5-aminocyclylmethyloxazolidin-2-one derivatives

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to antibacterial compounds of formula (I) , where one or two of U, V, W and X represent N, the remaining ones represent CH or, in case X, can also represent CRa, where Ra represents fluorine; R1 represents alcoxygroup, halogen or cyanogroup; R2 represents H, CH2OH, CH2N3, CH2NH2, alkylcarbonylaminomethyl or triazol-1-ylmethyl; R3 represents H or, when n=1, R3 can also represent OH, NH2, NHCOR6 or triazol-1-yl; A represents CR4; K represents O, NH, OCH2, NHCO, NHCH2; CH2NH5 CH2CH2, CH=CH, CHOHCHOH or CHR5; R3 represents H or together with R5 forms bond, or R4 can also represent OH, when K is not O, NH, OCH2 or NHCO; R5 represents OH or together with R4 forms bond; R6 represents alkyl; m=0 or 1 and n=0 or 1; and G is specified in i.1 of the formula; and to salt of such compound.

EFFECT: obtaining antibacterial compounds.

19 cl, 1 tbl, 44 ex

 

The present invention relates to new derivatives of 5-aminocyclohexanol-2-it, a pharmaceutical antibacterial composition containing them and the use of these compounds for the preparation of drugs 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 pressure 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 slow 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. and Pseudomonas aeruginosa, the main sources of infections, making them resistant to many drugs and causes difficulties in treatment, until Neuve is moznosti treatment at all:

S. aureus is resistant against β-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 multilocational resistance gram-negative strains such as Enterobacteriacea and Pseudomonas aeruginosa, is constantly increasing, resulting in the re-emerging organisms, such such organisms like Acinetobacter spp., which were highlighted during therapy with the currently used antibiotics, have become a real problem in hospitals. Consequently, there is a need for new antibacterial agents are able to overcome multilocational resistance of gram-negative bacteria such as A. baumannii, ESBL-produced by E. coli and Klebsiella species, and Pseudomonas aeruginosa (George H. Talbot et al., Clinical Infectious Diseases, (2006), 42, 657-68).

In addition, microorganisms resistant infections, more p is isnauda as causes or contributing factors of some chronic diseases, like peptic ulcers or heart disease.

WO 02/50040 describes some piperazine derivatives as antibacterial agents, including at least two compounds having the structure (A1) and (A2)below:

WO 2004/032856 discloses inhibitors of the receptor of the chemokine CCR8 formula (A3)

where

n=0 or 1; m=0 or 1; p=1, 2 or 3;

Ar represents an unsubstituted chinoline, [1,5]naphthyridine or pyridinyl; or substituted chinoline, [1,5]naphthyridine or pyridinyl one or more radicals selected from (preferably) C1-6alkoxygroup, halogen and cyanopropyl; and

R is preferably unsubstituted or substituted phenyl-lower alkyl, unsubstituted or substituted pyridyl-lower alkyl, unsubstituted or substituted indolyl-lower alkyl, unsubstituted or substituted N-(lower alkyl)indolyl-lower alkyl, unsubstituted or substituted chinoline-lower alkyl, unsubstituted or substituted naphthyl-lower alkyl, unsubstituted or substituted benzofuranyl-lower alkyl, unsubstituted or substituted benzothiophene-lower alkyl; where, in the case of a substitution group is substituted by one or more radicals selected from the group comprising From1-6alkoxygroup,1-6alkyl, halogen, cyano what the Rupp and trihalomethyl.

In addition, WO 2004/050036 describes the antibacterial compounds of formula (A4)

where

one of Z1, Z2, Z3, Z4and Z5is N, one is CR1aand the remainder are CH, or one or two of Z1, Z2, Z3, Z4and Z5are independently CR1aand the remainder are CH;

R1and R1aare independently preferably hydrogen, halogen, C1-6alkoxygroup or cyano;

each R2represents independently preferably hydrogen, HE or NH2;

R3represents H or unsubstituted or substituted C1-6alkyl;

R4represents a group-U-R5where U is CH2, C=O or SO2and R5is preferably bicyclic heterocyclic ring system such as 4H-benzo[1,4]oxazin-3-one-6-yl, 4H-benzo[1,4]thiazin-3-one-6-yl, 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl or 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl.

The applicant has unexpectedly found that the compounds of formula (I), described below, applicable as antibacterial agents.

Various embodiments of the present invention is as follows:

i) the Invention primarily relates to compounds of formu the uly (I)

where

one or two (and preferably two) of U, V, W and X are N, the others represent CH or, in the case of X, may also represent CRawhere Rais fluorine;

R1is alkoxygroup, halogen or cyano;

R2represents N, CH2HE, CH2N3CH2NH2alkylcarboxylic or triazole-1-ylmethyl;

R3represents H or, when n=1, R3can also be a HE, NH2, NHCOR6or triazole-1-yl;

But a CR4;

It represents Oh, NH, OCH2, NHCO, NHCH2CH2NH, CH2CH2, SN=SN, SNANNON or CHR5;

R4represents H or, together with R5forms a bond, or R4can also be a HE, when It is Oh, NH, OCH2or NHCO;

R5is a HE or, together with R4forms a bond;

R6represents alkyl;

m=0 or 1 and n=0 or 1; and

G represents a group

where Z1represents N, Z2represents CH and Z3represents CH; or

Z1represents CH, Z2represents N and Z3represents CH or N; or

Z1the submitted is a CH, Z2represents CH and Z3represents CH or N;

the ring R is selected from the following groups:

in which Q represents O or S;

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

The compounds of formula (I) can contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. The substituents at the double bond may be present in the Z - or E-configuration, unless otherwise noted. The compounds of formula (I) can therefore be represented as a mixture of stereoisomers, or, preferably, pure stereoisomers. Mixtures of stereoisomers may be separated by methods known to experts in the field of technology.

The relative configuration (xR*yR*) stereoisomers, where x and y are integers, denoted as total from the following example: 6-{(R)-5-[(3R*,4R*)-3-(6-methoxyquinazoline-4-yloxy)-4-[1,2,3]triazole-1-iparralde-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-he is referred to as 6-{(R)-5-[(3R,4R)-3-(6-methoxyquinazoline-4-yloxy)-4-[1,2,3]triazole-1-iparralde-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one, or 6-{(R)-5-[(3S,4S)-3-(6-methoxyquinazoline-4-yloxy)-4-[1,2,3]triazole-1-iparralde-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one, the mixture of the two stereoisomers.

In the following paragraphs presents the definitions of the various chemical residue for compounds according to the invention. These 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 groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The term "C1-xalkyl" (x represents an integer) refers to a linear or branched alkyl group containing from 1 to x carbon atoms.

The term "alkoxygroup", used alone or in combination, refers to a saturated linear or branched alkoxygroup containing from one to four carbon atoms. Typical examples of alkoxygroup include a methoxy group, ethoxypropan, propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, sec-butoxypropyl and tert-butoxypropan. The term "C1-xalkoxygroup" refers to linear or branched alkoxygroup containing from 1 to x carbon atoms.

The term "halogen" skidding is carried out by fluorine, chlorine, bromine or iodine, preferably by fluorine or chlorine.

The term "alkylcarboxylic" refers to a methyl group in which one hydrogen atom substituted by alkylcarboxylic, with an alkyl group represents previously described. Typical examples alquilervillapeniscola groups include, but are not limited to, methylaminomethyl and ethylaminoethanol (preferably methylaminomethyl).

Connection interrupted wavy line, in the present description indicates the point of attachment of the radical. For example, the radical as shown below,

is 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ilen group.

In addition, in the present description, when It is asymmetric radical, the left part of the radical is presented below (for example, in co2) attached to the aromatic fragment

while the right side presents radical (for example, CH2in OCH2) attached to piperidinium fragment

In addition, the term "room temperature"used in the present description, 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 of interest to the shaft, 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"located before temperature "Y" refers in the customary application to the temperature interval of Y minus 10 C to Y plus 10°C., and preferably to an interval of Y minus 5 to Y plus 5 C.

ii) In another embodiment, the invention relates to compounds of formula (I)with the values specified in option (i) above or their salts (among which the pharmaceutically acceptable salts are preferred), where G represents the following groups:

or

where Z1, Z2, Z3and Q have the values listed in option (i) above.

iii) In another embodiment, the invention relates to compounds of formula (I)having the values listed in option i) or ii) above or their salts (among which the pharmaceutically acceptable salts are preferred), where

R1is alkoxygroup;

R3represents H or, when n=1, R3can also be a HE, NH2or triazole-1-yl;

It represents Oh, NH, OCH2, NHCO, NHCH2CH2CH2, SN=SN, SNANNON or CHR5where R5matter, the decree is installed in option (i) above; and

G represents a group

where Z represents N or CH, and ring R is selected from the following groups:

in which Q represents O or S.

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

where

U and V each represents N and W and X each represent CH, or U and V each represent CH and W and X each represent N, or U and W each represent N, and V and X each represents CH;

R1is alkoxygroup (and, preferably, a methoxy group);

R2represents N, CH2HE, CH2N3CH2NH2alkylcarboxylic or triazole-1-ylmethyl;

R3is an And, or, when n=1, R3can also be a HE, NH2or triazole-1-yl;

But a CR4;

It represents O, NH, NHCO, NHCH2CH2CH2, SN=SN, SNANNON or CHR5;

R4represents H or, together with R5forms a bond, or R4can also be a HE, when It is not O, NH or NHCO;

R5is a HE, or together with R4forms a link;/p>

m=0 or 1 and n=0 or 1; and

G represents one of the groups below

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

v) According to a preferred variant implementation of the present invention the compounds of formula (I)with the values specified in the options (i)-(iv) above or their salts (among which the pharmaceutically acceptable salts are preferred), must be such that R1was1-3alkoxygroup (preferably a methoxy group or ethoxypropane and, in particular, methoxy group).

vi) Another preferred implementation of the present invention relates to compounds of formula (I)with the values specified in the options (i)-(v) above or their salts (among which the pharmaceutically acceptable salts are preferred), where U and V each represents N and W and X each represent CH, or U and V each represent CH and W and X each represent N, or U and W each represent N, and V and X each represent CH.

vii) According to one of preferred embodiments of the present invention (vi)above, the compounds of formula (I) or their salts (among which the pharmaceutically acceptable salts are the two which are preferred) must be such as in which U and V each represent N, and W and X each represent CH.

viii) According to another preferred variant implementation of the present invention (vi)above, the compounds of formula (I) or their salts (among which the pharmaceutically acceptable salts are preferred) must be such that U and V each represent CH and W and X each represents N.

ix) According to another preferred variant implementation of the present invention (vi)above, the compounds of formula (I) or their salts (among which the pharmaceutically acceptable salts are preferred) must be such that U and W each represent N, and V and X each represent CH.

x) Another another preferred implementation of the present invention relates to compounds of formula (I)having the values indicated in the embodiments i)to ix)above or their salts (among which the pharmaceutically acceptable salts are preferred) where:

It represents NHCO or NHCH2And represents CH, type each = 0 and R2and R3each represents H;

It represents About And represents CH, type each = 0 and R2and R3each represents H;

It represents O, NHCO, CH2CH2or SSN, And represents CH, m=1 and n=0 and R2and R3each represents H;

It represents About And represents CH, m=0 and n=1, R2represents N and R3represents IT;

It represents About And represents CH, m and n each = 1 and R2and R3each represents H;

It represents About And represents CH, m=0 and n=1, R2represents N and R3represents NH2or triazole-1-yl;

It represents About And represents CH, m=1 and n=0, R2represents CH2HE, CH2NH2acetamidomethyl or triazole-1-ylmethyl and R3represents N;

It is a CR5But a CR4, R4and R5together form a bond (i.e. the EA group represents a CH=C), m and n each = 1 and R2and R3each represents H;

It is a CHR5, R5is a HE, BUT a CR4, R4HE is a type for every = 1 and R2and R3each represents H; or

It is SNANNON, AND represents CH, m=1 and n=0 and R2and R3each represents N.

xi) According to one preferred options x), the present invention relates to compounds of formula (I) or their salts (among which which is pharmaceutically acceptable salts are preferred in which:

It represents NHCO or NHCH2And represents CH, m and n are each = 0 and R2and R3each represents H;

It represents About And represents CH, m and n are each = 0 and R2and R3each represents H;

It represents O, NHCO, CH2CH2or CH=CH, And represents CH, m=1 and n=0 and R2and R3each represents H;

It represents About And represents CH, m=0 and n=1, R2represents N and R3represents IT;

It represents About And represents CH, m and n each = 1 and R2and R3each represents H;

It represents About And represents CH, m=0 and n=1, R2represents N and R3represents NH2or triazole-1-yl;

It represents About And represents CH, m=1 and n=0, R2represents CH2HE, CH2NH2acetamidomethyl or triazole-1-ylmethyl and R3represents N; or

It is a CR5But a CR4, R4and R5together form a bond (i.e., the KA group represents a CH=C), each = 1 and R2and R3each represents N.

xii) Preferably, the compounds of formula (I) according to variant (xi) or their salts (among which the pharmaceutically acceptable salts yavlyaetsyaprostota) shall be such as in which:

It represents NHCO or NHCH2And represents CH, m and n are each = 0 and R2and R3each represents H;

It represents About And represents CH, m and n are each = 0 and R2and R3each represents H;

It represents O, NHCO, CH2CH2or CH=CH, And represents CH, m=1 and n=0 and R2and R3each represents H;

It represents About And represents CH, m=0 and n=1, R2represents N and R3represents IT;

It represents About And represents CH, m and n each = 1 and R2and R3each represents H;

It represents About And represents CH, m=0 and n=1, R2represents N and R3represents NH2or triazole-1-yl;

It represents About And represents CH, m=1 and n=0, R2represents CH2HE or triazole-1-ylmethyl and R3represents N; or

It is a CR5But a CR4, R4and R5together form a bond (i.e., the EA group represents a CH=C), each = 1 and R2and R3each represents N.

xiii) preferably, the compounds of formula (I) according to variant (xi) or their salts (among which the pharmaceutically acceptable salts are preferred and must be such in which a represents CH and:

It represents NHCO or NHCH2, m and n are each = 0 and R2and R3each represents H;

It represents O, m and n are each = 0 and R2and R3each represents H;

It represents O, NHCO, CH2CH2or CH=CH, m=1 and n=0 and R2and R3each represents H;

It represents Oh, m=0 and n=1, R2represents N and R3represents IT; or

It represents O, m and each n = 1 and R2and R3each represents N.

xiv) According to another preferred variant x), the present invention relates to compounds of formula (I) or their salts (among which the pharmaceutically acceptable salts are preferred) where:

It is a CHR5, R5is a HE, BUT a CR4, R4HE is a, m and n each = 1 and R2and R3each represents H;

It is SNANNON, AND represents CH, m=1 and n=0 and R2and R3each represents N.

xv) According to one of embodiments of the present invention, the compounds of formula (I) or their salts (among which the pharmaceutically acceptable salts are preferred), have the meanings given in one of the options (i)-(xiii), should the ü such in which m and n are each = 0.

xvi) According to the following one of the embodiments of the present invention, the compounds of formula (I) or their salts (among which the pharmaceutically acceptable salts are preferred), have the meanings given in one of the options (i)-(xiii)shall be such that m=0 and n=1.

xvii) According to another variant implementation of the present invention, the compounds of formula (I) or their salts (among which the pharmaceutically acceptable salts are preferred), have the meanings given in one of the options (i)-(xiv)shall be such that m=1 and n=0.

xviii) According to another another variant implementation of the present invention, the compounds of formula (I) or their salts (among which the pharmaceutically acceptable salts are preferred), have the meanings given in one of the options (i)-(xiv)shall be such that m and n are each = 1.

xix) According to another another variant implementation of the present invention, the compounds of formula (I)have the meanings given in one of the options (i)-(xviii) above or their salts (among which the pharmaceutically acceptable salts are preferred) must be such that the ring R of a group G is a

where Q represents O or S (and, in particular, S).

XX) According to the another another variant implementation of the present invention, the compounds of formula (I)have the meanings given in one of the options (i)-(xviii) above or their salts (among which the pharmaceutically acceptable salts are preferred) must be such that the ring R of a group G is a

xxi) Preferably, the compounds of formula (I)having values above embodiments, xix or XX), or their salts (among which the pharmaceutically acceptable salts are preferred) must be such that Z denotes CH.

xxii) More preferably, the compounds of formula (I)having values above embodiments, xix or XX), or their salts (among which the pharmaceutically acceptable salts are preferred) must be such that the group G is a 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl or 2,3-dihydrobenzo[1,4]dioxin-6-yl (in particular, 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl).

xxiii) a Special variant of the present invention relates to compounds of formula (I)have the meanings given in one of the options (i)-(xiii) and (xv)-xxii) above or their salts (among which the pharmaceutically acceptable salts are preferred), where K represents O or co2.

xxiv) Another preferred variant of the present invention relates to compounds of formula (I)having the values shown in the nome of the options (i)-(xiii) and (xv)-xxii) above, or their salts (among which the pharmaceutically acceptable salts are preferred), where K represents NH, NHCO or NHCH2.

xxv) According to the sub-option special option xxiv) the compounds of formula (I)have the meanings given in one variation xxiv) above or their salts (among which the pharmaceutically acceptable salts are preferred) must be such that It represents NH.

xxvi) According to another sub-option special option xxiv), the compounds of formula (I)have the meanings given in one variation xxiv) above or their salts (among which the pharmaceutically acceptable salts are preferred) must be such that It represents NHCO.

xxvii) According to another sub-option special option xxiv), compounds having the meanings given in one variation xxiv) above or their salts (among which the pharmaceutically acceptable salts are preferred) must be such that It represents NHCH2.

xxviii) Another preferred variant of the present invention relates to compounds of formula (I)having the meanings given above, in one embodiment, (i)-(xxii)or their salts (among which the pharmaceutically acceptable salts are preferred), where K represents CH2CH2, SN=SN, SNANNON or CHR5.

p> xxix) Particularly preferred are the compounds of formula (I)have the meanings given in one of the options (i)-(iv):

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

6-{(R)-5-[(R)-3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4D-benzo[1,4]thiazin-3-one;

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

(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-[3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-oxazolidin-2-he;

6-{(R)-5-[(2S,4S)-2-hydroxymethyl-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(R)-5-[(2S,4S)-2-azidomethyl-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

(6-methoxy[1,5]naphthiridine-4-yl)amide 1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]azetidin-3-carboxylic acid;

(6-methoxy[1,5]naphthiridine-4-yl)amide 1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]pyrrolidin-3-carboxylic acid;

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

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

6-((R)-5-{3-[(1R,2R)-1,2-d is hydroxy-2-(6-methoxy[1,5]naphthiridine-4-yl)ethyl]pyrrolidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;

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

6-((R)-5-{4-hydroxy-4-[hydroxy(3-methoxyaniline-5-yl)methyl]piperidine-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;

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

6-{(R)-5-[(2S,4S)-2-aminomethyl-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(R)-5-[(3R*,4R*)-3-(6-methoxyquinazoline-4-yloxy)-4-[1,2,3]triazole-1-iparralde-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

N-{(2S,4S)-4-(6-methoxyquinazoline-4-yloxy)-1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]pyrrolidin-2-ylmethyl}ndimethylacetamide;

6-{(R)-5-[(3R*,4R*)-3-amino-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(R)-5-[(2S,4S)-4-(6-methoxyquinazoline-4-yloxy)-2-[1,2,3]triazole-1-iletilenlerin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

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

6-{(R)-5-[(3R*,4R*)-3-hydroxy-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(R)-5-[(3R*,4R*)-3-hydroxy-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,thiazin-3-one;

and their salts (in particular pharmaceutically acceptable salts).

xxx) in Addition, especially preferred are the following compounds of formula (I)having values presented in one of the options (i)-(iv):

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

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

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

(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-[(R)-3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-oxazolidin-2-he;

(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-[(S)-3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]oxazolidin-2-he;

6-{(R)-5-[(2S,4S)-2-hydroxymethyl-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(R)-5-[(2S,4S)-2-azidomethyl-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

(6-methoxy[1,5]naphthiridine-4-yl)amide 1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]azetidin-3-carboxylic acid;

(6-methoxy[1,5]naphthiridine-4-yl)amide (R)-1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]pyrrolidin-3-carboxylic acid;

(6-methoxy[1,5]naphthiridine-4-yl)amide (S)-1-[(R)-2-the CSR-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]pyrrolidin-3-carboxylic acid;

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

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

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

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

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

6-((R)-5-{(S)-3-[(1R,2R)-l,2-dihydroxy-2-(6-methoxy[1,5]naphthiridine-4-yl)ethyl]pyrrolidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;

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

6-((R)-5-{4-hydroxy-4-[(R)-hydroxy-(3-methoxyaniline-5-yl)methyl]piperidine-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;

6-((R)-5-{4-hydroxy-4-[(S)-hydroxy-(3-methoxyaniline-5-yl)-methyl]piperidine-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;

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

6-{(R)-5-[(2S,4S)-2-aminomethyl-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one

6-{(R)-5-[(3R*,4R*)-3-(6-methoxyquinazoline-4-yloxy)-4-[1,2,3]triazole-1-iparralde-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

N-{(2S,4S)-4-(6-methoxyquinazoline-4-yloxy)-1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]pyrrolidin-2-ylmethyl} ndimethylacetamide;

6-{(R)-5-[(3R*,4R*)-3-amino-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(R)-5-[(2S,4S)-4-(6-methoxyquinazoline-4-yloxy)-2-[l,2,3]triazole-l-iletilenlerin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

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

6-{(R)-5-[(3R*,4R*)-3-hydroxy-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{(R)-5-[(3R*,4R*)-3-hydroxy-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;

and their salts (in particular pharmaceutically acceptable salts).

xxxi) in Addition, the following compounds of formula (I)having values presented in one of the options (i)-(iv), particularly preferred:

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

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

6-{(R)-5-[3-(6-methoxyquinoline-4-the laminitis)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one;

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

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

6-((R)-5-{3-[(3-fluoro-6-methoxyquinoline-4-ylmethyl)amino]azetidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]oxazin-3-one;

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

(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-[3-(6-methoxyquinazoline-4-intoximeter)azetidin-1-ylmethyl]oxazolidin-2-he;

6-{(R)-5-[4-(6-methoxyquinazoline-4-yloxy)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one;

N-{(3R*,4R*)-4-(6-methoxyquinazoline-4-yloxy)-1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]pyrrolidin-3-yl}ndimethylacetamide;

(R)-3-(6,7-dihydro[1,4]like[2,3-C]pyridazin-3-yl)-5-[3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]oxazolidin-2-it (especially such as (R)-3-(6,7-dihydro[1,4]like[2,3-C]pyridazin-3-yl)-5-[(R)-3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]oxazolidin-2-one or (R)-3-(6,7-dihydro-[1,4]like[2,3-C]pyridazin-3-yl)-5-[(R)-3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-oxazolidin-2-one);

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

6-{(R)-5-[4-(6-methoxy[15]naphthiridine-4-ylamino)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one;

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

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

4-{1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-6-yl)oxazolidin-5-ylmethyl]azetidin-3-ylamino} - quinoline-6-carbonitrile;

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

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

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

(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-[3-(6-methoxy[1,5]naphthiridine-4-ylamino)azetidin-1-ylmethyl]oxazolidin-2-he;

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

(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-[3-(6-methoxyquinoline-4-yloxy)azetidin-1-ylmethyl]oxazolidin-2-he;

and their salts (in particular pharmaceutically acceptable salts).

The compounds of formula (I) according to the invention, i.e. according to one of the options (i)-(xxxi), are suitable for use as chemotherapeutic active compounds in medicine and veterinary medicine and as substances for preserving inorganic and organic materials, in cast the STI, 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 similar bacteria organisms, and 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, including pneumonia, otitis media, sinusitis, bronchitis, tonsillitis, and mastoiditis related to infection caused by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Enterococcus faecalis, E. faecium, E. casseliflavus, S. epidermidis, S. haemolyticus, 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, β-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracyclines, makali is s; uncomplicated infections of skin and soft tissue abscesses and postpartum sepsis associated with infection caused by Staphylococcus aureus, coagulability susceptible (i.e., S. epidermidis, S. haemolyticus, and the like), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcal groups C-F (the smallest colony streptococci), viridans streptococci, Corynebacterium minutissimum, Clostridium spp. or Bartonella henselae; uncomplicated acute urinary tract infections related to infection caused by Staphylococcus aureus, coagulability species Staphylococcus or Enterococcus spp.; urethritis and cervicitis; sexually transmitted diseases related to 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. pneumonias, 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; Chechnya protozoal infections associated with infection caused by Cryptosporidium spp.; dental infection associated with 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 related to infection caused by Helicobacter pylori or Chlamydia pneumoniae.

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

The compounds of formula (I) according to the present invention are applied, in addition, for the treatment of protozoal infections caused by Plasmodium malaria, Plasmodium falciparum, Toxoplasma gondii, Pneumocystis carinii, Trypanosoma brucei and Leishmania spp.

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

One aspect of the present invention relates therefore to the use of compounds of formula (I) according to the present invention or its pharmaceutically acceptable salt to obtain drugs in the prevention or treatment of bacterial infections is Peccei.

As in medicine, a bacterial infection to be treated with the use of compounds of formula (I) or their pharmaceutically acceptable salts) and in veterinary medicine to treat such species as, for 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) includes a reference to salts (in particular pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.

The term "pharmaceutically acceptable salts" refers to non-toxic, inorganic and/or organic basic additive salts. Reference may be made to the publication: "Salt selection for basic drugs". Int. J. Pharm. (1986), 33, 201-217.

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, Remington, 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, optionally in combination with other pharmaceutically acceptable substances in dosage 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 of treating a bacterial infection in a patient, comprising the introduction of the named patient pharmaceutically active amount of a compound of formula (I) or its pharmaceutically acceptable salt.

In addition, any preferences indicated for the compounds of formula (I) or the compounds, salts, compositions containing the compounds or salts thereof, uses of the compounds or its salts, and the like) are applicable mutatis mutandis to compounds of formula (ICE).

Moreover, the compounds of formula (I) can be applied for disinfection, for example, for processing surgical instruments to remove pathogenic bacteria and bacterial or aseptic cleaning is Emesene or surfaces. For these purposes the compounds of formula (I) can be applied in the form of a solution or spray.

According to the invention, the compounds of formula (I) can be obtained using the methods described below.

Obtaining compounds of formula (I)

Abbreviations:

In the description and examples, the following abbreviations are used:

AC is acetyl, Asón - acetic acid, AD - mix α-1,4-bis(dihydroquinoline)phthalazine, K3Fe(CN)6, K2CO3and K2OsO42H2Oh, AD - mix β-1,4-bis(dihydroquinoline)phthalazine, K3Fe(CN)6, K2CO3and K2OsO42H2O, BINAP - 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene, Boc - tert-butoxycarbonyl, Cbz - benzyloxycarbonyl, CBI - 1,1'-carbonyldiimidazole, DC - dicyclohexylcarbodiimide, DHM - dichloromethane, 1,2-EDC - 1,2-dichloroethane, DEAD - diethylazodicarboxylate, (DHQ)2PHAL - 1,4-bis(digitonin)phthalazine), (DHQD)2PHAL - 1,4-bis(dihydropyridin)phthalazine), DYADS - diisobutyldimethoxysilane, DEBUG - diisobutylaluminium, DIPEA - N,N-diisopropylethylamine, DMAP - 4-dimethylaminopyridine, 1,2-DME - 1,2-dimethoxyethane, DMF is N,N-dimethylformamide, DMSO is dimethylsulfoxide, DPEphos - bis(2-diphenylphosphinoethyl)ether, EA - ethyl acetate, EDC hydrochloride, 1-(3-diethylaminopropyl)-3-ethylcarbodiimide, ESW - electrospray ionization, EQ, equivalent, ether - diethyl ether, Et is ethyl, BB - high Vacu is mA KHMDS - hexamethyldisilazide potassium, HPLC - high performance liquid chromatography, LDA - sitedisability, m-HPBK - m-chloroperbenzoic acid, and Me is methyl, MeCN is acetonitrile, min-min, MS - mass spectroscopy, MS - methanesulfonyl (mesyl), n-Bu is n-butyl, NMO - N-oxide N-methylmorpholine, N-MP - N-organic, Pd/C is palladium on coal, Ph is phenyl, rat. - racemic, RT - room temperature, TBAF - tetrabutylammonium, TBDMS - tert-butyldimethylsilyl, TMCOTf - tert-butyldichlorosilane, tBu is tert-butyl, tea is triethylamine, TEMPO is 2,2,6,6-tetramethyl-1-piperidinyloxy-, Tf - trifloromethyl (triflic), TPA - triperoxonane acid, THF is tetrahydrofuran, TMS is trimethylsilyl, Ts - p-toluensulfonyl, Z (amino acids) - benzyloxycarbonyl.

The General reaction techniques:

The General reaction method 1: protection of the amino group

Amines generally protect such groups as the Alloch, Cbz, Boc or Fmoc. Using the reaction of an amine with allyl or benzylchloride, di-tert-BUTYLCARBAMATE or Fmoc-C1 in the presence of a base such as NaOH, tea, DMAP or imidazole. They can be protected as N-benzyl derivatives obtained by reaction with benzylbromide or benzylchloride in the presence of a base such as Na2CO3or tea. Alternatively, N-benzyl derivatives can be obtained through the om reductive amination in the presence of benzaldehyde and borhydride reagent such as NaBH4, NaBH3CN or NaBH(SLA)3in a solvent such as EtOH. In addition, other methods include amine protective groups described in Protecting Groups in Organic Synthesis, 3rd Ed (1999), 494-653; T.W.Greene, P.G.M. Wuts (Publisher: John Wiley and Sons, Inc., New York, N.Y.).

The General reaction method 2: protection of hydroxyl group:

Alcohols protect, turning them into silyl ethers (usually TBDMS or TRIPS), using the reaction of the alcohol with the desired similiarites (TBDMS-C1 or TRIPS-C1) 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. TBDMS group can also be introduced by reaction with Trimbath the presence of lutidine. In addition, other protective methods include alcohol groups described in Protecting Groups in Organic Synthesis, 3rdEd (1999), 23-147; T.W.Greene, P.G.M. Wuts (Publisher: John Wiley and Sons, Inc., New York, N.Y.).

The General reaction method 3: remove protection from a hydroxyl group:

Silylamine group is removed either through the use of sources of fluorine anion such as TBAF in THF, HF in MeCN or HF pyridine in THF in a temperature range from 0°C to +40°C, or in acidic conditions using Asón in a mixture of THF/Meon or HCl in the Meon. Other methods of removal TRIMS and TRIPS groups are presented in the publication: Protecting Groups in Organic Synthesis 3rdEd; 1999, pages 133-139 and 142-143 respectively; T.W.Greene, P.G.M. Wuts; (Publisher: John Wiley and Sons, Inc., New York, N.Y.). Other obsemedage removal of the protective spirit of the groups described in the publication: Protecting Groups in Organic Synthesis, 3rdEd (1999), 23-147; T.W.Greene, P.G.M. Wuts (Publisher: John Wiley and Sons, Inc., New York, N.Y.).

The General reaction method 4: getting oxazolidinone through glyadelova esters:

The corresponding carbamates derived from aniline or 2-aminopyridine, is introduced into the reaction in a dry solvent such as THF or DMF, with a strong organic base such as n-BuLi in the temperature range from -100°C to +30°C, or with tert-BuOLi or tert-BuOK or KHMDS at temperatures from -100°C to -30°C in DMF or THF. The anion reacts at these temperatures with the corresponding epoxide, after which the reaction mixture is left to spontaneously warm to room temperature.

General reaction technique 5: catalyzed by metal reaction cross-condensation of N and O arilirovaniya:

Aromatic halide or triflate enter into reaction with the appropriate amine in the presence of palladium catalyst (as described in J. Am. Chem. Soc. (1997), 119, 3395-96 or J. Org. Chem. (2007), 72, 2232-2235) and base such as tert-BuOK or LDA at a temperature of from +20°C to +100°C. In a variant of the Goldberg reaction carried out using aromatic halide or triflate and covenants, carbamate or amine in the presence of CuI, inorganic base such as K2CO3or K3PO4in the temperature range from +40°C up to +110°C, as described in: Tetrahedron Letters (2006), 47, 1181-86 or J. Am. Chem. Soc. (2001), 123, 7727-29. For kataliziruemogo metal N-arilirovaniya 2-oxazolidinone reaction is carried out in the presence of CuI, 1,1,1-Tris(hydroxymethyl)ethane and Cs2CO3(Org. Lett. (2006), 8, 5609-5612) or Pd(OAc)2and Depos in the presence of K3PO4(J. Org. Chem. (2007), 72, 2232-2235).

The General reaction method 6: reaction Mitsunobu:

Condensation on Mitsunobu was proposed by O. Mitsunobu in Synthesis (1981), 1. The reaction between the phenol, a triol or a sulfonamide and alcohol is carried out in the presence of DEAD or DYADS and PPh3. The reaction can be carried out using a number of solvents such as DMF, THF or DHM, and in a wide temperature range from -78°C to 50°C).

The General reaction method 7: alkylation:

Derived amine is introduced into reaction with the compound of the formula alkyl-L2where L2represents OMs, OTf, OTs, Cl, Br or I, or a corresponding derivative having a side group L2as noted earlier, allyl or gomoallilnymi halide in the presence of inorganic bases such as K2CO3or organic base such as tea in a solvent such as THF, in a temperature range from 0°C to +80°C. details can be found 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.779.

The General reaction method 8: activation of alcohol:

Alcohol injected into reaction with MsCl, TfCl or TsCI in the presence of a base such as tea in a dry, aproto the nom solvent such as pyridine, THF or DHM, in the temperature range from -30°C to +50°C. In the case triftoratsetata or methansulfonate can also be used Tf2O or Ms2O. These sulfonates can be introduced into the reaction with sodium iodide in acetone in the temperature range from +40°C up to +80°C to obtain the corresponding improsoned.

The General reaction method 9: amide condensation:

Carboxylic acid is introduced into the reaction with the amine in the presence of an activating agent such as DCC, EDC, HOBT, anhydride n-propylphosphonic acid, GATA, CBI or di-(N-Succinimidyl)carbonate, in a dry aprotic solvent such as DHL, MeCN or DMF, in a temperature range from -20°C to +60°C (see: G. Benz in Comprehensive Organic Synthesis, B.M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 6, p.381). Alternatively, the carboxylic acid can be activated by converting it into the corresponding acid chloride by reaction with oxalylamino or thionyl chloride, undiluted or diluted with a solvent type DHM, in the temperature range from -20°C to +60°C. Other activating agents can be found in the publication: Comprehensive Organic Transformations. A guide to Functional Group Preparations; 2 Edition, R.C.Larock, Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1999. Section nitriles, carboxylic acids and derivatives, p.1941-1949.

The General reaction method 10: CIS-dihydroxypropane:

Diol get dihydroxyvitamin the eating of the corresponding ethylene derived using catalytic amounts of osmium tetroxide in the presence of deoxidant such as NMO in an aqueous solvent such as mixtures 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 α or AD-mix β in the presence of methanesulfonamide in a mixture of water/2-methyl-2-propanol as described in Chem. Rev. (1994), 94, 2483. The orientation of the induction depends on the chiral ligand contained in AD mixture, or digitonin-base ligand in AD-mix α or dihydropyridin-base ligand in AD-mix β.

The General reaction method 11: remove aminosidine groups:

Benzylcarbamoyl exempt from protection by hydrogenolysis over the catalysts of noble metals (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 methyl alcohol or dioxane or TFA (undiluted or diluted), in a solvent such as DHM. Other common methods of removal of the protective amino group described in: Protecting Groups in Organic Synthesis, 3rdEd (1999), 494-653; T.W.Greene, P.G.M. Wuts (Publisher: John Wiley and Sons, Inc., New York, N.Y.).

The General reaction method 12: remove protection from katalinich groups:

Ketal converted into the corresponding ketone under acidic conditions using dilute aqueous HCl solution in Meon, a diluted aqueous solution of Asón, or using acidic resins such as Amberlite IR120H or DOWEX

50W8, in a mixture of water will dissolve the l such as Meon/water or THF/water, in the temperature range from 20°C to 80°C.

The General reaction method 13: oxidation of alcohols into acids:

The alcohols can be can be directly oxidized to the corresponding acid using various methods described in: Comprehensive Organic Transformations. A guide to Functionnal Group Preparations; 2ndEdition, R.C.Larock, Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1999. Section nitriles, carboxylic acids and derivatives, p.1646-1648. Among these methods are often used [bis(acetoxy)iodine]benzene in the presence of TEMPO, reagents Jones (CrO3/H2SO4), NaIO4in the presence of RuCl3, KMnO4or pyridine/H2Cr2O7.

The General reaction method 14: getting alkene by the condensation reaction the Wittig or Julia sets:

The Wittig reaction:

Alkene RaCH=CHRbcan be obtained by the reaction of RaCHO with postrana Ph3P=CHRb. For the reaction used a wide variety of solvents such as, for example, toluene or THF, in a temperature range from -10°C to 100°C. the Required fosfory obtained from the corresponding halide of phosphonium Ph3P+CH2RbHal-(Hal denotes a halogen atom) in the presence of a base such as alkylate potassium (for example, tert-BuOK), LiHMC, KHMDS or n-BuLi. The phosphonium salts are obtained from the corresponding halide HalCH2Rband PPh3p and heated under reflux in a solvent such as toluene or MeCN.

Condensation Julia sets:

Alkene RaCH=CHRbcan be obtained by using the condensation reaction by Julia sets sulfone RbCH2SO2Rcand aldehyde RaCHO in the presence of a base such as LiHMC or KHMDS, in a solvent such as 1,2-DME, DMF or toluene, as described Blakemore, P.R in J. Chem. Soc., Perkin, Trans. 1 (2002), 2563-2585. Required sulfon receive from the corresponding sulfide RbCH2SRcusing oxidation. To perform this reaction can be used a number of oxidizing agents such as m-HPBC in a solvent such as DHL, oxone®in a solvent such as an aqueous solution Meon (see: Tetrahedron Lett. (1981), 22, 1287), or an aqueous solution of hydrogen peroxide in the presence of tetrahydrate of heptamolybdate of ammonia in EtOH (see: J. Org. Chem. (1963), 28, 1140). The sulfide is obtained from the corresponding alcohol RbCH2OH, using the reaction of condensation Mitsunobu. An alternative way of obtaining the intermediate sulfide requires conversion of the alcohol RbCH2OH in the active iodide with subsequent application of the General reaction method 8. The latter serves as an alkylating agent is 1-phenyl-1H-tetrazol-5-thiol. The alkylation reaction is carried out in the presence of inorganic bases such as KOH or NaOH, in a solvent such as EtOH, at a temperature ranging from 20°C to 70°C. Alkene RaRa'C=CHRbcan be obtained by reaction of the ketone RaCORa'with postrana Ph3P=CHRbas explained above.

The General reaction method 15: hydrolysis of ester to carboxylic acid:

When the ester side chain is a linear alkyl, hydrolysis is usually carried out by treatment with alkali metal hydroxide such as LiOH, KOH or NaOH in a mixture of water/dioxane or water/THF, in a temperature range from 0°C to +80°C. When the ester side chain represents a tert-Bu, the hydrolysis can be carried out using concentrated or diluted TFA or HCl in an organic solvent such as ether or THF. When the ester side chain represents an allyl group, the reaction is carried out in the presence of tetrakis(triphenylphosphine)palladium(0) in the presence of acceptor allyl cation such as morpholine, dimedone or hydride inputs of TBT in the temperature range from 0°C to +50°C, in a solvent such as THF. When the ester side chain represents benzyl, the reaction is carried out in hydrogen atmosphere in the presence of a noble metal as a catalyst such as Pd/C, in a solvent such as Meon, THF or EA. Further techniques, including the introduction of other protective acid groups and the General methods of disposal of the Oia, described in: Protecting Groups in Organic Synthesis, 3rdEd (1999), 369-441; T.W. Greene, P.G.M. Wuts (Publisher: John Wiley and Sons, Inc., New York, N.Y.).

The General reaction method 16: restoration of ketones and aldehydes to the corresponding alcohols:

Aldehydes and ketones can be restored to the corresponding alcohols using a wide range of remedial agents, as described in Larock, R.C. in Comprehensive Organic Transformations A guide to Functional Group Preparations, 2ndEd., Wiley, New York, Chichester, Weinheim, Brisbane, Singapore, Toronto (1999), Section Alcohols and phenols; p.1075-1110. Most preferred among them are LiAlH4and NaBH4.

The General reaction method 17: recovery of ester to the corresponding alcohol:

Ester can be recovered in the corresponding alcohol using a variety of reducing agents, as described by Larock, R.. in Comprehensive Organic Transformations A guide to Functional Group Preparations, 2ndEd., Wiley, New York, Chichester, Weinheim, Brisbane, Singapore, Toronto (1999), Section Alcohols and phenols; p.1114 to 1120. Most preferred among them are LiAlH4or DIVAN.

The General reaction method 18: reductive amination:

The reaction between the amine and the aldehyde or ketone is carried out in conditions using solvents, allowing you to remove the formed water by physical or chemical methods (e.g., by distillation azeotrope solvent-water mixture or pretentiously agents such as molecular sieves, MgSO4or Na2SO4). Such solvents are typically toluene, hexane, THF, DHM or 1,2-EDC, or mixture of solvents such as 1,2-EDC/Meon. The reaction can be catalysed using traces of acid (usually Asón). The intermediate formed Imin restore using a suitable reductive agent (e.g., NaBH4, NaBHCN3or NaBH(SLA)3) or by hydrogenation over a catalyst of a noble metal such as Pd/C. the Reaction proceeds in the temperature range from -10°C to 110°C, preferably in the range from 0°C to 60°C. the Reaction can also be carried out in the same container, in proton solvents such as Meon or water, in the presence of complex picoline-borane (Tetrahedron (2004), 60, 7899-7906).

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 means of optimization techniques.

In sections (a)-p), below, describes the General methods of preparing compounds of formula (I). Obtaining complex Prohm is filling compounds and the basic structural units described below. General synthetic methods that are repeatedly used in the schemes below, described in the above section entitled "General reaction techniques". Unless otherwise noted, common groups U, V, W, X, R1, R2, R3, A, K, G, m and n have the meanings given for formula (I).

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

derivative of carboxylic acid of the formula (III)

where L0and L00both represent chlorine, OCCl3imidazolyl or succinimidylester, or L0represent chlorine and L00represents OCCl3. This reaction is preferably carried out in a dry aprotic solvent such as DHL or THF, in the presence of an organic base such as tea or pyridine, in a temperature range from -30°C to +80°C. In the presence of one or more of the free alcohol or amine groups on a, K, R2or R3these functional group protect (see General reaction methods 1 and 2) before the reaction and is removed after the reaction (see General reaction methods 3 and 11).

b) the compounds of formula (I) can be also obtained by the reaction of compounds of formula (IV)

with the anion of the compounds of formula (V)

where R represents alkyl or benzyl. This reaction is carried out using General reaction method 4.

C) Compounds of formula (I), where a denotes CH and K stands About or co2can be obtained by reaction of compounds of formula (VI)

where o represents 0 or 1, with the compound of formula (VII)

where L1represents chlorine, bromine or OTf, in a solvent such as dioxane, N-MP or DMF, in a temperature range from about +20°C to about +120°C, optionally in the presence of a catalyst, as described in the General reaction technique 5, or, when L1is a HE, under the reaction conditions Mitsunobu, following the General reaction method 6.

g) Compounds of the formula (I), where a denotes CH and K represents NHCO, can be obtained by reaction of compounds of formula (VIII)

with the compound of the formula (VIIa,)

following the General reaction method 9.

Alternatively, the compounds of formula (I), where a denotes CH and represents NHCO, can be also obtained by the reaction of carboxamido obtained, in turn, of the carboxylic acid of formula (VIII)with compounds of the formula (VII), where L represents OTf, following the General reaction method 5.

d) the compounds of formula (I) can be also obtained what odensala the compounds of formula (IX)

with the compound of the formula (X)

where L2represents OMs, OTf, OTs, chlorine, bromine or iodine, following the General reaction method 7.

(e) Compounds of formula (I), where a denotes CH and K denotes SN=SN can be obtained by reaction of compounds of formula (XI)

where L3represents a P+Ph3Hal-or SO2Rdwhere Rdrepresents 1-phenyl-1H-tetrazol-5-yl or benzothiazol-2-yl and Hal represents halogen, with a compound of formula (XII)

in a solvent such as toluene, dioxane or THF, in a temperature range from about -20°to about +120°C, in the presence of a base, as described in the General reaction method 14.

g) Compounds of formula (I), where KA denotes SN=S, can be obtained by reaction of compounds of formula (XIII)

with the compound of the formula (XIV)

where L4denotes P+Ph3Hal-Hal represents halogen, in a solvent such as toluene, dioxane or THF, in a temperature range from about -20°to about +120°C, in the presence of a base, as described in the General reaction method 14.

C) the compounds of formula (I) can also be obtained by reaction of compounds of formula (XV

with the compound of the formula L5-G, where L5represents OTf or halogen such as bromine or iodine. This reaction is carried out following the General reaction method 5. In the case when the group G is such that Z represents N, the reaction is carried out in the presence of NaH.

I) the compounds of formula (I), where a denotes CH, and K stands For CH2CH2can be obtained by hydrogenation of the corresponding compounds of formula (I), where K denotes CH=CH, over a catalyst of a noble metal such as Pd/C.

th) the compounds of formula (I), where a denotes CH and represents CH(OH)CH(OH), can be obtained by CIS-dihydroxypropane the corresponding compounds of formula (I), where K denotes SN=SN, following the General reaction method 10.

K) the compounds of formula (I) where a denotes SNON and represents CH(OH), can be obtained by CIS-dihydroxypropane the corresponding compounds of formula (I), where K is a CHR5But a CR4and R4together with R5forms a link (i.e. K-a is a CH=C), following the General reaction method 10.

l) the compounds of formula (I), where K denotes NH or NHCH2can be obtained from amines of the formula (XIa)

where o=0 or 1, with the compound of formula (VII), where L1means OT following the General reaction method 7.

m) the compounds of formula (I), where R3denotes NH2or R2denotes CH2NH2can be obtained from the corresponding derivatives of formula (I), where R3denotes the N3or R2denotes CH2N3the reaction with PPh3in the presence of water.

h) Compounds of the formula (I), where R3means NHCOR6receive from the corresponding compounds of formula (I), where R3denotes NH2after reaction with the compound of the formula R6COZ, where Z represents Oh or halogen, following the General reaction method 9.

(o) Compounds of formula (I), where R3means triazole-1-yl, or R2means triazole-1-ylmethyl can be obtained from the corresponding derivatives of formula (I), where R3denotes the N3or R2denotes CH2N3using the reaction with acetylene or bicyclo[2.2.1]hepta-2,5-diene.

p) the compounds of formula (I), where K denotes CH2NH and a denotes CH, can be obtained by reductive amination of amines of the formula (XIa), where o=0, with aldehydes of the formula (XII), following the General reaction method 18.

The compounds of formula I obtained according to the above General synthetic methods can then be optionally converted into their salts, preferably their pharmaceutical is acceptable salt.

In addition, when the compounds of formula (I) are obtained in the form of a mixture of enantiomers, the enantiomers can be separated using methods known to experts in the field of technology, for example by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-O1(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 of chiral HPLC are: isocrates the application of a mixture of eluent A (EtOH, in the presence or absence of an amine such as triethylamine, diethylamine) and eluent B (hexane)at the expiration of from 0.8 to 150 ml/min

Obtaining compounds of formula (II) and (IV):

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

Allyl derivatives of the formula (XVI) can be converted (scheme 1) into the corresponding epoxides of formula (IV) or by direct epoxidation of terminal double bonds, or by CIS-dihydroxypropane using OsO4/NMO (General reaction method 10), or, as described by V. Van Rheenen et al. in Tetrahedron Lett. (1976), 23, 1973-76, with subsequent conversion into the corresponding epoxides after metilirovaniya or tiliouine, and ring closure in basic conditions using, for example, tea. When there is a need for the tsya chiral epoxides, they can be obtained through hydrolytic kinetic separation (GOR), catalyzed by chiral (salen)Co(III) complex (e.g., [(R,R)-N,N'-bis-(3,5-di-tert-butylchloride)-1,2-cyclohexanediamine-(2-)]cobalt(III) racemic mixture of epoxides, as described by Jacobsen et al. in J. Am. Chem. Soc. (2002), 124, 1307-1315 and Science (1997), 277, 936-938. Alternatively, chiral epoxides can be obtained from allyl derivatives of the formula (XVI) or through Shi chiral epoxidation using a chiral ketone, as described in the ACE. Chem Res. (2004), 37, 488-496, or by chiral CIS-dihydroxypropane using AD mixtures, following the General reaction method 10, followed by the formation of nelfinavir primary alcohol, following the General reaction method 8, and the formation of epoxide in basic terms.

The epoxides of formula (IV) can be obtained (scheme 1) by reaction of amines of formula (IX) with epichlorohydrin, or, optionally, with one of the two enantiomers of epichlorohydrin, optionally in the presence of MgSO4, followed by the formation of epoxide after treatment with base such as tert-BuOK in DMF.

The epoxides of formula (IV) can then be introduced into reaction with amines of the formula G-NH2resulting compounds of the formula (II).

In the case of aromatic N-oxide or N-oxide of a tertiary amine formed during oxidation with the adiya's, they can be restored to the appropriate naphthiridine, quinoline or hintline or to the corresponding tertiary amine by desoxyribose zinc dust in an acidic environment and acetic anhydride and formic acid, respectively, as described in Bioorg. Med. Chem. Lett. (2007), (17), 3322-3329 and Chemistry Letters (1985), 10, 1517-1520.

Obtaining compounds of formula (V):

The carbamates of the formula (V) can be obtained from the appropriate (usually commercially available amines of the formula G-NH;, following the General reaction method 1.

Obtaining compounds of formula (VI) and (VIII):

The compounds of formula (VI) and (VIII) can be obtained as shown in the diagram below 2.

In scheme 2, PG is a silyl protective group such as TBDMS or TRIPS, Rerepresents an alkyl group such as methyl or ethyl, or benzyl group.

Amines of the formula (XVIII) can be introduced into the reaction (scheme 2) with a derivative of formula X, where L2represent OMs, OTf, OTs, chlorine, bromine or iodine, following the General reaction method 7. The compounds of formula (VI) is obtained by removal of the protective group of intermediate compounds of formula (XIX), following the General reaction method 3.

The compounds of formula (VIII) can be obtained by hydrolysis of the ester groups of intermediate compounds of formula (XXI),following the General reaction method 15. These compounds can also be obtained by oxidation of compounds of formula (VI), where n=1, following the General reaction method 13. The compounds of formula (XXI) is obtained from intermediates of formula (XX) and (X) (where L2represents OMs, OTf, OTs, chlorine, bromine or iodine), using General reaction method 7.

Obtaining compounds of formula (VII):

The required quinoline, [1,5]-naphthiridine, hinzelin and cinoxacin derivatives of the formula (VII), where L1represents Br or commercially available, or can be obtained according to literature methods. For example, compounds where L1=Br, W=N and X=V=U=CH, receive according to WO 2003/087098, compounds, where L1=Br, W=V=N and X=U=CH, receive according to WO 2006/032466, compounds, where L1=Br, X=N and U=V=W=CH, or where L1=Cl, W=N and X=V=U=CH, receive according to WO 2004/089947, and compounds, where L1=Cl, V=N and X=W=U=CH, receive according to WO 2005/019215.

The compounds of formula VII, where L1=Br, can be obtained from compounds of formula (VIIb)

using reaction PBr3in DMF at a temperature of about 40°C.

The compounds of formula (VII), where L1=OTf, can be obtained from compounds of formula (VIIb), defined above, by reaction Tf2O (using General reaction method 8) or N,N-bis(trifloromethyl)of aniline in the presence of tea.

Obtaining compounds of formula (VIIa):

The connection forms of the crystals (VIIa) can be obtained by the reaction of corresponding compounds of the formula (VII), where L1represents OTf, with ammonia in a solvent, such DHM or THF, or with a hydrochloride of n-Propylamine in pyridine, in a temperature range from -20°C to 100°C (R. Radinov, Synthesis (1986), 886). 4-Aminobenzophenone derivatives of the formula (VIIa) can also be obtained from corresponding compounds of formula (VII), where L1represents chlorine, by reaction with ammonia in the same conditions.

Obtaining compounds of formula (VIIb):

The compounds of formula (VIIb) are commercially available or can be obtained according to the methods described in WO 2006/32466 (V=N and X=U=W=SN), or in WO 2004/02490 (U=V=N and X=W=CH).

Obtaining compounds of formula (IX):

The compounds of formula (I)X can be obtained as shown in the diagram below, 3.

In figure 3, PG2represents aminosidine group such as Cbz or Boc.

The compounds of formula (IX) can be obtained (scheme 3) by removing the protective group from compounds of formula (XXII), following the General reaction method 11.

The compounds of formula (XXII), where K denotes O(CH2)nand n=0 or 1, can be obtained (scheme 3) by reaction of the derivatives of formula (VII), where L1represents a bromine or OTf, with alcohols of the formula (XXIII), where n=0 or 1, as described in part b) of the section "Obtaining compounds of formula (I).

The compounds of formula (XXII), where K denotes NCO, can be obtained (scheme 3) by reaction of the amino derivatives of formula (VIIa) with acids of the formula (XXIV), where Rfdenotes H, as described in "Obtaining compounds of formula (I), part g).

The compounds of formula (XXII), where K denotes SN=SN can be obtained (scheme 3) reaction of aldehydes of the formula (XII) with compounds of formula (XXV), where L3represents a P+Ph3Hal-or SO2Rdwhere Rdrepresents 1-phenyl-1H-tetrazol-5-yl or benzothiazol-2-yl, Hal represents a halogen atom, as described in "Obtaining compounds of formula (I), part (e).

The compounds of formula (XXII), where K-means SN=S, (i.e., where K is a CHR5But a CR4and R4together with R5forms a bond) can be obtained (scheme 3) by reacting the ketone derivative of formula (XXVI) with compounds of the formula (XIV), where L4represents a P+Ph3Hal-a Hal represents a halogen atom, as described in "Obtaining the compounds of formula (I), g)).

The compounds of formula (XXII), where K denotes CH2CH2can be obtained by hydrogenation of derivatives of formula (XXII), where K denotes SN=SN, as described in "Obtaining compounds of formula (I), part I). In the special case where PG2means Cbz, the compound of formula (IX)where oboznachen 2CH2get direct way.

In addition, the compounds of formula (XXII), where KA denotes SONS(HE), can be obtained by CIS-hydroxylation derivatives of the formula (XXII), where KA denotes SN=S, as described in "Obtaining the compounds of formula (I), part K).

Obtaining compounds of formula (X):

The compounds of formula (X) can be obtained either by breaking tert-butyl-dimethylsilicone with amines of the formula G-NH2with further education oxazolidinone, following the method described in part (a) of the Chapter "Obtaining compounds of formula (I), and removing TBDMS protective group using General reaction method 3, or from the carbamates of the formula (V) and glycidylether using General reaction method 4, followed by conversion of the hydroxy-group in the OMs, OTf, OTs, chlorine, bromine or idgruppo, using methods described in the section "General reaction techniques 8".

Obtaining compounds of formula (XI):

The compounds of formula (XI), where L3means PPh3+Hal-obtained from compounds of formula (VI), where o=1, after converting the alcohol function in the corresponding mesilate and halide, following the General reaction method 8, and reaction with PPh3. The compounds of formula (XI), where L3means SO2Rdreceive from the alcohol of formula (VI), where o=1, using the General reaction method 14 in which the group, describing condensation on Julia sets.

Obtaining compounds of formula (XIa):

The compounds of formula (XIa) are obtained by transformation of compounds of formula (VI) in their corresponding mesylates using General reaction method 8, followed by reaction with sodium azide and restoration of the azide group to the corresponding amine using PPh3and water.

Obtaining compounds of formula (XII):

The required quinoline, [1,5]-naphthyridine, hinoksalinovym and hintline derivatives of the formula (XII), where R1represents OMe, or commercially available, or can be obtained using the literature methods. For example, compounds where U=W=N and X=V=SN, receive according to WO 2006/032466, connections, where V=N and W=X=U=SN, receive according to WO 2006/032466, connections, where U=V=N and W=X=SN, receive according to WO 2006/021448 and connections, where U=N and V=W=X=CH, receive according to WO 2006/046552.

Obtaining compounds of formula (XIII):

The compounds of formula (XIII)where R3denotes H, can be obtained as shown in the diagram below, 4.

Scheme 4 o=0 or 1.

The compounds of formula (XIII) can be obtained (scheme 4) using acidic removal of the protective group with Catalinas function compounds of formula (XXVIII)using General reaction method 12. The compounds of formula (XXVIII) is obtained from compounds of formula (XXVII) and (X)after the UYa General reaction method 7.

Obtaining compounds of formula (XIV):

The required quinoline, [1,5]-naphthyridine, hinoksalinovym and hintline derivatives of the formula (XIV)where R1means OMe and L4denotes P+PH3Hal-can be obtained, as shown in the diagram below, 5.

The compounds of formula (XII) can be recovered (scheme 5) alcohols of the formula (XIVa) (overall reaction method 16), which can be converted into the corresponding compounds of formula (XIVb), where Hal represents halogen (for example, when Hal denotes bromine, by reaction with PBr3). The compounds of formula (XIV) are obtained by reaction of compounds of formula (XIVb) with PPh3.

Obtaining compounds of formula (XV):

Intermediate compounds of formula (XV) can be obtained by the reaction of epoxides of formula (IV) with sodium azide followed by hydrogenation over a catalyst of a noble metal such as Pd/C, or a reaction to the OED, or the subsequent transformation of the corresponding carbamate with CbzCl or Vos2O. Oxazolidinone ring is then formed through reaction with NaH. These compounds can be also obtained by the reaction of compounds of formula (IX) with benzyloxy-2-illecillewaet or one of its enantiomers, with the General reaction method 4 before processing NaH.

Obtaining input connections

The compounds of formula (XVI) can be obtained by alkylation of compounds of formula (IX) allylbromide in the presence of a base such as tea.

The compounds of formula (XVIII) can be obtained by removal of the protective group of the alcohols of the formula (XXIII)using General reaction method 2, with the subsequent removal aminosidine group using General reaction method 11.

The compounds of formula (XX) can be obtained by removing the protective group from compounds of formula (XXIV)using General reaction method 11. The compounds of formula (XXIV), where Rfdenotes methyl, can be obtained by esterification carboxylic acids of the formula (XXIV), where Rfdenotes H, for example, esterification with diazomethane or TMS-diazomethane.

The compounds of formula (XXIII), where o=0, can be obtained by reduction of the ketone function of the derivatives of formula (XXVI), following the General reaction method 16. The compounds of formula (XXIII), where o=1, can be obtained by reduction of the ester function of compounds of formula (XXIV), where Rfdenotes methyl, using General reaction method 17.

The compounds of formula (XXIII), where o=0, m=n=1, R3denotes N and R2denotes CH2N3can be obtained from tert-butyl ether 4-[[(1,1-dimethylethyl)dimethylsilane]oxy]-2-(hydroxymethyl)-1-piperidinecarboxylic acid obtained, the AK is described in WO 2007/122103, after transferring into the corresponding mesylates (following the General reaction method 8 and reaction with sodium azide) and removal of the BOC-protective group as described in the General reaction technique 11. The compounds of formula (XXIII), where o=0, m=n=1, R2denotes N and R3denotes NH2can be obtained by reduction of the corresponding tert-butyl-3-azido-4-hydroxy-1-piperidinecarboxylate (obtained according to WO 02/096426) using the above method with the subsequent removal of the BOC-protective group as described in the General reaction technique 11. The compounds of formula (XXIII), where o=1, m=n=1, R2denotes N and R3denotes NH2can be obtained according to WO 01/81347.

Carboxylic acids of the formula (XXIV), where Rfmeans, R2denotes H, R3denotes H, PG2means Cbz and m=n=0, or m=n=1 or m=1 and n=0, are commercially available. Other carboxylic acids of the formula (XXIV) can be obtained as shown in the diagram below, 6.

Carboxylic acids of the formula (XXIV), where Rfdenotes H, m=n=1 or m=1 and n=0, R2denotes CH2HE and R3denotes H, can be obtained (scheme 6) from the corresponding esters of the formula (XXIX) or (XXX), described in the publications EP 334244 and Tetrahedron (1995), 51 (31), 8545-54, respectively, using the standard methodology is (hydrolysis of ester according to General reaction method 15 and hydrolysis of ester, followed by reduction, as described in the General reaction technique 17).

The precursor compounds of the formula (XXV), i.e. the compounds of formula (XXV), where L3maybe OMs, OTs, or halogen such as iodine, can be obtained from alcohols of formula (XXIII), where o=1, using the General reaction method 8. The compounds of formula (XXV), where L3means PPh3+Hal-get a reaction named predecessors (L3is halogen) with PPh3. The compounds of formula (XXV), where L3means SO2Rdcan be obtained from these precursors using General reaction method 14, a section describing the condensation on Julia sets.

Ketones of the formula (XXVI), where R2denotes H, PG2means Cbz and m=n=0, or m=n=1 or m=1 and n=0, are commercially available. Ketones of the formula (XXVI), where m=n=1 or m=1 and n=0, and K stands For CH2OH, can be obtained from the corresponding commercially available esters (R2= Coolkill) via recovery according to the General reaction method 17.

The compounds of formula (XXVII) can be obtained by protection of the ketone group of compounds of formula (XXVI) with ethanediol or 1,3-propane diol in the presence of p-TsOH, with the subsequent removal aminosidine group, as described in the General reaction technique 11.

Separate embodiments of the present izaberete the Oia are described in the following examples, which in detail illustrate the invention, and in no way limiting its scope.

Examples

General methods:

Method a: remove the BOC-protective group:

The BOC-protected amine (1 mmol) is dissolved in DHM (2 ml), and then add Et3SiH (1.05 mmol) (optional) and TFA (2 ml). The mixture is stirred at room temperature for 1 h, concentrated in vacuo and transferred to a mixture of DGM/NH4OH. The organic layer is washed with water, dried over MgSO4and concentrate under reduced pressure.

Method B: alkylation of amines iodides and mesylates:

A solution of amine (1 mmol in the case of iodine; 1-2 mmole if mesylates), mesilate/iodide (1 mmol) and DIPEA (1.1 mmol) in dry DMSO is heated at a temperature of 70°C. until the reaction is completed (1-3 days). After cooling to room temperature, add water and EA and the share phase. The aqueous layer was extracted two times EA and the combined organic layers washed with water (three times) and brine, dried over MgSO4and concentrate under reduced pressure. The residue is purified by column chromatography.

Method: nucleophilic aromatic substitution of 4-chloro-6-methoxyquinazoline:

To a solution of hydroxycodone (1 mmol) and 4-chloro-6-methoxyquinazoline (1 mmol) in N-MP (2 ml) at a temperature of 0°C was added NaH (1 mmol, 60%solution in mineral m in the following). The mixture was stirred at 0°C. until completion of the reaction (usually within 1-4 h), quenched with water and extracted with EA. The combined organic layers are washed several times with water and brine, dried over MgSO4and concentrate under reduced pressure. The residue is purified by column chromatography.

Method G: amide condensation with GATA:

To a solution of DIPEA (4 mmol), amine (1 mmol) and acid (1 mmol)dissolved in DMF (2 ml) is added GATA (2 mmol) at room temperature. The resulting mixture was stirred at room temperature until completion of the reaction, then add water and EA, the phases are separated and the aqueous phase extracted with ethyl acetate. The combined organic layers are washed several times with water and brine, dried over MgSO4and concentrate under reduced pressure. The residue is purified by column chromatography.

Method D: nucleophilic aromatic substitution:

A mixture of helgaleena or aristigueta (1 mmol), amine (1 mmol) and DIPEA (1.2 mmol) in N-MP (4 ml) is heated at a temperature of 70-80°C until completion of the reaction, after which water is added and the mixture extracted with ethyl acetate. The combined organic layers washed with water (three times), brine, dried over MgSO4and concentrate under reduced pressure. The residue is purified by column chromatography.

Method E: Conde who sacia Buchwald:

In dried in a drying Cabinet flask was placed Allbreed or areshared (1 mmole), palladium(II)acetate (0.04 mmole), BINAP (0.08 mmole) or bis-(2-diphenylphosphino)phenyl ether (0.08 mmol), K3PO4(2.5 mmole) and amine (1 mmol). The mixture for several minutes to purge with argon. Then using a syringe add dioxane (1 ml) and the resulting suspension is blown with argon for 3 minutes Then the mixture is heated at a temperature of 85°C to complete the reaction. After that, the solvent is removed under reduced pressure and the residue extracted with a mixture of ethyl acetate with water. The organic layer was washed with brine, dried over MgSO4and concentrate under reduced pressure. The residue is purified by column chromatography.

Method W: hydrogenation of the Cbz-group:

Supension of benzylcarbamoyl (1 mmol) in Meon (6 ml) hydronaut over 5 or 10%Pd/C (200 mg) for 2 hours the Catalyst is filtered off, and the residue on the filter is washed Meon and DHM. The filtrate is concentrated under reduced pressure.

Method 3: reductive amination:

The solution of the primary amine (1 mmol) and aldehyde or ketone (1 mmol) in a mixture of EDC/Meon in the ratio of 1:1 (10 ml) was stirred at room temperature overnight. Then add NaBH4(2-5 EQ.) and the reaction continued for 1 h, after which the reaction mixture is diluted with DHM and aqueous solution of NH OH. The organic phase is washed with water, dried over MgSO4and concentrate.

Preparative methods:

Preparative method a: (S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ymetray ether methanesulfonate acid:

A.i. 6-[(S)-3-(trade-butyldimethylsilyloxy)-2-hydroxypropylamino]-4H-benzo[1,4]thiazin-3-one:

To a solution of tert-butultimately-((S)-1-oxiranylmethyl)silane (13,0 g, 69 mmol) in acetonitrile (220 ml) is added LiClO4(22 g, 207 mmol), and then 6-amino-4H-benzo[1,4]thiazin-3-one (11.4 g, 64 mmol) and the mixture is stirred at 50°C for 6 hours Then the solvent is removed in vacuo and the residue chromatographic (DHM/Meon/NH4OH in a ratio of from 1000:25:2 to 1000:100:2), getting named the title compound in the form of bignoniaceae foam (yield 11,16 g, 44%).

MS (ESI, m/z): 369,3 [M+H+].

A.ii. 6-[(S)-5-(tert-butyldimethylsilyloxy)-2-oxoacridine-3-yl]-4H-benzo[1.4]thiazin-3-one:

A solution of intermediate compound (A.i) (11,60 g, 30 mmol) and CBI (5,57 g, 33 mmole) in THF (130 ml) is heated at 50°C for 2 h, after which the mixture was concentrated in vacuo and partitioned between EA and water. A number of crystalline product is filtered and washed with water and ethyl acetate, receiving a total of 5.21 g of the product. The organic layer was washed with brine, dried over MgSO4and concentrate. About who headed the remainder of purified using column chromatography (DHM/Meon/NH 4OH in the ratio of 1000:50:4), receiving additional 2.28 g of product (total yield 7,49 g off-white solid, 63%).

MS (ESI, m/z): 395,1 [M+H+].

A.iii. 6-((S)-5-hydroxymethyl-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one:

Suspensio intermediate compounds (A.ii) (11,49 g, 29.1 mmol) in THF (29 ml) is treated TBAF (1-molar solution in THF, 29,1 ml). The yellow solution is stirred at 0°C for 3 h, and then distribute in a mixture of water and ethyl acetate. A number of crystalline product is filtered and washed with water and ethyl acetate, receiving of 6.49 g of the product. The aqueous phase is extracted with ethyl acetate (three times). The combined organic layers washed with brine, dried over MgSO4filter and concentrate. The crude product tracuriroot with EA, receiving additional of 1.23 g of product (total yield 7,72 g off-white solid, 95%).

MS (ESI, m/z): 281,3 [M+H+].

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

A solution of intermediate compound (A.iii) (2,77 g, 9.88 mmol) in anhydrous DHM (100 ml) and DIPEA (4,7 ml of 28.2 mmol) cooled to 0°C and added dropwise to him MsCl (1.07 ml, 13.8 mmol). The resulting mixture was stirred at 0°C for 1 h, then water is added, whereupon the mixture is extracted with DHM and obyedinenie the e organic layers washed with water. The yellow residue tracuriroot a mixture of EA/DHM/ether, getting named the title compound as a colorless solid (yield of 2.45 g, 69%).

1H NMR (DMSO-d6) δ: 10,57 (s, 1H), 7,31 (m, 2H), 7,10 (dd, J=8,5, 2.3 Hz, 1H), to 4.98 (m, 1H), 4,48 (m, 2H), 4,13 (t, J=9.4 Hz, 1H), 3,75 (dd, J=9,4, 6.4 Hz, 1H), 3.43 points (s, 2H), 3,23 (s, 3H). MS (ESI, m/z): 359,3 [M+H+].

Preparative method B: 6-((S)-5-iodomethyl-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one:

B. (S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ymetray ester toluene-4-sulfonic acid:

To a solution of intermediate compound (A.iii) (3.2 g, 11.5 mmol) and DMAP (1.40 g, 11.5 mmol) in DHM (80 ml), cooled to 0°C, add the tea (4.6 ml, 33.3 mmol) and a solution of TsCl (2.2 g, 11.5 mmol) in DHM (15 ml). The mixture is stirred at room temperature overnight, after which water is added. The formed solid is filtered off, getting named the title compound as a beige solid (yield 4,19 g, 84%).

MS (ESI, m/z): 435,2 [M+H+].

B. 6-((S)-5-iodomethyl-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one:

Suspensio intermediate compounds (B-i) (4,19 g, for 9.64 mmol) and NaI (5,78 g, 38,57 mmol) in acetone (70 ml) is heated under reflux for 5 hours, the Solvent is then evaporated and the residue extracted with a mixture of water/DHM, thus precipitating the desired product in the form of a solid pale pink is the response (output 3,39 g, 90%).

1H NMR (DMSO-d6) δ: 10,54 (s, 1H), 7,30 (m, 2H), 7,11 (dd, J=8,5, and 2.1 Hz, 1H), 4,69 (m, 1H), 4,13 (t, J=9.1 Hz, 1H), 3,57 (m, 3H), 3.43 points (s, 2H).

MS (ESI, m/z): to € 391.1 [M+H+].

Preparative method: 6-((R)-5-iodomethyl-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one:

On the basis of tert-butultimately-((R)-1-oxiranylmethyl)silane and using the methodology developed by preparative method B, stage B named in the title compound (enantiomeric antipode of the compound obtained in preparative method B) obtained as off-white solids (yield 120 mg, 33%).

MS (ESI, m/z): to € 391.1 [M+H+].

Preparative method G: (S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)oxazolidin-5-ymetray ether methanesulfonate acid:

G. 6-[(S)-3-(tert-butyldimethylsilyloxy)-2-hydroxypropylamino-4H-benzo[1,4]oxazin-3-one:

On the basis of 6-amino-4H-benzo[1,4]oxazin-3-one and using the methodology developed by preparative method And stage A.i., named in the title compound obtained as a light brown foam (yield of 5.2 g, 66%).

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

G. 6-[(S)-5-(tert-butyldimethylsilyloxy)-2-oxoacridine-3-yl]-4H-benzo[1,4]oxazin-3-one:

On the basis of the intermediate compound (G) and using the methodology developed by preparative method And stage A.ii named in the title compound obtained as a colorless solid (yield of 5.15 g, 91%).

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

G. 6-((S)-5-hydroxymethyl-2-oxoacridine-3-yl)-4H-benzo[1,4]oxazin-3-one:

On the basis of the intermediate compound (G) and using the methodology developed by preparative method And stage A.iii named in the title compound obtained as a colorless solid (yield of 3.14 g, 87%).

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

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

On the basis of the intermediate compound (G) and using the methodology developed by preparative method And stage A.iv named in the title compound obtained as off-white solids (yield 1.40 g, 44%).

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): 343,2 [M+H+].

Preparative method D: (S)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-iododeoxyuridine-2-he:

D.I. (S)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-hydroxymethylimidazole-2-he:

A solution of benzyl ether (2,3-dihydrobenzo[1,4]dioxin-6-yl)carbamino acid (3.0 g, 10.5 mmol) in THF (60 ml) cooled to a temperature of -78°C., then added dropwise n-BuLi (5.1 ml of a 2.5 molar solution in hexane, 1.2 EQ.). The mixture was stirred at -78°C for 1 h, and then heated to a temperature of -15°C and at this temperature, added dropwise (S)-glycidylether (1.98 g, 1.2 EQ.). See the camping stirred at room temperature overnight, then add Cs2CO3(spatula) and the mixture is heated at a temperature of 40°C. until completion of the conversion. After that, the mixture is diluted with EA and washed with saturated solution of NH4Cl and water. The organic layer is dried over MgSO4and concentrate. The connection is cleaned by column chromatography (hexane/ethyl acetate in the ratio 2:1, 1:1), obtaining the desired intermediate compound in the form of a beige solid (yield of 1.09 g, 41%).

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=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).

D. (S)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ymetray ether methanesulfonate acid:

A solution of intermediate compound (D) (1 g, 4 mmole) in DHM (20 ml) cooled to 0°C, add DIPEA (of 0.62 g, 1.2 EQ.) and MsCl (0,502 g, 1.1 EQ.) and stirred the mixture for 1 h at 0°C. the Mixture was then diluted with DHM and washed with water. The organic phase is dried over MgSO4and concentrate, getting called in the header mesilate in the form of a colorless solid (yield 1.26 g, 97%), which is used in the next stage without further purification.

MS (ESI, m/z): USD 329.8 [M+H+].

D. (S)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-iododeoxyuridine-2-he:

A mixture of intermediate compound (D-ii) (509 mg, 1.55 mmol) and NaI (92 mg, 6.18 mmol) in acetone (10 ml) is heated under reflux for 3 hours the Solvent is then 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, getting named the title compound as a light beige solid (exit 393 mg, 70%).

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).

MS (ESI, m/z): 362,1 [M+H+].

Preparative method E: (S)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-carboxylic acid:

To a solution of intermediate compound (D-i) (985 mg, to 3.92 mmol) in a mixture of water/MeCN (1:1 ratio) (20 ml), cooled to 0°C, add diacetoxybenzoic (2.83 g, 2.2 EQ.) and TEMPO (122 mg, 0.2 EQ.). The mixture is stirred at 0°C for 30 min and at room temperature over night, then add EA and saturated aqueous solution of Na2CO3, after which the phases are separated. The aqueous layer was washed once with ethyl acetate and then carefully acidified with 1-molar solution of HCl. The aqueous phase is extracted twice with ethyl acetate. The combined organic layers washed with brine, dried over MgSO4and concentrate under reduced pressure, obtaining mentioned in the title ol the product as a colorless solid (yield 847 mg, 81%).

MS (ESI. m/z): 266,3 [M+H+].

Examples

Example 1: 6-{(R)-5-[3-(6-methoxy[1,5]naphthiridine-4-yloxy)azetidin-1-ylmethyl-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

1.i. tert-butyl ether 3-(6-methoxy[1,5]naphthiridine-4-yloxy)azetidin-1-carboxylic acid

DYADS (0,69 ml, 3.45 mmol) are added dropwise to a suspension of 6-methoxy-[1,5]naphthiridine-4-ol (507 mg, 2.88 mmol), tert-butyl ester 3-hydroxyazetidine-1-carboxylic acid (commercial, 500 mg, 2.88 mmol) and PPh3(906 mg, 3.45 mmol) in THF (5 ml). This forms a clear solution, which was stirred at room temperature overnight. The mixture was then concentrated under reduced pressure and purified by column chromatography (hexane/ethyl acetate in the ratio 1:1), obtaining mentioned in the title intermediate compound as a yellow solid (yield 590 mg, 62%).

MS (ESI, m/z): 332,4 [M+H+].

1.ii. 8-(azetidin-3-yloxy)-2-methoxy[1,5]naphthiridine:

On the basis of the intermediate compound (1.i) and using method a, the desired intermediate compound obtained as yellow solid (yield 172 mg, 42%).

MS (ESI, m/z): reach 232.5 [M+H+].

1.iii. 6-{(R)-5-[3-(6-methoxy[1,5]naphthiridine-4-yloxy)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (1.ii) and the compound obtained in preparative method B,and using method B, the desired product is obtained as a colourless solid (5 mg, 3%).

1H NMR (CDCl3) δ: 8,56 (d, J=5.3 Hz, 1H), 8,42 (s, 1H), 8,15 (d, J=8,8 Hz, 1H), 7,45 (d, J=2.3 Hz, 1H), 7,25 (m, 1H), 7,11 (d,J=9,l Hz, 1H), to 6.88 (dd, J=8,8, 2.3 Hz, 1H), 6,66 (d, J=5.3 Hz, 1H), 5,04 (t, J=5,9 Hz, 1H), 4,71 (m, 1H), 4,06 (m, 6H), 3,90 (dd, J=8,8, 6,7 Hz, 1H)and 3.59 (m, 2H), 3,39 (s, 2H), 3,03 (m, 1H), 2,90 (m, 1H).

MS (ESI, m/z): 493,8 [M+H+].

Example 2: 6-{(R)-5-[(R)-3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

2.i. tert-butyl ether (R)-3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-carboxylic acid:

Based on tert-butyl ether (R)-3-hydroxypyrrolidine-1-carboxylic acid (commercial product) and 4-chloro-6-methoxyquinazoline and using method B, the desired product is obtained as a yellow oil (yield 1.54 g, 42%).

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

2.ii. 6-methoxy-4-((R)-pyrrolidin-3-yloxy)hinzelin:

On the basis of the intermediate compound (2.i) and using method a, the desired intermediate compound obtained as off-white solids (yield 458 mg, 43%).

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

2.iii. 6-{(R)-5-[(R)-3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (2.ii) and the compound obtained in preparative method B, and using method B, the desired product is obtained as a brown foam (yield 7 mg, 41%).

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

Example 3: 6-{(R)-5-[(S)-3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

Named in the title compound obtained as brown solid exit (exit 83 mg, 49%) on the basis of enantiomeric antipode intermediate compounds (2.ii) and using the method of example 2, step 2.iii.

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

Example 4: (R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-[(RS)-3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-illicit-2-he:

Named in the title compound obtained as a pale yellow foam (yield 33 mg, 32%) based on the racemate intermediate compounds (2.ii) and using the method of example 2, step 2.iii.

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

Example 5: 6-{(R)-5-[(2S,4S)-2-hydroxymethyl-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

5.i. tert-butyl ester (2S,4S)-2-(2,2-dimethylphenylacetic)-4-hydroxypyrrolidine-1-carboxylic acid:

To mix the solution wpew-butyl ether (S)-2-(2,2-dimethylphenylacetic)-4-oxopyrrolidin-1-carboxylic acid (50 g, 16.7 mmol; obtained according to WO 2007/017828) in the Meon (40 ml) is added NaBH4(1.90 g, 3 EQ.) portions with an interval of 30 min at a temperature of 0-5°C. the Mixture is stirred at 10°C for 2 h, after which it add water and see what camping is extracted DHM. The organic layer is dried over MgSO4and concentrate under reduced pressure, obtaining mentioned in the title intermediate compound in the form of a beige solid (yield of 4.13 g, 82%).

1H NMR (CDCl3) δ: was 4.42 (m, 1H), 4.26 deaths (m, 1H), 4,10-4,00 (m, 1H), 3,60 (m, 1H), 3,36 (m, 1H), 2,19 (m, 2H), 1,95 (m, 1H), of 1.46 (s, 9H), to 1.21 (s, 9H).

MC (ESI, m/z): 302,2 [M+H+].

5.ii. tert-butyl ester (2S,4S)-2-(2,2-dimethylphenylacetic)-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-carboxylic acid:

On the basis of the intermediate compound (5.i) and using method B, the desired intermediate compound obtained as a pale yellow foam (yield 1.56 g, 56%).

MC (ESI, m/z): 460,0 [M+H+].

5.iii. tert-butyl ester (2S,4S)-2-hydroxymethyl-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-carboxylic acid:

DEBUG (1,92 ml of 1.7 molar solution in toluene) is slowly added to a solution of intermediate compound (5.ii) (500 mg, 1.1 mmol) in toluene (16 ml) at -78°C. the Mixture is stirred at this temperature for 2 h and then quenched by the addition thereto of a saturated solution of Rochelle salt (1.5 ml). After that, the mixture is left to spontaneously warm to room temperature and diluted with ethyl acetate. The organic layer is dried over MgSO4and concentrate under reduced pressure, obtaining mentioned in the title intermediate compound in the form of pale yellow Tverdov the substance (yield 440 mg, 100%).

MS (ESI, m/z): 376,5 [M+H+].

5.iv. [(2S,4S)-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-2-yl]methanol:

On the basis of the intermediate compound (5-iii) and using method a, the desired intermediate compound obtained as a pale yellow solid (yield 162 mg, 50%).

MS (ESI, m/z): 276,2 [M+H+].

5.v. 6-{(R)-5-[(2S,4S)-2-hydroxymethyl-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (5.iv) and the compound obtained in preparative method B, and using method B, the desired product is obtained as a colourless foam (yield 40 mg, 41%).

1H NMR (CDCl3) δ: at 8.60 (s, 1H), to 8.41 (s, 1H), 7,80 (d, J=9.1 Hz, 1H), 7,43 (m, 1H), 7,34 (d, J=2.6 Hz, 1H), 7.23 percent (m, 1H), 7,11 (d, J=8,8 Hz, 1H), PC 6.82 (m, 1H), 5,71 (m, 1H), 4,74 (m, 1H), 3,97 (m, 1H), 3,91 (s, 3H)), 3,76 (m, 2H)and 3.59 (m, 2H), 3,39 (s, 2H), 3,17 (m, 1H), 2,97 (m, 2H), 2,80 (m, 2H), 2,54 (m, 1H), 2,22 (m, 1H).

MS (ESI, m/z): 538,2 [M+H+].

Example 6: 6-{(R)-5-[(2S,4S)-2-azidomethyl-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

6.i. tert-butyl ester (2S,4S)-2-azidomethyl-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-carboxylic acid:

Yellowish solution of the intermediate (5.iii) (603 mg, 1.61 mmol) in anhydrous DHM (7 ml) and DIPEA (0,825 ml, 3 EQ.) cooled to a temperature of 0°C. and MsCl pin (0.15 ml, 1.2 EQ.). The resulting mixture was stirred at 0°C in the tip is of 1 h, then add water and the mixture extracted with DHM. The organic layer is dried over MgSO4and concentrate under reduced pressure. To a solution of crude nelfinavir in DMF (6 ml) was added NaN3(165 mg, 1.5 EQ.). The resulting mixture was stirred at 80°C during the night. The solvent is evaporated without dried and the residue is dissolved in DHM. The organic layer is washed with water, dried over MgSO4and evaporated under reduced pressure, obtaining mentioned in the title intermediate compound as a brown oil (yield 621 mg, 92%).

MS (ESI, m/z): 401,4 [M+H+].

6.ii. 4-((3S,5S)-5-azidopyridine-3-yloxy)-6-methoxyquinazoline:

On the basis of the intermediate compound (6.i) and using method a, the desired intermediate compound obtained as brown oil (yield 465 mg, 100%).

MS (ESI, m/z): 302.3 [M+H+].

6.iii. 6-{(R)-5-[(2S,4S)-2-azidomethyl-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (6.ii) and the compound obtained in preparative method B, and using method B, the desired product is obtained in the form of a pale yellow foam (yield 131 mg, 30%).

MS (ESI, m/z): 563,3 [M+H+].

Example 7: (6-methoxy[1,5]naphthiridine-4-yl)amide 1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]azetidin-3-carboxylic acid:

7.1. tert-butyl ether 3-(6-methoxy[1,5]naphthiridine-4-ylcarbonyl)azetidin-1-carboxylic acid:

On the basis of 6-methoxy-[1,5]naphthiridine-4-ylamine and mono-tert-butyl ester azetidine-1,3-dicarboxylic acid using method G, the desired product is obtained in the form of a beige solid (yield 1.60 g, 60%).

MS (ESI, m/z): 359,4 [M+H+].

7.ii. (6-methoxy-[1,5]naphthiridine-4-yl)amide, azetidin-3-carboxylic acid:

On the basis of the intermediate compound (7.i) and using method a, the desired intermediate compound obtained as brown solid (yield 1.25 g, 100%).

1H NMR (CDCl3) δ: 10,35 (advanced, s, 1H), 8,71 (d, J=5.3 Hz, 1H), 8,53 (d, J=5.3 Hz, 1H), 8,21 (d, J=9.1 Hz, 1H), 7,15 (d, J=8,8 Hz, 1H), 4,10 (s, 3H), of 3.97 (m, 4H), 3,55 (m, 1H).

MC (ESI, m/z): 259,3 [M+H+].

7.iii. (6-methoxy-[1,5]naphthiridine-4-yl)amide 1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]azetidin-3-carboxylic acid:

On the basis of the intermediate compound (7.ii) and the compound obtained in preparative method and using method B, the desired product is obtained in the form of a pale yellow foam (yield 37 mg, 34%).

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

Example 8: (6-methoxy-[1,5]naphthiridine-4-yl)amide (RS)-1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]pyrrolidin-3-carboxylic acid:

Named in the title compound obtained as colorless solid is th substance (yield 25 mg, 22%), using the method of example 7 proceeding, however, in the synthesis of 1-tert-butyl ether rat-pyrrolidine-1,3-dicarboxylic acid.

MC (ESI, m/z): 535,4 [M+H+].

Example 9: 6-((R)-5-{(RS)-3-G(E)-2-(6-methoxy[1,5]naphthiridine-4-yl)vineale-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one:

9.i. tert-butyl ether (RS)-3-(1-phenyl-1H-tetrazol-5-sulfanilyl)pyrrolidin-1-carboxylic acid:

To a solution of 1-phenyl-1H-tetrazol-5-thiol (of 5.92 g, 33 mmole) in EtOH (80 ml) is added KOH (2.1 g, 38 mmol) and the mixture heated under reflux for 1 h, then added tert-butyl ether (RS)-3-iodomethylpropanes-1-carboxylic acid (9.0 g, 29 mmol) and heated under reflux for 3 h, after which water is added (70 ml) and most of the EtOH is removed under reduced pressure. The residue is extracted with ethyl acetate, and the organic layer washed with water and brine, dried over MgSO4and concentrate. Then, to the thus obtained crude sulfide in EtOH (200 ml) is added ammonium molybdate (7.0 g, 0.2 EQ.) and 30%H2About2(15 ml), the mixture is heated to a temperature of 65°C and stirred at this temperature for 3 hours Then add water (500 ml) and most of the EtOH is removed under reduced pressure. The residue is extracted with ethyl acetate. The organic layer is washed with 10%aqueous solution of Na2S2O3, water and races is I, dried over MgSO4and concentrate under reduced pressure, obtaining mentioned in the title intermediate compound in the form of a pale yellow oil (yield 9,48 g, 85%).

MS (ESI, m/z): 394,3 [M+H+].

9.ii. wpew-butyl ether (RS)-3-[(E)-2-(6-methoxy[1,5]naphthiridine-4-yl)vinyl]pyrrolidin-1-carboxylic acid:

To a suspension of 6-methoxy[1,5]naphthiridine-4-carbaldehyde (2.0 g, 10.6 mmol) and intermediate (9.i) (4,40 g of 1.05 equiv.) in 1,2-DME (60 ml), cooled down to -78°C. add dropwise a solution of KHMDS (a 0.5-molar in toluene, 34 ml). The mixture is stirred for 1 h at this temperature, then warmed to room temperature. After stirring for 45 min, water is added (150 ml) and ethyl acetate (150 ml). The two resulting layers separated, and the aqueous layer was extracted twice with ethyl acetate (200 ml). The combined organic layers dried over MgSO4filter and concentrate under reduced pressure. The residue is purified by column chromatography (heptane/ethyl acetate 1:1 ratio), getting named in the title intermediate compound as a yellow oil (yield 2.1 g, 56%).

MS (ESI, m/z): 356,3 [M+H+].

9.iii. (RS)-2-methoxy-8-((E)-2-pyrrolidin-3-elwenil)-[1,5]naphthiridine:

On the basis of the intermediate compound (9.ii) and using method a, the desired intermediate compound obtained as a yellow oil (o is d 187 mg, 100%).

MS (ESI, m/z): 256,5 [M+H+].

9.iv. 6-((R)-5-{(RS)-3-[(E)-2-(6-methoxy[1,5]naphthiridine-4-yl)vinyl]pyrrolidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (9.iii) and the compound obtained in preparative method and using method B, the desired product is obtained in the form of a pale yellow solid (yield 28 mg, 22%).

1H NMR (CDCl3) δ: 8,67 (dd, J=4,4, 2.3 Hz, 1H), scored 8.38 (m, 1H), 8,18 (d, J=9.1 Hz, 1H), 7,56 (dd, J=4,7, 2,9 Hz, 1H), 7,45 (m, 2H), 7,26 (m, 1H), 7,11 (d, J=9.1 Hz, 1H), of 6.96 (dd, J=8,8, 2.3 Hz, 1H), of 6.71 (m, 1H), 4,78 (m, 1H), 4,07 (m, 4H), a 3.87 (ddd, J=8,8, 6,7, 4,7 Hz, 1H), 3,41 (s, 2H), 3,20 is 2.80 (m, 6H), 2,62 (m, 1H), 2,22 (m, 1H), is 1.81 (m, 1H).

MS (ESI, m/z): 518,3 [M+H+].

Example 10: 6-((R)-5-{(RS)-3-D2-(6-methoxy[1,5]naphthiridine-4-yl)ethyl]pyrrolidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one:

10.i. tert-butyl ether (RS)-3-[2-(6-methoxy[1,5]naphthiridine-4-yl)ethyl]pyrrolidin-1-carboxylic acid:

A solution of intermediate compound (9.ii) (287 mg, 0.78 mmol) in ethyl acetate (10 ml) hydronaut over Pd/C (10%; 100 mg) for 1 h, the Catalyst was then filtered off and the remaining on the filter layer is washed with ethyl acetate. The filtrate is concentrated under reduced pressure, obtaining mentioned in the title intermediate compound as a gray oil (yield 267 mg, 96%).

MS (ESI, m/z): 358,3 [M+H+].

10.ii. (RS)-2-methoxy-8-(2-pyrrolidin-3-retil)-[1,5]naphthiridine:

On the basis of the intermediate compound (0.i) and using method a, desired intermediate compound obtained as a yellow oil (yield 165 mg, 86%).

MS (ESI, m/z): 258,2 [M+H+].

10.iii. 6-((R)-5-{(RS)-3-[2-(6-methoxy[1,5]naphthiridine-4-yl)ethyl]pyrrolidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (10.ii) and intermediate compound obtained in preparative method and using method B, the desired product is obtained as colorless solid (yield 25 mg,20%).

MS (ESI, m/z): 520,5 [M+H+].

Example 11: 6-((R)-5-{(RS)-3-[(1R,2R)-1,2-dihydroxy-2-(6-methoxy[1,5]naphthiridine-4-yl)ethyl]pyrrolidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one:

11.i. tert-butyl ether (RS)-3-[(1R,2R)-1,2-dihydroxy-2-(6-methoxy[1,5]naphthiridine-4-yl)ethyl]pyrrolidin-1-carboxylic acid:

To a suspension of intermediate compounds (9.ii) (662 mg, 1.86 mmol) in tert-BuOH (10 ml) and water (10 ml) add methanesulfonamide (213 mg, 1.2 EQ.) and AD-mixture of [3 (2.7 g). The reaction mixture was vigorously stirred at room temperature overnight. Then the reaction mixture was diluted with water and EA. Two layers are separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers washed with 10%aqueous solution of NaHSO3, water (50 ml) and brine, dried over MgSO4filter and concentrate without dried under reduced pressure, getting called in the header Prohm is the filling compound as a colourless foam (yield 660 mg, 91%).

MS (ESI, m/z): 390.4 [M+H+].

11.ii. tert-butyl ether (RS)-3-[(4R,5R)-5-(6-methoxy[1,5]naphthiridine-4-yl)-2,2-dimethyl[1,3]dioxolane-4-yl]pyrrolidin-1-carboxylic acid:

To a solution of intermediate compound (11.i) (371 mg, 0.95 mmol) in THF (10 ml) was added TsOH (199 mg, 1.1 EQ.) and 2,2-dimethoxypropane (0.35 ml, 3 EQ.). The mixture is stirred at room temperature for 36 h, after which add a saturated solution of sodium bicarbonate and ethyl acetate. Two layers are separated and the aqueous layer was extracted with EA. The combined organic layers washed with brine, dried over MgSO4filter and concentrate without dried. The remainder chromatographic (DHM/Meon/NH4OH in the ratio of 1000:50:4), getting named in the title intermediate compound as a colourless foam (yield 265 mg, 65%).

MS (ESI, m/z): 430,3 [M+H+].

11.iii. 6-((R)-5-{(RS)-3-[(4R,5R)-5-(6-methoxy[1,5]naphthiridine-4-yl)-2,2-dimethyl[1,3]dioxolane-4-yl]pyrrolidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one:

It chilled with ice to a solution of intermediate compounds (11.ii.) (220 mg, 0.51 mmol) in DHM (3 ml) was added dropwise in a nitrogen atmosphere 2,6-lutidine (of 0.24 ml, 4 EQ.) and OTf (of 0.24 ml, 2 EQ.). After 1 h at a temperature of 0°C. the reaction mixture was quenched by adding DHM. Two layers separated, the organic layer is dried over MgSO4filter and concentrate without dried under reduced pressure. RA is Toru thus obtained crude siliconbeat in THF (3 ml) is added TBAF (1-molar solution in THF, of 1.05 ml, 2 equiv.) then the reaction continued for 30 minutes the Solvent is evaporated and the residue chromatographic (DHM/Meon/NH4OH in the ratio of 1000:100:8)to give a yellow oil (yield 140 mg, 83%).

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

The resulting free amine (81 mg, 0.25 mmol) is injected into the reaction with the compound obtained in preparative method And using method B, and receiving the desired product as a brown oil (yield 78 mg, 54%).

MS (ESI, m/z): 592,4 [M+H+].

11.iv. 6-((R)-5-{(RS)-3-[(1R,2R)-1,2-dihydroxy-2-(6-methoxy[1,5]naphthiridine-4-yl)ethyl]pyrrolidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one:

A solution of intermediate compound (11.iii) (70 mg, 0.12 mmole) in aqueous solution of TFA (80%, 2 ml) is stirred at 40°C for 1 h Volatile fractions removed in vacuo and the residue is transferred into a saturated aqueous solution of sodium bicarbonate. The solid is filtered off, washed with water and lyophilizers. The remainder chromatographic (DHM/Meon/NH4OH in the ratio of 1000:100:8), getting named the title compound as a beige solid (yield 34 mg, 52%).

1H NMR (DMSO-d6) δ: 10,52 (m, 1H), total of 8.74 (d, J=4,7 Hz, 1H), 8,24 (dd, J=9,1, 0.6 Hz, 1H), 7,72 (d, J=4.4 Hz, 1H), 7,27 (m, 3H), to 7.09 (m, 1H), of 5.53 (m, 1H), and 5.30 (m, 1H), amounts to 4.76 (m, 1H), 4,32 (m, 1H), was 4.02 (m, 5H), 3,68 (m, 2H), 3,42 (s, 2H), 2,65 (m,6H), is 1.81 (m, 2H).

MC (ESI, m/z): is 552.5 [M+H+].

Example 12: 6-{(R)-5-[4-(3-methoxyaniline-5-ileti the Yong)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

12.i. (3-methoxyaniline-5-yl)methanol:

To a stirred suspension of 3-methoxyaniline-5-carbaldehyde (5.0 g, 26.6 mmol, obtained according to WO 2007/107965) in EtOH (200 ml), cooled to 0°C, one portion add NaBH4(1.1 g, 1.1 EQ.). The reaction mixture is then heated to room temperature and add THF (50 ml), forming a clear solution. The mixture was then stirred at room temperature for 30 min, add water (200 ml), after which the volatile components removed in vacuo. The residue is filtered off and washed with water. The solid is dried in a high vacuum, getting named in the title alcohol as a brown solid (yield 4.8 g, 95%).

MC (ESI, m/z): 191,3 [M+H+].

12.ii. 8-methyl bromide-2-methoxyphenoxy:

To a stirred solution of intermediate compound (12.i) (4.8 g, 25 mmol) in DMF (45 ml), pin PBr3(2.6 ml, 1.1 EQ.) at room temperature, forming a solid. The reaction mixture is then stirred for 30 min, then add sodium bicarbonate. The formed solid is filtered off, thoroughly washed with water and then lyophilizer, getting named in the title intermediate compound in the form of a beige solid (yield of 5.45 g, 85%).

1H NMR (CDCl3) δ: 8,51 (s, 1H), to 7.99 (dd, J=8,2, 1.5 Hz, 1H), 7,78 (dd, J=7,, 1.5 Hz, 1H), 7,52 (dd, J=8,2, 7,3 Hz, 1H), to 5.08 (s, 2H), 4,15 (s, 3H).

12.iii. (3-methoxyaniline-5-ylmethyl)triphenylphosphonium:

A solution of intermediate compound (12.ii) (4,54 g, 17.9 mmol) and PPh3(5,65 g, 1.2 EQ.) in toluene (100 ml) is heated under reflux for 6 hours After cooling to room temperature the precipitate is filtered and washed with ethyl acetate, getting named in the title intermediate compound in the form of a beige solid (yield 8,59 g, 93%).

1H NMR (DMSO-d6) δ: 8,43 (s, 1H), of 7.96 (dt, J=7,6, and 2.1 Hz, 1H), 7,83 (m, 3H), EUR 7.57 (m, 12H), to 5.56 (d, J=14,9 Hz, 2H), 3,74 (s, 3H).

12.iv. tert-butyl ester 4-(3-methoxyaniline-5-ylmethylene)piperidine-1-carboxylic acid:

A solution of n-BuLi (2 ml, 2,4-molar mixture of hexanol) pin in nitrogen atmosphere at a temperature of -78°C to a suspension of intermediate (12-iii) (2.50 g, is 4.85 mmol) in dry THF (20 ml). 15 min add a solution of tert-butyl methyl ether 4-oxopiperidin-1-carboxylic acid (0.97 g, 1 EQ.) in dry THF (15 ml) at room temperature. The mixture is stirred at room temperature overnight, after which it is cooled to a temperature of 0°C and quenched by adding saturated aqueous solution of NH4Cl and diluting with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3and brine, dried over MgSO4and concentrate under reduced pressure is. The residue is purified by column chromatography (heptane/EA in the ratio 2:1), obtaining mentioned in the title intermediate compound in the form of a pale yellow oil (yield 552 mg, 32%).

MS (ESI, m/z): 356,2 [M+H+].

12.v. 2-methoxy-8-piperidine-4-ylidenemethyl:

On the basis of the intermediate compound (12.iv) and using method a, the desired intermediate compound obtained as a dark yellow oil (yield 41 mg, 57%).

MS (ESI, m/z): 256,3 [M+H+].

12.vi. 6-{(R)-5-[4-(3-methoxyaniline-5-ylmethylene)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (12.v) and intermediate compound a and using method B, the desired product is obtained in the form of a beige solid (yield 24 mg, 34%).

MS (ESI, m/z): 518,4 [M+H+].

Example 13: 6-((R)-5-{4-hydroxy-4-[(RS)-hydroxy-(3-methoxyaniline-5-yl)metilpiperazin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one:

13.i. tert-butyl ether (RS)-4-hydroxy-4-[hydroxy-(3-methoxyaniline-5-yl)methyl] piperidine-1-carboxylic acid:

To a solution of intermediate compound (12. iv) (485 mg, 1.4 mmol) in DHM (3 ml) was added water (1 ml), NMO (192 mg, 1.2 EQ.) and osmate dihydrate potassium (20 mg). The resulting mixture was vigorously stirred at room temperature overnight. The mixture is then transferred into the water, and the organic layer washed nassen the m aqueous solution of Na 2S2O3. The aqueous layers extracted with DHM and the combined organic layers dried over MgSO4and concentrate. The residue is purified by column chromatography (DHM/Meon/NH4OH in the ratio of 1000:100:8), getting named in the title intermediate compound as a colourless foam (yield 318 mg, 60%).

MS (ESI, m/z): 390,3 [M+H+].

13.ii. tert-butyl ether (RS)-4-(3-methoxyaniline-5-yl)-2,2-dimethyl-1,3-dioxa-8-Aza-Spiro[4,5]decane-8-carboxylic acid:

On the basis of the intermediate compound (13.i) and using the method of example 11, stage 11.ii named in the title intermediate compound obtained as a yellow foam (yield 187 mg, 55%).

MS (ESI, m/z): 430,3 [M+H+].

13.iii. 6-{(R)-5-[(RS)-4-(3-methoxyaniline-5-yl)-2,2-dimethyl-1,3-dioxa-8-Aza-Spiro[4.5]Dec-8-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (13.ii) and using the method of example 11, stage 11.iii named in the title intermediate compound obtained as a colorless solid (yield 130 mg, 81%).

MS (ESI, m/z): 592,4 [M+H+].

13.iv. 6-((R)-5-{4-hydroxy-4-[(RS)-hydroxy-(3-methoxyaniline-5-yl)methyl]piperidine-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (13.iii) and using the method of example 11, stage 11.iv named in the title compound get in view of the beige solid (yield 56 mg, 48%).

1H NMR (CDCl3) δ: 8,49 (m, 1H), 7,97 (m, 2H), 7,58 (m, 2H), was 7.36 (s, 1H), 7.23 percent (m, 1H), to 6.88 (dd, J=8,8, 2.3 Hz, 1H), 5,13 (s, 1H), 4,70 (m, 1H), 4,06 (s, 3H), of 3.95 (t, J=8.5 Hz, 1H), to 3.67 (m, 1H), 3.46 in (s, 2H), 3,37 (s, 2H), 3,23 (m, 1H), 2,62 (m, 5H), to 1.86 (m, 1H), and 1.63 (m, 2H), 1,31 (m, 1H).

MS (ESI, m/z): is 552.5 [M+H+].

Example 14: 6-((R)-5-{3-[(6-methoxy[1,5]naphthiridine-4-ylamino)methyl]azetidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one:

14.i. (1-benzhydrylamine-3-ylmethyl)-(6-methoxy[1,5]naphthiridine-4-yl)amine:

On the basis of 6-methoxyquinoline-4-silt ether triftormetilfullerenov acid (obtained according to WO 00/40554) and 3-aminomethyl-1-diphenylethylenediamine (commercial product) and using method D, the desired intermediate compound allocate using column chromatography (DHM/Meon/NH4OH in the ratio of 100:50:4) as a colourless oil (yield 1.25 g, 35%).

MS (ESI, m/z): 411,1 [M+H+].

14.ii. azetidin-3-ylmethyl-(6-methoxy[1,5]naphthiridine-4-yl)amine:

A solution of intermediate compound (14.i) (50 mg, of 0.085 mmol) in DHM (0.5 ml), cooled to 0°C, treated with 1-chloritisation (35 mg, 2.5 EQ.) and leave spontaneously warm to room temperature. Then the reaction mixture was stirred overnight, then concentrated under reduced pressure. The residue is dissolved in Meon and stirred at room temperature for 3.5 hours the Solution is concentrated and the residue purified by the th column chromatography (DHM/Meon/NH 4OH in the ratio of 1000:200:16), getting named in the title intermediate compound as a colourless solid (5 mg, 24%).

MS (ESI, m/z): 245,1 [M+H+].

14.iii. 6-((R)-5-{3-[(6-methoxy[1,5]naphthiridine-4-ylamino)methyl]azetidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (14.ii) and the compound obtained in preparative method B, and using method B, the desired product is obtained as colorless solid (yield 2 mg, 19%).

MS (ESI, m/z): 507,1 [M+H+].

Example 15: 6-{(R)-5-[(2S,4S)-2-aminomethyl-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

To a solution of compound (6.iii) (35 mg, 0.065 mmol) in THF (1.5 ml) was added PPh3(33 mg, 2 EQ.) and water (0.01 ml). The mixture is heated at 50°C for 3 hours the Reaction mixture was then concentrated without dried and the residue purified by column chromatography (DHM/Meon/NH4OH in the ratio of 1000:200:16), getting named the title compound as a colourless solid (5 mg, 24%).

MS (ESI, m/z): 537,3 [M+H+].

Example 16: 6-{(R)-5-[(3R*,4R*)-3-(6-methoxyquinazoline-4-yloxy)-4-[1,2,3]triazole-1-iparralde-1-ylmethyl-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

16.i. wpew-butyl ether (3R*,4R*)-3-azido-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-carboxylic acid is:

Based on tert-butyl ether (3R*,4R*)-3-azido-4-hydroxypyrrolidine-1-carboxylic acid (obtained according to Tetrahedron Asymmetry (2001), 12, 2989) and using method B, the desired intermediate compound obtained as a yellow oil (yield of 2.18 g, 69%).

MS (ESI, m/z): 387,3 [M+H+].

16.ii. 4-((3R*,4R*)-4-azidopyridine-3-yloxy)-6-methoxyquinazoline:

On the basis of the intermediate compound (16.i) and using method a, the desired intermediate compound obtained as a yellowish solid (yield 984 mg, 61%).

MS (ESI, m/z): 287,3 [M+H+].

16.iii. 6-{(R)-5-[(3R*,4R*)-3-azido-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (16.ii) and the compound obtained in preparative method B, and using method B, the desired product is isolated in the form of a colorless solid (yield 61 mg, 20%).

MS (ESI, m/z): 549,3 [M+H+].

16.iv. 6-{(R)-5-[(3R*,4R*)-3-(6-methoxyquinazoline-4-yloxy)-4-[1,2,3]triazole-1-iparralde-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

A solution of intermediate compound (16.iii) (30 mg, by 0.055 mmol) and bicyclo[2.2.1]hepta-2,5-diene (20 mg, 4 equiv.) in dioxane (0.5 ml) is heated under reflux during the night. The mixture was then concentrated and purified by column chromatography (DHM/Meon/NH4OH in the ratio of 1000:50:4), getting mentioned in the title the connection information in the form of a yellow solid (yield 9 mg, 29%).

MS (ESI, m/z): 575,2 [M+H+].

Example 17: N-{(2S,4S)-4-(6-methoxyquinazoline-4-yloxy)-1-[(R)-2-oxo-3-(3-oxo-3.4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]pyrrolidin-2-ylmethyl}ndimethylacetamide:

To a solution of compound of example 15 (13 mg, 0.024 mmol) in DMF (0.5 ml) was added Asón (1 μl, 1 EQ.), DIPEA (9 μl, 3 EQ.), HOBT (3 mg, 1 EQ.) and EDC (6 mg, 1.2 EQ.) at room temperature. After stirring for 8 h at room temperature, water is added, and the mixture is then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4and concentrate. The residue is purified by column chromatography (DHM/Meon/NH4OH in the ratio of 1000:50:4), getting named the title compound as a yellow foam (yield 6 mg, 43%).

MS (ESI, m/z): 579,2 [M+H+].

Example 18: 6-{(R)-5-[(3R*,4R*)-3-amino-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

To a solution of compound (16.iii) (20 mg, 0.36 mmol) in THF (1.5 ml) was added PPh3(19 mg, 2 EQ.) and water (0,007 ml). The mixture is heated at 50°C for 3 hours the Reaction mixture was then concentrated without dried and the residue purified by column chromatography (DHM/Meon/NH4OH in the ratio of 1000:100:8), getting named the title compound as a yellow foam (yield 15 mg, 79%).

MS (ESI, m/z): 523,0 [M+H+].

Note the p 19: 6-{(R)-5-[(2S,4S)-4-(6-methoxyquinazoline-4-yloxy)-2-[1,2,3]triazole-1-iletilenlerin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

A solution of compound of example 6 (30 mg, 0,053 mmol) and bicyclo[2.2.1]hepta-2,5-diene (20 mg, 4 equiv.) in dioxane (0.5 ml) is heated under reflux during the night. The mixture was then concentrated and purified by column chromatography (DHM/Meon/NH4OH in the ratio of 1000:50:4), getting named the title compound as a yellow foam (yield 17 mg, 54%).

1H NMR (CDCl3) δ: 8,64 (s, 1H), 8,21 (d, J=0.6 Hz, 1H), 7,86 (d, J=9.1 Hz, 1H), 7,66 (m, 2H), 7,49 (m, 1H), 7,33 (m, 2H), 7.23 percent (m, 1H), 6,99 (m, 1H), 5,77 (m, 1H), 4,63 (m, 2H), 4,00-of 3.60 (m, 6H), to 3.58-to 3.36 (m, 4H), a 3.06 (m, 1H), 2,90 (m, 2H), 2,58(m, 1H), 2.05 is (m, 1H).

MC (ESI, m/z): 589,1 [M+H+].

Example 20: 6-{(R)-5-[4-(6-methoxyquinazoline-4-yloxy)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

20.i. tert-butyl ester 4-(6-methoxyquinazoline-4-yloxy)piperidine-1-carboxylic acid:

Based on tert-butyl ester 4-hydroxypiperidine-1-carboxylic acid (commercial product) and 4-chloro-6-methoxyquinazoline and using method B, the desired product is obtained as yellow solid (yield 649 mg, 50%).

MC (ESI, m/z): 360,5 [M+H+].

20.ii. 6-methoxy-4-(piperidine-4-yloxy)hinzelin:

On the basis of the intermediate compound (20.i) and using method a, the desired intermediate compound obtained as yellow solid (yield 469 mg, 100%).

MC (ESI, m/z): of 260.2 [M+H+].

20.iii. 6-{(R)-5-[4-(6-methoxyquinazoline-4-yloxy)piperidine-1-ylmethyl]-2-oxook solidin-3-yl}-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (20.ii) and the compound obtained in preparative method B, and using method B, the desired product is obtained as off-white solids (yield 66 mg, 49%).

1H NMR (DMSO-d6) δ: 10,53 (s, 1H), 8,64 (s, 1H), 7,83 (d, J=9.1 Hz, 1H), 7,56 (dd, J=9,1, 2,9 Hz, 1H), 7,34 (m, 3H), 7,12 (dd, J=8,8, 2.3 Hz, 1H), are 5.36 (m, 1H), 4,84 (m, 1H), 4,08 (m, 1H), with 3.89 (s, 3H), of 3.73 (m, 1H), 3,42 (s, 2H), 2,85 (m, 2H), was 2.76 (m, 2H), 2.49 USD (m, 2H), 2.05 is (m, 2H), of 1.84 (m, 2H).

MC (ESI, m/z): 522.2 [M+H+].

Example 21: 6-{(R)-5-[(3R*,4S*)-3-hydroxy-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

21.i. tert-butyl ether (3R*,4S*)-3,4-dihydroxypyrrolidine-1-carboxylic acid:

To a solution of tert-butyl ester 2,5-dihydropyrrol-1-carboxylic acid (commercial product, 1.0 g, 5,91 mmol) in tert-BuOH (25 ml) and water (25 ml) was added AD-mix α (0.75 g) and AD-mix β (0.75 g). The resulting mixture was stirred at room temperature overnight, and then add additional AD-mix α (0.5 g) and AD-mix β (0.5 g) and stirring is continued at room temperature overnight. Then add sodium bisulfite (10 g) and the mixture is stirred for 30 minutes the Phases are separated and the aqueous layer was extracted with a mixture DHM/Meon in the ratio of 9:1 (twice 40 ml). The organic layer is dried over MgSO4filter and concentrate under reduced pressure. The residue is purified by using the number of the night chromatography (DHM/Meon/NH 4OH in the ratio of 1000:100:8), getting named in the title intermediate compound as a colourless oil (yield 390 mg, 32%).

1H NMR (CDCl3) δ: 4,21 (extended t, J=3.8 Hz, 2H), 3,55 (m, 2H), and 3.31 (m, 2H), of 1.44 (s, 9H).

21.ii. tert-butyl ether (3R*,4S*)-3-hydroxy-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-carboxylic acid:

On the basis of the intermediate compound (21.i) (386 mg, 3.90 mmol) and 4-chloro-6-methoxyquinazoline (370 mg, 3.90 mmol) and using method B, the desired product is isolated in the form of a yellow oil (yield 346 mg, 50%).

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

21.iii. (3R*,4S*)-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-3-ol:

On the basis of the intermediate compound (21.ii) and using method a, the desired intermediate compound obtained as yellow solid (yield 101 mg, 40%).

MS (ESI, m/z): 262,3 [M+H+].

21.iv. 6-{(R)-5-[(3R*,4S*)-3-hydroxy-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (21.iii) and the compound obtained in preparative method B, and using method B, the desired product is obtained as a pale yellow foam (yield 66 mg, 66%).

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

Example 22: 6-{(R)-5-[(3R*,4R*)-3-hydroxy-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

22.i. tert-butyl ether (3R*,4R*)-3,4-dihydroxypyrrolidine the-1-carboxylic acid:

To a solution of tert-butyl methyl ether (1R*,5S*)-6-oxa-3-Aza-bicyclo[3.1.0]hexane-3-carboxylic acid (commercial product, 1.63 g, 8.80 mmol) in dioxane (8 ml) is added 2-molar aqueous solution of NaOH (30 ml) and the mixture is stirred at a temperature of 95°C for 2 h the Mixture was then evaporated and extracted three times with ethyl acetate. The combined organic layers washed with brine, dried over MgSO4and concentrate under reduced pressure. The crude product is triturated with EA, filtered, and washed with EA, getting named in the title intermediate compound as a yellow solid (exit 243 mg, 14%).

1H NMR (DMSO-d6) δ: 5,09 (s, 2H), 3,84 (s, 2H), and 3.31 (m, 2H), to 3.09 (m, 2H), of 1.37 (s, 9H).

22.ii. tert-butyl ether (3R*,4R*)-3-hydroxy-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-carboxylic acid:

On the basis of the intermediate compound (22.i) (240 mg, 1.18 mmol) and 4-chloro-6-methoxyquinazoline (230 mg, 1.18 mmol) and using method B, the desired product is obtained as a yellow oil (yield 189 mg, 44%).

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

22.iii. (3R*,4R*)-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-3-ol:

On the basis of the intermediate compound (22.i) and using method a, the desired intermediate compound obtained as a yellow foam (yield 74 mg, 54%).

MS (ESI, m/z): 262,4 [M+H+].

22.iv. 6-{(R)-5-[(3R*,4R*)-3-hydroxy-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacetate--yl}-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (22.iii) and the compound obtained in preparative method B, and using method B, the desired product is obtained as a pale yellow foam (yield 14 mg, 19%).

MS (ESI, m/z): 524,2 [M+H+].

Example 23: 6-{(R)-5-[3-(3-fluoro-6-methoxy-[1,5]naphthiridine-4-ylamino)azetidin-1-ylmethyl-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one:

23.i. benzyl ether of {1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)oxazolidin-5-ylmethyl]azetidin-3-yl}carbamino acid:

Proceeding from the compound obtained in preparative method G, and phenylmethanol ether (3-azetidinol)carbamino acid (commercial product, CAS 914348-04-2) and using method B, named in the title intermediate compound obtained as a colorless foam (yield 272 mg, 46%).

MS (ESI, m/z): 453,1 [M+H+].

23.ii. 6-[(R)-5-(3-aminoamides-1-ylmethyl)-2-oxoacridine-3-yl]-4H-benzo[1,4]oxazin-3-one:

On the basis of the intermediate compound (23.i) and using method W named in the title intermediate compound obtained as a colorless foam (yield 43 mg, 76%).

MS (ESI, m/z): 319,1 [M+H+].

23.iii. 6-{(R)-5-[3-(3-fluoro-6-methoxy[1,5]naphthiridine-4-ylamino)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one:

On the basis of the intermediate compound (23.ii) and 8-bromo-7-fluoro-2-methoxy-[1,5]naphthiridine (commercial product, CAS 724788-70-9) and using method named in the title compound obtained as a colorless solid (yield 24 mg, 48%).

1H NMR (CDCl3) δ: which 9.22 (s, 1H), of 8.37 (d, J=4.4 Hz, 1H), of 8.06 (d, J=9.1 Hz, 1H), 7,45 (d, J=2.3 Hz, 1H), 7,00 (d, J=9.1 Hz, 1H), to 6.88 (m, 1H), 6,74 (dd, J=8,8, 2.6 Hz, 1H), 6,03 (dd, J=7,0, 2.1 Hz, 1H), and 4.68 (m, 2H), 4,55 (s, 2H), 3,91 (m, 7H), of 3.28 (t, J=6,7 Hz, 2H), 2,89 (m, 2H).

MC (ESI, m/z): 495,1 [M+H+].

Example 24: 6-{(R)-5-[3-(6-methoxy-[1,5]naphthiridine-4-ylamino)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one:

Analogously to example 23, step 23.iii on the basis of 8-bromo-2-methoxy-1,5-naphthiridine (commercial product; CAS 881658-92-0) and intermediate (23. ii)named in the title compound obtained as a colorless solid (yield 14 mg, 26%).

1H NMR (CDCl3) δ: 9,36 (s, 1H), scored 8.38 (d, J=5.3 Hz, 1H), 8,12 (d, J=9.1 Hz, 1H), 7,50 (d, J=2.6 Hz, 1H), 7,05 (d, J=9.1 Hz, 1H), to 6.88 (m, 1H), of 6.71 (dd, J=8,8, 2.6 Hz, 1H), 6,36 (m, 2H), 4,69 (m, 1H), of 4.54 (s, 2H), 4,30 (m, 1H), 4.00 points (m, 6H), 3,85 (dd, J=8,5, 6.4 Hz, 1H), 3,29 (t, J=6,7 Hz, 2H), 2,97 (m, 1H), 2,85 (m, 1H).

MC (ESI, m/z): 477,0 [M+H+].

Example 25: 6-{(R)-5-[3-(6-methoxyquinoline-4-ylamino)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one:

Analogously to example 23, step 23.iii on the basis of 4-bromo-6-methoxyquinoline (commercial product; CAS 42881-66-3) and intermediate (23.ii)named in the title compound obtained as a colorless solid (yield 16 mg, 30%).

MC (ESI, m/z): 476,0 [M+H+].

Example 26: 6-((R)-5-{3-[(3-fluoro-6-labels and-[1,5]naphthiridine-4-ylmethyl)amino]azetidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]oxazin-3-one:

On the basis of the intermediate compound (23.ii) and 3-fluoro-6-methoxy-[1,5]naphthiridine-4-carbaldehyde (obtained according to WO 2006/032466) and using method 3, named in the title compound obtained as a colorless solid (yield 14 mg, 77%).

MC (ESI, m/z): 509,0 [M+H+].

Example 27: 6-((R)-5-{3-[(6-methoxy-[1,5]naphthiridine-4-ylmethyl)amino]azetidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]oxazin-3-one:

On the basis of the intermediate compound (23. ii) and 6-methoxy-[1,5]naphthiridine-4-carbaldehyde (obtained according to WO 2006/032466) and using method 3, named in the title compound obtained as a colorless solid (yield 12 mg, 29%).

MS (ESI, m/z): 490,9 [M+H+].

Example 28: 6-((R)-5-{3-[(3-fluoro-6-methoxyquinoline-4-ylmethyl)amino]azetidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]oxazin-3-one:

On the basis of the intermediate compound (23.ii) and 3-fluoro-6-methoxyquinoline-4-carbaldehyde (obtained according to WO 2007/105154) and using method 3, named in the title compound obtained as a colorless solid (yield 7 mg, 14%).

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

Example 29: 6-((R)-5-{3-[(6-methoxyquinoline-4-ylmethyl)amino]azetidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]oxazin-3-one:

On the basis of the intermediate compound (23.ii) and 6-methoxyquinoline-4-carbaldehyde (commercial product, CAS 4363-94-4) and using method 3, named in the title compounds is their gain in the form of a colorless solid (yield 8 mg, 31%).

MS (ESI, m/z): 490,1 [M+H+].

Example 30: (R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-[3-(6-methoxyquinazoline-4-intoximeter)azetidin-1-ylmethyl]oxazolidin-2-he:

30.i. tert-butyl ether 3-(6-methoxyquinazoline-4-intoximeter)azetidin-1-carboxylic acid:

On the basis of 1-tert-butoxycarbonyl-3-hydroxymethylation (commercial product; CAS 142253-56-3) and 4-chloro-6-methoxyquinazoline (commercial product; CAS 50424-28-7) and using the method mentioned in the title intermediate compound obtained as a yellow oil (yield 390 mg, 89%).

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

30.ii. 4-(azetidin-3-ylethoxy)-6-methoxyquinazoline:

On the basis of the intermediate compound (30.i) and using the method As mentioned in the title intermediate compound obtained as a colorless oil (yield 148 mg, 48%).

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

30.iii. (R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-[3-(6-methoxyquinazoline-4-intoximeter)azetidin-1-ylmethyl]oxazolidin-2-he:

On the basis of the intermediate compound (30.ii) and the compound obtained in preparative method D, and using method B, named in the title compound obtained as a colorless oil (yield 10 mg, 2%).

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

Example 31: 6-{(R)-5-[4-(6-methoxyquinazoline-4-yloxy)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one:

On the basis of the intermediate compound (20.ii) and the compound obtained in preparative method G, and using method B, named in the title compound obtained as a colorless oil (yield 19 mg, 16%).

MS (ESI, m/z): 506,2 [M+H+].

Example 32: N-{(3R*,4R)-4-(6-methoxyquinazoline-4-yloxy)-1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]pyrrolidin-3-yl}ndimethylacetamide:

To a solution of compound of example 18 (4 mg, 0.008 mmol) in DHM (1 ml) was added 1-acetylimidazole (1.1 EQ.) and DIPEA (1.2 EQ.). After stirring at room temperature for one day add 1-acetylimidazole (1.1 EQ.) and DIPEA (1.2 EQ.) and continue stirring at room temperature for 4 days. Then the colorless solution was concentrated under reduced pressure and purified by column chromatography (DHM/Meon/NH4OH in the ratio of 1000:50:4), getting named the title compound as a colourless solid (4 mg, 93%).

MS (ESI, m/z): 565,3 [M+H+].

Example 33: (R)-3-(6,7-dihydro-[1,4]like[2,3-C]pyridazin-3-yl)-5-[(RS)-3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]oxazolidin-2-he:

33.i. tert-butyl ether (RS)-3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-carboxylic acid:

Named in the header of the intermediate connection receive analogously to example 2, stage 1 l, from tert-butyl ether (RS)-3-hydroxypyrrolidine-1-carboxylic acid (commercial product, CAS 103057-44-9) as a pale yellow wt is a (output 764 mg, 43%).

MS (ESI, m/z): 346,3 [M+H+].

33.ii. 6-methoxy-4-((RS)pyrrolidin-3-yloxy)hinzelin:

On the basis of the intermediate compound (33.i) and using the method As mentioned in the title intermediate compound obtained as a pale yellow solid (yield 560 mg, 100%).

MS (ESI, m/z): 246,5 [M+H+].

33.hi. benzyl ether of {(S)-2-hydroxy-3-[(RS)-3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-yl]propyl}carbamino acid:

A solution of intermediate compound (33.ii) (133 mg, 0,544 mmol) and phenylmethanol ether [(2S)-oxiranylmethyl]carbamino acid (commercial product; CAS 247050-11-9, 1 EQ.) in a mixture of EtOH/H2About (in the ratio 9:1) was stirred at 80°C overnight, after which the mixture is concentrated under reduced pressure and purified by column chromatography (DHM/Meon/NH4OH in the ratio of 1000:50:4), getting named in the title intermediate compound as a yellow oil (yield 89 mg, 36%).

MS (ESI, m/z): 453,1 [M+H+].

33.iv. (S)-5-[(RS)-3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]oxazolidin-2-he:

To a solution of intermediate compound (33.iii) (89 mg, 0.20 mmol) in DMF (1 ml) was added NaH (55%solution in mineral oil, 9 mg, 1 EQ.). The reaction mixture was stirred at room temperature for 2 hours and Then water is added and the mixture extracted three times with ethyl acetate. The combined organic f the PS washed with water and brine, dried over MgSO4and concentrate. The residue is purified by column chromatography (DHM/Meon/NH4OH in the ratio of 1000:50:4), getting named in the title intermediate compound as a yellow oil (yield 12 mg, 18%).

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

33.v. (R)-3-(6,7-dihydro-[1,4]like[2,3-C]pyridazin-3-yl)-5-[(RS)-3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]oxazolidin-2-he:

On the basis of the intermediate compound (33.iv) and 3-chloro-6,7-dihydro-[1,4]like[2,3-C]pyridazine (commercial product; CAS 943026-40-2) and using method E, named in the title compound obtained as a pale yellow solid (3 mg, 21%).

MS (ESI, m/z): 481,1 [M+H+].

Example 34: 6-((R)-5-{3-[(3-methoxyaniline-5-ylmethyl)amino]azetidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]oxazin-3-one:

On the basis of the intermediate compound (23.ii) and 3-methoxyaniline-5-carbaldehyde (obtained according to WO 2007/107965) and using method 3, named in the title compound obtained as a colorless solid (yield 8 mg, 17%).

MS (ESI, m/z): 490,9 [M+H+].

Example 35: 6-{(R)-5-[4-(6-methoxy-[1,5]naphthiridine-4-ylamino)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one:

35.i. tert-butyl ether ({1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)oxazolidin-5-ylmethyl]piperidine-4-yl}carbamino acid:

On the basis of the connection is Oia, obtained in the preparative method G, and tert-butyl methyl ether piperidine-4-ylcarbamate acid (commercial product, CAS 73874-95-0) and using method B, named in the title intermediate compound obtained as a pale yellow solid (yield 721 mg, 69%).

MS (ESI, m/z): 447,2 [M+H+].

35.ii. 6-[(R)-5-(4-aminopiperidin-1-ylmethyl)-2-oxoacridine-3-yl]-4H-benzo[1,4]oxazin-3-one:

On the basis of the intermediate compound (35.i) and using the method As mentioned in the title intermediate compound obtained as a colorless solid (yield 362 mg, 65%).

MS (ESI, m/z): 347,1 [M+H+].

35.iii. 6-{(R)-5-[4-(6-methoxy[1,5]naphthiridine-4-ylamino)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one:

On the basis of the intermediate compound (35.ii) and 8-bromo-2-methoxy-1,5-naphthiridine (commercial product) and using method E, named in the title compound obtained as a pale yellow solid (yield 36 mg, 7%).

MS (ESI, m/z): 505,4 [M+H+].

Example 36: 6-{(R)-5-[3-(6-methoxy[1,5]naphthiridine-4-ylamino)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

36.i. tert-butyl ether ({1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]azetidin-3-yl}carbamino acid:

Proceeding from the compound obtained in preparative method B, and tert-butyl methyl ether, azetidin-3-incarbone the OIC acid (commercial product, CAS 91188-13-5) and using method B, named in the title intermediate compound obtained as yellow solid (yield 2,04 g, 58%).

MS (ESI, m/z): 435.2 [M+H+].

36.ii. 6-[(R)-5-(3-aminoamides-1-ylmethyl)-2-oxoacridine-3-yl]-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (36.i) and using the method As mentioned in the title intermediate compound obtained as a pale yellow solid (yield 1.22 g, 76%).

MS (ESI, m/z): 335,2 [M+H+].

36.iii. 6-{(R)-5-[3-(6-methoxy[1,5]naphthiridine-4-ylamino)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (36.ii) and 8-bromo-2-methoxy[1,5]naphthiridine (commercial product) and using method E, named in the title compound obtained as a pale yellow solid (yield 612 mg, 85%),

1H NMR (CDCl3) δ: a total of 8.74 (s, 1H), 8,39 (d, J=5.3 Hz, 1H), 8,10 (d, J=9.1 Hz, 1H), 7,47 (d, J=2.3 Hz, 1H), 7,25 (m, 1H), 7,06 (d, J=9.1 Hz, 1H), 6.89 in (dd, J=8,8, 2.3 Hz, 1H), 6,38 (d, J=5.3 Hz, 1H), of 6.31 (d, J=6.2 Hz, 1H), 4,71 (m, 1H), or 4.31 (m, 1H), was 4.02 (m, 6H), to 3.89 (dd, J=8,5, 6.4 Hz, 1H), 3,40 (s, 2H), 3,28 (td, J=6,7, and 3.2 Hz, 2H), 2,87 (m, 1H), 2,98 (m, 1H).

MC (ESI, m/z): 493,0 [M+H+].

Example 37: 6-{(R)-5-[3-(6-methoxyquinoline-4-ylamino)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (36.ii) and 4-bromo-6-methoxyquinoline (commercial product) and using method E, named in the header connection on ucaut in the form of a pale yellow solid (yield 504 mg, 70%).

1H NMR (CDCl3) δ: 8,30 (d, J=5.3 Hz, 1H), 7,82 (d, J=9.4 Hz, 1H), 7,40 (d, J=2.3 Hz, 1H), 7.23 percent (m, 3H), 7,12 (d, J=2.6 Hz, 1H), 6,83 (dd, J=8,5, 2.3 Hz, 1H), 6,14 (d, J=5.3 Hz, 1H)and 4.65 (m, 1H), 4.26 deaths (m, 1H), 3,93 (m, 6N), of 3.78 (dd, J=8,5, 6.4 Hz, 1H), 3,34 (m, 4H), of 2.92 (m, 1H), 2,81 (m, 1H).

MC (ESI, m/z): 492,1 [M+H+].

Example 38: 4-{1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]azetidin-3-ylamino)quinoline-6-carbonitrile:

On the basis of the intermediate compound (36.ii) and 4-bronchioles-6-carbonitrile (commercial product, CAS 642477-82-5) and using method E, named in the title compound obtained as a pale yellow solid (yield 225 mg, 77%).

MC (ESI, m/z): 487,5 [M+H+].

Example 39: 6-{(R)-5-[3-(6-ftorhinolon-4-ylamino)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (36.ii) and 4-bromo-6-ftorhinolona (commercial product, CAS 661463-17-8) and using method E, named in the title compound obtained as a pale yellow solid (yield 93 mg, 32%).

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

Example 40: 6-{(R)-5-[4-(6-methoxy[1,5]naphthiridine-4-ylamino)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

40.i. tert-butyl ether ({1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]piperidine-4-yl}carbamino acid:

Proceeding from the compound obtained in preparative method B, and tert-butyl methyl ether PIP is ridin-4-ylcarbamate acid (commercial product, CAS 73874-95-0) and using method B, named in the title intermediate compound obtained as a beige solid (yield 2,88 g, 49%).

MS (ESI, m/z): 463,2 [M+H+].

40.ii. 6-[(R)-5-(4-aminopiperidin-1-ylmethyl)-2-oxoacridine-3-yl]-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (40.i) and using the method As mentioned in the title intermediate compound obtained as a pale yellow foam (yield of 2.27 g, 100%).

MS (ESI, m/z): 363,1 [M+H+].

40.iii. 6-{(R)-5-[4-(6-methoxy[1,5]naphthiridine-4-ylamino)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (40.ii) and 8-bromo-2-methoxy-1,5-naphthiridine (commercial product) and using method E, named in the title compound obtained as a pale yellow solid (yield 355 mg, 41%).

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

Example 41: 6-{(R)-5-[4-(6-methoxyquinoline-4-ylamino)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one:

On the basis of the intermediate compound (40.ii) and 4-bromo-6-methoxyquinoline (commercial product) and using method E, named in the title compound obtained as a pale yellow solid (yield 102 mg, 12%).

MS (ESI, m/z): 520,5 [M+H+].

Example 42: (R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-[3-(6-methoxy[1,5]naphthiridine-4-ylamino)azetidin-1-ylmethyl]oxazolidin-2-he:

42.i. tert-butyl EF the R {1-[(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-oxoacridine-5-ylmethyl]azetidin-3-yl}carbamino acid:

A solution of the compound obtained in preparative method D, (3,16 g, 8.7 mmol) and tert-butyl methyl ether, azetidin-3-ylcarbamate acid (1.5 g, 1 EQ.) in dry DMSO (30 ml) is treated with DIPEA (1.8 ml) and heated at a temperature of 80°C for 72 h the Mixture is distributed between ethyl acetate and water, the organic phase is washed with water and brine, dried over MgSO4and concentrate. The residue is purified using accelerated chromatography (EA, EA/Meon in the ratio of 9:1+1% NH4OH), obtaining the desired intermediate compound in the form of a beige solid (yield 2.5 g, 71%).

1H NMR (DMSO d6) δ: 7,27 (dd, J=7,0, 0.9 Hz, 1H), to 7.09 (d, J=2.6 Hz, 1H), 6,94 (m, 1H), 6,83 (m, 1H), 4,57 (m, 1H), 4,21 (m, 1H), 4.00 points (m, 4H), 3,66 (dd, J=8,8, 6.4 Hz, 1H), 3,50 (q, J=7,0 Hz, 2H), 2.91 in (m. 2H), 2,65 (m, 2H), of 1.35 (s, 9H).

42.ii. (R)-5-(3-aminoamides-1-ylmethyl)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)oxazolidin-2-he:

On the basis of the intermediate compound (42.i) and using the method As mentioned in the title intermediate compound obtained as a colourless resin (yield of 1.33 g, 70%).

1H NMR (DMSO-d6) δ: to 7.09 (d, J=2.6 Hz, 1H), 6,94 (m, 1H), 6,83 (m, 1H), 4,56 (m, 1H), 4,21 (m, 4H), 3,98 (t, J=8,8 Hz, 1H), 3,66 (dd, J=8,8, 6,7 Hz, 1H), 3,50 (m, 3H), 3,38 (d, J=6,7 Hz, 2H), 2,65 (m, 4H).

42.iii. (R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-[3-(6-methoxy-[1,5]naphthiridine-4-ylamino)azetidin-1-ylmethyl]-oxazolidin-2-he:

On the basis of the intermediate compound (42.ii) (61 mg, 0.2 mmole) and 8-bromo-2-methoxy-1,5-naphthiridine (the commercial product) and using method E, named in the title compound obtained as a pale yellow solid (yield 71 mg, 77%).

1H NMR (CDCl3) δ: 8,40 (d, J=5.3 Hz, 1H), of 8.09 (d, J=9.1 Hz, 1H),? 7.04 baby mortality (m. 3H), 6,85 (d, J=8,8 Hz, 1H), 6,37 (d, J=5.3 Hz, 1H), of 6.31 (d, J=6,4 Hz, 1H)and 4.65 (m, 1H), 4,30 (m, 1H), 4,25 (s, 4H), of 4.05 (s, 3H), 3.98 (m, 4H), of 3.84 (dd, J=8,5, 6,7 Hz, 1H), 3,25 (t, J=6,7 Hz, 2H), of 2.93 (m, 1H), 2,81 (m, 1H).

MS (ESI, m/z): rub464.3 [M+H+].

Example 43: 6-{(R)-5-[3-(6-ftorhinolon-4-ylamino)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one:

43. i. 6-iodine-4-(4-methoxybenzyl)-4H-benzo[1,4]oxazin-3-one:

A solution of 6-iodine-4H-benzo[1,4]oxazin-3-one (6,88 g, 25 mmol) in DMF (50 ml) is treated with 4-methoxybenzylamine (3.8 ml, 28 mmol, 1.1 EQ.) and Cs2CO3(9,78 g, 30 mmol, 1.2 EQ.). The mixture is stirred at room temperature for 4 h and distributed between ethyl acetate (300 ml) and water (300 ml). The organic phase is washed with water (250 ml) and brine (200 ml), dried over MgSO4and concentrate. The residue is triturated with a mixture of MeOH/Et2O, the solid is filtered off, washed with a mixture of MeOH/Et2O and dried in high vacuum, getting named in the title intermediate compound in the form of a beige solid (yield of 7.8 g, 79%).

MS (ESI, m/z): 395,7 [M+H+].

43.ii. tert-butyl ether [1-(3-benzyloxycarbonylamino-2-hydroxypropyl)azetidin-3-yl]carbamino acid:

A solution of benzyl ether (S)-oxiranylmethyl the amine acid (9.3 g, 45 mmol, 1.5 EQ.) and tert-butyl methyl ether, azetidin-3-ylcarbamate acid (5.2 g, 30 mmol) in Meon (60 ml) is treated with MgSO4(7.9 g) and heated at 40°C for 3 hours the Mixture was partitioned between EA and the Meon (in the ratio 19:1) (150 ml) and water (200 ml). The aqueous layer was washed with a mixture of EA/Meon in the ratio of 19:1 (150 ml)and the combined organic phases are washed with brine (150 ml), dried over MgSO4and concentrate. The residue is triturated with ethyl acetate and filtered, obtaining mentioned in the title intermediate compound as a colorless solid (yield 3.4 g, 30%).

MS (ESI, m/z): 380,2 [M+H+].

43.iii. tert-butyl ether [1-((S)-2-oxoacridine-5-ylmethyl)azetidin-3-yl]carbamino acid:

A solution of intermediate compound (43. ii) (3.42 g, 9 mmol) in Meon (100 ml) is treated with K2CO3(1.35 g, 9.8 mmol, of 1.09 EQ.) and heated at 60°C for 4 h the Mixture was then concentrated in vacuo and purified using accelerated chromatography (EA/Meon ratio 19:1, 9:1+1% NH4OH), getting named in the title intermediate compound as a colorless solid (yield 2.3 g, 95%).

MS (ESI, m/z): 273,3 [M+H+].

43.iv. tert-butyl methyl ether (1-{(R)-3-[4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-2-oxoacridine-5-ylmethyl}azetidin-3-yl)carbamino acid:

Intermediate compounds is their (43.hi) (1 g, 3.7 mmol), intermediate compound (43.i) (1,46 g, 3.7 mmol, 1 EQ.), CuI (141 mg, 0.74 mmol, 0.2 EQ.) and K2CO3(1,02 g, 7.4 mmol, 2 EQ.) placed in a purged with argon vessel and add to this mixture of solids 1,2-diaminocyclohexane (0,091 ml, 0.74 mmol, 0.2 EQ.) and dioxane (22 ml). The resulting mixture is blown with argon and heated at 100°C for 2 days. The mixture is distributed between ethyl acetate and water, the organic phase is washed with water and brine, dried over MgSO4and concentrate. The residue is purified using accelerated chromatography (EA, EA/Meon in the ratio of 9:1+1% NH4OH), getting named in the title intermediate compound as a brown foam (yield of 1.14 g, 58%).

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

43.v. 6-[(R)-5-(3-aminoamides-1-ylmethyl)-2-oxoacridine-3-yl]-4-(4-methoxybenzyl)-4H-benzo[1,4]oxazin-3-one:

On the basis of the intermediate compound (43.iv) (1.13 g) and using the method As mentioned in the title intermediate compound obtained as a colourless resin (yield of 0.85 g, 92%).

MS (ESI, m/z): 439,5 [M+H+].

43.vi. 6-{(R)-5-[3-(6-ftorhinolon-4-ylamino)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4-(4-methoxybenzyl)-4H-benzo[1,4]oxazin-3-one:

On the basis of the intermediate compound (43. v) (429 mg, 1.9 mmol) and 4-bromo-6-ftorhinolona (commercial product) and using method E, named in the header of the intermediate joint is obtained as a pale yellow solid (yield 929 mg, 84%).

MS (ESI, m/z): 584,4 [M+H+].

43.vii. 6-{(R)-5-[3-(6-ftorhinolon-4-ylamino)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one:

A solution of intermediate compound (43.vi) (905 mg, 1.55 mmol) in TFA (15 ml) in a sealed container is heated at a temperature of 80°C during the night. Volatile components are removed under reduced pressure and the residue is distributed in the mixture DHM/Meon in the ratio of 9:1 (130 ml) and NH4OH (80 ml). The organic phase is washed with water (100 ml), dried over MgSO4and concentrate. The residue is crystallized from a mixture of DGM/Meon, getting named the title compound as a colorless solid (yield 0.5 g,70%).

1H NMR (CDCl3) δ: 8,40 (d, J=5.3 Hz, 1H), of 8.09 (d, J=9.1 Hz, 1H),? 7.04 baby mortality (m, 3H), 6,85 (d, J=8,8 Hz, 1H), 6,37 (d, J=5.3 Hz, 1H), of 6.31 (d, J=6,4 Hz, 1H), of 4.66 (m, 1H), 4,30 (m, 1H), 4,25 (s, 4H), of 4.05 (s, 3H), 3,98 (m, 3H), of 3.84 (dd, J=8,5, 6,7 Hz, 1H), 3,25 (t, J=6,7 Hz, 2H), 2,93 (m, 1H), 2,81 (m, 1H).

MS (ESI, m/z): rub464.3 [M+H+].

Example 44: (R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-[3-(6-methoxyquinoline-4-yloxy)azetidin-1-ylmethyl]oxazolidin-2-he:

44.i. 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-(3-hydroxyazetidine-1-ylmethyl)oxazolidin-2-he:

The compound obtained in preparative method D, (9 g, 25 mmol) and hydrochloride 3-hydroxyazetidine (4.1 g, 1.5 EQ.) condense, using method B and getting mentioned in the title intermediate compound in the form of a beige solid (yield 1.3 g, 17%).

MS (ESI, m/z): 307,3 [M+H+].

44.ii. (R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-[3-(6-methoxyquinoline-4-yloxy)azetidin-1-ylmethyl]oxazolidin-2-he:

DYADS (0,116 ml) pinned to a solution of intermediate compound (44.i) (0.15 g, 0.49 mmol), PPh3(0,141 g) and 6-methoxyquinoline-4-ol (0,086 g) in THF (1 ml). The mixture is stirred at room temperature for 1.5 h, concentrated in vacuo and purified using accelerated chromatography (EA, EA/Meon in the ratio of 9:1+1% NH4OH), getting named the title compound as a yellow oil (12 mg).

MS (ESI, m/z): 464,5 [M+H+].

Pharmacological properties of the compounds according to the invention

Analyses by the method of in vitro

Experimental methods:

These analyses are carried out in accordance with the description given in: "Methods for dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, 4th ed.; Approved standard NCCLS Document M7-A4; National Committee for Clinical Laboratory Standards: Villanova, PA, USA, 1997". The minimum inhibition concentration (MICs; mg/l) were determined in cation-regulated nutrient medium Mueller-Hinton Broth (BBL) using the method of microrasbora according to the NCCLS guidelines (National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility). The pH-value of the test environment is 7,2-7,3.

The results:

Join all of the above examples are tested regarding the effects on gram-positive and grammatically smear the AI.

Typical results of antibacterial tests are presented in the table below (MIC in mg/l).

ExampleM. catarrhalis A894ExampleM. catarrhalis A894
1≤0,03123≤0,031
2≤0,03124≤0,031
3≤0,03125≤0,031
4≤0,03126≤0,031
5≤0,03127≤0,031
6≤0,03128≤0,031

≤0,031
ExampleM. catarrhalis A894ExampleM. catarrhalis A894
7≤0,031 290,063
8≤0,031300,063
9≤0,03131≤0,031
10≤0,031320,25
110,125330,25
12≤0,031340,063
130,535≤0,031
14≤0,03136≤0,031
15≤0,031370,125
16≤0,031380,125
170,25390,063
1840≤0,031
190,063410,5
20≤0,03142≤0,031
21≤0,031430,25
22≤0,031448

1. The compound of formula (I)
,
where one or two of U, V, W and X are N, the others represent CH or, in the case of X, may also represent CRawhere Radenotes fluorine;
R1is alkoxygroup, halogen or cyano;
R2represents N, CH2OH, CH2N3CH2NH2alkylcarboxylic or triazole-1-ylmethyl;
R3represents H or, when n=1, R3can also be a HE, NH2, NHCOR6or triazole-1-yl;
But a CR4;
K represents O, NH, co2, NHCO, NHCH2CH2NH, CH2CH2, SN=SN, SNANNON or CHR5;
R4represents H or in the natural with R 5forms a bond, or R4can also be a HE, when K is O, NH, co2or NHCO;
R5is a HE or, together with R4forms a link;
R6represents alkyl;
m=0 or 1 and n=0 or 1 and
G represents a group

where Z1represents N, Z2represents CH and Z3represents CH; or
Z1represents CH, Z2represents N and Z3represents CH or N; or
Z1represents CH, Z2represents CH and Z3represents CH or N;
the ring R is selected from the following groups:

in which Q represents O or S;
or a salt of such compounds.

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

3. The compound of formula (I) according to claim 1, where
R1is alkoxygroup;
R3represents H or, when n=1, R3can also be a HE, NH2or triazole-1-yl;
K represents O, NH, co2, NHCO, NHCH2CH2CH2CH=CH, SNANNON or CHR5where the values of R5defined in claim 1; and
G represents a group

where Z presents yet a N or CH, and ring R defined in claim 1;
or a salt of such compounds.

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

5. The compound of formula (I) according to claim 1, where U and V each represents N and W and X each represent CH, or U and V each represent CH and W and X each represent N, or U and W each represent N and V and X each represents CH; or a salt of such compounds.

6. The compound of formula (I) according to claim 5, where R1represents a methoxy group; or a salt of such compounds.

7. The compound of formula (I) according to claim 1, where m and n are each = 0; or a salt of such compounds.

8. The compound of formula (I) according to claim 7, where R1represents a methoxy group; or a salt of such compounds.

9. The compound of formula (I) according to claim 1, where m=1 and n=0; or a salt of such compounds.

10. The compound of formula (I) according to claim 9, where R1represents a methoxy group; or a salt of such compounds.

11. The compound of formula (I) according to claim 1, where G represents 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl; or a salt of such compounds.

12. The compound of formula (I) according to claim 11, where R1represents a methoxy group; or a salt of such compounds.

13. The compound of formula (I) indicated in paragraph 12, where m and n are each = 0; or a salt of such compounds.

14. The compound of formula (I) indicated in paragraph 12, where m=1 and n=0; or a salt of such compounds.

15. The connection f is rmula (I) according to claim 1, which is selected from the following compounds:
6-{(R)-5-[3-(6-methoxy-[1,5]naphthiridine-4-yloxy)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-{(R)-5-[(R)-3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-{(R)-5-[(S)-3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-[3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]oxazolidin-2-he;
6-{(R)-5-[(2S,4S)-2-hydroxymethyl-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-{(R)-5-[(2S,4S)-2-azidomethyl-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
(6-methoxy[1,5]naphthiridine-4-yl)amide 1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]azetidin-3-carboxylic acid;
(6-methoxy[1,5]naphthiridine-4-yl)amide 1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]pyrrolidin-3-carboxylic acid;
6-((R)-5-{3-[(E)-2-(6-methoxy[1,5]naphthiridine-4-yl)vinyl]pyrrolidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;
6-((R)-5-{3-[2-(6-methoxy[1,5]naphthiridine-4-yl)ethyl]pyrrolidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;
6-((R)-5-{3-[(1R,2R)-1,2-dihydroxy-2-(6-methoxy[1,5]naphthiridine-4-yl)ethyl]pyrrolidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-Ben is about[1,4]thiazin-3-one;
6-{(R)-5-[4-(3-methoxyaniline-5-ylmethylene)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-((R)-5-{4-hydroxy-4-[hydroxy(3-methoxyaniline-5-yl)methyl]piperidine-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;
6-((R)-5-{3-[(6-methoxy[1,5]naphthiridine-4-ylamino)methyl]azetidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]thiazin-3-one;
6-{(R)-5-[(2S,4S)-2-aminomethyl-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-{(R)-5-[(3R*,4R*)-3-(6-methoxyquinazoline-4-yloxy)-4-[1,2,3]triazole-1-iparralde-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
N-{(2S,4S)-4-(6-methoxyquinazoline-4-yloxy)-1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]pyrrolidin-2-ylmethyl} ndimethylacetamide;
6-{(R)-5-[(3R*,4R*)-3-amino-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-{(R)-5-[(2S,4S)-4-(6-methoxyquinazoline-4-yloxy)-2-[1,2,3]triazole-1-iletilenlerin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-{(R)-5-[4-(6-methoxyquinazoline-4-yloxy)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-{(R)-5-[(3R*,4S*)-3-hydroxy-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-{(R)-5-[(3R*,4R*)-3-hydroxy-4-(6-methoxyquinazoline-4-yloxy)pyrrolidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one; or a salt of such compounds.

16. The compound of formula (I) according to claim 1, which is selected from the following compounds:
6-{(R)-5-[3-(3-fluoro-6-methoxy[1,5]naphthiridine-4-ylamino)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one;
6-{(R)-5-[3-(6-methoxy[1,5]naphthiridine-4-ylamino)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one;
6-{(R)-5-[3-(6-methoxyquinoline-4-ylamino)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one;
6-((R)-5-{3-[(3-fluoro-6-methoxy[1,5]naphthiridine-4-ylmethyl)amino]azetidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]oxazin-3-one;
6-((R)-5-{3-[(6-methoxy[1,5]naphthiridine-4-ylmethyl)amino]azetidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]oxazin-3-one;
6-((R)-5-{3-[(3-fluoro-6-methoxyquinoline-4-ylmethyl)amino]azetidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]oxazin-3-one;
6-((R)-5-{3-[(6-methoxyquinoline-4-ylmethyl)amino]azetidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]oxazin-3-one;
(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-[3-(6-methoxyquinazoline-4-intoximeter)azetidin-1-ylmethyl]oxazolidin-2-he;
6-{(R)-5-[4-(6-methoxyquinazoline-4-yloxy)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one;
N-{(3R*,4R*)-4-(6-methoxyquinazoline-4-yloxy)-1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]pyrrolidin-3-yl}ndimethylacetamide;
(R)-3-(6,7-dihydro[1,4]like[2,3-C]pyridazin-3-yl)-5-[3-(6-methoxyquinazoline-4-yloxy)pyrrolidin-ylmethyl]oxazolidin-2-he;
6-((R)-5-{3-[(3-methoxyaniline-5-ylmethyl)amino]azetidin-1-ylmethyl}-2-oxoacridine-3-yl)-4H-benzo[1,4]oxazin-3-one;
6-{(R)-5-[4-(6-methoxy[1,5]naphthiridine-4-ylamino)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one;
6-{(R)-5-[3-(6-methoxy[1,5]naphthiridine-4-ylamino)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-{(R)-5-[3-(6-methoxyquinoline-4-ylamino)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
4-{1-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)oxazolidin-5-ylmethyl]azetidin-3-ylamino}quinoline-6-carbonitrile;
6-{(R)-5-[3-(6-ftorhinolon-4-ylamino)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-{(R)-5-[4-(6-methoxy[1,5]naphthiridine-4-ylamino)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
6-{(R)-5-[4-(6-methoxyquinoline-4-ylamino)piperidine-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]thiazin-3-one;
(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-[3-(6-methoxy[1,5]naphthiridine-4-ylamino)azetidin-1-ylmethyl]oxazolidin-2-he;
6-{(R)-5-[3-(6-ftorhinolon-4-ylamino)azetidin-1-ylmethyl]-2-oxoacridine-3-yl}-4H-benzo[1,4]oxazin-3-one;
(R)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-5-[3-(6-methoxyquinoline-4-yloxy)azetidin-1-ylmethyl]-oxazolidin-2-he;
or a salt of such compounds.

17. The compound of formula (I) according to one of claims 1 to 16 or its pharmaceutically acceptable salt as a medicinal product for which ractice or treatment of bacterial infections.

18. Pharmaceutical composition for prevention or treatment of bacterial infections comprising as an active component a compound of the formula I according to one of claims 1 to 16 or its pharmaceutically acceptable salt and at least one therapeutically inert excipient.

19. The use of the compounds of formula I according to one of claims 1 to 16 or its pharmaceutically acceptable salts for preparing a medicinal product intended for the prevention or treatment of bacterial infections.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new fluorine-containing substituted 5-[2-(pyrid-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochlorides of general formula , R1 = H, (C1-C6) alkyl; R2, R3, R4, R5 = H, F, Cl, Br, (C1-C6) alkyl, (C1-C6) alkoxy; R6 = F, CF3. Also, the invention refers to pharmaceutical compositions based on the compound of formula (I), and to a method of decreasing uncontrolled protein aggregation in the nervous system involving administering the pharmaceutical preparation containing an effective amount of the compound of formula (I) to a patient.

EFFECT: new derived 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochlorides effective for decreasing uncontrolled protein aggregation in the nervous system are produced.

3 cl, 12 dwg, 2 tbl, 14 ex

FIELD: biotechnologies.

SUBSTANCE: new derivatives of triazolo[1,5-a]quinoline of general formula (I)

, where X means -NH-; R13-cyano; R1 and R2 mean H or methyl; R5-phenyl, possibly substituted, or 5- or 6-member heterocyclyl; R3 means phenyl or one atom of nitrogen containing 6-member heterocyclyl; R4 - one atom of nitrogen containing 6-member heterocyclyl or a group of the formula (a), , where R6 and R7 - independently mean C3-6cycloalkyl or C1-4alkyl; or a group of the formula (b) , where R8 and R9 mean C1-4alkyl; Z - oxygen or a group -NR12-, where R12 - hydrogen, C1-4alkyl, C3-6 cycloalkyl, benzyl, -CH2-acetyl, -CH2-CH2-O-CH2-CH3 or acetyl; W means nitrogen atom or a group -CH-; m and o mean 2; p and r mean zero or 1; t means zero; methods of their production, new intermediate compounds of described methods of production, a pharmaceutical composition containing these compounds, and application of compounds of common formula (I) and their pharmaceutical acceptable salts as ligands of adenosine A3 receptor in treatment of different diseases.

EFFECT: improved properties of compounds.

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to cyclic azaindole-3-carboxamides of formula (I) in any of its stereoisomeric forms or in the form of a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof or a physiologically acceptable solvate of any of them: wherein A is specified in O, S and C(Ra)2; Ra is specified in hydrogen and (C1-C4)-alkyl wherein the two groups Ra are independent from each other and may be identical or different; R is specified from hydrogen, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-, phenyl-(C1-C4)-alkyl-, (C1-C4)-alkyl-O-CO-CuH2u- and R1-NH-CO-CuH2u-, wherein all the groups R are independent from each other and may be identical or different; R1 is specified from hydrogen, (C1-C4)-alkyl and H2N-CO-(C1-C4)-alkyl-; R10 is specified from hydrogen, (C1-C6)-alkyl-O-CO-; R20 is specified from phenyl which is optionally substituted by one or more identical or different substitutes specified in halogen, (C1-C4)-alkyl and (C1-C4)-alkyl-O-; R30 is specified from (C3-C7)-cycloalkyl and phenyl, wherein phenyl is optionaly substituted by one or more identical or different substitutes specified in halogen and (C1-C6)-alkyl; R40 is specified in halogen, (C1-C4)-alkyl, phenyl-(C1-C4)-alkyl-, hydroxy, (C1-C4)-alkyl-O-, HO-CO-(C1-C4)-alkyl-O- and (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O-, wherein all the substitutes R40 are independent from each other and may be identical or different; one of the groups Y1, Y2, Y3 and Y4 represents N, while the others are identical or different groups CH or CR40; n is specified in 0, 1, 2 and 3; p and q which are independent from each other and may be identical or different being specified in 2 and 3; n is specified in 0, 1 and 2, wherein all the values are independent from each other and may be identical or different; wherein all the alkyl groups are independently from each other optionally substituted by one or more fluorine atoms; wherein all the phenyl groups found in R and R40 are independently from each other optionally substituted by one or more identical or different substitutes specified in halogen and (C1-C4)-alkyl. Besides, the invention describes a method for preparing a compound of formula I, a pharmaceutical compositions having renin inhibitory activity and containing the compound of formula I and to using the compound of formula I for making a therapeutic preparation.

EFFECT: described and prepared are the new compounds that inhibit the enzyme renin, and modulate activity of the renin-angiotensin system, and are effective for treating the diseases such as, eg hypertension.

7 cl, 141 ex, 8 tbl

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: present invention refers to pharmacy and medicine, and concerns using the pyridopyrazine derivatives for preparing a drug for treating or preventing the physiological and/or pathophysiological conditions associated withPI3K kinase inhibition in mammals.

EFFECT: invention provides high clinical effectiveness.

7 cl, 4 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a compound having chemical formula or a salt thereof, where: Ar is an optionally substituted heteroaryl; R1 in each case is independently selected from a group which includes halogen, lower alkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, monoalkylamino, dialkylamino, -O-R5, -N(R5)-R6 and -N(R5)-C(X)-R7; m equals 0 or 1; n equals 0, 1 or 2; R2 is hydrogen or a halogen; L2 is -S(O)2-; R3 is a lower alkyl, optionally substituted with fluorine, C3-6 cycloalkyl, optionally substituted with a lower alkyl, a 5- or 6-member nitrogen-containing heterocycloalkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkyl, fluorine-substituted lower alkyl, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio or fluorine-substituted lower alkylthio, aryl, optionally substituted with a halogen, lower alkyl, optionally substituted with a halogen or lower alkoxy, optionally substituted with a halogen, or a heteroaryl, optionally substituted with a halogen or a lower alkyl; L1 is selected from a group which includes -O-, -C(R12R13)-X-, -X-C(R12R13)-, -C(R12R13)-N(R11)-, -(R11)-C(R12R13)-, -C(X)-N(R11)-, -N(R11)-C(X)-; X is O; R11 is hydrogen; R4 is hydrogen or a lower alkyl; R5 and R6 in each case are independently selected from a group which includes hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where each is optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio, fluorine-substituted lower alkylthio, monoalkylamino, dialkylamino; R7 in each case is independently selected from a group which includes lower alkyl; where the terms "lower alkyl", "lower alkoxy", "lower alkylthio", "monoalkylamino", "dialkylamino", "cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", are as described in the claim. The invention also discloses a pharmaceutical composition for treating Raf kinase mediated diseases which is based on a compound of formula I; use of the compound of formula I to produce a medicinal agent is also disclosed.

EFFECT: novel compound which can be useful in treating diseases and conditions associated with aberrant activity of protein kinases is obtained and described.

9 cl, 13 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new polycyclic compounds, pharmaceutically acceptable salts thereof of general formula wherein R1 -phenyl, pyridyl, optionally substituted, or C3-7-cycloalkyl; R2 -H, -CH2R3, -C(=O)R3, -C(=O)N(R4)R3, and -SO2-pyridyl, wherein R3-H, C1-6 alkyl, C2-6 alkenyl, C3-7-cycloalkyl, -(CH2)m-phenyl -(CH2)m-(5-, 6- or 9-member heterocyclyl with 1-3 heteroatoms N, O or S); m is equal to 0-6; R4 -H; X represents O or S; the alkyl, alkenyl, cycloalkyl, phenyl and heterocyclyl groups may be substituted by one or more substitutes. A together with atoms whereto attached forms phenyl or heteroaryl with 1 or 2 nitrogen atoms, optionally substituted; B-C means -CH2-(CH2)z-, wherein z is equal to 1 or 2; D represents -CRIIIRIV-, wherein RIII and RIV are identical, and mean CH3 or H; or RIII and RIV together with the atom C whereto attached form a 3-member cycloalkyl ring, a pharmaceutical composition containing them, and the use of the above compounds for treating viral RSV infections.

EFFECT: new polycyclic compounds are described.

24 cl, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to azaindole-indole derivatives and pharmaceutically acceptable salts thereof of general formula: Y=Z (G), wherein Y means a group of azaindole of formula (Yl) Z means a group of indole of formula (Z1) or (Z2) wherein the values "=", R, R1, R1', R2, R3, R4, R2', R3, R4', R5' are presented in cl. 1 of the patent claim.

EFFECT: compounds inhibit cycline-dependent kinase that enables using them in a pharmaceutical composition.

6 cl, 3 dwg, 9 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives of formula I or pharmaceutically acceptable salts thereof, wherein R1 represents H; R2 represents (C1-3)alkyl; R3 represents (C1-4)alkyl optionally substituted by three halogen atoms; R4 represents H; X represents O; n is equal to 1 or 2 or 3; Y is specified in OH, NR5R6 and Z, wherein Z represents a saturated 5- or 6-member heterocyclic ring containing 1 heteroatom specified in NR7, wherein the ring can be substituted by oxo(C1-3)alkyl, hydroxy(C1-3)alkyl; or wherein Z represents an aromatic 5- or 6-member heterocyclic ring containing 1-2 heretoatoms specified in N wherein the ring can be substituted by (C1-3)alkyl; R5 and R6 optionally represent H, (C3-8)cycloalkyl or (C1-6)alkyl optionally substituted 1-2 times by halogen, OH, (C1-6)alkyloxy, CONR14R15, NR14R15 or a 6-member saturated heterocyclic group containing a heteroatom specified in NR8; or R5 and R6 together with a nitrogen atom whereto attached form a 5-10-member saturated heterocyclic ring optionally additionally containing 1, 3 heteroatoms specified in NR9, with the ring optionally substituted by OH, oxo, (C1-4)alkyl, hydroxy(C1-3)alkyl, CONR10R11 or NR10R11; R7 represents H; R8 represents (C1-3)alkyl; R9 represents H, (C1-3)alkyl, hydroxy(C1-3)alkyl, (C1-3)alkoxy(C1-3)alykl, (C1-6)alkylcarbonyl, (C1-6)alkyloxycarbonyl, CONR12R13 or a 6-member heteroaryl group containing 1-2 heteroatoms specified in N; R10 and R11 optionally represent H or (C1-3)alkyl; R12 and R13 optionally represent (C1-3)alkyl; or R14 and R15 optionally represent (C1-3)alkyl. Also, the invention refers to the use of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of formula I and a pharmaceutical composition thereof.

EFFECT: there are prepared new 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives effective for treating osteoporosis, atherosclerosis, inflammation and immune disorders, such as rheumatoid arthritis, psoriasis and chronic pain, such as neuropathic pain .

9 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline compounds of formula (I) and physiologically acceptable acid addition salts and N oxides thereof, wherein R denotes a polycyclic group of formula (R) wherein * indicates the quinolinyl radical binding site; A denotes (CH2)a, where a equals 0, 1, 2 or 3; B denotes (CH2)b, where b equals 0, 1, 2 or 3; X' denotes (CH2)x where x equals 0, 1, 2 or 3; Y denotes (CH2)y where y equals 0, 1, 2 or 3; provided that a+b=1, 2, 3 or 4, x+y=1, 2, 3 or 4, and a+b+x+y=3, 4, 5, 6 or 7; Q denotes N; R1 denotes hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, phenyl-C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, where phenyl rings in last two said groups are unsubstituted or carry 1, 2 or 3 substitutes selected from halogen, C1-C4-alkyl or C1-C4-halogenalkyl; R2 denotes hydrogen; R3 denotes hydrogen; p=0, 1 or 2; R4, if present, denotes C1-C4-alkyl and is bonded with X and/or Y, if p=2, two radicals R4, which are bonded with adjacent carbon atoms of X or Y, together can also denote a straight C2-C5-alkylene; q=0; n=0; m=0; X denotes S(O)2; which is located in position 3 of quinoline; Ar denotes a radical Ar1, wherein Ar1 is a phenyl, wherein the phenyl can be unsubstituted or can carry 1 substitute Rx wherein Rx denotes halogen, CN, C1-C6-alkyl, C1-C6-halogenalkyl, C1-C6-alkoxy, C1-C6-halogenalkoxy, C1-C6-alkylthio, C1-C6-halogenalkylthio, NRx1 Rx2, wherein Rx1 and Rx2 independently denote hydrogen, C1-C6-alkyl, or Rx1 and Rx2 together with a nitrogen atom form an N-bonded 5-, 6- or 7-member saturated heteromonocyclic ring or an N-boned 7-, 8-, 9- or 10-member saturated heterobicyclic ring, which are unsubstituted or carry 1, 2, 3 or 4 radicals selected from C1-C4-alkyl. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of treatment using the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel quinoline derivatives are obtained, which respond to modulation of the serotonin 5-HT6 receptor.

23 cl, 2 tbl, 44 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel pyridine derivatives pyridine1-A-pyridine2 of formula (1), where pyridine1 represents

, , or , ,

where asterisks stand for bond, which contains pyridine1 ring with A; R1 represents C1-5alkyl, C1-4alkoxygroup, C3-6-cycloalkyl, hydroxymethyl or NR1aR1b, R1a represents C1-4alkyl; R1b represents hydrogen or C1-3alkyl; or R1a and R1b, together with nitrogen atom, which is bound to pyridine, form pyrrolidine ring; R2 represents hydrogen or C1-4alkyl, or in case, when R1 represents C1-5alkyl or C3-6-cycloalkyl, R2 can additionally represent methoxygroup; R3 represents C1-4alkyl, C1-4alkoxygroup, C3-6-cycloalkyl or NR3aR3b; R3a represents C1-4alkyl; R3b represents hydrogen or C1-3alkyl; R4 represents C1-4alkyl or hydrogen; R5 represents C1-5alkyl, methoxygroup or NR5aR5b; and R6 represents C1-2alkyl; R5a represents C1-4alkyl; R5 represents hydrogen or C1-3alkyl; or R5 represents C1-2alkyl or methoxygroup; and R6 represents C1-5alkyl or NR6aR6b; R6a represents C1-4alkyl; R6b represents hydrogen or C1-3alkyl; R7 represents C1-5alkyl; R8 represents C1-2alkyl or methoxygroup; R9 represents C1-5alkyl; R10 represents C1-2alkyl; A represents

, , or ,

where asterisks stand for bond, binding pyridine1 ring with A; pyridine2 represents

, , or , ,

where asterisks stand for bond, which binds pyridine ring with A; R11 represents C1-4alkyl; C1-3alkyloxy group, hydroxymethyl or NR11aR11b; R,1a represents C1-3alkyl; R11b represents hydrogen or C1-2alkyl; R12 represents hydrogen or C1-4alkyl; R13 represents C1-4alkyl or NR13aR13b; R13a represents C1-4alkyl; R13b represents hydrogen or C1-2alkyl; R14 represents C1-2alkyl; R15 represents C1-4alkyl or NR15aR15b; and R16 represents C1-2alkyl; R15a represents C1-3alkyl; R15b represents hydrogen or C1-3alkyl; or R15 represents C1-2alkyl; and R16 represents C1-4alkyl or NR16aR16b; R16a represents C1-3alkyl; R16b represents hydrogen or C1-2alkyl; R17 represents C1-4alkyl; R18 represents C1-2alkyl or methoxygroup; R19 represents C1-4alkyl; and R20 represents C1-2alkyl; with exception of 3-(2-ethyl-4-pyridyl)-5-(2-ethyl-4-pyridyl)-1,2,4-oxadiazole; or pharmaceutically acceptable salt of such compound.

EFFECT: obtaining pyridine derivatives, which possess agonistic activity with respect to S1P1/EDG1.

15 cl, 2 tbl, 131 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel aminitriazole derivatives of formula (I), where A is phenyl, heterocyclyl or propan-1,3-diyl; E is *-C1-4alkyl-O-, -CH=CH- or , where asterisks stand for bond, through which binding with R1; Q- O or S occurs; R3 is hydrogen, C1-4alkyl, cyclopropyl, C1-4alkoxy-C1-4alkyl, benzyl or -CH2CH2C(O)O-tert-Bu; R1 is pyridyl or phenyl, possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, C1-4fluoroalkoxy, di-( C1-3alkyl)amino or C1-4alkoxy-C1-2alkyl; and R2 is -CO-C1-3alkyl,-CF2-C1-3alkyl or -SO2-C1-3alkyl; or their pharmaceutically acceptable salts, pharmaceutical composition, which contains them.

EFFECT: obtaining novel compounds for treatment of inflammatory disease or Alzheimer's disease.

20 cl, 105 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula 1:

or pharmaceutically acceptable salts thereof, where values of Cy1; Cy2; L1; L2, R; R1; Rx and Ry and R2 are given in claim 1.

EFFECT: compounds are suitable for use as Raf protein kinase inhibitors.

36 cl, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to polymorphous form of compound

,

which is characterised by picture of X-ray diffraction, including discriminatory peaks approximately 7.269, 9.120, 11.038, 13.704, 14.481, 15.483, 15.870, 16.718, 17.087, 17.473, 18.224, 19.248, 19.441, 19.940, 20.441, 21.469, 21.750, 22.111, 23.319, 23.763, 24.120, 24.681, 25.754, 26.777, 28.975, 29.609, 30.073 degree 2Θ. Invention also relates to method of obtaining polymorphous form of compound (IX), which includes processing of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-ylthiazol-2-ylamino)phenyl]benzamide with methanesulfonic acid at temperature from 20 to 80°C in solvent, selected from group, which includes methanol, ethanol, acetone, diethyl ether, dioxane and their mixtures.

EFFECT: obtaining polymorphous form of compound (IX), which remains dry at 80% relative humidity and thermodynamically stable at temperatures lower than 200°C.

7 cl, 3 dwg, 4 ex

Organic compounds // 2491285

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein V is specified in -O- or a single bond; W is specified in -N(R5)C(O)-, -S(O)t- and -C(O)O-; X is specified in C(H) or N; Y is specified in S, N(H) or N(CH3); p means 0 or 2; t means 1 or 2; R1 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by 1 or 2 halogroups, C3-7cycloalkylC1-6alkyl, 2,3-dihydro-1H-indenyl, C6arC1-6alkyl optionally substituted by one or two halogroups and heteroarylC1-6alkyl, wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen optionally oxidated, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9-member bicyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen, oxygen and sulphur, wherein monocyclic heteroaryl of the heteroarylalkyl group may be optionally substituted by one or two substitutes independently specified in a group consisting a halogroup, a cyanogroup, C1-6alkyl, haloC1-6alkyl and C1-6alkyl-O-C(O)-; R2 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by phenoxy, hydroxy C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, phenyl optionally substituted by a halogroup, haloC1-6alkyl, C6arC1-6alkyl (optionally substituted by a halogroup, haloC1-6alkyl or haloC1-6alkoxygroup), 2-oxo-imidazolidinyl, heterocyclylC1-6alkyl and heteroarylC1-6alkyl, wherein heterocyclyl of heterocyclylalkyl means 5- or 6-member monocycle containing oxygen, and wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocycle containing 1-3 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9- or 10-member bicycle containing 1 to 2 heteroatoms specified in a group consisting of nitrogen and sulphur, wherein monocyclic heteroaryl of the heteroaryl alkyl group may be optionally substituted by 1 or 2 substitutes independently specified in a group consisting of a halogroup, C1-6alkyl, haloC1-6alkyl and phenyl optionally substituted by a halogroup; R3 is specified in a group consisting of hydrogen and alkyl; two adjacent R4 groups together with carbon atoms whereto attached can form phenyl; R5 means hydrogen; or a pharmaceutically acceptable salt thereof.

EFFECT: preparing the heterocyclic derivatives which modulate activity of stearoyl CoA desaturase, methods of using the above derivatives for modulating activity of stearoyl CoA desaturase and pharmaceutical compositions containing the above derivatives.

26 cl, 1 tbl, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a 2H-chromen compound or a derivative thereof having action of a S1P1 agonist. The above may be used for preventing and/or treating a disease caused by undesired lymphocyte filtration, or a disease caused by abnormal cell proliferation or accumulation.

EFFECT: preparing the compounds for preventing and/or treating the disease caused by undesired lymphocyte filtration, or the disease caused by abnormal cell proliferation or accumulation.

8 cl, 131 tbl, 156 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of aminopyrazol with the formula of , where A, E, R1 and R2 have values specified in the invention claims, and to their pharmaceutically acceptable salts. Compounds of the formula (I) are agonists of the ALX receptor. Besides, the invention relates to a pharmaceutical composition on the basis of the compound of the formula (I) or its pharmaceutically acceptable salt and to application of these compounds for production of a medicinal agent for prevention or treatment of a disease selected from inflammatory diseases, wheezing diseases, allergic states, HIV-mediated retrovirus infections, cardiovascular diseases, neuroinflammations, neurological disorders, pain, prion-mediated diseases and amiloid-mediated diseases; and for modulation of immune responses.

EFFECT: higher efficiency of compound application.

23 cl, 1 tbl, 466 ex

FIELD: chemistry.

SUBSTANCE: invention provides to a high degree a safe pharmaceutical drug which is effective for diseases caused by MMP-2 and/or MMP-9. The pharmaceutical drug contains, as an active ingredient, at least one member selected from a group which consists of thiazole derivatives of formula (1): where R1 is a phenyl group which can have 1-3 lower alkoxy groups as substitutes in the phenyl ring, and R2 is a pyridyl group which can have 1-3 carboxyl groups as substitutes in the pyridine ring, or salts thereof.

EFFECT: high activity and use when treating diseases such as fibrosis and pulmonary emphysema.

4 cl, 4 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), stereoisomers, trans- and cis-isomers, racemates or pharmaceutically acceptable salts thereof, having modulating activity on histamine H3-receptors. In formula (I) m equals 0; one of R1 and R2 is selected from a group which includes hydrogen, C1-10alkoxycarbonyl, amido-, carboxy-, C3-8cycloalkyl, halogen, -NRARB, (NRARB)carbonyl, or a group of formula -L2-R6; the other of R1 and R2 is selected from a group which includes hydrogen, halogen; each of R3a and R3b is independently selected from a group which includes hydrogen; each of R4 and R5 is independently selected from a group which includes C1-10alkyl and C1-10hydroxyalkyl; or R4 and R5, taken together with a nitrogen atom to which each is bonded, form a heteroaromatic ring of the type (a) or (b), where Q1 is O or C; Q2 is -N(R20)-; R20 is selected from a group which includes hydrogen and C1-10alkoxycarbonyl; each of p1 and p2 is independently equal to 1, 2 or 3; each of q1, q2, q3, q4 and q5 are independently equal to 0, 1 or 2; and wherein each carbon atom in the ring is substituted with hydrogen or 0, 1 or 2 substitutes, independently selected from a group which includes hydrogen, hydroxy group, fluorine, C1-10alkyl, C1-10hydroxyalkyl and C1-10fluoroalkyl; R6 is a phenyl, heterocycle or heterocycloC1-4alkyl, wherein the heterocycle is a 4-6-member aromatic or non-aromatic ring which contains 1 or 2 heteroatoms independently selected from N, O and S, optionally condensed with a benzene ring, wherein the phenyl or heterocycle can be unsubstituted or optionally substituted with one or more substitutes independently selected from a group which includes C1-4alkoxy, C1-4alkyl, cyano, halogen and oxo-; L is a bond or C1-4alkylene; L2 is a bond, C1-4alkylene, -C(=O)-, -SO2N(R14a)-, -N(R14a)SO2-, -C(O)N(R14a)-, -N(Rl4a)C(O)- or -N(R15)-; R10 is selected from a group which includes hydrogen; R14a is selected from a group which includes hydrogen; R15 is selected from a group which includes hydrogen; and RA and RB are independently selected from a group which includes hydrogen, C1-10alkyl, C1-10acyl, C1-4halogenalkyl, C1-10alkoxycarbonyl, C3-8cycloalkyl and C3-8cycloalkylcarbonyl. The invention also relates to a pharmaceutical composition which contains compounds of formula (I), a method for selective modulation of effects of histamine H3-receptors, use of said compounds in producing a medicament for treating a condition or disorder modulated by histamine H3-receptors, as well as specific compounds of formula (I).

EFFECT: improved properties of compounds.

18 cl, 2 tbl, 154 ex

FIELD: chemistry.

SUBSTANCE: described are novel chiral cis-imidazolines selected from a group which includes 2-{4-[(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-acetamide, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(1,1-dioxohexahydrothiopyran-4-yl)-piperazin-1-yl]-methanone, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(3-methanesulphonylpropyl)-piperazin-1-yl]-methanone, 2-{4-[(4S,5R)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-N,N-bis-(2-methoxyethyl)-acetamide. 2-{1-[(48;5K)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperidin-4-yl}-acetamide and others described by the general structural formula (I), and pharmaceutical composition containing said compounds.

EFFECT: compounds can be used as anti-cancer agents, particularly as agents for treating solid tumours.

8 cl, 217 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel pyridine derivatives pyridine1-A-pyridine2 of formula (1), where pyridine1 represents

, , or , ,

where asterisks stand for bond, which contains pyridine1 ring with A; R1 represents C1-5alkyl, C1-4alkoxygroup, C3-6-cycloalkyl, hydroxymethyl or NR1aR1b, R1a represents C1-4alkyl; R1b represents hydrogen or C1-3alkyl; or R1a and R1b, together with nitrogen atom, which is bound to pyridine, form pyrrolidine ring; R2 represents hydrogen or C1-4alkyl, or in case, when R1 represents C1-5alkyl or C3-6-cycloalkyl, R2 can additionally represent methoxygroup; R3 represents C1-4alkyl, C1-4alkoxygroup, C3-6-cycloalkyl or NR3aR3b; R3a represents C1-4alkyl; R3b represents hydrogen or C1-3alkyl; R4 represents C1-4alkyl or hydrogen; R5 represents C1-5alkyl, methoxygroup or NR5aR5b; and R6 represents C1-2alkyl; R5a represents C1-4alkyl; R5 represents hydrogen or C1-3alkyl; or R5 represents C1-2alkyl or methoxygroup; and R6 represents C1-5alkyl or NR6aR6b; R6a represents C1-4alkyl; R6b represents hydrogen or C1-3alkyl; R7 represents C1-5alkyl; R8 represents C1-2alkyl or methoxygroup; R9 represents C1-5alkyl; R10 represents C1-2alkyl; A represents

, , or ,

where asterisks stand for bond, binding pyridine1 ring with A; pyridine2 represents

, , or , ,

where asterisks stand for bond, which binds pyridine ring with A; R11 represents C1-4alkyl; C1-3alkyloxy group, hydroxymethyl or NR11aR11b; R,1a represents C1-3alkyl; R11b represents hydrogen or C1-2alkyl; R12 represents hydrogen or C1-4alkyl; R13 represents C1-4alkyl or NR13aR13b; R13a represents C1-4alkyl; R13b represents hydrogen or C1-2alkyl; R14 represents C1-2alkyl; R15 represents C1-4alkyl or NR15aR15b; and R16 represents C1-2alkyl; R15a represents C1-3alkyl; R15b represents hydrogen or C1-3alkyl; or R15 represents C1-2alkyl; and R16 represents C1-4alkyl or NR16aR16b; R16a represents C1-3alkyl; R16b represents hydrogen or C1-2alkyl; R17 represents C1-4alkyl; R18 represents C1-2alkyl or methoxygroup; R19 represents C1-4alkyl; and R20 represents C1-2alkyl; with exception of 3-(2-ethyl-4-pyridyl)-5-(2-ethyl-4-pyridyl)-1,2,4-oxadiazole; or pharmaceutically acceptable salt of such compound.

EFFECT: obtaining pyridine derivatives, which possess agonistic activity with respect to S1P1/EDG1.

15 cl, 2 tbl, 131 ex

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