Field of Invention

Described are bridged compounds of the formula (I), their analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof. Provided herein are also the compositions and methods to treat fungal infection. These compounds are selective HDAC inhibitors that act as inherent antifungal compounds or augment the activity of other antifungal compounds such as azoles.

Background

Fungal infections (mycoses), are not as frequent as bacterial or viral infections, but have nonetheless been increasing in incidence in the human population over the past several years. This trend is largely as a consequence of increased number of cancer and immunocompromised patients who, owing to weakened immune system and the chronic nature of the diseases, are at greater risk. The fungi, like bacteria, have unique characteristics, distinct from their mammalian hosts, but at the same time they being eukaryotic like mammals, are much more complex organisms. Consequently, only a few drugs are aimed at interfering with cell division and have limited use. Most antifungal drugs are targeted to the cell membrane.

The principal predisposing factors for C. albicans infection are diabetes mellitus, general debility, immunodeficiency, indwelling catheters, antibiotics that alter normal bacterial flora and corticosteroids. Of these the infection of the skin occurs in moist, warm parts of the body such as the axilla, intergluteal folds, groin, or infrarnammary folds; it is most common in the obese and diabetic individuals. Interdigital web infection is common among those that work in wet conditions. (Jawetz Microbiology 19th ed; Antimicrobial Agents and Chemotherapy, 2002: 46(11): 3532-3539).

Candidiasis is treated with antifungal azoles such as topical agents and oral or intravenous fluconazole and itraconazole. The major limitation of antifungal azoles is their lack of fungicidal activity. Furthermore surviving yeasts provide a reservoir for the development of Azole resistance. (Antimicrobial Agents and Chemotherapy 2002; 46:3532-3539).

Azole class of antifungal agents includes the imidazoles (clotrimazole, miconazole, and ketoconazole) and the triazoles (fluconazole, itraconazole, isavucanazole, ravucanazole, posoconazole, voriconazole and terconazole).

Mechanism of action: Azoles interfere with the biosynthesis of major fungal membrane component ergosterol by inhibiting sterol C14-demethy1ation of cytochrome P-450 3-A dependent enzyme 14-a-lanosterol-demethy1ase, one of the about 20 enzymes involved in the biosynthesis of ergosterol. Inhibition of this critical enzyme in the ergosterol synthesis pathway leads to the depletion of ergosterol in the cell membrane and accumulation of toxic intermediate sterols, causing increased membrane permeability and inhibition of fungal growth. Azole antifungals can also inhibit many mammalian cytochrome P450-dependent enzymes involved in hormone synthesis or drug metabolism. Therefore, they are particularly susceptible to clinically significant drug interactions with other medications metabolized through the cytochrome P450 pathway.

One of the major differences is that the fungi rely on endogenous ergosterol biosynthesis, in contrast to mammalian cells that have the ability to incorporate exogenous sterol. This property may account for the selectivity of the azoles against fungi. (Lorian V. Antibiotics in Laboratory medicine. 4th ed; Crit. Rev. Biochem. Mol. Biol. 1999: 34:159-166; Curr. Opin. Microbiol. 2001,4:540-545).

Azole resistance has been documented in several species of Candida. The proposed mechanisms include alteration of 14-a-demethy1ase and upregulation of genes that encode for efflux pumps. In vitro, Azoles not only fail to kill but also fail to suppress growth of Candida completely, resulting in trailing growth as observed in broth microdilution assays. (Antimicrobial Agents and Chemotherapy, 2002; 46:3532-3539)
HDACs (Histone deacety1ases) are validated targets for anticancer and antiprotozoal therapy. The chromatin at any given point of time is controlled by opposing actions of two types of enzymes: Histone acety1transferases, which transfer an acety1 group from acety1 CoA to an e-amino group of lysine residues of histones loosening the nucleosomes, and HDACs that catalyze the hydrolysis of acetamides by removing acety1 groups and lead to the compaction of chromatin (The Oncologist, 2003; 8:389-391). It has been recognized in recent years that histone acety1ation and deacety1ation play important roles in eukaryotic gene regulation. The £-amino groups of lysine residues within the flexible amino-terminal tails of the core histones are the primary targets for acety1ation. These modifications reduce the electrostatic interaction between histones and DNA and therefore typically activate transcription by increasing the exposure of a promoter region to RNA polymerase and associated factors. (Nature, 1997, 389:349-352; Microbiol. Mol. Biol. Rev. 2000, 64:435-459). Inhibitors of HDAC selectively induce cellular differentiation, growth arrest and apoptosis in a broad spectrum of tumor cells, without affecting normal cells, which contributes to their known low-level of toxicity compared to other anticancer agents. (Curr. Med. Chem. 2005; 5:529-560).

HDACs are conserved in yeast. Five histone deacety1ase genes (HDA1, RPD3, HOS1, HOS2, and HOS3) have been cloned from Candida albicans and characterized. Sequence analysis and comparison with 12 additional fungal deacety1ases resulted in a phy1ogenetic tree composed of three major groups as shown in figure-1.

Figure-1 (Journal of Bacteriology 2001. 183:4614 - 4625) All the values are above 77%, suggesting that the nodes are significant and reflect the correct phy1ogeny. Proteins from different fungal species are indicated by two-letter prefixes: Ca, Candida albicans; An, Aspergillus nidulans; Sc, Saccharomyces cerevisiae; and Sp, Schizosaccharomyces pombe. In each group, the deacety1ase with the highest homology to each C. albicans deacety1ase is the S. cerevisiae homolog. (J. Bact. 2001; 183: 4614-4625).

C. albicans genome sequence encodes three proteins with >50% identity over much of their lengths to TSA (Trichostatin-A)-sensitive human and S. cerevisiae histone deacety1ases(HDAs). TSA is a potent and specific inhibitor of both mammalian and yeast histone deacety1ase activities. HDA1 and HDA6 of S. cerevisiae are examples of closely related human homologs. It is therefore anticipated that TSA and other HDAC inhibitors would affect C. albicans gene expression in some manner. Some HDAC inhibitors have no effect on C. albicans growth under optimal conditions, but they have clear effects on C. albicans trailing growth commonly observed with azoles. Trailing growth can cause the surviving yeast cells in becoming reservoirs for relapse. Smith and Edlind described that mammalian HDAC inhibitor TSA potentiated fluconazole activity against C. albicans and that TSA did not have any effect on Candida's growth by itself. (Antimicrobial Agents and Chemotherapy 2002; 46:3532-3539). The above two facts indicates the potential use of HDAC inhibitors as a synergistic agent in antifungal therapy. It is however, interesting to observe that the HDAC inhibitor activity of TSA was at concentrations at least 200-fold higher than concentrations toxic to mammalian cells (American Society For Microbiology abstract 2006, A-093).

HDAC inhibitor MGCD290 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 (WO 2008/021944). MGCD290 has entered the phase I clinical trials for determining the safety profile.

Hu et al "US20080139673A1", describes how HDAC inhibitors interact with antifungal azole compounds to potentiate the activity of such compounds.

There is a widespread need of the antifungal agents that overcome the drawbacks of the current antifungal agents, such as the azoles, include drug-drug interaction, drug resistance and possible toxic liver effects. It would be highly desirable to provide a new compound that has inherent activity and/or potentiates the activity of the antifungal agents. This motivated us to develop the compounds of selective HDAC inhibitors which act as inherent antifungal agent and/or augment/potentiates the activity of other antifungal agents.

Objective

One objective herein is to provide bridged compounds of the formula (I) and their analogs, tautomeric forms, stereoisomers, polymorphs, intermediates, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, prodrugs, metabolites and complexes thereof. The invention relates to compositions and methods to treat fungal infection. These compounds are selective HDAC inhibitors, that act as inherent antifungal compounds or that augments/potentiates the activity of other antifungal compounds such as azoles.

It is an object of the present invention to provide a compound to inhibit HDAC and/or arresting cell growth in fungal cells; and/or a process for the preparation of said compound; and/or a pharmaceutical composition comprising said compound; and/or an improved method for inhibiting HDAC in a fungal cell; and/or an improved method for the treatment of a condition mediated by HDAC; and/or an improved method for the treatment of fungal infections; or at least to provide the public with a useful choice.

Summary

In one embodiment, the present invention pertains to the bridged compounds of the formula (I), their analogs, derivatives, tautomeric forms, stereoisomers, polymorphs, solvates, intermediates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof which can be used for the treatment of protozoa and fungal infections;

R represents substituted or unsubstituted adamanty1, adamanty1alkeny1idene, aza-adamanty1, homoaza-adamanty1, noradamanty1, homoadamanty1, protoadamanty1 or heteroadamanty1;

X represents a bond, or the groups selected from alkeny1ene, alkyny1ene, heterocycloalky1, -OCONR9-, -NR9COO-, -NR9CONR5-, -CONR9-, -NR9CO-, -NR9-, -O- -S- -SO-, -CO-, -SO2- -OSO2NR9-, -NR9SO2NR5- -NR9SO20--CONR9CONR5-, -CONR9SO2NR5-, -CONR9NR5CO-, -SO2NR9CONR5-, -CONR9CR7R8CONR9-, -NR9COCR7R8NR9CO-, -NR9CR7R8CONR9-, and -NR9COCR7R8O-;

wherein R4, R5, R7, R8 and R9 independently represent hydrogen, optionally substituted groups selected from alky1, ary1, heteroary1, heterocycly1, cycloalky1 and cycloalkeny1 or R9 and R5 can combine together to form a ring having oxo, thioxo or -C=NR6 substituted;

A and B independently represent a bond, -CO-, -SO2- or substituted or unsubstituted groups selected from alky1ene, alkeny1ene, alkyny1ene, ary1ene, ary1alky1ene and heteroary1ene;

R represents substituted or unsubstituted ary1ene or heteroary1ene;

R represents -OR , ortho substituted aniline, amino ary1 or amino heteroary1, which may be optionally substituted, wherein R3 represents hydrogen, optionally substituted groups selected from alky1, ary1, heterocycly1 and -COR6, wherein R6 represents optionally substituted groups selected from alky1, ary1, heteroary1, cycloalky1 and heterocycly1;

E and E independently represent hydrogen, ary1, alky1 or halogens; where n is 1 or 2; with the proviso that, -A-X-B- is not a bond; when n=land R1 is pheny1ene, then -A-X-B- is not -CONH-;

when the groups R, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are substituted, the substituents which may be one or more and selected from but not limited to halogens such as fluorine, chlorine, bromine, iodine; hydroxy, nitro, cyano, azido, nitroso, oxo (=0), thioxo (=S), -SO2, amino, hydrazino, formy1, alky1, haloalky1 group such as trifluoromethy1, tribromomethy1, trichloromethy1 and the like; alkoxy, haloalkoxy such as -OCH2C1 and the like; ary1alkoxy such as benzy1oxy, pheny1ethoxy and the like; cycloalky1, cycloalky1oxy, ary1, heterocycly1, heteroary1, alky1amino, -COORa, -C(O)R , -C(S)Ra, -C(O)NRaRb, -C(S)NRaRb, -NRaC(O)NRbRc, -NRaC(S)NRbRc, -N(Ra)SORb, -N(Ra)SO2Rb, -NRaC(O)ORb, -NRaRb, -NRaC(O)Rb, -NRaC(S)Rb, -SONRaRb, -SO2NRaRb, -ORa, -ORaC(O)ORb, -OC(O)NRaRb, -OC(O)Ra, -RaNRRbRc, -RaORb, -SRa, -SORa and -SO2Ra, wherein Ra, Rb and RC in each of the above groups can be hydrogen, halogens, optionally substituted groups selected from alky1, alky1ene, cycloalky1, ary1, ary1alky1, heterocycly1, heteroary1 and heteroary1alky1; the substituents are optionally further substituted by one or more substituents as defined above.

In another mbodiment, the present invention pertains to the bridged compounds of the formula (la), their tautomeric forms, stereoisomers, polymorphs, solvates, intermediates, metabolites, prodrugs, analogs, derivatives, pharmaceutical compositions and pharmaceutically acceptable salts;

wherein R1 represents thiazoly1 or pheny1ene;

R represents -OR , wherein R3 represents hydrogen, optionally substituted groups selected from alky1, ary1, heterocycly1 and -COR6, wherein R6 represents optionally substituted groups selected from alky1, ary1, heteroary1, cycloalky1 and heterocycly1;
E and E independently represent hydrogen, or halogens; where n is 1 or 2;

R represents substituted or unsubstituted adamanty1, adamanty1alkeny1idene, aza-adamanty1, homoaza-adamanty1, and noradamanty1;

X represents a bond, or the groups selected from alkeny1ene, alkyny1ene, -OCONR9-, -NR9COO-, -NR9CONR5-, -CONR9-, -NR9CO-, -NR9-, -O-, -S-, -CONR9NR5CO-, -CONR9CR7R8CONR9-, -NR9CR7R8CONR9- and -NR9COCR7R8O-;

A and B independently represent a bond, -CO-, -SO2-, or substituted or unsubstituted groups selected from alky1ene group, alkeny1ene group, alkyny1ene group, ary1ene, ary1alky1ene and heteroary1ene; and R5, R7, R8 and R9 are as defined earlier.
with the proviso that,-A-X-B- is not a bond;

when n=l and R1 is pheny1ene, then -A-X-B- is not -CONH-;
In another embodiment, the present invention pertains to the bridged compounds of the formula (lb),

their tautomeric forms, stereoisomers, polymorphs, solvates, intermediates, metabolites, prodrugs, analogs, derivatives, pharmaceutical compositions and pharmaceutically acceptable salts;

wherein, E1 and E2 independently represent hydrogen or halogens;
R1 represents thiazoly1 or pheny1ene;

R represents substituted or unsubstituted adamanty1, adamanty1alkeny1idene, aza-adamanty1, homoaza-adamanty1, noradamanty1, homoadamanty1, protoadamanty1 and heteroadamanty1;

the linker A-X-B is selected from the group consisting of
-(C1-C6)alky1eneOCONR9-, -ary1ene(C1-C6)alky1eneOCONR9-, -CONR9-
-(C1-C6)alkeny1eneCONR9-, -ary1ene(C1-C6)alky1eneCONR9-, -CO(C1-C6alky1ene)-,
-(C1-C6)alky1eneCONR9-, -NR9CONR5-, -NR9(C,-C6)alky1eneCONR9-,
-NR9CO(C1-C6)alky1eneO-, -CONR9(C1-C6)alky1eneCONR5-,

-(C1-C6)alky1eneNR9S02-, -ary1ene-, -(C1-C6)alky1ene- -(C1-C6)alky1eneO-, -(C1-C6)alky1eneNR9-, -(Ci-C6)alky1ene NR9(C1-C6)alky1ene-, wherein one or two carbon atoms of the alky1ene is optionally replaced by a heteroatom independently selected from O, -NR9- or S; wherein R9 and R5 independently represents hydrogen, optionally substituted groups selected from alky1, ary1, heteroary1, heterocycly1, cycloalky1 and cycloalkeny1.

with the proviso that, when n=land R1 is pheny1ene, then -A-X-B- is not -CONH-;

Detailed description

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 "selectively" refers to mean that the HDAC inhibitory compounds and their use in the compositions and methods described herein achieve their purpose without being used in concentrations that are toxic to the host cells.

The term "alky1" refers to straight or branched aliphatic hydrocarbon groups having the specified number of carbon atoms, preferably 1-10 carbon atoms, more preferably 1-6 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 diradical of a branched or unbranched saturated hydrocarbon chain, having the specified number of carbon atoms, preferably 1-10 carbon atoms, more preferably 1-6 carbon atoms, which may be optionally substituted by one or
more substituents. Preferred alky1ene groups include, without limitation, methy1ene, ethy1ene, propy1ene, buty1ene 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, preferably 2-6 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 "alkeny1ene" refers to a linear divalent aliphatic hydrocarbon radical containing a carbon-carbon double bond and which may be straight or branched chain having about 2 to 10 carbon atoms, preferably 2-6 carbon atoms, which may be optionally substituted by one or more substituents. Preferred alkeny1ene groups include, without limitation, etheny1ene, propeny1ene, buteny1ene 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, preferably 2-6 carbon atoms, which may be optionally substituted by one or more substituents. Preferred alkyny1 groups include, without limitation, ethyny1, propyny1, butyny1 and the like.

The term "alkyny1ene" refers to a straight or branched divalent hydrocarby1 radicals having at least one carbon-carbon triple bond and having in the range of 2-12 carbon atoms, preferably 2-6 carbon atoms, which may be optionally substituted by one or more substituents. Preferred alkyny1ene groups include, without limitation, ethyny1ene, propyny1ene, butyny1ene, pentyny1ene and the like.

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

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, cycloocty1, perhydronaphthy1, adamanty1, homoadamanty1, noradamanty1 and norborny1 groups, bridged cyclic groups or spirobicyclic groups e.g spiro [4.4] non-2-y1 and the like.

The term "cycloalkeny1" refers to a non-aromatic cyclic ring 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.

Furthermore the term "heterocycly1" refers to a stable 3 to 15 membered ring radical, which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, 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 quaternized; and the ring radical may be partially or fully saturated. Preferred heterocycly1 groups include, without limitation, 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, piperidiny1, piperaziny1, homopiperaziny1, 2-oxoazepiny1, azepiny1, pyrroly1, 4-piperidony1, pyrrolidiny1, pyraziny1, pyrimidiny1, pyridaziny1, oxazoly1, oxazoliny1, triazoly1, indany1, isoxazoly1, isoxazolidiny1, thiazoly1, thiazoliny1, thiazolidiny1, isothiazoly1, quinuclidiny1, isothiazolidiny1, indoly1, isoindoly1, indoliny1, isoindoliny1, octahydroindoly1, octahydroisoindoly1, quinoly1, isoquinoly1, decahydroisoquinoly1, benzimidazoly1, thiadiazoly1, benzopyrany1, benzothiazoly1, benzooxazoly1, thieny1, morpholiny1, thiomorpholiny1, thiamorpholiny1 sulfoxide, fury1, tetrahydrofury1, tetrahydropyrany1, 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. The term "heteroary1ene" also refers to divalent heteroary1.

The term "heterocycloalky1" refers to a hydrocarby1 radical having alky1 group attached to the heterocycly1 ring.

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, indany1, bipheny1 and the like.

The term "ary1ene" also refers to ary1. Preferred ary1ene groups include, without limitation, pheny1ene, naphthy1ene, bipheny1ene and the like

The term "heteroadamanty1" refers to one or more carbon atoms in the adamantane ring replaced by nitrogen, oxygen or sulfur.

The term "adamanty1alkeny1idene" refers to a hydrocarby1 radical having alkeny1idene group attached to the adamanty1 ring.

The term "alkeny1idene" refers to a bivalent hydrocarbon group having one or more double bonds formed by mono or dialkeny1 substitution of methy1ene. Typical alkeny1idene radicals include, but are not limited to, etheny1idene, prop-1-en-l-y1idene, prop-2-en-l-y1idene, but-1-en-l-y1idene, but-2-en-l-y1idene, but-3-en-l-y1idene, buta-1,3-dien-1 -y1idene; cyclobut-2-en-1 -y1idene.

The term "alkoxy" refers to an alky1 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 trem "alky1amino" refers to an alky1 group attached via an amino linkage to the rest of the molecule. Preferred alky1amino group include, without limitation, methyamino, ethy1amino, propy1amino, isopropy1amino and the like.

The term "ary1alkoxy" refers to an alkoxy group attached to an ary1 substituent. Preferred ary1alkoxy groups include, without limitation, pheny1methy1 ether and the like.

The term "cycloalky1oxy" refers to cycloalky1 group attached via an oxygen linkage to the rest of the molecule, Preferred cycloalky1oxy groups include, wthout limitation, cyclopropy1oxy, cyclobuty1oxy, cyclopenty1oxy and the like.

The term "haloalkoxy" refers to a group resulting from the replacement of one or more hydrogen atoms from a C1-4 alkoxy group with one or more halogen atoms, which can be the same or different. Preferred haloalkoxy groups include, without limitation, -trifluoromethoxy, fluoromethoxy and the like.

The term "haloalky1" refers to an halogen group attached via an alky1 linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Preferred haloalky1 groups include, without limitation, -CH2C1-C2H5C1 and the like.
The term "bridged" as used herein, means a saturated bicyclic or tricyclic ring system. Bicyclic ring systems are exemplified by a cycloalky1 group, as defined herein, in which two non-adjacent carbon atoms of the cycloalky1 group are linked by an alky1ene bridge of 1-3 carbon atoms. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1] nonane. Tricyclic ring systems are exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alky1ene bridge of between one and three carbon atoms. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.03'7 ]nonane and tricyclo[3.3.1.13,7 ]decane (adamantane).

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 "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 "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 "derivative" refers to a chemical compound or molecule made from a parent compound by one or more chemical reactions such as, by oxidation, hydrogenation, alky1ation, esterification, halogenation and the like.

The stereoisomers are isomers that differ in the arrangement of their atoms in space. Compounds disclosed herein may exist as single stereoisomers, racemates and or mixtures of enantiomers and/or diastereomers. Stereoisomers include geometrical isomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the subject matter described. The methods for determination of stereochemistry, preparation and separation of the stereoisomers are well known in the art. (e.g., see "Advanced Organic Chemistry", 4th edition, March, Jerry, John Wiley & Sons, New York, 1992).

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

Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn and the like; salts of organic bases such as N, N'-diacety1ethy1enediamine, glucamine, triethy1amine, choline, dicyclohexy1amine, benzy1amine, trialky1amine, thiamine, guanidine, diethanolamine, a-pheny1ethy1amine, piperidine, morpholine, pyridine, hydroxyethy1pyrrolidine, hydroxyethy1piperidine, ammonium, substituted ammonium salts, aluminum 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, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.

The term "prodrugs" as used herein refers to any pharmacologically inactive or less active compound which, when metabolized or chemically transformed by a mammalian system is converted into a pharmacologically active compound of formula (I) of the present invention. For example, some of prodrugs are esters of the compound of formula (I), during metabolysis; the ester group is cleaved to form the active compound of formula (I). A general overview of prodrug is provided in H Surya Prakash Rao, Capping Drugs: Development of Prodrugs, Resonance, 2003, vol. 8,19-27

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 H1, H2A, H2B, H3, H4 and H5, from any species. Human HDAC proteins or gene products include but are not limited to, HDAC-1
HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9 and HDAC-10. The histone deacety1ase can also be derived from a protozoal or fungal source.

The term "histone deacety1ase inhibitor" is used to identify a compound having structure as defined herein, which is capable of interacting with histone deacety1ase and inhibiting its enzymatic activity. Inhibiting histone deacety1ase enzymatic activity means reducing the ability of histone deacety1ase to remove an acety1 group from histone. Such inhibition is specific, i.e. histone deacety1ase inhibitor reduces the ability of histone deacety1ase to remove an acety1 group from histone at a concentration that is lower than the concentration of inhibitor that is required to produce another, unrelated biological effect.

The present invention provides compounds, composition thereof and methods for selectively enhancing fungal sensitivity to antifungal compounds. In a preferred embodiment of the present invention, inhibitors of histone deacety1ase are more active against a fungal histone deacety1ase than a plant or mammalian histone deacety1ase; preferably the inhibitory activity is specific for fungal histone deacety1ase.

The term "antifungal agent" is a substance capable of inhibiting or preventing the growth, viability and/or reproduction of a fungal cell. Preferable antifungal agent is a broad spectrum antifungal agent. However, an antifungal agent can also be specific to one or more species of fungus.

Preferable antifungal agents are ergosterol synthesis inhibitor and include, but are not limited to azoles and phenpropimorph. Preferred azoles include imidazoles and triazoles. Further preferred antifungal agents include, but are not limited to, ketoconazole, itraconazole, fluconazole, voriconazole, posaconazole, ravuconazole and miconazole. Like azoles, phenpropimorph is an ergosterol synthesis inhibitor, but acts on the ergosterol reductase (ERG24) step of the synthesis pathway. Terbinafine, is also an ergosterol inhibitor, but acts on squalene epoxidase (ERG1) step.

In a preferred embodiment, compound of the present invention shows inherent activity against fungal species or synergistic activity with an antifungal agent against a fungal species, preferably at concentrations of inhibitor not toxic to mammalian cells. Preferably such antifungal agents are azole antifungal agents. Such combinations, and compositions thereof, can be used to selectively treat fungal infections.

The compounds of the present invention are also useful in the medicament for inhibiting HDAC in a fungal cell.

The compounds of the present invention are also useful in preparing a medicament for reducing resistance of a fungal cell to an antifungal agent, in a mammal suffering from the said fungal infection.

Apicidin, TSA (trichostatin A), sodium butyrate and trapoxin which are known HDAC inhibitors have been tested as an agent to enhance the sensitivity of selected fungal species to azole antifungal agents. Only TSA was able to enhance the sensitivity of Candida albicans. (Antimicrobial Agents and Chemotherapy 2002; 46:3532-3539).

However, the concentration of TSA required was higher than those toxic to mammalian cells. A major problem with current antifungal formulations is their toxicity to the infected host. The therapeutic index is preferably selective to the targeted fungus without being toxic to the host. Drawbacks to current antifungal agents, such as the azoles, include development of resistance, possible drug-drug interactions and possible toxic liver effects.

A term once described, the same meaning applies for it, throughout the patent. Representative compounds include:
1. Adamant-l-y1meth{4-[2-(hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}carbamate;
2. Adamant-2-y1ethl{4-[2-(hydroxy1arnino)-2-oxoethy1]-l,3-thiazol-2-y1}carbamate;
3. Adamant-l-y1ethy1{4-[2-(hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}carbamate;
4. 3-Chloroadamant-1 -y1methy1 {4-[2-(hydroxyamino)-2-oxoethy1]-1,3-thiazol-2-y1} carbamate;
5. Adamant-1 -y1methy1 {4-[ 1,1 -difluoro-2-(hydroxyamino)-2-oxoethy1]-1,3-thiazol-2-y1}carbamate;
6. 3 - [4( Adamant-1 -y1)pheny1]propy1- {4- [2-(hydroxyamino)-2-oxoethy1] -1,3 -thiazol-2-y1}carbamate;
7. 3 -(Adamant-1 -y1)propy1 {4- [2-(hydroxyamino)-2-oxoethy1] -1,3 -thiazol-2-y1} carbamate;
8. Tricyclo[3.3.1.03,7]non-3-y1methy1-N-{4-[2-(hydroxyamino)-2-oxoethy1]-l ,3-thiazol-2-y1} carbamate;
9. 3-(Tricyclo[3.3.1.03,7]non-3-y1)propy1{4-[2-(hydroxyamino)-2-oxoethy1]-1,3-thiazol-2-y1} carbamate;
10. 3-Pheny1adamant-1 -y1methy1{4-[2-(hydroxyamino)-2-oxoethy1]-1,3-thiazol-2-y1} carbamate;
11. 3-(Tricyclo[3.3.1.03'7]non-3-y1)propy1{4-[2-(hydroxyamino)-2-oxoethy1]-pheny1} carbamate;

12. N-{4-[2-(Hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}adamantane-l-carboxamide;
13. N-{4-[2-(Hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}adamantane-l-acetamide;
14. N-{4-[2-(Hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}-3-(3-chloroadamant-l-y1)acry1amide;
15. N-{4-[2-(Hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}-3-[4-(adamant-l-y1)pheny1]propanamide;
16. N-Hydroxy-2-[4-(3-oxo-3-(4-azatricyclo[4.3.1.13,8]undec-4-y1)propy1)pheny1]acetamide;
17. N- {4-[2-(Hydroxyamino)-2-oxoethy1]pheny1} -3-[4-(adamantan-1 -y1)pheny1]propanamide;
18. N-{4-[2-(Hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}-3-(tricyclo[3.3.1.03'7]non -3-y1)propanamide;
19. N-{4-[2-(Hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}-3-(3-pheny1adamant-l-y1)propanamide;
20. N- {4- [ 1,1-Difluoro-2-(hydroxyamino)-2-oxoethy1]-1,3-thiazol-2-y1}adamantane-1 -carboxamide;
21. 2-(2-{[(Adamant-1 -y1amino)carbony1]amino}-1,3-thiazol-4-y1)-N-hydroxyacetamide;
22. N-{4-[2-(Hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}-4-azatricyclo [4.3.1.13'8]undecane-4-carboxamide;
23. 2-(Adamant-l-y1amino)-N-{4-[2-(hydroxyamino)-2-oxoethy1]-l,3-thiazol-4-y1}acetamide;
24. 2-(3-Pheny1adamantan-1 -y1amino)-N-{4-[2-(hydroxyamino)-2-oxoethy1]-1,3-thiazol-2-y1}acetamide;
25. 2-{4-[2-(Adamant-1 -y1amino)-2-oxoethoxy]pheny1}-N-hydroxyacetamide;
26. N-[2-({4-[2-(Hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}amino)-2-oxoethy1]adamantane-1 -carboxamide;
27. 2-[4'-(Adamant-l-y1)bipheny1-4-y1]-iV-hydroxyacetamide;
28. 2-{2-[4-(Adamant-l-y1)buty1]-l,3-thiazol-4-y1}-Nhydroxyacetamide;
29. 2-{4-[4-(Adamant-l-y1)buty1]pheny1}-Nhydroxyacetamide;
30. 2-{4-[3-(Adamant-l-y1)propy1]pheny1}-Nhydroxyacetamide;
31. 2-{4-[3-(Adamant-l-y1)propoxy]pheny1}-Nhydroxyacetamide;
32. 2- {4-[4-(Adamant-2-y1)butoxy]pheny1} -N-hydroxyacetamide;
33. 2-{4-[3-(Adamant-l-y1)propanamino]pheny1}-Nhydroxyacetamide;
34. 2-(4-{[3-(Adamant-l-y1)propy1]aminosulfony1}pheny1)-jV-hydroxyacetamide;and
35. 2-(4-{[3-(Adamant-1 -y1)propy1]aminomethy1}pheny1)-A^-hydroxyacetamide.
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.
Conditions: Step 1: NH2OH.HCl, KOH and MeOH.

The said process for the preparation of the compounds of formula (I) comprises of the
following:

Step-1: Treating the compound of formula (2) with hydroxy1amine HC1 or R NH2 in
presence of inorganic base such as KOH and the like to give compound of formula (I).

It is to be noted that the compound of formula (2) includes other alky1 esters such as ethy1, isopropy1, t-buty1 and the like.

Compound of formula (2) is hydrolyzed to corresponding acid then reacted with R2R4NH to compound of formula (I).

There is also provided a process as shown in the Scheme la-li, for the preparation of
intermediate of the formula (2), wherein all the groups are as defined earlier.
Scheme la:

Step 1: Conditions: Triphosgene, Diisopropy1ethy1amine (DIPEA) and Dichloromethane (DCM) (when Z =OH/NH2) or Carbony1diimidazole (CDI), and Tetrahydrofuran (THF) (when Z =COOH or -NH-CH2-COOH).

Reacting compound of formula (la) and (lb), wherein Z =OH/NH2 with triphosgene or carbony1diimidazole in the presence of organic base such as DIPEA,triethy1amine and the like and solvent such as DCM and the like gives compound of formula (2) or reacting compound of formula (la) wherein Z =COOH with carbony1diimidazole followed by compound (lb) in solvent such as THF and the like gives compound of formula (2). Scheme lb:

Step 1: Conditions: EDCI, HOBt, DIPEA and DCM

Coupling the acid (lc) with the activating agent such as l-(3-dimethy1aminopropy1)-3-
ethy1carbodiimide hydrochloride (EDCI), hydroxy benzotriazole (HOBt) and the like in
the presence of the respective amine (1d) to yield the compound of the general formula
(2). Scheme lc:

Step 1: Conditions: Carbony1diimidazole (CDI), Triethy1amine (TEA) and Tetrahydrofuran (THF) Coupling the acid (lc) with CDI in presence of the organic base such as TEA and the solvent such as THF and the like in the presence of the respective amine (le) to yield the compound of the general formula (1f). Step 2:

Conditions: Diethy1aminosulfur trifluoride (DAST), 1,2 dichloroethane Reacting the compound of formula (If) with DAST in presence of the solvent such as 1, 2 dichloroethane and the like to yield the compound of general formula (2). Scheme Id:
Step1: Conditions: CH3SO3H,

Reacting the alcohol (1g) with bipheny1acetic acid (1h) in presence of acid such as
methanesulphonic acid and the like to yield the compound of the general formula (li).
Step 2: Conditions: H2SO4, MeOH.

The compound of formula (li) was esterified using acid catalyst in methanol and the like
to yield the compound of general formula (2).
Scheme le:

Step 1: Conditions: Trifluoroacetic anhydride (TFAA), TEA, P2S5.

Reacting compound of formula (lj) with trifluoroacetic anhydride in the presence of
organic base such as DIPEA, triethy1amine and the like and solvent such as THF and the like gives nitrile compound, which was reacting with phosphorus sulfide to yield
compound of formula (Ik).

Step 2: Conditions: H2SO4, MeOH.

Reacting the compound of formula (Ik) with 4-chloroethy1acetoacetate in refluxing
ethanol to yield the compound of general formula (2).

Scheme 1F

Step 1: Conditions: NaH, Pd/C.

Reacting compound of formula (lm) with sodium hydride in solvent such as THF and the
like, followed by appropriate aldehyde (11) gives alkene compound, which was further
reduced with Pd/C to yield compound of formula (1n).

Step 2: Conditions: KOH, Oxaly1 chloride, TMSdiazomethane, TEA, Silver benzoate.

The compound of formula (1n) was further one carbon homologated (Arndt eistert
reaction) to yield the compound of general formula (2).

Scheme lg:

Step 1: Conditions: NaH or K2CO3

Reacting compound of formula (lo) with appropriate compound of formula (lb) using
reagent like sodium hydride or potassium carbonate and the like in solvent such as THF
and the like to yield the compound of general formula (2).

Scheme 1n:

Step 1: Conditions: NaBH4 and Methanol:

Reductive amination of compound of formula (lq) with appropriate compound of formula
(lp) using reagent such as sodium borohydride and the like in solvent such as methanol
and the like to yield the compound of general formula (2).

Scheme li:

Step 1: Condition 1: W is Br, Z is NH2, Potassium carbonate, DMF

Reacting the compound of formula (la) with the compound of formula (lr) in presence of
base such as potassium carbonate and the like and solvent such as DMF and the like to
yield the compound of formula (2).

Condition 2: W is C1, Z is NH2, TEA, DCM.

Reacting the compound of formula (la) with the compound of formula (lr) in presence of
base such as TEA and the like and the solvent such as DCM and the like to yield the
compound of formula (2).

Intermediates:

Synthesis of adamantane-1-carboxy1ic acid (1-1):

A mixture of 1-hydroxyadamantane (50 g, 328 mmol) and formic acid (98%)(15.1 g, 328 mmol) were taken in 312.5 mL of concentrated (Con.) H2SO4 at 0 °C. The reaction mixture was stirred for 2 h and the mixture was then kept at 10 °C for overnight. Reaction mixture was poured into crushed ice, the solid obtained was filtered and washed with 2 L water and dried to afford the title compound (25 g, 42% yield) Synthesis of methy1 adamantane-1-carboxy1ate (1-2):

A mixture of adamantane-1-carboxy1ic acid (25 g, 138 mmol) and Con. H2SO4 (4 mL) were taken in 150 mL of methanol, and stirred at 80 °C for 3 h. The solvent was removed by evaporation and the residue was diluted with water (250 mL), extracted with EtOAc (2 x 250 mL). The organic layer was washed with water (2 x 150 mL), brine (100 mL) and dried over anhydrous Na2SO4, concentrated to give the crude compound which was purified by column chromatography, (product was eluted at 2% (EtOAc.Hexane)) to afford the pure title compound (21.8 g, 81% yield) Synthesis of adamant-1-y1methanol (1-3):

A suspension of Lithium Aluminium Hydride (LAH) (6.41 g, 168 mmol) in THF (250
mL) was cooled to 0 °C and methy1 adamantane-1-carboxy1ate (21.8 g, 112 mmol) in 50
mL of THF was added slowly at 0 °C for 30 minutes. After complete addition, the reaction mixture was stirred at room temperature (RT) for 45 minutes. EtOAc (100 mL) was added slowly at 0 °C followed by slow addition of water (20 mL) at 0 °C. Reaction mixture was filtered and filtrate was dried over anhydrous sodium sulphate, solvent was distilled out and dried to afford the pure product (17 g, 91% yield). Synthesis of adamantane-1-carbaldehyde (1-4):

To a suspension of pyridinium chloro chromate (23.17 g, 107.5 mmol) in DCM (150 mL)
was added adamant-1-y1methanol (10.5 g, 63.2 mmol) in DCM (100 mL) under stirring.
The resulting dark brown coloured reaction mixture was stirred at RT for 1 h. Reaction
mixture was diluted with diisopropy1 ether (750 mL) and filtered through celite, the filtrate was washed with aqueous IN NaOH (1 x 250 mL ) solution and water (2 x 150 mL). The organic layer was dried over anhydrous sodium sulphate, concentrated to afford the pure title compound (8.94 g, 86% yield).

Synthesis of methy1 (2E)-3-(adamant-l-y1)acry1ate (1-5):

A suspension of NaH (2.38 g, 99 mmol) in THF (200 mL) was cooled to 0 °C and trimethy1phosphonoacetate (12.89 g, 70.8 mmol) was added slowly at 0 °C, to give milky white solid. Resulting mixture was stirred for 15 minutes and adamantane-1-carbaldehyde (8.94 g, 54.5 mmol) in THF (100 mL) was added slowly at 0 °C. Reaction mixture was stirred at 5 °C for 1 h and the mixture was quenched with water (50 mL) and THF was distilled out. The sticky compound obtained was diluted with water (150 mL) and extracted with EtOAc (2 x 150 mL). EtOAc layer was dried over anhydrous Na2SO4, distilled and dried to afford the crude product (10.75g, 91% yield). Synthesis of (2£)-3-(adamant-l-y1)acry1ic acid (1-6):

To a solution of methy1 (2E)-3-(adamant-l-y1)acry1ate (12.75 g, 57.9 mmol) in methanol (150 mL) was added, a solution of NaOH (6.95 g, 173 mmol) in water (10 mL). The reaction mixture was stirred at 70 °C for 2 h. Methanol was evaporated and reaction mixture was diluted with water (150 mL), extracted with EtOAc (150 mL) and aqueous layer was acidified to pH 2 with dilute aqueous HC1. It was then allowed to stand at 4 °C for 30 minutes, the precipitated solid was filtered and dried under vacuum to give the pure title compound as a white solid (7.4 g, 62% yield). Synthesis of 3-(adamant-l-y1)propanoic acid (1-7):

10% Pd/C (20% w/w, 1.48 g) was added to a solution of (2E)-3-(adamant-l-y1)acry1ic acid (7.4 g, 35.9 mmol) in methanol (200 mL). The reaction was then purged with H2 (40 psi) and stirred for 15 minutes. The reaction mixture was filtered through a pad of celite, solvent was distilled out from filtrate and dried to afford the title compound as a white solid (7.31 g, 97% yield) Synthesis of methy1 3-(adamant-l-y1)propanoate (1-8):

A mixture of 3-(adamant-l-y1)propanoic acid (7.2 g, 34.6 mmol) and Con. H2SO4 (2 mL) were taken in 150 mL of methanol solution, and stirred at 80 °C for 3 h. The solvent was removed by evaporation and the residue was diluted with water (250 mL), extracted with EtOAc (2 x 250 mL). The organic layer was washed with water (2 x 150 mL), brine (1 x 100 mL) and dried over anhydrous Na2SO4, concentrated to afford the pure title compound (7.34 g, 95% yield ). Synthesis of 3-(adamant-l-y1)propan-l-ol (1-9):

A suspension of LAH (2.51 g, 66 mmol) in THF (100 mL) was cooled to 0 °C and methy1 3-(adamant-l-y1)propanoate (7.34 g, 33 mmol) in 50 mL of THF was added slowly at 0 °C for 30 minutes. After completion of addition, the reaction mixture was stirred at RT for 45 minutes. EtOAc (20 mL) was added slowly at 0 °C followed by slow addition of water (5 mL) at 0 °C. Reaction mixture was filtered and filtrate was dried over anhydrous sodium sulphate, concentrated to give the crude compound which was purified by column chromatography, (product was eluted at 1% (EtOAc.Hexane)) to afford the pure title compound as a viscous liquid (5.2 g, 81% yield).

Synthesis of 3-(adamant-l-y1)propanal (1-10):

To a suspension of pyridinium chlorochromate (7.75 g, 36 mmol) in DCM (50 mL) was added 3-(adamant-l-y1)propan-l-ol (3.5 g, 18 mmol) in DCM (50 mL) under stirring. The resulting dark brown coloured reaction mixture was stirred at RT for 1 h. Reaction mixture was diluted with diisopropy1 ether (150 mL) and filtered through celite, the filtrate was washed with aqueous IN NaOH (2 x 100 mL) solution and water (2 x 100 mL). The organic layer was dried over anhydrous sodium sulphate, concentrated to afford the pure title compound (3.13 g, 90% yield). Synthesis of ethy1 (2E,4E-5-(adamant-l-y1)penta-2,4-dienoate (1-11):

A suspension of NaH (1.18 g, 49 mmol) in THF (50 mL) was cooled to 0 °C and triethy1-4-phosphonocrotonate (8.83 g, 35 mmol) was added slowly at 0 °C. The resulting mixture was stirred for 15 minutes and adamantane-1-carbaldehyde (4.46 g, 27 mmol) in THF (50 mL) was added slowly at 0 °C. Reaction mixture was stirred at 5 °C for 1 h. It was then quenched with water (10 mL) and THF was distilled out. The sticky compound obtained was diluted with water (150 mL) and extracted with EtOAc (2 x 150 mL). EtOAc layer was dried over anhydrous Na2SO4, distilled and dried to afford the crude product (6.7 g, 95% yield). Synthesis of (2E,4E)-5-(adamant-l-y1)penta-2,4-dienoic acid (1-12):

To a solution of ethy1 (2E,4E)-5-(adamant-l-y1)penta-2,4-dienoate (6.7 g, 25 mmol) in methanol (60 mL) was added, a solution of NaOH (3.09g, 77 mmol) in water (5 mL). The reaction mixture was stirred at 70 °C for 2 h. Methanol was evaporated and diluted with water (150 mL), extracted with EtOAc (150 mL) and aqueous layer was acidified to pH 2 with dilute aqueous HC1 and allowed to stand at 4 °C for 30 minutes. The precipitated solid was filtered and dried to afford a white solid, which was purified by column chromatography using 5% (EtOAc:Hexane) as eluent, to afford the pure title compound (3 g, 50% yield).

Synthesis of 5-(adamant-l-y1)pentanoic acid (1-13):
10% Pd/C (20%, w/w, 0.4g ) was added to a solution of (2E,4E)-5-(adamant-l-y1)penta-2,4-dienoic acid (2 g, 8.6 mmol) in methanol (100 mL). The reaction was then purged with H2 (40 psi) and stirred for 15 minutes. The reaction mixture was filtered through a pad of celite, solvent was distilled out from filtrate and dried to afford the title compound as a white solid (1.72 g, 85% yield). Synthesis of 5-(adamant-l-y1)pentanamide (1-14):

A mixture of 5-(adamant-l-y1)pentanoic acid (1.72 g, 7.2 mmol), thiony1chloride (1.73g, 14.5 mmol) and two drop of DMF were taken in benzene (12 mL) and heated at 80 °C for 2 h. Benzene was distilled and residue was diluted with DCM (15 mL). It was then purged with ammonia and stirred for 30 minutes at 0 °C. The reaction mixture was diluted with water (100 mL), extracted with DCM (2 x 100 mL). The organic layer was washed with water (2 x 100 mL), brine (2 x 100 mL) and dried over anhydrous Na2SO4, concentrated to give the crude compound, which was further triturated with diethy1 ether (20 mL) to afford the pure title compound (1.41 g, 82% yield). Synthesis of 5-(adamant-l-y1)pentanenitrile (1-15):

5-(Adamant-l-y1)pentanamide (0.5 g, 2.1 mmol) in THF (10 mL) was cooled to 0 °C and trifluoroacetic anhydride (TFAA) (0.8 g, 3.8 mmol) followed by TEA (0.81g, 8 mmol) was added slowly at 0 °C under stirring, Reaction mixture was stirred at 0-5 °C for 3 h. It was diluted with water (100 mL), extracted with EtOAc (2 x 100 mL). The organic layer was washed with water (2 x 100 mL), brine (2 x 100 mL) and dried over anhydrous Na2SO4; concentrated to afford the crude title compound (0.4 g, 87% yield). Synthesis of 5-(adamant-l-y1)pentanethioamide (1-16):

P2S5 (1.63 g, 7.3 mmol) was taken in ethanol (20 mL) and heated at 90 °C at which temperature 5-(adamant-l-y1)pentanenitrile (0.4g, 1.8 mmol) in ethanol (5 mL) was added,

and stirred at 90 °C for 3 h. Ethanol was distilled and diluted with water (100 mL), extracted with EtOAc (2 x 100 mL). The organic layer was washed with water (2 x 100 mL), brine (100 mL) and dried over anhydrous Na2SO4, concentrated to give the crude compound, which was purified by a column chromatography. The product was eluted at 10% (EtOAc:Hexane) to afford the pure title compound (0.23 g, 50% yield ). MS m/z: 251.9 (M++l). Synthesis of adamantan-2-one oxime (1-17):

Adamantane-2-one (10 g, 66 mmol) was dissolved in hot ethanol (60 mL). To the hot
solution was added a solution of hydroxy1amine hydrochloride (10.6g, 15 mmol) in 2N
aqueous NaOH (50 mL). The mixture was then heated for 1 h. It was then concentrated in
vacuo to a volume ~ (40 mL), diluted with water (40 mL), and filtered. The solid was
filtered, washed with water and ethanol to afford the pure title compound (9.5 g, 86%
yield) Synthesis of 4-azatricyclo[4.3.1.13,8]undecan-5-one (1-18):

Adamantan-2-one oxime (5 g, 30 mmol) was added with stirring to polyphosphoric acid (150 g) at 130 °C over a period of 10 minutes. The oxime gradually dissolved while the mixture became light brown. The mixture was stirred at 125-130 °C for 30 minutes and was then cooled to RT, diluted with water (200 mL), extracted with DCM (2 x 100 mL). The organic layer was washed with water (2 x 100 mL), brine (2 x 100 mL) and dried over anhydrous Na2SO4,oncentrated to give the crude compound (2.42g, 48% yield). Synthesis of 4-azatricyclo[43.1.13,8]undecane (1-19):

A suspension of LAH (1.67 g, 44 mmol) in THF (50 mL) was cooled to 0 °C and 4-azatricyclo[4.3.1.13'8]undecan-5-one (2.42 g, 14.6 mmol) in 50 mL of THF was added slowly at 0 °C for 15 minutes. After completion of addition, the reaction mixture was stirred at 70 °C for 1 h. EtOAc (20 mL) was added slowly at 0 °C followed by slow addition of water (5 mL) at 0 °C. Reaction mixture was filtered and filtrate was dried over

anhydrous sodium sulphate, distilled and dried to give the crude sticky compound, which was treated with methanolic HC1 and methanol was distilled. The residue was triturated with diethy1 ether (20 mL) to afford the pure title compound as a hydrochloride salt (0.5 g, 18% yield) Synthesis of 3-(adamant-l-y1)propan-l-amine (1-20):

A suspension of LAH (0.55 g, 14.4 mmol) in THF (20 mL) was cooled to 0 °C and 3-(adamant-l-y1)propanamide (0.75 g, 3.6 mmol) in 10 mL of THF was added slowly at 0 °C for 15 minutes. After completion of addition, the reaction mixture was stirred at 70 °C for 3 h. EtOAc (20 mL) was added slowly at 0 °C followed by slow addition of water (5 mL) at 0 °C. Reaction mixture was filtered and filtrate was dried over anhydrous sodium sulphate, distilled and dried to give the crude sticky compound. This was treated with methanolic HC1 and methanol was distilled, residue was triturated with diethy1 ether (20 mL) to afford the pure title compound as a hydrochloride salt (0.34 g, 41% yield)

Synthesis of 2-methy1adamantan

3M Methy1magnesium chloride in THF (44 mL), was added through a canula to adamantan-2-one(10 g, 66.66 mmol) in THF (50 mL) at 0 °C. After stirring at 0 °C for 0.5 h, the reaction mixture was quenched by adding saturated NH4CI solution. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with water and brine, dried over Na2SO4 and the solvent was removed under reduced pressure to afford 2-methy1adamantan-2-ol (11 g, 99% yield) as an off-white solid. Synthesis of l-tricyclo[3.3.1.03'7]non-3-vlethanone(1-22):

2-Methy1adamantan-2-ol (11 g, 66.26 mmol) dissolved in a mixture of AcOH (11 mL) and CCl4 (44 mL) was added dropwise via an addition funnel to the ice bath cooled 4% NaOCl (182 mL) solution over a period of 15 minutes and the reaction mixture was stirred for 1.5 h. The two layers were separated, the aqueous layer was extracted with CCl4 and the combined organic layer was washed with water and brine, dried over Na2SO4 and the solvent was reduced to half the amount. Then it was refluxed for 1 h and the solvent was removed under reduced pressure. The residue was dissolved in methanol (150 mL), KOH (14 g) was added and the mixture was refluxed for 1 h .The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography to yield l-tricyclo[3.3.1.03'7]non-3-y1ethanone as viscous liquid (4.3 g, 40% yield). Synthesis of tricyclo[3.3.1.03,7]nonane-3-carboxy1ic acid (1-23):

To the ice bath cooled l-tricyclo[3.3.1.03'7]non-3-y1ethanone (3.8 g, 23.17 mmol) in dioxane (100 mL) and water (30 mL), NaOBr solution (50 mL) was added over a period of 20 minutes and the reaction mixture was stirred for 1 h. The reaction mixture was neutralized with con. HC1. White solid thrown out was washed with water and dried to afford the title product (2.08 g, 54% yield).

Synthesis of methy1 tricyclo[3.3.1.03'7]nonane-3-carboxy1ate (1-24):

A mixture of tricyclo[3.3.1.03,7]nonane-3-carboxy1ic acid (4.52 g, 27.20mmol) and Con.H2SO4 (2 mL) were taken in 20 mL of methanol and stirred at 80 °C for 2h. The solvent was removed by evaporation and the residue was diluted with water (100 mL), extracted with EtOAc (2 x 150 mL). The organic layer was washed with water (2 x 150 mL), brine (2 x 100 mL) and dried over anhydrous Na2SO4, concentrated to give the crude compound which was purified by column chromatography. The product was eluted at 4% (EtOAc:Hexane) to afford the pure title compound (2.65 g, 54% yield) Synthesis of tricyclo[3.3.1.03'7]non-3-y1methanol (1-25):

A suspension of LAH (1.68 g, 44.16 mmol) in THF (30 mL) was cooled to 0 °C and methy1 tricyclo[3.3.1.03'7]nonane-3-carboxy1ate (2.65g, 4.72 mmol) in 30 mL of THF was added slowly at 0 °C for 20 minutes. After completion of addition , the reaction mass was stirred at RT for 45 minutes. EtOAc (30 mL) was added slowly at 0 °C followed by slow addition of water (10 mL) at 0 °C. Reaction mixture was filtered and filtrate was dried over anhydrous sodium sulphate, distilled and dried to afford the pure product (1.75g, 78% yield).

Synthesis of tricyclo[3.3.1.03'7]nonane-3-carbaldehyde (1-26):

To a suspension of pyridinium chlorochromate (5 g, 23.05 mmol) in DCM (20 mL) tricyclo[3.3.1.03,7]non-3-y1methanol (1.752 g, 11.53 mmol) in DCM (30 mL) was added under stirring. The resulting dark brown coloured reaction mixture was stirred at RT for 1 h. Reaction mixture was diluted with diisopropy1 ether (150 mL) and filtered; the filtrate was washed with aqueous IN NaOH (2 x 150 mL) solution and water (2 x 150 mL). The organic layer was dried over anhydrous sodium sulphate, concentrated to afford the pure title compound (1.57g, 90% yield). Synthesis of methy1 (2E,3-tricyclo[3.3.1.03,7]non-3-y1acry1ate (1-27):

A suspension of NaH (0.55 g, 23.03 mmol) in THF (20 mL) was cooled to 0 °C and trimethy1phosphanoacetate (2.29 g, 12.56 mmol) was added slowly at 0 °C, to give milky white solid. Resulting mixture was stirred for 15 minutes and tricyclo[3.3.1.03'7]nonane-3-carbaldehyde (1.57 g, 10.46 mmol) in THF (30 mL) was added slowly at 0 °C. Reaction mixture was stirred at 5 °C for 1 h. It was quenched with water (25 mL) and THF was distilled. The sticky compound obtained was diluted with water (100 mL) and extracted with EtOAc (2 x 150 mL). EtOAc layer was dried over anhydrous Na2SO4, distilled and dried to afford the crude product (2.0 g, 87 % yield). Synthesis of methy1 3-tricyclo[3.3.1.03,7]non-3-y1propanoate (1-28):

10% Pd/C (10%, w/w, 0.2 g) was added to a solution of methy1 (2E)-3-tricyclo[3.3.1.0 ' ]non-3-y1acry1ate (2.0g, 9.09 mmol) in methanol (30 mL) . The reaction was then purged with H2 (40 psi) and stirred for 15 minutes. The reaction mixture was filtered through a bed of celite, filtrate was distilled and dried to afford the crude compound which was purified by column chromatography, product was eluted at 2% (EtOAc :Hexane) to afford the pure title compound (1.4g, 69% yield) Synthesis of 3-tricyclo[3.3.1.03'7]non-3-y1propanoic acid (1-29):

To a solution of methy1 3-tricyclo[3.3.1.03,7]non-3-y1propanoate (0.4 g, 1.80 mmol) in methanol (10 mL), solution of NaOH (0.144 g, 3.60 mmol) in water (2 mL) was added. The reaction mixture was stirred at 70 °C for 1 h. Methanol was evaporated and diluted with water (100 mL), extracted with EtOAc (150 mL) and aqueous layer was acidified (pH 2) with dilute 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 (0.35 g, 93% yield). Synthesis of 3-tricyclo[3.3.1.03'7]non-3-y1propan-l-ol (1-30):

A suspension of LAH (0.475 g, 12.5 mmol) in THF (10 mL) was cooled to 0 °C and methy1 3-tricyclo[3.3.1.03'7]non-3-y1propanoate (0.925 g, 4.16 mmol) in 30 mL of THF was added slowly at 0 °C for 20 minutes. After completion of addition, the reaction mixture was stirred at RT for 45 minutes. EtOAc (30 mL) was added slowly at 0 °C followed by slow addition of water (10 mL) at 0 °C. Reaction mixture was filtered and filtrate was dried over anhydrous sodium sulphate, solvent removed and dried to afford the pure product (0.7 g, 93% yield). Preparation of ethy1 (2E)-4-tricyclo[3.3.1.13,7]dec-2-y1idenebut-2-enoate (1-31):

To a suspension of sodium hydride (0.32 g, 13.3 mmol) in THF (5 mL) at 50 C was added triethy1 phosphonocrotonate (1.6 mL, 7.3 mmol) dropwise under stirring. Then the temperature was raised to RT and stirred for 30 minutes. 2-Adamantanone (1 g, 6.7 mmol) in THF (10 mL) was added and allowed to stir for an hour. Reaction mixture was diluted with water (100 mL) and extracted with ethy1 acetate (2 x 100 mL). Combined organic layer was washed with water (100 mL), dried over sodium sulphate, concentrated and dried to give the title compound (1.4 g, 86 % yield).

Example 1: Synthesis of adamant-1-y1methy1 {4-[2-(hydroxyammo)-2-oxoethy1]-l,3-thiazol-2-y1}carbamate

Step-I: Preparation of methy1 (2-amino-l,3-thiazol-4-y1)acetate hydrochloride salt:
(2-Amino-l,3-thiazol-4-y1)acetic acid (15 g, 95 mmol) was dissolved in methanol (100 mL). Thiony1 chloride (8 mL, 114 mmol) was then slowly added dropwise under stirring. Stirring was continued for 30 minutes. Methanol was distilled out completely. Pale yellow solid formed was washed with ethy1 acetate (4 x 50 mL) and dried to obtain methy1 (2-amino-l,3-thiazol-4-y1)acetate hydrochloride salt (20 g, 99 % yield). Step-II: Preparation of methy1 (2-{[(adamant-l-y1methoxy)carbony1]amino}-l,3-thiazol-4-y l)acetate:

Triphosgene (0.145 g, 0.49 mmol) was dissolved in DCM (1 mL). Adamant-1-y1methanol(I-3) (0.25 g, 1.5 mmol) and DIPEA (0.32 mL, 1.9 mmol) in DCM (2 mL) was added dropwise slowly at RT under stirring. After the addition, methy1 (2-amino-l,3-thiazol-4-y1)acetate hydrochloride salt (0.256 g, 1.5 mmol) and DIPEA (0.32 mL, 1.9 mmol) in DCM (2 mL) was added and stirred for 30 minutes. Reaction mixture was then diluted with water (70 mL) and extracted with ethy1 acetate (2 x 70 mL). Combined ethy1 acetate layer was washed with 1 % HC1 solution (2 x 50 mL), with water (100 mL) and dried over Na2SO4. The organic layer was then concentrated and dried. Crude compound was purified by column chromatography using 7 % ethy1acetate in hexane as the eluent to give the title compound (0.09 g, 16.5 % yield).

Step-Ill: Preparation of adamant-1-y1methy1 {4-[2-(hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}carbamate:

Potassium hydroxide (0.25 g, 4.4 mmol), dissolved in methanol (1 mL) was added to hydroxy1amine hydrochloride (0.308 g, 4.4 mmol), suspended in methanol (1 mL). Potassium chloride salt formed was filtered. The filtrate was added to methy1 (2-

{[(adamant-l-y1methoxy)carbony1]amino}-l,3-thiazol-4-y1)acetate (0.09 g, 0.25 mmol) and stirred for 15 minutes. Methanol was removed completely. Pasty mass obtained was diluted with water (30 mL) and pH was adjusted to 7 using dilute acetic acid. Solid obtained was filtered and dried. Crude compound was washed with diethy1 ether (2x3 mL) and dried to get title compound (0.016 g, 18 % yield). 1H NMR (DMSO-d6) 8 (ppm): 1.52 (7H, s, -CH2 & -CH), 1.60-1.68 (4H, m, -CH2), 1.96 (4H, s, -CH2), 3.29 (2H, s, -CH2), 3.75 (2H, s, -CH2), 6.80 (1H, s, Ar-H), 8.90 (1H, s, -NH), 10.60 (1H, s, -OH), 11.7 (1H, s, -NH). MS m/z: 366.1 (M++1). The following compounds were prepared according to the procedure given in Example 1:

Example 12: Synthesis of N-{4-[2-(hydroxyamino)-2-oxoethy1]-1,3-thiazol-2-y1}adamantane-l-carboxamide.
Step-I: Preparation of methy1 {2-[(adamant-l-y1carbony1)amino]-l,3-thiazol-4-vllaeetate:

Adamantane-1-carboxy1ic acid (1-1) (0.2 g, 1.1 mmol) was dissolved in THF (2 mL). CDI (1.67 mmol) was added slowly under stirring. Then methy1 (2-amino-l,3-thiazol-4-y1)acetate hydrochloride salt (0.23 g, 1.1 mmol) and TEA (0.15 mL, 1.1 mmol) in THF (3 mL) was added and heated to 80 °C for 4 h. Reaction mixture was then diluted with ethy1 acetate (100 mL) and washed with water (3 x 70 mL). Organic layer was dried over Na2SO4, concentrated and dried. Crude compound was purified by column chromatography using 10 % ethy1 acetate in hexane as an eluent to give methy1 {2-[(adamant-l-y1carbony1)amino]-l,3-thiazol-4-y1}acetate (0.2 g, 54 % yield). Step-II: Preparation of N-{4-[2-(hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1} adamantane-1 -carboxamide:

According to procedure given in example 1 step-Ill, methy1 {2-[(adamant-1-y1carbony1)amino]-l,3-thiazol-4-y1}acetate (0.2 g, 0.60 mmol) was converted to hydroxamate. Crude compound was washed with diethy1 ether (3x5 mL) and dried to get the title compound (0.11 g, 55 % yield). 1H NMR (DMSO-d6) 8 (ppm) : 1.68 (6H, s, -CH2), 1.91-1.92 (6H, d, -CH2), 1.99 (3H, s, -CH), 3.35 (2H, s, -CH2), 6.84 (1H, s, Ar-H), 8.85 (1H, s, -NH), 10.00 (1H, s, -OH), 11.31 (1H, s, -NH). MS m/z: 336.1 (M++1). The following compounds were prepared according to the procedure given in Example 12:

Example 20: Synthesis of N-{4-[l,l-difluoro-2-(hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}adamantane-l-carboxamide:

Step-I:

Preparation of ethy1 {2-[(adamant-l-y1carbony1)amino]-1,3-thiazol-4-y1}(oxo)acetate:

According to procedure given in example 12 step-I, adamantane-1-carboxy1ic acid (1-1) (0.250 g, 1.4 mmol) is coupled with ethy1 (2-amino-l,3-thiazol-4-y1)(oxo)acetate to give ethy1 {2-[(adamant-l-y1carbony1)amino]-l,3-thiazol-4-y1}(oxo)acetate. Product was purified by column chromatography using 10 % ethy1 acetate in hexane as an eluent to give ethy1 {2-[(adamant-l-y1carbony1)amino]4,3-thiazol-4-y1}(oxo)acetate (0.340 g, 67 % yield).

Step-II: Preparation of ethy1 {2-[(adamant-l-y1carbony1)amino]-l,3-thiazol-4-y1}(difluoro)acetate:

Ethy1 {2-[(adamant-l-y1carbony1)amino]-l,3-thiazol-4-y1}(oxo)acetate (0.110 g, 0.3 mmol) in 1,2-dichloroethane (1 mL) was cooled to 5 °C. Diethy1aminosulrur Trifluoride (DAST) (0.05 mL, 0.4 mmol) was added dropwise under continued stirring at 5 °C for 2 h. Then reaction temperature was raised to RT and stirring continued for 20 h. Reaction mixture was diluted with water (50 mL) and extracted with ethy1 acetate (2 x 50 mL). Combined ethy1 acetate layer was washed with water (50 mL) and dried over sodium sulphate. Organic layer was concentrated and dried. Product was purified by column chromatography using 8 % ethy1 acetate in hexane as an eluent to get ethy1 {2-[(adamant-l-y1carbony1)amino]-l,3-thiazol-4-y1}(difluoro)acetate (0.074 g, 63 % yield). Step-Ill: Preparation of N-{4-[l,l-difluoro-2-(hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}adamantane-l-carboxamide:

According to procedure given in example 1 step-III, ethy1 {2-[(adamant-l-y1carbony1)amino]-l,3-thiazol-4-y1}(difluoro)acetate (0.074 g, 0.2 mmol) was converted
to N-{4-[l,l-difluoro-2-(hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}adamantane-l-
carboxamide. Crude product was purified by flash chromatography using 9 % methanol in DCM as an eluent to get the title compound (0.022 g, 30 % yield). 1H NMR (DMSO-d6,) ppm): 1H NMR (DMSO-d6) 8 (ppm): 1.69 (6H, s, -CH2), 1.93 (6H, s, -CH2), 2.01 (3H, s, -CH), 7.58 (1H, s, Ar-H), 9.45 (1H, s, -NH), 11.70 (1H, s, -OH), 12.09 (1H, s, -NH). MS m/z: 372.0 (M++1).

Example 21: Synthesis of 2-(2-{[(adamanl-1-y lamino)carbony1] amino }-l,3-thiazol-4-y1)-N-hydroxyacetamide:
Step-I: Preparation of ethy1 (2-{[(adamant-l-y1amino)carbony1]amino}-l,3-thiazol-4-y1)acetate:

To a stirring solution of triphosgene (0.194 g, 0.65 mmol) in DCM (1 mL) was added a
solution of ethy1 (2-amino-l,3-thiazol-4-y1)acetate (370 mg, 2 mmol) and DIPEA (0.43
mL, 2.5 mmol) in DCM (3 mL). Adamantan-1-amine (300 mg, 2 mmol) and DIPEA (0.43 mL, 2.5 mmol) in DCM (2 mL) was added to reaction mixture and stirred for 30 minutes.

Reaction mixture was diluted with water (70 mL) and extracted with ethy1 acetate (100
mL). Organic layer was washed with 2 % HC1 solution (2 x 50 mL) and dried over sodium sulphate. Ethy1 acetate layer was then concentrated and dried. Product was purified by column chromatography using 0.5 % methanol in DCM as an eluent to give ethy1 (2- {[(adamant-l-y1amino)carbony1]amino}-l,3-thiazol-4-y1)acetate (0.095 g, 13 % yield).

Step-II: Preparation of 2-(2-{[(adamant-l-y1amino)carbony1]amino}-l,3-thiazol-4-
y1)-N-hydroxyacetamide:

According to procedure given in example 1 step-III, ethy1 (2-{[(adamant-1-y1amino)carbony1]amino}-l,3-thiazol-4-y1)acetate (0.095 g, 0.2 mmol) was converted to 2-(2-{[(adamant-l-y1amino)carbony1]amino}-l,3-thiazol-4-y1)-N-hydroxy acetamide. Crude product was washed with diethy1 ether (2x3 mL) and dried to give the title compound (0.016 g, 17 % yield). 1H NMR (DMSO-d6) 6 (ppm): 1.63 (6H, s, -CH2), 1.92 (6H, s, -CH2), 2.03 (3H, s, -CH), 3.24 (2H, s, -CH2), 6.30 (1H, s, -NH), 6.66 (1H, s, Ar-H), 8.81 (1H, s, -NH), 9.97 (1H, s, -OH), 10.52 (1H, s, -NH). MS m/z: 351.1 (M++l).

The following compound was prepared according to the procedure given in Example 21:
Example 23: Synthesis of 2-(adamant-l-y1amino)-N-{4-[2-(hydroxyamino)-2-oxoethy1]-l,3-thiazol-4-y1}acetamide:

Step-I: Preparation of methy1 {2-[(bromoacety1)amino]-l,3-thiazol-4-y1}acetate:
Methy1 (2-amino-l,3-thiazol-4-y1)acetate hydrochloride (0.5 g, 2.4 mmol) in DCM (10 mL) was cooled to 5 °C under stirring. Triethy1amine (0.84 mL, 6 mmol) was added slowly, followed by drop-wise addition of bromoacety1bromide (0.25 mL, 2.9 mmol) and stirring continued for 15 minutes. Reaction mixture was diluted with water (100 mL) and extracted with ethy1 acetate (2 x 70 mL). Organic layer was dried over sodium sulphate, concentrated and dried to get the title compound (0.68 g, 97 % yield). Step-II: Preparation of methy1 (2-{[(adamant-l-y1amino)acety1]amino}-l,3-thiazol-4-y1)acetate:
To a solution of adamantan-1-amine (0.3 g, 2 mmol) and methy1 {2-[(bromoacety1)amino]-l,3-thiazol-4-y1}acetate (0.64 g, 2.2 mmol) in DMF (5 mL) was added potassium carbonate (0.82 g, 6 mmol) under stirring. Reaction mixture was stirred at RT for 15 h and water was added (100 mL). The aqueous layer was extracted with ethy1 acetate (2 x 80 mL). Combined ethy1 acetate layers were washed with water (3 x 70 mL), dried over Na2SO4, concentrated and dried. Crude product was purified by columnchromatography using 0.5 % methanol in DCM as an eluent to give methy1 (2-{[(adamant-l-y1amino)acety1]amino}-l,3-thiazol-4-y1)acetate (0.22 g, 30 % yield).
Step-III: Preparation of 2-(adamant-l-yIamino)-N-{4-[2-(hydroxyamino)-2-
oxoethy1]-l,3-thiazol-4-y1}acetamide:

According to procedure given in example 1 step-Ill, methy1 (2-{[(adamant-1-y1amino)acety1]amino}-l,3-thiazol-4-y1)acetate (0.21 g, 0.58 mmol) was converted to 2-(adamant-1 -y1amino)-N- {4-[2-(hydroxyamino)-2-oxoethy1]-1,3-thiazol-4-y1} acetamide. Crude product was purified by flash chromatography using 21 % methanol in DCM as an eluent to give the title compound (0.018 g, 8 % yield). 1H NMR (DMSO- d6) 8 (ppm): 1.55-1.63 (12H, m, -CH2), 2.01 (3H, s, -CH), 3.36 (2H, s, -CH2), 3.40 (2H, s, -CH2), 6.90 (1H, s, Ar-H), 10.59 (1H, s, -NH). MS m/z: 365.1 (MN-1). The following compounds were prepared according to the procedure given in Example 23:
Example 26: Synthesis of N-[2-({4-[2-(hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}amino)-2-oxoethy1]adamantane-l-carboxamide:

Step-I: Preparation of methy1 [(adamant-l-y1carbony1)amino]acetate:
To a solution of adamantane-1-carboxy1ic acid (1-1) (0.5 g, 2.8 mmol) in DMF (10 mL) was added EDCI (l-(3-dimethy1aminopropy1)-3-ethy1carbodiimide hydrochloride) (1.07 g, 5.5 mmol), HOBt (N-hydroxybenzotriazole) (0.375 g, 2.8 mmol), glycine methy1ester hydrochloride (0.350 g, 22.8 mmol), followed by triethy1amine (1.24 mL, 8.9 mmol). The reaction mixture was stirred for 3 h and added to water (50 mL). The aqueous layer was extracted with ethy1 acetate (1 x 150 mL). Organic layer was washed with water (2 x 80 mL), brine solution (50 mL) and dried over anhydrous Na2SO4, followed by removal of solvent to give methy1 [(adamant-l-y1carbony1)amino]acetate (0.59 g, 84 % yield). Step-II: Preparation of [(adamant-l-y1carbony1)amino]acetic acid:

To a solution of methy1 [(adamant-l-y1carbony1)amino]acetate (0.59 g, 2.3 mmol) in methanol (10 mL) was added a solution of NaOH (188 mg, 4.6 mmol) in water (1 mL). The reaction mixture was stirred at 70 °C for 2 h, subsequently diluted with water (100 mL), acidified (pH 1) with dilute aqueous HC1. The aqueous layer was extracted with ethy1 acetate (2 x 70 mL), dried over sodium sulphate, concentrated to remove solvent and dried to give [(adamant-l-y1carbony1)amino]acetic acid (0.4 g, 71 % yield). Step-Ill: Preparation of methy1 [2-({[(adamant-l-y1carbony1)amino]acety1}amino)-
1,3-thaizol-4-y1] acetate:

Followed according to procedure given in example 12 step-I, [(adamant-1-
y1carbony1)amino]acetic acid (0.4 g, 1.7 mmol) reacted with methy1 (2-amino-l,3-thiazol- 4-y1)acetate hydrochloride salt (0.351 g, 1.7 mmol) to give methy1 [2-({[(adamanty1carbony1)amino]acety1}amino)-l,3-thaizol-4-y1]acetate. Crude product was purified by column chromatography using 1.5% methanol in DCM as an eluent to give the title compound (0.31 g, 47 % yield).

Step-IV: Preparation of N-|2-({4-[2-(hydroxyamino)-2-oxoethy1]-13-thiazol-2-
y1}amino)-2-oxoethy1]adamantane-l-carboxamide:

According to procedure given in example 1 step-Ill, methy1 [2-({ [(adamant-1-y1carbony1)amino] acety1} amino)-1,3 -thaizol-4-y1] acetate (0.3 g, 0.77 mmol) was converted to N-[2-({4-[2-(hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}amino)-2-oxoethy1]adamantane-2-carboxamide. Crude solid product was washed with diethy1 ether (3x5 mL), DCM (2x5 mL) and dried to get the title compound (0.026 g, 9 % yield). 1H NMR (DMSO-d6) 8 (ppm): 1.63-1.71 (6H, m, -CH2), 1.80 (6H, s, -CH2), 1.98 (3H, s, -CH), 3.32 (2H, s, -CH2), 3.88-3.89 (2H, d, -CH), 6.90 (1H, s, Ar-H), 7.72-7.74 (1H, s, -NH), 8.9 (1H, s, -NH), 10.60 (1H, s, -OH), 11.99 (1H, s, -NH). MS m/z: 393.1 (M++l). Example 27: Synthesis of 2-[4'-(adamant-l-y1)bipheny1-4-y1]-N-hydroxyacetamide:
Step-I: Preparation of 2-[4'-(adamant-l-y1)bipheny1-4-y1]acetic acid:

A suspension of 1-adamantanol (500 mg, 3.3 mmol) and bipheny1acetic acid (0.7 g, 3.3 mmol) in methane sulphonic acid (0.85 mL) was heated to 80 °C for 16 hours. Reaction mixture was diluted with water (100 mL). Solid obtained was filtered and dried to get 2-[4'-(adamant-l-y1)bipheny1-4-y1]acetic acid (1.02 g, 89 % yield). Step-II: Preparation of methy1 2-[4'-(adamant-l-y1)bipheny1-4-y1]acetate:

To a suspension of 2-[4'-(adamant-l-y1)bipheny1-4-y1]acetic acid (0.7 g, 2.1 mmol) in methanol (15 mL) was added con. sulphuric acid (0.2 mL) in drops and heated to 70 °C for 2 h. Methanol was evaporated under vacuum. Pasty mass obtained was dissolved in ethy1 acetate (100 mL) and washed with water (2 x 70 mL). Organic layer was dried over sodium sulphate, concentrated to remove solvent and dried. Crude compound was purified by flash chromatography using 7 % ethy1 acetate in hexane as an eluent to get methy1 2-[4'-(adamant-l-y1)bipheny1-4-y1]acetate (0.355 g, 46 % yield). Step-III: Preparation of 2-[4'-(adamant-l-y1)bipheny1-4-y1]-N-hydroxyacetamide:

According to procedure given m example 1 step-111, methy1 2-|4 -(adamant-l-y1)bipheny1-4-y1]acetate (0.355 g, 0.93 mmol) was converted to 2-[4'-(adamant-l-y1)bipheny1-4-y1]-N-hydroxyacetamide. Crude solid product was washed with diethy1 ether (5 mL x 2) and dried to give the title compound (0.015 g, 4.5 % yield). 1H NMR (DMSO-d6) 5 (ppm): 1.75 (6H, s, -CH2), 1.89 (6H, s, -CH2), 2.07 (3H, s, -CH), 3.33 (2H, s, -CH2), 7.31-7.33 (2H, d, Ar-H), 7.42-7.44 (2H, d, Ar-H), 7.56-7.58 (4H, m, Ar-H), 8.83 (1H, s, -OH) 10.67 (1H, s, -NH). MS m/z: 359.9 (MM). Example 28: Synthesis of 2-{2-[4-(adamant-l-y1)buty1]-l,3-thiazol-4-y1}-N-hydroxyacetamide:

Step-I: Preparation of ethy1 {2-[4-(adamant-l-y1)buty1]-l,3-thiazol-4-y1}acetate:

A mixture of 5-(adamant-l-y1)pentanethioamide (1-16) (0.18 g, 0.7 mmol), 4-chloroethy1
acetoacetate (0.13g, 0.78 mmol) was taken in ethanol (15 mL) and refluxed at 90 °C for 4
h. The solvent was removed by evaporation and the residue was diluted with water (100
mL), extracted with EtOAc (2 x 100 mL). The organic layer was washed with water (2 x
100 mL), brine (2 x 100 mL) and dried over anhydrous Na2SO4, concentrated to give the
crude compound which was purified by column chromatography, product was eluted at
3% (EtOAc:Hexane) to afford the pure title compound (0.13g, 52 % yield). MS m/z: 361.9 (M++1). Step-II

Preparation of 2-{2-[4-(adamant-l-y1)buty1]-l,3-thiazol-4-y1}-N-hydroxyacetamide:

According to procedure given in example 1 step-Ill, ethy1 {2-[4-(adamant-l-y1)buty1]-l,3-thiazol-4-y1}acetate (0.13 g, 0.36 mmol) was converted the title compound (0.08 g, 64% yield). 1H NMR (DMSO-d6) 5 (ppm): 1.23-1.32 (4H, m, -CH2), 1.43-1.67 (14H, m, adamanty1-H), 1.90 (3H, s, adamanty1-H & -CH2), 2.99-2.92 (2H, t, -CH2), 3.39 (2H, s, CH2), 7.19 (1H, s, Ar-H), 8.85 (1H, s, -NH), 10.6 (1H, s, -OH) MS m/z: 348.9 (M++l). Example 29: Synthesis of 2-{4-[4-(adamant-l-y1)buty1]pheny1}-N-hydroxyacetamide:
Step-I: Preparation of methy1 4-[(lE)-4-(adamant-l-y1)but-l-en-l-y1]benzoate:

A suspension of NaH (0.71 g, 29.6 mmol) in THF (50 mL) was cooled to 0 °C and methy1 4-[(dimethoxyphosphory1)methy1]benzoate (5.46 g, 21.1 mmol) was added slowly at 0 °C. The resulting mixture was stirred for 15 minutes and 3-(adamant-l-y1)propanal (I-10) (3.13 g, 16.3 mmol) in THF (50 mL) was added slowly at 0 °C. Reaction mixture was stirred at 5 °C for 1 h. It was quenched with water (10 mL) and THF was distilled. The sticky compound obtained was diluted with water (150 mL) and extracted with EtOAc (2 x 100 mL). EtOAc layer was dried over anhydrous Na2SO4, concentrated to give the crude compound which was purified by column chromatography, product was eluted at 1% (EtOAc:Hexane) to afford the pure title compound (1.5 g, 28 % yield) Step-II: Preparation of 4-[(LE)-4-(adamant-l-y1)but-l-en-l-y1]benzoic acid:

To a solution of methy1 4-[(lE)-4-(adamant-l-y1)but-l-en-l-y1]benzoate (1.5 g, 4.6 mmol) in methanol (50 mL) was added, a solution of NaOH (0.55 g, 13.8 mmol) in water (5 mL). The reaction mixture was stirred at 70 °C for 2 h. Methanol was evaporated and diluted with water (150 mL), extracted with EtOAc (150 mL) and aquous layer was acidified to pH 2 with dilute aqueous HC1 and allowed to stand at 4 °C for 0.5 h. The precipitated solic was filtered and dried to afford a white solid. (0.67 g, 47 % yield). MS m/z: 309.1 (M+-l) Step-III: Preparation of 4-[4-(adamant-l-y1)buty1]benzoic acid 10% Pd/C (20%, w/w, 0.14 g) was added to a solution of 4-[(lE)4-(adamant-l-y1)but-l-
en-l-y1]benzoic acid (0.67 g, 2.1 mmol) in methanol (100 mL) and THF (25 mL) . The
reaction was then purged with H2 and stirred for 15 minutes. The reaction mixture was
filtered through a pad of celite, filtrate was distilled and dried to afford the title compound as a white solid (0.57 g, 67% yield) MS m/z: 311.2 (M+-l) Step-IV: Preparation of ethy1 {4-[4-(adamant-l-y1)buty1]pheny1}acetate:

A mixture of 4-[4-(adamant-l-y1)buty1]benzoic acid (0.48 g, 1.5 mmol), oxaly1chloride (0.39g, 3.0 mmol) and two drop of DMF were taken in DCM (20 mL) and heated at 50 °C for 3 h. DCM was distilled and residue was diluted with 1:1 Acetonitrile:Tetrahydrofuran (ACN.THF) (10 mL) was added to a stirred solution of trimethy1sily1diazomethane 2 M in hexane (1.53 mL, 3 mmol) and TEA (0.42 mL, 3 mmol) in ACN:THF (10 mL) at 0 °C, and stirred at 0 °C for 3 h. Reaction mixture was quenched by adding saturated NaHCO3 (50 mL) solution and diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). EtOAc layer was dried over anhydrous Na2SO4, concentrated to give the crude compound which was purified by column chromatography, wherein product was eluted at 1% (EtOAc:Hexane) to afford the diazoketone derivative as yellow color solid (0.26 g). (0.26 g, 0.76 mmol) diazoketone derivative was dissolved in 15 mL of ethanol solution and heated at 90 °C , at which temperature freshly prepared solution of silver benzoate (0.035 g, 0.15 mmol) in TEA (0.31g, 3.0 mmol) was added and stirred at 90 °C for 45 minutes. The reaction mixture was cooled and filtered, filtrate was distilled and the residue was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). EtOAc layer was dried over anhydrous Na2SO4, concentrated to give the crude compound which was purified by column chromatography, product was eluted at 0.2% (EtOAc.Hexane) to afford the title compound (0.2 g, 37% yield) MS m/z: 372.2 (M++ NH4). Step-V: Preparation of 2-{4-[4-(adamant-l-y1)buty1]pheny1}-iV-hydroxyacetamide:

According to procedure given in example 1 step-Ill, ethy1 {4-[4-(adamant-l-y1)buty1]pheny1}acetate (0.2 g, 0.5 mmol was converted to hydroxamate to give a pasty mass, which was dissolved in water (15 mL) and the pH of the solution was adjusted to 8 using dil. acetic acid. The precipitated white solid was filtered, washed with water (100 mL) and dried. The solid was triturated with diethy1ether to afford the pure title compound (0.04 g, 21% yield). !H NMR (DMSO-d*) 8 (ppm): 1.24-1.26 (4H,m, -CH2), 1.42-1.67 (14H, m, adamanty1-H), 1.90 (3H, s, adamanty1-H & -CH2), 2.50-2.54 (2H, m, -CH2), 3.22 (2H, s, -CH2), 7.08-7.10 (2H, d, Ar-H), 7.13-7.15 (2H, d, Ar-H). MS m/z: 340.2 (MM). The following compound was prepared according to the procedure given in Example 29:
Step-I: Preparation of l-(3-bromopropy1)adamantane:

A suspension of l-(3-hydroxypropy1)adamantane (1-9) (1.4 g, 7.2 mmol) in hydrobromic acid (13 mL, 72 mmol) and cone, sulphuric acid (1 mL) was heated to 80 °C for 24 h. Reaction mixture was diluted with water (150 mL) and extracted with ethy1 acetate (2 x 100 mL). Combined organic layers were dried over sodium sulphate, concentrated and dried to get l-(3-bromopropy1)adamantane (1.25 g, 67 % yield). Step-II: Preparation of methy1 {4-(3-[adamant-l-y1]propy1oxy)pheny1}acetate:

To a solution of l-(3-bromopropy1)adamantane (0.31 g, 1.2 mmol) and methy1 (4-hydroxypheny1)acetate (0.2 g, 1.2 mmol) in DMF (3 mL) was added potassium carbonate (0.5 g, 3.6 mmol) under stirring. Reaction mixture was heated to 80 °C for 3 h and then added water (70 mL). The aqueous layer was extracted with ethy1 acetate (2 x 70 mL). Combined ethy1 acetate layers were washed with water (3 x 50 mL), dried over Na2SC»4, concentrated to remove solvent and dried. Crude product was purified by column chromatography using 2 % ethy1 acetate in hexane as an eluent to give methy1 {4-(3-[adamant-l-y1]propy1oxy)pheny1} acetate (0.255 g, 62 % yield).

Step-III: Preparation of 2-{4-[3-(adamant-l-y1)propoxy]pheny1}-N-
hydroxyacetamide.

Followed according to procedure given in example 1 step-III, methy1 {4-(3- [adamant-1-y1]propy1oxy)pheny1}acetate (0.255 g, 0.74 mmol) was converted to 2-{4-[3-(adamant-1-y1)propoxy]pheny1}-N-hydroxyacetamide. Crude product was purified by flash chromatography using 12 % methanol in DCM as an eluent to give the title compound (0.090 g, 35 % yield). *H NMR (DMSO-de) 8 (ppm): 1.13-1.17 (2H, m, -CH2), 1.46 (6H, s, -CH2), 1.58-1.68 (8H, m, -CH2), 1.92 (3H, s, -CH), 3.18 (2H, s, -CH2), 3.86-3.89 (2H, t, -CH2), 6.82-6.84 (2H, d, Ar-H), 7.13-7.15 (2H, d, Ar-H), 8.78 (1H, s, -OH) 10.58 (1H, s, -NH). MS m/z: 344.1 (M++1) & 342.1 (M-l). The following compounds were prepared according to the procedure given in Example 31:

Example 34: Synthesis of 2-(4-{[3-(adamant-l-y1)propy1amino]sulfony1}pheny1)-7V-hydroxyacetamide:

Step-I

Preparation of methy1 (4-{[3(adamant-l-y1propy1)amino]sulfony1}pheny1)acetate:
A mixture of 3-(adamant-l-y1)propan-l-amine (0.34 g, 1.4 mmol) and TEA (0.41 ml, 2.8 mmol) were taken in 15 mL of DCM and methy1 [4-(chlorosulfony1)pheny1]acetate (0.37g, 1.4 mmol) in 5 mL of DCM was added and stirred at RT for 2 h. Reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). EtOAc layer was dried over anhydrous Na2S04, concentrated to give the crude compound which was purified by column chromatography, product was eluted at 2% (EtOAc:Hexane) to afford the title compound (0.41g, 68% yield). MS m/z: 406 (M++l).

Step-II: Preparation of 2-(4-{[3-(adamant-l-y1)propy1amino]sulfony1}pheny1)-7V-hydroxy acetamide:

According to procedure given in example 1 step-III, methy1 (4-{[3 (adamant-1-y1propy1)amino]sulfony1}pheny1)acetate (0.21 g, 0.5 mmol was converted to hydroxamate to give a pasty mass, which was dissolved in water (50 mL) and the pH of the solution was adjusted to 8 by adding dilute acetic acid. The aqueous layer was extracted with EtOAc (2 x 50 mL), washed with brine solution (50 mL) and dried over anhydrous Na2S04, concentrated to give the crude compound which was purified by preparative HPLC to afford the pure title compound (0.015 g, 7 % yield). !H NMR (DMSO-de) 8 (ppm): 1.25-1.33 (4H, m, -CH2), 1.35-1.65 (12H, m, adamanty1-H), 1.89 (3H, s, adamanty1-H ), 2.62-2.647 (2H, m, -CH2), 3.4 (2H, s, -CH2), 7.44-7.46 (2H, d, Ar-H), 7.48-7.51 (1H, t, -NH) 7.69-7.72 (2H, d, Ar-H) 8.89 (1H, s, -NH), 10.72 (1H, s, -OH) MS m/z: 407.1 (M++1). Example 35: Synthesis of 2-(4-{[(3-(adamant-l-y1)propy1amino]methy1}pheny1)-iV-hydroxy acetamide:

Step-I

Preparation of methy1 (4-{[3-(adamant-l-y1)propy1amino]methy1}pheny1)acetate:
A mixture of 3-(adamant-l-y1)propan-l-amine.HCl (0.36 g, 1.5 mmol), triethy1amine (0.26 mL, 1.9 mmol) and methy1 (4-formy1pheny1)acetate (0.26 g, 1.5 mmol) in methanol (15 mL) was stirred at RT for 3 h. Sodium borohydride (0.096 g, 2.5 mmol) was added portion wise under stirring at 5 °C and resulting reaction mixture was stirred at RT for 30 minutes. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL), washed with brine solution (2 x 100 mL) and dried over anhydrous Na2SO4, concentrated to afford the pure title compound (0.12 g, 21% yield). Step-II: Preparation of 2-(4-{[(3-(adamant-l-y1)propy1amino]methy1}pheny1)-Ar-hydroxy acetamide:

According to procedure given in example 1 step-III, methy1 (4-{[3-(adamant-1-y1propy1)amino]methy1}pheny1)acetate (0.12 g, 0.3mmol) was converted to hydroxamate to give a pasty mass, which was dissolved in water (15 mL) and the pH of the solution was adjusted to 8 by adding dilute acetic acid. The precipitated white solid was filtered, washed with water (100 mL) and dried. The solid was triturated with diethy1ether to afford the pure title compound (0.075 g, 62% yield). 1H NMR (DMSO-d6) 5 (ppm): 1.25-1.42 (4H, m, -CH2), 1.51-1.80 (12H, m, adamanty1-H), 1.90 (3H, s, adamanty1-H ), 2.37-2.41 (2H, m, -CH2), 3.58-3.62 (2H, d, -CH2), 7.16-7.18 (2H, d, Ar-H), 7.21-7.23 (2H, d, Ar-H) 8.82 (1H, s, -NH), 10.62 (1H, s, -OH) MS m/z: 357.2 (M++1).

Assay to test the effect of HDAC Inhibitors on Azoles: Broth microdilution assays. Inoculum preparation:

Fresh overnight cultures are diluted in Rose Park Memorial Institute (RPMI) medium, incubated 4 h in ambient temperature, and then the concentration of inoculum is adjusted at twice the concentration needed to be achieved due to the dilution factor. Dilution with a single concentration of the HDAC-inhibitor:

Compounds to be tested are prepared in concentrations that are four-fold higher
than required to correct the dilution factor. While adding the compounds, the final DMSO
concentration should be <0.5%. An azole is serially two-fold diluted in a 96-well plate, an equal volume of the predetermined concentration of HDAC-inhibitor(HDACi) is added to each well, and the inoculum is added to each well and plates incubated for 24 h and 48 h in ambient temperature.

Dilutions for the Checkerboard technique: for assaying different concentrations of HDAC-inhibitor and Azoles.

In a 96-well microtitre plate, antifungal agent (azole) is added to row A in column
1 and serially diluted two-fold to rows B through G in column 1. Row H serves as antifungal-free control. Similarly, the HDAC-inhibitor is added to column 2 and serially diluted two-fold to columns 3 through 8 in row A. Column 9 serves as organism control and column 10 serves as HDAC-inhibitor-free control. Antifungal agent from each row is dispensed from column 2 through column 8 in their respective rows. Similarly HDAC-inhibitor from each column is dispensed from row B through row G in their respective columns and mixed well.

To the above, equal volume of the cells are added into wells and mixed well. Plates are incubated, in bags to minimize evaporation, in ambient temperature. Growth is measured by reading absorbance in a microplate reader; background due to the medium is subtracted from all samples. Minimum inhibitory concentration (MIC) is defined as the concentration inhibiting growth >80% for assays using RPMI.
Synergy, determined by the checker-board method, is defined as >4-fold decrease in MIC of the Azole in combination with the HDAC-inhibitor relative to the Azole alone. Table -1: Synergy of ketoconazole(Keto) with test compounds

ND: Not done
Table -2: Synergy of fluconazole(Flu) with test compounds

Table -3: Synergy of fluconazole with test compounds
Pan HDAC enzymatic assay.

To understand if the test compounds were binding to the fungal HDACs, an HDAC enzymatic assay was carried out using the Fluorogenic Class I HDAC substrate, Boc-Lys(Ac)-AMC.

Briefly yeast cell pellets were washed with sterile autoclaved water and resuspended in lysis buffer at pH 7.9 containing glass beads. Cells were lysed and centrifuged and the supernatant was incubated with test compounds in DMSO, diluted in assay buffer to appropriate concentrations along with substrate and incubated for 1 h. Reactions were terminated by the addition of TSA/SAHA and developed by the addition of developer and left at 37 °C for 15 minutes, before reading the plates in fluorimeter, Spectramax Gemini XS (Molecular Devices). Ex 360 Em 460. Table. 4. Inhibition of fungal Pan HDAC activity.

Hos2 enzyme assay:

Binding to one of the purified HDACs, Hos2, was studied by cloning, expressing and purifying the Hos2 protein. Briefly, Hos2 enzymatic assay was carried out using the Fluorogenic Class I HDAC substrate, Boc-Lys (Ac)-AMC. Test compounds were dissolved in DMSO and diluted in HDAC assay buffer.

Purified protein was incubated with test compound in assay buffer to appropriate concentrations along with substrate and incubated for 1h. Reactions were terminated by the addition of TSA/SAHA and developed by the addition of developer and left at 37 °C, before reading the plates in Spectramax Gemini XS (Molecular Devices) Fluorimeter at Ex 360 Em 460. Table -5 Inhibition of HOS-2 enzyme activity

SRB Assay (cell viability assay) in human cancer cell lines:

The DU145 cells (human prostate cancer cell line) were seeded in 96 well tissue culture plates and after overnight adherence, incubated with the indicated concentration of test compound, then plate was incubated for 48 h at 37 °C in CO2 and after that ice cold 30% TCA (10% of the well) was added to each well of the plate (for fixing adherence cells) and incubated at 4 °C for an hour, then plates were washed with slow running tap water. After that sulforhodamine B (SRB) solution was added to each well, incubated and then quickly the plates were rinsed four times with acetic acid to remove unbound dye, then the plate was kept at room temperature (Vanicha Vichai et al. Nature Protocols 2006, 1, 1112 - 1116) and 10 mM tris base was added to each well to solubilize the protein bound dye and the optical density (O.D.) was measured at 530 nm in a spectrophotometer. Table -6: Inhibition of cancer cell growth. Non-proliferative hPBMC assay Freshly isolated human peripheral blood mononuclear cells (hPBMC) suspension was seeded in 96 well tissue culture plates and immediately treated with test compound, then the plate was incubated for 48 h at 37 °C in CO2 and then CCK-8 (Cell counting kit-8 from Dojindo Laboratories, Japan) was added to each well (Kuhn D.M et al. J.Clin.Microbiol; 2003, 41: 506 - 508), incubated at 37 °C and the O.D. was measured at
450 nm in a spectrophotometer. IC50 values of the compounds were determined by
analyzing dose-response cell growth inhibition curves (GraphPad prism, 4).

Table -7 Inhibition of Non-proliferative hPBMCs.

Potentiation of antimicrobial activity of azoles by the HDAC inhibitors was ascertained by demonstrating the reduction in minimum inhibitory concentration of the azoles in their combination, and comparing with the activity of azoles alone [Tables. 1, 2 and 3]. The location of the target of HDAC inhibitors was identified by determining the binding of HDAC inhibitors to the panHDACs of fungal origin (C. albicans) [Table. 4]. This was further assayed with one of the purified HDACs - Hos2 [Table. 5]. These data demonstrate the synergistic activity of the HDAC inhibitors with azoles and that the mode of action is through the HDACs. The specificity of affinity of the HDAC inhibitors to fungal HDACs rather than human HDACs is demonstrated by the observations shown in Tables 6 & 7.

We Claim:

1. A Compound of formula
their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, solvates, intermediates, metabolites, prodrugs, pharmaceutical compositions and pharmaceutically acceptable salts thereof; wherein

R represents substituted or unsubstituted adamanty1, adamanty1alkeny1idene, aza-adamanty1, homoaza-adamanty1, noradamanty1, homoadamanty1, protoadamanty1 or heteroadamanty1;

X represents a bond, or the groups selected from alkeny1ene, alkyny1ene,
heterocycloalky1, -OCONR9-, -NR9COO-, -NR9CONR5-, -CONR9-, -NR9CO-, -NR9-,
-0-, -S-, -SO-, -CO-, -SO2-, -OSO2NR9-, -NR9SO2NR5-, -NR9SO2O-,
-CONR9CONR5-, -CONR9SO2NR5-, -CONR9NR5O-, -SO2NR9CONR5-,
-CONR9CR7R8CONR9-, -NR9COCR7R8NR9CO-, -NR9CR7R8CONR9-, and
-NR9COCR7R8O-;

wherein R4, R5, R7, R8 and R9 independently represent hydrogen, optionally substituted groups selected from alky1, ary1, heteroary1, heterocycly1, cycloalky1 and cycloalkeny1; or R9 and R5 can combine together to form a ring having oxo, thioxo or -C=NR6 substituted;

A and B independently represent a bond, -CO-, -SO2-, or substituted or unsubstituted groups selected from alky1ene group, alkeny1ene group, alkyny1ene group, ary1ene, ary1alky1ene and heteroary1ene;

R1 represents substituted or unsubstituted ary1ene or heteroary1ene;

R2 represents -OR3, ortho substituted aniline, amino ary1 and amino heteroary1, which are optionally substituted, wherein R3 represents hydrogen, optionally substituted groups selected from alky1, ary1, heterocycly1 and -COR6, wherein R6 represents optionally substituted groups selected from alky1, ary1, heteroary1, cycloalky1 and heterocycly1;

E and E independently represent hydrogen, ary1, alky1 or halogens; n is 1 or 2;
with the proviso that,-A-X-B- is not a bond;

when n=l and R1 is pheny1ene, then -A-X-B- is not -CONH-;

when the groups R, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are substituted, the substituents which are one or more and independently selected from halogens, hydroxy, nitro, cyano, azido, nitroso, oxo (=0), thioxo (=S), amino, hydrazino, formy1, alky1, haloalky1, alkoxy, haloalkoxy, ary1alkoxy, cycloalky1, cycloalky1oxy, ary1, heterocycly1, heteroary1, alky1amino, -COORa, -C(O)Rb, -C(S)Ra, -C(O)NRaRb, -C(S)NRaRb, -NRaC(0)NRbRc, -NRaC(S)NRbRc, -N(Ra)SORb, -N(Ra)SO2Rb, -NRaC(O)ORb, -NRaRb, -NRaC(O)Rb, -NRaC(S)Rb, -SONRaRb, -SO2NRaRb, -ORa, -ORaC(O)ORb, -OC(O)NRaRb, -OC(O)Ra, -OC(O)NRaRb, -RaNRbRc, -RaORb, -SRa, -SORa and -SO2Ra, wherein Ra, Rb and Rc in each of the above groups independently represent hydrogen, halogens, optionally substituted groups selected from alky1, alky1ene, cycloalky1, ary1, ary1alky1, heterocycly1, heteroary1 and heteroary1alky1; the substituents are optionally further substituted by one or more substituents as defined above. 2. The compound according to claim 1 having the formula (la), their tautomeric forms, stereoisomers, polymorphs, solvates, intermediates, metabolites, prodrugs, analogs, derivatives, pharmaceutical compositions and pharmaceutically acceptable salts;
wherein R1 represents thiazoly1 or pheny1ene;

R represents -OR , wherein R represents hydrogen, optionally substituted groups selected from alky1, ary1, heterocycly1 and -COR , wherein R represents optionally substituted groups selected from alky1, ary1, heteroary1, cycloalky1 and heterocycly1;

E1 and E2 independently represent hydrogen or halogens; n is 1 or 2;

R represents substituted or unsubstituted adamanty1, adamanty1alkeny1idene, aza-adamanty1, homoaza-adamanty1 and noradamanty1;

X represents a bond, or the groups selected from alkeny1ene, alkyny1ene, -OCONR9-, -NR9COO-, -NR9CONR5-, -CONR9-, -NR9CO-, -NR9-, -O-, -S-, -CONR9R5CO-, -CONR9CR7R8CONR9-, -NR9CR7R8CONR9- and -NR9COCR7R8O-;

A and B independently represent a bond, -CO-, -SO2-, or substituted or unsubstituted groups selected from alky1ene group, alkeny1ene group, alkyny1ene group, ary1ene, ary1alky1ene and heteroary1ene; and n, R , R , R and R are as defined earlier;
with the proviso that,-A-X-B- is not a bond;

when n=l and R1 is pheny1ene, then -A-X-B- is not -CONH-. 3. The compound according to claim 1, wherein: when alkoxy group is present, the alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy; when ary1oxy group is present, the ary1oxy group is selected from phenoxy and 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, t-buty1, penty1, hexy1, hepty1 or octy1; when alky1amino group is present, alky1amino group is methyamino, ethy1amino, propy1amino or isopropy1amino; when alky1ene group is present, the alky1ene group is methy1ene, ethy1ene, propy1ene, buty1ene or penty1ene; 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 alkeny1ene group is present, the alkeny1ene group is etheny1ene, propeny1ene, buteny1ene or penteny1ene; when the alkyny1 group is present, the alkyny1 group is ethyny1, propyny1 or butyny1; when alkyny1ene group is present, the alkyny1ene group is ethyny1ene, propyny1ene, butyny1ene or pentyny1ene; when cycloalky1 group is present, the cycloalky1 group is cyclopropy1, cyclobuty1, cyclopenty1, cyclohexy1, cycloocty1, cyclohepty1 or perhydronaphthy1; when cycloalky1oxy groups is present, cycloalky1oxy groups is cyclopropy1oxy, cyclobuty1oxy or cyclopenty1oxy; when cycloalkeny1 group is present, the cycloalkeny1 group is selected from cyclopenteny1 and cyclohexeny1; when heteroary1 group is present, the 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 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. 4. The compounds according to claim 1 selected from the group consisting of:

Adamant-1 -y1methy1 {4-[2-(hydroxyamino)-2-oxoethy1]-1,3-thiazol-2-y1} carbamate;
Adamant-2-y1ethy1{4-[2-(hydroxy1amino)-2-oxoethy1]-l,3-thiazol-2-y1}carbamate;
Adamant-1 -y1ethy1 {4-[2-(hydroxyamino)-2-oxoethy1]-1,3-thiazol-2-y1} carbamate;
3-Chloroadamant-1 -y1methy1 {4-[2-(hydroxyamino)-2-oxoethy1]-1,3-thiazol-2-
y1} carbamate;

Adamant-1 -y1methy1 {4- [1,1 -difluoro-2-(hydroxyamino)-2-oxoethy1] -1,3 -thiazol-2-
y1} carbamate;

3-[4(Adamant-l-y1)pheny1]propy1-{4-[2-(hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-
y1} carbamate;

3 -(Adamant-1 -y1)propy1 {4- [2-(hydroxyamino)-2-oxoethy1] -1,3 -thiazol-2-y1} carbamate;

Tricyclo[3.3.1.0 * ]non-3-y1methy1-N-{4-[2-(hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-
y1} carbamate;

3-(Tricyclo[3.3.1.03,7]non-3-y1)propy1{4-[2-(hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-
y1} carbamate;

3-Pheny1adamant-1 -y1methy1 {4-[2-(hydroxyamino)-2-oxoethy1]-1,3-thiazol-2-
y1} carbamate;

3 -(Tricyclo [3.3.1.03'7]non-3 -y1)propy1 {4- [2-(hydroxyamino)-2-oxoethy1] -
pheny1} carbamate;

N-{4-[2-(Hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}adamantane-l-carboxamide;

N-{4-[2-(Hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}adamantane-l-acetamide;

N- { 4- [2-(Hydroxyamino)-2-oxoethy1] -1,3 -thiazol-2-y1} -3 -(3 -chloroadamant-1 -
y1)acry1amide;

N-{4-[2-(Hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}-3-[4-(adamant-l-
y1)pheny1]propanamide;

JV-Hydroxy-2-[4-(3-oxo-3-(4-azatricyclo[4.3.1.13,8]undec-4-
y1)propy1)pheny1]acetamide;

N- {4- [2-(Hydroxyamino)-2-oxoethy1]pheny1} -3 -[4-(adamantan-1 -
y1)pheny1]propanamide;

N-{4-[2-(Hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}-3-(tricyclo[3.3.1.03,7]non -3-
y1)propanamide;

N- {4- [2-(Hydroxyamino)-2-oxoethy1]-1,3 -thiazol-2-y1} -3 -(3 -pheny1adamant-1 -
y1)propanamide;

N- {4- [ 1,1 -Difluoro-2-(hydroxyamino)-2-oxoethy1] -1,3-thiazol-2-y1} adamantane-1 -
carboxamide;

2-(2-{[(Adamant-l-y1amino)carbony1]amino}-l,3-thiazol-4-y1)-N-hydroxyacetamide;

N- {4- [2-(Hydroxyamino)-2-oxoethy1] -1,3 -thiazol-2-y1} -4-azatricyclo
[4.3.1.13'8]undecane-4-carboxamide;

2-( Adamant-1 -y1amino)-N- {4-[2-(hydroxyamino)-2-oxoethy1]-1,3-thiazol-4-
y1}acetamide;

2-(3 -Pheny1adamantan-1 -y1amino)-N- {4- [2-(hydroxyamino)-2-oxoethy1] -1,3 -thiazol-2-
y1}acetamide;

2- {4-[2-(Adamant-1 -y1amino)-2-oxoethoxy]pheny1} -N-hydroxyacetamide;
N-[2-({4-[2-(Hydroxyamino)-2-oxoethy1]-l,3-thiazol-2-y1}amino)-2-
oxoethy1]adamantane-1 -carboxamide;

2- [4' -(Adamant-1 -y1)bipheny1-4-y1] -N-hydroxyacetamide;

2-{2-[4-(Adamant-l-y1)buty1]-l,3-thiazol-4-y1}-A^-hydroxyacetamide;

2- { 4- [4-( Adamant-1 -y1)buty1]pheny1} - JV-hydroxyacetamide;

2- {4- [3 -(Adamant-1 -y1)propy1]pheny1} -N-hydroxyacetamide;

2- {4-[3-(Adamant-1 -y1)propoxy]pheny1} -N-hydroxyacetamide;

2-{4-[4-(Adamant-2-y1)butoxy]pheny1}-N-hydroxyacetamide;

2- {4- [3 -(Adamant-1 -y l)propanamino]pheny 1} -N-hydroxyacetamide;

2-(4- {[3 -(Adamant-1 -y1)propy1] aminosulfony1} pheny1)-N-hydroxyacetamide; and

2-(4-{[3-(Adamant-l-y1)propy1]aminomethy1}pheny1)-N-hydroxy acetamide. 5. A process for the preparation of compound of formula (I) according to claim 1, comprising reacting the compound of formula (2) or its acid with R2NH2 or R2R4NH,

wherein the groups R, A, X, B, R1, R2, R4, E1, E2, and n are as defined earlier.

6. A pharmaceutical composition comprising a compound of formula (I), according to claims 1, 2 or 4 and an effective amount of antifungal agent along with a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising a selective amount of compound of formula (I), according to claims 1, 2 or 4 along with a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 6, wherein the antifungal agent is ergosterol synthesis inhibitor selected from imidazole comprising clotrimazole, miconazole and ketoconazole; triazole comprising fluconazole, itarconazole, isavucanazole, ravucanazole, posoconazole, voriconazole and terconazole; and squalene epoxidase inhibitor comprising phenpropimorph and terbinafine.

9. Compound of formula (I) according to claims 1, 2 or 4, or its combination with antifungal agent for treating fungal infections.

10. Compound of formula (I) according to claims 1, 2 or 4, for inhibiting HDAC in a fungal cell.

11. A compound according to claims 1, 2 or 4, for reducing resistance of a fungal cell to an antifungal agent in a mammal.

12. A compound of formula (I) as claimed in claims 1, 2 or 4, a process for their preparation according to claim 5 and a use according to claims 9, 10, 11 and 12, substantially as herein described with reference to the examples.