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

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 deacety1ase (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 acety1ating 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 acety1ated hi stones 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 acety1ating status of the histone is governed by the balance activities of the histone acety1 transferase (HAT) and histone deacety1ase (HDAC).

The first isolation of histone deacety1ase 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 deacety1ase1 s (HDACs) are zinc hydrolases responsible for the deacety1ation of N-acety1 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 deacety1ases, 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 acety1ation 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, suberoy1anilide 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, Nail Cancer Inst,, 2000, 92, 1210-1216. More specifically WO 98/55449 and US 5369108 patents report alkanoy1 hydroxamates with HDAC inhibitory activity. Other compounds that are able to inhibit HDAC activity are Trichostatin A (TSA), PXD101, Tropoxin (TPX), Sodium butyrate (NaB), Sodium valproate (VPA), Cyclic hydroxamic acid containing peptides (CHAPs), Romidepsin, MGCD0103 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.t 2008, 57, 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 (CB1) 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).

W02004076386 discloses HDAC inhibitors of formula (C)

wherein, A is independently an unsubstituted or substituted bicyclic C9-10 heteroary1 group; Q is an acid leader group, and is independently an unsubstituted or substituted, saturated or unsaturated C1.7 alky1ene 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 the formula (I).

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

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 Heterocyclic compounds of the formula (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\ N, S, O or absent with the proviso that a minimum of three Wl, W2, W3 and W4 are always present;

Rx independently represents hydrogen, hydroxy, nitro, alkoxy, ary1oxy, heteroary1oxy, heteroalkoxy, halogen, -COORa, -C(0)Ra, -C(S)Ra, -C(0)NRaRb, -C(S)NRaRb, -NRaC(0)NRbRc, ~NRaC(S)NRbRc, -N(Ra)SORb, -N(Ra)S02Rb, -NRaC(0)0Rb, -NRaRb, -NRaC(0)Rb, - NRaC(S)Rb, -SONRaRb, S02NRaRb, ORa, ORaC(0)0Rb, -CiC(0)NRaRb, -OC(0)Ra, -OC(0)NRaRb, -RaNRbRc, -RaORb, -SRa, -SORa and -S02Ra, substituted or unsubstituted groups selected from alky1, alkeny1, alkyny1, cycloalky1, heterocycloalky1, ary1 and heteroary1, wherein Ra, Rb and Rc represent hydrogen, substituted or unsubstituted groups selected from alky1, alky1ene, ary1, ary1alky1, heteroary1, heteroary1alky1, heterocycloalky1, cycloalky1, and cy1coalkeny1; or Ra and Rb can be combined together to form a ring structures having 4-8 atoms;

X represents -CONR'OH, -CONR'R2, -CSNR'R2, -COOR1, -CHaNR'R2, substituted or unsubstituted groups selected from ary1, and heteroary1;

R1 and R2 independently represent hydrogen, substituted or unsubstituted groups selected from alky1, ary1, ary1alky1, heteroary1alky1, heteroary1, heterocycloalky1, cycloalky1, cy1coalkeny1;

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 alky1, ary1, heteroary1 or heterocycloalky1;

R3 represents -OR4, ortho substituted aniline, amino ary1 and amino heteroary1, which may be further substituted, wherein R4 represents hydrogen, optionally substituted groups selected from alky1, ary1, heterocycloalky1 and -COR5, wherein R5 represents optionally substituted groups selected from alky1, ary1, heteroary1, cycloalky1 and heterocycloalky1;

wherein n represents integer selected from 1-7;

when the groups Rx, 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 thioalky1, amino, hydrazino, formy1, alky1, haloalky1 group, alkoxy, haloalkoxy, ary1alkoxy , cycloalky1, cycloalky1oxy, ary1, heterocycloalky1, heteroary1, alky1amino, toly1, -COORa, -C(0)Ra, -C(S)Ra, -C(0)NRaRb, -C(S)NRaRb, -NRaC(0)NRbRc, -NRaC(S)NRbRc, -N(Ra)SORbs -N(Ra)S02Rb, -NRftC(0)0Rb, -NRaRb, -NRaC(0)Rb, -NRaC(S)Rb, -SONRaRb, -S02NRaRb, -ORfl, -0RaC(0)0Rb, -0C(0)NRaRb, -0C(0)Ra, -0C(0)NRftRb, -R'NrV, -RaORb,-SRa, -SORa and -S02Ra;

Detailed description

Novel quinolinone compounds of formula (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-Rx, N, S, O or absent with the proviso that minimum of three of W1, W2, W3 and W4 are always present;

Rx independently represents hydrogen, hydroxy, nitro, alkoxy, ary1oxy, heteroary1oxy, heteroalkoxy, halogen, -COOR*, -C(0)Ra, -C(S)Ra, -C(0)NRflRb, -C(S)NRaRb, -NRaC(0)NRbRc, -NRaC(S)NRbRcJ -N(Ra)SORb, -N(Ra)S02Rb, -NRaC(0)0Rb, -NRaRb, -NRaC(0)Rb, -NRaC(S)Rb, -SONRaRb, -S02NRaRb, -OR3, -0RaC(0)0Rb, -OC(0)NRilRb, 0C{0)R\ -0C(0)NRaRb, -RaNRbRc? R!1ORb, -SRa, -SORa and -S02Ra, substituted or unsubstituted groups selected from alky1, alkeny1, alkyny1, cycloalky1, heterocycloalky1, ary1 and heteroary1, wherein Ra, Rb and Rc represent hydrogen, substituted or unsubstituted groups selected from alky1, alky1ene, ary1, ary1alky1, heteroary1, heteroary1alky1, heterocycloalky1, cycloalky1, and cy1coalkeny1; or Ra and Rb can be combined together to form a ring structures having 4-8 atoms;

X represents -CONK1 OH, -CONR'R2, -CSNR'R2, -COOR1, -CHsNR'R2, or substituted or unsubstituted groups selected from ary1, and heteroary1;

R1 and R2 independently represent hydrogen, substituted or unsubstituted groups selected from alky1, ary1, ary1alky1, heteroary1alky1, heteroary1, heterocycloalky1, cycloalky1, cy1coalkeny1;

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 alky1, ary1, heteroary1 or heterocycloalky1;

R3 represents -OR4, art ho substituted aniline, amino ary1 and amino heteroary1, which may be further substituted, wherein R4 represents hydrogen, optionally substituted groups selected from alky1, ary1, heterocycloalky1 and -COR5, wherein R5 represents optionally substituted groups selected from alky1, ary1, heteroary1, cycloalky1 and heterocycloalky1;

wherein n represents integer selected from 1-7;

when the groups Rx, 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), thioalky1, amino, hydrazino, formy1, alky1, haloalky1 group; alkoxy, haloalkoxy, ary1alkoxy , cycloalky1, cycloalky1oxy, ary1, heterocycloalky1, heteroary1, alky1amino, toly1, -COORa, -C(0)Ra, -C(S)Rfl, -C(0)NRaRb -C(S)NRaRb, -NRaC(0)NRbRc, -NRaC(S)NRbRc, -N(Ra)SORb, -N(Ra)S02Rb, -NRaC(0)0Rb, -NRaRb, -NRaC(0)Rb, -NRaC(S)Rb, -SONRaRb, -S02NRaRb, -0Ra, -0RaC(0)0Rb, -0C(0)NRaRb, QC(0)Ra, -RaNRbRc, -RaORb,-SRa, -SORa and -S02Ra; 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 0 to 4 hetero atoms selected from Q, 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 pharmaceutical acceptable salts and compositions.
Pharmaceutically acceptable solvates may be hydrates or comprising of other solvents of crystallization such as alcohols.

The term "alky1" 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 alky1 groups include, without limitation, methy1, ethy1, n- propy1, isopropy1, buty1, isobuty1, t-buty1, penty1, hexy1, hepty1, octy1 and the like.

The term "alky1ene" 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 "alky1ene" as used herein include, but are not limited to, methy1ene, ethy1ene, n-propy1ene, n-buty1ene, and the like.

The term "ary1" refers to aromatic radicals having 6 to 14 carbon atoms, which may be optionally substituted by one or more substituents. Preferred ary1 groups include, without limitation, pheny1, naphthy1, tetrahydronapthy1, indany1, bipheny1 and the like.

The term "ary1alky1" refers to an ary1 group directly bonded to an alky1 group, which may be optionally substituted by one or more substituents. Preferred ary1alky1 groups include, without limitation, -CH2C6H5, -C2H4QH5 and the like.

Furthermore the term "heterocycly1" 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, 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 quatemized; and the ring radical may be partially or fully saturated. Preferred heterocycly1 groups include, without limitation, azetidiny1, acridiny1, benzodioxoly1, benzodioxany1, benzofurany1, carbazoly1, cinnoliny1, dioxolany1, indolizinyl, naphthyridiny1, perhydroazepiny1, phenaziny1, phenothiaziny1, phenoxaziny1, phthalaziny1, pyridy1, pteridiny1, puriny1, quinazoliny1, quinoxaliny1, quinoliny1, isoquinoliny1, tetrazoly1, imidazoly1, tetrahydroisoquinoliny1, 2- oxoazepiny1, azepiny1, pyrroly1, 4-piperidony1, piperony1, pyrrolidiny1, pyraziny1, pyrimidiny1, pyridaziny1, pyrazoly1, oxazoly1, oxazoliny1, triazoly1, indany1, isoxazoly1, isoxazolidiny1, thiazoly1, thiazoliny1, thiazolidiny1, thieny1, isothiazoly1, quinuclidiny1, isothiazolidiny1, indoly1, isoindoly1, indoliny1, isoindoliny1, octahydroindoly1, octahydroisoindoly1, decahydroisoquinoly1, benzimida2oly1, thiadiazoly1, benzopyrany1, benzothiazoly1, benzothiadiazoly1, benzooxadiazoly1, benzotriazoly1, benzothieny1, benzooxazoly1, oxadiazoly1, benzindazoly1, indazoly1, pheny1 piperidiny1, fury1, tetrahydrofury1, tetrahydropyrany1, piperaziny1, homopiperaziny1, piperidy1, piperidopiperidy1, morpholiny1, thiomorpholiny1, piperidony1, 2-oxopiperaziny1, 2-oxopiperidiny1, pyrrolidiny1, 2-oxopyrrolidiny1, oxazolidiny1, chromany1 and isochromany1. The term "heteroary1" refers to an aromatic heterocyclic ring radical as defined above. The heteroary1 ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of stable structure. These heteroary1 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 "heterocycloalky1" refers to a heterocyclic ring radical as defined above, The heterocycloalky1 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 "heteroary1alky1" refers to a heteroary1 group directly bonded to an alky1 group, which may be optionally substituted by one or more substituents. Preferred heteroary1alky! groups include, without limitation, -CHz-pyndiny1, -C2H4- fuiy1 and the like.

The term "cycloalkeny1" 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 cycloalkeny1 groups include, without limitation, cyclopropeny1, cyclopenteny1 and the like.

The term "cycloalky1" 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 cycloalky1 groups include, without limitation, cyclopropy1, cyclobuty1, cyclopenty1, cyclohexy1, cyclooctany1, perhydronaphthy1, adamanty1, noradamanty1 and norborny1 groups, bridged cyclic groups or spirobicyclic groups e,g spiro [4.4] non-2-y1 and the like.

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

The term "ary1oxy" refers to an ary1 group attached via an oxygen linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Preferred ary1oxy groups include, without limitation,-OPh -OCFkPh, - O-naphthy1 and the like.

An "ary1alkoxy group" (or ary1alky1oxy or aralkoxy) represents an ary1alky1 or aralky1 group that is attached to a compound via an oxygen on the alky1 portion of the ary1alky1. Preferred ary1alkoxy groups include, without limitation, -OCH^Ph, -OCH2- naphthy1.

The term "heteroary1oxy" refers to heteroary1 group attached via an oxygen linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Preferred heteroary1oxy groups include, without limitation, -O- pyridy1 -O-indoly1 and the like.

The term heteroalkoxy refers to a heteroary1alky1 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, - 0-CH2-Indoly1i-0-CH2-thiopheny1 and the like.

The term "alky1thio" refers to an alky1 group attached via a sulfur linkage to the rest of the molecule, which may be optionally substituted by one or more substituents, Preferred alky1thio groups include, without limitation, -SCH3, -SC2H5 and the like.

The term "alky1amino" refers to an alky1 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 alky1amino groups include, without limitation - NHCH3, -N(CH3)2, and the like.

The term "alkeny1" 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 alkeny1 groups include, without limitation, etheny1, 1-propeny1, 2-propeny1, iso-propeny1, 2-methy1-l-propeny1, 1-buteny1, 2-buteny1 and the like.

The term "alkyny1" refers to a straight or branched hydrocarby1 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 alkyny1 groups include, without limitation, ethyny1, propyny1, butyny1 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 and 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 acry1ate (e.g., polymethy1acry1ate), 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.

Pharmaceutical 1y 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'-diacety1ethy1enediamine, glucamine, triethy1amine, choline, dicyclohexy1amine, benzy1amine, trialky1amine, thiamine, guanidine, diethanolamine, a-pheny1ethy1amine, piperidine, morpholine, pyridine, hydroxyethy1pyrrolidine, hydroxy ethy1piper id ine, ammonium, substituted ammonium salts and the like. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, pheny1alanine, 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, tosy1ates, benzoates, salicy1ates, hydroxynaphthoates, benzene sulfonates, 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 deacety1ase" and "HDAC" are intended to refer to any one of a family of enzymes that remove acety1 groups from the e-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 HI, 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-10 and HDAC-I 1. The histone deacety1ase can also be derived from a protozoal or fungal source.

The term "histone deacety1ase inhibitor" or "inhibitor of histone deacety1ase" is used to identify a compound, which is capable of interacting with a histone deacety1ase and inhibiting its activity, more particularly its enzymatic activity. Inhibiting histone deacety1ase enzymatic activity means reducing the ability of a histone deacety1ase to remove an acety1 group from a histone. Preferably, such inhibition is specific, i.e. the histone deacety1ase inhibitor reduces the ability of histone deacety1ase to remove an acety1 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 either 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 G1 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 deacety1ase 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 deacety1ase protein is involved.

Deacety1ase 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. Opm., 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. 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 ah, (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-fluorouracil (5-FU), paclitaxel (PTX), oxaliplatin and irinotecan have been shown to have a synergistic anti-pro)iterative effect on cell lines, for example, in gastric cancer cell lines. (Zhang X. et ah, 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 methy1transferase, 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 ennanw inerapeuuc emuacy over uic Giucacy acnicvcu uy any ui uic agenus muuv; 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.

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-o\ohexy1]-4-oxo-N-pheny1-l,4-dihydroquinoline-3- carboxamide;

2) 7-Chloro-A-cyclopropyI-6-f!uoro-1 -[6-(hydroxyamino)-6-oxohexy1]-4-oxo-1,4- dihydroquinoline-3-carboxamide;

3) N-Benzy1-l-[6-(hydroxyamino)-6-oxohexy1]-4-oxo-l,4-dihydroquinoline-3- carboxamide;

4) N-(4-FluorophenyI)-1 -[6-(hydroxyamino)~6-oxohexy1]-4-oxo-1,4- dihydroquinoline-3-carboxamide;

5) vV-Adamanty1-1 -[6-(hydroxyamino)-6-oxohexy1]-4-oxo-l ,4-dihydroquinoline-3- carboxamide;

6) N-(2,4-Dimethoxybenzy1)-l-[6-(hydroxyamino)-6-oxohexy1]-4-oxo-l,4- dihydroquinoline-3-carboxamide;

7) 1 -[6-(Hydroxyamino)-6-oxohexy l]-A44-methoxybenzy1)-4-oxo-1,4- dihy droquinoline-3 -carboxamide;

8) 1 -[6-(Hydroxyamino)-6-oxohexy1]-N-(4-methoxypheny1)-4-oxo-l ,4- dihydroquinoIine-3-carboxamide;

9) l-[6-(Hydroxyamino)-6-oxohexy1]-4-oxo-A?-(thiophen-2-y1methy1)-l,4- dihydroquinoline-3-carboxamide;

10) A7-(4-Fluorobenzy1)-l-[6-(hydroxyamino)-6-oxohexy1]-4-oxo-l,4- d i hydroquino I ine-3-carboxamide;

11) 6-Fluoro-N-(4-fluoropheny1)-l-[6-(hydroxyamino)-6-oxohexy1]-4-oxo-l>4- dihydroquinoline-3-carboxamide;

12) 6-Fluoro-1 -[6-(hydroxyamino)-6-oxohexy1)-N-(4-methoxybenzy1)-] -4«oxo-1,4- dihydroquinoIine-3-carboxamide;

13) N-(4-Fluoropheny1)- l-[6-(hydroxyamino)-6-oxohexy1]-6-Methoxy-4-oxo-1,4-
dihydroquinoline-3-carboxamide;

14) N-(2,4-Dimethoxybenzy1)-l-[6-(hydroxyamino)-6-oxohexy1]-6-Methoxy-4-oxo- 1,4-dihydroquinoline-3-carboxamide;

15) 7-Bromo-jV-(2,4-dimethoxybenzy1)-'l-[6-(hydroxyamino)-6-oxohcxy1]-4-oxo-l,4- dihydroquinoline-3-carboxamide;

16) 7-Bromo-N-(4~fluoropheny1)-1 -[6-(hydroxyamino)-6-oxohexy1]-4-oxo-1,4- dihydroquinoIine-3-carboxamide;

17) N-(Benzo(d)thiazol-2-y1)-7-bromo-l-[6-(hydroxyamino)-6-oxohexy1]-4-oxo-l,4- dihydroquinoline-3-carboxamide;

18) 1 -[6-(Hydroxyamino)-6-oxohexy1]-6-Methoxy'A-(4-methoxypheny1)-4-oxo-1,4- dihydroquinoIine-3-carboxamide;

19) N-(2,4-Dimethoxypheny1)- l-[6-(hydroxyamino)-6-oxohexy1]-6-Methoxy-4-oxo- l,4-dihydroquinoline-3-carboxamide;

20) N-(2J4-Dimethoxypheny1)-6-flouro-l-[6-(hydroxyamino)'6-oxohexy1]-4'Oxo-l,4- dihydroquinoline-3-carboxamide;

21) 7-Bromo-N-(2,4-dimethoxypheny1)-l-(6-(hydroxyamino)-6-oxohexy1)-4-oxo- l,4-dihydroquinoline-3-carboxamide;

22) 1-(6-(Hydroxyamino)-6-oxohexy1)-6-methoxy-4-oxo-N-phenyI-1,4- dihydroquinoline-3-carboxamide;

23) N-(Benzo[d]thiazol-2-y1)-l-(6-(hydroxyamino)-6-oxohexy1)-4-oxo-l,4- dihydroquinoline-3-carboxatnide;

24) l-(6-(Hydroxyamino)-6-oxohexy1)-4-oxo-N-(pyridin-4-y1)-l)4-dihydroquinoHne' 3-carboxamide;

25) 6-Fluoro-l-(6-(hydroxyamino)-6-oxohexy1)-4-oxo-N-(pyridin-4-y1)-l,4- dihydroquinoline-3-carboxamide;

26) I-(6-(Hydroxyamino)-6-oxohexy1)-4-oxo-N-(thiazol-2-yI)-l,4-dihydroquinoIine- 3-carboxamide;

27) 6-Fluoro-1 -(6-(hydroxyamino)-6-oxohexy1)-4-oxo-N-pheny1-1,4- dihydroquinol ine-3-carboxamide;

28) N-(Bcnzo[d]thiazol-2-y1)-6-fluoro-1 -(6-(hydroxyamino)-6-oxohexyI)-4-oxo-1,4- dihydroquinoline-3 -carboxamide;

29) l-(6-(Hydroxyamino)-6-oxohexy1)-6,7-dimethoxy-4-oxo-N-pheny1-l ,4- dihydroquinol ine-3-carboxamide;

30) A7-(4-f-Buty1phcny1)- 1 -(6-(hydroxyamino)-6-oxohexy1)-4-oxo-1,4- dihydroquinoiine-3-carboxamide;

31) l-(6-(Hydroxyamino)-6-oxohexy1)-4-oxo-N-(3s4j5-trimethoxypheny1)-l,4- dihydroquinoline-3-carboxamide;

32) /¥-(3-Chloro-4-fluoropheny1)-1-(6-(hydroxyamino)-6-oxohexy1)-4-oxo-1,4- dihydroquinoIine-3-carboxamide;

33) 1 -(6-(Hydroxyamino)-6-oxohexy1)-N-(4-isopropy1pheny1)-4-oxo-1,4- dihydroquinollne-3-carboxamide;

34) .V-(6-Ethoxyben2o[d]thiazol-2-y1)-l-(6-(hydroxyamino)-6-oxohexy1)-4-oxo-l,4- d ihydroquino I ine-3-carboxamide;

35) l-(6-(Hydroxyamino)-6-oxohexy1)-N-(4-isopropy1pheny1)-6,7-dimethoxy-4-oxo- l,4-dihydroquinoline-3-carboxamide;

36) l-(6-(Hydroxyamino)-6-oxohexy1)-6-methoxy-4-oxo-l,4-dihydroquinoline-3- carboxy1ic acid;

37) 1-(6-(Hydroxyamino)-6-oxohexyI)-6-methoxy-N-(l -methy 1-3-pheny1- 1H-pyrazol- 5 –y1)-4-oxo-1,4-dihydroquinol ine-3 -carboxamide;

38) 1 -(6-(Hydroxyamino)-6-oxohexy1)-N-( 1 -methy1-3-pheny U1 H-pyrazol-5-y1)-4- oxo-l,4-dihydroquinoline-3-carboxamide;

39) A-(4-t-Buty1phenyI)-1 -(6-(hydroxyamino)-6-oxohexy1)-6-methoxy-4-oxo-1,4- dihydroquinoline-3-carboxamide;

40) 1 -(6-(Hydroxyamino)-6-oxohexy l)-N-(4-isopropy lpheny1)-6-methoxy-4-oxo-1,4- dihydroquinol ine-3-carboxamide;

41) N(2,4-Dimethy1pheny1)-l-(6'(hydroxyamino)-6-oxohexy1)-4-oxo-l,4- dihydroquinoline-3-carboxamide;

42) l-(6-(Hydroxyamino)-6-oxohexy1)-6-methoxy-4-oxo-N-(3,4,5-trimethoxypheny1)- l,4-dihydroquinoline-3-carboxamide;

43) 1 -(6'(Hydroxyamino)-6-oxohexy1)-6-methoxy'4-oxo-N-(4-(piperidin-l – y1)pheny1)-l,4-dihydroquino I ine-3-carboxamide;

44) l-(6-(Hydroxyamino)-6-oxohexvl)-N-(4-mcthyJbenzo[d]thia/ol-2-y1)-4-oxo-l,4- dihydroquinoline-3-carboxamide;

45) W-(Benzo[d]thiazoI-2-y1)-1 <6-(hydroxyamino)-6-oxohexy l)-6-methoxy-4-oxo- l,4-dihydroquinoiine-3-carboxamide;

46) N-(3-Chloro-4-fluorophenyI)-1 -(6-(hydroxyamino)-6-oxohexy1)-6-methoxy-4- oxo-l,4-dihydroquinoHne-3-carboxamide;

47) N-(4-C,hloropheny1)-1 -(6-(hydroxyamino)-6-oxohexy1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

48) N-(Bcnzo[djthiazol-6-y1)-1 -(6'(hydroxyamino)-6-oxohexy1)-4-oxo-l,4- dihydroquinol ine-3-carboxamide;

49) N-(Benzo[c][l ,2,5]thiadiazol-4-y1)-l-(6-(hydroxyamino)-6-oxohexy1)-6-methoxy- 4-oxo-l,4-dihydroquinoline-3-carboxamide;

50) N-(4-Chloropheny1)-l -(6-(hydroxyamino)-6-oxohexy1)-6-methoxy-4-oxo-1,4- dihydroquinol ine-3-carboxamide;

51) N(2,4-Dimethy1pheny1)-l-(6-(hydroxyamino)-6-oxohexyJ)-6-methoxy-4-oxo-lj4- d ihydroqu i nol ine-3-carboxamide;

52) 1 -(6-(Hydroxyamino)-6-oxohexy1)-6-methoxy-N-(4-(naphthalen- l-y1)thiazol-2- y1)-4-oxo-l,4-dihydroquinoline-3-carboxamide;

53) N-(Benzo[c][ 1,2,5]thiadiazol-4-yI)-1 -(6-(hydroxyamino)-6-oxohexy i)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

54) .Y-(4-/-Buty1pheny1)-6-tluoro-l-(6-(hydroxyamino)-6-oxohexy1)-4-oxo-l ,4- dihydroquinoUne-3-carboxamide;

55) l-(6-(Hydroxyamino)-6-oxohexy1)-4-oxo-N-(4-p-toly1thiazol'2-y1)-lj4- dihydroquinoline-3-carboxamide;

56) l-(4-(Hydroxyamino)'4-oxobuty1)-6-methoxy-N-(4'methoxypheny1)-4-oxo-l,4- dihydroquinoline-3-carboxamide;

57) N-(4-Chloropheny l)-6-fluoro-1 -(6-(hydroxyamino)-6-oxohexy1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

58) 6-Fluoro-I -(6-(hydroxyamino)-6-oxohexy1)-N-(4-methoxypheny1)-4-oxo-l ,4- d ihydroqu ino Iine-3 -carboxamide;

59) 1-(6-(2-Aminopheny1ammo)-6-oxohexy1)-4-oxo-N-pheny 1-1,4-dihydroquinoline-3- carboxamide;

60) 1 -(6'(2-Aminopheny1amino)-6-oxohexy1)-AT-(3-chloro-4-fluoropheny1)-4-oxo-l ,4- dihydroquinoline-3-carboxamide;

61) 1 -(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(4-fluoropheny I>4-oxo-1,4- dihydroquinoline-3-carboxamide;

62) l-(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(4-f-buty1pheny1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

63) l-(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(4-methoxypheny1)-4-oxo-l,4- dihydroquinoline-3 -carboxamide;

64) l-(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(4-isopropy1pheny1)-4-oxo-lJ4- dihydroquinoline-3-carboxamide;

65) l-(6-(2-Aminopheny1amino)-6'Oxohexy1)-N-(4-isopropy1pheny1)-6)7-dimethoxy-
4- oxo-l,4-dihydroquinoline-3-carboxamide;

66) l-(6-(2-Aminopheny1ammo)-6-oxohexy1)-6-methoxy-N-(4-methoxypheny1)-4- oxo-l,4-dihydroqumoline-3-carboxamide;

67) l-(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(4-isopropy1pheny1)-6-methoxy-4- oxo-1-dihydroquinoline-S -carboxamide;

68) l-(6-(2-Aminopheny1amino)-6-oxohexy1)-A''-(4-/-buty1pheny1)-6-methoxy-4-oxo- 1,4-d ihydroqu inol ine-3-carboxamide;

69) l-(6-(2-Aminopheny1amino)'6-oxohexyI)-N-(2(4-dimethy1pheny1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

70) l-(6-(2-Aminopheny1amino)-6-oxohexy1)-6-methoxy-4-oxo-N-(3,4,5- trimethoxypheny1)-l,4-dihydroquinoline-3-carboxamide;

71) 1-(6-(2-Aminopheny1amino)-6-oxohexy l)-N-( 1 -methy 1-3 -pheny1-1 #-pyrazol-5- y l)-4-oxo-1,4-dihydroquinol ine-3 -carboxam ide;

72) l-(6-(2-Aminopheny1amino)-6-oxohcxy1)-6-metlioxy-N-(l-methy1-3-pheny1-1//- pyrazol-5-y1)-4-oxo-I,4-dihydroquinoIine-3-carboxamide;

73) 1 -(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(4-chloropheny1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

74) l-(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(3-chloro-4-fluoropheny1)~6- methoxy-4-oxo-l,4-dihydroquinoline-3-carboxamide;

75) l-(6-(2-Aminopheny1amuio)-6-oxohexy1)-N-(4-methy1benzo[d]thiazoK2-y1)-4- oxo-l,4-dihydroquinoline-3-carboxamide;

76) 1 -(6-(2-Aminopheny1am ino)-6-oxohexy1)-N-(benzo[d]thiazoJ -6-y1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

77) l-(6-(2-Aminopheny1amino)-6-oxohexyJ)-N-(benzo[c][l,2,5]thiadiazol-4-y1)-6- methoxy-4-oxo-l,4-dihydroquinoIine-3-carboxamide;

78) l-(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(benzo[c][l P2,5]thiadiazol-4-yI)-4- oxo-l,4-dihydroquinoline-3-carboxamide;

79) l'(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(4-chloropheny1)-6-methoxy-4-oxo- 1,4-dihydroquinoline-3 -carboxam ide;

80) l-(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(2,4-dimethyIpheny1)-6-methoxy-4- oxo-1,4-dihydroquinoline-3-carboxamide;

81) 1 -(6-(2-Aminopheny1amino)-6-oxohexy1)-N-cyclopenty1-4-oxo-l ,4- dihydroquinoline-3-carboxamide;

82) 1 -(6-(2-AminophenyJamino)-6-oxohexy1)-N-(benzo[d]thiazol-2-y1)-4-oxo-1,4- dihydroquinoIine-3-carboxamide;

83) 1 -(6-(2-Aminopheny1amino)-6-oxohexyI)-N-(4-chlorophenyI)-6-fluoro-4-oxo-1,4- dihydroquinoline-3-carboxamide;

84) l-(6-(2-Aminopheny1amino)-6-oxohexy1)-6-fluoro-N-(4-methoxypheny1)-4-oxo- l,4-dihydroquinoline-3-carboxamide;

85) l-(4-(2-Aminopheny1amino)-4-oxobuty1)-6-methoxy-N-(4-methoxypheny1)-4- oxo-1,4-dihydroquinoline-3-carboxamide;

86) 1 -(6-(2-Aminopheny lamino)-6-oxohexy l)-N-(2-hydroxypheny1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

87) l-(4-(2-Aminopheny1amino)-4-oxobuty1)-N-(benzo[d]thiazol-2-y1)-6-fluoro-4- oxo-l,4-dihydroquinoline-3-carboxamide;

88) 6-(3-(Benzo[d]oxazol-2-y1)-4-oxoquinolin-1(4H)-yI)-N-hydroxyhexanamide; and

89) N-(2-Aminopheny1)-6-(3-(benzo[d]oxazoI-2-y1)-4-oxoquinoIin-l(4H)-y1) hexanamide.

There is also provided a process as shown in the following Scheme-1, 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-alky1ation of compound of formula (la) with the corresponding haloalky1esters in the presence of a base to give compound of formula (lb).

Step 2: Hydrolyzing the compound of formula (lb) 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 (lb) with NH2R3 and an inorganic base to give the compound of formula (I), wherein Rx, R1, R2, R3, X, W1, W2, W3, W4and 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-dimethy1aminopropy1)-3-ethy1carbodiimide.hydrochloride), Py-BOP [Benzotriazole-1 –y1-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, include triethy1amine, diisopropy1ethy1amine 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-oxohexy1]-4-oxo-N-pheny1-l,4- dihydro quinoline-3-carboxamide

Step-I: Preparation of methy1 6-(4-oxo-3-pheny1carbamoy1)quinolin-l-(4H)~y1) bexanoate

To a mixture of 4-oxo-N-pheny1-l,4-dihydroquinoline-3-carboxamide (0.5 g, 1,79 mmol) and anhydrous K2C03 (0.744 g, 5.39 mmol) in DMF (4 mL), methy1 6- bromohexanoate 0.75 mL (3.59 mmol) was added and heated under microwave at 125 °C for 20 minutes. The reaction mixture was poured into ice-cold water (10 mL) and extracted with ethy1 acetate (25 mL). The organic layer was washed with water, brine solution (each 10 mL). The organic layer was dried over NazSO,* and concentrated to afford the crude compound. The crude product was purified by column chromatography using 20% ethy1 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-oxohexy1]-4-oxo-N-pheny1-l,4- dihydro quinoline-3-carboxamide

Hydroxy1amine 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 °C. The resulting white precipitate was filtered and the filtrate was immediately added to a round bottom flask containing methy1 6-(4-oxo-3-pheny1carbamoy1)quinolin-l- (4H)-y1) 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 °C for 2 hours. The resulting solid was filtered to afford the title compound as colourless solid (0.080 g, 26.66 % yield). JH NMR (DMSO-d6) 6 (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 (1H, t, N-H), 7.35-7.39 (2H, t, N-H), 7.59-7.62 (1H, t, N-H), 7.73- 7,75 (2H, d, N-H), 7.88-7.98 (2H, m, N-H), 8.42-8.44 (IH, d, N-H), 8.68 (1H, s, - OH), 9.01 (1H, s, CH), 10.34 (1H, s, -NH), 12.44 (1H, s, -NH). MS m/z: 394.1 (MVl).
The following compounds were prepared according to the procedure given in Example 1


Example 59: Synthesis of l-(6-(2-aminupheny1amino)-6-oxohexy1)-4-oxo-N- pbeny1-l,4-dihydro quino]ine-3carboxamide

Step-I: Preparation of 6-(4-oxo-3-pbeny1carbamoy1)quinoIin-l-(4H)-y1) hexanoic acid

To a solution of methy1 6-(4-oxo-3-pheny1carbamoyI)quinolin-l-(4H)-y1) 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 °C 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 HC1 and allowed to stand at 4 °C 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-aminopheny1amino)-6-oxohexy1)-4-oxo-N-pheny1- l,4-dihydroquinoline-3carboxamide

To a solution of 6-(4-oxo-3-pheny1carbamoy1)quinolin-l-(4H)-y1) hexanoic acid (0.40 g, 1.2 mmol) in DMF (dimethy1 formamide) (5 mL) was added EDCI (l-(3- dimethy1aminopropy1)-3-ethy1carbodiimide hydrochloride) (0.49 g, 2.5 mmol), HOBt (N-hydroxybenzotriazole) (0.07 g, 0.5 mmol), o-pheny1enediamine (0,27 g, 2.5 mmol), followed by triethy1amine (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 ethy1 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 Na2SC>4, concentrated to give the crude compound. The crude yellow colored compound was triturated with diethy1 ether (20 mL) to afford the pure title compound as a colourless solid (0.250 g, 50.51% yield).1!! NMR (DMSO-d6) 5 (ppm): 1.39-1.41 (2H, m, -CH2), 1.63-1.66 (2H, m, -CH2), IMAM (2H, m, -CH2), 2.29-2.33 (2H, t, -CH2), 4.53-4.57 (2H, t, -CH2)t 4,79 (2H, s, -NH2), 6.49-6.53 (1H, m, N-H), 6.69-6.71 (1H, t, N-H), 6.86-6.89 (1H, m, N-H), 7.09-7.11 (1H, d, N-H), 7.36-7.39 (2H, t, N-H), 7.58-7.61 (1H, t, N-H), 7.73-7.75 (2H, m, N-H), 7.92-7.98 (2H, m, N-H), 7.58-7,61 (1H, t, N-H), 8.43-8.45 (1H, d, N-H), 9.03 (1H, s, =CH), 9.08 (1H, s, -NH), 12.44 (1H, s, -NH). MS m/z: 469.2 (M++I). The following compounds were prepared according to the procedure given in


Example 88: Synthesis of 6-(3-(benzo[d]oxazol-2-y1)-4-oxoquinolin-l(4H)-y1)-N- hydroxyhexanamide

Step-I: Preparation of 3-(benzo[d]oxazol-2-y1)quinolin-4(lH)-one

A mixture of 4-oxo-l,4-dihydroquinoline-3-carboxy1ic acid ( 0.2g, 1.05 mmol), o-aminophenol (0.138g, 1.3mmol) and polyphosphoric acid (5mL) were heated at 160°C for 4hrs. After cooling, water was added followed by the addition of 50% 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 methy1 6-(3-(benzo[d]oxazol-2-y1)-4-oxoquinolin-l(4H)- y1)hexanoate

To a mixture of 3-(benzo[d]oxazol-2-y1)quinolin-4(lH)-one (0.05 g, 1.9 mmol) and anhydrous K2C03 (0.078 g, 5.7 mmol) in DMF (5 mL), methy1 6- bromohexanoate (0.079g, 3.8 mmol) was added and heated under microwave at 125 °C for 20 minutes. The reaction mixture was poured into ice-cold water (10 mL) and extracted with ethy1 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% ethy1 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-y1)-4-oxoquinolin-l(4H>y1)-N- hydroxyhexanamide

Hydroxy1amine 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 °C. The resulting white precipitate was filtered and the filtrate was immediately taken in a round bottom flask containing methy1 6-(3-(benzo[d]oxazol-2-y1)-4-oxoquinolin~ l(4H)-y1)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 °C for 2 hours. The resulting solid was filtered to afford the title compound as colourless solid (0.080 g, 28.57 % yield.). 'H NMR (DMSO-d6) (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, N-H), 7.52-7,55 (1H, t, N-H), 7.73-7.76 (2H, m, N-H), 7.81-7.89 (2H, m, N-H), 8.34-8.36 (1H, d, N-H), 8.80 (1H, s, -OH), 9.01 (1H, s, =CH), 10,34 (1H, s, -NH). MS m/z: 392.1 (M"+l).

Example 89: Synthesis of N-(2-aminopheny1)-6-(3-(benzo[d]oxazol-2-y1)-4- oxoquinolin-l(4H)-y1)hexanamide

Step-I; Preparation of 6-(3-(benzo[d]oxazol-2-y1)-4-oxoquinolin-l(4H)- y1)hexanoic acid

To a solution of methy1 6-(3-(benzo[d]oxazol-2-yI)-4-oxoquinolin-l(4H)- y1)hexanoate (0.50 g, 1,28 mmol) (Step-Il 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 °C for 4 hours. The reaction mixture was diluted with water (100 mL) and acidified (pH 2) with dilute aqueous HC1 and allowed to stand at 4 °C 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 N-(2-aminopheny1)-6-(3-(benzo[d]oxazol-2-y1)-4- oxoquinolin-l(4H)-y1)hexanamide

To a solution of 6-(3-(benzo[d]oxazol-2-y1)-4-oxoquinolin-l(4H)-y1)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-pheny1enediamine (0,27 g, 2.5 mmol), followed by triethy1amine (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 ethy1 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 Na2SO4, concentrated to give the crude compound. The crude yellow colored compound was triturated with diethy1 ether (20 mL) to afford the pure title compound as a colorless solid (0.05 g, 10% yield). lH NMR (DMSO-d6) 5 (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 (1H, t, N-H), 6.68-6.70 (1H, d, N-H), 6.85-6,87 (IH, t, N- H), 7.09-7.11 (IH, d, N-H), 7.37-7.39 (2H, m, N-H), 7.52-7.55 (1H, t, N-H), 7.73- 7.75 (2H, m, N-H), 7.81-7.85 (1H, t, N-H), 7.89-7.91 (1H, d, N-H), 8.35-8.37 (1H, d, N-H), 9.04 (1H, s, CH), 9.07 (1H, s, -NH). MS m/z; 485.2 (M++I).

Anti-cancer experimental methods

Anti-cancer screen:

Experimental drugs were screened for anti-cancer activity in three cell lines using five concentrations for each compound. The cell lines - HCT 116 (colon), NC1H460 (lung) and U251 (glioma) were maintained in DMEM (Dulbecco's Modified Eagle's Medium) containing 10% fetal bovine serum, 96-well microtiter plates are inoculated with cells in 100 mL of cell suspension (5 x 104 cells/mL) for 24 hours at 37 °C, 5% C02, 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 (To)

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 and serial dilutions were carried out in complete growth medium at 2x strength such that 100 xL added to wells gave final concentrations (0.01, 0.1, 1, 10 and 100 nM) 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 L of 3-(4,5-dimethy1-2- thiazoly1)-2,5-dipheny1-2H-tetrazolium (MTT) solution per well was added to the 'To' plate and incubated for 3 hours at 37 °C in a CG2 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 DMSO per well. Plates were agitated to ensure dissolution of the formazan crystals in DMSO and absorbance was read at 570 nm (A$70).

Calculation of GIso, TGI and LCS0:

Percent growth (PG) is calculated relative to the control and zero measurement wells (To) as follows:

PG = (A570test - A570T0) / (A570control - A570T0) x 100 (If A570 test > A570T0)

PG - (A57otest - A570T0) / (A570T0) x 100 (If A570 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 Deacety1ase (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 acety1ated lysine side chain, is incubated with a sample containing HDAC activity (Mouse Liver Extract). Deacety1ation 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 mL. Mouse liver enzyme (10 mg/ml) was diluted 1: 6 with HDAC buffer. Enzyme cocktail was made of 10 mL of diluted enzyme and 30 mL of HDAC buffer. 40 mL of enzyme cocktail followed by 10 mL of test compound (1 mM and 10 mM) or buffer (control) was added to each well. The plate was pre-incubated at 37 °C for 5 minutes. The HDAC reaction was started by adding 50 mL of HDAC substrate Boc-Lys (Ac)- AMC (Bachem AG, Switzerland). The plate was incubated at 37 °C for 30 minutes. The reaction was stopped by adding 100 mL of Trypsin stop solution and incubating at 37 °C for 15-30 minutes. Measuring the fluorescence at excitation wavelength of 360mn 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 10μM. (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 HDAC1 enzyme activity

Benzamides are known to have potential HDAC class I specificity, active compounds of formula (I) in this series were tested for HDAC1 inhibitory activity. The assay was carried out, as previously described using recombinant HDAC1 enzyme (BIOMOL, USA) and following manufacturer's instructions. The results shown in table 2 indicate that these compounds inhibit HDAC1 enzyme, showed HDAC isoform specific activity and compared with standard compound MGCD0103.

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 pM), 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., Use of in vitro human metabolism studies in drug development. An industrial perspective. 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


We Claim:

1. A compound of formula (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-Rx, N, S, 0 or absent with the proviso that a minimum of three of W1, W2, W3 and W4 are always present;

Rx independently represents hydrogen, hydroxy, nitro, alkoxy, ary1oxy, heteroary1oxy, heteroalkoxy, halogen, -COORfl, -C(0)Ra, -C(S)Ra, -C(0)NRaRb, -C(S)NRaRb, -NRaC(0)NRbRc, -NRaC(S)NRbRc, -N(Ra)SORb, -N(Ra)S02Rb, -NRaC(0)ORb, -NRaRb, -NRaC(0)Rb, -NRaC(S)Rb, -SONRaRb, ~S02NRaRb, -ORa, -ORaC(0)ORb, -OC(0)NRaRb, -OC(0)Ra, -OC(0)NRaRb, -RaNRbRc, -RaORb, -SRa, -SORa or -S02Ra, substituted or unsubstituted groups selected from alky1, alkeny1, alkyny1, cycloalky1, heterocycloalky1, ary1 or heteroary1, wherein Ra, Rb and Rc represent hydrogen, substituted or unsubstituted groups selected from alky1, alky1ene, ary1, ary1alky1> heteroary1, heteroary1 alky1, heterocycloalky1, cycloalky1 and cy1coalkeny1; or Ra and Rb can be combined together to form a ring structures having 4-8 atoms;

X represents -CONR]OH, -CONR^2, -CSNRlR2, -COOR1, -CH2NR1R2, substituted or unsubstituted groups selected from ary1 or heteroary1; wherein: R1 and R independently represent hydrogen, substituted or unsubstituted groups selected from alky1, ary1, ary1alky1, heteroary1alky1, heteroary1, heterocycloalky1, cycloalky1 or cy1coalkeny1; 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 alky1, ary1, heteroary1 or heterocycloalky1;

R3 represents -OR4, ortho substituted aniline, amino ary1 and amino heteroary1, which may be further substituted, wherein R4 represents hydrogen,

optionally substituted groups selected from alky1, ary1, heterocycloalky1 and -COR5, wherein R5 represents optionally substituted groups selected from alky1, ary1, heteroary1, cycloalky1 and heterocycloalky1;

n represents an integer selected from 1-7;

when the groups Rx, R1, R2, R3, R4 and R3 are substituted, the substituents are one or more and are selected from halogens, hydroxy, nitro, cyano, azido, nitroso, oxo (O), thioxo (=S), thioalky1, amino, hydrazino, formy1, alky1, haloalky1 group, alkoxy, haloalkoxy, ary1alkoxy, cycloalky1, cycloalky1oxy, ary1, heterocycloalky1, heteroary1, alky1amino, toly1, -COORa, -C(0)Ra, -C(S)Ra, -C(0)NRaRb, -C(S)NRaRb, -NRaC(0)NRbRc, -NRaC(S)NRbRc, -N(Ra)SORb, -N(RR)S02Rb, -NRaC(0)ORb, -NRaRb, -NRaC(0)Rb, -NRaC(S)Rb, -SONRaRb, -S02NRaRb, -0Ra, -ORaC(0)ORb, -OC(0)NRaRb, -OC(0)Ra, -RaNRbRc, RaORb, -SRa, -SORa and -S02Ra; 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-ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or t-butoxy; when ary1oxy group is present, the ary1oxy group is selected from phenoxy or naphthy1oxy; when halogen is present, the halogen is fluorine, chlorine, bromine or iodine; when alky1 group is present, the alky1 group is methy1, ethy1, n-propy1, isopropy1, buty1, isobuty1, /-buty1, penty1, hexy1, hepty1 or octy1; when alkeny1 group is present, the alkeny1 group is etheny1, 1-propeny1, 2-propeny1, iso-propeny1, 2-methy1- 1-propeny1, 1-buteny1 or 2-buteny1; when the alkyny1 group is present, the alkyny1 group is ethyny1, propyny1 or butyny1; when cycloalky1 group is present, the cycloalky1 group is cyclopropy1, cyclobuty1, cyclopenty1, cyclohexy1, cycloocty1, cyclohepty1, perhydronaphthy1, adamanty1, bridged cyclic groups or spirobicyclic groups; when cycloalkeny1 group is present, the cycloalkeny1 group is selected from cyclopenteny1 and cyclohexeny1; when heterocycloalky1 or heteroary1 group is present, the heterocycloalky1 or heteroary1 group is a heterocycly1 selected from azetidiny1, acridiny1, benzodioxoly1, benzodioxany1, benzofurany1, carbazoly1, cinnoliny1, dioxolany1, indoliziny1, naphthyridiny1, perhydroazepiny1, phenaziny1, phenothiaziny1, phenoxaziny1, phthalaziny1, pyridy1, pteridiny1, puriny1, quinazoliny1, quinoxaliny1, quinoliny1, isoquinoliny1, tetrazoly1, imidazoly1, tetrahydroisoquinoliny1, 2-oxoazepiny1, azepiny1, pyrroly1, piperony1, pyrrolidiny1, pyraziny1, pyrimidiny1, pyridaziny1, pyrazoly1, oxazoly1, oxazoliny1, triazoly1, indany1, isoxazoly1, isoxazolidiny1, thiazoly1, thiazoliny1, thiazolidiny1, thieny1, isothiazoly1, quinuclidiny1, isothiazolidiny1, indoly1, isoindoly1, indoliny1, isoindoliny1, octahydroindoly1, octahydroisoindoly1, decahydroisoquinoly1, benzimidazoly1, thiadiazoly1, benzopyrany1, benzothiazoly1, benzothiadiazoly1, benzoxadiazoly1, benzotriazoly1, benzothieny1, benzoxazoly1, oxadiazoly1, benzindazoly1, indazoly1, pheny1 piperidiny1, fury1, tetrahydrofury1, tetrahydropyrany1, piperaziny1, homopiperaziny1, piperidy1, piperidopiperidy1, morpholiny1, thiomorpholiny1, piperidony1, 2-oxopiperaziny1, 2-oxopiperidiny1, pyrrolidiny1, 2-oxopyrrolidiny1, oxazolidiny1, chromany1 and isochromany1; when ary1 group is present, the ary1 group is pheny1, naphthy1, anthraceny1, indany1 or bipheny1; when alky1ene group is present, the alky1ene group is methy1ene, ethy1ene, propy1ene or buty1ene; when hydroxyalky1 group is present, the hydroxyalky1 group is hydroxymethy1 or hydroxyethy1; when haloalky1 group is present, the haloalky1 group is trifluoromethy1, tribromomethy1 or trichloromethy1; and when haloalkoxy group is present, the haloalkoxy group is selected from chloromethoxy, chloroethoxy, trifluoromethoxy, trifluoroethoxy or trichloromethoxy.

3. The compound according to claim 1 selected from the group consisting of:

l-[6-(Hydroxyamino)-6-oxohexy1]-4-oxo-N-pheny1-l(4-dihydroquinoline-3- carboxamide;

7-Chloro-N-cyclopropy1-6-fluoro-1 -[6-(hydroxyamino)-6-oxohexy1]-4-oxo-1,4- dihydroquinoline-3-carboxamide;

N-Benzy]-l-[6-(hydroxyarnino)-6-oxohexy1]-4-oxo-l,4-dihydroquinoline-3- carboxamide;

N-(4-Fluoropheny1)-1 -[6-(hydroxyamino)-6-oxohexy)]-4-oxo-l,4-dihydroquinoline-3- carboxamide;

N-Adamanty1-l-[6-(hydroxyamino)-6-oxohexy!]-4-oxo-l,4-dihydroquinoline-3- carboxamide;

N-(2,4-Dimethoxybenzy1)-l-[6-(hydroxyamino)-6-oxohexy1]-4-oxo-l,4- dihydroquinoIine-3-carboxamide;

l-[6-(Hydroxyamino)-6-oxohexy1]-N-(4-methoxybenzy1)-4-oxo-l,4- dihydroquinoline-3-carboxamide;

1 -[6-(Hydroxyamino)-6-oxohexy1]-N-(4-methoxypheny1)-4-oxo-l ,4- dihydroquinoline-3-carboxamide;

l-[6-(Hydroxyamino)-6-oxohexy1]-4-oxo-(thiophen-2-y1methy1)-l,4- dihydroquinoline-3-carboxamide;

N-(4-Fluorobenzy1)-l-[6-(hydroxyamino)-6-oxohexy1]-4-oxo-1,4-dihydroquinoline-3- carboxamide;

6-Fluoro-N-(4-fluoropheny1)-l-[6-(hydroxyamino)-6-oxohexy1]-4-oxo-l,4- dihydroquinoline-3-carboxamide;

6- Fluoro-1 -[6-(hydroxyamino)-6-oxohexy1)-N-(4-methoxybenzy I)-]-4-oxo-1,4- dihydroquinoline-3-carboxamide;

N-Fluoropheny1)-l-[6-(hydfoxyaminod-oxohexy1]-6-methoxy-4-oxo-l- dihydroquinoline-3-carboxamide;

N-(2,4-Dimethoxybenzy1)-l-[6-(hydroxyamino)-6-oxohexy1]-6'Methoxy-4-oxo-lJ4- dihydroquinoline-3-carboxamide;

7- Bromo-N-(2,4-dimethoxybenzy1)-l-[6-(hydroxyamino)-6-oxohexy1]-4-oxo-l,4- dihydroquinoline-3-carboxamide;

7-Bromo-A-(4-fluoropheny1)-l-[6-(hydroxyamino)-6-oxohexy1]-4-oxo-l,4- dihydroquinoline-3-carboxamidc;

N(Benzo(d)thiazoI-2-y l)-7-bromo-1 -[6-(hydroxyamino)-6-oxohexy1]-4-oxo-1,4- dihydroquinoline-3-carboxamide;

1 -[6-(Hydroxyamino)-6-oxohexy1]-6-methoxy-N-(4-methoxypheny1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

N-(2,4-Di methoxy pheny1)-l-[6-(hydroxyam ino)-6-oxohexy1]-6-methoxy-4-oxo-1,4- dihydroquinoline-3-carboxamlde;

N-(2,4-Dimethoxypheny1)-6-flouro-1 -[6-(hydroxyamino)-6-oxohexy1]-4-oxo-1,4- dihydroquinoline-3-carboxamide;

7-Bromo-N-(2,4-dimethoxypheny1)-1 -(6-(hydroxyamino)-6-oxohexy1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

1 -(6-(Hydroxyamino)-6-oxohexy1)-6-methoxy-4-oxo-N-pheny1-1,4-dihydroquinoline- 3-carboxamide;

N-(Benzo[d]thiazol-2-y1)-1 -(6-(hydroxyamino)-6-oxohexy1)-4-oxo-1,4- dihydroquinoIine-3-carboxamide;

l-(6-(Hydroxyamino)-6-oxohexy1)-4-oxo-N-(pyridin-4-y1)-l,4-dihydroquinoline-3- carboxamide;

6-Fluoro-1 -(6-(hydroxyamino)-6-oxohexy1)-4-oxo-N-(pyridin-4-y1)-1,4- dihydroquinoline-3-carboxamide;

l-(6-(Hydroxyamjno)-6-oxohexy])-4-oxo-N-(thiazol-2-y])-l,4-dihydroquinoJine-3- carboxamide;

6-Fluoro-l-(6-(hydroxyamino)-6-oxohexy1)-4-oxo-N-pheny1-l,4-dihydroquinoline-3- carboxamide;

N-(Benzo[d]thiazol-2-y1)-6-fluoro-l-(6-(hydroxyamino)-6-oxohexy1)-4-oxo-l,4- dihydroquinoline-3-carboxamide;

1 -(6-(Hydroxyamino)-6-oxohexy1)-6,7-dimethoxy-4-oxo-N-pheny1-1,4- dihydroquinoline-3-carboxamide;

N-(4-M3uty1pheny1)-1 -(6-(hydroxyamino)-6-oxohexy1)-4-oxo-1,4-dihydroquinoline- 3-carboxamide;

1 -(6-(Hydroxyamino)-6-oxohexy1)-4-oxo-N-(3,4,5-trimethoxypheny1)-1,4- dihydroquinoline-3-carboxamide;

N-(3-Chloro-4-fluoropheny])-l-(6-(hydroxyamino)-6-oxohcxy1)-4-oxo-l ,4- dihydroquino 1 ine-3 -carboxam ide;

1 -(6-(Hydroxyamino)-6-oxohexy1)-N-(4-isopropy1pheny1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

N-(6-Ethoxybenzo[d]thiazol-2-y1)-l -(6-(hydroxyamino)-6-oxohexy1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

1 -(6-(Hydroxyamino)-6-oxohexy1)-N-(4-isopropy1pheny1)-6J7-dimethoxy-4-oxo-1,4- dihydroquinoline-3-carboxamide;

l-(6-(Hydroxyamino)-6-oxohexy1)-6-methoxy-4-oxo-l,4-dihydroquinoline-3- carboxy1ic acid;
1 -(6-(Hydroxyamino)-6-oxohexy1)-6-methoxy-N-( 1 -methyi-3-pheny1-1 H-pyrazol-5- y1)-4-oxo-1,4-dihydroquinoline-3-carboxamide;

1 -(6-(Hydroxyamino)-6-oxohexy1)~N-( 1 -methy 1-3-pheny1-1 H-pyrazol-5-y1)-4-oxo- 1,4-dihydroquinol ine-3-carboxamide;

N-(4-/-Buty1pheny1)-l-(6-(hydroxyamino)-6-oxohexy1)-6-methoxy-4-oxo-l,4- dihydroquinoline-3-carboxamide;

1 -(6-(Hydroxyamino)-6-oxohexy1)-N-(4-isopropy1pheny1)-6-methoxy-4-oxo-1,4- dihydroqu inol ine-3 -carboxamide;

N-(2,4-Dimethy1pheny1)-l-(6-(hydroxyamino)-6-oxohexy1)-4-oxo-l,4- dihydroquinoline-3-carboxamide;

l-(6-(Hydroxyamino)-6-oxohexy1)-6-methoxy-4-oxo-N-(3,4,5-trimethoxypheny1)- 1,4-dihydroquinol ine-3 -carboxam ide;

1 -(6-(Hydroxyamino)-6-oxohexy1)-6-methoxy-4-oxo-N-(4-(piperidin-1 -y1)pheny1)~ l,4-dihydroquinoline-3-carboxamide;

l-(6-(Hydroxyamino)-6-oxohexy1)-N-(4-methy1benzo[d]thiazol-2-y1)-4-oxo-l,4- dihydroquinoUne-3-carboxamide;

N-(Benzo[d]thiazol-2-y1)-l-(6-(hydroxyamino)-6-oxohexy1)-6-methoxy-4-oxo-l,4- dihydroquinoline-3-carboxamide;

N-(3-Chloro-4-fluoropheny1)-l-(6-(hydroxyamino)-6-oxohexy1)-6-methoxy-4-oxo- l,4-dihydroquinoline-3-carboxamide;

N-(4-Chloropheny1)-1 -(6-(hydroxyamino)-6-oxohexy1)-4-oxo-1,4-dihydroquinoline- 3-carboxamide;

N-(Benzo[d]thiazol-6-y1)-l -(6-(hydroxyamino)-6-oxohexy1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

N-(Benzo[c] [1,2,5 ]thiadiazol-4-y1)-1-(6-(hydroxyamino)-6-oxohexy1)-6-methoxy-4- oxo-l,4-dihydroquinoline-3-carboxamide;

N-(4-Chloropheny1)- 1 -(6~(hydroxyamino)-6-oxohexy1)-6-methoxy-4-oxo-1,4- d ihydroquino 1 ine-3 -carboxamide;

N-(2,4-Dimethy!phenyI)-l-(6-(hydroxyamino)-6-oxohexy1)-6-methoxy-4-oxo-l,4' dihydroquinoline-3-carboxamide;

l-(6-(Hydroxyamino)-6-oxohexy1)-6-methoxy-N-(4-(naphthaIen-l-y1)thiazol-2-y1)-4- oxo-1,4-dihydroquinoline-3-carboxamide;

N-(Benzo[c][ 1,2,5]thiadiazol-4-y1)-l-(6-(hydroxyamino)-6-oxohexy1)-4-oxo-l ,4- dihy droquinoline-3-carboxam i de;

N-(4-/-Buty1pheny1)-6-fluoro-1 -(6-(hydroxyamino)-6-oxohexy1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

1 -(6-(Hydroxyamino)-6-oxohexy l)-4-oxo-N-(4-/?-toly1thiazol-2-y1)-1,4- dihydroquinoline-3 -carboxam ide;

l-(4-(Hydroxyamino)-4-oxobuty1)-6-methoxy-N-(4-methoxypheny1)-4-oxo-l,4- dihydroquinoline-3-carboxamide;

N-(4-Chloropheny1)-6-fluoro-I-(6-(hydroxyamino)-6-oxohexy1)-4-oxo-l,4- dihydroquinoline-3-carboxamide;

6-Fluoro-1 -(6-(hydroxyamino)-6-oxohexy1)-N-(4-methoxypheny1)-4-oxo-1,4- dihydroquinoline-3 -carboxamide;

l-(6-(2-Aminopheny1amino)-6-oxohexy1)-4-oxo-N-pheny1-l,4-dihydroquinoline-3- carboxamide;

l-(6-(2-AminophenyIamino)-6-oxohexy1)-N-(3-chloro-4-fluoropheny1)-4-oxo-l,4- dihydroquinoline-3-carboxamide;

1 -(6-(2-AminophenyIamino)-6-oxohexy1)~N-(4-fluoropheny1)-4-oxo-1,4- dihydroqu inoline-3 -carboxamide;

l-(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(4-/"buty1pheny1)-4-oxo-l,4- dihydroquino 1 ine-3 -carboxam ide;

l-(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(4-methoxypheny1)-4-oxo-l,4- dihydroquinoline-3-carboxamide;

1 -(6-(2-AminophenyIamino)-6-oxohexy l)-N-(4-isopropy1pheny1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

l-(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(4-isopropy1pheny1)-6,7-dimethoxy-4- oxo-1,4-dihydroquinol ine-3-carboxamide;

l-(6-(2-AminophenyIamino)-6-oxohexy1)-6-methoxy-N-(4-methoxypheny1)-4-oxo- l,4-dihydroquinoline-3-carboxamide;

l-(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(4-isopropy1pheny1)-6-methoxy-4-oxo-
1,4-dihydroquinol ine-3-carboxamide;

1 -(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(4-?-buty1phenyI)-6-methoxy-4-oxo-1,4- dihydroquinol ine-3 -carboxamide;
1 -(6-(2-Aminopheny1amino)-6-oxohexy l)-N-(2,4-dimethy1pheny1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

l-(6-(2-Aminopheny1amino)-6-oxohexyI)"6"methoxy-4-oxO'N'(3,4,5- trimethoxypheny1)-1,4-dihydroquinoline-3-carboxamide;

1-(6_(2-Aminopheny1amino)-6-oxohexy1)-N-(l-methy1-3-pheny1-lH-pyrazol-5-y1)-4- oxo-1,4-dihydroquinoline-3-carboxamide;

l-(6-(2-Aminopheny1amino)-6-oxohexy1)-6-methoxy-N-(l-methy1-3-pheny1-lH- pyrazol-5-y1)-4-oxo-l,4-dihydroquinoline-3-carboxamide; 1 -(6-(2-Aminopheny1amino)-6-oxohexy l)-N-(4-chloropheny1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

l-(6-(2-Aminophenyiamino)-6-oxohexy1)-N-(3-chloro-4-fluoropheny1)-6-methoxy-4- oxo-1,4-dihydroquinoline-3-carboxamide;

l-(6-(2-Aminopheny1amino)-6'Oxohexy1)-N-(4-methy1benzo[d]thiazol-2-y1)-4-oxo- l,4-dihydroquinoline-3-carboxamide;

1-(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(benzo[d]thiazoU6"y1)'4-oxo-1,4- dihydroquinoline-3-carboxamide;

1 -(6-(2-Aminopheny1amino)-6-oxohexy l)-N-(benzo[c][ 1,2,5 jthiadiazoI-4-y1)-6- methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide;

l-(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(benzo[c][l,2,5]thiadiazol-4-y1)-4-oxo- l,4-dihydroquinoline-3~carboxamide;

1 -(6-(2-Aminopheny1amino)-6-oxohexy l)-N-(4-chloropheny1)-6-methoxy-4-oxo-1,4- d ihydroquinol ine -3 -carboxamide;

l-(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(2?4-dimethy1pheny1)-6-methoxy-4-oxo- M-dihydroquinoline-3-carboxamide;

l-(6-(2-Aminopheny1amino)-6-oxohexy1)-N-cyclopenty1-4-oxo-lJ4-dihydroquinoline- 3-carboxamide;

1 -(6-(2-AminophenyIamino)-6-oxohexy l)-N-(benzo[d]thiazol-2-y1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

l-(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(4-chloropheny1)-6-fluoro-4-oxo-l,4- dihydroquinoIine-3-carboxamide;

1 -(6-(2-Aminopheny1amino)-6-0x0hexy1)-6-flu0r0-N-(4-meth0xypheny1)-4"0X0-1,4-
dihydroquinoline-3-carboxamide;

l-(4-(2-Aminopheny1amino)-4-oxobuty1)-6-methoxy-N-(4-methoxypheny1)-4-oxo- l,4-dihydroquinoline-3-carboxamide;

1 -(6-(2-Aminopheny1amino)-6-oxohexy1)-N-(2-hydroxypheny1)-4-oxo-1,4- dihydroquinoline-3-carboxamide;

l-(4-(2-Aminopheny!amino)-4-oxobuty1)-N-(benzo[d]thiazol-2-y1)-6-fluorO'4-oxo- 1,4-dihydroquinol ine-3-carboxamide;

6-(3-(Benzo[d]oxazol-2-y1)-4-oxoquinolin-l(4H)-y1)-N-hydroxyhexanamide; and
N-(2-AminophenyI)-6-(3-(benzo[d]oxazol-2-yI)-4-oxoquinolin-l(4H)-y1)hexanamide.

4. A process for the preparation of compound of formula (I) according to claim 1 comprising reacting the compound of formula (lb) or its hydrolysis product with R3NH2

5. 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.

6. 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.

7. 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.

8. 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 or absence of other clinically relevant cytotoxic agents or non-cytotoxic agents.

9. 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.

10. A method of treatment of inflammatory disorders selected from rheumatoid arthritis; inflammatory bowel disease; granuloma, sepsis and/or a method for the treatment of cancer-induced bone pain (CIBP), comprising administering to a subject suffering from the inflammatory disorders, a therapeutically effective amount of a compound according to claim 1 or claim 3.

11. A method of treatment of neurodegenerative disorders selected from Huntington's disease, Alzheimer's disease and Parkinson'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.