WO2004069145A2

WO2004069145A2 - Anticancer compounds, process for their preparation and pharmaceutical compositions containing them

Info

Publication number: WO2004069145A2
Application number: PCT/IB2004/000299
Authority: WO
Inventors: Manohar Sharma Vedula; Venkata Adiseshu Kattuboina; Javed Iqbal; Rajagopalan Ramanujam; Sriram Rajagopal; Naga Venkata Srinivasa Rao Mamidi; Ramanatham Josyula; Madhusudhan Gutta
Original assignee: Dr. Reddy's Laboratories Ltd.
Priority date: 2003-02-07
Filing date: 2004-02-06
Publication date: 2004-08-19
Also published as: WO2004069145A3

Abstract

The present invention relates to novel anticancer agents, their pharmaceutically acceptable salts, their geometrical isomers and their pharmaceutically acceptable compositions containing them. the present invention more particularly relates to novel quinazoline compounds, their pharmaceutically acceptable salts and their pharmaceutically acceptable compositions containing them. the novel quinazoline compounds have the general formula (I), where all symbols are as defined in the specification.

Description

NEW ANTICANCER COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING

THEM

Field of the Invention

The present invention relates to novel anticancer agents, their phamaceutically acceptable salts, their geometrical isomers, and their pharmaceutically acceptable compositions. The present invention more particularly relates to novel quinazoline compounds, their phamaceutically acceptable salts, their geometrical isomers and their pharmaceutically acceptable compositions; The novel quinazoline compounds have the general formula (I),

The present invention also relates to a process for the preparation of the above defined novel compounds of general formula (I), their phamaceutically acceptable salts, their geometrical isomers and their pharmaceutically acceptable compositions.

Back ground of the Invention

Many of the current treatment regimes for cell proliferation diseases such as psoriasis and cancer utilize compounds, which inhibit DNA synthesis. Such compounds are toxic to cells generally. But their toxic effects on rapidly dividing cells such as tumor cells can be beneficial. Alternative approaches such as antiproliferative agents which act by mechanisms other than the inhibition of DNA synthesis have the potential to display enhanced selectivity of action.

In recent years it has been discovered that a cell become cancerous by virtue of the transformation of a portion of its DNA into an oncogene. Several such oncogenes give rises to the production of peptides which are receptors for growth factors. The growth factor receptor complex subsequently leads to an increase in cell proliferation. Regardless of the nature of surface receptors protein kinases - and phosphotases along with phospholipases or essential machinery by which cell signal is transmitted within the cell (Marshall J C, Cell 80, 179-278, 1995). Mammalian cells use diverse signaling pathways to instruct the nucleus about genes to turn on and off in the regulation of cell growth and cell cycling. Extra cellular signals received at fransemembrane receptors are relayed into the cells by the signal transduction pathways (Pelech et al, Science 257, 1335, 1992), which have been implicated in a wide array of physiological processes such as induction of cell proliferation, differentiation or apoptosis (Davis et.al., J. Biol. Chem. 268, 14553, 1993). The mitogen activated protein kinase (MAPK) pathway (Raf-MEK-ERK phosphorylation cascade ) is a key signaling pathway linking signals from growth factors at cell surface receptors to transcription factors in the nucleus which confrol gene expression and function (Nishida et.al., Trends Biochem. Set, 19, 236, 1994). This pathway also serves oncogenic signals in cancer cells by linking signals from membrane receptor oncogenes and intracellular oncogenic kinases to the nucleus. Ras is an upstream activator of MAPK pathway and oncogenic forms of Ras are known. Ras is mutated in roughly in 30% of all human solid tumors, including 50 % of colon cancers and 90% of all pancreatic cancers (Bos J.L., et. al Cancer Res. 49, 4682, 1989; Kiaris, H. et. al, Int. J. Oncol. 1, 413, 1995). Very recently mutations of Raf {Nature, 417, 2002) also have been shown in human tumors. Over expression, hyperactivity or dysregulation of c-Raf (Callans, L. S., et. al., Annu. Surg. Oncol. 2, 38, 1995; El-Ashry, D., et. al., Oncogene, 15, 423, and 1997) has been shown to be associated with various human cancers and tumor cells. MEK (MAP kinase) and ERK (MAP kinase) are dysregulated in human cancers (Oka, H., et. al., Cancer Res., 55, 4182, 1995; Sivaraman, V. S., et al, J. Clin. Invest. 99, 1478, 1997) and over activation ofc-Raf is associated with dysregulated ERK and MEK in human tumors and tumor cell lines (Hoshino et al., Oncogene, 18, 813, 1999).

Thus, inhibitor of the MAPK pathway through inhibition of Raf, MEK or ERK offers a unique opportunity to block uncontrolled cell growth and therefore, has potential therapeutic utility in developing cancer agents (Stein, B et al., Annu. Rep. Med. Chem. 31, 289, 1996; Levitt, M.L., et al, Invest. New Drugs 17, 213, 1999)

Certain quinazoline compounds (WO09609294, WO09615118, WO09609294, WO09906378, WO0051587, WO00104111, WO00121594), cyanoquinolines (WO09843960, US 6,002,008) have been reported as kinase inhibitors. Summary of the Invention

With an objective of preparing novel quinazoline compounds useful for treating cancer. We focussed our research efforts in prepareing the novel quinazoline derivatives of the formula (I) as defined above.

One aspect of the present invention is, therefore, to provide novel quinazoline compounds of the formula (I) as defined above, their phamaceutically acceptable salts, their geometrical isomers and their pharmaceutically acceptable compositions.

Another aspect of the present invention is to provide pharmaceutical compositions containing compounds of the general formula (I), their phamaceutically acceptable salts, their geometrical isomers and their pharmaceutically acceptable compositions containing them with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.

Yet another aspect of the present invention is to provide pharmaceutical compositions containing compounds of formula (I), their phamaceutically acceptable salts, their geometrical isomers and their pharmaceutically acceptable compositions containing them with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.

Still yet another aspect of the present invention is to provide a process for the preparation of novel quinazoline derivatives of the formula (I) as defined above, their phamaceutically acceptable salts, their geometrical isomers and their pharmaceutically acceptable compositions containing them.

Detailed description of the Invention

The present invention relates to compounds having the general formula (I)

their phamaceutically acceptable salts, their geometrical isomers and their .pharmaceutically acceptable compositions containing them. where R¹ and R² represents hydrogen, halogen, hydroxy, nifro, cyano, amino, optionally substituted groups selected from alkyl,. cycloalkyl, alkoxy, cycloalkoxy, acyl, acyloxy, aryl, aryloxy, alkylthio, arylthio, aralkyl, aralkoxy, alkenyl, alkenyloxy, cycloalkenyloxy, aroyl, aroyloxy, heteroaryl, heterpcyclyl, heteroaryloxy, heterocyclyloxy, heteroaralkyl, heterocyclylalkyl, heteroaralkoxy, heterocyclylalkoxy, hetero aralkoxy alkoxy, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carboxylic acid or its derivatives, or sulfonic acid or its derivatives;

R³ repesents hydrogen, halogen, hydroxy, cyano, amino, -CH₂CN, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic acid or its derivatives, or sulfonic acid or its derivatives;

R⁴, R⁵ and R⁶ independently represent hydrogen, halogen, hydroxy, nifro, cyano, amino, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic acid or its derivatives, or sulfonic acid or its derivatives.

'W' represents optionally substituted groups selected from phenyl, naphthyl, pyrrolyl, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like.

Q represents N, -CH or C,

Y represents O, NH or CH₂, s, t are integers in the range of 0 to 5 and r, u are integers 0 or 1.

The substituents on R¹ and R² are selected from halogen, nitro, amino, alkylamino, dialkylamino, hydroxy, carboxv; cyano, oxo(=O), thio(=S), alkyl, cycloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, benzyloxy, acyl, acyloxy, aroyl, heteroaryl, aralkyl, alkylsulfonyl, alkylsulfinyl,^' arylsulfonyl, arylsulfinyl, alkylthio, arylthio or an optionally substituted 5 or 6 membered cyclic ring which may optionally contain 1-3 hetero atoms selected from O, S or N. A 5 or 6 membered cyclic rings formed may be selected from pyrrole, morpholine, thiomorpholine, benzothiazole, benzoimidazole, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, pyrrolidine and the like. The substituents on the above 5 or 6 membered cyclic rings are selected from halogen, nifro, amino, hydroxy, carboxy, cyano, =0, =S or alkyl. The substituents on R³, R⁴, R⁵ and R⁶ are selected from a halogen, nifro, amino, hydroxy, carboxy, cyano, oxo(O=), thioxo(S=), alkyl, cycloalkyl, alkoxy, cycloalkyl, aryl, acyl, aroyl, heteroaryl or aralkyl.

The substituents on the group represented by W are selected from halogen atom, hydroxy, carboxy, acyl, nifro, cyano, amino, acylarnino, oxo, thioxo, linear or branched optionally halogenated alkyl, optionally halogenated alkoxy, carboxylic or sulfonic acids and their derivatives.

Whenever substitutions are possible on the groups represented by R¹, R², R³, R⁴, R⁵, R⁶ and W, they may have 1 to 4 substituents, which may be identical or different.

Another embodiment of the present invention provides compound of formula (I)

where R¹, R², R³, R⁴, R⁵, R⁶, Q, s and t are as defined earlier; R' and R" independently represent hydrogen, halogen, hydroxy, carboxy, acyl, nitro, cyano, amino, acylarnino, =O, =S, linear or branched optionally halogenated alkyl, optionally halogenated alkoxy, carboxylic or sulfonic acids and their derivatives, which is represented by compound of formula (II); their phamaceutically acceptable salts, their geometrical isomers and their pharmaceutically acceptable compositions containing them.

In one embodiment of the compound of formula (II), Q represents N or -C-CN; R¹ and R² independently represent hydrogen, hydroxy, optionally substituted groups selected alkoxy, cycloalkoxy, acyloxy, aryloxy, aralkoxy, alkenyloxy, cycloalkenyloxy, aroyloxy, heteroaryloxy, heterocyclyloxy, heteroaralkoxy, heterocyclylalkoxy, heteroaralkoxyalkoxy; wherein the substituents on R¹ and R² may be selected from amino, alkylamino, dialkylamino, or an optionally substituted 5 or 6 membered cyclic ring which may optionally contain 1-3 hetero atoms selected from O, S or N. A 5 or 6 membered cyclic ring formed may be selected from pyrrole, morpholine, thiomorpholine, benzothiazole, benzoimidazole, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, pyrrolidine and the like; R³ represents hydrogen, halogen or alkyl;

's' represents 0, 't' represents 1;

R , R⁵ and R independently represent hydrogen, halogen, hydroxy, nifro, cyano, amino, optionally substituted groups selected from al yl, alkoxy;

R' and R" independently represent hydrogen, halogen, hydroxy, nitro, cyano, amino, linear or branched optionally halogenated alkyl, optionally halogenated alkoxy, carboxylic or sulfonic acids and their derivatives.

In another embodiment of the compound of formula (II), Q represents N or -C-CN;

I ?

R and R independently represent hydrogen, optionally substituted groups selected alkoxy, heteroaralkoxy, heterocyclylalkoxy, heteroaralkoxyalkoxy; wherein the substituents on R¹ and

R may be selected from amino, alkylamino, dialkylamino, pyrrole, morpholine, thiomorpholine, benzothiazole, benzoimidazole, pyridine, pyridazine, pyrimidine, pyrazine, piperidine or pyrrolidine;

R³ represents hydrogen;

's' represents 0, 't' represents 1;

R⁴, R⁵ and R⁶ independently represent hydrogen, halogen, optionally substituted groups selected from alkyl or alkoxy;

R' and R" independently represent hydrogen, halogen, linear or branched optionally halogenated alkyl, optionally halogenated alkoxy, carboxylic acids or their derivatives.

In another embodiment of the compound of formula (II), Q represents N; R¹ and R² independently represent hydrogen, optionally substituted groups selected alkoxy, heterocyclylalkoxy, heteroaralkoxy; wherein the substituents on R¹ and R² may be selected from amino, alkylamino, dialkylamino, pyrrole, morpholine, thiomorpholine, benzothiazole, benzoimidazole, pyridine, pyridazine, pyrimidine, pyrazine, piperidine or pyrrolidine; R³ represents hydrogen; 's' represents 0, 't' represents 1;

R⁴, R⁵ and R⁶ independently represent hydrogen, halogen, alkyl or alkoxy; R' and R" independently represent hydrogen or halogen, alkoxy, carboxylic acids or their derivatives. In another embodiment of the compound of formula (II), Q represents -C-CN;

1 9

R and R independently represent hydrogen, optionally substituted groups selected alkoxy, heterocyclylalkoxy, heteroaralkoxy; wherein the substituents on R¹ and R² may be selected from amino, alkylamino, dialkylamino, pyrrole, morpholine, thiomorpholine, benzothiazole, benzoimidazole, pyridine, pyridazine, pyrimidine, pyrazine, piperidine or pyrrolidine;

R³ represents hydrogen;

's' represents 0, ' represents 1;

R⁴, R⁵ and R⁶ independently represent hydrogen, halogen, alkyl or alkoxy;

R' and R" independently represent hydrogen or halogen, alkoxy, carboxylic acids or their derivatives.

One group of the preferred compounds of the formula (I), which is represented by formula (II) is: l-[4-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-fluoro-benzyl)-oxime, l-[4-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-chloro-benzyl)-oxime,

4- { 1 -[4-(Quinazolin-4-ylamino)-phenyl]-ethylideneaminooxymethyl} -benzonitrile, l-[4-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-(3,4-dichloro-benzyl)-oxime, l-[3-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-benzyl-oxime, l-[3-(Quinazolin-4-ylamiho)-phenyl]-ethanone O-(4-fluoro-benzyl)-oxime, l-[3-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-chloro-benzyl)-oxime, l-[4-Bromo-3-(quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-chloro-benzyl)-oxime, l-[4-Bromo-3-(quinazolin-4-ylamino)-phenyl]-ethanone O-benzyl-oxime, l-[4-Bromo-3-(quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-fluoro-benzyl)-oxime, l-[2-Methoxy-5-(quinazolin-4-ylamino)-phenyl]-ethanone-O-benzyl-oxime, l-[4-Methoxy-3-(quinazόlin-4-ylamino)-phenyl]-ethanone O-(4-fluoro-benzyl)-oxime.

Another group of the preferred compounds of the formula (I), which is represented by formula (II) is:

4- {4-[ 1 -(4-Fluoro-benzyloxyimino)-ethyl]-phenylamino} -7-isopropoxy-6-methoxy- quinoline-3 -carbonitrile, 4-[4-(l-Benzyloxyimino-ethyl)-phenylamino]-7-isopropoxy-6-methoxy-quinoline-3- carbonitrile, 4-{4-[l-(4-Chloro-benzyloxyimino)-ethyl]-phenylamino}-7-isopropoxy-6-methoxy-

. quinoline-3 -carbonitrile, 4-{4-[l-(3,4-Dichloro-benzyloxyimino)-ethyl]-phenylamino}-7-isopropoxy-6-methoxy- quinoline-3 -carbonitrile.

Another group of the preferred compounds of the formula (I), which is represented by formula (II) is: l-{4-[6-Methoxy-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime, 1 - {4-[6-Methoxy-7-(3-mo holin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanoήe-O-(4-fluoro-benzyl)-oxime, l-{4-[7-(3-Dimethylamino'-propoxy)-6-methoxy-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime, l-{4-[6-Methoxy-7-(3-piperidin-l-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime, 1 - {4-[6-Methoxy-7-(3-piperidin- 1 -yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyl-oxime, 1 - {4-[6-Methoxy-7-(3 -pyrrolidin- 1 -yl-propoxy)-quinazolin-4-ylamino] -phenyl} - ethanone-O-(4-chloro-benzyl)-oxime, 1 - {4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinazolin-4-ylamino]-phenyl} - ethanone-O-(2-chloro-4-fluoro-benzyl)-oxime, l-{4-[6-Methoxy-7-(3-piperidin-l-yl-ρropoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(2-chloro-4-fluoro-benzyl)-oxime, 1 - {4- [6-Methoxy-7-(3 -pyrrolidin- 1 -yl-propoxy)-quinazolin-4-ylamino]-phenyl } - ethanone-O-(2-chloro-4-fluoro-benzyl)-oxime, l-{4-[6-Methoxy-7-(3rpyrrolidin-l-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(2,4-dichloro-benzyl)-oxime, l-{4-[6-Methoxy-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(2-chloro-4-fluoro-benzyl)-oxime, l-{4-[6-Methoxy-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-chloro-benzyl)-oxime.

Another group of the preferred compounds of the formula (I), which is represented by formula (II) is: l-{4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime, l-{4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-chloro-benzyl)-oxime, l-{4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime, l-{4-[7-Methoxy-6-(3-pyrrolidin-l-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime, l-{4-[7-Methoxy-6-(3-piperidin-l-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone- O-benzyl-oxime, 1 - {4-[6-(3-Dimethylamino-propoxy)-7-methoxy-quinazolin-4-ylamino]-phenyl} - \ ethanone-O-benzyl-oxime, l-{4-[7-Metlιoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime, 1 - {4-[6-(3-Dimethylamino-propoxy)-7-methoxy-quinazolin-4-ylamino]-phenyl} - ethanone-O-(4-fluoro-benzyl)-oxime, l-{4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(2,4-dichlorp-benzyl)-oxime, 1 - {4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-(2-chloro-4-fluoro-benzyl)-oxime, l-{4-[7-Methoxy-6-(3-pyrrolidin-l-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(2,4-dichloro-benzyl)-oxime.

_. l-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-ethanone-O-benzyl-oxime, l-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-fluoro-benzyl)- oxime. Still another group of the preferred compounds of the formula (I), which is represented by formula (II) is:

1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyl-oxime succinate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]- phenyl}'-ethanone-O-benzyl-oxime acetate,

1 - {4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-(4-fluoro-benzyl)-oxime 2-hydroxyethane sulfonate, 1 - {4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyl-oxime 2-hydroxyethane sulfonate, 1 - {4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino].-phenyl} - ethanone-O- (4-chloro-benzyl)-oxime methanesulfonate, l-{4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O- (4-chloro-benzyl)-oxime hydrochloride, l-{4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O- (4-chloro-benzyl)-oxime nitrate, 1 - {4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-(4-chloro-benzyl)-oxime sulfate, l-{4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-chloro-benzyl)-oxime phosphate, l-{4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(2,4-dichloro-benzyl)-oxime methanesulfonate, 1 - {4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime L-glutamate, 1 - {4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime methane sulphonate, 1. {4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime malonate, 1 - {4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl } - ethanone-O-benzyloxime maleate, 1 - {4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime besylate (1:1), l-{4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime besylate (1:2), 1 - {4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime citrate, 1 - {4-[7-Methoxy-6-(3-morpholin-4-yl-piOpoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime hydrochloride, l-{4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime hydrobromide, 1 - {4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime L-tartarate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime fumerate (2:1), l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime L-aspartate, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime sulphate.

One group of the more preferred compounds of the formula (I), which is represented by formula (II) is: l-[4-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-fluoro-benzyl)-oxime, l-[4-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-chloro-benzyl)-oxime, 4- { 1 -[4-(Quinazolin-4-ylamino)-phenyl]-ethylideneaminooxymethyl} -benzonitrile, l-[4_(Quinazolin-4-ylamino)-phenyl]-ethanone-O-(3,4-dichloro-benzyl)-oxime.

Another group of the more preferred compounds of the formula (I), which is represented by formula (II) is:

l-{4-[6-Methoxy-7-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime, l-{4-[6-Methoxy-7-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime, l-{4-[6-Methoxy-7-(3-piperidin-l-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime, 1 - {4-[6-Methoxy-7-(3 -piperidin- 1 -yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyl-oxime,

1 - {4-[6-Methoxy-7-(3-piperidin- 1 -yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-(2-chloro-4-fluoro-benzyl)-oxime.

1 - {4-[7-Methoxy-6-(3-moφholin-4.-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyl-oxime, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - etlιanone-O-(4-chloro-benzyl)-oxime, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-(4-fluoro-benzyl)-oxime, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone O-(2,4-dichloro-benzyl)-oxime, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ^• ethanone-O-(2-chloro-4-fluoro-benzyl)-oxime.

1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-ρropoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-(4-fluoro-benzyl)-oxime, l-{4-[7-Methoxy-6-(3-piperidin-l-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime.

Another group of the more^' preferred compounds of the formula (I), which is represented by formula (II) is: l-{4-[7-Methoxy-6-(3-moφholin-4-yl-ρropoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime succinate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]- phenyl} -ethanone-O-behzyl-oxime acetate, l-{4-[7-Mefhoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime 2-hydroxyethane sulfonate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxinie L-glutamate, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone O-benzyloxime methane sulphonate, l-{4-[7-Methoxy-6-(3-nioφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone O-benzyloxime malonate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime maleate, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime besylate (1:1), 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime besylate (1:2), 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime citrate, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime hydrochloride, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-p^'henyl} - ethanone-O-benzyl-oxime hydrobromide, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime L-tartarate, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime fumerate (2:1), 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl } - ethanone-O-benzyl-oxime L-aspartate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime sulphate. Still another group of the more preferred compounds of the formula (I), which is represented by formula (II) is: l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime succinate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]- phenyl} -ethanone-O-benzyl-oxime acetate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylaιmno]-phenyl}- ethanone-O-benzyl-oxime 2-hydroxyethane sulfonate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime L-glutamate, l-{4-[7-Methoxy-6-(3-mθφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime methane sulphonate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime malonate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime maleate, 1. {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime besylate (1 :1), l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylaιmno]-phenyl}- ethanone-O-benzyloxime besylate (1:2), 1 _ {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime citrate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime hydrochloride, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyl-oxime hydrobromide, , l - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxinie L-tartarate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime fumerate (2:1), l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime L-aspartate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime sulphate.

Still yet another group of the more preferred compounds of the formula (I), which is represented by formula (II) is: l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone O-benzyl-oxime succinate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]- phenyl} -ethanone-O-benzyl-oxime acetate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime methane sulphonate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime maleate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime hydrochloride.

An essentially preferred .compound of the formula (I), which is represented by formula (II) is:

1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyl-oxime

An essentially preferred compound of the formula (I), which is represented by formula

(II) is:

1. {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-(4-chloro-benzyl)-oxime

(II) is: l.{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime

An essentially preferred compound of the formula (I), which is represented by formula (II) is: l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime

An. essentially preferred compound of the formula (I), which is represented by formula (II) is: l-{4-[7-Methoxy-6-(3-piperidin-l-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone- O-benzyl-oxime

An essentially preferred compound of the formula (I), which is represented by formula (II) is: l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]- phenyl} -ethanone-O-benzyl-oxime acetate

An essentially preferred compound of the formula (I), which is represented by formula (II) is: ^' l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone O-benzylόxime methane sulphonate

(II) is:

1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl } - ethanone-O-benzyloxime maleate

An essentially preferred compound of the foraiula (I), which is represented by formula (II) is: l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime^'hydrochloride

An essentially preferred compound of the formula (I), which is represented by formula (II) is: l-{4-[7-Methoxy-6-(3-moφholin-4-yl-prop'oxy)-quinazolin-4-ylamino]^'-phenyl}-. ethanone-O-benzyl-oxime succinate

Another embodiment of the present invention provides compound of formula (III)

where R¹, R², R³, R⁴, R⁵, R⁶, Q, s and t are as defined earlier; r represents 1; R' and R" independently represent hydrogen, halogen, hydroxy, carboxy, acyl, nitro, cyano, amino, acylarnino, oxo, thioxo, linear or branched optionally halogenated alkyl, optionally halogenated alkoxy, carboxylic or sulfonic acids and their derivatives, which is represented by compound of formula (III); their phamaceutically acceptable salts, their geometrical isomers and their pharmaceutically acceptable compositions containing them.

In another embodiment of the compound of formula (III), Q represents N or -C-CN; R¹ and R² independently represent hydrogen, optionally substituted groups selected alkoxy, heterocyclylalkoxy, heteroaralkoxy; wherein the substituents on R¹ and R² may be selected from amino, alkylamino, dialkylamino, pyrrole, morpholine, thiomoφholine, benzothiazole, benzoimidazole, pyridine, pyridazine, pyrimidine, pyrazine, piperidine or pyrrolidine; R³ represents hydrogen; represents 1-2, 't' represents 1;

R⁴, R⁵ and R⁶ independently represent hydrogen, halogen, alkyl or alkoxy; R' and R" independently represent hydrogen or halogen, alkoxy, carboxylic acids or their derivatives. A preferred compound of the formula (I), which is represented by formula (III) is: l-[4-(Quinazolin-4-ylamino)-phenoxy]-propan-2-one-O-benzyl-oxime

Another embodiment of the present invention provides compound of formula (IN)

where R¹, R², R³, R⁴, R⁵, R⁶, Q, s arid t are as defined earlier; u represents 1; R' and R" independently represent hydrogen, halogen, hydroxy, carboxy, acyl, nifro, cyano, amino, acylarnino, oxo, thioxo, linear or branched optionally halogenated alkyl, optionally halogenated alkoxy, carboxylic or sulfonic acids and their derivatives, which is represented by compound of formula (IN); their phamaceutically acceptable salts, their geometrical isomers and their pharmaceutically acceptable compositions containing them.

In another embodiment of the compound of formula (IN), Q represents Ν or -C-CΝ;

R¹ and R² independently represent hydrogen, optionally substituted groups selected alkoxy, heterocyclylalkoxy, heteroaralkoxy; wherein the substituents on R¹ and R² may be selected from amino, alkylamino, dialkylamino, pyrrole, morpholine, thiomoφholine, benzothiazole, benzoimidazole, pyridine, pyridazine, pyrimidine, pyrazine, piperidine or pyrrolidine; R³ represents hydrogen; represents 0, 't' represents 3;

R⁴, R⁵ and R⁶ independently represent hydrogen, halogen, alkyl or alkoxy; R' and R" independently represent hydrogen or halogen, alkoxy, carboxylic acids or their derivatives.

Another group of preferred compounds of the formula (I), which is represented by formula (III) is: l-[4-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-[3-(2-chloro-phenoxy)-propyl]-oxime 3-Methoxy-4-(3-{l-[4-(quinazolin-4-ylamino)-phenyl]- ethylideneaminooxy}-propoxy)-benzoic acid methyl ester l-[4-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-[3-(4-fluoro-phenoxy)- propyl]-oxime

Detailed description of the groups defined for R¹, R², R³, R⁴, R⁵, R⁶, W and the substituents defined over them:

O' represents oxygen, 'N' represents nitrogen, 'S' represents sulfur and 'C represents carbon atom.

'Halogen' atom represents fluorine, chlorine, bromine or iodine.

'Alkyl' group is linear or branched (Cι-Cιo)alkyl group. Exemplary alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl, heptyl, octyl and the like.

'Alkylamino' group is (Cι-Cιo)alkylamino, where (Cι-Cιo)alkyl groups is as defined as above. Exemplary alkylamino groups include methylamino, ethylamino, propylamino and the like.

'Dialkylamino' group is di(Cι-Cιo)alkylamino, where (Cι-Cιo)alkyl groups is as defined as above. Exemplary dialkylamino groups include dimethylamino, diethylamino, ethylmethylamino and the like.

'Cycloalkyl' group is (C -C₆)cycloalk^'yl group. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the, like.

Αlkoxy' is ( -Cιo)alkyl-O-, wherein (Cι-Cιo)alkyl group is as defined above. Exemplary alkyl groups include methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like.

'Haloalkoxy' or 'Halogenatedalkoxy' is halogen-( -Cιo)alkoxy, wherein halogen and .(Cι-Cιo)alkoxy groups are as defined above. Exemplary haloalkoxy groups include chloromethoxy, chloroethoxy, fluoromethoxy, fluoroethoxy, chloropropyloxy, chlorobutyloxy, fluoroiso-propyloxy and the like.

'Halogenatedalkyl' is halogen-(C|-C]₀)alkyl, wherein halogen and (Cι-Cιo)alkyl groups are as defined above. Exemplary halogenatedalkyl groups include chloromethyl, chloroethyl, fluorometliyl, ^■ fluoroethyl, chloropropyl, chlorobutyl, fluoroiso-propyl, trifluoromethyl and the like. 'Alkylsulfonyl' is (Cι-Cιo)alkylsulfonyl, where (Cι-C.o)alkyl group is as defined above. Exemplary alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl and the like

'Alkylthio' is ( -C₁₀)alkylthio, where (Cι-Cιo)alkyl group is as defined above. Exemplary alkylthio groups include methylthio, ethylthio and the like

'Alkylsulfinyl' is (Cι-Cιo)alkylsulfmyl, where ( -Cιo)alkyl group is as defined above. Exemplary alkylsulfinyl groups include mefhylsulfmyl, ethylsulfinyl and the like.

'Cycloalkoxy' is (C -C6)cycloalkoxy group. Exemplary cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy and the like.

'Acyl' is H-CO- or (Cι-Cιo)alkyl-CO-, where (d-Cιo)alkyl group is as defined above. Exemplary acyl groups include acetyl, propionyl, benzoyl and the like.

'Acylarnino' is H-CO-amino, (Cι-Cιo)alkyl-CO-amino, where (C Cιo)alkyl group is as defined above. Exemplary acylamino groups include acetylamino, propionylamino, benzoylamino and the like.

'Arylsulfonyl', where aryl group is as defined above. Exemplary arylsulfonyl groups include phenylsulfonyl, naphthylsulfonyl and the like.

'Arylsulfinyl', where aryl group is as defined above. Exemplary arylsulfinyl groups include phenylsulfmyl, naphthylsulfinyl and the like.

'Arylthio', where aryl group is as defined above. Exemplary arylthio groups include phenylthio, naphthylthio and the like.

'Acyloxy' is (Cι-Cιo)acyl-O- group, where acyl group is as defined above. Exemplary acyloxy groups include acetyloxy, propionyloxy, benzoyloxy and the like.

'Aryl' is monocylic or polycyclic ring system of about 6 to 14 carbon atoms. Exemplary groups include phenyl, nephthyl and like.

'Aryloxy' is aryl-O- group, where aryl group is as defined above. Exemplary aryloxy groups include phenoxy, naphthyloxy and the like.

'Alkylthio' is (Cι-Oιo)alkyl-S-, wherein (Cι-Cιo)alkyl is as defined above. Exemplary alkylthio groups include methylthio, ethylthio, propylthio and the like.

'Arylthio' is aryl-S-, wherein aryl group is as defined above. Exemplary arylthio groups include phenylthio and the like.

'Aralkyl' is aryl-(Cι-Cιo)alkyl group, where in aryl and (Cι-Cιo)alkyl groups are as defined above. Exemplary aralkyl groups include benzyl, 2-phenefhyl and the like. 'Aralkoxy' is aralkyl-O- group, wherein the aralkyl group as defined above. Exemplary aralkoxy groups include benzyloxy, 2-phenethyloxy and the like.

'Alkenyl' is (C₂-C₁₀)alkenyl group. Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.

'Alkenyloxy' is (C₂-Cι₀)alkenyl-O-, where (C₂-C₆)alkenyl group is as defined above. Exemplary alkeiiyl groups include ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy and the like.

'Cycloalkenyloxy' is (C₃-C₇)cycloalkenyl-O- group, where (C₃-C₇)cycloalkenyl group is as defined above. Exemplary cycloalkenyloxy groups include cycloethenyloxy, cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy and the like.

'Aroyl' is aryl-CO- group.. Exemplary aroyl groups include benzoyl, 1-naphthoyl and the like.

'Aroyloxy' is aroyl-O- group, wherein ^'aroyl group is as defined above. Exemplary aroyloxy groups include benzoyloxy, 1-naphthoyloxy and the like.

'Heteroaryl' is an aromatic monocyclic or polycyclic ring system of about 5 to about 10 carbon atoms, having 'at least one heteroatom selected from O, S or N. Exemplary heteroaryl groups include as pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, pyridazinyl, thienopyrimidyl, furyl, indolyl, isoindolyl, 1,3-benzodioxolyl, 1,3-benzoxathiolyl, quinazolinyl, pyridyl, thiophenyl, benzothiazolyl, benzoimidazolyl, pyrimidinyl and the like.

'Heterocyclyl' is monocyclic or polycyclic ring system of about 5 to about 10 carbon atoms, having at least one heteroatom selected from O, S or N. Exemplary heterocyclyl groups include as moφholinyl, thiomoφholinyl, piperidinyl, pyrrolidinyl and the like.

'Heteroaryloxy' is heteroaryl-O-, wherein heteroaryl group is as defined above. Exemplary heteroaryloxy groups include pyrazinyloxy, isothiazolyloxy, oxazolyloxy, pyrazolyloxy, pyrrolyloxy, pyridazinyloxy, thienopyrimidyloxy, furyloxy, indolyloxy, isoindolyloxy, 1,3-benzodioxolyloxy,- 1,3-benzoxathiolyloxy, quinazolinyloxy, pyridyloxy, thiophenyloxy, benzothiazolyloxy, benzoimidazolyloxy, pyridazinyloxy, pyrimidmyloxy and the like.

'Heterocyclyloxy' is heterocyclyl-O-, wherein heterocyclyl group is as defined above. Exemplary heterocyclyl groups include moφholinyloxy, thiomoφholinyloxy, piperidinyloxy, pyrrolidinyloxy and the like. 'Heteroaralkyl' is heteroaryl-(C]-Ci₀)alkyl group, wherein the heteroaryl and (C,- Cιo)alkyl groups are as defined above. Exemplary heteroaralkyl groups include pyrazinylmethyl, pyrazinylethyl, pyrazinylpropyl, pyrazinylbutyl, pyrazinylpentyl, pyn-olylmethyl, pyrrolylethyl, pyrrolylpropyl, pyrrolylbutyl, pyrrolylpentyl, and the like.

'Heterocycloalkyl' is heterocyclyl-(Cι-Cι₀)alkyl giOup, wherein the heterocyclyl and (Cι-Cιo)alkyl groups are as defined above. Exemplary heterocycloalkyl groups include moφholinylmethyl, moφholinylethyl, moφholinylpropyl, moipholinylbutyl, moφholinylpentyl, piperidinylmethyl, piperidinylethyl, piperidinylpropyl,, piperidinylbutyl, piperidinylpentyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl, pyrrolidinylbutyl, pyrrolidinylpentyl and the like.

'Heteroaralkoxy' is heteroaralkyl-O-, wherein heteroaralkyl group is as defined above. Exemplary heteroaralkoxy groups include pyrazinylmethoxy, pyrazinylethoxy, pyrazinylpropoxy, pyrazinylbujoxy, pyrazinylpentoxy, pyrrolylmethoxy, pyrrolylethxy, pyrrolylpropoxy, pyrrolylbutoxy, pyrrolylpentoxy and the like.

'Hetero cycloalkoxy' is heterocycloalkyl-O-, wherein heterocycloalkyl group is as defined above. Exemplary heterocycloalkoxy groups include moφholinylmethoxy, moφholinylethoxy, moφholinylpropoxy, moφholinylbutoxy, moφholinylpentoxy, piperidinylmethoxy, piperidinylethoxy, piperidinylpropoxy, piperidinylbutoxy, piperidinylpentoxy, pyrrolidinylmethoxy, pyrrolidinylethoxy, pyrrolidinylpropoxy, pyrrolidinylbutoxy, pyrrolidinylpentoxy and the like.

'Heteroaralkoxyalkoxy' is heteroaralkyl-O-(C]-Cιo)alkoxy, wherein heteroaralkyl and (Cι-Cιo)alkoxy groups are as defined above. Exemplary Heteroaralkoxy(Cι-Cιo)alkoxy groups include moφholinylmethoxymethoxy, moφholinylmethoxyethoxy, moφholinylmethoxypropoxy, moφholinylmethoxy butoxy, morpholinylmethoxypentoxy, piperidinylmethoxymethoxy, piperidinyl methoxyethoxy, piperidinylmethoxypropoxy, .piperidinylmethoxybutoxy, piperidinyl methoxypentoxy, pyrrolidinylmethoxymethoxy, pyrrolidinylmethoxyethoxy, pyrrolidinyl methoxypropoxy, pyrrolidinylmethoxybutoxy, φyrrolidinyl methoxypentoxy and the like.

'Acyl' is H-CO- or (Cι-Cιn)alkyl-CO-, where (Cι-Cιo)alkyl group is as defined above. Exemplary acyl groups include acetyl, propionyl, benzoyl and the like.

'Acyloxy' is (Cι-C₆)acyl-O- group, where acyl group is as defined above. Exemplary acyloxy groups include acetyloxy, propionyloxy, benzoyloxy and the like. 'Alkylcarbonyl' is (Cι-Cιn)alkyl-CO-, wherein (Cι-Cιn)alkyl group is as defined above. Exemplary alkylcarbonyl groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl and the like.

'Alkoxycarbonyl' is (Cι-Cιo)alkyl-O-CQ-, wherein (Cι-Cιo)alkyl group is as defined above. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, t- butoxycarbonyl and the like.

'Arylcarbonyl' is aryl-CO-, wherein aryl group is as defined above.. Exemplary arylcarbonyl groups include phenylcarbonyl, naphthylcarbonyl and the like.

'Aryloxycarbonyl' is aryl-O-CO-, wherein aryl group is as defined above. Exemplary aryloxycarbonyl groups include phenoxycarbonyl, naphthyloxycarbonyl and the like.

'Aralkoxycarbonyl' is aryl-(Cι-C₆)alkoxy-CO-, where aryl and (Cι-C₆)alkoxy are as defined above. Exemplary aralkoxycarbonyl groups include benzyloxycarbonyl, 2- phenethyloxycarbonyl and the like.

'Carboxylic acid or its derivatives' may be amides or esters. Exemplary carboxylic acid groups include CONH₂, CONHMe, CONMe₂, CONHEt, CONEt₂, CONHPh, COOCH₃, COOC₂H₅ or COOC₃H₇.

'Sulfonic acid or its derivatives' may be amides or esters. Exemplary sulfonic acid groups include SO₂NH₂, SO₂NHMe, SO₂NMe₂, SO₂NHCF₃, COOCH₃, COOC₂H₅, or COOC₃H₇.

All the above-described groups may be mono, di or tri substituted with 'suitable substituents'.

The present invention also- relates to a process for the preparation of the compound of formula (I) where all symbols are as defined earlier. The process is as shown in Scheme-I:

Scheme-1

The compound of formula (la) is converted to a compound of formula (lb) by using methods reported in the literature (J. Med. Chem., 1996(39)267-276, 1977(20)146-149, 1996(39)918-928, 1996(39), 1823-1835 and 1999(42)5369-5389; Bio. Org. Med. Chem. Lett., 1997, 7(4), 417-420 and 2000, 2477-2480; US patent no. 6,002,008).

The compound of formula (lb) is converted to a compound of formula (Ic), where X represents halogen atom, by using a reagent selected from thionyl chloride, oxalyl chloride, phosphorous trichloride (PC1 ), phosphorous pentachloride (PC1₅), phosphorousoxychloride and the like. The reaction may be carried out in the presence of catalyst such as dimethyl formamide, triethylamine, pyridine, dimethyl pyridine, 4-(dimethylamino)pyridine (4-DMAP) and the like. The solvent used in the reaction may be selected from dichloromethane, 1,2- dichloroethane, chloroform, carbontefrachloride and the like. The temperature of the reaction may be in the range of 20 to 100 °C. The duration of the reaction may be in the range of 0 to 24 hours, preferably 3 to 6 hours. Alternatively, formula (lb) may be converted to (Ic), where X represents -S-(Cι-Cιo)alkyl, in the presence of reagents such as phosphorous pentoxide, N,N'-dicyclohexyl-carbodiimide (DCC), calciumoxide, perchloric acid, friphenylphosphine (Ph₃P)/diethylazadicorboxylate (DEAD), Ph₃P/diisopropylazadicorboxylate (DIAD), pyridinium hydrochloride and the like. The solvent used in the reaction may be selected from pyridine. The reaction is carried out in the temperature range 10 to 80 °C. The duration of the reaction may in the range of 10 to 24 hours, preferably 10 to 16 hours. The base used in the reaction may be carried out in the presence of potassium hydroxide, sodium hydroxide and the like.

The compound of formula (Ic) is reacted with the compound of formula (Id), to obtain a compound of formula (Id), in the presence of solvent selected from alcohols, esters, ethers, aromatic solvents, aprotic solvents, carbon tefra chloride, chloroform, dichloromethane and the similar class of solvents. The alcohols may be selected from methanol, ethanol, butanol, tert-butanol, isopropanol and the like or mixtures thereof. The ethers may be selected from tetrahydrofuran, diglyme, 1,4-dioxane and the like. The aromatic solvents may be selected from toluene, xylene and the like. The aprotic solvents are selected from N, N- dimethylformamide, N,N-dimethyl acetamide, dimethylsulfoxide and the like. The temperature of the reaction may be in the range of 10 to 150 ° C, preferably in the range of 25 to 100 °C. The duration of the reaction may be in the range of 0.1 to 24 hours, preferably in the range of 1 to 3 hours.

The compound of formula (I) is obtained from compound of formula (Ie), by reacting with a compound of formula (If), in the presence of a suitable base selected from pyridine, 2- picoline, 3-picoline, 4-picoline, moφholine, 2,6-lutidine, N-methyl moi holine, 4-(N,N- dimethylamino)pyridine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), triethylamine and all other similar class of bases. The reaction may also be carried out in the presence of N-ethyldiisopropylamine alkali or alkaline earth metal carbonates, hydroxides or amides. The alkali or alkaline earth amides may be selected from sodium amide, sodium (bis(trimethylsilyl)amide), lithiumliexamethylphosphoramide (Lithium-HMDS), lithium hexamethyldiisopropylamide (Lithium-HMPA) and the like. The solvent used in the reaction may be selected from alcohols, esters, ethers, aromatic solvents, aprotic solvents, carbontefrachloride, chloroform, dichloromethane and the similar class of solvents. The alcohols may be selected from mefhanol, efhanol, isopropanol 'and the like or mixtures thereof. The ethers may be selected from tetrahydrofuran, diglyme, 1,4-dioxane and the like. The aromatic solvents may be selected from toluene, xylene and the like. The aprotic solvents are selected from N, N- dimethylformamide, N,N-dimethyl acetamide, dimthylsulfoxide and the like. The temperature of the reaction may be in the range of 10 to 150 °C, preferably in the range of 25 to 90 °C. The duration of the reaction may be in the range of 0.1 to 24 hours, preferably in the range of 1 to 3 hours.

In still another embodiment of the present invention there is provided another process for the preparation of compound of formula (2), where R⁸ represents alkoxy group, R¹⁰ represents R¹ or R², which represent optionally substituted alkoxy, aralkoxy, heteroaralkoxy or acyloxy groups and all other symbols are as defined in the description. The compound of formula (2) represents compound of formula (I), when R⁸ and R¹⁰ attached to the 6^th and 7^th positions of the hetero bicyclic ring. The process is as shown in Scheme-II:

Scheme-II

The compound of formula (2a) is converted to a compound of formula (2b), where R⁷ represents protecting groups such as acetyloxy, benzyloxy and the like, X represents a halogen atom, by using a reagent selected from thionyl chloride, oxalyl chloride, phosphorous oxychloride phosphorous trichloride, phosphorous pentachloride and the like. The reaction may be carried out in the presence of catalyst such as dimethyl formamide, triethylamine, pyridine, N-ethyldiisopropylamine, 4-(N,N-dimethylamino)pyridine and the like. The solvent used in the reaction may be selected from dichloromethane, dichloro ethane, chloroform, carbontetrachloride and the like. The temperature of the reaction may be in the range of 20 to 100 °C. The duration of the reaction may be in the range of 0 to 24 hours, preferably 3 to 6 hours (method(s) are reported in the literature (J. Med. Chem., 1996(39)267-276, 1977(20)146-149, 1996(39)918-928, 1996(39), 1823-1835 and 1999(42)5369-5389; Bio. Org. Med. Chem. Lett., 1997, 7(4), 417-420 and 2000, 2477-2480; US patent no. 6,002,008).

The compound of formula (2b) is reacted with the compound of formula (2c), to obtain a compound of formula (2d), in the presence of solvent selected from alcohols, esters, ethers, aromatic solvents, aprotic solvents, carbon t^'etra chloride, chloroform, dichloromethane and the similar class of solvents. The alcohols may be selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol and the like or mixtures thereof. The ethers may be selected from tetrahydrofuran, diglyme, 1,4-dioxane and the like. The aromatic solvents may be selected from toluene, xylene and the like. The aprotic solvents are selected from N, N-dimethylformamide, N,N-dimethyl acetamide, dimthylsulfoxide and the like. The reaction may be carried out in the presence of a base such as NaNO₃, KNO₃, Na CO₃, K₂COj, MgCO₃, pyridine, triethylamine, NaHCO₃, N-ethyldiisopropylamine, 4- (dimethylamino)pyridine, picoline, 2,6-lutidine and the like. The temperature of the reaction may be in the range of 10 to 150 °C, preferably in the range of 25 to 90 °C. The duration of the reaction may be in the range of 0.1 to 24 hours, preferably in the range of 1 to 5 hours.

The compound of formula (2d) is converted to a compound of formula (2e) by using a reagent selected from guanidine, NH₃, BF₃.Et₂O, BF₃.OEt₂O, sodium, CF₃OSO₂F, CH₃OSO₂F, PhSCH₃, trifluoroacetic acid, sodiumiodide, magnesiumbromide and other similar class of reagents! The solvent used in the reaction may be selected from tetrahydrofuran, benzene, toluene, dichloromethane, acetone, (Cι-Cιo)alcohol such as methanol, ethanol, propanol, isopropanol, tert-butyl alcohol and the like or mixtures thereof. The reaction may be carried out in the presence or absence of water. The reaction may be carried out in the presence or absence of a base. The base used in the reaction may be selected from sodium carbonate, potassium carbonoate, magnesium carbonate, sodium bi carbonate and the like. The reaction may be carried out in the temperature range of 0 to 100 °C, preferably in the range of 0 to 80 °C. The duration of the reaction may be in the range of 0.2 to 50 hours, preferably in the range of 0.5 to 45 hours.

The compound of formula (2e) is converted to a compound of formula (2f) by reacting with compound of formula (2e'), where R⁹ represents optionally substituted alkyl, aralkyl, heteroaralkyl, heterocyclylalkyl, aminoalkyl or acyl groups and X represents halogen atom, in the presence of a base selected from NH , pyridine, moφholine, 2,6-lutidine, N-methyl moipholine, 4-(N,N-dimethylamine) pyridine, DBU, DBN, triethylamine and all other similar class of bases. The reaction may also be carried out in the presence of alkali or alkaline earth metal carbonates, hydroxides or amides. The alkali or alkaline earth amides may be selected from sodium amide, sodium bis(frimethylsilyl)amide, lithium hexamethyl diisopropyl amide and the like. The solvent used in the reaction may be selected from alcohols, esters, ethers, aromatic solvents, aprotic solvents, carbon tetra chloride, chloroform, dichloromethane and the similar class of solvents. The alcohols may be selected from methanol, ethanol, isopropanol and the like or mixtures thereof. The ethers may be selected from tetrahydrofuran, diglyme, 1,4-dioxane and the like. The aromatic solvents may be selected from toluene, xylene and the like. The aprotic solvents are selected from N, N-dimethylformamide, N, N- dimethyl acetamide, dimthylsulfoxide and the like. The temperature of the reaction may be in the range of 10 to 150 °C, preferably in the range of 25 to 90 °C. The duration of the reaction may be in the range of 0.1 to 24 hours, preferably in the range of 1 to 3 hours.

The compound of formula (2) may be prepared from compound of formula (2f), by reacting with a compound of formula (2g), in the presence of a suitable base selected from pyridine, moφholine, 2,6-lutidine, N-methyl moφholine, dimethyl amine pyridine, DBU, DBN, triethylamine and all other similar class of bases. The reaction may also be carried out in the presence of alkali or alkaline earth metal carbonates, hydroxides or amides. The alkali or alkaline earth amides may be selected from sodium amide, sodium (bis(trimethylsilyl)amide, lithium hexarnethyl diisopropyl amide and the like. The solvent used in the reaction may be selected from alcohols, esters, ethers, aromatic solvents, aprotic solvents, carbon tetra chloride, chloroform, dichloromethane and the similar class of solvents. The alcohols may be selected from methanol, ethanol, isopropanol and the like or mixtures thereof. The ethers may be selected from tetrahydrofuran, 1,4-dioxane and the like. The aromatic solvents may be selected from toluene, xylene and the like. The aprotic solvents are selected from N, N-dimethylformamide, N,N-dimethyl acetamide, dimthylsulfoxide and the like. The temperature of the reaction may be in the range of 10 to 150 °C, preferably in the range of 25 to 90 °C. The duration of the reaction may be in the range of 0.1 to 24 hours, preferably in the range of 1 to 3 hours.

It is appreciated that in any of the above-mentioned reactions, any reactive group in the subsfrate molecule may be protected according to conventional chemical practice. Suitable protecting groups in any of the above mentioned reactions are tertiarybutyldimethylsilyl, methoxymethyl, triphenyl methyl, benzyloxycarbonyl, tetrahydropyran(THP) etc, to protect hydroxyl or phenolic hydroxy group; N-tert-butoxycarbonyl (N-Boc), N-benzyloxycarbonyl (N-Cbz), N-9-fluorenyl methoxy carbonyl (-N-FMOC), benzophenoneimine, propargyloxy carbonyl (POC) etc, for protection of amino or anilino group, acetal protection for aldehyde, ketal protection for ketone and the like. The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.

Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2- dimethylaminoethanol, N-ethylmoφholine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, mefhylglucamine, moφholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, diethanolamine, meglumine, ethylenediamine, N,N'-diphenylethylenediamine, N,N'- dibenzylethylenediamine, N-benzyl phenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, spermidine, and the like; chiral bases like alkylphenylamine, glycinol, phenyl glycinol and the like, salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyiOsine, cystine, cysteine, methionine, proline, hydroxy proline,- histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids such as D-isomers or substituted amino acids; guanidine, substituted guanidine wherein the substituents are selected from riitro, amino, alkyl such as methyl, ethyl, propyl and the like; alkenyl such as ethenyl, propenyl, butenyl and the like; alkynyl such as ethynyl, propynyl and the like; ammonium or substituted ammonium salts and aluminum salts. Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, halides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicyjates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.

The geometrical isomers of the present invention cover the mixture of E and Z isomers . or individual E and Z isomers.

The pharmaceutically acceptable salts are prepared by reacting the compounds of formula (I) wherever applicable with i to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in the presence of a solvent like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, tromethamine, guanidine and their derivatives etc. may also be used. Alternatively, acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, Sic acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in the presence of a solvent like ethyl acetate, ether, alcohols, acetone, THF, dioxane and the like. Mixture of solvents may also be used. The salts of amino acid groups and other groups may be prepared by reacting the compounds of formula (I)' with the respective groups in the presence of a solvent like alcohols, ketones, ether and the like. Mixture of solvents may also be used.

The term "therapeutically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or patient that is being sought.

It is to be understood that this invention is not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the puφose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

The present invention also provides pharmaceutical compositions, containing compounds of the general foraiula (I), as defined above, their pharmaceutically acceptable salts in combination with the usual pharmaceutically employed carriers, diluents and the like. The pharmaceutical compositions according to this invention can be used for the treatment of cancer.

The pharmaceutical compositions may be in the forms normally employed, such as tablets, capsules, powders, dispersible granules, cachets, suppositories, syrups, solutions, suspensions and the like, may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. . Such compositions typically contain from 0.1 to 50%, preferably 1 to 20% by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents

Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active compounds will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the compounds can be combined with a suitable solid, liquid carrier or diluent to form capsules, tablets, powders, dispersible granules, cachets, suppositories, syrups, solutions, suspensions, emulsions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like. For parenteral administration, the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically- acceptable acid addition salts or salts with base of the compounds. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.

Tablets, dragees or capsules having talc and / or a carbohydrate carried binder or the like are particularly suitable for any oral application. Preferably, carriers for tablets, dragees or capsules include lactose, corn starch and / or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.

The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the' severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the therapeutically effective amount of the drug required to prevent, counter or arrest the progress of the condition.

In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as 'carrier' materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drag components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or nec'essary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incoφorated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, soaium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

The compounds of the formula (I) or pharmaceutical compositions thereof as defined above are clinically administered to mammals, including human beings, via oral, parenteral and/or topical routes. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in circumstances where the patient cannot swallow the medication, or absoφtion following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally. By either route, the dosage is in the range of about 1 mg/kg to about 1000 mg / kg, preferably from about 1 mg to about 500 mg/kg of active ingredient, of the subject per day administered singly or as a divided dose. However, the optimum dosage whether for prevention or treatment for the individual subject being treated will be determined by the person responsible for treatment, Initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administering, eg. 2-4 times per day. It is to be understood that the dosages may vary depending upon the requirements of the patient. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary slcill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

The manner in which the compounds of this invention can be prepared is illustrated in the following examples, which demonstrate the preparation of typical species of the invention. In these examples, the identities of compounds, intermediates and final, were confirmed by infrared, nuclear magnetic spectral analyses as necessary. The examples are for the puφose of illustration only and should not be regarded as limiting the invention in any way. Example 1 l-[4-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-fluoro-benzyl)-oxime

Step (i : Preparation of 4-chloroquinazoline

A mixture of quinazoloήe (5 grams, 30 mmoles) (J. Med. Chem., 1977(20)146-149), 20..5mL of dimethyl formamide were taken in 30 mL of 1,2-dichloroethane and 20 mL of thionylchloride (32.5 grams, 270 mmoles) was added at 20-35 °C. Reaction mixture was heated at 90 °C for 2 hours, formation of clear solution was observed. Thionyl chloride was removed under vacuum. The resultant solid was dissolved in dichloromethane and filtered through 230-400 silica gel bed. The silica gel bed was washed with excess of dichloromethane and was concentrated to yield 5 grams of the 4-chloroquinazoline. Yield: 90% Step (ii): Preparation of l- 4-(Quinazolin-4-ylamino)-phenyl]-ethanone

A mixture of 4-chloroquinazoline (5 grams, 30.3 mmoles), obtained in step (i) and 4- aminoacetophenone (4.93 grams, 36 mmol) in 35 mL of isopropylalcohol was heated at 90 °C for 2 hours and allowed to stand at 20-35 °C for 3 hours, during which solid was precipitated. The solid was filtered and washed with diethyl ether to afford the pure yellow solid. Yield: 92%. Melting point: 231 °C.

Η-NMR (CDCl₃+DMSO-d₆): δ 9.0 (1H, d, J=8.6 Hz), 8.8 (1H, s), 8.1 (2H, d, J=8.0 Hz), 8.0 (2H, d, J=8.8 Hz), 7.9 (2H, d, J=8.8 Hz), 7.8 (2H, t, J=8.2 Hz), 2.4 (3H, s). Mass (m/z) CI: 264(M⁺), 136. Step (iii): l- 4-(Ouinazolin-4-ylamino -phenyl]-ethanone-O-(4-fluoro-benzyl)-oxime

A mixture of l-[4-(Quinazolin-4-ylamino)-phenyl]-ethanone (3.5 grams, 13 mmoles), obtained in step (ii) and 4-fluoro benzyloxyamine hydrochloride (J. Org. Chem., 1988, 53(13) 2997) (3.5 grams, 19.9 mmoles) in 24 mL of methanol and 2.69 mL (33 mmoles) of pyridine was heated at 70 °C for 3 hours. Removal of the solvent gave yellow residue which was purified by column chromatography over 100-200 silica gel. Elution with 1% methanol in dichloromethane afforded pure yellow solid. Yield: 30%, Melting point: 158_. °C.

Η-NMR CDC1₃: δ 9.9 (1H, s), 8.64 (1H, d, j=8.4 Hz) 8.0 (2H, d, j=8.8 Hz), 7.8 (2H, d, j=8.0 Hz), 7.7 (2H, d, j=8.6 Hz), 7.5 (4H, d, j=8.0 Hz), 7.2 (2H, t, j=8.8 Hz), 5.2 (2H, s), 2.3 (3H, s) Mass (m/z) CI: 387( *), 261, 247, 125, 109.

Examples 2-12 have been prepared according to the methodology as described in example-1:

Example 13

4-{4-[l-(4-Fluoro-benzyloxyimino)-ethyl]-phenylamino}-7-isopropoxy-6-methoxy- quinoline-3-carbonitriIe

Step (i): Preparation of 4-chloro-7-isopropoxy-6-methoxy-quinoline-3 -carbonitrile

A mixture of 7-isopropoxy-6-methoxy-4-oxo-3,4-dihydro-3-quinoline carbonitrile (Bio. Org. Med. Chem. Lett, 2002(12)2011-2014), (2 grams, 7.75 mmoles) and 0.100 mL of N,N- dimethyl formamide were taken in 30 mL of 1,2 dichloroethane, then thionyl chloride (11.5 mL, 155 mmoles) was added slowly at 20-35 °C, then the reaction temperature increased to reflux temperature (90 °C) for 2 hours. Thionyl chloride was removed under vacuum. Solid formed was dissolved in 1 L dichloromethane and passed through 230-400 mesh silica gel. The dichloromethane layer was concentrated to afford about 2 grams of product as a white solid (yield: 93.8%). Step (ii): Preparation of 4- 4-acetylanilino1-7-isopropoxy-6-methoxy-3-quinoline carbonitrile

A mixture of 4-chloro-7-isopropoxy-6-methoxy-quinoline-3 -carbonitrile (2 grams, 7.23 mmoles), obtained in step (i), and l-(4-amino phenyl)-l- ethanone (1.17 grams, 8.6 mmoles), and 30 mL of isopropanol were heated at 90 °C for 4 hours, and the reaction was left at 20-35 °C. The resultant solid was filtered and' washed with diethylether.to obtain 2.2 grams of yellowish solid was obtained. Yield: 81%. Melting point: >250°C

Mass (CI): 376(M⁺) (100%), 333, 318, 253, 150, 136, 120, 92.

Η-NMR(DMSO-d₆): δ 11.0 (1H, s), 9.0 (1H, s), 8.0 (2H, d, J=7.2 Hz), 7.6 (1H, d, J=8.6 Hz), 7.5 (2H, d, J=8.3 Hz), 6.5 (1H, d, J=8.5 Hz), 4.8 (1H, m), 3.9 (3H, s), 2.6 (3H, s),1.4 (6H, d). IR (KBr, cm^"1): 3434, 2976, 2662, 2223, 1679, 1637, 1583, 1505, 1455, 1415, 1311, 1268, 1101, 922, 888, 819, 762, 656, 592, 491.

Step fiii): Preparation of 4-{4- l-(4-Fluoro-benzyloxyimino)-ethyl1-phenylamino}-7- isopropoxy-6-methoxy-quinoline-3-carbonifrile

A mixture of 4-[4-acetylanilino]-7-isopropoxy-6-methoxy-3-quinoline carbonitrile (500 mg, 1.33 mmoles), obtained in step (ii), 4-fluorobenzyloxyamine hydro chloride (J. Org. Chem., 1988, 53(13), 2997) (354 mg, 2 mmol) were taken in 15 mL of methanol, then pyridine (0.219 mL, 2.66 mmoles) was added at 20-35 °C, the reaction temp increased to 90 °C and continued for 4 hours. The precipitated solid was filtered and washed with diethylether .This was purified by flash column chromatography using 230-400 mesh silica gel. Elution with 5% methanol in dichloromethane afforded 0.2 grams of pure compound. Melting point: 174-176 °C .

IR (KBr, cm^"1): 3439, 2925, 1635, 1580, 1511, 1455, 1275, 1224.5, 1103, 1018, 923, 876,

824, 558

1H-NMR(DMSO-d₆): δ 10.9 (lH,s), 8.9 (IH, s), 8.0 (IH, s), 7.8 (2H, d), 7.4 (5H, m), 7.2 (2H, t), 5.2 (2H, s), 4.8 (IH, m), 4.0 (3H, s), 2.6 (3H, s), 1.4 (6H, d).

Mass (CI): m/z 499(M+1), 498(M+), 375, 126,125(base peak), 124,109(100%), 96, 95.

Examples 14-16 have been prepared according o the methodology as described in example-13:

O 2004/06914

42

Example 17 l.{4_[6-Methoxy-7-(3-morphoIin-4-yl-propoxy)-quinazolm-4-ylamino]-pIιenyI}- ethanone-O-benzyl-oxime

Step (j): Preparation of 7-benzyloxy-4-chloro-6-methoxy quinazoline.

A mixture of 7- quinazoline (5 grams, 17.7 mmoles), and dimethyl formamide (1 mL) were taken in 75 mL of dichloroethane, thionyl chloride (30 mL, 398.2 mmol) was added slowly at 20-35 °C, and then reaction continued at 90 °C for 4 hours, clear solution indicated that the reaction was completed. Thionyl chloride was removed under vacuum, solid formed was dissolved in dichloromethane and passed through 230-400 mesh silica gel, then washed with 3 L of dichloromethane and concentrated. 4.3 grams of white solid was obtained. Yield: 80%.

Step (ii): Preparation of l-f4-(7-Benzyloxy-6-methoxy-quinazolin-4-ylamino)-phenyll- ethanone.

A mixture of 7-benzyloxy-4-chloro-6-methoxy quinazoline (4.2 grams, 14 mmoles), obtained in step (i) and l-(4-aminophenyl)-l -ethanone (2.26 grams,16.8 mmoles) were taken in 60 mL of isopropanol and reaction continued at 90 °C for 4 hours. The precipitated solid was filtered and washed with diethylether to afford 4.5 grams of light yellowish compound. Yield: 80%. Melting point: 174476 °C

Η-NMR(DMSO-d₆): δ 11.7 (IH, s), 8.9 (IH, s), 8.5 (IH, s), 8.07 (IH, d, J=8.79 Hz), 8.02 (2H, d, J=8.79 Hz), 7.98 (IH, d, J=8.79 Hz), 7.94 (IH, d, J=8.79 Hz), 7.5 (2H, d, J=10.7 Hz), 7.48 (IH, d, J=10.7 Hz), 7.45 (IH, d, J=6.3 Hz), 7.42 (IH, d, J=6.3 Hz), 5.3 (2H, s), 4.04 (3H, s), 2.5 (3H, s).

Mass (CI): m/z 401(M+2), 400(M+1), 399(M+), 253, 150, 136(100%).

IR (KBr, cm^"1): 3003, 2589., 1796, 1670, 1632, 1600, 1575, 1513, 1445, 1405, 1361, 1322,

1303, 1274, 1230, 1181, 1156, 1063, 1011, 966, 902, 870, 850, 827, 777, 749, 701, 650, 582,

541,499.

Step (iii): Preparation of l-r4-(7-Hydroxy-6-methoxy-quinazolin-4-ylamino)-phenyl]- ethanone

A mixture of l-[4-(7-benzyloxy-6-methoxy-quinazolin-4-ylamino)-phenyl]-ethanone (4.4 grams, llmmoles), obtained in step (ii), trifluoroaceticacid (42 mL, 550 mmoles) was heated at reflux temperature at 75 °C for 5 hours, clear solution was observed, then the reaction mixture was added slowly to ice water and the solid formed was filtered and washed with water to give 3.2 grams of brownish solid. Yield: 94%. Melting point: 234-236 °C

Η-NMR(DMSO-d₆): δ 11.1 (IH, s), 8.8 (IH, s), 8.1 (2H, d), 8.0 (2H, d), 7.8 (2H, d), 4.49 (IH, s), 4.0 (3H, s), 2.6 (3H, s). .

Mass (CI): m/z 311(M+2), 310(M+1)(100%), 309(M+), 181, 136, 91.

IR (KBicπf¹: 2645, 1673,.1637, 1582, 1518, 1464, 1427, 1367, 1332, 1277, 1178, 1060, 1006, 964, 829, 770, 718, 590, 502.

Step (iv): Preparation of l-|4-[7-(^'3-Chloro-propoxy)-6-methoxy-quinazolin-4-ylamino1- phenyll-ethanone

, _ , ..

WO 2004/069145

45

A mixture of l-[4-(7-Hydroxy-6-methoxy-quinazolin-4-ylamino)-phenyl]-ethanone (3.1 grams, 10 mmoles), obtained in step (iii), fused potassium carbonate (5.5 grams, 40 mmoles) were taken in dry dimethylformamide (30 mL) and stirred for 15 minutes at 20-35 °C, then 1- bromo-3-chloro propane (1.5 mL, 15 mmoles) was added at 20-35 °C for 12 hours. Water was added to the reaction flask and extracted with ethylacetate. Ethylacetate layer was dried and concentrated under vacuum to afford 2.8 grams of yellow solid. Yield: 73%. Melting point: 154-156 °C

Η-NMR (DMSO-d₆): δ 9 7 (IH, s), 8.5 (IH, s), 7.8-8.2 (4H, m), 7.2 (2H, d). 4.2 (2H, t), 4.0 (3H, s), 3.8 (2H, t), 2.5 (3H, s), 1.8 (2H, m) Mass (CI): m/z 386(M+1)(100%), 387(M+), 350, 322, 102, 90.

IR (KBr, cm^"1): 3200, 1659, 1630, 1603, 1577 , 1516, 1456, 1417, 1358, 1274, 1244, 1207, 1176, 1146, 1060, 1012, 962, 933, 847, 785, 659, 593.

Step (v): Preparation of l-{4-[6-Methoxy-7-(3-morpholin-4-yl-propoxy)-quinazolin-4- ylaminol-phenyl}-ethanone

A mixture of l-{4-[7-(3-Chloro-propoxy)-6-methoxy-quinazolin-4-ylamino]-phenyl}- ethanone (1 gram, 2.59 mmoles), obtained in step (iv), and potassium carbonate (1.4 grams, 10.36 mmoles), were taken in dimethylformamide (15 mL), then moφholine (0.450 mL, 5.19 mmoles) was added at 20-35 °C, then temperature increased to 80 °C, continued for 4 hours. Water was added to the reaction mixture and extracted with ethylacetate, dried and concentrated under vacuum to afford 0:7 grams of yellow solid. Yield: 61%. Melting point: 150-152 °C.

Η-NMR (DMSO-d₆): δ 9.7 (IH, s), 8.5 (IH, s), 8.0 (5H, m), 7.2 (IH, s), 4.2 (2H, t, 3=6.1 Hz), 4.0 (3H, s), 3.5 (4H, t), 3.3 (6H, m), 2.5 (3H, s), 2.0 (2H, m). Mass (CI): M/z 437(M+1), 436.

IR (KBr, cm^"1): 3271, 2967, 2954, 2825, 1673, 1629, 1601, 1577, 1514, 1457, 1420, 1389, 1358, 1308, 1244, 1209, 1183, 1114, 1066, 1013, 958, 922, 840, 785, 656, 593, 557, 504. Step (vi): Preparation of l-{4-[6-Methoxy-7-(3-moφholin-4-yl-propoxy -quinazolin-4- ylaminol -phenyll -ethanone-O-b enzyl-oxime

A mixture of l-{4-[6-Methoxy-7-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]- phenyl} -ethanone (0.2 grams, 0.45 mmoles), obtained in step (v), and phenyl methoxy amine (J. Org. Chem., 1988, 53(13)2997) (0.225 grams, 1.8 mmoles) were taken in 10 mL of methanol, then pyridine (0.140 mL, 1.8 mmoles) was added at 20-35 °C, and reaction continued at 90 ^°C for 4 hours. Methanol was removed under vacuum, solid was taken in ether and filtered. The solid was purified by flash column chromatography using 230-400 mesh silica gel elution of the column with 10% methanol in dichloromethane afforded 0.128 grams of pure compound . Yield: 50% Melting point: 140-141 °C

IR (KBr, cm^"1): 3178, 2924, 2854, 1699, 1624, 1582, 1511, 1459, 1419, 1387, 1366, 1308, 1283, 1149, 1117, 1024, 926, 838, 744, 702, 657, 623, 599, 557.

Η-NMR (DMSO-d₆): δ 9.5 (IH, s), 8.4 (IH, s), 7.9 (IH, d, J=8.8 Hz), 7.8 (2H, d, J=8.8 Hz), 7.7 (IH, d, j=8.8 Hz), 7.6 (IH, m, d=8.8 Hz), 7.4 (2H, d, J=4.4 Hz), 7.39 (2H, d, J=4.4 Hz), 7.35 (IH, d, J=7.4 Hz), 7.1 (IH, d), 5.2 (2H, s), 4.1 (2H, t), 3.9 (3H, s), 3.5 (2H, t), 3.3 (2H, t), 2.5 (4H, t), 2.4(2H, t), 2.2(3H, s), 1.9(2H, m). Mass (CI): m z 542(M+), 436, 316, 233, 183, 147,125, 109(100%), 91.

Examples 18-28 have been prepared according o the methodology as described in Example-17: 47

ExampIe-29 l-{4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazoIin-4-ylamino]-phenyl}- ethanone- O-benzyl-oxime

Step (i): Preparation of acetic acid 4-chloro-7-methoxy-quinazolin-6-ylester

7-Methoxy-4-oxo-3,.4-dihydro-6-quinazolinyl acetate (4 grams, 17.1 mmoles), was taken in 40 mL of dichloroethane and 24 mL of thionyl chloride we^'re added followed by 0.1 mL of dimethylformamide. The Contents were refluxed for 4-5 hours and 40 mL of dichloroethane was added, and solvent was evaporated in a rotavapor. The reaction mixture was dissolved in dichloromethane, passed through 230-400-mesh silica gel, concentrated and dried to yield the product (3.2 grams, Yield: 76%)

Step (ii): Preparation of Acetic ^' acid 4-(4-acetyl-phenylamino)-7-methoxy-quinazolin-6-yl ester

Acetic acid 4-chloro-7-methoxy-quinazolin-6-yl ester (3.2 grams, 12.6mmoles), obtained in step (i) was taken in 80 mL of isopropylalcohol and 4-amino acetophenone (2 grams, 14.8mmoles) was added and the contents refluxed for 2 hours. The reaction flask was left overnight and solid precipitated was filtered and dried under vacuum. Yield: 92%. Melting point: 250 °C

IR (KBr, cm^"1): 3029, 2619, 1777, 1677, 1643, 1574, 1527, 1438, 1363, 1264, 1294, 1267, 1175, 1152, 850, 815;

¹HNMR (DMSO-d₆): δ 11.5(1H, s), 8.9 (IH, s), 8.8 (IH, s), 8.0 (2H,_.d, J=8.6 Hz), 7.9 (2H, d, J=8.6), 7.5(1H, s), 4.0 (3H, s), 2.5 (3H, s), 2.4 (3H,s); Mass (m/z, CI) 352 (M+l, 100%) 310, 178, 136.

Step (iii): Preparation of l-f4-(6-Hvdroxy-7-methoxy-quinazolin-4-ylamino)-phenyl]- ethanone-O-benzyl-oxime

Acetic acid 4-(4-acetyl-phenylamino)-7-methoxy-quinazolin-6-yl ester (1.3 grams, 3.7mmoles), obtained in step (ii) O-benzyl hydroxyl amine (0.49 grams, 4.49 moles) (J. Org. Chem., 53(13), 1988 , 2997) were taken in 12 mL of methanol and 0.539 mL of pyridine was added and the contents were refluxed for 3 hours. The precipitated solid was filtered and dried under vacuum to give 1.2 grams of the product. Yield: 87%. Melting point. 177 °C IR (KBr, cm^"1): 3435, 2927, 2360, 1597, 1511, 1428, 1391, 1240, 1155, 920, 833, 558; 'HNMR (DMSO-d₆): δ 11.1(IH, s), 8.8 (IH, s), 8.1(1H, s), 8.0(1H, s), 7.5(2H, m), 7.4(4H, m), 7.2(3H, m), 5.8 (IH, s), 5.1(2H, s), 4.0(3H, s), 2.2(3H, s); Mass m/z(CI): 415 (M+l), 414 (M+), 125 (Base.peak), 109.

Step Civ): Preparation of l-{4-[6-(3-Chloro-propoxy)-7-methoxy-qumazolin-4-ylamino1- phenyl) -ethanone-O-benzyl-oxime

A mixture of l-[4-(6-hydroxy-7-methoxy-quinazolin-4-ylamino)-phenyl]-ethanone-O- benzyl-oxime (0.64 grams, 1.5mmoles), obtained in step (iii) and 0.85 grams of fused potassium carbonate were taken in dry dimethylformamide and stirred for 15 minutes then 0.85 mL of 1- bromo-3-chloro propane was added at 20-35 °C. The contents were stirred at 20-35 °C over night and water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with water and concentrated. The residue was purified by Flash column chromatography over 100-200 silica gel to afford 0.45 grams of product. Yield: 60%. Melting point: 224 °C

IR (KBr, cm^"1): 3294, 2933, 2873, 1625, 1575, 1512, 1426, 1311, 1244, 1209, 1145, 912, 741,

555.

1HNMR(DMSO-d₆): δ 11.1 (IH, s), 9.5 (IH), 8.4 (IH, s), 8.1 (IH, s), 7.9 (2H, d, J=8.8 Hz),

7.6 (2H, d, J=8.6 Hz), 7.3 (5H, m), 5.2 (IH, s), 4.3 (2H, J=5.9 Hz, t), 4.0 (3H, s), 3.8 (2H,

J=6.4 Hz, t), 2.2 (3H, s), 1.8 (2H, m).

Mass (CI): 491 (M+l, 100%)

Step (v : Preparation of l-{4-r7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4- ylaminol-phenyl^'. -ethanone-O-benzyl-oxime

l-{4-[6-(3-Chloro-propoxy)-7-methoxy-quinazolin-4-ylamino]-phenyl}-ethanone-O- benzyl-oxime (0.46 grams, 0.93 mmoles), obtained in step (iv) and fused potassium carbonate (0.518 grams, 3.7 mmoles) was taken in dry dimethylformamide stirred for 15 minutes at 20- 35 °C, and 0.122 mL of moφholine was added. The contents stirred for 5 hours at 80 °C. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried and concentrated to afford 0.350 grams of crude compound. The crude was purified by flash column chromatography using 100-200 mesh silica gel. Elution of the column with 30% Acetone in dichloromethane afforded 0.260 grams of pure compound. Yield: 52%, Melting point: 186-188 °C. IR(KBr, cm^"1): 3342, 2928, 1622, 1599, 1512, 1470, 1427, 1392, 1241, 1209, 1014, 981, 859.

'HNMR (CDC1₃): δ 8.6 (IH, s), 7.7 (4H, m), 7.6 (8H, m), 5.2 (2H, s), 4.2 (2H, J=6.4 Hz, t),

3.9 (3H, s), 3.7 (4H, m), 2.6 (6H, m), 2.5 (3H, s), 1.8 (2H, m).

Mass (m/z)(CI): 542 (M+l), 541(M⁺), 436, 434, 107(100%).

Example 30 l-{4-[7-Methoxy-6-(3-morpholin-4-yI-propoxy)-quinazoIin-4-yIamino]-phenyI}- ethanone-O-(4-chloro-benzyl)-oxime

Step (i): Preparation of acetic acid 4-chloro-7-methoxy-quinazolin-6-yl ester

7-Methoxy-4-oxo-3,4-dihydro-6-quinazolinyl acetate (4 g,rams 17.1 mmoles) was taken in 40 mL of dichloroethane and 24 mL of thionyl chloride were added followed by 0.1 mL of dimethylformamide. The Contents were refluxed for 4-5 hours and 40 mL of dichloromethane was added, and solvent was evaporated in a rotavapor. The reaction mixture was dissolved in dichloromethane, passed through 230-400 mesh silica gel, concentrated and dried to yield the product (3.2 grams, Yield: 76%)

Step (ii): Preparation of Acetic acid 4-(4-acetyl-phenylamino)-7-methoxy-quinazolin-6-yl ester

Acetic acid 4-chloro-7-methoxy-quinazolin-6-yl ester (3.2 grams, 12.6 mmoles), obtained in step (i), was taken in 80 mL of isopropyl alcohol and 4-amino acetophenone (2 grams, 14.8 mmoles) of) was added and the contents refluxed for 2 hours. The reaction flask was left overnight and solid precipitated was filtered and dried under vacuum. Yield: 92% Melting point: 250 °C. IR(KBr, cm^"1): 3029, 2619, 1777, 1677,-1643, 1574, 1527, 1438, 1363, 1264, 1294, 1267,

1175,1152,850,815.

'HNMR (DMSO-d₆): δ 11.5 (IH, s), 8.9 (IH, s), 8.8 (IH, s), 8.0 (2H, J=8.6 Hz, d), 7.9 (2H,

J=8.6, d), 7.5 (IH, s), 4.0 (3H, s), 2.5 (3H, s), 2.4 (3H, s)

Mass (m/z, CI): 352 (M+l,100%) 310, 178, 136,

Ste^p dip: Preparation of l-r4-f6-H^ydroxy-7-methoxy-quinazolin-4-ylamino)-phenyl^"]- ethanone

Acetic acid 4-(4-acetyl-phenylammo)-7-methoxy-quinazolin-6-yl ester (4 grams, 10.3 mmoles), obtained in step ,(ii) and 20 mL of aqueous ammonia were taken in 20 mL of methanol. The above contents were stirred at 20-35 °C for 2 hours. The solid formed was filtered and dried. The weight of the product was observed as 3 grams. Melting point: 260 °C.

'HNMR (DMSO-d₆): δ 9.75 (IH, s), 8.55 (IH, s), 8.15 (2H, J=8.5 Hz, d), 7.9 ( 2H, J=8.6 Hz, d), 7.25 (2H, s), 4.0 (3H, s), 2.5 (3H, s) Mass(m/z)(CI): 310 M⁺(100%).

IR (KBr, cm^"1): 3442, 3291, 2930, 1626, 1512, 1473, 1344, 1399, 1244, 1024, 914, 837, 559 Step (iv): Preparation of l-{4-[^"6-(3-Chloro-propoxy -7-methoxy-quinazolin-4-ylaminol- phenyl} -ethanone

l-[4-(6-Hydroxy-7-methoxy-quinazolin-4-ylamino)-phenyl]-ethanone (3 grams, 8.68 mmoles), obtained in step (iii) and fused potassium carbonate (5.3 grams, 38.3 mmoles) of were taken in dry dimethylformamide, stirred for 15 minutes and 1.14 moles of l-bromo-3- chloro propane was added and the contents were stirred at 20-35 °C for 12 hours. Water was added to the reaction mixture and extracted with ethyl acetate. Organic layer was washed with water and the solvent was evaporated. The weight of the product was 2.6 grams. Yield 76%. Melting point: 240 °C. 1HNMR (DMSO-d₆): δ 8.65 (IH, s), 8.05 (4H, m), 7.45 (IH, s), 7.25 (2H, s), 4.35 (2H, J=5.9

Hz, t), 3.95 (3H, s), 3.85 (2H, J-6.1 Hz, t), 2.6 (3H, s), 2.45(2H, m)

Mass (CI): m/z 386(M⁺,100%).

IR(KBr, cm^"1): 3350, 2930, 1653, 1578, 1520, 1470, 1426, 1275, 1242, 1204, 1144, 838, 653,

590

Step (v⁾: Preparation of l-(4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4- ylamino] -phenyl-ethanone

l-{4-[6-(3-Chloro-propoxy)-7-methoxy-quinazolin-4-ylamino]-phenyl} -ethanone (1.2 grams, 3.1 mmoles), obtained in step (iv) and fused potassium carbonate (1.9 grams,

13.7mmoles) was taken in dry dimetyhylformamide stirred for 15 minutes at 20-35 °C followed by 0.44 mL (5 mmoles) of moφholine. Reaction contents were stirred at 80 °C for 5 hours. Reaction mixture was exfracted with ethyl acetate and organic layer was given water washings. It was then concentrated and dried. The weight of the product observed was 0.7 grams. Yield 54%

Η-NMR (DMSO-d₆): δ 9.75 (IH, s), 8.5 (IH, s), 8.0 (5H, m), 7.2 (IH, s), 4.25 (2H, J=6.1

Hz, t), 4.0 (3H, s), 3.5 (4H, t), 2.5 (3H), 2.4 (6H, m), 2.0 (2H, m).

Mass (CI): m/z 437 (100%)!

IR (KBr, cm^"1): 3385, 2927, 1653, 1601, 1514, 1469, 1425, 1390, 1274, 1240, 1117, 846, 607.

Step (vi): Preparation of l-(4-F7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-

A mixture of l-{4-[7-methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]- phenyl} -ethanone (0.23 grams, 0.53 mmoles), obtained in step (v) and 0.155 grams (0.79 mmoles) of [(4-chloro benzyl)oxy] ammonium chloride (J. Org. Chem., .53(13), 1988 , 2997), 0.127 mL (1.5 mmoles) of pyridine were taken in 8 mL methanol and refluxed for 2 hours. Ice was added to the reaction mixture, extracted with ethyl acetate and ethyl acetate layer was washed with water, dried and concentrated. The Residue was purified by flash column chromatography over 100-200 silica gel to afford 0.2 grams of product. Yield: 66%

Melting point: 177-179 °C.

IR (KBr, cm^"1): 3425, 2931, 1634, 1520, 1439, 1278, 1233, 1012, 885.

'HNMR (CDCI3): δ 8.6(1H, s), 7.75 (3H, m), 7.5 (7H, m), 5.15 (2H, s), 4.25 (2H, J=6.5 Hz, i), 3.95 (3H, s), 3.75 (4H, m), 2.55 (6H, m), 2.25 (3H, s), 1.85 (2H, m).

Mass (CI): m/z 576 (M+), 141(100%) 436, 437, 405.

Examples 31-39 have been prepared according to the methodology as described in Examples 29 and 30:

j 5,1

7.0

1H-NMR (DMSO-d₆): δ 9.1 (IH, s), 8.5

(IH, s), 8.3 (IH, s), 7.9 (2H, d, J=8.6 Hz),

7.7 (2H, d, J=18.8 Hz), 7.6 (IH, s), 7.4

(2H, d, J=8.3 Hz), 7.3 (IH, s), 5.2 (2H, s),

4.3 (2H, t, J=6.5), 4.0 (3H, s), 2.55 (6H,

m), 2.25 (3H,s), 1.85 (6H,m).

Mass (CI): m/z.650 (M+), 594 (100%),

418,271,240,167, 100.

IR (KBr, cm^"1): 3386, 2924, 2480, 2360,

Chemical Name: 1629, 1577, 1508, 1471, 1437, 1422,

1 - {4-[7-Methoxy-6-(3 -pyrrolidin- 1 -yl-propoxy)- 1238, 1064, 1037, 875, 840, 558. quinazolin-4-ylamino]-phenyl}-ethanone-O-(2,4- dichloro-benzyl)-oxime

Example-40 l-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-ethanone-O-benzyl-oxime

Step (i): Preparation of l- 4-(^,6,7-Dimethoxy-quinazolin-4-ylamino)-phenyll-ethanone

6,7-Dimethoxy-4-chloro quinazoline (0.9 grams, 4mmoles) and 4-amino acetophenone (0.65 grams, 4.8 mmoles) were taken in 25 mL of isopropylalcohol, refluxed for 2 hours at 90 °C .The solid was filtered and washed with methanol. Yield: 63%.

IR (KBr, cm^"1): 3029, 2619, 1677, 1643, 1574, 1527, 1433, 1363, 1267, 1235, 1175, 1152,

1064, 850, 584.

'HNMR (DMSO-d₆): δ .9.1 (IH, s), 8.5 (IH, s), 7.9 (2H, d), 7.4 (2H, d), 7.3 (IH, s), 6.9 (IH, s), 4.0 (6H, s), 2.4 (3H, s). Mass (m/z) CI: 324(M+), 310.

Step (ii): Preparation of l-r4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyll-ethanone-O- benzyl-oxime

l-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-ethanone (0.3 grams, 0.92 mmoles), obtained in step (i) and benzyloxy amine (0.14 grams, 1.13mmoles) (J. Org. Chem., 53(13), 1988, 2997) were taken in 6 mL of methanol, and 0.29 mL (3.6 mmoles) of pyridine was added. The contents were refluxed for 2.5 hours at 90 °C. The solid was filtered, dried and purified by flash column chromatography over 100-200 silica gel. Elution of the column with 5% methanol in dichloromethane afforded the product. Yield: 52%>. Melting point: 196-198 °C.

IR (KBr, cm^"1): 3423, 3070,^ 2925, 2854, 1622, 1575, 1512, 1419, 1279, 1234, 1143, 1012, 850, 681.

'HNMR (DMSO-d₆): δ 9.1 (IH, s), 8.6 (IH, s), 8.1 (IH, s), 7.8 (2H, J=8.6 Hz, d), 7.7(2H, j=8.6 Hz, d), 7.4-7.3 (5H, m,), 7.2(1H, s), 5.2 (2H, s), 4.0 (6H, s), 2.4 (3H, s). Mass(m/z)CI: 429 (M+), 323, 125(100%), 109.

Example 41 has been prepared according o the methodology as described in example 40:

Example 42 l-[4-(Quinazolin-4-ylamino)-phenoxy]-propan-2-one-O-benzyl-oxime

Step (i): Preparation of l-(4-Nitro phenoxy acetone)

4-Nitrophenol (50 grams, 0.359 moles) was dissolved in dimethylformamide (150 mL) and cooled to 0 °C. Sodium hydride (24.12 grams, 0.718 moles) was added slowly under stirring. After the addition was completed, chloroacetone (43 mL, 0.538 moles) was added at 0 °C and the contents were stirred at 20-35 °C for 16 hours. The reaction mixture was poured into ice and was exfracted with ethyl acetate. The ethyl acetate extract was washed with water, dried and concentrated. The residue was purified by flash column chromatography over 100- 200 silica gel. Elution of the column with 10% ethyl acetate in petroleum ether afforded pure compound which solidified into a color less solid. (Yield: 23 grams, 33%). Step (ii): Prepartion of l-(4-amiho phenoxy) acetone

l-(4-Nitrophenoxy) acetone (5 grams, 0.0255 moles), obtained in step (i) was taken in absolute ethanol (75 mL) and stannous chloride di-hydrate (23 grams, 0.102 moles) was added and the contents were refluxed for 45 minutes. The reaction mixture was poured into ice water, basified with 10% aqueous sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extract was dried and concentrated to dryness to afford the amine as a pale brown solid (Yield: 4.1 grams, 96%). Step (iii): Preparation of l-|^~4-(4-Ouinazolinyl amino)phenoxyl acetone

l-(4-amino phenoxy) acetone (4.7 grams, 0.0284 moles), obtained in step (ii), and 4- chloro quinazoline (3.9 grams, 0.0237 moles) were taken in 50 mL of. isopropanol and refluxed for 0.5 hours and left overnight at 20-35 °C . The precipitated solid was filtered, washed with isopropanol followed by di-ethyl ether and dried to afford the product (Yield: 4.4 grams, 63 % ).

'HNMR (CDC1₃). δ 9.4 (IH, bs), 8,5 (IH, s), 8.0-6.8 (8H, m), 4.2 (2H, s), 2.4 (3H, s). Mass(m z) CI: 294 (M+l), 266, 238, 189. Step (iv): Prepartion of l-[4-(Quinazolin-4-ylamino)-phenoxy1-propan-2-one-O-benzyl-oxime

l-[4-(4-Quinazolinyl amino)phenoxy] acetone (4.25 grams, 0.0145 moles), obtained in step (iii) and O-benzyl hydroxyl aminehydrochloride (J. Org. Chem., 53(13), 1988 , 2997), (3.45 grams, 0.0217 moles) were taken in 75 mL methanol and pyridine (2.63 mL) was added at 20-35 °C. The contents were refluxed for 1 hour and the reaction mixture concentrated, and the residue purified by flash column chromatography over 100-200 silica gel. Elution of the column with 10%methanol in dichloromethane afforded pure compound as pale green solid (3,2 grams, 68%). Melting point: 129-130 °C.

IR (KBr, cm^"'): 3426, 2924, 2854, 1618, -1573, 1511, 1495, 1455, 1424, 1398, 1355, 1317, 1230, 1172, 1024, 920.

'HNMR (CDCI₃): δ 9.4 (IH, bs), 8.5(1H, s), 8.0-6.8 (13H, m), 5.1(2H, d), 4.4 (2H, s), 2.0 (3H, s).

Mass(m/z)CI: 399(M+1) , 293 -, 243, 236, 210, 206, 181. Example 43 l-[4-(Quinazolin-4-yIamino)-phenyI]-ethanone-O-[3-(2-chloro-phenoxy)-propyl]-oxime

Step (i): Preparation of l-[4-(Ouinazolin-4-ylamino)-phenyl]-ethanone oxime

A mixture of l-[4-(lH-quinazolin-4-ylideneamino)-phenyl]-efhanone (1 gram, 3.80 mmoles), hydroxylamine hydrochloride (0.528 grams, 7.6 mmoles), and pyridine (0.922 mL, 11 mmoless) were taken in 100 mL methanol and refluxed for 5 hours. The precipitated compound was filtered and dried to afford 0.5 grams of the compound as a pale yellow solid. Yield: 50% Step (ii). Preparation of l-chloro-2- (3-chlόropropoxy) benzene

A mixture of 2-chloro henol (10 mL, 98 mmoless), fused potassium carbonate (67.7 grams, 490 mmoles) and l-bromo-3-chloropropane (14.5 mL, 147 mmoles) were taken in 250 mL of N, N-dimethylformamide and stirred overnight at 20-35 °C. The reaction mixture was poured into water and extracted with ethylacetate. The ethylacetate extract was dried and concentrated to afford 20 grams of the product as a colorless liquid Yield: 100%> Step (iii): Preparation of l- 4-(Oumazolin-4-ylaιmno)-phenyll-ethanone-O-r3-(2-chloro- phenoxy)-propyl] -oxime

l-[4-(Quinazolin-4-ylamino)-phenyl]-ethanone oxime (0.150 grams, 0.53 mmoles), obtained in step (i) is taken in dimethylformamide and at 0 °C, 0.064 grams of NaH was added and stirred for 0.5 hours. To this reaction mixture was added l-chloro-2-(3- chloropropoxy)benzene (0.165 grams, 0.80 mmoles), obtained in step (ii) and the contents were stirred at 80 °C for 3 hours. Water was added to the reaction mixture and extracted with ethylacetate. The ethylacetate extract was washed with water, dried and concentrated to afford 0.180 grams of crude compound. The crude was purified by flash column chromatography using 230-400 mesh silica gel. Elution was done with 10% Acetone in dichloromethane to afford 0.160 grams of the compound as a solid. Yield: 41%. Melting point: 172 °C. IR (KBr, cm^"'): 3432, 3270, 2923, 1715, 1624, 1524, 1415, 1290, 1253, 1195, 1059, 896. 'HNMR (DMSO-d₆): δ 11.0 (IH, s), 8.4 (IH, s), 8.0-6.8 (12H, m), 4.5 (2H, J=6 Hz, t), 4.2 (2H, J=6 Hz, t), 2.2 (2H, m), 2.1 (3H, s). Mass (CI):447(M+1,100%).

Examples 44 and 45 have been prepared according o the methodology as described in example 43:

Example 46 l-{4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yIamino]-phenyl}-ethanone O-benzyl-oxime succinate

1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone O-benzyl-oxime, obtained in example 29, and succinic acid, were taken in round bottomed flask. Suspended in 10% water in isopropyl alcohol. Stirred at room temperature for 2 hours. Then refluxed for 2 hours. A clear solution is obtained. Filtered in hot condition and cooled back to 20 °C and filtered. Melting point of the final product is 169-171 °C. IR (KBr, cm^"1): 3323, 2955, 1725, 1627, 1575, 1515, 1235.

1H NMR (CDC1₃): δ 9.1 (IH, broad s), 8.3 (IH, s), 7.65 (2H, d), 7.75 (2H, d), 7.2-7.5 (6H, Complex m), 6.89 (IH, s), 5.25 (2H, s), 4.1 (2H, t), 3.8 (4H, m), 3.65 (3H, s), 2.8 (6H, m), 2.6 (4H, s), 2.3 (3H, s), 2.1 (2H, m). Mass (m/z) CI: 542 (M⁺¹), 434, 420, 405, 309

Examples 47-68 have been prepared according to the methodology as described in example 46:

Anti-cancer activity:

The compounds prepared in the prusent invention exhibited good in vitro anti-cancer activity towards vaπous human tumor cell lines.

Each test compound was screened against a battery of cell lines representing eight different types of cancers. In a typical procedure, IXI O⁴ cells were seeded into each well of 96 well plate in lOOμL volume of R.P I 1640 medium containing antibiotics and 10% FCS.

The plates were incubated al 37°C in presence of CO₂. After 24 h, test compounds were evaluated at five 10 fold dilutions ranging from 100 to 0.01 μM. To each test well 100μL of test compound solution was added and medium with vehicle was added tυ control wells and the plates were further incubated After 48 hours of incubation, plates were terminated by Sulforhodamme B method. The optical density which is proportional to protein mass, is then read by automated spectrophotometer plate reader at a wavelength of 515 nm. Readings were transferred to a microcomputer and mean 50 % Growth h-hibition (GI50). The compounds of the present invention showed anticancer activity, which can be seen from the data given below:

Claims

We claim:

1. A compound of formula (I)

1 * where R and R represents hydrogen, halogen, hydroxy, nitro, cyano, amino, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, acyl, acyloxy, aryl, aryloxy, alkylthio, arylthio, aralkyl, aralkoxy, alkenyl, alkenyloxy, cycloalkenyloxy, aroyl, aroyloxy, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, heteroaralkyl, heterocyclylalkyl, heteroaralkoxy, heterocyclylalkoxy, heteroaralkoxyalkoxy, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carboxylic acid or its derivatives, or sulfonic acid or its derivatives;

R repesents hydrogen, halogen, hydroxy, cyano, amino, -CH₂CN, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic acid or its derivatives, or sulfonic acid or its derivatives;

R⁴, R⁵ and R⁶ independently represent hydrogen, halogen, hydroxy, nitro, cyano, amino, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic acid or its derivatives, or sulfonic acid or its derivatives.

' W represents optionally substituted groups selected from phenyl, naphthyl, pyrrolyl, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like.

Q represents N, -CH or C,

Y represents O, NH or CH₂, s, t are integers in the range of 0 to 5 and r, u are integers 0 or 1; their phamaceutically acceptable salts and their geometrical isomers thereof.

When the groups represented by R and R are substituted, the substituents are selected from halogen, nitro, amino, alkylamino, dialkylamino, hydroxy, carboxy, cyano, oxo(=O), thio(=S), alkyl, cycloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, benzyloxy, acyl, acyloxy, aroyl, heteroaryl, aralkyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, alkylthio, arylthio or an optionally substituted 5 or 6 membered cyclic ring which may optionally contain 1-3 hetero atoms selected from O, S or N. A 5 or 6 membered cyclic rings formed may be selected from pyrrole, morpholine, thiomorpholine, benzothiazole, benzoimidazole, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, pyrrolidine and the like. The substituents on the above 5 or 6 membered cyclic rings are selected from halogen, nitro, amino, hydroxy, carboxy, cyano, =O, =S or alkyl.

When the groups represented by R³, R⁴, R⁵ and R⁶ are substituted, the substituents are selected from a halogen, nitro, amino, hydroxy, carboxy, cyano, oxo(O=), thioxo(S=), alkyl, cycloalkyl, alkoxy, cycloalkyl, aryl, acyl, aroyl, heteroaryl or aralkyl.

When the groups represented by W are substituted, the substituents are selected from halogen atom, hydroxy, carboxy, acyl, nitro, cyano, amino, acylamino, oxo, thioxo, linear or branched optionally halogenated alkyl, optionally halogenated alkoxy, carboxylic or sulfonic acids and their derivatives.

2. A compound as claimed in claim 1, wherein formula (I) as described by formula (II) below:

Where R¹ and R² represents hydrogen, halogen, hydroxy, nitro, cyano, amino, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, acyl, acyloxy, aryl, aryloxy, alkylthio, arylthio, aralkyl, aralkoxy, alkenyl, alkenyloxy, cycloalkenyloxy, aroyl, aroyloxy, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, heteroaralkyl, heterocyclylalkyl, heteroaralkoxy, heterocyclylalkoxy, heteroaralkoxyalkoxy, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; R³ repesents hydrogen, halogen, hydroxy, cyano, amino, -CH₂CN, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic acid or its derivatives, or sulfonic acid or its derivatives;

R , R⁵ and R⁵ independently represent hydrogen, halogen, hydroxy, nitro, cyano, amino, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic acid or its derivatives, or sulfonic acid or its derivatives.

' W' represents optionally substituted groups selected from phenyl, naphthyl, pyrrolyl, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like;

R' and R' ' independently represent hydrogen, halogen, hydroxy, carboxy, acyl, nitro, cyano, amino, acylamino, oxo, thioxo, linear or branched optionally halogenated alkyl, optionally halogenated alkoxy, carboxylic or sulfonic acids and their derivatives.

Q represents N, -CH or C, s, t are integers in the range of 0 to 5; their phamaceutically acceptable salts and their geometrical isomers thereof.

3. The compound of formula (II), as claimed in claim 2, wherein Q represents N or -C-CN;

R¹ and R² independently represent hydrogen, hydroxy, optionally substituted groups selected alkoxy, cycloalkoxy, acyloxy, aryloxy, aralkoxy, alkenyloxy, cycloalkenyloxy, aroyloxy, heteroaryloxy, heterocyclyloxy, heteroaralkoxy, heterocyclylalkoxy, heteroaralkoxyalkoxy; wherein the substituents on R¹ and R² may be selected from amino, alkylamino, dialkylamino, or an optionally substituted 5 or 6 membered cyclic ring which may optionally contain 1-3 hetero atoms selected from O, S or N. A 5 or 6 membered cyclic ring formed may be selected from pyrrole, morpholine, thiomorpholine, benzothiazole, benzoimidazole, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, pyrrolidine and the like;

R³ represents hydrogen, halogen or alkyl;

V represents 0, 't' represents 1;

R⁴, R⁵ and R⁶ independently represent hydrogen, halogen, hydroxy, nitro, cyano, amino, optionally substituted groups selected from alkyl, alkoxy; R' and R" independently represent hydrogen, halogen, hydroxy, nitro, cyano, amino, linear or branched optionally halogenated alkyl, optionally halogenated alkoxy, carboxylic or sulfonic acids and their derivatives.

4. The compound of formula (II), as claimed in claim 2, wherein Q represents N or -C-CN;

R³ represents hydrogen;

's' represents 0, 't' represents 1;

5. The compound of formula (II), as claimed in claim 2, wherein Q represents N;

R¹ and R² independently represent hydrogen, optionally substituted groups selected alkoxy, heterocyclylalkoxy, heteroaralkoxy; wherein the substituents on R and R may be selected from amino, alkylamino, dialkylamino, pyrrole, morpholine, thiomorpholine, benzothiazole, benzoimidazole, pyridine, pyridazine, pyrimidine, pyrazine, piperidine or pyrrolidine;

R³ represents hydrogen;

's' represents 0, 't' represents 1;

R⁴, R⁵ and R⁶ independently represent hydrogen, halogen, alkyl or alkoxy; ^•

6. The compound of formula (II), as claimed in claim 2, wherein Q represents -C-CN;

R¹ and R² independently represent hydrogen, optionally substituted groups selected alkoxy, heterocyclylalkoxy, heteroaralkoxy; wherein the substituents on R and R may be selected from amino, alkylamino, dialkylamino, pyrrole, moφholine, thiomorpholine, benzothiazole, benzoimidazole, pyridine, pyridazine, pyrimidine, pyrazine, piperidine or pyrrolidine;

R³ represents hydrogen;

's' represents 0, ^ct' represents 1;

R , R⁵ and R independently represent hydrogen, halogen, alkyl or alkoxy; ^•

7. A compound as claimed in claim 1, wherein formula (I) as described by formula (III) below:

1 9 where R and R represents hydrogen, halogen, hydroxy, nitro, cyano, amino, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, acyl, acyloxy, aryl, aryloxy, alkylthio, arylthio, aralkyl, aralkoxy, alkenyl, alkenyloxy, cycloalkenyloxy, aroyl, aroyloxy, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, heteroaralkyl, heterocyclylalkyl, heteroaralkoxy, heterocyclylalkoxy, heteroaralkoxyalkoxy, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carboxylic acid or its derivatives, or sulfonic acid or its derivatives;

R³ repesents hydrogen, halogen, hydroxy, cyano, amino, -CH₂CN, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic acid or its derivatives, or sulfonic acid^'or its derivatives;

R⁴, R⁵ and R⁶ independently represent hydrogen, halogen, hydroxy, nitro, cyano, amino, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic acid or its derivatives, or sulfonic acid or its derivatives. 'W' represents optionally substituted groups selected from divalent phenyl, naphthyl, pyrrolyl, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like;

R' and R" independently represent hydrogen, halogen, hydroxy, carboxy, acyl, nitro, cyano, amino, acylamino, oxo, thi xo, linear or branched optionally halogenated alkyl, optionally halogenated alkoxy, carboxylic or sulfonic acids and their derivatives.

Q represents N, -CH or C;

R' and R" independently represent hydrogen, halogen, hydroxy, carboxy, acyl, nitro, cyano, amino, acylamino, oxo, thioxo, linear or branched optionally halogenated alkyl, optionally halogenated alkoxy, carboxylic or sulfonic acids and their derivatives; s, t are integers in the range of 0 to 5 and r represents 1 ; their phamaceutically acceptable salts and their geometrical isomers thereof.

8. The compound of formula (III), as claimed in claim 7, wherein Q represents N or -C-CN;

1 9

R and R independently represent hydrogen, optionally substituted groups selected alkoxy,

' 1 heterocyclyalkoxy, heteroaralkoxy; wherein the substituents on R and R may be selected from amino, alkylamino, dialkylamino, pyrrole, morpholine, thiomorpholine, benzothiazole, benzoimidazole, pyridine, pyridazine, pyrimidine, pyrazine, piperidine or pyrrolidine;

R³ represents hydrogen;

's' represents 1-2, 't' represents 1;

R⁴, R⁵ and R⁶ independently represent hydrogen, halogen, alkyl or alkoxy;

9. A compound as claimed in claim 1, wherein formula (I) as described by formula (IV) below:

where R¹ and R² represents hydrogen, halogen, hydroxy, nitro, cyano, amino, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, acyl, acyloxy, aryl, aryloxy, alkylthio, arylthio, aralkyl, aralkoxy, alkenyl, alkenyloxy, cycloalkenyloxy, aroyl, aroyloxy, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, heteroaralkyl, heterocyclylalkyl, heteroaralkoxy, heterocyclylalkoxy, heteroaralkoxyalkoxy, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carboxylic acid or its derivatives, or sulfonic acid or its derivatives;

R , R⁵ and R⁶ independently represent hydrogen, halogen, hydroxy, nitro, cyano, amino, optionally substituted groups selected from allcyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic acid or its derivatives, or sulfonic acid or its derivatives.

'W' represents optionally substituted groups selected from divalent phenyl, naphthyl, pyrrolyl, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like;

Q represents N, -CH or C;

R' and R" independently represent hydrogen, halogen, hydroxy, carboxy, acyl, nitro, cyano, amino, acylamino, oxo, thioxo, linear or branched optionally halogenated allcyl, optionally halogenated alkoxy, carboxylic or sulfonic acids and their derivatives; s, t are integers in the range of 0 to 5 and u represents 1 ; their phamaceutically acceptable salts and their geometrical isomers thereof;

10. The compound of formula (IV), as claimed in claim 9, wherein Q represents N or -C-CN;

R¹ and R² independently represent hydrogen, optionally substituted groups selected alkoxy, heterocyclylalkoxy, heteroaralkoxy; wherein the substituents on R¹ and R² may be selected from amino, alkylamino, dialkylamino, pyrrole, morpholine, thiomorpholine, benzothiazole, benzoimidazole, pyridine, pyridazine, pyrimidine, pyrazine, piperidine or pyrrolidine;

R³ represents hydrogen; V represents 0, 't' represents 3;

R , R and R independently represent hydrogen, halogen, alkyl or alkoxy;

11. The compound of formula (I), as claimed in claim 1 , is selected from l-[4-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-fluoiO-benzyl)-oxime, l-[4-(Quinazolin-4-ylamino)-phenyl]-etlιanone-O-(4-chloro-benzyl)-oxime,

4-{l-[4-(Quinazolin-4-ylamino)-phenyl]-ethylideneaminooxymethyl}-benzonitrile, l-[4-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-(3,4-dichloro-benzyl)-oxime, l-[3-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-benzyl-oxime, l-[3-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-fluoro-benzyl)-oxime, l-[3-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-chloro-benzyl)-oxime, l-[4-Bromo-3-(quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-chloro-benzyl)-oxime, l-[4-Bromo-3-(quinazolin-4-ylamino)-phenyl]-efhanone-O-benzyl-oxime, l-[4-Bromo-3-(quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-fluoro-benzyl)-oxime, l-[2-Methoxy-5-(quinazolin-4-ylamino)-phenyl]-ethanone-O-benzyl-oxime, l-[4-Methoxy-3-(quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-fluoro-benzyl)-oxime.

12. The compound of formula (I), as claimed in claim 1, is selected from

4- {4-[ 1 -(4-Fluoro-benzyloxyimino)-ethyl] -phenylamino } -7-isopropoxy-6-methoxy- quinoline-3-carbonitrile, 4-[4-(l-Benzyloxyimino-ethyl)-phenylamino]-7-isopropoxy-6-methoxy-quinoline-3- carbonitrile, 4- {4-[ 1 -(4-Chloro-benzyloxyimino)-ethyl]-phenylamino} -7-isopropoxy-6-methoxy- quinoline-3-carbonitrile, 4-{4-[l-(3,4-Dichloro-benzyloxyimino)-ethyl]-phenylamino}-7-isopropoxy-6-methoxy- quinoline-3-carbonitrile.

13. The compound of formula (I), as claimed in claim 1, is selected from

1 - {4-[6-Methoxy-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyl-oxime, l-{4-[6-Methoxy-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime, 1 - {4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinazolin-4-ylamino]-phenyl} - ethanone-O-(4-fluoro-benzyl)-oxime, l-{4-[6-Methoxy-7-(3-piperidin-l-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime, 1 - {4-[6-Methoxy-7-(3 -piperidin- 1 -yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyl-oxime, 1 - {4-[6-Methoxy-7-(3 -pyrrolidin- 1 -yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-(4-chloro-benzyl)-oxime, l-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinazolin-4-ylamino]-phenyl}- ethanone-O-(2-chloro-4-fluoro-benzyl)-oxime, l-{4-[6-Methoxy-7-(3-piperidin-l-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(2-chloro-4-fluoro-benzyl)-oxime, l-{4-[6-Methoxy-7-(3-pyrrolidin-l-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(2-chloro-4-fluoro-benzyl)-oxime, 1 - {4-[6-Methoxy-7-(3-pyrrolidin- 1 -yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-(2,4-dichloro-benzyl)-oxime, 1 - {4-[6-Methoxy-7-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-(2-chloro-4-fluoro-benzyl)-oxime,

1 - {4-[6-Methoxy-7-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-(4-chloro-benzyl)-oxime.

14. The compound of formula (I), as claimed in claim 1, is selected from

l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-(4-chloro-benzyl)-oxime, 1. {4-[7-Methoxy-6-(3 -moφholin-4-yl-propoxy)-quinazolin-4-ylamino] -phenyl} - ethanone-O-(4-fluoro-benzyl)-oxime, 1. {4-[7-Methoxy-6-(3 -pyrrolidin- 1 -yl-propoxy)-quinazolin-4-ylamino] -phenyl } - ethanone-O-(4-fluoro-benzyl)-oxime, 1 - {4-[7-Methoxy-6-(3 -piperidin- l-yl-propoxy)-quinazolin-4-ylamino] -phenyl} -ethanone

O-benzyl-oxime, 1 - {4-[6-(3-Dimethylamino-propoxy)-7-methoxy-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyl-oxime, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime, 1^. {4-[6-(3-Dimethylamino-propoxy)-^'7-methoxy-quinazolin-4-ylamino]-phenyl} - ethanone-O-(4-fluoro-benzyl)-oxime, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-(2,4-dichloro-benzyl)-oxime, l-{4-[7-Methoxy-6-(3-moφholinr4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(2-chloro-4-fluoro-benzyl)-oxime, l-{4-[7-Methoxy-6-(3-pyrrolidin-l-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(2,4-dichloro-benzyl)-oxime.

15. The compound of formula (I), as claimed in claim 1, is selected from

_. l-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-ethanone-O-benzyl-oxime, l-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-fluoro-benzyl)- oxime.

16. The compound of formula (I), as claimed in claim 1, is selected from

1 - {4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyl-oxime succinate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]- phenyl}^'-ethanone-O-benzyl-oxime acetate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime 2-hydroxyethane sulfonate, l-{4_[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime 2-hydroxyethane sulfonate,

1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino].-phenyl} - ethanone-O- (4-chloro-benzyl)-oxime methanesulfonate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O- (4-chloro-benzyl)-oxime hydrochloride, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- efhanone-O- (4-chloro-benzyl)-oxime nitrate, l-{4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O- (4-chloro-benzyl)-oxime sulfate, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O- (4-chlorό-benzyl)-oxime phosphate, l-{4-[7-Methoxy-6-(37moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(2,4-dichloro-benzyl)-oxime methanesulfonate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime L-glutamate, 1 - {4-[7-Memoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime methane sulphonate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethahone-O-benzyloxime malonate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime maleate, l-{4-[7-Mefhoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime besylate (1:1), l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino].-phenyl}- ethanone-O-benzyloxime besylate (1:2), 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime citrate, ^• 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethano.ne-O-benzyloxime hydrochloride, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyl-oxime hydrobromide, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime L-tartarate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime fumerate (2:1), l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-qmnazolin-4-ylamino]-phenyl}- efhanone-O-benzyl-oxime L-aspartate, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime sulphate.

17. The compound of formula (I), as claimed in claim 1, is selected from l-[4-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-fluoro-benzyl)-oxime, l-[4-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-(4-chloro-benzyl)-oxime, 4- { 1 -[4-(Quinazolin-4-ylamino)-phenyl]-ethylideneaminooxymethyl} -benzonitrile, l-[4-(Quinazolin-4-ylamino)-phenyl]-ethanone-O-(3,4-dichloro-benzyl)-oxime.

18. The compound of formula (I), as claimed in claim 1, is selected from l-{4-[6-Methoxy-7-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime, l-{4-[6-Methoxy-7-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime, l-{4-[6-Methoxy-7-(3-piperidin-l-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime, 1 - {4-[6-Methoxy-7-(3-piperidin- 1 -yl-propoxy)-quinazolin-4-ylamino] -phenyl } - ethanone-O-benzyl-oxime, l-{4-[6-Methoxy-7-(3-piperidin-l-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(2-chloro-4-fluoro-benzyl)-oxime.

19. The compound of formula (I), as claimed in claim 1, is selected from l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-(4-chloro-benzyl)-oxime, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(2,4-dichloro-benzyl)-oxime, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(2-chloro-4-fluoro-benzyl)-oxime.

20. The compound of formula (I), as claimed in claim 1, is selected from

1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-(4-fluoro-benzyl)-oxime, l-{4-[7-Methoxy-6-(3-piperidin-l-yl-propoxy)-quinazolin-4-ylamino]-phenyl}-

.ethanone- O-benzyl-oxime.

21. The compound of formula (I), as claimed in claim 1 , is selected from l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime succinate, l-{4-[7-Mefhoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]- phenyl} -ethanone-O-benzyl-oxime acetate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime 2-hydroxyethane sulfonate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime L-glutamate, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime methane sulphonate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime malonate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime maleate,

Y

1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime besylate (1 :1), l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylaiΩino]-phenyl}- ethanone-O-benzyloxime besylate (1 :2), 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl } - ethanone-O-benzyloxime citrate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-ρhenyl}- ethanone-O-benzyloxime hydrochloride, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyl-oxime hydrobromide, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- efhanone-O-benzyloxime L-tartarate., 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime fumerate (2:1), l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime, L-aspartate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime, sulphate.

22. The compound of formula (I), as claimed in claim 1, is selected from

1 - {4- [7-Methoxy-6-(3 moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyl-oxime succinate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylanϋno]- phenyl} -ethanone-O-benzyl-oxime, acetate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime, 2-hydroxyethane sulfonate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime, L-glutamate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone O-benzyloxime, methane sulphonate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime, malonate, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime, maleate, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime, besylate (1:1), 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime, besylate (1:2), l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime, citrate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime, hydrochloride, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime, hydrobromide, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime, L-tartarate, 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime, fumerate (2:1), l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime, L-aspartate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime, sulphate.

23. The compound of formula (I), as claimed in claim 1, is selected from l-{4-[7-Methoxy-6-(3 moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime succinate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]- phenyl} -ethanόne-O-benzyl-oxime acetate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime methane sulphonate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime maleate, l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime hydrochloride.

24. The compound of formula (I), as claimed in claim 1 is l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime

25. The compound of formula (I), as claimed in claim 1 is l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-chloro-benzyl)-oxime

26. The compound of formula (I), as claimed in claim 1 is

1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-(4-fluoro-benzyl)-oxime

\

27. The compound of formula (I), as claimed in claim 1 is

1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - efhanone-O-(4-fluoro-benzyl)-oxime

28. The compound of formula (I), as claimed in claim 1 is l-{4-[7-Methoxy-6-(3-piperidin-l-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime

29. The compound of formula (I), as claimed in claim 1 is l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]- phenyl} -ethanone-O-benzyl-oxime acetate

30. The compound of formula (I), as claimed in claim 1 is

1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyloxime methane sulphonate

31. The compound of formula (I), as claimed in claim 1 is l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime maleate

32. The compound of formula (I), as claimed in claim 1 is l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime hydrochloride

33. The compound of formula (I), as claimed in claim 1 is l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyl-oxime succinate

34. A process for the preparation of compound of formula (I)

where R and R represents hydrogen, halogen, hydiOxy, nitro, cyano, amino, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, acyl, acyloxy, aryl, aryloxy, alkylthio, arylthio, aralkyl, aralkoxy, alkenyl, alkenyloxy, cycloalkenyloxy, aroyl, aroyloxy, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, heteroaralkyl, heterocyclylalkyl, heteroaralkoxy, heterocyclylalkoxy, heteroaralkoxyalkoxy, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carboxylic acid or its derivatives, or sulfonic acid or its derivatives;

R⁴, R⁵ and R⁶ independently represent hydrogen, halogen, hydroxy, nitro, cyano, amino, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic acid or its derivatives, or sulfonic acid or its derivatives. 'W' represents optionally substituted groups selected from divalent phenyl, naphthyl, pyrrolyl, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azairidolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like. Q represents N, -CH or C, Y represents O, N or CH₂, s, t are integers in the range of 0 to 5 and r, u are integers 0 or 1 ;

When the groups represented by R¹ and R² are substituted, the substituents are selected from halogen, nitro, amino, alkylamino, dialkylamino, hydroxy, carboxy, cyano, oxo(=O), thio(=S), alkyl, cycloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, benzyloxy, acyl, acyloxy, aroyl, heteroaryl, aralkyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, alkylthio, arylthio or an optionally substituted 5 or 6 membered cyclic ring which may optionally contain 1-3 hetero atoms selected from O, S or N. A 5 or 6 membered cyclic rings formed may be selected from pyrrole, ^■ moφholine, thiomoφholine, benzothiazole, benzoimidazole, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, pyrrolidine and the like. ^'The substituents on the above 5 or 6 membered cyclic rings are selected from halogen, nitro, amino, hydroxy, carboxy, cyano, =O, =S or alkyl.

When the groups represented by R³, R⁴, R⁵ and R⁶ are substituted, the substituents are selected from a halogen, nitro, amino, hydroxy, carboxy, cyano, oxo(O=), fhioxo(S=), alkyl, cycloalkyl, alkoxy, cycloalkyl, aryl, acyl, aroyl, heteroaryl or aralkyl.

Whenever substitutions are possible on the groups represented by R¹, R², R³, R⁴, R⁵, R⁶ and W, they may have 1 to 4 substituents, which may be identical or different, which comprises:

(i) converting the compound of formula (la)

where R¹, R² are as defined above, to a compound of formula (lb)

where R , R and R are as defined above,

(ii) converting the compound of formula (lb), to a compound of foraiula (lc)

X

^RYτV no

1 "^ where X represents halogen atom, R , R and R are as defined above,

(iii) reacting the compound of foraiula (lc), with a compound of formula (Id)

where all symbols are as defined above, to a compound of formula (le)

where all symbols are as defined above and

(iv) reacting the compound of formula (le), with a compound of formula (If)

where all symbols are as defined above, to obtain a compound of formula (I).

35. A process for the preparation of compound of formula (2)

where R¹⁰ represents R¹ or R², which represent optionally substituted alkoxy, aralkoxy, heterocyclylalkoxy, heteroaralkoxy or acyloxy groups.

R⁴, R⁵ and R⁶ independently represent hydrogen, halogen, hydroxy, nitro, cyano, amino, optionally substituted groups selected from allcyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic acid or its derivatives, or sulfonic acid or its derivatives.

'W' represents optionally substituted groups selected from divalent phenyl, naphthyl, pyrrolyl, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, ^' benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like. Q represents N, -CH or C, Y represents O, N or CH₂, s, t are integers in the range of 0, to 5 and r, u are integers 0 or 1;

When the groups represented by R¹ and R² are substituted, the substituents are selected from halogen, nitro, amino, alkylamino, diallcylamino, hydroxy, carboxy, cyano, oxo(=O), thio(=S), alkyl, cycloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, benzyloxy, acyl, acyloxy, aroyl, heteroaryl, aralkyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, alkylthio, arylthio or an optionally substituted 5 or 6 membered cyclic ring which may optionally contain 1-3 hetero atoms selected from O, S or N. A 5 or 6 membered cyclic rings formed may be selected from pyrrole, moφholine, hiomoφholine, benzothiazole, benzoimidazole, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, pyrrolidine and the like. The substituents on the above 5 or 6 membered cyclic rings are selected from halogen, nitro, amino, hydroxy, carboxy, cyano, =O, =S or alkyl.

(i) converting the compound of formula (2a)

where R⁷ represents protecting groups such as acetyloxy, benzyloxy and the like and all other symbols are as defined above, to a compound of formula 2(b)

where all symbols are as defined above,

(ii) reacting the compound of formula (2b), with a compound of formula (2c)

where all symbols are as defined abov.e, to a compound of formula (2d)

where all symbols are as defined above,

(iii) converting the compound of formula (2d), to a compound of foraiula (2e)

where all symbols are as defined above,

(iv) reacting the compound of foraiula (2e), with a compound of formula (2e')

R⁹-X (2e') where R⁹ represents optionally substituted alkyl, aralkyl, heteroaralkyl or acyl groups and X represents halogen atom, to obtain a compound of formula (2f)

where all symbols are as defined above and (v) reacting the compound of formula (2f), with a compound of formula (2g)

where all symbols are as defined above to obtain a compound of formula (2). The compound of formula (2) represents compound of formula (I), when R⁸ and R¹⁰ attached to the 6^th and 7^th positions of the hetero bicyclic ring.

36. A pharmaceutical composition, which comprises therapeutically effective amount of a compound of formula (I)

as claimed in claim 1, and a pharmaceutically acceptable carrier, diluent, excipient or solvate.

37. The pharmaceutical composition as claimed in claim 36, in the form of a tablet, capsule, powder, syrup, solution or suspension.

38. A method of treating cancer, which comprises administering therapeutically effective amount of a compound of formula (I) as claimed in claim 1 to a patient in need thereof.

39. A method of treating cancer, which comprises administering therapeutically effective amount of a compound of formula (I) as claimed in claim 1, to a patient in need thereof.

40. The pharmaceutical composistion of claim 36, wherein the compound of formula (I) is 1 - {4-[7-Methoxy-6-(3-_rmoφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone-O-benzyl-oxime

41. The pharmaceutical composistion of claim 35, wherein the compound of formula (I) is 1 - {4- [7-Methoxy-6-(3 -moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl } - ethanone-O-(4-chloro-benzyl)-oxime

42. The pharmaceutical composistion of claim 35, wherein the compound of formula (I) is l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime

43. The pharmaceutical composistion of claim 35, wherein the compound of formula (I) is l-{4-[7-Metl oxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-(4-fluoro-benzyl)-oxime

44. The pharmaceutical composistion of claim 35, wherein the compound of formula (I) is 1 - {4-[7-Methoxy-6-(3-piρeridin- 1 -yl-propoxy)-quinazolin-4-ylamino]-phenyl} -ethanone

O-benzyl-oxime

45. The pharmaceutical composistion of claim 35, wherein the compound of foraiula (I) is l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]- phenyl} -ethanone-O-benzyl-oxime, acetic acid

46. The pharmaceutical composistion of claim 35, wherein the compound of formula (I) is 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-ρhenyl} - ethanone O-benzyloxime, methane sulphonate

47. The pharmaceutical composistion of claim 35, wherein the compound of formula (I) is 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino].-phenyl} - ethanone O-benzyloxime, maleate

48. The pharmaceutical composistion of claim 35, wherein the compound of formula (I) is l-{4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl}- ethanone-O-benzyloxime, hydrochloride

49. The pharmaceutical composistion of claim 35, wherein the compound of formula (I) is 1 - {4-[7-Methoxy-6-(3-moφholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyl} - ethanone O-benzyl-oxime succinate