WO2013072903A1 - Nitroimidazoxadiazocine compounds - Google Patents

Abstract

This invention relates to nitroimidazoxadiazocine compounds having the general Formula I, pharmaceutical compositions and uses of the same. The invention also relates to methods of making such nitroimidazoxadiazocine compounds of Formula I.

Description

NITROIMIDAZOXADIAZOCINE COMPOUNDS

BACKGROUND OF THE INVENTION

The present invention relates to nitroimidazoxadiazocine compounds, to their preparation, and to their use as drugs, effective against Mycobacterium tuberculosis (M.tb), and other microbial infections, either alone or in combination with other treatments. The compounds may also be useful for the treatment of other infectious diseases such as malaria, trypanosomiasis, Chagas' disease, Leishmaniasis and Schistosomiasis.

The World Health Organization (WHO) estimates that about 1/3 of the global population is infected with Mycobacterium tuberculosis (M.tb), the bacterium that causes tuberculosis (TB) (WHO, 2010). According to the WHO report, nearly 8 million of the infected people develop active TB, of which nearly 2 million die annually from the disease.

A major problem associated with M.tb therapy is multi-drug resistance to the commonly used therapeutic options currently available to patients. Multidrug-Resistant TB (MDR-TB) is defined as resistance to the two most commonly used drugs in the current four-drug (or first-line) regimen, isoniazid and rifampin. The WHO treatment standards require that at least four drugs (rifampin, isoniazid, ethambutol and pyrazinamide) be used to treat TB, and to avoid the development of further resistance.

An estimated one-third of the 40 million people living with HIV/AIDS worldwide are co-infected with TB. Unfortunately, the current TB drug regimen is not compatible with certain common antiretroviral (ARV) therapies used to treat HIV/AIDS, requiring a change in regimen to avoid drug-drug interactions. Drug-resistant strains of tuberculosis are complicating efforts to control the global TB pandemic, and putting thousands of lives at risk. When first-line drugs fail, second-line drugs are used to treat MDR-TB. Unfortunately, some second-line drugs are toxic and can lead to negative side-effects. They must be taken for up to two years in order to eradicate the infection.

The costs of curing MDR-TB can be staggering— as much as 1400 times that of regular treatment. Expensive treatment is often out of reach to patients who are infected with drug-resistant strains.

Extensively Drug-Resistant TB (XDR-TB), also known as Extremely Drug- Resistant TB, is emerging as an even more ominous threat. XDR-TB is defined as TB that is resistant to any fluoroquinolone, and at least one of three injectable second-line drugs: capreomycin, kanamycin and amikacin. This makes XDR-TB treatment extremely complicated, with some strains proving to be virtually untreatable. According to the WHO, XDR-TB remains rare. Wherever second-line drugs to treat MDR-TB are being misused, the possibility of XDR-TB exists.

So long as TB is treated with a long, complex, decades-old drug regimen, drug resistance will continue to develop. There is therefore a need for the development of novel TB drugs, and effective processes for producing such drugs. The novel drugs are expected to work through new biological mechanisms of action to effectively tackle drug-susceptible and drug- resistant strains, and therefore allow for shorter regimens, reliably administered, thus minimizing the potential for further resistance.

Nitroimidazoles have recently been the subject of significant efforts to optimize anti M.tb activity, for example derivatives of PA-824 (1.1 ) and OPC-67863 (1.2) (Fig. 1 ), both of which are currently in Phase II clinical trials for the treatment of multi-drug resistant M.tb have been synthesized and reported extensively (Patents US 5,668,127, US 6, 087, 358, WO 2007075872 A2 and W0 2009/120789 A1 ; Sasaki, 2006; Palmer , 2010, Sutherland, 2010; Kmentova, 2010). Both PA-824 (1.1 ) and OPC-67863 (1.2) kill multidrug resistant M.tb.

Unlike most antimicrobial agents, PA-824 (1.1 ) has been shown to maintain potent antimicrobial activity either under aerobic or anaerobic conditions and works better than isoniazid, a standard regimen for M.tb. The discovery of PA-824 (1.1 ), OPC-67683 (1.2) and other derivatives has thus given new hope to the burden caused by TB. However, PA-824 (1.1 ) and OPC-67863 (1.2) both suffer from extremely low solubility and complicated formulations (Kim, 2009). This results in extremely low bioavailability for these compounds. More recently, new derivatives of PA-824 (1.1 ) aimed at overcoming the solubility issues associated with the parent drug have been reported (Kmentova, 2010).

Fused nitroimidazole derivatives such as the nitroimidazopyran PA-824 (1.1 ) and the nitroimidazoxazole OPC-67683 (1.2) are useful as anti- tubercular agents and so on. These derivatives are shown in Figure 1 . Different processes for making the imidazopyran PA-824 (1.1 ) have been reported (see WO 97/01562; US 2006/0063929 A1 ; Marsini, 2010); the original process (WO 97/01562), is shown in Figure 2.

The reagents and conditions required for the process in Figure 2 are as follows; (i) TBDMSCI, imidazole; (ii) EtOH, heat, 53%; (iii) PTS, DCM, 79%; (iv) TBAF, THF; (v) H₂0, AcOH, THF, heat, 79%.

According to the process described in the patent, the intermediate epoxide B, obtained from the reaction of enantiopure glycidal A and TBDMSCI is subsequently treated with 2,4-dinitroimidazole C in ethanol. Upon protection of the resulting secondary alcohol D with dihydropyran, the intermediate tetrahydropyran E is obtained; removal of the silyl-protecting group with TBAF results in the cyclized THP-protected imidazopyran F. Acid catalyzed removal of the THP-protecting group affords the imidazopyran derivative G with a free hydroxyl group, which is elaborated further into PA-824 (1 ). An improved alternative process for synthesizing PA-824 (1.1 ) has been reported in patent US2006/0063929A1 . Figure 3 details the process.

The reagents and conditions required for the process in Figure 3 are as follows (i) CsF, rt, neat; (ii) TBDMSCI, imidazole, DCM, rt; (iii) DCC, cat DMAP, rt; (iv) TBAF, THF, rt; (v) Ti(/PrO)₄, reflux.

Glycidal A is reacted with 2,4-dinitroimidazole under basic conditions without the need to protect the hydroxyl function of the epoxide, yielding diol H, which is then selectively mono-protected at the primary alcohol position to give the terf-butysilyl ether I. The secondary alcohol of the tert- butysilyl ether I is then esterified with benzoic acid to the ester J, which upon treatment with TBAF removes the silyl-protecting group. The liberated alkoxide (not shown) simultaneously cyclizes into the nitroimidazolpyran ester K. Treatment of K with base affords G, which is derivatized accordingly into PA-824 (1 ).

More recently, a method for the synthesis of PA-824 (1.1 ) that does not rely on epoxides has been disclosed in the literature, as depicted in Figure 4 (Marsini et at., 2010). The reagents and conditions required for the process of Figure 4 are as follows; (i) Imidazole, DCM, 78 - 82%; (ii) cat NaH, CI₃CCN, TBME, heptanes, 98%; (iii) N, TfOH, DCM, 80%; (iv) Q, K₂C0₃/Nal, DMF, 40 - 50%; (v) KOH/MeOH, 0 ^<C.

In this process, the enantiomerically enriched diol L is esterified by treatment with 4-methoxybenzoyl chloride M to afford ester N. On the other hand, the 4-trifluoromethylbenzyl alcohol O is converted to P by sequential reaction with benzyltrichloroacetimidate derived from p-(trifluoromethoxy) benzyl alcohol L and stoichiometric trifluoromethanesulfonic acid in dichloromethane, then N to generate P. Alkylation of 2-chloro-4- nitroimidazole Q with P is then effected under basic conditions to furnish R in modest yields, which upon treatment with potassium hydroxide in methanol cyclizes to PA-824 (1.1 ) via intermediate S. However, these methods for synthesizing PA-824 (1.1 ) and derivatives rely on reacting either 2,4-dinitroimidazole or the 2-halo-4-nitroimidazole and the corresponding substrates under thermal conditions, with prolonged heating, or relies on epoxides, at times fails with some bases and yields are particularly low to modest. In the present invention, we have developed a process for synthesizing nitroimidazoxadiazocine and its intermediates from 2,4-dinitroimidazole and appropriate alcohols under mild reaction conditions, resulting in high yields of products.

SUMMARY OF THE INVENTION

According to the first aspect of the invention, there is provided a compound represented by the general Formula (I).

or pharmaceutically acceptable salts, mixtures, optical or geometric isomers, esters or prodrugs thereof, wherein:

X is hydrogen, substituted or unsubstituted alkyl or cycloalkyi and Y is absent, or X is independently selected from CH₂, CH(CH₃), C=0, S0₂, substituted or unsubstituted pyrimidine, substituted or unsubstituted piperidine, 4-aminocyclohexane, and Y is absent or represents any one of Formulae I la— llg below:

Ma Mb Mc Md Me

R in Formulae lla-llg represents any one or more of H, F, CI, Br, CN, MeO, CF₃, OCHF₂, OCF₃, a carboxamide group C(0)NR₇R₈, reversed carboxamide NR₇C(0)R₈, carboxyl C(0)R₇, substituted or unsubstituted alkyl, alkenyl, alkynyl, substituted or unsubstituted alkyl amines, amide, aldehyde, substituted or unsubstituted phenyl, biphenyl, hydrazide, hydrazine, pyridine, dihydropyridine,morpholino, pyrrollidine, piperazine, naphthalene, oxophenyl, aryl sulphonamide, alkyl sulphonamide, cycloalkyl, alkoxy aryl, alkoxy alkyl, indole, pyrimidine, pyridazine, piperidine, imidazole, quinoline, sulfonyl, furan, thiophene, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, triazole, pyrrole or pyrazole at any one or more of the available ring positions;

When R in formula lla or lib is a carboxamide group C(0)NR₇R₈ or a reversed carboxamide NR₇C(0)R₈, or a carboxyl C(0)R₇, R₇ and R₈ represents any one of substituted or unsubstituted alkyl, phenyl, pyridiyl, cycloalkyl, piperidine, thiophene, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, triazole, pyrrole or pyrazole at any one or more of the available ring positions;

Ri and R₂ in Formula lid represent one or two of H, substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, piperidine, piperazine, alkyl sulfone, phenyl, phenylsulfone, alkylphenyl, biaryl, alkyl biaryl, pyridine, naphthalene, indole, pyrimidine, pyridazine, piperidine, imidazole, quinoline, sulfonyl, furan, thiophene, oxazole, benzyl, amide, isoxazole, thiazole, thiadiazole, triazole, pyrrole or pyrazole at any one or more of the available ring positions. Alternatively, Ri and R₂ together with the nitrogen atom to which they are attached form a morpholine ring, which may be substituted or unsubstituted.

R₃ in Formula lie represents OR₄ and NR₅R₆, wherein R₄ is any one of tert butyl, ethyl or H, and one of R₅ and R₆ is H, substituted or unsubstituted alkyl, cyclopropyl, methoxyethyl, cyclopropylmethyl, cyclohexylmethyl, morpholinoethyl, cyclobutyl, substituted or unsubstituted phenyl, benzyl, phenethyl, piperazine or piperidine. Alternatively R₅ and R₆ together with the nitrogen atom to which they are attached form a substituted or unsubstituted pyrrole, piperazine or piperidine ring.

When R in formula llf is a carboxyl group 0(0^, represents any one of substituted or unsubstituted alkyl, phenyl, benzyl, phenethyl, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, triazole, pyrrole or pyrazole at any one or more of the available ring positions;

In an embodiment of the invention X is CH₂ and Y is a compound of formula lie, wherein R₃ is OR₄ and R₄ is ethyl or tert butyl; X is CH₂ and Y is a compound of formula lie, wherein R₃ is 0R₄ and R₄ is H.

The phenyl or pyridine rings are substituted with one or more of Br, OMe, CF₃, OCF₃, OCH₂, OCHF2, -C(0)NR₁ R₂ or NR₁C(0)R₂, where Ri and R₂ are as defined above.

In an embodiment, X is CH₂ and Y is a substituted or unsubstituted biaryl. In particular, X is CH₂ and Y represents formula lla and R is selected from substituted or unsubstituted phenyl, pyridine, pyrimidyl, indole or a five- membered heterocycle. In an alternative embodiment, X is CH₂ and Y represents formula lib, wherein R is a substituted phenyl.

The biaryl may be an ο/ΐ/70-substituted biaryl, mefa-substituted biaryl or para-substituted biaryl.

The biaryl may be substituted with one or more of CF₃, NHBoc, C0₂Et, CN, OCF₃, furan, N0₂, C0₂H, F, isoxazole, OMe, OCH₃, pyrrole, a carboxamide group C(0)NR_! R₂, where Ri and R₂ are as defined above, or C(0)OR₄, where R is ethyl.

In an embodiment X is CH₂ and Y is a compound of formula lie, wherein R₃ is NR₅R₆, and R₅ or R₆ is one of H, NH, an aromatic or alkyl group; X is CH₂, Y is a compound of formula lie and R₅ or R₆ is one of substituted alkyl or cyclopropyl, or X is C=0 and Y represents cyclobutyl. In particular R₅ and R₆ represent H and any one or more of substituted or unsubstituted alkyl, cyclopropyl, methoxyethyl, cyclopropylmethyl, cyclohexylmethyl, morpholinoethyl, cyclobutyl, substituted or unsubstituted aniline, phenyl, benzyl, phenethyl, piperazine or piperidine.

In a further embodiment, X is C=0 and Y represents formula lid, wherein Ri and R₂ represents H any one of the compounds selected from alkyl, alkyl sulfonamide, or substituted or unsubstituted phenyl.

In an embodiment, X represents a substituted pyrimidine and Y is absent. In particular, the pyrimidine is substituted in the 4-position with CI, or an amine such as pyrrolidine, morpholine, tetrahydropyridine, cyclohexylmethanamine, substitutued or unsubstituted: aniline, benzylamine, phenethylamine, or piperazine.

In an embodiment, X represents a N-substituted piperidine and Y is absent. In particular, the piperidine is substituted as shown in formula llf with a substituted or unsubstituted alkyl group or substituted or unsubstituted carboxyl group C(0)Ri . When R in formula llf is a carboxyl group C(0)Ri , Ri represents any one of substituted or unsubstituted alkyl, phenyl, benzyl, phenethyl, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, triazole, pyrrole or pyrazole at any one or more of the available ring positions;

In a further embodiment, X is CH₂ and Y represents a substituted phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with a substituted or unsubstituted carboxamide group.

In a preferred embodiment, X is CH₃ or H and Y is absent; or X is CH₂ and

Y is -CH=CH₂, -CH=C(CH₃)₂ or CN; or X is CH₂ and Y is -C(0)-0-C(CH₃)₃, -C(0)-OH; or X is CH₂ and Y is phenyl or phenyl substituted with OMe, CF₃, OCF₃, OCF₂, Br at one or more of the ring positions; or where X is CH₂ and

Y is pyridine or pyridine substituted with Br. In another embodiment, X is CH₂ and Y is a substituted or unsubstituted biphenyl group, wherein when substituted the biphenyl is substituted with C0₂Et, F, CN or -N(0)-0-C(CH₃)₃.

X is CH₂, Y represents formula I la and R is unsubstituted or substituted pyridine, wherein when substituted the pyridine is substituted with -C(0)-0- C(CH₃)₃. Preferably, the substitution occurs on the nitrogen atom of the pyridine ring.

X is CH₂, Y is formula I la and R is substituted isoxazole, wherein the isoxazole is substituted with CH₃ at one or more of the ring positions or R is unsubstituted or substituted indole, wherein the indole group is substituted with CH₃. Preferably the substitution occurs on the nitrogen atom of the indole ring.

X is CH₂, Y is formula lib and R is substituted phenyl, wherein the phenyl group is substituted with C0₂Et, CF₃, CN or F.

In a preferred embodiment, R is substituted on the meta position of Formula lla or lib.

In another embodiment, X is CH₂, Y is formula lla and R is unsubstituted or substituted phenyl. When substituted, the phenyl may be substituted with C0₂Et, OMe, OCH₃, CF₃, OCF3, NHBoc, CN, F or N0₂ at any of the available ring positions.

X is CH₂, Y is formula lla and R is substituted or unsubstituted indole, furan or triazole. Prefereably the triazole is substituted with CF₃ and the indole is substituteded with CH₃.

X is CH₂, Y is formula lla and R is substituted or unsubstituted pyridine. When substituted, the substituents include MeO, CI, F.

X is CH₂, Y is formula lla, R is substituted or unsubstituted pyrimidine. The substituents are prefereably, OMe, CI or F. X is CH₂, Y is lib and R is substituted or unsubstituted phenyl. The substituents include, C0₂Et, CN, CF₃ or F.

In a preferred embodiment, R is substituted on the para position of Formula Ma or lib.

In another preferred embodiment X is CH₂, Y is formula I la and R is substituted or unsubstituted phenyl. The preferable substitutents include C0₂Et, CN or F. In a preferred embodiment, R is substituted on the ortho position of Formula lla.

X is CH₂, Y is formula lla and R is substituted phenyl, wherein the phenyl is substituted with any one of the amides as disclosed in compounds 8.5.1 - 8.5.6 and 8.6.1 -8.6.5 in Table 5.

X is CH₂, Y is lla and R is substituted phenyl, wherein the phenyl is substituted with F and any one of the amides as disclosed in compounds 8.7.1 -8.7.6 and 8.8.1 -8.8.5 in Table 6. The phenyl may be substituted at any of the available ring positions.

X is CH₂, Y is formula lib and R is substituted phenyl, wherein the phenyl is substituted with F and any one of the amides as disclosed in compounds 8.7.7-8.7.12, 8.7.14, 8.8.6-8.8.12, 8.9.1 -8.9.12 and 8.10.1 - 8.10.6 in Table 6. The phenyl may be substituted at any of the available ring positions.

X is CH₂, Y is lib and R is substituted phenyl, wherein the phenyl is substituted with F and C(0)OH. The substitution can take place at any of the available ring positions.

X is CH₂, Y is formula lie, R₃ is NR₅R₆, R₅ and R₆ are both CH₃ or R₅ is H and R₆ is CH₂CH₃.

X is CH₂, Y is lie, R₃ is NR₅R₆, R₅ is H and R₆ is selected from any one of the following groups, a methoxyethyl group, -CH(CH₃)₂, a cyclopropyl group, a cyclopropylmethyl group, a cyclohexylmethyl group, a morpholonoethyl group, a oxopyrrolpropyl group, or a cyclobutyl group.

Alternatively R₅ and R₆ together with the nitrogen atom to which they are attached from a pyrole group, or a piperazine group or a piperadine group. The piperazine group may be optionally substituted with a phenyl group, which phenyl group may be further substituted with F, C0₂Et or CN. The piperidine group may be optionally substituted with a phenyl group.

R₅ is H and R₆ is a substituted phenyl, wherein the phenyl is substituted with Br, CF₃, OCF₃ or -C(0)CH₃.

R₅ is H and R₆ is CH₂ substituted with a substituted phenyl, wherein the phenyl is substituted with Br, OMe, CF₃, OCF₃, or OCHF₂, or wherein the CH₂ is substituted with a biphenyl group, which may be further substituted with OCF₃.

R₅ is H and R₆ is CH₂CH₂ substituted with a substituted phenyl, wherein the phenyl is substituted with a CF3.

R₅ is H and R₆ is a substituted piperidine group. The piperidine group may be substituted with a substituted alkyl group, preferably substituted with a phenyl group.

X is C=0, Y is formula lla and R is Br,

X is C=0, Y is formula lie, wherein R is CH₂CH₃ or wherein R is a substituted indole, preferably the indole is substituted with a phenyl group, more preferably the indole and phenyl groups are fused. Alternatively, R is a substituted thiazole group, wherein the thiazole is substituted with phenyl. R may also be cyclobutyl.

X is C=0, Y is CH₂ substituted with a phenoxy group. X is C=0, Y is I If and R is a substituted phenyl, wherein the phenyl is substituted with CN.

X is C=0, Y is lib, R is Br.

X is C=0, Y is I la, R is a bromophenoxy group, benzyloxy group, oxyphenyl group, or a phenyl group.

X is C=0, Y is I la or lib and R is a phenyl group. Preferably the phenyl group is fused with formulae lla or lib.

X is C=0, Y is cyclohexyl.

X is C=0, Y is CH₂-CH₂ substituted with a bromophenyl group.

X is C=0, Y is lid, wherein is H and R₂ is selected from a phenylsulfonyl group, a tosyl group or a fluorophenyl sulfonyl group.

X is C=0, Y is lid, Ri is H and R₂ is selected from a tolyl, methoxyphenyl, cyanophenyl, fluorophenyl or chlorophenyl group, or wherein R₂ is CH₂ substituted with phenyl.

X is S0₂, Y is CH₃, imidazole which is preferably substituted with a methyl group, or Y is a substituted or unsubstituted phenyl group, wherein the phenyl is substituted with CN, CI, CH₃ or OCH₃.

X is pyrimidine, Y is an amine group selected from any one of the amines in compounds 15.1 .2-15.1 .1 1 as set out in Table 12.

X is pyrimidine and Y is a dihydropyridine, morpholino, pyrrolidine, or piperazine group. Prefereably the piperazine group is substituted with a phenyl group. The phenyl group may be further substituted with CN, F, C(0))CH₂CH₃.

X is CH₂, and Y is lla, R is amide selected from any of the amides iin compounds 16.1 .1 -16.1 .21 , 16.1 .23, 16.1 .27-16.1 .38 and 16.2.1 - 16.2.3. X is CH₂, Y is lla and R aldehyde group. Prefereably the R is the aldehyde as in compounds 16. 1 .22, 16.1 .24 - 16.1 .26.

X is CH₂ Y is lib and R is an amide group.

X is CHCH₃ and Y is lib, wherein R is a substituted phenyl group, wherein the phenyl is substituted with C(0)-OCH₂CH₃, CN, CF₃, F, OCF₃ or wherein the phenyl group is substituted with F and -C(0)NH-C₄H₇.

X is CH₂ and Y is lla, wherein R is an amine group. Preferably the amine group is selected from those disclosed in compounds 18.1 .1 -18.1 .4 in Table 17.

According to a preferred aspect of the invention, there is provided the following compounds of Formula I, namely;

7.1.1 4-Methyl-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]

oxadiazocine,

7.1.2 4-Allyl-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b]

[1 ,3,6]oxadiazo- cine,

7.1.3 9-Nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

7.1.4 tert-Butyl 2-(9-nitro-5,6-dihydro-2H-imidazo [2,1 -b][1 ,3,6] oxadiazo- cin-4(3H)-yl)acetate,

7.1.5 4-(3-Methylbut-2-en-1 -yl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

7.1.6 2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)acetonitrile,

7.1.7 2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)acetic acid,

7.2.1 4-Benzyl-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

7.2.2 9-Nitro-4-(pyridin-2-ylmethyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine, 9-Nitro-4-(pyridin-3-ylmethyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

4-(4-Methoxybenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

4-(2,4-Dimethoxybenzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(4-(trifluoromethyl)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(3-(trifluoromethyl)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(4-(trifluoromethoxy)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(3-(trifluoromethoxy)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(3-(Difluoromethoxy)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(4-(Difluoromethoxy)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((2-Bromopyridin-4-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((5-Bromopyridin-3-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((5-Bromopyridin-2-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(2-Bromobenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

4-(4-Bromobenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

4-(3-Bromobenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

4-((6-Bromopyridin-2-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((6-Bromopyridin-3-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine, tert-butyl 4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzoate,

4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)benzoic acid,

9-Nitro-4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl)- 3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(1 -(6-Bromopyridin-3-yl)ethyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

Ethyl 3'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4-carboxylate,

4-([1 ,1 '-Biphenyl]-3-ylmethyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(3-(pyridin-3-yl)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(3-(pyridin-4-yl)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((3'-Fluoro-[1 ,1 '-biphenyl]-3-yl)methyl)-9-nitro-3,4,5,6-tetrahydro- 2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

3'-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-[1 ,1 '-biphenyl]-3-carbonitrile,

4-(3-(3,5-Dimethyl-4,5-dihydroisoxazol-4-yl)benzyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(3-(1 H-lndol-6-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

tert-Butyl 4-(3-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)phenyl)-5,6-dihydropyridine-1 (2H)- carboxylate,

tert-Butyl (3'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazo -cin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4-yl) carbamate,

3'-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-[1 ,1 '-biphenyl]-4-carbonitrile,

4-(3-(1 -Methyl-1 H-indol-5-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine, Ethyl 4-(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazo cin-4

(3H)-yl)methyl)pyridin-2-yl)benzoate,

9-Nitro-4-((2-(4-(trifluoromethyl)phenyl)pyridin-4-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

Ethyl 4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazo cin-4(3H)-yl)methyl)pyridin-3-yl)benzoate,

Ethyl 4-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazo cin -4(3H)-yl)methyl)pyridin-2-yl)benzoate,

4-(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)pyridin-2- yl)benzonitrile,

4-((2-(3-Fluorophenyl)pyridin-4-yl)methyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(5-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)pyridin-3-yl)benzonitrile,

9-Nitro-4-((5-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((5-(3-Fluorophenyl)pyridin-3-yl)methyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(6-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)pyridin-2-yl)benzonitrile,

9-Nitro-4-((6-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((6-(3-Fluorophenyl)pyridin-2-yl)methyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

Ethyl 4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4 (3H)-yl)methyl)-[1 ,1 '-biphenyl]-4-carboxylate,

4-((4'-Methoxy-[1 ,1 '-biphenyl]-4-yl)methyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((3'-Methoxy-[1 ,1 '-biphenyl]-4-yl)methyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-((4'-(trifluoromethyl)-[1 ,1 '-biphenyl]-4-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine, 9-Nitro-4-((4'-(trifluoromethoxy)-[1 ,1 '-biphenyl]-4-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-((3'-(trifluoromethoxy)-[1 ,1 '-biphenyl]-4-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(4-(1 H-lndol-5-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-((3'-(trifluoromethyl)-[1 ,1 '-biphenyl]-4-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

tert-Butyl (4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazo-cin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-3-yl)carbamate, 4'-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-[1 ,1 '-biphenyl]-3-carbonitrile,

4-((3'-Fluoro-[1 ,1 '-biphenyl]-4-yl)methyl)-9-nitro-3,4,5,6-tetrahydro- 2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(4-(Furan-3-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

4-(4-(Furan-2-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

4-(4-(2-Methoxypyridin-3-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(4-(6-Methoxypyridin-3-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(4-(2-Methoxypyrimidin-5-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro- 2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-((2'-nitro-[1 ,1 '-biphenyl]-4-yl)methyl)-3,4,5,6-tetrahydro- 2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(4-(pyridin-3-yl)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(4-(pyridin-4-yl)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(4-(pyrimidin-5-yl)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(4-(2-Chloropyridin-4-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine, Ethyl 4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4 (3H)-yl)methyl)-[1 ,1 '-biphenyl]-3-carboxylate,

4-(4-(2-Fluoropyridin-3-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(4-(6-Fluoropyridin-3-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(4-(1 -Methyl- 1 H-indol-5-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

Ethyl 4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazo cin-4(3H)-yl)methyl)pyridin-2-yl)benzoate,

4-(5-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)pyridin-2-yl)benzonitrile,

4'-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-[1 ,1 '-biphenyl]-4-carbonitrile,

4-([1 ,1 '-Biphenyl]-4-ylmethyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-((6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((6-(3-Fluorophenyl)pyridin-3-yl)methyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

Ethyl 4-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazo cin-4(3H)-yl)methyl)pyridin-3-yl)benzoate,

4-(6-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)pyridin-3-yl)benzonitrile,

9-Nitro-4-((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((5-(3-Fluorophenyl)pyridin-2-yl)methyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-nitro-4-(4-(5-(trifluoromethyl)-4H-1 ,2,4-triazol-3-yl)benzyl)- 3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

Ethyl 2'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4-carboxylate,

2'-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-[1 ,1 '-biphenyl]-4-carbonitrile, 4-((3'-Fluoro-[1,1'-biphenyl]-2-yl)methyl)-9-nitro-3,4,5,6-tetrahydro- 2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-([1,1'-Biphenyl]-2-ylmethyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo [2,1-b][1,3,6]oxadiazocine,

4'-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-[1,1'-biphenyl]-4-carboxylic acid,

4'-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-[1,1'-biphenyl]-3-carboxylic acid,

N-lsopropyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1- b][1,3,6]oxadiazocin-4(3H)-yl)methyl)-[1,1'-biphenyl]-4- carboxamide,

Morpholino(4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1,3,6] oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4-yl)methanone, N-Cyclopropyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1,3,6] oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4-carboxamide, (4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)-[1,1'-biphenyl]-4-yl)(pyrrolidin-1-yl)methanone, (4-methylpiperazin-1-yl)(4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1- b][1,3,6]oxadiazocin-4(3H)-yl)methyl)-[1,1'-biphenyl]-4- yl)methanone,

N-ethyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1- b][1,3,6]oxadiazocin-4(3H)-yl)methyl)-[1,1'-biphenyl]-4- carboxamide,

N-Cyclopropyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1- b][1,3,6]oxadiazocin-4(3H)-yl)methyl)-[1,1'-biphenyl]-3- carboxamide,

(4-Methylpiperazin-1-yl)(4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1- b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1'-biphenyl]-3- yl)methanone,

N,N-dimethyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1,3,6]oxadiazocin-4(3H)-yl)methyl)-[1,1'-biphenyl]-3- carboxamide, N-Ethyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-3- carboxamide,

N-lsopropyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-3-carboxamide, 3-Fluoro-N-isopropyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]

oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4-carboxamide, 3-Fluoro-N-methyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4-carboxamide, N-(Cyclopropylmethyl)-3-fluoro-4'-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4- carboxamide,

N-Cyclobutyl-3-fluoro-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]

oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4-carboxamide, (3-Fluoro-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4- yl)(morpholino)methanone,

(3-Fluoro-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4-yl)(4- methylpiperazin-1 -yl)methanone,

(2-Fluoro-4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(4- methylpiperazin-1 -yl)methanone,

2-Fluoro-N,N-dimethyl-4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, (2-Fluoro-4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(pyrrolidin- 1 -yl)methanone,

N-Ethyl-2-fluoro-4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, 2-Fluoro-N-isopropyl-4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, N-Cyclopropyl-2-fluoro-4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, 2-Fluoro-4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzoic acid,

N-Cyclobutyl-2-fluoro-4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, 4-Fluoro-N-isopropyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-3- carboxamide,

N-Ethyl-4-fluoro-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-3- carboxamide,

N-Cyclopropyl-4-fluoro-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-3- carboxamide,

(4-Fluoro-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-3- yl)(pyrrolidin-1 -yl)methanone,

N-Cyclobutyl-4-fluoro-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]

oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-3-carboxamide, (2-Fluoro-5-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(4- methylpiperazin-1 -yl)methanone,

2-Fluoro-N,N-dimethyl-5-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, (2-Fluoro-5-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(pyrrolidin-1 - yl)methanone,

N-Ethyl-2-fluoro-5-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, 2-Fluoro-N-isopropyl-5-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, N-Cyclopropyl-2-fluoro-5-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, N-Cyclobutyl-2-fluoro-5-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, (2-Fluoro-4-(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(4- methylpiperazin-1 -yl)methanone,

2-Fluoro-N,N-dimethyl-4-(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, (2-Fluoro-4-(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(pyrrolidin-1 - yl)methanone,

N-Ethyl-2-fluoro-4-(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide,

2-Fluoro-N-isopropyl-4-(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, N-Cyclopropyl-2-fluoro-4-(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, (2-Fluoro-4-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(4- methylpiperazin-1 -yl)methanone,

2-Fluoro-N,N-dimethyl-4-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, (2-Fluoro-4-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(pyrrolidin-1 - yl)methanone,

N-Ethyl-2-fluoro-4-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide,

2-Fluoro-N-isopropyl-4-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, N-Cyclopropyl-2-fluoro-4-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, (2-Fluoro-5-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(4- methylpiperazin-1 -yl)methanone,

2-Fluoro-N,N-dimethyl-5-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, (2-Fluoro-5-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(pyrrolidin-1 - yl)methanone,

N-Ethyl-2-fluoro-5-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide,

2-Fluoro-N-isopropyl-5-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, N-Cyclopropyl-2-fluoro-5-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, N,N-Dimethyl-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)acetamide,

N-Ethyl-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)acetamide,

N-(2-Methoxyethyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)acetamide,

N-lsopropyl-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)acetamide,

N-Cyclopropyl-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)acetamide,

N-(Cyclopropylmethyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]

oxadiazocin-4(3H)-yl)acetamide,

N-(Cyclohexylmethyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]

oxadiazocin-4(3H)-yl)acetamide,

N-(2-Morpholinoethyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]

oxadiazocin-4(3H)-yl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(3-(2-oxopyrrolidin-1 -yl)propyl)acetamide, 2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-1 -(pyrrolidin-1 -yl)ethanone,

N-Cyclobutyl-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)acetamide,

N-(3-Bromophenyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)acetamide,

N-(4-Acetylphenyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)acetamide,

N-(4-Bromobenzyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)acetamide,

N-(4-Methoxybenzyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]

oxadiazocin-4(3H)-yl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(3-(trifluoromethyl)phenethyl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(4-(trifluoromethyl)benzyl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(4-(trifluoromethoxy)benzyl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(3-(trifluoromethyl)benzyl)acetamide,

N-(4-(Difluoromethoxy)benzyl)-2-(9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide,

N-(3-(Difluoromethoxy)benzyl)-2-(9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide,

1 -(4-(3-Fluorophenyl)piperazin-1 -yl)-2-(9-nitro-5,6-dihydro-2H- imidazo

[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)ethanone,

Ethyl 4-(4-(2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazo -cin-4(3H)-yl)acetyl)piperazin-1 -yl)benzoate,

N-(1 -Benzylpiperidin-4-yl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide,

4-(4-(2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H) -yl)acetyl)piperazin-1 -yl)benzonitrile,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-1 -(4-phenylpiperidin-1 -yl)ethanone,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(4-(trifluoromethyl)phenyl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(3-(trifluoromethyl)phenyl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(3-(trifluoromethoxy)phenyl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(3-(trifluoromethoxy)benzyl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-((4'-(trifluoromethoxy)-[1 ,1 '-biphenyl]-4-yl)methyl)acetamide, 2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N'-(3-(trifluoromethyl)phenyl)acetohydrazide_!

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N'-(4-(trifluoromethyl)phenyl)acetohydrazide,

N'-(3-Fluorophenyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)acetohydrazide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N'-(3-(trifluoromethoxy)phenyl)acetohydrazide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N'-(4-(trifluoromethoxy)phenyl)acetohydrazide,

N'-(2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)acetyl)-4-(trifluoromethoxy)benzohydrazide,

(3-Bromophenyl)(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methanone,

(4-Bromophenyl)(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methanone,

1 -(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yi)

propan-1 -one,

(1 H-lndol-2-yl)(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazo- cin-4(3H)-yl)methanone, (9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)(2-phenylthiazol-4-yl)methanone,

Cyclobutyl(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methanone,

1 -(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-2-phenoxyethanone,

4-(4-(9-Nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine

-4-carbonyl)piperidin-1 -yl)benzonitrile,

(5-Bromopyridin-2-yl)(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methanone,

(4-(4-Bromophenoxy)phenyl)(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methanone,

(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl) (quinolin-3-yl)methanone,

Naphthalen-2-yl(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadi- azocin-4(3H)-yl)methanone,

(4-(Benzyloxy)phenyl)(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methanone,

(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)(4-phenoxyphenyl)methanone,

Cyclohexyl(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methanone,

3-(4-Bromophenyl)-1 -(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)propan-1 -one,

[1 ,1 '-Biphenyl]-4-yl(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methanone,

3'-(9-Nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine-4-carbonyl)-[1 ,1 '-biphenyl]-4-carbonitrile, Benzyl-9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine- 4(3H)-carboxylate,

Ethyl-9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine- 4(3H)-carboxylate,

9-Nitro-N-(phenylsulfonyl)-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine-4(3H)-carboxamide,

9-Nitro-N-tosyl-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine- 4(3H)-carboxamide,

N-((4-Fluorophenyl)sulfonyl)-9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine-4(3H)-carboxamide,

9-Nitro-N-(p-tolyl)-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine-4(3H)-carboxamide,

N-(4-Methoxyphenyl)-9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine-4(3H)-carboxamide,

N-(4-Cyanophenyl)-9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine-4(3H)-carboxamide,

N-(4-Fluorophenyl)-9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine-4(3H)-carboxamide,

N-(4-Chlorophenyl)-9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine-4(3H)-carboxamide,

N-Benzyl-9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine-4(3H)-carboxamide,

4-(Methylsulfonyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]

oxadiazocine,

4-((1 -Methyl-1 H-imidazol-4-yl)sulfonyl)-9-nitro-3,4,5,6-tetrahydro- 2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)sulfonyl)benzonitrile,

4-((4-Chlorophenyl)sulfonyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo [2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(phenylsulfonyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]

oxadiazocine,

9-Nitro-4-tosyl-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine,

4-((4-Methoxyphenyl)sulfonyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo

[2,1 -b][1 ,3,6]oxadiazocine, 4-(2-Chloropyrimidin-4-yl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(4-(trifluoromethyl)phenethyl)pyrimidin-2-amine,

4-(2-((4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)pyrimidin-2-yl)amino)ethyl)benzonitrile,

N-(Furan-2-ylmethyl)-4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]

oxadiazocin-4(3H)-yl)pyrimidin-2-amine,

N-Benzyl-4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)pyrimidin-2-amine,

N-(4-(Dif luoromethoxy)benzyl)-4-(9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)pyrimidin-2-amine, 4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(4-(trifluoromethoxy)benzyl)pyrimidin-2-amine,

N-(3-Bromobenzyl)-4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)pyrimidin-2-amine,

4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine,

4-(9-Nitro-5,6-dihydro-2H-imidazo[2, 1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(4-(trifluoromethy l)benzyl)pyrimidin-2-amine,

N-(Cyclohexylmethyl)-4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b] [1 ,3,6]

oxadiazocin-4(3H)-yl)pyrimidin-2-amine,

4-(2-(5,6-Dihydropyridin-1 (2H)-yl)pyrimidin-4-yl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(2-Morpholinopyrimidin-4-yl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo

[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(2-(pyrrolidin-1 -yl)pyrimidin-4-yl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(2-(4-phenylpiperazin-1 -yl)pyrimidin-4-yl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine, 4-(4-(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)pyrimidin-2-yl)piperazin-1 -yl)benzonitrile,

4-(2-(4-(3-Fluorophenyl)piperazin-1 -yl)pyrimidin-4-yl)-9-nitro- 3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

Ethyl 4-(4-(4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazo-cin-4(3H)-yl)pyrimidin-2-yl)piperazin-1 -yl)benzoate, N,N-Dimethyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)benzamide,

N-Ethyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

N-Butyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-

4(3H)-yl) methyl) benzamide,

N-lsopropyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadi- azocin-4(3H)-yl)methyl)benzamide,

N-Cyclopropyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadi-azocin-4(3H)-yl)methyl)benzamide,

N-Cyclobutyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadi- azocin-4(3H)-yl)methyl)benzamide,

N-Benzyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadi- azocin-4(3H)-yl)methyl)benzamide,

N-(4-(Difluoromethoxy)phenyl)-4-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide, 4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethoxy)phenyl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluo romethyl)phenyl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(3-(trifluo romethyl)phenyl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(3-(trifluo romethoxy)phenyl)benzamide,

N-(3-(Difluoromethoxy)phenyl)-4-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazoc in-4(3H)-yl)methyl)benzamide, N-(3-(Difluoromethoxy)benzyl)-4-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazoc in-4(3H)-yl)methyl)benzamide, N-(4-(Difluoromethoxy)benzyl)-4-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazoc in-4(3H)-yl)methyl)benzamide, 4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethyl)benzyl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethoxy)benzyl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(3-(trifluoromethoxy)benzyl)benzamide,

N-(4-Methoxybenzyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethyl)phenethyl)benzamide,

4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(3-(trifluoromethyl)phenethyl)benzamide,

Morpholino(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)phenyl)methanone,

N-(3-Morpholinopropyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

(4-(2-Methoxyethyl)piperazin-1 -yl)(4-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)phenyl)methanone,

(4-Methylpiperazin-1 -yl)(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)phenyl)methanone,

(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)phenyl)(pyrrolidin-1 -yl)methanone,

N-(Cyclopropylmethyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)-N-phenylbenzamide,

N-(4-Fluorophenyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide, N-(3-lsopropoxyphenyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(2-(pyridin-2-yl)ethyl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(pyridin-4-ylmethyl)benzamide,

N-(3-Fluorobenzyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

N-(4-Cyanobenzyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

N-(3-Methoxybenzyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

N-(3-Methoxyphenethyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

N-(4-Cyanophenethyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(pyridin-3-yl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(5-(trifluoromethyl)-1 ,3,4-oxadiazol-2-yl)benzamide, 4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(5-(trifluoromethyl)-1 ,3,4-thiadiazol-2-yl)benzamide, 4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(3-(trifluoromethyl)isoxazol-5-yl)benzamide,

N-Methyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-N-(4- (trifluoromethoxy)phenyl)benzamide,

N-Methyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-N-(3- (trifluoromethyl)phenyl)benzamide,

N-Methyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-N-(3- (trifluoromethoxy)phenyl)benzamide, 5-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethoxy)phenyl)picolinamide,

5-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(3-(trifluoromethyl)phenyl)picolinamide,

5-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(3-(trifluoromethoxy)phenyl)picolinamide,

Ethyl 4-(5-(1 -(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)ethyl) pyridine-2-yl)benzoate,

4-(5-(1 -(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)ethyl)pyridin-2-yl)benzonitrile,

9-Nitro-4-(1 -(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)ethyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(1 -(6-(3-Fluorophenyl)pyridin-3-yl)ethyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(1 -(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)ethyl)- 3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

N-Cyclobutyl-2-f luoro-4-(5-(1 -(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)ethyl)pyridin-2-yl)benzamide, N-Cyclobutyl-2-f luoro-5-(5-(1 -(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)ethyl)pyridin-2-yl)benzamide, N-(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)benzyl)-1 -(4- (trifluoromethoxy)phenyl)methanamine,

N-(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)benzyl)-4-(trifluoromethoxy)aniline,

N-(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)benzyl)-3-(trifluoromethoxy)aniline,

N-(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)benzyl)-3-(trifluoromethyl)aniline,

N-(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)phenyl)-4-(trifluoromethoxy)benzamide,

N-(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)phenyl)-3-(trifluoromethoxy)benzamide, tert-Butyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl) piperidine-1 -carboxylate, 9-Nitro-4-(piperidin-4-yl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]

oxadiazocine,

(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)piperidin-1 -yl)(4-(trifluoromethoxy)phenyl)methanone,

(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)piperidin-1 -yl)(4-(trifluoromethyl)phenyl)methanone,

(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)piperidin-1 -yl)(3-(trifluoromethyl)phenyl)methanone,

tert-Butyl 2-(4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)piperidin-1 -yl)acetate,

2-(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)piperidin-1 -yl)acetic acid,

4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1 -carboxamide, tert-Butyl 4-((9-nitro-5,6-di hydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl) methyl)piperidine-1 -carboxylate, 9-Nitro-4-(piperidin-4-ylmethyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)piperidin-1 -yl)(4-(trifluoromethoxy)phenyl)methanone, 4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)piperidin-1 -yl)(3-(trifluoromethoxy)phenyl)methanone, 4-Nitrophenyl 4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)piperidine-1 -carboxylate,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1 -carboxamide, tert-Butyl (4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadia- zocin

-4(3H)-yl)cyclohexyl)carbamate,

4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)cyclohexanamine, 22.1.3 N-(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)cyclohexyl)-4-(trifluoromethoxy)benzamide,

22.1.4 N-(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)cyclohexyl)-3-(trifluoromethoxy)benzamide,

22.1.5 N-(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)cyclohexyl)-2-(4-(trifluoromethoxy)phenyl)acetamide,

22.1.6 1 -(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)cyclohexyl)-3-(4-(trifluoromethoxy)phenyl)urea,

23.1.1 tert-Butyl-3-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)azetidine-1 -carboxylate,

23.1.2 4-(Azetidin-3-ylmethyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

23.1.3 (3-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)azetidin-1 -yl)(4- (trifluoromethoxy)phenyl)methanone,

23.1.4 (3-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)azetidin-1 -yl)(3- (trifluoromethoxy)phenyl)methanone,

23.1.5 3-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethoxy)phenyl)azetidine-1 -carboxamide,

24.1.1 9-Nitro-4-((5-(4-(trifluoromethoxy)phenyl)-1 ,3,4-thiadiazol-2- yl)methyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

24.2.1 9-Nitro-4-((5-(4-(trifluoromethoxy)phenyl)-1 ,3,4-oxadiazol-2- yl)methyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine. or mixtures, optical or geometric isomers, pharmacologically acceptable salt derivatives and prodrugs thereof.

According to a second aspect of the invention, there is provided a process for producing the compound of Formula I, the method schematically represented as follows:

The process comprises the steps of substituting the N atom of an amino alcohol reactant via alkylation or reductive amination with an X-Y group

X X X

using either ^γ' or ^Y wherein X is CH, i.e ^Y wherein LG represents a leaving group and X and Y are as defined above, to produce a tertiary amine; reacting the tertiary amine with 2,4-dinitroimidazole under Mitsunobu reaction conditions to produce an intermediate which is then cyclized to produce the compound of Formula (I). In a preferred embodiment X is not C=0.

In the schematic representation above (i) represents TBDMSCI, Imidazole and DCM. The reaction is carried out at room temperature for about 12 hours, (ii) Represents K₂C0₃ and acetonitrile and the reaction is carried out at room temperature for about 24 hours, (iii) Represents PPh₃, DIAD and THF and the reaction is carried out for about 18 h. (iv) Represents TBAF and the reactions is carried out at room temperature for about 2 hours.

According to a third aspect of the invention, there is provided a process for producing the compound of Formula I, the method schematically represented as follows:

Compounds 7 - 13

LG=Leaving group

The process comprises the steps of substituting the N-atom of an amino alcohol with an alkyl or allyl group; reacting the substituted amino alcohol with 2,4-dinitroimidazole under Mitsunobu reaction conditions to produce an intermediate which is then cyclized; removing the alkyl or allyl group to form the intermediate; and reacting the intermediate with Y^' LG under basic conditions, wherein LG represents a leaving group and X and Y are as defined above, to produce a compound of Formula (I).

Alternatively ^{Y "}° (X=CH) is reacted with the intermediate under reducing conditions will also produce a compound of formula I.

In a preferred embodiment X is not X=0.

The reactants for step (ii) are PPh₃, DIAD and THF. The reaction is carried out for about 18 hours. The step (iii) reactant is TBAF. The reaction is carried out at room temperature for about 2 h. Step (iv) represents 1 - chloromethyl chloroformate and DCE. The reaction is carried out under reflux for about 12 h. The step (v) reactant is MeOH and the reaction is carried out under reflux for about 4 hours. Step (vi) represents K₂C0₃ and acetonitrile: water (1 :3). The reaction is carried out at room temperature for about 4 hours. The reactant for step (vii) is sodium triacetoxyborohydride in DCE and the reaction is carried out at room temperature for 12 hours. According to a fourth aspect of the invention, there is provided a compound of Formula I for use in a method of treating tuberculosis or other microbial infections, the method comprising the step of administering to a subject any one of the compounds of the formula I or their mixtures, pharmacologically acceptable salts, optical or geometric isomers, esters or prodrugs thereof.

In a preferred embodiment of the invention, the microbial infection is caused by Mycobacterium tuberculosis. These compounds may be useful for treatment of other infectious diseases such as malaria, trypanosomiasis, Chagas' disease, Leishmaniasis and Schistosomiasis.

There is also provided a method of treating tuberculosis or other microbial infections comprising the step of administering to the subject any one of the compounds of formula I or their mixtures, pharmacologicallay acceptable salts, optical or geometrical isomers, esters or prodrugs thereof. In a preferred embodiment of the invention, the microbial infection is caused by Mycobacterium tuberculosis. These compounds may be useful in methods of treating other infectious diseases such as malaria, trypanosomiasis, Chagas' disease, Leishmaniasis and Schistosomiasis.

According to a fifth embodiment of the invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of any one of the compounds of the formula I or their mixtures, pharmacologically acceptable salts, optical or geometric isomers, esters or prodrugs thereof.

The composition may be used in a method of treating tuberculosis in a subject. It may also be useful for treatment of other infectious diseases such as malaria, trypanosomiasis, Chagas' disease, Leishmaniasis and Schistosomiasis.

The composition may further include a pharmaceutically acceptable excipient, adjuvant, carrier, buffer, stabilizer or the like.

The compositions may be in tablet, capsule, powder or liquid form.

The compound or composition may be administered in a single dose, or multiple doses.

The compound or composition may be administered alone or in combination with other therapeutic agent(s).

According to a sixth embodiment of the invention, there is provided for the use of any one of the compounds of Formula I, or their mixtures pharmacologically acceptable salts, optical or geometric isomers, esters or prodrugs thereof, in the manufacture of a medicament for use in a method of treating tuberculosis or other microbial infections, the method comprising the step of administering to a subject the medicament. BRIEF DESCRIPTION OF THE FIGURES

The invention will now be described in more detail, by way of example only, with reference to the accompanying figures in which:

Figure 1 : shows the chemical structure of the prior art; PA-824 (1.1 ) and

OPC-67683 (1.2)

Figure 2: shows the original synthesis of the prior art; PA-824 (1.1 )

Figure 3: shows the improved synthesis of the prior art; PA-824 (1.1 ) Figure 4: shows the recent synthesis of the prior art; PA-824 (1.1 )

DETAILED DESCRIPTION OF THE INVENTION

The invention features novel bicyclic nitroimidazoxadiazocine compounds pharmaceutical compositions containing them, their medical use and methods of synthesising such compounds. Compounds of the invention are shown in Table 1 below.

Table 1 : Chemical structures of representative examples of preferred compounds

Exemplary methods for synthesising compounds of the invention are described herein. In the present invention, a method that is performed under mild reaction conditions using 2,4-dinitroimidazole and appropriately substituted alcohol resulting in high yields is disclosed.

The target nintroimidazoxadiazocine and its derivatives may be prepared by one of several methods described below:

Method I

H H ii Y^'^LG

N^OH TBDMSO '^OH

3.1.1 or iii γ'"·¾ TBDMSO' ^^OH

Compounds 7 - 9

(i) TBDMSCI, Imidazole, DCM, rt, 12 h; (ii) K₂C0₃, Acetonitrile, rt, 24 h; (iii) borohydride , DCE, rt, 12h (iv) PPh₃, DIAD, THF, 18 h; (v) TBAF, rt, 2 h

In Method I, substitution on the /V-atom can be achieved prior to cyclization to the nitroimidazoxadiazocine ring. Commercially available diethanolamine may be monoprotected as a TIPS, TMS, IPDMS, DEIPS, TBS, TBDPS, or DTBS ether, but most preferably as a TBDMS ether. The tertiary amine 5 may be generated from the secondary amine 3.1.1 and the corresponding aldehyde via reductive amination using a reducing agent such as lithium aluminium hydride, sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, but preferably from the corresponding alkyl halide (LG = CI, Br, I), mesylate (LG = OMs) or tosylate (LG = OTs), in solvent such ethanol, propanol, isopropanol, methanol, chloroform, DCM, DCE, dioxane, acetonitrile, dioxane, THF, DMF, NMP, DMSO, or a mixture of these, in the presence of a weak base such as triethylamine, or diisopropylethylamine, or aqueous inorganic base such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, or potassium carbonate; or the Finkelstein reaction, which first converts the chloride or bromide to the iodide, which may then be reacted with the amine in one-pot in the presence of the base. Coupling of 2,4-dinitroimidazole C to the tertiary amine 5 may be achieved under Mitsunobu reaction conditions using, triphenylphosphine in combination with an azodicarboxylate such as diethyl azidodicarboxylate (DEAD), di- te/t-butylazodicarboxylate (DBAD), or di-p-chlorobenzyl azodicarboxylate (DCAD), di-2-methoxyethyl azodicarboxylate (DMEAD), Di-p-nitrobenzyl azodicarboxylate (DNAD), but most preferably diisopropyl azidodicarboxylate (DIAD). The Mitsunobu reaction may be carried out in organic solvents such as chloroform, DCM, DCE, NMP, DMF, dioxane, DMSO, or a mixture of these, but most preferably in THF, at temperatures between -10 °C and 70 ^<€.

Steps (iii) and (iv) may be carried out in one-pot or stepwise. When the two steps are carried out in one pot, the product may be isolated as the salt of a mineral or organic acid, which upon basification and subsequent purification affords clean product. When the reaction is performed in two steps, the intermediate may be selectively isolated from by-products with or without need for chromatographic purification. Afterwards, the protecting group in the intermediate 6 may be removed by treatment with a basic fluoride source such as potassium fluoride or cesium fluoride, but most preferably with tetrabutylammonium fluoride (TBAF) to provide target molecules 7 - 9.

Method II

Alternatively, the target compounds may be synthesized by way of scheme 5. In this process, the /V-atom of the tertiary amine is substituted with either a methyl or allyl group that is later removed to unmask a basic /V-centre. Thus, the amino alcohol 5 is reacted with 2,4-dinitroimidazole under the conditions described in Method I to afford intermediate 6, which is then cyclized to 7 as described for Method I above.

\— / or vii Y' ^ΐ-η /""^ r, ... .

LG = Leaving group

(i) For R₃ = H, Allyl bromide, K₂C0₃, Acetonitrile, rt, 24 h; (ii) PPh₃, DIAD, THF, 18 h; (iii) TBAF, rt, 2 h; (iv) 1 -Chloromethyl chloroformate, DCE, reflux, 12 h; (v) MeOH, reflux, 4 h; (vi) K₂C0₃, Acetonitrile:water (1 :3), rt, 4 h. (vii) Borohydride

The methyl and allyl groups in 7 may be removed by treating the compound with 1 -chloroethyl chloroformate in chloroform, DCM or DCE at temperatures ranging from -10 °Q, to 70 °C, followed by refluxing the residue obtained after evaporation of chlorinated solvent in methanol. The intermediate 7.1.3 may be alkylated with aldehydes under reducing conditions, or with alkyl halides as described earlier.

Compounds of Formula I may occur in different geometric and enantiomeric forms, and both pure forms and mixtures of these separate isomers are included in the scope of this invention, as well as any physiologically functional or pharmacologically acceptable salt derivatives or pro-drugs thereof. Production of these alternate forms would be well within the capabilities of one skilled in the art.

The compounds in the present invention are designed to incorporate inherent solubilising groups within the core structures that improve aqueous solubility, and effectively bioavailability. The compounds of the invention are preferably formulated into pharmaceutical compositions for administration. The pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabilizer. A "therapeutically effective amount" is to be understood as an amount of a compound of Formula I that is sufficient to show antibacterial or anti-microbial effects. The actual amount, rate and time-course of administration will depend on the nature and severity of the disease being treated. Prescription of treatment is within the responsibility of general practitioners and other medical doctors. The pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabilizer should be nontoxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, such as cutaneous, subcutaneous, or intravenous injection, or by dry powder inhaler.

Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form. A tablet may comprise a solid carrier or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. A capsule may comprise a solid carrier such as gelatin. For intravenous, cutaneous or subcutaneous injection, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has a suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as sodium chloride injection, Ringer's injection, Lactated Ringer's injection. Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included as required.

The pharmaceutical composition can further comprise one or more additional anti-infective treatments. These anti-infective treatments can be any suitable treatment available commercially or from other sources that are known to effectively prevent or treat microbial infections, such as Mycobacterium tuberculosis.

The term "pharmacologically acceptable salt" used throughout the specification is to be taken as meaning any acid or base-derived salt formed from hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, isoethonic acids and the like, and potassium carbonate, sodium or potassium hydroxide, ammonia, triethylamine, triethanolamine and the like.

The term "pro-drug" means a pharmacological substance that is administered in an inactive, or significantly less active, form. Once administered, the pro-drug is metabolised in vivo into an active metabolite.

The term "therapeutically effective amount" means a nontoxic but sufficient amount of the drug to provide the desired therapeutic effect. The amount that is "effective" will vary from subject to subject, depending on the age and general condition of the individual, the particular concentration and composition being administered, and the like. Thus, it is not always possible to specify an exact effective amount. However, an appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. Furthermore, the effective amount is the concentration that is within a range sufficient to permit ready application of the formulation so as to deliver an amount of the drug that is within a therapeutically effective range.

Further aspects of the present invention will become apparent from the following description given by way of example only and with reference to the accompanying synthetic schemes.

Examples

All reagents were purchased from Sigma Aldrich except boronic acids and esters which were obtained from Boron Molecular. Starting materials that had to be prepared were synthesized according to published procedures. Flash, thin layer and preparative thin layer chromatography (TLC) were performed on silica gel and precoated plates purchased from Sigma Aldrich. Flash chromatography was performed using silica gel 60 as a normal phase adsorbent. Thin layer chromatography (TLC) spots were visualized with long-wave ultraviolet light followed by permanganate staining. Preparative thin layer chromatography (TLC) was performed using silica gel (SG) 60 F₂₅₄ plates (20 x 20 cm, 2000 microns) and the bands were visualized with long-wave ultraviolet light lamp.

Analytical chromatography was performed on an Agilent 1200 HPLC fitted with a Waters XBridge C18 (50 mm x 4.6 mm x 5 microns) that was coupled to a UV detector (280 nm) and an Agilent 6120 Quadrupole mass spectrophotometer in the positive mode. The flow rate was maintained at 1 mL/min on this system. Semi-preparative HPLC was carried out on an Agilent 1200 semi-preparative instrument fitted with a Waters XBridge C18 (100 mm x 19.0 mm x 5 microns) that was coupled to a UV/VIS detector (280 nm) and an automated fraction collector. The flow rate was maintained at 1 mL/min on this system. A solvent system utilizing acetic acid as the ion-pairing agent was employed. Solvent A consisted of 0.1 % acetic acid /H₂0 (v/v) and solvent B consisted of 0.1 % acetic acid/methanol (v/v). LC- MS analytical data for all compounds recorded can be found in Table 14. ¹ H NMR data were recorded either on an Oxford 200 MHz or on a Bruker AVANCE III 400 MHz spectrometer.

(2-Bromoethoxy)(tert-butyl)dimethylsilane (2)

TBDMSO. ^„

— Br

To a stirring solution of 2-bromoethanol (15.0 mL, 212 mmol) and imidazole (28.9 g, 425 mmol) in dichloromethane (200 mL) was added tert- butylchlorodimethylsilane (32.0 g, 212 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (300 mL) and extracted into dichloromethane (2 x 100mL). The organic layers were combined, washed with brine (100 mL), dried over sodium sulfate, filtered and evaporated to yield (2-bromoethoxy)(tert- butyl)dimethylsilane (46.3 g, 91 %) as a colourless oil. 1 H NMR (400 MHz CDCI₃) δ_Η ppm 0.00 (s, 6H); 0.82 (s, 9H); 3.27 (t, 2H); 3.80 (t, 2H).

2-((2-((ieri-Butyldimethylsilyl)oxy)ethyl)amino)ethanol (3.1.1)

The (2-bromoethoxy)(ter/-butyl)dimethylsilane (25 g, 84.0 mmol) and ethanolamine (95 mL, 1568 mmol) were stirred in acetonitrile at reflux for 1 hour. The reaction was allowed to cool to room temperature, quenched with water (500 mL) and extracted into ethyl acetate (3 x 100 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was filtered through a silica plug eluting first with 40 % ethyl acetate/hexane (250 mL) followed by 50% methanol/ethyl acetate (500 mL) to separate the 2-(bis(2-((ter/-butyldimethylsilyl) oxy)ethyl)amino)ethanol by product and yield 2-((2-((ter/-butyldimethylsilyl) oxy)ethyl)amino) ethanol (19.4 g, 85 %) as a colourless oil. ¹ H NMR (400 MHz CDCI₃) δ 0.06 (s, 6H); 0.90 (s, 9H); 2.73 (t, 2H); 2.78 (t, 2H); 3.64 (t, 2H); 3.72 (t, 2H). -((2-((ieri-Butyldimethylsilyl)oxy)ethyl)(methyl)amino)ethanol (3.1.2)

To a stirring solution of /V-methyl-A/JV-diethanolamine (27 mL, 252 mmol) was added sodium hydride (12.1 g, 303 mmol) portion wise at room temperature. The resulting reaction mixture was allowed to stir at room temperature for 45 minutes. Thereafter te/t-butylchlorodimethylsilane (38 g, 39.9 mmol) was added and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was poured into ether (200 mL) and washed successively with 10% aqueous potassium carbonate solution (50%) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The resulting oil was submitted through column chromatography (ethyl acetate /hexane) to yield 2-((2-((terf-butyldimethylsilyl) oxy) ethyl) (methyl) amino) ethanol (21 g, 90 mmol, 36%) as a colourless oil. 1 H NMR (400MHz CDCI₃) δ_Η ppm 0.08 (s, 6H); 0.92 (s, 9H); 2.34 (s, 3H); 2.59-2.62 (m, 4H); 3.59 (t, 2H); 3.72 (t, 2H) -((4-Dimethoxybenzyl)amino)ethanol (4.1.1)

4-Methoxybenzaldehyde (22.3 g, 164 mmol) was added to a stirring solution of ethanolamine (10.0 g, 164 mmol) in methanol (165 mL). The resulting solution was allowed to stir for 2 hours at room temperature. Thereafter sodium sulfate (-10 g) was added to the reaction mixture and was allowed to stir for a further 30 minutes. Sodium borohydride (9.29 g, 246 mmol) was added cautiously at 0 'Ό over 15 minutes. The reaction mixture was allowed to stir at room temperature for 18 hours. Thereafter the reaction mixture was filtered, evaporated and taken up into DCM (200 mL) and washed consecutively with saturated sodium carbonate solution (100 mL), water (100 mL) and brine. The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was submitted through a short column eluting with 20% ethyl acetate/hexane to remove starting materials and by-products followed by washing with methanol (500 mL). The solvent was removed in vacuo to yield 2-((4- methoxybenzyl)amino)ethanol (21 .4 g, 1 18 mmol, 72%) as a light yellow oil. 1 H NMR (400 MHz CDCI₃) δ_Η ppm 2.71 (t, 2H); 3.61 (t, 2H); 3.69 (s, 2H); 3.77 (s, 3H); 6.85 (d, 2H); 7.21 (d, 2H). -((2,4-Dimethoxybenzyl)amino)ethanol (4.1.2)

2,4-Dimethoxybenzaldehyde (54.4 g, 327 mmol) was added to a stirring solution of ethanolamine (20.0 g, 327 mmol) in methanol (400 mL). The resulting solution was allowed to stir for 2 hours at room temperature. Thereafter sodium sulfate (-20 g) was added to the reaction mixture and was allowed to stir for a further 30 minutes. Sodium borohydride (18.6 g, 491 mmol) was added cautiously at 0 'Ό over 15 minutes. The reaction mixture was allowed to stir at room temperature for 18 hours. Thereafter, the reaction mixture was filtered, evaporated and taken up into DCM (200 mL) and washed consecutively with saturated sodium carbonate solution (100 mL), water (100 mL) and brine (100 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was submitted through a short column eluting with 20 % ethyl acetate/hexane to remove starting materials and by-products followed by washing with methanol (1500 mL). The solvent was removed in vacuo to yield 2-((4-methoxybenzyl)amino)ethanol (54.1 g, 256 mmol, 78%) as a light yellow oil. 1 H NMR (200 MHz CDCI₃) δ_Η ppm 2.71 (t, 2H); 3.62 (t,2H); 3.70 (s, 2H); 3.80-3.90 (m, 6H); 6.44 (m, 2H); 7.15 (d, 1 H). -((3-(Trif luoromethoxy)benzyl)amino)ethanol (4.1.3)

3-(Trifluoromethoxy)benzaldehyde (1 .0 mL, 7.0 mmol) was added to a stirring solution of ethanolamine (1 .0 mL, 16.5 mmol) in methanol (20 mL). The resulting solution was allowed to stir for 2 hours at room temperature. Thereafter, sodium sulfate (~2 g) was added to the reaction mixture, which was allowed to stir for a further 30 minutes. Sodium borohydride (0.53 g, 13.9 mmol) was added cautiously at 0 °C over 15 minutes. The reaction mixture was allowed to stir at room temperature for 18 hours. Afterwards, the reaction mixture was filtered, evaporated and taken up into DCM (200 mL) and washed consecutively with saturated sodium carbonate solution (100 mL), water (100 mL) and brine (100 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated to give 2-((3- (trifluoromethoxy)benzyl)amino)ethanol (1 .7 g, 103%) contaminated with ethyl acetate. 1 H NMR (400 MHz CDCI₃) δ_Η ppm 2.80 (t, 2H); 3.67 (t, 2H); 3.83 (s, 2H); 7.10-7.36 (m, 4H). -((3-(Trif luoromethyl)benzyl)amino)ethanol (4.1.4)

3-(Trifluoromethyl)benzaldehyde ( 1 .0 mL, 7.47 mmol) was added to a stirring solution of ethanolamine (1 .0 mL, 18.7 mmol) in methanol (20 mL). The resulting solution was allowed to stir for 2 hours at room temperature. Thereafter, sodium sulfate (~2 g) was added to the reaction mixture and was allowed to stir for a further 30 minutes. Sodium borohydride (0.28 g, 248 mmol) was added cautiously at 0 'Ό over 15 minutes. The reaction mixture was allowed to stir at room temperature for 18 hours. Afterwards, the reaction mixture was filtered, evaporated and taken up into DCM (200 mL) and washed consecutively with saturated sodium carbonate solution (100 mL), water (100 mL) and brine (100 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was submitted through a short column eluting with 20 % ethyl acetate/hexane to remove starting materials and by-products followed by washing with methanol (100 mL). The solvent was removed in vacuo to yield a clear oil. This material was carried directly into the next step without characterisation. -((3-(Difluoromethoxy)benzyl)amino)ethanol (4.1.5)

3-(Difluoromethoxy)benzaldehyde (1 .0 mL, 7.0 mmol) was added to a stirring solution of ethanolamine (1 .1 mL, 18.8 mmol) in methanol (20 mL). The resulting solution was allowed to stir for 2 hours at room temperature. Thereafter sodium sulfate (~2 g) was added to the reaction mixture and was allowed to stir for a further 30 minutes. Sodium borohydride (0.57 g, 15.1 mmol) was added cautiously at 0 °C over 15 minutes. The reaction mixture was allowed to stir at room temperature for 18 hours. Thereafter the reaction mixture was filtered, evaporated and taken up into DCM (200 mL) and washed consecutively with saturated sodium carbonate solution (100 mL), water (100 mL) and brine (100 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. NMR of the residue indicated the presence of the product, 2-((3- (difluoromethoxy)benzyl)amino)ethanol (1 .67 g, 102%) and a bit of ethyl acetate. 1 H NMR (400 MHz CDCI₃) δ_Η ppm 2.81 (t, 2H); 3.67 (t, 2H); 3.82 (s, 2H); 6.33-6.70 (m, 1 H); 7.00-7.34 (m, 4H).

2-((4-(Difluoromethoxy)benzyl)amino)ethanol (4.1.6)

4-(Difluoromethoxy)benzaldehyde (1 .0 mL, 7.0 mmol) was added to a stirring solution of ethanolamine (1 .1 mL, 18.8 mmol) in methanol (20 mL). The resulting solution was allowed to stir for 2 hours at room temperature. Sodium borohydride (0.57 g, 15.1 mmol) was added cautiously at O 'C over 15 minutes. The reaction mixture was allowed to stir at room temperature for 18 hours. Thereafter the reaction mixture was filtered, evaporated and taken up into DCM (200 mL) and washed consecutively with saturated sodium carbonate solution (100 mL), water (100 mL) and brine (100 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. NMR of the residue indicated the presence of the product, 2- ((4-(difluoromethoxy)benzyl)amino)ethanol (1 .62 g, 99%) and a bit of ethyl acetate. 1 H NMR (400 MHz CDCI₃) δ_Η ppm 2.80 (t, 2H); 3.66 (t, 2H); 3.79 (s, 2H); 6.30-6.67 (m, 1 H); 7.08 (d, 2H); 7.32 (d, 2H).

2-(Allyl(2-((tert-butyldimethylsilyl)oxy)ethyl)amino)ethanol (5.1.1 )

A solution of allyl bromide (3.94 mL, 45.6 mmol) in acetone (500 mL) was treated with sodium iodide (32.4 g, 228 mmol). The mixture was refluxed for 1 hour. Potassium carbonate (25.2 g, 182 mmol) was added to the reaction. 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)ethanol 3.1.1 (10 g, 45.6 mmol) was dissolved in 300 mL acetone and added to the mixture and the reaction was stirred overnight, filtered and evaporated. The residue was submitted through column chromatography (100% EtOAc) to yield 2-(((5- bromopyridin-2-yl)methyl)(2-((tert- butyldimethylsilyl)oxy)ethyl)amino)ethanol (7.33 g, 28 mmol, 62 %). 1 H NMR (400 MHz CDCI₃) δ_Η ppm 0.06 (s, 6H); 0.89 (s, 9H); .2.62-2.68 (m, 4H) 3.2 (d, 2H); 3.54 (t, 2H); 3.66 (t, 2H); 5.12-5.19 (m, 2H), 5.78-5.88 (m, 1 H).

Ethyl 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(2-hydroxyethyl)amino) acetate (5.1.2)

To a stirred solution of 2-((2-((tert-butyldimethylsilyl) oxy) ethyl) amino) ethanol 3.1.1 (1 .0 g, 4.56 mmol) and potassium carbonate (1 .89 g, 13.7 mmol) in acetonitrile (80 mL) was added ethyl bromoacetate (0.56 mL, 5.01 mmol). The mixture was stirred over the weekend at room temperature. The crude mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (Na2S04), filtered and solvent removed under vacuum to yield a pale yellow oil. NMR of this material confirmed the product as ethyl 2-((2-((tert-butyldimethylsilyl) oxy)ethyl)(2-hydroxyethyl) amino)acetate (1 .30 g, 93%). 1 H NMR (400 MHz CDCI₃) δ_Η ppm 0.06 (s, 6H); 0.89 (s, 9H); .1 .25-1 .31 (m, 3H) 2.82-2.86 (m, 4H); 3.50-3.55 (m, 4H); 3.67-3.70 (m, 2H); 4.15-4.20 (m, 2H). ferf-Butyl 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(2-hydroxyethyl) amino)acetate (5.1.3)

To a stirred solution of 2-((2-((tert-butyldimethylsilyl)oxy) ethyl) amino) ethanol 3.1.1 (8.4 g, 38.3 mmol) and potassium carbonate (15.9 g, 1 15 mmol) in acetonitrile (150 mL) was added tert-butyl bromoacetate (6.79 mL, 45.9 mmol). The mixture was stirred over the weekend at room temperature. The crude mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (Na2S04), filtered and solvent removed under vacuum to yield a clear oil. NMR of this material confirmed the product as ethyl 2-((2-((tert-butyldimethylsilyl) oxy)ethyl)(2-hydroxy- ethyl)amino)acetate (12.06 g, 94%). 1 H NMR (400 MHz CDCI₃) δ_Η ppm 0.07 (s, 6H); 0.91 (s, 9H); 1 .47 (s, 9H); 2.82-2.86 (m, 4H); 3.40 (s, 2H); 3.52-3.55 (m, 2H); 3.68-3.80 (m, 2H).

2-(Benzyl(2-((tert-butyldimethylsilyl)oxy)ethyl)amino)ethanol (5.2.1 )

To a stirring mixture of potassium carbonate (3.78 g, 27.3 mmol) and 2-((2- ((ieri-butyldimethylsilyl)oxy)ethyl)amino)ethanol 3.1.1 (2 g, 9.12 mmol) in acetonitrile (50 mL) was added benzyl bromide (1 .30 mL, 10.9 mmol). The reaction was heated to reflux for 18 hours. The reaction mixture was filtered, evaporated and taken up into DCM (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was submitted through column chromatography (20-80% ethyl acetate/hexane) to yield 2- (allyl(2-((ie -butyldimethylsilyl)oxy)ethyl)amino)ethanol (2.53 g, 8.17 mmol, 90 %) as a colourless oil. 1 H NMR (400 MHz CDCI₃) δ_Η ppm 0.06 (s, 6H); 0.92 (s, 9H); 2.69-2.76 (m, 4H) 3.57 (t, 2H); 3.68 (t, 2H); 3.74 (s, 2H); 7.26- 7.34 (m, 5H). 2-((2-((teri-butyldimethylsilyl)oxy)ethyl)(pyridin-2-ylmethyl)amino) ethanol (5.2.2)

To a stirring mixture of potassium carbonate (5.04 g, 36.5 mmol) and 2-((2- ((ieri-butyldimethylsilyl)oxy)ethyl)amino)ethanol 3.1.1 (2 g, 9.12 mmol) in acetonitrile (50 mL) was added 2-(bromomethyl)pyridine, HBr (1 .81 mL, 10.9 mmol). The reaction was stirred overnight. The reaction mixture was filtered, evaporated and taken up into DCM (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was submitted through column chromatography (20-80 % ethyl acetate/hexane) to removel impurities then 100 % ethyl acetate was used to elute the product 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(pyridin-2-ylmethyl)amino)ethanol (1 .39 g, 4.48 mmol, 49 %) as a yellowish oil. 1 H NMR (400 MHz CDCI₃) δ_Η ppm 0.06 (s, 6H); 0.91 (s, 9H); .2.78-2.84 (m, 4H) 3.60 (t, 2H); 3.71 (t, 2H); 3.93 (s, 2H); 7.17-7.20 (m, 1 H), 7.45 (d, 1 H), 7.65-7.69 (m, 1 H), 8.55 (d, 1 H).

2-((2-((ie^Butyldimethylsilyl)oxy)ethyl)(pyridin-3-ylmethyl)amino) ethanol (5.2.3)

To a stirring mixture of potassium carbonate (5.04 g, 36.5 mmol) and 2-((2- ((ieri-butyldimethylsilyl)oxy)ethyl)amino)ethanol 3.1.1 (2 g, 9.12 mmol) in acetonitrile (50 mL) was added 3-(bromomethyl)pyridine, HBr (1 .81 mL, 10.9 mmol). The reaction was stirred overnight. The reaction mixture was filtered, evaporated and taken up into DCM (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was submitted through column chromatography (20-80 % ethyl acetate/hexane) to remove impurities then 100 % ethyl acetate was used to elute the product 2-((2- ((tert-butyldimethylsilyl)oxy)ethyl)(pyridin-3-ylmethyl)amino)ethanol (0.45 g, 1 .45 mmol, 16%) as a colourless oil. 1 H NMR (400cMHz CDCI₃) δ_Η ppm 0.06 (s, 6H); 0.91 (s, 9H); 2.78-2.75 (m, 4H) 3.90 (t, 2H); 3.69 (t, 2H); 3.76 (s, 2H); 7.26-7.29 (m, 1 H), 7.73 (d, 1 H), 8.52-8.54 (m, 2H).

2-((2-((ieri-Butyldimethylsilyl)oxy)ethyl)(4-methoxybenzyl)amino) ethanol (5.2.4)

To a stirring mixture of potassium carbonate (19.1 g, 138 mmol) and 2-((4- methoxybenzyl)amino)ethanol 4.1.1 (10.0 g, 55.2 mmol) in acetonitrile (100 mL) was added (2-bromoethoxy)(te/?-butyl)dimethylsilane 2 (13.2 g, 55.2 mmol). The reaction was heated to reflux for 18 hours. The reaction mixture was evaporated and taken up into DCM (200 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was submitted through column chromatography (20-70 % ethyl acetate/hexane) to yield 2-((2- ((ieri-butyldimethylsilyl)oxy)ethyl)(4-methoxy benzyl)amino)ethanol (15.0 g, 44.2 mmol, 80%) as a light yellow oil. 1 H NMR (400 MHz CDCI₃) δ_Η ppm 0.03 (s, 6H), 0.85 (s, 9H), 2.58-2.68 (m, 4H), 3.49 (t, 2H); 3.60 (t, 2H), 3.74 (s, 3H), 6.80 (d, 2H); 7.18 (d, 2H).

2-((2-((ieri-Butyldimethylsilyl)oxy)ethyl)(2,4-dimethoxybenzyl) amino)ethanol (5.2.5)

To a stirring mixture of potassium carbonate (36.8 g, 266 mmol) and 2-((4- methoxybenzyl)amino)ethanol 4.1.2 (22.5 g, 107 mmol) in acetonitrile (250 mL) was added (2-bromoethoxy)(ter/-butyl)dimethylsilane 2 (25.5 g, 107 mmol). The reaction was heated to reflux for 18 hours. The reaction mixture was filtered, evaporated and taken up into DCM (200 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was submitted through column chromatography (20-70% ethyl acetate/hexane) to yield 2- ((2-((te/?-butyldimethylsilyl) oxy)ethyl)(4-methoxybenzyl)amino)ethanol (19.7 g, 53.2 mmol, 50%) as a light yellow oil. 1 H NMR (200 MHz CDCI₃) δ_Η ppm 0.00 (s, 6H); 0.94 (s, 9H); 2.60-2.81 (m, 4H); 3.51 -3.72 (m, 6H); 3.83 (s, 6H); 6.40-7.52 (m, 2H); 7.18 (d, 1 H).

2-((2-((Tert-butyldimethylsilyl)oxy)ethyl)(3-(trifluoromethyl)benzyl) amino)ethanol (5.2.6)

To a stirred solution of 2-((3-(trifluoromethyl)benzyl)amino)ethanol 4.1.4 (1 .60 g, 7.30 mmol) and potassium carbonate (3.03 g, 21 .9 mmol) in acetonitrile (50 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane 2 (2.09 g, 8.76 mmol). The mixture was stirred overnight at room temperature. The crude mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (Na2S04), filtered and solvent removed under vacuum to yield a clear oil. NMR of this material confirmed the product as 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(3-(trifluoromethyl) benzyl)amino) ethanol (2.2 g, 80%). This material was carried directly into the next step without purification.

2-((2-((ieri-Butyldimethylsilyl)oxy)ethyl)(4-(trifluoromethyl)benzyl) amino)ethanol (5.2.7)

To a stirred solution of 2-((2-((tert-butyldimethylsilyl)oxy) ethyl) amino)ethanol 3.1.1 (0.9 g, 4.10 mmol) and potassium carbonate (1 .70 g, 12.3 mmol) in acetonitrile (80 mL) was added 1 -(bromomethyl)-4- (trifluoromethyl)benzene (1 .0 g, 4.18 mmol). The mixture was stirred overnight at room temperature. The crude mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (Na2S04), filtered and solvent removed under vacuum to yield a clear oil. The material was purified by column chromatography (10 % EtOAc/Hex). NMR of this material indicated the product, 2-((2-((tert-butyl dimethyl- silyl)oxy)ethyl)(4-(trifluoromethyl) benzyl)amino)ethanol (1 .02 g, 66%). 1 H NMR (400 MHz CDCI₃) δ_Η ppm 0.00 (s, 6H); 0.85 (s, 9H); 2.63-2.69 (m, 4H); 3.53 (t, 2H); 3.63 (t, 2H); 3.73 (s, 2H); 7.41 (d, 2H); 7.52 (d, 2H).

2-((2-((ieri-Butyldimethylsilyl)oxy)ethyl)(4-(trifluoromethoxy)benzyl) amino)ethanol (5.2.8)

To a stirred solution of 2-((2-((tert-butyldimethylsilyl)oxy) ethyl) amino) ethanol 3.1.1 (1 .0 g, 4.56 mmol) and potassium carbonate (1 .89 g, 13.7 mmol) in acetonitrile (80 mL) was added 1 -(bromomethyl)-4- (trifluoromethyl)benzene (0.75mL, 5.01 mmol). The mixture was stirred overnight at room temperature. The crude mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (Na2S04), filtered and solvent removed under vacuum to yield a clear oil. The material was taken directly into the next reaction without purification.

2-((2-((ieri-Butyldimethylsilyl)oxy)ethyl)(3-(trifluoromethoxy)benzyl) amino)ethanol (5.2.9)

To a stirred solution of 2-((3-(trifluoromethoxy)benzyl)amino)ethanol 4.1.3 (1 .60 g, 6.80 mmol) and potassium carbonate (2.82 g, 20.4 mmol) in acetonitrile (50 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane 2 (1 .95 g, 8.16 mmol). The mixture was stirred overnight at reflux. The crude mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (Na2S04), filtered and solvent removed under vacuum to yield a clear oil. The product was isolated by column chromatography (25 % EtOAc/75 % Hex) to yield a clear oil. NMR of this revealed the product, 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(3-(trifluoromethoxy) benzyl) amino)ethanol as well as some of the (2-bromoethoxy)(tert- butyl)dimethylsilane starting material. 1 H NMR (400 MHz CDCI₃) δ_Η ppm 0.00 (s, 6H); 0.82 (s, 9H); 2.72 (t, 2H); 3.31 (t, 2H); 3.59 (t, 2H); 3.75 (s, 2H); 3.81 (t, 2H); 7.01 -7.28 (m, 4H).

2-((2-((ieri-Butyldimethylsilyl)oxy)ethyl)(3-(difluoromethoxy)benzyl) amino)ethanol (5.2.10)

To a stirred solution of 2-((3-(difluoromethoxy)benzyl)amino)ethanol 4.1.5 (1 .60 g, 7.37 mmol) and potassium carbonate (3.05 g, 22.1 mmol) in acetonitrile (50 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane 2 (2.12 g, 8.84 mmol). The reaction was refluxed overnight. The crude mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (Na2S04), filtered and solvent removed under vacuum to yield a clear oil. The product was isolated by column chromatography (25% EtOAc/75% Hex) to yield a clear oil. NMR of this revealed the product, 2- ((2-((tert-butyldimethylsilyl)oxy)ethyl)(3-(difluoromethoxy)benzyl) amino) ethanol as well as some of the (2-bromoethoxy)(tert-butyl) dimethylsilane starting material. 1 H NMR (400 MHz CDCI₃) δ_Η ppm 0.00 (s, 6H); 0.82 (s, 9H); 2.59-2.64 (m, 4H); 3.47 (t, 2H); 3.59 (t, 2H); 3.63 (s, 2H); 6.23-6.60 (m, 1 H); 6.90-7.23 (m, 4H). 2-((2-((teri-Butyldimethylsilyl)oxy)ethyl)(4-(difluoromethoxy)benzyl) amino)ethanol (5.2.11 )

To a stirred solution of 2-((4-(difluoromethoxy)benzyl)amino)ethanol 4.1.6 (1 .60 g, 7.37 mmol) and potassium carbonate (3.05 g, 22.1 mmol) in acetonitrile (50 ml_) was added (2-bromoethoxy)(tert-butyl)dimethylsilane 2 (2.12 g, 8.84 mmol). The reaction was refluxed overnight. The crude mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (Na2S04), filtered and solvent removed under vacuum to yield a clear oil. The product was isolated by column chromatography (25% EtOAc/75% Hex) to yield a clear oil. NMR of this revealed the product, 2- ((2-((tert-butyldimethylsilyl)oxy)ethyl)(4-(difluoromethoxy)benzyl) amino) ethanol as well as some of the (2-bromoethoxy)(tert-butyl)dimethylsilane starting material. 1 H NMR (400 MHz CDCI₃) δ_Η ppm 0.05 (s, 6H); 0.80 (s, 9H); 2.57-2.63 (m, 4H); 3.47 (t, 2H); 3.57 (t, 2H); 3.61 (s, 2H); 6.21 -6.58 (m, 1 H); 6.97 (d, 2H); 7.23 (d, 2H).

2-((2-Bromobenzyl)(2-((ieri-butyldimethylsilyl)oxy)ethyl)amino)ethanol (5.2.12)

To a stirred solution of 2-((2-((tert-butyldimethylsilyl)oxy)ethyl) amino)ethanol 3.1.1 (5.0 g, 22.79 mmol) and potassium carbonate (9.45 g, 68.4 mmol) in acetonitrile (150 ml_) was added 2-bromobenzyl bromide (6.84 g, 27.3 mmol). The mixture was stirred overnight room temperature. The crude mixture was filtered, the solvent removed in vacuo, diluted with ethyl acetate and washed with water. The organic layer was dried (Na2S04), filtered and solvent removed under vacuum to yield a yellow oil. The residue was submitted through column chromatography and the product isolated. NMR of this material confirmed the product as 2-((2- bromobenzyl)(2-((tert-butyldimethylsilyl)oxy) ethyl) amino)ethanol. 1 H NMR (400MHz CDCI₃) δ_Η ppm 0.10 (s, 6H); 0.82 (s, 9H); 2.76 (m, 4H); 3.58 (t, 2H); 3.68 (t, 2H); 3.80 (s, 2H); 7.1 1 -7.57 (m, 4H).

2-((4-Bromobenzyl)(2-((ieri-butyldimethylsilyl)oxy)ethyl)amino)ethanol

(5.2.13)

A solution of 2-((2-((tert-Butyldimethylsilyl)oxy)ethyl)amino)ethanol 3.1.1 (10 g, 45.6 mmol) was taken up in acetonitrile (150 ml_), then potassium carbonate (7.55 g, 54.6 mmol) and 4-bromobenzyl bromide (1 1 .4 g, 45.6 mmol) added at once. The resulting reaction mixture was stirred for 4 h, then filtered to remove potassium carbonate. The filtrate was evaporated to dryness to afford a colourless oil that was purified by flash chromatography, eluting with EtOAc:Hex 1 :9. Solvent removal and concentration under high vacuum afforded 2-((4-bromobenzyl)(2-((tert-butyldimethylsilyl)oxy)ethyl) amino)ethanol (14 g, 79%) as a colourless oil.1 H NMR (400MHz CDCI₃) δ_Η ppm 0.10 (s, 6H), 0.82 (s, 9H), 2.7 - 2.75 (m, 4H), 3.13 (br s, 1 H), 3.51 (br t, 2H), 3.53 - 3.70 (m, 4H), 7.24 (d, 2H), 7.47 (d, 2H).

2-((3-Bromobenzyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)amino)ethanol (5.2.14)

A solution of 2-((2-((tert-Butyldimethylsilyl)oxy)ethyl)amino)ethanol 3.1.1 (10 g, 45.6 mmol) was taken up in acetonitrile (150 ml_), then potassium carbonate (7.55 g, 54.6 mmol) and 3-bromobenzyl bromide (1 1 .4 g, 45.6 mmol) added at once. The resulting reaction mixture was stirred for 4 h, then filtered to remove potassium carbonate. The filtrate was evaporated to dryness to afford a colourless oil that was purified by flash chromatography, eluting with EtOAc:Hex 1 :9. Solvent removal and concentration under high vacuum afforded 2-((3-bromobenzyl)(2-((tert-butyldimethylsilyl)oxy)ethyl) amino)ethanol (12.85 g, 73%) as a colourless oil that was used in the next step without further characterisation.

Diethyl pyridine-2,5-dicarboxylate (5.3)

Pyridine-2,5-dicarboxylic acid (20.0 g, 120 mmol) was dissolved in ethanol (200 mL) and treated with concentrated solution of sulfuric acid (2.0 mL, 36 mmol) in ethanol (20 mL). The reaction was heated under reflux for 4hrs, concentrated and dissolved in EtOAc (10 mL). The mixture was washed with water (50mL), brine (50 mL), dried over sodium sulfate, filtered and evapourated to afford diethyl pyridine-2,5-dicarboxylate (18 g, 67 %). 1 H NMR (400MHz CDCI₃) δ_Η ppm 1 .25 (t, 3H), 4.3 (q, 2H), 8.2 (d, 1 H), 8.4 (d, 1 H), 9.4 (s, 1 H).

5-(Ethoxycarbonyl)picolinic acid (5.4)

To a stirring solution of diethyl pyridine-2,5-dicarboxylate (3.49 g, 15.6 mmol) in ethanol (31 ml) was added sodium hydroxide pellets (0.66 g, 16.6 mmol). The reaction was heated at reflux for 4 h. The reaction was quenched with 2M HCI (1 1 mL) at the reflux temperature, allowed to cool to room temperature and then 0 C. The resulting precipitate was filtered, washed with ethanol (25 mL) and dried with heating under vacuum to afford the mono-acid as a white free flowing powder (2.1 g, 69%). 1 H NMR (400MHz CDCI₃) δ_Η ppm 1 .25 (t, 3H), 4.35 (q, 2H), 8.15 (d, 2H), 8.46 (d, 2H), 9.18 (s, 1 H). 5-(Hydroxymethyl)-N-(3-(trifluoromethoxy)phenyl)picolinamide (5.5.1)

To a stirring solution of 5-(ethoxycarbonyl)picolinic acid (500. Omg, 2.56 mmol) in DMF (10 ml) was added CDI (623 mg, 3.84 mmol). The reaction was allowed to stir for 10min and the 4-(trifluoromethyl)aniline (0.384 ml, 3.07 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the presence of the product. Water was added to the reaction and the white precipitate was filtered. NMR of the solid confirmed the product as ethyl 6-((3- (trifluoromethyl)phenyl)carbamoyl)nicotinate (0.65 g, 75 %). ¹ H NMR (400MHz CDCI₃) δ_Η ppm 1 .38 (t, 3H), 4.42 (q, 2H), 7.50 (d, 1 H), 7.63 (t, 1 H), 8.21 (d, 1 H), 8.31 (d, 1 H), 8.44 (s, 1 H), 8.55 (d, 1 H), 9.19 (s, 1 H), 1 1 .18 (s, 1 H).

Ethyl 6-((3-(trifluoromethoxy)phenyl)carbamoyl)nicotinate (5.5.2)

To a stirring solution of 5-(ethoxycarbonyl)picolinic acid (0.50 g, 2.56 mmol) in DMF (10 ml) was added CDI (0.623 g, 3.84 mmol). The reaction was allowed to stir for 10 min and the 3-(trifluoromethoxy)aniline (0.41 ml, 3.07 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the presence of the product. Water was added to the reaction and the white precipitate was filtered. LC- MS of the solid confirmed the product as ethyl 6-((3- (trifluoromethoxy)phenyl)carbamoyl)nicotinate (0.45 g, 50 %). ¹ H NMR (400MHz CDCI₃) δ_Η ppm 1 .36 (t, 3H), 4.39 (q, 2H), 7.13 (d, 1 H), 7.50 (t, 1 H), 7.94 (d, 1 H), 8.09 (s, 1 H), 8.29 (d, 1 H), 8.44 (d, 1 H), 9.19 (s, 1 H), 1 1 .1 1 (s, 1 H).

Ethyl 6-((4-(trifluoromethoxy)phenyl)carbamoyl)nicotinate (5.5.3)

To a stirring solution of 5-(ethoxycarbonyl)picolinic acid (0.50 g, 2.56 mmol) in DMF (10 ml) was added CDI (0.623 g, 3.84 mmol). The reaction was allowed to stir for 10 min and the 4-(trifluoromethoxy)aniline (0.41 ml, 3.07 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the presence of the product. Water was added to the reaction and the white precipitate was filtered. LC- MS of the solid confirmed the product as ethyl 6-((4- (trifluoromethoxy)phenyl)carbamoyl)nicotinate (0.91 g, 100 %). 1 H NMR (400MHz CDCI₃) δ_Η ppm 1 .37 (t, 3H), 4.40 (q, 2H), 7.39 (d, 2H), 8.04 (d, 2H), 8.30 (d, 1 H), 8.55 (d, 1 H), 9.19 (s, 1 H), 1 1 .04 (s, 1 H).

5-(Hydroxymethyl)-N-(3-(trifluoromethyl)phenyl)picolinamide (5.6.1 )

To a stirring solution of lithium borohydride (32.2 mg, 1 .48 mmol) in THF/ MeOH (20 ml, 1 :1 ) was added ethyl 6-((3- (trifluoromethyl)phenyl)carbamoyl)nicotinate (100 mg, 0.296 mmol). The reaction was allowed to stir for 1 hr and a LCMS was obtained. This indicated the reaction had gone to completion. The solvent was removed in vacuo and the residue taken up in EtOAc. The solution was washed with water, the organic layer dried and solvent removed in vacuo to yield an off- white solid. NMR confirmed this to be the product 5-(hydroxymethyl)-N-(3- (trifluoromethyl)phenyl)picolinamide (62 mg, 71 %). 1 H NMR (400MHz CDCI₃) δ_Η ppm 4.86 (s, 2H), 7.40 (d, 1 H), 7.50 (t, 1 H), 7.92 (d, 2H), 7.97 (d, 1 H), 8.08 (s, 1 H), 8.28 (d, 1 H), 8.61 (s, 1 H). 10.12 (s, 1 H).

5-(Hydroxymethyl)-N-(3-(trifluoromethoxy)phenyl)picolinamide (5.6.2)

To a stirring solution of lithium borohydride (277 mg, 12.7 mmol) in THF/ MeOH (20 ml, 1 :1 ) was added ethyl 6-((3- (trifluoromethoxy)phenyl)carbamoyl)nicotinate (900 mg, 2.54 mmol). The reaction was allowed to stir for 1 hr and a LCMS was obtained. This indicated the reaction had gone to completion. The solvent was removed in vacuo and the residue taken up in EtOAc. The solution was washed with water, the organic layer dried and solvent removed in vacuo and the product isolated using column chromatography to yield an off-white solid. NMR confirmed this to be the product 5-(hydroxymethyl)-N-(3- (trifluoromethoxy)phenyl)picolinamide (270 mg, 34%). 1 H NMR (400MHz CDCI₃) δ_Η ppm 4.86 (s, 2H), 7.01 (d, 1 H), 7.39 (t, 1 H), 7.63 (d, 2H), 7.85 (s, 1 H), 7.93 (d, 1 H), 8.28 (d, 1 H), 8.61 (s, 1 H). 10.09 (s,1 H).

5-(Hydroxymethyl)-N-(4-(trifluoromethoxy)phenyl)picolinamide (5.6.3)

To a stirring solution of lithium borohydride (277 mg, 12.7 mmol) in THF/ MeOH (20 ml, 1 :1 ) was added ethyl 6-((4- (trifluoromethoxy)phenyl)carbamoyl)nicotinate (900 mg, 2.54 mmol). The reaction was allowed to stir for 1 hr and a LCMS was obtained. This indicated the reaction had gone to completion. The solvent was removed in vacuo and the residue taken up in EtOAc. The solution was washed with water, the organic layer dried and solvent removed in vacuo to yield an white solid. LC-MS confirmed this to be the product 5-(hydroxymethyl)-N- (4-(trifluoromethoxy)phenyl)picolinamide (652 mg, 82%). The product was confirmed by LC-MS. See Table 19 for analytical data.

5-(Chloromethyl)-N-(4-(trifluoromethoxy)phenyl)picolinamide (5.7.1)

A solution of 5-(hydroxymethyl)-N-(3-(trifluoromethyl)phenyl)picolinamide (165 mg, 0.557 mmol) in DCM (6 ml) was treated with triethylamine (0.1 16 ml, 0.835 mmol). The mixture was stirred at room temperature for 10min. Tosyl chloride (127 mg, 0.668 mmol) was added to the reaction mixture and the reaction was stirred at ambient temperature overnight. The reaction was concentrated in vacuo and the product isolated by comlumn chromatography eluting 15% EtOAc in hexane. The product was confirmed by NMR. 1 H NMR (400MHz CDCI₃) δ_Η ppm 4.68 (s, 2H), 7.42 (d, 1 H), 7.51 (t, 1 H), 7.99 (d, 2H), 8.09 (s, 1 H), 8.32 (d, 1 H), 8.64 (s, 1 H), 10.09 (s, 1 H).

5-(Chloromethyl)-N-(4-(trifluoromethoxy)phenyl)picolinamide (5.7.2)

A solution of 5-(hydroxymethyl)-N-(4-(trifluoromethoxy)phenyl)picolinamide (624 mg, 2.00 mmol) in DCM (20 ml) was treated with triethylamine (0.418 ml, 3.00 mmol). The mixture was stirred at room temperature for 10 min. Tosyl chloride (457 mg, 2.40 mmol) was added to the reaction mixture and the reaction was stirred at ambient temperature overnight. The reaction was concentrated in vacuo and the product isolated by comlumn chromatography eluting 15% EtOAc in hexane. The product was confirmed by LC-MS. See Table 19 for analytical data. -(Chloromethyl)-N-(4-(trifluoromethoxy)phenyl)picolinamide (5.7.3)

A solution of 5-(hydroxymethyl)-N-(4-(trifluoromethoxy)phenyl)picolinamide (624 mg, 2.00 mmol) in DCM (20 ml) was treated with triethylamine (0.418 ml, 3.00 mmol). The mixture was stirred at room temperature for 10 min. Tosyl chloride (457 mg, 2.40 mmol) was added to the reaction mixture and the reaction was stirred at ambient temperature overnight. The reaction was concentrated in vacuo and the product isolated by comlumn chromatography eluting 15% EtOAc in hexane. The product was confirmed by NMR. 1 H NMR (400MHz CDCI₃) δ_Η ppm 4.68 (s, 2H), 7.25 (d, 2H), 7.81 (d, 2H), 7.95-7.98 (dd, 1 H), 8.31 (d, 1 H), 8.63 (s, 1 H), 10.02 (s, 1 H).

N-(4-(Hydroxymethyl)phenyl)-4-(trifluoromethoxy)benzamide (5.8.1)

To a stirring solution of 4-(trifluoromethoxy)benzoic acid (1 .00 g, 4.87 mmol) in DMF (10 ml) was added HATU (3.09 g, 8.12 mmol) and DIPEA (1 .42 ml_, 8.12 mmol). The reaction was allowed to stir for 10 min and the 4-amino benzyl alcohol (0.50 g, 4.06 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the presence of the product as well as some by-products. Water was added and the solution was extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo. The material was purified by column chromatography to yield the product as a white solid. Product confirmed by LC-MS. See Table 19 for analytical data. -(4-(Hydroxymethyl)phenyl)-3-(trifluoromethoxy)benzamide (5.8.2)

To a stirring solution of 3-(trifluoromethoxy)benzoic acid (1 .00 g, 4.87 mmol) in DMF (10 ml) was added HATU (1 .54 g, 4.06 mmol) and DIPEA (1 .42 mL, 8.12 mmol). The reaction was allowed to stir for 10 min and the 4-amino benzyl alcohol (0.50 g, 4.06 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the presence of the product. Water was added and the precipitate was filtered to yield a brownish solid. This was purified by column chromatography to yield the product as an off-white solid. The product was confirmed by LC-MS. See Table 19 for analytical data.

N-(4-formylphenyl)-4-(trifluoromethoxy)benzamide (5.9.1)

N-(4-(hydroxymethyl)phenyl)-4-(trifluoromethoxy)benzamide (0.45g, 1 .46 mmol) was dissolved in dichloromethane (5 mL) and sodium bromide (2.98 mg, 0.03 mmol) and 2,2,6, 6-tetramethyl-1 -piperidinyloxy (TEMPO) (4.52 mg, 0.03 mmol) were added. The reaction mixture was cooled to 0 °C in an ice-bath. Sodium hydrogen carbonate (0.24 g, 2.89 mmol) was dissolved in water (5 mL) and the resulting solution was mixed with sodium hypochlorite (5mL, 10-13%). This solution was added dropwise to the reaction mixture with vigorous stirring and the reaction mixture was further stirred overnight at room temperature. The solution was diluted with dichloromethane and washed with water and dried over sodium sulfate. The solvent was removed in vacuo to yield a yellow oil which solidified on standing. The product was confirmed by LC-MS. See Table 19 for analytical data.

N-(4-formylphenyl)-3-(trifluoromethoxy)benzamide (5.9.2)

N-(4-(hydroxymethyl)phenyl)-3-(trifluoromethoxy)benzamide (1 .20 g, 3.86 mmol) was dissolved in dichloromethane (10 mL) and sodium bromide (7.93 mg, 0.08 mmol) and 2,2,6,6-tetramethyl-1 -piperidinyloxy (TEMPO) (12.0 mg, 0.08 mmol) were added. The reaction mixture was cooled to 0 'Ό in an ice-bath. Sodium hydrogen carbonate (0.65 g, 7.71 mmol) was dissolved in water (8 mL) and the resulting solution was mixed with sodium hypochlorite (8 mL, 10-13%). This solution was added dropwise to the reaction mixture with vigorous stirring and the reaction mixture was further stirred overnight at room temperature. The solution was diluted with dichloromethane and washed with water and dried over sodium sulfate. The solvent was removed in vacuo to yield a white solid. The product was confirmed by LC-MS. See Table 19 for analytical data.

2-((iert-Butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl) -N-methylethanamine (6.1.1)

To a stirring solution of triphenylphosphine (2.25 g, 8.57mmol) in dry THF (100 mL) was added DIAD (1 .7 mL, 8.57 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2, 4-dinitro-1 /-/-imidazole (1 .5 g, 9.42 mmol). The reaction mixture was stirred for a further 20 minutes and 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)ethanol 3.1.2 (2 g, 8.57 mmol) in dry THF (20 ml_) was added and the reaction mixture stirred for 18 hours at room temperature. The solvent was evaporated to furnish a yellow oil which was submitted through a column to yield 2-((tert-butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl)- N-methylethanamine (4.4 g, 1 1 .8 mmol) with DIAD by-product which could not be separated. Confirmed by LC-MS. See Table 19 for analytical data.

N-(2-((ieri-Butyldimethylsilyl)oxy)ethyl)-N-(2-(2,4-dinitro-1 H-imidazol-1 - yl)ethyl)prop-2-en-1 -amine (6.1.2)

To a stirring solution of triphenylphosphine (16.2 g, 62 mmol) in dry THF (400 ml_) was added DIAD (12.5 ml_, 62 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2, 4-dinitro-1 /-/-imidazole (10.7 g, 68 mmol). The reaction mixture was stirred for a further 20 minutes and 2-(allyl(2-((tert-butyldimethylsilyl)oxy)ethyl)amino)ethanol 5.1.1 (16 g, 62 mmol) in dry THF (200 ml_) was added and the reaction mixture stirred for 18 hours at room temperature. The solvent was evaporated to furnish a yellow oil which was put through a column and the product was eluted with 80:20 HEX: EtOAc N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(2,4-dinitro- 1 H-imidazol-1 -yl) ethyl) prop-2-en-1 -amine (18 g, 45.1 mmol, 73%). See Table 19 for analytical data. l)oxy)ethyl)(2-(2,4-dinitro-1 H- (6.1.3)

To a stirring solution of tnphenylphosphine (1 .16 g, 4.26 mmol) in dry THF (50 mL) was added DIAD (0.83 mL, 4.26 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2, 4-dinitro-1 /-/-imidazole (0.74 g, 4.68 mmol). The reaction mixture was stirred for a further 20 minutes and 2-((te/t-butyldimethylsilyl)oxy)ethanol 5.1.2 (1 .30 g, 4.26 mmol) in dry THF (20 mL) was added and the reaction mixture stirred for 18 hours at room temperature. The solvent was evaporated to furnish a thick orange oil which was passed through a pad of silica (1 1 cm x 7 cm) eluting with EtOAc/Hex (1 :1 ). The solvent was removed in vacuo to yield a yellow oil. LC-MS of this indicated the presence of the product mass ion. LC-MS confirmed the product as ethyl 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(2- (2,4-dinitro-1 H-imidazol-1 -yl)ethyl)

amino)acetate (0.60 g, 32%). See Table 19 for analytical data. ieri-Butyl-2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(2-(2,4-dinitro-1 H- imidazol-1 -yl)ethyl) amino)acetate (6.1.4)

To a stirring solution of tnphenylphosphine (3.93 g, 14.9 mmol) in dry THF (90 mL) was added DIAD (2.91 mL, 14.9 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2,4-dinitro-1 /-/-imidazole (2.61 g, 16.5 mmol). The reaction mixture was stirred for a further 20 minutes and tert-butyl 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(2- hydroxyethyl)amino)acetate 5.1.3 (5.0 g, 14.9 mmol) in dry THF (30 ml_) was added and the reaction mixture stirred for 18 hours at room temperature. The solvent was evaporated to furnish a thick orange oil which was filtered through a pad of silica (1 1 cm x 7 cm) eluting with EtOAc/Hex (1 :1 ). The solvent was removed in vacuo to yield a yellow oil. LC-MS of this indicated the presence of the product mass ion. LC-MS confirmed the product as tert-butyl 2-((2-((tert-butyldimethylsilyl)oxy) ethyl)(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl)amino)acetate (5.10 g, 72%). See Table 19 for analytical data.

A/-Benzyl-2-((tert-butyldimethylsilyl)oxy)-A/-(2-(2,4-dinitro-1 H-imidazol- 1 -yl)ethyl)ethanamine (6.2.1)

To a stirring solution of triphenylphosphine (0.847 g, 3.23 mmol) in dry THF (50 ml_) was added DIAD (0.63 ml_, 3.23 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2, 4-dinitro-1 /-/-imidazole (0.562 g, 3.55 mmol). The reaction mixture was stirred for a further 20 minutes and 2-(benzyl(2-((tert-butyldimethylsilyl)oxy)ethyl)amino)ethanol 5.2.1 (1 .0 g, 3.23 mmol) in dry THF (10 ml_) was added and the reaction mixture stirred for 18 hours at room temperature. The solvent was evaporated to furnish a yellow oil which was put through a column (20 % EtOAC: 80 % Hex). ¹ H NMR revealed product and minor DIAD by-product. LC-MS confirmed product as N-benzyl-2-((tert-butyldimethylsilyl)oxy)-N-(2- (2,4-dinitro-1 H-imidazol-1 -yl)ethyl) ethanamine (1 .2 g, 2.67 mmol, 83%). Confirmed by LC-MS. See Table 19 for analytical data. 2-((tert-Butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl) - -(pyridin-2-ylmethyl)ethanamine (6.2.2)

To a stirring solution of triphenylphosphine (0.845 g, 3.23 mmol) in dry THF (50 mL) was added DIAD (0.63 mL, 3.23 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2, 4-dinitro-1 /-/-imidazole (0.561 g, 3.55 mmol). The reaction mixture was stirred for a further 20 minutes and 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(pyridin-2-ylmethyl) amino)ethanol 5.2.2 (1 .0 g, 3.23 mmol) in dry THF (10 mL) was added and the reaction mixture stirred for 18 hours at room temperature. The solvent was evaporated to furnish a yellow oil which was put through a column (20 % EtOAc:80 % Hex) 500 mL and the product was eluted with (50% EtOAc:50% Hex). ¹ H NMR revealed product and minor DIAD by-product. LC-MS confirmed product as 2-((tert-butyldimethylsilyl)oxy)-N-(2-(2,4- dinitro-1 H-imidazol-1 -yl)ethyl)-N-(pyridin-2-ylmethyl) ethanamine (0.45 g, 0.99 mmol, 31%). See Table 19 for analytical data.

2-((iert-Butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl) - -(pyridin-3-ylmethyl)ethanamine (6.2.3)

To a stirring solution of triphenylphosphine (0.380 g, 1 .45 mmol) in dry THF (50 mL) was added DIAD (0.28 mL, 1 .45 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2, 4-dinitro-1 /-/-imidazole (0.252 g, 1 .59 mmol). The reaction mixture was stirred for a further 20 minutes and 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(pyridin-3-ylmethyl) amino)ethanol 5.2.3 (0.45 g, 3.23 mmol) in dry THF (10 mL) was added and the reaction mixture stirred for 18 hours at room temperature. The solvent was evaporated to furnish a yellow oil which was put through a column (20 %EtOAc:80% Hex) (500 mL) and the product was eluted with 100 % EtOAc. LC-MS confirmed product as 2-((tert-butyldimethylsilyl)oxy)- N-(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl)-N-(pyridin-3-yl

methyl)ethanamine (1 .09 g, 1 .59 mmol). See Table 19 for analytical data.

2-((iert-Butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl) -N-(4-methoxybenzyl)ethanamine (6.2.4)

To a stirring solution of triphenylphosphine (10.8 g, 41 .2 mmol) in dry THF (180 mL) was added DIAD (8.00 mL, 41 .1 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2, 4-dinitro-1 /-/-imidazole (7.20 g, 45.5 mmol). The reaction mixture was stirred for a further 20 minutes and 2-((te/?-butyldimethylsilyl)oxy)ethanol 5.2.4 (14.0 g, 41 .2 mmol) in dry THF (20 mL) was added and the reaction mixture stirred for 18 hours at room temperature. The solvent was evaporated to furnish a thick orange oil which was dissolved in DCM (10 mL) and filtered through a pad of silica (1 1 cm x 7 cm). The solvent was removed in vacuo and the residue redissolved in DCM (300 mL), washed with 15% hydrogen peroxide solution (200 mL) and saturated sodium sulfite solution (200 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The resulting residue was triturated from hexanes to yield 2- ((ieri-butyldimethylsilyl)oxy)-/V-(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl)- V-(4- methoxybenzyl)ethanamine (15.42 g, 32.2 mmol, 58%) as a yellow solid. 1 H NMR (400MHz CDCI₃) δ_Η ppm 0.30 (s, 6H); 0.85 (s, 9H); 2.71 -2.80 (m, 2H); 2.85-2.90 (m, 2H); 3.46 (s, 2H); 3.75-3.78 (m, 5H); 4.38-4.46 (m, 2H); 6.68 (d, 2H); 6.83 (d, 2H); 8.15 (s, 1 H).

2-((iert-Butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl) -N-(2,4-dimethoxybenzyl)ethanamine (6.2.5)

To a stirring solution of triphenylphosphine (13.9 g, 53.0 mmol) in dry THF (280 mL) was added DIAD (10.3 mL, 53.0 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2, 4-dinitro-1 /-/-imidazole (9.20 g, 58.2 mmol). The reaction mixture was stirred for a further 20 minutes and 2-((2-((ie -butyldimethylsilyl)oxy)ethyl)(2,4-dimethoxybenzyl) amino)ethanol 5.2.5 (19.5 g, 52.8 mmol) in dry THF (20 mL) was added and the reaction mixture stirred for 18 hours at room temperature. The solvent was evaporated to furnish a thick orange oil which was dissolved in DCM (10 mL) and filtered through a pad of silica (1 1 cm x 7 cm). The solvent was removed in vacuo and the residue triturated. The yellow precipitate was redissolved in DCM (300 mL) and washed with 15 % hydrogen peroxide solution (200 mL) and saturated sodium sulfite solution (200 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The resulting residue was triturated to yield 2-((tert- butyldimethylsilyl)oxy)-/V-(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl)-/V-(4- methoxybenzyl)ethanamine (16.2 g, 31 .8 mmol, 60%) as a yellow solid contaminated with DIAD by-product. 1 H NMR (400MHz CDCI₃) δ 0.00 (s, 6H); 0.80 (s, 9H); 2.63-2.66 (m, 2H); 2.85-2.87 (m, 2H); 3.36 (s, 2H); 3.63- 3.65 (m, 5H); 3.68 (s, 3H); 4.25-4.27 (m, 2H); 6.14-6.19 (m, 2H); 6.67 (d, 1 H); 7.95 (s, 1 H). 2-((iert-Butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl) -N-(4-(trifluoromethoxy)benzyl)ethanamine (6.2.6)

To a stirring solution of triphenylphosphine (1 .04 g, 3.97 mmol) in dry THF (100 mL) was added DIAD (0.77 mL, 3.97 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2, 4-dinitro-1 /-/-imidazole (0.69 g, 4.37 mmol). The reaction mixture was stirred for a further 20 minutes and 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(4-(trifluoromethoxy) benzyl)amino)ethanol 5.2.8 (1 .5 g, 3.97 mmol) in dry THF (30 mL) was added and the reaction mixture stirred for 18 hours at room temperature. The solvent was evaporated to furnish a thick orange oil which was filtered through a pad of silica (1 1 cm x 7 cm) eluting with EtOAc/Hex (1 :1 ). The solvent was removed in vacuo to yield a yellow oil. LC-MS confirmed product as 2-((tert-butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H-imidazol-1 - yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)ethanamine (1 .75 g, 86%). See Table 19 for analytical data.

2-((iert-Butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl) -N-(3-(trifluoromethoxy)benzyl)ethanamine (6.2.7)

To a stirring solution of triphenylphosphine (0.73 g, 2.80 mmol) in dry THF (100 mL) was added DIAD (0.54 mL, 2.80 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2, 4-dinitro-1 /-/-imidazole (0.49 g, 3.07 mmol). The reaction mixture was stirred for a further 20 minutes and 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(3-(trifluoromethoxy) benzyl)amino)ethanol 5.2.9 (1 .10 g, 2.80 mmol) in dry THF (30 ml_) was added and the reaction mixture stirred for 18 hours at room temperature. The solvent was evaporated to furnish a yellow oil which was purified using column chromatography eluting 20 % EtOAc/Hexane. The solvent was evaporated to yield a yellow oil which was analysed using LC-MS. This indicated the mass ion of the product 2-((tert-butyldimethylsilyl)oxy)-N-(2- (2,4-dinitro-1 H-imidazol-1 -yl)ethyl)-N-(3-(trifluoromethoxy) benzyl) ethan- amine. This material (including the DIAD impurity) was taken directly into the next reaction without further purification. See Table 19 for analytical data.

2-((iert-Butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl) -N-(4-(trifluoromethyl)benzyl)ethanamine (6.2.8)

To a stirring solution of triphenylphosphine (0.71 g, 2.70 mmol) in dry THF (100 ml_) was added DIAD (0.53 ml_, 2.70 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2, 4-dinitro-1 /-/-imidazole (0.47 g, 2.97 mmol). The reaction mixture was stirred for a further 20 minutes and 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(4-(trifluoromethoxy) benzyl)amino)ethanol 5.2.7 (1 .02 g, 2.70 mmol) in dry THF (30 ml_) was added and the reaction mixture stirred for 18 hours at room temperature. The solvent was evaporated to furnish a yellow oil which was purified using column chromatography eluting 20% EtOAc/Hexane. The solvent was evaporated to yield a yellow oil which was analysed by LC-MS. This indicated the mass ion of the product 2-((tert-butyldimethylsilyl)oxy)-N-(2- (2,4-dinitro-1 H-imidazol-1 -yl)ethyl)-N-(4-(trifluoromethyl) benzyl) ethan- amine. This material (including the DIAD impurity) was taken directly into the next reaction without further purification. See Table 19 for analytical data.

2-((iert-Butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl) -N-(3-(trifluoromethyl)benzyl)ethanamine (6.2.9)

To a stirring solution of triphenylphosphine (1 .39 g, 5.32 mmol) in dry THF (100 mL) was added DIAD (1 .05 mL, 5.32 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2, 4-dinitro-1 /-/-imidazole (0.93 g, 5.86 mmol). The reaction mixture was stirred for a further 20 minutes and 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(4-(trifluoromethoxy) benzyl)amino)ethanol 5.2.6 (2.01 g, 5.32 mmol) in dry THF (30 mL) was added and the reaction mixture stirred for 18 hours at room temperature. The solvent was evaporated to furnish a yellow oil which was purified using column chromatography eluting 20 % EtOAc/Hexane. The solvent was evaporated to yield a yellow oil which was analysed by LC-MS. This indicated the mass ion of the product 2-((tert-butyldimethylsilyl)oxy)-N-(2- (2,4-dinitro-1 H-imidazol-1 -yl)ethyl)-N-(3-(trifluoro-methyl) benzyl) ethan- amine. This material (including the DIAD impurity) was taken directly into the next reaction without further purification. See Table 19 for analytical data. 2-((iert-Butyldimethylsilyl)oxy)-N-(3-(difluoromethoxy)benzyl)-N-(2- (2,4-dinitro-1 H-imidazol-1 -yl)ethyl)ethanamine (6.2.10)

To a stirring solution of triphenylphosphine (0.83 g, 3.20 mmol) in dry THF (100 mL) was added DIAD (0.62 mL, 3.20 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2, 4-dinitro-1 /-/-imidazole (0.56 g, 3.52 mmol). The reaction mixture was stirred for a further 20 minutes and 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(3-(difluoromethoxy) benzyl)amino)ethanol 5.2.10 (1 .20 g, 3.20 mmol) in dry THF (30 mL) was added and the reaction mixture stirred for 18 hours at room temperature. The solvent was evaporated to furnish a yellow oil which was purified using column chromatography eluting 20% EtOAc/Hexane. The solvent was evaporated to yield a yellow oil which was analysed using LC-MS. This indicated the mass ion of the product 2-((tert-butyldimethylsilyl)oxy)-N-(3- (difluoromethoxy)benzyl)-N-(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl)ethan- amine. This material (including the DIAD impurity) was taken directly into the next reaction without further purification. See Table 19 for analytical data.

2-((iert-Butyldimethylsilyl)oxy)-N-(4-(difluoromethoxy)benzyl)-N-(2- (2,4-dinitro-1 H-imidazol-1 -yl)ethyl)ethanamine (6.2.11)

To a stirring solution of triphenylphosphine (0.83 g, 3.20 mmol) in dry THF (100 mL) was added DIAD (0.62 mL, 3.20 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2, 4-dinitro-1 /-/-imidazole (0.56 g, 3.52 mmol). The reaction mixture was stirred for a further 20 minutes and 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(4-(difluoromethoxy) benzyl)amino)ethanol 5.2.11 (1 .20 g, 3.20 mmol) in dry THF (30 mL) was added and the reaction mixture stirred for 18 hours at room temperature. The solvent was evaporated to furnish a yellow oil which was purified using column chromatography eluting 20 % EtOAc/Hexane. The solvent was evaporated to yield a yellow oil which was analysed using LC-MS. This indicated the mass ion of the product 2-((tert-butyldimethylsilyl)oxy)-N-(4- (difluoromethoxy)benzyl)-N-(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl)ethan- amine. This material (including the DIAD impurity) was taken directly into the next reaction without further purification. See Table 19 for analytical data.

N-(2-Bromobenzyl)-2-((tert-butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H- imidazol-1 -yl)ethyl)ethanamine (6.2.12)

To a stirring solution of triphenylphosphine (2.87 g, 10.94 mmol) in dry THF (150 ml) was added DIAD (2.13 ml, 10.94 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2, 4-dinitro-1 /-/-imidazole (1 .90 g, 12.04 mmol). The reaction mixture was stirred for a further 20 minutes and 2-((2-bromobenzyl)(2-((tert-butyldimethylsilyl)oxy)ethyl) amino) ethanol 5.2.12 (4.25g, 10.94 mmol) in dry THF (30 ml) was added and the reaction mixture stirred for 18 hours at room temperature. The product was isolated using column chromatography, confirmed by LC-MS and taken directly into the next reaction without further purification. See Table 19 for analytical data.

N-(4-Bromobenzyl)-2-((ieri-butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H- pyrrol-1-yl)ethyl)ethanamine (6.2.13)

To a stirred solution of triphenylphosphine (12.97 g, 49.4 mmol) in THF (100 ml_) was added DIAD (9.6 ml_, 49.4 mmol) added via syringe and 2,4- dinitroimidazole ( 7.81 g, 49.4 mmol). The resulting solution was stirred for 30 min, then 2-((4-bromobenzyl)(2-((te/?-butyldimethylsilyl)oxy)ethyl) amino) ethanol 5.2.13 (19.2 g, 49.4 mmol) in THF (100 ml_) added via syringe. The reaction mixture was refluxed for 14 h, and evaporated to dryness. The oily residue was purified via flash chromatography, eluting with 65 % DCM: 35 % hexanes; the solvent was removed in vacuo and the residue triturated from hexane. The solids were filtered and dried under reduced pressure and dried to afford as a yellow solid (15.45 g, 59 %). See Table 19 for analytical data.

N-(3-Bromobenzyl)-2-((tert-butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H- pyrrol-1-yl)ethyl)ethanamine (6.2.14)

To a stirred solution of triphenylphosphine (0.57 g, 2.1 mmol) in THF (100 ml_) was added DIAD (0.41 ml_, 2.1 mmol) via syringe and 2,4- dinitroimidazole (0.33 g, 2.1 mmol). The resulting solution was stirred for 10 mm, then 2-((3-bromobenzyl)(2-((tert- butyldimethylsilyl)oxy)ethyl)amino)ethanol (8.39 g, 21 .6 mmol) in THF (2 ml_) added via syringe. The reaction mixture was stirred for 18 h. The solvent was removed in vacuo and the residue purified by chromatography, eluting with 65% EtoAc:hex. N-(3-bromobenzyl)-2-((tert- butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H-pyrrol-1 -yl)ethyl)ethanamine was obtained as yellow solid (0.45 g, 41 %). See Table 19 for analytical data.

4-Methyl-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1-b][1 ,3,6]

oxadiazocine (7.1.1)

To a stirring solution of 2-((tert-butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H- imidazol-1 -yl)ethyl)-N-methylethanamine 6.1.1 (4.4 g, 1 1 .8 mmol) in dry THF (500 ml_) was added 1 N TBAF (24 ml_, 23.6 mmol) dropwise. On addition of the TBAF the solution immediately turned from yellow to brownish. The reaction was allowed to stir over night at room temperature, the solvent was removed and the mixture purified with column chromatography. The product (4-methyl-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine (1 g, 4.7 mmol, 40 %) was obtained with TBAF salt impurities and due to the polar nature of the compound it could not be separated from the salt using column chromatography.

4-Allyl-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocine

To a stirring solution of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(2,4- dinitro-1 H-imidazol-1 -yl)ethyl)prop-2-en-1 -amine 6.1.2 (18 g, 45.1 mmol) in dry THF (2000 ml_) was added 1 N TBAF (90 ml_, 90 mmol) dropwise. On addition of the TBAF the solution immediately turned from yellow to brownish. The reaction was allowed to stir for 48h at room temperature. The solvent was removed and the crude product purified with column chromatography. Impurities were eluted with 50:50 Hex:EtOAc and the product with 80:20 Hex:EtOAc 4-allyl-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine(8.2 g, 34.4 mmol, 76%). Confirmed by LC-MS. See Table 19 for analytical data.

9-Nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine (7.1.3)

A solution of 4-allyl-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine 7.1.2 (3 g, 13 mmol) in DCE (40 ml_) was cooled to 0 °C in an ice-water bath, then 1 -chloroethyl chloroformate (4.1 ml_, 37.8 mmol) was added . After 10 min, the reaction mixture was elevated to ambient and refluxed (90 °C) overnight. The solvent was removed in vacuo and the residue taken up in MeOH (30 ml_). The solution was refluxed for 4h (70 °C) and cooled to room temperature.

The precipitate was filtered, washed with MeOH (20 ml_) and dried. ¹ H NMR analysis of the dried solids revealed this to be the hydrochloride salt of the desired amine (1 .7 g, 68%). See Table 19 for analytical data. ie^Butyl-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin- -yl)acetate (7.1.4)

This compound was synthesized by both methods detailed below. Method 1 :

To a stirring solution of te/t-butyl 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(2- (2,4-dinitro-1 H-imidazol-1 -yl)ethyl)amino)acetate 6.1.4 (5.10 g, 10.7 mmol) in dry THF (250 ml_) was added 1 N TBAF (16.15 ml_, 16.15 mmol) dropwise. On addition of the TBAF the solution immediately turned from yellow to brownish. The reaction was allowed to stir for 18 hours. The solvent was removed under reduced pressure and the residue taken up into DCM (100 ml_). The organic layer was washed with water (100 ml_) and brine (100 ml_). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was dissolved in 10ml_ EtOAc and triturated with hexane resulting in a yellow powder. NMR confirmed the product as tert-butyl 2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetate (2.0 g, 59%). Method 2:

To a stirring solution of 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine, 7.1.3 (500 mg, 2.52 mmol) in water/acetonitrile, (2:1 , 15 mL) was added potassium carbonate (1 .05 g, 7.57 mmol). The reaction was allowed to stir for 10 min and the tert-butyl 2-bromoacetate (0.373 mL, 2.52 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the product mass ion. The reaction was ~ 50 % complete. The reaction was warmed to 60 'C and allowed to stir for an hour. LC-MS was obtained which indicated quantitative conversion to product. Water was added to mixture which resulted in the precipitation of a pale yellow solid. This was filtered, dried. LC-MS confirmed the structure of the expected product tert-butyl 2-(9-nitro- 5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)acetate (623 mg, 79%). See Table 19 for analytical data.

4-(3-Methylbut-2-en-1-yl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1-b]

To a stirring solution of 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine, HCI 7.1.3 (80.0 mg, 0.341 mmol) in water/acetonitrile (2:1 )(3 mL) was added potassium carbonate (141 mg, 1 .023 mmol). The reaction was allowed to stir for 10 min and the 1 -bromo-3-methylbut-2-ene (0.05 mL, 0.409 mmol) was added. The reaction was warmed at 60 'C overnight. An LC-MS was obtained which indicated almost quantitative conversion. Water was added to mixture which resulted in the precipitation of a yellowish residue. This was filtered, dried and another LC-MS obtained which confirmed it as product. See Table 19 for analytical data.

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)-yl) acetonitrile (7.1.6)

To a stirring solution of 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine, HCI 7.1.3 (80.0 mg, 0.341 mmol) in water/acetonitrile (2:1 )(3 mL) was added potassium carbonate (141 mg, 1 .023 mmol). The reaction was allowed to stir for 10 min and the bromoacetonitrile (0.03 mL, 0.409 mmol) was added. The reaction was warmed at 60 'C over the weekend. An LC-MS was obtained which indicated almost quantitative conversion. Water was added to mixture which resulted in the precipitation of a brownish residue. This was filtered, dried and another LC-MS obtained which confirmed it as product. See Table 19 for analytical data.

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)-yl) acetic acid (7.1.7)

To a stirring solution of TFA (20.0 mL, 260 mmol) in water (1 mL) was added tert-butyl 2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)acetate 7.1.4 (4.0 g, 12.81 mmol). The reaction was allowed to stir for 2 hrs at room temperature. LC-MS of the reaction indicated the reaction to be complete. The solution was diluted with toluene and the volume of the solution reduced in vacuo. Diethyl ether was added and an off-white precipitate formed which was filtered off. This procedure was repeated until no further precipitate formed. LC-MS confirmed the expected product 2-(9- nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)acetic acid (2.8 g, 85%). See Table 19 for analytical data. 4-Benzyl-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1-b][1 ,3,6]

oxadiazocine (7.2.1)

To a stirring solution of tert-butyl 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(2- (2,4-dinitro-1 H-imidazol-1 -yl)ethyl)amino)acetate 6.2.1 (1 .2 g, 2.67 mmol) in dry THF (150 mL) was added 1 N TBAF (5.43 mL, 5.34 mmol) dropwise. On addition of the TBAF the solution immediately turned from yellow to brownish. The reaction was allowed to stir over the weekend at room temperature, impurities were eluted with 50% HEX: 50% EtOAc and the compound with 95% EtOAc: 5% MEOH. The compound was further purified using preparative TLC 98 % DCM: 2 % MEOH (0.048 g, 0.166 mmol, 6%). Confirmed with LC-MS. See Table 19 for analytical data.

9-Nitro-4-(pyridin-2-ylmethyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1-b]

To a stirring solution of 2-((tert-butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H- imidazol-1 -yl)ethyl)-N-(pyridin-2-ylmethyl)ethanamine 6.2.2 (0.3 g, 0.67 mmol) in dry THF (100 mL) was added 1 N TBAF (1 .33 mL, 1 .33 mmol) dropwise. On addition of the TBAF the solution immediately turned from yellow to brownish. The reaction was allowed to stir over the weekend at room temperature, impurities were eluted with 50% HEX: 50% EtOAc and the compound with 95% EtOAc: 5% MEOH (0.068 g, 0.24 mmol, 35%). Confirmed with LC-MS. See Table 19 for analytical data. 9-Nitro-4-(pyridin-3-ylmethyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1-b]

To a stirring solution of 2-((tert-butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H- imidazol-1 -yl)ethyl)-N-(pyridin-3-ylmethyl)ethanamine 6.2.3 (1 .09 g, 2.42 mmol) in dry THF (150 mL) was added 1 N TBAF (4.84 mL, 4.84 mmol) dropwise. On addition of the TBAF the solution immediately turned from yellow to brownish. The reaction was allowed to stir over the weekend at room temperature, impurities were eluted with 50% hexane: 50% EtOAc and the compound with 95% EtOAc: 5% MEOH (0.020 g, 0.069 mmol, 3%). 1 H NMR (400MHz CDCI₃) 5.2.73-2.75(t, 4H) 3.51 (s, 2H); 3.66-3.69 (t, 4H); 7.28-7.32 (m, 1 H), 7.71 (d, 1 H), 8.53-8.55 (m, 2H).

4-(4-Methoxybenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1-b]

[1 ,3,6]oxadiazocine (7.2.4)

To a stirring solution of 2-((te/t-butyldimethylsilyl)oxy)-A/-(2-(2,4-dinitro-1 H- imidazol-1 -yl)ethyl)-A/-(4-methoxybenzyl)ethanamine 6.2.4 (1 .80 g, 3.75 mmol) in dry THF (100 mL) was added 1 N TBAF (5.70 mL, 5.70 mmol) dropwise. The reaction was allowed to stir for 18 hours. The solvent was removed under reduced pressure and the residue taken up into DCM (100 mL). The organic layer was washed with water (100 mL) and brine (100 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was submitted through column chromatography (50-100 % ethyl acetate/hexane) to yield 4-(4- methoxybenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine (4.01 g, 12.6 mmol, 40%) as a yellow solid. 1 H NMR (400MHz CDCI₃) δ 2.80-2.89 (m, 4H); 3.65 (s, 2H); 3.76 (s, 3H); 4.03 (t, 2H); 418 (t, 2H); 6.78 (d, 2H); 6.93 (d, 2H); 7.38 (s, 1 H).

4-(2,4-Dimethoxybenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1-b]

[1 ,3,6]oxadiazocine (7.2.5)

To a stirring solution of 2-((ie -butyldimethylsilyl)oxy)-/V-(2,4-dimethoxy- benzyl)-/V-(2-(2,4-dinitro-1 /-/-imidazol-1 -yl)ethyl)ethanamine 6.2.5 (16.0 g, 31 .4 mmol) in dry THF (500 ml_) was added 1 N TBAF (50 ml_, 50.0 mmol) dropwise. The reaction was allowed to stir for 18 hours. The solvent was removed under reduced pressure and the residue taken up into DCM (100 ml_). The organic layer was washed with water (100 ml_) and brine (100 ml_). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was submitted through column chromatography (50-100 % ethyl acetate/hexane) to yield 4-(2,4- dimethoxybenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - £>][1 ,3,6]oxadiazocine (4.72 g, 13.6 mmol, 43%) as a cream solid. 1 H NMR (400MHz CDCI₃) δ 2.74 (t, 2H); 2.84 (t, 2H); 3.48 (s, 2H); 3.73-3.80 (m, 10H); 6.33-6.39 (m, 2H); 6.91 (d, 1 H); 7.16 (s, 1 H).

9-Nitro-4-(4-(trifluoromethyl)benzyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1- b][1 ,3,6]oxadiazocine (7.2.6)

To a stirring solution of 2-((tert-butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H- imidazol-1 -yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)ethanamine 6.2.8 (0.65 g, 1 .26 mmol) in dry THF (100 ml_) was added 1 N TBAF (1 .89 ml_, 1 .89 mmol) dropwise. The solution was left to stir overnight. The solvent was removed under reduced pressure to yield a yellow residue. LC-MS of this residue indicated the presence of presence of the product 9-nitro-4-(4- (trifluoromethyl)benzyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine. The product was isolated using preparative TLC. See Table 19 for analytical data.

9-Nitro-4-(3-(trifluoromethyl)benzyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1- b][1 ,3,6]oxadiazocine (7.2.7)

To a stirring solution 2-((tert-butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H- imidazol-1 -yl)ethyl)-N-(3-(trifluoromethyl)benzyl)ethanamine 6.2.9 (0.65 g, 1 .26 mmol) in dry THF (100 mL) was added 1 N TBAF (1 .89 mL, 1 .89 mmol) dropwise. The reaction was allowed to stir for 18 hours. The solvent was removed under reduced pressure to yield a yellow residue. LC-MS of this residue indicated the presence of the product 9-nitro-4-(3- (trifluoromethyl)benzyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]

oxadiazocine. The product was isolated using preparative TLC. See Table 19 for analytical data.

9-Nitro-4-(4-(trifluoromethoxy)benzyl)-3,4,5,6-tetrahydro-2H-imidazo -b][1 ,3,6]oxadiazocine (7.2.8)

To a stirring solution of2-((tert-butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H- imidazol-1 -yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)ethanamine 6.2.6 (1 .65 g, 3.19 mmol) in dry THF (100 mL) was added 1 N TBAF (4.78 mL, 4.78 mmol) drop wise. The reaction was allowed to stir for 18 hours. The solvent was removed under reduced pressure and the residue taken up into DCM (100 mL). The organic layer was washed with water (100 mL) and brine (100 mL). The organic layer was separated, dried over sodium sulfate and evaporated. The orange residue started to crystallise on standing. LC- MS of this solid confirmed the product 9-nitro-4-(4-(trifluoromethoxy) benzyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine (0.2 g, 17%). See Table 19 for analytical data.

9-Nitro-4-(3-(trifluoromethoxy)benzyl)-3,4,5,6-tetrahydro-2H-imidazo -b][1 ,3,6]oxadiazocine (7.2.9)

To a stirring solution 2-((tert-butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H- imidazol-1 -yl)ethyl)-N-(3-(trifluoromethoxy)benzyl)ethanamine 6.2.7 (0.3 g, 0.56 mmol) in dry THF (100 mL) was added 1 N TBAF (0.85 mL, 0.85 mmol) dropwise. The reaction was allowed to stir for 18 hours. The solvent was removed under reduced pressure to yield a yellow residue. LC-MS of this residue indicated the presence of the product9-nitro-4-(3- (trifluoromethoxy)benzyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine. The product was isolated using preparative TLC. See Table 19 for analytical data.

4-(3-(Difluoromethoxy)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1-b][1 ,3,6]oxadiazocine (7.2.10)

To a stirring solution 2-((tert-butyldimethylsilyl)oxy)-N-(3- (difluoromethoxy)benzyl)-N-(2-(2,4-dinitro-1 H-imidazol-1 - yl)ethyl)ethanamine 6.2.10 (0.75 g, 1 .45 mmol) in dry THF (100 mL) was added 1 N TBAF (2.18 mL, 2.18 mmol) dropwise. The reaction was allowed to stir for 18 hours. The solvent was removed under reduced pressure to yield a yellow residue. LC-MS of this residue indicated the presence of the product 4-(3-(difluoromethoxy)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo [2,1 -b][1 ,3,6]

oxadiazocine. The product was isolated using preparative TLC. See Table 19 for analytical data.

4-(4-(Difluoromethoxy)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1-b][1 ,3,6]oxadiazocine (7.2.11 )

To a stirring solution 2-((tert-butyldimethylsilyl)oxy)-N-(4- (difluoromethoxy)benzyl)-N-(2-(2,4-dinitro-1 H-imidazol-1 - yl)ethyl)ethanamine 6.2.11 (1 .0 g, 1 .94 mmol) in dry THF (100 mL) was added 1 N TBAF (2.91 mL, 2.91 mmol) dropwise. The reaction was allowed to stir for 18 hours. The solvent was removed under reduced pressure to yield a yellow residue. LC-MS of this residue indicated the presence of the product 4-(4-(difluoromethoxy)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo [2,1 -b][1 ,3,6]

oxadiazocine. The product was isolated using preparative TLC. See Table 19 for analytical data.

4-((2-Bromopyridin-4-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1-b][1 ,3,6]oxadiazocine (7.2.12)

A solution of 2-bromo-4-(chloromethyl)pyridine (0.442g, 0.202mmol) in acetone (5 mL) was treated with sodium iodide (0.151 g, 1 .01 mmol). The mixture was refluxed for an hour. Potassium carbonate (0.167 g, 1 .21 mmol) was added to the reaction. 9-Nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine 7.1.3 (0.04 g, 0.202 mmol) was dissolved in acetone and added to the stirring mixture. The reaction mixture was filtered, evaporated and submitted through preparative HPLC to obtain 4- ((2-bromopyridin-4-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b] [1 ,3,6]oxadiazocine (9.1 mg, 0.025 mmol, 13%). See Table 19 for analytical data.

4-((5-Bromopyridin-3-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1-b][1 ,3,6]oxadiazocine (7.2.13)

A solution of 3-bromo-5-(chloromethyl)pyridine(0.042 g, 0.202 mmol) in acetone (5 mL) was treated with sodium iodide (0.151 g, 1 .01 mmol). The mixture was refluxed for an hour. Potassium carbonate (0.167 g, 1 .21 mmol) was added to the reaction.9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2, 1 - b][1 ,3,6]oxadiazocine 7.1.3 (0.04 g, 0.202 mmol) was dissolved in acetone and added to the stirring mixture. The reaction mixture was filtered, evaporated and submitted through preparative HPLC to obtain 4-((5- bromopyridin-3-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b] [1 ,3,6] oxadiazocine (26.9 g, 0.073 mmol, 36%). See Table 19 for analytical data.

4-((5-Bromopyridin-2-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo -b][1 ,3,6]oxadiazocine (7.2.14)

A solution of 5-bromo-2-(chloromethyl)pyridine (0.42 g, 0.202 mmol) in acetone (5 mL) was treated with sodium iodide (0151 g, 1 .01 mmol). The mixture was refluxed for an hour. Potassium carbonate (0.167 g, 1 .21 mmol) was added to the reaction. 9-Nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine 7.1.3 (0.04 g, 0.20 mmol) was dissolved in acetone and added to the stirring mixture. The reaction mixture was filtered, evaporated and submitted through preparative HPLC to obtain 4- ((5-bromopyridin -2- yl) methyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo [2,1 - b][1 ,3,6]oxadiazocine (18.7 mg, 0.051 mmol, 25%). See Table 19 for analytical data.

4-(2-Bromobenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1-b]

To a stirring solution of crude N-(2-bromobenzyl)-2-((tert- butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl)ethanamine 6.2.12 (8.0 g, 15.14 mmol) in dry THF (200 mL) was added 1 N TBAF (30.3 ml_,30.3 mmol) drop wise. The reaction was allowed to stir overnight at room temperature. LC-MS of the reaction mixture indicated the presence on the product mass ion (M+Na). The solvent was evaporated in vacuo and the residue taken into EtOAc, washed with water and the organic layer separated, dried over sodium sulphate and evaporated to yield a yellow oil. This oil was taken up into 20 mL EtOAc and triturated with hexane. The resulting yellow powder and was filtered. LC-MS of this powder confirmed the product as 4-(2-bromobenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo [2,1 -b][1 ,3,6] oxadiazocine (1 .9 g, 34%). See Table 19 for analytical data.

4-(4-Bromobenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1-b]

[1 ,3,6]oxadiazocine (7.2.16)

A solution of N-(4-bromobenzyl)-2-((tert-butyldimethylsilyl)oxy)-N-(2-(2,4- dinitro-1 H-pyrrol-1 -yl)ethyl)ethanamine 6.2.13 (4.00 g, 7.58 mmol) in anhydrous THF (500 mL) was stirred at room temperature, then TBAF (4.4 mL, 15.2 mmol) added via syringe. The resulting solution was stirred for 2 h. The solvent was removed in vacuo, then the residue purified via flash chromatography, eluting with EtOAc:Hex 65:35. The desired product, 4-(4- bromobenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6

]oxadiazocine was obtained as a yellow solid. See Table 19 for analytical data.

4-(3-Bromobenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1-b]

[1 ,3,6]oxadiazocine (7.2.17)

To a stirred solution of triphenylphosphine (12.97 g, 49.4 mmol) in THF (100 ml_) was added DIAD (9.6 ml_, 49.4 mmol) added via syringe and 2,4- dinitroimidazole ( 7.81 g, 49.4 mmol). The resulting solution was stirred for 30 min, then 2-((3-bromobenzyl)(2-((te/?-butyldimethylsilyl)oxy) ethyl) amino)ethanol 5.2.14 (19.2 g, 49.4 mmol) in THF (100 ml_) added via syringe. The reaction mixture was refluxed for 14 h, and evaporated to dryness. The oily residue was purified via flash chromatography, eluting with 65 % DCM: 35 % hexanes; the solvent was removed in vacuo and the residue triturated from hexane. The solids were filtered and dried under reduced pressure and dried to afford N-(4-bromobenzyl)-2-((tert- butyldimethylsilyl)oxy)-N-(2-(2,4-dinitro-1 H-pyrrol-1 -yl)ethyl)ethanamine as a yellow solid that was used directly in the next step without further characterisation.

A solution of N-(4-bromobenzyl)-2-((tert-butyldimethylsilyl)oxy)-N-(2-(2,4- dinitro-1 H-pyrrol-1 -yl)ethyl)ethanamine (4.00 g, 7.58 mmol) in anhydrous THF (500 ml_) was stirred at room temperature, then TBAF (4.4 ml_, 15.2 mmol) added via syringe. The resulting solution was stirred for 2 h. The solvent was removed in vacuo, then the residue purified via flash chromatography, eluting with EtOAc:Hex 65:35. The desired product, 4-(4- bromobenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine was obtained as a yellow solid . See Table 19 for analytical data.

4-((6-Bromopyridin-2-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1-b][1 ,3,6]oxadiazocine (7.2.18)

A solution of 2-bromo-6-(chloromethyl)pyridine (1 .0 g, 5.05 mmol) in acetone (50 ml) was treated with sodium iodide (3.8 g, 25.2 mmol). The mixture was refluxed for an hour, potassium carbonate (4.2 g, 30.3 mmol) was added to the reaction. 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine, 7.1.3 (1 g, 5.05 mmol) was dissolved in acetone and added to the mixture and stirred overnight. The reaction mixture was filtered and evaporated. The crude was dissolved in a mixture of ethyl acetate and methanol (95%:5%) and filtered through a pad of silica. The silica was washed a few times with the ethyl acetate and methanol mixture. The washings were combined and the solvent evaporated to yield 4-((6- bromopyridin-2-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine (1 .7 g, 4.6 mmol, 92 %) with 68 % purity. The sample was further purified using prep HPLC. See Table 19 for analytical data.

4-((6-Bromopyridin-3-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1-b][1 ,3,6]oxadiazocine (7.2.19)

A solution of 2-bromo-5-(chloromethyl)pyridine (1 .0 g, 5.05 mmol) in acetone (50 ml) was treated with sodium iodide (3.8 g, 25.2 mmol). The mixture was refluxed for an hour, potassium carbonate (4.2 g, 30.3 mmol) was added to the reaction. 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine, 7.1.3 (1 g, 5.05 mmol) was dissolved in acetone and added to the mixture and stirred overnight. The reaction mixture was filtered and evaporated. The crude was dissolved in a mixture of ethyl acetate and methanol (95%:5%) and filtered through a pad of silica. The silica was washed a few times with the ethyl acetate and methanol mixture. The washings were combined and the solvent evaporated to yield 4-((6- bromopyridin-3-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine (1 .3 g, 3.5 mmol, 70%) with 85 % purity. The sample was further purified using prep HPLC. See Table 19 for analytical data. tert-Butyl 4-((9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin- -yl)methyl)benzoate (7.2.20)

9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine

hydrochloride, 7.1.3 (2.0 g, 8.52 mmol) was taken up in acetonitrile (4 mL), then added to a solution of potassium carbonate (3.53 g, 25.6 mmol) in water (12 mL). The biphasic mixture was stirred at ambient temperature then tert-butyl 4-(chloromethyl)benzoate (2.32 g, 10.23 mmol) was added in one portion. The resulting mixture was stirred for 48 h at ambient temperature, diluted with water (50 mL) and the product precipitated out of solution. The precipitate was filterd dried to afford a pale yellow solid, tert- butyl 4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)benzoate (1 .30 g, 39.3 %). See Table 19 for analytical data.

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)benzoic acid (7.2.21 )

To a stirring solution of TFA (6.40 ml, 82 mmol) in water (2ml) was added tert-butyl 4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)benzoate (1 .6 g, 4.12 mmol). The reaction was allowed to stir for 2 hrs at room temperature. LC-MS of the reaction indicated the reaction to be complete. The solution was diluted with toluene and the volume of the solution reduced in vacuo. Ethyl acetate was added and an off-white precipitate formed which was filtered off. This procedure was repeated until no further precipitate formed, to give 4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzoic acid (0.850 g, 66.2 %).

9-Nitro-4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl)- -tetrahydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocine (7.2.22)

To a stirring solution of 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine, HCI, 7.1.3 (2.0 g , 8.52 mmol) in water/acetonitrile (1 :3)(25 ml) was added potassium carbonate (3.53 g, 25.6 mmol). The reaction was allowed to stir for 10 min and 2-(4-(bromomethyl)phenyl)- 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (3.04 g, 10.2 mmol) was added. The solution was stirred overnight at room temperature. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried and the solvent removed in vacuo to yield a yellow oil. This was purified by column chromatography to yield a pale yellow oil which solidified into a white solid on standing. NMR of this material confirmed the product as 9-nitro-4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine (1 .84g, 52%). 1 H NMR (400MHz CDCI₃) δ ppm 1 .34 (s, 12H); 2.84-2.88 (m, 4H); 3.75 (s, 2H); 4.02-4.05 (m, 2H); 4.17-4.19 (m, 2H); 7.08 (d, 2H); 7.42 (s, 1 H); 7.71 (d, 2H). 4-(1-(6-Bromopyridin-3-yl)ethyl)-9-nitro-3,4,5,6-tetrahyd

imidazo[2,1-b][1 ,3,6]oxadiazocine (7.2.23)

A solution of 2-bromo-5-(1 -chloroethyl)pyridine (1 .25 g, 5.67 mmol) in acetone (40 mL) was heated to reflux in a round bottom flask equiped with a magnetic stirrer. Sodium iodide (1 .47 g, 9.84 mmol) was added in one portion, and the resulting mixture allowed to reflux for 1 h. Afterwards, potassium carbonate (1 .36 g, 9.84 mmol) and 9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine, HCI (0.77 g, 3.28 mmol) were added in succession. The reaction mixture was stirred overnight (36 h).

The reaction mixture was cooled to room temperature and filtered to removed inorganics. The inorganics were washed (2 x 30 mL) and the filtrate evaporated to dryness. Water (30 mL) was added to the residue, the resulting precipitate was washed in succession with water (100 mL) and hexane (300 mL). The amorphous solid was dried under reduced pressure to afford 4-(1 -(6-bromopyridin-3-yl)ethyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]

oxadiazocine (2.1 g, 97%) as a beige solid.

Examples of mefa-substituted biaryl compounds.

Boronic acid/ pinacol ester (1 .2 eq.), 7.2.12 or 7.2.13 or 7.2.17 or 7.2.18 and PdCI₂(dppf) (0.1 eq.) were suspended in ethanol (3 mL). The reaction was degassed with nitrogen for 1 minute and then sodium carbonate (2 eq.) in 1 mL water was added. The reaction mixture was heated at reflux overnight, cooled, filtered through a plug of celite and rinsed with chloroform (5 mL). The solvent was removed in vacuo and the crude material was purified by preparative TLC (75% EtOAc/hexane) to give the appropriate compound with structure shown in the table below. Table 2. Preferable mefa-substituted biaryls

Compound Compound

Structure

Number Name

8.1.1 Ethyl 3'-((9-nitro-

5,6-dihydro-2H- imidazo[2,1 - b][1 ,3,6]oxadiazo cin-4(3H)- yl)methyl)-[1 ,1 '- biphenyl]-4- carboxylate

8.1.2 4-([1 ,1 '-Biphenyl]-

3-ylmethyl)-9- nitro-3,4,5,6- tetrahydro-2H- imidazo[2,1 - b][1 ,3,6]oxadiazo cine

8.1.3 9-Nitro-4-(3-

(pyridin-3- yl)benzyl)-3,4,5,6- tetrahydro-2H- imidazo[2,1 - b][1 ,3,6]oxadiazo cine

8.1.4 9-Nitro-4-(3-

(pyridin-4- yl)benzyl)-3,4,5,6- tetrahydro-2H- imidazo[2,1 - b][1 ,3,6]oxadiazo cine

Compound Compound

Structure

Number Name

8.1.5 4-((3'-Fluoro-[1,1'- biphenyl]-3- yl)methyl)-9-nitro-

3,4,5,6- tetrahydro-2H-

F imidazo[2,1- b][1,3,6]oxadiazo cine

8.1.6 3'-((9-Nitro-5,6- dihydro-2H- imidazo[2,1- b][1,3,6]oxadiazo cin-4(3H)-

CN yl)methyl)-[1,1'- biphenyl]-3- carbonitrile

8.1.7 4-(3-(3,5-

Dimethyl-4,5- dihydroisoxazol-

4-yl)benzyl)-9- nitro-3,4,5,6- tetrahydro-2H- imidazo[2,1- b][1,3,6]oxadiazo cine

8.1.8 4-(3-(1H-lndol-6- yl)benzyl)-9-nitro-

3,4,5,6- tetrahydro-2H- imidazo[2,1- b][1,3,6]oxadiazo cine Compound Compound

Structure

Number Name

8.1.9 fert-Butyl 4-(3-((9- nitro-5,6-dihydro-

2H-imidazo[2,1- b][1,3,6]oxadiazo cin-4(3H)- yl)methyl)phenyl)- o 5,6- dihydropyridine- 1(2H)-carboxylate

8.1.10 fert-Butyl (3'-((9- nitro-5,6-dihydro- 2H-imidazo[2,1- b][1,3,6] oxadiazocin-4(3H)- yl)methyl)-[1,1'- biphenyl]-4- ylcarbamate

8.1.11 3'-((9-Nitro-5,6- dihydro-2H- imidazo[2,1- b][1,3,6]oxadiazo cin-4(3H)- yl)methyl)-[1,1'- biphenyl]-4- carbonitrile

8.1.12 4-(3-(1-Methyl-

1 H-indol-5- yl)benzyl)-9-nitro-

3,4,5,6- tetrahydro-2H- imidazo[2,1- b][1,3,6]oxadiazo cine

8.1.13 Et0₂C

Ethyl 4-(4-((9- nitro-5,6-dihydro-

2H-imidazo[2,1- b][1,3,6]oxadiazo cin-4(3H)- yl)methyl)pyridin-

2-yl)benzoate

Compound Compound

Structure

Number Name

8.1.24 4-((6-(3-

Fluorophenyl)pyri din-2-yl)methyl)-

9-nitro-3,4,5,6- tetrahydro-2H- imidazo[2,1 - b][1 ,3,6]oxadiazo cine

General synthesis of para-substituted biaryls

Boronic acid/ pinacol ester (1 .2 eq.), 7.2.14 or 7.2.16 or 7.2.19 and

PdCI₂(dppf) (0.1 eq.) were suspended in ethanol (3 mL). The reaction was degassed with nitrogen for 1 minute and then sodium carbonate (2 eq.) in 1 mL water was added. The reaction mixture was heated at reflux overnight, cooled, filtered through a plug of celite and rinsed with chloroform (5 mL).

The solvent was removed in vacuo and the crude material was purified by preparative TLC (75% EtOAc/hexane) to give the appropriate compound with structure shown in the table below.

Table 3. Preferable para-substituted biaryls

Example

Structure Compound Name

Number

8.2.1

Ethyl 4'-((9-nitro-5,6-dihydro- 2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)- [1 ,1 '-biphenyl]-4-carboxylate

8.2.2 4-((4'-Methoxy-[1 ,1 '-biphenyl]- 4-yl)methyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine

General synthesis of biaryls from 4-(2-bromobenzyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine (7.2.15)

Boronic acid/ pinacol ester (1 .2 eq.), 4-(2-bromobenzyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine 7.2.15 and PdCI₂(dppf) (0.1 eq.) were suspended in ethanol (3 mL). The reaction was degassed with nitrogen for 1 minute and then sodium carbonate (2 eq.) in 1 mL water was added. The reaction mixture was heated at reflux overnight, cooled, filtered through a plug of celite and rinsed with chloroform (5 mL). The solvent was removed in vacuo and the crude material was purified by preparative TLC (75% EtOAc/hexane) to give the appropriate compound with structure shown in the table below.

Table 4. Preferable orffto-substituted biaryls

4'-((9-Nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)-yl) methyl)-[1 ,1 '-biphenyl]-4-carboxylic acid (8.4.1)

Method 1

To a stirring solution of ethyl 4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4-carboxylate 8.2.1 (0.5 g, 1 .15 mmol) in methanol and water was added lithium hydroxide monohydrate (0.48 g, 1 1 .5 mmol). The solution was stirred at room temperature for 16 hours. LC-MS of the mixture indicated mostly product but also some starting material. The solution was filtered and the solvent removed in vacuo. The residue was diluted with water (10 ml_) and a few drops of HCL added. The resulting precipitate was filtered and dried on the filter paper. The material was used directly in the next reaction without any further purification.

Method 2:

4-Bromobenzoic acid (0.58 g, 2.90 mmol), 9-nitro-4-(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine, 7.2.22 (1 .0 g, 2.41 mmol), sodium carbonate (0.51 g, 4.83 mmol) and PdCI2(dppf) (0.18 g, 0.241 mmol) were suspended in ethanol (20 ml) and water (10 ml). The reaction was degassed with nitrogen for 10 minutes and heated at 60 'Ό over the weekend. The mixture was filtered and the product isolated by removal of the solvent to yield a brownish solid. 4'-((9-Nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)-yl) methyl)-[1 ,1 '-biphenyl]-3-carboxylic acid (8.4.2)

3-bromobenzoic acid (0.58 g, 2.90 mmol), 9-nitro-4-(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine, 7.2.22 (1 .0 g, 2.41 mmol), sodium carbonate (0.51 g, 4.83 mmol) and PdCI2(dppf) (0.18 g, 0.241 mmol) were suspended in ethanol (20 ml) and water (10 ml). The reaction was degassed with nitrogen for 10 minutes and heated at 60 'Ό over the weekend. The mixture was filtered and the product isolated by removal of the solvent to yield a brownish solid. General procedure for the synthesis of amides from 4'-((9-Nitro-5,6- dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)-yl)

methyl)-[1 ,1 '-biphenyl]-4-carboxylic acid (8.4.1 ) or 4'-((9-Nitro-5,6- dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)-yl)

methyl)-[1 ,1 '-biphenyl]-3-carboxylic acid (8.4.2)

To a stirring solution of 8.4.1 or 8.4.2 (60.0 mg, 0.147 mmol) in DMF (2 ml_) was added CDI (47.6 mg, 0.294 mmol). The reaction was allowed to stir for 10min and the amine (1 .2 eq) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the presence of the product mass ion in both positive and negative modes. The product was isolated by preparative HPLC. Table 5. Preferable Biaryl amides

carboxamide

General procedure for the synthesis of F-substituted aza-biaryl amide derivatives from 4-((2-Bromopyridin-4-yl)methyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine (7.2.12), 4-((6- Bromopyridin-2-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1- b][1 ,3,6]oxadiazocine (7.2.18) and 4-((6-Bromopyridin-3-yl)methyl)-9- nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine (7.2.19) To a stirring solution of 4-borono-2-fluorobenzoic acid or 5-borono-2- fluorobenzoic acid (250.0mg, 1 .359 mmol) in DMF (4 ml) was added CDI (264 mg, 1 .631 mmol). The reaction was allowed to stir for 10min and the amine (0.227 ml, 2.04 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the presence of the product. Water was added to the reaction and the product was extracted with EtOAc. The solvent was removed in vacuo to yield a product which was characterized by LCMS and coupled to (7.2.12, 7.2.18 and 7.2.19) using the Suzuki coupling reaction below. General procedure for synthesis of biaryl amide derivatves

(87 mg, 0.33 mmol), (7.2.12, 7.2.18 and 7.2.19) (100.0 mg, 0.27 mmol) and PdCI2(dppf) (20 mg, 0.027 mmol) were suspended in ethanol (3 ml). The reaction was degassed with nitrogen for 10 minutes and then sodium carbonate (58mg, 0.543 mmol) in 1 ml water was added. The reaction mixture was heated at reflux overnight, cooled and filtered through a milipore filter cartridge. The solvent was removed in vacuo and the crude material was purified by prep HPLC/ TLC to yield F-substituted aza-biaryl amide derivatives.

Table 6: Preferable F-Substituted Aza-Biaryl Amide Derivatives

Example

Compound Structure Chemical Name

No.

\

2-Fluoro-N,N-dimethyl-4-(6-((9-nitro- 5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]

8.9.8

oxadiazocin-4(3H)-yl)methyl)pyridin- 2-yl)benzamide

(2-Fluoro-4-(6-((9-nitro-5,6-dihydro- 2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-

8.9.9

4(3H)-yl)methyl)pyridin-2-yl)phenyl) (pyrrolidin-1 -yl)methanone

N-Ethyl-2-fluoro-4-(6-((9-nitro-5,6- dihydro-2H-imidazo[2,1 -b][1 ,3,6]

8.9.10

oxadiazocin-4(3H)-yl)methyl)pyridin- 2-yl)benzamide

H

2-Fluoro-N-isopropyl-4-(6-((9-nitro- 5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]

8.9.11

oxadiazocin-4(3H)-yl)methyl)pyridin- 2-yl)benzamide

General procedure for the synthesis of amides from 2-(9-nitro-5,6- dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)-yl)acetic acid (7.1.7)

To a stirring solution of 2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetic acid 7.1.7 (100 mg, 0.390 mmol) in DMF(3 ml_), was added a solution of CDI in DMF (0.557 ml_, 0.429 mmol) and the mixture was left to stir for 30min at room temperature. To this solution was added (0.468 mol, 1 .2 eq.) of the amine and the mixture was left to stir overnight at room temperature. LC-MS of the crude showed evidence of the expected product. Water was added to the mixture and the product extracted using ethyl acetate, washed with saturated sodium bicarbonate solution and dried over sodium sulphate. The crude mixture was evaporated to dryness and the product was purified by preparative TLC in 100% ethyl acetate to afford the desired products 9. Table 7. Preferable A/-Meth lene Amides

h s benzohydrazide

General procedure for the synthesis of amides from 9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine hydrochloride (7.1.3)

To a stirring solution of the carboxylic acid (0.469 mmol, 1 .1 eq.) in DMF (4 ml) was added CDI (0.51 1 mmol, 1 .2 eq.). The mixture was left to stir for 30 min at room temperature. To this solution was added 9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine hydrochloride 7.1.3 (100 mg, 0.426 mmol 1 .0 eq.), and the mixture left to stir overnight at room temperature. LC-MS of the crude reaction mixture showed evidence of the expected product. Water was added to the mixture and the product extracted using ethyl acetate, washed with saturated sodium bicarbonate solution and dried over sodium sulphate. The crude mixture was evaporated to dryness and the product was purified by preparative TLC in 100% ethyl acetate to afford the desired products 10.

Table 8. Preferable direct amides

Example No. Compound Structure Chemical Name

[1 ,1 '-Biphenyl]-4-yl(9-nitro-5,6- dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-

10.1.17 yl)methanone o

3'-(9-Nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine-4- carbonyl)-[1 ,1 '-biphenyl]-4-carbonitrile (11.1.1 )

(4-cyanophenyl)boronic acid (27.8 mg, 0.189 mmol), 4-(3-bromobenzyl)-9- nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine 10.1.1 (60 mg, 0.157 mmol) and PdCI₂(dppf) (12 mg, 0.016 mmol) were suspended in ethanol (30 mL). The reaction was degassed with nitrogen for 2 minutes and then sodium carbonate (33.4 g, 0.315 mmol) in 1 mL water was added. The reaction mixture was heated at reflux overnight. A small amount of solution was filtered through a millipore filter and an LC-MS obtained. This indicated the presence of the product mass ion. The remaining solution was filtered through the millipore filter, dried over sodium sulfate and the solvent removed in vacuo to yield a reddish solid. This was suspended in EtOAc and filtered. See Table 19 for analytical data.

Benzyl 9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine-4(3H)- carboxylate (12.1.1)

To a stirring solution of 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine, HCI 7.1.3 (80.0 mg, 0.341 mmol) in water/acetonitrile

(2:1 )(3 mL) was added sodium bicarbonate (57.3 mg, 0.682 mmol). The reaction was allowed to stir for 10min and the benzyl chloroformate (0.058 mL, 0.409 mmol) was added. The solution was stirred overnight at room temperature. Water was added to the solution resulting in a white precipitate, which was filtered and identified as the desired product. See Table 19 for analytical data.

Ethyl 9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine-4(3H)- carboxylate (12.1.2)

To a stirring solution of 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine, HCI 7.1.3 (80.0 mg, 0.341 mmol) in water/acetonitrile (2:1 )(3 mL) was added sodium bicarbonate (57.3 mg, 0.682 mmol). The reaction was allowed to stir for 10 min and the ethyl chloroformate (0.04 mL, 0.409 mmol) was added. The solution was stirred overnight at room temperature. Water was added to the solution resulting in a white precipitate, which was filtered and identified as the desired product. See Table 19 for analytical data.

Examples of sulfonylurea compounds synthesised from 9-nitro- 3,4,5,6-tetrahydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocine, HCI (7.1.3)

To a stirring solution of 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine, HCI 7.1.3 (160.0 mg, 0.682 mmol) in DMF (3 mL) was added DIPEA (0.298 mL, 1 .705 mmol). The reaction was allowed to stir for 10min and the sulfonyl isocyanate (1 .5eq) was added. The solution was stirred overnight at room temperature. The products were isolated using the semi preparative-HPLC. See Table 19 for analytical data.

Examples of urea compounds synthesised from 9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine, HCI (7.1.3)

To a stirring solution of 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine, HCI 7.1.3 (160.0 mg, 0.682 mmol) in DMF (3 mL) was added DIPEA (0.298 mL, 1 .705 mmol). The reaction was allowed to stir for 10min and the isocyanate (1 .5eq) was added. The solution was stirred overnight at room temperature. The products were isolated using the semi preparative-HPLC.

Table 10. Preferable Ureas

Example

Compound Structure Chemical Name No.

H 9-Nitro-N-(p-tolyl)-5,6-dihydro-2H-

13.2.1 imidazo[2,1 -b][1 ,3,6]oxadiazocine- 4(3H)-carboxamide

N-(4-Methoxyphenyl)-9-nitro-5,6-

13.2.2 dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine-4(3H)-carboxamide

O ^L oMe Example

Compound Structure Chemical Name No.

N-(4-Cyanophenyl)-9-nitro-5,6-

13.2.3 dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine-4(3H)-carboxamide

N-(4-Fluorophenyl)-9-nitro-5,6-

13.2.4 dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine-4(3H)-carboxamide

N-(4-Chlorophenyl)-9-nitro-5,6-

13.2.5 dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine-4(3H)-carboxamide

N-Benzyl-9-nitro-5,6-dihydro-2H-

13.2.6 imidazo[2,1 -b][1 ,3,6]oxadiazocine-

4(3H)-carboxamide

o

Examples of sulfonamide compounds synthesised from 9-nitro- 3,4,5,6-tetrahydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocine, HCI (7.1.3)

To a stirring solution of 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine, HCI, 7.1.3 (80.0mg, 0.341 mmol) in DMF (3 ml) was added DIPEA (0.18 ml, 1 .023 mmol). The reaction was allowed to stir for

10min and the sulfonyl chloride (1 .2eq) was added. The solution was stirred overnight at room temperature. Water was added and the resulting precipitate filtered.

Table 11. Preferable Sulfonamides

4-(2-Chloropyrimidin-4-yl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine (15.1.1)

To a mixture of 2,4-dichloropyrimidine (3.81 g, 25.6 mmol) and 9-nitro- 3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine HCI, 7.1.3 (3 g, 12.8 mmol) in 300 ml_ of ethanol DIPEA (22.3 ml_, 128 mmol) was added. The reaction was allowed to stir on the ice-bath for 5 minutes and was refluxed at 75-80 ° overnight. After cooling to 25 ° , the reaction was filtered to yield 4-(2-chloropyrimidin-4-yl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6] oxadiazocine (2.3 g). The rest of the solution was evaporated to reduce the amount of ethanol to 20ml and the mixture was left to stand in an ice bath more solid was obtained (0.56 g). Combined mass 2.86 g, 9.21 mmol, 72 %). See Table 19 for analytical data.

Examples of pyrimidine compounds synthesized from 4-(2- chloropyrimidin-4-yl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine (15.1.1)

To a mixture of (100 mg 0.32 mmol) 4-(2-chloropyrimidin-4-yl)-9-nitro- 3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine and 3 eq of amine in 1 ml_ of ethylene glycol, (0.225 ml , 1 .28 mmol) DIPEA was added. The mixture was heated at 130 'Ό for 26 h. The mixture was cooled to ambient temperature and 1 ml of methanol added. The reaction was purified using prep TLC and further purified with prep HPLC to yield final products.

Table 12. Preferable Pyrimidine derivatives

General procedure for the synthesis of amides from 4-((9-nitro-5,6- dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzoic

acid (7.2.21 )

To a stirring solution of 4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzoic acid (80 mg, 0.241 mmol) in DMF(4 ml), was added CDI (43 mg, 0.265 mmol) and the mixture left to stir for 30min at room temperature. To this solution was added (0.265 mmol, 1 .1 eq.) of amine and the mixture left to stir overnight at room temperature. Water was added to the mixture and the product extracted using ethyl acetate, washed with saturated sodium bicarbonate solution and dried over sodium sulphate. The crude mixture was evaporated to dryness and the product was purified by preparative TLC in 100% ethyl acetate to afford the desired products 16.

Table 13. Preferable Benzylamides

Example

Compound Structure Chemical Name No.

16.1.1

N,N-Dimethyl-4-((9-nitro-5,6- dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl) benzamide

16.1.2

N-Ethyl-4-((9-nitro-5,6-dihydro- 2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl) benzamide

16.1.3

N-Butyl-4-((9-nitro-5,6-dihydro- 2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl) benzamide

Example Compound Structure

Chemical Name No.

16.1.17

4-((9-Nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]

oxadiazocin-4(3H)-yl)methyl)-N-

(4-(trifluoromethoxy)benzyl) benzamide

16.1.18 4-((9-Nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]

oxadiazocin-4(3H)-yl)methyl)-N-

(3-(trifluoromethoxy)benzyl) benzamide

16.1.19

N-(4-Methoxybenzyl)-4-((9-nitro- 5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)benzamide

16.1.20 4-((9-Nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]

oxadiazocin-4(3H)-yl)methyl)-N-

(4-(trifluoromethyl)phenethyl) benzamide

16.1.21 4-((9-Nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]

oxadiazocin-4(3H)-yl)methyl)-N-

(3-(trifluoromethyl)phenethyl) benzamide

16.1.22

Morpholino(4-((9-nitro-5,6- dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)phenyl)methanone

16.1.23 o N-(3-Morpholinopropyl)-4-((9- nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]

oxadiazocin-4(3H)-yl)methyl) benzamide

16.1.24 (4-(2-Methoxyethyl)piperazin-1 - yl)(4-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin -4(3H)-yl)methyl)phenyl) methanone

Example

Compound Structure Chemical Name No.

16.2.3 4-((9-Nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)-N-

(3-(trifluoromethyl)isoxazol-5- yl)benzamide

16.3 N methylated amides

A solution of the respective amide (0.168 mmol) in DMF (2 ml) was treated with sodium hydride 60% (20.2 mg, 0.505 mmol). Methyl iodide (1 .683 mmol) was added and the mixture was warmed at 40^ overnight. The reaction was monitored by LC-MS. On completion, water was added to the reaction and the solution was extracted with EtOAc. The organic layer was dried over sodium sulfate and the solvent removed in vacuo. The respective products were isolated by column chromatography.

Table 14: Nmethylated amides

General procedure for the synthesis of pyridyl amides (16.4.1 -3) from 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine hydrochloride (7.1.3)

A solution of respective chloride (0.324 mmol) in acetone (15 ml) was treated with sodium iodide (0.971 mmol, 3eq). The mixture was refluxed for an hour. Potassium carbonate (0.971 mmol, 3eq) was added to the reaction. 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine hydrochloride 7.1.3 (0.324 mmol, 1 eq) was dissolved in 15 ml acetone and added to the mixture and the reaction was stirred at 55 'Ό for 16 hrs. The reaction was filtered and the solvent evaporated. The residue was purified by column chromatography to yield the product as a white solid.

Table 15. Preferable pyridyl amides

General procedure for the synthesis of N-methylated biaryls from 4-(1- (6-bromopyridin-3-yl)ethyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1- b][1 ,3,6]oxadiazocine (7.2.23)

Boronic acid (1 .2eq), 4-(1 -(6-bromopyridin-3-yl)ethyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine (7.2.23) (100.0 mg, 0.26

mmol) and PdCI2(dppf) (0.1 eq) were suspended in ethanol (3 ml). The

reaction was degassed with nitrogen for 10 minutes and then sodium

carbonate (55mg, 0.52 mmol) in 1 ml water was added. The reaction

mixture was heated at reflux overnight, cooled and filtered through a

milipore filter cartridge. The solvent was removed in vacuo and the crude

material was purified by prep HPLC

Table 16. Preferable N-methylated biaryls

Ethyl 4-(5-(1 -(9-nitro-5,6-dihydro -2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)ethyl) pyridin-2-yl)benzoate

4-(5-(1 -(9-Nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]

oxadiazocin-4(3H)-yl)ethyl) pyridin-2-yl)benzonitrile

9-Nitro-4-(1 -(6-(4- (trifluoromethyl)phenyl) pyridin- 3-yl)ethyl)-3,4,5,6-tetrahydro- 2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine

F

4-(1 -(6-(3-Fluorophenyl)pyridin- 3-yl)ethyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine

General procedure for the synthesis of reduced amides from benzylamides

A 2M solution of BH₃.SMe₂ in THF (4eq) was added dropwise to a solution benzylamide (1 eq) in dry THF (2 ml). The mixture was stirred at reflux for 9 hours under nitrogen. MeOH (1 ml) was slowly added to destroy excess BH₃. The crude LCMS spectrum had three peaks one for the starting material, product and a peak with a product mass minus two protons which was suspected to belong to the product structure with the reduced imidazole double bond (this will be further investigated later). The crude was purified using prep HPLC Table 17. Preferable Reduced Amides

N-(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)phenyl)-4-(trifluoromethoxy)benzamide (19.1.1)

A solution of 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxa- diazocine hydrochloride 7.1.3 (0.38 g, 1 .62 mmol) in DCE (20 ml) was treated with N-(4-formylphenyl)-4-(trifluoromethoxy)benzamide (0.50 g, 1 .62 mmol) followed by sodium triacetoxyborohydride (1 .72 g, 8.10 mmol) and acetic acid (0.093 ml) and the mixture was left to stir at room temperature for 2 hrs. The crude was evapourated to dryness and water was added to the mixture. The resulting precipitate was filtered. The material was purified by column chromatography to yield the product as a yellowish oil which solidified on standing. LCMS and NMR confirmed this material to be the product, N-(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)phenyl)-4-(trifluoromethoxy) benzamide. 1 H NMR (400MHz CDCI₃) δ ppm 2.72 (t, 2H); 2.90 (t, 2H); 3.68 (s, 2H); 4.09-4.10 (m, 4H); 6.96 (d, 2H); 7.53 (d, 2H); 7.62 (d, 2H); 8.06 (d, 2H); 8.09 (s, 1 H); 10.34 (s, 1 H).

N-(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)phenyl)-3-(trif luoromethoxy)benzamide (19.1.2)

A solution of 9-nitro-3,4,5,6- tetrahydro-2H-imidazo [2,1 -b][1 ,3,6] oxa- diazocine hydrochloride 7.1.3 (0.65 g, 2.77 mmol) in DCE (20 ml) was treated with N-(4-formylphenyl)-3-(trifluoromethoxy)benzamide (0.86 g, 2.77 mmol) followed by sodium triacetoxyborohydride (2.94 g, 13.9 mmol) and acetic acid (0.16 ml) and the mixture was left to stir at room temperature for 2 hrs. The crude was evapourated to dryness and water was added to the mixture. The precipitate was filtered. LC-MS showed this material to be slightly impure. The material was purified by column chromatography to yield the product as a yellow solid. LCMS and NMR confirmed this material to be the product, N-(4-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)phenyl)-4-(trifluoro- methoxy)benzamide. 1 H NMR (400MHz CDCI₃) δ ppm 2.75 (t, 2H); 2.91 (t, 2H); 3.69 (s, 2H); 4.10-4.12 (m, 4H); 6.99 (d, 2H); 7.59-7.71 (m, 4H); 8.00 (d, 1 H); 8.07 (s, 1 H); 10.33 (s, 1 H). tert-Butyl 4-((9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)piperidine-1-carboxylate (20.1.1)

A solution of 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6] oxa- diazocine hydrochloride (500 mg, 2.1 3 mmol) in DCE (10 ml) was treated with tert-butyl 4-oxopiperidine-1 -carboxylate (1 .3 g, 6.39 mmol) followed by Sodium triacetoxyborohydride (2.3 g, 10.65 mmol) and acetic acid (1 ml) and the mixture was left to stir at room temperature for 16 h. The mixture was evaporated to dryness and water was added, the product precipitated as a pale yellow solid. LC-MS confirmed the structure of the product t-butyl 4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)piperidine-1 -carboxylate (500 mg, 61 %). See Table 19 for analytical data.

9-nitro-4-(piperidin-4-yl)-3,4,5,6-tetrahydro-2H-imidazo[2,1-b][1 ,3,6] oxadiazocine (20.1.2)

To a stirring solution of TFA (10 ml, 131 mmol) in water (2ml) was added tert-butyl 4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)piperidine-1 -carboxylate (5.0 g, 13.1 1 mmol). The reaction was allowed to stir for 2 hrs at room temperature. The solvent was evaporated to dryness diluted with toluene and the volume of the solution reduced in vacuo. The product was obtained as a thick orange oil. LC-MS confirmed the product 9-nitro-4-(piperidin-4-yl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine (2.9 g, 79 %). See Table 19 for analytical data.

(4-(9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)- yl)piperidin-1-yl)(4-(trifluoromethoxy)phenyl)methanone (20.1.3)

To a stirring solution of 4-(trifluoromethoxy)benzoic acid (300 mg, 1 .455 mmol) in DMF(5 ml), was added CDI (260 mg, 1 .601 mmol) and the mixture was left to stir for 30min at room temperature. To this solution was added (246 mg, 0.873 mmol) of the amine 20.1.2 and the mixture was left to stir overnight at room temperature. LC-MS of the crude showed evidence of product. The mixture was purified usind prep-TLC (EtOAc 100%) and (4-(9- nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)piperidin-1 - yl)(4-(trifluoromethoxy)phenyl)methanone was isolated. See Table 19 for analytical data.

(4-(9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)- yl)piperidin-1-yl)(4-(trifluoromethyl)phenyl)methanone (20.1.4)

To a stirring solution of 4-(trifluoromethyl)benzoic acid (61 .4 mg, 0.323 mmol) in DMF (2 ml) was added HATU (123 mg, 0.323 mmol) and DIPEA (0.17 ml_, 0.969 mmol). The reaction was allowed to stir for 10 min and the 9-nitro-4-(piperidin-4-yl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine 20.1.2 (100 mg, 0.355 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the presence of the product. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to yield an orange oil. The product was isolated using Prep TLC. The product, (4-(9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)piperidin-1 -yl)(4- (trifluoromethyl)phenyl)methanone (64.0 mg, 44 %) was confirmed by LC- MS. See Table 19 for analytical data. (4-(9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)- yl)piperidin-1-yl)(3-(trifluoromethyl)phenyl)methanone (20.1.5)

Experimental tert-butyl 2-(4-(9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin- -yl)piperidin-1-yl)acetate (20.1.6)

9-Nitro-4-(piperidin-4-yl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine 20.1.2 (1 .95 g, 6.93 mmol) was taken up in acetonitrile (30 mL) and heated to 60°C to dissolve all material. Potassium tert-butoxide (1 .01 g, 9 mmol) was added in portions over 10 minutes, then tert-butyl bromoacetate (1 .2 mL, 8.1 mmol) was added via syringe. After 1 hour at 60 °C, LC-MS indicated conversion into product. The solvent was removed in vacuo, and the oily residue taken up in ethyl acetate (30 mL). The solids were filtered and washed with ethyl acetate (30 mL); the filtrate was evaporated to dryness then purified by chromatography. The product was obtained as a brown solid (550 mg, 20%). See Table 19 for analytical data.

2-(4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)piperidin-1-yl)acetic acid (20.1.7)

tert-Butyl 2-(4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)piperidin-1 -yl)acetate 20.1.6 (0.55 g, 1 .4 mmol) was dissolved in a 1 :3 water:TFA mixture (12 mL); the solution was heated at 55 'Ό for 1 h, after which LC-MS indicated consumption of starting material. The solvent was removed in vacuo, then the residue continually azeotroped with toluene to afford the acid 20.1.7 as a brown solid (0.45 g, 57%). See Table 19 for analytical data.

4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)-N- -(trifluoromethoxy)phenyl)piperidine-1-carboxamide (20.1.8)

To a stirring solution of 9-nitro-4-(piperidin-4-yl)-3,4,5,6-tetrahydro-2H- imidazo [2,1 -b][1 ,3,6]oxadiazocine 20.1.2 (l OO.Omg, 0.355 mmol) in DMF (2 ml) was added DIPEA (0.186 ml, 1 .066 mmol). The reaction was allowed to stir for 10min and the 1 -isocyanato-4-(trifluoromethoxy)benzene (0.064 ml, 0.427 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the product mass ion. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to yield an orange oil. The product was isolated using prep TLC. The product was confirmed by LC-MS. See Table 19 for analytical data. tert-Butyl 4-((9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin- -yl)methyl)piperidine-1-carboxylate (21.1.1)

A solution of 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6] oxadia- zocine hydrochloride (2.00 g, 8.52 mmol) in DCE (30 ml) was treated with tert-butyl 4-oxopiperidine-1 -carboxylate (1 .82 g, 8.52mmol) followed by sodium triacetoxyborohydride (9.03 g, 42.6 mmol) and acetic acid (0.49 ml) and the mixture was left to stir at room temperature for 16 h. The mixture was evaporated to dryness and water was added, the product was extracted with DCM as an off-white solid. LC-MS confirmed the structure of the product tert-butyl 4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)piperidine-1 -carboxylate (2.75 g, 69 %). See Table 19 for analytical data.

9-nitro-4-(piperidin-4-ylmethyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 - )

To a stirring solution of TFA (1 1 .0 ml, 143 mmol) in water (1 .0 ml) was added tert-butyl 4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadia- zocin-4(3H)-yl)methyl)piperidine-1 -carboxylate (2.75 g, 6.93 mmol). The reaction was allowed to stir overnight at room temperature. LC-MS of the reaction indicated complete conversion to product. The solvent was evaporated to dryness diluted with toluene and the volume of the solution reduced in vacuo. The product was obtained as a white solid. LC-MS confirmed the product 9-nitro-4-(piperidin-4-ylmethyl)-3,4,5,6-tetrahydro- 2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine (2.08 g, 100 %). See Table 19 for analytical data.

(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)piperidin-1-yl)(4-(trifluoromethoxy)phenyl)methanone

(21.1.3)

To a stirring solution of 4-(trifluoromethoxy)benzoic acid (69.8 mg, 0.339 mmol) in DMF (2 ml) was added HATU (129 mg, 0.339 mmol) and DIPEA (0.177 mL,1 .02 mmol). The reaction was allowed to stir for 10 min and the 9-nitro-4-(piperidin-4-ylmethyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine 21.1.2 (0.10 g, 0.339 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the presence of the product. Water was added and the precipitate was filtered to yield a brownish solid. This was purified by column chromatography to yield the product, (4-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)piperidin-1 -yl)(4- (trifluoromethoxy)phenyl)methanone, as an off-white solid. The product was confirmed by LC-MS. See Table 19 for analytical data.

(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)piperidin-1-yl)(3-(trifluoromethoxy)phenyl)methanone

To a stirring solution of 3-(trifluoromethoxy)benzoic acid (69.8 mg, 0.339 mmol) in DMF (2 ml) was added HATU (129 mg, 0.339 mmol) and DIPEA (0.177 ml_,1 .02 mmol). The reaction was allowed to stir for 10 min and the 9-nitro-4-(piperidin-4-ylmethyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine 21.1.2 (0.10 g, 0.339 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the presence of the product. Water was added and the precipitate was filtered to yield a brownish solid. This was purified by column chromatography to yield the product, (4-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)piperidin-1 -yl)(3- (trifluoromethoxy)phenyl)methanone as an off-white solid. The product was confirmed by LC-MS. See Table 19 for analytical data.

4-nitrophenyl 4-((9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadia- zocin-4(3H)-yl)methyl)piperidine-1-carboxylate (21.1.5)

stirring solution of 9-nitro-4-(piperidin-4-ylmethyl)-3,4,5,6-tetrahydro- idazo[2,1 -b][1 ,3,6]oxadiazocine 21.1.2 (300. Omg, 1 .016 mmol) in water/acetonitrile (2:1 )(6 ml) was added sodium bicarbonate (256 mg, 3.05 mmol). The reaction was allowed to stir for 10min and the 4-nitrophenyl carbonochloridate (246 mg, 1 .219 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the product mass ion. Water was added to the solution resulting in a whitish precipitate. This was filtered and another LC-MS obtained which confirmed the product, 4-nitrophenyl 4-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)piperidine-1 -carboxylate (260 mg, 56 %). See Table 19 for analytical data.

4-((9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1 -carboxamide

To a stirring solution of 9-nitro-4-(piperidin-4-ylmethyl)-3,4,5,6-tetrahydro- 2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine 21.1.2 (l OO.Omg, 0.339 mmol) in DMF (2 ml) was added DIPEA (0.177 ml, 1 .016 mmol). The reaction was allowed to stir for 10min and the 1 -isocyanato-4-(trifluoromethoxy)benzene (0.061 ml, 0.406 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the product mass ion. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to yield an orange oil. The product was isolated using prep TLC. The product, 4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethoxy) phenyl)piperidine-1 -carboxamide, was confirmed by LC-MS. See Table 19 for analytical data. tert-Butyl (4-(9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin- -yl)cyclohexyl)carbamate (22.1.1)

A solution of 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadia- zocine hydrochloride (1 .00 g, 4.26 mmol) in DCE (20 ml) was treated with tert-butyl (4-oxocyclohexyl)carbamate (909 mg, 4.26 mmol) followed by sodium triacetoxyborohydride (4.52 g, 21 .3 mmol) and acetic acid (0.244 ml) and the mixture was left to stir at room temperature overnight. LC-MS of the crude showed evidence of product. The product was isolated using column chromatography to yield the product, tert-Butyl (4-(9-nitro-5,6- dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)cyclohexyl)carbamate as a yellow solid (1 .42 g, 84 %). Product confirmed by LC-MS. See Table 19 for analytical data.

4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)cyclohexanamine (22.1.2)

tert-butyl (4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)cyclohexyl)carbamate (1 .50 g, 3.79 mmol) was treated with TFA (15.0ml, 195 mmol). The mixture was left to stir at 55 ^<C for 2hrs. LC-MS of the reaction mixture showed that the reaction had gone to completion. The solvent was removed in vacuo and the residue azeotroped five times with toluene to remove any residual TFA and water. The residue solidified on standing. This was confirmed by LC-MS to be the product, 4-(9-nitro-5,6- dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)cyclohexanamine (1 .01 g, 90 %). See Table 19 for analytical data. N-(4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)cyclohexyl)-4-(trifluoromethoxy)benzamide (22.1.3)

To a stirring solution of 4-(trifluoromethoxy)benzoic acid (87 mg, 0.422 mmol) in DMF (2 ml) was added HATU (160 mg, 0.422 mmol) and DIPEA (0.22 ml_, 1 .02 mmol). The reaction was allowed to stir for 10 min and the 4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)cyclohexanamine 22.1.2 (126 mg, 0.422 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the presence of the product. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to yield an orange oil. The product was isolated using column chromatography. The product, N-(4-(9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)cyclohexyl)-4- (trifluoromethoxy)benzamide (75.0 mg, 36%), was confirmed by LC-MS. See Table 19 for analytical data.

N-(4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)cyclohexyl)-3-(trifluoromethoxy)benzamide (22.1.4)

To a stirring solution of 3-(trifluoromethoxy)benzoic acid (87 mg, 0.422 mmol) in DMF (2 ml) was added HATU (160 mg, 0.422 mmol) and DIPEA (0.22 ml_, 1 .02 mmol). The reaction was allowed to stir for 10 min and the 4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)cyclohexanamine 22.1.2 (126 mg, 0.422 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the presence of the product. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to yield an orange oil. The product was isolated using column chromatography. The product, N-(4-(9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)cyclohexyl)-3- (trifluoromethoxy)benzamide (49.0 mg, 24 %) was confirmed by LC-MS. See Table 19 for analytical data.

N-(4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)cyclohexyl)-2-(4-(trifluoromethoxy)phenyl)acetamide (22.1.5)

To a stirring solution of 2-(4-(trifluoromethoxy)phenyl)acetic acid (75 mg, 0.341 mmol) in DMF (2 ml) was added HATU (130 mg, 0.341 mmol) and DIPEA (0.18 mL, 1 .02 mmol). The reaction was allowed to stir for 10 min and the 4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)cyclohexanamine 22.1.2 (101 mg, 0.341 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the presence of the product. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to yield an orange oil. The product was isolated using column chromatography. The product, N-(4-(9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)cyclohexyl)-2-(4- (trifluoromethoxy) phenyl)acetamide (53.0 mg, 31 %) was confirmed by LC- MS. See Table 19 for analytical data.

1 -(4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)cyclohexyl)-3-(4-(trifluoromethoxy)phenyl)urea (22.1.6)

To a stirring solution of 4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)cyclohexanamine (l OO.Omg, 0.339 mmol) in DMF (2 ml) was added DIPEA (0.177 ml, 1 .016 mmol). The reaction was allowed to stir for 10min and the 1 -isocyanato-4-(trifluoromethoxy)benzene (0.061 ml, 0.406 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the product mass ion. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to yield a yellowish oil. The product was isolated using column chromatography. The product, 1 -(4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)cyclohexyl)-3-(4-

(trifluoromethoxy)phenyl)urea (31 .0 mg, 18%) was confirmed by LC-MS. See Table 19 for analytical data. tert-butyl 3-((9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin- -yl)methyl)azetidine-1 -carboxylate (23.1.1)

A suspension of 9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine (1 .17 g, 5.9 mmol) was stirred in DCE (20 mL), then tert-butyl 3-formylazetidine-1 -carboxylate (1 .09 g, 5.9 mmol) in DCE (5 mL) added via syringe and stirring continued for 2 h. Sodium cyanoborohydride (2.5 g, 1 1 .8 mmol) was added and stirring continued for 48 h. The reaction was diluted with DCM (30 mL) and quenched with 1 N NaOH (20 mL). The organic phase was dried (sodium sulfate), evaporated to dryness and purified by chromatography, Solvent evaporation and subsequent drying afforded the product, tert-butyl 3-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)azetidine-1 -carboxylate as a pale yellow oil (1 .85 g, 85%). See Table 19 for analytical data. 4-(azetidin-3-ylmethyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - 1 ,3,6]oxadiazocine (23.1.2)

4-(azetidin-3-ylmethyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocine 23.1.1 (1 .6 g, 4.35 mmol) was taken up in TFA (15 ml_) and stirred overnight. LC-MS indicated complete conversion of starting materials into product. The acid was removed in vacuo, co-evaporating with toluene. The residue was taken up in methanol (20 ml_) and basified with Amberlyst-21 . The resins were filtered and the filtrate evaporated to dryness to afford an pale yellow oil that forms a yellow solid on standing (1 .29 g, 93%). See Table 19 for analytical data.

(3-((9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)azetidin-1-yl)(4-(trifluoromethoxy)phenyl)methanone (23.1.3)

To a stirring solution of 4-(trifluoromethyl)benzoic acid (100 mg, 0.485 mmol) in DMF (2 ml) was added HATU (184 mg, 0.485 mmol) and DIPEA (0.25 ml_, 1 .45 mmol). The reaction was allowed to stir for 10 min and the 4-(azetidin-3-ylmethyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine 23.1.2 (143 mg, 0.534 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the presence of the product. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to yield an orange oil. The product was isolated using Prep TLC. The product, (3-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl) azetidin-1 -yl)(4- (trifluoromethoxy)phenyl)methanone (67.0 mg, 30 %) was confirmed by LC- MS. See Table 19 for analytical data.

(3-((9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)azetidin-1-yl)(3-(trifluoromethoxy)phenyl)methanone (23.1.4)

To a stirring solution of 4-(trifluoromethyl)benzoic acid (100 mg, 0.485 mmol) in DMF (2 ml) was added HATU (184 mg, 0.485 mmol) and DIPEA (0.25 ml_, 1 .45 mmol). The reaction was allowed to stir for 10 min and the 4-(azetidin-3-ylmethyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine 23.1.2 (143 mg, 0.534 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the presence of the product. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to yield an orange oil. The product was isolated using Prep TLC. The product, (3-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl) azetidin-1 -yl)(3-

(trifluoromethoxy)phenyl)methanone (52.0 mg, 23 %) was confirmed by LC- MS. See Table 19 for analytical data.

3-((9-nitro-5,6-dihydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethoxy)phenyl)azetidine-1-carboxamide

To a stirring solution of 4-(azetidin-3-ylmethyl)-9-nitro-3,4,5,6-tetrahydro- 2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine 23.1.2 (l OO.Omg, 0.374 mmol) in DMF (2 ml) was added DIPEA (0.196 ml, 1 .122 mmol). The reaction was allowed to stir for 10min and the 1 -isocyanato-4-(trifluoromethoxy)benzene (0.068 ml, 0.449 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the product mass ion. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to yield an orange oil. The product was isolated using prep TLC. The product, 3-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethoxy) phenyl)azetidine-1 -carboxamide (51 .0 mg, 29 %) was confirmed by LC-MS. See Table 19 for analytical data.

9-nitro-4-((5-(4-(trifluoromethoxy)phenyl)-1 ,3,4-thiadiazol-2-yl)methyl)- -tetrahydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocine (24.1.1)

In a sealed tube, a solution of of N'-(2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetyl)-4-(trifluoromethoxy)benzohydrazide 9.2.1 (20 mg, 0.044 mmol) and Lawesson's reagent (19 mg, 0.048 mmol) was heated to reflux for 3 h and then allowed to cool to room temperature. The solvent was evaporated at reduced pressure and the residue purified by preparative HPLC to provide the thiadiazole 24.1.1 (15 mg, 75%). See Table 19 for analytical data.

9-nitro-4-((5-(4-(trifluoromethoxy)phenyl)-1 ,3,4-oxadiazol-2-yl)methyl)- -tetrahydro-2H-imidazo[2,1-b][1 ,3,6]oxadiazocine (24.2.1)

In a sealed tube, a suspension of N'-(2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetyl)-4-(trifluoromethoxy)benzohydrazide 9.2.1 (100 mg, 0.218 mmol) and triethylamine (80 uL, 0.574 mmol) at ambient temperature, then tosyl chloride (50 mg, 0.262 mmol) in one portion. The resulting mixture was stirred an additional 12 h. The clear solution was diluted with DCM (15 ml_), washed with water (2 x 15 ml_), dried and evaporated to dryness. The residue was purified by chromatography. 9-Nitro-4-((5-(4-(trifluoromethoxy)phenyl)-1 ,3,4-oxadiazol- 2-yl)methyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine was obtained as a white powder (85 mg, 88%). See Table 19 for analytical data.

The invention also provides for Formula I which is additionally substituted as set out in Formula la bel

R2 is an alkyl, preferably CH_3.

Examples of Formula la

R? R₂

'NH,

The process comprises the steps of substituting the N atom of an amino alcohol reactant via alkylation or reductive amination with an X-Y group using either ^{γ' "}LG or ^{Y "}° (X=CH), wherein LG represents a leaving group and X and Y are as defined above, to produce a tertiary amine; reacting the tertiary amine with 2,4-dinitroimidazole under Mitsunobu reaction conditions to produce an intermediate which is then cyclized to produce the compound of Formula (I). In a preferred embodiment X is not C=0.

In the schematic representation above step (i) represents K₂C0₃, the bromide and Ethanol/Water (4:1 ) and the reaction is carried out at reflux for about 24 hours. Step (ii) Represents Nal, K₂C0₃ and acetone and the reaction is carried out at reflux for about 24 hours. Step (iii) Represents sodium triacetoxyborohydride, DCE and the reaction is carried out at room temperature for 18 hours. Step (iv) Represents PPh₃, DIAD and THF and the reaction is carried out for about 18 h. Step (iv) Represents TBAF and the reactions is carried out at room temperature for about 2 hours.

Specific examples:

2-((2-((tert-Butyldimethylsilyl)oxy)ethyl)amino)-2-methylpropan-1 -ol (25.1.1)

A solution of (2-bromoethoxy)(tert-butyl)dimethylsilane (15.0 g, 62.7 mmol), potassium carbonate (26.0 g, 188 mmol) and 2-amino-2-methylpropan-1 -ol (27.9 g, 314 mmol) in ethanohwater was heated at 70 ^ for 48 hours. The solution was cooled and filtered, the solvent removed in vacuo and the residue diluted with water and extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to yield a clear oil. This material was purified using column chromatography to yield the product as a clear oil that soidified on standing. Product confirmed by NMR. 1 H NMR (400MHz CDCI₃) δ_Η ppm 0.02 (s, 6H); 0.84 (s, 9H); 1 .04 (s, 6H); 2.55 (t, 2H); 3.21 (s, 2H); 3.63 (t, 2H) tert-Butyl 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(1 -hydroxy-2- methylpropan-2-yl)amino)acetate (25.2.1)

A solution of tert-butyl 2-bromoacetate (0.60 mL, 4.06 mmol) in acetone (60 ml) was treated with sodium iodide (1 .83 g, 12.2 mmol). The mixture was refluxed for an hour. Potassium carbonate (1 .68 g, 12.2 mmol) was added to the reaction. 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2- methylpropan-1 -ol (0.99 g, 4.06 mmol) was added to the mixture and the reaction was stirred at 50 °C for 48 hrs. The mixture was filtered and the solvent removed in vacuo to yield a clear oil. The suspected product was isolated by column chromatography to yield a clear oil. NMR of this material indicated the product. 1 H NMR (400MHz CDCI₃) δ_Η ppm 0.00 (s, 6H); 0.83 (s, 9H); 1 .00 (s, 6H); 1 .04 (s, 2H); 1 .40 (s, 9H); 2.73 (t, 2H); 3.16 (t, 2H); 3.30 (s, 2H); 3.38 (s, 1 H); 3.56 (t, 2H). tert-Butyl 4-(((2-((tert-butyldimethylsilyl)oxy)ethyl)(1 -hydroxy-2- methylpropan-2-yl)amino)methyl)benzoate (25.2.2)

A solution of tert-butyl 4-(chloromethyl)benzoate (3.02 g, 13.34 mmol) in acetone (100 ml) was treated with sodium iodide (5.45 g, 36.4 mmol). The mixture was refluxed for an hour. Potassium carbonate (5.03 g, 36.4 mmol) was added to the reaction. 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)- 2-methylpropan-1 -ol (3.00 g, 12.1 mmol) was added to the mixture and the reaction was stirred at 50°C for 18 hrs. The mixture was filtered and the solvent removed in vacuo to yield a clear oil. The suspected product was isolated using column chromatography to yield a clear oil. LC-MS confirmed the product. See Table 19 fro analytical data. tert-Butyl 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(1 -(2,4-dinitro-1 H- imidazol-1 -yl)-2-methylpropan-2-yl)amino)acetate (25.3.1)

To a stirring solution of tnphenylphosphine (0.58 g, 2.21 mmol) in dry THF (30 ml) was added DIAD (0.43 ml, 2.21 mmol) dropwise under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2, 4-dinitro-1 /--imidazole (0.35 g, 2.21 mmol). The reaction mixture was stirred for a further 20 minutes and tert- butyl 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(1 -hydroxy-2-methylpropan-2- yl)amino) acetate (0.80 g, 2.21 mmol) in dry THF (20 ml) was added and the reaction mixture stirred for 18 hours at room temperature. LC-MS (neg mode) of the reaction mixture indicated the product. The solvent was evaporated in vacuo and the product isolated by column chromatography to yield a yellow oil. This was confirmed to be the product by LC-MS. See Table 19 fro analytical data. tert-Butyl 4-(((2-((tert-butyldimethylsilyl)oxy)ethyl)(1 -(2,4-dinitro-1 H- imidazol-1 -yl)-2-methylpropan-2-yl)amino)methyl)benzoate (25.3.2)

To a stirring solution of tnphenylphosphine (1 .65 g, 6.31 mmol) in dry THF (100 ml) was added DIAD (1 .23 ml, 6.31 mmol) dropwise under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 15 minutes followed by addition of 2, 4-dinitro-1 /-/-imidazole (0.99 g, 6.31 mmol). The reaction mixture was stirred for a further 20 minutes and tert- butyl 4-(((2-((tert-butyldimethylsilyl)oxy)ethyl)(1 -hydroxy-2-methylpropan-2- yl)amino) methyl)benzoate (2.76 g, 6.31 mmol) in dry THF (50 ml) was added and the reaction mixture stirred for 18 hours at room temperature. LC-MS of the crude indicated the product. The solvent was removed in vacuo and the product isolated by column chromatography to yield a yellow oil. LC-MS confirmed the product. See Table 19 fro analytical data. tert-Butyl 2-(5,5-dimethyl-9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)acetate (25.4.1)

To a stirring solution of 1 N TBAF (2.23 ml, 2.23 mmol) in dry THF (50 ml) was added crude tert-butyl 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(1 -(2,4- dinitro-1 H-imidazol-1 -yl)-2-methylpropan-2-yl)amino)acetate (0.56 g, 1 .12 mmol) dropwise. On addition the solution immediately turned from yellow to blue. The reaction was allowed to stir overnight at room temperature. LCMS of the crude reaction mixture indicated the presence of the product. The product was isolated by column chromatography to yield the suspected product as a yellow oil. LC-MS confirmed the product. See Table 19 fro analytical data. tert-butyl 4-((5,5-Dimethyl-9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)benzoate (25.4.2)

To a stirring solution of 1 N TBAF (4.2 ml, 4.15 mmol) in dry THF (150 ml) was added crude tert-butyl 4-(((2-((tert-butyldimethylsilyl)oxy)ethyl)(1 -(2,4- dinitro-1 H-imidazol-1 -yl)-2-methylpropan-2-yl)amino)methyl)benzoate (1 .20 g, 2.08 mmol) drop wise. On addition the solution immediately turned from yellow to blue. The reaction was allowed to stir overnight at room temperature. LCMS of the crude reaction mixture indicated the presence of the product. The product was isolated using column chromatography. LCMS confirmed the product. See Table 19 fro analytical data.

2-(5,5-Dimethyl-9-nitro-5,6-dihydro-2H-imidazo[2,1- yl)acetic acid (25.5.1)

A solution of tert-butyl 2-(5,5-dimethyl-9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetate (0.18 g, 0.529 mmol) in water (1 ml) was treated with TFA (10 mL, 189 mmol). The mixture was refluxed for an hour. LC-MS of the reaction mixture showed the product. The solvent was removed in vacuo and the residue azeotroped with toluene three times. The resulting yellow oil solidified on standing. Product confirmed by LCMS. See Table 19 fro analytical data.

2-(5,5-Dimethyl-9-nitro-5,6-dihydro-2H-imidazo[2,1- b][1 ,3,6]oxadiazocin-4(3H)-yl)-N'-(4- (trifluoromethyl)phenyl)acetohydrazide (25.6.1)

To a stirring solution of 2-(5,5-dimethyl-9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetic acid (150 mg, 0.528 mmol) in DMF (2 ml) was added HATU (201 mg, 0.528 mmol) and DIPEA (0.28 mL, 1 .58 mmol). The reaction was allowed to stir for 10 min and the (4- (trifluoromethyl)phenyl)hydrazine, HCI (123 mg, 0.580 mmol) was added. The solution was stirred for 3 hours at room temperature. An LC-MS was obtained which indicated the presence of the product. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to yield a reddish oil. The product was isolated using Prep TLC. The product was confirmed by LC-MS. See Table 19 fro analytical data. -((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-amine (26.1.1)

A solution of 2-amino-2-methylpropanol (8.9 g, 100 mmol) was dissolved in anhydrous THF (100 mL), then added drop wise to a suspension of 60% dispersion NaH in oil (5.0 g, 125 mmol) and TBDMSCI (15.06 g, 100 mmol). After 30 min, tic indicated complete conversion into product. The reaction was quenched with ice-cold water and evaporated to dryness. The residue was taken up in ethyl acetate (200 mL) and washed with water (50 mL). The organic portion was dried (sodium sulfate) and evaporated to dryness to afford 1 -((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-amine (17.3 g, 70%) as a colourless oil that was used in the next step without further purification. 1 H NMR (400 MHz CDCI₃) 0.01 (s, 6H), 0.92 (s, 9H), 1.21 (s, 6H), 3.88 (s, 2H).

2-((1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)amino)ethanol

2-((1 -((tert-Butyldimethylsilyl)oxy)-2-methylpropan-2-yl)amino)ethanol (4.52 g, 22.2 mmol) was taken up in ethanol (40 mL) and heated to reflux while stirring. A solution of potassium carbonate (3.84 g, 27.8 mmol) in water (10 mL) was added, followed by bromoethanol (1.6 mL) via syringe. The resulting reaction mixture was stirred at reflux for 36 h. The organic solvent was removed in vacuo and the residue diluted with water (50 mL). The product was extracted with ethyl acetate (3 x 150 mL); the combined organic extracts were dried (sodium sulfate) and concentrated in vacuo to afford as a pale yellow oil (3.85 g, 70%). It was used in the next step without further purification.

2-(allyl(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2- yl)amino)ethanol (26.3.1)

A solution of sodium iodide (6.4 g, 42.7 mmol) in acetone (60 mL) was stirred at ambient temperature, then allyl bromide (3.2 mL, 37 mmol) added via syringe. The resulting cloudy suspension was warmed to reflux and left to stir for 1 h. Potassium carbonate (7.3 g, 52.8 mmol) and 2-((1 -((tert- butyldimethylsilyl)oxy)-2-methylpropan-2-yl)amino)ethanol (8.7 g, 35.2 mmol) in acetone (60 mL) were added in succession. The resulting mixture was heated for 8 h with periodic monitoring by tic. The suspension was filtered and evaporated to dryness. The residue was purified by column chromatography (eluent: EtOAc: Hex 2:3) was obtained as a yellow oil, (6.76 g, 67%). 1 H NMR (400 MHz CDCI₃) 0.01 (s, 6H), 0.85 (s, 9H), 1 .10 (s, 6H), 2.72 (t, 2H), 3.32 (d, 2H), 3.40 (s, 2H), 3.43 (t, 2H), 4.98 (d, 1 H), 5.10 (d, 1 H), 4.76 (m, 1 H).

N-(1 -((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-N-(2-(2,4- dinitro-1 H-imidazol-1-yl)ethyl)prop-2-en-1 -amine (26.4.1)

Triphenylphosphine (6.17 g, 23.5 mmol) was dissolved in dry THF (40 mL), then DIAD (4.75 g, 23.5 mmol) and 2,4-dinitroimidaole (3.72 g, 23.5 mmol) added in succession. The reaction mixture was stirred for 30 min at ambient temperature, then 2-(allyl(1 -((tert-butyldimethylsilyl)oxy)-2- methylpropan-2-yl)amino)ethanol (6.76 g, 23.5 mmol) in dry THF (20 mL) added drop wise. The reaction mixture was stirred for 1 h after which TLC indicated complete consumption of starting materials. The solvent was removed in vacuo and the residue purified by column chromatography, eluting with 100% DCM. The desired N-(1 -((tert-Butyldimethylsilyl)oxy)-2- methylpropan-2-yl)-N-(2-(2,4-dinitro-1 H-imidazol-1 -yl)ethyl)prop-2-en-1 - amine was obtained a s thick brown oil. 1 H NMR (400 MHz CDCI₃) 0.02 (s, 6H), 0.80 (s, 9H), 0.90 (s, 6H), 3.01 (m, 4H), 3.34 (s, 2H), 4.36 (t, 2H), 4.81 (d, 1 H), 4.90 (d, 1 H), 5.1 13 (m, 1 H), 8.1 (s, 1 H).

4-Allyl-3,3-dimethyl-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1- b 1 ,3,6]oxadiazocine (26.5.1)

A solution of N-(1 -((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-N-(2- (2, 4-dinitro-1 H-imidazol-1 -yl)ethyl)prop-2-en-1 -amine (4.7 g, 1 1 mmol) in anhydrous THF (500 mL) was stirred at ambient temperature, then 1 M TBAF solution in THF (22 mL, 22 mmol) added over 30 minutes. The reaction mixture was stirred for 18 before being concentrated in vacuo to a thick brown oil. The oily residue was purified by chromatography on silica gel eluting with EtAOc:DCM 5:19. Upon solvent removal and subsequent drying, was obtained as a brown oil (2.9 g, 99%). 1 H NMR (400 MHz CDCI₃) 0.97 (s, 6H), 2.81 (br t, 2H), 3.1 1 (t, 2H), 3.85 (t, 2H), 4.26 (s, 2H), 4.96-5.00 (m, 2H), 5.45 - 5.55 (m, 2H), 7.42 (s, 1 H).

See Table 19 fro analytical data.

Biological studies

The minimum inhibitory concentrations (MICs) were determined by the Microplate Alamar Blue Assay (MABA), (Collins et al., 1997; Falzari et al., 2005). Compounds were evaluated for their activity against M.tb H₃₇Rv was grown in Middlebrook 7H12. The plates were incubated at 37°C; on the seventh day of incubation, Alamar blue was added to all wells. After incubation at 37°C for 16 to 24 h, the fluorescence of the wells was read. The MIC was defined as the lowest concentration effecting a reduction in fluorescence of 90% relative to the mean of replicate bacteria-only controls.

Screening for the activity of the compounds against bacteria in the non- replicating state that models clinical persistence used a luminescence- based low-oxygen-recovery assay (LORA), where M.tb H₃₇Rv grown in Middlebrook 7H12 were first adapted to low oxygen conditions by extended culture. The LORA were performed in Middlebrook 7H12 broth. The plates were incubated at 37°C for 10 days and then transferred to an ambient gaseous condition (5% C0₂-enriched air) incubator for a 28-h "recovery." On day 1 1 (after the 28-h aerobic recovery), the cultures were transferred to white 96-well microtiter plates for determination of luminescence. (Cho et al., 2007). The results are indicated below in Table 13.

Table 18. In Vitro Test Results.

Class no. Structure MIC MABA

(μΜ).1.1-7.2.23 4->100

= CH or N

Class no. Structure MIC MABA

(μΜ) .1.1-22.1.6

5-80 .1.1-23.1.5

10-80 .1.1-24.2.1

5-40

Xi = 0 or S

Table 19: LC-MS analytical data

ND = not etermne

REFERENCES

The content of each of the documents listed below is hereby incorporated by reference.

PATENT DOCUMENTS

US 5,668,127,

US 6, 087, 358,

WO 2007075872 A2

W0 2009/120789 A1

WO 97/01562;

US 2006/0063929 A1

NON PATENT DOCUMENTS

WHO Global TB Control Report 2010

Sasaki et al., J. Med. Chem, 2006, 49, 7854

Palmer et al., J. Med. Chem, 2010, 53, 282

Sutherland et al., J. Med. Chem, 2010, 53, 855

Kim et al., J Med Chem, 2009, 52, 1329

Kmentova et al., J. Med. Chem, 2010, 53, 8421

Marsini et al., J. Org. Chem., 2010, 75, 7479

Collins, L.A. et al., Antimicrob. Agents Chemother. 1997,41 , 1004

Falzari et al., Antimicrob. Agents Chemother. 2005, 49, 1447

Cho et al., Antimicrob. Agents Chemother. 2007, 51 , 1380

Abbreviations used

1 , 1 '-Carbonyldiimidazole CDI

1 ,2-Dichloroethane DCE

Antiretroviral ARV

Di-2-methoxyethyl azodicarboxylate DMEAD

Dichloromethane DCM

Diethyl azidodicarboxylate DEAD

Diethylisopropylsilyl DEIPS

Diisopropyl azidodicarboxylate DIAD

Dimethyl sulfoxide DMSO

Dimethylformamide DMF

Dimethylisopropylsilyl IPDMS

Di-para-chlorobenzyl azodicarboxylate DCAD

Di-para-nitrobenzyl azodicarboxylate DNAD

Di-ieri-butylazodicarboxylate DBAD

Di-ieri-butyldimethylsilylene DTBS

Extensively Drug-Resistant Tuberculosis XDR-TB

High-Performance Liquid Chromatography HPLC

Human Immunodeficiency Virus /Acquired Immune

Deficiency Syndrome HIV/AIDS

Liquid chromatography-mass spectrometry LC-MS

Low-Oxygen-Recovery Assay LORA

O-Methane sulfonyl OMs

Microplate Alamar Blue Assay MABA

Minimum Inhibitory Concentrations MICs

Multidrug-Resistant Tuberculosis MDR-TB

Mycobacterium tuberculosis M.tb

Λ/,/V-Diisopropylethylamine DIPEA DIEA

A/-Methyl-2-pyrrolidone NMP

Nuclear magnetic resonance NMR

Silica Gel SG te/t-Butyldimethylsilyl TBS/TBDMS te/t-Butyldiphenylsilyl TBDPS

Tetrabutylammonium fluoride TBAF Tetrahydrofuran THF

Tetrahydropyranyl THP

Tetraisopropyldisilylene TIPDS

Thin Layer Chromatography TLC

O-para-Toluene sulfonyl OTs

Triet ylamine Et₃N/TEA

Triethylsilyl TES

Triisopropylsilyl TIPS

Trimethylsilyl TMS

Triphenylphosphine PPh₃

Tuberculosis TB

Ultraviolet UV

World Health Organization WHO

Claims

Claims

1 . A compound of the Formula (I).

or pharmaceutically acceptable salts, mixtures, optical or geometric isomers, esters or prodrugs thereof, wherein:

X is hydrogen, substituted or unsubstituted alkyl or cycloalkyi and Y is absent, or X is independently selected from CH₂, CH(CH₃), C=0, S0₂, substituted or unsubstituted pyrimidine, substituted or unsubstituted piperidine, 4-aminocyclohexane, and Y is absent or represents any one of Formulae lla - llg below:

llf "9

R is substituted at any one or more of the available ring positions and is selected from H, F, CI, Br, CN, MeO, CF₃, OCHF₂, OCF₃, a carboxamide group C(0)NR₇R₈, reversed carboxamide, NR₇C(0)R₈, carboxyl C(0)R₇, substituted or unsubstituted: alkyl, alkenyl, alkynyl, alkyl amines, amide, aldehyde, phenyl, preferably biphenyl, hydrazide, hydrazine, pyridine, dihydropyridine, morpholino, pyrrolidine, piperazine, naphthalene, oxophenyl, aryl sulphonamide, alkyl sulphonamide, cycloalkyi, alkoxy aryl, alkoxy alkyl, indole, pyrimidine, pyridazine, piperidine, imidazole, quinoline, sulfonyl, furan, thiophene, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, triazole, pyrrole or pyrazole;

Ri and R₂ is selected from any one of H, substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, piperidine, piperazine, alkyl sulfone, phenyl, phenylsulfone, alkylphenyl, biaryl, alkyl biaryl, pyridine, naphthalene, indole, pyrimidine, pyridazine, piperidine, imidazole, quinoline, sulfonyl, furan, thiophene, oxazole, benzyl, amide, isoxazole, thiazole, thiadiazole, triazole, pyrrole or pyrazole; or and R₂ together with the nitrogen atom to which they are attached form a morpholine ring, which may be substituted or unsubstituted;

R₃ is OR₄ or NR₅R₆, wherein R₄ is any one of tert butyl, ethyl or H; R5 and R₆ is any one of H, substituted or unsubstituted: alkyl, cyclopropyl, methoxyethyl, cyclopropylmethyl, cyclohexylmethyl, morpholinoethyl, cyclobutyl, phenyl, benzyl, phenethyl, piperazine, piperidine, or R₅ and R₆ together with the nitrogen atom to which they are attached form a pyrrole, piperazine or piperidine ring, which may be substituted or unsubstituted.

R₇ and R₈ is selected from any one of substituted or unsubstituted: alkyl, phenyl, benzyl, phenethyl, pyridiyl, cycloalkyl, piperidine, thiophene, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, triazole, pyrrole or pyrazole.

2. A compound according to claim 1 , wherein the compound of Formula I is additionally substituted as shown in the Formula la:

wherein R₂ in Formula la is an alkyl, preferably CH₃

3. A compound according to claim 1 , wherein X is CH₂ and Y is a compound of formula lie, wherein R₃ is OR₄ and R₄ is ethyl or tert butyl.

4. A compound according to claim 1 , wherein X is CH₂ and Y is a compound of formula lie, wherein R₃ is OR₄ and R₄ is H.

5. A compound according to claim 1 , wherein X is CH₂ and Y is a substituted or unsubstituted phenyl or pyridine group.

6. A compound according to claim 1 , wherein X is CH₂, Y represents formula lla and R is selected from any one of substituted or unsubstituted; phenyl, an amide group, an amine group, an aldehyde group, pyridine, pyrimidyl, pyrimidine, isoxazole, furan, trizole, indole or a five-membered heterocycle.

7. A compound according to claim 1 , wherein X is CH₂, Y represents formula lib and wherein R is a substituted phenyl or an amide group.

8. A compound according to any one of claims 5 to 7, wherein when substituted, the phenyl or pyridine groups are substituted at any one or more of the available ring positions with Br, OMe, CH₃, CF₃, C0₂Et, OCF₃, OCH₂, OCH₃, NHBoc, CN, F, CI, N0₂, OCHF_2, C(0)-0-C(CH₃)₃ or C(0)NR₇R₈, wherein R₇ and R₈ is selected from any one of H or substituted or unsubstituted alkyl, cycloalkyl, morpholine, piperidine, piperazine, phenyl, benzyl, amide or phenethyl.

9. A compound according to any one of the preceding claims, wherein X is CH₂ and Y is a substituted or unsubstituted biaryl.

10. A compound according to claim 9, wherein X is CH₂ and Y is a meta- substituted biaryl.

1 1 . A compound according to claim 9, wherein X is CH₂ and Y is a para- substituted biaryl.

12. A compound according to claim 9, wherein X is CH₂, and Y is an orf/70-substituted biaryl.

13. A compound according to any one of claims 9 to 12, wherein the biaryl is substituted at any one or more of the available ring positions and is selected from CF₃, NHBoc, C0₂Et, CN, OCF₃, furan, N0₂, C0₂H, F, isoxazole, OMe, OCH₃, pyrrole, carboxamide C(0)NR₇R₈, or C(0)OR₄ , where R₇ and R₈ are as defined in claim 1 and R₄ is ethyl.

14. The compound according to claim 1 , wherein X is CH_2, Y is a compound of formula I la and R is a phenyl substituted with an amide group.

15. The compound according to claim 14, wherein the phenyl is further substituted with F.

16. The compound according to claim 1 , wherein X is CH₂, Y is a compound of formula lib and R is a phenyl group which is substituted with F and an amide group or C(0)OH.

17. A compound according to claim 1 , wherein X is CH₂ and Y is a compound of formula lie, R₃ is NR₅R_6, wherein R₅ is H and R₆ is selected from any one of substituted or unsubstituted; alkyl, preferably CH₃, CH₂CH₃, CH(CH₃)_2, methoxyethyl, cyclopropyl, cyclopropylmethyl, cyclohexylmethyl, morpholonoethyl, oxopyrrolpropyl, cyclobutyl or a substituted phenyl or piperadine group.

18. A compound according to claim 1 , wherein X is CH₂, Y is a compound of formula lie, R₃ is NR₅R₆ and wherein R₅ and R₆ together with the nitrogen atom to which they are attached form any one of the following groups, a pyrole, piperazine or piperadine, optionally substituted with a phenyl group.

19. The compound according to claim 18, wherein the phenyl group is further substituted with any one of F, C0₂Et or CN.

20. A compound according to claim 1 , wherein X is C=0 and Y represents any one or more of H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, substituted or unsubstituted: alkyl, phenyl, indole, thiazole, pyrolidine, pyridine or naphthalene.

21 . The compound according to claim 1 , wherein X is C=0, Y is formula I la or lib and R is selected from any one of Br, bromophenoxy, benzuloxy, oxyphenyl or a phenyl group.

22. A compound according to claim 1 , wherein X is C=0 and Y represents formula lid, wherein is H and R₂ is selected from any one of H, a phenylsulfonyl, tosyl toly, methoxyphenyl, cyanophenyl, fluorophenyl, chlorophenyl or a fluorophenyl sulfonyl group, alkyl, alkyl sulfonamide, or substituted or unsubstituted phenyl.

23. The compound of claim 1 , wherein X is S0_2, and Y is CH₃, substituted or unsubstituted phenyl or imidazole.

24. A compound according to claim 1 , wherein X is pyrimidine and Y is an optionally substituted amine group, dihydropyridine, morpholino, pyrrolidine or piperazine group.

25. The compound of according to claim 1 , wherein X is CH(CH₃)₂ and Y is formula lib, wherein R is a substituted phenyl group, wherein the phenyl is substituted with C(0)-0-CH₂CH_3, CN, CF₃, F, OCF₃.

26. A compound according to any one of the preceding claims, wherein the compound is:

7.1.1 4-Methyl-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

7.1.2 4-Allyl-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b]

[1 ,3,6]oxadiazo- cine,

7.1.3 9-Nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

7.1.4 tert-Butyl 2-(9-nitro-5,6-dihydro-2H-imidazo [2,1 -b][1 ,3,6] oxadiazo- cin-4(3H)-yl)acetate,

7.1.5 4-(3-Methylbut-2-en-1 -yl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

7.1.6 2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)acetonitrile,

7.1.7 2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)acetic acid,

7.2.1 4-Benzyl-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

7.2.2 9-Nitro-4-(pyridin-2-ylmethyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

7.2.3 9-Nitro-4-(pyridin-3-ylmethyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

7.2.4 4-(4-Methoxybenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

7.2.5 4-(2,4-Dimethoxybenzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

7.2.6 9-Nitro-4-(4-(trifluoromethyl)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

7.2.7 9-Nitro-4-(3-(trifluoromethyl)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

7.2.8 9-Nitro-4-(4-(trifluoromethoxy)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

7.2.9 9-Nitro-4-(3-(trifluoromethoxy)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine, 4-(3-(Difluoromethoxy)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(4-(Difluoromethoxy)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((2-Bromopyridin-4-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((5-Bromopyridin-3-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((5-Bromopyridin-2-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(2-Bromobenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

4-(4-Bromobenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

4-(3-Bromobenzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

4-((6-Bromopyridin-2-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((6-Bromopyridin-3-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

tert-butyl 4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzoate,

4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)benzoic acid,

9-Nitro-4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl)- 3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(1 -(6-Bromopyridin-3-yl)ethyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

Ethyl 3'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4-carboxylate,

4-([1 ,1 '-Biphenyl]-3-ylmethyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(3-(pyridin-3-yl)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine, 9-Nitro-4-(3-(pyridin-4-yl)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((3'-Fluoro-[1 ,1 '-biphenyl]-3-yl)methyl)-9-nitro-3,4,5,6-tetrahydro- 2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

3'-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-[1 ,1 '-biphenyl]-3-carbonitrile,

4-(3-(3,5-Dimethyl-4,5-dihydroisoxazol-4-yl)benzyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(3-(1 H-lndol-6-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

tert-Butyl 4-(3-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)phenyl)-5,6-dihydropyridine-1 (2H)- carboxylate,

tert-Butyl (3'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazo -cin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4-yl) carbamate,

3'-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-[1 ,1 '-biphenyl]-4-carbonitrile,

4-(3-(1 -Methyl-1 H-indol-5-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

Ethyl 4-(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazo cin-4(3H)-yl)methyl)pyridin-2-yl)benzoate,

9-Nitro-4-((2-(4-(trifluoromethyl)phenyl)pyridin-4-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

Ethyl 4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazo cin-4(3H)-yl)methyl)pyridin-3-yl)benzoate,

Ethyl 4-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazo cin -4(3H)-yl)methyl)pyridin-2-yl)benzoate,

4-(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)pyridin-2- yl)benzonitrile,

4-((2-(3-Fluorophenyl)pyridin-4-yl)methyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(5-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)pyridin-3-yl)benzonitrile, 9-Nitro-4-((5-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((5-(3-Fluorophenyl)pyridin-3-yl)methyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(6-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)pyridin-2-yl)benzonitrile,

9-Nitro-4-((6-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

-((6-(3-Fluorophenyl)pyridin-2-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-

2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

Ethyl 4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4 (3H)-yl)methyl)-[1 ,1 '-biphenyl]-4-carboxylate,

4-((4'-Methoxy-[1 ,1 '-biphenyl]-4-yl)methyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((3'-Methoxy-[1 ,1 '-biphenyl]-4-yl)methyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-((4'-(trifluoromethyl)-[1 ,1 '-biphenyl]-4-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-((4'-(trifluoromethoxy)-[1 ,1 '-biphenyl]-4-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-((3'-(trifluoromethoxy)-[1 ,1 '-biphenyl]-4-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(4-(1 H-lndol-5-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-((3'-(trifluoromethyl)-[1 ,1 '-biphenyl]-4-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

tert-Butyl (4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazo-cin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-3-yl)carbamate, 4'-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-[1 ,1 '-biphenyl]-3-carbonitrile,

4-((3'-Fluoro-[1 ,1 '-biphenyl]-4-yl)methyl)-9-nitro-3,4,5,6-tetrahydro- 2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(4-(Furan-3-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine, 4-(4-(Furan-2-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

4-(4-(2-Methoxypyridin-3-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(4-(6-Methoxypyridin-3-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(4-(2-Methoxypyrimidin-5-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro- 2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-((2'-nitro-[1 ,1 '-biphenyl]-4-yl)methyl)-3,4,5,6-tetrahydro- 2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(4-(pyridin-3-yl)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(4-(pyridin-4-yl)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(4-(pyrimidin-5-yl)benzyl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(4-(2-Chloropyridin-4-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

Ethyl 4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4 (3H)-yl)methyl)-[1 ,1 '-biphenyl]-3-carboxylate,

4-(4-(2-Fluoropyridin-3-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(4-(6-Fluoropyridin-3-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(4-(1 -Methyl-1 H-indol-5-yl)benzyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

Ethyl 4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazo cin-4(3H)-yl)methyl)pyridin-2-yl)benzoate,

4-(5-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)pyridin-2-yl)benzonitrile,

4'-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-[1 ,1 '-biphenyl]-4-carbonitrile,

4-([1 ,1 '-Biphenyl]-4-ylmethyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine, 9-Nitro-4-((6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((6-(3-Fluorophenyl)pyridin-3-yl)methyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

Ethyl 4-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazo cin-4(3H)-yl)methyl)pyridin-3-yl)benzoate,

4-(6-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)pyridin-3-yl)benzonitrile,

9-Nitro-4-((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((5-(3-Fluorophenyl)pyridin-2-yl)methyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-nitro-4-(4-(5-(trifluoromethyl)-4H-1 ,2,4-triazol-3-yl)benzyl)- 3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

Ethyl 2'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4-carboxylate,

2'-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-[1 ,1 '-biphenyl]-4-carbonitrile,

4-((3'-Fluoro-[1 ,1 '-biphenyl]-2-yl)methyl)-9-nitro-3,4,5,6-tetrahydro- 2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-([1 ,1 '-Biphenyl]-2-ylmethyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4'-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-[1 ,1 '-biphenyl]-4-carboxylic acid,

4'-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-[1 ,1 '-biphenyl]-3-carboxylic acid,

N-lsopropyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4- carboxamide,

Morpholino(4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4- yl)methanone, N-Cyclopropyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1- b][1,3,6]oxadiazocin-4(3H)-yl)methyl)-[1,1'-biphenyl]-4- carboxamide,

(4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)-[1,1'-biphenyl]-4-yl)(pyrrolidin-1-yl)methanone, (4-methylpiperazin-1-yl)(4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1- b][1,3,6]oxadiazocin-4(3H)-yl)methyl)-[1,1'-biphenyl]-4- yl)methanone,

N-ethyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1- b][1,3,6]oxadiazocin-4(3H)-yl)methyl)-[1,1'-biphenyl]-4- carboxamide,

N-Cyclopropyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1- b][1,3,6]oxadiazocin-4(3H)-yl)methyl)-[1,1'-biphenyl]-3- carboxamide,

(4-Methylpiperazin-1-yl)(4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1- b][1,3,6]oxadiazocin-4(3H)-yl)methyl)-[1,1'-biphenyl]-3- yl)methanone,

N,N-dimethyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1,3,6]oxadiazocin-4(3H)-yl)methyl)-[1,1'-biphenyl]-3- carboxamide,

N-Ethyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1- b][1,3,6]oxadiazocin-4(3H)-yl)methyl)-[1,1'-biphenyl]-3- carboxamide,

N-lsopropyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1- b][1,3,6]oxadiazocin-4(3H)-yl)methyl)-[1,1'-biphenyl]-3- carboxamide,

3-Fluoro-N-isopropyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1- b][1,3,6]oxadiazocin-4(3H)-yl)methyl)-[1,1'-biphenyl]-4- carboxamide,

3-Fluoro-N-methyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1- b][1,3,6]oxadiazocin-4(3H)-yl)methyl)-[1,1'-biphenyl]-4- carboxamide, N-(Cyclopropylmethyl)-3-fluoro-4'-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4- carboxamide,

N-Cyclobutyl-3-fluoro-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4- carboxamide,

(3-Fluoro-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4- yl)(morpholino)methanone,

(3-Fluoro-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-4-yl)(4- methylpiperazin-1 -yl)methanone,

(2-Fluoro-4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(4- methylpiperazin-1 -yl)methanone,

2-Fluoro-N,N-dimethyl-4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, (2-Fluoro-4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(pyrrolidin- 1 -yl)methanone,

N-Ethyl-2-fluoro-4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, 2-Fluoro-N-isopropyl-4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, N-Cyclopropyl-2-fluoro-4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, 2-Fluoro-4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzoic acid, N-Cyclobutyl-2-fluoro-4-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, 4-Fluoro-N-isopropyl-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-3- carboxamide, N-Ethyl-4-fluoro-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-3- carboxamide,

N-Cyclopropyl-4-fluoro-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-3- carboxamide,

(4-Fluoro-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-3- yl)(pyrrolidin-1 -yl)methanone,

N-Cyclobutyl-4-fluoro-4'-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-[1 ,1 '-biphenyl]-3- carboxamide,

(2-Fluoro-5-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(4- methylpiperazin-1 -yl)methanone,

2-Fluoro-N,N-dimethyl-5-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, (2-Fluoro-5-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(pyrrolidin- 1 -yl)methanone,

N-Ethyl-2-fluoro-5-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, 2-Fluoro-N-isopropyl-5-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, N-Cyclopropyl-2-fluoro-5-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, N-Fyclobutyl-2-fluoro-5-(5-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, (2-Fluoro-4-(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(4- methylpiperazin-1 -yl)methanone,

2-Fluoro-N,N-dimethyl-4-(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, (2-Fluoro-4-(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(pyrrolidin- 1 -yl)methanone,

N-Ethyl-2-fluoro-4-(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, 2-Fluoro-N-isopropyl-4-(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, N-Cyclopropyl-2-fluoro-4-(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, (2-Fluoro-4-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(4- methylpiperazin-1 -yl)methanone,

2-Fluoro-N,N-dimethyl-4-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, (2-Fluoro-4-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(pyrrolidin- 1 -yl)methanone,

N-Ethyl-2-fluoro-4-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, 2-Fluoro-N-isopropyl-4-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, N-Cyclopropyl-2-fluoro-4-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, (2-Fluoro-5-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(4- methylpiperazin-1 -yl)methanone,

2-Fluoro-N,N-dimethyl-5-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, (2-Fluoro-5-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)phenyl)(pyrrolidin- 1 -yl)methanone,

N-Ethyl-2-fluoro-5-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, 2-Fluoro-N-isopropyl-5-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, N-Cyclopropyl-2-fluoro-5-(6-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)pyridin-2-yl)benzamide, N,N-Dimethyl-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide,

N-Ethyl-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)acetamide,

N-(2-Methoxyethyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide,

N-lsopropyl-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide,

N-Cyclopropyl-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide,

N-(Cyclopropylmethyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide,

N-(Cyclohexylmethyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide,

N-(2-Morpholinoethyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(3-(2-oxopyrrolidin-1 -yl)propyl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-1 -(pyrrolidin-1 -yl)ethanone,

N-Cyclobutyl-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide,

N-(3-Bromophenyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide,

N-(4-Acetylphenyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide,

N-(4-Bromobenzyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide,

N-(4-Methoxybenzyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide, 2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(3-(trifluoromethyl)phenethyl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(4-(trifluoromethyl)benzyl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(4-(trifluoromethoxy)benzyl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(3-(trifluoromethyl)benzyl)acetamide,

N-(4-(Difluoromethoxy)benzyl)-2-(9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide,

N-(3-(Difluoromethoxy)benzyl)-2-(9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide,

1 -(4-(3-Fluorophenyl)piperazin-1 -yl)-2-(9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)ethanone,

Ethyl 4-(4-(2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazo -cin-4(3H)-yl)acetyl)piperazin-1 -yl)benzoate,

N-(1 -Benzylpiperidin-4-yl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetamide,

4-(4-(2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)acetyl)piperazin-1 -yl)benzonitrile,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-1 -(4-phenylpiperidin-1 -yl)ethanone,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(4-(trifluoromethyl)phenyl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(3-(trifluoromethyl)phenyl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(3-(trifluoromethoxy)phenyl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(3-(trifluoromethoxy)benzyl)acetamide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-((4'-(trifluoromethoxy)-[1 ,1 '-biphenyl]-4-yl)methyl)acetamide, 2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N'-(3-(trifluoromethyl)phenyl)acetohydrazide, 2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N'-(4-(trifluoromethyl)phenyl)acetohydrazide,

N'-(3-Fluorophenyl)-2-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetohydrazide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N'-(3-(trifluoromethoxy)phenyl)acetohydrazide,

2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N'-(4-(trifluoromethoxy)phenyl)acetohydrazide,

N'-(2-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)acetyl)-4-(trifluoromethoxy)benzohydrazide,

(3-Bromophenyl)(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methanone,

(4-Bromophenyl)(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methanone,

1 -(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)propan-1 -one,

(1 H-lndol-2-yl)(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazo- cin-4(3H)-yl)methanone,

(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)(2-phenylthiazol-4-yl)methanone,

Cyclobutyl(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methanone,

1 -(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-2-phenoxyethanone,

4-(4-(9-Nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazo cine-4-carbonyl)piperidin-1 -yl)benzonitrile,

(5-Bromopyridin-2-yl)(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methanone,

(4-(4-Bromophenoxy)phenyl)(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methanone,

(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)(quinolin-3-yl)methanone

Naphthalen-2-yl(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadi- azocin-4(3H)-yl)methanone, (4-(Benzyloxy)phenyl)(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methanone,

(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)(4-phenoxyphenyl)methanone,

Cyclohexyl(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methanone,

3-(4-Bromophenyl)-1 -(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)propan-1 -one,

[1 ,1 '-Biphenyl]-4-yl(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methanone,

3'-(9-Nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine-4-carbonyl)-[1 ,1 '-biphenyl]-4-carbonitrile, Benzyl-9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine- 4(3H)-carboxylate,

Ethyl-9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine- 4(3H)-carboxylate,

9-Nitro-N-(phenylsulfonyl)-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine-4(3H)-carboxamide,

9-Nitro-N-tosyl-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine- 4(3H)-carboxamide

N-((4-Fluorophenyl)sulfonyl)-9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine-4(3H)-carboxamide,

9-Nitro-N-(p-tolyl)-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine-4(3H)-carboxamide,

N-(4-Methoxyphenyl)-9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine-4(3H)-carboxamide,

N-(4-Cyanophenyl)-9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine-4(3H)-carboxamide,

N-(4-Fluorophenyl)-9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine-4(3H)-carboxamide,

N-(4-Chlorophenyl)-9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine-4(3H)-carboxamide,

N-Benzyl-9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine-4(3H)-carboxamide, 4-(Methylsulfonyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

4-((1 -Methyl-1 H-imidazol-4-yl)sulfonyl)-9-nitro-3,4,5,6-tetrahydro- 2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)sulfonyl)benzonitrile,

4-((4-Chlorophenyl)sulfonyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(phenylsulfonyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine

9-Nitro-4-tosyl-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

4-((4-Methoxyphenyl)sulfonyl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(2-Chloropyrimidin-4-yl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(4-(trifluoromethyl)phenethyl)pyrimidin-2-amine,

4-(2-((4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)pyrimidin-2-yl)amino)ethyl)benzonitrile,

N-(Furan-2-ylmethyl)-4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)pyrimidin-2-amine,

N-Benzyl-4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)pyrimidin-2-amine,

N-(4-(Dif luoromethoxy)benzyl)-4-(9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)pyrimidin-2-amine, 4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(4-(trifluoromethoxy)benzyl)pyrimidin-2-amine,

N-(3-Bromobenzyl)-4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)pyrimidin-2-amine,

4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine,

4-(9-Nitro-5,6-dihydro-2H-imidazo[2, 1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(4-(trifluoromethy l)benzyl)pyrimidin-2-amine N-(Cyclohexylmethyl)-4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b] [1 ,3,6]oxadiazocin-4(3H)-yl)pyrimidin-2-amine,

4-(2-(5,6-Dihydropyridin-1 (2H)-yl)pyrimidin-4-yl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine

4-(2-Morpholinopyrimidin-4-yl)-9-nitro-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(2-(pyrrolidin-1 -yl)pyrimidin-4-yl)-3,4,5,6-tetrahydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(2-(4-phenylpiperazin-1 -yl)pyrimidin-4-yl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(4-(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)pyrimidin-2-yl)piperazin-1 -yl)benzonitrile,

4-(2-(4-(3-Fluorophenyl)piperazin-1 -yl)pyrimidin-4-yl)-9-nitro- 3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

Ethyl 4-(4-(4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazo-cin-4(3H)-yl)pyrimidin-2-yl)piperazin-1 -yl)benzoate, N,N-Dimethyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6] oxadiazocin-4(3H)-yl)methyl)benzamide,

N-Ethyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

N-Butyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-

4(3H)-yl) methyl) benzamide,

N-lsopropyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadi- azocin-4(3H)-yl)methyl)benzamide,

N-Cyclopropyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadi-azocin-4(3H)-yl)methyl)benzamide,

N-Cyclobutyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadi- azocin-4(3H)-yl)methyl)benzamide,

N-Benzyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadi- azocin-4(3H)-yl)methyl)benzamide,

N-(4-(Difluoromethoxy)phenyl)-4-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide, -((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethoxy)phenyl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluo romethyl)phenyl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(3-(trifluo romethyl)phenyl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(3-(trifluo romethoxy)phenyl)benzamide,

N-(3-(Difluoromethoxy)phenyl)-4-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazoc in-4(3H)-yl)methyl)benzamide, N-(3-(Difluoromethoxy)benzyl)-4-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazoc in-4(3H)-yl)methyl)benzamide N-(4-(Difluoromethoxy)benzyl)-4-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazoc in-4(3H)-yl)methyl)benzamide 4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethyl)benzyl)benzamide

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethoxy)benzyl)benzamide

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(3-(trifluoromethoxy)benzyl)benzamide , N-(4-Methoxybenzyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethyl)phenethyl)benzamide,

4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(3-(trifluoromethyl)phenethyl)benzamide,

Morpholino(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)phenyl)methanone,

N-(3-Morpholinopropyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

(4-(2-Methoxyethyl)piperazin-1 -yl)(4-((9-nitro-5,6-dihydro-2H- imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)phenyl)methanone, (4-Methylpiperazin-1 -yl)(4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)phenyl)methanone,

(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)phenyl)(pyrrolidin-1 -yl)methanone,

N-(Cyclopropylmethyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)-N-phenylbenzamide,

N-(4-Fluorophenyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

N-(3-lsopropoxyphenyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(2-(pyridin-2-yl)ethyl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(pyridin-4-ylmethyl)benzamide,

N-(3-Fluorobenzyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

N-(4-Cyanobenzyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

N-(3-Methoxybenzyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

N-(3-Methoxyphenethyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

N-(4-Cyanophenethyl)-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(pyridin-3-yl)benzamide,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(5-(trifluoromethyl)-1 ,3,4-oxadiazol-2-yl)benzamide, 4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(5-(trifluoromethyl)-1 ,3,4-thiadiazol-2-yl)benzamide, 4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(3-(trifluoromethyl)isoxazol-5-yl)benzamide, N-Methyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-N-(4- (trifluoromethoxy)phenyl)benzamide,

N-Methyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-N-(3- (trifluoromethyl)phenyl)benzamide,

N-Methyl-4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)-N-(3- (trifluoromethoxy)phenyl)benzamide,

5-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethoxy)phenyl)picolinamide,

5-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(3-(trifluoromethyl)phenyl)picolinamide,

5-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(3-(trifluoromethoxy)phenyl)picolinamide,

Ethyl 4-(5-(1 -(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)ethyl) pyridine-2-yl)benzoate,

4-(5-(1 -(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)ethyl)pyridin-2-yl)benzonitrile,

9-Nitro-4-(1 -(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)ethyl)-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

4-(1 -(6-(3-Fluorophenyl)pyridin-3-yl)ethyl)-9-nitro-3,4,5,6- tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

9-Nitro-4-(1 -(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)ethyl)- 3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine,

N-Cyclobutyl-2-f luoro-4-(5-(1 -(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)ethyl)pyridin-2-yl)benzamide, N-Cyclobutyl-2-f luoro-5-(5-(1 -(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)ethyl)pyridin-2-yl)benzamide, N-(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)benzyl)-1 -(4- (trifluoromethoxy)phenyl)methanamine,

N-(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)benzyl)-4-(trifluoromethoxy)aniline, N-(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)benzyl)-3-(trifluoromethoxy)aniline,

N-(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)benzyl)-3-(trifluoromethyl)aniline,

N-(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)phenyl)-4-(trifluoromethoxy)benzamide,

N-(4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)methyl)phenyl)-3-(trifluoromethoxy)benzamide, tert-Butyl 4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl) piperidine-1 -carboxylate, 9-Nitro-4-(piperidin-4-yl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)piperidin-1 -yl)(4-(trifluoromethoxy)phenyl)methanone,

(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)piperidin-1 -yl)(4-(trifluoromethyl)phenyl)methanone,

(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)piperidin-1 -yl)(3-(trifluoromethyl)phenyl)methanone,

tert-Butyl 2-(4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)piperidin-1 -yl) acetate,

2-(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)piperidin-1 -yl)acetic acid,

4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1 -carboxamide, tert-Butyl 4-((9-nitro-5,6-di hydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl) methyl)piperidine-1 -carboxylate, 9-Nitro-4-(piperidin-4-ylmethyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)piperidin-1 -yl)(4-(trifluoromethoxy)phenyl)methanone, 4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)piperidin-1 -yl)(3-(trifluoromethoxy)phenyl)methanone, 4-Nitrophenyl 4-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 , 3, 6]oxadiazocin-4(3H)-yl)methyl)piperidine-1 -carboxylate, 4-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1 -carboxamide, tert-Butyl (4-(9-nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadia- zocin-4(3H)-yl)cyclohexyl)carbamate,

4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)cyclohexanamine

N-(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)cyclohexyl)-4-(trifluoromethoxy)benzamide,

N-(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)cyclohexyl)-3-(trifluoromethoxy)benzamide,

N-(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)cyclohexyl)-2-(4-(trifluoromethoxy)phenyl)acetamide, 1 -(4-(9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin- 4(3H)-yl)cyclohexyl)-3-(4-(trifluoromethoxy)phenyl)urea,

tert-Butyl 3-((9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)azetidine-1 -carboxylate, 4-(Azetidin-3-ylmethyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine,

(3-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)azetidin-1 -yl)(4-(trifluoromethoxy)phenyl)methanone, (3-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)azetidin-1 -yl)(3-(trifluoromethoxy)phenyl)methanone, 3-((9-Nitro-5,6-dihydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocin-4(3H)- yl)methyl)-N-(4-(trifluoromethoxy)phenyl)azetidine-1 -carboxamide, 9-Nitro-4-((5-(4-(trifluoromethoxy)phenyl)-1 ,3,4-thiadiazol-2- yl)methyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine, 9-Nitro-4-((5-(4-(trifluoromethoxy)phenyl)-1 ,3,4-oxadiazol-2- yl)methyl)-3,4,5,6-tetrahydro-2H-imidazo[2,1 -b][1 ,3,6]oxadiazocine, tert-Butyl 2-(5,5-dimethyl-9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetate,

2-(5,5-Dimethyl-9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)acetic acid,

25.1.3 2-(5,5-Dimethyl-9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)-N'-(4-

(trifluoromethyl)phenyl)acetohydrazide,

25.2.1 tert-Butyl 4-((5,5-dimethyl-9-nitro-5,6-dihydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocin-4(3H)-yl)methyl)benzoate,

26.1.1 4-Allyl-3,3-dimethyl-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine or pharmaceutically acceptable salts, mixtures, optical or geometric isomers, esters or prodrugs thereof.

27. A process for producing the compound of Formula I,

the process comprising the steps of; substitution of the nitrogen atom of an amino alcohol reactant

X x

with either formula i) ^{Y "LG} or ii) ^Y via alkylation or reductive amination, to produce a tertiary amine; wherein LG represents a leaving group, Y is as defined in claim 1 , X in formula i) is as defined in claim 1 , provided that X is not C=C\ X in formula ii) is CH, reacting the substituted amino alcohol with 2,4-dinitroimidazole under Mitsunobu reaction conditions; cyclization of the product of step b) to produce the compound of Formula (I).

28. A process for producing the compound of Formula I

the process comprising the steps of; a) substitution of the nitrogen atom of an amino alcohol with an alkyl group, preferably CH₃ or an allyl group;

b) reacting the substituted amino alcohol with 2,4-dinitroimidazole under Mitsunobu reaction conditions to produce an intermediate;

c) cyclisation of the intermediate;

d) removal of the methyl or allyl group from the intermediate;

X x e) reacting the product of step d) with i) ^{γ' "}LG ₀r ii) ^Y , to produce a compound of Formula (I), wherein LG represents a leaving group, Y is as defined in claim 1 , X in formula ii) is CH, X in formula i) is as defined in claim 1 , provided that X is not C=0.

29. The process according to claims 27 or 28, wherein the amino alcohol is diethanolamine.

30. The process according to any one of claims 27 to 29, wherein prior to step a) the amino alcohol is first monoprotected using an ether selected from triisopropylsilyl, trimethylsilyl , dimethylisopropylsilyl , diethylisopropylsilyl , te/t-Butyldimethylsilyl, te/t-Butyldiphenylsilyl, or di-te/t-butyldimethylsilylene ether, preferably terf-Butyldimethylsilyl.

31 . The process according to any of claims 27 to 30, wherein the step of substitution with ^Y ¾ j_s carried out in a reducing agent, preferably lithium aluminium hydride, sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride and in the presence of a solvent selected from ethanol, propanol, isopropanol, methanol, chloroform, dichloromethane, dichloroethane, dioxane, acetonitrile, dioxane, tetrahydrofuran, dimethylformamide, /V-Methyl- 2-pyrrolidone, dimethyl sulfoxide , or a mixture thereof.

32. The process according to any of claims 27 to 30, wherein the step of substitution with ^{γ' "}LG is carried out in a solvent selected from ethanol, propanol, isopropanol, methanol, chloroform, dichloromethane, dichloroethane, dioxane, acetonitrile, dioxane, tetrahydrofuran, dimethylformamide, A/-Methyl-2-pyrrolidone, dimethyl sulfoxide or a mixture thereof and in the presence of a weak base, preferably triethylamine, diisopropylethylamine, or an aqueous inorganic base, preferably sodium bicarbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide or potassium carbonate.

33. The process according to any one of claims 26 to 32, wherein the reaction with 2,4-dinitroimidazole is carried out in the presence of triphenylphosphine in combination with an azodicarboxylate, preferably diethyl azidodicarboxylate (DEAD), di-tert- butylazodicarboxylate (DBAD), di-p-chlorobenzyl azodicarboxylate (DCAD), di-2-methoxyethyl azodicarboxylate (DMEAD), di-p- nitrobenzyl azodicarboxylate (DNAD) or diisopropyl azidodicarboxylate (DIAD), more preferably, DIAD; and in the presence of an organic solvent selected from chloroform, tetrahydrofuran , dichloromethane, dichloroethane, A/-Methyl-2- pyrrolidone , dimethylformamide, dioxane, dimethyl sulfoxide or a mixture thereof.

The process according to claim 33, wherein the organic solvent THF and the reaction is carried out at a temperature of between 10°C and 70°C.

35. The process according to any one of claims 26 to 34, wherein the cyclisation step is carried out in the presence of a basic fluoride source, preferably potassium fluoride, cesium fluoride or tetrabutylammoinium fluoride (TBAF), more preferably TBAF.

36. The process according to any one of claims 26 to 35, wherein the leaving group (LG) is selected from CI, Br, I, or a mesylate or tosylate group.

The process according to any one of claims 26 to 36, wherein the X-Y group is first subjected to Finkelstein reaction conditions.

38. A process for producing the compound of Formula I as defined in any one of claims 27 or 29 to 37, the process represented as follows:

wherein step (i) involves reacting the reactant with a mixture of tert- Butyldimethylsilylchloride, imidazole and dichloromethane, step (ii) is carried out in the presence of K₂C0₃ and acetonitrile, step (iii) is carried out in a mixture of borohydride and dichloroethane, step (iv) is carried out in a mixture of PPh3, DIAD and tetrahydrofuran and step (v) is carried out in tetrabutylammonium fluoride

39. The process according to claim 38, wherein the reaction is carried out at room temperature and steps (i) to (iv) are carried out for about 12 hours, 24 hours, 18 hours and 2 hours respectively.

40. The process according to claim 28, wherein step d) is carried out by (i) treating the compound of step c) with 1 -chloroethyl chloroformate in chloroform, dichloromethane or dichloroethane, or a mixture thereof, followed by (ii) evaporation of the chlorinated solvent and (iii) reflux of the residue from step (ii) in methanol.

41 . The process according to claim 40, wherein the reaction is carried out at a temperature ranging from -10°C-70°C.

A process for producing the compound of Formula I as defined claim 28 or 29 to 37, the process schematically represented follows:

TBDMSO"" -"' ^s/SOH

6

LG=Leaving group

wherein, step (ii) involves reacting compound 5 with a mixture of PPh₃, diisopropyl azidodicarboxylate and tetrohydrofuran, step (iii) is carried out in tetrabutylammonium fluoride, step (iv) is carried out in a mixture of 1 -chloromethyl chloroformate and dichloroethane, step (v) is carried out in MeOH, step (vi) is carried out in a mixture of K₂C0₃ and acetonitrile:water (1 :3), and step (vii) is carried out in a mixture of sodium triacetoxyborohydride in dichloroethane.

43. The process according to claim 42, wherein compound 5 is produced

H

by reaction of TBDMSO ^ ^ OH _wjth allyl bromide, K₂C0₃ and acetonitrile at room temperature for 24 hours.

44. The process according to claim 42, wherein steps (ii) to (vi) are carried out at room temperature for about 18 hours, 2 hours, 12 hours, 4 hours and 4 hours respectively.

45. The process according to any one claims 27 to 44, wherein prior to step a), the amino alcohol is first substituted with R_2, in order to produce Formula la

wherein R₂ is an alkyl, preferably CH₃.

46. A pharmaceutical composition comprising a therapeutically effective amount of Formula I according to any one of claims 1 to 26.

47. The composition according to claim 46, wherein the composition further includes a pharmaceutically acceptable excipient, adjuvant, carrier, buffer, stabilizer or the like.

48. The composition according to claim 46 or 47, wherein the composition is in a tablet, capsule, powder or liquid form.

49. A compound of Formula I according to any one of claims 1 to 26, or the composition according to any one of claims 46 to 48 for use in a method of treating tuberculosis or other microbial infections, the method comprising the step of administering to a subject the composition or compound.

50. The compound or composition according to claim 49, wherein the microbial infection is caused by Mycobacterium tuberculosis.

51 . A compound of Formula I according to any one of claims 1 to 26 or the composition according to any one of claims 46 to 48 for use in a method of treating infectious diseases including malaria, trypanosomiasis, Chagas' disease, Leishmaniasis and Schistosomiasis, the method comprising the step of administering to a subject the composition or compound.

52. The compound or composition according to any one of claims 49 to 51 , wherein the compound or composition is administered in a single dose, or multiple doses.

53. The compound or composition according to any one of claims 49 to 52 wherein the compound or composition is administered alone or in combination with another therapeutic agent or agents.

54. Use of a compound of Formula I according to any one of claims 1 to 26 in the manufacture of a medicament for use in a method of treating tuberculosis or other microbial infections, the method comprising the step of administering to a subject the medicament.

55. The use according to claim 54, wherein the microbial infection is caused by Mycobacterium tuberculosis.

56. Use of a compound of Formula I according to any one of claims 1 to 26 in the manufacture of a medicament for use in a method of treating infectious diseases including malaria, trypanosomiasis, Chagas' disease, Leishmaniasis and Schistosomiasis, the method comprising the step of administering to a subject the medicament.

57. The use according to any one of claims 54 to 56, wherein the medicament is administered in a single dose, or multiple doses. The use according to any one of claims 54 to 57, wherein the medicament is administered alone or in combination with another therapeutic agent or agents.