Title of Invention	NEW ANTICANCER COMPOUNDS : PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
Abstract	The present invention relates to novel anticancer agents, their derivatives, their analogs, their stereoisomers, their tautomers, their geometric isomers, their polymorphs, their phamaceutically acceptable salts, their pharmaceutically acceptable solvates and their pharmaceutically acceptable compositions. The present invention more particularly relates to novel quinazoline compounds, their derivatives, their analogs, their stereoisomers, their tautomers, their enantiomers, their geometric isomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and their pharmaceutically acceptable compositions. The novel quinazoline compounds have the general formula (I),

Title of Invention

NEW ANTICANCER COMPOUNDS : PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract

The present invention relates to novel anticancer agents, their derivatives, their analogs, their stereoisomers, their tautomers, their geometric isomers, their polymorphs, their phamaceutically acceptable salts, their pharmaceutically acceptable solvates and their pharmaceutically acceptable compositions. The present invention more particularly relates to novel quinazoline compounds, their derivatives, their analogs, their stereoisomers, their tautomers, their enantiomers, their geometric isomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and their pharmaceutically acceptable compositions. The novel quinazoline compounds have the general formula (I),

Full Text	Field of the Invention The present invention relates to novel anticancer agents, their derivatives, their analogs, their stereoisomers, their tautomers, their geometric isomers, their polymorphs, their phamaceutically acceptable salts, their pharmaceutically acceptable solvates and their pharmaceutically acceptable compositions. The present invention more particularly relates to novel quinazoline compounds, their derivatives, their analogs, their stereoisomers, their tautomers, their enantiomers, their geometric isomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and their pharmaceutically acceptable compositions. The novel quinazoline compounds have the general formula (I), where R1 and R2 represents hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, acyl, acyloxy, aryl, aryloxy, alkylthio, arylthio, aralkyl, aralkoxy, alkenyl, alkenyloxy, cycloalkenyloxy, aroyl, aroyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, heteroaralkoxyalkoxy, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carboxylic aC1d or its derivatives, or sulfonic aC1d or its derivatives. R repesents hydrogen, halogen, hydroxy, cyano, amino, CH3CN, substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic aC1d or its derivatives, or sulfonic aC1d or its derivatives. R4, R5 and R6 independently represent hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic aC1d or its derivatives, or sulfonic aC1d or its derivatives. "W represents substituted or unsubstituted 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 or -CH, Y represents oxygen or nitrogen, s, t are integers in the range of 0 to 5 and r, u are integers 0 or l.The present invention also relates to pharmaceutical compositions containing compounds of general formula (I) or mixtures thereof. The present invention also relates to a process for the preparation of the above defined novel compounds of general formula (I), their derivatives, their analogs, their stereoisomers, their tautomers, their geometric isomers, their eantiomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and their pharmaceutically acceptable compositions. The compounds of the present invention either alone or in combination with other cytotoxic durgs exhibited significant in vitro anti-tumor activity against a wide range of human tumor cell lines. 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 benefiC1al. 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 transemembrane receptors are relayed into the cells by the signal transduction pathways (Pelech et al., SC1ence 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 control gene expression and function (Nishida et.al.. Trends Biochem. SC1., 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. 7, 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 assoC1ated 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 assoC1ated 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. Objective of the Invention With an objective of preparing novel quinazoline compounds useful for treating cancer, and other proliferative diseases like psoriasis, restenosis, auto immune diseases or atherosclerosis. We focussed our research efforts in prepared the novel quinazoline derivatives of the formula (I) as defined above. The main objective of the present invention is, therefore, to provide novel quinazoline compounds of the formula (I) as defined above, their derivatives, their analogs, their stereoisomers, their tautomers, their geometric isomers, their enantiomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures. Another objective of the present invention is to provide pharmaceutical compositions containing compounds of the general formula (I), their derivatives, their analogs, their stereoisomers, their tautomers, their geometric isomers, their enantiomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates containing them or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions. Still another objective of the present invention is to provide pharmaceutical compositions containing compounds of formula (I), their derivatives, their analogs, their stereoisomers, their tautomers, their geometric isomers, their enantiomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, containing them or their mixtures in combination with one or more pharmaceutically acceptable active compounds with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions. Still another objective of the present invention is to provide a process for the preparation of novel quinazoline derivatives of the formula (I) as defined above, their derivatives, their analogs, their stereoisomers, their tautomers, their geometric isomers, their enantiomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceufical compositions containing them or their mixtures having enhanced acfivity, no toxic effect or reduced toxic effect. Detailed Description of the Invention The present invention relates to compounds having the general formula (I) " their derivatives, their analogs, their stereoisomers, their tautomers, their polymorphs, their geometric isomers, their phamaceutically acceptable salts, their pharmaceutically acceptable solvates and their pharmaceutically acceptable compositions. where R1 and R2 represents hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, acyl, acyloxy, aryl, aryloxy, alkylthio, arylthio, aralkyl, aralkoxy, alkenyl, alkenyloxy, cycloalkenyloxy, aroyl, aroyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, heteroaralkoxyalkoxy, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carboxylic aC1d or its derivatives, or sulfonic aC1d or its derivatives. R3 repesents hydrogen, halogen, hydroxy, cyano, amino, -CH2CN, substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic aC1d or its derivatives, or sulfonic aC1d or its derivatives. R4, R5 and R6 independently represent hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic aC1d or its derivatives, or sulfonic aC1d or its derivatives. "W represents substituted or unsubstituted groups selected from divalent phenyl, naphthyl, pyrrolyl, pyridyl, quinolinyl, benzoftiryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like. Q represents N or -CH, Y represents oxygen or nitrogen, 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 a halogen, nitro, amino, alkylamino, dialkylamino, hydroxy, carboxy, cyano, oxo(0=), thio(S=), alkyl, cycloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, benzyloxy, acyl, acyloxy, aroyl, heteroaryl, aralkyl, alkylsulfonyl, alkylsulfmyl, arylsulfonyl, arylsulfinyl, alkylthio, arylthio or a substituted or unsubstituted 5 or 6 membered cyclic ring which may optionally contain one or two hetero atoms selected from oxygen, sulfur or nitrogen. 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, oxo(0=), thioxo(S=) or alkyl. The substituents on R3 R4, R5 and R6 are selected from a halogen, nitro, amino, hydroxy, carboxy, cyano, oxo(0=), thio(S=), alkyl, cycloalkyl, alkoxy, cycloalkyl, aryl, acyl, aroyl, heteroaryl or aralkyl. The substituents on the group represented by W are selected from a halogen atom, hydroxy, carboxy, acyl, nitro, cyano, amino, acylamino, thio, linear or branched optionally halogenated alkyl, optionally halogenated alkoxy, carboxylic or sulfonic aC1ds and their derivatives. The above groups are defined as follows: "Halogen" atom represents fluorine, chlorine, bromine or iodine. "Alkyl" group is linear or branched (C1-C10)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 (C1-C10)alkylamino, where (C1-C10)alkyl groups is as defined as above. Exemplary alkylamino groups include methylamino, ethylamino, propylamine and the like. "Dialkylamino" group is di(C1-C10)alkylamino, where (C1-C10)alkyl groups is as defined as above. Exemplary dialkylamino groups include dimethylamino, diethylamino, ethylmethylamino and the like. "Cycloalkyl" group is (C3-C6)cycloalkyl group. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. "Alkoxy" is (C1-C10)alkyl-O-, wherein (C1-C10)alkyl group is as defined above. Exemplary alkyl groups include methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like. "Cycloalkoxy" is (C3-C6)cycloalkoxy group. Exemplary cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy and the like. "Acyl" is H-CO- or (C1-C10)alkyl-CO-, where (C1-C10)alkyl group is as defined above. Exemplary acyl groups include acetyl, propionyl, benzoyl and the like. "Acyloxy" is (C1-C10)acyl-O- group, where acyl group is as defined above. Exemplary acyloxy groups include acetyloxy, propionyloxy, benzoyloxy and the Hke. "Aryl" is monocylic or multicyclic ring system of about 6 to 14 carbon atoms. Exemplary groups include phenyl, nephthyl and like. "Aryloxy" is aryl-0- group, where aryl group is as defined above. Exemplary aryloxy groups include phenoxy, naphthyloxy and the like. "Alkylthio" is (C1-C10)alkyl-S-, wherein (C1-C10)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-(C1-C10)alkyl group, where in aryl and (C1-C10)alkyl groups are as defined above. Exemplary aralkyl groups include benzyl, 2-phenethyl and the like. "Aralkoxy" is aralkyl-0- 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-C10)alkenyl-0-, where (C2-C6)alkenyl group is as defined above. Exemplary alkenyl groups include ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy and the like. "Cycloalkenyloxy" is (C1-Cyjcycloalkenyl-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-0- group, wherein aroyl group is as defined above. Exemplary aroyloxy groups include benzoyloxy, 1-naphthoyloxy and the like. "Heteroaryl" is an aromatic monocyclic or multicyclic 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, morpholinyl, thiomorpholinyl, benzothiazolyl, benzoimidazolyl, pyridazinyl, pyrimidinyl, piperidinyl, pyrrolidinyl and the like. "Heteroaryloxy" is heteroaryl-0-, 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, morpholinyloxy, thiomorpholinyloxy, benzothiazolyloxy, benzoimidazolyloxy, pyridazinyloxy, pyrimidinyloxy, piperidinyloxy, pyrrolidinyloxy and the like. "Heteroaralkyl" is heteroaryl-(C1-C10)alkyl group, wherein the heteroaryl and (C1- C10)alkyl groups are as defined above. Exemplary heteroaralkyl groups include pyrazinylmethyl, pyrazinylethyl, pyrazinylpropyl, pyrazinylbutyl, pyrazinylpentyl, pyrrolylmethyl, pyrrolylethyl, pyrrolylpropyl, pyrrolylbutyl, pyrrolylpentyl, morpholinylmethyl, morpholinylethyl, morpholinylpropyl, morpholinylbutyl, morpholinylpentyl, piperidinylmethyl, piperidinylethyl, piperidinylpropyl,, piperidinylbutyl, piperidinylpentyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl, pyrrolidinylbutyl, pyrrolidinylpentyl nd the like. "Heteroaralkoxy" is heteroaralkyl-0-, wherein heteroaralkyl group is as defined above. Exemplary heteroaralkoxy groups include pyrazinylmethoxy, pyrazinylethoxy, pyrazinylpropoxy, pyrazinylbutoxy, pyrazinylpentoxy, pyrrolylmethoxy, pyrrolylethxy, pyrrolylpropoxy, pyrrolylbutoxy, pyrrolylpentoxy, morpholinylmethoxy, morpholinylethoxy, morpholinylpropoxy, morpholinylbutoxy, morpholinylpentoxy, piperidinylmethoxy, piperidinylethoxy, piperidinylpropoxy, piperidinylbutoxy, piperidinylpentoxy, pyrrolidinylmethoxy, pyrrolidinylethoxy, pyrrolidinylpropoxy, pyrrolidinylbutoxy, pyrrolidinylpentoxy and the like. "Heteroaralkoxy(C1-C10)alkoxy" is heteroaralkyl-0-(C1-C10)alkoxy, wherein heteroaralkyl and (C1-C10)alkoxy groups are as defined above. Exemplary Heteroaralkoxy(C1-C10)alkoxy groups include morpholinylmethoxymethoxy, morpholinylmethoxyethoxy, morpholinylmethoxypropoxy, morpholinylmethoxy butoxy, morpholinylmethoxypentoxy, piperidinylmethoxymethoxy, piperidinyl methoxyethoxy, piperidinylmethoxypropoxy, piperidinylmethoxybutoxy, piperidinyl methoxypentoxy, pyrrolidinylmethoxymethoxy, pyrrolidinylmethoxyethoxy, pyrrolidinyl methoxypropoxy, pyrrolidinylmethoxybutoxy, pyrrolidinyl methoxypentoxy and the like. "Acyl" is H-CO- or (C1-C10)alkyl-CO-, where (C1-C10)alkyl group is as defined above. Exemplary acyl groups include acetyl, propionyl, benzoyl and the like. "Acyloxy" is (C1-C6)acyl-0- group, where acyl group is as defined above. Exemplary acyloxy groups include acetyloxy, propionyloxy, benzoyloxy and the like. "AlkylcarbonyF is (C1-C10)alkyl-CO-, wherein (C1-C10)alkyl group is as defined above. Exemplary alkylcarbonyl groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl and the like. "Alkoxycarbonyl" is (C1-C10)alkyl-O-CO-, wherein (C1-C10)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-0-CO-, wherein aryl group is as defined above. Exemplary aryloxycarbonyl groups include phenoxycarbonyl, naphthyloxycarbonyl and the like. "Aralkoxycarbonyl" is aryl-(C\|-C6)alkoxy-CO-, where aryl and (C1-C6)alkoxy are as defined above. Exemplary aralkoxycarbonyl groups include benzyloxycarbonyl, 2-phenethyloxycarbonyl and the like. "Carboxylic aC1d or its derivatives" may be amides or esters. Exemplary carboxylic aC1d groups include CONH2, CONHMe, CONMe., CONHEt, CONEtj, CONHPh, COOCH,, COOC2H5 or COOC3H7. "Sulfonic aC1d or its derivafives" may be amides or esters. Exemplary sulfonic aC1d groups include SO2NH2, S02NHMe, S02NMe2, 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 in the description. 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 a 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 oxy chloride and the like. The reaction may be carried out in the presence of catalyst such as dimethyl formamide, triethylamine, pyridine, dimethyl pyridine and the like. The solvent used in the reaction may be selected from dichloromethane, dichloroethane, chloroform, carbontetrachloride and the like. The temperature of the reaction may be in the range of room temperature to 100 °C. The duration of the reaction may be in the range of 0 to 24 h, preferably 3 to 6 h. Alternatively, formula (lb) may be converted to (Ic), where X represents -S-(C1-C6)alkyl, in the presence of reagents such as P2O5 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 h, preferably 10 to 16 h. The base used in the reaction may be carried out in the presence of KOH, NaOH 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 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 h, preferably in the range of 1 to 3 h. The compound of formula (1) is obtained from compound of formula (le), by reacting with a compound of formula (If), in the presence of a suitable base selected from pyridine, marpholine, 2,6-lutidine, N-methyl morpholine, dimethyl amine pyridine, diaza bicycle[5.4.0], triethyl mine 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 hexa methyl 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 h, preferably in the range of 1 to 3 h. In still another embodiment of the present invention there is provided another process for the preparation of compound of formula (2) where R* represents alkoxy group, R"" represents R" or R^, which represent substituted or unsubstituted 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 R* and R"° attached to the 3"^^ and 4"^ positions of the hetero bicyclic ring. The process is as shown in Scheme-11: 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 h, preferably in the range of 0.5 to 45 h. The compound of formula (2e) is converted to a compound of formula (2f) by reacting with compound of formula (2e"), where R^ represents substituted or unsubstituted alkyl, aralkyl, heteroaralkyl or acyl groups and X represents halogen atom, in the presence of a base selected from NH3, pyridine, marpholine, 2,6-lutidine, N-methyl morpholine, dimethyl amine pyridine, diaza bicycle[5.4.0], triethyl amine 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 hexa methyl 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 h, preferably in the range of 1 to 3 h. The compound of formula (2) may be prepared from compound of formula (20, by reacting with a compound of formula {2g), in the presence of suitable a base selected from pyridine, marpholine, 2,6-lutidine, N-methyl morpholine, dimethyl amine pyridine, diaza bicycle[5.4.0], triethyl mine 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 hexa methyl 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 h, preferably in the range of 1 to 3 h. It is appreC1ated that in any of the above-mentioned reactions, any reactive group in the substrate 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-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, 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, glyC1nol, phenyl glyC1nol and the like, salts of natural amino aC1ds such as glyC1ne, alanine, valine, leuC1ne, isoleuC1ne, norleuC1ne, tyrosine, cystine, cysteine. methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino aC1ds such as D-isomers or substituted amino aC1ds; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alky! 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 aC1d addition salts where appropriate which are. " sulphates, nitrates, phosphates, perchlorates, borates, halides, acetates, tartrates, maleates, C1trates, sucC1nates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols. Particularly useful compounds according to this invention include: OH The compounds of the present invention may contain geometrical isomers, hi such cases the compounds of the present invention cover the mixture of E and Z isomers or individual E and Z isomers. The compounds of the present invention may be used either alone or in combination with other class of drugs such as topoisomerase inhibitors, signal transaction inhibitors, estrogen modulators, micro tubule inhibitors, spindle poisioners. The compounds of the present invention are useful in the treatment of resistant cancers such as BCRP (breast cancer resistant protein), EGFR (epidermal growth factor receptor), MDR (multi drug resistant protein), Mutant P53 protein and the like. The enantiomers may be prepared by using reactants in their single enantiomeric form in the process wherever applicable or by conducting the reaction in the presence of reagents or catalysts in their single enantiomeric form. The single enantiomers may also be prepared by resolving the racemic mixture by conventional methods. The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral aC1ds such as mandelic aC1d, camphorsulfonic aC1d, tartaric aC1d, lactic aC1d, and the like wherever applicable or chiral bases such as bruC1ne, C1nchona alkaloids and their derivatives and the like. Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley IntersC1ence, 1981). Where appropriate the compounds of formula (I) may be resolved by treating with chiral amines, aminoaC1ds, aminoalcohols derived from aminoaC1ds; conventional reaction conditions may be employed to convert aC1d into an amide; the diastereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula (I) may be prepared by hydrolyzing the pure diastereomeric amide. The pharmaceutically acceptable salts are prepared by reacting the compounds of formula (I) wherever applicable with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calC1um 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, aC1d addition salts wherever applicable are prepared by treatment with aC1ds such as hydrochloric aC1d, hydrobromic aC1d, nitric aC1d, sulfuric aC1d, phosphoric aC1d, p-toluenesulphonic aC1d, methanesulfonic aC1d, acetic aC1d, C1tric aC1d, maleic aC1d salicylic aC1d, hydroxynaphthoic aC1d, ascorbic aC1d, palmitic aC1d, sucC1nic aC1d, benzoic aC1d, benzenesulfonic aC1d, tartaric aC1d and the like in the presence of a solvent like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvent may also be used. The salts of amino aC1d 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 etc. Mixture of solvents may be used. Various polymorphs of a compound of general formula (I) forming part of this invention may be prepared by crystallization of compound of formula (1) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Heating or melting the compound followed by gradual or fast cooling may also obtain polymorphs. The presence of polymorphs may be determined by solid probe nmr spectroscopy, IR spectroscopy, differential scarming calorimetry, powder X-ray diffraction or such other techniques. The present invention also provides pharmaceutical compositions, containing compounds of the general formula (I), as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates 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 bacterial infections. They can also be used for the treatment of bacterial infections assoC1ated with multidrug resistance. Pharmaceutically acceptable solvates of compound of formula (I) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of formula (I) in the presence of a solvent such as water, methanol, ethanol etc., preferably water and recrystallizing by using different cr>"stallization techniques. The regioisomers of compound of formula (I) may be prepared by modifying the reaction conditions, use of reagents like aC1d to base or base to aC1d or by reaction with free base hydrazine instead of its salt with diketone. The molar proportion also can change the regioisomer formation. The geometrical isomers, stereoisomers and tautomers of the present invention can be prepared by the conventional methods available in the literature. The pharmaceutical compositions may be in the forms normally employed, such as tablets, capsules, powders, 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 1 to 20 %, preferably 1 to 10 % 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 suffiC1ent to provide the desired dosage in the The compound of formula (2a) is converted to a compound of formula (2b), where R^ 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 oxy chloride and the like. The reaction may be carried out in the presence of catalyst such as dimethyl formamide, triethylamine, pyridine, dimethyl pyridine and the like. The solvent used in the reaction may be selected from dichloromethane, dichloroethane, chloroform, carbontetrachloride and the like. The temperature of the reaction may be in the range of room temperature to 100 °C. The duration of the reaction may be in the range of 0 to 24 h, preferably 3 to 6 h (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; 5/o. 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 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, dimthyisulfoxide and the like. The reaction may be carried out in the presence of a base such as NaNo3, KNO3, Na2C03, K2CO3, MgC03, pyridine, triethylamine, NaHC03 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 h, preferably in the range of 1 to 3 h. The compound of formula (2d) is converted to a compound of formula (2e) by using a reagent selected from KCN, guanidine, NH3, BFj.Et.O, BF3.0Et20, Mg, H2O2, wet CH3CN. sodium, CF3OSO2F, CH3OSO2F, PhSCH3, CF3COOH, Nal, MgBr2, SnBr2, AcBr, calC1um, dimethyldioxirane and other similar class of reagents. The solvent used in the reaction may be selected from THF, benzene, toluene, dichloromethane, acetone, alcohol such as methanol, ethanol, propanol, isopropanol, re/-/-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 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, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavorants, sweeteners, exC1pients 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 aC1d addition sahs 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. In addition to the compounds of formula (I) the pharmaceutical compositions of the present invention may also contain or be co-administered with one or more known drugs selected from clinically useful cytotoxic and anticancer agents such as taxol, taxotere, vinblastine, topoisomerase inhibitors like irinotecan, topotecan etc., and other cytotoxic agents. The compounds of the formula (1) as defined above are clinically administered to mammals, including human beings, via either oral or parenteral routes. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in C1rcumstances where the patient cannot swallow the medication, or absorption 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 0.5 mg/kg to about 50 mg / kg body weight of the subject per day administered singly or as a divided dose. However, the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage. The invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Example 1 l-[4-(Qulnazoiin-4-ylamino)-phenyl]-ethanoneO-(4-fluoro-benzyl)-oxime Step (i): Preparation of 4-chloroquinazoline A mixture of quinazolone (5 g, 30 mmol) {J. Med. Chem.. 1977(20)146 -149), 2 mL of dimethyl formamide were taken in 30 mL of 1,2-dichloroethane and 20 mL of thionylchloride (32.5 g, 270 mmol) was added at room temperature. Reaction mixture was heated at 90 °C for 2 h, 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 g of the 4-chloro quinazoline. Yield: 90% Step (ii): Preparation of l-[4-(Quinazolin-4-ylamino)-phenyl1-ethanone A mixture of 4-chloroquinazoline (5 g, 30.3 mmol), obtained in step (i) and 4- aminoacetophenone (4.93 g, 36mmol) in 35 mLof isopropyl alcohol was heated at 90 °C for 2 h and allowed to stand at room temperature for 3 h, during which solid was preC1pitated. The sohd was filtered and washed with diethyl ether to afford the pure yellow solid. Yield (92%). Mp:231 °C: "H-NMR (CDCb+DMSO-dft), ,6H: 9.0 (IH, d, J=8.6Hz), 8.8 (IH, 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) C1: 264(M"), 136. Step (iii): l-[4-(0uinazolin-4-ylamino)-phenyl1-ethanone 0-(4-fluoro-benzyl)-oxime A mixture of l-[4-(Quinazolin-4-ylamino)-phenyl]-ethanone (3.5 g, 13 mmol), obtained in step (ii) and 4-fluoro benzyloxy amine hydrochloride (J J. Org. Chem., 1988, 53(13) 2997) (3.5 g, 19.9 mmol) in 24 mL of methanol and 2.69 mL (33 mmol) of pyridine was heated at 70 C for 3 h. 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%) Mp: 158 °C. •H-NMR CDCl3,5H: 9.9 (IH, s), 8.67 (IH, s), 8.64 (IH, d, J=8.4 Hz) 8.0 (2H, d, J=8.8 Hz), 7.8 (2H, d, J=8.0Hz), 7.7 (2H, d, J=8.6Hz), 7.5 (4H, d, J=8.0Hz), 7.2 (2H, t, J=8.8Hz). Mass (m/z) C1: 387(M), 261,247,125,109. Examples 2-12 can be prepared by the procedure as described in example-1: Example 13 4-{4-[l-(4-FIuoro-benzyIoxyimino)-ethyl]-phenylamino}-7-isopropoxy-6-methoxy- quinoIine-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 g, 7.75 mmol) and 0.100 mL of dimethyl formamide were taken in 30 mL of 1,2 dichloroethane, then thionyl chloride (11.5 mL, 155 mmol) was added slowly at room temperature, then the reaction temperature increased to reflux temperature (90 °C) for 2 h . 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 g of product as a white solid (yield: 93.8%). Step (ii): Preparation of 4-[4-acetvlanilino1-7-isopropoxv-6-methoxy-3-quinoline carbonitrile A mixture of 4-chloro-7-isopropoxy-6-methoxy-quinoline-3-carbonitrile (2 g, 7.23 mmol), obtained in step (i), and l-(4-amino phenyl)-!- ethanone (1.17 g, 8.6 mmol), and 30 mL of isopropanol were heated at 90 °C for 4 h, and the reaction was left at room temperature. The resultant solid was filtered and washed with diethylether.to obtain 2.2 g of yellowish solid was obtained (yield : 81%). Mp: >250"C Mass (C1): 376(M^) (100%), 333,318,253,150,136,120,92. "H-NMR(DMS0-d6): 511.0 (IH, s), 9.0 (IH, s), 8.0 (2H, d, J=7.2Hz), 7.6 (IH, d, J=8.6Hz), 7.5 (2H, d, J=8.3Hz), 6.5 (IH, d, J=8.5Hz), 4.8 (IH, m), 3.9 (3H, s), 2.6 (3H, s),1.4 (6H, d). IR (KBr)cm"": 3434, 2976, 2662, 2223, 1679, 1637, 1583, 1505, 1455, 1415, 1311, 1268, 1101, 922, 888, 819, 762, 656, 592, 491. Step (iii): Preparation of 4-(4-{[(4-fluorobenzyl)oxylethanimidoyUanilino)-7-isoprnnoxy-6-methoxy-3-quinolinecarbonitrile A mixture of 4-[4-acetylanilino]-7-isopropoxy-6-methoxy-3-quinoline carboniirile (500 mg, 1.33 mmol), obtained in step (ii), 4-fIuorobenzyloxyamine 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 mmol) was added at room temperature, the reaction temp increased to 90 °C and continued for 4 h. The preC1pitated 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 g of pure compound. Melting point: 174-176 "C IR(KBr):cm-"3439,2925,1635,1580,1511,1455,1275,1224.5,1103,1018,923,876,824,558 •H-NMR(DMS0-d6): 5 10.9 (lH,s), 8.9 (IH, s), 8.0 (IH, s), 7.8 (2H, d), 7.4 (4H, 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 (C1): m/z 499(M+1), 498(M+),375,126,125(base peak),124,109(100%),96,95. Examples 14-16 can be prepared by the procedure as described in example-13: Example 17 l-{4-[6-Methoxy-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-yIamino]-phenyl}-ethanone O-benzyloxime Step (i): Preparation of 7-benzvloxy-4-chloro-6-methoxy quinazoline. A mixture of 7-benzyloxy-6-methoxy quinazoline (5 g. 17.7 mmol), and dimethyl formamide (1 mL) were taken in 75 mL of dichloroethane, thionyl chloride (30 mL, 398.2 mmol) was added slowly at room temperature, and then reaction continued at 90 °C for 4 h, 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 g of white solid was obtained. Yield:80%. Step (ii): Preparation of l-r4-(7-Benzvloxv-6-methoxv-quina2olin-4-ylamino)-phenvl1-ethanone. A mixture of 7-benzyloxy-4-chloro-6-methoxy quinazoline (4.2 g, 14 mmol), obtained in step (i) and l-(4-aminophenyl)-l-ethanone (2.26 g,16.8 mmol) were taken in 60 mL of isopropano! and reaction continued at 90 °C for 4 h. The preC1pitated solid was filtered and washed with diethylether to afford 4.5 g of light yellowish compound. Yield: 80%. Mpt: 174-176°C "H-NMR(DMSO-do): 5 11.7 (IH, s), 8.9 (IH, s), 8.5 (IH, s), 8.07 (IH, d. J=8.79Hz), 8.02 (2H, d, J=8.79Hz), 7.98 (IH, d, J=8.79Hz), 7.94 (IH, d, J=8.79Hz), 7.5 (2H, d, J=10.7Hz), 7.48 (IH, d, J=10.7Hz), 7.45 (IH, d, J=6.3Hz), 7.42 (IH, d, J=6.3Hz), 5.3 (2H, s), 4.04 (3H, s), 2.5 (3H, s). Mass (C1): m/z 401(M+2), 400(M+1), 399(M+), 253, 150, 136(100%). IR (KBr): cm"" 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-[4-(7-Hvdroxv-6-methoxv-quinazolin-4-vlamino)-phenvl1- ethanone A mixture of l-[4-(7-benzyloxy-6-methoxy-quinazolin-4-ylamino)-phenyl]-ethanone (4.4 g, llmmol), obtained in step (ii), trifluoroaceticaC1d (42 mL, 550 mmol) was heated at reflux temperature at 75 °C for 5 h, 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 g of brownish solid. Yield: 94%. Melting point: 234-236 "C "H-NMR(DMS0-d6): 5 11.1 (IH, s), 8.8 (IH, s), 8.1 (2H, d), 8.0 (2H, d), 7.8 (2H, d), 4.49 (lH,s),4.0(3H,s),2.6(3H,s). Mass(C1):m/z311(M+2),310(M+l)(100%), 309(M+), 181, 136,91. IR (KBr)cm"": 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-r7-(3-Chloro-propoxy)-6-methoxy-quinazolin-4-ylamino1- phenyl} -ethanone A mixture of l-[4-(7-Hydroxy-6-methoxy-quinazolin-4-ylamino)-phenyl]-ethanone (3.1 g, 10 mmol), obtained in step (iii), fused potassium carbonate (5.5 g, 40 mmol) were taken in dry dimethylformamide (30 mL) and stirred for 15 min at room temperature, then l-bromo-3-chloro propane (1.5 mL, 15 mmol) was added at room temperature and temperature increased to 80 °C and refluxed for 4 h. Water was added to the reaction flask and extracted with ethylacetate. Ethylacetate layer was dried and concentrated under vacuum to afford 2.8 g of yellow solid. Yield: 73%. Mp: 154-156 °C "H-NMR (DMSO-do): 6 9 7 (IH, s), 8.5 (IH, s), 7.8-8.2 (4H, m), 7.2 (2H, d). Mass (C1)^ m/z 386(M+1)(100%), 387(M+), 350, 322, 102, 90. IR (KBr)cm-":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-r6-Methoxv-7-(3-morpholin-4-vl-propoxv)-quinazoIin-4-y lamino 1 -phenyl} -ethanone A mixture of l-{4-[7-(3-Chloro-propoxy)-6-methoxy-quinazolin-4-ylamino]-phenyl}- ethanone (1 g, 2.59 mmol), obtained in step (iv), and potassium carbonate (1.4 g, 10.36 mmol), were taken in dimethylformamide (15 mL), then morpholine (0.450 mL, 5.19 mmol) was added at room temperature, then temperature increased to 80 °C, continued for 4 h. Water was added to the reaction mixture and extracted with ethylacetate, dried and concentrated under vacuum to afford 0.7 g of yellow solid. Yield:61%. Mpt: 150-152 °C. "H-NMR(DMS0-d6): 5 9.7 (IH, s), 8.5 (IH, s), 8.0 (5H, m), 7.2 (IH, s), 4.2 (2H, t, J=6.1Hz). 4.0 (3H, s), 3.5 (4H, t), 3.3 (6H, m), 2.5 (3H, s), 2.0 (2H, m). Mass (C1): M/z 437(M+1), 436. IR (KBr): cm""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-r6-Methoxy-7-(3-morpholin-4-vl-propoxv)-quinazolin-4- ylaminol-phenyl ] -ethanone-0-benzyl-oxime A mixture of l-{4-[7-(3-Chloro-propoxy)-6-methoxy-quinazoIin-4-ylamino]-phenyU-ethanone (0.2 g, 0.45 mmol), obtained in step (v), and phenyl methoxy amine {J. Org. Chem., 1988, 53(13)2997) (0.225 g, 1.8 mmol) were taken in 10 mL of methanol, then pyridine (0.140 mL, 1.8 mmol) was added at room temperature, and reaction continued at 90^C for 4 h. 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 DCM afforded 0.128 g of pure compound . Yield: 50% Melting point: MO-Ml^C lR(KBr)cm"": 3178,2924,2854,1699,1624,1582,1511,1459,1419,1387,1366,1308,1283, 1149, 1117,1024,926,838,744,702,657,623,599,557. "H-NMR(DMSO-d6)5: 9.5 (IH, s), 8.4 (IH, s), 7.9 (IH, d, J=8.8Hz), 7.8 (2H, d, J=8.8Hz), 7.7 (IH, d, J=8.8Hz), 7.6 (IH, m, d=8.8Hz), 7.4 (2H, d, J=4.4Hz), 7.39 (2H, d, J=4.4Hz), 7.35 (IH, d, J=7.4Hz), 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 (C1): m/z 542(M+), 436,316,233,183,147,125,109(100%), 91. Examples 18-28 can be prepared by the procedure as described in example-17: Step (i): Synthesis of acetic aC1d 4-chloro-7-methoxv-quinazolin-6-ylester 4 g (17.1 mmol) of 7-methoxy-4-oxo-3,4-dihydro-6-quinazolinyl acetate was taken in 40 mL of dichloroethane and 24 mL of thionyl chloride were added followed by 0.1 mL of DMF. 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 g, Yield: 76% Step (ii): Preparation of Acetic aC1d 4-(4-acetyl-phenylamino)-7-methoxy-quina2olin-6-yl ester 3.2 g (12.6mmol) of Acetic aC1d 4-chloro-7-methoxy-quinazoHn-6-yl ester, obtained in step (i) was taken in 80 mL of IPA and 2 g(14.8mmol) 4-amino acetophenone was added and the contents refluxed for 2 hours. The reaction flask was left overnight and solid preC1pitated was filtered and dried under vacuum. Yield: 92% Melting point: 250"C lR:(KBr)cm"" 3029.2619,1777,1677,1643,1574,1527,1438,1363,1264, 1294,1267,1175,1152,850, 815,"HNMR (DMSO -d6, 5 ) 11.5(s,lH) 8.9(s,lH)8.8(s,lH) 8 (d,J=8.6Hz,2H) 7.9(d,J=8.6,2H) 7.5(s,lH) 4(s,3H) 2.5(s,3H) 2.4(s,3H) Mass; (m/z,C1) 352 (M+1,100%) 310,178,136, Step (iii): Preparation of l-r4-(6-Hvdroxy-7-methoxy-quinazoIin-4-ylamino)-phenvl\|-ethanone 0-benzyl-oxime 1.3 g (3.7mmol) of acetic aC1d 4-(4-acetyl-phenylamino)-7-methoxy-quinazolin-6-yl ester, obtained in step (ii) 0.49 g(4.49 mol) of 0-benzyl hydroxyl amine (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 h. The preC1pitated solid was filtered and dried under vacuum to give 1.2 g of the product. Yield: 87%. Mp. 177 °C lR(KBr, cm-"): 3435,2927,2360,1597,1511,1428,1391,1240,1155,920,833,558. "HNMR (DMS0-d6) 6: 11.11(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), 5.1(2H, s), 4.0(3H, s), 2.6(3H, s). Mass m/z(C1): 415 (M+1), 414 (M+), 125 (Base peak), 109. Step (iv): Preparation of l-{4-r6-(3-Chloro-propoxy)-7-methoxy-quinazolin-4-ylamino1- phenylj-ethanone 0-benzyl-oxime A mixture of 0.64 g (l.Smmol) of l-[4-(6-hydroxy-7-methoxy-quinazoIin-4-ylamino)-phenyl]-ethanone-0-benzyl-oxime, obtained in step (iii) and 0.85 g of fused potassium carbonate were taken in dry dimethylformamide and stirred for 15 min then 0.85 mL of l-chloro-3-bromo propane was added at room temperature. The contents were stirred at room temperature 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 i 00-200 silica gel to afford 0.45 g of product. Yield: 60%. Mp: 224 °C l.R(KBr)cm"" :3294,2933,2873,1625,1575,1512,1426,1311,1244,1209,1145,912,741,555. "HNMR(DMSO-d6)5: 9.5(H), 8.4(s,lH), 8.1(s,lH), 7.9(d, J-8.8Hz, 2H), 7.6(d, J=8.6Hz,2H), 7.3(m,5H), 5.2(1H, s), 4.3 (2H, ,J-5.9Hz, t), 4.0(3H, s), 3.8(2H, J=6.4Hz,t), 2.5(3H, s), 1.8(2H,m). Mass (C1); 491 (M+1,100%) Step (v): Preparation of l-{4-r7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4- ylaminol-phenyl I-ethanone 0-benzyl-oxime 0.46 g (0.93 mmol) of l-{4-[6-(3-Chloro-propoxy)-7-methoxy-quinazolin-4-ylamino]-phenyl}-ethanone 0-benzyl-oxime, obtained in step (iv) and 0.518 g (3.7mmol) of fused potassium carbonate was taken in dry DMF stirred for 15 minutes at room temperature, and 0.122 mL of morpholine was added. The contents stirred for 5 h 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 g 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 DCM afforded 0.260 g of pure compound. Yield :52% Mp: 186-188 °C. lR(KBr):cm"".: 3342,2928,1622,1599,1512,1470,1427,1392,1241,1209,1014,981,859. "HNMR(CDCl3)5: 8.6(1H, s), 7.7(4H, m), 7.6(8H, m), 5.2(2H, s), 4.2(2H, J=6.4Hz, t), 3.9(3H, s), 3.7(4H, m), 2.6(6H, m), 2.5(3H, s), 1.8(2H, m). Mass; (m/z)(C1): 542(M+1), 541(M^), 436,434,107(100%). Example 30 l-{4-[7-Methoxy-6-(3-niorpholin-4-yl-propoxy)-quinazoUn-4-ylaininol-phenyl}-ethanone Step (i): Synthesis of acetic aC1d 4-chloro-7-methoxv-quinazolin-6-yl ester C1 Ac-°YV^N 4 g (17.1rhmol) of 7-methoxy-4-oxo-3,4-dihydro-6-quinazolinyl acetate was taken in 40 mL of dichloroethane and 24 mL of thionyl chloride were added followed by 0.1 mL of DMF. The Contents were refluxed for 4-5 h and 40 mLof dichloromethane was added, and solvent was evaporated in a rota vapor. The reaction mixture was dissolved in dichloromethane, passed through 230-400-mesh silica gel, concentrated and dried to yield the product (3.2 g, Yield: 76%) Step (ii): Preparation of Acetic aC1d 4-(4-acetyl-phenylamino)-7-methoxy-quinazolin-6-yl ester 3.2 g (12.6 mmol) of acetic aC1d 4-chloro-7-methoxy-quinazolin-6-yl ester, obtained in step (i), was taken in 80 mL of isopropyl alcohol and 2 g (14.8 mmol) of 4-amino acetophenone was added and the contents refluxed for 2 h. The reaction flask was left overnight and solid preC1pitated was filtered and dried under vacuum. Yield: 92% Mp: 250 °C. IR:(KBr)cm"" : 3029.2619,1777,1677,1643,1574,1527,1438,1363,1264, 1294,1267,1175,1152,850,815. "HNMR (DMSO-d6,)5: 11.5(1H, s), 8.9 (IH, s), 8.8(1H, s), 8.0 (2H, J=8.6Hz, d) 7.9(2H, J-8.6, d), 7.5(1 H, s), 4.0(3H, s), 2.5(3H, s), 2.4(3H, s) Mass (m/z,Cl): 352 (M+1,100%) 310,178,136, Step (iii): Preparation of l-[4-(6-Hydroxy-7-methoxy-quinazolin-4-ylamino)-phenyl1- ethanone 4 g of acetic aC1d 4-(4-acetyl-phenylamino)-7-methoxy-quinazolin-6-yl ester (10.3 mmol), obtained in step (ii) and 20 mL of aq.ammonia were taken in 20 mL of methanol. The above contents were stirred at room temperature for 2 h. The solid formed was filtered and dried. The weight of the product was observed as 3 g. Mp: 260 °C. "HNMR (DMSO-dfi) 6: 9.75(1H, s), 8.55(1H, s), 8.15(2H, J=8.5Hz, d), 7.9( 2H, J=8.6Hz, d), 7.25(2H, s), 4.5(3H, s), 2.5(3H, s) Mass(m/z)(C1): 310 M( 100%). IR (ECBr)cm-"): 3442, 3291, 2930, 1626, 1512, 1473, 1344, 1399, 1244, 1024, 914, 837, 559 Step (iv): Preparation of l-{4-[6-(3-Chloro-propoxy)-7-methoxv-quina2olin-4-ylamino1- phenyll-ethanone 3 g (8.68 mmol) of l-[4-(6-hydroxy-7-methoxy-quinazolin-4-ylamino)-phenyl]-ethanone, obtained in step (iii) and 5.3 g (38.3 mmol) of fused potassium carbonate were taken in dry dimethylformamide, stirred for 15 min and 1.14 mol of l-chloro-3-bromo propane was added and the contents were stirred at room temperature for 12 h. 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 g.Yield 76%. Mp: 240 °C "HNMR (DMS0-d6) 5; 8.65(1H, s), 8.05(4H, m), 7.45(1H, s), 7.25(2H, s), 4.35(1H, J=5.9Hz, t), 3.95(3H, s), 3.85(2H, J=6.1Hz, t), 2.6(3H, s), 2.45(2H, m) Mass (C1): m/z 386(M^100%). IR(KBr)cm"": 3350, 2930, 1653, 1578, 1520, 1470, 1426, 1275, 1242, 1204, 1144, 838, 653, 590 Step (v): Preparation of l-{4-r7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazoiin-4-ylamino]-phenyl} -ethanone 1.2 g (3.1 mmol) of l-{4-[6-(3-Chloro-propoxy)-7-methoxy-quinazolin-4-ylamino]-phenyl}-ethanone, obtained in step (iv) and 1.9 g (13.7mmol) of fused potassium carbonate was taken in dry dimetyhylformamide stirred fori5 min at room temperature followed by 0.44 mL (5 mmol) of morpholine. Reaction contents were stirred at 80 °C for 5 h. Reaction mixture was extracted 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 g.yield 54% "H-NMR(DMSO-d6)5: 9.75(1H, s), 8.5(1H, s), 8.0 (5H, m), 7.2(1H, s), 4.25(2H, J=6.1Hz, t), 4(s, 3H), 3.5(4H, t), 2.5(3H), 2.4(6H, m), 2.0(2H, m). Mass (C1): m/z 437 (100%). IR(KBr)cm"": 3385, 2927, 1653, 1601, 1514, 1469, 1425, 1390, 1274, 1240, 1117,846,607. Step (vi): Preparation of l-{4-[7-Methoxv-6-(3-morpholin-4-yl-propoxv)-quinazolin-4- A mixture of 0.23 g (0.53 mmol) of l-{4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)- quinazolin-4-ylamino]-phenyl}-ethanone, obtained in step (v) and 0.155 g (0.79 mmol) of [(4-chloro benzyl)oxy]ammonium chloride (J. Org. Chem., .53(13), 1988 , 2997), 0.127 mL (1.5 mmol) of pyridine were taken in 8 mL methanol and refluxed for 2 h. Ice was added to the reaction mixture, extracted with ethyl acetate and ethyl acetate layer was washed with water and concentrated and dried. The Residue was purified by flash column chromatography over 100-200 silica gel to afford 0.2 g of product. Yield: 66% Mp. 177-179 °C. lR(KBr)cm-": 3425, 2931, 1634, 1520, 1439, 1278, 1233, 1012, 885. "HNMR(CDCl3)5: 8.6(1H, s), 7.75(3H, m), 7.5(7H, m), 5.15(2H, s), 4.25(2H, J=6.5Hz, t), 3.95(3H, s), 3.75(4H, m), 2.55(6H, m), 2.25(3H, s), 1.85(2H, m). Mass (C1): m/z 576 (M+), 141(100%) 436, 437,405. Examples 31-39 can be prepared by the procedure as described in examples-29 and 30: Example-40 l-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyll-ethanone O-benzyl-oxime Step (i): Preparation of l-r4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl1-ethanone 0.9 g (4mmol) of 6,7-dimethoxy 4-chloro quinazoline,0.65 g (4.8 mmol) of 4-amino acetophenone were taken in 25 mL of isopropylalcohol, refluxed for 2 h at 90 C .The solid was filtered and washed with methanol. Yield: 63%. IR(KBr)cm"": 3029, 2619, 1677, 1643, 1574, 1527, 1433, 1363, 1267, 1235, 1175, 1152, 1064,850,584. "HNMR(DMS0-d6)^.- .9.1(1H, s), 7.9(2H, d), 7.4(2H, d),7.3 (IH, s), 6.9(1H, s), 4.0(6H, s), 2.4(3H, s). Mass(m/z)C1. 324(M+), 310. J Step (ii): Preparation of l-f4-(6,7-Dimethoxv-quinazolin-4-vlamino)-phenyl1-ethanone O-benzyl-oxime 0.3 g (0.92mmol) of l-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-ethanone, obtained in step (i) and ,0.14 g (1.13mmol) of benzyloxy amine(J. Org. Chem., 53(13), 1988, 2997) were taken in 6 mL of methanol, and 0.29 mL(3.6 mmol)of pyridine was added . The contents were refluxed for 2.5 h 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%. Mp: 196-198 °C. IR(KBr) cm"": 3423, 3070, 2925,2854,1622,1575, 1512, 1419, 1279, 1234, 1143, 1012, 850,681. "HNMR (DMSO-d6)5: 9.1 (IH, s), 8.6 (IH, s), 8.1 (IH, s), 7.8 (2H, J=8.6Hz, d), 7.7(2H, J=8.6Hz, 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)C1:429(M+),323,125(100%), 109. Examples 41 can be prepared by the procedure as described in example 40: Example 42 N4-(4-(2-Phenyl metboxyimino propoxy) Phenyl)-4-quinazolinamine Step (i): Preparation of l-(4-Nitro phenoxy acetone). 4-Nitro phenol (50gr, 0.359moles) was dissolved in dimethylformamide (150 mL) and cooled to 0 °C . Sodium hydride (24.12 g, 0.718 moles) was added slowly under stirring. After the addition was completed, chloro acetone (43 mL, 0.538 moles) was added at 0 °C and the contents were stirred at room temperature for 16 h. The reaction mixture was poured into ice and was extracted 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. (23 g, 33% ). Step (ii): Prepartion of l-(4-amino phenoxy acetone) 1 .(4.Nitrophenoxy) acetone (5 g, 0.0255 moles), obtained in step (i) was taken in absolute ethanol (75 mL) and stannous chloride di-hydrate (23 g, 0.102 moles) was added and the contents were refluxed for 45 min. The reaction mixture was poured into ice water, basified with 10% aq. 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.(4.1 g, 96%). I Step (iii): Preparation of l-[4-(4-Quinazolinyl amino)phenoxy1acetone l-(4-amino phenoxy) acetone (4.7 g, 0.0284 moles), obtained in step (ii) and 4-chloro quinazoline (3.9 g, 0.0237 moles) were taken in 50 mL of Isopropanol and refluxed for 0.5 h and left overnight at room temperature . The preC1pitated solid was filtered, washed with isopropanol followed by di-ethyl ether and dried to afford the product (4.4 g, 63 % ). "HNMR(CDCl3).5: 2.4(3H, s), 4.2(2H, s), 6.8-8.0 (13H, m), 8.5(1H, s), 9.4(1H, bs). Mass(m/z) C1: 294 (M+1), 266, 238, 189. Step (iv): Prepartion of N4-(4-(2-Phenyl methoxyimino propoxy)phenyl)-4-Quinazolinamine l-[4.(4-Quinazolinyl amino)phenoxy]acetone (4.25 g, 0.0145 moles), obtained in step (iii) and 0-benzyl hydroxyl amine.hydrochloride (J. Org. Chem., 53(13), 1988 , 2997), (3.45 g, 0.0217 moles) were taken in 75 mL methanol and pyridine (2.63 mL) was added at room temperature. The contents were refluxed for 1 h 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 g, 68%) Mp: 129-130 °C. IR (KBr)cm-": 3426, 2924, 2854, 1618, 1573, 1511, 1495, 1455, 1424, 1398, 1355, 1317, 1230, 1172, 1024,920. "HNMR (CDC13): 2.0(3H, s), 4.4(2H, s), 5.1(2H, d), 6.8-8.0(13H, m), 8.5(1H, s), 9.4(1H, bs). Mass(m/z)C1: 399(M+1), 293 , 243, 236, 210, 206, 181. Example 43 l-[4-(Quinazolin-4-ylamino)-phenyll-ethanoneO-[3-(2-chIoro-phenoxy)-p ropyi]-oxime Step (i): Preparation of l-[4-(Quinazolin-4-ylamino)-phenvl1-ethanone oxime hydroxylamine hydrochloride (0.528 g, 7.6 mmols), and pyridine (0.922 mL, 11 mmols) were taken in 100 mL methanol and refluxed for 5 h. The preC1pitated compound was filtered and dried to afford 0.5 g of the compound as a pale yellow solid. Yield: 50% Step (ii). Preparation of l-chloro-2- (3-chloropropoxy) benzene A mixture of 2-chloro phenol (10 mL, 98 mmols), fused potassium carbonate (67.7 g, 490 mmols) and l-bromo-3-chloropropane (14.5 mL, 147 mmols) are taken in 250 mL dimethylformamide and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extract was dried and concentrated to afford 20gr of the product as a colorless liquid Yield: 100% Step (iii); Preparation of l-r4-(0uinazolin-4-ylamino)-phenyl1-ethanone 0-[3-(2-chloro- phenoxv)-propyl1-oxime 0.150 g (0.53 mmols) of l-[4-(lH-quinazolin-4-ylidencamino)-phenyl]-ethanone oxime, obtained in step (i) is taken in dimethylformamide and at 0 °C, 0.064 g of NaH was added and stirred for 0.5 h.To this reaction mixture was added 0.165 g (0.80 mmols) of l-chloro-2-(3-chloropropoxy)benzene, obtained in step (ii) and the contents were stirred at 80 °C for 3 h. 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 0.180 g 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 g of the compound as a solid-.Yield: 41%. Mp: 172 °C I.R(KBr)cm-": 3432,3270,2923,1715,1624,1524,1415,1290,1253,1195,1059,896. "HNMR(DMSO-d6)5: 11.0(1H, s), 8.4(1H, s) 6.8-8.0(12H, m), 4.5(2H, j=6Hz, t) ,4.2(2H„ J=6Hz, t), 2.2(2H, m), 2.1(3H, s). Mass (C1):447(M+1,100%). Examples 44 and 45 can be prepared by the procedure as described in example 43: Example 46 l-{4-[7-Methoxy-6-(3-morpholin-4-yI-propoxy)-quinazolin-4-ylaminoj-phenyl}-ethanone O-benzyl-oxime acetic aC1d salt l-{4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyI}-ethanone O-benzyl-oxime (0.6 g ,1.1 mmol) was taken in 15 mL of ethanol and refluxed at 90 °C for 3 h, IN solution of methanesulfonicaC1d 1.1 mL(0.106 g) was added and refluxed for 30 h and ethanol was removed under vacuum. The resultant solid was taken in ether and stirred for 20 min and filtered to afford 0.420 g of colorless solid Yield: 60%. Mp. 233 °C Examples 47-55 can be prepared by the procedure as described in example 46: Anti-cancer activity: The compounds prepared in the present invention exhibited good in vitro anti-cancer activity towards various 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, 1X10 cells were seeded into each well of 96 well plate in lOO^iL volume of RPMI 1640 medium containing antibiotics and 10% FCS. The plates were incubated at 37"C in presence of CO2. After 24 h, test compounds were evaluated at five 10 fold dilutions ranging from 100 to 0.01 Μ.M. TO each test well l00μL of test compound solution was added and medium with vehicle was added to control wells and the plates were further incubated. After 48 h of incubation, plates were terminated by Sulforhodamine 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 Inhibition (GI50). The compounds of the present invention showed anticancer activity, which can be seen from the data given below: Lymphocyte Proliferation: Human lymphocytes were isolated from whole blood by using Ficoll Hypaque Plus (Amersham). On day one, 1 million lymphocytes were seeded into each well of 96 well plate in 100 μL volume of RPMI 1640 medium containing 10%FCS and Phytohemagglutitin A at 10 μg/ml 1 μg/well concentration. Plates were incubated at 37°C in CO2 incubator for 24 h. Test compounds at various concentrations were added to test wells and only medium with vehicle was added to control wells. After 48 h of incubation 0.5 mC1 of tritiated thymidine was added to each well. After 24 h of thymidine addition the cells were harvested and the incorporated radioactivity was determined. Stimulation Index (SI) was calculated using the formula, A^ = Average CPM of treated wells, A*" = Average CPM of control wells. We claim 1. A compound of formula (I) where R1 and R2 represents hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, acyl, acyloxy, aryl, aryloxy, alkylthio, arylthio, aralkyl, aralkoxy, alkenyl, alkenyloxy, cycloalkenyloxy, aroyl, aroyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, 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, substituted or unsubstituted 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, substituted or unsubstituted 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 substituted or unsubstituted 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 or -CH, Y represents oxygen or nitrogen, s, t are integers in the range of 0 to 5 and r, u are integers 0 or 1. their derivatives, their analogs, their stereoisomers, their tautomers, their polymorphs, their phamaceutically acceptable salts, their pharmaceutically acceptable solvates and their pharmaceutically acceptable compositions 2. The compound of formula (I), as claimed in claim 1, wherein the substituents on R1 andR2 are selected from halogen, nitro, amino, alkylamino, dialkylamino, hydroxy, carboxy, cyano, oxo(0=), thio(S=), alkyl, cycloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, benzyloxy, acyl, acyloxy, aroyl, heteroaryl, aralkyl, alkylsulfonyl, alkylsulfmyl, arylsulfonyl, arylsulfinyl, alkylthio, arylthio or a substituted or unsubstituted 5 or 6 membered cyclic ring which may optionally contain one or two hetero atoms selected from oxygen, sulfur or nitrogen. 3. The compound as claimed in claim 1, wherein the substituents on R3, R4, R5 and R6 are selected from a halogen, nitro, amino, hydroxy, carboxy, cyano, oxo(0=), thio(S=), alkyl, cycloalkyl, alkoxy, cycloalkyl, aryl, acyl, aroyl, heteroaryl or aralkyl. 4. The compound as claimed in claim 1, wherein the substituents on W are selected from halogen atom, hydroxy, carboxy, acyl, nitro, cyano, amino, acylamino, thio, linear or branched optionally halogenated alkyl, optionally halogenated alkoxy, carboxylic or sulfonic acids and their derivatives. 5. The compoimd as claimed in claim 2, wherein the 5 or 6 memebered cyclic ring is selected from pyrrole, morpholine, thiomorpholine, benzothiazole, benzoimidazole, pyridine, pyridazine, pyrimidine, pyrazine, piperidine or pyrrolidine. 6. The compound as claimed in claim 2, wherein the substitutents on a 5 or 6 memebered cyclic ring as defined in claim 2, are selected from halogen, nitro, amino, hydroxy, carboxy, cyano, oxo(0=), thioxo(S=) or alkyl. 7. The compound of the formula (I) as claimed in claim 1, selected from the group consisting of: 8. The compound of formula (I), as claimed in claim 1 or 7, wherein the pharmaceutically acceptable salt is selected from the group consisting of Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases, chiral bases, natural amino acids, unnatural amino acids, substituted amino acids, guanidine, substituted guanidine salts; ammonium, substituted ammonium salts, aluminum salts or acid addition salts. 9. The compound of formula (I), as claimed in claim 8, wherein the salts of organic bases are selected from -the group consisting of N,N"-diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, 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, or spermidine. 10. The compound of formula (I) as claimed in claim 8, wherein the salts of chiral bases are selected from the group consisting of alkylphenylamine, glycinol, or phenyl glycinol. 11. The compound of formula (I) as claimed in claim 8, wherein the salts of natural amino acids are selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, serine, threonine, or phenylalanine. 12. The compound of formula (I), as claimed in claim 8, wherein the salts of unnatural amino acid, substituted amino acids are selected from the group consisting of D-isomers, guanidine, and substituted guanidine wherein the substituents are selected from the group consisting of nitro, amino, alkyl, alkenyl or alkynyl. 13.. A compound of formula (I) as claimed in claim 8, wherein the acid addition salt is selected from the group consisting of sulphates, nitrates, phosphates, perchlorates, borates, halides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, or ketoglutarates. 14. A process for the preparation of compound of formula (I) where R and R represents hydrogen, halogen, hydroxy? nitro, cyano, amino, substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, acyl, acyloxy, aryl, aryloxy, alkylthio, arylthio, aralkyl, aralkoxy, alkenyl, alkenyloxy, cycloalkenyloxy, aroyl, aroyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, 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, substituted or unsubstituted 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, substituted or unsubstituted 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 substituted or unsubstituted 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 or -CH, Y represents oxygen or nitrogen, s, t are integers in the range of 0 to 5 and r, u are integers 0 or 1. their derivatives, their analogs, their stereoisomers, their tautomers, their polymorphs, their phamaceutically acceptable salts and their pharmaceutically acceptable solvates 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 (1 b), to a compound of formula (1 c) where X represents halogen atom, R1, R2 and R3 are as defined above, (iii) reacting the compound of formula (1 c), 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 (1 e), with a compound of formula (1 f) where all symbols are as defined above, to obtain a compound of formula (I) (v) and if desire converting the compound obtained in to its derivatives, its anolagous, its tutomaric form, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically solvates by conventionals methods.. 15. A process for the preparation of compound of formula (2) where R1 and R2 represents substituted or unsubstituted alkoxy, aralkoxy, heteroaralkoxy or acyloxy groups. R3 repesents hydrogen, halogen, hydroxy, cyano, amino, -CH2CN, substituted or unsubstituted 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, substituted or unsubstituted 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 substituted or unsubstituted groups selected from divalent phenyl, naphthyl, pyrrolyl, pyridyl, quinolinyl, benzofiaryl, dihydrobenzofiiryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like. Q represents N or -CH, Y represents oxygen or nitrogen, s, t are integers in the range of 0 to 5 and r, u are integers 0 or 1. their derivatives, their analogs, their stereoisomers, their tautomers, their polymorphs, their phamaceutically acceptable salts, their pharmaceutically acceptable solvates and their pharmaceutically acceptable compositions. which comprises: (i) converting the compound of formula (2a) where R 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 above, to a compound of formula (2d) where all symbols are as defined above, (iii) converting the compound of formula (2d), to a compound of formula (2e) where all symbols are as defined above, (iv) reacting the compound of formula (2e), with a compound of formula (2e") where R9 represents substituted or unsubstituted 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 3rd and 4th positions of the hetero bicyclic ring (vi) and if desire converting the compound obtained in to its derivatives, its anolagous, its tutomaric form, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically solvates by conventionals methods. 16. A pharmaceutical composition, which comprises an effective amount of a compound of formula (I) as defined in claim 1, and a pharmaceutically acceptable carrier, diluent, excipient or solvate. 17. A pharmaceutical composition as claimed in claim 16, in the form of a tablet, capsule, powder, syrup, solution or suspension. 18. A pharmaceutical composition which comprises an effective amount of a compound of formula (I) as defined in claim 7, and a pharmaceutically acceptable carrier, diluent, excipient or solvate. 19. A pharmaceutical composition as claimed in claim 19, in the form of a tablet, capsule, powder, syrup, solution or suspension.

Full Text

Field of the Invention
The present invention relates to novel anticancer agents, their derivatives, their analogs, their stereoisomers, their tautomers, their geometric isomers, their polymorphs, their phamaceutically acceptable salts, their pharmaceutically acceptable solvates and their pharmaceutically acceptable compositions. The present invention more particularly relates to novel quinazoline compounds, their derivatives, their analogs, their stereoisomers, their tautomers, their enantiomers, their geometric isomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and their pharmaceutically acceptable compositions. The novel quinazoline compounds have the general formula (I),

where R1 and R2 represents hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, acyl, acyloxy, aryl, aryloxy, alkylthio, arylthio, aralkyl, aralkoxy, alkenyl, alkenyloxy, cycloalkenyloxy, aroyl, aroyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, heteroaralkoxyalkoxy, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carboxylic aC1d or its derivatives, or sulfonic aC1d or its derivatives. R repesents hydrogen, halogen, hydroxy, cyano, amino, CH3CN, substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic aC1d or its derivatives, or sulfonic aC1d or its derivatives. R4, R5 and R6 independently represent hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic aC1d or its derivatives, or sulfonic aC1d or its derivatives. "W represents substituted or unsubstituted 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 or -CH, Y represents oxygen or nitrogen, s, t are integers in the range of 0 to 5 and
r, u are integers 0 or l.The present invention also relates to pharmaceutical compositions containing compounds of general formula (I) or mixtures thereof.
The present invention also relates to a process for the preparation of the above defined novel compounds of general formula (I), their derivatives, their analogs, their stereoisomers, their tautomers, their geometric isomers, their eantiomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and their pharmaceutically acceptable compositions.
The compounds of the present invention either alone or in combination with other cytotoxic durgs exhibited significant in vitro anti-tumor activity against a wide range of human tumor cell lines.
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 benefiC1al. 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 transemembrane receptors are relayed into the cells by the signal transduction pathways (Pelech et al., SC1ence 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 control gene expression and function (Nishida et.al.. Trends Biochem. SC1., 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.
7, 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 assoC1ated 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 assoC1ated 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.
Objective of the Invention
With an objective of preparing novel quinazoline compounds useful for treating cancer, and other proliferative diseases like psoriasis, restenosis, auto immune diseases or atherosclerosis. We focussed our research efforts in prepared the novel quinazoline derivatives of the formula (I) as defined above.

The main objective of the present invention is, therefore, to provide novel quinazoline compounds of the formula (I) as defined above, their derivatives, their analogs, their stereoisomers, their tautomers, their geometric isomers, their enantiomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures.
Another objective of the present invention is to provide pharmaceutical compositions containing compounds of the general formula (I), their derivatives, their analogs, their stereoisomers, their tautomers, their geometric isomers, their enantiomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates containing them or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
Still another objective of the present invention is to provide pharmaceutical compositions containing compounds of formula (I), their derivatives, their analogs, their stereoisomers, their tautomers, their geometric isomers, their enantiomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, containing them or their mixtures in combination with one or more pharmaceutically acceptable active compounds with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
Still another objective of the present invention is to provide a process for the preparation of novel quinazoline derivatives of the formula (I) as defined above, their derivatives, their analogs, their stereoisomers, their tautomers, their geometric isomers, their enantiomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceufical compositions containing them or their mixtures having enhanced acfivity, no toxic effect or reduced toxic effect.
Detailed Description of the Invention
The present invention relates to compounds having the general formula (I)

" their derivatives, their analogs, their stereoisomers, their tautomers, their polymorphs, their geometric isomers, their phamaceutically acceptable salts, their pharmaceutically acceptable solvates and their pharmaceutically acceptable compositions.
where R1 and R2 represents hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, acyl, acyloxy, aryl, aryloxy, alkylthio, arylthio, aralkyl, aralkoxy, alkenyl, alkenyloxy, cycloalkenyloxy, aroyl, aroyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, heteroaralkoxyalkoxy, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carboxylic aC1d or its derivatives, or sulfonic aC1d or its derivatives. R3 repesents hydrogen, halogen, hydroxy, cyano, amino, -CH2CN, substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic aC1d or its derivatives, or sulfonic aC1d or its derivatives. R4, R5 and R6 independently represent hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroraryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy, carboxylic aC1d or its derivatives, or sulfonic aC1d or its derivatives. "W represents substituted or unsubstituted groups selected from divalent phenyl, naphthyl, pyrrolyl, pyridyl, quinolinyl, benzoftiryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like. Q represents N or -CH, Y represents oxygen or nitrogen, 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 a halogen, nitro, amino, alkylamino, dialkylamino, hydroxy, carboxy, cyano, oxo(0=), thio(S=), alkyl, cycloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, benzyloxy, acyl, acyloxy, aroyl, heteroaryl, aralkyl, alkylsulfonyl, alkylsulfmyl, arylsulfonyl, arylsulfinyl, alkylthio, arylthio or a substituted or unsubstituted 5 or 6 membered cyclic ring which may optionally contain one or two hetero atoms selected from oxygen, sulfur or nitrogen. 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, oxo(0=), thioxo(S=) or alkyl.
The substituents on R3 R4, R5 and R6 are selected from a halogen, nitro, amino, hydroxy, carboxy, cyano, oxo(0=), thio(S=), alkyl, cycloalkyl, alkoxy, cycloalkyl, aryl, acyl, aroyl, heteroaryl or aralkyl.
The substituents on the group represented by W are selected from a halogen atom, hydroxy, carboxy, acyl, nitro, cyano, amino, acylamino, thio, linear or branched optionally halogenated alkyl, optionally halogenated alkoxy, carboxylic or sulfonic aC1ds and their derivatives.
The above groups are defined as follows:
"Halogen" atom represents fluorine, chlorine, bromine or iodine.
"Alkyl" group is linear or branched (C1-C10)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 (C1-C10)alkylamino, where (C1-C10)alkyl groups is as defined as above. Exemplary alkylamino groups include methylamino, ethylamino, propylamine and the like.
"Dialkylamino" group is di(C1-C10)alkylamino, where (C1-C10)alkyl groups is as defined as above. Exemplary dialkylamino groups include dimethylamino, diethylamino, ethylmethylamino and the like.
"Cycloalkyl" group is (C3-C6)cycloalkyl group. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
"Alkoxy" is (C1-C10)alkyl-O-, wherein (C1-C10)alkyl group is as defined above. Exemplary alkyl groups include methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like.
"Cycloalkoxy" is (C3-C6)cycloalkoxy group. Exemplary cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy and the like.
"Acyl" is H-CO- or (C1-C10)alkyl-CO-, where (C1-C10)alkyl group is as defined above. Exemplary acyl groups include acetyl, propionyl, benzoyl and the like.

"Acyloxy" is (C1-C10)acyl-O- group, where acyl group is as defined above. Exemplary acyloxy groups include acetyloxy, propionyloxy, benzoyloxy and the Hke.
"Aryl" is monocylic or multicyclic ring system of about 6 to 14 carbon atoms. Exemplary groups include phenyl, nephthyl and like.
"Aryloxy" is aryl-0- group, where aryl group is as defined above. Exemplary aryloxy groups include phenoxy, naphthyloxy and the like.
"Alkylthio" is (C1-C10)alkyl-S-, wherein (C1-C10)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-(C1-C10)alkyl group, where in aryl and (C1-C10)alkyl groups are as defined above. Exemplary aralkyl groups include benzyl, 2-phenethyl and the like.
"Aralkoxy" is aralkyl-0- 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-C10)alkenyl-0-, where (C2-C6)alkenyl group is as defined above. Exemplary alkenyl groups include ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy and the like.
"Cycloalkenyloxy" is (C1-Cyjcycloalkenyl-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-0- group, wherein aroyl group is as defined above. Exemplary aroyloxy groups include benzoyloxy, 1-naphthoyloxy and the like.
"Heteroaryl" is an aromatic monocyclic or multicyclic 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, morpholinyl, thiomorpholinyl, benzothiazolyl, benzoimidazolyl, pyridazinyl, pyrimidinyl, piperidinyl, pyrrolidinyl and the like.
"Heteroaryloxy" is heteroaryl-0-, 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, morpholinyloxy, thiomorpholinyloxy, benzothiazolyloxy,
benzoimidazolyloxy, pyridazinyloxy, pyrimidinyloxy, piperidinyloxy, pyrrolidinyloxy and the like.
"Heteroaralkyl" is heteroaryl-(C1-C10)alkyl group, wherein the heteroaryl and (C1-
C10)alkyl groups are as defined above. Exemplary heteroaralkyl groups include
pyrazinylmethyl, pyrazinylethyl, pyrazinylpropyl, pyrazinylbutyl, pyrazinylpentyl,
pyrrolylmethyl, pyrrolylethyl, pyrrolylpropyl, pyrrolylbutyl, pyrrolylpentyl,
morpholinylmethyl, morpholinylethyl, morpholinylpropyl, morpholinylbutyl,
morpholinylpentyl, piperidinylmethyl, piperidinylethyl, piperidinylpropyl,, piperidinylbutyl, piperidinylpentyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl, pyrrolidinylbutyl, pyrrolidinylpentyl nd the like.
"Heteroaralkoxy" is heteroaralkyl-0-, wherein heteroaralkyl group is as defined above.
Exemplary heteroaralkoxy groups include pyrazinylmethoxy, pyrazinylethoxy,
pyrazinylpropoxy, pyrazinylbutoxy, pyrazinylpentoxy, pyrrolylmethoxy, pyrrolylethxy,
pyrrolylpropoxy, pyrrolylbutoxy, pyrrolylpentoxy, morpholinylmethoxy, morpholinylethoxy,
morpholinylpropoxy, morpholinylbutoxy, morpholinylpentoxy, piperidinylmethoxy,
piperidinylethoxy, piperidinylpropoxy, piperidinylbutoxy, piperidinylpentoxy,
pyrrolidinylmethoxy, pyrrolidinylethoxy, pyrrolidinylpropoxy, pyrrolidinylbutoxy, pyrrolidinylpentoxy and the like.
"Heteroaralkoxy(C1-C10)alkoxy" is heteroaralkyl-0-(C1-C10)alkoxy, wherein heteroaralkyl and (C1-C10)alkoxy groups are as defined above. Exemplary Heteroaralkoxy(C1-C10)alkoxy groups include morpholinylmethoxymethoxy, morpholinylmethoxyethoxy, morpholinylmethoxypropoxy, morpholinylmethoxy butoxy, morpholinylmethoxypentoxy, piperidinylmethoxymethoxy, piperidinyl methoxyethoxy, piperidinylmethoxypropoxy, piperidinylmethoxybutoxy, piperidinyl methoxypentoxy, pyrrolidinylmethoxymethoxy,

pyrrolidinylmethoxyethoxy, pyrrolidinyl methoxypropoxy, pyrrolidinylmethoxybutoxy, pyrrolidinyl methoxypentoxy and the like.
"Acyl" is H-CO- or (C1-C10)alkyl-CO-, where (C1-C10)alkyl group is as defined above. Exemplary acyl groups include acetyl, propionyl, benzoyl and the like.
"Acyloxy" is (C1-C6)acyl-0- group, where acyl group is as defined above. Exemplary acyloxy groups include acetyloxy, propionyloxy, benzoyloxy and the like.
"AlkylcarbonyF is (C1-C10)alkyl-CO-, wherein (C1-C10)alkyl group is as defined above. Exemplary alkylcarbonyl groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl and the like.
"Alkoxycarbonyl" is (C1-C10)alkyl-O-CO-, wherein (C1-C10)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-0-CO-, wherein aryl group is as defined above. Exemplary aryloxycarbonyl groups include phenoxycarbonyl, naphthyloxycarbonyl and the like.
"Aralkoxycarbonyl" is aryl-(C|-C6)alkoxy-CO-, where aryl and (C1-C6)alkoxy are as defined above. Exemplary aralkoxycarbonyl groups include benzyloxycarbonyl, 2-phenethyloxycarbonyl and the like.
"Carboxylic aC1d or its derivatives" may be amides or esters. Exemplary carboxylic aC1d groups include CONH2, CONHMe, CONMe., CONHEt, CONEtj, CONHPh, COOCH,, COOC2H5 or COOC3H7.
"Sulfonic aC1d or its derivafives" may be amides or esters. Exemplary sulfonic aC1d groups include SO2NH2, S02NHMe, S02NMe2, 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 in the description. 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 a 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 oxy chloride and the like. The reaction may be carried out in the presence of catalyst such as dimethyl formamide, triethylamine, pyridine, dimethyl pyridine and the like. The solvent used in the reaction may be selected from dichloromethane, dichloroethane, chloroform, carbontetrachloride and the like. The temperature of the reaction may be in the

range of room temperature to 100 °C. The duration of the reaction may be in the range of 0 to 24 h, preferably 3 to 6 h. Alternatively, formula (lb) may be converted to (Ic), where X represents -S-(C1-C6)alkyl, in the presence of reagents such as P2O5 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 h, preferably 10 to 16 h. The base used in the reaction may be carried out in the presence of KOH, NaOH 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 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 h, preferably in the range of 1 to 3 h.
The compound of formula (1) is obtained from compound of formula (le), by reacting with a compound of formula (If), in the presence of a suitable base selected from pyridine, marpholine, 2,6-lutidine, N-methyl morpholine, dimethyl amine pyridine, diaza bicycle[5.4.0], triethyl mine 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 hexa methyl 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 h, preferably in the range of 1 to 3 h.
In still another embodiment of the present invention there is provided another process for the preparation of compound of formula (2) where R* represents alkoxy group, R"" represents R" or R^, which represent substituted or unsubstituted 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 R* and R"° attached to the 3"^^ and 4"^ positions of the hetero bicyclic ring. The process is as shown in Scheme-11:

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 h, preferably in the range of 0.5 to 45 h.
The compound of formula (2e) is converted to a compound of formula (2f) by reacting with compound of formula (2e"), where R^ represents substituted or unsubstituted alkyl, aralkyl, heteroaralkyl or acyl groups and X represents halogen atom, in the presence of a base selected from NH3, pyridine, marpholine, 2,6-lutidine, N-methyl morpholine, dimethyl amine pyridine, diaza bicycle[5.4.0], triethyl amine 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 hexa methyl 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 h, preferably in the range of 1 to 3 h.
The compound of formula (2) may be prepared from compound of formula (20, by reacting with a compound of formula {2g), in the presence of suitable a base selected from pyridine, marpholine, 2,6-lutidine, N-methyl morpholine, dimethyl amine pyridine, diaza bicycle[5.4.0], triethyl mine 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 hexa methyl 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 h, preferably in the range of 1 to 3 h.
It is appreC1ated that in any of the above-mentioned reactions, any reactive group in the substrate 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-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, 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, glyC1nol, phenyl glyC1nol and the like, salts of natural amino aC1ds such as glyC1ne, alanine, valine, leuC1ne, isoleuC1ne, norleuC1ne, tyrosine, cystine, cysteine. methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino aC1ds such as D-isomers or substituted amino aC1ds; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alky! 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 aC1d addition salts where appropriate which are.

" sulphates, nitrates, phosphates, perchlorates, borates, halides, acetates, tartrates, maleates, C1trates, sucC1nates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
Particularly useful compounds according to this invention include:

OH

The compounds of the present invention may contain geometrical isomers, hi such cases the compounds of the present invention cover the mixture of E and Z isomers or individual E and Z isomers.
The compounds of the present invention may be used either alone or in combination with other class of drugs such as topoisomerase inhibitors, signal transaction inhibitors, estrogen modulators, micro tubule inhibitors, spindle poisioners.
The compounds of the present invention are useful in the treatment of resistant cancers such as BCRP (breast cancer resistant protein), EGFR (epidermal growth factor receptor), MDR (multi drug resistant protein), Mutant P53 protein and the like.
The enantiomers may be prepared by using reactants in their single enantiomeric form in the process wherever applicable or by conducting the reaction in the presence of reagents or catalysts in their single enantiomeric form. The single enantiomers may also be prepared by

resolving the racemic mixture by conventional methods. The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral aC1ds such as mandelic aC1d, camphorsulfonic aC1d, tartaric aC1d, lactic aC1d, and the like wherever applicable or chiral bases such as bruC1ne, C1nchona alkaloids and their derivatives and the like. Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley IntersC1ence, 1981). Where appropriate the compounds of formula (I) may be resolved by treating with chiral amines, aminoaC1ds, aminoalcohols derived from aminoaC1ds; conventional reaction conditions may be employed to convert aC1d into an amide; the diastereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula (I) may be prepared by hydrolyzing the pure diastereomeric amide.
The pharmaceutically acceptable salts are prepared by reacting the compounds of formula (I) wherever applicable with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calC1um 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, aC1d addition salts wherever applicable are prepared by treatment with aC1ds such as hydrochloric aC1d, hydrobromic aC1d, nitric aC1d, sulfuric aC1d, phosphoric aC1d, p-toluenesulphonic aC1d, methanesulfonic aC1d, acetic aC1d, C1tric aC1d, maleic aC1d salicylic aC1d, hydroxynaphthoic aC1d, ascorbic aC1d, palmitic aC1d, sucC1nic aC1d, benzoic aC1d, benzenesulfonic aC1d, tartaric aC1d and the like in the presence of a solvent like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvent may also be used. The salts of amino aC1d 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 etc. Mixture of solvents may be used.
Various polymorphs of a compound of general formula (I) forming part of this invention may be prepared by crystallization of compound of formula (1) under different

conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Heating or melting the compound followed by gradual or fast cooling may also obtain polymorphs. The presence of polymorphs may be determined by solid probe nmr spectroscopy, IR spectroscopy, differential scarming calorimetry, powder X-ray diffraction or such other techniques.
The present invention also provides pharmaceutical compositions, containing compounds of the general formula (I), as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates 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 bacterial infections. They can also be used for the treatment of bacterial infections assoC1ated with multidrug resistance.
Pharmaceutically acceptable solvates of compound of formula (I) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of formula (I) in the presence of a solvent such as water, methanol, ethanol etc., preferably water and recrystallizing by using different cr>"stallization techniques.
The regioisomers of compound of formula (I) may be prepared by modifying the reaction conditions, use of reagents like aC1d to base or base to aC1d or by reaction with free base hydrazine instead of its salt with diketone. The molar proportion also can change the regioisomer formation.
The geometrical isomers, stereoisomers and tautomers of the present invention can be prepared by the conventional methods available in the literature.
The pharmaceutical compositions may be in the forms normally employed, such as tablets, capsules, powders, 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 1 to 20 %, preferably 1 to 10 % 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 suffiC1ent to provide the desired dosage in the

The compound of formula (2a) is converted to a compound of formula (2b), where R^ 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 oxy chloride and the like. The reaction may be carried out in the presence of catalyst such as dimethyl formamide, triethylamine, pyridine, dimethyl pyridine and the like. The solvent used in the reaction may be selected from dichloromethane, dichloroethane, chloroform, carbontetrachloride and the like. The temperature of the reaction may be in the range of room temperature to 100 °C. The duration of the reaction may be in the range of 0 to 24 h, preferably 3 to 6 h (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; 5/o. 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 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, dimthyisulfoxide and the like. The reaction may be carried out in the presence of a base such as NaNo3, KNO3, Na2C03, K2CO3, MgC03, pyridine, triethylamine, NaHC03 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 h, preferably in the range of 1 to 3 h.
The compound of formula (2d) is converted to a compound of formula (2e) by using a reagent selected from KCN, guanidine, NH3, BFj.Et.O, BF3.0Et20, Mg, H2O2, wet CH3CN. sodium, CF3OSO2F, CH3OSO2F, PhSCH3, CF3COOH, Nal, MgBr2, SnBr2, AcBr, calC1um, dimethyldioxirane and other similar class of reagents. The solvent used in the reaction may be selected from THF, benzene, toluene, dichloromethane, acetone, alcohol such as methanol, ethanol, propanol, isopropanol, re/-/-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

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, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavorants, sweeteners, exC1pients 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 aC1d addition sahs 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.
In addition to the compounds of formula (I) the pharmaceutical compositions of the present invention may also contain or be co-administered with one or more known drugs selected from clinically useful cytotoxic and anticancer agents such as taxol, taxotere, vinblastine, topoisomerase inhibitors like irinotecan, topotecan etc., and other cytotoxic agents.
The compounds of the formula (1) as defined above are clinically administered to mammals, including human beings, via either oral or parenteral routes. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in C1rcumstances where the patient cannot swallow the medication, or absorption 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 0.5 mg/kg to about 50 mg / kg body weight of the subject per day administered singly or as a divided dose. However, the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage.
The invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Example 1 l-[4-(Qulnazoiin-4-ylamino)-phenyl]-ethanoneO-(4-fluoro-benzyl)-oxime

Step (i): Preparation of 4-chloroquinazoline

A mixture of quinazolone (5 g, 30 mmol) {J. Med. Chem.. 1977(20)146 -149), 2 mL of dimethyl formamide were taken in 30 mL of 1,2-dichloroethane and 20 mL of thionylchloride (32.5 g, 270 mmol) was added at room temperature. Reaction mixture was heated at 90 °C for 2 h, 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 g of the 4-chloro quinazoline. Yield: 90% Step (ii): Preparation of l-[4-(Quinazolin-4-ylamino)-phenyl1-ethanone

A mixture of 4-chloroquinazoline (5 g, 30.3 mmol), obtained in step (i) and 4-
aminoacetophenone (4.93 g, 36mmol) in 35 mLof isopropyl alcohol was heated at 90 °C for 2
h and allowed to stand at room temperature for 3 h, during which solid was preC1pitated. The
sohd was filtered and washed with diethyl ether to afford the pure yellow solid. Yield (92%).
Mp:231 °C:
"H-NMR (CDCb+DMSO-dft), ,6H: 9.0 (IH, d, J=8.6Hz), 8.8 (IH, 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) C1: 264(M"), 136.
Step (iii): l-[4-(0uinazolin-4-ylamino)-phenyl1-ethanone 0-(4-fluoro-benzyl)-oxime

A mixture of l-[4-(Quinazolin-4-ylamino)-phenyl]-ethanone (3.5 g, 13 mmol), obtained in step (ii) and 4-fluoro benzyloxy amine hydrochloride (J J. Org. Chem., 1988, 53(13) 2997) (3.5 g, 19.9 mmol) in 24 mL of methanol and 2.69 mL (33 mmol) of pyridine was heated at 70 C for 3 h. 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%) Mp: 158 °C.
•H-NMR CDCl3,5H: 9.9 (IH, s), 8.67 (IH, s), 8.64 (IH, d, J=8.4 Hz) 8.0 (2H, d, J=8.8 Hz), 7.8 (2H, d, J=8.0Hz), 7.7 (2H, d, J=8.6Hz), 7.5 (4H, d, J=8.0Hz), 7.2 (2H, t, J=8.8Hz). Mass (m/z) C1: 387(M*), 261,247,125,109.
Examples 2-12 can be prepared by the procedure as described in example-1:

Example 13
4-{4-[l-(4-FIuoro-benzyIoxyimino)-ethyl]-phenylamino}-7-isopropoxy-6-methoxy-
quinoIine-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 g, 7.75 mmol) and 0.100 mL of dimethyl
formamide were taken in 30 mL of 1,2 dichloroethane, then thionyl chloride (11.5 mL, 155
mmol) was added slowly at room temperature, then the reaction temperature increased to
reflux temperature (90 °C) for 2 h . 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 g of product as a white solid
(yield: 93.8%).
Step (ii): Preparation of 4-[4-acetvlanilino1-7-isopropoxv-6-methoxy-3-quinoline carbonitrile

A mixture of 4-chloro-7-isopropoxy-6-methoxy-quinoline-3-carbonitrile (2 g, 7.23 mmol), obtained in step (i), and l-(4-amino phenyl)-!- ethanone (1.17 g, 8.6 mmol), and 30 mL of isopropanol were heated at 90 °C for 4 h, and the reaction was left at room temperature. The resultant solid was filtered and washed with diethylether.to obtain 2.2 g of yellowish solid was obtained (yield : 81%). Mp: >250"C
Mass (C1): 376(M^) (100%), 333,318,253,150,136,120,92.
"H-NMR(DMS0-d6): 511.0 (IH, s), 9.0 (IH, s), 8.0 (2H, d, J=7.2Hz), 7.6 (IH, d, J=8.6Hz), 7.5 (2H, d, J=8.3Hz), 6.5 (IH, d, J=8.5Hz), 4.8 (IH, m), 3.9 (3H, s), 2.6 (3H, s),1.4 (6H, d). IR (KBr)cm"": 3434, 2976, 2662, 2223, 1679, 1637, 1583, 1505, 1455, 1415, 1311, 1268, 1101, 922, 888, 819, 762, 656, 592, 491.
Step (iii): Preparation of 4-(4-{[(4-fluorobenzyl)oxylethanimidoyUanilino)-7-isoprnnoxy-6-methoxy-3-quinolinecarbonitrile

A mixture of 4-[4-acetylanilino]-7-isopropoxy-6-methoxy-3-quinoline carboniirile (500 mg, 1.33 mmol), obtained in step (ii), 4-fIuorobenzyloxyamine 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 mmol) was added at room temperature, the reaction temp increased to 90 °C and continued for 4 h. The preC1pitated 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 g of pure compound.
Melting point: 174-176 "C
IR(KBr):cm-"3439,2925,1635,1580,1511,1455,1275,1224.5,1103,1018,923,876,824,558

•H-NMR(DMS0-d6): 5 10.9 (lH,s), 8.9 (IH, s), 8.0 (IH, s), 7.8 (2H, d), 7.4 (4H, 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 (C1): m/z 499(M+1), 498(M+),375,126,125(base peak),124,109(100%),96,95.
Examples 14-16 can be prepared by the procedure as described in example-13:

Example 17
l-{4-[6-Methoxy-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-yIamino]-phenyl}-ethanone
O-benzyloxime

Step (i): Preparation of 7-benzvloxy-4-chloro-6-methoxy quinazoline.

A mixture of 7-benzyloxy-6-methoxy quinazoline (5 g. 17.7 mmol), and dimethyl formamide (1 mL) were taken in 75 mL of dichloroethane, thionyl chloride (30 mL, 398.2 mmol) was added slowly at room temperature, and then reaction continued at 90 °C for 4 h, 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 g of white solid was obtained. Yield:80%.
Step (ii): Preparation of l-r4-(7-Benzvloxv-6-methoxv-quina2olin-4-ylamino)-phenvl1-ethanone.

A mixture of 7-benzyloxy-4-chloro-6-methoxy quinazoline (4.2 g, 14 mmol), obtained in step
(i) and l-(4-aminophenyl)-l-ethanone (2.26 g,16.8 mmol) were taken in 60 mL of isopropano!
and reaction continued at 90 °C for 4 h. The preC1pitated solid was filtered and washed with
diethylether to afford 4.5 g of light yellowish compound.
Yield: 80%.
Mpt: 174-176°C
"H-NMR(DMSO-do): 5 11.7 (IH, s), 8.9 (IH, s), 8.5 (IH, s), 8.07 (IH, d. J=8.79Hz), 8.02
(2H, d, J=8.79Hz), 7.98 (IH, d, J=8.79Hz), 7.94 (IH, d, J=8.79Hz), 7.5 (2H, d, J=10.7Hz),
7.48 (IH, d, J=10.7Hz), 7.45 (IH, d, J=6.3Hz), 7.42 (IH, d, J=6.3Hz), 5.3 (2H, s), 4.04 (3H,
s), 2.5 (3H, s).
Mass (C1): m/z 401(M+2), 400(M+1), 399(M+), 253, 150, 136(100%).
IR (KBr): cm"" 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-[4-(7-Hvdroxv-6-methoxv-quinazolin-4-vlamino)-phenvl1-
ethanone

A mixture of l-[4-(7-benzyloxy-6-methoxy-quinazolin-4-ylamino)-phenyl]-ethanone (4.4 g,
llmmol), obtained in step (ii), trifluoroaceticaC1d (42 mL, 550 mmol) was heated at reflux
temperature at 75 °C for 5 h, 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 g of brownish solid. Yield: 94%.
Melting point: 234-236 "C
"H-NMR(DMS0-d6): 5 11.1 (IH, s), 8.8 (IH, s), 8.1 (2H, d), 8.0 (2H, d), 7.8 (2H, d), 4.49
(lH,s),4.0(3H,s),2.6(3H,s).
Mass(C1):m/z311(M+2),310(M+l)(100%), 309(M+), 181, 136,91.
IR (KBr)cm"": 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-r7-(3-Chloro-propoxy)-6-methoxy-quinazolin-4-ylamino1-
phenyl} -ethanone

A mixture of l-[4-(7-Hydroxy-6-methoxy-quinazolin-4-ylamino)-phenyl]-ethanone (3.1 g, 10 mmol), obtained in step (iii), fused potassium carbonate (5.5 g, 40 mmol) were taken in dry dimethylformamide (30 mL) and stirred for 15 min at room temperature, then l-bromo-3-chloro propane (1.5 mL, 15 mmol) was added at room temperature and temperature increased to 80 °C and refluxed for 4 h. Water was added to the reaction flask and extracted with ethylacetate. Ethylacetate layer was dried and concentrated under vacuum to afford 2.8 g of yellow solid. Yield: 73%. Mp: 154-156 °C "H-NMR (DMSO-do): 6 9 7 (IH, s), 8.5 (IH, s), 7.8-8.2 (4H, m), 7.2 (2H, d).

Mass (C1)^ m/z 386(M+1)(100%), 387(M+), 350, 322, 102, 90.
IR (KBr)cm-":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-r6-Methoxv-7-(3-morpholin-4-vl-propoxv)-quinazoIin-4-y lamino 1 -phenyl} -ethanone

A mixture of l-{4-[7-(3-Chloro-propoxy)-6-methoxy-quinazolin-4-ylamino]-phenyl}-
ethanone (1 g, 2.59 mmol), obtained in step (iv), and potassium carbonate (1.4 g, 10.36
mmol), were taken in dimethylformamide (15 mL), then morpholine (0.450 mL, 5.19 mmol)
was added at room temperature, then temperature increased to 80 °C, continued for 4 h.
Water was added to the reaction mixture and extracted with ethylacetate, dried and
concentrated under vacuum to afford 0.7 g of yellow solid. Yield:61%.
Mpt: 150-152 °C.
"H-NMR(DMS0-d6): 5 9.7 (IH, s), 8.5 (IH, s), 8.0 (5H, m), 7.2 (IH, s), 4.2 (2H, t, J=6.1Hz).
4.0 (3H, s), 3.5 (4H, t), 3.3 (6H, m), 2.5 (3H, s), 2.0 (2H, m).
Mass (C1): M/z 437(M+1), 436.
IR (KBr): cm""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-r6-Methoxy-7-(3-morpholin-4-vl-propoxv)-quinazolin-4-
ylaminol-phenyl ] -ethanone-0-benzyl-oxime

A mixture of l-{4-[7-(3-Chloro-propoxy)-6-methoxy-quinazoIin-4-ylamino]-phenyU-ethanone (0.2 g, 0.45 mmol), obtained in step (v), and phenyl methoxy amine {J. Org. Chem.,

1988, 53(13)2997) (0.225 g, 1.8 mmol) were taken in 10 mL of methanol, then pyridine
(0.140 mL, 1.8 mmol) was added at room temperature, and reaction continued at 90*^C for 4 h.
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 DCM afforded 0.128 g of pure compound . Yield: 50%
Melting point: MO-Ml^C
lR(KBr)cm"": 3178,2924,2854,1699,1624,1582,1511,1459,1419,1387,1366,1308,1283, 1149,
1117,1024,926,838,744,702,657,623,599,557.
"H-NMR(DMSO-d6)5: 9.5 (IH, s), 8.4 (IH, s), 7.9 (IH, d, J=8.8Hz), 7.8 (2H, d, J=8.8Hz),
7.7 (IH, d, J=8.8Hz), 7.6 (IH, m, d=8.8Hz), 7.4 (2H, d, J=4.4Hz), 7.39 (2H, d, J=4.4Hz),
7.35 (IH, d, J=7.4Hz), 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 (C1): m/z 542(M+), 436,316,233,183,147,125,109(100%), 91.
Examples 18-28 can be prepared by the procedure as described in example-17:

Step (i): Synthesis of acetic aC1d 4-chloro-7-methoxv-quinazolin-6-ylester

4 g (17.1 mmol) of 7-methoxy-4-oxo-3,4-dihydro-6-quinazolinyl acetate was taken in 40 mL of dichloroethane and 24 mL of thionyl chloride were added followed by 0.1 mL of DMF. 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 g, Yield: 76%
Step (ii): Preparation of Acetic aC1d 4-(4-acetyl-phenylamino)-7-methoxy-quina2olin-6-yl ester

3.2 g (12.6mmol) of Acetic aC1d 4-chloro-7-methoxy-quinazoHn-6-yl ester, obtained in step (i) was taken in 80 mL of IPA and 2 g(14.8mmol) 4-amino acetophenone was added and the contents refluxed for 2 hours. The reaction flask was left overnight and solid preC1pitated was filtered and dried under vacuum. Yield: 92% Melting point: 250"C lR:(KBr)cm"" 3029.2619,1777,1677,1643,1574,1527,1438,1363,1264, 1294,1267,1175,1152,850, 815,"HNMR (DMSO -d6, 5 ) 11.5(s,lH) 8.9(s,lH)8.8(s,lH) 8 (d,J=8.6Hz,2H) 7.9(d,J=8.6,2H) 7.5(s,lH) 4(s,3H) 2.5(s,3H) 2.4(s,3H) Mass; (m/z,C1) 352 (M+1,100%) 310,178,136,

Step (iii): Preparation of l-r4-(6-Hvdroxy-7-methoxy-quinazoIin-4-ylamino)-phenvl|-ethanone 0-benzyl-oxime

1.3 g (3.7mmol) of acetic aC1d 4-(4-acetyl-phenylamino)-7-methoxy-quinazolin-6-yl ester,
obtained in step (ii) 0.49 g(4.49 mol) of 0-benzyl hydroxyl amine (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 h. The preC1pitated solid was filtered and dried under vacuum to
give 1.2 g of the product. Yield: 87%. Mp. 177 °C
lR(KBr, cm-"): 3435,2927,2360,1597,1511,1428,1391,1240,1155,920,833,558.
"HNMR (DMS0-d6) 6: 11.11(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), 5.1(2H, s), 4.0(3H, s), 2.6(3H, s).
Mass m/z(C1): 415 (M+1), 414 (M+), 125 (Base peak), 109.
Step (iv): Preparation of l-{4-r6-(3-Chloro-propoxy)-7-methoxy-quinazolin-4-ylamino1-
phenylj-ethanone 0-benzyl-oxime

A mixture of 0.64 g (l.Smmol) of l-[4-(6-hydroxy-7-methoxy-quinazoIin-4-ylamino)-phenyl]-ethanone-0-benzyl-oxime, obtained in step (iii) and 0.85 g of fused potassium carbonate were taken in dry dimethylformamide and stirred for 15 min then 0.85 mL of l-chloro-3-bromo propane was added at room temperature. The contents were stirred at room temperature 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 i 00-200 silica gel to afford 0.45 g of product. Yield: 60%. Mp: 224 °C
l.R(KBr)cm"" :3294,2933,2873,1625,1575,1512,1426,1311,1244,1209,1145,912,741,555. "HNMR(DMSO-d6)5: 9.5(H), 8.4(s,lH), 8.1(s,lH), 7.9(d, J-8.8Hz, 2H), 7.6(d, J=8.6Hz,2H), 7.3(m,5H), 5.2(1H, s), 4.3 (2H, ,J-5.9Hz, t), 4.0(3H, s), 3.8(2H, J=6.4Hz,t), 2.5(3H, s), 1.8(2H,m).

Mass (C1); 491 (M+1,100%)
Step (v): Preparation of l-{4-r7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-
ylaminol-phenyl I-ethanone 0-benzyl-oxime

0.46 g (0.93 mmol) of l-{4-[6-(3-Chloro-propoxy)-7-methoxy-quinazolin-4-ylamino]-phenyl}-ethanone 0-benzyl-oxime, obtained in step (iv) and 0.518 g (3.7mmol) of fused potassium carbonate was taken in dry DMF stirred for 15 minutes at room temperature, and 0.122 mL of morpholine was added. The contents stirred for 5 h 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 g 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 DCM afforded 0.260 g of pure compound. Yield :52% Mp: 186-188 °C.
lR(KBr):cm"".: 3342,2928,1622,1599,1512,1470,1427,1392,1241,1209,1014,981,859. "HNMR(CDCl3)5: 8.6(1H, s), 7.7(4H, m), 7.6(8H, m), 5.2(2H, s), 4.2(2H, J=6.4Hz, t), 3.9(3H, s), 3.7(4H, m), 2.6(6H, m), 2.5(3H, s), 1.8(2H, m). Mass; (m/z)(C1): 542(M+1), 541(M^), 436,434,107(100%). Example 30 l-{4-[7-Methoxy-6-(3-niorpholin-4-yl-propoxy)-quinazoUn-4-ylaininol-phenyl}-ethanone

Step (i): Synthesis of acetic aC1d 4-chloro-7-methoxv-quinazolin-6-yl ester
C1 Ac-°YV^N

4 g (17.1rhmol) of 7-methoxy-4-oxo-3,4-dihydro-6-quinazolinyl acetate was taken in 40 mL of dichloroethane and 24 mL of thionyl chloride were added followed by 0.1 mL of DMF. The Contents were refluxed for 4-5 h and 40 mLof dichloromethane was added, and solvent was evaporated in a rota vapor. The reaction mixture was dissolved in dichloromethane, passed through 230-400-mesh silica gel, concentrated and dried to yield the product (3.2 g, Yield: 76%)
Step (ii): Preparation of Acetic aC1d 4-(4-acetyl-phenylamino)-7-methoxy-quinazolin-6-yl ester
3.2 g (12.6 mmol) of acetic aC1d 4-chloro-7-methoxy-quinazolin-6-yl ester, obtained in step
(i), was taken in 80 mL of isopropyl alcohol and 2 g (14.8 mmol) of 4-amino acetophenone
was added and the contents refluxed for 2 h. The reaction flask was left overnight and solid
preC1pitated was filtered and dried under vacuum. Yield: 92% Mp: 250 °C.
IR:(KBr)cm"" : 3029.2619,1777,1677,1643,1574,1527,1438,1363,1264,
1294,1267,1175,1152,850,815.
"HNMR (DMSO-d6,)5: 11.5(1H, s), 8.9 (IH, s), 8.8(1H, s), 8.0 (2H, J=8.6Hz, d) 7.9(2H,
J-8.6, d), 7.5(1 H, s), 4.0(3H, s), 2.5(3H, s), 2.4(3H, s)
Mass (m/z,Cl): 352 (M+1,100%) 310,178,136,
Step (iii): Preparation of l-[4-(6-Hydroxy-7-methoxy-quinazolin-4-ylamino)-phenyl1-
ethanone
4 g of acetic aC1d 4-(4-acetyl-phenylamino)-7-methoxy-quinazolin-6-yl ester (10.3 mmol), obtained in step (ii) and 20 mL of aq.ammonia were taken in 20 mL of methanol. The above contents were stirred at room temperature for 2 h. The solid formed was filtered and dried. The weight of the product was observed as 3 g. Mp: 260 °C.
"HNMR (DMSO-dfi) 6: 9.75(1H, s), 8.55(1H, s), 8.15(2H, J=8.5Hz, d), 7.9( 2H, J=8.6Hz, d), 7.25(2H, s), 4.5(3H, s), 2.5(3H, s)

Mass(m/z)(C1): 310 M*( 100%).
IR (ECBr)cm-"): 3442, 3291, 2930, 1626, 1512, 1473, 1344, 1399, 1244, 1024, 914, 837, 559
Step (iv): Preparation of l-{4-[6-(3-Chloro-propoxy)-7-methoxv-quina2olin-4-ylamino1-
phenyll-ethanone
3 g (8.68 mmol) of l-[4-(6-hydroxy-7-methoxy-quinazolin-4-ylamino)-phenyl]-ethanone, obtained in step (iii) and 5.3 g (38.3 mmol) of fused potassium carbonate were taken in dry dimethylformamide, stirred for 15 min and 1.14 mol of l-chloro-3-bromo propane was added and the contents were stirred at room temperature for 12 h. 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 g.Yield 76%. Mp: 240 °C "HNMR (DMS0-d6) 5; 8.65(1H, s), 8.05(4H, m), 7.45(1H, s), 7.25(2H, s), 4.35(1H, J=5.9Hz, t), 3.95(3H, s), 3.85(2H, J=6.1Hz, t), 2.6(3H, s), 2.45(2H, m) Mass (C1): m/z 386(M^100%).
IR(KBr)cm"": 3350, 2930, 1653, 1578, 1520, 1470, 1426, 1275, 1242, 1204, 1144, 838, 653, 590
Step (v): Preparation of l-{4-r7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazoiin-4-ylamino]-phenyl} -ethanone

1.2 g (3.1 mmol) of l-{4-[6-(3-Chloro-propoxy)-7-methoxy-quinazolin-4-ylamino]-phenyl}-ethanone, obtained in step (iv) and 1.9 g (13.7mmol) of fused potassium carbonate was taken in dry dimetyhylformamide stirred fori5 min at room temperature followed by 0.44 mL (5 mmol) of morpholine. Reaction contents were stirred at 80 °C for 5 h. Reaction mixture was extracted 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 g.yield 54% "H-NMR(DMSO-d6)5: 9.75(1H, s), 8.5(1H, s), 8.0 (5H, m), 7.2(1H, s), 4.25(2H, J=6.1Hz, t), 4(s, 3H), 3.5(4H, t), 2.5(3H), 2.4(6H, m), 2.0(2H, m).

Mass (C1)*: m/z 437 (100%).
IR(KBr)cm"": 3385, 2927, 1653, 1601, 1514, 1469, 1425, 1390, 1274, 1240, 1117,846,607.
Step (vi): Preparation of l-{4-[7-Methoxv-6-(3-morpholin-4-yl-propoxv)-quinazolin-4-

A mixture of 0.23 g (0.53 mmol) of l-{4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-
quinazolin-4-ylamino]-phenyl}-ethanone, obtained in step (v) and 0.155 g (0.79 mmol) of
[(4-chloro benzyl)oxy]ammonium chloride (J. Org. Chem., .53(13), 1988 , 2997), 0.127 mL
(1.5 mmol) of pyridine were taken in 8 mL methanol and refluxed for 2 h. Ice was added to
the reaction mixture, extracted with ethyl acetate and ethyl acetate layer was washed with
water and concentrated and dried. The Residue was purified by flash column chromatography
over 100-200 silica gel to afford 0.2 g of product. Yield: 66%
Mp. 177-179 °C.
lR(KBr)cm-": 3425, 2931, 1634, 1520, 1439, 1278, 1233, 1012, 885.
"HNMR(CDCl3)5: 8.6(1H, s), 7.75(3H, m), 7.5(7H, m), 5.15(2H, s), 4.25(2H, J=6.5Hz, t),
3.95(3H, s), 3.75(4H, m), 2.55(6H, m), 2.25(3H, s), 1.85(2H, m).
Mass (C1): m/z 576 (M+), 141(100%) 436, 437,405.
Examples 31-39 can be prepared by the procedure as described in examples-29 and 30:

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

Step (i): Preparation of l-r4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl1-ethanone

0.9 g (4mmol) of 6,7-dimethoxy 4-chloro quinazoline,0.65 g (4.8 mmol) of 4-amino
acetophenone were taken in 25 mL of isopropylalcohol, refluxed for 2 h at 90 C .The solid
was filtered and washed with methanol. Yield: 63%.
IR(KBr)cm"": 3029, 2619, 1677, 1643, 1574, 1527, 1433, 1363, 1267, 1235, 1175, 1152,
1064,850,584.
"HNMR(DMS0-d6)^.- .9.1(1H, s), 7.9(2H, d), 7.4(2H, d),7.3 (IH, s), 6.9(1H, s), 4.0(6H, s),
2.4(3H, s).
Mass(m/z)C1. 324(M+), 310.

J
Step (ii): Preparation of l-f4-(6,7-Dimethoxv-quinazolin-4-vlamino)-phenyl1-ethanone O-benzyl-oxime
0.3 g (0.92mmol) of l-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-ethanone, obtained
in step (i) and ,0.14 g (1.13mmol) of benzyloxy amine(J. Org. Chem., 53(13), 1988, 2997)
were taken in 6 mL of methanol, and 0.29 mL(3.6 mmol)of pyridine was added . The contents
were refluxed for 2.5 h 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%. Mp: 196-198 °C.
IR(KBr) cm"": 3423, 3070, 2925,2854,1622,1575, 1512, 1419, 1279, 1234, 1143, 1012,
850,681.
"HNMR (DMSO-d6)5: 9.1 (IH, s), 8.6 (IH, s), 8.1 (IH, s), 7.8 (2H, J=8.6Hz, d),
7.7(2H, J=8.6Hz, 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)C1:429(M+),323,125(100%), 109.
Examples 41 can be prepared by the procedure as described in example 40:

Example 42
N4-(4-(2-Phenyl metboxyimino propoxy) Phenyl)-4-quinazolinamine

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

4-Nitro phenol (50gr, 0.359moles) was dissolved in dimethylformamide (150 mL) and cooled to 0 °C . Sodium hydride (24.12 g, 0.718 moles) was added slowly under stirring. After the addition was completed, chloro acetone (43 mL, 0.538 moles) was added at 0 °C and the contents were stirred at room temperature for 16 h. The reaction mixture was poured into ice and was extracted 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. (23 g, 33% ). Step (ii): Prepartion of l-(4-amino phenoxy acetone)

1 .(4.Nitrophenoxy) acetone (5 g, 0.0255 moles), obtained in step (i) was taken in absolute ethanol (75 mL) and stannous chloride di-hydrate (23 g, 0.102 moles) was added and the contents were refluxed for 45 min. The reaction mixture was poured into ice water, basified with 10% aq. 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.(4.1 g, 96%).

I
Step (iii): Preparation of l-[4-(4-Quinazolinyl amino)phenoxy1acetone

l-(4-amino phenoxy) acetone (4.7 g, 0.0284 moles), obtained in step (ii) and 4-chloro quinazoline (3.9 g, 0.0237 moles) were taken in 50 mL of Isopropanol and refluxed for 0.5 h and left overnight at room temperature . The preC1pitated solid was filtered, washed with isopropanol followed by di-ethyl ether and dried to afford the product (4.4 g, 63 % ). "HNMR(CDCl3).5: 2.4(3H, s), 4.2(2H, s), 6.8-8.0 (13H, m), 8.5(1H, s), 9.4(1H, bs). Mass(m/z) C1: 294 (M+1), 266, 238, 189. Step (iv): Prepartion of N4-(4-(2-Phenyl methoxyimino propoxy)phenyl)-4-Quinazolinamine

l-[4.(4-Quinazolinyl amino)phenoxy]acetone (4.25 g, 0.0145 moles), obtained in step (iii) and 0-benzyl hydroxyl amine.hydrochloride (J. Org. Chem., 53(13), 1988 , 2997), (3.45 g, 0.0217 moles) were taken in 75 mL methanol and pyridine (2.63 mL) was added at room temperature. The contents were refluxed for 1 h 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 g, 68%) Mp: 129-130 °C.
IR (KBr)cm-": 3426, 2924, 2854, 1618, 1573, 1511, 1495, 1455, 1424, 1398, 1355, 1317,
1230, 1172, 1024,920.
"HNMR (CDC13): 2.0(3H, s), 4.4(2H, s), 5.1(2H, d), 6.8-8.0(13H, m), 8.5(1H, s), 9.4(1H, bs).
Mass(m/z)C1: 399(M+1), 293 , 243, 236, 210, 206, 181.
Example 43 l-[4-(Quinazolin-4-ylamino)-phenyll-ethanoneO-[3-(2-chIoro-phenoxy)-p
ropyi]-oxime

Step (i): Preparation of l-[4-(Quinazolin-4-ylamino)-phenvl1-ethanone oxime

hydroxylamine hydrochloride (0.528 g, 7.6 mmols), and pyridine (0.922 mL, 11 mmols) were taken in 100 mL methanol and refluxed for 5 h. The preC1pitated compound was filtered and dried to afford 0.5 g of the compound as a pale yellow solid. Yield: 50% Step (ii). Preparation of l-chloro-2- (3-chloropropoxy) benzene

A mixture of 2-chloro phenol (10 mL, 98 mmols), fused potassium carbonate (67.7 g, 490
mmols) and l-bromo-3-chloropropane (14.5 mL, 147 mmols) are taken in 250 mL
dimethylformamide and stirred overnight at room temperature. The reaction mixture was
poured into water and extracted with ethyl acetate. The ethyl acetate extract was dried and
concentrated to afford 20gr of the product as a colorless liquid Yield: 100%
Step (iii); Preparation of l-r4-(0uinazolin-4-ylamino)-phenyl1-ethanone 0-[3-(2-chloro-
phenoxv)-propyl1-oxime

0.150 g (0.53 mmols) of l-[4-(lH-quinazolin-4-ylidencamino)-phenyl]-ethanone oxime, obtained in step (i) is taken in dimethylformamide and at 0 °C, 0.064 g of NaH was added and stirred for 0.5 h.To this reaction mixture was added 0.165 g (0.80 mmols) of l-chloro-2-(3-chloropropoxy)benzene, obtained in step (ii) and the contents were stirred at 80 °C for 3

h. 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 0.180 g 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 g of the compound as a solid-.Yield: 41%. Mp: 172 °C
I.R(KBr)cm-": 3432,3270,2923,1715,1624,1524,1415,1290,1253,1195,1059,896. "HNMR(DMSO-d6)5: 11.0(1H, s), 8.4(1H, s) 6.8-8.0(12H, m), 4.5(2H, j=6Hz, t) ,4.2(2H„ J=6Hz, t), 2.2(2H, m), 2.1(3H, s). Mass (C1):447(M+1,100%).
Examples 44 and 45 can be prepared by the procedure as described in example 43:

Example 46
l-{4-[7-Methoxy-6-(3-morpholin-4-yI-propoxy)-quinazolin-4-ylaminoj-phenyl}-ethanone O-benzyl-oxime acetic aC1d salt

l-{4-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-ylamino]-phenyI}-ethanone O-benzyl-oxime (0.6 g ,1.1 mmol) was taken in 15 mL of ethanol and refluxed at 90 °C for 3 h, IN solution of methanesulfonicaC1d 1.1 mL(0.106 g) was added and refluxed for 30 h and ethanol was removed under vacuum. The resultant solid was taken in ether and stirred for 20 min and filtered to afford 0.420 g of colorless solid Yield: 60%. Mp. 233 °C
Examples 47-55 can be prepared by the procedure as described in example 46:

Anti-cancer activity:
The compounds prepared in the present invention exhibited good in vitro anti-cancer activity towards various 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, 1X10 cells were seeded into each well of 96 well plate in lOO^iL volume of RPMI 1640 medium containing antibiotics and 10% FCS.
The plates were incubated at 37"C in presence of CO2. After 24 h, test compounds were evaluated at five 10 fold dilutions ranging from 100 to 0.01 Μ.M. TO each test well l00μL of test compound solution was added and medium with vehicle was added to control wells and the plates were further incubated. After 48 h of incubation, plates were terminated by Sulforhodamine 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 Inhibition (GI50). The compounds of the present invention showed anticancer activity, which can be seen from the data given below:

Lymphocyte Proliferation:
Human lymphocytes were isolated from whole blood by using Ficoll Hypaque Plus (Amersham). On day one, 1 million lymphocytes were seeded into each well of 96 well plate in 100 μL volume of RPMI 1640 medium containing 10%FCS and Phytohemagglutitin A at 10 μg/ml 1 μg/well concentration. Plates were incubated at 37°C in CO2 incubator for 24 h. Test compounds at various concentrations were added to test wells and only medium with vehicle was added to control wells. After 48 h of incubation 0.5 mC1 of tritiated thymidine was added to each well. After 24 h of thymidine addition the cells were harvested and the incorporated radioactivity was determined. Stimulation Index (SI) was calculated using the formula,

A^ = Average CPM of treated wells, A*" = Average CPM of control wells.

We claim

1. A compound of formula (I)

where R1 and R2 represents hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, acyl, acyloxy, aryl, aryloxy, alkylthio, arylthio, aralkyl, aralkoxy, alkenyl, alkenyloxy, cycloalkenyloxy, aroyl, aroyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, 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, substituted or unsubstituted 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, substituted or unsubstituted 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 substituted or unsubstituted 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 or -CH, Y represents oxygen or nitrogen, s, t are integers in the range of 0 to 5 and r, u are integers 0 or 1.
their derivatives, their analogs, their stereoisomers, their tautomers, their polymorphs, their phamaceutically acceptable salts, their pharmaceutically acceptable solvates and their pharmaceutically acceptable compositions

2. The compound of formula (I), as claimed in claim 1, wherein the substituents on R1
andR2 are selected from halogen, nitro, amino, alkylamino, dialkylamino, hydroxy, carboxy,
cyano, oxo(0=), thio(S=), alkyl, cycloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy,
aryl, aryloxy, benzyloxy, acyl, acyloxy, aroyl, heteroaryl, aralkyl, alkylsulfonyl, alkylsulfmyl,
arylsulfonyl, arylsulfinyl, alkylthio, arylthio or a substituted or unsubstituted 5 or 6 membered
cyclic ring which may optionally contain one or two hetero atoms selected from oxygen,
sulfur or nitrogen.
3. The compound as claimed in claim 1, wherein the substituents on R3, R4, R5 and R6
are selected from a halogen, nitro, amino, hydroxy, carboxy, cyano, oxo(0=), thio(S=), alkyl,
cycloalkyl, alkoxy, cycloalkyl, aryl, acyl, aroyl, heteroaryl or aralkyl.
4. The compound as claimed in claim 1, wherein the substituents on W are selected from halogen atom, hydroxy, carboxy, acyl, nitro, cyano, amino, acylamino, thio, linear or branched optionally halogenated alkyl, optionally halogenated alkoxy, carboxylic or sulfonic acids and their derivatives.
5. The compoimd as claimed in claim 2, wherein the 5 or 6 memebered cyclic ring is selected from pyrrole, morpholine, thiomorpholine, benzothiazole, benzoimidazole, pyridine, pyridazine, pyrimidine, pyrazine, piperidine or pyrrolidine.
6. The compound as claimed in claim 2, wherein the substitutents on a 5 or 6 memebered cyclic ring as defined in claim 2, are selected from halogen, nitro, amino, hydroxy, carboxy, cyano, oxo(0=), thioxo(S=) or alkyl.
7. The compound of the formula (I) as claimed in claim 1, selected from the group
consisting of:

8. The compound of formula (I), as claimed in claim 1 or 7, wherein the
pharmaceutically acceptable salt is selected from the group consisting of Li, Na, K, Ca, Mg,
Fe, Cu, Zn, Mn; salts of organic bases, chiral bases, natural amino acids, unnatural amino
acids, substituted amino acids, guanidine, substituted guanidine salts; ammonium, substituted
ammonium salts, aluminum salts or acid addition salts.
9. The compound of formula (I), as claimed in claim 8, wherein the salts of organic
bases are selected from -the group consisting of N,N"-diacetylethylenediamine, betaine,
caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N-
ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine,
morpholine, 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, or
spermidine.
10. The compound of formula (I) as claimed in claim 8, wherein the salts of chiral bases
are selected from the group consisting of alkylphenylamine, glycinol, or phenyl glycinol.
11. The compound of formula (I) as claimed in claim 8, wherein the salts of natural amino
acids are selected from the group consisting of glycine, alanine, valine, leucine, isoleucine,
norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine,
ornithine, lysine, arginine, serine, threonine, or phenylalanine.
12. The compound of formula (I), as claimed in claim 8, wherein the salts of
unnatural amino acid, substituted amino acids are selected from the group consisting of D-isomers, guanidine, and substituted guanidine wherein the substituents are selected from the group consisting of nitro, amino, alkyl, alkenyl or alkynyl.

13.. A compound of formula (I) as claimed in claim 8, wherein the acid addition salt is selected from the group consisting of sulphates, nitrates, phosphates, perchlorates, borates, halides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, or ketoglutarates. 14. A process for the preparation of compound of formula (I)

where R and R represents hydrogen, halogen, hydroxy? nitro, cyano, amino, substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, acyl, acyloxy, aryl, aryloxy, alkylthio, arylthio, aralkyl, aralkoxy, alkenyl, alkenyloxy, cycloalkenyloxy, aroyl, aroyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, 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, substituted or unsubstituted 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, substituted or unsubstituted 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 substituted or unsubstituted 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 or -CH, Y represents oxygen or nitrogen, s, t are integers in the range of 0 to 5 and r, u are integers 0 or 1.

their derivatives, their analogs, their stereoisomers, their tautomers, their polymorphs, their
phamaceutically acceptable salts and their pharmaceutically acceptable solvates
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 (1 b), to a compound of formula (1 c)

where X represents halogen atom, R1, R2 and R3 are as defined above,
(iii) reacting the compound of formula (1 c), 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 (1 e), with a compound of formula (1 f)

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

(v) and if desire converting the compound obtained in to its derivatives, its anolagous, its tutomaric form, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically solvates by conventionals methods.. 15. A process for the preparation of compound of formula (2)

where R1 and R2 represents substituted or unsubstituted alkoxy, aralkoxy, heteroaralkoxy or
acyloxy groups. R3 repesents hydrogen, halogen, hydroxy, cyano, amino, -CH2CN,
substituted or unsubstituted 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, substituted or
unsubstituted 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 substituted
or unsubstituted groups selected from divalent phenyl, naphthyl, pyrrolyl, pyridyl, quinolinyl,
benzofiaryl, dihydrobenzofiiryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl,
azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like.
Q represents N or -CH,
Y represents oxygen or nitrogen,
s, t are integers in the range of 0 to 5 and
r, u are integers 0 or 1.
their derivatives, their analogs, their stereoisomers, their tautomers, their polymorphs, their
phamaceutically acceptable salts, their pharmaceutically acceptable solvates and their
pharmaceutically acceptable compositions.
which comprises:
(i) converting the compound of formula (2a)

where R 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 above, to a compound of formula (2d)

where all symbols are as defined above,
(iii) converting the compound of formula (2d), to a compound of formula (2e)

where all symbols are as defined above,
(iv) reacting the compound of formula (2e), with a compound of formula (2e")

where R9 represents substituted or unsubstituted 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 3rd and 4th positions of the hetero bicyclic ring
(vi) and if desire converting the compound obtained in to its derivatives, its anolagous, its tutomaric form, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically solvates by conventionals methods.
16. A pharmaceutical composition, which comprises an effective amount of a compound
of formula (I)

as defined in claim 1, and a pharmaceutically acceptable carrier, diluent, excipient or solvate.
17. A pharmaceutical composition as claimed in claim 16, in the form of a tablet, capsule, powder, syrup, solution or suspension.
18. A pharmaceutical composition which comprises an effective amount of a compound of formula (I) as defined in claim 7, and a pharmaceutically acceptable carrier, diluent, excipient or solvate.
19. A pharmaceutical composition as claimed in claim 19, in the form of a tablet, capsule, powder, syrup, solution or suspension.

Documents:

108-mas-2003 abstract-duplicate.pdf

108-mas-2003 abstract.jpg

108-mas-2003 abstract.pdf

108-mas-2003 claims-duplicate.pdf

108-mas-2003 claims.pdf

108-mas-2003 correspondence-others.pdf

108-mas-2003 correspondence-po.pdf

108-mas-2003 description (complete)-duplicate.pdf

108-mas-2003 description (complete).pdf

108-mas-2003 form-1.pdf

108-mas-2003 form-18.pdf

108-mas-2003 form-3.pdf

108-mas-2003 pct search report.pdf

108-mas-2003 pct.pdf

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Patent Number

216471

Indian Patent Application Number

108/MAS/2003

PG Journal Number

13/2008

Publication Date

31-Mar-2008

Grant Date

13-Mar-2008

Date of Filing

07-Feb-2003

Name of Patentee

DR. REDDY`S LABORATORIES LTD.

Applicant Address

7-1-27, Ameerpet, Hyderabad, Andhra Pradesh, 500 016,

Inventors:

#	Inventor's Name	Inventor's Address
1	VEDULA MANOHAR SHARMA	7-1-27, Ameerpet, Hyderabad, Andhra Pradesh 500 016,
2	KATTUBOINA VENKATA ADISESHU	7-1-27, Ameerpet, Hyderabad, Andhra Pradesh 500 016,
3	JAVED IQBAL	7-1-27, Ameerpet, Hyderabad, Andhra Pradesh 500 016,
4	RAMANUJAM RAJAGOPALAN	7-1-27, Ameerpet, Hyderabad, Andhra Pradesh 500 016,
5	SRIRAM RAJAGOPAL	7-1-27, Ameerpet, Hyderabad, Andhra Pradesh 500 016,
6	NAGA VENKATA SRINIVASA RAO MAMIDI	7-1-27, Ameerpet, Hyderabad, Andhra Pradesh 500 016,

PCT International Classification Number

C07D 239/94

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA