Oxazolidine antibiotics

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

 

The present invention relates to new oxazolidinones antibiotic compounds, to pharmaceutical antibacterial composition containing them and the use of these compounds in the manufacture of a medicinal product for the treatment of infections (e.g. bacterial infections). These compounds are used as antimicrobial agents, effective against a number of pathogens of humans and animals, including, among others, gram-positive and gram-negative aerobic and anaerobic bacteria and mycobacteria.

The intensive use of antibiotics has a selective evolutionary effects on microorganisms, contributing to the production in them genetically formed of the mechanisms of resistance. Modern medical and socio-economic behavior exacerbates the problem of resistance development, creating conditions for the gradual growth of pathogenic microorganisms, for example, artificial joints, and in terms of long-term support of the reserves of the host, for example, immunological "compromised" patients.

In the hospital the increasing number of strains of Staphylococcus aureus. Streptococcus pneumoniae, Enterococcus spp. Pseudomonas aeruginosa, i.

the main sources of infections, making them resistant to many drugs and causes difficulties p. and treatment until a cure is not possible at all:

S. aureus is resistant with respect to p-lactam, quinolone, and now even to vancomycin;

S. pneumoniae is becoming resistant against penicillin or quinolone antibiotics and even to new macrolides;

- Enteroccocci are resistant against chinolone and vancomycin and β-lactam antibiotics have no effective impact on these strains;

- Enterobacteriacea are resistant against cephalosporin and chinolone;

- P. aeruginosa are resistant with respect to P-lactam and chinolone.

In addition, the propagation velocity multilatina-resistant gram-negative strains such as Enterobacteriacea and Pseudomonas aeruginosa, uniformly increases, resulting in the re-emerging organisms, such such organisms like Acinetobacter spp. Clostridium difficile, which were selected during therapy with the currently used antibiotics, have become a real problem in hospitals. Therefore, in medicine there is a great need for new antibacterial agents are able to overcome multilocational resistance of gram-negative bacteria such as A. baumannii, ESBL-producing E. coli and Klebsiella strains and Pseudomonas aeruginosa (Clinical Infectious Diseases (2006), 42, 657-68).

In addition, microo the organisms, cause resistant infections are increasingly recognized as causes or contributing factors of some chronic diseases such as peptic ulcers or heart disease.

The naphthiridine-2-about and quinoline-2-about antibiotic compounds have already been described in the following publications: WO 2006/134378, WO 2006/137485, WO 2007/138974, WO 2008/006648, WO 2008/009700, WO 2008/071961, WO 2008/071964 and WO 2008/071981.

The quinoline-naphthiridine or cinoxacin-spirooxazines antibiotic compounds were also described in WO 2008/026172.

The authors proposed at the present time a new class oxazolidinone antibiotics corresponding to the formula (I)below.

Various embodiments of the present invention is as follows:

i) the Invention primarily relates to compounds of formula (I)

where

R1is alkoxygroup (preferably, a methoxy group) or a halogen (preferably fluorine);

U and V each independently from each other represents C or N;

means a connection or missing;

W represents CH or N, or, whenno, W represents CH2or NH,

provided that U, V and W do not all represent N;

A represents a bond or CH2 ;

R2is an And, or, provided that a represents a CH2can also be a HE;

m and n are each independently from each other 0 or 1;

D represents CH2or communication;

G represents a phenyl group which is once or twice substituted in m - and/or p-position(s) by substituents selected from alkyl, C1-3alkoxygroup and halogen (preferably fluorine), With1-3alkoxylation preferably represents a linear C1-3alkoxygroup and is in para-position, or G represents one of the groups G1and G2

where

Z1, Z2and Z3each represents CH, or Z1and Z2each represents CH and Z3represents N, or Z1represents CH, Z2represents N and Z3represents CH or N, or Z1represents N and Z2and Z3each represents CH; and

X represents N or CH and Q represents O or S;

it should be borne in mind that if the type of each is 0, then a represents a CH2;

and to the salts (in particular pharmaceutically acceptable salts) of compounds of formula (I).

In the following paragraphs p is estaline definitions of the various chemical fragments for compounds according to the invention. The above definitions are intended for uniform application throughout the description and in the claims, unless otherwise specified, and if the definitions are not subject to wider or, conversely, a narrower interpretation.

The term "alkyl", used alone or in combination, refers to a saturated linear or branched alkyl group containing from one to four carbon atoms. Typical examples of alkyl Grupp include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butl and tert-butyl. The term "C1-xalkyl" (x is an integer) refers to a linear or branched alkyl group containing from one to x carbon atoms. Preferred alkyl groups are methyl and ethyl. The most preferred alkyl group is methyl.

The term "alkoxygroup", used alone or in combination, refers to a linear or branched alkyl group containing from one to four carbon atoms. The term "Cx-yalkoxygroup" (in this case, x and y each is an integer) refers to alkoxygroup according to the definition given above, containing from x to y carbon atoms. For example, C1-3alkoxygroup contains from one to three carbon atoms. Typical examples of alkoxygroup include a methoxy group, ethoxypropan, n-p is epoxypropyl and isopropoxy. Preferred examples are methoxy group and ethoxypropan.

The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably by fluorine or chlorine.

In this patent publication, communication, interrupted wavy line indicates the point of attachment of the radical to the rest of the molecule. For example, the radical as shown below

represents 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl.

The present invention also includes isotope-labeled compounds, in particular, marked with H (deuterium) the compounds of formula (I), with labeled compounds are identical to the compounds of formula (I) and differ only in that one or more atoms replaced by an atom having the same atomic number but differing in atomic weight of the atoms occurring in nature. Labeled isotope compounds, in particular, labeled2H (deuterium) the compounds of formula (I)and their salts included in the scope of the present invention. Substitution of hydrogen heavier isotope2H (deuterium) leads to greater metabolic stability, for example, that in vivo increases the half-life or reduces the required dosage, or may lead to reduced inhibition of P450 enzymes, which improves the security profile. In one embodiment, izaberete the Oia, the compounds of formula (I) are not labeled with the isotope, or they state only one or more deuterium atoms. In modifications of the compounds of formula (I) are not in the state of the isotope. Isotopically labeled compounds of formula (I) can be obtained analogously to the methods described below, but using appropriate isotopic variants of the respective reagents or starting materials.

The term "pharmaceutically acceptable salts" refers to non-toxic additive salts of inorganic or organic acids and/or bases. More detailed information can be found in the publication "Salt selection for basic drugs". Int. J. Pharm., (1986), 33, 201-217.

In addition, the term "room temperature"as used herein, refers to a temperature of 25°C.

When we are not talking about temperatures, the term "approximately", located in front of the numerical value "X"refers in the customary application to the interval of X minus 10% of X to X plus 10% of X, and preferably to an interval of X minus 5% of X to X plus 5% of X. In the special case regarding temperatures, the term "approximately"in front of the temperature "Y" refers in the customary application to the temperature interval of Y minus 10 C to Y plus 10°C, and preferably, the interval of Y minus 5 to Y plus 5 C.

ii) In particular, the invention relates to compounds of formula (I), which are also the enemy formula (I CE)

where

R1is alkoxygroup (preferably, a methoxy group);

V represents CH;

U and W each represent CH anddenotes a bond, or U represents CH, W represents N anddenotes a bond, or U and W each represent N anddenotes a bond, or U represents CH, W represents CH2andno;

A represents a bond or CH2;

R2represents H or, provided that a represents a CH2can also be a HE;

m and n are each independently from each other 0 or 1;

D represents CH2or communication;

G represents a phenyl group which is substituted once in the m-position and once substituted in p-position substituents selected from alkyl (preferably methyl) or halogen (preferably fluorine), or G represents one of the groups G1and G2,

,

where Q represents O or S;

it should be borne in mind that, if each type is 0, then a represents a CH2;

and to the salts (in particular pharmaceutically praml is incompatible salts) of compounds of formula (I CE).

iii) According to a preferred variant implementation of the present invention, the compounds of formula (I)above in the embodiments i) or ii)shall be such that R1is alkoxygroup or fluorine (preferably, C1-3alkoxygroup, in particular, methoxy group or ethoxypropan, most preferably a methoxy group).

iv) Another variant of implementation of the present invention relates to compounds of formula (I)above in the embodiments i), ii) or iii), wheremeans a connection.

v) According to one sub-variant of a variant embodiment of the invention (iv), the compounds of formula (I)above in option iv)shall be such that W represents CH.

vi) According to another sub-variant of a variant embodiment of the invention (iv), the compounds of formula (I)above in option iv)shall be such that W represents n

vii) Another variant implementation of the present invention relates to compounds of formula (I)above in the embodiments i), ii) or iii), whereis missing.

viii) According to one sub-variant of a variant embodiment of the invention vii), compounds of formula (I)above in option (vii)shall be such that W represents the CHz.

ix) According to the SNO another sub-variant of a variant embodiment of the invention (vii), the compounds of formula (I)above in option (vii)shall be such that W represents NH.

x) One main variant of implementation of the present invention relates to compounds of formula (I)above in embodiments of the invention (i)-(ix), in which V represents CH.

xi) According to one sub-variant of the main variants of implementation of the present invention x), the compounds of formula (I)above in the main embodiment of the invention x)must be such that U represents CH.

xii) According to another sub-variant of the main variant of the invention, x), the compounds of formula (I)above in the main embodiment of the invention x)must be such that U represents n

xiii) the Other main variant of implementation of the present invention relates to compounds of formula (I)presented in one of the embodiments of the invention (i)-(ix), in which V represents n

xiv) the Following variant of implementation of the present invention relates to compounds of formula (I)above in the embodiment of the invention (i)-(xiii), in which a represents a bond.

xv) Preferably, the compounds of formula (I)above in the embodiment of the invention xiv)should pattacini, in which type each represents 1.

xvi) Another variant implementation of the present invention relates to compounds of formula (I)above in the embodiment of the invention (i)-(xiii), in which a represents CH;.

xvii) According to one sub-variant of a variant embodiment of the invention xvi), the compounds of formula (I)above in the embodiment of the invention xvi)shall be such that each type represents a 0.

xviii) According to another sub-variant of a variant embodiment of the invention xvi), the compounds of formula (I)above in the embodiment of the invention xvi)shall be such, in which one of m and n is 0, and the other is 1.

xix) According to another sub-variant of a variant embodiment of the invention xvi), the compounds of formula (I)above in the embodiment of the invention xvi)shall be such that each type is 1.

XX) One main variant of implementation of the present invention relates to compounds of formula (I)shown above in one of the embodiments of the invention xvi)-(xix), in which R represents N.

xxi) the Other main variant of implementation of the present invention relates to compounds of formula (I)shown above in one of the embodiments of the invention xvi)-(xix), in which R before the hat is HE.

xxii) Another another variant implementation of the present invention relates to compounds of formula (I)shown above in one of the embodiments of the invention (i)-(xxi), in which D represents CH3.

xxiii) Another another variant implementation of the present invention relates to compounds of formula (I)shown above in one of the embodiments of the invention (i)-(xxi), in which D represents a bond.

xxiv) One main variant of implementation of the present invention relates to compounds of formula (I)shown above in one of the embodiments of the invention (i)-(xxiii), in which G represents a group of formula G, or in a variant related to the variant embodiment of the invention (ii), the group G1.

xxv) Preferably, the compounds of formula (I)above in the embodiment of the invention xxiv)shall be such that each of Z, Z hz, if present, represents CH (i.e., G is a 2,3-dihydrobenzo[1,4]dioxin-6-yl).

xxvi) the Other main variant of implementation of the present invention relates to compounds of formula (I)shown above in one of the embodiments of the invention (i)-(xxiii), in which G represents a group of formula G2or option relating to a variant embodiment of the invention (ii), g is the foam G 2.

xxvii) Preferably, the compounds of formula (I)above in the embodiment of the invention xxvi)shall be such that X, if present, represents CH (i.e., G is a 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl or 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl).

xxviii) Another variant implementation of the present invention relates to compounds of formula (I)shown above in one of the embodiments of the invention (i)-(xxiii), or in which G represents a phenyl group, which is once or twice substituted in m - and/or p-position(s) by substituents selected independently of one another from C1-4of alkyl, C1-3alkoxygroup and halogen (preferably fluorine), With1-3alkoxylation, if present, preferably is a linear C1-3alkoxygroup located in the p-position, or in variants relating to the variant embodiment of the invention (ii), where G represents a phenyl group which is substituted once in the m-position and once substituted in p-position substituents, independently selected from each other from C1-4of alkyl and halogen (preferably fluorine).

xxix) Preferably, the compounds of formula (I)above in the embodiment of the invention xxviii)shall be such that in the cat the matrix G represents a phenyl group, which is once or twice substituted in m - and/or p-position(s) by substituents selected independently of one another from methyl, ethyl, metoxygroup, ethoxypropan and halogen (preferably fluorine), methoxy - or amoxicillian, if present, is in p-position, or in the embodiment of the invention relating to a variant embodiment of the invention (ii), such that G represents a phenyl group which is substituted once in the m-position and once substituted in p-position substituents selected independently from a friend from methyl and fluorine.

xxx) In particular, the compounds of formula (I)above in the embodiment of the invention xxviii)shall be such that G represents 3-fluoro-4-were.

xxxi) According to one particular variant of implementation of the present invention, the compounds of formula (I)above in one of the embodiments of the invention (i)-(xxx)must have the stereochemistry shown below.

xxxii) According to another particular variant of implementation of the present invention, the compounds of formula (I)above in one of the embodiments of the invention (i)-(xxx)must have the stereochemistry shown below.

xxxiii) is Particularly preferred is the tsya the following compounds of formula (I), presented above in the embodiment of the invention (i) or (ii):

6-{(R)-5-[3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(R)-5-[3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

1-{1-[(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ylmethyl]azetidin-3-ylmethyl}-7-methoxy-1H-quinoline-2-he;

6-{(R)-5-[3-(7-methoxy-2-oxo-2H-cinoxacin-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-((R)-5-{2-[3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-yl]ethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;

6-((R)-5-{2-[3-(7-methoxy-2-oxo-2H-cinoxacin-1-ylmethyl)azetidin-1-yl]ethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;

6-{(R)-5-[4-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

1-{1-[(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ylmethyl]piperidine-4-ylmethyl}-7-methoxy-1H-quinoline-2-he;

1-{1-[(R)-3-(3-fluoro-4-were)-2-oxoacridine-5-ylmethyl]piperidine-4-ylmethyl}-7-methoxy-1H-quinoline-2-he;

6-{(R)-5-[3-(7-methoxy-2-oxo-3,4-dihydro-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(S)-5-[3-(7-methoxy-2-oxo-3,4-dihydro-2H-quinoline-l-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(R)-5-[3-(methoxy-2-oxo-3,4-Dihydro-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one;

6-{(R)-5-[3-(7-methoxy-2-oxo-2H-cinoxacin-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one;

1-{1-[(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ylmethyl]azetidin-3-ylmethyl}-7-methoxy-1-cinoxacin-2-he;

6-methoxy-4-{1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]piperidine-4-yl}-4H-pyrido[2,3-6]pyrazin-3-one;

6-methoxy-4-{1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)oxazolidin-5-ylmethyl]piperidine-4-yl}-4H-pyrido[2,3-6]pyrazin-3-one;

6-{(R)-5-[(R)-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(R)-5-[3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(S)-5-[3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-((S)-5-{2-[3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;

6-((S)-5-{2-[3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;

4-{1-[(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ylmethyl]piperidine-4-yl}-6-methoxy-4H-pyrido[2,3-6]pyrazin-3-one;

6-methoxy-4-(1-{2-[(5)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-yl]ethyl}piperidine-4-yl)-4H-pyrido[2,36]pyrazin-3-one;

4-{1-[(R)-3-(3-fluoro-4-were)-2-oxoacridine-5-ylmethyl]piperidine-4-yl}-6-methoxy-4H-pyrido[2,3-6]pyrazin-3-one;

6-methoxy-4-(1-{2-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-yl]ethyl}piperidine-4-yl)-4H-pyrido[2,3-6]pyrazin-3-one;

and their salts (in particular pharmaceutically acceptable salts).

xxxiv Further object of the present invention includes the following compounds of formula (I)above in embodiments of the invention (i) or (ii):

6-{(R)-5-[3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(R)-5-[3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

1-{1-[(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ylmethyl]azetidin-3-ylmethyl}-7-methoxy-1-quinoline-2-he;

6-{(R)-5-[3-(7-methoxy-2-oxo-2H-cinoxacin-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-((R)-5-{2-[3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-yl]ethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;

6-((R)-5-{2-[3-(7-methoxy-2-oxo-2H-cinoxacin-1-ylmethyl)azetidin-1-yl]ethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;

6-{(R)-5-[4-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

1-{1-[(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ilma is Il]piperidine-4-ylmethyl}-7-methoxy-1-quinoline-2-he;

1-{1-[(R)-3-(3-fluoro-4-were)-2-oxoacridine-5-ylmethyl]piperidine-4-ylmethyl}-7-methoxy-1-quinoline-2-he;

6-{(R)-5-[3-(7-methoxy-2-oxo-3,4-dihydro-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(S)-5-[3-(7-methoxy-2-oxo-3,4-dihydro-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(R)-5-[3-(7-methoxy-2-oxo-3,4-dihydro-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one;

6-{(R)-5-[3-(7-methoxy-2-oxo-2H-cinoxacin-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one;

1-{1-[(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ylmethyl]azetidin-3-ylmethyl}-7-methoxy-1-cinoxacin-2-he;

6-methoxy-4-{1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]piperidine-4-yl}-4H-pyrido[2,3-b]pyrazin-3-one;

6-methoxy-4-{1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)oxazolidin-5-ylmethyl]piperidine-4-yl}-4H-pyrido[2,3-b]pyrazin-3-one;

6-{(R)-5-[(S)-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(R)-5-[(S)-3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(R)-5-[(S)-3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(S)-5-(R)-3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(S)-5-[(S)-3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-((S)-5-{2-[(S)-3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;

6-((R)-5-{2-[(S)-3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;

6-((R)-5-{2-[(S)-3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;

6-((R)-5-{2-[(S)-3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;

4-{1-[(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ylmethyl]piperidine-4-yl}-6-methoxy-4D-pyrido[2,3-6]pyrazin-3-one;

6-methoxy-4-(1-{2-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-yl]ethyl}piperidine-4-yl)-4H-pyrido[2,3-6]pyrazin-3-one;

4-{1-[(R)-3-(3-fluoro-4-were)-2-oxoacridine-5-ylmethyl]piperidine-4-yl}-6-methoxy-4H-pyrido[2,3-6]pyrazin-3-one;

6-methoxy-4-(1-{2-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-yl]ethyl}piperidine-4-yl)-4H-pyrido[2,3-6]pyrazin-3-one;

and their salts (in particular pharmaceutically acceptable salts).

xxxv) the Invention, in particular, refers to groups of compounds of formula (I)selected from the compounds listed in embodiment from which retene xxxiii), these groups of compounds, in addition, comply with one of the embodiments of the invention iii)-xxxii), as well as to the salts (in particular pharmaceutically acceptable salts) of such compounds.

xxxvi) the Invention also relates to groups of compounds of formula (I)selected from the compounds listed in embodiment of the invention xxxiv), these groups of compounds, in addition, comply with one of the embodiments of the invention ih)-xxxii), as well as to the salts (in particular pharmaceutically acceptable salts) of such compounds.

The compounds of formula (I) according to the invention, i.e. according to one of the options (i)-(xxxvi), are suitable for use as chemotherapeutic active compounds in medicine and veterinary medicine and as substances for preserving inorganic and organic materials, in particular all types of organic materials, for example polymers, lubricants, paints, fibres, leather, paper and wool.

Compounds according to the present invention are particularly active against bacteria and bacteria-like organisms. They are therefore particularly suitable for humans and animals in the prophylaxis and chemotherapy of local and systemic infections caused by these pathogens, and diseases associated with bacterial infections, VK is UCA pneumonia, otitis media, sinusitis, bronchitis, tonsillitis, and mastoiditis related to infection caused by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Enterococcusfaecalis, E.faecium, E. casseliflavus, S. epidermidis, S. haemolyticis or Peptostreptococcus spp.; pharyngitis, rheumatic fever, and glomerulonephritis related to infection caused by Streptococcus pyogenes, groups C and G streptococci, Corynebacterium diphtheriae, or Actinobacillus haemolyticum; infections of the upper respiratory tract associated with infection caused by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae; infections of the blood and tissues, including endocarditis and osteomyelitis, caused by S. aureus, S. haemolyticus, Enterococcus faecalis, E. faecium, E. durans, including hereditary resistance to known antibacterial agents such as, not limited to, p-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracyclines and macrolides; uncomplicated skin infections and soft tissue abscesses and postpartum sepsis associated with infection caused by Staphylococcus aureus, coagulability susceptible (ie, S. epidermidis, S. haemolyticus, and the like), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcal groups C-F (the smallest colony streptococci), viridans streptococci, Corynebacterium MUHUtissimum, Clostridium spp. Bartonella henselae; uncomplicated acute urinary tract infections related to infection caused by Staphylococcus aureus, coagulability species staphyloccocal or Enterococcus spp.; urethritis and cervicitis; disease, p is expressed sexually, associated with infection caused by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrhoeae; toxicosis associated with infection caused by S. aureus (food poisoning and toxic shock syndrome), or groups a, b and C streptococci; ulcers related to infection caused by Helicobacter pylori; systemic febrile syndrome associated with infection caused by Borrelia recurrentis; Lyme disease related to infection caused by Borrelia burgdorferi; conjunctivitis, keratitis, and dacryocystitis associated with infection caused by Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. Influenzae, or Listeria spp.; disseminated Mycobacterium avium complex (MAC)associated with infection caused by Mycobacterium avium, or Mycobacterium intracellulare; infection caused by Mycobacterium tuberculosis, M. leprae, M. paratuberculosis, M. Kansasii, or M. chelonei; gastroenteritis related to infection caused by Campylobacter jejuni; intestinal protozoal infections associated with infection caused by Cryptosporidium spp.; dental infection related to infection caused by viridans streptococci; persistent cough related to infection caused by Bordetella pertussis; gas gangrene related to infection caused by Clostridium perfringens or Bacteroides spp.; and atherosclerosis or cardiovascular disease, svyazannoye with infection caused by Helicobacter pylori or Chlamydia pneumoniae.

The compounds of formula (I) according to the present invention are applied, in addition, for the manufacture of lekarstvennoj the means for treatment of infections caused by such bacteria as E. coli, Klebsiella pneumoniae and other enterobacteria, Acinetobacter spp., Stenothrophomonas maltophilia, Neisseria meningitidis. Bacillus cereus. Bacillus anthracis, Corynebacterium spp., Propionibacterium acnes and bacteroids spp.

The compounds of formula (I) according to one of the options (i)-(xxxvi) shall apply, in addition, when lecenje protocoling of infections caused by Plasmodium malaria, Plasmodiumfalciparum, Toxoplasma gondii, Pneumocystis carimi, Trypanosoma brucei and Leishmania spp.

Presents a list of pathogens should be considered only as examples and in no way as limiting the list.

The compounds of formula (I) according to one of the options (i)-(xxxvi) or their pharmaceutically acceptable salts can be used for preparation of medicines, and as a result are suitable for the prevention or treatment of bacterial infections.

One aspect of the present invention relates to the use of compounds of formula (I) according to one of the options (i)-(xxxvi) or its pharmaceutically acceptable salt for the manufacture of a medicine for prevention or treatment (particularly for the treatment of bacterial infections. Another aspect of the present invention relates to the compound of formula (I) according to one of the options (i)-(xxxvi), or its pharmaceutically acceptable salts, for the prevention or treatment (particularly for the treatment of bacterial detail the functions.

Thus, the compounds of formula (I) according to one of the options (i)-(xcv) or their pharmaceutically acceptable salts can be used for the manufacture of medicines and are suitable for the prevention or treatment of a bacterial infection selected from the group including respiratory tract infections, otitis media, middle ear infections, meningitis, infections of the skin and deep tissues (complicated or uncomplicated), pneumonia (including hospital acquired pneumonia), bacteremia, endocarditis, intraabdominal infections, gastrointestinal infections, Clostridium difficile infections, urinary tract infections, sexually transmitted infections, infections caused by foreign bodies, osteomyelitis, Lyme disease, topical infections, eye infections, tuberculosis and tropical diseases (e.g. malaria), and especially for the prevention or treatment of a bacterial infection selected from the group including respiratory tract infections, otitis media, middle ear infections, meningitis, infections of the skin and deep tissues (complicated or uncomplicated), pneumonia (including hospital acquired pneumonia), bacteremia.

Just as in medicine, a bacterial infection to be treated with the use of compounds of formula (I) or their pharmaceutically acceptable salts) in veterinary medicine for the treatment of such species as the example pigs, ruminants, horses, dogs, cats and poultry.

The present invention relates to pharmacologically acceptable salts and compositions and formulations based on the compounds of formula (I).

Any reference to a compound of formula (I) in this description, and particularly in embodiments of the invention presented above) implies a reference to salts (in particular pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.

The pharmaceutical composition according to the present invention contains at least one compound of formula (I) or its pharmaceutically acceptable salt as an active agent and optionally carriers and/or diluents and/or additives, and may also contain additional known antibiotics.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicines, for example, in the form of pharmaceutical compositions for enteral and parenteral administration.

The manufacture of pharmaceutical compositions is carried out by a method known to anyone skilled in the art (see, for example, ReMHHgton, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by introduction of the described compounds of formula (I) or their pharmaceutically acceptable salts, neobythites is but in combination with other pharmaceutically acceptable substances, in medicinal form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carriers and, if desired, usual pharmaceutical excipients.

Another aspect of the invention relates to a method for prevention and treatment of bacterial infection in a patient, which consists in the introduction of the indicated patient pharmaceutically active amount of a compound of formula (I) according to one of the options (i)-(xxxvi) or its pharmaceutically acceptable salt.

In addition, any references and (sub-)embodiments of the invention are specified for compounds of the formula (I) (whether yourself compounds, their salts, compositions containing the compounds or their salts, compounds or their salts and the like) also apply to compounds of formula (ICE)-

In addition, the compounds of formula (I) can also be used for disinfection, i.e. removal of pathogenic microbes and bacteria from the surface of the instruments or aseptic cleaning of the air space and premises. For these purposes the compounds of formula (I) can be applied in the form of a solution or spray.

The compounds of formula (I) can be obtained in accordance with Angeles, the invention using the methods described below.

Obtaining compounds of formula (I)

Abbreviations:

In the description and examples of COI is lesuuda the following abbreviations:

AC is acetyl, Asón - acetic acid, AD-mix α - 1,4-bis(dihydroquinoline)phthalazine, K3Fe(JV)6To2CO3and K2OsO42H2O, AD-mix β -1,4-bis(dihydroquinoline)phthalazine, K3Fe(JV)6To2CO3and K2OsO42H2Oh, Side-tert-butoxycarbonyl, Bs - 4-brompheniramine, CBS-benzyloxycarbonyl, QC - column chromatography on silica gel, CBI -1,1-carbonyldiimidazole, DHM - dichloromethane, DIPEA - N,N-diisopropylethylamine, DMAP - 4-dimethylaminopyridine, DMF is N,N-dimethylformamide, DMSO is dimethylsulfoxide, EA - ethyl acetate, ESI is electrospray ionization, EQ. equivalent, ether - diethyl ether, Et is ethyl, EtOH - ethanol, Fmoc - 9-fluorenylmethoxycarbonyl, Gex-hexane, hept-heptane, h for hour(s), KHMDS - hexamethyldisilazide potassium, LC - liquid chromatography, m-HPBK - m-chloroperbenzoic acid, and Me is methyl, MeCN is acetonitrile, Meon - methanol, min - min, Ms - methanesulfonyl (mesyl), MS - mass spectroscopy, n-BuLi is n-utility, Nf - nonattributable, NMO - N oxide N-methylmorpholine, Ns - 3-nitrophenylarsonic, Pd/C is palladium on coal, Pd(OH)2/C - dihydroxy palladium on coal, Ph is phenyl, Rog - pyridine, rat - racemic, CT room temperature, TBAF-tetrabutylammonium, TBDMS - tert-butyldimethylsilyl, TRIPS - tert-butyldiphenylsilyl, TBME - tert-butyl methyl ether, tea-Tr is ethylamine, Tf - trifloromethyl (triflic), TPA - triperoxonane acid, TTF is tetrahydrofuran, and TLC is thin layer chromatography, Ts - p-toluensulfonyl.

General synthetic methods:

General synthetic method 1 (alkylation of amine):

The corresponding amino derivatives enter into reaction with the corresponding derivative containing a group Y1, Y2or Y3where Y1, Y2and Y3each independently from each other represents OMs, OTf, OTs, Cl, Br or I, in the presence of inorganic bases such as2CO3, s3or organic base such as tea in a solvent such as THF, DMF or DMSO, at temperatures from 0°C to +80°C. Details can be found in the publication: Comprehensive Organic Transformations. A guide to Functionnal Groups Preparations; 2ndEdition, R. C. Larock, Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1999. Section Amines, p.779.

General synthetic method 2 (removal aminosidine groups):

Benzylcarbamoyl protective group is removed by hydrogenation over a catalyst of a noble metal (such as Pd/C or Pd(OH)2/C). The BOC-group is removed under acidic conditions such as Hcl in an organic solvent, such as Meon or dioxane, or undiluted or diluted TFA in a solvent such as DHM. In addition, General methods of removal aminosidine groups described publikacii: T.W. Greene, P.G.M. Wuts, Protecting Groups in Organic Synthesis, 3rdEd (1999), 494-653 (Publisher: John Wiley and Sons, Inc., New York, N.Y.).

General synthetic method 3 (removal of the hydroxyl protective groups):

Silyl ester group is removed using either the sources of the fluoride anion, such as TBAF in THF, in a temperature range from 0°C to +40°C, or HF in MeCN in the temperature range from 0°C to +40°C, or by using acidic conditions such as Asón in a mixture of THF/Meon or Hcl in the Meon. Other methods used to remove TRIMS and TRIPS groups represented in T.W. Greene, P.G.M. Wuts, Protecting Groups in Organic Synthesis, 3rdEd (1999), pages 133-139 and 142-143, respectively (Publisher: John Wiley and Sons, Inc., New York, N.Y.). In addition, General methods for the removal of the protective spirit of the groups described in T.W. Greene, P.G.M. Wuts, Protecting Groups in Organic Synthesis, 3rdEd (1999), 23-147 (Publisher: John Wiley and Sons, Inc., New York, N.Y.).

In the special case alkylcarboxylic protective group free alcohol can be obtained under the action of an inorganic base such as2CO3, in a solvent such as Meon.

General synthetic method 4 (activation of alcohol):

Alcohol injected into reaction with BsCI, MsCI, NfCl, NsCl, TfCl or TsCl in the presence of an organic base such as tea, DIPEA or pyridine, in a dry aprotic solvent such as DHL, THF or pyridine, in a temperature range from -10°C to 25°C. Alternatively, the alcohol may be introduced into reaction with Ms2/sub> O or Tf2O. Activated intermediate compound may be further converted into its corresponding iodine - or bromine derivatives by reaction of the activated alcohol with Nal or NaBr in a solvent such as acetone.

General synthetic method 5 (oxidation of alcohols):

Alcohols can be converted into the corresponding aldehydes or ketones by oxidation Svernu (see: D. Swern et al., J. Org. Chem. (1978), 43, 2480-2482) or Dess-Martin (see: D.B. Dess and J.C. Martin, J. Org. Chem. (1983), 48, 4155), respectively.

General synthetic method 6 (CIS-dihydroxypropane):

Diol obtained by dihydroxypropane corresponding ethylene derived using catalytic amounts of osmium tetroxide in the presence of a co-oxidant such as N-MO in aqueous solvent such as a mixture of acetone with water or DHM with water (see: Cha, J. K. Chem. Rev. (1995), 95, 1761-1795). Chiral CIS-diols obtained using AD-mix a or AD-mixture of P in the presence of methanesulfonamide in a mixture of water with 2-methyl-2-propanol as described in Chem. Rev. (1994), 94, 2483. The orientation of the introduction depends on the chiral ligand contained in the AD-mixture: or ligand-based dihydroquinine, AD-mixture a, or ligand-based dihydropyridine, AD-mixture of R.

General synthetic method 7 (protection of alcohols):

Alcohols protect, turning them into complex silyl ethers (Oba is but TBDMS or TRIPS esters). Alcohol injected into the reaction with the required similiarites (TBDMS or TRIPS) in the presence of a base such as imidazole or tea in a solvent such as DHL or DMF, in a temperature range from +10°C to +40°C. Methods, including other alcohol protective group described in the publication: T.W. Greene, P.G.M. Wuts, Protecting Groups in Organic Synthesis, 3rd Ed (1999), 23-147 (Publisher: John Wiley and Sons, Inc., New York, N.Y.).

General synthetic method 8 (hydrogenation of the double bond):

Unsaturated derivatives, dissolved in a solvent such as Meon, EA or THF, hydronaut over a catalyst of a noble metal such as Pd/C or Pd(OH)2/C or Raney Ni. At the end of the reaction the catalyst is filtered off and the filtrate is evaporated under reduced pressure. Alternatively, the recovery is carried out by catalytic exchange hydrogenation using Pd/C and ammonium formate as the hydrogen source.

General preparative methods:

Obtaining compounds of formula (I):

The compounds of formula (I) can be obtained using the methods below, the methods described in the examples, or similar methods. Optimum reaction conditions may vary depending on the specific reagents or solvents, but such conditions may be changed by a specialist in the field of engineering by generally accepted wholesale the optimization methods.

In sections a)to f)below, describes the General methods of preparing compounds of formula (I). In these sections, unless otherwise indicated, the total group or integers m, n, R1, R2A , b, D, U, V, W, G and Q and optional linkhave values according to the formula (I). Other abbreviations used are given in the experimental part. Some common examples of groups U, V, W, R2and G may differ from those illustrated in the examples and in the following schemes, as they require the use of protective grouppretoria protective groups are well known from the art (see, for example, "Protective Groups in Organic Synthesis, by T.W. Greene, P.G.M. Wuts, Wiley-Interscience, 1999).

a) the compounds of formula (I) can be obtained by reaction of compounds of formula (II)

with the compound of the formula (III)

,

where Y1denotes a halogen such as bromine or iodine, or a group OSO2R3where Radenotes alkyl, CF3or tolyl and p is 1 or 2, with the General reaction method 1.

b) Compounds of formula (I) can be obtained by reaction of compounds of formula (IV) with the compound of the formula (V)

where Y2denotes a halogen such as bromine or iodine, or a group OSO2Rawhere Raoboznachaet is alkyl, CF3or tolyl, using General reaction method 1.

(C) Compounds of formula (I), where a denotes CH2and R2IT refers, can be obtained by reaction of compounds of formula (IV)shown above in section b), with the compound of formula (VI)

in the presence of Cs2CO3or NaH in a polar solvent such as DMF, in a temperature range from 60°C to 140°C.

d) the compounds of formula (I), where W denotes N and "----" represents a bond, can be obtained by reaction of compounds of formula (VII)

(VII) with the compound of the formula CHOCOORbwhere Rbdenotes alkyl, or alkylbromides in the presence of a base such as2CO3with subsequent cyclization in acidic environment such as Asón in hot toluene, and aromatization by processing MnO2or H2About2.

(e) Compounds of formula (I)can also be obtained by reaction of compounds of formula (VIII)

with the compound of the formula (IX)

,

where Xarepresents OTf or halogen such as chlorine, bromine or iodine. This reaction is carried out under the conditions described for catalyzed by metals N-arilirovaniya 2-oxazolidinone or amides, in particular, used the eat Cul and 1,1,1-Tris(hydroxymethyl)ethane in the presence of Sz 2CO3(Org. Lett. (2006), 8, 5609-5612), or Pd(OAc)2and DPEphos in the presence of K3RHO4followed, if necessary, removing the protective group PG0according to the General reaction method 2.

f) Compounds of the formula (I), where W represents CH2or NH andno, can be obtained by the reaction of hydrogenation of the corresponding compounds of formula (I), wheremeans a connection, according to the General reaction method 8 or by restoring the corresponding compounds of formula (I) with NaBH4in a solvent such as EtOH.

The compounds of formula (I)thus obtained can, if needed, converted into their salts, preferably their pharmaceutically acceptable salts.

In addition, whenever the compounds of formula (I) are obtained in the form of mixtures of enantiomers, the enantiomers can be separated using methods known to any expert in the field of technology, for example by preparation and separation of the diastereomeric salts or by HPLC on a chiral stationary phase such as a Regis Whelk-01(R,R) (10 μm) column, Daicel ChiralCel OD-H (5-10 μm) column, or Daicel ChiralPak IA (10 μm) or AD-H (5 μm) column. Typical conditions for chiral HPLC include socratous mixture of eluent A (EtOH, in the presence or absence of an amine such as triethylamine,diethylamine) and eluent (hexane), at a speed of expiration from 0.8 to 150 ml/min of Compounds of formula (I)obtained as mixtures of diastereomers can be separated by a combination of chromatography on silica gel, HPLC and crystallization methods.

The formation of compounds of formulas (II)to(IX):

The compounds of formula (II) can be obtained as described in the diagram below, 1.

In scheme 1, Y3denotes a halogen such as bromine or iodine, or a group OSO2Rawhere Radenotes alkyl, CF3or tolyl, and PG1means aminosidine group such as CBZ, Side or Fmoc.

The compounds of formula (I-1), where a represents CH; or a bond and R2denotes H, or, provided that a represents CH2, R2can also refer to IT, is introduced into reaction with compounds of the formula (IV) (overall reaction method 1). Aminosidine group in the intermediate compound (1-2) can then be removed (total reaction method 2) to obtain the compounds of formula (II). Compounds of the formulas (1-2) and (II), whereno, can be obtained by hydrogenation of compounds of the formulas (1-2) and (II), wheredenotes a bond, or by restoring them using NaBH4in a solvent such as tO.

The compounds of formula (III) can be obtained as described in the above is Oh scheme 2 below.

Scheme 2

In scheme 2, PG2is an alcohol protective group such as C(O)Rbwhere Rbdenotes alkyl, or TBDMS or TRIPS.

The compounds of formula (III) can be obtained from the corresponding alcohols of formula (11-2) after activation of the alcohol function (General reaction method 4). Alcohols of formula (11-2) can be obtained by reaction of epoxides of the formula (11-1) with the anions of the carbamates of the formula GNHCOOR, where R represents alkyl or benzyl, in the presence of a base such as CNDS or tert-butyl lithium, followed by removal of the protective alcohol group (General reaction method 3). Alternatively, the epoxides of the formula (11-1) is injected into the reaction with amines of the formula GNHs in the presence of LiClO4formed aminopyrene derivative is administered in response to the OED, remove the protective spirit group, using General reaction method 3 and receiving the intermediate compounds of formula (II-2).

The compounds of formula (IV), wheredenotes a bond, or are commercial products, (U=V=W=CH; R1=MeO or F) or can be obtained according to known methods (for example, U=N,V=N, W=CH; U=CH, V=N, W=CH; U=N, V=CN, W=N; U=N, V=CN, W=CH; U=CH, V=CN, W=N and R1=OMe; see WO 2008/009700, WO 2006/134378 and J. Heterocycl. Chem. (1986), 23(2), 501-504). The compounds of formula (IV), where U=V=W=SN no, can be obtained according to WO 2006/134378 or similar to the description in WO 2006/090272.

The compounds of formula (V) can be obtained as described in the diagram below, 3.

Scheme 3

In figure 3, PG represents a protective alcohol group such as TBDMS or TRIPS.

The compounds of formula (III-1) can react with compounds of the formula (III) (overall reaction method 1). Protective alcohol group in the intermediate compounds of formula (III-2) can be removed (total reaction method 3). Received an alcohol derivative of the formula (III-3) can be transformed into their corresponding activated intermediate compounds of formula (V) (overall reaction method 4).

The compounds of formula (VI) can be obtained as described in the diagram below 4.

Scheme 4

The alcohols of the formula (IV-1) (i.e. the compounds of formula (III-3) scheme 3, where a denotes a bond) can be oxidized to the corresponding ketone analogues of the formula (IV-2) (General reaction technique 5). These ketones can then be converted into the corresponding epoxy derivative of the formula (VI) or a direct epoxydecane using iodide trimethylsilane, or by sequentially conducted Wittig reaction with methyltriphenylphosphonium with subsequent epoxydecane about eutocic compounds of the formula (IV-3) with m-CHPBK.

The compounds of formula (VII) can be obtained as described in the diagram below, 5.

Scheme 5

In scheme 5, X represents a halogen such as bromine or chlorine. Nitro-derivatives of the formula (V-1) can react with the intermediate compounds of formula (V-2). The obtained intermediate compound of formula (V-3) can then be restored in the corresponding amino derivatives of formula (VII) by hydrogenation over a catalyst of a noble metal such as Pd/C or Raney Nickel. Other methods of recovery of nitro compounds described in Comprehensive Organic Transformations. A guide to Functional Group Preparations; 2ndEdition, R. C. Larock, Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, (1999). Section Amines; p.821.

The compounds of formula (VIII) can be obtained as described in the diagram below, 6.

Scheme 6

In scheme 6, p represents 1 or 2.

Accordingly, the intermediate compounds of formula (II) can react with the allyl - or homoallylamines according to the General reaction method 1. Intermediate compounds of formula (VI-1) can be consistently dihydroxypropane according to the General reaction method 6, activated by turning in monomethylated according to the General reaction method 4 and sallisbury in the presence of a base such as2WITH 3, in a solvent such as Meon or tea. The resulting epoxides of the formula (VI-2) can be introduced into the reaction with sodium azide followed by hydrogenation over a catalyst of a noble metal such as Pd/C, or by reaction with RRS in the presence of water. The obtained intermediate amines by reaction with benzyl or alkylchlorosilanes can be converted into the corresponding carbamates, after processing them using NaH can be obtained oxazolidinone formula (VIII).

Some compounds of formula (IX) are commercially available (for example, joints, where G=G2, Q=O and Z Is N: CAS 337463-99-7; G=G2Q=S and Z=CH: CAS 6376-70-1; G=G2, Q=O and Z=CH: CAS 7652-29-1).

The compound of formula (IX), where G denotes G, Z represents N, Q denotes S and Xadenotes CL, can be obtained as shown below in scheme 7.

Scheme 7

Accordingly, the bromo derivatives of formula (VII-1)obtained according to WO 2008/065198, may be introduced into reaction with bromoacetylation, then the obtained derivative of the formula (VII-2) is injected into the reaction thioacetate sodium in the presence of NaOMe, thus obtaining the compound of formula (IX), where G denotes G2, Z represents N, Q denotes S and Xadenotes CL.

The compounds of formula (IX), where G denotes G, X represents CH and Q represents O or S and Y4indicates OTf, and compounds, where G appears the t G 1each of the Z1, Z2and Z3represents CH and Y4denotes the OTf can be obtained from the corresponding alcohol of the parent compounds (Xa=HE) and Tf2O according to the General reaction method 4. The last of the compounds are commercial products (CAS 53412-38-7; CAS 10288-72-9) or can be obtained as described in EP 106 816.

Getting some intermediate compounds:

The compounds of formula (1-1) can be obtained as shown below in scheme 8.

Scheme 8

The compounds of formula (1-1) can be obtained from the corresponding alcohols of formula (VIII-1) or (VIII-4) using General reaction method 4 (see scheme 8). The original alcohols of the formula (VIII-1) is commercially available. The original alcohols of the formula (VIII-4) can be obtained from alcohols of formula (VIII-1) as a result of oxidation (General reaction technique 5), Wittig reaction with methyltriphenylphosphonium followed by CIS-dihydroxypropane (General reaction method 6).

The compounds of formula (II-1), where p is 1 and PG2denotes C(O)Rb, Rbthis denotes alkyl, commercially available. The compound of the formula (11-1), where p is 2 and PG2means TBDMS, can be obtained according to WO 2007/144423 or EP 518672.

The compounds of formula (III-1) can be obtained by protection of the alcohol function of the joint is of the formula (VIII-1) (overall reaction method 7) and remove aminosidine group (General reaction method 2).

The compounds of formula (IV-1) correspond to compounds of the formula (III-3), where a denotes the connection.

The compounds of formula (V-1), where Xbdenotes bromine, R1denotes a methoxy group or a fluorine and U denotes N or CH, are commercially available.

The compounds of formula (V-2) can be obtained from compounds of formula (V), where Y2denotes a halogen such as iodine, or OSO2Rawhere Radenotes alkyl, CF3or tolyl, by reaction with NaN3with subsequent restoration using h3in the presence of water.

Particular embodiments of the invention are described in the following examples, which serve to further illustrate the invention, and in no way limiting its scope.

Examples

All temperatures are given in °C. Compounds are characterized by means of1H-NMR (300 MHz) (Varian Oxford); or1H-NMR (400 MHz) (Bruker Advance 400); chemical shifts are given in memorial plaques relative to the solvent used; the multiplets: s=singlet, d=doublet, t=triplet, q=quadruplet, p=pentablet, Gex=sextet, hept=septet, m=multiplet, br=advanced, constant interaction are given in Hz. Alternative compounds were characterized using LC-MS (Sciex API 2000 with Agilent 1100 Binary Pump with DAD and ELSD or Agilent quadrupole MS 6140 with Agilent 1200 Binary Pump, DAD and ELSD); by TLC (TLC-plates from Merck, silica gel 60 F2542OH, to be used for column chromatography, represents a 25%aqueous solution.

HPLC is performed on a stationary phase such as a column quick resolution Bond SB 18 (1,8 µm)or column rapid resolution Eclipse Bond Plus 18 (1,8 µm). Typical conditions for HPLC include a gradient of eluent A (water/acetonitrile in the ratio of 95:5 with 0.1% formic acid, with or without 5 mmol/l ammonium formate) and eluent B (acetonitrile/water in a ratio of 95:5 with 0.1% formic acid, with or without 5 mmol/l ammonium formate), with a flow rate of 0.8 to 5 ml/min Racemate can be separated into the enantiomers as described previously. Preferred conditions for chiral HPLC following: column ChiralPak AD (4.6 x 250 mm, 5 μm), using isocrates mixture (for example, in the ratio 10:90) as eluent A (EtOH, in the presence of diethylamine in number, for example, 0.1%) and eluent B (hexane)at room temperature, with the flow rate, for example, 0.8 ml/min

General methods:

Method a (removal of the BOC-protective group):

The BOC-protected amine (1 mmol) is dissolved in DHM (5 ml) and treated with Et3SiH (optional; 0.2 ml, 1.1 EQ.) and TFA (2 ml). The mixture is stirred at room temperature for 1 h, conc is between vacuum and transferred into the mixture DHM/aqueous solution of NH 4OH. The organic layer is washed with water, dried over MgSO4and concentrate under reduced pressure.

Method b: alkylation of amines iodides:

A solution of amine (1 mmol), iodide (1 mmol) and DIPEA (1.1 mmol) in dry DMSO is heated to a temperature of 70°C. until the reaction is completed (1-3 days). After cooling, add water and ethyl acetate and the phases razdevayutsya layer is more than two times extracted with ethyl acetate, the combined organic layers washed with water (three times) and brine, dried over MgSO4and concentrate under reduced pressure, then the residue purified by column chromatography.

Method: alkylation of amines by mesylates

A solution of amine (1.0 to 2.3 mmol), nelfinavir (1 mmol) and DIPEA (1.1 mmol) in dry DMSO is heated to a temperature of 70°C. until the reaction is completed (2-5 days). After cooling, add water and ethyl acetate and the phases razdevayutsya layer is more than two times extracted with ethyl acetate, the combined organic layers washed with water (three times) and brine, dried over MgSO4and concentrate under reduced pressure, then the residue purified by column chromatography.

Experiment A: 6-((5')-5-Iodomethyl-2-oxoacridine-3-yl)-4H-benzo[1.4]thiazin-3-one

A.i. 6-((8)-3-Chloro-2-hydroxypropylamino)-4H-benzo[L thiazin-3-one

A suspension of 6-amino-4H-benzo[14]thiazin-3-one (18.0 g, 100 mmol; commercial product) and Ca(OTf)2(0.5 EQ.) in MeCN (800 ml) is heated at 50° for 1 hour Then add (5')-epichlorohydrin (18.5 g, 200 mmol) and the reaction mixture was stirred at room temperature for 72 h and at 45°C for 24 h Volatile fractions are removed under reduced pressure. After treatment with water and extraction with ethyl acetate named in the title intermediate compound is crystallized from ethyl acetate, receiving a beige solid (17,38 g, 64%yield).

MS (ESI, m/z): 273,2 [M+H+].

A.ii. 6-((8)-5-Chloromethyl-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one

A solution of intermediate compound (A.i) (39,3 g, 144 mmol) and CBI (28,0 g, 1.2 EQ.) in THF (1 l) is heated at a temperature of 50°C during the night. The reaction mixture was then concentrated under reduced pressure and distributed between ethyl acetate and water. The aqueous layer was extracted several times with ethyl acetate, the combined organic layers dried over MgSO4and koncentriruiutsia purified by column chromatography (EA/heptane 2:1, EA), getting named in the title intermediate compound in the form of a beige solid (34,2 g, 79%yield).

MS (ESI, m/z): 299,1 [M+H+].

A.iii. 6-((8')-5-Iodomethyl-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one

A mixture of intermediate compound (A.ii) (14.0 g, 46,mmole) and Nal (3 EQ.) in 2-butanone (150 ml) is heated at 85°C for 2 days. After cooling to room temperature the reaction mixture was diluted with 10%aqueous solution of Na2S2O3(300 ml) and the mixture ether/EA (150 ml), vigorously stirred for 10 min and filtrational the residue is washed with water and ether and dried in high vacuum, obtaining a pale beige solid. The phase of the combined filtrates share, after which the organic phase is washed with brine, dried over MgSO4and concentrate, receiving a pale beige solid. Solids of both processes combine, getting named the title compound as a pale beige solid (15.0 g, 82%yield).

MS (ESI, m/z): 391,4 [M+H+].

Experiment: (S)-3-(2.3-Dihydrobenzo[1,4]dioxin-6-yl)-5-iododeoxyuridine-2-he

B.i. (S)-3-(2.3-Dihydrobenzo[1,4]dioxin-6-yl)-5-hydroxymethylimidazole-2-he

To a solution of benzyl ether (2,3-dihydrobenzo[1,4]dioxin-6-yl)carbamino acid (13,0 g, 45.6 mmol) in THF (220 ml), cooled down to -78°C., added dropwise n-BuLi (29.5 ml 2,36-molar solution in hexane, 1.1 EQ.). The reaction mixture was stirred at -78°C for 1 h, heated to a temperature of -15°C and at this temperature is added dropwise (S)-glycidylether (7,37 g, 1.1 equiv.) then stirred at room temperature overnight. Then add Cs2/sub> CO3(with a spatula), the reaction mixture is heated at a temperature of 40°C. to complete the reaction, diluted with ethyl acetate and washed with saturated aqueous NH4Cl and water. The organic layer is dried over MgSO4and koncentriruiutsia purified by column chromatography (hexane/EA in the ratio 2:1, then 1:1), obtaining mentioned in the title intermediate compound as a gray solid (? 7.04 baby mortality g, 62%yield).

1H NMR (DMSO-d6) δ: 7,13 (d, J=2.5 Hz, 1H), of 6.96 (dd, J=2,5, and 8.9 Hz, 1H), 6,86 (d, J - a 8.9 Hz, 1H), 5,16 (t. J=5.8 Hz, 1H), 4,70-4,50 (m, 1H), 4,30-4,10 (m, 4H), 4,10-3,90 (m, 1H), 4.80 to 4,70 (m, 1H), 4,70-4,60 (m, 1H), 4,60-4,50 (m, 1H).

(II. (8)-3-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ymetray ether methanesulfonate acid

A solution of intermediate compound (B.i) (7.0 g, 27.9 mmol) in DHM (140 ml) cooled to 0°C, add DIPEA (5,70 ml, 1.2 EQ.) and MsCI (2,40 ml, 1.1 equiv.) then the reaction mixture was stirred for 1 h at this temperature. Then the reaction mixture was diluted with DHM and washed with water. The organic phase is dried over MgSO4and concentrate, getting named in the title intermediate compound as a colourless solid (9.0 g, 98%yield).

MS (ESI, m/z): 330,3 [M+H+].

B.iii. (S)-3-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-5-iododeoxyuridine-2-he

The mixture promezhutochnogo the connection ((II) (9.0 g, 27.3 mmol) and Nal (16.4 g, 4 EQ.) in acetone (150 ml) is heated under reflux for 20 hours the Solvent is evaporated and the residue extracted with a mixture of water with DHM, the Organic layer washed with brine, dried over MgSO4and concentrate under reduced pressure. The residue is triturated with a mixture of ether/EA, getting named the title compound as off-white solids (6,91 g, 70%yield).

1H NMR (CDCl3) δ: 7.07 (d, J=2,6 Hz. 1H), 6,98 (dd, J=9,1, 2.6 Hz, 1H), 6,85 (d, J=8,9 Hz, 1H), and 4.68 (m, 1H), 4,24 (s, 4H), 4,10 (t, J=9.1 Hz, 1H), and 3.72 (dd, J=9,1, 5,9 Hz, 1H), 3.46 in (m, 1H), 3.33 and (m, 1H).

MC (ESI, m/z): 362,2 [M+H+].

Experiment: 6-[(7?)-5-(2-Jodeci)-2-oxoacridine-3-yl-4D-benzo[1,4]thiazin-3-one

C.i. (2R)-tert-Butultimately-(2-oxiranylmethyl)silane and (2S)-4-(tert-butyldimethylsilyloxy)butane-1,2-diol

Named in the title intermediate compound obtained analogto method described Kishi et al., Org. Lett. (2005), 7, 3997, (the intermediate connection S2-3) via hydrolytic kinetic decomposition of (RS)-tert-butultimately-(2-oxiranylmethyl)silane (obtained according to J. Org. Chem. (2008), 73, 1093). Two compounds were isolated using column chromatography (heptane/EA in the ratio 2:1).

First aliremove connection: (2R)-tert-butultimately-(2-oxiranylmethyl)silane (colorless oil; 25,3 g, 48%yield).

1H NMR (l3) δ: of 3.77 (t, J=6.4 Hz, 2H), 3.04 from(m, 1H), 2,78 (m, 1H), of 2.51 (dd, J=5.0 and 2.9 Hz, 1H), 1,74 (m, 2H), 0,90 (d, J=0.6 Hz, 9H), is 0.06 (s, 6H).

Second aliremove connection: (2S)-4-(tert-butyldimethylsilyloxy)butane-1,2-diol (colorless oil; 24,9 g, 43%yield).

1H NMR (CDCl3) δ: the 3.89 (m, 3H), 3,62 (s, 1H), 3,53 (m, 1H), 3,42 (advanced, s, 1H), to 2.29 (m, 1H), 1,70 (m, 2H), of 0.90 (s, 9H), and 0.09 (s, 6H).

C.ii. 6-[(R)-4-('t-Butyldimethylsilyloxy)-2-hydroxyethylamino]-4H-benzo[1,4]thiazin-3-one

A solution of 6-amino-4H-benzo[1,4]thiazin-3-it is 10.68 g, 59.3 mmol; commercial product) and (2R)-tert-butultimately-(2-oxiranylmethyl)silane (first aliremove connection stage C.i, 12.0 g, 59.3 mmol) in a mixture tO/N2About (in the ratio of 9:1, 320 ml) is heated at a temperature of 80°C for 2 days, after which the mixture is concentrated under reduced pressure. The residual of the original aniline can be removed using a mixture Et2O/MeOH, followed by filtration. The filtrate containing the product are concentrated under reduced pressure, obtaining mentioned in the title intermediate compound as a brown oil (18,8 g, 83%yield), which is used in the next stage without purification.

MS (ESI. m/z): 383,2 [M+H+].

C.iii. 6-{(R)-5-[2-(tert-Butyldimethylsilyloxy)ethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one

A solution of intermediate compound (C.ii) (23,5 g, 49.1 mmol) and CBI (to 9.57 g, 1.2 EQ.) in THF (250 ml) is heated at a temperature of 50°C during the night, the media and the mixture concentrated under reduced pressure and distributed between ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate, and the combined organic layers dried over MgSO4and koncentriruiutsia purified by column chromatography (DHM/Meon/NH4HE in a ratio of 1000:50:4), getting named in the title intermediate compound as a colourless solid (8,4 g, 42%yield).

MS (ESI, m/z): 409.3 [M+H+].

C.iv. 6-[(R)-5-(2-Hydroxyethyl)-2-oxoacridine-3-yl]-4H-benzo[1.4]thiazin-3-one

A solution of intermediate compound (C.iii) (8,4 g, 20.6 mmol) in THF (50 ml) is treated with tetrabutylammonium (1-molar solution in THF, to 24.7 ml, 1.2 EQ.) at a temperature of 0°C, and the solution was stirred at the same temperature for 6 hours Then the reaction mixture was partitioned between water and ethyl acetate and the aqueous phase extracted with ethyl acetate (three times). The combined organic layers washed with water and brine, dried over MgSO4and koncentriruiutsia triturated with a mixture of Et2About/EA, getting named in the title intermediate compound as off-white solids (4,79 g, 79%yield).

MS (ESI, m/z): 295,5 [M+H+].

.v. 2-[(R)-2-Oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-yl]ethyl ester methanesulfonic acid

A solution of intermediate compound (C.iv) (4.7 g, 16.0 mmol) and DIPEA (7,54 ml, 2.9 EQ.) in anhydrous DHM (80 ml) and ohlord the Ute to a temperature of 0°C and added dropwise MsCl (1.50 ml, 1.2 EQ.). The resulting mixture is stirred at 0°C for 1 h, after which water is added and DHM and the phases are separated. The organic layer is dried over MgSO4and concentrate under reduced pressure. The residue is purified by column chromatography (DHM/Meon/NH4HE in a ratio of 1000:50:4), getting named in the title intermediate compound as off-white solids (5,80 g, 98%yield).

MS (ESI, m/z): 373,4 [M+H+].

C.vi. 6-[(R)-5-(2-Jodeci)-2-oxoacridine-3-yl]-4H-benzo[1,4]thiazin-3-one

A suspension of intermediate compounds (C.v) (3.5 g, 9.4 mmol) and Nal (to 4.23 g, 3 EQ.) in 2-butanone (35 ml) is heated at a temperature of 85°C during the night. After cooling, the reaction mixture is diluted with a mixture of ether/EA (20 ml) and treated with 10%aqueous solution of Na2S2O3(60 ml). After stirring for 10 minutes the phases are separated, and the aqueous layer washed with ethyl acetate. The combined organic layers washed with water (twice), dried over MgSO4and concentrate under reduced pressure. The residue is triturated with a mixture of Et2About/EA, getting named the title compound as off-white solids (3,52 g, 93%yield).

MS (ESI, m/z): 405,0 [M+H+].

Experiment D: (S)-3-(3-Fluoro-4-were)-5-iododeoxyuridine-2-he

D.i (S)-3-(3-Fluoro-4-were)-5-hydroxymethylimidazole the-2-he

A mixture of 3-fluoro-4-methylaniline (commercial product; a 1.25 g, 10 mmol), a saturated aqueous solution of Mancos (10 ml) and acetone (10 ml) is treated by adding dropwise benzylchloride (1.70 g, of 1.41 ml, 1 EQ.). After the termination of allocation of CO2the reaction mixture is distributed between ethyl acetate and saturated aqueous Panso3, the organic layer is dried over MgSO4and concentrate under reduced pressure. The resulting benzylcarbamoyl dissolved in THF (50 ml), cooled in a stream of argon at -78°C, after which the pin n-BuLi (2,5-molar solution in a mixture of hexanol, 6,45 ml, 1.1 EQ.) and the resulting solution was stirred for 1 h at the same temperature. The reaction mixture is left then spontaneously heat up to a temperature of -15°C, which is added dropwise (5)-glycidylether (1,69 ml, 1.1 EQ.). The mixture is stirred at room temperature overnight, added with a spatula Cs2CO3, stirred at room temperature for 3 h, and then add the NH4Cl and ethyl acetate and the phases razdevayutsya phase is extracted again with ethyl acetate, the combined organic extracts are washed several times with an aqueous solution of NH4Cl, then brine, dried over Na2SO4and kontsentrirovannoe orange solid is triturated with ethyl acetate, produces is named in the title intermediate compound as a pale yellow solid (1.18 g, 53%yield).

MS (ESI, m/z): 226,3 [M+H+].

D.ii. (S)-3-(3-Fluoro-4-were')-2-oxoacridine-5-ymetray ether methanesulfonate acid

A solution of intermediate compound (D.i) (4,70 g, 20.9 mmol) in DHM (200 ml) cooled to 0°C, add DIPEA (9,9 ml, 2.9 EQ.) and MsCl (2.0 ml, 1.2 EQ.), then the reaction mixture was stirred for 1 h at 0°C, then diluted DHM and washed with water. The organic phase is dried over MgSO4and koncentriruiutsia triturated with ether, getting named in the title intermediate compound as a yellow solid (6,37 g, 100%yield).

1H NMR (Dl3) δ: of 7.36 (dd, J=11,7, 2.3 Hz, 1H). 7,13 (m, 2H), 4,91 (m, 1H), 4,46 (m, 2H), 4,13 (t, J=9.1 Hz, 1H), 3,92 (dd, J=9,1, 6.2 Hz, 1H), 3,10 (s, 3H), of 2.25 (d,J=1.8 Hz, 3H).

MS (ESI, m/z): 330,3 [M+H+].

D.iii. (S)-3-(3-Fluoro-4-were)-5-iododeoxyuridine-2-he

A mixture of intermediate compound (D.ii) (6,30 g, 20.8 mmol) and Nal (12.5 g, 4 EQ.) in acetone (100 ml) is heated under reflux for 3 hours the Solvent is evaporated and the residue extracted with a mixture of water/DHM. The organic layer was washed with brine, dried over MgSO4and concentrate under reduced pressure. The residue is triturated with a mixture of ether/EA, getting named the title compound as a pinkish solid (6.3 g, 91%yield).

MS (ESI, m/z): 335,8 [M+H+].

In this experiment the UNT E: (5)-2-Oxo-3-(3-oxo-3.4-dihydro-2H-benzo[1.4]oxazin-6-yl)oxazolidin-5-ymetray ether methanesulfonate acid

E.i. 6-[(S)-3-(tert-Butyldimethylsilyloxy)-2-hydroxypropylamino]-4H-benzo[1.4]oxazin-3-one

To a solution of tert-butultimately-((S)-1-oxiranylmethyl)silane (commercial product; 4,25 g, 22.6 mmol) in MeCN (70 ml) is added LiClO4(7.20 g, 3 EQ.), and then 6-amino-4H-benzo[1,4]oxazin-3-one (commercial product; 3,70 g, 1 EQ.), then the reaction mixture was stirred at 50°C for 6 hours Then the solvent is removed under reduced pressure and the residue purified by column chromatography (DHM/Meon/NH4HE is in the ratio 1000/25/2), getting named in the title intermediate compound as a pale brown foam (5,25 g, 66%yield).

MS (ESI, m/z): 353,3 [M+H+].

E.ii. 6-[(S)-5-(tert-Butyldimethylsilyloxy)-2-oxoacridine-3-yl]-4H-benzo[1,arszyn-3-one

A solution of intermediate compound (E.i) (10,24 g, 29 mmol) and CBI (9,71 g, 2 EQ.) in THF (140 ml) is heated at 50°C for 2 h; then the reaction mixture was concentrated under reduced pressure and distributed between ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4, concentrated and triturated with Et2O, getting named in the title intermediate compound as a pale yellow solid (6,30 g, 57%yield).

MS (ESI, m/z): to 379.2 [M+H+].

E.iii. 6-((S)-5-Hydroxymethyl-2-oksaoksa ridin-3-yl)-4H-benzo[1,4]oxazin-3-one

A suspension of intermediate compounds (E.ii) (6,30 g, 16.6 mmol) in THF (15 ml) is treated TBAF (1-molar solution in THF, 16.6 ml) at 0°C, and the solution was stirred at the same temperature for 3 h, and then partitioned between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate (three times). The combined organic layers washed with brine, dried over MgSO4and koncentriruiutsia triturated with ethyl acetate, getting named in the title intermediate compound as a colourless solid (3,49 g, 79%yield).

MS (ESI, m/z): 265,5 [M+H+].

E.iv. (S)-2-oxo-3-(3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)oxazolidin-5-ymetray ether methanesulfonate acid

A suspension of intermediate compounds (E.iii) (4,93 g, 18.7 mmol) in anhydrous DHM (110 ml) is treated with DIPEA (12.0 ml of 3.75 EQ.), then the reaction mixture is cooled to a temperature of 0°C and portions added thereto Ms2O (4,88 g, 1.5 EQ.). The resulting mixture is stirred at 0°C for 15 min, then water is added and stirring is continued for 15 min at room temperature. Precipitated precipitated product is filtered, washed with water and DHM. The obtained solid is triturated with a mixture DHM/Meon/NH4HE (in a ratio of 1000:25:2), getting named the title compound as a colourless firmly what about the matter (there are 3,785 g, 60%yield).

1H NMR (DMSO-d6) δ: of 10.72 (s, 1H), 7,29 (dd, J=2,1, 0.6 Hz, 1H), 6,94 (m, 2H), 4.95 points (m, 1H), to 4.52 (s, 2H), 4,49 (m, 2H), 4,11 (t, J=9.1 Hz, 1H), to 3.73 (m, 2H), 3,23 (s, 3H).

MS (ESI, m/z): 343,3 [M+H+].

Experiment F: 6-((R)-5-Iodomethyl-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one

F.i. 6-((R)-3-Chloro-2-hydroxypropylamino)-4H-benzo[1,4]thiazin-3-oneA solution of 6-amino-4H-benzo[1,4]thiazin-3-one (18,39 g, 102 mmole;

a commercial product) and (R)-epichlorohydrin (8.0 ml, 1 EQ.) in a mixture tO/N2About in the ratio of 9:1 (450 ml) is heated at a temperature of 80°C during the night. The mixture was then concentrated under reduced pressure. The residual of the original aniline is removed by addition of a mixture of E2About/EA, followed by filtration. The filtrate containing the product are concentrated under reduced pressure, obtaining mentioned in the title intermediate compound in the form of a beige solid (22,52 g, 81%yield), which is used in the next stage without purification.

MS (ESI, m/z): 273,2 [M+H+].

F.ii. 6-((R)-5-Chloromethyl-2-oxoacridine-3-yl)-4H-benzo[1.4]thiazin-3-one

A solution of intermediate compound (F.i) (22,0 g, 81.0 mmol) and CBI (15.7 g, 1.2 EQ.) in THF (500 ml) is heated at a temperature of 50°C during the night. The reaction mixture was then concentrated under reduced pressure and partitioned between DHM and water. The aqueous layer was extracted again DHM, the combined organic layers washed with a 0.5-m is a regular solution model HC1 (twice) and water, dried over MgSO4and koncentriruiutsia triturated with a mixture DHM/Meon, getting named in the title intermediate compound as a yellow solid (8,79 g, 36%yield). MS (ESI, m/z): 299,1 [M+H+].

F.iii. 6-((R)-5-Iodomethyl-2-oxoacridine-3-yl)-4H-benzo[1.4]thiazin-3-one

A mixture of intermediate compound (F.ii) (8,75 g, 29 mmol) and Nal (13,17 g, 3 EQ.) in 2-butanone (75 ml) is heated at 85°C for 4 days. After cooling to room temperature the reaction mixture was diluted with 10%aqueous solution of Na2S2O3(150 ml) and the mixture ether/EA (75 ml). The mixture is then vigorously stirred for 10 min and filtered. The solid residue washed with water and ether and dried in high vacuum, receiving off-white solid (9,27 g, 81%yield).

1H NMR (DMSO-d6) δ: 10,56 (s, 1H), 7,31 (m, 2H), 7,12 (dd, J for 8.5, 2.3 Hz, 1H), 4,71 (m, 1H), 4,14 (t, J=9.1 Hz, 1H)and 3.59 (m, MN), and 3.31 (s, 2H).

MS (ESI, m/z): 390,9 [M+H+].

Experiment G: 6-[(8')-5-(2-Jodeci)-2-oxoacridine-3-yl]-4H-benzo[1,4]thiazin-3-one

Station. (S)-4-(tert-Butyldimethylsilyloxy)-2-hydroxybutanoic ester toluene-4-sulfonic acid

To a solution of (2S)-4-(tert-butyldimethylsilyloxy)butane-1,2-diol (23.9 g, 108 mmol; second aliremove connection in the experiment, the stage C.i), DMAP (2.65 g, 0.2 EQ.) in DHM (80 ml), cooled to 0°C, add the tea (43,8 ml, 2.9 EQ.) the solution of TsCl (20.7 g, 1.1 EQ.) in DHM (15 ml). Then the reaction MES stirred at room temperature for 5 h, transferred into a saturated aqueous NaHCOs solution and extracted with DHM. The organic layer is dried over MgSO4and concentrate. The residue is purified by column chromatography (heptane/EA in the ratio 2:1), obtaining mentioned in the title intermediate compound as a colourless oil (31,3 g, 77%yield).

1H NMR (CDCl3) δ: 7,80 (d, J=7,6 Hz, 2H), 7,34 (d, J=7,6 Hz, 2H), was 4.02 (m, ZN), of 3.80 (m, 2H), 2,45 (s, MN), to 1.70 (m, 2H), 1.27mm (m, 1H), 0,87 (s, 9H), of 0.05 (s, 6H).

G.ii. (2S)-tert-Butultimately-(2-oxiranylmethyl')silane

To a solution of intermediate compound (Station) (31.1 g, 83.1 mmol) in THF (350 ml) is added 2-molar solution of NaOH (35 ml)and the reaction mixture is vigorously stirred at room temperature for 3 h, then transferred into a 1-molar solution of NaOH (200 ml) and extracted with TBME (twice). The combined organic layers washed with water and brine, dried over MgSO4and kontsentrirueshsya oil is purified by distillation through a nozzle Kugele (about 70°C at pressures of 0.1 mbar), getting named in the title intermediate compound as a colourless oil (14,7 g, 87%yield).

1H NMR (CDCl3) δ: of 3.77 (t, J=6.4 Hz, 2H), 3.04 from (m, 1H), 2,78 (m, 1H), of 2.51 (dd, J=5,0. 2,9 Hz, 1H), 1,74 (m, 2H), 0,90 (d, J=0.6 Hz, 9H), is 0.06 (s, 6H).

G.iii. 6-[(8)-4-(tert-Butyldimethylsilyloxy)-2-g is proximately]-4H-benzo[1,4]thiazin-3-one

A solution of 6-amino-4H-benzo[1,4]thiazin-3-OHa (8.0 g, 44.5 mmol;

a commercial product) and intermediate (G.ii) (9.0 g, 1 EQ.) in a mixture of EtOH/H2O in the ratio of 9:1 (250 ml) is heated at a temperature of 80°C for 2 days, after which the reaction mixture is concentrated under reduced pressure. The residual of the original aniline is removed by addition of a mixture of Et2O/Meon, followed by filtration. The filtrate containing the product are concentrated under reduced pressure, obtaining mentioned in the title intermediate compound as a brown oil (14,58 g, 86%yield), which is used in the next stage without purification.

MS (ESI, m/z): 383,2 [M+H+].

G.iv. 6-{(8)-5-[2-(tert-Butyldimethylsilyloxy)etyl-2-oxoacridine-3-yl}-4H-benzo[1.4]thiazin-3-one

A solution of intermediate compound (G.iii) (14.5 g, 37.9 mmol) and CBI (at 8.60 g, 1.4 EQ.) in THF (180 ml) is heated at 50°C overnight, after which the reaction mixture is concentrated under reduced pressure and distributed between ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate, the combined organic layers dried over MgSO4and koncentriruiutsia purified by column chromatography (DHM/Meon/MERCON in the ratio of 1000:50:4), getting named in the title intermediate compound as a colourless solid (5,56 g, 36%yield.

MS (ESI, m/z): 409.3 [M+H+].

G.v. 6-[(8)-5-(2-Hydroxyethyl)-2-oxoacridine-3-yl]-4H-benzo[1,4]thiazin-3-one

A solution of intermediate compound (G.iv) (5.50 g, 13.6 mmol) in THF (30 ml) is treated TBAF (1-molar solution in THF, and 16.3 ml, 1.2 EQ.) at 0°C. Then the solution was stirred at the same temperature for 6 h, after which the reaction mixture is distributed between water and ethyl acetate and the aqueous phase extracted with ethyl acetate (three times). The combined organic layers washed with water (three times) and brine, dried over MgSO4and koncentriruiutsia triturated with a mixture of Et2O/EA, getting named in the title intermediate compound as off-white solids (is 3.08 g, 77%yield).

MS (ESI, m/z): 295,5 [M+H+].

G.vi. 2-[(8')-2-Oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1.4]thiazin-6-yl)oxazolidin-5-yl]ethyl ester methanesulfonic acid

A solution of intermediate compound (G.v) (3.0 g, 10.2 mmol) and DIPEA (4.8 ml, 2.9 EQ.) in anhydrous DHM (50 ml) cooled to 0°C and treated, adding dropwise, MsCl (of 0.96 ml, 1.2 EQ.). The resulting reaction mixture is stirred at 0°C for 1 h, add water and DHM and phase razdelautoraznoe.biz layer is dried over MgSO4and concentrate under reduced pressure. The residue is triturated with ether, getting called in the header premiato the Noah compound as off-white solids (of 3.64 g, 96%yield).

MS (ESI, m/z): 373,4 [M+H+].

G.vii. 6-[(8)-5-(2-Jodeci)-2-oxoacridine-3-yl]-4H-benzo[1.4]thiazin-3-one

A suspension of intermediate compounds (G.vi) (2.5 g, 6.7 mmol) and Nal (3,02 g, 3 EQ.) in 2-butanone (25 ml) is heated at a temperature of 85°C during the night. After cooling, the reaction mixture is diluted with a mixture of ether/EA (20 ml) and treated with 10%aqueous solution Massses (60 ml). After stirring for 10 minutes the phases are separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers washed with water (twice), dried over MgSO4and concentrate under reduced pressure. The residue is triturated with a mixture of EtaO/DA, getting named in the title intermediate compound as a pale orange solid (2,11 g, 78%yield).

1H NMR (DMSO-d6) δ: 10,55 (s, 1H), 7,30 (m, 2H),? 7.04 baby mortality (dd, J=8,5, 2.3 Hz, 1H), and 4.68 (m, 1H), 4,10 (t, J=8,8 Hz, 1H), 3,70 (dd, J=8,8, 6,7 Hz, 1H), 3,41 (s, 2H), 3,29 (m, 2H), 2,23 (m, 2H).

MS (ESI, m/z): 405,1 [M+H+].

Example 1: 6-{(R)-5-[3-Hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1L]thiazin-3-one

l.i. mpew-Butyl ester 3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-carboxylic acid

The solution wpew-butyl ether oxa-5-azaspiro[2.3]hexane-5-carboxylic acid (69 mg; obtained according to WO 2007/044515) in DMF (1 ml) are added to a suspension of 7-methoxy-2(1ST)-Hinayana (60 m is; a commercial product) and SZDSZ (223 mg, 2 EQ.) in DMF (2 ml), after which the reaction mixture is stirred at a temperature of 80°C for 10 days. Then the solvent is removed under reduced pressure and the residue partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers are dried over Na2SO4, filtered, evaporated and purified by column chromatography (DHM/Meon in the ratio from 19:1 to 9:1), obtaining mentioned in the title intermediate compound as a yellow oil (12 mg, 10%yield).

MS (ESI, m/z): 361,3 [M+H+].

l.ii. 1-(3-Hydroxyazetidine-3-ylmethyl)-7-methoxy-1H-quinoline-2-he

On the basis of the intermediate compound (l.i) (12 mg) and using the method As mentioned in the title intermediate compound obtained as a yellow oil (8 mg, 92%yield).

1H NMR (DMSO-d6) δ: 7.61 (d, J=9.4 Hz, 1H), 7,39 (m, 2H), for 6.81 (dd, J=8,5, 1.5 Hz, 1H), 6.48 in (d, J=9.4 Hz. 1H)and 4.65 (s, 2H), 3,86 (s, 4H).

l.iii. 6-{(R)-5-[3-Hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one

On the basis of the intermediate compound (l.ii) (8 mg) and the compound of the experiment, and using the method mentioned in the title compound obtained as a colorless solid (4 mg, 22%yield).

1H NMR (CDCl3) δ: 7,86 (s, 1H), 7,71 (d, J=9.4 Hz, 1H), 7,53 (d, J=8.5 Hz, 1H), 7,42 (m, 2H),7,29 (d, J=8.5 Hz, 1H), 6,97 (dd, J=8,8, 2.3 Hz, 1H), 6.89 in (dd, J=8,5, 1.8 Hz, 1H), 6,60 (d, J=9.4 Hz, 1H), of 6.31 (s, 1H)and 4.65 (m, 3H), 4,08 (t, J=8,8 Hz, 1H), a 3.87 (m, 4H), to 3.58 (m, 3H), 3,41 (s, 2H), is 3.08 (m, 2H,), 2,87 (dd, J=5,9, 3.5 Hz, 2H).

MS (ESI, m/z): 522,9 [M+H+].

Example 2: 6-{(R)-5-[3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl')azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1.4]thiazin-3-one

2.i. tert-Butyl ether 3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-carboxylic acid

A suspension of 7-methoxy-2(1H)-Hinayana (405 mg; commercial product) in DMF (10 ml) is treated with NaH (111 mg, 50%dispersion in oil). The mixture is stirred at room temperature for 30 min, then add a solution of tert-butyl ester 3-[[(methylsulphonyl)oxy]methyl]-1-azetidinone acid (674 mg; obtained according to WO 02/066470) in DMF (2 ml). The reaction mixture is heated at a temperature of 100°C during the night, and then distributed between ethyl acetate and water. The organic phase is dried over MgSO4concentrate under reduced pressure and purified by column chromatography (heptane/EA ratio from 2:1 to 0:1). Second aliremove connection is isolated in the form of a colourless foam (350 mg, 44%yield).

1H NMR (l3) δ: to 7.59 (d, J=9.4 Hz, 1H), of 7.48 (d, J=8.5 Hz, 1H), 6,83 (dd, J=8,5, 2.3 Hz, 1H), 6,76 (d, J=2.3 Hz, 1H), of 6.52 (d, J=9.4 Hz, 1H), 4,5 (advanced, 2H), 3,95 (m, 4H), 3,91 (s, 3H), 3.04 from (m, 1H), of 1.42 (s, 9H).

MS (ESI, m/z): 345,2 [M+H+].

2.ii. 3-(7-Methoxy-2-OK what about-2H-quinoline-1-ylmethyl)azetidin

On the basis of the intermediate compound (2.i) (350 mg) and using the method As mentioned in the title intermediate compound obtained as a yellowish foam (200 mg, 80%yield).

1H NMR (CDCl3S: 7,58 (d, J=9.4 Hz, 1H), 7,45 (d, J=9.1 Hz, 1H), for 6.81 (m, 2H), of 6.52 (d, J=9.4 Hz, 1H), 4,51 (d, J=7,0 Hz, 2H), 3,91 (s, 3H), of 3.60 (m, 4H), and 2.27 (m, 1H).

2.iii. 6-{(R)-5-[3-(7-Methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one

On the basis of the intermediate compound (2.ii) (65 mg) and the compound of the experiment, and using the method mentioned in the title compound obtained as a beige foam (28 mg, 21%yield).

MS (ESI, m/z): 507,0 [M+H+].

Example 3: 1-{1-[(R)-3-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ylmethyl]azetidin-3-ylmethyl}-7-methoxy-1H-quinoline-2-he

On the basis of the intermediate compound (2.ii) (65 mg) and the compound of the experiment In (106 mg), and using the method mentioned in the title compound obtained as a beige foam (30 mg, 23%yield).

1H NMR (Dl3) δ: to 7.59 (d, J=9.4 Hz, 1H), 7,46 (d, J=9.1 Hz, 1H), was 7.08 (d, J=2.6 Hz, 1H), 7,00 (m, 1H), 6,83 (m, 3H), of 6.52 (d, J=9.4 Hz, 1H), 4,47 (dd, J=6,7, 1.8 Hz, 2H), 4,24 (s, 4H), 3,92 (m, MN), 3,81 (m, 1H), of 3.25 (m, 2H), 2,77 (s, 2H).

MS (ESI, m/z): 478,0 [M+H+].

Example 4: 6-{(R)-5-[3-(7-Methoxy-2-oxo-2H-cinoxacin-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1.4]thiazin-3-one

4.1. tert-Butyl ether 3-(7-methoxy-2-oxo-2H-Hino is Salin-1-ylmethyl)azetidin-1-carboxylic acid

Using the method of example 2, step 2.i, but on the basis of 7-methoxy-2(1ST)-khinoksalinona (1,00 g; obtained according to WO 2006/134378) and tert-bouteloua ester 3-[[(methylsulphonyl)oxy]methyl]-1-azetidinone acid (1.65 g;

obtained according to WO 02/066470), the second aliremove connection was allocated in the form of a yellow oil (700 mg, 35%yield).

MS (ESI. m/z): 346,2 [M+H+].

4.ii. 3-(7-Methoxy-2-oxo-2H-cinoxacin-1-ylmethyl)azetidin

On the basis of the intermediate compound (4.i) (700 mg) and using the method As mentioned in the title intermediate compound obtained as an orange foam (400 mg, 80%yield).

MS (ESI, m/z): 246,4 [M+H+].

4.iii. 6-{(R)-5-[3-(7-Methoxy-2-oxo-2H-cinoxacin-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one

On the basis of the intermediate compound (4.ii) (90 mg) and the compound of the experiment And (157 mg) and using the method mentioned in the title compound obtained as brown solid (20 mg, 11%yield).

1H NMR (DMSO-d6) δ: 10,54 (d, J=0.6 Hz, 1H), 8,03 (s, 1H), 7,73 (d, J=9.7 Hz, 1H), 7,30 (m, 2H), 6,98 (m, 2H), to 4.41 (d, J=6,4 Hz, 2H), 3,99 (d, J 0.6 Hz, 1H), with 3.89 (s, 3H), 3,68 (m, 1H), 3,42 (s, 2H), 3,06 (m, 2H), 2,68 (m, 2H).

MS (ESI, m/z): 508,2 [M+H+].

Example 5: 6-((R)-5-{2-[3-(7-Methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-yl]ethyl}-2-oxoacridine-3-yl')-4H-benzo[1,4]thiazin-3-one

On the basis of the intermediate compound (2.ii) (65 mg) and the compound of the experimental the NTA (118 mg), and using the method mentioned in the title compound obtained as a beige foam (47 mg, 34%yield).

MS (ESI, m/z): 521,4 [M+H+].

Example 6: 6-((R)-5-{2-[3-(7-methoxy-2-oxo-2H-cinoxacin-1-ylmethyl)azetidin-1-yl]ethyl}-2-oxoacridine-3-yl)-4H-benzo[1.4]thiazin-3-one

On the basis of the intermediate compound (4.ii) (90 mg) and compound experiment (148 mg) and using the method mentioned in the title compound obtained as a beige foam (54 mg, 28%yield).

MS (ESI, m/z): 522,3 [M+H+].

Example 7: 6-{(R)-5-[4-(7-Methoxy-2-oxo-2H-quinoline-1-ylmethyl)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1.4]thiazin-3-one

7.i. tert-Butyl ester 4-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)piperidine-1-carboxylic acid

Using the method of example 2, step 2.i, but on the basis of 7-methoxy-2(1H)-Hinayana (350 mg; commercial product) and tert-butyl ester 4-[[(methylsulphonyl)oxy]methyl]-1-piperidinecarboxylic acid (645 mg; commercial product), the second aliremove connection is isolated in the form of a colourless foam (227 mg; 30%yield).

MS (ESI, m/z): 373,3 [M+H+].

7.ii. 4-(7-Methoxy-2-oxo-2H-quinoline-1-ylmethyl)piperidine

On the basis of the intermediate compound (7.i) (327 mg) and using the method As mentioned in the title intermediate compound obtained as a colorless foam (210 mg, 88%yield).

1H NMR (Dl3) δ: to 7.59 (d. J=9.4 Hz, 1H), 7,47(m, 1H), PC 6.82 (m, 2H), 6,53 (d, J=9.4 Hz, 1H), 4,18 (m, 2H), 3,91 (s, 3H), 3,10 (m, 2H), 2,55 (td, J=12,3, 2,6 Hz, 2H), 2.06 to (s, 2H), 1,67 (m, 2H), 1,42 (m, 2H).

7.iii. 6-{(R)-5-[4-(7-Methoxy-2-oxo-2H-quinoline-1-ylmethyl)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one

On the basis of the intermediate compound (7.ii) (70 mg) and the compound of the experiment And (110 mg)using the method mentioned in the title compound obtained as a yellowish foam (53 mg, 38%yield).

1H NMR (DMSO-d6) δ: 10,53 (s, 1H), 7,80 (d, J=9.4 Hz, 1H), 7,63 (d, J=8,8 Hz, 1H), 7,30 (m, 2H), 7,12 (m, 1H), 6.90 to (m, 2H), 6,40 (d, J=9.4 Hz, 1H), 4,15 (m, 2H), was 4.02 (m, 1H), a 3.87 (s, 3H), 3.43 points (s, 2H), 2,60 (m, 2H), 1,99 (m, 2H), 1,50 (m, 2H), l,35(m,2H).

MS (ESI, m/z): 535,5 [M+H+].

Example 8: 1-{1-[(R)-3-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ylmethyl]piperidine-4-ylmethyl}-7-methoxy-1H-quinoline-2-he

On the basis of the intermediate compound (7.ii) (70 mg) and the compound of the experiment In (102 mg), and using the method mentioned in the title compound obtained as a yellowish foam (48 mg, 37%yield).

1H NMR (DMSO-d6) δ: 7,79 (d, J=9.4 Hz, 1H), 7,63 (d, J=8.5 Hz, 1H), 7,10 (d, J=2.6 Hz, 1H), to 6.88 (m, 4H), 6,40 (d, J=9.4 Hz, 1H), 4,21 (m, 6H), is 4.03 (d, J=1.8 Hz, 2H), a 3.87 (s. MN), 2,60 (m, 2H), 1,98 (s, MN), 1,50 (m, 2H), 1,35 (m, 2H).

MS (ESI, m/z): 506,3 [M+H+].

Example 9: 1-{1-[(7?)-3-(3-Fluoro-4-were)-2-oxoacridine-5-iletiler-4-ylmethyl}-7-methoxy-1-quinoline-2-he

On the basis of the intermediate compound (7.ii) (70 mg) and the compound of experiment D (94 mg), and using method B, on the bath in the title compound obtained as a yellowish foam (30 mg, 24%yield).

MS (ESI, m/z): 480,3 [M+H+].

Example 10: 6-{(R)-5-[3-(7-Methoxy-2-oxo-3,4-dihydro-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1L]thiazin-3-one

10. i. tert-Butyl ether 3-(7-methoxy-2-oxo-3,4-dihydro-2H-quinoline-1-ylmethyl)azetidin-1-carboxylic acid

Using the method of example 2, step 2.i, but on the basis of 3,4-dihydro-7-methoxy-2(1H)-Hinayana (obtained according to WO 2006/134378; 886 mg) and tert-butyl ester 3-[[(methylsulphonyl)oxy]methyl]-1-azetidinone acid (1459 mg; obtained according to WO 02/066470)named in the title compound obtained as a colorless oil (1223 mg; 71%yield).

1H NMR (DMSO-d6) δ: 7,07 (dd, J=7,9, 0.6 Hz, 1H), 6,54 (m, 2H), 4,18 (d, J --7,3 Hz, 2H), 3.94 (t, J=8.5 Hz, 2H), of 3.77 (m, 5H), of 2.81 (m, 2H), 2,62 (m, 2H), USD 1.43 (s, 9H).

MS (ESI, m/z): 347,2 [M+H+].

10. ii. 3-(7-Methoxy-2-oxo-3,4-dihydro-2H-quinoline-1-ylmethyl)azetidin

On the basis of the intermediate compound (10.i) (1223 mg) and using the method As mentioned in the title intermediate compound obtained as a colorless oil (565 mg, 65%yield).

MS (ESI, m/z): of 247.5 [M+H+].

IQ.iii. 6-{(R)-5-[3-(7-Methoxy-2-oxo-3.4-dihydro-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1.4]thiazin-3-one

On the basis of the intermediate compound (10.ii) (110 mg) and the compound of the experiment And (191 mg), and using the method In the named header connection receive the form of a yellowish foam (74 mg, 32%yield).

MS (ESI, m/z): 509,1 [M+H+].

Example 11: 6-{(S)-5-[3-(7-Methoxy-2-oxo-3,4-dihydro-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one

On the basis of the intermediate compound (10. ii) (110 mg) and the compound of the experiment, F (191 mg) and using the method mentioned in the title compound obtained as a yellowish foam (75 mg, 33%yield).

1H NMR (DMSO-d6) δ: 10,53 (s, 1H), 7,30 (m, 2H), to 7.09 (m, 2H), 6,62 (d, J=2.3 Hz, 1H), 6,56 (dd, J=8,2, 2.3 Hz, 1H), br4.61 (s, 1H), was 4.02 (m, MN), and 3.72 (m. 3H), 3,42 (s, 2H), 3,29 (m, 7H), 2.95 and (m, 2H), 2,70 (m, 5H).

MS (ESI, m/z): 509,1 [M+H+].

Example 12: 6-{(R)-5-[3-(7-Methoxy-2-oxo-3,4-dihydro-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4D-benzo[1,4]oxazin-3-he

On the basis of the intermediate compound (10.ii) (110 mg) and the compound of the experiment E (160 mg), and using the method mentioned in the title compound obtained as a yellowish foam (50 mg, 23%yield).

MS (ESI, m/z): 493,1 [M+H+].

Example 13: 6-{(R)-5-[3-(7-Methoxy-2-oxo-2H-cinoxacin-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one

On the basis of the intermediate compound (4.ii) (90 mg) and the compound of the experiment E (125 mg) and using the method mentioned in the title compound obtained as brown solid (20 mg, 11%yield).

MS (ESI, m/z): 492,2 [M+H+].

Example 14: 1-{1-[(R)-3-(2,3-Dihydrobenzo[1.4]dioxin-6-yl-2-oxoacridine-5-ylmethyl]azetidin-3-ylmethyl}-7-methoxy-1H-cinoxacin-2-he

On the basis of the intermediate compound (4.ii) (90 mg) and the compound of the experiment In (135 mg) and using the method mentioned in the title compound obtained as a brown foam (22 mg, 12%yield).

MS (ESI, m/z): 479,3 [M+H+].

Example 15: 6-Methoxy-4-{1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1.4]thiazin-6-yl)oxazolidin-5-ylmethyl]piperidine-4-yl}-4H-pyrido[2.3-b]pyrazin-3-one

15. i tert-Butyl ester 4-(6-methoxy-3-nitropyridine-2-ylamino)piperidine-1-carboxylic acid

A mixture of 4-amino-1-BOC-piperidine (commercial product; 6.7 g, 35 mmol), 2-chloro-6-methoxy-3-nitropyridine (1 EQ.) and K2CO3(1 EQ.) in MeCN (100 ml) and DMF (30 ml) is heated at 60°C for 3 h, after which the reaction mixture is filtered and concentrated in vacuo. The residue is transferred into a mixture of ether/water in the ratio 1:1, the organic phase is dried over MgSO4and concentrate. The residue is triturated with ethyl acetate and filtered, obtaining 4.5 g of pure product. The filtrate is concentrated and purified by column chromatography (heptane/EA ratio 9:1, 4:1, 2:1), receiving another portion of the product. In General, the obtained 8.5 g (70%yield) of yellow solid.

1H NMR (CDCl3) δ: 8,62 (m, 1H), 8,31 (d, J=9.4 Hz, 1H), 6,07 (d, J=9.1 Hz, 1H), 4,32 (m, 1H), of 4.05 (m, 2H), 3,95 (s, 3H), to 3.02 (s, 2H), 2,10 (m, 2H), 1,60 (s, 3H), l,47(m,9H).

15.ii. tert-Butyl ester 4-(3-amino-6-methoxypyridine-2-ylamino)piperid the n-1-carboxylic acid

A solution of intermediate compound (15.i) (8,45 g) in a mixture of EtOH/EA (in the ratio 1:1; 300 ml) hydronaut over 10%Ro/C for 4 h, then the catalyst is filtered off, the filtrate is evaporated under reduced pressure and the residue purified by column chromatography (heptane/EA in the ratio 1:2)to give a red solid (5.4 g, 70%yield).

MS (ESI, m/z): 323,3 [M+H+].

15.iii. tert-Butilovyi ester 4-[3-(ethoxycarbonylmethylene)-6-methoxypyridine-2-ylamino]piperidine-1-carboxylic acid

A suspension of intermediate compounds (15.ii) (5,38 g), ethylbromoacetate (2.9 g), K2CO3(4.6 g) in a mixture of DMF/MeCN (in the ratio 1:2, 120 ml) was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate is evaporated under reduced pressure. The residue is dissolved in a mixture of EA/Meon (in the ratio of 19:1, 200 ml) and washed with water. The organic phase is dried over MgSO4, filtered, concentrated under reduced pressure and purified by column chromatography (heptane/EA in the ratio 2:1, then 1:1)to give a dark oil (5.29 g; 77%yield).

MS (ESI, m/z): 409,4 [M+H+].

15.iv. tert-Butyl ester 4-(6-methoxy-3-oxo-3H-pyrido[2,3-B]pyrazin-4-yl)piperidine-1-carboxylic acid

A solution of intermediate compound (15.iii) (5,26 g) in toluene (240 ml) is treated Asón (1 ml) and the mixture is heated clicks Tim fridge during the night in an atmosphere of N 2. The reaction mixture was concentrated under reduced pressure, the residue is dissolved in DHM (200 ml) and treated with MnO2(21.2 g) at room temperature for 6 hours Then the reaction mixture is filtered, the filtrate is evaporated under reduced pressure and purified by column chromatography (heptane/EA in the ratio 2:1, then 1:1)to give a beige solid (2.3 g, 49%yield).

1H NMR (DMSO-d6) δ: 8,11 (d, J=8.5 Hz, 1H), 8,07 (s, 1H), 6,83 (d, J=8.5 Hz, 1H), 5,42 (m, 1H), 4,11 (m, 2H), 3,93 (s, MN), 2,77 (m, 4H), and 1.63 (m, 2H), 1,40 (s,9H).

MS (ESI, m/z): 361,4 [M+H+].

15. v. 6-Methoxy-4-piperidine-4-yl-4H-pyrido[2.3-b]pyrazin-3-one

On the basis of the intermediate compound (15.iv) (2.30) and using the method As mentioned in the title intermediate connection receive (223 mg, 13%yield) after purification using column chromatography (DHM/Meon in the ratio 19:1 then 9:1+1% NH40H) in the form of a yellow solid.

MS (ESI, m/z): 261,2 [M+H+].

15.vi. 6-Methoxy-4-{1-[(R)-2-oxo-3-('3-oxo-3,4-dihydro-2H-benzo[1.4]thiazin-6-yl)oxazolidin-5-ylmethyl]piperidine-4-yl}-4H-pyrido[2,3-b]pyrazin-3-one

On the basis of the intermediate compound (15.v) (101 mg) and the compound of the experiment And (167 mg) and using the method mentioned in the title compound obtained as a beige solid (71 mg, 35%yield).

1H NMR (DMSO-d6) δ: 10,57 (d, J 0.6 Hz, 1H), 8,11 (d, J=8.5 Hz, 1H), with 8.05 (s, 1H), 7,33 (m, 2H), 7,14 (m, N), 6,83 (d,J=8.5 Hz, 1H), around 4.85 (m, 1H), 4,03 (s, 1H), 3,91 (s, MN), 3,76 (m, 1H), 3,44 (s, 3H), is 3.08 (m, 2H), 2,93 (m, 2H), by 2.73 (m, 2H), and 2.27 (m, 2H), l,16(m,2H).

MC (ESI, m/z): 523,1 [M+H+].

Example 16: 6-Methoxy-4-{1-[(7?)-2-oxo-3-(3-oxo-3.4-dihydro-2H-benzo[1.4]oxazin-6-yl')oxazolidin-5-ylmethyl]piperidine-4-yl}-4h-pyrido[2.3-d]pyrazin-3-one

On the basis of the intermediate compound (15.v) (100 mg) and the compound of the experiment E (145 mg) and using the method mentioned in the title compound obtained as a beige solid (64 mg, 32%yield).

1H NMR (DMSO-d6) δ: of 10.72 (s, 1 H), 8,11 (d, J=8.5 Hz, 1H), with 8.05 (s, 1H), 7,33 (t, J=1.5 Hz, 1H), 6,97 (d, J=1.5 Hz, 2H), 6,83 (d, J=8.5 Hz, 1H), 5.25 in (m, 1H), a 4.83 (m, 1H), 4,54 (m, 2H), of 4.05 (m, 1H), to 3.92 (s, 3H), of 3.75 (m, 1H), of 3.07 (m, 2H), 2,92 (m, 2H), 2,72 (d, J=5.6 Hz, 2H), and 2.27 (m, 2H), 1,59 (m, 2H).

MC (ESI, m/z): 507,2 [M+H+].

Example 17: 6-{(R)-5-[(R)-3-(7-Methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one

17.1. tert-Butyl ether (S)-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl-pyrrolidin-1-carboxylic acid

Using the method of example 2, stage 1 l, but on the basis of 7-methoxy-2(1ST)-Hinayana (obtained according to WO 2006/134378; 500 mg) and tert-bouteloua ester 3-[[(methylsulphonyl)oxy]methyl]-1-pyrrolidinecarboxylic acid (797 mg; obtained according to J. Med. Chem. (1999), 42, 677-690), the second aliremove compound obtained as a colorless oil (240 mg, 23%yield).

1H NMR (Dl3) δ: 7,60 (d, J=9.4 Hz, 1H), of 7.48 (d, J=8,8 Hz, 1H), for 6.81 (m, 2H), 6,53 (d, J=9 Hz, 1H), 3,91 (m, 3H), 3,52 (m, 2H), 3,35 (m, 2H), was 2.76 (m, 1H), 1,89(m,4H), of 1.45 (m,9H).

17. ii. (S)-7-Methoxy-1-pyrrolidin-3-ylmethyl-1H-quinoline-2-he

On the basis of the intermediate compound (17. i) (220 mg) and using the method As mentioned in the title intermediate compound obtained as a colorless oil (120 mg, 75%yield).

1H NMR (CDCl3) δ; a 7.62 (d, J=9.4 Hz, 1H), 7,49 (d, J=8,8 Hz, 1H), 6,84 (m, 2H), 6,53 (d, J=9.4 Hz. 1H), to 4.41 (m, 1H), 4,19 (m, 1H), 3,92 (s, 3H), 3,48 (s, 1H), or 3.28 (m, 1H), to 3.02 (m, 3H), 2,80 (m, 1H), 2,01 (m, 1H), 1,78 (m, 1H).

17.iii. 6-{(R)-5-[(R)-3-(7-Methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1.4]thiazin-3-one

On the basis of the intermediate compound (17.ii) (100 mg) and the compound of the experiment And (151 mg) and using the method mentioned in the title compound obtained as a beige solid (8 mg, 4%yield).

MS (ESI, m/z): 521,2 [M+H+].

Example 18: 6-{(R)-5-[(RS)-3-Hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one

18.i. tert-Butyl ether rat-3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-carboxylic acid

A solution of 7-methoxy-1H-quinoline-2-she (650 mg, 3.7 mmol) and tert-butyl methyl ether 1-oxa-5-azaspiro[2.4]heptane-5-carboxylic acid (1 EQ., commercial product) in DMF (10 ml) is treated with Ssgss (1 EQ.), then heated at 70°C for the night. Mix the ZAT is distributed between ethyl acetate and water, the organic phase is washed with water and brine, dried over MgSO4and kontsentriruyutsya purified by column chromatography (EA/heptane 1:1, EA)to give the desired intermediate compound in the form of a yellowish oil (650 mg, 47%yield).

1H NMR (CDCl3) δ: of 7.70 (d, J=9.4 Hz, 1H), 7,52 (d, J=8.5 Hz, 1H), 6.87 in (m, 2H), 6,60 (d, J=9.4 Hz, 1H), 4,59 (m, 1H), 4,45 (m, 1H), with 3.89 (s, 3H), 3,49 (m, 6H), 1,40 (advanced s, 9H).

18.ii. rat-1-(3-Hydroxypyrrolidine-3-ylmethyl)-7-methoxy-1H-quinoline-2-he

On the basis of the intermediate compound (18.i) (600 mg) and using the method As mentioned in the title intermediate compound obtained as a colorless oil (440 mg, 100%yield).

1H NMR (l3) δ: to 7.67 (d, J=9.4 Hz, 1H), 7,47 (d, J=8,8 Hz, 1H), 7,25 (m, 1H), 6,85 (dd, J=8,5, and 2.1 Hz, 1H), 6,55 (d, J=9.4 Hz, 1H), 4,56 (m, 2H), 3,88 (s, 3H), 3,21 (m, 5H), for 2.01 (m, 2H).

18.iii. 6-{[R]-5-[(RS)-3-Hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one

On the basis of the intermediate compound (18.ii) (100 mg) and the compound of the experiment And (142 mg) and using the method mentioned in the title intermediate compound obtained as a beige solid (41 mg, 21%yield).

MS (ESI, m/z): 537,2 [M+H+].

Example 19: 6-{(R)-5-[(RS)-3-Hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-47^-benzo[1,4]thiazin-3-one

Based on ispropagated connection (18.ii) (100 mg) and the compound of the experiment, F (142 mg) and using the method In, named in the title compound obtained as a beige solid (31 mg, 16%yield).

MS (ESI, m/z): 537,2 [M+H+].

Example 20: 6-((S)-5-{2-[(RS)-3-Hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one

On the basis of the intermediate compound (18.ii) (100 mg) and the compound of the experiment G (147 mg) and using the method mentioned in the title compound obtained as a gray solid (10 mg, 5%yield).

MS (ESI, m/z): 551,2 [M+H+].

Example 21: 6-((R)-5-{2-[(RS)-3-Hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one

On the basis of the intermediate compound (18.ii) (100 mg) and compound experiment (147 mg) and using the method mentioned in the title compound obtained as a beige solid (47 mg, 23%yield).

MS (ESI, m/z): 551,2 [M+H+].

Example 22: 4-{1-[(R)-3-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ylmethyl]piperidine-4-yl}-6-methoxy-4H-pyrido[2,3-6]pyrazin-3-one

On the basis of the intermediate compound (15.v) (143 mg) and the compound of the experiment In (218 mg) and using the method mentioned in the title compound obtained as a beige solid (82 mg, 30%yield).

MS (ESI, m/z): 494,2 [M+H+].

Example 23: 6-Methoxy-4-(1-{2-[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)about Catholicon-5-yl]ethyl}piperidine-4-yl)-4H-pyrido[2,3-6]pyrazin-3-one

On the basis of the intermediate compound (15.v) (130 mg) and the compound of the experiment G (222 mg) and using the method mentioned in the title compound obtained as a beige solid (201 mg, 75%yield).

MS (ESI, m/z): 537,2 [M+H+].

Example 24: 4-{1-[(R)-3-(3-Fluoro-4-were)-2-oxoacridine-5-ylmethyl]piperidine-4-yl}-6-methoxy-4H-pyrido[2,3-6]pyrazin-3-one

On the basis of the intermediate compound (15.v) (143 mg) and the compound of experiment D (202 mg) and using the method mentioned in the title compound obtained as a beige solid (41 mg, 16%yield).

MS (ESI, m/z): 468,2 [M+H+].

Example 25: 6-Methoxy-4-(1-{2-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-yl]ethyl}piperidine-4-yl)-4H-pyrido[2,3-6]pyrazin-3-one

On the basis of the intermediate compound (15.v) (130 mg) and intermediate (C.v) (204 mg) and using the method mentioned in the title compound obtained as a beige solid (137 mg, 51%yield).

MS (ESI, m/z): 537,2 [M+H+].

Pharmacological properties of the compounds according to the invention

Analyses of in vitro

Experimental methods

The minimum inhibition concentration (MICs; in mg/l) were determined in cation-regulated nutrient medium Mueller-Hinton Broth using the method of microrasbora described in "Methods for Dilution Antimicrobial Susceptibility Tests for Bateria that Grow Aerobically", Approved standard, 7th ed., Clinical and Laboratory Standards Institute (CLSI) Document M7-A7, Wayne, PA, USA, 2006.

Results

Connect all of the examples tested on the impact on some gram-positive and gram-negative bacteria such as S. aureus, E.faecalis, S. pneumoniae, M. catarrhalis, A. baumanii, E. coli or P. aeruginosa. The results of antibacterial tests are presented in the table below (MIC in mg/l).

ExampleMIC for M catarrhalis A894ExampleMIC for M catarrhalis A894
1≤0,031140,25
2≤0,03115≤0,031
3≤0,06316≤0,031
4≤0,03117≤0,031
5≤0,03118≤0,031
6≤0,03119 ≤0,031
7≤0,03120≤0,031
8121≤0,031
9122≤0,031
10≤0,03123≤0,031
11≤0,03124≤0,031
120,525≤0,031
13≤0,031

ADDITIONAL EXPERIMENTAL DATA

Example 26: 6-methoxy-4-(1-{2-[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]-thiazin-6-yl)oxazolidin-5-yl]ethyl)piperidine-4-yl)-1,4-dihydro-2H-pyrido[2,3-b]pyrazin-3-one

To a cooled to 0°C solution of the compound from example 23 (80,5 mg) in DHM/methanol 3:1 (4.8 ml) was added NaBH4(11.3 mg). The reaction mixture was stirred at room temperature for 8 hours the Mixture was divided between DHM/methanol in the ratio 9:1 and 1% of water is a solution of NH 4OH. The organic phase was washed with brine, dried over MgSO4and concentrated under reduced pressure. The residue was purified by using chromatographie in column (DHM/methanol+NH4OH 1%), getting after stirring the residue in ether, specified in the title compound in the form of a solid white (53 mg, yield 66%).

MS (ESI, m/z): 539,2 [M+H+].

Example 21: 6-methoxy-4-(1-{2-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]-thiazin-6-yl)oxazolidin-5-yl]ethyl}piperidine-4-yl)-1,4-dihydro-2H-pyrido[2,3-b]pyrazin-3-one

Choose compound from example 25 (of 53.7 mg) and using the same method as for the preparation of compounds according to example 26, has been specified in the title compound in the form of a solid white color (30 mg, yield 56%).

MS (ESI, m/z): 539,2 [M+H+].

Example 28: 6-methoxy-4-{1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]piperidine-4-yl)-1,4-dihydro-2H-pyrido[2,3-b]pyrazin-3-one

Choose compound from example 15 (56 mg) and using the same method as for the preparation of compounds according to example 26, has been specified in the title compound in the form of solid off-white color (29 mg, 51%yield).

MS (ESI, m/z): 525,2 [M+H+].

Example 29: 6-{(S)-5-[4-(6-methoxy-3-oxo-3H-pyrido[2,3-b]pyrazin-4-yl)-piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-pyrido[3,2-b][1,4]thiazin-3-one

Choose intermediate connection 15.v (78 mg) and 6-[(5R)-5-[[(m is tilsley)oxy]-methyl]-2-oxo-3-oxazolidinyl]-2H-pyrido[3,2-6]-1,4-thiazin-3(4H)-he (108 mg; prigotovlenn according to the document WO 2010/041194) and using the procedure has been specified in the title compound as a colourless solid (18 mg, yield 11%).

MS (ESI, m/z): 524,0 [M+H+].

Example 30: 6-{(S)-5-[4-(6-methoxy-3-oxo-3H-pyrido[2,3-b]pyrazin-4-yl)-piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-pyrido[3,2-b][1,4]oxazin-3-one

Choose intermediate connection 15.v (78 mg) and 6-[(5R)-5-[[(methylsulphonyl)oxy]-methyl]-2-oxo-3-oxazolidinyl]-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-he (103 mg; prepared according to WO 2013/021363) and using procedure C, was obtained is listed in the title compound in the form of a colorless solid (25 mg, yield 16%).

1H NMR (DMSO-d6) δ: 8,09 (m, 1H); 8,03 (m, 1H); 7,58 (m, 1H); 7,42 (m, 1H); PC 6.82 (m, 1H); 5.25 in (m, 1H); 4,82 (m, 1H); 4,59 (m, 2H); of 3.97 (m, 3H); of 3.85 (m, 1H); to 3.36 (m, 1H); 3.04 from (m, 2H); 2,87 (m, 2H); by 2.73 (m, 2H); and 2.26 (m, 2H); was 1.58 (m, 2H).

MS (ESI, m/z): 508,1 [M+H+].

Example 31: 6-(((R)-5-{2-[3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-yl]-ethyl}-2-oxoacridine-3-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-one

31.i. Ethyl ester (6-{(R)-5-[2-(tert-butyldimethylsilyloxy)ethyl]-2-oxo-oxazolidin-3-yl}-2-nitropyridine-3-yloxy)acetic acid:

Suspension K2CO3(of 11.26 g), CuI (388 mg), (R)-5-[2-(tert-butyldimethylsilyloxy)-ethyl]oxazolidin-2-she (10.0 g; prepared according to WO 2009/104159), ethyl ether (6-bromo-2-nitropyridine-3-yloxy)acetic acid (12,43 g; prepared according to document the NTU WO 2004/002992) and N,N-dimethylethylenediamine (0,92 ml) in dioxane (305 ml) was degirolami by ozonation with argon and was delegirovali at 100°C in throughout the night. The obtained dark brown mixture was filtered through diatomaceous earth (Celite), the filtrate was evaporated under reduced pressure and the residue was purified by chromatography on a column (Hept/EA 2:1 to 0:1), obtaining a solid beige color (16.0 g; yield 84%).

MS (ESI, m/z): 470,3 [M+H+].

31.ii. 6-[(R)-5-(2-hydroxyethyl)-2-oxoacridine-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one:

A suspension of ammonium chloride (13,67 g) and iron (8,56 g) in a mixture of MeOH/water (204 ml; 1:1) was heated to 50°C, then to the suspension was added dropwise a solution of intermediate 31 l (16.0 g) in MeOH (360 ml) and further stirred at 68°C for 2.5 hours Hot suspension was filtered through a substrate made of diatomaceous earth (Celite). The filtrate was diluted with acetic acid (112 ml) and stirred at 95°C for 2 h the Reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The suspension was cooled to 0°C, filtered and the collected solid fraction by filtration, getting a solid beige color (9,54 g; yield 100%).

MS (ESI, m/z): 280,1 [M+H+].

31.iii. 2-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-yl]ethyl ester methanesulfonic acid:

A suspension of intermediate compounds 31.ii (4,2 g) in DHM (65 ml) was cooled to -40°C and treated with methanesulfonamide (1.6 ml) for 1 hours

The reaction mixture was diluted with saturated aqueous p is the target NaHCO 3and the aqueous phase was extracted with DHM. The combined organic layers were dried over MgSO4concentrated under reduced pressure and the residue triturated in TBME/DHM/methanol, getting a solid pinkish-orange color (732 mg, yield 17%).

MS (ESI, m/z): 358,2 [M+H+].

31.iv. 6-((R)-5-{2-[3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-yl]-ethyl}-2-oxoacridine-3-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-one:

Choose intermediate substance 2.ii (64 mg) and intermediate substance 31.iii (50 mg) and using procedure C, was obtained is listed in the title compound as yellowish solid substance (13 mg, yield 18%).

MS (ESI, m/z): 506,0 [M+H+].

Example 32: 6-((R)-5-{2-[3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-yl]-ethyl)-2-oxoacridine-3-yl)-4H-pyrido[3,2-b)[1,4]thiazin-3-one

Choose intermediate substance 2.ii (61 mg) and 6-[(5R)-5-[2-[(methylsulphonyl)oxy]-ethyl]-2-oxo-3-oxazolidinyl]-2H-pyrido[3,2-b]-1,4-thiazin-3(4H)-he (50 mg; prepared according to WO 2010/041194) and using procedure C, was obtained is listed in the title compound in the form of a solid yellow (4 mg, yield 5%).

MS (ESI, m/z): 522,0 [M+H+].

Example 33: 6-{(R)-5-[3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-yl methyl]-2-oxoacridine-3-yl}-4H-pyrido[3,2-b][1,4]thiazin-3-one

Choose intermediate substance 2.ii (50 mg) and 6-[(5R)-5-[[(methylsulphonyl)oxy]-methyl]-2-oxo-3-oxazolidinyl]-2H-pyrid the[3,2-6]-1,4-thiazin-3(4H)-he (64 mg; prepared according to the document WO 2010/041194) and using procedure C, has been specified in the title compound in the form of solid yellow (4 mg, yield 6%).

MS (ESI, m/z): 507,9 [M+H+].

Pharmacological properties of the compounds according to the invention the Method of the experiment;

The minimum inhibiting concentration (MIC; mg/l) were determined in cation-controlled environment Mueller-Hinton (Mueller-Hinton Broth), by way of microrasbora according to the manual "Methods of tests of antimicrobial sensitivity dilution for bacteria growing under aerobic conditions" (the"Procedures for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically"), Approved standard, 7-thed., Institute for clinical and laboratory standards (CLSI) document M7-A7, Wayne, PA, USA, 2006.

The results:

Tested and the activity of all compounds against several gram-negative and gram-positive bacteria, such as S.aureus, .faecalis, S.pneumoniae, .catarrhalis, .baumanii, E. coli or .aeruginosa. The results of the study antibacterial activity against Moraxella catarrhalis A, Staphylococcus aureus was ATSS 29213 and Streptococcus pneumoniae was ATSS 49619 in the Table below (MIC in mg/l).

Connection exampleMoraxella catarrhalis AS.aureus was ATSS 29213S.pnemoniae ADS 49619
1≤0,031≤0,0310,063
2≤0,031≤0,031≤0,031
30,063≤0,0310,25
4≤0,031≤0,031≤0,031
5≤0,031≤0,031≤0,031
6≤0,031≤0,031≤0,031
7≤0,031≤0,031≤0,031
810,254
910,0631
10≤0,031≤0,0310,063
11 ≤0,031≤0,0310,5
120,50,254
13≤0,031≤0,0310,125
140,250,0631
15≤0,031≤0,031≤0,031
16≤0,031≤0,031≤0,031
17≤0,031≤0,031≤0,031
18≤0,031≤0,031≤0,031
19≤0,031≤0,031≤0,031
20≤0,031≤0,0310,5

Connection PR is a measure Moraxella catarrhalis AS.aureus ATCC 29213S.pneumoniae ATCC49619
21≤0,0310,1250,25
22≤0,031≤0,0310,063
23≤0,031≤0,031≤0,031
24≤0,031≤0,031≤0,031
25≤0,031≤0,0310,063
26≤0,031≤0,0160,125
270,063≤0,0160,125
28≤0,031≤0,0160,031
29≤0,016≤0,0160,031
30 ≤0,016≤0,016≤0,016
31118
320,514
330,250,254

1. The compound of formula (I)
R1

where
R1is alkoxygroup or halogen;
U and V each independently from each other represents CH or N;
"----" means a connection or missing;
W represents CH or N, or if "----" is missing, then W represents CH2or NH,
provided that U, V and W do not all represent N;
A represents a bond or CH2;
R2represents H, or if a denotes CH2also can represent IT;
m and n are each independently from each other 0 or 1;
D represents CH2or communication;
G represents a phenyl group which is once or twice substituted in the meta and/or para-position(s) by substituents selected from alkyl, C1-3alkoxygroup and halogen, or G is one of the groups Gsup> 1and G2:

where Z1, Z2and Z3each represents CH; and
X represents N or CH and Q represents O or S;
it should be borne in mind that if the type of one is equal to 0, then a represents a CH2;
or pharmaceutically acceptable salt of such compounds.

2. The compound of formula (I) according to claim 1, which is a compound of formula (ICE)

where
R1is alkoxygroup;
V represents CH;
U and W each represent CH and "----" represents a bond, or U represents CH, W represents N and "----" represents a bond, or U and W each represent N and "----" represents a bond, or U represents CH, W represents CH2and "----" is missing;
A represents a bond or CH2;
R2represents H, or if a denotes CH2also can represent IT;
m and n are each independently from each other 0 or 1;
D represents CH2or communication;
G represents a phenyl group which is substituted once in the meta-position and once substituted in the para-position substituents selected from alkyl and halogen, or G is one of the groups G1and G2,:

it should be borne in mind that if the type of one is equal to 0, then a represents a CH2;
or pharmaceutically acceptable salt of such compounds.

3. The compound of formula (I) according to claim 1, where R1represents a methoxy group; or a pharmaceutically acceptable salt of such compounds.

4. The compound of formula (I) according to claim 3, where "----" represents a bond; or a pharmaceutically acceptable salt of such compounds.

5. The compound of formula (I) according to claim 3, where the "----" is absent; or a pharmaceutically acceptable salt of such compounds.

6. The compound of formula (I) according to claim 4, where a represents a bond; or a pharmaceutically acceptable salt of such compounds.

7. The compound of formula (I) according to claim 4, where a represents CH2; or a pharmaceutically acceptable salt of such compounds.

8. The compound of formula (I) according to claim 7, where R2is a HE;
or pharmaceutically acceptable salt of such compounds.

9. The compound of formula (I) according to one of items 1 to 8, where G is a group of the formula

where Q represents O or S,
or pharmaceutically acceptable salt of such compounds.

10. The compound of formula (I) according to claim 1, which is selected from the following compounds:
6-{(R)-5-[3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-{(R)-5-[3(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
1-{1-[(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ylmethyl]azetidin-3-ylmethyl}-7-methoxy-1H-quinoline-2-he;
6-{(R)-5-[3-(7-methoxy-2-oxo-2H-cinoxacin-1-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-((R)-5-{2-[3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)azetidin-1-yl]ethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;
6-((R)-5-{2-[3-(7-methoxy-2-oxo-2H-cinoxacin-1-ylmethyl)azetidin-1-yl]ethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;
6-{(R)-5-[4-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
1-{1-[(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ylmethyl]piperidine-4-ylmethyl}-7-methoxy-1H-quinoline-2-he;
1-{1-[(R)-3-(3-fluoro-4-were)-2-oxoacridine-5-ylmethyl]-piperidine-4-ylmethyl}-7-methoxy-1H-quinoline-2-he;
6-{(R)-5-[3-(7-methoxy-2-oxo-3,4-dihydro-2H-quinoline-1-ylmethyl)-azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-{(S)-5-[3-(7-methoxy-2-oxo-3,4-dihydro-2H-quinoline-1-ylmethyl)-azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-{(R)-5-[3-(7-methoxy-2-oxo-3,4-dihydro-2H-quinoline-1-ylmethyl)-azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one;
6-{(R)-5-[3-(7-methoxy-2-oxo-2H-cinoxacin-l-ylmethyl)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one;
1-{1-[(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ylmethyl]azetidin-3-elmet the l}-7-methoxy-1H-cinoxacin-2-he;
6-methoxy-4-{1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]piperidine-4-yl}-4H-pyrido[2,3-b]pyrazin-3-one;
6-methoxy-4-{1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)oxazolidin-5-ylmethyl]piperidine-4-yl}-4H-pyrido[2,3-b]pyrazin-3-one;
6-{(R)-5-[(R)-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-{(R)-5-[3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)-pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-{(S)-5-[3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)-pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-((S)-5-{2-[3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)-pyrrolidin-1-yl]ethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;
6-((R)-5-{2-[3-hydroxy-3-(7-methoxy-2-oxo-2H-quinoline-1-ylmethyl)-pyrrolidin-1-yl]ethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;
4-{1-[(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ylmethyl]piperidine-4-yl}-6-methoxy-4H-pyrido[2,3-b]pyrazin-3-one;
6-methoxy-4-(1-{2-[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-yl]ethyl}piperidine-4-yl)-4H-pyrido[2,3-b]pyrazin-3-one;
4-{1-[(R)-3-(3-fluoro-4-were)-2-oxoacridine-5-ylmethyl]-piperidine-4-yl}-6-methoxy-4H-pyrido[2,3-b]pyrazin-3-one;
6-methoxy-4-(1-{2-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-yl]ethyl}piperidine-4-yl)-4H-pyrido[2,3-b]pyrazin-3-is n;
or pharmaceutically acceptable salt of such compounds.

11. The compound of formula (I) according to one of items 1 to 10, or its pharmaceutically acceptable salt as a medicine for the treatment of bacterial infections.

12. Pharmaceutical composition for treating bacterial infections comprising as active ingredient a compound of the formula (I) according to one of items 1 to 10, or its pharmaceutically acceptable salt, and at least one therapeutically inert excipient.

13. The use of the compounds of formula (I) according to one of items 1 to 10, or its pharmaceutically acceptable salt for the manufacture of a medicine for the prevention or treatment of bacterial infections.

14. The compound of formula (I) according to one of items 1 to 10, or its pharmaceutically acceptable salt, intended for the prevention or treatment of bacterial infections.



 

Same patents:

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 compounds of general formula or , where Ar1 represents phenyl group, optionally substituted with one or several identical or non-identical halogen atoms; R1 represents hydrogen atom; R4, R5, R6a, R6b represent hydrogen atoms; Y, Z independently represent linear C1-4 alkylene group, optionally substituted with one linear C1-4 alkyl group; Ar2 stands for condensed with benzene 5-membered heterocyclic ring, containing one nitrogen atom and one sulphur atom, substituted with one linear C1-4 alkyl group, or derivative of 5- or 6-membered heterocyclic ring, containing one nitrogen atom and one sulphur atom, condensed with heteroaromatic 6-memebered ring, containing one or two nitrogen atoms, substituted with one linear C1-4 alkyl group, linear C1-4 alkoxygroup or group -NR7R8, where R7 and R8 independently stand for hydrogen atom, linear or branched C1-4 alkyl group, or R7 and R8 together with nitrogen atom form group of general formula , where R2, R3 represent linear C1-4 alkyl groups, A stands for group -CHR12, oxygen atom or group -NR9, where R12 and R9 stand for hydrogen atom or linear C1-4 alkyl group, m has value 1 or 2, n has value 1 or 2, o has value 0 or 1, p has value 0 or 1, Q stands for group -O-, group -N--H or group -N--CO-R10, where R10 stands for linear C1-4 alkyl group or -NH-R11 group, where R11 represents linear C1-4 alkyl group; and to their salts. Invention also relates to methods of obtaining therein and to based on them pharmaceutical composition, possessing antagonistic activity with respect to receptor CCR3.

EFFECT: obtained are novel compounds and based on them pharmaceutical compositions, which can be applied in medicine for obtaining medication, intended for treating asthma, allergic rhinitis, atopic dermatitis, eczema, inflammatory intestinal diseases, ulcerous colitis, Crohn's disease, allergic conjunctivitis, multiple sclerosis or HIV-infection and AIDS-associated diseases.

14 cl, 3 tbl, 26 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: chemistry.

SUBSTANCE: invention relates to a method of producing substituted 7,8-dicyanopyrimido[2,1-b][1,3]benzothiazoles of general formula (I)

where a R=CH3, R1=C6H5; b R=CH3, R1=4-CH3OC6H4; c R=CH3, R1=2-thienyl; d R=C6H5, R1=4-CH3OC6H4. The method is carried out by reacting 4-bromo-5-nitrophthalonitrile with esters of 2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acids in the presence of triethylamine, which is used as a deprotonating agent. The reaction takes place at temperature of 18…35°C and molar ratio of reactants (1):(2):(TEA)=1:1:2, for 12-30 hours in dimethylformamide solution. Further, the reaction mass is diluted with water, the water being in tenfold excess, at temperature T=0…25°C; the tarry residue released is decanted from the aqueous layer and recrystallised from alcohol; the precipitate of the end product is filtered and dried on air.

EFFECT: synthesis of compounds which are used as precursors for producing phthalocyanines.

1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I, including stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof: where Z1 is CR1; Z2 is CR2; Z3 is CR3 or N; Z4 is CR4 or N; where (i) X1 is N and X2 is S or (iv) X1 is S and X2 is CR7; R1, R2, R3, R4 and R7 are independently selected from H, F, Cl, Br, I, -CN, -CH2OR10, -(C1-C12 alkylene)NR10R11, -(C1-C12 alkylene)NR12C(=O)R10, -CO2R10, -C(=O)N(R10)OR11, -NR10R11, -C(=O)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10C(=O)OR11, -C(=O)NR10(C1-C12 alkylene)NR10C(=O)R11, -C(=O)NR10(C1-C12 alkylene)R11, -C(=O)NR10(C1-C12 alkylene)R10, -C(=NR10)NR10R11, -NR12C(=O)R10, -NR12C(=O)OR11, -NR12C(-O)NR10R11, -NR12C(=O)(C1-C12 alkylene)NR10R11, NR12(C=O)C1-C12 alkylene)NR11(C=O)R12, -C≡CR10, C1-C20 heteroaryl, said heteroaryl being an unsaturated carbocyclic residue containing 5-6 ring atoms, where 1-4 ring atoms are nitrogen atoms, and phenyl, where the heteroaryl and phenyl are optionally substituted with one or two groups selected from -CH2OH, -(CH2)2OH, -CH2CO2H, -CN, -CH2NH2, -(CH2)2N(CH3)2, -CH3, -CO2H, -CH2CO2CH3, -NH2 and -S(O)2CH3; A is selected from -C(=O)NR5R6, -C(=S)NR5R6, phenyl and C1-C20 heteroaryl, said heteroaryl being an unsaturated carbocyclic residue containing 5-10 ring atoms, 1-4 of which are heteroatoms selected from nitrogen, oxygen or sulphur, C1-C20 heteroaryl and phenyl are optionally substituted with one or three groups independently selected from C1-C12 alkyl, -(C1-C12 alkylene)NR10R11, -CH3, oxo, -CO2CH3, -NH2, 1-methylpiperid-4-yl, isopropyl, isobutyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, benzoimidazolyl, benzyl and phenyl, where the alkyl, benzoimidazolyl and phenyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CF3, -CH2OH, -CH3, -C(=O)NHCH3, -NH2, -OH, -OCH3, -CH2OCH3, -C(=O)N(CH3)2, -N(CH3)2, -C(CH3)2OH, -CH(CH3)2, -CH2(1H-1,2,4-triazol-5-yl) and C(=O)4-methylpiperazin-1-yl; R5 is selected from C1-C12 alkyl, optionally substituted with one group independently selected -NH2, -NHCOCH3 and -OH; R6 is selected from pyridinyl and phenyl, each optionally substituted with one or two groups independently selected from F, Cl, Br, I, -CN, -CF3, -C(=O)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10R11 and -C(=O)NR10R11; R10, R11 and R12 are independently selected from H, C1-C12 alkyl, C1-C12 alkylene-phenyl, cyclopentyl, pyridinyl and imidazolyl, where C1-C12 alkyl, cyclopentyl are optionally substituted with one or two groups independently selected from -CH2OH, -N(CH3)2, -NHCOCH3, -OH and -S(O)2CH3; or R10 and R11 together with a nitrogen atom to which they are bonded form a C5-C6 heterocyclic ring containing one or two heteroatoms selected from nitrogen and oxygen, or pyrazolyl, optionally substituted with one or two groups independently selected -CH3, -NH2, -N(CH3)2; -OH and oxo. The invention also relates to a pharmaceutical composition having PI3K inhibiting activity based on said compounds.

EFFECT: obtaining novel compounds which can be used in medicine for treating cancer.

25 cl, 5 dwg, 2 tbl, 331 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to new compounds represented with common formula (I) to its pharmaceutically acceptable salts that have inhibiting activity in relation to products of amyloid β-protein (Aβ42) or decomposition with ferment of beta-site of amyloid-β (BACE1) precursor. In general formula , circle A represents aryl chosen from phenyl, which can be replaced with substitutes with number of 1 to 3, which have been chosen from a group of substitutes α, 5-6-membered heteroalkyl with sulphur atom as heteroatom that can have 1 to 3 substitutes chosen from a group of substitutes α, or 9-10-membered benzo-condensed heterocyclic group having 2 atoms of oxygen in heterocyclic part of the above group, which can be replaced with substitutes with number of 1 to 3, which have been chosen from the group of substitutes α, L means ordinary bond, -NRLCO- (in which RL means hydrogen atom) or -NRLCO-C1-6alkyl (in which RL means hydrogen atom). Circle B represents 5-6-membered heteroaryl or saturated heterocyclic group with 1-3 heteroatoms in a cycle, which have been chosen from a group of hydrogen, oxygen or sulphur atoms, each of which can have 1 to 3 substitutes chosen from the group of substitutes α, or 9-10-membered benzo-condensed group having 2 oxygen atoms in heterocyclic part of the above group, X means methylene that can have 1 to 2 substitutes chosen from the group of substitutes α, Y means methylene that can have 1 to 2 substitutes chosen from the group of substitutes α, and Z means oxygen atom. The rest substitutes are specified in the claim.

EFFECT: compounds can be used for treatment of neurodegenerative diseases caused with Aβ presented with Alzheimer disease as a typical case.

9 cl, 13 dwg, 12 tbl, 88 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzodiazepine compounds of general formula , wherein each R1, R2, R3 and R4 independently represent hydrogen or alkyl, or R2 and R3 together represent lower alkylene; A1 is lower alkylene optionally substituted by hydroxy; and R5 is a fragment of formula , wherein each R6 and R7 independently represents hydrogen, lower alkyl, cycloalkyl, phenyl, furyl, thienyl, pyrazolyl, etc.; each XA and XB independently represents a bond, lower alkylene, -CO-, -SO2- etc., a pharmaceutical composition containing them, and using the above compound as the pharmaceutical composition or for preparing the same.

EFFECT: new compounds may be used for preventing and treating cardiac arrhythmia.

8 cl, 1047 ex, 78 tbl

Iap inhibitors // 2491276

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula: U1-M-U2, where U1 and U2 have general formula (I), where: G stands for: IVb IVd ive, and values M, X1, X2, R2, R3, R3', R4, R4', R5, R5', R6, R6', R7, Z7, Z2, Z3, Z4, Q2 are given in item 1 of the formula.

EFFECT: compounds can be applied for induction of apoptosis in cell.

37 cl, 13 dwg, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 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: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a number of bicyclic nitroimidazole-replaced phenyloxazolydinones of the following structural formula (I):

,

containing nitroimidazole circle, or to its pharmaceutically acceptable salt; where R1 represents hydrogen, (C1-C6)alkyl or aryl; n is equal to 0, 1 or 2; X1 and X2 independently represent H, CF3, CI, OCF3 or F; G represents -OH, triazole or -NHCOR2; R2 represents (C1-C6)alkyl, cycloalkyl or aryl; and L represents a bond or a linker group chosen from any combination 2-3 of the following groups: 1) (C1-C6)alkylene, 2) (C3-C8)cycloalkylene, 3) arylene, arylene-replaced CN, ore arylene-replaced F, 4) group chosen from the group consisting of

,

where R10 represents H, CF3, hydroxyl, amino, alkyl, alkylamino, alkoxy or aryl, and R13 represents H, hydroxyl, amino, alkyl, alkyl amino, alkoxy or aryl, or R13 in combination with nitroimidazole circle can form spiral-shaped structure, 5) -C(=O)-, 6) -O-, 7) -S(O)n-, in which n is equal to 0.1 or 2, 8) -N(R3)-, 9) -C(R4)=C(R5)-, R3 represents hydrogen, (C1-C6) alkyl or aryl, and R4 and R5 represent hydrogen, (C1-C6) alkyl or aryl, or R4 and R5 can be combined together so that they can form a bond. Besides, the invention refers to pharmaceutical composition for treatment of bacterial infection based on compounds of formula I, as well as to a bacterial infection treatment method.

EFFECT: invention describes new compounds that have antibacterial activity against a line of wild type and stable lines of pathogenic microorganisms, and as a result, are suitable for prevention, control and treatment of a number of human and mammal bacterial infections caused by these pathogenic microorganisms such as bacillus Kochii.

15 cl, 93 ex, 1 tbl, 22 dwg

FIELD: biotechnologies.

SUBSTANCE: invention refers to derivatives of oxazolopyrimidine in any of their stereoisomeric forms, or in the form of a mixture of stereoisomeric forms specified in Claim 1.

EFFECT: oxazolopyrimidine derivatives having agonistic activity in relation to Edg-1 receptor.

5 tbl, 319 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel heterocyclic nitrogen- and oxygen-containing compounds having insecticidal activity. In formulae (A) (B) (C) (D) R1 is a 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/ or sulphur atom, a halogen-substituted 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/or sulphur atom, a substituted or unsubstituted phenyl, where the substitutes are one or more groups selected from a group consisting of halogen atoms, C1-4 halogen alkyl or C1-4 chloroalkoxyl; R5, R6, R7, R8 and R9 are H, saturated or unsaturated C1-4 alkyl, halogen atom, saturated or unsaturated C1-4 alkoxyl, saturated C1-4 halogenalkoxyl, C1-4 alkylcarbonyl, C1-8 alkyl ester, C1-4 alkylsulphonyl, phenyl, benzyl or trifluoromethane sulphonyl ether group; Y is nitro, cyano, trifluoromethyl, trifluoroacetyl or trifluoromethylsuphonyl. Values of radicals R, R2-R4 are given in the claim.

EFFECT: invention also relates to an agrochemical composition containing said compounds, use of the agrochemical composition in pest control and a method of producing said compounds.

12 cl, 7 tbl, 36 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described macrocyclic phenylcarbamates of formula (I), wherein A represents -C(=O)OR1 or -C(=O)-NH-SO2-R2, wherein R1 represents hydrogen or C1-C6alkyl; R2 represetns C3-7cycloalkyl, phenyl, thiazolyl or pyridyl each of which is optionally substituted by one or more substituted specified in C1-6alkyl, C1-6alkoxy, trifluoromethyl and halogen; X represents N or CH; E represents NR5; R5 represents hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl or C3-7cycloalkyl; n is equal to 4 or 5; wherein a dash line -----, adjoining the fragment -(CH2)n-, represents a double bond; and wherein the dash line in a five-merous cycle including X, represents a single bond, and R7 represents hydrogen; R8 is such as specified in the patent claim, or N-oxide thereof, a pharmaceutically acceptable additive salt or a pharmaceutically acceptable solvate possessing antiviral activity, and used as HCV inhibitors; as well as pharmaceutical compositions containing the above compounds as an active ingredient.

EFFECT: preparing the pharmaceutically acceptable additive salt or pharmaceutically acceptable solvate possessing antiviral activity.

10 cl, 23 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazo[4,5-b]pyrazine derivatives of general formula or to its pharmaceutically acceptable salt wherein: R1 represents either aryl unsubstituted or substituted by one of the groups: halogen, hydoxyl, C1-6alkyl, C1-6alkoxyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, NHC1-6alkylC1-6alkoxy, C1-6alkylhydroxy, -C(O)NH2, -C(O)OC1-6alkyl, -C(O)NH C1-6alkyl, cyano, carboxy, heteroaryl and heterocycloalkyl; or heteroaryl unsubstituted or substituted by one of the groups: C1-6alkoxy, hydroxy, -C1-6alkyl, NH2 and NHC1-6alkyl; heterocycloalkyl unsubstituted or substituted by one group =O; and R2 represents H; unsubstituted C3-4alkyl; C1-4alkyl substituted by C5-6cycloalkyl unsubstituted or substituted by one group specified in amino, hydroxyl, C1-6alkoxy, or heterocycloalkyl unsubstituted or substituted by 1-2 groups specified in =O, C1-6alkyl; or C5-6cycloalkyl substituted by one group specified in hydroxyl, C1-6alkoxyl, C1-6alkylC1-6alkoxy, C1-6alkylhydroxy, CONH2; or substituted ir unsubstituted heterocycloalkyl; wherein aryl represents an aromatic structure consisting of 6-10 carbon atoms containing one ring or two condensed rings; wherein heteroaryl represents a 5-10-member aryl ring system containing 1-2 heteroatoms specified in nitrogen, oxygen and sulphur; wherein heterocycloalkyl represents a 5-9-member nonaromatic cycloalkyl wherein 1-2 heteroatoms specified in nitrogen and oxygen; provided the compound does not represent 1,3-dihydro-5-phenyl-2H-imidazo[4,5-b]pyrazin-2-one. Also, the invention refers to the specific imidazo[4,5-b]pyrazine derivatives, to a based pharmaceutical composition, to a method of treating or preventing cancer, inflammatory conditions, immunological diseases, metabolic conditions, and to a method of kinase inhibition in a cell expressing said kinase.

EFFECT: there are produced new imidazo[4,5-b]pyrazine derivatives showing effective biological properties.

17 cl, 2 tbl, 210 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

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