WO2011058582A1 - Histone deacetylase inhibitors for the treatment of fungal infections - Google Patents

Abstract

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. The invention relates to compositions and methods to treat fungal infection. These compounds are selective HDAC inhibitors that act as inherent antifungal compounds or enhance the activity of other antifungal compounds such as azoles.

Description

HISTONE DEACETYLASE INHIBITORS FOR THE TREATMENT OF FUNGAL

INFECTIONS

Field

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 inframammary 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 19^th ed; Antimicrobial Agents and Chemotherapy, 2002: 46(1 1): 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-demethylation of cytochrome P-450 3-A dependent enzyme 14-a-lanosterol-demethylase, 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. 4^th 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-demethylase 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 deacetylases) 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 acetyltransferases, which transfer an acetyl group from acetyl CoA to an ε-amino group of lysine residues of histones loosening the nucleosomes, and HDACs that catalyze the hydrolysis of acetamides by removing acetyl groups and lead to the compaction of chromatin (The Oncologist, 2003; 8:389-391). It has been recognized in recent years that histone acetylation and deacetylation play important roles in eukaryotic gene regulation. The ε-amino groups of lysine residues within the flexible amino-terminal tails of the core histones are the primary targets for acetylation. 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 deacetylase genes (HDA1, RPD3, HOS1, HOS2, and HOS3) have been cloned from Candida albicans and characterized. Sequence analysis and comparison with 12 additional fungal deacetylases resulted in a phylogenetic 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 phylogeny. 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 deacetylase with the highest homology to each C. albicans deacetylase 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 deacetylases(HDAs). TSA is _. a potent and specific inhibitor of both mammalian and yeast histone deacetylase 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, metabolites, prodrugs, pharmaceutical compositions and pharmaceutically acceptable salts thereof;

R represents substituted or unsubstituted adamantyl, adamantylalkenylidene, aza-adamantyl, homoaza-adamantyl, noradamantyl, homoadamantyl, protoadamantyl or heteroadamantyl;

X represents a bond, or the groups selected from alkenylene, alkynylene, heterocycloalkyl, -OCONR⁹-, -NR⁹COO-, -NR⁹CONR⁵-, -CONR⁹-, -NR⁹CO-, -NR⁹-, -0-, -S-, -SO- -CO-, -S0₂- -OS0₂NR⁹-, -NR⁹S0₂NR⁵-, -NR⁹S0₂0- -CONR⁹CONR⁵-, -CONR⁹S0₂NR⁵-, -CONR^R^O- -S0₂NR⁹CONR⁵- -CONR⁹CR⁷R⁸CONR⁹-, -NR⁹COCR⁷R⁸NR⁹CO-, -NR⁹CR⁷R⁸CONR⁹-, and -NR⁹COCR⁷R⁸0-;

wherein R⁴, R⁵, R⁷, R⁸ and R⁹ independently represent hydrogen, optionally substituted groups selected from alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl and cycloalkenyl or R⁹ and R⁵ can combine together to form a ring having oxo, thioxo or -C=NR⁶ substitutent;

A and B independently represent a bond, -CO-, -S0₂- or substituted or unsubstituted groups selected from alkylene, alkenylene, alkynylene, arylene, arylalkylene and heteroarylene;

R¹ represents substituted or unsubstituted arylene or heteroarylene;

R² represents -OR³, ortho substituted aniline, amino aryl or amino heteroaryl, which may be optionally substituted, wherein R represents hydrogen, optionally substituted groups selected from alkyl, aryl, heterocyclyl and -COR⁶, wherein R⁶ represents optionally substituted groups selected from alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl;

E¹ and E² independently represent hydrogen, aryl, alkyl or halogens;

n is an integer selected from 1 to 2;

with the proviso that,

-A-X-B- is not a bond;

when n=l and R¹ is phenylene, 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), -S0₂, amino, hydrazino, formyl, alkyl, haloalkyl group such as trifluoromethyl, tribromomethyl, trichloromethyl and the like; alkoxy, haloalkoxy such as -OCH₂Cl and the like; arylalkoxy such as benzyloxy, phenylethoxy and the like; cycloalkyl, cycloalkyloxy, aryl, heterocyclyl, heteroaryl, alkylamino, -CQOR³, -C(0)R^b, -C(S)R^a, -C(0)NR^aR^b, -C(S)NR^aR^b, -NR^aC(0)NR^bR^c, -NR^aC(S)NR^bR^c, -N(R^a)SOR^b, -N(R^a)S0₂R^b, -NR^aC(0)OR^b, -NR^aR^b, -NR^aC(0)R^b, -NR^aC(S)R^b, -SONR^aR^b, -S0₂NR^aR^b, -OR^a, -OR^aC(0)OR^b, -OC(0)NR^aR^b, -OC(0)R^a, -R^R , - R^aOR^b, -SR^a, -SOR^a and -S0₂R^a, wherein R^a, R^b and R° in each of the above groups can be hydrogen, halogens, optionally substituted groups selected from alkyl, alkylene, cycloalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl and heteroarylalkyl; the substituents are optionally further substituted by one or more substituents as defined above.

In another embodiment, 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 thiazolyl or phenylene;

R² represents -OR³, wherein R³ represents hydrogen, optionally substituted groups selected from alkyl, aryl, heterocyclyl and -COR⁶, wherein R⁶ represents optionally substituted groups selected from alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl;

E¹ and E² independently represent hydrogen, or halogens;

n is an integer selected from 1 to 2;

R represents substituted or unsubstituted adamantyl, adamantylalkenylidene, aza-adamantyl, homoaza-adamantyl and noradamantyl;

X represents a bond, or the groups selected from alkenylene, alkynylene, -OCONR⁹-, -NR⁹COO-, -NR⁹CONR⁵-, -CONR⁹-, -NR⁹CO-, -NR⁹-, -0-, -S-, -CONR'WCO- -CONR⁹CR⁷R⁸CONR⁹-, -NR⁹CR⁷R⁸CONR⁹- and

-NR⁹COCR⁷R⁸0-;

A and B independently represent a bond, -CO-, -S0₂-_; or substituted or unsubstituted groups selected from alkylene, alkenylene, alkynylene, arylene, arylalkylene and heteroarylene; 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 phenylene, 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, E and E independently represent hydrogen or halogens;

R¹ represents thiazolyl or phenylene;

R represents substituted or unsubstituted adamantyl, adamantylalkenylidene, aza-adamantyl, homoaza-adamantyl, noradamantyl, homoadamantyl, protoadamantyl and heteroadamantyl;

the linker A-X-B is selected from the group consisting of

-(Ci-C₆)alkyleneOCONR⁹-, -arylene(C₁-C₆)alkyleneOCONR⁹-, -CONR⁹-, -(d-C₆)alkenyleneCONR⁹- -arylene(Ci-C₆)alkyleneCONR⁹- -CO(C,-C₆alkylene)-, -(C₁-C₆)alkyleneCONR⁹-, -NR⁹CONR⁵-,

-NR⁹(Ci-C₆)alkyleneCONR⁹-, -NR⁹CO(C₁-C₆)alkyleneO-, -CONR⁹(C₁-C₆)alkyleneCONR⁵-, -(C₁-C₆)alkyleneNR⁹S0₂-, -arylene- -(Q- C₆)alkylene-, -(C₁-C₆)alkyleneO-, -(d-C₆)alkyleneNR⁹-,

-(C₁-C₆)alkyleneNR⁹(C₁-C₆)alkylene-, wherein one or two carbon atoms of the alkylene 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 alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl and cycloalkenyl; with the proviso that, when n=l and Rl is phenylene; -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 "alkyl" 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 alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl and the like.

The term "alkylene" refers to a 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 alkylene groups include, without limitation, methylene, ethylene, propylene, butylene and the like.

The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched chain having about 2 to 10 carbon atoms, preferably 2-6 carbon atoms, which may be optionally- substituted by one or more substituents. Preferred alkenyl groups include, without limitation, ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl-l-propenyl, 1- butenyl, 2-butenyl and the like.

The term "alkenylene" 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 alkenylene groups include, without limitation, ethenylene, propenylene, butenylene and the like.

The term "alkynyl" refers to a straight or branched hydrocarbyl radicals having at least one carbon-carbon triple bond and having in the range of 2-12 carbon atoms, preferably 2-6 carbon atoms, which may be optionally substituted by one or more substituents. Preferred alkynyl groups include, without limitation, ethynyl, propynyl, butynyl and the like.

The term "alkynylene" refers to a straight or branched divalent hydrocarbyl 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 alkynylene groups include, without limitation, ethynylene, propynylene, butynylene, pentynylene and the like. The term "halo" or "halogen" herein refers to fluorine, chlorine, bromine or iodine.

The term "cycloalkyl" refers to non-aromatic mono or polycyclic ring system of about 3 to 12 carbon atoms, which may be optionally substituted by one or more substituents. The polycyclic ring denotes hydrocarbon systems containing two or more ring systems with one or more ring carbon atoms in common i.e. a spiro, fused or bridged structures. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, perhydronaphthyl, adamantyl, homoadamantyl, noradamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups e.g spiro [4.4] non-2-yl and the like.

The term "cycloalkenyl" 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 cycloalkenyl groups include, without limitation, cyclopropenyl, cyclopentenyl and the like.

Furthermore the term "heterocyclyl" refers to a stable 3 to 15 membered ring radical, which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, 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 heterocyclyl groups include, without limitation, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, homopiperazinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, thienyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, furyl, tetrahydrofuryl, tetrahydropyranyl, chromanyl and isochromanyl. The term "heteroaryl" refers to an aromatic heterocyclic ring radical as defined above. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of stable structure. The term "heteroarylene" also refers to divalent heteroaryl.

The term "heterocycloalkyl" refers to a hydrocarbyl radical having alkyl group attached to the heterocyclyl ring.

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

The term "arylene" also refers to aryl. Preferred arylene groups include, without limitation, phenylene, naphthylene, biphenylene and the like

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

The term "adamantylalkenylidene" refers to a hydrocarbyl radical having alkenylidene group attached to the adamantyl ring.

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

The term "alkoxy" refers to an alkyl group attached via an oxygen linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Preferred alkoxy groups include, without limitation, -OCH_3; -OC₂H₅ and the like.

The trem "alkylamino" refers to an alkyl group attached via an amino linkage to the rest of the molecule. Preferred alkylamino group include, without limitation, methyamino, ethylamino, propylamino, isopropylamino and the like.

The term "arylalkoxy" refers to an alkoxy group attached to an aryl substituent. Preferred arylalkoxy groups include, without limitation, phenylmethyl ether and the like.

The term "cycloalkyloxy" refers to cycloalkyl group attached via an oxygen linkage to the rest of the molecule, Preferred cycloalkyloxy groups include, wthout limitation, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and the like. The term "haloalkoxy" refers to a group resulting from the replacement of one or more hydrogen atoms from a C_1-4 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 "haloalkyl" refers to an halogen group attached via an alkyl linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Preferred haloalkyl groups include, without limitation, -CH₂Cl_j -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 cycloalkyl group, as defined herein, in which two non-adjacent carbon atoms of the cycloalkyl group are linked by an alkylene 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 alkylene bridge of between one and three carbon atoms. Representative examples of tricyclic- ring systems include, but are not limited to, tricyclo[3.3.1.0 ³'⁷ Jnonane and tricyclo[3.3.1.1 ³'⁷ Jdecane (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, alkylation, 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'-diacetylethylenediamine, glucamine, triethylamine, choline, dicyclohexylamine, benzylamine, trialkylamine, thiamine, guanidine, diethanolamine, cc-phenylethylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, ammonium, substituted ammonium salts, aluminum salts and the like. Salts also include amino acid salts such as glycine, alanine; cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc. Salts may include acid addition salts, where appropriate, which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.

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 deacetylase" and "HDAC" are intended to refer to any one of a family of enzymes that remove acetyl groups from the ε-amino groups of lysine residues at the N-terminus of a histone. Unless otherwise indicated by context, the term "histone" is meant to refer to any histone protein, including HI, 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 deacetylase can also be derived from a protozoal or fungal source.

The term "histone deacetylase inhibitor" is used to identify a compound having structure as defined herein, which is capable of interacting with histone deacetylase and inhibiting its enzymatic activity. Inhibiting histone deacetylase enzymatic activity means reducing the ability of histone deacetylase to remove an acetyl group from histone. Such inhibition is specific, i.e. histone deacetylase inhibitor reduces the ability of histone deacetylase to remove an acetyl 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 deacetylase are more active against a fungal histone deacetylase than a plant or mammalian histone deacetylase; preferably the inhibitory activity is specific for fungal histone deacetylase.

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- 1 -ylmethyl { 4- [2-(hydroxyamino)-2-oxoethyl] - 1 ,3 -thiazol-2- yl} carbamate; 2. Adamant-2-ylethyl{4-[2-(hydroxylamino)-2-oxoethyl]-l,3-thiazol-2- yl} carbamate;

3. Adamant- 1 -ylethyl {4- [2-(hydroxyamino)-2-oxoethyl] - 1 ,3 -thiazol-2-yl } carbamate;

4. 3 -Chloroadamant- 1 -ylmethyl {4- [2-(hydroxyamino)-2-oxoethyl] - 1 ,3 -thiazol-2- yl} carbamate;

5. Adamant- 1 -ylmethyl { 4- [ 1 , 1 -difluoro-2-(hydroxyamino)-2-oxoethyl] - 1 ,3 -thiazol-2- yl} carbamate;

6. 3-[4(Adamant-l-yl)phenyl]propyl-{4-[2-(hydroxyamino)-2-oxoethyl]-l,3-thiazol- 2-yl}carbamate;

7. 3-(Adamant- 1 -yl)propyl{4-[2-(hydroxyamino)-2-oxoethyl]- 1 ,3-thiazol-2- yl} carbamate;

8. Tricyclo[3.3.1.0³'⁷]non-3-ylmethyl-N-{4-[2-(hydroxyamino)-2-oxoethyl]-l,3- thiazol-2-yl } carbamate;

9. 3-(Tricyclo[3.3.1.0³'⁷]non-3-yl)propyl{4-[2-(hydroxyamino)-2-oxoethyl]-l ,3- thiazol-2-yl} carbamate;

10. 3 -Phenyladamant- 1 -ylmethyl { 4-[2-(hydroxyamino)-2-oxoethyl] - 1 ,3 -thiazol-2- yl} carbamate;

11. 3 -(Tricyclo [3.3.1.0³'⁷]non-3 -yl)propyl {4- [2-(hydroxyamino)-2-oxoethyl] - phenyl } carbamate ;

12. N- {4-[2-(Hydroxyamino)-2-oxoethyl]- 1 ,3 -thiazol-2-yl } adamantane- 1 - carboxamide;

13. N- {4-[2-(Hydroxyamino)-2-oxoethyl]- 1 ,3-thiazol-2-yl } adamantane- 1 -acetamide;

14. N-{4-[2-(Hydroxyamino)-2-oxoethyl]-l,3-thiazol-2-yl}-3-(3-chloroadamant-l- yl)acrylamide;

15. N-{4-[2-(Hydroxyamino)-2-oxoethyl]-l,3-thiazol-2-yl}-3-[4-(adamant-l- yl)phenyl]propanamide;

16. N-Hydroxy-2-[4-(3-oxo-3-(4-azatricyclo[4.3.1.1³'⁸]undec-4- yl)propyl)phenyl] acetamide;

17. N-{4-[2-(Hydroxyamino)-2-oxoethyl]phenyl}-3-[4-(adamantari-l- yl)phenyl]propanamide;

18. N- {4- [2-(Hydroxyamino)-2-oxoethyl]- 1 ,3 -thiazol-2-yl } -3 - (tricyclo [3.3.1.0³'⁷]non -3 -yl)propanamide ; 9. N-{4-[2-(Hydroxyamino)-2-oxoethyl]-l ,3-thiazol-2-yl}-3-(3-phenyladamant-l - yl)propanamide;

0. N- {4-[ 1 , 1 -Difluoro-2-(hydroxyamino)-2-oxoethyl]- 1 ,3-thiazol-2-yl } adamantane- 1-carboxamide;

1. 2-(2- { [(Adamant- 1 -ylamino)carbonyl] amino } - 1 ,3-thiazol-4-yl)-N- hydroxyacetamide ;

2. N-{4-[2-(Hydroxyamino)-2-oxoethyl]-l,3-thiazol-2-yl}-4-azatricyclo

[4.3.1. l³'⁸]undecane-4-carboxamide;

3. 2-(Adamant- 1 -ylamino)-N- {4-[2-(hydroxyamino)-2-oxoethyl]- 1 ,3-thiazol-4- yl}acetamide;

4. 2-(3-Phenyladamantan- 1 -ylamino)-N- {4-[2-(hydroxyamino)-2-oxoethyl]- 1 ,3- thiazol-2-yl } acetamide;

5. 2-{4-[2-(Adamant-l-ylamino)-2-oxoethoxy]phenyl}-N-hydroxyacetamide;

6. N-[2-({4-[2-(Hydroxyamino)-2-oxoethyl]-l,3-thiazol-2-yl}amino)-2- oxoethyl] adamantane- 1 -carboxamide;

7. 2-[4' -(Adamant- 1 -yl)biphenyl-4-yl]-N-hydroxyacetamide;

8. 2- {2- [4-(Adamant- 1 -yl)butyl]- 1 ,3 -thiazol-4-yl } -N-hydroxyacetamide;

9. 2-{4-[4-(Adamant-l-yl)butyl]phenyl}-N-hydroxyacetamide;

0. 2-{4-[3-(Adamant-l-yl)propyl]phenyl}-N-hydroxyacetamide;

1. 2-{4-[3-(Adamant-l-yl)propoxy]phenyl}-N-hydroxyacetamide;

2. 2-{4-[4-(Adamant-2-yl)butoxy]phenyl}-N-hydroxyacetamide;

3. 2-{4-[3-(Adamant-l-yl)propanamino]phenyl}-iV-hydroxyacetamide;

4. 2-(4-{[3 -(Adamant- 1 -yl)propyl] aminosulfonyl } phenyl)-N-hydroxyacetamide ; and 5. 2-(4- { [3-(Adamant- 1 -yl)propyl]aminomethyl}phenyl)-N-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.

Scheme 1

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 hydroxylamine HC1 or R²NH₂ 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 alkyl esters such as ethyl, isopropyl, t-butyl 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.

Schem

Step 1: Conditions: Triphosgene, ; Diisopropylethylamine (DIPEA) and Dichloromethane (DCM) (when Z =OH/NH₂) or Carbonyldiimidazole (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 carbonyldiimidazole in the presence of organic base such as DIPEA,triethylamine 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 carbonyldiimidazole 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-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI), hydroxy benzotriazole (HOBt) and the like in the presence of the respective amine (Id) to yield the compound of the general formula (2).

Scheme lc:

Step 1: Conditions: Carbonyldiimidazole (CDI), Triethylamine (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 (If).

Step 2:

Conditions: Diethylaminosulfur 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).

Sche

Step 1: Conditions: CH₃S0₃H,

Reacting the alcohol (lg) with biphenylacetic acid (lh) in presence of acid such as methanesulphonic acid and the like to yield the compound of the general formula (li). Step 2: Conditions: H₂S0₄, 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:

A NH? ^SteP ¹

R" ^A^C- > . „Α^_ν, ΕΚ .ΝΗ₂ ' Step 2 _R- A „E ,

Λ R ^x Y + 4-CIEAA . ,

(1j) ^U (1k) S (2)

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, triethylamine 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 (lk).

Step 2: Conditions: H₂S0₄, MeOH.

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

Scheme If:

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 (In).

Step 2: Conditions: KOH, Oxalyl chloride, TMSdiazomethane, TEA, Silver benzoate. The compound of formula (In) was further one carbon homologated (Arndt eistert reaction) to yield the compound of general formula (2).

Scheme lg:

Step 1 : Conditions: NaH or K₂C0₃

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).

Schem

Step 1: Conditions: NaB¾ 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 CI, 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 adaniantane-l-carboxylic 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.) H₂S0₄ 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 methyl adamantane-l-carboxylate (1-2):

A mixture of adamantane-l-carboxylic acid (25 g, 138 mmol) and Con. H₂S0₄

(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 Na₂S0_4; 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-l-ylmethanol

A suspension of Lithium Aluminium Hydride (LAH) (6.41 g, 168 mmol) in THF (250 mL) was cooled to 0 °C and methyl adamantane-l-carboxylate (21.8 g, 1 12 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-l-carbaldeh de (1-4):

To a suspension of pyridinium chloro chromate (23.17 g, 107.5 mmol) in DCM

(150 mL) was added adamant- 1-ylmethanol (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 diisopropyl 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 methyl (2E)-3-(adamant-l-yl)acrylate (1-5):

A suspension of NaH (2.38 g, 99 mmol) in THF (200 mL) was cooled to 0 °C and trimethylphosphonoacetate (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-l- 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 Na₂S0₄, distilled and dried to afford the crude product (10.75g, 91% yield). Synthesis of (2 )-3-(adamant-l-y

To a solution of methyl (2£)-3 -(adamant- 1 -yl)acrylate (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 HCl. 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-yl)prop

Pd/C (10%, 1.48 g) was added to a solution of (2£)-3-(adamant-l-yl)acrylic 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 methyl 3-(adamant- -yl)propanoate (1-8):

A mixture of 3-(adamant-l-yl)propanoic acid (7.2 g, 34.6 mmol) and Con. H S0₄ (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 Na₂S0_4, concentrated to afford the pure title compound (7.34 g, 95% yield ).

Synthesis of 3-(adamant-l-yI)propan-l-ol 1-9):

A suspension of LAH (2.51 g, 66 mmol) in THF (100 mL) was cooled to 0 °C and methyl 3 -(adamant- l-yl)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-yl)propanal (1-10):

To a suspension of pyridinium chlorochromate (7.75 g, 36 mmol) in DCM (50 mL) was added 3-(adamant-l-yl)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 diisopropyl 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 ethyl (2E,4E)-5-(adamant-l- l)penta^2,4-dienoate (I- 11):

A suspension of NaH (1.18 g, 49 mmol) in THF (50 mL) was cooled to 0 °C and triethyl-4-phosphonocrotonate (8.83 g, 35 mmol) was added slowly at 0 °C. The resulting mixture was stirred for 15 minutes and adamantane-l-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 Na₂S0₄, distilled and dried to afford the crude product (6.7 g, 95% yield).

Synthesis of (2E,4E)-5-(adamant-l- l)penta-2,4-dienoic acid (1-12):

To a solution of ethyl (2E,4E)-5-(adamant-l-yl)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-yl)pentanoic acid (1-13):

Pd/C (10%, 0.4 g ) was added to a solution of (2£,4£)-5 -(adamant- l-yl)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-yl)pentanamide (1-14):

A mixture of 5 -(adamant- l-yl)pentanoic acid (1.72 g, 7.2 mmol), thionylchloride (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 Na₂S0_4; concentrated to give the crude compound, which was further triturated with diethyl ether (20 mL) to afford the pure title compound (1.41 g, 82% yield).

Synthesis of 5-(adamant-l-yl)pentanenitrile 1-15):

5 -(Adamant- l-yl)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 (0.8 lg, 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 Na₂S0_4; concentrated to afford the crude title compound (0.4 g, 87% yield).

Synthesis of 5-(adamant-l-yl)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-yl)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 Na₂S0_4i 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 hydroxylamine 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[4.3.1.1 ' ]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 Na₂S0_4> concentrated to give the crude compound (2.42g, 48% yield).

Synthesis of 4-azatricyclo[4.3.1.1³'⁸]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 diethyl ether (20 mL) to afford the pure title compound as a hydrochloride salt (0.5 g, 18% yield)

Synthesis of 3-(adamant-l-yl)pro an-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- 1 -yl)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 diethyl ether (20 mL) to afford the pure title compound as a hydrochloride salt (0.34 g, 41% yield)

Synthesis of 2-methyladaman

3M Methylmagnesium 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 NH₄C1 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 Na₂S0₄ and the solvent was removed under reduced pressure to afford 2-methyladamantan-2-ol (11 g, 99% yield) as an off-white solid.

Synthesis of l-tricyclo[3.3.1.0 ' ]non-3-ylethanone (1-22):

2-Methyladamantan-2-ol (11 g, 66.26 mmol) dissolved in a mixture of AcOH (1 1 mL) and CC1₄ (44 mL) was added drop wise 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 CC1₄ and the combined organic layer was washed with water and brine, dried over Na₂S0₄ 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-ylethanone as viscous liquid (4.3 g, 40% yield).

Synthesis of tricyclo[3.3.1.0³'⁷]nonane-3-carboxylic acid (1-23):

To the ice bath cooled l-tricyclo[3.3.1.0³'⁷]non-3-ylethanone (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 methyl tricyclo[3.3. rboxylate (1-24):

A mixture of tricyclo[3.3.1.0³'⁷]nonane-3-carboxylic acid (4.52 g, 27.20mmoi) and Con.H₂S0₄ (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 Na₂S0_4; 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 tricycIo[3.3.1.0³'⁷]non-3-ylmethanol (1-25):

A suspension of LAH (1.68 g, 44.16 mmol) in THF (30 mL) was cooled to 0 °C and methyl tricyclo[3.3.1.0 ' ]nonane-3-carboxylate (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-ylmethanol (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 diisopropyl 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 methyl (2£ -3-tri lacrylate (1-27):

A suspension of NaH (0.55 g, 23.03 mmol) in THF (20 mL) was cooled to 0 °C and trimethylphosphanoacetate (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 Na₂S0₄, distilled and dried to afford the crude product (2.0 g, 87 % yield).

Synthesis of methyl 3-tricycIo[3.3.1.0³'⁷]non-3-ylpropanoate (1-28):

Pd/C (10%, 0.2 g) was added to a solution of methyl (2£)-3- tricyclo[3.3.1.0³'⁷]non-3-ylacrylate (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-ylpropanoic acid (1-29):

To a solution of methyl 3-tricyclo[3.3.1.0³'⁷]non-3-ylpropanoate (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-ylpropan-l-ol (1-30):

A suspension of LAH (0.475 g, 12.5 mmol) in THF (10 mL) was cooled to 0 °C and methyl 3-tricyclo[3.3.1.0^3,7]non-3-ylpropanoate (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 ethyl (2E)-4-tricyclo[3.3.1.13,7]dec-2-ylidenebut-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 triethyl 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 ethyl 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-l-ylmethyl {4-[2-(hydroxyamino)-2-oxoethyl]- l,3-thiazol-2-yl}carbamate

Step-I: Preparation of methyl (2-amino-l,3-thiazol-4-yl)acetate hydrochloride

(2-Amino-l,3-thiazol-4-yl)acetic acid (15 g, 95 mmol) was dissolved in methanol (100 mL). Thionyl 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 ethyl acetate (4 x 50 mL) and dried to obtain methyl (2-amino-l,3-thiazol-4-yl)acetate hydrochloride salt (20 g , 99 % yield).

Step-II: Preparation of methyl (2-{[(adamant-l-ylmethoxy)carbonyl]amino}-l,3- thiazol-4-yl)acetate:

Triphosgene (0.145 g, 0.49 mmol) was dissolved in DCM (1 mL). Adamant- 1- ylmethanol(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, methyl (2-amino- l,3-thiazol-4-yl)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 ethyl acetate (2 X 70 mL). Combined ethyl acetate layer was washed with 1 % HC1 solution (2 x 50 mL), with water (100 mL) and dried over Na₂S0₄. The organic layer was then concentrated and dried. Crude compound was purified by column chromatography using 7 % ethylacetate in hexane as the eluent to give the title compound (0.09 g, 16.5 % yield). Step-III: Preparation of adamant- 1-ylmethyl {4-[2-(hydroxyamino)-2-oxoethyl]- l,3-thiazol-2-yl}carbamate:

Potassium hydroxide (0.25 g, 4.4 mmol), dissolved in methanol (1 mL) was added to hydroxylamine hydrochloride (0.308 g, 4.4 mmol), suspended in methanol (1 mL). Potassium chloride salt formed was filtered. The filtrate was added to methyl (2- {[(adamant-l-ylmethoxy)carbonyl]amino}-l,3-thiazol-4-yl)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 diethyl ether (2 x 3 mL) and dried to get title compound (0.016 g, 18 % yield). 1H NMR (DMSO-d₆) 5 (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), 1 1.7 (1H, s, -NH). MS m/z: 366.1 (M⁺+l).

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

Example 12: Synthesis of 7V-{4-[2-(hydroxyamino)-2-oxoethyl]-l,3-thiazol-2- yl}adamantane-l-carboxamide.

Step-I: Preparation of methyl {2-[(adamant-l-ylcarbonyl)amino]-l,3-thiazol-4- yljacetate:

Adamantane-l-carboxylic 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 methyl (2-amino-l,3-thiazol- 4-yl)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 ethyl acetate (100 mL) and washed with water (3 x 70 mL). Organic layer was dried over Na₂S0₄, concentrated, and dried. Crude compound was purified by column chromatography using 10 % ethyl acetate in hexane as an eluent to give methyl {2- [(adamant-l-ylcarbonyl)amino]-l,3-thiazol-4-yl}acetate (0.2 g, 54 % yield).

Step-II: Preparation of N-{4-[2-(hydroxyainino)-2-oxoethyl]-l,3-thiazol-2- yl}adamantane-l-carboxamide:

According to procedure given in example 1 step-III, methyl {2-[(adamant-l- ylcarbonyl)amino]-l,3-thiazol-4-yl}acetate (0.2 g, 0.60 mmol) was converted to hydroxamate. Crude compound was washed with diethyl ether (3 x 5 mL) and dried to get the title compound (0.1 1 g, 55 % yield). 1H NMR (DMSO-d₆) δ (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⁺+l).

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

12:

-

CH₂), 6.84 (1H, s, Ar-H), 8.83 (1H, s, -NH),

10.57 (1H, s, -OH), 12.08 (1H, s, -NH). MS m/z: 350.1(M⁺+1).

Ή NMR (DMSO-d₆) δ (ppm): 1.46-1.49 (6H, m, -CH₂), 1.57 (2H, s, -CH), 1.76-1.80 (2H, m, -CH₂), 1.74-1.83 (4H, m, -CH₂), 2.12 (2H, s, -

19 CH), 2.37-2.41 (2H, t, -CH₂), 3.34 (2H, s, CH₂),

6.86 (1H, s, Ar-H), 7.16-7.17 (1H, m, Ar-H),

7.27-7.31 (2H, m, Ar-H) 7.34-7.36 (2H, m, Ar- H), 8.81 (1H, s, -NH), 10.56 (1H, s, -OH), 12.05 (1H, s, -NH). MS m/z: 440.1(M⁺+1).

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

Step-I:

Preparation of ethyl {2-[(adamant-l-ylcarbonyl)amino]-l,3-thiazol-4- yl}(oxo)acetate:

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

Step-II: Preparation of ethyl {2-[(adamant-l-ylcarbonyl)amino]-l,3-thiazol-4- yl}(difluoro)acetate:

Ethyl {2-[(adamant-l-ylcarbonyl)amino]-l,3-thiazol-4-yl}(oxo)acetate (0.110 g, 0.3 mmol) in 1,2-dichloroethane (1 mL) was cooled to 5 °C. Diethylaminosulfur 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 ethyl acetate (2 x 50 mL). Combined ethyl 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 % ethyl acetate in hexane as an eluent to get ethyl {2-[(adamant-l-ylcarbonyl)amino]-l,3-thiazol-4-yl}(difluoro)acetate (0.074 g, 63 % yield).

Step-III: Preparation of N-{4-[l,l-difluoro-2-(hydroxyamino)-2-oxoethyl]-l,3- thiazol-2-yl}adamantane-l-carboxamide:

According to procedure given in example 1 step-III, ethyl { 2- [(adamant- 1- yIcarbonyl)amino]-l,3-thiazol-4-yl}(difluoro)acetate (0.074 g, 0.2 mmol) was converted to N- {4- [ 1 , 1 -difluoro-2-(hydroxyamino)-2-oxoethyl] - 1 ,3 -thiazol-2- yl}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). Ή NMR (DMSO-d₆) δ (ppm): 1H NMR (DMSO-d₆) δ (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), 1 1.70 (1H, s, -OH), 12.09 (1H, s, -NH). MS m/z: 372.0 (M⁺+l).

Example 21: Synthesis of 2-(2-{[(adamant-l-ylamino)carbonyl]amino}-l,3-thiazol- 4-yI)-N-hydroxyacetamide:

Step-I: Preparation of ethyl (2-{[(adamant-l-ylamino)carbonyl]amino}-l,3- thiazol-4-yl)acetate:

To a stirring solution of triphosgene (0.194 g, 0.65 mmol) in DCM (1 mL) was added a solution of ethyl (2-amino-l,3-thiazol-4-yl)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 ethyl acetate (100 mL). Organic layer was washed with 2 % HC1 solution (2 x 50 mL) and dried over sodium sulphate. Ethyl acetate layer was then concentrated and dried. Product was purified by column chromatography using 0.5 % methanol in DCM as an eluent to give ethyl (2-{[(adamant-l-ylamino)carbonyl]amino}-l ,3-thiazol-4-yl)acetate (0.095 g, 13 % yield).

Step-II: Preparation of 2-(2-{[(adamant-l-ylamino)carbonyl]amino}-l,3-thiazol-4- yl)-N-hydroxyacetamide:

According to procedure given in example 1 step-III, ethyl (2- {[(adamant- 1- ylamino)carbonyl]amino}-l,3-thiazol-4-yl)acetate (0.095 g, 0.2 mmol) was converted to 2-(2- { [(adamant- 1 -ylamino)carbonyl] amino } - 1 ,3 -thiazol-4-yl)-N-hydroxy acetamide. Crude product was washed with diethyl ether (2 x 3 mL) and dried to give the title compound (0.016 g, 17 % yield). Ή NMR (DMSO-d₆) δ (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 :

Ex. Structure Analytical Data

Example 23: Synthesis of 2-(adamant-l-ylamino)-N-{4-[2-(hydroxyamino)-2- oxoethy 1] - 1 ,3-thiazol-4-y 1} acetamide :

Step-I: Preparation of methyl {2-[(bromoacetyl)amino]-l,3-thiazol-4-yl}acetate:

Methyl (2-amino-l,3-thiazol-4-yl)acetate hydrochloride (0.5 g, 2.4 mmol) in DCM (10 mL) was cooled to 5 °C under stirring. Triethylamine (0.84 mL, 6 mmol) was added slowly, followed by drop-wise addition of bromoacetylbromide (0.25 mL, 2.9 mmol) and stirring continued for 15 minutes. Reaction mixture was diluted with water (100 mL) and extracted with ethyl 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 methyl (2-{[(adamant-l-ylamino)acetyI]amino}-l,3- thiazol-4-yl)acetate:

—

To a solution of adamantan-1 -amine (0.3 g, 2 mmol) and methyl {2- [(bromoacetyl)amino]-l, 3 -thiazol-4-yl} 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 ethyl acetate (2 x 80 mL). Combined ethyl acetate layers were washed with water (3 x 70 mL), dried over Na₂S0₄, concentrated and dried. Crude product was purified by column chromatography using 0.5 % methanol in DCM as an eluent to give methyl (2-{[(adamant-l-ylamino)acetyl]amino}-l,3-thiazol-4-yl)acetate (0.22 g, 30 % yield). Step-Ill: Preparation of 2-(adamant-l-ylamino)-N-{4-[2-(hydroxyamino)-2- oxoethyl] -1 ,3-thiazol-4-yl}acetamide:

According to procedure given in example 1 step-Ill, methyl (2- {[(adamant- 1 - ylamino)acetyl]amino}-l,3-thiazol-4-yl)acetate (0.21 g, 0.58 mmol) was converted to 2-(adamant-l-ylamino)-N-{4-[2-(hydroxyamino)-2-oxoethyl]-l,3-thiazol-4- yl}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) δ (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 (M⁺+l).

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

23:

Example 26: Synthesis of N-[2-({4-[2-(hydroxyamino)-2-oxoethyl]-l,3-thiazol-2- yl}amino)-2-oxoethyl]adamantane-l-carboxamide:

Step-I: Preparation of methyl [(adamant-l-ylcarbonyl)amino]acetate:

To a solution of adamantane-l-carboxylic acid (1-1) (0.5 g, 2.8 mmol) in DMF (10 mL) was added EDO (l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (1.07 g, 5.5 mmol), HOBt (N-hydroxybenzotriazole) (0.375 g, 2.8 mmol), glycine methylester hydrochloride (0.350 g, 22.8 mmol), followed by triethylamine (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 ethyl acetate (1 x 150 mL). Organic layer was washed with water (2 x 80 mL), brine solution (50 mL) and dried over anhydrous Na₂S0₄, followed by removal of solvent to give methyl [(adamant- 1- ylcarbonyl)amino]acetate (0.59 g, 84 % yield).

Step-II: Preparation of [(adamant-l-ylcarbonyl)amino]acetic acid:

To a solution of methyl [(adamant- l-ylcarbonyl)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 HCl. The aqueous layer was extracted with ethyl acetate (2 x 70 mL), dried over sodium sulphate, concentrated to remove solvent and dried to give [(adamant- l-ylcarbonyl)amino] acetic acid (0.4 g, 71 % yield).

Step-III: Preparation of methyl [2-({[(adamant-l- ylcarbonyl)amino] acety l}amino)-l ,3-thaizol-4-yl] acetate:

Followed according to procedure given in example 12 step-I, [(adamant- 1- ylcarbonyl)amino] acetic acid (0.4 g, 1.7 mmol) reacted with methyl (2-amino-l ,3- thiazol-4-yl)acetate hydrochloride salt (0.351 g, 1.7 mmol) to give methyl [2- ({[(adamantylcarbonyl)amino]acetyl}amino)-l,3-thaizol-4-yl]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-oxoethyl]-l,3-thiazol-2- yl}amino)-2-oxoethyl]adamantane-l-carboxamide:

According to procedure given in example 1 step-III, methyl [2-( {[(adamant- 1- ylcarbonyl)amino]acetyl}amino)-l,3-thaizol-4-yl]acetate (0.3 g, 0.77 mmol) was converted to N-[2-({4-[2-(hydroxyamino)-2-oxoethyl]-l,3-thiazol-2-yl}amino)-2- oxoethyl]adamantane-2-carboxamide. Crude solid product was washed with diethyl ether (3 x 5 mL), DCM (2 x 5 mL) and dried to get the title compound (0.026 g, 9 % yield). 1H NMR (DMSO-d₆) δ (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), 1 1.99 (1H, s, -NH). MS m/z: 393.1 (M⁺+l).

Example 27: Synthesis of 2-[4'-(adamant-l-y.)bipheny--4-yl]-N- hydroxyacetamide:

Step-I: Preparation of 2-[4'-(adamant-l-yl biphenyl-4-yl]acetic acid:

A suspension of 1 -adamantanol (500 mg, 3.3 mmol) and biphenylacetic 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- 1 -yl)biphenyl-4-yl] acetic acid (1.02 g, 89 % yield).

Step-II: Preparation of methyl 2-[4'-(adamant-l-yl)biphenyl-4-yl]acetate:

To a suspension of 2- [4' -(adamant- l-yl)biphenyl-4-yl] 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 ethyl 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 % ethyl acetate in hexane as an eluent to get methyl 2-[4'-(adamant-l-yl)biphenyl-4-yl]acetate (0.355 g, 46 % yield).

Step-III:Preparation of 2-[4'-(adamant-l-yl)biphen l-4-yl]-N-hydroxyacetamide:

According to procedure given in example 1 step-III, methyl 2- [4 ' -(adamant- 1- yl)biphenyl-4-yl] acetate (0.355 g, 0.93 mmol) was converted to 2- [4 '-(adamant- 1- yl)biphenyl-4-yl]-N-hydroxyacetamide. Crude solid product was washed with diethyl ether (5 mL x 2) and dried to give the title compound (0.015 g, 4.5 % yield). Ή NMR (DMSO-d₆) δ (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 (M⁺-l).

Example 28:

Synthesis of 2-{2-[4-(adamant-l-yl)butyl]-l,3-thiazol-4-yl}-N-hydroxyacetamide:

Step-I: Preparation of ethyl {2-[4-(adamant-l-yl)butyl]-l,3-thiazol-4-yl}acetate:

A mixture of 5-(adamant-l-yl)pentanethioamide (1-16) (0.18 g, 0.7 mmol), 4- chloroethyl 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 Na₂S0_4, 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⁺+l).

Step-II

Preparation of 2-{2-[4-(adamant-l-yl)butyl]-l,3-thiazol-4-yl}-7V- hydroxyacetamide:

According to procedure given in example 1 step-Ill, ethyl {2-[4-(adamant-l-yl)butyl]- l,3-thiazol-4-yl}acetate (0.13 g, 0.36 mmol) was converted the title compound (0.08 g, 64% yield). 1H NMR (DMSO-d₆) δ (ppm): 1.23-1.32 (4H, m, -CH₂), 1.43-1.67 (14H, m, adamantyl-H), 1.90 (3H, s, adamantyl-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-yl)butyl]phenyl}-A^r-hydroxyacetamide:

Step-I: Preparation of methy n-l-yl]benzoate:

A suspension of NaH (0.71 g, 29.6 mmol) in THF (50 mL) was cooled to 0 °C and methyl 4-[(dimethoxyphosphoryl)methyl]benzoate (5.46 g, 21.1 mmol) was added slowly at 0 °C. The resulting mixture was stirred for 15 minutes and 3 -(adamant- 1- yl)propanal (1-10) (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 Na₂S0₄, 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-[(l£)-4-(adamant-l-yl)but-l-en-l-yl]benzoic acid:

To a solution of methyl 4-[(lE)-4-(adamant-l-yl)but-l-en-l-yl]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 30 minutes. The precipitated solid 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-yI)butyl]benzoic acid:

10% Pd/C (20%, w/w, 0.14 g) was added to a solution of 4-[(lE)-4-(adamant-l-yl)but- l-en-l-yl]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 ethyl {4-[4-(adamant-l-yl)butyl]phenyl}acetate:

A mixture of 4-[4-(adamant-l-yl)butyl]benzoic acid (0.48 g, 1.5 mmol), oxalylchloride (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 trimethylsilyldiazomethane 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 NaHC0₃ (50 mL) solution and 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, 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 (0.3 lg, 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 Na₂S0₄, 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-yl)butyl]phenyl}-N- hydroxyacetamide:

According to procedure given in example 1 step-III, ethyl {4-[4-(adamant-l- yl)butyl]phenyl} 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 diethylether to afford the pure title compound (0.04 g, 21% yield). Ή NMR (DMSO-d₆) δ (ppm): 1.24-1.26 (4H,m, -CH₂), 1.42-1.67 (14H, m, adamantyl-H), 1.90 (3H, s, adamantyl-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 (M⁺-l).

The following compound was prepared according to the procedure given in Example

29:

Example 31: Synthesis of 2-{4-[3-(adamant-l-yl)propoxy]phenyl}-N- hydroxyacetamide:

Step-I: Preparation of l-(3-bromo ropyl)adamantane:

A suspension of l-(3-hydroxypropyl)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 ethyl acetate (2 x 100 mL). Combined organic layers were dried over sodium sulphate, concentrated and dried to get l-(3-bromopropyl)adamantane (1.25 g, 67 % yield).

Step-II: Preparation of methyl {4-(3-[adamant-l-yl]propyloxy)phenyl}acetate:

To a solution of l-(3-brOmopropyl)adamantane (0.31 g, 1.2 mmol) and methyl (4- hydroxyphenyl)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 ethyl acetate (2 x 70 mL). Combined ethyl acetate layers were washed with water (3 x 50 mL), dried over Na₂S0₄, concentrated to remove solvent and dried. Crude product was purified by column chromatography using 2 % ethyl acetate in hexane as an eluent to give methyl {4-(3-[adamant-l-yl]propyloxy)phenyl}acetate (0.255 g, 62 % yield).

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

Followed according to procedure given in example 1 step-Ill, methyl {4-(3-[adamant- l-yl]propyloxy)phenyl}acetate (0.255 g, 0.74 mmol) was converted to 2-{4-[3- (adamant-l-yl)propoxy]phenyl}-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). 1H NMR (DMSO-d₆) δ (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⁺+l) & 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-yl)propylamino]sulfonyl}phenyl)- iV-hydroxyacetamide:

Step-I

Preparation of methyl (4-{[3(adamant-l-ylpropyl)amino]sulfonyl}phenyI)acetate:

A mixture of 3 -(adamant- l -yl)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 methyl [4-(chlorosulfonyl)phenyl]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 (0.41 g, 68% yield). MS m/z: 406 (M⁺+l).

Step-II: Preparation of 2-(4-{[3-(adamant-l-yl)propylamino]sulfonyl}phenyl)-N- hydroxy acetamide:

According to procedure given in example 1 step-Ill, methyl (4- {[3 (adamant- 1- ylpropyl)amino]sulfonyl}phenyl)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 Na₂S0_4> concentrated to give the crude compound which was purified by preparative HPLC to afford the pure title compound (0.015 g, 7 % yield). 1H NMR

(DMSO-d₆) δ (ppm): 1.25-1.33 (4H, m, -CH₂), 1.35-1.65 (12H, m, adamantyl-H), 1.89 (3H, s, adamantyl-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⁺+l).

Example 35: Synthesis of 2-(4-{[(3-(adamant-l-yl)propylamino]methyl}phenyl)-N- hydroxy acetamide:

Step-I

Preparation of methyl (4-{[3-(adamant-l-yl)propylamino]methyl}phenyl)acetate:

A mixture of 3-(adamant-l-yl)propan-l-amine.HCl (0.36 g, 1.5 mmol), triethylamine (0.26 mL, 1.9 mmol) and methyl (4-formyIphenyl)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 Na₂S0_4; concentrated to afford the pure title compound (0.12 g, 21% yield). Step-II: Preparation of 2-(4-{[(3-(adamant-l-yl)propyIamino]methyI}phenyI)-7V- hydroxy acetamide:

According to procedure given in example 1 step-III, methyl (4- {[3 -(adamant- 1- ylpropyl)amino]methyl}phenyl)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 diethylether to afford the pure title compound (0.075 g, 62% yield). 1H NMR (DMSO- d₆) δ (ppm): 1.25-1.42 (4H, m, -CH₂), 1.51-1.80 (12H, m, adamantyl-H), 1.90 (3H, s, adamantyl-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⁺+l).

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 deerease 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

8 >8 0.5/0.5

9 >8 0.25/1

10 >8 0.25/4

11 >8 0.5/1

15 >8 0.25/8

16 >8 0.25/4

17 8 0.25/1

18 >8 0.25/1

19 >8 0.5/1

22 >8 . ND

23 >8 ND

24 >8 ND

25 >8 0.5/4

27 4 0.25/1

28 4 0.25/2

29 2 0.25/0.5

30 2 0.25/0.5

31 2 0.25/0.5

33 2 0.25/0.5

34 >8 0.25/1

35 >8 ND

TSA >4 0.25/0.5

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 lh. Reactions were terminated by the addition of TSA/S AHA 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 HO S -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 C0₂ 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 tfis 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 C0₂ 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.

Claims

We Claim:

1. A Compound of formula (I)

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

R represents substituted or unsubstituted adamantyl, adamantylalkenylidene, aza-adamantyl, homoaza-adamantyl, noradamantyl, homoadamantyl, protoadamantyl or heteroadamantyl;

X represents a bond, or the groups selected from alkenylene, alkynylene, heterocycloalkyl, -OCONR⁹-, -NR⁹COO-, -NR⁹CONR⁵-, -CONR⁹-, -NR⁹CO-, -NR⁹-, -0-, -S-, -SO-, -CO-, -S0₂- -OS0₂NR⁹-, -NR⁹S0₂NR⁵-, -NR⁹S0₂0-, -C0NR⁹C0NR⁵-, -CONR⁹S0₂NR⁵-, -CONR^R^O- -S0₂NR⁹C0NR⁵-, -CONR⁹CR⁷R⁸CONR⁹-, -NR⁹COCR⁷R⁸NR⁹CO-, -NR⁹CR⁷R⁸CONR⁹-, and -NR⁹COCR⁷R⁸0-;

wherein R⁴, R⁵, R⁷, R⁸ and R⁹ independently represent hydrogen, optionally substituted groups selected from alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl and cycloalkenyl; or R⁹ and R⁵ can combine together to form a ring having oxo, thioxo or - C=NR⁶ substitutent;

A and B independently represent a bond, -CO-, -S0₂-, or substituted or unsubstituted groups selected from alkylene group, alkenylene, alkynylene, arylene, arylalkylene and heteroarylene;

R¹ represents substituted or unsubstituted arylene or heteroarylene;

R² represents -OR³, ortho substituted aniline, amino aryl and amino heteroaryl, which are optionally substituted, wherein R represents hydrogen, optionally substituted groups selected from alkyl, aryl, heterocyclyl and -COR⁶, wherein R⁶ represents optionally substituted groups selected from alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl;

E¹ and E² independently represent hydrogen, aryl, alkyl or halogens;

n is an integer selected from 1 to 2;

with the proviso that, -A-X-B- is not a bond;

when n=l and R¹ is phenylene, 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, formyl, alkyl, haloalkyl, alkoxy, haloalkoxy, arylalkoxy, cycloalkyl, cycloalkyloxy, aryl, heterocyclyl, heteroaryl, alkylamino, -COOR³, -C(0)R^B, -C(S)R^A, -C(0)NR^AR^B, -C(S)NR^AR^B, -NR^AC(0)NR^BR^C, -NR^AC(S)NR^BR^C, -N(R^A)SOR^B, -N(R^a)S0₂R^B, -NR^AC(0)OR^B, -NR^AR^B, -NR^AC(0)R^B, -NR^AC(S)R^B, -SONR^AR^B, -S0₂NR^AR^B, -OR^A, -OR^AC(0)OR^B, -OC(0)NR^AR^B, -OC(0)R^A, -OC(0)NR^AR^B, -R^R , -R^AOR^B, -SR^A, -SOR^A and -S0₂R^A, wherein R^A, R^B and R^C in each of the above groups independently represent hydrogen, halogens, optionally substituted groups selected from alkyl, alkylene, cycloalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl and heteroarylalkyl; 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 thiazolyl or phenylene;

R² represents -OR³, wherein R³ represents hydrogen, optionally substituted groups selected from alkyl, aryl, heterocyclyl and -COR⁶, wherein R⁶ represents optionally substituted groups selected from alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl;

E¹ and E² independently represent hydrogen or halogens;

n is an integer selected from 1 to 2;

R represents substituted or unsubstituted adamantyl, adamantylalkenylidene, aza-adamantyl, homoaza-adamantyl and noradamantyl;

X represents a bond, or the groups selected from alkenylene, alkynylene,

-OCONR⁹-, -NR⁹COO-, -NR⁹CONR⁵-, -CONR⁹-, -NR⁹CO-, -NR⁹-, -0-, -S-, -CONR^^CO-, -CONR⁹CR⁷R⁸CONR⁹-, -NR⁹CR⁷R⁸CONR⁹- and

-NR⁹COCR⁷R⁸0-;

A and B independently represent a bond, -CO-, -S0₂-_; or substituted or unsubstituted groups selected from alkylene, alkenylene, alkynylene, arylene, arylalkylene and heteroarylene; and R⁵, R⁷, R⁸ and R⁹ are as defined earlier;

with the proviso that,

-A-X-B- is not a bond;

when n=land R¹ is phenylene, 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 aryloxy group is present, the aryloxy group is selected from phenoxy and naphthyloxy; when halogen is present, the halogen is fluorine, chlorine, bromine or iodine; when alkyl group is present, the alkyl group is methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl or octyl; when alkylamino group is present, alkylamino group is methyamino, ethylamino, propylamino or isopropylamino; when alkylene group is present, the alkylene group is methylene, ethylene, propylene, butylene or pentylene; when alkenyl group is present, the alkenyl group is ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl-l- propenyl, 1-butenyl or 2-butenyl; when alkenylene group is present, the alkenylene group is ethenylene, propenylene, butenylene or pentenylene; when the alkynyl group is present, the alkynyl group is ethynyl, propynyl or butynyl; when alkynylene group is present, the alkynylene group is ethynylene, propynylene, butynylene or pentynylene; when cycloalkyl group is present, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl or perhydronaphthyl; when cycloalkyloxy groups is present, cycloalkyloxy groups is cyclopropyloxy, cyclobutyloxy or cyclopentyloxy; when cycloalkenyl group is present, the cycloalkenyl group is selected from cyclopentenyl and cyclohexenyl; when heteroaryl group is present, the heteroaryl group is a heterocyclyl selected from azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, piperonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, oxazolyl, oxazolinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, oxadiazolyl, benzindazolyl, indazolyl, phenyl piperidinyl, furyl, tetrahydrofuryl, tetrahydropyranyl, piperazinyl, homopiperazinyl, piperidyl, piperidopiperidyl, morpholinyl, thiomorpholinyl, piperidonyl, 2-oxopiperazinyl, 2- oxopiperidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, oxazolidinyl, chromanyl and isochromanyl; when aryl group is present, the aryl group is phenyl, naphthyl, anthracenyl, indanyl or biphenyl; when hydroxyalkyl group is present, the hydroxyalkyl group is hydroxymethyl or hydroxyethyl; when haloalkyl group is present, the haloalkyl group is trifluoromethyl, tribromomethyl or trichloromethyl; and when haloalkoxy group is present, the haloalkoxy group is selected from chloromethoxy, chloroethoxy, trifluoromethoxy, trifluoroethoxy or trichloromethoxy.

4. The compounds according to claim 1 selected from the group consisting of:

Adamant- 1 -ylmethyl { 4-[2-(hydroxyamino)-2-oxoethyl] - 1 ,3 -thiazol-2-yl } carbamate;

Adamant-2-ylethyl{4-[2-(hydroxylamino)-2-oxoethyl]-l ,3-thiazol-2-yl}carbamate;

Adamant- 1 -ylethyl {4- [2-(hydroxyamino)-2-oxoethyl] - 1 ,3 -thiazol-2-yl } carbamate;

3-Chloroadamant- 1 -ylmethyl{4-[2-(hydroxyamino)-2-oxoethyl]- 1 ,3-thiazol-2- yl} carbamate;

Adamant- 1 -ylmethyl {4- [ 1 , 1 -difluoro-2-(hydroxyamino)-2-oxoethyl] - 1 ,3 -thiazol-2- yl} carbamate;

3 - [4( Adamant- 1 -yl)phenyl]propyl- {4- [2-(hydroxyamino)-2-oxoethyl] - 1 ,3 -thiazol-2- yl} carbamate;

3-(Adamant-l-yl)propyl{4-[2-(hydroxyamino)-2-oxoethyl]-l,3-thiazol-2- yl} carbamate;

Tricyclo[3.3.1.0^3,7]non-3-ylmethyl-N-{4-[2-(hydroxyamino)-2-oxoethyl]-l ,3- thiazol-2-yl}carbamate;

3 -(Tricyclo [3.3.1.0³'⁷]non-3 -yl)propyl { 4- [2-(hydroxyamino)-2-oxoethyl] -1,3- thiazol-2-yl}carbamate;

3 -Phenyladamant- 1 -ylmethyl {4-[2-(hydroxyamino)-2-oxoethyl] - 1 ,3 -thiazol-2- yl} carbamate; 3-(Tricyclo[3.3.1.0 ' ]non-3-yl)propyl {4-[2-(hydroxyamino)-2-oxoethyl]- phenyl} carbamate;

N- { 4- [2-(Hydroxyamino)-2-oxoethyl] - 1 ,3 -thiazol-2-yl } adamantane- 1 -carboxamide; N-{4-[2-(Hydroxyamino)-2-oxoethyl]-l,3-thiazol-2-yl}adamantane-l-acetamide; N-{4-[2-(Hydroxyamino)-2-oxoethyl]-l,3-thiazol-2-yl}-3-(3-chloroadamant-l- yl)acrylamide;

N- { 4- [2-(Hydroxyamino)-2-oxoethyl]- 1 ,3-thiazol-2-yl } -3 - [4-(adamant- 1 - yl)phenyl] propanamide ;

N-Hydroxy-2-[4-(3-oxo-3-(4-azatricyclo[4.3.1.1³'⁸]undec-4- yl)propyl)phenyl]acetamide;

N-{4-[2-(Hydroxyamino)-2-oxoethyl]phenyl}-3-[4-(adamantan-l- yl)phenyl]propanamide;

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

N- {4- [2-(Hydroxyamino)-2-oxoethyl] - 1 ,3 -thiazol-2-yl } -3 -(3 -phenyladamant- 1 - yl)propanamide;

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

2-(2- { [(Adamant- 1 -ylamino)carbonyl] amino } - 1 ,3 -thiazol-4-yl)-N- hydroxy acetamide;

N-{4-[2-(Hydroxyamino)-2-oxoethyl]-l,3-thiazol-2-yl}-4-azatricyclo

[4.3.1. l³'⁸]undecane-4-carboxamide;

2-(Adamant-l-ylamino)-N-{4-[2-(hydroxyamino)-2-oxoethyl]-l ,3-thiazol-4- yl}acetamide; ^"

2-(3-Phenyladamantan-l -ylamino)-N-{4-[2-(hydroxyamino)-2-oxoethyl]-l ,3- thiazol-2-y 1 } acetamide ;

2- {4-[2-(Adamant- 1 -ylamino)-2-oxoethoxy]phenyl} -N-hydroxy acetamide;

N-[2-({4-[2-(Hydroxyamino)-2-oxoethyl]-l,3-thiazol-2-yl}amino)-2- oxoethyl] adamantane- 1 -carboxamide;

2- [4 ' -(Adamant- 1 -yl)biphenyl-4-yl] -N-hydroxyacetamide ;

2-{2-[4-(Adamant-l-yl)butyl]-l,3-thiazol-4-yl}-N-hydroxyacetamide;

2-{4-[4-(Adamant- 1 -yl)butyl]phenyl} -N-hydroxyacetamide;

2-{4-[3-(Adamant-l-yl)propyl]phenyl}-N-hydroxyacetamide; 2- {4-[3-(Adamant- 1 -yl)propoxy]phenyl} -N-hydroxyacetamide;

2-{4-[4-(Adamant-2-yl)butoxy]phenyl}-N-hydroxyacetamide;

2- {4- [3 -(Adamant- 1 -yl)propanarnino]phenyl } -N-hydroxyacetamide;

2-(4-{[3-(Adamant-l-yl)propyl]aminosulfonyl}phenyl)-N-hydroxyacetamide; and 2-(4-{ [3-(Adamant- 1 -yl)propyl]aminomethyl}phenyl)-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,

R-^A-X R

(2) O

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. Use of a compound according to claims 1, 2 or 4, for preparing a medicament in treating fungal infections.

10. Use of a compound according to claims 1 , 2 or 4, for preparing a medicament for inhibiting HDAC in a fungal cell. -

11. Use of a selective and synergistic amount of a compound according to claims 1, 2 or 4, in combination with antifungal agent for preparing a medicament for the treatment of fungal infection in a mammal.

12. Use of a compound according to claims 1, 2 or 4, for preparing a medicament for reducing resistance of a fungal cell to an antifungal agent in a mammal.

13. A compound of formula (I) as claimed in claims 1 , 2 or 4, substantially as herein described with reference to the examples.

14. A process for the preparation of compound of formula (I) as claimed in claim 5, substantially as herein described with reference to the examples.

15. Use of a compound as claimed in claims 9, 10, 1 1 or 12, substantially as herein described with reference to the examples.