WO2016128867A1

WO2016128867A1 - Azetidinone containing compounds and their use in treatment of bacterial infections

Info

Publication number: WO2016128867A1
Application number: PCT/IB2016/050598
Authority: WO
Inventors: Vijaykumar Jagdishwar Patil; Sushilkumar MAURYA; Mahesh Vithalbhai Patel
Original assignee: Wockhardt Limited
Priority date: 2015-02-12
Filing date: 2016-02-05
Publication date: 2016-08-18

Abstract

Compounds of Formula (I), their preparation and use in preventing or treating bacterial infections are disclosed.

Description

AZETIDINONE CONTAINING COMPOUNDS AND THEIR USE IN TREATMENT OF BACTERIAL INFECTIONS

PRIORITY APPLICATION(S)

This application claims priority to Indian Patent Application No. 463/MUM/2015 filed on February 12, 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 azetidinone containing compounds, their preparation and their 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 resistance. Several antibacterial agents have been described in the prior art (for example, see PCT International Application Nos. PCT/US 2010/060923, PCT EP2010/067647, PCT/US2010/052109, PCT/US2010/048109, PCT/GB2009/050609, PCT/EP2009/056178, PCT/US2009/041200, PCT/IB2012/054290, PCT/IB2012/054296, PCT/FR01/02418, PCT/IB2013/053092, PCT/IB2012/054706, PCT/JP2013/064971, PCT/IB2012/002675, PCT/US2013/034562 and PCT/US2013/034589).

However, there remains a need for potent antibacterial agents for preventing and/or treating bacterial infections, including those caused by resistant bacteria that are resistant to known antibacterial agents. The inventors have now surprisingly discovered azetidinone containing compounds having antibacterial activity.

SUMMARY OF THE INVENTION

Accordingly, there are provided azetidinone containing 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 aspect, there are provided compounds of Formula (I):

Formula (I)

or a stereoisomer or a pharmaceutically acceptable derivative thereof; wherein:

Ri is H or S0₃M;

R₂ and R3 are each independently:

(a) hydrogen or

R4 is:

(a) H,

(b) NH₂,

(c) CO,

(d) OH,

(e) =N-OR₅ or

(f) NHOR5;

R5 is Ci-Ce alkyl optionally substituted with NH₂, halogen or CF₃;

A is:

(a) aryl optionally substituted with one or more substituents independently selected from H, OH, OR₅, SH, SR₅, NH₂, F or CN,

(b) heteroaryl optionally substituted with one or more substituents independently selected from H, OH, OR₅, SH, SR₅. NH₂, F or CN,

(c) cycloalkyl optionally substituted with one or more substituents independently selected from H, OH, OR₅, SH, SR₅, NH₂, F or CN, or

(d) heterocycloalkyl optionally substituted with one or more substituents independently selected from H, OH, OR₅, SH, SR₅, NH₂, F or CN;

M is hydrogen or a cation; n is 0, 1, 2 or 3.

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

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

In yet another 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 aspect, there is provided a method for preventing or treating bacterial infection in a subject, said method 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 another aspect, there is provided a method for preventing or treating a bacterial infection in a subject, said method comprising administering to said subject: (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 one aspect, there is provided a method of inhibiting beta-lactamase enzymes, wherein said method comprises administering a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof.

In another aspect, there is provided a method of inhibiting beta-lactamase enzymes, wherein said method comprises administering a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof.

In yet another aspect, there is provided a method for increasing antibacterial effectiveness of an antibacterial agent in a subject, said method 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 specification are set forth 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 hmitation 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 specification discloses novel azetidinone containing compounds having antibacterial properties.

The term "Q-C6 alkyl" as used herein refers to branched or unbranched acyclic hydrocarbon radical with 1 to 6 carbon atoms. Typical non-limiting examples of "Ci-Ce alkyl" include methyl, ethyl, n-propyl, iso-propyl, «-butyl, sec-butyl, z^'so-butyl, tert-butyl, «-pentyl, iso- pentyl, feri-pentyl, neopentyl, seopentyl, 3-pentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2- dimethylbutyl, 2,3-dimethylbutyl and the like. The "Ci-Ce alkyl" may be unsubstituted, or substituted with one or more substituents. Typical, non-limiting examples of such substituents include halogen, alkoxy, CN, SH, COOH, COOCi-C₆alkyl, CONH₂, OH, NH₂, NHCOCH₃, cycloalkyl, heterocyclo alkyl, heteroaryl, 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, S0₂-alkyl, S0₂-aryl, OS0₂-alkyl, OS0₂-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.

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, S0₂-alkyl, S0₂-aryl, OS0₂-alkyl, OS0₂-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.

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 Ci-C₆ alkyl, halogen, alkoxy, CN, SH, COOH, COOCi- C₆alkyl, CONH₂, OH, NH₂, NHCOCH₃, heterocycloalkyl, heteroaryl, aryl, S0₂-alkyl, S0₂-aryl, OS0₂-alkyl, OS0₂-aryl and the like.

The term "heterocycloalkyl" as used herein refers to four 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 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 Q-C6 alkyl, halogen, alkoxy, CN, COOH, CONH₂, OH, NH₂, NHCOCH3, heteroaryl, aryl, S0₂-alkyl, S0₂-aryl, OS0₂- aryl and the like.

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 iraws-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. (/. 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, trifluoro acetic acid, methanesulphonic 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, potassium carbonate, potassium bicarbonate 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 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 "extended spectrum beta-lactamase" (ESBL) as used herein includes those beta- lactamase enzymes, which are capable of conferring bacterial resistance to various beta-lactam antibacterial agents such as penicillins, cephalosporins, aztreonam and the like.

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, Mg, Ca, NH4+, (CI¾CH2)3N and the like.

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

Formula (I)

or a stereoisomer or a pharmaceutically acceptable derivative thereof;

wherein: Ri is H or S0₃M;

R₂ and R3 are each independently:

(a) hydrogen or

R4 is:

(a) H,

(b) NH₂,

(c) CO,

(d) OH,

(e) =N-OR₅ or

(f) NHOR5;

R5 is Ci-Ce alkyl optionally substituted with NH₂, halogen or CF₃; A is:

(b) heteroaryl optionally substituted with one or more substituents independently selected from H, OH, OR₅, SH, SR₅, NH₂, F or CN,

M is hydrogen or a cation; n is 0, 1 , 2 or 3.

In some embodiments, there are provided compounds of Formula (I), wherein A is heteroaryl selected from tetrazole, triazole, pyrazole, imidazole or pyrrol.

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

(2S,5R)-N- { [(3-((2Z)-2-(2-amino- 1 ,3-thiazol-5-yl)-2-(methoxyimino)amino)-4-oxoazetidin- 2-yl]methyloxy}-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5 ?)-N- { [(3-amino)-4-oxo- l-sulfoazetidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)- l ,6- diazabicyclo[3.2.1]octane-2-carboxamide;

3-amino-2-{ [({ [(25,5 ?)-6-benzyloxy-7-oxo- l ,6-diazabicyclo[3.2.1]oct-2- yljcarbonyl} amino) oxy] methyl}-4-oxoazetidine- l-sulfonic acid;

(2S,5 ?)-N- { [(2S,35)-3-amino-4-oxoazetidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)- l,6- diazabicyclo [3.2. l]octane-2-carboxamide; (2S,5?)-N-{[(2S,3S)-3-((2Z)-2-(2-amino-l,3-thiazol-5-yl)-2-(methoxyimino)amino)-4- oxoazetidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2- carboxamide;

(2S,5R)-N- { [(25,35 -3-(2-(2-amino-l ,3-t iazol-4-yl)acetylamino)-4-oxoazetidin-2-yl] methyloxy}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2.1]octane-2-carboxamide;

({ [ 2S,5R)- 2-({ [(2S,3S)-3-(2-phenylacetylamino)-4- oxoazetidin-2- yl]methoxy} carbamoyl)-7-oxo-l,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide;

({[(2S,5i?)-2-({[(25,35)-3-(2-(3-thienyl)acetylamino)-4-oxoazetidin-2- yl]methoxy}carbamoyl)-7-oxo-l,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide;

(25,5?)-N-{[(25 ¾-3-((S)-2-amino-3-(4-hydroxyphenyl)propanoylamino)-4-oxoazetidin- 2-yl] methyloxy}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2.1]octane-2-carboxamide; 2,2,2- trifluoro acetic acid;

(2S,5?)-N-{[(2S,35)-3-((R)-2-amino-2-(4-hydroxyphenyl)acetylamino)-4-oxoazetidin-2-yl] methyloxy}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2.1]octane-2-carboxamide;2,2,2-trifluoroacetic acid;

(25,5?)-N-({(25,35 -4-oxo-3-[(lH-tetrazol-l-ylacetyl)amino]azetidin-2-yl}methyloxy)-7- oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5?)-N-({(2S,35)-4-oxo-3 (2H-tetrazol-2-ylacetyl)amino]azetidin-2-yl}methyloxy)-7- oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5tf)-N-({(2S,3S>4-oxo-3-[(lH-l,2,3-triazol-l-y^

-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5?)-N-({(25,35 -4-oxo-3-[(2H-l,2,3 riazol-2-ylacetyl)amino]azetidin-2-yl}methylox^^ -7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5?)-N-({(2S,3S)-4-oxo-3-[(lH-l,2-pyrazol-l-ylacetyl)amino]azetidin-2-yl}methyloxy) - 7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5?)-N-({(2S,35 -4-oxo-3-[(lH-l,3-imidazol-l-ylacetyl)amino]azetidin-2-yl}methyloxy) -7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5«)-N-({(25,35 -4-oxo-3-[(lH-pyrrole-l-ylacetyl)aniino]azetidin-2-yl}methyloxy)-7- oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

({ [(2S,5R)- 2-({ [(2S,3S)-3-(2-chloro-3,4-di ydroxyphenylcarbonylamino)-4- oxoazetidin-2- yl]methoxy}carbamoyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2. l]octane-2- carboxamide

({[(2S,5i)-2-({[(25,35)-3-(5-hydroxy-4-oxo-l,4-di ydropyridin-2-carbonylamino)-4- oxoazetidin-2-yl]methoxy}carbamoyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2- carboxamide or a stereoisomer or a pharmaceutically acceptable derivative thereof. In some embodiments, non-limiting examples of compounds according to invention include:

Sodium salt of (25,5^)-N- { [(3-((2Z)-2-(2-amino ,3 hiazol-5-yl)-2-(methoxyimino)amino) -4-oxoazetidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)- l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,5^)-N- { [(3-amino)-4-oxo- l-sulfoazetidin-2-yl]methyloxy}-7-oxo-6- (sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of 3-amino-2-{ [({ [(25,5R)-6-benzyloxy-7-oxo- l,6-diazabicyclo[3.2.1]oct-2- yljcarbonyl} amino) oxy] methyl}-4-oxoazetidine- l-sulfonic acid;

Sodium salt of (25,5^)-N- { [(25,35)-3-amino-4-oxoazetidin-2-yl] methyloxy } -7-oxo-6- (sulfooxy)- 1 ,6-diazabicyclo [3.2.1]octane-2-carboxamide;

Sodium salt of (25,5 ?)-N-{ [(2S,3S)-3-((2Z)-2-(2-amino- l ,3-thiazol-5-yl)-2-(methoxyimino) amino)-4-oxoazetidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2- carboxamide;

Sodium salt of (2S,5R)-N- { [(2S,35)-3-(2-(2-amino- l,3-thiazol-4-yl)acetylamino)-4- oxoazetidin-2-yl] methyloxy }-7-oxo-6-(sulfooxy)- 1,6-diazabicyclo [3.2. l]octane-2-carboxamide;

Sodium salt of ({ [(25,5/?)- 2-({ [(25,35)-3-(2-phenylacetylamino)-4- oxoazetidin-2-yl] methoxy} carbamoyl)-7-oxo- l,6-diazabicyclo[3.2.1]oct-6-yl]oxy} sulfonyl)oxidanide;

Sodium salt of ({ [(25,5 ?)-2-({ [(25,35)-3-(2-(3-thienyl)acetylamino)-4-oxoazetidin-2- yl]methoxy}carbamoyl)-7-oxo- l,6-diazabicyclo[3.2.1]oct-6-yl]oxy} sulfonyl)oxidanide;

Sodium salt of (25,5/?)-N-{ [(25,35)-3-((S)-2-amino-3-(4-hydroxyphenyl)propanoylamino)- 4-oxoazetidin-2-yl] methyloxy }-7-oxo-6-(sulfooxy)- 1,6-diazabicyclo [3.2.1]octane-2-carboxamide; 2,2,2-trifluoroacetic acid;

Sodium salt of (25,5/?)-N-{ [(25,35)-3-((R)-2-amino-2-(4-hydroxyphenyl)acetylamino)-4- oxoazetidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide; 2,2,2-trifluoroacetic acid;

Sodium salt of (25,5/?)-N-({ (25,35)-4-oxo-3-[(lH-tetrazol- l-ylacetyl)amino]azetidin-2- yl}methyloxy)-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,5/?)-N-({ (25,35)-4-oxo-3-[(2H-tetrazol-2-ylacetyl)amino]azetidin-2- yljmethyloxy) -7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,5/?)-N-({ (25,35)-4-oxo-3-[( lH- l ,2,3-triazol- l-ylacetyl) amino ] azetidin- 2-yl}methyloxy)-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,5/?)-N-({ (25,35)-4-oxo-3-[(2H- l ,2,3-triazol-2-ylacetyl) amino] azetidin- 2-yl}methyloxy)-7-oxo -6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,5/?)-N-({(25,35)-4-oxo-3-[( lH- l ,2-pyrazol- l-ylacetyl) amino ] azetidin-2- yl}methyloxy)-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of (25,5 ?)-N-({ (25,35 -4-oxo-3-[(lH-l,3-imidazol- l-ylacetyl) amino ] azetidin- 2-yl}methyloxy)-7-oxo-6-(sulfooxy)- l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,5 ?)-N-({ (25,35)-4-oxo-3-[(lH-pyrrole- l-ylacetyl)amino]azetidin-2- yl}methyloxy)-7-oxo-6-(sulfooxy)- l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of ({ [(25^,,5«)-2-({ [(25,35)-3-(2-chloro-3,4-dihydroxyphenylcarbonylamino)-4- oxoazetidin-2- yl]methoxy}carbamoyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2- carboxamide

Sodium salt of ({ [(25,5R)-2-({ [(2S,3S)-3-(5-hydroxy-4-oxo- l,4-dihydropyridin-2- carbonylamino)-4-oxoazetidin-2-yl]methoxy}carbamoyl)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2.1]octane-2-carboxamide or a stereoisomer thereof.

In general, the compounds of the invention can be prepared according to the general procedures given in Scheme 1, Scheme 2 and Scheme 3. 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 general, compound of Formula (I) can be prepared by following the general procedures adopted in Scheme 1, Scheme 2, and Scheme 3. First a compound of Formula (XI) is synthesized according to general procedures disclosed in Scheme 1. Typically, /?-anisidine is condensed with ethylglyoxylate in presence of a suitable solvent to obtain a compound of Formula (III). Typical, non-limiting examples of a suitable solvent used in conversion of p-anisidine to compound of Formula (III) include dichloromethane, dichloroethane, toluene, diisopropylether, dioxane or a mixture thereof. The compound of Formula (III) is then reacted with phthalimido acetyl chloride (II) in presence of a base and a suitable solvent to obtain a cyclized compound of Formula (IV). Typical, non-limiting examples of base include triethylamine, triisopropylamine, N- ethyldiisopropylamine or a mixture thereof. Typical, non-limiting examples of a suitable solvent used in conversion of a compound of Formula (III) to a compound of Formula (IV) include in presence of a suitable solvent such as dichloromethane, dichloroethane, toluene, diisopropylether, dioxane or a mixture thereof.

The phthalimido group of a compound of Formula (IV) is removed by treating with a suitable hydrazinolysis reagent to obtain a compound of Formula (V). Typical, non-limiting examples of hydrazinolysis reagent include methyl hydrazine, hydrazine and the like. The free amino group of a compound of Formula (V) is protected to obtain a compound of Formula (VI). The compound of Formula (V) is reacted with a suitable amino group protecting reagent in presence of a suitable base and a suitable solvent to obtain a compound of Formula (VI). Typical, non-limiting examples of a suitable amino group protecting reagent include di-feri-butyl- dicarbonate, benzylchloroformate, tritylchloride and the like. Typical, non-limiting examples of a suitable base include diisopropylethyl amine, triethylamine, pyridine, aqueous solution of sodium bicarbonate and the like. Typical non-limiting examples of a suitable solvent include dichloromethane, dichloroethane, acetone or a mixture thereof. The compound of Formula (VI) is reduced in presence of a suitable reagent such as sodium borohydride to obtain a compound of Formula (VII). Further, the compound of Formula (VII) is converted to a compound of Formula (VIII). In some embodiments, the compound of Formula (VII) is reacted with N-hydroxy phthalimide in presence of triphenylphosphine and diethylazodicarboxylate to obtain a compound of Formula (VIII). The N-dearylation of a compound of Formula (VIII) is carried in presence of a suitable reagent to obtain a compound of Formula (IX). In some embodiments, the compound of Formula (VIII) is treated with eerie ammonium nitrate to obtain a compound of Formula (IX). The compound of Formula (IX) is treated with ieri-butyl dimethlsilyl chloride (TBDMS) in presence of dimethylaminopyridine to obtain a compound of Formula (X). Finally, the phthalimido group of a compound of Formula (X) is cleaved by the action of a suitable reagent such as hydrazine to obtain a compound of Formula (XI).

The compound of Formula (XI) is then converted to a compound of Formula (I), wherein R₂=R₃=H by following the reaction scheme as disclosed in Scheme 2. The compound of Formula (XI) is reacted with sodium salt of (25, 5R)-6-(benzyloxy)-7-oxo- l,6-diazabicyclo[3.2.1]octane-2- carboylic acid (XII) (prepared according to the procedure disclosed in International Patent Application No. PCT/IB2013/059264) in presence of a suitable coupling agent to obtain a compound of Formula (XIII). Typical, non-limiting examples of coupling agent include l-ethyl-3- (3-dimethyl aminopropyl)carbodiimide hydrochloride, hydroxybenzotriazole or a mixture thereof. The compound of Formula (XIII) is de-benzylated by carrying out hydrogenation reaction in presence of suitable catalyst such as palladium over carbon and a suitable solvent to obtain a compound of Formula (XIV). The debenzylated compound (XIV) is reacted with a suitable sulphonating reagent in presence of a suitable solvent under inert atmosphere, to obtain a sulphonated compound. Typical, non-limiting examples of sulphonating reagent include sulphur trioxide pyridine complex, sulphur trioxide dimethylformamide complex and the like. Typical, non- limiting examples of a suitable solvent include pyridine, dichloromethane, dimethylformamide or a mixture thereof. The sulphonated compound is further converted to corresponding tetrabutylammonium salt. In some embodiments, the sulfonated compound is treated with tetrabutylammonium hydrogen sulfate or tetrabutylammonium acetate to obtain a compound of Formula (XV). The protecting groups of compound of Formula (XV) are finally removed with a suitable deprotecting agent in presence of suitable solvent at a temperature of about - 15°C to about -10°C to obtain a compound of Formula (I), wherein R₂=R₃=H. Typical, non- limiting examples of deprotecting agent include triflouroacetic acid, hydrochloric acid, 6N hydrochloric acid in dioxane and the like.

The compound of Formula (I), wherein R2=R3=H is then converted to a compound of Formula (I), wherein only R₃=H, by following the reaction scheme as disclosed in Scheme 3. The compound of Formula (I), wherein R2=R₃=H, is reacted with a compound of Formula (XVI) in presence of a suitable coupling agent. In some embodiments, compound of Formula (I), wherein R₂=R₃=H, is reacted with a compound of Formula (XVI) in presence of N-hydroxybenzotriazole hydrate and diisopropylcarbodiimide to obtain a compound of Formula (I) wherein only R₃=H.

The compounds according to the invention are isolated as zwitterion or as pharmaceutically acceptable salts. In some embodiments, compounds according to invention are isolated as sodium salts. The sodium salt formation is achieved by contacting the tetrabutylammonium intermediate compound with sodium exchange resin. In some embodiments, sodium exchange resin used is DOWEX^® 50WX8, 50-100 mesh and the eluent is 10% tetrahydrofuran in water.

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.

N-dearylation

Scheme 1

Compound of Formula (I) ;

wherein R₂=R₃=H

Scheme 2

(XVI) Compound of Formula (I), Compound of Formula (I),

wherein R₂=R₃=H wherein R₃ is H

Scheme 3

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-lacatamse 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, there are provided pharmaceutical compositions comprising a (2S,5R)-N-{ [(3-((2¾-2-(2-amino- l,3-thiazol^

methyloxy}-7-oxo-6-(sulfooxy)- l,6-diazabicyclo[3.2.1]octane-2-carboxamide or a stereoisomer or a pharmaceutically acceptable derivative thereof.

In some other embodiments, there are provided pharmaceutical compositions comprising: (a) (25,5^)-N-{ [(3-((2Z)-2-(2-armno- l,3-thiazol-5-yl)-2-(methoxyimino)amino)-4-oxoazetidin-2- yl] methyloxy}-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide 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) (25,5 ?)-N-{ [(3-((2Z)-2-(2-arnino- l,3-thiazol-5-yl)-2-(methoxyimino)amino)-4-oxoazetidin-2- yl] methyloxy}-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide 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) (2S,5R)-N-{ [(3-((2Z)-2-(2-amino- l,3-thiazol-5-yl)-2-(methoxyimino)amino)-4-oxoazetidin-2- yl] methyloxy}-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide 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) (2S,5R)-N-{ [(3-((2Z)-2-(2-arnino- l,3-thiazol-5-yl)-2-(methoxyimino)amino)-4-oxoazetidin-2- yl] methyloxy}-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide 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) (25,5^)-N-{ [(3-((2Z)-2-(2-armno- l,3-thiazol-5-yl)-2-(methoxyimino)amino)-4-oxoazetidin-2- yl] methyloxy}-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta- lac atamse 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 (25,5^)-N- { [(3-((2Z)-2-(2-amino- l,3-thiazol-5-yl)-2- (methoxyimino)amino)-4-oxoazetidin-2-yl] methyloxy}-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo [3.2.1]octane-2-carboxamide 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) (25,57?)-N- { [(3-((2Z)-2-(2-amino- l,3-thiazol-5-yl)-2- (methoxyimino)amino)-4-oxoazetidin-2-yl] methyloxy}-7-oxo-6-(suh¾oxy)- l ,6-diazabicyclo [3.2.1]octane-2-carboxamide 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) (25,5 ?)-N- { [(3-((2Z)-2-(2-amino- l,3-thiazol-5-yl)-2- (methoxyimino)amino)-4-oxoazetidin-2-yl] methyloxy}-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo [3.2.1]octane-2-carboxamide 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) (25,57?)-N- { [(3-((2Z)-2-(2-amino- l,3-thiazol-5-yl)-2- (methoxyimino)amino)-4-oxoazetidin-2-yl] methyloxy}-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo [3.2.1]octane-2-carboxamide 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) (25,5 ?)-N- { [(3-((2Z)-2-(2-amino- l,3-thiazol-5-yl)-2- (methoxyimino)amino)-4-oxoazetidin-2-yl] methyloxy}-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo [3.2.1]octane-2-carboxamide 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 methods for preventing or treating a bacterial infection in a subject, said methods comprising administering to said subject a pharmaceutical composition comprising: (a) (25,5 ?)-N- { [(3-((2Z)-2-(2-amino- l,3-thiazol-5-yl)-2- (methoxyimino)amino)-4-oxoazetidin-2-yl] methyloxy}-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo [3.2.1]octane-2-carboxamide 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 (2S,5R)-N- { [(3-((2Z)-2-(2-amino-l,3-thiazol-5-yl)-2-(methoxyimino)amino)-4-oxoazetidin-2-yl] methyloxy}- 7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide 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) (25,57?)- N-{ [(3-((2Z)-2-(2-amino- l,3-thiazol-5-yl)-2-(methoxyimino)amino)-4-oxoazetidin-2-yl] methyloxy}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide 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) (25,5/?)- N"{ [(3-((2Z)-2-(2-amino- l,3-thiazol-5-yl)-2-(methoxyimino)amino)-4-oxoazetidin-2-yl] methyloxy}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide 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) (25,5/?)- N-{ [(3-((2Z)-2-(2-amino- l,3-thiazol-5-yl)-2-(methoxyimino)amino)-4-oxoazetidin-2-yl] methyloxy}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide 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) (25,5/?)- N-{ [(3-((2Z)-2-(2-amino- l,3-thiazol-5-yl)-2-(methoxyimino)amino)-4-oxoazetidin-2-yl] methyloxy}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide 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) (25,5/?)- N-{ [(3-((2Z)-2-(2-amino- l,3-thiazol-5-yl)-2-(methoxyimino)amino)-4-oxoazetidin-2-yl] methyloxy}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide 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, penems, carbapenems, 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, biapenem 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, oxacephem, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftiofur, cefquinome, cefovecin, CXA-101, 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-hmiting 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 a 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. The ability of compositions and methods according to the present invention to treat such resistant bacteria with typical beta- lactam antibiotics represents a significant improvement in the art.

In some embodiments, there is provided a method of inhibiting beta-lactamase enzymes, wherein said method comprises administering a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof.

In some embodiments, there is provided a method of inhibiting beta-lactamase enzymes, wherein said method comprises administering a pharmaceutical composition comprising a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof.

In some embodiments, there is provided a method for preventing or treating a bacterial infection in a subject, said infection being caused by one or more beta-lactamase enzymes, wherein the method comprises administering to said subject 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 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.

Example 1

(2S,5R)-A^-{[(3-((2Z)-2-(2-amino-l,3-thiazol-5-yl)-2-(methoxyimino)amino)-4-oxoazetidin-2-yl] methyloxy}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide

Step A: Synthesis of [cis-tert-butyl (l-(teri-butyldimethylsilyl)-2-{[amino-oxy] methyl}-4- oxoazetidin-3-yl)carbamate] (Scheme 1):

Step 1: Preparation of cis-ethyl 3-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-l-(4- methoxyphenyl)-4-oxoazetidine-2-carboxylate:

To a stirred solution of p-anisidine (5.0 g, 0.0406 mol) in dichloromethane (15 ml) was added anhydrous sodium sulphate (9.2 g, 0.070 mol) under argon atmosphere. The solution was cooled to 0°C and to this was added ethyl glyoxylate (4.2 g, 0.0406 mol, 50% toluene solution) diluted with dichloromethane (50 ml). The mixture was stirred at about 25°C for 2 hour. The resulting mixture was filtered through bed of sodium sulphate and celite and the filtrate was dried over sodium sulphate. The solvent was evaporated under reduced pressure (at about 200 mm Hg) and the residue was dried under high- vacuum (at about 4 mm Hg). The obtained crude product was dissolved in anhydrous dichloromethane (85 ml), under argon, and the solution obtained was cooled to 0°C and triethylamine (4.92 g, 0.049 mol) dissolved in dichloromethane (14 ml) was added. To the above solution was added phthalimido acetyl chloride (9.07 g, 0.0406 mol) dissolved in dichloromethane (40 ml) over a period of about 1.5 hours. The resulting mixture was stirred at 25°C for 18 hours. The reaction mixture was concentrated to half the volume and the remaining solution was washed sequentially with IN hydrochloric acid (2 x 40 ml), water (1 x 40 ml), 2% sodium bicarbonate (2 x 40 ml) and water (1 x 40 ml). The organic layer was dried over sodium sulphate and the solvent was evaporated under reduced pressure. The residue was re-crystallized from ethyl acetate (40 ml) and filtered. The solid was dried under high vacuum to furnish 7 g of diethyl 3-( 1 ,3-dioxo- 1 ,3-dihydro-2H-isoindol-2-yl)- l-(4-methoxyphenyl)-4-oxoazetidine-2- carboxylate in 44% yield.

Step 2: Preparation of ci^'s-ethyl 3-amino-l-(4-methoxyphenyl)-4-oxoazetidine-2-carboxylate:

To a solution of czs-ethyl 3-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-l-(4-methoxyphenyl)- 4-oxoazetidine-2-carboxylate 18.65 g, 0.047 mol) in dichloromethane (187 ml), was added methyl hydrazine (4.7 ml, 0.102 mol) at 0°C. The reaction mixture was allowed to warm to room temperature and was stirred for 16 hour. The resulting solution was filtered to remove any solids and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (180 ml) and was washed with water (2 x 40 ml). The organic layer was dried over sodium sulphate and the solvent was evaporated under reduced pressure to obtain lOg of ds-ethyl 3-amino- l-(4-methoxyphenyl)-4-oxoazetidine-2-carboxylate in 81% yield.

Step 3; Preparation of czs-ethyl 3-[(teri-butoxycarbonyl)amino]-l-(4-niethoxyphenyl)-4- oxoazetidine-2-carboxylate:

To a stirred solution of czs-efhyl 3-amino-l-(4-methoxyphenyl)-4-oxoazetidine-2- carboxylate (9.0 g, 0.034 mol) in dichloromethane (180 ml), was added drop wise dhsopropylethyl amine (12 ml, 0.069 mol) and di-ierf-butyl-dicarbonate (15 ml, 0.069 mol), under inert atmosphere at 0°C. The reaction mixture was stirred at ambient temperature for about 24 hours. The resulting mixture was washed sequentially with 5% potassium dihydrogen phosphate solution (2 x 180 ml), 5% sodium hydrogen carbonate (2 x 180 ml) and saturated brine solution (1 x 180 ml). The organic layer was dried over sodium sulphate and the solvent was evaporated under reduced pressure. The residue obtained was triturated with diethyl ether to furnish 9.92g of cis- ethyl 3-[(ieri-butoxycarbonyl)amino]-l-(4-methoxyphenyl)-4-oxoazetidine-2-carboxylate as a white solid in 80% yield.

Step 4: Preparation of cis-tert-butyl [2-(hydroxymethyl)-l-(4-methoxyphenyl)-4- oxoazetidin-3-yl] carbamate:

To a stirred solution of cz5-ethyl-3-[(ieri-butoxycarbonyl)amino]-l-(4-methoxyphenyl)-4- oxoazetidine-2-carboxylate (15. Og, 0.041 mol) in a mixture of tetrahydrofuran (375 ml) and water (375 ml) was added sodium borohydride (6.6 g, 0.168 mol) at 0°C. The cooling was removed and reaction was stirred at room temperature for 4 hours. The tetrahydrofuran was evaporated under reduced pressure and the aqueous layer was poured in to 500 ml of dichloromethane. The so obtained solution was acidified with IN hydrochloric acid to obtain the pH in the range of 2-3. The aqueous layer was then extracted with additional dichloromethane (4 x 200 ml). Combined organic layers were washed with 5% sodium hydrogen carbonate (300 ml) and dried over sodium sulphate. The solvent was evaporated under reduced pressure to afford 11.6 g of cis-tert-b tyl [2- (hydroxymethyl)-l-(4-methoxyphenyl)-4-oxoazetidin-3-yl]carbamate as white solid in 87% yield.

Step 5: Preparation of [cis-2[[(l,3-dihydrol,3-dioxo-2H-isoindol-2-yl)oxy]methyl]-l-(4- methoxyphenyl)-4-oxo-3-aze-tidinyl]carbamic acid 1,1-dimethylethyl ester:

To a solution of cis-tert-butyl [2-(hydroxymethyl)- l-(4-methoxyphenyl)-4-oxoazetidin-3- yl] carbamate (9.0 g, 0.027 mol) in tetrahydrofuran (200 ml), was added N-hydroxy phthalimide (4.5 g, 0.027 mol) and triphenyl phosphine (9.5 g, 0.036 mol) under stirring. The solution was cooled to about 0°C and to this was added diethyl azodicarboxylate (6.2g, 0.036 mol) dropwise. The reaction was allowed to stir at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in dichloromethane (50 ml) and further diluted with ether (50 ml) and cooled to 0°C. The separated solid was filtered and washed with a solution of dichloromethane and ether (1 :1) (250 ml) and the filtrate obtained was concentrated. The obtained solid precipitate was again washed with a solution of dichloromethane and ether (1 : 1) (125 ml) to provide 11 g of [cis-2[[(l,3-dihydrol,3-dioxo-2H-isoindol-2-yl)oxy]methyl]-l-(4- methoxyphenyl)-4-oxo-3-aze-tidinyl]carbamic acid 1, 1-dimethylethyl ester as white solid in 87 % yield.

Step 6: Preparation of [cis-tert-butyl (2-{[(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)oxy]methyl}-4-oxoazetidin-3-yl)carbamate]:

A stirred solution of [cis-2-[[(l,3-dihydrol,3-dioxo-2H-isoindol-2-yl)oxy]methyl]-l-(4- methoxyphenyl)-4-oxo-3-azetidinyl]carbamic acid 1,1-dimethylethyl ester (17.0 g, 0.036 mol) in acetonitrile (510 ml) was cooled at 0°C. To this was added eerie ammonium nitrate (59.5 g, 0.109 mol) dissolved in water (402 ml) in small portions and the resulting mixture was stirred at room temperature for 1 hour. Then, the mixture was diluted with water (640 ml) and extracted with ethyl acetate (3 x 400 ml). The combined organic layers were washed with 10% sodium sulphite (200 ml), 5% sodium hydrogen carbonate (200 ml) and brine (100 ml). The organic layer was finally dried over sodium sulphate and the solvent was then evaporated under reduced pressure to obtain 9.2 g of [cis-tert-butyl (2-{ [(l,3-dioxo- l,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-4-oxoazetidin-3- yl)carbamate] in 70% yield.

Step 7: Preparation of [cis-tert-butyl (l-(tert-butyldimethylsilyl)-2-{[(l,3-dioxo-l,3-dihydro- 2H-isoindol-2-yl)oxy]methyl}-4-oxoazetidin-3-yl)carbamate]:

To a stirred solution of [cis-tert-butyl (2-{ [(l,3-dioxo- l,3-dihydro-2H-isoindol-2- yl)oxy]methyl}-4-oxoazetidin-3-yl)carbamate] (4.7 g, 0.0132 mol) in dimethylformamide (50 ml) was added triethyl amine (3.8 ml, 0.026 mol) in one portion, under argon atmosphere at 0°C. To this reaction mixture were added successively terf -butyl dimethyl silyl chloride (4.06 g, 0.026 mol) and 4-dimethylaminopyridine (0.315 g, 0.00266 mol). The reaction was stirred at room temperature for about 16 hour. The resulting mixture was diluted with ethyl acetate (250 ml) and the mixture was washed with water (2 x 100 ml). The organic layer was dried over sodium sulphate and the solvent was evaporated under reduced pressure. The residue obtained was then purified by silica gel column chromatography using mixtures of ethyl acetate and hexane as mobile phase. Evaporation of the solvent from the combined fractions gave 4.8 g of [cis-tert-butyl (l-(feri- butyldimethylsilyl)-2-{ [(l,3-dioxo- l,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-4-oxoazetidin-3- yl)carbamate] in 77% yield.

Analysis:

1H NMR (CDC1₃, 400 MHz): δ 7.86 (m, 2H), 7.77 (m, 2H), 6.42 (d, 1H), 5.40 (dd, 1H) 4.68 (dd, 1H), 4.15 (d, 1H), 4.05 (m, 1H), 1.48 (s, 9H), 0.99 (s, 9H), 0.39 (s, 3H), 0.35 (s, 3H). Mass: 474.3 (M-l); for Molecular Formula of C₂₃H₃₃N₃O₆S1 and Molecular Weight of

475.61.

Step 8: Preparation of [cis-tert-b tyl (l-(ieri-butyldimethylsilyl)-2-{ [amino-oxy]methyl}-4- oxoazetidin-3-yl)carbamate] :

To a stirred solution of [cis-tert-butyl (l-(tert-butyldimethylsilyl)-2-{ [(l,3-dioxo- l,3- dihydro-2H-isoindol-2-yl)oxy]methyl}-4-oxoazetidin-3-yl)carbamate] (4.6g, 0.0097 mol) in dichloromethane (70 ml) was added hydrazine monohydrate (0.97g, 0.0194 mol) under argon atmosphere and at about 0 °C. The cooling was removed and reaction was stirred at room temperature for one hour. The resulting mixture was filtered through a bed of celite and washed with dichloromethane (35 ml). The combined filtrate was washed with water (10 ml) and the organic layer was dried over sodium sulphate. The solvent was evaporated under reduced pressure and residue was further dried under high vacuum (at about 4 mm Hg) to obtain 3.3g of [cis-tert- butyl (l-(tert-butyldimethylsilyl)-2-{ [amino-oxy]methyl}-4-oxoazetidin-3-yl)carbamate], which was used as such without further purification.

Analysis:

1H NMR (CDCI₃, 400 MHz): δ 5.54 (s, 2H), 5.45 (d, 1H), 5.19 (dd, 1H), 3.94-3.81 (m, 3H), 1.44 (s, 9H), 0.96 (s, 9H), 0.284 (s, 3H), 0.237 (s, 3H).

Mass: 346.3 (M+l); for Molecular Formula of CisH^iNsC^Si and Molecular Weight of

345.51.

Step B: Synthesis of (25,5 ?)-N-{[cis-3-amino-4-oxoazetidin-2-yl]methyloxy}-7-oxo-6-(sulfo- oxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide (Scheme 2):

Step 1: Preparation of (25,5/f)-N-{[cis-l-(iert-butyldimethylsilyl)-3-(0-tert-butyl carboxy)amino-4-oxoazetidin-2-yl]methyloxy}-7-oxo-6-(benzyl-oxy)-l,6-diazabicyclo[3.2.1] octane-2-carboxamide:

To a stirred solution of sodium (2S,5 ?)-6-(benzyloxy)-7-oxo- l,6-diazabicyclo[3.2.1]octane- 2-carboxylic acid (2.7 g, 0.0096 mol) in dimethylformamide (20 ml) were added successively 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.75 g, 0.0144 mol) and hydroxybenzotriazole (1.30 g, 0.0096 mol), under argon atmosphere at about 0°C. After 15 minutes of stirring, [cis-tert-butyl (l-(tert-butyldimethylsilyl)-2-{ [amino-oxy]methyl}-4-oxoazetidin-3- yl)carbamate] (3.3 g, 0.0096 mol) dissolved in dimethylformamide and 4-methyl morpholine (4.2 ml, 0.029 mol) were added. The cooling bath was removed and reaction was allowed to warm to room temperature and stirred further for 16 hours. The resulting mixture was diluted with ethyl acetate (100 ml) and washed with water (2 x 50 ml). The combined aqueous layers were again extracted with ethyl acetate (50 ml). The pooled organic layers were dried over sodium sulphate and solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using mixture of ethyl acetate and hexane as eluent. Evaporation of the combined fractions under reduced pressure gave 2.3 g of (25,5 ?)-N-{ [cw- l-(ieri-butyldimethylsilyl)-3-(0- tert-butyl carboxy)amino-4-oxoazetidin-2-yl]methyl oxy}-7-oxo-6-(benzyl-oxy)- l,6-diazabicyclo [3.2.1]octane-2-carboxamide in 40% yield.

Analysis:

1H NMR (CDCI₃, 400 MHz): δ 9.20 (d, 1H), 7.43 (m, 5H), 6.81 (d, 1H), 6.28 (d, 1H) 5.62 (m, 2H), 5.07 (d, 1H), 4.93 (d, 1H), 4.44-3.96 (m, 4H), 3.38 (m, 1H), 2.98 (d, 2H), 2.79 (d, 1H), 2.33 (m, 1H), 2.07 (m, 2H), 1.69 (s, 3H), 1.47 (s, 9H), 0.96 (s, 9H), 0.31(s, 3H), 0.30 (s, 3H), 0.25 (s, 3H), 0.24 (s, 3H).

Mass: 602.4 (M-l); for Molecular Formula of C₂₉H₄₅N₅O₇S1 and Molecular Weight of

603.78. Step 2; Preparation of (25,5 ?)-N-{[cis-3-amino-4-oxoazetidin-2-yl]methyloxy}-7-oxo-6-(sulfo- oxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide:

To a solution of (25,5i?)-N-{ [cw- l-(ieri-butyldimethylsilyl)-3-(0-ierf-butyl carboxy)amino- 4-oxoazetidin-2-yl]methyloxy}-7-oxo-6-(benzyl-oxy)- l,6-diazabicyclo[3.2.1]octane-2- carboxamide (0.6 g, 0.99 mmol) in a mixture of dichloro methane (6 ml) and dimethylformamide (6 ml) at room temperature, was added palladium over carbon (120 mg, 20 wt %) under hydrogen balloon pressure and stirred for 3 hours. After completion (as monitored by thin layer chromatography), the reaction mixture was filtered through a bed of celite and solid residue was washed with additional dichloromethane (2 x 10 ml). The combined filtrate was concentrated under reduced pressure and dimethylformamide was removed under high vacuum (4 mm Hg) to obtain a residue. The residue was dissolved in pyridine (3.0 ml) and sulphur trioxide pyridine complex (0.787 g, 4.95 mmol) was added. The reaction mixture was stirred for 18 hours under argon atmosphere and monitored by thin layer chromatography and electrospray mass spectrometry (ES- MS). After completion, the reaction mixture was diluted with dichloromethane (20 ml) and filtered. The residue was washed with dichloromethane (10 ml). The solvent was evaporated under reduced pressure and dried under high-vacuum. The obtained residue was dissolved in 100 ml of aqueous 0.5 M potassium dihydrogen phosphate solution and the solution was extracted with diethyl ether (20 ml). To the aqueous solution was added tetra n-butyl hydrogen sulfate (0.370 g, 1.089 mmol) and stirred for 15 minutes. The resulting mixture was extracted with dichloromethane (3 x 50 ml) and the pooled organic layers were washed with water (2 x 50 ml) and dried over sodium sulphate. The organic layer was then evaporated under reduced pressure to obtain the crude tetrabutylammonium salt (0.600 g, 0.718 mmol). The so obtained crude tetrabutylammonium salt (0.600 g, 0.718 mmol) was dissolved in tetrahydrofuran (10 ml) under argon atmosphere and cooled to about 0°C. To this was added tetrabutylammonium fluoride solution (0.188 g, 0.718 mmol, 0.720 ml of 1.0 M) and the reaction mixture was allowed to stir at room temperature for 2 hours. After completion, (monitored by thin layer chromatography) the solvent was evaporated under reduced pressure and residue obtained was purified by column chromatography. Elution with v/v mixtures of dichloromethane: methanol, and evaporation of the solvent from the combined fractions furnished the tetrabutylammonium salt (0.415 g, 0.575 mmol).

To a stirred solution of tetrabutylammonium salt (0.415 g, 0.575 mmol) in dichloromethane (2 ml) was added cooled trifluoro acetic acid (1.2 ml) drop wise, under argon atmosphere at - 10°C. The reaction was monitored with ES-MS. After completion (about 2 hours), the reaction mixture was diluted with hexane (25 ml), and stirred for 30 minutes. The hexane layer was decanted and the residual solid was washed repeatedly with hexane (2 x 25 ml) ether (3 x 25 ml), acetonitrile (2 x 10 ml) and ether (2 x 10 ml). The obtained solid was dried under high-vacuum (4 mm Hg) to obtain 0.170 g of (2S,5^)-N- { [ci5-3-amino-4-oxoazetidin-2-yl]methyloxy}-7-oxo-6-(sulfo-oxy)-l,6- diazabicyclo[3.2.1]octane-2-carboxamide as a off-white solid in 45% yield.

Analysis:

Melting point: 172-174°C

1H NMR (DMSO-de, 400 MHz): δ 11.90 (s, 1H), 8.75 (bs, 3H), 4.90 (d, 1H), 3.98-4.16 (m, 4H), 3.80 (d, 1H), 2.99 (m, 2H), 1.87-2.05 (m, 2H), 1.65- 1.74 (m, 2H);

Mass: 378.2 (M-l); for Molecular Formula of CnHnNsOgS and Molecular Weight of

379.35.

Isolation of the isomer used in step 3 of step A: To a stirred solution of the of cw-ethyl 3-amino- l-(4-methoxyphenyl)-4-oxoazetidine-2-carboxylate (41.7 g, 0.1579 mol) in 1000 ml acetonitrile under inert atmosphere was added di-p-tolyoyl D (+) tartaric acid (60.65 g, 0.1579 mol). The solution was heated at 70°C till it become clear when heating was removed and stirred at 25°C for 16 hours. Then, reaction mass was filtered and solid cake was washed with 50 mL of chilled acetonitrile. The solid was transferred to flask and was added acetonitrile (300 mL) and solution was heated at 70°C till it become clear and stirred at 25°C for 16 hours and filtered and washed with cooled acetonitrile (50 ml). The whole sequence was repeated 5 times and finally solid was dried under high- vacuum (4 mm Hg) (11.9 g; chiral HPLC purity 100 % of S-isomer). Next, solid (11.9 g, 0.018 mol) was transferred to flask and was added dichloro methane (75 ml) at 25°C. To the above solution was added sodium hydrogen carbonate (3.85 g, 0.0459 mol) dissolved in water (60 ml) dropwise. Solution was stirred at 25°C till it become clear. The dichloro methane layer was separated and was washed with water (2 x 25 ml), dried over sodium sulfate and dried under high- vacuum (4 mm Hg) to obtain (2S,3S)-ethyl 3-amino-l-(4-methoxyphenyl)-4-oxoazetidine-2- carboxylate as white solid in 11 % yield.

Step C; Synthesis of (25,5 ?)-^-{[(3-((2Z)-2-(2-amino-l,3-thiazol-5-yl)-2-

(methoxyimino)amino)-4-oxoazetidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo

[3.2.1]octane-2-carboxamide (Scheme 3):

To a stirred solution of the (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (0.106g, 0.527 mmol) in dimethylformamide (2 ml) were added successively N-hydroxybenzotriazole hydrate (0.072 g, 0.527 mmol) and diisopropyl carbodimide (0.074 g, 0.579 mmol) under inert atmosphere at about 0°C. The cooling bath was removed and reaction mixture was stirred at ambient temperature (25°C) for about 45 minutes. To the resulting reaction mixture a solution of (2S,5R)-N-{ [cis-3-amino-4-oxoazetidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo

[3.2.1]octane-2-carboxamide (0.200 g, 0.527 mmol) and triethyl amine (0.107 g, 1.05 mmol) in dimethylformamide (2 ml) was added drop wise at 0°C. After 17 hour of stirring, the completion of reaction was monitored by ES-MS. The reaction mixture was allowed to cool to about -10°C and the separated diisopropyl urea was removed by filtration. To the obtained filtrate, tertabutylammonium hydrogen sulphate (0.196 g, 0.579 mmol) was added and the mixture was stirred for about 2 hour. The solvent was then removed under reduced pressure and residue was purified by column chromatography, to obtain the corresponding tetrabutylammonium salt (O. lOOg, 0.124 mmol).

The above obtained TBA salt (0.100 g, 0.124 mmol) was dissolved in dichloromethane (0.300 ml) and to this was added trifluoro acetic acid (0.200 ml) under inert atmosphere at about -10°C. After 30 minutes of stirring, the reaction mixture was diluted with hexane (9 ml) and stirred further for 1 hour. Then the hexane layer was decanted from the separated solid. The solid residue was washed sequentially with hexane (2 x 6 ml), diethyl ether (2 x 3 ml), acetonitrile (2 x 3 ml), and diethyl ether (2 x 3 ml). The solid obtained was dried under high-vacuum (4 mm Hg) below 40 °C to obtain 0.05 g of the titled product as off-white solid in 17% yield.

The compounds of Example 2-10 (Table 1) were prepared using the procedure described in Example 1 by using appropriate reagents.

Formula (I)

BIOLOGICAL ACTIVITY DATA

The biological activity of representative compounds according to the invention against various bacterial strains was investigated by following methods:

(a) Beta-lactamase inhibition assay for the determination of IC50:

The degree of inactivation of beta lactamase activity was determined with Nitrocefin as a substrate employing a spectrophotometric assay. The concentration of compounds which caused 50 % reduction in hydrolysis of Nitrocefin (ΙΟΟμΜ) i.e. IC_50, was measured after 10 minutes of pre incubation (37°C) of the crude enzymes and inhibitors. The change in colour of Nitrocefin from yellow to red was considered as an endpoint of the reaction, which was measured at 485nm by UV- spectrophotometer. The IC₅₀ was calculated by plotting Sigmoidal dose response curve using GraphPad-v5 software.

As can be seen in Table 2, the compounds of present invention exhibited beta-lactamase inhibition.

(b) Method for the determination of combination MIC:

The Minimum Inhibitory Concentration (MIC) determination for the combinations was carried out in Muller Hinton Agar (MHA) (BD, USA) according to Clinical and Laboratory Standards Institute (CLSI) recommendations, (Clinical and Laboratory Standards Institute (CLSI), Performance Standards for Antimicrobial Susceptibility Testing, 20^th Informational Supplement, M 100-S20, Volume 30, No. 1, 2010). In short, the test strains were adjusted to deliver about 10⁴ CFU per spot with a multipoint inoculator (Applied Quality Services, UK). The plates were poured with MHA containing doubling concentration range of Ceftazidime in combination with constant concentration (4ug/ml) of compound of Formula (I). The plates were inoculated and were incubated at 35°C for 18 hours. MICs were read as the lowest concentration of drug that completely inhibited bacterial growth. 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 the compounds according to the invention. The obtained results suggest that the compounds according to invention increase antibacterial effectiveness of an antibacterial agent when said antibacterial agent is co-administered with a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof.

Claims

1. A compound of Formula (I):

Formula ( I)

or a stereoisomer or a pharmaceutically acceptable derivative thereof;

wherein:

Ri is H or S0₃M; R₂ and R3 are each independently:

(a) hydrogen or

R4 is:

(a) H,

(b) NH₂,

(c) CO,

(d) OH,

(e) =N-OR₅ or

(f) NHOR5;

R5 is Ci-Ce alkyl optionally substituted with NH₂, halogen or CF₃;

A is:

M is hydrogen or a cation; n is 0, 1, 2 or 3.

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

(25,5 ?)-N-{[(3-((2Z)-2-(2-amino-l,3-thia^^

2-yl]methyloxy}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5?)-N-{[(3-amino)-4-oxo-l-sulfoazetidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2.1]octane-2-carboxamide;

3-amino-2-{ [({ [(25,5?)-6-benzyloxy-7-oxo-l,6-diazabicyclo[3.2. l]oct-2- yl]carbonyl} amino) oxy] methyl}-4-oxoazetidine-l-sulfonic acid;

(25,5?)-N-{[(2S ¾-3-amino-4-oxoazetidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-l,6- diazabicyclo [3.2. l]octane-2-carboxamide;

(25,5«)-N-{[(2S,3S)-3-((2Z)-2-(2-arnino-l,3-thiazol-5-yl)-2-(methoxyimino)amino)-4- oxoazetidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2- carboxamide;

(2S,5?)-N-{[(2S 5 -3-(2-(2-armno-l,3-thiazol-4-yl)acetylamino)-4-oxoazetidin-2-yl] methyloxy}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2. l]octane-2-carboxamide;

({ [(25,5/?)- 2-({ [(25,35)-3-(2-phenylacetylamino)-4- oxoazetidin-2- yl]methoxy} carbamoyl)-7-oxo-6-(sulfooxy)- 1 ,6-diazabicyclo [3.2.1 ]octane-2-carboxamide

({[(25,5/?)-2-({[(25,35)-3-(2-(3-thienyl)acetylamino)-4-oxoazetidin-2- yl]methoxy}carbamoyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2.1]octane-2-carboxamide;

(25,5/?)-N-{[(25 5)-3-((S)-2-armno-3-(4-hydroxyphenyl)propanoylamino)-4-oxoazetidin- 2-yl] methyloxy}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2.1]octane-2-carboxamide; 2,2,2- trifluoro acetic acid;

(25,5/?)-N-{[(25,35)-3-((R)-2-amino-2-(4-hydroxyphenyl)acetylamino)-4-oxoazetidin-2-yl] methyloxy}-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2.1]octane-2-carboxamide;2,2,2-trifluoroacetic acid;

(25,5/?)-N-({(25,35)-4-oxo-3-[(lH-tetrazol-l-ylacetyl)amino]azetidin-2-yl}methyloxy)-7- oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5/?)-N-({(25,35)-4-oxo-3-[(2H-tetrazol-2-ylacetyl)amino]azetidin-2-yl}methyloxy)-7- oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5/?)-N-({(25,35)-4-oxo-3 (lH-l,2,3 riazol-l-ylacetyl)amino]azetidin-2-yl}methyloxy) -7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5/?)-N-({(25,35)-4-oxo-3-[(2H-l,2,3-triazol-2-ylacetyl)amino]azetidin-2-yl}methyloxy) -7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5/?)-N-({(25,35)-4-oxo-3-[(lH-l,2-pyrazol-l-ylacetyl)amino]azetidin-2-yl}methyloxy) - 7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(25,5/?)-N-({(25,35)-4-oxo-3 (lH-l,3-imidazol -ylacetyl)amino]azetidin-2-yl}methyloxy) -7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5tf)-N-({ (2S,3S 4-oxo-3-[(lH-pyrrole- l-ylacetyl)am^

oxo-6-(sulfooxy)- l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

({ [(2S,5R> 2-({ [(25,35)-3-(2-chloro-3,4-dihydroxyphenylcarbonylamino)-4- oxoazetidin-2- yl]methoxy}carbamoyl)-7-oxo-6-(sulfooxy)- l,6-diazabicyclo [3.2. l]octane-2- carboxamide

({ [(2S,5i?)-2-({ [(25,35)-3-(5-hydroxy-4-oxo- l,4-di ydropyridin-2-carbonylamino)-4- oxoazetidin-2-yl]methoxy}carbamoyl)-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2- carboxamide or a stereoisomer or a pharmaceutically acceptable derivative thereof.

3. A compound according to Claim 1 , selected from:

Sodium salt of (2S,5i?)-N- { [(3-((2Z)-2-(2-amino- 1 hiazol-5-yl)-2-(methoxyimino)amino) -4-oxoazetidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)- l,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-N- { [(3-amino)-4-oxo-l-sulfoazetidin-2-yl]methyloxy}-7-oxo-6- (sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of 3-amino-2- { [({ [(25,5i?)-6-benzyloxy-7-oxo- l,6-diazabicyclo[3.2.1]oct-2- yl]carbonyl} amino) oxy] methyl}-4-oxoazetidine- l-sulfonic acid;

Sodium salt of (25,5 ?)-N-{ [(25,3S)-3-amino-4-oxoazetidin-2-yl]methyloxy}-7-oxo-6- (sulfooxy)- 1 ,6-diazabicyclo [3.2.1]octane-2-carboxamide;

Sodium salt of (2S,5R)-N-{ [(2S,3S)-3-((2Z)-2-(2-amino- l ,3-thiazol-5-yl)-2-(methoxyimino) amino)-4-oxoazetidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2- carboxamide;

Sodium salt of (25^,,5«)-N- { [(25^,,35)-3-(2-(2-amino- l,3-thiazol-4-yl)acetylamino)-4- oxoazetidin-2-yl] methyloxy }-7-oxo-6-(sulfooxy)- 1,6-diazabicyclo [3.2. l]octane-2-carboxamide;

Sodium salt of ({ [(2S,5R)- 2-({ [(2S,3S)-3-(2-phenylacetylamino)-4- oxoazetidin-2-yl] methoxy} carbamoyl)-7-oxo-6-(sulfooxy)- 1,6-diazabicyclo [3.2. l]octane-2-carboxamide;

Sodium salt of ({ [(25,5 ?)-2-({ [(25,35)-3-(2-(3-thienyl)acetylamino)-4-oxoazetidin-2- yl]methoxy}carbamoyl)-7-oxo-6-(sulfooxy)- 1,6-diazabicyclo [3.2.1]octane-2-carboxamide;

Sodium salt of (25,5 ?)-N-{ [(25,35)-3-((S)-2-amino-3-(4-hydroxyphenyl)propanoylamino)- 4-oxoazetidin-2-yl] methyloxy }-7-oxo-6-(sulfooxy)- 1,6-diazabicyclo [3.2.1]octane-2-carboxamide; 2,2,2-trifluoroacetic acid;

Sodium salt of (25,5 ?)-N-{ [(25,3S)-3-((R)-2-amino-2-(4-hydroxyphenyl)acetylamino)-4- oxoazetidin-2-yl] methyloxy }-7-oxo-6-(sulfooxy)- 1,6-diazabicyclo [3.2.1]octane-2-carboxamide; 2,2,2-trifluoroacetic acid;

Sodium salt of (25,5^)-N-({ (25,35)-4-oxo-3 (lH etrazol- l-ylacetyl)amino]azetidin-2- yl}methyloxy)-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of (2S,5 ?)-N-({ (2S,35)-4-oxo-3-[(2H-tetrazol-2-ylacetyl)amino]azetidin-2- yljmethyloxy) -7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,5 ?)-N-({(25,35)-4-oxo-3-[( lH- l ,2,3-triazol- l-ylacetyl) amino ] azetidin- 2-yl}methyloxy)-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,5/?)-N-({(25,35)-4-oxo-3-[(2H- l ,2,3-triazol-2-ylacetyl) amino] azetidin- 2-yl}methyloxy)-7-oxo -6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,5R)-N-({(25,3S)-4-oxo-3-[( lH- l ,2-pyrazol- l-ylacetyl) amino ] azetidin-2- yl}methyloxy)-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25^,,5 ?)-N-({ (25',35)-4-oxo-3-[(lH- l,3-imidazol- l-ylacetyl) amino ] azetidin- 2-yl}methyloxy)-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of (25,5 ?)-N-({ (25,35')-4-oxo-3-[( lH-pyrrole- l-ylacetyl)amino]azetidin-2- yl}methyloxy)-7-oxo-6-(sulfooxy)- l ,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Sodium salt of ({ [(2S,5 ?)-2-({ [(2S,3S)-3-(2-chloro-3,4-dihydroxyphenylcarbonylamino)-4- oxoazetidin-2- yl]methoxy}carbamoyl)-7-oxo-6-(sulfooxy)- l,6-diazabicyclo[3.2.1]octane-2- carboxamide;

Sodium salt of ({ [(25,5^)-2-({ [(2S,35)-3-(5-hydroxy-4-oxo- l ,4-dihydropyridin-2- carbonylamino)-4-oxoazetidin-2-yl]methoxy}carbamoyl)-7-oxo-6-(sulfooxy)- l ,6- diazabicyclo[3.2.1]octane-2-carboxamide; or a stereoisomer thereof.

4. A pharmaceutical composition comprising a compound according to any one of the Claims 1 to 3.

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

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

7. The pharmaceutical composition according to Claim 5, wherein the antibacterial agent is a beta- lactam antibacterial agent.

8. The pharmaceutical composition according to Claim 5, wherein the antibacterial agent is a antibiotic selected from the 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, latamoxef, ertapenem, doripenem, imipenem, meropenem and biapenem.

9. The pharmaceutical composition according to Claim 5, wherein the antibacterial agent is selected from the group consisting of ceftazidime, cefepime, cefpirome, ceftaroline, ceftibuten, ceftolozane, piperacillin doripenem, meropenem and imipenem.

10. The pharmaceutical composition according to Claim 5, comprising (a) (2S,5^)-N- { [(3-((2Z)-2-(2-armno-l,3-thiazol-5-yl)-2-(methoxyimino)amino)-4-oxoazetidin-2-yl] methyloxy }- 7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

11. A method for preventing or treating a bacterial infection in a subject, the method comprising administering to said subject a compound according to any one of the Claims 1 to 3.

12. A method for preventing or treating a bacterial infection in a subject, the method comprising administering to said subject a pharmaceutical composition according to any one of the Claims 4 to 11.

13. A method for preventing or treating a bacterial infection in a subject, the method comprising administering to said subject: (a) a compound of Formula (I) according to Claim 1 or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

14. The method according to Claim 13, wherein compound of Formula (I) is (25,5R)-N- { [(3-((2Z)-2-(2-armno-l,3-thiazol-5-yl)-2-(methoxyimino)amino)-4-oxoazetidin-2-yl] methyloxy }- 7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide or a stereoisomer or a pharmaceutically acceptable derivative thereof.

15. A method for increasing antibacterial effectiveness of an antibacterial agent in a subject, the method comprising co- administering said antibacterial agent or a pharmaceutically acceptable derivative thereof with a compound of Formula (I) according to Claim 1 or a stereoisomer or a pharmaceutically acceptable derivative thereof.