WO2011031740A1 - Antibacterial fluoroquinolone analogs - Google Patents

Abstract

Compounds having antibacterial activity are disclosed. The compounds have one of the following structures (I) or (II): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein A, B, D, E, G, W, R₁, R₂, R₃, R₄, R₅, R₆ and R₇ are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

Description

ANTIBACTERIAL FLUOROQUINOLONE ANALOGS

STATEMENT OF GOVERNMENT INTEREST

This invention was made with government support under Contract No. HDTRA1-07-C-0005, awarded by the Defense Threat Reduction Agency, an agency of the United States Department of Defense. The government has certain rights in this invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) of U.S.

Provisional Patent Application No. 61/240,918 filed September 9, 2009. The foregoing application is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention is directed to novel fluoroquinolone compounds, and methods for their preparation and use as therapeutic or prophylactic agents. Description of the Related Art

Antibiotics are chemical substances produced by various species of microorganisms (bacteria, fungi, actinomycetes) that suppress the growth of other microorganisms and may eventually destroy them. However, common usage often extends the term antibiotics to include synthetic antibacterial agents, such as the sulfonamides, oxazolidinones, or quinolones, that are not products of microbes. The number of antibiotics that have been identified now extends into the hundreds, and many of these have been developed to the stage where they are of value in the therapy of infectious diseases. Antibiotics differ markedly in physical, chemical, and pharmacological properties, antibacterial spectra, and mechanisms of action. In recent years, knowledge of molecular mechanisms of bacterial, fungal, and viral replication has greatly facilitated rational development of compounds that can interfere with the life cycles of these microorganisms.

At least 30% of all hospitalized patients now receive one or more courses of therapy with antibiotics, and millions of potentially fatal infections have been cured. At the same time, these pharmaceutical agents have become among the most misused of those available to the practicing physician. One result of widespread use of antimicrobial agents has been the emergence of resistance, which in turn has increasingly rendered existing antibiotics inactive against multi-drug resistant pathogens and has created an ever-increasing need for new drugs.

The fluoroquinolone class of antibiotics are a powerful tool in combating bacterial infections. Fluoroquinolones have been used extensively to treat respiratory tract infections (including for example, bronchitis, pneumonia, tuberculosis), urinary tract infections, diarrhea, postoperative -wound infections, bone and joint infections, skin infections, inflammation of the prostate, ear infections, various sexually transmitted diseases, various infections that affect people with AIDS, and other conditions, in animals and humans. Fluoroquinolones are active against a wide spectrum of Gram-positive and Gram-negative bacteria. For example, various fluoroquinolones have been found to be effective against Staphylococcus aureus, Streptococcus pneumoniae, coagulase-negative staphylococci, Streptococcus pyogenes, Staphylococcus epidermis, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Pseudomonas aeruginosa, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter diversus, Citrobacter freundii, Haemophilus influenzae, and Neisseria gonorrhea, and other organisms. Indeed, the mounting resistance of Staphylococcus aureus to both penicillin and erythromycin has made the fluoroquinolone antibiotics a viable alternative for the treatment of skin diseases and pneumoniae.

Fluoroquinolones were first developed in the early 1960s. The first precursor of fluoroquinolones, nalidixic acid, was approved by the FDA in 1963 for the treatment of urinary tract infections. Nalidixic acid is rapidly absorbed after oral administration and is excreted into the urine in bactericidal concentrations. Nalidixic acid, however, has several limitations that has prevented its use in other types of infections. Specifically, nalidixic acid has a narrow spectrum of activity and microorganisms easily developed resistance to the drug. The development of other fluoroquinolones by chemically altering the basic structure of nalidixic acid, however, has led to improved fluoroquinolones that are more effective against resistant bacteria and effective against a broader range of bacteria.

Ciprofloxacin was approved by the FDA in 1986 for the oral treatment of bacterial infections and set a benchmark especially for Gram-negative organisms. More compounds from the fluoroquinolone class were approved in the following years: levofloxacin (1993, initially approved as the racemate ofloxacin in 1985), gatifloxacin (1999), moxifloxacin (1999), and gemifloxacin (2003), to just name a few. The latter compounds were greatly improved for their potency against Gram-positive organisms including S. aureus and S. pneumoniae such that they even cover multi-drug resistant organisms (gemifloxacin for S. pneumoniae). However, the level of resistance has constantly be on the rise especially in Gram-negative organisms and reached an extent that many clinical isolates can not be treated any longer with the currently approved fluoroquinolones. The two major reasons for this observation are mutations of the target proteins (mutations in the "quinolone-resistance determining region" or QRDR in the genes encoding gyrase and topoisomerase IV) and an increased level of efflux (more important in Gram-negative organisms). See, e.g., Bryskier, A., "Flurorquinolones" in Antimicrobial Agents: Antibacterials and Antifungals, Bryskier, A. ed., ASM Press, Washington, D.C., 2005, pp 668-788; Domagala, J.M. and Hagen, S.E., "Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not" in Quinolone Antimicrobial Agents, 3^rd ed., Hooper, D.C. and Rubinstein, E. eds., ASM Press, Washington, D.C., 2003, pp 3-18; Gootz, T.D. and Brighty, K.E., "Fluoroquinolone Antibacterials: SAR, Mechanism of Action, Resistance, and Clinical Aspects" Medicinal Research Reviews 16(5): 433-486 (1996); and Zhanel, G.G, et al., "A Critical Review of the Fluoroquinolones: Focus on Respiratory Tract Infections" Drugs 62(1): 13-59 (2002). Accordingly, while progress has been made in this field, there remains a need in the art for new chemical entities that possess antibacterial activity against fluoroquinolone-resistant clinical isolates. The present invention fulfills this need and provides further related advantages.

BRIEF SUMMARY OF THE INVENTION

In brief, the present invention is directed to novel fluoroquinolone compounds having antibacterial activity, including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and the use of such compounds in the treatment of bacterial infections .

In one embodiment, compounds having one of the following structures (I) or (II) are provided:

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof,

wherein:

A, B and D are as follows:

A is -C(R_8b)₂-, -C(=0)-, -C(R_8b)(OR_8a)-, -C(R_8b)(N(R_8a)₂)-, -C(=NOR_8a)-, -S(=O)- or -SO₂-;

B is -C(R_8b)₂-, -C(=0)-, -C(R_8b)(OR_8a)-, -C(R_8b)(N(R_8a)₂)-, -C(=NOR_8a)-, -O-, -S-, -S(=O)-, -SO₂- or -N(R _a)-; and

D is -C(R_8b)₂-, -C(=OK -O-, -S-, -S(=O)-, -SO₂-, -N(R_8a)-, -C(R_8b)(OR_8a)- or -C(R_8b)(N(R_8a)₂)-;

or B-D, taken together, are -C(R_8b)=C(R_8b)-, -N=C(R_8b)

HC CH E is -C(R_8c)₂- or -C(=0)-;

G is hydrogen or methyl;

W is -0-, -S-, -S(=0)-, -S0₂-, -N(R_8d)- or -C(R_8e)₂-;

Ri is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;

R₂ is hydrogen, methyl or amino;

R₃ is hydrogen, fluorine or chlorine;

each R4, R_5> Re, R₇ are, independently, hydrogen, halogen, amino, hydroxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted alkylamino or -N(R_8a)₂, or j and R₅, taken together, are =CHR_8b, =NOR_8a, = NR₈a or =0 or, together with the atom to which they are attached, form an optionally substituted carbocyclic or heterocyclic ring having from 3 to 6 ring atoms, or and R₇, taken together, are =CHR_8b, =NOR_8a, =N R_8a or =0, or, together with the atom to which they are attached, form an optionally substituted carbocyclic or heterocyclic ring having from 3 to 6 ring atoms, or R₅ and Re, R₅ and R₇, R4 and R^ R₄ and R₇, R4 and R_8d, R₅ and Rg_d, R4 and Rg_e or R₅ and Rg_e, taken together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms;

each R_8a is, independently, hydrogen, Cj-C₆ alkyl, C₃-C₆ cycloalkyl, Cj- C₆ cycloalkylalkyl or -C(=0)R_8c; each R_8b is, independently, hydrogen, halogen, Ci-C₆ alkyl, C₃-C₆ cycloalkyl, Ci-C haloalkyl or C C₆ cycloalkylalkyl;

each Rg_c is, independently, hydrogen or CrC₆ alkyl;

each Rg_d is, independently, hydrogen, Ci-C₆ alkyl optionally substituted with one or more of hydroxyl, -N(Rg_a)₂ and halogen, or C₃-C₆ cycloalkyl optionally substituted with one or more of hydroxyl, -N(R_8a)₂ and halogen, or R₄ and R₈d or R₅ and R_8d, taken together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms; and

each R_8e is, independently, hydrogen, hydroxyl, -N(R_8a)₂ or Q-Q alkyl optionally substituted with one or more of hydroxyl, -N(R_8a)₂ and halogen, or two R_8e groups, taken together with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms which is optionally substituted with one or more of hydroxyl, -N(R_8a)₂ and halogen, or R4 and R_8e or R₅ and R_8e, taken together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms.

In another embodiment, a pharmaceutical composition is provided comprising a compound having structure (I) or (II), or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

In another embodiment, a method of using a compound having structure

(I) or (II) in therapy is provided. In particular, the present invention provides a method of treating a bacterial infection in a mammal, comprising administering to the mammal an effective amount of a compound having structure (I) or (II), or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.

These and other aspects of the invention will be apparent upon reference to the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, one skilled in the art will understand that the invention may be practiced without these details.

Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, that is as "including, but not limited to".

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

"Amino" refers to the -NH₂ radical.

"Cyano" refers to the -CN radical.

"Hydroxy" or "hydroxyl" refers to the -OH radical.

"Imino" refers to the =NH substituent.

"Nitro" refers to the -N0₂ radical.

"Oxo" refers to the =0 substituent.

"Thioxo" refers to the =S substituent.

"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), having from one to twelve carbon atoms (C)-Ci₂ alkyl), preferably one to eight carbon atoms (Ci-C₈ alkyl) or one to six carbon atoms (Cj-C₆ alkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (wo-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (/-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl, prop-l-enyl, but-l-enyl, pent-l-enyl, penta-l,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted. "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, which is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), and having from one to twelve carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, «-butenylene, propynylene, «-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single or double bond and to the radical group through a single or double bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain may be optionally substituted.

"Alkoxy" refers to a radical of the formula -OR_a where R_a is an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted.

"Alkylamino" refers to a radical of the formula -NHR_a or -NR_aR_a where each R_a is, independently, an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted.

"Thioalkyl" refers to a radical of the formula -SR_a where R_a is an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group may be optionally substituted.

"Aryl" refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For purposes of this invention, the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, s-indacene, 5-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals that are optionally substituted.

"Aralkyl" refers to a radical of the formula -Rb-Rc where R_b is an alkylene chain as defined above and Rc is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group may be optionally substituted.

"Cycloalkyl" or "carbocyclic ring" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted.

"Cycloalkylalkyl" refers to a radical of the formula -RbRd where ¾ is an alkylene chain as defined above and R_g is a cycloalkyl radical as defined above. C C₆ cycloalkylalkyl refers to a radical wherein the alkylene chain has from one to six carbon atoms. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group may be optionally substituted.

"Fused" refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the invention. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.

"Halo" or "halogen" refers to bromo, chloro, fluoro or iodo. "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.

"Heterocyclyl" or "heterocyclic ring" refers to a stable 3- to 18-membered non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, Unless stated otherwise specifically in the specification, a heterocyclyl group may be optionally substituted.

"N-heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a N-heterocyclyl group may be optionally substituted.

"Heterocyclylalkyl" refers to a radical of the formula -RbRe where ¾ is an alkylene chain as defined above and Re is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group may be optionally substituted. "Heteroaryl" refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. For purposes of this invention, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[¾][l,4]dioxepinyl, 1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1- oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group may be optionally substituted.

"N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group may be optionally substituted.

"Heteroarylalkyl" refers to a radical of the formula -Rt,R_f where ¾ is an alkylene chain as defined above and R_f is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group may be optionally substituted.

The term "substituted" used herein means any of the above groups (i.e., alkyl, alkylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, CI, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are replaced with -NR_gR_h, -NR_gC(=0)R_h, -NR_gC(=0)NR_gR_h, -NR_gC(=0)OR_h, -NR_gS0₂R_h, -OC(=0)NR_gR_h, -OR_g, -SR_g, -SOR_g, -S0₂R_g, -OS0₂R_g, -S0₂OR_g, =NS0₂R_g, and -S0₂NR_gR_h. "Substituted also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=0)R_g, -C(=0)OR_g, -C(=0)NR_gR_h, -CH₂S0₂R_g, -CH₂S0₂NR_gR_h. In the foregoing, R_g and R_h are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl. "Substituted" further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl group. In addition, each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.

"Prodrug" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. Thus, the term "prodrug" refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention. Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et al., A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention. Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amide derivatives of amine functional groups in the compounds of the invention and the like.

The invention disclosed herein is also meant to encompass all pharmaceutically acceptable compounds of structures (I) and (II) being isotopically- labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ⁿC, ¹³C, ¹⁴C, ^,3N, ¹⁵N, ¹⁵0, ¹⁷0, ¹⁸0, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶C1, ¹²³I, and ¹²⁵I, respectively. These radiolabelled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action. Certain isotopically-labelled compounds of structures (I) and (II), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon- 14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ⁿC, ¹⁸F, ¹⁵0 and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of structures (I) and (II) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples set forth below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

The invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising administering a compound of this invention to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabelled compound of the invention in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.

"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

"Mammal" includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.

"Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

"Pharmaceutically acceptable carrier, diluent or excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

"Pharmaceutically acceptable salt" includes both acid and base addition salts.

"Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene- 1, 5 -disulfonic acid, naphthalene-2-sulfonic acid, 1 -hydroxy-2 -naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, j>-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

"Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. Often crystallizations produce a solvate of the compound of the invention. As used herein, the term "solvate" refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compound of the invention may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent.

A "pharmaceutical composition" refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.

"Effective amount" or "therapeutically effective amount" refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment, as defined below, of a bacterial infection in the mammal, preferably a human. The amount of a compound of the invention which constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.

"Treating" or "treatment" as used herein covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes:

(i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it;

(ii) inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or

(iv) relieving the symptoms resulting from the disease or condition, i.e., relieving pain without addressing the underlying disease or condition. As used herein, the terms "disease" and "condition" may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.

The compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (/?)- or (S)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (i?)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centres of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another. A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any said compounds.

"Bacterial infection" refers to the establishment of a sufficient population of a pathogenic bacteria in a patient to have a deleterious effect on the health and well-being of the patient and/or to give rise to discernable symptoms associated with the particular bacteria.

"Fluoroquinolone antibiotic resistant bacterium" or "fluoroquinolone- resistant bacterium" refers to bacterium against which at least one of the following known fluoroquinolone antibiotics, namely, ciprofloxacin, levofloxacin, moxifloxacin and gemifloxacin, has a minimum inhibitory concentration (MIC) greater than or equal to 4 μg/mL.

As noted above, in one embodiment of the present invention, compounds having antibacterial activity are provided, the compounds having one of the following structures (I) or (II):

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof,

wherein:

A, B and D are as follows:

A is -C(R_8b)₂-, -C(=0)-, -C(R_8b)(OR_8a)-, -C(R_8b)(N(R_8a)₂) -C(=NOR_8a)-, -S(=0)- or -S0₂-;

B is -C(R_8b)₂-, -C(=0)-, -C(R_8b)(OR_8a)-, -C(R_8b)(N(R_8a)₂) -C(=NOR_8a)-, -0-, -S-, -S(=0)-, -S0₂- or -N(R_8a)-; and D is -C(R_8b)₂-, -C(=0)-, -0-, -S-, -S(=0)-, -S0₂-, -N(R_8a)-, -C(R_8b)(OR_8a)- or -C(R_8b)(N(R_8a)₂)-;

or A-B, taken together, are -C(R_8b)=C(R_8b)-, -C(R_8b)=N- or

or B-D, taken together, are -C(R_8b)=C(R_8b)-, -N=C(R_8b> or

HC CH

E is -C(R_8c)₂- or -C(=0)-;

G is hydrogen or methyl;

W is -0-, -S-, -S(=0)-, -S0₂-, -N(R_8d)- or -C(R_8e)₂-;

Ri is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;

R₂ is hydrogen, methyl or amino;

R₃ is hydrogen, fluorine or chlorine;

each R^, R_5, R^, R₇ are, independently, hydrogen, halogen, amino, hydroxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted alkylamino or -N(R_8a)₂, or R4 and R₅, taken together, are =CHR_8b, =NOR_8a, = R_8a or =0 or, together with the atom to which they are attached, form an optionally substituted carbocyclic or heterocyclic ring having from 3 to 6 ring atoms, or R$ and R₇, taken together, are =CHR_8b, =NOR_8a, =NNR_8a or =0, or, together with the atom to which they are attached, form an optionally substituted carbocyclic or heterocyclic ring having from 3 to 6 ring atoms, or R₅ and Re, R₅ and R₇, R4 and R^ R4 and R₇, R₄ and R₈₍₁, R₅ and Rgd, R4 and R_8e or R₅ and R_8e, taken together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms; each Rg_a is, independently, hydrogen, Cj-C₆ alkyl, C₃-C₆ cycloalkyl, Cj- C₆ cycloalkylalkyl or -C(=0)R_8c;

each Rg_b is, independently, hydrogen, halogen, Ci-C₆ alkyl, C₃-C₆ cycloalkyl, C_!-C₆ haloalkyl or Q-Q cycloalkylalkyl;

each R_8c is, independently, hydrogen or Cj-C₆ alkyl;

each R_8d is, independently, hydrogen, Cj-C₆ alkyl optionally substituted with one or more of hydroxyl, -N(R_8a)2 and halogen, or C₃-C₆ cycloalkyl optionally substituted with one or more of hydroxyl, -N(R_8a)2 and halogen, or R4 and R₈d or R₅ and R_8d, taken together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms; and

each R_8e is, independently, hydrogen, hydroxyl, -N(R_8a)₂ or Q-Q alkyl optionally substituted with one or more of hydroxyl, -N(Rg_a)₂ and halogen, or two R_8e groups, taken together with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms which is optionally substituted with one or more of hydroxyl, -N(Rg_a)₂ and halogen, or R4 and R_8e or R5 and R_8e, taken together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms.

In certain embodiments, A-B-D, taken together, are -CH₂CH₂CH2-, -CH(CH₃)CH₂CH₂-, -C(CH₃)₂CH₂CH₂-, -CH₂CH=CH-, -CH=CHCH₂-, -CH(OR_8a)CH₂CH₂-, -C(CH₃)(OR_8a)CH₂CH₂-, -CH(N(R_8a)₂)CH₂CH₂-,

-C(CH₃)(N(R_8a)₂)CH₂CH₂-, -C(=NOR_8a)CH₂CH₂-, -C(=0)N(R_8a)CH₂-,

-CH₂CH(OR_8a)CH₂-, -CH₂C(CH₃)(OR_8a)CH₂-, -CH₂CH(N(R_8a)₂)CH₂-,

-CH₂C(=NOR_8a)CH₂-, -CH₂C(=0)CH₂-, -CH₂C(CH₃)₂CH₂-, -CH₂OCH₂-, -CH₂SCH₂-, -CH₂S(=0)CH₂-, -CH₂S0₂CH₂-, -CH₂N(R_8a)CH₂-, -CH₂CH₂CH(CH₃)-, -CH₂CH₂C(CH₃)₂-, -CH₂C(=0)N(R_8a)-, -CH₂N(R_8a)C(=0)-, -CH₂S0₂N(R_8a)-, -CH₂N(R_8a)S0₂-, -CH₂CH₂0-, -CH₂CH₂N(R_8a)-, -CH₂CH₂S-, -CH₂CH₂S(=0)- or -CH₂C¾S0₂-.

In certain embodiments, A-B-D, taken together, are -C(R_8b)₂C(R_8b)₂C(R_8b)₂-, -C(R_8b)₂C(R_8b)=C(R_8b)- or -C(R_8b)=C(R_8b)C(R_8b)₂-. In such embodiments, each R₈ may be hydrogen. In certain embodiments, A is -CH₂-. In such embodiments, B-D, taken together, may be -C(R_8b)₂0-, -OC(R_8b)₂-, -C(R_8b)₂S-, -SC(R_8b)₂-, -C(R_8b)₂N(R_8a)-, -N(R_8a)C(R_8b)₂-, -C(R_8b)₂C(R_8b)₂-, -C(R_8b)=C(R_8b)- or -N=C(R_8b)-. In addition, R_8a and R_8b may be hydrogen, Ci-C₆ alkyl or C_!-C₆ cycloalkyl.

In certain embodiments, B is -CH₂-. In such embodiments, A may be

-C(R_8b)₂- and D may be -C(R_8b)₂- or -0-. In addition, R_8b may be hydrogen, Q-C₆ alkyl or Q-Q cycloalkyl.

In certain embodiments, B is -0-. In such embodiments, A may be -C(R_8b)₂- and D may be -C(R_8b)₂-. In addition, R_8b may be hydrogen, Cj-C₆ alkyl or C_\- C₆ cycloalkyl.

In certain embodiments, B is -S-. In such embodiments, A may be -C(R_8b)₂- and D may be -C(R_8b)₂-. In addition, R_8b may be hydrogen, C_\-C alkyl or Ci- Ce cycloalkyl.

In certain embodiments, D is -CH₂-. In such embodiments, A-B, taken

-CH₂S-, -CH₂S(=0)-, -CH₂S0₂-, -CH₂N(R_8a)-, -N(R_8a)CH₂-, -CH(OR_8a)CH₂-, -CH(N(R_8a)₂)CH₂-, -CH₂CH(N(R_8a)₂)-, -C(=0)N(R_8a)-, -CH₂C(=0)-, -CH₂CH(OR_8b)- or -C(R_8b)=N-. In addition, R_8a and R_8b may be hydrogen, C C₆ alkyl or Cj-C₆ cycloalkyl.

In certain embodiments, D is -0-. In such embodiments, A-B, taken

together, may be -CH₂CH₂-, -CH=CH-, -CH(OR_8a)CH₂-, , -CH(N(R_8a)₂)CH₂-, -C(CH₃)₂CH₂-, -CH₂C(CH₃)₂-, -CH₂CH(R_8b)- or -CH(R_8b)CH₂-. In addition, R_8aand R_8b may be hydrogen, Ci-C₆ alkyl or C C₆ cycloalkyl.

In certain embodiments, D is -N(R_8a)-. In such embodiments, R_8a may be hydrogen or methyl. In addition, A-B, taken together, may be -CH₂CH(R_8b)-, -CH(R_8b)CH₂-, -C(CH₃)₂CH₂-, -CH₂C(CH₃)₂-, -CH(OR_8a)CH₂-, -CH(N(R_8a)₂)CH₂-, -CH₂C(=0)- or -CH₂S0₂-. In addition, R_8a and R_8b may be hydrogen, Cj-C₆ alkyl or Ci-C₆ cycloalkyl.

In certain embodiments, B-D, taken together, are -C(R b)=C(R₈b)-. In such embodiments, A may be -C(Rg_b)₂-. In addition, R₈ may be hydrogen, Ci-C₆ alkyl or Ci-C6 cycloalkyl.

In certain embodiments of structure (I), W is -0-, -S-, -S(=0)- or -S0₂-.

In certain embodiments of structure (I), W is -C(R_8e)₂- and the compound has the following structure (I- A):

In such embodiments, each R_8e may be hydrogen.

In certain embodiments of structure (I), W is -N(R_8d)- and the compound has the following structure (I-B):

(I-B)

In such embodiments, R_8d may be hydrogen.

In certain embodiments, one of each ^ and R₅, taken together, and the compound has one of the following structures (I-B-1) or (I-B-2):

(I-B-l) (I-B-2)

In certain embodiments, R4, R₅, Re and R₇ are, independently, hydrogen, amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylamino or -N(R_8a)₂. In further embodiments, R4, R , Re and R₇ may each be hydrogen. In other further embodiments, R4, R₅ and ¾ may each be hydrogen, one R₇ may be hydrogen, and one R₇ may be amino, substituted alkyl, substituted cycloalkyl, alkylamino, or -N(R_8a)₂, wherein substituted alkyl is -(C!-C₆ alkyl)N(R_8a)₂ and substituted cycloalkyl is -(C₃-C₆ cycloalkyl)N(R_8a)₂. In such embodiments, each R_8a may be hydrogen and one R₇ may be -NH₂, -CH₂NH₂, -CH(CH₃)NH₂, -C(CH₃)₂NH₂, or 1-amino-cycloprop-l-yl. In other further embodiments, R4, Re and R₇ may each be hydrogen, one R₅ may be hydrogen and one R5 may be amino, substituted alkyl, substituted cycloalkyl, alkylamino, or -N(R_8a)₂, wherein substituted alkyl is -(Cj- C₆ alkyl)N(R_8a)₂ and substituted cycloalkyl is -(C₃-C₆ cycloalkyl)N(R_8a)2. In such embodiments, each R_8a may be hydrogen and one R₅ may be -NH_2j -C¾NH₂, -CH(CH₃)NH₂, -C(CH₃)₂NH₂, or 1-amino-cycloprop-l-yl.

In certain embodiments, one of each R4 and R₅, taken together, are

=N(OR_ga) or =0.

In certain embodiments, one of each R6 and R₇, taken together, are =N(OR_8a) or =0.

In certain embodiments, one of each R₄ and R₅, taken together with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms. In certain embodiments, one of each ¾ and R₇, taken together with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms.

In certain embodiments, R_\ is optionally substituted alkyl. For example, Ri may be Cj-C₆ alkyl.

In certain embodiments, R] is optionally substituted cycloalkyl. For example, Rj may be cyclopropyl.

In certain embodiments, R₂ is hydrogen.

In certain embodiments, R₃ is fluorine.

In certain embodiments, R₃ is hydrogen.

In certain embodiments, E is -CH₂-.

In certain embodiments, E is -C(=0)-.

In certain embodiments, E is -CH(CH₃)- or -C(CH₃)₂-.

In certain embodiments, G is hydrogen.

It is understood that any embodiment of the compounds of structures (I) and (II), as set forth above, and any specific substituent set forth herein for a A, B, D, E, G, W, R], R₂, R₃, R₄, R₅, R and R₇ group in the compounds of structures (I) and (II), as set forth above, may be independently combined with other embodiments and/or substituents of compounds of structures (I) and (II) to form embodiments of the inventions not specifically set forth above. In addition, in the event that a list of substitutents is listed for any particular A, B, D, E, G, W, Ri, R₂, R₃, R4, R₅, Re and R₇ group in a particular embodiment and/or claim, it is understood that each individual substituent may be deleted from the particular embodment and/or claim and that the remaining list of substituents will be considered to be within the scope of the invention.

It is further understood that in the present description, any specific combination set forth herein for the A, B and D groups in the compounds of structures (I) and (II) is specific with respect to the position of such groups. For example, it is understood that the terminology "A-B-D, taken together, are -CH₂N(R_8a)S0₂-" indicates that A is -CH₂-, B is -N(R_8a)- and D is -S0₂-. It is further understood that in the present description, combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions result in stable compounds. For example, in the above embodiments of the compounds of structures (I) and (II), it is understood that:

(i) A and B are not both -S(=0)-, -S0₂- or -C(=0 ;

(ii) B and D are not both -0-, -S-, -S(=0)-, -S0₂- or -C(=0)-;

(iii) B and D are not both -0-, -S-, -S(=0)- or -NR_8a-;

(iv) A and D are not both -S(=0)-, -S0₂- or -C(=0)-;

(v) if B is -C(R_8a)₂, then A and D are not both -0-, -S-, -S(=0 or -NR_8a-;

(vi) if B is -CR_8bOR_8a- or -CR_8bN(R_8a)₂-, then D is not -NR_8i -S-;

(vii) if B is -NR_8a-, then A is not -S(=0)- or -S0₂- and D is not -0-, -S-, -S(=0)- or -NR_8a-;

(viii) if A is -CRgbORga- or -CR₈bN(R_8a)₂-, then B is not -NR_8a-, -O- or

-S-; and

(ix) if D is -CR_8bOR_8a- or -CR_8bN(R_8a)₂-, then B is not -NR_8a-, -O- or

-S-.

For the purposes of administration, the compounds of the present invention may be administered as a raw chemical or may be formulated as pharmaceutical compositions. Pharmaceutical compositions of the present invention comprise a compound of structure (I) or (II) and a pharmaceutically acceptable carrier, diluent or excipient. The compound of structure (I) or (II) is present in the composition in an amount which is effective to treat a particular disease or condition of interest - that is, in an amount sufficient to treat a bacterial infection, and preferably with acceptable toxicity to the patient. The antibacterial activity of compounds of structure (I) and (II) can be determined by one skilled in the art, for example, as described in the Examples below. Appropriate concentrations and dosages can be readily determined by one skilled in the art. The compounds of the present invention possess antibacterial activity against a wide spectrum of gram positive and gram negative bacteria, as well as enterobacteria and anaerobes. Representative susceptible organisms generally include those Gram-positive and Gram-negative, aerobic and anaerobic organisms whose growth can be inhibited by the compounds of the invention, such as species of Staphylococcus, Enterococcus, Streptococcus, Sarcina, Escherichia, Enter obacter, Klebsiella, Pseudomonas, Burkholderia, Acinetobacter, Aeromonas, Proteus, Campylobacter, Pasteurella, Citrobacter, Legionella, Neisseria, Bordetella, Baccillus, Bacteroides, Moraxella, Morganella, Edwardsiella, Peptococcus, Clostridium, Providencia, Salmonella, Stenotrophomonas, Shigella, Serratia, Haemophilus, Vibrio and Yersinia, and other similar organisms, as well as Mycobacterium organisms, such as Mycobacterium tuberculosis, Mycobacterium avium, and the like.

For example, in certain embodiments, the compounds possess antibacterial activity against the following bacteria: Enterococcus faecium, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus (Group C/F), Streptococcus (Group G), Viridans group streptococci, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter Iwoffii, Aeromonas hydrophila, Bordetella pertussis, Burkholderia cepacia, Campylobacter jejuni, Citrobacter diversus, Citrobacter freundii, Enterobaeter aerogenes, Enterobacter agglomerans, Enterobacter sakazaki, Edwardsiella tarda, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa, Pseudomonas fluorescens, Salmonella enteritidis, Salmonella typhi, Serratia liquefaciens, Serratia marcescens, Shigella boydii, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Stenotrophomonas maltophilia, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, Yersinia enterocolitica, Clostridium difficile and Clostridium perfringens. In addition, in certain embodiments, the compounds of the present invention have MIC < 2 μ^ηιΐ, for each of (i) one or more Gram-negative bacteria selected from the group consisting of Acinetobacter anitratus, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter Iwoffii, Aeromonas hydrophila, Bordetella pertussis, Burkholderia cepacia, Campylobacter jejuni, Citrobacter diversus, Citrobacter freundii, Enterobaeter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Enterobacter sakazaki, Escherichia coli, Edwardsiella tarda, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Pasteur ella multocida, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa, Pseudomonas fluorescens, Salmonella enteritidis, Salmonella typhi, Serratia liquefaciens, Serratia marcescens, Shigella boydii, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Stenotrophomonas maltophilia, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus and Yersinia enterocolitica; and (ii) one or more Gram-positive bacteria selected from the group consisting of Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus (Group C/F), Streptococcus (Group G), Streptococcus pneumoniae, Streptococcus pyogenes, Viridans group streptococci, Clostridium difficile and Clostridium perfringens. In particular, in certain embodiments, the compounds of the present invention have MIC < 2 μg/mL for each of (i) one or more Gram-negative bacteria selected from the group consisting of Acinetobacter baumannii, Acinetobacter calcoaceticus, Burkholderia cepacia, Citrobacter freundii, Enterobaeter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Pseudomonas aeruginosa, Salmonella enteritidis, Serratia liquefaciens, Serratia marcescens, Shigella dysenteriae, Shigella flexneri and Yersinia enterocolitica, and (ii) one or more Gram-positive bacteria selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus pneumoniae.

In addition, it has been discovered that, in certain embodiments, the compounds of the present invention possess antibacterial activity against bacterial species resistant to conventional fluoroquinolone antibiotics, such as fluoroquinolone resistant Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Enterobaeter aerogenes, Enterobacter cloacae, Providencia stuartii or Serratia marcescens bacterium. In particular, fluoroquinolone resistant Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus or Streptococcus pneumoniae bacterium.

Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration of agents for serving similar utilities. The pharmaceutical compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the teachings of this invention.

A pharmaceutical composition of the invention may be in the form of a solid or liquid. In one aspect, the carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form. The carrier(s) may be liquid, with the compositions being, for example, an oral syrup, injectable liquid or an aerosol, which is useful in, for example, inhalatory administration.

When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.

As a solid composition for oral administration, the pharmaceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer. In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for either parenteral or oral administration should contain an amount of a compound of the invention such that a suitable dosage will be obtained.

The pharmaceutical composition of the invention may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device.

The pharmaceutical composition of the invention may be intended for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition of the invention may include various materials, which modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active ingredients. The materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule.

The pharmaceutical composition of the invention in solid or liquid form may include an agent that binds to the compound of the invention and thereby assists in the delivery of the compound. Suitable agents that may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.

The pharmaceutical composition of the invention may consist of dosage units that can be administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One skilled in the art, without undue experimentation may determine preferred aerosols.

The pharmaceutical compositions of the invention may be prepared by methodology well known in the pharmaceutical art. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system. The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy.

Compounds of the invention, or pharmaceutically acceptable derivatives thereof, may also be administered simultaneously with, prior to, or after administration of one or more other therapeutic agents. Such combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of the invention and one or more additional active agents, as well as administration of the compound of the invention and each active agent in its own separate pharmaceutical dosage formulation. For example, a compound of the invention and the other active agent can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral dosage formulations. Where separate dosage formulations are used, the compounds of the invention and one or more additional active agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens.

The following Examples illustrate various methods of making compounds of this invention, i.e., compound of structure (I) and (II):

(II) wherein A, B, D, E, G, W, Rj, R₂, R₃, R4, R₅, R6 and R₇ are as defined above. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below, other compounds of structure (I) and (II) not specifically illustrated below by using the appropriate starting components and modifying the parameters of the synthesis as needed, for example, using starting components and parameters as set forth in co-pending International PCT Patent Application No. US2009/33946 entitled "Antibacterial Fluoroquinolone Analogs" filed February 12, 2009, which application is incorporated herein by reference in its entirety. In general, starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described in this invention.

It will be appreciated by those skilled in the art that in the methods described herein the functional groups of intermediate compounds may need to be protected by suitable "protecting groups". Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include, for example, trialkylsilyl or diarylalkylsilyl (for example, triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS) or trimethylsilyl (TMS)), fert-butoxycarbonyl (Boc), allyloxycarbonyl (Alloc), carboxybenzyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), trichloroethoxycarbonyl (Troc), trityl (Trt), benzyl, methoxybenzyl, dimethoxybenzyl, chlorobenzyl, dichlorobenzyl, trifluoroacetic acid amide (TFA), phenacyl amide and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(0)-R" (where R" is alkyl, aryl or arylalkyl), -methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the art would appreciate, the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although such protected derivatives of compounds of this invention may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs", as defined herein.

Furthermore, all compounds of the invention which exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid by methods known to one skilled in the art. Salts of the compounds of the invention can be converted to their free base or acid form by standard techniques.

The following examples are provided for purposes of illustration, not limitation.

EXAMPLES

Example 1

6

7

1 -Benzyl-4-tert-butyl-2-( 2-( 1 -cyclopropyl-3 -(^"ethoxycarbonyl)-6,7-difluoro-4-oxo- 1 ,4- dihvdroquinolin-8-yloxy)ethyl)piperazine-l ,4-dicarboxylate (3)

Ethyl- 1 -cyclopropyl-6,7-difluoro-8-hydroxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxylate (1) (309 mg, 1 mmol) and 1 -benzyl-4-/er/-butyl-2-(2- hydroxyethyl)piperazine-l,4-dicarboxylate (2) (364 mg, 1 mmol) were combined in THF (5 mL) with stirring at RT. 4-(diphenylphosphino)pyridine (263 mg, 1 mmol) was added and followed by 4 equal portions of diisopropyl azodicarboxylate (193 μί, 1.0 mmol) added in THF (4 mL) delivered over 20 minutes. After 4 hours stirring at room temperature, an additional portion of THF (10 mL) was added to the reaction which was then stirred overnight. Solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with 0.1 M potassium hydrogen sulfate, saturated sodium chloride, dried over sodium sulfate (anh.), filtered and evaporated. The residue was taken up in dichloromethane and subjected to preparative TLC eluting with 5% methanol/DCM. After collecting the correct band, the desired product (3) was obtained (703 mg). m/z 657 (MH⁺), along with some 338 (MH⁺) and 400 (MH⁺) material.

Ethyl-8-(2-(^'4-(tert-butoxycarbonvnpiperazin-2-vnethoxy)-l-cvclopropyl-6J-difluoro-

4-oxo-l ,4-dihvdroquinoline-3-carboxylate (4)

Compound (3) (703 mg) was dissolved in methanol (30 mL), the flask evacuated and backfilled with nitrogen several times. 5% Pd on carbon (70 mg) was added and reaction was subjected to hydrogenation under balloon pressure. After 3 hours, the reaction was complete judging by LC/MS analysis. The reaction was filtered over celite to remove catalyst and the solvent was evaporated under reduced pressure.

The residue was dissolved in minimum dichloromethane and subjected to preparative TLC eluting with 5% methanol/DCM. Product 4 eluted with Rf ~ 0.2. The obtained product (4) (18 mg) was used direct in the next reaction. LC/MS 522.1 (MH⁺).

Preparation of Compound (5)

Ethyl-8-(2-(4-(tert-butoxycarbonyl)piperazin-2-yl)ethoxy)- 1 - cyclopropyl-6,7-difluoro-4-oxo-l,4-dihydroquinoline-3-carboxylate (4) (18 mg, 34 mmol) was dissolved in acetonitrile N-methylpyrrolidine (800 μϊ,, 10:1 v:v) and triethylamine (4.8 μί) was added to the mixture. The mixture was heated to 92 °C with stirring for 4 hours at which time LC/MS analysis showed 5% conversion. The acetonitrile was removed under vacuum and replaced with N-methylpyrrolidine (400 μΙ_) and additional triethylamine (20 μΐ and heated to 120 °C. After 12 hrs, LC/MS analysis of the reaction showed >95% conversion to product. The reaction was diluted with ethyl acetate (10 mL), washed with saturated sodium bicarbonate (5 x 2 mL), saturated sodium chloride, dried over sodium sulfate (anh.), filtered and evaporated. The residue was dissolved in minimum dichloromethane and purified by preparative TLC eluting with 5% MeOH/DCM. Product eluted with Rf 0.22 on analytical TLC as blue fluorescent band under UV light. After isolating the correct band, the product (5) was obtained (20 mg). LC/MS analysis showed pure product with 502.1 (MH⁺).

Preparation of Compound (7)

Compound (5) from the previous procedure (20 mg, 40 mmol) was treated with 50% TFA/DCM (0.5 mL) at room temperature under nitrogen atmosphere. After 15 min, LC/MS showed complete deprotection. After the TFA and DCM were evaporated under vacuum, the residue was taken up in diethyl ether and evaporated. The process of diethyl ether dissolution and evaporation was repeated twice more. Residue containing compound 6 was dissolved in THF/MeOH (600 ί; 2:1 v:v) and treated with LiOH (2 M aq; 160 μί) with stirring at 50 °C. After 30 min., the solvent was removed under vacuum and the residue was taken up in ethanol: water (2 mL, 1:1 v:v). The pH of the mixture was carefully adjusted to 3 with 1M HC1. The mixture was then extracted with ethyl acetate (6 x 2 mL) until no more product was detected by TLC. The combined organic layers were dried over sodium sulfate (anh.), evaporated, and placed on high vacuum to remove last traces of solvent. The residue was triturated with ethyl acetate:diethyl ether (3x2 mL, 1:6 v:v) to give product (7) (1.3 mg) as a tan solid. LC/MS 374.1 (MH⁺).

Example 2

6 Benzyl-3-(2-(l-cvclopropyl-3-(ethoxycarbonylV6J-difluoro-4-oxo-l,4- dihvdroquinolin-8-yloxy ethyl morpholine-4-carboxylate (3)

Ethyl-1 -cyclopropyl-6,7-difluoro-8-hydroxy-4-oxo-l ,4- dihydroquinoline-3-carboxylate (1) (1 mmol) and benzyl 3-(2- hydroxyethyl)morpholine-4-carboxylate (2) (1 mmol) were combined in THF (5 mL) with stirring at RT. 4-(diphenylphosphino)pyridine (263 mg, 1 mmol) was added and followed by 4 equal portions of diisopropyl azodicarboxylate (193 \L, 1.0 mmol) added in THF (4 mL) delivered over 20 minutes. After 4 hours stirring at room temperature, an additional portion of THF (10 mL) was added to the reaction which was then stirred overnight. Solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with 0.1 M potassium hydrogen sulfate, saturated sodium chloride, dried over sodium sulfate (anh.), filtered and evaporated. The residue was taken up in dichloromethane and subjected to preparative TLC eluting with 5% methanol/DCM. After collecting the correct band, the desired product (3) was obtained. Ethyl-l-cvclopropyl-6,7-difluoro-8-(2-(morpholin-3-yl)ethoxy)-4-oxo-l,4- dihydroquinoline-3-carboxylate (4)

Compound (3) (700 mg) was dissolved in methanol (30 mL), the flask evacuated and backfilled with nitrogen several times. 5% Pd on carbon (70 mg) was added and reaction was subjected to hydrogenation under balloon pressure. After 3 hours, the reaction was complete judging by LC/MS analysis. The reaction was filtered over celite to remove catalyst and the solvent was evaporated under reduced pressure. The residue was dissolved in minimum dichloromethane and subjected to preparative TLC eluting with 5% methanol/DCM. Product (4) eluted with Rf ~ 0.2. The obtained product was used directly in the next reaction.

Preparation of Compound (5)

Ethyl-l-cyclopropyl-6,7-difluoro-8-(2-(morpholin-3-yl)ethoxy)-4-oxo- l,4-dihydroquinoline-3-carboxylate (4) (34 mmol) was dissolved in N- methylpyrrolidine (1200 μΐ,) and triethylamine (25 μϋ) was added to the mixture. The mixture was heated to 120 °C with stirring. After 12 hrs, LC/MS analysis of the reaction showed >95% conversion to product. The reaction was diluted with ethyl acetate (10 mL), washed with saturated sodium bicarbonate (5 x 2 mL), saturated sodium chloride, dried over sodium sulfate (anh.), filtered and evaporated. The residue was dissolved in minimum dichloromethane and purified by preparative TLC eluting with 5% MeOH/DCM. After isolating the correct band, the product (5) was obtained.

Preparation of Compound (6)

Compound (5) from the previous procedure (40 mmol) was dissolved in THF/MeOH (600 μί; 2:1 v:v) and treated with LiOH (2 M aq; 160 μΐ) with stirring at 50 °C. After 30 min. LC/MS analysis of the reaction showed >95% conversion to product, the solvent was removed under vacuum and the residue was taken up in ethanohwater (2 mL, 1 :1 v:v). The pH of the mixture was carefully adjusted to 3 with 1M HCl. The mixture was then extracted with ethyl acetate (6 2 mL) until no more product was detected by TLC. The combined organic layers were dried over sodium sulfate (anh.), evaporated, and placed on high vacuum to remove last traces of solvent. The residue was triturated with ethyl acetate: diethyl ether (3x2 mL, 1 :6 v:v) to give product (6) as a tan solid.

6

(i?Vl-benzyl-4-tgrt-butyl-2-(3-(l-cvclopropyl-3-(ethoxycarbonyl)-6J-difluoro-4-oxo- 1.4-dihvdroquinolin-8-yl)prop-2-vnyl)piperazine- 1 ,4-dicarboxylate (3)

(R)- 1 -benzyl-4-ter/-butyl-2-(prop-2-ynyl)piperazine- 1 ,4-dicarboxylate

(1) (1.026 mmol) and ethyl- l-cyclopropyl-6,7-difluoro-4-oxo-8- (trifluoromethylsulfonyloxy)-l,4-dihydroquinoline-3-carboxylate (2) (1.026 mmol) were combined in a 40 mL scintillation vial and then placed under nitrogen via partial vacuum evacuation and backfill with nitrogen. Then, triphenylphosphine (67 mg, 0.25 mmol) and tetrahydrofuran (10 mL) were added and the reaction was sparged with nitrogen for 3-4 minutes. Then, N,N-diisopropylethylamine (0.357 mL, 2.05 mmol) and tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.10 mmol) were added with continued sparging (~3 min) and then finally copper(I) iodide (39 mg, 0.20 mmol) was added and the resultant clear, yellow-colored reaction mixture was heated at 60 °C for 8-9 hr and then checked by HPLC/LCMS and TLC. Analysis after this period of time shows complete consumption of the starting triflate and formation of the desired coupled product, based on MS. The crude reaction was diluted with ethanol (-10 mL) and then stirred for 5 minutes before filtering through a short plug of Celite 545 to remove the precipitated salts. The filtrate was concentrated in vacuo and then subjected to regular phase silica gel chromatography on a 40 g silica gel cartridge, eluting with 0 to 30% ethyl acetate in DCM to afford the purified product (3).

(i?,Z)-Ethyl-8-(3-(4-(tert-butoxycarbonyl)piperazin-2-yl prop-l-enyl -l-cvclopropyl- 6 J-difluoro-4-oxo-L4-dihvdroquinoline-3-carboxylate (4)

(i?)-l-Benzyi-4-/ert-butyl-2-(3-(l-cyclopropyl-3-(ethoxycarbonyl)-6,7- difluoro-4-oxo- 1 ,4-dihydroquinolin-8-yl)prop-2-ynyl)piperazine- 1 ,4-dicarboxylate (3) (0.7959 mmol) was dissolved in ethanol (30 mL) and then the reaction was partially evacuated with vacuum and then back filled with nitrogen x3 before adding palladium on barium sulfate, reduced (0.36 g). The reaction was then partially evacuated and back filled with hydrogen x3, sparged with 3-1L balloons filled with hydrogen, and then maintained under an atmosphere of hydrogen with a hydrogen filled balloon and checked after 30-45 minutes for completion. The reaction was checked at this time, showing no progress. More hydrogen was added (by sparging) and continued under an atmosphere of hydrogen for several hours with no change. The reaction mixture was filtered through a short plug of Celite 545 and then rinsed with 20 mL of ethanol. The filtrate (in a 100 mL flask) was sparged with nitrogen for 3 minutes and then placed under an atmophere of nitrogen and 10% palladium on carbon (85 mg) was added. The reaction vessel was then partially evacuated and back-filled with hydrogen (x3) and then kept under an atmosphere of hydrogen with a balloon. The reaction was checked after 2-3 hrs and found to be complete, with no apparent over-reduction. The reaction was filtered through a short plug of Celite 545 and then the filtrate was concentrated in vacuo. Silica gel chromatography using 0 to 35% ethyl acetate in CH₂C1₂ afforded purified product (4).

Compound (5)

(i?,Z)-Ethyl-8-(3-(4-(tert-butoxycarbonyl)piperazin-2-yl)prop- 1 -enyl)- 1 - cyclopropyl-6,7-difluoro-4-oxo-l,4-dihydroquinoline-3-carboxylate (4) (0.730 mmol) was transferred to a 40-mL scintillation vial and then placed under an atmosphere of nitrogen before dissolving in acetonitrile (20 mL) and adding N,N- diisopropylethylamine (0.32 mL, 1.8 mmol). The resulting solution was sparged with nitrogen for 2 minutes and then capped and heated at 55 °C overnight (-10 hr) with stirring. After this period of time, the reaction was checked by HPLC for completion. HPLC shows complete consumption of the starting material. The reaction mixture was concentrated in vacuo and then subjected to silica gel chromatography (40 g silica gel column), eluting with 0, 2.5, 5, 7.5 and 10% methanol in chloroform (-300 mL each). The fractions containing product were combined to afford the cyclized product. The crude cylized product was put in a 40-mL scintillation vial, at room temperature and under an atmosphere of nitrogen, was dissolved in methylene chloride (25 mL) and trifluoroacetic acid (1.12 mL, 14.6 mmol) was added in one portion. The reaction was stirred overnight (-10 hr) at ambient temperature and then checked by HPLC. After this period of time, the reaction was determined to be complete based on HPLC and the solvent was removed with a stream of nitrogen. Then, the resulting film was taken up in 2% MeOH/CHCl₃ and washed once with 10% aqueous ammonium hydroxide solution (-20 mL) and then once with brine (-20 mL), dried over MgS0₄, filtered and concentrated in vacuo to afford the cyclized product (5). Compound (6)

Compound (5) (0.0604 mmol) was dissolved in tetrahydrofuran (5 mL) and then potassium trimethylsilanolate (10.3 mg, 0.0725 mmol) was added. The reaction was stirred for 30 minutes and then checked by TLC (20% methanol/CHCl₃) and a small amount of product (6) is formed. The reaction was stirred an additional two hours before checking again. After this period of time, the reaction has progress a small amount. Thus, an additional lot of potassium trimethylsilanolate (8.1 mg, 0.063 mmol) in acetonitrile (1 mL) was added with continued stirring for 2 hr before checking again. After this period of time, the reaction was complete. Acetic acid was added dropwise to reach pH was 6-7 and then the reaction was concentrated in vacuo and subjected to prep HPLC for purification using the conditions described above to afford the final product (6).

Example 4

(i?)-Ethyl-8-(4-(benzyloxycarbonylamino -5 -(tert-butoxycarbonylamino pent- 1 -ynyl - l-cyclopropyl-6,7-difluoro-4-oxo-L4-dihydroquinoline-3 -carboxylate (3)

Boc, Cbz, 1,2-diamine alkyne (1) (1 mmol) and ethyl- l-cyclopropyl-6,7- difluoro-4-oxo-8-(trifluoromethylsulfonyloxy)- 1 ,4-dihydroquinoline-3 -carboxylate (2) (1 mmol) were combined in a 40 mL scintillation vial and then placed under nitrogen via partial vacuum evacuation and backfill with nitrogen. Then, triphenylphosphine (67 mg, 0.25 mmol) and tetrahydrofuran (10 mL) were added and the reaction was sparged with nitrogen for 3-4 minutes. Then, N. N-diisopropylethylamine (0.357 mL, 2.05 mmol) and tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.10 mmol) were added with continued sparging (~3 min) and then finally copper(I) iodide (39 mg, 0.20 mmol) was added and the resultant clear, yellow-colored reaction mixture was heated at 60 °C for 8-9 hr and then checked by HPLC/LCMS and TLC. Analysis after this period of time shows complete consumption of the starting triflate and formation of the desired coupled product, based on MS. The crude reaction was diluted with ethanol (-10 mL) and then stirred for 5 minutes before filtering through a short plug of Celite 545 to remove the precipitated salts. The filtrate was concentrated in vacuo and then subjected to regular phase silica gel chromatography on a 40 g silica gel cartridge, eluting with 0 to 30% ethyl acetate in DCM to afford the purified product (3). (i?,Z)-Ethyl-8-(4-amino-5-(tgrt-butoxycarbonylamino)pent- 1 -enyl)- 1 -cyclopropyl-6,7- difluoro-4-oxo- 1 ,4-dihydroquinoline-3-carboxylate (4)

(i?)-Ethyl-8-(4-(benzyloxycarbonylamino)-5-(tert- butoxycarbonylamino)pent- 1 -ynyl)- l-cyclopropyl-6,7-difluoro-4-oxo- 1 ,4- dihydroquinoline-3-carboxylate (3) (0.80 mmol) was dissolved in ethanol (30 mL) and then the reaction was partially evacuated with vacuum and then back filled with nitrogen x3 before adding 10% palladium on carbon (85 mg) was added. The reaction vessel was then partially evacuated and back-filled with hydrogen (x3) and then kept under an atmosphere of hydrogen with a balloon. The reaction was checked after 2-3 hrs and found to be complete, with no apparent over-reduction. The reaction was filtered through a short plug of Celite 545 and then the filtrate was concentrated in vacuo. Silica gel chromatography using 0 to 35% ethyl acetate in CH₂C1₂ afforded purified product (4).

(i?,Z)-Ethyl-8-((tgrt-butoxycarbonylamino)methyl^')-l-cvclopropyl-6-fluoro-4-oxo- 4J,8,9-tetrahvdro-lH-azepino[2,3-hlquinoline-3-carboxylate (5)

( ?,Z)-Ethyl-8-(4-amino-5-(tert-butoxycarbonylamino)pent- 1 -enyl)- 1 - cyclopropyl-6,7-difluoro-4-oxo-l,4-dihydroquinoline-3-carboxylate (4) (0.7 mmol) was transferred to a 40-mL scintillation vial and then placed under an atmosphere of nitrogen before dissolving in acetonitrile (20 mL) and adding N,N- diisopropylethylamine (0.32 mL, 1.8 mmol). The resulting solution was sparged with nitrogen for 2 minutes and then capped and heated at 55 °C overnight (-10 hr) with stirring. After this period of time, the reaction was checked by HPLC for completion. HPLC shows complete consumption of the starting material. The reaction mixture was concentrated in vacuo and then subjected to silica gel chromatography (40 g silica gel column), eluting with 0, 2.5, 5, 7.5 and 10% methanol in chloroform (-300 mL each). The fractions containing product were combined to afford the cyclized product (5).

Preparation of Compound (6)

(i?,Z)-Ethyl-8-((tert-butoxycarbonylamino)methyl)-l-cyclopropyl-6- fluoro-4-oxo-4,7,8,9-tetrahydro-lH-azepino[2,3-h]quinoline-3-carboxylate (5) (0.5 mmol) was dissolved in THF (5 ml) follow by the addition of collidine (0.6 mmol). To the stirred and cooled 0 °C reaction, 2-chloroacetyl chloride (0.5 mmol) was added dropwise. The reaction to form the amide was complete following the addition by LCMS. The reaction was diluted with EtOAc (50 ml) and washed with water (5 ml), IN citrate (5 ml), water (5 ml) and brine (5 ml). The organic phase was dried over Na₂S0₄, filtered and evaporated under reduced pressure. The residue was immediately dissolved in DCM (10 ml) and TFA (0.5 ml) at RT with stirring. The reaction was complete by LCMS after 10 min. The reaction was evaporated under reduced pressure and taken up in THF (10 ml). Excess of NN-diisopropylethylamine (0.5 ml) was added to the reaction beyond the point where the mixture was basic as judged by pH paper. The reaction mixture was heated to 60 °C for 10 min at which time the annulation to the monoketopiperazine was complete by LCMS. The solvent was removed under reduced pressure and the residue purifed by silica gel chromatography (20 g silica gel column), eluting with 0, 5, and 10% methanol in chloroform (-50 mL each). The fractions containing product were combined to afford the cyclized product (6).

Compound (7)

Compound (6) (0.03 mmol) was dissolved in acetonitrile (1 mL) and then 70 of a 0.500 M aqueous sodium hydroxide was added. The reaction was stirred for 2 hr at 50 °C and checked by HPLC. The reaction was -60% complete at this time. An additional 10 μΐ, of 0.500 M of aqueous sodium hydroxide was added with continued heating. After 3 hr the reaction was complete and was neutralized to ~pH 7 by the use of acetic acid (1-2 drops as required). Then, the crude product was lyophilized and then purified by prep HPLC using 0 to 95% ACN with 0.1 % TFA on a CI 8 column. After collecting the purified fractions, the product (7) was obtained.

Example 5

All reactions were performed under an atmosphere of nitrogen.

Analytical HPLC was performed using an Agilent 1100 HPLC with one of the following methods:

Method A: Agilent Scalar CI 8 150' x 4.6 mm 5 micron column; 1.5 mL/min; solvent A— water (0.1% TFA); solvent B— acetonitrile (0.07% TFA, gradient: 10 min 95%A to 95%B; 5 min hold; then recycle; UV detection @ 214, 250 and 280 nm.

Method B: Agilent XDB CI 8 50 x 4.6 mm/1.8 micron column; 1.5 mL/min; solvent A— water (0.1% TFA), solvent B— acetonitrile (0.07% TFA); gradient: 5 min 95% A to 95% B then 1 min hold, 1 min 95% B to 95% A then 30 sec hold; UV detection @ 210, 254, and 280 nm.

Method C: Agilent Eclipse XBD C8 column; solvent A— water (0.1%

TFA); solvent B— acetonitrile (0.07% TFA, gradient: 10 min 95%A to 95%B; 5 min hold; then recycle; UV detection @ 214, 250 and 280 nm.

Preparative HPLC condition— Method D: Phenomenex Luna 250 x

21.20 mm, 10 micron; solvent A is 0.07% TFA in acetonitrile; solvent B is 0.10% TFA in water; 26 minute run; gradient: 5% to 80%) A over 10 minutes; from 80% to 100% A over 5 minutes; hold 100% A for 5 minutes; 100% to 5%> A over 5 minutes; hold 1 minute then recycle; detection at 285 nm.

Prep HPLC conditions— Method E: Phenomenex Luna 250 x 30.00 mm,

10 micron; solvent A is 0.07% TFA in acetonitrile; solvent B is 0.10% TFA in water; rate is 20 mL/min; 30 minute run; 5%> to 70% A over 14 minute ramp; 3 minute ramp from 80% to 100% A; hold 100% A for 3 minutes; ramp down from 100% to 5% A over 5 minutes; hold 10 minutes then recycle.

Thin layer chromatography (TLC) was performed using Silylcycle

SiliaPlate TLC plates, 60A, 250 microns, order #TLGSR1001 1B-723.

Ethyl-7-r(2S)-4-(tgrt-butoxycarbonyl)-2-(hydroxymethvDpiperazin-l-vn-l- cyclopropyl-6-fluoro-8-formyl-4-oxo-l,4-dihvdroquinoline-3-carboxylate (3)

tert-Butyl-(3S)-3-(hydroxymethyl)piperazine-l-carboxylate (1) (0.543 g,

0.00251 mol) and N-methylpyrrolidinone (20 mL) were added to a 40 mL vial. Ethyl- 1 -cyclopropyl-6,7-difluoro-8-formyl-4-oxo- 1 ,4-dihydroquinoline-3-carboxylate (2) (0.807 g, 0.00251 mol) and N,N-diisopropylethylamine (1.31 mL, 0.00753 mol) were added and the reaction was heated at 50 °C overnight. The reaction was checked by HPLC and LC/MS and was shown to be -50% complete. The heat was increased to 75 °C overnight. HPLC showed the reaction to be -85% complete with an impurity forming. The reaction was stopped and the mixture was diluted with water. The aqueous was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with water (3 x 50 mL) and brine (25 mL). The organic layer was then dried with sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography on 120 g of silica gel using 15% to 50% acetone in dichloromethane as the eluent to afford 800 mg (62%) of the desired product (3) as a yellow solid. MS ES⁺ 518.2 m/z for [C₂₆H₃₂FN₃0₇+H]⁺; MS ES^" 516.2 m/z for [C₂₆H₃₂FN₃0₇-H]\

Ethyl- SaS^-M-cvclopropyl-g-fiuoro-l l-oxo-S-itrifluoroacetylVSJa^^^ T LM- octahydro- 1 H-pyrazino[2', Γ : 3 ,4] |^" 1 ,4]oxazepino [5 ,6-h]quinoline- 12-carboxylate (4)

Ethyl-7-[(25)-4-(tert-butoxycarbonyl)-2-(hydroxymethyl)piperazin-l- yl]-l-cyclopropyl-6-fluoro-8-formyl-4-oxo-l,4-dihydroquinoline-3-carboxylate (3) (0.783 g, 1.51 mmol) was dissolved in methylene chloride (20 mL) and sodium triacetoxyborohydride (0.641 g, 3.02 mmol) was added in one portion. The reaction was allowed to stir for 3 days. After this period of time, the reaction was quenched with water (20 mL) and allowed to stir for 15 min. The layers were separated in a separatory funnel and the aqueous layer was extracted once with dichloromethane (20 mL). The organic layer was then dried with sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved once more in methylene chloride (20 mL) and 10- camphorsulfonic acid (1.76 g, 7.56 mmol) was added. After 2 days, the reaction was stopped at -50% conversion. The product mixture contained -50% cyclized material with the Boc protecting-group still on and -50% uncyclized material where the Boc protecting-group had fallen off. Trifluoroacetic acid (3 mL, 40 mmol) was added to the reaction and allowed to stir overnight. The next day all of the Boc had been cleaved. The reaction was concentrated to remove the excess TFA and quenched with 10% ammonium hydroxide. The mixture was extracted with methylene chloride (3x 100 mL). The diol amine was water soluble. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in acetonitrile and ethanol. Acetic acid, ethyl trifluoroacetate (2 niL, 20 mmol) and N,N- diisopropylethylamine (1 niL, 6 mmol) were added and the reaction was allowed to stand for 3 days. The reaction was checked after this time period and was determined to be complete. The reaction was concentrated and dissolved once more in methylene chloride (20 mL), 10-Camphorsulfonic acid (2 g) was added, and the reaction was allowed to stir overnight. After this period of time, the reaction was complete by based on LC/MS analysis. The reaction was diluted with methylene chloride (100 mL) and washed with water (3 x 100 mL). The organic layer was then dried with sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography on 40g of silica gel using 50-80% ethyl acetate in hexanes as the eluant to afford 205 mg (27%) of the desired product (4) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-^) 5 ppm 8.62 (s, 1 H), 8.07 (dd, J= 12.34, 3.21 Hz, 1 H), 5.23 - 5.47 (m, 1 H), 5.06 (br. s., 1 H), 4.39 (q, J= 6.84 Hz, 2 H), 3.44 - 4.18 (m, 10 H), 1.41 (t, J= 7.05 Hz, 3 H), 1.17 - 1.35 (m, 2 H), 0.90 (br. s., 1 H), 0.80 (br. s., 1 H); MS ES⁺ 498.4 m/z for [C₂₃H₂₃F₄N₃0₅+H]⁺.

(3sS)- 14-cvclopropyl-9-fiuoro- 1 1 -oxo-3,3aA5,6,7, 11 , 14-octahydro- 1 H-pyrazino|^"2', :3,4][l,4]-oxazepino[5,6-h]quinoline-12-carboxylic acid trifluoroacetate (5)

Ethyl-(3 aS)- 14-cyclopropyl-9-fluoro- 11 -oxo-5-(trifluoroacetyl)- 3,3a,4,5,6,7,l l,14-octahydro-lH-pyrazino-[2', :3,4]-[l,4]oxazepino[5,6-h]quinoline- 12-carboxylate (4) (0.041 g, 0.082 mmol) was dissolved in acetonitrile (1 mL, 20 mmol), and then water (0.750 mL, 41.6 mmol) and 1.0 M sodium hydroxide (0.247 mL, 0.247 mmol) were added. The reaction was stirred at room temperature for 2 hours. After this period of time, the reaction was 50% complete based on HPLC analysis. The reaction was heated to 40°C for an additional 2 hours and was found to be complete based on HPLC analysis after this time period. 10% Acetic acid (~8 drops) was added until the pH was ~7, and the reaction was concentrated to remove the acetonitrile. The mixture was purified by preparative HPLC (Method E). The pure fractions were combined and concentrated to remove the acetonitrile and the resultant solution was lyophilized to yield 35 mg of the TFA salt of (5) (87%) as an off white solid. 1H NMR (400 MHz, DMSO-dS) δ ppm 8.83 - 9.26 (m, 2 H), 8.78 (s, 1 H), 7.94 (d, J= 12.02 Hz, 1 H), 4.98 - 5.60 (m, 2 H), 3.01 - 4.52 (m, 11 H), 1.06 - 1.31 (m, 2 H), 0.71 - 1.02 (m, 2 H); MS ES⁺ 374.2 m/z for [Ci₉H₂₀F₁N₃O₄+H]⁺. EthvH 3 aSV 14-cvclopropyl-9-fluoro- 11 -oxo-3.3 a.4.5.6.7.11.14-octahydro- 1 H- pyrazino[2', 1 ' :3.4] - 1 ,4] oxazepino [5.6-h] quinoline- 12-carboxylate (6)

Ethyl-(3aS)-14-cyclopropyl-9-fluoro-l l-oxo-5-(trifluoroacetyl)- 3,3a,4,5,6,7, 1 1 , 14-octahydro- lH-pyrazino[2', :3,4] [ 1 ,4]oxazepino[5,6-h]quinoline- 12- carboxylate (4) (0.106 g, 0.213 mmol) was dissolved in ethanol (10 mL). Next, 1.0 M potassium carbonate (0.426 mL, 0.426 mmol) was added and the reaction was allowed to stir at room temperature overnight. HPLC analysis after this period of time indicated 100% conversion with 5% of the ester hydrolysis product (6) present. The reaction was then dried with sodium sulfate, filtered and concentrated in vacuo. The residue was carried on as is to the next step. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (s, 1 H), 7.60 (d, J= 12.44 Hz, 1 H), 5.32 (d, J = 14.72 Hz, 1 H), 5.10 (br. s, 1 H), 4.20 (dd, J = 6.84, 5.60Hz, 3 H), 3.99 (t, J = 6.84 Hz, 2 H), 3.89 (d, J= 7.67 Hz, 1 H), 3.87 (br. s., 2 H), 3.07 (d, J = 6.84 Hz, 2 H), 3.11 (br. s., 1 H), 1.26 (t, J = 6.95 Hz, 3 H),1.15 (d, J = 6.43 Hz, 3 H), 0.85 (d, J = 12.44 Hz, 1 H), 0.79 - 0.91 (m, 1 H), 0.72 (dd, J = 10.88, 4.04 Hz, 1 H).

Ethyl-(3aS)- 14-cyclopropyl-9-fluoro-5 -methyl- 11 -oxo-3 ,3 a,4,5 ,6,7, 11 , 14-octahydro- lH-pyrazino-[2', :3,4in.4]oxazepinor5.6-h]quinoline-12-carboxylate (7)

Ethyl-(3 aS 14-cyclopropyl-9-fiuoro- 11 -oxo-3 ,3 a,4,5 ,6,7, 11 , 14- octahydro- 1 H-pyrazino [2', 1 ' : 3 ,4] [ 1 ,4] oxazepino [5 ,6-h] quinoline- 12-carboxylate (6) (0.078 g, 0.19 mmol) was dissolved in formic acid (1.47 mL, 38.9 mmol). Then 37% formaldehyde(0.723 mL, 9.72 mmol) was added and the reaction was heated in an 80°C oil bath. The reaction was checked after 1 hour and the reaction was complete. The solvent was removed under a stream of nitrogen to give crude (7) as the formic acid salt. The crude product was carried on to the hydrolysis step without further purification. MS ES⁺ 416.3 m/z for [C₂₂H26F₁N₃0₄+H]⁺. (3aS -14-Cvclopropyl-9-fluoro-5-methyl-l l-oxo-3 a,4,5,6.7J l,14-octahvdro-lH- pyrazino \2 1 ' : 3 ,4] - [ 1 ,4] oxazepino [5,6-h] quinoline- 12-carboxylic acid trifluoroacetate (8)

Ethyl-(3a5)-14-cyclopropyl-9-fluoro-5-methyl-l l-oxo-

3,3a,4,5,6,7,l l,14-octahydro-lH-pyrazino[2', :3,4][l,4]oxazepino[5,6-h]quinoline-12- carboxylate, formic acid salt (1 :1) (7) (0.090 g, 0.20 mmol) was dissolved in acetonitrile (1 mL) and water (3.0 mL). Then 1.0 M sodium hydroxide (1.56 mL, 1.56 mmol) was then added the reaction was heated at 50°C overnight. After this period of time, the reaction was determined to be complete. The reaction was cooled to ambient temperature and then 10% acetic acid (~8 drops) was added until the pH was ~7. The reaction was concentrated to remove the acetonitrile and then lyophilized. The crude product was purified by preparative HPLC (Method E). The pure fractions were combined and concentrated to remove the acetonitrile. The solution was lyophilized to yield 61 mg (62%) of the TFA salt of (8) as a white solid. 1H NMR (400 MHz, DMSO- dS) δ ppm 9.66 - 10.42 (m, 1 H), 8.71 - 8.84 (m, 1 H), 7.71 - 8.19 (m, 1 H), 3.13 - 5.69 (m, 12 H), 2.79 - 3.02 (m, 3 H), 1.21 (br. s., 2 H), 0.71 - 1.07 (m, 2 H). MS ES⁺ 388.1 m/z for [C₂₀H₂₂F₁N₃O₄+H]⁺.

Example 6

Ethyl-l-cvclopropyl-6-fluoro-8-formyl-7-((2S.3i? -2-(hvdroxymethylV3-(^,2.2,2- trifluoroacetamido¼zepan- 1 -yD-4-oxo- 1 ,4-dihvdroquinoline-3 -carboxylate (3 )

A mixture of 2,2,2-trifluoro-N-((2S,3i?)-2-(hydroxymethyl)azepan-3- yl)acetamide (1) (1.45 mmol), ethyl-7,8-difluoro-9-formyl-5-oxo-2,5-dihydro-lH- thiazolo[3,2-a]quinoline-4-carboxylate (2) (1.16 mmol) in N-methylpyrrolidinone (5 mL) was treated with N.N-diisopropylethylamine (0.28 mL) dropwise and the mixture was heated at 50 °C for 3 h, whereupon it was determined by LCMS that the reaction was complete. The reaction mixture was cooled, diluted with 50 mL ethyl acetate and washed with two 50 mL portions of H₂0 and 50 mL brine. The organic phase was dried over Na₂S0₄, filtered and concentrated. The material was purified by flash chromatography (40 g flash silica gel; 2-6% MeOH/CH₂Cl₂) to yield the title compound (3) as a solid.

Ethyl-l-cvclopropyl-6-fluoro-8-(hvdroxymethyl -7-((2_l$',3i? -2-(hvdroxymethyl)-3- (2,2,2-trifluoroacetamido)azepan- 1 -yl)-4-oxo- 1 ,4-dihydroquinoline-3-carboxylate (4)

A solution of ethyl- 1 -cyclopropyl-6-fluoro-8-formyl-7-((2S,3i?)-2- (hydroxymethyl)-3-(2,2,2-trifluoroacetaniido)azepan-l-yl)-4-oxo-l,4-dihydroquinoline- 3-carboxylate (3) (0.662 mmol) in methylene chloride (13 mL) was treated with sodium triacetoxyborohydride (281 mg, 1.32 mmol) in one portion and stirred at room temperature till complete. After 22 h, the reaction was complete by HPLC. The reaction mixture was diluted with 15 mL CH₂C1₂ and 1 mL MeOH and washed with 20 mL sat NaHC0₃ solution. The aqueous phase was back extracted with 10 mL CH₂C1₂ and the combined organic extracts were washed with 10 mL portions of H₂0 and brine and dried over Na₂S0₄. The solution was filtered and concentrated to a residue which was purified by flash chromatography (30 g flash silica gel, 3-10% EtOH/CH₂Cl₂) to yield the title compound (4) as a solid.

Compound (5)

A solution of ethyl- 1 -cyclopropyl-6-fluoro-8-(hydroxymethyl)-7-

((2S,3i?)-2-(hydroxymethyl)-3-(2,2,2-trifluoroacetamido)azepan-l-yl)-4-oxo-l ,4- dihydroquinoline-3-carboxylate (4) (0.223 mmol) in methylene chloride (12 mL) was treated dropwise with trifluoroacetic acid (0.43 mL, 5.6 mmol). The reaction mixture was stirred at room temperature till complete. After 70 h, the reaction was complete by HPLC. The reaction mixture was diluted with 5 mL CH₂C1₂ and washed with 5 mL sat NaHC0₃ solution. The aqueous phase was washed with 5 mL CH₂Cl₂ and the combined organic phase was dried over Na₂S0₄. The solution was filtered and concentrated under reduced pressure. The material was purified by flash chromatography (25 g flash silica gel, 2-6% EtOH/CH₂Cl₂) to yield the title compound (5) as a solid.

Compound (6)

A mixture of compound (5) (0.090 mmol) in methanol (2.50 mL) and water (1 mL) was treated with potassium carbonate (38 mg, 0.27 mmol) in one portion and the mixture was stirred at room temperature for 110 h. An additional equivalent of K₂C0₃ was added and stirring was continued for 24 h, upon which time HPLC indicated the reaction was complete. The reaction mixture was concentrated to remove the methanol and the aqueous phase was treated drop wise with 10% aq AcOH till the pH of the solution was 7 as judged by pH paper. A white solid began to fall out of solution and the mixture was allowed to sit at room temperature overnight. The solid was filtered and washed with a water (1ml) followed by diethyl ether (4 ml) to produce a solid. The material was treated with 0.1 M of trifluoroacetic acid in water (1.08 mL) and 1 mL H₂0 and the solution was lyophilized to yield the title compound (6) as a solid.

Example 7

Minimum inhibitory concentrations (MIC) were determined by reference Clinical and Laboratory Standards Institute (CLSI) broth microdilution methods per M7-A7 [2006]. Quality control ranges utilizing E. coli ATCC 25922, P. aeruginosa ATCC 27853 and S. aureus ATCC 29213, and interpretive criteria for comparator agents were as published in CLSI M100-S17 [2007]. Briefly, serial two-fold dilutions of the test compounds were prepared at 2X concentration in Mueller Hinton Broth. The compound dilutions were mixed in 96-well assay plates in a 1:1 ratio with bacterial inoculum. The inoculum was prepared by suspension of a colony from an agar plate that was prepared the previous day. Bacteria were suspended in sterile saline and added to each assay plate to obtain a final concentration of 5x10⁵ CFU/mL. The plates were incubated at 35 °C for 20 hours in ambient air. The MIC was determined to be the lowest concentration of the test compound that resulted in no visible bacterial growth as compared to untreated control. Data for certain representative compounds is shown in Table 1 below. Table 1

* MIC Key:

MIC's of 1.0 μ^ηιΐ, or less = A

MIC's of greater than 1.0 μg/mL to 8.0 μg/mL = B

MIC's of greater than 8.0 μξ/π _^ = C

All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification are incorporated herein by reference, in their entirety to the extent not inconsistent with the present description.

From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims

What is claimed is:

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof,

wherein:

A, B and D are as follows:

A is -C(R_8b)₂-, -C(=0)-, -C(R_8b)(OR_8a)-, -C(R_8b)(N(R_8a)₂ , -C(=NOR_8a)-, -S(=0)- or -S0₂-;

B is -C(R_8b)₂-, -C(=0)-, -C(R_8b)(OR_8a)-, -C(R_8b)(N(R_8a)₂)-, -C(=NOR_8a)-, -0-, -S-, -S(=0)-, -S0₂- or -N(R_8a)-; and

D is -C(R_8b)₂-, -C(=0)-, -0-, -S-, -S(=0)-, -S0₂-, -N(R_8a)-, -C(R_8b)(OR_8a)- or -C(R_8b)(N(R_8a)₂)-;

or A-B, taken together, are -C(R_8b)=C(R_8b)-, -C(R_8b)=N- or

HC CH

; or

or B-D, taken together, are -C(R_8b)=C(R_8b)-, -N=C(R_8b)- or

HC CH

E is -C(R_8c)₂- or -C(=0)-;

G is hydrogen or methyl; W is -0-, -S-, -S(=0)-, -S0₂-, -N(Rgd)- or -C(R_8e)₂-;

R] is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;

R₂ is hydrogen, methyl or amino;

R₃ is hydrogen, fluorine or chlorine;

each R4, R_5j R₆, R₇ are, independently, hydrogen, halogen, amino, hydroxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted alkylamino or -N(R_8a)2, or R4 and R₅, taken together, are =CHR _b, =NORga, =NNR_8a or =0 or, together with the atom to which they are attached, form an optionally substituted carbocyclic or heterocyclic ring having from 3 to 6 ring atoms, or R₆ and R₇, taken together, are =CHRgb, =NOR_8a, =NNRg_a or =0, or, together with the atom to which they are attached, form an optionally substituted carbocyclic or heterocyclic ring having from 3 to 6 ring atoms, or R₅ and R₆, R₅ and R₇, R₄ and R_{6j t} and R₇, R₄ and Rg_d, R5 and Rg_d, 4 and Rg_e or R₅ and Rg_e, taken together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms;

each Rg_a is, independently, hydrogen, Ci-C₆ alkyl, C₃-C₆ cycloalkyl, Ci- C₆ cycloalkylalkyl or -C(=0)R_8c;

each Rg_b is, independently, hydrogen, halogen, Ci-C₆ alkyl, C3-C6 cycloalkyl, Ci-C₆ haloalkyl or Ci-C₆ cycloalkylalkyl;

each Rg_c is, independently, hydrogen or Ci-C₆ alkyl;

each Rg_d is, independently, hydrogen, Ci-C₆ alkyl optionally substituted with one or more of hydroxyl, -N(Rg_a)₂ and halogen, or C₃-C₆ cycloalkyl optionally substituted with one or more of hydroxyl, -N(Rg_a)₂ and halogen, or R₄ and Rgd or R₅ and Rg_d, taken together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms; and

each R_8e is, independently, hydrogen, hydroxyl, -N(R_8a)₂ or Ci-C₆ alkyl optionally substituted with one or more of hydroxyl, -N(R_8a)₂ and halogen, or two R_8e groups, taken together with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms which is optionally substituted with one or more of hydroxyl, -N(R_8a)₂ and halogen, or R₄ and R_8e or R₅ and R_8e, taken together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms.

2. A compound of claim 1 wherein A-B-D, taken together, are -CH₂CH₂CH₂-, -CH(CH₃)CH₂CH₂-, -C(CH₃)₂CH₂CH₂-, -CH₂CH=CH-, -CH=CHCH₂-, -CH(OR_8a)CH₂CH₂-, -C(CH₃)(OR_8a)CH₂CH₂-, -CH(N(R_8a)₂)CH₂CH₂-, -C(CH₃)(N(R_8a)₂)CH₂CH₂-, -C(=NOR_8a)CH₂CH₂-, -C(=0)N(R_8a)CH₂-, -CH₂CH(OR_8a)CH₂-, -CH₂C(CH₃)(OR_8a)CH₂-, -CH₂CH(N(R_8a)₂)CH₂-, -CH₂C(=NOR_8a)CH₂-, -CH₂C(=0)CH₂-, -CH₂C(CH₃)₂CH₂-, -CH₂OCH₂-, -CH₂SCH₂-, -CH₂S(=0)CH₂-, -CH₂S0₂CH₂-, -CH₂N(R_8a)CH₂-, -CH₂CH₂CH(CH₃)-, -CH₂CH₂C(CH₃)₂-, -CH₂C(=0)N(R_8a)-, -CH₂N(R_8a)C(=0)-, -CH₂S0₂N(R_8a)-, -CH₂N(R_8a)S0₂-, -CH₂CH₂0-, -CH₂CH₂N(R_8a)-, -CH₂CH₂S-, -CH₂CH₂S(=0)- or -CH₂CH₂S0₂-.

3. A compound of claim 1 wherein A-B-D, taken together, are -C(R_8b)₂C(R_8b)₂C(R_8b)₂-, -C(R_8b)₂C(R_8b)=C(R_8b)- or -C(R_8b)=C(R_8b)C(R_8b)₂-.

4. A compound of claim 3 wherein A-B-D, taken together, are -C(R_8b)₂C(R_8b)₂C(R_8b)₂-.

5. A compound of claim 3 wherein A-B-D, taken together, are -C(R_8b)₂C(R_8b)=C(R_8b)-.

6. A compound of claim 3 wherein A-B-D, taken together, are -C(R_8b)=C(R_8b)C(R_8b)₂-.

7. A compound of any one of claims 4-6 wherein each R_8b is hydrogen.

8. A compound of claim 1 wherein A is -CH₂-.

9. A compound of claim 8 wherein B-D, taken together, are -C(R_8b)₂0-, -OC(R_8b)₂-, -C(R_8b)₂S-, -SC(R_8b)₂-, -C(R_8b)₂N(R_8a)-, -N(R_8a)C(R_8b)₂-, -C(R_8b)₂C(R_8b)₂-, -C(R_8b)=C(R_8b)- or -N=C(R_8b)-.

10. A compound of claim 9 wherein R_8a and R_8b are hydrogen, Ci-C₆ alkyl or C)-C₆ cycloalkyl.

11. A compound of claim 1 wherein B is -CH₂-.

12. A compound of claim 1 1 wherein A is -C(R_8b)₂- and D is -C(R_8b)₂- or -0-.

13. A compound of claim 12 wherein R_8b is hydrogen, Ci-C₆ alkyl or C]-C₆ cycloalkyl.

14. A compound of claim 1 wherein B is -0-.

15. A compound of claim 14 wherein A is -C(R₈ )₂- and D is

-C(R_8b)₂-.

16. A compound of claim 15 wherein R_8b is hydrogen, Ci-C₆ alkyl or Ci-C₆ cycloalkyl.

17. A compound of claim 1 wherein B is -S-.

18. A compound of claim 17 wherein A is -C(R_8b)₂- and D is

-C(R_8b)₂-.

19. A compound of claim 18 wherein R_8b is hydrogen, Ci-C₆ alkyl or Ci-C₆ cycloalkyl.

20. A compound of claim 1 wherein D is -CH₂-.

21. A compound of claim 20 wherein A-B, taken together, are

H

-CH₂CH(R_8b)-, -CH(R_8b)CH₂-, -C(CH₃)₂CH₂-, -CH₂C(CH₃)₂-, / \ -C(R_8b)=C(R_8b)-, -CH₂C(=NOR_8a)-, -C(=NOR_8a)CH₂-, -CH₂0-, -CH₂S-, -CH₂S(=0)-, -CH₂S0₂-, -CH₂N(R_8a)-, -N(R_8a)CH₂-, -CH(OR_8a)CH₂-, -CH(N(R_8a)₂)CH₂-, -CH₂CH(N(R_8a)₂)-, -C(=0)N(R_8a)-, -CH₂C(=0)-, -CH₂CH(OR_8b)- or -C(R_8b)=N-.

22. A compound of claim 21 wherein R_8a and R_8b are hydrogen, C_\- C₆ alkyl or Q-C₆ cycloalkyl.

23. A compound of claim 1 wherein D is -0-.

24. A compound of claim 23 wherein A-B, taken together, are

H

-CH₂CH₂-, -CH=CH-, -CH(OR_8a)CH₂-, / \ , -CH(N(R_8a)₂)CH₂-,

-C(CH₃)₂CH₂-, -CH₂C(CH₃)₂-, -CH₂CH(R_8b)- or -CH(R_8b)CH₂-.

25. A compound of claim 24 wherein R_8a and R_8b are hydrogen, C|- C₆ alkyl or Ci-C₆ cycloalkyl.

A compound of claim 1 wherein D is -N(R| compound of claim 26 wherein R_8a is hydrogen or methyl.

28. A compound of claim 26 or 27 wherein A-B, taken together, are -CH₂CH(R_8b)-, -CH(R_8b)CH₂-, -C(CH₃)₂CH₂-, -CH₂C(CH₃)₂-, -CH(OR_8a)CH₂-, -CH(N(R_8a)₂)CH₂-, -CH₂C(=0)- or -CH₂S0₂-.

29. A compound of claim 28 wherein R_8a and Rg_b are hydrogen, d- C₆ alkyl or Ci-C₆ cycloalkyl.

30. A compound of claim 1 wherein B-D, taken together, are -C(R_8b)=C(R_8b)-.

31. A compound of claim 30 wherein A is -C(R_8b)₂-.

32. A compound of claim 31 wherein R_8b is hydrogen, Ci-C₆ alkyl or Ci-C₆ cycloalkyl.

33. A compound of any one of claims 1-32 of structure (I) wherein W is -0-, -S-, -S(=0)- or -S0₂-.

34. A compound of any one of claims 1-32 of structure (I) wherein W is -C(R_8e)₂- having the following structure (I-A):

(I-A)

35. A compound of claim 34 wherein each R_8e is hydrogen.

36. A compound of any one of claims 1-32 of structure (I) wherein W is -N(Rgd)- having the following structure (I-B):

37. A compound of claim 36 wherein R_8ci is hydrogen.

38. A compound of claim 36 wherein one of each R₄ and R₅, taken together, are =0 and the compound has one of the following structures (I-B-1) or (I-B- 2):

(I-B-1) (I-B-2)

39. A compound of any one of claims 1-38 wherein each R4, R₅, R₆ and R₇ are, independently, hydrogen, amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylamino or -N(R_8a)₂.

40. A compound of claim 39 wherein each R4, R₅, R₆ and R₇ are hydrogen.

41. A compound of claim 39 wherein each ¾, R₅ and R₆ are hydrogen, one R₇ is hydrogen and one R₇ is amino, substituted alkyl, substituted cycloalkyl, alkylamino, or -N(R_8a)₂, wherein substituted alkyl is -(Ci-C₆ alkyl)N(R_8a)₂ and substituted cycloalkyl is -(C₃-C₆ cycloalkyl)N(R_8a)2.

42. A compound of claim 41 wherein each R_8a is hydrogen.

43. A compound of claim 42 wherein one R₇ is -NH_2> -CH₂NH₂, -CH(CH₃)NH₂, -C(CH₃)₂NH₂, or 1-amino-cycloprop-l-yl.

44. A compound of claim 39 wherein each R4, R₆ and R₇ are hydrogen, one R₅ is hydrogen and one R₅ is amino, substituted alkyl, substituted cycloalkyl, alkylamino, or -N(R_8a)₂, wherein substituted alkyl is -(Ci-C₆ alkyl)N(R_8a)₂ and substituted cycloalkyl is -(C₃-C₆ cycloalkyl)N(R_8a)₂.

45. A compound of claim 44 wherein each R_8a is hydrogen.

46. A compound of claim 45 wherein one R₅ is -NH_2> -CH₂NH₂, -CH(CH₃)NH₂, -C(CH₃)₂NH₂, or 1 -amino-cycloprop-l-yl.

47. A compound of any one of claims 1-38 wherein one of each R₄ and R₅, taken together, are =N(OR_8a) or =0.

48. A compound of any one of claims 1-38 wherein one of each R₆ and R₇, taken together, are =N(OR_8a) or =0.

49. A compound of any one of claims 1-38 wherein one of each R4 and R₅, taken together with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms.

50. A compound of any one of claims 1-38 wherein one of each R₆ and R₇, taken together with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms.

51. A compound of any one of claims 1-50 wherein Ri is optionally substituted alkyl.

52. A compound of claim 51 wherein Ri is Ci-C₆ alkyl.

53. A compound of any one of claims 1-50 wherein Ri is optionally substituted cycloalkyl.

54. A compound of claim 53 wherein Rj is cyclopropyl.

55. A compound of any one of claims 1-54 wherein R₂ is hydrogen.

56. A compound of any one of claims 1-55 wherein R₃ is fluorine.

57. A compound of any one of claims 1 -55 wherein R₃ is hydrogen.

58. A compound of any one of claims 1 -57 wherein E is -CH₂-.

59. A compound of any one of claims 1-57 wherein E is -C(=0)-.

60. A compound of any one of claims 1 -57 wherein E is -CH(C¾)- or -C(CH₃)₂-.

61. A compound of any one of claims 1-60 wherein G is hydrogen.

62. A pharmaceutical composition comprising a compound of any one of claims 1-61 , or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

63. A method of treating a bacterial infection in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of any one of claims 1-61 or a composition of claim 62.

64. A method of claim 63 wherein the bacterial infection is caused by a fluoroquinolone antibiotic resistant bacterium.

65. A method of claim 64 wherein the fluoroquinolone antibiotic resistant bacterium is a fluoroquinolone resistant Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Enterobaeter aerogenes, Enterobacter cloacae, Providencia stuartii or Serratia marcescens bacterium.

66. A method of claim 65 wherein the fluoroquinolone antibiotic resistant bacterium is a fluoroquinolone resistant Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus or Streptococcus pneumoniae bacterium.

67. A method of claim 63 wherein the bacterial infection is caused by Enterococcus faecium, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus (Group C/F), Streptococcus (Group G), Viridans group streptococci, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter Iwoffii, Aeromonas hydrophila, Bordetella pertussis, Burkholderia cepacia, Campylobacter jejuni, Citrobacter diversus, Citrobacter freundii, Enterobaeter aerogenes, Enterobacter agglomerans, Enterobacter sakazaki, Edwardsiella tarda, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa, Pseudomonas fluorescens, Salmonella enteritidis, Salmonella typhi, Serratia liquefaciens, Serratia marcescens, Shigella boydii, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Stenotrophomonas maltophilia, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, Yersinia enterocolitica, Clostridium difficile and Clostridium perfringens.

68. A method of claim 63 wherein the compound has MIC < 2 μg/mL for each of:

(i) one or more Gram-negative bacteria selected from the group consisting of Acinetobacter anitratus, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter Iwoffii, Aeromonas hydrophila, Bordetella pertussis, Burkholderia cepacia, Campylobacter jejuni, Citrobacter diversus, Citrobacter freundii, Enterobaeter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Enterobacter sakazaki, Escherichia coli, Edwardsiella tarda, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa, Pseudomonas fluorescens, Salmonella enteritidis, Salmonella typhi, Serratia liquefaciens, Serratia marcescens, Shigella boydii, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Stenotrophomonas maltophilia, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus and Yersinia enterocolitica; and

(ii) one or more Gram-positive bacteria selected from the group consisting of Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus (Group C/F), Streptococcus (Group G), Streptococcus pneumoniae, Streptococcus pyogenes, Viridans group streptococci, Clostridium difficile and Clostridium perfringens.

69. A method of claim 68 wherein the compound has MIC < 2 μg/mL for each of:

(i) one or more Gram-negative bacteria selected from the group consisting of Acinetobacter baumannii, Acinetobacter calcoaceticus, Burkholderia cepacia, Citrobacter freundii, Enterobaeter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Pseudomonas aeruginosa, Salmonella enteritidis, Serratia liquefaciens, Serratia marcescens, Shigella dysenteriae, Shigella flexneri and Yersinia enterocolitica, and

(ii) one or more Gram-positive bacteria selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus pneumoniae.

70. A method of claim 63 wherein the bacterial infection is caused by Mycobacterium tuberculosis or Mycobacterium avium.