UA64704C2 - Quinazoline derivatives, a method for preparing thereof (variants), a pharmaceutical composition and a method for obtaining an antiangiogenic effect and/or effect of vascular permeability - Google Patents

Abstract

The invention relates to quinazoline derivatives of formula (I) [wherein: Y1 represents -O-, -S-, -CH2-, -SO-, -SO2-, NR5CO, -CONR6-, -SO2NR7-, -NR8SO2- or -NR9- (wherein R5, R6, R7, R8 and R9 each independently represents hydrogen, alkyl or alkoxyalkyl); R1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, alkyl, alkoxy, alkylthio, amino or alkylamino. R2 represents hydrogen, hydroxy, halogeno, alkyl, alkoxy, trifluoromethyl, cyano, amino or nitro; m is an integer from 1 to 5; R3 represents hydroxy, halogeno, alkyl, alkoxy, alkanoyloxy, trifluoromethyl, cyano, amino or nitro; R4 represents a group which is or which contains an optionally substituted pyridone, phenyl or aromatic heterocyclic group] and salts thereof; processes for their preparation and pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient. The compounds of formula (I) and the pharmaceutically acceptable salts thereof inhibit the effects of VEGP, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis. (I)

Description

The present invention relates to quinazoline derivatives, methods of their preparation, pharmaceutical compositions containing them as an active component, methods of treatment of painful conditions associated with angiogenesis and/or increased permeability of blood vessels, and their use in the production of medicinal products used to provide antiangiogenic effects and/or effects of reducing the permeability of blood vessels in warm-blooded animals, such as humans.

Normal angiogenesis plays an important role in various processes, including embryonic development, wound healing, and some components of the reproductive function of women!

Undesirable or pathological angiogenesis has been associated with diseases including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaloshi sarcoma, and hemangioma (Rap eyi ai, 1995, Ttepaz RNiaptasoi!. 5si. 16: 57-66; BoiKtap, 1995, Maishge Medaisipe 1: 27-31). It is believed that vascular permeability plays a role in both normal and pathological physiological processes (SyPpap-Vome eyi ai, 1993, Epdosiipoodu 133: 829-837; Zepdeg eyi a), 1993, Sapseg apa Meiavziaviv

Journal, 12: 303-324). Some polypeptides have already been identified! with activity stimulating the growth of endothelial cells and migo, including acidic and basic factors! growth of fibroblasts (ago and res) and vascular endothelial growth factor (MESRE). Due to limited expression, the activity of MESE, in contrast to the activity of the growth factors POE, is relatively specific in relation to endothelial cells. It has recently been proven that MESE is an important stimulator of both normal and pathological angiogenesis (Daketap ei ai, 1993, EpaosgipoIodu, 133: 848-859; Koisp ei ai, 1995, Vgeazi Sapseg Nezeeagsi apa Tgeaitepi, 36: 139-155) and vascular permeability (Soppoiiu ei ai, 1989, 9. Vioi. Spet. 264: 20017-20024). Antagonism of the action of MESE as a result of sequestration of MESE with an antibody can lead to inhibition of tumor growth (Kit et al., 1993, Maishge 362: 841-844).

Receptor tyrosine kinase (ETK5) is important for the transmission of biochemical signals through the plasma membrane of cells. This is a transmembrane molecule! usually consist of an extracellular ligand-binding domain connected through a site in the plasma membrane to the intracellular domain of tyrosine kinases. The binding of the ligand to the receptor increases the stimulation of the tyrosine kinase activity associated with the receptor, which leads to the phosphorylation of tyrosine residues both on the receptor and on other intracellular molecules. These changes in phosphorylated tyrosine initiate a signaling cascade leading to various cellular reactions. Currently, at least nineteen separate subfamilies of CTCs, characterized by amino acid sequence homology, have been identified. One of these subfamilies currently consists of the Pt5-like tyrosine kinase receptor (P or PIJ), a receptor containing a domain with a kinase insert, KOE. (also called RIK-1), and the second Yat5-like tyrosine kinase receptor,

EMY4. Two of these related CTCs (EK and KO), as it was established, bind MESE with high affinity (Oe Mgiez ei aiYi, 1992, Zsiepse 255: 989-991; Teptap ei ai, 1992, Viospet. Viorpuz. Sot. 1992, 187 : 1579-1586). Binding of MESE to specified receptors expressed in heterologous cells was due to changes in the state of tyrosine phosphorylation in cellular proteins and calcium currents.

Compounds that have good activity against receptor tyrosine kinase! epidermal growth factor (ESF), disclosed in European patent Me0566226. The present invention is based on the discovery of compounds that unexpectedly suppress the effect! MESE, which is useful for the treatment of diseases associated with angiogenesis and/or increased vascular permeability, such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, arterial restenosis, autoimmune diseases, acute inflammation and eye diseases with proliferation of retinal vessels. The compounds of the present invention show higher efficacy against the tyrosine kinase of MESE receptors than against the tyrosine kinase of ESE receptors. In addition, the compounds of the present invention show significantly higher effectiveness against the tyrosine kinases of MESE receptors than against the tyrosine kinases of ECE or ECE K1 receptors. Thus, the compounds of the present invention, which have already been tested, have activity against the tyrosine kinase of MECE receptors, thanks to which they can be used in an amount sufficient to inhibit the tyrosine kinases of MECE receptors without showing significant activity against the tyrosine kinase of ESE receptors or tyrosine kinases! ESE of K1 receptors.

In accordance with one aspect of the present invention, a quinazoline derivative of formula I: and 3 is proposed

Shi, 7 asanas woo! Well, where:

U" represents -O-, -5-, -СНе-, -50-, -BO2-, -MA?SO-, -"SOMNA-, -BO2МВ"-, -MAZ5O"- or -MAU- (where B ",

A, VU, Va and B? independently represent each hydrogen, C1-zalkyl or C1-zalkoxy Cgzalkyl);

B' represents hydrogen, hydroxy, halogen, nitro, trifluoromethyl, cyano, C1-zalkyl, C1-zalkoxy, C1-zalkylthio or MVV" (where B'E and B", which can be the same or different, represent each hydrogen or Csi -zalkyl);

B: represents hydrogen, hydroxy, halogen, C1-zalkyl, C1-zalukoxy, trifluoromethyl, cyano, amino or nitro; t represents an integer from 1 to 5;

AZ represents hydroxy, C-zalkyl halogen, Sizalkoxy, Sizalkanoyloxy, trifluoromethyl, cyano,

amino or nitro;

B: selected from one of the following eight groups: 1) X' (where X! represents a pyridonic group, a phenyl group or a 5- or b-membered aromatic heterocyclic group with 1-3 heteroatoms selected from OO, M and 5, and pyridonic , a phenyl or heterocyclic group can bear up to 5 substituents selected from halogen, amino, C1-alkyl, C1-4 alkoxy, C1-hydroxyalkyl, C1-aminoalkyl, C3-zalkylamino, C1-hydroxyalkyl, carboxy, cyano, -SOMA !2B!Z and -MA"SOV!5 (where 2, BZ, DIA and B, which can be the same or different, represent each hydrogen, C1-zalkyl or C1-zalkoxy-

Ci-zalkyl); 2) Si-valkyluX! (where X! - such as a certain higher);

C) Soalkenil! (where X! - such as a certain higher); 4) So-valkynylu! (where X! - such as a certain higher); 5) SivalkylugH! (where U? represent -O-, -5-, -50-, -502-, -ОСО-, -МВ'"ЯСО-, -"СОМВ!-, -502МВ"8-, -

MA!Z50"- or -MA820- (where B, B!", B!8, DV'3, and h independently represent each hydrogen, C1-zalkyl or

C-zalkoxyC2-zalkyl) and X! - such as a certain one); 6) SozalkenyluzZh! (where UZ represents -О-, -5-, -50-, -502-, -ОСО-, -МВ?!СО-, -СОМА2-, -502МА28-, -

MA?5O»- or -MA25- (where 2", ID22, ID, VD? and 25 independently represent each hydrogen, C1-zalkyl or

C-zalkoxyCg2-zalkyl) and X! - such as a certain one); 7) Sgvalkynylu"X! (where U" represents -O-, -5-, -50-, -502-, - ОСО-, -МА29СО-, -"СОМВ2"-, -БО»2МВ28-, -

MAg950»2- or -MVZO- (where 26, B", Be, where in Zo independently represent each hydrogen, Ci-zalkyl or

C-zalkoxyCg2-zalkyl) and X! - such as a certain one); and 8) C-zalkyl?C-zalkylX! (where U? represent -O-, -5-, -50-, -502-, -MAZSO-, -"SOMAZ2-, -502М83-, -

MAZVO"- or -MAZ5- (where VZ! IDZ2, DZZ, VdZya and 35 independently represent each hydrogen, Ci-zalkyl or

C-zalkoxyC2g-zalkyl) and X! - such as defined above); 7 represents -MIN-, -О-, -5- or -СНе-; provided that when РЕ" is selected from one of the above groups 1), 2) and 5) and X' represents unsubstituted phenyl or substituted phenyl with 1-2 substituents selected from halogen, C1-alkyl and C1--alkoxy, then t represents an integer from C to 5 and/or 7 represents -O-, -5- or -SNeo-|, and its salts.

Mainly in! represents -O-, -5-, -CHe-, -MASO-, -MAZ5O»- or -MAU- (where 5, BB and Z independently represent each hydrogen, C1-alkyl or C1-haloxyethyl).

Preferably, Y" represents -O-, -5-, -CHe-, -MA?CO-, -MA8350"- or -MH- (where E? and 28 independently represent each hydrogen, C1-alkyl or C1-haloxyethyl).

More preferably, U" represents -O-, -5-, -CH2- or -MH-, in particular -O-.

In the second embodiment of the present invention, U! represent -O-, -MA?ZSO- or -

MAZ5O»- or (where EZ and EZ independently represent each hydrogen or Ci-halalkyl).

In another embodiment of the present invention, U! represent -MNSO-.

In one of the variants of the implementation of the present invention EC! represent hydrogen, hydroxy, C1-zalkyl, C1-zalkoxy, Czalkylthio or ME'OV'"! (where B'b and B" are as defined above). However, it is convenient when B represents hydrogen, hydroxy, cyano, nitro, trifluoromethyl, C1-6alkyl, C1-6alkyloxy or amino.

B' mainly represents hydrogen, hydroxy, C1-6alkyl, C1-6lkoxy or amino.

IN! are preferably hydrogen, hydroxy, methyl, methyl, methoxy or oztoxy, more preferably hydrogen, hydroxy, methyl or methoxy, in particular hydrogen, methyl or methoxy, but especially methoxy.

In the second embodiment of the present invention P! represents hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, ztyl, methoxy or ztoxy.

IN? represents mainly hydrogen, halogen, amino or nitro.

Preferably B: represents hydrogen, chlorine or nitro, but especially hydrogen.

In one of the embodiments of the present invention, EZ is hydroxy, halogen, C1-zalkyl, C1-zalkoxy, trifluoromethyl, cyano, amino or nitro.

Whenever, in the second variant of the implementation of the present invention, one of the BZ substituents represents meta-hydroxy, and the other one or other vibrations! each of halogen and methyl.

In the second variant of the implementation of the present invention, the phenyl group bearing (RZyu) represents a group of formulas! Ia:

Kk V

Kk (where:

Be represents hydrogen, methyl, fluorine or chlorine;

IN? represent hydrogen, methyl, methoxy, bromine, fluorine or chlorine;

B: represents hydrogen or hydroxy;

VU represents hydrogen, fluorine or chlorine, especially hydrogen or fluorine.

In another embodiment of the present invention, the phenyl group carrying (PZ)t is preferably a group of the formula! Yes, where:

Ve represents hydrogen, fluorine or chlorine;

IN? represent hydrogen, methyl, methoxy, bromine, fluorine or chlorine, especially hydrogen, methyl or chlorine;

B: represents hydrogen or hydroxy; and

VU represents hydrogen; under the conditions that each of 2, B? and E: does not represent hydrogen.

The phenyl group bearing (BZ) is preferably a 3-hydroxy-4-

methylphenyl, 2-fluoro-5-hydroxy-4-methylphenyl, 2-fluoro-4-bromophenyl, 2-fluoro-4-chloro-5-hydroxyphenyl or 4-chloro-2-fluorophenyl group.

In a specific embodiment of the present invention, the phenyl group carrying (PZ)t is a 3-hydroxy-4-methylphenyl group, but especially a 2-fluoro-5-hydroxy-4-methylphenyl group.

In another embodiment of the present invention, the phenyl group carrying (PZ)t is a 4-chloro-2-fluorophenyl group.

Mainly in? represents -O-, -5-, -50-, -502-, -MV'ESO-, -MAV!50"- or -MA29- (where В'Е, ВЗ and

IN? independently represent each hydrogen, C1-halalkyl or C1-haloxyethyl).

Preferably in? represents -O-, -5-, -50-, -5O2-or -MA2O- (where BO represents hydrogen, C1-alkyl or C1-haloxyethyl).

Are you sick preferably? represents -5-, -0- or -MV2O- (where BO represents hydrogen or C-C alkyl), and most preferably it represents -O- or -MV2O- (where B2O is as defined above).

Predominantly UZ represents -О-, -5-, -50-, -502-, -МВ2!СО-, -МА2"50"- or -МА25- (where В", В and

A independently represents each hydrogen, C-alkyl or C-haloxyethyl).

Preferably, UZ represents -O-, -5-, -50-, -BOg-or -MA2- (where E25 represents hydrogen, C1-alkyl or C1-haloxyethyl).

More preferably, UZ represents -O- or -MA2:- (where 2? represents hydrogen or Ci-halalkyl).

Predominantly U" represents -O-, -5-, -50-, -505-, -МВ29СО-, -МА2280»- or -MAVZO- (where 226, VD29 and

BZ independently represent each hydrogen, C1-halalkyl or C1-haloxyethyl).

Preferably, Y" represents -O-, -5-, -50-, -502- or -MAZO- (where ZO represents hydrogen, C1-alkyl or C1-haloxyethyl).

More preferably, Y" represents -O- or -MAZO- (where 239 represents hydrogen or C1-halalkyl).

Mainly in? represents -O-, -5-, -50-, -5O2-or -MAZ5- (where ЕЗ5 represents hydrogen, C1-alkyl or C1-haloxyethyl).

Preferably in? represents -5-, -O- or -MV2:- (where BZ represents hydrogen, C1-alkyl or C1-haloxyethyl).

Preferably, t represents 2 or 3. 2 may, for example, represent -MH- or -O-, but preferably 2 represents -MH-.

X' preferably represents a pyridone group or a 5- or b-membered aromatic heterocyclic group with 1-3 heteroatoms selected from O, M and 5, and the pyridone or heterocyclic group may be substituted as described above.

When X' represents a 5- or b-membered aromatic heterocyclic group, it preferably has 1 or 2 heteroatoms selected from 0, M and 5, of which M is more preferred, and may be substituted as described above.

X! represents, in particular, a pyridone, pyridyl, imidazolyl, thiazolyl, thienyl, triazolyl or pyridazinyl group, which may be substituted as described above, and more specifically a pyridone, pyridyl, imidazolyl, thiazolyl or triazolyl group, especially a pyridone, pyridyl, imidazolyl or triazolyl group, which can be substituted as described above.

When B" represents CsalkylX!, CsvalkenylX!, SvalkynylX! or C-zalkylU?CsalkylX! and xX! represents a nitrogen-containing 6b--lene aromatic heterocyclic group, this group is predominantly connected to an alkyl, alkenyl or alkynyl fragment through the carbon atom of the X' group, and the specified group is such that the nitrogen atom is located in para-position in relation to the carbon atom connected to the alkyl, alkenyl or alkynyl fragment.

The C-alkyl fragment can, if required, be -(CHn)n-.

When V'-U! represents X!-(CHn)n-U1- and n represents an integer from 0 to 5, U! represents -O-, -

МН-, -8- or -СН2- and X' represents a nitrogen-containing b-membered aromatic heterocyclic group, which is mainly connected to -(CHg)y-U!- through the carbon atom of the groups! X", and the specified group is such that the nitrogen atom is in the para-position in relation to the carbon atom connected to -(СНа)п-У-.

In another interesting example, X' represents pyrimidine, which can be substituted as described above.

In one of the variants of the implementation of the present invention, X'" represents a pyridonic, phenyl or 5- or b-membered aromatic heterocyclic group with 1-3 heteroatoms selected from O, M and 5, and this group can preferably carry up to 2 substituents ( more preferably to one substituent), selected from the groups of substituents described above.

In the definition of X', suitable substituents are selected from halogen, C1-alkyl, C1-alkoxy, and cyano, and more suitable substituents are selected from chlorine, fluorine, methyl, and xtyl.

A suitable P" is chosen from the following eight groups: 1) X (where X' is as defined above); 2) C-zalkylX! (where X! is as defined above);

C) C3-alkenyl! (where X! - such as a certain higher); 4) So-valkynylu! (where X! - such as a certain higher);

B) Si-valkylugH! (where U? and X! are as defined above); 6) Sz-zgalkeniluZH! (where UZ and X! are as defined above); 7) Sz-zgalkinilu"X! (where U" and X! are as defined above); 8) Co-zalkyl? Si-halkylu! (where U? and X! are as defined above).

Preferential RE" is selected from the following eight groups: 1) X (where X' is as defined above); 2) C-alkyluX! (where X! is as defined above); 3) 1-X'prop- 1-en-33-yl, 1-X'but-2-en-4-yl, 1-X'but-1-en-3-yl, 1-X'pent-2-en-4-yl or 2-H'pent-3-en-5-yl

(where X! is as defined above, provided that when B" represents 1-X'prop-1-en-3Z-yl, then X! is attached to the alkenyl group through a carbon atom); 4) 1-X' prop-1-yn-Z-yl, 1-X'but-2-yn-4-yl, 1-X'but-1-yn-3-yl, 1-X'pent-2-yn-4- yl or 2-X'pent-3-yn-5-yl (where X! is as defined above, provided that when P" represents 1-X'prop-1-yn-3-yl, then X attached to an alkynyl group through a carbon atom); 5) Si-galkilugH! (where U? and X! are as defined above); 6) 1-(X'X3)prop-1-en-3-yl, 1-(X3)but-2-en-4-yl, 1-(X'X3)-but-1-en-3- yl, -1-(XU3)pent-2-en-4-yl or 2-(XU)pent-3-en-5-yl (where UZ and X! are as defined above); 7) 1--X1UZprop-1-yn-3-yl, 1-(X'MU)but-2-yn-4-yl,. 1-(XM)-but-1-yn-3-yl, 1-(X'Y)pent-2-yn-4-yl or 2-(X"Y)pent-3Z-yn-5-yl ( where M" and X! are as defined above); and 8) Co-zalkyl? Si-halkyl! (where U? and X! are as defined above).

Preferred P" is selected from the following eight groups: 1) X (where X' is as defined above); 2) C-alkyl! (where X! is as defined above);

C) 1-X'but-2-en-4-yl (where X is as defined above); 4) 1-X'but-2-yn-4-yl (where X! is as defined above); 5) Si-galkilugH! (where U? and X! are as defined above); 6) 1-(X'U3)but-2-en-4-yl (where UZ and X! are as defined above); 7) 1-01but-2-yn-4-yl (where MU" and X! are as defined above); and 8) ztylu"methyl! (where U? and X! - such as are more specific).

More preferably, compounds of formula (I) are compounds of formula (Ia): and: 3

I Go, 7: iv) ' and r husnug M (where B", V, VZ, t, X, U and 7 - such as defined above, p represents an integer, and O to B represent a direct connection, -O-, - 5-, -50-, -5O2-, -MAZSO-, -"SOMAZ-, -502M838-, -MAZ50"- or -MA2O- (where 36, ВЗ, ВЗ8, З in Во independently represent each hydrogen, Si -zalkyl or C-zalkoxyCo- zalkyl)).

Predominantly, ХУ represents a direct bond, -О-, -5-, -50-, -502- or -МАВ- (where o represents hydrogen, C1-alkyl or C1-haloxyethyl).

Preferably, UU represents a direct bond, -О-, -5- or -МН-.

More preferably, UU represents a direct connection.

Preferably n represents an integer from 0 to 3, and preferably from 1 to 3.

Thus, for example, in a specific embodiment of the present invention, compounds of formula I are compounds of formula Ia, where:

ГИ represents -О-, -МН-, -5- or -СНе-; n represents an integer from 0 to 5;

X' represents a phenyl group or a 5- or b-membered aromatic heterocyclic group with 1-3 heteroatoms selected from O, -M and 5, and the phenyl or heterocyclic group can carry up to 5 substituents selected from halogen, C-alkyl , C-alkoxy, C-"hydroxyalkyl, C-ahydroxyalkyl, carboxy, cyano, -SOMA"B2 and -MAZSOV (where B", B, BZ and c, which may be the same or different, represent each hydrogen or C-4alkyl );

B' represents hydrogen, hydroxy, C1-zalkyl, C1-zalkoxy, C1-zalkylthio or MeV" (where C and B, which can be the same or different, represent each hydrogen or C1-zalkyl);

IN? represent hydrogen, hydroxy, halogen, C1-6alkyl, C1-zalkoxy, trifluoromethyl, cyano, amino or nitro; t represents an integer from 1 to 5;

VAZ represents hydrogen, halogen, C1-zalkyl, C1-zalkoxy, Sizalkanoyloxy, trifluoromethyl, cyano, amino or nitro; 7 represents -MH- or -O-; and

Uu5 represents a direct connection; provided that when X! represents unsubstituted phenyl or substituted phenyl with 1-2 substituents selected from halogen, C-4-alkyl and C-4-alkoxy, then t represents an integer from C to or 7 represents -O-); or their salts.

Preferred compounds according to the present invention are: 4-(3-hydroxy-4-methylanilino)-b-methoxy-7-(3-pyridylmethoxy)quinazoline 4-(3-hydroxy-4-methylanilino)-b-methoxy-7-( 3-thienylmethoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-pyridyloxy)zthoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy- 7-(2-|M-methyl-M-(4-pyridyl)|aminoethoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-|2-(2-oxo-1,2 -dihydro-1-pyridyl)zoxyquinazoline 7-(4-cyanobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy -7-(3-(2-methylimidazol-1-yl)propoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methyl-4-pyridyl)methoxy)quinazoline 4- (4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(2-oxo-1,2-dihydro-1-pyridyl)propoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-6 -methoxy-7-(3-(1-methylimidazol-2-ylthio)propoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-pyridyloxy)propoxy)quinazoline 4 -(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridylthio)zthoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(3-pyridyloxy)zthoxy)quinazoline

7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylanilino)quinazoline 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)quinazoline 4-(4-chloro-2-fluoro) -5-hydroxyanidino)-6b-methoxy-7-(2-methylthiazol-4-yl)methoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-thienyl)methoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(M-methyl-M-(pyridazin-4-yl)amino)zthoxy)quinazoline 4-(4-chloro-2-fluoroanilino )-6-methoxy-7-(2-(M-methyl-M-(b-methylpyrimidin-4-yl)amino)zthoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-7-(2-( 3,5-dimethyl-(1,2,4|-triazol-4-yl)zthoxy)-6b-methoxyquinazoline 4-(4-chloro-2-fluoroanilino)-7-(2-(2,4-dimethylimidazol- 1-yl)zthoxy)-6-methoxyquinazoline 4-(4-chloro-2-fluoroanilino)-7-(2-(2,5-dimethylimidazol-1-yl)zthoxy)-6-methoxyquinazoline 4-(3-hydroxyanilino )-7-(2-(imidazol-1-yl)zthoxy)-b-methoxyquinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1,2,4-triazol- 4-yl)zthoxy)quinazoline 4-(4-bromo-2-fluoroanilino)-7-(2-(11,2,4|I-triazol-1-yl)zthoxy)-6-methoxyquinazoline and their salts, in in particular, hydrochloride!.

The following compounds according to the present invention are particularly preferred: 4-(3-hydroxy-4-methylanilino)-b-methoxy-7-(4-pyridylmethoxy)quinazoline 4-(3-hydroxy-4-methylanilino)-6b-methoxy-7 -(2-pyridylmethoxy)quinazoline 4-(3-hydroxy-4-methylanilino)-b-methoxy-7-(1-methylimidazol-2-ylmethoxy)quinazoline 4-(3-hydroxy-4-methylanilino)-b-methoxy -7-(2-methylthiazol-4-ylmethoxy)quinazoline 7-(2-acetamidothiazol-4-ylmethoxy)-4-(3-hydroxy-4-methylanilino)-b-methoxyquinazoline 4-(3-hydroxy-4-methylanilino )-b-methoxy-7-(4-pyridylpropoxy)quinazoline 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylpropoxy)quinazoline 4-(2-fluoro-5 -hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)quinazoline 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylanilino)-b-methoxyquinazoline 4-(4-chloro- 2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyloxy)zthoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-|2-(4-oxo-1, 4-dihydro-1-pyridyl)zthoxyquinazoline 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylphenoxy)-b-methoxyquinazoline 4-(2-ft or-5-hydroxy-4-methylanilino)-6b-methoxy-7-((2-methylthiazol-4-yl)methoxy)quinazoline 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(4 -pyridylmethoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-7-(2-«(imidazol-1-yl)zthoxy)-6-methoxyquinazoline 4-(2-fluoro-5-hydroxy-4-methylanilino) -6-methoxy-7-((1-methyl-imidazol-2-yl)methoxy)quinazoline 7-(2-acetamidothiazol-4-yl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino )-b-methoxyquinazoline 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-b-methoxyquinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-( 4-pyridyl)propoxy)quinazoline 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline 4-(2-fluoro-5-hydroxy -4-methylanilino)-7-(2-imidazol-1-yl)zthoxy)-6-methoxyquinazoline 4-(4-chloro-2-fluoro-5-hydroxyanilino)-7-(2-imidazol-1-yl) zthoxy)-6-methoxyquinazoline 4-(2-fluoro-5-hydroxy-4-methylanilino)-6b-methoxy-7-(2-(4-pyridyl)zthoxy)quinazoline 4-(2-fluoro-5-hydroxy- 4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyl)stok si)quinazoline 4-(3-hydroxy-4-methylanilino)-b6-methoxy-7-((1-methylbenzimidazol-2-yl)methoxy)quinazoline 7-(2-chloro-6-methyl-4-pyridyl)methoxy )-4(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline 4-(4-chloro-2-fluorophenoxy)-6b-methoxy-7-(4-pyridyl)methoxy)quinazoline 4-(4 -chloro-2-fluoroanilino)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-methylimidazole-1 -yl)zthoxy)quinazoline 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline 4-(2-chloro-4-pyridyl)methoxy) -4-(2-fluoro-5-hydroxy-4-methylanilino)-6b-methoxyquinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methylimidazol-2-ylthio) zthoxy)quinazoline 7-(3,4-difluorobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6- Methoxy-7-(1-methylimidazol-2-yl)methoxy)quinazoline 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(1-methylimidazol-2-yl)methoxy)quinazoline 4-(2 -fluoro-5-hydroxy-4-methylanilino)-7-(2-(1,2,4-triazol-1-yl)zthoxy)quinazoline 4-(4-chloro-2-fluoro-5-hy hydroxyanilino)-6-methoxy-7-((2-thienyl)methoxy)quinazoline 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-(4-pyridyl)zthoxy) Quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1,2,4-triazol-1-yl)zthoxy)quinazoline 4-(2-fluoro-5-hydroxy-4 -methylanilino)-7-((4-pyridyl)carboxyamido)quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(M-(4-pyridyl)amino)zthoxy)quinazoline 4 -(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methylimidazol-2-yl)zthoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-7-(2-cyano -4-pyridyl)methoxy)-6-methoxyquinazoline and their salts, in particular the hydrochloride, of which the following are particularly preferred: 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4- pyridyloxy)zthoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-|2-(4-oxo-1,4-dihydro-1-pyridyl)zthoxyquinazoline 4-(4-chloro-2 -fluoroanilino)-7-(2-«(imidazol-1-yl)zthoxy)-6-methoxyquinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy )quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyl)zthoxy)quinazoline 4-(4-chloro-2-fluoro anilino)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-methylimidazol-1-yl)zthoxy) quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methylimidazol-2-ylthio)zthoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy- 7-(2-(1,2,4-triazol-1-yl)zthoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(M-(4-pyridyl) amino)zthoxy)quinazoline 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methylimidazol-2-yl)zthoxy)quinazoline 4-(4-chloro-2-fluoroanilino)- 7-(2-cyano-4-pyridyl)methoxy)-6-methoxyquinazoline and their salts, in particular hydrochloride.

The second compound of interest is 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyrimidinylmethoxy)quinazoline and its salts, in particular the hydrochloride.

In order to avoid ambiguity, it should be understood that when the described group is referred to as "more defined", it covers the first, broadest definition and each and every one of the preferred definitions for this group!

As used herein, the term "alkyl" includes both straight and branched alkyl groups, but references to individual alkyl groups, such as "propyl" refer specifically to the straight chain. A similar rule applies to other generic terms. Unless otherwise specified, the term "alkyl" refers primarily to chains with 1-6 carbon atoms, preferably with 1-4 carbon atoms. As used herein, the term "alkyl" includes, unless otherwise specified, "alkyl"-O-group!, in which "alkyl" is as defined above.

The term "aryl", as used herein, refers, unless otherwise specified, to a cycloaryl group, which may, if necessary, bear one or more substituents selected from halogen, alkyl, alkoxy, nitro, trifluoromethyl, and cyano (where alkyl and alkoxy - such as definitely higher). The term "aryloxy" as used herein includes, unless otherwise specified, "aryl"-

O-group, in which "aryl" is as defined above. The term "sulfonyloxy" as used herein refers to alkylsulfonyloxy and arylsulfonyloxy groups, in which "alkyl" and "aryl" are as defined above. The term "alkanoyl" as used herein includes, unless otherwise specified, alkyl-O groups in which "alkyl" is as defined above, for example ztanoyl refers to CH3C-:O. As used herein, the term "alkenyl" includes, unless otherwise specified, both straight and branched chain alkenyl groups, but references to an individual alkenyl group), such as 2-butenyl, specifically refer only to straight chain groups. Unless otherwise specified, the term "alkenyl" refers primarily to a chain with 2-6 carbon atoms, preferably 4-5 carbon atoms. As used herein, the term "alkynyl" includes, unless otherwise specified, both straight and branched chain alkynyl groups, but references to an individual alkynyl group), such as 2-butynyl, specifically refer only to straight chain groups. Unless otherwise specified, the term "alkynyl" refers primarily to chains with 2-6 carbon atoms, preferably 4-5 carbon atoms.

In formula I defined above, hydrogen is located in positions 2 and 8 of the quinazoline group!.

It should be understood that within the scope of the present invention there are quinazoline formulas! | or its salt may exhibit tautomerism and that the drawings of the formulas in this description may represent only one of the possible tautomeric forms. It is clear that the invention covers any tautomeric form that inhibits the tyrosine kinase activity of MESE receptors, and is not limited to any one tautomeric form shown in the formula drawings.

It should also be understood that some quinazodiene formulas and their salts can exist in solvated and non-solvated forms, such as the hydrated form! It is clear that the present invention covers all such solvated forms that inhibit the tyrosine kinase activity of MESE receptors.

In order to avoid any ambiguity, it is necessary to understand that when U! represent, for example, the group of formulas -МА?СО-, then the nitrogen-bearing group B? attached to the quinazoline ring and the carbonyl (CO) group attached to the VU, and when M! represents, for example, a group of formulas! -

СОМВ-, then a carbonyl group is attached to the quinazoline ring, and the РУ group, bearing a nitrogen atom, is attached to B". A similar rule applies to other groups В" linking two atoms, such as -МАЗ5О2- and -502МВ8"-. When M! represents -MV-, the BU group, bearing a nitrogen atom, is connected to the quinazoline ring and to B". A similar rule applies to other groups. It should also be understood that when M! represented by -MA?- and the group KU? represent C-zalkoxySozalkyl, then the Sozalkyl fragment is connected to the nitrogen atom of the M! group, and the same rule applies to the other groups.

To avoid any doubt, it is necessary to understand that when in compounds of formulas! B" represents, for example, a group of formulas! the terminal C-zalkyl fragment is connected, and when is B? represent, on the contrary, the group of formulas SgovalkenylX!, then c M! a C2-alkenyl fragment is attached, and the same rule applies to the other groups. When B represents the 1-X'prop-1-en-3-yl group, then the X group is attached to the first carbon atom! And the third carbon atom is connected to U", and when 2" represents the 2-X'pent-3-en-5-yl group, then the X group! is attached to the second carbon atom, and the fifth carbon atom is connected to U", and the same rule applies to the second groups.

In order to avoid any doubt, it is necessary to understand that when X! carries a Si4aminoalkyl substituent, then to X! a C-4 alkyl fragment is attached, and when X! carries as a C-zalkylamino substituent, that is

An amino fragment is attached to X', and the same rule applies to other groups.

The present invention relates to the compounds of formula I, described above, as well as to their salts.

Salts for use in pharmaceutical compositions must! are pharmaceutically acceptable salts, and other salts may be useful for obtaining compounds of formulas I and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts according to the present invention can, for example, include acid-addition salts of the above-described compounds of formulas |, which are considered sufficiently basic for the formation of such salts. Such acid-addition salts include, for example, salts with inorganic acids, such as hydrohalic acid! (in particular, hydrochloric or hydrobromic acid, of which hydrochloric acid is especially preferred) and sulfuric or phosphoric acid, as well as salts with organic acids that give pharmaceutically acceptable anions, such as, for example, trifluoroacetic, citric or maleic acid. In addition, when combining formulas! | sufficiently acidic, pharmaceutically acceptable salts can be formed! with an inorganic substance or an organic base giving a pharmaceutically acceptable cation. Such salts include, for example, an alkali metal salt,

such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt or, for example, a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

The compound of formula I or its salt and other compounds according to the present invention (such as defined above) can be obtained by any known method used to obtain chemically related compounds. Such methods include, for example, what is described in applications

Me0520722, Me0566226, Me0602851 and Me0635498 for a European patent. Such a way! serve as an additional feature of the present invention and descriptions! below Necessary source material! can be obtained by standard methods of organic chemistry. The preparation of such starting materials is described in the attached non-limiting examples. Or the necessary source material! can be obtained by similar methods of description, understandable to specialists in the field of organic chemistry.

The following methods (a)-(e) and (І)-(m) constitute additional features of the present invention.

Synthesis of compounds of formula (a) Compounds of formulas! And their salts can be obtained by the interaction of compounds of the formula PI:

IN

VE house (1) 4 Z A

В-У М (where К!, 82, В' and М! are such as defined above, and Й! represents a descending group) with a combination of formulas! IM: (and gn (where 7, VZ and t - such as defined above) with obtaining the combined formulas | and their salts.

A suitable removable group I! is, for example, a halogen, alkoxy- (preferably C1-alkoxy-), aryloxy- or sulfonyloxy group, for example, chlorine, bromine, methoxy-, phenoxy-, methanesulfonyloxy- or toluene-4-sulfonyloxy.

The reaction is mainly carried out in the presence of either an acid or a base. Such an acid is, for example, an anhydrous inorganic acid such as hydrochloric acid.

Such a base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, tristhylamine, morpholine, M-methylmorpholine or diazabicyclo!|5.4.F0)undec-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. If such a base is, for example, an alkali metal hydride, for example, sodium hydride, or an alkali or alkaline earth metal amide, for example, sodium amide or sodium bis(trimethylsilyl)amide. The reaction is preferably carried out in the presence of an inert solvent or diluent, for example, an alcohol or a complex sulfur such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride or carbon tetrachloride, a simple sulfur such as tetrahydrofuran or 1,4 -dioxane, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as M,M-dimethylformamide, M,M-dimethylacetamide, M-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is generally carried out at a temperature in the interval, for example, 10-1507C, preferably in the interval 20-80.

The compound according to the present invention can be obtained by the described method in the form of a free base or in the form of a salt with an acid of the formulas H-Y", where Y! has a value defined above. When it is necessary to obtain a free base from a salt, the salt can be treated with a base defined above , with the use of traditional methods. (p) When the group of formulas! Ir: (and (where EZ and t - such as defined above) represent a phenyl group bearing one or several hydroxy groups, the compound of the formulas! I and its salts can be obtained by removal of protection from compounds of formulas U:

In in! (m)

OHM

8 in M (where ХУ", т, В, В, ВУ, В" and 7 are as defined above. P represents a phenolic hydroxy protecting group and p' represents an integer from 1 to 5, equal to the number of hydroxy protecting groups, and the difference t-p' is equal to the number of EZ substituents, which are not protected by hydroxy). The addition of the phenolic hydroxy-protecting group P can make an ordinary organic chemist from those protective groups that are included in common literature, such as "Rgoiesiime sgoyir5 ip Ogdapis Zupipeviv" by T.M. sSgeepe apa A.M. Mushiv, 2nd ed. UMSheu 1991, which includes simple ethers (for example, methyl, methoxymethyl, allyl, and benzyl), simple silyl ethers (for example, tert-butyldiphenylsilyl and tert-butyldimethylsilyl), complex ethers! (for example, acetate and benzoate) and carbonate! (for example, methyl and benzyl carbonates). Removal of such phenolic hydroxy-protecting groups! can be carried out by any known method, including reaction conditions specified in the general literature, such as the one mentioned above, or a similar method. The reaction conditions are preferably such that it is possible to obtain the hydroxy derivative without unexpected reactions in other places in the original and target compounds. For example, when the protecting group P is acetate, the transformation is expediently carried out by treating the quinazoline derivative with a base defined above, including ammonia and its mono- and dialkylation derivatives, preferably in the presence of a protic solvent or cosolvent such as water or an alcohol, for example, methanol or ztanol Such a reaction can be carried out in the presence of an additional inert solvent or diluent, defined above, at a temperature in the range of 0-507C, preferably at or around 207C. (c) Get an indication of the combination of formulas; And their salts, in which the substituent "U" represents -O-, -

With- or -MAZ-, it is possible by means of interaction (expediently in the presence of a basis, such as defined above) of the compound of the MI formula:

To

VI uy

IN! (E)

OHM

And 2. A

NU M

(where t, U", B", B2, VZ and 7 are as defined above) with a combination of formulas! MII: ve (MI) (where R" and I! are as defined above); It represents a leaving group, for example, a halogen or a sulfonyloxy group, such as bromine or a methanesulfonyloxy group. The reaction is preferably carried out in the presence of a base (as defined above in method (a)) and preferably in an inert solvent or diluent (as defined above in method (a)) preferably at a temperature in the range of, for example, 10-150°C, preferably at or around 50°C. (4) Compounds formulas! And their salts can be obtained by implementing the interaction of compounds of the MI formula: where 7 is the same (MI)

OO OM pot

With the compound of formula IX:

В-М-Н (ИХ) (where I, V, V? VZ, VO, 7, you are M! - such as definitely more). The reaction is expediently carried out in the presence of a base (such as defined above in method (a)) and preferably in an inert solvent or diluent (such as defined above in method (a)) preferably at a temperature in the interval, for example, 10-1507"C, preferably at or near 1007C. (e) Compounds of the formulas ! and their salts, in which B" represents C-zalkylX? |where X? is selected from the following three groups: 1) X (where X' is as defined above); 2) LC (where U" represents -O-, -5-, -505-, -MA""CO-, -MA"85O2- or -MVZ- (where B", BZ and Z independently represent each hydrogen, Sisalkyl or C-zalkoxyC»zalkyl) and XX! - such as defined above); and

C) u8SysalkylX (where UZ represents -O-, -5-, -"502-, -MAROSO-, -MAP50"- or -MAP2- (where BO, VU and v independently represent each hydrogen, Ci-zalkyl or Ci- zalkoxyCg2-zalkyl) and X' - as defined above) can be obtained by implementing the interaction of compounds of the formulas X: and where 7

In (X)

M

(where SG, M, B, B, BZ, 7 and t are as defined above, and BEZ represents Cylalkyl) with a compound of formula XI:

Х:-Н (ХІ) (where Х2 is as defined above) to obtain the compound of formulas I. The reaction is expediently carried out in the presence of a base (as specified above in method (a)) and preferably in the presence of an inert solvent or diluent ( such as indicated above in method (a)) at a temperature in the interval, for example, 0-1507C, preferably approximately at 5070. () Indication of the combination of formulas! And their salts, in which the substituent E! represented by ME'OV!, where one or both radicals B? and B!!! represent Si-zalkyl, they can be obtained by implementing the interaction of compounds of formulas I! in which the substituent B' is an amino group, and the alkylating agent is preferably in the presence of a base defined above. Such alkylating agents are a C-zalkyl fragment, carrying a certain more cleavable (leaving) fragment, such as C-zalkyl halides, for example, C-zalkyl chloride, -bromide or -iodide. The reaction is preferably carried out in the presence of an inert solvent or diluent (as defined above in method (a)) at a temperature in the range of, for example, 10-100"C, preferably approximately at ambient temperature. (9) Compounds of formulas I! and their salts, in which one or more substituents B!, B? or BZ represent an amino group, can be obtained by reduction of the corresponding compound of formulas I, in which the substituent(s) is in the corresponding position(s) of the quinazoline and/or phenyl ring represents a nitro group(s). The recovery is expediently carried out as described below in method (i). The combination of formulas i! and its salts, in which the substituent(s) in the corresponding position(s) of quinazoline and/or of the phenyl ring represent(s) a nitro group(s), can be obtained by the methods described above (a-ex and below (i-m), using quinazoline selected from compounds of the formulas (I-XXMII), in which the substituent(s) in according to nitro group(s) in the position(s) of the quinazoline and/or phenyl ring.

Synthesis of intermediate compounds (compounds of the formula II) and their salts constitute an additional feature of the present invention.

Such compounds, in which H' represents a halogen, can, for example, be obtained by halogenation of compounds of the formula XI:

IS:

E (Y

MN (XI!) vya sh (where В", В2, В' and У! are as defined above).

Suitable halogenating agent! include hydrogen halide! inorganic acids, for example, thionyl chloride, phosphorus chloride (IP), phosphorus oxychloride (M) and phosphorus chloride (M). The halogenation reaction is expediently carried out in the presence of an inert solvent or diluent, such as, for example, a halogenated solvent such as methylene chloride, trichloromethane or carbon tetrachloride, or an aromatic hydrocarbon solvent such as benzene or toluene.

The reaction is expediently carried out at a temperature in the interval, for example, 10-150"C, preferably in the interval 40-100760.

Combinations of formulas! XII and their salts, which constitute an additional feature of the present invention, can, for example, be obtained by implementing the interaction of compounds of formulas XII:

A: (9)

Whew! re. (XI!)

Eve; also (where EE", V? and I! - such as defined above) with the combination of formulas IX, defined above.

The reaction is expediently carried out in the presence of a base (such as defined above in method (a)) and preferably in the presence of an inert solvent or diluent (such as defined above in method (a)) at a temperature in the range, for example, 10-1507C, preferably at or around 1007C.

Compounds of formula XII and their salts can also be obtained by cyclization of compounds of formulas XIM: in 19)

IN

ВАХ МН, (where В", В, В? and У! - as defined above, and А! represents a hydroxy-, alkoxy- (preferably C-4-alkoxy-) or amino group) with the formation of compounds of the formulas! XIiY or its salts .

Cyclization can be carried out by implementing the interaction of the formulas! KHIM, where A! represents a hydroxy- or alkoxy group, with formamide or its equivalent capable of causing cyclization to obtain a compound of the formula! XII or Ego salts, for example, (3-(dimethylamino)-2-azaprop-2-enylidenedimethylammonium chloride. Cyclization is expediently carried out in the presence of formamide as a solvent or in the presence of an inert solvent or diluent, such as simple sulfur, for example, 1,4 -dioxane. The cyclization is expediently carried out at an elevated temperature, preferably in the range of 80-200°C. Compounds of the formulas XII can also be obtained by cyclization of the compounds of the formulas XIM, where A! represents an amino group, with formic acid or its equivalent, capable of causing cyclization, with compounds of formulas ХІІІІ or ego salts.

Equivalences of formic acids capable of causing cyclization include, for example, tri-C3-C4-Alkoxymethane, for example, tristhoxymethane and trimethoxymethane. Cyclization is expediently carried out in the presence of a catalytic amount of anhydrous acid, such as sulfonic acid, for example, p-toluenesulfonic acid, and an inert solvent or diluent, such as, for example, a halogenated solvent, such as methylene chloride, trichloromethane or carbon tetrachloride, simple sulfur , such as distyl sulfur or tetrahydrofuran, or an aromatic hydrocarbon solvent such as toluene. Cyclization is expediently carried out at a temperature in the range, for example, 10-100"C, preferably in the range 20-5070.

Combinations of formulas! Chemical compounds and their salts, which are an additional feature of the present invention, can be obtained, for example, by reducing nitro groups! in compounds of formulas ХУ:

Yu

0)

VE

Izha m : o 0) (where EE", 82, VM! and A! are as defined above) with obtaining the compound of the formulas! CHM, defined below. The reduction of nitro groups is expediently carried out by any method known for the implementation of such a transformation. The reduction can is carried out, for example, by hydrogenating a solution of a nitro compound in the presence of a solvent or diluent, such as that specified above, and in the presence of a metal catalyst, such as palladium or platinum.

The second reducing agent is, for example, an activated metal, such as activated iron (obtained, for example, by washing iron powder with a diluted acid solution, such as hydrochloric acid). So, for example, the reduction can be carried out by heating a mixture of a nitro compound and an activated metal in the presence of a solvent or diluent, such as a mixture of water and alcohol, for example, methanol or ethanol, to temperatures! in the interval, for example, 50-150"7C, preferably at 70"C or thereabouts.

Compounds of the XM formulas and their salts, which constitute an additional feature of the present invention, can, for example, be obtained by implementing the interaction of the compounds of the XMI formulas: b2 (c) in 1 -O and t o) (where B", B2, 17 and A! - such as defined above) with a compound of formulas IX defined above.

The interaction of compounds of the formulas KhMI and IH is expediently carried out under the conditions described above for method (i).

Compounds of the HM formulas and their salts can, for example, be obtained by implementing the interaction of the compounds of the HMI formulas!:

IN

(in)

IN! | ! оо (ХМ) well Mm'o (о; (where В", В, М! and А! are such as defined above, under the condition that M! does not represent -СНе-) with a combination of formulas! MY, defined above , with obtaining a compound of the formulas !ХМ, defined above. The interaction of compounds of the formulas ХМиІІ and MI! is expediently carried out under the conditions described above for method (c).

Compounds of formulas I and their salts can also be obtained, for example, by means of interaction of the compounds of formulas! ХМ: в ий 1 во (ХМ) 4 well М (where В", В? and У" are as defined above, under the conditions that М! does not represent -СН»- and И? represents a leaving protective group) с combination of formulas! MiI, more precisely, with obtaining a compound of the formula IIi, in which I" is represented by I 2.

It is advisable to use the combination of formulas! ХМІІІ, in which I? represents a phenoxy group, which, if necessary, can carry up to 5 substituents, preferably up to 2 substituents selected from halogen, nitro or cyano. The reaction is expediently carried out under the conditions described above for method (c).

Compounds of the HMII formula! and their salts, such as certain ones above, can beat, for example, receive! by removing protection! with compounds of formulas XIX: g 1 and M (XIX) 2

P-U M (where B", B, P, U and 12 are as defined above). Deprotection can be carried out by methods well known in the literature), for example, when P represents a benzyl group, deprotection can be carried out by hydrogenolysis or by treatment with trifluoroacetic acid.

One combination of formulas! If desired, II can be converted into a second compound of formula II, in which the fragment I" is the second. So, for example, the compound of formula II, in which I! differs from halogen,

for example, represents an optional substitution of phenoxy, it is possible to transform it into a compound of the formulas! And, in which And represents a halogen, by hydrolysis of the combination of formulas! PI (in which G' differs from halogen) with obtaining a compound of the formulas! ХІІІ, defined above, after that in the compound of the formula! XII, obtained as described above, introduces a halide to obtain a compound of the formula I, in which I" represents a halogen. (i) Compounds of the formulas! M and their salts constitute an additional feature of the present invention and can be obtained, for example, by reacting the compound of formulas II, defined above, with a combination of formulas XX: (In ry

Sov (XX) yin (where EZ, t, p", P and 7 are as defined above). The reaction can be carried out, for example, as described above for method (a).

Compounds of the formula M and their salts can also be obtained by implementing the interaction of the compounds of the formulas! XXI

Where

VE

2 thing (OR (XXI)

OHM

Ivu M (where B", 82, 17, 7, VAZ, t, p' and P - such as defined above) with a combination of formulas! IX, defined above. The reaction can be carried out, for example, as described above for method (a).

Compounds of the formula M and their salts can also be obtained by implementing the interaction of the compounds of the formulas! XXIII: Mesh

Whew! and

D (OR) (XXII)

M is not y (where В", В2, ВУ, М, 7, Р, р' and t - such as defined above, provided that У! does not represent -

SnNeg-) with a combination of formulas! MII, definitely more. The reaction can be carried out, for example, as described above for method (c).

Compounds of the XXI formulas and their salts can be obtained, for example, by implementing the interaction of the compounds of the formulas! XXI:

EC

IN! are (XXI!) and zm (where ВЕ", В? and И! - such as are defined above, and И!" in clauses 4 and 7 can be the same or different) with the connection of the formula! XX, definitely more. The reaction can be carried out, for example, as described above for method (a).

Compounds of the formula XXI and their salts can be obtained by the interaction of the compounds of the formulas XX and XX, defined above, under the conditions described above for method (a), with obtaining the compounds of the formulas! XXII:

EE. /j vo (OR (XXIM) shi M ve o (where B", 82, VZ, P, 2, M, p' and t - such as defined above, provided that U! does not represent -

SnNe-) and then remove the protection! with compounds XXIM, for example, as described above in section (Her). (its Compounds of formulas! MI and their salts, defined above, can be obtained! by removing protection from the compounds of the XXU formulas:

Du

AND

7

In (XXM)

OHM

P-u" c (where B", B2, VZ, P, 72, M! and t - as defined above), for example, as described above in section (Her).

Compounds of formulas XXM and their salts can be obtained by the interaction of compounds of formulas XIX and IM, defined above, under the conditions described above for method (a), with obtaining compounds of formulas! XHM or ego salts. (m) Combinations of formulas! MI and their salts, defined above, can be obtained by the interaction of compounds of formulas XXI and IM, defined above, and the reaction can be carried out by the method described above in (a). (m) Compounds of the formula X, more specifically, and their salts can be obtained, for example, by the interaction of the compounds of the formulas! MI, defined above, with the compound of the formula

ХХМИ: (1-84 1 (ХХМИ) (where Y" and Z are as defined above) with obtaining a compound of the formulas! X. The reaction can be carried out, for example, by the method described above in (c).

Compounds of formula X and their salts can also be obtained, for example, by removing the protection! with the combination of formulas! XXMI!:

In! 7

In (OR) (XXMIII)

WHAT I tm (where I, 83, M, V", Vg, VU, R, t and r! - such as defined above), for example, by the method described above in (b).

Compounds of formulas XXMII and their salts can be obtained, for example, by the interaction of compounds of formulas XXI! and ХХМИ, defined above, under the conditions described above for method (c).

When a pharmaceutically acceptable salt of a compound of formulas is needed! And, it can be obtained, for example, by reacting the specified compound, for example, with an acid using traditional methods.

Many of the intermediate compounds defined in this description are new compounds, for example, intermediate compounds of the formulas IP, U, XII, XIM and XU, and these compounds constitute an additional feature of the present invention.

As an additional feature of the present invention, intermediate compounds of the formulas MI, X, XXI, XXII, XXIM, XXM and XXMIII are also proposed.

Identification of compounds that strongly inhibit the activity of tyrosine kinases associated with

MESE-receptors, such as EC and/or COC, and which inhibit angiogenesis and/or increased vascular permeability, is desirable and is the subject of the present invention. These properties can be estimated, for example, using one or more of the methods described below. (a) Test for inhibition of receptor tyrazin kinase! ip migo

So the test determines the ability of the test compound to inhibit the activity of tyrosine kinases. DNA-encoded cytoplasmic domains of MESE receptors or epidermal growth factor (ESF) receptors can be obtained by general gene synthesis (Edmaga5

M., Ipgegpayopa! Vioyesppoodu ar 5(3), 19-25, 1987) or by cloning. Then they can be expressed in a suitable system of expression to obtain a polypeptide with tyrosine kinase activity. For example, it was found that the cytoplasmic domains of MESE and ESE receptors, which were obtained by the expression of recombinant protein in insect cells, show significant tyrosine kinase activity. In the case of the MESE-receptor EII (MeX51602 in the Genbank catalog) 1,766 DNA fragment encoding most of the cytoplasmic domain, starting with methionine 783 and including the termination codon, which (fragment) was described by Bu Zpirsua eii (Opsodepe, 1990, 5: 519-524 ), was isolated from cDNA and cloned into a baculovirus transfer vector (for example, rASUMI (see Tne Vasshomigiz Ehrgezviop buvziet: A I aroghaiyugu Sshide, G.A. Kipd apa A.O. Rozzevye,

Spartap apa NaiYi, 1992) or pAs360 or rVineVasnNivz (Ipmygodep Sogrogayop)). This recombinant construct was cotransfected into insect cells (e.g., Zrodoriega yidiregaa 21 (5121)) with viral DNA (e.g., RPpagtipdep Wassho(soi4)) to obtain a recombinant baculovirus. standard manuals, for example, Zatyuogok ei ai, 1989, MyIesshag siopipd - A

I arogayugu Mapiai, 2nd edition, Soii Zrgipd Nagroshig Garogaiyugu Rgez5 apa O'Keyu eyi ai, 1992, Vasshomigy5

Ehrghezviop Mesiogz - A I arogayugu Mapia!, MU.N. Egeetap apa So, Mem Mogk). For other tyrosine kinases, for use in tests, cytoplasmic fragments starting with methionine 806 (KOE, catalog Me! 04947 in Genbank) and methionine 668 (ESE receptor, catalog MeX0O0588 in Genbank) can be cloned and expressed in a similar manner.

To express SEI-tyrosine kinase activity, cells 5121 were infected with pure SEP-recombinant plague virus! with a multiplicity of infection equal to 3, and collected after 48 hours. Collected cells were washed with ice-cooled phosphate-salt buffer solution (PB5) (10 mM sodium phosphate pH 7.4, 138 mM Mass, 2.7 mM KSI), then resuspended in ice-cooled NMTO/PM5E (20 mM Nerez pH 7.5, 150 mM Mass, 1095 0/0 glycerol, 195 0/0 Tgtyop X100, 1.5 mM MaoSi», 1 mM ethylene glycol-bis (aminoethyl sphyre) M,M,M',M'-tetraacetic acid (ESTA), 1 mM PM5E (phenylmethylsulfonyl fluoride); PM5E was added immediately before use from a freshly prepared 100 mM solution in methanol) with the use of NMTO/PM5E for 10 million cells. The suspension was centrifuged for 10 minutes at 13,000 rpm at 4°C, the supernatant (enzyme stock) was removed and stored as aliquot samples at -70°C. Each new sample of the enzyme from the reserve was titrated during the analysis by diluting it with an enzyme diluent (100 mM Nerez pH 7.4, 0.2 mM Mazmox, 0.195 0/0 Tiop X100, 0.2 mM dithiothreit). For a typical sample, the enzyme is diluted in a ratio of 1 to 2000 with an enzyme diluent and 50 μl of the diluted enzyme is used for each cell for analysis.

A stock of substrate solution was prepared from an arbitrary copolymer containing tyrosine,

for example, Poly-(Glu, Ala, Tyr) 6:3:1 (bBidta RZ899), stored in РВ5 (1mg/ml) at -20"C and diluted with РВ5 in a ratio of 1 to 500 to cover the plates.

A day before the test, 100 μl of the diluted substrate solution was distributed over all the cells of the plates for analysis (Mips Tachyzogr immunoplates with 96 cells) and, after closing them, they were left overnight at 4.

On the day of the test, the substrate solution was removed and the cells of the plates were washed once with РВ5OT (РВ5 containing 0.0595 0/0 Tzheep 20) and once with 50MM Nerez with pH 7 4.

The test compound was diluted with 1095 dimethyl sulfoxide (DMSO) and 25 μl of the diluted compound was transferred to cells in washed plates. All control cells contained 1095 DMSO instead of the compound. Twenty-five microliters of 40 mM Mpsig, containing 3 µm of adenosine-5'-triphosphate (ATP, ATP), was added to "all" cells, excluding the "empty" control cell, which contained MpsSi" without ATP. To start the reaction, 50 μl of freshly diluted enzyme was added to each cell, and the plates were incubated at room temperature for 20 minutes. Then the liquid was drained and the cells were washed twice with RVOT. One hundred microliters of muscle antibody to phosphotyrosine Id (Orviage Vioespoiod Ips., product 05-321), diluted in a ratio of 1 to 6000 using РВ5OT, containing 0.595 m/o bovine serum albumin (B5A), was added to each cell, and the plates were incubated for 1 hours at room temperature, after which the liquid was drained and the cells were washed twice with RVT. One hundred microliters of horseradish peroxidase-linked (HER) sheep antibody to murine Id (Ategzpat, product of MXA 931), diluted in a ratio of 1 to 500 using

RBBT containing 0.595 m/o B5BA and the plates were incubated for 1 hour at room temperature, after which the liquid was drained and the cells were washed twice with RB5T. One hundred microliters of 2,2'-azino-bis(3-zylbenzthiazoline-6-sulfonic acid) (AVT) solution, freshly prepared using one 50 mg tablet of AVT5 (Voephipdeg 1204 521) in 50 ml of a freshly prepared mixture of 50 mM phosphate citrate buffer and 0 .0395 of sodium perborate (obtained from one capsule (Zidta P4922) with phosphate citrate buffer and sodium perborate (ROSV) per 100 ml of distilled water). Then the plates were incubated for 20-60 minutes at room temperature until the value of the optical density of "all" control cells, measured at 405 nm using a spectrophotometer for reading from the plates, was approximately 1.0. Values in "empty" (without ATP) and "all" (without compound) control cells were used to determine the degree of dilution of the tested compound, which gave 5095 inhibition of enzymatic activity. (p) Analysis of NOMES ip myo cell proliferation

This analysis determines the ability of the tested compound to inhibit growth factor-stimulated proliferation of human umbilical vein endothelial cells (NOMES).

NOMES cells were cultured in MSOV 131 (sirso VK) w- 7,590 0/0 fetal calf serum (ES5) and seeded (at passage 2-8) in MSOV 131 w 295 0/0 ES5 w Zmkg/ml heparin w 1μg/ml hydrocortisone at a concentration of 1000 cells per cell in plates with 96 cells. After at least 4 hours, the appropriate growth factor (namely MESE Zng/ml, ESE Zng/ml or p-EOE 0.Zng/ml) and the compound were loaded.

Then the cultures were incubated for 4 days at 37°C with 7.595 С. On the fourth day, the cultures were exposed to a pulse (1 μCi/cell) of tritium-labeled thymidine (Ateg5pat, product

TVA 61) and incubated for 4 hours. Cells were collected using a device (Totiek) for collecting cells from 96-well plates and then analyzed for tritium incorporation using a beta counter. Incorporated radioactivity in cells, expressed in CRT (counts per minute), was used to measure the inhibition of growth factor-stimulated cell proliferation by compounds. (c) Analysis of ip mimo edema of the uterus of cows

So the test determines the measure of the compounds' ability to reduce the sharp increase in mass! uterus in mice, which occurs in the first 4-6 hours after strogen stimulation. That is, the premature increase in the mass of the uterus is caused, as it has long been known, by edema, caused by increased permeability of the vascular network of the uterus, and recently Sciipap-Vome apa Kooz (Epdoshypoiodu, 1993, 133: 829-837) demonstrated a close temporal relationship of mRNA in the uterus with increased expression of MESBE.

These inventors found that the previous administration of a neutralizing monoclonal antibody to MESE to rats significantly reduces the sharp increase in uterine mass, which confirms the significant influence of MESE on the increased mass.

A group of 20-22-day-old rats was injected with one subcutaneous dose of estradiol benzoate (2.5 μg/kg) in solvent or only solvent. In the latter case, there was a control group! unstimulated mice. At various times before the administration of estradiol benzoate, test compounds were administered orally. Five hours after the administration of estradiol benzoate, sleep! they killed them in a humane way, and their uteruses were cut, dried with blotting paper, and suspended.

I used the 5itsdepi T test, compared the increase in mass! uteri in groups treated with the test compound and estradiol benzoate and only with estradiol benzoate. Inhibition of the effect of estradiol benzoate was considered significant at p-e0.05.

In accordance with the second aspect of the present invention, there is provided a pharmaceutical composition that contains a certain higher compound of formula I or its pharmaceutically acceptable salt in combination with a pharmaceutically acceptable filler or carrier.

The composition can be in a form suitable for oral administration, for example, in the form of tablets or capsules, for parenteral administration (including intravenous, subcutaneous, intra-axillary, intravascular injection or infusion) in the form of a sterile solution, suspension or emulsion, for local administration in the form of an ointment or cream or for rectal administration in the form of a suppository. In general, the composition described above can be prepared in a traditional way, using traditional fillers.

It is expedient to have the compositions according to the present invention in the form of a dosage form. The compound is administered topically to a warm-blooded animal with a dose in the interval of 5-

5,000 mg per square meter of animal body area, i.e. approximately 0.1-100mg/kg. A dose in the range, for example, 1-100mg/kg, preferably 1-50mg/kg is considered a therapeutically effective dose and generally is. The dosage form, such as a tablet or capsule, usually contains, for example, 1-250 mg of the active component.

In accordance with another aspect of the present invention, a certain higher combination of formulas is proposed! And or it is a pharmaceutically acceptable salt for use in a therapeutic method of treating the human or animal body.

According to the inventors, it has now been established that the compounds of the present invention inhibit the tyrosine kinase activity of MESE-receptors, and therefore of interest! their antiangiogenic effects and/or ability to reduce vascular permeability.

Thus, according to this aspect of the present invention, the use of a compound of formulas I or its pharmaceutically acceptable salt is proposed for the manufacture of a medicinal product providing an anti-angiogenic effect and/or an effect of reducing vascular permeability in a warm-blooded animal, such as a human.

In accordance with another aspect of the present invention, a method of obtaining an anti-angiogenic effect and/or an effect of reducing vascular permeability in a warm-blooded animal, such as a human, in need of such treatment is proposed, which (method) includes the introduction of an effective amount of the specified compound of the above formulas into the specified animal! And or ego pharmaceutically acceptable salt.

As mentioned above, the amount of the dose required for the therapeutic or prophylactic treatment of a specific disease must be changed depending on the subject of treatment, the method of administration and the severity of the disease to be treated. It is preferable to use a daily dose in the range of 1-50 mg/kg. However, the daily dose must be changed depending on the subject of treatment, the method of administration and the severity of the disease to be treated. Therefore, the optimal dose can be determined by a practicing physician treating a particular patient.

The above-described antiangiogenic treatment and/or treatment to reduce vascular permeability may be used as a single therapeutic method or may include the use of one or more other substances and methods of treatment, except for the compound of the present invention. Such complex treatment can be provided by simultaneous, sequential or separate application of individual treatment components. In the field of medical oncology, it is common practice to combine different types of treatment to cure each cancer patient. In medical oncology, the second component(s) of such a complex treatment, in addition to the above-described treatment of angiogenesis and/or reduction of vascular permeability, may include surgery, radiation therapy, or chemotherapy. Such chemotherapy may include three main categories of drugs: () other antiangiogenic agents, the mechanism of action of which differs from the one described above (for example, Linomid, an inhibitor of Sur3Z integrin action, angiostatin, razoxin, thalidomide); (i) cytostatic agents, such as anti-estrogens (for example, tamoxifen, toremifene, raloxifene, droloxifene, iodoxifen), progestogens (for example, megestrol acetate), aromatase inhibitors! (e.g., anastrozole, letrazol, vorazole, zxemestane), antiprogestogens, antiandrogens (e.g., flutamide, nilutamide, bicalutamide, cyproterone acetate), agonists and antagonists (HEN (luteinizing hormone-releasing hormone) (e.g., goserelin acetate, luprolide), testosterone inhibitors -Bo-dihydroreductases (for example, finasteride), anti-invasive agents (for example, metalloproteinase inhibitors, such as marimastat, and urokinase activator plasminogen receptor inhibitors) and growth factor inhibitors (such growth factors include, for example, ESS, ESS factor, platelet growth factor and hepatocyte growth factor, and such inhibitor! include antibodies to growth factors, antibodies to growth factor receptors, tyrosine kinase inhibitor and serine-threonine kinase inhibitor); and (and antiproliferative and antitumor agents and their combinations used in medical oncology, such , as an antimetabolite! (for example, antifolate!, such as methot rexat, fluoropyrimidines, such as 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside); antitumor antibiotics (for example, anthracyclines), such as doxorubicin, daunomycin, zpyrubicin and idarubicin, mitomycin-C, dactinomycin, mithramycin); platinum production! (for example, cisplatin, carboplatin); alkylating agents (for example, nitrogen mustard, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosoureas, thiotope); antimitotic means (for example, alkaloid! periwinkle, such as vincristine, and taxoid, such as taxol, taxotere); topoisomerase inhibitors (for example, zpypodophyllotoxin, such as ztoposide and teniposide, amsacrine, topotecan).

As indicated above, the compounds of the present invention are interesting for their anti-angiogenic effects and/or effects of reducing vascular permeability. Such compounds are thought to be useful in a wide range of diseases, including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, and eye diseases with proliferation of retinal vessels. In particular, it is expected that such compounds of the present invention will slow down the growth of primary and recurrent solid tumors, for example, of the colon, mammary gland, prostate gland, lung and skin. More specifically, it is possible to expect that such compounds according to the present invention will suppress the growth of specified primary and recurrent tumors, called MESBE, especially those tumors whose growth and spread are largely dependent on MESBE, for example, some tumors of the colon, mammary gland). prostate gland, lung, external female genital organs and skin.

In addition to their use in therapeutic medicine, the combination of formulas! And their pharmaceutically acceptable salts are useful! also as pharmacological tools in the development and standardization of test systems for evaluating the effects of inhibitors of the tyrosine kinase activity of MESE receptors in laboratory animals, such as cats, dogs, rabbits, monkeys, rats and mice, in particular, in the search for new therapeutic agents.

It should be understood that the term "zphyr" when used in this description means diztilovy zphyr.

The present invention is illustrated by the following non-limiting examples, in which, unless otherwise indicated: () layering was carried out on a rotary evaporator in a vacuum, and processing operations were carried out after the removal of final solids, such as desiccants, by filtration; (its work was carried out at ambient temperature), i.e. in the range of 18-25"С, and in an atmosphere of an inert gas, such as argon; (ii) column chromatography (flsh-method) and liquid chromatography at medium pressure (HPLC) filled with silica MegskK KieseiYide! (art. 9385) or reversed-phase silicon dioxide Megek Hispgorger KR-18 (art. 9303) produced by E. MegskK, Darmstadt, Germany; (m) melting point not corrected and determined using the device

Mettler 5Rb2 for determining the melting temperature, a device with an oil bath or a device

Kofflera with hot tiles; (m) structures of the target products of the formulas! | confirmed by the methods of nuclear (mainly proton) magnetic resonance (NMR) and mass spectrometry; Proton magnetic resonance chemical shift values were measured on the delta scale, and the multiplets of the peaks mean the following: c - singlet, d - doublet, t - triplet, m - multiplet, w - broad, kv - quartet; (mi) the intermediate compound was not fully characterized in any way, and the purity was assessed by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), infrared (IR) spectroscopy or NMR analysis; (mine) used it! following abbreviations:

DMFf - M,M-dimethylformamide

DMSO - dimethyl sulfoxide

MMP - 1-methyl-2-pyrrolidone

THFf - tetrahydrofuran

TEA - trifluoroacetic acid.

Example 1

At ambient temperature, 2M aqueous solution of sodium hydroxide (0.33 ml, O0.bmmol). The mixture was stirred for 10 minutes at ambient temperature), the solvents were partially evaporated, water was added to the residue, and the solution was acidified with 0.1 M hydrochloric acid to pH 6. The precipitate was filtered off, washed with water and dried under vacuum, resulting in 4-(3-hydroxy- 4-methylanilino)-b-methoxy-7-(4-pyridylmethoxy)quinazoline hydrochloride (67mg, 87905).

T. pl. 249-25176С

IR NMR spectrum: (DMSOαb) 2.13 (s, ZN); 4.01 (c, 2H), 5.40 (c, 2H); 7.05 (sh.s, 2H); 7.24 (s, 1H); 7.34 (c, 1H); 7.51 (d, 2H); 7.92 (c, 1H); 8.44 (s, 1H); 8.63 (d, 2H); 9.34 (c, 1H); 9.47 (sh.s, 1H)

MO-E5I: 389 (MN

Elemental analysis: C 61.4 H 5.3 M 12.8 was found

Sg2NhoMmaOz:1.8Н20:0.2НСЙ trebuet С 61.7 Н 5.6 M 13.195

The starting material was obtained as follows:

A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (10 g, 0.04 mol) (U. May. Spec. 1977, vol. 20, 146-149) and Gold's reagent (7.4 g, 0.05 mol) in dioxane (100 ml) was mixed and heated under reflux for 24 hours. Sodium acetate (3.02 g, 0.037 mol) and acetic acid (1.65 ml, 0.029 mol) were added to the reaction mixture and the mixture was heated for another 3 hours. The mixture was evaporated, water was added to the residue, the solid was filtered off, washed with water and dried (M9504). Recrystallization from acetic acid! gave 7-benzyloxy-β6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 8495).

A mixture of 7-benzyloxy-b6-methoxy-3,4-dihydroquinazolin-4-one (2.82 g, 0.01 mol), thionyl chloride (40 ml) and

DMF (0.28 ml) was stirred and heated under reflux for 1 hour. The mixture was evaporated, the residue was dissolved in toluene and evaporated to dryness to obtain 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (3.45 g).

A mixture of 7-benzyloxy-4-chloro-b6-methoxyquinazoline hydrochloride (2.18g, 6.47mmol), 33-acetoxy-4-methylaniline (1.32g, dSmmol) and isopropanol (50ml) was stirred and heated under reflux for 71 time The mixture was cooled to ambient temperatures). The precipitate was filtered off, washed with isopropanol and zephyr, resulting in 4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazoline hydrochloride (2.69g, 8995).

A mixture of 4-(3-acetoxy-4-methylanilino)-7-benzyloxy-3-methoxyquinazoline hydrochloride (2.68g, 5.75mmol), 1095 palladium on activated carbon (0.27g) in methanol (50ml), DMF (12ml) and trichloromethane (5O0ml) was stirred at ambient temperature under hydrogen (1.5 atmospheres) for 30 minutes. The catalyst was filtered off and the filtrate was evaporated. The final solid was triturated in a sieve, filtered and dried under vacuum at 5070 s to obtain 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (2.1 g, 10090).

To a solution of 4-(3-acetoxy-4-methylanilino)-7-hydroxy-b6-methoxyquinazoline hydrochloride (375mg, 1mmol) in DMF (16bml) was added at ambient temperature! potassium carbonate (415mg, Zmmol) and 4-(bromomethyl)pyridine hydrobromide (U. Ogd. Spega. 1958, 23, 575, 27v8mg, 1.1mmol). The reaction mixture was heated at 60"C for 2 hours. The mixture was evaporated and the residue was distributed between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried (Mad5O4) and evaporated. The residue was purified by column flash chromatography, eluting with a mixture of methylene chloride-

methanol (95/5) to give 4-(3-acetoxy-4-methylanilino)-b-methoxy-7-(4-pyridylmethoxy)quinazoline (9Zmg, 2290).

T. pl. 201-2027S

IN NMR spectrum: (DMSOZdv) 2.12 (s, ZN); 2.34 (c, ZN); 4.02 (c, ZN); 5.40 (c, 2H); 7.27 (s, 1H); 7.30 (d, 1H); 7.51 (d, 2H); 7.62 (s, 1H); 7.65 (d, 1H); 7.91 (s, 1H); 8.47 (s, 1H); 8.63 (d, 2H); 9.53 (s, 1H)

MO-E5I: 453 |MMai", 431 |IMNI"

Elemental analysis: C 65.4 H 5.5 M 12.7 was found

SgaNggiMaOa4:0.6H2gO trebuete C 65.3 H 5.3 M 12.7905 3-Acetoxy-4-methylaniline, used as a starting material, was obtained as follows:

To a mixture of 2-methyl-5-nitrophenol (2.5 g, 16.3 mmol) and 1M aqueous sodium hydroxide solution (24.5 ml) was added at ambient temperature acetic anhydride (1.9 ml, 20.3 mmol). The mixture was stirred for 40 minutes, the solid was filtered off, and the filtrate was extracted with ethyl acetate.

The organic layer was combined, washed with a saturated aqueous solution of sodium chloride, dried (M9505) and evaporated to obtain 2-acetoxy-4-nitrotoluene (3.1 g, 10095). A mixture of this material (3.1g, 15.9mmol) and 1095 palladium on activated carbon (0.12g) in ethyl acetate (5X0ml) was stirred at ambient temperature under a hydrogen atmosphere for 2 hours. The catalyst was filtered off and the filtrate was evaporated to obtain 3-acetoxy-4-methylaniline (2.45 g, 94960).

Example 2

Using a procedure similar to that described for the starting material in Example 1, 4-(3-acetoxy-4-methylanilino)-7-hydroxy-b6-methoxyquinazoline hydrochloride (750 mg) was reacted with 3-(bromomethyl)pyridine hydrobromide (Sap. U Spet. 1978, 56, 3068) (378 mg) to obtain 4-(3-acetoxy-4-methylanilino)-b-methoxy-7-(3-pyridylmethoxy)quinazoline (293 mg, 3490).

T. pl. 113-11576

IR NMR spectrum: (DMSOα) 2.09 (s, ZN); 2.30 (c, ZN); 3.94 (c, ZN); 5.32 (c, 2H); 7.27 (d, 1H); 7.32 (s, 1H); 7.43-7.A6 (m, 1H); 7.58 (s, 1H); 7.59-7.63 (m, 1H); 7.85 (c, 1H); 7.89-7.92 (m, 1H); 8.45 (c, 1H); 8.57 (dd, 1H); 8.71 (d, 1H); 9.48 (s, 1H)

MO-E5I: 453 |MMai", 431 |IMNI

Elemental analysis: found C 64.4 H 5.7 M 11.7

SgaNggMaOa4:0.85H2O requires C 64.7 H 5.4 M 12.69

Example C

The compound synthesized in Example 2 was additionally subjected to basic cleavage of the acetoxy-protecting group using a procedure similar to that described in Example 1, and as a result 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-( Z-pyridylmethoxy)quinazoline (215mg, 8395).

T. pl. 258-25970

IN NMR spectrum: (OMSOdv) 2.12 (s, ZN); 3.94 (c, ZN); 5.34 (c, 2H); 7.05 (c, 2H); 7.32 (s, 1H); 7.35 (c, 1H); 7.46-7.49 (m, 1H); 7.88 (s, 1H); 7.93-7.95 (m, 1H); 8.43 (s, 1H); 8.60 (dd, 1H); 8.74 (d, 1H); 9.33 (c, 1H); 9.35 (s, 1n)

MO-E5I: 411 |MMai!", 389 MN"

Elemental analysis: found C 59.2 H 5.5 M 12.6

Cg2NhoMmaOz: ZNgO-0.07 NSI trebuett C 59.4 H 5.9 M 12.695

Example 4 4-(3-Acetoxy-4-methylanilino)-6-methoxy-7-(2-pyridylmethoxy)quinazoline (17Omg, 0.339mmol) was subjected to primary cleavage of the acetoxy-protecting group using a procedure similar to that described in example 1, resulting in 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-pyridylmethoxy)quinazoline hydrochloride (58 mg, 3890).

T. pl. 236-2387S

IN NMR spectrum: (DMSOZdb) 2.30 (s, ZN); 3.97 (c, ZN); 5.34 (c, 2H); 7.02 (s, 2H); 7.23 (s, 1H); 7.33 (c, 1H); 7.36-7.39 (m, 1H); 7.56 (d, 1H); 7.84-7.88 (m, 1H); 7.87 (s, 1H); 8.39 (s, 1H); 8.91 (d, 1H); 9.32 (s, 2H)

MO-E5I: 389 (MN

Elemental analysis: C 55.8 H 5.5 M 11.8 was found

Cg2NhoMmaOz: ZNgO-0.75NSII trebuett C 56.2 H 5.7 M 11.995

The starting material was obtained as follows:

Using a procedure similar to that described for the starting material in Example 1, 4-(3-acetoxy-4-methylanilino)-7-hydroxy-β6-methoxyquinazoline hydrochloride (376 mg) was reacted with 2-(chloromethyl)pyridine hydrochloride (328 mg) to obtain 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(2-pyridylmethoxy)quinazoline (17Omg, 40965).

IN NMR spectrum: (DMSOZdv) 2.12 (s, ZN); 2.34 (c, ZN); 4.00 (c, ZN); 5.37 (c, 2H); 7.29 (s, 1H); 7.31 (c, 1H); 7.39-7.42 (m, 1H); 7.58-7.66 (m, ZN); 7.87-7.90 (m, 1H); 7.91 (c, 1H); 8.47 (s, 1H); 8.64 (d, 1H); 9.52 (s, 1H)

Example 5 4-(3-Acetoxy-4-methylanilino)-6-methoxy-7-(2-pyrimidin-4-ylmethoxy)quinazoline (496 mg, 1.15 mmol) was subjected to basic cleavage of the acetoxy-protecting group using a procedure similar to that , which is described in example 1, and as a result 4-(3-hydroxy-4-methylanilino)-3-methoxy-7-(pyrimidin-4-ylmethoxy)quinazoline (278 mg, 6290) was obtained.

T. pl. 290-2917S

IN NMR spectrum: (DMSOdv) 2.13 (s, ZN); 4.02 (c, ZN); 5.43 (c, 2H); 7.05 (c, 2H); 7.24 (s, 1H); 7.35 (c, 1H); 7.67 (d, 1H); 7.92 (c, 1H); 8.41 (c, 1H); 8.89 (d, 1H); 9.24 (c, 1H); 9.36 (c, 1H); 9.38 (s, 1H)

MO-E5I: 390 MN"

Elemental analysis: found С 58.8 Н 5.4 М16.3

SgiNi»M5Oz:2.2H20O requires C 58.8 H 5.5 M 16.390

The starting material was obtained as follows:

I used a procedure similar to that described for the starting material in example 1, 4-(3-

acetoxy-4-methylanilino)-7-hydroxy-b6-methoxyquinazoline hydrochloride (560 mg) was reacted in the presence of catalytic potassium iodide with 4-(chloromethyl)iupyrimidine (375 mg) to obtain 4-(3-acetoxy-4-methylanilino)-b- methoxy-7-(pyrimidin-4-ylmethoxy)quinazoline (496 mg, 74905).

IN NMR spectrum: (DMSOZdv) 2.13 (s, ZN); 2.35 (c, ZN); 4.03 (c, ZN); 5.44 (c, 2H); 7.27 (s, 1H); 7.31 (d, 1H); 7.62-7.68 (m, ZN); 7.93 (c, 1H); 8.47 (s, 1H); 8.89 (d, 1H); 9.24 (d, 1H); 9.54 (c, 1H) 4-(Chloromethyl)pyrimidine was synthesized as follows:

A mixture of 4-methylpyrimidine (2g, 21.2mmol), M-chlorosuccinimide (4.26g, 31.9mmol) and dibenzoyl peroxide (500mg) in carbon tetrachloride (100ml) was heated at 80°C for 2 hours.

After cooling, the mixture was filtered and the filtrate was evaporated. The final oil was purified by flash chromatography using methylene chloride as a solvent, and as a result, 4-(chloromethyl)pyrimidine was obtained as an orange oil (1 g, 3790).

Example 6

A solution of 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (400 mg, 1.06 mmol) (prepared as described for the starting material in Example 1), 2-chloromethyl-1-methylimidazole hydrochloride (354 mg , 2.12 mmol) and potassium carbonate (585 mg) in DMF (15 ml) were heated at 60°C for 15 hours. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Md5ZOa4) The residue was diluted with methanol (20 ml) and 2M sodium hydroxide solution (1 ml) was added.

After stirring for 1 hour, the reaction mixture was diluted with water (20 ml) and a 2M solution of hydrochloric acid was added! (Zml). The resulting solid was filtered, washed with water and dried under vacuum to obtain 4-(3-hydroxy-4-methylanilino)-b-methoxy-7-(1-methylimidazol-2-ylmethoxy)quinazoline hydrochloride (150 mg, 2990).

T. pl. 257-2607S

IR NMR spectrum: (DMSOαb) 2.17 (s, ZN); 3.95 (c, ZN); 4.03 (c, ZN); 5.68 (c, 2H); 7.02 (dd, 1H); 7.16 (c, 2H), 7.64 (c, 1H); 7.72 (s, 1H); 7.80 (c, 1H); 8.42 (s, 1H); 8.8 (c, 1H); 9.7 (c, 1H); 11.38 (s, 1H)

MO-E5I: 392 (MN

Elemental analysis: C 51.7 H5.5M 142 was found

SgiNai M503:1.65Н20-1.9НСЙII requires С 51.4 Н 5.4 М 14390

Example 7

A solution of 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (400 mg, 1.06 mmol) (prepared as described for the starting material in Example 1), 4-chloromethyl-2-methylthiazole hydrochloride (390 mg , 2.12 mmol), potassium carbonate (438 mg) and potassium iodide (40 mg) in DMF (15 ml) were heated at 60°C for 15 hours. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed brine, dried (Mud5O»4) and evaporated. The residue was diluted with methanol (10ml) and a 2M sodium hydroxide solution (2ml) was added. After stirring for 1 hour, the reaction mixture was diluted with water (20ml) and a 2M solution of hydrochloric acid (3ml ).The resulting solid was filtered off, washed with water and dried under vacuum to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-methylthiazol-4-ylmethoxy)quinazoline hydrochloride (30mg, 5995).

T. pl. 243-24576S

IR NMR spectrum: (DMSOαb) 2.17 (s, ZN); 2.7 (c, ZN); 4.0 (c, ZN); 5.35 (c, 2H); 7.0 (dd, 1H); 7.12 (d, 1H); 7.16 (d, 1H); 7.58 (s, 1H); 7.75 (c, 1H); 8.3 (c, 1H); 8.8 (c, 1H); 9.5-9.8 (sh.s, 1H); 11 3(s, 1H)

MO-E5I: 409 (МН

Elemental analysis: found C 519 35.0M 11.6 5 6.8

SgiNgoMaOz5:1NgO-1.7 NOI requires C 51.6 N 4.9 M 11.5 5 6.690

Example 8

A 2M aqueous solution was added to a solution of 4-(3-acetoxy-4-methylanilino)-b-methoxy-7-(3-thienylmethoxy)quinazoline (200 mg, 0.45 mmol) in a mixture of methylene chloride-methanol (1/1) (20 ml) sodium hydroxide (0.67 ml, 1.35 mmol). The mixture was stirred for 35 minutes at ambient temperature, the solvent was layered, water was added to the residue, and the solution was extracted with ethyl acetate.

The organic layer was washed with water, brine, then dried (Mo95O4) and evaporated to obtain a white solid. Then the solid was dissolved in a saturated solution of hydrochloric acid in methanol (10 ml) and stirred for 10 minutes. The solid product was filtered off and dried under vacuum, resulting in 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline hydrochloride (127 mg, 66905).

T. pl. 246-248"7C

IR NMR spectrum: (DMSOαb) 2.15 (s, ZN); 3.98 (c, ZN); 5.32 (c, 2H); 6.98 (dd, 1H); 7.10 (c, 1H); 7.14 (d, 1H); 7.25 (d, 1H); 7.40 (c, 1H); 7.61 (dd, 1H); 7.70 (d, 1H); 8.12 (c, 1H); 8.74 (s, 1H); 9.60 (c, 1H)

MO-E5I: 394 (МН

Elemental analysis: found С 58.3Н48М9.457.3 С 17.5

SaiNioMzOz5:0.2H20.:0.95NSII requires C 58.4 NAM 7.4 57.4 C17.895

The starting material was obtained as follows:

Using a procedure similar to that described for the starting material in Example 1, 4-(3-acetoxy-4-methylanilino)-7-hydroxy-β6-methoxyquinazoline hydrochloride (400 mg) was reacted in the presence of catalytic potassium iodide with 3-chloromethylthiophene (doigpa 1958, 4202) (168 mg) to give 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline (210 mg, 4690).

T. pl. 201-2037S

IR NMR spectrum: (DMSOαb) 2.11 (s, ZN); 2.32 (c, ZN); 3.95 (c, ZN); 5.27 (c, 2H); 7.23 (dd, 1H); 7.28 (d, 1H); 7.32 (s, 1H); 7.58-7.66 (m, 4H); 7.85 (c, 1H); 8.46 (s, 1H); 9.49 (s, 1H)

MO-E5I: 436 (МН

Elemental analysis: found С630Н52М91 5 7.3

SgziNgiMzO45:0.3H2O requires C 62.7 H5.O M 9.5 5 7.396

Example 9 7-(2-Acetamidothiazol-4-ylmethoxy)-4-(3-acetoxy-4-methylanilino)-b-methoxyquinazoline (220mg, 0.44mmol) was subjected to basic cleavage of the acetoxy-protecting group using a procedure similar to that as described in example 8, and as a result 7-(2-acetamidothiazol-4-ylmethoxy)-4-(3-hydroxy-4-methylanilino)-6b-methoxyquinazoline hydrochloride (41 mg, 1995) was obtained.

T. pl. 202-204"7C

IR NMR spectrum: (DMSOαb) 2.16 (s, ZN); 2.17 (c, ZN); 4.01 (c, ZN); 5.31 (c, 2H); 6.98 (dd, 1H); 7.10 (d, 1H); 7.17 (d, 1H); 7.34 (c, 1H); 7.47 (s, 1H); 8.22 (c, 1H); 8.80 (s, 1H); 9.68 (sh.s, 1H)

MO-E5I: 452 (МН

Elemental analysis: found C 47.1 H 4.7 M 12.55 5.8 SI 12.2

Сг2Най М5045:2Н20:2НСЙИ requires С47,2Н4,9 М 12,5 5 5,7 SI 12,796

The starting material was obtained as follows:

Using a procedure similar to that described for the starting material in Example 1, 4-(3-acetoxy-4-methylanilino)-7-hydroxy-β6-methoxyquinazoline hydrochloride (400 mg) was reacted in the presence of catalytic potassium iodide with 2-acetamido-4 -chloromethylthiazol (252mg) to give 7-(2-acetamidothiazol-4-ylmethoxy)-4-(3-acetoxy-4-methylanilino)-6-methoxyquinazoline (220mg, 4295).

IN NMR spectrum: (DMSOZav) 2.13 (s, ZN); 2.15 (c, ZN); 2.35 (c, ZN); 3.97 (c, ZN); 5.24 (c, 2H); 7.24-7.31 (m, 2H); 7.37 (c, 1H); 7.63-7.66 (m, 2H); 7.87 (s, 1H); 8.48 (s, 1H); 9.50 (c, 1H)

MO-E5I: 494 (МН

Example 10 4-(3-Acetoxy-4-methylanilino)-7-(3,5-dimethylisoxazol-4-ylmethoxy)-b-methoxyquinazoline (342mg, 00.7bmmol) was subjected to basic cleavage of the acetoxy-protecting group using a procedure similar to the one described in example 8, and as a result 4-(3-hydroxy-4-methylanilino)-7-(3,5-dimethylisoxazol-4-ylmethoxy)-6-methoxyquinazoline hydrochloride (209mg, 62965) was obtained.

T. pl. 252-2547S

IR NMR spectrum: (DMSOαb) 2.20 (s, ZN); 2.29 (c, ZN); 2.52 (s, ZN); 4.03 (c, ZN); 5.23 (c, 2H); 7.03 (dd, 1H); 7.15 (d, 1H); 7.19 (d, 1H); 7.44 (s, 1H); 8.22 (with 1H); 8.82 (s, 1H); 9.67 (s, 1H)

MO-E5I: 407 (МН

Elemental analysis: found C 59.1 H 5.4 M 12.6 СІ18.0

Сг2НггМаОа4:0.25Н20-1НСЙИ trebuet С 59.1 Н 5.3 M 12.5 SI 7.990

The starting material was obtained as follows:

Using a procedure similar to that described for the starting material in Example 1, 4-(3-acetoxy-4-methylanilino)-7-hydroxy-β6-methoxyquinazoline hydrochloride (400 mg) was reacted in the presence of potassium iodide (1 mg) with 4-chloromethyl -3,5-dimethylisoxazole (177 mg) to give 4-(3-acetoxy-4-methylanilino)-7-(3,5-dimethylisoxazol-4-ylmethoxy)-b6-methoxyquinazoline (342 mg, 7295).

IR NMR spectrum: (DMSOαb) 2.18 (s, ZN); 2.33 (c, ZN); 2.35 (c, ZN); 2.46 (c, ZN); 3.98 (c, ZN); 4.98 (c, 2H); 7.00 (c, 1H); 7.15 (c, 1H); 7.22-7.25 (m, 1H); 7.32 (s, 1H); 7.43 (dd, 1H); 7.51 (c, 1H); 8.66 (s, 1H)

Example 11

A solution of 4-(3-acetoxy-4-methylanilino)-7-hydroxy-3-methoxyquinazoline hydrochloride (400 mg, 1.0 mmol) (prepared as described for the starting material in Example 1), 4-(3-chloropropyl)pyridyl hydrochloride ( 410 mg, 2.1 mmol), potassium carbonate (438 mg) and potassium iodide (40 mg) in

DMF (15ml) was heated at 60°C for 15 hours. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (M95O4) and evaporated. The residue was diluted with methanol (20ml) and a 2M solution was added sodium hydroxide (2 ml). After stirring for 1 hour, the reaction mixture was diluted with water (20 ml) and concentrated hydrochloric acid (1 ml) was added. The resulting solid was filtered off and purified by preparative HPLC C18 using a methanol-water gradient (0950-8095) as a solvent. After evaporation of methanol, concentrated hydrochloric acid (0.33 ml) was added and the solution was evaporated to dryness. After trituration with acetone, the solid was filtered off and dried under vacuum to obtain 4-(3-hydroxy-4-methylanilino)-b-methoxy -7-(4-pyridylpropoxy)quinazoline hydrochloride (305mg, 5990).

T. pl. 278-2827S

IR NMR spectrum: (DMSOαb) 2.15 (s, ZN); 2.3 (m, 2H); 3.1 (m, 2H); 3.96 (c, ZN); 4.24 (t, 2H); 6.98 (dd, 1H); 7.15 (m, 2H); 7.44 (s, 1H); 7.96 (d, 2H); 8.31 (c, 1H); 8.77 (c, 1H); 8.81 (d, 2H); 9.7 (sh.s, 1H); 11.34 (s, 1H)

MO-E5I: 417 (MNE

Elemental analysis: found C 57.3 5.4 M 11.0

SgaNgaMaOz:0.7 NgO-1.95NSII requires C 57.6 N 5.5 M 11.290

The starting material was obtained as follows:

Thionyl chloride (1.6 mL) was added to a solution of 4-pyridinepropanol (2 g, 14.5 mmol) in trichloromethane (20 mL) cooled at 0°C. After stirring for 1 hour at ambient temperature, and then for 1 hour at 60 "C, the solvent was evaporated and the residue triturated with zephyr, resulting in 4-(3-chloropropyl)pyridyl hydrochloride as a white solid.

IR NMR spectrum: (DMSOαb) 2.15 (m, 2H); 3.02 (t, 2H); 3.69 (t, 2H); 7.96 (d, 2H); 8.84 (d, 2H)

Example 12

A solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (410 mg, 1.00 mmol), 4-(3-chloropropyl)pyridyl hydrochloride (480 mg, 2.5 mmol), potassium carbonate (480mg) and potassium iodide (40mg) in DMF (15ml) were heated at 60°C for 15 hours. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Mad5O4) and evaporated . The residue was diluted with methanol (10ml) and 2M sodium hydroxide solution (2ml) was added. After stirring for 1 hour, the reaction mixture was diluted with water (20ml) and concentrated hydrochloric acid (0.5ml) was added. The resulting solid was filtered and purified by preparative HPLC C18 using a gradient of a methanol-water mixture (0905-8095) as a solvent.

After layering of methanol, concentrated hydrochloric acid (0.3 ml) was added and the solution was layered to dryness. After trituration with acetone, the solid was filtered off and dried under vacuum to obtain 4-(2-fluoro-5-hydroxy-4-methylanilino)-b-methoxy-7-(4-pyridylpropoxy)quinazoline hydrochloride (243Zmg, 4895).

T. pl. 246-248"7C

IN NMR spectrum: (DMSOZdb) 2.16 (s, ZN); 2.30 (m, 2H); 3.09 (t, 2H); 3.95 (c, ZN); 4.26 (1, 2H); 6.90 (d, 1H); 7.11 (d, 1H); 7.41 (c, 1H); 7.94 (d, 2H); 8.3 (c, 1H); 8.77 (c, 1H); 8.80 (d, 2H); 9.7 (sh.s, 1H); 11.46 (0.1H)

MO-E5I: 435 (МН

Elemental analysis: found C 55.3 5.3M10.2 C113.0

SgaNgziMaOZE: 0.9H20.-1.95NSII trebuett С 55.3 Н52 M 10.7 SI 13.395

The starting material was obtained as follows:

A solution of (4-fluoro-2-methyl-5-nitrophenyl)methylcarbonate (3g, 133mmol) (prepared as described in

EP 0307777 A2) in ethanol (bOml) containing platinum oxide! (IM) (300mg), stirred under hydrogen at 0.3 atmospheres! within 1 hour. After filtering and evaporating the solvent, 2-fluoro-

B5-methoxycarbonyloxy-4-methylaniline as a solid (2.6g, 100905).

H NMR spectrum: (SOCI3) 2.07 (s, ZN); 3.87 (c, ZN); 6.52 (d, 1H); 6.80 (d, 1H)

A solution of 7-benzyloxy-4-chloro-b-methoxyquinazoline hydrochloride (800 mg, 2.4 mmol) (prepared as described for the starting material in Example 1) and 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (57 mg, 2.89 mmol ) in isopropanol (20 ml) was heated under reflux for 2 hours. After cooling to ambient temperature, the solid was filtered off, washed with isopropanol and dried under vacuum to obtain 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (1.0 g, 87905).

IN NMR spectrum: (DMSOdv; SEZSOOOB) 2 2 (c, ZN); 3.85 (c, ZN); 4.0 (c, ZN); 5.37 (c, 2H); 7.3-7.55 (m, 8H); 8.13 (c, 1H); 8.86 (s, 1H)

MO-E51I: 4 64 |MNI"

A solution of 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (700mg, 1.45mmol) in DMF (10ml), methanol (10ml) and trichloromethane (TOml) containing 1095 palladium on activated carbon (100 mg), stirred under a hydrogen atmosphere for 1 hour. After filtering and evaporating the solvent, the precipitate was triturated with zephyr, filtered and dried under vacuum to obtain 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-β6-methoxyquinazoline hydrochloride (57mg, 9890).

IN NMR spectrum: (DMSOZav) 2.23 (s, ZN); 3.87 (c, ZN); 4.01 (c, ZN); 7.37 (c, 1H); 7.45 (d, 1H); 7.5 (d, 1H); 8.20 (c, 1H); 8.77 (c, 1H); 11.95 (c, 1H); 11.79 (s, 1H)

MO-E5I: 374 (МН

Example 13

A stirred solution of 4-chloro-b-methoxy-7-(4-pyridylmethoxy)quinazoline (35 mg, 0.1 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (15 mg, 0.1 mmol) in a mixture of ether solution of hydrogen chloride (2 ml) and isopropanol (5 ml) were heated under reflux for 4 hours. The precipitated product was collected by filtration, washed with acetone and dried under vacuum, resulting in 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)-quinazoline hydrochloride (23 mg, 4795).

T. pl. 257-2607S

IN NMR spectrum: (DMSOZdv) 2.15 (s, ZN); 4.08 (c, ZN); 5.60 (c, 2H); 6.90 (d, 1H); 7.07 (d, 1H); 7.47 (s, 1H); 7.93 (sh.d, 2H); 8.74 (0.1H); 8.89 (sh.d, 2H); 9.62 (sh.s, 1H); 11.46 (s, 1H)

MO-E5I: 407 (МН

Elemental analysis: found C 52,834.6 M 10.9

Sg2NioMaOzE-1NgO2NSII requires C 53.1 N 4.6 M 11395

The original chloroquinazoline was obtained as follows:

Sodium hydride (400 mg of 8095 suspension in paraffin oil, 13.3 mmol) was added to a solution of phenol (1.26 g, 13.3 mmol) in dry M-methylpyrrolidone (20 ml) and the mixture was stirred for 10 minutes.

Then 7-benzyloxy-4-chloro-b6-methoxyquinazoline hydrochloride (1.6 g, 4.7 mmol) was added (prepared as described for the starting material in Example 1) and the reaction mixture was heated at 110°C for 2 hours. The mixture was cooled, water was added to it and the mixture was extracted with ethyl acetate (3x100 ml).

Then unite and extract! washed with 2M sodium hydroxide solution, water and brine. Removal of the solvent under reduced pressure gave 7-benzyloxy-b-methoxy-4-phenoxyquinazoline (1.6 g, 9595) as a yellowish solid.

IN NMR spectrum: (DMSOZdb) 3.98 (s, ZN); 5.37 (c, 2H); 7.25-7.6 (m, 11); 7.60 (c, 1H); 8.54 (s, 1H)

MO-E5I: 359 (MH 7-Benzyloxy-b-methoxy-4-phenoxyquinazoline (16Omg, 0.44 mmol) was heated under reflux for 30 minutes. The solvent was removed by evaporation and the residue was treated with an aqueous solution of sodium bicarbonate. the product was collected by filtration, washed with water and dried to obtain 7-hydroxy-b-methoxy-4-phenoxyquinazoline (105 mg, 8895).

IN NMR spectrum: (DMSOdv) 4.00 (s, ZN); 7.20 (s, 1H); 7.25-7.35 (m, ZN); 7.4-7.55 (m, 2H); 7.58 (s, 1H); 10.73 (s, 1H)

MO-E5I: 269 (MN

A mixture of 7-hydroxy-6-methoxy-4-phenoxyquinazoline (95 mg, 0.35 mmol), 4-chloromethylpyridine hydrochloride (120 mg, 0.74 mmol) and potassium carbonate (200 mg, 1.4 mmol) in DMF (5 ml) was heated at 80°C for 2 hours. The reaction mixture was allowed to cool, water was added to it, and the mixture was extracted with ethyl acetate (3x5Oml). Then the combined extracts were washed with water and dried (M95054). The solvent was removed by evaporation, and the residue was triturated with a ethyl acetate-hexane mixture, resulting in 6b-methoxy-4-phenoxy-7-(4-pyridylmethoxy)quinazoline (44 mg, 3595) as a white solid.

IN NMR spectrum: (DMSOdv) 4.02 (s, ZN); 5.47 (c, 2H); 7.25-7.35 (m, ZN); 7.45 (c, 1H); 7.4-7.55 (m, AN); 7.62 (c, 1H); 8.52 (s, 1H); 8.63 (dd, 2H)

MO-E5I: 360 (MN

A solution of β-methoxy-4-phenoxy-7-(4-pyridylmethoxy)quinazoline (200 mg, 0.5 mmol) in 2 M hydrochloric acid (15 ml) was heated under reflux for 90 minutes. The reaction mixture was allowed to cool and neutralized to pH 6-7 with an aqueous ammonia solution. The precipitated product was extracted with a mixture of methanol-methylene chloride (1:9) and the extracted solution was dried (Mdzoz).

Removal of the solvent by evaporation gave b-methoxy-7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (9mg, 5795) as a gray solid.

IR NMR spectrum: (DMSOαb) 3.93 (s, ZN); 5.35 (c, 2H); 7.18 (c, 1H); 7.48 (s, 1H); 7.50 (m, 2H); 8.04 (s, 1H); 8.62 (m, 2H)

MO-E5I: 284 (МН

Phosphorus oxytrichloride ( 0.1 ml) and the mixture was heated under reflux for 1 hour. Volatile substances were removed by evaporation, and the residue was partitioned between methylene chloride and an aqueous ammonia solution. The organic extract was separated, dried (Mad5O.x) and the solvent was removed from it by evaporation. The residue was purified by chromatography on silica, eluting with ethyl acetate and passing through mixtures of increasing polarity to a mixture of methanol-methylene chloride (1/9), and as a result, 4-chloro-b-methoxy-7-(4-pyridylmethoxy)quinazoline (4Omg , 41960).

IN NMR spectrum: (DMSOdv) 4.04 (s, ZN); 5.47 (c, 2H); 7.46 (s, 1H); 7.50 (d, 2H); 7.53 (s, 1H); 8.60 (d, 2H); 8.85 (s, 1H)

MO-E5I: 302 MN"

The initial aniline was obtained as described below:

Methyl chloroformate (b, ml, 88 mmol) was added over 30 minutes to a solution of 4-fluoro-2-methylphenol (10 g, 79 μmol) in 695% aqueous sodium hydroxide solution at 0"C. The mixture was stirred for 2 hours and then extracted with ethyl acetate (100 ml) .

IN NMR spectrum: (DMSOdv) 2.14 (s, ZN); 3.81 (c, ZN); 7.05 (m, 1H); 7.1-7.25 (m, 2H)

A mixture of concentrated nitric acid was slowly added to a solution of 4-fluoro-2-methylphenylmethylcarbonate (11.34g, b2mmol) in concentrated sulfuric acid (bml)! (bml) and concentrated sulfuric acid! (bml) with temperature maintenance! of the reaction mixture below 5076.

The mixture was stirred for 2 hours, and then water and ice were added and the precipitated product was collected by filtration. The crude product was purified by chromatography on silica, eluting with a mixture of methylene chloride-hexane with a transition through mixtures of increasing polarity to a mixture of methanol-methylene chloride (1/19), and as a result, 4-fluoro-2-methyl-5-nitrophenol (2, 5g, 2290) in the form of a solid substance.

IN NMR spectrum: (OMSOiv; СозЗЗСОО0Б)) 2.31 (0, ZN); 7.38 (d, 1H); 7.58 (d, 1H)

MO-E5I: 171 (MNE

A mixture of 4-fluoro-2-methyl-5-nitrophenol (2.1 g, 13 mmol), iron powder (1 g, 13 mmol) and iron (II) sulfate (1.5 g, 10 mmol) in water (40 mL) was heated under reflux in for 4 hours. The reaction mixture was allowed to cool, neutralized with a 2M aqueous solution of sodium hydroxide and extracted with ethyl acetate (100 ml). The tetraacetate extract was dried (Md5O4) and the solvent was removed from it by evaporation, resulting in 2-fluoro-5-hydroxy-4-methylaniline (0.8g, 4795) as a solid.

IN NMR spectrum: (DMSOdv) 1.94 (s, ZN); 4.67 (c, 2H); 6.22 (d, 1H); 6.65 (d, 1H); 8.68 (s, 1H)

MO-E5I: 142 (MNE

Example 14

A solution of 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (259 mg, 0.54 mmol) (prepared as described for the starting material in Example 12) in methanol (15 mL), containing a 1M solution of sodium hydroxide (1.bml), was stirred at room temperature for 1 hour. After adding water (15 ml), concentrated hydrochloric acid (1 ml) was added and the mixture was stirred at ambient temperature for 15 minutes. After layering with methanol, the precipitate was filtered off, washed with water and dried under vacuum to obtain 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (192 mg, 8095).

T. pl. 294-2987S

IN NMR spectrum: (DMSOZdv) 2.2 (s, ZN); 4.05 (c, ZN); 5.35 (c, 2H); 6.9 (d, 1H); 7.12 (d, 1H); 7.35-7.5 (m, 4H); 7.55-7.6 (m, 2H); 8.25 (s, 1H); 8.8 (c, 1H); 9.7 (c, 1H); 11.35 (s, 1H)

MO-E5I: 406 (МН

Elemental analysis: C62.3H4.9M 9.3 was found

SgziNgoMzOzE:0.16Н20-1НСЙИ requires С 62.1 Н 4.8 M 9.595

Example 15

A mixture of //4-(4-chloro-2-fluoroanilino)-7-hydroxy-b-methoxyquinazoline (200 mg, 0.6 mmol), 2-(2-chlorozthoxy)pyridine hydrochloride (120 mg, 0.6 bimol) and potassium carbonate (260 mg , 1.9 mmol) in DMF (25 ml) was heated at 90"C for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The extract was dried (M950O4) and the solvent was removed by layering. The residue was purified by column chromatography eluting with ethyl acetate-methanol mixtures ( from 100/0 to 90/10) and as a result obtained 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-pyridyloxy)zthoxy)quinazoline (20 mg, 790) in the form of completely white solid.

IN NMR spectrum: (DMSOZdv) 3.99 (s, ZN); 4.35 (t, 2H); 4.42 (t, 2H); 6.22 (t, 1H); 6.40 (d, 1H); 7.42 (s, 1H); 7.55 (d, 2H); 7.71 (d, 1H); 7.85 (t, 1H); 8.55 (d, 1H); 9.62 (s, 1H)

MO-E5I: 441 (МН

The starting material was obtained as follows:

A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.34 g, 4 mmol) (prepared as described for the starting material in Example 1) and 4-chloro-2-fluoroaniline (444 μL, 4 mmol) in isopropanol (40 mL) heated under reflux for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with isopropanol and then with ether and dried under vacuum to obtain 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (1.13 g, 6490).

T. pl. 239-2427S

IN NMR spectrum: (DMSOZdv) 4.0 (s, ZN); 5.36 (c, 2H); 7.39-7.52 (m, 9H); 8.1 (c, 1H); 8.75 (s, 1H)

MO-E5I: 410 (MN

Elemental analysis: C 592H4.3M 9.4 was found

Sg2Ni?7MzSIBO" 1NSII requires С59.2Н4.1 M 9.4195

A solution of 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (892g, 2mmol) in

TEA (10 ml) was heated under reflux for 50 minutes. After cooling, the mixture was dried on ice. The precipitate was collected by filtration, dissolved in methanol (10 ml) and basified to pH 11 with hydrogen ammonia. After concentration by evaporation, the solid product was collected by filtration, washed with water and then with sulfur and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b-methoxyquinazoline as a yellow solid (460 mg, 7295) .

T. pl. 141-14376С

IR NMR spectrum: (DMSOαb) 3.95 (s, ZN); 7.05 (c, 1H); 7.35 (d, 1H); 7.54-7.59 (m, 2H); 7.78 (c, 1H); 8.29 (s, 1n)

MO-E5I: 320-322 |MNI

To a solution of 2-(2-hydroxyzthoxy)pyridine (700 mg, 5.04 mmol) (U. Ogd. Spet. 1977, 42, 1500) in trichloromethane (20 ml) at 5"C was added thionyl chloride (0.55 ml, 7.55 mmol) The mixture was stirred for 1 hour at 5"C, allowed to warm to ambient temperature and stirred for another 1 hour. Volatile substances were removed by evaporation and azeotropic distillation with toluene, and as a result 2-(2-chloroethoxy)pyridine hydrochloride (97Omg, 99905) was obtained.

IN NMR spectrum: (DMSOdv) 3.90 (t, 2H); 4.20 (t, 2H); 6.22 (d, 1H); 6.40 (d, 1H); 7.44 (dd, 1H); 7.64 (d, 1H)

MO-E5I: 158 (MN

Example 16

To a stirred solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b-methoxyquinazoline (2.23 g, 7 mmol) (obtained as described for the starting material in Example 15) in methylene chloride (bOml) was added under nitrogen triphenylphosphine (5.5g, 21mmol) and then 2-I(M-methyl-M-(4-pyridyl)|aminoethanol (1.49g, 9.bmmol) (prepared as described in EP 0359389 At). Then distyl azodicarboxylate (3.65 g, 21 mmol) was added dropwise and the mixture was stirred at ambient temperature for 2 h. ethyl acetate (200 mL) was added and the mixture was stirred for another 2 h. The solid product was collected by filtration, washed with ethyl acetate, dried under vacuum and finally was purified by column chromatography eluting with a mixture of methylene chloride-methanol (75/25, and then 60/40 and 50/50), which gave a white solid. The purified product was dissolved in a mixture of methylene chloride-methanol and the insoluble material was filtered off. To the filtrate was added a solution of of hydrogen chloride (10 ml of ZM solution) and removed by evaporation of volatile substances. The residue was triturated with zephyr and the solid product was collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-N-methyl-M-(4-pyridyl)|aminozoxy) ) of quinazoline hydrochloride (2.75 g, 7595) as a white solid.

T. pl. 222-22776

IN NMR spectrum: (DMSOde; SEZSOOOB) 3.29 (s, ZN); 3.95 (c, ZN); 4.16 (t, 2H); 4.48 (t, 2H); 7.05 (sh.s, 1H); 7.37 (c, 2H); 7.42 (d, 1H); 7.58 (t, 1H); 7.65 (dd, 1H); 8.18 (c, 1H); 8.28 (sh.s, 2H); 8.86 (s, 1H)

MO-E5I: 454 (МН

Elemental analysis: found C 51.2 H 4.8 M 12.9

SgziNgi M5O»SIE:0.9H2O.2NSIII trebuett C 50.9 H 4.6 M 12.9965

Example 17

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b6-methoxyquinazoline (30 mg, 0.94 mmol) (prepared as described for the starting material in Example 15), 4-(2-chloroethoxy)pyridine hydrochloride ( 155mgH, 0.79mmol) and potassium carbonate (260mg, 1.9mmol) in MMP (20ml) were heated at 90"C for 2 hours, allowed to cool to ambient temperature and stirred for another 18 hours. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (Md5O»4) and the solvent was removed from it by evaporation. The residue was purified by column chromatography eluting with methyl chloride-methanol mixtures (from 100/0 to 95/5) and as a result 4-(4-chloro- 2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyloxy)zthoxy)quinazoline (20mg, 795).

T. pl. 200-2027S

IN NMR spectrum: (DMSOdye) 3.90 (s, ZN); 4.50 (c, 4H); 7.04 (d, 2H); 7.26 (s, 1H); 7.33 (dd, 1H); 7.5-7.6 (m, 2H); 7.80 (c, 1H); 8.35 (s, 1H); 8.39 (d, 2H); 9.52 (s, 1H)

MO-E5I: 441 (MNE

The starting material was obtained as follows:

Thionyl chloride (0.75 ml, 10 mmol) was added to a solution of 4-(2-hydroxyzthoxy)pyridine (0.9g, b.5mmol) (U.Spet. 5os. RegKkip II, 1987, 1867) in trichloromethane (20ml) at 5"C ). Volatile substances were removed by evaporation and azeotropic distillation with toluene, resulting in 4-(2-chloroethoxy)pyridine hydrochloride (1.3 g, 10095).

IR NMR spectrum: (DMSOαb) 4.03 (t, 2H); 4.62 (t, 2H); 7.58 (d, 2H); 8.77 (d, 2H)

MO-E5I: 158 (MN

Example 18

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b6-methoxyquinazoline (30 mg, 0.94 mmol) (prepared as described for the starting material in Example 15), 1-(2-chlorozyl)-1 ,2-dihydro-2-pyridone (175 mg, 11 mmol) (U. At. Spet. os. 1951, 73, 3635) and potassium carbonate (260 mg, 1.9 mmol) in DMF (3 mL) were heated at 80"C for 3 hours, allowed to cool to ambient temperature and stirred for another 18 hours. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (Md50O") and the solvent was removed from it by evaporation. The residue was purified by column chromatography eluting with methyl chloride-methanol mixtures -trisethylamine (from 100/0/0 to 70/30/0.5) and as a result obtained 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-oxo-1, 2-dihydro-1-pyridyl)zthoxy|quinazoline (5Omg, 1290).

T. pl. 209-21176С

IN NMR spectrum: (DMSOdve) 3.94 (s, ZN); 4.35 (t, 2H); 4.41 (t, 2H); 6.22 (dd, 1H); 6.40 (d, 1H); 7.14 (c, 1H); 7.35 (dd, 1H); 7.42 (ddd, 1H); 7.5-7.6 (m, 2H); 7.70 (d, 1H); 7.80 (c, 1H); 8.35 (s, 1H); 9.53 (s, 1H)

MO-E5I: 441 (МН

Example 19

To a stirred solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b-methoxyquinazoline (300 mg, 0.94 mmol) (obtained as described for the starting material in Example 15) and tributylphosphine (0.69 ml, 2 .8 mmol) in methylene chloride (20 ml) under nitrogen at 5"C was added 1-(3-hydroxypropyl)-1,4-dihydro-4-pyridone (220 mg, 1.44 mmol) in methylene chloride (4 ml), and then 1.1 -(azodicarbonyl)dipiperidine (720 mg, 2.8 mmol). The mixture was stirred at 5"C for 3 hours, allowed to warm to ambient temperature, and stirred for another 18 hours. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic phase was separated, dried (Md5O4) and the solvent was removed from it by layering. The residue was purified by column chromatography eluting with mixtures of methyl chloride-methanol-trisethylamine (from 100/0/0 to 70/30/0.5) and as a result 4-(4-chloro-2-fluoroanilino)-b-methoxy-7 -I3-(4-oxo-1,4-dihydro-1-pyridyl)propoxyquinazoline (48mg, 1195).

T. pl. 5225076

IN NMR spectrum: (DMSOZv 3.56 (m, 2H); 4.00 (s, ЗН); 3.54 (t, 2H); 4.38 (t, 2H); 7.42 (d, 1H ); 7.5-7.65 (m, 5H); 8.43 (s, 1H); 8.65-8.75 (m, 4H)

MO-E5I: 455 (МН

The starting material was obtained as follows:

Sodium hydride (946 mg of 50905 suspension in mineral oil, 19.7 mmol) was added to a solution of 4-hydroxypyridine (1.88 g, 19.7 mmol) in DMF (50 ml) and the mixture was stirred for 30 minutes. 2-(3-bromopropoxy)tetrahydropyran (4.0 g, 17.9 mmol) was added (9. Spect. bos. 1963, 3440) and the mixture was heated at 100"C for 3 hours. The reaction mixture was allowed to cool, diluted with water and extracted ethyl acetate.

The extract was washed with water, dried (Md5O54) and the solvent was removed from it by evaporation. The residue was purified by column chromatography eluting with methyl chloride-methanol mixtures (from 100/0 to 95/5) and as a result 1-|3-(tetrahydropyran-2-yloxy)propyl|)|-1,4-dihydro-4- pyridone (1.5 g, 35905).

IR NMR spectrum: (DMSOdb) 1.35-1.75 (m, 6H); 1.95 (t, 2H); 3.35-3.5 (m, 2H); 3.65-3.8 (m, 2H); 4.12 (t, 2H); 4.57 (s, 1H); 6.95 (c, 2H); 7.94 (s, 2H)

A solution of 1-3-(tetrahydropyran-2-yloxy)propyl|-1,4-dihydro-4-pyridone (0.75 g, 3.1 mmol) in acetic acid (d3 ml), THF (4 ml) and water (4 ml) was heated at 50"C for 4 hours. Volatile substances were removed by evaporation to give 1-(3-hydroxypropyl)-1,4-dihydro-4-pyridone (480 mg, 9995) as an off-white solid.

IR NMR spectrum: (DMSOdv) 1.9-1.95 (m, 2H); 1.97-2.05 (m, 2H); 4.0-4.1 (m, 2H); 6.91 (m, 2H); 8.36 (m, 2H)

MO-E5I: 154 (МН

Example 20

To a stirred solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b-methoxyquinazoline (230 mg, 0.7 mmol) (obtained as described for the starting material in Example 15) and tributylphosphine (0.53 ml, 2 ,1 mmol) in methylene chloride (20 ml) under nitrogen at 5"C was added 1-(2-hydroxyethyl)-1,4-dihydro-4-pyridone (221 mg, 1.6 mmol). 1,1- (azodicarbonyl)dipiperidine (552 mg, 2.2 mmol) and the mixture was stirred at 5"C for 2 hours, allowed to warm to ambient temperature and stirred for another 18 hours. The mixture was diluted with zephyr, the insoluble material was filtered off, and the solvent was evaporated from the filtrate. The residue was distributed between ethyl acetate and water, the organic phase was separated and dried (Md5ZO4) and the solvent was evaporated. The residue was dissolved in acetone and an aqueous solution of hydrogen chloride (1.2 ml of 3M solution) was added. The mixture was allowed to stand for 15 minutes, and the precipitated product was collected by filtration, washed with zephyr and dried, resulting in 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-oxo- 1,4-dihydro-1-pyridyl)ethoxy|quinazoline hydrochloride (54mg, 1695).

IR NMR spectrum: (DMSOαb) 3.98 (s, ZN); 4.63 (dd, 2H); 4.83 (dd, 2H); 7.42 (d, 1H); 7.50 (c, 1H); 7.56 (d, 1H); 7.6-7.65 (m, ZN); 8.39 (s, 1H); 8.77 (c, 1H); 8.80 (c, 2H)

MO-E5I: 441 (MNI"

The starting material was obtained as follows: To a solution of 4-hydroxypyridine (2.5 g, 2.6 mmol) in

Sodium hydride (1.27 g of 50956 suspension in mineral oil, 26.4 mmol) was added to DMF (50 ml) and the mixture was stirred for 30 minutes. 2-(2-bromooxy)tetrahydropyran (5.0 g, 23.9 mmol) (U. At. Spet. os. 1948, 70, 4187) was added to DMF (5 ml) and the mixture was heated at 80°C for 3 hours. The reaction mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (M950O4) and the solvent was removed from it by layering. The residue was purified by column chromatography eluting with methyl chloride-methanol mixtures (from 100/0 to 97/3) and in as a result, 1-(2-(tetrahydropyran-2-yloxy)ethyl|-1,4-dihydro-4-pyridone (1.5 g, 28905) was obtained.

IR NMR spectrum: (DMSOαb) 1.39-1.68 (m, 6Н); 3.39-3.44 (m, 1H); 3.64-3.78 (m, 2H); 3.86-3.92 (m, 1H); 4.20 (t, 2H); 4.64 (c, 1H); 6.95 (d, 2H); 8.36 (d, 2H)

MO-E5I: 224 (МН

A solution of 1-(2-(tetrahydropyran-2-yloxy)zyl|-1,4-dihydro-4-pyridone (500 mg, 2.23 mmol) in acetic acid (4 mL), THF (2 mL), and water (mL) was heated at 45"C for 4 hours. Volatile substances were removed by evaporation to give 1-(2-hydroxyethyl)-1,4-dihydro-4-pyridone (221 mg, 7190) as an off-white solid.

IR NMR spectrum: (DMSOαb) 3.70 (t, 2H); 4.06 (t, 2H); 6.95 (d, 2H); 8.37 (d, 2H)

Example 21

A solution of 7-benzyloxy-4-chloro-b-methoxyquinazoline hydrochloride (132 mg, 0.4 mmol) (obtained as described for the starting material in Example 1) and 2-fluoro-5-methoxycarbonyloxy-4-methylphenol (96 mg, 0.48 mmol ) in pyridine (2 ml) was heated under reflux for 3 hours. The mixture was filtered, the solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (Mo5O.4) and the solvent was evaporated from it.

The residue was purified by column chromatography eluting with a mixture of methylene chloride and sulfur (70/30).

The resulting solid was crystallized from methylene chloride and methanol to obtain 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6-methoxyquinazoline (120 mg 64965).

IN NMR spectrum: (DMSOZav) 2.15 (s, ZN); 3.98 (c, ZN); 5.35 (c, 2H); 6.75 (d, 1H); 7.13 (d, 1H); 7.37 (d, 1H); 7.45 (t, 2H); 7.48-7.56 (m, ZN); 7.58 (s, 1H); 8.54 (s, 1H); 9.65 (sh.s, 1H)

MO-E5I: 454 (МН

Elemental analysis: C67.8H4.9 M 6.9 was found

SgzNioM2gOl 0.1H2O trebuett C 67.7 H 4.7 M 6.990

The starting material was obtained as follows:

A mixture of (4-fluoro-2-methyl-5-nitrophenyl)methylcarbonate (8g, Zb5mmol) (ER 0307777 A?) and platinum oxide (IM) (174mg) in ethanol (100ml) and ethyl acetate (7/Oml) was stirred under hydrogen at a pressure of 1.3 atmospheres! within 1.5 hours. The catalyst was removed by filtration through diatomaceous earth and the solvent was evaporated. The residue was purified by column chromatography eluting with a mixture of petroleum sulfur-ethyl acetate (7/3) and as a result 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (6.56 g, 94905) was obtained in the form of an oil that crystallized.

IN NMR spectrum: (SOSIz) 2.09 (s, ZN); 3.66 (sh.s, 2H); 3.90 (c, ZN); 6.54 (d, 1H); 6.83 (d, 1H)

A solution of sodium nitrite (1.63g, 23mmol) in water (19ml) with ice (48g) was added dropwise to a solution of 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (3.93g, 20mmol) in 3595 sulfuric acid (4vml) at 0"C. The reaction mixture was stirred at 0"C for 30 minutes and a solution of copper nitrate trihydrate (467g, 1.93mol) in water (/80ml) was added to it, and then copper oxide (2.65g, 18 mmol).

The solution was extracted with ethyl acetate, the organic layer was washed with brine and dried (Md5OH), after which the solvent was evaporated. The residue was purified by column chromatography eluting with a mixture of petroleum sulfur-ethyl acetate (8/2) and as a result 2-fluoro-5-methoxycarbonyloxy-4-methylphenol (2.13 g, 5395) was obtained as a yellow solid.

IN NMR spectrum: (SOSIz) 2.13 (s, ZN); 3.91 (c, ZN); 5.11 (sh.s, 1H); 6.78 (d, 1H); 6.93 (d, 1H)

Example 22

A mixture of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (470 mg, mmol), 4-chloromethyl-2-methylthiazole hydrochloride (3-8 mg, 2 mmol), potassium carbonate (414 mg, 3 mmol) and potassium iodide (40 mg) in DMF (15 ml) were heated at 60"C for 24 hours. The mixture was allowed to cool and partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried (MdzOa) and the solvent was evaporated from it. The residue was dissolved in methanol (15 ml) and added 1 M sodium hydroxide solution (2 ml), then the mixture was stirred for minutes. Concentrated hydrochloric acid (0.5 ml) was added. The solvent was evaporated.

The residue was purified by reversed-phase VLC with elution with a gradient of methanol (0-70905) in water.

Concentrated hydrochloric acid (0.3 ml) was added to the combined fractions of the pure product and the solvent was evaporated. The residue was triturated with acetone, filtered, washed with acetone and dried under vacuum at 557°C to obtain 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-((2-methylthiazol-4-yl )methoxy)quinazoline hydrochloride (225mg, 4895).

IR NMR spectrum: (DMSOαb) 2.17 (s, ZN); 2.69 (c, ZN); 4.00 (c, ZN); 4.7 (sh.s, 1H); 5.34 (c, 2H); 6.91 (d, 1H); 7.1 (d, 1nH); 7.60 (c, 1H); 7.74 (c, 1H); 8.33 (c, 1H); 8.79 (c, 1H); 11.5 (s, 1H)

MO-E5I: 427 |NOUNS

The starting material was obtained as follows: A mixture of (4-fluoro-2-methyl-5-nitrophenyl)methylcarbonate (Zg, 13 mmol) (ER 0307777 Ag) and platinum oxide! (IM) (30Omg) in ethanol (bOml) was stirred under hydrogen at a pressure of 0.3 atmospheres! within 1 hour. The catalyst was removed by filtration through diatomaceous earth and the solvent was added to obtain 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (2.6 g, 10095) as a solid.

IN NMR spectrum: (SOSIz) 2.07 (s, ZN); 3.87 (c, ZN); 6.52 (d, 1H); 6.80 (d, 1H)

A solution of 7-benzyloxy-4-chloro-b-methoxyquinazoline hydrochloride (800 mg, 2.4 mmol) (prepared as described for the starting material in Example 1) and 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (570 mg, 2.89 mmol ) in isopropanol (20 ml) was heated under reflux for 2 hours.

The mixture was allowed to cool to ambient temperature, the precipitated solid was filtered off, washed with isopropanol and dried under vacuum to obtain 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6b-methoxyquinazoline hydrochloride (1, 0g, 77905).

IN NMR spectrum: (DMSOae; SEZSOObB) 2.2 (s, ZN); 3.85 (c, ZN); 4.0 (c, ZN); 5.37 (c, 2H); 7.3-7.55 (m, 8H); 8.13 (c, 1H); 8.86 (0.1H)

MO-E5I: 464 (МН

A mixture of 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (700mg, 1.4mmol) and 1095 palladium on activated carbon (100mg) in DMF (10ml), methanol (100ml) and trichloromethane (100 ml) were stirred under hydrogen at a pressure of 1 atmosphere for 1 hour. The catalyst was filtered through diatomaceous earth and the solvent was evaporated. The residue was triturated with zephyr, collected by filtration and dried under vacuum to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (57mg, 9890).

IR NMR spectrum: (DMSOαb) 2.23 (s, ZN); 3.87 (c, ZN); 4.01 (c, ZN); 7.37 (c, 1H); 7.45 (d, 1H); 7.5 (d, 1H); 8.20

(c, 1H); 8.77 (c, 1H); 11.95 (c, 1H); 11.79 (s, 1H)

MO-E5I: 374 (МН

Example 23

A mixture of 4-chloro-7-(4-pyridylmethoxy)quinazoline hydrochloride (350 mg, thymol) and 2-fluoro-5-hydroxy-4-methylaniline (155 mg, 1.1 mmol) (prepared as described for the starting material in Example 13) in isopropanol (15 ml) was heated under reflux for 1 hour. The resulting precipitate was collected by filtration and purified by reverse-phase VLC using a gradient (0-7595) of methanol in water. Concentrated hydrochloric acid (0.5 ml) was added to the combined fractions of the pure product and the solvent was evaporated, resulting in 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(4-pyridylmethoxy)quinazoline hydrochloride (14mg, 2895) .

IR NMR spectrum: (DMSOαb) 2.16 (s, ZN); 5.69 (c, 2H); 6.19 (d, 1H); 7.1 (d, 1H); 7.48 (d, 1H); 7.66 (dd, 1H); 8.06 (d, 2H); 8.84 (s, 1H); 8.86 (d, 1H); 8.90 (d, 2H); 9.7 (sh.s, 1H); 11.71 (s, 1H)

MO-E5I: 377 (MN

Elemental analysis: found C 50.9 H 4.9 M 11.1

С21Ни7 МО» 2,4Н20.2НСЙII trebuett С. 51,2 Н 4,9 М 11,495

The starting material was obtained as follows:

Sodium hydride (0.72 g of 6090 suspension in mineral oil, 13 mmol) was added to a solution of 4-hydroxymethylpyridine (4 g, Zbmmol) in THF (30 mL), and the mixture was heated under reflux for 15 minutes. 7-fluoro-3,4-dihydroquinazolin-4-one (1 g, mmol) was added (U. Spet. 5os. Razdel B, 1967, 449), THF was evaporated, and the mixture was heated at 120"C for 30 minutes. The mixtures gave the rest was diluted with water (40 ml) and brought to pH 8 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and then with sulfur and dried under vacuum to obtain 7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (1.12g, 7190).

IR NMR spectrum: (DMSOdv) 5.35 (s, 2H); 7.15-7.22 (m, 2H); 75 (d, 2H); 8.05 (d, 1H); 8.07 (c, 1H); 8.6 (d, 2H)

A mixture of 7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (320mg, 1.2bmmol), DMF (1 drop) and thionyl chloride (10ml) was heated at 60°C for 1 hour. Volatile substances were evaporated and the residue was triturated with zephyr, collected by filtration, washed with zephyr and dried under vacuum, resulting in 4-chloro-7-(4-pyridylmethoxy)quinazoline hydrochloride (435mg, 9890).

IR NMR spectrum: (DMSOdv) 5.7 (s, 2H); 7.32 (s, 1H); 7.35 (d, 1H); 8.1-8.2 (m, ZN); 8.62 (s, 1H); 9.0 (d, 2H)

MO-E5I: 272 (MNE

Example 24

K suspensions of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (16mg, 0.5mmol), tributylphosphine (30mg, 1.5mmol) and 2-(imidazol-1-yl)ztanol (67mg) , 0.bmmol) (U. Med. Spet. 1993, 25, 4052-4060) in methylene chloride (38 ml) was added dropwise to a solution of 1,1-"(azodicarbonyl)dipiperidine (378 mg, 1.5 mmol) in methylene chloride (5 ml) and the mixture was stirred for an hour at ambient temperature. Acetic acid (bOmg, immole) was added and the solvent was evaporated. The solid residue was adsorbed on silica gel and purified by column chromatography eluting with a methylene chloride-methanol mixture (9/1, and then 8/2). The resulting white solid was dissolved in a mixture of methylene chloride-methanol and a solution of 5M hydrochloric acid was added! in isopropanol. The solvent was evaporated and the solid was triturated with sulfur, filtered, washed with sulfur and dried under vacuum, resulting in 4-(4-chloro-2-fluoroanilino)-7-(2-imidazol-1-yl)zthoxy)-6- methoxyquinazoline hydrochloride (180mg, 7490).

IN NMR spectrum: (DMSOdv) 4.01 (s, ZN); 4.62 (t, 2H); 4.76 (t, 2H); 7.44 (dd, 1H); 7.48 (s, 1H); 7.59 (t, 1H); 7.66 (dd, 1H); 7.72 (s, 1H); 7.84 (s, 1H); 8.41 (c, 1H); 8.78 (s, 1H); 9.22 (s, 1H)

MO-EZ5I: 414 NAMES"

Elemental analysis: found C 48.3 H 4.1 M 14.0

SgoNi?7M50»SIE:0.4NgO.2NSY trebuett C 48.6 H4.0 M 142965

The starting material was obtained as follows:

A solution of 7-benzyloxy-4-chloro-b-methoxyquinazoline hydrochloride (1.2 g, 3.5 mmol) (prepared as described for the starting material in Example 1) and 4-chloro-2-fluoroaniline (444 μl, 4 mmol) in isopropanol ( 40ml) was heated under reflux for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with isopropanol and then with ether and dried under vacuum to obtain 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (1.13 g, 71925).

T. pl. 239-2427S

IR NMR spectrum: (DMSOαb) 4.0 (s, ZN); 5.36 (c, 2H); 7.39-7.52 (m, 9H); 8.1 (c, 1H); 8.75 (s, 1H)

MO-E5I: 410 (MN

Elemental analysis: C 592H4.3M 9.4 was found

Sg2Ni7MzO»2SIE:- NSI requires S. 59.2 4.1 M 9.495

A solution of 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (892g, 2mmol) in

TEA (10 ml) was heated under reflux for 50 minutes. After cooling, the mixture was dried on ice. The precipitate was collected by filtration, dissolved in methanol (10 ml) and basified to pH 11 with hydrogen ammonia. After concentration by evaporation, the solid product was collected by filtration, washed with water and then with sulfur and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b-methoxyquinazoline (46mg, 7290) as a yellow solid .

T. pl. 141-14376С

IR NMR spectrum: (DMSOαb) 3.95 (s, ZN); 7.05 (c, 1H); 7.35 (d, 1H); 7.54-7.59 (m, 2H); 7.78 (c, 1H); 8.29 (s, 1n)

MO-E5I: 320 MN"

Example 25

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b6-methoxyquinazoline (448 mg, 1.4 mmol) (prepared as described for the starting material in Example 24) and potassium carbonate (676 mg, 4.9 mmol) in DMF (10 ml) was stirred at ambient temperature for 10 minutes. 4-Chloromethyl-2-methylthiazole hydrochloride (31O0mg, 1.6v8mmol) was added and the mixture was heated at 70°C for 3.5 hours. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was separated, washed with water and dried (Md5O54), after which the solvent was evaporated. The solid residue was purified by column chromatography eluting with a mixture of methylene chloride-acetonitrile-methanol (50/45/5, and then 50/40/10). The resulting pure solid was dissolved in a mixture of methylene chloride-methanol and a solution of 5 M hydrogen chloride in isopropanol (1 ml) was added. Partial evaporation resulted in the precipitation of a white solid. The solid was collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7 -(2-methylthiazol-4-yl)methoxy)quinazoline hydrochloride (240mg, 3595).

T. pl. 220-22576С

IN NMR spectrum: (DMSOdv) 2.68 (s, ZN); 4.0 (c, ZN); 5.36 (c, 2H); 7.46 (dd, 1H); 7.54 (s, 1H); 7.61 (t, 1H); 7.7 (d, 1H); 7.71 (c, 1H); 8.26 (c, 1H); 8.83 (s, 1H)

MO-E5I: 431 (MN

Elemental analysis: found C 49.33 4.0 M 11.3

SgoNivMaO» SI 5:0.3NgO-1.5NSII trebuett C 48.9 N 3.7 M 11.495

Example 26

Using a procedure similar to that described in Example 25, 4-(4-chloro-2-fluoroanilino)-7-hydroxy-β6-methoxyquinazoline (224 mg, 0.7 mmol) (prepared as described for the starting material in example 24) and 2-chloromethyl-1-methylimidazole hydrochloride (140 mg, 0.8 mmol) to obtain 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylimidazol-2-yl)methoxy)quinazoline hydrochloride (150 mg, 4490).

IN NMR spectrum: (DMSOdb) 3.94 (s, ZN); 4.02 (c, ZN); 5.69 (c, 2H); 7.44 (dd, 1H); 7.6 (t, 1H); 7.64 (s, 1H); 7.67 (dd, 1H); 7.72 (d, 1H); 7.81 (d, 1H); 8.46 (s, 1H); 8.81 (s, 1H)

MO-E5I: 414 MNE"

Elemental analysis: found C 48.7 H 4.6 M 13.6

СгоНи?7М5О2СИР:0.5Н202НСИИ 0.25 isopropanol requires С 48.8 Н 4.3 M 13.795

Example 27

A mixture of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (47Omg, mmol) (obtained as described for the starting material in Example 22), 2-chloromethyl-1-methylimidazole hydrochloride (335mg, 2mmol), potassium carbonate (414mg,

zmmol) and potassium iodide (20mg) in DMF (15ml) were heated at 60°C for 2 hours. The mixture was allowed to cool and partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (M9504) and evaporated from it solvent The crude product was dissolved in methanol (20ml), 2M sodium hydroxide solution (1ml) was added and the mixture was stirred for 15 minutes.

Concentrated hydrochloric acid (0.5 ml) was added and the solvent was evaporated.

The crude product was purified by reversed-phase chromatography eluting with a mixture of methanol and water (1/1). Concentrated hydrochloric acid (0.33 ml) was added to the combined fractions containing the pure product and the solvent was evaporated, resulting in 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-((1- methylimidazol-2-yl)methoxy)quinazoline hydrochloride (100 mg, 21965).

IR NMR spectrum: (DMSOαb) 2.17 (s, ZN); 3.95 (c, ZN); 4.01 (c, ZN); 5.70 (c, 2H); 6.92 (d, 1H); 7.12 (d, 1H); 7.63 (c, 1H); 7.77 (s, 1H); 7.83 (s, 1H); 8.43 (s, 1H); 8.82 (s, 1H); 9.7 (sh.s, 1H); 11.62 (sh.s, 1H)

MO-E5I: 410 |MNI"

Example 28

Using a procedure similar to that described in example 27, chemically combined 4-(2-fluoro-

β5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-β6-methoxyquinazoline hydrochloride (47mg, 1.14mmol) (prepared as described for the starting material in Example 22) and 2-acetamido-4-chloro-methylthiazole (381mg, 1 .68 mmol) to obtain 7-(2-acetamidothiazol-4-yl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline (135 mg, 2595).

IN NMR spectrum: (DMSOdv; SEZSOOO) 2.16 (s, ZN); 2.19 (c, ZN); 4.00 (c, ZN); 5.33 (c, 2H); 6.91 (d, 1H); 7.12 (d, 1H); 7.33 (c, 1H); 7.49 (s, 1H); 8.16 (c, 1H); 8.82 (s, 1H)

MO-E5I: 470 (MN

Elemental analysis: C 51.5 N 4.5 M 13.8 was found

Сг2НгоМ5О4Е5:0.4Н20.0.95НСЙII trebuett С 51.7 Н 4.3 М 13.795

Example 29

A suspension of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (169 mg, 0.5 mmol) (obtained as described for the starting material in Example 1) and 4-chloro-2-fluoro-5-hydroxyaniline (97 mg, 0.5 mmol ) (ER 061741 A?) in isopropanol (5 ml) was heated under reflux for 2 hours.

The resulting precipitate was collected by filtration, washed with isopropanol and ether, and dried under vacuum to obtain 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxyquinazoline hydrochloride (197 mg, 8590).

IN NMR spectrum: (DMSOZdv) 4.0 (s, ZN); 5.36 (c, 2H); 7.15 (d, 1H); 7.4-7.5 (m, 4H); 7.52 (c, 1H); 7.54 (d, 2H); 8.23 (s, 1H); 8.8 (c, 1H); 10.6 (c, 1H); 11.39 (sh.s, 1H)

MO-E5I: 426 (MN

Elemental analysis: C 57.134.2M 8.9 was found

C22Ni?7MzOzSIE:0.15Hn20-1HCI0.4 isopropanol requires C 56.8 H 4.0 M 9.095

Example 30

To a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (448 mg, 14 mmol) (obtained as described for the starting material in Example 24), tributylphosphine (84 mg, 4.2 mmol) and 4-(3-hydroxypropyl)pyridine (322 mg, 2.4 mmol) in methylene chloride (15 ml) was added dropwise to a solution of 1,1'-(azodicarbonyl)dipiperidine (1.06 g, 4.2 mmol) in methylene chloride (15 ml) and the mixture was stirred From time at ambient temperature". Acetic acid (126 mg, 2.1 mmol) was added and the solvent was evaporated. the stock was purified by column chromatography eluting with a mixture of methylene chloride-methanol (95/5). The purified product was triturated with zephyr, the resulting solid was collected and dissolved in methylene chloride (20 ml). A 5M solution (0.7 ml) of hydrogen chloride in isopropanol was added, the solution was diluted with isopropanol (5 ml) and concentrated by evaporation to a total volume of 4 ml. Zephyr was added and the resulting solid was filtered off, washed with zephyr and dried under vacuum, resulting in 4-(4-chloro-2-fluoroanilino)-6b-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline hydrochloride (520 mg, 7390).

IN NMR spectrum: (DMSOdv) 2.30 (m, 2H); 3.09 (t, 2H); 3.97 (c, ZN); 4.27 (t, 2H); 7.42 (s, 1H); 7.44 (d, 1H); 7.59 (t, 1H); 7.67 (dd, 1H); 7.95 (d, 2H); 8.34 (s, 1H); 8.8 (c, 1H); 8.82 (d, 2H)

MO-EZ5I: 439 MNI"

Elemental analysis: found C 53.6 H 4.8 M 10.7

SgziNgoma OSI:0.5Н202НС.0.1 isopropanol trebuet C 53.1 N 4.6 M 10695

Example 31

To a solution of 4-(4-chloro-2-fluoro-5-methoxycarbonyloxyanilino)-6b-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline (1.28g, 2.5mmol) in methanol (13ml) was added 2 M aqueous solution of sodium hydroxide (1.5 ml, Zmmol) and the mixture was stirred for 2 hours at ambient temperature.

Water was added and the mixture was adjusted to pH 7 with 2M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried under vacuum. The solid substance was dissolved in methylene chloride (Zb0ml) and methanol (5ml) and a solution of 5M hydrogen chloride in isopropanol (2.5ml) was added. The solution was diluted with isopropanol and concentrated under vacuum to a total volume of 10 ml.

The resulting solid was collected by filtration, washed with isopropanol and then with ether and dried under vacuum, resulting in 4-(4-chloro-2-fluoro-5-hydroxyanilino)-b-methoxy-7-(3-(4-pyridyl) propoxy)quinazoline hydrochloride (924mg, 7090).

IR NMR spectrum: (DMSOdv) 2.3 (t, 2H); 3.12 (t, 2H); 4.0 (c, ZN); 4.28 (t, 2H); 7.18 (d, 1H); 7.4 (c, 1H); 7.52 (d, 1H); 7.95 (d, 2H); 8.32 (s, 1H); 8.82 (s, 1H); 8.84 (d, 2H); 10.65 (c, 1H); 11.65 (sh.s, 1H)

MO-E5I: 455 (МН

Elemental analysis: found C 51.984.5 M 10.7

SgziNgomaOzSIE:0.55Н20-1.9НСЙИ requires С 51.5 Н 4.7 M 10.590

The starting material was prepared as follows: To a solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-b-methoxyquinazoline hydrochloride (1.38 g, 3.5 mmol) (obtained as described for the starting material in 22), tributylphosphine (2g, 10.5mmol) and 4-(3-hydroxypropyl)pyridine (720mg, 5.25mmol) in methylene chloride (25ml) was added dropwise to a solution of 1,1-("azodicarbonyl)dipiperidine (2.52g , 10 mmol) in methylene chloride (10 ml) and the mixture was stirred for 2.5 hours at ambient temperature. The solvent was evaporated and the residue was rubbed with petroleum jelly! m zfirom. The solid product was collected by filtration and purified by column chromatography eluting with a mixture of methylene chloride-methanol (95/5), resulting in 4-(4-chloro-2-fluoro-5-methoxycarbonyloxyanilino)-b-methoxy-7-(3- (4-pyridyl)propoxy)quinazoline (1.2g, 6795).

IN NMR spectrum: (DMSOZdv) 2.18 (m, 2H); 2.84 (t, 2H); 3.90 (c, ZN); 3.97 (c, ZN); 4.2 (t, 2H); 7.21 (c, 1H); 7.3 (d, 2H); 7.72-7.82 (m, ZN); 8.41 (c, 1H); 8.47 (d, 2H); 9.67 (s, 1H)

MO-E5I: 513 (МН

Example 32

To a solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(2-(imidazol-1-yl)zthoxy)-6-methoxyquinazoline (257mg, 5.5mmol) in methanol (5ml) was added 2M aqueous solution of sodium hydroxide (0.3ml, bmol) and the mixture was stirred for 1 hour at 40"C. Water and 1M hydrochloric acid (0.bml) were added, and the mixture was concentrated to half the volume by evaporation. The resulting solid was collected by filtration, dissolved in a mixture of methylene chloride-methanol and added a solution of 7 M hydrogen chloride in isolropanol (0.4 ml). The volatile substances were evaporated, the solid residue was triturated with sulfur, collected by filtration and dried under vacuum, resulting in 4-Methylanilino)-7-(2-imidazol-1-yl)zthoxy)-6-methoxyquinazoline hydrochloride (16Omg, 6090).

T. pl. 195-2207С "H NMR spectrum: (DMSOαb) 2.16 (s, ЗН); 4.0 (s, ЗН); 4.63 (t, 2Н); 4.76 (t, 2Н); 6, 90 (d, 1H); 7.1 (d, 1H); 7.44 (s, 1H); 7.72 (s, 1H); 7.83 (s, 1H); 8.31 (s, 1H ); 8.76 (s, 1H); 9.20 (s, 1H); 9.7 (s, 1H); 11.4 (sh.s, 1H)

MO-E5I: 410 (MN

Elemental analysis: found C 52.3 H 5.1 M 13.7

Сг21НгоМ5ОзЕ:0,3НгоО-1,9НС10,22 isopropanol trebuet С 52,3 Н 4,9 М 14195

The starting material was obtained as follows:

To a solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (261 mg, 0.7 mmol) (obtained as described for the starting material in Example 22), triphenylphosphine (367 mg, 1.4 mmol) and 2-(imidazol-1-yl)ztanol (94 mg, 0.84 mmol) (9. Mea.

Spent 1993, 25, 4052-4060) in methylene chloride (5 ml) was added distilazodicarboxylate (16 Ω, 1.4 mol) and the mixture was stirred for 1 hour at ambient temperature. Acetic acid (42 mg, 0.7 mmol) was added and the solvent was evaporated. The residue was triturated with zephyr, the solid was collected by filtration, dried under vacuum and purified by chromatography eluting with a mixture of methylene chloride-methanol (9/1 and then 8/2), resulting in 4-(2-fluoro-5-methoxycarbonyloxy- 4-methylanilino)-7-(2-(imidazol-1-yl)zthoxy-6-methoxyquinazoline (250mg, 7695).

Example 33

To a suspension of 4-(4-chloro-5-diphenyl-tert-butylsilyloxy-2-fluoroanilino)-7-(2-(imidazol-1-yl)zthoxy)-6-methoxyquinazoline (186 mg, 0.28 mmol) in THF (5 ml) was added with a 1M solution of tetrabutylammonium fluoride

THF (50 μl, 0.5 mmol) and the mixture was stirred at 40"C for 1 hour. Water was added and the organic solvent was evaporated. The resulting precipitate was filtered off, washed with water and dried by azeotropic distillation with ethanol. The solid was dissolved in a methylene chloride-methanol mixture and a solution of 5 M hydrogen chloride in isopropanol (0.5 ml) was added. The volatile substances were evaporated and the residue was dissolved in isopropanol (1 ml) and sulfur was added. The resulting precipitate was filtered, stirred with sulfur and dried under vacuum to obtain 4-(4-chloro-2-fluoro- 5-Hydroxyanilino)-7-(2-(imidazol-1-yl)zthoxy)-b-methoxyquinazoline hydrochloride (110mg, 78905).

IN NMR spectrum: (DMSOdv) 4.01 (s, ZN); 4.63 (t, 2H); 4.75 (t, 2H); 7.17 (d, 1H); 7.46 (s, 1H); 7.51 (d, 1H); 7.72 (s, 1H); 7.83 (s, 1H); 8.36 (c, 1H); 8.79 (c, 1H); 9.21 (c, 1H); 10.63 (sh.s, 1H); 11.6 (sh.s, 1H)

MO-E5I: 430 (MN

Elemental analysis: C 45.7 H 3.9 M 12.8 was found

СгоНи?М5ОзСИЕ-1Н20-2НСИ-0.09 isopropanol:0.09 methylene chloride requires С 45.8 Н41 М 13190

The starting material was prepared as follows: A mixture of 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxyquinazoline (2.35 g, 7 mmol) (obtained as described in Example 29), imidazole ( 1.2g, 17.5mmol), tert-butyldiphenylsilyl chloride (2.1g, 7.7mmol) and 4-(dimethylamino)pyridine (20mg, 0.1bmmol) in DMF (10ml) were stirred for 2 hours at ambient temperature.

Water (100 ml) and ethyl acetate (30 ml) were added, the resulting precipitate was collected by filtration, washed with water and dried under vacuum to obtain 7-benzyloxy-4-(4-chloro-5-diphenyl-tert-butylsilyloxy-2-fluoroanilino)-6b -Methoxyquinazoline (2g, 4390).

IN NMR spectrum: (DMSOdv) 1.09 (s, 9H); 3.86 (c, ZN); 5.25 (c, 2H); 7.04 (d, 1H); 7.23 (s, 1H); 7.32-7.5 (m, 11H); 7.58 (d, 1H); 7.65-7.72 (m, 5H); 8.1 (c, 1H); 9.25 (sh.s, 1H)

MO-E5I: 663 MN"

A mixture of 7-benzyloxy-4-(4-chloro-5-diphenyl-tert-butylsilyloxy-2-fluoroanilino)-b-methoxyquinazoline (2g, Zmmol) and 1095 palladium on activated carbon (400mg) in DMF (20ml), methanol ( 20 ml) and ethyl acetate (20 ml) were stirred under hydrogen at a pressure of 1.7 atmospheres for 2 hours.

The catalyst was filtered off and the solvent was evaporated. The residue was purified by column chromatography eluting with a methylene chloride-methanol mixture (95/5, and then 90/10). The purified product was triturated with zephyr, collected by filtration and dried under vacuum to obtain 4-(4-chloro-5-diphenyl-tert-butylsilyloxy-2-fluoroanilino)-7-hydroxy-b-methoxyquinazoline (1.65 g, 9595).

IN NMR spectrum: (DMSOZ) 1.09 (c, 9H); 3.87 (c, ZN); 7.00 (c, 1H); 7.07 (d, 1H); 7.4-7.5 (m, 6H); 7.55 (d, 1H); 7.62 (c, 1H); 7.7 (m, 4H); 8.04 (s, 1H); 9.15 (sh.s, 1H); 10.34 (sh.s, 1H)

To a solution of 4-(4-chloro-5-diphenyl-tert-butylsilyloxy-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (288 mg, 0.5 mmol), triphenylphosphine (262 mg, thymol) and 2-(imidazole-1 -yl) of ethanol (b2mg, 0.55mmol) (U. Mey. Spet. 1993, 25, 4052-4060) in methylene chloride (5ml) was added distylazodicarboxylate (174mg, 1mmol) and the mixture was stirred for 1 hour at ambient temperature. Acetic acid (30 mg, 0.5 mmol) was added and volatile substances were evaporated. The residue was triturated with zephyr, the solid was collected by filtration and dried under vacuum, resulting in 4-(4-chloro-5-diphenyl-tert-butylsilyloxy-2-fluoroanilino)-7-(2-«(imidazol-1-yl )ztoxy)-6b-methoxyquinazoline (186bmg, 55905).

MO-E5I: 668 MN"

Example 34

A suspension of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-b-methoxy-7-(2-(4-pyridyl)zthoxy)quinazoline (300 mg, 0.6 mmol) and 2M aqueous sodium hydroxide solution (0. 38ml, 0O.7bmmol) in methanol (bml) was stirred at ambient temperature! within 2 hours.

Water was added and the mixture was adjusted to pH 7 with 2M hydrochloric acid. The precipitate was collected by filtration, washed with water and dried under vacuum. The solid was dissolved in a methylene chloride-methanol mixture and a 5M solution of hydrogen chloride in isopropanol (0.5 ml) was added. The mixture was diluted with isopropanol and the solvents (methylene chloride and methanol) were evaporated. The resulting precipitate was collected by filtration, washed with methylene chloride and dried under vacuum to obtain 4-(2-fluoro-5-hydroxy-4-methylanilino)-6b-methoxy-7-(2-(4-pyridyl)zthoxy)quinazoline hydrochloride (27mg, 949).

IN NMR spectrum: (DMSOZdv) 2.16 (s, ZN); 3.5 (t, 2H); 3.99 (c, ZN); 4.57 (t, 2H); 6.89 (d, 1H); 7.12 (d, 1H); 7.44 (s, 1H); 7.98 (d, 2H); 8.24 (s, 1H); 8.78 (s, 1H); 8.81 (d, 2H); 9.7 (sh.s, 1H); 11.38 (sh.s, 1H)

MO-E5I: 421|MNI

Elemental analysis: C 55.5 H 5.3 was found

SgziNgi MaOzE: 0.3H2gO 1 NS. 0.3 isopropanol trebuet C 55.6 H 5.1

The starting material was obtained as follows: To a suspension of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-b-methoxyquinazoline hydrochloride (261 mg, 0./mmol) (obtained as described for the starting material in Example 22), triphenylphosphine (367 mg, 1.4 mmol) and 2-(4-pyridyl)ztanol (104 mg, 0.84 mmol) (2 pyg. Or5Ppspei. KPpit. 1958, 28, 103-110) in methylene chloride was added distylazodicarboxylate (244 mg, 1 .4 mmol) and the mixture was stirred for 30 minutes at ambient temperature. The solvent was evaporated. The residue was suspended in zephyr and the zephyr was drained.

The resulting crude oil was purified by column chromatography eluting with a mixture of methylene chloride-methanol (90/10), resulting in 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-b-methoxy-7-(2-(4- pyridyl)zoxy)quinazoline (30Omg, 9090).

IN NMR spectrum: (DMSOZdb) 2.18 (s, ZN); 3.16 (t, 2H); 3.84 (c, ZN); 3.92 (c, ZN); 4.44 (t, 2H); 7.24 (s, 1H); 7.29 (d, 1H); 7.40 (d, 2H); 7.79 (c, 1H); 8.35 (s, 1H); 8.49 (d, 2H); 9.51 (s, 1H)

MO-E5I: 501 |MMai"

Example 35

Using a procedure similar to that described in Example 34, 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6b-methoxy-7-(3-thienylmethoxy)quinazoline (220 mg, 0.47 mmol) was treated with 2M hydrogen sodium hydroxide solution (0.47 ml) and as a result 4-(2-fluoro-5-hydroxy-4-methylanilino)-b-methoxy-7-(3-thienylmethoxy)quinazoline hydrochloride (180 mg, 8695) was obtained.

IN NMR spectrum: (DMSOZdv) 2.17 (s, ZN); 3.98 (c, ZN); 5.34 (c, 2H); 6.89 (d, 1H); 7.15 (d, 1H); 7.27 (d, 1H); 7, A7 (c, 1H); 7.65 (dd, 1H); 7.75 (c, 1H); 8.18 (c, 1H); 8.77 (c, 1H); 9.7 (sh.s, 1H)

MO-E5I: 412 (MNE

Elemental analysis: C 55,534.5M 9.0 was found

SaiNivMzOzE5:0.2H20.1HCI-0.09 isopropanol requires C 55.9 4.4 M 9.295

The starting material was obtained as follows: Using a procedure similar to that described for the starting material in Example 34, chemically combined 4-(2-fluoro-5-methoxycarbonyloxy-

4-methylanilino)-7-hydroxy-b-methoxyquinazoline hydrochloride (261 mg, 0.7 mmol) (prepared as described for the starting material in Example 22) with 3-thiophene methanol (96 mg, 0.84 mmol) and after purification by flash chromatography 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6b-methoxy-7-(3-thienylmethoxy) quinazoline (220 mg, 67905) was obtained by elution with a mixture of methylene chloride-methanol (98/2).

IR NMR spectrum: (DMSOαb) 2.18 (s, ZN); 3.85 (c, ZN); 3.93 (c, ZN); 5.27 (c, 2H); 7.23 (d, 1H); 7.30 (d, 1H); 7.32 (s, 1H); 7.40 (d, 1H); 7.59 (dd, 1H); 7.66 (c, 1H); 7.81 (c, 1H); 8.35 (c, 1H); 9.53 (s, 1H)

MO-E5I: 492 |MMai!"

Example 36

A mixture of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (187 mg, 0.5 mmol) (prepared as described for the starting material in Example 22), 4-bromomethylbenzonitrile ( 147mg, 0.75mmol) and potassium carbonate (173mg, 1.25mmol) in DMF (5ml) were heated at 50°C for 1 hour. Methanol (5ml) and potassium carbonate (138mg, 1mmol) were added and the mixture was stirred at 65°C. C for 2 hours. The solvent was evaporated, water was added to the residue, and the mixture was adjusted to pH 7 with 2M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried under vacuum. The solid was purified by column chromatography eluting with a mixture of methylene chloride and methanol (95/5). The purified product was ground with zephyr, collected by filtration and dried. The solid was dissolved in a methylene chloride-isopropanol mixture and a 5M solution of hydrogen chloride in isopropanol (0.5 ml) was added. The mixture was concentrated by evaporation and the resulting precipitate was filtered, washed with methylene chloride and dried under vacuum to obtain 7-(4-cyanobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (bomg, 2595).

T. pl. 265-270"7C

IR NMR spectrum: (DMSOαb) 2.17 (s, ZN); 4.02 (c, ZN); 5.47 (c, 2H); 6.89 (d, 1H); 7.11 (d, 1H); 7.38 (s, 1H); 7.71 (d, 2H); 7.93 (d, 2H); 8.23 (s, 1H); 8.75 (s, 1H); 9.67 (c, 1H); 11.24 (sh.s, 1H)

MO-E5I: 431 (MN

Elemental analysis: C61.2 H 4.5 M 11.7 was found

SgaNioMaOzE.: 0.1H2gO.-1NCI trebuett C 61.5 H 4.3 M 12.095

Example 37

To a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (319.5 mg, 1 mmol) (obtained as described for the starting material in Example 24), triphenylphosphine (524 mg, 2 mmol) and 2 -(4-pyridyl)ztanol (160 mg, 1.25 mmol) (2 pyg. Or5pspei. Kpit. 1958, 28, 103-110) in methylene chloride (7 ml) was added dropwise distylazodicarboxylate (315 μl, 2 mmol). The mixture was stirred for 1 hour at ambient temperature and the solvent was evaporated. The residue was triturated with zephyr, and the solid substance was filtered off and purified by column chromatography eluting with a mixture of methylene chloride-acetonitrile-methanol (85/10/5). The purified solid product was dissolved in a mixture of methylene chloride (5 ml) and methanol (5 ml) and a 5 M solution of hydrochloric acid was added! in isopropanol (0.5 ml). After dilution with isopropanol (20 ml), the mixture was concentrated by evaporation. The precipitated solid was collected by filtration and dried under vacuum to obtain 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyl)zthoxy)quinazoline hydrochloride (125 mg, 2595)

T. pl. 189-19170

IN NMR spectrum: (DMSOdv; SEZSOOOB) 3.55 (t, 2Н); 3.99 (c, ZN); 4.64 (t, 2H); 7.46 (s, 1H); 7.48 (d, 1H); 7.62 (t, 1H); 7.67 (dd, 1H); 8.16 (d, 2H); 8.17 (s, 1H); 8.88 (c, 1H); 8.94 (d, 1H)

MO-E5I: 425 (МН

Elemental analysis: C 520H4.3 M 111 was found

Сг2НивиМмаО» СИ:0.5Н20-1.95НСЙII trebuett C 52.3 4.2 M 11.19

Example 38

To a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (319.5 mg, Tmmol) (obtained as described for the starting material in Example 24), potassium carbonate (442 mg, 3.2 mmol ) and potassium iodide (33 mg, 02 mmol) in DMF (25 ml) at ambient temperature, 3-(chloromethyl)pyridine hydrochloride (328 μl, 2 mmol) was added, after which the reaction mixture was heated at 80°C for 2.5 hours. The mixture was allowed to cool and evaporated volatile substances. The residue was dissolved in a mixture of ethyl acetate (1U9ml) and methanol (1ml) and insoluble materials were filtered off. The solvent was evaporated from the filtrate and the residue was purified by column chromatography eluting with a mixture of methylene chloride-acetonitrile-methanol (50/45/5)3. The purified product was dissolved in hot methylene chloride and added to a saturated aqueous solution of hydrogen chloride. -b-methoxy-7-((3-pyridyl)methoxy)quinazoline hydrochloride (103 Zmg, 25905)

T. pl. 216-22176С

IN NMR spectrum: (DMSOdv) 4.03 (s, ZN); 5.48 (s, 2H); 7.47 (d, 1H); 7.54 (s, 1H); 7.65 (t, 1H); 7.7-7.8 (m, 2H); 8.25 (d, 1H); 8.35 (c, 1H); 8.75 (d, 1H); 8.84 (s, 1H); 8.90 (c, 1H); 11.65 (sh.s, 1H)

MO-E5I: 411 (МН

Elemental analysis: found C 51.934.2 M 11.4

Si NivMmaO» SI 0.8NgO-1.6NSi trebuett C 52.2 H 4.0 M 11.695

Example 39

Using a procedure similar to that described in Example 38, (4-chloro-2-fluoroanilino)-7-hydroxy-b6-methoxyquinazoline (319.5 mg, Tmmol) (obtained as described for the starting material in Example 24) was dropped interaction with 2-(chloromethyl)pyridine hydrochloride (331Ocl, 1.9 mmol) and as a result 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-pyridyl)methoxy)quinazoline (146 bmg, 3390) was obtained .

T. pl. 215-2187S

IN NMR spectrum: (DMSOZdv) 3.98 (s, ZN); 5.4 (c, 2H); 7.3 (c, 1H); 7.32-7.42 (m, 2H); 7.52-7.62 (m, ZN); 7.85 (c, 1H); 7.90 (t, 1H); 8.35 (s, 1H); 8.65 (d, 1H); 9.6 (s, 1H)

MO-E5I: 411 (МН

Elemental analysis: found C 59.7 N 3.9 M 13.1

SgiNivMaO»2СIE-0.5Н2О requires С 60.1 Н 4.1 M 13.395

Example 40

To a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (2500 mg, 0.78 mmol) (obtained as described for the starting material in Example 24), triphenylphosphine (410 mg, 1.5 mmol) and 2-(1-methylimidazol-2-yl)ztanol (147mg, 1.15mmol) (ER 0675112 AT) in methylene chloride (4ml) was added dropwise distylazodicarboxylate (128μl, 1.5mmol) and the mixture was stirred for 30 minutes at ambient temperature . Triphenylphosphine (143 mg, 0.52 mmol) and distilazodicarboxylate (d85 μl, 1 mol) were added and the mixture was stirred for 1 hour at ambient temperature. The solid product was filtered off and washed with methylene chloride. The solid was dissolved in a mixture of methylene chloride (25ml) and methanol (25ml) and a 2.9M hydrogen chloride solution (2ml) was added. The mixture was concentrated by evaporation and the product was collected by filtration, washed with zephyr and dried under vacuum to obtain 4-(4-chloro-2-fluoroanilino)-6b-methoxy-7-(2-(1-methylimidazol-2-yl)zthoxy) quinazoline hydrochloride (13 Zmg, 3495).

T. pl. 224-22970

IR NMR spectrum: (DMSOαb) 3.26 (t, 2H); 3.94 (c, ZN); 4.0 (c, ZN); 4.59 (t, 2H); 7.43 (d, 1H); 7.46 (s, 1H); 7.6 (t, 1); 7.6-7.7 (m, ZN); 8.41 (c, 1H); 8.78 (s, 1H); 11.75 (sh.s, 1H)

MO-E5I: 428 (МН

Elemental analysis: found C 48.8 H 4.4 M 13.4

SziNioM5O2 STE: 1H2O.:2NSII trebuett C 48.6 H 4.5 M 13.595

Example 41

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b6-methoxyquinazoline (319.5 mg, Tmmol) (obtained as described for the starting material in Example 24), potassium carbonate (414mg, Tmmol) and iodide potassium (16 mg, 0.1 mmol) and 4-chloromethylpyrimidine (257 mg, 2 mmol) in DMF (20 mL) were heated at 80°C for 2 hours. The solvent was added and the residue was triturated with water. The solid was collected by filtration and dried under vacuum. The solid was purified by column chromatography eluting with a mixture of methylene chloride-methanol (95/5).

The resulting solid product was collected by filtration, washed with methanol and then pentane and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(pyrimidin-4-yl)methoxy)quinazoline hydrochloride (172 mg, 4290 ).

T. pl. 237-2397S

IN NMR spectrum: (DMSOdv; SEZSOOB) 4.07 (s, ZN); 5.53 (c, 2H); 7.40 (c, 1H); 7.46 (dd, 1H); 7.65 (t, 1H); 7.68-7.72 (m, 2H); 8.26 (c, 1H); 8.35 (c, 1H); 8.91 (d, 1H); 9.25 (s, 1H)

MO-E5I: 412 (МН

Elemental analysis: C 49.5 H 3.6 M 141 was found

SgoNi5IM5O» SE:0.5Н20-1.85НСЙII trebuett С 49.2 Н 3.7 M 14390

The starting material was obtained as follows:

A solution of 4-methylpyrimidine (2g, 21.2mmol), M-chlorosuccinimide (4.26bg, 31.9mmol) and benzoyl peroxide (500mg, 2.1mmol) in tetrachloride (100ml) was heated at 80°C for 2 hours.

The mixture was allowed to cool, the insoluble material was filtered off, and the solvent was evaporated from the filtrate. The residue was purified by column chromatography eluting with methylene chloride, resulting in 4-chloromethylpyrimidine (257 mg, 1095)

IR NMR spectrum: (DMSOαb) 4.81 (s, 2H); 7.70 (d, 1H); 8.88 (d, 1H); 9.21 (s, 1H)

Example 42

To a solution of 4-(3-acetoxy-4-methylanilino)-b-methoxy-7-((1-methylbenzimidazol-2-yl)methoxy)quinazoline (290 mg, 0.bmmol) in methanol (15 ml) and methylene chloride (12 ml) 2M sodium hydroxide solution (900 μl) was added and the mixture was stirred for 25 minutes at ambient temperature.

The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine and dried (Md5O), after which the solvent was evaporated. The solid residue was purified by column chromatography eluting with a mixture of methylene chloride-methanol (97/3 and 95/53. The purified white solid was suspended in methanol (20 ml) and a 7.5M solution of hydrochloric acid in methanol (2 equivalents) was added. The solid was collected by filtration, washed with methanol and then pentane and dried under vacuum at 5070 s to obtain 4-(3-hydroxy-4-methylanilino)-b-methoxy-7-((1-methylbenzimidazol-2-yl)methoxy)quinazoline hydrochloride (106 mg, 3795 )

IN NMR spectrum: (DMSOdv; SEZSOOO) 2.17 (s, ZN); 4.04 (c, ZN); 4.15 (c, ZN); 6.01 (c, 2H); 7.0 (dd, 1H); 7.11 (d, 1H); 7.18 (d, 1H); 7.6-7.75 (m, ZN); 7.89 (d, 1H); 8.05 (d, 1H); 8.27 (s, 1H); 8.86 (s, 1H)

MO-E5I: 469 |MMai"

The starting material was obtained as follows:

A solution of 4-methylbenzimidazole (2.5g, 19mmol) (U.Spet. bos. 1989, 2820-2828) and paraformaldehyde (2) was heated at 165"C for 30 minutes. Additional paraformaldehyde (1g) was added and heating was continued for another 2 The mixture was allowed to cool and purified by column chromatography eluted with methylene chloride and then with a mixture of methylene chloride-methanol (95/5), resulting in 2-hydroxymethyl-1-methylbenzimidazole (1.34 g, 4590).

IN NMR spectrum: (DMSOv) 3.84 (s, ZN); 4.73 (c, 2H); 5.57 (sh.s, 1H); 7.19 (t, 1H); 7.25 (t, 1H); 7.54 (d, 1H); 7.60 (d, 1H)

MO-E5I: 185 |MMai

A solution of 2-hydroxymethyl-1-methylbenzimidazole (1.1 g, b, mmol) in thionyl chloride (10 ml) was stirred at ambient temperature! for 15 minutes and then heated under reflux for 15 minutes. Volatile substances were evaporated and the residue was purified by column chromatography eluting with a mixture of methylene chloride-methanol (95/5), resulting in 2-

chloromethyl-1-methylbenzimidazole (506mg, 3695)

IN NMR spectrum: (DMSOv; SEZSOOO) 4.07 (s, ZN); 5.38 (c, 2H); 7.6-7.7 (m, 2H); 7.9 (d, 1H); 8.05 (dd, 1H)

MO-E5I: 181 NAMES

A mixture of 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (24mg, 0.b4mmol) (prepared as described for the starting material in Example 1), potassium carbonate (310mg, 2.25mmol) , potassium iodide (10mg, 0.0b4mmol) and 2-chloromethyl-1-methylbenzimidazole (153mg, 0.7mmol) in DMF (12ml) were heated at 65"C for 3 hours. 2-chloromethyl-1-methylbenzimidazole ( 90mg, 0.41mmol) and potassium carbonate (165mg, 1.2mmol) and heating was continued for another 2 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine and dried (Md5O)"), then The solvent was evaporated. )methoxy)quinazoline (292mg, 95965)

MO-E5I: 506 |MMai"

Example 43

K suspensions of 7-(2-chloro-6-methyl-4-pyridyl)methoxy)-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline (ZbOmg, 0./mmol) in methanol ( 1Oml), cooled at 57C, a 2M aqueous solution of sodium hydroxide (700μl, 1.4mmol)) was added, and then the mixture was stirred for 30 minutes at ambient temperature. The solvent was evaporated and the residue was diluted with water (10 ml) and the mixture was adjusted to pH 7 with 1M hydrochloric acid. The resulting substance was filtered, washed with water and zephyr, and dried under vacuum. The solid substance was dissolved in methanol (5 ml) and a 7 M solution of hydrogen chloride in methanol (3 ml) was added. The precipitate was collected by filtration, washed with methanol and dried under vacuum to obtain 7-((2-chloro-6-methyl-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6- methoxyquinazoline hydrochloride (27 Zmg, 7495)

IN NMR spectrum: (DMSOdv; SEZSOOOB) 2.18 (s, ZN); 2.50 (c, ZN); 4.04 (c, ZN); 5.42 (c, 1H); 6.9 (d, 1H); 7.12 (d, 1H); 7.35 (c, 1H); 7.38 (s, 1H); 7.42 (s, 1H); 8.21 (c, 1H); 8.81 (s, 1H)

MO-E5I: 455 |MN)U

Elemental analysis: C 498H4.8M 10.0 was found

SgziNgomaOzSIE1.5H20-1.9NSII trebuett C 50.1 H 4.6 M 10.295

The starting material was obtained as follows: Solution of 2-chloro-6-methyl-4-pyridinecarboxylic acid! (2g, 12mmol) in ethanol (100ml) and concentrated sulfuric acid (10ml) was heated under reflux for 2 hours. Volatile substances were evaporated and the residue was dissolved in methylene chloride. The solution was washed with a saturated aqueous solution of sodium bicarbonate and brine and dried (M9504), after which the solvent was evaporated. The residue was purified by column chromatography eluting with a mixture of ethyl acetate and petroleum ether (1/9) and as a result, ethyl 2-chloro-6-methyl-4-pyridinecarbosylate (2 g, 8695) was obtained

IN NMR spectrum: (DMSOαb) 1.41 (t, ZN); 2.6 (c, ZN); 4.40 (sq., 2H); 7.63 (c, 1H); 7.69 (s, 1H)

MO-E5I: 200 (MN

Elemental analysis: C 54.4 H 5.3 7.0 was found

SeNioMO»siI trebuett C 54.1 H 5.0 M 7.095

To a solution of 2-chloro-b6-methyl-4-pyridinecarboxylate (1.85 g, 9.26 mmol) in THF (40 ml) cooled at 0"C, lithium aluminum hydride (35 mg, 9.26 mmol) was added in portions. The mixture was stirred for 15 minutes at 0"C and acetic acid (2 ml) was added. The mixture was distributed between ethyl acetate and water, and the aqueous layer was adjusted to pH 7.5 with 595% aqueous sodium bicarbonate solution. The organic layer was separated, washed with water and brine and dried (Md5oO), after which the solvent was evaporated. The residue was purified by column chromatography eluting with a mixture of ethyl acetate-petroleum ether (35/65) and as a result 2-chloro-4-hydroxymethyl-4-methylpyridine (1.28 g, 88965) was obtained

IR NMR spectrum: (DMSOαb) 1.92 (t, 1Н); 2.53 (c, ZN); 4.70 (d, 2H); 7.06 (c, 1H); 7.16 (s, 1H)

MO-E5I: 157 (MN

Elemental analysis: C 53.1 H5.3M 8.7 was found

C7NeMoOSsIi trebuet C 53.3 H 5.1 M 8.990

To a solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (3500 mg, 0.94 mmol) (obtained as described for the starting material in Example 22), triphenylphosphine (492 mg, 1.88mmol) and 2-chloro-4-hydroxymethyl-6-methylpyridine (17mg, 1.12mmol) in methylene chloride (30ml) was added dropwise distilazodicarboxylate (296μl, 1.88mmol) and the mixture was stirred for 30 minutes at ambient temperature. The solvent was evaporated and the residue was purified by column chromatography eluting with a ethyl acetate-methylene chloride (75/25) mixture.

The purified product was triturated with zephyr and dried under vacuum to obtain 7-((2-chloro-6-methyl-4-pyridyl)methoxy)-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-b-methoxyquinazoline ( 37 Zmg, 7895)

IR NMR spectrum: (DMSOαb) 2.15 (s, ZN); 2.5 (c, ZN); 3.85 (c, ZN); 3.98 (c, ZN); 5.35 (c, 2H); 7.25 (s, 1H); 7.3 (d, 1H); 7.35 (c, 1H); 7.4 (m, 2H); 7.85 (c, 1H); 8.35 (s, 1H); 9.58 (s, 1H)

MO-EZ5I: 513 NAMES"

Example 44

A mixture of 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-β6-methoxyquinazoline (112 mg, 0.35 mmol), potassium carbonate (138 mg, 1 mmol) and 4-(chloromethyl)pyridine hydrochloride (59 mg, 0.3 mmol) in DMF (2 ml) was heated at 80"7C for 1 hour. The mixture was allowed to cool and distributed between ethyl acetate and water. The organic layer was separated, washed with water and brine and dried (Md95O54), after which the solvent was evaporated.

The residue was purified by column chromatography eluting with a mixture of methylene chloride-methanol (95/5) and as a result 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline (115 mg, 8095).

T. pl, 197-19870

IR NMR spectrum: (DMSOαb) 4.03 (s, ZN); 5.46 (c, 2H); 7.45 (d, 1H); 7.49 (s, 1H); 7.5 (d, 2H); 7.58 (t, 1H); 7.62 (c, 1H); 7.22 (dd, 1H); 8.58 (s, 1H); 8.65 (d, 2H)

MO-E5I: 412 (MN).

Elemental analysis: found C 59.5 3.9 M 9.6

C2g1Ni5MzOzSIE:0.8H2gO requires C 59.2 H 3.9 M 9.990

The starting material was obtained as follows:

4-Chloro-2-fluorophenol (264 mg, 1 .9 mmol) and the mixture was heated under reflux for 45 minutes. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with 0.1 M hydrochloric acid, water and brine and dried (Md5O»4), after which the solvent was evaporated.

The solid residue was triturated with petroleum jelly and the crude product was collected by filtration and purified by flash chromatography eluting with a mixture of methylene chloride and sulfur (9/1), resulting in 7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6 -Methoxyquinazoline (474 mg, 7795) in the form of a cream-colored solid.

T. pl. 179-1807S

IR NMR spectrum: (DMSOa) 3.99 (s, ZN); 5.36 (c, ZN); 7.35-7.5 (m, 4H); 7.55-7.65 (m, 5H); 7.72 (d, 1H); 8.6 (s, 1n)

MO-E5I: 411 (МН

Elemental analysis: C63.4 H41 M 6.8 was found

Cg22NivSiEM2Oz:0.06H2gO:0.05C NosSi" trebuett C 63.6 H 3.9 M 6.790

A solution of 7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (451 mg, 1.1 mmol) in TPA (4.5 ml)

It was heated under reflux for 3 hours. The mixture was diluted with toluene and volatile substances were evaporated. The residue was triturated with methylene chloride, collected by filtration, washed with zephyr and dried under vacuum to obtain /4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (320 mg, 90965).

IN NMR spectrum: (DMSOZdv) 4.0 (s, ZN); 7.27 (s, 1H); 7.43 (dd, 1H); 7.56 (t, 1H); 7.57 (s, 1H); 7.72 (dd, 1H); 8.5 (s, 1H)

MO-E5I: 321 |MNI

Example 45

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b6-methoxyquinazoline (320 mg, 1 mmol) (prepared as described for the starting material in Example 24), potassium carbonate (414 mg, 1 mmol), potassium iodide ( 40mg) and 4-(chloromethyl)pyridine hydrochloride (250mg, 1.5mmol) in DMF (15ml) were heated at 60°C for 2 hours. The mixture was allowed to cool and partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine and dried (Md5O5"), after which the solvent was evaporated. The residue was suspended in ethanol (20ml) and concentrated hydrochloric acid (0.5Mml) was added.

Volatile substances were evaporated and the solid residue was subjected to azeotropic distillation with toluene. The solid product was recrystallized from propanol to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline hydrochloride (335 mg, 70905)

IN NMR spectrum: (DMSO db) 4.1 (s, ZN); 5.69 (c, 2H); 7.46 (dd, 1H); 7.52 (c, 1H); 7.62 (t, 1H); 7.69 (dd, 1); 8.03 (d, 2H); 8.55 (s, 1H); 8.83 (s, 1H); 8.93 (d, 2H)

MO-E5I: 411 MN)"

Elemental analysis: C51.033.9 M 11.2 was found

C21Niz Ma» STE: 0.5Н2гО-1.95НСЙII trebuett С 51.4 Н 3.9 M 11.495

Example 46

To a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (16mg, 0.5mmol) (obtained as described for the starting material in Example 24), triphenylphosphine (393mg, 1.5mmol) and 2-(M-(2,6-dimethyl-4-pyridyl)-M-methylamino)ztanol (125 mg, 0.1 mmol) in methylene chloride (5 ml) was added dropwise to distyl azodicarboxylate (261 mg, 1.5 mmol) and the mixture was stirred 2 hours at ambient temperature. Methanol (10 drops) was added and the mixture was poured into a column with neutral aluminum oxide, and the product was separated by eluting with a mixture of methylene chloride-acetonitrile-methanol (60/35/35). The purified solid product was triturated with zephyr and collected by filtration. The solid substance was dissolved in a mixture of methylene chloride-methanol, and 3M was added with an aqueous solution of hydrogen chloride (ml). The solid was filtered off, washed with zephyr and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-(2-(M-(2,6-dimethyl-4-pyridyl)-M-methylamino)zthoxy) -6-methoxyquinazoline (17Omg, 61905).

T. pl. 208-21270С

IR NMR spectrum: (DMSOdv; SEZSOObB)) 2.52 (s, 6Н); 3.26 (c, ZN); 3.98 (c, ZN); 4.12 (t, 2H); 4.46 (t, 2H); 6.8 (sh.s, 1H); 7.1 (sh.s, 1H); 7.38 (s, 1H); 7.46 (dd, 1H); 7.62 (t, 1H); 7.67 (dd, 1H); 8.18 (c, 1H); 8.89 (s, 1H)

MO-E5I: 482 MN)"

Elemental analysis: C 52.2H 5.2 M 122 was found

Сg25Наг5М5О2С1Е-1Н2О-2НСЙ trebuet С 52.4 Н 5.1 М 12.296

The starting material was obtained as follows:

A solution of 4-chloro-2,6-dimethylpyridine (849 mg, mmol) (U. Nei Spet. 1990, 1841) in 2-(methylamino)ztanol (1.35 g, 13 mmol) and 3M ether solution of hydrogen chloride (3 drops) was heated at 140"C for 1 hour. The reaction mixture was allowed to cool and diluted with water. The insoluble material was filtered off and the aqueous filtrate was poured into a suspension of magnesium sulfate (50 mg) in ethyl acetate (100 ml). The insoluble material was filtered off and the filtrate was dried (Md5O"), then The solid residue was triturated with zephyr, collected by filtration and dried under vacuum at 507°C to obtain 2-(M-(2,6-dimethyl-4-pyridyl)-M-methylamino)ztanol (960 mg, 9095).

T. pl. 139-144"7C

IN NMR spectrum: (SOCI3) 2.4 (c, 6H); 3.0 (c, ZN); 3.51 (t, 2H); 3.81 (t, 2H); 6.26 (s, 2H)

MO-E5I: 181 MN)"

Example 47

To a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (16mg, 0.5mmol) (obtained as described for the starting material in Example 24), triphenylphosphine (393mg, 1.5mmol) and 2-(M-(4-pyridyl)amino)ztanol (97mg, 0.7mmol) in methylene chloride (dml) was added dropwise distylazodicarboxylate (261mg, 1.hmol) and the mixture was stirred for 2 hours at ambient temperature. The mixture was diluted with acetyl acetate (5 ml), the solid product was collected by filtration and purified by column chromatography on an aluminum oxide column, eluting with a mixture of methylene chloride-acetonitrile-methanol (60/35/5)3. The purified solid was triturated with zephyr and collected by filtration. The solid substance was dissolved with a mixture of methylene chloride-methanol, and an aqueous solution of hydrogen chloride (0.5 ml) was added to the mixture. Volatile substances were evaporated and the solid residue was suspended in sapphire, filtered, washed with sapphire and dried under vacuum to obtain 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(M-(4-pyridyl)amino) )ztoxy)quinazoline hydrochloride (95mg, 37905)

IN NMR spectrum: (DMSOdvye; SEZSOObB) 3.87 (t, 2Н); 4.00 (c, ZN); 4.43 (t, 2H); 6.97 (dd, 1H); 7.15 (dd, 1H); 7,AZ (c, 1H); 7.46 (dd, 1H); 7.66 (t, 1H); 7.68 (dd, 1H); 8.12 (d, 1H); 8.21 (c, 1H); 8.34 (d, 1H); 8.89 (s, 1H)

MO-E5I: 440 |MN)U.

Elemental analysis: found C 50.0n4.3 M 13.2

Сг2НеМ5О2 СИ 0.8НгО2НСИИ requires С 50.0 N 4.3 M 13.295

The starting material was obtained as follows:

Using a procedure similar to that described for the starting material in Example 46, 4-chloropyridine (3g, 20mmol) was treated with aminoethanol (6.1g, 0./mmol) to give 2-(M-(4-pyridyl)aminoethanol (400mg , 2590).

T. pl. 110-11176

IN NMR spectrum: (SOCI3) 3.3 (m, 2H); 3.81 (m, 2H); 4.94 (sh.s, 1H); 6.44 (d, 2H); 8.13 (d, 2H)

MO-E5I: 138 MN)"

Example 48

Using a procedure similar to that described in Example 47, 3-(M-methyl-M-(4-pyridyl)amino)propanol (116 mg, 0.7 mmol) was treated with 4-(4-chloro-2-fluoroanilino)-7 -hydroxy-6-methoxyquinazoline (16 mg, 0.5 mmol) (prepared as described for the starting material in Example 24) to give 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(3-( M-methyl-M-(4-pyridyl)amino)propoxy)quinazoline hydrochloride (15mg, 5595).

T. pl. 243-248"7C

IR NMR spectrum: (DMSOiv; SEZSOOO) 2.2 (t, 2H); 3.21 (t, ZN); 3.82 (t, 2H); 4.0 (c, ZN); 4.31 (t, 2H); 6.95 (sh.s, 1H); 7.2 (sh.s, 1H); 7.39 (c, 1H); 7.46 (dd, 1H); 7.62 (t, 1H); 7.68 (dd, 1H); 8.2 (c, 1H); 8.3 (sh.s, 2H); 8.87 (s, 1n)

MO-E5I: 469 MN)"

Elemental analysis: found C 51.4 H 5.1 M 12.9

SgaNgzim5O»2 СЕ -1.2Н20-1.95НСЙ trebuet С 51.4 Н 4.9 M 12.59

The starting material was obtained as follows:

Using a procedure similar to that described in Example 46, 4-chloropyridine (885 mg, 59 mmol) and 3-(methylamino)propanol (2.1 g, 0.23 mmol) (Teigapedop Gen. 1994, 35, 1545-1548) were heated in for 8 hours to obtain 3-(M-methyl-M-(4-pyridyl)amino)propanol (979mg, 6195).

IN NMR-selector: (SOSIv; SEZSOOB) 1.8-1.9 (m, 2H); 3.16 (c, ZN); 3.6-3.75 (m, 4H); 6.8 (sh.s, 2H); 8.30 (d, 2H)

MO-E5I: 166 MN)"

Example 49

To a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (16mg, 0.5mmol) (obtained as described for the starting material in Example 24), triphenylphosphine (393mg, 1.5mmol) and 1-(2-hydroxyethyl)-2-methylimidazole (88mg, 0.7mmol) (Spet. Are5. 1964, 60, 2949) in methylene chloride (3ml) was added dropwise distylazodicarboxylate (261mg, 1.5mmol) and the mixture was stirred for 2 hours at ambient temperature. The mixture was diluted with zephyr (8 ml) and the solid product was filtered off. The solid substance was dissolved with a mixture of methylene chloride-methanol, and 3M was added with an aqueous solution of hydrogen chloride (0.5 ml). The resulting precipitate was collected by filtration, washed with zephyr and dried under vacuum to obtain 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-methylimidazod-1-yl)zthoxy)quinazoline hydrochloride (180 mg, 72905).

IN NMR spectrum: (DMSOiv; SEZSOOB) 2.79 (s, ZN); 4.02 (c, ZN); 4.59 (t, 2H); 4.72 (t, 2H); 7.40 (c, 1H); 7.45 (d, 1H); 7.60 (c, 1H); 7.62 (t, 1H); 7.67 (dd, 1H); 7.71 (c, 1H); 8.23 (s, 1H); 8.89 (s, 1H)

MO-E5I: 428 |MN)-

Elemental analysis: found C 47.9 H 4.7 M 13.3

Si NioM5O» CE -1,4Н20.2 1НСЙИ trebuet С 47,6 Н 4,6 M 13,295

Example 50

To a solution of 1-(3-hydroxypropyl)imidazole (102 mg, 0.8 mmol) (ER 0060696 At), 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b-methoxyquinazoline (200 mg, 0.2 mmol) ( obtained as described for the starting material in example 24) and triphenylphosphine (492 mg, 1.9 mmol) in methylene chloride (4 ml) was added dropwise distylazodicarboxylate (295 μg, 1.9 mmol) and the mixture was stirred for 2 hours at ambient temperature. The solvent was evaporated and the residue was purified by chromatography eluting with a mixture of methylene chloride-acetonitrile-methanol (60/35/5)3. The purified solid was dissolved in a methylene chloride-methanol mixture and a 5M aqueous solution of hydrogen chloride (2 ml) was added.

Volatile substances were layered and the solid residue was suspended in zephyr, collected by filtration, washed with zephyr and dried under vacuum to obtain 4-(4-chloro-2-fluoroanilino)-7-(3Z3-"imidazol-1-yl)propoxy)-b -methoxyquinazoline hydrochloride (114mg, 3690).

IN NMR spectrum: (DMSOe; SEZSOOOB) 2.5 (m, 2H); 3.99 (c, ZN); 4.32 (t, 2H); 4.45 (t, 2H); 7.39 (c, 1H); 7.45 (dd, 1H); 7.61 (t, 1H); 7.66 (dd, 1H); 7.71 (c, 1H); 7.84 (s, 1H); 8.19 (c, 1H); 8.77 (c, 1H); 9.20 (s, 1H)

MO-E5I: 428 MN)"

Elemental analysis: C48.2H4.5M 13.2 was found

Si NioM5O» CE -1.2Н20-1.9НСЙII trebuett C 48.6 N 4.5 M 13.595

Example 51

7-(2- bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6b-methoxyquinazoline (98 mg, 0.23 mmol) and the mixture was heated at 40"C for 30 minutes. The reaction mixture was allowed to cool and partitioned between ammonium chloride and ethyl acetate. Organic the layer was separated, washed with water and brine and dried (M9504), and then the solvent was evaporated.

The purified solid product was triturated with zephyr and collected by filtration. The solid substance was dissolved in a mixture of methylene chloride-methanol, and a 3% aqueous solution of hydrogen chloride (0.5 ml) was added.

Volatile substances were evaporated and the residue was crystallized from methylene chloride and sulfur. The solid was filtered off, washed with zephyr and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-methyl-4H-1,2,3-triazol-3- ilthio)zoxy)quinazoline hydrochloride (9Omg, 7996).

IN NMR spectrum: (DMSOiv; SEZSOOB) 3.78 (s, ZN); 3.81 (t, 2H); 3.99 (c, ZN); 4.57 (t, 2H); 7.40 (c, 1H); 7.46 (dd, 1H); 7.62 (t, 1H); 7.67 (dd, 1H); 8.16 (c, 1H); 8.89 (s, 1H); 9.68 (С1Н)

MO-E5I: 461 NAMES

Elemental analysis: C 43.7 H 3.9 M 14.9 was found

SgoNivMvO2СIE51Н2гО:2НСЙII trebuett С 43.5 Н 4.0 М 15.29

The starting material was obtained as follows:

To a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (320 mg, 1 mmol) (obtained as described for the starting material in Example 24) and potassium carbonate (552 mg, 4 mmol) in DMF ( 5 ml), heated at 357"C, 1,2-dibromoethane (725 mg, 4 mmol) was added in portions of 70 μl every 30 minutes.

After completion of the addition, the mixture was stirred for another 30 minutes and then distributed between ethyl acetate and water. The organic layer was separated, washed with water and brine and dried (Md5O4), after which the solvent was evaporated. The residue was triturated with a mixture of petroleum sulfur and sulfur, and the solid was filtered off and dried under vacuum, resulting in 7-(2-bromoethoxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (200 mg, 4790).

IR NMR spectrum: (DMSOαb) 3.89 (t, 2H); 3.96 (c, ZN); 4.51 (t, 2H); 7.23 (s, 1H); 7.35 (dd, 1H); 7.55 (dd, 1H); 7.59 (t, 1H); 7.83 (s, 1H); 8.36 (c, 1H); 9.57 (s, 1H)

MO-E5I: 428 (МН

Example 52

Using a procedure similar to that described in Example 51, 7-(2-bromoethoxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (98 mg, 0.23 mmol) (prepared as described for the starting material and example 51) was treated with 5-mercapto-1-methyltetrazole (40 mg, 0.35 mmol) to obtain 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(1-methyltetrazol-5-ylthio) )ztoxy)quinazoline hydrochloride (55mg, 4496).

IR NMR spectrum: (DMSOiv; SEZSOObF) 3.8 (t, 2H); 3.97 (c, 6H); 4.57 (t, 2H); 7.35 (c, 1H); 7.46 (dd, 1H); 7.62 (t, 1H); 7.70 (dd, 1H); 8.12 (c, 1H); 8.87 (s, 1H)

MO-E5I: 462 MN)"

Elemental analysis: C 45.1 H 3.7 M 19.3 was found

SieNi7iMch702SIE5:0.5H20-1NSIII trebuett C 45.0 H 3.8 M 19.395

Example 53

To a solution of /2-methyl-1-(3-hydroxypropyl)imidazole (131 mg, 093 mmol) (ER 0060696), triphenylphosphine (492 mg, 1.8 mmol) and 4-(4-chloro-2-fluoroanilino)-7-hydroxy- b-methoxyquinazoline (200mg,

0.6b2mmol) (obtained as described for the starting material in example 24) in methylene chloride (4ml) was added dropwise distilazodicarboxylate (295μl, 1.9mmol) and the mixture was stirred for 2 hours at ambient temperature. 2-methyl-1-(3-hydroxypropyl)imidazole (4 mg, 0.3 mmol), triphenylphosphine (82 mg, 0.3 mmol) and distylazodicarboxylate (50 μl, 0.3 mmol) were also added, and the mixture was stirred for another 3 hours. Volatile substances were layered and the residue was purified by column chromatography eluting with a mixture of methylene chloride-methanol (93/7). The purified solid substance was dissolved in methylene chloride and a 3% aqueous solution of hydrogen chloride (2 ml) was added. Volatile substances were evaporated and the solid residue was suspended in zephyr, collected by filtration, washed with zephyr and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6b-methoxy-7-(3-(2-methylimidazol-1- il)propoxyquinazoline hydrochloride (104 mg, 32965).

IN NMR spectrum: (DMSOdv; SEZSOOOB)) 2.4 (t, 2Н); 2.60 (c, ZN); 4.0 (c, ЗН), 4.3-4.4 (m, 4Н); 7.41 (c, 1H), 7.46 (dd, 1H); 7.58 (s, 1H); 7.62 (t, 1H); 7.67 (dd, 1H); 7.70 (c, 1H); 8.21 (c, 1H); 8.88 (s, 1H)

MO-E5I: 442 (МН

Elemental analysis found C 49.8 N 5.0 M 12.5

Сг2Най М5О2 СИ: 1Н2О0:2НСИ-0.23 зфир requires С 50.1 Н 5.0 M 12.795

Example 54

A solution of 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methylaminoethoxy)quinazoline hydrochloride hydrate (135 mg, 0.3 mmol) and 2-chloropyrimidine (bbmg, 0.00 mmol) in M,M-diisopropylethylamine (2 ml) was heated under reflux for 1 hour. Allowed the mixture to cool, rubbed it with zephyr. The solid product was collected by filtration and purified by column chromatography eluting with a mixture of methylene chloride-methanol (95/5). The purified oil was crystallized from zephyr and the solid substance was filtered off. Then the solid substance was dissolved in a mixture of methylene chloride-methanol, and a 3M solution of hydrogen chloride (0.5 ml) was added. The suspension was diluted with zephyr and the solid product was collected by filtration, washed with zephyr and dried under vacuum to obtain 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(M-methyl-M-(pyrimidine-2 -yl)amino)ztoxy)quinazoline hydrochloride (52mg,

IN NMR spectrum: (DMSOdv; SEZSOOOB) 3.36 (s, 1H); 3.9 (c, ZN); 4.22 (t, 2H); 4.51 (t, 2H); 6.94 (t, 1H); 7.36 (c, 1H); 7.46 (d, 1H); 7.63 (t, 1H); 7.66 (dd, 1H); 8.08 (s, 1H); 8.62 (d, 2H); 8.9 (c, 1H).

MO-E5I: 455 |MNI"

Elemental analysis: found C 49.8 H 4.4 M 15.9

Сг2НгоМеО2СТЕ-1,1НгО-1,5НСИИ requires С 49.9 Н 4.5 M 15.9965

The starting material was obtained as follows:

A solution of di-tert-butyldicarbonate (4.52g, 20mmol) was added to a solution of 2-(methylamino)ztanol (4.52g, 20mmol) in water (100ml) and THF (10ml) and the mixture was stirred for 18 hours at ambient temperature. Organic solvents were evaporated and the residue was distributed between water and zephyr.

The organic layer was separated, washed with a 0.1M solution of hydrochloric acid and brine and dried (M9504), after which the solvent was evaporated to obtain 2-(M-methyl-M-tert-butoxycarbonylamino)ztanol (Zg, 85905) in the form of oil.

IN NMR spectrum: (SOCI3) 1.46 (c, 9H); 2.92 (c, ZN); 3.39 (t, 2H); 3.74 (t, 2H)

MO-E5I: 176 (MN

A solution of 2-M-methyl-M-tert-butoxycarbonylamino)ztanol (116 mg, 0.7 mmol) in methylene chloride (ml) was added to a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b-methoxyquinazoline (160 mg , 0.5 mmol) (obtained as described for the starting material in Example 24) and triphenylphosphine (393 µg, 1.mmol) in methylene chloride (5 mL). Then distilazodicarboxylate (261 mg, 1.5 mmol) was added dropwise and the mixture was stirred at ambient temperature! within 4 hours. The reaction mixture was filtered into a silica column and eluted with a gradient of methylene chloride-acetonitrile-methanol mixture (from 70/30/0 to 70/20/10). The partially purified product was additionally purified by column chromatography with gradient elution of a mixture of methylene chloride-sphyr-methanol (from 60/40/0 to 60/10/30). The pure oil was crystallized from zephyr, collected by filtration and washed to give 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(M-methyl-M-tert-butoxycarbonylamino) zthoxy)quinazoline (45mg , 6395).

T. pl. 194-19670C

IN NMR spectrum: (SOCI3) 1.46 (c, 9H); 3.05 (sh.s., ZN); 3.72 (sh.s, 2H); 4.02 (c, ZN); 4.27 (sh.s, 2H); 7.0 (c, 1H); 7.,2-7,3 (m, ZN); 8.54 (t, 1H); 8.69 (s, 1H)

MO-E5I: 499 |MMai"

Elemental analysis: found C 57.2 H 5.7 M 11.5

SgzNoviMmaO4STE.:0.3H2gO requires C 57.3 H 5.6 M 11.695

To a solution of 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(M-methyl-M-tert-butoxycarbonylamino)zthoxy)quinazoline (390 mg, 0.82 mmol) in methylene chloride (4 ml) was added TEA (4 ml) and the mixture was stirred for 2 hours at ambient temperature. Toluene was added and volatile substances were evaporated. The residue was dissolved in methylene chloride and added to the 3M aqueous solution of hydrogen chloride (ml). The resulting precipitate was collected by filtration, washed with zephyr and dried under vacuum to obtain /4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(methylamino)zthoxy)quinazoline hydrochloride (290 mg, 79905).

IN NMR spectrum: (DMSOiv; SEZSOOB) 2.74 (s, ZN); 3.53 (t, 2H); 4.05 (c, ZN); 4.53 (t, 2H); 7.46 (d, 1H); 7.47 (s, 1H); 7.6-7.7 (m, 2H); 8.24 (s, 1H); 8.91 (s, 1H)

MO-E5I: 377 |MNI"

Elemental analysis: found C 45.8 N 5.0 M 12.0

SivNizimaO2STe-1.1H2O.2NSII trebuett C 46.0 H4.8 M 11.995

Example 55

To a suspension of 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(methylamino)z-thoxy)quinazoline hydrochloride hydrate (9mg, 0.1mmol) (obtained as described for the starting material in Example 54) in methylene chloride (Zml) was added isonicotinoyl chloride (Zbmg, 0.2 mmol) and then tristhylamine (80 mg, 0.8 mmol) was added dropwise. The mixture was stirred for 30 minutes at ambient temperature), after which the solvent was evaporated. The residue was partitioned between ethyl acetate and water, the organic layer was separated, washed with brine and dried (Md5OAi), after which the solvent was evaporated. The residue was dissolved in methylene chloride, and a 3% aqueous solution of hydrogen chloride (0.5 ml) was added. The suspension was diluted with zephyr and the precipitate was collected by filtration, washed with zephyr and dried under vacuum to obtain 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(M-methyl-M-(pyridylcarbonyl)amino) ztoxy) quinazoline hydrochloride (75 mg, 6795).

IN NMR spectrum: (DMSOdv; SEZSOOO; 952C) 3.1 (s, ZN); 3.8-3.9 (sh.s, 2H); 4.1 (c, ZN); 4.4-4.6 (sh.s, 2H); 7.4-7.45 (m, 2H); 7.55 (dd, 1H); 7.65 (t, 1H); 7.9-8.0 (sh.s, 2H); 8.28 (s, 1H); 8.8 (c, 1H); 8.95 (c, 2H).

MO-E5I: 482 (МН

Elemental analysis: C 51.7 N 4.6 M 12.0 was found

SgaNgi M5OzSTE-1NgO-1.7 NSI trebuett C 51.5 H 4.6 M 12.395

Example 56

A mixture of 7-(4-pyridylthio)-3,4-dihydroquinazolin-4-one (100 mg, 0.4 mmol), thionyl chloride (20 mL) and DMF (0.1 mL) was heated under reflux for 1.5 hours. Volatile substances were evaporated and the residue subjected to azeotropic distillation with toluene. A solution of 3-hydroxy-4-methylaniline (53 mg, 0.04 mmol) in isopropanol (100 ml) was added to the solid residue, and the mixture was heated under reflux for 2 hours. The mixture was allowed to cool, the precipitated product was collected by filtration, washed with isopropanol and dried to obtain 4-(3-hydroxy-4-methylanilino)-7-(4-pyridylthio)quinazoline hydrochloride (10 mg, 7395).

IN NMR spectrum: (DMSOdv) 2.17 (s, ZN); 7.05 (dd, 1H); 7.17 (d, 1H); 7.19 (c, 1H); 7.64 (d, 2H); 8.00 (d, 1H); 8.20 (c, 1H); 8.66 (d, 2H); 8.92 (s, 1H); 9.05 (d, 1H).

MO-E5I: 361 NAMES"

Elemental analysis: C 53.23 4.6 M 11.8 was found

SgoNivMm«O5:1H2gO:2NSY trebuett C 53.2 H 4.4 M 12490

The starting material was obtained as follows:

A solution of 2-amino-4-fluorobenzoic acid (Zg, 19.3 mmol) in formamide (ZOml) was heated at 1507 for 18 hours. The reaction mixture was poured into water with ice (1/1, 250 ml). The precipitated solid was collected by filtration, washed with water and dried to obtain 7-fluoro-3,4-dihydroquinazolin-4-one (2.6 g, 8290).

To a solution of 4-mercaptopyridine (8.12 g, 7 mmol) in DMF (100 ml) was added sodium hydride (3.3 g, 5090 suspension in mineral oil, bUmmol) and the mixture was stirred for 30 minutes. 7-Fluoro-3,4-dihydroquinazolin-4-one (1.5 g, "ummol) was added and the reaction mixture was heated at 100"C for 4 hours. The mixture was allowed to stand, diluted with water and extracted with ethyl acetate. The organic extract was washed water and brine and dried (Md50O054), after which the solvent was evaporated. on (500mg, 695).

IR NMR spectrum: (DMSOαb) 7.24 (d, 2H); 7.54 (dd, 1H); 7.70 (d, 1H); 8.10 (c, 1H); 8.14 (d, 1H); 8.44 (d, 2H)

MO-E5I: 256 |MNI

Example 57

A mixture of 4-chloro-2-fluoro-3-hydroxyaniline (118 mg, 0.7 mmol) (ER 061741) and 4-chloro-6-methoxy-7-((4-pyridyl)methoxy)quinazoline (200 mg, 0.7 mmol) (obtained as described for the starting material in Example 13) in isopropanol (10 ml) and a sterile solution of hydrogen chloride (5 ml) was heated at 80"C for 2 hours, after which the mixture was allowed to cool. The precipitated product was collected by filtration, washed isopropanol and dried to obtain /4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline hydrochloride (100 mg, 31905).

IR NMR spectrum: (DMSOαb) 3.96 (s, ZN); 5.38 (c, 2H); 7.14 (d, 1H); 7.24 (s, 1H); 7.38 (d, 1H); 7.48 (d, 2H); 7.82 (c, 1H); 8.32 (s, 1H); 8.58 (d, 2H); 9.48 (c, 1H).

MO-E5I: 427 | NOUNS 144

Example 58

A mixture of /7-(2-chloro-4-pyridyl)methoxy-b6-methoxy-3,4-dihydroquinazolin-4-one (150 mg, 0.47 mmol), phosphoryl chloride (0.2 ml) and M,M-dimethylaniline (0 ,2ml) in toluene (5ml) was heated under reflux for 1 hour. Volatiles were evaporated and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and dried (M950O4), after which the solvent was evaporated. A solution of 2-fluoro-5-hydroxy-4-methylaniline (b7 mg, 0.47 mmol) (obtained as described for the starting material in Example 13) was added to the solid residue, and the mixture was heated under reflux for 2 hours. The mixture was allowed to cool and the precipitated product was collected by filtration, washed with acetone and dried to obtain 7-(2-chloro-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6- methoxyquinazoline hydrochloride (7Omg, 3090).

T. pl. 245-2507S

IN NMR spectrum: (DMSOVdv) 2.30 (s, ZN); 4.10 (c, ZN); 5.45 (c, 2H); 6.90 (d, 1H); 7.10 (d, 1H); 7.35 (c, 1H); 7.50 (d, 1H); 7.65 (c, 1H); 8.25 (s, 1H); 8.45 (d, 1H); 8.75 (s, 1H); 9.60 (sh.s, 1H); 11.30 (c, 1H)

MO-E5I: 441 (MNE

Elemental analysis: found C 53.7 34.0 M 10.9

Сг22НивМаОЗЕСИ-1Н2О-1НСИ trebuett C 53.4 H 4.3 M 11395

The starting material was obtained as follows:

To the mixture of 4-(2-chloropyridine)carboxylic acid! (950 mg, mmol) and DMF (0.05 ml) in methylene chloride (20 ml), oxalyl chloride (0.5 ml) was added and the mixture was stirred at ambient temperature! within 1 hour. Volatile substances were evaporated and ethanol (1 Oml) was added to the residue, after which the mixture was stirred at ambient temperature for 18 hours. Water was added and the mixture was extracted with ethyl acetate (3x25 ml). The extracts were combined, dried (M95O4) and then the solvent was evaporated to give 4-(2-chloropyridyl)carboxylate (700 mg, 6395) as a brown oil.

IN NMR spectrum: (DMSOαb) 1.30 (t, ZN); 4.37 (sq., 2H); 7.80 (m, 2H); 8.60 (d, 1H)

To a stirred solution of 4-(2-chloropyridine)carboxylate (700 mg, 3.dmol) in sulfur (1 mL) at 0"C, lithium aluminum hydride (3 mL of a 1 M solution in sulfur, 5 mmol) was added dropwise. The mixture was allowed to warm to ambient temperature and washed zephyr and 2M sodium hydroxide solution (2 ml). The insoluble material was filtered off), the organic phase was separated, and the aqueous layer was extracted with zephyr (3x25 ml). The extracts were combined and dried (Mud50O4), after which the solvent was evaporated to obtain 2-chloro-4-hydroxymethylpyridine (18 , 3395) in the form of brown oil, which, standing, crystallized.

IN NMR spectrum: (DMSOdv) 4.55 (s, 2H); 5.50 (sh.s, 1H); 7.32 (d, 1H); 7.20 (s, 1H); 8.30 (d, 1H)

A mixture of 2-chloro-4-hydroxymethylpyridine (180 mg, 1.25 mmol), thionyl chloride (0.2 ml) in toluene was stirred at ambient temperature! within 1 hour. The volatiles were evaporated to give 2-chloro-4-chloromethylpyridine hydrochloride (180 mg, 0.9 mmol). To this crude product was added a mixture of 7-hydroxy-β6-methoxy-4-phenoxyquinazoline (268 mg, 1 mmol) (prepared as described for the starting material in Example 13), potassium carbonate (680 mg, 5 mmol) in DMF (10 mL) and the mixture was heated at 90"C for 1 hour. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate (3x7Oml). The extracts were combined, washed with water (3 times) and brine, and dried (Ma5O4), after which the solvent was layered to obtain 7 -((2-chloro-4-pyridyl)methoxy)-b-methoxy-4-phenoxyquinazoline (26bOmg, 6695) as a solid.

IN NMR spectrum: (DMSOav) 4.00 (s, ZN); 5.45 (c, 2H); 7.30 (m, ZN); 7, 42 (c, 1H); 7.4-7.5 (m, ZN); 7.60 (c, 1H); 7.62 (c, 1H); 8.44 (d, 1H) 8.52 (c, 1H).

MO-E5I: 394 (МН

A mixture of 7-(2-chloro-4-pyridyl)methoxy-b-methoxy-4-phenoxyquinazoline (260mg, 0.1/mmol) and 2M hydrochloric acid! (15 ml) was heated at 857C for 2 hours. The mixture was allowed to cool and then brought to pH 6-7 with sodium bicarbonate solution. The resulting precipitate was collected by filtration and dried to obtain 7-(2-chloro-4-pyridyl)methoxy)-6-methoxy)-3,4-

dihydroquinazolin-4-one (16Omg, 7690).

IR NMR spectrum: (DMSOαb) 3.90 (s, ZN); 5.36 (c, 2H); 7.18 (c, 1H); 7.45 (m, 2H); 7.46 (s, 1H); 7.59 (c, 1H); 8.42 (d, 1H).

MO-E5I: 318 (МН

Example 59

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxy-quinazolyline (950 mg, Zmmol) (obtained as described for the starting material in Example 24), 2-bromo-4-bromomethylpyridine (765 mg , zmmol) and potassium carbonate (2.38g, 17mmol) in DMF (10ml) were heated at 80°C for 2 hours. The mixture was allowed to cool, poured into water and extracted with ethyl acetate. whereupon the solvent was evaporated and the residue was subjected to azeotropic distillation with toluene. 4-chloro-2-fluoroanilino)-6-methoxyquinazoline (647mg, 4495).

T. pl. 210-21276С

IR NMR spectrum: (DMSOα) 3.98 (s, ZN); 5.40 (c, 2H); 7.25 (s, 1H); 7.30 (d, 1H); 7.50 (c, 1H); 7.50 (d, 1H); 7.55 (m, 2H); 7.74 (c, 1H); 7.86 (s, 1H); 8.35 (sh.s, 1H); 8.42 (d, 1H); 9.56 (c, 1H).

MO-E5I: 48 9 |MNI"

Elemental analysis: C 520 3.2M 11.2 was found

C2iNi5MaO»2VgSIE requires C 51.5 H 3.1 M 11.49

The starting material was obtained as follows:

A mixture of 2-bromo-4-methylpyridine (12.2g), M-bromosuccinimide (30g) and 2,2'-azobis(2-methylpropionitrile) (100mg) in carbon tetrahydrochloride (200ml) was heated under reflux for 2.5 hours

The mixtures were allowed to cool and then the insoluble material was filtered off. The solvent was evaporated from the filtrate and the residue was purified by filtration through a layer of silica eluting with a mixture of ethyl acetate-hexane (10/1), resulting in 2-bromo-4-bromomethylpyridine

IR NMR spectrum: (DMSOαb) 4.65 (s, 2H); 7.50 (d, 1H); 7.42 (s, 1H); 7.70 (c, 1H); 8.35 (d, 1H)

MO-E5I: 250 (MN

Example 60

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazolyline (bOmg, 2mmol) (prepared as described for the starting material in Example 24), 4-chloromethyl-2-cyanopyridine hydrochloride (620mg,

Zmmol) and potassium carbonate (1.0g, 7mmol) in DMF (Zml) were heated at 80"C for 30 minutes. The mixture was allowed to cool, poured into water and extracted with ethyl acetate. The combined extracts were dried (Ma5O4), after which the solvent was evaporated and the residue was subjected to azeotropic distillation with toluene. The residue was triturated with a mixture of ethyl acetate-hexane and the solid product was filtered and purified by column chromatography eluting with ethyl acetate and additional chromatography with a methylene chloride-methanol mixture (99/1). The purified product was recrystallized from a mixture of ethyl acetate-hexane to obtain 4-(4-chloro-2-fluoroanilino)-7-((2-cyano-4-pyridyl)methoxy)-6-methoxyquinazoline (35mg, 490).

T. pl. 209-2137S

IR NMR spectrum: (DMSOαb) 3.98 (s, ZN); 5.44 (c, 2H); 7.26 (s, 1H); 7.34 (dd, 1H); 7.53 (dd, 1H); 7.58 (d, 1H); 7.80 (d, 1H); 7.85 (c, 1H); 8.27 (s, 1H); 8.95 (c, 1H); 8.80 (d, 1H); 9.60 (c, 1H)

MO-E5I: 436 |MNI"

Elemental analysis: C 60.3 H 3.4 M 16.1 was found

Сg2Ни5М5О»2СИЕ trebuett C 60.6 H 3.5 M 16.195

The starting material was obtained as follows:

Tetrabutylammonium fluoride (9 ml, 1 M solution in THF) was added to a solution of 2-cyano-4-dimethyl-tert-butylsilyloxymethylpyridine (1.4 g, 5.mmol) (U. Nei. Spet. 1993, 30, 631) in THF (15 ml) , 9 mmol) and the mixture was stirred for 2 hours at ambient temperature. Water was added and volatile substances were evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. United extract! dried (Md5O") and evaporated the solvent to obtain 2-cyano-4-hydroxymethylpyridine (0.55 g, 73905).

IR NMR spectrum: (DMSOαb) 4.65 (s, 2H); 5.70 (t, 1H); 7.70 (d, 1H); 7.95 (c, 1H); 8.75 (d, 1H).

A mixture of 2-cyano-4-hydroxymethylpyridine (0.51g, 3, 3mmol) and thionyl chloride (0.bml) in toluene (20ml) was stirred at room temperature for 1 hour. Volatile substances were evaporated and the residue subjected to azeotropic distillation with toluene, resulting in 4-chloromethyl-2-cyanopyridine hydrochloride (b62Omg, 8695).

IR NMR spectrum: (DMSOαb) 4.75 (s, 2H); 7.75 (dd, 1H); 8.05 (s, 1H); 8.34 (d, 1H).

Example 61

A mixture of 7-((b-chloro-2-oxo-1,2-dihydropyrid-4-yl)methoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (190 mg,

0.4 mmol), thionyl chloride (ml) and DMF (0.1 ml) were heated under reflux for 2 hours.

Volatile substances were evaporated and the residue subjected to azeotropic distillation with toluene. A solution of 4-chloro-2-fluoroaniline (1 mL) in isopropanol (15 mL) was added to the solid residue, and the mixture was heated under reflux for 3 hours. The mixture was allowed to cool and the precipitated product was collected by filtration, washed with isopropanol and dried to obtain 4-(4-chloro-2-fluoroanilino)-7-((b-chloro-2-oxo-1,2-dihydropyrid-4- yl)methoxy)-6-methoxyquinazoline hydrochloride (110mg, 4195).

T. pl. 271-273"C (expanded)

IN NMR spectrum: (DMSOdv) 4.08 (s, ZN); 5.35 (c, 2H); 6.70 (c, 1H); 7.00 (c, 1H); 7.30 (c, 1H); 7.40 (d, 1H); 7.60 (m, 2H); 8.30 (c, 1H); 8.75 (c, 1H).

MO-E5I: 461 NAMES"

The starting material was obtained as follows:

A mixture of 2,6-dichloro-4-hydroxymethylpyridine (1.72 g, ppm) and 4095 g of an aqueous solution of sodium hydroxide (5 ml) in methanol (50 ml) was heated under reflux for 24 hours. The mixture was allowed to cool and then the volatile substances were evaporated. The residue was extracted with ethyl acetate and the solvent was evaporated from the extracts. The residue was recrystallized from a ethyl acetate-hexane mixture to obtain 2-

chloro-4-hydroxymethyl-b6-methoxypyridine (490 mg, 2895).

IR NMR spectrum: (DMSOαb) 3.80 (s, ZN); 4.45 (d, 2H); 5.45 (t, 1H); 6.70 (c, 1H); 6.98 (s, 1H)

To a solution of 2-chloro-4-hydroxymethyl-b-methoxypyridine (0.9g, 5.2mmol) in toluene (10ml) was added thionyl chloride (1.0ml) and the mixture was stirred at ambient temperature for 1 hour.

Volatile substances were evaporated and the residue was subjected to azeotropic distillation with toluene and dried under vacuum to obtain 2-chloro-4-chloromethyl-b-methoxypyridine hydrochloride (0.88 g, 74905).

IR NMR spectrum: (DMSOαb) 3.85 (s, ZN); 4.70 (c, 2H); 6.90 (c, 1H); 7.15 (s, 1H)

A mixture of 7-hydroxy-b-methoxy-4-phenoxyquinazoline (1.1 g, 4.1 mmol) (obtained as described for the starting material in Example 13), 2-chloro-4-chloromethyl-b-methoxypyridine hydrochloride (0.88 g , C3.9mmol) and potassium carbonate (2.0g, 14mmol) in DMF (20ml) were heated at 80°C for 1 hour. The mixture was allowed to cool and the precipitated product was collected by filtration, washed with water and dried to obtain 7- ((2-chloro-6-methoxy-4-pyridyl)methoxy)-6-methoxy-4-phenoxyquinazoline (1.38g, 7995).

IN NMR spectrum: (SOSIz) 3.95 (s, ZN); 4.04 (c, ZN); 5.20 (c, 2H); 6.70 (0.1H); 6.95 (c, 1H); 7.18 (m, ZN); 7.30 (t, 1H); 7.40 (t, 2H); 7.58 (s, 1H); 8.52 (c, 1H).

MO-E5I: 424 (МН

A mixture of 7-((2-chloro-6-methoxy-4-pyridyl)methoxy b-methoxy-4-phenoxyquinazoline (400 mg, 0.95 mmol) and 2 M hydrochloric acid (20 mL) was heated under reflux for 3 hours. the mixture was cleaned, adjusted to pH 6-7 with an aqueous ammonia solution. The resulting precipitate was collected by filtration, washed with water and dried, resulting in crude 7-( )methoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (190mg, 6090).

Example 62

To a solution of 4-hydroxymethyl-2-methoxypyridine (0.59g, 4.2mmol) in toluene (100ml) was added thionyl chloride (0.bml) and the mixture was stirred at ambient temperature! within 1.5 hours.

Volatiles were evaporated and the residue was subjected to azeotropic distillation with toluene and dried under vacuum to obtain crude 4-chloromethyl-2-methoxypyridine hydrochloride (0.50 g, 2.mmol), which was used immediately. This product was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (420 mg, 1.3 mmol) (obtained as described for the starting material in Example 24) and potassium carbonate (1, 0g, 7mmol) in DMF (dml) and the resulting mixture was heated at 75"C for 2 hours. The mixture was cooled, washed with water, and the precipitated solid was collected by filtration, washed with water and dried, resulting in 4-( 4-chloro-2-fluoroanilino)-7-((2-methoxy-4-pyridyl)methoxy)-6-methoxyquinazoline (14Omg, 25965).

T. pl. 202-204"7C

IR NMR spectrum: (DMSOαb) 3.85 (s, ZN); 3.98 (c, ZN); 5.35 (c, 2H); 6.88 (c, 1H); 7.05 (d, 1H); 7.24 (s, 1H); 7.35 (dd, 1H); 7.54 (dd, 1H); 7.58 (t, 1H); 7.84 (s, 1H); 8.11 (d, 1H); 8.35 (s, 1H); 9.58 (sh.s, 1H).

MO-E5I: 441 (МН

Elemental analysis: found C 59.9 N 4.1 M 12.4

Sg2NivM«OzSIE requires C 59.9 H 41 M 12.79

The starting material was obtained as follows:

A mixture of 2-hydroxypyridine-4-carboxylate (1.0 g, mmol) (Spet. Abe. 1957, 8740 c), methyl iodide (ml) and silver carbonate (I) (1.64 g, in toluene (20 ml)) was heated under reflux in for 2 hours. The mixture was allowed to cool and then the insoluble material was removed by filtration through diatomaceous earth, after which its layer was washed with ethyl acetate. The filtrate was washed with water, dried (M95054) and then the solvent was evaporated to obtain ethyl 2-methoxypyridine-4-carboxylate (0. 93g, 86905) in the form of yellow oil.

IN NMR spectrum: (SOSIz) 1.30 (t, ZN); 3.90 (c, ZN); 4.30 (sq., 2H); 7.24 (s, 1H); 7.35 (d, 1H); 8.20 (d, 1H).

MO-E5I: 182 (МН

A mixture of acetyl 2-methoxypyridine-4-carboxylate (0.93g, 5mmol) in sulfur (5ml) was added to lithium aluminum hydride (0.3g, dmmol) in sulfur (100ml) cooled to 5°C, and the mixture was stirred for 2 hours. water, filtered through a mixture of diatomaceous earth and washed this layer with ethyl acetate. The filtrate was extracted with ethyl acetate and the combined extracts were washed with brine, dried (M95054) and then the solvent was evaporated to obtain 4-hydroxymethyl-2-methoxypyridine (0.64g, 8995) in the form yellow oil

IN NMR spectrum: (SOSIz) 3.86 (s, ZN); 4.62 (c, 2H); 6.65 (c, 1H); 6.76 (d, 1H); 8.05 (d, 1H).

MO-E5I: 140 (MN

Example 63

To a solution of 4-hydroxymethyl-2-methyllyridine (240 mg, 1.9 mmol) in toluene (100 ml) was added thionyl chloride (0.3 ml) and the mixture was stirred at ambient temperature! within 2 hours.

Volatile substances were evaporated, and the residue was subjected to azeotropic distillation with toluene and dried under vacuum to obtain crude 4-chloromethyl-2-methpyridine hydrochloride, which was used immediately. This product was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (510 mg, 1.6 mmol) (prepared as described for the starting material in Example 24) and potassium carbonate (1, 4 g, 10 mmol) in DMF (8 mL) for 90 hours. The mixture was diluted with water and the precipitated solid was collected by filtration, washed with water and dried, resulting in 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((2-methyl-4-pyridyl)methoxy )quinazoline (290 mg, 4395), a sample of which was recrystallized from a ethyl acetate-hexane mixture.

T. pl. 221-2247S

IN NMR spectrum: (SOSIv) 2.50 (s, ZN); 4.00 (c, ZN); 5.20 (c, 2H); 6.98 (c, 1H); 7.15 (d, 1H); 7.2 (m, 4H); 8.45 (m, 2H); 8.60 (c, 1H).

Elemental analysis: found C61,H4,2M 13.2

Sg2NiviMmaO»SIE trebuett C 62.2 H 4.3 M 13.295

The starting material was obtained as follows:

Oxalyl chloride (19g, 15mmol) was added to 2-chloro-6-methylpyridine-4-carboxylic acid (1.7g, 1b0mmol) in methylene chloride (30ml) and the mixture was stirred for 2 hours. Volatile substances were evaporated and methanol (20 ml) was added to the residue. The mixture was stirred for 1 hour and then the volatiles were layered to obtain methyl 2-chloro-6-methylpyridine-4-carboxylate (1.85 g, 10095) as an off-white solid.

IN NMR spectrum: (SOSIz) 2.55 (s, ZN); 3.90 (c, ZN); 7.55 (s, 1H); 7.60 (c, 1H).

MO-E5I: 186 MNI"

A mixture of methyl 2-chloro-β6-methylpyridine-4-carboxylate (1.89 g, 1 mmol) and 1095 palladium on activated carbon (200 mg) in methanol (100 ml) was stirred under hydrogen at a pressure of 5 atmospheres.

The catalyst was filtered off and volatile substances were evaporated from the filtrate. The residue was treated with 1095% aqueous sodium hydroxide solution and extracted with zephyr (3x30ml). Combined extract! dried (Md5O54) and the solvent was evaporated to give methyl 2-methylpyridine-4-carboxylate (80mg, 5390) as an oil.

A solution of methyl 2-methylpyridine-4-carboxylate (300 mg, mmol) in sulfur (5 mL) was added to lithium aluminum hydride (340 mg, mmol) in sulfur (100 mL) cooled to 5"C, and the mixture was stirred for 2 hours. Water was added, filtered through layer of diatomaceous earth and washed this layer with ethyl acetate.

The filtrate was extracted with ethyl acetate and the combined extracts! washed with brine, dried (Md5O4) and then the solvent was evaporated to give 4-hydroxymethyl-2-methylpyridine (240 mg, 3895) as a yellow oil.

IN NMR spectrum: (SOSIz) 2.48 (s, ZN); 5.44 (c, 2H); 7.00 (d, 1H); 7.10 (c, 1H); 8.40 (d, 1H).

MO-E5I: 124 (МН

Example 64

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350mg, 0.9mmol) (prepared as described for the starting material in Example 24), 2-(2-chloroethylthio)-1 -methylimidazole hydrochloride (203mg, 0.95mmol) and potassium carbonate (30mg, 2.2mmol) in MRM (20ml) were heated at 90°C for 2 hours. The mixture was allowed to dry, diluted with water and extracted with amyl acetate. The combined extract was washed with water and dried (M9504), after which the solvent was removed. -(1-methylimidazol-2-ylthio)zthoxy)quinazoline (75 mg, 1795) as a solid.

MO-E5I: 460 (MN

IN NMR spectrum: (DMSOv) 3.46 (s, ZN); 3.93 (c, ZN); 4.39-4 44 (m, AN); 7.13 (dd, 2H); 7.23 (s, 1H); 7.31 (dd, 1H); 7.49-7.60 (m, 2H); 7.79 (c, 1H); 8.37 (s, 1H); 9.51 (s, 1H)

Elemental analysis: C 52.8 N 4.0 M 14.3 was found

Si NioM5O2 STE 1H2O requires C 52.8 N 4.4 M 14.79

The starting material was obtained as follows:

To a solution of 2-mercapto-1-methylimidazole (3.45g, 30mmol) in a 2M aqueous solution of sodium hydroxide (30ml) was added 2-chlorozethanol (3g, 37mmol) and the mixture was heated at 100°C for 2 hours. The combined extract was dried (Mad5O4) and then the solvent was evaporated to give 2-(2-hydroxyethylthio)-1-methylimidazole (3.9g, 8290).

IN NMR spectrum: (DMSOZdv) 3.04 (t, 2H); 3.30 (c, ZN); 3.54 (t, 2H); 5.00 (c, 1H); 6.87 (s, 1H); 7.20 (s, 1H)

To a solution of 2-(2-hydroxyethylthio)-1-methylimidazole (1.81g, 11mmol) in trichloromethane (20ml) at 570 was slowly added thionyl chloride (1.41ml, 19mmol). The mixture was stirred for 1 hour at 5"C, and then for 3 hours at ambient temperature. Volatile substances were evaporated and the residue was subjected to azeotropic distillation with toluene, resulting in 2-(chloromethylthio)-1-methylimidazole hydrochloride (1.5 g, 7795).

IR NMR spectrum: (DMSOαb) 3.58 (t, 2H); 3.78 (c, ZN); 3.80 (t, 2H); 7.78 (d, 1H); 7.83 (d, 1H)

Example 65

To a solution of 1-(3-hydroxypropyl)-1,2-dihydro-2-pyridone (7700 mg, 5 mmol) in dichloromethane (15 ml) at 5 °C was added thionyl chloride (0.55 ml, 7.5 mmol). The mixture was stirred at 5 °C. C for 1 hour, and then at ambient temperature for 2 hours. Volatiles were layered and the residue was subjected to azeotropic distillation with toluene and dried under vacuum to obtain crude 1-(3-chloropropyl)-1,2-dihydro-2-pyridone (500 mg), which was used immediately. Part of this product (206 mg, 1.2 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b-methoxyquinazoline (3500 mg, 1.0 mmol) (obtained as described for the starting material in Example 24) and potassium carbonate (30 mg, 2.2 mmol) in MRM (20 ml) and the reaction mixture was heated at 90°C for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extract was washed with water and dried (M950: 5), after which the solvent was added. -(3-(2-oxo-1,2-dihydro-1-pyridyl)propoxy)quinazoline (194mg, 5095).

T. pl. 216-2187S

IN NMR spectrum: (DMSOZdv) 2.18 (m, 2H); 3.90 (c, ZN); 4.06 (t, 2H); 4.15 (t, 2H); 6.18 (t, 1H); 6.38 (d, 1H); 7.15 (c, 1H); 7.30-7.42 (m, 2H); 7.50-7.64 (m, ZN); 7.79 (c, 1H); 8.34 (c, ZN); 9.50 (c, 1H).

MO-E5I: 455 (МН

Elemental analysis: found C 59.4 H 4.6 M 12.1

SgziNhomMaOzSiE:0.5H2O requires C 59.6 H 4.6 M 12.195

The starting material was obtained as follows:

To a solution of 2-hydroxypyridine (2.35 g, 24 mmol) in DMF (50 ml) was added sodium hydride (1.31 g of 50905 suspension in mineral oil, 7 mmol) and the mixture was stirred for 30 minutes. 2-(3-bromopropoxy)tetrahydropyran (5.0 g, 22.5 mmol) was added (U.Spet. bos. 1963, 3440) and the mixture was heated at 100"C for 3 hours and then stirred at ambient temperature for 18 hours

The reaction mixture was diluted with water and extracted with ethyl acetate. Unification of extracts! washed with water and dried (M9504), after which the solvent was added. The residue was purified by column chromatography eluting with methylene chloride-methanol mixtures (from 100/0 to 97/3) and as a result 1-(3-(2-tetrahydropyranyloxy)propyl)-1,2-dihydro-2-pyridone (1, 6g, 30905).

IR NMR spectrum: (DMSOdv) 1.39-1.75 (m, 6H); 1.85 (m, 2H); 3.24-3.42 (m, ZN); 3.58-3.74 (m, 2H); 3.90 (t, 2H); 4.52 (s, 1H); 6.18 (t, 1H); 6.35 (d, 1H); 7.38 (dd, 1H); 7.60 (dd, 1H).

MO-EZ5I: 238 MNI and 2-(3-(2--tetrahydropyranyloxy)propyloxy)pyridine (1.43g, 27905).

IR NMR spectrum: (DMSOdv) 1.38-1.70 (m, 6H); 1.90 (m, 2H); 3.30 (m, ZN); 3.34-3.50 (m, 2H); 3.62-3.80 (m, 2H); 4.30 (t, 2H); 4.52 (s, 1H); 6.78 (d, 1H); 6.92 (dd, 1H); 7.64 (m, 1H); 8.15 (dd, 1H).

MO-EZ5I: 238 MNI"

A solution of 1-(3-(2-tetrahydropyranyloxy)propyl)-1,2-dihydro-2-pyridone (1.0g, 4.5mmol) in acetic acid (13ml), THF (4ml) and water (2ml) was heated at 50"C for 4 hours. Volatile substances were evaporated and the residue was subjected to azeotropic distillation with toluene, resulting in 1-(3-hydroxypropyl)-1,2-dihydro-2-pyridone (68Omg, 9995) as an off-white solid substance

IR NMR spectrum: (DMSOαb) 1.74 (m, 2H); 3.38 (m, 2H); 3.90 (t, 2H); 4.58 (c, 1H); 6.18 (dd, 1H); 6.38 (d, 1H); 7.38 (m, 1H); 7.60 (dd, 1H).

Example 66

To a solution of 2-(3-hydroxypropylthio)-1-methylimidazole (1.25g, 7.3mmol) in dichloromethane (25ml) at 570 was added thionyl chloride (0.80ml, 11mmol). The mixture was stirred at 5"C for 1 hour and then at ambient temperature for 2 hours. The volatiles were evaporated and the residue was subjected to azeotropic distillation with toluene and dried under vacuum to obtain crude 2-(3-chloropropylthio)-1-methylimidazole hydrochloride. (1.0 g), which was used immediately. A portion of this product (226 mg, 1.0 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b-methoxyquinazoline (35 mg, 1.0 mmol) (obtained as described for the starting material in Example 24) and potassium carbonate (30 mg, 2.2 mmol) in MRM (20 ml) and the reaction mixture was heated at 907 C for 2 hours. The mixture was allowed to dry, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and dried (M9504), after which the solvent was evaporated. The residue was purified by column chromatography eluting with methylene chloride-methanol mixtures (from 100/0 to 95/5) to give 4-(4-chloro-2- fluoroanilino)-b-methoxy-7-(3-(1-methylimidazol-2-ylthio) )propoxy)quinazoline (29 mg, boron).

T. pl. 199-2017C

IR NMR spectrum: (DMSOv) 2.22 (m, 2H); 3.44 (c, ZN); 3.94 (c, ZN); 4.10 (14.4H); 7.10 (d, 2H); 7.30 (dd, 1H); 7.50-7.60 (m, 2H); 7.79 (c, 1H); 8.34 (s, 1H); 9.50 (c, 1H).

MO-E5I: 474 (МН

Elemental analysis: found C 50.934.8 M 13.2

Сг2Най М5О»2 СИ 5:2.5Н20 requires С 50.9 Н 5.1 М 13.59

The starting material was obtained as follows:

To a solution of 2-mercapto-1-methylimidazole (2.26 g, 19 mmol) in DMF (100 ml) was added sodium hydride (0.95 g of 5095 suspension in mineral oil, 20 mmol) and the mixture was stirred for 30 minutes. 2-(3-bromopropoxy)tetrahydropyran (5.0 g, 22.5 mmol) was added (U.Spet. bos. 1963, 3440) and the mixture was heated at 100"C for 3 hours and then stirred at ambient temperature for 18 hours

The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extract was washed with water and dried (M9504), after which the solvent was evaporated. The residue was purified by column chromatography eluting with mixtures of methylene chloride-methanol (from 100/0 to 97/3) and as a result 1-methyl-2-(3-(2-t-tetrahydropyranyloxy)propylthio)imidazole (2.5g, 5590 ).

IR NMR spectrum: (DMSOαb) 1.38-1.72 (m, 6Н); 1.80 (m, 2H); 3.0 (t, 2H); 3.36-3.43 (m, 2H); 3.58 (c, ZN); 3.62-3.78 (m, 2H); 4.50 (c, 1H); 6.90 (c, 1H); 7.21 (c, 1H).

A solution of 1-methyl-2-(3-(2-tetrahydropyranyloxy)propylthio)-1-imidazole (2.0g, 7.dmol) in acetic acid (dml), THF (4ml) and water (2ml) was heated at 50 C for 4 hours.Volatiles were evaporated and the residue was subjected to azeotropic distillation with toluene, resulting in 2-(3-hydroxypropylthio)-1-methylimidazole (1.3g, 10095) as an off-white solid.

IN NMR spectrum: (DMSOZdv) 1.68 (m, 2H); 2.98 (t, 2H); 3.42 (t, 2H); 3.57 (c, ZN); 4.10 (c, 1H); 6.90 (d, 1H); 7.20 (d, 1H).

Example 67

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol) (prepared as described for the starting material in Example 24), 4-(3-chloropropoxy)pyridine hydrochloride ( 206 mg, 1.10 mmol) and potassium carbonate (30 mg, 2.2 mmol) in MRM (20 ml) were heated at 90°C for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extract was washed with water and dried ( M95O4), after which the solvent was evaporated. The residue was purified by column chromatography eluting with mixtures of methylene chloride-methanol (from 100/0 to 95/5) to obtain 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-( 3-(4-pyridyloxy)propoxy)quinazoline (257 mg, 5695).

T. pl. 138-140 "S

IN NMR spectrum: (DMSOZdv) 2.25 (m, 2H); 3.92 (c, ZN); 4.24 (t, 2H); 4.30 (t, 2H); 6.98 (dd, 2H); 7.20 (s, 1H); 7.31 (dd, 1H); 7.55 (dd, 2H); 7.79 (c, 1H); 8.32-8.38 (m, ZN); 9.50 (c, 1H).

MO-E5I: 455 (МН

Elemental analysis: C 58.4 H 4.7 M 11.8 was found

SgziNgomaOzSIE-1H2O requires C 58.4 N 4.7 M 11.895

The starting material was obtained as follows:

A mixture of 4-chloropyridine (7g, 47mmol), ethylene glycol (17.9g, 235mmol) and sodium hydroxide (4.67g, 195mmol) in DMSO (80ml) was heated at 100°C for 24 hours. Most of the solvent was decanted and the residue was diluted with ice water. The aqueous mixture was extracted with acetyl acetate, the extracts were combined, dried (M95O4) and then the solvent was layered. The residue was purified by column chromatography eluting with methylene chloride-methanol mixtures (from 100/0 to 97/3) to give 4-(3-hydroxypropoxy)pyridine (3.2g, 45905).

To a solution of 4-(3-hydroxypropoxy)pyridine (3.1 g, 20 mmol) in trichloromethane (40 ml) at 5 °C was slowly added thionyl chloride (2.2 ml, 30 mmol). The mixture was stirred for 1 hour at 5 °C, and then for 2 hours at ambient temperature. The volatiles were evaporated, and the residue was subjected to azeotropic distillation with toluene and dried under vacuum, resulting in 4-(3-chloropropoxy)pyridine hydrochloride (3.81 g, 9195) as a solid.

IR NMR spectrum: (DMSOαb) 2.22 (m, 2H); 3.80 (t, 2H); 4.42 (t, 2H); 7.55 (d, 2H); 8.72 (d, 2H).

MO-E5I: 172 (MNE

Example 68

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol) (prepared as described for the starting material in Example 24), 4-(2-chloroethylthio)pyridine hydrochloride ( 252mgH, 1.2mmol) and potassium carbonate (454mg, 3.3mmol) in MRM (30ml) were heated at 90"C for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extract was washed with water and dried ( M95O4), after which the solvent was evaporated. The residue was purified by column chromatography eluting with ethyl acetate-methanol mixtures (from 100/0 to 75/25) to obtain 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-( 2-(4-pyridylthio)zthoxy)quinazoline (1Zmg, 3905).

T. pl. 182-1867S

IR NMR spectrum: (DMSOαb) 3.58 (t, 2H); 3.90 (c, ZN); 4.40 (t, 2H); 7.20 (s, 1H); 7.32 (d, 1H); 7.40 (d, 2H); 7.50-7.60 (m, 2H); 7.80 (c, 1H); 8.32 (s, 1H); 8.38 (d, 2H); 9.57 (c, 1H).

MO-E5I: 457 (МН

The starting material was obtained as follows:

Sodium hydride (890 mg of 50905 suspension in mineral oil, 19 mmol) was added to a solution of 4-mercaptopyridine (2.34 g, 21 mmol) in DMF (75 mL) and the mixture was stirred for 30 minutes. 2-(2-Bromothoxy)tetrahydropyran (4.0 g, 19 mmol) was added (U. At. Spet. os. 1948, 70, 4187) and the mixture was heated at 100"C for 3 hours and then stirred at ambient temperature! within 18 hours.

The reaction mixture was diluted with water and extracted with ethyl acetate. Unification of extracts! washed with water and dried (M9504), after which the solvent was added. The residue was purified by column chromatography eluting with mixtures of methylene chloride-methanol (from 100/0 to 97/3) and as a result 4-(2-tetrahydropyran-2-yloxy)zylthio)pyridine (2.8g, 56905) was obtained.

IN NMR spectrum: (DMSOdv) 1.35-1.64 (m, 6H); 3.35-3.42 (m, 1H); 3.58-3.82 (m, ZN); 4.60 (c, 1H); 7.30 (dd, 2H); 8.33 (dd, 2H).

A solution of 4-(2-tetrahydropyran-2-yloxy)zylthio)pyridine (2.73g, 11mmol) in acetic acid (8ml),

THF (4 ml) and water (2 ml) were heated at 50°C for 4 hours. Volatile substances were evaporated and the residue was subjected to azeotropic distillation with toluene, resulting in 4-(2-hydroxystilthio)pyridine (1.39 Hg, 7995) as off-white solid.

IR NMR spectrum: (DMSOαb) 3.10 (t, 2H); 3.60 (sq., 2H); 5.00 (t, 1H); 7.22 (d, 2H); 8.30 (d, 2H).

Thionyl chloride (0.98 ml, 13.5 mmol) was slowly added to a solution of 4-(2-hydroxyethylthio)pyridine (1.39 g, 9.0 mmol) in trichloromethane (25 ml) at 5 °C. The mixture was stirred for 1 hour at 5 °C. and then 2 hours at ambient temperature. The volatiles were evaporated, and the residue was subjected to azeotropic distillation with toluene and dried under vacuum to obtain 4-(2-chlorozylthio)pyridine hydrochloride (500 mg, 2 695) as a solid.

IN NMR spectrum: (DMSOαb) 3.65 (t, 2Н); 3.90 (t, 2H); 7.90 (d, 2H); 8.60 (d, 2H).

MO-E5I: 174 (МН

Example 69

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol) (prepared as described for the starting material in Example 24), 3-(2-chlorozthoxy)pyridine hydrochloride ( 234 mgH, 1.2 mmol) and potassium carbonate (456 mg, 3.0 mmol) in MRM (20 ml) were heated at 90"C for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extract was washed with water and dried ( M95O4), after which the solvent was evaporated. The residue was purified by column chromatography eluting with mixtures of methylene chloride-methanol (from 100/0 to 95/5) to obtain 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-( 2-(3-pyridyloxy)zthoxy)quinazoline (95mg, 2095).

T. pl. 188-19070

IR NMR spectrum: (DMSOαb) 3.90 (s, ZN); 4.45 (m, 4H); 7.24 (s, 1H); 7.18 (dd, 1H); 7.42-7.60 (m, ZN); 7.80 (c, 1H); 8.20 (d, 1H); 8.35 (c, 2H); 9.50 (c, 1H).

MO-E5I: 441 (МН

Elemental analysis; found C 55.0 N 3.9 M 11.8

Cg2NivMaozSTE:2NgO requires C 55.4 N 4.6 M 11.795

The starting material was obtained as follows:

Sodium hydride (1.02 g of 50905 suspension in mineral oil, 42 mmol) was added to a solution of 3-hydroxypyridine (2.01 g, 2 mmol) in DMF (50 ml) and the mixture was stirred for 30 minutes. 2-(2-Bromothoxy)tetrahydropyran (4.0 g, 19 mmol) was added (U. At. Spet. os. 1948, 70, 4187) and the mixture was heated at 100"C for 3 hours and then stirred at ambient temperature! within 18 hours.

The reaction mixture was diluted with water and extracted with ethyl acetate. Unification of extracts! washed with water and dried (M9504), after which the solvent was added. The residue was purified by column chromatography eluting with mixtures of methylene chloride-methanol (from 100/0 to 97/3) and as a result 3-(2-(tetrahydropyran-2-yloxy)zthoxy)pyridine (2.28g, 48965) was obtained.

IN NMR spectrum: (DMSOdv) 1.38-1.65 (m, 6H); 3.40 (m, 1); 3.65-3.79 (m, 2H); 3.85-3.95 (m, 1H); 4.20 (t, 2H); 4.62 (c, 1H); 7.30 (dd, 1H); 7.39 (dd, 1H); 8.15 (d, 1H); 8.29 (d, 1H).

MO-E5I: 224 (МН

A solution of 3-(2-tetrahydropyran-2-yloxy)zthoxy)pyridine (1.54g, 7mmol) in acetic acid (8ml), THF (4ml) and water (2ml) was heated at 50°C for 4 hours. The volatiles were evaporated substances and the residue were subjected to azeotropic distillation with toluene, resulting in 3-(2-hydroxyzthoxy)pyridine (82Omg, 8695) in the form of an off-white solid.

IN NMR spectrum: (DMSOdv) 3.70 (t, 2H); 4.05 (t, 2H); 4.85 (c, 1H); 7.25 (dd, 1H); 7.37 (dd, 1H); 8.10 (d, 1H); 8.24 (d, 1H).

MO-E5I: 140 (MN

Thionyl chloride (0.89 ml, 12 mmol) was slowly added to a solution of 3-(2-hydroxyzthoxy)pyridine (1.13 g, 8.0 mmol) in trichloromethane (20 ml) at 57C. The mixture was stirred at 5"C for 1 hour and then at ambient temperature for 2 hours. Volatile substances were evaporated and the residue was subjected to azeotropic distillation with toluene and dried under vacuum to obtain /3-(2-chlorozthoxy)pyridine hydrochloride ( Z0Omg, 1995) in the form of a solid substance.

IR NMR spectrum: (DMSOαb) 3.99 (t, 2H); 4.42 (t, 2H); 7.82 (dd, 1H); 8.05 (dd, 1H); 8.42 (d, 1H); 8.62 (s, 1H)

Example 70

To a solution of 7-benzyloxy-4-chloroquinazoline hydrochloride (307 mg, 1 mmol) in 2-pentanol (5 mL) was added 2-fluoro-5-hydroxy-4-methylaniline (170 mg, 1.3 mmol) (prepared as described for the starting material in example 13) and the mixture was stirred at 120"C for 2 hours. The mixture was allowed to cool and the resulting precipitate was collected by filtration, washed with isopropanol and sulfur, and dried under vacuum at 70"C to obtain //7-benzyloxy-4-(2 -fluoro-5-hydroxy-4-methylanilino)quinazoline hydrochloride (331mg, 8090).

IR NMR spectrum: (DMSOαb) 2.16 (s, ZN); 5.36 (c, 2H); 6.88 (d, 1H); 7.12 (d, 1H); 7.3-7.65 (m, 7H); 8.68 (d, 1H); 8.82 (s, 1H); 9.68 (c, 1H); 11.4 (s, 1H)

MO-E5I: 376 (MN

Elemental analysis: C63.7 H4.8 M 10.0 was found

Sg2NivMzO" in 1HC1 requires C 64.2 N 4.7 M 10.295

The starting material was obtained as follows:

Sodium (368 mg, 1 mmol) was added to benzyl alcohol (10 ml, 9 mmol) and the mixture was heated at 148"C for 30 minutes. 7-fluoro-3,4-dihydroquinazolin-4-one (656 mg, 4 mmol) was added (U. Spet See

Section B, 1967, 449) and the mixture was kept at 148"C for 24 hours. The reaction mixture was allowed to cool, poured into water (170 ml) and the aqueous mixture was adjusted to pH 3 with concentrated hydrochloric acid and acid. The precipitate was collected by filtration, washed with water and zephyr and dried under vacuum to obtain 7-benzyloxy-3,4-dihydroquinazolin-4-one (890 mg, 8995) as a white solid.

T. pl. 267-2697S

IR NMR spectrum: (DMSOiv; SEZSOOOB) 5.32 (s, 2H); 7.25 (d, 1H); 7.32-7.52 (m, 6H); 8.12 (d, 1H); 8.99 (c, 1H)

MO-E5I: 252 (МН

Elemental analysis: found C 71.434.9 M 10.7

Si5Ni2M2O2:0.04H2gO requires C 71.2 4.8 M 11.19

A mixture of 7-benzyloxy-3,4-dihydroquinazolin-4-one (800 mg, 3.17 mmol) and DMF (100 μL) in thionyl chloride (20 mL, 0.27 mmol) was heated under reflux for 3 hours. Excess thionyl chloride was removed by evaporation, and the residue was subjected to azeotropic distillation with toluene and dried under vacuum to obtain 7-benzyloxy-4-chloroquinazoline hydrochloride (8335 mg, 8690) as a cream-colored solid.

T. pl. 131-13276С

IN NMR spectrum: (DMSOdv; SEZSOOOB)) 5.32 (s, 2H); 7.29 (d, 1H); 7.34-7.52 (m, 6H); 8.12 (d, 1H); 9.03 (s, 1H)

MO-E5I: 270 (MN

Example 71

Using a procedure similar to that described in Example 70, 7-benzyloxy-4-chloroquinazoline hydrochloride (307 mg, 1 mmol) (prepared as described for the starting material in Example 70) was treated with 4-chloro-2-fluoro-5-hydroxyaniline ( 193 mg, 1.2 mmol) (ER 061741 A?2) to obtain 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)quinazoline hydrochloride (407 mg, 9490).

T. pl. 253-2577S

IR NMR spectrum: (DMSOαb) 5.37 (s, 2H); 7.16 (d, 1H); 7.32-7.5 (m, AN); 7.54 (s, 1H); 7.56 (d, 2H); 7.59 (dd, 1H); 8.73 (d, 1H); 8.86 (s, 1H); 10.63 (sh.s, 1H); 11.69 (sh.s, 1H)

MO-E5I: 396 MN"

Elemental analysis: found C 578338 9.7

C21Ni5MzO»2СIE:0.3НгО 1 NS requires С 57.6 Н 3.8 M 9.695

Example 72

Using a procedure similar to that described in Example 36, 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-β6-methoxyquinazoline hydrochloride (224 mg, 0.bmmol) (prepared as described for the starting material in Example 22) was treated with 4-bromomethyl-1,2-difluorobenzene (149 mg, 0.72 mmol) to obtain 7-(3,4-difluorobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)- 6-methoxyquinazoline hydrochloride (9Omg, 3195).

IR NMR spectrum: (DMSOαb) 2.17 (s, ZN); 4.0 (c, ZN); 5.33 (c, 2H); 6.88 (d, 1H); 7.11 (d, 1H); 7.38 (s, 1H); 7.41 (m, 1H); 7.55 (m, 1H); 7.62 (m, 1H); 8.17 (s, 1H); 8.75 (s, 1H); 9.68 (c, 1H); 11.15 (c, 1H)

MO-E5I: 442 (МН

Elemental analysis: C 58,034.3 M 8.7 was found

SgzNivMzOzEz:0.9HCI10.08 isopropanol requires C 58.3 H 4.1 M 8.890

Example 73

To a solution of 4-(4-chloro-5-diphenyl-tert-butylsilyloxy-2-fluoroanilino)-b-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazoline (207 mg, 0.3 mmol) in THF (5 ml), cooled at 5"C, tetrabutylammonium fluoride (5 ml of 1 M solution in THF, 0.62 mmol) was added, and the mixture was stirred for 1 hour at ambient temperature. Water was added and volatile substances were evaporated. The solid residue was dissolved in a methylene chloride-methanol mixture and added 5 M solution of hydrogen chloride in isopropanol (0.3 ml). The solvent was evaporated and the solid residue was resuspended in silica, collected by filtration, washed with silica and dried under vacuum to obtain 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6b- methoxy-7-(1-methylimidazol-2-yl)methoxy)quinazoline hydrochloride (99mg, 6390).

IN NMR spectrum: (DMSOZdv) 3.93 (s, ZN); 4.01 (c, ZN); 5.67 (c, 2H); 7.16 (d, 1H); 7.52 (d, 1H); 7.58 (s, 1H); 7.70 (c, 1H); 7.78 (c, 1H); 8.31 (c, 1H); 8.8 (c, 1H); 10.58 (s, 1H); 11.35 (sh.s, 1H)

MO-E5I: 430 (MN

Elemental analysis: C 45.8 H 4.3 M 12.9 was found

SgoNi?7M5OzSIE-1,4H20.2NSY trebuett C 45.5 H 4.2 M 13.395

The starting material was obtained as follows:

To a solution of 4-(4-chloro-5-diphenyl-tert-butylsilyloxy-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (4000 mg, 0.7 mmol) (obtained as described for the starting material in Example 33), 2g-hydroxymethyl-1-methylimidazole (82 mg, 0.8 mmol) (U.Spet. Bob. 1927, 3128-3136) and triphenylphosphine (365 mg, 1.4 mmol) in methylene chloride (12 ml) cooled at 0"C were added distyl azodicarboxylate (219 μl, 1.44 mmol) was added dropwise. The mixture was stirred for 1 hour at ambient temperature, and 2-hydroxymethyl-1-methylimidazole (bZmg, 0.69 mmol), triphenylphosphine (91 mg, 0.34 mmol) and distyl azo dicarboxylate (54 μl, 0 .34 mmol). The mixture was stirred for 1 hour at ambient temperature and the solvent was evaporated. The residue was purified by column chromatography eluting with a mixture of methylene chloride-methanol (94/6) and as a result 4-(4-chloro-5-diphenyl-tert-butylsilyloxy) was obtained -2-fluoroanilino)-b-methoxy-7-(1-methylimidazol-2-yl)methoxy)quinazoline (116mg, 25965).

IN NMR spectrum: (SOSIz) 1.16 (s, ZN); 3.75 (c, ZN); 3.93 (c, ZN); 5.28 (s, 2H); 6.84 (s, 1H); 6.91 (s, 1H); 7.02 (c, 1H); 7.17 (d, 1H); 7.32-7.48 (m, 8H); 7.78 (2d, AN); 8.08 (s, 1H); 8.18 (d, 1H)

Example 74

A mixture of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxyquinazoline hydrochloride (40O0mg, 0.98mmol), 2-chloromethyl-1-methylimidazole hydrochloride (210mg, 1.25mmol), potassium carbonate (580mg, 4, 2mol) and potassium iodide (17mg, O0.immol) in DMF (20ml) were stirred at 65°C for 4.5 hours and then at ambient temperature for 17 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (М950О4:4) and the solvent was layered from it. The solid residue was purified by column chromatography eluting with a mixture of methylene chloride-methanol (97/3), which gave a yellow solid (258g). the substance was dissolved in methanol (5 ml) and a 1 M aqueous solution of sodium hydroxide (bbOcl, 0.6 mmol) was added. The mixture was stirred for 15 minutes, water was added, and the mixture was adjusted to pH 7 with concentrated hydrochloric acid. The aqueous mixture was extracted with ethyl acetate and combined organic the extract was washed with water and brine and dried (Md5Oa), after which the solvent was evaporated. The residue was purified by flash chromatography eluting with a mixture of methylene chloride and methanol (95/5). The purified solid product was dissolved in methanol and a methanol solution of hydrogen chloride (1.5 ml of a 7.5 M solution) was added. Volatile substances were evaporated and the solid residue was suspended in pentane, collected by filtration, washed with pentane and dried under vacuum, resulting in 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(1-methylimidazol-2-yl) )methoxy)quinazoline hydrochloride (105mg, 4490).

IR NMR spectrum: (DMSOαb) 2.16 (s, ZN); 3.92 (c, ZN); 5.71 (c, 2H); 6.90 (d, 1H); 7.1 (d, 1H); 7.52 (d, 1H); 7.64 (d, 1H); 7.71 (c, 1H); 7.78 (c, 1H); 8.77 (d, 1H); 8.82 (s, 1H); 9.7 (sh.s, 1H); 11.45 (sh.s, 1H)

MO-E5I: 380 (MN

Elemental analysis: found C 52.2 H 5.0 M 15.1

SgoNivim5O»2:0.9Н20-1.8НСЙII trebuet C 52.1 N 4.7 M 15.295

The starting material was obtained as follows:

Sodium (368 mg, 1 mmol) was added to benzyl alcohol (10 ml, 9 mmol) and the mixture was heated at 14870 for 30 minutes. 7-fluoro-3,4-dihydroquinazolin-4-one (656 mg, 4 mmol) was added (U. Spet. 5os., section

B, 1967, 449) and the mixture was kept at 148"C for 24 hours. The reaction mixture was allowed to dry, poured into water (1700 ml) and the aqueous mixture was adjusted to pH with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water and then zephyr and dried under vacuum to give 7-benzyloxy-3,4-dihydroquinazolin-4-one (890 mg, 8995) as a white solid.

T. pl. 267-2697S

IN NMR spectrum: (DMSOdv; SEZSOOOB)) 5.32 (s, 2H); 7.25 (d, 1H); 7.32-7.52 (m, 6H); 8.12 (d, 1H); 8.99 (c, 1H)

MO-E5I: 252 (МН

Elemental analysis: found C 71.434.9 M 10.7

Si5Ni2M2O»:0.04Н2О requires С71.2Н4.8 M 11195

A mixture of 7-benzyloxy-3,4-dihydroquinazolin-4-one (800 mg, 3.17 mmol) and DMF (100 μL) in thionyl chloride (20 mL, 0.27 mmol) was heated under reflux for 3 hours. Excess thionyl chloride was removed by evaporation, and the residue was subjected to azeotropic distillation with toluene and dried under vacuum to obtain 7-benzyloxy-4-chloroquinazoline hydrochloride (835 mg, 86905) as a cream-colored solid.

T. pl. 131-13276С

IN NMR spectrum: (DMSOdv; SEZSOOOB)) 5.32 (s, 2H); 7.29 (d, 1H); 7.34-7.52 (m, 6H); 8.12 (d, 1H); 9.03 (s, 1H)

MO-E5I: 270 (MN

To a solution of 7-benzyloxy-4-chloroquinazoline hydrochloride (1g, 3.7mmol) in pentanol (15ml) at 12070 was added 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (883mg, 44mmol) (obtained as described for the starting material in example 12) and the mixture was heated under reflux for 4 hours.

The mixture was allowed to cool and the resulting precipitate was collected by filtration, washed with isopropanol and then with ether and dried under vacuum to obtain 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (1.65 g, 9795) in the form cream-colored solid.

T. pl. 219-2207S

IN NMR spectrum: (DMSOZdv) 2.22 (s, ZN); 3.86 (c, ZN); 5.37 (c, 2H); 7.30-7.60 (m, 9H); 8.60 (d, 1H); 8.80 (s, 1H); 11.2 (s, 1H)

MO-E5I: 434 (МН

Elemental analysis; found C 60.1 H 4.9 M 8.5

SgaNgoMzO 1 HCI-0.5H2O trebuet C 60.2 H 4.6 M 8.890 7-Benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (1.53 Gg, 3.25 mmol) and 1095 palladium on activated carbon (1830mg) in a mixture of methanol (/5ml), DMF (bml) and trichloromethane (30ml) was stirred under hydrogen at a pressure of 1.5 atmospheres! within 45 minutes.

The catalyst was filtered through diatomaceous earth and the solvent was evaporated from the filtrate.

The residue was triturated with zephyr, collected by filtration and dried under vacuum to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxyquinazoline hydrochloride (1.23g, 8495) as an orange solid.

T. pl. 205-2107С

IR NMR spectrum: (DMSOαb) 2.22 (s, ZN); 3.85 (c, ZN); 7.24 (d, 1H); 7.35 (dd, 1H); 7.42 (d, 1H); 7.45 (d, 1H); 8.58 (d, 1H); 8.81 (s, 1H); 11.40 (c, 1H); 11.76 (s, 1H)

MO-E5I: 344 (МН

Example 75

K suspensions of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (261 mg, 0.7 mmol) (obtained as described for the starting material in Example 22), triphenylphosphine (367 mg, 1.4 mmol) and 2-(1,2,4-triazol-1-yl)ztanol (95 mg, 0.84 mmol) (App. RIagt. Rg. 1977, 35, 503-508) in methylene chloride (5 ml) were added dropwise distylazodicarboxylate (244 mg, 1.4 mmol). The mixture was stirred for 1 hour at ambient temperature, and triphenylphosphine (184 mg, 0.7 mmol), 2-(1,2,4-triazol-1-yl)ztanol (bZmg, 0.5 mmol) and distylazodicarboxylate (122 mg, 0, 7 mmol). The mixture was stirred for another 2.5 hours and the solvent was evaporated. The residue was dissolved in methanol (5 ml) and a 2 M aqueous solution of sodium hydroxide (2 ml) was added. The mixture was stirred for 20 minutes and distributed between zephyr and water. The aqueous layer was acidified with 2M hydrochloric acid to pH 7, and the resulting precipitate was collected by filtration, washed with water and dried under vacuum. The resulting solid was dissolved in a methylene chloride-methanol mixture and a 5M solution of hydrogen chloride in isopropanol (0.5 ml) was added. Volatile substances were evaporated and the solid was resuspended in sapphire, filtered, washed with sapphire and dried under vacuum to obtain 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-(1,2,4-triazole) -1-yl)zoxy)quinazoline hydrochloride (180mg, 5695).

IN NMR spectrum: (DMSOZdv) 2.16 (s, ZN); 3.97 (c, ZN); 4.59 (t, 2H); 4.74 (t, 2H); 6.9 (d, 1H); 7.10 (d, 1H); 7.37 (c, 1H); 8.03 (c, 1H); 8.23 (s, 1H); 8.62 (s, 1H); 8.79 (c, 1H); 9.7 (sh.s, 1H); 11.4 (s, 1H)

MO-E5I: 411 (МН

Elemental analysis: C 53.2H4.8M 18.4 was found

SgonioMvOZE 0.1 H2HO-1.2NHII trebuett C 52.7 H 4.5 M 18.495

Example 76

To a solution of 4-(4-chloro-5-diphenyl-tert-butylsilyloxy-2-fluoroanilino)-6b-methoxy-7-((3-thienyl)methoxy)quinazoline (224mg, 0.33mmol) in THF (5ml), cooled at 5"C, tetrabutylammonium fluoride was added (bO3ml of a 1M solution in THF, 0.67 mmol). After stirring for 1 hour at ambient temperature, water was added. THF was evaporated. The precipitate was filtered off and dried by azeotropic distillation with ethanol. The solid was dissolved in a mixture of methylene chloride-methanol and added a 5M solution of hydrochloric acid in isopropanol. Volatile substances were evaporated. The residue was suspended in zephyr, collected by filtration, stirred with zephyr and dried under vacuum to obtain /4-(4-chloro-2-fluoro-5-hydroxyaniline )-6-methoxy-7-((3-thienyl)methoxy)quinazoline hydrochloride (132mg, 8590).

T. pl. 277-281"

IR NMR spectrum: (DMSOαb) 3.99 (s, ZN); 5.34 (c, 2H); 7.15 (d, 1H); 7.26 (d, 1H); 7.49 (s, 1H); 7.53 (d, 1H); 7.61 (m, 1H); 7.75 (c, 1H); 8.22 (c, 1H); 8.8 (c, 1H); 10.59 (s, 1H); 11.38 (sh.s, 1H)

MO-E5I: 432 (МН

Elemental analysis: C 51,033.5M 8.9 was found

SgoNi5MzOzSiie5:0.1H2O-1NSIIi trebuett C 51.1 H 3.5 M 8.995

The starting material was obtained as follows:

To a solution of 4-(4-chloro-5-diphenyl-tert-butylsilyloxy-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (4000 mg, 0.7 mmol) (obtained as described for the starting material in Example 33), To 3-thiophene methanol (119mg, Tmmol) and triphenylphosphine (456mg, 1.7mmol) in methylene chloride (12ml) cooled at 0"С, distylazodicarboxylate (274μl, 1.7mmol) was added dropwise. The mixture was stirred for 2 hours at ambient temperature, the solvent was evaporated and the residue was purified by column chromatography eluting with a mixture of methylene chloride and sulfur (95/5). -(4-chloro-5-diphenyl-tert-butylsilyloxy-2-fluoroanilino)-33-methoxy-7-((3-thienyl)methoxy)quinazoline (223mg, 4795).

IR NMR spectrum: (DMSOv) 1.09 (c, 9H); 3.85 (c, ZN); 5.23 (c, 2H); 7.04 (d, 1H); 7.21 (d, 1H); 7.25 (s, 1H); 7.4-7.5 (m, 6H); 7.58 (m, 2H); 7.62-7.75 (m, 6H); 8.1 (c, 1H); 9.22 (sh.s, 1H)

Example 77

To a solution of 4-(4-chloro-5-diphenyl-tert-butylsilyloxy-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (4000 mg, 0.7 mmol) (obtained as described for the starting material in Example 33), triphenylphosphine (456 mg, 1.7 mmol) and 2-(4-pyridyl)ztanol (128 mg, Tmmol) (2 pyg. Orepspei. Kpit. 1958, 28, 103-110) in methylene chloride (12 ml) cooled at 0"С, added distyl azodicarboxylate (274 μL, 1.7 mmol) was added dropwise. The mixture was stirred for 2 h at ambient temperature and the solvent was evaporated. The residue was purified by column chromatography eluting with methylene chloride-methanol (97/3) to give a white solid (416 mg). Part of this solid substance (390 mg) was dissolved in THF (bml), the solution was cooled to 0"C and tetrabutylammonium fluoride (1.1 ml of a 1M solution in THF, 1.1 mmol) was added, and the mixture was stirred for 2 hours at ambient temperature. Water was added, the solvent was evaporated, and the resulting precipitate was collected by filtration. The solid was dissolved in a methylene chloride-methanol mixture and a 5M solution of hydrogen chloride in isopropanol (0.5 ml) was added. The volatiles were evaporated and the solid was resuspended in isopropanol, collected by filtration, washed with isopropanol and sulfur, and dried under vacuum to obtain 4-(4-chloro-2-fluoro-5-hydroxyanilino)-

b-methoxy-7-(2-(4-pyridyl)zthoxy)quinazoline hydrochloride (123mg, 4295).

IR NMR spectrum: (DMSOiv; СозЗЗСОООО) 3.49 (t, 2Н); 3.99 (c, ZN); 4.6 (t, 2H); 7.16 (d, 1H); 7.41 (c, 1H); 7.51 (d, 1H); 8.05 (sh.s, 2H); 8.19 (c, 1H); 8.84 (s, 1H); 8.86 (sh.s, 2H)

MO-E5I: 441 (МН

Elemental analysis: found C 50.4 NN 4.7 M 10.0

Сг2НивиМаозСИЕ-1.1Н20-1.8НСЙИ0.23 isopropanol trebuet C 50.5 N 4.5 M 10.495

Example 78

Using a procedure similar to that described in Example 77, 4-(4-chloro-5-diphenyl-tert-butylsilyloxy-2-fluoroanilino)-7-hydroxy-β6-methoxyquinazoline (300 mg, 0.52 mmol) (obtained as as described for the starting material in example 33) was treated with 4-hydroxymethyl-2-methylthiazole (100 mg,

0.87 mmol) to obtain 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((2-methylthiazol-4-yl)methoxy)quinazoline hydrochloride (132 mg, 5290).

IN NMR spectrum: (DMSOZdv) 2.68 (s, ZN); 4.00 (c, ZN); 5.35 (c, 2H); 7.17 (d, 1H); 7.52 (d, 1H); 7.56 (c, 1H); 7.72 (s, 1H); 8.29 (s, 1H); 8.83 (s, 1H); 10.63 (sh.s, 1H); 11.58 (s, 1H)

MO-E5I: 447 |MNI"

Elemental analysis: found C48,233.7 M 11.2

SgonivMaozSiE5:0.6NgO-1 2NSII trebuett C 47.9 N 3.7 M 11.295

The starting material was obtained as follows:

A solution of 4-chloromethyl-2-methylthiazole (1.84 g, 1 mmol) in water (09 ml) and concentrated hydrochloric acid (2 ml) was heated under reflux for 20 hours. The mixture was cooled, adjusted to pH 5 with a 2M aqueous solution of sodium hydroxide, and extracted with ethyl acetate.

The organic extract was washed with water and brine and dried (M9504), after which the solvent was evaporated. the residue was purified by column chromatography eluting with a mixture of methylene chloride-methanol (97/3) and as a result 4-hydroxymethyl-2-methylthiazole (8000 mg, 5490) was obtained.

IN NMR spectrum: (SOSIz) 2.72 (s, ZN); 2.92 (sh.s, 1H); 4.73 (c, 2H); 7.03 (s, 1H)

Example 79

To a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.bmol) (obtained as described for the starting material in Example 24), 3-thiophene methanol (107 mg, 0. 93mmol) and triphenylphosphine (328mg, 1.2mmol) in methylene chloride (bml) cooled at 0°C, distylazodicarboxylate (197μl, 12mmol) was added dropwise. The mixture was stirred for 2 hours at ambient temperature and triphenylphosphine (157mg, 0 .57 mmol), 3-thiophene methanol (107 mg, 0.93 mmol) and distyl azodicarboxylate (98.5 μL, 0.5 mmol). The mixture was stirred for 2 hours at ambient temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and the solution was washed with water and brine and dried (Md5O»5), after which the solvent was evaporated. The residue was purified by column chromatography eluting with a mixture of methylene chloride-ethyl acetate (4/6). The resulting oil was dissolved in ether and a 5M solution of hydrogen chloride in isopropanol (ml) was added. The resulting precipitate was filtered, washed zf and dried under vacuum to obtain 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((3-thienyl)methoxy)quinazoline hydrochloride (59 mg 2090).

IN NMR spectrum: (DMSOZv) 3.99 (s, ZN); 5.34 (c, 2H); 7.25 (d, 1H); 7.43 (d, 1H); 7.45 (c, 1H); 7.58-7.63 (m, 2H); 7.7 (dd, 1H); 7.72 (dd, 1H); 8.17 (s, 1H); 8.78 (s, 1H)

MO-E5I: 416 (МН

Elemental analysis: found С 53.5Н 3.7 M 9.0

SgoNi5MzO» SI 5:0.95NSIII requires С 53.3 N 3.6 M 9.390

Example 80

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b6-methoxyquinazoline (250 mg, 0.78 mmol) (prepared as described for the starting material in Example 24), 2-acetamido-4-chloromethylthiazole (164 mg ,

0.8 mmol) and potassium carbonate (216 mg, 1.5 mmol) in DMF (5 ml) were stirred at 40°C for 7 hours.

The mixture was distributed between ethyl acetate and water, and the aqueous layer was adjusted to pH 7 with 2M hydrochloric acid. The organic phase was washed with water and brine and dried (Md5O54), after which the solvent was evaporated. The residue was purified by column chromatography eluting with a methylene chloride-methanol mixture (95/53. The purified solid was dissolved in a methylene chloride-methanol mixture and a 5M solution of hydrogen chloride in isopropanol (1.0 ml) was added. Volatile substances were evaporated to obtain a solid substance, which was triturated with , collected by filtration and dried under vacuum, resulting in 7-((2-acetamidothiazol-4-yl)methoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (96mg, 2490).

T. pl. 194-202"

IR NMR spectrum: (DMSOαb) 2.14 (s, ZN); 4.0 (c, ZN); 5.31 (c, 2H); 7.34 (c, 1H); 7.45 (dd, 1H); 7.52 (c, 1H); 7.60 (t, 1H); 7.68 (dd, 1H); 8.30 (c, 1H); 8.81 (s, 1H)

MO-E5I: 474 (МН

Elemental analysis: found C 46.93 3.8 M 13.2

С21Ни7М5озСИЕ5:1.1Н2О-1.1НСЙII trebuett С 47.3 Н 3.8 М 13.195

Example 81

To a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (30 mg, 0.93 mmol) (obtained as described for the starting material in Example 24), 2-(1,2,4 -triazol-1-yl)ztanol (159 mg, 1.4 mmol) (App. RPagt. g. 1977, 35, 503-508) and triphenylphosphine (492 mg, 1.8 mmol) in methylene chloride (100 ml) were added dropwise distylazodicarboxylate (295 μl , 1.9 mmol). The mixture was stirred for 2 hours at ambient temperature, and triphenylphosphine (246 mg, 0.9 mmol) and distylazodicarboxylate (147 μl, 0.9 mmol) were additionally added. The mixture was stirred for 1 hour at ambient temperature, and the resulting precipitate was collected by filtration, washed with methylene chloride and sulfur, and dried under vacuum. That is, the solid substance was suspended in a methylene chloride-methanol mixture and a 5M solution of hydrogen chloride in isopropanol (1.0 ml) was added. Volatile substances were evaporated and the residue was ground with zephyr. The resulting solid was filtered off, washed with zephyr and dried under vacuum to obtain 4-(4-chloro-2-

fluoroanilino)-6-methoxy-7-(2-(1,2,4-triazol-1-yl)zoxy)quinazoline hydrochloride (219mg, 52965).

T. pl. 169-174 "S

IN NMR spectrum: (DMSOZdv) 3.99 (s, ZN); 4.60 (t, 2H); 4.74 (t, 2H); 7.43 (d, 1H); 7.45 (c, 1H); 7.59 (t, 1H); 7.67 (dd, 1H); 8.06 (s, 1H); 8.41 (c, 1H); 8.68 (s, 1H); 8.83 (s, 1H)

MO-E5I: 415 (МН

Elemental analysis: C 47.0 N 4.3 M 16.5 was found

StieNivMeO2SiE-1.61H20-1HC1-:0.35 isopropanol trebuett C 47.0 N 4.4 M 164965

Example 82

To a solution of 1-(33-hydroxypropyl)-(1,2,4|griazole (119 mg, 0.9 mmol) (ER 0060696 At), 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b-methoxyquinazoline (200mg, 0.2mmol) (obtained as described for the starting material in Example 24) and triphenylphosphine (492mg, 1.9mmol) in methylene chloride (4ml) were added dropwise distylazodicarboxylate (295ml, 1.9mmol) and the mixture was stirred for 3 hours at ambient temperature. The mixture was purified by column chromatography eluting with a mixture of methylene chloride-acetonitrile-methanol (60/32/8). The purified product was triturated with a mixture of pentane and ether, collected by filtration and dried under vacuum to give a white solid. Solid was dissolved in a mixture of methylene chloride-methanol and a sulfur solution of hydrogen chloride was added (1 ml of a 5M solution). Volatile substances were evaporated. The solid residue was suspended in sulfur, collected by filtration, washed with sulfur and dried under vacuum to obtain 4-(4-chloro-2-fluoroanilino) -b-methoxy-7-(3-(1,2,4- triazol-1-yl)propoxy)quinazoline hydrochloride (121mg, 3990).

IR NMR spectrum: (DMSOav; SEZSOOO) 2.44 (t, 2H); 4.0 (c, ZN); 4.3 (t, 2H); 4.5 (t, 2H); 7.32 (s, 1H); 7.47 (dd, 1H); 7.62 (t, 1H); 7.70 (dd, 1H); 8.08 (s, 1H); 8.41 (c, 1H); 8.87 (s, 1H); 9.10 (0.1H)

MO-E5I: 429 (MN

Elemental analysis: found C 47.8 H 4.2 M 16.6

SgonivMvO» SI .0.21Н2О.-2НСЙII trebuett С 47.5 Н 4.1 М 16.69

Example 83

To a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (128 mg, 0.4 mmol) (obtained as described for the starting material in Example 24), triphenylphosphine (314 mg, 1.2 mmol) and 2-(M-methyl-M-(pyridazin-4-yl)amino)ztanol (8mg, 0.52mmol) in methylene chloride (5ml) was added dropwise distylazodicarboxylate (209μl, 1.2mmol) and the mixture was stirred for 2 hours at room temperature environment. The solvent was evaporated, the residue was triturated with zephyr, and the resulting solid was collected by filtration. The solid was purified by column chromatography eluting with mixtures of methylene chloride-methanol (9/1 and then 8/2) to obtain a white solid. That is, the solid substance was dissolved in a mixture of methylene chloride-methanol and an aqueous solution of hydrogen chloride (0.5 ml of a 4M solution) was added. Volatile substances were evaporated and the residue was triturated with ether, collected by filtration and dried under vacuum to obtain 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(M-methyl-M-(pyridazine-4) -yl)amino)ztoxy)quinazoline hydrochloride (11Omg, bo).

IR NMR spectrum: (DMSOαb) 3.11 (s, ZN); 3.89 (c, ZN); 3.94 (t, 2H); 4.37 (t, 2H); 6.85 (dd, 1H); 7.21 (c, 1H); 7.35 (dd, 1H); 7.55 (dd, 1H); 7.59 (t, 1H); 7.8 (c, 1H); 8.36 (c, 1H); 8.59 (d, 1H); 8.90 (d, 1H); 9.57 (s, 1H)

Elemental analysis: found C 47.2 H 4.6 M 14.7

Сг2НгоМеО2Сие-1,5Н20.2,15НСЙИ trebuet С 47.2 Н 4.5 M 15.09

The starting material was obtained as follows:

A solution of 4-bromo-3,6-dichloropyridazine (1.11 g, Zmmol) (U. Spet. bos, Reikip Tgapv I, 1974, 696) and 2-(methylamino)ztanol (0.75 g, 10 mmol) in isopropanol (10 ml ) was heated under reflux for 30 minutes. The solvent was evaporated, the residue was distributed between methylene chloride and water, and the aqueous layer was adjusted to pH 9 with solid potassium carbonate. The organic layer was separated, washed with brine and dried (Md5O»4), after which the solvent was evaporated. The residue was triturated with zephyr, collected by filtration and dried under vacuum to obtain 2-(M-(3,6-dichloropyridazin-4-yl)-M-methylamino)ztanol (1 g, 9090).

IN NMR spectrum: (SOCI3) 2.1 (sh.s, 1H); 3.09 (c, ZN); 3.71 (t, 2H); 3.93 (t, 2H); 6.8 (s, 1H)

MO-E5I: 221 (MN

A mixture of 2-(M-(3,6-dichloropyridazin-4-yl)-M-methylamino)ztanol (444mg, 2mmol) and 1095 palladium on activated carbon (150mg) in ztanol (15ml), methanol (5ml) and aqueous ammonia (15 ml) was stirred under hydrogen at a pressure of 3 atmospheres for 4 hours. The catalyst was filtered off and the solvent was evaporated from the filtrate. The residue was dissolved in methylene chloride, the insoluble material was filtered off, and the solvent was evaporated from the filtrate. The residue was purified by column chromatography on neutral aluminum oxide eluting with mixtures of methylene chloride-methanol (95/5, and then 90/10). The purified product was triturated with petroleum jelly and the solid product was collected by filtration and dried under vacuum to give 2-(M-methyl-M-(pyridazin-4-yl)-amino)ztanol (275 mg, 9195).

IN NMR spectrum: (SOSIz) 3.06 (s, ZN); 3.57 (t, 2H); 3.89 (t, 2H); 6.52 (dd, 1H); 8.48 (d, 1H); 8.54 (d, 1H)

MO-E5I: 153 (MN

Example 84

A 2M aqueous solution of hydroxide sodium (500 μl, 1.1 mmol) and the mixture was stirred for 1 hour at ambient temperature.The mixture was diluted with water and adjusted to pH 6 with 2M hydrochloric acid.

The resulting solid was filtered off, washed with water and dried under vacuum. The solid substance was dissolved in a methylene chloride-methanol mixture and an isopropanol solution of hydrogen chloride (0.7 ml of a 5M solution) was added. Volatile substances were evaporated and the solid residue was triturated with zephyr, collected by filtration, washed with zephyr and dried under vacuum to obtain 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-((4-pyridyl)carboxamido)quinazoline hydrochloride ( 241mg, 9395).

MO-E5I: 390 (MN

IN NMR spectrum: (DMSOie; SEZSOOO) 2.2 (s, ZN); 6.94 (d, 1H); 7.13 (d, 1H); 8.18 (d, 1H); 8.53 (d, 2H); 8.68 (s, 1H); 8.77 (d, 1H); 8.94 (c, 1H); 9.20 (d, 2H)

Elemental analysis: C 52.0 N 4.3 M 14.3 was found

SaiNivM5O»21.2Н20-1.95НСЙII trebuett C 52.3 N 4.3 M 145965

The starting material was obtained as follows:

A mixture of 7-nitro-3,4-dihydroquinazolin-4-one (U.Spet. os, 1950, 1104-1111) (5 g, 26 mmol) in thionyl chloride (50 ml) and DMF (ml) was heated under reflux for 1 5 hours.

Excess thionyl chloride was removed by evaporation, and the residue was subjected to azeotropic distillation with toluene. The residue was suspended in ether, collected by filtration and dried under vacuum to obtain 4-chloro-7-nitroquinazoline hydrochloride (6.4 g, 10090).

IR NMR spectrum: (DMSOαb) 8.26 (dd, 1Н); 8.36 (d, 1H); 8.40 (c, 1H); 8.42 (dd, 1H)

MO-E5I: 209 (MN

A solution of 4-chloro-7-nitroquinazoline hydrochloride (2.46 g, 1.0 mmol) and 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (2.2 g, 11 mmol) (prepared as described for the starting material in Example 12) in isopropanol ( 25ml) was heated at 50"C for 1 hour. The mixture was cooled and the precipitated solid was collected by filtration and recrystallized from a methylene chloride-methanol-isopropanol mixture to obtain 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino) -7- nitroquinazoline hydrochloride (1.8g, 4595) as a yellow solid.

IN NMR spectrum: (DMSOZdv) 2.21 (s, ZN); 3.86 (c, ZN); 7.40 (d, 1H); 7.46 (d, 1H); 8.49 (dd, 1H); 8.63 (c, 1H); 8.84 (s, 1H); 8.89 (d, 1H)

MO-E5I: 373 (МН

Elemental analysis: C 50.0 N 3.6 M 13.8 was found

Si7NiziMaO5E 1 NS trebuett C 50.0 H 3.5 M 13.795

A mixture of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-nitroquinazoline hydrochloride (5.3g, 133mmol) and 1095 palladium on activated carbon (1g) in ztanol (100ml), ztanol solution of hydrogen chloride (1.9ml 7M solution) and methanol (20 ml) were stirred under hydrogen at a pressure of 1.7 atmospheres for 75 minutes. The catalyst was filtered through diatomaceous earth, the filter layer was washed with methylene chloride, methanol, and sulfur, and the solvent was evaporated from the filtrate, resulting in 7-amino-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (4.8 g, 9795) as a yellow solid.

IR NMR spectrum: (DMSOαb) 2.22 (s, ZN); 3.87 (c, ZN); 6.77 (c, 1H); 7.08 (dd, 1H); 7.15 (m, 2H); 7.41 (m, 2H); 8.35 (d, 1H); 8.63 (c, 1H); 11.03 (s, 1H)

MO-E5I: 343 NAMES"

A solution of 7-amino-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (0.45g, 1.2mmol) and isonicotinoyl chloride hydrochloride (296mg, 1.6bmmol) in pyridine (15ml) was stirred for 2 hours at ambient temperature medium, and then 1 hour at 40°C. Additional isonicotinoyl chloride hydrochloride (84 mg, 0.4 mmol) was added and the mixture was stirred at 40°C for 2 hours.

Volatile substances were evaporated and the mixture was diluted with water. The aqueous mixture was adjusted to pH 7 and extracted with ethyl acetate. The combined extracts were washed with brine and dried (Ma5O»5), after which the solvent was evaporated. The residue was purified by flash chromatography eluting with methylene chloride-methanol mixtures (95/5, and then 92/8). The purified solid was triturated with zephyr, collected by filtration, washed with zephyr and dried under vacuum to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-((4-pyridyl)carboxamido)quinazoline (264 mg, 4990 ).

IN NMR spectrum: (DMSOdv) 2.19 (s, ZN); 3.86 (c, ZN); 7.31 (d, 1H); 7.45 (d, 1H); 7.92 (d, 2H); 7.98 (d, 1H); 8.31 (c, 1H); 8.43 (d, 1H); 8.47 (s, 1H); 8.83 (d, 2H); 9.78 (sh.s, 1H); 10.89 (sh.s, 1H)

Example 85

To a solution of 4-chloro-b-methoxy-7-(2-(M-methyl-M-(b-methyl-pyrimidin-4-yl)amino)zthoxy)quinazoline hydrochloride (140 mg, 0.35 mmol) in isopropanol (5 ml) 4-chloro-2-fluoroaniline (77 mg, 0.53 mmol) was added and the mixture was heated under reflux for 1 hour.

The solvent was evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with brine and dried (Md5Oy), after which the solvent was evaporated. The residue was purified by flash chromatography eluting with a methylene chloride-methanol (95/5) mixture. The purified solid substance was triturated in a mixture of methylene chloride-methanol and an aqueous solution of hydrogen chloride (1 ml of a 5M solution) was added. Volatile substances were evaporated and the residue was triturated with zephyr, collected by filtration, washed with zephyr and dried under vacuum to obtain /4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(M-methyl-M- (b-methylpyrimidin-4-yl)amino)zthoxy)quinazoline hydrochloride (75mg, 3990).

IR NMR spectrum: (DMSOdv; SEZSOOOB) 2.46 and 2.47 (2s, ZN); 3.35 and 3.42 (2s, ZN); 3.97 and 3.98 (2s, 3H); 42 (sh.s, 1H); 4.3 (sh.s, 1H); 4.5 (sh.s, 2H); 7.051 and 7.3 (2s, 1H); 7.4 and 7.5 (m, 2H); 7.62 (t, 1H); 7.7 (d, 1H); 8.25 (sh.s, 1H); 8.8 and 8.9 (2c, 2H)

MO-E5I: 469 (МН

The starting material was obtained as follows:

Sodium hydride (1, 44g of 6095 suspension in mineral oil, Zbmmol) and the mixture was stirred for 1.5 hours. Chloromethyl pivalate (5.65 g, 37.5 mmol) was added dropwise and the mixture was stirred for 2 hours at ambient temperature. The mixture was diluted with ethyl acetate (100 ml) and poured into water with ice (400 ml) and a 2 M solution of hydrochloric acid (4 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. United extract! washed with brine and dried (M950"), after which the solvent was evaporated. The residue was triturated with a mixture of kerosene and petroleum kerosene, and the solid was collected by filtration and dried under vacuum, resulting in 7-benzyloxy-b6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (10 g , 8490).

IN NMR spectrum: (DMSOdv) 1.11 (c, 9H); 3.89 (c, ZN); 5.3 (c, 2H); 5.9 (c, 2H); 7.27 (s, 1H); 7.35 (m, 1H); 7.47

(t, 2H); 7.49 (d, 2H); 7.51 (c, 1H); 8.34 (s, 1H)

A mixture of 7-benzyloxy-b-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (7g, 17.7mmol) and 1095 palladium on activated carbon (700mg) in ethyl acetate (250ml), DMF (50ml), methanol (50ml) and acetic acid (0.7ml) were stirred under hydrogen at atmospheric pressure for 40 minutes.

The catalyst was filtered off and the solvent was evaporated from the filtrate. The residue was triturated with zephyr, collected by filtration and dried under vacuum, resulting in 7-hydroxy-3-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (4.36g, 80905).

IR NMR spectrum: (DMSOαb) 1.1 (c, 9Н); 3.89 (c, ZN); 5.89 (c, 2H); 7.0 (c, 1H); 7.48 (s, 1H); 8.5 (s, 1H)

To the suspension / 7-hydroxy-b-methoxy-3-((pivaloyloxy)-methyl)-3,4-dihydroquinazolin-4-one (918mg,

zmmol), triphenylphosphine (1g, 3.9mmol) and 2-(M-methyl-M-(tert-butyl-carbonyl)amino)ztanol (682mg, 3.9mmol), obtained as described below, in methylene chloride (20ml ) was added dropwise distilazodicarboxylate (679 mg, 3.9 mmol) and the mixture was stirred for 1 hour at ambient temperature. Additional 2-(M-methyl-M-(tert-butylcarbonyl)amino)ztanol (105mg, 0.bmmol), triphenylphosphine (786mg, Zmmol) and distylazodicarboxylate (522mg, Zmmol) were added and the mixture was stirred for 30 minutes at ambient temperature. The mixture was concentrated to half the volume by evaporation and purified by column chromatography eluting with mixtures of methylene chloride and sulfur (from 7/3 to 1/1), which gave b-methoxy-7-(2-(M-methyl-M-(tert- butylcarbonyl)amino)zthoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.3g, 9890).

IN NMR spectrum: (SOCI3) 1.2 (c, 9H); 1.45 (c, 9H); 3.05 (sh.s., ZN); 3.72 (sh.s, 2H); 3.98 (c, ZN); 4.25 (sh.s, 2H); 5.95 (c, 2H); 7.1 (sh.s, 1H); 7.6 (c, 1H); 8.2 (s, 1H)

Solution //b-methoxy-7-(2-(M-methyl-M-(tert-butylcarbonyl)amino)zthoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1, 39g, Zmmol) in methylene chloride (4ml) and THF (4ml) were stirred at ambient temperature! within 1 hour. Toluene was added and volatile substances were evaporated.

The residue was triturated with zephyr and the resulting solid was collected by filtration. The solid was dissolved in water, sodium bicarbonate was added, and the aqueous mixture was extracted with methylene chloride. The organic extract was dried (Md5O5) and the solvent was evaporated. The residue was triturated with zephyr and the solid was collected by filtration, resulting in 6b-methoxy-7-(2-(methylamino)zthoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (800mg, 7390).

IN NMR spectrum: (DMSOdv; SEZSOOOB) 1.13 (s, 9Н); 2.72 (c, ZN); 3.45 (sh.s, 2H); 3.95 (c, ZN); 4.5 (t, 2H); 5.94 (c, 2H); 7.31 (c, 1H); 7.6 (c, 1H); 8.47 (s, 1H)

MO-E5I: 364 |MNI"

A solution of b-methoxy-7-(2-(methylamino)zthoxy)-3-(pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (3b3mg, 1mmol) and 4-chloro-6-methylpyrimidine (257mg, 2mmol) ) (U. Nei. Spet., 1969, 6, 879) in M,M-diisopropylethylamine (2 ml) was heated under reflux for 30 minutes. The volatiles were evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine and dried (Md50»4), after which the solvent was evaporated. The residue was purified by column chromatography eluting with a mixture of methylene chloride-methanol (95/5) and as a result b-methoxy-7-(2-(M-methyl-M-(b-methylpyrimidin-4-yl)amino)zthoxy)- 3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (Z3b5mg, 8090).

IN NMR spectrum: (SOSI") 1.19 (c, 9H); 2.36 (c, ZN); 3.18 (c, ZN); 3.95 (c, ZN); 4.09 (t, 2H); 4.34 (t, 2H); 5.9 (c, 2H); 6.3 (c, 1H); 7.14 (c, 1H); 7.63 (c, 1H); 8.17 (s, 1H); 8.5 (s, 1H)

MO-E5I: 456 (МН

Solution of β-methoxy-7-(2-(M-methyl-M-(β-methylpyrimidin-4-yl)amino)zthoxy)-3-((pivaloyloxy)methyl)-

3,4-dihydroquinazolin-4-one (3b5mg, O0.dmmol) in a methanolic ammonia solution (30ml of 3M solution) was stirred at ambient temperature! within 16 hours. Volatile substances were evaporated, the residue was triturated with zephyr, the solid was collected by filtration, washed with zephyr and dried under vacuum, resulting in b-methoxy-7-(2-(M-methyl-M-(b-methylpyrimidin-4-yl) amino)zthoxy)-3,4-dihydroquinazolin-4-one (250mg, 92905).

IN NMR spectrum: (DMSOiv; SEZSOOOB) 2.44 (s, ZN); 3.32 and 3.39 (2s, ZN); 3.86 and 3.87 (2s, ZN); 4.12 (t, 1H); 4.25 (t, 1H); 4.42 (m, 2H); 7.02 and 7.23 (2s, 1H); 7.24 (t, 1H); 7.50 (c, 1H); 8.55 and 8.8 (2m, 1H); 8.78 and 8.80 (2s, 1H)

MO-E5I: 342 (МН

A mixture of b-methoxy-7-(2-(M-methyl-M-(b-methylpyrimidin-4-yl)amino)zthoxy)-3,4-dihydroquinazolin-4-one (250mg, 0.73mmol) in thionyl chloride ( 5ml) and DMF (0.1ml) were heated under reflux for 1 hour. The mixture was diluted with toluene and volatile substances were evaporated. The residue was triturated with a mixture of methylene chloride and sulfur, and the solid was collected by filtration and dried under vacuum to give 4-chloro-b-methoxy-7-(2-(M-methyl-M-(b-methylpyrimidin-4-yl)-amino) )ztoxy)quinazoline hydrochloride (26Omg, 9090). 2-(M-methyl-M-(tert-butylcarbonyl)amino)ztanol was obtained as follows:

A solution of di-tert-butyldicarbonate (4.52g, 20mmol) in THF (10ml) was added to a solution of 2-(M-methylamino)ztanol (1.5g, 20mmol) in a mixture of water (1Oml) and THF (1Oml). The mixture was stirred at ambient temperature for 18 hours, THF was evaporated, and the aqueous residue was distributed between zephyr and water. The organic layer was washed with water and brine, dried (Ma5O") and evaporated to obtain 2-(M-methyl-M-(tert-butylcarbonyl)amino)ztanol (Zg, 85905).

IN NMR spectrum: (SOCI3) 1.46 (c, 9H); 2.92 (c, ZN); 3.39 (t, 2H); 3.75 (t, 2H)

MO-E5I: 176 (MN

Example 86

K / suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200mg, 0.6b2mmol) (obtained as described for the starting material in example 24), 2-(3,5- Dimethyl-/1,2,A|griazol-4-yl)ztanol (114mg, 0.8mmol) (ER 0329357 A1) and triphenylphosphine (492mg, 1.8mmol) in methylene chloride (4ml) were added dropwise distylazodicarboxylate (295μl, 1 .8 mmol) and the mixture was stirred for 1 hour at ambient temperature. The precipitated solid was collected by filtration, washed with zephyr and dried under vacuum. The solid substance was dissolved in a methylene chloride-methanol mixture and an aqueous solution of hydrogen chloride (2 ml of a 4.5 M solution) was added. Volatile substances were evaporated and the residue was suspended in zephyr, collected by filtration, washed with zephyr and dried under vacuum to obtain 4-(4-chloro-2-fluoroanilino)-7-(2-(3,5-dimethyl-|1,2, 4|-triazol-4-yl)ethoxy)-6-methoxyquinazoline hydrochloride (184mg, 5490).

IN NMR spectrum: (DMSOdv; SEZSOOOB) 2.78 (s, 6H); 4.03 (c, ZN); 4.57 (t, 2H); 4.75 (t, 2H); 7.37 (c, 1H); 7.46 (d, 1H); 7.64 (t, 1H); 7.66 (d, 1H); 8.31 (c, 1H); 8.87 (s, 1H)

MO-E5I: 443 (МН

Elemental analysis: C 48.0 N 4.6 M 16.1 were found

Сг21НгоМеО2 STE: 1Н2гО-1.85НСЙII trebuett С 47.7 Н 4.6 M 15.99

Example 87

To a solution of a mixture (75/25) of 2-(2,4-dimethylimidazol-1-yl)ztanol and 2-(2,5-dimethylimidazol-1-yl)ztanol (114mg, 0.8immol), 4-(4- chloro-2-fluoroanilino)-7-hydroxy-b-methoxyquinazoline (20mg, 0.2mmol) (obtained as described for the starting material in Example 24) and triphenylphosphine (492mg, 1.9mmol) in methylene chloride (4ml) were added dropwise distilazodicarboxylate (295 μl, 1.5 mmol) and the mixture was stirred for 4 hours at ambient temperature. Triphenylphosphine (49mg, 0.18mmol), a mixture of imidazolylstanols (26mg, 0.18mmol) and distylazodicarboxylate (29μl, 0.18mmol) were also added, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration, washed with methylene chloride and dried under vacuum. The solid substance was dissolved in a mixture of methylene chloride-methanol and an aqueous solution of hydrogen chloride (1.5 ml of a 4.5 M solution) was added. Volatile substances were evaporated and the solid residue was suspended in zephyr, collected by filtration, washed with zephyr and dried under vacuum to obtain a mixture (75/25) 4-(4-chloro-2-fluoroanilino)-7-(2-(2,4- dimethylimidazol-1-yl)zthoxy)-6-methoxyquinazoline hydrochloride and /4-(4-chloro-2-fluoroanilino)-7-(2-(2,5-dimethylimidazol-1-yl)zthoxy)-6-methoxyquinazoline hydrochloride (159 mg , 4890).

IN NMR spectrum: (DMSOdye; SEZSOOOB) 2.23 and 2.43 (2s, ZN); 2.73 and 2.76 (2s, ZN); 4.02 (c, ZN); 4.6 (sh.s, 2H); 4.6 and 4.75 (m, 2H); 7.3-7.5 (m, ZN); 7.61 (t, 1H); 7.68 (d, 1H); 8.24 (s, 1H); 8.88 (s, 1H)

MO-E5I: 442 (МН

Elemental analysis: found C 49.9 H 4.6 M 13.3

Сг2Най М5О»2СИЕ-1.1Н20-1.85НСИИ requires С 50.1 Н 4.8 М 13.39

The starting material was obtained as follows:

Distillazodicarboxylate (1.5g, 15.6mmol) was added portionwise to a suspension of sodium hydride (93bmg 6096 suspension in mineral oil, 23mmol) in DMF (8ml) and the mixture was stirred for 30 minutes at ambient temperature. 2-bromoethanol (1.6 bml, 23 mmol) was added and the mixture was stirred at 100°C for 16 hours. The solvent was evaporated and concentrated hydrochloric acid (ml) was added to the residue. The resulting solid was purified by column chromatography on neutral aluminum oxide eluting with methylene chloride-methanol (97/3) and then column chromatography with elution with mixtures of methylene chloride-methanol (93/7, and then 90/10) and as a result a mixture (75/25) of 2-(2,4-dimethylimidazole-1- yl)ztanol and 2-(2,5 dimethylimidazol-1-yl)ztanol (6500 mg, 2990).

MO-E5I: 140 (MN

Example 88

To a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (16mg, 0.5mmol) (obtained as described for the starting material in Example 24), triphenylphosphine (393mg, 1.5mmol) and 2-(3-pyridyl)ztanol (8 bmg, 0.7 mmol) (9. Negegosushi. Spet. 1992, 29, 1663) in methylene chloride (bml) was added dropwise distylazodicarboxylate (23 bml, 1.5 mmol) and the mixture was stirred for 4 hours at ambient temperature. The mixture was immediately filtered into a silica column and eluted with a mixture of methylene chloride-acetonitrile-methanol (60/35/5). The purified solid was dissolved in a mixture of methylene chloride-methanol and an aqueous solution of hydrogen chloride (1.5 ml of a 4.5 M solution) was added. Volatile substances were evaporated and the solid residue was suspended in sulfur, collected by filtration, washed with sulfur and dried under vacuum to obtain 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(3-pyridyl)zthoxy) quinazoline hydrochloride (154 mg, 5290).

IR NMR spectrum: (DMSOdv; SEZSOOO) 3.45 (t, 2Н); 4.01 (c, ZN); 4.56 (t, 2H); 7.44 (s, 1H); 7.46 (d, 1H); 7.61 (t, 1H); 7.67 (d, 1H); 8.13 (t, 1H); 8.19 (c, 1H); 8.71 (d, 1H); 8.88 (c, 1H); 8.9 (d, 1H); 9.01 (s, 1H)

MO-E5I: 425 (МН

Elemental analysis: C 52.7 H 4.3 was found

Сг2НивиМмаО» СИ 0.8НгО-1.8НСЙII trebuett С 52.3 Н 4.395

Example 89

To a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (16mg, 0.5mmol) (obtained as described for the starting material in Example 24), triphenylphosphine (393mg, 1.5mmol) and 2-(b-methyl-2-pyridyl)ztanol (96mg, 0.7mmol) (U.Spet. bos. A, 1971, 388) in methylene chloride (bml) was added dropwise distylazodicarboxylate (236μl, 1.5mmol) and the mixture was stirred for 16 hours at ambient temperature. The mixture was immediately filtered into a silica column and eluted with a mixture of methylene chloride-methanol (95/5). The purified solid was dissolved in a mixture of methylene chloride-methanol and a dilute solution of hydrogen chloride (1.5 ml of a 4.5 M solution) was added. The mixture was diluted with zephyr and the resulting precipitate was collected by filtration, washed with zephyr and dried under vacuum to obtain /4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(6-methyl-2-pyridyl)zthoxy ) of quinazoline hydrochloride (97 mg, 34905).

IN NMR spectrum: (DMSOiv; SEZSOOB) 2.78 (s, ZN); 3.64 (t, 2H); 3.98 (c, ZN); 4.67 (t, 2H); 7.46 (s, 1H); 7.48 (sh.s, 1H); 7.62 (t, 1H); 7.68 (dd, 1H); 7.85 (d, 1H); 7.94 (d, 1H); 8.19 (c, 1H); 8.48 (t, 1H); 8.88 (s, 1H)

MO-E5I: 439 (MN

Elemental analysis: found С 52.7 Н4.5М 10.7

SgziNhomMaO2 STE: 1 H2gO-1,6NSII trebuett C 52.9 H4.6 M 10.795

Example 90

A mixture of 4-chloro-7-(2-(imidazol-1-yl))zthoxy)-6-methoxyquinazoline (49 mg, 0.1 mmol) and 3-

hydroxyaniline (21 mg, 0.19 mmol) in isopropanol (3 ml) and an isopropanol solution of hydrogen chloride (O0.2 ml of a 5M solution) were stirred at 80°C for 1 hour. The precipitated solid was filtered off, washed with isopropanol and sulfur, and dried under vacuum with obtaining 4-(3-hydroxyanilino)-7-(2-(imidazol-1-yl)thoxy)-6-methoxyquinazoline hydrochloride (56 mg, 9390).

IN NMR spectrum: (DMSOdye; SEZSOOO) 4.01 (s, ZN); 4.64 (t, 2H); 4.78 (t, 2H); 6.71 (d, 1H); 7.1 (m, 2H); 7.28 (t, 1); 7.41 (c, 1H); 7.74 (c, 1H); 7.83 (s, 1H); 8.21 (c, 1H); 8.87 (s, 1H); 9.22 (s, 1H)

MO-E5I: 378 NAMES"

Elemental analysis: C 52.7 H 4.9 M 15.1 was found

SgoNioM5Oz:0.6NgO-1.85NSII requires C 52.7 H 4.9 M 15.49

The starting material was obtained as follows:

To the suspension / 7-hydroxy-b-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (612 mg, 2 mmol) (obtained as described for the starting material in example 85), 2- (imidazol-1-yl)ztanol (280 mg, 2.5 mmol) (U. Mea. Spet. 1993, 25, 4052-4060) and triphenylphosphine (655 mg, 2.5 mmol) in methylene chloride (1 Oml) at 5"C were added distilazodicarboxylate (435 mg, 2.5 mmol) dropwise. The mixture was stirred for 10 minutes at 5"C and then for 1 hour at ambient temperature. The mixture was immediately poured into a silica column and eluted with a methylene chloride-methanol (95/5) mixture to obtain )-3,4-dihydroquinazolin-4-one (64Omg, 8095).

IN NMR spectrum: (SOCI3) 1.19 (c, 9H); 3.98 (c, ZN); 4.34 (m, 2H); 4.45 (m, 2H); 5.94 (c, 2H); 7.02 (c, 1H); 7.07 (c, 1H); 7.11 (c, 1H); 7.64 (s, 1H); 7.67 (c, 1H); 8.17 (s, 1H)

MO-E5I: 423 |Mpayi!"

Elemental analysis: C 58.33 6.4 M 13.9 was found

SgoNgaMaO5:0.7NgO requires C 58.2 6.2 M 13.690

A solution of //7-(2-«(imidazol-1-yl)zthoxy)-b-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (640 mg, 1.6 mmol) in saturated methanol solution of ammonia (110 ml) was stirred for 15 hours at ambient temperature. Volatile substances were evaporated and the solid was triturated with zephyr, collected by filtration and dried under vacuum to obtain 7-(2-(imidazol-1-yl)zthoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (412mg, 9090).

IN NMR spectrum: (OMSOvv) 3.89 (s, ZN); 4.4-4.5 (m, 4H); 6.9 (c, 1H); 7.16 (c, 1H); 7.28 (c, 1H); 7.47 (s, 1H); 7.7 (c, 1H); 7.99 (c, 1H)

MO-E5I: 287 (МН

Elemental analysis: found C 57.8 H 5.2 M 19.3

CiaNiaMaOz:0.3H2gO requires C 57.7 N 5.1 M 192965

A mixture of 7-(2-«(imidazol-1-yl)zthoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (412mg, 1.44mmol), thionyl chloride (5ml) and DMF (0.2ml) was heated with a reverse refrigerator for 1 hour. The mixture was diluted with toluene and volatile substances were evaporated. The residue was suspended in methylene chloride, cooled to 0"C and an aqueous solution of sodium bicarbonate was added. The resulting precipitate was collected by filtration and dried under vacuum to obtain 4-chloro-7-(2-(imidazol-1-yl)zthoxy)-6- methoxyquinazoline (258 mg, 59965).

IN NMR spectrum: (OMSOvv) 4.01 (s, ZN); 4.47 (m, 2H); 4.53 (m, 2H); 6.89 (c, 1H); 7.27 (s, 1H); 7.41 (c, 1H); 7.49 (s, 1H); 7.70 (c, 1H); 8.88 (s, 1H)

MO-E5I: 327 |MMai"

Example 91

To a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (15 Ωg, 0.47 mmol) (obtained as described for the starting material in Example 24), 2-(1,2,4 -triazol-4-yl)ztanol (b4mg, 0.5bmmol) and triphenylphosphine (369mg, 1.4mmol) in methylene chloride (5ml) was added dropwise distylazodicarboxylate (220μl, 1.4mmol) and the mixture was stirred for 30 minutes at ambient temperature. 2-(1,2,4-triazol-4-yl)ztanol (1 mg, 0.14 mmol), triphenylphosphine (37 mg, 0.14 mmol) and distylazodicarboxylate (22 μl, 0.14 mmol) were also added, and the mixture was stirred for 1 hour at temperature environment. The precipitated solid was collected by filtration, washed with methylene chloride and dried under vacuum. The solid substance was dissolved in a methylene chloride-methanol mixture and sprinkled with an ether solution of hydrogen chloride (1.5 ml of a 2.2 M solution).

Volatile substances were layered and the solid residue was suspended in zephyr, collected by filtration, washed with zephyr and dried under vacuum to obtain 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1,2,4- triazol-4-yl)ztoxy)quinazoline hydrochloride (9Zmg, 4095).

IN NMR spectrum: (DMSOie; SEZSOOO) 4.02 (s, ZN); 4.66 (t, 2H); 4.85 (t, 2H); 7.41 (c, 1H); 7.46 (dd, 1H); 7.62 (t, 1H); 7.69 (dd, 1H); 8.11 (c, 1H); 8.89 (s, 1H); 9.55 (s, 2H)

MO-E5I: 415 (МН

Elemental analysis: C 45.9 H 3.7 M 171 was found

StieNivMeO" SI:0.5Н20.2НСЙ requires С 45.9 Н 3.9 M 16.995

The starting material was obtained as follows:

A solution of M,M-dimethylformamidazine (1g, 7mmol) (U.Spet. 5os. C, 1967, 1664), p-toluenesulfonic acid! (45 mg) and ethanolamine (4.3 g, 7 mmol) in benzene (15 ml) were heated under reflux for 8 hours. The mixture was filtered, the solvent was evaporated, and the residue was purified by column chromatography eluting with mixtures of methylene chloride-methanol (90/10, and then 85/15), resulting in 2-(1,2,4-triazol-4-yl)ztanol ( 328mg, 4190).

IN NMR spectrum: (SOCI3) 3.97 (t, 2H); 4.11 (t, 2H); 4.9 (sh.s, 1H); 8.06 (s, 2H)

MO-E5I: 113 (MN

Example 92

Co osmes / 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b-methoxyquinazoline (200mg, 0.63mmol), 3- benzyloxypropanol (150μl, 0.95mmol) and tributylphosphine (459μl, 1.9bmmol) 1,1--(azodicarbonyl)dipiperidine (480mg, 1.9mmol) was added in portions to methylene chloride (20ml) at 5°C. The reaction mixture was stirred for 1 hour at 5"C and then for 18 hours at ambient temperature. The mixture was diluted with zephyr and stirred for 15 minutes. The insoluble material was filtered off and the volatiles were separated from the filtrate. The residue was partitioned between ethyl acetate and water and the organic layer was separated and dried (M9504 ), after which the solvent was evaporated. A 1 M aqueous solution of hydrogen chloride was added to the residue, the volume of the resulting solution was reduced by layering, and the resulting precipitate was collected by filtration and dried to obtain 7-(3-benzyloxypropoxy)-4-(4-chloro-2-fluoroanilino) -6-methoxyquinazoline hydrochloride (9O0mg, 31905).

IN NMR spectrum: (SOCI3) 2.12 (t, 2H); 3.62 (t, 2H); 4.00 (t, ZN); 4.28 (t, 2H); 4, 45 (c, 2H); 7.21-7.38 (m, 6H); 7.42 (d, 1H); 7.60 (t, 1H); 7.64 (dd, 1H); 8.22 (c, 1H); 8.80 (s, 1H)

MO-E5I: 468 (МН

Example 93

K osmes /4-(4-chloro-2-fluoroanilino)-7-hydroxy-b6-methoxyquinazoline (315mg, mmol), 4-hydroxymethyl-2-pyridinecarboxylate (250mg, 1.4mmol) (U. Nei Spet. 1993 , 30, 631-635) and tributylphosphine (800 μl, Zmmol) in methylene chloride (500 ml) at 0"С, 1,1'-(azodicarbonyl)dipiperidine (840 mg, Zmmol) was added in portions. The mixture was allowed to warm to ambient temperature for 2 hour, the insoluble material was filtered off, and the filtrate was washed with water and brine and dried (Ma»25O4), after which the solvent was evaporated. The residue was purified by column chromatography eluting with methylene chloride-methanol mixtures (from 10/0 to 9/1). The purified product was recrystallized from mixture of methylene chloride-hexane to obtain 4-(4-chloro-2-fluoroanilino)-7-(2-zthoxycarbonylpyrid-4-yl)methoxy-b6-methoxyquinazoline (285 mg, 60905).

T. pl. 212-2147S

IN NMR spectrum: (DMSOdv) 1.30 (t, ZN); 3.96 (c, ZN); 4.35 (sq., 2H); 5.45 (c, 2H); 7.14 (c, 1H); 7.35 (dd, 1H); 7.5-7.6 (m, 2H); 7.85 (c, 1H); 8.15 (c, 1H); 8.35 (c, 1H); 8.75 (d, 1H); 9.55 (s, 1H)

Elemental analysis: found C 58.9 N 4.4 M 12.0

SgaNgoSie MaO4:0.5H20O trebuet C 58.7 H 4.4 M 11.595

Example 94

To a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (640mg, 2mmol), 4-hydroxymethyl-2-(methylamino)pyridine (385mg, 2.8mmol) and tributylphosphine (1.bml , mmol) in methylene chloride (50 ml) at 0"C, 1,1"-(azodicarbonyl)dipiperidine (1.68 g, mmol) was added in portions. Allow the mixture to warm up to ambient temperature! in 2 hours, insoluble material was filtered out! and the filtrate was washed with water and brine and dried (Ma250O4), after which the solvent was evaporated. The residue was purified by column chromatography eluting with methylene chloride-methanol mixtures (from 10/0 to 9/1).

The purified product was dissolved in an acetone-methanol mixture and a 1M aqueous solution of hydrogen chloride was added. The resulting precipitate was collected by filtration and dried to obtain 4-(4-chloro-2-fluoroanilino)-7-(2-(methylamino)pyrid-4-ylmethoxy-6-methoxyquinazoline hydrochloride (395 mg, 45905).

IR NMR spectrum: (DMSOαb) 2.95 (d, ZN); 4.05 (c, ZN); 5.42 (s, 2H); 6.90 (d, 1H); 7.15 (c, 1H); 7.40 (d, 1H); 7.44 (s, 1H); 7.58 (t, 1H); 7.62 (dd, 1H); 7.95 (d, 1H); 8.46 (s, 1H); 8.75 (s, 1H); 9.06 (sh.s, 1H); 11.83 (sh.s, 1H)

MO-E5I: 440 (MN

The starting material was obtained as follows:

A mixture of 2-chloro-4-hydroxymethylpyridine (1.0 g, mmol) (obtained as described for the starting material in Example 58) and methylamine (3095 mL of a solution in ethanol) was heated in a Carius tube for 16 hours at 200°C. The mixture was dried, partitioned between a saturated aqueous solution of sodium hydrogencarbonate and methyl acetate. The organic layer was separated and dried (M95O4), after which the volatile substances were layered in. The residue was purified by column chromatography eluting with ethyl acetate and as a result 4-hydroxymethyl-2-(methylamino ) pyridine (44Omg, 4695) in the form of yellow oil.

IR NMR spectrum: (DMSOαb) 2.72 (d, ZN); 4.35 (d, 2H); 5.15 (t, 1H); 6.30 (sh.d, 1H); 6.35 (d, 1H); 6.38 (s, 1H); 7.85 (d, 1H)

Example 95

To a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (640 mg, 2 mmol), 4-hydroxymethyl-2-(dimethylamino)pyridine (426 mg, 2.9 mmol) and tributylphosphine (1.6 ml , mmol) in methylene chloride (5 Oml) at 0"C, 1,1-(azodicarbonyl)dipiperidine (1.68 g, mmol) was added in portions. The mixture was allowed to warm to ambient temperature for 2 hours, the insoluble material was filtered off, and the filtrate was washed with water and brine and dried (Ma»5Oy), after which the solvent was evaporated. The residue was purified by column chromatography eluting with methylene chloride-methanol mixtures (from 100:0 to 95:53. The purified product was dissolved in an acetone-methanol mixture and a 1M aqueous solution of hydrogen chloride was added. The resulting precipitate was collected by filtration and dried to obtain 4-(4-chloro-2-fluoroanilino)-7-(2-(dimethylamino)pyrid-4-yl)umethoxy-6-methoxyquinazoline hydrochloride (305 mg, 30905).

T. pl. 29070

IN NMR spectrum: (DMSOZdv) 3.05 (s, 6H); 4.05 (c, ZN); 5.45 (c, 2H); 6.95 (d, 1H); 7.35 (c, 1H); 7.42 (dd, 1H); 7.56 (t, 2H); 7.62 (dd, 1H); 8.00 (d, 1H); 8.55 (s, 1H); 9.80 (c, 1H); 11.95 (sh.s, 1H)

MO-E5I: 454 (МН

Elemental analysis: found C 47.2 H 4.9 M 12.1

Sg2zNai SIEM5O»:ZNSI-NgO requires C 47.6 N 4.5 M 12.195

The starting material was obtained as follows:

A mixture of 2-chloro-4-hydroxymethylpyridine (1.0 g, 7 mmol) (obtained as described for the starting material in Example 58) and dimethylamine (3095 mL of a solution in ethanol) was heated in a Carius tube for 16 hours at 200°C. The mixture was cooled, distributed between a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate. The organic layer was separated and dried (Md5O4), after which the volatile substances were evaporated. The residue was purified by column chromatography eluting with ethyl acetate and as a result 4-hydroxymethyl-2-(dimethylamino )pyridine (g, 9495) in the form of yellow oil.

IN NMR spectrum: (DMSOαb) 3.00 (c, 6Н); 4.40 (d, 2H); 5.20 (t, 1H); 6.45 (d, 1H); 6.55 (c, 1H); 7.96 (d, 1H)

MO-E5I: 153 (MN

Example 96

A mixture of 4-(3-hydroxyprop-2-en-1-yl)pyridine (180 mg, 1.3 mmol) and thionyl chloride (0.3 mL) in toluene (1 mL) was stirred at room temperature for 2 hours. Volatiles were evaporated to give crude 4-(3-chloroprop-2-en-1-yl)pyridine hydrochloride (180 mg, 0.94 mmol). This product was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-b6-methoxyquinazoline (500 mg, 1.6 mmol) and potassium carbonate (500 mg, 4.9 mmol) in DMF (20 mL) and the mixture was stirred at 100"C for 1 hour. The reaction mixture was cooled, partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine and dried (Mod5Oa), after which the solvent was evaporated. The residue was purified by column chromatography eluting with methylene chloride-methanol mixtures (from 100/0 to 95/5), and then by reversed-phase (C18) VZLC with elution with methanol-water mixtures (from 30/70 to 50/50) and as a result obtained 4-(4-chloro-2- fluoroanilino)-b-methoxy-7-(3-(pyrid-4-yl)prop-2-en-1-yloxy)quinazoline (15 mg, 490).

IN NMR spectrum: (DMSOZdv) 4.00 (s, ZN); 5.05 (d, 2H); 6.93 (d, 1H); 7.11 (dt, 1H); 7.40 (c, 1H); 7.40-7.43 (m, 2H); 7.60 (t, 1H); 7.65 (d, 1H); 7.80 (m, 2H); 8.05 (s, 1H); 8.70 (sh.s, 2H)

MO-E5I: 437 (МН

The starting material was obtained as follows: n-butyllithium (25 ml of a 1.6 M solution in hexane, 40 mmol) was added dropwise to a stirred suspension of 2-hydroxy-ztyltriphenylphosphonium bromide (7.74 g, 20 mmol) in THF (5 Oml) at -70"C, giving the mixture was heated to -30"C and stirred for 2 hours. 4-pyridinecarboxaldehyde (2.16 g, 20 mmol) was added to the resulting red solution, the mixture was stirred for 1 hour at -307C and then cooled to -70"C. n-butyllithium (12.5 ml of a 1.6M solution in hexane, 20 mmol ) and the reaction mixture was stirred at -70"C for 1 hour. The mixture was quenched with isopropanol and allowed to warm to ambient temperatures." A saturated aqueous solution of ammonium chloride was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 5 mL).

The combined extract was washed with brine and dried (М95О4), after which the volatile substances were evaporated. The residue was purified by column chromatography eluted with ethyl acetate and the result was 4-(3-hydroxyprop-2-en-1-yl)pyridine.

MO-E5I: 136 (MN

Example 97

A suspension of 4-chloro-7-(2-(1,2,4-triazol-1-yl)zthoxy)-6-methoxyquinazoline (214mg, 0.7mmol), 4-bromo-2-fluoroaniline (16b0mg, 0.84mmol ) in an isopropanol solution of hydrogen chloride (ml of a 5M solution) and isopropanol (5 ml) were heated at 80°C for 1 hour. bromo-2-fluoroanilino)-7-(2-(1,2,4-triazol-1-yl)zoxy)-6-methoxyquinazoline hydrochloride (55 mg, 1590).

IN NMR spectrum: (DMSOdv) 3.99 (s, ZN); 4.62 (t, 2H); 4.75 (t, 2H); 7.37 (c, 1H); 7.5-7.7 (m, 2H); 7.81 (d, 1H); 8.04 (s, 1H); 8.24 (s, 1H); 8.63 (c, 1H); 8.84 (s, 1H); 11.52 (s, 1H)

MO-E5I: 459 (МН

Elemental analysis: C 41.8 H 3.4 M 15.6 was found

Си9НивеВгЕМеО»:0.8Н2гО-1.9НСЙII trebuet С 42.0 Н 3.6 M 15.595

The starting material was obtained as follows:

To a solution of /7-hydroxy-β6-methoxy-3-"((pivaloyloxy) methyl)-3,4-dihydroquinazolin-4-one / (1.7 g, 5.55 mmol), 2-(1,2,4- of triazol-1-yl)ztanol (791mg, 7mmol) (App. RPapt. Rg. 1977, 35, 503-508) and triphenylphosphine (1.8g, 7mmol), cooled at 5"С, distylazodicarboxylate (1, iml, 7 mmol). The mixtures were allowed to warm to ambient temperature and stirred for 1 hour. The mixture was immediately poured into a silica column and eluted with a mixture of methylene chloride-methanol (95/5) to obtain b-methoxy-3-(( pivaloyloxy)methyl)-7-(2-(1,2,4-triazol-1-yl)zthoxy-3,4-dihydroquinazolin-4-one (1.64 g, 74905).

IN NMR spectrum: (DMSOiv; SEZSOOOB) 1.12 (s, 9H); 3.87 (c, ZN); 4.57 (t, 2H); 4.74 (t, 2H); 5.92 (c, 2H); 7.24 (s, 1H); 7.51 (c, 1H); 8.36 (d, 1H); 8.41 (c, 1H); 9.02 (d, 1H)

MO-E5I: 424 |MMai"

Elemental analysis: C 56.54 6.0 M 17.6 was found

SiONgzM5O5 requires C 56.9 N 5.8 M 17.90

A solution of β-methoxy-3-((pivaloyloxy)methyl)-7-(2-(1,2,4-triazol-1-yl)zthoxy-3,4-dihydroquinazolin-4-one (1.6g, 4 ammol) in a saturated methanolic solution of ammonia (25 ml) was stirred at ambient temperature for 2 days. ,2,4-triazol-1-yl)ethoxy-3,4-dihydroquinazolin-4-one (1.11 g, 9895).

IN NMR spectrum: (DMSOZdv) 3.84 (s, ZN); 4.51 (t, 2H); 4.65 (t, 2H); 7.16 (c, 1H); 7.44 (s, 1H); 7.89 (c, 1H); 7.99 (c, 1H); 8.55 (s, 1H)

MO-E5I: 287 | MG

Elemental analysis: found C 53.9 H 4.6 M 24.6

SizNizM5Oz trebuett C 54.4 H 4.6 M 24.4965

A solution of b-methoxy-7-(2-(1,2,4-triazol-1-yl)zthoxy-3,4-dihydroquinazolin-4-one (1.11 g, 3.8 mmol) and

DMF (0.bml) in thionyl chloride (15ml) was heated under reflux for 1 hour. The mixture was cooled, toluene was added and volatile substances were evaporated. The residue was distributed between methylene chloride and water, and the aqueous layer was adjusted to pH 8.5 with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with brine and dried (Md5O"), after which the solvent was evaporated. The residue was purified by column chromatography eluting with a mixture of methylene chloride-methylene (95/5). The purified solid was triturated with zephyr, collected by filtration, washed with water and then with zephyr and dried under vacuum to obtain 4-chloro-b-methoxy-7-(2-(1,2,4-triazol-1-yl)zthoxy) quinazoline (756 mg, 6590).

IN NMR spectrum: (DMSOdv) 3.97 (s, ZN); 4.65 (dd, 2H); 4.70 (dd, 2H); 7.39 (c, 1H); 7.52 (c, 1H); 7.99 (c, 1H);

8.57 (s, 1H); 8.89 (s, 1H)

MO-E5I: 306 |MNI 7

Example 98

Below are the views! a typical dosage form containing a combination of formulas! I or its pharmaceutically acceptable salt (further compound X), for therapeutic or prophylactic application to humans: (a) Tablet | mg/tablet

Compound X 100

Lactose RI. EEig 182.75

Croscarmellose sodium 12.0

Cornstarch paste (595 m/o) 2.25

Magnesium stearate 3.0 (in) Tablet HER mg/tablet

Connection X 50

Lactose RI. EEig 223.75

Croscarmellose sodium 6.0

Corn starch 15.0

Polyvinylpyrrolidone (595 m/o paste) 2.25

Magnesium stearate 3.0 (s) Tablet PI mg/tablet

Compound X 1.0

Lactose RI. Yeig 93.25

Croscarmellose sodium 4.0

Paste from corn starch (595 m/o) 0.75

Magnesium stearate 1.0 (a) Capsule mg/tablet

Connection X 10

Lactose RI. Yeig 488.5

Magnesium stearate 1.5 (e) Injection solution I (5Omg/ml)

Connection X 5.095 m/o 1Tn. Sodium hydroxide solution 15.095 0/0

About Tn. Hydrochloric acid (to regulate pH to 7.6)

Polyethylene glycol 400 4.595 m/o

Water for injection up to 10090 (0 Injection solution of HER (TOmg/ml)

Compound X 1.095 m/o

Sodium phosphate BP 3.690 m/o

About Tn. Sodium hydroxide solution /-15.0905 0/0

Water for injection up to 10090 (mg/ml, - diluted (9) Injection solution with its buffer to pH b)

Compound X 0.195 m/o

Sodium phosphate BP 2.26905 m/o

Citric acid 0.3895 m/o

Polyethylene glycol 400 3.595 m/o

Water for injection up to 10095

Note

More description of medicinal forms! can be received! by ordinary means, known in the field of pharmaceuticals. Tablets (a)-(cC) can have an insoluble coating applied by traditional methods, for example, a coating of adethylphthalyl cellulose!.

Claims (20)

1. Derivative of quinazoline of formula I: 7 1 roy, which is U M from (1) where "U represents -O-, -5-, -MA? CO-, where ЕZ represents hydrogen; B! represents hydrogen or C-alkoxy ; B? represents hydrogen; t represents an integer from 1 to 5; BZ represents hydroxy, halogen, C1-zalkyl, C1-zalkoxy, C1-alkanoyloxy, trifluoromethyl or cyano; B: chosen from one of the following groups: 1) XX, which represents a pyridonic group, a phenyl group or a 5- or b-membered aromatic heterocyclic group with 1-3 heteroatoms selected from 0, M and 5, and a pyridonic, phenyl or heterocyclic group can carry 1-2 substituents selected from halogen , amino, C1-4-alkyl, C1-3-alkyl, C1-hydroxyalkyl, C1-aminoalkyl, C1-4alkylamino, C1-hydroxyalkyl, carboxy, cyano, -SOMV'EV'Z and -"MAESOV" (where B, BZ, Die and B", which can be the same or different, represent each hydrogen, Ci-4zalkyl or Ci-zalkoxyCo-zalkyl); 2) Ci-alkyl!", where X! - such as a certain one; 3) C-zalkenyl!", where X! is as defined above; 4) C-zalkylu2X", where U2 represents -O-, -5-, -50-, -505-, -MV'ЕСО-, -MA!Z50" - or -MA2O- (where B!E, BZ and OH independently represent each hydrogen, Ci-zalkyl or Ci-zalkoxyCg-zalkyl and X! - as defined above); and 5) Ci-zalkylCi-zalkylX" (where M5 represents -O-, -MAZISO-, -MAZ5O2- or -MAZ5-, where BZ! BZ and p independently represent each hydrogen, Ci-zalkyl or Ci-zalkoxyCg-zalkyl and X! - as defined above); 2 represents -MH- or -O-; provided that when P" is selected from one of the descriptions of more than one group 1), 2) and 4) and X' represents unsubstituted phenyl or substituted phenyl with 1-2 substituents selected from halogen, C-alkyl and C-alkyl, then t represents an integer from C to 5 and/or 2 represents -O-; and their salts. 2. Production of quinazoline according to claim 1, where E! is methoxy. 3. Production of quinazoline according to claim 1 or claim 2, where 2 represents hydrogen. 4. Derivatives of quinazoline according to any of the previous points, where the phenyl group, carrying (BZ)t, represents a group of formulas! IN? represent hydrogen, methyl, methoxy, bromine, fluorine or chlorine; A: represents hydrogen or hydroxy; and VU represents hydrogen, fluorine or chlorine. 5. Production of quinazoline according to any of the previous items, where 7 represents MH. 6. Production of quinazoline according to any of the preceding points, where U! represent -O-. 7. The production of quinazoline according to any of the preceding paragraphs, where the fragment X! in group B" represents a pyridone group or a 5- or b-membered aromatic heterocyclic group with 1-3 heteroatoms selected from O, M and 5, and the pyridone or heterocyclic group can be substituted if necessary as defined in point 1 . 8. Derivative of quinazoline according to claim 7, where fragment X! represents a pyridone, pyridyl, imidazolyl, thiazolyl, thienyl, triazolyl or pyridazinyl group, which, if necessary, can be substituted as defined in point 1. 9. Derivative of quinazoline according to any of the previous items, where P" represents the group X!-U6-(CHa)n-, where U represents a direct bond, -O-, -5- or -МН-, n represents an integer up to Zy xx! - as defined in any item 1, 7 and 8. 10. Derivative of quinazoline according to claim 1, selected from: 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(4-pyridyloxy)zthoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(4-oxo-1,4-dihydro-1-pyridyl)zthoxy|quinazoline; 4-(4-chloro-2-fluoroanilino) )-7-(2-«(imidazol-1-yl)zthoxy)-6-methoxyquinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(3-(4-pyridyl)propoxy) quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(4-pyridyl)zthoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7- ((4-pyridyl)methoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(2-methylimidazol-1-yl)zthoxy)quinazoline; 4-(4-chloro -2-fluoroanilino)-b-methoxy-7-(2-(1-methylimidazol-2-ylthio)zthoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(1,2,4-triazol-1-yl)zthoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(M-(4-pyridyl)amino)zthoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(1-methylimidazol-2-yl)zthoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-7-(2-cyano-4-pyridyl)methoxy)-6-methoxyquinazoline; and their salts. 11. Derivative of quinazoline according to claim 1, selected from: 4-(3-hydroxy-4-methylanilino)-b-methoxy-7-(4-pyridylmethoxy)quinazoline; 4-(3-hydroxy-4-methylanilino)-b-methoxy-7-(2-pyridylmethoxy)quinazoline; 4-(3-hydroxy-4-methylanilino)-b-methoxy-7-(1-methylimidazol-2-ylmethoxy)quinazoline; 4-(3-hydroxy-4-methylanilino)-b-methoxy-7-(2-methylthiazol-4-ylmethoxy)quinazoline; 7-(2-acetamidothiazol-4-ylmethoxy)-4-(3-hydroxy-4-methylanilino)-b-methoxyquinazoline; 4-(3-hydroxy-4-methylanilino)-b-methoxy-7-(4-pyridylpropoxy)quinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridyl-)propoxy)quinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)quinazoline; 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylanilino)-b-methoxyquinazoline; 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6-methoxyquinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-methylthiazol-4-yl)methoxy)quinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(4-pyridylmethoxy)quinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazoline; 7-(2-acetamidothiazol-4-yl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-b-methoxyquinazoline; 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-b-methoxyquinazoline; 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-imidazol-1-yl)-ztoxy)-b-methoxyquinazoline; 4-(4-chloro-2-fluoro-5-hydroxyanilino)-7-(2-imidazol-1-yl)zoxy)-6-methoxyquinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-(4-pyridyl)zthoxy)quinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline; 4-(3-hydroxy-4-methylanilino)-b-methoxy-7-((1-methylbenzimidazol-2-yl)methoxy)quinazoline; 7-(2-chloro-6-methyl-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-b-methoxyquinazoline; 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline; 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline; 7-(2-chloro-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6b-methoxyquinazoline; 7-(3,4-difluorobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-b-methoxyquinazoline; 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(1-methylimidazolyl)methoxy)quinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-(1,2,4-triazol-1-yl)zthoxy)quinazoline; 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((3-thienyl)methoxy)quinazoline; 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-(4-pyridyl)zthoxy)quinazoline; 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-((4-pyridyl)carboxamido)quinazoline; and their salts. 12. Derivative of quinazoline according to claim 1, selected from: 4-(3-hydroxy-4-methylanilino)-b-methoxy-7-(3-pyridylmethoxy)quinazoline; 4-(3-hydroxy-4-methylanilino)-b-methoxy-7-(3-thienylmethoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(2-pyridyloxy)zthoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-|M-methyl-M-(4-pyridyl)|aminozoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(2-oxo-1,2-dihydro-1-pyridyl)zthoxy|quinazoline; 7-(4-cyanobenzyloxy)-4- (2-fluoro-5-hydroxy-4-methylanilino)-b-methoxyquinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(3-(2-methylimidazol-1-yl)propoxy) quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-methyl-4-pyridyl)methoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(3-(2-oxo-1,2-dihydro-1-pyridyl)propoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(3-(1-methylimidazol-2-ylthio)propoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(3-(4-pyridyloxy)propoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(4-pyridylthio)zthoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(3-pyridyloxy)zthoxy)quinazoline; 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylanilino)quinazoline; 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)quinazoline; 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((2-methylthiazol-4-yl)methoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(3-thienyl)methoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(M-methyl-M-(pyridazin-4-yl)amino)zthoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(M-methyl-M-(b-methylpyrimidin-4-yl)amino)zthoxy)quinazoline; 4-(4-chloro-2-fluoroanilino)-7-(2-(3,5-dimethyl/1/1 2,4|triazol-4-yl)zthoxy)-6-methoxyquinazoline; 4-(4-chloro-2-fluoroanilino)-7-(2-(2,4-dimethylimidazol-1-yl)-zthoxy)-b-methoxyquinazoline; 4-(4-chloro-2-fluoroanilino)-7-(2-(2,5-dimethylimidazol-1-yl)-zthoxy)-b-methoxyquinazoline; 4-(3-Hydroxyanilino)-7-(2-(imidazol-1-yl)zthoxy)-b-methoxyquinazoline; 4-(4-chloro-2-fluoroanilino)-b-methoxy-7-(2-(1,2,4-triazol-4-yl)zthoxy)quinazoline; 4-(4-bromo-2-fluoroanilino)-7-(2-(1,2,4|-triazol-1-yl)zthoxy)-6-methoxyquinazoline; and their salts. 13. Production of quinazoline according to any of the preceding items in the form of a pharmaceutically acceptable salt. 14. The method of obtaining quinazoline derivatives of the formula I or their salts according to claim 1, which includes the interaction of the compound of the formula PI: E2 1 ! to М я В У М with (11) where В", В, В' and У! are as defined in claim 1, and И represents a descending group, with a compound of the formula IM: 3 АК in в ; (M) where 2, WITHOUT and t - such as the definitions in claim 1, with the receipt of the combined formulas I and their salts, and, in case of necessity, when a pharmaceutically acceptable salt of the quinazoline derivative of the formula I is required, the resulting compound is reacted with an acid or a base to obtain the required pharmaceutically acceptable salt. 15. The method of obtaining quinazoline derivatives of formula I or their salts according to claim 1, in which the group of formula II: (83) p, (PV) where ЕЗ and t are as defined! in claim 1, is a phenyl group bearing one or several hydroxy groups, which includes the removal of the protective group from the compounds of the formulas U: ЕЗ Е? g r! 1 (ОР)И СМ о КА-хе1 М НО where У", т, В", В, ВУ, В" and 7 are as defined in claim 1, P represents a phenolic hydroxy-protecting group and p' represents an integer from 1 to 5, equal to the number of protected hydroxy groups, and the difference t-p' is equal to the number of substituents KZ, which are not protected hydroxy groups, and, in case of necessity, when a pharmaceutically acceptable salt of the quinazoline derivative of formulas 1 is required, the resulting compound is reacted with an acid or a base with obtaining the required pharmaceutically acceptable salt. 16. The method of obtaining quinazoline derivatives of formulas I or their salts according to claim 1, in which the substituent M! represents -O- or -5, which includes the interaction of the compounds of the MI formula: Z vo z 7 1 r M i NU M z (M) where t, KE! В, ВЗ and 2 - as defined in claim 17 and У" has a higher meaning, with the combination of the formula MY: 8-1, (MI) where B" is as defined in claim 1, and Г! - outgoing group, and, in case of necessity, when a pharmaceutically acceptable salt of the quinazoline derivative formulas is required! And, the resulting compound is reacted with an acid or a base to obtain the required pharmaceutically acceptable salt. 17. The method of obtaining derivative quinazoline formulas! | or their salts according to claim 1, which includes the interaction of the combination of formulas! E: M schi I M z (MI!) where В", В, VU, 7 and t - such as the definitions in claim 1, and И! the outgoing group, with the combination of formulas IX: 8-1 - NIX), where P" and U" are as defined in claim 1, and when a pharmaceutically acceptable salt of the quinazoline derivative of the formula is required! And, the resulting compound is reacted with an acid or base to obtain the required pharmaceutically acceptable salt. 18. The method of obtaining derivative quinazoline formulas! Or their salts according to claim 1, in which EE? represent C-alkyl X?, where X2 is selected from the following three groups: 1) X, where X! as defined in claim 1; 2) Ж, where У" represent -О-, -5-, -50-, -502-, -"МВА""СО-, -МА850" - or -МА"З-, where "7, ВЗ and ВЗ each independently represents hydrogen, C1-zalkyl or C1-zalkoxyCe-zalkyl, and X' is as defined in item 1; and C) U8C1-zalkylX", where UZ represents -O-, -MAROSO-, -MAP5O" - or -"MAR2-, where EMO, V! and 2 each independently represent hydrogen, C1-zalkyl or C1-zalkoxyC0-zalkyl, and X! as defined in claim 1, which includes the interaction of a compound of the formula X: en 1 OM zm AL 1. p53. M1 I. -E -y , (y where ХУ", В", Ве, ВУ, 7 and t - such as they are defined in claim 1, and Г! -the leaving group, and З represent C-5 alkyl, with a compound of the formula ХХ: ХХ: - Н(Х)І, where Х?2 is as defined in this paragraph above, with the preparation of the compound of the formulas I, and, in case of necessity, when a pharmaceutically acceptable salt of the quinazoline derivative of the formula 1 is required, they interact of the resulting compound with an acid or a base to obtain the required pharmaceutically acceptable salt. 19. A pharmaceutical composition containing as an active component a quinazoline derivative of formula I, as defined in claim 1, or its pharmaceutically acceptable salt in combination with a pharmaceutically acceptable filler or carrier. 20. The method of obtaining an anti-angiogenic effect and/or the effect of reducing vascular permeability in a warm-blooded animal in need of such treatment, including the introduction of an effective amount of the compound of the formulas into the specified animal! And or ego pharmaceutically acceptable salt according to claim 1.