WO2017002087A1

WO2017002087A1 - Nitrogen containing bicyclic compounds and their use in treatment of bacterial infections

Info

Publication number: WO2017002087A1
Application number: PCT/IB2016/053971
Authority: WO
Inventors: Vijaykumar Jagdishwar Patil; Ravikumar Tadiparthi; Velupillai LOGANANTHAN; Deepak Dekhane; Piyush Ambalal PATEL; Prasad DIXIT; Mahesh Vithalbhai Patel
Original assignee: Wockhardtlimited
Priority date: 2015-07-02
Filing date: 2016-07-01
Publication date: 2017-01-05

Abstract

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

Description

NITROGEN CONTAINING BICYCLIC COMPOUNDS AND THEIR USE IN TREATMENT OF BACTERIAL INFECTIONS

PRIORITY APPLICATION(S)

This application claims priority to Indian Patent Application No. 2545/MUM/2015 filed on July 02, 2015, the disclosures of which is incorporated herein by reference in its entirety as if fully rewritten herein.

FIELD OF THE INVENTION

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

BACKGROUND OF THE INVENTION

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

Several antibacterial agents have been described in the prior art (for example, see PCT International Application Nos. PCT/US 2010/060923, PCT/EP2010/067647, PCT/US2010/052109, PCT/US2010/048109, PCT/GB2009/050609, PCT/FR01/02418, PCT/EP2009/056178, PCT/US2009/041200, PCT/IB2012/054290, PCT/IB2013/053092, PCT/IB2012/054296 and PCT/IB2012/054706, PCT/JP2013/064971, PCT/IB 2012/002675, 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 bacteria that are resistant to known antibacterial agents.

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

SUMMARY OF THE INVENTION

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

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

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

Ri is:

(a) hydrogen,

(b) Ci-C₆ alkyl optionally substituted with one or more substituents independently selected from OR₃, NR₃R₄, SR₃, SOR₃, S0₂R₃, CN, halogen, COOR₃, CONR₃R4, NR₃COR4, or NR₃CONR4R₅,

(d) CN,

(e) SOR₃,

(f) S0₂R₃ or

(g) OR₃;

R₂ is:

(a) hydrogen,

(b) Ci-C₆ alkyl optionally substituted with one or more substituents independently selected from OR₃, NR₃R₄, SR₃, SOR₃, S0₂R₃, CN, halogen, COOR₃, CONR₃R4, NR₃COR4, NR₃CONR4R₅, =NOCH₃, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

(c) cycloalkyl optionally substituted with one or more substituents independently selected from OR₃, NR₃R₄, SR₃, SOR₃, S0₂R₃, CN, (CH₂)_nNR₃R₄, halogen, COOR₃, CONR₃R4, NR₃COR4 or NR₃CONR4R₅,

(d) heterocycloalkyl optionally substituted with one or more substituents independently selected from OR₃, NR₃R₄, SR₃, SOR₃, S0₂R₃, CN, (CH₂)_nNR₃R4, halogen, COOR₃, CONR₃R4, NR₃COR4 or NR₃CONR4R₅,

(e) aryl optionally substituted with one or more substituents independently selected from OR₃, NR₃R₄, SR₃, SOR₃, S0₂R₃, CN, (CH₂)_nNR₃R₄, halogen, COOR₃, CONR₃R4, NR₃COR4 or NR₃CONR4R₅ or

(f) heteroaryl optionally substituted with one or more substituents independently selected from OR₃, NR₃R₄, SR₃, SOR₃, S0₂R₃, CN, (CH₂)_nNR₃R₄, halogen, COOR₃, CONR₃R4, NR₃COR4 or NR₃CONR4R₅;

R₃, R₄ and R5 are each independently:

(a) hydrogen or

(b) Ci-C₆ alkyl; n is 0, 1, 2 or 3;

M is hydrogen or a cation.

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

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

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

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

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

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

In yet another general 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 invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the following description including claims.

DETAILED DESCRIPTION OF THE INVENTION

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

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

The term "Ci-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-C₆ alkyl" include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, z^'so-butyl, tert-butyl, n-pentyl, z^'so-pentyl, ieri-pentyl, neopentyl, sec-pentyl, 3-pentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3- dimethylbutyl and the like. The "Ci-C₆ alkyl" may be unsubstituted, or substituted with one or more substituents. Typical, non-limiting examples of such substituents include halogen, alkoxy, CN, SH, COOH, COOCi-C₆alkyl, CONH₂, OH, NH₂, NHCOCH₃, cycloalkyl, heterocycloalkyl, heteroaryl, aryl and the like.

The term "cycloalkyl" as used herein refers to three to seven member cyclic hydrocarbon radicals. The cycloalkyl group optionally incorporates one or more double or triple bonds, or a combination of double or triple bonds, but which is not aromatic. Typical, non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The cycloalkyl may be unsubstituted, or substituted with one or more substituents. Typical, non-limiting examples of such substituents include Ci-C₆ alkyl, halogen, alkoxy, CN, SH, COOH, COOCi-Cealkyl, CONH₂, OH, NH₂, NHCOCH₃, heterocycloalkyl, heteroaryl, aryl, S0₂-alkyl, S0₂-aryl, OS0₂-alkyl, OS0₂-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. In some embodiments, the term "aryl" refers to six to fourteen membered monocyclic or polycyclic aromatic hydrocarbon radical.

The term "heteroaryl" as used herein refers to a monocyclic or polycyclic aromatic hydrocarbon group wherein one or more carbon atoms have been replaced with heteroatoms selected from nitrogen, oxygen, and sulfur. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Typical, non- limiting example of heteroaryl groups include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, pyrrolyl, thienyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazonyl, isoxazolyl, oxadiazolyl, oxatriazolyl, isothiazolyl, thiatriazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, tetrazolo-pyridazinyl, purinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzothiophenyl, carbazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzotriazolyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, acridinyl, naphthothienyl, thianthrenyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl,indazolyl, phthalazinyl, naphthyridinyl, qinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, beta-carbolinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like. The heteroaryl group may be unsubstituted, or substituted with one or more substituents. Typical, non-limiting examples of such substituents include Ci-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. In some embodiments, the term "heteroaryl" refers to five to fourteen membered monocyclic or polycyclic aromatic hydrocarbon radical. The term "heterocycloalkyl" as used herein refers to three to seven member cycloalkyl group containing one or more heteroatoms selected from nitrogen, oxygen or sulfur. The heterocycloalkyl group optionally incorporates one or more double or triple bonds, or a combination of double bonds and triple bonds, but which is not aromatic. Typical, non- limiting example of heterocycloalkyl groups include 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 Ci-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 irans-forms), as well as mixtures thereof, are embraced within the scope of the invention. In general, a reference to a compound is intended to cover its stereoisomers and mixture of various stereoisomers.

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

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

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

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

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

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

The terms "pharmaceutically effective amount" or "therapeutically effective amount" or "effective amount" as used herein refer to an amount, which has a therapeutic effect or is the amount required to produce a therapeutic effect in a subject. For example, a "therapeutically effective amount" or "pharmaceutically effective amount" or "effective amount" of an antibacterial agent or a pharmaceutical composition is the amount of the antibacterial agent or the pharmaceutical composition required to produce a desired therapeutic effect as may be judged by clinical trial results, model animal infection studies, and/or in vitro studies (e.g. in agar or broth media). Such effective amount depends on several factors, including but not limited to, the microorganism (e.g. bacteria) involved, characteristics of the subject (for example height, weight, sex, age and medical history), severity of infection and particular type of the antibacterial agent used. For prophylactic treatments, a prophylactically effective amount is that amount which would be effective in preventing the bacterial infection.

The term "administration" or "administering" refers to and includes delivery of a composition, or one or more pharmaceutically active ingredients to a subject, including for example, by any appropriate method, which serves to deliver the composition or its active ingredients or other pharmaceutically active ingredients to the site of infection. The method of administration may vary depending on various factors, such as for example, the components of the pharmaceutical composition or type/nature of the pharmaceutically active or inert ingredients, site of the potential or actual infection, the microorganism involved, severity of the infection, age and physical condition of the subject and a like. Some non-limiting examples of ways to administer a composition or a pharmaceutically active ingredient to a subject according to this invention include oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drop and mouthwash. In case of a pharmaceutical composition comprising more than one ingredients (active or inert), one of the ways of administering such composition is by admixing the ingredients (e.g. in the form of a suitable unit dosage form such as tablet, capsule, solution, powder or a like) and then administering the dosage form. Alternatively, the ingredients may also be administered separately (simultaneously or one after the other) as long as these ingredients reach beneficial therapeutic levels such that the composition as a whole provides a synergistic and/or desired effect.

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

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

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

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

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

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

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

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

The term "EDC" as used herein refers to l-ethyl-3-(3-dimethylamino propyl)carbodiimide.

The term "HOBt" as used herein refers to 1-hydroxybenzotriazole.

The term "Boc anhydride" as used herein refers to di-ie/t-butyl dicarbonate.

The term "TBAA" as used herein refers to tetrabutylammonium acetate.

The term "Boc" as used herein refers to ie/t-butyloxycarbonyl.

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

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

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

Ri is:

(a) hydrogen,

(d) CN,

(e) SOR₃,

(f) S0₂R₃ or

(g) OR₃;

R₂ is:

(a) hydrogen,

(f) heteroaryl optionally substituted with one or more substituents independently selected from OR₃, NR₃R₄, SR₃, SOR₃, S0₂R₃, CN, (CH₂)_nNR₃R₄, halogen, COOR₃, CONR₃R4, NR₃COR4 or NR₃CONR4R₅; R₃, R4 and R5 are each independently: hydrogen or

Ci-C₆ alkyl; n is 0, 1, 2 or 3;

M is hydrogen or a cation.

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

(25)-Pyrrolidin-2-ylmethyl ({[(25,5?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] carbonyl}amino)acetate;

Ethyl ({[(25,5?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)acetate;

(25, 5R)- ({[(25)-l(piperidin-2-yl)ethyl-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] carbonyl}amino)propionate;

(25)-l(Piperidin-2-yl)ethyl ({[(25,5?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] carbonyl}amino)acetate;

(25)-Piperidin-2-ylmethyl ({[(25,5?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] carbonyl}amino)propionate;

(25)-Piperidin-2-ylmethyl ({[(25,5?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] carbonyl}amino)acetate;

2-Aminoethyl ({[(25,5?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl} amino) acetate;

(25)-Pyrrolidin-2-ylmethyl (25)-({[(25,5?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] carbonyl}amino)propanoate;

Methyl (25)- methyl({[(25,5?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl} amino) acetate;

Methyl (2?)-4-(methylsulfinyl)-2-({[(25,5?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1] oct-2- yl] carbonyl } amino)butanoate ;

Methyl (2tf)-4-(methylsulfanyl)-2-({ [(25,5tf)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2.1 ]oct-2- yl] carbonyl } amino)butanoate ;

2- Cyano({[(25,5?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl} amino) acetate;

Methyl (2tf)-4-(methylsulfonyl)-2-({ [(25,5tf)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2.1 ]oct-2- yl] carbonyl}amino)butanoate;

Ethyl (25)-2-hydroxy-3-({[(25,5?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2- yl]carbonyl} amino)propanoate;

Methyl (25)-2-amino-3-({[(25,5?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2- yl]carbonyl} amino)propanoate;

Methyl (25)-3-amino-2-[({[(25,5?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2- y 1] c arbo ny 1 } amino ) methyl] prop ano ate ;

Methyl (2?)-3-hydroxy-2-[({[(25,5?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] c arbo ny 1 } amino ) methyl] prop ano ate ;

(2tf)-l(Piperidin-2-yl)ethyl ({[(25,5?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] carbonyl}amino)acetate;

Ethyl (2?)-3-hydroxy-2-[({[(25,5?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] c arbo ny 1 } amino ) methyl] prop ano ate ;

(2tf)-Pyrrolidin-2-ylmethyl ({[(25,5?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] carbonyl}amino)acetate; (25, 4 ?)-4-Hydroxypyrrolidin-2-ylmethyl ({ [(25,5R)-7- -oxo -6- (sulfooxy)- 1,6- diazabicyclo[3.2 l]oct-2-yl] carbonyl}amino)acetate;

(25, 45)-4-Hydroxypyrrolidin-2-ylmethyl ({ [(2S,5R)-7- -oxo -6- (sulfooxy)- 1,6- diazabicyclo[3.2 l]oct-2-yl] carbonyl}amino)acetate;

(25, 4 ?)-4-Aminopyrrolidin-2-ylmethyl ({ [(25,5R)-7- -oxo- -6- (sulfooxy)- 1,6- diazabicyclo[3.2 l]oct-2-yl] carbonyl}amino)acetate;

(25, 45)-4-Aminopyrrolidin-2-ylmethyl ({ [(25,5R)-7 -oxo -6- (sulfooxy)- 1,6- diazabicyclo[3.2 l]oct-2-yl] carbonyl}amino)acetate;

(25, 4 ?)-4-Cyanopyrrolidin-2-ylmethyl ({ [(25,5R)-7- -oxo -6- (sulfooxy)- 1,6- diazabicyclo[3.2 l]oct-2-yl] carbonyl}amino)acetate;

(25, 45)-4-Cyanopyrrolidin-2-ylmethyl ({ [(25,5R)-7- -oxo- -6- (sulfooxy)- 1,6- diazabicyclo[3.2 l]oct-2-yl] carbonyl}amino)acetate; or a stereoisomer or a pharmaceutically acceptable derivative thereof.

In some other embodiments, non-limiting examples of compounds according to the invention include:

Sodium salt of (25)-pyrrolidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of ethyl ({ [(25,5 ?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2.1 ]oct-2- yl]carbonyl} amino)acetate;

Sodium salt of (25, 5R)- ({ [(25)-l(piperidin-2-yl)ethyl-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)propionate;

Sodium salt of (25)-l(piperidin-2-yl)ethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of (25)-piperidin-2-ylmethyl ({ [(25,5R)-7-oxo~6-(sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)propionate;

Sodium salt of (25)-piperidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of 2-aminoethyl ({ [(25,5 ?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2.1 ]oct-2- yl]carbonyl} amino) acetate;

Sodium salt of (25)-pyrrolidin-2-ylmethyl (25)-({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)propanoate;

Sodium salt of methyl (25)- methyl({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2.1 ]oct-2- yl]carbonyl} amino) acetate;

Sodium salt of methyl (2R)-4-(methylsulfinyl)-2-({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2.1] oct-2-yl]carbonyl}amino)butanoate;

Sodium salt of methyl (2R)-4-(methylsulfanyl)-2-({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)butanoate;

Sodium salt of 2- cyano({ [(25,5 ?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2.1 ]oct-2- yl]carbonyl} amino) acetate;

Sodium salt of methyl (2R)-4-(methylsulfonyl)-2-({ [(25',5R)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)butanoate;

Sodium salt of ethyl (25)-2-hydroxy-3-({ [(25,5 ?)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl]carbonyl} amino )propano ate;

Sodium salt of methyl (25)-2-amino-3-({ [(25,5 ?)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl]carbonyl} amino )propano ate;

Sodium salt of methyl (25)-3-amino-2-[({ [(25,5 ?)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl]carbonyl} amino)methyl]propanoate;

Sodium salt of methyl (2R)-3-hydroxy-2-[({ [(25',5R)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)methyl]propanoate; Sodium salt of (27?)-l(piperidin-2-yl)ethyl { [(25,57?; oxo (sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of ethyl (27?)-3-hydroxy-2- { [(25,57?; oxo (sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)methyl]propanoate;

Sodium salt of (27?)-pyrrolidin-2-ylmethyl { [(25,57?; oxo (sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of (25, 47?)-4-hydroxypyrrolidin-2-ylmethyl { [(25,57?; oxo (sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of (25, 45)-4-hydroxypyrrolidin-2-ylmethyl { [(25,57?; oxo (sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of (25, 47?)-4-aminopyrrolidin-2-ylmethyl { [(25,57?; ^■oxo (sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of (25, 45)-4-aminopyrrolidin-2-ylmethyl { [(25,57?; oxo (sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of (25, 47?)-4-cyanopyrrolidin-2-ylmethyl { [(25,57?; oxo (sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of (25, 45)-4-cyanopyrrolidin-2-ylmethyl { [(25,57?; oxo (sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate; or a stereoisomer thereof.

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

In one general aspect, a compound of Formula (I) can be prepared by the general procedure as described in Scheme 1. A compound of Formula (II) is first treated with a suitable carboxyl group activating reagent, followed by treatment with esterifying agent to obtain a compound of Formula (III). Typical, non-limiting examples of carboxyl group activating compounds include thionyl chloride, oxalyl chloride, phosphorous trichloride, phosphorous oxychloride, phosphorous pentachloride, a- bromoacetyl bromide, pivaloyl chloride, diphenylphosphonic azide dicyclohexylcarbodiimide, diisopropylcarbodiimide, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), Ι,Γ-carbonyldiimidazole, di-ie/t-butyldicarbonate, acetic anhydride, ethyl chloro formate, 2-ethoxy- l- ethoxycarbonyl-l,2-dihydroquinoline (EDDQ), 1 -hydro xybenzotriazole (HOBt), N- hydroxysuccinimide, l-hydroxy-7-aza-lH-benzotriazole, 4-(N,N-dimethylamino)pyridine, 2- propanephosphonic acid anhydride, 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium salts, bis-trichloromethylcarbonate or triphosgene, p-nitrophenol (PNP) and the pentafluorophenol (PFP), 4- trifluoromethyl benzoic anhydride, 2-methyl-6-nitrobenzoic anhydride and the like. Typical non- limiting examples of esterifying agent include methanol, ethanol and the like.

A compound of Formula (III) is coupled with a compound of Formula (IV) [(25,57?)-6- benzyloxy-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxylic acid sodium salt (prepared as per the procedure disclosed in WO2014135929)] in presence of a base, coupling agent and a solvent at a temperature of about 15°C to about 35°C for about 10 hours to about 24 hours to obtain a coupled compound of Formula (V). Typical, non- limiting examples of base are N- methyl morpholine, N- methyl pyrrolidine, N-ethyl diisopropylamine and the like. Typical, non-limiting examples of coupling reagent are EDC.HC1, HOBt, 2-(lH-Benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluoropho sphate (HB TU) , 1 - [B is(dimethy lamino ) methylene] - 1 H- 1 ,2, 3 -triazo lo [4 , 5 -b] pyridinium 3-oxid hexafluoropho sphate (HATU) or a mixture thereof. Typical, non-limiting examples of solvent include dimethylformamide, dimethylacetamide and the like. The compound of Formula (V) is hydro lyzed to obtain a compound of Formula (VI). In some embodiments, compound of Formula (V) is hydrolyzed with a suitable reagent such as lithium hydroxide in presence of a suitable solvent such as water, tetrahydrofuran or a mixture thereof at a temperature of about 15°C to about 35°C for about 10 hours to about 24 hours to obtain a compound of Formula (VI).

The compound of Formula (VI) is reacted with a hydroxyl compound of Formula (VII) to obtain a compound of Formula (VIII). The compound of Formula (VI) is reacted with a compound of Formula (VII) in presence of a coupling agent and a solvent at temperature of about 0°C to about 35°C for about 10 hours to about 24 hours to obtain a compound of Formula (VIII). Typical, non-limiting examples of coupling reagent are EDC.HCl, HOBt, 2-(lH-Benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (HBTU), (l-[Bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU) or a mixture thereof. Typical, non- limiting examples of solvent include dimethylformamide, dimethylacetamide and the like. In some embodiments, the compound of Formula (VI) is reacted with a compound of Formula (VII) in presence of EDC.HCl and HOBt at temperature of about 25°C for about 16 hours to obtain a compound of Formula (VIII).

The compound of Formula (VIII) is debenzylated by subjecting it for hydrogenolysis by using hydrogen source in presence of transition metal catalyst in a suitable solvent such as methanol, ethanol, methanol dichloromethane mixture, N,N dimethylformamide dichloro methane mixture, ethyl acetate, tetrahydrofuran, or ethyl acetate and tetrahydrofuran mixture at a temperature ranging from about 10°C to about 60°C for about 1 hour to about 14 hours to provide a compound of Formula (IX). Typical, non-limiting examples of hydrogen source include hydrogen gas, ammonium formate, cyclohexene, lithium -liquid ammonia, ammonia - ie/t-butanol, sodium - liquid ammonia - tert- butanol, triethyl silyl hydride and the like. Typical, non-limiting examples of transition metal catalyst include 5% palladium on carbon, 10% palladium on carbon, 20% palladium hydroxide on carbon, Raney-Nickel and the like. In some embodiments, compound of Formula (VIII) is treated with 10% palladium on carbon in presence of hydrogen gas and suitable solvent and at temperature of about 25°C for about 5 hours to provide a compound of Formula (IX). In some embodiments, the solvent used in conversion of a compound of Formula (VIII) to a compound of Formula (IX) is methanol.

In some embodiments, a compound of Formula (V), wherein R = R₂', is directly converted to debenzylated compound of Formula (IX) by carrying out hydrogenolysis in presence of hydrogen source, transition metal catalyst and a suitable solvent.

The compound of Formula (IX) is sulfonated by reacting with suitable sulfonating reagent in a suitable solvent such as pyridine, dichloromethane or N,N-dimethylformamide, at a temperature ranging from about 0°C to about 80°C for about 1 hour to about 24 hours. Typical non-limiting examples of sulfonating reagent include sulfur trioxide pyridine complex, sulfur trioxide trimethylamine complex, sulfur trioxide triethylamine complex, sulfur trioxide N,N-dimethylaniline complex, sulfur trioxide 2-methylpyridine complex, sulfur trioxide dioxane complex, sulfur trioxide thioxane complex, sulfur trioxide dimethyl sulfide complex, sulfur trioxide dimethylsulfoxide complex, sulfur trioxide Ν,Ν-dimethylformamide complex and the like. In some embodiments, compound of Formula (IX) is reacted with dimethylformamide sulfur trioxide complex in presence of pyridine and dichloromethane at a temperature of about 10°C for about 1 hour to provide the sulfonated compound.

The obtained sulfonated compound is converted into corresponding tetrabutylammonium salt of Formula (X). In some embodiments, the sulfonated compound is treated with tetrabutylammonium acetate (TBAA) to provide tetrabutylammonium salt of sulfonic acid compound of Formula (X). The compound according to the invention is then isolated as zwitterions, by removing the protecting groups of compound of Formula (X). The compound of Formula (X) is reacted with suitable deprotecting agent such as trifluoro acetic acid in presence of a suitable solvent such as dichloromethane, chloroform or acetonitrile, at a temperature ranging from about -15°C to about 40°C for about 0.5 hour to about 14 hours. In some embodiments, compound of Formula (X) is treated with trifluoro acetic acid in presence of dichloromethane at temperature of about 0°C to about -10°C for about 1 hour to provide a compound of Formula (I).

The compound of Formula (X) may also be converted to compound of Formula (I), wherein M is a cation. In some embodiments, compound of Formula (X) is dissolved in suitable solvent such as 10% tetrahydrofuran: water mixture and was passed through the column packed with Dowex 50WX8 200 Na resin or passing through Indion 225 Na resin to provide sodium salt of compound of Formula (I). In some embodiments, compound of Formula (X) was dissolved in suitable solvent such as acetone, tetrahydrofuran, ethanol, isopropanol, acetonitrile or a mixture thereof, and thereby treating with sodium ethylhexanoate or potassium ethylhexanoate to provide sodium or potassium salt of compound of Formula (I).

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

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

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

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

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

(i) Sulphonation

(ii) TBAA

Compound of Formula (I)

wherein M is H or cation

Scheme 1

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, ceftolozane 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, ceftolozane or pharmaceutically acceptable derivative thereof.

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

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

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

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

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

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

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

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

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

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

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

In some embodiments, pharmaceutical compositions according to the invention are formulated into a dosage form such that the compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and the antibacterial agent or a pharmaceutically acceptable derivative thereof, are present in the composition as admixture or as 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 pharmaceutically effective amount of 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 pharmaceutically effective amount of 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 pharmaceutically effective amount of a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof.

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

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

EXAMPLES

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

Example 1

Synthesis of (25)-pyrrolidin-2-ylmethyl ({[(25,5/f)-6-(sulfooxy)-7-oxo-l,6- diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)acetate:

Step 1; Synthesis of ethyl aminoacetate hydrochloride:

To a stirred solution of glycine (40 g, 0.53 mol) in ethanol (400 ml), thionyl chloride (158.49 g, 1.33 mol) was added drop-wise at 0°C. The reaction mixture was allowed to warm to room temperature and stirring continued further for 16 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residual syrup was diluted with diethyl ether (200 ml) and then stirred for 15 minutes. The separated solid was filtered and washed with additional diethyl ether (40 ml). The solid was quickly transferred to a round bottom flask and dried under reduced pressure to obtain 62 g of ethyl aminoacetate hydrochloride white solid in 84% yield.

Step 2: Synthesis of ethyl ({[(2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]oct-2-yl] carbonyl}amino)acetate:

To a stirred solution of (25, 5 ?)-6-benzyloxy-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxylic acid sodium salt (prepared as per the procedure disclosed in WO2014135929) (100 g, 0.33 mol) in dimethylformamide (1 L) were added EDC.HC1 (96.05 g, 0.50 mol), N,N-Diisopropylethylamine (129.90 g, 1.0 mol) and HOBt (45.26 g, 0.33 mol) successively at 25°C. To this was added ethyl aminoacetate hydrochloride (37 g, 0.34 mol) and the reaction mixture was stirred further for 16 hours. The obtained reaction mixture was slowly poured into 6 L of water, and stirred further for 1 hour. The resulting mixture was extracted with ethyl acetate (2x500 ml). The ethyl acetate extract was washed with water, dried over sodium sulfate and the solvent was evaporated under reduced pressure to obtain 82 g of the titled product as white solid in 69% yield.

Step 3: Synthesis of ({[(25,5/f)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl} amino)acetic acid: A solution of lithium hydroxide (1.39 g, 33 mmol) in 24 ml of water was added slowly to a stirred solution of above obtained ester compound (12 g, 33 mmol) in tetrahydrofuran (120 ml) at 0°C. The resulting mixture was stirred further for 1 hour at 0°C. The completion of the reaction was monitored by thin layer chromatography. After completion, the reaction mixture was diluted with ethyl acetate (120 ml) and water (100 ml) and the mixture was stirred further for 5 minutes. The aqueous layer was separated and the pH was adjusted to 2.5-3 with 2N aqueous hydrochloride. The mixture was extracted with dichloromethane (2x60 ml), dried over sodium sulfate and the solvent distilled under reduced pressure to obtain 9.3 g of the titled product as white solid in 85% yield.

Step 4: Synthesis of (25)-N-fioc-pyrrolidin-2-ylmethyl ({[(2S,5/?)-6-(benzyloxy)-7-oxo-l,6- diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)acetate:

To a stirred solution of ({ [(2S,5 ?)-6-(benzyloxy)-7-oxo- l,6-diazabicyclo[3.2.1]oct-2- yl]carbonyl}amino)acetic acid (4 g, 11.9 mmol) in dichloromethane (40 ml) were added EDC.HC1 (3.43 g, 17.9 mmol), 4-dimethylaminopyridine (2.19 g, 17.9 mmol) successively at room temperature. N-fioc-L-prolinol (2.5 g, 12 mmol) was added to the mixture and stirred further for 16 hours. The resulting mixture was concentrated under reduced pressure, the crude product dissolved in ethyl acetate (40 ml), washed with saturated ammonium chloride solution (2x10 ml) and brine wash (10 ml). The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue chromatographed over a column of silica gel (60- 120 mesh size) using mixture of acetone: hexane (20:80) as an eluent. The combined solvent fractions were evaporated to provide 1.9 g of the titled product as white solid in 31% yield.

Step 5: Synthesis of (25)-N-fioc-pyrrolidin-2-ylmethyl ({[(25,5/f)-6-(hydroxy)-7-oxo-l,6- diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)acetate:

To a stirred solution of (25)-N-fioc-pyrrolidin-2-ylmethyl ({ [(25,5 ?)-6-(benzyloxy)-7-oxo- l,6- diazabicyclo[3.2.1]oct-2-yl]carbonyl} amino)acetate (1.9 g, 36 mmol) in methanol (19 ml) containing 10% palladium over carbon (50% wet; 190 mg), was hydrogenated at 25°C. After 1 hour the thin layer chromatography indicates the completion of the reaction. The resulting reaction mixture was filtered through celite bed and the residue washed with 5 ml of methanol. The solvent from the combined filtrate was evaporated under reduced pressure to obtain 1.5 g of the titled product as white solid in 96% yield. This was used as such for the next reaction.

Step 6: Synthesis of tetrabutylammonium salt of (25)-N-fioc-pyrrolidin-2-ylmethyl ({[(25,5/f)-6- (sulfooxy)-7-oxo-l,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)acetate:

A pyridine sulphur trioxide complex (2.91 g, 18.2 mmol) was added to a stirred solution of the above obtained hydroxy compound (1.5g, 3.6 mmol) in pyridine (15 ml), under argon atmosphere at 25°C. The reaction mixture was stirred for 16 hours at 25°C. The resulting mixture was filtered through Whatman filter paper and the residue was washed with 20 ml of dichloromethane. The solvent from the combined filtrate was evaporated under reduced pressure to obtain the product as oil. The oil was dissolved in 0.5M potassium dihydrogen phosphate solution (150 ml) and stirred for 0.5 hour at 25°C. The reaction mixture was washed with ethyl acetate (2x50 ml). To the aqueous layer tetra butyl ammonium hydrogen sulphate (1.24 g, 3.6 mmol) was added and the mixture was stirred for 3 hour at 25°C. The resulting mixture was extracted with dichloromethane (2x20 ml). The combined organic extracts were dried over sodium sulfate and the solvent evaporated under reduced pressure to obtain the product as oil. The obtained oil was purified by column chromatography over silica gel (60- 120 mesh size) and eluted with a mixture of dichloromethane: methanol (96: 4). The solvent from the combined fractions were evaporated to provide 1.7 g of the titled product as white solid in 63% yield.

Step 7: Synthesis of (25)-pyrrolidin-2-ylmethyl ({[(25,5/f)-6-(sulfooxy)-7-oxo-l,6-diazabicyclo

[3.2.1]oct-2-yl]carbonyl}amino)acetate: To a stirred solution of above obtained tetrabutylammonium salt (1.7 g, 2.2 mmol) in dichloromethane (8.5 ml) was added trifluoro acetic acid (4.25 ml) under argon atmosphere at 0°C. The reaction mixture was stirred further for 1 hour at 0°C. The progress of reaction was monitored by taking mass spectra. Upon the completion of the reaction, resulting reaction mixture was diluted with diethyl ether (17 ml) under stirring for 10 minutes and the separated solid was filtered. The obtained solid was then stirred with acetonitrile (17 ml), filtered and washed with fresh acetonitrile (5 ml). The solid was dried under reduced pressure to obtain 320 mg of (25)-pyrrolidin-2-ylmethyl ({ [(2S,5R)-6- (sulfooxy)-7-oxo- l,6-diazabicyclo [3.2.1]oct-2-yl]carbonyl}amino)acetate as white solid in 59% yield.

Analysis:

Mass: 407.3 (M+l); for Molecular Formula of C₁₄H₂₂N₄O₈S and Molecular Weight of 406.42; 1H NMR (400MHz, DMSO-d₆): δ 8.92 (1H, s), 8.58 (1H, s), 8.43 (1H, s), 4.17-4.28 (2H, m), 3.97-4.01 (4H, m), 3.07 (2H, t, J= 6.8 Hz), 3.01 (2H, s), 2.05 (2H, s), 1.55- 1.89 (6H, m).

Example 2

Synthesis of sodium salt of ethyl ({[(25,5/f)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2- yl] carbonyljamino) acetate :

Step 1; Synthesis of ethyl aminoacetate hydrochloride:

Thionyl chloride (158.49 g, 1.33 mol) was added drop-wise, to a stirred solution of glycine (40 g, 0.53 mol) in Ethanol (400 ml), at 0°C. The reaction mixture was allowed to warm to room temperature and stirred further for 16 hours. The resulting mixture was concentrated under reduced pressure. The residual syrup was diluted with diethyl ether (200 ml) and then stirred for 15 minutes. The separated solid was filtered and washed with additional diethyl ether (40 ml), The solid was quickly transferred to a round bottom flask and dried under reduced pressure to obtain 62 g of the titled product as a white solid in 84% yield.

Step 2: Synthesis of ethyl ({[(25,5/f)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]oct-2- yl] carbonyljamino) acetate :

To a stirred solution of (25,5 ?)-6-benzyloxy-7-oxo- l,6-diazabicyclo[3.2.1]octane-2-carboxylic acid sodium salt (prepared as per the procedure disclosed in WO2014135929) (100 g, 0.33 mol) in dimethylformamide (1 L) were added successively EDC.HC1 (96.05 g, 0.50 mol), N,N- diisopropylethylamine (129.90 g, 1.0 mol) and HOBt (45.26 g, 0.33 mol) at 25°C. To this mixture was added ethyl aminoacetate hydrochloride (37 g, 0.34 mol) and the reaction mixture was stirred for 16 hour. The resulting mixture was slowly poured into 6 liters of water and stirred further for 1 hour. The reaction mixture was finally extracted with ethyl acetate (2x500 ml). The ethyl acetate extract was washed with water, dried over sodium sulfate and the solvent evaporated under reduced pressure to obtain the 82 g of the titled product as white solid in 69% yield.

Step 3: Synthesis of ethyl ({[(25,5/f)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2.1]oct-2- yl] carbonyljamino) acetate :

A stirred solution of ethyl ({ [(2S,5 ?)-6-(benzyloxy)-7-oxo- l,6-diazabicyclo[3.2.1]oct-2- yl]carbonyl}amino)acetate (2.5 g, 6.9 mmol) in methanol (25 ml) containing 10% palladium over carbon (50% wet; 250 mg) was hydrogenated at 25°C. After completion of the reaction (as monitored by thin layer chromatography) the resulting mixture was filtered through celite bed and the catalyst was washed with 5 ml of methanol. The combined filtrate was concentrated under reduced pressure to obtain the 1.72 g of the titled product as white solid in 92% yield. The obtained compound was used as such for the next reaction without any further purification

Step 4: Synthesis of tetrabutylammonium salt of ethyl ({[(25,5/f)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)acetate:

To a stirred solution of ethyl ({ [(2S,5 ?)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2.1]oct-2- yl]carbonyl}amino)acetate (1.7 g, 6.2 mmol) in pyridine (17 ml) was added pyridine sulphur trioxide complex (4.98 g, 31 mmol) for 16 hours at 25°C. After completion of reaction (as monitored by thin layer chromatography), the reaction mixture was filtered and the residue washed with 20 ml of dichloromethane The combined filtrate was evaporated under reduced pressure to obtain a oil. The oil was dissolved in 0.5M potassium dihydrogen phosphate solution (170 ml) and stirred for 0.5 hour at 25°C. The resulting mixture was washed with ethyl acetate (20 ml). To the aqueous layer tetrabutyl ammonium hydrogen sulphate (2.12 g, 6.2 mmol) was added and the solution was stirred for 3 hours at 25°C. The resulting mixture was extracted with dichloromethane (2 x 20 ml). The organic layer was separated, dried over sodium suphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography using silica gel (60-120 mesh size). The column was eluted with a mixture of dichloromethane: methanol (5:95) as an eluent. The combined fractions were evaporated under reduced pressure to obtain 1.5 g of the titled product as white solid in 40% yield.

Step 5: Synthesis of sodium salt of ethyl ({[(25,5/f)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo

[3.2.1]oct-2-yl]carbonyl}amino)acetate:

The tetrabutylammonium salt of ethyl ({ [(25,5 ?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2.1]oct-2-yl]carbonyl}amino)acetate (1.5 g, 3.8 mmol) was dissolved in water (5 ml) and poured into sodium ion exchange resin column and eluted with 10% tetrahydrofuran in water. The combined fractions were concentrated under reduce pressure and the residue crystallized by trituration with diethyl ether (6 ml) to obtain 290 mg of sodium salt of ethyl ({ [(25,5 ?)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)acetate as white solid in 31% yield.

Analysis:

Melting Point: 148-152°C;

Mass: 352.2 (M+l) as free acid, for Molecular weight of 373.31 and Molecular Formula of

DMSO-d₆): δ 8.38-8.40 (1H, m), 4.07-4.13 (2H, m), 4.00 (1H, s), 3.90- 3.96 (1H, m), 3.71-3.77 (2H, m), 3.58-3.64 (1H, m), 3.06 (2H, s), 2.07-2.13 (1H, m), 1.84-1.87 (1H, s), 1.54-1.77 (3H, m), 1.19 (3H, d, J=14.0 Hz);

Purity as determined by HPLC: 91.19%.

Compounds of Examples 3 to 8 and 19 to 27 (Table 1) were prepared by using the procedure described in Example 1 and using corresponding hydroxyl compound of Formula (VII) in place of N- fioc-L-prolinol. Compounds of Examples 9 to 18 (Table 1) were prepared by using the procedure described in Example 2. For compounds of Examples 15 and 16, the intermediate tetrabutylammonium salt was deprotected as per step 7 of Example 1 to obtain corresponding zwitterions.

BIOLOGICAL ACTIVITY DATA

The biological activity of representative compounds according to the invention in combination with antibacterial agent was investigated against various bacterial strains.

Method for the determination of 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, 20th 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 representative compounds according to present invention. The plates were inoculated and were incubated at 35°C for 18 hour. MICs were read as the lowest concentration of drug that completely inhibited bacterial growth. The Table 2 depicts the antibacterial activity profile of compounds according to present invention against various bacterial strains. These compounds when tested alone exhibited higher MIC values in comparison to standard.

The combinations of compounds according to present invention were also tested for their antibacterial activity in combination with Ceftazidime. The plates were poured with MHA containing doubling concentration range of Ceftazidime in combination with constant concentration (4 μ§/ιη1) of representative compounds of Formula (I). The Table 3 shows the MIC values of Ceftazidime in presence of compounds according to the invention (at 4 μ^ιηΐ) against various bacterial strains. As shown in Table 3, the MIC value of Ceftazidime was significantly lowered in presence of compounds according to the invention. Table 3. Antibacterial activity of representative compounds according to the invention in combination with Ceftazidime

Ceftazidime MIC (expressed in mcg/ml)

K.

E. coli E. coli E. E. K. K.

Sr. Compounds pneumoniae

NCTC NCTC coli coli pneumoniae pneumoniae ATCC

13352 13353 M50 7MP H521 H525 700603

1. Ceftazidime alone 32 > 32 32 > 32 > 32 > 32 > 32

Ceftazidime +

2. 1 2 0.5 0.5 4 16 8 Example 2 (4mcg/ml)

Ceftazidime +

3. 1 2 0.5 1 8 32 16 Example 9 (4mcg/ml)

Ceftazidime +

4. 2 > 32 1 8 > 32 > 32 > 32 Example 10 (4mcg/ml)

Ceftazidime +

5. 1 16 0.25 2 > 32 8 4 Example 11 (4mcg/ml)

Ceftazidime +

6. 1 4 0.5 1 8 16 8 Example 12 (4mcg/ml)

Ceftazidime +

7. 1 4 0.25 0.5 4 32 8 Example 14 (4mcg/ml)

Ceftazidime +

8. 1 4 0.5 2 - 16 8 Example 17 (4mcg/ml)

Ceftazidime +

9. 4 16 2 16 >32 >32 >32 Example 18 (4mcg/ml)

Ceftazidime +

10 <0.06 <0.06 <0.06 <0.06 1 0.12 0.12 Example 20 (4mcg/ml)

Claims

1. A compound of Formula (I):

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

Ri is:

(a) hydrogen,

(d) CN,

(e) SOR₃,

(f) S0₂R₃ or

(g) OR₃;

R₂ is:

(a) hydrogen,

R₃, R₄ and R5 are each independently:

(a) hydrogen or

(b) Ci-C₆ alkyl; n is 0, 1, 2 or 3;

M is hydrogen or a cation.

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

(25)-Pyrrolidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] carbonyl}amino)acetate;

Ethyl ({ [(25,5 ?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)acetate;

(25, 5R)- ({ [(25)-l(piperidin-2-yl)ethyl-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] carbonyl}amino)propionate;

(25)-l(Piperidin-2-yl)ethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] carbonyl}amino)acetate;

(25)-Piperidin-2-ylmethyl ({ [(25,5R)-7-oxo~6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] carbonyl}amino)propionate;

(25)-Piperidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] carbonyl}amino)acetate;

2-Aminoethyl ({ [(25,5 ?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl} amino) acetate;

(25)-Pyrrolidin-2-ylmethyl (25)-({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] carbonyl}amino)propanoate;

Methyl (25)- methyl({ [(25,5 ?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl} amino) acetate;

Methyl (2R)-4-(melhylsulfmyl)-2-({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1] oct-2- yl]carbonyl} amino)butanoate;

Methyl (2R)-4-(methylsulfanyl)-2-({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2.1 ]oct-2- yl] carbonyl } amino)butanoate ;

2- Cyano({ [(25,5 ?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl} amino) acetate;

Methyl (2R)-4-(methylsulfonyl)-2-({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo [3.2.1 ]oct-2- yl] carbonyl}amino)butanoate;

Ethyl (25)-2-hydroxy-3-({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2- yl]carbonyl} amino)propanoate;

Methyl (25)-2-amino-3-({ [(25,5 ?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2- yl]carbonyl} amino)propanoate;

Methyl (25)-3-amino-2-[({ [(25,5 ?)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2- y 1] c arbo ny 1 } amino ) methyl] prop ano ate ;

Methyl (2R)-3-hydroxy-2-[({ [(25',5R)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] c arbo ny 1 } amino ) methyl] prop ano ate ;

(2tf)-l(Piperidin-2-yl)ethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] carbonyl}amino)acetate;

Ethyl (2R)-3-hydroxy-2-[({ [(25',5R)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] c arbo ny 1 } amino ) methyl] prop ano ate ;

(2tf)-Pyrrolidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]oct-2-yl] carbonyl}amino)acetate;

(25, 4tf)-4-Hydroxypyrrolidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

(25, 45)-4-Hydroxypyrrolidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

(25, 4tf)-4-Aminopyrrolidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

(25, 45)-4-Aminopyrrolidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

(25, 4tf)-4-Cyanopyrrolidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate; (25, 45)-4-Cyanopyrrolidin-2-ylmethyl ({ [(2S,5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

(35)-PyrroUdin-3-yl({ [(25,5R)-7-oxo-6-(sulfooxy)- l,6-diazabicyclo[3.2.1]oct-2-yl]

carbonyl } amino ) acetate ; or a stereoisomer or a pharmaceutically acceptable derivative thereof.

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

Sodium salt of (25)-pyrrolidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of ethyl ({ [(25,5 ?)-7-oxo-6-(sulfooxy)- l,6-diazabicyclo [3.2.1 ]oct-2- yl]carbonyl} amino)acetate;

Sodium salt of (25, 5R)- ({ [(25)- l(piperidin-2-yl)ethyl-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)propionate;

Sodium salt of (25)- l(piperidin-2-yl)ethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of (25)-piperidin-2-ylmethyl ({ [(2S,5R)-7-oxo— 6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)propionate;

Sodium salt of (25)-piperidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of 2-aminoethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)- l,6-diazabicyclo [3.2.1 ]oct-2- yl]carbonyl} amino) acetate;

Sodium salt of (25)-pyrrolidin-2-ylmethyl (25)-({ [(25,5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)propanoate;

Sodium salt of methyl (25)- methyl({ [(25,5R)-7-oxo-6-(sulfooxy)- l,6-diazabicyclo [3.2.1 ]oct-2- yl]carbonyl} amino) acetate;

Sodium salt of methyl (2R)-4-(methylsulfinyl)-2-({ [(25',5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2.1] oct-2-yl]carbonyl}amino)butanoate;

Sodium salt of methyl (2R)-4-(methylsulfanyl)-2-({ [(25,5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)butanoate;

Sodium salt of 2- cyano({ [(25,5R)-7-oxo-6-(sulfooxy)- l,6-diazabicyclo [3.2.1 ]oct-2- yl]carbonyl} amino) acetate;

Sodium salt of methyl (2R)-4-(methylsulfonyl)-2-({ [(25',5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)butanoate;

Sodium salt of ethyl (25)-2-hydroxy-3-({ [(25,5tf)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl]carbonyl} amino )propano ate;

Sodium salt of methyl (25)-2-amino-3-({ [(25,5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl]carbonyl} amino )propano ate;

Sodium salt of methyl (25)-3-amino-2-[({ [(25,5tf)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl]carbonyl} amino)methyl]propanoate;

Sodium salt of methyl (2R)-3-hydroxy-2-[({ [(25',5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)methyl]propanoate;

Sodium salt of (2tf)- l(piperidin-2-yl)ethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of ethyl (2R)-3-hydroxy-2-[({ [(25',5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)methyl]propanoate;

Sodium salt of (2tf)-pyrrolidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of (25, 4 ?)-4-hydroxypyrrolidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate; Sodium salt of (25, 45)-4-hydroxypyrrolidin-2-ylmethyl ({ [(2S,5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of (25, 4 ?)-4-aminopyrrolidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of (25, 45)-4-aminopyrrolidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of (25, 4 ?)-4-cyanopyrrolidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of (25, 45)-4-cyanopyrrolidin-2-ylmethyl ({ [(25,5R)-7-oxo-6-(sulfooxy)- l,6- diazabicyclo[3.2. l]oct-2-yl] carbonyl}amino)acetate;

Sodium salt of (35)-Pyrrolidin-3-yl({ [(25,5 ?)-7-oxo-6-(sulfooxy)- l,6-diazabicyclo[3.2.1]oct-2- yl] carbonyl}amino)acetate; or a stereoisomer thereof.

4. A pharmaceutical composition comprising a compound according to any one of 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 a group consisting of aminoglycosides, ansamycins, carbacephems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, penems, carbapenems, monobactams, nitrofurans, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines, or 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 cephalosporin antibiotic selected from a group consisting of cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetrile, cefotiam, cefotaxime, cefsulodin, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide, cefbuperazone, cefozopran, cefepime, cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime, cefteram, cefetamet, cefcapene, cefditoren, cefuroxime, cefuroxime, ceftaroline and ceftolozane.

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

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