WO2008036420A2 - 9-(heteroaryl)-isothiazolo[5,4-b]quinoline-3,4-diones and related compounds as anti-infective agents - Google Patents

Abstract

The invention provides compounds and salts of Formula (I) and Formula (II); which possess antimicrobial activity. The invention also provides novel synthetic intermediates useful in making compounds of Formula (I) and Formula (II). The variables R<SUB>2</SUB>, R<SUB>3</SUB>, R<SUB>5</SUB>, R<SUB>6</SUB>, R<SUB>7</SUB>, A<SUB>8</SUB> and R<SUB>9</SUB> are defined herein. Certain compounds of Formula (I) and Formula (II) disclosed herein are potent and/or selective inhibitors of bacterial DNA synthesis and bacterial replication. The invention also provides antimicrobial compositions, including pharmaceutical compositions, containing one or more compounds of Formula (I) or Formula (II) and one or more carriers, excipients, or diluents. Such compositions may contain a compound of Formula (I) or Formula (II) as the only active agent or may contain a combination of a compound of Formula (I) or Formula (II) and one or more other active agents. The invention also provides methods for treating microbial infections in animals.

Description

9-(HETEROARYL)-ISOTHIAZOLO[5,4-B]QUINOLINE-3,4-DIONES AND RELATED COMPOUNDS AS ANTI-INFECTIVE AGENTS

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority from U.S. Provisional Application 60/826,408 filed September 21, 2006, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] Disclosed herein are 9-(heteroaryl)-isothiazolo[5,4-b]quinoline-3,4-diones and related compounds, in which the 9-position substituent is generally a substituted or un- substituted heteroaryl containing one or more nitrogen atoms, useful as antimicrobial agents. Certain compounds provided herein possess potent antibacterial, antiprotozoal, or antifungal activity. Particular compounds provided herein are also potent and/or selective inhibitors of prokaryotic DNA synthesis and prokaryotic reproduction. The invention also provides antimicrobial compositions, including pharmaceutical compositions, containing one or more carrier, diluents, and/or excipients. The invention provides pharmaceutical compositions containing a 9- (heteroaryl)-isothiazolo[5,4-b]quinoline-3,4-dione or related compound as the only active agent or containing a 9-(heteroaryl)-isothiazolo[5,4-b]quinoline-3,4-dione or related compound in combination with one or more other active agent, such as one or more other antimicrobial or antifungal agent. The invention further provides methods for treating or preventing microbial infections in animals by administering an effective amount of a 9-(heteroaryl)-isothiazolo[5,4- b]quinoline-3,4-dione or related compound to an animal suffering from or susceptible to microbial infection. The invention also provides methods of inhibiting microbial growth and survival by applying an effective amount of a 9-(heteroaryl)-isothiazolo[5,4-b]quinoline-3,4- dione or related compound.

[0003] The invention also provides novel intermediates useful for the synthesis of 9- (heteroaryl)-isothiazolo[5,4-b]quinoline-3,4-diones and related compounds. The invention further provides methods of synthesis of 9-(heteroaryl)-isothiazolo[5,4-b]quinoline-3,4-diones or related compounds. BACKGROUND OF THE INVENTION

[0004] Antimicrobial. compounds are compounds capable of destroying or suppressing the growth or reproduction of microorganisms, such as bacteria, protozoa, mycoplasma, yeast, and fungi. The mechanisms by which antimicrobial compounds act vary. However, they are generally believed to function in one or more of the following ways: by inhibiting cell wall synthesis or repair; by altering cell wall permeability; by inhibiting protein synthesis; or by inhibiting synthesis of nucleic acids. For example, beta-lactam antibacterials inhibit the essential penicillin binding proteins (PBPs) in bacteria, which are responsible for cell wall synthesis. Quinolones act, at least in part, by inhibiting synthesis of DNA, thus preventing the cell from replicating.

[0005] Many attempts to produce improved antimicrobials yield equivocal results. Indeed, few antimicrobials are produced that are truly clinically acceptable in terms of their spectrum of antimicrobial activity, avoidance of microbial resistance, and pharmacology. There is a continuing need for broad-spectrum antimicrobials, and a particular need for antimicrobials effective against resistant microbes.

[0006] Pathogenic bacteria are known to acquire resistance via several distinct mechanisms including inactivation of the antibiotic by bacterial enzymes (e.g., beta-lactamases that hydrolyze penicillin and cephalosporins); removal of the antibiotic using efflux pumps; modification of the target of the antibiotic via mutation and genetic recombination (e.g., penicillin-resistance in Neiserria gonorrhea); and acquisition of a readily transferable gene from an external source to create a resistant target (e.g., methicillin-resistance in Staphylococcus aureus). There are certain Gram-positive pathogens, such as vancomycin-resistant Enterococcus faecium, which are resistant to virtually all commercially available antibiotics.

[0007] Resistant organisms of particular note include methicillin-resistant and vancomycin- resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci, fluoroquinolone-resistant E. coli, cephalosporin-resistant aerobic gram-negative rods and imipenem- resistant Pseudomonas aeruginosa. These organisms are significant causes of nosocomial infections and are clearly associated with increasing morbidity and mortality. The increasing numbers of elderly and immunocompromised patients are particularly at risk for infection with these pathogens. Therefore, there is a large unmet medical need for the development of new antimicrobial agents. In recent years Methicillin Resistant Staphylococcus Aureus (MRSA) infections have become more common, particularly in institutional and hospital settings. Up to 60% of staphylococcus infections are attributable to methicillin resistant strains in some parts of the United States. Some MRSA strains are now resistant to both Vancomycin and Gentamicin, drugs once considered the last defense against staphylococcus infections. Thus, there is a particularly urgent need for drugs effective against MRSA strains.

[0008] The present invention fulfills this need, and provides further related advantages.

SUMMARY OF THE INVENTION

[0009] The invention provides compounds of Formula I and Formula II (shown below) and includes 9-(heteroaryl)-isothiazolo[5,4-b]quinoline-3,4-diones or related compounds, which possess antimicrobial activity. The invention provides compounds of Formula I and Formula II, which possess potent and/ or selective antibacterial, antiprotozoal, or antifungal activity. The invention also provides compositions containing one or more compounds of Formula I or Formula II, or a salt, solvate, or prodrug, such as an acylated prodrug of such a compound, and one or more carriers, excipients, or diluents.

[0010] The invention further comprises methods of treating and preventing microbial infections, particularly bacterial and protozoal infections by administering an effective amount of a compound of Formula I or Formula II to a eukaryote suffering from or susceptible to a microbial infection. These microbial infections include bacterial infections, for example E. coli infections, Staphylococcus infections, including Methicillin Resistant Staphylococcus Aureus infections, Salmonella infections and protozoal infections, for example Chlamydia infections. The invention is particularly includes methods of preventing or treating microbial infections in mammals, including humans, but also encompasses methods of preventing or treating microbial infections in other animals, including fish, birds, reptiles, and amphibians.

[0011] Methods of treatment include administering a compound of Formula I or Formula II as the single active agent or administering a compound of Formula I or Formula II in combination with one or more other therapeutic agent, such as an antibacterial, an antifungal, an antiviral, an interferon or other immune system modulator, an efflux-pump inhibitor, a beta- lactamase inhibitor, an anti-inflammatory, or another compound of Formula I or Formula II. [0012] The invention also provides methods of inhibiting microbial growth and survival by applying an effective amount of a 9-(heteroaryl)-isothiazolo[5,4-b]quinoline-3,4-diones or related compound. The invention includes, for example, methods of inhibiting microbial growth and survival on medical instruments by applying a composition containing a compound of Formula I or Formula II.

[0013] Thus, the invention include compounds and pharmaceutically acceptable salts of Formula I and Formula II

Q R₅ Q

a II

[0014] Within Formula I and II the variables A₁, R₂, R₃, R₅, R₆, R₇, A₈, and R₉ carry the values set forth below.

[0015] A₁ is S, O, SO, or SO₂.

[0016] R₂ is hydrogen; or R₂ is C₁-C₈alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, (C₃- C₇cycloalkyl)C₀-C4carbohydryl, (C₄-C₇cycloalkenyl)C₀-C₄carbohydryl, (aryl)C₀-C₄carbohydryl, or (C₂-C₆heterocycloalkyl)Co-C₄carbohydryl, each of which is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, C₁-C₄alkyl, C₁- C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, mono- and di-C₁-C4alkylamino, CrQalkanoyl, C₁- C₄alkylthio, =NORi₀, =NR₁₀, -0(C=O)Ri₀, -(C=O)NR₁₀R₁₁, -0(C=O)NR₁₀R₁₁, -(C=O)OR₁₀, -(C=O)NR₁₀OR₁₁, -NR₁₀(C=O)R₁₁, -NR₁₀(C=O)OR_n, -NR₁₀(C=O)NR₁₁R₁₂, -NR₁₀(C=S)NR₁₁R₁₂, -NR₁₀NR₁₁R₁₂, -SO₃R₁₀, -(S=O)OR₁₀, -SO₂R_n, -SO₂NR₁₀R₁₁, and -NR₁₀SO₂Ri₃; wherein R₁₀, R₁₁, and R₁₂ are independently hydrogen, C₁-C₄alkyl, or aryl, and Rj₃ is C₁^alkyl or aryl.

[0017] R₃ is hydrogen, C₁-C₆alkyl, C₂-C₆alkanoyl, mono- or di-C₁-C_όalkylcarbamate, or Q-C_όalkylsulfonate; each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, Q-G_talkoxy, mono- and di-C₁-C₄alkylamino, C₁- C₂haloalkyl, and Q-Qhaloalkoxy. [0018] R₅ is hydrogen, halogen, hydroxy, amino, cyano, nitro, Or-NHNH₂; or

[0019] R₅ is C₁-C₄alkyl, C₁-C₄alkoxy, mono- or di-(C_!-C₄)alkylamino, mono-, di- or tri- (C₁-C₄)alkylhydrazinyl, C₂-C4alkanoyl, Q-dalkylester, C₁-C₂haloalkyl, or d-C₂haloalkoxy; each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, amino, halogen, oxo, C₁-C₄alkoxy, C₁-C₂haloalkyl, d-C₂haloalkoxy, and mono- and di-(C]- C4)alkylamino.

[0020] R₆ is hydrogen, halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C_!-C₄alkoxy, mono- or di-(C₁-C₄)alkylamino, -SO₃R₁₀, -SO₂R₁₀, or -SO₂NR₁₀R₁₁.

[0021] R₇ is halogen, -0(SO₂)CF₃, or -N₂BF₄.

[0022] Or, R₇ is a carbon-linked substituent XR_A, wherein X is absent, -CH₂-CH₂-, - CH=CH-, -(C=O)-, -(C=O)NH-, or -C≡C-; wherein R_A is C₂-C₆alkyl, C₃-C₇cycloalkyl, C₄- C₇cycloalkenyl, phenyl, a 7-10 membered bicyclic saturated, partially unsaturated, or aromatic carbocyclic group, or a 5- to 6-membered saturated, partially unsaturated, or aromatic heterocylic group bound via a carbon atom when X is absent or bound via a carbon or nitrogen atom when X is -CH₂-CH₂-, -CH=CH-, or -C≡C-, or R_A is a 7-10 membered bicyclic saturated, partially unsaturated, or aromatic heterocylic group bound via a carbon atom when X is absent or bound via a carbon or nitrogen atom when X is -CH₂-CH₂-, CH=CH- or -C≡C-; or

[0023] R₇ is a nitrogen-linked monocyclic heterocycloalkyl group, which has 4 to 8 ring members, including 0, 1, or 2 additional ring heteroatoms independently chosen from N, O, and S, or

[0024] R7 is a nitrogen-linked C₁-C₄alkylamino substituted with a 5 or 6-membered heteroaryl group having 1 or 2 heteroatoms independently chosen from N, O, and S, or substituted with a heterocycloalkyl group, which has 4 to 8 ring members, including 1 or 2 ring heteroatoms independently chosen from N, O, and S, or

[0025] R7 is a nitrogen-linked heterocycloalkyl or heterocycloalkenyl group, each of which has 4 to 8 ring members, including 0, 1, or 2 additional ring heteroatoms independently chosen from N, O, and S, forming part of a bicyclic system with a 3- to 8-membered cycloalkyl or heterocycloalkyl ring in fused or spiro orientation; or

[0026] R7 is a nitrogen-linked 6-membered heterocycloalkyl group, having 0, 1 or 2 additional ring heteroatoms independently chosen from N, O, and S, and bridged with a methylene or ethylene bridge. [0027] Each of which R₇ other than halogen, -0(SO₂)CF₃, and -N₂BF₄, is substituted with 0 to 5 substituents independently chosen from (i), (ii), and (iii); wherein

(i) is chosen from halogen, hydroxy, amino, cyano, and nitro;

(ii) is chosen from hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C(_JaIkOXy(C₀- C₄alkyl), mono- and di-(C₀-C₆)alkylamino, Q-Qhaloalkyl, C₁-C₂haloalkoxy, C₃- C₇cycloalkyl(C₀-C₄carbohydryl), C₃-C₇cycloalkyl(Co-C₄carbohydryl-0-), C₄-C₇cycloalkenyl(C₀- C₄carbohydryl), aryl(C₀-C₆carbohydryl), aryl(d-C₄alkoxy), C₂-C₆heterocycloalkyl(C₀- C₄carbohydryl), heteroaryl(C₀-C₆carbohydryl), Q-C_όalkylthio, =NOR₁₀, =NR₁₀, -(Co- C₄alkyl)(C=O)Ri₀, -(C₀-C₄^yI)O(C=O)R₁₀, -(C₀-C₄alkyl)(C=O)NR₁₀R₁₁, -(C₀- C₄alkyl)O(C=O)NR₁₀Rπ, -(C₀-C₄alkyl)(C=O)OR₁₀, -(C₀-C₄^yI)NR₁₀(C=O)R_{1 u} -(C₀- C₄alkyl)NRio(C=0)OR₁₁, -(Co-C₄alkyl)NR₁₀(C=0)NR₁₁R₁₂, -(C₀-C₄alkyl)NR₁₀(C=0)(C₁- C₄ lCyI)NR₁ !(C=O)O-R₁₂, -(Co-C₄alkyl)NR_lo(C=S)NRπRi₂, -(C₀-C₄₃HCyI)NR₁₀NR₁₁R₁₂, -(C₀- C₄alkyl)N=NR₁₃, -(C₀-C₄alkyl)SO₃R₁₀, -(C₀-C₄alkyl)(S=O)OR₁₀, -(C₀-C₄alkyl)SO₂R₁₃, -(C₀- C₄₃HCyI)SO₂NR₁₀R₁₁, and -(Co-C₄alkyl)NR₁₀S0₂R₁₃; wherein R₁₀, R₁₁, and R₁₂ are independently hydrogen, d-C₄alkyl, or aryl, and Rj₃ is C₁-C₄alkyl or aryl; and

(iii) is chosen from -OR_D, -(C=O)R₀, -SO₂R₀, -SO₃R₀, -NRi₀SO₂R_D, where R₀ is C₁- C₄alkyl, C₃-C₇cycloalkyl(C₀-C₂alkyl), C₂-C₆heterocycloalkyl(C₀-C₂alkyl), aryl(C₀-C₂alkyl), or heteroaryl(C₀-C₂alkyl); wherein R₁₀ is hydrogen, C₁-C₄alkyl, or aryl.

[0028] Wherein each of (ii) and (iii) is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH, -CONH₂, C₁-C₄alkyl, C₂- C₄alkenyl, C₂-C₄alkynyl, Q-Qalkoxy, C₁-C₄alkoxycarbonyl, C₃-C₇cycloalkyl(Co- C₄carbohydryl), C₃-C₇cycloalkyl(C₀-C₄alkoxy), mono- and di-(C₁-C₄)alkylamino, C₁- C₂haloalkyl, d-C₂haloalkoxy, C₂-C₄alkanoyl and phenyl.

[0029] A8 is N or CR₈.

[0030] Wherein, R₈ is hydrogen, halogen, hydroxy, amino, cyano, nitro, or -NHNH₂; or R₈ is C₁-C₄alkyl, C₁-C₄alkoxy, mono- or di-(C₁-C₄)alkylamino, mono-, di-, or tri- (C₁-C₄) alkylhydrazinyl, C₂-C₄alkanoyl, C₁-C₄alkylester, C₁-C₂haloalkyl, or C₁-C₂haloalkoxy; each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, amino, halogen, oxo, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and mono- and di-(C₁- C₄)alkylamino. [0031] R9 is pyridine, pyrazine, pyridazine, or pyrimidine, each of which is substituted with 0 to 4 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, (C₃-C₇cycloalkyl)C₀- C₄alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkoxy, mono- and di-(C_!-C₄)alkylamino, Q-Qhaloalkyl, C₁- C₂haloalkoxy, and C₂-C₄alkanoyl.

[0032] The invention also provides methods of synthesizing compounds of Formula I and Formula II.

DETAILED DESCRIPTION OF THE INVENTION CHEMICAL DESCRIPTION AND TERMINOLOGY

[0033] Prior to setting forth the invention in detail, it may be helpful to provide definitions of certain terms to be used herein. Compounds of the present invention are generally described using standard nomenclature.

[0034] In certain situations, the compounds of Formula I and Formula II may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g. asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. For compounds having asymmetric centers, it should be understood that all of the optical isomers and mixtures thereof are encompassed. In addition, compounds with carbon- carbon double bonds may occur in Z- and E-forms, with all isomeric forms of the compounds being included in the present invention. In these situations, the single enantiomers, i.e., optically active forms can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates. Resolution of the racemates can also be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.

[0035] Where a compound exists in various tautomeric forms, the invention is not limited to any one of the specific tautomers, but rather includes all tautomeric forms.

[0036] The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include ¹¹C, ¹³C, and ¹⁴C.

[0037] Certain compounds are described herein using a general formula that includes variables, e.g. Aj, R₂, R₃, R₅, R₆, R₇, A₈, and R₉. Unless otherwise specified, each variable within such a formula is defined independently of other variables. Thus, if a group is said to be substituted, e.g. with 0-2 R*, then said group may be substituted with up to two R* groups and R* at each occurrence is selected independently from the definition of R*. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. When a group is substituted by an "oxo" substituent a carbonyl bond replaces two hydrogen atoms on a carbon. An "oxo" substituent on an aromatic group or heteroaromatic group destroys the aromatic character of that group, e.g. a pyridyl substituted with oxo is a pyridone.

[0038] The term "substituted", as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. When a substituent is oxo (i.e., =0), then 2 hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation into an effective therapeutic agent. Unless otherwise specified substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent the point of attachment of this substituent to the core structure is in the alkyl portion.

[0039] The exception to naming substituents into the ring is when the substituted is listed with a dash ("-") or a double bond ("=") that is not between two letters or symbols. In that case the dash or double bond symbol is used to indicate a point of attachment for a substituent. For example, -CONH₂ is attached through the carbon atom.

[0040] As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms. Thus, the term C₁- C₆ alkyl as used herein includes alkyl groups having from 1 to about 6 carbon atoms. When C₀-C_n alkyl is used herein in conjunction with another group, for example, (aryl)C₀-C₄ alkyl, the indicated group, in this case aryl, is either directly bound by a single covalent bond (Co), or attached by an alkyl chain having the specified number of carbon atoms, in this case from 1 to about 4 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, and sec-pentyl.

[0041] "Alkenyl" as used herein, indicates a hydrocarbon chain of either a straight or branched configuration having one or more carbon-carbon double bond bonds, which may occur at any stable point along the chain. Examples of alkenyl groups include ethenyl and propenyl.

[0042] "Alkynyl" as used herein, indicates a hydrocarbon chain of either a straight or branched configuration having one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl.

[0043] "Alkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n- propoxy, i- propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2- pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3- methylpentoxy. An "(alkoxy)alkyl group is an alkoxy group as defined herein attached through its oxygen atom to an alkyl bridge where the point of attachment to the substituted group is in the alkyl group.

[0044] "Alkanoyl" indicates an alkyl group as defined above, attached through a keto (- (C=O)-) bridge. Alkanoyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms. For example a C₂alkanoyl group is an acetyl group having the formula CH₃(C=O)-.

[0045] As used herein, the terms "mono- or di-alkylamino" or "mono- and di- alkylamino" indicate secondary or tertiary alkyl amino groups, wherein the alkyl groups are as defined above and have the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino. A mono- or di-(C₃-C₆)(C₀- C4)alkylamino group is an alkyl amino substituent in which a first alkyl group is chosen from C₃- C₆alkyl and a second alkyl group is chosen from Co-G^alkyl, wherein C₀ indicates the absence of a second alkyl group, i.e. a mono-Cs-Cόalkylamino.

[0046] The term "mono- or di-alkylcarbamate" indicates 1 or 2 independently chosen alkyl groups, as define above, attached through a carbamate (-0(C=O)NRR) linkage where R represents the alkyl groups. Mono-alkylcarbamate groups have the formula (-0(C=O)NHR). [0047] The term "alkylester" indicates an alkyl group as define above attached through an ester linkage. The ester linkage may be in either orientation, e.g. a group of the formula - O(C=O)alkyl or a group of the formula -(C=O)Oalkyl.

[0048] The term "mono-, di-, or tri-alkylhydrazinyl" indicates from 1 to 3 independently chosen alkyl groups as defined above attached through a single-bonded nitrogen-nitrogen linkage. At least one of the alkyl groups is attached to the terminal nitrogen (the nitrogen not bound to the core structure). When the term mono- or di-alkylhydrazinyl is used only the terminal nitrogen is alkyl substituted. Examples of alkylhydrazinyl groups include 2-butyl-l- hydrazinyl, 2-butyl-2-methyl-l-hydrazinyl, and 1 ,2-dimethyl-2 -propyl- 1-hydrazinyl.

[0049] The term "alkylsulfonate" indicates an alkyl group as defined above attached through a sulfonate linkage (e.g. a group of the formula -S(=O)₂O-alkyl).

[0050] The term "alkylthio" indicates an alkyl group as defined above attached through a sulfur linkage, i.e. a group of the formula alkyl-S-. Examples include ethylthio and pentylthio.

[0051] As used herein, the term "aminoalkyl" indicates an alkyl group as defined above substituted with at least one amino substituent. Similarly, the term "hydroxyalkyl" indicates an alkyl group as defined above, substituted with at least one hydroxyl substituent. hi certain instances the alkyl group of the aminoalkyl or hydroxyalkyl group may be further substituted.

[0052] As used herein, the term "aryl" indicates aromatic groups containing only carbon in the aromatic ring or rings. Typical aryl groups contain 1 to 3 separate, fused, or pendant rings and from 6 to about 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion to a 5 to 7-membered saturated cyclic group that optionally contains 1 or 2 heteroatoms independently chosen from N, O, and S, to form, for example, a 3,4- methylenedioxy-phenyl group. Aryl groups include, for example, phenyl, naphthyl, including 1- naphthyl and 2-naphthyl, and bi-phenyl.

[0053] "Carbohydryl" as used herein, includes both branched and straight-chain hydrocarbon groups, which are saturated or unsaturated, having the specified number of carbon atoms. When C₀-C_n carbohydryl is used herein in conjunction with another group, for example, (cycloalkyl)C₀-C4carbohydryl, the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (C₀), or attached by a carbohydryl chain, such as an alkyl chain, having the specified number of carbon atoms, in this case from 1 to about 4 carbon atoms. Examples of carbohydryl groups include C₁-QaIlCyI, such as methyl, or 5-butyl, C₂-C₆alkynyl such as hexynyl, and C₂-C₆ alkenyl, such as l-propenyl.

[0054] In the term "(aryl)alkyl", aryl and alkyl are as defined above, and the point of attachment is on the alkyl group. This term encompasses, but is not limited to, benzyl, phenylethyl, and piperonyl. Likewise, in the term (aryl)carbohydryl, aryl and carbohydryl are as defined above and the point of attachment is on the carbohydryl group, for example a phenylpropen-1-yl group. Similarly, in the term (aryl)alkoxy, aryl and alkoxy are as defined above and the point of attachment is through the oxygen atom of the alkoxy group; if the alkoxy is a Coalkoxy the aryl is attached through an oxygen bridge.

[0055] "Cycloalkyl" as used herein, indicates saturated hydrocarbon ring groups, having the specified number of carbon atoms, usually from 3 to about 8 ring carbon atoms, or from 3 to about 7 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl as well as bridged or caged saturated ring groups such as norborane or adamantane.

[0056] "Cycloalkenyl" as used herein, indicates an unsaturated, but not aromatic, hydrocarbon ring having at least one carbon-carbon double bond. Cycloalkenyl groups contain from 4 to about 8 carbon atoms, usually from 4 to about 7 carbon atoms. Examples include cyclohexenyl and cyclobutenyl.

[0057] In the terms "(cycloalkyl)alkyl," "(cycloalkyl)carbohydryl)," and "(cycloalkyl)alkoxy" the terms cycloalkyl, alkyl, carbohydryl, and alkoxy are as defined above, and the point of attachment is on the alkyl, carbohydryl, or alkoxy group respectively. These terms include examples such as cyclopropylmethyl, cyclohexylmethyl, cyclohexylpropenyl, and cyclopentylethyoxy.

[0058] In the terms "(cycloalkenyl)alkyl" "(cycloalkenyl)carbohydryl" the terms cycloalkenyl, alkyl, and carbohydryl are as defined above, and the point of attachment is on the alkyl or carbohydryl group respectively. These terms include examples such as cyclobutenylmethyl, cyclohexenylmethyl, and cyclohexylpropenyl.

[0059] "Haloalkyl" indicates both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, generally up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

[0060] "Haloalkoxy" indicates a haloalkyl group as defined above attached through an oxygen bridge.

[0061] "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, or iodo.

[0062] As used herein, "heteroaryl" indicates a stable 5- to 7-membered monocyclic or 7- to 10- membered bicyclic heterocyclic ring which contains at least 1 aromatic ring that contains from 1 to 4, or preferably from 1 to 3, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heteroaryl group is not more than 2. It is particularly preferred that the total number of S and O atoms in the heteroaryl group is not more than 1. A nitrogen atom in a heteroaryl group may optionally be quaternized. When indicated, such heteroaryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion to a 5 to 7-membered saturated cyclic group that optionally contains 1 or 2 heteroatoms independently chosen from N, O, and S, to form, for example, a [l,3]dioxolo[4,5-c]pyridyl group. Examples of heteroaryl groups include, but are not limited to, pyridyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benz[b]thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, and 5,6,7,8-tetrahydroisoquinoline.

[0063] hi the terms "(heteroarylalkyl" and "heteroaryl(carbohydryl)," heteroaryl, alkyl, and carbohydryl are as defined above, and the point of attachment is on the alkyl or carbohydryl group respectively. These terms include such examples as pyridylmethyl, thiophenylmethyl, and pyrrolyl(l -ethyl).

[0064] The term "heterocycloalkyl" indicates a saturated cyclic group containing from 1 to about 3 heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. Heterocycloalkyl groups have from 3 to about 8 ring atoms, and more typically have from 5 to 7 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl groups. A nitrogen in a heterocycloalkyl group may optionally be quaternized.

[0065] The term "heterocyclic group" indicates a 4-6 membered saturated, partially unsaturated, or aromatic ring containing from 1 to about 4 heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon or a 7-10 membered bicyclic saturated, partially unsaturated, or aromatic heterocylic ring system containing at least 1 heteroatom in the two ring system chosen from N, O, and S and containing up to about 4 heteroatoms independently chosen from N, O, and S in each ring of the two ring system. Unless otherwise indicated, the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. When indicated the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen atom in the heterocycle may optionally be quaternized. It is preferred that the total number of heteroatoms in a heterocyclic groups is not more than 4 and that the total number of S and O atoms in a heterocyclic group is not more than 2, more preferably not more than 1. Examples of heterocyclic groups include, pyridyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benz[b]thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, dihydroisoindolyl, 5,6,7,8-tetrahydroisoquinoline, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl.

[0066] Additional examples heterocyclic groups include, but are not limited to, phthalazinyl, oxazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzoisoxolyl, dihydro-benzodioxinyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta- carbolinyl, isochromanyl, chromanonyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, 5 pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromanyl, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N- oxide, thiazolyl N-oxide, indolizinyl N oxide, indazolyl N- oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, tetrazolyl N- oxide, benzothiopyranyl S-oxide, and benzothiopyranyl S,S- dioxide.

[0067] As used herein "active agents" are compounds that have pharmaceutical utility, e.g. may be used to treat a patient suffering from a disease or condition, or may be used prophylacticly to prevent the onset of a disease or condition in a patient, or that may be used to enhance the pharmaceutical activity of other compounds.

[0068] "Pharmaceutical compositions" are compositions comprising at least one active agent, such as a compound or salt of Formula I or Formula II, and at least one other substance, such as a carrier, excipient, or diluent. Pharmaceutical compositions meet the U.S. FDA's GMP (good manufacturing practice) standards for human or non-human drugs.

[0069] "Salts" of the compounds of the present invention include inorganic and organic acid and base addition salts. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts.

[0070] "Pharmaceutically acceptable salts" includes derivatives of the disclosed compounds wherein the parent compound is modified by making non-toxic acid or base salts thereof, and further refers to pharmaceutically acceptable solvates of such compounds and such salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non- toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH₂)_n-COOH where n is 0-4, and the like. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0071] The term "prodrugs" includes any compounds that become compounds of Formula I when administered to a mammalian subject, e.g., upon metabolic processing of the prodrug. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate and like derivatives of functional groups (such as alcohol or amine groups) in the compounds of Formula I and Formula II.

[0072] The term "therapeutically effective amount" of a compound of this invention means an amount effective, when administered to a human or non-human patient, to provide a therapeutic benefit such as an amelioration of symptoms, e.g., an amount effective to decrease the symptoms of a microbial infection, and or an amount sufficient to reduce the symptoms of a bacterial, fungal, or protozoal infection. In certain circumstances a patient suffering from a microbial infection may not present symptoms of being infected. Thus a therapeutically effective amount of a compound is also an amount sufficient to prevent a significant increase or significantly reduce the detectable level of microorganism or antibodies against the microorganism in the patient's blood, serum, other bodily fluids, or tissues. The invention also includes using compounds of Formula I and Formula II in prophylactic therapies. In the context of prophylactic or preventative treatment a "therapeutically effective amount" is an amount sufficient to significantly decrease the treated animal's risk of contracting a microorganism infection. A significant reduction is any detectable negative change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p < 0.05. ANTIMICROBIAL COMPOUNDS

[0073] As used herein, the following numbering system will apply to the core 9H- isothiazolo[5,4-b]quinoline-3,4-dione (when A₁ = sulfur) structure or the core 9H-isoxazolo[5,4- b]quinoline-3,4-dione (when A₁ = oxygen) structure. The numbers 1 through 9 refer specifically to positions within the tricyclic ring system whereas the letters A, B and C refer to the specific six (rings A and B) or five (ring C) membered rings as shown below.

[0074] Certain embodiments include compounds of Formula I and tautomers thereof of Formula II in which the variables R₂ to R₇, A₈, are as follows.

[0075] R₂ is hydrogen, or R₂ is d-C₆alkyl, C₂-C₆alkenyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl, (aryl)C₀-C₄alkyl, or (C₂-C₆heterocycloalkyl)C₀-C₂alkyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -CONH₂, C₁-C₄alkyl, Q^alkoxy, d-C₂haloalkyl, d-C₂haloalkoxy, and mono- and di-(C_!- C₄)alkylamino, and C₂-C₄alkanoyl.

[0076] R₃ is hydrogen, Q-Cealkyl, or C₂-C₆alkanoyl.

[0077] R₅ is hydrogen, halogen, hydroxy, amino, Q-Qalkyl, C₁-C₂alkoxy, mono- or di- (C₁-GOalkylamino, or mono- or di-(C₁-C4)alkylhydrazinyl.

[0078] R₆ is hydrogen, halogen, hydroxy, amino, cyano, d-Gjalkyl, C_!-C₄alkoxy, mono- or di-(C₁-C₄)alkylamino.

[0079] R₇ is a carbon-linked substituent XR_A, wherein X is absent, -CH₂-CH₂-, -CH=CH- , -(C=O)-, or -C≡C-; wherein R_A is C₃-C₇cycloalkyl, phenyl, pyrid-3-yl, pyrid-4-yl, pyrimidin- 5-yl, furan-3-yl, quinolin-3-yl, quinolin-5-yl, quinolin-6-yl, isoindol-5-yl, tetrahydroisoquinolin- 5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl, tetrahydroisoquinolin-8-yl, or indol- 5-yl. [0080] Or, R₇ is a nitrogen-linked heterocycloalkyl group, which has 4 to 8 ring members, or

[0081] R₇ is a nitrogen-linked C₁-C4alkylamino substituted with a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently chosen from N, O, and S, or substituted with a heterocycloalkyl group, which has 4 to 8 ring members, including 1 or 2 ring heteroatoms independently chosen from N, O, and S, or

[0082] R7 is a nitrogen-linked heterocycloalkyl or heterocycloalkenyl group, each of which has 4 to 8 ring members, including 0, 1, or 2 additional ring heteroatoms independently chosen from N, O, and S, forming part of a bicyclic system with a 3- to 8-membered cycloalkyl or heterocycloalkyl ring in fused or spiro orientation; or

[0083] R7 is a nitrogen-linked 6-membered heterocycloalkyl group, 0, 1 or 2 additional ring heteroatoms independently chosen from N, O, and S, and bridged with a methylene or ethylene bridge.

[0084] Each of which R₇ is substituted with 0 or 1 or more substituents independently chosen from (a) and 0 or 1 substituents chosen from (b); wherein (a) is chosen from halogen, hydroxy, amino, nitro, d-C₄alkyl, d-C^alkoxy, C₁-C₂haloalkyl, and d-C₂haloalkoxy, and (b) is oxo, amino, cyano, hydroxyC₁-C4alkyl, aminoQ^alkyl, C!-C₆alkylthio, C₂-C₆alkanoyl, (mono- or di-C₁-C4alkyl)aminoC₀-C4alkyl, (C3-C₇cycloalkyl)C₀-C4alkyl, (C₃-C₇cycloalkyl)aminoC₀- C₄alkyl, (C₃-C₇cycloalkyl)(C₁-C₄alkyl)aminoCo-C₄alkyl, (heterocycloalkyl)C₀-C₄alkyl, (5- membered heteroaryl) C₀-C₄alkyl, or (aryl)Co-C₄alkyl.

[0085] Each of (b) other than oxo and cyano is substituted with 0 to 2 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH, -CONH₂, Q- C4alkyl, C₂-C4alkenyl, C₂-C4alkynyl, C₁-C4alkoxy, mono- and di-(C₁-C4)alkylamino, C₁- C₂haloalkyl, and C₁-C₂haloalkoxy.

[0086] A8 is N or CR₈; wherein R₈ is hydrogen, halogen, hydroxy, amino, cyano, nitro, or -NHNH₂; or R₈ is C₁-C₆alkyl, d-C_δalkoxy, (C₃-C₇cycloalkyl)C₀-C₂alkyl substituted with 0 or 1 or more halogen substituents, (C₃-C₇cycloalkyl)C₀-C₂alkoxy substituted with 0 or 1 or more halogen substituents, mono- or di-(C₁-C4)alkylamino, mono-, di-, or Ui-(C₁^) alkylhydrazinyl, C₂-C₄alkanoyl, Cj-C₂haloalkyl, or d-C₂haloalkoxy.

[0087] R9 is pyridine, pyrazine, pyridazine, or pyrimidine, each of which is substituted with 0 to 4 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, - COOH, -CONH₂, C₁-C₄EIlCyI, C₂-C₄alkenyl, C₂-C₄alkynyl, d-C₄alkoxy, (C₃-C₇cycloalkyl)C₀- C₄alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkoxy, mono- and di-(C₁-C₄)alkylamino, C₁-C₂HaIOaIlCyI, C₁- C₂haloalkoxy, and C₂-C₄alkanoyl.

[0088] In addition to the compounds of Formula I and Formula II described above, the invention also includes compounds of Formula I and Formula II in which the variables (e.g. A₁, R₂, R₃, R_A, etc.) are independently defined as described below. The A₁ variable

[0089] (1) A₁ is S; e.g. compounds and salts of Formula III and Formula IV are included herein.

[0090] (2) Ai is SO; e.g. compounds and salts of Formula V and VI are included herein:

[0091] (3) A₁ is SO₂; e.g. compounds and salts of Formula VII and VIII are included herein.

[0092] (4) A₁ is O; e.g. compounds and salts of Formula IX and X are included herein.

F DC

F ula X

The R2 variable (compounds and salts of Formula I):

[0093] (1) R₂ is hydrogen, C₁-C₆alkyl or (C₃-C₇cycloalkyl)C₀-C₄alkyl.

[0094] (2) R₂ is hydrogen. The R₃ variable (compounds and salts of Formula II):

[0095] (1) R₃ is hydrogen, C₁-QaHCyI, or C₂-C₆alkanoyl.

[0096] (2) R₃ is hydrogen. The Rs variable

[0097] (1) R₅ is hydrogen, halogen, amino, Q-Qalkyl, C₁-C_∑alkoxy, mono- or di-(d- C₄)alkylamino, or mono- or di-(C₁-C₄)alkylhydrazinyl.

[0098] (2) R₅ is hydrogen. The Rβ variable

[0099] (1) R₆ is hydrogen, halogen, or amino.

[0100] (2) R₆ is fluoro or hydrogen. The R₇ variable

[010I] (I) R₇ is halogen, -0(SO₂)CF₃, or -N₂BF₄.

[0102] (2) R₇ is a carbon-linked substituent XR_A, wherein X is absent, -CH₂-CH₂-, -CH=CH-, -(C=O)-, -(C=O)NH-, or -C≡C-; wherein R_A is C₂-C₆alkyl, C₃-C₇cycloalkyl, C₄- C₇cycloalkenyl, phenyl, a 7-10 membered bicyclic saturated, partially unsaturated, or aromatic carbocyclic group, or a 5-6 membered saturated, partially unsaturated, or aromatic heterocylic group bound via a carbon atom when X is absent or bound via a carbon or nitrogen atom when X is -CH₂-CH₂-, -CH=CH-, or -C≡C-, or R_A is a 7-10 membered bicyclic saturated, partially unsaturated, or aromatic heterocylic group bound via a carbon atom when X is absent or bound via a carbon or nitrogen atom when X is -CH₂-CH₂-, CH=CH- or -C≡C-.

[0103] (3) R₇ is C₁-C₈alkyl, C₂-C₆alkanoyl, (C₃-C₇cycloalkyl)C₀-C₄carbohydryl, (aryl)Co-C4carbohydryl, (aryl)(C=O)-, or Carbon-linked (C₂-C6heterocycloalkyl)Co- C₄carbohydryl, each of which is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, C]-C₄alkyl, Q-Qalkoxy, d-Qhaloalkyl, C₁- C₂haloalkoxy, mono- and di-(C₁-C₄)alkylamino, C₂-C₄alkanoyl, C₁-C4alkylthio, -0(C=O)Ri₀, -(C=0)NRioRii, -0(C=O)NR₁₀RiI, -(C=O)ORi₀, -(C=O)NRi₀ORn, -NRi₀(C=O)R_n, -NRi₀(C=O)ORi₁, -NRi₀(C=O)NR₁₁R₁₂, -NRi₀(C=S)NRi₁R₁₂, -NR₁₀NRi₁R₁₂, -SO₃R₁₀, -(S=O)OR₁₀, -SO₂R₁₃, -SO₂NR₁₀Ri₁, or -NRi₀SO₂R₁₃; wherein R₁₀, Rn, and R₁₂ are independently hydrogen, C₁-C₄alkyl, or aryl, and R]₃ is C₁-C₄alkyl or aryl.

[0104] (4) R₇ is C₁-Cβalkyl, (C₃-C₇cycloalkyl)Co-C₄carbohydryl, (aryl)C₀- C₄carbohydryl, or (C₂-C₆heterocycloalkyl)Co-C₄carbohydryl, each of which is substituted with O to 5 substituents independently chosen from halogen, hydroxy, amino, cyano, d-Gjalkyl, C₁- C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, Cι-C₄aminoalkyl, (C₃-C₇cycloalkyl)d- C₄aminoalkyl, mono- and di-(C₁-C₄)alkylamino, C₂-C₄alkanoyl , -(C=O)NR₁₀Rn, -NR₁₀(C=O)R₁₁, wherein R₁₀ and R₁₁ are independently hydrogen, C₁-Gjalkyl, or aryl.

[0105] (5) R₇ is Q-Qalkyl or (aryl)C₀-C₄alkyl, each of which is substituted with O to 5 substituents independently chosen from halogen, hydroxy, amino, cyano, Q^alkyl, C₁- C4alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C!-C₂hydroxyalkoxy, mono- and di-C₁- C4alkylamino, C₂-C₄alkanoyl, -(C=O)NR₁₀R₁₁, -NR₁₀(C=O)R₁₁; wherein R₁₀ and R₁₁ are independently hydrogen, C₁-C4alkyl, or aryl.

[0106] (6) R₇ is XR_A, wherein X is absent, -CH₂-CH₂-, -CH=CH-, -(C=O)-, or -C≡C-; wherein R_Ais C₃-C₇cycloalkyl, phenyl, pyrid-3-yl, pyrid-4-yl, pyrimidin-5-yl, furan-3- yl, quinolin-3-yl, quinolin-5-yl, quinolin-6-yl, isoindol-5-yl, tetrahydroisoquinolin-5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl, tetrahydroisoquinolin-8-yl, or indol-5-yl, wherein each of which R₇ is substituted with O or 1 or more substituents independently chosen from (a) and O or 1 substituents chosen from (b); where (a) and (b) carry the definitions set forth above.

[0107] (7) R₇ is C₃-C₇cycloalkyl, phenyl, pyrid-3-yl, pyrid-4-yl, pyrimidin-5-yl, furan-3-yl, quinolin-3-yl, quinolin-5-yl, quinolin-6-yl, isoindol-5-yl, tetrahydroisoquinolin-5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl, tetrahydroisoquinolin-8-yl, or indol-5-yl. Each of which R₇ is substituted with O or 1 or more substituents independently chosen from halogen, hydroxy, Q-G_talkyl, C₁-C^aIkOXy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, Each of which R₇ is also substituted with O or 1 amino, cyano, C₁-C₂hydroxyalkoxy, mono- and di-C₁- C₄alkylamino, C₂-C₄alkanoyl, (C₃-C₇cycloalkyl)C₀C₂alkyl, (heterocycloalkyl(C₀-C₂alkyl, or aryl.

[0108] (8) R₇ is a nitrogen-linked heterocycloalkyl group, which has 4 to 8 ring members, including 0, 1 or 2 additional ring heteroatoms independently chosen from N, O, and S which heterocycloalkyl, which R₇ is substituted with 0 or 1 or more substituents independently chosen from (a) and 0 or 1 substituents chosen from (b);

[0109] (9) R₇ is a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or azepanyl group substituted with substituted with 0 to 2 substituents independently chosen from or more of (a) and 0 or 1 substituents (b).

[0110] (10) R₇ is a pyrrolidinyl group, which is substituted with 0 to 2 substituents independently chosen from one or more of (a) and 0 or 1 substituents (b).

[OH l] (I l) R₇ is pyrrolidinyl group optionally substituted with 1 methyl or halogen substituent and substituted with one group (b) wherein (b) is oxo, amino, cyano, hydroxyQ- C₄alkyl, aminoC₁-C₄alkyl, C₂-C₄alkanoyl, (mono- or di-C₁-C₄alkyl)aminoCo-C₄alkyl, (C₃- C₇cycloalkyl)Co-C₂alkyl substituted with amino, (C₃-C₇cycloalkylamino)C₀-C₄alkyl, or (C₃- C₇cycloalkyl)(C₁-C₄alkyl)aminoCo-C₄alkyl.

[0112] (12) R₇ is a pyrrolidinyl group substituted with a (5-membered heteroaryl)C₀- C₄alkyl, which is substituted with 0 to 2 independently chosen from 0 to 2 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH, -CONH₂, C₁- C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₁- C₂haloalkyl, and C₁-C₂haloalkoxy.

[0113] (13) R₇ is a pyrrolidinyl group substituted with a (5-membered heteroaryl)Co- C₄alkyl and the 5-membered heteroaryl is an imidazolyl, thiazolyl, furanyl, oxazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, or oxadiazolyl, each of which R₇ is substituted with 0 to 2 independently chosen from 0 to 2 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH, -CONH₂, d-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁- C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

[0100] (14) R₇ is a pyrrolidinyl group substituted with a (5-membered heteroaryl)C₀- C₄alkyl wherein the 5-membered heteroaryl is a thiazolyl methyl group substituted with amino or an oxazolyl methyl group substituted with amino.

[0101] (15) R₇ is

[0102] ( 16) R₇ is a group of formula

wherein R15 is (a) or (b); R₁₆ is O, 1, or more substituents independently chosen from chloro, fluoro, methyl, or methoxy; and R₁₇ is hydrogen, chloro, fluoro, amino, methyl, ethyl, methoxy, C₁-C₆ alkyl substituted with amino or hydroxy, or mono- or di-(Co-C4)alkylamino In certain embodiments Ri₅ is oxo, cyano, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl, acetyl, (mono- or di-C₁-C₂alkylamino)C₁-C₄alkyl, cyclopropyl substituted with amino, or (C₃- C₇cycloalkylamino)Co-C₄alkyl; and R₁₆ is 0 or 1 substituent chosen from hydroxy, amino, chloro, and methyl.

[0103] (17) R₇ is a group of the formula

[0104] (15) R₇ is a nitrogen-linked Cj-C₄alkylamino substituted with a 5 or 6- membered heteroaryl group having 1 or 2 heteroatoms independently chosen from N, O, and S, or substituted with a heterocycloalkyl group, which has 4 to 8 ring members, including 1 or 2 ring heteroatoms independently chosen from N, O, and S. Each of which R₇ is substituted with 0 or 1 or more substituents independently chosen from (a) and 0 or 1 substituents chosen from (b).

[0105] (16) R₇ is C₁-C₂alkylamino substituted with pyridyl, piperazinyl, piperidinyl, or morpholinyl, each of which is substituted with 0, 1, or 2 substituents independently chosen from halogen, methyl, and methoxy.

[0106] (17) R₇ is a nitrogen-linked heterocycloalkyl or heterocycloalkenyl group, each of which has 4 to 8 ring members, including 0, 1, or 2 additional ring heteroatoms independently chosen from N, O, and S, forming part of a bicyclic system with a 3- to 8-membered cycloalkyl or heterocycloalkyl ring in fused or spiro orientation, Each of which R₇ is substituted with 0 or 1 or more substituents independently chosen from (a) and 0 or 1 substituents chosen from (b), where (a) and (b) carry the definitions set forth above.

[0107] (18) R₇ is a piperidinyl, piperazinyl, or pyrrolidinyl group, which is part of a bicyclic system having a spiro attached C₃-C₄cycloalkyl, dioxolanyl, or azetidinyl group, which bicyclic system is substituted with 0, 1, or 2 substituents independently chosen from halogen, hydroxy, amino, oxo, cyano, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy. [0108] ( 19) R₇ is a group of formula:

The A₈ variable

[0109] (1) A₈ is nitrogen.

[0110] (2) A₈ Is CR₈.

[0111] (3) A₈ is CR₈, and R₈ is hydrogen, halogen, C₁-C₂alkyl, C₁-C₂alkoxy, C₁- C₂haloalkyl, or C₁-C₂haloalkoxy.

[0112] (4) A₈ is CR₈, and R₈ is hydrogen, halogen, or d-C₂alkoxy.

[0113] (5) A₈ is CR₈ and R₈ is methoxy. The R₉ Variable

[0114] (1) R₉ is pyridine, pyrazine, pyridazine, or pyrimidine, each of which is substituted with 1 to 4 substituents independently chosen from halogen, amino, C₁-C₄alkyl, and mono- and di-(C₁-C4)alkylamino.

[0115] (2) R₉ is pyridine which is substituted with 1 to 4 substituents independently chosen from halogen, amino, Cj^alkyl, and mono- and di-(C₁-C₄)alkylamino; [0116] (3) R.₉ is pyridine, which is substituted with 1 to 4 substituents independently chosen from halogen, amino, Q^alkyl, and mono- and di-(C₁-C4)alkylamino. [0117] (4) R.9 is pyridine group of the formula

2O

wherein R₂₀ is hydrogen or C₁.C-jalkyl; and R₂₁ and R₂₂are independently chosen halogen substituents. In some embodiments R₂₀ is hydrogen, and R₂i and R₂₂ are both fluoro.

[0118] Any of the above conditions may be combined, so long as a stable compounds of Formula I results. For example the invention includes compounds and salts of Formula I in which condition (2) is met for variables R₂, R₅, and R^, condition (10) is met for the R₇ variable, condition (3) is met for A₈ and condition (4) is met for R₉. Thus, the invention includes compounds and salts in which:

R₂ and R₅ are hydrogen;

R₆ is fluoro or hydrogen;

R₇ is a pyrrolidinyl group, which is substituted with 0 to 2 substituents independently chosen from one or more of (a) and 0 or 1 substituent (b);

A₈ is CR₈, and R« is hydrogen, halogen, Q-Qalkyl, d-C₂alkoxy, Cι-C₂haloalkyl, or Cj- C₂haloalkoxy; and

R₉ is pyridine group of the formula

₂₀ 21 wherein R₂₀ is hydrogen or C_1-C₄alkyl; and R₂₁ and R₂₂are independently chosen halogen substituents. In some embodiments R₂₀ is hydrogen, and R₂i and R₂₂ are both fluoro. [0119] In one embodiment, the invention includes compounds of Formulas XI and XII shown below:

wherein R₆ is hydrogen or halogen; and R₈ is hydrogen, halogen, C₁-C₂alkyl, C₁-C₂alkoxy, trifluoromethyl, or trifluoromethoxy. In other embodiments R₈ is hydrogen, halogen, C]-C₂alkyl, or C!-C₂alkoxy or R₈ is methoxy.

[0120] Certain compounds of Formula I and Formula II possess potent antibacterial, antifungal, and/or anti-protozoal activity. Particular compounds of the invention exhibit Minimum Inhibitory Concentrations (MIC) of 64 μg/ ml or less against Staphyloccocus aureus and/ or Escherichia coli in a standard assay for determining the MIC of a compound against these bacteria, such as the assay provided in Example 5 below. Preferred compounds of the Formula I and II exhibit MIC values of 10 μg/ ml or less against Staphyloccocus aureus and/ or Escherichia coli. More preferred compound of the Formula I and II exhibit MIC values of 4 μg/ ml or less, or even more preferably 1 μg/ ml or less, against Staphyloccocus aureus and/ or Escherichia coli.

[0121] Certain compounds of Formula I and Formula II are selective antimicrobial agents; having the ability to kill or inhibit the growth or reproduction of microbial organisms, while having little or no effect on the cells of fish, amphibians, reptiles, birds, or mammals. The selectivity of compounds of Formula I and Formula II may be assessed by determining the CC₅₀ (the concentration at which 50% of the cells are killed) for cultured cells of a higher animal, such as a fish, reptiles, amphibian, bird, or mammal. Certain compounds of the invention exhibit a CC₅₀ of greater that 100 micromolar for mammalian cells. Certain compounds of the invention exhibit a CC₅₀ of greater than 100 micromolar for cultured human hepatocytes, and also exhibit MIC values of 64 μg/ ml or less, preferably 10 μg/ ml or less, or more preferably 4 μg/ ml or less, or still more preferably 1 μg/ ml or less against Staphylococcus aureus and/ or Escherichia coli.

[0122] Without wishing to be bound to any particular theory it is believed that the antimicrobial properties of compounds of Formula I and Formula II are due to the ability to these compounds to inhibit the activity of microbial DNA gyrases while having little or no effect on the analogous enzyme, Topoisomerase II, present in higher organisms. Certain preferred compound of the invention are 100- fold or more selective for bacterial DNA gyrases than for mammalian, particularly human, Topoisomerase II.

SYNTHETIC INTERMEDIATES

[0123] The invention also includes novel intermediates useful for the synthesis of antimicrobial compounds of Formula I and Formula II. Compounds in which R₇ is a substituent, XR_A, attached via a carbon-carbon are formed by coupling reactions occur between (XR_A)-M and R-Y in the presence of catalyst Q, where M is Li, Mg, B, Al, Si, Zn, Cu, Zr, or Sn; where Y is I, Br, Cl, -0(SO₂)CF₃, or -N₂BF₄; and where Q is Fe, Ni, Cu, Pd, or Rh. In certain embodiments M is Boron, di-substituted with OH, OG, or G, where G is an optionally substituted straight, branched or cyclic alkyl group, or other suitable group; Y is Br, and where Q is Pd. A general review of this chemistry can be found in Tamao, K and Miyaura, N. Topics in Current Chemistry 219: 1-9 (2002). A review of the use of coupling reagents in which M is Boron with a listing of potential boronates, palladium catalysts, and reaction conditions can be found in Miyaura, N. Topics in Current Chemistry 219: 11-59 (2002).

[0124] Thus, the invention includes synthetic intermediates of Formula XIII and XIV

FU

F useful for synthesis of compounds of Formula I and II in which R₇ is a substituent bound via a carbon-carbon bond. Within Formula XIII and Formula XIV A₁, Ag, R₂, R₃, R₅, R₆, and R₉ carry the definitions set forth above and Y is I, Br, Cl, -0(SO₂)CF₃, or -N₂BF₄. These intermediates are coupled to compounds of the Formula (XR_A)-M where X and R_A carry the definitions set forth above.

[0125] The invention also includes synthetic intermediates of Formula XIII and XIV, above, in which Y is fluoro. Such compounds are useful for synthesis of compounds of Formula I and Formula II in which R₇ is a substituent bound via a nitrogen-carbon bond.

ANTI-MICROBIAL AND PHARMACEUTICAL PREPARATIONS

[0126] The invention provides anti-microbial compositions, including anti-bacterial compositions, comprising a compound or salt thereof of Formula I or Formula II, together with a carrier, diluent, and/or excipient.

[0127] In certain embodiments the invention provides pharmaceutical compositions comprising a compound or salt thereof of Formula I or Formula II.

[0128] Compounds and salts of Formula I and Formula II can be administered as the neat chemical, but are preferably administered as a pharmaceutical composition or formulation. Accordingly, the invention provides pharmaceutical formulations comprising a compound or pharmaceutically acceptable salt of Formula I or Formula II, together with one or more pharmaceutically acceptable carrier, excipients, adjuvant, diluent, or other ingredient. The pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution.

[0129] Compounds and salts of the invention can be administered as the neat chemical, but are preferably administered as a pharmaceutical composition or formulation. Accordingly, the invention provides pharmaceutical formulations comprising a compound or pharmaceutically acceptable salt of Formula I, together with one or more pharmaceutically acceptable carriers, excipients, adjuvant, diluent, or other ingredients.

[0130] Compounds and salts of the invention may be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, via buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage unit formulations. Compounds and salts of Formula I may be prepared and administered as orally administrable liquid formulations, suspensions, emulsions, dispersible powders, solid oral dosage forms such as tablets or capsules, injectable and parenteral formulations, suppositories, topical formulations, sublingual, buccal, or nasal dosage forms.

[0131] The invention also includes methods for making pharmaceutical compositions comprising a compound or salt of Formula I.

[0132] Excipients must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the animal being treated. An excipient can be inert or it can possess pharmaceutical benefits. The amount of excipient employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.

[0133] Carriers and excipients are selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, a compound or salt of Formula I may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like. Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated I in the mixture

[0134] Also included herein are pharmaceutical compositions comprising pharmaceutical formulations in a unit dosage form, hi such form, the preparation is subdivided into i suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.

[0135] Examples of binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Examples of lubricants useful in pharmaceutical dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Examples of disintegrants include starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate. Disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below.

[0136] Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of I any one or more of the components or active ingredients to optimize the therapeutic effects, i.e. HCV inhibitory activity and the like. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices: impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.

[0137] Amount of compound or salt of Formula I in a unit dose may be generally varied or adjusted from about 1.0 milligram to about 1,000 milligrams, from about 1.0 to about 950 milligrams, from about 1.0 to about 500 milligrams, or from about 1 to about 250 milligrams, according to the particular application and the potency of the compound. The actual dosage employed may be varied depending upon the patient's age, sex, weight and severity of the condition being treated.

[0138] The invention includes solid dosages forms such as tablets and capsules. In some embodiments a compound or salt of Formula I comprises about 5 percent to about 95 percent by weight of the solid dosage form. A capsule is a dosage form administered in a special container or enclosure containing an active agent. The active agent may be present in solid, liquid, gel, or powder form, or any other pharmaceutically acceptable form. A capsule shell may be made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch or other material. Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives. Conventional methods for preparing tablets are known. Such methods include dry methods such as direct compression and compression of granulation produced by compaction, or wet methods or other special procedures. Conventional methods for preparing other solid dosage forms, for example, capsules, suppositories and the like are also well known.

[0139] Also included are solid form preparations that are intended to be converted shortly before use to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

[0140] Liquid form preparations include solutions, suspensions, and emulsions. Examples of liquid pharmaceutical preparations include water or water-propylene glycol solutions for parenteral injections and sweetened solutions for oral dosage forms, suspensions, and emulsions. Liquid form preparations may also include solutions for intranasal administration. [0141] Aerosol preparations suitable for inhalation include solutions and: solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as inert, compressed gas, e.g. nitrogen.

[0142] Suppository formulations may contain a low melting wax such as a mixture of fatty acid glycerides such as cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized: molds, allowed to cool and thereby solidify.

[0143] The compounds of the invention may also be deliverable transdermally. The transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are

[0144] An oral gel is a formulation in which the active agent dispersed or solubilized in a hydrophillic semi-solid matrix. An oral gel may be administered as a complete dosage form or may be contained in a capsule.

[0145] Diluents often comprise a major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potato; and celluloses such as microcrystalline cellulose. The amount of diluent in the composition may be, for example, about 10 to about 90% by weight of the total composition, about 25 to about 75%, about 30 to about 60% by weight, or about 12 to about 60%.

[0146] Disintegrants are materials added to a pharmaceutical composition to help it break apart (disintegrate) and release the active agent. Suitable disintegrants include starches; including "cold water soluble" modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust I bean, karaya, guar, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures. The amount of disintegrant in the composition can range, for example, from about 2 to about 15% by weight of the composition or from about 4 to about 10% by weight.

[0147] Binders are substances that bind or "glue" powders together and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose; starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as; methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate. The amount of binder in the composition can range, for example, from about 2 to about 20% by weight of the composition, or from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.

[0148] Lubricants are substances added to a pharmaceutical formulation to enable the tablet, granules, etc. after it has been compressed, to release from the; mold or die by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and di-leucine. Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press. The amount of lubricant in the composition can range, for example, from about 0.2 to about 5% by weight of the composition, from about 0.5 to about 2%, or from about 0.3 to about 1.5% by weight.

[0149] Glidents are materials that prevent caking and improve the flow characteristics of granulations, so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition can range, for example, from about 0.1% to about 5% by weight of the total composition or from about 0.5 to about 2% by weight.

[0150] Coloring agents provide coloration to the composition or dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent can vary, for example from about 0.1 to about 5% by weight of the composition or from about 0.1 to about 1%.

PACKAGED FORMULATIONS

[0151] The invention includes packaged pharmaceutical formulations. Such packaged formulations include a pharmaceutical composition containing one or more compounds or salts of Formula I or Formula II in a container and instructions for using the composition to treat an animal (typically a human patient) suffering from a microorganism infection) or prevent a microorganism infection in an animal.

[0152] The instructions may also be instructions for using the composition to treat a patient suffering from a bacterial infection, such as a S. aureus infection.

[0153] In all of the foregoing the compounds of the invention can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication.

METHODS OF TREATMENT

[0154] The invention includes methods of preventing and treating microorganism infections, particularly bacterial and protozoal infections, by administering an effective amount of one or more compounds of Formula I or Formula II to an animal at risk for a microorganism infection or suffering from a microorganism infection. The animal may be a fish, amphibian, reptile or bird, but is preferably a mammal. Methods of treating and preventing microorganism infections in livestock animals, companion animals, and human patients are particularly preferred.

[0155] The compounds disclosed herein are useful for preventing and treating bacterial infections in animals. Furthermore compounds of the invention may be used to treat a variety of conditions not attributed to bacterial infections. These include diseases and disorders caused fungal infections, mycoplasma infections, protozoal infections, or other conditions involving infectious organisms.

[0156] hi some circumstances an effective amount of a compound of Formula I or Formula II may be an amount sufficient to reduce the symptoms of the microorganism infection. Alternatively an effective amount of a Compound of Formula I may be an amount sufficient to significantly reduce the amount of microorganism or antibodies against the detectable in a patient's tissues or bodily fluids.

[0157] Methods of treatment also include inhibiting microorganism replication in vivo, in an animal at risk for a microorganism infection or suffering from such an infection, by administering a sufficient concentration of a compound of Formula I and Formula II to inhibit bacterial survival in vitro. By "sufficient concentration" of a compound administered to the patient is meant the concentration of the compound available in the animal's system to prevent or combat the infection. Such a concentration by be ascertained experimentally, for example by assaying blood concentration of the compound, or theoretically, by calculating bioavailability. The amount of a compound sufficient to inhibit bacterial survival in vitro may be determined with a conventional assay for bacterial survival such as the Minimum Inhibitory Concentration (MIC) Assay disclosed in Example 5, which follows.

[0158] The invention also includes using compounds of Formula I and Formula II in prophylactic therapies. In the context of prophylactic or preventative treatment an effective amount of a compound of the invention is an amount sufficient to significantly decrease the treated animal's risk of contracting a microorganism infection.

[0159] Compounds of the invention are particularly useful for treating and preventing infectious disorders. These include for example: ocular infections such as conjunctivitis; urinary tract and genital infections, such as complicated urinary tract infections, acute urinary tract and genital infections, such as pyelonephritis, cervical gonococcal infections, cystitis, urethral chlamydial infections, cervical chlamydial infections, urethral gonococcal infections, and prostatitis, respiratory infections, such as lower respiratory tract infections, acute sinusitis, acute exacerbations of chronic bronchitis, community-acquired pneumonia, and nosocomial pneumonia, skin infections, such as skin-structure infections, impetigo, folliculitis, boils, scalded skin syndrome, and cellulites, and other infections such as bone infections, joint infections, infectious diarrhea, typhoid fever, intra-abdominal infections, gynecologic infections, including toxic shock syndrome, pelvic infections, and post-surgical infections.

[0160] The disclosed compounds are useful for treating infections caused by the following microorganisms:

[0161] Aerobic Gram-positive Microorganisms: Including but not limited to Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus (including methicillin S. aureus), Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pneumoniae, Streptococcus pyogenes , Staphylococcus haemolyticus, and Staphylococcus hominis;

[0162] Aerobic Gram-negative Microorganisms: Including but not limited to Campylobacter jejuni, Citrobacter diversus, Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa, Stenotrophomonas maltophila, Salmonella typhi, Serratia marcescens, Shigella boydii. Shigella dysenteriae, Shigella flexneri, Shigella sonnei. Acinetobacter Iwoffi, Aeromonas hydrophila, Edwardsiella tarda, Enter obacter aerogenes, Klebsiella oxytoca, Legionella pneumophila, Pasteurella multocida, Salmonella enteritidis, Vibrio cholerae, Vibrio par ahaemolyticus, Vibrio vulnificus, Yersinia enterocolitica and H. Pylori.

[0163] Non-bacterial microorganisms: Mycoplasma, Legionella and Chlamydia.

[0164] Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.

[0165] Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most infectious disorders, a dosage regimen of 4 times daily or less is preferred and a dosage regimen of 1 or 2 times daily is particularly preferred.

[0166] It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

COMBINATION ADMINISTRATION

[0167] The compounds of the invention may also be useful in combination with other pharmaceutically active agents such as antibacterial agents, antiviral agents, antifungal agents, antiinflammatories, interferon, efflux-pump inhibitors, and beta-lactamase inhibitors. Antibiotic agents include any molecule that tends to prevent, inhibit or destroy life and as such, includes anti-bacterial agents, anti-fungicides, anti-viral agents, and anti-parasitic agents.

[0168] Pharmaceutical compositions of the invention include single dosage forms containing of a compound of Formula I and/or Formula II and one or more other active agent, dosage forms containing more than one compound of Formula I and/ or Formula II, and separate administration of a compound of Formula I and/or Formula II with another active agent. [0169] The following active agents, which are useful in combinations of the invention, may be isolated from an organism that produces the agent or synthesized by methods known to those of ordinary skill in the art of medicinal chemistry or purchased from a commercial source.

[0170] Anti-bacterial antibiotic agents include, but are not limited to, penicillins, cephalosporins, carbacephems, cephamycins, carbapenems, monobactams, aminoglycosides, glycopeptides, quinolones, tetracyclines, macrolides, and fluoroquinolones (see Table below). Examples of antibiotic agents include, but are not limited to, Penicillin G (CAS Registry No.: 61- 33-6); Methicillin (CAS Registry No.: 61-32-5); Nafcillin (CAS Registry No.: 147-52-4); Oxacillin (CAS Registry No.: 66- 79-5); Cloxacillin (CAS Registry No.: 61-72-3); Dicloxacillin (CAS Registry No.: 3116-76-5); Ampicillin (CAS Registry No.: 69-53-4); Amoxicillin (CAS Registry No.: 26787-78-0); Ticarcillin (CAS Registry No. : 34787-01-4); Carbenicillin (CAS Registry No.: 4697-36-3); Mezlocillin (CAS Registry No.: 51481-65-3); Azlocillin (CAS Registry No.: 37091-66-0); Piperacillin (CAS Registry No.: 61477-96-1); Imipenem (CAS Registry No.: 74431-23-5); Aztreonam (CAS Registry No.: 78110-38-0); Cephalothin (CAS Registry No.: 153-61-7); Cefazolin (CAS Registry No.: 25953-19-9); Cefaclor (CAS Registry No.: 70356-03-5); Cefamandole formate sodium (CAS Registry No.: 42540-40-9); Cefoxitin (CAS Registry No.: 35607-66-0); Cefuroxime (CAS Registry No.: 55268-75-2); Cefonicid (CAS Registry No.: 61270-58-4); Cefmetazole (CAS Registry No.: 56796-20-4); Cefotetan (CAS Registry No.: 69712-56-7); Cefprozil (CAS Registry No.: 92665-29-7); Loracarbef (CAS Registry No.: 121961-22-6); Cefetamet (CAS Registry No.: 65052-63-3); Cefoperazone (CAS Registry No.: 62893-19-0); Cefotaxime (CAS Registry No.: 63527-52-6); Ceftizoxime (CAS Registry No.: 68401-81-0); Ceftriaxone (CAS Registry No.: 73384-59-5); Ceftazidime (CAS Registry No. : 72558-82-8); Cefepime (CAS Registry No.: 88040-23-7); Cefixime (CAS Registry No.: 79350-37-1); Cefpodoxime (CAS Registry No.: 80210-62-4); Cefsulodin (CAS Registry No.: 62587-73-9); Fleroxacin (CAS Registry No.: 79660-72-3); Nalidixic acid (CAS Registry No.: 389-08-2); Norfloxacin (CAS Registry No.: 70458-96-7); Ciprofloxacin (CAS Registry No.: 85721-33- 1); Ofloxacin (CAS Registry No.: 82419-36-1); Enoxacin (CAS Registry No.: 74011-58-8); Lomefloxacin (CAS Registry No.: 98079-51-7); Cinoxacin (CAS Registry No.: 28657-80-9); Doxycycline (CAS Registry No.: 564-25_:0); Minocycline (CAS Registry No.: 10118-90-8); Tetracycline (CAS Registry No. : 60-54-8); Amikacin (CAS Registry No.: 37517-28-5); Gentamicin (CAS Registry No.: 1403-66-3); Kanamycin (CAS Registry No.: 8063-07-8); Netilmicin (CAS Registry No.: 56391-56-1); Tobramycin (CAS Registry No.: 32986-56-4); Streptomycin (CAS Registry No.: 57-92-1); Azithromycin (CAS Registry No.: 83905-01-5); Clarithromycin (CAS Registry No.: 81103-11-9); Erythromycin (CAS Registry No.: 114-07-8); Erythromycin estolate (CAS Registry No.: 3521-62-8); Erythromycin ethyl succinate (CAS Registry No.: 41342-53-4); Erythromycin glucoheptonate (CAS Registry No.: 23067-13-2); Erythromycin lactobionate (CAS Registry No.: 3847-29-8); Erythromycin stearate (CAS Registry No.: 643-22-1); Vancomycin (CAS Registry No.: 1404- 90-6); Teicoplanin (CAS Registry No.: 61036-64-4); Chloramphenicol (CAS Registry No.: 56-75-7); Clindamycin (CAS Registry No.: 18323-44-9); Trimethoprim (CAS Registry No.: 738-70-5); Sulfamethoxazole (CAS Registry No.: 723-46-6); Nitrofurantoin (CAS Registry No.: 67-20-9); Rifampin (CAS Registry No.: 13292-46-1); Mupirocin (CAS Registry No.: 12650-69-0); Metronidazole (CAS Registry No.: 443-48-1); Cephalexin (CAS Registry No.: 15686-71-2); Roxithromycin (CAS Registry No.: 80214-83-1); Co- amoxiclavuanate; combinations of Piperacillin and Tazobactam; and their various salts, acids, bases, and other derivatives.

[0171] Anti-fungals agents include but are not limited to Amphotericin B, Candicidin, Dermostatin, Filipin, Fungichromin, Hachimycin, Hamycin, Lucensomycin, Mepartricin, Natamycin, Nystatin, Pecilocin, Perimycin, Azaserine, Griseofulvin, Oligomycins, Neomycin, Pyrrolnitrin, Siccanin, Tubercidin, Viridin, Butenafine, Naftifme, Terbinafine, Bifonazole, Butoconazole, Chlordantoin, Chlormidazole, Cloconazole, Clotrimazole, Econazole, Enilconazole, Fenticonazole, Flutrimazole, Isoconazole, Ketoconazole, Lanoconazole, Miconazole, Omoconazole, Oxiconazole, Sertaconazole, Sulconazole, Tioconazole, Tolciclate, Tolindate, Tolnaftate, Fluconawle, Itraconazole, Saperconazole, Terconazole, Acrisorcin, Amorolfϊne, Biphenamine, Bromosalicylchloranilide, Buclosamide, Calcium Propionate, Chlorphenesin, Ciclopirox, Cloxyquin, Coparaffinate, Diamthazole, Exalamide, Flucytosine, Halethazole, Hexetidine, Loflucarban, Nifuratel, Potassium Iodide, Propionic Acid, Pyrithione, Salicylanilide, Sodium Propionate, Sulbentine, Tenonitrozole, Triacetin, Ujothion, Undecylenic Acid, and Zinc Propionate.

[0172] Antiviral agents include, but are not limited to, Acyclovir, Cidofovir, Cytarabine, Dideoxyadenosine, Didanosine, Edoxudine, Famciclovir, Floxuridine, Ganciclovir, Idoxuridine, Inosine Pranobex, Lamivudine, MADU, Penciclovir, Sorivudine, Stavudine, Trifluridine, Valacyclovir, Vidarabine, Zalcitabine, Zidovudine, Acemannan, Acetylleucine, Amantadine, Amidinomycin, Delavirdine, Foscarnet, Indinavir, Interferon-α, Interferon-β, Interferon-γ, Kethoxal, Lysozyme, Methisazone, Moroxydine, Nevirapine, Podophyllotoxin, Ribavirin, Rimantadine, Ritonavir, Saquinavir, Stailimycin, Statolon, Tromantadine, and Xenazoic Acid.

[0173] Antiinflammatory agents include, but are not limited to, Enfenamic Acid, Etofenamate, FIufenamic Acid, Isonixin, Meclofenamic Acid, Mefenamic Acid, Niflumic Acid, Talniflumate, Terofenamate, Tolfenamic Acid, Aceclofenac, Acemetacin, Alclofenac, Amfenac, Amtolmetin Guacil, Bromfenac, Bufexamac, Cinmetacin, Clopirac, Diclofenac, Etodolac, Felbinac, Fenclozic Acid, Fentiazac, Glucametacin, Ibufenac, Indomethacin, Isofezolac, Isoxepac, Lonazolac, Metiazinic Acid, Mofezolac, Oxametacine, Pirazolac, Proglumetacin, Sulindac, Tiaramide, Tolmetin, Tropesin, Zomepirac, Bumadizon, Butibufen, Fenbufen, Xenbucin, Clidanac, Ketorolac, Tinoridine, Alminoprofen, Benoxaprofen, Bermoprofen, Bucloxic Acid, Carprofen, Fenoprofen, Flunoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin, Piketoprofen, Pirprofen, Pranoprofen, Protizinic Acid, Suprofen, Tiaprofenic Acid, Ximoprofen, Zaltoprofen, Difenamizole, Epirizole, Apazone, Benzpiperylon, Feprazone, Mofebutazone, Morazone, Oxyphenbutazone, Phenylbutazone, Pipebuzone, Propyphenazone, Ramifenazone, Suxibuzone, Thiazolinobutazone, Acetaminosalol, Aspirin, Benorylate, Bromosaligenin, Calcium Acetylsalicylate, Diflunisal, Etersalate, Fendosal, Gentisic Acid, Glycol Salicylate, Imidazole Salicylate, Lysine Acetylsalicylate, Mesalamine, Morpholine Salicylate, I-Naphthyl Salicylate, Olsalazine, Parsalmide, Phenyl Acetylsalicylate, Phenyl Salicylate, Salacetamide, Salicylamide O-Acetic Acid, Salicylsulfuric Acid, Salsalate, Sulfasalazine, Ampiroxicam, Droxicam, Isoxicam, Lornoxicam, Piroxicam, Tenoxicam, epsilon-Acetamidocaproic Acid, S- Adenosylmethionine, 3-Amino-4-hydroxybutyric Acid, Amixetrine, Bendazac, Benzydamine, alpha-Bisabolol, Bucolome, Difenpiramide, Ditazol, Emorfazone, Fepradinol, Guaiazulene, Nabumetone, Nimesulide, Oxaceprol, Paranyline, Perisoxal, Proquazone, Superoxide Dismutase, Tenidap, Zileuton, 21-Acetoxypregnenolone, Alclometasone, Algestone, Amcinonide, Beclomethasone, Betamethasone, Budesonide, Chloroprednisone, Clobetasol, Clobetasone, Clocortolone, Cloprednol, Corticosterone, Cortisone, Cortivazol, Deflazacort, Desonide, Desoximetasone, Dexamethasone, Difiorasone, Diflucortolone, Difluprednate, Enoxolone, Fluazacort, Flucloronide, Flumethasone, Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone, Fluorometholone, Fluperolone Acetate, Fluprednidene Acetate, Fluprednisolone, Flurandrenolide, Fluticasone Propionate, Formocortal, Halcinonide, Halobetasol Propionate, Halometasone, Halopredone Acetale, Hydrocortamate, Hydrocortisone, Loteprednol Etabonale, Mazipredone, Medrysone, Meprednisone, Methylprednisolone, Mometasone Furoate, Paramethasone, Prednicarbate, Prednisolone, Prednisolone 25- Diethylamino-acetate, Prednisolone Sodium Phosphate, Prednisone, Prednival, Prednylidene, Rimexolone, Tixocortol, Triamcinolone, Triamcinolone Acetonide, Triamcinolone Benetonide, and Triamcinolone Hexacetonide.

[0174] Compounds of the invention may be combined with one or more Beta lactamase inhibitor when used in combination with a beta-lactam class antibiotic, such as penicillin or cephalosporins. Beta-lactamase inhibitors include, but are not limited to Clavulanic acid, Sulbactam, Sultamacillin, and Tazobactam.

[0175] Compounds of the invention may also be combined with one or more efflux pump inhibitor, such as a quinazolinone efflux pump inhibitors, d-ornithine-d-homophenylalanine-3- aminoquinoline, Phe-Arg-b-naphthylamide, propafenone, a phenothiazine or thioxanthene efflux pump inhibitor, l-aza-9-oxafluorenes, N-[4-[2-(3,4-dihydro-6,7-dimethoxy-2(lH)- isoquinolinyl)ethyl]phenyl]-9, 10-dihydro-5-methoxy-9-oxo-4-Acridinecarboxamide, reserpine, Milbemycin, Cinchonine, Verapamil, L-phenylalanyl-N-2-naphthalenyl-L-Argininamide (and analogs), 5'-methoxyhydnocarpin-D, methylxanthines, FK506, a cyclosporine efflux pump inhibitor, Nocardamine and other siderophores, Amiodarone, Cyclosporin A, RoI 1-2933 (DMDP), Quinidine, and the optical isomers of Propranolol, Quinine (SQl) and Quinidine, Quinine- 10, 11 -epoxide, Quercetin, Amitriptyline, Taxuspine C derivatives, Emodin, MC- 002434; Agosterol A; Pheophorbide; pyridoquinolines such as 2,2'-[(2,8,10-trimethylpyrido[3,2- g]quinoline-4,6-diyl)bis(oxy)]bis[N,N-dimethyl-ethanamine, Gitonavir, and Gemfibrozil.

SYNTHESIS OF COMPOUNDS

[0176] The compounds of the invention are prepared according to methods well-known to those skilled in the art of organic chemical synthesis. The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available.

[0177] It is recognized that the skilled artisan in the art of organic chemistry can readily carry out standard manipulations of organic compounds without further direction. Examples of such manipulations are discussed in standard texts such as J. March, Advanced Organic Chemistry. John Wiley & Sons, 1992.

[0178] The skilled artisan will readily appreciate that certain reactions are best carried out when other functionalities are masked or protected in the compound, thus increasing the yield of the reaction and/or avoiding any undesirable side reactions. Often, the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many such manipulations can be found in, for example, T. Greene, Protecting Groups in Organic Synthesis. John Wiley & Sons, 1981.

[0179] In addition, it is recognized that one optical isomer, including a diastereomer and enantiomer, or a stereoisomer, may have favorable properties over the other. When a racemic mixture is discussed herein, it is clearly contemplated to include both optical isomers, including diastereomers and enantiomers, or one stereoisomer substantially free of the other.

[0180] This invention is further illustrated by the following examples that should not be construed as limiting.

EXAMPLES ABBREVIATIONS

[0181] The following abbreviations are used in the reaction schemes and synthetic examples, which follow. This list in not meant to be an all-inclusive list of abbreviations used in the application as additional standard abbreviations, which are readily understood by those skilled in the art of organic synthesis, may also be used in the synthetic schemes and examples. Aq. - Aqueous

DMF - N,N-Dimethylformamide DMSO - Dimethyl sulfoxide EtOAc- Ethyl Acetate Me - Methyl MeI - Methyl Iodide NMP - N-Methylpyrrolidone PPh₃ - Triphenyl phosphate rt - Room Temperature THF - Tetrahydrofuran GENERAL METHODS.

[0182] All nonaqueous reactions are performed under an atmosphere of dry argon gas (99.99%) using oven- or flame-dried glassware. Microwave-assisted syntheses are conducted in a commercial microwave reactor (Discover System, CEM Corporation). The progress of reactions is monitored using thin-layer chromatography (TLC) on glass plates coated with Merck silica gel 60 (F₂₅₄). Flash column chromatography is performed on Merck silica gel 60 (230-400 mesh). NMR spectra are recorded at ambient temperature using a Bruker Avance 300 spectrometer (¹H at 300.1 MHz, ¹³C at 75.5 MHz, and ¹⁹F at 282.4 MHz). The chemical shifts for ¹H and ¹³C are reported in parts per million (δ) relative to external tetramethylsilane and are referenced to signals of residual protons in the deuterated solvent. The chemical shifts for ¹⁹F are reported in parts per million (S) relative to external fluorotrichloromethane. Assignment of NMR data is based on two-dimensional correlation experiments (¹H-¹H COSY, ¹H-¹³C HMQC, ¹H-¹³C HMBC, and ¹H-¹H NOESY) and the usual principles of NMR spectroscopy (the magnitudes of coupling constants and chemical shifts). Analytical HPLC is performed using a YMC Pack Pro Cl 8 50 x 4.6 mm 5 μm column with an isocratic elution of 0.24 min at 90:10 H₂OiCH₃CN containing 0.1% TFA followed by a 4-min linear gradient elution from 90:10 to 10:90 at a flow rate of 2.5 mL/min with UV detection at 254 nm. Unless noted otherwise, preparative HPLC is performed using a YMC Pack Pro Cl 8 150 x 20.0 mm 5 μm column with an isocratic elution of 0.24 min at 97:3 H₂O:CH₃CN containing 0.1% TFA followed by a 10-min linear gradient elution from 97:3 to 0:100 at a flow rate of 18.0 mL/min with UV detection at 254 nm. Low-resolution mass spectra are recorded on a Thermo Finnigan Surveyor MSQ instrument (operating in APCI mode) equipped with a Gilson liquid chromatograph. Unless noted otherwise, the quasi-molecular ions, [M + H]⁺, observed in the low-resolution mass spectra are the base peaks. Elemental analyses are performed at Atlantic Microlab, Inc. (Norcross, GA). EXAMPLE 1. SYNTHESIS OF AN 8-SUBSTITUTED 9-(6-AMINO-3,5-DIFLUOROPYRIDIN-2-YL)-6- FLUORO-7-(2-METHYLPYRIDIN-4-YL)LSOTHIAZOLO[5,4-B]QUINOLINE-3,4(2H,9H)-DIONE

EXAMPLE 2. SYNTHESES OF 8-SUBSTITUTED 9-(6-AMINO-3,5-DIFLUOROPYRIDIN-2-YL)-6-FLUORO- 7-(3-HYDROXYAZETIDIN-1-YL)-ISOTHIAZOLO[5,4-B]QUINOLINE-3,4(2H,9H)-DIONE

[0183] The 8-Substituted 9-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-7-(3- hydrόxyazetidin-l-yl)-isothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione is prepared in accordance with the synthetic scheme outlined below.

EXAMPLE 3. SYNTHESIS OF 9-(6-AMINO-3,5-DIFLUOROPYRIDIN-2-YL)-6-FLUORO-7-(3-

HYDROXYAZETIDIN- 1-YL)ISOTHIAZOLO[5,4-B]QUINOLINE-3,4(2H, 9H)-DIONE (Compound 1).

Step 1. 2,4,5-Trifluorobenzoyl chloride (A).

[0184] 2,4,5-trifluorobenzoyl chloride (2) is prepared from 2,4,5-trifluorobenzoic acid as described previously. [Reuman, M.; et. al, J. Med. Chem. (1995) 38, 2531-2540]. Thionyl chloride (8 ml) is added to a solid 2,4,5-trifluoro-3-methoxy-benzoic acid (154 mg, 0.75 mmole ). The reaction mixture is refluxed for 4 hours. It is distilled to remove excess thionyl chloride and further dried under vacuum at rt for the further reaction. Step 2. 3-Oxo-3 -(2, 4, 5-tήfluoro-phenyl)-propionic acid ethyl ester (B).

[0185] Intermediate A is used to prepare B as described previously [Wierenga, W.; Skulnick, H. I. J. Org. Chem. 1979, 44, 310-311].

[0186] A mixture of ethyl hydrogen malonate (0.18mL, 1.50mmole) and dipyridyl ( 1 crystal ) is dissolved in THF (1OmL) and cooled to -75⁰C under argon. n-BuLi (2.8 mL, 4.48 mmole, 5.9 equiv.) is added slowly at -75⁰C to the reaction mixture. The mixture is warmed to - 5⁰C for about two minutes until there is no further disappearance of pink color (to be sure the amount of BuLi is adequate to form the dianion), cooled to -75⁰C, and added slowly to a solution of 2,4,5-trifluorobenzoyl chloride (0.75 mmole) in THF (2-3mL). The resulting reaction mixture is warmed up to room temperature, diluted with ethyl acetate (5OmL), acidified with IN HCl with stirring. The organics were washed with 5% NaHCO₃ (30mLx2), brine (50mLx2), dried over Na₂SO₄, and concentrated. The resulting oil is purified by SiO₂ column (4Og SiO₂ column, 20% EtOAc in hexanes, 40 min. gradient) to give 185mg (89%) of B as a white solid. Step 3. Ethyl 3, 3-bis(methylthio)-2-(2, 4, 5-trimethylbenzoyl)acrylate (C).

[0187] NaH (2.1 equiv., 60 % in mineral oil, 63 mg) is added to a stirred solution of 3- Oxo-3-(2,4,5-trifluoro-phenyl)-propionic acid ethyl ester (B) (0.75 mmole, 185 mg) in dry DMF (8 mL) under argon at it The reaction is stirred at rt for 0.5 hour. CS₂ (1.6 equiv., 1.2 mmole, 0.07mL) is added and the reaction mixture is stirred at rt until the starting material is all consumed. CH₃I (5 equiv., 3.75 mmole, 0.23mL) is then added. The reaction is stirred at rt until completion, (usually, 1-2 hours.) The reaction mixture is then diluted with EtOAC (2OmL) and sat. NH₄Cl (1OmL) solution. The water layer is extracted with EtOAc twice (15mLx2) and the organics are combined. The combined organic layer is washed with brine (20mLx3), dried with Na₂SO₄ and concentrated in vacuo. The resulting crude us purified by SiO₂ gel column chromatography (40% EtOAc in hexanes, gradient) to give C 144 mg (55% yield). Step 4. Ethyl l-(6-(allylamino)-3,5-difluoropyridin-2-yl)-6, 7-difluoro-2-(methylthio)-4- oxo- 1,4 dihydroquinoline-3-carboxylate (D).

[0188] C (0.41 mmole) obtained above is dissolved in DMSO (6mL), K₂CO₃ (5 equiv., 280 mg) is added and the mixture is heated to 100⁰C. N-mono-allyl-3,5-difluoropyridine-2,6- diamine in toluene (1 equiv., 76 mg) is added through a condenser at 100⁰C. The reaction mixture is kept at 100⁰C under Argon until completion. The reaction mixture is concentrated in vacuo and purified by SiO₂ gel column (50% EtOAc in Hexanes, gradient) to give 48 mg (25 % yield) of D.

Step 5. Ethyl l-(6-(allylamino)-3,5-difluoropyridin-2-yl)-6, 7-difluoro-2-mercapto-4-oxo-l,4 dihydroquinoline-3-carboxylate (E).

[0189] Sodium hydrogen sulfide (9 mg, 0.15 mmole, 1.5 equiv.) is added to a stirred solution of D (48mg, 0.1 mmole) in DMF (4 mL) under argon at room temperature. The reaction is stirred at 4O⁰C until completion. It was diluted with water, acidified with IN HCl to ~ pH 2, and extracted with EtOAc (15mLx2). The organic layer was washed with brine (10mLx4), dried over Na₂SO₄, and concentrated in vacuo. The crude was purified by pTLC (SiO₂, lmm, 20 % CH₃OH in CHCl₃) to give E (31mg, 70%).

Step 6. 9-6(but-3-allylamino)-3, 5-difluoropyridin-2-yl)-6, 7-difluoroisothiazolo[5 ,4-b] quinoline- 3,4-(2H,9H)-dione (F).

[0190] NaHCO₃ solution (58 mg, ImI water) and hydroxylamine-O-sulfonic acid (33 mg, 0.3 mmole, 4.2 eq.) are added to a stirred solution of E (31 mg, 0.07 mmole) in THF (3mL). The reaction mixture was stirred at room temperature for ~ 3 hours. The reaction mixture is acidified by addition of 0.5 N HCl to acidic pH and dried. The resulting solid is purified by HPLC and dried to give 24 mg (60%, TFA salt) of F as a white solid.

Step 7. 9-(6-(allylamino)-3,5-difluoropyήdin-2-yl)-6-fluoro-7-(3-hydroxyazetidin-l- yl)isothiazolo[5,4-b]quinoline-3,4-(2H,9H)-dione {G).

[0191] 3-Hydroxyaminoazetidine hydrochloride salt (12mg, 0.11 mmole, 2.5 equiv.) is added to a solution of F (24 mg, 0.044 mmole) in CH₃CN (1 mL), pyridine (ImL), and NMP (N- methylpyrrolidine, (3mL). The reaction mixture is heated to 100 ⁰C with stirring until completion. The reaction is cooled, ImL diethyl ethyl ether is added, and the ppt. is decanted. The precipitate is washed with diethyl ether (lmLx2) and dried to give 13mg (62%) of G.

Step 8. 9-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxyazetidin-l-yl)isothiazolo[5,4- b]quinoline-3,4-(2H,9H)-dione (Compound 1).

[0192] Rh(Ph₃P)₃Cl (5%, 0.0014 mmole)is added to a solution of G (13mg) in CH₃CN (3 ml) and water (0.5mL). The reaction mixture is heated to 50⁰C until completion. The catalyst is filtered off and the filtrate concentrated to give 6mg (50%) of Compound 1. EXAMPLE 4. ADDITIONAL 9-(HETEROARYL)-ISOTHIAZOLO[5,4-B]QUINOLINE-3,4(2H,9H)-DIONES [0193] The following compounds are prepared by the method illustrated in Example 3. Certain compounds of this Example exhibit an EC50 of less than 1 micromolar in the assay described in Example 5.

EXAMPLE 5. ANTIMICROBIAL ACTIVITY OF COMPOUNDS - MINIMUM INHIBITORY CONCENTRATION (MIC) ASSAY

[0194] The antimicrobial activity of the compounds of the invention may be evaluated by a number of methods, including the following visual minimum inhibitory concentration (MIC) assay. This assay determines the minimum concentration of compound required to inhibit growth of a bacterial strain.

[0195] Whole-cell antibacterial activity is determined by broth microdilution using conditions recommended by the NCCLS (see National Committee for Clinical Laboratory Standards. 2001. Performance standards for antimicrobial susceptibility testing: 11^th informational supplement. Vol. 21, no. 1, MlOO-SI l. National Committee for Clinical Laboratory Standards, Wayne, PA). Test compounds are dissolved in DMSO and diluted 1:50 in Mueller-Hinton II broth (Becton-Dickinson) to produce a 256 μg/ml stock solution, hi a 96-well microtiter plate, the compound solution is serially two-fold diluted in Mueller-Hinton II broth. After the compounds are diluted, a 50 μl aliquot of the test organism (~1 x 10⁶ cfu/mL) is added to each well of the microtiter plate. The final test concentrations ranges from 0.125-128 μg/mL. Inoculated plates are incubated in ambient air at 37°C for 18 to 24 hours. The organisms selected for testing included laboratory strains S. aureus ATCC 29213 and E. coli ATCC 25922 (strains purchased from American Type Culture Collection, Manassas, VA)m , S. aureus FQR700699, and Paeruginosa 27853. The minimum inhibitory concentration (MIC) is determined as the lowest concentration of compound that inhibited visible growth of the test organism.

EXAMPLE 6. CELL VIABILITY STAINING WITH ALAMAR BLUE

[0196] To determine whether the microcidal effect observed against S. aureus and E. coli is specific to bacterial cells, compounds are screened for cell viability effects on several human cell types.

[0197] Optimal cell density is first determined by plating cells in a 96-well plate standard sterile tissue culture plates in 100 μl media, 10%FBS at six cell densities from 500 cells/ well to 15,000 cells/ well. A cell free well containing only media is used as a control. Cells are incubated at 37 oC in a 5% CO₂ incubator for 24 hours. 10% culture volume (lOul) of Alamar Blue (Biosource, DALl 100, 10OmL) is then added. Cells are incubated at 37 oC in a 5% CO2 incubator and read in a Victor V plate reader, 544nm excitation, 590nm emission, at 3, 4, and 24 hours after the addition of Alamar Blue. The cell number vs. change in fluorescence is plotted to determine linearity of signal vs. cell number. The optimal density varies between 500-15,000 cells/well depending on the specific cell type. The optimal density is selected based on the highest number of cells that is still in the linear response range. Determination of Compound Cytotoxicity

[0198] Cells are plated at optimal cell density in a standard sterile tissue culture 96 well plate, and incubated at 37 ⁰C O/N in a 5% CO₂ incubator. 12 to 48 hours post-plating media is removed. The cells are washed 1 or 2 times with IX PBS and replaced with fresh media containing the test compound in 1% DMSO. 24 to 72 hours after addition of compound, the media is removed, and the cells washed 1 to 2 times with IX PBS. Fresh media containing 1/10 volume of Alamar Blue is then added. Plates are incubated 4 hours at 37 oC in a 5% CO2 incubator and read in a Victor V plate reader, 544 nm excitation, 590 nm emission.

[0199] Compounds are diluted to 20 micromolar in 1% DMSO and media and screened in duplicate to obtain single concentration cytotoxicity data. Eight concentration points from 0.78 micromolar to 100 micromolar, run in duplicate, are used to determine cyctotoxicity CC50 values. Cells with 1% DMSO and media are used as a negative control, compounds having a known CC50 against a particular cell type are used as positive controls.

[0200] The change in fluorescence vs. concentration of test compound is plotted to determine the cytotoxicity of the compound.

[0201] Sample media conditions, optimal plating densities, and positive control compounds for two cell types screened are presented in Table III.

[0202] Preferred compounds disclosed in Example 1 and 2 exhibit CC50 values greater than 10 uM against each of the cell lines listed below. Other cell types that may be used include but are not limited to Balb/3TC, CEM-SS, HeLa, Hep2, HepG2, HT-29, MRC-5, SK-N-SH, U- 87 MG, 293T, and Huh-7. More preferred are compounds with a CC50 value greater than 50 uM. Most preferred are compounds with a CC50 value greater than 100 uM. Should the most preferred compounds have CC50 greater than 10 micromolar.

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula

or a tautomer thereof of the formula

or a pharmaceutically acceptable salt thereof, wherein

R₂ is hydrogen, or

R₂ is d-C₆alkyl, C₂-C₆alkenyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl, (aryl)C₀-C₄alkyl, or (C₂-

Ceheterocycloalkyl)C₀-C₂alkyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -CONH₂, C₁-C₄alkyl, Q-Qalkoxy, C₁-C₂haloalkyl, Q-C^aloalkoxy, and mono- and di- (C₁-C₄)alkylamino, and C₂-C₄alkanoyl;

R₃ is hydrogen, C₁-C₆alkyl, or C₂-C₆alkanoyl;

R₅ is hydrogen, halogen, hydroxy, amino, C₁-C∑alkyl, d-C₂alkoxy, mono- or di-(C₁- C4)alkylamino, or mono- or di-(C₁-C4)alkylhydrazinyl;

R₆ is hydrogen, halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, mono- or di-(C₁- C₄)alkylamino;

R₇ is a carbon-linked substitutent XR_A, wherein X is absent, -CH₂-CH₂-, -CH=CH-, -(C=O)-, or -C≡C-; wherein R_A is C₃-C₇cycloalkyl, phenyl, pyrid-3-yl, pyrid-4-yl, pyrimidin-5-yl, furan-3-yl, quinolin-3-yl, quinolin-5-yl, quinolin-6-yl, isoindol-5-yl, tetrahydroisoquinolin-5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl, tetrahydroisoquinolin-8-yl, or indol-5-yl, or

R₇ is a nitrogen-linked heterocycloalkyl group, which has 4 to 8 ring members, or

R₇ is a nitrogen-linked C₁-C₄alkylamino substituted with a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently chosen from N, O, and S, or substituted with a heterocycloalkyl group, which has 4 to 8 ring members, including 1 or 2 ring heteroatoms independently chosen from N, O, and S, or R₇ is a nitrogen-linked heterocycloalkyl or heterocycloalkenyl group, each of which has 4 to 8 ring members, including 0, 1, or 2 additional ring heteroatoms independently chosen from N, O, and S, forming part of a bicyclic system with a 3- to 8-membered cycloalkyl or heterocycloalkyl ring in fused or spiro orientation; or R₇ is a nitrogen-linked 6-membered heterocycloalkyl group, 0, 1 or 2 additional ring heteroatoms independently chosen from N, O, and S, and bridged with a methylene or ethylene bridge; Each of which R₇ is substituted with 0 or 1 or more substituents independently chosen from (a) and 0 or 1 substituents chosen from (b); wherein

(a) is chosen from halogen, hydroxy, amino, nitro, d-C₄alkyl, d-C₄alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, and

(b) is oxo, amino, cyano, hydroxyC_!-C₄alkyl, aminoC₁-C₄alkyl, C₁-C₆alkylthio, C₂- Qalkanoyl, (mono- or di-C₁-C₄alkyl)aminoC₀-C₄alkyl, (C₃-C₇cycloalkyl)Co-C₄alkyl, (C₃- C₇cycloalkyl)aminoC₀-C₄alkyl, (C₃-C₇cycloalkyl)(C₁-C₄alkyl)aminoC₀-C₄alkyl, (heterocycloalkyl)Co-C₄alkyl, (5-membered heteroaryl) C₀-C₄alkyl, or (aryl)C₀-C₄alkyl, where each of (b) other than oxo and cyano is substituted with 0 to 2 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH, -CONH₂, d-Gjalkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, d-C₄alkoxy, mono- and di-(d- C₄)alkylamino, d-C₂haloalkyl, and d-C₂haloalkoxy;

A₈ is N or CR₈; wherein

R₈ is hydrogen, halogen, hydroxy, amino, cyano, nitro, or -NHNH₂; or

R₈ is C₁-Qalkyl, C₁-C₆alkoxy, (C₃-C₇cycloalkyl)C₀-C₂alkyl substituted with 0 or 1 or more halogen substituents, (C₃-C₇cycloalkyl)C₀-C₂alkoxy substituted with 0 or 1 or more halogen substituents, mono- or di-(C₁-C4)alkylamino, mono-, di-, or Ui-(C₁-C₄) alkylhydrazinyl, C₂-C₄alkanoyl, d-C₂haloalkyl, or d-C₂haloalkoxy;

R₉ is pyridine, pyrazine, pyridazine, or pyrimidine, each of which is substituted with 0 to 4 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -CONH₂, d-C4alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, d-C₄alkoxy, (C₃-C₇cycloalkyl)C₀- C₄alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkoxy, mono- and di-(C₁-C₄)alkylamino, C₁- C₂haloalkyl, C₁-C₂haloalkoxy, and C₂-C₄alkanoyl.

2. A compound or salt of Claim 1 , wherein

R₂ is hydrogen, d-C_δalkyl or (C₃-C₇cycloalkyl)C₀-C₄alkyl;

R₃ is hydrogen, Q-Qalkyl, or C₂-C₆alkanoyl;

R₅ is hydrogen, halogen, amino, C₁-C₂alkyl, d-C₂alkoxy, mono- or di-(C₁-C₄)alkylamino, or mono- or di-(C₁-C₄)alkylhydrazinyl; R₆ is hydrogen, halogen, or amino: A₈ is CR₈; and

R₈ is hydrogen, halogen, C₁-C₂alkyl, C₁-C₂BIkOXy, trifluoromethyl, or trifluoromethoxy; and R9 is pyridine, pyrazine, pyridazine, or pyrimidine, each of which is substituted with 1 to 4 substituents independently chosen from halogen, amino, C₁-C₄alkyl, and mono- and di-

(C i -C₄)alkylamino.

3. A compound or salt of Claim 2, wherein R9 is pyridine group of the formula

R22

Hiy X

R '20 ^21 wherein

R₂₀ is hydrogen or C_1-C₄alkyl; and

R_2I and R₂₂are independently chosen halogen substituents.

V

4. A compound or salt of Claim 3, wherein R₂, R₃, R₅, and R₂₀ are all hydrogen; R₆ is fluoro or hydrogen;

R₈ is hydrogen, halogen, C]-C₂alkyl, or Q-Qalkoxy; and R₂₁ and R₂₂ are both fluoro.

5. A compound or salt of Claim 4, wherein R₈ is methoxy.

6. A compound or salt of Claim 2, wherein

R₇ is XR_A, wherein X is absent, -CH₂-CH₂-, -CH=CH-, -(C=O)-, or -C=C-; wherein R_Ais

C₃-C₇cycloalkyl, phenyl, pyrid-3-yl, pyrid-4-yl, pyrimidin-5-yl, furan-3-yl, quinolin-3-yl, quinolin-5-yl, quinolin-6-yl, isoindol-5-yl, tetrahydroisoquinolin-5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl, tetrahydroisoquinolin-8-yl, or indol-5-yl, wherein each of which R₇ is substituted with 0 or 1 or more substituents independently chosen from halogen, hydroxy, C_ϊ-C₄alkyl, C₁-QaIkOXy, d-C₂haloalkyl, and Q-C^aloalkoxy, each of which R₇ is also substituted with 0 or 1 amino, cyano, C₁-Qhydroxyalkoxy, mono- and di-C₁-C₄alkylamino, C₂-C₄alkanoyl, (C₃-C₇cycloalkyl)C₀C₂alkyl, (heterocycloalkyl(C₀- C₂alkyl, or aryl.

7. A compound or salt of Claim 2, wherein

R₇ is a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or azepanyl group substituted with substituted with 1 methyl or halogen substituent and substituted with one group (b) wherein (b) is oxo, amino, cyano, hydroxyC₁-C₄alkyl, aminoQ-C-jalkyl, C₂- C₄alkanoyl, (mono- or di-C₁-C₄alkyl)aminoCo-C₄alkyl, (C₃-C₇cycloalkyl)Co-C₂alkyl substituted with amino, (C₃-C₇cycloalkylamino)Co-C₄alkyl, or (C₃-C₇cycloalkyl)(C_!- C₄alkyl)aminoCo-C₄alkyl.

8. A compound or salt of Claim 2, wherein

R₇ is a pyrrolidinyl group substituted with a (5-membered heteroaryl)C₀-C₄alkyl, which is substituted with 0 to 2 independently chosen from 0 to 2 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH, -CONH₂, Q^alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₁- C₂haloalkyl, and C₁-C₂haloalkoxy. wherein the 5-membered heteroaryl is an imidazolyl, thiazolyl, furanyl, oxazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, or oxadiazolyl group.

9. A compound of Claim 18, wherein R₇ is

10. A compound or salt of Claim 12 wherein R₇ is a group of formula

wherein R₁₅ is (a) or (b); R₁₆ is 0, 1, or more substituents independently chosen from chloro, fluoro, methyl, or methoxy; and R₁₇ is hydrogen, chloro, fluoro, amino, methyl, ethyl, methoxy, C₁-C₆ alkyl substituted with amino or hydroxy, or mono- or di-(Co-C₄)alkylamino.

11. A compound or salt of Claim 10, wherein R₁₅ is oxo, cyano, hydroxyd-C₄alkyl, aminoC₁-C₄alkyl, acetyl, (mono- or (Ii-C₁-

C₂alkylamino)C₁-C₄alkyl, cyclopropyl substituted with amino, or (C₃-

C₇cycloalkylamino)C₀-C₄alkyl; and R₁₆ is 0 or 1 substituent chosen from hydroxy, amino, chloro, and methyl.

12. A compound or salt of Claim 2, wherein R₇ is

13. A compound or salt of Claim 2, wherein:

R₇ is a nitrogen-linked d-C₄alkylamino substituted with a 5 or 6-membered heteroaryl group having 1 or 2 heteroatoms independently chosen from N, O, and S, or substituted with a heterocycloalkyl group, which has 4 to 8 ring members, including 1 or 2 ring heteroatoms independently chosen from N, O, and S; each of which R₇ is substituted with 0 or 1 or more substituents independently chosen from (a) and 0 or 1 substituents chosen from (b)

14. A compound or salt of Claim 13 , wherein

R₇ is C₁-C₂alkylamino substituted with pyridyl, piperazinyl, piperidinyl, or morpholinyl, each of which is substituted with 0, 1 , or 2 substituents independently chosen from halogen, methyl, and methoxy.

15. A compound or salt of Claim 2, wherein

R₇ is a nitrogen-linked heterocycloalkyl or heterocycloalkenyl group, each of which has 4 to 8 ring members, including 0, 1, or 2 additional ring heteroatoms independently chosen from N, O, and S, forming part of a bicyclic system with a 3- to 8-membered cycloalkyl or heterocycloalkyl ring in fused or spiro orientation, each of which R₇ is substituted with 0 or 1 or more, substituents independently chosen from (a) and 0 or 1 substituents chosen from (b).

16. A compound or salt of Claim 15, wherein

R₇ is a piperidinyl, piperazinyl, or pyrrolidinyl group, which is part of a bicyclic system having a spiro attached C₃-C₄cycloalkyl, dioxolanyl, or azetidinyl group, which bicyclic system is substituted with 0, 1, or 2 substituents independently chosen from halogen, hydroxy, amino, oxo, cyano, C₁-C₂alkyl, d-C₂alkoxy, C!-C₂haloalkyl, and Q-Qhaloalkoxy.

17. A compound or salt of Claim 1 of the formula

wherein

R₆ is hydrogen or halogen; and

R₈ is hydrogen, halogen, C₁-C₂alkyl, C₁-C_∑alkoxy, trifiuoromethyl, or trifluoromethoxy.

18. A pharmaceutical composition comprising a compound or salt of any one of Claims 1 to 37, together with a carrier, diluent, and/or excipient.

19. The pharmaceutical composition of Claim 18, wherein the composition is formulated as an injectable fluid, an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution.

20. A pharmaceutical composition comprising a compound or salt of Claim 1 in combination with another one or more antibacterial agent, antiprotozoal agent, antifungal agent, antiviral agent, interferon, efflux-pump inhibitor, or beta-lactamase inhibitor.

21. A method for treating or preventing a bacterial or protozoal infection comprising administering a therapeutically effective amount of a compound or salt of Claim 1 to a mammal in need thereof.

22. The method of Claim 21 , wherein the bacterial or protozoal infection is a urinary tract infection, pyelonephritis, lower respiratory tract infection, skin infection, skin-structure infection, urethral gonococcal infection, cervical gonococcal infection, urethral chlamydial infection, cervical chlamydial infection, bone infection, joint infection, gram-negative bacterial infection, infectious diarrhea, typhoid fever, prostatitis, acute sinusitis, acute exacerbation of chronic bronchitis, pneumonia, intra-abdominal infection, gynecologic infection, or pelvic infection.

23. The method of Claim 22, wherein the mammal is a human.