FIELD OF THE INVENTION

The present invention relates to the field of pharmaceutical industry of antimicrobial agents. The present invention particularly relates to the compounds and methods of making them that are useful as an intermediate for the preparation of active pharmaceutical ingredients, such as: anti-bacterial, anti-cancer, anti-HIV, anti-parasitic, anti-tuberculosis, anti-leishmanasis agents etc., as well as imaging agents. More particularly, the present invention relates to 1,1- dialkylethane-l,2-diols and process for the preparation thereof.

BACKGROUND OF THE INVENTION

Tuberculosis remains a leading infectious cause of death worldwide. The existing treatment of tuberculosis requires a lengthy therapy and often needs a combination of three or four different drugs (first-line drug regimen such as isoniazide, pyrazinamide, and rifampin and several second line drug regimen including ethionamide, para-aminosalicylic acid, kanamycin, amikacin, capreomycin, ciprofloxacin, streptomycin, etc.).

During the period of last six to seven decades, nitroimidazole [J. Med. Chem. 2017, 60, 7636-7657] based drugs have played a very important role in combating infections of various types. One of major outcomes of all these efforts is the discovery and development of Delamanid, a nitro-dihydro-imidazooxazole derivative, for the treatment of multidrug- resistant tuberculosis (MDR-TB). PCT application, W02004033463A1 reports 2,3-dihydro- 6-nitroimidazo[2,l-b]oxazoles, including Delamanid (Compound 1572, page 970 of 1084) and process for the preparation thereof. In addition to Delamanid, several other nitroimidazole s have also been studied, such as:

Delamanid

Plos Medicine, 2006, 3 (11 ), e466. (IIIM-114)

W02004033463A1 Org. Biomol. Chem. 2015, 13, 3610-3624

Eur. J. Med. Chem., 1989, 24, 631 Eur J Pharm Sci 2014, 65, 147-155. Several methods have been reported for the synthesis of above discussed nitroimidazole molecules. The goal of all the methods of prior-art has been to prepare the nitroimidazole molecules by making and combining the three fragments, viz. the halonitroimidazole or dinitroimidazole fragment (A), the central chiral three-carbon fragment (B) either as an epoxide or as the equivalent diole and the phenolic fragment (C).

In the first approach, the halonitroimidazole or dinitroimidazole is coupled with the three- carbon chiral epoxide to prepare the intermediate (D), which is coupled with the phenolic fragment (C) to form intermediate (E) and finally converted to the target molecule, as shown below:

les In the second approach, the phenolic fragment is first coupled with the chiral three-carbon fragment to generate a diol intermediate (F) which is later coupled with imidazole derivative to form intermediate (E) which in turn is converted to the target molecule, as shown below.

Kuppuswamy Nagrarjan and coworkers (Eur. J. Med. Chem. 24 (1989) 631-633) reports following process of Scheme (I); wherein nitroimidazole derivatives is reported to possess antitubercular activity. Treatment of starting material 2,4-dinitroimidazole (1-1) with an epoxide compound (1-2) in presence of anhydrous sodium acetate in hot absolute alcohol provided separable mixtures of isomers of nitroimidazole derivates (1-3), (1-4) and (1-5). 2- Nitro-group in these reactions acted as a leaving group.

Scheme (I)

WO 2004/033463 and J. Med. Chem. 2006, 49, 7854 describe 2,3-dihydro-6- nitroimidazo[2,l-b]oxazozles derivatives with focus on Delamanid. An epoxide compound of formula (II-l) is treated with the phenol of formula (II-2), wherein R ¹ is a hydrogen atom or lower alkyl group, R ² is a substituted piperidyl group or a substituted piperazinyl group and X ¹ is a halogen atom or a nitro group, to produce a tertiary alcohol intermediate (II-3) which is converted to final compound (II-4) as shown in Scheme (II).

Scheme (II)

WO 2011/151320 relating to nitroimidazole derivatives possessing radioactive or non- radioactive halogen atoms, reports treatment of the epoxide (III-l) with 4-halophenol (III-2) to provide the halo containing compound (III-3).

Scheme (III)

WO 2004/035547 describes a process for producing 1-substituted 4-nitroimidazole compounds, an intermediate for various medicines and agricultural chemicals, especially as an intermediate for anti-tubercular agents. Treatment of halonitroimidazole (IV-1) (or corresponding sulfoxide) with an epoxy-sulfonate (IV-2) provide an intermediate (IV-3), which is treated with a nucleophile (IV-4) to provide (IV-5) and finally the target (IV-6).

Scheme (IV)

WO 2008/140090 also describes following process of Scheme (V). 1,4-cyclohexanedione (V- 2) is treated with a piperidine derivative (V-l) in the presence of PTSA to provide a salt of phenol (V-3). After freeing the salt, the phenol (V-3) is treated with epoxide (V-4) to provide another epoxide (V-5) which finally provided (V-7), when treated with nitroimidazole derivative (V-6).

Scheme (V)

WO/2011/093529 describes an organic sulfonyloxy group containing compound of formula (VI-4). A diol compound (VI-1) is coupled with a piperidine derivative (VI-2) in the presence of catalytic amounts of Pd2dba3 and ^l BuXPhos along with sodium tert-butoxide in toluene. The resulting diol (VI-3) is converted to the epoxide (VI-5). Coupling of epoxide (VI-5) with halonitroimidazole (VI-6) provided the target molecule (VI-8) via an intermediate (VI-7).

Scheme (VI) WO 2016158737 A1 also describes process for the preparation of nitroimidazole derivative. 4-(4-trifluoromethoxyphenoxy)piperidine (VII-1) is allowed to react with hydroquinone (VII-2) at high temperature to provide l-(4-hydroxyphenyl)-4-(4- trifluoromethoxyphenoxy)piperidine (VII-3). Subsequently, treatment of (VII-3) with an oxirane (VII-4) provides a diol (VII-5), which is converted to another epoxide (VII-6); which is further converted to target (VII-9) through intermediate (VII-8).

Scheme (VII) The diol intermediate (F), as mentioned above, can alternatively be prepared by allylation of the phenol (C) to generate an intermediate of type (G) followed by asymmetric dihydroxylation reaction. This type of reaction is the subject matter of the present invention. The diol compounds of type (F) can be further converted to the targeted nitrodihydroimidazooxazole molecule s .

OBJECT OF THE INVENTION

The main objective of the invention is to provide a novel and practical route of synthesis of intermediates and derivatives of 6-nitro-2,3-dihydroimidazo[2,l-b]oxazoles that are useful for the treatment of various bacterial and parasitic infections. Another objective of the invention is to provide route of synthesis for preparation of the derivatives of chiral 1,1 -dialky lethane- 1,2-diols. Yet another objective of the invention is to provide a practical and novel route of synthesis of Delamanid.

SUMMARY OF THE INVENTION

In an aspect, the present invention provides a compound of general Formula (I), or a salt or an isomer thereof

Formula (I) wherein A is substituted or unsubstituted or branched or unbranched C1-C6 alkyl group;

W is substituted or unsubstituted carbon, wherein n = 0, 1, 2, or 3;

Y is substituted or unsubstituted carbon, nitrogen, oxygen or a sulfur atom;

Z is substituted or unsubstituted alkyl, aryl, or heteroaryl group, wherein a substituent is independently selected from groups such as H, X, NO2, CN, COOH, COOR, OH, OR, OAr, OHetAr, SH, S(0) _n R, SAr, SHetAr, substituted or unsubstituted alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl, NH ₂ , NHR, NHAr, NH-HetAr, NR ₂ , NAr ₂ , NHetAr ₂ , CONR ₂ , OC(0)OR, OC(0)NR; wherein X = F, Cl, Br or I;

R is substituted or unsubstituted alkyl;

Ar is substituted or unsubstituted aryl;

HetAr is substituted or unsubstituted heteroaryl; and n = 0, 1 or 2.

In another aspect, the compounds of general Formula (I) are 1,1 -dialky lethane-l,2-diols.

In another aspect, the present invention provides a process for the preparation of compound of general Formula (I), or a salt or an isomer thereof

Formula (I) wherein A, W, Y, Z and n are as defined above. In another aspect, the present invention provides a process of making the diol compounds of Formula (I), from corresponding alkene compounds of Formula (IA) employing asymmetric dihyroxylation.

Formula (I A) wherein A, W, Y, Z and n are as defined above.

In another aspect, the present invention provides a process of making the diol compounds of Formula (I), from corresponding alkene compounds of Formula (IA) employing Sharpless asymmetric dihyroxylation; wherein the alkene (IA) is allowed to react with a suitable asymmetric catalyst in a suitable solvent at a suitable temperature for a suitable time period.

In another aspect, the present invention provides a process for the preparation of alkene compounds of Formula (IA), comprising: alkylation/allylation of corresponding phenol with methallyl halide or other suitable allyl halide derivatives in presence of a suitable base and a suitable solvent.

In another aspect, the l,l-dialkylethane-l,2-diols of Formula (I) are selected from the group, comprising compounds of following formula:

In yet another aspect, the present invention provides use of compound of general Formula (I) for the preparation of 6-nitro-2,3-dihydroimidazo[2,l-b]oxazole derivatives of following formula (H):

In yet another aspect, 6-nitro-2,3-dihydroimidazo[2,l-b]oxazole derivatives of formula (H) are selected from the group, comprising of following compounds, and the like:

In yet another aspect, the present invention provides compound of following formula:

In yet another aspect, the present invention provides antibacterial compounds of following formula:

In yet another aspect, the present invention provides compounds of formula (003R) and (003S) for the treatment of mycobacterial infections.

In yet another aspect, the present invention provides antitubercular pharmaceutical composition of compounds of formula (003R) and (003S). BRIEF DESCRIPTION OF DRAWINGS

Figure 1: HPLC chromatogram of crude reaction mixture of compound of Formula (009) for determination of % ee.

Figure 2: HPLC chromatogram of crude reaction mixture of compound of Formula (017) for determination of %ee. Figure 3: Anti-TB In vivo efficacy data of compound 003(R) in mice model of infection

DETAILED DESCRIPTION OF THE INVENTION

In an aspect, the present invention provides a compound of general Formula (I), or a salt or an isomer thereof

Formula (I) wherein A is substituted or unsubstituted or branched or unbranched C1-C6 alkyl group;

W is substituted or unsubstituted carbon, wherein n = 0, 1, 2, or 3;

Y is substituted or unsubstituted carbon, nitrogen, oxygen or a sulfur atom;

Z is substituted or unsubstituted alkyl, aryl, or heteroaryl group, wherein a substituent is independently selected from groups such as H, X, NO2, CN, COOH, COOR, OH, OR, OAr, OHetAr, SH, S(0) _n R, SAr, SHetAr, substituted or unsubstituted alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl, NH ₂ , NHR, NHAr, NH-HetAr, NR ₂ , NAr ₂ , NHetAn, CONR _¾ OC(0)OR, OC(0)NR; wherein

X = F, Cl, Br or I;

R is substituted or unsubstituted alkyl;

Ar is substituted or unsubstituted aryl;

HetAr is substituted or unsubstituted heteroaryl; and n = 0, 1 or 2.

In yet another aspect, the Z in Formula (I) can be an aryl group independently substituted by N-Het group, wherein N-Het represents and is independently selected from one of the N- containing alkyl or aryl system such as acridine, azabenzotriazole, azaindole, azepane, azepine, azetidine, aziridine, benzimidazole, benzotriazole, carbazole, cinnoline, cyclopenta[b]pyridine, deazapurine, diazepine, dihydropyridine, imidazopyridine, imidazole, imidazolidine, imidazopyridazine, imidazopyridine, imidazopyrimidine, indazole, indole, indoline, indolizine, isoindole, isoquinoline, naphthyridine, oxindole, phenanthroline, phenazine, phthalazine, piperazine, piperidine, pteridine, purine, pyrazine, pyrazole, pyrazolidine, pyrazoline, pyrazolopyridine, pyridazine, pyridine, pyridopyridazine, pyrimidine, pyrolidine, pyrrole, pyrrolepyrimidine, pyrroline, pyrrolopyridazine, pyrrolopyrimidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, triazanaphthalene, triazine, triazole, triazolepyridine, triazolopyrazine, triazolopyridine, and their isomers, preferably on para position.

In an aspect, the present invention provides a compound of general Formula (I), selected from the group, comprising:

In another aspect, the compounds of general Formula (I) are l, l-dialkylethane- l,2-diols, selected from the group.

In another aspect, the present invention provides a process for the preparation of compound of general Formula (I), or a salt or an isomer thereof

Formula (I) wherein A, W, Y, Z and n are as defined above.

In another aspect, the present invention provides a process of making the diol compounds of Formula (I), from corresponding alkene compounds of Formula (IA) employing asymmetric dihyroxylation. Formula (IA) wherein A, W, Y, Z and n are as defined above.

In another aspect, the present invention provides a compound of Formula (IA), selected from the group, comprising:

In another aspect, the present invention provides a process of making the diol compounds of Formula (I), from corresponding alkene compounds of Formula (IA) employing Sharpless asymmetric dihyroxylation; wherein the alkene (IA) is allowed to react with a suitable asymmetric catalyst in a suitable solvent at a suitable temperature for a suitable time period

Formula (IA) Formula (I) wherein A, W, Z and n are as defined above.

Suitable asymmetric catalysts include, but are not limited to, AD-mix a [(DHQ)2PHAL, the phthalazine adduct with dihydroquinine] or AD-mix b [(DHQD)2PHAL, the phthalazine adduct with dihydroquinidine], or the like.

Suitable solvents include, but are not limited to, polar solvents, preferably polar-protic solvents. Preferably, the suitable solvents include, water, acetone, butanone, methanol, ethanol, isopropanol, butanol, tert-butanol , or the like, or mixture thereof. Most preferably, the suitable solvent is a mixture of tert-butyl alcohol and water.

The suitable temperature for the reaction is about - 30 °C to 40 °C. Preferably, the suitable temperature range is - 5 °C to 25 °C. The suitable time period for the reaction is 4 hrs to 24 hrs, though it is variable with respect to reactants and reaction conditions.

In another aspect, the l,l-dialkylethane-l,2-diols of Formula (I) are compounds of following formula:

In yet another aspect, the present invention provides use of compound of general Formula (I) for the preparation of 6-nitro-2,3-dihydroimidazo[2,l-b]oxazole derivatives of following formula (H):

In yet another aspect, 6-nitro-2,3-dihydroimidazo[2,l-b]oxazole derivatives of formula (H) are selected from the group, comprising of following compounds, and the like:

In yet another aspect, the present invention provides compound of following formula:

In yet another aspect, the present invention provides antibacterial compounds of following formula:

In yet another aspect, the present invention provides compounds of formula (003R) and (003S) for the treatment of mycobacterial infections.

In yet another aspect, the present invention provides antitubercular pharmaceutical composition of compounds of formula (003R) and (003S).

In another aspect, the present invention provides a process for the preparation of alkene compounds of Formula (IA), comprising: alkylation/allylation of corresponding phenol with methallyl halide (for e.g. Methallyl chloride, Methallyl bromide, Methallyl iodide or other suitable allyl halide ( e.g. allyl bromide, allyl chloride or allyl iodide) derivatives in presence of a suitable base (e.g. potassium carbonate, Cesium carbonate or sodium hydride) and a suitable solvent (e.g. acetonitrile, acetone, DMF) at a suitable temperature (range from 60-70 °C) for a suitable time period (2-4 hrs.)

The allylation step serves as a protecting group for the phenolic OH for subsequent reactions as well as attachment of the three carbon fragment to the molecule thereby saving two steps of protection and deprotection that are required otherwise.

In yet another aspect, the alkenes of Formula (IA), e.g. compounds of Formula ((001), (005) etc.), can be either commercially available or can be prepared by simple synthetic methods. The corresponding phenolic compound is allowed to react with methallyl halide (or any other allyl halide) in the presence of a suitable base, e.g. potassium carbonate etc., in a suitable solvent, e.g. DMF, at about 50-100 °C, preferably at 60-70 °C, for about 6-12 hrs;

In another aspect, the processes for the alkenes of Formula (IA), e.g. compounds of Formula (008, Oil, 016 etc.), may be difficult and require multiple steps of preparation.

In yet another aspect, a phenol compound of Formula (007) can be prepared through cycloaddition reaction between 4-azidophenol (R6), prepared by azidation of 4-aminophenol (R5), and l-(prop-2-yn-l-yloxy)-4-(trifluoromethoxy)benzene (R4), prepared by propargylation of 4-trifluoromethoxyphenol (R2) with propargyl halide (R3).

In yet another aspect, a phenol compound of Formula (010) can be prepared through cycloaddition reaction between 4-hydroxybenzaldehyde oxime (Rll), prepared from 4- hydroxy benzaldehyde (R9), and l-(prop-2-yn-l-yloxy)-4-(trifluoromethoxy)benzene (R8), prepared by propargylation of 4-trifluoromethoxyphenol (R7) with propargyl halide (R3).

In yet another aspect, a phenol compound of Formula (016) can be prepared by allylation of a phenol compound of Formula (013) using methallyl chloride as an allylating reagent, followed by Cul mediated N-arylation using unprotected 4-hydroxypiperidine as an amine source to provide alcohol of Formula (015), and finally O-arylation under the Mitsunobu reaction conditions.

In yet another aspect, the compound of Formula (016) can also be prepared by N-arylation of compound of Formula (014) using commercially available 4-(4- (trifluoromethoxy)phenoxy)piperidine as an amine source.

Scheme for the preparation of compound of Formula (016) via using commercial available 4- (4-(trifluoromethoxy)phenoxy)piperidine:

Figure 1 illustrates HPLC chromatogram of crude reaction mixture of compound of Formula (009) for determination of % ee. Part-A of the Figure 1 shows the peaks of racemic isomer

(RS) of compound Formula (009). Part-B shows the peaks of optically pure R-isomer of compound of Formula (009). Part-C shows the predominant peak of optically pure S-isomer of compound of Formula (009). Figure 2 illustrates HPLC chromatogram of crude reaction mixture of compound of Formula (017) for determination of % ee. Part-A of the Figure 2 shows the peaks of racemic isomer (RS) of compound Formula (017). Part-B shows the peaks of optically pure R-isomer of compound of Formula (017). Part-C shows the predominant peak of optically pure S-isomer of compound of Formula (017).

TABLE 1: List of compounds

DEFINITIONS

The terminology as used in this disclosure uses a number of special terms that are defined as follows:

As used herein, the modifier "about" should be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression "from about 1 to about 4" also discloses the range "from 1 to 4." When used to modify a single number, the term "about" may refer to ±10% of the said number including the indicated number. For example, "about 10% " may cover a range of 9% to 11%, and "about 1" means from 0.9-1.1.

As used herein, the term“alkyl” refers to an organic group derived from alkane. It also refers, by itself or as part of another substituent, to a straight or branched monovalent hydrocarbon containing up to 1-20 carbon atoms; an “alkyl” group may also be represented as -(CRlR2)n-, where R1 and R2 are independently hydrogen or are independently absent, and for example, m is 1 to 8, and such representation is also intended to cover both saturated and unsaturated alkyl groups; number designators indicate the number of carbon atoms in any substituent, like, C1-C20 means one to twenty carbon atoms; variables or substituents such as Rl, R2, R3, R4, R5 that each of the R groups can be independently defined by any one of the alkyl groups and can be either the same of different groups; the term“substituted alkyl” refers to such straight or branched chain radicals of 1 to 7 carbons wherein one or more hydrogens have been replaced by a hydroxy, amino, nitro, halo, trifluoromethyl, cyano,— NH(lower alkyl),— N(lower alkyl)2, lower alkoxy, lower alkylthio or carboxy; the term“substituted alkyl” refers to the groups like methyl, ethyl, propyl, isopropyl, vinyl, allyl, n-butyl, i-butyl, and t-butyl, 1-propenyl, isoprepenyl, ethynyl, 1-propynyl, 2 -prop ynyl,

1.3-butadienyl, pental,3-dienyl, pental,4-dienyl, hexa-l,3-dienyl, hexa-l,3,5-trienyl, and the like the term“lower alkyl” refers to straight or branched chain radicals having one to four carbons; the term“substituted lower alkyl” refers to such straight or branched chain radicals having one to four carbons wherein one hydrogen has been replaced by a hydroxy, amino, halo, trifluoromethyl, cyano, -NH(lower alkyl),— N(lower alkyl)2, lower alkoxy, lower alkylthio, or carboxy; the term“alkenyl” refers to straight or branched chain radicals of 3 to 7 carbon atoms having one or two double bonds; it also refers to a straight or branched monovalent hydrocarbon containing 2-20 carbon atoms (e.g., C2-C10 or C2-C4) and one or more double bonds. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, propenylene, allyl, and

1.4-butadienyl; the term“substituted alkenyl” refers to such straight or branched radicals of 3 to 7 carbons having one or two double bonds wherein a hydrogen has been replaced by a hydroxy, amino, halo, trifluoromethyl, cyano, — NH(lower alkyl), — N(lower alkyl)2, lower alkoxy, lower alkylthio, or carboxy; the term“alkynyl” refers to a straight or branched monovalent hydrocarbon containing 2-20 carbon atoms (e.g., C2-C10) and one or more triple bonds. Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 1- and 2-butynyl, and l-methyl-2-butynyl; the term“alkoxy” refers to an -O-alkyl radical. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy; the terms“lower alkoxy” and“lower alkylthio” refer to such lower alkyl groups as defined above attached to an oxygen or sulfur; the term“acyloxy” refers to an -0-C(0)-R radical in which R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; the term“amino” refers to NH2, alkylamino, or arylamino; the term“alkylamino” refers to an -N(R)-alkyl radical in which R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; the terms “amido” and “carbamido” refer to -NRC(0)R' and -C(0)NRR' radicals respectively, in which each of R and R', independently, can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; the term“cycloalkyl” refers to saturated rings of 3 to 7 carbon atoms; it also refers to a monovalent saturated hydrocarbon ring system having 3 to 30 carbon atoms (e.g., C3-C12). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,4-cyclohexylene, cycloheptyl, cyclooctyl, and adamantyl; the term“cycloalkenyl” refers to a monovalent non-aromatic hydrocarbon ring system having 3 to 20 carbons (e.g., C3-C20) and one or more double bonds. Examples include cyclopentenyl, cyclohexenyl, fluorenyl, and cycloheptenyl; the term“heterocycloalkyl” refers to a monovalent nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se). Examples include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, 4-tetrahydropyranyl, and tetrahydrofuranyl; the term “heterocycloalkenyl” refers to a monovalent nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se) and one or more double bonds; examples of heterocycloalkenyl groups include, but are not limited to, pyranyl, dihydrobenzimidazolyl and l,3-dihydrospiro[benzo[d]imidazol-2, 1 '-cyclopentane] -4-yl; the term“aryl” refers to phenyl, 1 -naphthyl, and 2-naphthyl; it also refers to a monovalent 6- carbon monocyclic, 10-carbon bicyclic, 14-carbon tricyclic aromatic ring system. Examples include, but are not limited to, phenyl (“Ph”), naphthyl, pyrenyl, anthryl, and phenanthryl. The term“aryloxyl” refers to an -O-aryl; the term“substituted aryl” refers to phenyl, 1-naphthyl; and 2-naphthyl having a substituent selected from lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, trifluoromethyl, amino, -NH(lower alkyl), and -N(lower alkyl)2, di- and tri-substituted phenyl, 1-naphthyl, or 2-naphthyl wherein said substituents are selected from methyl, methoxy, methylthio, halo, hydroxy, and amino; the term“arylamino” refers to an -N(R)-aryl in which R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;

The term“heteroaryl” refers to phenyl, 1 -naphthyl, and 2-naphthyl; it also refers to a monvalent aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se). Examples of heteroaryl groups include pyridyl, pyrrolyl, furyl, imidazolyl, indazolyl, benzimidazolyl, pyrimidinyl, thienyl, oxazolyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, and thiazolyl. In other words this term refers to unsaturated monocyclic rings of 5 or 6 atoms containing one or two O and S atoms and/or one to four N atoms provided that the only other atoms in said monocyclic ring are C atoms and that the total number of O, S and N atoms is four or less and bicyclic rings wherein the five or six membered ring as defined above is fused to a phenyl or pyridyl ring, said heteroaryl ring is attached by way of an available carbon or nitrogen atom; and said monocyclic or bicyclic ring can be substituted at an available carbon atom by lower alkyl of 1 to 4 carbons, halo, hydroxy, benzyl, or cyclohexylmethyl, or can be substituted at an available nitrogen atom by benzyloxymethyl, p-toluene sulfonyl, 2,4- dinitrophenyl, lower alkyl of 1 to 4 carbons, benzyl or benzhydryl; the term“form” as used herein refers to either a polymorphic form of the compound, or a salt form of a compound, or both a polymorphic form and a salt form; and the term“halogen” or“halo” refers to chloro, bromo, fluoro, and iodo; Alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, amino, aryl, and heteroaryl mentioned above include both substituted and unsubstituted moieties;

Possible substituents on amino, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl include, but are not limited to, Cl -CIO alkyl, C2- C10 alkenyl, C2-C10alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, Cl- C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C10 alkylamino, arylamino, C 1 -CIO alky limino, arylimino, Cl- C10 alkyl sulfonimino, arylsulfonimino, hydroxy, halo, oxo (0=), thioxo (S=), thio, silyl, Cl- C10 alkylthio, arylthio, Cl -CIO alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, mercapto, amido, thioureido, thiocyanato, sulfonamido, guanidine, ureido, cyano, nitro, nitroso, azido, acyl, thioacyl, acyloxy, carbamido, carbamyl (— C(0)NH2), carboxyl (— COOH), and carboxylic ester;

On the other hand, possible substituents on alkyl, alkenyl, alkylene, alkenylene, heteroalkylene, heteroalkenylene, or alkynyl include all of the above-recited substituents except C1-C10 alkyl;

Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl can also be fused with each other by sharing one or more atoms (e.g., to form a spiro compound); wherein R groups when present, are each independenly a substituent selected from the group consisting of -F. -Cl, -Br, -I, -CH3, -OH, -SH, -SCH3, -NH2, NHR’, -NR’R” (wherein each R’ and R” is independently H or Cl -3 alkyl, -CN, -N02, -OCH3. -alkyl as defined herein, substituted alkyl, substituted aryl, heteroaryl and substituted hetoroaryl; X, Y, Z are each independently -CH2- or N, provided that at least one of X, Y, and z is N and X is O, S, or NH when X is a divalent group in the ring.

EXAMPLES

Specific description of the most preferred aspects:

Scheme VIII EXAMPLE I, STEP 1: Synthesis of (S)-2-methylnonane-l, 2-diol (002)(S):

In a 100 ml round-bottomed flask equipped with magnetic stirring bar was placed tert-butyl alcohol: water (1:1, 30 ml) and AD-mix-a (12 gm). Stirred the mixture at room temperature until two clear phases were produced; the lower (aqueous) phase was bright yellow. Vigorous stirring was required to dissolve all the AD-mix. The mixture was cooled to 0 °C (some of the dissolved salts precipitated). Added 2-methylnon-l-ene (001) (5 gm, 35.12 mmol) and continued to stir the mixture vigorously at 0 °C (temperature is important!), followed the progress of the reaction by TLC. The resulting mixture was stirred vigorously at 0 °C for 6 h and 1.93 g (15.3 mmol) of sodium sulfite was added. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. Dichloromethane (20 ruL) and water (40 ruL) were added successively and the reaction mixture was extracted with portions of DCM. The combined organic phase was dried over anhydrous MgSC , filtered and concentrated under diminished pressure to afford a crude oil. The residue was purified by chromatography on a silica gel column with gradient elution with 4:1 hexanes/ethyl acetate as colorless oil (002)(S). Yield (4.4 gm, 71%).

Synthesis of (R)-2-methylnonane-l, 2-diol (002)(R):

In a 100 ml round-bottomed flask equipped with magnetic stirring bar was placed tert-butyl alcohokwater (1:1, 30 ml) and AD-mix-b (5.5 gm). Stir the mixture at room temperature until two clear phases are produced; the lower (aqueous) phase should be bright yellow. Vigorous stirring is required to dissolve all the AD-mix. The mixture was cooled to 0 °C (some of the dissolved salts may precipitate). Add 2-methylnon-l-ene (001) (2 gm, 35.12 mmol) and continue to stir the mixture vigorously at 0 °C (temperature is important!), following the progress of the reaction by TLC. The resulting mixture was stirred vigorously at 0 ^~ C for 6 h and 1.93 g (15.3 mmol) of sodium sulfite was added. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. Dichloromethane (20 mL) and water (40 mL) were added successively and the reaction4 mixture was extracted with portions of DCM. The combined organic phase was dried over anhydrous MgSCL, filtered and concentrated under diminished pressure to afford a crude oil. The residue was purified by chromatography on a silica gel column with gradient elution with 4:1 hexanes/ethyl acetate as colorless oil (002). Yield (1.6 gm, 58%).

STEP 2: Synthesis of (R)-2-heptyl-2-methyloxirane (002-EPR):

In a 100 ml round-bottomed flask, (R)-2-methylnonane-l, 2-diol 002 (1.6 gm, 2 mmol) was taken into DCM solvent and add triethylamine (0.960 mL, 4 mmol) followed by the addition of methanesulfonyl chloride (280 pL, 2.2 mmol) dropwise at 0 °C and stirred at room temperature for a period of 2 h. Then solvent was evaporated and extract with ethyl acetate and aqueous layer. The organic solvent was evaporated to afford the mesylated product as gummy material and used as such for the next reaction. In the next step, mesylated compounds was dissolved in ethyl acetate and DBU (300 pL, 4 mmol) was added and stirred the reaction mixture for a period of 2 h and then water was added to the reaction mixture and extract with ethyl acetate and evaporate the organic layer under rotary evaporator followed by purification over 100-200 silica gel and ethyl acetate: hexane (40:60) as eluent to afford the compound 002-EP as brown gummy liquid. (1.4 gm, yield 85 %).

Synthesis of (S)-2-heptyl-2-methyloxirane (002-EPS):

In a 100 ml round-bottomed flask, (S)-2-methylnonane-l, 2-diol 002S (800 mg, 2 mmol) was taken into DCM solvent and add triethylamine (0.480 mL, 4 mmol) followed by the addition of methanesulfonyl chloride (140 pL, 2.2 mmol) dropwise at 0 °C and stirred at room temperature for a period of 2 h. Then solvent was evaporated and extract with ethyl acetate and aqueous layer. The organic solvent was evaporated to afford the mesylated product as gummy material and used as such for the next reaction. In the next step, mesylated compounds was dissolved in ethyl acetate and DBU (150 pL, 4 mmol) was added and stirred the reaction mixture for a period of 2 h and then water was added to the reaction mixture and extract with ethyl acetate and evaporate the organic layer under rotary evaporator followed by purification over 100-200 silica gel and ethyl acetate: hexane (40:60) as eluent to afford the compound 002-EPS as brown gummy liquid. (700 mg, yield 82 %). STEP 3: Synthesis of (R)-l-(2-chloro-4-nitro-lH-imidazol-l-yl)-2-methylnonan-2-ol and 2-heptyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,l-b]oxazoles (003R):

A solution of 2-chloro-4-nitro- 1 /7-imidazole (1.0 g, 8.2 mmol), epoxide 002-EP(S) (1.32 g, 9.86 mmol) and triethylamine (2.28 mL, 16.4 mmol) in ethyl acetate (4.0 mL) was heated at 60-65 °C for 6 h. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give uncyclised intermediate. TLC (EtOAc:hexane 4:6): R _j = 0.20; Yield: 69%. Then intermediate (1.0 gm, 3 mmol) was dissolved in anhydrous DMF and added the cesium carbonate (2.2 gm, 6 mmol) and stir the reaction mixture at 50 °C for 2 hrs. Water (20 mL) were added successively and the reaction mixture was extracted with portions of ethyl acetate. The combined organic phase was dried over anhydrous MgSC , filtered and concentrated under diminished pressure to afford a crude material. The residue was purified by chromatography on a silica gel column with gradient elution with 4:1 hexanes/ethyl acetate as light yellow solid product (003R). Yield (61 %).

Synthesis of (S)-l-(2-chloro-4-nitro-lH-imidazol-l-yl)-2-methylnonan-2-ol and 2-heptyl- 2-methyl-6-nitro-2,3-dihydroimidazo[2,l-b]oxazoles (003S) :

A solution of 2-chloro-4-nitro- 1/7- imidazole (1.0 g, 8.2 mmol), epoxide 002-EP(R) (660 mg, 9.86 mmol) and triethylamine (1.14 mL, 16.4 mmol) in ethyl acetate (2.0 mL) was heated at 60-65 °C for 6 h. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give uncyclised intermediate. TLC (EtOAc:hexane 4:6): R _j = 0.20; Yield: 69%. Then intermediate (1.0 gm, 3 mmol) was dissolved in anhydrous DMF and added the cesium carbonate (2.2 gm, 6 mmol) and stir the reaction mixture at 50 °C for 2 hrs. Water (20 mL) were added successively and the reaction mixture was extracted with portions of ethyl acetate. The combined organic phase was dried over anhydrous MgSCU, filtered and concentrated under diminished pressure to afford a crude material. The residue was purified by chromatography on a silica gel column with gradient elution with 4:1 hexanes/ethyl acetate as light yellow solid product (003S). Yield (57 %).

¾ NMR of 003: NMR (400 MHz, CDCb) d 7.47 (s, 1H), 4.02 (d, / = 10.2 Hz, 1H), 3.91 (d, / = 10.2 Hz, 1H), 1.85 - 1.76 (m, 3H), 1.57 (s, 3H), 1.29 - 1.16 (m, 10H), 0.81 (t, / = 6.1 Hz). sssl3C NMRQ00 MHz, CDC13) d 156.07 (s), 147.27 (s), 112.60 (s), 95.89 - 95.69 (m), 54.01 (s), 40.11 (s), 31.63 (s), 29.47 (s), 28.98 (s), 25.54 (s), 23.26 (s), 22.54 (s), 13.98 (s).

Scheme (IX) EXAMPLE II, STEP 1: Synthesis of l-((2-methylallyl)oxy)-4-(trifluoromethoxy)benzene (005):

The starting material 4-trifluromethoxyphenol (004) (5 gm, 28 mmol, 1 equiv.) and K2CO3 (7.8 gm, 56 mmol, 2 equiv) were suspended in DMF. Then methallyl chloride (3 mL, 36.4 mmol, 1.3 equiv) was added and the reaction was heated to 70 °C for a period of 12 hrs. After cooling, the mixture was diluted with ethyl acetate and transferred to a separating funnel. The organic phase was washed twice with water and once with brine. Drying over MgSCL, filtration, and rotary evaporation provided the crude material. The residue was separated by column chromatography on a silica gel with petroleum ether/ethyl acetate (9:1) as the eluent to afford the corresponding allyl ethers product (005). (Yield 93%).

EXAMPLE II, STEP 2: Synthesis of (R)-2-methyl-3-(4- trifluoromethoxy)phenoxy)propane -1,2-diol (006)(R):

In a 100 ml round-bottomed flask equipped with magnetic stirring bar was placed tert-butyl alcohol: water (1:1, 30 ml) and AD-mix-a (4 gm). Stir the mixture at room temperature until two clear phases are produced; the lower (aqueous) phase should be bright yellow. Vigorous stirring is required to dissolve all the AD-mix. The mixture was cooled to 0 °C (some of the dissolved salts may precipitate). Add l-((2-methylallyl)oxy)-4-(trifluoromethoxy)benzene (005) (1 gm, 4.31 mmol) and continue to stir the mixture vigorously at 0 °C to room temperature (temperature is important!), following the progress of the reaction by TLC. The resulting mixture was stirred vigorously at room temperature for a period of 6-12 h and 1.93 g (15.3 mmol) of sodium sulfite was added. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. DCM (20 mL) and water (40 mL) were then added successively and the reaction mixture was extracted with portions of DCM. The combined organic phase was dried over anhydrous MgSCC, filtered and concentrated under diminished pressure to afford a crude oil. The residue was purified by chromatography on a silica gel column with gradient elution with 4:1 hexanes/ethyl acetate as colorless oily material (006) (R). Yield 1.0 gm (88%).

STEP 3: Epoxidation

Synthesis of (R)-2-methyl-2-((4-(trifluoromethoxy)phenoxy)methyl)oxirane (006-EP):

In a 100 ml round-bottomed flask, (R)-2-methyl-3-(4-(trifluoromethoxy)phenoxy)propane- l,2-diol006 (0.360 gm, 2 mmol) was taken into DCM solvent and add triethylamine (0.240 mL, 4 mmol) followed by the addition of methanesulfonyl chloride (70 pL, 2.2 mmol) dropwise at 0 °C and stirred at room temperature for a period of 2 h. Then solvent was evaporated and extract with ethyl acetate and aqueous layer. The organic solvent was evaporated to afford the mesylated product as gummy material and used as such for the next reaction. In the next step, mesylated compounds was dissolved in ethyl acetate and DBU (60 pL, 4 mmol) was added and stirred the reaction mixture for a period of 2 h and then water was added to the reaction mixture and extract with ethyl acetate and evaporate the organic layer under rotary evaporator followed by purification over 100-200 silica gel and ethyl acetate: hexane (40:60) as eluent to afford the compound 006-EP (R) as brown gummy liquid. (0.240 gm, yield 85 %).

STEP 4: Ring opening and cyclisation

Synthesis of (R)-2-methyl-6-nitro-2-((4-(trifluoromethoxy)phenoxy)methyl) -2,3- dihydroimidazo[2,l-b]oxazole (VL-2098):

A mixture of epoxide 006-EP (R) (240 mg, lmmol), 2-bromo-4-nitro-lH-imidazole (190 mg, 1 mmol), and DIPEA (2.0 mL) were taken in a sealed tube and heated at 115 °C for a period of 2 h. Upon cooling the reaction mixture, dichloromethane was added and evaporated to get crude product and used for the next reaction. To the stirred solution of crude product in anhydrous DMF was added caesium carbonate and stirred the reaction mixture for 2 h at 50 °C and then upon completion of reaction, add water and extract the reaction mixture with ethyl acetate. Then evaporate the solvent and purified the reaction mixture with silica gel 100-200 eluting with 40 % ethyl acetate: dichloromethane gave compound VL-2098 as white solid (172 mg, 48%). [a]D ²⁵ + 7° (c 1, Chloroform) ¾ NMR (400 MHz, CDCb) d 7.53 (s, 1H), 7.11 (d, / = 8.8 Hz, 2H), 6.81 (d, 7 = 9.1 Hz, 2H), 4.46 (d, / = 10.3 Hz, 1H), 4.19 (d, / = 10.1 Hz, 1H), 4.05 (dd, / = 10.0, 8.0 Hz, 2H), 1.75 (s, 3H). LC-MS (ESI+): m/z calcd. for (M+H) ⁺ 360.20.

Scheme X

EXAMPLE III, STEP 1: Synthesis of l-(4-((2-methylallyl)oxy)phenyl)-4-((4- (trifluoromethoxy)phenoxy)methyl)-lH-l, 2, 3-triazole, (008):

The starting material 4-(4-((4-(trifluoromethoxy) phenoxy) methyl)-lH-l, 2, 3-triazol-l-yl) phenol (007) (5 gm, 14.24 mmol, 1 equiv.) and K2CO3 (4 gm, 28.48 mmol, 2 equiv) were suspended in DMF. Then methallyl chloride (1.7 mL, 18.15 mmol, 1.3 equiv) was added and the reaction was heated to 70 °C for a period of 2 hrs. After cooling, the mixture was diluted with EtOAc and transferred to a separating funnel. The organic phase was washed twice with H2O and once with brine. Drying over MgSC , filtration, and rotary evaporation provided the crude material. The residue was separated by column chromatography on a silica gel with petroleum ether/ethyl acetate (9:1) as the eluent to afford the corresponding allyl ethers products (008). (Yield 86%).

EXAMPLE III, STEP 2: Synthesis of (S)-2-methyl-3-(4-(4-((4-(trifhioromethoxy) phenoxy) methyl)-lH-l,2,3-triazol-l-yl)phenoxy)propane-l, 2-diol (009)(S):

In a 100 ml round-bottomed flask equipped with magnetic stirring bar was placed tert-butyl alcohol: water (1:1, 40 ml) and AD-mix-b (gm). Stir the mixture at room temperature until two clear phases are produced; the lower (aqueous) phase should be bright yellow. Vigorous stirring is required to dissolve all the AD-mix. The mixture was cooled to 0 °C some of the dissolved salts may precipitate). Add l-(4-((2-methylallyl)oxy)phenyl)-4-((4- (trifluoromethoxy)phenoxy) methyl)- 1H- 1,2, 3-triazole (008) (1 gm, 2.47 mmol) and continue to stir the mixture vigorously at 0 °C (temperature is important!), following the progress of the reaction by TLC. The resulting mixture was stirred vigorously at 0 ^C C for 6 h and 19 g (15.3 mmol) of sodium sulfide was added. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. Dichloromethane (20 mL) and water (40 mL) were then added successively and the reaction mixture was extracted with portions of DCM. The combined organic phase was dried over anhydrous MgSCL, filtered and concentrated under diminished pressure to afford a crude oil. The residue was purified by chromatography on a silica gel column with gradient elution with 4: 1 hexanes/ethyl acetate as brownish gummy solid (009)(S). Yield (950 mg, 88%).

Synthesis of (R)-2-methyl-3-(4-(4-((4-(trifluoromethoxy)phenoxy)methyl)-l H-l,2,3- triazol-l-yl)phenoxy)propane-l,2-diol (009)(R) :

In a 100 ml round-bottomed flask equipped with magnetic stirring bar was placed tert-butyl alcohokwater (1: 1, 40 ml) and AD-mix-a (2.81 gm). Stir the mixture at room temperature until two clear phases are produced; the lower (aqueous) phase should be bright yellow. Vigorous stirring is required to dissolve all the AD-mix. The mixture was cooled to 0 °C some of the dissolved salts may precipitate). Add l-(4-((2-methylallyl)oxy)phenyl)-4-((4- (trifluoromethoxy)phenoxy)methyl)-lH-l, 2, 3-triazole (008) (4 gm, 9.87 mmol) and continue to stir the mixture vigorously at 0 °C (temperature is important!), following the progress of the reaction by TLC. The resulting mixture was stirred vigorously at 0 ^' C for 6 h and 19 g (15.3 mmol) of sodium sulfide was added. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. Dichloromethane (20 mL) and water (40 mL) were then added successively and the reaction mixture was extracted with portions of DCM. The combined organic phase was dried over anhydrous MgSCL, filtered and concentrated under diminished pressure to afford a crude oil. The residue was purified by chromatography on a silica gel column with gradient elution with 4: 1 hexanes/ethyl acetate as brownish gummy solid (009) (R). Yield (3.9 gm, 90%).

Step 4: Epoxidation

Synthesis of (R)-l-(4-((2-methyloxiran-2-yl)methoxy)phenyl)-4-((4- (trifluoromethoxy)phenoxy)methyl)-lH-l, 2, 3-triazole (009-EP):

In a 100 ml round-bottomed flask, (R)-2-methyl-3-(4-(4-((4- (trifluoromethoxy)phenoxy)methyl)- 1 H- 1 ,2,3 -triazol- 1 -yl)phenoxy)propane- 1 ,2-diol 009 (3.6 gm, 2 mmol) was taken into DCM solvent and add triethylamine (2.4 mL, 4 mmol) followed by the addition of methanesulfonyl chloride (0.684 mL, 2.2 mmol) dropwise at 0 °C and stirred at room temperature for a period of 2 h. Then solvent was evaporated and extract with ethyl acetate and aqueous layer. The organic solvent was evaporated to afford the mesylated product as gummy material and used as such for the next reaction. In the next step, mesylated compounds was dissolved in ethyl acetate and DBU (0.596 mL, 4 mmol) was added and stirred the reaction mixture for a period of 2 h and then water was added to the reaction mixture and extract with ethyl acetate and evaporate the organic layer under rotary evaporator followed by purification over 100-200 silica gel and ethyl acetate: hexane (40:60) as eluent to afford the compound 009-EP(R) as brown gummy liquid. (2.4 gm, yield 85 %).

Step 5: Ring opening and cyclisation

Synthesis of (R)-2-methyl-6-nitro-2-((4-(4-((4-(trifluoromethoxy)phenoxy) methyl)-lH- l,2,3-triazol-l-yl)phenoxy)methyl)-2,3-dihydroimidazo[2,l-b] oxazole (IIIM-019):

A mixture of epoxide 009-EP (R) (2.4 gm, 5 mmol), 2-bromo-4-nitro-lH-imidazole (730 mg, 5 mmol), and DIPEA (2.0 mL) were taken in a sealed tube and heated at 115 °C for a period of 2 h. Upon cooling the reaction mixture, dichloromethane was added and evaporated to get crude product and used for the next reaction. To the stirred solution of crude product in anhydrous DMF was added caesium carbonate and stirred the reaction mixture for 2 h at 50 °C and then upon completion of reaction, add water and extract the reaction mixture with ethyl acetate. Then evaporate the solvent and purified the reaction mixture with silica gel 100-200 eluting with 40 % ethyl acetate: dichloromethane gave final compound IIIM-019 as white solid (300 mg, 48%). [a]D ²⁵ + 7° (c 1, Chloroform)

Scheme XI

EXAMPLE IV, STEP 1: Synthesis of 5-(4-fluorophenethyl)-3-(4-((2-methylallyl)oxy) phenyl)isoxazole (Oil): The starting material 4-(5-((4-fluorophenoxy) methyl)isoxazol-3-yl)phenol (010) (5 gm, 17.55 mmol, 1 equiv.) and K2CO3 (4.8 gm, 35.1 mmol, 2 equiv) were suspended in DMF. Then methallyl chloride (2.04 mL, 22.75 mmol, 1.3 equiv) was added and the reaction was heated to 70 °C for a period of 2 hrs. After cooling, the mixture was diluted with EtOAc and transferred to a separating funnel. The organic phase was washed twice with water and once with brine. Drying over MgSC , filtration, and rotary evaporation provided the crude material. The residue was separated by column chromatography on a silica gel with petroleum ether/ethyl acetate (9:1) as the eluent to afford the corresponding allyl ethers products (Oil). (5.5 gm, Yield 93%).

EXAMPLE IV, STEP 2: Synthesis of (R)-3-(4-(5-(4-fluorophenethyl)isoxazol-3- yl)phenoxy)-2-methylpropane-l,2-diol (012)(R):

In a 100 ml round-bottomed flask equipped with magnetic stirring bar was placed tert-butyl alcohol: water (1:1, 40 ml) and AD-mix-a (13.45 gm). Stir the mixture at room temperature until two clear phases are produced; the lower (aqueous) phase should be bright yellow. Vigorous stirring is required to dissolve all the AD-mix. The mixture was cooled to 0 °C some of the dissolved salts may precipitate). Add 5-((4-fluorophenoxy)methyl)-3-(4-((2- methylallyl)oxy)phenyl)isoxazole (Oil) (4 gm, 11.79 mmol) and continue to stir the mixture vigorously at 0 °C (temperature is important!), following the progress of the reaction by TLC. The resulting mixture was stirred vigorously at 0 °C for 6 h and 19 g (15.3 mmol) of sodium sulfide was added. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. Twenty milliliters of DCM and 40 mL of water were then added successively and the reaction mixture was extracted with portions of DCM. The combined organic phase was dried over anhydrous MgSCC, filtered and concentrated under diminished pressure to afford a crude oil. The residue was purified by chromatography on a silica gel column with gradient elution with 4:1 hexanes/ethyl acetate as brownish gummy product (012)(R). Yield (4.0 gm, 90%).

Step 4: Epoxidation

Synthesis of (R)-5-((4-fluorophenoxy)methyl)-3-(4-((2-methyloxiran-2- yl)methoxy)phenyl)isoxazole (012-EP(R)) :

In a 100 ml round-bottomed flask, ((R)-3-(4-(5-((4-fluorophenoxy)methyl)isoxazol-3- yl)phenoxy)-2-methylpropane-l,2-diol 012 (1.8 gm, 2 mmol) was taken into DCM solvent and add triethylamine (1.2 mL, 4 mmol) followed by the addition of methanesulfonyl chloride (0.342 mL, 2.2 mmol) dropwise at 0 °C and stirred at room temperature for a period of 2 h. Then solvent was evaporated and extract with ethyl acetate and aqueous layer. The organic solvent was evaporated to afford the mesylated product as gummy material and used as such for the next reaction. In the next step, mesylated compounds was dissolved in ethyl acetate and DBU (0.596 mL, 4 mmol) was added and stirred the reaction mixture for a period of 2 h and then water was added to the reaction mixture and extract with ethyl acetate and evaporate the organic layer under rotary evaporator followed by purification over 100-200 silica gel and ethyl acetate: hexane (40:60) as eluent to afford the compound 012-EP (R) as brown gummy liquid. (1.2 gm, yield 81 %).

Step 5: Ring opening and cyclisation

Synthesis of (R)-2-((4-(5-((4-fluorophenoxy)methyl)isoxazol-3-yl)phenoxy) methyl)-2- methyl-6-nitro-2,3-dihydroimidazo[2,l-b]oxazole (IIIM-114):

A mixture of epoxide 012-EP (R) (2.4 gm, 5 mmol), 2-bromo-4-nitro-lH-imidazole (1.4 gm, 5 mmol), and DIPEA (4.0 mL) were taken in a sealed tube and heated at 115 °C for a period of 2 h. Upon cooling the reaction mixture, dichloromethane was added and evaporated to get crude product and used for the next reaction. To the stirred solution of crude product in anhydrous DMF was added caesium carbonate and stirred the reaction mixture for 2 h at 50 °C and then upon completion of reaction, add water and extract the reaction mixture with ethyl acetate. Then evaporate the solvent and purified the reaction mixture with silica gel 100-200 eluting with 40 % ethyl acetate: dichloromethane gave final compound IIIM-114 as white solid (0.800 gm, 48%).

Scheme XII EXAMPLE V, STEP 1: Synthesis of the l-iodo-4-((2-methylallyl)oxy)benzene (014):

The starting material 4-Iodophenol (013) (20 gm, 91mmol, 1 equiv.) and K2CO3 (182 mmol, 2 equiv.) were suspended in DMF. Then methallyl chloride (118.3 mmol, 1.3 equiv) was added and the reaction was heated to 70 °C for a period of 2 hrs. After cooling, the mixture was diluted with EtOAc and transferred to a separating funnel. The organic phase was washed twice with H2O and once with brine. Drying over MgSC , filtration, and rotary evaporation provided the crude material. The residue was separated by column chromatography on a silica gel with petroleum ether/ethyl acetate (9:1) as the eluent to afford the corresponding allyl ethers products (014). (24 gm, Yield 97%).

EXAMPLE V, STEP 2: Synthesis of the l-(4-((2-methylallyl)oxy)phenyl)piperidin-4-ol (015): TABLE 2: Optimization for general reaction conditions for N-arylation

TABLE 3: Optimization of catalyst and ligand mol% for N-arylation

An oven-dried flask was charged with copper iodide (5 gm, 0.3 mmol) and L-proline (6.0 gm, 0.6 mmol). The flask was evacuated with high N2 atmosphere & then fitted with a rubber septum. DMSO (80 mL) was next added, as well as the aryl iodide (014) (25 gm, 91 mmol), which was added at this stage. The resulting blue solution was stirred for 10 min before adding 4-hydroxypiperidine (27.3 gm, 273.0 mmol). The resulting mixture was stirred at room temperature until completion (12-36 hrs). Upon completion, the reaction mixture was diluted with 70 mL of a 1M aqueous solution of sodium hydroxide and extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give the desired pure product as solid (015) (20 gm, Yield 88 %).

EXAMPLE V, STEP 3: Synthesis of l-(4-((2-methylallyl)oxy)phenyl)-4-(4- (trifluoromethoxy)phenoxy)piperidine (016) :

TABLE 4: Optimization for general reaction conditions for O-arylation

To a solution of 4-hydroxypiperidine derivative (015) (10 gm, 40 mmoL) in THF (60 ml) was added PPI13 (15 g, 60 mmoL) and further a solution of 4-triflouromethoxyphenol (5.6 mL, 44 mmoL) and DEAD (9.8 mL) was added dropwise thereto under ice-cooling, followed by stirring at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and to the obtained residue was added an aqueous sodium hydroxide solution, followed by extraction with EtOAc. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: EtOAc=4:l (V/V)) to obtain l-(4-((2- methylallyl)oxy)phenyl)-4-(4-(trifluoromethoxy)phenoxy)piper idine (016) (10 gm, Yield 63%).

EXAMPLE V, STEP 4: Synthesis of (R)-2-methyl-3-(4-(4-(4-

(trifluoromethoxy)phenoxy) piperidin-l-yl)phenoxy)propane-l,2-diol (017)(R):

In a 100 ml round-bottomed flask equipped with magnetic stirring bar was placed tert-butyl alcohokwater (1:1, 30 ml) and AD-mix-a (12 gm). Stir the mixture at room temperature until two clear phases are produced; the lower (aqueous) phase should be bright yellow. Vigorous stirring is required to dissolve all the AD-mix. The mixture was cooled to 0 °C some of the dissolved salts may precipitate). Add l-(4-((2-methylallyl) oxy) phenyl)-4-(4- (trifluoromethoxy) phenoxy) piperidine (016) (5 gm, 12.28 mmol) and continue to stir the mixture vigorously at 0 °C (temperature is important!), following the progress of the reaction by TLC. The resulting mixture was stirred vigorously at 0 "C for 6 h and 1.93 g (15.3 mmol) of sodium sulfide was added. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. Twenty milliliters of DCM and 40 mL of water were then added successively and the reaction mixture was extracted with portions of DCM. The combined organic phase was dried over anhydrous MgSCL, filtered and concentrated under diminished pressure to afford a crude oil. The residue was purified by chromatography on a silica gel column with gradient elution with 4:1 hexanes/ethyl acetate as brownish gummy material (017)(R). Yield (4.4 gm, 86%). Enantiomeric excess can be determined by using chiral HPLC technique by using chiral pack column.

Step 5: Epoxidation

Synthesis of (/?)-2-hydroxy-2-methyl-3-(4-(4-(4-(trifluoromethoxy)phenoxy )piperidin-l- yl)phenoxy)propyl methanesulfonate and (/?)-l-(4-((2-methyloxiran-2- yl)methoxy)phenyl)-4-(4-trifluoromethoxy)phenoxy) (017-EP) :

In a 100 ml round-bottomed flask, (R)-2-methyl-3-(4-(4-(4-(trifluoromethoxy)phenoxy) piperidin-l-yl)phenoxy)propane-l,2-diol 017 (0.9 gm, 2 mmol) was taken into DCM solvent and add triethylamine (0.570 mL, 4 mmol) followed by the addition of methanesulfonyl chloride (0.170 mL, 2.2 mmol) dropwise at 0 °C and stirred at room temperature for a period of 2 h. Then solvent was evaporated and extract with ethyl acetate and aqueous layer. The organic solvent was evaporated to afford the mesylated product as gummy material and used as such for the next reaction. In the next step, mesylated compounds was dissolved in ethyl acetate and DBU (0.596 mL, 4 mmol) was added and stirred the reaction mixture for a period of 2 h and then water was added to the reaction mixture and extract with ethyl acetate and evaporate the organic layer under rotary evaporator followed by purification over 100-200 silica gel and ethyl acetate: hexane (40:60) as eluent to afford the compound 017-EP(R) as brown gummy liquid. (0.7 gm, yield 82 %).

STEP 6: Ring opening and cyclisation

Synthesis of l-(2-bromo-4-nitro-lH-imidazol-l-yl)-2-methyl-3-(4-(4-(4-

(trifluoromethoxy)phenoxy)piperidin-l-yl)phenoxy)propan-2 -ol and 2-methyl-6-nitro-2- ((4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-l-yl)phenoxy)m ethyl)-2,3- dihydroimidazo[2, 1 -b] oxazoles (Delamanid) :

Table 5: Optimization for general reaction conditions for epoxide ring opening

A mixture of epoxide 017-EP(R) (424 mg, lmmol), 2-bromo-4-nitro-lH-imidazole (190 mg, 1 mmol), and DIPEA (2.0 mL) were taken into a sealed tube and heated to 115 °C for a period of 12 h. Upon cooling the reaction mixture, dichloromethane was added and evaporated to dryness under reduced pressure and then residue was purified on silica gel 100- 200 and then eluted with 0.5% EtOAc/CH2C12 gave the desired compound (552 mg) in a yield of 90%. To the stirred solution of uncyclized compound (307 mg, 0.5 mol) in anhydrous DMF, caesium carbonate was taken and stirred the reaction mixture for 2 h at 50 °C and then upon completion of reaction, add water and extract with ethyl acetate. Then evaporate the solvent and purified the reaction mixture with silica gel 100-200 eluting with 40 % ethyl acetate: dichloromethane gave compound Delamanid as white solid (185 mg,

70%). Mp 195-196 7.58 (s,lH), 7.17-7.15 (d, J= 8.0 Hz, 2H), 6.84- 6.91 (m, 4H), 6.81-6.78 (d, J= 12.0 Hz, 2H), 4.53-4.50 (d, J =12.0 Hz, 1H), 4.46-4.41 (1H, m), 4.21-4.18 (d, J= 10.2 Hz, 1H), 4.07-4.04 (dd, J = 12.0 Hz, 2H), 3.41-3.35(m, 2H), 3.04- 2.98 (m, 2H), 2.14-2.09 (m, 2H), 1.99-1.93 (m, 2H), 1.78 (s, 3H); ¹⁹ F NMR (CDCb, 376 MHz): d -58.32; ¹³ C NMR (101 MHz, CDCh) d 155.92, 151.71, 146.89, 122.50,119.29 (q, JC-F = 256.54 Hz,) 118.56, 116.84, 115.57, 112.54, 93.24, 72.70, 72.23, 51.43, 47.86, 30.57, 23.16; [a]D25 - 12° (c 1, Chloroform); HRMS (ESI+) calcd. for C25H25F3N4O6 535.180 ([M+H] ⁺ , found 535.179.

Biological evaluation:

In vitro activity against M. tuberculosis H37RV

METHOD: MIC was determined by broth dilution method against M. tuberculosis H37RV (ATCC 27294; American Type Culture Collection, Manassas, VA, USA), M. tuberculosis MDR (resistant to isoniazid and rifampicin) and one of the laboratory generated mutant M. tuberculosis Rif ^R (resistant to rifampicin) ¹⁰ using micro-broth dilution method. The bacterial strains were grown for 10 to 15 days in Middlebrook 7H9 broth (Difco Laboratories, Detroit, Mich.) supplemented with 0.5% (v/v) glycerol, 0.25% (v/v) Tween 80 (Himedia, Mumbai India), and 10% ADC (albumin dextrose catalase, Becton Dickinson, Sparks, MD) under shaking conditions at 37 °C in 5% CO2 to facilitate exponential-phase growth of the organism. Bacterial suspension was prepared by suspending M. tuberculosis growth in normal saline containing 0.5% tween 80 and turbidity was adjusted to 1 McFarland (McF) standard which is equivalent to 1.0 x 10 ⁷ CFU/mL. The 2-fold serial dilutions of compounds were prepared in Middle brook 7H9 (Difco laboratories) for M. tuberculosis in 100 pL per well in 96-well U bottom microtitre plates (Tarson, Mumbai, India). The above-mentioned bacterial suspension was further diluted 1:10 in the growth media and 100 pL volume of this diluted inoculum was added to each well of the plate resulting in the final inoculum of 1.0 x 10 ⁶ CFU/mL in the well and the final concentrations of compounds ranged from 0.015 to 32 pg/mL. The plates were incubated at 37 °C for seven days in 5% CO2. For evaluation of results (Resaurin Microtitre Assay) REMA method was used. After incubation, 15 pL of 0.04% resazurin and 12.5 pL of 20% tween 80 was added in each well of plate including media and growth controls. After 48 h incubation, plates were read visually and the minimum concentration of the compound showing no change of colour was recorded as MIC.

Result:

The compound of general formula 003 as claimed, wherein said compound exhibits an in vitro anti-tuberculosis activity against H37RV Mycobacterium tuberculosis having MIC ranging from 0.25- 0.015 pg/ml The compound of formula (003R) shown significant in vitro activity having MIC of 0.015 pg/ml.

1 ⁰⁰³ 0.25

2 003R 0.015

3 003S 0.010

4 IIIM/MCD-019 ₀ .12

5 Delamanid 0.007 aMIC: Minimum inhibitory concentration and

H ₃₇ RV: Virulent strain of Mycobacterium tuberculosis ;

In vivo efficacy study of compound 003R:

Dose Preparation:

Compound of formula 003R was dissolved in minimum amount of DMSO and then mixed in alcohol so as to make final volume upto 5% ethanol and 95% PEG 400 (v/v) mixed. Compounds were dissolved to make final concentration of 25 mg/kg while isoniazid was prepared at same concentration of 25 mg/kg. A total of 200 pL volume of respective dose was administered orally (oral gavage) in a bio safety cabinet to each group. Same volume of mixture i.e. 5% ethanol and 95% PEG 400 (v/v) was given to placebo group. A group of mice was kept without dosing which served as control.

Method:

In this particular study we prepared nine groups, and each group was equipped with four B ALB/c mice with average weight 18- 22 gram. M. tuberculosis H37Rv was grown in 7H9 medium, supplemented with 10% ADC. After 14 days culture was diluted at final strength of 1 McF. 20 pi of this culture was administered through the left nasal route. Dosing was initiated after the first day of infection, and three mice from early control was also dissected on the same time, that allows to enumerate mycobacterium established within the lungs. After two weeks, mice from late control and treated group were sacrificed, and left lung was taken out. It allows to monitor the reduction in bacilli burden after the treatment, and compared with early and late control. Left lung was removed during dissection and dispensed in 1ml NST, and samples were homogenized. Serial dilutions of individual samples were performed (up to 10-6). 20m1 from every dilution was spotted on 7H10 agar plates supplemented with 10%ADC and PANTA antibiotics. M. tuberculosis growth was observed after 28 days and CFU was measured.

Result:

The compounds 003R was evaluated for the in vivo efficacy in intranasal mice model of acute infection in Balb/c mice. After one week of post MTB infection, the compounds were orally administered at 25 mg/kg once daily for two weeks. Compound having formula 003R has shown the significant 1.2 log CFU (colony forming unit) reduction compared to the untreated control (late control, group run parallel without drug treatment) and 1.8 log colony forming unit reduction as compared to the early control (group at the start of treatment).

ADVANTAGES OF PRESENT INVENTION

The present invention deals with novel process of preparation of chiral l,l-dialkylethane-l,2- diols of Formula (I) as useful intermediates for the synthesis of 6-nitro-2,3- dihydroimidazo[2,l-b]oxazole related compounds.

For introduction of the only chiral center in useful 6-nitro-2,3-dihydroimidazo[2,l-b]oxazole related compounds the present invention employs Sharpless dihydroxylation which has many advantages over Sharpless epoxidation (usually employed in the prior art) like simple recipe (single commercially available reagent mixture), reaction conditions (near room temperature instead of -40 to -10 °C for epoxidation), reaction time (2-12 hrs vs ~2 days), solvent advantage (water/tert-butanol mixture vs anhydrous DCM and absolute anhydrous conditions), as well as ease of operation. The present invention provides a concise route for key intermediate of the TB drug Delamanid while reducing the number of reaction steps and improving the cost effectiveness of the drug molecule.

The present invention eliminates the need for the protection groups for halophenol as well as 4-hydroxypiperidine fragment. Halophenol is allylated with methallyl chloride which essentially serves as a protecting group as well as an attachment of three carbon fragment. Cu mediated N-arylation methodology makes it possible to use unprotected piperidine, eliminates the need for use of expensive and toxic palladium based catalyst and also eliminate the need for high temperature reaction conditions for a prolonged period of time. The present invention provides new compounds, such as: l-(4-((2-methylallyl)oxy)phenyl)-4- ((4-(trifluoromethoxy)phenoxy)methyl)-lH- 1,2,3-triazole (008), (R)-2-methyl-3-(4-(4-((4- (trifluoromethoxy)phenoxy)methyl)- 1H- 1 ,2,3 -triazol- 1 -yl)phenoxy)propane- 1 ,2-diol (009),

5-((4-fluorophenoxy)methyl)-3-(4-((2-methylallyl)oxy)phen yl)isoxazole (Oil), (R)-3-(4-(5- ((4-fluorophenoxy)methyl)isoxazol-3-yl)phenoxy)-2-methylprop ane-l,2-diol (012), l-(4-((2- methylallyl)oxy)phenyl)piperidin-4-ol (015) and l-(4-((2-methylallyl)oxy)phenyl)-4-(4- (trifluoromethoxy)phenoxy)piperidine (016); (R)-l-(2-chloro-4-nitro-lH-imidazol-l-yl)-2- methylnonan-2-ol and 2-heptyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,l-b]oxazoles (003R and 003S) etc.