Nitroimidazooxazine and nitroimidazooxazole analogues and use thereof

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to nitroimidazooxazine derivatives of general formula I, where n equals 1, V and W independently denote H or CH3, and one of X and Y is H and the other is one of the formulae and , where formula IIa includes a single ring labelled at position 3 and position 4 and containing R1 as a substitute, and formula IIb includes a first ring labelled at position 3 and position 4 and containing as substitutes both R2 and a terminal ring, labelled at position 4 and containing R1 as a substitute, where the single ring of formula IIa and the first ring and the terminal ring of formula IIb include C, CH, or N at each ring position, where the single ring of formula IIa and the first ring and the terminal ring of formula IIb independently contain no more than two nitrogen atoms; Z in formulae IIa and IIb is CH2 or a direct bond, R1 is independently any one or two of H, F, C1, CF3, OCF3 or OCH2Ph, and R2 is H. The invention also relates to a pharmaceutical composition based on the compound of formula I, a method of preventing and treating a microbial infection based on use of the compound of formula , and specific nitroimidazooxazine derivatives.

EFFECT: obtaining novel compounds with useful biological activity.

7 cl, 21 dwg, 3 tbl

 

Prior art

[0001] this application claims priority from provisional patent application U.S. serial number 61/230422 entitled "Nitroimidazolidin and nitroimidazole analogues and their application", filed July 31, 2009, the complete contents of which are incorporated into this description by reference.

[0002] the Present invention relates to nitroimidazolidin and nitroimidazolidin counterparts, to receive them and to their use as drugs, effective againstMycobacterium tuberculosisand as Antiprotozoal funds, either alone or in combination with other treatments.

[0003] Tuberculosis remains a major infection, which is the cause of death spread throughout the world (estimated mortality was 1.3 million in 2008), while in the last time, this infection has intensified, which is attributed to the increased susceptibility of HIV patients and also due to the growth of the incidence of strains with multiple drug resistance and the emergence of strains with strong drug resistance. Current drug therapy for TB treatment is long and complex and involves a combination of several drugs (usually isoniazid is a, rifampin, pyrazinamide and ethambutol), administered daily for over 6 months. In addition, these drugs are relatively ineffective against the persistent form of the disease, which is assumed to occur in the majority of cases (Ferrara et al., 2006). Drugs of the second line, used in long-term combined therapies for poliglecaprone-resistant disease (usually more than 2 years), in most cases, have a low activity level or higher toxicity compared to existing primary tools. Often the treatment is incomplete, which leads to a high number of relapses and increased drug resistance, which highlights the urgent need for new, more effective medicines.

[0004] Chagas Disease affects about 9 million people, mainly in South America, and leads to about 14,000 cases of deaths annually. The reason that causes this disease is a protozoan parasiteTrypanosoma cruzithat is transmitted to humans by blood-sucking insects. Two currently available drugs for treatment, nifurtimox and benznidazol demonstrate the efficiency, which is limited to the acute phase of the disease and only some pathogenic strains. These l the drug funds also have serious side effects, and this, together with the necessary long-term and expensive treatment, leads to the fact that patients not adequately respond to treatment, as well as to the development of drug resistance (Cavalli et al., 2009).

[0005] Leishmaniasis affect nearly 12 million people in about 90 countries and lead to around 51,000 cases of deaths annually. They are especially common in the Indian subcontinent and in East Africa, where the parasiteLeishmania donovaniis the cause of this disease. This parasite is transmitted to humans through the bite of female mosquitoes, and he is responsible for the most severe form, visceral leishmaniasis (Kala-Azar), which triggers a chronic disease of the liver and spleen and is fatal if not treated by chemotherapy. Primary treatment includes drugs on the basis of antimony meglumin antimonate (glucantime) and stibogluconate sodium (pentostam), discovered more than 50 years ago, which have severe unwanted side effects. Their introduction in low doses over a long period of time has led to an increasing number of cases of drug resistance, such that they can no longer be used in India (Cavalli et al., 2009). Means of the second stage have the same problems of toxicity, which indicates a real need for safer, more effective treatments.

[0006] It is the fact highly desirable to provide new nitroimidazolidin and nitroimidazole analogues with unexpectedly high activity against both aerobic (replicate), and hypoxic (latent or persistent) culturesMycobacterium tuberculosisfor use as anti-TB drugs, and/or unexpectedly high activity againstTrypanosoma cruziorLeishmania donovanifor use as Antiprotozoal funds, and for the treatment of other microbial infections.

Brief description of the invention

[0007] the Present invention relates to nitroimidazolidin and nitroimidazole analogues, processes for their preparation and to the use of such compounds as tools for the treatment ofMycobacterium tuberculosisfor use as anti-TB medicines for use as anti-protozoal funds with unexpectedly high activity againstTrypanosoma cruziorLeishmania donovanifor the treatment of other microbial infections.

[0008] the fact that nitroimidazolidin PA-824 was recently introduced to the stage of clinical trials is very important because this compound shows good in vitro and in vivo activity againstMycobacterium tuberculosisboth the active and persistent forms (Tyagi et al., 2005). Related 2-nitroimidazo[2,1-b]oxazol, OPC-67683, is also under clinical trials (Sasaki et al., 2006). The structure of these compounds is shown in Fig.1. Not wishing to be bound by theory, suggest that the mechanism of action of PA-84 involves the release of nitric oxide (Singh et al., 2008), after the recovery stage, in the way that, dependent on bacterial glucose-6-phosphate-dehydrogenase (FGD1) and its cofactor F420 (Stover et al., 2000). Studies using chips on mutant strains of wild-type, as for FGD1 and F420, showed that 151-amino acid (17,37 kDa) protein with unknown function, Rv3547, apparently, is critical for this activation (Manjunatha et al., 2006). Carried out recently mechanistic studies of the reductive chemistry of PA-824 confirm this point of view (Anderson et al., 2008). Nitroimidazolidin analogues and nitroimidazole analogues and their use in tuberculosis have been described previously (U.S. patent 5668127 and 6087358; Jiricek et al., WO 2007075872A2; Li et al., 2008; Kim et al., 2009; Nagarajan et al., 1989; Ashtekar et al., 1993; Sasaki et al., 2006; Matsumoto et al., 2006; Tsubochi et al., WO 2005042542A1 and WO 2004033463 A1; JP 2005330266A; EP 1555267A1).

[0009] In a first aspect the present invention relates to a compound having the General structural formula I:

where n is 0 or 1,

V and W independently represent H or CH3and

one of X or Y represents H and the other represents one of the formulas IIa or IIb, where formulas IIa and IIb have the General structure:

where the formula IIb includes the first ring marked at position 3 and position 4 and containing as substituents as R2and to Navoi ring, marked in position 4 and containing R1as a substitute,

Z in formulas IIa and IIb represents CH2or a direct link, and

R1and R2each represents any one or two of H, F, Cl, I, CN, CF3, OCF3, OCH3, OCH2Ph, Aza (-CH= replaced by a group-N=) or diaza (-CH=CH - replaced by a group-N=N-, -CH=CH-CH= replaced by a group-N=CH-N= or-CH=CH-CH=CH - replaced by a group-N=CH-CH=N-) in any of the available positions in the ring;

provided that when n is 0, V, W and X all represent H, and Y represents the formula IIa, where Z represents a CH2or a direct link, then R1is not H;

and provided that when n is 0, V and X both represent H, and W represents CH3and Y represents the formula IIa, where Z represents a direct bond, then R1is not H, 4-Cl, 4-I, 4-CF3, 4-OCH3or 4-OCF3;

and provided that when n is 0, V and X both represent H, and W represents CH3and Y represents the formula IIb, where Z represents a direct bond, an end ring is in position 4 at the first ring, and R2represents H, then R1is not H or 4-Aza.

[0010] a More preferred subclass of compounds includes compounds having the General structural formula I, as defined above, where:

n is 0 or 1,/p>

V and W independently represent H or CH3and

one of X or Y represents H and the other represents one of the formulas IIa or IIb, where formulas IIa and IIb have the General structure:

where the formula IIb includes the first ring marked at position 3 and position 4 and containing as substituents as R2and the end ring marked in position 4 and containing R1as a substitute,

Z in formulas IIa and IIb represents CH2or a direct link,

R1is a 4-F, 4-CN, 4-I, 4-CF3, 3-OCF3, 4-OCF3, 4-OCH2Ph or 3-Aza-4-OMe, and

R2represents H, Aza (-CH= replaced by a group-N=) or diaza (-CH=CH - replaced by a group-N=N-, -CH=CH-CH= replaced by a group-N=CH-N= or-CH=CH-CH=CH - replaced by a group-N=CH-CH=N-) in any of the available positions in the ring;

provided that when n is 0, V, W and X all represent H, and Y represents the formula IIa, where Z represents a CH2or a direct link, then R1is not H;

and provided that when n is 0, V and X both represent H, and W represents CH3and Y represents the formula IIa, where Z represents a direct bond, then R1is not H, 4-Cl, 4-I, 4-CF3, 4-OCH3or 4-OCF3;

and provided that when n is 0, V and X both represent H, and W p is ecstasy a CH 3and Y represents the formula IIb, where Z represents a direct bond, an end ring is in position 4 at the first ring, and R2represents H, then R1is not H or 4-Aza.

[0011] These compounds, and their mixtures, isomers, physiologically functional salt derivatives and prodrugs are useful for the prevention or treatment ofMycobacterium tuberculosisfor use as anti-TB drugs for use as Antiprotozoal funds with unexpectedly high activity againstTrypanosoma cruziorLeishmania donovanifor the treatment of other microbial infections.

Brief description of drawings

[0012] In Fig.1 presents the structure of the compounds of PA-824 and OPC-67683;

[0013] in Fig.2 presents the General structure of the representative compounds listed in table 1;

[0014] in Fig.3 shows the General scheme of synthesis for the preparation of representative compounds;

[0015] in Fig.4 shows the General scheme of synthesis for the preparation of representative compounds;

[0016] in Fig.5 shows the General scheme of synthesis for the preparation of representative compounds;

[0017] in Fig.6 shows the General scheme of synthesis for the preparation of representative compounds;

[0018] in Fig.7 shows the General scheme of synthesis for the preparation of representative compounds;

[0019] in Fig.8 a is redstavlena General scheme of synthesis for the preparation of representative compounds;

[0020] in Fig.9 shows the General scheme of synthesis for the preparation of representative compounds;

[0021] in Fig.10 shows the General scheme of synthesis for the preparation of representative compounds;

[0022] in Fig.11 shows the General scheme of synthesis for the preparation of representative compounds;

[0023] in Fig.12 shows the General scheme of synthesis for the preparation of representative compounds;

[0024] in Fig.13 shows the General scheme of synthesis for the preparation of representative compounds;

[0025] in Fig.14 shows the General scheme of synthesis for the preparation of representative compounds;

[0026] in Fig.15 shows the General scheme of synthesis for the preparation of representative compounds;

[0027] in Fig.16 shows the General scheme of synthesis for the preparation of representative compounds;

[0028] in Fig.17 shows the General scheme of synthesis for the preparation of representative compounds;

[0029] in Fig.18 shows the structure of representative compounds 1-20 shown in table 1 and examples 1-3;

[0030] in Fig.19 shows the structures of representative compounds 21-38 shown in table 1 and examples 1-3;

[0031] in Fig.20 shows the structures of representative compounds 39-58 shown in table 1 and examples 1-3; and

[0032] in Fig.21 presents the structures of representative compounds 59-75 shown in table 1 and examples 1-3.

A detailed description of repectfully of embodiments of the invention

[0033] the Present invention relates to nitroimidazolidin and nitroimidazole analogues, processes for their preparation and to the use of compounds for the prevention or treatment ofMycobacterium tuberculosisfor use as anti-TB drugs for use as Antiprotozoal funds with unexpectedly high activity againstTrypanosoma cruziorLeishmania donovanifor the treatment of other microbial infections.

[0034] In the first aspect of the present invention relates to a compound having the General structural formula I:

where n is 0 or 1,

V and W independently represent H or CH3and

one of X or Y represents H and the other represents one of the formulas IIa or IIb, where formulas IIa and IIb have the General structure:

where the formula IIb includes the first ring marked at position 3 and position 4 and containing as substituents as R2and the end ring marked in position 4 and containing R1as a substitute,

Z in formula IIa and IIb represents CH2or a direct link, and

R1and R2each represents any one or two of H, F, Cl, I, CN, CF3, OCF3, OCH3, OCH2Ph, Aza (-CH= replaced by a group-N=) or diaza (-CH=CH - replaced by a group-N=N-, -CH=C-CH= replaced by group N=CH-N=, or-CH=CH-CH=CH - replaced by a group-N=CH-CH=N-) in any of the available positions in the ring;

provided that when n is 0, V, W and X all represent H, and Y represents the formula IIa, where Z represents a CH2or a direct link, then R1is not H;

and provided that when n is 0, V and X both represent H, and W represents CH3and Y represents the formula IIa, where Z represents a direct bond, then R1is not H, 4-Cl, 4-I, 4-CF3, 4-OCH3or 4-OCF3;

and provided that when n is 0, V and X both represent H, and W represents CH3and Y represents the formula IIb, where Z represents a direct bond, an end ring is in position 4 at the first ring, and R2represents H, then R1is not H or 4-Aza.

[0035] More preferred subclass of compounds includes compounds having the General structural formula I, as defined above, where:

n is 0 or 1,

V and W independently represent H or CH3and

one of X or Y represents H and the other represents one of the formulas IIa or IIb, where formulas IIa and IIb have the General structure:

where the formula IIb includes the first ring marked at position 3 and position 4 and containing as substituents as R2and oncewe ring, marked in position 4 and containing R1as a substitute,

Z in formulas IIa and IIb represents CH2or a direct link,

R1is a 4-F, 4-CN, 4-I, 4-CF3, 3-OCF3, 4-OCF3, 4-OCH2Ph or 3-Aza-4-OMe, and

R2represents H, Aza (-CH= replaced by a group-N=) or diaza (-CH=CH - replaced by a group-N=N-, -CH=CH-CH= replaced by a group-N=CH-N= or-CH=CH-CH=CH - replaced by a group-N=CH-CH=N-) in any of the available positions in the ring;

provided that when n is 0, V, W and X all represent H, and Y represents the formula IIa, where Z represents a CH2or a direct link, then R1is not H;

and provided that when n is 0, V and X both represent H, and W represents CH3and Y represents the formula IIa, where Z represents a direct bond, then R1is not H, 4-Cl, 4-I, 4-CF3, 4-OCH3or 4-OCF3;

and provided that when n is 0, V and X both represent H, and W represents CH3and Y represents the formula IIb, where Z represents a direct bond, an end ring is in position 4 at the first ring, and R2represents H, then R1is not H or 4-Aza.

[0036] the Most preferred compounds of formula I are the following:

A. 6-nitro-2-{[4-(triptoreline)phenoxy]methyl}-2,3-dihydroimidazo the[2,1-b][1,3]oxazole (compound 1 of table 1 and Fig.18);

B. 2-{[4-(benzyloxy)phenoxy]methyl}-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 2 of table 1 and Fig.18);

C. 2-{[(4'-fluoro[1,1'-biphenyl]-4-yl)oxy]methyl}-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 3 of table 1 and Fig.18);

D. 6-nitro-2-({[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]oxy}methyl)-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 4 of table 1 and Fig.18);

E. 6-nitro-2-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]oxy}methyl)-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 5 of table 1 and Fig.18);

F. 6-nitro-2-[({5-[4-(triptoreline)phenyl]-2-pyridinyl}oxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 6 of table 1 and Fig.18);

G. 2-{[4-(benzyloxy)phenoxy]methyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 7 of table 1 and Fig.18);

H. 2-{[4-(6-methoxy-3-pyridinyl)phenoxy]methyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 8 of table 1 and Fig.18);

I. 4'-[(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazol-2-yl)methoxy][1,1'-biphenyl]-4-carbonitrile (compound 9 of table 1 and Fig.18);

J. 2-{[(4'-fluoro[1,1'-biphenyl]-4-yl)oxy]methyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 10 of table 1 and Fig.18);

K. 2-methyl-6-nitro-2-({[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]oxy}methyl)-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 11 in table 1 and Fig.18);

L. 2-methyl-6-nitro-2-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]oxy}methyl)-2,3-dihydroimidazo[2,1-b][1,3]oxazol (link is (12) of table 1 and Fig.18);

M. 2-({[5-(4-forfinal)-2-pyridinyl]oxy}methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 13 of table 1 and Fig.18);

N. 2-methyl-6-nitro-2-[({5-[4-(triptoreline)phenyl]-2-pyridinyl}oxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 14 of table 1 and Fig.18);

O. 2-({[6-(4-forfinal)-3-pyridinyl]oxy}methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 15, table 1 and Fig.18);

P. 2-methyl-6-nitro-2-[({6-[4-(triptoreline)phenyl]-3-pyridinyl}oxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 16 of table 1 and Fig.18);

Q. 2-({[5-(4-forfinal)-2-pyrimidinyl]oxy}methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 17 of table 1 and Fig.18);

R. 2-methyl-6-nitro-2-[({5-[4-(triptoreline)phenyl]-2-pyrimidinyl}oxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 18 of table 1 and Fig.18);

S. 2-({[2-(4-forfinal)-5-pyrimidinyl]oxy}methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 19 of table 1 and Fig.18);

T. 2-methyl-6-nitro-2-[({2-[4-(triptoreline)phenyl]-5-pyrimidinyl}oxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 20 of table 1 and Fig.18);

U. 2-({[5-(4-forfinal)-2-pyrazinyl]oxy}methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 21 table 1 and Fig.19);

V. 2-methyl-6-nitro-2-[({5-[4-(triptoreline)phenyl]-2-pyrazinyl}oxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 22 of table 1 and Fig.19);

W. 6-nitro-({[4-(triptoreline)benzyl]oxy}methyl)-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 23 in table 1 and Fig.19);

X. 2-({[4-(benzyloxy)benzyl]oxy}methyl)-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 24 of table 1 and Fig.19);

Y. 2-methyl-6-nitro-2-({[4-(triptoreline)benzyl]oxy}methyl)-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 25 of table 1 and Fig.19);

Z 2-({[4-(benzyloxy)benzyl]oxy}methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 26 table 1 and Fig.19);

AA. 2-nitro-7-{[4-(triptoreline)phenoxy]methyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 27 of table 1 and Fig.19);

BB. 7-{[4-(benzyloxy)phenoxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 28 in table 1 and Fig.19);

CC. 7-{[(4'-fluoro[1,1'-biphenyl]-4-yl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 29 in table 1 and Fig.19);

DD. 2-nitro-7-({[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 30 in table 1 and Fig.19);

EE. 2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 31 in table 1 and Fig.19);

FF. 7-({[5-(4-forfinal)-2-pyridinyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 32 in table 1 and Fig.19);

GG. 2-nitro-7-[({5-[4-(triptoreline)phenyl]-2-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 33 in table 1 and Fig.19);

ΗΗ. 7-({[6-(4-forfinal)-3-pyridinyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 34 in table 1 and Fig.19;

II. 2-nitro-7-[({6-[4-(triptoreline)phenyl]-3-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 35 table 1 and Fig.19);

JJ. 7-methyl-2-nitro-7-{[4-(triptoreline)phenoxy]methyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 36 in table 1 and Fig.19);

KK. 7-{[4-(benzyloxy)phenoxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 37 table 1 and Fig.19);

LL. 7-{[(4'-fluoro[1,1'-biphenyl]-4-yl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 38 table 1 and Fig.19);

MM. 7-methyl-2-nitro-7-({[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 39 in table 1 and Fig.20);

NN. 7-methyl-2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 40 table 1 and Fig.20);

O.O. 7-({[5-(4-forfinal)-2-pyridinyl]oxy}methyl)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 41 table 1 and Fig.20);

PP. 7-methyl-2-nitro-7-[({5-[4-(trifluoromethyl)phenyl]-2-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 42 table 1 and Fig.20);

QQ. 7-methyl-2-nitro-7-[({5-[4-(triptoreline)phenyl]-2-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 43 table 1 and Fig.20);

RR. 7-({[6-(4-forfinal)-3-pyridinyl]oxy}methyl)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 44 table 1 and Fig.20);

SS. 7-methyl-2-nitro-7-[({6-[4-(t is iformity)phenyl]-3-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 45 in table 1 and Fig.20);

TT. 7-methyl-2-nitro-7-[({6-[4-(triptoreline)phenyl]-3-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 46 in table 1 and Fig.20);

UU. 2-nitro-7-({[3-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 47 table 1 and Fig.20);

VV. 2-nitro-7-({[4-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 48 table 1 and Fig.20);

WW. 7-({[4-(benzyloxy)benzyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 49 in table 1 and Fig.20);

XX. 2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-3-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 50 table 1 and Fig.20);

YY. 2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 51 table 1 and Fig.20);

ZZ. 7-methyl-2-nitro-7-({[3-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 52 in table 1 and Fig.20);

AAA. 7-methyl-2-nitro-7-({[4-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 53 table 1 and Fig.20);

The BBB. 7-({[4-(benzyloxy)benzyl]oxy}methyl)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 54 table 1 and Fig.20);

CCC. 7-methyl-2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-3-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 55 table 1 and Fig.20);

The DDD. 7-methyl-2-nitro-7-({[4'-(triptoreline)[1,1'-[the Nile]-4-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 56 table 1 and Fig.20);

The EEE. (7R)-7-methyl-2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 57 table 1 and Fig.20);

FFF. (7S)-7-methyl-2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 58 table 1 and Fig.20);

GGG. 2-nitro-6-{[4-(triptoreline)phenoxy]methyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 59 table 1 and Fig.21);

HHH. (6R)-2-nitro-6-{[4-(triptoreline)phenoxy]methyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 60 table 1 and Fig.21);

III. (6S)-2-nitro-6-{[4-(triptoreline)phenoxy]methyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 61 table 1 and Fig.21);

JJJ. 6-{[(4'-fluoro[1,1'-biphenyl]-4-yl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 62 table 1 and Fig.21);

KKK. 2-nitro-6-({[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 63 table 1 and Fig.21);

LLL. 2-nitro-6-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 64 table 1 and Fig.21);

MMM. 6-({[5-(4-forfinal)-2-pyridinyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 65 table 1 and Fig.21);

NNN. 2-nitro-6-[({5-[4-(trifluoromethyl)phenyl]-2-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 66 table 1 and Fig.21);

OOO. 2-nitro-6-[({5-[4-(triptoreline)phenyl]-2-pyridinyl}oxy)m is Teal]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 67 table 1 and Fig.21);

PPP. 6-({[6-(4-forfinal)-3-pyridinyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 68 table 1 and Fig.21);

QQQ. 2-nitro-6-[({6-[4-(trifluoromethyl)phenyl]-3-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 69 in table 1 and Fig.21);

RRR. 2-nitro-6-[({6-[4-(triptoreline)phenyl]-3-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 70 table 1 and Fig.21);

The SSS. 2-nitro-6-({[3-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 71 table 1 and Fig.21);

TTT. 2-nitro-6-({[4-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 72 table 1 and Fig.21);

UUU. 6-({[4-(benzyloxy)benzyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 73 table 1 and Fig.21);

VVV. 2-nitro-6-({[4'-(triptoreline)[1,1'-biphenyl]-3-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 74 table 1 and Fig.21), and

WWW. 2-nitro-6-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 75 table 1 and Fig.21).

[0037] the compounds of formula I may exist in different geometric and enantiomeric forms, and as a pure form and mixtures of these individual isomers are included within the scope of the present invention, and any physiologically functional or pharmacologically acceptable salt derivatives or prodrugs is. The receipt of such alternative forms should not be difficult for professionals in this field.

[0038] the Present invention also relates to methods of preventing or treating tuberculosis, protozoa and other microbial infections, such asMycobacterium tuberculosis,Trypanosoma cruziandLeishmania donovaniincluding the stage of introduction of the compounds of formula I.

[0039] In another aspect the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compounds of formula I, defined above, and pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabilizer. By "therapeutically effective amount" refers to the amount of the compounds of formula I that is sufficient for the manifestation of antibacterial or antimicrobial effects. The actual amount, frequency and duration of injection depends on the nature and severity of the disease to be treated. The treatment prescribed by General practitioners and other doctors. Pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabilizer should be non-toxic and should not adversely affect the efficacy of the active ingredient. The specific nature of the media or other substance depends on route of administration, which can be represented as per the General route of administration or by injection, such as intradermal, subcutaneous, intravenous injection, or using a dry powder inhaler.

[0040] Pharmaceutical compositions for oral administration can be in the form of tablets, capsules, powder or liquid. The tablet may include a solid carrier or adjuvant. Liquid pharmaceutical compositions typically contain a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Can be included physiological saline solution, dextrose or other saccharide or glycols, such as ethylene glycol, propylene glycol or polyethylene glycol. The capsule may contain a solid carrier such as gelatin. For intravenous, intradermal or subcutaneous injection of the active ingredient must be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Specialists with relevant expertise, will be able to obtain suitable solutions using, for example, isotonic medium, such as a solution of sodium chloride for injection, ringer's solution for injection containing lactate ringer's solution for injection. Preservatives, stabilizers, buffers, antioxidants and/or other additives can be included, as necessary is on.

[0041] the Pharmaceutical composition can also contain one or more additional therapeutic agents against infection. Such a therapeutic agent against infection can be any suitable, commercially available therapeutic agent or available from other sources, which is known as effective for the prevention or treatment of microbial infections, such asMycobacterium tuberculosis,Trypanosoma cruziand/orLeishmania donovani.

[0042] In another aspect is provided the application for obtaining a medicinal product, comprising a therapeutically effective amount of the compounds of formula I, defined above, to introduce the subject. Also provided is a method of obtaining the compounds of formula I.

[0043] the Term "pharmacologically acceptable salt" used in the present description should be understood as meaning any salt of the acid or base formed from hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, ititonovul acids and the like, and potassium carbonate, sodium hydroxide or potassium hydroxide, ammonia, triethylamine, triethanolamine and the like.

[0044] the Term "prodrug" means a pharmaceutical agent that is administered in an inactive and is and is essentially a less active form. After the introduction of the prodrug is metabolized in vivo to the active metabolite.

[0045] the Term "therapeutically effective amount" means a non-toxic quantity of a drug, but which is sufficient to provide the desired therapeutic effect. The amount that is "effective" for different subjects will be different, depending on the age and General condition of the subject, specific input concentration and composition, etc. Thus, it is not always possible to determine exactly what the number is effective. However, a suitable effective amount in each case will be able to determine a specialist in this area, with average qualifications, using routine experimentation. In addition, the effective amount is a concentration within sufficient so that you can easily use the composition for delivery of a quantity of drugs within a therapeutically effective amount.

[0046] the Term "Aza" means the group-CH=, which is replaced with-N= in the connection. The term "Diaz" means the group-CH=CH-, which is replaced with-N=N-, group-CH=CH-CH=, which is replaced with-N=CH-N=, or the group-CH=CH-CH=CH-, which is replaced with-N=CH-CH=N-, in the connection.

[0047] Other aspects of the present invention will be Acevi who are from the following description, presented exclusively by means of examples, with reference to the accompanying schematic synthesis.

EXAMPLE 1. General scheme of synthesis

[0048] the Compound can be obtained by the General methods shown in schemes 1 to 15, which is shown in Fig.3-17, or using any other suitable method. In the following description schemes 1-15 refer to representative compounds are presented in table 1 below and in Fig.2 and 18-21.

Table 1
Representative compounds
NoFig.2 StructureRFormulaSo pl. (°C)Tests
1A4-OCF3(X=H)C13H10F3N3O5170-172C,H,N
2A4-OCH2Ph (X=H)C19H17N3O5208-210C,H,N
3A4-[(4-F)phenyl] (X=H)C18H14FN3O4224-226
4A4-[(4-CF3)phenyl] (X-H)C19H14F3N3O4210-211
5A4-[(4-OCF3)phenyl] (X=H)C19H14F3N3O5200-201C,H,N
6A2-Aza, 4-[(4-OCF3)phenyl] (X=H)Cl8H13F3N4O5127-130
7A 4-OCH2Ph (X=Me)C20H19N3O5162 to 165C,H,N
8A4-[(6-OMe)3-pyridyl)] (X=Me)C19H18N4O5217-219C,H,N
9A4-[(4-CN)phenyl] (X=Me)C20H16N4O4180-181C,H,N
10A4-[(4-F)phenyl] (X=Me)C19H16FN3O4180-181C,H,N
11A4-[(4-CF3)phenyl] (X=Me)C20H16F3N3O4219-220C,H,N
12A4-[(4-OCF3)phenyl] (X=Me) C20H16F3N3O5209-211C,H,N
13A2-Aza, 4-[(4-F)phenyl] (X=Me)C18H15FN4O4162-164
14A2-Aza, 4-[(4-OCF3)phenyl] (X=Me)C19H15F3N4O5172-174C,H,N
15A3-Aza, 4-[(4-F)phenyl] (X=Me)C18H15FN4O4180-181
16A3-Aza, 4-[(4-OCF3)phenyl] (X=Me)C19H15F3N4O5209-211C,H,N
17A2,6-diaza, 4-[(4-F)phenyl] (X=Me)C17H14FN5 O4196 decomp.C,H,N
18A2,6-diaza, 4-[(4-OCF3)phenyl] (X=Me)C18H14F3N5O5227 decomp.C,H,N
19A3,5-diaza, 4-[(4-F)phenyl] (X=Me)C17H14FN5O4201-203
20A3,5-diaza, 4-[(4-OCF3)phenyl] (X=Me)C18H14F3N5O5223-225C,H,N
21A2,5-diaza, 4-[(4-F)phenyl] (X=Me)C17H14FN5O4200-201C,H,N
22A2,5-diaza, 4-[(4-OCF3)phenyl)] (X=Me)C18H14F3Nsub> 5O5222-224C,H,N
23B4-OCF3(X=H)C14H12F3N3O5134-135C,H,N
24B4-OCH2Ph (X=H)C20H19N3O5123-124C,H,N
25B4-OCF3(X=Me)C15H14F3N3O5110-111C,H,N
26B4-OCH2Ph (X=Me)C21H21N3O5130-131C,H,N
27C4-OCF3(X=H)C14H12F3N3O5138-140 C,H,N
28C4-OCH2Ph (X=H)C20H19N3O5
0,25 H2O
222-224C,H,N
29C4-[(4-F)phenyl] (X=H)C19H16FN3O4217-219C,H,N
30C4-[(4-CF3)phenyl] (X=H)C20H16F3N3O4242-245C,H,N
31C4-[(4-OCF3)phenyl] (X=H)C20H16F3N3O5197-199C,H,N
32C2-Aza, 4-[(4-F)phenyl] (X=H)C18H15FN4O4180-181
33C2-Aza, 4-[(4-OCF3)phenyl] (X=H)C19H15F3N4O5161-163C,H,N
34C3-Aza, 4-[(4-F)phenyl] (X=H)C18H15FN4O4204-206
35C3-Aza, 4-[(4-OCF3)phenyl] (X=H)C19H15F3N4O5161-163C,H,N
36C4-OCF3(X=Me)C15H14F3N3O5134-136C,H,N
37C4-OCH2Ph (X=Me)C21H21N3O5174-176C,H,N
38C 4-[(4-F)phenyl] (X=Me)C20H18FN3O4160-162C,H,N
39C4-[(4-CF3)phenyl] (X=Me)C21H18F3N3O4196-198C,H,N
40C4-[(4-OCF3)phenyl] (X=Me)C21H18F3N3O5186-188C,H,N
41C2-Aza, 4-[(4-F)phenyl] (X=Me)C19H17FN4O4145-147C,H,N
42C2-Aza, 4-[(4-CF3)phenyl] (X=Me)C20H17F3N4O4212-214C,H,N
43C2-Aza, 4-[(4-OCF3)phenyl] (X=Me) C20H17F3N4O5195-198C,H,N
44C3-Aza, 4-[(4-F)phenyl] (X=Me)C19H17FN4O4203-204C,H,N
45C3-Aza, 4-[(4-CF3)phenyl] (X=Me)C20H17F3N4O4215-217C,H,N
46C3-Aza, 4-[(4-OCF3)phenyl] (X=Me)C20H17F3N4O5202-203C,H,N
47D3-OCF3(X=H)C15H14F3N3O5100-112C,H,N
48D4-OCF3(X=H)C15H14F3N 3O5158-160C,H,N
49D4-OCH2Ph (X=H)C21H21N3O5151-153C,H,N
50D3-[(4-OCF3)phenyl] (X=H)C21H18F3N3O5117-119C,H,N
51D4-[(4-OCF3)phenyl] (X=H)C21H18F3N3O5159-161C,H,N
52D3-OCF3(X=Me)C16H16F3N3O5108-110C,H,N
53D4-OCF3(X-Me)C16H16F3N3O5100-10 C,H,N
54D4-OCH2Ph (X=Me)C22H23N3O5109-111C,H,N
55D3-[(4-OCF3)phenyl] (X=Me)C22H20F3N3O580-82C,H,N
56D4-[(4-OCF3)phenyl] (X=Me) (rat)C22H20F3N3O5150-152C,H,N
57D4-[(4-OCF3)phenyl] (X=Me) (7-R)C22H20F3N3O5165-167C,H,N
58D4-[(4-OCF3)phenyl] (X=Me) (7-S)C22H20F3N3O5162-164 C,H,N
59E4-OCF3(rat)C14H12F3N3O5141-143C,H,N
60E4-OCF3(6-R)C14H12F3N3O5138-139C,H,N
61E4-OCF3(6-S)C14H12F3N3O5139-140C,H,N
62E4-[(4-F)phenyl]C19H16FN3O4201-203C,H,N
63E4-[(4-CF3)phenyl]C20H16F3N3O4218 to 221C,H,N
64 E4-[(4-OCF3)phenyl]C20H16F3N3O5192-194C,H,N
65E2-Aza, 4-[(4-F)phenyl]C18H15FN4O4160-161C,H,N
66E2-Aza, 4-[(4-CF3)phenyl]C19H15F3N4O4180-182C,H,N
67E2-Aza, 4-[(4-OCF3)phenyl]C19H15F3N4O5182-183C,H,N
68E3-Aza, 4-[(4-F)phenyl]C18H15FN4O4214-216C,H,N
69E3-Aza, 4-[(4-CF )phenyl]C19H15F3N4O4233-235C,H,N
70E3-Aza, 4-[(4-OCF3)phenyl]C19H15F3N4O5180-181C,H,N
71F3-OCF3C15H14F3N3O560-61C,H,N
72F4-OCF3C15H14F3N3O592-93C,H,N
73F4-OCH2PhC21H21N3O5150-151C,H,N
74F3-[(4-OCF3)phenyl]C21H18F3 N3O578-80C,H,N
75F4-[(4-OCF3)phenyl]C21H18F3N3O5135-138C,H,N

[0049] In scheme 1, shown in Fig.3, used the following reagents and conditions: (i) RPhOH, K2CO3, acetone, boiling under reflux, 36-52 hour; (ii) the connection77, 78or79, DIPEA, 105°C, 6.5 to 12 h; (iii) NaH, DMF, 0°C, 45 min; (iv) NaH, DMF, 0°C, 80 min, then 17°C, 60 min; (v) ArB(OH)2, 2M Na2CO3, toluene, EtOH, DMF, Pd(dppf)Cl2in an atmosphere of N2, 88-90°C, 50 to 90 minutes Catalyzed basis of the interaction of 2-bromo-4(5)-intorimidazole (80) or 2-chloro-4(5)-intorimidazole (81with epoxides77-79[obtained by alkylation of the corresponding 4-substituted phenols using 2-(methyl bromide)oxirane (76)] gave the alcohols82-84who was subjected to reaction ring closure using NaH, with the formation of compounds 1 and 2, tables 1 and iodide85respectively. Reaction mix according to the method of Suzuki connection 85 with arylboronic acids were then given connection3-5table 1.

[0050] In scheme 2, shown in Fig.4, used the following Reagan the s and conditions: (i) 70°C, 16 h; (ii) NaH, DMF, -20 to -10°C, 50 min; (iii) 1% HCl in 95% EtOH, 20°C, 6 h, and then 4°C for 2.5 days; (iv) 4-OCF3PhB(OH)2, 2M Na2CO3, toluene, EtOH, Pd(dppf)Cl2in an atmosphere of N2, 85-88°C, 3 h; (v) 90, NaH, DMF, 0-20°C, 2.5 hours. The interaction of 2,4-dinitroanisole (86with epoxide87gave alcohol88, which was subjected to reaction ring closure using NaH, with subsequent acid catalyzed by disilylgermane, obtaining alcohol90. Carried out with the assistance NaH alkylation connection90herperidin92[obtained by the reaction of a combination of Suzuki 5-bromo-2-herperidin (91) with 4-(triptoreline)phenylboronic acid] then gave the connection6table 1.

[0051] In scheme 3, shown in Fig.5, used the following reagents and conditions: (i) A-BnOPhOH, K2CO3, acetone, boiling under reflux, 24 h; (ii) m-CPBA, Na2HPO4CH2Cl2, 0-20°C, 3.5 h; (iii) 4-IPhOH, K2CO3, NaI, DMF, 70-73°C, 32 h; (iv) the connection80, DIPEA, 107°C, 14-15 hour; (v) NaH, DMF, 0°C, 50-75 min; (vi) ArB(OH)2, 2M Na2CO3, toluene, EtOH, Pd(dppf)Cl2in an atmosphere of N2, 90°C, 45 minutes Catalyzed basis of the interaction of 2-bromo-4(5)-intorimidazole (80with epoxides95and96[received by metallizirovanaya 4-(benzyloxy)phenol using chloride93with further epoxydecane, or by al is eleirovania 4-itfinal using 2-(chloromethyl)-2-methyloxirane ( 97)] gave the alcohols98and99who was subjected to reaction ring closure using NaH, getting connection7tables 1 and iodide100respectively. The reaction of a combination of Suzuki connections100with arylboronic acids were then given connection8-12table 1.

[0052] In scheme 4, is shown in Fig.6, used the following reagents and conditions: (i) TFA, anisole, CH2Cl2, 20°C, 4 h; (ii) the connection91or 5-Br,2-l or 2.5-diversin, NaH, DMF, 0-20°C, 2-3 h; (iii) ArB(OH)2, 2M Na2CO3, toluene, EtOH, (DMF), Pd(dppf)Cl2in an atmosphere of N2, 89-90°C, 1.8 to 3 hours. Carried out with the assistance NaH alkylation reaction alcohol101[received from the connection26by acid catalyzed removal of 4-(benzyloxy)benzylamine side chain] 5-bromo-2-herperidin (91), 5-bromo-2-chloropyrimidine and 2.5-dibromopyrazine gave bromides102-104who was subjected to reaction combination with Suzuki arylboronic acids, with formation of compounds13, 14, 17, 18, 21and22table 1.

[0053] In scheme 5, is shown in Fig.7, used the following reagents and conditions: (i) 6-Br-3-pyridinol, NaH, DMF, 0-20°C, 10 min, then 50°C, 4 h; (ii) ArB(OH)2, 2M Na2CO3, toluene, EtOH, DMF, Pd(dppf)Cl2in an atmosphere of N2, 90°C, 3 h; (iii) EtOCH2CH2Cl, K2CO3, DMF, 20°C, 16 h; (iv) ArB(OH)2, 2MNa 2CO3, toluene, EtOH, Pd(dppf)Cl2in an atmosphere of N2, 86°C, 2-2,5 h; (v) a 1.25 M HCl in MeOH, 20°C, 0-12 hour, then 53°C, 2-4 h; (vi)111or112, NaH, DMF, 0-20°C, 10-30 min, then 50-60°C, 3 h; (vii) NaH, DMF, 0°C, 35-80 minutes Catalyzed basis of the interaction of the epoxide105(obtained in stage 2 of the connection80through epoxidation of the corresponding alkene, as described by Ding et al., in WO 2008008480A2) with 6-bromo-3-pyridinol gave bromide106, which was subjected to reaction combination with Suzuki arylboronic acids, with formation of compounds15and16table 1. Such reactions connection105with arylpyrimidines111and112[obtained from 2-chloro-5-pyrimidine (107through consistent implementation ethoxymethylene protection of the hydroxyl group, the reaction of a combination of Suzuki with arylboronic acids, with subsequent acid catalyzed removal of the protective group] gave a mixture of alcohol precursors (113or114and end connections19or20table 1. Carried out with the assistance NaH reaction ring closure of these mixtures (or, preferably, purified alcohols113or114then gave the connection19and20table 1.

[0054] In scheme 6, is shown in Fig.8, used the following reagents and conditions: (i) 4-OCF3BnBr or 4-BnOBnCl, NaH, DMF, 0-20°C, 7-21 h; (ii) the connection80, DIPEA, 107-108°C, 13-16 hour; (iii) NaH, DM is A, 0°C, 65-80 min; (iv) m-CPBA, Na2HPO4CH2Cl2, 0-20°C, 2.5 to 3.5 hours. Carried out with the assistance NaH alkylation reaction of glycidol (115) using substituted benzylchloride gave epoxides116and117that was sequentially subjected to base catalyzed interaction with 2-bromo-4(5)-nitroimidazole (80) and then carried out using NaH closure ring intermediate alcohols (118and119), with connections23and24table 1. Similar reactions of epoxides123and124[derived from 2-methyl-2-propen-1-ol (120) via alkylation using substituted benzylchloride, followed by epoxydecane] connection80gave the alcohols125and126that was also subjected to reaction ring closure using NaH, obtaining compounds25and26table 1.

[0055] In scheme 7, shown in Fig.9, used the following reagents and conditions: (i) Br(CH2)2CH=CH2, K2CO3, DMF, 66-73°C, 4.5 to 12 h; (ii) m-CPBA, Na2HPO4CH2Cl2, 0-20°C, 50 h; (iii) 4-OCF3PhOH, K2CO3, MEK, 81°C, 12 h; (iv) NaH, DMF, 0-20°C, 2-2,5 h; (v) OsO4NMO, CH2Cl2, 20°C, 4 h; (vi) TIPSCl, imidazole, DMF, 20°C, 18 h; (vii) 1% HCl in 95% EtOH, 20°C, 35 hours; (viii) 4-BnOPhOH or 4-IPhOH, DEAD, PPh3, THF, 0-20°C, 32-51 hour; (ix) ArB(OH)2, 2M Na2CO3, toluene, EtOH, DMF Pd(dppf)Cl 2in an atmosphere of N2, 90°C, 90 min Catalyzed basis of the interaction of the epoxide129[obtained from 2-chloro-4(5)-intorimidazole (81through alkylation by 4-bromo-1-butene, followed by epoxydecane] 4-cryptomaterial gave alcohol130, which was subjected to reaction ring closure using NaH, getting connection27table 1. Such a reaction ring closure monoamino diol132[obtained from 2-bromo-4(5)-intorimidazole (80through alkylation by 4-bromo-1-butene, followed by dihydroxypropane and TIPS protection of the primary alcohol] and acid catalyzed disilylgermane gave alcohol134. The reaction of Mitsunobu connection134with the appropriate phenols gave the connection28tables 1 and iodide135. The reaction of a combination of Suzuki connections135with arylboronic acids were then given connection29-31table 1.

[0056] In scheme 8, shown in Fig.10, used the following reagents and conditions: (i) the connection91, NaH, DMF, 0-20°C, 2.5 h; (ii) ArB(OH)2, 2M Na2CO3, toluene, EtOH, DMF, Pd(dppf)Cl2in an atmosphere of N2, 90°C, 2.5 h; (iii) 6-Br-3-pyridinol, K2CO3, MEK, 82-85°C, 28 h; (iv) NaH, DMF, 0-20°C, 2.5 hours. Carried out with the assistance NaH alkylation of alcohol134when using 5-bromo-2-herperidin (91) gave the bromide136that is what has adversely reaction combination with Suzuki arylboronic acids, obtaining compounds32and33table 1. Alternatively, the base catalyzed interaction of the epoxide129with 6-bromo-3-pyridinol with further carried out with the assistance NaH shorting rings obtained alcohol137gave the bromide138that was also subjected to reaction combination with Suzuki arylboronic acids, with formation of compounds34and35table 1.

[0057] In scheme 9, is shown in Fig.11, used the following reagents and conditions: (i) I(CH2)2C(CH3)=CH2, K2CO3, DMF, 61°C, 20 h; (ii) m-CPBA, Na2HPO4CH2Cl2, 0-20°C, 4 h; (iii) RPhOH, K2CO3, MEK, 82-83°C for 8-10 h; (iv) NaH, DMF, 0-20°C, 2-2,5 h; (v) ArB(OH)2, 2M Na2CO3, toluene, EtOH, DMF, Pd(dppf)Cl2in an atmosphere of N2, 90°C, 100-105 minutes Catalyzed basis of the interaction of the epoxide140[obtained from 2-chloro-4(5)-intorimidazole (81through alkylation by 4-iodine-2-methyl-1-butene (obtained by iodination of 3-methyl-3-butene-1-ol as described Helmboldt et al., 2006), with subsequent epoxydecane] with the appropriate phenols gave alcohols141-143who was subjected to reaction ring closure using NaH, obtaining compounds36and37tables 1 and iodide144respectively. The reaction of a combination of Suzuki connections144with arylboronic acids were then given connection8-40 table 1.

[0058] In scheme 10, shown in Fig.12, used the following reagents and conditions: (i) I(CH2)2C(CH3)=CH2, K2CO3, DMF, 60°C, 11 h; (ii) OsO4NMO, CH2Cl2, 20°C, 4 h; (iii) TIPSCl, imidazole, DMF, 20°C, 6 days; (iv) NaH, DMF, 0-20°C, 2.5 h, then 46°C, 3.2 hours; (v) 1% HCl in 95% EtOH, 44°C, 3 days; (vi) the connection91, NaH, DMF, 0-20°C, 2.5 h; (vii) ArB(OH)2, 2M Na2CO3, toluene, EtOH, DMF, Pd(dppf)Cl2in an atmosphere of N2, 90°C, 120-135 min; (viii) 6-Br-3-pyridinol, K2CO3, MEK, 84°C, 18.5 hours; (ix) NaH, DMF, 0-20°C, 2.5 hours. Carried out with the assistance NaH ring closure monoamino diol147[obtained from 2-bromo-4(5)-intorimidazole (80through alkylation by 4-iodine-2-methyl-1-butene (obtained by iodination of 3-methyl-3-butene-1-ol as described Helmboldt et al., 2006), with subsequent dihydroxypropane and TIPS-protection of the primary alcohol] and acid catalyzed disilylgermane gave alcohol149. Carried out with the assistance NaH alkylation connection149using 5-bromo-2-herperidin (91) gave the bromide150, which was subjected to reaction combination with Suzuki arylboronic acids, with formation of compounds41-43table 1. Alternatively, the base catalyzed interaction of the epoxide140with 6-bromo-3-pyridinol with further carried out with the assistance NaH shorting rings obtained is of Porta 151gave the bromide152that was also subjected to reaction combination with Suzuki arylboronic acids, with formation of compounds44-46table 1.

[0059] In scheme 11, shown in Fig.13, used the following reagents and conditions: (i) RBnBr or 4-BnOBnCl, NaH, DMF, 0-20°C, 2.5 to 7 hours; (ii) 4-OCF3PhB(OH)2, 2M Na2CO3, toluene, EtOH, Pd(dppf)Cl2in an atmosphere of N2, 90°C, 20-25 minutes is Carried out by means of NaH alkylation reaction of alcohols134and149using substituted benzylchloride gave compound47-49and52-54tables 1 and iodides153-156. The reaction of a combination of Suzuki compounds153-1564-triftormetilfullerenov acid then gave compound50, 51, 55and56table 1.

[0060] In scheme 12, shown in Fig.14, used the following reagents and conditions: (i) Ac2O, pyridine, 20°C, 38 hours; (ii) preparative chiral HPLC (ChiralPak IA, 40% EtOH/hexane); (iii) K2CO3, an aqueous solution of MeOH, 20°C, 4 h; (iv) 4-BrBnBr, NaH, DMF, 0-20°C, 3 h; (v) 4-OCF3PhB(OH)2, 2M Na2CO3, toluene, EtOH, Pd(dppf)Cl2in an atmosphere of N2, 88°C, 75 min preparative chiral HPLC of racemic acetate connection157[derived from alcohol149by acetylation] gave the enantiomers of compounds158and161that hydrolyzed to enantiomeric alcohols159and162. Carried out with the assistance NaH reaction is alkilirovanija these alcohols using 4-bromobenzylamine gave bromides 160and163that was subjected to the Suzuki reaction for the combination of 4-triftormetilfullerenov acid, with formation of compounds57and58table 1.

[0061] In scheme 13, shown in Fig.15, used the following reagents and conditions: (i) I2, PPh3, imidazole, CH2Cl2, 0-8°C, 5 h; (ii) RPhOH, K2CO3, acetone, 50°C, 6-11 h; (iii) I25NaBH4, THF, 0°C, 3-4 h, then 20°C, 13 h, then 30% H2O2, 3h). NaOH, 0-20°C, 3 h; (iv) I2, PPh3, imidazole, CH2Cl2, 20°C for 12-15 h; (v) 80, K2CO3, DMF, 84-88°C, 33-37 hour; (vi) 1% HCl in 95% EtOH, 20°C, 7-12 hour; (vii) NaH, DMF, 0-20°C, 4-5 h; (viii) preparative chiral HPLC (ChiralPak IA, 27% EtOH/hexane); (ix) ArB(OH)2, 2M Na2CO3, toluene, EtOH, DMF, Pd(dppf)Cl2in an atmosphere of N2, 90°C, 90 min Hydroporinae alkenes166and167[obtained by alkylation of the corresponding phenols with iodide165obtained by iodination of 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-propen-1-ol (164) (Chen et al., US 2007213341 A1, by monosilane 2-methylene-1,3-propane diol)] gave the alcohols168and169that were converted into the iodide170and171. Alkylation of 2-bromo-4(5)-intorimidazole (80these iodides catalyzed by acid disilylgermane and implemented with the help NaH ring closure of the obtained alcohols174and175then gave compounds is their 59tables 1 and iodide176respectively. The reaction of a combination of Suzuki connections176with arylboronic acids also gave compound62-64table 1.

[0062] In figure 14, shown in Fig.16, used the following reagents and conditions: (i) the connection80, K2CO3, DMF, 82°C, 24 h; (ii) 1% HCl in 95% EtOH, 20°C, 4 h, then 4°C, 12 h; (iii) NaH, DMF, 0-20°C, 3.5 h; (iv) the connection91, NaH, DMF, 0-20°C, 3 h; (v) ArB(OH)2, 2M Na2CO3, toluene, EtOH, DMF, Pd(dppf)Cl2in an atmosphere of N2, 90°C, 2-2,5 h; (vi) RBnBr or 4-BnOBnI, NaH, DMF, 0-20°C, 0.5 to 3 h; (vii) 4-OCF3PhB(OH)2, 2M Na2CO3, toluene, EtOH, Pd(dppf)Cl2in an atmosphere of N2, 90°C, 20 minutes Alkylation of 2-bromo-4(5)-intorimidazole (80) iodide177(see Curran et al., 1998, stage 4, based on the 2-methylene-1,3-propane diol and acid catalyzed disilylgermane product (178) gave diol179, which was subjected to reaction ring closure using NaH, obtaining alcohol180. Carried out with the assistance NaH alkylation connection180using 5-bromo-2-herperidin (91) gave the bromide181, which was subjected to reaction combination with Suzuki arylboronic acids, with formation of compounds65-67table 1. Such alkylation of alcohol180with the help of suitable substituted benzylchloride gave compound71-73tables 1 and t is the train iodobenzylamine esters 182and183. The reaction of a combination of Suzuki compounds182and1834-(triptoreline)phenylboronic acid then gave compound74and75table 1.

[0063] In scheme 15, shown in Fig.17, used the following reagents and conditions: (i) 6-Br-3-pyridinol, DEAD, PPh3, THF, 0°C, 1 hour, followed by 20°C, 41 hours; (ii) 1% HCl in 95% EtOH, 20°C, 13 h; (iii) NaH, THF, 20°C, 1 h, then TBDMSCl, 20°C, 100 min; (iv) I2, PPh3, imidazole, CH2Cl2, 20°C, 18 h; (v) the connection80, K2CO3, DMF, 87°C, 42 hour; (vi) TBAF, THF, 20°C, 4 h; (vii) NaH, DMF, 0-20°C, 200 rpm; (viii) ArB(OH)2, 2M Na2CO3, toluene, EtOH, DMF, Pd(dppf)Cl2in an atmosphere of N2, 90°C, 140 minutes, the Reaction Mitsunobu 6-bromo-3-pyridinol with known alcohol184(see Kim et al., 2001, through similarobama and hydroporinae 2-methylene-1,3-propane diol and acid catalyzed disilylgermane product (185) gave diol186. Monosilane connection186gave alcohol187, which was converted into iodide188. Alkylation of 2-bromo-4(5)-intorimidazole (80using connection188disilylgermane and implemented with the help NaH ring closure of the obtained alcohol190gave the bromide191. The reaction of a combination of Suzuki connections191with arylboronic acids were then given connection68-70table 1.

EXAMPLE 2. Ways to get

[0064] A. Synthesis of 6-nitro-2-{[4-(is reformatory)phenoxy]methyl}-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 1 of table 1)

when using the method of scheme 1

[0065] a Mixture of 4-cryptomaterial (0,152 ml of 1.17 mmol), K2CO3(260 mg, at 1.17 mmol) and 2-(methyl bromide)oxirane (76) (0,30 ml, 3,51 mmol) in anhydrous acetone (3 ml) was stirred in a sealed tube at 59°C for 36 hours. The resulting mixture was filtered, washed with CH2Cl2then the filtrate was evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-15% CH2Cl2/pentane first gave head a fraction, and subsequent elution with a mixture of 20-25% CH2Cl2/pentane gave 2-{[4-(triptoreline)phenoxy]methyl}oxirane (77) (similarly obtained Cao et al., WO 2008112483A2 when using epichlorohydrin) (260 mg, 95%) as oil;

1H NMR (CDCl3) δ 7,14 (user.DD, J=9,0, 0.6 Hz, 2H), 6,91 (dt, J=9,1, 3.0 Hz, 2H), 4,23 (DD, J=11,1, 3.1 Hz, 1H), 3,94 (DD, J=11,1, 5.7 Hz, 1H), 3,34 (m, 1H), only 2.91 (DD, J=4,8, 4,2 Hz, 1H), 2,75 (DD, J=4,9, and 2.6 Hz, 1H).

[0066] the Mixture of epoxide 77 (200 mg, 0,854 mmol), 2-bromo-4(5)-intorimidazole (80) (180 mg, 0,938 mmol) and diisopropylethylamine (0.75 ml, or 4.31 mmol) was stirred in a sealed tube at 105°C for 6.5 hours and then cooled. The product was dissolved in CH2Cl2(15 ml), washed with aqueous solution of NaHCO3(15 ml) and the aqueous layer was then extracted with CH2Cl2(4×15 ml). The combined organic extracts were evaporated to dryness and the residue XP which was maturational on silica gel. Elution CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 0-1% EtOAc/CH2Cl2gave 1-(2-bromo-4-nitro-1H-imidazol-1-yl)-3-[4-(triptoreline)phenoxy]-2-propanol (82) (255 mg, 70%) as a white solid: so square (MeOH/CH2Cl2/hexane) 139-141°C;

1H NMR [(CD3)2SO] δ charged 8.52 (s, 1H), 7,30 (user.DD, J=9,1, 0.7 Hz, 2H), 7,05 (dt, J=9,2, 3.1 Hz, 2H), 5,66 (user.s, 1H), 4,28 (DD, J=13.3-inch, 3.3 Hz, 1H), 4,21 (m, 1H), 4,13 (DD, J=13.3-inch, 8.0 Hz, 1H), 4,01 (d, J=5.0 Hz, 2H); elemental analysis: (C13H11BrF3N3O5) C, H, N.

[0067] a Solution of alcohol 82 (242 mg, 0,568 mmol) in anhydrous DMF (5 ml) in an atmosphere of N2at 0°C was treated with 60% NaH (36 mg, 0.90 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. After stirring at 0°C for 45 minutes the reaction mixture was cooled (CO2/acetone), was suppressed with a mixture of ice/water solution of NaHCO3(15 ml) was added to a saturated salt solution (40 ml) and was extracted with CH2Cl2(6×50 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel, elwira CH2Cl2with connection 1 (171 mg, 87%) as a cream solid: so square (MeOH/CH2Cl2/hexane) 170-172°C;

1H NMR [(CD3)2SO] δ is 8.16 (s, 1H), 7,31 (user.DD, J=9,1, 0.8 Hz, 2H), 7,05 (dt, J=9,2, 3.1 Hz, 2H), 5,74 (m, 1H), 4,50 (DD, J=10,8, and 8.9 Hz, 1H), 4,46 (DD, J=11,5, 2.8 Hz, 1H), 4,39 (DD, =11,5, 5,2 Hz, 1H), 4,22 (DD, J=10,8, 6.5 Hz, 1H); elemental analysis: (C13H10F3N3O5) C, H, N.

[0068] B. Synthesis of 2-{[4-(benzyloxy)phenoxy]methyl}-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 2 of table 1) when using the method of scheme 1

[0069] the Alkylation of 4-(benzyloxy)phenol using 2-(methyl bromide)oxirane (76), as in example 2A, followed by chromatography of the product on silica gel with elution with a mixture of 0-25% CH2Cl2/petroleum ether (head of the faction) and then a mixture of 25% CH2Cl2/petroleum ether gave 2-{[4-(benzyloxy)phenoxy]methyl}oxirane (78) (described Kopka et al., 2003, using epichlorohydrin) (79%) as a white solid: so pl. (CH2Cl2/pentane) 61-62°C;

1H NMR (CDCl3) δ 7,44-7,28 (m, 5H), 6.90 to (dt, J=9,3, 2,8 Hz, 2H), 6,85 (dt, J=9,3, 2,8 Hz, 2H), 4,16 (DD, J=11,1, 3.3 Hz, 1H), 3,92 (DD, J=11,1, 5.6 Hz, 1H), 3,32 (m, 1H), 2,89 (DD, J=4,8, 4.3 Hz, 1H), 2,73 (DD, J=5.0 and 2.7 Hz, 1H).

[0070] the interaction of the epoxide 78 with 2-bromo-4(5)-nitroimidazole (80), as in example 2A, within 12 hours, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then with a mixture of 1-2% EtOAc/CH2Cl2gave 1-[4-(benzyloxy)phenoxy]-3-(2-bromo-4-nitro-1H-imidazol-1-yl)-2-propanol (83) (74%) as a pale yellow solid: so square (MeOH/CH2Cl2/hexane) 160-162°C;

1H NMR [(D 3)2SO] δ of 8.50 (s, 1H), 7,46-7,28 (m, 5H),6,94 (dt, J=9,2, 2,9 Hz, 2H), to 6.88 (dt, J=9,2, 2,9 Hz, 2H), ceiling of 5.60 (user.d, J=4,6 Hz, 1H), 5,04 (s, 2H), 4,27 (DD, J=13,0, 2.7 Hz, 1H), 4,16 (m, 1H), 4,11 (DD, J=13,1, 8,2 Hz, 1H), 3,93 (DD, J=10,0, 4.8 Hz, 1H), 3,89 (DD, J=10,1, a 5.3 Hz, 1H); elemental analysis: (C19H18BrN3O5) C, H, N.

[0071] ring Closure of alcohol 83 using NaH as in example 2A, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then with a mixture of 1-2% MeOH/CH2Cl2gave compound 2 (94%) as a cream solid: so pl. (CH2Cl2/hexane) 208-210°C;

1H NMR [(CD3)2SO] δ of 8.15 (s, 1H), 7,45-7,28 (m, 5H), to 6.95 (dt, J=9,2, 3.0 Hz, 2H), to 6.88 (dt, J=9,2, 3.0 Hz, 2H), 5,70 (m, 1H), of 5.05 (s, 2H), 4,48 (DD, J=10,7, a 8.9 Hz, 1H), 4,35 (DD, J=11,6, 2.8 Hz, 1H), 4,28 (DD, J=11,6, 5,1 Hz, 1H), 4,20 (DD, J=10,8, 6.5 Hz, 1H); elemental analysis: (Cl9H17N3O5) C, H, N.

[0072] C. Synthesis of 2-{[(4'-fluoro[1,1'-biphenyl]-4-yl)oxy]methyl}-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 3 of table 1) when using the method of scheme 1

[0073] the Alkylation of 4-itfinal when using 2-(methyl bromide)oxirane (76), as in example 2A, within 52 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-10% CH2Cl2/petroleum ether (head of the faction) and then a mixture of 20-25% CH2Cl2/petroleum ether gave 2-[(4-iodinate)methyl]OK the Iran (79) (described Apparu et al., 2000 when using glycidylmethacrylate) (89%) as a white solid: so pl. (CH2Cl2/petroleum ether) 67-68°C;

1H NMR (CDCl3) δ 7,56 (dt, J=9,0, 2.7 Hz, 2H), 6,70 (dt, J=9,0, 2.7 Hz, 2H), 4,20 (DD, J=11,1, 3.1 Hz, 1H), 3,92 (DD, J=11,1, 5.7 Hz, 1H), 3.33 and (m, 1H), 2,90 (DD, J=4,8, 4.3 Hz, 1H), 2,74 (DD, J=4,9, and 2.6 Hz, 1H).

[0074] the interaction of the epoxide 79 with 2-chloro-4(5)-nitroimidazole (81) and diisopropylethylamine as in example 2A (but with water extraction washing 6 times with a mixture of 10% MeOH/CH2Cl2), followed by chromatography of the product on silica gel with elution with a mixture of 0-0,5% MeOH/CH2Cl2(head of the faction) and then a mixture of 0.5-1% MeOH/CH2Cl2gave 1-(2-chloro-4-nitro-1H-imidazol-1-yl)-3-(4-iodinate)-2-propanol (84) (83%) as a yellow solid: so square (MeOH/H2O) 174-176°C;

1H NMR [(CD3)2SO] δ 8,49 (s, 1H), 7,60 (dt, J=8,9, 2.7 Hz, 2H), for 6.81 (dt, J=9,0, 2.7 Hz, 2H), 5,66 (user.s, 1H), 4,28 (DD, J=12,8, and 2.6 Hz, 1H), 4,19 (m, 1H), 4,14 (DD, J=12,9, 8.0 Hz, 1H), 3,97 (d, J=4,6 Hz, 2H); HRESIMS calculated for C12H11ClIN3NaO4m/z [M+Na]+447,9346, 445,9375 found 447,9322, 445,9366.

[0075] ring Closure of alcohol 84 using NaH as in example 2A, at 0°C for 80 minutes and then at 17°C for 60 minutes, followed by chromatography of the product on silica gel with elution with a mixture of 0-40% EtOAc/petroleum ether (head of the faction) and then a mixture of 40% EtOAc/petroleum ether and 0-0,5% MeOH/CH2Cl2gave 2-[(4-IO is phenoxy)methyl]-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazol (85) (77%) as a pale yellow solid: so pl. (MeOH/CH2Cl2/hexane) 198-199°C;

1H NMR [(CD3)2SO] δ of 8.15 (s, 1H), to 7.61 (dt, J=8,9, and 2.6 Hz, 2H), 6,80 (dt, J=9,0, 2,6 Hz, 2H), 5,72 (m, 1H), 4,49 (DD, J=10,7, 9.0 Hz, 1H), to 4.41 (DD, J=11,6, 2.7 Hz, 1H), 4,35 (DD, J=11,6, 5,2 Hz, 1H), 4,20 (DD, J=10,8, 6.5 Hz, 1H); elemental analysis: (C12H10IN3O4) C, H, N.

[0076] Stir a mixture of iodide 85 (250 mg, 0,646 mmol), 4-ftorhinolonovy acid (163 mg, of 1.16 mmol) and Pd(dppf)Cl2(95 mg, 0.13 mmol) in DMF (5.6 ml), toluene (4.4 ml) and EtOH (2.5 ml) was degirolami for 11 minutes (vacuum pump) and then typed N2. Added 2M aqueous solution of Na2CO3(1.3 ml, 2.6 mmol) via syringe and stir the mixture again degirolami for 11 minutes, then typed N2. The resulting mixture was stirred at 88°C for 70 minutes, then cooled, diluted aqueous solution of NaHCO3(50 ml) and was extracted with CH2Cl2(6×50 ml). The extracts were evaporated to dryness and the residue was chromatographically on silica gel, elwira mixture 0-0,5% MeOH/CH2Cl2(head of the faction) and then a mixture of 0.5% MeOH/CH2Cl2with obtain compound 3 (191 mg, 83%) as a pale brown solid: so square (MeOH/CH2Cl2/hexane) 224-226°C;

1H NMR [(CD3)2SO] δ 8,18 (s, 1H), 7,65 (DDT, J=8,9, 5,4, 2.7 Hz, 2H), to 7.59 (dt, J=8,8, 2,6 Hz, 2H), 7,25 (TT, J=8,9, 2.7 Hz, 2H), 7,03 (dt, J=8,8, 2,6 Hz, 2H), USD 5.76 (m, 1H), 4,51 (DD, J=10,8, and 9.0 Hz, 1H), 4,47 (DD, J=11,6, 2,8 Hz, 1H), to 4.41 (DD, J=11,6, a 5.3 Hz, 1H), 4,23 (DD,J=10,8, 6,5 Hz, 1H); APCI MS m/z 356 [M+H].

[0077] D. Synthesis of 6-nitro-2-({[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]oxy}methyl)-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 4 of table 1) when using the method of scheme 1

[0078] the Reaction mix Suzuki iodide 85 and 4-(trifluoromethyl)phenylboronic acid, as in example 2C, for 90 minutes, followed by chromatography of the product on silica gel with elution with a mixture of 0-0,5% MeOH/CH2Cl2(head of the faction) and then a mixture of 0.5% MeOH/CH2Cl2gave compound 4 (77%) as a cream solid: so square (MeOH/CH2Cl2/hexane) 210-211°C;

1H NMR [(CD3)2SO] δ 8,19 (s, 1H), 7,86 (user.d, J=8,2 Hz, 2H), to 7.77 (user.d, J=8,4 Hz, 2H), 7,71 (dt, J=8,8, 2.5 Hz, 2H), to 7.09 (dt, J=8,9, and 2.6 Hz, 2H), 5,77 (m, 1H), to 4.52 (DD, J=10,7, 9.0 Hz, 1H), 4,50 (DD, J=11,6, 2.8 Hz, 1H), 4,43 (DD, J=11,6, a 5.3 Hz, 1H), 4,24 (DD, J=10,8, 6.5 Hz, 1H); APCI MS m/z 406 [M+H]+.

[0079] E. Synthesis of 6-nitro-2-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]oxy}methyl)-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 5 in table 1) using the method of scheme 1

[0080] the Reaction mix Suzuki iodide 85 and 4-(triptoreline)phenylboronic acid, as in example 2C, for 50 minutes, followed by chromatography of the product on silica gel with elution CH2Cl2gave compound 5 (83%) as a pale pink solid: so pl. (CH2Cl2/exan) 200-201°C;

1H NMR [(CD3)2SO] δ 8,18 (s, 1H), 7,74 (user.d, J=8,8 Hz, 2H), to 7.64 (user.d, J=8,8 Hz, 2H), 7,41 (user.d, J=8.1 Hz, 2H), 7,06 (user.d, J=8,8 Hz, 2H), USD 5.76 (m, 1H), to 4.52 (DD, J=10,5, 9.0 Hz, 1H), 4,49 (DD, J=11,6, and 2.6 Hz, 1H), 4,42 (DD, J=11,6, 5,2 Hz, 1H), 4,23 (DD, J=10,7, 6.5 Hz, 1H); elemental analysis: (C19H14F3N3O5) C, H, N.

[0081] F. Synthesis of 6-nitro-2-[({5-[4-(triptoreline)phenyl]-2-pyridinyl}oxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 6 of table 1) when using the method of scheme 2

[0082] a Mixture of 2,4-dinitroanisole (86) (2,02 g, 12.8 mmol) and tert-butyl(dimethyl)silyl-2-oxiranylmethyl ether (87) (3,84 g of 20.4 mmol) was stirred at 70°C for 16 hours. Received the cooled mixture was diluted with EtOAc (300 ml), washed with aqueous solution of NaHCO3(3×50 ml), water (2×50 ml) and saturated salt solution (50 ml) and then the solvent was removed. Chromatography of the residue on silica gel with elution with a mixture of 10-20% EtOAc/petroleum ether gave 1-{[tert-butyl(dimethyl)silyl]oxy}-3-(2,4-dinitro-1H-imidazol-1-yl)-2-propanol (88) (described Otera et al., US 2006063929A1 based on 2,4-dinitroanisole and glycidol) (2,63 g, 60%) as a yellow oil;

1H NMR (CDCl3) δ 8,01 (s, 1H), 4,78 (DD, J=13,9, 2,9 Hz, 1H), 4,46 (DD, J=14,0, 8,3 Hz, 1H), 4,08 (m, 1H), 3,76 (DD, J=10,4, 4.6 Hz, 1H), to 3.67 (DD, J=a 10.5, 5.0 Hz, 1H), 2,60 (user.s, 1H), to 0.92 (s, 9H), of 0.11 (s, 6H); APCI MS m/z 300 [M+H-HNO2]+.

[0083] a Solution of alcohol 88 (2,04 g of 5.89 mmol) in betwedn the m DMF (20 ml) in an atmosphere of N 2at -20°C was treated with 60% NaH (0.34 g, 8.50 mmol). After stirring at a temperature of from -20 to -10°C for 50 minutes, the reaction mixture was extinguished EtOAc and water (150 ml) and was extracted with EtOAc (500 ml). The extract was washed with water (2×100 ml) and saturated salt solution (100 ml), then extracted with EtOAc (100 ml) and then the solvent was removed. Chromatography of the residue on silica gel with elution with a mixture of 40-67% EtOAc/petroleum ether gave 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazol (89) (1.13 g, 64%) as a pale yellow solid: so square (EtOAc/petroleum ether) 142-144°C;

1H NMR (CDCl3) δ 7,52 (s, 1H), 5,33 (m, 1H), 4,29 (d, J=7.2 Hz, 2H), of 4.05 (DD, J=11,9, 3.5 Hz, 1H), 3,86 (DD, J=11,9, 2.8 Hz, 1H), 0,81 (s, 9H), 0,08, of 0.03 (2s, 2× 3H); elemental analysis: (C12H21N3O4Si) C, H, N.

[0084] the Suspension salelologa ether 89 (503 mg, 1,68 mmol) in 1% HCl in 95% EtOH (desirelove described Cunico et al., 1980) (27 ml) was stirred at room temperature for 6 hours and then kept at 4°C for 2.5 days. The resulting solution was neutralized by adding dropwise 7M NH3in MeOH (2 ml) under stirring, and then concentrated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-2% MeOH/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 2-5% MeOH/CH2Cl2gave (6-nitro-2,3-dihydroimidazo[,1-b][1,3]oxazol-2-yl)methanol (90) (described Sehgal et al., 1981, through the interaction of 2,4-dinitroanisole and glycidol) (299 mg, 97%) as a white solid after trituration with CH2Cl2): so pl. (CH2Cl2) 166-169°C;

1H NMR [(CD3)2SO] δ 8,10 (s, 1H), 5.40 to (m, 1H), 5,27 (t, J=5.6 Hz, 1H), 4,36 (DD, J=10,5, 8,8 Hz, 1H), 4,11 (DD, J=10,5, 6.4 Hz, 1H), 3,80 (DDD, J=12,8, to 5.4, 3.0 Hz, 1H), 3,65 (DD, J=12,8, 5,8, 3,9 Hz, 1H); elemental analysis: (C6H7N3O4) C, H, N.

[0085] Stir a mixture of 4-(triptoreline)phenylboronic acid (1.55 g, 7,53 mmol) and Pd(dppf)Cl2(367 mg, 0,502 mmol) in toluene (50 ml) and EtOH (25 ml) was degirolami within 15 minutes (vacuum pump) and then typed N2. Added 2M aqueous solution of Na2CO3(12.5 ml, 25,0 mmol) via syringe, stir the mixture again degirolami for 15 minutes and then typed N2with the subsequent addition of 5-bromo-2-herperidin (91) (0,53 ml of 5.15 mmol). The resulting mixture was stirred at 85-88°C for 3 hours, then cooled, diluted aqueous solution of NaHCO3(100 ml) and was extracted with CH2Cl2(4×100 ml). The extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-10% CH2Cl2/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 10-20% CH2Cl2/petroleum ether gave 2-fluoro-5-[4-(triptoreline)phenyl]pyridine (92) (1,32 g, 100%) as white solids is: so pl. (CH2Cl2/petroleum ether) 58-60°C;

1H NMR (CDCl3) δ of 8.40 (d, J=2.5 Hz, 1H), 7,94 (DDD, J=8,4, 7,6 to 2.6 Hz, 1H), 7,55 (dt, J=8,8, 2.5 Hz, 2H), 7,33 (user.d, J=8.0 Hz, 2H), 7,02 (DD, J=8,5, 3.0 Hz, 1H); HRESIMS calculated for C12H8F4NO m/z (MH+) 258,0537 found 258,0531.

[0086] the Mixture of alcohol 90 (300 mg, of 1.62 mmol) and herperidin 92 (1,255 g, 4,88 mmol) in anhydrous DMF (6 ml) in an atmosphere of N2at 0°C was treated with 60% NaH (96 mg, of 2.40 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. After stirring at room temperature for 2.5 hours the reaction mixture was cooled (CO2/acetone), was suppressed with a mixture of ice/water solution of NaHCO3(10 ml) was added to a saturated salt solution (40 ml) and was extracted with CH2Cl2(6×50 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-20% CH2Cl2/petroleum ether firstly gave the head of the faction (including the restored connection 92) and subsequent elution with a mixture of CH2Cl2gave compound 6 (5.5 mg, 0.8 per cent) in the form of a cream solid: so pl. (CH2Cl2/pentane) 127-130°C;

1H NMR (CDCl3) δ 8,32 (DD, J=2.5 and 0.7 Hz, 1H), 7,80 (DD, J=8,5, 2.5 Hz, 1H), 7,58 (s, 1H), 7,53 (dt, J=8,8, 2.5 Hz, 2H), 7,31 (user.DD, J=8,7, 0.8 Hz, 2H), 6,83 (DD, J=8,6, 0.7 Hz, 1H), 5,69 (m, 1H), 4,80 (DD, J=12,4, 4.0 Hz, 1H), and 4.75 (DD, J=12,4, a 4.1 Hz, 1H), 4,45 (DD, J=10,2, to 8.7 Hz, 1H), 4,35 (DD, J=10,2, 6.5 G is, 1H); APCI MS m/z 423 [M+H]+.

[0087] G. Synthesis of 2-{[4-(benzyloxy)phenoxy]methyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 7 of table 1) when using the method of scheme 3

[0088] a Mixture of 4-(benzyloxy)phenol (2,01 g, 10.1 mmol), K2CO3(1.60 g, 11.6 mmol) and 3-chloro-2-methylpropene (93) (2.00 ml, of 20.4 mmol) in anhydrous acetone (2.5 ml) was stirred in a sealed tube at 58°C for 24 hours. The resulting mixture was filtered, washed with CH2Cl2then the filtrate was evaporated to dryness and the residue was chromatographically on silica gel. Elution with petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 25% CH2Cl2/petroleum ether gave 1-(benzyloxy)-4-[(2-methyl-2-propenyl)oxy]benzene (94) (Karrer, F. DE 2312518) (1,74 g, 68%) as a white solid: so pl. (CH2Cl2/hexane) 62-64°C;

1H NMR (CDCl3) δ 7,45-7,29 (m, 5H), 6.90 to (dt, J=9,3, 2,8 Hz, 2H), 6,85 (dt, J=9,3, 2,8 Hz, 2H), 5,08 (m, 1H), free 5.01 (s, 2H), 4,79 (m, 1H), to 4.38 (s, 2H), equal to 1.82 (s, 3H).

[0089] 3-Chloroperbenzoic acid (1,43 g of a 50% solution, 4.14 mmol) was added to an ice mixture of compound 94 (500 mg, 1.97 mmol) and powdered Na2HPO4(974 mg, 6,86 mmol) in CH2Cl2(20 ml) and the resulting mixture was stirred at room temperature for 3.5 hours. Added a cooled aqueous solution of Na2SO3(50 ml-10% solution) and the mixture was extracted with CH 2Cl2(3×50 ml). The extracts are then washed with cooled aqueous solution of Na2SO3(50 ml of 10% solution), aqueous solution of NaHCO3(50 ml) and saturated salt solution (50 ml). The combined extracts were then evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 25% CH2Cl2/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 25-33% CH2Cl2/petroleum ether gave 2-{[4-(benzyloxy)phenoxy]methyl}-2-methyloxiran (95) (460 mg, 87%) as a white solid: so pl. (CH2Cl2/pentane) 105-107°C;

1H NMR (CDCl3) δ 7,44-7,28 (m, 5H), 6.90 to (dt, J=9,3, 2,9 Hz, 2H), 6,85 (dt, J=9,3, 2,9 Hz, 2H), free 5.01 (s, 2H), 3,97 (d, J=10.5 Hz, 1H), 3,90 (d, J=10.5 Hz, 1H), 2,85 (d, J=4,8 Hz, 1H), 2,71 (d, J=4,8 Hz, 1H), 1,47 (s, 3H); elemental analysis: (C17H18O3) C, H, N.

[0090] the interaction of the epoxide 95 with 2-bromo-4(5)-nitroimidazole (80), as in example 2A, at 107°C for 14 hours, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then the mixture 0-1% EtOAc/CH2Cl2gave 1-[4-(benzyloxy)phenoxy]-3-(2-bromo-4-nitro-1H-imidazol-1-yl)-2-methyl-2-propanol (98) (86%) as a pale yellow solid: so square (MeOH/CH2Cl2/hexane) 148-150°C;

1H NMR [(CD3)2SO] δ 8,31 (s, 1H), 7,45-7,28 (m, 5H), 6,94 (dt, J=9,2, 3.0 Hz, 2H), 6.87 in (dt, J=9,2, 3.0 Hz, 2H), 5,41 (s, 1H), 504 (C, 2H), 4,22 (d, J=14,3 Hz, 1H), 4,15 (d, J=14,3 Hz, 1H), 3,76 (d, J=9.5 Hz, 1H), and 3.72 (d, J=9.4 Hz, 1H), 1,19 (s, 3H); elemental analysis: (C20H20BrN3O5) C, H, N.

[0091] ring Closure of alcohol 98 using NaH as in example 2A, for 50 minutes, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then the mixture 0-1% EtOAc/CH2Cl2gave compound 7 (92%) as a pale yellow solid: so pl. (CH2Cl2/hexane) 162 to 165°C;

1H NMR (CDCl3) δ rate of 7.54 (s, 1H), 7,43-7,28 (m, 5H), 6.89 in (dt, J=9,1, 3.0 Hz, 2H), 6,78 (dt, J=9,1, 3.1 Hz, 2H), free 5.01 (s, 2H), 4,48 (d, J=10,2 Hz, 1H), 4,17 (d, J=10.1 Hz, 1H), a 4.03 (d, J=10,2 Hz, 1H), 4.00 points (d, J=10,2 Hz, 1H), to 1.76 (s, 3H); elemental analysis: (C20H19O5) C, H, N.

[0092] N. Synthesis of 2-{[4-(6-methoxy-3-pyridinyl)phenoxy]methyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 8 of table 1) when using the method of scheme 3

[0093] a Mixture of 4-itfinal (2.00 g, 9.09 mmol), powdered K2CO3(2,54 g, 18.4 mmol), NaI (364 mg, 2,43 mmol) and 2-(chloromethyl)-2-methyloxirane (97) (0,90 ml, 9,31 mmol) in anhydrous DMF (5 ml) was stirred in a sealed tube at 70°C for 15 hours. Again, was added 2-(chloromethyl)-2-methyloxiran (97) (0,18 ml of 1.86 mmol) and the mixture is then stirred at 73°C for 17 hours. The cooled mixture was added to a mixture of ice/water solution of NaHCO3(100 ml), and ek is was tragically Et 2O (5×100 ml). The extracts were washed with water (100 ml), then evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-15% CH2Cl2/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 15-20% CH2Cl2/petroleum ether gave 2-[(4-iodinate)methyl]-2-methyloxiran (96) (1,81 g, 69%) as a white solid: so pl. (CH2Cl2/pentane) 40-41°C;

1H NMR (CDCl3) δ of 7.55 (dt, J=9,0, 2.7 Hz, 2H), 6,70 (dt, J=9,0, 2.7 Hz, 2H), 4,01 (d, J=10.5 Hz, 1H), 3,90 (d, J=10.5 Hz, 1H), 2,85 (d, J=4,7 Hz, 1H), 2,72 (d, J=4,7 Hz, 1H), 1,47 (s, 3H); elemental analysis: (C10H11IO2) C, H, N.

[0094] the interaction of the epoxide 96 with 2-bromo-4(5)-nitroimidazole (80), as in example 2A, at 107°C for 15 hours, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then the mixture 0-1% EtOAc/CH2Cl2gave 1-(2-bromo-4-nitro-1H-imidazol-1-yl)-3-(4-iodinate)-2-methyl-2-propanol (99) (85%) as a foam (after trituration in a mixture of Et2O/pentane);

1H NMR (CDCl3) δ of 8.04 (s, 1H), to 7.59 (dt, J=9,0, 2.7 Hz, 2H), 6,66 (dt, J=9,0, 2.7 Hz, 2H), 4,27 (d, J=14,5 Hz, 1H), 4.16 the (d, J=14,5 Hz, 1H), 3,86 (d, J=9,2 Hz, 1H), 3,82 (d, J=9,2 Hz, 1H), 2,44 (s, 1H), 1,35 (s, 3H); elemental analysis: (C13H13BrIN3O4.0,1 Et2O) C, H, N.

[0095] ring Closure of alcohol 99 using NaH as in example 2A, for 75 minutes, followed by chromatography is the product on silica gel with elution CH 2Cl2gave 2-[(4-iodinate)methyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (100) (92%) as a cream solid: so square (MeOH/CH2Cl2/hexane) 181-183°C;

1H NMR (CDCl3) δ EUR 7.57 (dt, J=9,0, 2.7 Hz, 2H), 7,54 (s, 1H), 6,63 (dt, J=9,0, 2.7 Hz, 2H), 4,46 (d, J=10,2 Hz, 1H), 4,20 (d, J=10.1 Hz, 1H), 4,05 (d, J=9.9 Hz, 1H), a 4.03 (d, J=10.1 Hz, 1H), 1,78 (s, 3H); elemental analysis: (C13H12IN3O4) C, H, N.

[0096] Stir a mixture of iodide 100 (40,1 mg, 0,100 mmol), 6-methoxy-3-pyridineboronic acid (23,8 mg, 0,156 mmol) and Pd(dppf)Cl2(7,3 mg, 9,98 µmol) in toluene (1.7 ml) and EtOH (0.6 ml) was degirolami within 4 minutes (vacuum pump) and then typed N2. Added 2M aqueous solution of Na2CO3(0,30 ml of 0.60 mmol) via syringe, stir the mixture again degirolami for 4 minutes and then typed N2. The resulting mixture was stirred at 90°C for 45 minutes, then cooled, diluted aqueous solution of NaHCO3(50 ml) and was extracted with CH2Cl2(4×50 ml). The extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-3% EtOAc/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 4% EtOAc/CH2Cl2gave compound 8 (32 mg, 84%) as a cream solid: so square (MeOH/CH2Cl2/pentane) 217-219°C;

1H NMR (CDCl3) δ 8,32 (user.d, J=2.2 Hz, 1H), 7,72 (DD, J=8,6, and 2.6 Hz, 1H), 7.5 (a, 1H), 7,44 (dt, J=8,8, 2.5 Hz, 2H), 6,92 (dt, J=8,8, 2.5 Hz, 2H), 6,79 (d, J=8.5 Hz, 1H), 4,51 (d, J=10,2 Hz, 1H), 4,27 (d, J=10.1 Hz, 1H), 4,13 (d, J=10.1 Hz, 1H), 4,05 (d, J=10,2 Hz, 1H), of 3.97 (s, 3H), of 1.80 (s, 3H); elemental analysis: (C19H18N4O5) C, H, N.

[0097] I. Synthesis of 4'-[(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazol-2-yl)methoxy][1,1'-biphenyl]-4-carbonitrile (compound 9 of table 1) when using the method of scheme 3

[0098] the Reaction mix Suzuki iodide 100 and 4-cyanophenylacetic acid, as in example 2H, followed by chromatography of the product on silica gel with elution with a mixture of 0-0,5% EtOAc/CH2Cl2(head of the faction) and then a mixture of 0.5-1% EtOAc/CH2Cl2gave compound 9 (45%) as a cream solid: so pl. (CH2Cl2/pentane) 180-181°C;

1H NMR (CDCl3) δ of 7.70 (dt, J=8,6, 1.8 Hz, 2H), 7.62mm (dt, J=8,6, 1.8 Hz, 2H), 7,56 (s, 1H), 7,53 (dt, J=8,9, and 2.6 Hz, 2H), 6,95 (dt, J=8,9, and 2.6 Hz, 2H), 4,51 (d, J=10,2 Hz, 1H), 4,30 (d, J=10,2 Hz, 1H), 4,15 (d, J=10,2 Hz, 1H), 4,06 (d, J=10,2 Hz, 1H), is 1.81 (s, 3H); elemental analysis: (C20H16N4O4) C, H, N.

[0099] J. Synthesis of 2-{[(4'-fluoro[1,1'-biphenyl]-4-yl)oxy]methyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 10 of table 1) when using the method of scheme 3

[00100] the Suzuki Reaction mix iodide 100 and 4-ftorhinolonovy acid, as in example 2H, followed by chromatography of the product on silica gel is when elution with a mixture of CH 2Cl2(head of the faction) and then the mixture 0-1% EtOAc/CH2Cl2gave compound 10 (84%) as a cream solid: so square (MeOH/CH2Cl2/pentane) 180-181°C;

1H NMR (CDCl3) δ 7,56 (s, 1H), 7,50-the 7.43 (m, 4 H), 7,10 (TT, J=8,7, and 2.6 Hz, 2H), 6,91 (dt, J=8,8, 2,6 Hz, 2H), 4,51 (d, J=10,2 Hz, 1H), 4,27 (d, J=10.1 Hz, 1H), 4,13 (d, J=10.1 Hz, 1H), 4,05 (d, J=10,2 Hz, 1H), 1,80 (s, 3 H); elemental analysis: (C19Hl6FN3O4) C, H, N.

[0100] K. Synthesis of 2-methyl-6-nitro-2-({[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]oxy}methyl)-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 11 in table 1) using the method of scheme 3

[0101] the Reaction mix Suzuki iodide 100 and 4-(trifluoromethyl)phenylboronic acid, as in example 2H, followed by chromatography of the product on silica gel with elution with a mixture of 0-0,5% EtOAc/CH2Cl2(head of the faction) and then a mixture of 0.5% EtOAc/CH2Cl2gave compound 11 (88%) as a cream solid: so pl. (CH2Cl2/pentane) 219-220°C;

1H NMR (CDCl3) δ to 7.67 (d, J=8.5 Hz, 2H), 7,63 (d, J=8.5 Hz, 2H), 7,56 (s, 1 H), 7,53 (dt, J=8,8, 2.5 Hz, 2H), 6,95 (dt, J=8,8, 2.5 Hz, 2H), 4,51 (d, J=10,2 Hz, 1H), 4,29 (d, J=10.1 Hz, 1H), 4,14 (d, J=10.1 Hz, 1H), 4,06 (d, J=10,2 Hz, 1 H), of 1.81 (s, 3H); elemental analysis: (C20H16F3N3O4) C, H, N.

[0102] L. Synthesis of 2-methyl-6-nitro-2-({[4'-triptoreline)[1,1'-biphenyl]-4-yl]oxy}methyl)-2,3-dihydroimidazo[2,1-b][1,3]oxazole (soedinenie table 1) using the method of scheme 3

[0103] the Reaction mix Suzuki iodide 100 and 4-(triptoreline)phenylboronic acid, as in example 2H, followed by chromatography of the product on silica gel with elution CH2Cl2gave compound 12 (90%) as a cream solid: so square (MeOH/CH2Cl2/pentane) 209-211°C;

1H NMR (CDCl3) δ 7,56 (s, 1H), 7,53 (dt, J=8,8, 2.5 Hz, 2H), of 7.48 (dt, J=8,8, 2.5 Hz, 2H), 7,26 (m, 2H), 6,92 (dt, J=8,8, 2.5 Hz, 2H), 4,51 (d, J=10,2 Hz, 1H), 4,28 (d, J=10.1 Hz, 1H), 4,13 (d, J=10.1 Hz, 1H), 4,05 (d, J=10,2 Hz, 1H), is 1.81 (s, 3H); elemental analysis: (C20H16F3N3O5) C, H, N.

[0104] M. Synthesis 2-({[5-(4-forfinal)-2-pyridinyl]oxy}methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 13 of table 1) when using the method of scheme 4

[0105] Triperoxonane acid (25,4 ml, 0,342 mol) was added dropwise to a stirred mixture of 2-({[4-(benzyloxy)benzyl]oxy}methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (26) (see example 2Z) (2,53 g, 6,40 mmol) and anisole (7,0 ml, 64 mmol) in CH2Cl2(100 ml) (cooled in a water bath). After stirring at room temperature for 4 hours the solvent was removed by blowing into the current of the N2. The oily residue was treated with excess amount of solid NaHCO3, then was diluted to 15% MeOH/CH2Cl2(100 ml) and the mixture was stirred at room is the temperature for 30 minutes, then filtered. The filtrate was evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-1% MeOH/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 1-2% MeOH/CH2Cl2gave (2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazol-2-yl)methanol (101) (described Tsubouchi et al., WO 2004033463A1 through 3 stages, based on 2-chloro-4(5)-intorimidazole (81) and 2-[(methoxyethoxy)methyl]-2-methyloxirane) (1,215 g, 95%) as a cream solid: so square (MeOH/CH2Cl2/hexane) 174-176°C;

1H NMR [(CD3)2SO] δ of 8.09 (s, 1H), 5,41 (t, J=5.7 Hz, 1H), 4,24 (d, J=a 10.6 Hz, 1H), a 4.03 (d, J=10,7 Hz, 1H), 3,64 (DD, J=12,2, 5.6 Hz, 1H), 3,54 (DD, J=12,2, 5,9 Hz, 1H) and 1.51 (s, 3H); elemental analysis: (C7H9N3O4) C, H, N.

[0106] 5-Bromo-2-herperidin (91) (0.25 ml, 2,43 mmol) was added to a solution of alcohol 101 (200 mg, 1.01 mmol) in anhydrous DMF (4.5 ml) in an atmosphere of N2at 0°C. the resulting mixture was treated with 60% NaH (64 mg, 1,60 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. Again, was added 5-bromo-2-herperidin (91) (0.25 ml, 2,43 mmol) and the mixture was stirred at room temperature for 2 hours, then cooled (CO2/acetone), was suppressed with a mixture of ice/water solution of NaHCO3(15 ml) was added to a saturated salt solution (40 ml) and was extracted with CH2Cl2(8×40 ml). The combined extracts were evaporated to dryness and the mod is to have chromatographically on silica gel. Elution CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 0-1,5% EtOAc/CH2Cl2gave 2-{[(5-bromo-2-pyridinyl)oxy]methyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazol (102) (130 mg, 36%) as a cream solid: so pl. (CH2Cl2/hexane) 151-153°C;

1H NMR (CDCl3) δ 8,17 (DD, J=2.5 and 0.5 Hz, 1H), 7,68 (DD, J=8,8, 2.5 Hz, 1H), 7,52 (s, 1H), 6,60 (DD, J=8,7, 0.6 Hz, 1H), 4,58 (d, J=12.0 Hz, 1H), 4,50 (d, J=12.0 Hz, 1H), to 4.41 (d, J=10,2 Hz, 1H), 4,01 (d, J=10,2 Hz, 1H), of 1.76 (s, 3H); elemental analysis: (C12H11BrN4O4) C, H, N.

[0107] Stir a mixture of bromide 102 (77,2 mg, 0,217 mmol), 4-ftorhinolonovy acid (58 mg, 0,415 mmol) and Pd(dppf)Cl2(to 43.5 mg, to 59.4 mmol) in DMF (2.3 ml), toluene (1.6 ml) and EtOH (1.1 ml) was degirolami within 9 minutes (vacuum pump) and then typed N2. Added 2M aqueous solution of Na2CO3(with 0.55 ml, 1.1 mmol) via syringe, stir the mixture again degirolami for 9 minutes and then typed N2. The resulting mixture was stirred at 90°C for 3 hours, then cooled, diluted aqueous solution of NaHCO3(50 ml) and was extracted with CH2Cl2(6×50 ml). The extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-1% EtOAc/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 1-2% EtOAc/CH2Cl2gave compound 13 (60mg, 74%) as a cream solid: so pl. (CH2Cl2/hexane) 162-164°C;

1H NMR (CDCl3) δ of 8.28 (DD, J=2.5 and 0.6 Hz, 1H), 7,76 (DD, J=8,5, 2.5 Hz, 1H), 7,55 (s, 1H), 7,46 (DDT, J=8,9, 5,2, 2,6 Hz, 2H), 7,14 (TT, J=8,7, and 2.6 Hz, 2H), 6.75 in (DD, J=8,5, 0.7 Hz, 1H), 4,67 (d, J=11,9 Hz, 1H), 4,58 (d, J=11,9 Hz, 1H), 4,47 (d, J=10,2 Hz, 1H), Android 4.04 (d, J=10,2 Hz, 1H), 1,79 (s, 3H); APCI MS m/z 371 [M+H]+.

[0108] N. Synthesis of 2-methyl-6-nitro-2-[({5-[4-(triptoreline)phenyl]-2-pyridinyl}oxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 14 of table 1) when using the method of scheme 4

[0109] the Reaction mix Suzuki bromide 102 and 4-(triptoreline)phenylboronic acid as in example 2M, followed by chromatography of the product on silica gel with elution CH2Cl2gave compound 14 (80%) as a cream solid: so pl. (CH2Cl2/pentane) 172-174°C;

1H NMR (CDCl3) δ 8,31 (d, J=2.1 Hz, 1H), 7,78 (DD, J=8,6, 2.5 Hz, 1H), 7,55 (s, 1H), 7,52 (user.d, J=8,8 Hz, 2H), 7,30 (user.d, J=8,2 Hz, 2H), 6,76 (d, J=8.7 Hz, 1H), and 4.68 (d, J=11,9 Hz, 1H), 4,58 (d, J=11,9 Hz, 1H), 4,47 (d, J=10,2 Hz, 1H), Android 4.04 (d, J=10,2 Hz, 1H), 1,80 (s, 3H); elemental analysis: (C19H15N4O5) C, H, N.

[0110] O. Synthesis 2-({[6-(4-forfinal)-3-pyridinyl]oxy}methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 15, table 1) using the method of scheme 5

[0111] a Mixture of 2-bromo-1-[(2-methyl-2-oxiranyl)methyl]-4-nitro-1H-imidazole(105) (obtained in stage 2 of the connection 80 via epoxidation of the corresponding alkene, as described by Ding et al., WO 2008008480A2) (1,011 g, 3,86 mmol) and 6-bromo-3-pyridinol (615 mg, of 3.53 mmol) in anhydrous DMF (12 ml) in an atmosphere of N2at 0°C was treated with 60% NaH (180 mg, 4,50 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. After stirring at room temperature for 10 minutes and then at 50°C for 4 hours the reaction mixture was cooled (CO2/acetone), was suppressed with a mixture of ice/water solution of NaHCO3(20 ml) was added to a saturated salt solution (100 ml) and was extracted with CH2Cl2(6×100 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-50% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 50-75% EtOAc/petroleum ether and EtOAc gave the crude solid, which was then chromatographically on silica gel. Elution CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 0.3-0.5% MeOH/CH2Cl2gave 2-{[(6-bromo-3-pyridinyl)oxy]methyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazol (106) (described by Ding et al., WO 2009120789A1, based on the connection 105 through a similar procedure) (564 mg, 45%) as a cream solid: so square (MeOH/CH2Cl2/hexane) 148-150°C;

1H NMR [(CD3)2SO] δ to 8.14 (s, 1H), 8,10 (DD, J=3.2, and 0.3 Hz, 1H), 7,56 (DD, J=8,7, 0,4 Hz, 1H), 7,39 (DD, J=8,8, 3.2 G is, 1H), 4,42 (d, J=11,1 Hz, 1H), 4,39 (d, J=11,1 Hz, 1H), to 4.38 (d, J=11.0 cm Hz, 1H), 4,19 (d, J=11.0 cm Hz, 1H), 1,68 (s, 3H); elemental analysis: (C12H11BrNO4) C, H, N.

[0112] the Reaction mix Suzuki bromide 106 and 4-ftorhinolonovy acid as in example 2M, followed by chromatography of the product on silica gel with elution with a mixture of 0-0,5% MeOH/CH2Cl2(head of the faction) and then a mixture of 0.5% MeOH/CH2Cl2gave compound 15 (74%) as a cream solid: so square (MeOH/CH2Cl2/hexane) 180-181°C;

1H NMR [(CD3)2SO] δ 8,32 (d, J=2,8 Hz, 1H), 8,18 (s, 1H), 8,05 (DDT, J=8,9, 5,6, and 2.6 Hz, 2H), to $ 7.91 (d, J=8,8 Hz, 1H), of 7.48 (DD, J=8,8, 3.0 Hz, 1H), 7,27 (TT, J=8,9, and 2.6 Hz, 2H), 4,47 (d, J=11.0 cm Hz, 1H), 4,43 (d, J=11,1 Hz, 1H), to 4.41 (d, J=11.0 cm Hz, 1H), 4,22 (d, J=11.0 cm Hz, 1H), 1,71 (s, 3H); APCI MS m/z 371 [M+H]+.

[0113] P. Synthesis of 2-methyl-6-nitro-2-[({6-[4-(triptoreline)phenyl]-3-pyridinyl}oxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 16 of table 1) when using the method of scheme 5

[0114] the Reaction mix Suzuki bromide 106 and 4(triptoreline)phenylboronic acid as in example 2M, followed by chromatography of the product on silica gel with elution with a mixture 0-0,33% MeOH/CH2Cl2(head of the faction) and then a mixture of 0.33% MeOH/CH2Cl2gave compound 16 (67%) as a cream solid: so square (MeOH/CH2Cl2/hexane) 209-211°C;

1H NMR [(CD3)2SO] δ 8.3 (l, J=2,9 Hz, 1H), 8,18 (s, 1H), 8,13 (user.d, J=8,9 Hz, 2H), of 7.97 (d, J=8,8 Hz, 1H), 7,51 (DD, J=8,8, 3.0 Hz, 1H), 7,44 (user.d, J=8,2 Hz, 2H), 4,48 (d, J=11,1 Hz, 1H), of 4.44 (d, J=11.2 Hz, 1H), 4,42 (d, J=11,1 Hz, 1H), 4,22 (d, J=11.0 cm Hz, 1H), 1,71 (s, 3H); elemental analysis: (C19H15F3N4O5) C, H, N.

[0115] Q. Synthesis 7-({[5-(4-forfinal)-2-pyrimidinyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 17 of table 1) when using the method of scheme 4

[0116] the Mixture of alcohol 101 (see example 2M) (100 mg, 0,502 mmol) and 5-bromo-2-chloropyrimidine (156 mg, 0,806 mmol) in anhydrous DMF (2.5 ml) in an atmosphere of N2at 0°C was treated with 60% NaH (32 mg, 0.80 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. After stirring at room temperature for 140 minutes, the reaction mixture was cooled (CO2/acetone), was suppressed with a mixture of ice/water solution of NaHCO3(10 ml) was added to a saturated salt solution (40 ml) and was extracted with CH2Cl2(6×50 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-0,25% MeOH/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 0.25-0.5% MeOH/CH2Cl2gave 2-{[(5-bromo-2-pyrimidinyl)oxy]methyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazol (103) (described by Ding et al., WO 2009120789 A1, based on connection 101, through a similar % the fool) (163 mg, 91%) as a cream solid: so square (MeOH/CH2Cl2/hexane) 224-226°C;

1H NMR [(CD3)2SO] δ 8,77 (s, 2H), 8,14 (s, 1H), br4.61 (s, 2H), to 4.41 (d, J=11.0 cm Hz, 1H), 4,20 (d, J=11,1 Hz, 1H), 1,70 (s, 3H); elemental analysis: (C11H10BrN5O4) C, H, N.

[0117] the Reaction mix Suzuki bromide 103 and 4-ftorhinolonovy acid as in example 2M, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then a mixture of 0.5% MeOH/CH2Cl2gave compound 17 (22%) as a pale yellow solid: so pl. (CH2Cl2/pentane) 196°C decomp.;

1H NMR [(CD3)2SO] δ of 8.92 (s, 2H), 8,18 (s, 1H), 7,79 (user.DD, J=8,8, 5,4 Hz, 2H), 7,34 (user.t, J=8,9 Hz, 2H), 4,69 (d, J=12.0 Hz, 1H) and 4.65 (d, J=12.0 Hz, 1H), of 4.44 (d, J=11.0 cm Hz, 1H), 4,22 (d, J=11.0 cm Hz, 1H), 1,72 (s, 3H); elemental analysis: (C17H14FN5O4) C, H, N.

[0118] R. Synthesis of 2-methyl-6-nitro-2-[({5-[4-(triptoreline)phenyl]-2-pyrimidinyl}oxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 18 of table 1) when using the method of scheme 4

[0119] the Reaction mix Suzuki bromide 103 and 4-(triptoreline)phenylboronic acid as in example 2M for 2 hours, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then a mixture of 0.25% MeOH/CH2Cl2gave compound 18 (80%) as a cream solid: so pl. (CH2Cl2/hexane) 227°C decomp.;

1H NMR [(CD3)2SO] δ 8,96 (s, 2H), 8,18 (s, 1H), 7,87 (user.d, J=8.7 Hz, 2H), 7,50 (user.d, J=8,2 Hz, 2H), 4,70 (d, J=12.0 Hz, 1H), 4,67 (d, J=12.0 Hz, 1H), of 4.44 (d, J=11.0 cm Hz, 1H), 4,22 (d, J=11.0 cm Hz, 1H), 1,72 (s, 3H); elemental analysis: (C18H14F3N5O5) C, H, N.

[0120] S. Synthesis 2-({[2-(4-forfinal)-5-pyrimidinyl]oxy}methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 19 of table 1) when using the method of scheme 5

[0121] Stir a mixture of 2-chloro-5-pyrimidine (107) (1,00 g, 7,66 mmol) and chloromethylation ether (1.75 ml of 18.9 mmol) in anhydrous DMF (2.5 ml) was treated with K2CO3(2.15 g, 15.6 mmol). After stirring at room temperature for 16 hours the mixture was added to a mixture of ice/water solution of NaHCO3(100 ml) and was extracted with a mixture of 50% Et2O/petroleum ether (5×100 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-1% Et2O/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 1-10% Et2O/petroleum ether gave 2-chloro-5-(ethoxyethoxy)pyrimidine (108) (1.27 g, 88%) as oil;

1H NMR (CDCl3) δ 8,43 (s, 2H), 5,27 (s, 2H), 3,74 (kV, J=7,1 Hz, 2H), 1,23 (t, J=7,1 Hz, 3H); HRESIMS calculated for C7Hl0ClN2O2m/z [M+H]+191,0396, 189,0425 found 191,0397, 189,0426.

[012] Stir a mixture of 4-ftorhinolonovy acid (282 mg, 2.02 mmol) and Pd(dppf)Cl2(199 mg, 0,272 mmol) in toluene (14 ml) and EtOH (7 ml) was degirolami within 10 minutes (vacuum pump) and then typed N2. Added 2M aqueous solution of Na2CO3(3.3 ml, 6.6 mmol) via syringe, stir the mixture again degirolami for 10 minutes and then typed N2with the subsequent addition of chloropyrimidine 108 (260 mg, 1.38 mmol). The resulting mixture was stirred at 86°C for 2.5 hours, then cooled, diluted aqueous solution of NaHCO3(50 ml) and was extracted with CH2Cl2(5×50 ml). The extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-2% Et2O/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 2% Et2O/petroleum ether gave 5-(ethoxyethoxy)-2-(4-forfinal)pyrimidine (109) (312 mg, 91%) as a white solid: so square (petroleum ether) 42-44°C;

1H NMR (CDCl3) δ 8,58 (s, 2H), at 8.36 (DDT, J=9,0, 5,6, 2.5 Hz, 2H), 7,14 (TT, J=8,8, 2.5 Hz, 2H), and 5.30 (s, 2H), of 3.77 (q, J=7,1 Hz, 2H), 1,25 (t, J=7,1 Hz, 3H); HRESIMS calculated for C13H13FN2O2m/z [M+H]+249,1034 found 249,1039.

[0123] a Simple ether 109 (301 mg, to 1.21 mmol) was treated with a 1.25 M solution of HCl in MeOH (10 ml) and the mixture was stirred at 53°C for 4 hours. Received the cooled solution was diluted with ice water (100 ml) and was extracted with CH2Cl2(5×80 ml). United ex is rakti was evaporated to dryness, and the residue triturated in pentane, to obtain 2-(4-forfinal)-5-pyrimidine (111) (225 mg, 98%) as a white solid: so square (pentane) 200-202°C;

1H NMR [(CD3)2SO] δ 10,55 (very user.s, 1H), 8,42 (s, 2H), 8,29 (DDT, J=9.1, or, 5,7, and 2.6 Hz, 2H), 7,28 (TT, J=9,0, 2,6 Hz, 2H); HRESIMS calculated for C10H8FN2O m/z [M+H]+191,0615 found 191,0616.

[0124] a Mixture of 2-bromo-1-[(2-methyl-2-oxiranyl)methyl]-4-nitro-1H-imidazole (105) (obtained in stage 2 of the connection 80, through epoxidation of the corresponding alkene, as described by Ding et al., WO 2008008480A2) (279,5 mg, 1.07 mmol) and pyrimidine 111 (201 mg, 1.06 mmol) in anhydrous DMF (3 ml) in an atmosphere of N2at 0°C was treated with 60% NaH (54 mg, 1.35 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. After stirring at room temperature for 30 minutes and then at 60°C for 3 hours the reaction mixture was cooled (CO2/acetone), was suppressed with a mixture of ice/water solution of NaHCO3(5 ml) was added to a saturated salt solution (50 ml) and was extracted with CH2Cl2(8×50 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-33% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 50% EtOAc/petroleum ether gave 1-(2-bromo-4-nitro-1H-imidazol-1-yl)-3-{[2-(4-forfinal)-5-pyrimidinyl]oxy}-2-methyl-2-propanol (113) (76 m is, 16%) in the form of butter;

1H NMR (CDCl3) δ 8,46 (s, 2H), at 8.36 (DDT, J=9,0, 5,5, 2.5 Hz, 2H), of 8.09 (s, 1H), 7,15 (TT, J=8,7, 2.5 Hz, 2H), 4,32 (d, J=14.6 Hz, 1H), 4,21 (d, J=14,5 Hz, 1H), a 4.03 (d, J=9,2 Hz, 1H), 3,99 (d, J=9.1 Hz, 1H), 2,59 (s, 1H)that was 1.43 (s, 3H); HRESIMS calculated for C17H16BrFN5O4m/z [M+H]+454,0345, 452,0364 found 454,0342, 452,0358.

[0125] Further elution of the above described column EtOAc gave the crude solid, which was then purified by chromatography on silica gel. Elution with a mixture of 0-2% EtOAc/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 2-5% EtOAc/CH2Cl2gave compound 19 (135 mg, 34%) as a cream solid: so square (MeOH/CH2Cl2/hexane) 201-203°C;

1H NMR 8,63 (s, 2H), 8,33 (DDT, J=9,0, 5,7, and 2.6 Hz, 2H), 8,18 (s, 1H), 7,32 (TT, J=8,9, and 2.6 Hz, 2H), 4,57 (d, J=11,1 Hz, 1H), 4,53 (d, J=11,1 Hz, 1H), 4,42 (d, J=11.0 cm Hz, 1H), 4,22 (d, J=11.0 cm Hz, 1H), 1,71 (s, 3H); APCI MS m/z 372 [M+H]+.

[0126] ring Closure of alcohol 113 using NaH (1.8 equiv.) as in example 2A, for 35 minutes, followed by chromatography of the product on silica gel with elution with a mixture of 0-2% EtOAc/CH2Cl2(head of the faction) and then a mixture of 2-5% EtOAc/CH2Cl2gave an additional amount of compound 19 (67%).

[0127] T. Synthesis of 2-methyl-6-nitro-2-[({2-[4-(triptoreline)phenyl]-5-pyrimidinyl}oxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 20 of table 1) when using the method of scheme 5

[0128] the Reaction of a combination of Suzuki chloropyrimidine 108 (see example 2S) and 4-(triptoreline)phenylboronic acid, as in example 2S above, within 2 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-2% Et2O/petroleum ether (head of the faction) and then with a mixture of 2% Et2O/petroleum ether gave 5-(ethoxyethoxy)-2-[4-(triptoreline)phenyl]pyrimidine (110) (91%) as a white solid: so square (petroleum ether) 41-43°C;

1H NMR (CDCl3) δ at 8.60 (s, 2H), to 8.41 (dt, J=9,0, 2.4 Hz, 2H), 7,30 (user.DD, J=9,0,0,9 Hz, 2H), 5,31 (s, 2H), of 3.77 (q, J=7,1 Hz, 2H), 1,25 (t, J=7,1 Hz, 3H); HRESIMS calculated for C14H14F3N2O3m/z [M+H]+315,0951 found 315,0944.

[0129] a Simple ester 110 (379 mg, to 1.21 mmol) was treated with a 1.25 M solution of HCl in MeOH (11 ml) and the mixture was stirred at room temperature for 12 hours and then at 53°C for 2 hours. Received the cooled solution was diluted with water (50 ml) and was extracted with CH2Cl2(5×50 ml). The combined extracts were evaporated to dryness, and the residue is triturated in pentane, to obtain 2-[4-(triptoreline)phenyl]-5-pyrimidine (112) (305 mg, 99%) as a white solid: so square (pentane) 156-157°C;

1H NMR (CDCl3) δ to 8.45 (s, 2H), scored 8.38 (dt, J=8,9, 2.4 Hz, 2H), 7,29 (user.DD, J=8,9, 0.7 Hz, 2H), ceiling of 5.60 (user.s, 1H); HRESIMS calculated for C11H8N2O2m/z [M+H]+257,0532 found 257,0526.

[0130] the MCA is ü 2-bromo-1-[(2-methyl-2-oxiranyl)methyl]-4-nitro-1H-imidazole (105) (obtained in stage 2 of the connection 80, through epoxidation of the corresponding alkene, as described by Ding et al., WO 2008008480A2) (165 mg, 0,630 mmol) and pyrimidine 112 (160 mg, of 0.625 mmol) in anhydrous DMF (2 ml) in an atmosphere of N2at 0°C was treated with 60% NaH (33,5 mg, 0,838 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. After stirring at room temperature for 10 minutes and then at 50°C for 3 hours the reaction mixture was cooled (CO2/acetone), was suppressed with a mixture of ice/water solution of NaHCO3(5 ml) was added to a saturated salt solution (50 ml) and was extracted with CH2Cl2(6×50 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-33% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution EtOAc gave the crude mixture of compounds 20 and alcohol 114 with an open ring (95 mg). The solution mixture in anhydrous DMF (2 ml) in an atmosphere of N2at 0°C was treated with 60% NaH (6.3 mg, 0,158 mmol), then degirolami, again tightly closed in an atmosphere of N2and was stirred at 0°C for 80 minutes. The reaction mixture was suppressed and subjected to processing as described above, then the product was purified by chromatography on silica gel, elwira mixture 0-2% EtOAc/CH2Cl2(head of the faction) and then a mixture of 3-5% EtOAc/CH2Cl2with the connection 20 (62 mg, 23%) as a cream solid: so pl. (MeOH/CH2Cl2/hexane) 223-225°C;

1H NMR [(CD3)2SO] δ 8,66 (s, 2H), 8,40 (dt, J=8,9, 2.4 Hz, 2H), 8,18 (s, 1H), 7,49 (user.d, J=8,2 Hz, 2H), 4,59 (d, J=11,1 Hz, 1H), 4,55 (d, J=11,1 Hz, 1H), 4,43 (d, J=11,1 Hz, 1H), 4,23 (d, J=11.0 cm Hz, 1H), 1,72 (s, 3H); elemental analysis: (C18H14F3N5O5) C, H, N.

[0131] U. Synthesis 2-({[5-(4-forfinal)-2-pyrazinyl]oxy}methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 21 in table 1) using the method of scheme 4

[0132] a Solution of alcohol 101 (see example 2M) (350 mg, of 1.76 mmol) in anhydrous DMF (7 ml) in an atmosphere of N2at 0°C was treated with 60% NaH (104 mg, 2,60 mmol) and 2,5-dibromopyrazine (837 mg, to 3.52 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. After stirring at room temperature for 3 hours the reaction mixture was cooled (CO2/acetone), was suppressed with a mixture of ice/water solution of NaHCO3(20 ml) was added to a saturated salt solution (80 ml) and was extracted with CH2Cl2(6×100 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 0-2% EtOAc/CH2Cl2gave 2-{[(5-bromo-2-pyrazinyl)oxy]methyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazol (104) (428 mg, 68%) as a white solid: so square (MeOH/CH2 Cl2/hexane) 198-200°C;

1H NMR [(CD3)2SO] δ 8,44 (d, J=1.3 Hz, 1H), 8,16 (d, J=1.3 Hz, 1H), 8,14 (s, 1H), to 4.62 (s, 2H), and 4.40 (d, J=11.0 cm Hz, 1H), 4,19 (d, J=11.0 cm Hz, 1H), 1,70 (s,3H); elemental analysis: (C11H10BrN5O4) C, H, N.

[0133] Stir a mixture of bromide 104 (140,2 mg, 0,394 mmol), 4-ftorhinolonovy acid (104 mg, 0,743 mmol) and Pd(dppf)Cl2(29,8 mg, up 40.7 mmol) in toluene (6 ml) and EtOH (2.4 ml) was degirolami within 8 minutes (vacuum pump) and then typed N2. Added 2M aqueous solution of Na2CO3(1.0 ml, 2.0 mmol) via syringe and stir the mixture again degirolami for 8 minutes and then typed N2. The resulting mixture was stirred at 89°C for 110 minutes and then was cooled, diluted aqueous solution of NaHCO3(50 ml) and was extracted with CH2Cl2(5×50 ml). The extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 2-3% EtOAc/CH2Cl2gave compound 21 (112 mg, 77%) as a cream solid: so square (MeOH/CH2Cl2/hexane) 200-201°C;

1H NMR [(CD3)2SO] δ 8,80 (d, J=1.2 Hz, 1H), with 8.33 (d, J=1.3 Hz, 1H), 8,17 (s, 1H), 8,08 (user.DD, J=8,8, 5.5 Hz, 2H), 7,33 (user.t, J=8,9 Hz, 2H), 4,70 (d, J=12,5 Hz, 1H), 4,66 (d, J=12,5 Hz, 1H), 4,43 (d, J=11,1 Hz, 1H), 4,22 (d, J=11.0 cm Hz, 1H), 1,72 (s, 3H); elemental analysis: (C17H14FN5O4) C, H, N.

[0134] V. Synthesis of 2-methyl-6-nitro-2-[({5-[4-(triptoreline)phenyl]-2-pyrazinyl}oxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 22 of table 1) when using the method of scheme 4

[0135] the Reaction mix Suzuki bromide 104 and 4-(triptoreline)phenylboronic acid, as in example 2U, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then with a mixture of 1-2,5% EtOAc/CH2Cl2gave compound 22 (81%) as a cream solid: so square (MeOH/CH2Cl2/hexane) 222-224°C;

1H NMR [(CD3)2SO] δ cent to 8.85 (d, J=1.3 Hz, 1H), at 8.36 (d, J=1.4 Hz, 1H), 8,17 (s, 1H), 8,16 (user.d, J=9.1 Hz, 2H), 7,49 (user.d, J=8,2 Hz, 2H), 4,69 (s, 2H), of 4.44 (d, J=11.0 cm Hz, 1H), 4,22 (d, J=11.0 cm Hz, 1H), 1,73 (s,3H); elemental analysis: (C18H14F3N5O5) C, H, N.

[0136] W. Synthesis of 6-nitro-2-({[4-(triptoreline)benzyl]oxy}methyl)-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 23 in table 1) using the method of scheme 6

[0137] a Mixture of glycidol (115) (303 mg, 4.09 to mmol) and 4-(triptoreline)benzylbromide (0,810 ml of 5.06 mmol) in anhydrous DMF (6 ml) in an atmosphere of N2at 0°C was treated with 60% NaH (246 mg, 6,15 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. After stirring at room temperature for 7 hours the mixture was cooled (CO2 /acetone), was suppressed with a mixture of ice/water solution of NaHCO3(20 ml), was added to water (100 ml) and was extracted with EtOAc (4×100 ml). The extracts were washed with saturated salt solution (100 ml) was evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-5% Et2O/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 5-10% Et2O/petroleum ether gave 2-({[4-(triptoreline)benzyl]oxy}methyl)oxiran (116) (625 mg, 62%) as oil;

1H NMR (CDCl3) δ 7,38 (dt, J=8,7, 2,3 Hz, 2H), 7,20 (user.DD, J=8,7, 0.7 Hz, 2H), to 4.62 (d, J=12.0 Hz, 1H), 4,56 (d, J=12.0 Hz, 1H), 3,82 (DD, J=11,5, 2.8 Hz, 1H), 3,43 (DD, J=11,5, 6.0 Hz, 1H), 3,21 (m, 1H), 2,82 (DD, J=4,9, 4,2 Hz, 1H), 2.63 in (DD, J=5.0 and 2.7 Hz, 1H); HRESIMS calculated for C11H11F3NaO3m/z [M+Na]+271,0552 found 271,0557.

[0138] the interaction of the epoxide 116 with 2-bromo-4(5)-nitroimidazole (80), as in example 2A, at 107°C for 13 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then with a mixture of 1-2% EtOAc/CH2Cl2gave 1-(2-bromo-4-nitro-1H-imidazol-1-yl)-3-{[4-(triptoreline)benzyl]oxy}-2-propanol (118) (61%) as a white solid: so square (CΗ2Cl2/pentane) 80-81°C;

1H NMR (CDCl3) δ of 7.95 (s, 1H), 7,35 (dt, J=8,7, 2,3 Hz, 2H), 7.23 percent (OSiR.d, J=8.7 Hz, 2H), 4,57 (s, 2H), 4,20 (DD, J=13,6, 2,9 Hz, 1H), 4,14 (m, 1H), 4,07 (DD, J=13,4, and 7.1 Hz, 1H) and 3.59 (DD, J=9,6, 4,2 Hz, 1H), 3.46 in (DD, J=9,6, 5,3 is C, 1H), 2,61 (d, J=5.0 Hz, 1H); HRESIMS calculated for C14H14BrF3N3O5m/z [M+H]+442,0044, 440,0063 found 442,0044, 440,0061; elemental analysis: (C14H13BrF3N3O5) H, N. C: calculated, 38,20; found, 38,61.

[0139] ring Closure of alcohol 118 using NaH as in example 2A, for 65 minutes, followed by chromatography of the product on silica gel with elution CH2Cl2gave compound 23 (90%) as a cream solid: so pl. (CH2Cl2/hexane) 134-135°C;

1H NMR (CDCl3) δ 7,53 (s, 1H), 7,29 (dt, J=8,7, 2,1 Hz, 2H), 7,20 (user.d, J=8.0 Hz, 2H), 5,42 (m, 1H), 4,32 (DD, J=10,0, 8.6 Hz, 1H), 4.26 deaths (DD, J=10,0, 6.5 Hz, 1H), 3,89 (DD, J=11,3, 3,9 Hz, 1H), 3,78 (DD, J=11,3, 3.5 Hz, 1H); elemental analysis: (C14H12F3N3O5) C, H, N.

[0140] X. Synthesis of 2-({[4-(benzyloxy)benzyl]oxy}methyl)-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 24 of table 1) when using the method of scheme 6

[0141] the Alkylation of glycidol (115) using 4-(benzyloxy)benzylchloride, as in the example 2W, 10 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-7,5% Et2O/petroleum ether (head of the faction) and then a mixture of 7.5-10% Et2O/petroleum ether gave the crude oil, which was then chromatographically on silica gel. Elution with a mixture of 0-50% CH2Cl2/petroleum EF the p first gave head a fraction, and subsequent elution with a mixture of 50-66% CH2Cl2/petroleum ether gave 2-({[4-(benzyloxy)benzyl]oxy}methyl)oxiran (117) (32%) (described Cousse et al., EP 187096A1 based on epichlorohydrin and 4-(benzyloxy)benzyl alcohol) in the form of butter;

1H NMR (CDCl3) δ 7,45-7,29 (m, 5H), 7,27 (dt, J=8,8, 2,3 Hz, 2H), 6,95 (dt, J=8,7, 2.5 Hz, 2H), 4,54 (d, J=11,6 Hz, 1H), 4,48 (d, J=11,6 Hz, 1H), and 3.72 (DD, J=11,5, 3.2 Hz, 1H), 3,42 (DD, J=11,4, 5.8 Hz, 1H), 3,17 (m, 1H), and 2.79 (DD, J=5,0, 4,2 Hz, 1H), 2,60 (DD, J=5,1, 2.7 Hz, 1H); HRESIMS calculated for C17H18NaO3m/z [M+Na]+293,1148 found 293,1143.

[0142] the interaction of the epoxide 117 with 2-bromo-4(5)-nitroimidazole (80), as in example 2A, at 108°C for 14 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then a mixture of 2-4% EtOAc/CH2Cl2gave 1-{[4-(benzyloxy)benzyl]oxy}-3-(2-bromo-4-nitro-1H-imidazol-1-yl)-2-propanol (119) (73%) as white solids: I. pl. (CH2Cl2/hexane) 122-123°C;

1H NMR (CDCl3) δ 7,88 (s, 1H), 7,46-7,30 (m, 5H), from 7.24 (dt, J=8,6, 2.4 Hz, 2H), 6,98 (dt, J=8,7, 2.4 Hz, 2H), to 5.08 (s, 2H), to 4.52 (d, J=11.5 Hz, 1H), 4,48 (d, J=11.5 Hz, 1H), 4,18-4,01 (m, 3H), 3,55 (DD, J=9,7, 4.0 Hz, 1H), 3,39 (DD, J=9,6, 5,1 Hz, 1H), 2,48 (d, J=5.3 Hz, 1H); elemental analysis: (C20H20BrN3O5) C, H, N.

[0143] ring Closure of alcohol 119 using NaH as in example 2A, for 80 minutes, followed by chromatography of the product on silica gel with LWIR is the so called CH 2Cl2(head of the faction) and then with a mixture of 1-2% EtOAc/CH2Cl2gave compound 24 (88%) as a cream solid: so pl. (CH2Cl2/hexane) 123-124°C;

1H NMR (CDCl3) δ 7.50 for (s, 1H), 7,45-7,29 (m, 5H), 7,19 (dt, J=8,7, 2.4 Hz, 2H), 6,95 (dt, J=8,6, 2.4 Hz, 2H), lower than the 5.37 (m, 1H), 4,54 (d, J=11.7 Hz, 1H), 4,50 (d, J=11.7 Hz, 1H), 4,27 (DD, J=10,0, 8.5 Hz, 1H), 4,22 (DD, J=10,0, 6,5 Hz, 1H), 3,82 (DD, J=11,2, 4,2 Hz, 1H), of 3.73 (DD, J=and 11.2, 3.6 Hz, 1H); elemental analysis: (C20H19N3O5) C, H, N.

[0144] Y. Synthesis of 2-methyl-6-nitro-2-({[4-(triptoreline)benzyl]oxy}methyl)-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 25 of table 1) when using the method of scheme 6

[0145] a Solution of 2-methyl-2-propen-1-ol (120) (2,34 ml, 27.8 mmol) in anhydrous DMF (10 ml, then 2×2 ml to rinse) was added to a suspension of 60% NaH (1,32 g, up 33.1 mmol) in anhydrous DMF (10 ml) in an atmosphere of N2at 0°C, and the resulting mixture was stirred at 0°C for 30 minutes. Was added 4-(triptoreline)benzylbromide (5,1 ml, 31.9 per mmol) and the mixture was stirred at room temperature for 21 hours. The resulting mixture was added to a mixture of ice/water solution of NaHCO3(200 ml) and was extracted with 25% EtOAc/petroleum ether (2×200 ml) and 50% EtOAc/petroleum ether (3×200 ml). The extracts were washed with water (200 ml), volatile solvents were removed and the residual oil was chromatographically on silica gel. Elution with petroleum ether first Dawa what about the head of the faction, then further elution with a mixture of 0-15% CH2Cl2/petroleum ether gave 1-{[(2-methyl-2-propenyl)oxy]methyl}-4-(triptoreline)benzene (121) (6,57 g, 96%) as oil, which was used directly in the next stage;

1H NMR (CDCl3) δ 7,37 (dt, J=8,7, 2,3 Hz, 2H), 7,19 (user.d, J=8.0 Hz, 2H), 5,00 (m, 1H), 4,94 (m, 1H), 4,48 (s, 2H), 3,94 (s, 2H), 1.77 in (s, 3H).

[0146] Epoxidation of alkene 121 when using 3-chloroperbenzoic acid, as in example 2G, followed by chromatography of the product on silica gel with elution with a mixture of 0-15% CH2Cl2/petroleum ether (head of the faction) and then a mixture of 15-75% CH2Cl2/petroleum ether and CH2Cl2gave 2-methyl-2-({[4-(triptoreline)benzyl]oxy}methyl)oxiran (123) (93%) in the form of butter;

1H NMR (CDCl3) δ 7,37 (dt, J=8,7, 2.4 Hz, 2H), 7,19 (user.d, J=7.9 Hz, 2H), 4,59 (d, J=12.1 Hz, 1H), 4,54 (d, J=12.1 Hz, 1H), 3,61 (d, J=11,1 Hz, 1H), 3,44 (d, J=11,1 Hz, 1H), 2,75 (d, J=4.9 Hz, 1H), 2,64 (d, J=4.9 Hz, 1H), 1,40 (s, 3H); HRESIMS (NH3) calculated for C12H17F3O3N m/z [M+H+NH3]+280,1161 found 280,1144.

[0147] the interaction of the epoxide 123 from 2-bromo-4(5)-nitroimidazole (80), as in example 2A, at 108°C for 15 hours, followed by chromatography of the product on silica gel with elution CH2Cl2gave 1-(2-bromo-4-nitro-1H-imidazol-1-yl)-2-methyl-3-{[4-(triptoreline)benzyl]oxy}-2-propanol (125) (94%) as a pale yellow oil;

p> 1H NMR (CDCl3) δ of 8.00 (s, 1H), 7,33 (dt, J=8,6, and 2.3 Hz, 2H), 7,22 (user.d, J=8.0 Hz, 2H), 4,56 (s, 2H), 4,15 (d, J=14,8 Hz, 1H), Android 4.04 (d, J=14,5 Hz, 1H), 3,39 (s, 2H), of 2.51 (s, 1H), 1,22 (s, 3H); HRESIMS calculated for C15H16BrF3N3O5m/z [M+H]+456,0200, 454,0220 found 456,0197, 454,0221.

[0148] ring Closure of alcohol 125 using NaH as in example 2A, for 80 minutes, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then the mixture 0-1% EtOAc/CH2Cl2gave compound 25 (87%) as a pale yellow solid: so pl. (CH2Cl2/hexane) 110-111°C;

1H NMR (CDCl3) δ 7.50 for (s, 1H), 7,26 (user.d, J=8,4 Hz, 2H), 7,19 (user.d, J=8,3 Hz, 2H), 4,59 (d, J=12.3 Hz, 1H), 4,56 (d, J=12.3 Hz, 1H), 4,36 (d, J=10.0 Hz, 1H), 3,91 (d, J=10.0 Hz, 1H), and 3.72 (d, J=10,7 Hz, 1H) and 3.59 (d, J=a 10.6 Hz, 1H), 1,65 (s, 3H); elemental analysis: (C15H14F3N3O5) C, H, N.

[0149] Z. Synthesis of 2-({[4-(benzyloxy)benzyl]oxy}methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (compound 26 in table 1) using the method of scheme 6

[0150] a Solution of 2-methyl-2-propen-1-ol (120) (1,17 ml of 13.9 mmol) in anhydrous DMF (5 ml, then 2×1 ml to rinse) was added to a suspension of 60% NaH (674 mg, about 16.9 mmol) in anhydrous DMF (5 ml) in an atmosphere of N2at 0°C and the mixture was stirred at 0°C for 30 minutes. Was added a solution of 4-(benzyloxy)benzylchloride (a 3.87 g of 16.6 mmol) in the same DMF (6 ml, then 2×2 ml rinse) and the mixture was stirred at room temperature for 16 hours. The resulting mixture was added to a mixture of ice/water solution of NaHCO3(100 ml) and was extracted with EtOAc (4×100 ml). The extracts were washed with water (100 ml), EtOAc was removed and the residual oil was chromatographically on silica gel. Elution with petroleum ether firstly gave the head of the faction, and then further elution with a mixture of 0-25% CH2Cl2/petroleum ether gave 1-(benzyloxy)-4-{[(2-methyl-2-propenyl)oxy]methyl}benzene (122) (described Wennerberg et al., 1999, through alkylation of 4-(benzyloxy)benzyl alcohol) (3,48 g, 93%) as oil, which was used directly in the next stage;

1H NMR (CDCl3) δ 7,45-7,28 (m, 5H), 7,27 (dt, J=8,5, 2.4 Hz, 2H), 6,95 (dt, J=8,7, 2.4 Hz, 2H), 5,07 (s, 2H), 4,99 (m, 1H), 4,91 (m, 1H), 4,42 (s, 2H), 3,91 (s, 2H), 1,76 (s, 3H).

[0151] Epoxidation of alkene 122 using 3-chloroperbenzoic acid, as in example 2G, for 2.5 hours, followed by chromatography of the product on silica gel with elution with a mixture of 50% CH2Cl2/petroleum ether (head of the faction) and then a mixture of 50-80% CH2Cl2/petroleum ether and CH2Cl2gave 2-({[4-(benzyloxy)benzyl]oxy}methyl)-2-methyloxiran (124) (95%) in the form of butter;

1H NMR (CDCl3) δ 7,45-7,29 (m, 5H), 7,26 (dt, J=8,7, 2.4 Hz, 2H), 6,95 (dt, J=8,7, 2.5 Hz, 2H), 5,07 (s, 2H), to 4.52 (d, J=11,6 Hz, 1H), 4,47 (d, J=11,6 Hz, 1H), 3,54 (d, J=11.0 cm Hz, 1H), 342 (d, J=to 11.0 Hz, 1H), 2,73 (d, J=4.9 Hz, 1H), 2,62 (d, J=4.9 Hz, 1H), 1.39 in (s, 3H); HRESIMS calculated for C18H20O3m/z (M+) 284,1412 found 284,1416.

[0152] the interaction of the epoxide 124 with 2-bromo-4(5)-nitroimidazole (80), as in example 2A, at 108°C for 16 hours, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then a mixture of 0-2% EtOAc/CH2Cl2gave 1-{[4-(benzyloxy)benzyl]oxy}-3-(2-bromo-4-nitro-1H-imidazol-1-yl)-2-methyl-2-propanol (126) (100%) as a pale yellow oil;

1H NMR (CDCl3) δ 7,94 (s, 1H), 7,46-7,30 (m, 5H), 7,22 (dt, J=8,6, 2.4 Hz, 2H), 6,98 (dt, J=8,7, 2.5 Hz, 2H), to 5.08 (s, 2H), 4,50 (d, J=11.5 Hz, 1H), 4,47 (d, J=11.5 Hz, 1H), 4,11 (d, J=14.4 Hz, 1H), 4.00 points (d, J=14.4 Hz, 1H), to 3.34 (s, 2H), by 2.55 (s, 1H), 1,17 (s, 3H); HRESIMS calculated for C21H23BrN3O5m/z [M+H]+478,0796, 476,0816 found 478,0792, 476,0809.

[0153] ring Closure of alcohol 126 using NaH (1.5 equiv.) as in example 2A, for 80 minutes, followed by chromatography of the product on silica gel with elution CH2Cl2gave compound 26 (97%) as a cream solid: so pl. (CH2Cl2/hexane) 130-131°C;

1H NMR (CDCl3) δ of 7.48 (s, 1H), 7,45-7,29 (m, 5H), 7,16 (dt, J=8,7, 2.4 Hz, 2H), 6,94 (dt, J=8,7, 2.4 Hz, 2H), is 5.06 (s, 2H), to 4.52 (d, J=11.7 Hz, 1H), 4,47 (d, J=11.7 Hz, 1H), 4,32 (d, J=10.0 Hz, 1H), 3,86 (d, J=10.0 Hz, 1H), to 3.67 (d, J=a 10.6 Hz, 1H), 3,53 (d, J=a 10.6 Hz, 1H), 1,62 (s, 3H); elemental analysis: (C21H21N3O5) C, H, N.

[0154] AA Synthesis of 2-nitro-7-{[4-(triptoreline)phenoxy]methyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 27 of table 1) when using the method of scheme 7

[0155] 4-Bromo-1-butene (2.65 ml of 26.1 mmol) was added to a mixture of 2-chloro-4(5)-intorimidazole (81) (2.50 g, 17,0 mmol) and K2CO3(7,88 g, to 57.0 mmol) in anhydrous DMF (12 ml) in an atmosphere of N2and the mixture was stirred at 66°C for 12 hours. Received the cooled mixture was added to a mixture of ice/water solution of NaHCO3(140 ml) and was extracted with a mixture of 50% EtOAc/petroleum ether (5×100 ml). The extracts were washed with water (100 ml), then evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-10% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 10-20% EtOAc/petroleum ether gave 1-(3-butenyl)-2-chloro-4-nitro-1H-imidazole (127) (2,82 g, 82%) as a cream solid: so square (Et2O/pentane) 56-58°C;

1H NMR (CDCl3) δ 7,72 (s, 1H), grade of 5.74 (DDT, J=17.1 to, to 10.2, 6.9 Hz, 1H), 5,18 (DQC, J=10,3, 1.0 Hz, 1H), 5,12 (DQC, J=17,1, 1.3 Hz, 1H), 4.09 to (t, J=6.9 Hz, 2H), 2,58 (kW, J=6,9, 1,1 Hz, 2H); HRESIMS calculated for C7H9ClN3O2m/z [M+H]+204,0349, 202,0378 found 204,0350, 202,0377.

[0156] Epoxidation of alkene 127 when using 3-chloroperbenzoic acid, as in example 2G, for 50 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-10% EtOAc/petroleum ether (head of the faction) and then a mixture of 20-30% EtOAc/petroleum ether firstly gave the recovered alkene 127 (0,49 g, 17%). Suirou is the mixture of 0-5% Et 2O/CH2Cl2gave the crude product, which was then chromatographically on silica gel, elwira CH2Cl2(head of the faction) and then a mixture of 0-5% Et2O/CH2Cl2pick 2-chloro-4-nitro-1-[2-(2-oxiranyl)ethyl]-1H-imidazole (129) (73%) as a pale yellow solid: so square (CΗ2Cl2/hexane) 51-52°C;

1H NMR (CDCl3) δ 7,81 (s, 1H), 4,28-4,16 (m, 2H), 2,98 of 2.92 (m, 1H), 2,85 (DD, J=4,7, 4.0 Hz, 1H), 2,53 (DD, J=4,8, and 2.6 Hz, 1H), 2,35 was 2.25 (m, 1H), 1,87-to 1.77 (m, 1H); HRESIMS calculated for C7H9ClN3O3m/z [M+H]+220,0298, 218,0327 found 220,0297, 218,0322.

[0157] 4-Cryptomaterial (0,375 ml, 2.89 mmol) was added to a mixture of epoxide 129 (250 mg, 1.15 mmol) and powdered K2CO3(558 mg, 4.04 mmol) in anhydrous 2-butanone (3 ml) in an atmosphere of N2and the mixture was stirred at 81°C for 12 hours. Received the cooled mixture was diluted with water (50 ml) and was extracted with CH2Cl2(4×50 ml). The extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-25% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 25-33% EtOAc/petroleum ether gave 4-(2-chloro-4-nitro-1H-imidazol-1-yl)-1-[4-(triptoreline)phenoxy]-2-butanol (130) (306 mg, 67%) as a pale yellow oil;

1H NMR (CDCl3) δ a 7.85 (s, 1H), 7,16 (user.DD, J=9,1, 0.8 Hz, 2H), to 6.88 (dt, J=9,2, 3.0 Hz, 2H), 4,37-4,24 (m, 2H), was 4.02-3,93 (m, 2H), 386 (DD, J=10,0, 7.8 Hz, 1H), 2,47 (DD, J=4.2, and 1.1 Hz, 1H), 2,13-to 1.98 (m, 2H); HRESIMS calculated for C14H14ClF3N3O3m/z [M+H]+398,0540, 396,0569 found 398,0538, 396,0567.

[0158] Further elution of the above column with a mixture of 66% EtOAc/petroleum ether gave the crude solid (72 mg), which was then chromatographically on silica gel. Elution CH2Cl2gave head a fraction, and subsequent elution with a mixture of 0-3% EtOAc/CH2Cl2gave compound 27 (61 mg, 15%) as a cream solid: so pl. (CH2Cl2/hexane) 138-140°C;

1H NMR (CDCl3) δ was 7.45 (s, 1H), 7,17 (user.DD, J=9,1, 0.7 Hz, 2H), 6,91 (dt, J=9,2, 3.0 Hz, 2H), and 4.75 (m, 1H), or 4.31 (DD, J=10,2, a 4.3 Hz, 1H), 4.26 deaths-4.09 to (m, 3H), 2,52 of-2.32 (m, 2H); elemental analysis: (C14H12F3N3O5) C, H, N.

[0159] Stir a solution of alcohol 130 (305 mg, 0,771 mmol) in anhydrous DMF (5 ml) in an atmosphere of N2at 0°C was treated with 60% NaH (49 mg, of 1.23 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. After stirring at room temperature for 2.5 hours the reaction mixture was cooled (CO2/acetone), was suppressed with a mixture of ice/water solution of NaHCO3(10 ml) was added to a saturated salt solution (40 ml) and was extracted with CH2Cl2(6×50 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel. The elution mixture is 25-40% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 50-66% EtOAc/petroleum ether gave an additional amount of compound 27 (217 mg, 78%) as a pale yellow solid (see data above).

[0160] BB. Synthesis of 7-{[4-(benzyloxy)phenoxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 28 in table 1) using the method of scheme 7

[0161] a Mixture of 2-bromo-4(5)-intorimidazole (80) (2.50 g, 13,0 mmol), 4-bromo-1-butene (2.00 ml, of 19.7 mmol) and K2CO3(of 5.39 g of 39.0 mmol) in anhydrous DMF (25 ml) in an atmosphere of N2was stirred at 73°C for 4.5 hours. Received the cooled mixture was added to a mixture of ice/water solution of NaHCO3(200 ml) and was extracted with EtOAc (4×200 ml). The extracts were washed with water (200 ml), then evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-10% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 20% EtOAc/petroleum ether gave 2-bromo-1-(3-butenyl)-4-nitro-1H-imidazole (128) (2,96 g, 92%) as a pale yellow waxy solid: so pl. 28-30°C;

1H NMR (CDCl3) δ to 7.77 (s, 1H), of 5.75 (DDT, J=17.1 to, to 10.2, 6.9 Hz, 1H), 5,18 (DQC, J=10,2, 1.1 Hz, 1H), 5,12 (DQC, J=17,1, and 1.4 Hz, 1H), 4.09 to (t, J=7,0 Hz, 2H), 2,59 (kW, J=6,9, 1.2 Hz, 2H); HRFABMS calculated for C7H9BrN3O2m/z [M+H]+247,9858, 245,9878 found 247,9860, 245,9882.

[0162] osmium Tetroxide (3,75 ml of 4% aqueous solution, 0.64 mmol) was added to a solution of alkene 128 (3.00 g, 12.2 mmol) and 4-methylmorpholine N-oxide (2.16 g, 18.4 mmol) in CH2Cl2(75 ml) and the mixture is then stirred at room temperature for 4 hours. The precipitate was isolated by filtration, washed with CH2Cl2and water and then dried, to obtain 4-(2-bromo-4-nitro-1H-imidazol-1-yl)-1,2-butanediol (131) (2,39 g, 70%) as a cream solid: so square (THF/Et2O/pentane) 99-101°C;

1H NMR [(CD3)2SO] δ 8,55 (s, 1H), 4,77 (d, J=5.0 Hz, 1H), 4,58 (t, J=5.6 Hz, 1H), 4,14 (m, 2H), 3,42 (m, 1H), 3,34 (dt, J=10,7, a 5.4 Hz, 1H), 3,24 (dt, J=10,7, 5,9 Hz, 1H), 1,98 (DTD, J=13,7, 7,9, and 3.2 Hz, 1H), 1.69 in (dddd, J=13,6, 9,1, 7,4, 6.0 Hz, 1H); elemental analysis: (C7H10BrN3O4) C, H, N.

[0163] the filtrate Obtained above was added to a mixture of ice/water solution of Na2SO3(100 ml) and was extracted with EtOAc (3×100 ml). The aqueous layer was saturated with salt and then was extracted with EtOAc (7×100 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 50-67% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 67% EtOAc/petroleum ether and EtOAc gave an additional amount of diol 131 (728 mg, 21%).

[0164] Triisopropylsilane (2,50 ml, 11.7 mmol) was added to a solution of diol 131 (3.11 g, 11.1 mmol) and imidazole (1.66 g, 24.4 mmol) in anhydrous DMF (30 ml) in an atmosphere of N2and then the mixture was stirred at room temperature for hasaw. The resulting mixture was added to a mixture of ice-water (200 ml) and was extracted with EtOAc (4×200 ml). The extracts were washed with water (200 ml), then evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-20% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 20-33% EtOAc/petroleum ether gave 4-(2-bromo-4-nitro-1H-imidazol-1-yl)-1-[(triisopropylsilyl)oxy]-2-butanol (132) (4,60 g, 95%) as a white solid: so square (CΗ2Cl2/pentane) 90-91°C;

1H NMR (CDCl3) δ 7,89 (s, 1H), 4,24 (DD, J=7,7, 6.2 Hz, 2H), 3,74 (DD, J=9,6, 3.5 Hz, 1H), 3,62 (m, 1H), 3,53 (DD, J=9,6, 6,8 Hz, 1H), 2,59 (d, J=3.8 Hz, 1H), 1,95-to 1.82 (m, 2H), 1,17-of 1.03 (m, 21H); elemental analysis: (C16H30BrN3O4Si) C, H, N.

[0165] Stir a solution of alcohol 132 (2,45 g, 5,61 mmol) in anhydrous DMF (25 ml) in an atmosphere of N2at 0°C was treated with 60% NaH (388 mg, to 9.70 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. After stirring at room temperature for 2 hours the reaction mixture was cooled (CO2/acetone), was suppressed with a mixture of ice/water solution of NaHCO3(20 ml), diluted with ice water (150 ml) and was extracted with EtOAc (8×80 ml). The extracts were washed with saturated salt solution (100 ml), then evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-25% EtOAc/petroleum ether firstly gave the head of the faction, the subsequent elution with a mixture of 25% EtOAc/petroleum ether gave 2-nitro-7-{[(triisopropylsilyl)oxy]methyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (133) (1.77 g, 89%) as a pale yellow solid: so pl. (CH2Cl2/pentane) 121-123°C;

1H NMR (CDCl3) δ 7,42 (s, 1H), 4,45 (m, 1H), 4,17 (DDD, J=12,3, 5,8, and 3.7 Hz, 1H), 4,06 (DDD, J=12,3, 10,3, a 5.4 Hz, 1H), a 4.03 (DD, J=10,7, a 4.1 Hz, 1H), 3,95 (DD, J=10,7, 5.8 Hz, 1H), 2,37 (dddd, J=14,5, 5,5, 3,6, 2.8 Hz, 1H), 2,27 (DTD, J=14,5, 10,1, 5.8 Hz, 1H), 1,17-of 1.03 (m, 21H); elemental analysis: (C16H29N3O4Si) C, H, N.

[0166] the Suspension salelologa ether 133 (1,627 g, 4,58 mmol) in 1% HCl in 95% EtOH (desirelove described Cunico et al., 1980) (58 ml) was stirred at room temperature for 35 hours. The resulting solution was cooled (CO2/acetone), neutralized by adding dropwise 7M NH3in MeOH (7 ml) under stirring, and then concentrated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-2% MeOH/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 2% MeOH/CH2Cl2gave (2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-yl)methanol (134) (877 mg, 96%) as a pale yellow solid: so square (THF/MeOH/CH2Cl2/hexane) 179-181°C;

1H NMR [(CD3)2SO] δ of 8.04 (s, 1H), 5,12 (t, J=5.8 Hz, 1H), 4,48 (DTD, J=10,2, 4,7, 2.5 Hz, 1H), 4,13 (DDD, J=12,5, 5,8, 3.0 Hz, 1H), Android 4.04 (DDD, J=12,4, 11,0, 5,1 Hz, 1H), to 3.64 (m, 2H), 2,18 (DTD, J=14,4, 5,0, 2.8 Hz, 1H), 2,03 (DTD, J=14,4, 10,6, 5.7 Hz, 1H); elemental analysis: (C7H9N3O4) C, H, N.

[0167] Diethylazodicarboxylate (0,070 ml, 0.45 mmol) to relax is whether dropwise to a suspension of alcohol 134 (52,4 mg, to 0.263 mmol), triphenylphosphine (104 mg, 0,397 mmol) and 4-(benzyloxy)phenol (of 79.5 mg, 0,397 mmol) in anhydrous THF (1.0 ml) and the resulting mixture was stirred at room temperature for 51 hours. The solvent was removed and the residue was chromatographically on silica gel. Elution with a mixture of 0-1% EtOAc/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 4% EtOAc/CH2Cl2gave a crude solid, which was then chromatographically on silica gel. Elution with a mixture of 0-33% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 4% MeOH/CH2Cl2gave compound 28 (36 mg, 36%) as a cream solid: so square (MeOH/CH2Cl2/hexane) 222-224°C;

1H NMR [(CD3)2SO] δ 8,07 (s, 1H), 7,46-7,28 (m, 5H), 6,99-6,89 (m, 4H), a 4.86 (m, 1H), 4,27-to 4.14 (m, 3H), 4.09 to (DDD, J=12,5, 10,9, and 5.2 Hz, 1H), 2,35 was 2.25 (m, 1H), 2,25-2,12 (m, 1H); elemental analysis: (C20H19N3O5.0,25 H2O) C, H, N.

[0168] CC. Synthesis of 7-{[(4'-fluoro[1,1'-biphenyl]-4-yl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 29 in table 1) using the method of scheme 7

[0169] Diethylazodicarboxylate (0,070 ml, 0.45 mmol) was added dropwise to a suspension oxazinones alcohol 134 (see example 2BB above) (251 mg, of 1.26 mmol), triphenylphosphine (448 mg, 1,71 mmol) and 4-itfinal (377 mg, 1,71 mmol) in anhydrous THF (3.0 ml) at 0°C in an atmosphere of N 2and the resulting mixture was stirred at room temperature for 32 hours. The solvent was removed and the residue was chromatographically on silica gel. Elution CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 0-2% EtOAc/CH2Cl2gave a crude solid, which was then chromatographically on silica gel. Elution with a mixture of 0-50% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 10% MeOH/CH2Cl2gave 7-[(4-iodinate)methyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (135) (433 mg, 86%) as a cream solid: so square (MeOΗ/CΗ2Cl2/hexane) 224-227°C;

1H NMR [(CD3)2SO] δ 8,08 (s, 1H), 7.62mm (dt, J=9,0, 2.7 Hz, 2H), 6,86 (dt, J=9,0, 2.7 Hz, 2H), 4,89 (m, 1H), or 4.31 (DD, J=11,1, 3,4 Hz, 1H), 4,25 (DD, J=11,1, 5.8 Hz, 1H), 4,18 (DDD, J=12,6, 5,8, 3.0 Hz, 1H), 4.09 to (DDD, J=12,5, 10,8, 5,2 Hz, 1H), 2,35-of 2.26 (m, 1H), 2,25-2,12 (m, 1H); elemental analysis: (C13H12IN3O4) C, H, N.

[0170] Stir a mixture of iodide and 135 (50,1 mg, 0.125 mmol), 4-ftorhinolonovy acid (31.5 mg, 0,225 mmol) and Pd(dppf)Cl2(14.1 mg, 0.019 mmol) in toluene (1 ml), EtOH (0.6 ml) and DMF (1.5 ml) was degirolami within 5 minutes (vacuum pump) and then typed N2. Added 2M aqueous solution of Na2CO3(and 0.40 ml, 0.80 mmol) via syringe, stir the mixture again degirolami for 5 minutes and then typed N2.The resulting mixture was stirred at 90°C for 90 minutes, then cooled, diluted aqueous solution of NaHCO3(50 ml) and was extracted with CH2Cl2(4×50 ml). The extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-1% EtOAc/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 1-2% EtOAc/CH2Cl2gave compound 29 (42 mg, 91%) as a cream solid: so square (MeOH/CH2Cl2/pentane) 217-219°C;

1H NMR [(CD3)2SO] δ of 8.09 (s, 1H), 7,66 (DDT, J=8,9, 5,4, 2.7 Hz, 2H), 7,60 (dt, J=8,8, 2,6 Hz, 2H), 7,25 (TT, J=8,9, 2.7 Hz, 2H), to 7.09 (dt, J=8,8, 2,6 Hz, 2H), is 4.93 (m, 1H), 4,37 (DD, J=11,1, 3,4 Hz, 1H), 4,32 (DD, J=11,1, 5.7 Hz, 1H), 4,20 (DDD, J=12,6, 5,8, 3.0 Hz, 1H), 4,11 (DDD, J=12,5, 10,8, and 5.2 Hz, 1H), 2,38-of 2.30 (m, 1H), 2,29-of 2.16 (m, 1H); elemental analysis: (C19H16FN3O4) C, H, N.

[0171] DD. Synthesis of 2-nitro-7-({[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 30 in table 1) using the method of scheme 7

[0172] the Reaction mix Suzuki iodide 135 and 4-(trifluoromethyl)phenylboronic acid, as in example 2CC above, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then with a mixture of 1-2% EtOAc/CH2Cl2gave compound 30 (88%) as a cream solid: so square (MeOH/CH2Cl2/pentane) 242-245°C;

1H NMR [(CD3)2 SO] δ of 8.09 (s, 1 H), 7,86 (user.d, J=8,2 Hz, 2H), to 7.77 (user.d, J=8,3 Hz, 2H), 7,72 (DTT, J=8,9, 2.5 Hz, 2H), 7,14 (dt, J=8,8, 2.5 Hz, 2 H), 4,94 (m, 1H), and 4.40 (DD, J=11,1, 3,4 Hz, 1H), 4,34 (DD, J=11,1, 5.8 Hz, 1 H), is 4.21 (DDD, J=12,5, 5,8, 3.0 Hz, 1H), 4,12 (DDD, J=12,5, 10,9, and 5.2 Hz, 1H), 2,39-of 2.30 (m, 1H), 2,29-2,17 (m, 1H); elemental analysis: (C20H16F3N3O4) C, H, N.

[0173] EE. Synthesis of 2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 31 in table 1) using the method of scheme 7

[0174] the Reaction mix Suzuki iodide 135 and 4-(triptoreline)phenylboronic acid, as in example 2CC above, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then with a mixture of 1-2% EtOAc/CH2Cl2gave compound 31 (89%) as a cream solid: so pl. (CH2Cl2/pentane) 197-199°C;

1H NMR [(CD3)2SO] δ of 8.12 (s, 1H), of 7.75 (dt, J=8,8, 2.5 Hz, 2H), 7,65 (dt, J=8,9, 2.5 Hz, 2H), 7,42 (user.d, J=8.0 Hz, 2H), 7,11 (dt, J=8,9, 2.5 Hz, 2H), 4,94 (m, 1H), to 4.38 (DD, J=11,1, 3.3 Hz, 1H), 4,32 (DD, J=11,1, 5.8 Hz, 1H), 4,20 (DDD, J=12,5, 5,7, 2.8 Hz, 1H), 4,11 (DDD, J=12,4, 11,0, 5,1 Hz, 1H), 2,38-to 2.29 (m, 1H), 2,28-of 2.15 (m, 1H); elemental analysis: (C20H16F3N3O5) C, H, N.

[0175] FF. Synthesis 7-({[5-(4-forfinal)-2-pyridinyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 32 in table 1) using the method of scheme 8

[0176] 5-Bromo-2-herperidin (91) (0,52 ml of 5.05 mmol) was added to a solution of oxazinones alcohol 134 (see example 2BB) (500 mg, 2.51 mmol) in anhydrous DMF (10 ml) in an atmosphere of N2at 0°C. the resulting mixture was treated with 60% NaH (151 mg, of 3.78 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. Again, was added 5-bromo-2-herperidin (91) (0,52 ml of 5.05 mmol), the mixture was stirred at room temperature for 2.5 hours, then cooled (CO2/acetone), was suppressed with a mixture of ice/water solution of NaHCO3(30 ml) was added to a saturated salt solution (100 ml) and was extracted with CH2Cl2(8×100 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-1% EtOAc/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 2-4% EtOAc/CΗ2Cl2gave 7-{[(5-bromo-2-pyridinyl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (136) (778 mg, 87%) as a white solid: so square (MeOΗ/CΗ2Cl2/hexane) 182-184°C;

1H NMR [(CD3)2SO] δ 8,30 (DD, J=2,6, 0.5 Hz, 1H), 8,07 (s, 1H), 7,95 (DD, J=8,8, 2.6 Hz, 1H),6,91 (DD, J=8,8, 0.6 Hz, 1H), 4,90 (m, 1H), 4,58 (DD, J=12,0, 3.3 Hz, 1H), to 4.52 (DD, J=12,0, 6.0 Hz, 1H), 4,17 (DDD, J=12,6, 5,8, 2,8 Hz, 1H), 4.09 to (DDD, J=12,5, 11,0, 5,2 Hz, 1H), 2,34-of 2.26 (m, 1H), 2,23-2,11 (m, 1H); elemental analysis: (C12H11BrN4O4) C, H, N.

[0177] the Reaction mix Suzuki bromide 136 and 4-ftoh is sivoronova acid (2.0 equiv.) as in example 2M, for 2.5 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-3% EtOAc/CΗ2Cl2(head of the faction) and then a mixture of 3% EtOAc/CH2Cl2gave compound 32 (91%) as a cream solid: so square (MeOH/CH2Cl2/hexane) 180-181°C;

1H NMR [(CD3)2SO] δ of 8.47 (DD, J=2.5 and 0.5 Hz, 1H), of 8.09 (s, 1H), with 8.05 (DD, J=8,6, and 2.6 Hz, 1H), 7,72 (DDT, J=8,9, 5,4, 2.7 Hz, 2H), 7,30 (TT, J=8,9, 2.7 Hz, 2H), 6,98 (DD, J=8,6, 0.6 Hz, 1H), 4,94 (m, 1H), with 4.64 (DD, J=12,0, 3,4 Hz, 1H), 4,58 (DD, J=12,0, 6,1 Hz, 1H), 4,19 (DDD, J=12,6, 5,8, 2.7 Hz, 1H), 4,10 (DDD, J=12,4, 11,1, 5,1 Hz, 1H), 2,37-of 2.28 (m, 1H), 2.26 and and 2.13 (m, 1H); APCI MS m/z 371 [M+H]+.

[0178] GG. Synthesis of 2-nitro-7-[({5-[4-(triptoreline)phenyl]-2-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 33 in table 1) using the method of scheme 8

[0179] the Reaction mix Suzuki bromide 136 and 4-(triptoreline)phenylboronic acid as in example 2M, for 2.5 hours, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then the mixture 0-2,5% EtOAc/CH2Cl2gave compound 33 (90%) as a cream solid: so pl. (CH2Cl2/hexane) 161-163°C;

1H NMR (CDCl3) δ 8,32 (d, J=2.0 Hz, 1H), 7,79 (DD, J=8,5, 2.5 Hz, 1H), 7,53 (user.d, J=8.7 Hz, 2H), 7,45 (s, 1H), 7,30 (user.d, J=8.1 Hz, 2H), 6,86 (d, J=8.6 Hz, 1H), 4,84 (m, 1H), 4.72 in (DD, J=11,7, 5,1 Hz, 1H), 4,66 (DD, J=11,7, a 4.9 Hz, 1H),4,21 (DDD, J=12,4, 5,8, 3,4 Hz, 1H), 4,13 (DDD, J=12,4, 10,4, and 5.5 Hz, 1H), 2,48-of 2.30 (m, 2H); elemental analysis: (C19H15F3N4O5) C, H, N.

[0180] HH. Synthesis 7-({[6-(4-forfinal)-3-pyridinyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 34 in table 1) using the method of scheme 8

[0181] a Mixture of epoxide 129 (see example 2AA) (1,004 g, 4.61 mmol), 6-bromo-3-pyridinol (4,015 g of 23.1 mmol) and powdered K2CO3(3,319 g of 24.0 mmol) in anhydrous 2-butanone (10 ml) in an atmosphere of N2was stirred at 82-85°C for 28 hours. Received the cooled mixture was diluted with water (100 ml) and was extracted with a mixture of 25% EtOAc/CH2Cl2(3×100 ml). The extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-40% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 40% EtOAc/petroleum ether gave 1-[(6-bromo-3-pyridinyl)oxy]-4-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-butanol (137) (667 mg, 37%) as a cream solid: so square (MeOΗ/CΗ2Cl2/pentane) 112-114°C;

1H NMR [(CD3)2SO] δ 8,56 (s, 1H), 8,12 (d, J=3.1 Hz, 1H), 7,53 (d, J=8,8 Hz, 1H), 7,39 (DD, J=8,8, 3.2 Hz, 1H), 5,28 (user.d, J=4.5 Hz, 1H), 4,24 (DD, J=14,0, 5.8 Hz, 1H), 4,18 (DD, J=14,2, 7,3 Hz, 1H), 3,99 (DD, J=10,0, a 4.9 Hz, 1H), 3.96 points (DD, J=10,0, 5.5 Hz, 1H), 3,82 (m, 1H), 2.06 to (DTD, J=13,9, 7,7, 3,4 Hz, 1H), 1,90 (DDT, J=13,7, 9,2, of 6.7 Hz, 1H); HRESIMS calculated for C12H13BrClN4O4/sub> m/z [M+H]+394,9754, 392,9782, 390,9803 found 394,9753, 392,9777, 390,9797.

[0182] Further elution of the above column EtOAc gave the crude substance with a closed ring, which was then chromatographically on silica gel. Elution with a mixture of 0-0,5% MeOH/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 0.5% MeOH/CH2Cl2gave 7-{[(6-bromo-3-pyridinyl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (138) (51 mg, 3%) as a cream solid: so square (MeOΗ/CΗ2Cl2/hexane) 200-202°C;

1H NMR [(CD3)2SO] δ 8,19 (d, J=3.2 Hz, 1H), 8,08 (s, 1H), 7,58 (d, J=8.7 Hz, 1H), 7,47 (DD, J=8,8, 3.2 Hz, 1H), 4.92 in (m, 1H), 4,43 (DD, J=11,2, 3.3 Hz, 1H), 4,37 (DD, J=11,2, 5.8 Hz, 1H), 4,19 (DDD, J=12,5, 5,8, 3.0 Hz, 1H), 4,10 (DDD, J=12,5, 10,9, and 5.2 Hz, 1H), 2,36-of 2.27 (m, 1H), 2.26 and and 2.13 (m, 1H); elemental analysis: (C12H11BrN4O4) C, H, N.

[0183] ring Closure of alcohol 137 using NaH (1.6 equiv.) as in the example 2AA, followed by chromatography of the product on silica gel with elution with a mixture of 0-0,5% MeOH/CH2Cl2(head of the faction) and then a mixture of 0.5-0.75% MeOH/CH2Cl2gave an additional amount of compound 138 (87%) as a pale yellow solid (see above).

[0184] the Reaction mix Suzuki bromide 138 and 4-ftorhinolonovy acid as in example 2M, for 2.5 hours, followed by chromatography of the product on silica gel with elution with a mixture 0-05% MeOH/CH 2Cl2(head of the faction) and then a mixture of 0.5% MeOH/CH2Cl2gave compound 34 (87%) as a cream solid: so square (MeOH/CH2Cl2/hexane) 204-206°C;

1H NMR [(CD3)2SO] δ 8,43 (user.d, J=2.7 Hz, 1H) 8,11 (s, 1H), 8,07 (DDT, J=8,9, 5,6, 2.7 Hz, 2H), 7,94 (user.d, J=8.7 Hz, 1H), 7,56 (DD, J=8,8 3,0 Hz, 1H), 7,28 (TT, J=8,9, and 2.6 Hz, 2H), 4,96 (m, 1H), 4,47 (DD, J=and 11.2, 3.2 Hz, 1H), to 4.41 (DD, J=11,2, 5.8 Hz, 1H), 4,20 (DDD, J=12,5, 5,7, 2,9 Hz, 1H), 4,11 (DDD, J=12,4, 11,0, a 5.1 Hz, 1H), 2,38-of 2.30 (m, 1H), 2,29-of 2.16 (m, 1H); APCI MS m/z 371 [M+H]+.

[0185] II. Synthesis of 2-nitro-7-[({6-[4-(triptoreline)phenyl]-3-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 35 table 1) using the method of scheme 8

[0186] the Reaction mix Suzuki bromide 138 and 4-(triptoreline)phenylboronic acid as in example 2M, for 2.5 hours, followed by chromatography of the product on silica gel with elution with a mixture 0-0,33% MeOH/CH2Cl2(head of the faction) and then a mixture of 0.33% MeOH/CH2Cl2gave compound 35 (87%) as a cream solid: so square (MeOH/CH2Cl2/hexane) 161-163°C;

1H NMR [(CD3)2SO] δ 8,46 (d, J=2,9 Hz, 1H), 8,15 (user.d, J=8,8 Hz, 2H), 8,11 (s, 1H), to 7.99 (d, J=8,8 Hz, 1H), to 7.59 (DD, J=8,8, 3.0 Hz, 1H), 7,45 (user.d, J=8,2 Hz, 2H), 4,96 (m, 1H), 4,49 (DD, J=and 11.2, 3.2 Hz, 1H), 4,43 (DD, J=11,2, 5.8 Hz, 1H), 4,20 (DDD, J=12,5, 5,6, 2.7 Hz, 1H), 4,12 (DDD, J=12,4, 11,0, 5,2 Hz, 1H), 2,39-of 2.30 (m, 1H), 2,29-of 2.16 (m, 1H); elemental analysis: (C19 15F3N4O5) C, H, N.

[0187] JJ. Synthesis of 7-methyl-2-nitro-7-{[4-(triptoreline)phenoxy]methyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 36 in table 1) using the method of scheme 9

[0188] a Solution of 4-iodine-2-methyl-1-butene (obtained by iodination of 3-methyl-3-butene-1-ol as described Helmboldt et al., 2006) (2,01 g of 10.3 mmol) in anhydrous DMF (3 ml, then 3×1 ml to rinse) was added to a stirred mixture of 2-chloro-4(5)-intorimidazole (81) (1,00 g, to 6.80 mmol) and powdered K2CO3(2.83 g, 20,5 mmol) in anhydrous DMF (6.5 ml) in an atmosphere of N2and the mixture was stirred at 61°C for 20 hours. Received the cooled mixture was added to a mixture of ice/water solution of NaHCO3(100 ml) and was extracted with EtOAc (4×100 ml). The extracts were washed with dilute salt solution (100 ml), then evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-10% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 10-15% EtOAc/petroleum ether gave 2-chloro-1-(3-methyl-3-butenyl)-4-nitro-1H-imidazole (139) (1,15 g, 78%) as a white solid: so square (CΗ2Cl2/pentane) 68-69°C;

1H NMR (CDCl3) δ 7,71 (s, 1H), 4,90 (m, 1H), 4,69 (m, 1H), 4,13 (t, J=7,1 Hz, 2H), 2,52 (user.t, J=7,1 Hz, 2H), 1,80 (s, 3H); HRFABMS calculated for C8H11ClN3O2m/z [M+H]+218,0510, 216,0540 found 218,0512, 216,044.

[0189] Epoxidation of alkene 139 when using 3-chloroperbenzoic acid, as in example 2G, for 4 hours, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then a mixture of 0-5% EtOAc/CH2Cl2gave 2-chloro-1-[2-(2-methyl-2-oxiranyl)ethyl]-4-nitro-1H-imidazole (140) (88%) as a cream solid: so pl. (CH2Cl2/pentane) 82-85°C;

1H NMR (CDCl3) δ for 7.78 (s, 1H), 4,12 (t, J=7,6 Hz, 1H), 2,66 (d, J=4.4 Hz, 1H), 2,62 (d, J=4.4 Hz, 1H), 2,19 (dt, J=14,3, 7.7 Hz, 1H), 2,04 (dt, J=14,3, 7,4 Hz, 1H), 1.39 in (s, 3H); HRFABMS calculated for C8H11ClN3O3m/z [M+H]+234,0459, 232,0489 found 234,0466, 232,0488.

[0190] the interaction of the epoxide 140 with 4-cryptomaterial, as in the example 2AA, at 82°C for 10 hours, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then a mixture of 0-2% EtOAc/CH2Cl2gave 4-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-methyl-1-[4-(triptoreline)phenoxy]-2-butanol (141) (77%) as a pale yellow oil;

1H NMR (CDCl3) δ 7,81 (s, 1H), 7,17 (user.DD, J=9,1, 0.7 Hz, 2H), 6.90 to (dt, J=9,2, 3.1 Hz, 2H), 4,29 (DDD, J=14,1, and 9.5, 6.3 Hz, 1H), 4,24 (DDD, J=14,1, 9,6, 6.5 Hz, 1H), 3,85 (d, J=9.0 Hz, 1H), 3,82 (d, J=9.0 Hz, 1H), 2,23 (DDD, J=13,8, to 9.3, 6.5 Hz, 1H), of 2.21 (s, 1H), 1,40 (s, 3H); HRESIMS calculated for C15H16ClF3N3O5m/z [M+H]+412,0697, 410,0725 found 412,0700, 410,0722.

[0191] the Circuit Kohl is and alcohol 141 using NaH, as in the example 2AA, within 2 hours, followed by chromatography of the product on silica gel with elution with a mixture of 25-33% EtOAc/petroleum ether (head of the faction) and then a mixture of 50% EtOAc/petroleum ether gave compound 36 (61%) as a cream solid: so pl. (CH2Cl2/pentane) 134-136°C;

1H NMR (CDCl3) δ was 7.45 (s, 1H), 7,16 (user.DD, J=9,1, 0.8 Hz, 2H), 6.87 in (dt, J=9,2, 3.0 Hz, 2H), 4,21-was 4.02 (m, 4H), of 2.51 (DDD, J=14.5 m, 7,4, 6.0 Hz, 1H, in), 2.25 (dt, J=14,5, 6.2 Hz, 1H), 1,60 (s, 3H); elemental analysis: (C15H14F3N3O5) C, H, N.

[0192] KK. Synthesis of 7-{[4-(benzyloxy)phenoxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 37 table 1) using the method of scheme 9

[0193] the interaction of the epoxide 140 (see example 2U) with 4-(benzyloxy)phenol as in example 2AA, at 82°C for 10 hours, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then with a mixture of 2% EtOAc/CH2Cl2gave 1-[4-(benzyloxy)phenoxy]-4-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-methyl-2-butanol (142) (79%) in the form of butter;

1H NMR (CDCl3) δ 7,79 (s, 1H), 7,44-7,29 (m, 5H), 6,92 (dt, J=9,2, 3.0 Hz, 2H), 6,83 (dt, J=9,2, 3.0 Hz, 2H), 4,28 (DDD, J=14,0, 9,7, 6,1 Hz, 1H), 4,23 (DDD, J=14,0, 9,7, 6.3 Hz, 1H), 3,81 (d, J=9.1 Hz, 1H), of 3.77 (d, J=9.0 Hz, 1H), 2,29 (s, 1H), 2,22 (DDD, J=13,8, 9,6, 6.2 Hz, 1H), 2,02 (DDD, J=13,6, 9,7, 6.5 Hz, 1H), 1,38 (s, 3H); HRESIMS calculated for C21H23ClN3O 5m/z [M+H]+434,1293, 432,1321 found 434,1298, 432,1319.

[0194] ring Closure of alcohol 142 using NaH (1.4 equiv.) as in the example 2AA, followed by chromatography of the product on silica gel with elution with a mixture of 0-33% EtOAc/petroleum ether (head of the faction) and then EtOAc gave the crude product, which was then chromatographically on silica gel. Elution with a mixture of 0-2,5% EtOAc/CH2Cl2first gave head a fraction, and then further elution with a mixture of 2.5% EtOAc/CH2Cl2gave compound 37 (53%) as a cream solid: so pl. (CH2Cl2/hexane) 174-176°C;

1H NMR [(CD3)2SO] δ 8,07 (s, 1H), 7,45-7,28 (m, 5H), 6,94 (dt, J=9,3, 2,9 Hz, 2H), 6.89 in (dt, J=9,3, 2,9 Hz, 2H), 5,04 (s, 2H), 4,21-4,06 (m, 2H), 4,10 (s, 2H), 2,37 (DDD, J=14.5 m, 7,9, 6.2 Hz, 1H), 2,17 (dt, J=14,4, 5.8 Hz, 1H), to 1.48 (s, 3H); elemental analysis: (C21H21N3O5) C, H, N.

[0195] LL. Synthesis of 7-{[(4'-fluoro[1,1'-biphenyl]-4-yl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 38 table 1) using the method of scheme 9

[0196] the interaction of the epoxide 140 (see example 2JJ) with 4-idenya, as in the example 2AA, at 83°C for 8 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-2% EtOAc/CH2Cl2(head of the faction) and then a mixture of 5% EtOAc/CH2Cl2gave 4-(2-chloro-4-nitro-1H-imidazol-1-yl)-1-(4-iodinate)-2-meth is l-2-butanol (143) (81%) as a cream solid: so pl. (CH2Cl2/pentane) 91-93°C;

1H NMR (CDCl3) δ 7,80 (s, 1H), to 7.59 (dt, J=8,9, and 2.6 Hz, 1H), 6,69 (dt, J=8,9, and 2.6 Hz, 1H), 4,28 (DDD, J=14,1, a 9.6, 6.3 Hz, 1H), 4,23 (DDD, J=14,1, 9,4, 6.5 Hz, 1H), 3,82 (d, J=9.0 Hz, 1H), 3,79 (d, J=9.0 Hz, 1H), 2,22 (DDD, J=13,8, 9,2, 6.5 Hz, 1H), 2,20 (s, 1H), 2,02 (DDD, J=13,8, a 9.6, 6.6 Hz, 1H), 1.39 in (s, 3H); HRESIMS calculated for C14H16ClIN3O4m/z [M+H]+453,9840, 451,9869 found 453,9832, 451,9857.

[0197] ring Closure of alcohol 143 using NaH (1.5 equiv.) as in the example 2AA, followed by chromatography of the product on silica gel with elution with a mixture of 0-33% EtOAc/petroleum ether (head of the faction) and then a mixture of 0-5% EtOAc/CH2Cl2gave 7-[(4-iodinate)methyl]-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (144) (74%) as a pale yellow solid: so pl. (CH2Cl2/hexane) 170-172°C;

1H NMR (CDCl3) δ EUR 7.57 (dt, J=9,0, 2.7 Hz, 2H), 7,44 (s, 1H 6,64 (dt, J=9,0, 2.7 Hz, 2H), 4,19-of 4.05 (m, 2H), 4,07 (d, J=9.6 Hz, 1H), was 4.02 (d, J=9.6 Hz, 1H), 2.49 USD (DDD, J=14.5 m, 7,4, 6.0 Hz, 1H), 2,24 (DDD, J=14.5 m, of 6.4 and 5.9 Hz, 1H), was 1.58 (s, 3H);elemental analysis: (C14H14IN3O4) C, H, N.

[0198] the Reaction mix Suzuki iodide 144 and 4-ftorhinolonovy acid, as in example 2CC, for 100 minutes, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then with a mixture of 1-2% EtOAc/CH2Cl2give compound 38 (90%) as a pale yellow-orange solid: the.sq. (CH2Cl2/pentane) 160-162°C;

1H NMR (CDCl3) δ 7,51-7,44 (m, 5H), 7,10 (TT, J=8,7, and 2.6 Hz, 2H), 6,92 (dt, J=8,8, 2,6 Hz, 2H), 4,23-4,06 (m, 4H), of 2.53 (DDD, J=14,4, 7,2, 6.0 Hz, 1H), 2,28 (DDD, J=14.5 m, 6,8 and 5.9 Hz, 1H), 1,62 (s, 3H); elemental analysis: (C20H18FN3O4) C, H, N.

[0199] MM. Synthesis of 7-methyl-2-nitro-7-({[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 39 in table 1) using the method of scheme 9

[0200] the Reaction mix Suzuki iodide 144 (see example 2LL) and 4-(trifluoromethyl)phenylboronic acid, as in example 2CC, for 100 minutes, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then a mixture of 1% EtOAc/CH2Cl2give compound 39 (87%) as a cream solid: so pl. (CH2Cl2/pentane) 196-198°C;

1H NMR (CDCl3) to 7.67 δ (user.d, J=8.5 Hz, 2H), 7,63 (user.d, J=8,4 Hz, 2H), 7,54 (dt, J=8,8, 2,6 Hz, 2H), 7,46 (s, 1H), of 6.96 (dt, J=8,8, 2,6 Hz, 2H), 4,23-4,08 (m, 4H), of 2.54 (DDD, J=14.5 m, and 7.3, 6.0 Hz, 1H), 2,28 (DDD, J=14.5 m, and 6.6 and 5.9 Hz, 1H), 1,62 (s, 3H); elemental analysis: (C21H18F3N3O4) C, H, N.

[0201] NN. Synthesis of 7-methyl-2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 40, table 1) using the method of scheme 9

[0202] the Reaction mix Sousa and iodide 144 (see example 2LL) and 4-(triptoreline)phenylboronic acid, as in example 2CC, within 105 minutes, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then a mixture of 1% EtOAc/CH2Cl2gave compound 40 (89%) as pale yellow-pink solids: I. pl. (CH2Cl2/pentane) 186-188°C;

1H NMR (CDCl3) δ 7,53 (dt, J=8,8, 2.5 Hz, 2H), 7,49 (DD, J=8,8, 2,6 Hz, 2H), 7,46 (s, 1H), 7,26 (user.DD, J=8,7, 0.8 Hz, 2H), 6,94 (dt, J=8,8, 2,6 Hz, 2H), 4,23-4,07 (m, 4H), of 2.53 (DDD, J=14.5 m, 7,2, 6.0 Hz, 1H), 2,28 (DDD, J=14.5 m, 6,7 and 5.9 Hz, 1H), 1,62 (s, 3H); elemental analysis: (C21H18F3N3O5) C, H, N.

[0203] OO. Synthesis 7-({[5-(4-forfinal)-2-pyridinyl]oxy}methyl)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 41 table 1) using the method of scheme 10

[0204] a Solution of 4-iodine-2-methyl-1-butene (obtained by iodination of 3-methyl-3-butene-1-ol as described Helmboldt et al., 2006) (2,68 g, 13.7 mmol) in anhydrous DMF (5 ml, then 2×2 ml+1 ml rinse) was added to a stirred mixture of 2-bromo-4(5)-intorimidazole (80) (2.00 g, 10.4 mmol) and powdered K2CO3(4.35 g, to 31.5 mmol) in anhydrous DMF (10 ml) in an atmosphere of N2and the resulting mixture was stirred at 60°C for 11 hours. Received the cooled mixture was added to a mixture of ice/water solution of NaHCO3(120 ml) and was extracted with EtOAc (×100 ml). The extracts were washed with dilute salt solution (100 ml), then evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-10% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 20-25% EtOAc/petroleum ether gave 2-bromo-1-(3-methyl-3-butenyl)-4-nitro-1H-imidazole (145) (2,296 g, 85%) as a white solid: so square (CΗ2Cl2/pentane) 90-92°C;

1H NMR (CDCl3) δ 7,76 (s, 1H), 4,90 (m, 1H), 4,70 (m, 1H), 4,12 (t, J=7.2 Hz, 2H), 2,52 (user.t, J=7,1 Hz, 2H), is 1.81 (s, 3H); elemental analysis: (C8H10BrN3O2) C, H, N.

[0205] osmium Tetroxide (2.55 ml of 4% aqueous solution, 0,417 mmol) was added to a solution of alkene 145 (2.15 g, of 8.27 mmol) and 4-methylmorpholine N-oxide (1,49 g, 12.7 mmol) in CH2Cl2(55 ml) and the mixture is then stirred at room temperature for 4 hours. The mixture was cooled (-20°C), slowly diluted with petroleum ether (70 ml) was again cooled (-20°C) and the resulting precipitate was isolated by filtration, washed with petroleum ether and water, dried, obtaining 4-(2-bromo-4-nitro-1H-imidazol-1-yl)-2-methyl-1,2-butanediol (146) (1,53 g, 63%) as pale-grayish-brown solid: so square (MeOH/CH2Cl2/pentane) 121-123°C;

1H NMR [(CD3)2SO] δ 8,58 (s, 1H), 4,69 (user.t, J=5.3 Hz, 1H), to 4.41 (user.s, 1H), 4,13 (t, J=8,1 Hz, 2H), 3,24 (DD, J=10,6, and 5.6 Hz, 1H), 3,18 (DD, J=10,7, 5.6 Hz, 1H), 1,89 (dt, J=13.3-inch, 8.1 Hz, 1H), equal to 1.82 (dt, J=13.3-inch, 8.1 Hz, 1H), of 1.09 (s, 3H); elemental analysis: (C8H12BrN3O4) C, H, N.

[0206] Obtained in the previous phase aqueous portion was saturated with salt and extracted with EtOAc (6×100 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 50-67% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 67-80% EtOAc/petroleum ether gave an additional amount of compound 146 (882 mg, 36%).

[0207] Triisopropylsilane (2.00 ml, 9,35 mmol) was added to a solution of diol 146 (2,507 g, charged 8.52 mmol) and imidazole (1,278 g of 18.8 mmol) in anhydrous DMF (25 ml) in an atmosphere of N2and then the mixture was stirred at room temperature for 3 days. Again added triisopropylsilane (0,50 ml, 2.34 mmol) and the mixture was stirred at room temperature for 3 days. The resulting mixture was added to ice water (130 ml) and was extracted with EtOAc (4×100 ml). The extracts were washed with water (100 ml), then evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-10% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 33% EtOAc/petroleum ether gave 4-(2-bromo-4-nitro-1H-imidazol-1-yl)-2-methyl-1-[(triisopropylsilyl)oxy]-2-butanol (147) (3,658 g, 95%) as a white solid: so square (CΗ2Cl2/pentane) 73-75°C;

1H NMR (CDCl3) δ 7,8 (s, 1H), 4.26 deaths (DDD, J=14,1, 10,3, 5.8 Hz, 1H), 4,19 (DDD, J=14,1, 10,3, 6.0 Hz, 1H), of 3.56 (s, 2H), 2,52 (s, 1H), 2,11 (DDD, J=13,6, 10,3, 5.8 Hz, 1H), 1,87 (DDD, J=13,6, 10,3, 6.0 Hz, 1H), 1,25 (s, 3H), 1,21 of-1.04 (m, 21H); elemental analysis: (C17H32BrN3O4Si) C, H, N.

[0208] Stir a solution of alcohol 147 (of 3.60 g, 8,00 mmol) in anhydrous DMF (35 ml) in an atmosphere of N2at 0°C was treated with 60% NaH (550 mg, of 13.8 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. After stirring at room temperature for 2.5 hours and then at 46°C for 190 minutes, the reaction mixture was cooled (CO2/acetone), was suppressed with a mixture of ice/water solution of NaHCO3(40 ml), diluted with ice water (140 ml) and was extracted with EtOAc (5×80 ml). The combined extracts were washed with saturated salt solution (80 ml), then evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-15% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 15-25% EtOAc/petroleum ether gave 7-methyl-2-nitro-7-{[(triisopropylsilyl)oxy]methyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (148) (2,599 g, 88%) as a pale yellow solid: so pl. (CH2Cl2/pentane) 112-114°C;

1H NMR (CDCl3) δ 7,41 (s, 1H), 4,14 (DDD, J=12,4, 6,9, 5.8 Hz, 1H), a 4.03 (DDD, J=12,4, 7,3, 5.8 Hz, 1H), 3,84 (d, J=10,2 Hz, 1H), of 3.77 (d, J=10,2 Hz, 1H), 2,37 (DDD, J=14,4, 7,2, 5.8 Hz, 1H), 2,11 (DDD, J=14,4, of 6.9 and 5.9 Hz, 1H), 1,45 (s, 3H), 1,16-0,97 (m, 21H); elemental and the Alize: (C 17H31N3O4Si) C, H, N.

[0209] a Suspension salelologa ether 148 (2,518 g, for 6.81 mmol) in 1% HCl in 95% EtOH (desirelove described Cunico et al., 1980) (90 ml) was stirred at 44°C for 3 days. The resulting solution was cooled (CO2/acetone), neutralized by adding dropwise 7M NH3in MeOH (8 ml) and NaHCO3(0.10 g, 1,19 mmol) under stirring, and then concentrated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-1% MeOH/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 1.5% MeOH/CH2Cl2give (7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-yl)methanol (149) (1,285 g, 88%) as a pale yellow solid: so square (MeOH/CH2Cl2/hexane) 199-201°C;

1H NMR [(CD3)2SO] δ 8,03 (s, 1H), 5,22 (t, J=5.7 Hz, 1H), 4,13 (dt, J=12,9, 6.0 Hz, 1H), 4,05 (DDD, J=13,0, to 8.1, 5.6 Hz, 1H), 3,54 (DD, J=11,6, and 5.5 Hz, 1H), 3,48 (DD, J=11,6, 5.8 Hz, 1H), of 2.21 (DDD, J=14,4, 8,1, 5,9 Hz, 1H), 2,00 (dt, J=14,4, 5.8 Hz, 1H), 1,32 (s, 3H); elemental analysis: (C8H11N3O4) C, H, N.

[0210] a Solution of alcohol 149 (200 mg, 0,938 mmol) in anhydrous DMF (4 ml) in an atmosphere of N2at 0°C was treated with 60% NaH (53,8 mg, 1.35 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. Was added 5-bromo-2-herperidin (91) (0,245 ml of 2.38 mmol), the mixture was stirred at room temperature for 2.5 hours and then cooled (COsub> 2/acetone), was suppressed with a mixture of ice/water solution of NaHCO3(10 ml) was added to a saturated salt solution (40 ml) and was extracted with CH2Cl2(10×50 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 1-3% EtOAc/CH2Cl2gave 7-{[(5-bromo-2-pyridinyl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (150) (269 mg, 78%) as a cream solid: so pl. (CH2Cl2/pentane) 172-174°C;

1H NMR (CDCl3) δ 8.17 and (OSiR.d, J=2.2 Hz, 1H), to 7.67 (DD, J=8,8, 2.5 Hz, 1H), only 6.64 (DD, J=8,7, 0,4 Hz, 1H), 4,49 (d, J=11.5 Hz, 1H), 4,42 (d, J=11,4 Hz, 1H), 4,17 (dt, J=12,7, 6,1 Hz, 1H), 4.09 to (DDD, J=12,6, 7,7, 5.8 Hz, 1H), 2,45 (DDD, J=14.5 m, of 7.6 and 5.9 Hz, 1H), 2,18 (dt, J=14,6, 6,1 Hz, 1H), 1.57 in (s, 3H); elemental analysis: (C13H13BrN4O4) C, H, N.

[0211] the Reaction mix Suzuki bromide 150 and 4-ftorhinolonovy acid as in example 2M, within 135 minutes, followed by chromatography of the product on silica gel with elution with a mixture of 0-3% EtOAc/CH2Cl2(head of the faction) and then a mixture of 3-5% EtOAc/CH2Cl2gave compound 41 (92%) as a cream solid: so pl. (CH2Cl2/pentane) 145-147°C;

1H NMR (CDCl3) δ of 8.28 (d, J=2.5 Hz, 1H), 7,76 (DD, J=8,6, 2.5 Hz, 1H), 7,46 (DDT, J=8,8, 5,1, 2,6 Hz, 2H), 7,45 (s, 1H), 7,14 (TT, J=8,6, and 2.6 Hz, 2H), to 6.88 (d, J=8.6 Hz, 1H), 4,58 (d, J=11,4 Hz, 1H) 4,50 (d, J=11,4 Hz, 1H), 4,20 (DDD, J=12,6, of 6.5 and 6.1 Hz, 1H), 4,10 (DDD, J=12,6, 7,3, 5.8 Hz, 1H), 2.49 USD (DDD, J=14,4, 7,3, 6.0 Hz, 1H), of 2.21 (DDD, J=14,4, 6,6, 6.0 Hz, 1H), 1,61 (s, 3H); elemental analysis: (C19H17FN4O4) C, H, N.

[0212] PP. Synthesis of 7-methyl-2-nitro-7-[({5-[4-(trifluoromethyl)phenyl]-2-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 42 table 1) using the method of scheme 10

[0213] the Reaction mix Suzuki bromide 150 and 4-(trifluoromethyl)phenylboronic acid as in example 2M for 2 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-2% EtOAc/CH2Cl2(head of the faction) and then a mixture of 3-5% EtOAc/CH2Cl2gave compound 42 (91%) as a cream solid: so pl. (CH2Cl2/pentane) 212-214°C;

1H NMR (CDCl3) δ 8,35 (DD, J=2.5 and 0.4 Hz, 1H), 7,82 (DD, J=8,6, 2.5 Hz, 1H), 7,71 (user.d, J=8,2 Hz, 2H), 7.62mm (user.d, J=8.1 Hz, 2H), 7,46 (s, 1H), PC 6.82 (DD, J=8,7, 0,4 Hz, 1H), 4,60 (d, J=11,4 Hz, 1H), to 4.52 (d, J=11,4 Hz, 1H), 4,21 (DDD, J=12,6, a 6.5, 6.0 Hz, 1H), 4,11 (DDD, J=12,7, 7,4, 5.8 Hz, 1H), 2,50 (DDD, J=14,6, 7,4, 5,9 Hz, 1H), 2,22 (DDD, J=14.5 m, and 6.5, 6.0 Hz, 1H), 1,61 (s, 3H); elemental analysis: (C20H17F3N4O4) C, H, N.

[0214] QQ. Synthesis of 7-methyl-2-nitro-7-[({5-[4-(triptoreline)phenyl]-2-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 43 table 1) using the method of scheme 10

[0215] the Reaction with Etania Suzuki bromide 150 and 4-(triptoreline)phenylboronic acid, as in example 2M for 2 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-2% EtOAc/CH2Cl2(head of the faction) and then the mixture 2-3,5% EtOAc/CH2Cl2gave compound 43 (92%) as a cream solid: so pl. (CH2Cl2/pentane) 195-198°C;

1H NMR (CDCl3) δ 8,31 (DD, J=2.5 and 0.7 Hz, 1H), 7,78 (DD, J=8,5, and 2.6 Hz, 1H), 7,52 (dt, J=8,8, 2.5 Hz, 2H), 7,45 (s, 1H), 7,30 (user.DD, J=8,7, 0.8 Hz, 2H), 6,79 (DD, J=8,6, 0.7 Hz, 1H), 4,59 (d, J=11,4 Hz, 1H), 4,50 (d, J=11,4 Hz, 1H), 4,20 (DDD, J=12,6, 6,7 and 5.9 Hz, 1H), 4,10 (DDD, J=12,6, 7,4, 5.8 Hz, 1H), 2.49 USD (DDD, J=14.5 m, of 7.4 and 5.9 Hz, 1H), of 2.21 (DDD, J=14.5 m, and 6.6 and 5.9 Hz, 1H), 1,61 (s, 3H); elemental analysis: (C20H17F3N4O5) C, H, N.

[0216] RR. Synthesis 7-({[6-(4-forfinal)-3-pyridinyl]oxy}methyl)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 44 table 1) using the method of scheme 10

[0217] the interaction of the epoxide 140 (see example 2JJ) with 6-bromo-3-pyridinol, as in the example 2AA, at 84°C in a period of 18.5 hours, followed by chromatography of the product on silica gel with elution with a mixture of 25-40% EtOAc/petroleum ether (head of the faction) and then a mixture of 40-50% EtOAc/petroleum ether gave 1-[(6-bromo-3-pyridinyl)oxy]-4-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-methyl-2-butanol (151) (70%) as pale yellow-brown foam;

1H NMR (CDCl3) δ of 8.09 (DD, J=3,0, 0.3 Hz, 1H), 7,80 (s, 1H), 7,41 (DD, J=8,7, 0,4 Hz, 1H), 7,13 (DD, J=8,7, and 3.2 Hz, 1H), 4,9 (DDD, J=14,2, 9,4, 6.4 Hz, 1H), 4,25 (DDD, J=14,1, 9,4, 6,7 Hz, 1H), 3,89 (d, J=8,9 Hz, 1H), 3,86 (d, J=9.0 Hz, 1H), 2,22 (DDD, J=13,9, to 9.3, 6.5 Hz, 1H), 2,18 (s, 1H), 2,04 (DDD, J=13,8, 9,4, 6,7 Hz, 1H), 1,42 (s, 3H); HRESIMS calculated for C13H15BrClN4O4) m/z [M+H]+408,9910, 406,9939, 404,9960 found 408,9920, 406,9945, 404,9966.

[0218] ring Closure of alcohol 151 using NaH (1.5 equiv.) as in the example 2AA, followed by chromatography of the product on silica gel with elution with a mixture of 0-50% EtOAc/petroleum ether (head of the faction) and then a mixture of 0-2% MeOH/CH2Cl2gave 7-{[(6-bromo-3-pyridinyl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (152) (66%) as a pale yellow solid: so pl. (CH2Cl2/hexane) 170-171°C;

1H NMR (CDCl3) δ of 8.06 (DD, J=3.1 and 0.3 Hz, 1H), 7,46 (s, 1H), 7,40 (DD, J=8,7, 0.3 Hz, 1H), 7,11 (DD, J=8,7, and 3.2 Hz, 1H), 4,21-4,07 (m, 4H), 2,52 (DDD, J=14.5 m, 8,1, 6.3 Hz, 1H), 2,24 (dt, J=14.5 m, 5.7 Hz, 1H), 1,60 (s, 3H); elemental analysis: (C13H13BrN4O4) C, H, N.

[0219] the Reaction mix Suzuki bromide 152 and 4-ftorhinolonovy acid as in example 2M for 2 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-3% EtOAc/CH2Cl2(head of the faction) and then a mixture of 3-7% EtOAc/CH2Cl2gave compound 44 (88%) as a cream solid: so pl. (CH2Cl2/hexane) 203-204°C;

1H NMR [(CD3)2SO] δ 8,39 (d, J=2,8 Hz, 1H), 8,10 (s, 1H), 8,06 (DDT, J=9,0, 5,6, and 2.6 Hz, 2H), 7,92 d, J=8,8 Hz, 1H), 7,53 (DD, J=8,8, 3.0 Hz, 1H), 7,27 (TT, J=8,9, and 2.6 Hz, 2H), 4,33 (s, 2H), 4,25-4,11 (m, 2H), 2,42 (DDD, J=14.5 m, 8,2, 6.2 Hz, 1H), of 2.21 (dt, J=14,4, 5.7 Hz, 1H), of 1.52 (s, 3H); elemental analysis: (C19H17FN4O4) C, H, N.

[0220] SS. Synthesis of 7-methyl-2-nitro-7-[({6-[4-(trifluoromethyl)phenyl]-3-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 45 in table 1) using the method of scheme 10

[0221] the Reaction mix Suzuki bromide 152 (see example 2RR) and 4-(trifluoromethyl)phenylboronic acid as in example 2M, within 130 minutes, followed by chromatography of the product on silica gel with elution with a mixture of 0-3% EtOAc/CH2Cl2(head of the faction) and then a mixture of 4-7% EtOAc/CH2Cl2give compound 45 (65%) as a cream solid: so pl. (CH2Cl2/hexane) 215-217°C;

1H NMR [(CD3)2SO] δ 8,46 (d, J=2,9 Hz, 1H), 8,25 (user.d, J=8.1 Hz, 2H), 8,10 (s, 1H), of 8.06 (d, J=8,8 Hz, 1H), 7,81 (user.d, J=8,3 Hz, 2H), to 7.59 (DD, J=8,8, 3.0 Hz, 1H), 4,36 (s, 2H), 4.26 deaths-4,11 (m, 2H), 2,42 (DDD, J=14.5 m, 8,1, 6.0 Hz, 1H), of 2.21 (dt, J=14,4, 5.7 Hz, 1H), 1,53 (s, 3H); elemental analysis: (C20H17F3N4O4) C, H, N.

[0222] TT. Synthesis of 7-methyl-2-nitro-7-[({6-[4-(triptoreline)phenyl]-3-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 46 in table 1) using the method of scheme 10

[0223] the Reaction mix Suzuki bromide 152 (see example 2RR) is 4-(triptoreline)phenylboronic acid, as in example 2M, within 130 minutes, followed by chromatography of the product on silica gel with elution with a mixture of 0-4% EtOAc/CH2Cl2(head of the faction) and then a mixture of 5-7% EtOAc/CH2Cl2gave compound 46 (84%) as a cream solid: so pl. (CH2Cl2/pentane) 202-203°C;

1H NMR [(CD3)2SO] δ 8,42 (d, J=2,8 Hz, 1H), 8,14 (dt, J=8,9, and 2.6 Hz, 2H), 8,10 (s, 1H), of 7.97 (d, J=8,8 Hz, 1H), 7,56 (DD, J=8,8, 3.0 Hz, 1H), 7,44 (user.DD, J=8,8, 0.8 Hz, 2H), 4,34 (s, 2H), 4,25-4,11 (m, 2H), 2,42 (DDD, J=14.5 m, 8,2, 6,1 Hz, 1H), of 2.21 (dt, J=14,4, 5.7 Hz, 1H), of 1.52 (s, 3H); elemental analysis: (C20H17F3N4O5) C, H, N.

[0224] UU. Synthesis of 2-nitro-7-({[3-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 47 table 1) using the method of scheme 11

[0225] a Mixture of oxazinones alcohol 134 (see example 2BB above) (31.8 mg, 0,160 mmol) and 3-(triptoreline)benzylbromide (0,040 ml, 0,247 mmol) in anhydrous DMF (3 ml) in an atmosphere of N2at 0°C was treated with 60% NaH (9.5 mg, 0,238 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. After stirring at room temperature for 2.5 hours the mixture was cooled (CO2/acetone), was suppressed with a mixture of ice/water solution of NaHCO3(10 ml) was added to a saturated salt solution (40 ml) and was extracted with CH2Cl2(4×50 ml). The combined extracts was evaporated on the dry and the residue was chromatographically on silica gel. Elution with a mixture of 0-1% EtOAc/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 1-2% EtOAc/CH2Cl2gave compound 47 (44 mg, 74%) as a cream solid: so pl. (CH2Cl2/pentane) 110-112°C;

1H NMR (CDCl3) δ 7,41 (s, 1H), 7,41-7,35 (m, 1H), 7.23 percent (OSiR.d, J=7.8 Hz, 1H), 7,19-7,13 (m, 2H), to 4.62 (s, 2H), 4,58 (m, 1H), 4,15 (DDD, J=12,4, 5,8, and 3.7 Hz, 1H), 4,06 (DDD, J=12,3, 10,1, 5.6 Hz, 1H), 3,84 (DD, J=10,6, a 4.3 Hz, 1H), 3,78 (DD, J=10,6, 5,1 Hz, 1H), 2,40-of 2.21 (m, 2H); elemental analysis: (C15H14F3N3O5) C, H, N.

[0226] VV. Synthesis of 2-nitro-7-({[4-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 48 table 1) using the method of scheme 11

[0227] the Alkylation oxazinones alcohol 134 (see example 2BB above) when using 4-(triptoreline)benzylbromide (1.9 EQ.) and NaH (1.7 equiv.) as in the example 2UU above, within 165 minutes, followed by chromatography of the product on silica gel with elution with a mixture of 0-0,5% MeOH/CH2Cl2(head of the faction) and then a mixture of 0.5% MeOH/CH2Cl2give compound 48 (69%) as a cream solid: so pl. (CH2Cl2/hexane) 158-160°C;

1H NMR (CDCl3) δ 7,41 (s, 1H), 7,34 (dt, J=8,8, 2,3 Hz, 2H), 7,20 (user.d, J=7.9 Hz, 2H), br4.61 (s, 2H), br4.61-of 4.54 (m, 1H), 4,14 (DDD, J=12,4, 5,7, and 3.7 Hz, 1H), 4,06 (DDD, J=12,3, 10,0, 5.8 Hz, 1H), 3,82 (DD, J=10,7, 4,4 Hz, 1H), 3,78 (DD, J=10,7, a 4.9 Hz, 1H), 2,38-of 2.21 (m, 1H); ele is entry analysis: (C 15H14F3N3O5) C, H, N.

[0228] WW. Synthesis of 7-({[4-(benzyloxy)benzyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 49 in table 1) using the method of scheme 11

[0229] the Alkylation oxazinones alcohol 134 (see example 2BB above) when using 4-(benzyloxy)benzylchloride (3.0 EQ.) and NaH (1.5 equiv.) as in the example 2UU above, for 3 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then a mixture of 1% EtOAc/CH2Cl2give compound 49 (20 mg, 25%) as a cream solid: so pl. (CH2Cl2/hexane) 151-153°C;

1H NMR (CDCl3) δ 7,45-7,29 (m, 6H), 7,22 (dt, J=8,7, 2.4 Hz, 2H), 6,95 (dt, J=8,7, 2.4 Hz, 2H), 5,07 (s, 2H), 4,54 (m, 1H), to 4.52 (s, 2H), 4,11 (DDD, J=12,3, 5,8, 3,9 Hz, 1H), was 4.02 (DDD, J=12,3, 10,0, 5.5 Hz, 1H), 3,78 (DD, J=10,5, the 4.3 Hz, 1H), 3,71 (DD, J=10.5V, and 5.5 Hz, 1H), 2,33 (dddd, J=14,5, 5,4, 3,8, 3.0 Hz, 1H), 2,23 (DTD, J=14,6, or 9.8 and 5.9 Hz, 1H); elemental analysis: (C21H21N3O5) C, H, N.

[0230] XX. Synthesis of 2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-3-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 50 table 1) using the method of scheme 11

[0231] the Alkylation oxazinones alcohol 134 (see example 2BB above) when using 3-iodobenzylamine (1,36 EQ.) and NaH (1.5 equiv.) as in the example 2UU above, for 3 the aces, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then a mixture of 1,5-2% EtOAc/CH2Cl2gave 7-{[(3-iodobenzyl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (153) (65%) as a cream solid: so pl. (CH2Cl2/hexane) 131-133°C;

1H NMR (CDCl3) δ 7,65 (user.s, 1H), to 7.64 (user.d, J=7.5 Hz, 1H), 7,41 (s, 1H), 7,26 (m, 1H), to 7.09 (TD, J=7,4, 1.0 Hz, 1H), 4,57 (m, 1H), of 4.54 (s, 2H), 4,15 (DDD, J=12,3, 5,8, 3.8 Hz, 1H), 4,06 (DDD, J=12,3, 10,0, 5.5 Hz, 1H), 3,82 (DD, J=10,6, a 4.3 Hz, 1H), 3,76 (DD, J=10,6, 5,1 Hz, 1H), 2,39-of 2.21 (m, 2H); elemental analysis: (C14H14IN3O4) C, H, N.

[0232] Stir a mixture of iodide 153 (30,2 mg, 0,0727 mmol), 4-(triptoreline)phenylboronic acid (20,8 mg, 0,101 mmol) and Pd(dppf)Cl2(2.3 mg, 3.14 mmol) in toluene (1.7 ml) was degirolami within 4 minutes (vacuum pump) and then typed N2. Added EtOH (0.6 ml) and 2M aqueous solution of Na2CO3(0,30 ml of 0.60 mmol) via syringe, the mixture was stirred at 90°C for 20 minutes, then cooled, diluted aqueous solution of NaHCO3(50 ml) and was extracted with CH2Cl2(4×50 ml). The extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-1% EtOAc/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 1-1,5% EtOAc/CH2Cl2give compound 50 (30 mg, 92%) as renovage solids: I. pl. (CH2Cl2/pentane) 117-119°C;

1H NMR (CDCl3) δ of 7.60 (dt, J=8,7, 2.4 Hz, 2H), 7,52-7,47 (m, 2H), 7,44 (t, J=7.8 Hz, 1H), 7,40 (s, 1H), 7,32-7,26 (m, 3H), of 4.67 (s, 2H), 4,59 (m, 1H), 4,14 (DDD, J=12,3, 5,7, and 3.8 Hz, 1H), 4,05 (DDD, J=12,3, 10,0, 5.6 Hz, 1H), 3,86 (DD, J=10,7,4,3 Hz, 1H), 3,80 (DD, J=10,7, 5.0 Hz, 1H), 2.40 a-2,22 (m, 2H); elemental analysis: (C2lH18F3N305) C, H, N.

[0233] YY. Synthesis of 2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 51 table 1) using the method of scheme 11

[0234] the Alkylation oxazinones alcohol 134 (see example 2BB above) when using 4-iodobenzylamine (1,35 EQ.) and NaH (1.5 equiv.) as in the example 2UU above, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then a mixture of 1-1,5% EtOAc/CH2Cl2gave 7-{[(4-iodobenzyl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (154) (61%) as a cream solid: so pl. (CH2Cl2/hexane) 169-171°C;

1H NMR (CDCl3) δ to 7.68 (dt, J=8,3, 2.0 Hz, 2H), 7,41 (s, 1H), 7,05 (user.d, J=8,3 Hz, 2H), 4,56 (m, 1H), of 4.54 (s, 2H), 4,14 (DDD, J=12,3, 5,7, and 3.8 Hz, 1H), 4,05 (DDD, J=12,3, 10,0, 5.6 Hz, 1H), 3,80 (DD, J=10,6, a 4.3 Hz, 1H, in), 3.75 (DD, J=10,6, 5.0 Hz, 1H), 2,37-of 2.20 (m, 2H); HRFABMS calculated for C14H15IN3O4m/z [M+H]+416,0107 found 416,0105.

[0235] the Reaction mix Suzuki iodide 154 and 4-(triptoreline)phenylboronate sour is s, as in the example 2XX above, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then a mixture of 1-1,5% EtOAc/CH2Cl2give compound 51 (85%) as a cream solid: so pl. (CH2Cl2/pentane) 159-161°C;

1H NMR (CDCl3) δ to 7.59 (dt, J=8,8, 2.5 Hz, 2H), 7,54 (user.d, J=8,2 Hz, 2H), 7,41 (s, 1H), 7,39 (user.d, J=8,3 Hz, 2H), 7,29 (user.d, J=8.0 Hz, 2H) and 4.65 (s, 2H), 4,59 (m, 1H), 4,15 (DDD, J=12,3, 5,8, 3.8 Hz, 1H), 4,06 (DDD, J=12,3, 10,0, 5.6 Hz, 1H), 3,85 (DD, J=10,6, a 4.3 Hz, 1H), 3,80 (DD, J=10,6, 5,1 Hz, 1H), 2,41-of 2.23 (m, 2H); elemental analysis: (C21H18F3N3O5) C, H, N.

[0236] ZZ. Synthesis of 7-methyl-2-nitro-7-({[3-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 52 table 1) using the method of scheme 11

[0237] the Alkylation oxazinones alcohol 149 (see example 200) using 3-(triptoreline)benzylbromide (1.6 EQ.) and NaH (2.0 equiv.) as in the example 2UU above, for 3 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then a mixture of 1-1,5% EtOAc/CH2Cl2give compound 52 (83%) as a cream solid: so pl. (CH2Cl2/pentane) 108-110°C;

1H NMR (CDCl3) δ 7,38 (s, 1H), was 7.36 (t, J=8.0 Hz, 1H), 7,19-7,10 (m, 3H), 4,58 (s, 2H), 4,10 (DDD, J=12,5, of 6.9 and 5.9 Hz, 1H), was 4.02 (DDD, J=12,5, 7,1, 5,9 Hz, H), the 3.65 (d, J=10,2 Hz, 1H), 3,61 (d, J=10,2 Hz, 1H), of 2.38 (DDD, J=14,4, 7,1, 6.0 Hz, 1H), 2,12 (DDD, J=14.5 m, 6,9, 6.0 Hz, 1H), 1,48 (s, 3H); elemental analysis: (C16H16F3N3O5) C, H, N.

[0238] AAA. Synthesis of 7-methyl-2-nitro-7-({[4-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 53 table 1) using the method of scheme 11

[0239] the Alkylation oxazinones alcohol 149 (see example 200) using 4-(triptoreline)benzylbromide (1.6 EQ.) and NaH (1.8 equiv.) as in the example 2UU above, for 3 hours, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then a mixture of 1.5% EtOAc/CH2Cl2give compound 53 (83%) as a cream solid: so pl. (CH2Cl2/pentane) 100-101°C;

1H NMR (CDCl3) δ 7,39 (s, 1H), 7,28 (user.d, J=8.7 Hz, 2H), 7,18 (user.d, J=8.0 Hz, 2H), 4,56 (s, 2H), 4.09 to (DDD, J=12,5, to 6.8 and 5.9 Hz, 1H), was 4.02 (DDD, J=12,5, to 7.3 and 5.9 Hz, 1H), 3,64 (d, J=10,2 Hz, 1H), 3,60 (d, J=10,2 Hz, 1H), of 2.38 (DDD, J=14.5 m, 7,2, 5,9 Hz, 1H), 2,11 (DDD, J=14.5 m, 6,7, 6,0 Hz, 1H), 1,47 (s, 3H); elemental analysis: (C16H16N3O5) C, H, N.

[0240] the BBB. Synthesis of 7-({[4-(benzyloxy)benzyl]oxy}methyl)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 54 table 1) using the method of scheme 11

[0241] the Alkylation oxazinones alcohol 149 (see example 200) using 4-(b is siloxy)benzylchloride (2.8 equiv.) and NaH (1.6 equiv.) as in the example 2UU above, for 7 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then a mixture of 1% EtOAc/CH2Cl2gave compound 54 (41%) as a cream solid: so pl. (CH2Cl2/pentane) 109-111°C;

1H NMR (CDCl3) δ 7,45-7,29 (m, 6H), 7,16 (dt, J=8,6, and 2.3 Hz, 2H), 6,93 (dt, J=8,6, 2.4 Hz, 2H), is 5.06 (s, 2H), 4,48 (d, J=11.5 Hz, 1H), 4,45 (d, J=11,6 Hz, 1H), a 4.03 (DDD, J=12,5, 7,6, 5.8 Hz, 1H), 3,95 (dt, J=12,5, 6.2 Hz, 1H), to 3.58 (d, J=10.1 Hz, 1H), 3,54 (d, J=10.1 Hz, 1H), 2,34 (dt, J=14,5, 6.2 Hz, 1H), 2,08 (DDD, J=14,4, 7,6, 6.0 Hz, 1H), 1,45 (s, 3H); elemental analysis: (C22H23N3O5) C, H, N.

[0242] CCC. Synthesis of 7-methyl-2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-3-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 55 table 1) using the method of scheme 11

[0243] the Alkylation oxazinones alcohol 149 (see example 200) when using 3-iodobenzylamine (1.6 EQ.) and NaH (1.8 equiv.) as in the example 2UU above, for 3.5 hours, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then a mixture of 0-2% EtOAc/CH2Cl2gave 7-{[(3-iodobenzyl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (155) (69%) as a cream solid: so pl. (CH2Cl2/pentane) 122-125°C (decomp.);

1H NMR (CDCl3) δ 7,63 (OSiR. the, J=7.9 Hz, 1H), 7,58 (m, 1H), 7,40 (s, 1H), 7,19 (user.d, J=7.7 Hz, 1H), 7,06 (t, J=7.7 Hz, 1H), 4,49 (s, 2H), 4,11 (DDD, J=12,4, 7,3, 5.8 Hz, 1H), 4,01 (DDD, J=12,5, 6,7, 6.0 Hz, 1H), 3,63 (d, J=10,2 Hz, 1H), 3,60 (d, J=10,2 Hz, 1H), 2,37 (DDD, J=14,4, 6,7, 6.0 Hz, 1H), 2,12 (DDD, J=14,4, 7,3, 6.0 Hz, 1H), 1,47 (s, 3H); elemental analysis: (C15H16IN3O4) C, H, N.

[0244] the Reaction mix Suzuki iodide 155 and 4-(triptoreline)phenylboronic acid, as in example 2H, for 25 minutes, followed by chromatography of the product on silica gel with elution with a mixture of 0-0,5% EtOAc/CH2Cl2(head of the faction) and then a mixture of 1% EtOAc/CH2Cl2give compound 55 (94%) as a cream solid: so pl. (CH2Cl2/pentane) 80-82°C;

1H NMR (CDCl3) δ 7,58 (dt, J=8,8, 2.5 Hz, 2H), 7,49 (user.dt, J=6A, 1.5 Hz, 1H), 7,43 (user.s, 1H), 7,41 (t, J=7,6 Hz, 1H), 7,37 (s, 1H), 7,30 (user.DD, J=8,7, 0.8 Hz, 2H), 7,25 (m, 1H), to 4.62 (s, 2H), 4,11 (DDD, J=12,4, 7,1, 5.8 Hz, 1H), 4.00 points (DDD, J=12,5, of 6.9 and 5.9 Hz, 1H), 3,68 (d, J=10,2 Hz, 1H), 3,63 (d, J=10,2 Hz, 1H), 2,39 (DDD, J=14,4, 6,9, 6.0 Hz, 1H), a 2.12 (DDD, J=14,4, 7,1, 6.0 Hz, 1H), 1,48 (s, 3H); elemental analysis: (C22H20F3N3O5) C, H, N.

[0245] DDD. Synthesis of 7-methyl-2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 56 table 1) using the method of scheme 11

[0246] the Alkylation oxazinones alcohol 149 (see example 200) using 4-iodobenzylamine (1.7 EQ.) and NaH (1.9 equiv.) as Primera 2UU above, within 3 hours, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then a mixture of 1% EtOAc/CH2Cl2gave 7-{[(4-iodobenzyl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (156) (54%) as a cream solid: so pl. (CH2Cl2/pentane) 130-132°C;

1H NMR (CDCl3) δ to 7.67 (dt, J=8,3, 2.0 Hz, 2H), 7,39 (s, 1H), 6,99 (user.d, J=8,3 Hz, 2H), 4,49 (s, 2H), 4.09 to (DDD, J=12,5, 7,0, 5,9 Hz, 1H), 4,01 (DDD, J=12,5, 7,1, 5,9 Hz, 1H), 3,62 (d, J=10,2 Hz, 1H), to 3.58 (d, J=10,2 Hz, 1H), 2,37 (DDD, J=14,4, 7,0, 6.0 Hz, 1H), 2,10 (DDD, J=14,4, 6,9, 6,0 Hz, 1H), 1,46 (s, 3H); elemental analysis: (C15H16IN3O4) C, H, N.

[0247] the Reaction mix Suzuki iodide 156 and 4-(triptoreline)phenylboronic acid, as in example 2H, for 25 minutes, followed by chromatography of the product on silica gel with elution with a mixture of 0-0,5% EtOAc/CH2Cl2(head of the faction) and then a mixture of 0.5-1% EtOAc/CH2Cl2give compound 56 (92%) as a cream solid: so square (CΗ2Cl2/pentane) 150-152°C;

1H NMR (CDCl3) δ 7,58 (dt, J=8,8, 2.5 Hz, 2H), 7,52 (dt, J=8,3, 1.9 Hz, 2H), 7,38 (s, 1H), 7,32 (user.d, J=8,3 Hz, 2H), 7,28 (user.DD, J=8,8, 0.8 Hz, 2H), br4.61 (d, J=12.0 Hz, 1H), 4,58 (d, J=12.0 Hz, 1H), 4,11 (DDD, J=12,4, 7,3, 5.8 Hz, 1H), 4,01 (DDD, J=12,5, 6,7, 6.0 Hz, 1H), to 3.67 (d, J=10,2 Hz, 1H), 3,63 (d, J=10,2 Hz, 1H), 2.40 a (DDD, J=14.5 m, 6,7, 6.0 Hz, 1H), 2,13 (DDD, J=14.5 m, and 7.3, 6.0 Hz, 1H), 1,48 (s, 3H); elemental analysis:(C22H20F3N3Osub> 5) C, H, N.

[0248] the EEE. Synthesis of (7R)-7-methyl-2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 57 table 1) using the method of scheme 12

[0249] Ac2O (3.6 ml, was 38.1 mmol) was added to a stirred suspension of the alcohol 149 (see example 200) (807 mg, with 3.79 mmol) in anhydrous pyridine (7.0 ml). After stirring at room temperature for 38 hours the mixture was diluted with CH2Cl2was added to ice water (150 ml) and was extracted with CH2Cl2(5×100 ml). The extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 1-6% EtOAc/CH2Cl2gave 7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-yl]acetate (157) (962 mg, 100%) as a cream solid: so square (CΗ2Cl2/hexane) 145-147°C;

1H NMR (CDCl3) δ 7,44 (s, 1H), 4,27 (d, J=11,9 Hz, 1H), 4,20 (d, J=11,9 Hz, 1H), 4,14 (dt, J=12,7, 5,9 Hz, 1H), 4,08 (DDD, J=12,7, 8,3, 5.6 Hz, 1H), 2,32 (DDD, J=14.5 m, 8,3, 6,1 Hz, 1H), 2,10 (dt, J=14.5 m, 5.7 Hz, 1H), 2,09 (s, 3H), of 1.50 (s, 3H); HRFABMS calculated for C10H14N3O5w/z [M+H]+256,0934 found 256,0941.

[0250] the Racemic acetate 157 (990 mg) was separated into pure enantiomers by means of preparative chiral HPLC using a column ChiralPak IA and socratous system solution is a dye 40% EtOH in hexane, at a flow rate of 6 ml/minute, receiving, first, [(7S)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-yl]methyl acetate (161) (427 mg, 43%) as a cream solid, which was used directly in the next stage;

1H NMR (CDCl3) δ 7,44 (s, 1H), 4,27 (d, J=11,9 Hz, 1H), 4,20 (d, J=11,9 Hz, 1H), 4,14 (dt, J=12,7, 5,9 Hz, 1H), 4,08 (DDD, J=12,7, 8,3, 5.6 Hz, 1H), 2,32 (DDD, J=14.5 m, 8,3, 6,1 Hz, 1H), 2,10 (dt, J=14.5 m, 5.7 Hz, 1H), 2,09 (s, 3H), of 1.50 (s, 3H); [α]D26-6,0° c and 1.00, CHCl3).

[0251] the above-Described preparative chiral HPLC of racemic acetate 157, second, gave [(7R)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-yl]acetate (158) (428 mg, 43%) as a cream solid, which was used directly in the next stage;

1H NMR (CDCl3) δ 7,44 (s, 1H), 4,27 (d, J=11,9 Hz, 1H), 4,20 (d, J=11.8 Hz, 1H), 4,14 (dt, J=12,7, 5,9 Hz, 1H), 4,08 (DDD, J=12,7, 8,3, 5.6 Hz, 1H), 2,32 (DDD, J=14.5 m, 8,3, 6,1 Hz, 1H), 2,10 (dt, J=14.5 m, 5.7 Hz, 1H), 2,09 (s, 3H), of 1.50 (s, 3H); [α]D266,0° c and 1.00, CHCl3).

[0252] the Water (4 ml) was added dropwise to a stirred mixture of (R)-acetate 158 (427 mg, 1,67 mmol) and K2CO3(256 mg, of 1.85 mmol) in MeOH (36 ml). After stirring at room temperature for 4 hours the mixture was cooled on ice and treated with 0.1 M HCl (37 ml, 3,70 mmol). The solvents were removed under reduced pressure and the residue was chromatographically on silica gel. Elution with a mixture of 0-1% MeOH/CH2Cl first gave head a fraction, and subsequent elution with a mixture of 1-2 .5% MeOH/CH2Cl2gave [(7R)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-yl]methanol (159) (343 mg, 96%) as a pale yellow solid, which was used directly in the next stage;

1H NMR [(CD3)2SO] δ 8,03 (s, 1H), 5,23 (user.t, J=5.4 Hz, 1H), 4,13 (dt, J=13,0, 6.0 Hz, 1H), 4,05 (DDD, J=12,9, to 8.1, 5.6 Hz, 1H), 3,54 (DD, J=11,6, a 4.9 Hz, 1H), 3,48 (DD, J=11,6, 5,2 Hz, 1H), of 2.21 (DDD, J=14,4, 8,1, 5,9 Hz, 1H), 2,00 (dt, J=14,4, 5.8 Hz, 1H), of 1.32 (s, 3H); [α]D27-16,0° (c 1.00 each, DMF).

[0253] the Alkylation of (R)-alcohol 159 using 4-bromobenzylamine (1.3 EQ.) and NaH (1.5 equiv.) as in the example 2UU above, for 3 hours, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then a mixture of 1% EtOAc/CH2Cl2give (7R)-7-{[(4-bromobenzyl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (160) (349 mg, 57%) as a white solid: so pl. (CH2Cl2/hexane) 157-159°C;

1H NMR (CDCl3) δ 7,46 (dt, J=8,3, 2.0 Hz, 2H), 7,39 (s, 1H), 7,12 (user.d, J=8,3 Hz, 2H), 4,50 (s, 2H), 4.09 to (DDD, J=12,5, 6,9, 6.0 Hz, 1H), 4,01 (DDD, J=12,5, 7,0, 6.0 Hz, 1H), 3,62 (d, J=10,2 Hz, 1H), to 3.58 (d, J=10,2 Hz, 1H), 2,37 (DDD, J=14,4, 7,0, 6.0 Hz, 1H), 2,10 (DDD, J=14,4, 6,9, 6,1 Hz, 1H), 1,46 (s, 3H); [α]D2730,0° c and 1.00, CHCl3); HRFABMS calculated for C15H17BrN3O4m/z [M+H]+384,0382, 382,0402 found 384,0385, 382,0398.

[0254]Stir a mixture of bromide 160 (to 347.5 mg, 0,909 mmol), 4-(triptoreline)phenylboronic acid (283 mg, 1.37 mmol) and Pd(dppf)Cl2(101 mg, was 0.138 mmol) in toluene (16 ml) and EtOH (6 ml) was degirolami within 10 minutes (vacuum pump) and then typed N2. Added 2M aqueous solution of Na2CO3(3.0 ml, 6.0 mmol) via syringe, stir the mixture again degirolami for 10 minutes and then typed N2. The resulting mixture was stirred at 88°C for 75 minutes, then cooled, diluted aqueous solution of NaHCO3(100 ml) and was extracted with CH2Cl2(6×100 ml). The extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-0,5% EtOAc/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 0.5-1.5% EtOAc/CH2Cl2give compound 57 (381 mg, 90%) as a cream solid: so pl. (CH2Cl2/hexane) 165-167°C;

1H NMR (CDCl3) δ 7,58 (dt, J=8,7, 2.4 Hz, 2H), 7,52 (user.d, J=8,2 Hz, 2H), 7,38 (s, 1H), 7,32 (user.d, J=8.1 Hz, 2H), 7,28 (user.d, J=8.1 Hz, 2H), br4.61 (d, J=12.1 Hz, 1H), 4,58 (d, J=12.1 Hz, 1H), 4,11 (DDD, J=12,4, 7,2, 5.8 Hz, 1H), 4,01 (DDD, J=12,6, of 6.5 and 6.1 Hz, 1H), to 3.67 (d, J=10,2 Hz, 1H), 3,63 (d, J=10,2 Hz, 1H), 2.40 a (DDD, J=14,4, 6,6, 6,1 Hz, 1H), 2,13 (DDD, J=14.5 m, and 7.3, 6.0 Hz, 1H), 1,48 (s, 3H); [α]D2737,0° c and 1.00, CHCl3); elemental analysis: (C22H20F3N3O5) C, H, N.

[0255] FFF. Synthesis of (7S)-7-methyl-2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]methoxy}methyl)-6,7-digitron-imidazo[2,1-b][1,3]oxazine (compound 58 table 1) using the method of scheme 12

[0256] the Hydrolysis of (S)-acetate 161 (426 mg, 1,67 mmol) by using the K2CO3in a mixture of MeOH/water as in example 2EEE above, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% MeOH/CH2Cl2(main fraction) and then with a mixture of 1-2 .5% MeOH/CH2Cl2gave [(7S)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-yl]methanol (162) (343 mg, 96%) as a pale yellow solid, which was used directly in the next stage;

1H NMR [(CD3)2SO] δ 8,03 (s, 1H), 5,22 (user.t, J=5.7 Hz, 1H), 4,13 (dt, J=13,0, 6.0 Hz, 1H), 4,05 (DDD, J=12,9, to 8.1, 5.6 Hz, 1H), 3,54 (DD, J=11,6, a 5.4 Hz, 1H), 3,48 (DD, J=11,6, 5.7 Hz, 1H), of 2.21 (DDD, J=14,4, 8,1, 5,9 Hz, 1H), 2,00 (dt, J=14,4, 5.8 Hz, 1H), of 1.32 (s, 3H); [α]D2718,0° (c 1.00 each, DMF).

[0257] the Alkylation of (S)-alcohol 162 when using 4-bromobenzylamine (1,35 EQ.) and NaH (1.55 EQ.), as in the example 2UU above, for 3 hours, followed by chromatography of the product on silica gel with elution CH2Cl2(head of the faction) and then a mixture of 1% EtOAc/CH2Cl2give (7S)-7-{[(4-bromobenzyl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (163) (373 mg, 61%) as a white solid: so square (CΗ2Cl2/hexane) 159-161°C;

1H NMR (CDCl3) δ 7,46 (dt, J=8,4, 2,1 Hz, 2H), 7,39 (s, 1H), 7,12 (dt, J=8,4, 2,1 Hz, 2H), 4,50 (s, 2H), 4.09 to (DDD, J=12,5, 7,0, 5.8 Hz, 1H), 4,01 (DDD, J=12,5, 7,1, 5,9 Hz, 1H), 3,62 (d, J=10,2 Hz, H), to 3.58 (d, J=10,2 Hz, 1H), 2,37 (DDD, J=14,4, 7,1,5,9 Hz, 1H), 2,10 (DDD, J=14.5 m, 7,0, 5,9 Hz, 1H), 1,46 (s, 3H); [α]D27-32,0° (c 1.00, it CHCl3); HRFABMS calculated for C15H17BrN3O4m/z [M+H]+384,0382, 382,0402 found 384,0374, 382,0393.

[0258] the Reaction mix Suzuki bromide 163 and 4-(triptoreline)phenylboronic acid, as in example 2EEE, followed by chromatography of the product on silica gel with elution with a mixture of 0-0,5% EtOAc/CH2Cl2(head of the faction) and then a mixture of 0.5-1% EtOAc/CH2Cl2give compound 58 (415 mg, 92%) as a cream solid: so pl. (CH2Cl2/hexane) 162-164°C;

1H NMR (CDCl3) δ 7,58 (dt, J=8,8, 2.5 Hz, 2H), 7,52 (user.d, J=8,3 Hz, 2H), 7,38 (s, 1H), 7,32 (user.d, J=8,3 Hz, 2H), 7,28 (user.DD, J=8,8, 0.8 Hz, 2H), br4.61 (d, J=12.1 Hz, 1H), 4,58 (d, J=12.1 Hz, 1H), 4,11 (DDD, J=12,4, 7,3, 5.8 Hz, 1H), 4,01 (DDD, J=12,5, of 6.6 and 6.1 Hz, 1H), to 3.67 (d, J=10,2 Hz, 1H), 3,63 (d, J=10,2 Hz, 1H), 2.40 a (DDD, J=14,4, 6,7, 6.0 Hz, 1H), 2,13 (DDD, J=14,4, 7,3, 6.0 Hz, 1H), 1,48 (s, 3H), [α]D27-36,0° (c 1.00, it CHCl3); elemental analysis: (C22H20F3N3O5) C, H, N.

[0259] GGG. Synthesis of 2-nitro-6-{[4-(triptoreline)phenoxy]methyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 59 table 1) using the method of scheme 13

[0260] a Solution of iodine (1,49 g of 5.85 mmol) in anhydrous CH2Cl2(3×10 ml), then 4×1 ml to rinse) was added dropwise to a stirred mixture of imidazole (0,441 g, 6.48 in the mol) and triphenylphosphine (1.50 g, 5,71 mmol) in anhydrous CH2Cl2(3 ml) at 0°C in an atmosphere of N2. After stirring at 0°C for 30 minutes was added a solution of 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-propen-1-ol (164) (described by Chen et at., US 2007213341 A1, by monosilane 2-methylene-1,3-propane diol) (1,00 g, 4,94 mmol) in anhydrous CH2Cl2(4 ml, then 4×1 ml rinse) and the mixture was stirred at 0-8°C for 5 hours. The mixture was carefully concentrated under reduced pressure and the residual oil was chromatographically on silica gel. Elution with pentane first gave head a fraction, and subsequent elution with a mixture of 10% CH2Cl2/pentane gave tert-butyl(dimethyl)silyl-2-(iodomethyl)-2-propenyloxy ether (165) (1,46 g, 95%) as a volatile pink oil which was used directly in the next stage;

1H NMR (CDCl3) δ 5,31 (user.s, 1H), 5,19 (d, J=1.3 Hz, 1H), or 4.31 (s, 2H), 3,95 (s, 2H), to 0.92 (s, 9H), of 0.10 (s, 6H).

[0261] a Mixture of iodide 165 (4,63 g of 14.8 mmol), 4-(triptoreline)phenol (3,10 ml of 23.9 mmol) and powdered K2CO3(of 3.56 g of 25.8 mmol) in acetone (10 ml) was stirred at 50°C for 11 hours. Received the cooled mixture was diluted with ice water (100 ml) and was extracted with CH2Cl2(4×100 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-3% CH2Cl2/Petrola the initial ether firstly gave the head of the faction, and subsequent elution with a mixture of 5-10% CH2Cl2/petroleum ether gave tert-butyl(dimethyl)[(2-{[4-(triptoreline)phenoxy]methyl}-2-propenyl)oxy]silane (166) (3.12 g, 58%) as a colourless oil;

1H NMR (CDCl3) δ 7,12 (user.d, J=9.0 Hz, 2H), 6.90 to (dt, J=9,1, 2,9 Hz, 2H), 5,27 (d, J=0.7 Hz, 1H), 5,20 (d, J=1.1 Hz, 1H), of 4.54 (s, 2H), 4,24 (s, 2H), of 0.91 (s, 9H), of 0.07 (s, 6H); HRFABMS calculated for C17H26F3O3Si m/z [M+H]+363,1603 found 363,1604.

[0262] a Solution of iodine (825 mg, 3.25 mmol) in anhydrous THF (5 ml, then 2×3 ml to rinse) was added dropwise (over 70 minutes) to a stirred mixture of alkene 166 (a total of 5.21 g, 14.4 mmol) and powdered NaBH4(257 mg, 6,79 mmol) in anhydrous THF (18 ml) at 0°C in an atmosphere of N2. After stirring at 0°C for 3 hours and then at room temperature for 13 hours, the mixture was again cooled to 0°C, was treated with 30% solution of H2O2(6.8 ml) and 3n. a solution of NaOH (6.8 ml) and then stirred at room temperature for 3 hours. Then added water (160 ml) and the mixture was extracted with EtOAc (4×160 ml). The extracts were washed with saturated salt solution (80 ml) was evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-3,5% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 4-8% EtOAc/petroleum ether gave 3-{[tert-butyl(dimethyl)silyl]oxy}-2-{[4-triptoreline)the dryer is XI]methyl}-1-propanol (168) (3,32 g, 61%) as a colourless oil;

1H NMR (CDCl3) δ 7,13 (user.d, J=9.0 Hz, 2H), 6.89 in (dt, J=9,1, 3.0 Hz, 2H), 4,08 (DD, J=9,3, and 6.6 Hz, 1H), Android 4.04 (DD, J=9,3, 6.0 Hz, 1H), 3,94-3,81 (m, 4H), of 2.36 (DD, J=6,1, 5,2 Hz, 1H), 2,19 (m, 1H), 0,89 (s, 9H), 0.07 respectively, of 0.05 (2s, 6H); HRFABMS calculated for C17H28F3O4Si m/z [M+H]+381,1709 found 381,1707.

[0263] a Solution of iodine (2,89 grams, or 11.4 mmol) in anhydrous CH2Cl2(6×10 ml, then 5 ml+2 ml rinse) was added dropwise (over 100 minutes) to a stirred mixture of the alcohol 168 (3.28 g, to 8.62 mmol), imidazole (1.50 g, 22,0 mmol) and triphenylphosphine (2.83 g, the 10.8 mmol) in anhydrous CH2Cl2(20 ml) in an atmosphere of N2. After stirring at room temperature for 15 hours the mixture was concentrated under reduced pressure and the residue was chromatographically on silica gel. Elution with petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 5-20% CH2Cl2/petroleum ether gave tert-butyl(3-iodine-2-{[4-(triptoreline)phenoxy]methyl}propoxy)dimethylsilane (170) (3,90 g, 92%) as a pale brown oil;

1H NMR (CDCl3) δ 7,13 (user.DD, J=9,1, 0.7 Hz, 2H), 6.89 in (dt, J=9,1, 3.0 Hz, 2H), 4,01 (DD, J=9,3, 5.7 Hz, 1H), 3,94 (DD, J=9,3, 6.2 Hz, 1H, in), 3.75 (DD, J=10,1, 5.6 Hz, 1H), 3,70 (DD, J=10,1, 5.6 Hz, 1H), 3,39 (DD, J=10,1, 5,9 Hz, 1H), 3,37 (DD, J=10,1, 6.0 Hz, 1H), 2,10 (Sept., J=5.8 Hz, 1H), 0,89 (s, 9H), of 0.07, 0.06 to (2s, 6H); HRCIMS calculated for C17H27F3IO3Si m/z [M+H]+491,0726, n is Geno 491,0721.

[0264] a Mixture of iodide 170 (to 3.89 g of 7.93 mmol), 2-bromo-4(5)-intorimidazole (80) (1.68 g, 8,77 mmol) and powdered K2CO3(1.90 g, 13.7 mmol) in anhydrous DMF (20 ml) was stirred at 84-88°C for 37 hours. Received the cooled mixture was diluted with ice water (100 ml) and was extracted with EtOAc (5×100 ml). The extracts were washed with saturated salt solution (100 ml), then extracted with EtOAc (50 ml), then evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-7% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 7-15% EtOAc/petroleum ether gave 2-bromo-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2-{[4-(triptoreline)phenoxy]methyl}propyl)-4-nitro-1H-imidazole (172) (3.57 g, 81%) as a pale yellow oil;

1H NMR (CDCl3) δ of 7.82 (s, 1H), 7,16 (user.DD, J=9,1, 0.7 Hz, 2H), 6,85 (dt, J=9,1, 3.0 Hz, 2H), 4.26 deaths (d, J=7,1 Hz, 2H), 3.96 points (d, J=5.6 Hz, 2H), of 3.77 (DD, J=10,6, 5,1 Hz, 1H), to 3.67 (DD, J=10,6, a 4.7 Hz, 1H), of 2.51 (m, 1H), to 0.92 (s, 9H), 0,08, of 0.07 (s, 6H); HRFABMS calculated for C20H28BrF3N3O5Si m/z [M+H]+556,0913, 554,0934 found 556,0921, 554,0938.

[0265] Silloway ether 172 (3.42 g, 6,17 mmol) was treated with a solution of 1% HCl in 95% EtOH (desirelove described Cunico et al., 1980) (31 ml) and the mixture was stirred at room temperature for 12 hours. The resulting solution was cooled (CO2/acetone), neutralized by adding dropwise 7M NH3in MeOH (6,6 ml) and AC is shivani, then was concentrated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-30% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 40-50% EtOAc/petroleum ether gave 3-(2-bromo-4-nitro-1H-imidazol-1-yl)-2-{[4-(triptoreline)phenoxy]methyl}-1-propanol (174) (2,48 g, 91%) as a white solid: so pl. (CH2Cl2/pentane) 97-99°C;

1H NMR (CDCl3) δ 7,88 (s, 1H), 7,17 (user.d, J=8.5 Hz, 2H), to 6.88 (dt, J=9,1, 3.0 Hz, 2H), 4,34 (DD, J=14,4, 7,4 Hz, 1H), 4,3 l (DD, J=14,4, and 7.1 Hz, 1H), 4,06 (DD, J=9,6, 5.7 Hz, 1H), a 4.03 (DD, J=of 9.6, 4.8 Hz, 1H), 3,88 (dt, J=10,8, and 4.4 Hz, 1H), 3,76 (dt, J=10,8, a 4.9 Hz, 1H), 2,54 (m, 1H), 1,72 (t, J=4.4 Hz, 1H); HRFABMS calculated for C14H14BrF3N3O5m/z [M+H]+442,0049, 440,0069 found 442,0053, 440,0063.

[0266] Stir a solution of alcohol 174 (2,48 g, 5,64 mmol) in anhydrous DMF (50 ml) in an atmosphere of N2at 0°C was treated with 60% NaH (345 mg, 8,63 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. After stirring at room temperature for 4 hours the reaction mixture was cooled (CO2/acetone), was suppressed with a mixture of ice/water solution of NaHCO3(30 ml) was added to a saturated salt solution (200 ml) and was extracted with CH2Cl2(8×100 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-1% EtOAc/CH2Cl2first gave head the s fraction, and subsequent elution with a mixture of 1,5-2% EtOAc/CH2Cl2give compound 59 (1,407 g, 69%) as a pale yellow solid: so pl. (CH2Cl2/hexane) 141-143°C;

1H NMR (CDCl3) δ was 7.45 (s, 1H), 7,17 (user.DD, J=9,1, 0.7 Hz, 2H), to 6.88 (dt, J=9,2, 3.0 Hz, 2H), to 4.62 (DDD, J=11,5, 3,2, 0.8 Hz, 1H), 4,50 (DD, J=11,6, 7,3 Hz, 1H), 4,27 (DDD, J=12,5, 5,6, 0.7 Hz, 1H), 4,17 (DD, J=12,4, 7,1 Hz, 1H), 4,13 (DD, J=9,6, 5.7 Hz, 1H), 4,07 (DD, J=9,6, 6,7 Hz, 1H), 2,88 (m, 1H); elemental analysis: (C14H12F3N3O5) C, H, N.

[0267] HHH. Synthesis of (6R)-2-nitro-6-{[4-(triptoreline)phenoxy]methyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 60 table 1) using the method of scheme 13

[0268] the Racemic ester 59 (1.18 g) was separated into pure enantiomers preparative chiral HPLC using a column ChiralPak IA and socratous system solvent 27% EtOH in hexane, to obtain, firstly, the connection 60 (510 mg, 43%) as a white solid: so pl. (CH2Cl2/hexane) 138-139°C;

1H NMR (CDCl3) δ was 7.45 (s, 1H), 7,17 (user.DD, J=9,0, 0.6 Hz, 2H), to 6.88 (dt, J=9,2, 3.0 Hz, 2H), to 4.62 (DDD, J=11,5, 3,2, 0.7 Hz, 1H), 4,50 (DD, J=11,5, 7,3 Hz, 1H), 4,27 (user.DD, J=12,4, 5.6 Hz, 1H), 4,17 (DD, J=12,4, 7,0 Hz, 1H), 4,13 (DD, J=9,6, 5.7 Hz, 1H), 4,07 (DD, J=9,6, 6,7 Hz, 1H), 2,88 (m, 1H); [α]2614° {c, to 1.00, CHCl3); elemental analysis: (C14H12F3N3O5) C, H, N.

[0269] III. Synthesis of (6S)-2-nitro-6-{[4-(triptoreline)phenoxy]methyl}-6,7-dihydro-5H-imide is zo[2,1-b][1,3]oxazine (compound 61 table 1) using the method of scheme 13

[0270] preparative chiral HPLC ester 59 (see example 2HHH above) again gave compound 61 (509 mg, 43%) as a white solid: so pl. (CH2Cl2/hexane) 139-140°C;

1H NMR (CDCl3) δ was 7.45 (s, 1H), 7,17 (user.DD, J=9,1, 0.6 Hz, 2H), to 6.88 (dt, J=9,1, 3.0 Hz, 2H), to 4.62 (DDD, J=11,5, 3,2, 0.6 Hz, 1H), 4,50 (DD, J=11,5, 7,3 Hz, 1H), 4,27 (user.DD, J=12,4, 5,2 Hz, 1H), 4,17 (DD, J=12,5 and 7.1 Hz, 1H), 4,13 (DD, J=9,6, 5.7 Hz, 1H), 4,07 (DD, J=9,6, 6,7 Hz, 1H), 2,88 (m, 1H); [α]26-14° (c 1.00, it CHCl3); elemental analysis: (C14H12F3N3O5) C, H, N.

[0271] JJJ. Synthesis of 6-{[(4'-fluoro[1,1'-biphenyl]-4-yl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 62 table 1) using the method of scheme 13

[0272] the Alkylation of 4-itfinal when using iodide 165 (see example 2GGG) and K2CO3as in example 2GGG above, within 6 hours, followed by chromatography of the product on silica gel with elution with petroleum ether (head of the faction) and then a mixture of 5% CH2Cl2/petroleum ether gave tert-butyl({2-[(4-iodinate)methyl]-2-propenyl}oxy)dimethylsilane (167) (94%) in the form of butter;

1H NMR (CDCl3) δ rate of 7.54 (dt, J=8,9, 2.7 Hz, 2H), 6,70 (dt, J=8,9, 2.7 Hz, 2H), 5.25-inch (d, J=1.0 Hz, 1H), 5,19 (d, J=1.2 Hz, 1H), 4,51 (s, 2H), 4,23 (s, 2H), of 0.91 (s, 9H), 0.07 to (2s, 6H); HRFABMS calculated for C16H26IO2Si m/z [M+H]+405,0747 found 405,0739.

[0273] a Solution of the ode (282 mg, 1.11 mmol) in anhydrous THF (1.5 ml, then 2×0.75 ml to rinse) was added dropwise (over 40 minutes) to a stirred mixture of alkene 167 (1,71 g, to 4.23 mmol) and powdered NaBH4(90 mg, of 2.38 mmol) in anhydrous THF (5.5 ml) at 0°C in an atmosphere of N2. After stirring at 0°C for 4 hours and then at room temperature for 13 hours, the mixture was again cooled to 0°C, was treated with 30% solution of H2O2(2.4 ml) and 3n. a solution of NaOH (2.4 ml) and then stirred at room temperature for 3 hours. Then added water (50 ml) and the mixture was extracted with EtOAc (4×50 ml). The extracts were washed with saturated salt solution (50 ml), evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-2% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 4-5% EtOAc/petroleum ether gave 3-{[tert-butyl(dimethyl)silyl]oxy}-2-[(4-iodinate)methyl]-1-propanol (169) (1.26 g, 71%) as a pale yellow oil;

1H NMR (CDCl3) δ of 7.55 (dt, J=9,0, 2.7 Hz, 2H), 6,69 (dt, J=9,0, 2.7 Hz, 2H), 4,06 (DD, J=9,3, 6,7 Hz, 1H), 4,01 (DD, J=9,3, 5,9 Hz, 1H), 3,93-of 3.80 (m, 4H), of 2.36 (DD, J=6.3, in a 5.1 Hz, 1H), 2,17 (Sept., J=5.4 Hz, 1H), 0,89 (s, 9H), 0,06, of 0.05 (2s, 6H); HRFABMS calculated for C16H28IO3Si m/z [M+H]+423,0853 found 423,0849.

[0274] Iodination of alcohol 169 when using the I2, PPh3and imidazole as in example 2GGG above, within 12 hours, with subsequent x is omatography product on silica gel with elution with a mixture of 0-5% CH 2Cl2/petroleum ether (head of the faction) and then a mixture of 5-10% CH2Cl2/petroleum ether gave tert-butyl{3-iodine-2-[(4-iodinate)methyl]propoxy}dimethylsilane (171) (94%) as a colourless oil;

1H NMR (CDCl3) δ of 7.55 (dt, J=9,0, 2.7 Hz, 2H), of 6.68 (dt, J=9,0, 2.7 Hz, 2H), 3,98 (DD, J=9,4, 5.7 Hz, 1H), 3,92 (DD, J=9,4, 6.2 Hz, 1H), 3,74 (DD, J=10,1, 5.6 Hz, 1H), 3,69 (DD, J=10,1, 5.6 Hz, 1H), 3,38 (J=10,0, 5,9 Hz, 1H), the 3.35 (DD, J=10,0, 6,1 Hz, 1H), 2,09 (Sept., J=5.8 Hz, 1H), 0,89 (s, 9H), 0.06 to (2s, 6H); HRFABMS calculated for C16H27I2O2Si m/z [M+H]+532,9870 found 532,9864.

[0275] the Alkylation of 2-bromo-4(5)-intorimidazole (80) using iodide 171 and K2CO3as in example 2GGG above, in the next 33 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-7% EtOAc/petroleum ether (head of the faction) and then a mixture of 8-15% EtOAc/petroleum ether gave 2-bromo-1-{3-{[tert-butyl(dimethyl)silyl]oxy}-2-[(4-iodinate)methyl]propyl}-4-nitro-1H-imidazole (173) (80%) as white solids: so pl. (CH2Cl2/pentane) 81-83°C;

1H NMR (CDCl3) δ 7,81 (s, 1H), EUR 7.57 (dt, J=9,0, 2.7 Hz, 2H), only 6.64 (dt, J=9,0, 2,6 Hz, 2H), 4,24 (d, J=7,1 Hz, 1H), 3,93 (d, J=5.6 Hz, 1H), 3,76 (DD, J=10,6, 5,1 Hz, 1H), 3,66 (DD, J=10,6, a 4.7 Hz, 1H), 2,50 (m, 1H), of 0.91 (s, 9H), of 0.07 (2s, 6H); HRFABMS calculated for C19H28BrIN3O4Si m/z [M+H]+598,0057, 596,0077 found 598,0070, 596,0082.

[0276] the Hydrolysis salelologa ether 173 when using 1% HCl in 95% EtOH, as in CA is re 2GGG above, within 7 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-30% EtOAc/petroleum ether (head of the faction) and then a mixture of 40-50% EtOAc/petroleum ether gave 3-(2-bromo-4-nitro-1H-imidazol-1-yl)-2-[(4-iodinate)methyl]-1-propanol (175) (86%) as a white solid: so pl. (CH2Cl2/pentane) 109-111°C;

1H NMR (CDCl3) δ 7,87 (s, 1H), 7,58 (dt, J=9,0, 2.7 Hz, 2H), 6,66 (dt, J=9,0, 2.7 Hz, 2H), 4,33 (DD, J=14,4, 7,3 Hz, 1H), 4,29 (DD, J=14,4, and 7.1 Hz, 1H), a 4.03 (DD, J=9,6, 5.7 Hz, 1H), 4,00 (DD, J=9,6, and 7.8 Hz, 1H), 3,86 (DDD, J=10,9, 4,6, 4.3 Hz, 1H, in), 3.75 (dt, J=10,8, a 4.9 Hz, 1H), 2,52 (m, 1H), 1,72 (t, J=4.4 Hz, 1H); HRFABMS calculated for C13H14BrIN3O4m/z [M+H]+483,9192, 481,9212 found 483,9200, 481,9211.

[0277] ring Closure of alcohol 175 using NaH as in example 2GGG, for 5 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then a mixture of 1,5-2% EtOAc/CH2Cl2gave 6-[(4-iodinate)methyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (176) (78%) as a pale yellow solid: so pl. (CH2Cl2/pentane, rubbing) 239-240°C;

1H NMR [(CD3)2SO] δ of 8.09 (s, 1H), 7,60 (dt, J=9,0, 2.7 Hz, 2H), PC 6.82 (dt, J=9,0, 2.7 Hz, 2H), 4,59 (DD, J=10,9, 2,9 Hz, 1H), of 4.44 (DD, J=11,0, 7.2 Hz, 1H), 4,28 (DD, J=12,5, a 5.4 Hz, 1H), 4.09 to (DD, J=10,0, 6,7 Hz, 1H), 4,06 (DD, J=10,0, 6,7 Hz, 1H), a 4.03 (DD, J=12,5, 7,0 Hz, 1H), 2,82 (m, 1H); elemental analysis: (C13H12IN3O4) C, H,N.

[0278] the Reaction mix Suzuki iodide 176 and 4-ftorhinolonovy acid, as in example 2CC above, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then with a mixture of 1-2% EtOAc/CH2Cl2give compound 62 (92%) as a pale pink solid: so pl. (CH2Cl2/pentane) 201-203°C;

1H NMR [(CD3)2SO] δ 8,11 (s, 1H), 7,65 (dt, J=8,9, 2.7 Hz, 2H), to 7.64 (dt, J=8,8, 2.7 Hz, 2H), to 7.59 (dt, J=8,8, 2.5 Hz, 2H), 7,25 (TT, of 8.9, 2.7 Hz, 2H), 7,05 (dt, J=8,8, 2,6 Hz, 2H), 4,63 (DD, J=10,9, 2,9 Hz, 1H), 4,48 (DD, J=11,0, 7,3 Hz, 1H), or 4.31 (DD, J=12,5, a 5.4 Hz, 1H), 4,16 (DD, J=10,0, 6,7 Hz, 1H), 4,12 (DD, J=10,0, 6,7 Hz, 1H), 4,07 (DD, J=12,6, 7,0 Hz, 1H), 2,86 (m, 1H); elemental analysis: (C19H16FN3O4) C, H, N.

[0279] KKK. Synthesis of 2-nitro-6-({[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 63 table 1) using the method of scheme 13

[0280] the Reaction mix Suzuki iodide 176 (see example 2JJJ above) and 4-(trifluoromethyl)phenylboronic acid, as in example 2CC above, followed by chromatography of the product on silica gel with elution 0-1% EtOAc/CH2Cl2(head of the faction) and then with a mixture of 1-2% EtOAc/CH2Cl2give compound 63 (90%) as a cream solid: so pl. (CH2Cl2/pentane) 218 to 221°C;

1H NMR [(CD3)2SO] δ 8,11 (s, 1H), 7,85 (user.d, J=8,2 Hz, 2H), to 7.77 (user.d, J=8,3 Hz, 2H), 7,71 (dt, J=8,8, 2.5 Hz, 2H), 7,10 (dt, J=8,8, 2.5 Hz, 2H), 4,63 (DD, J=10,9, 2,9 Hz, 1H), 4,48 (DD, J=11,0, 7.2 Hz, 1H), 4,32 (DD, J=12,5, and 5.5 Hz, 1H), 4,18 (DD, J=10,0, 6,7 Hz, 1H), 4,15 (DD, J=10,0, 6,7 Hz, 1H), 4,08 (DD, J=12,6, 7,0 Hz, 1H), 2,87 (m, 1H); elemental analysis: (C20H16F3N3O4) C, H, N.

[0281] LLL. Synthesis of 2-nitro-6-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 64 table 1) using the method of scheme 13

[0282] the Reaction mix Suzuki iodide 176 (see example 2JJJ above) and 4-(triptoreline)phenylboronic acid, as in example 2CC above, followed by chromatography of the product on silica gel with elution CH2Cl2give compound 64 (93%) as a cream solid: so pl. (CH2Cl2/pentane) 192-194°C;

1H NMR (CDCl3) δ rate of 7.54 (dt, J=8,7, 2.4 Hz, 2H), 7,50 (dt, J=8,7, 2.5 Hz, 2H), 7,46 (s, 1H), 7,26 (m, 2H), of 6.96 (dt, J=8,7, 2.4 Hz, 2H), 4,63 (DD, J=11,5, 3.1 Hz, 1H), to 4.52 (DD, J=11,5, 7,4 Hz, 1H), 4,28 (DD, J=12,4, 5.6 Hz, 1H), 4,20 (m, 1H), 4,18 (DD, J=10,0, 5.7 Hz, 1H), 4,12 (DD, J=9,7, 6,7 Hz, 1H), 2.91 in (m, 1H); elemental analysis: (C20Hl6F3N3O5) C, H, N.

[0283] MMM. Synthesis 6-({[5-(4-forfinal)-2-pyridinyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 65 table 1) using the method of scheme 14

[0284] a Mixture of 2-bromo-4(5)-intorimidazole (80) (3,373 g, 17.6 mmol), 6-(iodomethyl)-2,2,3,3,9,9,10,10 about tameil-4,8-dioxa-3,9-delaunayn (177) (described by Curran et al., 1998 in 4 stages on the basis of 2-methylene-1,3-propane diol) (6,79 g of 15.3 mmol) and powdered K2CO3(5.10 g, 36,9 mmol) in anhydrous DMF (40 ml) in an atmosphere of N2was stirred at 82°C for 24 hours. Received the cooled mixture was added to ice water (200 ml) and was extracted with EtOAc (3×200 ml). The extracts were washed with water (200 ml), then extracted with EtOAc (200 ml) and then washed with saturated salt solution (150 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-2% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 3-5% EtOAc/petroleum ether gave 2-bromo-1-[3-{[tert-butyl(dimethyl)silyl]oxy}-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)propyl]-4-nitro-1H-imidazole (178) (7,35 g, 95%) as a white solid: so square (pentane) 51-53°C;

1H NMR (CDCl3) δ 7,83 (s, 1H), 4,12 (d, J=7.2 Hz, 2H), 3,61 (DD, J=10,4, 5.5 Hz, 2H), of 3.56 (DD, J=10,4, 5.0 Hz, 2H), 2,15 (m, 1H), of 0.91 (s, 18H), 0,07 (2C, 2× 6H); elemental analysis: (C19H38BrN3O4Si2) C, H, N.

[0285] the Suspension salelologa ether 178 (7,35 g, 14.5 mmol) in 1% HCl in 95% EtOH (desirelove described Cunico et al., 1980) (150 ml) was stirred at room temperature for 4 hours and then kept at 4°C for 12 hours. The resulting solution was cooled (CO2/acetone), neutralized by adding dropwise 7M NH in MeOH (9.8 ml) under stirring, and then concentrated to dryness and the residue was chromatographically on silica gel. Elution with a mixture 33-75% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 75% EtOAc/petroleum ether and EtOAc gave 2-[(2-bromo-4-nitro-1H-imidazol-1-yl)methyl]-1,3-propandiol (179) (3,42, 85%) as a white solid: so square (MeOΗ/CΗ2Cl2/hexane) 110-112°C;

1H NMR [(CD3)2SO] δ of 8.50 (s, 1H) and 4.65 (t, J=5.0 Hz, 2H), 4,07 (d, J=7,3 Hz, 2H), 3,41 (m, 4H), to 2.06 (m, 1H); elemental analysis: (C7H10BrN3O4) C, H, N.

[0286] Stir a solution of diol 179 (3,44 g, 12.3 mmol) in anhydrous DMF (30 ml) in an atmosphere of N2at 0°C was treated with 60% NaH (1,72 g, 43,0 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. After stirring at room temperature for 3.5 hours the reaction mixture was cooled (CO2/acetone), was suppressed with a mixture of ice/water solution of NH4Cl (20 ml) and aqueous solution of NaHCO3(20 ml) was added to a saturated salt solution (150 ml) and was extracted with CH2Cl2(3×150 ml), 10% MeOH/CH2Cl2(6×150 ml) and EtOAc (15×150 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-2% MeOH/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 2-3% MeOH/CH2Cl2gave the crude product (1.88 g), which then chromatographically on silica gel. Elution with a mixture of 50-90% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 90% EtOAc/petroleum ether and EtOAc gave (2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)methanol (180) (1,649 g, 67%) as a pale yellow solid: so square (MeOH/CH2Cl2/hexane) 130-131°C;

1H NMR [(CD3)2SO] δ of 8.06 (s, 1H), 4,96 (t, J=5,1 Hz, 1H), 4,49 (DDD, J=10,9, 3,3, 0.9 Hz, 1H), 4,30 (DD, J=10,9, 7.9 Hz, 1H), 4,15 (DDD, J=12,5, 5,4, 0.8 Hz, 1H), 3,90 (DD, J=12,5, 7.7 Hz, 1H), 3,47 (m, 2H), 2.40 a (m, 1H); elemental analysis: (C7H9N3O4) C, H, N.

[0287] the Alkylation oxazinones alcohol 180 when using 5-bromo-2-herperidin (91) (2.0 EQ.) and NaH (1,74 equiv.) as in the example 200, for 3 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-0,25% MeOH/CH2Cl2(head of the faction) and then a mixture of 0.25-0.5% MeOH/CH2Cl2gave 6-{[(5-bromo-2-pyridinyl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (181) (67%) as a white solid: so square (MeOΗ/CΗ2Cl2/hexane) 233-235°C;

1H NMR [(CD3)2SO] δ of 8.27 (DD, J=2.5 and 0.4 Hz, 1H), 8,07 (s, 1H), to 7.93 (DD, J=8,8, 2.6 Hz, 1H),6,85 (DD, J=8,9, 0.5 Hz, 1H), 4,60 (DD, J=11,0, 2.7 Hz, 1H), of 4.44 (DD, J=11,1, 7,4 Hz, 1H), 4,36 (DD, J=11,0, 6,7 Hz, 1H), 4,33 (DD, J=11,0, 6,7 Hz, 1H), 4,27 (DD, J=12,5, a 5.4 Hz, 1H), Android 4.04 (DD, J=12,6, 7,1 Hz, 1H), 2,85 (m, 1H); elemental analysis: (C12H11BrN4O4) C,H, N.

[0288] the Reaction mix Suzuki bromide 181 and 4-ftorhinolonovy acid (2.0 equiv.) as in example 2M, for 2.5 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-5% EtOAc/CH2Cl2(head of the faction) and then a mixture of 5-6% EtOAc/CH2Cl2give compound 65 (93%) as a cream solid: so pl. (CH2Cl2/pentane) 160-161°C;

1H NMR (CDCl3) δ 8,29 (DD, J=2.5 and 0.6 Hz, 1H), 7,78 (DD, J=8,8, 2.5 Hz, 1H), 7,46 (DDT, J=8,9, 5,2, 2,6 Hz, 2H), 7,44 (s, 1H), 7,14 (TT, J=6,5, and 2.6 Hz, 2H), 6,83 (DD, J=8,6, 0.7 Hz, 1H), with 4.64 (DDD, J=11,4, 3,3, 1.0 Hz, 1H), of 4.54 (DD, J=11,3, 6.2 Hz, 1H), 4,49 (DD, J=11,3, 6.5 Hz, 1H), 4,45 (DD, J=11,5, 7.9 Hz, 1H), 4.26 deaths (DDD, J=12,4, 5,6, and 0.9 Hz, 1H), 4,10 (DD, J=12,4, 7.7 Hz, 1H), equal to 2.94 (m, 1H); elemental analysis: (C18H15FN4O4) C, H, N.

[0289] NNN. Synthesis of 2-nitro-6-[({5-[4-(trifluoromethyl)phenyl]-2-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 66 table 1) using the method of scheme 14

[0290] the Reaction mix Suzuki bromide 181 (see example 2MMM) and 4-(trifluoromethyl)phenylboronic acid as in example 2M, within 130 minutes, followed by chromatography of the product on silica gel with elution with a mixture of 0-4% EtOAc/CH2Cl2(head of the faction) and then a mixture of 5-6% EtOAc/CH2Cl2give compound 66 (94%) as a cream solid: so pl. (CH2Cl2/pentane) 180-182°C;

1H NMR (CDClsub> 3) δ scored 8.38 (DD, J=2.5 and 0.5 Hz, 1H), 7,87 (DD, J=8,6, and 2.6 Hz, 1H), 7,73 (user.d, J=8,2 Hz, 2H), to 7.64 (user.d, J=8.1 Hz, 2H), of 7.48 (s, 1H), 6.89 in (DD, J=8,6, 0.6 Hz, 1H), 4,66 (DDD, J=11,4, 3,3, 0.9 Hz, 1H), 4,57 (DD, J=11,3, 6.3 Hz, 1H), to 4.52 (DD, J=11,3, 6.4 Hz, 1H), 4,49 (DD, J=11,5, 7.9 Hz, 1H), 4,29 (DDD, J=12,4, 5,6, the 0.8 Hz, 1H), 4,13 (DD, J=12,4, 7,6 Hz, 1H), 2,98 (m, 1H); elemental analysis: (C19H15F3N4O4) C, H, N.

[0291] OOO. Synthesis of 2-nitro-6-[({5-[4-(triptoreline)phenyl]-2-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 67 table 1) using the method of scheme 14

[0292] the Reaction mix Suzuki bromide 181 (see example 2MMM) and 4-(triptoreline)phenylboronic acid as in example 2M for 2 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-4% EtOAc/CH2Cl2(head of the faction) and then a mixture of 4-5% EtOAc/CH2Cl2give compound 67 (93%) as a cream solid: so pl. (CH2Cl2/pentane) 182-183°C;

1H NMR (CDCl3) δ 8,31 (DD, J=2.5 and 0.7 Hz, 1H), 7,80 (DD, J=8,6, and 2.6 Hz, 1H), 7,52 (dt, J=8,8, 2,6 Hz, 2H), 7,44 (s, 1H), 7,30 (user.DD, J=8,7, 0.8 Hz, 2H), at 6.84 (DD, J=8,6, 0.6 Hz, 1H), with 4.64 (DDD, J=11,5, 3,3, 0.9 Hz, 1H), 4,54 (DD, J=11,3, 6.2 Hz, 1H), 4,50 (DD, J=11,2, 6.4 Hz, 1H), 4,46 (DD, J=11,4, 7.9 Hz, 1H), 4.26 deaths (DDD, J=12,4, 5,6, 0.8 Hz, 1H), 4,10 (DD, J=12,4, 7,6 Hz, 1H), 2.95 and (m, 1H); elemental analysis: (C19H15F3N4O5) C, H, N.

[0293] the PPP. Synthesis 6-({[6-(4-forfinal)-3-pyridinyl]oxy}methyl)-2-nitro-6,7-digitron-imidazo[2,1-b][1,3]oxazine (compound 68 table 1) using the method of scheme 15

[0294] Diethylazodicarboxylate (3,445 ml of 22.2 mmol) was added dropwise to a stirred mixture of 3-{[tert-butyl(dimethyl)silyl]oxy}-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-propanol (184) (described by Kim et al., 2001, through similarobama and hydroporinae 2-methylene-1,3-propane diol) (5,706 g of 17.1 mmol), 6-bromo-3-pyridinol (3,571 g of 20.5 mmol) and triphenylphosphine (5,386 g of 20.5 mmol) in anhydrous THF (55 ml) at 0°C in an atmosphere of N2. After stirring at 0°C for 1 hour and then at room temperature for 41 hours the mixture was concentrated under reduced pressure and the residue was chromatographically on silica gel. Elution with a mixture of 0-5% Et2O/petroleum ether firstly gave the head of the faction, and subsequent elution with a mixture of 5% Et2O/petroleum ether gave 2-bromo-5-[3-{[tert-butyl(dimethyl)silyl]oxy}-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)propoxy]pyridine (185) (8,09 g, 97%) as a colourless oil;

1H NMR (CDCl3) δ of 8.06 (d, J=3.0 Hz, 1H), 7,35 (DD, J=8,7, 0.3 Hz, 1H), 7,11 (DD, J=8,7, and 3.2 Hz, 1H), a 4.03 (d, J=5,9 Hz, 2H), of 3.73 (DD, J=10,1, 5.7 Hz, 1H), 3,69 (DD, J=10,0, 6.0 Hz, 1H), 2,16 (Sept., J=5.8 Hz, 1H), from 0.88 (s, 18H), 0,03 (2s, 12H); HRESIMS calculated for C21H41BrNO3Si2m/z [M+H]+492,1783, 490,1803 found 492,1786, 490,1804.

[0295] Silloway ether 185 (11,06 g of 22.5 mmol) was treated with 1% HCl in 95% EtOH (desirelove described Cunico et al., 1980) (200 ml) and the mixture AC is stirred at room temperature for 13 hours. The resulting solution was cooled (CO2/acetone), neutralized by adding dropwise 7M NH3in MeOH (10 ml) under stirring, and then concentrated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-3% MeOH/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 5% MeOH/CH2Cl2gave 2-{[(6-bromo-3-pyridinyl)oxy]methyl}-1,3-propandiol (186) (5,56 g, 94%) as a white solid: so pl. (CH2Cl2) 90-91°C;

1H NMR (CDCl3) δ 8,07 (d, J=3.1 Hz, 1H), was 7.36 (d, J=8.7 Hz, 1H), 7,12 (DD, J=8,7, 3.1 Hz, 1H), 4,15(d, J=6,1 Hz, 1H), 3,95 (dt, J=10,8, a 4.9 Hz, 1H), 3,92 (dt, J=10,8, a 5.3 Hz, 1H), 2,24 (m, 1H), 1,99 (t, J=5,1 Hz, 2H); elemental analysis: (C9H12BrNO3) C, H, N.

[0296] a Suspension of diol 186 (5,25 g, 20.0 mmol) in anhydrous THF (66 ml) in an atmosphere of N2was stirred at room temperature until dissolved solids (~10 minutes), then was treated with 60% NaH (0,829 g of 20.7 mmol), was quickly degirolami and again tightly closed in an atmosphere of N2. After stirring at room temperature for 60 minutes to yield a white precipitate) was added tert-butyldimethylsilyl (3,21 g, is 21.3 mmol) and the mixture was stirred at room temperature for 100 minutes. The resulting mixture was concentrated under reduced pressure and the residue was chromatographically on silica gel. Elution with a mixture of 0-33% Et2O/a Petro is any ether firstly gave the head of the faction, and subsequent elution with a mixture of approximately 33-50% Et2O/petroleum ether gave 3-[(6-bromo-3-pyridinyl)oxy]-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-propanol (187) (5,97 g, 79%) as a colourless oil;

1H NMR (CDCl3)8 8,07 (d, J=3.1 Hz, 1H), was 7.36 (d, J=8.7 Hz, 1H), 7,12 (DD, J=8,7, 3.1 Hz, 1H), 4,12 (DD, J=9,2, and 6.6 Hz, 1H), 4.09 to (DD, J=9,2, 5,9 Hz, 1H), 3,94-of 3.80 (m, 4H), and 2.27 (DD, J=6,3, 4.8 Hz, 1H), 2,18 (Sept., J=5.4 Hz, 1H), 0,89 (s, 9H), 0,06, of 0.05 (2s, 6H); HRESIMS calculated for C15H27BrNO3Si m/z [M+H]+378,0918, 376,0938 found 378,0912, 376,0931,

[0297] Iodination of alcohol 187 the use of I2, PPh3and imidazole as in example 2GGG above, for 18 hours, followed by chromatography of the product on silica gel with elution with petroleum ether and pentane (head of the faction) and then a mixture of 5-25% Et2O/pentane gave 2-bromo-5-[3-{[tert-butyl(dimethyl)silyl]oxy}-2-(iodomethyl)propoxy]pyridine (188) (97%) as a colourless oil;

1H NMR (CDCl3) δ 8,07 (d, J=3.0 Hz, 1H), 7,37 (DD, J=8,7, 0.3 Hz, 1H), 7,11 (DD, J=8,7, and 3.2 Hz, 1H), 4,06 (DD, J=9,2, 5.7 Hz, 1H), 3,99 (DD, J=9,2, 6,1 Hz, 1H), 3,74 (DD, J=10,1, 5.6 Hz, 1H), 3,70 (DD, J=10,1, 5.5 Hz, 1H), to 3.36 (d, J=6.0 Hz, 2H), 2,12 (Sept., J=5.8 Hz, 1H), 0,89 (s, 9H), 0.06 to (2s, 6H); HRESIMS calculated for C15H26BrINO2Si m/z [M+H]+487,9935, 485,9955 found 487,9931, 485,9952.

[0298] the Alkylation of 2-bromo-4(5)-intorimidazole (80) when using iodide 188 and K2CO3as in example 2GGG above, within 42 hours, followed by chromatography of the product is on silica gel with elution with a mixture of 0-20% EtOAc/petroleum ether (head of the faction) and then a mixture of 20-33% EtOAc/petroleum ether gave 2-bromo-5-[3-(2-bromo-4-nitro-1H-imidazol-1-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)propoxy]pyridine (189) (73%) as a cream solid: so pl. (CH2Cl2/hexane) 132-134°C;

1H NMR (CDCl3) δ with 8.05 (d, J=3.0 Hz, 1H), 7,82 (s, 1H), 7,40 (DD, J=8,7, 0,4 Hz, 1H), 7,06 (DD, J=8,7, and 3.2 Hz, 1H), 4,25 (d, J=7.2 Hz, 2H), 4,01 (d, J=5.7 Hz, 2H), of 3.77 (DD, J=10,7, a 4.9 Hz, 1H), 3,66 (DD, J=10,6, 4.6 Hz, 1H), of 2.53 (m, 1H), of 0.91 (s, 9H), 0,08, of 0.07 (2s, 6H); elemental analysis: (C18H26Br2N4O4Si) C, H, N.

[0299] Tetra-n-butylammonium (13,0 ml of 1M solution in THF, at 13.0 mmol) was added dropwise to the mixed solution salelologa ester 189 (of 6.78 g, 12.3 mmol) in anhydrous THF (140 ml) and the mixture was stirred at room temperature for 4 hours. The resulting solution was concentrated under reduced pressure, then diluted with ice water (120 ml) and was extracted with EtOAc (5×120 ml). The extracts were washed with saturated salt solution (100 ml), then evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-80% Et2O/petroleum ether, petroleum ether and the mixture 0-1% MeOH/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 2-3% MeOH/CH2Cl2gave 3-(2-bromo-4-nitro-1H-imidazol-1-yl)-2-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-propanol (190) (are 5.36 g, 100%) as a pale yellow foam;

1H NMR (CDCl3) δ 8,07 (d, J=3.0 Hz, 1H), 7,89 (s, 1H), 7,40 (d, J=8.7 Hz, 1H), to 7.09 (DD, J=8,7, and 3.2 Hz, 1H), 4,32 (d, J=7.2 Hz, 2H), 4.09 to (d, J=5.5 Hz, 2H), a 3.87 (DD, J=10,7, a 4.7 Hz, 1H, in), 3.75 (DD, J=10,8, and 4.8 Hz, 1H), to 2.57 (m, 1H); HRESIMS vechicle what about C 12H13Br2N4O4m/z [M+H]+438,9258, 436,9278, 434,9298 found 438,9262, 436,9279, 434,9299.

[0300] ring Closure of alcohol 190 using NaH (1,35 equiv.) as in the example 2GGG, for 200 minutes, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% MeOH/CH2Cl2(head of the faction) and then a mixture of 1-3% MeOH/CH2Cl2gave 6-{[(6-bromo-3-pyridinyl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (191) (71%) as a pale yellow solid: so square (MeOH/CH2Cl2/hexane) 197-199°C;

1H NMR [(CD3)2SO] δ 8,15 (user.d, J=3.0 Hz, 1H), 8,10 (s, 1H), 7,56 (DD, J=8,7, 0.3 Hz, 1H), 7,42 (DD, J=8,8, 3.2 Hz, 1H), 4,60 (DD, J=11,0, 2.7 Hz, 1H), 4,45 (DD, J=11,0, 7,0 Hz, 1H), 4,29 (DD, J=12,5, and 5.5 Hz, 1H), 4,20 (DD, J=10,0, 6,8 Hz, 1H), to 4.17 (DD, J=10,0, 6,7 Hz, 1H), of 4.05 (DD, J=of 12.6, 6.8 Hz, 1H), 2,85 (m, 1H); elemental analysis: (C12H11BrN4O4) C, H, N.

[0301] the Suzuki Reaction mix bromide 191 and 4-ftorhinolonovy acid as in example 2M, within 140 minutes, followed by chromatography of the product on silica gel with elution with a mixture of 0-4% EtOAc/CH2Cl2(head of the faction) and then a mixture of 5-6% EtOAc/CH2Cl2give compound 68 (85%) as pale yellow-brown solid: so square (MeOH/CH2Cl2/hexane) 214-216°C;

1H NMR [(CD3)2SO] δ scored 8.38 (d, J=2,8 Hz, 1H), 8,11 (s, 1H), 8,06 (DDT, J=8,9, 5,6, and 2.6 Hz, 2H), to $ 7.91 (d, J=8,8 Hz, 1H), 7,51 (DD, J=8,8, 3.0 Hz, 1H), 7,27 (dt, J=8,9, ,6 Hz, 2H), 4,63 (DD, J=11,0, 2,9 Hz, 1H), 4,49 (DD, J=11,1, 7,1 Hz, 1H), 4,32 (DD, J=12,5, and 5.5 Hz, 1H), 4,25 (DD, J=10,0, 6,8 Hz, 1H), 4,22 (DD, J=10,0, 6,7 Hz, 1H), 4,08 (DD, J=12,6, 6,9 Hz, 1H), 2,89 (m, 1H); elemental analysis: (C18H15FN4O4)C, H, N.

[0302] QQQ. Synthesis of 2-nitro-6-[({6-[4-(trifluoromethyl)phenyl]-3-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 69 table 1) using the method of scheme 15

[0303] the Reaction mix Suzuki bromide 191 (see example 2PPP) and 4-(trifluoromethyl)phenylboronic acid as in example 2M, within 140 minutes, followed by chromatography of the product on silica gel with elution with a mixture of 0-4% EtOAc/CH2Cl2(head of the faction) and then a mixture of 4-5% EtOAc/CH2Cl2give compound 69 (41 mg, 69%) as a pale yellow solid: so square (MeOH/CH2Cl2/hexane) 233-235°C;

1H NMR [(CD3)2SO] δ to 8.45 (d, J=2.7 Hz, 1H), 8,24 (user.d, J=8.1 Hz, 2H), 8,12 (s, 1H), with 8.05 (d, J=8,9 Hz, 1H), 7,81 (user.d, J=8,3 Hz, 2H), EUR 7.57 (DD, J=8,8, 3.0 Hz, 1H), with 4.64 (DD, J=11,0, 2,9 Hz, 1H), 4,50 (DD, J=11,1, 7,1 Hz, 1H), 4,32 (DD, J=12,5, a 5.4 Hz, 1H), 4,28 (DD, J=10,0, 6,7 Hz, 1H), 4,25 (DD, J=10,1, 6,7 Hz, 1H), 4.09 to (DD, J=of 12.6, 6.8 Hz, 1H), 2,90 (m, 1H); elemental analysis: (C19H15F3N4O4) C, H, N.

[0304] RRR. Synthesis of 2-nitro-6-[({6-[4-(triptoreline)phenyl]-3-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (compound 70 table 1) using the method of scheme 15

[0305] the Reaction mix Suzuki bromide 191 (see example 2PPP) and 4-(triptoreline)phenylboronic acid as in example 2M, within 140 minutes, followed by chromatography of the product on silica gel with elution with a mixture of 0-4% EtOAc/CH2Cl2(head of the faction) and then a mixture of 4-5% EtOAc/CH2Cl2give compound 70 (55 mg, 89%) as a cream solid: so square (MeOH/CH2Cl2/hexane) 180-181°C;

1H NMR [(CD3)2SO] δ to 8.41 (d, J=2.7 Hz, 1H), 8,14 (dt, J=8,9, 2.5 Hz, 2H), 8,11 (s, 1H), of 7.96 (d, J=8.7 Hz, 1H), 7,54 (DD, J=8,8, 3.0 Hz, 1H), 7,44 (user.DD, J=8,8, 0.8 Hz, 2H), with 4.64 (DD, J=10,9, 2,9 Hz, 1H), 4,49 (DD, J=11.0 in, and 7.1 Hz, 1H), 4,32 (DD, J=12,5, a 5.4 Hz, 1H), 4.26 deaths (DD, J=10,1, 6,7 Hz, 1H), 4,23 (DD, J=10,1, 6,7 Hz, 1H), 4.09 to (DD, J=of 12.6, 6.8 Hz, 1H), 2,89 (m, 1H); elemental analysis: (C19H15F3N4O5) C, H, N.

[0306] the SSS. Synthesis of 2-nitro-6-({[3-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 71 table 1) using the method of scheme 14

[0307] the Alkylation oxazinones alcohol 180 (see example 2MMM) using 3-(triptoreline)benzylbromide and NaH (1.6 equiv.) as in the example 2UU above, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then a mixture of 1.5% EtOAc/CH2Cl2give compound 71 (56%) as a cream solid: so pl. (CH2Cl2/pentane)60-61°C;

1H NMR (CDCl3) δ 7,40 (s, 1H), 7,39 (t, J=7.8 Hz, 1H), 7,21 (user.d, J=7.8 Hz, 1H), 7,20-7,14 (m, 2H), of 4.54 (s, 2H), 4,51 (DDD, J=11,5, 3,4, and 0.9 Hz, 1H), 4,36 (DD, J=11,4, and 7.8 Hz, 1H), 4,15 (DDD, J=12,3, 5,6, 0.8 Hz, 1H), a 4.03 (DD, J=12,3, 7.5 Hz, 1H), 3,62 (DD, J=9,6, 5.8 Hz, 1H), of 3.57 (DD, J=9,6, and 6.6 Hz, 1H), 2,68 (m, 1H); elemental analysis: (C15H14F3N3O5) C, H, N.

[0308] TTT. Synthesis of 2-nitro-6-({[4-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 72 table 1) using the method of scheme 14

[0309] the Alkylation oxazinones alcohol 180 (see example 2MMM) when using 4-(triptoreline)benzylbromide (1.9 EQ.) and NaH (1.6 equiv.) as in the example 2UU above, for 3 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then with a mixture of 2% EtOAc/CH2Cl2give compound 72 (59%) as a cream solid: so pl. (CH2Cl2/hexane) 92-93°C;

1H NMR (CDCl3) δ 7,40 (s, 1H), 7,32 (dt, J=8,7, 2,3 Hz, 2H), 7,21 (user.d, J=8.0 Hz, 2H), to 4.52 (s, 2H), 4,51 (DDD, J=11,3, 3,3, 0.9 Hz, 1H), 4,36 (DD, J=11,4, and 7.8 Hz, 1H), 4,15 (DDD, J=12,3, 5,6, 0.8 Hz, 1H), was 4.02 (DD, J=12,3, 7.5 Hz, 1H), 3,62 (DD, J=a 9.6 and 5.9 Hz, 1H), of 3.56 (DD, J=9,6, 6,5 Hz, 1H), to 2.67 (m, 1H); elemental analysis: (C15H14F3N3O5) C, H, N.

[0310] UUU. Synthesis of 6-({[4-(benzyloxy)benzyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 73 table 1) in ISOE is lovanii method of scheme 14

[0311] a Solution of 4-(benzyloxy)benzylidene (described in the literature Cativiela et al., 1995, through iodination of 4-(benzyloxy)benzyl alcohol) (98 mg, 0,302 mmol) in anhydrous DMF (0.3 ml, then 2×0.4 ml to rinse) was added to a solution of oxazinones alcohol 180 (see example 2MMM) (a 30.7 mg, 0,154 mmol) in anhydrous DMF (1 ml) in an atmosphere of N2at 0°C. the Mixture was treated with 60% NaH (8,8 mg, 0.22 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. After stirring at room temperature for 35 minutes, the mixture was cooled (CO2/acetone), was suppressed with a mixture of ice/water solution of NaHCO3(10 ml) was added to a saturated salt solution (40 ml) and was extracted with CH2Cl2(3×50 ml) and EtOAc (3×50 ml). The combined extracts were evaporated to dryness and the residue was chromatographically on silica gel. Elution with a mixture of 0-2% EtOAc/CH2Cl2first gave head a fraction, and subsequent elution with a mixture of 2-3% EtOAc/CH2Cl2gave the crude product (20 mg), which was then chromatographically on silica gel. Elution with a mixture of 25-40% EtOAc/petroleum ether firstly gave the head of the faction, and subsequent elution EtOAc gave compound 73 (15 mg, 25%) as a white solid: so pl. (CH2Cl2/hexane) 150-151°C;

1H NMR (CDCl3) δ 7,46-7,29 (m, 6H), 7,20 (dt, J=8,6, 2.4 Hz, 2H), of 6.96 (dt, J=8,7, 2.4 Hz, 2H), 5,07 (s, 2H) 4,48 (DDD, J=11,4, 3,3, 0.8 Hz, 1H), 4,46 (d, J=11,6 Hz, 1H), 4,43 (d, J=11,6 Hz, 1H), 4,32 (DD, J=11,4, 7.9 Hz, 1H), 4.09 to (user.DD, J=12,3, and 5.5 Hz, 1H), 3,99 (DD, J=12,3, 7,6 Hz, 1H), of 3.56 (DD, J=9,6, 5.7 Hz, 1H), 3,50 (DD, J=9,6, 6,7 Hz, 1H), 2,62 (m, 1H); elemental analysis: (C21H21N3O5) C, H, N.

[0312] VVV. Synthesis of 2-nitro-6-({[4'-(triptoreline)[1,1'-biphenyl]-3-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 74 table 1) using the method of scheme 14

[0313] a Mixture of oxazinones alcohol 180 (see example 2MMM) (to 200.3 mg, 1.01 mmol) and 3-jodensavanne (406 mg, 1.37 mmol) in anhydrous DMF (7.5 ml) in an atmosphere of N2at 0°C was treated with 60% NaH (57 mg, 1,43 mmol), then quickly degirolami and again tightly closed in an atmosphere of N2. After stirring at room temperature for 140 minutes, the mixture was cooled (CO2/acetone), was suppressed with a mixture of ice/water solution of NaHCO3(10 ml) and was diluted with water (40 ml) to precipitate the crude solid, which was separated by filtration and washed with water and petroleum ether (0,49 g). The filtrate was extracted with EtOAc (3×80 ml) and then the extracts were washed with saturated salt solution (50 ml). The combined extracts were evaporated to dryness, the residue was combined with the previously obtained solid substance was chromatographically on silica gel. Elution with a mixture of 0-1% EtOAc/CH2Cl2first gave head a fraction, and subsequent suirou is of a mixture of 1-2% EtOAc/CH 2Cl2gave 6-{[(3-jobensis)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (182) (184 mg, 44%) as a cream solid: so pl. (CH2Cl2/hexane) 127-130°C;

1H NMR (CDCl3) δ 7,69 to 7.62 (m, 2H), 7,40 (s, 1H), 7,24 (m, 1H), 7,10 (user.t, J=8.0 Hz, 1H), 4,51 (DD, J=11,4, 3.1 Hz, 1H), 4,48 (d, J=12.3 Hz, 1H), of 4.44 (d, J=and 12.2 Hz, 1H), 4,35 (DD, J=11,4, 7.7 Hz, 1H), 4,14 (DD, J=12,3, and 5.5 Hz, 1H), was 4.02 (DD, J=12,3, 7,4 Hz, 1H), 3,60 (DD, J=9,6, 5.8 Hz, 1H), 3,54 (DD, J=9,6, 6,7 Hz, 1H), 2,66 (m, 1H); elemental analysis: (C14H14IN3O4) C, H, N.

[0314] the Reaction mix Suzuki iodide 182 and 4-(triptoreline)phenylboronic acid, as in example 2XX above, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then a mixture of 1-1,5% EtOAc/CH2Cl2give compound 74 (92%) as a cream solid: so pl. (CH2Cl2/pentane) 78-80°C;

1H NMR (CDCl3) δ 7,58 (dt, J=8,8, 2.5 Hz, 2H), 7,51 (dt, J=7,8, 1.5 Hz, 1H), of 7.48-7,42 (m, 2H), 7,37 (s, 1H), 7,33-7,26 (m, 3H), br4.61 (d, J=11,9 Hz, 1H), 4,57 (d, J=12.0 Hz, 1H), 4,51 (DDD, J=11,4, 3,2, 0.7 Hz, 1H), 4,37 (DD, J=11,4, 7,6 Hz, 1H), 4,13 (DD, J=12,4, and 5.5 Hz, 1H), a 4.03 (DD, J=12,3, 7,4 Hz, 1H), 3,64 (DD, J=9,6, 5.8 Hz, 1H), to 3.58 (DD, J=9,6, 6,7 Hz, 1H), to 2.67 (m, 1H); elemental analysis: (C21H18F3N3O5) C, H, N.

[0315] WWW. Synthesis of 2-nitro-6-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (compound 75 table 1) when using spasopeschany 14

[0316] the Alkylation oxazinones alcohol 180 (see example 2MMM) when using 4-jodensavanne and NaH (1.4 equiv.) as in the example 2UU above, for 3 hours, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then a mixture of 3% EtOAc/CH2Cl2gave 6-{[(4-jobensis)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin (183) (42%) as a white solid: so pl. (CH2Cl2/hexane) 161-163°C;

1H NMR (CDCl3) δ of 7.70 (dt, J=8,3, 2.0 Hz, 2H), 7,40 (s, 1H), 7,03 (user.d, J=8,3 Hz, 2H), 4,50 (DDD, J=11,4, 3,3, 0.8 Hz, 1H), 4,46 (s, 2H), 4,34 (DD, J=11,4, and 7.8 Hz, 1H), 4,13 (DDD, J=12,3, 5,6, 0.8 Hz, 1H), 4,00 (DD, J=12,3, 7,6 Hz, 1H) and 3.59 (DD, J=9,6, 5.8 Hz, 1H), 3,53 (DD, J=9,6, 6,5 Hz, 1H), 2,65 (m, 1H); HRFABMS calculated for C14H15IN3O4m/z [M+H]+416,0107 found 416,0108.

[0317] the Reaction mix Suzuki iodide 183 and 4-(triptoreline)phenylboronic acid, as in example 2XX above, followed by chromatography of the product on silica gel with elution with a mixture of 0-1% EtOAc/CH2Cl2(head of the faction) and then a mixture of 1-1,5% EtOAc/CH2Cl2give compound 75 (95%) as a cream solid: so pl. (CH2Cl2/pentane) 135-138°C;

1H NMR (CDCl3) δ to 7.59 (dt, J=8,8, 2.5 Hz, 2H), 7,55 (dt, J=8,3, 1.9 Hz, 2H), 7,40 (s, 1H), 7,37 (user.d, J=8,3 Hz, 2H), 7,29 (user.DD, J=8,7, 0.8 Hz, 2H), 4,57 (s, 2H), to 4.52 (DDD, J=11,4, 3,3, 0.8 Hz, 1H), 4,37 (DD, J=1,4, 7,8 Hz, 1H), 4,15 (DDD, J=12,3, 5,6, 0.7 Hz, 1H), Android 4.04 (DD, J=12,3, 7.5 Hz, 1H), 3,64 (DD, J=9,6, 5.8 Hz, 1H), to 3.58 (DD, J=9,6, and 6.6 Hz, 1H), 2,68 (m, 1H); elemental analysis: (C21H18F3N3O5) C, H, N.

EXAMPLE 3. Biological activity and stability

[0318] the Biological activity of the compounds of the present invention was evaluated as follows. The results are presented below in table 2.

[0319](a) the Minimum inhibiting concentration (MIC)

Compounds were evaluated for their activity against replicatingMycobacterium tuberculosis8-day microplate analysis using Alamar blue reagent (added at day 7) to determine growth (MABA) (Collins et al., 1997; Falzari et al., 2005). The lowest concentration of compound that provides inhibition of >90%, was considered as MIC. For screening the activity of compounds against bacteria in rereplacenocase condition, which simulates the clinical persistence, used the 11-day high-performance fluorescent analysis with low regeneration of oxygen (LORA), where bacteriaM. tuberculosiscontaining plasmid with acetamidine promoter, managing bacterial luciferase gene, first adapted to conditions of low oxygen content using extended culture (Cho et al., 2007).

[0320](b) Analysis of cytotoxicity using mammalian cells

It was assessed is against VERO cells (CCL-81, American Type Culture Collection) when exposed for 72 hours in the analysis using tetrazolium dye (Falzari et al., 2005).

[0321](c) Antiprotozoal screening

Compounds were evaluated for their activity against amastigoteTrypanosoma cruziand against amastigoteLeishmania donovani(free or encapsulated in macrophages), in accordance with the following protocols:

[0322](i) analysis of theTrypanosoma cruzi

L-6 cells (2×103in the medium (100 μl RPMI 1640, supplemented with 2 mm 1-glutamine plus 10% thermoactivation fetal calf serum) were sown in 96-well microtiter plates (Costar™) and incubated at 37°C (5% CO2within 1 day. Added a suspension (50 μl) of trypomastigoteTrypanosoma cruzi(5×103strain Tulahuen C2C4, containing the gene for β-galactosidase) and cells were incubated at 37°C (5% CO2) within 48 hours to establish infection. The medium was removed and replaced with fresh medium, and infected cells are then incubated at 37°C (5% CO2within 96 hours, or in the environment as such, or in the presence of serial (3-fold) dilutions of the tested compounds (initially received in the form of 10 mg/ml initial solution in DMSO and diluted in medium). Benznidazol used as a standard in each assay. After incubation were added chlorfenapyr red glycoside (100 mm) in 0.1% Nonidet P40/PBS (50 μl) and (6 the aces) was measured spectral absorption capacity at 540 nm and used to calculate IC 50.

[0323](ii) Analysis axenicallyLeishmania donovani

Grown in axenically conditions amastigoteL. donovani(MHOM-ET-67/L82) from a healthy culture in log phase were sown at a density of 1×106/ml of medium (SM, pH 5,4 plus 10% thermoactivation fetal calf serum) in 96-well microtiter plates (Costar™) and incubated at 37°C (5% CO2) for 70 hours, either as such, or in the presence of serial (3-fold) dilutions of the tested compounds (initially received in the form of 10 mg/ml initial solution in DMSO and diluted in medium). Miltefosin used as a standard in each assay. After incubation, each well was added restoredby fluorescent dye and incubation continued for another 2 hours. The values of the IC50was determined on the basis of the fluorescence measurements.

[0324](iii) analysis of themacrophages,infected withLeishmania donovani

Svezheproseyannuyu murine macrophages in medium (RPMI 1640 plus 10% thermoactivation fetal calf serum) were incubated at 37°C (5% CO2) for 24 hours and then infected (1:3 macrophages to amastigotes) axenically culture amastigoteL. donovani(MHOM-ET-67/L82) in the environment (SM, pH 5,4 plus 10% thermoactivation fetal calf serum). Infected macrophages were sown at a density of 1.2×106/ml (by razvedeni is in RPMI+10% FCS) in a 16-hole slides (Lab-tek™) and incubated at 37°C (5% CO 2) within 24 hours. The medium was removed and replaced with fresh medium (RPMI 1640+10% FCS), and this was repeated after mixing. Infected macrophages were then incubated at 37°C (5% CO2within 96 hours, or in the environment as such, or in the presence of serial (3-fold) dilutions of the tested compounds (initially received in the form of 10 mg/ml initial solution in DMSO and diluted in medium). Miltefosin used as a standard in each assay. After removal of the medium and holes slides were fixed (5 min 100% MeOH) and stained with 10% Giemsa for 10 minutes). The ratio of infected to uninfected macrophages was determined by examination under a microscope and then calculated IC50using linear regression analysis.

td align="center" namest="c5" nameend="c6"> L. donovani
Table 2
In vitro biological activity of selected compounds of table 1
NoMIC (µm)IC50(nm)IC50(ng/ml)
MABA (aerobic)LORA (aerobic)VEROT. cruzi
Axenmacro
70,5324ND3,20,0160,40
80,0414>1284,10,0170,38
90,043,7>1281,20,0160,20
100,04511>1282,00,0400,23
110,08>128>128 180,0280,47
120,08764>1289,40,0160,74
250,2534>1280,240,0290,22
260,3050>1280,340,0130,36
47the 3.815ND1,10,0410,084
490,463,0>1280,550,0480,065
500,245,1>1286,3 0,0410,15
510,0551,5>128150,0460,17
540,201,4>1280,740,0470,095
710,3315>1280,560,200,65
722,47,9460,620,0890,55
733,1351132,80,160,53
740,222,9>1280,940,16 0,54
750,30>128>1280,470,200,67

[0325] In vitro microsomal stability and in vivo biological activity of selected compounds of the present invention was also evaluated as follows, and the results are presented in table 3.

[0326](a) the stability of the compounds in human and rat microsomes

Compound (1 μm) were incubated at 37°C with the combined preparations of human liver microsomes or CD-1 mice (final protein concentration of 0.5 mg/ml) and NADPH regenerating system (MgCl2, 3.3 mm; G6P, 3.3 mm; G6PD, and 0.4 Units/ml; NADP+, 1.3 mm) in phosphate buffer (75 mm, pH 7.4) using a final volume of 200 μl. Compounds were dissolved in DMSO so that the final concentration of DMSO was 0.5%. The reaction was stopped at the time point 0 and 60 minutes by addition of MeCN (100 μl) containing 0.2 μm of metopropol, as an internal standard. The samples were diluted 10× and centrifuged, then conducted the analysis of LC-MS/MS using ionization elektrorazpredelenie and SRM monitoring using a gradient LC method. LC the peak areas were integrated and expressed as the ratio of the peak areas of the analyte/IS PAR), and the average value for each time point was calculated from data obtained in two iterations. Residual percentage was calculated as follows:

% residual.=100×(Average PART60/Average PART0)

[0327](b) In vivo analysis of the sharp TV infection in mice

BALB/c mice were infected via aerosol with a suspension of ~2×106colony forming units (CFU) of M. tuberculosis Erdman/ml (Falzari et al., 2005). Each compound was administered orally to a group of 7 or 8 mice at 100 mg/kg daily, 5 days a week for 3 weeks starting on day 11 after infection. Compounds were administered as a suspension in 0.5% CMC/0,08% Tween 80 in water. Mice were killed at day 31 and determined the number of CFU in the lungs and compared with SOME mice, which were injected only carrier, at this point of time. PA-824 was used as positive control in each experiment and the results were presented as the ratio of the average reduction in CFU in mice treated with compound/average reduction of CFU in mice treated with PA-824. In this analysis PA-824 was called up to 2.5-3 log reduction of CFU.

Table 3

Microsomal stability and in vivo biological activity of the compounds selected from table 1

NoMicrosome assay
(% OS is Aton.)
In vivo efficacy against RA-824
PeopleMouse
PA-82482941,00
128281112
2568300,025
727141ND

REFERENCE DOCUMENTS

The content of each of the documents listed below are included in the present description by reference.

Patent documents U.S.

U.S. patent 5668127

U.S. patent 6087358

US 2006063929A1

International patent documents

DE 2312518

EP 1555267

JP 2005/330266

WO 2004/033463

WO 2005/042542

WO 2007/075872

WO 2008/112483

WO 2009/120789

Non-patent publication

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1. The compound having the General structural formula I:

where n is 1,
V and W independently represent N or CH3and
one of X or Y is N and the other represents one of the formulas IIa or IIb, where formulas IIa and IIb have the General structure:

where the formula IIa includes a single ring marked at position 3 and position 4 and containing R1as Deputy, and the formula IIb includes the first ring marked at position 3 and position 4 and soda is containing as substituents as R 2and the end ring marked in position 4 and containing R1as a substitute,
where a single ring of formula IIa and the first ring and the end ring of the formula IIb include C, CH or N at each position in the ring, where the only ring of formula IIa and the first ring and the end ring of the formula IIb independently contain not more than two nitrogen atoms;
Z in formulas IIa and IIb represents CH2or a direct link,
R1independently represent any one or two of H, F, C1, CF3, OCF3or OCH2Ph, and
R2represents N.

2. Connection on p. 1, where:
n is 1,
V and W independently represent N or CH3and
one of X or Y is N and the other represents one of the formulas IIa or IIb, where formulas IIa and IIb have the General structure:

where the formula IIa includes a single ring marked at position 3 and position 4 and containing R1as Deputy, and the formula IIb includes the first ring marked at position 3 and position 4 and containing as substituents as R2and the end ring marked in position 4 and containing R1as a substitute,
where the first ring of the formula IIb include C, CH or N at each position in the ring, where the first ring of the formula IIb include no more than two nitrogen atoms is, and only the ring of formula IIa and the end ring of the formula IIb include both With or SN at each position in the ring,
Z in formulas IIa and IIb represents CH2or a direct link,
R1is a 4-F, 4-CF3, 3-OCF3, 4-OCF3or 4-OCH2Ph, and
R2represents N.

3. The pharmaceutical composition intended for the prevention and treatment of microbial infection, containing a therapeutically effective amount of the compounds under item 1.

4. The pharmaceutical composition according to p. 3, optionally containing pharmaceutically acceptable excipient, adjuvant, carrier, buffer, stabilizer or a mixture.

5. Method of prevention and treatment of microbial infection involving the introduction of a pharmaceutical composition according to p. 3.

6. The method according to p. 5, where microbial infection caused by Mycobacterium tuberculosis, Trypanosoma cruzi or Leishmania donovani.

7. A compound selected from the group including:
A. 2-nitro-7-{[4-(triptoreline)phenoxy]methyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
B. 7-{[4-(benzyloxy)phenoxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
C. 7-{[(4'-fluoro[1,1'-biphenyl]-4-yl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
D. 2-nitro-7-({[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
E. 2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]OK asin;
F. 7-({[5-(4-forfinal)-2-pyridinyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
G. 2-nitro-7-[({5-[4-(triptoreline)phenyl]-2-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
N. 7-({[6-(4-forfinal)-3-pyridinyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
I. 2-nitro-7-[({b-[4-(triptoreline)phenyl]-3-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
J. 7-methyl-2-nitro-7-{[4-(triptoreline)phenoxy]methyl}-6,7 dihydro-5H-imidazo[2,1-b] [1,3]oxazin;
K. 7-{[4-(benzyloxy)phenoxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
L. 7-{[(4'-fluoro[1,1-biphenyl]-4-yl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
M 7-methyl-2-nitro-7-({[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
N. 7-methyl-2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
O. 7-({[5-(4-forfinal)-2-pyridinyl]oxy}methyl)-7-methyl-2-nitro-6, 7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
R. 7-methyl-2-nitro-7-[({5-[4-(trifluoromethyl)phenyl]-2-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
Q. 7-methyl-2-nitro-7-[({5-[4-(triptoreline)phenyl]-2-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
R. 7-({[6-(4-forfinal)-3-pyridinyl]oxy}methyl)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
S. 7-methyl-2-nitro-7-[({6-[4-(trifluoromethyl)phenyl]-3-pyridinyl}oxy)methyl]-6,7-dihydr the-5H-imidazo[2,1-b][1,3]oxazin;
So 7-methyl-2-nitro-7-[({6-[4-(triptoreline)phenyl]-3-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
U. 2-nitro-7-({[3-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
V. 2-nitro-7-({[4-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
W. 7-({[4-(benzyloxy)benzyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
X. 2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-3-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
Y. 2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
Z. 7-methyl-2-nitro-7-({[3-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b] [1,3]oxazin;
AA. 7-methyl-2-nitro-7-({[4-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b] [1,3]oxazin;
CENTURIES. 7-({[4-(benzyloxy)benzyl]oxy}methyl)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
SS. 7-methyl-2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]3-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
DD. 7-methyl-2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]4-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
HER. (7R)-7-methyl-2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
FF. (7S)-7-methyl-2-nitro-7-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
GG. 2-nitro-6-{[4-(triptoreline)phenoxy]methyl}6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
HH. (6R)-2-nitro-6-{[4-(triptoreline)phenoxy]methyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
II. (6S)-2-nitro-6-{[4-(triptoreline)phenoxy]methyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
JJ. 6-{[(4'-fluoro[1,1'-biphenyl]-4-yl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
QC. 2-nitro-6-({[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
LL. 2-nitro-6-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
MM. 6-({[5-(4-forfinal)-2-pyridinyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
NN. 2-nitro-6-[({5-[4-(trifluoromethyl)phenyl]-2-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
OO. 2-nitro-6-[({5-[4-(triptoreline)phenyl]-2-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
PP. 6-({[6-(4-forfinal)-3-pyridinyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
QQ. 2-nitro-6-[({6-[4-(trifluoromethyl)phenyl]-3-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
RR. 2-nitro-6-[({6-[4-(triptoreline)phenyl]-3-pyridinyl}oxy)methyl]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
SS. 2-nitro-6-({[3-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
TT. 2-nitro-6-({[4-(triptoreline)benzyl]oxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
UU. 6-({[4-(benzyloxy)benzyl]oxy}methyl)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin;
VV. 2-nitro-6-({[4'-(triptoreline)[1,1'-biphenyl]-3-and the]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin and
WW. 2-nitro-6-({[4'-(triptoreline)[1,1'-biphenyl]-4-yl]methoxy}methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin; and
mixtures thereof, optical or geometrical isomers, pharmaceutically acceptable salt derivatives.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to isoxazoline FAAH inhibitors of formula (I) or their pharmaceutically acceptable forms, wherein each of G, Ra, Rb, Rc and Rd has a value described in the present application, to pharmaceutical compositions, and methods of treating a FAAH-mediated condition.

EFFECT: developing the method of treating the FAAH-mediated condition.

32 cl, 22 tbl, 351 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula , where R1 represents hydroxyadamantyl, methoxycarbonyladamantyl, carboxyadamantyl, aminocarbonyladamantyl or aminocarbonylbicyclo[2.2.2]octanyl and where A represents CR5R6; or phenyl, chlorobenzyl, benzyl, chlorophenylethyl, phenylethyl, difluorobenzyl, dichlorophenyl, trifluoromethylphenyl or difluorophenylethyl and where A represents CR5R6; R2 and R3 together with nitrogen atom N* and carbon atom C*, which they are bount to, form group or ; R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, arylalkyl, arylalkoxygroup, arylalkoxyalkyl, hydroxyalkyl, aryl, heteroarylalkyl, heteroaryloxyalkyl, substituted aryl, substituted heteroarylalkyl or substituted heteroaryloxyalkyl, where substituted aryl, substituted heteroarylalkyl and substituted heteroaryloxyalkyl are substituted with 1-3 substituents, independently selected from alkyl, cycloalkyl, cyanogroup, halogen, halogenalkyl, hydroxygroup and alkoxygroup; R5 represents hydrogen; R6represents hydrogen; as well as to their pharmaceutically acceptable salts and esters, which can be used as 11b-HSD1 inhibitors.

EFFECT: obtaining compounds which can be used as 11b-HSD1 inhibitors.

9 cl, 1 tbl, 103 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of formula I or their pharmaceutically acceptable salts, wherein R1 means phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen or 5-6-merous heteroaryl; R2 is phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen, halogen-C1-6alkyl, halogen-C1-6alkoxy, C1-6 alkylsulphonyl, nitrile, etc. R3 means H or C1-6 alkyl; X - -O-, -NRa-,-S(O)m- or CRbRc, wherein Ra - H, C1-6 alkyl or C1-6 alkylcarbonyl; Rb and Rc mean H or together with the atom to which they are attached, form 5-merous cycle additionally containing 2 oxygen atoms; m is equal to 0-2; Y means -NRc-, wherein Rc - H or C1-6 alkyl.

EFFECT: compounds can find application in medicine for treating autoimmune and inflammatory diseases related to P2X7 purinoceptor.

15 cl, 1 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene citrate salt. The invention also refers to pharmaceutical compositions containing the above citrate, and methods for using citrate in treating several conditions.

EFFECT: what is prepared is the new 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene salt and the pharmaceutical compositions on the basis thereof which can find application in medicine for treating a proliferative disorder.

17 cl, 30 dwg, 5 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein R1 represents an alkoxy group or halogen; each U and V independently represents CH or N; "----" means a bond or is absent; W represents CH or N, or if "----" is absent, then W represents CH2 or NH, provided not all U, V and W represent N; A represents a bond or CH2; R2 represents H, or provided A means CH2, then it also can represent OH; each m and n are independently equal to 0 or 1; D represents CH2 or a bond; G represents a phenyl group that is single or double substituted in meta- and/or para-position(s) by substitutes specified in alkyl, C1-3alkoxy group and halogen, or G represents one of the groups G1 and G2: wherein each Z1, Z2 and Z3 represents CH; and X represents N or CH and Q represents O or S; it should be noted that provided each m and n are equal to 0, then A represents CH2; or a pharmaceutically acceptable salt of such compound. Besides, the invention refers to a pharmaceutical composition for treating a bacterial infection containing an active ingredient presented by a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert additive.

EFFECT: preparing the oxazolidine compounds applicable for preparing a drug for treating and preventing the bacterial infections.

14 cl, 8 dwg, 2 tbl, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of general formula [I]: or their pharmacologically acceptable salts, wherein R1 is C1-6 alkyl; R2 is C1-6 alkoxy; m and n mean 1; W means N; the ring A represents fragments of formula , or that can be substituted; X1 is a single bond, C1-6 alkylene group or -C(O)NR3-, wherein R3 is hydrogen, C1-6 alkyl or phenyl; and the ring B represents fragments of formula [5]-[11]: that can be substituted, and a pharmaceutical composition containing them.

EFFECT: new compounds possess activity inhibiting the amyloid beta production, and are effective as a therapeutic agent for treating an Aβ-caused disease, such as Alzheimer disease or Down syndrome.

10 cl, 48 tbl, 399 ex

FIELD: chemistry.

SUBSTANCE: invention relates to antibacterial compounds of formula (I), where R1 represents alkoxygroup; U, V and W each represents CH or one of U, V and W represents N, and each other represents CH; A represents CH2 or O; G represents CH=CH-E, where E represents phenyl group, mono- or di-substituted with halogen, or G represents group of one of the formulas given below , , where Z represents CH or N, Q represents O or S and K represents O or S; or salt of such compound. In addition, invention also relates to pharmaceutical composition based on formula (I) compound for prevention or treatment of bacterial infection, as well as to application of claimed compounds for obtaining medication for prevention or treatment of bacterial infection.

EFFECT: novel compounds, which can be applied in treatment of bacterial infection, are obtained and described.

23 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of nucleoside derivatives - 1,2,5-oxadiazoles of general structural formula I where R1 and R2 are selected from phenylsulphonyl, substituted with one or more halogen atoms, nitro groups, carboxy groups, alkyl halides, CH3, OCH3, OCF3; X is selected from N or N→O; or R1 and R2 form a group, where R', R", R'" and R'''' are independently selected from hydrogen; halogens; nitro groups, hydroxy group, carboxy group, CH3; CH2Br; OCH3; phenylsulphonyl; phenylthio group; or the following groups: R' and R" can also be merged into one of the following common rings for inhibiting human immunodeficiency virus (HIV) replication. The invention also relates to a pharmaceutical composition based on compounds of formula I and a method of inhibiting HIV-1 subtypes A and B integrase, including forms which are resistant to raltegravir.

EFFECT: detecting novel activity in compounds of formula I, which can be used in medicine as HIV replication inhibitors.

3 cl, 5 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a 2,4-diamino-1,3,5-triazine derivative of general formula I, having protein kinase inhibitor properties, use thereof and a pharmaceutical composition based thereon. In general formula I Y is CH2, CHR', O, S, S(O) or S(O)2; X1, X2, X3 are independently selected from a CH groups or N; R1 is a C1-8 aliphatic group, C3-8 cycloalkyl, C6-10 aryl, ethylene-dioxyphenyl, methylene dioxyphenyl, pyridyl, each of which is optimally substituted with one or more identical or different groups R"; R' is hydrogen, OH, halogen, such as F, Cl, Br, I, or carboxyl or carboxamide, optimally N-substituted with (C1-6)alkyl, or cyano or halo(C1-8)alkyl, (C1-8)alkoxy, piperidinyl, optimally substituted with methyl; R" is R' or RD; R21, R22, R23, R24 are independently selected from groups F, Cl, Br, I, CN, (C1-16)alkyl; furthermore, R21 and R22 and/or R23 and R24 can be combined and represent one oxo (=O) group or together with a carbon atom can form a spirocycle containing 3 to 7 carbon atoms; furthermore, R21 and R24 together with two carbon atoms can form an aliphatic or aromatic ring containing 4 to 8 atoms, optionally substituted with one or more groups R'; RD is an oxo group =O or =S.

EFFECT: invention can be used to treat autoimmune or cancerous diseases, rheumatoid arthritis and non-Hodgkin lymphoma.

13 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of genetic engineering, molecular biology and vaccinology. Claimed is polyepitopic anti-tuberculosis vaccine construction for formation of immune response, which provides induction of immune response of CD8+ T-lymphocytes, consisting of universal polyepitopic immunogen, containing CTL-epitopes, selected from immunodominant antigens of M. tuberculosis, fused from N-end with ubiquitin, and having amino acid sequence SEQ ID NO: 1.

EFFECT: vaccine construction provides achievement of effective therapeutic T-cell immune response not only due to antigenspecific cytotoxic CD8+ T-lymphocytes but also intensive response of CD4+ T-lymphocytes.

1 tbl, 11 dwg

FIELD: medicine.

SUBSTANCE: invention concerns Mycobacterium tuberculosis growth inhibitors representing (+) and (-)-enantiomers of derivatives of usnic acid containing a furilidene furanone fragment, namely (10R,4Z)-8,13-dihydroxy-7,10-dimethyl-4-(2-furanylmethylidene)-5,16-dioxatetracyclo[7.7.0.02.6.010.15]hexadeca-1,6,8,12,14-pentaen-3,11-dione 4a and (10S,4Z)-8,13-dihydroxy-7,10-dimethyl-4-(2-furanylmethylidene)-5,16-dioxatetracyclo[7.7.0.02.6.010.15]hexadeca-1,6,8,12,14-pentaen-3,11-dione 4b

EFFECT: inhibitors possess the high antimicrobial activity.

2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 1-(2-chloroquinolin-3-yl)-4-dimethylamino-2-(naphthalen-1-yl)-1-phenylbutan-2-ol of general formula I or their pharmaceutically acceptable salts with acids, where R1 denotes H, R2+R3 denotes -O-(CH2)n-O-, where n=1-2, which forms additional dioxane and 1,3-dioxolane rings. The invention also relates to a method of producing a compound of formula I and to use of the compound of formula I in treating infectious mycobacterial diseases.

EFFECT: obtaining novel compounds with useful biological activity.

4 cl, 2 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: for treatment of patients with pulmonary tuberculosis with accompanying non-specific bronchitis at the background of carrying out standard anti-tuberculosis therapy from the first day of treatment additionally daily for 3 months the preparation Wobenzym is introduced in a dose of 1 tablet 2 times per day, 30 minutes before meal, and inhalation with a solution of the preparation Hixozide in a dose of 350 mg in 10 ml of water for injections is performed 2 times per week, the course constitutes 24 procedures.

EFFECT: method makes it possible to increase treatment efficiency by indices of infiltration resorption, closing of the decay cavities and abacillation.

1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: for complex therapy of the first time identified pulmonary tuberculosis traditional anti-tuberculosis therapy is carried out. After two weeks of anti-tuberculosis chemotherapy, complex physiotherapy is performed. In the morning 40-60 minutes after meal ultrasound inhalation with an inhibitor of proteases contrykal in a dose of 5000 UNITS, diluted in 3-4 ml of an isotonic solution of sodium chloride is carried out. Inhalation is carried out at a temperature of the solution of 35°C for 10 minutes on the apparatus "Vulkan-1". 20 minutes after inhalation magnetic infrared laser therapy (MIL-therapy) is performed from the apparatus "Rikta-04/4" on affected zones of the lungs by contact method of the application of the apparatus emitter. Frequency of the laser impact constitutes 5-50 Hz. Average power of infrared light-diode radiation is 60±30 mW, an impact with constant magnetic field is realised with induction 35±10 mT for 1-5 min. The course of treatment constitutes 30-40 daily procedures as well.

EFFECT: enhancement of infiltration resorption, closing decay cavities in the shorter period, arrest of intoxication symptoms by the end of the first month of treatment, reduction of terms of elimination of clinical and laboratory manifestations of tuberculosis.

3 cl, 2 ex

FIELD: medicine.

SUBSTANCE: drug preparation for treating tuberculosis contains an active substance isoniaside, and a pharmaceutical carrier tiozol gel with the isoniaside concentration of 5.7-54.5 wt % and the tiozol gel concentration of 45.5-94.3 wt %.

EFFECT: higher clinical effectiveness in tuberculosis and lower toxicity.

2 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: claimed is a cocrystalline form of fenbufen with pyrazinamide, where molar ratio of fenbufen with pyrazinamide constitutes 1:1, which has an endothermal peak from 148 to 152°C by the data of measurements by means of differential scanning calorimetry and peaks at 2θ(°) 7.38, 10.43, 11.04, 21.67 by the data of measurement of polycrystal X-ray radiation diffraction.

EFFECT: increased rate and level of solubility of the crystalline form of fenbufen and its suitability for application in the pharmaceutical industry.

2 ex, 7 dwg

FIELD: medicine.

SUBSTANCE: with underlying antituberculous therapy from the first day of treatment, a therapeutic course is added with an oral administration of preparations Wobenzym and Thiotriazoline; Wobenzym is administered for 4 months in a dose of 1 tablet once a day 30 minutes before breakfast, while Thiotriazoline is administered for the first 15 days in a dose of 100 mg 2 times a day, from the 16th to 45th day in a dose of 100 mg 1 time a day, on the 46th day, Thiotriazoline is withdrawn.

EFFECT: method enables higher clinical effectiveness and reduced rate of an adverse hepatotoxic response to the antituberculous preparations due to improving the immune status and peroxidation values.

6 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: rifabutin is dissolved in a water-miscible solvent which dissolves rifabutin better than water does; a rifabutin solution is prepared; gelatin is dissolved in water to prepare a gelatin solution; the rifabutin solution is slowly added to the gelatin solution while stirring to prepare a semi-product. The semi-product is dried in a spray drier or lyophilised to prepare a product. The prepared product is used as a part of a pharmaceutical composition for treating mycobacteriosis and Helicobacter pylori infection.

EFFECT: higher bioavailability of rifabutin.

46 cl, 8 tbl, 5 ex, 7 dwg

FIELD: chemistry.

SUBSTANCE: invention represents 3-aminosubstituted 6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazines, which applied as anti-tuberculosis medications make it possible to increase activity and specificity of antimicrobacterial action, extend its spectrum (impact on atypical strains of mycobacteria) as well as reduce toxicity in comparison with analogues.

EFFECT: toxicity of claimed compounds is 10-20 times lower than toxicity of anti-tuberculosis medications applied in medicine.

5 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) or (I'): Z-X1-(-CH2-CH2-O-)n-Yp-D (I), D-Yp-(-CH2-CH2-O-)n-X1-Z (l'), where: Z is a reactive carboxylic ether selected from a group consisting of N-succinimidyl, N-sulphosuccinimidyl, N-phthalimidyl, N-sulphophthalimidyl, 2-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 3-sulpho-4-nitrophenyl, 3-carboxy-4-nitrophenyl and a trifluorophenyl ester, or haloacetamide; D is maytansinoid; X is an aliphatic structural unit; Y is an aliphatic structural unit linked to the maytansinoid through a thioether bond; where said aliphatic structural unit, represented by X or Y, is a simple or branched alkyl group with 1-20 carbon atoms in the chain, a cyclic alkyl group having 3-10 carbon atoms, a simple or branched alkenyl group, having 2-15 carbon atoms in the chain or a simple or branched alkynyl group, having 2-15 carbon atoms in the chain; 1 equals 0 or 1; p equals 0 or 1; and n is an integer from 1 to 2000. The invention also relates to a conjugate of a cell-binding agent, and cytotoxic maytansinoid, where the cell-binding agent is an antibody.

EFFECT: obtaining compounds and conjugates, as well as pharmaceutical compositions based thereon, which can be used in medicine to treat tumours, autoimmune diseases, graft rejection, graft-versus-host disease, viral infections and parasitic infections.

20 cl, 38 dwg, 10 ex

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