Beta-lactamase inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: present application describes substituted bicyclic beta-lactams of formula I: which are class A and class C β-lactamase inhibitors wherein X, R1 and R2 are specified in the application, as well as a method for producing them. The compounds of formula I and their pharmaceutically acceptable salts are applicable for preparing a pharmaceutical composition and for producing a drug. The declared compounds are applicable for treating bacterial infections, optionally in a combination with a β-lactam antibiotic. Particularly, the compounds may be used with such β-lactam antibiotics, as e.g. imipenem, piperacillin or ceftazidime to control microorganisms resistant to β -lactam antibiotics due to the presence of β-lactamases.

EFFECT: preparing the composition for treating bacterial infections.

28 cl, 117 ex, 3 tbl, 3 dwg

 

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the priority of provisional patent application U.S. No. 61/011533 (filed on January 18, 2008), the contents of which are incorporated into this description by reference in its entirety.

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to new inhibitors of beta-lactamases and their application against the resistance of bacteria to antibiotics. More specifically, the invention relates to compositions and methods for overcoming the resistance of bacteria to antibiotics.

The LEVEL of TECHNOLOGY

Resistance of bacteria to antibiotics has become one of the most serious problems of modern health care. In publishing Cohen, Science 1992, 257: 1051-1055 reported that infections caused by resistant to the action of medicines by bacteria, often lead to longer hospital stay, higher mortality and increased cost of treatment. In the publication Neu, Science 1992, 257: 1064-1073 reported that the need for new antibiotics will continue to grow due to the fact that bacteria have a remarkable ability to develop resistance to new drugs, quickly turning them into ineffective. In the publication Anderson, Nature America 1999, 5; 147-149 it is noted that the process of dissemination is through the phenomenon of resistance to antibiotics is a pandemic, and argues that the solution to this growing serious health problems require an interdisciplinary approach.

This crisis has caused the various studies to elucidate the mechanism underlying the resistance of bacteria. Thus, article Coulton et al., Progress in Medicinal Chemistry 1994, 31: 297-349 claimed that the widespread use of penicillins and cephalosporins resulted in β-lactamase, the family of bacterial enzymes that catalyze the hydrolysis of β-laktamovogo ring, which is present in most of the currently used antibiotics. Recently in the publication Dudley, Pharmacotherapy 1995, 15: 9S-14S it was reported that resistance mediated β-lactamases is the main aspect of the reasons for the development of resistance of bacteria to antibiotics. Currently available synthetic or natural inhibitors of β-lactamases are clavulanic acid, which is a metabolite of the fungus Streptomyces clavuligerus, and two semi-synthetic antibiotic, sulbactam and tazobactam. In patent documents US 5698577, US 5510343, US 6472406 and publications Hubschwerlen et al., J. Med. Chem. 1998, 41: 3961 and Livermore et al., J. Med. Chem. 1997, 40: 335 to 343 describes some synthetic inhibitors of β-lactamases.

Other sources of information relating to this question are as follows.

In the patent document US 2003/019941 A1 discloses several azabicyclic compounds, including specific 7-oxo-6-azabicyclo[3.2.1]octane-2-carboxamide, and their use as antibacterial means.

In the patent document US 2004/0157826 A1 describes several heterobicyclic compounds, including certain derivative diazepamtablets and diazepamtablets, and their use as antibacterial funds and inhibitors of β-lactamases.

In the patent document WO 2008/039420 A2 discloses a specific 7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfoxy-2-carboxamide and their use as inhibitors of beta-lactamases.

In the publication Poole, Cell Mol. Life Set 2004, 61: 2200-2223 provides an overview of the resistance of bacterial pathogens to β-lactamase antibiotics and approaches to overcome this resistance.

Currently available inhibitors of β-lactamases unable to counteract the ever-increasing diversity of β-lactamases. There is therefore a need for new inhibitors of β-lactamases.

The INVENTION

The present invention relates to certain compounds diazabicyclo carboxamide and carboxylate, which are inhibitors of beta-lactamases. Compounds and their pharmaceutically acceptable salts are used in combination with beta-lactamase antibiotics in the treatment of bacterial infections, particularly bacterial infections that are resistant to the action is s antibiotics. More specifically, the present invention includes compounds of formula I:

and their pharmaceutically acceptable salts, where:

the link labeled "a"is a simple bond or a double bond;

when the link is a simple link, X is:

(1) CH2,

(2) CH2CH2,

(3) CH2CH2CH2,

(4) CH-CH,

(5) CH2-CH-CH, or

(6) CH-CH-CH2;

when bond a is a double bond, X is:

(1) CH,

(2) CH-CH2or

(3) CH-CH=CH;

R1is:

(1) C(O)N(R3R4,

(2) C(O)OR3or

(3) C(O)OR5;

R2is SO3M, OSO3M, SO2NH2, PO3M, OPO3M, CH2CO2M, CF2CO2M, or CF3;

M is H or a pharmaceutically acceptable cation;

R3is:

(1) C1-8by alkyl, substituted a total of from 1 to 4 substituents selected from the group consisting of (i) from zero to 2 N(RARB(ii) from zero to 2, RCand (iii) from zero to 1 of AryA, HetA, or HetB,

(2) CycA,

(3) HetA,

(4) AryA,

(5) HetB, or

(6) AryB;

R4is H or C1-8the alkyl, optionally substituted with N(RARB;

or, alternatively, when R1is C(O)N(R3R4, R3and R4together with the N atom to which they are both attached, form is asimenia monocyclic ring with the number of members from 4 to 9, containing 1 heteroatom in addition to the nitrogen attached to R3and R4selected from N, O and S, where S is optionally oxidized to S(O) or S(O)2; where monocyclic ring optionally condensed, connected by a bridge or Spiro with saturated heterocyclic ring with the number of members from 4 to 7 containing from 1 to 3 heteroatoms, independently selected from N, O and S, where S is optionally oxidized to S(O) or S(O)2with the formation of a bicyclic ring system where the resulting monocyclic ring or bicyclic ring system optionally substituted with 1 or 2 substituents each of which is independently: (1) C1-6the alkyl, (2) C1-6perakyla, (3) (CH2)1-2G, where G is OH, O-C1-6the alkyl, O-C1-6perakyla, N(RARBC(O)N(RARBC(O)RA, CO2RAor SO2RA, (4) O-C1-6the alkyl, (5) O-C1-6perakyla, (6) OH, (7) oxo, (8) halogen, (9) N(RARB, (10) C(O)N(RARB, (11) C(O)RA, (12) C(O)-C1-6perakyla, (13) C(O)ORAor (14) S(O)2RA;

R5is C1-8by alkyl, substituted by 1 or 2 substituents, each of which is independently N(RA)C(O)-AryA;

CycA is C4-9cycloalkyl, which is optionally substituted in total with 1 to 4 will replace the lei, selected from zero to 2 (CH2)nN(RARBand from zero to 2 (CH2)nRC;

HetA is a saturated or mono-unsaturated heterocyclic ring with the number of members from 4 to 9, containing from 1 to 3 heteroatoms, independently selected from N, O and S, where each S in a ring optionally oxidized to S(O) or S(O)2and either 1 or 2 carbon atoms in the ring optionally oxidized to C(O); where the ring is optionally condensed with C3-7cycloalkyl; and where optionally condensed, saturated or mono-unsaturated ring optionally substituted by a total of from 1 to 4 substituents selected from zero to 2 (CH2)nN(RARBand from zero to 2 (CH2)nRC;

AryA is phenyl which is optionally substituted in total with 1 to 4 substituents selected from zero to 2 (CH2)nN(RARBand from zero to 2 (CH2)nRC;

HetB is a heteroaromatic ring with 5 or 6 members containing 1 to 4 heteroatoms selected from 1 to 3 N atoms, zero or 1 atom of O, and zero or 1 S atom, where the heteroaromatic ring is optionally condensed with a saturated heterocyclic ring with the number of members from 5 to 7, containing 1 or 2 heteroatoms independently selected from N, O and S, where each S in a ring optionally oxidized to S(O)or S(O) 2and either 1 or 2 carbon atoms in the unfused ring, optionally oxidized to C(O); and where it is not necessary condensed heteroaromatic ring optionally substituted by a total of from 1 to 4 substituents selected from zero to 2 (CH2)nN(RARBand from zero to 2 (CH2)nRC;

AryB is a bicyclic ring system in which the phenyl condensed with a saturated heterocyclic ring with the number of members from 5 to 7, containing from 1 to 3 heteroatoms, independently selected from N, O and S, where each S in a ring optionally oxidized to S(O) or S(O)2and where the bicyclic ring system is optionally substituted in total with 1 to 4 substituents selected from zero to 2 (CH2)nN(RARBand from zero to 2 (CH2)nRC;

each n independently is an integer which is 0, 1, 2, or 3;

each RAis independently H or C1-8by alkyl;

each RBis independently H or C1-8by alkyl;

each RCis independently C1-6the alkyl, OH, O-C1-8the alkyl, OC(O)-C1-8the alkyl, C(=NH)NH2, NH-C(=NH)NH2, halogen, CN, C(O)RAC(O)ORAC(O)N(RARB, SO2RA, SO2N(RARB, pyridium, pyrrolidinium, piperidinium, piperazinil, morpholinyl is, or thiomorpholine;

and provided that:

(A) when R1is C(O)OR3and R3is AryA, then AryA is not (i) unsubstituted phenyl, (ii) phenyl substituted with NH2, (iii) phenyl, substituted with OH, (iii) phenyl, substituted with O-C1-6the alkyl, (iv) phenyl substituted by one or more halogen, or (v) phenyl, substituted with C1-6by alkyl;

(B) when R1is C(O)OR3and R3is C1-6the alkyl substituted with HetB , then HetB is not pyridium;

(C) when R1is C(O)OR3and R3is CH2-AryA or CH2CH2-AryA, then AryA is not (i) unsubstituted phenyl, (ii) phenyl substituted with NH2, OH, O-C1-6the alkyl or C1-6the alkyl, or (iii) phenyl substituted by one or more Halogens;

(D) when R1is C(O)N(R3R4, R3is AryA, CH2-AryA or CH2CH2-AryA, and R4is H or C1-6the alkyl, then AryA is not unsubstituted phenyl, phenyl substituted with N(CH3)2or phenyl substituted with C(O)NH2;

(E) when R1is C(O)N(R3R4, R3is C1-6the alkyl substituted with HetB, and R4is H or C1-6the alkyl, then HetB is not pyridium; and

(F) when R1what is C(O)OR 3and R3is C1-6the alkyl substituted with RCthen RCis not C(O)NH2.

The compounds of formula I inhibit β-lactamase and synergistic increase the antibacterial action of β-lactamase antibiotics (e.g. imipenem, ceftazidime and piperazillina) against bacteria normally resistant to β-lactamase antibiotics in the presence of β-lactamase. Compounds of the present invention is effective against β-lactamase class A and class C, and their combination with beta-lactamase antibiotics, such as imipenem, ceftazidime or piperacillin, can provide effective treatment of bacterial infections caused by β-lactamase class A and class C produced by microorganisms. Accordingly, the present invention includes combinations of the compounds of formula I with β-lactamase antibiotic suitable for use against β-lactamase class C, produced with bacteria such asPseudomonas spp., and against β-lactamase class A, produced with bacteria such asKlebsiella spp. The invention also includes compositions containing a compound of formula I or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. In addition, the invention includes methods of treating bacterial infections and inhibiting bacterial growth utensileria the compounds of formula I or its salts, or combination, or composition containing the compound or its salt.

Embodiments of the flavors implementation aspects and characteristic features of the present invention hereinafter or will be described or become apparent from the following description, examples and the attached claims.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 shows powder x-ray for the crystalline monohydrate described in example 1D.

Figure 2 shows the curve of differential scanning calorimetry (DSC) for the crystalline monohydrate described in example 1D.

DETAILED description of the INVENTION

As noted above, the present invention includes compounds of formula I, which compounds are inhibitors of beta-lactamases, suitable for use in combination with beta-lactamase antibiotics for treatment of bacterial infections.

The term "inhibitor of β-lactamase" refers to a compound that can inhibit the activity of β-lactamase. The inhibition activity of β-lactamase means the inhibition of the activity of β-lactamase class A, C, or D. In the case of antimicrobial applications it is preferable that the concentration at which achieved 50% inhibition, was approximately 100 micrograms/ml or less, or about 50 micrograms/ml or less, or about 25 microg the AMM/ml The terms β-lactamase class A, class C, and class "D" are well known terms for specialists in this area, and they are described in the monograph Waley, The Chemistry of β-lactamase. Page Ed., Chapman & Hall, London, (1992) 198-228.

The term "β-lactamase" refers to a protein that is able to inactivate β-laktamovogo antibiotic. β-Lactamase may be the enzyme that catalyzes the hydrolysis of β-laktamovogo ring β-lactoovo antibiotic. Of particular interest here are the microbial β-lactamase. β-Lactamase may be, for example, serine β-lactamases. Of interest β-lactamase are lactamases, which are described, for example, in the monograph Waley, The Chemistry of β-lactamase, Page Ed., Chapman & Hall, London, (1992) 198-228. Representing a special interest β-lactamase include β-lactamase class C from Pseudomonas aeruginosa or Enterobacter cloacae P99 (hereinafter referred to as P99 β-lactamase) and a beta-lactamase class A from Klebsiella spp.

The term "antibiotic" refers to a compound or composition that reduce the viability of the microorganism, or which inhibit the growth or proliferation of a microorganism. The phrase "inhibiting the growth or proliferation" means an increase in generation time (i.e. the time required for a dividing bacterial cells or to double the population), at least about 2 times. The preferred antibiotics are antibiot the key, which can increase the generation time of at least about 10 times or more (e.g., at least about 100 times or even indefinitely, as in the case of the death of all cells). When used in this description it is additionally assumed that the antibiotic includes antimicrobial, bacteriostatic or bactericidal agent. Examples of antibiotics suitable for use from the point of view of the present invention include penicillins, cephalosporins and carbapenems.

The term "β-laktamovogo antibiotic" refers to a compound with antibiotic properties, which contains β-laktamovogo functionality. Non-limiting examples of β-lactamase antibiotics, appropriate from the point of view of the invention include penicillins, cephalosporins, Panama, carbapenems, and carbapenems.

The first embodiment of the present invention (alternatively referred to here as an implementation option E1") is a compound of formula I (otherwise referred to here as "compound I"), as defined above (i.e. defined above in the section "summary of the invention"), or its pharmaceutically acceptable salt; and provided that:

(A) when R1is C(O)OR3then R3is AryA;

(B) when R1is C(O)OR3then R3is not C1-8by alkyl, substituted with Het;

(C) when R1is C(O)OR3then R3is not C1-8the alkyl substituted with AryA;

(D) when R1is C(O)N(R3R4; R3is AryA or C1-8the alkyl substituted with AryA, and R4is H or C1-8the alkyl, then AryA is not unsubstituted phenyl, phenyl substituted with 1 or 2 N(RARBor phenyl substituted with 1 or 2 C(O)N(RARB;

(E) when R1is C(O)N(R3R4and R4is H or C1-8the alkyl, then R3is not C1-8the alkyl substituted with HetB; and

(F) when R1is C(O)OR3and R3is C1-8the alkyl substituted with RCthen RCis not C(O)N(RARB.

The second embodiment of the present invention (an implementation option E2) is defined above for the compound of formula I, or its pharmaceutically acceptable salt; and provided that:

(A) when R1is C(O)OR3then R3is AryA;

(B) when R1is C(O)OR3then R3is not C1-8the alkyl substituted with HetB;

(C) when R1is C(O)OR3then R3is not C1-8the alkyl substituted with AryA;

(D) when R1is C(O)N(R3R4then R3 is AryA or C1-8the alkyl substituted with AryA;

(E) when R1is C(O)N(R3R4then R3is not C1-8the alkyl substituted with HetB; and

(F) when R1is C(O)OR3then R3is not C1-8the alkyl substituted with RC.

The third embodiment of the present invention (an implementation option E3) is a compound of formula I, or its pharmaceutically acceptable salt; where:

R1is:

(1) C(O)N(R3R4or

(2) C(O)OR3;

R3is:

(1) C1-8by alkyl, substituted a total of from 1 to 4 substituents selected from the group consisting of (i) from zero to 2 N(RARB(ii) from zero to 2, RCand (iii) from zero to 1 of AryA, HetA, or HetB,

(2) CycA,

(3) HetA,

(4) AryA, or

(5) HetB;

R4is H or C1-8the alkyl, optionally substituted with N(RARB;

HetA is a saturated heterocyclic ring with the number of members from 4 to 9, containing from 1 to 3 heteroatoms, independently selected from N, O and S, where the saturated heterocyclic ring is optionally totally substituted with from 1 to 4 substituents selected from zero to 2 (CH2)nN(RARBand from zero to 2 (CH2)nRC;

each RCis independently C1-6what Kilom, OH, O-C1-8the alkyl, C(=NH)NH2, NH-C(=NH)NH2, halogen, CN, pyridium, pyrrolidinium, or piperidinyl; and

all other variables are defined above; and provided that:

(A) when R1is C(O)OR3and R3is AryA, then AryA is not (i) unsubstituted phenyl, (ii) phenyl substituted with NH2, (iii) phenyl, substituted with OH, (iii) phenyl, substituted with O-C1-6of alkyl, (iv) phenyl substituted by one or more Halogens; or (v) phenyl, substituted with C1-6of alkyl;

(B) when R1is C(O)OR3and R3is C1-6the alkyl substituted with HetB, then HetB is not pyridium;

(C) when R1is C(O)OR3and R3is CH2-AryA or CH2CH2-AryA, then AryA is not (i) unsubstituted phenyl, (ii) phenyl substituted with NH2, OH, O-C1-6the alkyl or C1-6the alkyl, or (iii) phenyl substituted by one or more Halogens;

(D) when R1is C(O)N(R3R4, R3is AryA, CH2-AryA or CH2CH2-AryA, and R4is H or C1-6the alkyl, then AryA is not unsubstituted phenyl or phenyl substituted with N(CH3)2; and

(E) when R1is C(O)N(R3R4, R3is C1-6the alkyl substituted with HetB, and R4what is H or C 1-6the alkyl, then HetB is not pyridium.

The fourth embodiment of the present invention (an implementation option E4) is a compound of formula I as defined in embodiment E3, or its pharmaceutically acceptable salt; and provided that:

(A) when R1is C(O)OR3then R3is AryA;

(B) when R1is C(O)OR3then R3is not C1-6the alkyl substituted with HetB;

(C) when R1is C(O)OR3then R3is not C1-6the alkyl substituted with AryA;

(D) when R1is C(O)N(R3R4then R3is AryA or C1-6the alkyl substituted with AryA; and

(E) when R1is C(O)N(R3R4then R3is not C1-6the alkyl substituted with HetB.

The fifth embodiment of the present invention (variant implementation E5) is a compound of formula I as defined in embodiment E3, or its pharmaceutically acceptable salt; and provided that:

(A) when R1is C(O)OR3then R3is AryA;

(B) when R1is C(O)OR3then R3is not C1-6the alkyl substituted with HetB;

(C) when R1is C(O)OR3then R3is not C1-6the alkyl, replacing the military with AryA;

(D) when R1is C(O)N(R3R4then R3is AryA or C1-6the alkyl substituted with AryA; and

(E) when R1is C(O)N(R3R4then R3is not C1-6the alkyl substituted with HetB.

The sixth embodiment of the present invention (an implementation option E6) is a compound of formula I, or its pharmaceutically acceptable salt, where the "a" is a simple bond; X is-CH2or

-CH2CH2-; and all other variables are defined above or defined in any of the above embodiments.

The seventh embodiment of the present invention (variant implementation E7) is a compound of formula I, or its pharmaceutically acceptable salt, where the "a" is a simple bond; X is-CH2-and all other variables are defined above or defined in any of the above embodiments.

The eighth embodiment of the present invention (variant implementation E8) is a compound of formula I, or its pharmaceutically acceptable salt, where the "a" is a simple bond; X is-CH2CH2-; and all other variables are defined above or defined in any of the above embodiments.

The ninth embodiment this is about the invention (variant implementation e) is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)N(R3R4; and all other variables are defined above or defined in any one of the preceding embodiments. In the aspect of this case for R1is C(O)NH(R4).

The tenth embodiment of the present invention (an implementation option E10) is a compound of formula I, or its pharmaceutically acceptable salt, where R2is OSO3M; and all other variables are defined above or defined in any of the preceding embodiments.

The eleventh embodiment of the present invention (variant implementation E11) is a compound of formula I, or its pharmaceutically acceptable salt, where R2is OSO3H; and all other variables are defined above or defined in any of the preceding embodiments.

The twelfth embodiment of the present invention (variant implementation E12) is a compound of formula I, or its pharmaceutically acceptable salt, where R3is: (1) C1-4by alkyl, substituted a total of from 1 to 4 substituents selected from the group consisting of (i) from zero to 2 N(RARB(ii) from zero to 2, RCand (iii) from zero to 1 of AryA, HetA, or HetB, (2) CycA, (3) HetA, (4) AryA, or (5) HetB; and all other variables are defined the s above or defined in any of the preceding embodiments.

The thirteenth embodiment of the present invention (variant implementation E13) is a compound of formula I, or its pharmaceutically acceptable salt, where R3is (CH2)2-3N(RARB, (CH2)1-3-AryA, (CH2)1-3-HetA, (CH2)1-3-HetB, CycA, HetA, AryA, or HetB; and all other variables are defined above or defined in any of the preceding embodiments.

The fourteenth embodiment of the present invention (variant implementation E14) is a compound of formula I, or its pharmaceutically acceptable salt, where R3is HetA, CH2-HetA, CH2CH2-HetA, CH(CH3)-HetA, or CH(CH2OH)-HetA; and all other variables are defined above or defined in any of the preceding embodiments. The first sub-option exercise option exercise E14 is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)N(R3R4; R3defined above, in the embodiment, E14; and all other variables are defined above in the embodiment, E14.

The fifteenth embodiment of the present invention (variant implementation of the E15 motorway) is a compound of formula I, or its pharmaceutically acceptable salt, where R3is HetA, CH2-HetA, or CH2CH2-HetA; which all other variables are defined above or defined in any of the preceding embodiments. The first sub-option exercise of option exercise of the E15 motorway is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)N(R3R4; R3defined above, in the embodiment, the E15 motorway; and all other variables are defined above in the embodiment, the E15 motorway.

The sixteenth embodiment of the present invention (variant implementation e) is a compound of formula I, or its pharmaceutically acceptable salt, where R3is HetA, or CH2-HetA; and all other variables are defined above or defined in any of the preceding embodiments. The first sub-option exercise option exercise e is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)N(R3R4; R3defined above, in the embodiment, a; and all other variables are defined above in the embodiment, e.

The seventeenth embodiment of the present invention (variant implementation E17) is a compound of formula I, or its pharmaceutically acceptable salt, where R3is HetA; and all other variables are defined above or defined in any of the preceding embodiments. The first sub-option exercise option exercise E17 is a compound of formula I, or it is pharmaceutically acceptable salt, where R1is C(O)N(R3R4; R3defined above in embodiment E17; and all other variables are defined above in embodiment E17.

The eighteenth embodiment of the present invention (variant implementation E18) is a compound of formula I, or its pharmaceutically acceptable salt, where R3is HetA; HetA is a saturated heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, azepane, and asokamala; where rich heterocycle optionally substituted with N(RARBand optionally substituted with 1 or 2 (CH2)nRC; each RCis independently C1-6the alkyl, OH, O-C1-8the alkyl, C(=NH)NH2, NH-C(=NH)NH2, halogen, CN, pyridium, pyrrolidinium, or piperidinyl; and all other variables are defined above or defined in any of the preceding embodiments.

The nineteenth embodiment of the present invention (variant implementation E19) is a compound of formula I, or its pharmaceutically acceptable salt, where R3is HetA; HetA is:

where the asterisk indicates the place of attachment of HetA to the rest of the connection; T is H or RC; RCis C1-6the alkyl, OH, O-C1-8the alkyl, C(=N)NH 2, NH-C(=NH)NH2, halogen, CN, pyridium, pyrrolidinium, or piperidinyl; and all other variables are defined above or defined in any of the preceding embodiments.

The twentieth embodiment of the present invention (variant implementation E20) is a compound of formula I, or its pharmaceutically acceptable salt, where R3is HetA; HetA is:

or

where the asterisk indicates the place of attachment of HetA to the rest of the connection; T is H or RC; RCis1-6the alkyl, OH, O-C1-8the alkyl, C(=NH)NH2, NH-C(=NH)NH2, halogen, CN, pyridium, pyrrolidinium, or piperidinyl; and all other variables are defined above or defined in any of the preceding embodiments. In the aspect of this case for T is H.

Twenty-first embodiment of the present invention (variant implementation E21) is a compound of formula I, or its pharmaceutically acceptable salt, where HetA is optionally condensed, saturated heterocyclic ring selected from the group consisting of azetidine, pyrrolidine, oxopyrrolidin (for example, 2-oxo-pyrrolidinyl), piperidinyl, piperazinil, tetrahydropyranyl, tetrahydrothiopyran the La, morpholinyl, 1,1-dissidocerida-dipiradol, azepane, oxazepine, asokamala, and azabicyclo[3.1.0]cyclohexyl, where the heterocycle optionally substituted with 1 or 2 (CH2)nN(RARBand optionally substituted by 1 or 2 (CH2)nRCand all other variables are defined above or defined in any of the preceding embodiments. The first sub-option exercise option exercise E21 is a compound of formula I, or its pharmaceutically acceptable salt, where R3is HetA, HetA and all other variables are defined above in embodiment E21. The second sub-option exercise option exercise E21 is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)N(R3R4; R3is HetA; and HetA and all other variables are defined above in embodiment E21. In the aspect of implementation of this option and its sub-options implementation HetA optional monogamist using (CH2)nN(RARBand optionally substituted with 1 or 2 (CH2)nRC.

Twenty-second embodiment of the present invention (variant implementation E22) is a compound of formula I, or its pharmaceutically acceptable salt, where HetA is saturated, heterocyclic the sky ring, selected from the group consisting of pyrrolidinyl, piperidinyl, azepane, and asokamala; where the heterocycle optionally substituted with 1 or 2 (CH2)nN(RARBand optionally substituted with 1 or 2 (CH2)nRC; and all other variables are defined above or defined in any of the preceding embodiments. The first sub-option exercise option exercise E22 is a compound of formula I, or its pharmaceutically acceptable salt, where R3is HetA; and HetA and all other variables are defined above in the embodiment, E22. The second sub-option exercise option exercise E22 is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)N(R3R4; R3is HetA; and HetA and all other variables are defined above in the embodiment, E22. In the aspect of implementation of this option and its sub-options implementation HetA optional monogamist using (CH2)nN(RARBand optionally substituted with 1 or 2 (CH2)nRC.

The twenty-third embodiment of the present invention (variant implementation e) is a compound of formula I, or its pharmaceutically acceptable salt, where HetA is defined or in the embodiment, E21, or in the variant OS is enforced E22; each RCis independently OH, O-C1-4the alkyl, C(=NH)NH2, NH-C(=NH)NH2, Cl, Br, F, or CN; and all other variables are defined above or defined in any of the preceding embodiments. In the first sub-option, the implementation of R3is HetA; and HetA defined above, in the embodiment, E21. In the second sub-option, the implementation of R1is C(O)N(R3R4; R3is HetA; and HetA defined above, in the embodiment, E22. In the aspect of implementation of this option and its sub-options implementation HetA optional monogamist using (CH2)nN(RARBand optionally substituted with 1 or 2 (CH2)nRC.

Twenty-fourth embodiment of the present invention (variant implementation e) is a compound of formula I, or its pharmaceutically acceptable salt, where HetA is a heterocyclic ring, or in certain embodiment, E21 or in the embodiment, E22; a heterocyclic ring in HetA optionally substituted with halogen, C1-3of alkyl, O-C1-3of alkyl, NH2N(H)-C1-3of alkyl, N(-C1-3the alkyl)2CH2NH2CH2N(H)-C1-3of alkyl, CH2N(-C1-3the alkyl)2or piperidinyl; and all other variables are defined above or defined in any of predest the actual operation of embodiments. In the first sub-option, the implementation of R3is HetA; and HetA defined above, in the embodiment, e. In the second sub-option implementation, R1is C(O)N(R3R4; R3is HetA; and HetA defined above, in the embodiment, e.

Twenty-fifth embodiment of the present invention (variant implementation E25) is a compound of formula I, or its pharmaceutically acceptable salt, where HetA is a heterocyclic ring, or in certain embodiment, E21 or in the embodiment, E22; a heterocyclic ring in HetA optionally substituted with F, CH3, OCH3, NH2N(H)CH3N(CH3)2CH2NH2CH2N(H)CH3CH2N(CH3)2or piperidinyl; and all other variables are defined above or defined in any of the preceding embodiments. In the first sub-option, the implementation of R3is HetA; and HetA defined above, in the embodiment, E25. In the second sub-option, the implementation of R1is C(O)N(R3R4; R3is HetA; and HetA defined above, in the embodiment, E25.

The twenty-sixth embodiment of the present invention (variant implementation E) is a compound of formula I, or its pharmaceutically acceptable salt, where HetA is the heterocycle is ical ring, selected from the group consisting of azetidine, pyrrolidine, pyrazolidine, piperidine, piperazinil, azepane, oxazepine, oxazolidinyl, isoxazolidine, morpholine, and tetrahydropyranyl, where the heterocyclic ring optionally substituted with 1 or 2 substituents each of which is independently C1-3the alkyl, CH2NH2CH2N(H)-C1-3the alkyl, CH2N(-C1-3alkyl)2O-C1-3the alkyl, Cl, Br, F, NH2N(H)-C1-3the alkyl, N(-C1-3alkyl)2C(O)NH2C(O)N(H)-C1-3the alkyl, C(O)N(-C1-3alkyl)2C(O)-C1-3the alkyl, C(O)O-C1-3the alkyl, OC(O)-C1-3the alkyl, S(O)2-C1-3the alkyl, S(O)2NH2, S(O)2N(H)-C1-3the alkyl, or S(O)2N(-C1-3alkyl)2; and all other variables are defined above or defined in any of the preceding embodiments. The first sub-option exercise option exercise E is a compound of formula I, or its pharmaceutically acceptable salt, where R3is HetA, CH2-HetA, CH2CH2-HetA; and HetA and all other variables are defined above in the embodiment, E. The second sub-option exercise option exercise E is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)OR3; R3the C is HetA, CH2-HetA, CH2CH2-HetA; and HetA and all other variables are defined above in the embodiment, E. In the aspect of implementation of this option and its sub-options for the implementation of R2is OSO3H.

Twenty-seventh embodiment of the present invention (variant implementation E27) is a compound of formula I, or its pharmaceutically acceptable salt, where HetA is a heterocyclic ring selected from the group consisting of azetidine, pyrrolidine, pyrazolidine, piperidine, piperazinil, azepane, oxazepine, oxazolidinyl, isoxazolidine, morpholine, and tetrahydropyranyl, where the heterocyclic ring optionally substituted with 1 or 2 substituents each of which is independently CH3CH2NH2CH2N(H)CH3CH2N(CH3)2, OCH3, Cl, Br, F, NH2N(H)CH3N(CH3)2C(O)NH2C(O)N(H)CH3C(O)N(CH3)2C(O)CH3C(O)OCH3, OC(O)CH3, S(O)2CH3, S(O)2NH2, S(O)2N(H)CH3or S(O)2N(CH3)2; and all other variables are defined above or defined in any of the preceding embodiments. The first sub-option exercise of option exercise of E27 is a compound of formula I, or its pharmaceutically acceptable salt, where R 3is HetA, CH2-HetA, CH2CH2-HetA; and HetA and all other variables are defined above in the embodiment, E27. The second sub-option exercise of option exercise of E27 is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)OR3; R3is HetA, CH2-HetA, CH2CH2-HetA; and HetA and all other variables are defined above in the embodiment, E27. In the aspect of implementation of this option and its sub-options for the implementation of R2is OSO3H.

Twenty-eighth embodiment of the present invention (variant implementation E28) is a compound of formula I, or its pharmaceutically acceptable salt, where AryA is phenyl which is optionally substituted with 1 or 2 substituents each of which is independently C1-3the alkyl, CH2NH2CH2N(H)-C1-3the alkyl, CH2N(-C1-3alkyl)2O-C1-3the alkyl, Cl, Br, F, NH2N(H)-C1-3the alkyl, N(-C1-3alkyl)2C(O)NH2C(O)N(H)-C1-3the alkyl, C(O)N(-C1-3alkyl)2C(O)-C1-3the alkyl, C(O)O-C1-3the alkyl, OC(O)-C1-3the alkyl, S(O)2-C1-3the alkyl, S(O)2NH2, S(O)2N(H)-C1-3the alkyl, S(O)2N(-C1-3alkyl)2, pyrrolidinium, piperidinium, morpholinium, CH2-pyrrolidinyl is, CH2-piperidinium, or CH2-morpholinyl; and all other variables are defined above or defined in any of the preceding embodiments. The first sub-option exercise of option exercise of the E28 is a compound of formula I, or its pharmaceutically acceptable salt, where R3is AryA; and AryA and all other variables are defined above in embodiment E28. The second sub-option exercise of option exercise of the E28 is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)OR3; R3is AryA; and AryA and all other variables are defined above in embodiment E28. In the aspect of implementation of this option and its sub-options for the implementation of R2is OSO3H.

Twenty-ninth embodiment of the present invention (variant implementation E) is a compound of formula I, or its pharmaceutically acceptable salt, where AryA is phenyl which is optionally substituted with 1 or 2 substituents each of which is independently CH3CH2NH2CH2N(H)CH3CH2N(CH3)2, OCH3, Cl, Br, F, NH2N(H)CH3N(CH3)2C(O)NH2C(O)N(H)CH3C(O)N(CH3)2C(O)CH3C(O)OCH3, OC(O)CH3, S(O)2CH3, S(O)2NH2,S(O) 2N(H)CH3or S(O)2N(CH3)2, pyrrolidinium, piperidinium, morpholinium, CH2-pyrrolidinium, CH2-piperidinium, or CH2-morpholinyl; and all other variables are defined above or defined in any of the preceding embodiments. The first sub-option exercise option exercise E is a compound of formula I, or its pharmaceutically acceptable salt, where R3is AryA; and AryA and all other variables are defined above in the embodiment, E. The second sub-option exercise option exercise E is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)OR3; R3is AryA; and AryA and all other variables are defined above in the embodiment, E. In the aspect of implementation of this option and its sub-options for the implementation of R2is OSO3H.

The thirtieth embodiment of the present invention (variant implementation E30) is a compound of formula I, or its pharmaceutically acceptable salt, where R3is HetB; and all other variables are defined above or defined in any of the preceding embodiments. The first sub-option exercise of option exercise of the E30 is a compound of formula I, or its pharmaceutically acceptable salt, g is e R 1is C(O)N(R3R4; R3defined above, in the embodiment, E30; and all other variables are defined above in embodiment E30.

Thirty-first embodiment of the present invention (variant implementation e) is a compound of formula I, or its pharmaceutically acceptable salt, where R3is HetB; HetB is a heteroaromatic ring selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, pyridyl, and pyrimidinyl, where the heteroaromatic ring optionally monogamist using (CH2)nN(RARBand optionally substituted with 1 or 2 (CH2)nRCgroups; each RCis independently C1-6the alkyl, OH, O-C1-8the alkyl, C(=NH)NH2, NH-C(=NH)NH2, halogen, CN, pyridium, pyrrolidinium, or piperidinyl; and all other variables are defined above or defined in any of the preceding embodiments.

The thirty-second embodiment of the present invention (variant implementation e) is a compound of formula I, or its pharmaceutically acceptable salt, where R3is HetB; HetB is pyridium, which is optional monogamist using N(RARBand optionally substituted with 1 or 2 RCgroups; each RCis independently researched the mo C 1-6the alkyl, OH, O-C1-8the alkyl, C(=NH)NH2, NH-C(=NH)NH2, halogen, CN, pyridium, pyrrolidinium, or piperidinyl; and all other variables are defined above or defined in any of the preceding embodiments.

Thirty-third embodiment of the present invention (variant implementation E) is a compound of the formula or its pharmaceutically acceptable salt, where R3is HetB; HetB is; U=H, N(RARBor RC; RCis independently C1-6the alkyl, OH, O-C1-8the alkyl, C(=NH)NH2, NH-C(=NH)NH2, halogen, CN, pyridium, pyrrolidinium, or piperidinyl; and all other variables are defined above or defined in any of the preceding embodiments. In the aspect of this case for U is in the ortho-position relative to the N atom in pyridinyl. In a characteristic of this aspect of U is H, NH(C1-4alkyl), N(C1-4alkyl)2or O-C1-4the alkyl.

Thirty-fourth embodiment of the present invention (variant implementation E34) is a compound of formula I, or its pharmaceutically acceptable salt, where HetB is a heteroaromatic compound selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, thiazolyl, Pipa is idolatrie, pyrrolidinyl, piperidinyl, and pyrrolopyridine, where the heteroaromatic ring is optionally substituted with 1 or 2 (CH2)nN(RARBand optionally substituted with 1 or 2 (CH2)nRCgroups; and all other variables are defined above or defined in any of the preceding embodiments. The first sub-option exercise of option exercise of the E34 is a compound of formula I, or its pharmaceutically acceptable salt, where R3is HetB; and HetB and all other variables are defined above in the embodiment, E34. The second sub-option exercise of option exercise of the E34 is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)N(R3R4; R3is HetB; and HetB and all other variables are defined above in the embodiment, E34. In the aspect of implementation of this option and its sub-options implementation heteroaromatic ring HetB optional monogamist using (CH2)nN(RARBand optional Samusenko with 1 or 2 (CH2)nRC. In another aspect of this variant implementation and its sub-options implementation heteroaromatic ring HetB optional monogamist with NH2N(H)-C1-3of alkyl, N(-C1-3alkyl)2 CH2NH2CH2N(H)-C1-3the alkyl, or CH2N(-C1-3alkyl)2; and optionally substituted with 1 or 2 substituents each of which is independently C1-3the alkyl, pyrrolidinyl, piperidinyl, piperazinil, morpholinium, or thiomorpholine. In another aspect of this variant implementation and its sub-options implementation heteroaromatic ring HetB optional monogamist with NH2N(H)CH3N(CH3)2CH2NH2CH2N(H)CH3or CH2N(CH3)2; and optionally substituted with 1 or 2 substituents each of which is independently CH3, pyrrolidinium, piperidinium, piperazinil, morpholinium, or thiomorpholine. In another aspect of this variant implementation and its sub-options for the implementation of R2is OSO3H.

Thirty-fifth embodiment of the present invention (variant implementation E) is a compound of formula I, or its pharmaceutically acceptable salt, where R3is AryA; and all other variables are defined above or defined in any of the preceding embodiments. The first sub-option exercise option exercise E is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)N(R R4; R3is AryA; and AryA and all other variables are defined above in the embodiment, E. In the aspect of implementation of this option and its sub-options for the implementation of R2is OSO3H.

Thirty-sixth embodiment of the present invention (variant implementation E36) is a compound of formula I, or its pharmaceutically acceptable salt, where AryA is phenyl which is optionally substituted with 1 or 2 substituents each of which is independently C1-3the alkyl, CH2NH2CH2N(H)-C1-3the alkyl, CH2N(-C1-3alkyl)2O-C1-3the alkyl, Cl, Br, F, NH2N(H)-C1-3the alkyl, N(-C1-3alkyl)2C(O)NH2C(O)N(H)-C1-3the alkyl, C(O)N(-C1-3alkyl)2C(O)-C1-3the alkyl, C(O)O-C1-3the alkyl, OC(O)-C1-3the alkyl, S(O)2-C1-3the alkyl, S(O)2NH2, S(O)2N(H)-C1-3the alkyl, S(O)2N(-C1-3alkyl)2, pyrrolidinium, piperidinium, morpholinium, CH2-pyrrolidinium, CH2-piperidinium or CH2-morpholinyl; and all other variables are defined above or defined in any of the preceding embodiments. The first sub-option exercise of option exercise of the E36 is a compound of formula I, or its pharmaceutically acceptable salt, where R3is ArA; and AryA and all other variables are defined above in the embodiment, E36. The second sub-option exercise of option exercise of the E36 is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)N(R3R4; R3is AryA; and AryA and all other variables are defined above in the embodiment, E36. In the aspect of implementation of this option and its sub-options for the implementation of R2is OSO3H.

Thirty-seventh embodiment of the present invention (variant implementation E) is a compound of formula I, or its pharmaceutically acceptable salt, where AryA is phenyl which is optionally substituted with 1 or 2 substituents each of which is independently CH3CH2NH2CH2N(H)CH3CH2N(CH3)2, OCH3, Cl, Br, F, NH2N(H)CH3N(CH3)2C(O)NH2C(O)N(H)CH3C(O)N(CH3)2C(O)CH3C(O)OCH3, OC(O)CH3, S(O)2CH3, S(O)2NH2, S(O)2N(H)CH3or S(O)2N(CH3)2, pyrrolidinium, piperidinium, morpholinium, CH2-pyrrolidinium, CH2-piperidinium, or CH2-morpholinyl; and all other variables are defined above or defined in any of the preceding embodiments. The first sub-option OS the enforced option exercise E is a compound of formula I, or its pharmaceutically acceptable salt, where R3is AryA; and AryA and all other variables are defined above in the embodiment, E. The second sub-option exercise option exercise E is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)N(R3R4; R3is AryA; and AryA and all other variables are defined above in the embodiment, E. In the aspect of implementation of this option and its sub-options for the implementation of R2is OSO3H.

Thirty-eighth embodiment of the present invention (variant implementation E38) is a compound of formula I, or its pharmaceutically acceptable salt, where AryA is phenyl which is optionally substituted with 1 or 2 substituents each of which is independently CH3CH2NH2CH2N(H)CH3CH2N(CH3)2, OCH3, Cl, Br, F, NH2N(H)CH3N(CH3)2C(O)NH2C(O)N(H)CH3C(O)N(CH3)2C(O)CH3C(O)OCH3, OC(O)CH3, S(O)2CH3, S(O)2NH2, S(O)2N(H)CH3, S(O)2N(CH3)2, pyrrolidinium, piperidinium, morpholinium, CH2-pyrrolidinium, CH2-piperidinium, or CH2-morpholinyl; and all other variables are defined above or defined in any of PR is testuya of embodiments. The first sub-option exercise of option exercise of the E38 is a compound of formula I, or its pharmaceutically acceptable salt, where R3is AryA; and AryA and all other variables are defined above in the embodiment, E38. The second sub-option exercise of option exercise of the E38 is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)N(R3R4; R3is AryA; and AryA and all other variables are defined above in the embodiment, E. In the aspect of implementation of this option and its sub-options for the implementation of R2is OSO3H.

Thirty-ninth embodiment of the present invention (variant implementation E39) is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)N(R3R4; R3and R4together with the N atom to which they are both attached, form a heterocycle selected from the group consisting of:

and

where the ring is optionally substituted with 1 or 2 substituents each of which is independently C1-3the alkyl, CF3CH2OH, CH2O-C1-3the alkyl, CH2OCF3CH2NH2CH2N(H)-C1-3the alkyl, CH2N(-C1-3alkyl)2O-C1-3the alkyl, OCF3 , oxo, Cl, Br, F, NH2N(H)-C1-3the alkyl, N(-C1-3alkyl)2C(O)NH2C(O)N(H)-C1-3the alkyl, C(O)N(-C1-3alkyl)2C(O)-C1-3the alkyl, C(O)O-C1-3the alkyl, or S(O)2-C1-3by alkyl; and all other variables are defined above or defined in any of the preceding embodiments. In the aspect of this case for R2is OSO3H.

The fortieth embodiment of the present invention (variant implementation E40) is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)N(R3R4; R3and R4together with the N atom to which they are both attached, form a heterocycle selected from the group consisting of:

and

where the ring is optionally substituted with 1 or 2 substituents each of which is independently CH3, CF3CH2OH, CH2OCH3CH2OCF3CH2NH2CH2N(H)CH3CH2N(CH3)2, OCH3, OCF3, oxo, Cl, Br, F, NH2N(H)CH3N(CH3)2C(O)NH2C(O)N(H)CH3C(O)N(CH3)2C(O)CH3C(O)OCH3or S(O)2CH3; and all other variables are defined above or defined in any of the preceding embodiments. In the aspect of ecogovernance implementation of R 2is OSO3H.

Forty-first embodiment of the present invention (variant implementation E) is a compound of formula I, or its pharmaceutically acceptable salt, where R3is AryB; and all other variables are defined above or defined in any of the preceding embodiments. The first sub-option exercise option exercise E is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)N(R3R4; R3is AryB; and AryB and all other variables are defined above in the embodiment, E. In the aspect of implementation of this option and sub-option implementation R2is OSO3H.

Forty-second embodiment of the present invention (variant implementation E) is a compound of formula I, or its pharmaceutically acceptable salt, where R3is AryB; AryB is a bicyclic ring selected from the group consisting of 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 2,3-dihydro-1H-isoindolyl and 2,3-dihydro-1H-indolyl, where the bicyclic ring optionally substituted with 1 or 2 substituents, each of which is independently C1-3the alkyl, CH2NH2CH2N(H)-C1-3the alkyl, CH2N(-C1-3alkyl)2O-C1-3the alkyl, Cl, Br, F, NH 2N(H)-C1-3the alkyl, N(-C1-3alkyl)2C(O)NH2C(O)N(H)-C1-3the alkyl, C(O)N(-C1-3alkyl)2C(O)-C1-3the alkyl, C(O)O-C1-3the alkyl, OC(O)-C1-3the alkyl, S(O)2-C1-3the alkyl, S(O)2NH2, S(O)2N(H)-C1-3the alkyl, S(O)2N(-C1-3alkyl)2, pyrrolidinium, piperidinium, morpholinium, CH2-pyrrolidinium, CH2-piperidinium, or CH2-morpholinyl; and all other variables are defined above or defined in any of the preceding embodiments. The first sub-option exercise option exercise E is a compound of formula I, or its pharmaceutically acceptable salt, where R3is AryB; and AryB and all other variables are defined above in the embodiment, E. The second sub-option exercise option exercise E is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)N(R3R4; R3is AryB; and AryB and all other variables are defined above in the embodiment, E. In the aspect of implementation of this option and its sub-options for the implementation of R2is OSO3H.

Forty-third embodiment of the present invention (variant implementation E43) is a compound of formula I, or its pharmaceutically acceptable salt, where R3is AryB; AryB is a bicyclic ring selected from the group consisting of 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 2,3-dihydro-1H-isoindolyl and 2,3-dihydro-1H-indolyl, where the bicyclic ring optionally substituted with 1 or 2 substituents, each of which is independently CH3CH2NH2CH2N(H)CH3CH2N(CH3)2, OCH3, Cl, Br, F, NH2N(H)CH3N(CH3)2C(O)NH2C(O)N(H)CH3C(O)N(CH3)2C(O)CH3C(O)OCH3, OC(O)CH3, S(O)2CH3, S(O)2NH2, S(O)2N(H)CH3or S(O)2N(CH3)2, pyrrolidinium, piperidinium, morpholinium, CH2-pyrrolidinium, CH2-piperidinium, or CH2-morpholinyl; and all other variables are defined above or defined in any of the preceding embodiments. The first sub-option exercise option exercise E43 is a compound of formula I, or its pharmaceutically acceptable salt, where R3is AryB and AryB and all other variables are defined above in the embodiment, E43. The second sub-option exercise option exercise E43 is a compound of formula I, or its pharmaceutically acceptable salt, where R1is C(O)N(R3R4; R3is AryB and AryB and all other variables opredeleniya in the embodiment, E43. In the aspect of implementation of this option and its sub-options for the implementation of R2is OSO3H.

Forty-fourth embodiment of the present invention (variant implementation E) is a compound of formula I, or its pharmaceutically acceptable salt, where R4is H or C1-4the alkyl, optionally substituted with N(RARB; and all other variables are defined above or defined in any of the preceding embodiments. In the aspect of this case for R4is H or C1-4the alkyl.

Forty-fifth embodiment of the present invention (variant implementation e) is a compound of formula I, or its pharmaceutically acceptable salt, where R4is H, C1-3the alkyl, or (CH2)2-3N(RARB; and all other variables are defined above or defined in any of the preceding embodiments. In the aspect of this case for R4is H or C1-3the alkyl.

Forty-sixth embodiment of the present invention (variant implementation E) is a compound of formula I, or its pharmaceutically acceptable salt, where R4is H or stands; and all other variables are defined above or defined in any of the preceding embodiments.

With the OK the seventh embodiment of the present invention (variant implementation E) is a compound of formula I, or its pharmaceutically acceptable salt, where R4is H; and all other variables are defined above or defined in any of the preceding embodiments.

Forty-eighth embodiment of the present invention (variant implementation E) is a compound of formula I, or its pharmaceutically acceptable salt, where each RAis independently H or C1-4by alkyl; each RBis independently H or C1-4by alkyl; and all other variables are defined above or defined in any of the preceding embodiments.

Forty-ninth embodiment of the present invention (variant implementation E) is a compound of formula I, or its pharmaceutically acceptable salt, where each RAis independently H or C1-3by alkyl; each RBis independently H or C1-3by alkyl; and all other variables are defined above or defined in any of the preceding embodiments.

The fiftieth embodiment of the present invention (an implementation option E50) is a compound of formula I, or its pharmaceutically acceptable salt, where each RAis independently H or CH3; each RBis independently H or CH3; and all other variables are defined above or defined in any of the preceding is adequate options for the implementation.

Fifty-first embodiment of the present invention (variant implementation e) is a compound of formula I, or its pharmaceutically acceptable salt, where each RCis independently C1-4the alkyl, OH, O-C1-4the alkyl, C(=NH)NH2, NH-C(=NH)NH2, halogen, CN, pyridium, pyrrolidinium, or piperidinyl; and all other variables are defined above or defined in any of the preceding embodiments.

Fifty-second embodiment of the present invention (variant implementation E) is a compound of formula I, or its pharmaceutically acceptable salt, where each RCis independently OH, O-C1-4the alkyl, C(=NH)NH2, NH-C(=NH)NH2, Cl, Br, F, or CN; and all other variables are defined above or defined in any of the preceding embodiments.

Fifty-third embodiment of the present invention (variant implementation e) is a compound of formula I, or its pharmaceutically acceptable salt, where each RCis independently C1-3the alkyl, O-C1-3the alkyl, Cl, Br, F, C(O)NH2C(O)N(H)-C1-3the alkyl, C(O)N(-C1-3alkyl)2C(O)-C1-3the alkyl, C(O)O-C1-3the alkyl, OC(O)-C1-3the alkyl, S(O)2-C1-3the alkyl, S(O)2NH2, S(O)2N(H)-C1-3the alkyl, S(O)2N(-C1-3alkyl)2 , pyrrolidinium, piperidinium, morpholinium, CH2-pyrrolidinium, CH2-piperidinium, or CH2-morpholinyl; and all other variables are defined above or defined in any of the preceding embodiments.

Fifty-fourth embodiment of the present invention (variant implementation E) is a compound of formula I, or its pharmaceutically acceptable salt, where each RCis independently CH3, OCH3, Cl, Br, F, C(O)NH2C(O)N(H)CH3C(O)N(CH3)2C(O)CH3C(O)OCH3, OC(O)CH3, S(O)2CH3, S(O)2NH2, S(O)2N(H)CH3or S(O)2N(CH3)2, pyrrolidinium, piperidinium, morpholinium, CH2-pyrrolidinium, CH2-piperidinium, or CH2-morpholinyl; and all other variables are defined above or defined in any of the preceding embodiments.

Unless expressly stated otherwise, or as is clear from the context, conditions A-F installed to define the connection I in the section "summary of the invention", just here for the previous and subsequent embodiments. From the context it is clear, for example, that when any one of embodiments E17-E120 include in the earlier definition of compound I, none of the conditions is not applied. In addition, in those cases is Ah, when any variant of implementation refers to an implementation option E1 or an implementation option E2, and includes an implementation option E1 or variant implementation of E2, it includes installed conditions A-F in those cases, when you use any of them. In addition, it should be borne in mind that the definition of the variables in the conditions can be specifically designed to reflect the definitions of the variables in variants of implementation, which are included. For example, when an implementation option a (that is, R1is C(O)N(R3R4include in an implementation option E1, then the condition can be formulated as follows (where A, B, C and F do not apply) and provided that:

(D) when R3is AryA or C1-6the alkyl substituted with AryA, and R4is H or C1-6the alkyl, then AryA is not unsubstituted phenyl or phenyl substituted with 1 or 2 N(RARB; and

(E) when R4is H or C1-6the alkyl, then R3is not C1-6the alkyl substituted with HetB.

As another example, when the connection is definitely in the second sub-option exercise option exercise E36 (that is, R1 is C(O)N(R3R4; R3is AryA; and AryA and all other variables are defined above in the embodiment, E36), tatoglu it should be borne in mind, that the following condition applies: provided that AryA is not unsubstituted phenyl, phenyl substituted with N(CH3)2or phenyl substituted with C(O)NH2. In addition, it should be borne in mind that the optional conditions of options exercise of E1 and E2, can, as appropriately adapted, to be applied as an option. Condition-based case for E1, for example, is: and provided that AryA is not unsubstituted phenyl, phenyl substituted with 1 or 2 NH2N(H)-C1-3the alkyl and N(-C1-3alkyl)2or phenyl substituted with 1 or 2 C(O)NH2C(O)N(H)-C1-3the alkyl and C(O)N(-C1-3alkyl)2.

The first class of compounds of the present invention (alternatively referred to here as "C1") includes compounds of formula I and their pharmaceutically acceptable salts, where R1is C(O)N(R3R4; R3is HetA; and all other variables are defined above. In the aspect of this class R4is H.

The first subclass of the first class (alternatively referred to here as "a subclass of C1-S1") includes compounds of formula I and their pharmaceutically acceptable salts, where R1is C(O)N(R3R4; R3is HetA; and HetA is a saturated heterocyclic ring selected the C group, consisting of pyrrolidinyl, piperidinyl, azepane, and asokamala, where rich heterocycle optionally monogamist using N(RARBand optionally substituted with 1 or 2 (CH2)nRC; and all other variables are defined above. In the aspect of this subclass of R4is H.

The second subclass of the first class (a subclass of C1-S2) includes the compounds of formula I and their pharmaceutically acceptable salts, where all variables are specified in the subclass C1-S1, except that each RCis independently OH, O-C1-4the alkyl, C(=NH)NH2, NH-C(=NH)NH2, Cl, Br, F, or CN. In the aspect of this subclass of R4is H.

A third subclass of the first class (a subclass of C1-S3) includes the compounds of formula I, selected from the group consisting of:

and their pharmaceutically acceptable salts; where T is H or (CH2)2-3RC; and RCand R2each independently as defined above or defined in any of the preceding embodiments. In one aspect of this subclass of T is H. In another aspect of this subclass of R2is OSO3H or SO3H. In yet another aspect of this subclass of T is H and R2is OSO3H or SO3H. In yet another aspect of this subclass of T is H and R2is what I OSO 3H. In yet another aspect of this subclass, each RCis independently C1-6the alkyl, OH, O-C1-8the alkyl, C(=NH)NH2, NH-C(=NH)NH2, halogen, CN, pyridium, pyrrolidinium, or piperidinyl. In a characteristic of this aspect of R2is OSO3H.

The second class of compounds of the present invention (class C2) includes the compounds of formula I and their pharmaceutically acceptable salts, where R1is C(O)N(R3R4; R3is HetB; and all other variables are defined above. In the aspect of this class R4is H.

The first subclass of the second class (a subclass of C2-S1) includes the compounds of formula I and their pharmaceutically acceptable salts, where R1is C(O)N(R3R4; R3is HetB; and HetB is a heteroaromatic ring selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, pyridyl, and pyrimidinyl, where the heteroaromatic ring optionally monogamist using (CH2)nN(RARBand optionally substituted with 1 or 2 (CH2)nRCgroups; and all other variables are defined above. In the aspect of this subclass of R4is H.

The second subclass of the second class (a subclass of C2-S2) includes the compounds of formula I and their pharmaceutically acceptable salts, where all variables are specified in the sub-class C2-S1, and is shutting down, each RCis independently OH, O-C1-4the alkyl, C(=NH)NH2, NH-C(=NH)NH2, Cl, Br, F, or CN. In the aspect of this subclass of R4is H.

A third subclass of the second class (a subclass of C2-S3) includes the compounds of formula I and their pharmaceutically acceptable salts, where R1is C(O)N(R3R4; R3is HetB; and HetB is pyridium, which is optional monogamist using N(RARBand optionally substituted with 1 or 2 RCgroups. In the aspect of this subclass of R4is H.

A fourth subclass of the second class (a subclass of C2-S4) includes the compounds of formula I and their pharmaceutically acceptable salts, where all variables are specified in the subclass C2-S3, except that each RCis independently OH, O-C1-4the alkyl, C(=NH)NH2, NH-C(=NH)NH2, Cl, Br, F, or CN. In the aspect of this subclass of R4is H. In another aspect of this subclass, each RCis independently C1-6the alkyl, OH, O-C1-8the alkyl, C(=NH)NH2, NH-C(=NH)NH2, halogen, CN, pyridium, pyrrolidinium, or piperidinyl.

A fifth subclass of the second class (a subclass of C2-S5) includes the compounds of formula I, selected from the group consisting of:

and their pharmaceutically acceptable salts, where RCis C1-6 the alkyl, OH, O-C1-8the alkyl, C(=NH)NH2, NH-C(=NH)NH2, halogen, CN, pyridium, pyrrolidinium, or piperidinyl; and R2, RAand RBeach independently defined above. In the aspect of this subclass N(RARBis NH(C1-4alkyl) or N(C1-4alkyl)2and RCis O-C1-4the alkyl. In another aspect of this subclass of R2is OSO3H or SO3H. In yet another aspect of this subclass of R2is OSO3H. In yet another aspect of this subclass N(RARBis NH(C1-4alkyl) or N(C1-4alkyl)2; RCis O-C1-4by alkyl; and R2is OSO3H or SO3H. Other aspects of this subclass includes compounds of formula B1a, B1b, and B1c and their pharmaceutically acceptable salts, where RC, R2, RAand RBeach independently defined in any of the preceding embodiments; that is, each unique combination of these variables is different aspect.

The third class of compounds of the present invention (class C3) includes the compounds of formula I, selected from the group consisting of:

and(20); and their pharmaceutically acceptable salts;

where T is H, C1-3the alkyl, pyrrolidin-3-yl, piperidine-4-yl, (H 2)2-3-O-C1-3the alkyl, (CH2)2-3OH, (CH2)2-3F, (CH2)2-3-piperidinyl, (CH2)2-3-pyrrolidinium; and T' is H, Cl, Br, F, C1-3the alkyl, O-C1-3the alkyl, OH, NH2N(H)-C1-3the alkyl, or N(-C1-3alkyl)2; and R2defined above.

The first subclass of the third class (a subclass of C3-S1) includes the compounds of formula (A1)to(A20) and their pharmaceutically acceptable salts, where R2is OSO3H; and all other variables are defined above in the class C1.

The second subclass of the third class (a subclass of C3-S2) includes the compounds of formula (A1)to(A20) and their pharmaceutically acceptable salts; where T is H, CH3pyrrolidin-3-yl, piperidine-4-yl, (CH2)2-3OCH3, (CH2)2-3OH, (CH2)2-3F, (CH2)2-3-piperidinyl, (CH2)2-3-pyrrolidinium; T' is H, F, O-C1-3the alkyl, OH, NH2N(H)CH3N(CH3)2; and R2defined above. In the aspect of this subclass of R2is OSO3H.

A third subclass of the third class (a subclass of C3-S3) includes the compounds of formula (A1)to(A20) and their pharmaceutically acceptable salts; where T is H; T' is H, F, OCH3or OH; and R2is OSO3H.

The fourth class of compounds of the present invention (class C4) includes the compounds of formula I, selected from the group consisting of:/p>

(B9), and their pharmaceutically acceptable salts;

where V, V', V", Y, Y' and Z each independently selected from the group consisting of H, CH3, pyrrolidinyl, piperidinyl, piperazinil, morpholinyl, thiomorpholine, CH2-pyrrolidinyl, CH2-piperidinyl, CH2-piperazinil, CH2-morpholinyl, CH2-thiomorpholine, NH2N(H)CH3N(CH3)2CH2NH2CH2N(H)CH3and CH2N(CH3)2; provided that:

(i) at least one of V, V' and V" is H; and

(ii) at least one of Y and Y' is H.

The first subclass of the fourth class (subclass C4-S1) includes the compounds of formula (B1)-(B9) and their pharmaceutically acceptable salts; where at least two of V, V' and V" are H; and R2is OSO3H.

Another embodiment of the present invention is a compound selected from the group consisting of the above-mentioned compounds of examples 1-117 (or, alternatively, compounds 1-117) and their pharmaceutically acceptable salts.

Another embodiment of the present invention is a compound selected from the group consisting of the above-mentioned compounds of examples 1-13 (i.e. connections 1-13) and their pharmaceutically acceptable salts.

Another embodiment of the present invention t is aetsa connection, selected from the group consisting of compounds 1, 2, 4 and 6-9 and their pharmaceutically acceptable salts.

Another embodiment of the present invention is a compound selected from the group consisting of:

(2S,5R)-7-oxo-N-piperidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-N-[4-(aminomethyl)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-[(3R)pyrrolidin-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-6-(sulfoxy)-N-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-(5-piperidine-4-espiridion-2-yl)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

piperidine-4-ylmethyl(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; and their pharmaceutically acceptable salts.

Another embodiment of the present invention is (2S,5R)-7-oxo-N-piperidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (i.e., the compound of example 1, or, alternatively, compound 1) or its pharmaceutically acceptable salt.

Another embodiment of the present invention is (2S,5R)-N-[4-(aminomethyl)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (i.e., the compound of example 9, or, alternatively, compound 9) or the pharmaceutically priemysel.

Another embodiment of the present invention is (2S,5R)-7-oxo-N-[(3R)pyrrolidin-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (i.e., the compound of example 14, or connection 14) or its pharmaceutically acceptable salt.

Another embodiment of the present invention is compound 1 in the form of a crystalline monohydrate. Crystalline monohydrate is characterized by a powder x-ray shown in figure 1, and the curve of differential scanning calorimetry (DSC), is shown in figure 2. Crystalline monohydrate can be obtained as described in part A, in example 1D. In one embodiment, the crystalline monohydrate is characterized by a powder x-ray obtained using copper Kα radiation (i.e. radiation source is a combination of Cu Kα1 and Kα2 radiation), which comprises 2Θ values (i.e. reflections at 2Θ values in degrees of about 15.6, 17.4 and 20,4. In this embodiment, and any similar options for implementation that follow, the term "about" means modifying each of 2Θ values. In another embodiment, the crystalline monohydrate is characterized by a powder x-ray obtained using copper Kα radiation which comprises 2Θ values in degrees of about 15.6, 17.4 years, 20,4, 24,0, 26,3, and 29,3. In e is e one embodiment, the crystalline monohydrate is characterized by a powder x-ray, obtained using copper Kα radiation which comprises 2Θ values in degrees of about 13,5, 15,5, 15,6, 17,4, 18,7, 19,7, 20,4, 21,7, 22,6, 24,0, 24,3, 25,9, 26,3, 26,6, 27,0, 27,5, 29,3, 30,0, 31,3, 32,4, 32,9, 33,1, 34,0, 34,7, 35,5 and 38.9.

In yet another embodiment, the crystalline monohydrate of compound 1 is characterized by a diagram of the intensity distribution (PDF trace)obtained from powder x-ray figure 1. Chart intensity distribution gives the imprint of the interatomic distances, which determine the crystalline monohydrate. Chart intensity distribution can be obtained as described in patent document WO 2005/082050. In one aspect of this variant implementation of the crystalline monohydrate is characterized by a parts diagram of the intensity distribution corresponding to the 2Θ values in degrees of about 15.6, 17.4 and 20.4 in the powder x-ray. In another aspect of this variant implementation of the crystalline monohydrate is characterized by a parts diagram of the intensity distribution corresponding to the 2Θ values in degrees of about 15.6, 17.4 years, 20,4, 24,0, 26,3, and 29,3 on powder x-ray. In another aspect of this variant implementation of the crystalline monohydrate is characterized by a parts diagram of the intensity distribution corresponding to the 2Θ values in degrees of about 13,5, 15,5, 15,6, 17,4, 18,7, 19,7, 20,4, 21,7, 22,6, 24,0, 24,3, 25,9, 26,3, 26,6, 7,0, 27,5, 29,3, 30,0, 31,3, 32,4, 32,9, 33,1, 34,0, 34,7, 35,5 and 38.9 in powder x-ray.

The term "at or about" changing the number (for example, kg, litre or equivalents) of a substance or composition, or the magnitude of the physical property, or the value of the parameter characterizing the stage of the process (for example, the temperature at which carry out stage of the process), or other similar parameters, refers to the deviation of the numerical values which may occur, for example, when conventional methods of measurement, manipulation and sampling used in the preparation, research and/or application of a substance or composition; due to inadvertent error in these procedures; due to differences in the manufacture, source, or purity of the ingredients used for the receipt or application of the compositions or methods; and other similar reasons. In the specific case of 2Θ values in degrees described herein powder x-ray the term "about" generally means the value of ±0.1.

Another embodiment of the present invention is a compound of formula I, or its pharmaceutically acceptable salt, as defined above or as defined in any of the above embodiments, the sub-options of implementation, aspects, classes or subclasses, where the compound or its salt is almost pure form is. Used herein, the term "almost pure" means that at least about 60 wt.%, typically, at least about 70 wt.%, preferably, at least about 80 wt.%, more preferably, at least about 90 wt.% (for example, from about 90 wt.% up to 99 wt.%), even more preferably, at least about 95 wt.% (for example, from about 95 wt.% up to 99 wt.%, or from about 98 wt.% to 100 wt.%), and most preferably at least about 99 wt.% (for example, 100 wt.%) product containing the compound of the formula I or salts thereof (for example, a product isolated from the reaction mixture, giving the compound or salt), make up the compound or salt. The degree of purity of the compounds or salts can be determined using the standard method of analysis, such as thin layer chromatography, gel electrophoresis, high performance liquid chromatography and/or mass spectrometry. If you use more than one method of analysis, and methods provide in the experiment, significant differences in the degree of defined purity, then the method that provides the highest degree of cleanliness is a priority. The compound or salt is 100% pure and is a compound or salt, which contains no detectable impurities, determined by the standard method of analysis. As for the connection is subramania, which has one or more centers of asymmetry and may exist as mixtures of stereoisomers, almost a pure compound can be either almost pure mixture of stereoisomers, or almost pure individual diastereoisomer or enantiomer.

Other embodiments of the present invention include the following:

(a) a Pharmaceutical composition comprising an effective amount defined above of compounds of formula I, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

(b) the Pharmaceutical composition according to paragraph (a), optionally comprising an effective amount of β-laktamovogo antibiotic.

(c) the Pharmaceutical composition according to paragraph (b), where beta laktamovogo antibiotic selected from the group consisting of imipenem, ertapenem, Meropenem, doripenem, biapenem, panipenem, tikarcillina, ampicillin, amoxicillin, carbenicillin, piperazillina, azlocillin, mezlocillin, tikarcillina, cefoperazone, Cefotaxime, Ceftriaxone, and ceftazidime.

(d) the Pharmaceutical composition according to paragraph (b), where β-lactamase antibiotic is imipenem.

(e) the Pharmaceutical composition according to paragraph (b), where β-lactamase antibiotic ceftazidime is.

(f) the Pharmaceutical composition according to paragraph (b), where β-lactamase antibiotic a Ki is piperacillin.

(g) the Pharmaceutical composition according to paragraph (a), optionally comprising an effective amount of β-laktamovogo antibiotic and inhibitor DHP.

(h) the Pharmaceutical composition according to paragraph (g), where beta lactamase antibiotic is imipenem, and DHP inhibitor is cilastatin or its pharmaceutically acceptable salt.

(i) a Combination of effective amounts defined above of compounds of the formula or its pharmaceutically acceptable salts and β-laktamovogo antibiotic.

(j) Combination under paragraph (i), where beta laktamovogo antibiotic selected from the group consisting of imipenem, ertapenem, Meropenem, doripenem, biapenem, panipenem, tikarcillina, ampicillin, amoxicillin, carbenicillin, piperazillina, azlocillin, mezlocillin, tikarcillina, cefoperazone, Cefotaxime, Ceftriaxone, and ceftazidime.

(k) Combination under paragraph (i), where β-lactamase antibiotic is imipenem.

(l) Combination under paragraph (i), where β-lactamase antibiotic ceftazidime is.

(m) Combination under paragraph (i), where β-lactamase antibiotic is piperacillin.

(n) a Combination of effective amounts defined above of compounds of formula I or its pharmaceutically acceptable salt, β-laktamovogo antibiotic and inhibitor DHP.

(o) Combination under paragraph (n), where beta lactamase antibiotic is imipenem, and inhib the torus DHP is cilastatin or its pharmaceutically acceptable salt.

(p) a Method of treating a bacterial infection, which includes an introduction to the subject in need of such treatment a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt, optionally in combination with effektnym amount of beta-laktamovogo antibiotic.

(q) a Method of treating a bacterial infection, which includes an introduction to the subject in need of such treatment a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt in combination with effective amounts of beta-laktamovogo antibiotic and inhibitor DHP.

(r) a Method of treating a bacterial infection, which includes an introduction to the subject in need of such treatment a therapeutically effective amount of a composition according to paragraphs (a), (b), (c), (d), (e), (f), (g) and (h).

(s) a Method of treating a bacterial infection, which includes an introduction to the subject in need of such treatment a therapeutically effective amount of a combination of items (i), (j), (k), (l), (m), (n) and (o).

(t) a Method of treating a bacterial infection in paragraphs (p), (q), (r)or (s), where the bacterial infection is caused byPseudomonas spp. orKlebsiella spp.

The present invention also includes a compound of formula I or its pharmaceutically acceptable salt, (i) for use in medicine, (ii) for the use as a drug for the treatment of bacterial infections or (iii) for use in preparation (or manufacture) of the medicinal product for the treatment of bacterial infections. In these applications, the compounds of the present invention can optionally be used in combination with one or more β-lactamase antibiotics and/or one or more inhibitors of DHP.

Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods for the points above (a)-(t) and use stated in the previous paragraph, where used herein, the compound of the present invention is a compound of one of the above-described embodiments, the sub-options of implementation, classes or subclasses. In these embodiments, the implementation of the connection may not necessarily be used in the form of pharmaceutically acceptable salts.

Additional embodiments of the present invention include each of the pharmaceutical compositions, combinations, methods and uses, as stated in the previous paragraphs, where used herein, the compound of the present invention or its salt is almost pure. With regard to pharmaceutical compositions comprising a compound of formula I or its salt and a pharmaceutically acceptable carrier and optionally one or more auxiliary substances, it should be in the Doo, the term "almost pure" refers directly to the compound of formula I or its salts; that is, the purity of the active ingredient in the composition.

Used herein, the term "alkyl" refers to monovalent linear or branched, saturated aliphatic hydrocarbon radical, having the number of carbon atoms in the specified interval. For example, "C1-8alkyl or C1-C8alkyl") refers to any of artelinic, heptylene, hexylene and pantiliner alkyl isomers as well as n-, ISO-, sec - and tert-butile, n - and isopropyl, ethyl and stands. As another example, "C1-6alkyl or C1-C6alkyl") refers to any of exiling and pantiliner alkyl isomers as well as n-, ISO-, sec - and tert-butile, n - and isopropyl, ethyl and stands. As another example, "C1-4alkyl" refers to n-, ISO-, sec - and tert-butile, n - and isopropyl, ethyl and stands.

The term "halogenated" refers to a certain higher alkyl group in which one or more hydrogen atoms have been substituted with halogen (i.e. F, Cl, Br and/or I). For example, "C1-6halogenated" (or "C1-C6halogenated") relates to defined above, C1-C6linear or branched alkyl group with one or more halogen substituents. The term "foralkyl has an is a logical value, except that the halogen substituents are limited to fluorine. Suitable foralkyl include a number (CH2)0-4CF3(that is, trifluoromethyl, 2,2,2-triptorelin, 3,3,3-Cryptor-n-propyl, and so forth).

The term "halogen" or "halo"refers to fluorine, chlorine, bromine and iodine (alternatively, referred to as fluorine, chlorine, bromine, and iodine).

The term "cycloalkyl" refers to any monovalent monocyclic ring alkane having the number of carbon atoms in the specified interval. For example, "C4-9cycloalkyl" (or "C4-C9cycloalkyl") refers to cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and ciclesonide, and "C4-7cycloalkyl" refers to cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "C(O)" refers to the carbonyl, the terms "S(O)2and SO2" each refer to sulfonyl. The term "S(O)" refers to the sulfinil.

The symbol "*" at the end of the communication relates to the place of attachment of functional groups or other chemical fragment to the rest of the molecule, of which he is.

If definitely not restricted, the term "substituted" refers to one or multiple substitutions using the named substituent, provided that such single and multiple substitution (including multiple substitution at the same laid and is chemically possible. Unless expressly stated otherwise, the substitution using a named substituent is permitted on any atom in the ring (for example, cycloalkyl, phenyl, heteroaromatic ring, or a saturated heterocyclic ring), provided that such substitution in the ring is chemically possible and results in a stable connection. However, it should be borne in mind that can be specified degree of substitution. For example, the expression "totally optional substituted with from 1 to 4 substituents selected from zero to 2 N(RARBand from zero to 2, RCmeans that may not necessarily be present in the aggregate 4 of the Deputy with up to 2 substituents N(RARBand maximum 2 RCgroups. As another example, the expression "AryA is neither unsubstituted phenyl or phenyl substituted with 1 or 2 N(RARB" means that AryA is not phenyl, phenyl, monosubstituted by N(RARBor phenyl, disubstituted with N(RARBor AryA defined somewhere in another place.

Defined here HetA is a saturated or mono-unsaturated heterocyclic ring with the number of members from 4 to 9, containing from 1 to 3 heteroatoms, independently selected from N, O and S, where the ring is optionally condensed with C3-7cycloalkyl. Saturated heterocyclics the e ring, suitable for use as HetA include, for example, azetidine, piperidinyl, morpholinyl, thiomorpholine, thiazolidine, isothiazolinones, oxazolidinyl, isoxazolidine, pyrrolidinyl, imidazolidinyl, piperazinil, tetrahydrofuranyl, tetrahydrothieno, pyrazolidine, hexahydropyridine, tiziani, mousepanel, azepane, diazepan, asomani (=octahedrally), isononyl (=octahydro-1H-azavinyl), tetrahydropyranyl, tetrahydropyranyl, and dioxane. Suitable monounsaturated heterocyclic rings include, for example, rings, corresponding saturated rings presented in the preceding sentence, except that they contain a double bond (for example, the double bond carbon-carbon). Saturated heterocyclic ring condensed with cycloalkyl and suitable for use as HetA include, for example,.

Defined here HetB is optionally substituted heteroaromatic ring containing from 1 to 4 heteroatoms selected from 1 to 3 N atoms, zero or 1 O atom, and zero or 1 S atom, where the heteroaromatic ring is optionally condensed with a saturated heterocyclic ring with the number of members from 5 to 7, containing 1 or 2 heteroatoms independently selected from N, O and S, where each S in a ring are not acelerado S(O) or S(O) 2and either 1 or 2 carbon atoms in the unfused ring, optionally oxidized to C(O). Heteroaromatic ring, suitable for use as HetB, include, for example, pyridyl (also referred to as pyridinol), pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxadiazolyl, thiazolyl, isothiazolin, and thiadiazolyl. Condensed ring, suitable for use as HetB, include, for example,and.

Unless expressly stated otherwise in a particular context, any of these different cyclic rings and ring systems can be attached to the rest of the compound via any atom in the ring (that is, any carbon atom or any heteroatom, provided that it leads to the formation of stable compounds.

Unless expressly stated otherwise, all present here the intervals are incorporating intervals. For example, a heteroaromatic ring described as containing from 1 to 4 heteroatoms"means that the ring may contain 1, 2, 3 or 4 heteroatoms. In addition, it should be borne in mind that any present here the interval includes within itself the scope of all of peginterferon inside this interval. That is, for example, it is assumed that the heterocyclic ring described as containing from 1 to 4 heteroatoms", includes as its aspects heterocyclic ring containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms or 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatom, 3 heteroatoms, and 4 heteroatoms.

When any variable (for example, RAor RB) appears more than one time in any constituent or in formula I or in any other formula depicting and describing compounds of the present invention, a definition for each event occurrence does not depend on its determination for each of the other cases of emergence. In addition, combinations of substituents and/or variables are permitted only if such combinations result in the formation of stable compounds.

A stable connection is the connection that can be received and allocated, and whose structure and properties are or may in the result of the measures taken to remain unchanged for a time period sufficient to be able to use the connection described here for purposes (e.g., introduction to a subject for therapeutic purposes). Compounds of the present invention are limited to stable compounds described forms of the Loy I.

Compounds of the present invention have at least two centers of asymmetry and may have one or more centers in the result of the presence of certain substituents and/or substitution groups. Accordingly, the compounds of the invention may exist as mixtures of stereoisomers or as individual diastereomers, or enantiomers. All isomeric forms of these compounds, or individually, or in mixtures, are included in the scope of the present invention.

The term "connection" refers to the free form of the compound and any of its hydrate or MES, provided that they are stable. A hydrate is a compound formed a complex with water, and MES is a compound formed a complex with an organic solvent.

As indicated above, the compounds of the present invention can be used in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to salts that has the effectiveness of the parent compound and which is not biologically or otherwise undesirable (for example, is neither toxic nor otherwise harmful to the recipient). A suitable pharmaceutically acceptable salt is a salt formed by processing the compounds of the invention (e.g. compounds of formula (I) with the help of nomalanga the equivalent of a weak base (for example, sodium carbonate, sodium bicarbonate, potassium bicarbonate, or sodium acetate). In this case, M is a cation such as Na+in the case of treatment with sodium base.

When M is H (e.g., R2is OSO3H), and the compound of the invention contains an internal basis, which is capable of protonation (e.g., R1contains basic nitrogen), it should be borne in mind that the compound can exist in the form in which the inner base of the fully protonated using M=H, so that R2has a negative charge (for example, R2=OSO3-internal base has a positive charge, or partially protonated, so that R2has a partial negative charge, or is not protonated. Similarly, when M is H and the compound of the invention contains two or more internal reasons, which are capable of protonation (e.g., R1contains two or more basic nitrogen), it should be borne in mind that the compound can exist in a form in which one or more of the internal grounds fully protonated using M=H, or two or more of the internal grounds every sufficiently protonated, so that R2has a negative charge, or that one or more of the grounds partially protonated, so th is R 2has a partial negative charge, or that none of the grounds is not protonated. The present invention includes all such forms of the compounds. Although these compounds can be in the form of the inner salt (i.e. zwitter-ion), they are considered as compounds of the invention, and not as their pharmaceutically acceptable salts.

On the other hand, for compounds of the invention, which contains an internal basis (for example, R1contains basic nitrogen), the pharmaceutically acceptable salt is a salt formed by processing the compounds corresponding amount of acid (e.g. hydrochloric acid, triperoxonane acid, methanesulfonic acid, or other acid), so that the inner base is protonated by the acid with the positive charge of the protonated base, offset by a negative counterion (e.g., chloride, TRIFLUORIDE, methanesulfonate, or other similar counterion). For compounds of the invention containing two internal grounds (for example, R1contains two basic nitrogen), other pharmaceutically acceptable salt is a salt formed as a result of processing the connection using the appropriate amount of acid, so that one of the internal grounds protonated sulfonic group keys is the notes, present in the molecule (that is, R2has a negative charge), and another is protonated by the acid with the positive charge of the protonated base, offset by a suitable negative counterion. Another pharmaceutically acceptable salt of the compounds of the invention containing two internal grounds, can be obtained by treating the compounds with the appropriate acid (e.g. sulfuric acid, HCl, methanesulfonic acid, or TFA), so that the sulfonic acid group present in the molecule, remains protonated (i.e. M = H) and internal bases are protonated and also connected with a suitable negative counterion (e.g., sulfonate). As is apparent from the above, the specific nature and type of pharmaceutically acceptable salts, which can be obtained will depend on the nature of concrete connections subjected to processing (e.g., the presence or absence of major Izotov in R1), and used machining conditions; for example, they will depend on the choice and amount of acid or base, which is processed by the connection, the pH of the processing environment, the number and choice of buffer (if used), and other similar factors. It should be borne in mind that the present invention includes satipy and form pharmaceutically acceptable salts of the compounds of the present invention.

As stated above, the present invention includes pharmaceutical compositions containing a compound of formula I of the present invention, optionally one or more other active ingredients (e.g., β-laktamovogo antibiotic), and a pharmaceutically acceptable carrier. Characteristics of the carrier will depend on the method of introduction. The term "pharmaceutically acceptable" it is meant that the ingredients of the pharmaceutical composition should be compatible with each other, do not interfere with the effectiveness of the active ingredient (ingredient), and are not dangerous (e.g., toxic) for the recipient. Thus, compositions according to the invention can, in addition to the inhibitor, contain diluents, fillers, salts, buffers, stabilizers, soljubilizatory, and others well known in the art materials.

In addition, as stated above, the present invention includes a method of treating a bacterial infection, which includes an introduction to the subject in need of such treatment a therapeutically effective amount of the compounds of formula I, or its pharmaceutically acceptable salts, optionally in combination with a beta-lactamase antibiotic and/or a DHP inhibitor. Used herein, the term "subject" (or, alternatively, "patient"refers to an animal, preferably, the milk is itausa, most preferably the person who was the object of treatment, research or experiment. The term "introduction" and its variants (e.g., "introduction" connection) with respect to the compound of formula I refers to the maintenance of a person in need of treatment a compound or its pharmaceutically acceptable salt. When you provide a compound or its salt in combination with one or more other active ingredients (e.g., antibiotic carbapenem or DHP inhibitor, or both), it should be borne in mind that the "introduction" and its variants each include the provision of a compound or its salt and other substances at the same time or at different times. When substance combination is administered simultaneously, they can be put together in a single composition or they can be entered separately. It should be borne in mind that the "combination of active substances may be a composition containing all of the active substance, or multiple tracks, each of which contains one or more active substances. In the case of two active substances, the combination may be either a single composition comprising both substances, or two separate tracks, each of which includes one of the substances; in the case of three active substances, the combination may be one or composition, including all three substances, three separate to the position, each of which includes one of the substances, or two songs, one of which includes two substances and the other includes a third substance; and so on.

Compositions and combinations of the present invention is administered appropriately in effective amounts. Used herein, the term "effective amount" means that amount of active compound or pharmaceutical agents causing biological or medicinal response in a tissue, system, animal or human, which is determined by the researcher, veterinarian, medical doctor or other Clinician. In one embodiment, the effective amount is a therapeutically effective amount to alleviate symptoms of the disease or condition being treated (e.g., treatment of conditions associated with bacterial infection and/or bacterial resistance to the action of the medicinal product). In another embodiment, an effective amount is a "prophylactically effective amount" for the prevention of the symptoms of the disease or condition, who want to prevent. The term here also includes the amount of active compound sufficient to inhibit β-lactamase, and therefore is called the desired response (i.e., "inhibition effective amount"). When the active connection(i.e. active ingredient) is injected in the form of a salt, references to the amount of the active ingredient refers to the form of the free acid or free base form of the connection.

Introduction the composition of the present invention is accordingly parenteral, oral, sublingual, transdermal, topical, intranasal, intratrahealno, or intrarectal, where the composition is suitably prepared for administration by the selected method by means well known in the art of cooking methods, including, for example, methods for the preparation and injection dosage forms are described in chapters 39, 41, 42, 44 and 45 monographs Remington - The Science and Practice of Pharmacy. 21st edition, 2006. In one embodiment, compounds of the invention are administered intravenously in a hospital setting. In another embodiment, the introduction is oral administration in the form of tablets or capsules or other similar form. When implementing the system introduction, therapeutic composition is administered appropriately at a dose sufficient to achieve concentrations of inhibitor in the blood of at least about 1 microgram/ml, preferably about 10 micrograms/ml, and more preferably about 25 micrograms/ml For the localized introduction effective may be significantly lower concentrations than these, and valid can be significantly bol is e high concentration.

Intravenous administration of the compounds of the invention can be carried out by dissolving the powder form of the compound with an acceptable solvent. Suitable solvents include, for example, physiological solutions (e.g., 0.9% sodium chloride solution for injection and sterile water (for example, sterile water for injection, bacteriostatic water for injection with methylparaben and propylparaben, or bacteriostatic water for injection with 0.9% benzyl alcohol). Powder form of the compound can be obtained by irradiation connection with gamma rays or by lyophilization of a solution of the compound, after which the powder can be stored (e.g. in a sealed ampoule) at room temperature or below until it is not subject to dissolution. The concentration of compounds in the resulting solution may be, for example, in the range of from about 0.1 mg/ml to 20 mg/ml

The present invention also includes a method of inhibiting bacterial growth, which includes the introduction in bacterial cell culture or bacterial infected cell culture, tissue, or organism, inhibiting effective amount of the compounds of formula I. Additional embodiments of the invention include the just described method of inhibiting bacterial growth, DG is used in the connection of the present invention is a compound of one of the above embodiments, sub-options exercise or classes. In these embodiments, the implementation of the connection may not necessarily be used in the form of pharmaceutically acceptable salts. The method may include the introduction of the compounds of formula I in an experimental cell culture in vitro to prevent growth resistant to β-lactam bacteria. The method may alternatively include the introduction of the compounds of formula I to an animal, including humans, to prevent the growth resistant to β-lactam bacteria in vivo. In these cases, the compound of formula I is usually administered in conjunction with β-lactamase antibiotic.

Compounds of the invention can be used for the treatment, prevention or inhibition of bacterial growth or infections caused by bacteria that are resistant to β-lactamase antibiotics. More specifically, the bacteria can be β-lactamase positive strains that are highly resistant to the action of β-lactamase antibiotics. The terms "unstable" and "stable" are widely used conventional experts in this field (see, for example, publications Payne et al., Antimicrobial Agents and Chemotherapy 38:767-772 (1994); Hanaki et al., Antimicrobial Agents and Chemotherapy 30:11.20-11.26 (1995)). For the purposes of this invention, the strains of bacteria that are highly resistant to imipenem, are the strains against which the minimum concentration of inhibitor (MIC) of imipenem is > 16 µg/ml, and the bacteria strains that have low resistance to imipenem, are the strains against which the minimum concentration of inhibitor (MIC) of imipenem is >4 mg/ml

Compounds of the invention can be used in combination with antibiotic means for treating infections caused by strains producing β-lactamase class C, in addition to those infections that are attributed to the antibacterial spectrum of the antibiotic funds. Examples of bacteria that produce β-lactamase class C are Pseudomonas aeruginosa, Enter obacler cloacae, Klebsiella pneumoniae, Escherichia coli and Acinetobacter baumannii.

It is often useful to use the compound of formula I in a mixture or in combination with carbapenem, penicillin, cephalosporin or other β-lactamase antibiotic, or its prodrug. It is often useful to use the compound of formula I in combination with one or more β-lactamase antibiotics in connection with the properties of the compounds to inhibit β-lactamases of class C. As already mentioned, the compound of formula I and β-laktamovogo antibiotic can be entered separately (simultaneously or at different times) or in the form of a single composition containing both active ingredients.

Carbapenems, penicillins, cephalosporins and other β-laktamovogo antibiotics suitable for use in the present invention include those in which the gadfly known they are unstable, or are sensitive to the action of β-lactamase class C, and those for which it is known that they have some degree of resistance to the action of β-lactamase class C

When the compounds of formula I combined with antibiotic carbapenem, it may also be added inhibitor dehydropeptidase (DHP). Many carbapenems sensitive to the effects of renal enzyme, known as DHP. This impact or disruption may reduce the effectiveness of carbapenemase antibacterial agents. Inhibitors of DHP and their use with carbapenems are disclosed, for example, in patent documents US 4539208, US 4616038, US 4880793 and US 5071843. The preferred DHP inhibitor is 7-(L-2-amino-2-carboxymethylthio)-2-(2,2-dimethylcyclopropanecarboxylic)-2-geptanona acid or its pharmaceutically acceptable salt.

Carbapenems, suitable for co-injection with the compounds of the present invention include imipenem, Meropenem, biapenem, (4R,5S,6S)-3-[3S,5S)-5-(3-carboxyphenylazo)pyrrolidin-3-ylthio]-6-(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo-[3.2.0]hept-2-ene-2-carboxylic acid chloride (1S,5R,6S)-2-(4-(2-(((carbamoylmethyl)-1,4-diazoniabicyclo-[2.2.2]-Oct-1-yl)-ethyl-(1,8-Naftalan)methyl)-6-[1(R)-hydroxyethyl]-1-methylcarbamyl-2-em-3-carboxylate chloride*Florida?*, BMS181139 ([4R-[alpha,beta,beta(R*)]]-4-[2-[(Aminogen is methyl)amino]-ethyl]-3-[(2-cyanoethyl)thio]-6-(1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), BO2727 (monohydrochloride [4R-3[3S*,5S*(R*)],alpha,beta,beta(R*)]]-6-(1-hydroxyethyl)-3-[[5-[1-hydroxy-3-(methylamino)propyl]-3-pyrrolidinyl]thio]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), E1010 (hydrochloride (1R,5S,6S)-6-[1(R)-hydroxymethyl]-2-[2(S)-[1(R)-hydroxy-1-[pyrrolidin-3(R)-yl]-methyl]pyrrolidin-4(S)-ylsulphonyl]-1-methyl-1-carb-2-stump-3-carboxylic acid) and S4661 ((1R,5S,6S)-2-[(3S,5S)-5-(sulfamoylbenzoyl)pyrrolidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-l-methylcarbamyl-2-em-3-carboxylic acid), chloride (1S,5R,6S)-1-methyl-2-{7-[4-(aminocarbonylmethyl)-1,4-diazoniabicyclo(2.2.2)-Octan-1-yl]-methylfluorene-9-one-3-yl}-6-(1R-hydroxyethyl)karbapin-2-em-3-carboxylate.

Penicillins, suitable for co-injection with the compounds of the present invention include benzylpenicillin, phenoxymethylpenicillin, carbenicillin, azidocillin, propicillin, ampicillin, amoxicillin, ampicillin, tikarcillin, ciclacillin, pirinelli, azlotillin, mezlocillin, sulbenicillin, piperacillin, and other well known penicillins. Penicillins can be used in the form of their prodrugs; for example, in the form of in vivo gidrolizuyushchie esters, for example acetoxymethyl, pivaloyloxymethyl, α-ethoxycarbonylmethylene and palidrome esters of ampicillin, benzylpenicillin and amoxicillin; in the form of an aldehyde or ketone adducts of penicillins containing 6-α-aminoacetophenone b is covoy chain (for example, hetacillin, metampicillin and similar derivative of amoxicillin); and esters of carbenicillin and tikarcillina, for example phenyl and indinavir α-esters.

Cephalosporins, suitable for co-injection with the compounds of the present invention include cefatrizine, tsefaloridin, cefalotin, Cefazolin, cephalexin, cefacetrile, cefapirin, cefamandole NAPAT, cefradine, 4-hydroxycobalamin, cephaloglycin, cefoperazon, cefsulodin, ceftazidime, cefuroxime, cefmetazole, Cefotaxime, Ceftriaxone, and other known cephalosporins, each of which can be used in the form of its prodrugs.

β-Laktamovogo antibiotics in addition to penicillins and cephalosporins, which can be put together with the compounds of the present invention include aztreonam, latamoxef (trade mark moxalactam), and other known β-laktamovogo antibiotics such as carbapenems type of imipenem, Meropenem, or (4R,5S,6S)-3-[(3S,5S)-5-(3-carboxyphenylazo)pyrrolidin-3-ylthio]-6-(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, each of which can be used in the form of its prodrugs.

In one embodiment, the antibiotic, simultaneously introduced with the compound of the present invention, are selected from the group consisting of imipenem, Meropenem and (4R,5S,6S)-3-[(3S,5 S)-5-(3-carboxyphenylazo the l)pyrrolidin-3-ylthio]-6-(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.

In another embodiment, the antibiotic, simultaneously introduced with the compound of the present invention, are selected from the group of penicillins, consisting of ampicillin, amoxicillin, carbenicillin, piperazillina, azlocillin, mezlocillin, and tikarcillina. These penicillins may not necessarily be used in the form of their pharmaceutically acceptable salts, for example their sodium salts. Ampicillin or amoxicillin may, alternatively, be used in the form of fine particles in the form of zwitter ions (usually in the form of three-hydrate ampicillin or three-hydrate amoxicillin) for use in suspensions imposed in the form of injections or infusions. In the aspect of this case for penicillin, jointly introduced with the compound of the present invention is amoxicillin, not necessarily in the form of its sodium salt, or three-hydrate.

In another embodiment, the antibiotic, simultaneously introduced with the compound of the present invention, are selected from the group of cephalosporins, consisting of Cefotaxime, Ceftriaxone and ceftazidime, each of which is optionally used in the form of their pharmaceutically acceptable salts, for example their sodium salts.

At joint application with β-lactamase antibiotic combination of compounds of the invention and an antibiotic may produce a synergistic effect. T is rmini "synergy" and "synergistic" indicate what is the effect in the case of joint introduction of two or more drugs is a greater value than would be expected based on the effect achieved when the individual introduction connections. Without going into theory of this question, however, it is believed that the compounds of the present invention are inhibitors of β-lactamases, which prevents the decomposition of β-lactamase antibiotics, thereby increasing their efficiency and providing a synergistic effect.

Used here abbreviations include the following: acac = acetylacetonate; AIBN = 2,2-azobisisobutyronitrile; BLI = inhibitor of beta-lactamase; Bn = benzyl; BOC (or Boc) = tertbutyloxycarbonyl; BOC-ON = 2-(tertbutoxycarbonyl-amino)-2-phenylacetonitrile; BOC-OSN = N-tertbutoxycarbonyl)-succinimide; BOP = benzotriazol-1 yloxy)Tris(dimethylamino)-phosphonium hexaflurophosphate; BSA = bovine serum albumin; CBZ (or Cbz) = carbobenzoxy (alternatively, benzyloxycarbonyl); COD = cyclooctadiene; DBU = 1,8-diazabicyclo-[5.4.0]undec-7-ene; DCC = dicyclohexylcarbodiimide; DCE = 1,2-dichloroethane; DCM = dichloromethane; DIPEA = diisopropylethylamine (or base Chunga); DMAC = N,N-dimethylacetamide; DMAP = 4-dimethylaminopyridine N,N-dimethylaminopyridine; DME = 1,2-dimethoxyethane; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; DS = differential scanning calorimetry; Et = ethyl; EtOAc = ethyl acetate; HMDS = hexamethyldisilazide; HOBT = 1-hydroxybenzotriazole; HOPO = 2-hydroxypyridine-N-oxide; HPLC = high performance liquid chromatography; IPA = isopropyl alcohol; IPAc = isopropylacetate; i-Pr = isopropyl; LC/MS = liquid chromatography/mass spectrometry; Me = methyl; MHBII = medium Mueller-Hinton type II; MIC = minimum inhibitory koncentracija; MSA = methansulfonate acid; NMP = N-methylpyrrolidone; PG = protective group; Ph = phenyl; TEA = triethylamine; TFA = triperoxonane acid; TFE = 2,2,2-triptorelin; THF = tetrahydrofuran; TLC = thin layer chromatography; TSB = trypticase-soy broth; TsOH = pair-toluensulfonate acid; XRPD = powder x-ray.

Compounds of the present invention can be easily obtained in accordance with the following further schemes reactions and examples, or modifications of them, using readily available starting materials, reagents and conventional synthesis procedures, including, for example, the techniques described in the patent document US 7112592. In these reactions, you can also use options, which themselves are known to specialists in this area, and is not mentioned in more detail. In addition, other methods of obtaining compounds of the invention will be easily understood by an ordinary specialist in this field, using the following schemes reactions and examples. If not specified and the hache, all variables are defined above.

Carboxamide compounds of the present invention, in which a is a simple bond and X is (CH2)1-3can be obtained, as shown in figure 1:

Bicyclic intermediate compound A can be obtained as described in patent document US 7112592, or using his usual modifications. The side chain may be attached by reaction of the acid (A) with the amine B (where, if necessary, in Amin introducing a protective group) at a known technique in standard conditions for the formation of amide. For example, the acid solution A and the amine B (1-2 molar equivalents) in a solvent (for example, halogenoalkane, such as dry dichloromethane or chloroform) may be mixed at room temperature with successive addition of triethylamine (1-2 equivalents), HOBT (1-2 equivalents), and EDC (1-2 equivalents) at room temperature under nitrogen atmosphere. The resulting reaction mixture can then be stirred at room temperature until until fully complete the reaction (for example, for about 8 to 24 hours), and then the reaction mixture can be concentrated under vacuum, and the residue purified using column chromatography on silica gel or by using HPLC, gives amide C. removing the protective the th group, represents benzyl ether, to obtain the intermediate compounds of hydrocelectomy D, can be carried out by hydrogenation or, in some cases, by hydrolysis catalyzed by acid. For example, to a solution of benzyl ether in a suitable solvent (for example, alcohol such as methanol or ethanol, alkyl acetate, such as EtOAc or ether, such as THF) can be added palladium on coal (0.05 to 0.5 equiv.) and the resulting mixture is stirred in hydrogen atmosphere (1-3 atmosphere) up until the reaction is completed (for example, for about 1 to 24 hours), as determined using the appropriate current control methods, such as TLC or HPLC. After completion of the reaction hydroxylated D can be extracted using traditional methods. For example, the reaction mixture can be filtered, and the filtrate concentrated to obtain the crude hydroxylamine D, which in many cases can be used directly in the next stage without additional purification. If additional cleaning is necessary or desirable, crude hydroxylated D can be purified by column chromatography on silica gel or HPLC to obtain pure hydroxylamine D. Sulfatization intermediate compound D with getting sulfate E can be implemented using sulfatizing is its reagent in an appropriate solvent. So, the solution hydrocelectomy D in an aprotic solvent (for example, tertiary amide, such as pyridine, DMF or DMAC) at room temperature may be added to the complex of sulfur trioxide with pyridine (2-10 equivalents). The resulting mixture may be mixed at room temperature until, until the end of the reaction (for example, for about 4 to 24 hours), completion of which is controlled by an HPLC or LC/MS. To bring the reaction to the end if necessary, may be added an additional amount of a complex of sulfur trioxide with pyridine. The purified reaction product can be obtained using traditional methods, such as filtration of the reaction mixture, concentrating the filtrate under vacuum, the suspension concentrate in a saturated aqueous solution of potassium dihydrophosphate, washing the aqueous solution with a suitable organic solvent (such as EtOAc), adding to the aqueous layer of excess acid tetrabutylammonium sulfate, extraction of the mixture with an organic solvent (such as EtOAc 4X), combining the organic layers, drying the combined organic layers over sodium sulfate, and concentration under vacuum obtaining tetrabutylammonium salt intermediate compound E. In cases where the side chain is missing protective group, product the reaction Sul is alizatsii is a compound of formula I of the present invention. When the protective group is introduced into the side chain amide (for example, benzylamine or benzyl ester, BOC amine, or CBZ amine)group can be removed by means known in the art method of obtaining the compounds of formula I. More specifically, the compounds of formula I containing an amino group in the side chain (for example, R3is aminoalkyl), the amino group is usually protects to prevent the occurrence of unwanted side reactions during the synthesis process. Protection can be properly carried out by the use of BOC, CBZ, or similar protective group.

Carboxylate compounds of the present invention, in which a is a simple bond and X is (CH2)1-3can be obtained, as shown in diagram 2:

Figure 2 ether G is obtained by interaction of the intermediate bicyclic derivative of A urea with alcohol side chain F (where, if necessary, in alcohol injected protective group) in the presence of tarifitsiruemih reagent (e.g., 1-2 equivalents of DCC or EDC) in the presence of a catalyst (for example, 0.05 to 0.25 equivalents of DMAP) in an aprotic solvent (such as ether, such as diethyl ether or THF, or halogenoalkane, such as dichloromethane) at a temperature in the range of from about 0°C to 35°C until until the end of the reaction (on the example, for about 1-24 hours), completion of which is controlled by TLC or HPLC. The intermediate compound G can then converted into the compound of the present invention by successive syntheses (dibenzylamine, sulfation, and removing the protection in the side chain (if necessary), analogous to the syntheses described in scheme 1 for the synthesis of amide analogues.

Carboxamide compounds of the present invention, in which a is a simple bond and X is CH=CH (see T below), and compounds in which a is a double bond and X is CH2(see connection W below), can be obtained as depicted in scheme 3:

As shown in scheme 3, the protected amino acid J can be subjected to reaction combination with the amine B (1-2 molar equivalents) in a solvent (for example, halogenoalkane, such as dry dichloromethane or chloroform) under stirring at room temperature the sequential addition of triethylamine (1-2 equivalents), HOBT (1-2 equivalents), and EDC (1-2 equivalents) in nitrogen atmosphere. The resulting reaction mixture may then be peremesheno at room temperature until, until the end of the reaction (for example, for about 8 to 24 hours), and the intermediate amide can be removed by OSU known methods (for example, concentrating the reaction mixture under vacuum, purification of the residue via column chromatography on silica gel or HPLC). Then BOC protective group can be removed by means well known in the art methods of obtaining an amine, which may be subjected to recovery aminirovanie with aldehyde L in the reaction with a reducing agent, such as cyanoborohydride sodium (1-3 molar equivalents) or other similar reducing agent, at a temperature from 0°C to room temperature in an alcohol solvent such as methanol, ethanol, or other alcohols. The reaction mixture may be mixed until then, until the end of the reaction (for example, for about 1 to 24 hours), and then using known methods extract Amin K (for example, concentrate the reaction mixture under vacuum and purify the residue by chromatography). Then Amin K can be allerban by connecting M in the presence of a strong base, such as DBU (~1 equivalent), or other similar reasons, in an aromatic hydrocarbon solvent such as benzene, toluene, or other similar solvent, to obtain the intermediate compounds of urea, which is extracted by known methods (for example, by washing the reaction mixture with an aqueous solution of acid, the concentration of the washed mixture padmakumar, and purification of the residue by chromatography). Then the acetate protective group can be removed by well known methods, and the resulting primary hydroxyl group can be activated by reaction with from about 1 to 1.5 equivalents of Teilhard, triflate anhydride, or other similar compounds in dinucleophiles solvent (e.g. dichloromethane, ether, benzene, and so on) at low temperature (for example, from 0°C to 25°C). Then the activated hydroxyl group can be processed using dinucleophiles base, such as DBU, trebuchet potassium, tributyltin, or other similar basis, at a low temperature (for example, from 0°C to 25°C) obtaining collisioning intermediate compound Q, which can be extracted and purified using standard extraction methods. For cyclization diolefines intermediate compound Q can be used are well known to specialists in this field methods metathesis of olefins. For example, the compound Q can be treated with a catalytic amount (0.05 to 0.25 equivalents) of the catalyst of verification for the metathesis of olefins in a suitable solvent (e.g. benzene, toluene, tetrahydrofuran, or other similar solvent) at a temperature of about 25°C with getting cyclohexane product, then protect the health of the group PG on hydroxylamine may be removed by well known methods, and received hydroxylated sulfation with getting sulfate. For example, a solution of hydroxylamine in an aprotic solvent (for example, tertiary amide, such as pyridine, DMF or DMAC) can be processed by a complex of sulfur trioxide with pyridine (2-10 equivalents) at about 25°C to obtain the desired product, which can be extracted and purified using standard methods of obtaining connection T. In cases where the side chain protective group is absent, the reaction product of sulfatization is a compound of formula I of the present invention. When the protective group introduced into the side chain amide (for example, benzylamine or ester, BOC amine, or CBZ amine)group can be removed by means known in the art method of obtaining the compounds of formula I. Beta-gamma olefin in T can be Samaritan in a paired connection with amidocarbonyl side chain by processing T junctions using dinucleophiles base (for example, trebuchet potassium, sodium hydride, or other similar reasons) in dinucleophiles solvent (for example, tertbutanol, tetrahydrofuran, ether, or other similar solvent) at a temperature from 0°C to 25°C. alternatively, the olefin can be Samaritan in the paired connection in acidic conditions using such acids as triptorelin AlfaNova acid or other acid, or acidic ion-exchange resin in dinucleophiles solvent (for example, tertbutanol, tetrahydrofuran, ether, or other similar solvent) at a temperature from 0°C to 25°C. the Obtained olefin isomer W can be extracted and selected using standard extraction methods.

Generally speaking, when a chemical group in the compound is called here a "protected" or talks about the introduction of a protective group", this means that the chemical group used in modified form to prevent unwanted side reactions at the protected position. Protective group suitable for use in obtaining the compounds of the present invention, and methods for the introduction and removal of such protective groups are well known in the art and include groups and the methods described in the monographs Protective Groups in Organic Chemistry, ed. J.F. W. McOmie, Plenum Press, 1973 and in T.W. Greene &P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 3rd edition, 1999, 2nd edition, 1991, the contents of which is given here by reference.

The present invention also includes the method (alternatively called method P) of obtaining the compounds of formula P-II:

which includes:

(A) contacting ilide ketosulfone formula P-I:

with iridium, rhodium, or ruthenium catalyst obtained with the em connection P-II;

where:

pG is a protective group for an amine selected from the group consisting of carbamates and benzylamino;

RUis CH3or phenyl;

RVis CH3or phenyl;

R4is H or C1-4by alkyl;

T' is H, Cl, Br, F, C1-3the alkyl, O-C1-3the alkyl, OH, NH2N(H)-C1-3the alkyl, or N(-C1-3alkyl)2;

p is zero, 1 or 2; q is zero, 1 , or 2; and p + q = zero, 1, 2, or 3.

Connection P-II is an intermediate compound used in the synthesis of specific compounds of the present compounds. The protective group for amines PGmay be a carbamate (i.e. protecting group of the formulain which R is optionally substituted alkyl, allyl, optionally substituted benzyl, or other such Deputy or benzylamino (i.e. protecting group of the formulain which Ar is optionally substituted phenyl). Suitable urethane and benzylamine protective groups and methods for their formation and removal are described in the monographs Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973 and in T.W. Greene &P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rdedition, 1999, and 2ndedition, 1991. In one embodiment, PGis (1) C(=O-(CH2)0-1-CH=CH2, (2) C(=O)-O-CH2-phenyl, in which phenyl is not battelino substituted with from 1 to 3 substituents, each of which is independently halogen, -NO2, -C1-4the alkyl, or-O-C1-4the alkyl, (3) C(=O)-O-C1-4the alkyl, or (4) CH2-phenyl, in which phenyl optionally substituted with 1 to 3 substituents each of which is independently halogen, -NO2, -C1-4the alkyl, or-O-C1-4the alkyl. In another embodiment, PGis tertbutyloxycarbonyl (Boc), allyloxycarbonyl (Alloc), benzyloxycarbonyl (Cbz), p-methoxybenzenediazonium, p-nitrobenzenediazonium, p-bromobenzyloxycarbonyl, p-chlorobenzenesulfonyl, 2,4-dichlorobenzenesulfonyl or benzyl. In another embodiment, PGis Cbz.

Other embodiments of compounds P-II include the following: (1) RUand RVare both CH3or are both phenyl; (2a) T' is H or F; (2b) T' is H; (3a) R4is H or CH3; (3b) R4is H. One or more of these embodiments (1)to(3) can be combined with each other and/or with variants of the implementation described above for PGwhere each such combination is a separate option for the connection of the P-II.

Stage A involves the intramolecular NH introduction using ilide ketosulfone with the formation of the cyclic product. Chemical properties ylides used in the process A, provide a safety advantage in comparison with alternative methods, using diazomethane (explosive), for the formation of diazoketone, which can then be used for cyclization. Stage A can also provide high output. For example, the output stage when using A catalytic amount of [Ir(COD)Cl]2may be 85% or higher.

Stage A is carried out in an organic solvent. Suitable solvents include toluene, dichloromethane, DCE, DMF, THF, chlorobenzene, 1,2-dichlorobenzene, cyclopentylmethyl ether, acetonitrile, IPAc, nitromethane, triptoreline, methyl ethyl ketone, DME, and 2-MeTHF. The preferred solvent is toluene.

The cyclization stage A is carried out in the presence of Ir, Rh, or Ru catalyst. Suitable catalysts include [Ir(COD)Cl]2, RuCl2(PPh3)3, Ru(DMSO)4Cl2, [RuCl2(cimal)]2, [RuI2(cimal)]2, (cyclopentadienyl)Ru(PPh3)2(inden)RuCl(PPh3)2Rh2(OAc)4Rh2(TFA)4, (COD)2IrBF4, IrCI(CO)(PPh3)2, IrCl(CO)3Ir(COD)(acac), Ir(CO)2(acac), (methylcyclopentadienyl)(COD)Ir, or (cyclohexyl)3P)3(COD)Ir(pyridine). The class of suitable catalysts consists of [Ir(COD)Cl]2, RuCl2(PPh3)3, Ru(DMSO)4Cl2, [RuCl2(cimal)]2, [RuI2 (cimal)]2, (cyclopentadienyl)Ru(PPh3)2(inden)RuCl(PPh3)2Rh2(OAc)4Rh2(TFA)4. the preferred catalyst is [Ir(COD)Cl]2. The catalyst is usually used in an amount of about 0.25 to 5 mole percent of the compound P-I, and more typically used in amounts of from about 0.5 to 2 mole percent.

The reaction in stage A can be suitably carried out at a temperature in the range of from about 50°C to 130°C, and it is usually carried out at a temperature in the range of from about 70°C to 110°C.

A variant of the method P includes only the above-described stage A, where PGis Cbz, to obtain compound P-IIa (= connection P-II in which PGsubstituted with Cbz), and further includes:

(B) treating compound P-IIa using a reducing agent to obtain compounds of formula P-III:

and

(C) contacting compound P-III with sulphonylchloride formula R^-SO2W in the presence of a tertiary amine base to obtain the compounds of formula P-IV:

where W is halogen; and R^ is (1) phenyl, optionally substituted with from 1 to 3 substituents each of which is independently C1-4the alkyl, C1-4halogenation, O-C1-4the alkyl, O 1-4halogenation, Cl, Br, F, or NO2, (2) C1-4by alkyl; or (3) C1-4halogenation.

Stage B is carried out in an organic solvent. Suitable solvents include toluene, dichloromethane, THF, isopropyl alcohol and acetonitrile. Preferred solvents are toluene and THF.

Suitable reducing agents at stage B include LiBH4, NaBH4, KBH4, (Me4N)BH4, LiAlH(O-t-Bu)3, LiBH(OEt)3and Al(O-i-Pr)3/IPA. The class of suitable reducing agents consists of LiBH4, NaBH4and KBH4. Preferred reducing agents include LiBH4and NaBH4. The reducing agent is usually used in an amount of about 1 to 2 equivalents per equivalent of compound P-IIa, and more typically used in amounts of about 1 to 1.3 equivalents.

The reaction in stage B can be carried out suitably at a temperature in the range of from about -20°C to 40°C, and it is usually carried out at a temperature in the range of from about -15°C to 0°C.

Stage C is carried out in an organic solvent. Suitable solvents include dichloromethane, THF, ethyl acetate and MTBE. The preferred solvent is dichloromethane.

Examples of sulphonylchloride suitable for use in stage C, include methanesulfonate, chloromethanesulfonyl-chloride, dichlorocyclohexane, benzene is sulfonylurea, p-triftoratsetilatsetonom, p-toluensulfonate, p-bromobenzonitrile, p-forbindelsesfaneblad, and p-methoxybenzenesulfonamide. The class of suitable sulphonylchloride consists of chloromethanesulfonyl, p-triftormetilfullerenov and p-brabanthallen-chloride. The preferred sulphonylchloride is p-triftoratsetilatsetonom. Sulfonylmethane usually used in an amount of about 1 to 2 equivalents per equivalent of compound P-III, and more typically used in amounts of about 1 to 1.5 equivalents (for example, about 1.3 equivalents).

Suitable tertiary amine at the stage C is three-C1-4alkylamine. The class of suitable amines consists of TEA, DIPEA, and diethylethanolamine. DIPEA is the preferred base. The base is usually used in an amount of about 1 to 3 equivalents per equivalent of compound P-III, and more typically used in amounts of from about 1.1 to 2 equivalents (e.g., about 1.8 equivalents).

The reaction at the stage C can be carried out suitably at a temperature in the range of from about 0°C to 40°C, and it is usually carried out at a temperature in the range of from about 10°C to 25°C.

Another variant of the method P includes only the above-described stages A, B, and C, where PGthe two who is Cbz, to obtain compound P-IV, and further includes:

(D) contacting compound P-IV with N-Boc-O-benzylhydroxylamine in the presence of a base to obtain the compounds of formula P-V:

and

(E) treating compound P-V acid to obtain the compounds of formula P-VI:

Stage D is carried out in an organic solvent. Suitable solvents include DMAC, DMF, NMP, THF and DME. The preferred solvent is NMP.

Suitable base at the stage D include Li, trebuchet, Na, trebuchet, K trebuchet, cesium carbonate, KHMDS, NaHMDS. The class of suitable bases consists of Li of tributyrate, Na of trebuchet and K trebuchet. The preferred base is K trebuchet. The base is usually used in an amount of about 1 to 2 equivalents per equivalent of compound P-IV, and more typically used in amounts of about 1 to 1.5 equivalents (for example, about 1.3 equivalents).

N-Boc-O-benzylhydroxylamine usually used in stage D in amounts of about 1 to 2 equivalents per equivalent of compound P-IV, and more typically used in amounts of about 1 to 1.5 equivalents (for example, about 1.3 equivalents).

The reaction at the stage D can be carried out suitably at a temperature in the range of from about 30°C to 60°C and it is usually carried out ol the temperature in the range of from about 35°C to 45°C.

Stage E is carried out in an organic solvent. Suitable solvents include DCM and acetonitrile.

Suitable acid at the stage of E include sulfonic acid. Suitable acid at the stage of E include methanesulfonate acid, triftormetilfullerenov acid, chloromethanesulfonyl acid, benzosulfimide acid, p-toluensulfonate acid, p-bromobenzophenone acid, p-methoxybenzenesulfonyl acid, and p-cryptomaterial-sulfonic acid. The class of suitable acids consists of p-toluensulfonate acid and methanesulfonic acid. The preferred acid is methansulfonate acid. The acid is usually used in an amount of about 1 to 6 equivalents per equivalent of compound P-V, and more typically used in an amount of about 3 to 5 equivalents.

The reaction at the stage E can be carried out suitably at a temperature in the range of from about 25°C to 60°C, and it is usually carried out at a temperature in the range of from about 30°C to 40°C.

Another variant of the method P includes only the above-described stages A, B, C, D and E, where PGis Cbz, to obtain compound P-VI, and further includes:

(F) contacting compound P-VI with phosgene, diphosgene or triphosgene in the presence of a tertiary amine base, and then adding vodno the acid solution to obtain the compounds of formula P-VII:

and

(G) contacting compound P-VII with a hydrogen source in the presence of a hydrogenolysis catalyst and in the presence of Boc-forming reagent to obtain the compound of formula P-VIII:

Stage F is carried out in an organic solvent. Suitable solvents include DCM and acetonitrile. The preferred solvent is DCM.

Suitable acid at the stage F include hydrochloric acid, sulfuric acid, triperoxonane acid, and phosphoric acid. The preferred acid is phosphoric acid. The acid is usually used in an amount of about 1 to 6 equivalents per equivalent of compound P-VI, and more typically used in an amount of about 3 to 5 equivalents (for example, about 3.2 equivalents).

Suitable tertiary amine at the stage F is three-C1-4alkylamine. The class of suitable amines consists of TEA, DIPEA, and diethylethanolamine. DIPEA is the preferred base. The base is usually used in an amount of about 1 to 6 equivalents per equivalent of compound P-VI, and more typically used in an amount of about 3 to 5 equivalents (for example, about 3.2 equivalents).

Triphosgene, diphosgene, or phosgene are usually used in stage F in an amount of about 0.5 to 1 equivalent per equivalent connection is s P-VI and more typically used in an amount of about 0.7 to 1 equivalent (e.g., about 0.8 equivalent). Triphosgene is more preferable in comparison with diphosgene and phosgene.

Contacting compound P-VI with triphosgene, diphosgene, or with phosgene at a stage F can be carried out suitably at a temperature in the range of from about -15°C to 0°C, and it is usually carried out at a temperature in the range of from about 35°C to 45°C. Subsequent addition of and reaction with the acid can be carried out suitably at a temperature in the range of from about 0°C. to 25°C.

Stage G is carried out in an organic solvent. Suitable solvents include ethyl acetate, DMAC, tertbutanol, and THF. The preferred solvent is THF.

Appropriate Boc-forming reagents at the stage of G include distritbution, tributylphosphine, BOC-ON and BOC-OSN. The preferred reagent is distritbution. The reagent is usually used in amounts of from about 0.9 to 3 equivalents per equivalent of compound P-VII, and more typically used in amounts of from about 0.9 to 1.5 equivalents (for example, from about 0.95 to 1.1 equivalent).

The source of hydrogen at the stage of G is typically hydrogen gas, optionally in a mixture with a carrier gas, which is chemically inert under the reaction conditions, ispolzuemykh at the stage of G (for example, nitrogen or a noble gas such as helium or argon). Pressure is not the determining aspect in stage G, although it is reasonable to use the atmospheric pressure and the pressure above atmospheric. The pressure is typically at least about 2 psig (about 115 kPa). The source of hydrogen, alternatively, may be a molecule is the vector of hydrogen, such as ammonium formate, cyclohexene, or cyclohexadiene.

The consumption of hydrogen is not a determinant of the way, although usually use at least a stoichiometric amount of gaseous hydrogen or other hydrogen source.

The hydrogenolysis catalyst comprises supported on a carrier or no carrier metal of Group 8 or supported on a carrier or no carrier compound, salt or complex of a metal of Group 8. The catalyst, which is usually used at the stage of G, is supported on a carrier or nenalezena metallic Pd or supported on a carrier or no carrier compound, salt or complex of Pd. Suitable catalyst carriers include carbon, silicon oxide, aluminum oxide, silicon carbide, aluminum fluoride, and calcium fluoride. The class of suitable catalysts consists of Pd mobiles (i.e., fine particles of metallic palladium), Pd(OH)2and Pd/C (i.e. palladium on the carrier from coal). Pd/C yavlyaetsyaprostota a catalyst for hydrogenolysis. The catalyst is usually used in an amount of about 5 to 20 wt.% regarding the number of compounds VI, and more typically used in an amount of about 5 to 15 wt.% (for example, about 10 wt.%).

The reaction at the stage of G can be carried out suitably at a temperature in the range of from about 10°C to 50°C, and it is usually carried out at a temperature in the range of from about 15°C to 30°C.

A modification of the method P includes just described A stage where the compound of formula P-II is a compound p-2:

where A stage includes:

(A) contacting ilide ketosulfone p-1:

with a catalyst selected from the group consisting of a dimer of chloride cyclooctadiene, RuCl2(PPh3), Ru(DMSO)4Cl2and Rh2(TFA)4with connection p-2.

Another modification of the method P only includes that described in the previous sub-option implementation phase A to obtain compound p-2, and further includes:

(B) treating compound p-2 with a reducing agent selected from the group consisting of Li borohydride, Na borohydride and K borohydride, to obtain compound p-3:

and

(C) contacting compound p-3 sulphonylchloride formula R^-SO2W in prisutstvuyuschuyu three-C 1-4the alkylamine with obtaining the compounds of formula p-4:

where

W is chlorine; and

R^ is stands, chlorochilon, phenyl, 4-Bromphenol, 4-cryptomaterial, or 4-were.

Another modification of the method P only includes that described in the previous sub-option of the implementation of stage A, B and C to obtain compound p-4, and additionally includes:

(D) contacting compound p-4 with N-Boc-O-benzylhydroxylamine in the presence of a base selected from the group consisting of Li of tributyrate, Na of tributyrate, K trebuchet and K Aminata obtaining compound p-5:

and

(E) treating compound p-5 using an acid selected from the group consisting of methanesulfonic acid, chloromethanesulfonyl acid, p-toluensulfonate acid and benzosulfimide acid, to obtain the compounds of formula p-6:

Another modification of the method P only includes that described in the previous sub-option of the implementation of stage A, B, C, D and E to obtain compound p-6, and further includes:

(F) contacting compound p-6 triphosgene in the presence of a base three-C1-4the alkylamine, and then adding an aqueous solution of phosphoric acid to obtain compound p-7:

and

(G) contacting compound p-7 with hydrogen in the presence of Pd catalyst and Boc-forming reagent selected from the group consisting of distritbution and BOC-ON, to obtain the compound p-8:

Solvents, reagents, catalysts, reaction number reaction temperature, and so forth described above for stages A-F in the way of P, leading to the connection P-VIII, and in variants of implementation applicable to stages A-F, described in the previous sub-options for implementation, leading to the compound p-8, except in those cases where the sub-options of the implementation of one or more of these variables overlap with clearly defined limits. For example, a modification of the method P that describes the connection to p-2 from compound p-1, limits the catalyst used in stage A, to a specific group of Ir, Ru and Rh catalysts. Accordingly, the proposed method P above the expanded disclosure of suitable catalysts are not applicable to this sub-option implementation.

It should be borne in mind that it is assumed that the solvents, reagents, catalysts, reaction number reaction temperature, and so forth, as described above with respect to method P and its variants implementation and modifications done by the means, are only illustrations and do not limit the scope of the method. For example, an organic solvent used on any of the stages A-G may be any organic substance, which under the reaction conditions used at this stage, is in a liquid state, is chemically inert, and can be dissolved, suspended, and/or dispersing reactive substances and any reagents, in order to result in contact of the reacting substances and reagents and to provide the course of the reaction. Similar considerations apply to the choice of the bases, catalysts, and other reagents used in the stages of the method. In addition, each of the stages can be carried out at any temperature at which can significantly proceed the reaction, which receive the desired product. Reacting substances, catalysts and reagents at this stage can be used in any quantities, which lead to the formation of at least some amount of the desired product. Needless to say that the goal of each stage is usually the achievement of a high degree of conversion (e.g., at least about 60% and preferably higher) starting materials in combination with high yield (e.g., at least about 50% and preferably higher) required cont the mswb, and is the preferred choice of solvents, reagents, catalysts, reaction quantities, temperatures, and so forth, which can be achieved relatively high degree of conversion and outputs the product, and the preferred choice is the condition in which can be achieved optimal degree of conversion and outputs. Specific solvents, reagents, catalysts, reaction number reaction temperature, and so forth, as described above with respect to method P and its implementation options and sub-options for implementation, can provide a high degree of conversion and outputs.

The present invention also includes a compound selected from the group consisting of:

and

where:

PGis a protective group for an amine selected from the group consisting of carbamates and benzylamino;

RUis CH3or phenyl;

RVis CH3or phenyl;

R4is H or C1-4by alkyl;

T' is H, Cl, Br, F, C1-3the alkyl, O-C1-3the alkyl, OH, NH2N(H)-C1-3the alkyl, or N(-C1-3alkyl)2;

p is zero, 1 or 2; q is zero, 1, or 2; p+q = zero, 1, 2, or 3; and

R^ is:

(1) f is'neil, optionally substituted with from 1 to 3 substituents each of which is independently C1-4the alkyl, C1-4halogenation, OC1-4the alkyl, O-C1-4halogenation, Cl, Br, F, or NO2;

(2) C1-4by alkyl; or

(3) C1-4halogenation.

The present invention also includes a compound selected from the group consisting of:

and

where R^ is the stands, chlorochilon, phenyl, 4-Bromphenol, 4-cryptomaterial, or 4-were.

The following examples serve only to illustrate the invention and its implementation. The examples should not be construed as limitations of the scope or the invention.

PREPARATIVE EXAMPLE 1

(4R,6S)-3-(Benzyloxy)-2-oxo-1,3-diazabicyclo[2.2.1]-heptane-6-carboxylic acid

Stage 1: 2-Allyl 1-tertbutyl(2S,4S)-4-hydroxypyrrolidine-1,2-di carboxylate

Distritbution (0,532 ml, 2,291 mmol) was added to a solution of CIS-4-hydroxy-L-Proline (265 mg, 2.02 mmol) in DMF (5 ml) and aqueous sodium hydroxide solution (2 ml, 2 mmol). The reaction mixture was stirred at room temperature overnight. Added allylbromide (of 0.18 ml of 2.08 mmol), and obtained the offer was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water diluted aqueous HCl, water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under vacuum to obtain these compounds in the form of a clear oil.

Stage 2: cleaners containing hydrochloride salt of allyl (4S)-4-hydroxy-L-prolinate have been obtained

Added hydrochloric acid (4,2 M solution in dioxane, 5 ml, 21 mmol) to a solution of 2-allyl 1-tertbutyl (2S,4S)-4-hydroxypyrrolidine-1,2-in primary forms (1,05 g, to 4.87 mmol) in dichloromethane (20 ml). The resulting mixture was stirred at room temperature for 4 hours, then concentrated under vacuum to obtain these compounds.

Stage 3: Allyl (4S)-4-hydroxy-1-(TRIFLUOROACETYL)-L-prolinate have been obtained

Added THF (18 ml) to cleaners containing hydrochloride salt of allyl (4S)-4-hydroxy-L-prolinate have been obtained (1,011 g, to 4.87 mmol). The resulting suspension was cooled to 0°C, was added triethylamine (3.0 ml, 21.5 mmol) and then triperoxonane anhydride (2 ml, of 14.2 mmol). The resulting mixture was stirred at 0°C for 30 minutes, then added the water. The resulting solution was stirred at room temperature for 30 minutes, then was diluted with ethyl acetate and washed with 1N HCl solution, water, dilute sodium bicarbonate solution, dried over magnesium sulfate, filtered and koncentrira is whether under vacuum. In order to hydrolyze any triftoratsetata ether, which could be formed as a by-product, the residue was placed in tetrahydrofuran (11.5 ml) and water (11.5 ml). The obtained turbid solution was stirred at room temperature for 7 hours. The obtained clear solution was diluted with ethyl acetate and washed with aqueous 5% sodium bicarbonate solution and brine, then dried over magnesium sulfate, filtered, concentrated under vacuum to obtain the crude product. The crude product was purified by chromatography on silica gel to obtain the above compound as a pale brown oil.

Stage 4: Allyl (4R)-4-[(benzyloxy)amino]-1-(TRIFLUOROACETYL)-L-prolinate have been obtained

A solution of allyl (4S)-4-hydroxy-1-(TRIFLUOROACETYL)-L-prolinate have been obtained (844 mg, and 3.16 mmol) in acetonitrile (16 ml) was cooled to -10°C was added 2,6-lutidine (of 0.62 ml, 5,32 mmol), then triftormetilfullerenov anhydride (0,85 ml of 5.15 mmol). After the addition the temperature was raised to 0°C. the Reaction mixture was stirred at 0°C for 1 hour, then added O-benzylhydroxylamine (1 ml, 8,67 mmol) and 2,6-lutidine (of 0.62 ml, 5,32 mmol). The reaction mixture was heated to room temperature over night. Then the reaction mixture was diluted with ethyl acetate and washed with aqueous 5% sodium bicarbonate solution and brine, su is or over magnesium sulfate, was filtered and concentrated under vacuum. The brown oily residue (to 2.57 g) was subjected to chromatography on silica gel, was suirable first with a mixture of 95:5 dichloromethane:ethyl acetate and at the end of the 80:20 dichloromethane:ethyl acetate to obtain these compounds in the form of a pale yellow solid.

Stage 5: Allyl (4R)-4-[(benzyloxy)amino]-L-prolinate have been obtained

A solution of allyl (4R)-4-[(benzyloxy)amino]-1-(TRIFLUOROACETYL)-L-prolinate have been obtained (1.19 g, 3,20 mmol) in methanol (9.5 ml) was slowly added to a solution of sodium borohydride (312 mg, 8.25 mmol) in methanol (9.5 ml) at -10°C. the Reaction mixture is slowly warmed up to 0°C, then stirred at 0°C for 3 hours. Added additional amount of sodium borohydride (0.29 grams, to 7.67 mmol) at 0°C, and the reaction mixture was stirred at 0°C for three hours, then was added silica gel (pre-absorption of the crude product to chromatography), and the solvent was removed under vacuum. The residue was subjected to chromatography on silica gel, was suirable a mixture of 15:9:1 dichloromethane:ethyl acetate:methanol to obtain these compounds in the form of a colorless oil.

Stage 6. 2-Allyl 1-tertbutyl (2S,4R)-4-[(benzyloxy)amino]pyrrolidin-1,2, in primary forms

A solution of allyl (4R)-4-[(benzyloxy)amino]-L-prolinate have been obtained (1.2 g, 4,34 mmol) in dichloromethane (29 ml) was added to distritbution (1.1 ml, 4,34 mmol), and polucen the th mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum, and the residue was subjected to chromatography on silica gel, was suirable hexane, then with a mixture of 4:1 hexane:ethyl acetate to obtain these compounds in the form of a transparent resin.

Stage 7: 2-Allyl 1-tertbutyl (2S,4R)-4-{(benzyloxy)-[(trichloromethane)carbonyl]amino}pyrrolidin-1,2, in primary forms

Diphosgene (0.1 ml, 0,804 mmol) was slowly added to a solution of 2-allyl 1-tertbutyl (2S,4R)-4-[(benzyloxy)amino]pyrrolidin-1,2-in primary forms (261 mg, 0,745 mmol) and triethylamine (0,13 ml, 0,933 mmol) in dichloromethane (4 ml) at 0°C. the Reaction mixture was stirred at 0°C for 4 hours, then kept at room temperature during the night. The reaction mixture was subjected to chromatography on silica gel, was suirable first with hexane, then with a mixture of 4:1 hexane:ethyl acetate to obtain these compounds in the form of a transparent resin.

Stage 8: Allyl (4R,6S)-3-(benzyloxy)-2-oxo-1,3-diazabicyclo[2.2.1]heptane-6-carboxylate

Hydrochloric acid (4,2 M solution in dioxane, 16 ml of 70.4 mmol) was added to 2-allyl 1-tertbutyl (2S,4R)-4-{(benzyloxy)[(trichloromethane)carbonyl]amino}pyrrolidin-1,2-in primary forms (80 mg, 1,49 mmol). The resulting mixture was stirred at room temperature overnight, then the solvent was removed under vacuum. Was added to the residue dichloromethane (82 ml) and then triethylamine (of 0.62 ml of 4.45 mmol. The resulting mixture was stirred at room temperature overnight, then the solvent was removed under vacuum. The residue was subjected to chromatography on silica gel (ISCO chromatography system using a gradient from hexane for 2 minutes to a mixture of 7:3 hexane:ethyl acetate for 6 minutes, with time for 3 minutes and transfer to 100% EtOAc over 8 minutes with obtaining these compounds are in the form of a clear oil.

Stage 9: (4R,6S)-3-(Benzyloxy)-2-oxo-1,3-diazabicyclo-[2.2.1]heptane-6-carboxylic acid

2-Ethylhexanoate sodium (0.5 M in ethyl acetate, 2.5 ml, 1.25 mmol) was added to a solution of allyl (4R,6S)-3-(benzyloxy)-2-oxo-1,3-diazabicyclo[2.2.1]heptane-6-carboxylate (459 mg, of 1.52 mmol), 1,1'-bis(diphenylphosphino)ferienparadies(II)-dichloride with dichloromethane (116 mg, 0.14 mmol) in tetrahydrofuran (7,6 ml). The reaction mixture was stirred at room temperature for 2 hours (precipitate formed). Added acetone (37 ml). The resulting mixture was stirred at room temperature for 2 hours, and the mixture was centrifuged. Collected solid was washed him with acetone and ether and dried under vacuum to obtain these compounds in the form of a brown solid. LC-MS (positive ionization) m/e 363 (M+H)

EXAMPLE 1

(2S,5R)-7-oxo-N-piperidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-ka is boxlid

Stage 1: tertbutyl 4-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)piperidine-1-carboxylate

To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (0,141 g, 0,509 mmol) (note: this is an intermediate compound disclosed in patent document US 7112592 in example 32b) in dry dichloromethane (3 ml) was sequentially added 4-amino-1-BOC-piperidine (0,1532 g, 0,765 mmol), triethylamine (0.16 ml, 1,148 mmol), HOBT (0,1145 g, 0,748 mmol), and EDC (0,1455 g, 0,759 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum, and the residue was purified using HPLC (column 30×100 mm Waters Sunfire; 5 micron; 35 ml/minute; 210 nm; from 15% to 100% CH3CN + 0,05% TFA/water + 0.05% of TFA for 15 minutes; the desired product elute 50% of CH3CN + 0,05% TFA/water + 0.05% of TFA) to give the titled compound.

Stage 2: tertbutyl 4-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)piperidine-1-carboxylate

Palladium on coal (30,5 mg; 10% Pd/C) was added to a solution of tertbutyl 4-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo-[3.2.1]Oct-2-yl]carbonyl}amino)piperidine-1-carboxylate (151 mg, 0.33 mmol) in methanol (3 ml)and the resulting mixture was stirred in hydrogen atmosphere (the Mallon are optimistic about) for 3 hours. Analysis by TLC showed that the reaction was held until the end. The reaction mixture was filtered through a microfilter, and the filtrate was concentrated under vacuum to obtain these compounds in the form of a yellow oil.

Stage 3: N,N,N-Tributylin-1 amine[({(2S,5R)-7-oxo-2-[(piperidine-4-ylamino)carbonyl]-1,6-diazabicyclo[3.2.1]Oct-6-yl}oxy)sulfonyl]oxidase

To a solution of tertbutyl 4-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)piperidine-1-carboxylate (36 mg, 0,098 mmol) in pyridine (0.5 ml) was added to the complex of sulfur trioxide with pyridine (70 mg, 0,440 mmol). The mixture was stirred at room temperature under nitrogen atmosphere overnight. Analysis by LC/MS showed that the reaction was incomplete. The reaction mixture was filtered, and the solid is washed with dry pyridine and dichloromethane. The filtrate was collected and concentrated under vacuum. The residue was re-dissolved in dry pyridine (0.75 ml), and added a complex of sulfur trioxide with pyridine (31 mg) and then activated 4A molecular sieves. The reaction mixture was stirred for 4 hours, but changes that are controlled using LC/MS, were not observed. The reaction mixture was filtered, and the sieve was rinsed with dichloromethane. The filtrate was concentrated under vacuum and suspended in a saturated aqueous solution of potassium dihydrophosphate. The mixture p is washed with ethyl acetate. Collected aqueous layer was added tetrabutylammonium hydrosulfate (0,034 mg, 0,098 mmol). The mixture was stirred for 10 minutes, then was extracted with EtOAc (4X). The organic layers were combined, dried over sodium sulfate, and concentrated under vacuum to obtain these compounds in the form of a yellow oil.

Stage 4: (2S,5R)-7-oxo-N-piperidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of N,N,N-tributylin-1 amine[({(2S,5R)-7-oxo-2-[(piperidine-4-ylamino)carbonyl]-1,6-diazabicyclo[3.2.1]-Oct-6-yl}oxy)sulfonyl]occitanica (of 22.4 mg, 0,050 mmol) in anhydrous dichloromethane (2 ml) at 0°C under nitrogen atmosphere was added dropwise triperoxonane acid (0.1 ml, 1,298 mmol). The reaction mixture was stirred for 1 hour, then concentrated under vacuum. To the residue was added ether and the resulting white precipitate was collected by centrifugation. The solid was washed with ether (2X) to give the titled compound, contaminated with tetrabutylammonium hydrosulfate and pyridine. The solid is triturated with acetonitrile (2X), and collected white solid by centrifugation to obtain these compounds in the form of a white solid. LC-MS (negative ionization) m/e 347 (M-H); LC-MS (positive ionization) m/e 349 (M+H), 381 (M+Na);1H NMR (600 MHz, D2O; without attribution) (δ, ppm) 4,19 (1H, userd, J=2.5 Hz), 3,98-4,06 (2H,m), 3,47 (2H, userd, J=13 Hz), and 3.31 (1H, userd, J=12 Hz), 3,12 (2H, userid, J=13.3 Hz), 3,06 (1H, d, J=12 Hz), 2,04-of 2.21 (m, 4H), 1,87-of 1.95 (1H, m), 1,72 of-1.83 (m, 3H).

EXAMPLE 1A

(2S,5R)-7-oxo-N-piperidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1: tertbutyl 4-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)piperidine-1-carboxylate

To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (1,484 g, 5.37 mmol) in dry dichloromethane (60 ml) was sequentially added triethylamine (of 1.88 ml, 13,49 mmol), iodide 2-chloro-1-methylpyridine (1.60 g, 6.26 mmol)and 4-amino-1-BOC-piperidine (1.30 grams, of 6.49 mmol) at room temperature under nitrogen atmosphere. The reaction mixture then was heated to 50°C for 1 hour. The reaction mixture was concentrated under vacuum and was purified by chromatography on silica gel by Isco Combiflash (40 g silica gel, 40 ml/min, 254 nm, from 15% to 100% EtOAc/hexane to 14 column volumes, then 100% EtOAc for 4 column volumes; a named connection was suirable with 65% ethyl acetate/hexane) to give the titled compound as a pale orange solid.

Stage 2: tertbutyl 4-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)piperidine-1-carboxylate

Palladium on coal (394 mg; 10% Pd/C) was added to a solution of the product from the study is 1 (1,81 g, 3.95 mmol) in methanol (50,6 ml)and the resulting mixture was stirred in hydrogen atmosphere (balloon) overnight. Analysis by LC/MS indicated that the reaction was incomplete. To the reaction mixture was added acetic acid (6 drops) and an additional amount of catalyst (159 mg of 10% Pd/C), and the resulting mixture was stirred in hydrogen atmosphere (balloon) for another 90 minutes. To the reaction mixture was added an additional amount of catalyst (0,2085 g 10% Pd/C) and continued stirring in an atmosphere of hydrogen for 2.5 hours, followed by analysis of LC-MS made the conclusion that the reaction proceeded completely. The reaction mixture was filtered through a layer of cellite, and the collected solid was well washed with MeOH. The filtrate was concentrated under vacuum to obtain these compounds in the form of a colorless oil which was used without purification in the next stage.

Stage 3 : tertbutyl-4-({[(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)piperidine-1-carboxylate

To a solution of product from step 2 (1,455 g, 3.95 mmol; theoretical output stage 2) in dry pyridine (30 ml) was added to the complex of sulfur trioxide with pyridine (3.2 g, 20,11 mmol) at room temperature under nitrogen atmosphere. Received a thick mixture was stirred for weeks. The reaction mixture was filtered, and the white insoluble the solid was well washed with dichloromethane. The filtrate was concentrated under vacuum. The residue is then drove away in the form of an azeotrope with toluene to remove excess pyridine to obtain these compounds, which is then used without purification in the next stage.

Stage 4: (2S,5R)-7-oxo-N-piperidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a mixture of the product from step 3 (1,772 g, 3.95 mmol; theoretical output stage 3) in dry dichloromethane (30 ml) at 0°C under nitrogen atmosphere was slowly added triperoxonane acid (6,1 ml, 79 mmol). The reaction mixture was instantly turned into a solution. After 1 hour the reaction mixture was added an additional amount triperoxonane acid (8 ml). The reaction mixture was stirred at 0°C until analysis LC-MS, it was possible to conclude that the completion of the reaction, and then concentrated under vacuum. The residue is triturated with ether (3X) to remove excess TFA and organic impurities. The obtained white insoluble solid was collected by centrifugation, dried under vacuum, then purified using preparative HPLC (column 250×of 21.2 mm Phenomenex Synergi Polar-RP 80A; 10 micron; 35 ml/minute; 210 nm; 0% to 30% methanol/water for 15 minutes; the named compound was suirable with 10% methanol/water). Fractions containing the titled compound were combined and liofilizirovanny during the night with obtaining Nazvanov the connection in the form of a white solid. LC-MS (negative ionization) m/e 347 (M-H).

EXAMPLE 1C

(2S,5R)-7-oxo-N-piperidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Step 1: Benzyl 4-[(tertbutoxycarbonyl)amino]piperidine-1-carboxylate

4-(N-BOC-amino)piperidine (17 kg, 84,88 mol) was dissolved in DCM (90 kg), was added triethylamine (10,14 kg, 100,16 mol)and the resulting solution was cooled to 0-5°C. was Added over 45 minutes benzylchloride (16,51 kg, 96,76 mol), while maintaining the temperature <25°C, after which the solution was subjected to aging for 30 minutes at 20°C. and Then for 10 minutes was added 2M HCl (61 kg, 118,13 mol), while maintaining the temperature < 25°C. the Mixture was stirred for 10 minutes and then the stirring was stopped and gave the opportunity for the phases to delaminate. Then phase from each other were separated, and the organic phase was subjected to distillation under vacuum to a volume of 35 liters Then added isopropylacetate (89 kg), and the mixture was concentrated by vacuum distillation at a temperature lower than 35°C, up to a volume of ~50 l for crystallization of the named product. Then within 10 minutes was added heptane (47 kg), and the resulting suspension was cooled and subjected to aging at 20°C for 20 minutes, and then subjected to aging the suspension was filtered, washed with heptane (17 kg), and dried on the filter in the current of the N2with poluchayemyye product as a white solid (24,7 kg, 87 %).1H NMR (CDCl3) 7,33 (5H, m)to 5.13 (2H, s), 4,47 (1H, m), 4,11 (2H, m), 3,61 (1H, m), with 2.93 (2H, m), of 1.94 (2H, m)of 1.45 (9H, s) and of 1.30 (2H, m).

Step 2: Benzyl 4-aminopiperidine-1-carboxylate

4-(N-BOC amino)-CBz piperidine (24,4 kg, 73,42 mol), THF (65 kg) and 5 M HCl (23,0 kg, 110,13 mol) were mixed and heated to 30-35°C for ~2 hours and then at 55°C over night. After cooling the reaction mixture to 10°C was added dichloromethane (97 kg) and 10 M NaOH (7,97 kg, 145,12 mol), while maintaining the temperature <25°C. the Phases were separated, and the organic phase is washed with 25 wt.% NaCl (27.5 kg). The washed organic phase was subjected to distillation at atmospheric pressure to a volume of 70 liters Then added dichloromethane (162 kg), and the mixture was concentrated by distillation to a volume of 120 l with getting this product in the form of a solution in DCM (17,2 kg, 100%.).1H NMR (CDCl3) 7,33 (5H, m), 5,14 (2H, s), 4,14 (2H, users), 2,87 (3H, m)and 1.83 (2H, m)of 1.66 (3H, m) and 1.28 (2H, m).

Step 3: Benzyl 4-{[1-(tertbutoxycarbonyl)-5-oxo-L-propyl]amino}piperidine-1-carboxylate

2 Hydroxypyridine-N-oxide (811 g of 7.3 mol), L-pyro-glutamic acid (9,43 kg, 73 mol), benzyl 4-aminopiperidine-1-carboxylate (17,1 kg in dichloromethane, volume 120 l, 73 mol) and dichloromethane (80 kg) were mixed together and subjected to aging at 20°C for 10 minutes with the formation of a thick suspension. To the suspension was added on the of hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (16.8 kg, 87,6 mol), while maintaining the temperature <30°C. Then the suspension was subjected to aging at 25°C for 30 minutes, after which was added 1 M hydrochloric acid (94 kg, 85,5 mol). The phases were left to settle overnight and then separated, and then the organic phase is washed with 2 M sodium carbonate (109 kg) and then the solvent was changed to acetonitrile to a final volume of 50 l was Added toluene (88,2 kg) and the mixture was cooled to 0°C. To the mixture was added distritbution (18,32 kg, 83,95 mol) and 4-dimethylaminopyridine (223 g and 1.83 mol)and the solution was heated to 25°C and subjected to aging during the night. The mixture was then concentrated by distillation to a volume of 80 liters was Added an additional amount of toluene (88,2 kg), and the mixture was further concentrated to 50 HP Added isopropylacetate (30 kg), and the resulting suspension was subjected to aging for 10 minutes. Then, to the suspension was added dropwise heptane (70 kg) for 30 minutes, and the suspension was subjected to aging for 30 minutes, then filtered, washed with a mixture of isopropylacetate/heptane (22.5 kg/17,4 kg), and then dried under vacuum at 55°C with obtaining the named product as a white solid (27.5 kg, to 95.5 wt.%, 82%).1H NMR (CDCl3) 7,33 (5H, m), to 6.19 (1H, m)to 5.13 (2H, s), 4,48 (1H, DD), is 4.15 (2H, m), of 3.97 (1H, m), 2,95 (2H, m), 2,73 (1H, d, Tr)and 4.65 (1H, m), 2,61 (1H, m)to 2.18 (2H, m)of 1.45 (9H, s) and of 1.30 (2H, m).

Stage 4: Benzyl 4-({N-(t is ebookseller)-6-[dimethyl-(oxido)-λ 4-sulfanilate]-5-oxo-L-norall}amino)piperidine-1-carboxylate

Trebuchet potassium (9,58 kg, 85,38 mol) was added in three portions to a solution of iodide trimethylsulfoxonium (18,79 kg, 85,38 mol) in DMF (115 kg) at 15-25°C. the Suspension was subjected to aging at 20-25°C for one hour, then added in four portions of the source reagent benzyl 4-{[1-(tertbutoxycarbonyl)-5-oxo-L-prolyl]amino}piperidine-1-carboxylate (27,17 kg, 60,99 mol) over 30 minutes, and then subjected to aging for 30 minutes at 20°C. Was added water (54 kg) and seed material (10 g) (note: the crystallization can be carried out without the use of seed, but it is preferable to use a seed crystal, as it usually produces a product with more consistent quality and higher output), and the suspension was subjected to aging at 20°C for 30 minutes. Was added for 1 hour and 10% NaCl solution (543 kg)while maintaining the temperature below 25°C. the Suspension was then cooled to 3°C for 1 hour and subjected to aging during the night at 3°C, after which the suspension was filtered, washed three times with water (136 l 82 l 82 l), and dried under vacuum at 55°C, to obtain the titled product as a yellow solid (32,8 kg, 83%).1H NMR (CDCl3) 7,49 (1H, users), 7,33 (5H, m), of 5.83 (1H, users), to 5.13 (2H, s), 4,48 (1H, s)4,08 (3H, m), of 3.96 (1H, m), of 3.45 (3H, s), 3,41 3H, C)3,03 (2H, m), is 2.41 (1H, m), 2,24 (1H, m), of 1.94 (4H, m), 1,68 (5H, s) and 1.44 (12H, s).

Stage 5: Tertbutyl (2S)-2-[({1-[(benzyloxy)carbonyl]

piperidine-4-yl}amino)carbonyl]-5-oxopiperidine-1-carboxylate

From the solution of the dimer of chloride cyclooctadiene (336,3 g, 0,502 mol) in toluene (318 kg) was removed oxygen by degassing using 3 cycles of vacuum degassing, followed by bubbling nitrogen through the solution for 30 minutes, after which the solution was heated to 105°C. From a solution of the original reagent ilide (27,0 kg, 50,22 mol) in DMF (128 kg) at 25°C was removed oxygen by degassing using 3 cycles of vacuum degassing, followed by bubbling nitrogen through the solution for 30 minutes. Degassed solution was then added to a hot solution of the catalyst in the course of 30 minutes while maintaining the temperature of the reaction mixture above 102°C. the Reaction mixture was subjected to aging at 105°C for 40 minutes, and then cooled to 20°C. the Organic reaction mixture was washed twice with 5 wt.% a solution of lithium chloride (81 l × 2), then water (81 l). The organic and aqueous phases were separated, and then removed from the organic phase toluene by distillation under vacuum to a volume of 130 l, and whisked phase kept chilled before it be used directly in the next stage.

Stage 6: tratbho the Il (2S,5S)-2-[({1-[(benzyloxy)carbonyl]

piperidine-4-yl}amino)carbonyl]-5-hydroxypiperidine-1-carboxylate

A solution of lithium borohydride (22,2 kg 4,1 M solution in THF, 101,9 mol) was diluted with THF (290 kg), after which was added methanol (3,26 kg) at 20°C, and subjected to aging for 30 minutes before cooling to -4°C. subjected To aging the solution of the borohydride solution was added ketone in toluene (46,8 kg in ~4 ml/l solution in toluene, 101,9 mol)while maintaining the temperature of the reaction mixture <0°C. the Reaction was stopped with a solution of acetic acid (30,6 kg, 509,5 mol, dissolved in 183 kg of methanol), while maintaining the temperature <20°C. After stopping the reaction, the reaction mixture was then subjected to aging at 20°C for 1 hour, after which it was concentrated under vacuum to a volume of 184 liters) was Added methanol (203 kg), and the mixture is kept under vacuum to a volume of 184 liters) was Added isopropanol (294 kg), and the mixture is kept under vacuum to a volume of 184 l, while maintaining the internal temperature of ~30°C. was Added a seed (5 g) (note: crystallization can be carried out without the use of seed, but it is preferable to use a seed crystal, as it usually produces a product with more consistent quality and higher output), and the mixture was subjected to aging for 1 hour for the formation of the seed layer. ZAT is m was added water (560 kg) for ~60 minutes then was added isopropanol (111 kg). The suspension was filtered, washed three times with MTBE (30 kg, 35 kg, 5 kg), and then dried under vacuum at 55°C with getting this product (26,74 kg, 57% yield on the ylides).1H NMR (CDCl3) 7,33 (5H, m), 6,17 (1H, users), to 5.13 (2H, s), br4.61 (1H, m), 4,11 (3H, m), of 3.94 (1H, m)to 3.64 (1H, m), 2,98 (2H, m), 2,59 (1H, DD), 2,33 (1H, m), of 1.94 (4H, m), 1,71 (1H, m), and 1.63 (2H, m)to 1.48 (9H, s) and 1.35 (2H, m).

Stage 7: Tertbutyl (2S,5S)-2-[({1-[(benzyloxy)carbonyl]piperidine-4-yl}amino)carbonyl]-5-({[4-(trifluoromethyl)phenyl]sulfonyl}oxy)piperidine-1-carboxylate

The source reagent alcohol (26,6 kg, 57,7 mol) was dissolved in dichloromethane (120 kg) and was passed through the cartridge with activated carbon. To a solution of alcohol was added N,N-dimethylaminopyridine (1.06 kg, 8,66 mol) and TEA (11,1 kg, 109,63 mol)was then added 4-triftoratsetilatsetonom (18,0 kg, 73,6 mol) in solution in dichloromethane (30 kg) for 20 minutes at a temperature <25°C. the Mixture was then subjected to aging for 3 hours, after which was added water (110 kg), while maintaining the temperature <25°C. the Phases were separated, and the organic phase is washed twice with water (80 kg × 2), then aqueous HCl solution (15 l of concentrated 37 wt.% HCl in water (80 kg)). The organic layer was diluted with dichloromethane (75 kg) and was subjected to distillation under vacuum to 72 L. Then added MTBE (157 kg) and the mixture kept under vacuo is ω up to 170 l for crystallization of the product. The suspension was subjected to aging for 1 hour and then was added heptane (58 kg) for ~20 minutes, and the suspension was subjected to aging at 20°C for 18 hours. Subjected to aging the suspension is then filtered, washed with heptane (20 kg) and MTBE (40 kg), and dried on the filter in a stream of nitrogen in a confluence 24 hours from receipt of the above product (38.3 kg, 98%).1H NMR (CDCl3) to 8.20 (2H, d), a 7.85 (2H, d), 7,33 (5H, m)6,09 (1H, users), to 5.13 (2H, s), 4,59 (1H, m), 4,46 (1H, m), 4,10 (3H, m), 3,91 (1H, m), 2,96 (2H, m)of 2.75 (1H, m), 2,33 (1H, m), 1,58 (1H, m)to 1.48 (9H, s) and 1.35 (2H, m).

Stage 8: Benzyl 4-[({(2S,5R)-5-[(benzyloxy)amino]

piperidine-2-yl}carbonyl)amino]piperidine-1-carboxylate

N-Boc-O-benzylhydroxylamine (8.65 g, of 38.7 mmol, as a solution in a volume of 38 ml DMAC) was added to a solution of trebuchet potassium (4.35 g, of 38.7 mmol) in DMAC (80 ml), while maintaining the temperature between 18°C and 25°C. the Solution was subjected to aging for 30 minutes, after which it was turned into a suspension. Was added to the suspension source sulfonate reagent (20 g, and 29.9 mmol)dissolved in DMAC (40 ml)for 15 minutes at 20°C, and the resulting mixture was heated to 40°C for 3.5 hours and then kept at 20°C during the night. To the mixture was added water (350 ml), while maintaining the temperature <30°C. Then was added DCM (350 ml), and separated phases. The organic phase is washed three times with water (350 ml × 3). Then washed organizations the definition phase was subjected to distillation at atmospheric pressure to a volume of 90 ml, then added methanesulfonyl acid (10 ml)and the solution was heated to 35-40°C for 8 hours. Then the solution was cooled to 20°C and was added 2n NaOH (200 ml), then was added DCM (90 ml). The phases were separated, and the organic phase washed with water (90 ml), and then the solvent was replaced at atmospheric pressure in acetonitrile volume of 50 ml For crystallization of the product was added p-toluensulfonate acid (4 g, 1 equivalent per product) in the form of a solution in acetonitrile (40 ml) at 40°C. Then was added MTBE (45 ml), and cooled suspension of up to 20°C, subjected her to ageing at 20°C for 1 hour, and then filtered to obtain the above product in the form of monotonicity crystalline salt (9,8 g, 53%).1H NMR (CDCl3) of 7.75 (1H, users), to 7.59 (2H, d), of 7.36 (5H, m), 7,20 (3H, m), 7,14 (2H, d), 6,98 (2H, d), and 5.30 (1H, m), 5,10 (2H, m), 4,37 (2H, s), 3,88 (3H, m), 3,61 (2H, m), 3,23 (2H, m), 2,22 (3H, s), of 1.65 (1H, m), 1.26 in (5H, m) to 1.21 (3H, m).

Stage 9: Benzyl 4-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)piperidine-1-carboxylate

Benzyl 4-[({(2S,5R)-5-[(benzyloxy)amino]piperidine-2-yl}carbonyl)amino]piperidine-1-carboxylate in the form tosylate salt (8.1 kg, 12,68 mol) is suspended in dichloromethane (108 kg), after which was added 5 wt.% NaHCO3(42 kg, 25,36 mol)and the resulting biphasic mixture was intensively stirred for 30 minutes. The phases were separated, and the organic the positive phase was washed with water (40.5 kg). Then the organic phase was subjected to distillation at atmospheric pressure to a volume of ~20 l, then added DCM (108 kg). Was then added DIPEA (5.25 kg, 40,58 mol)and the mixture was cooled to 0~5°C. was Added in four portions triphosgene (3,01 kg, 10,14 mol), while maintaining the temperature <10°C. After 30 minutes was added a dilute solution of phosphoric acid (equal to 4.97 kg 85 wt.% phosphoric acid in 32 kg of water), and the mixture was subjected to aging at 20°C during the night. The phases were separated, and the organic phase was washed with 5 wt.% NaHCO3(26 kg) and water (25 kg). The organic phase is then subjected to distillation at atmospheric pressure to a volume of 30 L. Then added ethanol (77 kg) and introduced the seed (10 g) (note: the crystallization can be carried out without the use of seed, but it is preferable to use a seed crystal, as it usually produces a product with more consistent quality and higher output). The suspension was subjected to distillation under vacuum to a volume of 33 l, then was added dropwise heptane (55 kg). Then the suspension was cooled to 0°C, filtered, washed with a mixture of 3:1 heptane:ethanol (30 l), and dried on the filter in a stream of nitrogen to obtain the above product (5,90 kg, 94%).1H NMR (CDCl3) to 7.35 (10h, m), to 6.57 (1H, d), 5,14 (2H, c), 5,07 (1H, d), to 4.92 (1H, d), of 4.13 (2H, m), of 3.95 (1H, m)to 3.89 (1H, d), and 3.31 (1H, c), 2,99 (3H, m), 2,65 (1H, d), of 2.38 (1H, m), of 1.94 (4H, m)of 1.62 (2H, m) and of 1.34 (2H, m).

Stage 10: Tertbutyl 4-({[(2S,5R)-6-g is droxy-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)piperidine-1-carboxylate

Benzyl 4-({[(2R,5S)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo-[3.2.1]Oct-2-yl]carbonyl}amino)piperidine-1-carboxylate source reagent (1.9 kg and 97 wt.%) and Boc2O (0,776 kg) was loaded into a glass flask, and dissolved solids in THF (15 l). The solution is then loaded into the reactor for hydrogenation with Pd(OH)2(184,3 g) and another portion of THF (10,8 l). The reaction was carried out at a partial pressure of H245 psig, 23°C for 5 hours. After completion of the reaction, which was determined using HPLC analysis, the solution was filtered through solka flok to remove the catalyst, and the filter cake washed with THF. Then in the filtrate and the washings were replaced solvent in EtOAc by distillation under vacuum to a volume of 10 l was Used approximately 30 l of EtOAc to replace the solvent, and using1H NMR it was determined that the content of THF after distillation at constant volume (10 l at a maximum temperature of 20°C) was ~4 mol.% THF:EtOAc. The resulting slurry in EtOAc was subjected to aging at room temperature for 1 hour, then added hexane (4 l) for 1 hour at room temperature. The suspension was subjected to aging for 1 hour, after which a concentrations were determined in the supernatant (set: ~6 mg/g). The solid is then filtered and washed with a solution of 60% EtOAc/hexane (3×3 l and was dried under vacuum and in the current of the N 2at room temperature to obtain the above product (80% yield in the allocation of the product).1H NMR (400 MHz, CDCl3): 8,60 (users, 1H), to 6.67 (d, J=8,2 Hz, 1H), 4,12-4,00 (m, 2H), 4,00-3,91 (m, 1H), 3,89 (d, J=7.8 Hz, 1H), 3,81 is 3.76 (m, 1H), 3,19 (dt, J=11,2, 2,9 Hz, 1H), 2,90 (t, J=11,9 Hz, 2H) 2,82 (d, J=11.3 Hz, 1H), 2,45 (DD, J=15,0, 6,7 Hz, 1H), 2.21 are 2,11 (m, 1H), 2,02-of 1.85 (m, 3H), 1,80 was 1.69 (m, 1H), 1,48 (c, 9H), 1,44-of 1.30 (m, 2H)

Stage 11: Sulfate salt tetrabutylammonium

Tertbutyl 4-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo-[3.2.1]Oct-2-yl]carbonyl}amino)piperidine-1-carboxylate (3.0 kg), THF (30 l), 2-picoline (1,61 l) and the complex pyridine-SO3(4,54 kg) was loaded into a flask in nitrogen atmosphere. Exothermic effect was not observed. The heterogeneous mixture was subjected to stirring overnight (~15 hours). Then was added DCM (8 l), and the mixture was concentrated by distillation under vacuum, removing the ~30 l of THF/DCM. Added additional amount of DCM (28 l)was then added water (20 l). The flask was placed in an ice bath and added K2HPO4(2,20 kg) for 4 minutes, then washed with water (1 l). Was then added BU4NHSO4(2.90 kg) for 10 minutes followed by the addition of water (4 liters). A two-phase mixture was stirred for 30 minutes, after which the lower organic layer was transferred into an extractor with a capacity of 100 l passing through the filter. Remaining in the flask and the aqueous layer washed with additional amounts of the om DCM (2×4 l), and then also transferred to the extractor. It was also transferred a small amount of water layer (~2 l)and the two layers were separated. The organic layer was returned to the extractor and washed with water (1×6 l). the pH was 4.5. The organic layer was separated and loaded into a new flask passing through the filter. The mixture was subjected to the procedure for replacing the solvent in 2,2,2-triptoreline by distillation under vacuum (final volume 34 l) and used as is in the next stage. The water content, determined by titration according to Karl Fisher was 1900 h/million

During the experiment on a smaller scale, using the same technique as a result of evaporation were obtained solid substance, which was filmed1H NMR spectra.1H NMR (400 MHz, CDCl3): of 6.65 (d, J=8,4 Hz, 1H), 4,37-4,32 (m, 1H), 4,18-4,00 (m, 2H), 4,00-to 3.89 (m, 1H), a 3.87 (d, J=7.7 Hz, 1H), 3,36-of 3.27 (m, 9H), 2.95 and-and 2.79 (m, 2H), 2,75 (d, J=11,4 Hz, 1H), 2,42 (DD, J=15,0, 6,9 Hz, 1H) 2,24-2,11 (m, 2H), 1,96-of 1.81 (m, 3H), 1,74 is 1.60 (m, 8H), of 1.47 (s, 9H), of 1.46 (m, 8H), of 1.39 (m, 2H), 1,01 (t, J=7,3, 12H)

Step 12: (2S,5R)-7-Oxo-N-piperidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

The salt solution Bu4N+-OSO3in TFE (34 l) used in the same form in which it was received at the previous stage with an estimated yield of 100%. The reaction mixture was cooled in an ice bath, and added HBF4-Et2O (1,57 l) is via the dropping funnel over the course of 11 minutes at a temperature of from 18°C to 22°C. The obtained white suspension was subjected to stirring overnight (12 hours). Deleted TFE (~15 l) by distillation under vacuum. Then was added DCM (15 l). In the extractor with a capacity of 100 l was downloaded pyrogen-free water (35 l) and NaHCO3(274 g), and the solution was cooled to 13°C. In the extractor with vacuum endured the reaction mixture with a temperature of 11-13°C. the Reaction flask was washed with additional DCM (5 l), and the suspension is also transferred to the extractor. The reaction mixture was heated to 18.5°C and added pyrogen-free water (12 l) to dissolve all solids. The final pH value was 4.5. The organic layer was separated, and the aqueous layer washed with DCM (2×16 l). Analysis of the aqueous layer showed the presence of 2.38 kg (83.8 percent).

The aqueous layer was loaded into a clean flask. The solution was concentrated by distillation under vacuum and then by azeotropic distillation with IPA. At this point,1H NMR analysis of the relationship IPA:H2O indicated the presence of 13.4 liters of water and 24.6 l IPA. Added IPA (22 l). White white crystalline substance was filtered off, washed with a mixture of 7:1 IPA:pyrogen-free water (16 l) and dried under vacuum in a stream of nitrogen at room temperature to obtain the above product in the form of a crystalline channel hydrate, 1.5 wt.% water. (Output = 1,715 kg, 57.4% of the total in stages 11 and 12.)1H NMR (400 MHz, DMSO-d6): 8,3 (OSiR.the, 2H), 8,21 (d, J=7.8 Hz, 1H), 4,01 (s, 1H), 3,97-of 3.85 (m, 1H, in), 3.75 (d, J=6,5 Hz, 1H) 3,28 (DD, J=12,9, 2.5 Hz, 2H) 3,05-of 2.93 (m, 4H), 2,08-of 1.97 (m, 1H), 1,95-to 1.79 (m, 3H), 1,75-to 1.59 (m, 4H).

EXAMPLE 1D

Crystalline monohydrate of (2S,5R)-7-oxo-N-piperidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Section A: Getting

Amorphous (2S,5R)-7-oxo-N-piperidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1 g) and deionized water (5 ml) was added in a glass flask, and the resulting suspension was stirred at room temperature until until the powder x-ray (see part B) did not specify that completely changed into another form. Then the crystalline substance was collected by gravity filtration and dried at room temperature.

Alternatively, the crystalline slurry may be selected by evaporative removal, which, due to the fact that the crystalline hydrate is soluble in water (about 55 g/ml at room temperature)may lead to higher output.

Drying can cause dehydration of the crystals, and, therefore, should not be used conventional methods of drying using vacuum and/or high temperatures. By controlling the relative humidity of the environment, which is drying, you can minimize or avoid dehydration. For example, to exclude Digi is ratatsii, the crystals may be subjected to drying using a current of nitrogen for controlling the moisture content (for example, in the range of values of relative humidity from about 40% to 70%).

Crystalline hydrate may also be obtained by suspension in a mixture of isopropyl alcohol and water and the use of any of the above-mentioned separation methods. A suitable ratio of isopropyl alcohol to water is about 7:1 by volume).

Section b: characterization

Powder x-ray crystalline monohydrate obtained in accordance with the method described in section A, was shot on the powder x-ray diffractometer Philips Panalytical X'pert Pro with remote P W3040/60 continuous scanning from 4 to 40 degrees 2Θ. Source used copper K radiation-alpha 1 (Kaα1) and K-alpha 2 (Kα2). The experiment was carried out with the sample at room temperature and in contact with the environment. Powder x-ray is shown in figure 1. Powder x-ray include the following 2Θ values and the corresponding d-constant:

Table 1
Powder x-ray crystalline monohydrate
Peak No.2 Theta
16,513,5
2the 5.715,5
35,6the 15.6
45,117,4
5the 4.718,7
64,519,7
74,420,4
84,121,7
9the 3.822,6
103,724,0
113,624,3
123,425,9
133,326,3
143,3 26,6
153,227,0
163,227,5
173,029,3
182,930,0
192,831,3
202,732,4
212,732,9
222,633,1
232,634,0
242,534,7
252,535,5
262,338,9

Crystalline monohydrate obtained in accordance with the method described in section A, was investigated using differential scanning calorie is and TA Instruments DSC Q 1000 (DSC) at a heating rate of 10°C/min from 25°C to 350°C in an open aluminum crucible in a nitrogen atmosphere. DSC curve (see figure 2) was characterized by an endotherm due to water loss in the beginning of the emergence of endotherm at a temperature of 22.5°C and an enthalpy change equal to 186 Joule/gram. Decomposition was observed at temperatures above 270°C.

Thermogravimetric analysis (TGA) of the crystalline monohydrate obtained in accordance with the method described in section A, was carried out on the device TA Instruments TGA Q 500 in nitrogen atmosphere at heating rate 10°C/min from 25°C to 300°C. Thermogravimetric analysis showed a weight loss of 4.9 wt.% up to 100°C with subsequent decomposition above 270°C. the weight Loss of 4.9 wt.% corresponds to the loss of 1 mol of water per mol of compound that corresponds to the monohydrate.

EXAMPLE 2

(2S,5R)-N-[(4S)-Azepin-4-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1: Tertbutyl (4S)-4-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)azepin-1-carboxylate

To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (51,7 mg, 0,187 mmol) in dry dichloromethane (2 ml) was sequentially added a solution tertbutyl (4S)-4-aminoethan-1-carboxylate (69 mg, 0,275 mmol), triethylamine (0,090 ml, 0,646 mmol), HOBT (42,5 mg, 0,278 mmol), and EDC (54,7 mg, 0,285 mmol) at room temperature in a nitrogen atmosphere. The reaction mixture is PE is amasyali at room temperature over night. Concentrated the reaction mixture under vacuum, and the residue was purified using HPLC on a column (30×100 mm Waters Sunfire, was suirable using a mixture of 15% to 100% CH3CN+0,05% TFA/water + 0.05% of TFA for 15 minutes to obtain after drying these compounds are in the form of a white solid.

Stage 2: Tertbutyl (4S)-4-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)azepin-1-carboxylate

Palladium on coal (11.8 mg; 10% Pd/C) was added to a solution of tertbutyl (4S)-4-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)azepin-1-carboxylate (49,7 mg, 0.33 mmol) in methanol (1.5 ml)and the resulting mixture was stirred in hydrogen atmosphere (balloon) for 3 hours. Analysis by TLC showed that the reaction proceeded completely. The reaction mixture was filtered through a microfilter, and the filtrate was concentrated under vacuum obtaining contaminated with impurities named compound as a white foam (44,8 mg)which was used without purification in the next stage.

Stage 3: N,N,N-Tributylin-1 Amini{[((2S,5R)-2-{[(4S)-azepin-4-ylamino]carbonyl}-7-oxo-1,6-diazabicyclo[3.2.1]Oct-6-yl)oxy]sulfonyl}oxidant

To a solution contaminated with impurities tertbutyl (4S)-4-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)azepin-1-carboxylate (40,2 mg, 0,105 mmol) in pyridine (1 ml) was added to the complex of sulfur trioxide with pyrid the nom (42,1 mg, 0,265 mmol). The mixture was stirred at room temperature under nitrogen atmosphere overnight. Analysis by LC/MS showed that the reaction was not complete. Added additional amount of pyridine, and then an additional amount of a complex of sulfur trioxide with pyridine (40 mg). The resulting mixture was stirred at room temperature for five hours. The reaction mixture was filtered and the solid washed with dichloromethane. The filtrate was concentrated under vacuum and suspended in a saturated aqueous solution of potassium dihydrophosphate. The resulting mixture was extracted with ethyl acetate. The aqueous layer was collected and added tetrabutylammonium hydrosulfate (0.036 mg, 0,105 mmol). The mixture was stirred for 10 minutes, then was extracted with EtOAc (4X). The organic layers were combined, dried over sodium sulfate, and concentrated under vacuum to obtain these compounds in the form of a colorless oil.

Stage 4: (2S,5R)-N-[(4S)-Azepin-4-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of N,N,N-tributylin-1 Amini{[((2S,5R)-2-{[(4S)-azepin-4-ylamino]carbonyl}-7-oxo-1,6-diazabicyclo-[3.2.1]Oct-6-yl)oxy]sulfonyl}occitanica (30.9 mg, 0,067 mmol) in anhydrous dichloromethane (7 ml) at 0°C under nitrogen atmosphere was added dropwise triperoxonane acid (0.5 ml, 6.5 mmol). The reaction mixture was stirred for d is Oh hours then concentrated under vacuum. To the residue was added ether and the resulting white precipitate was collected by centrifugation. The residue was purified via HPLC on a column of Phenomenex Synergy Polar-RP 80A and liofilizirovanny with obtaining these compounds are in the form of a white solid. LC-MS (negative ionization) m/e 361 (M-H); LC-MS (positive ionization) m/e 385 (M+Na);1H NMR (600 MHz, D2O; without attribution) (δ, ppm) to 4.17 (1H, userd, J=3 Hz), 3.96 points-a 4.03 (2H, m), 3.27 to to 3.38 (3H, m), 3,15-up 3.22 (2H, m), to 3.02 (1H, d, J=12 Hz), 1,62-to 2.18 (m, 12H).

EXAMPLE 3

(2S,5R)-N-[(4R)-Azepin-4-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

A named connection can be obtained by substituting in the procedure of synthesis example 2 tertbutyl (4R)-4-aminoethan-1-carboxylate to tertbutyl (4S)-4-aminoethan-1-carboxylate.

EXAMPLE 4

(2S,5R)-7-Oxo-N-[(3R)pyrrolidin-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide

Stage 1: Tertbutyl (3R)-3-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)pyrrolidin-1-carboxylate

To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (53 mg, 0,192 mmol) in dry dichloromethane (2 ml) was added sequentially a solution of tertbutyl (3R)-3-aminopyrrolidine-1-carboxylate (5 mg, in 0.288 mmol), triethylamine (0,061 ml, 0,441 mmol), HOBT (to 44.1 mg, in 0.288 mmol), and EDC (55,2 mg, in 0.288 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for six hours. The reaction mixture was concentrated under vacuum, and the residue was purified using HPLC on a column (30×100 mm Waters Sunfire, elwira using a mixture of 15% to 100% CH3CN + 0,05% TFA/water + 0.05% of TFA for 15 minutes obtaining these compounds.

Stage 2: Tertbutyl (3R)-3-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)pyrrolidin-1-carboxylate

Palladium on coal (9,18 mg; 10% Pd/C) was added to a solution of tertbutyl (3R)-3-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)pyrrolidin-1-carboxylate (38 mg, of 0.085 mmol) in methanol (2 ml)and the resulting mixture was stirred in hydrogen atmosphere (balloon) for 3 hours. Analysis by TLC showed that the reaction proceeded completely. The reaction mixture was filtered through a microfilter, and the filtrate was concentrated under vacuum obtaining contaminated with impurities named connection in the form of oil.

Stage 3: N,N-Demotivated-1 amine({[(2S,5R)-2-({[(3R)-1-(tertbutoxycarbonyl)pyrrolidin-3-yl]amino}carbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]Oct-6-yl]oxy}sulfonyl)oxidase

To a solution of tertbutyl (3R)-3-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)PI is Raiden-1-carboxylate (30 mg, of 0.085 mmol) in pyridine (1 ml) was added to the complex of sulfur trioxide with pyridine (53,9 mg, 0,339 mmol) and 4A Molekulyarnye sieves. The mixture was stirred at room temperature under nitrogen atmosphere overnight. Analysis by LC/MS showed that the reaction was incomplete. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was subjected to chromatography on HPLC to extract unreacted source reagent, which was re-subjected to the interaction with the reaction conditions. The combined product is suspended in a saturated aqueous solution of potassium dihydrophosphate. The resulting mixture was washed with ethyl acetate. The aqueous layer was collected and added tetrabutylammonium hydrosulfate. The mixture was stirred for 10 minutes, then was extracted with EtOAc (4X). The organic layers were combined, dried over sodium sulfate, and concentrated under vacuum to obtain these compounds in the form of a colorless oil.

Stage 4: (2S,5R)-7-Oxo-n-[(3R)pyrrolidin-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of N,N-demotivated-1 amine({[(2S,5R)-2-({[(3R)-1-(tertbutoxycarbonyl)pyrrolidin-3-yl]amino}carbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]Oct-6-yl]oxy}sulfonyl)occitanica (2 mg, 0.046 mmol) in anhydrous dichloromethane (0.5 ml) at 0°C under nitrogen atmosphere was added dropwise triperoxonane acid (0,525 ml 0,046 the mole). The reaction mixture was stirred for two hours, then concentrated under vacuum. To the residue was added ether and the resulting white precipitate was collected by centrifugation. Was purified with HPLC on a column of Phenomenex Synergy Polar-RP 80A and liofilizirovanny with obtaining these compounds are in the form of a white solid. LC-MS (negative ionization) m/e 333 (M-H); LC-MS (positive ionization) m/e 336 (M+H);1H NMR (600 MHz, D2O; without attribution) (δ, ppm) 4,50-of 4.54 (1H, m), 4,20 (1H, DD, J=3.6 Hz), a 4.03 (1H, userd, J=7 Hz), of 3.54 (1H, DD, J=7,13 Hz), 3,40-of 3.48 (1H, m), 3,30-to 3.35 (2H, m), 3,24 (1H, DD, J=5,13 Hz)} of 3.07 (1H, d, J=12 Hz), 2,31-2,37 (1H, m), 2,15-of 2.20 (1H, m), 2.00 in of 2.10 (2H, m), 1,88-to 1.98 (1H, m), 1,76-of 1.84 (1H, m).

EXAMPLE 5

(2S,5R)-N-Asokan-5-yl-7-oxo-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide

A named connection can be obtained by substituting in the procedure of synthesis example 1 tertbutyl 5-aminoethan-1-carboxylate for 4-amino-1-BOC-piperidine.

EXAMPLE 6

(2S,5R)-7-Oxo-N-pyridin-4-yl-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide

Stage 1: (2S,5R)-6-(Benzyloxy)-7-oxo-N-pyridin-4-yl-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (51,5 mg, 0,186 mmol) in dry dichloromethane (5 ml) after avatele was added triethylamine (0,065 ml, 0,466 mmol), iodide 2-chloro-1-methylpyridine (and 63.4 mg, 0,248 mmol)and 4-aminopyridine (19.2 mg, 0,204 mmol) at room temperature under nitrogen atmosphere. The reaction mixture then was heated to 50°C for 1.5 hours. Analysis by LC/MS showed that the reaction proceeded completely. The reaction mixture was concentrated and purified using HPLC on a column (30×100 mm Waters Sunfire with obtaining after lyophilization of the named compound as an orange solid.

Stage 2: (2S,5R)-6-Hydroxy-7-oxo-N-pyridin-4-yl-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Palladium on coal (13.2 mg; 10% Pd/C) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-N-pyridin-4-yl-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide (52,7 mg, 0.15 mmol; joint product of two experiments) in methanol (1.5 ml)and the resulting mixture was stirred in hydrogen atmosphere (balloon) for 5 hours. Analysis by TLC and HPLC showed the presence of a small amount of unreacted source reagent. Added an additional amount of catalyst (5.6 mg), and the resulting mixture was stirred in hydrogen atmosphere (balloon) for 1 hour. The reaction mixture was filtered through a microfilter, and the filtrate was concentrated under vacuum to obtain these compounds in the form of a colorless oil.

Stage 3: (2S,5R)-7-Oxo-N-pyridin-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

K R is the target (2S,5R)-6-hydroxy-7-oxo-N-pyridin-4-yl-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (9,2 mg, 0.035 mmol) in dry pyridine (0.5 ml) was added to the dried 4A molecular sieves and a complex of sulfur trioxide with pyridine (22 mg, was 0.138 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred for four hours. The reaction mixture was filtered, and the solid is washed with dichloromethane, acetonitrile, and methanol. The filtrate was concentrated under vacuum, and the residue triturated with ethyl acetate. The residue was dried under vacuum, was dissolved in a saturated aqueous solution of sodium dihydrophosphate and purified using the HPLC column Phenomenex Synergi Polar-RP 80A obtaining after lyophilization these compounds are in the form of a white solid. LC-MS (negative ionization) m/e 341 (M-H); LC-MS (positive ionization) m/e 343 (M+H);1H NMR (600 MHz, D2O; netnanny) (δ, ppm) to 8.57 (2H, users), 8,15 (2H, users), 4,27 (1H, userd, J=7 Hz), 4,20 (1H, users), to 3.33 (1H, d, J=12 Hz), 3,10 (1H, d, J=12 Hz), 2,28 of-2.32 (1H, m), 2,08-2,11 (1H, m), 1.93 and-to 1.98 (1H, m), 1,83-of 1.88 (1H, m,).

EXAMPLE 7

(2S,5R)-N-(2-Methoxypyridine-4-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1: (2S,5R)-6-(Benzyloxy)-N-(2-methoxypyridine-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (38,9 mg, 0,141 mmol) in dry dichloromethane (2 ml) successively to allali the triethylamine (0,049 ml, 0,352 mmol), iodide 2-chloro-1-methylpyridine (53,3 mg, 0,209 mmol)and 2-methoxy-4-aminopyridine (20.2 mg, 0,163 mmol) at room temperature under nitrogen atmosphere. The reaction mixture then was heated to 50°C for 1.5 hours. Analysis by LC/MS showed that the reaction proceeded completely. The reaction mixture was concentrated and purified using HPLC on a column (30×100 mm Waters Sunfire with obtaining after lyophilization of the named compound as an orange solid.

Stage 2: (2S,5R)-6-Hydroxy-N-(2-methoxypyridine-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Palladium on coal (13,4 mg; 10% Pd/C) was added to a solution of (2S,5R)-6-(benzyloxy)-N-(2-methoxypyridine-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (43,6 mg, 0,114 mmol) in methanol (1 ml)and the resulting mixture was stirred in hydrogen atmosphere (balloon) overnight. Analysis by HPLC showed that the reaction proceeded completely. The reaction mixture was filtered through a microfilter, and the filtrate was concentrated under vacuum to obtain these compounds in the form of contaminated impurities colorless oil.

Stage 3: (2S,5R)-N-(2-Methoxypyridine-4-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of (2S,5R)-6-hydroxy-N-(2-methoxypyridine-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (33 mg, 0,114 mmol) in dry pyridine (1 ml) was added to the complex of sulfur trioxide with pyridi the Ohm (111 mg, 0,696 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred for four hours. The reaction mixture was filtered, and the solid is washed with dichloromethane, acetonitrile, and methanol. The filtrate was concentrated under vacuum, and the residue triturated with ethyl acetate, then dried under vacuum, was dissolved in a saturated solution of sodium dihydrophosphate and purified using the HPLC column Phenomenex Synergi Polar-RP 80A with obtaining materials of solid, which was further purified by column Waters Sunfire with obtaining a white solid, which was further purified using HPLC on a column of Phenomenex Synergi Polar-RP 80A obtaining after lyophilization these compounds are in the form of a white solid. LC-MS (negative ionization) m/e 371 (M-H); LC-MS (positive ionization) m/e 373 (M+H);1H NMR (600 MHz, D2O; without attribution) (δ, ppm) 8,10 (1H, userd, J=6 Hz), to 7.59 (1H, s), 7,41 (1H, d, J=6 Hz), 4.26 deaths (1H, userd, J=7 Hz), 4,23 (1H, users), 4,07 (3H, s)to 3.36 (1H, d, J=12 Hz), 3,12 (1H, d, J=12 Hz), 2,29 is 2.33 (1H, m), 2,10-and 2.14 (1H, m), 1.93 and of 1.99 (1H, m), 1,84-1,90 (1H, m).

EXAMPLE 8

(2S,5R)-N-[2-(Dimethylamino)pyridine-4-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1: (2S,5R)-6-(Benzyloxy)-N-[2-(dimethylamino)pyridine-4-yl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of (2S,5R)-6-(phenylmethoxy)-7-the CSR-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (37,3 mg, is 0.135 mmol) in dry dichloromethane (2.5 ml) was sequentially added triethylamine (0,047 ml, 0,338 mmol), iodide 2-chloro-1-methylpyridine (to 38.3 mg, 0.15 mmol)and 2-dimethylamino-4-aminopyridine (21,7 mg, 0,158 mmol) at room temperature under nitrogen atmosphere. The reaction mixture then was heated to 50°C for 1.5 hours. Analysis by LC/MS showed that the reaction proceeded completely. The reaction mixture was concentrated and purified using HPLC on a column (30×100 mm Waters Sunfire with obtaining after lyophilization these compounds are in the form of a cream solid.

Stage 2: (2S,5R)-N-[2-(Dimethylamino)pyridine-4-yl]-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Palladium on coal (10,4 mg; 10% Pd/C) was added to a solution of (2S,5R)-6-(benzyloxy)-N-[2-(dimethylamino)pyridine-4-yl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (of 47.8 mg, 0,121 mmol) in methanol (2 ml)and the resulting mixture was stirred in hydrogen atmosphere (balloon) overnight. Analysis by HPLC showed that the reaction proceeded completely. The reaction mixture was filtered through a microfilter, and the filtrate was concentrated under vacuum to obtain these compounds in the form of a colorless oil, which was used in the next stage without additional purification.

Stage 3: (2S,5R)-N-[2-(Dimethylamino)pyridine-4-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of (2S,5R)-N-[2-(di is ethylamino)pyridine-4-yl]-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (37 mg, 0,121 mmol) in dry pyridine (1.5 ml) was added to the complex of sulfur trioxide with pyridine (92 mg, 0,578 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred for seven hours. Analysis of an aliquot by NMR showed that the reaction was incomplete. Added additional amount of pyridine (2 ml) and a complex of sulfur trioxide with pyridine (60 mg), and the resulting mixture was stirred at room temperature under nitrogen atmosphere. The reaction mixture was concentrated under vacuum, and the residue was purified using HPLC on a column of Phenomenex Synergi Polar-RP 80A with getting contaminated by the impurities of the product, which was further purified by column Waters Sunfire with obtaining after lyophilization these compounds are in the form of a white solid. LC-MS (negative ionization) m/e 384 (M-H); LC-MS (positive ionization) m/e 386 (M+H);1H NMR (600 MHz, D2O; unreferenced) (δ, ppm) to 7.77 (1H, userd, J=6 Hz), 7,41 (1H, s)6,94 (1H, d, J=6 Hz), to 4.23 (2H, users), to 3.36 (1H, d, J=12 Hz), 3,18 (6H, s), 3,11 (1H, d, J=12 Hz), 2,29 of-2.32 (1H, m), 2,10-and 2.14 (1H, m), 1.93 and-1,99 (1H, m), 1,84-1,90 (1H, m).

EXAMPLE 9

(2S,5R)-N-[4-(Aminomethyl)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1: Tertbutyl [4-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)benzyl]carbamate

To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diaza the cyclo[3.2.1]octane-2-carboxylic acid (29,9 mg, to 0.108 mmol) in dry dichloromethane (3 ml) was sequentially added triethylamine (0,038 ml, 0,271 mmol), iodide 2-chloro-1-methylpyridine (41.0 mg, 0,160 mmol)and 4-(N-BOC-aminomethyl)aniline (30,6 mg, was 0.138 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was then heated to 60°C for 2 hours. Analysis by LC/MS showed no unreacted starting material. The reaction mixture was concentrated and purified using the HPLC column Waters Sunfire with obtaining these compounds.

Stage 2: Tertbutyl [4-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl)carbonyl}amino)benzyl] carbamate

Palladium on coal (7.8 mg; 10% Pd/C) was added to a solution of product from step 1 (35 mg, 0,073 mmol) in methanol (2 ml)and the resulting mixture was stirred in hydrogen atmosphere (balloon) overnight. Analysis using LC-MS showed that the reaction proceeded completely. The reaction mixture was filtered through a microfilter, and the filtrate was concentrated under vacuum, which was distilled from azeotrope with toluene, to obtain the titled compound as a white solid.

Stage 3: Tertbutyl [4-({[(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)benzyl]carbamate

To a solution of product from step 2 (of 28.9 mg, 0,074 mmol) in dry pyridine (1 ml) was added to the complex of sulfur trioxide with pyridine (60,3 mg, 0,379 mmol) at room temperature is round in nitrogen atmosphere. The mixture was stirred at room temperature overnight. Analysis using LC-MS showed that the reaction was about 50%. In the reaction mixture was added an additional amount of a complex of sulfur trioxide with pyridine (64.4 mg) and continued stirring at room temperature. After 7 hours the analysis using LC-MS showed that the reaction mixture is predominantly the product. The reaction mixture was filtered, and the insoluble solid was well washed with dichloromethane. The filtrate was concentrated under vacuum, and the residue was subjected to distillation in the form of an azeotrope with toluene to remove excess pyridine. Thus obtained crude titled compound was used without further purification in the next reaction.

Stage 4: (2S,5R)-N-[4-(aminomethyl)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a mixture of the product from step 3 (34.8 mg, 0,074 mmol) in dry dichloromethane (3 ml) at 0°C under nitrogen atmosphere was added triperoxonane acid (1.0 ml, 13 mol). Adding triperoxonane acid all solid instantly dissolved, the solution was stirred for 1.5 hours, the resulting analysis using LC-MS showed that the reaction proceeded completely. The reaction mixture was concentrated under vacuum, and the residue triturated with ether to remove excess triperoxonane KIS is the notes and organic impurities. The obtained sticky solid was dried under vacuum and kept in the freezer over night. The crude product was purified using HPLC on a column of Phenomenex Synergi Polar-RP 80A obtaining after lyophilization contaminated by the impurities of the named compound as a white solid. The solid is triturated with acetonitrile (3X) to give the pure titled compound as a white solid. LC-MS (negative ionization) m/e 369 (M-H); LC-MS (positive ionization) m/e 354 (M+H-NH3);1H NMR (600 MHz, D2O; without attribution) (δ, ppm) 7,53 (2H, d, J=8.5 Hz), 7,46 (2H, d, J=8.5 Hz), to 4.23 (2H, users), 4,11 (2H, s), 3,39 (1H, d, J=12 Hz), 3,18 (1H, d, J=12 Hz), 2,27-2,31 (1H, m), 2,09 with 2.14 (1H, m), 1,90-2,00 (1H, m), 1,813-1,89 (1H, m).

EXAMPLE 10

(2S,5R)-7-oxo-2-[(piperidine-4-ylamino)carbonyl]-1,6-diazabicyclo[3.2.1 ]octane-6-sulfonic acid

Stage 1: Tertbutyl 4-[({(2S,5R)-7-oxo-6-[(phenoxycarbonyl)oxy]-1,6-diazabicyclo[3.2.1]Oct-2-yl}carbonyl)amino]piperidine-1-carboxylate

The solution finishontasklaunch (1.25 EQ.) in dichloromethane was added to a solution of pyridine (1.25 equiv.) 4-dimethylaminopyridine (0.1 EQ.) and tertbutyl 4-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)

piperidine-1-carboxylate (see example 1, step 2) in dichloromethane. The resulting mixture was stirred at room temperature is in the night, then cooled in an ice bath, and the reaction was stopped by adding water. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by chromatography on silica gel with obtaining these compounds.

Stage 2: Tertbutyl 4-({[(2S,5R)-7-oxo-1,6-diazabicyclo-[3.2.1]Oct-2-yl]carbonyl}amino)piperidine-1-carboxylate

AIBN (0.1 EQ.) was added to a solution of tertbutyl 4-[({(2S,5R)-7-oxo-6-[(phenoxycarbonyl)oxy]-1,6-diazabicyclo[3.2.1]Oct-2-yl}carbonyl)amino]piperidine-1-carboxylate in dry benzene and the resulting mixture was heated to boiling under reflux. Solution was added to anti-hydride (1.25 EQ.) in benzene for one hour, and the resulting mixture was boiled under reflux for a further 3 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by chromatography on silica gel with obtaining these compounds.

Stage 3: (2S,5R)-2-({[1-(Tertbutoxycarbonyl)piperidine-4-yl]amino}carbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-sulfonic acid

The product of stage 2 were subjected to sulfate crystallization in accordance with the method of stage 3 of example 1 to obtain these compounds.

Stage 4: (2S,5R)-7-oxo-2-[(piperidine-4-ylamino)carbonyl]-1,6-disabi is yclo[3.2.1]octane-6-sulfonic acid

Filmed protection (2S,5R)-2-({[1-(tertbutoxycarbonyl)piperidine-4-yl]amino}carbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane-6-sulfonic acid in accordance with the method of stage 4 of example 1 to obtain these compounds.

EXAMPLE 11

(4R,6S)-2-Oxo-N-piperidine-4-yl-3-(sulfoxy)-1,3-diazabicyclo[2.2.1]heptane-6-carboxamide

A named connection can be obtained by substituting in the procedure of example 1 (4R,6S)-3-(benzyloxy)-2-oxo-1,3-diazabicyclo[2.2.1]-heptane-6-carboxylic acid (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid.

EXAMPLE 12

(4R,6S)-2-Oxo-N-[(4S)-azepin-4-yl]-3-(sulfoxy)-1,3-diazabicyclo[2.2.1 ]heptane-6-carboxamide

A named connection can be obtained by substituting in the procedure of example 2 (4R,6S)-3-(benzyloxy)-2-oxo-1,3-diazabicyclo-[2.2.1]heptane-6-carboxylic acid (2S,5R)-6-(phenylmethoxy)- 7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid.

EXAMPLE 13

(4R,6S)-2-Oxo-N-pyridin-4-yl-3-(sulfoxy)-1,3-diazabicyclo[2.2.1]heptane-6-carboxamide

A named connection can be obtained by substituting in the procedure of example 6 (4R,6S)-3-(benzyloxy)-2-oxo-1,3-diazabicyclo-[2.2.1]heptane-6-carboxylic acid for (S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid.

EXAMPLE 14

(2S,5R)-7-Oxo-N-[(3S)pyrrolidin-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1: Tertbutyl (3S)-3-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)pyrrolidin-1-carboxylate

To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (1 g, 3.62 mmol) in dry dichloromethane (30 ml) was sequentially added dimethylaminopyridine (884 mg, from 7.24 mmol), EDC (1,388 g of 7.24 mmol), and tributyl (3S)-3-aminopyrrolidine-1-carboxylate (742 mg, 3,98 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for weeks. The reaction mixture was then concentrated under vacuum, and the residue was purified using HPLC on a column (30 × 100 mm Waters Sunfire, was suirable using a mixture of 15% to 100% CH3CN + 0,05% TFA/water + 0.05% of TFA for 15 minutes obtaining these compounds are in the form of a white solid.

Stage 2: Tertbutyl (3S)-3-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)pyrrolidin-1-carboxylate

Palladium on coal (335 mg; 10% Pd/C) was added to a solution of product from step 1 (1.4 g, a 3.15 mmol) in methanol (30 ml)and the resulting mixture was stirred in hydrogen atmosphere (balloon) for 1 hour. Analysis using LC-MS showed that the reaction was completely the firm. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain these compounds in the form of oil, which was used without purification in the next stage.

Stage 3: Tertbutyl 3-({[(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)pyrrolidin-1-carboxylate

To a solution of product from step 2 (1,11 g and 3.15 mmol, theoretical yield stage 2) in pyridine (10 ml) was added to the complex of sulfur trioxide with pyridine (of 2.51 g of 15.75 mmol). The mixture was stirred at room temperature under nitrogen atmosphere overnight. Added dichloromethane, and the mixture was filtered. The collected solid was washed with dichloromethane (4X), and the combined filtrates were concentrated under vacuum. The residue was used without purification in the next stage.

Stage 4: (2S,5R)-7-oxo-N-[(3S)pyrrolidin-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of product from step 3 (1,37 g and 3.15 mmol, theoretical yield stage 3) in anhydrous dichloromethane (5 ml) at 0°C under nitrogen atmosphere was added dropwise TFA (2 ml, 26 mmol). The reaction mixture was stirred for two hours, then concentrated under vacuum. To the residue was added ether and the resulting white precipitate was collected by centrifugation (rubbing with ether was repeated two more times). The obtained solid was purified via HPLC on a column of Phenomene Synergy Polar-RP 80A, was suirable a mixture of methanol/water and liofilizirovanny with obtaining these compounds are in the form of a white solid. LC-MS (negative ionization) m/e 333 (M-H). LC-MS (positive ionization) m/e 335 (M+H), 357 (M+Na);1H NMR (600 MHz, D2O; without attribution) (δ, ppm) 4,51 (1H, m), 4,16 (1H, userd, J=2,6 Hz), 3,99 (1H, d, J=7 Hz), of 3.54 (1H, DD, J=7,13 Hz), 3,40-3,50 (1H, m), 3,30 is 3.40 (1H, m), 3,20-3,30 (2H, m), to 3.02 (1H, d, J=12 Hz), 2,30-to 2.40 (1H, m), 2,10-of 2.20 (1H, m), 2.00 in of 2.10 (2H, m), 1,83-of 1.93 (1H, m), 1,72 and 1.80 (1H, m).

EXAMPLE 15

(2S,5R)-N-[(3R,4S)-3-Foreperiod-4-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1: Tertbutyl-(3R,4S)-4-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)-3-foreperiod-1-carboxylate

To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (2,108 g, 7,63 mmol) in anhydrous dimethylformamide (15 ml) was added BOP (of 4.05 g, to 9.15 mmol)and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 5 minutes. Then add diisopropylethylamine (2.66 ml, 15,26 mmol), and then the solution tertbutyl (3R,4S)-4-amino-3-foreperiod-1-carboxylate (1,665 g, 7,63 mmol) in 20 ml of dichloromethane. The resulting solution was stirred at room temperature under nitrogen atmosphere for 2 hours, then concentrated under vacuum, and the residue was distributed between those who acetate and water. The aqueous layer was washed twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified using flash chromatography on silica gel (installation Isco Combiflash 120 g of silica gel, 80 ml/min, 254 nm, from 0% to 100% EtOAc/hexane for 6 column volumes, then 100% EtOAc to 9 volumes of the column; a named connection was suirable using 100% EtOAc). Collected fractions containing the pure titled compound, and concentrated under vacuum to obtain a brown solid. The fractions containing contaminated by impurities, the product was collected and re-subjected to purification using HPLC (column 30×100 mm Sunfire, 5 micron; 35 ml/min, from 10% to 100% CH3CN + 0,1% TFA/water + 0.1% of TFA for 15 minutes; the named compound was suirable at 70% CH3CN + 0.1% OF TFA). The fractions containing pure product were combined and concentrated under vacuum. The resulting aqueous residue was then extracted with ethyl acetate. The organic layer was collected and dried over magnesium sulfate. Concentration under vacuum gave a white solid, which was combined with material that has been isolated using chromatography on silica gel, to obtain the titled compound.

Stage 2: Tertbutyl-(3R,4S)-4-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)-3-foreperiod-1-carboxylate

To a solution cont the KTA with stage 1 (3,0175 g, 6,33 mmol) in methanol (80 ml) and ethyl acetate (20 ml) was added 10% palladium on coal (0.73 g, 6,86 mmol)and the reaction mixture was stirred in hydrogen atmosphere (balloon) overnight. Analysis by LC/MS showed that the reaction proceeded completely. The reaction mixture was filtered through a microfilter, and the collected solid was well washed with methanol. The filtrate was concentrated under vacuum and subjected to distillation in the form of an azeotrope with toluene to obtain these compounds in the form of a yellow foam which was used directly in the next stage without purification.

Stage 3: Tertbutyl (3R,4S)-4-({[(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)-3-foreperiod-1-carboxylate

To a solution of product from step 2 (2,59 g, 6.7 mmol, theoretical yield stage 2) in pyridine (30 ml) was added to the complex of sulfur trioxide with pyridine (of 5.40 g, 34 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 3 hours, then was added an additional amount of a complex of sulfur trioxide with pyridine (of 5.40 g, 34 mmol)and the reaction mixture was stirred at room temperature overnight. Then added dichloromethane, and the mixture was filtered. The collected solid was thoroughly washed with dichloromethane, and the combined filtrates were concentrated under vacuum to obtain the crude named joint is. The residue was used without purification in the next stage.

Stage 4: (2S,5R)-N-[(3R,4S)-3-foreperiod-4-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of product from step 3 (3.13 g, 6.7 mmol, theoretical yield stage 3) in anhydrous dichloromethane (50 ml) at 0°C under nitrogen atmosphere was added dropwise triperoxonane acid (10 ml, 130 mmol). The reaction mixture was heated to room temperature, then was stirred for two hours. Added additional amount triperoxonane acid (6 ml, 78 mol)and the reaction mixture was stirred at room temperature for 3 hours, then concentrated under vacuum. To the residue was added ether and the resulting white precipitate was collected by centrifugation (rubbing with ether was repeated two more times). The obtained solid was purified via HPLC on a column of Phenomenex Synergy Polar-RP 80A, suirable a mixture of methanol/water and liofilizirovanny with obtaining these compounds are in the form of a cream solid, which according to NMR data contained ~6% of pyridine. This contaminated by impurities, the product was ground and was twice dispersively using ultrasound with acetonitrile (solid material was isolated by centrifugation) to give the titled compound as a white solid. LC-MS (negative ionization) m/e 365 (M-H).

The USE of the 16

(2S,5R)-7-Oxo-6-(sulfoxy)-N-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1: Tertbutyl-6-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (53.3 per mg, the rate of 0.193 mmol) in dry dichloromethane (2 ml) was sequentially added triethylamine (0,067 ml, 0,482 mmol), iodide 2-chloro-1-methylpyridine (58,7 mg, 0,230 mmol)and 6-amino-2-N-BOC-1,2,3,4-tetrahydroisoquinoline (54,8 mg, 0,221 mmol) at room temperature under nitrogen atmosphere. The reaction mixture then was heated to 50°C for 45 minutes, then the reaction product was concentrated under vacuum. Attempts to dissolve the reaction product additionally separated by (2:1:1 CH3CN/DMSO/water), HPLC were unsuccessful, so it is distributed between the aqueous layer and dichloromethane. The organic layer was collected, dried over sodium sulfate, concentrated under vacuum and set aside for separate cleaning. The aqueous layer was also collected and purified using HPLC (column 30×100 mm Waters Sunfire; 5 micron; 35 ml/min; 210 nm; from 15% to 100% CH3CN + 0,05% TFA/water + 0.05% of TFA for 15 minutes; the named compound was suirable at 80% CH3CN + 0,05% TFA/water + 0.05% of TFA). Fractions containing the titled compound, life who was seravalli during the night with obtaining these compounds are in the form of a white sticky solid. The organic layer from operations distribution of the crude product was purified using preparative TLC (plate 1000 micron silica gel with elution with a mixture of 50% ethyl acetate/hexane) to give the titled compound. Both parties named compounds were combined and used without further purification in the next stage.

Stage 2: Tertbutyl-6-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of product from step (to 79.6 mg, of) 0.157 mmol) in methanol (4 ml) and ethyl acetate (2 ml) was added 10% palladium on coal (18 mg)and the reaction mixture was stirred in hydrogen atmosphere (balloon) overnight. Analysis by LC/MS showed that the reaction was incomplete, so I added an additional amount of 10% palladium on coal (10 mg)and the reaction mixture was stirred in hydrogen atmosphere (balloon) for 6 hours. The reaction mixture was filtered through a microfilter, and the collected solid was well washed with methanol. The filtrate was concentrated under vacuum and kept in the form of an azeotrope with toluene to obtain these compounds in the form of a light brown oil which was used directly in the next stage without purification.

Stage 3: Tertbutyl-6-({[(2S,5R)-7-oxo-6-sulfoxy-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)-3,4-dihydrothieno the Lin-2(1H)-carboxylate

To a solution of product from step 2 (64,6 mg, 0,155 mmol) in pyridine (1.5 ml) was added to the complex of sulfur trioxide with pyridine (129,5 mg, 0,814 mmol). The mixture was stirred at room temperature under nitrogen atmosphere during the week. Then added dichloromethane, and the mixture was filtered. The collected solid was thoroughly washed with dichloromethane, and the combined filtrates were concentrated under vacuum to obtain the crude titled compound. The residue was used without purification in the next stage.

Stage 4: (2S,5R)-7-oxo-6-(sulfoxy)-N-(1,2,3,4-Tetra-hydroisoquinoline-6-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of product from step 3 (77 mg, 0,155 mmol, theoretical yield stage 3) in anhydrous dichloromethane (3 ml) at 0°C under nitrogen atmosphere was added dropwise triperoxonane acid (1 ml, 13 mmol). The reaction mixture was stirred for one hour, then concentrated under vacuum. To the residue was added ether and the resulting white precipitate was collected by centrifugation (rubbing with ether was repeated two more times). The obtained solid was purified via HPLC on a column of Phenomenex Synergy Polar-RP 80A, suirable a mixture of methanol/water and liofilizirovanny with obtaining these compounds are in the form of a white solid. LC-MS (negative ionization) m/e 395 (M-H).

EXAMPLE 17

(2S,5R)-7-Oxo-N-(5-piperidine-4-pyridin-2-yl)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Stage 1: (2S,5R)-6-(benzyloxy)-N-(5-bromopyridin-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (0.400 g, 1,448 mmol) in dry dichloromethane (17,66 ml) was sequentially added triethylamine (0,504 ml, 3.62 mmol), iodide 2-chloro-1-methylpyridine (0,433 g 1,694 mmol)and 2-amino-5-bromopyridin (0,311 g 1,795 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated to 50°C for 1 hour, then was purified on installing HPLC associated with mass-spectrometer (column 30×100 mm Waters Sunfire; 5 micron; 50 ml/min, acetonitrile/water with 0.1% TFA over 15 minutes). Fractions containing the titled compound was concentrated under vacuum, then liofilizirovanny during the night with obtaining these compounds are in the form of a yellow solid.

Stage 2: 6-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)-3',6'-dihydro-3,4'-bi-pyridine-1'(2'Η)-carboxylate

Tertbutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridines-1(2H)-carboxylate (215 mg, 0,696 mmol) was added to the product from step 1 (150 mg, 0,348 mmol) in the reaction flask, then added dichloride bis(triphenylphosphine)-palladium(II) (24 mg, 0.035 mmol), then 1 M aqueous solution of carbonate of soda is I (0,869 ml, 0,869 mmol) and acetonitrile (0,899 ml). The reaction mixture was degirolami, then put on a short time on a pre-heated up to 70°C oil bath, then cooled to room temperature and filtered. The filtrate was concentrated under vacuum, and the residue was purified using column chromatography on silica gel, was suirable a mixture of ethyl acetate/hexane (0-50% for 1500 ml, then 50-100% for 750 ml) to give the titled compound as a yellow oil.

Stage 3: 4-[6-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)pyridine-3-yl]piperidine-1-carboxylate

To a mixture of the product from step 2 (50 mg, 0,094 mmol) in ethyl acetate (6 ml) was added 10% palladium on coal (becomes 9.97 mg). The reaction mixture was stirred in hydrogen atmosphere (balloon) overnight, then filtered. The filtrate was concentrated under vacuum to obtain these compounds in the form of a colorless oil which was used without purification in the next stage.

Stage 4: 4-[6-({[(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Oct-2-yl]carbonyl}amino)pyridine-3-yl]piperidine-1-carboxylate

To a solution of product from step 3 (30 mg, 0,067 mmol) in dry pyridine (1.5 ml) was added pyridine complex with sulfur trioxide (53,6 mg of 0.337 mmol) at room temperature, in the dark, under nitrogen atmosphere. The reaction mixture was stirred for weeks, then filtered (collected the solid substance was well washed with dichloromethane). The filtrate was concentrated under vacuum to obtain these compounds in the form of a colorless oil which was used without purification in the next stage.

Stage 5: (2S,5R)-7-oxo-N-(5-piperidine-4-espiridion-2-yl)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of product from step 4 (35 mg, 0,067 mmol; theoretical output stage 4) in dry dichloromethane (3 ml) was added triperoxonane acid (0,00513 ml 0,067 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred for 30 minutes, then concentrated under vacuum. The residue is triturated with ether to remove excess triperoxonane acid and soluble organics impurities. The obtained solid substance was dried, dissolved in water and purified using preparative HPLC on a column of Phenomenex Synergy Polar-RP 80A, suirable a mixture of methanol/water and liofilizirovanny with obtaining these compounds. LC-MS (negative ionization) m/e 424 (M-H).

EXAMPLE 18

Piperidine-4-ylmethyl(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate

Stage 1: [1-(tertbutoxycarbonyl)piperidine-4-yl]methyl-(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate

The hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (109 mg, or 0.57 mmol) and 4-dimethyl shall aminopyridin (69,6 mg, of 0.57 mmol) were added sequentially to a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (105 mg, 0.38 mmol) in dry dichloromethane at room temperature. Then add tertbutyl 4-(hydroxymethyl)piperidine-1-carboxylate (123 mg, or 0.57 mmol)and the reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified using preparative HPLC to obtain these compounds.

Stage 2: [1-(tertbutoxycarbonyl)piperidine-4-yl]methyl-(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate

To a mixture of the product from step 1 (100 mg, 0,211 mmol) in methanol was added 10% palladium on coal (6,74 mg). The reaction mixture was stirred in hydrogen atmosphere (balloon) overnight, then filtered. The filtrate was concentrated under vacuum to obtain these compounds, which was used without purification in the next stage.

Stage 3: [1-(tertbutoxycarbonyl)piperidine-4-yl]methyl-(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate

To a solution of product from step 2 (50 mg, 0.13 mmol) in dry pyridine (1 ml) was added pyridine complex with sulfur trioxide (104 mg, 0,652 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred overnight, then filtered (collected solid well amywali dichloromethane). The filtrate was concentrated under vacuum to obtain these compounds, which was used without purification in the next stage.

Stage 4: piperidine-4-ylmethyl(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate

TFA was added to the product from step 3 to 0°C in nitrogen atmosphere. The reaction mixture was stirred for 1 hour, then concentrated under vacuum. The residue is triturated with ether to remove excess triperoxonane acid and soluble organics impurities. The obtained solid substance was dried, dissolved in water and purified using preparative HPLC on a column of Phenomenex Synergy Polar-RP 80A, suirable a mixture of methanol/water and liofilizirovanny with obtaining these compounds. LC-MS (negative ionization) m/e 362 (M-H).

EXAMPLES 19-56

The procedure described in example 1A, was used to obtain the following compounds, where specified as the source reagent in stage 1 amine was replaced with 4-amino-1-BOC-piperidine.

ExampleAminProduct
19A and 19B
(racemic mixture)
Selected diastereomers (diastereoisomer 1 and diastereoisomer 2) formula:

[Diastereomers were suirable from the column for HPLC (column Phenomenex Synergi Polar RP80A 250×21,2 mm, 10 micron, gradient elution of 35 ml/min a mixture of from 0% to 40% methanol/water over 15 min; detection at 210 nm). The first diastereoisomer (diastereoisomer 1) was suirable with 15% methanol/water, and the second diastereoisomer (diastereoisomer 2) suirable at 18% methanol/water. The absolute stereochemistry of the two diastereomers was not defined. One of the diastereomers is (2S,5R)-7-oxo-N-[(3R)piperidine-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide, and the other is the corresponding (3S)-isomer].
20
(2S,5R)-7-oxo-N-azetidin-3-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]
octane-2-carboxamide
21
(2S,5R)-7-oxo-N-[(3R)pyrrolidin-3-yl]-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]-octane-2-carboxamide
22
(2S,5R)-7-oxo-N-[(4R)-azepin-4-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide
23
(2S,5R)-7-oxo-N-[1-methylpiperidin-4-yl]-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]-octane-2-carboxamide

24
(racemic forms)

A mixture of (2S,5R)-7-oxo-N-[(3S,4S)-3-foreperiod-4-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide and its 3R,4R diastereoisomer
25
(2S,5R)-7-oxo-N-[(3S,4R)-3-foreperiod-4-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
26
(2S,5R)-7-oxo-N-[(3S,4R)-3-methoxy-piperidine-4-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
27
(2S,5R)-N-(1,1-dissidocerida-2H-thiopyran-4-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

28
(2S,5R)-N-[(3R,4R)-4-aminopyrrolidine-3-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
29
(2S,5R)-N-[(3R,4R)-4-hydroxypyrrolidine-3-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
30
(2S,5R)-N-[(3R,4S)-4-hydroxypyrrolidine-3-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
31
(2S,5R)-N-[(3R,4S)-4-ftorpirimidinu-3-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

32
(2S,5R)-N-[(3S,4R)-4-ftorpirimidinu-3-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
33
(2S,5R)-7-ox is-N-[(3S)-1-piperidine-4-yl-2-oxopyrrolidin-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
34
(2S,5R)-7-oxo-N-[(3R)-1-piperidine-4-yl-2-oxopyrrolidin-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
35
(2S,SR)-N-[(3S,4R)-3-perasaan-4-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide

36
(2S,5R)-N-[(3R,4S)-3-perasaan-4-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide
37
(2S,5R)-N-[(3-torasemide-3-yl)-methyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide
38
(2S,5R)-7-oxo-N-(pyrrolidin-2-yl-methyl)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide
39
(2S,5R)-7-oxo-N-(piperidine-2-ylmethyl)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide
40
(2S,5R)-7-oxo-N-(piperidine-4-yl-methyl)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide

41
(2S,5R)-N-(2-hydroxy-1-piperidine-4-ileti}-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
42
(2S,5R)-N-[(2S)-1,4-oxazepan-2-ylmethyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide
43
(2S,5R)-N-[(2R)-1,4-oxazepan-2-ylmethyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide
44
(2S,5R)7-oxo-N-(2-piperidine-retil)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide
45
(2S,5R)-7-oxo-N-(2-piperidine-1-retil)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide

46
(2S,5R)-7-oxo-N-(2-piperazine-1-retil)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide
47
(2S,5R)-N-3-azabicyclo[3.1.0]Gex-6-yl-7-oxo-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide
48
(2S,5R)-N-methyl-7-oxo-N-piperidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide
49
(2S,5R)-2-{[2-(aminomethyl)piperidine-1-yl]carbonyl}-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Octan-7-he

50
(2S,5R)-2-[(4-aminopiperidin-1-yl)-carbonyl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Octan-7-he
51
(2S,5R)-2-(piperazine-1-ylcarbonyl)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]-octane-7-he
52
(2S,5R)-2-(2,7-diazaspiro[3.5]non-2-ylcarbonyl)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Octan-7-he
53
(2S,5R)-2-(hexahydrofuro[3,4-c]
pyrrol-2(1H)-ylcarbonyl)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Octan-7-he
54
(2S,5R)-2-{[(3R)-3-aminopyrrolidine-1-yl]
the carbonyl}-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Octan-7-he

55
(2S,5R)-2-{[(3S)-3-aminopyralid the n-1-yl]
the carbonyl}-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Octan-7-he
56
(2S,5R)-2-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Octan-7-he

EXAMPLES 57-90

The procedure described in example 6, was used to obtain the compounds of examples 57-77 and 80-90 where specified as the starting material amine was replaced in stage 1 by 4-aminopyridine. The procedure described in example 17 was used to obtain the compounds of examples 78 and 79, where specified as the source material pyridine was replaced on stage 1 at 2-amino-5-bromopyridin.

ExampleAminProduct
57
(2S,5R)-N-[4-(aminomethyl)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide
58
(2S,5R)-N-[3-(aminomethyl)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide
59
(2S,5R)-N-[2-aminomethyl)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]-octane-2-carboxamide
60
(2S,5R)-N-{4-[(methylamino)methyl]-phenyl}-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
61
(2S,5R)-N-{3-[(methylamino)methyl]-phenyl}-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
62
(2S,5R)-N-{4-[(dimethylamino)methyl]-phenyl}-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

63
(2S,5R)-N-{4-[(pyrrolidinyl)methyl]-phenyl}-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
64
(2S,5R)-7-oxo-6-(sulfoxy)-N-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
65
(2S,5R)-N-(2,3-dihydro-1H-isoindole-5-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
66
(2S,5R)-N-(2,3-dihydro-1H-indol-5-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
67
4-({[(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Oct-2-yl]-carbonyl}amino)benzoic acid

68
(2S,5R)-N-[4-(aminocarbonyl)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
69
(2S,5R)-N-[4-(aminosulfonyl is)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
70
(2S,5R)-N-[3-(aminocarbonyl)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
71
(2S,5R)-7-oxo-N-pyridin-3-yl-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]
octane-2-carboxamide
72
(2S,5R)-7-oxo-N-pyridin-2-yl-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]
octane-2-carboxamide

73
(2S,5R)-N-(2,6-dipyrrole-1-yl-pyridine-4-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
74
(2S,5R)-N-(6-aminopyridine-2-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]
octane-2-carboxamide
75
(2S,5R)-N-[4-(dimethylamino)pyridine-2-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
76
(2S,5R)-N-[4-(aminomethyl)pyridine-2-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

77
(2S,5R)-N-[5-(aminomethyl)pyridine-2-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
78
(2S,5R)-N-(4-piperidine-4-espiridion-2-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
79
(2S,5R)-N-(6-piperidine-4-espiridion-2-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
80
(2S,5R)-N-(5-piperazine-1-espiridion-2-yl)-7-oxo-6-(is ultacet)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

81
(2S,5R)-N-(5-morpholine-4-espiridion-2-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
82
(2S,5R)-N-(5-pyrrolidin-1-yl-pyridin-2-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
83
(2S,5R)-7-oxo-N-pyrazin-2-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide
84
(2S,5R)-7-oxo-N-pyrimidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide
85
(2S,5R)-7-oxo-N-(2-piperazine-1-yl-pyrimidine-4-yl)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

86
(2S,5R)-N-(1-methyl-1H-imidazol-2-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
87
(2S,5R)-N-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
88
(2S,5R)-7-oxo-6-(sulfoxy)-N-1,3-thiazol-2-yl-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide
89
(2S,5R)-7-oxo-6-(sulfoxy)-N-(4,5,6,7-tetrahydro[1,3]thiazolo-[5,4-c]
pyridine-2-yl)-1,6-diazabicyclo[3.2.1]
octane-2-carboxamide
90
(2S,5R)-N-(6,7-dihydro-5H-pyrrolo-[3,4-b]pyridine-2-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide

EXAMPLES 91-117

The procedure described in example 18, was used to obtain the following compounds, where specified as the source material is and the alcohol was replaced by the stage 1 on tertbutyl 4-(hydroxy-methyl)piperidine-1-carboxylate.

ExampleAminProduct
91
(4S)-azepin-4-yl(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxylate
92
(4R)-azepin-4-yl(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxylate
93
piperidine-4-yl(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxylate

94
(3R)pyrrolidin-3-yl(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
95
(3S)pyrrolidin-3-yl(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-Carbo is Silat
96
azetidin-3-yl(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxylate
97
(3S,4R)-3-foreperiod-4-yl-(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
98
(3R,4S)-3-foreperiod-4-yl-(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]
octane-2-carboxylate

99
(3R,4R)-3-foreperiod-4-yl-(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]
octane-2-carboxylate
100
(3S,4S)-3-foreperiod-4-yl-(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]
octane-2-carboxylate
101
(3S,4S)-4-foreperiod-3-yl-(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]
octane-2-carboxylate
102
(3S,4R)-4-foreperiod-3-yl-(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]
octane-2-carboxylate
103
(3R,4S)-4-ftorpirimidinu-3-yl-(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]
octane-2-carboxylate

104
(3S,4R)-4-ftorpirimidinu-3-yl-(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]
octane-2-carboxylate
105
(3R,4R)-4-ftorpirimidinu-3-yl-(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]
octane-2-carboxylate
106
(3S,4S)-4-ftorpirimidinu-3-yl-(2S,5R)-7-oxo-6-(Sul is fooxy)-1,6-diazabicyclo[3.2.1]
octane-2-carboxylate
107
(4S)-isoxazolidine-4-yl(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
108
(4R)-isoxazolidine-4-yl(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate

109
pyrazolidine-4-yl(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxylate
110
2-amino-ethyl(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxylate
111
2-piperidine-1-retil(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
112
2-piperidine-4-retil(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
113
(4 methylpiperidin-4-yl)methyl-(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]
octane-2-carboxylate

114
1,4-oxazepan-2-ylmethyl(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
115
4-(aminomethyl)phenyl(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
116
2-{[3,4-bis(atomic charges)benzoyl]amino}-ethyl(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxylate
117br/> 2-{[3,4-bis(atomic charges)benzoyl]amino}-1-{{[3,4-bis(atomic charges)benzoyl]amino}methyl)
ethyl(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate

EXAMPLE 118

Enzyme activity: the definition of the IC50

The enzyme activity of class C was determined in the presence of the test inhibitor using a spectrophotometric study in relation to the manufactured substrate, nitrocefin. The AmpC enzyme (P. aeruginosa.) and the substrate was dissolved in 100 mm KH2PO4buffer (pH 7). The buffer also contains 0.005% of BSA. In the study of the test inhibitor was dissolved in DMSO and diluted 1:20, resulting in the final concentration was in the range of from 50 μm to is 0.0002 μm. In 96-well-microplate test inhibitor was incubated with the enzyme beta-lactamase for 40 minutes at ambient temperature, was added the substrate solution, and continued the incubation for a further 40 minutes. Spectrophotometric reaction was stopped by addition of 2.5 n acetic acid, and measured the absorbance at a wavelength of 492 nm. The value of the IC50were determined from semi-log graphical dependency of the inhibition of the enzyme concentration of the inhibitor, when this curve was obtained using 4-parametric approximation.

The enzyme activity of a class defined with the help of such the e testing Protocol, which was described above for the enzyme class C, except that instead of AmpC enzyme used enzyme KPC-2 (K. pneumoniae).

Typical compounds of the present invention shown in this study, the inhibitory activity against β-lactamase class C and class A. for Example, in this study were exposed to the test compounds of examples 1, 2, 4 and 6-9, and it was found that they have the following meanings IC50in table 2. Table 3 shows the survey data for other examples of the compounds.

The study Protocol synergism

The study determined the concentration of the inhibitor of β-lactamases needed to reduce MIC for β-laktamovogo antibiotic half, one quarter, one eighth, one sixteenth to one thirty-second against strains of bacteria that are normally resistant to the action of the investigational antibiotic. This study conducted by titration BLI in consecutive breeding horizontally tiralongo microplate, and, at the same time, tetroe antibiotic when serial dilution down vertically tiralongo microplate, and then inocula tablet using the analyzed bacterial strain and allowing the bacteria to multiply in the night. Each hole located in chess the order on this tablet contains a different combination of concentrations of the inhibitor and antibiotic, giving the opportunity to spend a full definition of any synergism between them.

The combination of bacterial strain/antibiotic:

CL 5701 (Pseudomonas aeruginosa; Pa AmpC)/imipenem

MB 2646 (Enterobacter cloacae; P99)/ceftazidime

CL 5513 {Klebsiella pneumoniae; SHV-5)/ceftazidime

CL 6188 {Acinetobacter baumanii; Oxa40)/imipenem

CL 6569 (Klebsiella pneumoniae; KPC-2)/imipenem

CL 5761 {Klebsiella pneumoniae; KPC-3)/imipenem

CLB 21648 {Acinetobacter baumanii; Ab AmpC)/imipenem

The usual method of "checkerboard":

1. All wells in rows B-H microplate MIC 2000 fill 100 ál MHBII + 1% DMSO.

2. All wells in row A of the microplate MIC 2000 fill 100 ál of 2X MHBII + 2% DMSO.

3. 100 ál of 4X the desired final concentration of the antibiotic added to well A1 tablet MIC 2000.

4. 100 ál of 2X the desired final concentration of the antibiotic is added to the wells A2-A12 tablets MIC 2000.

5. 100 μl of serially diluted from series A to series G each tablet MIC 2000.

6. 100 μl is removed from each well in row G of each tablet MIC 2000.

7. 100 ál of 2X the desired final concentration of the antibiotic (MHBII + 1% DMSO) is added to all wells in column 1 titration microplate.

8. 100 μl of serially diluted from column 1 to column 11 for each tablet MIC 2000.

9. 100 μl is removed from each well in column 11 of each tablet is MIC 2000.

10. The tablets then inoculant using inoculator MIC 2000 by growing the test strain (TSB) overnight.

11. Tablets incubated at 37°C for approximately 20 hours and appreciate the growth visually.

Environment (all sterilized in an autoclave prior to any addition of DMSO):

MHBII + 1% DMSO
MHBII adjusted cations (BBL™)4.4 g
DMSO2.0 ml
Distilled water198,0 ml
2X MHBII + 2% DMSO
MHBII adjusted cations (BBL™)8.8 g
DMSO4,0 ml
Distilled water196,0 ml
1,02X MHBII
MHBII adjusted cations (BBL™)4.4 g
Distilled water198,0 ml
1,1X MHBII + 1% DMSO
MHBII adjusted cations (BBL™)4.4 g
DMSO2.0 ml
Distilled water178,0 ml
TSB

Trypticase-soy broth (BBL™) was used as prescribed on the bottle.

Synergies can be expressed as the ratio of the minimum inhibitory concentration (MIC) of the test antibiotic in the absence of the inhibitor of β-lactamase to MIC the same feel of the antibiotic in the presence of an inhibitor of β-lactamase. A ratio equal to one (1)indicates that the inhibitor of β-lactamase does not affect the efficiency of the antibiotic. A ratio greater than one (1)indicates that the inhibitor of β-lactamase causes a synergistic effect when combined with the introduction of the antibiotic agent. Preferred inhibitors of β-lactamases of the present invention are characterized by synergies with respect to at least about 2, more preferably the compounds were characterized by synergies with respect to at least about 4, even more preferably at least about 8, and most preferably at least about 16. Alternatively, synergistic effective which can be expressed in the form factor, again, using the concentration of BLI for the lowest MIC of the antibiotic. Thus, if the MIC of the antibiotic is 20 μg/ml and 1.5 μm concentration BLI MIC reduces to 5 μg/ml, a synergistic effect is fourfold or is 4X synergies" at 1.5 μm BLI.

Typical compounds of the present invention exhibit a synergistic effect. For example, it has been found that the compounds of examples 1, 2, 4 and 6-9 had 2X synergies at concentrations in the range from 100 μm or less. Synergistic concentration for examples 1, 2, 4 and 6-9 against the strain CL5701 P. aeruginosa and strain CL6569Klebsiella pneumoniaeare shown in table 2.

Table 2
Data for biological studies
ExampleR ( * ) indicates place of incorporation)P.a. AmpC
IC50
(nM)
2X/4X/8X synergies CL5701
(µm)1
K.p. KPC-2 IC50(nM)16X/32X/64X synergies CL6569 (µm)2
14652086,25/12,5/12,5
2693,12/6,25/6,252456,25/12,5/25
429000100/100/>100440050/100/100
6612,5/25/1005450/50/100
71,150/100/>100825/50/>100
81,6of 12.5/100/>1001,625/25/50
9200,78/3,12/6,25 726,25/6,25/12,5
Sul-bactam1700054/>150/>30033000>500/>500/>500

1. This concentration for 2X, 4X and 8X with imipenem against strain CL5701P. aeruginosa. For example, the concentration of 6.25 μm compound of example 1 reduces MIC for imipenem against strain CL5701P. aeruginosa8 times (8X synergism).

2. This concentration for 16X, 32X and 64X with imipenem against strain CL6569K. pneumoniae. For example, the concentration of 12.5 μm compound of example 1 reduces MIC for imipenem against strain CL6569K. pneumoniae64 times (64X synergism).

It should be noted that the data shown in table 3, in the same way and using the same enzymes as in table 2. Examples 2, 6, 7 and 8 in table 3 duplicate data for these samples in table 2, except that the values of the IC50for AmpC in table 3 for examples 7 and 8 are 11 nm and 16 nm vs. 1.1 nm and 1.6 nm, respectively, for the corresponding examples in table 2, and the value of the IC50for KPC-2 in table 3 of example 8 is 16 nm 1.6 nm in table 2.

In addition, it should be noted that the compound of example 1 in table 2 and the compound of example 1A in table 3 are one and the same connection. Meant what I IC 50for KPG-2 for sample 1 in table 2 and 1A in table 3 are 208 nm and 210 nm, respectively. These two values could be obtained in different experiments, or they can provide data of the same experiment.

Table 3
Data for biological studies
Example No.M-H(m/e)1K.p.
KPC-2
IC50(nm)
P.a.
AmpC
IC50(nm)
1A347210465
236124569
6341546
7371811
83841616
14333355110
1536513049
163951914
17424286
1836210180
19a34748064
19b347240480
20319171000
21333430029100
22361225520
23361240500
2436590110
2536527020
26377290120
273961509,5
28348660740
293492502500
303495202250
31351190150
3235171019
3343021620
3443028045
3537915013
3637913018
3735112040
38347120250
39361190530
403617730
41391320700
42379110100
4337910015
443754511
45375150180
463769642

47345100007204836125002904936178075005034788205133352022005237310005905335933100054333320084055333150014005636116002705736972 205836910434593691092926038356186138378226239754186342385226439519146538160166638141566738410116838330 7694192277038326371341423772341361,27347813051574356118753844103763701300277370423784244700,87942424 27080425152

81427175
82410104
83342586
84342550,8
8542620260
86344135240
87346840200
88347361,8
894023910
90 382NANA
91362683
92362640033000
933489170
94334403000
9533421210
9632018600
973662649
98366946
99366840
100366433
1011581
102366476
103352339
1043522438
10535213200
10635210200
1073361139
1083361162
10933562700
11030830610
111376201200
112 37613165
113376836
11437811340
115370224
11652870440
1177771261
1. the values obtained using LC-MS (negative ionization mode).

Although the above description discloses the basic ideas of the present invention using examples to illustrate, however, the implementation of the invention encompasses all of the usual changes, improvements and/or modifications which fall under the scope of the following claims. The contents of all referenced herein publications, patents and patent applications listed here by reference, where in case of any discrepancy the present description will be becoming the public force.

1. The compound of the formula I

or its pharmaceutically acceptable salt,
where X is:
(1) CH2or
(2) CH2CH2;
R1is C(O)N(R3R4,
R2is OSO3M;
M is H or a pharmaceutically acceptable cation;
R3is:
(1) C1-8by alkyl, substituted with HetA,
(2) HetA,
(3) AryA,
(4) HetB, or
(5) AryB;
R4is N or C1-8by alkyl;
or alternatively, R3and R4together with the N atom to which they are both attached, form a saturated monocyclic ring with the number of members from 4 to 6, containing 1 heteroatom in addition to the nitrogen attached to R3and R4representing N; where monocyclic ring optionally condensed or Spiro with saturated heterocyclic ring with the number of members from 5 to 6, containing 1 heteroatom represents N, with the formation of a bicyclic ring system where the resulting monocyclic ring or bicyclic ring system optionally substituted with 1 substituent that is (3) (CH2)1-2G, where G is N(RARBor (2) N(RARB;
HetA is a saturated or mono-unsaturated heterocyclic ring with the number of members from 4 to 9, containing from 1 to 2 hetero the volume, independently selected from N, O and S, where each S in a ring optionally oxidized to S(O)2and 1 carbon atom in the ring is optionally oxidized to S(O); where the ring is optionally condensed with C3-7cycloalkyl and where optionally condensed, saturated or mono-unsaturated ring optionally substituted total with 1 substituent selected from (CH2)nN(RARBand (CH2)nRC;
AryA is phenyl which is optionally substituted in total with 1 substituent selected from (CH2)nN(RARBand (CH2)nRC,
HetB is a heteroaromatic ring with 5 or 6 members containing 1 heteroatom selected from 1 to 2 N atoms and from 1 atom of S, where the heteroaromatic ring is optionally condensed with a saturated heterocyclic ring with the number of members from 5 to 7, containing 1 heteroatom represents N, where optional condensed heteroaromatic ring optionally substituted total with 1 to 2 substituents selected from (CH2)nN(RARBand (CH2)nRC;
AryB is a bicyclic ring system in which the phenyl condensed with a saturated heterocyclic ring with the number of members from 5 to 6, containing 1 heteroatom represents N;
each n is not avisio is an integer, that equals 0 or 1;
each RAis independently N or C1-8by alkyl;
each RBis independently N or C1-8by alkyl;
each RCis independently C1-6the alkyl, HE, O-C1-8by alkyl, halogen, C(O)ORAC(O)N(RARB, SO2N(RARB, pyridium, pyrrolidinium, piperidinium, piperazinil or morpholinyl;
and provided that:
(D) when R is AryA or1-8the alkyl substituted with AryA, then AryA is not unsubstituted phenyl, phenyl substituted with N(RAR8or phenyl substituted with C(O)N(RARB.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, where R2is OSO3H.

3. The compound according to claim 1 or its pharmaceutically acceptable salt, where R3is HetA, CH2-HetA, or CH2CH2-HetA.

4. The compound according to claim 3 or its pharmaceutically acceptable salt, where HetA is optionally condensed, saturated heterocyclic ring selected from the group consisting of azetidine, pyrrolidine, oxopyrrolidin, piperidinyl, piperazinil, tetrahydropyranyl, tetrahydropyranyl, morpholinyl, 1,1-deoxycorticosterone, azepane, oxazepine, asokamala, and azabicyclo[3.1.0]-hexyl, where the heterocycle optionally substituted with (C 2)nN(RARBand optionally substituted with (CH2)nRC.

5. The compound according to claim 3 or its pharmaceutically acceptable salt, which is a compound selected from the group consisting of:







and

where T is H, C1-3the alkyl, pyrrolidin-3-yl or piperidine-4-yl and T' is H, Cl, Br, F, C1-3the alkyl, O-C1-3the alkyl, HE, NH2N(H)-C1-3the alkyl, or N(-C1-3alkyl)2.

6. The compound according to claim 5 or its pharmaceutically acceptable salt, where T is H, CH3pyrrolidin-3-yl or piperidine-4-yl and T' is H, F, O-C1-3the alkyl, OH, NH2N(H)CH3N(CH3)2.

7. The compound according to claim 1, or its pharmaceutically acceptable salt, where R3is HetB.

8. The connection according to claim 7 or its pharmaceutically acceptable salt, where Het is a heteroaromatic compound, selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, thiazolyl, piperidinyl, pyrrolidinyl, piperidinyl and pyrrolopyridine, where the heteroaromatic ring is optionally substituted with 1 or 2 (CH2)nN(RARBand optionally substituted with 1 or 2 (CH2)nRCgroups.

9. The connection according to claim 7 or its pharmaceutically acceptable salt, which is a compound selected from the group consisting of:



and

where V, V', V”, Y, Y' and Z each independently selected from the group consisting of H, CH3, pyrrolidinyl, piperidinyl, piperazinil, morpholinyl, CH2-pyrrolidinyl, CH2-piperidinyl, CH2-piperazinil, CH2-morpholinyl, NH2N(H)CH3N(CH3)2CH2NH2CH2N(H)CH3and CH2N(CH3)2provided that:
(i) at least one of Y and Y' is H.

10. The compound according to claim 1 or its pharmaceutically acceptable salt, where R3is AryA.

11. The compound of claim 10 or its pharmaceutically acceptable whom I Sol, where AryA is phenyl which is optionally substituted with 1 substituent that is1-3the alkyl, CH2NH2CH2N(H)-C1-3the alkyl, CH2N(-C1-3alkyl)2O-C1-3the alkyl, Cl, Br, F, NH2N(H)-C1-3the alkyl, N(-C1-3alkyl)2C(O)NH2C(O)N(H)-C1-3the alkyl, C(O)N(-C1-3alkyl)2With(O)O-C1-3the alkyl, S(O)2NH2, S(O)2N(H)-C1-3the alkyl, S(O)2N(-C1-3alkyl)2, pyrrolidinium, piperidinium, morpholinium, CH2-pyrrolidinium, CH2-piperidinium or CH2-morpholinium.

12. The compound according to claim 1 or its pharmaceutically acceptable salt, where R3and R4together with the N atom to which they are both attached, form heterocyclyl selected from the group consisting of:
and
where the ring is optionally substituted with CH2NH2CH2N(H)-C1-3the alkyl, CH2N(-C1-3alkyl)2, NH2N(H)-C1-3the alkyl or N(-C1-3alkyl)2.

13. The compound according to claim 1 or its pharmaceutically acceptable salt, where R3is AryB.

14. The connection 13 or its pharmaceutically acceptable salt, where AryB is a bicyclic ring selected from the group consisting of 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 2,3-dihydro-1H-isoindolyl and 2,3-dihydro-1H-indolyl.

15. The compound according to claim 1, which is a compound selected from the group consisting of the following compounds:
(2S,5R)-7-oxo-N-piperidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[(4S)-azepin-4-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[(4R)-azepin-4-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-[(3R)pyrrolidin-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-[(3S)pyrrolidin-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-asokan-5-yl-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-pyridin-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-(2-methoxypyridine-4-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[2-(dimethylamino)pyridine-4-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[4-(aminomethyl)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-2-[(piperidine-4-ylamino)carbonyl]-1,6-diazabicyclo[3.2.1]octane-6-sulfonic acid;
(4R,6S)-2-oxo-N-piperidine-4-yl-3-(sulfoxy)-1,3-diazabicyclo[2.2.1]heptane-6-carboxamide;
(4R,6S)-2-oxo-N-[(4S)-azepin-4-yl]-3-(sulfoxy)-1,3-diazabicyclo[2.21]heptane-6-carboxamide;
(4R,6S)-2-oxo-N-pyridin-4-yl-3-(sulfoxy)-1,3-diazabicyclo[2.2.1]heptane-6-carboxamide; and their pharmaceutically acceptable salts.

16. The compound according to claim 1, which is a compound selected from the group consisting of the following compounds:
(2S,5R)-7-oxo-N-[(3R)pyrrolidin-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[(3R,4S)-3-foreperiod-4-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-6-(sulfoxy)-N-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-(5-piperidine-4-espiridion-2-yl)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
the diastereoisomer 1 (2S,5R)-7-oxo-N-[(3)piperidine-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
the diastereoisomer 2 (2S,5R)-7-oxo-N-[(3)piperidine-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-azetidin-3-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-[(3R)pyrrolidin-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-[(4R)-azepin-4-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-[1-methylpiperidin-4-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-[(3S,4S)-3-foreperiod-4-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide or 3R,4R a diastereoisomer or a mixture thereof;
(2S,5R)-7-oxo-N-[(3S,4R)-3-foreperiod-4-yl]-6-(when looksi)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-[(3S,4R)-3-methoxypiperidine-4-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-(1,1-dissidocerida-2H-thiopyran-4-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[(3R,4R)-4-aminopyrrolidine-3-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[(3R,4R)-4-hydroxypyrrolidine-3-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[(3R,4S)-4-hydroxypyrrolidine-3-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[(3R,4S)-4-ftorpirimidinu-3-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[(3S,4R)-4-ftorpirimidinu-3-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-[(3S)-1-piperidine-4-yl-2-oxopyrrolidin-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-[(3R)-1-piperidine-4-yl-2-oxopyrrolidin-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[(3S,4R)-3-perasaan-4-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[(3R,4S)-3-perasaan-4-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[(3-torasemide-3-yl)methyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-(pyrrolidin-2-ylmethyl)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R-)-7-oxo-N-(piperidine-2-ylmethyl)-6-(sulfoxy)-1,6-diaza icicle[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-(piperidine-4-ylmethyl)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[(2S)-1,4-oxazepan-2-ylmethyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[(2R)-1,4-oxazepan-2-ylmethyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-(2-piperidine-4-retil)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-(2-piperidine-1-retil)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-(2-piperazine-1-retil)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-3-azabicyclo[3,1 .0]Gex-6-yl-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-methyl-7-oxo-N-piperidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-2-{[2-(aminomethyl)piperidine-1-yl]carbonyl}-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Octan-7-he;
(2S,5R)-2-[(4-aminopiperidin-1-yl)carbonyl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Octan-7-he;
(2S,5R)-2-(piperazine-1-ylcarbonyl)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Octan-7-he;
(2S,5R)-2-(2,7-diazaspiro[3.5]non-2-ylcarbonyl)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Octan-7-he;
(2S,5R)-2-(hexahydrofuro[3,4-C]pyrrol-2(1H)-ylcarbonyl)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Octan-7-he;
(2S,5R)-2-{[(3R)-3-aminopyrrolidine-1-yl]carbonyl}-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Octan-7-he;
(2S,5R)-2-{[(3S)-3-aminopyrrolidine-1-yl]carbonyl}-6-(sulfoxy)-1,6-diazabicyclo[can-7-he;
(2S,5R)-2-{[3-(dimethylamino)pyrrolidin-1-yl]-carbonyl}-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]Octan-7-he;
(2S,5R)-N-[4-(aminomethyl)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[3-(aminomethyl)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[2-(aminomethyl)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-{4-[(methylamino)methyl]phenyl}-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-{3-[(methylamino)methyl]phenyl}-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-{4-[(dimethylamino)methyl]phenyl}-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-{4-[(pyrrolidinyl)methyl]phenyl}-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-6-(sulfoxy)-N-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-(2,3-dihydro-1H-isoindole-5-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-(2,3-dihydro-1H-indol-5-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
4-({[(2S,5R)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]Oct-2-yl]carbonyl}amino)benzoic acid;
(2S,5R)-N-[4-(aminocarbonyl)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[4-(aminosulfonyl)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[3-(aminaka bonyl)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-pyridin-3-yl-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-pyridin-2-yl-6-(sulfoxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide;
(2S,5R)-N-(2,6-dipyrrole-1-espiridion-4-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-(6-aminopyridine-2-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[4-(dimethylamino)pyridine-2-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[4-(aminomethyl)pyridine-2-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[5-(aminomethyl)pyridine-2-yl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-(4-piperidine-4-espiridion-2-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-(6-piperidine-4-espiridion-2-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-(5-piperazine-1-espiridion-2-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-(5-morpholine-4-espiridion-2-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-(5-pyrrolidin-1-yl-pyridin-2-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-pyrazin-2-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1] octane-2-carboxamide;
(2S,5R)-7-oxo-N-pyrimidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-(2-piperidin-1-Yeremey-4-yl)-6(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-(1-methyl-1H-imidazol-2-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-6-(sulfoxy)-N-1,3-thiazol-2-yl-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-6-(sulfoxy)-N-(4,5,6,7-tetrahydro[1,3]-thiazolo[5,4-C]pyridine-2-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-yl)-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; and
their pharmaceutically acceptable salts.

17. The compound according to claim 1,which is a compound selected from the group consisting of the following compounds:
(2S,5R)-7-oxo-N-piperidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-N-[4-(aminomethyl)phenyl]-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-[(3R)pyrrolidin-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-6-(sulfoxy)-N-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;
(2S,5R)-7-oxo-N-(5-piperidine-4-espiridion-2-yl)-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; and
their pharmaceutically acceptable salts.

18. The connection 17, which is (2S,5R)-7-oxo-N-piperidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide or its pharmaceutically acceptable salt.

19. The connection p is 1, which is (2S,5R)-7-oxo-N-[(3S)pyrrolidin-3-yl]-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide or its pharmaceutically acceptable salt.

20. The compound according to claim 1 which is (2S,5R)-7-oxo-N-piperidine-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide in the form of a crystalline monohydrate.

21. Pharmaceutical composition having inhibitory activity against β-lactamase class a and class C, which includes an effective amount of a compound according to any one of claims 1 to 20, or its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier.

22. The pharmaceutical composition according to item 21, which further includes beta-laktamovogo antibiotic.

23. A method of treating a bacterial infection, which includes an introduction to the subject in case of need of such treatment (i) a therapeutically effective amount of a compound according to any one of claims 1 to 20, or its pharmaceutically acceptable salts, optionally in combination with a beta-lactamase antibiotic or (ii) the pharmaceutical composition according to item 21 or 22.

24. The use of compounds according to any one of claims 1 to 20, or its pharmaceutically acceptable salts, optionally in combination with a beta-lactamase antibiotic in the manufacture of drugs having inhibitory activity against β-lactamase class a and classes.

25. The method of obtaining the compounds of formula P-VIII

which includes:
(A) contacting ilide ketosulfone formula P-I

with iridium, rhodium or ruthenium catalyst to obtain compound P-II,
where PGis Cbz;
Connection P-II is a compound P-IIa
;
RUis CH3or phenyl;
RVis CH3or phenyl;
R4is N or C1-4by alkyl;
T' is H, Cl, Br, F, C1-3the alkyl, O-C1-3the alkyl, OH, NH2N(H)-C1-3the alkyl, or N(-C1-3alkyl)2;
p is zero, 1 or 2; q is zero, 1 or 2 and p+q = zero, 1, 2, or 3;
(C) treating compound P-IIa reducing agent to obtain compounds of formula P-III

and (C) contacting compound P-III with sulphonylchloride formula R^-SO2W in the presence of a tertiary amine base to obtain the compounds of formula P-IV

where W is halogen and
R^ is;
(1) phenyl, optionally substituted with from 1 to 3 substituents each of which is independently1-4the alkyl, C1-4halogenation, O-C1-4the alkyl, O-C1-4halogenation, Cl, Br, F, or NO2;
(2)1-4the alkyl or
(3) (C1-4halogenic the scrap;
(D) contacting compound P-IV with N-Boc-O-benzylhydroxylamine in the presence of a base to obtain the compounds of formula P-V

(E) treating compound P-V acid to obtain the compounds of formula P-VI

(F) contacting compound P-VI with phosgene, diphosgene or triphosgene in the presence of a tertiary amine and then adding an aqueous solution of acid to obtain the compounds of formula P-VII

and (G) contacting compound P-VII with a hydrogen source in the presence of a hydrogenolysis catalyst and in the presence of Boc-forming reagent to obtain the compound of formula P-VIII

26. The method according A.25) where the compound of formula P-II is a compound R-2

which includes:
(A) contacting ilide ketosulfone R-1:

with a catalyst selected from the group consisting of dimer chloride cyclooctadiene iridium, RuCl2(PPhs), Ru(DMSO)4Cl2and Rh2(TFA)4pick R-2;
(C) treating compound p-2 a reducing agent selected from the group consisting of Li borohydride, Na borohydride and K borohydride, to obtain compound p-3

and (C) contacting compound p-3 sulphonylchloride formula R^-S 2W in the presence of a base three-From1-4the alkylamine with obtaining the compounds of formula p-4

where W is chlorine and
R^ is stands, chlorochilon, phenyl, 4-Bromphenol, 4-cryptomaterial or 4-were;
(D) contacting compound p-4 with N-Boc-O-benzylhydroxylamine in the presence of a base selected from the group consisting of Li tert-butyl, Na tert-butyl, K tert-butyl and K Amiata, to obtain the compound R-5

and (E) treating compound R-5 acid selected from the group consisting of methanesulfonic acid, chloromethanesulfonyl acid, p-toluensulfonate acid and benzosulfimide acid, to obtain the compounds of formula R-6

(F) contacting compound p-6 triphosgene in the presence of a base three-From1-4the alkylamine and then adding an aqueous solution of phosphoric acid to obtain compound p-7

and (G) contacting compound p-7 with hydrogen in the presence of Pd-catalyst and Boc-forming reagent selected from the group consisting of dicret-BUTYLCARBAMATE and Boc-ON, to obtain the compound p-8
.

27. A compound selected from the group consisting of;


and
where PGis Cbz;
RUis CH3or phenyl;
RVis CH3or phenyl;
R4is H or C1-4by alkyl;
T' is H, Cl, Br, F, C1-3the alkyl, O-C1-3the alkyl, OH, NH2N(H)-C1-3the alkyl, or N(-C1-3alkyl)2;
p is zero, 1 or 2; q is zero, 1 or 2 and p+q = zero, 1, 2, or 3;
R^ is:
(1) phenyl, optionally substituted with from 1 to 3 substituents each of which is independently1-4the alkyl, C1-4halogenation, O-C1-4the alkyl, O-C1-4halogenation, Cl, Br, F, or NO2;
(2)1-4the alkyl or
(3) (C1-4halogenation.

28. Connection item 27, which is selected from the group consisting of


and
where R^ is the stands, chlorochilon, phenyl, 4-Bromphenol, 4-cryptomaterial, or 4-were.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae

and ,

which can be used to inhibit lipid kinase, including PI3K, and treat lipid kinase-mediated disorders. Values of radicals are given in claim 1.

EFFECT: improved properties of the compound.

11 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae and including their stereoisomers, as well as pharmaceutically acceptable salt, where X denotes O or S; R1 is selected from H, F, CI, Br, I, CN, -CR14R15-NR16R17, -CR14R15-NHR10, -(CR14R15)NR10R11, -(CR14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -(CR14R15)mOR10, -(CR14R15)nS(O)2R10, -C(OR10)R11R14, -C(R14)=CR18R19, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NR12OR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NHR12, -NR12C(=Y)R10, -S(O)2R10, -S(O)2NR10R11, C2-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C4 carbocyclyl, piperidinyl, thiopyranyl, phenyl or C5-C6 heteroaryl; R2 is selected from H, C2-C12 alkyl and thiazolyl; R3 denotes a condensed bicyclic heteroaryl selected from indazole, indole, benzoimidazole, pyrrolopyridine, imidazopyridine and quinoline; R10, R11 and R12 independently denote H, C2-C12 alkyl, C3 carbocyclyl, heterocyclyl selected from pyrrolidine, morpholine and piperazine, phenyl or heteroaryl selected from pyrazole, pyridine, benzothiophene; or R10 and R11 together with a nitrogen atom with which they are bonded possibly form a saturated C3-C6 heterocyclic ring, possibly containing one additional ring atom selected from N or O, where said heterocyclic ring is possibly substituted with one or more groups independently selected from oxo, (CH2)mOR10, NR10R11, SO2R10, C(=O)R10, NR12S(O)R11, C(=Y)NR10R11, C1-C12 alkyl and heterocyclyl selected from pyrrolidine; R14 and R15 are independently selected from H or C1-C12 alkyl; R16 and R17 independently denote H or phenyl; R18 and R19 together with a carbon atom with which they are bonded form a C3-C20 heterocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, phenyl, heteroaryl, piperidinyl and condensed bicyclic heteroaryl possibly substituted with one or more groups independently selected from F, CI, Br, I, CF3, -C(=Y)R10, -C(=Y)OR10, oxo, R10, -C(=Y)NR10R11, -(CR14R15)nNR10R11, -NR10R11, -NR12C(=Y)R10, -NR12C(=Y)NR10R11, -NR12SO2R10, OR10, SR10, -S(O)2R10, -S(O)2NR10R11, possibly substituted with carbocyclyl, selected from cyclopropyl, possibly substituted heterocyclyl selected from piperazine, possibly substituted with alkyl and alkylsulphonyl, pyrrolidine, morpholine, piperdine, possibly substituted CH3, phenyl and possibly substituted heteroaryl selected from imidazole and triazole; Y denotes O; m equals 0, 1 or 2; n equals 1 and t equals 2. The invention also relates to a pharmaceutical composition which modulates lipid kinase activity, based on said compounds.

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used to treat lipid kinase-mediated diseases, for example, cancer.

48 cl, 2 tbl, 372 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula where R1 is selected from H, F, CI, Br, CF3, C1-C6 alkoxy and OH; R2 is selected from H and C1-C6 alkyl; n equals 1-5; m equals 0 or 1; and Y is selected from CH2, NR3, (NR3R4)+X-, O and S; R3 and R4 are independently selected from H and C1-C4 alkyl; and X- is selected from pharmaceutically acceptable anions. The invention also relates to a method of producing said compound and to an antiviral pharmaceutical composition based on said compound of formula (I).

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used in medicine to treat a viral diseases such as herpes.

19 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: described is a compound of general formula: [1], where R1 denotes an optionally substituted C2-C12 alkyl, aryl or heterocyclic group which can be a mono- or bicyclic 5-11-member radical, where the heteroatoms can be nitrogen, oxygen or sulphur; X1 denotes C2-C4 an alkylene group; X2 denotes a bond; X3 denotes a group of general formula NR3 or CR4R5NR3 (where R3 denotes a hydrogen atom, optionally substituted lower alkyl group or imino-protective group) and R4 and R5 are identical or different, and each denotes a hydrogen atom or a lower alkyl group or bond; X4 denotes a lower alkylene or lower alkenylene or lower alkynylene group, which can be substituted with one or more oxo groups or a bond; X5 denotes a sulphur atom or bond; Y1 denotes an optionally substituted divalent 4-, 5- or 6-member alicyclic hydrocarbon residue or an optionally subsituted divalent 5- or 6-member alicyclic amine residue, where the heteroatoms can be nitrogen or oxygen; Z1, Z2, Z3, Z4, Z5 and Z6 are identical or different, and each denotes a nitrogen atom or a group of general formula CR7 (where R7 denotes a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted amino group, or an amino group substituted with one or more C1-6 alkyl groups, a lower alkyl group, a cycloalkyl, a lower alkoxy group or a monocyclic 5-member heterocyclic group which can be substituted with one or more halogen atoms, where the heteroatoms can be nitrogen, acid or sulphur or a group of general formula Q1CO2R10 (where R10 denotes a carboxyl-protective group and Q1 denotes a lower alkenylene group), provided that at least one of Z3, Z4, Z5 and Z6 denotes a nitrogen atom, or salt thereof. The invention also describes an antimicrobial agent based on said compound.

EFFECT: novel compounds which can be used as antimicrobial agents are obtained and described.

25 cl, 176 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of vinflunine ditartrate, production method thereof and use thereof in therapy, especially for cancer pathology treatment.

EFFECT: high stability and wide variety of galenic forms.

8 cl, 3 ex, 5 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a compound presented by formula (1), to its salt or hydrate where in formula R1 represents a methylene group, R2 represents a phenyl group which can contain a substitute(s), or a heterocyclic group which can contain a substitute(s), the cycle A represents a 6- or 7-members cycle (where cycle-making atoms of the cycle A different from a sulfur atom in position 6 are carbon atoms), and R3 represents a hydrogen atom, or 1-3 equal or different substitutes used to substitute the cycle A where the possible substitutes are specified in clause 1 of the patent claim. Also, the invention refers to a pharmaceutical composition exhibiting an anticancer activity, on the basis of the compound presented by formula (1).

EFFECT: there are produced new compounds and pharmaceutical composition on their basis which can find application in medicine for cancer treatment.

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds (la) of formula applied as tyrosine kinase c-Met inhibitors. , where: LA is selected from ,

or ; RA is selected from:

or each RA2 and RA6 represents hydrogen; RA3 represents RAr; or RA3, RA4 and carbon atoms whereto attached form 6-members aryl, optionally substituted, in the amount up to 4 by independent groups RAr, or a 5-6-members heterocyclyl or heteroaryl ring containing at least one O, N or S atom; R represents -OH; RA5 represents hydrogen or RAr; LB represents a covalent bond or -N(R*)-; RB represents halogen, NH2 or C1-8aliphatic group, optionally substituted by R; a 6-10-members aryl ring; a 3-7-members carbocyclyl ring, a 5-10-members heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms, where each said aryl or heteroaryl ring is optionally substituted, in the amount up to five by independent groups RAr; R represents halogen, -R°, -SR°, Ph, optionally substituted R° or -C(O)OR°; each RAr is independently selected from halogen, -R°, -OR°, -SR°, Ph, optionally substituted in the amount up to five by independent groups -R°, -CN, -N(R°)2 or -C(O)OR°; or two adjacent groups RAr taken together, represent 1,2-methylenedixy or 1,2-ethylenedixy; each R* represents hydrogen; and each R° represents independently hydrogen, an optionally substituted C1-6aliphatic radical or an unsubstituted 5-6-members heteroaryl or heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms.

EFFECT: invention refers to pharmaceutically acceptable compositions containing the compounds under the invention, and methods of application of the compositions in treatment of various proliferative disorders.

10 cl, 4 tbl, 548 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I in which A denotes X denotes O; R denotes H; R1 denotes OH, CN, a nitro group, NH2, NR2CSR8, NR2CONR2R9, NR2C SNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted with Ar or He, cycloalkenyl containing 5-8 carbon atoms, alkoxy group containing 1-4 carbon atoms, cycloalkoxy group containing 3-7 carbon atoms, cycloalkylalkoxy group containing 4-7 carbon atoms, fluorinated alkoxy group containing 1-4 carbon atoms, fluorinated hydroxyalkyl containing 1-4 carbon atoms, hydroxyalkoxy group containing 2-4 carbon atoms, an ordinary hydroxyalkoxy group containing 2-4 carbon atoms, monoalkylamino group containing 1-4 carbon atoms, dialkylamine group, where each alkyl group independently contains 1-4 carbon atoms, alkoxycarbonyl containing 2-6 carbon atoms, Het or OAr; R2 denotes H, alkyl containing 1-4 carbon atom, cycloalkyl containing 3-7 carbon atoms, and cycloalkyl alkyl containing 4-7 carbon atoms; R6 and R7 independently denote H, alkyl containing 1-4 carbon atoms, cycloalkyl containing 3-7 carbon atoms, or cycloalkylalkyl containing 4-7 carbon atoms, or R6 and R7 together denote an alkylene group containing 4-6 carbon atoms, which forms a ring with an N atom; R8 denotes alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 3-6 carbon atoms, alkynyl containing 3-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group is unsubstituted or substituted with Ar, cycloalkyl containing 3-7 carbon atoms, or Het; R9 denotes Ar or Het; R10 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar, or NR6R7; Ar denotes an aryl group containing 6-10 carbon atoms, which is unsubstituted or substituted once or several times with an alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, halogen, cyano group or combinations thereof; and Het denotes dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl or naphthyridinyl, which is unsubstituted or substituted once or several times with halogen, aryl containing 6-10 carbon atoms, which is optionally substituted with alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, oxo group, -CXR11 or combinations thereof, or R11 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar or Het; or pharmaceutically acceptable salts thereof, where formula IA is attached to the rest of the bonding molecule in the 3, 4 or 7 positions. The invention also relates to a pharmaceutical composition and to use of compounds in any of claims 1-37.

EFFECT: obtaining novel biologically active compounds, having nicotinic acetylcholine receptor subtype α7 ligand activity.

59 cl, 316 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula IB , where radicals R1-R5 have values, given in invention formula. In range of claimed invention also described are pharmaceutical compositions, which include compounds of IB formula, and methods of application of such compounds and compositions for treatment of different malfunctions, mainly selected from immune response reactions.

EFFECT: compounds by claimed invention have inhibiting action with respect to proteinkinases and, in particular with respect to JAK-3, ROCK or Aurora kinases.

55 cl, 6 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: disclosed is an agent which is 1,5-bis-(4-dodecyl-1,4-diazoniabicyclo[2.2.2]octan-1-yl)pentane dichloride dibromide with a structural formula shown on dwg. 1, which can be used to treat viral diseases of animals (e.g., bovine virus diarrhoea), accompanied by bacterial infections. Synthesis of the disclosed compound takes place in methanol as a solvent in 20-24 hours with molar ratio of the following components: 1-dodecyl-4-aza-1-azoniabicyclo[2.2.2]octane chloride to 1,5-dibromopentane equal to 1:(2.0-2.16), with 80.4-83.7% output of the end product.

EFFECT: agent has low toxicity, is stable during storage at room temperature for 3 years, has marked antibacterial action on pathogenic strains of microorganisms.

1 cl, 2 dwg, 3 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: described are novel diaminotriazole compounds of general formula

(values of radicals are given in the claim), pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds, a method of inhibiting JAK2 and JAK3 kinase activity and use of the novel compounds to produce a medicinal agent for treating several diseases.

EFFECT: high efficiency of the compounds.

19 cl, 3 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds selected from a group consisting of compounds of formula: and or to their pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition, as well as to using at least one compound under cl.1 and/or its pharmaceutically acceptable salts.

EFFECT: preparing new biologically active compounds which exhibit the properties of cycline-dependent kinase inhibitors.

11 cl, 86 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, where A denotes -CH2-, -O- or -NR'-, in which R' denotes hydrogen or C1-6alkyl, or R' and R4 form C2-5alkylene; R1 denotes hydrogen, amine group, C1-6alkyl, hydroxy group, -NR'R", (C0-6alkylene)-NR'R", where R' and R" are independently selected from a group comprising hydrogen, C1-6alkyl, heteroalkyl, formyl, C1-6alkylcarbonyl, arylcarbonyl optionally substituted with halogenalkyl, C1-6alkylsulphonyl, arylsulphonyl or -(C0-6alkylene)-OR', where R' denotes hydrogen, C1-6alkyl, formyl or C1-6alkylcarbonyl; R2 , R2 and R2 independently denote hydrogen, halogen, C1-6alkyl or C1-6alkoxy group; R3 denotes hydrogen, C1-6alkyl, aryl-C1-6alkyl, aryl optionally substituted with halogen, or heteroaryl, where the heteroaryl is a monocyclic or bicyclic ring containing 5-6 ring atoms and at least one aromatic ring containing one or three ring heteroatoms selected fron N, O and S, where the remaining ring atoms are carbon atoms, and the bonding site of the heteroaryl radical must be on the aromatic ring; R4 denotes hydrogen, C1-6alkyl, aryl, C3-7cycloalkyl-C1-6alkyl, aryl-C1-6alkyl; R5 denotes hydrogen or C1-6alkyl; or R4 and R5 together with the carbon atom to which they are bonded, form an optionally substituted C3-7cycloalkyl ring; R6 denotes hydrogen or C1-6alkyl; and pharmaceutically acceptable salts thereof, where the term "aryl" denotes phenyl or naphthyl. The invention also relates to a pharmaceutical composition based on compounds of formula I and having a inhibitory activity towards chymase.

EFFECT: novel compounds which can inhibit chymase are obtained and can be used as medicinal agents.

22 cl, 79 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described novel compounds of formula (I), where R1 represents hydroxymethyl; R2 is selected from -C(O)NR4R5; HET-1 represents 5- or 6-member heteroaryl ring, bound by atom C; R3 represents halogeno; R4 and R5 together with nitrogen atom, to which they are bound, can form heterocyclyl ring system, as it is defined for HET-3; HET-3 represents possibly substituted azetidinyl; m equals 1; n equals 0, 1 or 2; or their pharmaceutically acceptable salt, which can be applied as glucokinase (GLK) activators or active ingredient of pharmaceutical compositions, also described are methods of obtaining them.

EFFECT: creation of novel compounds applied as glucokinase (GLK) activators in treatment of diabetes.

13 cl, 40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I , in which A denotes hydrogen, B denotes methyl or B is in a trans-position relative oxygen; X denotes CH2; Y denotes a group of formula , , ,

, or ;

, in which the left-hand bond is to an oxygen atom, and the right-hand bond is to the group R; R denotes 5-indolyl; in form of a free base or an acid addition salt. The invention also relates to a pharmaceutical composition, to use of compounds in any of claims 1-7, to a method of preventing and treating psychiatric and neurodegenerative disorders in a person, as well as a method of treating and preventing diseases or pathological condition in which α7 nAChR activation plays a role.

EFFECT: obtaining novel biologically active compounds having α7 nAChR agonist activity.

16 cl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds which are N-substituted 1,4-diazabicyclo[2.2.2.]octane derivatives. The offered compounds exhibit antiviral activity and can find application in medicine as active components for the development of dosage forms used for treating viral diseases.

EFFECT: higher antiviral activity of the compound.

7 dwg, 4 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds of formulae and , in which radicals and symbols assume values defined in the formula of invention, e.g. to 1H-indazoles, 1,2-benzisoxazoles and 1,2-benzisothiazoles. Said compounds are receptor ligands of the α-7 nAChR subtype. The invention also relates to a pharmaceutical composition containing the said compounds.

EFFECT: possibility of using the said compounds to make medicinal agents for treating diseases associated with impaired functioning of nicotinic acetylcholine receptors and their abnormal functioning, primarily in brain cells.

46 cl, 85 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula I and their pharmaceutically acceptable salts. In structural formula I , X is oxygen; Y is oxygen; Y1 Y2, R7 and R4 represent H; X1 and X2 are independently selected from a group consisting of hydrogen, an alkyl group containing 1 to 5 carbon atoms, in which one or more hydrogen atoms of the alkyl group can be substituted with a halogen, aryl group containing 6 to 10 carbon atoms or a cycloalkyl group containing 3 to 9 carbon atoms, or a 5-9-member heterocyclic group with 2 heteroatoms selected from N and O, or a cycloalkyl group containing 5 to 9 carbon atoms; values of the rest of the radicals are given in the formula of invention. The invention also pertains to a pharmaceutical composition having properties of selective inhibitors of type IV phosphodiesterase, containing a therapeutically effective amount of the invented compound.

EFFECT: increased effectiveness of the compounds.

6 cl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (III) in form of a free base or an acid addition salt, use thereof as a pharmaceutical agent for preventing, treating and/or inhibiting progression of psychotic and neurodegenerative disorders, as well as pharmaceutical compositions based on said compound.

EFFECT: novel compound which can be used to prevent, treat or inhibit progression of diseases or a pathologic condition in which nAChR α7 activation participates or plays a role.

8 cl, 2 ex

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