DESC:NITROGEN CONTAINING COMPOUNDS

RELATED PATENT APPLICATIONS

This application claims the priority to and benefit of Indian Provisional Patent Application No. 201721015501 filed on May 02, 2017; the disclosures of which are incorporated herein by reference in its entirety as if fully rewritten herein.

FIELD OF THE INVENTION

The invention relates to nitrogen containing compounds, their preparation, compositions comprising these compounds and their use in treating infections.

BACKGROUND OF INVENTION

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

Several antibacterial agents have been described in the prior art (for example, see PCT International Application Nos. PCT/US2010/060923, PCT/EP2010/067647, PCT/US2010/052109, PCT/US2010/048109, PCT/GB2009/050609, PCT/FR01/02418, PCT/EP2009/056178, PCT/US2009/041200, PCT/IB2012/054290, PCT/IB2013/053092, PCT/IB2012/054296, PCT/IB2012/054706, PCT/JP2013/064971, PCT/IB2012/002675, PCT/US2013/034562, PCT/US2013/034589, PCT/IB2015/050455, PCT/IB2015/050462 and PCT/IB2015/050466). However, there remains a need for development of antibacterial agents for treating bacterial infections, including those caused by bacteria that are resistant to known antibacterial agents.

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

SUMMARY OF THE INVENTION

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

wherein:

A is 9 to 20 membered fused ring system optionally substituted with one or more substituents selected from C1-C6 alkyl optionally substituted with halogen, OR2, NR2R3, NO2, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; halogen; OR2; CN; COOR2; CONR2R3; SR2; NR2R3; NO2; aryl; heteroaryl; cycloalkyl or heterocycloalkyl;

wherein A is attached through nitrogen atom;

Y is H, C1-C6 alkyl, OR2 or NR2R3;

R2 and R3 are each independently selected from:
(a) hydrogen or
(b) C1-C6 alkyl optionally substituted with one or more substituents selected from halogen, NR4R5, CONR4R5, CN, OR4 or COOR4;

R4 and R5 are each independently selected from:
(a) hydrogen or
(b) C1-C6 alkyl optionally substituted with one or more substituents selected from OH, halogen, NH2, CONH2, CN, OCH3, or COOH;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

In yet another aspect, there are provided methods for increasing antibacterial effectiveness of an antibacterial agent in a subject, the methods comprising co-administering said antibacterial agent with a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt 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 term “C1-C6 alkyl” as used herein refers to branched or unbranched acyclic hydrocarbon radical with 1 to 6 carbon atoms. Typical non-limiting examples of “C1-C6 alkyl” include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, tert-pentyl, neopentyl, sec-pentyl, 3-pentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and the like. The “C1-C6 alkyl” may be unsubstituted, or substituted with one or more substituents. Typical, non-limiting examples of such substituents include halogen, alkoxy, CN, SH, COOH, COOC1-C6alkyl, CONH2, OH, NH2, NHCOCH3, cycloalkyl, heterocycloalkyl, heteroaryl, aryl and the like.

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

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

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

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

The term “fused ring system” as used herein refers to ring system having at least two rings, wherein each ring has at least 2 atoms in common with another ring. A fused ring system as used herein may include aromatic (i.e. aryl or heteroaryl) as well saturated or unsaturated non-aromatic rings or may be composed of separate aromatic and non-aromatic moieties. The term fused ring system may include benzo-fused heteroaryl wherein one of the rings is benzene and the other is a heteroaryl ring; or may include heteroaryl-fused cycloalkyl wherein one of the rings is cycloalkyl and the other is heteroaryl. Typical non-limiting examples of fused ring system include indolyl, indolinyl, isoindolyl, indazolyl, isoindolinyl, benzimidazolyl, indolizinyl, 3H-indolyl, indolyl, indazolyl, purinyl, imidazothiazole, imidazothiophene, triazolothiophene, triazolothiazole carbazole, benztriazolyl, imidazopyridine, triazolopyridine, triazolopyrimidine, benzpyrazole, benzpyrrole, imidazopyrazine and the like.

The term “halogen” or halo as used herein refers to chlorine, bromine, fluorine or iodine.
The term “Bn” as used herein refers to benzyl group. The term “Boc” as used herein refers to tert-butyloxycarbonyl group.

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

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

The term “pharmaceutically acceptable derivative” as used herein refers to and includes any pharmaceutically acceptable salt, pro-drug, metabolite, ester, ether, hydrate, polymorph, solvate, complex, and adduct of a compound described herein which, upon administration to a subject, is capable of providing (directly or indirectly) the parent compound.

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

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

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

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

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

The term “growth” as used herein refers to a growth of one or more microorganisms and includes reproduction or population expansion of the microorganism (e.g. bacteria). The term “growth” also includes maintenance of on-going metabolic processes of the microorganism, including the processes that keep the microorganism alive. The term, “effectiveness” as used herein refers to ability of a treatment, or a composition, or one or more pharmaceutically active ingredients to produce a desired biological effect in a subject. For example, the term “antibacterial effectiveness” of a composition or of an antibacterial agent refers to the ability of the composition or the antibacterial agent to prevent or treat bacterial infection in a subject.

The term “antibacterial agent” as used herein refers to any substance, compound, a combination of substances, or a combination of compounds capable of: (i) inhibiting, reducing or preventing growth of bacteria; (ii) inhibiting or reducing ability of a bacteria to produce infection in a subject; or (iii) inhibiting or reducing ability of bacteria to multiply or remain infective in the environment. The term “antibacterial agent” also refers to compounds capable of decreasing infectivity or virulence of bacteria. The term “beta-lactamase” or “beta-lactamase enzyme” as used herein refers to any enzyme or protein or any other substance that breaks down a beta-lactam ring. The term “beta-lactamase” includes enzymes that are produced by bacteria and have the ability to hydrolyze the beta-lactam ring in a beta-lactam compound, either partially or completely.

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

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

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

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

wherein:

A is 9 to 20 membered fused ring system optionally substituted with one or more substituents selected from C1-C6 alkyl optionally substituted with halogen, OR2, NR2R3, NO2, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; halogen; OR2; CN; COOR2; CONR2R3; SR2; NR2R3; NO2; aryl; heteroaryl; cycloalkyl or heterocycloalkyl;

wherein A is attached through nitrogen atom;

Y is H, C1-C6 alkyl, OR2 or NR2R3;

R2 and R3 are each independently selected from:
(a) hydrogen or
(b) C1-C6 alkyl optionally substituted with one or more substituents selected from halogen, NR4R5, CONR4R5, CN, OR4 or COOR4;

R4 and R5 are each independently selected from:
(a) hydrogen or
(b) C1-C6 alkyl optionally substituted with one or more substituents selected from OH, halogen, NH2, CONH2, CN, OCH3, or COOH;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

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

(2S,5R)-N'-(1H-benzimidazol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(5-nitro-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(6-nitro-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(6-amino-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(5-amino-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[2-(aminomethyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[2-(3-amino propyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[2-(4-aminophenyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[2-(4-aminobenzyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[2-(piperazin-1-yl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)- 7-oxo-6-(sulfooxy)-N'-(4,5,6,7-tetrahydro-2H-benzotriazol-2-ylacetyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[2-(ethyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-(1H-indol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-(1H-benzotriazol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1] octane-2-carbohydrazide;
(2S,5R)- N'-{[2-(hydroxymethyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2R,5S)-N'-{[2-(phenyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[2-(benzyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-(2H-benzotriazol-2-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-(1H-indazol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-7-oxo-N'-(9H-purin-9-ylacetyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(6-carbamoyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(5-carbamoyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(6-cyano-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(5-cyano-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(6-ethoxycarbonyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(5-ethoxycarbonyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(6-hydroxymethyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(5-hydroxymethyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-(3H-imidazo[4,5-b]pyridin-3-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-(1H-imidazo[4,5-b]pyridin-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2,6-diamino-9H-purin-9-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2-amino-6-hydroxy-9H-purin-9-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2,6-diaminomethyl-9H-purin-9-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2-amino-6-ethoxycarbonyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2-amino-5-ethoxycarbonyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

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

Sodium salt of (2S,5R)-N'-(1H-benzimidazol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(5-nitro-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6 -nitro-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6-amino-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(5-amino-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[2-(aminomethyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[2-(3-amino propyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[2-(4-aminophenyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[2-(4-aminobenzyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Trifluoroacetic acid salt of (2S,5R)-N'-{[2-( piperazin-1-yl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)- 7-oxo-6-(sulfooxy)-N'-(4,5,6,7-tetrahydro-2H-benzotriazol-2-ylacetyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[2-(ethyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-(1H-indol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-(1H-benzotriazol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)- N'-{[2-(hydroxymethyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2R,5S)-N'-{[2-(phenyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[2-(benzyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-(2H-benzotriazol-2-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-(1H-indazol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-7-oxo-N'-(9H-purin-9-ylacetyl)-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6-carbamoyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6- (sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(5-carbamoyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6- (sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6-cyano-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(5-cyano-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6-ethoxycarbonyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(5-ethoxycarbonyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6-hydroxymethyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(5-hydroxymethyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-(3H-imidazo[4,5-b]pyridin-3-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-(1H-imidazo[4,5-b]pyridin-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2,6-diamino-9H-purin-9-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2-amino-6-hydroxy-9H-purin-9-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2,6-diaminomethyl-9H-purin-9-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2-amino-6-ethoxycarbonyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2-amino-5-ethoxycarbonyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;

or a stereoisomer thereof.

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

In one aspect, the compounds according to invention are prepared according to general procedure given in Scheme 1. A compound of Formula (III), Sodium salt of (2S, 5R)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carboxylic acid, (prepared as per the procedure disclosed in International Patent Application No. PCT/IB2013/059264) is treated with a compound of Formula (II) in presence of a suitable coupling agent and a suitable solvent at a temperature ranging from about -15°C to about 60°C for about 1 to about 24 hours to obtain a compound of Formula (IV). Typical, non-limiting examples of suitable coupling agents include dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), diisopropylcarbodiimide (DIC), 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOsu), 1-Hydroxy-7-azabenzotriazolo (HOAt), (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidhexafluoro phosphate) (HATU), (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) (PyBOP), Bromotripyrrolidinophosphonium hexafluorophosphate (PyBrop), O-(7-azabenzotrizol-1-yl)-1,3-dimethyl-1,3-trimethylene uronium hexafluorophosphate (HAMTU), 2-(5-Norborene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU), 2-(2-Pyridon-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) and the like. Typical, non-limiting examples of suitable solvents include N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, chloroform, dichloromethane, tetrahydrofuran, acetonitrile, water and their appropriate combinations and the like.

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

The compound of Formula (V) is sulfonated by reacting with suitable sulfonating reagent in a suitable solvent such as pyridine, dichloromethane or N,N-dimethylformamide, at a temperature ranging from about 0°C to about 80°C for about 1 hour to about 24 hour. Typical non-limiting examples of suitable sulfonating reagent include sulfur trioxide pyridine complex, sulfur trioxide trimethylamine complex, sulfur trioxide triethylamine complex, sulfur trioxide N,N-dimethylaniline complex, sulfur trioxide 2-methylpyridine complex, sulfur trioxide dioxane complex, sulfur trioxide thioxane complex, sulfur trioxide dimethyl sulfide complex, sulfur trioxide dimethylsulfoxide complex, sulfur trioxide N,N-dimethylformamide complex and the like. The obtained sulfonated compound was converted to corresponding tetrabutylammonium salt of Formula (VI). In some embodiments, the sulfonated compound is treated with tetrabutylammonium hydrogen sulfate (TBAHS) to obtain tetrabutylammonium salt of sulfonic acid compound of Formula (VI).

In some embodiments, compound of Formula (VI) is obtained according to procedure disclosed in Scheme 2. In some embodiments, the compound of Formula (IIA) is reacted with a compound of Formula (IIIA) to obtain a compound of Formula (VI). The compound of Formula (IIA) is coupled with a compound of Formula (IIIA), and this is followed by tetrabutylammonium salt formation to obtain a compound of Formula (VI).

The compound according to the invention is then isolated as zwitterions, by removing the protecting groups of compound of Formula (VI). The compound of Formula (VI) is reacted with suitable deprotecting agent such as trifluoroacetic 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 hours to about 14 hour to obtain a compound of Formula (I).

The compound of Formula (VI) may also be converted to pharmaceutically acceptable salts of compound of Formula (I). In some embodiments, compound of Formula (VI) was 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 (VI) was dissolved in suitable solvent such as acetone, tetrahydrofuran, ethanol, isopropanol or acetonitrile and thereby treating with sodium ethylhexanoate or potassium ethylhexanoate to provide sodium or potassium salt of compound of Formula (I).

In another general aspect, there are provided pharmaceutical compositions comprising a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions according to the invention may include one or more pharmaceutically acceptable carriers or excipients or a like. Typical, non-limiting examples of such carriers or excipients 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 and a like.

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 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 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, intra-respiratory, intra-peritoneal, intra-muscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intra-tracheal, intra-rectal, vaginal, gene gun, dermal patch, eye drop, ear drop or mouthwash.

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.

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

In some embodiments, there are provided methods for treating or preventing 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 salt thereof.

In general, the compounds, pharmaceutical compositions and method disclosed herein are useful in treating and/or preventing bacterial infections. Advantageously, the compounds, compositions and methods disclosed herein are also effective in treating or preventing 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 treated or prevented using the compounds, compositions and/or methods according to 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.

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

EXAMPLES

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

Preparation 1: Synthesis of (Benzimidazol-1-yl)acetohydrazide:

Step 1: Synthesis of ethyl (benzimidazol-1-yl)acetate: To a stirred solution of 1H-benzimidazole (30 g, 0.254 mol) in dimethylformamide (300 ml) was added potassium carbonate (42.17 g, 0.305 mol) at 25°C. After 30 minutes, ethyl bromoacetate (28.3 ml, 0.254 mol) was added dropwise under continuous stirring at 0°C. After 16 hours the completion of the reaction was confirmed with the help of TLC. The insoluble material was filtered and the filtrate was distilled under reduced pressure. The residue was partitioned in mixture of dichloromethane and water (300 ml : 300 ml). The dichloromethane layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 47 gram of crude ethyl (benzimidazol-1-yl)acetate in 91% yield.
Analysis:
Mass: 205.2 (M+1) for Molecular Weight: 204.2 and Molecular Formula: C11H12N2O2.
1H NMR (400 MHz, DMSO-d6): ? 7.94 (s, 1H), 7.34-7.26 (m, 4H), 4.90 (s, 2H), 4.25 (q, 2H, J = 7.2 Hz ), 1.27 (t, 3H, J = 7.2 Hz).

Step 2: Synthesis of (Benzimidazol-1-yl)acetohydrazide: To the solution of ethyl (benzimidazol-1-yl)acetate (47 g, 0.230 mol, prepared according to the procedure described in step-1) in ethanol (470 ml) was added hydrazine hydrate (13.4 ml, 0.276 mol) at 25°C under stirring. After 18 hours, the completion of the reaction was monitored by performing TLC. After completion of the reaction, di-isopropyl ether (313 ml) was added to the reaction mixture and cooled to 5°C. The reaction mass was stirred for 30 minutes at 5°C and the formed precipitates were filtered under reduced pressure. The solid obtained was dried under vacuum to obtain 30 gram of (Benzimidazol-1-yl)acetohydrazide in 68% yield.
Analysis:
Mass: 191.2 (M+1) and 189.2 for (M-H) for Molecular Weight: 190.2 and Molecular Formula: C9H10N4O.
1H NMR (400 MHz, DMSO-d6): ? 9.51 (brs, 1H), 8.16 (s, 1H), 7.65 (d, 1H, J = 7.6 Hz ), 7.47 (d, 1H, J = 7.6 Hz ), 7.28-7.18 (m, 2H), 4.87 (s, 2H), 4.34 (brs, 2H).

Preparation 2: Synthesis of a mixture of (5-Nitro-1H-benzimidazol-1-yl)acetic acid and (6-Nitro-1H-benzimidazol-1-yl)acetic acid:

Step 1: Synthesis of a mixture of 5-nitro-1H-benzimidazole: To pre-cooled solution of sulphuric acid (100 ml) was added benzimidazole (20 g, 0.169 mol) under stirring at 0-5°C. After 10 minutes, concentated nitric acid (12 ml) was slowly added by maintaining the temperature below 5°C. After 2 hours, the reaction mixture was allowed to warm to 25°C and then further stirred for 1 hour. The completion of the reaction was monitored by TLC. After completion, the reaction mixture was slowly poured into ice-water (1000 ml) and stirred for 30 minutes at 0°C. The precipitated solid was filtered and washed with water (200 ml). The obtained product was dried at 40°C for 2 hour at 4 mm Hg to yield 27.5 gram of the titled product in 99% yield.
Analysis:
Mass: 164.0 (M+1) for Molecular Weight: 163 and Molecular Formula: C7H5N3O2.

Step 2: Synthesis of a mixture of ethyl (5-nitro-1H-benzimidazol-1-yl)acetate and ethyl (6 -nitro-1H-benzimidazol-1-yl)acetate: To a solution of mixture of 5-nitro-1H-benzimidazole (28 g, 0.171 mol, obtained from the step 1) in dimethylformamide (560 ml) was added potassium carbonate (26 g, 0.188 mol) under stirring. After 15 minutes, solution of ethyl bromoacetate (20 ml, 0.170 mol) was slowly added under stirring. The completion of the reaction was monitored by TLC. After 16 hours, the reaction mixture was filtered and the residue was washed with dimethylformamide (60 ml). Filtrate was slowly poured into chilled water (4000 ml). The precipitated compound was filtered and washed with water (600 ml). The obtained solid was dried at 40°C for 2 hours under high vacuum to provide 32 gram of mixture of ethyl (5 -nitro-1H-benzimidazol-1-yl)acetate and ethyl (6 -nitro-1H-benzimidazol-1-yl)acetate in 75% yield.

Analysis:
Mass: 250.1 (M+1) for Molecular Weight: MW: 249 and Molecular Formula: C11H11N3O4.

Step 3: Synthesis of a mixture of (5-nitro-1H-benzimidazol-1-yl)acetic acid and (6-nitro-1H-benzimidazol-1-yl)acetic acid: A solution of lithium hydroxide (0.337 g, 0.00803 mol) in water (4 ml) in water was slowly added to the solution of mixture of ethyl (5-nitro-1H-benzimidazol-1-yl)acetate and ethyl (6-nitro-1H-benzimidazol-1-yl)acetate (2 g, 0.00803 mol, obtained from step 2) in tetrahydrofuran (20 ml) under stirring at 0-5°C. The completion of the reaction mixture was monitored by TLC. After 16 hours, the pH of reaction mass was adjusted to 2 by addition of 2N HCl. Stirring was continued for additional 15 minutes at 0°C. The precipitated product was filtered and washed with tetrahydrofuran (10 ml). The obtained product was dried at 4mm Hg at 40°C for 1 hour to yield 1.6 gram of the titled compound as pinkish solid in 90% yield.
Analysis:
Mass: 222.0 (M+1) for Molecular Weight: 221 and Molecular Formula: C9H7N3O4.

Preparation 3: Synthesis of a mixture of tert-butyl 1-(2-hydrazino-2-oxoethyl)-1H-benzimidazol-5-ylcarbamate and tert-butyl 1-(2-hydrazino-2-oxoethyl)-1H-benzimidazol-6-ylcarbamate:

Step 1: Synthesis of a mixture of ethyl {5-[(tert-butoxycarbonyl)amino]-1H-benzimidazol-1-yl}acetate and ethyl {6-[(tert-butoxycarbonyl)amino]-1H-benzimidazol-1-yl}acetate: To a solution of ethyl (5-nitro-1H-benzimidazol-1-yl)acetate and ethyl (6-nitro-1H-benzimidazol-1-yl)acetate (10 g, 0.0401 mol, prepared according to the step 2 of preparation 2) in tetrahydrofuran (50 ml) in Parr Shaker apparatus was added palladium over carbon (10%, wet) under stirring. Hydrogen gas was flushed at 3.5 kg pressure. The completion of the reaction was monitored by thin layer chromatography. After 3 hours, the reaction mass was filtered through hyflow bed and residue was washed with tetrahydrofuran (25 ml). The filtrate was distilled under reduced pressure. To the resulted concentrated mass was added tetrahydrofuran (50 ml) to obtain a clear solution. To this solution was slowly added Boc-anhydride (10 ml, 0.0435mol) at 0°C, followed by sulphamic acid (3.84 g, 0.0401 mol). The reaction mixture was allowed to attain a temperature of 25°C. The completion of the reaction was monitored by TLC. After 16 hours, the reaction mixture was concentrated to remove out tetrahydrofuran completely. The obtained concentrated mass was dissolved in dichloromethane (100 ml) and washed with water (2 x 50 ml. The organic layer was dried over anhydrous sodium sulfate and concentrated on rotary-evaporator under reduced pressure to yield 13 gram of the titled compound as solid in 101 % yield.
Analysis:
Mass: 320.0 (M+1) for Molecular Weight: 319 and Molecular Formula: C16H21N3O4.

Step 2: Synthesis of a mixture of tert-butyl 1-(2-hydrazino-2-oxoethyl)-1H-benzimidazol-5-ylcarbamate and tert-butyl 1-(2-hydrazino-2-oxoethyl)-1H-benzimidazol-6-ylcarbamate: To the solution of mixture of ethyl {5-[(tert-butoxycarbonyl)amino]-1H-benzimidazol-1-yl}acetate and ethyl {6-[(tert-butoxycarbonyl)amino]-1H-benzimidazol-1-yl}acetate (12.5 g, 0.0391 mol) (obtained from step 1) in ethanol (60 ml) was added hydrazine hydrate monohydrate (3 ml) under stirring. The reaction mixture was heated to reflux. The completion of the reaction was confirmed with TLC. The reaction mixture was cooled to 25°C and ethanol was distilled out completely. To the resulting concentrated mass was added diisopropyl ether (60 ml) and stirred for 30 minutes. The precipitated compound was filtered and washed with diisopropyl ether (30 ml). The obtained compound was dried under reduced pressure at 40°C for 1 hour to yield 11 gram of the titled product as solid in 92% yield.
Analysis:
Mass: 306 (M+1) for Molecular Weight: 305 and Molecular Formula: C14H19N5O3.

Preparation 4: Synthesis of 2-(1H-benzotriazol-1-yl)acetohydrazide:

Step 1: Synthesis of ethyl 1H-benzotriazol-1-ylacetate and ethyl 2H-benzotriazol-2-ylacetate: To a clear solution of 1H-Benzotriazole (20 g, 0.168 mol) in dimethylformamide (100 ml), potassium carbonate (25.48 g, 0.155 mol) was added under stirring at 25-30ºC. After 10 minutes, to the resulting mass was added benzyl bromide (25.18 g, 0.168 mol) under stirring. The completion of the reaction was confirmed by performing TLC (Hexane: Acetone 6.5:3.5). Reaction mixture was slowly added to cold water (800 ml) under stirring, the separated white precipitate was filtered and washed with water (50 ml) to yield 22 gram of the crude product. The crude compound was purified by column chromatography using mixture of hexane and acetone as an eluent. The upper spot was isolated at 15-20% concentration of acetone in hexane and yielded 5.9 gram of ethyl 2H-benzotriazol-2-ylacetate. The lower spot isolated at 25-30% concentration of acetone in hexane provided 12 gram of ethyl 1H-benzotriazol-1-ylacetate as white compound. The overall yield was 52%.
Analysis:
Ethyl 1H-benzotriazol-1-ylacetate:
Mass: 206.1 (M+1) for Molecular Weight: 205.2 and Molecular Formula: C10H11N3O2.
1H NMR (400 MHz, DMSO-d6): ? 8.09 (d, 1H, J = 8.4 Hz), 7.54-7.26 (m, 3H), 5.42 (s, 2H), 4.28-4.23 (q, 2H, J = 7.2Hz), 1.26 (t, 3H, J = 6.8 Hz).

Ethyl 2H-benzotriazol-2-ylacetate:
Mass: 206.1 (M+1) for Molecular Weight: 205.2 and Molecular Formula: C10H11N3O2.
1H NMR (400 MHz, DMSO-d6): ? 7.89-7.87 (m, 2H), 7.42-7.26 (m, 2H), 5.51 (s, 2H), 4.30-4.25 (q, 2H, J =7.2Hz), 1.28 (t, 3H, J = 7.2 Hz).

Step 2: Synthesis of 2-(1H-benzotriazol-1-yl)acetohydrazide: To a clear solution of ethyl 1H-benzotriazol-1-ylacetate (4.0 g, 0.0195 mol, obtained from the step-1, lower spot as per TLC) in ethanol (40 ml) was added hydrazine hydrate (1.46 g, 0.0293 mol) at 25-30oC under stirring. The progress of reaction was monitored by performing TLC (Chloroform: Methanol 9:1). After complete consumption of starting materials the volatiles were removed under reduced pressure, and to the resulting yellow mass was added diethyl ether (50 ml) under stirring. The obtained precipitate was filtered and washed with ether (2 x 20 ml) to obtain 3 grams of 2-(1H-benzotriazol-1-yl)acetohydrazide in 80% yield.
Analysis:
Mass: 192.1 (M+1) for Molecular Weight: 191.18 and Molecular Formula: C8H9N5O.

Preparation 5: Synthesis of 2H-benzotriazol-2-ylacetic acid:

To a solution of ethyl 2H-benzotriazol-2-ylacetate (1.5 g, 0.0073 mol, product from step 1 of preparation 4, upper spot as per TLC) in tetrahydrofuran (7.5 ml) was slowly added a solution of lithium hydroxide (0.308 g, 0.0073 mol) in water (7.5 ml) under stirring at 0-5°C. The completion of reaction was monitored by performing TLC (Hexane: Acetone 6.5:3.5). After completion of the reaction (about 2 hours), pH of the reaction mass was adjusted to 2 by using 2N HCl. The reaction mixture was stirred further for 15 minutes at 0°C. The precipitates thus formed were filtered and washed with water (5 ml). The obtained compound was dried at 40°C for 1 hour under reduced pressure to yield 1gram of 2H-benzotriazol-2-ylacetic acid as white solid in 77 % yield.
Analysis:
Mass: 176.1 (M-1) for Molecular Weight: 177.1 and Molecular Formula: C8H7N3O2.
1H NMR (400 MHz, DMSO-d6): ? 13.56 (s, 1H), 7.95-7.93 (m, 2H), 7.47-7.45 (m, 2H), 5.66 (s, 2H).

Preparation 6: Synthesis of 2-(2H-benzotriazol-1-yl)acetohydrazide:

To a clean dry flask was charged ethyl 2H-benzotriazol-2-ylacetate (3.0 g, 0.0146 mol, upper spot as per TLC product obtained from Step1 of preparation 4) in ethanol (30 ml). To this solution was added hydrazine hydrate (1.09 g, 0.0219 mol) at 25-30ºC and progress of reaction was monitored by TLC (Chloroform: Methanol, 9:1). After complete consumption of starting material the volatiles were removed under reduced pressure to obtain yellowish residue. To the residue was added (50 ml) diethyl ether and stirred to obtain precipitates of required compound. The product was filtered and washed with ether (2 × 20 ml) to yield 2.7 g of 2-(2H-benzotriazol-2-yl)acetohydrazide in 96% yield.
Analysis:
Mass: 192.1 (M+1) for Molecular Weight: 191.18 and Molecular Formula: C8H9N5O.

Preparation 7: Synthesis of 2-(tert-Butyldimethylsilyloxymethyl) 1H-benzimidazol-1-yl] acetohydrazide:

Step 1: Synthesis of Ethyl [2-(tert-Butyldimethylsilyloxymethyl) 1H-benzimidazol-1-yl] acetate: To a solution of 2-(tert-Butyldimethylsilyloxymethyl) 1H-benzimidazole (25 g, 0.0954 mol, prepared according to the literature procedures described in Indian Journal of organic chemistry, 9(2), 41-57, 2013 and WO2001095910) in dimethylformamide (250 ml), potassium carbonate (14.5 g, 0.105 mol) was added under stirring, After 30 minutes, ethyl bromoacetate (11 ml, 0.0955 mol) was added slowly and stirring continued further at 25°C for 16 hours. Completion of the reaction was confirmed by performing TLC. Dimethylformamide was evaporated under reduced pressure completely and to the obtained reaction mass water (200 ml) was added and then extracted with ethyl acetate (250 ml). The organic layer was washed with water (250 ml) and then with brine (250 ml). The collected organic layer was dried over anhydrous sodium sulfate and concentrated on rota-evaporator under reduced pressure to yield 34 g of ethyl [2-(tert-Butyldimethylsilyloxymethyl) 1H-benzimidazol-1-yl] acetate as solid compound.
Analysis:
Mass: 349 (M+1) for Molecular Weight: 348 and Molecular Formula: C18H28N2O3Si.

Step 2: Synthesis of 2-(tert-Butyldimethylsilyloxymethyl) 1H-benzimidazol-1-yl] acetohydrazide: Hydrazine hydrate monohydrate (6 ml) was slowly added to a solution of ethyl [2-(tert-butyldimethyl silyloxymethyl) 1H-benzimidazol-1-yl] acetate (28 g, 0.0804 mol, obtained from step-1) in ethanol (140 ml), reaction mixture was heated to reflux for 16 hours under stirring. Completion of the reaction was confirmed by performing TLC. Reaction mixture was cooled to 25°C and ethanol was evaporated under reduced pressure. To this resulted concentrated mass, diethyl ether (140 ml) was added and stirred for 30 minutes. Precipitated compound was filtered and washed with diethyl ether (50 ml), and dried at 40°C for 1 hour under reduced pressure to yield 23 g of 2-(tert-butyldimethylsilyloxymethyl) 1H-benzimidazol-1-yl] acetohydrazide as solid compound in 86% yield.
Analysis:
Mass: 335 (M+1) for Molecular Weight: 334 and Molecular Formula: C16H26N4O2Si.
1H NMR (DMSO-d6): ? 9.48 (s, 1H), 7.61 (d, 1H, J = 7.6 Hz), 7.46 (d, 1H, J =7.2 Hz), 7.25-7.17 (m, 2H), 4.92 (s, 4H), 4.30 (s, 2H), 0.860 (s, 9H), 0.064 (s, 6H).

Preparation 8: Synthesis of 2-(2-ethyl-1H-benzimidazol-1-yl)acetohydrazide:

Step 1: Synthesis of 2-ethyl-1H-benzimidazole: Propionic acid (103 ml) was added to a solution of o-phenylene diamine (50 g, 0.462 mol) in water (184 ml) containing concentrated HCl (123 ml) under stirring. Then the reaction mass was heated to 95-98°C. After completion of 6 hours of stirring, the completion of the reaction was confirmed by performing TLC. Reaction mass was slowly poured into ice water and basified using aqueous ammonia. The reaction mixture was stirred for 30 minutes and the formed precipitates were filtered and washed with water (200 ml). The obtained solid compound was dried at 40°C for 3 hours under reduced pressure to yield 62 g of 2-ethyl-1H-benzimidazole as solid compound in 92% yield.
Analysis:
Mass: 145.0 (M+1) for Molecular Weight: 146 and Molecular Formula: C9H10N2.

Step 2: Synthesis of ethyl (2-ethyl-1H-benzimidazol-1-yl)acetate: To a solution of 2-ethyl-1H-benzimidazole (30 g, 0.205 mol, product from step 1) in dimethylformamide (300 ml), potassium carbonate (31 g, 0.224 mol) was added under stirring, followed by the addition of ethylbromoacetate (24 ml, 0.208 mol) in portion wise and continued stirred for 16 hours. The completion of the reaction was confirmed by performing the TLC. Dimethylformamide was distilled out completely and water (200 ml) was added to the concentrated mass. The formed precipitates were filtered and washed with water (100 ml); and further dried at 40°C for 2 hours under reduced pressure to yield 31 g of ethyl (2-ethyl-1H-benzimidazol-1-yl)acetate as solid compound in 65% yield.
Analysis:
Mass: 233.1 (M+1) for Molecular Weight: 232 and Molecular Formula: C13H16N2O2.

Step 3: Synthesis of 2-(2-ethyl-1H-benzimidazol-1-yl)acetohydrazide: Hydrazine hydrate monohydrate was slowly added to a solution of ethyl (2-ethyl-1H-benzimidazol-1-yl)acetate (30 g, 0.129 mol, product from step 2) in ethanol (150 ml) under stirring and then the reaction mixture was heated to reflux. After completion of 6 hours of reflux, the completion of the reaction was confirmed by performing the TLC. Reaction mixture was allowed to cool to 25°C and the formed precipitates of compound were filtered and washed with ethanol (30 ml). The obtained product was dried at 40°C for 2 hours under reduced pressure to yield 23 g of 2-(2-ethyl-1H-benzimidazol-1-yl)acetohydrazide as off-white solid in 82% yield.
Analysis:
Mass: 219 (M+1) for Molecular Weight: 218 and Molecular Formula: C11H14N4O.
1H NMR (DMSO-d6): ? 9.51 (s, 1H), 7.55 (d, 1H, J = 6.8 Hz), 7.39 (d, 1H, J = 6.4 Hz), 7.18-7.11 (m, 2H), 4.79 (s, 2H), 4.33 (d, 2H, J = 3.6 Hz), 2.83 (q, 2H, J = 7.6 Hz), 1.32 (t, 3H, J = 7.6 Hz).

Preparation 9: Synthesis of tert-butyl [1-(2-hydrazino-2-oxoethyl)-1H-benzimidazol-2-yl]methylcarbamate: Hydrazine hydrate monohydrate (7 ml) was slowly added to a solution of ethyl (2-{[(tert-butoxycarbonyl)amino]methyl}-1H-benzimidazol-1-yl)acetate (15 g, 0.0450 mol, prepared according to the procedure described in J.Med.chem., 45(25), 5556-5563, 2003) in ethanol (150 ml) under stirring and then the reaction mixture was heated to reflux. After completion of 4 hours of reflux the reaction mixture was cooled to 25°C and ethanol was evaporated under reduced pressure completely to dryness, to this concentrated mass was added diethyl ether (150 ml) and stirred for 30 minutes. The precipitates formed were filtered and washed with diethyl ether (50 ml), compound was dried at 40°C for 1 hour under reduced pressure and yielded 11.3 gram of tert-butyl [1-(2-hydrazino-2-oxoethyl)-1H-benzimidazol-2-yl]methylcarbamate as off-white solid in 79% yield.
Analysis:
Mass: 320 (M+1) for Molecular Weight: 319 and Molecular Formula: C15H21N5O3.
1H NMR (DMSO-d6): ? 9.55 (s, 1H), 7.59 (d, 1H, J = 7.2 Hz), 7.44 (d, 1H, J = 6.8 Hz), 7.37 (s, 1H), 7.23-7.19 (m, 2H), 4.90 (s, 2H), 4.45 (s, 2H), 4.36 (s, 2H), 1.40 (s, 9H).

Preparation 10: Synthesis of tert-butyl 3-[1-(2-hydrazino-2-oxoethyl)-1H-benzimidazol-2-yl]propylcarbamate:

The tert-butyl 3-[1-(2-hydrazino-2-oxoethyl)-1H-benzimidazol-2-yl]propylcarbamate was prepared according to the procedure described in preparation 9 by using ethyl (2-{[(tert-butoxycarbonyl)amino]propyl}-1H-benzimidazol-1-yl)acetate (prepared according to the procedure described for ethyl (2-{[(tert-butoxycarbonyl)amino]methyl}-1H-benzimidazol-1-yl)acetate in J.Med.Chem., 45(25), 5556-5563, 2003).
Analysis:
Mass: 346.1 (M-1) for Molecular Weight: 347.4 and Molecular Formula: C17H25N5O3.
1H NMR (DMSO-d6): ? 9.51 (s, 1H), 7.52 (d, 1H, J = 7.2 Hz), 7.37 (d, 1H, J = 8.0 Hz), 7.13-7.11 (m, 2H), 6.88 (s, 1H), 4.78 (s, 2H), 4.31 (s, 2H), 3.04-3.02 (m, 2H), 2.79 (t, 2H), 1.90-1.88 (m, 2H), 1.35 (s, 9H).

Preparation 11: Synthesis of 2-[2-(4-(tert-butoxycarbonyl)aminophenyl)-1H-benzimidazol-1-yl]acetohydrazide:

The 2-[2-(4-(tert-butoxycarbonyl)aminophenyl)-1H-benzimidazol-1-yl]acetohydrazide was prepared according to the procedure described in preparation 9 by using ethyl 2-{4-[(tert-butoxycarbonyl)amino]phenyl}-1H-benzimidazole-1-carboxylate (prepared according to the procedure described for ethyl (2-{[(tert-butoxycarbonyl)amino]methyl}-1H-benzimidazol-1-yl)acetate in J.Med.Chem., 45(25), 5556-5563, 2003).
Analysis:
Mass: 382.3 (M+1) for Molecular Weight: 381.4 and Molecular Formula: C20H23N5O3.
1H NMR (DMSO-d6): ? 9.64 (s, 1H), 9.57 (s, 1H), 7.73-7.61 (m, 5H), 7.44 (d, 1H, J = 8Hz), 7.25-7.23 (m, 2H), 4.82 (s, 2H), 4.41 (s, 2H), 1.50 (s, 9H)

Preparation 12: Synthesis of 2-[2-(4-tert butoxycarbonyl aminobenzyl)-1H-benzimidazol-1-yl]acetohydrazide:

The 2-[2-(4-tert butoxycarbonyl aminobenzyl)-1H-benzimidazol-1-yl]acetohydrazide was prepared according to the procedure described in preparation 9 by using ethyl 2-{4-[(tert-butoxycarbonyl)amino]benzyl}-1H-benzimidazole-1-carboxylate (prepared according to the procedure described for ethyl (2-{[(tert-butoxycarbonyl)amino]methyl}-1H-benzimidazol-1-yl)acetate in J.Med.Chem., 45(25), 5556-5563, 2003).
Analysis:
Mass: 396.4 (M+1) for Molecular Weight: 395.4 and Molecular Formula: C21H25N5O3.
1H NMR (DMSO-d6): ? 9.49 (s, 1H), 9.27 (s, 1H), 7.56-7.54 (m, 1H), 7.42-7.36 (m, 2H), 7.20-7.15 (m, 5H,), 4.76 (s, 2H), 4.31 (s, 2H), 4.16 (s, 2H), 1.44 (s, 9H).

Preparation 13: Synthesis of {2-[4-(tert-butoxycarbonyl)piperazin-1-yl]-1H-benzimidazol-1-yl}acetohydrazide:

The {2-[4-(tert-butoxycarbonyl)piperazin-1-yl]-1H-benzimidazol-1-yl}acetohydrazide was prepared according to the procedure described in preparation 9 by ethyl 2-[4-(tert-butoxycarbonyl)piperazin-1-yl]-1H-benzimidazole-1-carboxylate (prepared according to the procedure described for ethyl (2-{[(tert-butoxycarbonyl)amino]methyl}-1H-benzimidazol-1-yl)acetate in J.Med.Chem., 45(25), 5556-5563, 2003).
Analysis:
Mass: 375.4 (M+1) for Molecular Weight: 374.4 and Molecular Formula: C18H26N6O3.
1H NMR (DMSO-d6): ? 9.58 (s, 1H), 7.45-7.43 (m, 1H), 7.24-7.22 (m, 1H), 7.13-7.08 (m, 2H), 5.50 (brs, 2H,), 4.64 (s, 2H), 3.49 (m, 4H), 3.17-3.11 (m, 4H), 1.43 (s, 9H).

Example 1

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

Step 1: Synthesis of (2S,5R)-N'-(1H-benzimidazol-1-ylacetyl)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide: To a solution of sodium (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (34.46 g, 0.115 mol, prepared according to the procedure described in International Patent Application No. PCT/IB2013/059264) in water (344 ml) was added EDC.HCl (44.12 g, 0.230 mol) under stirring. After completion of 30 minutes, (benzimidazol-1-yl)acetohydrazide (20 g, 0.105 mol, prepared as per the procedure described in Preparation 1) was added to the reaction mixture followed by addition of HOBT (16.06 g, 0.105 mol) in portion wise under stirring. After completion of 16 hours stirring the solid thus obtained was filtered on Buchner funnel, the crude solid product was further purified by silica gel (60-120 mesh) column chromatography using mixture of methanol and dichloromethane as an eluant to obtain 28.5 gram of (2S,5R)-N'-(1H-benzimidazol-1-ylacetyl)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide in 60.5% yield.
Analysis:
Mass: 449.4 for (M+1) and 447.4 for (M-H) for Molecular Weight: 448.49 and Molecular Formula: C23H24N6O4.
1H NMR (400 MHz, CDCl3): ? 9.70 (brs, 1H), 8.76 (brs, 1H), 7.83 (s, 1H), 7.56 (d, 1H, J = 8.0 Hz ), 7.42-7.30 (m, 6H), 7.26 (t, 1H, J = 7.2 Hz ), 7.19 (t, 1H, J = 7.2 Hz ), 5.15 (d, 1H, J = 11.6 Hz ), 4.87 (s, 2H), 4.86 (d, 1H, J = 10.0 Hz ), 3.91 (d, 1H, J = 6.8 Hz ), 3.26 (brs, 1H), 3.03 (d, 1H, J = 12.0 Hz ), 2.94 (d, 1H, J = 12.0 Hz ),2.24-2.16 (m, 1H), 1.96-1.82 (m, 2H), 1.60-1.52 (m, 1H).

Step 2: Synthesis of (2S,5R)-N'-(1H-benzimidazol-1-ylacetyl)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide: To a solution of (2S,5R)-N'-(1H-benzimidazol-1-ylacetyl)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (5 g, 0.116 mol, obtained from step-1) in methanol (75 ml) was added 10% palladium on carbon (1.25 g) and hydrogen gas was purged. After completion of 2 hours the reaction completion was confirmed by performing TLC. The reaction mass was filtered through celite bed to remove 10% palladium on carbon, and concentrated under reduced pressure to yield 3.99 gram of (2S,5R)-N'-(1H-benzimidazol-1-ylacetyl)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (about 100% yield), which was used in the next step without further purification.

Step 3: Synthesis of tetrabutylammonium salt of (2S,5R)-N'-(1H-benzimidazol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide: To a clear solution of (2S,5R)-N'-(1H-benzimidazol-1-ylacetyl)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (3.99 g, 0.011 mol) in dimethylformamide (25 ml) was added sulfur trioxide-dimethylformamide complex (2.04 g, 0.133 mol) under continuous stirring at 5-10°C. The reaction mixture was stirred for 30 minutes at same conditions and the progress of the reaction was monitored by performing TLC. After completion of the reaction tetrabutylammonium acetate (4 g, 0.133 mol) solution in water (13.3 ml) was added under stirring. After 1 hour, completion of reaction was confirmed by performing the TLC. The resulting reaction mass was concentrated at 4mm Hg. The obtained residue was partitioned in dichloromethane and water (50 ml: 50 ml). The collected dichloromethane layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude compound was purified by silica gel (60-120 mesh) column chromatography using mixture of methanol and dichloromethane as an eluant. The pure fractions obtained were concentrated to yield 4 gram of tetrabutylammonium salt of (2S,5R)-N'-(1H-benzimidazol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide in 52.7% yield.
Analysis:
Mass: 439.2 (M+1) and 437.2 (M-1) for Molecular Weight: 679.89 and Molecular Formula: C32H53N7O7S.
1H NMR (400 MHz, CDCl3): ? 10.10 (brs, 1H), 8.78 (brs, 1H), 8.09 (s, 1H), 7.63 (d, 1H, J = 8.0 Hz ), 7.52 (d, 1H, J = 8.0 Hz ), 7.26 (t, 1H, J = 7.2 Hz ), 7.18 (t, 1H, J = 7.2 Hz ), 5.15 (d, 1H, J = 16.8 Hz ), 5.03 (d, 1H, J = 16.8 Hz ), 4.20 (brs, 1H), 3.98 (d, 1H, J = 8.0 Hz ), 3.23-2.95 (m, 10H), 2.34-2.28 (m, 1H), 2.12-2.04 (m, 1H), 1.92-1.80 (m, 1H), 1.70-1.42 (m, 9H), 1.41-1.20 (m, 8H), 1.00-0.80 (m, 12H).

Step 4: Sodium salt of (2S,5R)-N'-(1H-benzimidazol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide: In a proper sized column packed with INDION 225 Na resin (350 g), millipore water (~2 liters) was eluted followed by 10% tetrahydrofuran in water (~1 liter). A solution of tetrabutylammonium salt of (2S,5R)-N'-(1H-benzimidazol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (7.1 g, 0.104 mol) in tetrahydrofuran (7 ml) was loaded on column and slowly eluted with 10% tetrahydrofuran in water. The fractions containing the product were collected together and concentrated at 4 mm Hg. The resulting aqueous layer was washed with dichloromethane (2×70 ml). Finally the resulted aqueous layer was concentrated under high vacuum at about 35°C to yield 3.8 grams of sodium salt of (2S,5R)-N'-(1H-benzimidazol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazidein 79% yield.
Analysis:
Mass: 439.2 (M+1) and 437.2 (M-1) as free acid for Molecular Weight: 460.4 and Molecular Formula: C16H17N6O7S.Na.
1H NMR (400 MHz, DMSO-d6): ? 10.38 (brs, 1H), 10.10 (brs, 1H), 8.19 (s, 1H), 7.66 (d, 1H, J = 8.0 Hz ), 7.49 (d, 1H, J = 8.0 Hz ), 7.30-7.19 (m, 2H), 5.03 (s, 2H), 3.97 (brs, 1H), 3.84 (d, 1H, J = 7.6 Hz ), 3.15 (d, 1H, J = 12.0 Hz ), 2.96 (d, 1H, J = 12.0 Hz ), 2.06-1.98 (m, 1H), 1.90-1.56 (m, 3H).

Example 2

Synthesis sodium salt of (2S,5R)-N'-[(5 -nitro-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide and (2S,5R)-N'-[(6 -nitro-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide:

Step 1: Synthesis of tetrabutylammonium salt of (2S,5R)-N'-[(5 -nitro-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide and tetrabutylammonium salt of (2S,5R)-N'-[(6 -nitro-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide: To a solution of mixture of (5 & 6-nitro-1H-benzimidazol-1-yl)acetic acid (1.5 gm, 0.006 mole, prepared as per the procedure described in Preparation 2)) in dimethylformamide (15 ml) was added EDC.HCl (1.3 g, 0.006 mol) at room temperature under stirring. To this reaction mixture was added N-methylmorpholine (2.2 ml, 0.02 mol) and then HOBT (1.0 g, 0.006 mol) under continuous stirring. To this resulting mixture was added (2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (1.7 g, 0.006 mol, prepared according to the procedure described in International Patent Application No. PCT/IB2016/053965) at 10°C. After one hour of stirring at the same condition, the reaction mixture was allowed to attain room temperature. After 17 hours, the completion of the reaction was confirmed by performing TLC. To this resulting reaction mass a solution of tetrabutylammonium acetate (2 g, 0.006 mol) in water (6 ml) was slowly added and stirred for 2 hours. Dimethylformamide and water was evaporated under reduced pressure and co-evaporated with xylene (2×20 ml) till dryness. To the resulting concentrated mass water (20 ml) was added and extracted with dichloromethane (2×20 ml). The combined organic layer was washed with water (10 ml) and then the organic layer was dried over anhydrous sodium sulfate. The dried organic layer was concentrated under reduced pressure to yield crude oily mass (3.2 g). The crude compound was column purified by using mixture of dichloromethane and water as an eluent. The compound containing fractions were collected and evaporated to yield 1.6 gram of the product. The obtained product contained about 28% HOBT and it was further purified by adding water (30 ml) and N-methylmorpholine (1 ml). The obtained mixture was extracted with dichloromethane (2×20 ml). Combined organic layer was washed with water (20 ml) and dried over anhydrous sodium sulfate and finally evaporated under reduced pressure to yield 1.3 grams of pure compound mixture in 30%.
Analysis:
Mass: 484.1 (M+1) as free acid for Molecular Weight: 724 and Molecular Formula: C32H52N8O9S.

Step 2: Synthesis of sodium salt of (2S,5R)-N'-[(5 -nitro-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide and sodium salt of (2S,5R)-N'-[(6 -nitro-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide: Indion 225 Na resin was loaded on column and it was eluted with water (500 ml) and 10% tetrahydrofuran in water (500 ml). A solution of tetrabutylammonium salt of (2S, 5R)-N'-[(5 & 6 -nitro-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide mixture (1.2 g, 0.0016 mol, obtained from step 1) in tetrahydrofuran (2.4 ml) was diluted with water (18 ml) and passed through Indion 225 Na ion exchange resin and then eluted by 10% tetrahydrofuran in water. The fractions containing compound were collected and concentrated on rotavapour till dryness to provide 0.650 g of sodium salt of (2S,5R)-N'-[(5 & 6-nitro-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide as a white solid in 78% yield.
Analysis:
Mass: 484.1 (M+1) as free acid for Molecular Weight: 505.3 and Molecular Formula: C16H16N7O9S.Na.

Example 3

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

Step 1: Synthesis and separation of (2S,5R)-6-benzyloxy-N'-[(5-(tert butoxycarbonyl amino)-1H-benzimidazol-1-yl)acetyl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide and (2S,5R)-6-benzyloxy-N'-[(6-(tert butoxycarbonyl amino)-1H-benzimidazol-1-yl)acetyl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide: To a solution of sodium (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (6 g, 0.02 mol, prepared according to the procedure described in International Patent Application No. PCT/IB2013/059264) in water (60 ml) was added EDC.HCl (8.4 gm, 0.0439 mole) at room temperature under stirring. A mixture of tert-butyl 1-(2-hydrazino-2-oxoethyl)-1H-benzimidazol-5-ylcarbamate and tert-butyl 1-(2-hydrazino-2-oxoethyl)-1H-benzimidazol-6-ylcarbamate (6 g, 0.0196 mol, prepared according to the procedure described in Preparation 3) was added; and this was followed by addition of HOBT (3 g, 0.0196 mol) under stirring. After 4 hours, N-methyl morpholine (8.2 ml) was added and then the reaction mixture was extracted with dichloromethane (2×60 ml). The combined organic layer was washed with water (2×30 ml) and dried over anhydrous sodium sulfate; the organic layer was evaporated under reduced pressure to provide 22 g of oily mass as crude product. This crude oily mass was purified by column chromatography (silica 60-120) using mixture of dichloromethane and methanol as an eluent. The upper spot provided 1.6 g of (2S,5R)-6-benzyloxy-N'-[(6-(tert butoxy carbonyl amino)-1H-benzimidazol-1-yl)acetyl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide, and the lower spot provided 1.8 g of (2S,5R)-6-benzyloxy-N'-[(5-(tert butoxy carbonyl amino)-1H-benzimidazol-1-yl)acetyl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide with overall yield of 31%.
Analysis:
Upper spot: (2S,5R)-6-benzyloxy-N'-[(6-(tert butoxy carbonyl amino)-1H-benzimidazol-1-yl)acetyl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide
Mass: 564.5 (M+1) for Molecular Weight: 563 and Molecular Formula: C28H33N7O6.
1H NMR (400 MHz, DMSO-d6): ? 10.36 (s, 1H), 10.05 (s, 1H), 9.37 (s, 1H), 8.07 (s, 1H), 7.77 (s, 1H), 7.51-7.33 (m, 6H), 7.11-7.08 (m, 1H), 4.99-4.09 (m, 4H), 3.84 (d, 1H, J = 7.6 Hz), 3.66 (1H, s), 3.15 (d, 1H, J = 6.0 Hz ), 2.86 (d, 1H, J =11.2 Hz), 2.02-1.98 (m, 1H ), 1.83 (s, 1H), 1.76-1.59 (m, 2H), 1.48 (s, 9H).

Lower spot: (2S,5R)-6-benzyloxy-N'-[(5-(tert butoxy carbonyl amino)-1H-benzimidazol-1-yl)acetyl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide.

Mass: 564.3 (M+1) for Molecular Weight: 563 and Molecular Formula: C28H33N7O6.
1H NMR (400 MHz, DMSO-d6): ? 10.34 (s, 1H), 10.04 (s, 1H), 9.23 (s, 1H), 8.05 (s, 1H,), 7.77 (s, 1H), 7.45-7.29 (m, 7H), 4.96-4.89 (m, 4H), 3.84 (d, 1H, J = 7.6 Hz), 3.66 (s, 1H), 3.14 (d, 1H, J = 12.0 Hz), 2.87 (d, 1H, J = 12.0 Hz), 2.04-1.99 (m, 1H ), 1.84 (s, 1H), 1.76-1.58 (m, 2H), 1.48 (s, 9H).

Step 2: Synthesis of (2S,5R)-6-hydroxy-N'-[(6-(tert butoxycarbonyl amino)-1H-benzimidazol-1-yl)acetyl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide: To a solution of (2S,5R)-6-benzyloxy-N'-[(6-(tert butoxycarbonyl amino)-1H-benzimidazol-1-yl)acetyl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (1.5 g, 0.0026 mol, obtained from step 1) in dichloromethane (7.5 ml) and dimethylformamide (7.5 ml) was added 10% palladium on carbon (2.25 g) and hydrogen gas was purged continuously at 25°C. The completion of the reaction was monitored by thin layer chromatography. After completion, the resulting mixture was filtered through hyflow bed and the residue washed with mixture of dichloromethane and dimethylformamide (1:1, 15 ml). The combined filtrate was evaporated to obtain 1.3 g of (2S,5R)-6-hydroxy-N'-[(6-(tert-butoxycarbonyl amino)-1H-benzimidazol-1-yl)acetyl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide and this material was directly used without further purifications in the next step.

Step 3: Synthesis of tetra butylammonium salt of (2S,5R) - N'-[(6-(tert-butoxycarbonyl amino)-1H-benzimidazol-1-yl)acetyl]- 7-oxo-6-(sulfooxy) - 1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide: To a solution of (2S,5R)-6-hydroxy-N'-[(6-(tert-butoxy carbonyl amino)-1H-benzimidazol-1-yl)acetyl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (1.3 g) in dimethylformamide (15 ml) was added sulfur trioxide dimethylformamide complex (0.611 g, 0.0039 mol) at 0°C under stirring. It was allowed to attain temperature of 25°C. The completion of the reaction was monitored by thin layer chromatography. After about 2 hours the reaction mass cooled to 0°C and a solution of tetra butylammonium acetate (3.8 g, 0.0126 mol) in water (13 ml) was added. The reaction mixture was allowed to attain temperature of 25°C. After 1 hour of continuous stirring the completion of the reaction was confirmed with thin layer chromatography. The dimethylformamide and water was removed by evaporation under reduced pressure, and this was followed by co-evaporation with xylene (2×15 ml). The resulted mass was partitioned in mixture of dichloromethane and water (1: 1, 30 ml). The two layers were separated and the aqueous layer was extracted with dichloromethane (15 ml) and combined organic layer was dried over anhydrous sodium sulfate. The dried organic layer was concentrated to dryness to yield 3 g of the crude compound. This crude compound was purified by column chromatography (silica gel 60-120 mesh) and using mixture of methanol and dichloromethane as an eluent. The collected pure fractions were concentrated to provide 0.35 g of tetra-butylammonium salt of (2S,5R)-6-sulphoxy-N'-[(6-(tert-butoxy carbonyl amino)-1H-benzimidazol-1-yl)acetyl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide in 21% yield.
Analysis:
Mass: 552.2 (M-1) as free acid for Molecular Weight: 794 and Molecular Formula: C37H62N8O9S.

Step 4: (2S,5R)-N'-[(6-amino-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide: To a pre cooled solution of tetrabutylammonium salt of (2S,5R)-6-sulphoxy-N'-[(6-(tert-butoxy carbonyl amino)-1H-benzimidazol-1-yl)acetyl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (0.450 g, 0.00057 mol) in dichloromethane (3 ml) was slowly added trifluoroacetic acid (2.3 ml) at 0°C. The progress of the reaction was monitored by thin layer chromatography. After about 1 hour, trifluoroacetic acid and dichloromethane was evaporated completely at 35°C under reduced pressure. The resulted concentrated mass was triturated with diethyl ether (2×10 ml) and then stirred for 1 hour at 25°C in dichloromethane (10 ml). The precipitates thus formed were filtered and washed with dichloromethane (5 ml). The compound thus obtained was dried at 40°C for 1hour under reduced pressure to provide 250mg of (2S,5R)-N'-[(6-amino-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide in 97% yield.
Analysis:
Mass: 454.2 (M+1); for Molecular Weight: 453.4 and Molecular Formula: C16H19N7O7S.
1H NMR (400 MHz, DMSO-d6): ? 10.47 (s, 1H), 10.16 (s, 1H), 9.10 (s, 1H), 7.56 (d, 1H, J = 8.8 Hz), 6.95 (d, 1H, J = 8.8 Hz), 6.85 (s, 1H), 5.17 (s, 2H), 4.06-3.40 (brs, 4H), 3.86 (d, 1H, J = 7.2 Hz), 3.13 (d, 1H, J =12.0 Hz), 2.98 (d, 1H, J = 11.6 Hz), 2.04-1.99 (m, 1H ), 1.90-1.56 (m, 3H).

The compounds of Examples 4 to 9 (Table 1) were prepared by following the procedure described in Example 3, wherein appropriately protected corresponding hydrazides were used in place of tert-butyl 1-(2-hydrazino-2-oxoethyl)-1H-benzimidazol-5-ylcarbamate and tert-butyl 1-(2-hydrazino-2-oxoethyl)-1H-benzimidazol-6-ylcarbamate mixture. The compounds of Examples 17 and 18 (Table 1) were prepared by following the procedure described for Example 2. The synthesis of Example 10 is achieved by purging hydrogen gas for longer duration which resulted in hydrogenation of aromatic ring of benztriazole along with debenzylation, further conversions to sulfonation, tetrabutylammonium salt formation and finally sodium salt formation was achieved by following the procedures described for Example 1. The compounds of Examples 11 to 18 (Table 1) were prepared by following the procedure described in Example 1 using appropriate hydrazides, which were prepared according the procedures described under preparations or as per the literature procedures.

Table 1
Example No. Compound Starting Reagent Analysis
4
1H NMR (400 MHz, DMSO-d6): ? 10.46 (s, 1H), 10.15 (s, 1H), 9.08 (s, 1H), 7.51 (d, 1H, J = 8.8 Hz), 7.04 (brs, 1H), 6.99 (d, 1H, J = 8.4 Hz), 5.20 (s, 2H), 4.06 (brs, 1H), 3.98 (s, 1H), 3.85 (d, 1H, J = 7.6 Hz), 3.80-3.38 (m, 2H), 3.12 (d, 1H, J = 11.2 Hz), 2.97 (d, 1H, J = 11.6 Hz), 2.04-1.99 (m, 1H ), 1.90-1.56 (m, 3H);
Mass as free acid: 454.1 (M+1); Molecular Formula: C16H19N7O7S.
5

1H NMR (400 MHz, DMSO-d6): ? 10.48 (s, 1H), 10.13 (s, 1H), 8.59 (s, 3H), 7.69 (d, 1H, J = 7.6 Hz), 7.60 (d, 1H, J = 7.6 Hz), 7.34-7.25 (m, 2H), 5.09 (s, 2H), 4.44 (s, 2H), 3.98 (s, 1H), 3.85 (d, 1H, J = 7.2 Hz), 3.11 (d, 1H, J = 12 Hz), 2.97 (d, 1H, J = 12 Hz), 2.03-1.98 (m, 1H ), 1.84 (s, 1H), 1.74-1.57 (m, 2H);
Mass as free acid: 468.3 (M+1); Molecular Formula: C17H21N7O7S.

6


1H NMR (400 MHz, DMSO-d6): ? 10.48 (s, 1H), 10.14 (s, 1H), 7.77-7.70 (m, 4H), 7.41 (brs, 2H), 5.15 (s, 2H), 4.05 (brs, 1H), 3.97 (s, 1H), 3.84 (d, 1H, J = 7.2 Hz), 3.18-3.08 (m, 3H), 2.99-2.90 (m, 3H), 2.12-1.97 (m, 3H ), 1.92-1.54 (m, 3H);
Mass as free acid: 496.3 (M+1); Molecular Formula: C19H25N7O7S.
7

1H NMR (400 MHz, DMSO-d6): ? 14.80 (s, 3H), 10.56 (s, 1H), 10.23 (s, 1H), 7.92-7.76 (m, 2H), 7.64-7.47 (m, 4H), 6.82 (s, 2H, J = 8.4Hz), 5.25-5.14 (m, 2H), 4.00 (s, 1H), 3.89 (d, 1H, J = 6.4 Hz), 3.14 (d, 1H, J = 12 Hz), 3.00 (d, 1H, J = 10.8 Hz), 2.06-2.02 (m, 1H), 1.92-1.58 (m, 3H);
Mass as free acid: 530.4 (M+1); Molecular Formula: C22H23N7O7S.
8

1H NMR (400 MHz, DMSO-d6): ? 10.56 (s, 1H), 10.20 (s, 1H), 7.83 (d, 1H, J = 7.6 Hz), 7.72 (d, 1H, J = 8.0 Hz), 7.53-7.49 (m, 2H), 7.24 (d, 2H, J = 8.0 Hz), 6.96 (d, 2H, J = 7.2 Hz), 5.32 (s, 2H), 4.45 (s, 2H), 4.10-3.40 (m, 5H), 3.13 (d, 1H, J = 12 Hz), 2.99 (d, 1H, J = 10 Hz), 2.07-2.00 (m, 1H), 1.90-1.59 (m, 3H);
Mass as free acid: 544.4(M+1); Molecular Formula: C23H25N7O7S.
9

1H NMR (400 MHz, DMSO-d6): ? 10.45 (1H, s), 10.17 (1H, s), 8.84 (2H, s), 7.53-7.52 (2H, m), 7.29-7.27 (2H, m), 4.98-4.87 (2H, s), 4.00 (1H, s), 3.87 (1H, d, J= 7.6 Hz), 3.47 (4H, m), 3.35 (4H, m), 3.14 (1H, d, J= 12 Hz), 2.99 (1H, d, J= 11.6 Hz), 2.07-2.00 (1H, m), 1.85 (1H, s), 1.73-1.56 (2H, m);
Mass as free acid: 521.4 (M-1); Molecular Formula: C20H26N8O7S.C2HO2F3.
10

1H NMR (400 MHz, DMSO-d6): ? 10.45 (brs, 1H), 10.17 (brs, 1H), 8.84 (brs, 2H), 7.58-7.50 (m, 2H), 7.32-7.27 (m, 2H), 4.98-4.86 (m, 2H), 4.00 (s, 1H), 3.87 (d, 1H, J = 7.6 Hz), 3.60-3.52 (m, 4H), 3.40-3.28 (m, 4H), 3.14 (d, 1H, J = 12.0 Hz), 2.99 (d, 1H, J = 11.6 Hz), 2.07-2.00 (m, 1H), 1.90-1.56 (m, 3H);
Mass as free acid: 442.3 (M-1); Molecular Formula: C15H20N7O7S.Na.
11

1H NMR (400 MHz, DMSO-d6): ? 10.2 (brs, 2H), 7.55 (d, 1H, J = 7.2 Hz), 7.47 (d, 1H, J = 6.8 Hz), 7.20-7.10 (m, 2H), 4.93 (s, 2H), 3.96 (s, 1H), 3.81 (d, 1H, J = 7.2 Hz), 3.12 (d, 1H, J = 11.6 Hz), 2.95 (d, 1H, J = 12.0 Hz), 2.87 (q, 2H, J =7.6 Hz), 2.05-2.00 (m, 1H ), 1.89-1.57 (m, 3H), 1.33 (t, 3H, J = 7.6 Hz);
Mass as free acid: 467.2 (M+1); Molecular Formula: C18H21N6O7S.Na.
12

1H NMR (400 MHz, DMSO-d6): d 10.14 (brs, 2H), 7.54 (d, 1H, J = 8.0 Hz ), 7.41 (d, 1H, J = 8.4 Hz), 7.34 (d, 1H, J = 3.2 Hz), 7.13 (t, 1H, J = 7.2 Hz), 7.03 (t, 1H, J = 7.2 Hz), 6.44 (d, 1H, J = 2.8 Hz), 4.89 (s, 2H ), 3.97 (s, 1H), 3.83 (d, 1H, J = 7.2 Hz), 3.18 (d, 1H, J =12.0 Hz), 2.96 (d, 1H, J = 11.6 Hz), 2.03 (dd, 1H, J = 5.2, 6.0 Hz), 1.83-1.58 (m, 3H);
Mass as free acid: 436.4 (M+1); Molecular Formula: C17H18N5O7S.Na.
13

1H NMR (400 MHz, DMSO-d6): d 10.42 (s, 1H), 10.16 (s, 1H), 8.05 (d, 1H, J = 8.0 Hz), 7.82 (d, 1H, J = 8.0 Hz), 7.64-7.55 (m, 1H), 7.43-7.39 (m, 1H), 5.56 (s, 2H), 4.04-3.83 (m, 2H), 3.14-2.94 (m, 2H), 2.05-1.54 (m, 4H);
Mass as free acid: 438.2 (M-1); Molecular Formula: C15H16N7O7S.Na.
14

1H NMR (400 MHz, DMSO-d6): ? 10.20 (s, 2H), 7.60 (d, 1H, J = 7.6 Hz), 7.50 (d, 1H, J = 8 Hz), 7.25-7.17 (m, 2H), 5.8 (brs, 1H), 5.07 (s, 2H), 4.71 (s, 2H), 3.96 (s, 1H), 3.82 (d, 1H, J = 7.2 Hz), 3.12 (d, 1H, J = 12 Hz), 2.95 (d, 1H, J = 11.6 Hz), 2.05-1.99 (m, 1H ), 1.82 (s, 1H), 1.73-1.57 (m, 2H);
Mass as free acid: 469.2 (M+1); Molecular Formula: C17H19N6O8S.Na.
15

1H NMR (400 MHz, DMSO-d6): ? 10.20 (s, 2H), 7.86 (d, 2H, J = 4 Hz), 7.69 (m, 1H), 7.58-7.54 (m, 4H), 7.31-7.24 (m, 2H), 4.93 (s, 2H), 3.98 (s, 1H), 3.85 (d, 1H, J = 6.8 Hz), 3.14 (d, 1H, J =11.2 Hz), 2.99 (d, 1H, J = 11.2 Hz), 2.08-2.03 (m, 1H), 1.84 (s, 1H), 1.78-1.56 (m, 2H);
Mass as free acid: 515.3 (M+1); Molecular Formula: C22H21N6O7S.Na.
16

1H NMR (400 MHz, DMSO-d6): ? 10.4 (s, 2H), 7.56 (d, 2H, J = 9.6 Hz), 7.50 (d, 2H, J = 8 Hz), 7.33-7.15 (m, 5H), 4.95 (s, 2H), 4.26 (s, 2H), 3.98 (s, 1H,), 3.85 (d, 1H, J = 7.6 Hz), 3.16 (d, 1H, J = 12 Hz), 2.98 (d, 1H, J = 11.6 Hz), 2.06-2.01 (m, 1H), 1.85 (s, 1H), 1.74-1.59 (m, 2H);
Mass as free acid: 529.4 (M+1) Molecular Formula: C23H23N6O7S.Na.
17

1H NMR (400 MHz, DMSO-d6): ? 10.43 (s, 1H), 10.13 (s, 1H), 7.95-7.92 (m, 2H), 7.47-7.45 (m, 2H), 5.56 (s, 2H), 3.97 (s, 1H), 3.84 (d, 1H, J = 7.2 Hz), 3.17-2.94 (m, 2H), 2.07-1.58 (m, 4H);
Mass as free acid: 438.3 (M-1); Molecular Formula: C15H16N7O7S.Na.
18


1H NMR (400 MHz, DMSO-d6): ? 10.10 (brs, 2H), 8.08 (s, 1H), 7.77 (d, 1H, J = 8.0 Hz ), 7.68 (d, 1H, J = 8.0 Hz ), 7.39 (t, 1H, J = 8.0 Hz ), 7.15 (t, 1H, J = 8.0 Hz ), 5.20 (s, 2H), 3.97 (brs, 1H), 3.82 (d, 1H, J = 7.2 Hz ), 3.15 (d, 1H, J = 11.6 Hz ), 2.95 (d, 1H, J = 11.6 Hz ), 2.08-1.98 (m, 1H), 1.90-1.56 (m, 3H);
Mass as free acid: 437.3 (M-1); Molecular Formula: C16H17N6O7S.Na.

BIOLOGICAL ACTIVITY DATA

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

Table 2. Antibacterial activity of representative compounds according to invention (expressed as MICs (mcg/ml).
Compounds Strains
K. pneumoniae
ATCC 700603 E. coli
NCTC 13352 E. coli
NCTC 13353 E. coli
M 50 E. coli
7 MP K. pneumoniae
H521 K. pneumoniae
H525
Example 1 >32 0.12 0.5 1 1 1 1
Example 2 >32 1 1 4 4 4 4
Example 3 >32 0.25 0.5 1 2 1 1
Example 4 >32 0.25 0.5 1 1 1 1
Example 5 >32 2 0.5 1 2 2 1
Example 6 >32 2 2 4 2 2 2
Example 7 >32 >32 >32 >32 >32 >32 >32
Example 8 >32 16 16 16 32 32 32
Example 9 >32 8 4 8 32 8 4
Example 10 >32 16 16 8 >32 32 32
Example 11 >32 2 4 8 8 8 8
Example 12 >32 4 2 4 8 4 4
Example 13 >32 0.25 0.25 0.5 0.5 1 1
Example 14 >32 1 1 2 2 2 2
Example 15 >32 16 4 8 32 16 16
Example 16 >32 8 8 8 >32 8 8
Example 17 >32 2 1 4 4 2 2
Cefepime 0.5 4 32 > 32 16 32 32
,CLAIMS:We Claim

1. A compound of Formula (I):

wherein:

A is 9 to 20 membered fused ring system optionally substituted with one or more substituents selected from C1-C6 alkyl optionally substituted with halogen, OR2, NR2R3, NO2, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; halogen; OR2; CN; COOR2; CONR2R3; SR2; NR2R3; NO2; aryl; heteroaryl; cycloalkyl or heterocycloalkyl;

wherein A is attached through nitrogen atom;

Y is H, C1-C6 alkyl, OR2 or NR2R3;

R2 and R3 are each independently selected from:

(a) hydrogen or
(b) C1-C6 alkyl optionally substituted with one or more substituents selected from halogen, NR4R5, CONR4R5, CN, OR4 or COOR4;

R4 and R5 are each independently selected from:

(a) hydrogen or
(b) C1-C6 alkyl optionally substituted with one or more substituents selected from OH, halogen, NH2, CONH2, CN, OCH3, or COOH;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

2. The compound as claimed in Claim 1, selected from:

(2S,5R)-N'-(1H-benzimidazol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(5-nitro-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-[(6-nitro-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(6-amino-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(5-amino-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[2-(aminomethyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[2-(3-amino propyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[2-(4-aminophenyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[2-(4-aminobenzyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[2-(piperazin-1-yl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)- 7-oxo-6-(sulfooxy)-N'-(4,5,6,7-tetrahydro-2H-benzotriazol-2-ylacetyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[2-(ethyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-(1H-indol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-(1H-benzotriazol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1] octane-2-carbohydrazide;
(2S,5R)- N'-{[2-(hydroxymethyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2R,5S)-N'-{[2-(phenyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-{[2-(benzyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-(2H-benzotriazol-2-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1] octane-2-carbohydrazide;
(2S,5R)-N'-(1H-indazol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
(2S,5R)-7-oxo-N'-(9H-purin-9-ylacetyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(6-carbamoyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(5-carbamoyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(6-cyano-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(5-cyano-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(6-ethoxycarbonyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(5-ethoxycarbonyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(6-hydroxymethyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(5-hydroxymethyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-(3H-imidazo[4,5-b]pyridin-3-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-(1H-imidazo[4,5-b]pyridin-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2,6-diamino-9H-purin-9-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2-amino-6-hydroxy-9H-purin-9-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2,6-diaminomethyl-9H-purin-9-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2-amino-6-ethoxycarbonyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
(2S,5R)-N'-[(2-amino-5-ethoxycarbonyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

3. The compound as claimed in Claim 1, selected from:

Sodium salt of (2S,5R)-N'-(1H-benzimidazol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(5-nitro-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1] octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6 -nitro-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6-amino-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(5-amino-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[2-(aminomethyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[2-(3-amino propyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[2-(4-aminophenyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[2-(4-aminobenzyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Trifluoroacetic acid salt of (2S,5R)-N'-{[2-( piperazin-1-yl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)- 7-oxo-6-(sulfooxy)-N'-(4,5,6,7-tetrahydro-2H-benzotriazol-2-ylacetyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[2-(ethyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-(1H-indol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-(1H-benzotriazol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)- N'-{[2-(hydroxymethyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2R,5S)-N'-{[2-(phenyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-{[2-(benzyl)-1H-benzimidazol-1-yl]acetyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-(2H-benzotriazol-2-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-(1H-indazol-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-7-oxo-N'-(9H-purin-9-ylacetyl)-6-(sulfooxy)-1,6-diazabicyclo [3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6-carbamoyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6- (sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(5-carbamoyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6- (sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6-cyano-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(5-cyano-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6-ethoxycarbonyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(5-ethoxycarbonyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(6-hydroxymethyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(5-hydroxymethyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-(3H-imidazo[4,5-b]pyridin-3-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-(1H-imidazo[4,5-b]pyridin-1-ylacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2,6-diamino-9H-purin-9-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2-amino-6-hydroxy-9H-purin-9-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2,6-diaminomethyl-9H-purin-9-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2-amino-6-ethoxycarbonyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;
Sodium salt of (2S,5R)-N'-[(2-amino-5-ethoxycarbonyl-1H-benzimidazol-1-yl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide;

or a stereoisomer thereof.

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

5. Use of a compound as claimed in any one of the Claims 1 to 3, in treating or preventing a bacterial infection.

6. Use of a pharmaceutical composition as claimed in Claim 4, in treating or preventing a bacterial infection.