, which is necessarily has 1 or 2 substituents, which may be the same or different, selected from halogen, C4i-Cv-alkyl, C0-Cv-alkenyl, C0-Cv-alkynyl and C1-C8- alkoxy, d) and where any which heterocyclyl group within the B 'substituent optionally has 1 or 2 oxo or thioxo substituents; n represents 0,1,2 or 3; and "each KZ group, which may be the same or different, is selected from halogen, trifluoromethyl, cyano, nitro, C hydroxy, amino, carboxy, carbamoyl, C.i-Cv-alkyl, Co-Cv-alkenyl, C.i-Cv-alkynyl, C.i-Cv-alkoxy, C.Ci-Cv-alkenyloxy, Co- C-alkynyloxy, C-Cv-alkylthio, C-Cv-alkylsulfinyl, C-Cv-alkylsulfonyl, C-Cv-alkylamino, di-IS4-Cv-alkylamino, C-Cv- Alkoxycarbonyl, M-C4-Cv-alkylcarbamoyl,

M,M-di-IS 41-Cv-alkyl)carbamoyl, Co-Cv-alkanoyl, Co-Cv-alkanoyloxy, Co-Cv-alkanoylamino,

M-C.4-Cv-alkyl-Co-Cv-alkanoylamino, C3-Cv-alkenoylamino, M-C4-Cv-alkyl-C3-Cv-alkenoylamino,

C3-Cv-alkynoylamino, M-C4-Cv-alkyl-C3-Cv-alkynoylamino, M-C4-Cv-alkylsulfamoyl, co M,M-di-IIS 1-Cv-alkyl|sulfamoyl, C--Cv-alkanesulfonylamino and M-C.4-Cv-alkyl-C-Cv-alkanesulfonylamino, or with av! formula groups:

Ge o -X in I And where X? is a simple bond or selected from O and M (B 77), where K" is hydrogen or C 4-Cv-alkyl, O Her CL" is halogen-C 4-Cv-alkyl, hydroxy-C4 -Cv-alkyl, C4-Cv-Alkoxy-C4-Cv-Alkyl, Cyano-C4-Cv-Alkyl,

ГЯ6) amino-C.Ci-alkyl, C-Ci-alkylamino-C4-Ci-alkyl or di-I|C--Ci-alkylIamino-C.-Ci-alkyl, or from the group of the formula: -X7-05 where X'" represents a simple bond or selected from O, 5, 80, 502, MSH(К "3, СО, СН(ОВ"У, СОМ(В 3),

МВ'СО, 502МЩ(873), МВ )5О0», сС(В3»О, с(В3»5 and MK З)С(В73)», where KZ is hydrogen or

F! C.-C.-alkyl, and OZ is aryl, aryl-C.1-C.alkyl, heteroaryl, heteroaryl-C.4-C.alkyl, heterocyclyl or heterocyclyl-C.-C.alkyl, which is necessarily has 1 or 2 substituents, which may be the same or different, selected from halogen, C4i-Cv-alkyl, C0-Cv-alkenyl, C0-Cv-alkynyl, and C--Cv-alkoxy, and any heterocyclyl group within O? optionally has 1 or 2 oxo or thioxo substituents; or a pharmaceutically acceptable salt thereof.

According to a further embodiment of the invention, a quinazoline derivative of the formula I is provided, as defined above, where 7 is O, 5, 50, 505, СНо or МН; in t is 0,1,2 or 3; each group B", which may be the same or different, is selected from halogen, trifluoromethyl, cyano, isocyano,

nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, Ci-Cv-alkyl, Co-Cv-alkenyl, Co-Cv-alkynyl,

C.i-Cv-Alkoxy, C.-Cv-alkenyloxy, C.-Cv-alkynyloxy, C.-Cv-alkylthio, C.-Cv-alkylsulfinyl,

C.4-Cv-alkylsulfonyl, C.-Cv-alkylamino, di-IS4-Cv-alkyl|amino, C.1-Cv-alkoxycarbonyl,

M-C4-Cv-alkylcarbamoyl, M,M-di-|C4-Cv-alkyl|carbamoyl, Co-Cv-alkanoyl, Co-Cv-alkanoyloxy,

Co-Cv-alkanoylamino, M-C4-Cv-alkyl-Co-Cv-alkanoylamino, Ca3-Cv-alkenoylamino,

M-C.4-Cv-alkyl-C3-Cv-alkenoylamino, Ca-Cv-alkynoylamino, M-C4-Cv-alkyl-C3-Cv-alkynoylamino,

M-C.4-Cv-alkylsulfamoyl, M, M-di-(C4-Cv-alkyl|sulfamoyl, cSi-Cv-alkanesulfonylamino and

M-C4-Cv-alkyl-C4-Cv-alkanesulfonylamino, or from the group of the formula: 70 aZx - where X" is a simple bond or selected from 0, 5, 50, 505, ШЭ), СО, CH(ОВУ ), COM), SceCO, 5OM(B, SCHO", OS)", ZS(K)" and SCHAS(B7)", where EC" represents hydrogen or C /-Cv-alkyl, and C) represents oaryl , aryl-C--Cv-alkyl, C3-C,cycloalkyl, C3-C,-cycloalkyl-C.i-Cv-alkyl, C3-C,-cycloalkenyl,

C3-C3-C6cycloalkenyl-C-C6-alkyl, heteroaryl, heteroaryl-C,4-C6-alkyl, heterocyclyl or 75 heterocyclyl-C1-C6-alkyl, or (K")d represents C1-C3-alkylenedioxy, and where the adjacent carbon atoms in any Co-Cv-alkylene chain within B" of the substituent are optionally separated by a group inserted into the chain selected from VU), ShcheUSO, 5OM(VU), M(8U)50", СН-СН and С-С, where is V? is hydrogen or C-C-C-alkyl or, if the inserted group is M(e), then 2? can also be Co-Cv-alkanoyl, and where any CH.-CH- or HC-C- group within EC! the substituent does not necessarily have a substituent selected from halogen, carboxy, carbamoyl, C.-Cv-alkoxycarbonyl,

M-C4-Cv-alkylcarbamoyl, M,M-di-|C.--Cv-alkylIcarbamoyl, amino-C--Cv-alkyl, C.--Cv-alkylamino-C.i-Cv-alkyl and di- IS--Cv-alkyl|iamino-C.-Cv-alkyl or from the group of the formula: c

O02-x2- o where is X? represents a simple bond or selected from CO and M(K CO, where BC? represents hydrogen or

C.-C-alkyl, and 02? represents aryl, aryl-C 1-Ce-alkyl, heteroaryl, heteroaryl-C.4-C-alkyl, heterocyclyl or heterocyclyl-C -C-alkyl, sch and where any CH or CHnu group within KE! the substituent does not necessarily have on each specified CH or CHnu group one or more halogen or C.-Ce-alkyl substituents or a substituent selected from hydroxy, cyano, | "c) amino, carboxy, carbamoyl, oxo, thioxo, S.--Svaloxy, C.i-Cv-alkylthio, C.-Cv-alkylsulfinyl, so

C.4-Cv-alkylsulfonyl, C.-Cv-alkylamino, di-IS4-Cv-alkyl|amino, C.1-Cv-alkoxycarbonyl,

M-C4-Cv-alkylcarbamoyl, M,M-di-|C4-Cv-alkyl|carbamoyl, Co-Cv-alkanoyl, Co-Cv-alkanoyloxy, 2

Co-Cv-alkanoylamino, M-C4-Cv-alkyl-Co-Cv-alkanoylamino, M-C4-Cv-alkylsulfamoyl, co

M,M-di-IS 4-Cv-alkyl|sulfamoyl, C-Co-alkanesulfonylamino and M-C.4-Cv-alkyl-C4-Cv-alkanesulfonylamino, or from the group of the formula: -X3-a3 where X is simple connection or selected from 0, 5, 50, 505, ШЧЕ), СО, СН(OK 7, СОМ), Шче ЛсСО, « 40. 502587, ШЧА780», С(В 720, С(К 55 and ШЧА LS(B 7)", where KE" is hydrogen or C 4-Ce-alkyl, and 03 is oaryl, aryl-Ci-Cv-alkyl, C3-C,-cycloalkyl, Ca-C,-cycloalkyl -Ci-Cv-alkyl, C3-C,-cycloalkenyl, "with C3-C,-cycloalkenyl-C -Ce-alkyl, heteroaryl, heteroaryl-C.4-Cv-alkyl, heterocyclyl or heterocyclyl-C.-Ce- alkyl," and wherein any aryl, heteroaryl, or heterocyclyl group within the substituent on EC" optionally has 1, 2, or 3 substituents, which may be the same or different, selected from halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, C.-Cv-alkyl, C.-Cv-alkenyl, C.-Cv-alkynyl, C.-Cv-alkoxy, co-Cv-alkenyloxy, C.-Cv-alkynyloxy, C.-Cv- alkylthio, C.-Cv-alkylsulfinyl, C.-Cv-alkylsulfonyl, o C.4-Cv-alkylamino, di-I C4-Cv-alkyl|amino, C.-Cv-alkoxycarbonyl, M-C.4-Cv-alkylcarbamoyl,

M,M-di-IS 41-Cv-alkyl)carbamoyl, Co-Cv-alkanoyl, Co-Cv-alkanoyloxy, Co-Cv-alkanoylamino, o M-C.4-Cv-alkyl-Co-Cv-alkanoylamino, M-C4-Cv-alkylsulfamoyl, M, M-di-(C4-Cv-alkyl|sulfamoyl, about 50 Si-Ce-alkanesulfonylamino, M-C.--Cv-alkyl-Ci-Co-alkanesulfonylamino and C.- C3-alkylenedioxy, or from the group of the formula: do) -X3-b8 where X" represents a simple bond or selected from O and M(E U), where E? represents hydrogen or C-C-C-alkyl, and 28 is a halogen-C 4-Cv-alkyl, hydroxy-C--Cv-alkyl, C.i-Cv-alkyl-C.i-Cv-alkyl, cyano-Ci-Cv-alkyl, 25 amino-C. 4-Cv-alkyl, C.-Cv-alkylamino-C -Ce--alkyl, di-IS4-Cv-alkyl|Iamino-C4-Cv--alkyl,

HF) Co-Cv-alkanoylamino-C.-Ce-alkyl or C.i.-C.-Alkoxycarbonylamino-C 4-Ce-alkyl, or from the group of the formula: kyu -X5-44 where X? is a simple bond or selected from OO, M(B 79) and CO, where К"О is hydrogen or 60 C Sralkyl, and 07 is aryl, aryl-C 1-Ce-alkyl, heteroaryl, heteroaryl- C.4-Cv-alkyl, heterocyclyl or heterocyclyl-C.-Cv-alkyl, which optionally has 1 or 2 substituents, which may be the same or different, selected from halogen, C4-Cv-alkyl, Co-Cv- alkenyl, C 1 -C 1 -alkynyl and C 1 -C 2 -alkoxy, and wherein any heterocyclyl group within the substituent on B optionally has 1 or 2 oxo or thioxo substituents; 65 n represents 0, 1, 2 or 3; and each C group, which may be the same or different, is selected from halogen, trifluoromethyl, cyano, nitro,

hydroxy, amino, carboxy, carbamoyl, C.i-Cv-alkyl, C.i-Cv-alkenyl, C.i.-Cv-alkynyl, C.i-Cv-alkoxy,

Co-Cv-alkenyloxy, Co-Cv-alkynyloxy, C.-Cv-alkylthio, C.-Cv-alkylsulfinyl, C.-Cv-alkylsulfonyl,

C.4-Cv-alkylamino, di-C.4-Cv-alkyl|amino, C.-Cv-alkoxycarbonyl, M-C.4-Cv-alkylcarbamoyl,

M,M-di-IS 41-Cv-alkyl)carbamoyl, Co-Cv-alkanoyl, Co-Cv-alkanoyloxy, Co-Cv-alkanoylamino,

M-C.4-Cv-alkyl-Co-Cv-alkanoylamino, C3-Cv-alkenoylamino, M-C4-Cv-alkyl-C3-Cv-alkenoylamino,

C3-Cv-alkynoylamino, M-C4-Cv-alkyl-C3-Cv-alkynoylamino, M-C4-Cv-alkylsulfamoyl,

M,M-di-IS 4-Cv-alkyl|sulfamoyl, C-Co-alkanesulfonylamino and M-C.4-Cv-alkyl-C4-Cv-alkanesulfonylamino, or from the group of the formula: 70 -X5v! where ХУ is a simple connection or selected from О and М(В "7), where КЕ"? is hydrogen or C 4-Cv-alkyl, and K' is a halogen-C 4-Cv-alkyl, hydroxy-Ci-Cv-alkyl, C.-Cv-alkyl-C.4-Cv-alkyl, cyano- C.4-Ce-alkyl, amino-C.-Ce-alkyl, Ci-Cv-alkylamino-C4-Ce-alkyl or di-I|C--Cv-alkylIamino-C.-Ce-alkyl, or from the group formulas: -Х7-о5 where X'" is a simple bond or selected from О, 5, 50, 50 5, ШЭ"), СО, СН(ОВ З), СОМ(В 3),

Mm(В3)сОо, 5802М(8"3), М(З)50», с(К3ДО, с(ВЗ»В и М З)с(В"З)», where KZ is hydrogen or

CC alkyl, and OZ is aryl, aryl-C 4-C 4-alkyl, heteroaryl, heteroaryl-C-C 4-alkyl, heterocyclyl. or heterocyclyl-C 1 -C 1 -alkyl, which optionally has 1 or 2 substituents, which may be the same or different, 2o selected from halogen, C 1 -C 2 -alkyl, C 1 -C 2 -alkenyl, C 2 -C 2 -alkynyl and C-C-Alkoxy, and any heterocyclyl group within C? optionally has 1 or 2 oxo or thioxo substituents; or a pharmaceutically acceptable salt thereof.

In this invention, the general term "alkyl" includes both straight chain alkyl groups and branched chain alkyl groups such as propyl, isopropyl and tert-butyl. as well as C 3-C,-cycloalkyl groups, such as p

C-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, as well as C3-C.-cycloalkyl-C.-C.sub.3-alkyl groups such as cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, o 2-cyclopentylethyl, cyclohexylmethyl and 2-cyclohexylethyl. However, with respect to specific alkyl groups such as "propyl" only straight chain groups are meant, and with specific branched chain alkyl groups such as "isopropyl" are meant only branched chain groups, and with specific He cycloalkyl groups such as "cyclopentyl" refer only to 5-membered ring structures. A similar condition applies to other general terms, for example, C -C0-Alkoxy includes C3-C5-cycloalkyloxy group of its C3-C5-cycloalkyl-C.-C0-Alkoxy group, for example, methoxy, ethoxy, propoxy, isopropoxy, "9 cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, 2-cyclopropylethoxy, cyclobutylmethoxy, 2-cyclobutylethoxy and cyclopentylmethoxy; C4-C6-alkylamino includes o C3-C6-cycloalkylamino groups and C3-C5-cycloalkyl-C4-Co-alkylamino groups, for example methylamino, ethylamino, opropylamino, cyclopropylamino, cyclobutylamino, cyclohexylamino, cyclopropylmethylamino, 2-cyclopropylethylamino, cyclobutylmethylamino , 2-cyclobutylethylamino and cyclopentylmethylamino; and di-y

C-C-alkyl)|iamino includes di-|C3-Ceo-cycloalkyl|iamino groups and di-(C33-Cv-cycloalkyl-C.-C-alkyl|iamino groups, for example dimethylamino, diethylamino, dipropylamino, M- cyclopropyl-M-methylamino,

M-cyclobutyl-M-methylamino, M-cyclohexyl-M-ethylamino, M-cyclopropylmethyl-M-methylamino, with M-(2-cyclopropylethyl)-M-methylamino and M-cyclopentylmethyl-M-methylamino. It is also intended that since certain compounds of formula I above may exist in optically active or racemic forms due to the presence of one or more asymmetric carbon atoms, the invention encompasses any such optically active or racemic form which has the above activity. The synthesis of optically active forms can be carried out using standard methods of organic chemistry, which are well known in the art, for example, by carrying out the synthesis from optically active starting substances or by separating the racemic form. Similarly, the determination of the above activity can be carried out by means of standard laboratory techniques to be given later. (4) Suitable values for the general radicals given above are the values given below. or for an aryl group within the C group, is, for example, phenyl or naphthyl, preferably phenyl. o) A suitable value for any of the "C" groups (0 or 03) when it is a C3-C1-cycloalkyl or for

C3-C1-cycloalkyl group within the group "C is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo|2,2,1|heptyl and a suitable value for any of the groups'C" (0 or 03, 22 when it is a C 3-C,.-cycloalkenyl or for a C 3-C,.-cycloalkenyl group within the "C" group is,

HF) for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. A suitable value for any of the groups "5 (0007-05) when it is a heteroaryl or for a heteroaryl group within the group "C is, for example, an aromatic 5-membered or 6-membered monocyclic ring or a 9-membered or a 10-membered bicyclic ring having up to and including five ring heteroatoms selected from oxygen, nitrogen, and sulfur, such as furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, benzofuranyl, indolyl, benzthienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinolinyl, or naphthyridinyl.

A suitable value for any of the "C" groups (01-05) when it is heterocyclyl or for a 65 heterocyclyl group within the "0" group is, for example, a non-aromatic saturated or partially saturated 3-10 membered monocyclic or bicyclic ring, which has up to and including five heteroatoms selected from oxygen, nitrogen and sulfur, for example oxyranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothienyl, 1,1-dioxotetrahydrothienyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl, 1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl, preferably tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1,1 -dioxotetrahydro-4H-1,4-thiazinyl, piperidinyl or piperazinyl A suitable value for such a group having 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolide inyl, 2-thioxopyrrolidinyl, 70 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.

A suitable value for the "C" group, when it is a heteroaryl-C 4-Sev-alkyl, is, for example, heteroarylmethyl, 2-heteroarylethyl and 3-heteroarylpropyl. The invention covers corresponding suitable values for the "Y" groups, if, for example, there is no heteroaryl-C 4 -C 1 -alkyl group, and another group such as /5 aryl-C 1 -C 2 -alkyl, C 3 -C 1 -cycloalkyl-C 1 -C 2 -alkyl, Ca 3 -C 1 -cycloalkenyl-C 4 -Cv-alkyl or heterocyclyl-C -Cv-alkyl group.

It is also implied that in the 2nd position in the quinazoline ring in the structural formula | there is a hydrogen atom. In this regard, the substituents in' can be located only in the 5th, bth, 7th or 8th positions in the quinazoline ring, that is, the 2nd position remains unsubstituted. In addition, it is also implied that the KZ group, which can be located in the 2,3-methylenedioxypyridyl group within the structural formula I, can be located in any of its 5- or 6-membered ring parts, i.e., the BK З group can be located in the pyridyl ring or in the methylene group within the 2,3-methylenedioxypyridyl group.

For example, the KZ group can be a methyl group, which is located in the methylene part of the 2,3-methylenedioxypyridyl group, that is, the 2nd and 3rd positions on the pyridyl group carry an ethylenedioxy c group. Preferably, any group B C, which is located in the 2,3-methylenedioxypyridyl group within Ge) of the structural formula I, is located in its pyridyl ring. Also, it is additionally implied that when there are several CU groups, these VC groups can be the same or different.

Suitable values for any of the B groups (B 7-K73) or for various groups within the B or KZ substituents include: (а) for halogen: fluorine, chlorine, bromine, and iodine; c for C1-C8-alkyl: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl and 2-cyclopropylethyl; for C1-C8-alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl; (ав) for Co-Cv-alkenyl: vinyl, isopropenyl, allyl and but-2-enyl; c for C0-C6-alkynyl: ethynyl, 2-propynyl and but-2-ynyl; for С1-Св-Alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for Co-Cv-alkenyloxy: vinyloxy and allyloxy; « for Co-Cv-alkynyloxy: ethynyloxy and 2-propynyloxy; C for C1-C8-alkylthio: methylthio, ethylthio and propylthio; c for C1-C6-alkylsulfinyl: methylsulfinyl and ethylsulfinyl; :z" for C1-Cd-alkylsulfonyl: methylsulfonyl and ethylsulfonyl; for С1-Св-alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; for di-C1-C6-alkylamino: dimethylamino, diethylamino M-ethyl-M-methylamino and diisopropylamino; (ee) for C1-C6-Alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl: o for M-C41-C6-alkylcarbamoyl: M-methylcarbamoyl, M-ethylcarbamoyl and M-propylcarbamoyl; for M,M-di-|ІС1-Св- M,M-dimethylcarbamoyl, M-ethyl-M-methylcarbamoyl and M,M-diethylcarbamoyl; (95) alkyl)carbamoyl: about 50 for Co-Cv-alkanoyl: acetyl, propionyl and isobutyryl; for Co-Cv-alkanoyloxy: acetoxy and propionyloxy; g" for Co-Svd-alkanoylamino: acetamido and propionamido; for M-methylacetamido and M-methylpropionamido;

M-C1-Cv-alkyl-C20-Cv-alkanoylamino: 59 for M-C1-Cvd-alkylsulfamoyl: M-methylsulfamoyl and M-ethylsulfamoyl;

HF) For M,M-di-IC1-Cv-alkyl|sulfamoyl: M,M-dimethylsulfamoyl; ko for С1-Св- methanesulfonylamino and ethanesulfonylamino; alkanesulfonylamino: for M-methylmethanesulfonylamino and M-methylethanesulfonylamino; 60 M-C1-Cv-alkyl-C 1-Cv-alkanesulfonyl amino: for C3-Cv-alkenoylamino: acrylamido, methacrylamido and crotonamido; for M-methylacrylamido and M-methylcrotonamido; m-C1-Cv-alkyl-C3-Cv-alkenoylamino: 6B for C3-Cv-alkynoylamino: propiolamido;

for M-methylpropiolamido;

M-C1-Cv-alkyl-C3-Cv-alkynoylamino: for amino-C1-Cv-alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl and 3-aminopropyl, for C1-Cv-alkylamino-C1-Cv-alkyl. methylaminomethyl, ethylaminomethyl, 1-methylaminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl and

C-methylaminopropyl; for dimethylaminomethyl, diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and di-C1-C6-alkyl)amino-C1-C6-alkyl: C-dimethylaminopropyl; for halo-C1-Cv-alkyl: chloromethyl, 2-fluoroethyl, 2-chloroethyl, 1-chloroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl,

C-chloropropyl, C,C-difluoropropyl and 3,3,C-trifluoropropyl; for hydroxy-C1-C6-alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl; for C1-C1-Alkoxy-C1-C1-Alkyl: methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl; for cyano-Co-Cv-alkyl: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and 3-cyanopropyl; for acetamidomethyl, propionamidomethyl and 2-acetamidoethyl; and

C2-Cv-alkanoylamino-C 1-Cv-alkyl: for methoxycarbonylaminomethyl,

C1-Cv-Alkoxycarbonylamino-C 1-Cv ethoxycarbonylaminomethyl, tert-butoxycarbonylaminomethyl and 2-methoxycarbonylaminoethyl. -alkyl:

A suitable value for (B)tl if it represents a C/4-C3-alkylenedioxy group or for a C1-C3-alkylenedioxy group within the B substituent is, for example, methylenedioxy, ethylenedioxy, isopropylidenedioxy or ethylenedioxy and their oxygen atoms located in adjacent positions in the ring.

If, as defined above, the group K" forms a group of the formula 27-X "- and, for example, X' is an OS(B 7)" binding group, then a carbon atom, not an oxygen atom, OS(BK 7) » of the binding group is attached to the quinazoline ring, and the oxygen atom is attached to the 07 group. In the same way, if, for example, the CH3 group is within the KV! the substituent carries a group of the formula -X2-O3 and, for example, XO is a C(B. 720 binding group, then also) a carbon atom, not an oxygen atom, C(K 7250 of the binding group is attached to the CH group, and the oxygen atom is attached to the SU group. A similar condition applies to the attachment of the groups of the formulas 22-X and -X7-F5,

As defined above, adjacent carbon atoms in any Co-Cv-alkylene chain within the EK" of the CM substituent may not necessarily be separated by an interchain group such as O, COM(B Y) or C--C. For example , o when the C-C group is inserted into the ethylene chain within the 2-morpholinoethoxy group, a 4-morpholinobut-2-ynyloxy group is formed and, for example, when the SOMH group is inserted into the ethylene chain within the o

C-methoxypropoxy group is formed, for example, 2-(2-methoxyacetamido)ethoxy group. (av)

If, as defined above, any CH 2-CH- or HC--C- group within B! the substituent does not necessarily have a substituent in the co-terminal СНо- or НС-- position, such as the group of the formula С2-Х-, where X? is, for example,

МНСО and 02 is a heterocyclyl-C 4-C 4-alkyl group, then suitable BK "substituents that are formed in this case include, for example, M-Heterocyclyl-C 4-C 4-alkyl|carbamoylvinyl groups, such as "

M-(2-pyrrolidin-1-ylethyl)carbamoyl vinyl or /M-Heterocyclyl-C4-C6-alkyl|carbamoylethynyl groups such

M-(2-pyrrolidin-1-ylethyl)carbamoylethynyl. - c If, as defined above, any CH 5» or CH» group within B! the substituent does not necessarily have one or more halogen or C.-C.-alkyl substituents on each of the specified CHo or CH" groups, then suitable 1 or "» 2 halogen or C.-C.-alkyl substituents are on each specified CH »5 group and suitable 1, 2 or C such substituents are on each indicated CH»z group.

If, as defined above, any CH 5" or CH3 group within B of the substituent does not necessarily have a substituent on each of the specified CHo or CH" groups, as defined above, then the suitable substituents B" that are formed in this case are include, for example, hydroxy-substituted heterocyclyl-C-C-C-alkoxy groups, such as 2-hydroxy-3-piperidinopropoxy and /2-hydroxy-3-morpholinopropoxy, hydroxy-substituted amino-Co-C-C-alkoxy o groups, such such as 3-amino-2-hydroxypropoxy, hydroxy-substituted C 4--Cv-alkylamino-Co-Cv-alkoxy groups, such as o 20 2-hydroxy-3-methylaminopropoxy, hydroxy-substituted di-|C--Cv- alkylamino-Co-Cv-alkoxy groups such as

3-dimethylamino-2-hydroxypropoxy, hydroxy-substituted heterocyclyl-C--Cv-alkylamino groups, such as g» 2-hydroxy-3-piperidinopropylamino and 2-hydroxy-3-morpholinopropylamino, hydroxy-substituted amino-Co-Cv- alkylamino groups such as 3-amino-2-hydroxypropylamino, hydroxy-substituted

C4-C6-alkylamino-Co-C6-alkylamino groups such as 2-hydroxy-3-methylaminopropylamino, hydroxy-substituted 22 di-IC4-C6-alkylamino-Co-C6-alkylamino groups such as C-dimethylamino-2- hydroxypropylamino, hydroxy-substituted

HF) C-C-Alkoxy groups, such as 2-hydroxyethoxy, C 4-C-Alkoxy-substituted C-C-Alkoxy groups, such as 2-methoxyethoxy and C-ethoxypropoxy, C-C-Alkylsulfonyl-substituted C .--C 1 -Alkoxy groups, such as di 2-methylsulfonyletoxy and heterocyclyl-substituted C 1 -C 1 -alkylamino-C 1 -C 2 -alkyl groups, such as 2-morpholinoethylaminomethyl, 2-piperazin-1-ylethylaminomethyl and 3-morpholinopropylaminomethyl . 60 It is meant that in those cases, as defined above, when any SN o or SNuz group within B! the substituent does not necessarily have a substituent on each specified CH» or CH» group, as defined above, then such an optional substituent can be on the CH 5» or CH» group within the limits of the substituents defined above, which can be on the aryl, heteroaryl or heterocyclyl group within the VE substituent. For example, IF KE" includes an aryl or heteroaryl group that is substituted by a C 4 -C 4 -alkyl group, then the C 4 -C 4 -alkyl group may optionally be substituted on the CH" or CH" group by one of its substituents, as defined above.

For example, if B includes a heteroaryl group that is substituted, for example, by a C 1-Cv-alkylamino-C 4-Cv-alkyl group, then the terminal CH3 group of the C.i-Cbe-alkylamino group can be additionally substituted, for example,

C.-Cv-alkylsulfonyl group or Co-Cv-alkanoyl group. For example, the group KE" can be a heteroaryl group, such as a thienyl group, which is substituted with an M-(2-methylsulfonylethyl)aminomethyl group such that K' is, for example, 5-IM-(2-methylsulfonylethyl)aminomethylhiene-2 -il group.

Additionally, if, for example, B includes a heterocyclyl group, such as a piperidinyl or piperazinyl group, which is substituted at its nitrogen atom, for example, a C 5 -C 1 -alkanoyl group, then the terminal CHase group

Co-Cv-alkanoyl group can additionally be substituted, for example, by a di-Cv-Cv-alkylamino group. For example, the group in! can be M-(2-dimethylaminoacetyl)piperidin-4-yl group or 4-(-2-dimethylaminoacetyl)piperazin-1-yl group.

A suitable pharmaceutically acceptable salt of a compound of formula I is, for example, an acid addition salt of a compound of formula I, for example an acid addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of formula I which is sufficiently acidic, for example an alkali metal or alkaline earth metal salt, such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base, such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

Preferred new compounds according to the invention are, for example, quinazoline derivatives of the formula | or pharmaceutically acceptable salts thereof, in which, unless otherwise specifically stated, each of 7, t, B 7, pi KZ has any of the values specified above or in paragraphs (a) through (c) below: ( a) 7 represents O, 5, 50, 505, СНо or МН; (B) 7 represents 0; (c) 7 represents MM; . 1 and c (4) t is 1 or 2, and each group K ", which may be the same or different, is selected from halogen, trifluoromethyl, hydroxy, amino, carbamoyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl , C-C-alkynyl, C-C-alkoxy, (o)

Co-Cv-alkenyloxy, Co-Cv-alkynyloxy, C.i-Cv-alkylamino, di-I|C--Cv-alkyl|amino, M-C.i-Co-alkylcarbamoyl,

M,M-di-IS 4-Cv-alkyl)carbamoyl, Co-Cv-alkanoylamino, M-C.4-Cv-alkyl-Co-Cv-alkanoylamino, C3-Cv-alkenoylamino,

M-C4-Cv-alkyl-C3-Cv-alkenoylamino, C3-Cv-alkynoylamino and M-C.i-Cv-alkyl-C3-Cv-alkynoylamino, or from the group of the formula: az. - where X' represents a simple bond or selected from O, ЧЕ7), COM(В"), ЧЕС CO and OS(В7)", where B" represents (c hydrogen or C.-Ce-alkyl, and OO! represents aryl, aryl-C 4 -C 4 -alkyl, cycloalkyl-C 1 -C 6 -alkyl, heteroaryl, heteroaryl-C 4 -C 6 -alkyl, heterocyclyl or heterocyclyl-C 1 -C 6 -alkyl, o and where adjacent carbon atoms in any Co-Cv-alkylene chain within K" of the substituent are not necessarily d) separated by a group inserted into the chain, selected from О, МУ), СОМ(ЕУ), ШЭУ)СО, СНАСН and С-- C, where KE? is hydrogen or C 1 -C 1 -alkyl, or, if the inserted group is M(E 7 ), then KE? can also be

C.-Cv-alkanoyl, " and where any CH.-CH- or HC--C- group within the KE of the substituent does not necessarily have a substituent selected from carbamoyl in the terminal СНо- or HC-- position with c, M-C.--Cv-alkylcarbamoyl, /M,M-di-|C--Cv-alkyl|carbamoyl, C-amino-C.-Cv-alkyl, C-Cv-alkylamino-C 1-Cv-alkyl and di-IS4-Cv-alkyl|iamino-C.4-Cv-alkyl or from the group of the formula: and O2-X2- where X? is a simple bond or is CO or M(K 9)CO, where K9 is hydrogen or

C.-C-alkyl, and O2? is heteroaryl, heteroaryl-C 1 -C 1 -alkyl, heterocyclyl or heterocyclyl-C 4 -C 1 -alkyl, co and where any CH or CHnu group within KE! the substituent optionally has one or more halogen groups on each indicated CH or CHu (ав) group or a substituent selected from hydroxy, amino, oxo, C. -alkylamino, di-IS--Cv-alkylamino, Co-Cv-alkanoyloxy, Co-Cv-alkanoylamino |i

M-C4-Cv-alkyl-Cv-Cv-alkanoylamino, or from the group of the formula: o 50 -x3.oz

Kz where XZ is a single bond or selected from O, ME U), COM(B 7), ЖЭ ЗСО and С(Б 720, where K" is hydrogen or C-Cv-alkyl, and 3 is heteroaryl , heteroaryl-C 4 -C 1 -alkyl, heterocyclyl or heterocyclyl-C 1 -C 2 -alkyl, 22 and where any aryl, heteroaryl or heterocyclyl group within the substituent at 2! optionally has

Gee! 1, 2 or C substituents, which may be the same or different, selected from halogen, trifluoromethyl, hydroxy, amino, carbamoyl, C1-C8-alkyl, C0-C8-alkenyl, C0-C8-alkynyl, C1-C8 -alukoxy, C.i-Cv-alkylsulfonyl, co M-Ci-Cv-alkylcarbamoyl, /- M,M-di-IS--Cv-alkyl|carbamoyl, C.i-Cv-alkanoyl and C.i-C3-alkylenedioxy , or optionally has 1 substituent selected from the group of the formula: 60 -X3-v8 where X" is a simple bond or selected from O and M(E U), where E? is hydrogen or С.-Св -alkyl, and 28 is a halogen-C 4-Cv-alkyl, hydroxy-Ci-Cv-alkyl, C.i-Cv-alkyl-C.--Cv-alkyl, cyano-Ci-Cv-alkyl, amino- C.4-Cv-alkyl, C.-Cv-alkylamino-C.-Cv-alkyl, di-IS4-Cv-alkyl|Iamino-C.4-Cv-alkyl,

Co-Ce-alkanoylamino-C -Ce-alkyl or C.i-Co-alkoxycarbonylamino-C 4-Ce-alkyl, and from the group of the formula: bo -X5.c0 where X? is a simple bond or selected from О, М(В 79) and СО, where КО is hydrogen or

C-C-alkyl, and "FO" is heterocyclyl or heterocyclyl-C 4-C-alkyl, which optionally has 1 or 2 substituents, which may be the same or different, selected from halogen, C 4-C-alkyl and C 1 -C 6 -Alkoxy, c and wherein any heterocyclyl group within the substituent on B! optionally has 1 or 2 oxo substituents; (e) t represents 1 or 2, and each group KK" which may be the same or different, selected from fluorine, chlorine, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, propyl, butyl, vinyl, allyl, but-3-enyl, pent-4-enyl, hex-5-enyl, ethynyl, 2 -propynyl, but-3-ynyl, pent-4-ynyl, hex-5-ynyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, allyloxy, but-3-enyloxy, pent-4-enyloxy, hex-b-enyloxy , ethynyloxy, 2-propynyloxy, but-3-ynyloxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, M-methylcarbamoyl, M,M-dimethylcarbamoyl, acetamido, propionamido , acrylamido and propiolamido, or from the formula group: ah. 75 where X' is a simple bond or selected from О, МН, СОМН, МНСО and OSН 5 and 0! is phenyl, benzyl, cyclopropylmethyl, 2-thienyl, 1-imidazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 2-, 3- or 4-pyridyl, 2-imidazol-1-ylethyl, 3-imidazol-1-ylpropyl, 2-(1,2,3-triazolyl)ethyl, 3-(1,2,3-triazolyl)propyl, 2-(1,2,4 -triazolyl)ethyl, 3-(1,2,4-triazolyl)propyl, 2-, 3- or 4-pyridylmethyl, 2-(2-, 3- or 4-pyridyl)ethyl, 3-(2-, 3 - or 4-pyridyl)propyl, tetrahydrofuran-Z-yl, 3-or 4-tetrahydropyranyl, 1-, 2- or Z-pyrrolidinyl, morpholino, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl , piperidino, piperidin-3-yl, piperidin-4-yl, 1-, 3- or 4-homopiperidinyl, piperazin-1-yl, homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl , 3- or 4-piperidinylmethyl, 1-, 3- or 4-homopiperidinylmethyl, 2-pyrrolidin-1-ylethyl,

C-pyrrolidin-2-ylpropyl, pyrrolidin-2-yl methyl, 2-pyrrolidin-2-ylethyl, C-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl, 2-morpholinoethyl, C-morpholinopropyl, 4-morpholinobutyl, sc 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethyl, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propyl , 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, 2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl, o 2-piperidin-4-ylethyl, 3-piperidin-4-ylpropyl, 2-homopiperidin- 1-ylethyl, 3-homopiperidin-1-ylpropyl, 2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl, 3-(1,2,3,6-tetrahydropyridin-1-yl)propyl, 4-(1,2,3,6-tetrahydropyridin-1-yl)butyl, 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl, 4-piperazin-1-ylbutyl, 2-homopiperazin-1- ylethyl or 3-homopiperazin-1-ylpropyl, and where the adjacent carbon atoms in any Co-Cv alkylene chain within the B" substituent are optionally separated by an interchain group selected from O, MH, M(Me) , SOMN, MNSO, SNASN and С-С, with and where any CH. has a substituent selected from carbamoyl, M-methylcarbamoyl, M-ethylcarbamoyl, M-propylcarbamoyl,

M,M-dimethylcarbamoyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, methylaminomethyl, 00 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl,

C-dimethylaminopropyl or 4-dimethylaminobutyl, or from the group of the formula:

О02-х2- « where is X? is a single bond or is CO, MHSO or M(Me)CO and O 2 is pyridyl, C pyridylmethyl, 2-pyridylethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin- 3-yl, c piperidin-4-yl, piperazin-1-yl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, c» 4-pyrrolidin-1-ylbutyl, pyrrolidine -2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidincetyl,

3-piperidinopropyl, 4-piperidinobutyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl or 4-piperazin-1-ylbutyl, (c) and where any CH" or CH" group within K' of the substituent does not necessarily have on each indicated CH" or CH" group one or more fluorine or chlorine groups or a substituent selected from hydroxy, amino, oxo, methoxy, methylsulfonyl, methylamino, dimethylamino, diisopropylamino, M-ethyl-M-methylamino, M-isopropyl-M-methylamino, (ab) 50 M- methyl-M-propylamino, acetoxy, acetamido and M-methylacetamido or from the group of the formula: -X3-a3 more) where X? is a single bond or selected from О, МН, СОМН, МНСО and CH 20 and OZ is pyridyl, pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidine -4-yl, piperazin-1-yl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl,

Z-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, Z-morpholinopropyl, 2-piperidincetyl, Z-piperidinopropyl, (F) piperidin-Z-ylmethyl, 2-piperidin-Z-ylethyl, piperidin-4-ylmethyl, 2-piperidine -4-ylethyl, 2-piperazin-1-ylethyl, or 3-piperazin-1-ylpropyl, and wherein any aryl, heteroaryl, or heterocyclyl group within the substituent on K" optionally has either 1, 2, or C substituents , which may be the same or different, selected from fluorine, chlorine, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, allyl, 2-propynyl, methoxy, methylsulfonyl, M-methylcarbamoyl,

M,M-dimethylcarbamoyl, acetyl, propionyl, isobutyryl, methylenedioxy, ethylidenedioxy and isopropylidenedioxy, or optionally has 1 substituent selected from the group of the formula: -X3-в8 65 where X" represents a single bond or selected from O and MH and B 8 is 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-rifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 33,3,3-trifluoropropyl, 2-hydroxyethyl, 3-hydroxypropyl ,

2-methoxyethyl, 3-methoxypropyl, cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl, methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl, and from the group of the formula: -X5.c0 where X? is a single bond or selected from O, MH and CO and 0 7 is pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl , piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl or 70 3-piperazin-1-ylpropyl, each optionally having 1 or 2 substituents which may be the same or various selected from fluorine, chlorine, methyl and methoxy, and where any heterocyclyl group within the substituent on VC does not necessarily have 1 or 2 oxo substituents; () t represents 1 and the K" group is located in the 5th, 6th or 7th position or t is 2 and the B" groups, which may be the same or different, are located in the 5th and 7th positions position or in the 6th and 7th position and 12 each B! selected from hydroxy, amino, methyl, ethyl, propyl, butyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, but-3-enyloxy, pent-4-enyloxy, hex-b-enyloxy, but- 3-ynyloxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran- 4-yloxy, cyclopropylmethoxy, 2-imidazol-1-ylethoxy, 3-imidazol-1-ylpropoxy, 2-(1,2,3-triazol-1-yl)ethoxy, 3-(1,2,3-triazol- 1-yl)upropoxy, 2-(1,2,4-triazol-1-yl)ethoxy, 3-(1,2,4-triazol-1-yl)upropoxy, pyrid-2-ylmethoxy, pyrid-Z- ylmethoxy, pyrid-4-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy, 2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy, 3-pyrid-3-ylpropoxy, 3- pyrid-4-ylpropoxy, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3- yloxy, pyrrolidin-2-ylmethoxy, 2-pi rolidin-2-ylethoxy, p

3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, (9 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, 3-(1, 1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidine-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidine- 4-ylmethoxy, 2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1- ylpropoxy, sc 2-(1,2,3,6-tetrahydropyridin-1-yl)ethoxy 3-(1,2,3,6-tetrahydropyridin-1-yl)upropoxy, av! 4-(1,2,3 ,6-tetrahydropyridin-1-yl)butoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy, 2-homopiperazin-1-ylethoxy, 3-homopiperazin-1-ylpropoxy , 2-pyrrolidin-1-ylethylamino, o

C-pyrrolidin-1-ylpropylamino, 4-pyrrolidin-1-ylbutylamino, pyrrolidin-3-ylamino, pyrrolidin-2-ylmethylamino, av 2-pyrrolidin-2-ylethylamino, C-pyrrolidin-2-ylpropylamino, 2-morpholinoethylamino, C -morpholinopropylamino,

Zo 4-morpholinobutylamino, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethylamino, so 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl) propylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 4-piperidinobutylamino, piperidin-3-ylamino, piperidin-4-ylamino, piperidin-33-ylmethylamino, 2-piperidin-3-ylethylamino, piperidin-4-ylmethylamino, 2-piperidin- 4-ylethylamino, « 2-homopiperidin-1-ylethylamino, 3-homopiperidin-1-ylpropylamino, 2-piperazin-1-ylethylamino, - 70 3-piperazin-1-ylpropylamino, 4-piperazin-1-ylbutylamino, 2-homoperazine -1-ylethylamino or 3-homopiperazin-1-ylpropylamino, :z" and where the adjacent carbon atoms in any Co-Cv alkylene chain within K" of the substituent are optionally separated by an interchain group selected from O, МН, Х(Ме), СН-СН and С-С, and if В is a vinyl or ethynyl group, then the ВК! substituent does not necessarily have СНо- or

Go! HC-position is a substituent selected from M-(2-dimethylaminoethyl)carbamoyl, M-(3Z-dimethylaminopropyl)carbamoyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl and 4-dimethylaminobutyl, or from the group of the formula: (95) 042-X2- o 50 where X? is a single bond or is MHCO or M(Me)CO and O2 is imidazolylmethyl, 2-imidazolylethyl, 3-imidazolylpropyl, pyridylmethyl, 2-pyridylethyl, 3-pyridylpropyl, pyrrolidin-1-ylmethyl,

Co) 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidincetyl, 3-piperidinopropyl, 4-piperidinobutyl, 22-piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidine -4-ylethyl, piperazin-1-ylmethyl,

Gee! 2-piperazin-1-ylethyl, 3-piperazin-1-yl propyl or 4-piperazin-1-ylbutyl, and where any CH or CHnu group within KE! the substituent optionally has on each specified CH or CHnu de group one or more fluorine or chlorine groups or a substituent selected from hydroxy, oxo, amino, methoxy, methylsulfonyl, methylamino, dimethylamino, diisopropylamino, M-ethyl-M-methylamino, M -isopropyl-M-methylamino, 60 M-methyl-M-propylamino, acetoxy, acetamido and M-methylacetamido, and where any phenyl, imidazolyl, triazolyl, pyridyl or heterocyclyl group within the substituent on KE" optionally has 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, ethoxy, M-methylcarbamoyl,

M,M-dimethylcarbamoyl, methylenedioxy, ethylidenedioxy and isopropylidenedioxy, and pyrrolidin-2-yl, 65 piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, or homopiperazin-1-yl group within the EC" of the neoobov substituent necessarily substituted near the nitrogen atom by allyl, 2-propynyl, methylsulfonyl, ethylsulfonyl, acetyl, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl,

3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl,

C-dimethylaminopropyl, 2-pyrrolidin-1-ylethyl, C-pyrrolidin-1-ylpropyl, 2-morpholinoethyl,

3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazine-1-ylethyl or

With -piperazin-1-ylpropyl, the last 8 of the above substituents each optionally have 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, 70 and wherein any heterocyclyl group in within the substituent on VC does not necessarily have 1 or 2 oxo substituents; (e) t is 1 and the B group is located in the 7th position or t is 2 and the B" groups, which may be the same or different, are located in the b and 7th positions and each B group is selected from hydroxy , amino, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy , pyrrolidin-Z-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, Z-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, Z-morpholinopropoxy, 4-morpholinobutoxy, 2-(1,1-dioxotetrahydro- 4H-1,4-thiazin-4-yl)ethoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidine -3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, 2-piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidine -1-ylpropoxy, 3-(1,2,3,6-tetrahydropyridin-1-yl)upropoxy, 2-piperazin-1-ylethoxy, Z-pipera zin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy, and where adjacent carbon atoms in any C0-C8 alkylene chain within K" of the substituent are optionally separated by an interchain group , selected from О, МН, СН-СН and С-С, and where any СН or СНу group within КЕ! the substituent optionally has one or more chlorine groups on each specified CH or CHnu group or a substituent selected from hydroxy, oxo, amino, methoxy, methylsulfonyl, (3-methylamino, dimethylamino, diisopropylamino, M-ethyl-M-methylamino, M -isopropyl-M-methyl amino and acetoxy, and wherein any heterocyclyl group within the substituent on B! optionally has 1 or 2 substituents, which may be the same or different, selected from fluorine, chlorine, trifluoromethyl, hydroxy, amino . the group within EC" of the substituent o is optionally substituted near the nitrogen atom by methyl, ethyl, propyl, allyl, 2-propynyl, methyl sulfonyl, acetyl, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2, 2--riftoethyl or cyanomethyl, o and where any heterocyclyl group within the substituent on B does not necessarily have 1 a because 2 oxo substituents; c (n) t is 1 and the group KE is located in the 5th position or t is 2 and the groups K", which can be the same or different, are located in the 5th and 7th positions and each group B is selected from hydroxy, amino, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, dimethylamino, « diethylamino, acetamido, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, 2-pyrrolidin-1-ylethoxy,

C-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, - c 2-pyrrolidin-2-ylethoxy, C-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, h» 4-morpholinobutoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, " 3-(1,1-dioxotetrahydro-4H-1,4-thiazine 2-piperidinoethoxy -4-ylethoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, (ee) 3-(1,2,3,6-tetrahydropyridin-1-yl)upropoxy, 2-piperazin-1-ylethoxy . " of the substituent is optional and are separated by a group inserted into the chain selected from О, МН, СН-СН and С-С, (c) 50 and where any CH" or CH" group within ah K' of the substituent optionally has on each specified CH" or CH3" group one or more chlorine groups or a substituent selected from hydroxy, oxo, amino, methoxy, methylsulfonyl, methylamino, dimethylamino, diisopropylamino, M-ethyl-M- methylamino, M-isopropyl-M-methylamino and acetoxy, and where any heterocyclyl group within the substituent on B! optionally has 1 or 2 substituents which in May be the same or different, selected from fluorine, chlorine, trifluoromethyl, hydroxy, amino, methyl, ethyl, methoxy, methylenedioxy, ethylidenedioxy and isopropylidenedioxy, and pyrrolidin-2-yl, pyrrolidin- Z-yl, (F, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl) group within the EC" substituent is optionally substituted near the nitrogen atom by methyl, ethyl, propyl, allyl, 2-propynyl, methylsulfonyl, acetyl, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-rifluoroethyl, or cyanomethyl, and where any heterocyclyl group within the substituent on B is optional necessarily has 1 or 2 oxo substituents; () t represents 2 and groups B ", which can be the same or different, located in the b-th and 7-th positions and the group B in the b-th position is selected from hydroxy, methoxy, ethoxy and propoxy, and group B' in the 7th position is selected from methoxy, ethoxy, propoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 65 4-pyrrolides n-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,

3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy,

2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy, 2-piperidin-4-ylethoxy, 2- Homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 3-(1,2,3,6-tetrahydropyridin-1-yl)upropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2 -homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy, and where any CH» or CH3 group within VK! the substituent optionally has on each indicated CH» or CH3 group one or more chlorine groups or a substituent selected from hydroxy, oxo, amino, methoxy, methylsulfonyl, methylamino, dimethylamino, diisopropylamino, M-ethyl-M-methylamino, M-isopropyl -M-methylamino and acetoxy, 70 and where any heterocyclyl group within the substituent on BC! optionally has 1 or 2 substituents, which may be the same or different, selected from fluorine, chlorine, trifluoromethyl, hydroxy, amino, methyl, ethyl, methoxy, methylenedioxy, ethylenedioxy and isopropylidenedioxy, and pyrrolidin-2-yl, pyrrolidin-Z -yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within the KK" substituent is optionally substituted near the nitrogen atom by methyl, ethyl, propyl, allyl, 2-propynyl , methylsulfonyl, acetyl, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, or cyanomethyl, and wherein any heterocyclyl group within the substituent on B optionally has 1 or 2 oxo substituents ; () t represents 2 and groups B ", which can be the same or different, located in the 5th and 7th positions and the group BK " in the 5th position is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3-yloxy, pyrrolidin-2-yl methoxy,

3-piperidinyloxy, 4-piperidinyloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, and group B! in the 7th position is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, ch 2-pyrrolidin-2- ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, (o) 3- (1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)upropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, 2-piperidin-3-ylethoxy, 2-piperidin-4-ylethoxy, 2 -homopiperidine-1-ylethoxy,

3-homopiperidin-1-ylpropoxy, 3-(1,2,3,6-tetrahydropyridin-1-yl)upropoxy, 2-piperazin-1-ylethoxy,

3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy, and where any CHo or CH3 group within VE! the substituent optionally has on each specified CH» or CH3 group one or more chlorine groups or a substituent selected from hydroxy, oxo, amino, methoxy, methylsulfonyl, methylamino, dimethylamino, diisopropylamino, M-ethyl-M-methylamino, M -isopropyl-M-methylamino and acetoxy, and where any heterocyclyl group within the substituent on B! optionally has 1 or 2 substituents, which o may be the same or different, selected from fluorine, chlorine, trifluoromethyl, hydroxy, amino, methyl, ethyl, o methoxy, methylenedioxy, ethylenedioxy and isopropylidenedioxy, and pyrrolidin-2-yl, pyrrolidin -Z-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within B substituent is optionally substituted near the nitrogen atom by methyl, ethyl, propyl, allyl, 2- propynyl, methyl sulfonyl, "acetyl, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2--rifluoroethyl or

Cyanomethyl, - c and where any heterocyclyl group within the substituent on B does not necessarily have 1 or 2 oxo substituents; "with (K) n represents 0; " (I) n represents 1 or 2 and KU groups, which may be the same or different, are located in the 5th and/or bth positions of 2,3-methylenedioxypyridine-4 -yl group and selected from halogen, trifluoromethyl, cyano, hydroxy, Cs-Cv-alkyl, Cs-Cv-alkenyl, Cs-Cv-alkynyl and C4-Cv-alkoxy; so (t) n represents 1 or 2 and groups В З, which may be the same or different, located in the 5th and/or av! b positions of the 2,3-methylenedioxypyridin-4-yl group and selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl , methoxy and ethoxy; o (n) n represents 0 or n represents 1 and the BK Z group is located in the B5th or bth position of (ав) 50 2,3-methylenedioxypyridin-4-yl group, preferably in the 5th position, and selected from fluorine, chlorine, bromine, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy; and (o) n is 1 and the group B is located in the 5-position of 2,3-methylenedioxypyridine-4- yl group and selected from fluorine, chlorine, bromine, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy.

Also preferred novel compounds of the invention include, for example, quinazoline derivatives of formula I, or pharmaceutically acceptable salts thereof, in which, unless specifically indicated otherwise, each of 7, t, K 1, pi BZ has any (F, with values indicated above, provided that: ko (A) KE" substituents can be located only in the 5th, bth and/or 7th positions on the quinazoline ring, i.e. the 2nd and 8th positions remain unsubstituted ; or 60 (B) substituents EE" can be located only in the 6b and/or 7th positions on the quinazoline ring, that is, the 2nd, 5th and 8th positions remain unsubstituted.

A preferred compound according to the invention is a quinazoline derivative of formula I, in which: 7 is O or MM; t is 1 and the KV group is located in the 5th, b or 7th position or t is 2 and the VC groups" 65 which can be the same or different, located in the 5th and 7th positions or in the 6th and 7th positions and each K" group is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, vinyl, ethynyl, methoxy, ethoxy,

propoxy, isopropoxy, butoxy, pentyloxy, but-3-enyloxy, pent-4-enyloxy, hex-b-enyloxy, but-3-ynyloxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, cyclopropylmethoxy, 2-imidazol-1-ylethoxy, 3-imidazol-1-ylpropoxy, 2-(1,2,3-triazol-1-yl)ethoxy, 3-(1,2,3-triazol-1-yl)upropoxy, 2-(1,2,4-triazol-1-yl)ethoxy , 3-(1,2,4-triazol-1-yl)upropoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyrid-4-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3- ylethoxy, 2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy, 3-pyrid-3-ylpropoxy, 3-pyrid-4-ylpropoxy, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 70 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,

3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, 3-(1,1- dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4- ylmethoxy, 2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 2-(1,2,3,6-tetrahydropyridin-1-yl)ethoxy 3-(1,2,3,6-tetrahydropyridin-1-yl)upropoxy, 4-(1,2,3,6-tetrahydropyridin- 1-yl)butoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy, 2-homopiperazin-1-ylethoxy, 3-homopiperazin-1-ylpropoxy, 2-pyrrolidin- 1-ylethylamino,

C-pyrrolidin-1-ylpropylamino, 4-pyrrolidin-1-ylbutylamino, pyrrolidin-3-ylamino, pyrrolidin-2-ylmethylamino, 2-Pyrrolidin-2-ylethylamino, C-pyrrolidin-2-ylpropylamino, 2-morpholinoethylamino, C- morpholinopropylamino, 4-morpholinobutylamino, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethylamino, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl) propylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 4-piperidinobutylamino, piperidin-3-ylamino, piperidin-4-ylamino, piperidin-33-ylmethylamino, 2-piperidin-3-ylethylamino, piperidin-4-ylmethylamino, 2-piperidin- 4-ylethylamino, 2-homopiperidin-1-ylethylamino, 3-homopiperidin-1-ylpropylamino, 2-piperazin-1-ylethylamino,

Z-piperazin-1-ylpropylamino, 4-piperazin-1-ylbutylamino, 2-homopiperazin-1-ylethylamino or i)

3-homopiperazin-1-ylpropylamino, and where adjacent carbon atoms in any Co-Cv alkylene chain within the K' substituent are optionally separated by an interchain group selected from О, МН, Х(Ме), CH- SN and S-S, Ge and if EC! is a vinyl or ethynyl group, then the KE! does not necessarily have in the equine СНо- or о

HC-position is a substituent selected from M-(2-dimethylaminoethyl)carbamoyl, M-(3Z-dimethylaminopropyl)carbamoyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl, me) 2-dimethylaminoethyl, 3-dimethylaminopropyl and 4-dimethylaminobutyl, or from the group of the formula: o 02-X. 2 poison st? boo! d) where X- is a simple bond or is МНСО or M(Me)СоО and 0 is imidazolylmethyl, 2-imidazolylethyl, 3-imidazolylpropyl, pyridylmethyl, 2-pyridylethyl, 3-pyridylpropyl, pyrrolidine-1- ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, z piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2 -piperidin-4-ylethyl, piperazin-1-ylmethyl, c 2-piperazin-1-ylethyl, C-piperazin-1-ylpropyl or 4-piperazin-1-yl butyl, :c" and where any CH or CHu group within KE! the substituent optionally has on each specified CH or CHnu group one or more fluorine or chlorine groups or a substituent selected from hydroxy, oxo, amino, methoxy, methylsulfonyl, methylamino, dimethylamino, diisopropylamino, M-ethyl-M-methylamino, M- isopropyl-M-methylamino, o M-methyl-M-propylamino, acetoxy, acetamido and M-methylacetamido, and where any phenyl, imidazolyl, triazolyl, pyridyl or heterocyclyl group within the o substituent on KE" optionally has 1 or 2 substituents, which may be the same or different, selected from 2) fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, ethoxy, M-methylcarbamoyl,

M,M-dimethylcarbamoyl, methylenedioxy, ethylidenedioxy and isopropylidenedioxy, and pyrrolidin-2-yl, o piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within the KK" of the substituent

Kz is optionally substituted near the nitrogen atom by allyl, 2-propynyl, methylsulfonyl, ethylsulfonyl, acetyl, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl,

3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 5, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl,

C-dimethylaminopropyl, 2-pyrrolidin-1-ylethyl, C-pyrrolidin-1-ylpropyl, 2-morpholinoethyl,

F, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, the last 8 of the above substituents each optionally having 1 or 2 substituents which may be the same or different, selected from fluorine, chlorine, methyl and methoxy, 60 and where any heterocyclyl group within the substituent on B optionally has 1 or 2 oxo substituents; n represents 0 or n represents 1 and the KZ group is located in the 5th or bth position of the 2,3-methylenedioxypyridin-4-yl group and is selected from fluorine, chlorine, bromine, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy; or a pharmaceutically acceptable acid addition salt thereof. 65 A further preferred compound according to the invention is a quinazoline derivative of formula I, in which: 7 is MH;

t represents 2 and groups VK", which can be the same or different, located in the b-th and 7-th positions and the group B! in the b-th position is selected from hydroxy, methoxy, ethoxy and propoxy, and the group B' in The 7th position is selected from methoxy, ethoxy, propoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidine-3-yloxy, pyrrolidine-2-ylmethoxy, 2- pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, 3 -(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidine-3-yloxy, piperidin-4-yloxy, piperidine-3- ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy, 2-piperidin-4-ylethoxy, 70. 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 3-(1,2,3 ,6-tetrahydropyridin-1-yl)upropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy, and where What CH" or CHz group within the VC! the substituent optionally has on each indicated CH» or CH3 group one or more chlorine groups or a substituent selected from hydroxy, oxo, amino, methoxy, methylsulfonyl, methylamino, dimethylamino, diisopropylamino, M-ethyl-M-methylamino, M-isopropyl -M-methylamino and acetoxy, and where any heterocyclyl group within the substituent on B! optionally has 1 or 2 substituents, which may be the same or different, selected from fluorine, chlorine, trifluoromethyl, hydroxy, amino, methyl, ethyl, methoxy, methylenedioxy, ethylenedioxy and isopropylidenedioxy, and pyrrolidin-2-yl, pyrrolidin-Z -yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within the KK" substituent is optionally substituted near the nitrogen atom by methyl, ethyl, propyl, allyl, 2-propynyl , methylsulfonyl, acetyl, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-rifluoroethyl, or cyanomethyl, and wherein any heterocyclyl group within the VC substituent optionally has 1 or 2 oxo substituents: n represents 0 or n represents 1 and the KZ group is located in the 5th or bth position of the 2,3-methylenedioxypyridin-4-yl group and is selected from chlorine, bromine, trifluoromethyl, cyano, hydroxy, methyl , ethyl, methoxy and ethoxy; o or its pharmaceutically acceptable acid addition salt.

A further preferred compound according to the invention is a quinazoline derivative of formula I, in which: 7 is MH; sch zot is 2 and the first BK " group is a b-methoxy group and the second B " group is located in the 7th position and is selected by Kk! 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-(3k5,45k)-3,4-methylenedioxypyrrolidin-1-yl|stoxy, 3-(3k5,455)-3,4-methylenedioxypyrrolidine -1-yl|propoxy, c 2-morpholinoethoxy, Z-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, 3-(1,1-dioxotetrahydro-4H- 1,4-thiazin-4-yl)upropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, o 2-piperidin-3-ylethoxy, 2-(M-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy, so 3-(M-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy, 2-(M-methylpiperidin-4-yl)ethoxy,

3-piperidin-4-ylpropoxy, 3-(M-methylpiperidin-4-yl)propoxy, 2-(1,2,3,6-tetrahydropyridin-1-yl)ethoxy, 3-(1,2,3,6 -tetrahydropyridin-1-yl)upropoxy, 2-(4-hydroxypiperidin-1-yl)ethoxy, 3-(4-hydroxypiperidin-1-yl)propoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy , « 4-piperazin-1-ylbutoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-ylpropoxy, pe) c 4-(4-methylpiperazin-1-yl)butoxy, 2-(4-allylpiperazin-1-yl)ethoxy, 3-(4-allylpiperazin-1-yl)upropoxy, 2-(4-prop-2-ynylpiperazin-1-yl)letoxy, 3-(4-prop- 2-ynylpiperazin-1-yl)propoxy, ;" 2-(4-methylsulfonylpiperazin-1-yl)ethoxy, 3-(4-methylsulfonylpiperazin-1-yl)upropoxy, 2-(4-acetylpiperazin-1-yl)ethoxy, 3-(4-acetylpiperazin-1-yl) upropoxy, 4-(4-acetylpiperazin-1-yl)butoxy, 2-(4-isobutyrylpiperazin-1-yl)ethoxy, 3-(4-isobutyrylpiperazin-1-yl)upropoxy,

Go! 4-(4-isobutyrylpiperazin-1-yl)butoxy, 2-I4-(2-fluoroethyl)piperazin-1-yl|ethoxy, 3-I4-(2-fluoroethyl)piperazin-1-yl|Ipropoxy, 2-( 4-(2,2,2-trifluoroethyl)piperazin-1-yl|ethoxy, o 3-I4-(2,2,2-trifluoroethyl)piperazin-1-yl|Ipropoxy, 2-(4-cyanomethylpiperazine-1- yl)ethoxy, 2) 3-(4-cyanomethylpiperazin-1-yl)propoxy, 2-(2-(4-methylpiperazin-1-yl)ethoxy|ethoxy, 2-chloroethoxy, 5or 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulfonylethoxy, 3-methylsulfonylpropoxy, 2-(2-methoxyethoxy)ethoxy, o 2-(4-pyridyloxy)ethoxy, 3-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy; and

Kz n represents 0 or n represents 1 and the group K Z is located in the 5th or bth position of the 2,3-methylenedioxypyridin-4-yl group and is selected from fluorine, chlorine, bromine, trifluoromethyl and cyano; or a pharmaceutically acceptable acid addition salt thereof.

A further preferred compound according to the invention is a quinazoline derivative of formula I, in which: 7 is MM; o t is 2 and the first BK " group is a b-methoxy group and the second B " group is located in the 7th position and is selected as Kk! 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-(3K5,454)-3,4-methylenedioxypyrrolidin-1-yl|ethoxy, 3-(3K5,455K)-3,4--methylenedioxypyrrolidine -1-yl|propoxy, 60 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-(4-allylpiperazin-1-yl)ethoxy, 3-(4-allylpiperazin-1-yl)propoxy, 2-(4-prop-2-ynylpiperazin-1-yl)ethoxy, 3-(4-prop- 2-ynylpiperazin-1-yl)propoxy, 2-(4-acetyl piperazin-1-yl)ethoxy, 3-(4-acetyl piperazin-1-yl)upropoxy, 2-(4-isobutyrylpiperazin-1-yl)ethoxy , 3-(4-isobutyrylpiperazin-1-yl)propoxy, 65 2-I4-(2,2,2-trifluoroethyl)piperazin-1-yl|ethoxy and 3-(4-(2,2,2-trifluoroethyl) piperazin-1-yl|Ipropoxy; and n represents 1 and the KZ group is located in the 6th position of the 2,3-methylenedioxypyridin-4-yl group and is selected from chlorine and bromine; or a pharmaceutically acceptable acid addition salt thereof.

A further preferred compound according to the invention is a quinazoline derivative of formula I, in which: 7 is MH; t represents 2 and groups VK", which can be the same or different, located in the 5th and 7th positions and the group B' in the 5th position is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, tetrahydrofuran-3 -yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,

3-piperidinyloxy, 4-piperidinyloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, cyclobutyloxy, 70 cyclopentyloxy and cyclohexyloxy, and the group K' in the 7th position is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-yl propoxy, 4-pyrrolidin-1-ylbutoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4 -morpholinobutoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)upropoxy, 2 -piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, 2-piperidin-3-ylethoxy, 2-piperidin-4-ylethoxy, 2-homopiperidine-i-ylethoxy,

3-homopiperidin-1-ylpropoxy, 3-(1,2,3,6-tetrahydropyridin-1-yl)upropoxy, 2-piperazin-1-ylethoxy,

3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-yl propoxy, and where any CH or CHnu group within KE! the substituent optionally has on each specified CH or CHnu group one or more chlorine groups or a substituent selected from hydroxy, oxo, amino, methoxy, methylsulfonyl, methylamino, dimethylamino, diisopropylamino, M-ethyl-M-methylamino, M-isopropyl- M-methylamino and acetoxy, where any heterocyclyl group within the substituent on B! optionally has 1 or 2 substituents, which may be the same or different, selected from fluorine, chlorine, trifluoromethyl, hydroxy, amino, methyl, ethyl, methoxy, methylenedioxy, ethylenedioxy and isopropylidenedioxy, and pyrrolidin-2-yl, pyrrolidin-Z -yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, or homopiperazin-1-yl group within the KK" of the substituent of ch 29 is optionally substituted near the nitrogen atom by methyl, ethyl, propyl, allyl, 2 -propynyl, methyl sulfonyl, Ge) acetyl, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-rifluoroethyl or cyanomethyl, and where any heterocyclyl group within the substituent on B is optional has 1 or 2 oxo substituents, where p is 0 or p is 1 and the KZ group is located in the 5th or bth position of the 2,3-methylenedioxypyridin-4-yl group and is selected from fluorine, chlorine, bromine , trifluoromethyl, cyano, hydroxy, o methyl, ethyl, methoxy and ethoxy; CO or its pharmaceutically acceptable acid addition salt.

A further preferred compound according to the invention is a quinazoline derivative of formula I, in which: o 7 is MH; so t is 1 and group B ! is located in the 5th position and is selected from ethoxy, propoxy, isopropoxy, butoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrothien-3-yloxy, 1,1-dioxotetrahydrothien-3-yloxy, tetrahydrothiopyran-4-yloxy , 1,1-dioxotetrahydrothiopyran-4-yloxy, "

M-methylazetidin-3-yloxy, M-ethylazetidin-3-yloxy, M-isopropylazetidin-3-yloxy, pyrrolidin-3-yloxy,

M-methylpyrrolidin-Z-yloxy, pyrrolidin-2-ylmethoxy, Z-piperidinyloxy, M-methylpiperidin-Z-yloxy, 2c 4-piperidinyloxy, M-methylpiperidin-4-yloxy, M-allylpiperidin-4-yloxy, M- prop-2-ynylpiperidin-4-yloxy, M-acetylpiperidin-4-yloxy, M-methylsulfonylpiperidin-4-yloxy, M-(2-methoxyethyl)piperidin-4-yloxy, i" piperidin-Z-ylmethoxy, M -methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, M-methylpiperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, or t is 2 and the first B" group is located in the 5th position and is selected from the group of substituents, co listed immediately above, and the second K' group is located in the 7th position and is selected from 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-(z3K5,454)-3,4-methylenedioxypyrrolidine-1 -yl|iethoxy, 3-K(Z3K5,4554)-3,4-methylenedioxypyrrolidin-1-yl|propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, (65) 2-(1,1-dioxotetrahydro-4H-1, 4-thiazin-4-yl)ethoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, o 20 2-piperidinoethoxy, З- piperidinopropoxy, 2-piperidin-3-ylethoxy, 2-(M-methylpiperidin-3-yl)ethoxy,

3-piperidin-3-ylpropoxy, 3-(M-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy,

IR) 2-(-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy, 3-(M-methylpiperidin-4-yl)propoxy, 2-(1,2,3,6-tetrahydropyridin-1- yl)ethoxy, 3-(1,2,3,6-tetrahydropyridin-1-yl)propoxy, 2-(4-hydroxypiperidin-1-yl)ethoxy, 3-(4-hydroxypiperidin-1-yl)propoxy, 2 -piperazin-1-ylethoxy, 223-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy, 2-(4-methylpiperazin-1-yl)ethoxy,

Gee! 3-(4-methylpiperazin-1-yl)propoxy, 4-(4-methylpiperazin-1-yl)butoxy, 2-(4-allylpiperazin-1-yl)ethoxy, 3-(4-allylpiperazin-1-yl) propoxy, 2-(4-prop-2-ynylpiperazin-1-yl)ethoxy, where 3-(4-prop-2-ynylpiperazin-1-yl)propoxy, 2-(4-methylsulfonylpiperazin-1-yl)ethoxy, 3-(4-methylsulfonylpiperazin-1-yl)upropoxy, 2-(4-acetylpiperazin-1-yl)ethoxy, 60 3-(4-acetylpiperazin-1-yl)upropoxy, 4-(4-acetylpiperazin-1-yl) )butoxy, /2-(4-isobutyrylpiperazin-1-yl)ethoxy, 3-(4-isobutyrylpiperazin-1-yl)propoxy, 4-(4-isobutyrylpiperazin-1-yl)butoxy, 2-I(4-( 2-fluoroethyl)piperazin-1-yl|ethoxy, 3-I4-(2-fluoroethyl)piperazin-1-yl|propoxy, 2-I(4-(2,2,2-trifluoroethyl)piperazin-1-yl| ethoxy, 3-I(4-(2,2,2-trifluoroethyl)piperazin-1-yl|propoxy, 2-(4-cyanomethylpiperazin-1-yl)ethoxy, 3-(4-cyanomethylpiperazin-1-yl)propoxy , 2-(2-(4-methyl b5 piperazin-1-yl)ethoxy|ethoxy, 2-chloroethoxy, 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulfonylethoxy,

3-methylsulfonylpropoxy, 2-(2-methoxyethoxy)ethoxy, 2-(4-pyridyloxy)ethoxy, 3-pyridylmethoxy and

2-cyanopyrid-4-ylmethoxy; n represents 0 or n represents 1 and the KZ group is located in the 5th or bth position of the 2,3-methylenedioxypyridin-4-yl group and is selected from chlorine, bromine, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy; or a pharmaceutically acceptable acid addition salt thereof.

A further preferred compound according to the invention is a quinazoline derivative of formula I, in which: 7 is MH; t is 1 and the BC group is located in the 5th position and is selected from propoxy, isopropoxy, 70 tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3-yloxy, M-methylpyrrolidine-3-yloxy, pyrrolidine -2-ylmethoxy, 3-piperidinyloxy, M-methylpiperidin-3-yloxy, 4-piperidinyloxy,

M-methylpiperidin-4-yloxy, M-allyltperidin-4-yloxy, M-prop-2-ynylpiperidin-4-yloxy,

M-acetylpiperidin-4-yloxy, M-methylsulfonylpiperidin-4-yloxy, piperidin-3-ylmethoxy,

M-methylpiperidin-3Z-ylmethoxy, piperidin-4-ylmethoxy, M-methylpiperidin-4-ylmethoxy, cyclobutyloxy, 75Ccyclopentyloxy and cyclohexyloxy, or t is 2 and the first BK" group is located in the 5th position and is selected from the group of substituents , listed immediately above, and the second K' group is located in the 7th position and is selected from 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-(z3K5,454)-3,4-methylenedioxypyrrolidine-1 -yl|iethoxy, 3-К(З3К5,4554)-3,4-methylenedioxypyrrolidin-1-yl|propoxy, 2-morpholinoethoxy, З-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazine -4-yl)ethoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-piperidin-3-ylethoxy, 2-(M -methylpiperidine-3-yl)ethoxy,

3-piperidin-3-ylpropoxy, 3-(M-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy, 2-(M-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy, 3-(M-methylpiperidin-4-yl)propoxy, 2-(1,2,3,6-tetrahydropyridin-1-yl)ethoxy, 3-(1,2,3,6-tetrahydropyridin-1-yl)propoxy , c 2-(4-hydroxypiperidin-1-yl)ethoxy, 3-(4-hydroxypiperidin-1-yl)propoxy, 2-piperazin-1-ylethoxy, d)

3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 4-(4-methylpiperazin-1 -yl)butoxy, 2-(4-allylpiperazin-1-yl)ethoxy, 3-(4-allylpiperazin-1-yl)propoxy, 2-(4-prop-2-ynylpiperazin-1-yl)ethoxy, 3- (4-prop-2-ynylpiperazin-1-yl)upropoxy, 2-(4-methylsulfonylpiperazin-1-yl)ethoxy, c 8-(4-methylsulfonylpiperazin-1-yl)upropoxy, 2-(4-acetylpiperazin-1 -yl)ethoxy, o 3-(4-acetylpiperazin-1-yl)upropoxy, 4-(4-acetylpiperazin-1-yl)butoxy, /2-(4-isobutyrylpiperazin-1-yl)ethoxy, 3-(4 -isobutyrylpiperazin-1-yl)propoxy, 4-(4-isobutyrylpiperazin-1-yl)butoxy, me) 2-I(4-(2-fluoroethyl)piperazin-1-yl|ethoxy, 3-I4-(2- fluoroethyl)piperazin-1-yl|propoxy, o 2-I(4-(2,2,2-trifluoroethyl)piperazin-1-yl|ethoxy, 3-I(4-(2,2,2-trifluoroethyl)piperazine -1-yl|propoxy, 2-(4-cyanomethylpiperazin-1-yl)ethoxy, 3-(4-cyanomethylpiperazin-1-yl)propoxy, so 2-(2-(4-methylpiperazin-1-yl)ethoxy| ethoxy, 2-chloroethoxy, 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulfonylethoxy, 3-me tylsulfonylpropoxy, 2-(2-methoxyethoxy)ethoxy, /2-(4-pyridyloxy)ethoxy,

3-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy; "n is 0 or n is 1 and the KZ group is located in the 5th or bth position - 70 of the 2,3-methylenedioxypyridin-4-yl group and is selected from chlorine, bromine, trifluoromethyl, cyano, hydroxy, methyl , with ethyl, methoxy and ethoxy;

With" or its pharmaceutically acceptable acid addition salt.

A further preferred compound according to the invention is a quinazoline derivative of formula I, in which: 7 is MH; because 15 t is 1 and the group BK' is located in the 5th position and is selected from propoxy, isopropoxy, tetrahydropyran-4-yloxy, 4-piperidinyloxy and M-methylpiperidin-4-yloxy, o or t is 2 and the first B " group is located in the 5th position and is selected from the group of substituents listed immediately above, and the second K' group is located in the 7th position and is selected from 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2 -(З3Кк5,45К)-3,4-methylenedioxypyrrolidin-1-yl|ethoxy, o 3-К(З3К5,4554)-3,4-methylenedioxypyrrolidin-1-yl|propoxy, 2-morpholinoethoxy, З-morpholinopropoxy,

Ge 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy , 3-piperidinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1 -yl)propoxy, two 2 (4-allylpiperazin-1-yl)ethoxy, 3-(4-allylpiperazin-1-yl)upropoxy, 2-(4-prop-2-ynylpiperazin-1-yl)ethoxy, 3- (4-prop-2-ynylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy,

F) 3-(4-acetylpiperazin-1-yl)propoxy, 2-(4-isobutyrylpiperazin-1-yl)ethoxy, ka 3-(4-isobutyrylpiperazin-1-yl)propoxy, 2-I(4-(2 ,2,2-trifluoroethyl)piperazin-1-yl|ethoxy and 3-I4-(2,2,2-trifluoroethyl)piperazin-1-yl|propoxy; and in n represents 0 or n represents 1 and the group K C is located in the 5- or b-position of the 2,3-methylenedioxypyridin-4-yl group and is selected from fluorine, chlorine, bromine, trifluoromethyl, and cyano; or a pharmaceutically acceptable acid addition salt thereof.

A further preferred compound according to the invention is a quinazoline derivative of formula I, in which: 7 is MH; 65 t is 2 and the first B' group is located in the 5th position and is selected from isopropoxy and tetrahydropyran-4-yloxy, and the second KK" group is located at the 7th position and is selected from 2-pyrrolidin-1-ylethoxy,

З-pyrrolidin-1-ylpropoxy, 2-(З3К5,45К)-3,4-methylenedioxypyrrolidin-1-ilyethoxy, 3-К(З3К5,4554)-3,4-methylenedioxypyrrolidin-1-yl|propoxy, 2-morpholinoethoxy . 1-yl)upropoxy, 2-(4-allylpiperazin-1-yl)ethoxy, 3-(4-allylpiperazin-1-yl)upropoxy, 2-(4-prop-2-ynylpiperazin-1-yl)ethoxy, 3 -(4-prop-2-ynylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy, 3-(4-acetylpiperazin-1-yl)propoxy, 2-(4-isobutyrylpiperazine-1 -yl)ethoxy, 3-(4-isobutyrylpiperazin-1-yl)propoxy, 2-I(4-(2-hydroxyethyl)piperazin-1-yl|ethoxy, 70. 3-I4-(2-hydroxyethyl)piperazin- 1-yl|propoxy, 2-I(4-(2,2,2-trifluoroethyl)piperazin-1-yl|ethoxy, 3-I4-(2,2,2-trifluoroethyl)piperazin-1-yl|Ipropoxy, 2-ID-(2-dimethylaminoacetyl)piperazin-1-yl|ethoxy and 3-(4--2-dimethylaminoacetyl)piperazin-1-yl|Ipropoxy; and n represents 1 and the KZ group is located in the 5th position of 2 ,3-met ylenedioxypyridin-4-yl group and selected from chlorine and bromine; or a pharmaceutically acceptable acid addition salt thereof.

A further preferred compound according to the invention is a quinazoline derivative of formula I, in which: 7 is MH; t is 2 and the first BK' group is located in the 5B position and is selected from isopropoxy and tetrahydropyran-4-yloxy, and the second KK" group is located at the 7th position and is selected from 2-pyrrolidin-1-ylethoxy, З- pyrrolidin-1-ylpropoxy, 2-(ЗК5,455)-3,4-methylenedioxypyrrolidin-1-yl|ethoxy, 3-К(З3К5,4554)-3,4-methylenedioxypyrrolidin-1-yl|propoxy, 2-morpholinoethoxy , 3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)upropoxy, 2-(4-allylpiperazin-1-yl) ethoxy, 3-(4-allylpiperazin-1-yl)upropoxy, 2-(4-prop-2-ynylpiperazin-1-yl)ethoxy, 3-(4-prop-2-ynylpiperazin-1-yl)propoxy, 2 -(4-acetylpiperazin-1-yl)ethoxy, c 3-(4-acetylpiperazin-1-yl)upropoxy, 2-(4-isobutyrylpiperazin-1-yl)ethoxy, o 3-(4-isobutyrylpiperazin-1-yl) )propoxy, 2-I(4-(2,2,2-trifluoroethyl)piperazin-1-yl|ethoxy and 3-I4-(2,2,2-trifluoroethyl)piperazin-1-yl|Ipropoxy; and p represents is 1 and the KZ group is located in the 5th position of the 2,3-methylenedioxypyridin-4-yl group and is selected from chlorine and bromine; c or its pharmaceutically acceptable acid addition salt. at

A further preferred compound according to the invention is a quinazoline derivative of formula I, in which: 7 is MH; i) t is 2 and the first BK' group is located in the 5B position and is selected from isopropoxy and av tetrahydropyran-4-yloxy, and the second B' group is located at the 7th position and is selected from 2-pyrrolidin-1-ylethoxy . -yl)ethoxy, 2-(4-prop-2-ynylpiperazin-1-yl)ethoxy, 3-(4-prop-2-ynylpiperazin-1-yl)upropoxy, 2-(4-acetylpiperazin-1-yl) ethoxy, 2-ID-(2-hydroxyethyl)piperazin-1-yl|ethoxy and 2-ID-(2-dimethylaminoacetyl)piperazin-1-yl|ethoxy; and z p is 1 and the group B is located in the 5th position of the 2,3-methylenedioxypyridin-4-yl group and is a chlorine group; :z" or its pharmaceutically acceptable acid addition salt.

A further preferred compound according to the invention is a quinazoline derivative of formula I, in which: 415 7 is MH;

Go! t is 2 and the first B' group is located in the 5th position and is selected from isopropoxy and tetrahydropyran-4-yloxy, and the second KK" group is located at the 7th position and is selected from 2-pyrrolidin-1-ylethoxy, o 2 -(z3К5,454)-3,4-methylenedioxypyrrolidin-1-yl|ethoxy, 2-morpholinoethoxy, 2-piperidinoethoxy, oz 2-piperazin-1-ylethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2 -(4-prop-2-ynylpiperazin-1-yl)ethoxy, 2-(4-acetylpiperazin-1-yl)ethoxy, 2-I4-(2-hydroxyethyl)piperazin-1-yl|ethoxy and o 2-ID --(2-dimethylaminoacetyl)piperazin-1-yl|ethoxy; and that) n is 1 and the BC group is located in the 5-position of the 2,3-methylenedioxypyridin-4-yl group and is a chlorine group; or pharmaceutically acceptable acid addition salt.

A further preferred compound according to the invention is a quinazoline derivative of formula I, in which: 7 is MH;

Ф, : 1 : : 1 t is 2 and the first K " group is a 5-isopropoxy group and the second KK group is located in the 7th ko position and is selected Kk! 2-pyrrolidin-1-ylethoxy, 2-(z3K5, 454)-3,4-methylenedioxypyrrolidin-1-yl|ethoxy, 2-morpholinoethoxy, 2-piperidinoethoxy, 2-piperazin-1-ylethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 60 2-(4- acetylpiperazin-1-yl)ethoxy and 2-(4-(2-hydroxyethyl)piperazin-1-yl|ethoxy; and n is 1 and group B C is located in the 5th position of 2,3-methylenedioxypyridin-4-yl group and is a chlorine group, or its pharmaceutically acceptable acid addition salt.

A further preferred compound according to the invention is a quinazoline derivative of formula I, in which: because 7 is MH;

t is 2 and the first B" group is a 5-isopropoxy group and the second B group is located in the 7th position and is selected from 0 2-((3ЗК5,451)-3,4-methylenedioxypyrrolidin-1-yl|utoxy, /2-piperazin-1-ylethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2-(4-acetylpiperazin-1-yl)ethoxy and 2-I(4-(2-hydroxyethyl)piperazin-1- yl|ethoxy; and n represents 1 and group B C is located in the 5th position of the 2,3-methylenedioxypyridin-4-yl group and represents a chlorine group; or its pharmaceutically acceptable acid addition salt.

Preferred compounds according to the invention are, for example, quinazoline derivatives of formula I, which are described in example 3, and in examples 6(1)-6(7) below. 70 A preferred compound according to the invention is, for example, a quinazoline derivative of formula I selected from: 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-b-methoxy-7-(3-(4-prop-2 -ynylpiperazin-1-yl)propoxy)quinazoline, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-I3-(4-isobutyrylpiperazin-1-yl)upropoxy)|-b-methoxyquinazoline, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-b-methoxy-7-13-(4-(2,2,2-trifluoroethyl)piperazin-1-yl|Ipropoxy)x inazoline and 4 -(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-methoxy-7-(2-(4-prop-2-ynylpiperazin-1-yl)ethoxy)quinazoline; or its pharmaceutically acceptable acid addition salt.

A further preferred compound according to the invention is, for example, a quinazoline derivative of formula I selected from: 7-(2-(4-acetylpiperazin-1-yl)ethoxy)|-4-(5-chloro-2,3-methylenedioxypyrid-4- ylamino)-5-tetrahydropyran-4-yloxy iquinazoline, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-2-(3K5,455)-3,4-methylenedioxypyrrolidin-1-yl| ethoxy)-5-tetrahydropyran-4-yloxyquinazoline, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(2-(4-prop-2-ynylpiperazin-1-yl)ethoxy| -5-tetrahydropyran-4-yloxyquinazoline, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-I3-(4-prop-2-ynylpiperazin-1-yl)upropoxy|-5-tetrahydropyran - c 4-yloxyquinazoline, o 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(2-morpholinoethoxy)-5-tetrahydropyran-4-yloxyquinazoline and 4-(5-chloro-2, 3-methylenedioxypyrid-4-ylamino)-7-(3-morpholinopropoxy)-5-tetrahydropyran-4-yloxyquinazoline; or its pharmaceutically acceptable acid addition salt.

A further preferred compound according to the invention is, for example, a quinazoline derivative of formula I selected from: He 7-(2-(4-acetylpiperazin-1-yl)ethoxy|-4-(5-chloro-2,3-methylenedioxypyrid-4- ylamino)-5-isopropoxyquinazoline, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxy-7-(2-piperazine-1-ylethoxy)quinazoline, o 4-(5-chloro- 2,3-methylenedioxypyrid-4-ylamino)-7-12-I4-(2-hydroxyethyl)piperazin-1-ylisoethoxy)-5-isopropoxyquinazoline, 4-(5-chloro-2,3-methylenedioxypyrid-4- ylamino)-5-isopropoxy-7-(2-pyrrolidin-1-ylethoxy)quinazoline, o 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxy-7-(2-piperidinoethoxy) quinazoline, (ee) 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxy-7-(2-morpholinoethoxy)quinazoline, 4-(5-chloro-2,3-methylenedioxypyrid-4 -ylamino)-5-isopropoxy-7-(3-morpholinopropoxy)quinazoline, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxy-7-(2-(4-prop-2 -ynylpiperazin-1-yl)ethoxy|" quinazoline, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxy-7-(2-(4-methylpiperazine- 1-yl)ethoxy)quinazoline and - with 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-2-I4-(-2-dimethylaminoacetyl)piperazin-1-yl|ethoxy)-5 - isoprop and oxyquinazoline; "» or its pharmaceutically acceptable acid additive salt.

A quinazoline derivative of formula I or a pharmaceutically acceptable salt thereof may be prepared by any known method suitable for the preparation of related chemical compounds. Such methods, when (ee) are used to obtain a quinazoline derivative of formula I, represent an additional variant of the implementation of the invention and are illustrated by the following characteristic variants of the method, in which, unless specifically indicated otherwise, t, B, 7, n and BZ have any what are the values given above. The necessary starting materials can be obtained (65) using standard techniques of organic chemistry. The preparation of such starting materials is described together with about 50 following typical variants of methods of preparation and accompanying examples. Alternatively, the required starting materials are obtained by methods similar to those given, which are common for

IK) an average specialist in the field of organic chemistry. (a) To obtain those compounds of formula I, in which 7 is an O, 5 or M(VK 2) group, the interaction of quinazoline of formula I

F) name) 60 b5

where I represents a leaving group and t and EC" have any of the meanings given above, except that any functional group is optionally protected, with a compound of the formula PI

PI

( in c with I o not o y

Zo o 0-/ Fo «c) where 7 represents О, 5, or Ш(К 2) ип, ВЗ ии КВ? have any of the meanings given above, except that (ee) any functional group is optionally protected, after which any protecting group present is removed by conventional methods.

A suitable reaction can be carried out in the presence of a suitable acid or in the presence of a suitable base. A suitable acid is, for example, an inorganic acid such as, for example, hydrogen chloride or hydrogen bromide. A suitable base is, for example, an organic amine base, such as, for example, pyridine, ts 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, M-methylmorpholine or h»diazabicyclo|5,4,0undec-7 -ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, " for example, sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal amide, for example, sodium hexadimethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.co A suitable displacing group I is, for example, a halogen, alkoxy, aryloxy or sulfonyloxy group, for example chlorine, bromo, methoxy, phenoxy, pentafluorophenoxy, methanesulfonyloxy or toluene-4-sulfonyloxy group The reaction is generally carried out in the presence of a suitable inert solvent o or diluent, for example an alcohol or an ether such as methanol, ethanol, isopropanol or o 50 ethyl acetate, a halogenated solvent such as methyl nchloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene, or

Co) of a bipolar aprotic solvent, such as M,M-dimethylformamide, M,M-dimethylacetamide, M-methyl pyrrolide n-2-one or dimethylsulfoxide. The reaction, as a rule, is carried out at a temperature in the interval, for example, 0-2502C, for example, in the interval 0-12096.

As a rule, a quinazoline of formula I can interact with a compound of formula I in the presence of an aprotic

HF) of a solvent such as M,M-dimethylformamide, suitably in the presence of a base, for example potassium carbonate or sodium hexadimethyldisilazane, and at a temperature in the range, for example, 0-1502C, preferably in the range, for example, 0-7090.

A quinazoline derivative of the formula | can be obtained in the implementation of such a method in the form of a free base, 60 or alternatively, it can be obtained in the form of a salt with an acid of the formula H-Y, in which I. has the value indicated above. If it is desired to obtain the free base from the salt, the salt can be treated with a suitable base, such as an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, M-methylmorpholine, or diazabicyclo| 5,4,0Iundec-7-ene, or, for example, carbonate or hydroxide of an alkali or alkaline earth metal, for example, sodium carbonate, potassium carbonate, or calcium carbonate, sodium hydroxide, or potassium hydroxide.

Protecting groups can generally be selected from any groups described in the literature or known to one skilled in the art of chemistry, as long as it is acceptable to protect a given group, and can be introduced by conventional methods. Protecting groups can be removed using any conventional method described

In the literature or a known specialist in the field of chemistry, if it is suitable for removing a given protective group, these methods are chosen so that the removal of the protective group is accompanied by minimal damage to groups that are in the rest of the molecule.

Specific examples of protecting groups are given below, in which for convenience "lower", such as lower alkyl, means that the group used preferably has 1-4 carbon atoms. It is also intended that such 7/0 examples are not exhaustive. While specific examples of methods for removing protective groups are described below, they are also not exhaustive. The use of protecting groups and methods of deprotection, which are not specifically described here, undoubtedly fall within the scope of the invention.

The carboxy-protecting group can be a residue of an aliphatic or arylaliphatic alcohol, which forms a complex ester, or a silanol, which forms a complex ester (the specified alcohol or silanol preferably contains 1-20 carbon atoms). Examples of carboxy-protecting groups are C.-Si10-alkyl groups with a straight or branched chain (for example, isopropyl and tert-butyl); lower alkoxy-lower alkyl groups (eg, methoxymethyl, ethoxymethyl, and isobutoxymethyl); lower acyloxy-lower alkyl groups, (eg, acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example, 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl); aryl-lower alkyl groups (eg, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl, and phthalidyl); tri(lower alkyl)silyl groups (for example, trimethylsilyl and tert-butyldimethylsilyl); tri(lower alkyl)silyl-lower alkyl groups (for example, trimethylsilylethyl); and Co-C6-alkenyl groups (eg, allyl). Methods that are more suitable for removing carboxy-protecting groups include, for example, cleavage catalyzed by an acid, a base, a metal, or an enzyme. with

Examples of protecting groups for the hydroxyl group are lower alkyl groups (eg, tert-butyl). lower alkenyl groups (for example, allyl); lower alkanoyl groups (for example, acetyl); lower alkoxycarbonyl i) groups (for example, tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example, allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (e.g., trimethylsilyl and zo tert-butyldimethylsilyl) and aryl-lower alkyl (e.g., benzyl) groups.

Examples of amino protecting groups are formyl, aryl-lower alkyl groups (eg, benzyl and o-substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-4-anisylmethyl c and furylmethyl groups; lower alkoxycarbonyl (eg, tert-butoxycarbonyl); lower alkenyloxycarbonyl (eg, allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example, o benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); co trialkylsilyl (for example, trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for example, methylidene) and benzylidene and substituted benzylidene groups.

Suitable methods for removing hydroxy and amino protecting groups are, for example, acid, base, metal or enzyme catalyzed hydrolysis for groups such as 2-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolysis for groups such as 2 -nitrobenzyloxycarbonyl. with c The main manual, which describes the conditions of reactions and reagents, is (Admapsed Ogdapis Spetizighu, 4th ed., under the editorship of). Magsp, published dopyp UmMieu 5 bopz 1992, as well as "Rgoiesiime Zgotsirz ip Ogdapis Zupipeziv" , 2nd ed., edited by T. sgeep / others, also published Doip Umieu 4 op, as a basic guide to protective groups.

The starting substances of quinazoline of formula II can be obtained using conventional methods, such as (as described in international patent applications MO 01/94341 and M/O 02/163521Y, for example, 1,4-dihydroquinolin-4-one

Go! formulas IM («c) M (95)

Ge Sho 6, piz N z

M

(KK) GU g t A t M 60 where t and KE" have any of the meanings indicated above, except that any functional group, if necessary, is protected, may be reacted with a halogenating agent such as thionyl chloride, phosphoryl chloride or a mixture of carbon tetrachloride and triphenylphosphine, after which any protecting group present is removed by conventional methods, for the 4-Chloroquinazoline thus obtained can be converted, if necessary, into

4-pentafluorophenoxyquinazoline by reaction with pentafluorophenol in the presence of a suitable base such as potassium carbonate in the presence of a suitable solvent such as M,M-dimethylformamide.

Starting substances of 4-amino-2,3-methylenedioxypyridine (formula I, for example, if 7 is MM)

Can be obtained by conventional methods as described in the examples. The corresponding starting substances of 4-hydroxy- and 4-mercapto-2,3-methylenedioxypyridine (formula PS, if 7 represents O or 5, respectively) can be obtained using conventional techniques. (b) To obtain those compounds of formula I in which at least one EC group is a group of formula 07-X. where from! represents aryl-C1-C1-alkyl, C3-C1-cycloalkyl-C1-C1-alkyl,

C.-C,-cycloalkenyl-C.-C.-alkyl, heteroaryl-Ci-Cv-alkyl or heterocyclyl-Ci--Cv-alkyl group or an optionally substituted alkyl group and X' represents an oxygen atom, a combination, suitable in the presence of a suitable desiccant, quinazoline of formula M

IN

(B

M s (Kz 2 0) in (8) but her r Ge)

M o d) where t, B", 7, pi EZ have any of the values specified above, except that any functional group is, if necessary, protected with a suitable alcohol in which any functional group, if necessary, protected, after which any protecting group present is removed by conventional methods. A suitable drying agent is, for example, a carbodiimide reagent such as dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a mixture of an azo compound such such as diethyl or di-tert-butyl c azodicarboxylate and a phosphine such as triphenylphosphine. The reaction is suitably carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range of, for example, 10-1502C, preferably at or around ambient temperature . The reaction is suitably carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at (a) a temperature in the range of, for example, 10-150°C, preferably at or around ambient temperature environment (c) For the preparation of those compounds of formula I, in which the group KE" contains C.i-Cv-alkyloxy or substituted C.i-Cv-alkoxy o group or C.i-Cv-alkylamino or substituted C.i-Cv-alkylamino group, interaction, suitable in the presence of an acceptable base, as defined above, of a quinazoline derivative of the formula MI (name) 60 b5

3 MI (U) p

M chu 7 o'clock 0--/ still

M where I is a leaving group as defined above and 7 peak C has any of the above values except that any functional group is optionally protected with an alcohol or an amine that is c suitable, after which any protecting group present is removed by conventional methods. at

The reaction is suitably carried out in the presence of an acceptable inert diluent or carrier, as defined above, and at a temperature in the range of 10-1502C, preferably at 502 or about 5020. (7) To obtain those compounds of formula I, in which K" represents an amino- a substituted C 1 -C 1 -alkoxy group (such as 2-(d-methylpiperazin-1-yl)ethoxy or a 3-dimethylaminopropoxy group), the interaction of a compound of the formula | where B !c represents a halogen-substituted C 1 -C 1 -alkoxy group with a nitrogen-containing heterocyclic compound or a suitable amine.

The reaction is suitably carried out in the presence of an acceptable inert diluent or carrier, as defined in i) above, and at a temperature in the range of 10-1802C, preferably in the range of 60-12026. o (e) To obtain those compounds of the formula I, in which K " is an amino-hydroxy-disubstituted C 4-C 4-alkyl

With a group (such as 2-hydroxy-3-pyrrolidin-1-ylpropoxy or 3-|M-allyl-M-methylamino)|-2-hydroxypropoxy), interaction with compounds of formula I, in which the group EK! contains an epoxy-substituted C.1-C.sub.6-alkyl group with a heterocyclic compound or a suitable amine.

The reaction is suitably carried out in the presence of an acceptable inert diluent or carrier, as defined above, and at a temperature in the range of 10-1506C, preferably at or near ambient temperature. c (e) To obtain those compounds of the formula I, in which 7 is a ZO or 5О 5 group, oxidation of the compound "c" of the formula I, in which 7 is a 5-group.

Conventional oxidants and reaction conditions for such partial or complete oxidation of the sulfur atom are well known to those skilled in the art of organic chemistry. o (e) To obtain those compounds of formula I in which group B contains an M-acylated heterocyclic group, acylation, suitable in the presence of a suitable base, as defined above, of a quinazoline derivative of formula I in which group B! contains a heterocyclic group that has an unsubstituted MH group. Suitable acylating agents are well known to one of ordinary skill in the art and are exemplified in Example 50. For example, a compound of formula I, in which group B" contains a piperidinyl or piperazinyl group, which has an unsubstituted MH group, can be reacted under normal reaction conditions with an optionally substituted carboxylic acid or its reactive derivative.

A suitable reactive derivative of an optionally substituted carboxylic acid is, for example, a carboxylic acid halide; amide of carboxylic acid; a mixed anhydride, for example, an anhydride formed by the interaction of a carboxylic acid and a chloroformate, such as isobutyl chloroformate; the reaction product of a carboxylic acid with a carbodiimide, such as dicyclohexyl carbodiimide or 1-(3-dimethylaminopropyl)-3-ethyl i) carbodiimide; the reaction product of a carboxylic acid with a mixture of an azo compound, such as diethyl or di-tert-butyl ime) azodicarboxylate, and a phosphine, such as triphenylphosphine; or the reaction product of a carboxylic acid with a uronium salt, such as hexafluorophosphate (M) 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium. For example, a suitable amino-substituted carboxylic acid is MM-dimethylglycine and its suitable reactive derivative is 2-dimethylaminoacetyl chloride.

A suitable reaction is carried out in the presence of a suitable inert diluent or carrier, as defined above, and at a temperature in the range of 10 -1509C, preferably at or near ambient temperature. 65 If a pharmaceutically acceptable salt of a quinazoline derivative of formula I is desired, for example an acid addition salt, it can be obtained, for example, by reacting said quinazoline derivative with a suitable acid by conventional techniques.

Many of the intermediates described in this invention are novel and constitute an additional embodiment of the invention. For example, many compounds of the formula HER

PI

3) (short circuit)

M

IN

I NA o 0-/ IN y y y y where 7 represents 0, 5, or ShK 2) ip, VZ and 82 have any values indicated above, are new compounds.

For example, although the starting materials of 4-amino-2,3-methylenedioxypyridine (formula II, e.g. if 7 is MM) can be prepared by conventional techniques as described in the examples, compounds such as 4-amino-5-chloro- 2,3-methylenedioxypyridine, are new compounds that constitute an additional variant of the implementation of the invention.

Biological studies of Fr

The following studies can be used to determine the actions of the compounds according to the present invention as inhibitors of c-Zgs tyrosine kinases, as inhibitors in the conditions of the proliferation of c-Zgs transfected fibroblast cells, as inhibitors in the conditions of the migration of AB549 human lung tumor cells, as inhibitors in the under conditions of ip, growth in hairless mice of xenotransplanted tissues A549 and for inhibition under conditions of ip of mygo potassium channel, which is encoded by PEKO. | "c) (a) Study of the enzyme under conditions of ip migo so

The ability of the studied compounds to inhibit the phosphorylation of tyrosine in the polypeptide substrate by the enzyme c-Zgs kinase was evaluated using the generally accepted method of solid-phase enzyme immunoassay /C2 (Eiiva). co

Substrate solution (100 μg/ml solution of polyamino acids polybium, Tug) 4:1 (Zidt catalog according to MoRO275) in phosphate-buffered saline (PBS), which contains 0.2 mg/ml sodium azide. was added to each well of a 96-well immunoassay tablet (Mips) (catalogue number 439454) and the tablets were sealed and stored at 42C for 16 hours. The excess of the substrate solution was discarded, and aliquots of bovine serum albumin (BSA; 1500 μl of a 575,000 s solution in FBS) were transferred to each well for the study, which is covered with the substrate, and incubated for 1 hour at ambient temperature to block nonspecific binding. The wells of the studied tablets were washed alternately with FBS, which contains 0.05 vol. 95 tween with 20 (FBST) and Nerez buffer pH7.4 (50 mM, zOOμcl/well), after that they were blotted dry.

Each studied compound was dissolved in dimethylsulfoxide and diluted with distilled water, obtaining a series of dilutions (from 100 μM to 0.001 μM). Portions (25 μl) of each dilution of the studied compound were transferred to wells in washed tablets for research. "Common" control wells contained diluted

DMSO instead of compound. Aliquots (25 µl) of an aqueous solution of magnesium chloride (8 mM) containing co-adenosine-5'-triphosphate (ATP; 40 mM) were added to all tested wells, except for the "blank" control wells, which contained magnesium chloride without ATP.

Active human c-5gs kinase (recombinant enzyme expressed in insect 519 cells; obtained from Orzia (e Vioespoiodu Ips. product 14-117) was diluted immediately before use in the ratio

GI 1:10,000 enzyme solvent containing 100 mM Nerez buffer pH 7 4, 0.2 mM sodium orthovanadate, 2 mM dithiothreitol and 0.0295 BSA. To start the reaction, aliquots (5 µl) of freshly diluted enzyme were added to each well, and the plates were incubated at ambient temperature for 20 minutes.

The supernatant liquid in each well was discarded and the wells were washed twice with PBST. Mouse anti-phosphotyrosine antibodies (Orziaye Vioyespoiodu Ips. product 05-321; 100μl) were diluted in a ratio of 1:6000 PBST, which (F. contains 0.5 vol.96) and added to each well. The tablets were incubated for 1 hour at room temperature medium. The supernatant liquid was discarded and each well was washed with PBST (x4). Horseradish peroxidase (HPP)-coupled with sheep anti-mouse Id antibody (Ategepat catalog number MXA 931; 10µl) was diluted 1:500 in PBST, which contains 0.506b.95 BSA, and added to each well. The plates were incubated for 1 hour at ambient temperature. The supernatant liquid was discarded and the wells were washed with PBST (x4).

The ROZV capsule (Zidt catalog number P4922) was dissolved in distilled water (1000 ml), obtaining phosphate-citrate buffer pH5 (50 mM), which contains 0.0395 sodium perborate. An aliquot (5 Oml) of this buffer 65 was mixed with a tablet of 50 mg of 2,2'-azinobis(3-ethylbenzothiazoline-b-sulfonic acid) (ABTS; Voengipdeg catalog

Mo1204 521). Aliquots (100 μl) of the obtained solution were added to each well. The plates were incubated for 20 to 60 minutes at ambient temperature until the optical density of the "total" control wells, measured at 405 nm using a spectrophotometer for analyzing the plates, was approximately 1.0. "Blank" (without ATP) and "total" (without compound) control values were used to determine the concentration range of the tested compound, which provides inhibition of enzyme activity by 50905. (b) Proliferation study of fibroblasts transfected with c-Zgs MIN ZT3Z (c-5gs 313). in the conditions of ip mygo

With the help of this study, the ability of the tested compound to inhibit the proliferation of ZT3 fibroblast cells of mice from the National Institute of Health (MINH), which were stably transfected with an activating mutant (U5ZOE) of human c-5gs, was determined. 70 Using a technique similar to that described by Zpaomau et al. in Seiya 1987, 49, 65-73, MIN ZTZ3 cells were transfected with an activating mutant (U5Z30E) of human c-5gs. The obtained c-5gs ZTZ cells were seeded typically at a density of 1.5x107 cells per well in 96-well transparent plates for the study of treated tissue culture (Soviag), each of which contained a medium for the study, which includes Igla's medium, modified

Dulbecco's (OMEM; bidta) plus 0.595 fetal calf serum (FTS), 2 mM glutamine, 100 bod./ml penicillin, and 75 O.1 mg/ml streptomycin in 0.995 aqueous sodium chloride solution. Tablets were incubated overnight at 372 in a humidified incubator (7.595 CO2:9590 air).

The studied compounds were dissolved in DMSO, obtaining a 10 mM stock solution. Aliquots of the mother liquor were diluted with the OMEM medium described above and added to the appropriate wells. Serial dilutions were made to obtain the range of studied concentrations. Each plate had control wells where no test compound was added. Tablets were incubated overnight at 372C in a humid incubator (7.595 CO»2:95960 air).

The HgO-labeled reagent (Voepijipdeg Mapppeit catalog number 647 229) was diluted 1:100 in

OMEM medium containing 0.595 FBS, and aliquots (2 µM) were added to each well, giving a final concentration of 1 µM). Tablets were incubated at 37°C for 2 hours. The medium was drained. In every hole. A denaturing solution was added to the CM (RichOepai solution, Voephipdeg MapPpeit catalog number 647 2291; 5µM) and the tablets were placed in a tablet shaker at ambient temperature for 45 minutes.

The supernatant was drained and the wells were washed with FBS (200 μl per well). Anti-VaO-peroxidase solution (Voeyipdeg Mapppeit catalog number 647 229) was diluted 1:100 in FBS containing 195 BSA and 0.02595 dried skimmed milk (Magme! (registered trademark), Rgetieg Vemegadez, Statford, SW ) CM aliquot (100 μl) of the obtained solution was added to each well. Tablets were placed in a tablet shaker at ambient temperature for 90 minutes. Wells were washed with FBS (x5) to ensure removal of unbound antibody conjugate. The tablets were blotted dry and a solution of i) tetramethylbenzidine substrate was added to each well | catalog number Voepgipdeg Mapppeit 647 229); 100 μl). The tablets were gently shaken in a tablet shaker until no color appeared over a period of 10 to 20 minutes. The optical density of the wells was measured at b9 Ohm. The amount of CO cell proliferation inhibition was determined in the range of concentrations for each studied compound and the antiproliferative IC value was calculated. (c) Study of microdroplet migration under the conditions of ip mygo "

In this study, the ability of the investigated compound to inhibit the migration of attached mammalian cell lines, for example, the human tumor cell line A5B49, was determined. t s KRMI medium (Zidta), which contains 1095 FTS, 190 I-glutamine and 0.390 agarose (Oso catalog Mo0142-011), "" was heated to 372C in a water bath. The mother 295 aqueous agar solution was autoclaved and stored at 4296. " An aliquot (1.5 ml) of agar solution was added to the KRMI medium (1 Oml) immediately before use.

AB49 cells (registration MOATSS SSI 185) were suspended at a concentration of 2x10' cells/ml in the medium and maintained at a temperature of 3726.

A drop (2 µl) of the cell/agarose mixture was pipetted into the center of each well of a 9b-well (a) flat-bottom microtiter plate with untreated tissue culture (Virbu eepgiip catalog

Mob42000). The tablets were briefly placed on ice to rapidly solidify the drops containing agarose. Aliquots (9µl) of the medium cooled to 42С were transferred to each well, this operation was carried out carefully so as not to destroy the microdroplets. The studied compounds were diluted with a 10 mM stock solution in DMSO,

Kz using KRMI medium as described above. Aliquots (1 µl) of diluted test compounds were transferred to the wells, this operation was also carried out carefully so as not to destroy the microdroplets. Tablets were incubated at 372C in a humid incubator (7.595 CO2:9595 air) for approximately 48 hours.

Migration was assessed visually and the distance of migration was measured to the edge of the agar drop. Inhibition of IC migration was determined by constructing curves of the average migration value measured at the concentration

HF) of the studied compound. d (d) Study of the growth of A5B49 xenotransplants in the conditions of IP mimo

In this study, the ability of the compounds to inhibit the growth of human carcinoma A5b49 as a tumor in 60 athymic hairless mice (line AIdegieu Ragk pi/pi) was determined. In total, approximately 5x109 AB49 cells in matrigel

Catalog of VesKiop OisKipwop Mo40234| was injected into the left rear lateral part of the trunk of each studied mouse by subcutaneous injection, and the resulting tumors grew for 14 days. The size of the tumor was measured twice a week using a caliper and the theoretical volume of the tumor was calculated. The animals were divided into control and treatment groups based on approximately the same mean tumor volume. 65 Test compounds were prepared as a granular suspension in 196 polysorbate filler and administered orally once daily for approximately 28 days. The effect on tumor growth was determined.

(e) Inhibition study of the potassium channel encoded by NEKO

In this study, the ability of the test compound to inhibit the residual current that passes through the potassium channel, which is encoded by PECO, was determined.

Human embryonic kidney (HEK) cells expressing the PECO-encoded channel were grown in Eagle's minimal essential medium (EMEM; (Zidta-Aidgis catalog number M2279)) supplemented with 1095 fetal calf serum (I abiesip Ipiegpaiopa!; product number 4-101 -500), with 1095 M1 serum-free supplement (Edd Thesppoiodiev; product number 70916) and 04 mg/ml Sepeiyisip 5418 |Zidta-Agiagispi; catalog number 7034). One or two days prior to each experiment, cells were isolated from tissue culture flasks using accutase (Assciase) (TO Bioiodase) using standard tissue culture methods.

Then they were placed on glass coverslips and left in the wells of a 12-well plate and covered with 2 ml of growth medium.

For each recorded cell, a glass coverslip containing the cells was placed on the bottom of the chamber

Reggreh containing solution for incubation (see below) at ambient temperature (5202). This 75 camera was fixed on the stage of an inverted phase-contrast microscope. Immediately after placing the cover glass in the chamber, the incubation solution was perfused into the chamber from the gravity reservoir for 2 minutes at a rate of 2 ml/min. After that, the perfusion was stopped.

A small pipette made of borosilicate glass tube, (zC120E, Nagmaga Arragai5), using

P-97 micropipette ejector (Ziuybeg Ipzigitepi So.) was filled with pipette solution (see below). The pipette was connected to the main unit of the "raisp-siatr" amplifier (Ahoraispy 2008, Ahop Ipvigitepiv) using a silver/silver chloride wire. The grounding device of the main unit was connected to the grounding electrode. It consisted of a silver/silver chloride wire immersed in 395 agar prepared with 0.85905 sodium chloride.

Cells were recorded in the "whole cell" configuration of the "raisp siatr" method. After the "trial", which was carried out at the output potential of -VOmV (set by the amplifier), and the corresponding correction of the additional resistance of the capacitive resistance of the controls, electrophysiological support (Siatrekh, Ahop Ipvigitepiv) was used to set the output potential (-380mV) and submit the voltage protocol. This protocol was applied every 15 o seconds and consisted of a 1s step to nk4O0mV followed by a 1s step to -50mV. For the corresponding current, each applied voltage protocol was low-pass filtered with an amplifier at 1kHz. Then the filtered signal was quickly obtained by converting this analog signal from the amplifier to a digital one in a digital converter. Then the signal, converted to digital form, was recorded using the Siatrekh computer software (Ahop Ipzigitepiv). Current was sampled at kHz during the initial potential and at the stage up to 40 mV. Then the sampling frequency c was set to 5kHz for the rest of the voltage protocol.

The composition, pH and osmolality of the solution for incubation and the solution for the pipette are given in the table presented below. (oo) ma 10000305 « o Z - i . that's it! 000106 has 8111

BT 16111 (ee)

F s i at

Co.)

The amplitude of the residual current of the potassium channel, which is coded by PEKOS, after the stage from n40mV to -50mV, was quickly recorded using the software Siatrekh (Akhop Ipzigitepiv). After stabilization of the amplitude of the residual current, the incubation solution, which contains the solvent for the tested compound, was applied to the cell. Provided that the use of solvent did not significantly affect the amplitude

Ф) of the residual current, after which the general action curve for the compound was constructed depending on the concentration. The action of the tested compound for each tested concentration was quantified by expressing the amplitude of the residual current for a given concentration of the tested compound in percentage terms in comparison with the presence of the solvent. The efficacy of the test compound (IC) was determined by processing the percentage inhibition values obtained for the concentration-effect relationship for the four parameters of the Hill equation using a standard data processing package. If the obtained level of inhibition for the highest tested concentration did not exceed 5095, no efficiency values were obtained and the percentage inhibition value for this concentration was given in quotation marks. 65 Research of cytochrome P450 isoenzymes can be carried out using standard methods.

Although the pharmacological properties of compounds of formula I differ due to structural differences, as expected, in general, compounds of formula | have activity at the following concentrations or doses in one or more of the above studies (a), (b), (c) and (d):

Test (a): IS in the interval, for example, 0.001-10 μmol;

Test (6): IC in the interval, for example, 0.01-20 μmol;

Test (c): activity in the interval, for example, 0.1-25μmol;

Test (g): activity in the interval, for example, 1-200mg/kg/day.

In general, many of the preferred compounds of formula I, which are described below as examples, have activity at the following concentrations or doses in one or more of the above tests (a), (b), (c) and (d): 70 Test (a): IC in the interval, for example, 0.001-10 μmol;

Test (6): IS in the interval, for example, 0.01 µmole;

Experiment (c): activity in the interval, for example, 0.1 µmole;

Test (g): activity in the interval, for example, 1-200mg/kg/day.

The tested compounds according to the present invention did not show physiologically unacceptable toxic effects in 7/5 study (g) when administered in effective doses. Thus, no adverse toxic effects are expected upon administration of a compound of formula I or a pharmaceutically acceptable salt thereof, as defined above, in the dose range specified below.

According to a further embodiment of the invention, a pharmaceutical composition is provided which contains a quinazoline derivative of formula I or a pharmaceutically acceptable salt thereof, as indicated above, in combination with a pharmaceutically acceptable diluent or carrier.

The compositions of the invention may be in forms suitable for oral administration (eg, tablets, pellets, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for local administration ( for example, in the form of pastes, ointments, gels, aqueous or oily solutions or suspensions), for administration by inhalation (for example, in the form of a finely divided powder or liquid aerosol), for administration by inhalation (for example, in the form of a finely divided powder), or for parenteral administration (for example, in the form of a sterile and) aqueous or oily solution for intravenous, subcutaneous, intramuscular administration, or in the form of a suppository for rectal administration).

Compositions according to the invention can be obtained by conventional methods using conventional pharmaceutical excipients well known in this field. Thus, compositions intended for oral administration may contain, for example, one or more dyes, sweeteners, flavorings and/or preservatives. with

The amount of active ingredient that is required to obtain a single dosage form in combination with one or more excipients mainly depends on the organism to be treated and on the specific route of administration. For example, a dosage form intended for oral administration to humans, as a rule, contains, for example, from 0.bmg to 00.bg of the active substance (more preferably from 0.5 to 1000mg, for example from 1 to 30mg) in combination with a suitable and an acceptable amount of fillers, which can vary from about 5 to about 98 95 of the total weight of the composition.

The dose of a compound of formula I for treatment or prophylaxis usually varies depending on the nature and severity of the conditions, the age and sex of the animal or human, and the route of administration, and is determined according to well-known approaches in medicine. . The compound of formula I, which is used for treatment or prevention, is usually administered in a daily dose in i? interval, for example, from 0.1 mg/kg to 75 mg/kg of the patient's body weight, and, if necessary, can be divided into several doses. In general, lower doses are used for parenteral administration. So, for example, for intravenous administration, a dose in the interval, for example, from 0.1mg/kg to ZOmg/kg is usually used

Go! body weight Similarly, for administration by inhalation, a dose in the interval, for example, from

O,O5mg/kg to 25mg/kg of body weight. Oral administration, usually in tablet form, is preferred, however. o Of course, a standard dosage contains from about 0.5 mg to 0.5 g of a compound according to the present invention. 2) According to a further embodiment of the invention, a quinazoline derivative of formula I or a pharmaceutically acceptable salt thereof, as defined above, is provided for use in a method of therapeutic treatment for humans or animals.

Ge As mentioned above, it is known that the dominant role of the non-receptor tyrosykinase c-Zgs is in the regulation of cell motility, which is necessary for the progression of a localized tumor through the stages of dissemination through the bloodstream, invasion into other tissues, and initiation of the growth of metastatic tumors. We found that quinazoline derivatives according to the present invention have an effective antitumor effect, which is believed to be achieved by inhibiting one or more tyrosine-specific non-receptor protein kinases, such as c-5gs (F) kinase, which are involved in the stepwise transmission of signals that determine the invasiveness and migration ability of metastasizing tumor cells.

Thus, the quinazoline derivatives of the present invention are valuable as antitumor agents, particularly as selective inhibitors of the motility, dissemination and invasiveness of malignant mammalian cells, resulting in the inhibition of metastatic tumor growth. More preferably, the quinazoline derivatives of the present invention are valuable as anti-invasive agents for controlling the spread and/or treating solid tumor disease. More preferably, the compounds of the present invention are expected to be useful for the prevention or treatment of those tumors that are sensitive to the inhibition of one or more of the various non-receptor 65 tyrosine kinases, such as c-5gs kinase, involved in the signaling cascade that drives invasiveness. and the ability of metastasizing tumor cells to migrate. In addition, the compounds of the present invention are expected to be useful in the prevention or treatment of those tumors that are mediated by inhibition of the c-5gs enzyme only, or by partial inhibition of this enzyme, i.e., the compounds can be used to produce an inhibitory effect on the c-5gs enzyme in a warm-blooded animal that needs one

Treatment. As expected, the compounds of the present invention are particularly useful for the prevention or treatment of solid tumor disease.

According to this embodiment of the invention, there is provided a quinazoline derivative of formula I or a pharmaceutically acceptable salt thereof, as defined above, for use as an anti-invasive agent for controlling the spread and/or treating solid tumor disease. 70 According to a further embodiment of the invention, the use of a quinazoline derivative of formula I or a pharmaceutically acceptable salt thereof, as defined above, is provided for the preparation of a medicinal product for use as an anti-invasive agent for controlling the spread and/or treating a solid tumor disease.

According to a further embodiment of the invention, there is provided a method of obtaining an anti-invasive effect 7/5 by restraining the spread and/or treating a solid tumor disease in a warm-blooded animal, such as a human, in need of such treatment, which involves administering to said animal an effective amount of a quinazoline derivative of formula I or of its pharmaceutically acceptable salt as defined above.

According to a further embodiment of the invention, the use of a quinazoline derivative of formula I or a pharmaceutically acceptable salt thereof, as defined above, is provided for the preparation of a medicinal product 2o for use in the prevention or treatment of solid tumor disease in a warm-blooded animal, such as a human.

According to a further embodiment of the invention, there is provided a method of preventing or treating a solid tumor disease in a warm-blooded animal, such as a human, in need of such treatment, which involves administering to said animal an effective amount of a quinazoline derivative of the formula | or a pharmaceutically acceptable salt thereof as defined above.

According to a further embodiment of the invention, there is provided the use of a quinazoline derivative (8) of formula I or a pharmaceutically acceptable salt thereof, as defined above, for the preparation of a medicament for use in the prevention or treatment of those tumors which are sensitive to inhibition of non-receptor tyrosine kinases, such as -5gs kinase involved in the step-by-step transmission of signals that cause invasiveness and the ability to migrate metastasizing tumor cells.

According to a further embodiment of the invention, there is provided a method of preventing or treating those tumors that are sensitive to the inhibition of non-receptor tyrosine kinases, such as c-Zgs kinase, which are involved in step-by-step signaling that determines the invasiveness and migration ability of metastasizing tumor cells, which involves the introduction of an effective amount of a quinazoline derivative of the formula | or a pharmaceutically acceptable salt thereof, as defined above. co

According to a further embodiment of the invention, the use of a quinazoline derivative of formula I or its pharmaceutically acceptable salt, as defined above, is provided for the preparation of a medicinal product for use to obtain an inhibitory effect on c-Zgs kinase.

The anticancer treatment described above can be used as monotherapy, or, in addition to the quinazoline derivative according to the invention, conventional surgical methods or radiotherapy or pt) with chemotherapy can also be used. Such chemotherapy may include one or more of the following classes of anticancer agents: () other anti-invasive agents (eg, metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activator receptor function); (i) antiproliferative/antitumor drugs and their combinations used in oncology, such as alkylating agents (for example, cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,

Go! chlorambucil, busulfan and nitrosoureas); antimetabolites (eg antifolates such as fluoropyrimidines such as B5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea; o antitumor antibiotics (eg anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, 2) epirubicin, idarubicin , mitomycin-C, dactinomycin and mithramycin); antimitotic agents (eg, periwinkle alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxoids such as taxol and taxotere); and o topoisomerase inhibitors (eg, epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and

Ge camphothecin); (her) cytostatic agents, such as anti-estrogens (eg, tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxifen), antiandrogens (eg, bicalutamide, flutamide, nilutamide, and dv Cyproterone acetate), HNKN antagonists or agonists | NCNs (eg goserelin, leuprorelin and buserelin), progestogens (eg megestrol acetate), aromatase inhibitors (eg anastrozole, letrozole, vorazole and

F) exemestane) and 5a-reductase inhibitors, such as finasteride; ka(im) growth factor inhibitors, for example, such inhibitors include growth factor antibodies, growth factor receptor antibodies (eg, anti-egtoB2 antibody trastuzumab (|Negseriiptm| and anti-egB1 bo antibody cetuximab |C225)), farnesyltransferase inhibitors . quinazolin-4-amine (gefitinib, 201839), M-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, 051-774). and b-acrylamido-M- (3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example, inhibitors of the platelet-derived growth factor b5 family and, for example, inhibitors of the hepatocyte growth factor family; (M) antiangiogenic substances, such as those that inhibit the action of vascular endothelial growth factor, (for example,

antibody to vascular endothelial growth factor bevacizumab (|Amaviiptm|, compounds that (described in international patent applications MUO 97/22596, MO 97/30035, MO 97/32856 and MO 98/133541) and compounds that act by a different mechanism (e.g., linomid, AMVZ integrin inhibitors, and angiostatin); (mi) substances that damage vessels, such as combretastatin A4 and compounds (described in international patent applications UMO 99/02166, MO 00/40529, UMO 00/41669 , UMO 01/92224, MO 02/04434 and MO 02/082131; (my) antisense therapy, e.g., one that targets the targets listed above, such as I5I5 2503, antisense therapy based on the hav gene; (my) methods gene therapy, including, for example, methods of replacing aberrant genes, such as methods of 7/o aberration of roZ or aberration of VKSAT or VKSA2, SOERT (prodrug therapy directed at the enzyme gene) methods using cytosine deaminase, thymidine kinase or bacterial nitroreductase and methods of increasing resistance the patient to chemotherapy or radiotherapy therapies such as gene therapy for multidrug resistance; and (their) methods of immunotherapy, including, for example, methods of increasing the immunogenicity of tumor cells /5 of the patient in ex mimo and ip mimo conditions, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, methods of reducing the activity of T -cells, methods using transfected immune cells, such as cytokine-transfected dendritic cells, methods using cytokine-transfected tumor cell lines and methods using anti-idiotypic antibodies.

Such combined treatment can be carried out by simultaneous, sequential or separate administration of individual components for treatment. Such combination products contain compounds according to the present invention within the applicable doses described earlier in this invention and another pharmaceutically active substance within the applicable doses.

According to this variant implementation of the invention, a dosage form is provided which contains a quinazoline derivative of formula I, as indicated above, and an additional antitumor agent, as indicated above, for the combined treatment of a malignant neoplasm. at

Although the compounds of formula I are primarily valuable as therapeutic agents for use in warm-blooded animals (including humans), they are also useful in those cases where it is desired to inhibit the actions of c-Zgso. Thus, they are useful as pharmacological standards for use in the development of Ha

New biological test systems and for the search for new pharmacological agents.

Further, the invention is illustrated by the following examples, in which, as a rule: o (Y) actions were carried out at ambient temperature, that is, in the range of 17-259C and in the atmosphere of an inert gas such as argon, unless specifically indicated otherwise; (i) evaporation was carried out by rotary evaporation in a vacuum, and the usual treatment procedure was carried out after removing the remains of solid substances by filtration; ee(ii) column chromatography (using the flash method) and medium pressure liquid chromatography (MI ROS) were carried out on silicon dioxide MegsKk KiezeiYide! (Ag. 9385) or Megsk Iispgorger, KR-18 (Ag. 9303) reversed-phase silica obtained from E. MegskK, Darmstadt, Germany or high-pressure liquid chromatography (HPLC) was performed on C18 reversed-phase silica , for example on a preparative column with an inverted phase Yuupatakh C-18 bOA; - with (im) for the outputs, if they are presented, the maximum values may not necessarily be reached; ts (M) in general, the final products of the formula | had sufficient microanalysis and their structure was confirmed by nuclear magnetic resonance (NMR) and/or mass spectral methods; mass spectral data were usually obtained by fast atom bombardment (FAB) using a Riakogt spectrometer, and, if appropriate, data of positively charged ions or data of negatively charged ions were collected; NMR values of chemical (ee) shifts were measured on the delta scale (proton magnetic resonance spectra were measured using a UCheoi MM EX 400 spectrometer, operating at a field strength of 400 MHz, a Magiap Setipi 2000 spectrometer, o working at field strength ZOOMHCts, or spectrometer Vhykeg AMZ3Z0O0, working at field strength

LLC ZOOMG these; the following abbreviations were used: 5, singlet; 4, doublet; Her, triplet; d, quartet; t, multiplet; Bg, wide; o(mi) intermediates were generally not fully characterized and purity was determined using

From thin-layer chromatography, NRI C, infrared (IR) and/or NMR analyses; (my) melting points are unrelated and were determined using an automatic device for determining the melting points of MeshSheg 5Rb2 or an oil bath device; melting points for the final products of the formula | determined after crystallization from a common organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in addition; o (my) if certain compounds are obtained as an acid addition salt, for example, a monohydrochloride salt or a dihydrochloride salt, then the stoichiometry of the salt is determined based on the number and nature of the basic groups in the compound, the exact stereochemistry of the salt is usually not determined, for example, using elemental analysis data; (their) when the substituent on the amino group in the 4th position of the quinazoline ring is described, the following chemical nomenclature "2,3-methylenedioxypyrid-4-yl" is used in the following examples, while in the description and in the claims of the patent application this group is often described as a 2,3-methylenedioxypyridin-4-yl group"; to avoid any ambiguity, it is meant that each of these terms refers to the group of the formula b5 t- cm and o oZ--/ (C the following abbreviations are used:

DMF M,M-dimethylformamide

DMSO dimethylsulfoxide

THF tetrahydrofuran

DMA M,M-dimethylacetamide

Example 1 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(3-chloropropoxy)-6-methoxyquinazoline

Sodium hexamethyldisilazane M solution in TIF; 0.734 ml) was added to a solution of 4-amino-5-chloro-2,3-methylenedioxypyridine (0.12 g) in DMF (4 ml), which was cooled to 0 2С, and the mixture was stirred for 15 minutes. A portion (0.1 g) of 4-chloro-7-(3-chloropropoxy)-6-methoxyquinazoline was added and the resulting mixture was stirred and allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous solution of ammonium chloride. The organic phase c was washed with water and saline solution, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography using mixtures of increasing polarity of methylene chloride and ethyl acetate as eluent, followed by mixtures of increasing polarity of methylene chloride and acetonitrile. In this way, the title compound was obtained in the form of a white foam (0.11 g); NMR spectrum: (dDMSOav and СО5СО020) 2.3 (t, 2H), 3.8 (t, 2H), 4.05 (v, 3H), 44 (y 2H), 6.3 (v, 2H) , 7.4 (8, 1H), 7.9 (c, 1H), 8.15 (c, 1H), 8.95 (c, 1H); Mass spectrum: MAN" 423 and 425. av 4-Amino-5-chloro-2,3-methylenedioxypyridine, which was used as a starting material, was obtained in the following way:

Bromochloromethane (20 ml) was added to a mixture of 5-chloro-2,3-dihydroxypyridine (ZOg), cesium carbonate (1007) and "Z

DMF (100ml), and the mixture was stirred and heated to 90°C for 3.5 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was purified by column chromatography on silica using methylene chloride as eluent. In this way, 5-chloro-2,3-methylenedioxypyridine was obtained in the form of a white solid (4.7 g); NMR spectrum: (DMSOa in) 6.25 (8, 2H), 7.5 (in, 1H), 7.65 (in, 1H). « du A mixture of diisopropylamine (8.2ml) and THF (100ml) was cooled to -702С and n-butyllithium - (2.5M in hexane, 24ml) was added dropwise. The mixture was stirred at -709С for an additional 20 minutes. Solution

SOovoloro from min and chloro-2,3-methylenedioxypyridine (4.2g) in THF (40ml) was added over 10 minutes and the reaction mixture was stirred at -702C for 1 hour. Anhydrous carbon dioxide was bubbled into the reaction mixture for 30 minutes. The resulting reaction mixture was allowed to warm up to the temperature of the surrounding heath. Water (20 ml) was added and the organic solvent was evaporated. The residue was acidified to pH2 by

Go! addition of 1 n. aqueous solution of hydrochloric acid. The resulting solid was isolated and washed successively with water and diethyl ether and dried in a vacuum at 409C. B-chloro-2,3-methylenedioxypyridine-4-carboxylic acid (3,6) was obtained in this way; C NMR spectrum: (DMSOdv) 103, 120, 121, 138, (95) 140, 158, 163.

The mixture of substances obtained in this way, diphenylphosphorylazide (3.bml), anhydrous tert-butanol (13.5ml), triethylamine (4.2ml) and 1,4-dioxane (b3ml) was stirred and heated to 1009 for 3 hours. The mixture was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica using a 9:11 mixture of methylene chloride and ethyl acetate as eluent. In this way, tert-butyl 5-chloro-2,3-methylenedioxypyrid-4-ylcarbamate (3.8g) was obtained; NMR spectrum: (DMSOdv) 1.45 (v, 9H), 6.2 (v, o 2H), 7.7 (8, 1H), 9.2 (8, 1H).

The substance obtained in this way was dissolved in methylene chloride (35 ml) and the solution was cooled to 02s. ime) Trifluoroacetic acid (1 bml) was added and the mixture was stirred at 09 for 3 hours. The mixture was allowed to warm to ambient temperature and stirred for 16 hours. Solvent 60 was evaporated and the residue was diluted with a mixture of water and ice and neutralized to pH 7 by adding 2 n. of an aqueous solution of sodium hydroxide, at this time the temperature of the mixture was maintained at 02С. The resulting mixture was extracted with methylene chloride and the extract was dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica using a 19:11 mixture of methylene chloride and diethyl ether as eluent. 4-amino-5-chloro-2,3-methylenedioxypyridine (2g) was obtained in this way; for NMR spectrum: (DMSOdv) 6.1 (5, 2H), 6.2 (8, 2H), 7.45 (in, 1H); C NMR spectrum: (DMSOdv) 100, 112, 125, 136, 138,

157; Mass spectrum: MAN" 173. 4-Chloro-7-(3-chloropropoxy)-6-methoxyquinazoline, which was used as a starting material, was obtained as follows:

Ammonium formate (45g) was added in portions over 1 hour and 15 minutes to a stirred mixture of 7-benzyloxy-6b-methoxy-3,4-dihydroquinazolin-4-one (international patent application UMO 02/163521, example 1 given therein; 20g) , 10950 palladium-on-charcoal catalyst (3.3g), its DMF (53Oml) and the reaction mixture were stirred for an additional 30 minutes. The catalyst was removed by filtration and the solvent was evaporated. In this way, 7-hydroxy-b-methoxy-3,4-dihydroquinazolin-4-one (8.65 g) was obtained; NMR spectrum: (DMSOYAv) 3.9 (in, ЗН), 70...7.0 (in, 1Н), 7.45 (8, 1Н), 7.9 (in, 1Н).

The mixture of substances obtained in this way, acetic anhydride (b3 ml) and pyridine (7.5 ml) was heated to 1002 for 4.5 hours. The resulting mixture was left to settle at ambient temperature for 16 hours. The mixture was poured into a stirred mixture (400 ml) of ice and water. The resulting precipitate was isolated and dried in a vacuum. During the analysis, it was established that the hydrolysis of the acetate group in the 4th position of quinazoline was 75 incomplete. Therefore, the mixture was further hydrolyzed with water (1500 ml) and pyridine (several drops) at 9023 for minutes. The resulting mixture was cooled to ambient temperature and the solid was collected by filtration, washed with water and dried under vacuum. In this way, 7-acetoxy-b-methoxy-3,4-dihydroquinazolin-4-one (7.4g) was obtained; NMR spectrum: (DMSOd) 2.3 (85, ЗН), 3.9 (в, ЗН), 7.45 (85, 1Н), 7.65 (в, 1Н), 8.05 (в, 1Н ).

A mixture of part (2 g) of the substance obtained in this way, thionyl chloride (32 ml) and DMF (5 drops) was stirred and heated in a reflux flask for 1.5 hours. The mixture was cooled to ambient temperature and excess thionyl chloride was evaporated. Toluene was added to the residue and evaporated. The obtained residue was diluted with methylene chloride (15 ml) and a 10:1 mixture (80 ml) of methanol and a saturated aqueous solution of ammonium hydroxide was added. The resulting mixture was stirred and heated to 809 for 10 D/CM minutes. The mixture was cooled to ambient temperature and evaporated. Water was added to the residue and the mixture was neutralized by adding a dilute aqueous solution of hydrochloric acid. The resulting precipitate was collected by filtration and dried in a vacuum at 3523 for 16 hours. 4-chloro-7-hydroxy-b6-methoxyquinazoline (1.65 g) was obtained in this way;) NMR spectrum: (DMSOαb) 4.0 (v, 3H), 7.25 (8, 1H), 7.4 (c, 1H), 8.8 (8, 1H). Gee!

Di-tert-butyl azodicarboxylate (2.3g) was added in portions over several minutes to a stirred mixture of 4-chloro-7-hydroxy-b-methoxyquinazoline (1.65g), 3-chloropropanol (0.7ml), triphenylphosphine (2. 6g) and methylene chloride (10 Oml) and the reaction mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated to a volume of about 30 ml by evaporation and the residue was purified by column chromatography on silica using mixtures of increasing polarity of petroleum ether (40-6092) and ethyl acetate as eluent. In this way, 4-chloro-7-(33-chloropropoxy)-6-methoxyquinazoline was obtained as a white solid (2g); NMR spectrum: (DMSOa in) 2.3 (t, 2H), 3.8 (t, 2H), 4.05 (in, 3H), 4.4 (t, 2H), 7.45 (8, 1H), 7.55 (in, 1H), 8.9 (in, 1H).

Example 2 « 7-(2-chloroethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-methoxyquinazoline

Using a technique similar to that described in example 1, 4-chloro-7-(2-chloroethoxy)-b-methoxyquinazoline C was subjected to interaction with 4-amino-5-chloro-2,3-methylenedioxypyridine, obtaining the title compound at » outputs 9296; NMR spectrum: (DMSOYav and 2032050) 405 (8, ЗН), 4.1 (6 2Н), 4.55 (6 2Н), 6.3 (в, 2Н), 74 (в, 1Н), 7, 9 (c, 1H), 8.15 (c, 1H), 8.95 (c, 1H); Mass spectrum: MAN" 409 and 411. 4-Chloro-7-(2-chloroethoxy)-6-methoxyquinazoline, which was used as a starting material, was obtained as follows: 1,2-Dichloroethane (400 ml) was added to the stirred mixture 7-hydroxy-b-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (international patent application UUO 02/16352, example 2, note (41); 85g), potassium carbonate (77g) Her DMF (400 mL), and the reaction mixture was heated to 702 °C for 16 h. The reaction mixture was cooled to ambient temperature and filtered at (α) 20. The filtrate was evaporated and the solid thus obtained was washed with water and dried

Kz over phosphorus pentoxide at 502С. The substance obtained in this way was purified by means of column chromatography on silicon dioxide, using mixtures of increasing polarity of methylene chloride and ethyl acetate as an eluent. 7-(2-chloroethoxy)-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one was obtained in this way as a white solid (65,67); NMR spectrum: (SOSI") 1.2 (v, 9H), 3.9 (B 2H), 4.0 (v, ЗН), 4.4 (5 2H), 5.95 (v, 2H), 7.1 (v, 1H), (F; 7.7 (8, 1H), 8.2 (5, 1H); Mass spectrum: MAN" 369 and 371. ka A mixture of substances obtained in this way and a saturated solution of gaseous of ammonia in methanol (1.bl) was stirred at ambient temperature for 2 days. The solvent was concentrated by evaporation to about 1/4 of the original volume and the precipitate was collected by filtration and washed with diethyl ether. This gave 7-(2- chloroethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one in the form of a white solid (44g); NMR spectrum: (DMSOdv) 3.9 (in, 3H), 4.05 (in 2H), 44 (, 2H), 7.15 (in, 1H), 7.45 (in, 1H), 8.0 (in, 1H); Mass spectrum: MAN" 255 and 257.

A mixture of a portion (5 g) of the substance obtained in this way, thionyl chloride (28 ml) and DMF (0.7 ml) was stirred and heated to 8023 for 1.5 hours. Excess thionyl chloride was evaporated, toluene was added and evaporated.

The solid that remained was suspended in ice water and basified to pH 7 by adding 2 N. of an aqueous solution of sodium hydroxide, after which a saturated aqueous solution of sodium bicarbonate was added. The resulting solid was collected by filtration, washed with water and diethyl ether, and dried over phosphorus pentoxide under vacuum. The substance obtained in this way was purified by means of column chromatography on silicon dioxide, using mixtures of increasing polarity of methylene chloride and acetonitrile as an eluent. 4-chloro-7-(2-chloroethoxy)-6-methoxyquinazoline (3.06bg) was obtained in this way; NMR spectrum: (SOCI3) 3.95 (h, 2H), 4.1 (h, 3H), 4.5 (h, 2H), 7.35 (h, 1H), 7.45 (h, 1H ), 8.9 (in, 1H); Mass spectrum: MAN" 273 and 275.

Example C 70 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-b-methoxy-7-(3-(4-prop-2-ynylpiperazin-1-yl)propoxy)quinazoline

A mixture of 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(3-chloropropoxy)-6-methoxyquinazoline (0.08 g), 1-prop-2-ynylpiperazine (0.047 g), potassium iodide (0.01g) and DMA (2ml) were mixed and heated to 802C for 3.5 hours. The solvent was evaporated and the residue was partitioned between methylene chloride and saturated aqueous ammonium chloride. The organic phase was dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica using a 19:11 mixture of methylene chloride and methanol and then a 9:11 mixture of methylene chloride and saturated methanolic ammonium as eluent. The resulting resin was ground into powder in diethyl ether. In this way, the title compound was obtained as a solid (0.066 mg); NMR spectrum: (DMSOa b and SRzSO20O) 2.3 (t, 2H), 3.2-3.6 (rg t, 10H), 3.75 (5, 1H), 3.95 (rg 85, 2H ), 4.0 (v, 3H), 4.35 (t, 2H), 6.3 (v, 2H), 7.4 (8, 1H), 7.9 (8, 1H), 8.15 (c, 1H), 8.95 (c, 1H); Mass spectrum: MAN"511 and 513. 1-Prop-2-ynylpiperazine, which was used as a starting material, was obtained as follows:

Propargyl bromide (8095 solution in toluene; 40ml) was added dropwise over 10 minutes to a stirred mixture of 1-tert-butoxycarbonylpiperazine (50g), potassium carbonate (74.2g) and acetonitrile (2L), which was cooled to 02Сb. The mixture was stirred for 1.5 hours and allowed to warm to ambient temperature. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica using mixtures of increasing polarity of methylene chloride and ethyl acetate as eluent. In this way, tert-butyl 4-prop-2-ynylpiperazine-1-carboxylate was obtained in the form of oil (45.5 g); NMR spectrum: (SOSI") 1.4 (in, 9H), 2.2 (8, 1H), 2.45 (t, 4H), 3.3 (5, 2H), 3.45 (t, 4H).

A solution of the substance obtained in this way in methylene chloride (100 ml) was slowly added to a solution of CM hydrogen chloride gas in 1,4-dioxane (4M, 4500 ml). The reaction was slightly exothermic, a precipitate was formed, and carbon dioxide was also released. The mixture was stirred at ambient temperature for 1 hour. The resulting mixture was evaporated and the residue was suspended in methylene chloride. A solution of gaseous ammonia in methanol (7M, 11 Oml) was added and the mixture was stirred at ambient temperature for 15 minutes. The mixture was filtered and the filtrate was evaporated. Oil was obtained, which crystallized upon settling. In this way, 1-prop-2-inylpiperazine (23g) was obtained; NMR spectrum: (SOSI) 2.2 (in, 1), 2.5. FO (Bg 5, 4H), 2.85 (t, 4H), 3.25 (in, 2H).

Example 4 7-(2-chloroethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-tetrahydropyran-4-yloxyquinazoline "

Using a technique similar to that described in example 1, 4-chloro-7-(2-chloroethoxy)-5-tetrahydropyran-4-yloxyquinazoline was subjected to interaction with ts 4-amino-5-chloro-2,3-methylenedioxypyridine, obtaining the specified in the title, the compound at the exit is 37905; "» NMR spectrum: (SOSI) 2.0 (t, 2H), 2.3 (t, 2H), 3.65 (t, 2H), 3.9 (t, 2H), 4.1 (t , 2H), 4.4 (t, 2H), 4.8 (t, " 1H), 6.2 (5, 2H), 6.65 (v, 1H), 6.9 (v, 1H), 7.8 (c, 1H), 8.6 (c, 1H), 9.5 (c, 1H); Mass spectrum: MAN" 479 and 481. 4-Chloro-7-(2-chloroethoxy)-5-tetrahydropyran-4-yloxyquinazoline, which was used as a starting material, was obtained as follows: di-tert-butyl azodicarboxylate (0.338 g) was added to stirred mixture of 4-chloro-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline (international patent application MO 01/94341, example 15, note (101); 0.25g), 2-chloroethanol (0.07ml), triphenylphosphine (0.385g) and methylene chloride (15ml), and the reaction mixture was stirred at ambient temperature for 1 hour. increasing polarity of petroleum ether "(Kkip. g" 40-6025) and ethyl acetate as an eluent. in this way, 4-chloro-7-(2-chloroethoxy)-5-tetrahydropyran-4-yloxyquinazoline was obtained in the form of a solid substance (0.17g ); NMR spectrum: (SOCI3) 2.0 (t, 2H), 2.15 (t, 2H), 3.7 (t, 2H), 3.95 (Ii, 2H), 4.1 (t , 2H), 4.4 (and, 2H), 4.8 (t, 1H), 6.7 (in, 22 1H), 6.95 (5, 1H), 8.85 (in, 1H).

HF) Example 5 7-(2-chloroethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxyquinazoline o Using a technique similar to that described in example 1, 4-chloro-7- (2-chloroethoxy)-5-isopropoxyquinazoline was reacted with 60 4-amino-5-chloro-2,3-methylenedioxypyridine to give the title compound in a yield of 86905;

NMR spectrum: (SOCI3) 1.55 (y, 6H), 3.9 (, 2H), 4.4 (Ii, 2H), 4.9 (t, 1H), 6.2 (v, 2H), 6.6 (85, 1H), 6.85 (in, 1H), 7.75 (in, 1H), 8.6 (in, 1H), 9.65 (in, 1H); Mass spectrum: MAN" 437 and 439. 4-Chloro-7-(2-chloroethoxy)-5-isopropoxyquinazoline, which was used as a starting material, was obtained as follows: di-tert-butyl azodicarboxylate (28.9 g) was added to the stirred mixture

7-benzyloxy-5-hydroxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (international patent application UUO 01/94341, example 15, note |81); 30g), isopropanol (7.33ml), triphenylphosphine (32.95g) and methylene chloride (350ml), which was cooled to 0 2С. The reaction mixture was allowed to warm to ambient temperature and stirred for 1.5 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using mixtures of increasing polarity of methylene chloride and methanol as eluent. 7-benzyloxy-5-isopropoxy-3,4-dihydroquinazolin-4-one was obtained in this way as a solid (23.8 g); NMR spectrum: (DMSOa in) 7.89 (in, 1H), 7.5-7.3 (t, 5H), 6.75 (8, 1H), 6.62 (8, 1H), 5, 24 (8, 2H), 4.65 (t, 1H), 1.29 (a, 6H). 70 Ammonium formate (48.4 g) was added to a stirred mixture of 7-benzyloxy-5-isopropoxy-3,4-dihydroquinazolin-4-one (23.8 g), 1095 palladium on carbon catalyst (2.8 g) and

DMF (ZOOml), and the resulting mixture was stirred at ambient temperature for 2 hours.

The mixture was filtered and the filtrate was evaporated. The substance obtained in this way was ground into a powder in water, the pH value of the solution was adjusted to 7. The solid substance obtained in this way was collected by filtration, washed with water and diethyl ether, and dried over phosphorus pentoxide in a vacuum. In this way, 7-hydroxy-5-isopropoxy-3,4-dihydroquinazolin-4-one was obtained as a white solid (15.9 g);

NMR spectrum: (DMSOαb) 1.3 (4, 6H), 4.57 (t, 1H), 6.42 (in, 1H), 6.5 (in, 1H), 7.8 (in, 1H ).

The mixture of substances obtained in this way, acetic anhydride (34 ml) and pyridine (0.62 ml) was heated to 709 for 30 minutes. The reaction mixture was cooled to ambient temperature and excess acetic anhydride was evaporated. The white solid obtained was added to hot water (802, 250ml) and the mixture was vigorously stirred and heated to 8023 for 20 minutes. The mixture was cooled to ambient temperature and the solid was isolated and dried over phosphorus pentoxide.

In this way, 7-acetoxy-5-isopropoxy-3,4-dihydroquinazolin-4-one (17.86 g) was obtained; NMR spectrum: (DMSOαb) 7.97 (in, 1H), 6.91 (8, 1H), 6.85 (in, 1H), 4.65 (t, 1H), 2.32 (in, ЗН ), 1.33 (y, EN). Gee!

A mixture of part (5.4 g) of the substance obtained in this way, triphenylphosphine (10.8 g), carbon tetrachloride (12 ml) and 1,2-dichloroethane (500 ml) was stirred and heated to 709C for 2 hours. The mixture was cooled to ambient temperature and the solvent was evaporated. The residue was dissolved in a 0.5M solution of gaseous ammonia in 1,4-dioxane (25Oml) and the mixture was heated to 709 for 10 minutes. The solvent was evaporated and the residue was cooled in an ice-water bath. Methylene chloride and water were added, and the pH value of the aqueous layer was adjusted to 7 by adding dilute aqueous hydrochloric acid. The mixture was filtered. at

The organic phase was dried over magnesium sulfate and evaporated to give 4-chloro-7-hydroxy-5-isopropoxyquinazoline as a foam, which was used without further purification. co

Di-tert-butyl azodicarboxylate (7.9 g) was added to a stirred mixture of 4-chloro-7-hydroxy-5-isopropoxyquinazoline obtained in this way, 2-chloroethanol (1.5 ml), triphenylphosphine (8 g) and methylene chloride (200 ml ), and the reaction mixture was stirred at ambient temperature 99 for 4 hours. The mixture was concentrated by evaporation and the residue was purified by column chromatography on silica using mixtures of increasing polarity of petroleum ether (bp. 40-60) and ethyl acetate as eluent. In this way, 4-chloro-7-(2-chloroethoxy)-5-isopropoxyquinazoline (2.5 g) was obtained; NMR spectrum: (SOSI") 1.45 (y, 6H), 3.9 (y, 2H), 4.4 (y, 2H), 4.75 (t, 1H), 6.65 (8, 1H), 6.9 (in, 1H), 8.8 (8, 1H).

Example 6 c) c Using a procedure similar to that described in Example C, a suitable 7-halo-alkoxyquinazoline "» was reacted with a suitable heterocyclyl compound to give the compounds listed in Table I. Unless "not specifically stated otherwise, each compound listed in Table I , was obtained as a free base. (ee) («c) (95) at 50

Co.)

F) name) 60 b5

Table!

House nm o 0-/

And M

(d)

And more

Me compounds (Кт (Кв ше " 21 b-methoxy-7-43-14-(2,2,2-trifluoroethyl)piperazine-1- B-chloro o i o (4 B-tetrahydropyran-4-yloxy-7- (2-(4-Acetylpiperazine-i-5-chlor vel po M to (Br b-tetrahydropyran-4-yloxy-7-2-(3K5,458)-3,А- B-khpor o sha ni nu SOLO bbioproloct b vdetitiyervon Yari be 0000

Hl Bazopropoxy-7-412-Y(3K5,455K)-3,4-B-khporsha Y a (C bomorbolyuetnutyuyeya lu 00 - 7 SOV dbbchyamenntiperavnniaiiietokitmekya bler » is (22) 112 5-2-(3K5,45K)- 3,4-methylenedioxypyrrolidine-1-5-xpro od shchi o " (716 bibrnettne et Be

GF! 6-3-(385,4A58)-3,4-methylenedioxypyrrolidine-1-5-chloro

She eishshyi 60 b5

PI B-tetrahydropyran-4-yloxy-7-(2-(4-prop-2-ynylpiperazin-15-chloro 1-yl)ethoxy) 19) B-tetrahydropyran-4-yloxy-7-(2-morpholinoethoxy) o -chloro o) B-tetrahydropyran-4-yloxy-7--3-morpholinopropoxy) 5-xpor (21 B-tetrahydropyran-4-yloxy-7-(3-(4-prop-2-ynylpiperazine- /5-chloro 1-yl)propoxy 22 B-isopropoxy-7-(2-piperazin-1-ylethoxy) 5-khpor 7 : 7 t (231 5-isopropoxy-7-42-14-(2-tihydroxyethyl)piperazine-1-5 -chloro ip|ethoxy) (24) 5-isopropoxy-7-(2-pyrrolidin-1-ylethoxy) 5-chloro (251 5-Isopropoxy-7-(2-piperidinoethoxy) 5-xpor (261 B-isopropoxy-7 -(2-morpholinoethoxy) 5-chloro (271 5-isopropoxy-7-12-(4-prop-2-ynilliperazin-1-yl)ethoxy| 15-chloro o (281 B-isopropoxy-6-2-I( 35,45K)-3,4-dimethoxypyrrolidine-|5-chloro 1-yl|ethoxy) ch 6-2-(385,458)-3,4-ethylidenedioxypyrrolidine-1-5-chloro oyl|ethoxy)-5-isopropoxy He ) (301 o-isopropoxy-7-12-(4-methylpiperazin-1-yl)ethoxy) 5-khpor o 7 7 g) (3 5-isopropoxy-7--3-morpholinopropoxy) o-khpor

IZ2I 7-(3-morpholinopropoxy) 5-khpor : : «

IZZI 7-13-(4-acetylpiperazin-1-yl)propoxy) B-xpor - c ЖЗ4Й b-methoxy-7-H2-(4-prop-2-ynylpiperazin-1-yl)ethoxy| hydrogen n ИЗБИ b-methoxy-7-I3-(4-prop-2-ynylpiperazin-1-yl)propoxy) /Ivoden, oo Notes

PI The reactants were 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(3-chloropropoxy)-6-methoxyquinazoline and 1-isobutyrylpiperazine. c The reaction mixture was heated to 12092C for 3 hours. The reaction product was purified by column chromatography on a C18 reversed-phase silica column (UUa column (eg, Zutteig, 5 micron silica o silicon, diameter 19 mm, length 100 mm), using a mixture of decreasing polarity of water and acetonitrile

Ge (containing 195 acetic acid) as eluent. The substance obtained in this way was dissolved in methylene chloride and an ion-exchange resin (diethylaminopolystyrene resin, 4 equivalents) was added, and the mixture was stirred for

30 minutes. The mixture was filtered and the filtrate was evaporated. 5B The resulting residue was triturated in pentane to give the desired product in a yield of 5195, which had the following characteristics; NMR spectrum: (SOSI") 1.1 (a, 6H), 2.1 (t, 2H), 2.45 (t, 4H), 2.55 (t, 2H), 2.75 (t, 1H), (F. 3.5 (t, 2H), 3.6 (t, 2H), 4.0 (v, 3H), 4.25 (5 2H), 61 (v, 2H), 7, 1 (rg 8, 1H), 7.3 (in, 1H), 7.75 (in, 1H), ko 8.7 (Bg 8, 1H); Mass spectrum: MAN" 543 and 545. 1-Isobutyrylpiperazine , which was used as the starting material, was obtained as follows: isobutyryl chloride (3.25 ml) was added dropwise to a stirred mixture of 1-benzylpiperazine (5 g), triethylamine (4.35 ml) and methylene chloride (75 ml), which was cooled to 02. the mixture was allowed to warm to ambient temperature and stirred for 1 hour. The mixture was partitioned between methylene chloride 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, 65 using a mixture of 3: 2 a mixture of methylene chloride and ethyl acetate as an eluent. In this way, 1-benzyl-4-isobutyryl piperazine (5.95 g) was obtained as an oil; NMR-spec ktr: (SOSI 3) 1.1 (a, 6H), 2.45 (t, 4H), 2.8

(t, 1H), 3.5 (t, 4H), 3.65 (t, 2H), 7.3 (t, BN); Mass spectrum: MAN" 247.

The mixture of substances obtained in this way, cyclohexene (7Oml), a catalyst of palladium oxide on carbon (2090; 1.17) and ethanol (120ml) was stirred and heated to 802 for 3 hours. The catalyst was removed by filtration and the solvent was evaporated to give 1-isobutyrylpiperazine (3.7g) as a solid;

NMR spectrum: (SOSI") 1.05 (y, EN), 2.75 (t, 1H), 2.8 (t, 4H), 3.45 (t, 2H), 3.55 (t, 2H).

I The reactants were 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(3-chloropropoxy)-6-methoxyquinazoline and 1-2,2,2-trifluoroethyl)piperazine. The reaction mixture was heated to 1202C for 3 hours. The reaction product was purified 70 by column chromatography on a C18 reversed-phase silica column (UmMaiegv column

Zutteig, 5 micron silica, diameter 19mm, length 100mm) using a mixture of reduced polarity water and acetonitrile (containing 195 acetic acid) as eluent. The substance obtained in this way was dissolved in methylene chloride and an ion exchange resin (diethylaminopolystyrene resin, 4 equivalents) was added and the mixture was stirred for 30 minutes. The mixture was filtered and the filtrate was evaporated. The resulting residue 75 was triturated in pentane to give the desired product in a yield of 7295, which had the following characteristics;

NMR spectrum: (SOCI3) 2.1 (t, 2H), 2.5 (t, 6H), 2.7 (t, 4H), 2.95 (4, 2H), 4.05 (v, ЗН), 425 ( i, 2H), 6/1 (5, 2H), 7.1 (Bg 8, 1H), 7.3 (8, 1H), 7.75 (c, 1H), 8.35 (Bg 5, 1H ); Mass spectrum: MAN" 555 and 557; Elemental analysis: revealed C, 51.8; H, 5.0; M, 14.8; SoaNovSiezMeO, required C, 51.9; H, 4.7; M, 15196. 1-2 ,2,2-Trifluoroethyl)piperazine, which was used as a starting material, was obtained as follows: 2,2,2-Trifluoroethyl trifluoromethanesulfonate (8.20) was added to a stirred mixture of 1-tert-butoxycarbonylpiperazine (bg), potassium carbonate (5 .77g) and acetonitrile (30ml), and the resulting mixture was stirred at ambient temperature for 16 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica using mixtures of increasing polarity of petroleum ether (MU 40-602С) and ethyl acetate as an eluent. In this way, tert-butyl 4-(2,2,2-trifluoroethylpiperazine-1-carboxylate) was obtained as a solid (8.1 g); o

NMR spectrum: (SOSI") 1.45 (b, 9H), 2.6 (t, 4H), 2.95 (a, 2H), 3.4 (t, 4H).

Hydrogen chloride gas was bubbled through a solution of tert-butyl 4-(2,2,2-trifluoroethylpiperazine-1-carboxylate (8g) in ethyl acetate (50ml) for 1.5 hours. A precipitate formed and carbon dioxide was also evolved.

The precipitate was collected by filtration, washed with ethyl acetate and dried under vacuum. In this way, 1-(2,2,2-trifluoroethyl)piperazine hydrochloride (7 g) was obtained; NMR spectrum: (DMSOα and СЕ53СО20) 2.85 (t, 4H), 3.1 (t, 4H), o 3.35 (a, 2H).

The substance obtained in this way was suspended in methylene chloride and a saturated methanolic ammonia solution (20 ml) was added. The resulting mixture was stirred at ambient temperature for 20 minutes. The mixture was filtered and the filtrate was evaporated at ambient temperature under vacuum.

In this way, 1-(2,2,2-trifluoroethyl)piperazine was obtained, which was used without any additional purification.

3) The reactants were 7-(2-chloroethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-methoxyquinazoline and 1-prop-2-ynylpiperazine. "

The desired product was obtained at the output of 5290, which had the following characteristic data;

NMR spectrum: (DMSOd; and SRZ3SO.20) 3.3 (Bg 85, 4H), 3.6 (Bg 5, 4H), 3.75 (rg 85, ЗН), 3.95 (in, 2H), 4.05 (in, C with ZN), 4.65 (Her, 2H), 6.3 (in, 2H), 7.5 (in, 1H), 7.9 (in, 1H), 8.2 (85, 1H), 9.0 (in, 1H); Mass spectrum: MAN" 497 and 499;

From" Elemental analysis: revealed C, 56.3; M, 5.4; M, 16.2; Soa/NoBSIMeO, 0.7 MoO required C, 56.6; M, 5.2; M, 16.5905.

I The reactants were 7-(2-chloroethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-tetrahydropyran-4-yloxyquinazoline and 1-acetylpiperazine. The reaction mixture was heated to 802 for 3 hours and then to 1102 for 5 hours. The reaction product was purified by column chromatography on a reversed-phase C18 silica column (Uuagez Zutteig column, 5 micron silica, 19 mm diameter, 100 mm length), using a mixture of reduced polarity of water and acetonitrile (containing 190 acetic acid) as an eluent. The organic solvents were evaporated and the pH of the aqueous phase was adjusted to 7.5. The solution was extracted with methylene chloride and (av) 50 the organic phase was dried over magnesium sulfate and evaporated. The resulting residue was triturated in diethyl ether to give the desired product in a yield of 4595 , which had the following characteristic data: NMR spectrum: iz (СОСИ3) 2.0 (t, 2Н), 2.1 (v, ЗН), 2.3 (t, 2Н), 2.6 (t, 4Н) , 2.95 (t, 2H), 3.55 (t, 2H), 3.65 (t, 4H), 41 (t, 2H), 4.3 (t, 2H), 4.8 (t, 1H), 6.2 (in, 2H), 6.6 (85, 1H), 6.9 (8, 1H), 7.8 (8, 1H), 8.65 (in, 1H), 9, 5 (in, 1H); Mass spectrum: MAN" 571 and 573; Elemental analysis: detected C, 55.3; H, 5.4; M, 13.9; C 27Na"SIMvOv 1H20O requires C, 55.1 , H, 5.7, M, 14.3.

HF) IB The reactants were 7-(2-chloroethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-tetrahydropyran-4-yloxyquinazoline and (z3k5,45K)-3,4 -methylenedioxypyrrolidine. The reaction mixture was heated to 802C for 3 hours and then to 1102C for 5 hours. The reaction product was purified by column chromatography on a C18 reversed-phase silica column (Uuyeghe Zutteig column, 5 micron silica, 19 mm diameter, 100 mm length), using a mixture of reduced polarity water and acetonitrile (containing 195 acetic acid) as eluent.

Organic solvents were evaporated and the pH value of the aqueous phase was adjusted to 7.5. The solution was extracted with methylene chloride and the organic phase was dried over magnesium sulfate and evaporated. The obtained residue was ground into powder in diethyl ether, obtaining the desired product in a yield of 6995, which had the following characteristic data; NMR spectrum: (SOCI3) 2.0 (t, 2H), 2.3 (t, 2H), 2.4 (t, 2), 2.3 (5 2H), 3.3 (a, 2H) , 3.55

(t, 2H), 4.1 (t, 2H), 4.3 (6 2H), 4.65 (t, 2H), 4.8 (t, 1H), 4.9 (v, 1H), 5.2 (in, 1H), 62 (8, 2H), 6.6 (5, 1H), 69 (in, 1H), 7.8 (8, 1H), 8.65 (in, 1H), 9.5 (85, 1H); Mass spectrum: MAN" 558 and 560; Elemental analysis: revealed C, 56.5; M, 5.3; M, 12.5; SobNovSIM5BO, 0.2 OR required C, 56.2; M, 5.3; M, 12.290 .(z3k5,455K)-3,4-Methylenedioxypyrrolidine, which was used as a starting material, was obtained in the following way:

A solution of di-tert-butyl dicarbonate (VocO, 78.95 g) in ethyl acetate (125 ml) was added dropwise to a stirred mixture of Z-pyrroline (25 g; purity 6595, containing pyrrolidine) and ethyl acetate (125 ml), which was cooled to 02С. The reaction temperature was maintained at 5-10 during addition. The resulting reaction mixture 70 was allowed to warm to ambient temperature overnight. The reaction mixture was successively washed with water, O0.1N. aqueous solution of hydrochloric acid, water, saturated aqueous solution of sodium bicarbonate and salt solution, dried over magnesium sulfate and evaporated. In this way, a 2:1 mixture of tert-butyl 3-pyrroline-1-carboxylate was obtained in the form of a colorless oil (62 g), NMR: (SOCI3) 1.45 (in, 9H), 4.1 (a,

AN), 6.75 (t, 2H), and tert-butyl pyrrolidine-1-carboxylate, NMR: (SOCI") 1.5 (b, 9H), 1.8 (Bg 5, 4H), 3.Z (Lg 5, 4H).

A solution of the mixture of substances obtained in this way in acetone (X0O0ml) was added dropwise to the mixture

of M-methylmorpholine-M-oxide (28.45g), osmium tetroxide (1g) and water (5000ml), while the reaction temperature was maintained below 2520. Then the reaction mixture was stirred at ambient temperature for 5 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with saline, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silicon dioxide using mixtures of increasing polarity of petroleum ether (item 1410-6022) and ethyl acetate as eluent and additionally by column chromatography on silicon dioxide using a mixture of increasing polarity of methylene chloride and methanol. In this way, tert-butyl (3К5,45К)-3,4-dihydroxypyrrolidine-1-carboxylate was obtained in the form of oil (34.6 g);

NMR spectrum: (SOSI") 1.45 (v, 9H), 2.65 (t, 2H), 3.35 (t, 2H), 3.6 (t, 2H), 4.25 (t, 2H). with

A solution of tert-butyl (3K5,45K)-3,4-dihydroxypyrrolidine-1-carboxylate (34.6g) in DMF (400ml) was cooled to 0-59 and sodium hydride (6095 dispersion in mineral oil, 0.375 mol) was added in portions. . The reaction mixture was stirred at 52C for 1 hour. Dibromomethane (15.bml) was added and the reaction mixture was stirred at 59 for 30 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. DMF was evaporated and the residue was partitioned between ethyl acetate and water. with

The organic phase was washed with water and saline, dried over magnesium sulfate and evaporated. sou

The residue was purified by column chromatography on silica using mixtures of increasing polarity of petroleum ether (zip, 10-602C) and ethyl acetate as eluent. In this way, they received tert-butyl (С3К5,45К)-3,4-methylenedioxypyrrolidine-1-carboxylate in the form of a colorless oil (19.77 g); at

NMR spectrum: (SOSI") 1.45 (in, 9H), 3.35 (t, 2H), 3.75 (Bg 5, 2H), 4.65 (t, 2H), 4.9 (in , 1H), 5.1 (8, 1H).

A chilled 5M solution of hydrogen chloride in isopropanol (150ml) was added to a solution of tert-butyl co (z3k5.45K)-3,4-methylenedioxypyrrolidine-1-carboxylate (19.7g) in methylene chloride (500ml), which was cooled in an ice bath. The reaction mixture was allowed to warm to ambient temperature and stirred for 4 hours. The solvent was evaporated and the residue was triturated in diethyl ether. The precipitate was collected by filtration, washed with diethyl ether and dried. In this way, 3,4-methylenedioxypyrrolidine hydrochloride was obtained as a beige solid (13.18g); NMR spectrum: c (DMSO av) 3.15 (t, 2H), 3.35 (t, 2H), 4.65 (v, 1H), 4.8 (t, 2H), 5.1 (8 , 1H). The substance obtained in this way was suspended in diethyl ether and a saturated methanolic solution of ammonia was added. The resulting mixture was stirred at ambient temperature for 10 minutes.

The mixture was filtered and the solvent was evaporated at ambient temperature under vacuum. In this way, (3K5,45K)-3,4-methylenedioxypyrrolidine was obtained, which was used without any additional purification. av) IEI The reactants were 7-(2-chloroethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxyquinazoline and 1-acetylpiperazine.

Mami The reaction mixture was heated to 85°C for 8 hours. The reaction product was purified by column chromatography (α) 50 on silica, using mixtures of increasing polarity of methylene chloride and methanol as eluent. The product was obtained in a yield of 8995, which had the following characteristic data: bp, 208-210; NMR spectrum : (SOSI") 1.55 (y, 6H), 2.1 (8, ЗН), 2.6 (t, 4H), 2.9 ( 2H), 3.5 (, 2H), 3.7 (b 2H), 4.25 (I, 2H), 4(85 (t, 1H), 6.15 (c, 2H), 6.55 (5, 1H), 6.85 (c, 1H), 7.75 (in, 1H), 8.6 (8, 1H), 9.6 (in, 1H); Mass spectrum: MAN" 529 and 531; Elemental analysis: revealed C, 57.0; H, 5 .7; M, 15.7; CoBNooSIMeO" required C, 56.8; H, 5.5; M, 15.9905. t The reactants were (F) 7-(2-chloroethoxy)-4-(5- chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxyquinazoline and co(z3k5,45K)-3,4-methylenedioxypyrrolidine. The reaction mixture was heated to 95° for 3 hours. The reaction product was purified by column chromatography on a C18 silica column with reversed phase (column of UMaiege Zutteinu, 5 micron silicon dioxide, diameter 19 mm, length 100 mm), using a mixture of decreasing polarity of water and acetonitrile (containing 195 acetic acid) as eluent. The organic solvents were evaporated and the pH value of the aqueous phase was adjusted to 7. The solution was extracted with methylene chloride and the organic phase was dried over magnesium sulfate and evaporated. The resulting residue was triturated in diethyl ether, obtaining the desired product in a yield of 64905, which had the following characteristic data; NMR spectrum: (SOSI") 1.55 (49, 6H), 5 235 (t, 2H), 2.9 (B 2H), 3.25 (0, 2H), 4.25 (6 2H), 4.6 (t, 2H), 4.85 (t, 1H), 4.9 (v, 1H), 5.15 (8, 1H), 6.15 (z, 2H), 6.55 (z , 1H), 6.85 (from, 1H), 7.75 (in, 1H), 8.6 (from, 1H), 9.6 (in, 1H); Mass spectrum: MAN" 516 and 518; Elemental analysis: C, 54.7; H, 5.2; M, 13.2; SoaNovSIMBOv 0.5 NoO required C, 54.9; H, 5.2; M, 13, 3965.

IVI The reactants were 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-(2-chloroethoxy)-7-methoxyquinazoline (the preparation of which is described in example 7 below) and morpholine. The reaction mixture was heated to 1202C for 16 hours. The desired product was obtained at output 6995, which had the following characteristic data; NMR spectrum: (SOCI3 and СО5СО20) 3.3 (t, 4Н), 3.5 (2Н), 3.95 (t, 4Н), 4.05 (в, ЗН), 4.6 (I, 2Н ), 6.15 (in, 2H), 7.6 (8, 1H), 7.8 (5, 2H), 8.6 (in, 1H); Mass spectrum: MAN" 460 and 462; Elemental analysis: found C, 53.45; H, 4.8; M, 14.55 С24Но2СИМо" in 0.55 НоО required C, 53.7; H, 5.0; M, 14.990 70 IU) The reactants were 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-(2-chloroethoxy)-7-methoxyquinazoline and 1-methylpiperazine. The reaction mixture was heated to 1202C for 16 hours. The reaction product was purified by means of column chromatography on a column of silicon dioxide UUaiege X-Tega (C18 reverse phase, 5 microns, diameter 19 mm, length 100 mm;

University of California, Ips., Milford, MA 1757, USA) and eluted with mixtures of decreasing polarity of ammonium carbonate buffer (2 g/L in water) and acetonitrile. Suitable fractions were collected, the organic solvent was evaporated, and the resulting mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate and evaporated. In this way, the desired product was obtained at the output of 2990, which had the following characteristic data; NMR spectrum: (SOCI3 and СО5С2050) 2.7 (in, ZN), 3.25-3.35 (rg t, 1OH), 4.05 (in,

ЗН), 4.45 (i, 2Н), 6.15 (в, 2Н), 7.55 (в, 1Н), 7.7 (8, 1Н), 7.8 (в, 1Н), 8, 65 (c, 1H); Mass spectrum: MAN" 473 and 475; Elemental analysis: revealed C, 54.9; H, 5.3; M, 17.1; Co2NoBSIMeO, 0.4 NoO required C, 55.0; H, 5.4 ; M, 17596.

PO The reactants were 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-(2-chloroethoxy)-7-methoxyquinazoline and pyrrolidine. The reaction mixture was heated to 1202C for 16 hours. The desired product was obtained at output 4195, which had the following characteristic data; NMR spectrum: (SOCI3 and СО5СО020) 2.15 (t, 4H), 3.3-3.6 (rg 5, 4H), 3.7 (0 2H), 4.05 (z, ЗН), 465 , D KS 29 2H), 6.15 (5, 2H), 7.65 (v, 1H), 7.8 (v, 1H), 7.9 (v, 1H), 8.65 (5, 1H ); Mass spectrum: MAN" 444 and 446; Elemental Ge) analysis: revealed C, 55.0; H, 5.0; M, 14.9; C24NooSIM5O, 0.7 NoO required C, 55.25; H, 5 ,2; M, 15.3965.

PI The reactants were 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-(2-chloroethoxy)-7-methoxyquinazoline and 1-acetylpiperazine.

The reaction mixture was heated to 1202C for 16 hours. The desired product was obtained at the output of 5195, which had the following characteristic data with 30; NMR spectrum: (SOCI3 and СО5СО020) 2.15 (85, ЗН), 3.1 (t, 2Н), 3.2 (t, 2Н), 34 (6 2Н), 3.75 Units (t, 2Н ), 3.85 (t, 2H), 4.0 (v, ЗН), 4.55 ( 2H), 6.15 (v, 2H), 7.6 (8, 1H), 7.7 (8 , 1H), 7.8 (in, 1H), 8.6 (8, 1H); Mass spectrum: MAN" 501 and 503. o 121 The reactants were F 35 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-(2-chloroethoxy)-7-methoxyquinazoline and so (3K5 ,455)-3,4-methylenedioxypyrrolidine. The reaction mixture was heated to 1202 for 16 hours. The desired product was obtained in a yield of 73905, which had the following characteristic data: NMR spectrum: (SOCI3 and 2052050) 2.95 (t, 2H), 3.45 (B 2H), 3.65 (9, 2H), 4.05 (in, ЗН), 4.55 (6 2Н), 4.8 (t, ЗН), 5.2 (8, 1Н ), 6.15 (v, 2H), 7.6 (v, 1H), 7.75 (v, 1H), 7.8 (v, 1H), 8.65 (v, 1H); Mass spectrum : MAN" 488 and 490. « 40 (131) The reactants were Sh-c 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-(3-chloropropoxy)-7-methoxyquinazoline (the preparation of which is described in Example 8 below) and pyrrolidine. The reaction mixture was heated to 1202 for 16 hours. The desired "" product was obtained in a yield of 5095, which had the following characteristic data; . , 6.1 (in, 2H), 7.6 (8, 1H), 7.75 (in, 1H), 7.8 45 (in, 1H), 8.65 (5, 1H); Mass spectrum: MAN" 458 and 460; Elemental analysis: revealed C, 57.3; H, 5.4; M, 14.5; (ee) SooNo SIMOX 0.15 H2oO required C, 57.4; H, 5.3; M, 15.290. o 141 The reactants were 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-(3-chloropropoxy)-7-methoxyquinazoline and morpholine. The reaction mixture o was heated to 1202C for 16 hours. The desired product was obtained in a yield of 7295, which had the following characteristic data: NMR spectrum: (SOCI) 2.1 (t, 2H), 2.5 (t, 4H), 2.6 ( B 2H), 3.7 (t, 4H), 4.05 (c, 3H), 4.25 (i, 2H), 6.1 (c, 2H), 7.05 (c, 1H), 7 ,15 (v, 1H), 7.3 (v, 1H), 7.75 (v, 1H), 8.7 (v, 1H); Mass spectrum: MEN" 474 and 476. and" (15 ) The reactants were 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-(3-chloropropoxy)-7-methoxyquinazoline and 1-acetylpiperazine.

The reaction mixture was heated to 1202C for 16 hours. The desired product was obtained at output 3995, which had the following characteristic data; NMR spectrum: (СОСИ3 and СО5СО050) 2.15 (in, ЗН), 2.35 (t, 2Н), 3.15-3.3 (t, 6Н), 3.8 (t,

HF) 2H), 3.9 (t, 2H), 4.0 (v, ЗН), 4.3 (I, 2M), 6.15 (5, 2H), 7.6 (v, 1H), 7.65 (in, 1H), 7.8 (in, 1H), 8.65 (in,

GF 1H); Mas; spectrum: MAN" 515 and 517. 16 The reactants were 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-(3-chloropropoxy)-7-methoxyquinazoline and 1-acetylpiperazine.

The reaction mixture was heated to 1202C for 16 hours. The desired product was obtained at output 2795, which had the following characteristic data; NMR spectrum: (СОСИ3 and СО5С2О020) 2.3 (t, 2Н), 2.7 (v, ЗН), 3.3 (6 2Н), 34 (t, 4Н), 3.5 (t, AN) , 4.0 (in, ZN), 4.3 (Her, 2H), 6.15 (in, 2H), 7.6 (in, 1H), 7.65 (in, 1H), 7.8 ( c, 1H), 8.65 (c, 1H); Mass spectrum: MAN" 487 and 489. 65 PI The reactants were 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-(3-chloropropoxy)-7-methoxyquinazoline and

(z3k5,45K)-3,4-methylenedioxypyrrolidine. The reaction mixture was heated to 959 for 3 hours. The reaction product was purified by column chromatography on a C18 reversed-phase silica column (column

MUaiegz Butteigu, 5 micron silicon dioxide, diameter 1U9mm, length 100mm), using a mixture of

By reducing the polarity of water and acetonitrile (containing 175 acetic acid) as an eluent. The organic solvents were evaporated and the pH value of the aqueous phase was adjusted to 7. The solution was extracted with methylene chloride and the organic phase was dried over magnesium sulfate and evaporated. The resulting residue was triturated in diethyl ether, obtaining the desired product in a yield of 5795, which had the following characteristic data; NMR spectrum: (SOCI»z and СО3СО50) 2.3 (t, 2H), 3.3 (t, 2H), 3.4 (, 2H), 3.6 (49, 2H), 4.0 ( в, ЗН), 4.3 ( 2Н), 4.8 (t, ЗН), 5.2 (в, 1Н), 6.15 70. (в, 2Н), 7.55 (в, 1Н), 7.6 (c, 1H), 7.8 (c, 1H), 8.6 (c, 1H); Mass spectrum: MAN" 502 and 504. pe) The reactants were 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(2-chloroethoxy)-5-tetrahydropyran-4-yloxyquinazoline and 1 -prop-2-ynylpiperazine The reaction mixture was heated to 802C for 3 hours and then to 110922 for 5 hours.

The reaction product was purified using column chromatography on a column of silica U/ai (eg X-Teigta 75. (C18 reverse phase, 5 microns, diameter 19 mm, length 100 mm) and eluted with mixtures of decreasing polarity of ammonium carbonate buffer (2 g/l in water) and acetonitrile.The appropriate fractions were collected, the organic solvent was evaporated, and the resulting mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate.

The organic phase was dried over magnesium sulfate and evaporated. In this way, the desired product was obtained at the output of 5495, which had the following characteristic data; NMR spectrum: (DMSOav and 2052050) 1.85 (t, 2H), 2.15 (t, 2H), 2.5-3.0 (t, 1OH), 3.15 (85, 1H), 3 .3 (85, 2H), 3.55 (5 2H), 3.9 (t, 2H), 4.35 (t, 2H), 5.05 (t, 71H), 6.2 (in, 2H ), 6.9 (in, 2H), 7.8 (in, 1H), 8.5 (5, 1H); Mass spectrum: MAN" 567 and 569; Elemental analysis: found C, 55.9; H, 5.6; M, 14.0; SovNazySIMeO" 2 NoO required C, 55.8; H, 5.85; M, 13.9905 (19) Using the conditions detailed in note (e) immediately above, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(2-chloroethoxy)-5-tetrahydropyran-4-yloxyquinazoline was subjected to with interaction with morpholine, obtaining the desired product at the yield of 4895, which had the following characteristic data; o

NMR spectrum: (DMSOaB and 20532020) 1.8 (t, 2H), 2.15 (t, 2H), 2.55 (t, 4H), 2.8 (t, 2H), 3.5 (t , 2H), 3.6 (t,

AN), 3.9 (t, 2H), 4.3 (Her, 2H), 5.1 (t, 1H), 6.2 (v, 2H), 6.9 (t, 2H), 7, 8 (in, 1H), 8.45 (in, 1H); Mass spectrum MAN" 530 and 532; Elemental analysis: revealed C, 51.8; H, 5.8; M, 12.1; Co5NovSIMmOv 2.5 NoO required C, 52.2; H, 5.8; M, 12.296. with

The reactants were 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(3-chloropropoxy)-5-tetrahydropyran-4-yloxyquinazoline (described in example 9 below) and morpholine. The desired product was obtained at output 3095, which had the following characteristic data; She

NMR spectrum: (SOCI3 and SRZCO2O) 2.05 (t, 2H), 2.35 (t, 4H), 3.15 (t, 2H), 3.45 (t, 2H), 3.75 (t , 4H), 39(t, "with 2H), 4.2 (t, 6H), 5.0 (t, 1H), 6.3 (v, 2H), 6.85 (v. 1H), 7 .0 (in, 1H), 7.9 (in, 1H), 8.7 (8, 1H); Mass spectrum: MAN" 544 and 546. (211 The reactants were 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(3-chloropropoxy)-5-tetrahydropyran-4-yloxyquinazoline and 1-prop-2-ynylpiperazine The reaction product was purified by column chromatography on a C18 reversed-phase silica column (Uu/Aeg Zutteig column, 5 micron silica, 19 mm diameter, 10 mm length) using a depolarized mixture of water and acetonitrile (containing 195 acetic acid) as C7Z70 eluent. The organic solvents were evaporated and the pH of the aqueous phase was adjusted to 9. The solution was extracted with methylene chloride and the organic phase was dried over magnesium sulfate and evaporated. The resulting residue was triturated in pentane to give the desired product at output 4895, which had the following characteristic data;

NMR spectrum: (DMSOα and СО5СО20) 1.85 (t, 2H), 2.0 (t, 2H), 2.15 (t, 2H), 2.5-2.8 (rg t, 10OH), 3.15 (v, 1H), 3.3 (v, 2H), 3.55 (2H), 3.9 (t, 2H), 4.2 (5 2H), 5.05 (t, 71H) , 6.2 (in, 2H), 6.85 (85, 1H), 6.9 (in, 395 1H), 7.8 (in, 1H), 8.45 (in, 1H); Mass spectrum MAN" 581 and 583. (ee) 221 The reactants were (ав) 7-(2-chloroethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxyquinazoline and piperazine. This was obtained required product in a yield of 3095, which had the following characteristic data: NMR spectrum: (SOCI 3) 1.55 (y, 6H), 2.6 (t, 4H), 2.85 (5 2H), 2.95 ( t, 4H), 4.25 (2H), 4.85 (t, 7H), 6.15 (in, 2H), 6.55 (in, 1H), 6.85 (in, 1H), 7, 75 (in) (5, 1H), 8.6 (in, 1H), 9.6 (in, 1H); Mass spectrum: MAN" 487 and 489; Elemental analysis: found C, 55.4; H, 5.5; M,

GC 16.4; SozN.; SIMeOH 0.1 BO 0.6 But it is necessary C, 55.65; H, 5.8; M, 16.6905.

I23I The reactants were 7-(2-chloroethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxyquinazoline and 1-(2-hydroxyethyl)piperazine. The reaction mixture was heated to 8593 for 8 hours. The reaction product was purified by column chromatography on silica using mixtures of increasing polarity (F. methylene chloride and methanol as eluent. The substance obtained in this way was triturated in diethyl ether to give the desired product in a yield of 6795, which had the following characteristic data: NMR spectrum: (SOSI»z) 1.5 (a, 6H), 2.5-2.7 (rg t, 12H), 3.65 (i, 2H), 4.25 (i, 2H), 4.8 (t, 1H), 6.15 (v, 2H), 6.6 (85, 1H), 6.85 (v, 1H), bo 07.25 (8, 1H), 7.75 (in, 1H), 8.6 (in, 1H), 9.6 (in, 1H); Mass spectrum: MAN" 531 and 533; Elemental analysis: revealed C, 55.4; H, 6.05; M, 15.2; CoBNaziSIMeOv 0.1 OR 0.5 NoO required C, 55.7; H, 6.1; M, 15.35965. (241 The reactants were 7-(2-chloroethoxy)-4-( 5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxyquinazoline and pyrrolidine. The reaction mixture was heated to 802 for 4 hours. The reaction product was purified by column chromatography on a C18 65 reversed-phase silica column (U/alex column bZutteiigu, 5 micro n silicon dioxide, diameter 19 mm, length 100 mm), using a mixture of reduced polarity of water and acetonitrile (containing 190 acetic acid) as eluent. The organic solvents were evaporated and the pH value of the aqueous phase was adjusted to 9. The solution was extracted with methylene chloride and the organic phase was dried over magnesium sulfate and evaporated. The resulting residue was triturated in pentane to give the desired product in a yield of 62905, which had the following characteristics; NMR spectrum: (SOCI3) 1.55 (y, 6H), 1.85 (t, 4H), 2.6 (t, 4H), 2.95 (B 2H), 4.25 (6 2H), 4.85 (t, 1H), 6.15 (v, 2H), 6.6 (v, 1H), 6.85 (v, 1H), 7.75 (v, 1H), 8.6 (v , 1H), 9.6 (in, 1H); Mass spectrum: MAN" 472 and 474; Elemental analysis: revealed C, 58.3; H, 5.4; M, 14.7; SozNovSYMBO, required C, 58.5; H, 5.55; M, 14.8905. ( 25) Using the conditions detailed in footnote (241 immediately above, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(2-chloroethoxy)-5-tetrahydropyran-4-yloxyquinazoline was subjected to 70 with piperidine to give the desired product in yield 5295, which had the following characteristics;

NMR spectrum: (SOCI5) 1.45 (t, 2H), 1.55 (ai, EN), 1.65 (t, 4H), 2.5 (t, 4H), 2.85 (Yi, 2H ), 4.25 (i, 2H), 4.85 (t, 1H), 6.15 (v, 2H), 6.6 (v, 1H), 6.85 (v, 1H), 7.75 (c, 1H), 8.6 (c, 1H), 9.6 (c, 1H); Mass spectrum: MAN" 486 and 488;

Elemental analysis: revealed C, 59.3; H, 5.9; M, 14.4; С2АНовСИМБО, need С, 59.3; H, 5.8; M, 144965. (261 Using the conditions detailed in note (241 immediately above, 75 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(2-chloroethoxy)-5-tetrahydropyran-4 -yloxyquinazoline was reacted with morpholine, obtaining the desired product in a yield of 5795, which had the following characteristic data: NMR spectrum: (SOCI3) 1.55 (a, 6H), 2.6 (t, 4H), 2.85 (B 2H), 3.75 (t, 4H), 4.25 (i, 2H), 4.85 (t, 1H), 6.15 (v, 2H), 6.55 (v, 1H), 6, 85 (8, 1H), 7.75 (5, 1H), 8.6 (v, 1H), 9.6 (v, 1H); Mass spectrum: MAN" 488 and 490; Elemental analysis: revealed С , 56.6; Н, 5.4; М, 14.2; СозНовбСИМО" required С, 56.6; Н, 5.4; М, 14.3596. 27 Using the conditions described in detail in the note (241 immediately above , 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(2-chloroethoxy)-5-tetrahydropyran-4-yloxyquinazoline was reacted with 1-prop-2-ynylperazine, obtaining the desired product in 4195, which had the following characteristic data; ), 3.3 (in, 2H), 425 (1, 2H), 4.85 (t, 1H), 6.15 (5, 2H), 6.55 (in, 1H), 6.85 (in, 1H), 7 .75 (in, 1H), 8.6 (in, 1H), 9.6 (in, 1H); Mass spectrum MAN" 525 "М 29 527; Elemental analysis: C, 59.3; H, 5.4; M, 15.85; SobNooSIMeO" required C, 59.5; H, 5.6; M, 16.095. He ) (28) The reactants were 7-(2-chloroethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxyquinazoline and (3K5,45k5)-3,4-dimethoxypyrrolidine. the desired product at output 7895, which had the following characteristic data;

NMR spectrum: (DMSOd and СО5СО20) 1.45 (a, 6Н), 2.7 (t, 2Н), 3.0 (t, 2Н), 3.15 (t, 2Н), 3.3 (c, 6Н), 3.75 s (t, 2H), 4.25 (I, 2H), 5.5 (t, 1H), 6.2 (5, 2H), 6.8 (v, 1H), 6.85 ( c, 1H), 7.8 (c, 1H), 8.45 (5.1H); Mass spectrum; MAN" 532 is and 534; Elemental analysis: revealed C, 56.0; H, 5.6; M, 12.85; CoBNzoSIMmOv 0.3 NoO required C, 56.25; H, 5.7; M, p 13,190. (z3k5,45K)-3,4-dimethoxypyrrolidine, which was used as a starting material, was obtained in the following way: av

A solution of tert-butyl (3K5,45K)-3,4-dihydroxypyrrolidine-1-carboxylate (1g) in DMF (20ml) was cooled to 0-5oC and sodium hydride (6095 dispersion in mineral oil, 0.433g) was added in portions. The reaction mixture was stirred at 59C for 1 hour. Methyl iodide (0.675 mL) was added and the reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. DMF was evaporated and the residue was partitioned between diethyl ether and water. The organic phase was washed with water and saline, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica using mixtures of increasing polarity of petroleum ether (e.g. 4740-6022) and ethyl acetate as eluent. In this way, tert-butyl (3ZK5,45K)-3,4-dimethoxypyrrolidine-1-carboxylate was obtained in the form of oil (1.06 g); NMR spectrum: (SOSI 3) 1.45 (in, 9H), 3.35 (t, 1H), 3.45 (5, 6H), 3.5 (t, 2H), 3.55 (t, 1H), 3.85 (t, 2H).

A cooled 5M solution of hydrogen chloride in isopropanol (3 ml) was added to a solution of tert-butyl and (3k5,45K)-3/4-dimethoxypyrrolidine-1-carboxylate (1g) in methylene chloride (25ml), which was cooled on ice baths The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. The solvent was evaporated. In this way, hydrochloride (3K545K)-3,4-dimethoxypyrrolidine was obtained in the form of oil (0.72g); NMR spectrum: (DMSOa in) 3.1 (t, 2H), 3.25 (t, 2H), 3.35 (in, 6H), 4.0 (t, 2H), 9.3 (Bbg in 1H), 9.5 (rg in, 1H). ("in The substance obtained in this way was dissolved in methylene chloride and a 7M methanolic solution of ammonia was added

Kz (O.2 ml). The resulting mixture was stirred at ambient temperature for 5 minutes. The mixture was filtered and the solvent was evaporated at ambient temperature under vacuum. In this way, (3К5,45К)-3,4-dimethoxypyrrolidine was obtained, which was used without any additional purification. (29) Using the conditions detailed in note (24| immediately above, except that the product was triturated in diethyl ether instead of pentane, (F) 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino )-7-(2-chloroethoxy)-5-tetrahydropyran-4-yloxyquinazoline was reacted with (3K5,455K)-3,4-ethylidenedioxypyrrolidine to give the desired product in yield 6795, which had the following characteristic data: NMR spectrum: .(SOSI") 1.45 (a, zn), 1.55 (a, 6H), 2.3 (y, 2H), 2.95 (t, 2H), 3.25 (a, vo 2H) , 425 (5 2H), 4.55 (t, 2H), 4.8 (t, 71H), 5.0 (t, 71H), 6.15 (v, 2H), 6.55 (v, 1H ), 6.85 (v, 1H), 7.75 (v, 1H), 8.6 (85, 1H), 9.6 (v, 1H); Mass spectrum MAN" 530 and 532; Elemental analysis : found C, 56.7, H, 5.5, M, 12.9;

Со5НовСИМ5ОБ 0.1 EBO is required C, 56.8; H, 5.4; M, 13,096. (3К5,455К)-3,4-Ethylidenedioxypyrrolidine, which was used as a starting material, was obtained as follows: 65 A solution of tert-butyl and (3К5,45К)-3,4-dihydroxypyrrolidine-1-carboxylate (0.5g) in methylene chloride (15 ml) was cooled to 0-592C and dimethyl acetal of acetaldehyde (0.782 ml) and 4-toluenesulfonic acid (0.025 g) were successively added. The reaction mixture was stirred at ambient temperature for 2 hours.

The resulting mixture was evaporated and the residue was purified by column chromatography on silicon dioxide, using mixtures of increasing polarity of petroleum ether (Tsuip. 40-602C) and ethyl acetate as eluent. In this way, tert-butyl (Z3K5,45K)-3,4-ethylidenedioxypyrrolidine-1-carboxylate was obtained in the form of oil (0.484 g); NMR spectrum: (SOSI") 1.4 (d, ZN), 1.45 (B, UM), 3.3 (t, 2H), 3.8 (t, 2H), 4.6 (t, 2H), 5.0 (4, 1H).

A chilled 5M solution of hydrogen chloride in isopropanol (4ml) was added to a solution of tert-butyl (z3k5.45K)-3,4-ethylidenedioxypyrrolidine-1-carboxylate (0.475g) in methylene chloride (25ml), which was cooled in an ice bath. The reaction mixture was allowed to warm to ambient temperature and stirred 7/0 for 2 hours. The solvent was evaporated and the residue was triturated in diethyl ether. The precipitate was collected by filtration, washed with diethyl ether and dried. In this way, (3k5.45K)-3,4-ethylidenedioxypyrrolidine hydrochloride (0.28g) was obtained; NMR spectrum: (DMSOα and СО5СО20) 1.35 (a, zn), 3.1 (a, 2H), 3.4 (a, 2H), 4.75 (c, 2H), 4.9 (a , 1H).

The substance obtained in this way was dissolved in methylene chloride and a 7 M methanolic solution of ammonia 75 (0.2 ml) was added. The resulting mixture was stirred at ambient temperature for 5 minutes. The mixture was filtered and the solvent was evaporated at ambient temperature under vacuum. In this way, (Z3K5,45K)-3,4-ethylidenedioxypyrrolidine was obtained, which was used without any additional purification.

The reactants were 7-(2-chloroethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)quinazoline and 1-methylpiperazine. The desired product was obtained at output 7495, which had the following characteristic data; NMR spectrum: (SOCI3 and СОО5СО020); Mass spectrum: MAN" 501 and 503; Elemental analysis: revealed C, 57.5; H, 6.5; M, 16.0;

С.4Ноо СИМОХ 0.23 Н2оО requires С, 57.8; H, 6.1; M, 16.25.

IZ1I The reactants were 7-(3-chloropropoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxyquinazoline (the preparation of which is described in example 12 below) and morpholine. We received the desired product at output 39965, which had the following characteristic data; NMR spectrum: (SOCI3) 1.55 (0, 6H), 2.05 (t, 2H), 2.45 (t, 4H), 2.55 (, 2H), 3.7 (t, 4H) , 4.15 (5, 2H), 4.85 (t, 1H), 6.15 (v, 2H), 6.5 (v, 1H), 6.85 (v, 1H), 7.75 ( c, 1H), 8.6 (c, 1H), 9.6 (c, 1H); Mass spectrum: MAN" 502 and 504; Elemental analysis: revealed C, 57.3; H, 5.65; M, 13.6; C24NovSIMmO" in required C, 57.4; H, 5.6; M, 13.9596.

The reactants were 7-(3-chloropropoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)quinazoline c (the preparation of which is described in example 13 below) and morpholine. The desired product was obtained at output 4596, which had the following characteristic data; NMR spectrum: (DMSOa and Ce3SO2O) 2.3 (t, 2H), 3.15 (t, 2H), 3.35 (t, 2H), 3.5 (t, 2H), 3.7 (t , 2H), 4.05 (t, 2H), 4.35 (t, 2H), 6.3 (5, 2H), 7.35 (v, 1H), 7.6 (a, 1H), 7 .9 (in, 1H), 8.7 (40, 1H), 9.05 (in, 1H); Mass spectrum: MAN" 444 and 446; Elemental analysis: found C, 57.0; H, 5.1; M, 15.7; Со4Но»СИМ5Од o required C, 56.8; H, 5.0; M , 15.89.

IZZI The reactants were 7-(3-chloropropoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)quinazoline and 1-acetylpiperazine. The desired product was obtained at output 3495, which had the following characteristic data; NMR spectrum: (DMSOаb and СР5СО20) 2.05 (in, ЗН), 2.3 (in, 2Н), 3.0 (t, 2Н), 3.15 (t, 7Н), 3.3-3 ,4 (t, 4H), 3.6 (t, 2H), 4.05 (t, 1H), 4.35 (t, 2H), 4.5 (t, 1H), 6.3 (in, 2H), 7.35 (v, 1H), 7.6 (y, 1H), 7.9 (v, 1H), 8.7 (d, yin), "HC 9.0 (8, 1H); Mass spectrum MAN" 485 and 487; Elemental analysis: revealed C, 56.9; H, 5.4; M, 16.6; SozNovSIM6OH 0.15 7 70 BO required C, 57.1; H, 5.4; M, 16,996. c IZAI The reactants were 7-(2-chloroethoxy)-4--2,3-methylenedioxypyrid-4-ylamino)quinazoline (the preparation of which is described in example 14 below) and 1-prop-2-ynylpiperazine. After cooling of the reaction mixture and evaporation of the solvent, the residue was triturated in water and the resulting precipitate was isolated, washed with water and diethyl ether and dried. The desired product was obtained in a yield of 6095, which had the following characteristic data: co 395 NMR spectrum: (SOCI3) 2, 26 (in, 1H), 2.8-2.6 (t, 8H), 2.97 (B 2H), 3.3 (in, 2H), 4.03 (in, ЗН), 4.33 ( i, 2H), 6.14 (c, 2H), 6.98 (c, 1H), 7.12 (Bg c, 1H), 7.30 (c, 1H), 7.73 (4, 1H) . -methylenedioxypyrid-4-ylamino)quinazoline (the preparation of which is described in example 15 below) and 1-prop-2-ynylpiperazine. The desired product was obtained at the output of 5790, which had the following characteristic data; NMR spectrum: (SOSI»z) 2.13 (t, 2H), 2.26 (v, 1H), 2.6 (t, TON), 3.31 («v) (5, 2H), 4 ... 1H), 7.72 (9, tn),

GI 8.08 (4, 1H), 8.76 (in, 1H); Mass spectrum: MAN" 477.

Example 7 6-(2-chloroethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-methoxyquinazoline

Using a technique similar to that described in example 1, 4-chloro-6-(2-chloroethoxy)-7-methoxyquinazoline was reacted with 4-amino-5-chloro-2,3-methylenedioxypyridine, obtaining the title compound at (Ф 59906; 1H), 7.2 (v, co 1H), 7.35 (v, 1H), 7.75 (v, 1H), 8.75 (v, 1H); Mass spectrum: MAN" 409 and 411, 4-Chloro-6-(2-chloroethoxy)-7-methoxyquinazoline, which was used as a starting material, was obtained in the following way:

A mixture of b-acetoxy-7-methoxy-3,4-dihydroquinazolin-4-one (international patent application MO 96/15118, example 391; 8g), thionyl chloride (8VOml) and DMF (0.8ml) was stirred and heated to 802 for 1.5 hours. The mixture was cooled to ambient temperature and the thionyl chloride was evaporated. The substance obtained in this way was suspended in toluene and evaporated to dryness (twice). The resulting residue was diluted with 65 methylene chloride (5 ml) and a 10:11 mixture (290 ml) of methanol and a saturated aqueous solution of ammonium hydroxide was added. The resulting mixture was stirred and heated to 802 for 5 minutes. The solvent was evaporated and the remaining solid was suspended in water. The basicity of the mixture was adjusted to pH7 by adding a dilute aqueous solution of hydrochloric acid. The resulting solid was collected by filtration, washed with water and dried under vacuum over phosphorus pentoxide. In this way, 4-chloro-6-hydroxy-7-methoxyquinazoline (6.08 g) was obtained, which was used without additional purification; NMR spectrum: (DMSO av) 4.05 (in, 3H), 7.4 (8, 1H), 7.45 (in, 1H), 8.8 (in, 1H).

Di-tert-butyl azodicarboxylate (1.5-3 ml) was added in portions over several minutes to a stirred mixture of 4-chloro-b-hydroxy-7-methoxyquinazoline (1 g), 2-chloroethanol (0.382 ml), triphenylphosphine (1.74 g) and methylene chloride (ZOml) and the reaction mixture was stirred at ambient temperature for 7/0 2 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using mixtures of increasing polarity of methylene chloride and ethyl acetate as eluent. In this way, 4-chloro-6-(2-chloroethoxy)-7-methoxyquinazoline was obtained as a white solid (1.06 g); NMR spectrum: (SOSI") 3.95 (i, 2H), 4.05 (in, 3H), 4.45 (I, 2H), 7.35 (in, 1H), 7.4 (in, 1H), 8.9 (in, 1H).

Example 8 6-(3-chloropropoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-methoxyquinazoline

Using a technique similar to that described in Example 1, 4-chloro-6-(3-chloropropoxy)-7-methoxyquinazoline was reacted with 4-amino-5-chloro-2,3-methylenedioxypyridine to give the title compound in a yield of 5890 ; NMR spectrum: (SOCI5) 2.4 (t, 2H), 3.8 (6 2H), 4.05 (8, ЗН), 4.35 (I, 2H), 6.15 (v, 2H) , 7.05 (in, 1H), 7.2 (8, 1H), 7.3 (8, 1H), 7.75 (in, 1H), 8.7 (8, 1H); Mass spectrum: MAN" 423 20 1425. 4-Chloro-6-(3-chloropropoxy)-7-methoxyquinazoline, which was used as a starting material, was obtained as follows:

Di-tert-butyl azodicarboxylate (1.84 g) was added in portions over several minutes to a stirred mixture of 4-chloro-6-hydroxy-7-methoxyquinazoline (1.2 g), 3-chloropropanol (0.572 ml), triphenylphosphine (21) and " with methylene chloride (3 mL) and the reaction mixture was stirred at ambient temperature for

From hours The mixture was evaporated and the residue was purified by column chromatography on silica, and9) using mixtures of increasing polarity of methylene chloride and ethyl acetate as eluent. The substance obtained in this way was ground into powder in diethyl ether. The resulting solid was isolated and dried in a vacuum. In this way, 4-chloro-6-(3-chloropropoxy)-7-methoxyquinazoline was obtained in the form of a white solid substance (0.84 g);) NMR spectrum. (SOSIi) 2.4 (t, 2H), 3.8 (B 2H), 4.05 (v, 3H), 4.35 (5 2H), 7.35 (v, 1H), 7.45 ( 85, 1H), 8.9 (in, 1H). at

Example 9 with 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(3-chloropropoxy)-5-tetrahydropyran-4-yloxyquinazoline

Using a technique similar to that described in example 1, - 4-xpor-7-(3-chloropropoxy)-5-tetrahydropyran-4-yloxyquinazoline was subjected to interaction with o 4-amino-5-chloro-2,3-methylenedioxypyridine, obtaining the specified in the header, the connection at the exit is 7895;

Mass spectrum: MAN" 493 and 495. 4-Chloro-7-(3-chloropropoxy)-5-tetrahydropyran-4-yloxyquinazoline, which was used as a starting material, was obtained as follows:

Using a technique similar to that described in example 4, in the part that concerns the preparation of - c starting substances, 4-chloro-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline (2.5 g) was subjected to interaction with a 3-chloropropanol . In this way, the desired starting substance was obtained in a yield of 2195; NMR spectrum: (DMSOаb , and СЕ3СО20О) 1.7 (t, 2H), 2.0 (t, 2H), 2.25 (t, 2H), 3.55 (t, 2H), 3.8 (i, 2H), 3.9 (t, 2H), 4.3 (B 2H), 4.95 (t, 1H), 6.8 (5, 1H), 6.9 (8.1H), 9.2 (in, 1H).

Example 10 (ee) 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(2,4-dimethoxybenzyloxy)-5-isopropoxyquinazoline o Using a method similar to that described in example 1, 4-chloro -7-(2,4-dimethoxybenzyloxy)-5-isopropoxyquinazoline was subjected to the interaction of Kk! (95) with 4-amino-5-chloro-2,3-methylenedioxypyridine to give the title compound in yield 7595; o 50 NMR spectrum:. (SOCIz) 1.55 (y, 6H), 3.8 (5, ЗН), 3.85 (в, ЗН), 4.8 (t, 1Н), 5.15 (5, 2Н), 6, 15 (v, 2H), 6.5 (t, 2H), 6.6 (v, 1H), 7.0 (v, 1H), 7.35 (y, 1H), 7.75 (v, 1H ), 8.6 (in, 1H), 9.6 (in, 1H); Mass spectrum: MAN" 525 and 527.

IR) 4-Chloro-7-(2,4-dimethoxybenzyloxy)-5-isopropoxyquinazoline, which was used as a starting material, was obtained as follows:

Sodium hydride (6095 dispersion in mineral oil; 40 g) was added in portions to a solution of isopropanol (SOg) in

DMF (500 ml), which was cooled to 5 2С. The mixture was allowed to warm to ambient temperature

GF! medium and stirred for 60 minutes. 5,7-difluoro-3,4-dihydroquinazolin-4-one was added (international patent application MO 01/94341); 9Og) and the mixture was stirred at ambient temperature for 3 hours. The mixture was poured into water (1 liter) and, with intensive stirring, glacial acetic acid was added to acidify the mixture to pH5. The resulting solid was isolated, washed with water and diethyl ether 60 and dried in a vacuum. In this way, 7-fluoro-5-isopropoxy-3,4-dihydroquinazolin-4-one (79g) was obtained; NMR spectrum: (DMSOa) 1.91 (5, 6H), 4.73 (t, 1H), 6.89 (t, 1H), 6(95 (t, 1H), 7.96 (v, 1H ); Mass spectrum: Men" 223.

A mixture of /7-fluoro-5-isopropoxy-3,4-dihydroquinazolin-4-one (61 g), 2,4-dimethoxybenzyl alcohol (138 g), potassium tert-butoxide (185 g) and THF (1.5 liters) was stirred and was heated in a reflux flask for 18 hours. After cooling, the solvent was evaporated and a mixture of methylene chloride (400 ml) and water was added

(b0Oml). Upon cooling, the 2-phase mixture was neutralized by adding 2 n. aqueous hydrochloric acid.

The mixture was filtered and the organic phase was separated, dried over magnesium sulfate and evaporated. The residue was triturated in diethyl ether. in this way was obtained ij0007-2,4-dimethoxybenzyloxy)-5-isopropoxy-3,4-dihydroquinazolin-4-one (68g); NMR spectrum: (DMSOy5) 1.28 (v, b6H), 3.78 (5, ЗН), 3.82 (v, ЗН), 4.63 (t, 71Н), 5.06 (v, 2Н ), 6.55 (t, 2H), 6.62 (8, 1H), 6.71 (c, 1H), 7.33 (a, 1H), 7.88 (c, 1H); Mass spectrum: MAN" 371.

A mixture of part (4g) of the substance obtained in this way, phosphorus oxychloride (1.98g), diisopropylethylamine (3.6g) and methylene chloride (10O0ml) was stirred and heated to 759 for 3 hours. The mixture was cooled and evaporated. The residue was dried in vacuo for 1 hour and purified by column chromatography on silica using a 20:3 mixture of methylene chloride and ethyl acetate as eluent. In this way, 4-chloro-7-(2,4-dimethoxybenzyloxy)-5-isopropoxyquinazoline was obtained as a solid (2.637); NMR spectrum: (СОСИ5) 1.46 (5, ЗН), 1.47 (з, ЗН), 3.83 (в, ЗН), 3.85 (в, ЗН), 4.68 (t, 1Н), 5, 16 (v, 2H), 6.52 (t, 2H), 6.65 (5, 1H), 7.06 (v, 1H), 7.33 (j, 1H), 8.78 (v, 1H ); Mass spectrum: MAN" 389.

Example 11 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-hydroxy-5-isopropoxyquinazoline

Trifluoroacetic acid (4.5 ml) was added to a solution of 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(2,4-dimethoxybenzyloxy)-5-isopropoxyquinazoline (0.53 g) in methylene chloride (Uml ) and the reaction mixture was stirred at ambient temperature for 30 minutes. The solvents were evaporated, obtaining the di-trifluoroacetic acid salt (0.618 g) of the desired compound. Part of this salt was dissolved in methylene chloride (2 ml) and a 7 M methanolic solution of ammonia was added. The mixture was filtered and the filtrate was evaporated. In this way, the title compound was obtained; Mass spectrum: MAN" 375 and 377.

Example 12 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(3-chloropropoxy)-5-isopropoxyquinazoline c

A mixture of 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-hydroxy-5-isopropoxyquinazoline He) salt of di-trifluoroacetic acid (0.615 g), 1,3-dichloropropane (0.38 ml), carbonate potassium (0.56 bg) and DMF (bml) were stirred and heated to 802 for 5 hours. After cooling, the solids were filtered off and the filtrate was evaporated. The residue was purified by column chromatography on silica using a 24:11 mixture of methylene chloride and methanol as eluent. In this way, the compound indicated in the title was obtained (0.32 g); NMR spectrum: (SOSIIIa) 1.55 (0, 6H), 2.3 (t, 2H), 3.8 (y, 2H), 4.25 (y, 2H), 4.9 (t, o 1H), 6.15 (8, 2H), 6.5 (8, 1H), 6.9 (8, 1H), 7.75 (5, 1H), 8.6 (in, 1H), 9, 6 (c, 1H).

Example 13 me) 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(3-chloropropoxy)quinazoline o

Using a technique similar to that described in example 1, 4-chloro-7-(3-chloropropoxy)quinazoline 3o was subjected to interaction with 4-amino-5-chloro-2,3-methylenedioxypyridine, obtaining the title compound with a yield of 8995; NMR spectrum: (DMSOα and СЕР53СО250) 2.25 (t, 2H), 3.8 (6 2H), 4.35 (, 2H), 6.25 (v, 2H), 7.35 (v, 1H ), 7.6 (d, 1H), 7.9 (c, 1H), 8.7 (9, 1H), 9.0 (c, 1H). 4-Chloro-7-(33-chloropropoxy)quinazoline, which was used as a starting material, was obtained in the following way:

Sodium hydride (6095 dispersion in mineral oil; 2.92g) was added in portions over 45 minutes to a stirred mixture of 1,3-propanediol (5.3ml) and DMF (20ml), which was cooled to 02С. The resulting mixture was stirred at ambient temperature for 1 hour and then heated to 6bO2eb. "from 7-fluoro-3,4-dihydroquinazolin-4-one was added | international patent application M/O 01/04102, example 2, note

I121Y; 2d) and the reaction mixture was stirred and heated to 1152 for 3.5 hours. The reaction mixture was cooled to 02C and water (50 ml) was added. The mixture was acidified to pH 5.0 2N. aqueous hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried under vacuum over phosphorus pentoxide at 4026.

The solid obtained in this way was washed with diethyl ether and dried again under vacuum. In this way, 7-(3-hydroxypropoxy)-3,4-dihydroquinazolin-4-one (2.1 g) was obtained; NMR spectrum: (DMSOαb) 1.9 (t, 2H),

Ha 3.6 (t, 2H), 4.15 (t, 2H), 4.6 (Bg in, 2H), 7.1 (t, 2H), 8.05 (t, 2H); Mass spectrum: MAN" 221.

A mixture of 7-(33-hydroxypropoxy)-3,4-dihydroquinazolin-4-one (1g), 1,2-dichloroethane (50ml), triphenylphosphine (5.24g) and carbon tetrachloride (2.9ml) was stirred and heated to 709 for 2 hours. Solvent

Kz was evaporated and the residue was purified by column chromatography on silica, using first methylene chloride, and then gradually increasing the polarity of the solvent to a 9:1 mixture of methylene chloride and methanol as eluent. In this way, 4-chloro-7-(3-chloropropoxy)quinazoline was obtained (1.23 g; which contains 0.bmol of triphenylphosphine oxide per mol of product); Mass spectrum: MAN" 393 and 395.

Example 14 o 7-(2-chloroethoxy)-4--2,3-methylenedioxypyrid-4-ylamino)-6-methoxyquinazoline sodium hexamethyldisilazane (1M solution in THF; 2ml) was added dropwise to a mixture of 4-amino-2, of 3-methylenedioxypyridine (0.138g), 4-chloro-7-(2-chloroethoxy)-b-methoxyquinazoline (0.272g) and THF (Bml), 60 which was cooled to 02. The mixture was stirred at 09 for 1 hour. The resulting mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The reaction mixture was sharply cooled by adding glacial acetic acid (0.12 ml). The solvents were evaporated and the residue was partitioned between methylene chloride and aqueous ammonium hydroxide. The organic layer was collected and concentrated to a small volume. Diethyl ether was added and a precipitate formed. The resulting solid 65 was isolated, washed with diethyl ether and dried. In this way, the title compound was obtained (0.245 g); NMR spectrum: (DMSOdv) 3.97 (v, ZN), 4.04 (t, 2H), 4.45 (t, 2H), 6.12 (v, 2H), 7.13 (Bg a, tn),

7.25 (in, 1H), 7.60 (y, 1H), 7.83 (8, 1H), 8.47 (in, 1H), 9.87 (Bg in, 1H); Mass spectrum: MAN" 375. 4-Amino-2,3-methylenedioxypyridine, which was used as a starting material, was obtained as follows:

Dibromomethane (31.5ml) was added to a mixture of 2,3-dihydroxypyridine (3g), potassium carbonate (62g) and MMR (200ml) and the mixture was stirred and heated to 90°C for 16 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was partitioned between diethyl ether (5 x 100 ml) and water (200 ml). The organic extracts were combined and concentrated in a vacuum to a volume of approximately 20 ml. Petroleum ether (MU 40-602C; Zb0Oml) was added and the solution was washed with saline solution. The organic layer was separated and evaporated. In this way, 2,3-methylenedioxypyridine was obtained in the form of a liquid (5.1 g); NMR spectrum: (SOSI 5) 70 6.05 (v, 2H), 6.76 (t, 1H), 6.99 (y, 1H), 7.65 (a, 1H).

Using a technique similar to that described in the second paragraph in that part of example 1, which concerns the preparation of the starting substance 4-amino-5-chloro-2,3-methylenedioxypyridine, 2,3-methylenedioxypyridine was subjected to interaction with carbon dioxide, obtaining 2,3- methylenedioxypyridine-4-carboxylic acid with a yield of 8090;

NMR spectrum: (DMSOαb) 6.24 (c, 2H), 7.13 (a, 1H); 7.63 (4, 1H).

Using a technique similar to that described in the third paragraph in that part of example 1, which concerns the preparation of starting substances, 2,3-methylenedioxypyridine-4-carboxylic acid was subjected to interaction with diphenylphosphoryl azide and anhydrous tert-butanol, obtaining tert-butyl 2,3-methylenedioxypyride -4-ylcarbamate in a yield of 6295; Mass spectrum: MAN" 239.

Using a technique similar to that described in the last paragraph in that part of example 1, which concerns the preparation of starting substances, tert-butyl 2,3-methylenedioxypyrid-4-ylcarbamate was subjected to interaction with trifluoroacetic acid, obtaining 4-amino-2,3-methylenedioxypyridine at outputs 8095; NMR spectrum: (SOSI") 3.98 (t, 2H), 5.98 (v, 2H), 6.24 (y, 1H), 7.44 (y, 1H); Mass spectrum: MAN 139,

Example 15 7-(3-chloropropoxy)-4-(2,3-methylenedioxypyrid-4-ylamino)-b-methoxyquinazoline c 29 Using a technique similar to that described in example 14, Ge) 4-chloro-7-(3- chloropropoxy)-b-methoxyquinazoline was reacted with 4-amino-2,3-methylenedioxypyridine, obtaining the title compound in yield 6896 NMR spectrum: (DMSOαb) 2.26 (t, 2H), 3.83 (t, 2H ), 3.96 (5, ЗН), 428 (t, 2Н), 6.12 (в, 2Н), 7.15 (рга, 1), 7.25 (в, 1Н), 7.61 ( y, 1), 7.81 (in, 1H), 8.49 (in, 1H), 9.79 (Brg 8, 1H); Mass spectrum: MAN" 389. sch

Example 16 about 7-(2-(4-acetylpiperazin-1-yl)ethoxy)|-4-(2,3-methylenedioxypyrid-4-ylamino)-5-tetrahydropyran-4-yloxyquinazoline

Using a technique similar to that described in example 1, Shk 7-(2-(4-acetylpiperazin-1-yl)ethoxy|-4-chloro-5-tetrahydropyran-4-yloxyquinazoline (0.113g) was subjected to the interaction of sz3z with 4-amino -2,3-methylenedioxypyridine (0.036g). The reaction mixture was quenched with glacial acetic acid (0.031g) and diluted with methanol. The mixture was evaporated and the residue was purified by column chromatography on a C18 reversed-phase silica column (UUa column (egv Zutteig, 5 micron silica, diameter 20 mm, length 100 mm), using a mixture of reduced polarity of water and acetonitrile (containing 1956 acetic acid) as eluent. The substance thus obtained was diluted with 7 M methanolic ammonia solution. The mixture was evaporated and the substance obtained in this way was dissolved in methylene chloride. The solution -o was dried over magnesium sulfate and evaporated, obtaining the title compound in the form of a foam with a yield of 5390; NMR spectrum: (SOCI3) 2.02 (t, 2H), 2.1 (in, ZN), 2.22 (t, 2H), 2 .6 (t, 4H), 2.9 (t, 2H), 3.51 (t, :z» 2H), 3.6 (t, 2H), 3.66 (t, 2H), 4.1 (t, 2H), 4.25 (t, 2H), 4.73 (t, 1H), 6.13 (v, 2H), 6.59 (v, 1H), 6.9 (v, 1H) , 7.7 (9, 1H), 8.36 (d, 1H), 8.66 (c, 1H); Mass spectrum MAN" 537. 415 7-(2-(4-Acetylpiperazin-1-yl)ethoxy|-4-chloro-5-tetrahydropyran-4-yloxyquinazoline, which was used as a starting material, was obtained as follows:

Sodium hydride (6095 dispersion in mineral oil; 0.bg) was added in portions to a solution ("c") of 4-hydroxytetrahydropyran (0.78g) in DMF (10ml), which was cooled to 52C. The mixture was allowed to warm to ambient temperature and stirred for 15 minutes. 20 5,7-difluoro-3,4-dihydroquinazolin-4-one (international patent application MUO 01/943411; 0.9 g) was added and the mixture was stirred at ambient temperature for 30 minutes. The mixture was poured into water (100 ml) and, with intensive stirring, glacial acetic acid was added to acidify the mixture to pH5. The resulting solid was isolated, washed with water and diethyl ether and dried under vacuum. 7-Fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (1.17) was obtained in this way: NMR spectrum: (DMSO₃) 1.6-1.75 (t, 2H) , 1.9-2.0 (t, 2H), 3.5-3.6 (t, 2H), 3.85-3.95 (t, 2H), 4.8 (t, 1H), 6 .9 (t, 1H), 7.05 (t, 1H), 8.0 (v, 1H); Mass spectrum: MAN" 265.

F) After repeating the previous reaction, a mixture of 7-fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one co (5.3g), 2-piperazine-1-ylethanol (3.9g), tert -potassium butoxide (6.7g) and THF (200ml) were mixed and heated in a reflux flask for 3 hours. The second part (6.7 g) of potassium tert-butoxide was added and the mixture was heated in a reflux flask for an additional 12 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was purified by column chromatography on silica using mixtures of increasing polarity of methylene chloride and 7M methanolic ammonia as eluent. The substance obtained in this way was ground into powder in diethyl ether. bBo0/7-(2-piperazin-1-ylethoxy)-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one was obtained in this way. (5.27); NMR spectrum: (DMSOa» and

СЕзСО2О) 1.75 (t, 2H), 2.03 (t, 2H), 3.2-4.0 (t, 14H), 4.59 (t, 2H), 4.92 (t, 1H) , 6.88 (8, 1H), 6.9 (in,

1H), 9.28 (in, 1H); Mass spectrum: MAN" 375.

Acetic anhydride (1.51 ml) was added dropwise to a stirred mixture of 7-(2-piperazin-1-ylethoxy)-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (5 g) and water (20 ml) and the resulting mixture was stirred at ambient temperature for 10 minutes. The reaction mixture was evaporated and the residue was triturated in diethyl ether. The resulting solid was isolated, washed with diethyl ether and dried under vacuum. 7-(2-(4-acetylpiperazin-1-yl)ethoxy|-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (5.5 g) was obtained in this way; NMR spectrum: (DMSOaz and SRZCO2O) 1.75 (t, 2H), 2.03 (t, 2H), 2.08 (v, ЗН), 3.0-4.2 (t, 1З3Н), 4.56 (t, ЗН ), 4.94 (t, 1H), 70... 6.84 (v, 1H), 6.9 (v, 1H), 9.21 (v, 1H); Mass spectrum: MAN" 417.

A mixture of part (0.416 g) of the substance obtained in this way, triphenylphosphine (0.655 g), carbon tetrachloride (0.34 ml) and 1,2-dichloroethane (200 ml) was stirred and heated to 7092C for 1.5 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using mixtures of increasing polarity of methylene chloride and 7M methanolic ammonia (solvent gradient from 75 1956 to 395 methanolic ammonia) as eluent. In this way, 7-(2-(4-acetylpiperazin-1-yl)ethoxy|-4-chloro-5-tetrahydropyran-4-yloxyquinazoline was obtained in the form of a solid substance (0.35 g); NMR spectrum: (SOCIa) 2 ,0 (t, 2H), 2.1 (v, ЗН), 2.12 (t, 2H), 2.58 (t, 4H), 2.9 (t, 2H), 3.51 (t, 2H), 3.68 (t, 4H), 4.05 (t, 2H), 4.25 (t, 2H), 4.75 (t, 1H), 6.62 (v, 1H), 6, 94 (in, 1H), 8.82 (in, 1H); Mass spectrum: MAN" 435 and 437.

Example 17 7-(2-(4-acetylpiperazin-1-yl)ethoxy)|-4-(2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxyquinazoline

Using a technique similar to that described in example 16, 7-(2-(4-acetylpiperazin-1-yl)ethoxy|-4-chloro-5-isopropoxyquinazoline was subjected to interaction with 4-amino-2,3-methylenedioxypyridine, obtaining indicated in title compound, yield 5596; NMR spectrum; SM (SOCI5) 1.55 (b, 3H), 1.56 (b, 3H), 2.1 (b, 3H), 2.59 (t, 4H) , 2.89 (t, 2H), 3.51 (t, 2H), 3.67 (t, 2H), o 4.24 (t, 2H), 4.85 (t, 1H), 6.13 (c, 2H), 6.57 (c, 1H), 6.85 (c, 1H), 7.71 (a, 1H), 8.41 (a, tn), 8.66 (c, 1H) ; Mass spectrum: MAN" 495. 7-(2-(4-Acetylpiperazin-1-yl)ethoxy|-4-chloro-5-isopropoxyquinazoline, which is required as a starting material, was obtained as follows using techniques analogous to those of , described in that part of Example 16, which concerns the preparation of starting substances. o 5,7-Difluoro-3,4-dihydroquinazolin-4-one was subjected to the reaction of Kk! with isopropanol, obtaining 7-fluoro-5-isopropoxy-3,4- dihydroquinazolin-4-one in a yield of 7390; NMR spectrum: (DMSOiv) 1.31 (in, 6H), 4.73 (t, o 1H), 6.89 (t, 1H), 6.95 (t, 1H), 7.9 6 (c, 1H); Mass spectrum: MAN" 223. av

The substance obtained in this way was subjected to interaction with 2-piperazin-1-ylethanol, obtaining 5-isopropoxy-7-(2-piperazin-1-ylethoxy)-3,4-dihydroquinazolin-4-one in a yield of 6395; NMR spectrum: (SOCI5) 1.45 09 (5, ZN), 1.46 (z, ZN), 2.4-3.0 (t, 1OH), 4.2 (Yi, 2H), 4, 62 (t, 1H), 6.51 (8, 1H), 6.72 (8, 1H), 7.9 (v, 1H).

The substance obtained in this way was reacted with an excess of acetic anhydride, but methylene chloride was used instead of water as a reaction solvent. The reaction mixture was stirred at ambient temperature for 15 minutes. The mixture was distributed between methylene chloride and 7 70 saturated aqueous solution of sodium bicarbonate. The organic layer was washed with water and saline, dried over magnesium sulfate and evaporated. The residue was ground into powder in a mixture of acetonitrile and diethyl ether. 7-(2--4-acetylpiperazin-1-yl)ethoxy|-5-isopropoxy-3,4-dihydroquinazolin-4-one was obtained in this way in a yield of 7095; NMR spectrum: (SOCI3) 1.46 (in, ZN), 1.47 (in, ZN), 2.1 (8, ZN), 2.58 (t, 4H), 2.87 (i, 2H ), 3.5 (t, 2H), 3.66 (t, 2H), 4.21 so that (B, 2H), 4.63 (t, 1H), 6.51 (c, 1H), 6 .72 (8, 1H), 7.9 (in, 1H), 9.9 (Bg 8, 1M); Mass spectrum: MAN" 375.

The substance obtained in this way was reacted with carbon tetrachloride and triphenylphosphine, (а) obtaining // 7-(2-(4-acetylpiperazin-1-yl)ethoxy|-4-chloro-5-isopropoxyquinazoline in a yield of 6895, which this was used without additional purification.

Example 18 (ав) 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-2-I4-(-2-dimethylaminoacetyl)piperazin-1-yl|ethoxy)-5-isoprop

KZ oxyquinazoline 4-(5-Chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxy-7-(2-piperazin-1-ylethoxy)quinazoline (0.2 g) was added to a stirred mixture of 2-dimethylaminoacetyl chloride hydrochloride ( 0.097 g), triethylamine (0.15 ml) and 5 methylene chloride (bml), which was cooled to 0 2С. The reaction mixture was allowed to warm to ambient temperature and was stirred for 2 hours. A second portion of each hydrochloride (F) of 2-dimethylaminoacetyl chloride (0.097g) and triethylamine (0.057ml) was added, and the reaction mixture was stirred at

GI at ambient temperature for 1b hours all night. Methylene chloride (5 Oml) was added and the reaction mixture was extracted twice with a saturated aqueous solution of sodium bicarbonate. The organic phase was dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica using solvent mixtures of increasing polarity, starting with a 9:1 mixture of methylene chloride and methanol and ending with a 90:8:2 mixture of methylene chloride, methanol and a saturated methanolic ammonia solution. In this way, the compound indicated in the title was obtained in the form of a foam (0.155 g);

NMR spectrum: (SOSI") 1.55 (4, 6H), 2.3 (b, 6H), 2.6 (t, 4H), 2.9 (B 2H), 31 (b, 2H). 3.65 (t, 4H), 4.25 (I, 2H), 485 (z, 65 HO), 6.15 (v, 2H), 6.55 (z, 1H), 6.85 (8, 1H), 7.75 (in, 1H), 8.6 (8, 1H), 9.6 (5, 1H); Mass spectrum: MEN" 572 and 574;

Elemental analysis: revealed C, 55.1; H, 6.1; M, 16.8; С27НадСИМ7Ов 0.75 NoО requires C, 55.4; H, 6.1; M, 16.79.

Example 19 7-(M-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-(5-chloro-2.3-methylenedioxypyrid-4-ylamino)-6-methoxyquinase olin

Using a technique similar to that described in Example 1, a solution of 4-amino-5-chloro-2,3-methylenedioxypyridine (0.193g) in DMF (2ml) was added to a stirred suspension of sodium hydride (6095 dispersion in mineral oil, 0.048g) in DMF (2 mL) and the mixture was stirred at ambient temperature for 15 minutes. A solution of 7-(M-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-chloro-b6-methoxyquinazoline was added |international patent application MO 7/0 92/16352 (note (24) in example 2 of this application; 0.38g| in DMF (4 mL) and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and brine. The organic phase was dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica using a 49:11 mixture methylene chloride and methanol. In this way, the title compound was obtained as a solid (0.24 g); 7/5 NMR spectrum: (DMSOdv) 1.29 (t, 2H), 1.45 (5, 9H), 1.8 (t, 2H), 2.04 (t, 7H), 2.83 (t, 2H), 4.0 (t, 7H), 8.12 (bg 8, 2H), 7.17 ( Bg in, 1H), 7.72 (t, 2H), 8.37 (Bg in, 1H), 9.37 (Bg 5, 1H); Mass spectrum MAN" 544 and 546.

Example 20 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-b-methoxy-7-(piperidin-4-ylmethoxy)quinazoline

Trifluoroacetic acid (Iml) was added to a solution of 7-(M-TROT-butoxycarbonylpiperidin-4-ylmethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-methoxyquinazoline (0.253g) in methylene chloride (1Oml) and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated. Toluene was added to the residue and the mixture was evaporated.

The residue was purified by column chromatography on silicon dioxide (IzoYishsche CH column) using 7M methanolic ammonia solution as eluent. In this way, we received the Ge! indicated in the title! compound in the form of a solid substance (0.187 g); NMR spectrum: (DMSOa 6) 1.25 (t, 2H), 1.75 (a, 2H), 1.93 (t, 1H), (5) 2.54 (t, 2H), 3.0 (4, 2H), 3.93 (in, 3H), 3.98 (a, 2H), 6.17 (in, 2H), 7.15 (in, 1H), 7.76 (8, 1H) , 7.78 (in, 1H), 8.23 (in, 1H); Mass spectrum: MAN" 444 and 446.

Example 21 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-I(M-(2-dimethylaminoacetyl)piperidin-4-ylmethoxy|-b-methoxyxinazolin

Diisopropylethylamine (0.118 ml) was added to a mixture of 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-b-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (0.15 g), about

M,M-dimethylglycine (0.042g), hexafluorophosphate (M) 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium o (0.154g) and DMF (3ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with ethyl acetate and washed with saline. The organic solution was dried over 90% magnesium sulfate and evaporated. The residue was purified by column chromatography on silicon dioxide, using a mixture of 100:3 methylene chloride and 7M methanolic ammonia solution as eluent. In this way, the title compound was obtained as a solid (0.051 g); NMR spectrum: (DMSOy b). 1.11-1.36 " (t, 2H), 1.83 (y, 2H), 2.11 (t, 1H), 2.19 (v, 6H), 2.61 (B 1), 3 ... c, 2H), 7.19 (Bg c, 1H), 7.78 (t, 2H), 8.39 (rg c, 1H), 9.71 (Bg c, 1H); Mass spectrum: MAN o, p 7 529 and 531. "from Example 22 " 7-(2-(4-acetylpiperazin-1-yl)ethoxy)|-4-(5-chloro-2,3-methylenedioxypyrid-4 -ylamino)-5-isopropoxyquinazoline

A mixture of 7-(2-chloroethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxyquinazoline (248), 1-acetylpiperazine (21g), potassium iodide (18g) and DMA (500ml ) were stirred and heated to 1002C for 4 hours. The solvent was evaporated and the residue was partitioned between methylene chloride (1 liter) and water (500 ml). Water layer av! extracted with methylene chloride. The organic solutions were combined, washed with saline, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silicon dioxide, using mixtures of increasing polarity of methylene chloride and methanol (from a mixture of 20:1 to a mixture of av! 20 10:11) as an eluent. After evaporation of the solvent, the substance obtained in this way was ground into a powder in diethyl ether. In this way, the title compound was obtained in the form of a white solid (26.2 g); dl 208-210. 7-(2-Chlorethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxyquinazoline, which was used as a starting material, was obtained as follows:

Sodium hexamethyldisilazane (1M solution in THF, 1b4ml) was added dropwise over one hour to

HF) of a mixture, cooled on ice, of 4-chloro-7-(2,4-dimethoxybenzyloxy)-5-isopropoxyquinazoline (320), t of 4-amino-5-chloro-2,3-methylenedioxypyridine (15.6 g) and THF (430ml), at this time the temperature of the reaction mixture was maintained at approximately 32C. After the addition, the reaction mixture was allowed to warm to ambient temperature and stirred for 2.5 hours. The reaction mixture was cooled to 60 02 and a mixture of acetic acid (9U.4ml) and water (250ml) was added. The mixture was evaporated and the residue was distributed between methylene chloride and water, the basicity of the aqueous phase was adjusted to 7.5 by adding Z n. aqueous solution of hydrochloric acid. The organic phase was separated and the aqueous phase was extracted three times with methylene chloride. The organic layers were combined, washed with saline, dried over magnesium sulfate and evaporated. The resulting solid substance was ground into powder in ethyl acetate. 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(2,4-dimethoxybenzyloxy)-5-isopropoxyquinazoline was obtained in this way as a white solid (38g); Mass spectrum: MAN" 525 and 527.

Triethylsilane (70 mL) and trifluoroacetic acid (48 mL) were added alternately to an ice-cooled solution of 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(2,4-dimethoxybenzyloxy)-5-isopropoxyquinazoline ( 37.7) in methylene chloride (5 bOml) and the resulting reaction mixture was stirred at ambient temperature for 1 hour. Solvents were evaporated in high vacuum. The resulting solid was triturated in ethyl acetate. The substance obtained in this way was isolated, washed with ethyl acetate and dried in a high vacuum. In this way, the salt of di-trifluoroacetic acid was obtained (and (37.4 g of 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7 -hydroxy-5-isopropoxyquinazoline, which was used without 70 additional purification.

Potassium carbonate (34.6 g) was added to a mixture of di-trifluoroacetic acid salt and 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-hydroxy-5-isopropoxyquinazoline (49 g), 1,2-dichloroethane (44O0ml) and DMF (245ml) and the mixture was stirred and heated to 902 for 3.5 hours. An additional portion (7g) of potassium carbonate was added and the mixture was stirred at 9023 for an additional hour. The reaction mixture was cooled to 75 ambient temperature and the solids were filtered off and washed with methylene chloride.

The filtrate and washings were combined and evaporated. The resulting residue was purified by column chromatography on silica using mixtures of increasing polarity of methylene chloride and methanol (from a 50:1 mixture to a 2071 mixture) as eluent. 7-(2-chloroethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxyquinazoline was obtained in this way as a white solid (37.1 g); Mass spectrum: MAN" 437 and 439.

Claims (18)

The formula of the invention p 1. Quinazoline derivative of the formula | (5) (B (0 zem KA c o 0--/ o B! o mu - o in which 7 represents О, 5, 50, 505, ШЧА) or C(B2)" group in which each group K ?, which can be the same. /-::00 or different, represents hydrogen or C1-C6-alkyl; t represents 1, 2 or 3; and BK! substituents can be located in the 5th, b and/or the 7-position of the quinazoline ring, provided that the 5-position is substituted; "each group B", which may be the same or different, is selected from halogen, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, C4-Cv-alkyl, Co-Cv-alkenyl, Co-Cv-alkynyl, but) C.i-Cv-Alkoxy, Co-Cv-alkenyloxy, C.-Cv-alkynyloxy, C.-Cv-alkylthio, C.-Cv-alkylsulfinyl, : » C.4-Cv-alkylsulfonyl, C.-Cv- alkylamino, di-IS--Sn-alkyl|amino, C.-Cv-Alkoxycarbonyl, U 00 -C.-Ce-alkylcarbamoyl, MM -di-(IS4i-Cv-alkyl|carbamoyl, Co-Cv-alkanoyl, Co-Cv-alkanoyloxy, Co-Cv-alkanoylamino, M - Cb4-Cv-alkyl-Co-Cv-alkanoylamino, Co C3-Cv-alkenoylamino, and: -Cb4-Cv-alkyl-C3-Cv-alkenoylamino, o Ca-Cv-alkynoylamino, U 0 -C.-Ce-alkyl -C3-Cv-alkynoylamino, M 0 -C4-Cv-alkylsulfamoyl, M m -di-(C4-Cv-alkyl)isulfamoyl, C.i-Cv-alkanesulfonylamino and U -C.4-Cv-alkyl-C .-Co-alkanesulfonylamino, or from the Ha ShK group of the formula: go ah where X" is a simple bond or selected from 0, 5, 50, 505, ЭЭ), СО, СН(OKU), СОМ), Эче СО . -alkyl, Ca-C,-cycloalkyl, C3-C,-cycloalkyl-Ci-Cv-alkyl, C3-C,-cycloalkenyl, C3-C,-cycloalkenyl-C -Cv-alkyl, heteroaryl, heteroaryl-C4-Cv -alkyl, heterocyclyl or o heterocyclyl-C 1-Cv-alkyl, or (K")t represents C.-C3-alkylenedioxy, o and where adjacent carbon atoms in any Co-Cv-alkylene chain in within VK! of the substituent are optionally separated by a group inserted into the chain, selected from О, 5, 50, 505, Ш(КУ), СО, СН(OKU), СОМ), ШХAZСО, 60 5О.М(2), М(29)50 », SN-SN and be C, where is VE? is hydrogen or C 1-Cv-alkyl or, if the inserted group is M(e), then E? can also be Co-Cv-alkanoyl, and where any CH.-CH- or HC - C -- group within EC! the substituent does not necessarily have a substituent selected from halogen, carboxy, carbamoyl, C-C-C-alkoxycarbonyl, 7-C4-Cv-alkylcarbamoyl, MM -di(ЕЯ -Cv-alkyl|carbamoyl, amino-C.4-Ce-alkyl, -BO0- C.-Cv-alkylamino-C-Cv-alkyl and di-(Ci-Cv-alkylamino-C.-Ce-alkyl or from the group of the formula: O2-X2- where X is a simple bond or selected from CO and M(K 9U)CO, where KU is hydrogen or C.-C-alkyl, and 02? represents aryl, aryl-C 1-Ce-alkyl, heteroaryl, heteroaryl-C.4-C-alkyl, heterocyclyl or heterocyclyl-C -C-alkyl, and where any CH or CHnu group within KE! the substituent optionally has one or more halogen or C.-Cv-alkyl substituents on each specified CH or CHnu group or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, oxo, thioxo, C.--Svaloxy, C .i-Cv-alkylthio, C.-Cv-alkylsulfinyl, C.4-Cv-alkylsulfonyl, C.-Cv-alkylamino, di-IS--Cv-alkyl|amino, C.-Cv-Alkoxycarbonyl, U 00 -C.-Ce-alkylcarbamoyl, MM -di-(IS4i-Cv-alkyl|carbamoyl, Co-Cv-alkanoyl, Co-Cv-alkanoyloxy, /5 Co-Cv-alkanoylamino, In 0 -C.-Cv-alkyl-Co-Cv-alkanoylamino, In -C.-Cv-alkylsulfamoyl, MM -di-(C4-Cv -alkyl|isulfamoyl, C.-Cv-alkanesulfonylamino and In -C.- C-alkyl-Ci-Co-alkanesulfonylamino, or from the group of the formula: -X3-a3 where X is a simple bond or selected from 0, 5, 50, 505, ШЭ), СО, CH(OK 7, СОМ) , Also ЛсСО, 50О2МЩ(27, ШЧА780», С(2720, С(К7о5 and ШЧА С(В 7»), where VK" represents hydrogen or C /-Cv-alkyl, and Z represents oaryl, aryl-Si- Cl-alkyl, C3-C,-cycloalkyl, Ca-C,-cycloalkyl-Ci-Cv-alkyl, C3-C,-cycloalkenyl, C3-C,-cycloalkenyl-C -Ce-alkyl, heteroaryl, heteroaryl-C. 4-C1-alkyl, heterocyclyl, or heterocyclyl-C1-C6-alkyl, and wherein any aryl, heteroaryl, or heterocyclyl group within the C" substituent optionally has 1, C2, or C substituents, which may be the same or various selected from halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, car bamoyl, C.i-Cv-alkyl, C.i-Cv-alkenyl, C.i-Cv-alkynyl, C.i-Cv-alkoxy, o Co-Cv-alkenyloxy, C.-Cv-alkynyloxy, C.-Cv-alkylthio, C.-Cv-alkylsulfinyl, C.-Cv-alkylsulfonyl, C.4-Ce-alkylamino, di-C4-C6-alkyl|iamino, C.-Cv-Alkoxycarbonyl, U 00 -C.-Ce-alkylcarbamoyl, MM -di-(IS4i-Cv-alkyl|carbamoyl, Co-Cv-alkanoyl, He cC.-Cv-alkanoyloxy, o Co-Cv-alkanoylamino . -Cv-alkyl-C4-Cv-alkanesulfonylamino and so on C.-C3-alkylenedioxy, or from the group of the formula: -X3-v8 (ee) where X" represents a simple bond or selected from O and M(E U), where E? represents hydrogen or C.-Cv -alkyl, and 28 is a halogen-C 1-Cv-alkyl, hydroxy-C--Cv-alkyl, C.i-Cv-alkoxy-Ci-Cv-alkyl, cyano-C.-4-Ce-alkyl, amino-C4-Cv-alkyl, C.4-Cv-alkylamino-C.-Cv-alkyl, di--C4--Cv-alkyl|Iamino-C4-Cv-alkyl, " Co-Cv-alkanoylamino-C. -Ce-alkyl or C.i-C.-Alkoxycarbonylamino-C 4-Ce-alkyl, or from the group of the formula: from needles c! - - where X? is a simple bond or selected from OO, M(B 79 ) and CO, where CO is hydrogen or . "» C.-C.-alkyl, and FO represents aryl, aryl-C. and -C.-alkyl, heteroaryl, heteroaryl-C.-C.-alkyl, heterocyclyl or heterocyclyl-C.-C.-alkyl, which necessarily has 1 or 2 substituents, which may be the same or different, selected from halogen, C4-C8-alkyl, C0-C8-alkenyl, C0-C8-alkynyl and C--C8-alkoxy, (ee) and where any which heterocyclyl group within B!substituent optionally has 1 or 2 oxo- or o-thioxo substituents; n is 0, 1, 2 or 3; and o each CZ group, which may be the same or different, is selected from halogen, trifluoromethyl . -alkynyloxy, C.-Cv-alkylthio, C.-Cv-alkylsulfinyl, C.-Cv-alkylsulfonyl, C.4-Ce-alkylamino, di-IS4-Cv-alkyl|iamino, C.-Cv-Alkoxycarbonyl, U 00 -C.-Ce-alkylcarbamoyl, MM -di-(IS4i-Cv-alkyl|carbamoyl, Co-Cv-alkanoyl, Co-Cv-alkanoyloxy, Co-Cv-alkanoylamino, M - Cb4-Cv-alkyl-Co-Cv-alkanoylamino, HF) C3-Cv-alkenoylamino, and: -Cb4-Cv-alkyl-Co-Cv-alkenoylamino, GI Ca-Cv-alkynoylamino, M -C4-Cv-alkyl- Ca-Cv-alkynoylamino, 8 -C.-Cv-alkylsulfamoyl, MM -di-(C4-Cv -alkyl)isulfamoyl, C.i-Cv-alkanesulfonylamino and U -C.4-Cv-alkyl-C.-Co -alkanesulfonylamino, or from group 60 of the formula: -X85.B! where is x is a simple bond or selected from O and M (B 77), where K" is hydrogen or C 4-Cv-alkyl, Y Kk" is halogen-C 1-Cv-alkyl, hydroxy-C- -Cv-alkyl, C.4-Cv-alkyl-C--Cv-alkyl, cyano-Ci-Cv-alkyl, 65 amino-C.4-Cv-alkyl, C4-Cv-alkylamino-C /-Cv- alkyl or di-C1-C1-alkyl|amino-C1-C1-alkyl, or from the group of the formula: -X7-05 where X'" represents a simple bond or selected from O, 5, 50, 50 5, MORE "), CO, CH(ОВ З), СОМ(В 3), Mm(В'ЗсО, 5о2m(В), m(3)8О0", с(В3ю»О, с(в'З»в and M (ВЗ)с(В73)», where ВЗ is hydrogen or C.-C.-alkyl, and OZ is aryl, aryl-C.1-C.alkyl, heteroaryl, heteroaryl-C.4-C.alkyl, heterocyclyl or 9 heterocyclyl-C.4-C.alkyl, which is optional has 1 or 2 substituents, which may be the same or different, selected from halogen, C4i-C6-alkyl, C0-C6-alkenyl, C0-C6-alkynyl, and C--C6-alkoxy, and any heterocyclyl group within WITH? optionally has 1 or 2 oxo- or thioxo substituents; or a pharmaceutically acceptable salt thereof. 2. Quinazoline derivative of formula I or its pharmaceutically acceptable salt according to item 1, where 7 is MH. 3. A quinazoline derivative of formula I or its pharmaceutically acceptable salt according to item 1, where t is 1 and the K" group is located in the 5th position or t is 2 and the B" groups, which may be the same or different, are located in the 5 -th and 7th position and each group KE" is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, but-3-enyloxy, pent- 4-enyloxy, hex-b-enyloxy, but-3-ynyloxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy, tetrahydrofuran- 3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, cyclopropylmethoxy, 2-imidazol-1-ylethoxy, 3-imidazol-1-ylpropoxy, 2-(1,2,3-triazol-1-yl)ethoxy , 3-(1,2,3-triazol-1-yl)upropoxy, 2-(1,2,4-triazol-1-yl)ethoxy, 3-(1,2,4-triazol-1-yl) upropoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyrid-4-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy xy, 2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy, 3-pyrid-3-ylpropoxy, 3-pyrid-4-ylpropoxy, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 2-pyrrolidin-1-ylethoxy, Z-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, Z-pyrrolidin-2- ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, ch 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, 3-(1,1-dioxotetrahydro-4H-1 ,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, o piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2- piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 2-(1 ,2,3,6-tetrahydropyridin-1-yl)ethoxy 3-(1,2,3,6-tetrahydropyridin-1-yl)upropoxy, 4-(1,2,3,6-tetrahydropyridin-1-yl) )butoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy, 2-g homopiperazine-1-ylethoxy, Z-homopiperazin-1-ylpropoxy, 2-pyrrolidin-1-ylethylamino, 2Z-pyrrolidin-1-ylpropylamino, 4-pyrrolidin-1-ylbutylamino, pyrrolidin-3-ylamino, pyrrolidin-2-ylmethylamino , so 2-pyrrolidin-2-ylethylamino, 3-pyrrolidin-2-ylpropylamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 4-morpholinobutylamino, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl )letylamino, | "c) 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 4-piperidinobutylamino, piperidine-3-ylamino, piperidin-4-ylamino , piperidin-33-ylmethylamino, 2-piperidin-3-ylethylamino, piperidin-4-ylmethylamino, 2-piperidin-4-ylethylamino, 2-homopiperidin-1-ylethylamino, 3-homopiperidin-1-ylpropylamino, 2-piperazine-1 -ylethylamino, 3-piperazin-1-ylpropylamino, 4-piperazin-1-ylbutylamino, 2-homopiperazine-1-ylethylamino or " 20 3-homopiperazin-1-ylpropylamino, w-v c and where adjacent carbon atoms in any Co-Cv-alkylene chain within B! substitute is optional . are separated by a group inserted into the chain, selected from О, МН, М(Ме), СН-СНИ and Се С, о and if ЕК! is a vinyl or ethynyl group, then the KE! optionally has in the final СНо- or НС position a substituent selected from "Y -(2-dimethylaminoethyl)carbamoyl, M -(3-dimethylaminopropyl)carbamoyl, o 175 methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl and 4-dimethylaminobutyl, or from the group of the formula: о ох.оз where Х is a single bond or is МНСО or М(Ме)СО and O2 is imidazolylmethyl, 2- imidazolylethyl, 3-imidazolylpropyl, pyridylmethyl, 2-pyridylethyl, 3-pyridylpropyl, pyrrolidin-1-ylmethyl, o 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl, pyrrolidin-2 -ylmethyl, Kz 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinecetyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidine- 3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl or 4- pipe razin-1-ylbutyl, and where any CH or CHnu group within KE! the substituent optionally has one or more fluorine or chlorine groups on each indicated CH or CHnu group or a substituent selected from hydroxy, oxo, amino, methoxy, ime) methylsulfonyl, methylamino, dimethylamino, diisopropylamino, Y ethyl- Y methylamino, Y isopropyl-N.methylamino, m-methyl-"-propylamino, acetoxy, acetamido, and "-methylacetamido, and wherein any phenyl, imidazolyl, triazolyl, pyridyl, or heterocyclyl group within the substituent on B optionally has 1 or 2 substituents, which may be the same or different, selected from fluorine, chlorine, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, ethoxy, "7-methylcarbamoyl, β5 M m -dimethylcarbamoyl, methylenedioxy, ethylenedioxy and isopropylidenedioxy, and pyrrolidine -2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within B substituent is optionally substituted near the nitrogen atom by allyl, 2-propynyl, methylsulfonyl, ethylsulfonyl, acetyl, propionyl, isobutyryl , 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl , C-aminopropyl, 2-methylaminoethyl, C-methylaminopropyl, 2-dimethylaminoethyl, C-dimethylaminopropyl, 2-pyrrolidin-1-ylethyl, C-pyrrolidin-1-ylpropyl, 2-morpholinoethyl, C-morpholinopropyl, 2-piperidinoethyl, C -piperidinopropyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, the last 8 of the above substituents each optionally having 1 or 2 70 substituents which may be the same or different, selected from fluorine, chlorine, methyl and methoxy, and where any heterocyclyl group within the substituent on VC does not necessarily have 1 or 2 oxo substituents. 4. A quinazoline derivative of formula I or its pharmaceutically acceptable salt according to item 1, where t is 1 and the VE group is located in the 5th position or t is 2 and groups B ", which can be the same or different, are located in the 5- m and 7th positions and each BC group is selected from hydroxy, amino, methyl, ethyl, 72 methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, tetrahydrofuran-3-yloxy, tetrahydropyran-4 -yloxy, 2-pyrrolidin-1-ylethoxy, Z-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, Z-pyrrolidine -2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(1,1-dioxotetrahydroin-1,4-thiazin-4-yl)ethoxy, - 3-(1,1-dioxotetrahydro- yin -1,4-thiazin-4-yl)propoxy, 720 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, 3-piperidinyloxy, 4-piperidinyloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidine -3-ylethoxy, 2-piperids n-4-ylethoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 3-(1,2,3,6-tetrahydropyridin-1-yl)upropoxy, 2-piperazin-1-ylethoxy, C -piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy, 3-homopiperazin-1-ylpropoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, and where adjacent carbon atoms in any Co-Cv-alkylene chain within the K" substituent optionally i) separated by a chained group selected from О, МН, СНА-СНИ and СС, and where any СН» or СН»z group within B! the substituent optionally has on each specified CH» or CH3 group one or more chlorine groups or a substituent selected from hydroxy, oxo, amino, methoxy, methylsulfonyl, methylamino, dimethylamino, diisopropylamino, "-ethyl- "-methylamino, "- isopropyl-"-methylamino and acetoxy, o and where any heterocyclyl group within the substituent on B! optionally has 1 or 2 substituents, which may be the same or different, selected from fluorine, chlorine, trifluoromethyl, hydroxy, amino, methyl, ethyl, methoxy, methylenedioxy, ethylenedioxy and isopropylidenedioxy, and pyrrolidin-2-yl, pyrrolidin- The 3-yl, o piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within B" of the substituent c is optionally substituted near the nitrogen atom by methyl, ethyl, propyl, allyl, 2-propynyl, methylsulfonyl, acetyl, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-rifluoroethyl, or cyanomethyl, " and where any heterocyclyl group within the substituent on KK optionally has 1 or 2 oxo substituents. 5. A quinazoline derivative of formula I or its pharmaceutically acceptable salt according to item 1, where t represents 2 and - c of group B", which can be the same or different, located in the 5th and 7th positions and group B in the 5- position selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, 4-piperidinyloxy, piperidine -3-ylmethoxy, piperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, and group B" in the 7th position is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-pyrrolidin-1-ylethoxy, co C -pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(1, 1-dioxotetrahydro-YAN-1,4-thiazin-4-yl)ethoxy, 3-(1,1-dioxotetrahydro-An-1,4-thiazin-4-yl)propoxy, o 50 2-piperidinoethoxy, 3-piperidinopropoxy , 4-piperidinobutoxy, 2-piperidin-3-ylet oxy, 2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, which) 3-(1,2,3,6-tetrahydropyridin-1-yl)propoxy, 2-piperazine -1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy, and where any CHo or CHz group within VE! the substituent optionally has one or more chlorine groups on each specified CH» or CH3 group or a substituent selected from hydroxy, oxo, amino, methoxy, methylsulfonyl, He! methylamino, dimethylamino, diisopropylamino, "-ethyl- "U -methylamino, "-isopropyl- "-methylamino and acetoxy, GI and where any heterocyclyl group within the substituent on BC! optionally has 1 or 2 substituents, which may be the same or different, selected from fluorine, chlorine, trifluoromethyl, hydroxy, amino, methyl, ethyl, vo methoxy, methylenedioxy, ethylenedioxy and isopropylidenedioxy, and pyrrolidin-2-yl, pyrrolidin- Z-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, or homopiperazin-1-yl group within K" of the substituent is optionally substituted near the nitrogen atom by methyl, ethyl, propyl, allyl, 2- propynyl, methylsulfonyl, acetyl, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-rifluoroethyl, or cyanomethyl, 65 and wherein any heterocyclyl group within the KK substituent optionally has 1 or 2 oxo substituents. 6. A quinazoline derivative of formula I or its pharmaceutically acceptable salt according to item 1, where n is 1 and the BEZ group is located in the 5th position of the 2,3-methylenedioxypyridin-4-yl group and is selected from fluorine, chlorine, bromine, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy. 7. Quinazoline derivative of formula I according to item 1, where: 7 is O or MH; t is 1 and the group B' is located in the 5th position or t is 2 and the groups B", which may be the same or different, are located in the 5th and 7th positions and each group B! is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, but-3-enyloxy, pent-4-enyloxy, hex-b-enyloxy, but-3-ynyloxy, pent-4-ynyloxy, hex-5-ynyloxy, 70 methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy , cyclopropylmethoxy, 2-imidazol-1-ylethoxy, 3-imidazol-1-ylpropoxy, 2-(1,2,3-triazol-1-yl)ethoxy, 3-(1,2,3-triazol-1-yl) )upropoxy, 2-(1,2,4-triazol-1-yl)ethoxy, 3-(1,2,4-triazol-1-yl)upropoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyrid -4-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy, 2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy, 3-pyrid-3-ylpropoxy, 3-pyrid-4 -ilprop oxy, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin- 2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(1,1-dioxotetrahydroin-1,4-thiazine-4 -yl)ethoxy, - 3-(1,1-dioxotetrahydroin-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4 -yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidine -1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 2-(1,2,3,6-tetrahydropyridin-1-yl)ethoxy 3-(1,2,3,6-tetrahydropyridin-1-yl)upropoxy, 4-(1,2,3,6-tetrahydropyridin-1-yl)butoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy, 2-homopiperazin-1- ylethoxy, 3-homopiperazin-1-ylpropoxy, 2-pyrrolidin-1-ylethylamino, Ge ) C-pyrrolidin-1-ylpropylamino, 4-pyrrolidin-1-ylbutylamino, pyrrolidin-3-ylamino, pyrrolidin-2-ylmethylamino, 2-pyrrolidin-2-ylethylamino, C-pyrrolidin-2-ylpropylamino, 2-morpholinoethylamino, C -morpholinopropylamino, 4-morpholinobutylamino, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethylamino, - se 3-(1,1-dioxotetrahydro-YAN /-1,4-thiazine- 4-yl)propylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 4-piperidinobutylamino, piperidin-3-ylamino, piperidin-4-ylamino, piperidin-33-ylmethylamino, o 2-piperidin-3-ylethylamino, piperidin-4-ylmethylamino . -ylbutylamino, 2-homopiperazine-1-ylethylamino or 3-homopiperazin-1-ylpropylamino, (ee) and where the adjacent carbon atoms in any Co-Cv alkylene chain within VK! of the substituent are optionally separated by a group inserted into the chain selected from О, МН, М(Ме), СН-СНИ, and Се С, and if K" represents a vinyl or ethynyl group, then the КЕ substituent does not necessarily have in the terminal СНо- or " The position bears a substituent selected from Y-(2-dimethylaminoethyl)carbamoyl, "-(3-dimethylaminopropyl)carbamoyl, c methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl, h" 2-dimethylaminoethyl, C -dimethylaminopropyl and 4-dimethylaminobutyl, or from the group of the formula: and 2-X. where is x is a single bond or is MHSO or M(Med)CO and 02 is imidazolylmethyl, 2-imidazolylethyl, 3-imidazolylpropyl, pyridylmethyl, 2-pyridylethyl, 3-pyridylpropyl, pyrrolidin-1-ylmethyl, or 2-pyrrolidine -1-ylethyl, 3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl, pyrrolidin-2-ylmethyl, av! 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidincetyl, 3-piperidinopropyl, 4-piperidinobutyl, o piperidin-3-ylmethyl , 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperazin-1-ylmethyl, av | 20 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl or 4-piperazin-1-ylbutyl, "with and where any CHo or CHz group within the VE! substituent does not necessarily have on each indicated CH" or CHz group one or more fluorine or chlorine groups or a substituent selected from hydroxy, oxo, amino, methoxy, methylsulfonyl, methylamino, dimethylamino, Disopropylamino, ".ethyl-"-methylamino, Y isopropyl- U.methylamino, "-methyl- "-propylamino, acetoxy, acetamido GF) and "-methylacetamido, GI and where any phenyl, imidazolyl, triazolyl, pyridyl or heterocyclyl group within the substituent on KE" optionally has 1 or 2 substituents, which may be the same or various selected from fluorine, chlorine, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, ethoxy, M -methylcarbamoyl, MM -dimethylcarbamoyl, methylenedioxy, ethylidenedioxy and isopropylidenedioxy, and pyrrolidin-2-yl, piperidin-3- yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within the B substituent is optional placed near the nitrogen atom by allyl, 2-propynyl, methylsulfonyl, ethylsulfonyl, acetyl, 65 propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3 ,3,3-trifluoropropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, -B4- 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2- piperidinoethyl, 3-piperidinopropyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, the last 8 of the above substituents each optionally having 1 or 2 substituents, which may be the same or different, selected from fluorine, chlorine , methyl and methoxy, and where any heterocyclyl group within the substituent on VC does not necessarily have 1 or 2 oxo substituents; n represents 0 or n represents 1 and the KZ group is located in the 5th or bth position of the 2,3-methylenedioxypyridin-4-yl group and is selected from fluorine, chlorine, bromine, trifluoromethyl, cyano, hydroxy, 70 methyl , ethyl, methoxy and ethoxy; or a pharmaceutically acceptable acid addition salt thereof. 8. Quinazoline derivative of formula I according to item 1, where: 7 is MH; t represents 2 and K" groups, which can be the same or different, located in the 5th and 7th positions 75 and the VB' group in the 5th position is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, tetrahydrofuran- 3-yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, 4-piperidinyloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, and the group B! in the 7th position is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, 2-pyrrolidin-2 -ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(1,1-dioxotetrahydro-4n-1,4-thiazin-4-yl)ethoxy, 3-(1 ,1-dioxotetrahydroin-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, 2-piperidin-3-ylethoxy, 2-piperidin-4-ylethoxy, 2-homopiperidine -1-ylethoxy, He!3-homopiperidin-1-ylpropoxy, 3-(1,2,3, 6-tetrahydropyridin-1-yl)upropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy, and where any CH" or CHNa group within K' of the substituent optionally has on each indicated CH» or CH3 group one or more chlorine groups or a substituent selected from hydroxy, oxo, amino, methoxy, methylsulfonyl, methylamino, dimethylamino, diisopropylamino, "-ethyl- "-methylamino, Y -isopropyl- "-methylamino and acetoxy, with Zo and where any heterocyclyl group within the substituent on B! optionally has 1 or 2 substituents, which ("c") may be the same or different, selected from fluorine, chlorine, trifluoromethyl, hydroxy, amino, methyl, ethyl, co-methoxy, methylenedioxy, ethylidenedioxy and isopropylidenedioxy, and pyrrolidine-2 -yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, or homopiperazin-1-yl group within the KK" of the substituent o is optionally substituted near the nitrogen atom by methyl, ethyl, propyl, allyl, 2-propynyl, methylsulfonyl, co acetyl, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-rifluoroethyl or cyanomethyl, and where any heterocyclyl group within the substituent on KK optionally has 1 or 2 oxo substituents; "n is 0 or n is 1 and the KZ group is located in the 5th or bth position of the 2,3-methylenedioxypyridin-4-yl group and is selected from fluorine, chlorine, bromine, trifluoromethyl, cyano, hydroxy, - with methyl, ethyl, methoxy and ethoxy; and or its pharmaceutically acceptable acid addition salt."» 9. Quinazoline derivative of formula I according to item 1, where: 7 is MH; t is 1 and the BK' group is located in the 5th position and is selected from propoxy, isopropoxy, (ee) tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3-yloxy, M-methylpyrrolidin-3-yloxy, (ав) pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, m-methylpiperidin-3-yloxy, 4-piperidinyloxy, 8-methylpiperidin-4-yloxy, "-allylpiperidin-4-yloxy, "y-prop-2-ynylpiperidine -4-yloxy, M o 20 -acetylpiperidin-4-yloxy, M -methylsulfonylpiperidin-4-yloxy, Kz piperidin-Z-ylmethoxy, in -methylpiperidin-Z-ylmethoxy, piperidin-4-ylmethoxy, "-methylpiperidin-4- ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, or t is 2 and the first B' group is in the 5-position and selected from the group of substituents 22 listed immediately above, and the second K' group is in the 7-position and is selected from HF ) 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-(3K5,454)-3,4-methylenedioxypyrrolidin-1-yl|ethoxy, 3-K(3K5,4554)-3,4- methylenedioxypyrrolidin-1-yl|propoxy, 2-morpholinoethoxy, 3-mor folinopropoxy, o 2-(1,1-dioxotetrahydroin-1,4-thiazin-4-yl)ethoxy, - 3-(1,1-dioxotetrahydroin-1,4-thiazin-4-yl)propoxy, in 2-piperidinoethoxy, 3-piperidinopropoxy, 2-piperidin-3-ylethoxy, 2--M-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy, 3-(m-methylpiperidin-33-yl)propoxy , 2-piperidin-4-ylethoxy, 2-4-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy, 3-(008-methylpiperidin-4-yl)/propoxy, 2-(1,2, 3,6-tetrahydropyridin-1-yl)ethoxy, 3-(1,2,3,6-tetrahydropyridin-1-yl)upropoxy, 65 2-(4-hydroxypiperidin-1-yl)ethoxy, 3-(4- hydroxypiperidin-1-yl)propoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 4-(4-methylpiperazin-1-yl)butoxy, 2-(4-allylpiperazin-1-yl)ethoxy, 3-(4-allylpiperazin-1-yl) propoxy, 2-(4-prop-2-ynylpiperazin-1-yl)ethoxy, 3-(4-prop-2-ynylpiperazin-1-yl)upropoxy, 2-(4-methylsulfonylpiperazin-1-yl)ethoxy, 3 -(4-methylsulfonylpiperazin-1-yl)upropoxy, 2-(4-acetylpiperazin-1-yl)ethoxy, 3-(4-acetylpiperazin-1-yl)upropoxy, 4-(4-acetylpiperazin-1-yl)butoxy , /2-(4-isobutyrylpiperazin-1-yl)ethoxy, 3-(4-isobutyrylpiperazin-1-yl)propoxy, 4-(4-isobutyrylpiperazin-1-yl)butoxy, 2-I(4-(2- fluoroethyl)piperazin-1-yl|ethoxy, 3-I4-(2-fluoroethyl)piperazin-1-yl|propoxy, 2-I(4-(2,2,2-trifluoroethyl)piperazin-1-yl|ethoxy, 3-I(4-(2,2,2-trifluoroethyl)piperazin-1-yl|propoxy, 7/0. 2-(4-cyanomethylpiperazin-1-yl)ethoxy, 3-(4-cyanomethylpiperazin-1-yl)propoxy, 2-(2-(4-methylpiperazin-1-yl)ethoxy|ethoxy, 2-chloroethoxy, З- chloropropoxy, 4-chlorobutoxy, 2-methylsulfonylethoxy, 3-methylsulfonylpropoxy, 2-(2-methoxyethoxy)ethoxy, 2-(4-pyridyloxy)ethoxy, 3-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy; n is 0 or n is 1 and the group K C is located in the 5th or bth position of the 75 2,3-methylenedioxypyridin-4-yl group and is selected from chlorine, bromine, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy; or its pharmaceutically acceptable acid addition salt. 10. Quinazoline derivative of formula I according to item 1, where: 7 is MH; t is 2 and the first B' group is located in the 5th position and is selected from isopropoxy and tetrahydropyran-4-yloxy, and the second B group is located at the 7th position and is selected from 2-pyrrolidine-1-ylethoxy, 3-pyrrolidine -1-ylpropoxy, 2-(З3К5,45К)-3,4-methylenedioxypyrrolidin-1-ilyethoxy, 3-К(З3К5,4554)-3,4-methylenedioxypyrrolidin-1-yl|propoxy, 2-morpholinoethoxy, З- morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, c 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl) )propoxy, 2-(4-allylpiperazin-1-yl)ethoxy, o 3-(4-allylpiperazin-1-yl)propoxy, 2-(4-prop-2-ynylpiperazin-1-yl)ethoxy, 3-( 4-prop-2-ynylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy, 3-(4-acetylpiperazin-1-yl)propoxy, 2-(4-isobutyrylpiperazin-1-yl) )ethoxy, 3-(4-isobutyrylpiperazin-1-yl)upropoxy, 2-I4-(2-hydroxyethyl)piperazin-1-yl|iethoxy, c 3-I4-(2-hydroxyethyl)piperazin-1-yl|Ipropoxy , 2-I4-(2,2,2-trifluoroethyl)piperazin-1-yl|ethoxy, o 3-I4-(2,2,2-trifluoroethyl)pi perazin-1-yl|propoxy, 2-(4--2-dimethylaminoacetyl)piperazin-1-yl|ethoxy and 3-(4--2-dimethylaminoacetyl)piperazin-1-yl|Ipropoxy; and (ze) n represents 1 and the BZ group is located in the 5th position of the 2,3-methylenedioxypyridin-4-yl group and is selected from chlorine and bromine; 3o or its pharmaceutically acceptable acid addition salt. co 11. Quinazoline derivative of formula I according to item 1, where: 7 is MH; t is 2 and the first B' group is located in the 5B position and is selected from isopropoxy and tetrahydropyran-4-yloxy, and the second B! the group is located in the 7th position and is selected from 2-pyrrolidin-1-ylethoxy, from 70Z-pyrrolidin-1-ylpropoxy, 2-(Z3K5,45K)-3,4-methylenedioxypyrrolidin-1-ylethoxy, with 3-K (С3К5,4554)-3,4-methylenedioxypyrrolidin-1-yl|propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, :3» 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)upropoxy, 2-(4-allylpiperazin-1-yl)ethoxy, 3-(4-allylpiperazin-1-yl)upropoxy, 2-(4-prop-2-ynylpiperazin- 1-yl)ethoxy, 3-(4-prop-2-ynylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy, bo 15 3-(4-acetylpiperazin-1-yl)propoxy , 2-(4-isobutyrylpiperazin-1-yl)ethoxy, 3-(4-isobutyrylpiperazin-1-yl)propoxy, 2-I(4-(2,2,2-trifluoroethyl)piperazin-1-yl|ethoxy and (ab) 3-I4-(2,2,2-trifluoroethyl)piperazin-1-yl|Ipropoxy; and o n is 1 and the BZ group is located in the 5th position of the 2,3-methylenedioxypyridin-4-yl group and selected 5r From chlorine and bromine; o or its pharmaceutically acceptable acid addition salt. Kz 12. Quinazoline derivative of formula I according to item 1, where: 7 is MH; t is 2 and the first B' group is located in the 5B position and is selected from isopropoxy and tetrahydropyran-4-yloxy, and the second B! the group is located in the 7th position and is selected from 2-pyrrolidin-1-ylethoxy, 2-(z3K5,454)-3,4-methylenedioxypyrrolidin-1-ylethoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, F, 2- piperidinoethoxy, 2-piperazin-1-ylethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, co 2-(4-prop-2-ynylpiperazin-1-yl)letoxy, 3-(4-prop-2- ynylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy, 2-I4-(2-hydroxyethyl)piperazin-1-yl|ethoxy and bo 0 2-IID4-(2-dimethylaminoacetyl)piperazine -1-yl|ethoxy; and n is 1 and the VE group is located in the 5th position of the 2,3-methylenedioxypyridin-4-yl group and is a chlorine group; or a pharmaceutically acceptable acid addition salt thereof. 13. Quinazoline derivative of formula I according to item 1, where: 65 7 is MH; t is 2 and the first B" group is a 5-isopropoxy group and the second B group is located in the 7th -58v- position and selected from 0/0 2-(3К5,455К)-3,4-methylenedioxypyrrolidin-1-yl)ethoxy, 2-piperazin-1-ylethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2- (4-acetylpiperazin-1-yl)ethoxy and 2-I(4-(2-hydroxyethyl)piperazin-1-yl|ethoxy; and n is 1 and group B C is located in the 5-position 2,3-methylenedioxypyridine -4-yl group and is a chlorine group, or a pharmaceutically acceptable acid addition salt thereof. 14. Quinazoline derivative of formula I according to item 1, selected from: 7-(2-(4-acetylpiperazin-1-yl)ethoxy)|-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5 -tetrahydropyran-4-yloxy iquinazoline, 70 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-2-(3K5,455)-3,4-methylenedioxypyrrolidin-1-yl|ethoxy)- 5-tetrahydropyran-4-yloxyquinazoline, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(2-(4-prop-2-ynylpiperazin-1-yl)ethoxy|-5- tetrahydropyran-4-yloxyquinazoline, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-I3-(4-prop-2-ynylpiperazin-1-yl)upropoxy|-5-tetrahydropyran- 75 4 -yloxyquinazoline, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(2-morpholinoethoxy)-5-tetrahydropyran-4-yloxyquinazoline and 4-(5-chloro-2,3-methylenedioxypyrid- 4-ylamino)-7-(3-morpholinopropoxy)-5-tetrahydropyran-4-yloxyquinazoline, or its pharmaceutically acceptable acid addition salt. 15. Quinazoline derivative of formula I according to item 1, selected from: 7-(2-(4-acetylpiperazin-1-yl)ethoxy|-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5- isopropoxyquinazoline, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxy-7-(2-piperazin-1-ylethoxy)quinazoline, 4-(5-chloro-2,3-methylenedioxypyrid- 4-ylamino)-7-12-I4-(2-hydroxyethyl)piperazin-1-yl|ethoxy)-5-isopropoxyxinoline, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5- isopropoxy-7-(2-pyrrolidin-1-ylethoxy)quinazoline, Gα 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxy-7-(2-piperidinoethoxy)quinazoline, o 4- (5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxy-7-(2-morpholinoethoxy)quinazoline, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxy -7-(3-morpholinopropoxy)quinazoline, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxy-7-(2-(4-prop-2-ynylpiperazin-1-yl) ethoxy)quinazoline, 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoline and Ge 4-(5- chloro-2,3-methylenedioc Cypyrid-4-ylamino)-7-2-I(4--2-dimethylaminoacetyl)piperazin-1-yl|ethoxy)-5-isopropoxyquinazoline; or a pharmaceutically acceptable acid addition salt thereof. co 16. The method of obtaining a quinazoline derivative of the formula I or its pharmaceutically acceptable salt according to item 1, in which: o (a) to obtain those compounds of the formula I, in which 7 represents the group O, 5 or M(B 2), the interaction of quinazoline 00 of the formula HER G ; (I) dO and h | 4 - c (Bohr m ;» where I is a leaving group, and t and B " have any of the values as defined in clause 1, in addition, any functional group, if necessary, is protected, with compound of the formula PI (B (B so en o "A Ga (8) o" 0-y where 7 represents О, 5 or SHK 2) and n, VZ and B? have any of the values as defined in clause 1, except that any functional group is, if necessary, protected, after which any protecting group present is removed by conventional methods; (b) to obtain those compounds of formula I in which at least one KE group is formula group ah, (F. where o! represents aryl-C 1 -C 1 -alkyl, C 3 -C 1 -cycloalkyl-C 1 -C 2 -alkyl, І 1 -C 1 -cycloalkenyl-C 1 -C 2 -alkyl, heteroaryl-Si -C6-alkyl or heterocyclyl-C--C6-alkyl group or an optionally substituted alkyl group and X" is an oxygen atom, quinazoline compound of the formula M 60 b5 (vl that Zeen KA (i o SUB no | A vs y de t, B", 7, p and VZ have any of the values as defined in clause 1, in addition, any functional group, if necessary, protected, with a suitable alcohol in which any functional group is, if necessary, protected, after which any protecting group present is removed by conventional methods; (c) to prepare those compounds of formula I in which group K contains C. -Cv-alkyloxy or substituted 75 C.-Salkoxy group or C.-Cv-alkylamino or substituted C.i-Cv-alkylamino group, the interaction of the quinazoline derivative of the formula MI (B ; MO shk o o 0-y Dt m-n! In where where Y represents a leaving group and 7, p Kk Z have any of the values as defined in clause 1, except that any functional group is optionally protected with an alcohol or an amine, which is suitable, after which any protecting group present is removed by conventional methods; (d) to obtain those compounds of formula I in which B is an amino-substituted C 1 -C 1 - alkoxy group, with the reaction of a compound of formula I, where K' is a halogen-substituted C)4-Cv-alukoxy group with a nitrogen-containing heterocyclic compound or a suitable amine; (e) to obtain those compounds of formula I, in which K 7 is an aminohydroxide-substituted C.-C.-Alkoxy group, interaction of the compound of formula I, in which the KE group contains an epoxy-substituted C.--C.-Alkoxy group, (ав) c5 With a heterocyclic compound or a suitable amine; co (e) to obtain those compounds of formula I, in which 7 is a BO or 5О 5 group, oxidation of a compound of formula I, in which 7 is a 5-group; or (is) to obtain those compounds of the formula I, in which the group K contains a "-acylated heterocyclic group, " acylation of a quinazoline derivative of the formula I, where the group BK" contains a heterocyclic group that has an unsubstituted 70 MH group; 8 c and if a pharmaceutically acceptable salt of a quinazoline derivative of formula I is needed, it is obtained by "" interaction of the specified quinazoline derivative with a suitable acid according to a generally accepted method. 17. A pharmaceutical composition containing a quinazoline derivative of formula I or its pharmaceutically acceptable salt according to item 1 in combination with a pharmaceutically acceptable diluent or carrier. 18. A quinazoline derivative of formula I or its pharmaceutically acceptable salt according to item 1 for use in a method of therapeutic treatment of a person or animal. o 19. The use of a quinazoline derivative of formula I or its pharmaceutically acceptable salt according to item 1 for the preparation of a medicinal product for use as an anti-invasive agent for controlling the spread and/or for the treatment of a solid tumor disease. o 50 Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 14, 10.09.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. F) name) 60 b5