Field
Described are novel pyridyl carboxamides of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutical acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof, having anti-proliferative activity.

Also described herein is the process for the preparation of the above said novel compound of formula (I), their derivatives, analogs, stereoisomers, polymorphs, hydrates, solvates, pharmaceutical acceptable salts, pharmaceutical compositions, metabolites, prodrugs and intermediates useful in the preparation of such compounds.

The compounds described herein are useful for the treatment of proliferative diseases such as cancer.

Background

Cancer may affect people at all ages, but risks tend to increase with age, due to the fact that DNA damage becomes more apparent in the aging DNA. Cancer is one of the principal causes of death in developed countries, more than 11 million people are diagnosed with cancer every year, and it is estimated that there will be 16 million new cases every year by 2020.

Every cell constantly faces decisions. Should it divide Or should it differentiate? Or should it die (Apoptosis)? Proper development and tissue homeostasis rely on the correct balance between division and apoptosis. Too much apoptosis leads to tissue atrophy such as in Alzheimer's disease. Too much proliferation or too little apoptosis leads to cancer. Cancer is a disease of multifactorial origin characterized by uncontrolled division of cells; when the cancer cell faces spatial restrictions, due to uncontrolled proliferation in an organ of the body, the ability of the cell to invade other distinct tissues occurs by a process defined as "metastasis" the stage in which cancer cells are transported through the bloodstream or the lymphatic system.

The most common treatment for easily accessible cancer is surgical removal of diseased tissues and radiation. The choice of treatment for in-accessible tumors is chemotherapy.

Also chemotherapy is given as additional insurance for most cancers as it is difficult to access the extent of metastasis. Majority of the chemotherapeutic drugs can be broadly divided into alkylating agents, anti-metabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, etc. Some agents don't directly interfere with DNA, including monoclonal antibodies and kinase inhibitors. In addition, some drugs may be used which modulate tumor cell behaviour without directly attacking those cells; hormone treatments fall into this category of adjuvant therapies.

Many quinolone derivatives having anti-infective activities are known in the literature.
WO/2004/091504 discloses quinobenzoxazines analogs, which can interact with regions of DNA that can form quadruplexes and act as tumor suppressing agents,

wherein A is H, F, or NR'2; V is H, halo, or NR'R2; Z is O, S, NRl or CH2; U is OR2 or NRlR2; X is OR2, NRlR2, halo, azido or SR2; R1 is H or Ci.6 alkyl, R1 is H or CM0 alkenyl optionally containing one or more non-adjacent hetero atoms; W is heteroaryl or aryl group.

US 4762831 discloses 1,8-bridged 4-qu\nolone-3-carboxylic acids of the following formula having antibacterial activity, wherein Y is COOH, CN, COOR7, CONRV; R7 represents Ct-C4 alkyl, R8 and R9 represents H or C1-C4 alkyl or substituted phenyl; X1 represents H, nitro, alkyl having 1-3 carbon, halogen; X2 represents halogen, alkyl having 1-3 carbon, alkylsulphonyl, phenylsulphonyl; X5 is H, halogen, methyl; Z represents O, amino radical, substituted alkyl radicals; R1, R2, R3, R4, R5 and R6 represent H and substituted alkyl group having I- 6 carbons.

Objective

One objective herein is to provide novel pharmacological agents viz., pyridyl carboxamides of the formula (I). Another objective herein is to provide a method of preventing or treating proliferative diseases by administering a therapeutic amount of compound of the formula (J).

Yet another objective herein is to provide a cost effective process for the preparation of compounds of formula (I), their derivatives analogs, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites, prodrugs and intermediates useful in the preparation of such compounds.

Summary

Described are novel pyridyl carboxamides of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutical ly acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof which can be used for the treatment of proliferative disease, wherein X and V may be same or different and independently represent H, halogen, CN, NO2, NH2, NR3R4, COOH, COOR1, CONR3R4, optionally substituted groups selected from alkyl and alkoxy; R represents alkyl, cycloalkyl, aryl, alkanol, carboxylic acid and its derivatives; R1 represents H, optionally substituted groups selected from alkyl and cycloalkyl; R2 represents -CH2COOH, -CH2CONR3R4, halogen, optionally substituted groups selected from amino, monoalkylamino, dialkylamino, alkyl, alkoxy, -N-alkyl, -N-alkanol, aryl and heterocyclyl. Preferred heterocyclyl groups include, the following, without limitation,

R3 and R4 may be same or different and independently represent H, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy and amino.

Detailed description

Novel py ridyl carboxamides of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutical^ acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof which can be used for the treatment of diseases associated with proliferation, wherein X and Y may be same or different and independently represents H, halogen, CN, N02, NH2, NR3R4, COOH, COOR1, CONR3R4, optionally substituted groups selected from alkyl and alkoxy; R represents alkyl, cycloalkyl, aryl, alkanol and carboxylic acid and its derivatives; R1 represents H, optionally substituted groups selected from alkyl and cycloalkyl; R2 represents -CH2COOH, ~CH2CONR3R4, halogen, optionally substituted groups selected from amino, monoalkylamino, dialkylamino, alkyl, alkoxy, -N-alkyl, -N-alkanoI, aryl and heterocyclyl, Preferred heterocyclyl groups include, the following, without limitation,

R3 and R4 may be same or different and independently represents H, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy and amino.

Definitions:

The term "alkyl" as employed herein refers to both saturated or unsaturated straight or branched chain aliphatic groups having the specified number of carbon atoms, which may be optionally substituted by one or more substituents. Preferred alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl pentyl, hexyl, heptyl, octyl, ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl, ethynyl, propynyl, butnyl and the like.

The term "alkoxy" refers to an alkyl group attached via an oxygen linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Preferred alkoxy groups include, without limitation, -OCH3, -OC2H5 and the like.

The term "cycloalkyl" as employed herein includes saturated and partially unsaturated monocyclic or polycyclic hydrocarbon groups having 3 to 12 carbons, which may be optionally substituted by one or more substituents. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl and the like.

The term "alkanol" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups bearing a hydroxyl group having the specified number of carbon atoms; for example, "C^ alkanol" denotes alkanol having 1 to 6 carbon atoms. Examples of alkanol include, but are not limited to, hydroxymethyl, hydroxyethyl, 3-hydroxy-n-propyl, 2-hydroxy-i-propyl, 4-hydroxy-n-butyl, and the like.

The term "halogen" as employed herein refers to chlorine, bromine, fluorine or
iodine.

The term "aryl" refers to monocyclic or polycyclic aromatic radicals having 6 to 14 carbon atoms, which may be optionally substituted by one or more substituents. Preferred aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, indanyl, biphenyl and the like.

The term "aryloxy" refers to an aryl group directly bonded to an oxygen atom, which may be optionally substituted by one or more substituents. Preferred aryloxy groups include, without limitation, phenoxy, naphthoxy and the like.

The "heterocyclyl" as employed herein includes saturated and unsaturated heterocyclic ring radical, which may be optionally substituted by one or more substituents. The heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Furthermore the term "heterocyclyl" refers to a stable 3 to 15 membered ring radical, which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus,-6- oxygen and sulfur. For purposes of this invention the heterocyclic ring radical may be monocyclic, or polycyclic ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; Preferred heterocyclyl groups include, without limitation, l,3-oxazolidin-2-one, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pyrimidinyl, pteridinyl, purinyl, quinazolinyl, qunioxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisoquniolyl, piperidinyl, piperazinyl, homopiperazinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrroJidinyl, pyrrolidin-2-one, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quiniclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquniolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, bezopyranyl, benzothiazolyl, benzooxaolyl, thienyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, furyl, tetrahydropuryl, tetrahydropyranyl, chromanyl, isochromanyl and the like.

The term "substituted" when the groups R1, R2, R3 and R4 are substituted by one or more suitable substituents include, without limitation, halogens such as fluorine, chlorine, bromine, iodine; hydroxy; nitro; cyano; azido; nitroso; hydrazine; formyl; alkyl; haloalkyl; haloalkoxy; cycloalkyl; aryl; alkoxy; aryloxy; acyl; acyloxy; acyloxyacyl; heterocyclyl; amino; monoalkylamino; dialkylamino; acylamino; alkoxycarbonyl; aryloxycarbonyl; alkylsulfonyl; arylsulfonyl; alkylsulfinyl; arylsulfinyl; alkylthio; arylthio; sulfamoyl; alkoxyalkyl and carboxylic acids and its derivatives such as amide, ester, acyl, haloacyl and the like. The substituents may be further substituted.

Furthermore, the compound of formula (I) can be its derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, solvates, intermediates, metabolites, prodrugs or pharmaceutical^ acceptable salts and pharmaceutical compositions, Pharmaceutically acceptable solvates may be hydrates or comprising of other solvents of crystallization such as alcohols..

It is understood that included in the family of compounds of Formula (I) are isomeric forms including diastereoisomers, enantiomers, tautomers, geometrical isomers,
"R" or "S" configurational isomers or a mixture of R and S isomers. It is also understood
that some isomeric form such as diastereomers, enantiomers and geometrical isomers can
be separated by physical and or chemical methods and by those skilled in the art, Compounds disclosed herein may exist as single stereisomers, racemates, and or mixtures of enantiomers and or diastereomers. AN such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the subject matter described.

The phrase "pharmaceutically acceptable" refers to compounds or compositions that are physiologically tolerable and do not typically produce allergic or similar untoward reaction, including but not limited to gastric upset or dizziness when administered to mammal.

Pharmaceutically acceptable salts include salts derived from inorganic bases such as like Li, Na, K, Ca, Mg, Fe, Cu, Zn and Mn; salts of organic bases such as N, IST- diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, benzylamine, trialkylamine and thiamine, guanidine, diethanolamine, a-phenylethylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, and the like, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc. Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.

Disclosed herein are prodrugs of the compound, which on administration undergoes chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of a compound, which are readily convertible in vivo into a compound of the invention.

The active compounds disclosed can also be prepared in any solid or liquid physical form, for example the compound can be in a crystalline form, in amorphous form an have any particle size. Furthermore, the compound particles may be micronized or nanoized, or may be agglomerated, particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical forms.

The compounds described herein also exhibit polymorphism. This invention further includes different polymorphs of the compounds described herein. The term polymorph refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectra, melting point and the like.

In addition to the above listed compounds, it is intended to encompass the use of
homologs and analogs of such compounds. In this context, homologs are molecules
having substantial structural similarities to the above-described compounds and analogs
are molecules having substantial biological similarities regardless of structural similarities.

Described herein also provides a pharmaceutical composition, containing one or more of the compounds of the general formula (I) as defined above, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, pharmaceutical acceptable salts, pharmaceutical acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like* useful for the treatment of and/or proliferative disorders.

The pharmaceutical composition 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 inject able solutions or suspensions. The compositions may be prepared by processes known in the art, Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Suitable routes of administration include systemic, such as orally or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. Thus for oral administration, the compounds can be combined with a suitable solid or 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, excipients and the like. For parenteral administration, the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions, For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or alkali or alkaline earth metal salts of the compounds, The injectable solutions prepared in this manner can then be, administered intravenously, intraperitoneally, subcutaneously, or intramuscularly.

The compounds of formula (I) can also be administered as a pharmaceutical composition in a pharmaceutically acceptable carrier, preferably formulated for oral administration.

A term once described, the same meaning applies for it, through out the patent.
Representative compounds include;

1. (35)-9,l0-Difluoro-3-methyl-7-Oxo-A-(pyridin-4-yl)-2,3-dihydro-7H- [ 1,4]oxazino[2,3,4wy]quinoline-6-carboxamide;

2. (3S)-N-(3,5-Dichloropyridin-4-yl)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H- [l,4]oxazino[2,3,4-ij]quinoline-6-carboxamide;

3. (3S)-9-Fluoro-10-methoxy-3-methyI-7-oxo-N-(pyridin-4-yl)-2,3-dihydro-7H- [l,4]oxazino[2,3,4-ij]quinoline-6-carboxamide;

4. (3S)-N-(3,5-Dichloropyridin-4-yl)-9-fluoro-10-methbxy-3-methyl-7-oxo-2,3- dihydro-7H-[l,4Joxa2ino[2,3,4-ij]quinoline-6-carboxamide;

5. (3SV9-Fluoro-3-methyl-7-oxo-10-(2-oxo-1,3-oxazolidin-3-yl)-N-(pyridin-4-yl)- 2,3-dihydro-7H-[l,4]oxazino[2,3,4-ij]quinoline-6-carboxamide;

6. (3S)-9-Fluoro-3-methyl-7-oxo-10-(2-oxopyrrolidin-1-yl)-N-(pyridin-4-yl)-2,3- dihydro-7H-[l,4]oxazino[2,3,4-ij]quinoline-6-carboxamide; and

7. (3S)-9-Fluoro-10-[(2-hydroxyethyl)amino]-3-methyl-7-oxo-N-(pyridin-4-yl)-2,3- dihydro-7H-[l,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,

According to another feature, provided herein is a process as shown in the scheme 1, for the preparation of compounds of the formula (I), wherein all the groups are as defined earlier.

Condensing the compound of formula 1(a) with 4»aminopyridyl compounds of formula 2, wherein all the groups are as defined earlier, using reagents like BOP reagent (benzotriazole-1yl-oxy-tris-(dimethylamino)-phosphonium hexafluoro phosphate), hydroxy benzotriazole in the presence of a base or by preparing a compound of the formula 1(b) from 1(a), wherein Z represents halogen, 0C(0)R', OR; R represents substituted aryl group, more preferably p-nitroaiyl followed by treatment with 4- aminopyridyl compounds of formula 2 to get compound of the formula (I).
Scheme 1:

Another process for the preparation of the compound of the general formula (I) is depicted in Scheme 2, wherein all the groups are as defined earlier. Compounds of the general formula I can be prepared from the compound 1(a) by following the scheme 1, which in turn can be obtained by treating compound 1(b) with a nucleophile. Furthermore compound (I) can also be obtained from compound 1(c) by reacting with a nucleophile.
Scheme 2:

The invention is explained in detail in the examples given below which are provided by the way of illustration only and therefore should not be construed to limit the scope of the invention.

Example 1: Synthesis of (35)-9,10-difluoro-3-methyl-7-OXO-A(pyridin-4-yl)-2- dihydro-7H-[l,4]oxazino[2,3,4-(f]quinoline-6-carboxamide

2.2g of (3S)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-[l,4]oxazino[2,3,4- y]quinoline -6-carboxylic acid was dissolved in a mixture of 1.58g of triethylamine and 20mL of dichloromethane followed by addition of 5.8g of BOP reagent and was stirred at room temperature for 20 minutes. To this solution 0.883g of 4-aminopyridine was added and stirring was continued at room temperature for 2 days. After completion of the reaction, saturated NaHCOs solution was added to the flask and the reaction mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated under vacuum. The crude mass was purified by column chromatography with ethyl acetate and hexane to get 2.0g of the title compound (Yield 71.6%). 'HNMR (400MHz, DMSO*d6): 5 (ppm) 12.47 (s, IH), 9.06 (s, 1H), 8.49 (d, 2H), 7.83-82 (m, IH), 7.72 (d, 2H), 5.01 (brS, IH), 4.68 (d, IH), 4.50 (d, 1H), 1.48 (d, 3H); MS m/z: 358.1 (Nf+1).

Example 2: Synthesis of (3S)-N-(3,5-dichloropyridin-4-yl)-9,10-difluoro-3-methyl-7- oxo-2,3-dihydro-7H-[l»4]oxazino[2,3,4^quinoIine-6-carboxamide

Step~l:

Preparation of 4«nitrophenyl (3S)-9,10-difluoro-3-metbyl-7-oxo-2,3-dihydro-7H* [l,4]oxazino[2,3,4-ij]quinoline-6-carboxylate 0.56g of (SSJ-Q.l0-difluoroO-methyl-T-oxo^.S-dihydroWIl^oxazinop^^- /y]quinoline -6-carboxylic acid was added to a solution of 0.770g of EDCI and 0.028g of DMAP in JOmL of acetonitrile at room temperature and the mixture was stirred at same temperature for 10 minutes. To this solution 0.300g of 4-nitrophenol was added and stirring was continued at room temperature for another 2 days. The reaction mass was subsequently quenched with ice water and the precipitate was filtered and dried under vacuum to get 0.420g of the titled compound.

Step*2: Preparation of (3S)-N-(3,5-dichloropyridin-4-yI)-9,10-difluoro-3-methyl-7- oxo-2-dihydro-7H-[l,4]oxazino[2,4-y]quinolioe-6-carbaxamide

To a mixture of NaH (60%, 0.090g) in 3mL of DMF at 0-10 gC, 0.200g of 3,5- dichloroaminopyridine was added and the reaction mixture was stirred for 30 minutes. Then 0.400g of 4-nitrophenyl (3S)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H- [l,4]oxazino[2,3,4-ij]quinoline-6-carboxylate was added and stirring was continued for another 2 hours. After completion of the reaction ice was added to the reaction mass and it was extracted with dichloromethane. The organic layer was dried over anhydrous Na2S04, concentrated under vacuum and was subjected to column chromatography to get 0.170g of the title compound. lHNMR (400MHz, DMSO-d6): 5 (ppm) 12.22 (s, 1H), 9.08 (s, 1H), 8.85 (s, 2H), 7.88-83 (m, 1H), 5.01-4.99 (m. 1H), 4.68 (d, 1H), 4.49 (d, 1H), 1.48 (dt 3H); MS m/z: 426 (M+).

Example 3; Synthesis of (3S)-9-fluoro-10-methoxy-3-methyl-7-oxo-N-(pyridin-4-yl)- 2,3-dihydro-7H-[1,4]oxazino-2,3,4-ij]quinoline-6-carboxamidc

Step-1: Preparation of (3S)-9-fluoro-10-methoxy-3-methyl-7-oxo-2,3-dihydro-7H- [1,4]oxazino|2,3,4-/yJquinoJine-6-Ciirboxy]ic acid

To a mixture of 1.4g ofNaOMe (freshly prepared) and 1.54g of KF in 15mL of DMSO 2,5g of (3S)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-[l,4]oxazino[2,3,4-ij]quinoline -6-carboxylic acid was added and the reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, water was added and the pH was adjusted to 2 by adding dilute HC1. Subsequently the product was extracted with ethyl acetate; the organic layer was dried over anhydrous Na2SO4 and concentrated to afford 2.5g of the title product.

Step-2: Preparation of (3S)-9-fluoro-10-methoxy-3-methyl-7-oxo-N-(pyridin-4-yl)- 2,3-dihydro-7H-[l,4]oxazino[2,3,4-ij]quinoline-6-carboxamide

The title compound was prepared from (3S)-9-fluoro-l0-methoxy-3-methyl-7- oxo-2,3-dihydro-7H-[l,4]oxazino[2,354-y]quinoline-6-carboxylic acid was obtained in 46% yield following the procedure given in example 2. 'HNMR (400MHZ, DMSO-d6): 5 (ppm) 12.59 (s, IH), 9.01 (s, IH), 8.48 (d, 2H), 7.71-7.68 (m, 3H), 4.98-4.95 (m, IH), 4.62 (d, IH), 4.43 (d, IH), 4.02 (s, 3H), 1.44 (d, 3H); MS m/z: 370.1 (M++l).

Example 4: Synthesis of (3S)-IV-(3,5-dichloropyndin-4-yl)-9-fluoro-10-methoxy-3- methyl-7-oxo-2,3-dihvdr^7H-(l,4Joxazii?o[2,3,4-ij]quinoIine-6-carboxamide

The title compound was prepared from 4-nitrophenyl (3S)- 9-fluoro'10-methoxy-3- methyl-7-oxo-2,3-dihydro-7//-[l,4]oxazino[2,3,4-H]quinoline-6-carboxylate in 63% yield following the above procedure.'HNMR (400MHz, CDCI3): 6 (ppm) 12.31 (s, IH), 8.78 (s, IH), 8.56 (s, 2H), 7.88 (d, IH), 4.52-4.47 (m, 2H), 4.39-4.33 (m, IH), 4.15 (s, 3H), 1.64 (t, 3H); MS m/z: 438 (M+).

Example 5: Synthesis of (3S)-9-fluoro-3-methy]-7-oxo-10-(2-oxo-l,3-oxazolidin-3-yJ)- N-(pyridin-4-yl)-2,3-dihydro-7H-[l,4]oxazino[2^,4-ij]quinoline-6-carboxamide
O D t^ N

A mixture of 0.316g of (3iS)9,10-difluoro-3-methyl-7-oxo-A-(pyridin-4-y1)-2,3- dihydroZ-oxazinop-quinoline-carboxamide, J.15g of K2CO3 and 0J50g of 2-oxazolidinone in 20mL of THF was refluxed for 2 days. After completion of the reaction, water was added to the reaction mass, which was extracted with dichloromethane, the organic layer was washed with brine, dried over anhydrous Na2SC>4 and concentrated, The residual mass was subjected to silica gel column chromatography to yield 0.180g of the title compound.'HNMR (400MHz, DMSO-d6): 5 (ppm) 12.51 (s, IH), 9.07 (s, 1H), 8.49 (d, 2H), 7.76-7.72 (m, 3H), 5.00 (d, IH), 4.68 (d, IH), 4.60 (t, 2H), 4.49 (t, IH), 4.12-4.08 (m, IH), 3.93-3.89 (m, IH), 1.48 (d, 3H); MS m/z: 425 (M++l),

The following compounds were prepared according to the above procedure.

Anti-cancer experimental methods

Anti-cancer screen;

Experimental drugs are screened for anti-cancer activity in three cell lines for their GI50, TGI and LC50 values (using five concentrations for each compound). The cell lines are maintained in DMEM containing 10% fetal bovine serum. 96 well micro titer plates are inoculated with cells in IOOJJL for 24 hours at 37 °C, 5% C02, 95% air and 100% relative humidity. 5000 HCT 116 cells/well, 5000 NCIH 460 cells/well and 5000 U251 cells/well are plated. A separate plate with these cell lines is also inoculated to determine cell viability before the addition of the compounds (To).

Addition of experimental drugs:

Following 24-hour incubation, experimental drugs are added to the 96 well plates. Each plate contains one of the above cell lines and the following in triplicate: five different concentrations (0.01, 0.1, 1, 10 and 100μM) of four different compounds, appropriate dilutions of a cytotoxic standard and control (untreated) wells. Compounds are dissolved in DMSO to make 20mM stock solutions on the day of drug addition and frozen at -20 °C. Serial dilutions of these 20mM stock solutions are made in complete growth medium such that IOOJJL of these drug solutions in medium, of final concentrations equaling 0.01, 0.1, 1, 10 and 100μM can be added to the cells in triplicate. Standard drugs whose anti-cancer activity has been well documented and which are regularly used are doxorubicin and SAHA.

End-point measurement:

For T0 measurement, 24 hours after seeding the cells, 10/iL of 3-(4,5-dimethyl~2- thia2olyl)-2,5-diphenyl-2H-tetrazolium (MTT) solution per well is added and incubation carried out for 3'hours at 37 °C, 5% CO2, 95% air and 100% relative humidity, protected from light. Cells incubated with compounds for 48 hours are treated similarly except with the addition of 20L MTT solution per well and a subsequent incubation under the same conditions. After 3 hours of MTT incubation, well contents are aspirated carefully followed by addition of 150fiL DMSO per well. Plates are agitated to ensure solution of the formazan crystals in DMSO and absorbance read at 570nm.
Calculation of GI:

Percent growth is calculated for each compound's concentration relative to the control and zero measurement wells (To; viability right before compound addition). If a test well's O.D. value is greater than the To measurement for that cell line % Growth = (test - zero) / (control - zero) X 100

If a test well's 0,D, value is lower than the To measurement for that cell line, then, % Growth = (test - zero) / zero X 100

Plotting % growth versus experimental drug concentration, GI50 is the concentration
required to decrease % growth by 50%; TGI is the concentration required to decrease %
growth by 100% and LC50 is the concentration required to decrease % growth by 150%.
Representative results of gro

wth are shown below in the Table 1,
Table 1: Anticancer activity

We Claim:

1. A compound of formula (I),

derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutical acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof;

wherein, X and Y independently represents H; halogen; CN; NO2; NH2; NR3R4; COOH; COOR1; CONR3R4; substituted or unsubstituted groups selected from alkyl; and alkoxy;

R represents alkyl; cycloalkyl; aryl; alkanol; carboxylic acid and carboxylic acid derivatives;

R1 represents H; substituted or unsubstituted groups selected from alkyl; and cycloalkyl;
R2 represents -CH2COOH; -CH2CONR3R4; halogen; substituted or unsubstituted groups selected from amino; monoalkylamino; dialkylamino; alkyl; alkoxy; -N-alkyl; -N-alkanol; aryl; and heterocyclyl;

R3 and R4 represent H; substituted or unsubstituted groups selected from alkyl; cycloalkyl; alkoxy; and amino.

2. The compound of claim 1, wherein when halogen is present, the halogen is chlorine, bromine, fluorine or iodine; when alkyl group is present, the alkyl group is methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl,butyl, pentyl, hexyl, heptyl, octyl, ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl-1 -propenyl, l-butenyl 2-butenyl, ethynyl, propynyl or butnyl; when alkoxy group is present, the alkoxy group is -OCH3 or -OC2H5; when cycloalkyl group is present, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cyciooctyl; when aryl group is present, the aryl group is phenyl, naphthyl, anthracenyl, indanyl or biphenyl; when alkanol group is present, the alkanol group is hydroxymethyl, hydroxyethyl, 3-hydroxy-n-propyl, 2-hydroxy-i-propyl or 4-hydroxy- n-butyl; when carboxylic acid derivatives are present, the derivatives are amide, ester, acyl or haloacyl; when heterocyclyl group is present, the heterocyclyl group is 1,3- oxazolidin-2-one, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pyrimidinyl, pteridinyl, purinyl, quinazolinyl, qunioxalinyl, quinolinyl, isoquinolinyl tetrazoyl, imidazolyl, tetrahydroisoquniolyl, piperidinyl, piperazinyl, homopiperazinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrrol idin-2-one, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, triazolyl, indanyh isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quiniclidinyl, isothiazoHdinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquniolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, bezopyranyl, benzothiazolyl, benzooxaolyl, thienyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide^ furyl, tetrahydropuryl, tetrahydropyranyl, chromanyl or isochromanyl;

R1, R2, R3 and R4 groups are optionally substituted by one or more substituents selected from the group consisting of halogens comprising fluorine, chlorine, bromine and iodine; hydroxy; nitro; cyano; azido; nitroso; hydrazine; formyl; alkyl; haloalkyl; haloalkoxy; cycloalkyl; aryl; alkoxy; aryloxy; acyl; acyloxy; acyloxyacyl; heterocyciyl; amino; monoalkytamino; dialkylamino; acylamino; alkoxycarbonyl; aryloxycarbonyl; alkylsulfonyl; arylsulfonyl; alkylsulfinyl; arylsulfinyl; alkylthio; arylthio; sulfamoyl; alkoxyalkyl; carboxylic acid and carboxylic acid derivatives selected from the group consisting of amide, ester, acyl and haloacyl; the substituents which in turn are further substituted.

3. A compound according to claim 1, wherein R2 represents heterocyclic ring selected from the group consisting of

R3 and R4 represent H, substituted or unsubstituted groups selected from alkyl; cycloalkyl; alkoxy; and amino.

4. The compound of claim 1, selected from a group consisting of; (3S)-9,10-Difluoro-3-methyl-7-oxo-N-(pyridin-4-yl)-2,3-dihydro-7H-[l,4]oxazino[2,3,4-ij]quinoline-6-carboxamide;

(3S)-N-(3,5-Dichloropyridin(4-yl)-9,10-difluoro-3-methyI-7-oxo-2,3-dihydro-7H- [l,4]oxazino[2,3,4-ij]quinoline-6-carboxamide;

(3S)-9-Fluoro-l0-methoxy-3-methyl-7-oxo-N-(pyridin-4-yl)-2,3-dihydro-7H- [l,4]oxazino[2,3,4-ij]quinoline-6-carboxamide;

(3S)-N-(3,5-Dichloropyridin-4-yl)-9-fluoro-10-methoxy-3-methyl-7-oxo-2,3-dihydro- 7H-[l,4]oxazino[2,3,4-ij]quinoline-6-carboxamide;

(3S)-9-Fluoro-3-methyl-7-oxo-10-(2-oxo-1,3-oxazolidin-3—y1)-N-(pyridin-4-yl)-2,3- dihydro-7H-[1-[oxazino-ij]quinoline-carboxamide; (3S)-9-Fluoro-3-methyl-7-oxo-10-(2-oxopyrrolidin-l-yl)-N-(pyridin-4-yl)-2,3- dihydro-7H-[l,4]oxazino[2,3,4-ij]quinoline-6-carboxamide; and (3S)-9-Fluoro-10-[(2-hydroxyethyl)amino]-3-methyl-7-oxo-N-(pyridin-4-yI)-2,3- dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide.

5. A process for the preparation of compound of formula (I) as claimed in claim 1, by condensing a compound of formula 1(a) with 4-aminopyridyl compounds of formula 2, in the presence of a base wherein all the groups X, Y, R, R1 and R2 are as defined earlier,

6. A process for the preparation of compound of formula (I) as claimed in claim 1 comprising the steps of:
(a) preparing a compound of formula 1(b) from 1(a), wherein Z represents halogen, OC(O)RU OR; R represents substituted aryl group, more preferably p-nitroaryl group;
(b) reacting a compound of formula 1(b) with 4-aminopyridyl compounds of formula

7. The pharmaceutical composition comprising a compound of formula (I) according to claims 1, 2, 3 or 4, as an active ingredient, along with a pharmaceutically acceptable carrier, diluent, excipient or solvate.

8. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is a tablet, capsule, powder, syrup, solution, aerosol or suspension,

9. Compounds of formula (I) as claimed in claim 1 for treating proliferative conditions or cancer, comprising administering to a subject suffering from proliferative conditions or cancer, with the presence or absence of other clinically relevant cytotoxic agents or non-cytotoxic agents to a mammal in need thereof.

10. A compound according to claim 1 substantially as hereinbefore described with reference to any one of the examples.