DESC:PRIORITY APPLICATION(S)

This application claims priority to Indian Patent Application No. 2543/MUM/2015 filed on July 02, 2015, the disclosures of which is incorporated herein by reference in its entirety as if fully rewritten herein.

FIELD OF THE INVENTION

The invention relates to nitrogen containing bicyclic compounds, their preparation and their use in preventing or treating infections.

BACKGROUND OF THE INVENTION

Emergence of bacterial resistance to known antibacterial agents is becoming a major challenge in treating bacterial infections. One way forward to treat bacterial infections, and especially those caused by resistant bacteria, is to develop newer antibacterial agents that can overcome the bacterial resistant. Coates et al. (Br. J. Pharmacol. 2007; 152(8), 1147-1154.) have reviewed novel approaches to developing new antibiotics. However, the development of new antibacterial agents is a challenging task. For example, Gwynn et al. (Annals of the New York Academy of Sciences, 2010, 1213: 5-19) have reviewed the challenges in discovery of antibacterial agents.

Several antibacterial agents have been described in the prior art (for example, see PCT International Application Nos. PCT/US2010/060923, PCT/EP2010/067647, PCT/US2010/052109, PCT/US2010/048109, PCT/GB2009/050609, PCT/FR01/02418, PCT/EP2009/056178, PCT/US2009/041200, PCT/IB2012/054290, PCT/IB2013/053092, PCT/IB2012/054296, PCT/IB2012/054706, PCT/JP2013/064971, PCT/IB2012/002675, PCT/US2013/034562 and PCT/US2013/034589). However, there remains a need for development of antibacterial agents for preventing and/or treating bacterial infections, including those caused by bacteria that are resistant to known antibacterial agents.

The inventors have now surprisingly discovered novel nitrogen containing bicyclic compounds having antibacterial activity.

SUMMARY OF THE INVENTION

Accordingly, there are provided nitrogen containing bicyclic compounds, methods for preparation of these compounds, pharmaceutical compositions comprising these compounds, and methods for preventing or treating bacterial infection in a subject using these compounds.

In one general aspect, there are provided compounds of Formula (I):

or a stereoisomer or a pharmaceutically acceptable derivative thereof;

wherein:
R1 and R2 are each independently:

(a) hydrogen,
(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from OR3, NR3R4, SR3, halogen, CN, COOR3, CONR3R4, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
(c) cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, (CH2)nNR3R4, (CH2)nOR3, (CH2)nCN, (CH2)nCOOR3, (CH2)nCONR3R4, OR3, O(CH2)nNR3R4, O(CH2)nCN, O(CH2)nCOOR3, O(CH2)nCONR3R4, NR3R4, NH(CH2)nNR3R4, NH(CH2)nCN, NH(CH2)nCOOR3, NH(CH2)nCONR3R4, SR3, halogen, CN, COOR3, CONR3R4, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
(d) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, (CH2)nNR3R4, (CH2)nOR3, (CH2)nCN, (CH2)nCOOR3, (CH2)nCONR3R4, OR3, O(CH2)nNR3R4, O(CH2)nCN, O(CH2)nCOOR3, O(CH2)nCONR3R4, NR3R4, NH(CH2)nNR3R4, NH(CH2)nCN, NH(CH2)nCOOR3, NH(CH2)nCONR3R4, SR3, halogen, CN, COOR3, CONR3R4, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
(e) heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, (CH2)nNR3R4, (CH2)nOR3, (CH2)nCN, (CH2)nCOOR3, (CH2)nCONR3R4, OR3, O(CH2)nNR3R4, O(CH2)nCN, O(CH2)nCOOR3, O(CH2)nCONR3R4, NR3R4, NH(CH2)nNR3R4, NH(CH2)nCN, NH(CH2)nCOOR3, NH(CH2)nCONR3R4, SR3, halogen, CN, COOR3, CONR3R4, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
(f) heterocycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, (CH2)nNR3R4, (CH2)nOR3, (CH2)nCN, (CH2)nCOOR3, (CH2)nCONR3R4, OR3, O(CH2)nNR3R4, O(CH2)nCN, O(CH2)nCOOR3, O(CH2)nCONR3R4, NR3R4, NH(CH2)nNR3R4, NH(CH2)nCN, NH(CH2)nCOOR3, NH(CH2)nCONR3R4, SR3, halogen, CN, COOR3, CONR3R4, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
(g) CN,
(h) COR3,
(i) COOR3,
(j) NR3R4,
(k) CONR3R4,
(l) OR3, or
(m) R1 and R2 are joined together to form three to eight membered ring;

R3 and R4 are each independently:

(a) hydrogen,
(b) C1-C6 alkyl,
(c) cycloalkyl,
(d) aryl,
(e) arylalkyl,
(f) heteroaryl, or
(g) heterocycloalkyl;

n is 0 to 6;

M is hydrogen or a cation.
In one general aspect, there are provided pharmaceutical compositions comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof.

In another general aspect, there are provided methods for preventing or treating a bacterial infection in a subject, said methods comprising administering to said subject a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof.

In another general aspect, there are provided methods for preventing or treating a bacterial infection in a subject, said methods comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer, or a pharmaceutically acceptable derivative thereof.

In yet another general aspect, there are provided pharmaceutical compositions comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

In another general aspect, there are provided a methods for preventing or treating a bacterial infection in a subject, said methods comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

In another general aspect, there are provided methods for preventing or treating a bacterial infection in a subject, said methods comprising administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

In yet another general aspect, there are provided methods for increasing antibacterial effectiveness of an antibacterial agent in a subject, said methods comprising co-administering said antibacterial agent or a pharmaceutically acceptable derivative thereof with a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the following description including claims.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made to the exemplary embodiments, and specific language will be used herein to describe the same. It should nevertheless be understood that no limitation of the scope of the invention is thereby intended. Alterations and further modifications of the inventive features illustrated herein, which would occur to one skilled in the relevant art and having possession of this disclosure, are to be considered within the scope of the invention. It must be noted that, as used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise. All references including patents, patent applications, and literature cited in the specification are expressly incorporated herein by reference in their entirety.

The inventors have surprisingly discovered novel nitrogen containing bicyclic compounds having antibacterial properties.
The term “C1-C6 alkyl” as used herein refers to branched or unbranched acyclic hydrocarbon radical with 1 to 6 carbon atoms. Typical non-limiting examples of “C1-C6 alkyl” include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, tert-pentyl, neopentyl, sec-pentyl, 3-pentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and the like. The “C1-C6 alkyl” may be unsubstituted, or substituted with one or more substituents. Typical, non-limiting examples of such substituents include halogen, alkoxy, CN, SH, COOH, COOC1-C6alkyl, CONH2, OH, NH2, NHCOCH3, cycloalkyl, heterocycloalkyl, heteroaryl, aryl and the like.

The term “cycloalkyl” as used herein refers to three to seven member cyclic hydrocarbon radicals. The cycloalkyl group optionally incorporates one or more double or triple bonds, or a combination of double or triple bonds, but which is not aromatic. Typical, non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The cycloalkyl may be unsubstituted, or substituted with one or more substituents. Typical, non-limiting examples of such substituents include C1-C6 alkyl, halogen, alkoxy, CN, SH, COOH, COOC1-C6alkyl, CONH2, OH, NH2, NHCOCH3, heterocycloalkyl, heteroaryl, aryl, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl and the like.

The term “aryl” as used herein refers to a monocyclic or polycyclic aromatic hydrocarbon. Typical, non-limiting examples of aryl groups include phenyl, naphthyl, anthracenyl, flourenyl, phenanthrenyl, indenyl and the like. The aryl group may be unsubstituted, or substituted with one or more substituents. Typical, non-limiting examples of such substituents include C1-C6 alkyl, halogen, alkoxy, CN, COOH, CONH2, OH, NH2, NHCOCH3, heterocycloalkyl, heteroaryl, aryl, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl and the like. In some embodiments, the term “aryl” refers to a monocyclic or polycyclic aromatic hydrocarbon radical containing up to 14 ring atoms. In some embodiments, the term “aryl” refers to six to fourteen membered monocyclic or polycyclic aromatic hydrocarbon radical.

The term “heteroaryl” as used herein refers to a monocyclic or polycyclic aromatic hydrocarbon group wherein one or more carbon atoms have been replaced with heteroatoms selected from nitrogen, oxygen, and sulfur. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Typical, non-limiting example of heteroaryl groups include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, pyrrolyl, thienyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazonyl, isoxazolyl, oxadiazolyl, oxatriazolyl, isothiazolyl, thiatriazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, tetrazolo-pyridazinyl, purinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzothiophenyl, carbazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzotriazolyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, acridinyl, naphthothienyl, thianthrenyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl,indazolyl, phthalazinyl, naphthyridinyl, qinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, beta-carbolinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like. The heteroaryl group may be unsubstituted, or substituted with one or more substituents. Typical, non-limiting examples of such substituents include C1-C6 alkyl, halogen, alkoxy, CN, COOH, CONH2, OH, SH, SCH3, NH2, NHCOCH3, heterocycloalkyl, heteroaryl, aryl, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl and the like. In some embodiments, the term “heteroaryl” refers to a monocyclic or polycyclic aromatic hydrocarbon radical containing up to 14 ring atoms. In some embodiments, the term “heteroaryl” refers to five to fourteen membered monocyclic or polycyclic aromatic hydrocarbon radical.

The term “heterocycloalkyl” as used herein refers to three to seven member cycloalkyl group containing one or more heteroatoms selected from nitrogen, oxygen or sulfur. The heterocycloalkyl group optionally incorporates one or more double or triple bonds, or a combination of double bonds and triple bonds, but which is not aromatic. Typical, non-limiting example of heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, imidazolidin-2-one-yl, piperidinyl, oxazinyl, thiazinyl, piperazinyl, piperazin-2,3-dione-yl, morpholinyl, thiomorpholinyl, azepanyl, and the like. The heterocycloalkyl may be unsubstituted, or substituted with one or more substituents. Typical, non-limiting examples of such substituents include C1-C6 alkyl, halogen, alkoxy, CN, COOH, CONH2, OH, NH2, NHCOCH3, heteroaryl, aryl, SO2-alkyl, SO2-aryl, OSO2-aryl and the like.

The term “arylalkyl” as used herein refers to alkyl group substituted with one or more aryl group, wherein aryl group may be further substituted with one or more substituent independently selected from C1-C6 alkyl, C1-C6 haloalkyl, alkoxy, CN, COOH, CONH2, OH, NH2, NHCOCH3, nitro and the like. Typical, non-limiting examples of arylalkyl groups include benzyl, phenylethyl, phenylbutyl, phenylpentyl, naphthylmethyl and the like. The alkyl chain of arylalkyl group may optionally incorporate one or more double or triple bonds.

The term “halogen” or halo as used herein refers to chlorine, bromine, fluorine or iodine.

The term “stereoisomers” as used herein refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space. The compounds of Formula (I) may contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. It is intended, unless specified otherwise, that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers (including cis and trans-forms), as well as mixtures thereof, are embraced within the scope of the invention. In general, a reference to a compound is intended to cover its stereoisomers and mixture of various stereoisomers.

The term “optionally substituted” as used herein means that substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties. A “substituted” atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a selection from the indicated substituent group, provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound.

The term “pharmaceutically acceptable derivative” as used herein refers to and includes any pharmaceutically acceptable salt, pro-drug, metabolite, ester, ether, hydrate, polymorph, solvate, complex, and adduct of a compound described herein which, upon administration to a subject, is capable of providing (directly or indirectly) the parent compound. For example, the term “antibacterial agent or a pharmaceutically acceptable derivative thereof” includes all derivatives of the antibacterial agent (such as salts, pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, and adducts) which, upon administration to a subject, are capable of providing (directly or indirectly) the antibacterial agent.

The term “pharmaceutically acceptable salt” as used herein refers to one or more salts of a given compound which possesses the desired pharmacological activity of the free compound and which are neither biologically nor otherwise undesirable. In general, the “pharmaceutically acceptable salts” refer to salts that are suitable for use in contact with the tissues of human and animals without undue toxicity, irrigation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. (J. Pharmaceutical Sciences, 66; 1-19, 1977), incorporated herein by reference in its entirety, describes various pharmaceutical acceptable salts in details.

In general, the compounds according to the invention contain basic (e.g. nitrogen atoms) as well as acid moieties (e.g. compounds of Formula (I) wherein M is hydrogen). A person of skills in the art would appreciate that such compounds, therefore, can form acidic salts (formed with inorganic and/or organic acids), as well as basic salts (formed with inorganic and/or organic bases). Such salts can be prepared using procedures described in the art. For example, the basic moiety can be converted to its salt by treating a compound with a suitable amount of acid. Typical, non-limiting examples of such suitable acids include hydrochloric acid, trifluoroacetic acid, methanesulfonic acid or the like. Alternatively, the acid moiety may be converted into its salt by treating with a suitable base. Typical non-limiting examples of such bases include sodium carbonate, sodium bicarbonate, sodium ethylhexanoate, potassium carbonate, potassium bicarbonate, potassium ethyl hexanoate or the like. In case of compounds containing more than one functional group capable of being converted into salt, each such functional group may be converted to salt independently. For example, in case of compounds containing two basic nitrogen atoms, one of the basic nitrogen can form salt with one acid while the other basic nitrogen can form salt with another acid. Some compounds according to the invention contain both acidic as well as basic moieties, and thus can form inner salts or corresponding zwitterions. In general, all pharmaceutically acceptable salt forms of compound of Formula (I) according to invention including acid addition salts, base addition salts, zwitterions or the like are contemplated to be within the scope of the present invention and are generically referred to as pharmaceutically acceptable salts.

The term “infection” or “bacterial infection” as used herein includes presence of bacteria, in or on a subject, which, if its growth were inhibited, would result in a benefit to the subject. As such, the term “infection” in addition to referring to the presence of bacteria also refers to presence of other floras, which are not desirable. The term “infection” includes infection caused by bacteria.

The term “treat”, “treating” or “treatment” as used herein refers to administration of a medicament, including a pharmaceutical composition, or one or more pharmaceutically active ingredients, for prophylactic and/or therapeutic purposes. The term “prophylactic treatment” refers to treating a subject who is not yet infected, but who is susceptible to, or otherwise at a risk of infection (preventing the bacterial infection). The term “therapeutic treatment” refers to administering treatment to a subject already suffering from infection. The terms “treat”, “treating” or “treatment” as used herein also refer to administering compositions, or one or more of pharmaceutically active ingredients discussed herein, with or without additional pharmaceutically active or inert ingredients, in order to: (i) reduce or eliminate either a bacterial infection, or one or more symptoms of a bacterial infection, or (ii) retard progression of a bacterial infection, or one or more symptoms of a bacterial infection, or (iii) reduce severity of a bacterial infection, or one or more symptoms of a bacterial infection, or (iv) suppress clinical manifestation of a bacterial infection, or (v) suppress manifestation of adverse symptoms of a bacterial infection.

The terms “pharmaceutically effective amount” or “therapeutically effective amount” or “effective amount” as used herein refer to an amount, which has a therapeutic effect or is the amount required to produce a therapeutic effect in a subject. For example, a “therapeutically effective amount” or “pharmaceutically effective amount” or “effective amount” of an antibacterial agent or a pharmaceutical composition is the amount of the antibacterial agent or the pharmaceutical composition required to produce a desired therapeutic effect as may be judged by clinical trial results, model animal infection studies, and/or in vitro studies (e.g. in agar or broth media). Such effective amount depends on several factors, including but not limited to, the microorganism (e.g. bacteria) involved, characteristics of the subject (for example height, weight, sex, age and medical history), severity of infection and particular type of the antibacterial agent used. For prophylactic treatments, a prophylactically effective amount is that amount which would be effective in preventing the bacterial infection.
The term “administration” or “administering” refers to and includes delivery of a composition, or one or more pharmaceutically active ingredients to a subject, including for example, by any appropriate method, which serves to deliver the composition or its active ingredients or other pharmaceutically active ingredients to the site of infection. The method of administration may vary depending on various factors, such as for example, the components of the pharmaceutical composition or type/nature of the pharmaceutically active or inert ingredients, site of the potential or actual infection, the microorganism involved, severity of the infection, age and physical condition of the subject and a like. Some non-limiting examples of ways to administer a composition or a pharmaceutically active ingredient to a subject according to this invention include oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drop and mouthwash. In case of a pharmaceutical composition comprising more than one ingredients (active or inert), one of the ways of administering such composition is by admixing the ingredients (e.g. in the form of a suitable unit dosage form such as tablet, capsule, solution, powder or a like) and then administering the dosage form. Alternatively, the ingredients may also be administered separately (simultaneously or one after the other) as long as these ingredients reach beneficial therapeutic levels such that the composition as a whole provides a synergistic and/or desired effect.

The term “growth” as used herein refers to a growth of one or more microorganisms and includes reproduction or population expansion of the microorganism (e.g. bacteria). The term “growth” also includes maintenance of on-going metabolic processes of the microorganism, including the processes that keep the microorganism alive.

The term, “effectiveness” as used herein refers to ability of a treatment, or a composition, or one or more pharmaceutically active ingredients to produce a desired biological effect in a subject. For example, the term “antibacterial effectiveness” of a composition or of an antibacterial agent refers to the ability of the composition or the antibacterial agent to prevent or treat bacterial infection in a subject.

The term “synergistic” or “synergy” as used herein refers to the interaction of two or more agents so that their combined effect is greater than their individual effects.

The term “antibacterial agent” as used herein refers to any substance, compound, a combination of substances, or a combination of compounds capable of: (i) inhibiting, reducing or preventing growth of bacteria; (ii) inhibiting or reducing ability of a bacteria to produce infection in a subject; or (iii) inhibiting or reducing ability of bacteria to multiply or remain infective in the environment. The term “antibacterial agent” also refers to compounds capable of decreasing infectivity or virulence of bacteria.

The term “beta-lactamase” or “beta-lactamase enzyme” as used herein refers to any enzyme or protein or any other substance that breaks down a beta-lactam ring. The term “beta-lactamase” includes enzymes that are produced by bacteria and have the ability to hydrolyze the beta-lactam ring in a beta-lactam compound, either partially or completely.

The term “beta-lactamase inhibitor” as used herein refers to a compound capable of inhibiting activity of one or more beta-lactamase enzymes, either partially or completely.

The term “pharmaceutically inert ingredient” or “carrier” or “excipient” refers to and includes compounds or materials used to facilitate administration of a compound, for example, to increase the solubility of the compound. Typical, non-limiting examples of solid carriers include starch, lactose, dicalcium phosphate, sucrose, and kaolin. Typical, non-limiting examples of liquid carriers include sterile water, saline, buffers, non-ionic surfactants, and edible oils. In addition, various adjuvants commonly used in the art may also be included. These and other such compounds are described in literature, e.g., in the Merck Index (Merck & Company, Rahway, N.J.). Considerations for inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press., 1990), which is incorporated herein by reference in its entirety.

The term “subject” as used herein refers to vertebrate or invertebrate, including a mammal. The term “subject” includes human, animal, a bird, a fish, or an amphibian. Typical, non-limiting examples of a “subject” include humans, cats, dogs, horses, sheep, bovine cows, pigs, lambs, rats, mice and guinea pigs.

In general, the term cation includes Na, K, NH4+, (CH3CH2)3N and the like.

In one general aspect there are provided compounds of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof:

wherein:
R1 and R2 are each independently:
(a) hydrogen,
(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from OR3, NR3R4, SR3, halogen, CN, COOR3, CONR3R4, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
(c) cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, (CH2)nNR3R4, (CH2)nOR3, (CH2)nCN, (CH2)nCOOR3, (CH2)nCONR3R4, OR3, O(CH2)nNR3R4, O(CH2)nCN, O(CH2)nCOOR3, O(CH2)nCONR3R4, NR3R4, NH(CH2)nNR3R4, NH(CH2)nCN, NH(CH2)nCOOR3, NH(CH2)nCONR3R4, SR3, halogen, CN, COOR3, CONR3R4, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
(d) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, (CH2)nNR3R4, (CH2)nOR3, (CH2)nCN, (CH2)nCOOR3, (CH2)nCONR3R4, OR3, O(CH2)nNR3R4, O(CH2)nCN, O(CH2)nCOOR3, O(CH2)nCONR3R4, NR3R4, NH(CH2)nNR3R4, NH(CH2)nCN, NH(CH2)nCOOR3, NH(CH2)nCONR3R4, SR3, halogen, CN, COOR3, CONR3R4, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
(e) heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, (CH2)nNR3R4, (CH2)nOR3, (CH2)nCN, (CH2)nCOOR3, (CH2)nCONR3R4, OR3, O(CH2)nNR3R4, O(CH2)nCN, O(CH2)nCOOR3, O(CH2)nCONR3R4, NR3R4, NH(CH2)nNR3R4, NH(CH2)nCN, NH(CH2)nCOOR3, NH(CH2)nCONR3R4, SR3, halogen, CN, COOR3, CONR3R4, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
(f) heterocycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, (CH2)nNR3R4, (CH2)nOR3, (CH2)nCN, (CH2)nCOOR3, (CH2)nCONR3R4, OR3, O(CH2)nNR3R4, O(CH2)nCN, O(CH2)nCOOR3, O(CH2)nCONR3R4, NR3R4, NH(CH2)nNR3R4, NH(CH2)nCN, NH(CH2)nCOOR3, NH(CH2)nCONR3R4, SR3, halogen, CN, COOR3, CONR3R4, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
(g) CN,
(h) COR3,
(i) COOR3,
(j) NR3R4,
(k) CONR3R4,
(l) OR3, or
(m) R1 and R2 are joined together to form three to eight membered ring;

R3 and R4 are each independently:
(a) hydrogen,
(b) C1-C6 alkyl,
(c) cycloalkyl,
(d) aryl,
(e) arylalkyl,
(f) heteroaryl,
(g) heterocycloalkyl or

n is 0 to 6;

M is hydrogen or a cation.

Typical, non-limiting examples of compounds according to the invention include:

(2S,5R)-N'-[(2-methoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(2-benzyloxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'- [(2,5-dimethoxyphenyl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(3,4-dimethoxyphenyl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[4-(dimethylamino)phenyl] methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2-hydroxyphenyl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(3-methoxyphenyl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(6-methylpyridin-2-yl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(4-methoxyphenyl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1 ]octane-2-carbohydrazide;
(2S,5R)-N'-[(2-cyanophenyl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(4-cyanophenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(2,6-dimethoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2,4-dimethoxyphenyl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2,4,6-trimethoxyphenyl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-(furan-2-yl-methylidene)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-(thiophen-2-yl-methylidene)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[pyridin-2-ylmethylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(6-methoxypyridin-3-yl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2-methoxypyridin-3-yl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2-hydroxyphenyl)methylidene]-7-oxo-6-(sulfooxy)- 1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(3-hydroxypyridin-2-yl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-7-oxo-N'-(pyrrolidin-2-yl-methylidene)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-7-oxo-N'-[piperidin-2-ylmethylidene]-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-7-oxo-N'-[piperidin-4-ylmethylidene]-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(6-methoxypyridin-2-yl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[3-aminopropylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[4-(aminomethyl)phenyl] methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[1-(2,4-dimethoxyphenyl) ethylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1] octane-2-carbohydrazide;
(2S,5R)-7-oxo-N'-[1-phenylethylidene]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[1-(2-methoxyphenyl) ethylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-cyclopentylidene-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-(4-piperidinylidene)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[4-(2-(methylamino)ethoxy)phenyl]methylidene}-7-oxo-6- (sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[4-(2-(dimethylamino)ethoxy)phenyl]methylidene}-7-oxo-6- (sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{([4-(2-aminopropoxy)phenyl]methylidene}-7-oxo-6- (sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[4-(2-(dimethylamino)propoxy)phenyl]methylidene}-7-oxo-6-(sulfooxy) -1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[4-(2-aminoethoxy)-2-methoxyphenyl]methylidene}-7-oxo-6-(sulfooxy) -1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[3-(2-aminoethoxy)phenyl]methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{2-[4-(2-aminoethoxy)phenyl]ethylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-7-oxo-N'-(piperidin-4-ylidene)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[1-amino-3-phenylpropan-2-ylidene]-7-oxo-6-(sulfooxy) -1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[4-{(2S)-pyrrolidin-2-ylmethoxy}phenyl]methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[4-{(3R)-pyrrolidin-3-yloxy}phenyl]methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;

or a stereoisomer or a pharmaceutically acceptable derivative thereof.

In some other embodiments, typical, non-limiting examples of compounds according to the invention include:
Sodium salt of (2S,5R)-N'-[(2-methoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2-benzyloxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2,5-dimethoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(3,4-dimethoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[4-(dimethylamino)phenyl]methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2-hydroxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(3-methoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6-methylpyridin-2-yl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(4-methoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2-cyanophenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(4-cyanophenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2,6-dimethoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2,4-dimethoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2,4,6-trimethoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-(furan-2-yl-methylidene)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-(thiophen-2-yl-methylidene)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[pyridin-2-ylmethylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6-methoxypyridin-3-yl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2-methoxypyridin-3-yl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2-hydroxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(3-hydroxypyridin-2-yl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-7-oxo-N'-(pyrrolidin-2-yl-methylidene)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-7-oxo-N'-[piperidin-2-ylmethylidene]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-7-oxo-N'-[piperidin-4-ylmethylidene]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6-methoxypyridin-2-yl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[3-aminopropylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[4-(aminomethyl)phenyl]methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[1-(2,4-dimethoxyphenyl)ethylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-7-oxo-N'-[1-phenylethylidene]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[1-(2-methoxyphenyl)ethylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-cyclopentylidene-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide ;
Sodium salt of (2S,5R)-N'-(4-piperidinylidene)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[4-(2-(methylamino)ethoxy)phenyl]methylidene}-7-oxo-6- (sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[4-(2-(dimethylamino)ethoxy)phenyl]methylidene}-7-oxo-6- (sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{([4-(2-aminopropoxy)phenyl]methylidene}-7-oxo-6- (sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[4-(2-(dimethylamino)propoxy)phenyl]methylidene}-7-oxo-6-(sulfooxy) -1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[4-(2-aminoethoxy)-2-methoxyphenyl]methylidene}-7-oxo-6-(sulfooxy) -1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[3-(2-aminoethoxy)phenyl]methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{2-[4-(2-aminoethoxy)phenyl]ethylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-7-oxo-N'-(piperidin-4-ylidene)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1] octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[1-amino-3-phenylpropan-2-ylidene]-7-oxo-6-(sulfooxy) -1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[4-{(2S)-pyrrolidin-2-ylmethoxy}phenyl]methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[4-{(3R)-pyrrolidin-3-yloxy}phenyl]methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;

or a stereoisomer thereof.

In general, the compounds of the invention can be prepared according to the general procedures given in Scheme 1 and Scheme 2. A person of skills in the art would appreciate that the described method can be varied or optimized further to provide the desired and related compounds. In the following procedures all variables are as defined above.

In one general aspect, a compound of Formula (II), a key intermediate in the synthesis of compounds according to invention, can be prepared by the general procedure as described in Scheme 1. A compound of Formula (III), sodium salt of (2S, 5R)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carboxylic acid, (prepared as per the procedure disclosed in International Patent Application No. WO2014135929) is treated with a compound of Formula (IV) in presence of a suitable coupling agent and a suitable solvent at a temperature ranging from about -15°C to about 60°C for about 1 to about 24 hours to obtain a compound of Formula (V). Typical, non-limiting examples of suitable coupling agents include 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOsu), 1-hydroxy-7-azabenzotriazolo (HOAt), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate) (HATU), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrop), O-(7-azabenzotriazol-1-yl)-1,3-dimethyl-1,3-trimethylene uranium hexafluorophosphate (HAMTU), 2-(5-norborene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU), 2-(2-Pyridon-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), and the like, or a mixture thereof. Typical, non-limiting examples of suitable solvents include N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, chloroform, dichloromethane, tetrahydrofuran, acetonitrile, water, and the like, or a mixture thereof. In some embodiments, a compound of Formula (III) is reacted with a compound of Formula (IV) in presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), 1-hydroxybenzotriazole (HOBt), N-methyl morpholine (NMM) and water at a temperature of about 25°C for about 19 hours to obtain a compound of Formula (V).

The compound of Formula (V) is debenzylated by carrying out hydrogenolysis in presence of hydrogen, transition metal catalyst and a suitable solvent at a temperature ranging from about 10°C to about 60°C for about 1 hour to about 14 hour to provide a compound of Formula (VI). Typical, non-limiting examples of hydrogen source include hydrogen gas, ammonium formate, cyclohexene, lithium –liquid ammonia, ammonia – tert-butanol, sodium – liquid ammonia – tert-butanol, triethyl silyl hydride and the like. Typical, non-limiting examples of transition metal catalyst include 5% palladium on carbon, 10% palladium on carbon, 20% palladium hydroxide on carbon, Raney-Nickel and the like. Typical, non-limiting examples of suitable solvent include methanol, ethanol, dichloromethane, N,N dimethylformamide, ethyl acetate, tetrahydrofuran, and the like, or a mixture thereof. In some embodiments, compound of Formula (V) is treated with 10% palladium on carbon in presence of hydrogen gas at 4 kg atmospheric pressure and at temperature of about 25°C for about 2 hours to provide a compound of Formula (VI). In some embodiments, the solvent used in conversion of a compound of Formula (V) to a compound of Formula (VI) is methanol.

The compound of Formula (VI) is sulfonated by reacting with suitable sulfonating reagent in a suitable solvent such as pyridine, dichloromethane or N,N-dimethylformamide, at a temperature ranging from about 0°C to about 80°C for about 1 hour to about 24 hour. Typical, non-limiting examples of suitable sulfonating reagent include sulfur trioxide pyridine complex, sulfur trioxide trimethylamine complex, sulfur trioxide triethylamine complex, sulfur trioxide N,N-dimethylaniline complex, sulfur trioxide 2-methylpyridine complex, sulfur trioxide dioxane complex, sulfur trioxide thioxane complex, sulfur trioxide dimethyl sulfide complex, sulfur trioxide dimethylsulfoxide complex, sulfur trioxide N,N-dimethylformamide complex and the like. In some embodiments, compound of Formula (VI) is reacted with sulfur trioxide pyridine complex in presence of triethylamine and dichloromethane at a temperature of about 25°C for about 19-20 hours to provide the sulfonated compound. The obtained sulfonated compound is converted to its corresponding tetrabutylammonium salt of Formula (VII).

The compound of Formula (II) is then isolated as zwitterions, by removing the protecting groups of a compound of Formula (VII). The compound of Formula (VII) is treated with a suitable deprotecting agent in presence of a suitable solvent such as dichloromethane, chloroform or acetonitrile, at a temperature ranging from about -15°C to about 40°C for about 0.5 hours to about 14 hours to obtain a compound of Formula (II). In some embodiments, compound of Formula (VII) is treated with trifluoroacetic acid in presence of dichloromethane at temperature of about -10°C to about -5°C for about 4 hours to provide a compound of Formula (II).

The compound of Formula (II) is then converted to a compound of Formula (I) by following the procedure disclosed in Scheme 2. The compound of Formula (II) is reacted with a suitable aldehyde or ketone compound of Formula (VIII) in presence of a suitable solvent at a suitable temperature to provide a compound of Formula (XI). Typical, non-limiting examples of solvent include ethanol, methanol, butanol, 2-propanol, water, tetrahydrofuran, dimethylformamide, dimethylacetamide, dichloromethane, ethyl acetate, hexane, toluene or a mixture thereof. In some embodiments, the conversion of a compound of Formula (II) to a compound of Formula (XI) is carried out in presence of a suitable reagent selected from the group comprising of ammonium acetate, diisopropylethyl amine, glacial acetic acid, cerium (III) chloride, zinc perchlorate, 4-methyl benzene sulfonic acid, ammonium cerium (IV) nitrate and the like.

The compound of Formula (XI) can also be prepared by reacting (2S, 5R)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carboxylic acid (IX) with a hydrazinylidene compound of Formula (X). In some embodiments, a compound of Formula (IX) is reacted with a compound of Formula (X) in presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), 1-hydroxybenzotriazole (HOBt), N-methyl morpholine (NMM) and N,N-dimethyl formamide at a temperature of about 25°C. The obtained product is further subjected to hydrogenolysis under atmospheric hydrogen pressure in presence of transition metal catalyst and suitable solvent to obtain debenzylated product. The debenzylated compound is sulfonated to obtain a compound of Formula (XI) (as shown in Scheme 2).
In some embodiments, the substituents R1 and R2 of the reagents as shown in Scheme 2 are protected with suitable protecting groups. These protecting groups are later removed in the reaction with suitable deprotecting reagents.

The compound of Formula (XI) is further converted to corresponding tetrabutylammonium salt of Formula (XII). In some embodiments, compound of Formula (XI) is treated with tetrabutylammonium acetate (TBAA) to obtain a compound of Formula (XII). The compounds according to invention are isolated as zwitterions or as corresponding salts. In some embodiments, compounds according to invention are isolated as zwitterions, wherein a compound of Formula (XII) is treated with a suitable deprotecting agent in presence of a suitable solvent such as dichloromethane, chloroform, acetonitrile, and the like. In some embodiments, compound of Formula (XII) is treated with trifluoroacetic acid in presence of dichloromethane to provide a compound of Formula (I).

In some embodiments, compounds according to invention are isolated as pharmaceutically acceptable salts. In some embodiments, compounds according to invention are isolated as sodium salts, wherein a compound of Formula (XII) is dissolved in suitable solvent and passed through cation exchange resin. In some other embodiments, compound of Formula (XII) is dissolved in 10% tetrahydrofuran: water mixture and then passed through the column packed with cation exchange resin such as Dowex 50WX8 200 Sodium resin, Indion 225 Sodium resin and the like. In some embodiments, compound of Formula (XII) is dissolved in suitable solvent such as acetone, tetrahydrofuran, ethanol, isopropanol, acetonitrile, and the like, and treated with sodium ethylhexanoate or potassium ethylhexanoate to provide corresponding sodium or potassium salt of compound of Formula (I).

In some embodiments, there are provided pharmaceutical compositions comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided pharmaceutical compositions comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided pharmaceutical compositions comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, avibactam or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided pharmaceutical compositions comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided pharmaceutical compositions comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftalozane or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided pharmaceutical compositions comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent, or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided methods for preventing or treating a bacterial infection in a subject, said methods comprising administering to said subject a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided methods for preventing or treating a bacterial infection in a subject, said methods comprising administering to said subject a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof and (b) at least one beta-lactamase inhibitor or pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided methods for preventing or treating a bacterial infection in a subject, said methods comprising administering to said subject a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, avibactam, or pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided methods for preventing or treating a bacterial infection in a subject, said methods comprising administering to said subject a pharmaceutical composition comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided methods for preventing or treating a bacterial infection in a subject, said methods comprising administering to said subject a pharmaceutical composition comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent selected from selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftalozane or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided methods for preventing or treating a bacterial infection in a subject, said methods comprising administering to said subject a pharmaceutical composition comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or pharmaceutically acceptable derivative thereof and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided methods for preventing or treating a bacterial infection in a subject, said method comprising administering to said subject a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided methods for preventing or treating a bacterial infection in a subject, said methods comprising administering to said subject: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided methods for preventing or treating a bacterial infection in a subject, said methods comprising administering to said subject: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, avibactam, or pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided methods for preventing or treating a bacterial infection in a subject, said methods comprising administering to said subject: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one antibacterial agent or pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided methods for preventing or treating a bacterial infection in a subject, said methods comprising administering to said subject: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one antibacterial agent selected from selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftalozane or pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided methods for preventing or treating a bacterial infection in a subject, said methods comprising administering to said subject: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or pharmaceutically acceptable derivative thereof.

In some embodiments, the compositions and methods according to the invention use compounds of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof in combination with at least one antibacterial agent or a pharmaceutically acceptable derivative thereof. A wide variety of antibacterial agents can be used. Typical, non-limiting examples of antibacterial agents include one or more of antibacterial compounds generally classified as aminoglycosides, ansamycins, carbacephems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines, oxazolidinone and the like. Typical, non-limiting examples of aminoglycoside antibacterial agents include amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, arbekacin, streptomycin, apramycin and the like. Typical, non-limiting examples of ansamycin antibacterial agents include geldanamycin, herbimycin and the like. Typical, non-limiting examples of carbacephem antibacterial agents include loracarbef and the like. Typical, non-limiting examples of carbapenem antibacterial agents include ertapenem, doripenem, imipenem, meropenem and the like.

Typical, non-limiting examples of cephalosporin and cephamycin antibacterial agents include cefazolin, cefacetrile, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cephamycin, cefoxitin, cefotetan, cefmetazole, carbacephem, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, cxacephem, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftiofur, cefquinome, cefovecin, ceftolozane, ceftaroline, ceftobiprole and the like

Typical, non-limiting examples of lincosamide antibacterial agents include clindamycin, lincomycin and the like. Typical, non-limiting examples of macrolide antibacterial agents include azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spectinomycin, solithromycin and the like. Typical, non-limiting examples of monobactam antibacterial agents include aztreonam and the like. Typical, non-limiting examples of nitrofuran antibacterial agents include furazolidone, nitrofurantoin and the like. Typical, non-limiting examples of penicillin antibacterial agents include amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, ticarcillin and the like. Typical, non-limiting examples of polypeptide antibacterial agents include bacitracin, colistin, polymyxin B and the like.

Typical, non-limiting examples of quinolone antibacterial agents include ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, levonadifloxacin, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin and the like. Typical, non-limiting examples of sulfonamide antibacterial agents include mafenide, sulfonamidochrysoidine, sulfacetamide, sulfadiazine, sulfamethizole, sulfamethoxazole, sulfasalazine, sulfisoxazole, trimethoprim and the like. Typical, non-limiting examples of tetracycline antibacterial agents include demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, tigecycline and the like. Typical, non-limiting examples of oxazolidinone antibacterial agents include tedizolid, linezolid, ranbezolid, torezolid, radezolid and the like.

The pharmaceutical compositions according to the invention may include one or more pharmaceutically acceptable carriers or excipients or the like, Typical, non-limiting examples of such carriers or excipient include mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, lubricants, stabilizing agents, binding agents etc.

In some embodiments, pharmaceutical compositions according to the present invention are administered orally or parenterally.

The pharmaceutical compositions according to this invention can exist in various forms. In some embodiments, the pharmaceutical composition is in the form of a powder or a solution. In some other embodiments, the pharmaceutical compositions according to the invention are in the form of a powder that can be reconstituted by addition of a compatible reconstitution diluent prior to parenteral administration. Non-limiting example of such a compatible reconstitution diluent includes water.

In some other embodiments, the pharmaceutical compositions according to the invention are in the form of a frozen composition that can be diluted with a compatible diluent prior to parenteral administration.

In some other embodiments, the pharmaceutical compositions according to the invention are in the form ready to use for oral or parenteral administration.

In the methods according to the invention, the pharmaceutical composition and/or other pharmaceutically active ingredients disclosed herein may be administered by any appropriate method, which serves to deliver the composition or its constituents or the active ingredients to the desired site. The method of administration can vary depending on various factors, such as for example, the components of the pharmaceutical composition and nature of the active ingredients, the site of the potential or actual infection, the microorganism (e.g. bacteria) involved, severity of infection, age and physical condition of the subject. Some non-limiting examples of administering the composition to a subject according to this invention include oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drop, ear drop or mouthwash.

The compositions according to the invention can be formulated into various dosage forms wherein the active ingredients and/or excipients may be present either together (e.g. as an admixture) or as separate components. When the various ingredients in the composition are formulated as a mixture, such composition can be delivered by administering such a mixture to a subject using any suitable route of administration. Alternatively, pharmaceutical compositions according to the invention may also be formulated into a dosage form wherein one or more ingredients (active or inactive ingredients) are present as separate components. The composition or dosage form wherein the ingredients do not come as a mixture, but come as separate components, such composition/dosage form may be administered in several ways. In one possible way, the ingredients may be mixed in the desired proportions and the mixture is then administered as required. Alternatively, the components or the ingredients (active or inert) may be separately administered (simultaneously or one after the other) in appropriate proportion so as to achieve the same or equivalent therapeutic level or effect as would have been achieved by administration of the equivalent mixture.

In some embodiments, pharmaceutical compositions according to the invention are formulated into a dosage form such that the compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and the antibacterial agent or a pharmaceutically acceptable derivative thereof, are present in the composition as admixture or as separate components. In some other embodiments, pharmaceutical compositions according to the invention are formulated into a dosage form such that the compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and the antibacterial agent or a pharmaceutically acceptable derivative thereof, are present in the composition as separate components.
Similarly, in the methods according to the invention, the active ingredients disclosed herein may be administered to a subject in several ways depending on the requirements. In some embodiments, the active ingredients are admixed in appropriate amounts and then the admixture is administered to a subject. In some other embodiments, the active ingredients are administered separately. Since the invention contemplates that the active ingredients agents may be administered separately, the invention further provides for combining separate pharmaceutical compositions in kit form. The kit may comprise one or more separate pharmaceutical compositions, each comprising one or more active ingredients. Each of such separate compositions may be present in a separate container such as a bottle, vial, syringes, boxes, bags, and the like. Typically, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral) ore are administered at different dosage intervals. When the active ingredients are administered separately, they may be administered simultaneously or sequentially.

The pharmaceutical composition or the active ingredients according to the present invention may be formulated into a variety of dosage forms. Typical, non-limiting examples of dosage forms include solid, semi-solid, liquid and aerosol dosage forms; such as tablets, capsules, powders, solutions, suspensions, suppositories, aerosols, granules, emulsions, syrups, elixirs and a like.

In general, the pharmaceutical compositions and method disclosed herein are useful in preventing or treating bacterial infections. Advantageously, the compositions and methods disclosed herein are also effective in preventing or treating infections caused by bacteria that are considered be less or not susceptible to one or more of known antibacterial agents or their known compositions. Some non-limiting examples of such bacteria known to have developed resistance to various antibacterial agents include Acinetobacter, E. coli, Pseudomonas aeruginosa, Staphylococcus aureus, Enterobacter, Klebsiella, Citrobacter and a like. Other non-limiting examples of infections that may be prevented or treated using the compositions and/or methods of the invention include: skin and soft tissue infections, febrile neutropenia, urinary tract infection, intraabdominal infections, respiratory tract infections, pneumonia (nosocomial), bacteremia meningitis, surgical, infections etc.

Surprisingly, the compounds, compositions and methods according to the invention are also effective in preventing or treating bacterial infections that are caused by bacteria producing one or more beta-lactamase enzymes. In some embodiments, there are provided methods of inhibiting beta-lactamase enzymes, wherein said methods comprise administering a pharmaceutically effective amount of a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof. In some other embodiments, there are provided methods of inhibiting beta-lactamase enzymes, wherein said methods comprise administering a pharmaceutically effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof.

In general, the compounds of Formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof according to invention are also useful in increasing antibacterial effectiveness of antibacterial agent in a subject. The antibacterial effectiveness of one or more antibacterial agents may increased, for example, by co-administering said antibacterial agent or a pharmaceutically acceptable derivative thereof with a pharmaceutically effective amount of a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof according to the invention. In some embodiments, there is provided a method for increasing antibacterial effectiveness of the antibacterial agent in a subject, said method comprising co-administering said antibacterial agent or a pharmaceutically acceptable derivative thereof with a of a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. For example, those skilled in the art will recognize that the invention may be practiced using a variety of different compounds within the described generic descriptions.

EXAMPLES

The following examples illustrate the embodiments of the invention that are presently best known. However, it is to be understood that the following are only exemplary or illustrative of the application of the principles of the present invention. Numerous modifications and alternative compositions, methods and systems may be devised by those skilled in the art without departing from the spirit and scope of the present invention. The appended claims are intended to cover such modifications and arrangements. Thus, while the present invention has been described above with particularity, the following examples provide further detail in connection with what are presently deemed to be the most practical and preferred embodiments of the invention.

Preparation 1

Synthesis of (2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide:

Step-1: Synthesis of tert-butyl 2-{[(2S,5R)- 6-(benzyloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate:

To a solution of sodium salt of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (300 g, 1.007 mol) in water (2500 ml), was added HOBt (136 g, 1.007 mol) followed by EDC hydrochloride (289 g, 1.51 mol) and N-methyl morpholine (112 ml, 1.007 mol) at 25°C under stirring. The reaction mixture was stirred for 15 minutes and a solution of tert-butyl carbazate (133 g, 1.007 mol) in water (500 ml) was added under stirring. The stirring was continued at 25°C for 19 hours. Sticky oil separated out, water was decanted and the residue was taken in ethyl acetate (1.5 L) and washed with water (500 ml), brine (200 ml) and the collected organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to provide 270 g of the titled product as a white solid in 69% yield.
Analysis:
Mass: 389.3 (M-1): for Molecular Weight of 390 and Molecular Formula of C19H26N4O5;
1H NMR (CDCl3): ? 8.19 (brs, 1H), 7.46-7.34 (m, 5H), 6.40 (brs, 1H), 5.06 (d, 1H, J = 9.8 Hz), 4.91 (d, 1H, J = 10.2 Hz ), 4.00 (d, 1H, J = 7.2 Hz ), 3.29 (brs, 1H), 3.16-3.02 (m, 2H), 2.40-2.34 (m, 1H), 2.04-1.92 (m, 2H), 1.66-1.60 (m, 1H), 1.47 (s, 9H).

Step-2: Synthesis of tetrabutylammonium salt of tert-butyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate:

To a clear solution of tert-butyl 2-{[(2S,5R)- 6-(benzyloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate (135 g, 0.346 mol) in methanol (1350 ml) was added 10% palladium on carbon (27g). The suspension was stirred under atmospheric hydrogen pressure at 25°C for 2 hours. The catalyst was filtered over a celite bed and catalyst-containing bed was washed with additional methanol (1350 ml). The filtrate was concentrated and the resulted residue was dissolved in dichloromethane (500 ml) and to the resulted clear solution was added pyridine sulfur trioxide complex (133 g, 0.833 mol) and triethylamine (139 ml, 0.999 mol) under stirring. The suspension was stirred at a temperature of 25°C for 19 hours. To the clear solution was added tetrabutyl ammonium hydrogen sulfate (113 g, 0.333 mol) at 25°C and stirred for 1.5 hours. Diluted the reaction mixture with dichloromethane (500 ml) and the organic layer was washed with 10% aqueous potassium hydrogen sulfate solution (200 ml × 3), water (200 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to provide 150 g of the titled product as a white solid in 70% yield.
Analysis:
Mass: 379.2 (M-1) as free acid for Molecular Weight of 621.84 and Molecular Formula of C28H55N5O8S;
1H NMR (CDCl3): ? 8.22 (brs, 1H), 6.33 (brs, 1H), 4.33 (brs, 1H), 3.96 (d, 1H, J = 8.0 Hz), 3.40-3.22 (m, 9H), 3.14-3.06 (m, 1H), 2.42-2.34 (m, 1H), 2.22-2.12 (m, 1H) 1.96-1.82 (m, 1H), 1.78-1.60 (m, 9H), 1.54-1.38 (m, 17H), 1.04-0.95 (m, 12H).

Step-3: Synthesis of (2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide:

To a solution of tetrabutylammonium salt of tert-butyl 2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate (60 g, 0.0965 mol) in dichloromethane (300 ml) was added a solution of trifluoroacetic acid (300 ml) slowly by dropping funnel at -10°C over a period of 1 hours. The mixture was maintained at the same temperature under stirring for 4 hours. Solvents were removed at 25°C under high vacuum to provide a residue, which was washed with diethyl ether (50 ml × 3), with acetonitrile (50 ml × 3) and with dichloromethane (50 ml × 3). The residual solid was dried under high vacuum to provide 20 g of (2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide in74% yield.
Analysis:
Mass: 279.1 (M-1) for Molecular Weight of 280.26 and Molecular Formula of C17H12N4O6S;
1H NMR (DMSO-d6): ? 11.18 (brs, 1H), 9.39 (brs,2H), 4.04 (brs, 1H), 3.95 (d, 1H, J = 7.2 Hz), 3.06 (d, 1H, J = 12.0 Hz), 2.87 (d, 1H, J = 12.0 Hz), 2.16-2.00 (m, 1H), 1.92-1.72 (m, 1H), 1.80-1.58 (m, 2H).

Example 1

Synthesis of sodium salt of (2S,5R)-N'-[2-methoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Step-1: Synthesis of tetrabutylammonium salt of (2S,5R)-N'-[(2-methoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide:

To a clear solution of 2-methoxy benzaldehyde ( 0.971 g, 0.071mol) in tetrahydrofuran (20 ml), was added N, N-diisopropyl ethyl amine ( 2.47 ml, 0.0142 mol) followed by the addition of (2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (2 g, 0.071 mol, was prepared according to the procedure described in Preparation 1) at 25°C under stirring. The reaction mixture was stirred for 16 hours and to the reaction mixture was added a solution of tetrabutyl ammonium acetate (2.14 g, 0.071 mol) in tetrahydrofuran (10 ml) and stirred further 25°C for 22 hours. The solvent was evaporated and the resulted residue was taken in dichloromethane (200 ml) and washed with 10% aqueous potassium hydrogen sulfate solution (100 ml × 2) and finally organic layer was washed with water (100 ml). The organic layer was collected and dried over anhydrous sodium sulfate and evaporated under reduced pressure to yield a semi solid mass. The material was purified by using column chromatography by eluting with 4% methanol in dichloromethane. The compound containing fractions were collected and on concentration yielded 1 g of tetrabutylammonium salt of (2S,5R)-N'-[(2-methoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide as a white solid in 21.9% yield.
Analysis:
Mass: 397.2 (M-1) as free acid; for Molecular Weight of 639.86 and Molecular Formula of C31H53N5O7S;
1H NMR (CDCl3): ? 9.66 (s, 1H), 8.47(s, 1H), 8.08 (d, 1H, J = 7.6 Hz ), 7.37 (t, 1H, J = 7.2 Hz), 6.98 (t, 1H, J = 7.2 Hz ), 6.90 (d, 1H, J = 8.4 Hz), 4.38 (s, 1H), 4.06-4.02 (m, 1H), 3.90 (s, 3H), 3.44-3.28 (m, 9H), 2.90-2.86 (m, 1H), 2.54-2.48 (m, 1H), 2.24-2.16 (m, 1H) 2.00-1.86 (m, 1H),1.80-1.40 (m, 17H), 1.08 (t, 12H, J = 7.2 Hz ).

Step-2: Synthesis of sodium salt of (2S,5R)-N'-[(2-methoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide:

A solution of tetrabutylammonium salt of (2S,5R)-N'-[(2-methoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (1 g, 0.00156 mol, prepared in step -1) in tetrahydrofuran (4 ml) was passed through Indion 225 sodium ion exchange resin with 10% tetrahydrofuran in water as an eluent. Collected the fractions containing compound and concentrated on rotavapour till dryness. The resulted residue was washed with ether (10 ml × 4), dichloromethane (5 ml × 2) and dried under high vacuum to obtain 0.5 g of sodium salt of (2S,5R)-N'-[(2-methoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide as a white solid in 47% yield.
Analysis:
Mass: 399.3 (M+1) as free acid; for Molecular Weight: 420.37 and Molecular Formula: C15H17N4O7S.Na;
1H-NMR: 1H NMR (DMSO-d6): ? 11.67 (s, 1H), 8.69 (s, 1H), 7.79 (d, 1H, J = 7.6 Hz ), 7.38 (t, 1H, J = 8.0 Hz), 7.08 (d, 1H, J = 8.4 Hz ), 7.00 (t, 1H, J = 7.6 Hz), 4.02 (s, 1H), 3.92-3.84 (m, 1H), 3.84 (s, 3H), 3.02-2.98 (m, 2H), 2.10-2.02 (m, 1H), 1.98-1.68 (m, 3H).

Example 2

Synthesis of (2S,5R)-N'-[3-aminopropylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide:

Step-1: Synthesis of tetrabutylammonium salt of (2S, 5R)-N'-[3-N-tert-butoxycarbonylaminopropylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide:
The tetrabutylammonium salt of (2S,5R)-N'-[3-N-tert-butoxycarbonyl aminopropylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide was prepared according to the procedure described in step - 1 of Example 1.
Analysis:
Mass: 434.3 (M-1) for Molecular Weight of 676.92 and Molecular Formula of C31H60N6O8S;
1H NMR (CDCl3): ? 9.48 (brs, 1H), 7.44 (brs, 1H), 4.83 (brs, 1H), 4.37 (s, 1H), 3.94 (d, 1H, J = 8.4 Hz ), 3.42-3.24 (m, 10H), 2.84-2.80 (m, 1H), 2.60-2.42 (m, 3H) 2.24-2.14 (m, 1H),1.94-1.40 (m, 28H), 1.00 (t, 12H, J = 7.2 Hz ).

Step-2: Synthesis of (2S,5R)-N'-[3-aminopropylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide:

To a solution tetrabutylammonium salt of (2S,5R)-N'-[3-N-tert-butoxy carbonyl aminopropylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (0.900 g, 0.00133 mol) in dichloromethane (4.5 ml) was added a solution of trifluoroacetic acid (4.5 ml) drop-wise by syringe at -10°C over a period of 20 minutes. The mixture was maintained under stirring for 10 minutes. Then the reaction mass was treated with cyclohexane (10 ml × 3) and each time the cyclohexane layer was removed from the reaction mass yielded a thick syrup. This was treated with diethyl ether (10 ml) resulted into white solid formation. The solid formed was filtered and washed with diethyl ether (10 ml × 2), acetonitrile (25 ml × 2) and dichloromethane (25 ml × 2). The residual solid was dried under vacuum to provide 0.36 g of titled compound in 81% yield.
Analysis:
Mass: 334.3 (M-1); for Molecular Weight of 335.33 and Molecular Formula of C10H17N5O6S;
1H-NMR (DMSO-d6): ? 11.43 (s, 1H), 7.70 (brs, 3H), 7.64 (brs, 1H), 4.08-3.70 (m, 4H), 3.20-2.96 (m, 4H), 2.04-1.72 (m, 4H).

Example 3

Synthesis of (2S,5R)-7-oxo-N'-(pyrrolidin-2-yl-methylidene)-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide:

Step-1: Synthesis of tert-butyl (2S)-2-{[2-(methoxycarbonyl)hydrazinylidene] methyl} pyrrolidine-1-carboxylate:
To a solution of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (3.84 g, 0.0193 mol, was prepared according to the procedure described in International Patent Application No. WO2007039782) in tetrahydrofuran (10 ml) was added methyl carbazate (3.47 g, 0.0386 mol) at 25°C under stirring. The reaction mixture was stirred for 16 hours. The solvent was evaporated. The material was purified by using column chromatography using 35% ethyl acetate in hexane as an eluent. The compound containing fractions were collected and concentrated to provide 4.5 g of tert-butyl (2S)-2-{[2-(methoxycarbonyl)hydrazinylidene]methyl}pyrrolidine-1-carboxylate as a white solid in 72% yield.
Analysis:
Mass: 272.2 (M+1) for Molecular Weight of 271 and Molecular Formula of C12H21N3O4.
1H NMR (CDCl3): ? 7.78 (brs, 1H), 7.07 (brs, 1H), 4.48-4.34 (m, 1H), 3.80 (s, 3H), 3.54-3.32 (m, 2H), 2.22-1.80 (m, 4H), 1.43 (s, 9H).

Step-2: Synthesis of tert-butyl (2S)-2-(hydrazinylidenemethyl)pyrrolidine-1-carboxylate:

To a solution of tert-butyl (2S)-2-{[2-(methoxycarbonyl)hydrazinylidene] methyl} pyrrolidine-1-carboxylate (0.971 g, 0.071 mol) in ethanol (10 ml) was added hydrazine hydrate (2.47 ml, 0.0142 mol) at 25°C under stirring. The reaction mixture was stirred for 30 minutes at 80°C. The solvent was evaporated. The residue was taken in dichloromethane (25 ml) and washed with water (25 ml). The organic layer was dried over anhydrous sodium sulfate. The compound containing fractions were collected and concentrated to provide 2.5 g tert-butyl (2S)-2-(hydrazinylidenemethyl)pyrrolidine-1-carboxylate as a white solid in 71% yield.
Analysis:
Mass: 214.2 (M+1) for Molecular Weight of 213 and Molecular Formula of C10H19N3O2.
1H NMR (CDCl3): ? 7.18-6.96 (m, 1H), 5.16 (brs, 2H), 4.42-4.22 (m, 1H), 3.56-3.24 (m, 2H), 2.22-1.80 (m, 4H), 1.47 (s, 9H).

Step-3: Synthesis of (2S,5R)- 6-(benzyloxy)-7-oxo-N'-[(2S)-pyrrolidin-2-yl-methylidene-1-carboxylic acid tert-butyl ester]-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide:

To a clear solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (2 g, 0.00727 mol) in N,N-dimethylformamide (15 ml), was added HOBt (0.981 g, 0.00727 mol) followed by EDC hydrochloride (2.08 g, 0.0109 mol) and N-methyl morpholine (2.5 ml, 0.0218 mol) at 25°C under stirring. The reaction mixture was stirred for 15 minutes and a solution of tert-butyl (2S)-2-(hydrazinylidenemethyl)pyrrolidine-1-carboxylate (1.54 g, 0.00727 mol) in N,N-dimethylformamide (5 ml) was added under stirring. The stirring was continued at 25°C to 35°C for 16 hours and the resulting reaction mixture was poured into water (200 ml). The so obtained mixture was extracted with ethyl acetate (2 × 100 ml). The ethyl acetate layer was washed with water (1 × 50 ml) and brine (1 × 50 ml). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel by eluting with 45% ethyl acetate in hexane. The combined fractions were concentrated to provide 1 g of the titled product as a white solid in 13% yield.
Analysis:
Mass: 470.4 (M-1); for Molecular Weight of 471 and Molecular Formula of C24H33N5O5;
1H NMR (CDCl3): ? 9.33 (brs, 1H), 7.51 (d, 1H, J = 9.6 Hz ), 7.44-7.34 (m, 5H), 5.06 (d, 1H, J = 10.6 Hz), 4.91 (d, 1H, J = 10.6 Hz ), 4.54-4.38 (m, 1H), 4.02-3.90 (m, 1H), 3.56-3.33 (m, 3H), 3.06-2.98 (m, 1H), 2.80-2.66 (m, 1H), 2.46-2.38 (m, 1H), 2.30-1.82 (m, 7H) 1.50-1.38 (m, 9H).
Step-4: Synthesis of tetrabutylammonium salt of (2S,5R)-N'-[(2S)-pyrrolidin-2-yl-methylidene-1-carboxylic acid tert-butyl ester]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide:

To a clear solution of (2S,5R)-6-(benzyloxy)-7-oxo-N'-[(2S)-pyrrolidin-2-yl-methylidene-1-carboxylic acid tert-butyl ester]-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (0.500 g, 0.00106 mol) in methanol (5 ml) was added 10% palladium on carbon (125 mg). The suspension was stirred under atmospheric hydrogen pressure at 30°C for 1.5 hours. The catalyst was filtered over a celite bed and catalyst-containing bed was washed with additional methanol (5 ml). The filtrate was concentrated, and the resulted residue was dissolved in pyridine (2.5 ml) and to the clear solution was added pyridine sulfur trioxide complex (0.835 g, 0.00525 mol). The suspension was stirred at a temperature of 25°C to 35°C for overnight. The suspension was filtered and the solids were washed with dichloromethane (25 ml × 2). The filtrate was evaporated under vacuum and the residue was stirred in 0.5 N aqueous potassium dihydrogen phosphate solution (100 ml) for 0.5 hour. The resulted solution was washed with ethyl acetate (100 ml × 3) and layers were separated. Tetrabutylammonium sulfate (0.356 g, 0.00105 mol) was added to the aqueous layer and stirred for 2.5 hours at about 25°C. The mixture was extracted with dichloromethane (100 ml × 2). The combined organic extract was washed with brine (50 ml) and dried over anhydrous sodium sulfate and evaporated under vacuum to provide solid, that was triturated with hexane (25 ml × 3) and filtered to provide 0.36 g of the titled compound as white powder in 48% yield.
Analysis:
Mass: 460.4 (M-1) as free acid; for Molecular Weight of 702.96 and Molecular Formula of C33H62N6O8S;
1H NMR (CDCl3): ? 9.41 (brs, 1H), 7.60-7.34 (m, 1H), 4.58-4.34 (m, 2H), 4.04-3.92 (m, 2H), 3.56-3.20 (m, 10H), 2.88-2.74 (m, 1H), 2.48-2.40 (m, 1H) 2.26-1.80 (m, 2H),1.74-1.38 (m, 30H), 1.06-0.97 (m, 12H).

Step-5: Synthesis of (2S,5R)-N'-[(2S)-pyrrolidin-2-yl-methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide:

To a solution of tetrabutylammonium salt of (2S,5R)- N'-[(2S)-pyrrolidin-2-yl-methylidene-1-carboxylic acid tert-butylester]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (0.360 g, 0.000512 mol) in dichloromethane (1.8 ml) was added a solution of trifluoroacetic acid (1.8 ml) slowly by syringe at -5°C over a period of 5 minutes. The mixture was maintained under stirring for 1 hour. Solvents were removed below 40°C under high vacuum to provide a residue, which was triturated with diethyl ether (5 ml × 2) and with acetonitrile (5 ml × 2). The residual solid was dried under vacuum to provide 0.165 g of (2S,5R)-N'-[(2S)-pyrrolidin-2-ylmethylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide in 89% yield.
Analysis:
Mass: 360.3 (M-1) for Molecular Weight of 361.37 and Molecular Formula of C12H19N5O6S;
1H NMR (DMSO-d6): ? 11.78 (s, 1H), 9.20 (s,1H), 8.76 (s, 1H), 7.75 (d, 1H, J = 3.6 Hz), 4.22 (s, 1H), 4.02 (s, 1H), 3.87 (d, 1H, J = 6.4 Hz), 3.28-3.12 (m, 2H), 3.02 (d, 1H, J = 11.2 Hz), 2.86 (d, 1H, J = 11.6Hz), 2.22-1.64 (m, 8H).

The compounds of Examples 4 to 30 (Table 1) were prepared by following the procedure described in Example 1, wherein appropriately substituted aldehydes or ketones are used in place of 2-methoxy benzaldehyde. For preparation of compounds of Examples 27 to 30 (Table 1) dimethylformamide was used as solvent in place of tetrahydrofuran (in step 1 of Example 1). The compounds of Examples 31 to 38 (Table 1) were prepared by following the procedure described in Example 2 using appropriately substituted aldehydes. The compounds of Examples 39 and 40 (Table 1) were prepared by following the procedure described in Example 3 by using appropriately substituted hydrazinylidene compounds. The compounds according to invention are obtained in the form of pure E or Z isomers or mixture of E and Z isomers depending on the substitutions on the aldehyde / ketone moieties, experimental conditions or workup conditions used.

Table 1
Example No. Structure Starting Reagent H1 NMR (DMSO-d6) Mass as free acid
(Molecular Formula)
4.


? 11.76 (s, 1H), 8.74 (s, 1H), 7.84 (t, 1H, J = 8.0 Hz), 7.56-7.30 (m, 6H), 7.20 (d, 1H, J = 8.4 Hz ), 7.02 (t, 1H, J = 7.2 Hz), 5.18 (s, 2H), 4.01 (s, 1H), 3.87 (d, 1H, J = 6.4 Hz ), 3.01 (s, 2H), 2.08-2.02 (m, 1H), 1.98-1.68 (m, 3H) 475.4 (M+1)
(C21H21N4O7S.Na)

5.


? 11.70 (s, 1H), 8.66 (s, 1H), 7.31 (d, 1H, J = 2.4 Hz ), 7.06-6.96 (m, 2H), 4.02 (s, 1H), 3.88 (d, 1H, J = 6.4 Hz ), 3.79 (s, 3H), 3.74 (s, 3H), 3.02 (s, 2H), 2.08-2.02 (m, 1H), 1.96-1.68 (m, 3H) 429.3 (M+1)
(C16H19N4O8S.Na)

6.


? 11.52 (s, 1H), 8.26 (s, 1H), 7.32 (s, 1H), 7.14 (d, 1H, J = 8.0 Hz ), 7.00 (d, 1H, J = 8.4 Hz ), 4.02 (s, 1H), 3.89 (d, 1H, J = 6.0 Hz ), 3.80 (s, 6H), 3.02 (s, 2H), 2.10-2.02 (m, 1H), 1.96-1.68 (m, 3H) 429.3 (M+1)
(C16H19N4O8S.Na)

7.


? 11.32 (s, 1H), 8.19 (s, 1H), 7.48 (d, 2H, J = 8.4Hz ), 6.74 (d, 2H, J = 8.8 Hz ), 4.02 (s, 1H), 3.87 (d, 1H, J = 6.0 Hz ), 3.05 (s, 2H), 2.97 (s, 6H), 2.08-2.02 (m, 1H), 1.96-1.68 (m, 3H) 412.3 (M+1)
(C16H20N5O6S.Na)

8.

? 11.97 (s, 1H), 11.27 (s, 1H), 8.55 (s, 1H), 7.44 (d, 1H, J = 7.6 Hz ), 7.28 (t, 1H, J = 7.2 Hz), 6.94-6.86 (m, 2H), 4.03 (s, 1H), 3.94 (d, 1H, J = 5.6 Hz ), 3.08-2.96 (m, 2H), 2.12-2.08 (m, 1H), 1.96-1.70 (m, 3H) 383.2 (M-1)
(C14H15N4O7S.Na)

9.


? 11.66 (s, 1H), 8.32 (s, 1H), 7.38-7.32 (m, 1H), 7.24-7.20 (m, 2H), 7.02-6.96 (m, 1H), 4.03 (s, 1H), 3.91 (d, 1H, J = 6.4 Hz), 3.80 (s, 3H), 3.06-2.98 (m, 2H), 2.12-2.04 (m, 1H), 1.94-1.84 (m, 1H), 1.80-1.72 (m, 2H) 399.2 (M+1)
(C15H17N4O7S.Na)

10.

? 11.90 (s, 1H), 8.32 (s, 1H), 8.00-7.24 (m, 3H), 4.08-4.00 (m, 2H), 3.18-2.80 (m, 2H), 2.52 (s, 3H), 2.18-1.60 (m, 4H)

384.2 (M+1)
(C14H16N5O6S.Na)

11.

? 11.48 (s, 1H), 8.29 (s, 1H), 7.61 (d, 2H, J = 8.4Hz ), 7.00 (d, 2H, J = 8.4 Hz ), 4.02 (s, 1H), 3.88 (d, 1H, J = 6.4 Hz ), 3.80 (s, 3H), 3.02 (s, 2H), 2.08-2.04 (m, 1H), 1.96-1.70 (m, 3H)
399.2 (M+1)
(C15H17N4O7S.Na)
12.

? 12.13 (s, 1H), 8.77 (s, 1H), 8.07 (d, 1H, J = 7.6 Hz ), 7.90 (d, 1H, J = 8.0 Hz ), 7.78 (t, 1H, J = 7.6 Hz ), 7.59 (t, 1H, J = 7.2 Hz ), 4.03 (s, 1H), 3.88 (d, 1H, J = 5.6 Hz ), 3.10-2.94 (m, 2H), 2.10-2.04 (m, 1H), 1.98-1.70 (m, 3H) 394.2 (M+1)
(C15H14N5O6S.Na)

13.


? 11.90 (s, 1H), 8.42 (s, 1H), 7.90 (d, 2H, J = 8.4Hz ), 7.85 (d, 2H, J = 8.4 Hz ), 4.03 (s, 1H), 3.94 (d, 1H, J = 6.0 Hz ), 3.06-2.96 (m, 2H), 2.12-2.04 (m, 1H), 1.98-1.70 (m, 3H) 394.2 (M+1)
(C15H14N5O6S.Na)

14.

? 11.48 (s, 1H), 8.45 (s, 1H), 7.50-7.30 (m, 1H), 6.82-6.66 (m, 2H,), 4.06-3.98 (m, 1H), 3.92-3.76 (m, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.10-2.82 (m, 2H), 2.10-1.62 (m, 4H)
429.3 (M+1) (C16H19N4O8S.Na)

15.


? 11.50 (s, 1H), 8.58 (s, 1H), 7.76-7.70 (m, 1H), 6.64-6.58 (m, 2H), 4.01 (s, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.88-3.82 (m, 1H), 3.04-3.02 (m, 2H), 2.10-2.02 (m, 1H), 1.96-1.68 (m, 3H) 429.2 (M+1)
(C16H19N4O8S.Na)

16.


? 11.31 (s, 1H), 8.42 (s, 1H), 6.35 (s, 1H), 6.26 (s, 1H), 4.04-3.98 (m, 1H), 3.72-3.64 (m, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 3.10-2.82 (m, 2H), 2.20-1.62 (m, 4H) 459.2 (M+1) (C17H21N4O9S.Na)

17.


? 11.59 (s, 1H), 8.24 (s, 1H), 7.82-7.80 (m, 1H), 6.90-6.88 (m, 1H), 6.62-6.58 (m, 1H), 4.02 (s, 1H), 3.90-3.88 (m, 1H), 3.06-2.96 (m, 2H), 2.08-2.04 (m, 1H), 1.96-1.68 (m, 3H) 359.1 (M+1)
(C12H13N4O7S.Na)

18.


? 11.60 (s, 1H), 8.54 (s, 1H), 7.68-7.64 (m, 1H), 7.42-7.38 (m, 1H), 7.14-7.10 (m, 1H), 4.02 (s, 1H), 3.92-3.88 (m, 1H), 3.04-2.96 (m, 2H), 2.08-2.04 (m, 1H), 1.96-1.68 (m, 3H) 375.1 (M+1)
(C12H13N4O6S2.Na)

19.


? 15.00 (s, 1H), 8.78-8.76 (m, 1H), 8.07 (t, 1H, J = 7.6 Hz ), 7.76 (d, 1H, J = 7.6 Hz ), 7.65 (s, 1H), 7.56-7.50 (m, 1H), 4.06-4.00 (m, 2H), 3.18-3.12 (m, 1H), 2.88-2.82 (m, 1H), 2.30-2.22 (m, 1H), 1.96-1.60 (m, 3H) 370.1 (M+1)
(C13H14N5O6S.Na)

20.


? 11.65(s, 1H), 8.34 (brs, 2H), 8.05 (d, 1H, J = 8.8Hz ), 6.90 (d, 1H, J = 8.8 Hz ), 4.02 (s, 1H), 3.90 (s, 3H), 3.20-3.16 (m, 1H), 3.06-3.00 (m, 2H), 2.10-2.02 (m, 1H), 1.98-1.68 (m, 3H) 400.2 (M+1)
(C14H16N5O7S.Na)

21.


? 11.79 (s, 1H), 8.60 (s, 1H), 8.18-8.12 (m, 1H), 8.26-8.20 (m, 1H), 7.12-7.06 (m, 1H), 4.02 (s, 1H), 3.93 (s, 3H), 3.92-3.88 (m, 1H), 3.10-3.02 (m, 2H), 2.10-2.02 (m, 1H), 1.98-1.68 (m, 3H) 400.2 (M+1)
(C14H16N5O7S.Na)
22.


? 11.82 (brs, 1H), 8.29 (s, 1H), 7.77 (t, 1H, J = 8.0 Hz ), 7.34 (d, 1H, J = 7.6 Hz ), 6.84 (d, 1H, J = 8.0 Hz ), 4.10-4.08 (m, 1H), 4.03 (s, 3H), 3.96-3.90 (m, 1H), 3.10-2.98 (m, 2H), 2.10-1.62 (m, 4H) 400.2 (M+1)
(C14H16N5O7S.Na)
23.


? 12.14 (s, 1H), 11.64 (s, 1H), 8.60 (s, 1H), 8.16 (s, 1H), 7.42-7.30 (m, 2H), 4.06-3.98 (m, 2H), 3.14-3.04 (m, 1H), 2.98-2.92 (m, 1H), 2.22-2.14 (m, 1H), 1.98-1.68 (m, 3H) 386.2 (M+1)
(C13H14N5O7S.Na)
24.


? 11.26 (s, 1H), 7.73 (t, 1H, J = 5.6 Hz ), 7.23 (t, 1H, J = 6.8 Hz), 7.13 (d, 1H, J = 7.2 Hz ), 6.98 (d, 1H, J = 8.0 Hz ), 6.90 (t, 1H, J = 7.6 Hz), 3.97 (s, 1H), 3.82-3.76 (m, 1H), 3.79 (s, 3H), 3.48 (d, 2H, J = 5.2 Hz ), 3.04-2.94 (m, 2H), 2.04-1.62 (m, 4H); 411.3 (M-1)
(C16H19N4O7S.Na)

25.


? 11.26 (s, 1H), 7.67 (t, 1H, J = 5.6 Hz ), 7.12 (d, 2H, J = 9.2 Hz ), 6.88 (d, 2H, J = 9.2 Hz ), 3.98 (s, 1H), 3.80-3.76 (m, 1H), 3.71 (s, 3H), 3.46 (d, 2H, J = 5.6 Hz ), 3.04-2.92 (m, 2H), 2.04-1.62 (m, 4H); 411.3 (M-1)
(C16H19N4O7S.Na)

26.

? 11.46 (s, 1H), 8.26 (s, 1H), 7.58 (d, 2H, J = 8.4 Hz ), 6.99 (d, 2H, J = 8.4 Hz ), 4.14-4.08 (m, 2H), 4.00 (brs, 1H), 3.88 (d, 1H, J = 5.6 Hz), 3.04-2.96 (m, 2H), 2.70-2.62 (m, 2H), 2.23 (s, 6H), 2.10-1.58 (m, 4H). 454.3 (M-1)
(C18H24N5O7S.Na)
27.


? 9.36 (s, 1H), 7.13 (d, 1H, J = 8.4 Hz ), 6.72 (s, 1H), 6.66 (d, 1H, J = 8.4 Hz), 4.06-3.96 (m, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.76-3.72 (m, 1H), 2.92-2.76 (m, 2H), 2.17 (s, 3H), 2.10-1.54 (m, 4H) 443.3 (M+1)
(C17H21N4O8S.Na)

28.


? 10.42 (s, 1H), 7.84-7.76 (m, 2H), 7.44-7.34 (m, 3H), 4.12-4.00 (m, 2H), 3.26-3.20 (m, 1H), 3.08-2.98 (m, 1H), 2.25 (s, 3H), 2.02-1.72 (m, 4H) 383.2 (M+1)
(C15H17N4O6S.Na)

29.


? 9.30 (s, 1H), 7.52-6.94 (m, 4H), 4.10-3.70 (m, 2H), 3.81 (s, 3H), 3.26-2.72 (m, 2H), 2.21 (s, 3H), 2.20-1.54 (m, 4H) 413.2 (M+1)
(C16H19N4O7S.Na)
30.


? 9.92 (s, 1H), 4.04-3.94 (m, 2H), 3.22-3.18 (m, 1H), 3.02-2.98 (m, 1H), 2.36-2.22 (m, 4H), 1.98-1.62 (m, 8H) 347.2 (M+1)
(C12H17N4O6S.Na)
31.


? 11.52 (s, 1H), 8.30 (s, 1H), 7.94 (brs, 3H), 7.65 (d, 2H, J = 8.4 Hz ), 7.06 (d, 2H, J = 8.8 Hz ), 4.24-4.18 (m, 2H), 4.03 (brs, 1H), 3.89 (d, 1H, J = 5.6 Hz), 3.30-3.22 (m, 2H), 3.08-3.00 (m, 2H), 2.10-1.52 (m, 4H). 426.3 (M-1)
(C16H21N5O7S)
32.


? 11.76 (s, 1H), 8.23 (brs, 3H), 7.68 (s, 1H), 7.20 (d, 2H, J = 8.4 Hz ), 6.91 (d, 2H, J = 8.4 Hz ), 4.24-4.16 (m, 1H), 4.04 (brs, 1H), 3.84(d, 1H, J = 6.4 Hz), 3.74 (s, 3H), 3.08-2.90 (m, 4H), 2.04-1.62 (m, 4H). 440.3 (M-1)
(C17H23N5O7S)

33.

? 11.69 (s, 1H), 8.37 (s, 1H), 8.14 (brs, 3H), 7.73 (d, 2H, J = 8.4 Hz ), 7.52 (d, 2H, J = 8.0 Hz ), 4.12-4.00 (m, 3H), 3.92-3.88 (m, 1H),3.08-2.96 (m, 2H), 2.12-1.68 (m, 4H).
396.2 (M-1)
(C15H19N5O6S)
34.

? 11.52 (s, 1H), 8.57 (s, 1H), 7.91 (brs, 2H), 7.75 (d, 1H, J = 8.4 Hz ), 6.60-6.68 (m, 2H), 4.24-4.18 (m, 2H), 4.00 (brs, 1H), 3.82 (s, 3H), 3.28-3.20 (m, 3H), 3.02-2.98 (m, 2H), 2.06-1.52 (m, 4H). 456.4 (M-1)
(C17H23N5O8S)
35.

? 11.64 (s, 1H), 8.32 (s, 1H), 7.92 (brs, 3H), 7.40-7.28 (m, 2H), 7.23 (d, 1H, J = 7.6 Hz ), 7.03 (d, 1H, J = 8.0 Hz ), 4.24-4.18 (m, 2H), 4.01 (brs, 1H), 3.90 (d, 1H, J = 6.0 Hz), 3.30-3.20 (m, 2H), 3.08-2.96 (m, 2H), 2.08-1.52 (m, 4H). 426.3 (M-1)
(C16H21N5O7S)
36.

? 11.50 (s, 1H), 8.29 (s, 1H), 7.69 (brs, 3H), 7.62 (d, 2H, J = 8.8 Hz ), 7.01 (d, 2H, J = 8.4 Hz ), 4.18-4.08 (m, 2H), 4.02 (brs, 1H), 3.89 (d, 1H, J = 6.4 Hz), 3.04-2.94 (m, 4H), 2.12-1.52 (m, 6H). 440.4 (M-1)
(C17H23N5O7S)
37.

? 11.52 (brs, 1H), 9.11 (brs, 1H), 8.66 (brs, 1H), 8.28 (s, 1H), 7.64 (d, 2H, J = 8.8 Hz ), 7.04 (d, 2H, J = 8.8 Hz ), 4.34-4.28 (m, 1H), 4.14-4.08 (m, 1H), 4.01 (brs, 1H), 3.98-3.86 (m, 2H), 3.28-3.12 (m, 2H), 3.04-2.96 (m, 2H), 2.10-1.64 (m, 8H). 466.4 (M-1)
(C19H25N5O7S)
38.

? 11.52 (brs, 1H), 8.93 (brs, 2H), 8.30 (s, 1H), 7.64 (d, 2H, J = 8.4 Hz), 7.04 (d, 2H, J = 8.4 Hz ), 5.21 (brs, 1H), 4.03 (brs, 1H), 3.89 (d, 1H, J = 6.0 Hz), 3.52-3.26 (m, 4H), 3.08-2.98 (m, 2H), 2.32-1.68 (m, 6H). 452.2 (M-1)
(C18H23N5O7S)
39.


? 11.27 (s, 1H), 8.43 (s,1H), 8.16 (s, 1H), 7.59 (d, 1H, J = 4.4 Hz), 3.99 (s, 1H), 3.79 (d, 1H, J = 5.6 Hz), 3.30-3.12 (m, 3H), 3.03-2.87 (m, 4H), 2.08-1.52 (m, 8H) 374.15 (M-1)
(C13H21N5O6S)
40.


? 11.78 (s, 1H), 9.00 (s, 1H), 8.74 (s, 1H), 7.70 (s, 1H), 4.04-3.88 (m, 3H), 3.30-2.82 (m, 4H), 2.08-1.38 (m, 10H). 374.3 (M-1)
(C13H21N5O6S)

BIOLOGICAL ACTIVITY DATA

The biological activity of representative compounds according to the invention against various bacterial strains was investigated. In a typical study, overnight grown bacterial cultures were diluted appropriately and inoculated on the agar media containing doubling dilutions of the test compounds. Observations for growth or no growth was performed after 16-20 hours of incubation at 35 ± 2ºC in the ambient air. The overall procedure was performed as per Clinical and Laboratory Standards Institute (CLSI) recommendations, (Clinical and Laboratory Standards Institute (CLSI), Performance Standards for Antimicrobial Susceptibility Testing, 20th Informational Supplement, M07-A9, Volume 32, No. 2, 2012). Molten Mueller Hinton Agar (MHA) (BD, USA) containing serial dilutions of each antibacterial agent were poured on to the plates and allowed to solidify. Appropriate suspensions from the freshly grown cultures were prepared in normal saline so that about 104 CFU/spot of the organism was delivered on to the drug containing agar plates using automated multipoint inoculator (Mast, UK). The plates were incubated in Biochemical oxygen demand (BOD) incubator at 37ºC for 18 hours and then examined for growth. MICs were read as the lowest concentration of drug that completely inhibited bacterial growth. The Table 2 depicts the antibacterial activity profile of compounds according to present invention against various multidrug resistant bacterial strains. These compounds when tested alone exhibited higher MIC values.

Table 2. Antibacterial activity of representative compounds according to invention (expressed as MICs (mcg/ml).
Compounds Strains
K. pneumoniae
ATCC 700603 E. coli
NCTC 13352 E. coli
NCTC 13353 E. coli
M 50 E. coli
7 MP K. pneumoniae
H521 K. pneumoniae
H525
Example 1 > 32 32 32 32 > 32 32 32
Example 2 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 3 > 32 32 32 32 > 32 32 32
Example 4 > 32 32 32 32 > 32 32 32
Example 5 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 6 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 7 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 8 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 9 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 10 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 11 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 12 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 13 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 14 > 32 32 16 32 > 32 > 32 32
Example 15 > 32 32 32 32 > 32 32 16
Example 16 > 32 32 16 32 > 32 32 16
Example 17 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 18 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 19 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 20 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 21 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 22 > 32 > 32 > 32 32 > 32 > 32 > 32
Example 23 > 32 > 32 > 32 32 > 32 > 32 > 32
Example 24 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 27 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 28 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 29 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 30 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 31 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 33 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 37 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 38 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Example 39 > 32 32 32 32 > 32 32 32
Example 40 > 32 > 32 > 32 > 32 > 32 > 32 > 32
Ceftazidime 32 > 32 32 > 32 > 32 > 32 > 32
The compounds according to present invention were also tested for their antibacterial activity in combination with Ceftazidime. The plates were poured with MHA containing doubling concentration range of Ceftazidime in combination with constant concentration (at 4 mcg/ml) of representative compounds of Formula (I). The Table 3 shows the MIC values of Ceftazidime in presence of compounds according to the invention (at 4 mcg/ml). As shown in Table 3, the MIC value of Ceftazidime was significantly lowered in presence of compounds according to the invention.

Table 3. Antibacterial activity of representative compounds according to the invention in combination with Ceftazidime (expressed as MICs (mcg/ml).

Compounds Strains
K. pneumoniae
ATCC 700603 E. coli
NCTC 13352 E. coli
NCTC 13353 E. coli
M 50 E. coli
7 MP K. pneumoniae
H521 K. pneumoniae
H525
Ceftazidime alone 32 > 32 32 > 32 > 32 > 32 > 32
Ceftazidime +
Example 1 (4 mcg/ml) 0.5 0.5 0.5 1 4 8 8
Ceftazidime +
Example 2 (4 mcg/ml) 0.5 1 0.25 1 4 8 8
Ceftazidime +
Example 4 (4 mcg/ml) 1 1 0.5 1 4 8 8
Ceftazidime +
Example 5 (4 mcg/ml) 0.25 0.5 0.12 8 > 32 0.5 1
Ceftazidime +
Example 6 (4 mcg/ml) 1 2 0.5 1 8 16 16
Ceftazidime +
Example 7 (4 mcg/ml) 0.5 2 0.5 1 8 8 8
Ceftazidime +
Example 8 (4 mcg/ml) 1 2 0.5 1 8 16 8
Ceftazidime +
Example 9 (4 mcg/ml) 0.5 0.5 0.12 0.5 8 8 8
Ceftazidime +
Example 10 (4 mcg/ml) 0.5 2 0.5 05 8 16 8
Ceftazidime +
Example 11 (4 mcg/ml) 1 2 0.25 1 8 16 16
Ceftazidime +
Example 12 (4 mcg/ml) 2 8 0.25 2 32 32 32
Ceftazidime +
Example 13 (4 mcg/ml) 2 4 0.5 2 16 32 16
Ceftazidime +
Example 14 (4 mcg/ml) 0.5 1 0.5 1 4 8 8
Ceftazidime +
Example 15 (4 mcg/ml) 0.5 1 0.25 0.5 2 4 2
Ceftazidime +
Example 17 (4 mcg/ml) 0.5 1 0.25 0.5 4 8 4
Ceftazidime +
Example 18 (4 mcg/ml) 0.5 2 0.25 0.5 8 8 8
Ceftazidime +
Example 19 (4 mcg/ml) 0.5 2 0.5 1 8 16 8
Ceftazidime +
Example 20 (4 mcg/ml) 1 4 0.25 1 16 16 16
Ceftazidime +
Example 21(4 mcg/ml) 0.5 4 0.25 1 4 8 8
Ceftazidime +
Example 22 (4 mcg/ml) 0.5 2 0.25 2 8 16 16
Ceftazidime +
Example 23 (4 mcg/ml) 0.5 1 0.25 2 8 16 16
Ceftazidime +
Example 24 (4 mcg/ml) 0.5 2 0.5 1 - 8 8
Ceftazidime +
Example 26 (4 mcg/ml) 1 2 0.5 2 16 16 16
Ceftazidime +
Example 27 (4 mcg/ml) 1 4 0.25 1 8 16 8
Ceftazidime +
Example 28 (4 mcg/ml) 4 8 0.5 2 16 32 16
Ceftazidime +
Example 29 (4 mcg/ml) 1 4 0.5 2 8 16 16
Ceftazidime +
Example 30 (4 mcg/ml) 0.5 1 0.25 1 4 4 8
Ceftazidime +
Example 32 (4 mcg/ml) 0.5 1 0.25 1 4 4 2
Ceftazidime +
Example 37 (4 mcg/ml) 0.5 1 0.25 0.5 4 2 2
Ceftazidime +
Example 38 (4 mcg/ml) 0.5 1 0.5 1 4 4 4

,CLAIMS:1. A compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof:

wherein:

R1 and R2 are each independently:

(a) hydrogen,
(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from OR3, NR3R4, SR3, halogen, CN, COOR3, CONR3R4, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
(c) cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, (CH2)nNR3R4, (CH2)nOR3, (CH2)nCN, (CH2)nCOOR3, (CH2)nCONR3R4, OR3, O(CH2)nNR3R4, O(CH2)nCN, O(CH2)nCOOR3, O(CH2)nCONR3R4, NR3R4, NH(CH2)nNR3R4, NH(CH2)nCN, NH(CH2)nCOOR3, NH(CH2)nCONR3R4, SR3, halogen, CN, COOR3, CONR3R4, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
(d) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, (CH2)nNR3R4, (CH2)nOR3, (CH2)nCN, (CH2)nCOOR3, (CH2)nCONR3R4, OR3, O(CH2)nNR3R4, O(CH2)nCN, O(CH2)nCOOR3, O(CH2)nCONR3R4, NR3R4, NH(CH2)nNR3R4, NH(CH2)nCN, NH(CH2)nCOOR3, NH(CH2)nCONR3R4, SR3, halogen, CN, COOR3, CONR3R4, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
(e) heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, (CH2)nNR3R4, (CH2)nOR3, (CH2)nCN, (CH2)nCOOR3, (CH2)nCONR3R4, OR3, O(CH2)nNR3R4, O(CH2)nCN, O(CH2)nCOOR3, O(CH2)nCONR3R4, NR3R4, NH(CH2)nNR3R4, NH(CH2)nCN, NH(CH2)nCOOR3, NH(CH2)nCONR3R4, SR3, halogen, CN, COOR3, CONR3R4, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
(f) heterocycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, (CH2)nNR3R4, (CH2)nOR3, (CH2)nCN, (CH2)nCOOR3, (CH2)nCONR3R4, OR3, O(CH2)nNR3R4, O(CH2)nCN, O(CH2)nCOOR3, O(CH2)nCONR3R4, NR3R4, NH(CH2)nNR3R4, NH(CH2)nCN, NH(CH2)nCOOR3, NH(CH2)nCONR3R4, SR3, halogen, CN, COOR3, CONR3R4, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
(g) CN,
(h) COR3,
(i) COOR3,
(j) NR3R4,
(k) CONR3R4,
(l) OR3, or
(m) R1 and R2 are joined together to form three to eight membered ring;

R3 and R4 are each independently:

(a) hydrogen,
(b) C1-C6 alkyl,
(c) cycloalkyl,
(d) aryl,
(e) arylalkyl,
(f) heteroaryl, or
(g) heterocycloalkyl;

n is 0 to 6;

M is hydrogen or a cation.

2. The compound according to Claim 1, selected from:

(2S,5R)-N'-[(2-methoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(2-benzyloxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'- [(2,5-dimethoxyphenyl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(3,4-dimethoxyphenyl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[4-(dimethylamino)phenyl] methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2-hydroxyphenyl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(3-methoxyphenyl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(6-methylpyridin-2-yl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(4-methoxyphenyl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1 ]octane-2-carbohydrazide;
(2S,5R)-N'-[(2-cyanophenyl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(4-cyanophenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(2,6-dimethoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2,4-dimethoxyphenyl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2,4,6-trimethoxyphenyl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-(furan-2-yl-methylidene)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-(thiophen-2-yl-methylidene)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[pyridin-2-ylmethylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(6-methoxypyridin-3-yl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2-methoxypyridin-3-yl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2-hydroxyphenyl)methylidene]-7-oxo-6-(sulfooxy)- 1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(3-hydroxypyridin-2-yl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-7-oxo-N'-(pyrrolidin-2-yl-methylidene)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-7-oxo-N'-[piperidin-2-ylmethylidene]-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-7-oxo-N'-[piperidin-4-ylmethylidene]-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(6-methoxypyridin-2-yl) methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[3-aminopropylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[4-(aminomethyl)phenyl] methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[1-(2,4-dimethoxyphenyl) ethylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1] octane-2-carbohydrazide;
(2S,5R)-7-oxo-N'-[1-phenylethylidene]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[1-(2-methoxyphenyl) ethylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-cyclopentylidene-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-(4-piperidinylidene)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[4-(2-(methylamino)ethoxy)phenyl]methylidene}-7-oxo-6- (sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[4-(2-(dimethylamino)ethoxy)phenyl]methylidene}-7-oxo-6- (sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{([4-(2-aminopropoxy)phenyl]methylidene}-7-oxo-6- (sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[4-(2-(dimethylamino)propoxy)phenyl]methylidene}-7-oxo-6-(sulfooxy) -1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[4-(2-aminoethoxy)-2-methoxyphenyl]methylidene}-7-oxo-6-(sulfooxy) -1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[3-(2-aminoethoxy)phenyl]methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{2-[4-(2-aminoethoxy)phenyl]ethylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-7-oxo-N'-(piperidin-4-ylidene)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[1-amino-3-phenylpropan-2-ylidene]-7-oxo-6-(sulfooxy) -1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[4-{(2S)-pyrrolidin-2-ylmethoxy}phenyl]methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[4-{(3R)-pyrrolidin-3-yloxy}phenyl]methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;

or a stereoisomer or a pharmaceutically acceptable derivative thereof.
3. The compound according to Claim 1, selected from:

Sodium salt of (2S,5R)-N'-[(2-methoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2-benzyloxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2,5-dimethoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(3,4-dimethoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[4-(dimethylamino)phenyl]methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2-hydroxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(3-methoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6-methylpyridin-2-yl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(4-methoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2-cyanophenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(4-cyanophenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2,6-dimethoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2,4-dimethoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2,4,6-trimethoxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-(furan-2-yl-methylidene)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-(thiophen-2-yl-methylidene)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[pyridin-2-ylmethylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6-methoxypyridin-3-yl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2-methoxypyridin-3-yl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2-hydroxyphenyl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(3-hydroxypyridin-2-yl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-7-oxo-N'-(pyrrolidin-2-yl-methylidene)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-7-oxo-N'-[piperidin-2-ylmethylidene]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-7-oxo-N'-[piperidin-4-ylmethylidene]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6-methoxypyridin-2-yl)methylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[3-aminopropylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[4-(aminomethyl)phenyl]methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[1-(2,4-dimethoxyphenyl)ethylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-7-oxo-N'-[1-phenylethylidene]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[1-(2-methoxyphenyl)ethylidene]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-cyclopentylidene-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide ;
Sodium salt of (2S,5R)-N'-(4-piperidinylidene)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[4-(2-(methylamino)ethoxy)phenyl]methylidene}-7-oxo-6- (sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[4-(2-(dimethylamino)ethoxy)phenyl]methylidene}-7-oxo-6- (sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{([4-(2-aminopropoxy)phenyl]methylidene}-7-oxo-6- (sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[4-(2-(dimethylamino)propoxy)phenyl]methylidene}-7-oxo-6-(sulfooxy) -1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[4-(2-aminoethoxy)-2-methoxyphenyl]methylidene}-7-oxo-6-(sulfooxy) -1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[3-(2-aminoethoxy)phenyl]methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{2-[4-(2-aminoethoxy)phenyl]ethylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-7-oxo-N'-(piperidin-4-ylidene)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1] octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[1-amino-3-phenylpropan-2-ylidene]-7-oxo-6-(sulfooxy) -1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[4-{(2S)-pyrrolidin-2-ylmethoxy}phenyl]methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[4-{(3R)-pyrrolidin-3-yloxy}phenyl]methylidene}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;

or a stereoisomer thereof.

4. A pharmaceutical composition comprising a compound of Formula (I) according to any one of Claims 1 to 3.

5. A pharmaceutical composition according to Claim 4, further comprising at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

6. A pharmaceutical composition according to Claim 5, wherein the antibacterial agent is selected from a group consisting of aminoglycosides, ansamycins, penems, carbapenems, carbacephems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines, or oxazolidinone antibacterial agents.
7. A pharmaceutical composition according to Claim 5, wherein the antibacterial agent is a beta-lactam antibacterial agent.

8. A pharmaceutical composition according to Claim 5, wherein the antibacterial agent is a cephalosporin antibiotic selected from a group consisting of cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetrile, cefotiam, cefotaxime, cefsulodin, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide, cefbuperazone, cefozopran, cefepime, cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil or cefditoren pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, ceftaroline, ceftolozane, and latamoxef.

9. A method for preventing or treating a bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of a compound according to any of Claims 1 to 3.

10. A method for preventing or treating a bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical composition according to any one of Claims 4 to 8.