WO2010073078A2 - Heterocyclic compounds as hdac inhibitors - Google Patents

Abstract

The present invention relates to heterocyclic compounds of the general formula (I) their derivatives, analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, metabolites, prodrugs, pharmaceutically acceptable salts and compositions thereof. Also included is method for treatment of proliferative conditions and cancer, conditions mediated by HDAC, in a mammal comprising administering an effective amount of compound formula (I) as described above.

Description

HETEROCYCLIC COMPOUNDS AS HDAC INHIBITORS

Field

Described are novel quinolinone compounds of formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, metabolites, prodrugs, pharmaceutically acceptable salts and compositions thereof.

(I) Also described herein is the process for the preparation of the above said novel quinolinone compounds of formula (I), their analogs, stereoisomers, diastereomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites, prodrugs and intermediates useful in the preparation of such compounds. The compounds described herein are inhibitors of Histone deacetylase (HDAC) and also arrest cell growth in neoplastic cells, thereby inhibiting proliferation. These compounds can be used as therapeutic agents for diseases that are involved in cellular growth such as malignant tumors, autoimmune diseases, skin diseases, infections etc.

Background Transcriptional regulation is a major event in cell differentiation, proliferation and apoptosis. Transcriptional activation of a set of genes determines cell destination and for this reason transcription is tightly regulated by a variety of factors. One of its regulatory mechanisms involved in the process is an alteration in the tertiary structure of DNA, which affects transcription factors to their target DNA regiments. Nucleosomal integrity is regulated by the acetylating status of the core histone, with the result being permissiveness to transcription.

The regulations of transcription factor are thought to involve by changes in the structure of chromatin. Changing its affinity of histone proteins for coiled DNA in the nucleosome alters the structure of chromatin. Hypo acetylated histones are believed to have greater affinity to the DNA and form a tightly bound DNA-histone complex and render the DNA inaccessible to transcriptional regulation. The acetylating status of the histone is governed by the balance activities of the histone acetyl transferase (HAT) and histone deacetylase (HDAC).

The first isolation of histone deacetylase was described in 1964 from crude nuclear extracts of cells, but the molecular characterization of isoforms of the enzyme has been achieved recently. Inhibitors of histone deacetylase' s (HDACs) are zinc hydrolases responsible for the deacetylation of N-acetyl lysine residues of histone and non-histone protein substrates. Human HDACs are classified into two distinct classes, the HDACs and sirtuins. Further, the HDACs are divided into two subclasses based on their similarity to yeast histone deacetylases, RPD 3 (class I includes HDAC 1, 2, 3, 8 and 11) and Hda 1 (class II includes HDAC 4, 5, 6, 7, 9, and 10). All of the HDACs have a highly conserved zinc dependent catalytic domain. There is growing evidence that the acetylation state of proteins and thus the HDAC enzyme family plays a crucial role in the modulation of a number of biological processes, including transcription and cell cycle.

Given that apoptosis is a crucial factor for cancer progression, HDAC inhibitors are promising reagents for cancer therapy as effective inducers of apoptosis. Recently, suberoylanilide hydroxamic acid (SAHA) was launched as an antitumor agent for treating Cutaneous T-cell Lymphoma (CTCL) and is a known HDAC inhibitor. Several structural classes of HDAC inhibitors have been identified and are reviewed in Marks, P.A. et al., J. Natl. Cancer Inst., 2000, 92, 1210-1216. More specifically WO 98/55449 and US 5369108 patents report alkanoyl hydroxamates with HDAC inhibitory activity. Other compounds that are able to inhibit HDAC activity are Trichostatin A (TSA), PXDlOl, Tropoxin (TPX), Sodium butyrate (NaB), Sodium valproate (VPA), Cyclic hydroxamic acid containing peptides (CHAPs), Romidepsin, MGCDO 103 and MS-275. They also can de-repress these genes, resulting in antiproliferative effects in vitro and anti tumor effects in vivo. These HDAC inhibitors have been found to arrest growth and apoptosis in several types of cancer cells, including colon cancer, t-cell lymphoma and erythroleukemic cells (M. Paris, et.al., J. Med. Chem., 2008, 51, 1505-1529).

HDAC inhibitor MG3290 was found to be a potent, fungal selective potentiator of several azole antifungals in Aspergillus and Candida species including C. glabrata and also it was found to potentiate azole resistant C. glabrata mutant (US 2008/0139673).

US20060148806 discloses a compound of formula (A) having an excellent platelet agglutination inhibitory effect; in particular have excellent P2Y12 inhibitory effect and platelet agglutination inhibitory effect. Consequently the quinolone derivative and a pharmaceutically acceptable salt thereof are useful as a platelet agglutination inhibitor.

WO 2009053799 discloses the compounds of formula (B) as cannabinoid receptor modulators, in particular cannabinoid 1 (CBl) or cannabinoid 2 (CB2) receptor modulators. These compounds have ' utility in treating diseases, conditions and/or disorders modulated by a cannabinoid receptor (such as pain, neurodegenerative disorders, eating disorders, weight loss or control, and obesity).

WO2004076386 discloses HDAC inhibitors of formula (C)

- ftC_TOH wherein, A is independently an unsubstituted or substituted bicyclic Cg_-Io heteroaryl group; Q is an acid leader group, and is independently an unsubstituted or substituted, saturated or unsaturated Ci_-7 alkylene group having a backbone length of 4 or less. There is an unmet need to develop potent HDAC inhibitors that can overcome the dose limiting toxicity, drug-drug interaction and drug resistance. Serious side effects with existing chemotherapeutic agents motivated us to develop more potent and less toxic anticancer agents.

Objective One objective herein is to provide novel quinolinone derivatives of formula (I).

Another objective herein is to provide a pharmaceutical composition comprising novel quinolinone compounds of the formula (I) as an active ingredient.

(I) Yet another objective herein is to provide a method of preventing or treating proliferative diseases by administering a therapeutic amount of novel compound of the formula (I) or a pharmaceutically acceptable salt and/or prodrug.

Summary Described are heterocyclic compounds of the formula (I),

(I) their analogs, tautomeric forms, stereoisomers, polymorphs, solvates, intermediates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof; wherein W¹, W², W³ and W⁴ independently represent C-R^x, N, S, O or absent with the proviso that a minimum of three W¹, W², W³ and W⁴ are always present;

R^x independently represents hydrogen, hydroxy, nitro, alkoxy, aryloxy, heteroaryloxy, heteroalkoxy, halogen, -COOR^a, -C(O)R³, -C(S)R^a, -C(O)NR^aR^b, -C(S)NR^aR^b, -NR³C(O)NR¹¹R⁰, -NR^aC(S)NR^bR^c, -N(R^a)S0R^b, -N(R^a)SO₂R^b, -NR^aC(0)0R^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(S)R^b, -SONR^aR^b, -SO₂NR^aR^b, -OR^a, -0R^aC(0)0R^b, -OC(O)NR^aR^b, -OC(O)R^a, -OC(O)NR^aR^b, -R^aNR^bR^c, -R³OR^b, -SR³, -SOR^a, -SO₂R^a, substituted or unsubstituted groups selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein R^a, R^b and R^c represent hydrogen, substituted or unsubstituted groups selected from alkyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl and cylcoalkenyl; or R^a and R^b combine together to form a ring structures having 4-8 atoms;

X represents -CONR¹OH, -CONR¹R², -CSNR¹R², -COOR¹, -CH₂NR¹R², substituted or unsubstituted groups selected from aryl and heteroaryl;

R¹ and R² independently represent hydrogen, substituted or unsubstituted groups selected from alkyl, aryl, arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, cycloalkyl and cylcoalkenyl; or R¹ and R² can be combined together to form a ring structure having 4-8 atoms;

Z represents C-Y or N, wherein Y represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl or heterocycloalkyl;

R³ represents -OR⁴, ortho substituted aniline, amino aryl and amino heteroaryl, which may be further substituted, wherein R⁴ represents hydrogen, optionally substituted groups selected from alkyl, aryl, heterocycloalkyl and -COR⁵, wherein R⁵ represents optionally substituted groups selected from alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; wherein n represents integer selected from 1-7; when the groups R^x, R¹, R²,' R³, R⁴ and R⁵ are substituted, the substituents are one or more and are selected from halogens, hydroxy, nitro, cyano, azido, nitroso, oxo

(=0), thioxo (=S), thioalkyl, amino, hydrazino, formyl, alkyl, haloalkyl group, alkoxy, haloalkoxy, arylalkoxy , cycloalkyl, cycloalkyloxy, aryl, heterocycloalkyl, heteroaryl, alkylamino, tolyl, -COOR^a, -C(O)R³, -C(S)R³, -C(O)NR^aR^b, -C(S)NR^aR^b, -NR⁸C(O)NR⁶R', -NR³C(S)NR⁵R⁰, -N(R^a)SOR^b, -N(R^a)SO₂R^b, -NR^aC(O)OR^b, -NR^aR^b, -NR^aC(0)R^b, -NR³C(S)R⁵, -SONR^aR^b, -SO₂NR^aR^b, -OR³, -OR³C(O)OR^b, -OC(O)NR^aR^b, -OC(O)R³, -OC(O)NR³R^b, -R³NR¹¹R⁰, -R^aOR^b, -SR³, -SOR³ and -SO₂R³.

Detailed description

Novel quinolinone compounds of formula (I),

(I) their analogs, tautomeric forms, stereoisomers, polymorphs, solvates, intermediates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof; wherein W¹, W², W³ and W⁴ independently represent C-R^x, N, S, O or absent with the proviso that minimum of three of W¹, W², W³, and W⁴ are always present;

R^x independently represents hydrogen, hydroxy, nitro, alkoxy, aryloxy, heteroaryloxy, heteroalkoxy, halogen, -COOR³, -C(O)R³, -C(S)R³, -C(0)NR^aR^b, -C(S)NR^aR^b, -NR^aC(O)NR^bR°, -NR^aC(S)NR^bR°, -N(R^a)SOR^b, -N(R^a)SO₂R^b, -NR³C(O)OR", -NR³R^b, -NR^aC(O)R^b, -NR³C(S)R", -SONR³R", -SO₂NR³R", -OR³, -OR³C(O)OR", -OC(O)NR³R", -OC(O)R³, -OC(O)NR³R", -R³NR^bR°, -R^aOR^b, -SR^a, -SOR^a and -SO₂R^a, substituted or unsubstituted groups selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein R^a, R^b and R^c represent hydrogen, substituted or unsubstituted groups selected from alkyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, and cylcoalkenyl; or R^a and R^b combine together to form a ring structures having 4-8 atoms; X represents -CONR¹OH, -CONR¹R², -CSNR¹R², -COOR¹, -CH₂NR¹R², or substituted or unsubstituted groups selected from aryl, or heteroaryl;

R¹ and R² independently represent hydrogen, substituted or unsubstituted groups selected from alkyl, aryl, arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, cycloalkyl or cylcoalkenyl; or R¹ and R² can be combined together to form a ring structure having 4-8 atoms;

Z represents C-Y or N, wherein Y represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl or heterocycloalkyl; R³ represents -OR⁴, ortho substituted aniline, amino aryl and amino heteroaryl, which may be further substituted, wherein R⁴ represents hydrogen, optionally substituted groups selected from alkyl, aryl, heterocycloalkyl and -COR⁵, wherein R⁵ represents optionally substituted groups selected from alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; wherein n represents integer selected from 1-7; when the groups R^x, R¹, R², R³, R⁴ and R⁵ are substituted, the substituents are one or more and are selected from halogens ; hydroxy, nitro, cyano, azido, nitroso, oxo

(=0), thioxo (=S), thioalkyl, amino, hydrazino, formyl, alkyl, haloalkyl group; alkoxy, haloalkoxy, arylalkoxy , cycloalkyl, cycloalkyloxy, aryl, heterocycloalkyl, heteroaryl, alkylamino, tolyl, -COOR^a, -C(O)R^a, -C(S)R³, -C(0)NR^aR^b, -C(S)NR^aR^b,

-NR^aC(0)NR^bR^c, -NR^aC(S)NR^bR^c, -N(R^a)SOR^b, -N(R^a)SO₂R^b, -NR^aC(0)0R^b,

-NR^aR^b, -NR^aC(0)R^b, -NR^aC(S)R^b, -SONR^aR^b, -SO₂NR^aR^b, -0R^a, -OR^aC(O)OR^b,

-0C(0)NR^aR^b, -OC(O)R^a, -R^aNR^bR^c, -R^aOR^b, -SR^a, -SOR^a and -SO₂R^a; The substituents are further optionally substituted by one or more substituents as defined above.

Furthermore, when the groups R¹ and R² independently or together are cyclic rings, they represent substituted or unsubstituted 5 to 10 membered ring systems, and also the rings may be monocyclic or polycyclic, saturated, partially unsaturated or aromatic, containing O to 4 hetero atoms selected from O, S and N and the like. Furthermore, the compound of formula (I) can be its derivatives, analogs, tautomeric forms, stereoisomers, diastereomers, geometrical isomers, polymorphs, solvates, intermediates, metabolites, prodrugs or pharmaceutically acceptable salts and compositions.

Pharmaceutically acceptable solvates may be hydrates or comprising of other solvents of crystallization such as alcohols. The term "alkyl" refers to straight or branched aliphatic hydrocarbon groups having the specified number of carbon atoms, which are attached to the rest of the molecule by a single atom, 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 and the like. The term "alkylene" refers to a straight or branched chain divalent hydrocarbon radical having the specified number of carbon atoms, which may be optionally substituted by one or more substituents. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.

The term "aryl" refers to 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, tetrahydronapthyl, indanyl, biphenyl and the like.

The term "arylalkyl" refers to an aryl group directly bonded to an alkyl group, which may be optionally substituted by one or more substituents. Preferred arylalkyl groups include, without limitation, -CH₂C6H5, -C₂H₄C₆H₅ and the like.

Furthermore the term "heterocyclyl" refers to a stable 3- to 15 membered rings radical, which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention the heterocyclic ring radical may be monocyclic, bicyclic or tricyclic ring systems, and the nitrogen, phosphorus,¹ 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; and the ring radical may be partially or fully saturated. Preferred heterocyclyl groups include, without limitation, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, piperonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, oxazolyl, oxazolinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzothiadiazolyl, benzooxadiazolyl, benzotriazolyl, benzothienyl, benzooxazolyl, oxadiazolyl, benzindazolyl, indazolyl, phenyl piperidinyl, furyl, tetrahydrofuryl, tetrahydropyranyl, piperazinyl, homopiperazinyl, piperidyl, piperidopiperidyl, morpholinyl, thiomoφholinyl, piperidonyl, 2- oxopiperazinyl, 2-oxopiperidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, oxazolidinyl, chromanyl and isochromanyl. The term "heteroaryl" refers to an aromatic heterocyclic ring radical as defined above. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of stable structure.These heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of stable structure. The term "heterocycloalkyl" refers to a heterocyclic ' ring radical as defined above. The heterocycloalkyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. The term "heteroarylalkyl" refers to a heteroaryl group directly bonded to an alkyl group, which may be optionally substituted by one or more substituents. Preferred heteroarylalkyl groups include, without limitation, -CH₂-pyridinyl, -C₂H₄- furyl and the like.

The term "cycloalkenyl" refers to a non-aromatic cyclic ring containing radical containing about 3 to 8 carbon atoms with at least one carbon-carbon double bond, which may be optionally substituted by one or more substituents. Preferred cycloalkenyl groups include, without limitation, cyclopropenyl, cyclopentenyl and the like.

The term "cycloalkyl" refers to non-aromatic mono or polycyclic ring system of about 3 to 12 carbon atoms, which may be optionally substituted by one or more substituents. The polycyclic ring denotes hydrocarbon systems containing two or more ring systems with one or more ring carbon atoms in common i.e. a spiro, fused or bridged structures. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctanyl, perhydronaphthyl, adamantyl, noradamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups e.g spiro [4.4] non-2-yl 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, -OCHs₁ -OC₂H₅ and the like. The term "aryloxy" refers to an aryl group attached via an oxygen linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Preferred aryloxy groups include, without limitation,-OPh -OCH₂Ph, -O- naphthyl and the like.

An "arylalkoxy group" (or arylalkyloxy or aralkoxy) represents an arylalkyl or aralkyl group that is attached to a compound via an oxygen on the alkyl portion of the arylalkyl. Preferred arylalkoxy groups include, without limitation, -OCH₂Ph, -OCH₂- naphthyl.

The term "heteroaryloxy" refers to heteroaryl group attached via an oxygen linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Preferred heteroaryloxy groups include, without limitation, -O-pyridyl_, - O-indolyl and the like.

The term "heteroalkoxy" refers to a heteroarylalkyl group attached via an oxygen linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Preferred heteroalkoxy groups include, without limitation, -O- CH₂-Indolyl_, -O-CH₂-thiophenyl and the like.

The terni "alkylthio" refers to an alkyl group attached via a sulfur linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Preferred alkylthio groups include, without limitation, -SCH₃, -SC₂H₅ and the like.

The term "alkylamino" refers to an alkyl group as defined above attached via amino linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Preferred alkylamino groups include, without limitation -NHCH3, -N(CH₃)₂, and the like.

The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched chain having about 2 to 10 carbon atoms, which may be optionally substituted by one or more substituents.

Preferred alkenyl groups include, without limitation, ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl-l-proρenyl, 1-butenyl, 2-butenyl and the like.

The term "alkynyl" refers to a straight or branched hydrocarbyl radicals having at least one carbon-carbon triple bond and having in the range of 2-12 carbon atoms, which may be optionally substituted by one or more substituents. Preferred alkynyl groups include, without limitation, ethynyl, propynyl, butynyl and the like.

Compounds disclosed herein may exist as single stereoisomers, racemates and or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures there of are intended to be within the scope of the subject matter described.

The phrase "Pharmaceutically acceptable compounds or compositions" refers to compounds or compositions that are physiologically tolerable arid do not typically produce allergic or similar untoward reaction, including but not limited to gastric upset or dizziness when administered to mammal. The phrase "pharmaceutically acceptable carrier" is intended to include any or all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration, such as sterile pyrogen-free water. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used.

Solid carriers/diluents include, but are not limited to, a gum,' a starch (e.g., corn starch, pregelatinized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g., microcrystalline cellulose), an acrylate (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof. For liquid formulations, pharmaceutically acceptable carriers may be aqueous or non- aqueous solutions, suspensions, emulsions or oils. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Examples of oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-liver oil.

Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Al, Fe, Cu, Zn and Mn; salts of organic bases such as N, N'-diacetylethylenediamine, glucamine, triethylamine, choline, dicyclohexylamine, benzylamine, trialkylamine, thiamine, guanidine, diethanolamine, α-phenylethylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, ammonium, substituted ammonium salts and the like. 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.

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

The term "tautomer" refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. The term "metabolite" refers to compositions that result from a metabolic process. Examples of the results of metabolism on the compounds of the present invention include addition of -OH, hydrolysis and cleavage.

The term "analog" refers to a chemical compound that is structurally similar to another but differs slightly in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group. An analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.

The term "therapeutically effective amount" or "effective amount" is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.

The "pharmaceutical composition" may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, aerosols, suspensions and the like, may contain flavoring agents, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.

"Combination therapy" includes the administration of the subject compounds in further combination with other biologically active ingredients (such as, but are not limited to, different antineoplastic agent) and non-drug therapies (such as, but are not limited to, surgery or radiation treatment). The compounds described herein can be used in combination with other pharmaceutically active compounds, preferably, which will enhance the effect of the compounds of the invention. The compounds can be administered simultaneously or sequentially to the other drug therapy.

The compounds described herein can also be prepared in any solid or liquid physical form, for example the compound can be in a crystalline form, in amorphous form and 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 may also exhibit polymorphism. This invention further includes different polymorphs of the compounds of the present invention. 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.

The term "histone deacetylase" and "HDAC" are intended to refer to any one of a family of enzymes that remove acetyl groups from the ε-amino groups of lysine residues at the N-terminus of a histone. Unless otherwise indicated by context, the term "histone" is meant to refer to any histone protein, including Hl, H2A, H2B, H3, H4 and H5, from any species. Human HDAC proteins or gene products include but are not limited to, HDAC-I, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC-IO and HDAC-I l. The histone deacetylase can also be derived from a protozoal or fungal source.

The term "histone deacetylase inhibitor" or "inhibitor of histone deacetylase" is used to identify a compound, which is capable of interacting with a histone deacetylase and inhibiting its activity, more particularly its enzymatic activity. Inhibiting histone deacetylase enzymatic activity means reducing the ability of a histone deacetylase to remove an acetyl group from a histone. Preferably, such inhibition is specific, i.e. the histone deacetylase inhibitor reduces the ability of histone deacetylase to remove an acetyl group from a histone at a concentration that is lower than the concentration of the inhibitor that is required to produce some other, unrelated biological effect.

The invention also provides a method of treatment of cancer in patient including administration of a therapeutically effective amount of a compound of formula (I).

The present invention provides a method of treatment of a disorder caused by, associated with or accompanied by disruptions of cell proliferation and/or angiogenesis including administration of a therapeutically effective amount of a compound of formula (I).

The disorder is either a proliferative disorder or is selected from the group consisting of but is not limited to, cancer, inflammatory diseases/immune disorder, fibrotic diseases (e.g liver fibrosis), diabetes, autoimmune disease, chronic and acute neurodegenerative disease, Huntington's disease, Alzheimer's disease and infectious disease.

The compounds described herein are used in the treatment or prevention of cancer. The cancer can include solid tumors or hematologic malignancies.

The present invention provides a method of treatment of a disorder, disease or condition that can be treated by the inhibition of HDAC enzymes including administration of therapeutically effective amount of compound of formula (I). The invention provides a method of treatment of cancer in patient including administration of effective amount compound of formula (I). The cancer can be hematologic malignancy and this form of malignancy is selected from the group consisting of B-cell lymphoma, T-cell lymphoma and leukemia. In the case of solid tumors, the tumors are selected from the group consisting of but not limited to breast cancer, lung cancer, ovarian cancer, prostate cancer, head cancer, neck cancer, renal cancer, gastric cancer, colon cancer, pancreatic cancer and brain cancer.

As discussed above, the compounds of the present invention are useful for treating proliferative diseases. A proliferative disease includes, for example, a tumor disease and/or metastates. A proliferative disease that is refractory to the treatment with other chemotherapeutics; or a tumor that is refractory to treatment with other therapeutics due to multidrug resistance.

In certain embodiment, the proliferative disease may furthermore be a hyperproliferative condition such as leukemia, fibrosis, angiogenesis, psoriasis, atherosclerosis and smooth muscle proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.

In other embodiment; the compounds described herein are selectively toxic or toxic to rapidly proliferating cells than to normal cells, including, for example, human cancer cells, e.g. cancerous tumors, the compounds have significant antiproliferative effects and promotes differentiation, e.g.,^' cell cycle arrest and apoptosis. In addition, the compounds induce p21, cyclin-CDK interacting protein, which includes either apoptosis or Gl arrest in variety of cell lines.

Compounds of the present invention are able to slow tumor growth, stop tumor growth or bring about the regression of tumors and to prevent the formation of tumor metastates(including micrometastates) and the growth of metastates (including micrometastates). In addition they can be used in epidermal hyperproliferation (e.g., psoriasis), in prostate hyperplacia and in the treatment of neoplasiasis, including that of epithelial character, for example mammary carcinoma. It is also possible to use the compounds of the present invention in the treatment of diseases of immune system insofar as one or more individual deacetylase protein species or associated proteins are involved. Furthermore, the compounds of the present invention can be used also in the treatment of diseases of the central or peripheral nervous system where signal transmission by atleast one deacetylase protein is involved.

Deacetylase inhibitors are also appropriate for the therapy of disease related to transcriptional regulation of proteins involved in signal transduction, such as VEGF (Vascular endothelial growth factor) receptor, tyrosin kinase overexpression. Among these diseases are retinopathies, age related macular degeneration, psoriasis, hemangioblastoma, hemangioma, asteriosclerosis, muscle wasting conditions such as muscular dystrophies, cachexia, Huntington's syndrome, inflammatory diseases such as rheumatoid inflammatory diseases, including arthritis and arthritic conditions, such as chronic asthma, arterial or post-transplantational atherosclerosis, endometriosis and especially neoplastic disease and inflammatory bowel disease, granuloma, sepsis and the like.

Several HDAC inhibitors were shown to have both pro- and antiflammatory effects in a wide range of inflammation - relevant cell types. These inhibitors has shown promising effects in animal models in variety of inflammatory diseases such as arthritis, inflammatory bowel disease, septic shock, granuloma , airways inflammation and asthma (David P. Fairlie, et.al., Curr. Topics Med. Chem.., 2009, 9, 309-319, Zuomen, et.al, Exp. Opin.. Drug Disc, 2008, 3, 1041-1065).

In one aspect of the invention, compounds of formula (I) are used in the treatment of inflammatory disorders such' as 'rheumatoid arthritis, IBD, granuloma, sepsis and the like.

HDAC inhibitors are implicated in activities such as anti-angiogenic, anti- invasive and immunomodulatory that contribute to the inhibition of tumour development and progression.¹ They suppress neovascularization through alteration of genes that are directly involved in angiogenesis, which in addition to affecting nutrient supply to the primary tumour could also inhibit metastasis (Jessica E.B. et al., Nat. Rev. Drug Disc, 2006, 5, 769-784).

In another aspect of the invention, compounds of formula (I) are used in the treatment of proliferative conditions or cancer by inhibiting tumor angiogenesis and subsequent metastasis. HDAC inhibitors for the treatment of different CNS related disorders such as Huntington's disease, Parkinson's disease, Alzheimer's, aniexty, friedreich's ataxia is gaining pace and the compound EVP-0334 from Envivo pharmaceuticals is in the late preclinical satge for the treatment of Alzheimer disease and other related CNS disorder (Zukin, et.al., Curr. Opin. Pharmacol, 2008, 8, 57-64, L. M. Thompson, et.al., Nat. Rev. Drug Disc, 2008, 7, 854-868, Exp. Opin.. Drug Disc, 2008, 3, 1041-1065).

In another aspect of the invention, compounds of formula (I) are used in the treatment of neurodegenerative disorders such as Huntington's disease, Alzheimer's disease, Parkinson's disease and the like. Schroeder T. M. et al., (J. Bone Min. Res. 2005, 20, 2254-2263) and recent poster presentation at the AACR 2009 reported the use of HDAC inhibitors for reducing bone tumor burden. This in turn can result in the reduction of cancer induced bone pain (CIBP) (Abstract # 4556, presented at the Proceedings of the 100th Annual Meeting of the American Association for Cancer Research; 2009 Apr 18-22; Denver, CO. USA).

In another aspect of the invention, compounds of formula (I) are used in the treatment of cancer induced bone pain (CIBP)

HDAC inhibitors with cytotoxic agents such as 5-fiuorouracil (5-FU), paclitaxel (PTX), oxaliplatin and irinotecan have been shown to have a synergistic anti-proliferative effect on cell lines, for example, in gastric cancer cell lines. (Zhang X. et al., Oncol. Rep. 2006, 16, 563-568).

In another aspect of the invention, compounds of formula (I) in combination with cytotoxic agents such as 5-fluorouracil (5-FU), paclitaxel (PTX), oxaliplatin and irinotecan can be used to treat proliferative conditions or cancer. In another aspect, the compound may be administered in combination therapy by combining the compound of formula (I) with one or more separate agents, not limited to targets such as HDAC, Topoisomerase, DNA methyltransferase, heat shock proteins (e.g. HSP90), kinase and other matrix metalloproteinases.

A method of treatment of a proliferative condition or cancer or any of the above-mentioned diseases, comprising administering to a subject suffering from the proliferative condition or cancer or other above-mentioned diseases, a therapeutically effective amount of a compound of formula (I) with the presence or absence of other clinically relevant cytotoxic agents or non-cytotoxic agents to a mammal in need thereof.

In another aspect, the subject compounds may be combined with the antineoplastic agents (e.g. small molecules, monoclonal antibodies, antisense RNA and fusion proteins) that inhibit one or more biological targets. Such combination may enhance therapeutic efficacy over the efficacy achieved by any of the agents alone and may prevent or delay the appearance of resistant variants.

In another aspect, the subject compounds may be combined with the antifungal agents (e.g. azoles) that inhibits one or more biological targets. Such combination may enhance therapeutic efficacy over the efficacy achieved by any of the agents alone and may prevent or delay the appearance of resistant variants.

Use of a Compound of formula (I), for the manufacture of a medicament for the treatment of the above said diseases. The compounds of the invention are administered in combination with chemotherapeutic agents. Chemotherapeutic agents consist of a wide range of therapeutic treatments in the field of oncology. These agents are administered at various stages of the disease for the purposes of shrinking tumors, destroying remaining cancer cells left over after surgery, inducing remission, maintaining remission and/or alleviating symptoms relating to the cancer or its treatment.

The term "subject" as used herein is meant to include all mammals, and in particular humans, in need of treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound of formula (I) chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skill in the art.

A term once described, the same meaning applies for it, throughout the patent. Representative compounds include: 1) l-[6-(Hydroxyamino)-6-oxohexyl]-4-oxo-N-phenyl-l,4-dihydroquinoline-3- carboxamide; 2) 7-Chloro-N-cyclopropyl-6-fluoro-l-[6-(hydroxyamino)-6-oxohexyl]-4-oxo-l,4- d ihydroquinoline-3 -carboxamide ;

3) N-Benzyl- 1 -[6-(hydroxyamino)-6-oxohexyl]-4-oxo- 1 ,4-dihydroquinoline-3- carboxamide; 4) N-(4-Fluorophenyl)- 1 -[6-(hydroxyamino)-6-oxohexyl]-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

5) N-Adamantyl-l-[6-(hydroxyamino)-6-oxohexyl]-4-oxo-l,4-dihydroquinoline-3- carboxamide;

6) N-(2,4-Dimethoxybenzyl)-l-[6-(hydroxyamino)-6-oxohexyl]-4-oxo-l,4- dihydroquinoline-3-carboxamide;

7) 1 -[6-(Hydroxyamino)-6-oxohexyl]-N-(4-methoxybenzyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

8) 1 -[6-(Hydroxyamino)-6-oxohexyl]-N-(4-methoxyphenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 9) 1 -[6-(Hydroxyamino)-6-oxohexyl]-4-oxo-N-(thiophen-2-ylmethyl)- 1 ,4- dihydroquinoline-3-carboxamide;

10) N-(4-Fluorobenzyl)- 1 -[6-(hydroxyamϊno)-6-oxohexyl]-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

11 ) 6-Fluoro-N-(4-fluorophenyl)- 1 -[6-(hydroxyamino)-6-oxohexyl]-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

12) 6-Fluoro- 1 -[6-(hydroxyamino)-6-όxohexyl)-N-(4-methoxybenzyl)-]-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

13) N-(4-Fluorophenyl)- 1 -[6-(hydroxyamino)-6-oxohexyl]-6-Methoxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 14) N-(2,4-Dimethoxybenzyl)- 1 -[6-(hydroxyamino)-6-oxohexyl]-6-Methoxy-4-oxo- l,4-dihydroquinoline-3-carboxamide;

15) 7-Bromo-N-(2,4-dimethoxybenzyl)- 1 -[6-(hydroxyamino)-6-oxohexyl] -4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

16) 7-Bromo-N-(4-fluorophenyl)- 1 -[6-(hydroxyamino)-6-oxohexyl] -4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 17) N-(Benzo(d)thiazol-2-yl)-7-bromo- 1 -[6-(hydroxyamino)-6-oxohexyl]-4-oxo- 1 ,A- dihydroquinoline-3-carboxamide;

18) l-[6-(Hydroxyamino)-6-oxohexyl]-6-Methoxy-N-(4-methoxyphenyl)-4-oxo-l,4- dihydroquinoline-3-carboxamide; 19) N-(2,4-Dimethoxyphenyl)-l-[6-(hydroxyamino)-6-oxohexyl]-6-Methoxy-4-oxo- l,4-dihydroquinoline-3-carboxamide;

20) N-(2,4-Dimethoxyphenyl)-6-flouro- 1 -[6-(hydroxyamino)-6-oxohexyl]-4-oxo- 1 ,A- dihydroquinoline-3-carboxamide;

21 ) 7-Bromo-Ν-(2,4-dimethoxyphenyl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo- 1 ,A- dihydroquinoline-3-carboxamide;

22) 1 -(6-(Hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo-N-phenyl- 1 ,4- dihydroquinoline-3-carboxamide;

23) N-(Benzo[d]thiazol-2-yl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 24) 1 -(6-(Hydroxyamino)-6-oxohexyl)-4-oxo-Ν-(pyridin-4-yl)- 1 ,4-dihydroquinoline- 3-carboxamide;

25) 6-Fluoro- 1 -(6-(hydroxyamino)-6-bxohexyl)-4-oxo-N-(pyridin-4-yl)- 1 ,A- dihydroquinoline-3-carboxamide;

26) 1 -(6-(Hydroxyamino)-6-oxohexyl)-4-oxo-N-(thiazol-2-yl)- 1 ,4-dihydroquinoline-3- carboxamide;

27) 6-Fluoro-l -(6-(hydroxyamino)-6-oxohexyl)-4-oxo-N-phenyl-l ,4-dihydroquinoline- 3 -carboxamide;

28) N-(Benzo[d]thiazol-2-yl)-6-fluoro- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 29) 1 -(6-(Hydroxyamino)-6-oxohexyl)-6,7-dimethoxy-4-oxo-Ν-phenyl- 1 ,A- dihydroquinoline-3-carboxamide; 30) N-(4-/-Buty lphenyl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

31) 1 -(6-(Hydroxyamino)-6-oxohexy l)-4-oxo-Ν-(3 ,4,5 -trimethoxypheny I)- 1 ,A-» dihydroquinoline-3-carboxamide; 32) N-(3-Chloro-4-fluorophenyl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

33) 1 -(6-(Hydroxyamino)-6-oxohexyl)-Ν-(4-isopropylphenyl)-4-oxo- 1 ,4- dihydroquinol ine-3 -carboxamide ; 34) N-(6-Ethoxybenzo [d]thiazol-2-yl)- 1 -(6-(hydroxyamino)-6-oxohexy l)-4-oxo- 1,4- dihydroquinoline-3-carboxamide;

35) l-(6-(Hydroxyamino)-6-oxohexyl)-Ν-(4-isopropylphenyl)-6,7-dimethoxy-4-oxo- l,4-dihydroquinoline-3-carboxamide;

36) 1 -(6-(Hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo- 1 ,4-dihydroquinoline-3- carboxylic acid;

37) 1 -(6-(Hydroxyamino)-6-oxohexyl)-6-methoxy-N-( 1 -methyl-3-pheny 1- 1 H-pyrazol-

5-yl)-4-oxo-l,4-dihydroquinoline-3-carboxamide; 38) l-(6-(Hydroxyamino)-6-oxohexyl)-N-(l-methyl-3-phenyl-lH-pyrazol-5-yl)-4-oxo- l,4-dihydroquinoline-3-carboxamide; 39) N-(4-f-Buty lphenyl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

40) 1 -(6-(Hydroxyamino)-6-oxohexyl)-Ν-(4-isopropylphenyl)-6-methoxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

41 ) N-(2,4-Dimethylphenyl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo- 1 ,4- dihydroquinollne-3-carboxamide;

42) l-(6-(Hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo-Ν-(3,4,5-trimethoxyphenyl)- l,4-dihydroquinoline-3-carboxamide;

43) 1 -(6-(Hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo-N-(4-(piperidin- 1 -yl)phenyl)- l,4-dihydroquinoline-3-carboxamide; 44) 1 -(6-(Hydroxyamino)-6-oxohexyl)-N-(4-methylbenzo[d]thiazol-2-yl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 45)N-(Benzo[d]thiazol-2-yl)-l-(6-(hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo-l,4- dihydroquinoline-3-carboxamide;

46)N-(3-Chloro-4-fluorophenyl)-l-(6-(hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo- 1 ,4-dihydroquinoline-3 -carboxamide; 47) N-(4-Chlorophenyl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 48)N-(Benzo[d]thiazol-6-yl)-l-(6-(hydroxyamino)-6-oxohexyl)-4-oxo-l,4- dihydroquinoline-3-carboxamide; 49) N-(Benzo[c] [ 1 ,2,5]thiadiazol-4-yl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-6-methoxy-

4-oxo- 1 ,4-dihydroquinoline-3-carboxamide; 50)N-(4-Chlorophenyl)-l-(6-(hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo-l,4- dihydroquinoline-3-carboxamide;

51 ) N-(2,4-Dimethylphenyl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

52) 1 -(6-(Hydroxyamino)-6-oxohexyl)-6-methoxy-Ν-(4-(naphthalen- 1 -yl)thiazol-2-yl)- 4-oxo- 1 ,4-dihydroquinoline-3-carboxamide;

53)N-(Benzo[c][l,2,5]thiadiazol-4-yl)-l-(6-(hydroxyamino)-6-oxohexyl)-4-oxo-l,4- dihydroquinoline-3-carboxamide; 54) N-(4-/-Butylphenyl)-6-fluoro- 1 -(6-(hydroxyamino)-6-oxohexy l)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 55) l-(6-(Hydroxyamino)-6-oxohexyl)-4-oxo-Ν-(4-/7-tolylthiazol-2-yl)-l,4- dihydroquinoline-3 -carboxamide ;

56) 1 -(4-(Hydroxyamino)-4-oxobutyl)-6-methoxy-N-(4-methoxyphenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

57)N-(4-Chlorophenyi)-6-fluoro-l-(6-(hydroxyamino)-6-oxohexyl)-4-oxo-l,4- dihydroquinoline-3-carboxamide; 58) 6-Fluoro-l-(6-(hydroxyamino)-6-oxohexyl)-Ν-(4-methoxyphenyl)-4-oxo-l,4- dihydroquinoline-3-carboxamide; 59) l-(6-(2-Aminophenylamino)-6-oxohexyl)-4-oxo-N-phenyl-l,4-dihydroquinoline-3- carboxamide; 60) 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(3-chloro-4-fluorophenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

61) 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-fluorophenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 62) 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-t-butylphenyl)-4-oxo- 1 ,4- dihydroquinoline-3 -carboxamide ;

63) 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-methoxyphenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 64) 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-isopropylphenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

65) l-(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-isopropylphenyl)-6,7-dimethoxy-4- oxo-l,4-dihydroquinoline-3-carboxamide;

66) l-(6-(2-Aminophenylamino)-6-oxohexyl)-6-methoxy-N-(4-methoxyphenyl)-4-oxo- 1 ,4-dihydroquinoline-3-carboxamide;

67) l-(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-isopropylphenyl)-6-methoxy-4- OXO- 1 ,4-dihydroquinoline-3-carboxamide;

68) l-(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-?-butylphenyl)-6-rnethoxy-4-oxo- l,4-dihydroquinoline-3-carboxamide; 69) 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(2,4-dimethylphenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 70) l-(6-(2-Aminophenylamino)-6-oxohexyl)-6-methoxy-4-oxo-N-(3,4,5- trimethoxyphenyl)- 1 ,4-dihydroquinoline-3-carboxamide;

71) 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-Ν-( 1 -methyl-3-phenyl- 1 H-pyrazol-5 -y I)- 4-oxo- 1 ,4-dihydroquinoline-3-carboxamide;

72) l-(6-(2-Aminophenylamino)-6-oxohexyl)-6-methoxy-N-(l-methyl-3-phenyl-lH- pyrazol-5-yl)-4-oxo-l,4-dihydroquinoline-3-carboxamide;

73) 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-chlorophenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 74) 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(3-chloro-4-fluorophenyl)-6-methoxy- 4-oxo-l,4-dihydroquinoline-3-carboxamide;

75) l-(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-methylbenzo[d]thiazol-2-yl)-4- oxo-l,4-dihydroquinoline-3-carboxamide;

76) l-(6-(2-Aminophenylamino)-6-oxohexyl)-N-(benzo[d]thiazol-6-yl)-4-oxo-l,4- dihydroquinoline-3-carboxamide; 77) l-(6-(2-Aminophenylamino)-6-oxohexyl)-N-(benzo[c][l,2,5]thiadiazol-4-yl)-6- methoxy-4-oxo- 1 ,4-dihydroquinoline-3-carboxamide;

78) l-(6-(2-Aminophenylamino)-6-oxohexyl)-N-(benzo[c][l,2,5]thiadiazol-4-yl)-4- oxo-l,4-dihydroquinoline-3-carboxamide; 79) 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-chlorophenyl)-6-methoxy-4-oxo- l,4-dihydroquinoline-3-carboxamide; 80) l-(6-(2-Aminophenylamino)-6-oxohexyl)-N-(2,4-dimethylphenyl)-6-methoxy-4-

OXO- 1 ,4-dihydroquinoline-3-carboxamide;

81) 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-cyclopentyl-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

82) 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(benzo[d]thiazol-2-yl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

83) 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-chlorophenyl)-6-fluoro-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 84) 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-6-fluoro-N-(4-methoxyphenyl)-4-oxo- l,4-dihydroquinoline-3-carboxamide;

85) l-(4-(2-Aminophenylamino)-4-oxobutyl)-6-methoxy-N-(4-methoxyphenyl)-4-oxo- l,4-dihydroquinoline-3-carboxamide;

86) 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(2-hydroxyphenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide ;

87) l-(4-(2-Aminophenylamino)-4-oxobutyl)-N-(benzo[d]thiazol-2-yl)-6-fluoro-4-oxo- l,4-dihydroquinoline-3-carboxamide;

88) 6-(3-(Benzo[d]oxazol-2-yl)-4-oxoquinolin-l(4H)-yl)-N-hydroxyhexanamide; and 89)N-(2-Aminophenyl)-6-(3-(benzo[d]oxazol-2-yl)-4-oxoquinolin-l(4H)-yl) hexanamide.

There is also provided a process as shown in the following Scheme-I, for the preparation of compounds of the formula (I), wherein all the groups are as defined earlier.

The said process for the preparation of the compounds of formula (I) comprises of the following: Step 1: N-alkylation of compound of formula (Ia) with the corresponding haloalkylesters in the presence of a base to give compound of formula (Ib). Step 2: Hydrolyzing the compound of formula (Ib) with an inorganic base to give the corresponding acid. Coupling the acid with activating agents in the presence of an organic base along with the respective amine R³NH₂ to yield the compound of the general formula (I) or alternatively reacting the compound of formula (Ib) with NH₂R³ and an inorganic base to give the compound of formula (I), wherein R^x, R¹, R², R³, X, W¹, W², W³, W⁴ and n are as defined earlier.

The base as used in step 1, without limitation, includes K₂CO₃, Cs₂CO₃, NaH, Potassium t-butoxide and the like. The solvent as used in step I, without limitation, include DMF, THF, acetone and the like or a mixture thereof.

The inorganic base as used in step 2 without limitation, include NaOH, KOH and the like. The coupling agents as used in step 2 without limitation, include EDCI (1- (3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloride), Py-BOP [Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate], HOBt (1-hydroxybenzotriazole) and the like or a mixture thereof. The organic base as used in step 2, without limitation, includes triethylamine, diisopropylethylamine and the like. The solvents as used in step 2 without limitation include methanol, ethanol, THF, water and the like or a mixture thereof.

The examples given below are provided, by. the way of illustration only and therefore should not be construed to limit the scope of the invention.

Experimental Procedures:

Example 1: Synthesis of l-[6-(hydroxyamino)-6-oxohexyl]-4-oxo-N-phenyl-l,4- dibydro quinoline-3-carboxamide

Step-I: Preparation of methyl 6-(4-oxo-3-phenyIcarbamoyl)quinolin-l-(4H)-yl) hexanoate

To a mixture of 4-oxo-N-phenyl-l,4-dihydroquinoline-3-carboxamide (0.5 g,

1.79 mmol) and anhydrous K₂CO₃ (0.744 g, 5.39 mmol) in DMF (4 mL), methyl 6- bromohexanoate 0.75 mL (3.59 mmol) was added and heated under microwave at 125 ⁰C for 20 minutes. The reaction mixture was poured into ice-cold water (10 mL) and extracted with ethyl acetate (25 mL). The organic layer was washed with water, brine solution (each 10 mL). The organic layer was dried over Na₂SO₄ and concentrated to afford the crude compound. The crude product was purified by column chromatography using 20% ethyl acetate in hexane as an eluent. The pure fraction was concentrated to afford the title compound as colourless solid (0.3 g, 42.13 % yield). Step-II: Preparation of l-[6-(hydroxyamino)-6-oxohexyl]-4-oxo-N-phenyl-l,4- dihydro quinoline-3-carboxamide

Hydroxylamine hydrochloride (0.928 g, 13.26 mmol) in methanol (4 mL) was mixed with potassium hydroxide (0.742 g, 13.26 mmol) in methanol (4 mL) at 0 ⁰C.

The resulting white precipitate was filtered and the filtrate was immediately added to a round bottom flask containing methyl 6-(4-oxo-3-phenylcarbamoyl)quinolin-l-(4H)- yl) hexanoate (0.3 g, 0.74 mmol) and potassium hydroxide (0.165g, 2.95 mmol). The mixture was stirred at room temperature for 2 hours. The methanol quantity was reduced to half and diluted with ice-cold water (10 mL). The reaction mixture pH was adjusted to 8 using dilute acetic acid and kept in refrigerator at 10 ⁰C for 2 hours. The resulting solid was filtered to afford the title compound as colourless solid (0.080 g, 26.66 % yield). ¹H NMR (DMSOd₆) δ (ppm): 1.37-1.40 (2H, m, -CH₂), 1.52-1.58 (2H, m, -CH₂), 1.77-1.83 (2H, m, -CH₂), 1.93-1.99 (2H, t, -CH₂), 4.5-4.55 (2H, t, - CH₂), 7.08-7.12 (IH, t, Ar-H), 7.35-7.39 (2H, t, Ar-H), 7.59-7.62 (IH, t, Ar-H), 7.73- 7.75 (2H, d, Ar-H), 7.88-7.98 (2H, m, Ar-H), 8.42-8.44 (IH, d, Ar-H), 8.68 (IH, s, - OH), 9.01 (IH, s, =CH), 10.34 (IH, s, -NH), 12.44 (IH, s, -NH). MS m/z: 394.1 (M⁺+l).

The following compounds were prepared according to the procedure given in Example 1

Ex Structure Analytical Data

¹H NMR (DMSOd₆) δ (ppm): 0.53-0.54 (2H, m, -CH₂), 0.73-0.76 (2H, m, -CH₂), 1.29-1.31 (2H, m, -CH₂), 1.50- 1.54 (2H, m, -CH₂), 1.71-7.75 (2H,m, -CH₂), 1.92-1.95 (2H, m, -CH₂), 2.87-2.88 (IH, m, -CH), 4.46-4.50 (2H, t, -CH₂), 8.10-8.12 (IH, d, Ar-H), 8.29-8.30 (IH, d, Ar-

H), 8.66 (IH, s, -OH), 8.86 (IH, s, =CH), 9.80-9.81 (IH, d, -NH), 10.33 (IH, s, -NH). MS m/z: 410.1 (M⁺+l).

¹H NMR (DMSO-Cl₆) δ (ppm): 1.28-1.35 (2H, m, -CH₂), 1.49-1.57 (2H, m, -CH₂), 1.74-1.79 (2H, m, -CH₂), 1.92- 1.96 (2H, t, -CH₂), 4.45-4.48 (2H, t, -CH₂), 4.56-4.58 (2H, d, -CH₂), 7.24-7.27 (IH, m, Ar-H), 7.32-7.40 (4H, m, Ar-H), 7.53-7.56 (IH, t, Ar-H), 7.83-7.92 (2H, m, Ar-H), 8.34-8.36 (IH, d, Ar-H), 8.67 (IH, s, -OH), 8.89

(IH, s, =CH), 10.33 (IH, s, -NH), 10.37-10.40 (IH, t, - NH) MS m/z: 408.0 (M⁺+l). ¹H NMR (DMSO-de) δ (ppm): 1.33-1.37 (2H, m, -CH₂), 1.52-1.56 (2H, m, -CH₂), 1.78-1.82 (2H, m, -CH₂), 1.93- 1.96 (2H, t, -CH₂), 4.50-4.54 (2H, t, -CH₂), 7.19-7.23 (2H, t, Ar-H), 7.59-7.62 (IH, t, Ar-H), 7.75-7.78 (2H, m, Ar-H), 7.88-7.97 (2H, m, Ar-H), 8.42-8.44 (IH, d, Ar-

H), 8.68 (IH, s, -OH), 9.00 (IH, s, =CH), 10.34 (IH, s, - NH), 12.44 (IH, s, -NH). MS m/z: 412.1 (M⁺+l).

¹H NMR (DMSOd₆) δ (ppm): 1.29-1.31 (2H, m, -CH₂), 1.51-1.54 (2H, m, -CH₂), 1.67 (6H, s, adamantyl-H), 1.75-1.77 (2H, m, -CH₂), 1.92-1.95 (2H, t, -CH₂), 2.07 (9H, s, adamantyl-H), 4.41-4.43 (2H, t, -CH₂), 7.51-7.55 (IH, t, Ar-H), 7.82-7.90 (2H, m, Ar-H), 8.33-8.35 (IH,

d, Ar-H), 8.65 (IH, s, -OH), 8.79 (IH, s, =CH), 9.95 (IH, s, -NH), 10.32 (IH, s, -NH). MS m/z: 452.2 (M⁺+!).

¹H NMR (DMSO-de) δ (ppm): 1.32-1.38 (2H, m, -CH₂), 1.48-1.54 (2H, m, -CH₂), 1.76-1.78 (2H, m, -CH₂), 1.91- 1.95 (2H, t, -CH₂), 3.75 (3H, s, -OCH₃), 3.84 (3H, s, - OCH₃), 4.41-4.47 (4H, m, -CH₂), 6.47-6.50 (IH, m, Ar- H), 6.59-6.60 (IH, d, Ar-H), 7.14-7.17 (IH, d, Ar-H), 7.51-7.55 (IH, t, Ar-H), 7.82-7.90 (2H, d, Ar-H), 8.33-

8.35 (IH, d, Ar-H), 8.66 (IH, s, -OH), 8.85 (IH, s, =CH), 10.20-10.23 (IH, t, -NH), 10.32 (IH, s, -NH). MS m/z: 468.2 (M⁺+l).

¹H NMR (DMSO-de) δ (ppm): 1.31-1.35 (2H, m, -CH₂), 1.49-1.55 (2H, m, -CH₂), 1.75-1.79 (2H, m, -CH₂), 1.92- 1.95 (2H, t, -CH₂), 3.73 (3H, s, -OCH₃), 4.45-4.49 (4H, m, -CH₂), 6.90-6.92 (2H, d, Ar-H), 7.27-7.29 (2H, d, Ar-

H), 7.52-7.56 (IH, t, Ar-H), 7.83-7.91 (2H, m, Ar-H), 8.32-8.34 (IH, d, Ar-H), 8.67 (IH, s, -OH), 8.89 (IH, s, 1.92- (2H, Ar-

1.92-

1.91-

(2H,

t, -

1.82-

1.91- (4H, Ar-

1.92- (2H, Ar-

1.90- s, - ■

1.91- s, - Ar-

1.92-

1.93-

s,

1.91- s, - Ar-

1.91- s, -

1.92- s, - Ar-

8.67

1.92- s, - Ar-

1.92- (2H,

7.82-7.83 (IH, d, Ar-H), 7.92-7.94 (IH, d, Ar-H), 8.67 (IH, s, -OH), 8.93 (IH, s, =CH), 10.33 (IH, s, -NH), 12.55 (IH, s, -NH). MS m/z: 424.2 (M⁺+!).

¹H NMR (DMSO-de) δ (ppm): 1.34-1.36 (2H, m, -CH₂), 1.54-1.56 (2H, m, -CH₂), 1.82-1.84 (2H, m, -CH₂), 1.94- 1.96 (2H, t, -CH₂), 4.55-4.58 (2H, t, -CH₂), 7.33 (IH, m, Ar-H), 7.47 (2H, dd, Ar-H), 7.66 (IH, m, Ar-H), 7.78- 7.80 (IH, m, Ar-H), 8.0-8.04 (2H, m, Ar-H), 8.46-8.48 (IH, m, Ar-H), 8.68 (IH, s, -OH), 9.15 (IH, s, =CH),

10.34 (IH, s, -NH), 13.94 (IH, s, -NH). MS m/z: 451.1 (M⁺+!).

¹H NMR (DMSO-Cl₆) δ (ppm): 1.33-1.36 (2H, m, -CH₂), 1.52-1.56 (2H, m, -CH₂), 1.78-1.83 (2H, m, -CH₂), 1.92- 1.97 (2H, t, -CH₂), 4.52-4.56 (2H, t, -CH₂), 7.62-7.65 (IH, t, Ar-H), 7.71-7.73 (2H, d, Ar-H), 8.42-8.45 (IH, d, Ar-H), 8.47-8.49 (3H, m, Ar-H), 8.68 (IH, s, -OH),

9.04 (IH, s, =CH), 10.35 (IH, s, -NH), 12.71 (IH, s, - NH)- MS mZz^S-I (M⁺+!).

¹H NMR (DMSO-de) δ (ppm): 1.32-1.35 (2H, m, -CH₂), 1.51-1.56 (2H, m, -CH₂), 1.77-1.81 (2H, m, -CH₂), 1.92- 1.96 (2H, t, -CH₂), 4.53-4.57 (2H, t, -CH₂), 7.7-7.72 (2H, m, Ar-H), 7.82-7.84 (IH, m, Ar-H), 8.0-8.1 (2H, m, Ar-H), 8.4-8.5 (2H, d, Ar-H), 8.7 (IH, s, -OH), 9.04

(IH, s, =CH), 10.4 (IH, s, -NH), 12.57 (IH, s, -NH). MS m/z: 413.1 (M⁺+l).

¹H NMR (DMSO-d₆) δ (ppm): 1.34-1.38 (2H, m, -CH₂), 1.52-1.56 (2H, m, -CH₂), 1.80-1.83 (2H, m, -CH₂), 1.93- 1.96 (2H, t, -CH₂), 4.53-4.56 (2H, t, -CH₂), 7.28-7.29 (IH, d, Ar-H), 7.53-7.54 (IH, d, Ar-H), 7.62-7.66 (IH, t,

Ar-H), 7.91-8.01 (2H, m, Ar-H), 8.44-8.46 (IH, d, Ar- s, -

1.92-

d, Ar- s, -

m,

s,

1.88- s, -

1.33-

t,

1.93- s, - Ar-

s,

1.87-

1.79-

d, Ar- (IH,

1.81-

(IH,

H), 7.94-8.01 (2H, m, Ar-H), 8.45-8.47 (IH, d, Ar-H), 8.52 (IH, s, -OH), 9.12 (IH, s, =CH), 10.34 (IH, s, - NH), 13.77 (IH, s, -NH). MS m/z: 495.1 (M⁺+l).

¹H NMR (DMSO-Cl₆) δ (ppm): 1.19-1.21 (6H, d, -CH₃), 1.31-1.35 (2H, m, -CH₂), 1.48-1.56 (2H, m, -CH₂), 1.81- 1.87 (4H, m, -CH₂), 2.83-2.90 (IH, m, -CH), 3.91 (3H, s, -OCH₃), 4.00 (3H, s, -OCH₃), 4.5-4.54 (2H, t, -CH₂), 7.21-7.24 (3H, m, Ar-H), 7.61-7.63 (2H, d, Ar-H), 7.76 (IH, m, Ar-H), 8.78 (IH, s, -OH), 8.85 (IH, s, =CH),

10.25 (IH, s, -NH), 12.62 (IH, s, -NH). MS m/z: 496.2 (M⁺+!).

¹H NMR (DMSO-d₆) δ (ppm): 1.28-1.34 (2H, m, -CH₂), 1.50-1.54 (2H, m, -CH₂), 1.76-1.79 (2H, m, -CH₂), 1.91- 1.95 (2H, t, -CH₂), 3.92 (3H, s, -OCH₃), 4.53-4.57 (2H, t, -CH₂), 7.56-7.59 (IH, m, Ar-H), 7.74-7.75 (IH, d, Ar- H), 8.00-8.02 (IH, d, Ar-H), 8.67 (IH, s, -OH), 8.98

(IH, s, =CH), 10.33 (IH, s, -NH), 15.43 (IH, s, - COOH). MS m/z: 349.1 (M⁺+!).

¹H NMR (DMSO-d₆) δ (ppm): 1.38-1.4 (2H, m, -CH₂), 1.56-1.61 (2H, m, -CH₂), 1.84-1.86 (2H, m, -CH₂), 1.98- 2.00 (2H, t, -CH₂), 3.94 (3H, s, -OCH₃), 4.00 (3H, s, - NCH₃), 4.6-4.62 (2H, t, -CH₂), 6.96 (IH, s, Ar-H), 7.34- 7.38 (IH, t, Ar-H), 7.44-7.49 (2H, t, Ar-H), 7.57-7.6 (IH, dd, Ar-H), 7.82-7.85 (2H, d, Ar-H), 7.89-7.90 (IH, d, Ar-H), 8-8.02 (IH, d, Ar-H), 8.72 (IH, s, -OH), 9.03

(IH, s, =CH), 10.39 (IH, s, -NH), 13.12 (IH, s, -NH). MS m/z: 504.2 (M⁺+l). 1.93- (2H,

1.33-

- Ar-

1.92- -

7.07 (IH, s, Ar-H), 7.59-7.61 (IH, t, Ar-H), 7.89-7.97 (2H, m, Ar-H), 8.19-8.21 (IH, d, Ar-H), 8.43-8.45 (IH, t, Ar-H), 8.66 (IH, s, -OH), 9.00 (IH, s, =CH), 10.33 (IH, s, -NH), 12.20 (IH, s, -NH). MS m/z: 422.2 (M⁺+!).

¹H NMR (DMSO-de) δ (ppm): 1.33-1.35 (2H, m, -CH₂), 1.52-1.56 (2H, m, -CH₂), 1.79-1.81 (2H, m, -CH₂), 1.93- 1.96 (2H, t, -CH₂), 3.64 (3H, s, -OCH₃), 3.80 (6H, s, - OCH₃), 3.91 (3H, s, -OCH₃), 4.47-4.51 (2H, t, -CH₂), 7.11 (2H, s, Ar-H), 7.49-7.52 (IH, m, Ar-H), 7.81-7.82 (IH, d, Ar-H), 7.92-7.94 (IH, d, Ar-H), 8.92 (IH, s,

=CH), 9.01 (IH, s, -OH), 10.34 (IH, s, -NH), 12.48 (IH, s, -NH). MS m/z: 514.2 (M⁺+!).

¹H NMR (DMSO-de) δ (ppm): 0.84-0.86 (2H, m, -CH₂), 1.22-1.28 (4H, m, -CH₂), 1.33-1.35 (2H, m, -CH₂), 1.6- 1.64 (2H, m, -CH₂), 1.76-1.81 (2H, m, -CH₂), 1.93-1.97 (2H, t, -CH₂), 3.07-3.10 (4H, t, -CH₂), 3.91 (3H, s, - OCH₃), 4.48-4.52 (2H, t, -CH₂), 6.92-6.95 (2H, d, Ar- H), 7.51-7.55 (IH, m, Ar-H), 7.56-7.58 (2H, d, Ar-H),

7.81-7.82 (IH, d, Ar-H), 7.91-7.93 (IH, d, Ar-H), 8.66 (IH, s, -OH), 8.9 (IH, s, =CH), 10.33 (IH, s, -NH), 12.31 (IH, s, -NH). MS m/z: 507.2 (M⁺+!).

¹H NMR (DMSO-d₆) δ (ppm): 1.35-1.38 (2H, m, -CH₂), 1.54-1.57 (2H, m, -CH₂), 1.80-1.82 (2H, m, -CH₂), 1.94- 1.97 (2H, t, -CH₂), 2.42 (3H, s, -CH₃), 4.55-4.58 (2H, t, - CH₂), 7.26-7.28 (IH, d, Ar-H), 7.6-7.68 (2H, m, Ar-H), 7.8 (IH, s, Ar-H), 7.92-7.96 (IH, t, Ar-H), 8.0-8.01 (IH, m, Ar-H),' 8.45-8.48 (IH, m, Ar-H), 8.68 (IH, s, -OH),

9.11 (IH, s, =CH), 10.34 (IH, s, -NH), 13.82 (IH, s, - NH).'MS m/z: 465.1 (M⁺+l). 1.94- (2H,

s,

1.91- (2H,

1.85-

m,

s, -

1.94-

t,

1.93- (2H,

3.91 (2H,

1.87- -

-

1.94- (2H,

1.94-

t,

(2H, t, Ar-

1.94- t, -

13.73 (IH, s, -NH). MS m/z: 491.1 (M⁺+!).

¹H NMR (DMSO-d₆) δ (ppm): 1.99-2.03 (2H, m, -CH₂), 2.07-2.09 (2H, t, -CH₂), 3.75 (3H, s, -OCH₃), 3.92 (3H, s, -OCH₃), 4.48-4.52 (2H, t, -CH₂), 6.93-6.96 (2H, d, Ar-H), 7.5-7.53 (IH, m, Ar-H), 7.64-7.67 (2H, d, Ar-H), 7.81-7.83 (IH, d, Ar-H), 7.98-8.01 (IH, d, Ar-H), 8.76

(IH, s, -OH), 8.91 (IH, s, =CH), 10.44 (IH, s, -NH), 12.38 (IH, s, -NH). MS m/z: 426.1 (M⁺+!).

¹H NMR (DMSO-de) δ (ppm): 1.30-1.34 (2H, m, -CH₂), 1.51-1.53 (2H, m, -CH₂), 1.76-1.79 (2H, m, -CH₂), 1.92- 1.96 (2H, t, -CH₂), 4.53-4.56 (2H, t, -CH₂), 7.41-7.43 (2H, m, Ar-H), 7.76-7.78 (3H, m, Ar-H), 8.04-8.07 (2H, m, Ar-H), 8.66 (IH, s, -OH), 9.01 (IH, s, =CH), 10.33

(IH, s, -NH), 12.40 (IH, s, -NH). MS m/z: 446.1 (M⁺+l).

¹H NMR (DMSO-de) δ (ppm): 1.39-1.43 (2H, m, -CH₂), 1.54-1.56 (2H, m, -CH₂), 1.76-1.80 (2H, m, -CH₂), 1.92- 1.99 (2H, t, -CH₂), 3.91 (3H, s, -OCH₃), 4.49-4.53 (2H, t, -CH₂), 7.19-7.23 (2H, t, Ar-H), 7.49-7.52 (IH, m, Ar- H), 7.74-7.81 (3H, m, Ar-H), 7.91-7.93 (IH, d, Ar-H),

8.67 (IH, s, -OH), 8.93 (IH, s, =CH), 10.33 (IH, s, - NH), 12.56 (IH, s, -NH). MS m/z: 442.2 (M⁺+l).

Example 59: Synthesis of l-(6-(2-aminophenylamino)-6-oxohexyl)-4-oxo-N- phenyl-l,4-dihydro quinoline-3carboxamide

Step-I: Preparation of 6-(4-oxo-3-phenylcarbamoyl)quinolin-l-(4H)-yl) hexanoic acid

To a solution of methyl 6-(4-oxo-3-phenylcarbamoyl)quinolin-l-(4H)-yl) hexanoate (0.50 g, 1.5 mmol) (Step-1 product of Example-1) in methanol (10 mL) was added, a solution of NaOH (0.24 g, 6.1 mmol) in water (1 mL). The reaction mixture was stirred at 70 ⁰C for 4 hours or at room temperature for 12 hours. The reaction mixture was diluted with water (100 mL) and acidified (pH 2) with dilute aqueous HCl and allowed to stand at 4 ⁰C for 30 minutes, the precipitated solid was filtered and dried under vacuum to give a pure title compound as a white solid (0.40 g, 83% yield). Step-II: Preparation of l-(6-(2-aminophenylamino)-6-oxohexyl)-4-oxo-N-phenyl- l,4-dihydroquinoline-3carboxamide

To a solution of 6-(4-oxo-3-phenylcarbamoyl)quinolin-l-(4H)-yl) hexanoic acid (0.40 g, 1.2 mmol) in DMF (dimethyl formamide) (5 mL) was added EDCI (l-(3- dimethylaminopropyl)-3-ethylcarbodiimide. hydrochloride) (0.49 g, 2.5 mmol), HOBt (N-hydroxybenzotriazole) (0.07 g, 0.5 mmol), o-phenylenediamine (0.27 g, 2.5 mmol), followed by triethylamine (0.5 mL, 3.8 mmol). The reaction mixture was stirred for 3 hours at room temperature after which the mixture was added to cold water (50 mL). The aqueous layer was extracted with ethyl acetate (1 x 150 mL). The organic layer was washed with water (2 x 80 mL), brine (1 x 100 mL) and dried over anhydrous Na₂SO_4, concentrated to give the < crude compound. The crude yellow colored compound was triturated with diethyl ether (20 mL) to afford the pure title compound as a colourless solid (0.250 g, 50.51% yield^H NMR (DMSO-d₆) δ (ppm): 1.39-1.41 (2H, m, -CH₂), 1.63-1.66 (2H, m, -CH₂), 1.84-1.86 (2H, m, -CH₂), 2.29-2.33 (2H, t, - CH₂), 4.53-4.57 (2H, t, -CH₂), 4.79 (2H, s, -NH₂), 6.49-6.53 (IH, m, Ar-H), 6.69-6.71 (IH, t, Ar-H), 6.86-6.89 (IH, m, Ar-H), 7.09-7.11 (IH, d, Ar-H), 7.36-7.39 (2H, t, Ar- H), 7.58-7.61 (IH, t, Ar-H), 7.73-7.75 (2H, m, Ar-H), 7.92-7.98 (2H, m, Ar-H), 7.58- 7.61 (IH, t, Ar-H), 8.43-8.45 (IH, d, Ar-H), 9.03 (IH, s, =CH), 9.08 (IH, s, -NH), 12.44 (IH, s, -NH). MS m/z: 469.2 (M⁺H-I).

The following compounds were prepared according to the procedure given in Examples 59

t, - (IH,

m,

1).

t, - (IH,

t,

- (2H, 6.85- t,

Ar-H), 7.58-7.66 (2H, m, Ar-H), 7.86-7.98 (2H, t, Ar-H), 8.42- 8.44 (IH, d, Ar-H), 9.02 (IH, s, =CH), 9.06 (IH, s, -NH), 12.35 (IH, s, -NH). MS m/z: 525.3 (M⁺+!).

¹H NMR (DMSO-de) δ (ppm): 1.39-1.41 (2H, m, -CH₂), 1.63- 1.66 (2H, m, -CH₂), 1.84-1.86 (2H, m, -CH₂), 2.29-2.33 (2H, t, - CH₂), 3.75 (3H, s, -OCH₃), 4.53-4.57 (2H, t, -CH₂), 4.79 (2H, s, -NH₂), 6.49-6.53 (IH, t, Ar-H), 6.69-6.71 (IH, d, Ar-H), 6.86-

63 6.89 (IH, t, Ar-H), 6.94-6.96 (2H, d, Ar-H) 7.09-7.11 (IH, d, Ar- H), 7.58-7.61 (IH, t, Ar-H), 7.65-7.67 (2H, d, Ar-H), 7.86-7.90

(IH, t, Ar-H), 7.96-7.98 (IH, d, Ar-H), 8.42-8.44 (IH, d, Ar-H), 9.01 (IH, s, =CH), 9.07 (IH, s, -NH), 12.28 (IH, s, -NH). MS m/z: 499.2 (M⁺+!).

¹H NMR (DMSOd₆) δ (ppm): 1.16-1.21 (6H, d, -CH₃), 1.39- 1.43 (2H, m, -CH₂), 1.63-1.65 (2H, m, -CH₂), 1.86-1.88 (2H, m, -CH₂), 2.3-2.32 (2H, t, -CH₂), 2.86-2.9 (IH, m, -CH), 4.53-4.57 (2H, t, -CH₂), 4.79 (2H, s, -NH₂), 6.49-6.53 (IH, t, Ar-H), 6.69-

64 6.71 (IH, d, Ar-H), 6.86-6.9 (IH, t, Ar-H), 7.1-7.13 (IH, d, Ar- H), 7.23-7.25 (2H, d, Ar-H), 7.58-7.66 (3H, m, Ar-H), 7.86-7.90

(IH, t, Ar-H), 7.96-7.98 (IH, d, Ar-H), 8.42-8.44 (IH, d, Ar-H), 9.02 (IH, s, =CH), 9.05 (IH, s, -NH), 12.35 (IH, s, -NH). MS m/z: 511.3 (M⁺+!).

¹H NMR (DMSO-d₆) δ (ppm): 1.20-1.22 (6H, d, -CH₃), 1.37-1.4 (2H, m, -CH₂), 1.64-1.68 (2H, m, -CH₂), 1.88-1.91 (2H, m, - CH₂), 2.3-2.33 (2H, t, -CH₂), 2.85-2.88 (IH, m, -CH), 3.91 (3H, s, -OCH₃), 4.0O¹ (3H, s, -OCH₃), 4.56-4.58 (2H, t, -CH₂), 4.79

65 (2H, s, -NH₂), 6.48-6.52 (IH, t, Ar-H), 6.68-6.71 (IH, d, Ar-H), 6.85-6.89 (IH, t, Ar-H), 7.08-7.1 (IH, d, Ar-H), 7.22-7.24 (3H,

d, Ar-H), 7.62-7.64 (2H, d, Ar-H), 7.77 (IH, s, Ar-H), 8.87 (IH, s, =CH), 9.06 (IH, s, -NH), 12.62 (IH, s, -NH). MS m/z: 571.3 (M⁺+l). ¹H NMR (DMSO-de) δ (ppm): 1.38-1.42 (2H, m, -CH₂), 1.60- 1.67 (2H, m, -CH₂), 1.81-1.85 (2H, m, -CH₂), 2.28-2.32 (2H, t, - CH₂), 3.75 (3H, s, -OCH₃), 3.91 (3H, s, -OCH₃), 4.52-4.55 (2H, t, -CH₂), 4.79 (2H, s, -NH₂), 6.49-6.52 (IH, t, Ar-H), 6.68-6.70

66 (IH, d, Ar-H), 6.85-6.89 (IH, t, Ar-H), 6.93-6.96 (2H, d, Ar-H), 7.07-7.11 (IH, d, Ar-H), 7.46-7.49 (IH, m, Ar-H), 7.64-7.66

(2H, d, Ar-H), 7.81-7.82 (IH, d, Ar-H), 7.92-7.94 (IH, d, Ar-H), 8.93 (IH, s, =CH), 9.06 (IH, s, -NH), 12.39 (IH, s, -NH). MS m/z: 529.2 (M⁺+l).

¹H NMR (DMSO-d₆) δ (ppm): 1.19 (6H, s, -CH₃), 1.39-1.14 (2H, m, -CH₂), 1.60-1.66 (2H, m, -CH₂), 1.79-1.83 (2H, m, - CH₂), 2.28-2.32 (2H, t, -CH₂), 2.92-2.96 (IH, m, -CH), 3.91(3H, s, -OCH₃), 4.52-4.55 (2H, t, -CH₂), 4.79 (2H, s, -NH₂), 6.49-6.53

67 (IH, t, Ar-H), 6.68-6.70 (IH, d, Ar-H), 6.85-6.87 (IH, t, Ar-H), 7.09-7.11 (IH, d, Ar-H), 7.23-7.25 (2H, d, Ar-H), 7.46-7.49 (IH,

m, Ar-H), 7.63-7.65 (2H, d, Ar-H), 7.82-7.83 (IH, d, Ar-H), 7.92-7.95 (IH, d, Ar-H), 8.94 (IH, s, =CH), 9.06 (IH, s, -NH), 12.47 (IH, s, -NH). MS m/z: 541.2 (M⁺+!).

¹H NMR (DMSO-de) δ (ppm): 1.28 (9H, s, -CH₃), 1.39-1.42 (2H, m, -CH₂), 1.60-1.66 (2H, m, -CH₂), 1.79-1.83 (2H, m, - CH₂), 2.28-2.32 (2H, t, -CH₂), 3.91(3H, s, -OCH₃), 4.52-4.55 (2H, t,'-CH₂), 4.79 (2H, s, -NH₂), 6.51-6.53 (IH, t, Ar-H), 6.69-

68 6.71 (IH, d, Ar-H), 6.85-6.87 (IH, t, Ar-H), 7.09-7.11 (IH, d, Ar-H), 7.37-7.39 (2H, d, Ar-H), 7.46-7.49 (IH, m, Ar-H), 7.63-

7.66 (2H, d, Ar-H), 7.82-7.83 (IH, d, Ar-H), 7.92-7.95 (IH, d, Ar-H), 8.95 (IH, s, =CH), 9.06 (IH, s, -NH), 12.47 (IH, s, -NH). MS m/z: 555.2 (M⁺+l). ¹H NMR (DMSO-de) δ (ppm): 1.39-1.41 (2H, m, -CH₂), 1.63- 1.67 (2H, m, -CH₂), 1.84-1.86 (2H, m, -CH₂), 2.26 (3H, s, -CH₃), 2.29-2.33 (2H, t, -CH₂), 2.50 (3H, s, -CH₃), 4.54-4.56 (2H, t, - CH₂), 4.79 (2H, s, -NH₂), 6.49-6.52 (IH, t, Ar-H), 6.68-6.71 (IH, d, Ar-H), 6.85-6.87 (IH, t, Ar-H), 7.00-7.03 (IH, d, Ar-H), 7.07-7.11 (2H, m, Ar-H), 7.58-7.60 (IH, t, Ar-H), 7.88-7.90 (IH,

t, Ar-H), 7.96-7.98 (IH, d, Ar-H), 8.20-8.22 (IH, d, Ar-H), 8.43- 8.45 (IH, d, Ar-H), 9.03 (IH, s, =CH), 9.06 (IH, s, -NH), 12.20 (IH, s, -NH). MS m/z: 497.2 (M⁺+!).

¹H NMR (DMSO-de) δ (ppm): 1.38-1.42 (2H, m, -CH₂), 1.62- 1.65 (2H, m, -CH₂), 1.82-1.84 (2H, m, -CH₂), 2.28-2.32 (2H, t, - CH₂), 3.64 (3H, s, -OCH₃), 3.80 (6H, s, -OCH₃), 3.91 (3H, s, - OCH₃), 4.52-4.55 (2H, t, -CH₂), 4.79 (2H, s, -NH₂), 6.49-6.53 (IH, t, Ar-H), 6.68-6.70 (IH, d, Ar-H), 6.85-6.87 (IH, t, Ar-H), 7.09-7.12 (3H, m, Ar-H), 7.47-7.50 (IH, m, Ar-H), 7.81-7.82

(IH, d, Ar-H), 7.93-7.95 (IH, d, Ar-H), 8.95 (IH, s, =CH), 9.06 (IH, s, -NH); 12.48 (IH, s, -NH). MS m/z: 589.2 (M⁺+!).

¹H NMR (DMSO-de) δ (ppm): 1.41-1.43 (2H, m, -CH₂), 1.65- 1.68 (2H, m, -CH₂), 1.86-1.88 (2H, m, -CH₂), 2.3-2.34 (2H, t, - CH₂), 3.88 (3H, s, -NCH₃), 4.59-4.62 (2H, t, -CH₂), 4.79 (2H, s, -NH₂), 6.5-6.54 (IH, t, Ar-H), 6.69-6.71 (IH, d, Ar-H), 6.87-6.9 (2H, m, Ar-H), 7.04-7.06 (IH, d, Ar-H), 7.28-7.32 (IH, t, Ar-H), 7.39-7.43 (2H, t, Ar-H), 7.61-7.65 (IH, t, Ar-H), 7.75-7.77 (2H, d, Ar-H), 7.88-8 (2H, m, Ar-H), 8.44-8.46 (IH, d, Ar-H), 9.02

(IH, s, -NH), 9.03 (IH, s, =CH), 12.93 (IH, s, -NH). MS m/z: 549.2 (M⁺+l).

¹H NMR (DMSO-d₆) δ (ppm): 1.41-1.43 (2H, m, -CH₂), 1.62- 1.66 (2H, m, -CH₂), 1.83-1.86 (2H, m, -CH₂), 2.3-2.34 (2H, t, - CH₂), 3.88 (3H, 's, -OCH₃), 3.94 (3H, s, -NCH₃), 4.56-4.6 (2H, t, -CH₂), 4.8 (2H, s, -NH₂), 6.5-6.54 (IH, t, Ar-H), 6.69-6.71 (IH,

t, - (IH,

t,

t, - s, -

t, - s, -

Ar- (IH,

-NH₂), 6.47-6.52 (IH, t, Ar-H), 6.68-6.70 (IH, d, Ar-H), 6.85- 6.89 (IH, t, Ar-H), 7.09-7.11 (IH, d, Ar-H), 7.41-7.43 (2H, d, Ar-H), 7.47-7.50 (IH, m, Ar-H), 7.76-7.78 (2H, d, Ar-H), 7.81- 7.82 (IH, d, Ar-H), 7.93-7.95 (IH, d, Ar-H), 8.95 (IH, s, =CH), 9.06 (IH, s, -NH), 12.65 (IH, s, -NH). MS m/z: 533.2 (M⁺+l).

¹H NMR (DMSO-de) δ (ppm): 1.39-1.41 (2H, m, -CH₂), 1.62- 1.65 (2H, m, -CH₂), 1.82-1.85 (2H, m, -CH₂), 2.26 (3H, s, -CH₃), 2.29-2.33 (2H, t, -CH₂), 2.50 (3H, s, -CH₃), 3.98 (3H, s, -OCH₃), 4.54-4.56 (2H, t, -CH₂), 4.79 (2H, s, -NH₂), 6.49-6.52 (IH, t, Ar-

80 H), 6.68-6.71 (IH, d, Ar-H), 6.85-6.87 (IH, t, Ar-H), 7.00-7.03 (IH, d, Ar-H), 7.07-7.11 (2H, m, Ar-H), 7.45-7.48 (IH, m, Ar-

H), 7.81-7.82 (IH, d, Ar-H), 7.92-7.95 (IH, d, Ar-H), 8.22-8.24 (IH, d, Ar-H), 8.95 (IH, s, =CH), 9.06 (IH, s, -NH), 12.29 (IH, s, -NH). MS m/z: 527.2 (M⁺+l).

¹H NMR (DMSO-d₆) δ (ppm): 1.46-1.48 (2H, m, -CH₂), 1.49- 1.51 (2H, m, -CH₂), 1.60-1.74 (6H, m, -CH₂), 1.77-1.83 (2H, m, -CH₂), 1.89-1.94 (2H, m, -CH₂), 2.28 - 2.32 (2H, m, -CH₂), 4.23 -4.28 (IH, m, -CH), 4.47 - 4.51 (2H, m, -CH₂), 4.79 (2H, s, -

81 NH₂), 6.50-6.53 (IH, t, Ar-H), 6.69-6.71 (IH, d, Ar-H), 6.86- 6.88 (IH, t, Ar-H), 7.09-7.11 (IH, d, Ar-H), 7.52 - 7.56 (IH, t,

Ar-H), 7.83-7.85 (IH, t, Ar-H), 7.90-7.92 (IH, d, Ar-H), 8.33- 8.36 (IH, m, Ar-H), 8.86 (IH, s, =CH), 9.06 (IH, s, -NH), 10.07 (IH, s, -NH). MS m/z: 461.2 (M⁺+!).

¹H NMR (DMSO-de) δ (ppm): 1.43-1.45 (2H, m, -CH₂), 1.63- 1.67 (2H, m,¹ -CH₂), 1.84-1.88 (2H, m, -CH₂), 2.3-2.34 (2H, t, - CH₂), 4.59-4.63 (2H, t, -CH₂), 4.79 (2H, s, -NH₂), 6.48-6.52 (IH,

82 t, Ar-H), 6.68-6.71 (IH, d, Ar-H), 6.85-6.89 (IH, t, Ar-H), 7.1- 7.12 (IH, d, Ar-H), 7.31-7.35 (IH, t, Ar-H), 7.44-7.49 (IH, t,

Ar-H), 7.63-7.68 (IH, t, Ar-H), 7.78-7.81 (IH, d, Ar-H), 7.91- 7.95 (IH, t, Ar-H), 8.01-8.04 (2H, d, Ar-H), 8.46-8.49 (IH, d, t, - (IH,

m, s,

t, - (2H, s,

m,

Ar-

s,

t, - (IH,

t,

Example 88: Synthesis of 6-(3-(benzo[d]oxazol-2-yl)-4-oxoquinolin-l(4H)-yl)-N- hydroxyhexanamide

Step-I: Preparation of 3-(benzo[d]oxazol-2-yI)quinolin-4(lH)-one

A mixture of 4-oxo-l,4-dihydroquinoline-3-carboxylic acid ( 0.2g, 1.05 mmol), ø-aminophenol (0.138g, 1.3mmol) and polyphosphoric acid (5mL) were heated at 16O⁰C for 4hrs. After cooling, water was added followed by the addition of 50%

10 aqueous KOH solution (20ml). The solid that precipitated out was filtered washed with water and dried under vaccum (0.150 g, 54.55 % yield).

Step-II: Preparation of methyl 6-(3-(benzo[d]oxazol-2-yl)-4-oxoquinolin-l(4H)- yl)hexanoate

To a mixture of 3-(benzo[d]oxazol-2-yl)quinolin-4(lH)-one (0.05 g, 1.9 mmol) and anhydrous K₂CO₃ (0.078 g, 5.7 mmol) in DMF (5 mL), methyl 6-bromohexanoate

(0.079g, 3.8 mmol) was added and heated under microwave at 125 ⁰C for 20 minutes. The reaction mixture was poured into ice-cold water (10 mL) and extracted with ethyl acetate (25 mL). The organic layer was washed with water, brine solution each 10 mL.

The organic layer was dried over Na₂SO₄ and concentrated to afford the crude compound, was purified by column chromatography using 20% ethyl acetate in hexane as an eluent. The pure fraction was concentrated to afford the title compound as colourless solid (0.055 g, 74.32 % yield).

Step-III: Preparation of 6-(3-(benzo[d]oxazol-2-yl)-4-oxoquinolin-l(4H)-yl)-N- hydroxyhexanamide

Hydroxylamine hydrochloride (0.928 g, 13.26 mmol) in methanol (4 mL) was mixed with potassium hydroxide (0.742 g, 13.26 mmol) in methanol (4 mL) at 0 ⁰C.

The resulting white precipitate was filtered and the filtrate was immediately taken in a round bottom flask containing methyl 6-(3-(benzo[d]oxazol-2-yl)-4-oxoquinolin- l(4H)-yl)hexanoate (0.28g, 0.74 mmol) and potassium hydroxide (0.165g, 2.95 mmol).

The mixture was stirred at room temperature for 2 hours. The methanol quantity was reduced to half and diluted with ice-cold water (10 mL). The reaction mixture pH was adjusted to 8 using dilute acetic acid and kept in refrigerator at 10 ⁰C for 2 hours. The resulting solid was filtered to afford the title compound as colourless solid (0.080 g, 28.57 % yield.). ¹H NMR (DMSO-de) δ (ppm): 1.36-1.40 (2H, m, -CH₂), 1.51-1.59 (2H, m, -CH₂), 1.80-1.83 (2H, m, -CH₂), 1.93-1.99 (2H, t, -CH₂), 4.45-4.48 (2H, t, - CH₂), 7.37-7.40 (2H, m, Ar-H), 7.52-7.55 (IH, t, Ar-H), 7.73-7.76 (2H, m, Ar-H),

7.81-7.89 (2H, m, Ar-H), 8.34-8.36 (IH, d, Ar-H), 8.80 (IH, s, -OH), 9.01 (IH, s,

=CH), 10.34 (IH, s, -NH). MS m/z: 392.1 (M⁺H-I).

Example 89: Synthesis of N-(2-aminophenyl)-6-(3-(benzo[d]oxazol-2-yl)-4- oxoquinolin-l(4H)-yl)hexanamide

Step-I: Preparation of 6-(3-(benzo[d]oxazol-2-yl)-4-oxoquinolin-l(4H)-yl)hexanoic acid

To a solution of methyl 6-(3-(benzo[d]oxazol-2-yl)-4-oxoquinolin-l(4H)- yl)hexanoate (0.50 g, 1.28 mmol) (Step-II product of Example-88) in methanol (10 mL) was added, a solution of NaOH (0.24 g, 6.1 mmol) in water (1 mL). The reaction mixture was stirred at 70 ⁰C for 4 hours. The reaction mixture was diluted with water (100 mL) and acidified (pH 2) with dilute aqueous HCl and allowed to stand at 4 ⁰C for 30 minutes, the precipitated solid was filtered and dried under vacuum to give a pure title compound as a white solid (0.40 g, 83.33% yield).

Step-II: Preparation . • of .i/,N-(2-aminophenyl)-6-(3τ(benzo[d]oxazol-2-yI)-4- oxoquinolin-1 (4H)-yl)hexanamide

To a solution of 6-(3-(benzo[d]oxazol-2-yl)-4-oxoquinolin-l(4H)-yl)hexanoic acid (0.40 g, 1.06 mmol) in DMF (5 mL) was added EDCI (0.49 g, 2.5 mmol), HOBt (0.07 g, 0.5 mmol), o-phenylenediamine (0.27 g, 2.5 mmol), followed by triethylamine (0.5 mL, 3.8 mmol). The reaction mixture was stirred for 3 hours after which the mixture was added to cold water (50 mL). The aqueous layer was extracted with ethyl acetate (1 x 150 mL). The organic layer was washed with water (2 x 80 mL), brine (I x 100 mL) and dried over anhydrous Na₂SO₄, concentrated to give the crude compound. The crude yellow colored compound was triturated with diethyl ether (20 mL) to afford the pure title compound as a colorless solid (0.05 g, 10% yield). ¹H NMR (DMSO-d₆) δ (ppm): 1.42-1.48 (2H, m, -CH₂), 1.63-1.68 (2H, m, -CH₂), 1.85-1.88 (2H, m, -CH₂), 2.30-2.34 (2H, t, -CH₂), 4.48-4.52 (2H, t, -CH₂), 4.79 (2H, s, -NH₂), 6.47-6.51 (IH, t, Ar-H), 6.68-6.70 (IH, d, Ar-H), 6.85-6.87 (IH, t, Ar-H), 7.09-7.11 (IH, d^' Ar-H), 7.37-7.39 (2H, m, Ar-H), 7.52-7.55 (IH, t, Ar-H), 7.73-7.75 (2H, m, Ar-H), 7.81-7.85 (IH, t, Ar-H), 7.89-7.91 (IH, d, Ar-H), 8.35-8.37 (IH, d, Ar-H), 9.04 (IH, s, =CH), 9.07 (IH, s, -NH). MS m/z: 485.2 (M⁺+l).

Anti-cancer experimental methods Anti-cancer screen:

Experimental drugs were screened for, anticancer activity in three, cell lines using five concentrations for each compound. The cell lines - HCT 116 (colon), NCIH460 (lung) and U251 (glioma) were maintained, in DMEM (Dulbecco's Modified Eagle's Medium) containing 10% fetal bovine serum. ι96-well microtiter plates are inoculated with cells in 100 μL of cell suspension (5 x 10⁴ cells/mL) for 24 hours at 37 ⁰C, 5% CO₂, 95% air and 100% relative humidity. A separate plate with these cell lines is also inoculated to determine cell viability before the addition of the compounds (T₀) Addition of experimental drugs: Following 24-hour incubation,: test compounds were added to the 96 well plates. Each plate contains one of the above cell lines and the following samples in triplicate: five different dilutions (0.01, 0.1, 1, 10 and 100 μM) of four test compounds, appropriate dilutions of a cytotoxic standard . and growth medium (untreated) wells. Test compounds were dissolved in DMSO to prepare, 20 mM. stock solutions on the day of drug addition^' arid serial dilutions were carried out in complete growth medium at 2x strength such that 100 μL added to wells gave final concentrations (0.01, 0.1, 1, 10 and 100 μM) in the well. SAHA was used as standard drug in these experiments. End-point measurement:

For To measurement, 24 hours after seeding the cells, 20 μL of 3-(4,5-dimethyl-2- thiazolyl)-2,5-diphenyl-2H-tetrazolium (MTT) solution per well was added to the 'To' plate and incubated for 3 hours at 37 ⁰C in a CO₂ incubator. The plate containing cells and test compounds was treated similarly after 48 hours of incubation. After 3 hours of MTT addition, well contents were aspirated carefully followed by addition of 150 μL DMSO per well. Plates were agitated to ensure dissolution of the formazan crystals in DMSO and absorbance was read at 570 nm (A₅₇₀). Calculation Of GI₅₀, TGI and LC₅₀: Percent growth (PG) is calculated relative to the control and zero measurement wells (T₀) as follows:

PG = (A₅₇₀test - A₅₇₀T₀) / (A_S7ocontrol - A570T0) x 100 (IfA₅₇₀ test > A570T0) PG = (A₅7otest - A570T0) / (As7oTo) x 100 (IfA₅₇O test < A₅₇₀T₀), PG values are plotted against drug concentration to derive the following: GI₅₀ is the concentration required to decrease PG by 50% vs control; TGI is the concentration required to decrease PG by 100% vs control and LC₅₀ is the concentration required to decrease PG by 50% vs To. (Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. (Tim Mosmann, J. Immunol. Methods. 1983, 65, 55-63). Feasibility of high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines". (Anne Monks et. al., J. Natl. Cancer Inst., 1991, 83, 757-756).

Results for growth inhibition of the synthesized compounds are given in Table- 1. HDAC Activity screening: Histone Deacetylase (HDAC) Inhibition Assay using Boc-Lys (Ac)-AMC Substrate: Inhibition of HDAC has been implicated to modulate transcription and to induce apoptosis or differentiation in cancer cells. The fluorometric assay provides a fast and fluorescence based method that eliminates radioactivity, extractions or chromatography, as used in traditional assays. The assay is based on two steps. First, the HDAC fluorometric substrate, which comprises an acetylated lysine side chain, is incubated with a sample containing HDAC activity (Mouse Liver Extract). Deacetylation of the substrate sensitizes the substrate, in the second step; treatment with the Trypsin stop solution produces a fluorophore that can be easily analyzed using fluorescence plate reader.

Assay was done in 96-well black microplate and total volume of the assay was 100 μL. Mouse liver enzyme (10 mg/ml) was diluted 1: 6 with HDAC buffer. Enzyme cocktail was made of 10 μL of diluted enzyme and 30 μL of HDAC buffer. 40 μL of enzyme cocktail followed by 10 μL of test compound (1 μM and 10 μM) or buffer (control) was added to each well. The plate was pre-incubated at 37 ⁰C for 5 minutes. The HDAC reaction was started by adding 50 μL of HDAC substrate Boc-Lys (Ac)-AMC (Bachem AG, Switzerland). The plate was incubated at 37 ⁰C for 30 minutes. The reaction was stopped by adding 100 μL of Trypsin stop solution and incubating at 37 ⁰C for 15-30 minutes. Measuring the fluorescence at excitation wavelength of 360nm and emission wavelength of 460 nm monitored the release of AMC. Buffer alone and substrate alone served as blank. For selected compounds, IC₅₀ (50% HDAC inhibitory concentration) was determined by testing in a broad concentration range of 0.001, 0.01, 0.1, 1 and lOμM. (Dennis Wegener et al, Anal. Biochem, 2003, 321, 202-208). Results for anticancer-GIso and HDAC inhibition IC50 values are indicated in Table-1 and Table-2 Table -1: Inhibition of cancer cell growth and pan HDAC enzyme activity

HDAC inhibitors of compounds of formula (I) with hydroxamic acid moieties potently inhibited the enzyme activity, with IC50 values ranging from 0.036 nM to 410 nM concentrations. Some of the compounds showed potent anticancer activity against three cell lines, namely HCT 116, NCIH460, U251 and also HDAC inhibitory acivity when compared with the reference compound SAHA (Table- 1).

Table 2: Inhibition of cancer cell growth and HDACl enzyme activity

Benzamides are known to have potential HDAC class I specificity, active compounds of formula (I) in this series were tested for HDACl inhibitory activity. The assay was carried out, as previously described using recombinant HDACl enzyme (BIOMOL, USA) and following manufacturer's instructions. The results shown in table 2 indicate that these compounds inhibit HDACl enzyme, showed HDAC isoform specific activity and compared with standard compound MGCDO 103. In vitro metabolic stability in liver microsomes: Metabolic stability is defined as the percentage of parent compound lost over time in the presence of liver microsomes, liver S9, or hepatocytes, depending on the goal of the assay. By understanding the metabolic stability of compounds early in discovery, compounds can be ranked for further studies, and the potential for a drug candidate to fail in development as a result of pharmacokinetic reasons may be reduced.

Stock solutions of test compounds (in DMSO or water) were prepared in phosphate buffer (pH = 7.4). Incubation of reaction mixture including cryopreserved mouse liver microsomes (MLM) or human liver microsomes (HLM) (1 mg/mL), test compound (50 μM), and NADPH for different time points, e.g. 10, 15, 30, and 60 minutes or single time points, e.g. 60 minutes. Reaction is started by the addition of NADPH and stopped either immediately or after 60 minutes for screening assay or at 5, 15, 30 and 60 minutes for a more precise estimate of clearance by addition of ice- cold acetonitrile, followed by sample preparation. Determination of loss of parent compound (compared to zero time point control and/or no NADPH-control) was done using HPLC or LC-MS methods. Metabolism was expressed as percentage of test compound metabolized after a certain time. A marker reaction and marker substrate (e.g. testosterone) was employed as quality criteria of the metabolic capability of the microsomes. (Rodrigues, A.D., Biochem. Pharm., 1994, 48, 2147-2156). Metabolic stability was expressed as % metabolism of the compound after 30 minutes of incubation in the presence of active microsomes. Compound that had a % metabolism less than 30% were defined as highly stable. Compound that had a metabolism between 30% and 60% were defined as moderately stable and compounds that showed a % metabolism higher than 60% were defined as less stable. Several compounds have been found to show high to moderate stability. Table-3 shows the representative examples. Table -3: In vitro metabolic stability in liver microsomes

Claims

We Claim:

1. A compound of formula (I),

(I) their analogs, tautomeric forms, stereoisomers, polymorphs, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof; wherein:

W¹, W², W³ and W⁴ each independently represent C-R^x, N, S, O or absent with the proviso that a minimum of three of W¹, W², W³ and W⁴ are always present;

R^x independently represents hydrogen, hydroxy, nitro, alkoxy, aryloxy, heteroaryloxy, heteroalkoxy, halogen, -COOR^a, -C(O)R^a, -C(S)R³, -C(O)NR^aR^b, -C(S)NR^aR^b, -NR^aC(O)NR^bR^c, -NR^aC(S)NR^bR^c, -N(R^a)SOR^b, -N(R^a)SO₂R^b, -NR^aC(O)OR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(S)R^b, -SONR^aR^b, -SO₂NR^aR^b, -OR^a, -OR^aC(O)OR^b, -OC(O)NR^aR^b, -OC(O)R^a, -OC(O)NR^aR^b, -R^aNR^bR^c, -R^aOR^b, -SR^a, -SOR^a, -SO₂R^a, substituted or unsubstituted groups selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein: R^a, R^b and R^c represent hydrogen, substituted or unsubstituted groups selected from alkyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl or cylcoalkenyl; or R^a and R^b can be combined together to form a ring structures having 4-8 atoms;

X represents -CONR¹OH, -CONR¹R², -CSNR¹R², -COOR¹, -CH₂NR¹R², substituted or unsubstituted groups selected from aryl or heteroaryl;

R¹ and R² independently represent hydrogen, substituted or unsubstituted groups selected from alkyl, aryl, arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, cycloalkyl or cylcoalkenyl; or R and R can be combined together to form a ring structure having 4-8 atoms; Z represents C-Y or N, wherein Y represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl or heterocycloalkyl;

R³ represents -OR⁴, ortho substituted aniline, amino aryl and amino heteroaryl, which may be further substituted, wherein R⁴ represents hydrogen, optionally substituted groups selected from alkyl, aryl, heterocycloalkyl or -COR⁵, wherein R⁵ represents optionally substituted groups selected from alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; n represents an integer selected from 1-7; when the groups R^x, R¹, R², R³ _, R⁴ and R⁵ are substituted, the substituents are one or more and are selected from halogens, hydroxy, nitro, cyano, azido, nitroso, oxo (=0), thioxo (=S), thioalkyl, amino, hydrazino, formyl, alkyl, haloalkyl group, alkoxy, haloalkoxy, arylalkoxy, cycloalkyl, cycloalkyloxy, aryl, heterocycloalkyl, heteroaryl, alkylamino, tolyl, -COOR^a, -C(O)R³, -C(S)R^a, -C(O)NR^aR^b, -C(S)NR^aR^b, -NR^aC(O)NR^bR^c, -NR^aC(S)NR^bR^c, -N(R^a)SOR^b, -N(R^a)SO₂R^b, -NR^aC(O)OR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(S)R^b, -SONR^aR^b, -SO₂NR^aR^b, -OR^a, -OR^aC(O)OR^b, -OC(O)NR^aR^b, -OC(O)R³Z -R³NR¹⁵R⁰, -R^aOR^b, -SR^a, -SOR^a and -SO₂R³; The substituents are further optionally substituted by one or more substituents as defined above. 2. The compound according to claim 1, wherein: when alkoxy group is present, the alkoxy group is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or t-butoxy; when aryloxy group is present, the aryloxy group is selected from phenoxy or naphthyloxy; when halogen is present, the halogen is fluorine, chlorine, bromine or iodine; when alkyl group is present, the alkyl group is methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, f-butyl, pentyl, hexyl, heptyl or octyl; when alkenyl group is present, the alkenyl group is ethenyl, 1-propenyl, 2-propenyl, iso- propenyl, 2-methyl- 1-propenyl, 1-butenyl or 2-butenyl; when the alkynyl group is present, the alkynyl group is ethynyl, propynyl or butynyl; when cycloalkyl group is present, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl, perhydronaphthyl, adamantyl, bridged cyclic groups or spirobicyclic groups; when cycloalkenyl group is present, the cycloalkenyl group is selected from cyclopentenyl and cyclohexenyl; when heterocycloalkyl or heteroaryl group is present, the heterocycloalkyl or heteroaryl group is a heterocyclyl selected from azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, piperonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, oxazolyl, oxazolinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, oxadiazolyl, benzindazolyl, indazolyl, phenyl piperidinyl, furyl, tetrahydrofuryl, tetrahydropyranyl, piperazinyl, homopiperazinyl, piperidyl, piperidopiperidyl, morpholinyl, thiomorpholinyl, piperidonyl, 2-oxopiperazinyl, 2- oxopiperidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, oxazolidinyl, chromanyl and isochromanyl; when aryl group is present, the aryl group is phenyl, naphthyl, anthracenyl, indanyl or biphenyl; when alkylene group is present, the alkylene group is methylene, ethylene, propylene or butylene; when hydroxyalkyl group is present, the hydroxyalkyl group is hydroxymethyl or hydroxyethyl; when haloalkyl group is present, the haloalkyl group is trifluoromethyl,' tribromomethyl or trichloromethyl; and when haloalkoxy group is present, the haloalkoxy group is selected from chloromethoxy, chloroethoxy, trifiuoromethoxy, trifluoroethoxy or trichloromethoxy. 3. The compound according to claim 1 selected from the group consisting of: 1 -[6-(Hydroxyamino)-6-oxohexyl]-4-oxo-N-phenyl- 1 ,4-dihydroquinoline-3- carboxamide;

7-Chloro-N-cyclopropyl-6-fluoro-l-[6-(hydroxyamino)-6-oxohexyl]-4-oxo-l,4- dihydroquinoline-3-carboxamide;

N-Benzyl-l-[6-(hydroxyamino)-6-oxohexyl]-4-oxo-l,4-dihydroquinoline-3- carboxamide; N-(4-Fluorophenyl)-l-[6-(hydroxyamino)-6-oxohexyl]-4-oxo-l,4-dihydroquinoline-3- carboxamide; N-Adamantyl-l-[6-(hydroxyamino)-6-oxohexyl]-4-oxo-l,4-dihydroquinoline-3- carboxamide;

N-(2,4-Dimethoxybenzyl)-l-[6-(hydroxyamino)-6-oxohexyl]-4-oxo-l,4- dihydroquinoline-3-carboxamide; 1 -[6-(Hydroxyamino)-6-oxohexyl]-N-(4-methoxybenzyl)-4-oxo- 1 ,4-dihydroquinoline-

3-carboxamide;

1 -[6-(Hydroxyamino)-6-oxohexyl]-N-(4-methoxyphenyl)-4-oxo- 1 ,4-dihydroquinoline-

3-carboxamide;

1 -[6-(Hydroxyamino)-6-oxohexyl]-4-oxo-N-(thiophen-2-ylmethyl)- 1 ,4- dihydroquinoline-3-carboxamide;

N-(4-Fluorobenzyl)-l-[6-(hydroxyamino)-6-oxohexyl]-4-oxo-l,4-dihydroquinoline-3- carboxamide;

6-Fluoro-N-(4-fluorophenyl)- 1 -[6-(hydroxyamino)-6-oxohexyl]-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 6-Fluoro- 1 -[6-(hydroxyamino)-6-oxohexyl)-N-(4-methoxybenzyl)-]-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

N-(4-Fluorophenyl)- 1 -[6-(hydroxyamino)-6-oxohexyl]-6-methoxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

N-(2,4-Dimethoxybenzyl)- 1 -[6-(hydroxyamino)-6-oxohexyl]-6-Methoxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

7-Bromo-N-(2,4-dimethoxybenzyl)-l-[6-(hydroxyamino)-6-oxohexyl]-4-oxo-l,4- dihydroquinoline-3-carboxamide;

7-Bromo-N-(4-fluorophenyl)- 1 -[6-(hydroxyamino)-6-oxohexyl]-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; N-(Benzo(d)thiazol-2-yl)-7-bromo- 1 -[6-(hydroxyamino)-6-oxohexyl]-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; l-[6-(Hydroxyamino)-6-oxohexyl]-6-methoxy-Ν-(4-methoxyphenyl)-4-oxo-l,4- dihydroquinoline-3-carboxamide;

N-(2,4-Dimethoxyphenyl)- 1 -[6-(hydroxyamino)-6-oxohexyl]-6-methoxy-4-oxo- 1 ,4- dihydroquinoHne-3-carboxamide; N-(2,4-Dimethoxypheny l)-6-flouro- 1 - [6-(hydroxyamino)-6-oxohexy 1] -4-oxo- 1,4- dihydroquinoline-3 -carboxamide ;

7-Bromo-Ν-(2,4-dimethoxyphenyl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 1 -(6-(Hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo-N-phenyl- 1 ,4-dihydroquinoline-

3-carboxamide;

N-(Benzo[d]thiazol-2-yl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

1 -(6-(Hydroxyamino)-6-oxohexyl)-4-oxo-Ν-(pyridin-4-yl)- 1 ,4-dihydroquinoline-3- carboxamide;

6-Fluoro- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo-N-(pyridin-4-yl)- 1 ,4- dihydroquinoline-3-carboxamide; l-(6-(Hydroxyamino)-6-oxohexyl)-4-oxo-N-(thiazol-2-yl)-l,4-dihydroquinoline-3- carboxamide; 6-Fluoro- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo-N-phenyl- 1 ,4-dihydroquinoline-3- carboxamide;

N-(Benzo[d]thiazol-2-yl)-6-fluoro- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; l-(6-(Hydroxyamino)-6-oxohexyl)-6,7-dimethoxy-4-oxo-Ν-phenyl-l,4- dihydroquinoline-3-carboxamide;

N-(4-t-Butylphenyl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo- 1 ,4-dihydroquinoline-3- carboxamide; l-(6-(Hydroxyamino)-6-oxohexyl)-4-oxo-Ν-(3,^Ν4,5-trimethoxyphenyl)-l,4- dihydroquinoline-3-carboxamide; N-(3-Chloro-4-fluorophenyl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

1 -(6-(Hydroxyamino)-6-oxohexyl)-Ν-(4-isopropylphenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

N-(6-Ethoxybenzo[d]thiazol-2-yl)-l-(6-(hydroxyamino)-6-oxohexyl)-4-oxo-l,4- dihydroquinoline-3-carboxamide; 1 -(6-(Hydroxyamino)-6-oxohexyl)-N-(4-isopropylphenyl)-6,7-dimethoxy-4-oxo- 1 ,4- dihydroquinoline-3 -carboxamide ;

1 -(6-(Hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo- 1 ,4-dihydroquinoline-3- carboxylic acid; 1 -(6-(Hydroxyamino)-6-oxohexyl)-6-methoxy-N-( 1 -methyl-3 -phenyl- 1 H-pyrazol-5 - yl)-4-oxo- 1 ,4-dihydroquinoline-3 -carboxamide;

1 -(6-(Hydroxyamino)-6-oxohexyl)-N-( 1 -methyl-3 -phenyl- 1 H-pyrazol-5-yl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

N-(4-t-Butylphenyl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

1 -(6-(Hydroxyamino)-6-oxohexyl)-Ν-(4-isopropy lpheny l)-6-methoxy-4-oxo- 1,4- dihydroquinoline-3-carboxamide;

N-(2,4-Dimethylphenyl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo- 1 ,4- dihydroquinoline-3 -carboxamide ; 1 -(6-(Hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo-Ν-(3,4,5-trimethoxyphenyl)- 1 ,4- dihydroquinoline-3-carboxamide;

1 -(6-(Hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo-N-(4-(piperidin- 1 -yl)phenyl)- 1 ,4- dihydroquinoline-3 -carboxamide ;

1 -(6-(Hydroxyamino)-6-oxohexyl)-N-(4-methylbenzo[d]thiazol-2-yl)-4-oxo- 1 ,A- dihydroquinoline-3-carboxamide;

N-(Benzo[d]thiazol-2-yl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

N-(3-Chloro-4-fluorophenyl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; N-(4-Chlorophenyl)-l-(6-(hydroxyamino)-6-oxohexyl)-4-oxo-l,4-dihydroquinoline-3- carboxamide;

N-(Benzo[d]thiazol-6-yl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

N-(Benzo[c][l,2,5]thiadiazol-4-yl)-l-(6-(hydroxyamino)-6-oxohexyl)-6-methoxy-4- oxo- 1 ,4-dihydroquinoline-3-carboxamide; N-(4-Chlorophenyl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

N-(2,4-Dimethylphenyl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-6-methoxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 1 -(6-(Hydroxyamino)-6-oxohexyl)-6-methoxy-Ν-(4-(naphthalen- 1 -yl)thiazol-2-yl)-4- oxo-l,4-dihydroquinoline-3-carboxamide;

N-(Benzo[c] [ 1 ,2,5]thiadiazol-4-yl)- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

N-(4-t-Butylphenyl)-6-fluoro- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

1 -(6-(Hydroxyamino)-6-oxohexyl)-4-oxo-Ν-(4-/?-tolylthiazol-2-yl)- 1 ,4- dihydroquinoline-3-carboxamide;

1 -(4-(Hydroxyamino)-4-oxobuty l)-6-methoxy-N-(4-methoxyphenyl)-4-oxo- 1 ,4- d ihydroquinol ine-3 -carboxamide ; N-(4-Chlorophenyl)-6-fluoro- 1 -(6-(hydroxyamino)-6-oxohexyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

6-Fluoro- 1 -(6-(hydroxyamino)-6-oxohexyl)-Ν-(4-methoxyphenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

1 -(6-(2-Aminophenylamino)-6-oxohexyl)-4-oxo-N-phenyl- 1 ,4-dihydroquinoline-3- carboxamide;

1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(3-chloro-4-fluorophenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

1 -(6-(2-Aminophenylamino)-6-oxohexy l)-N-(4-fluorophenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-t-butylphenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-methoxyphenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-isopropylphenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; l-(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-isopropylphenyl)-6,7-dimethoxy-4-

OXO- 1 ,4-dihydroquinoline-3-carboxamide; l-(6-(2-Aminophenylamino)-6-oxohexyl)-6-methoxy-N-(4-methoxyphenyl)-4-oxo-

1 ,4-dihydroquinoline-3 -carboxamide; l-(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-isopropylphenyl)-6-methoxy-4-oxo- l,4-dihydroquinoline-3-carboxamide;

1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-/-butylphenyl)-6-methoxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(2,4-dimethylphenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; l-(6-(2-Aminophenylamino)-6-oxohexyl)-6-methoxy-4-oxo-N-(3,4,5- trimethoxyphenyl)- 1 ,4-dihydroquinoline-3-carboxamide;

1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(l -methyl-3-phenyl- 1 H-pyrazol-5-yl)-4- oxo- 1 ,4-dihydroquinoline-3-carboxamide; 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-6-methoxy-N-(l -methyl-3-phenyl- 1 H- pyrazol-5 -y l)-4-oxo- 1 ,4-dihydroquinoline-3 -carboxam ide ;

1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-chlorophenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; l-(6-(2-Aminophenylamino)-6-oxohexyl)-N-(3-chloro-4-fluoropheriyl)-6-methoxy-4- oxo- 1 ,4-dihydroquinoline-3-carboxamide; l-(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-methylbenzo[d]thiazol-2-yl)-4-oxo- l,4-dihydroquinoline-3-carboxamide;

1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(benzo[d]thiazol-6-yl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; l-(6-(2-Aminophenylamino)-6-oxohexyl)-N-(benzo[c][l,2,5]thiadiazol-4-yl)-6- methoxy-4-oxo- 1 ,4-dihydroquinoline-3-carboxamide; l-(6-(2-Aminophenylamino)-6-oxohexyl)-N-(benzo[c][l,

2,5]thiadiazol-4-yl)-4-oxo- l,4-dihydroquinoline-3-carboxamide;

1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-chlorophenyl)-6-methoxy-4-oxo- 1 ,A- dihydroquinoline-3-carboxamide; l-(6-(2-Aminophenylamino)-6-oxohexyl)-N-(2,4-dimethylphenyl)-6-methoxy-4-oxo- l,4-dihydroquinoline-3-carboxamide;

1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-cyclopentyl-4-oxo- 1 ,4-dihydroquinoline-

3-carboxamide; 1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(benzo[d]thiazol-2-yl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(4-chlorophenyl)-6-fluoro-4-oxo- 1 ,4- dihydroquinoline-3 -carboxamide ;

1 -(6-(2-Aminophenylamino)-6-oxohexyl)-6-fluoro-N-(4-methoxyphenyl)-4-oxo- 1 ,4- dihydroquinoline-3 -carboxamide ;

1 -(4-(2-Aminophenylamino)-4-oxobutyl)-6-methoxy-N-(4-methoxyphenyl)-4-oxo- 1,4- dihydroquinoline-3-carboxamide;

1 -(6-(2-Aminophenylamino)-6-oxohexyl)-N-(2-hydroxyphenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide; 1 -(4-(2-Aminophenylamino)-4-oxobutyl)-N-(benzo[d]thiazol-2-yl)-6-fluoro-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;

6-(3-(Benzo[d]oxazol-2-yl)-4-oxoquinolin-l(4H)-yl)-N-hydroxyhexanamide; and

N-(2-Aminophenyl)-6-(3-(benzo[d]oxazol-2-yl)-4-oxoquinolin-l(4H) - yl)hexanamide.

4. A compound of formula (Ib) for the preparation of compound of formula (I).

5. A process for the preparation of compound of formula (I) according to claim 1, comprising condensing the hydrolysis product of intermediate compound of formula (Ib) with R³NH₂, wherein all the groups W¹, W², W³, W⁴, X, Z and n are as defined earlier.

6. A process for the preparation of compound of formula (I) according to claim 1, comprising reacting intermediate compound of formula (Ib) with R³NH2, wherein all the groups W¹, W², W³, W⁴, X, Z and n are as defined earlier.

7. A pharmaceutical composition comprising a compound of formula (I), according to claim 1 or 3, as an active ingredient, along with a pharmaceutically acceptable carrier.

8. A method for inhibiting HDAC in a cell comprising treating the said cell with an effective amount of a compound according to claim 1 or 3.

9. A method of treatment of a disease or condition associated with HDAC, comprising administering to a subject suffering from the said disease or condition, a therapeutically effective amount of a compound according to claim 1 or claim 3.

10. A method of treatment of a proliferative condition or cancer, comprising administering to a subject suffering from the proliferative condition or cancer, a therapeutically effective amount of a compound according to claim 1 or 3.

11. A method of treatment of a proliferative condition or cancer, comprising administering to a subject suffering from the proliferative condition or cancer, a therapeutically effective amount of a compound according to claim 1 or 3, in the presence of other clinically relevant cytotoxic agents or non-cytotoxic agents.

12. A method of treatment of proliferative conditions or cancer by inhibiting tumor angiogenesis and the subsequent metastasis, comprising administering to a subject suffering from proliferative conditions, a therapeutically effective amount of a compound according to claim 1 or claim 3

13. A method of treatment of inflammatory disorders selected from rheumatoid arthritis, inflammatory bowel disease, granuloma and sepsis, comprising administering to a subject suffering from the inflammatory disorders, a therapeutically effective amount of a compound according to claim 1 or claim 3.

14. A method of treatment of neurodegenerative disorders selected from Huntington's disease and Alzheimer's disease, comprising administering to a subject suffering from the neurodegenerative disorders, a therapeutically effective amount of a compound according to claim 1 or claim 3.

15. A method for the treatment of cancer-induced bone pain (CIBP), comprising administering to a subject suffering from such a disorder, a therapeutically effective dose of compound according to claim 1 or claim 3.