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    公开号:AU2005331275A1
    申请号:U2005331275
    申请日:2005-11-10
    公开日:2006-11-09
    发明作者:Barton James Bradbury；Milind Deshpande；Akihiro Hashimoto；Edlaine Lucien；Michael John Pucci；Yongsheng Song；Qiuping Wang；Jason Allan Wiles
    申请人:Achillion Pharmaceuticals Inc；
    IPC主号:C07D513-04
    专利说明:
    WO 2006/118605 PCT/US2005/040725 1 8A,9-DIHYDRO-4AH-ISOTHIAZOLO[5,4-B]QUINOLINE-3,4-DIONES AND RELATED COMPOUNDS AS ANTI-INFECTIVE AGENTS CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority from U.S. Provisional Patent Application No. 60/626,961, filed November 11, 2004, which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] The present invention provides an 8a,9-dihydro-4a-H-isothiazolo[5,4 b]quinoline-3,4-diones, many of which are substituted at the 7-position with an oxime substituted heterocycloalkyl substituent, and related compounds, which possess antimicrobial activity. 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 provides anti-microbial compositions, including pharmaceutical compositions, containing one or more carrier, diluents, or excipients. The invention provides pharmaceutical compositions containing an 8a,9-dihydro-4a-H-isothiazolo[5,4-b]quinoline-3,4-dione or related compound as the only active agent or containing an 8a,9-dihydro-4a-H-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 provides methods for treating or preventing microbial infections in eukaryotes by administering an effective amount of an 8a,9-dihydro-4a-H-isothiazolo[5,4-b]quinoline-3,4-dione or related compound to a eukaryote suffering from or susceptible to microbial infection. The invention also provides methods of inhibiting microbial growth and survival by applying an effective amount of an 8a,9-dihydro 4a-H-isothiazolo[5,4-b]quinoline-3,4-dione or related compound. The invention also provides novel intermediates useful for the synthesis of 8a,9 dihydro-4a-H-isothiazolo[5,4-b]quinoline-3,4-diones and related compounds. The invention also provides methods of synthesis for 8a,9-dihydro-4a-H-isothiazolo[5,4-b]quinoline-3,4 diones and related compounds.
    WO 2006/118605 PCT/US2005/040725 2 BACKGROUND OF THE INVENTION [0003] 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. [0004] 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. Thus there is a continuing need for broad-spectrum antimicrobials, and a particular need for antimicrobials effective against resistant microbes. [0005] 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 Enterococcusfaeciumn, which are resistant to virtually all commercially available antibiotics. [0006] Resistant organisms of particular note include methicillin-resistant and vancomycin- resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumnoniae, vancomycin-resistant enterococci, fluoroquinolone-resistant E. coli, cephalosporin-resistant aerobic gram-negative rods and imipenem- resistant Pseudominonas aeruginosa. These organisms are significant causes ofnosocomial infections and are clearly associated with increasing morbidity and mortality. The increasing numbers of elderly and WO 2006/118605 PCT/US2005/040725 3 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. SUMMARY OF THE INVENTION [0007] The invention provides compounds of Formula I and Formula II (shown below) and includes 8a,9-dihydro-4a-H-isothiazolo[5,4-b]quinoline-3,4-diones and 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 Fonrmula II, or a salt, solvate, or prodrug, such as an acylated prodrug of such a compound, and one or more carriers, excipients, or diluents. [0008] 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, Salmonella infections and protozoal infections, for example Chlamydia infections. The invention 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. [0009] Methods of treatment include administering a compound of Formula I or Fonnula II as the single active agent or administering a compound of Formnnula 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. [0010] The invention also provides methods of inhibiting microbial growth and survival by applying an effective amount of an 8a,9-dihydro-4a-H-isothiazolo[5,4 b]quinoline-3,4-dione or related compound. The invention includes, for example, methods of WO 2006/118605 PCT/US2005/040725 4 inhibiting microbial growth and survival on medical instruments or on surfaces used for food preparation by applying a composition containing a compound of Formula I or Formula II. [0011] Thus, the invention include compounds and pharmaceutically acceptable salts of Formula I and Formula II
    R
    5 0 0 R 5 0 RA RA RA R 6 O R 0 A N-R 2
    R
    7 0 R3 N N 8 N A n ~ N' N A 8 N A (RBN R9 ( RBN ) R 9 RA RA RA RA Formula I Formula II Within Formula I and Formula II: [0012] A 1 is S, O, SO, or SO 2 . [0013] R 2 is hydrogen, or R 2 is C1-C8alkyl, C 2
    -C
    6 alkenyl, C 2
    -C
    6 alkynyl, (C 3 C 7 cycloalkyl)Co-C 4 carbohydryl, (C 4
    -C
    7 cycloalkenyl)Co-C 4 carbohydryl, (aryl)Co
    C
    4 carbohydryl, or (C 2
    -C
    6 heterocycloalkyl)Co-C 4 carbohydryl, each of which is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro,
    C
    1
    I-C
    4 alkyl, Ci-C 4 alkoxy, Ci-C 2 haloalkyl, C 1
    -C
    2 haloalkoxy, mono- and di-C 1
    -C
    4 alkylamino,
    C
    2
    -C
    4 alkanoyl, C -C 4 alkylthio,
    -O(C=O)R
    1 0 , -(C=O)NR 1 0
    R
    1 1 , -O(C=O)NRo 1 0
    R
    1 1 , -(C=O)ORo 10 , -(C=O)NRo 10
    OR
    1 1 , -NRio(C=O)RIt, -NRlo(C=O)ORil, -NRio(C=O)NRlIR 12 , -NRlo(C=S)NR 1 1
    R
    12 , NRioNRl1R12,
    -SO
    3 Ro 0 , -(S=O)ORo, -SO 2
    R
    13 , -SO2NR 1 0
    R
    11 , =N-ORio, and -NRIoSO 2
    R
    1 3 ; where each Rio, Rl 1 , and R 1 2 is independently hydrogen, CI-C 4 alkyl, or aryl, and each R 1 3 is independently C 1 C 4 alkyl or aryl. [0014] R 3 is hydrogen, Cl-C 6 alkyl, C 2
    -C
    6 alkanoyl, mono- or di-Ci-C 6 alkylcarbamate,
    C
    1
    -C
    6 alkylphosphate, or C 1
    -C
    6 alkylsulfonate; each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, Cx-C 4 alkoxy, mono- and di-C 1
    -C
    4 alkylamino, C 1
    -C
    2 haloalklyl, and C 1
    -C
    2 haloalkoxy. [0015] R 5 is hydrogen, halogen, hydroxy, amino, cyano, nitro, -NHNH 2 , C 1 C 2 haloalkyl, or C 1
    -C
    2 haloalkoxy; or WO 2006/118605 PCT/US2005/040725 5 [0016] R 5 is C 1
    -C
    4 al l, Ci-C 4 alkoxy, mono- or di-Ci-C 4 alkylamino, mono-, di-, or tri-C 1
    -C
    4 alkylhydrazinyl, C 2 -C4alkanoyl, or Ci-C 4 alkylester,; each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, amino, halogen, oxo, Ci
    C
    4 alkoxy, C1-C 2 haloalkyl, C1-C 2 haloalkoxy, and mono- and di-Cl-C 4 alkylamino. [0017] R 6 is hydrogen, halogen, hydroxy, amino, cyano, CI-C 4 alkyl, C1-C 4 alkoxy, mono- or di-CI-C 4 alkylamino, -SO 3
    R
    1 0 , -S0 2
    R
    1 0 , -SO 2
    NR
    1 0
    R
    1 l; where R 10 and R 11 carry the definitions set forth above. [0018] n is 1,2, or3;mis 1, 2, or3; andp is 0 or 1. [0019] Each RA is independently (i), (ii), or (iii); where (i) is hydrogen, hydroxy, amino, or cyano, (ii) is C 1
    -C
    6 alkyl, C 2
    -C
    6 alkenyl, C 2
    -C
    6 alkynyl, Ci-C 6 alkoxyCo-C 4 alkyl, mono- or di
    CI-C
    4 alkylamino, CI-C 2 haloalkoxy, (C 3
    -C
    7 cycloalkyl)Co-C 4 carbohydryl, (C 4 C 7 cycloalkenyl)Co-C 4 carbohydryl, (aryl)Co-C 6 carbohydryl, (aryl)C1-C 4 alkoxy, (C 2 C 6 heterocycloalkyl)Co-C 4 carbohydryl, (heteroaryl)Co-C 6 carbohydryl, C -C 6 alkylthio, -(Co
    C
    4 alkyl)O(C=O)Rio, -(Co-C 4 alkyl)(C=O)NRioRi, -(Co-C 4 alkyl)O(C=O)NRioRi1, -(Co-C 4 alkyl) (C=O)ORlo, -(Co-C 4 alkyl)NRo(C=O)R 1 1, -(Co-C 4 alkyl)NRio(C=O)OR11, -(Co-C 4 alkyl)NRio(C=O)NR11R 1 2 , -(Co-C 4 alkyl)NRo(C=S)NRi 1
    R
    1 2 , -(Co-C 4 alkyl)ONioNR 1 1
    R
    1 2 , -(Co-C 4 alCyl)N=NR 1 3 , -(Co-C 4 alkyl)SO 3 Rio, -(Co
    C
    4 alkyl)(S=O)ORio, -(Co-C 4 alkyl)SO 2
    R
    3 , -(Co-C 4 alkyl)SO 2 NRIoRi, -(Co
    C
    4 alkyl)NR 1 oSO 2 R1 3 ; =N-OH, or =N-O(Co-C 4 alkyl); (iii) is -ORD, -(C=O)RD, -SO2RD, -SO 3 RD, or -NRloSO 2 RD, where RD is CI-C 4 alkyl,
    (C
    3
    -C
    7 cycloalkyl)Co-C 2 alkyl, (C 2
    -C
    6 heterocycloalkyl)Co-C 2 alkyl, (aryl)Co-C 2 alkyl, or (heteroaryl)Co-C 2 alkyl; where each of (ii) and (iii) is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -(C=O)OCH 3 , CONH 2 , C1-C 4 alkyl, C 2
    -C
    4 alkenyl, C 2
    -C
    4 alkynyl, C 1
    -C
    4 alkoxy, (C 3
    -C
    7 cycloalkyl)Co
    C
    4 carbohydryl, (C 3
    -C
    7 cycloalkyl)Co-C 4 alkoxy, mono- and di-C1-C 4 alkylamino, C 1 C 2 haloalkyl, CI-C 2 haloalkoxy, and C 2
    -C
    4 alkanoyl. Or, any two RA bound to the same carbon atom may be joined to form a C 3 C 7 cycloalkyl, or a 3- to 7- membered heterocycloalkyl group; having 1 or 2 heteroatoms WO 2006/118605 PCT/US2005/040725 6 independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from CI-C 2 alkyl, and C 1
    -C
    2 alkoxy. Or, any two RAbound to different carbon atoms may be joined to form a C 3 C 7 cycloalkyl or a 3- to 7-membered heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from Ci-C 2 alkyl, and CI-C 2 alkoxy. RB is hydrogen or C 1
    -C
    4 alkyl. [0020] R 7 is hydrogen, or R 7 is C 1 -Csalkyl, C 2
    -C
    6 alkenyl, C 2
    -C
    6 alkynyl, C 2 C 6 alkanoyl, (C 3
    -C
    7 cycloalkyl)Co-C 4 carbohydryl, (C 4
    -C
    7 cycloalkenyl)Co-C 4 carbohydryl, (aryl)Co-C 4 carbohydryl, (aryl)(C=O)-, mono- or di-(CI-C 6 alkyl)carboxamide, C 1 C 6 alkylester,or (C 2
    -C
    6 heterocycloalkyl)Co-C 4 carbohydryl, each of which is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, C 1 C 4 alkyl, Ci-C 4 alkoxy, C 1
    -C
    2 haloalkyl, C1-C 2 haloalkoxy, mono- and di-C 1
    -C
    4 alkylamino, C 2 C 4 alkanoyl, Ci-C 4 alkylthio, -O(C=O)Ro 0 , -(C=O)NR 1 IoR 11 , -O(C=O)NRo 10
    R
    11 I, -(C=O)OR 10 , -(C=O)NRo 10
    OR
    1 1 , -NR 1 io(C=O)R 11 , -NR 1 o(C=O)OR 1 , -NR 1 o(C=O)NR 1 1
    R
    1 2 , -NRio(C=S)NRlIR1 2 , -NRioNRIIR 1 2 , -SO 3 RIo, -(S=O)ORlo, -S0 2
    R
    13 , -SO 2 NRo 10 RI1, or -NRIoSO 2
    R
    13 . [0021] A 8 is nitrogen or CRs; where R 8 is hydrogen, halogen, hydroxy, amino, cyano, nitro, or -NHNH 2 , or R 8 is C 1
    -C
    4 alkyl, Ci-C 4 alkoxy, mono- or di-C1-C 4 alkylamino, mono-, di-, or tri-Cl-C 4 alkylhydrazinyl, C 2
    -C
    4 alkanoyl, CI-C 4 alkylester, CI-C 2 haloalkyl, or C 1 C 2 haloalkoxy, each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, amino, halogen, oxo, C 1
    -C
    4 alkoxy, C 1
    -C
    2 haloalkyl, C1-C 2 haloalkoxy, and mono- and di-Ci-C 4 alkylamino. [0022] R 9 is C1-Csalkyl, (C 3
    -C
    7 cycloalkyl)Co-C 4 alkyl, or phenyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -CONH 2 , C 1
    -C
    4 alkyl, C 2
    -C
    4 alkenyl, C 2
    -C
    4 alkynyl, CI-C 4 alkoxy, (C 3 C 7 cycloalkyl)Co-C 4 alkyl, (C 3
    -C
    7 cycloalkyl)Co-C 4 alkoxy, mono- and di-C,-C 4 alkylamino, C 1 C 2 haloalkyl, C 1
    -C
    2 haloalkoxy, and C 2
    -C
    4 alkanoyl. The invention includes novel intermediates useful for the synthesis of compounds of Formula I and Formula II. The invention provides methods of synthesizing compounds of WO 2006/118605 PCT/US2005/040725 7 Formula I and Formula II comprising coupling an intermediate, wherein the intermediate is a compound of Formula I or Formula II in which R 7 is bromo, iodo, -O(SO 2
    )CF
    3 , or -N 2
    BF
    4 to an appropriate aryl or heteroaryl boronic acids, aryl or heteroaryl boronic acid esters, or compounds substituted with Li, Mg, B, Al, Si, Zn, Cu, Zr, or Sn at the point of coupling. DETAILED DESCRIPTION OF THE INVENTION CHEMICAL DESCRIPTION AND TERMINOLOGY [0023] Prior to setting forth the invention in detail, it may be helpful to provide definitions of certain termnns to be used herein. Compounds of the present invention are generally described using standard nomenclature. [0024] 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. [0025] 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. [0026] 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 11 C, 1 3 C, and 14
    C.
    WO 2006/118605 PCT/US2005/040725 8 [0027] Certain compounds are described herein using a general formula that includes variables, e.g. A 1 , R 2 , R 3 , Rs, R 6 , R 7 , As, and R 9 . 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. [0028] 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. [0029] The exception to naming substituents into the ring is when the substituted is listed with a dash ("-") or 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. [0030] 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 Ci- C 6 alkyl as used herein includes alkyl groups having from 1 to about 6 carbon atoms. When C 0 -Cn alkyl is used herein in conjunction with another group, for example, WO 2006/118605 PCT/US2005/040725 9 (aryl)Co-C 4 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. [0031] "Alkenyl" as used herein, indicates a hydrocarbon chain of either a straight or branched configuration having one or more carbon-carbon double bonds, which may occur at any stable point along the chain. Examples of alkenyl groups include ethenyl and propenyl. [0032] "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. [0033] "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 CO-Cn carbohydryl is used herein in conjunction with another group, for example, (aryl)C0-C4carbohydryl, the indicated group, in this case aryl, is either directly bound by a single covalent bond (CO), 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 include C1-C6alkyl, such as methyl, 5-butyl, C2-C6alkynyl such as hexynyl, and C2-C6 alkenyl, such as 1-propenyl. [0034] "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. [0035] "Allanoyl" 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)-.
    WO 2006/118605 PCT/US2005/040725 10 [0036] 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. [0037] The term "mono- or di-alkylcarbamate" indicates 1 or 2 independently chosen alkyl groups, as defined above, attached through a carbamate (-O(C=O)NRR) linkage where R represents the alkyl groups. Mono-alkylcarbamate groups have the formula ( O(C=O)NHR). [0038] The term "alkylester" indicates an alkyl group as defined 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. [0039] 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 alky1hydrazinyl groups include 2-butyl- 1-hydrazinyl, 2-butyl-2-methyl- 1-hydrazinyl, and 1,2-dimethyl-2-propyl- 1 hydrazinyl. [0040] The term "alkylsulfonate" indicates an alkyl group as defined above attached through a sulfonate linkage (e.g. a group of the formula -S(=O)20-alkyl). [0041] 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. [0042] 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, WO 2006/118605 PCT/US2005/040725 11 for example, a 3,4-methylenedioxy-phenyl group. Aryl groups include, for example, phenyl, naphthyl, including 1- naphthyl and 2-naphthyl, and bi-phenyl. [0043] 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-l-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 Co alkoxy the aryl is attached through an oxygen bridge. [0044] "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. [0045] "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. [0046] 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. [0047] 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. [0048] "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 WO 2006/118605 PCT/US2005/040725 12 ofhaloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl. [0049] "Haloalkoxy" indicates a haloalkyl group as defined above attached through an oxygen bridge. [0050] "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, or iodo. [0051] 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, 2, or 3 heteroatoms independently chosen from N, O, and S, to form, for example, a [1,3]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. [0052] In 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(1-ethyl). [0053] 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. A C 2
    -C
    7 heterocycloalkyl group contains from 2 to about 7 carbon ring atoms and at least one ring atom chosen from N, O, and S. Examples of heterocycloalkyl groups WO 2006/118605 PCT/US2005/040725 13 include morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl groups. A nitrogen in a heterocycloalkyl group may optionally be quaternized. [0054] The term "heterocyclic group" indicates a 5-6 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 quatemrnized. 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. [0055] Additional examples of 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, WO 2006/118605 PCT/US2005/040725 14 chromanyl, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrirnidinyl 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. [0056] 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. [0057] "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. [0058] "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. [0059] "Pharmaceutically acceptable salts" includes derivatives of the disclosed compounds wherein the parent compound is modified by making non-toxic acid or base salts WO 2006/118605 PCT/US2005/040725 15 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-(CH 2 )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). [0060] The term "prodrugs" includes any compounds that become compounds of Formula I or Formula II 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. [0061] 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 provide a positive effect on any indicia of disease, e.g. an amount sufficient to prevent a significant increase or significantly reduce the detectable level of virus or viral antibodies 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 WO 2006/118605 PCT/US2005/040725 16 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 [0062] For the purposes of this document, the following numbering system will apply to the core 9H-isothiazolo[5,4-b]quinoline-3,4-dione (when A 1 = sulfur) structure or core 9H isoxazolo[5,4-b]quinoline-3,4-dione (when A 1 = 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) member rings as shown below. 5 0 5 0 O-R3 4 4 6 3 6 3 A B CNH2 A B CN2 7S/ 7 >S 7 N S N S 8 H 1 8 H 1 9 9 Formula I Formula II [0063] 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. A, R 2 , R 3 , R 4 , etc. ) carry definitions other than those set forth above. Embodiments in which one or more of the following conditions is met are included in the invention: The A 1 variable [0064] (1) A 1 is S; e.g. compounds and salts of Formula II and Formnula IV are included herein.
    WO 2006/118605 PCT/US2005/040725 17
    R
    5 0
    R
    5 O R R RA RA R-R 2
    R
    7 0 RAA R6 ,N N nN A 8 N N N 8N
    "
    S '' R - m (R 9 RBN )m9 RA RA A RA Formula 111 Formula IV [0065] (2) A, is SO; e.g. compounds and salts of Formula V and VI are included herein:
    R
    5 0 R R 5 0 A ,OR RA A 6
    --
    R 3 RR70 /N-R SN 8 N S R1 N 8 N S (RBN ( RBN R9 O RA RA 9 P RA RA RA RA Formula V Formula VI [0066] (3) A 1 is SO2; e.g. compounds and salts of Formula VII and VIII are included herein.
    R
    5 0
    R
    5 0 R3
    R
    7 0 I N-R 2
    R
    7 0O N NN N S A 8 N" 1 o' b N N A 8 N / S (RBN P ) R 9 (RBN R 9 p m( RBN m RARA RA RA Formula VI Fonrmula VIII [0067] (4) A 1 is O; e.g. compounds and salts of Formula IX and X are included herein.
    WO 2006/118605 PCT/US2005/040725 18
    R
    6 R5 0 0 R 5 O O1R3 AARA RA R
    R
    7 0 N-R 2
    R
    7 RA AN N 0 x~~ RN N A 8 N (RBN )m (R R9 p(RBN: RA RA 4p_ m RA RA Formula IX Formula X The R 2 variable (compounds and salts ofFormula I): [0068] (1) R 2 is hydrogen, or R 2 is C1-C 6 alkyl or (C 3
    -C
    7 cycloalkyl)Co-C 4 alkyl, each of which is substituted with at least one substituent chosen from hydroxy, amino, COOH,
    -(C=O)NR
    1 oOR 1 , and -CONH 2 ; and is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -CONH 2 , CI-C 4 alkyl, C 1 C 4 alkoxy, CI-C 2 haloalkyl, C 1
    -C
    2 haloalkoxy, and mono- and di-C 1
    -C
    4 alkylamino, and C 2 C 4 alkanoyl. [0069] (2) R 2 is hydrogen. The R 3 variable (compounds and salts ofFormula II): [0070] (1) R 3 is Ci-C 4 alkyl or C 2
    -C
    4 alkanoyl. The R 5 variable [0071] (1) R 5 is hydrogen, amino, CI-C 2 alkyl, C1-C 2 alkoxy, mono- or di-C 1 C 4 alkylamino, or mono- or di-C 1
    -C
    4 alkylhydrazinyl. [0072] (2) R 5 is hydrogen, amino, mono- or di-CI-C 2 alkylamino, or mono- or di
    C
    1
    -C
    2 alkylhydrazinyl. [0073] (3) R 5 is hydrogen. The R 6 variable [0074] (1) R 6 is hydrogen, halogen, or amino. [0075] (2) R 6 is fluoro. The R 7 variable [0076] (1) R 7 is hydrogen or R 7 is Ci-Csallyl, C 2
    -C
    6 alkanoyl, (C 3 C 7 cycloaclkyl)Co-C 4 carbohydryl, (aryl)Co-C 4 carbohydryl, (aryl)(C=O)-, mono- or di-(Cl- WO 2006/118605 PCT/US2005/040725 19
    C
    6 alkyl)carboxamide, C 1
    -C
    6 alkylester, or (C2-C6heterocycloalkyl)Co-C 4 carbohydryl, each of which is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, CI-C 4 alkyl, CI-C 4 alkoxy, CI-C 2 haloalkyl, C1-C 2 haloalkoxy, mono- and di-C 1
    -C
    4 alkylamino, C 2
    -C
    4 alkanoyl, C 1
    I-C
    4 alkylthio, -O(C=O)Ro 10 , -(C=O)NRo 10 RI, -O(C=O)NRo 10
    R
    11 , -(C=0)ORo 10 , -(C=O)NRIoOR 1 1 , -NRio(C=O)R 11 , -NR 1 o(C=O)ORI 1 , -NRi 0 o(C=O)NRi 1
    R
    1 2 , -NR10o(C=S)NR 11
    R
    1 2 , -NR 1 0
    NR
    11
    R
    1 2 , -S0 3
    R
    10 o, -(S=O)ORo 10 , -S0O 2
    R
    13 ,
    -SO
    2
    NR
    1 0 R, or -NR 10
    SO
    2
    RI
    3 . [0077] (2) R 7 is hydrogen or R 7 is CI-Csalkyl, (C 3
    -C
    7 cycloalkyl)Co
    C
    4 carbohydryl, (aryl)Co-C 4 carbohydryl, or (C2-C6heterocycloalkyl)Co-C 4 carbohydryl, each of which is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, cyano, Ci-C 4 alkyl, C1-C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, mono- and di-C 1 C 4 alkylamino, C 2
    -C
    4 alkanoyl, -(C=O)NRio 0
    R
    1 , and -NR 1 o(C=O)R 1 . [0078] (3) R 7 is hydrogen or R 7 is C1-Csalkyl or (aryl)Co-C 4 alkyl, each of which is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, cyano, C 1
    I-C
    4 alkyl, C 1
    -C
    4 alkoxy, Cl-C 2 haloalkyl, C 1
    -C
    2 haloalkoxy, mono- and di-C 1 C 4 alkylamino, C 2
    -C
    4 alkanoyl, -(C=O)NRIORI, and -NRio(C=O)Rjj. [0079] (4) R 7 is hydrogen, Ci-C 2 alkyl, or benzyl. The variables n, mn, andp [0080] (1) n is 1; m is 2, p is 1 and RB is hydrogen; e.g. when A 1 is S, the compounds and salts of Formula XI and Formula XII are included herein.
    R
    5 0 R 5 O-R3 R71 N- R R71 N6 I RA R "N-R 2 I RARA / N N -A 8 8N N-A - N S HN A RA R 9 HN.Rd RA R 9 RA R RA RA RA RA Formula XI Formula XII [0081] (2) n is 1; m is 1, p is 1 and RB is hydrogen. [0082] (3) p is 0, e.g. when A is S, the compounds and salts of Formula XIII and XIV are included herein.
    WO 2006/118605 PCT/US2005/040725 20
    R
    5 O O R 5 O O-R 3 RA RA R6 ' RA RAR6
    R
    7 0 R ,N-R 2
    R
    7 0 N n N n N S N I NN A S m R9 MR9 RA A RA RA Formula XIII Formula XIV [0083] (4) p is 0, n is 1, and m is 2, e.g. when A 1 is S, the compounds and salts for Formula XV and XVI are included herein.
    R
    5 0 O R 5 0 0
    -R
    2
    R
    7 N RA RAR6 N-R 2
    R
    7 1 0 RA RAR6 N I 8 NN N A 8 N S. N - N- R9
    R
    9 RARARARA RARARARA Formula XV Formula XVI [0084] (5) p is 0, n is 2, and m is 2, e.g. when A 1 is S, the compounds and salts for Formula XVII and XVIII are included herein.
    R
    5 0 O R 5 0 O-R 3 RARA RA R 6 NRARA R6 RA I I N-R 2 RA'C N N A N RAN A 8 N S R9 R 9 R7-O "N RA R7O' RA RA RA RA RA RA RA Formula XVII Formula XVUI WO 2006/118605 PCT/US2005/040725 21 The variable RA [0085] (1) RA is independently (i), (ii), or (iii). Where (i) is hydrogen, hydroxy, amino, or cyano, (ii) is C1-C 6 alkyl, C 2
    -C
    6 alkenyl, C 2 C 6 alkynyl, (C 1
    -C
    6 alkoxy)Co-C 4 alkyl, mono- or di-C 1
    -C
    4 alkylamino, C 1
    -C
    2 haloalkoxy, (C 3 C7cycloalkyl)Co-C 4 carbohydryl, (C 4
    -C
    7 cycloalkenyl)Co-C 4 carbohydryl, (aryl)Co
    C
    6 carbohydryl, (aryl)C 1
    -C
    4 alkoxy, (C 2
    -C
    6 heterocycloalkyl)Co-C 4 carbohydryl, (heteroaryl)Co
    C
    6 carbohydryl, C 1
    -C
    6 alkylthio, -(Co-C 4 alkyl)(C=O)NR 1 oRII, -(Co-C 4 alkyl)NRio(C=O)RIl, =N-OH, or =N-O(Co-C 4 alkyl); and (iii) is -ORD or -(C=O)RD, where RD is C 1
    -C
    4 alkyl, (C 3 C 7 cycloalkyl)Co-C 2 alkyl, (C 2
    -C
    6 heterocycloalkyl)Co-C 2 alkyl, (aryl)Co-C 2 alkyl, or (heteroaryl)Co-C 2 alkyl. [0086] Each of (ii) and (iii) is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -(C=O)OCH 3 , -CONH 2 , C 1 C 4 alkyl, C 2
    -C
    4 alkenyl, C 2
    -C
    4 alkynyl, C 1
    I-C
    4 alkoxy, (C 3
    -C
    7 cycloalkyl)Co-C 4 carbohydryl, (C 3 C7cycloalkyl)Co-C 4 alkoxy, mono- and di-C 1
    -C
    4 alkylamino, C 1
    -C
    2 haloalkyl, C 1 C 2 haloalkoxy, and C 2
    -C
    4 alkanoyl. [0087] Or, any two RA bound to the same carbon atom may be joined to form a C 3 C 7 cycloalkyl or a 3- to 7- membered heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from C 1
    -C
    2 alkyl, and C 1
    -C
    2 alkoxy. [0088] Or, any two RA bound to different carbon atoms may be joined to form a C 3 C7cycloalkyl or a 3- to 7-membered heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from C 1
    -C
    2 alkyl and C 1
    -C
    2 alkoxy. [0089] (2) Each RA is independently (i) or (ii). Where (i) is hydrogen or amino, (ii) is C 1
    -C
    6 alkyl, (C 1
    -C
    6 alkoxy)Co-C 4 alkyl, mono- or di-C 1
    -C
    4 alkylamino, (C 3
    -C
    7 cycloalkyl)Co-C 4 carbohydryl, (aryl)Co-C 6 carbohydryl, (C 2 C 6 heterocycloalkyl)Co-C 4 carbohydryl, (heteroaryl)Co-C 6 carbohydryl, -(C0
    C
    4 alkyl)(C=O)NRio 0 RI 1 , -(Co-C 4 alkyl)NRio(C=O)Ri 1, =N-OH, or =N-O(Co-C 4 alkyl). [0090] Where each of (ii) is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -(C=O)OCH 3 , -CONH 2 , C 1
    -C
    4 alkyl, C 2
    -
    WO 2006/118605 PCT/US2005/040725 22
    C
    4 alkenyl, C 2
    -C
    4 alkynyl, CI-C 4 alkoxy, (C 3
    -C
    7 cycloalkyl)Co-C 4 carbohydryl, (C 3 C 7 cycloalkyl)Co-C 4 alkoxy, mono- and di-Ci-C 4 alkylamino, C 1
    -C
    2 haloalkyl, C 1 C 2 haloalkoxy, and C 2
    -C
    4 alkanoyl. [0091] Or, any two RA bound to the same carbon atom may be joined to form a C 3 C 7 cycloalkyl or a 3- to 7-membered heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from C 1
    -C
    2 alkyl, and Cl-C 2 alkoxy. [0092] Or, any two RA bound to different carbon atoms may be joined to form a C 3 C 7 cycloalkyl or heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from C1-C 2 alkyl, and CI-C 2 alkoxy. [0093] (3) Each RA is independently (i) or (ii). Where (i) is hydrogen or amino; and (ii) is Cl-C 6 alkyl, mono- or di-C 1
    -C
    4 alkylamino, (C 3
    -C
    7 cycloalkyl)Co-C 4 alkyl, (C 2 C 6 heterocycloalkyl)Co-C 4 alkyl, -(Co-C 4 alkyl)(C=O)NR 1 IoRi, -(Co-C 4 alkyl)NR10(C=O)Ri1, =N-OH, or =N-O(Co-C 4 alkyl). [0094] Each of (ii) is substituted with 0 to 3 substituents independently chosen from hydroxy, amino, cyano, and -CONH 2 . [0095] Any two RA bound to the same carbon atom may be joined to form a C 3 C 7 cycloalkyl or heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from Ci-C 2 alkyl and Cl-C 2 alkoxy. [0096] (4) Each RA is independently (i) or (ii); Where (i) is hydrogen or amino, and (ii) is C1-C 6 alkyl, (C 3
    -C
    7 cycloalkyl)Co-C 2 alkyl, or mono- or di-CI-C 4 alkylamino. [0097] Where, each of (ii) is substituted with 0 to 3 amino. [0098] Any two RA bound to the same carbon atom may be joined to form a C 3 C 7 cycloalkyl or a 3- to 7- membered heterocycloallkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from C 1
    -C
    2 alkyl and Ci-C 2 alkoxy. Or, any two RA bound to different carbon atoms may be joined to form a C 3 C 7 cycloalkyl or a membered heterocycloalkyl group having 1 or 2 heteroatoms independently WO 2006/118605 PCT/US2005/040725 23 chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from CI-C 2 alkyl and C 1
    -C
    2 alkoxy. [0101] (5) RA is independently hydrogen, C1-C 4 alkyl, or C 1
    -C
    4 alkyl substituted with one amino substituent. [0102] (6) RA is independently hydrogen, C 1
    -C
    4 alkyl, or C1-C 4 alkyl, and one or two RA is Ci-C 4 alkyl substituted with one amino substituent and the remaining RA are hydrogen. [0103] (7) Two RA bound to the same carbon atom are joined to form a C 3 C 7 cycloalkyl or a 3- to 7- membered heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from Ci-C 2 alkyl and CI-C 2 alkoxy; and the remaining RA are independently chosen from hydrogen, Ci-C 2 alkyl and CI-C 2 alkoxy. [0104] (8) Two RA bound to the same carbon atom are joined to form a C 3 C 4 cycloalkyl or a 3- to 4- membered heterocycloalkyl group having 1 N atom; each of which is substituted with 0 to 2 substituents independently chosen from C1-C 2 alkyl and C 1 C 2 alkoxy; and the remaining RA independently chosen from hydrogen, C 1
    -C
    2 alkyl and C 1 C 2 alkoxy. The A 8 variable [0105] (1) As is nitrogen. [0106] (2) As is CR 8 . [0107] (3) As is CR 8 , and R 8 is hydrogen, halogen, CI-C 2 alkyl, CI-C 2 alkoxy, C 1 C 2 haloalkyl, or Ci-C 2 haloalkoxy. [0108] (4) A 8 is CR 8 and Rs is hydrogen or methoxy. [0109] (5) As is CR 8 and R 8 is hydrogen. The R 9 Variable [0110] (1) R 9 is CI-C 4 alkyl, cyclopropyl, or phenyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, Ci-C 2 alIkyl, C 1 C 2 alkoxy, mono- and di-Ci-C 2 alkylamino, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy. [0111] (2) R 9 is C1-C 4 alkyl or cyclopropyl, or R 9 is phenyl substituted with 2 substituents chosen from halogen, hydroxy, amino, CI-C 2 alkyl, C-C 2 alkoxy, mono- and di
    C-C
    2 alkylamino, C 1
    -C
    2 haloalkyl, and C 1
    -C
    2 haloalkoxy. [0112] (3) R 9 is ethyl, t-butyl, cyclopropyl, or 2,4-difluorophenyl.
    WO 2006/118605 PCT/US2005/040725 24 [0113] (4) R 9 is cyclopropyl. [0114] Included herein are all embodiments described by any combination of the variable definitions given above that result in a stable compounds. For example, the invention includes compounds of Formula ITn (also shown above)
    R
    5 0 0 RA RA R 6
    N
    R
    7 0 N-R2 (RBN R 9 SRA Formula I[ wherein condition (2) is met for the R 2 variable, the R 5 variable, R 6 variable, and the R 7 variable condition (2) is met, for the A 8 variable and R 9 variable condition (3) is met, for the p, n, and m variables condition (4) is met and for the RA variable condition (5) is met. Thus, the invention includes compounds of Formula II1 in which: [0115] R 2 is hydrogen (condition (2) for the R 2 variable) [0116] R 5 is hydrogen, amino, mono- or di-C1-C2alkylamino, or mono- or di-C1-C2 alkylhydrazinyl (condition (2) for the R 5 variable); [0117] R 6 is fluoro (condition (2) for the R 6 variable); [0118] R 7 is hydrogen or R 7 is Ci-Csalkyl, (C 3
    -C
    7 cycloalkyl)Co-C 4 carbohydryl, (aryl)Co-C 4 carbohydryl, or (C 2
    -C
    6 heterocycloalkyl)Co-C 4 carbohydryl, each of which is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, cyano, CI-C 4 alkyl, C 1
    -C
    4 alkoxy, C 1
    -C
    2 haloalkyl, Cl-C 2 haloalkoxy, mono- and di-C 1 C 4 alkylamino, C 2
    -C
    4 alkanoyl, -(C=O)NRo 10 Rl, and -NR 1 o(C=O)R 11 (condition (2) for the R 7 variable); [0119] A 8 is CRs, and R 8 is hydrogen, halogen, Ci-C 2 alkyl, Ci-C 2 alkoxy, C 1 C 2 haloalkyl, or Ci-C 2 haloalkoxy (condition (3) for the A 8 varaible); [0120] R 9 is ethyl, t-butyl, cyclopropyl, or 2,4-difluorophenyl (condition (3) for the R 9 variable); [0121] p is 0, n is 1, and m is 2 (condition (4) for these variables); and [0122] RA is independently hydrogen, C 1
    -C
    4 alkyl, or Ci-C 4 alkyl substituted with one amino substituent (condition (5) for the RA variable).
    WO 2006/118605 PCT/US2005/040725 25 [0123] Also included herein are compounds of Formula I and Formula II in which: [0124] R 2 is hydrogen or C 1
    -C
    6 alkyl substituted with one substituent chosen from hydroxy, amino, -COOH, -(C=O)NRioORI, and -CONH 2 ; [0125] R 5 is hydrogen; [0126] R 6 is halogen or amino; [0127] R 7 is hydrogen, CI-C 2 alkyl, or benzyl; [0128] A 5 is nitrogen or CRs, and when A 8 is CRs, R 8 is hydrogen or methoxy [0129] R 9 is ethyl, t-butyl, cyclopropyl, or 2,4-difluorophenyl; and [0130] Each RA is independently hydrogen or C 1
    -C
    4 alkyl optionally substituted with one amino substituent; or any two RA bound to the same carbon atom may be joined to form a
    C
    3
    -C
    7 cycloalkyl or a 3- to 7-membered heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from CI-C 2 alkyl, and Ci-C 2 alkoxy; or any two RA bound to different carbon atoms may be joined to form a C 3
    -C
    7 cycloalkyl or heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from CI-C 2 alkyl, and C 1
    -C
    2 alkoxy. [0131] Certain compounds of Formula I and Formula II exhibit possess potent antibacterial, antifungal, and/or antiprotozoal activity. Particular compounds of the invention exhibit Minimum Inhibitory Concentrations (MIC) of 64 /Lg/ ml or less against Staphyloccocus aureus and/ or Eschericia 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 Ag/ ml or less against Staphyloccocus aureus and/ or Eschericia coli. More preferred compound of the Formula I and II exhibit MIC values of 4 Ag/ ml or less, or even more preferably 1 yg/ ml or less, against Staphyloccocus aureus and/ or Eschericia coli. [0132] 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 CC 50 (the concentration at which 50% of the cells are killed) for cultured cells of a higher WO 2006/118605 PCT/US2005/040725 26 animal, such as a fish, reptiles, amphibian, bird, or mammal. Certain compounds of the invention exhibit a CC 50 of greater than 100 micromolar for mammalian cells. Certain compounds of the invention exhibit a CC 50 of greater than 100 micromolar for cultured human hepatocytes, and also exhibit MIC values of 64 Itg/ ml or less, preferably 10 pg/ ml or less, or more preferably 4 /g/ ml or less, or still more preferably 1 yg/ ml or less against Staphyloccocus aureus and/ or Eschericia coli. [0133] 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 of 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 [0134] The invention includes novel intermediates useful for the synthesis of antimicrobial compounds of Formula I and Formula II. The intermediates include compounds of the Formula (a) and Formula (b): RA RA RA RA
    R
    7 0 R 7 0 R N-Cbz N n NH (RBN (RBNp m RA RA RA RA Formula (a) Formula (b) [0135] Compounds of Formula a are deprotected to form compounds of Formula b. Compounds of Formula (b) are coupled to compound of Formula (c) or Formula (d)
    R
    5 0O
    R
    5 O 0 R 3
    R
    6
    R
    6 ~ I N-R 2 I N F A 8 N AI F A 8 N A H H Formula (c) Formula (d) WO 2006/118605 PCT/US2005/040725 27 [0136] The variables R 7 , RA, and RB carry the definitions set forth for these variables in Formula I and Formula II, and in the embodiments described in the immediately preceding "Antimicrobial compounds" section. When RA or R 7 is an aminoalkyl group, the amino alkyl group may be protected, and then deprotected after the coupling reaction between the intermediate of Formula (b) and the compound of Formula (c) or Formula (d) is complete. [0137] Coupling may be effected by dissolving a compound of Formula (c) or Formula (d) in dimethylformamide (DMF), adding an intermediate of Formula (b), and heating the reaction mixture. [0138] Alternately the coupling may be effected by refluxing a mixture of boric acid, acetic anhydride, and acetic acid in a solvent, such as toluene. A compound of Formula (c) or (d) is added and the reaction mixture is refluxed for several more hours. The volatiles are then removed in vacuo. An intermediate of formula (b), triethyl amine (1 ml), and acetonitrile (10 ml) are then added to the residue, and the reaction mixture is refluxed for several hours. [0139] If the intermediate substituents, such as R 7 and RA, have been protected these groups are then deprotected. PHARMACEUTICAL PREPARATIONS [0140] 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. [0141] Compounds of general Formula I and Formula II may be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdemnnally, via buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, excipients, adjuvants, and vehicles. [0142] In addition to the subject compound, the compositions of the invention may contain a pharmaceutically acceptable carrier, one or more compatible solid or liquid filler WO 2006/118605 PCT/US2005/040725 28 diluents or encapsulating substances, which are suitable for administration to an animal. Carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the animal being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. [0143] Exemplary pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions. [0144] In particular, pharmaceutically acceptable carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. [0145] Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention. [0146] Effective concentrations of one or more of the compounds of the invention including pharmaceutically acceptable salts, esters or other derivatives thereof are mixed with a suitable pharmaceutical carrier, excipients, adjuvant, or vehicle. In instances in which the compounds exhibit insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as Tween, or WO 2006/118605 PCT/US2005/040725 29 dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as salts of the compounds or prodrugs of the compounds may also be used in fonrmulating effective pharmaceutical compositions. [0147] Upon mixing or addition of the compound(s) of Formula I and/or Formula II, the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the chosen carrier or vehicle. The effective concentration sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined. [0148] The pharmaceutical compositions containing compounds of general Formula I and/ or Formula II may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide pharmaceutically elegant and palatable preparations. Oral formulations contain between 0.1 and 99% of a compound of the invention and usually at least about 5% (weight %) of a compound of the present invention. Some embodiments contain from about 25% to about 50% or from 5% to 75 % of a compound of invention. Liquids formulations [0149] Compounds of the invention can be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, for example. Moreover, formulations containing these compounds can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can contain conventional additives, such as suspending agents (e.g., sorbitol syrup, methyl cellulose, glucose/sugar, syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats), emulsifying agents (e.g., lecithin, sorbitan monsoleate, or acacia), non-aqueous vehicles, which can include edible oils (e.g., WO 2006/118605 PCT/US2005/040725 30 almond oil, fractionated coconut oil, silyl esters, propylene glycol and ethyl alcohol), and preservatives (e.g., methyl or propyl p-hydroxybenzoate and sorbic acid). [0150] Orally administered compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the like. The pharmaceutically acceptable carriers suitable for preparation of such compositions are well known in the art. Oral formulations may contain preservatives, flavoring agents, sweetening agents, such as sucrose or saccharin, taste-masking agents, and coloring agents. [0151] Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent. Suspensions [0152] For a suspension, typical suspending agents include methylcellulose, sodium carboxymethyl cellulose, Avicel RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. [0153] Aqueous suspensions contain the active material(s) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents; may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol substitute, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan substitute. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl p-hydroxybenzoate.
    WO 2006/118605 PCT/US2005/040725 31 [0154] Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Emulsions [0155] Pharmaceutical compositions of the invention may also be in the form of oil in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. Dispersible powders [0156] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Tablets and Capsules [0157] Tablets typically comprise conventional pharmaceutically compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannmaitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are WO 2006/118605 PCT/US2005/040725 32 useful adjuvants for chewable tablets. Capsules (including time release and sustained release formnnulations) typically comprise one or more solid diluents disclosed above. The selection of carrier components often depends on secondary considerations like taste, cost, and shelf stability. [0158] Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac. [0159] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Injectable and Parenteral formulations [0160] Pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are useful in the preparation of injectables. [0161] Compounds of Formula I and Formula II may be administered parenterally in a sterile medium. Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intrathecal injection or infusion techniques. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
    WO 2006/118605 PCT/US2005/040725 33 Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. In compositions for parenteral administration the carrier comprises at least about 90% by weight of the total composition. Suppositories [0162] Compounds of Formula I and Formula II may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non- irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. Topicalformulations [0163] Compounds of the invention maybe formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Topical compositions of the present invention may be in any form including, for example, solutions, creams, ointments, gels, lotions, milks, cleansers, moisturizers, sprays, skin patches, and the like. [0164] Such solutions may be formulated as 0.01% -10% isotonic solutions, pH about 5-7, with appropriate salts. Compounds of the invention may also be formulated for transdermal administration as a transdermal patch. [0165] Topical compositions containing the active compound can be admixed with a variety of carrier materials well known in the art, such as, for example, water, alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like. [0166] Other materials suitable for use in topical carriers include, for example, emollients, solvents, humectants, thickeners and powders. Examples of each of these types of materials, which can be used singly or as mixtures of one or more materials, are as follows: Emollients, such as stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane 1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, iso-propyl isostearate, stearic acid, iso-butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, WO 2006/118605 PCT/US2005/040725 34 octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, iso-propyl myristate, iso-propyl palmitate, iso-propyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, and myristyl myristate; propellants, such as propane, butane, iso-butane, dimethyl ether, carbon dioxide, and nitrous oxide; solvents, such as ethyl alcohol, methylene chloride, iso-propanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran; humectants, such as glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin; and powders, such as chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically modified magnesium aluminium silicate, organically modified montmorillonite clay, hydrated aluminium silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, and ethylene glycol monostearate. [0167] The compounds of the invention may also be topically administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. Other formulations [0168] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol, and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methylcellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included. [0169] Compositions for inhalation typically can be provided in the form of a solution, suspension or emulsion that can be administered as a dry powder or in the form of an aerosol using a conventional propellant (e.g., dichlorodifluoromethane or trichlorofluoromethane).
    WO 2006/118605 PCT/US2005/040725 35 Additional components [0170] The compositions of the present invention may also optionally comprise an activity enhancer. The activity enhancer can be chosen from a wide variety of molecules that function in different ways to enhance antimicrobial effects of compounds of the present invention. Particular classes of activity enhancers include skin penetration enhancers and absorbtion enhancers. Pharmaceutical compositions of the invention may also contain additional active agents can be chosen from a wide variety of molecules, which can function in different ways to enhance the antimicrobial or therapeutic effects of a compound of the present invention. These optional other active agents, when present, are typically employed in the compositions of the invention at a level ranging from about 0.01% to about 15%. Some embodiments contain from about 0.1% to about 10% by weight of the composition. Other embodiments contain from about 0.5% to about 5% by weight of the composition. Packaged Formulations [0171] The invention includes packaged pharmaceutical formulations. Such packaged formulations include a pharmaceutical composition containing one or more compounds or salts of Formula I 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. [0172] 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 [0173] 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 and of 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 WO 2006/118605 PCT/US2005/040725 36 preventing microorganism infections in livestock animals, companion animals, and human patients are particularly preferred. [0174] 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. [0175] In some circumstances an effective amount of a compound of Formula I or Formula I 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. [0176] 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 or 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. [0177] The invention also includes using compounds of Formula I and Formula I 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. [0178] 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, WO 2006/118605 PCT/US2005/040725 . 37 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. [0179] The disclosed compounds are useful for treating infections caused by the following microorganisms: Aerobic Gram-positive Microorganisms: Including but not limited to Enterococcusfaecalis, Enterococcusfaeciumn, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus haemolyticus, and Staphylococcus hominis. Aerobic Gram-negative Microorganisms: Including but not limited to Caminpylobacterjejuni, Citrobacter diversus, Citrobacterfreundii, 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, Shigellaflexneri, Shigella sonnei. Acinetobacter Iwoffi, Aeromonas hydrophila, Edwardsiella tarda, Enterobacter aerogenes, Klebsiella oxytoca, Legionella pneumophila, Pasteurella multocida, Salmonella enteritidis, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, Yersinia enterocolitica and H. Pylorii. Non-bacterial microorganisms: Mycoplasma, Legionella and Chlamydia. [0180] 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 WO 2006/118605 PCT/US2005/040725 38 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. [0181] 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. [0182] 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 [0183] The compounds of the invention may also be useful in combination with other pharmaceutically active agents such as antibacterial agents, antiviral agents, antifimgal agents, anti-inflammatories, 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. [0184] 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. [0185] 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. [0186] Anti-bacterial antibiotic agents include, but are not limited to, penicillins, cephalosporins, carbacephems, cephamycins, carbapenems, monobactams, aminoglycosides, WO 2006/118605 PCT/US2005/040725 39 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 fonnate 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 WO 2006/118605 PCT/US2005/040725 40 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); Erytbromycin 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. [0187] 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, Naftifine, 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, Amorolfine, 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. [0188] 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-a, Interferon-0, Interferon-y, Kethoxal, Lysozyme, Methisazone, Moroxydine, Nevirapine, WO 2006/118605 PCT/US2005/040725 41 Podophyllotoxin, Ribavirin, Rimantadine, Ritonavir2, Saquinavir, Stailimycin, Statolon, Tromantadine, and Xenazoic Acid. [0189] Antiinflammatory agents include, but are not limited to, Enfenamic Acid, Etofenamate, Flufenamic 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, Diflorasone, Diflucortolone, Difluprednate, Enoxolone, Fluazacort, Flucloronide, Flumethasone, Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone, WO 2006/118605 PCT/US2005/040725 42 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. [0190] 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. [0191] 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, 1-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, Rol 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 [0192] 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 WO 2006/118605 PCT/US2005/040725 43 preparing the compounds of the invention are known, made by known methods, or are commercially available. [0193] 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. [0194] 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. [0195] The compounds of the invention may have one or more chiral center. As a result, one may selectively prepare one optical isomer, including diastereomers and enantiomers, over another, for example by chiral starting materials, catalysts or solvents, or may prepare both stereoisomers or both optical isomers, including diastereomers and enantiomers at once (a racemic mixture). Since the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, or stereoisomers may be separated using known methods, such as through the use of, for example, chiral salts and chiral chromatography. [0196] 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. [0197] The invention also includes all energetically accessible conformational and torsional isomers of the compounds disclosed.
    WO 2006/118605 PCT/US2005/040725 44 [0198] When the substituent R 7 in a compound of Formula I or Formula II is attached via an unsaturated aliphatic group, for example when R 7 is phenyl (C 2
    -C
    6 alkenyl), all geometric isomers of the compound are included. [0199] This invention is further illustrated by the following examples that should not be construed as limiting. The contents of all references, patents and published patent applications cited throughout this application are incorporated herein by reference. EXAMPLES ABBREVIATIONS [0200] The following abbreviations are used in the reaction schemes and synthetic examples, which follow. This list is 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. (Boc) 2 0 - Di-t-butyl dicarbonate Cbz-Cl - Benzyloxycarbonyl chloride DMF - N,N-Dimethylfonnrmamide DMSO - Dimethylsulfoxide Et 3 N - Triethyl amine Et 2 0 - Diethyl ether EtOH - ethanol EtOAc - Ethyl acetate PPh 3 - Triphenyl phosphate PTLC - Preparative thin layer chromatography t-BuOK - tert-Butyl oxide TsCl - Tosyl chloride THF - Tetrahydrofuran WO 2006/118605 PCT/US2005/040725 45 GENERAL METHODS [0201] 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 on glass plates coated with Merck silica gel 60 (F 254 ). Flash colunm chromatography is performnned on Merck silica gel 60 (230 400 mesh). Melting points are recorded on an Electrothermal Model IA9100 digital melting point apparatus; the reported values are the average of three measurements. NMR spectra are recorded at ambient temperature using a Bruker Avance 300 spectrometer (H at 300.1 MHz, 13C at 75.5 MHz, and 19 F at 282.4 MHz). The chemical shifts for 1 H and 13 C are reported in parts per million (b) 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 (b) relative to external fluorotrichloromethane. Assignment of 1 H and 13 C NMR data is based on extensive two-dimensional correlation experiments ( 1
    H-
    1 H COSY, 1
    H-
    13 C HMQC, H-13C HMBC, and H- H 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 C18 50 x 4.6 mm 5 man column with an isocratic elution of 0.24 min at 90:10 H 2 0:CH 3 CN 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 LUV detection at 254 nm. Preparative HPLC is performed using a YMC Pack Pro C18 150 x 20.0 mm 5 Am column with an isocratic elution of 0.24 min at 97:3 H 2 0:CH 3 CN 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 analysis is performed at Prevalere Life Sciences, Inc. (Whitesboro, NY).
    WO 2006/118605 PCT/US2005/040725 46 EXAMPLE 1. METHOD FOR THE PREPARATION OF 7-[(4Z)-3-AMINOMETHYL-4-METHOXYIMIO PYRROLIDIN-1-YL)]-9-CYCLOiPROPYL-6-FLUORO-9H-ISOTHiAZOLO[5,4-B]QUINOLINE-3 ,4-DIONE (12). [0202] 7-[(4Z)-3-Aminomethyl-4-methoxyimino-pyrrolidin-1-yl)]-9-cyclopropyl-6 fluoro-9H-isothiazolo[5,4-b]quinoline-3,4-dione (12) is prepared in accordance with the synthetic scheme set forth below. 0 O F FINH F N S 1A Step 1. 9-Cyclopropyl-6, 7-difluoro-9H-isothiazolo[5, 4-b] quinoline-3, 4-dione (1). [0203] 9-Cyclopropyl-6,7-difluoro-9H-isothiazolo[5,4-b]quinoline-3,4-dione is prepared from 2,4,5-trifluorobenzoic acid using the procedure of Chu (J. Heterocyclic Chem., (1990) 27: 839.). LCMS (API) m/z calcd for C 13 HsF 2
    N
    2 0 2 S 294 ([M +]); found 295 ([M+H]+). 1 H NMR (300 MHz, DMSO-d6): 8 1.25 (m, 2H), 1.36(m, 2H), 3.56(m, 1H), 8.04(dd, JH-F6 = 11 Hz, JH-F7=8.8Hz, 1H), 8.10 (dd, JH-F7= 11.6Hz, JH-F6= 5.8 Hz, 1H). 1 9 F NMR (DMSO-d6): 8 143.30 (d, J = 27 Hz), 130.12 (d, J= 27 Hz).
    WO 2006/118605 PCT/US2005/040725 47 EtO2C N'IH3 CI - CO 2 Et EtO2C N ,CO 2 Et Cbz-CI Eto2c N CO2 Et
    K
    2 00 3 , DMF H 2 K 2
    CO
    3 , THF Cbz 3 t-BuOK O 0 THF 0 0 N NaBH 4
    NH
    2 OMe-2 HCI N-Cbz EtOH N-Cbz pyridine ) N-Cbz HO 6 EtO 2 C 5 EtO 2 C 4 64 TsCI Et 3
    N/CH
    2
    CI
    2 O O O N NaN 3 N PPh 3 N TO N-Cbz TF N3 N-Cbz THF/H20 H2N-Cbz TsO THE..N/ THFHN3H.0 H 2 N. 7 8 9 Boc 2 0, K 2 CO3 0
    CH
    2
    CI
    2 /H20 O NH 1, A, DMF N 10% Pd/C N N/- N / H" NH 10 dO 2 tH H " -,N-Cbz Boe" H 2 E o RNH- 11 Bo =B/10 HCl/MeOH (12: R = Boc "13: R =H2+C Step 2. 3-(Ethoxycarbonylmethyl-amino)-propionic acid ethyl ester (2). [0204] A mixture of ethyl glycinate hydrochloride (25.0 g, 179 mmol) and K 2 CO3 (55.0 g, fine powder, 362 mmol) in DMF (300 ml) is stirred for 30 min at room temperature. Ethyl acrylate (19.7 g, 197 mmol) is added slowly (-30 min.) and the reaction mixture is then stirred at 80 oC for 8 hr. DMF is removed in vacuo and the residue extracted (2 x 200 mL) with EtOAc/H 2 0. The organic layer is washed with water (50 mL) and brine (50 mL), dried (Na 2
    SO
    4 ), and the EtOAc removed in vacuo. The residue is distilled (3 mm Hg, 100-105 °C) to afford 2 a clear oil. LCMS (API) m/z calc'd for C 9 H17NO 4 203 ([M+]); found 204 ([M+H]+). 1 H NMR (300 MHz, CDC1 3 ): 61.27 (mn, 6H), 2.24 (bs, 1H), 2.52 (t, J=5.1 Hz, 2H), 2.92 (t, J=6.9 Hz, 2H), 3.43 (s, 2H), 4.17 (mn, 4H).
    WO 2006/118605 PCT/US2005/040725 48 Step 3. 3-(Benzyloxycarbonyl-ethoxycarbonylminethyl-amino)-propionic acid ethyl ester (3). [0205] A mixture of Compound 2 (20.0 g, 98 mmol) and K 2
    CO
    3 (20.4 g, 148 mmol, fine powder) in CH 3 CN (500 ml), is stirred for 30 min. Cbz-C1 (14 ml, 99 mmol) is then added slowly. The reaction mixture is refluxed for 5 hr, additional Cbz-C1 (7 ml, 49 mrnol) is added, and the mixture is refluxed for 15 hr. The solvent is removed in vacuo, extracted (2 x 200 mL) with CHC13/H 2 0. The organic layer is washed with water (50 mL) and brine (50 mL), dried (Na 2
    SO
    4 ), and the CHC1 3 removed in vacuo. The residue is purified by flash chromatography (EtOAc/hexanes: 1/4) to afford 3 as a clear oil. LCMS (API) m/z calcd for
    C
    1 7
    H
    23 NO6 337 ([M ]); found 338 ([M+H]+). 1 H NMR (300 MHz, CDC1 3 ): J1.24 (min, 6H), 3.90-4.30 (m, 10H), 5.12 (s, 2H), 7.34-7.38 (min, 5H). Step 4. 4-Oxo-pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-ethyl ester (4). [0206] t-BuOK 9.6g (86 mmol) is added to a mixture of 3 (12.0 g, 36 mmol) in THF (300 ml). The reaction mixture is stirred for 2 hr, satu rated aq NH 4 C1 (50 ml) is then added. The THF is removed in vacuo. The residue is extracted with (2 x 150 mL) CHC1 3
    /H
    2 0 and the organic layer washed with water (50 mL) and brine (50 mL), dried (Na 2
    SO
    4 ), and the CHC1 3 is removed in vacuo. The residue is purified by flash chromatography (EtOAc) to afford 4 as a white solid. LCMS (API) m/z calcd for C 15
    H
    17 NO5 291 ([M+]); found 292 ([M+H]+). 1 HNMR (300 MHz, CDC1 3 ): 61.25-1.34 (min, 3H), 3.93-4.32 (min, 7H), 5.18 (s, 2H), 7.34-7.40 (min, 5H). Step. 5. 4-Methoxyimino-pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-ethyl ester (5). [0207] A mixture of 4 (2.0 g, 6.9 mmol) and O-methylhydroxylamine dihydrochloride (860 mg, 10.3 mmol) in pyridine (20 mL) is stirred at 80 'C for 4 hr. The pyridine is removed, toluene (20 ml) is added and then removed in vacuo. The residue is extracted with (2 x 50 mL) CHC 3
    /H
    2 0, the organic layer is washed with water (10 mL) and brine (10 mL), dried (Na 2
    SO
    4 ), and the CHC1 3 removed in vacuo. The residue is purified by flash chromatography (EtOAc/hexanes: 1/4) to afford 5 (1.82 g, 83 %) as a clear oil. LCMS (API) m/z calcd for C 1 6
    H
    20
    N
    2 0 5 320 ([M+]); found 321 ([M+H] ). 1 H NMR (300 MHz, CDC13): c,5 1.24-1.33 (min, 3H), 3.70-4.05 (min, 6H), 4.15-4.28. (min, 4H), 5.18 (s, 2H), 7.34-7.40 (min, 5H). Step 6. 3-Hydroxymniethyl-4-mnethoxyimino-pyrrolidine-1l-carboxylic acid benzyl ester (6).
    WO 2006/118605 PCT/US2005/040725 49 [0208] NaBH 4 (327 mg, 8.6 mmol) is added to a solution of 5 (1.39 g, 4.3 mmol) in EtOH (20 ml) at 0 oC and then stirred for 5 hr at room temperature. Saturated aqueous NaHCO 3 (2 ml) and EtOAc (2 ml) are then added, and the reaction mixture is stirred for additional 1 hr at room temperature. The solvents are then removed in vacuo. The residue is extracted with EtOAc/H 2 0 (2 x 50 mL) and organic layer is washed with water (10 mL) and brine (10 mL), dried (Na 2
    SO
    4 ), and the EtOAc removed in vacuo. The residue is purified by flash chromatography (EtOAc/hexanes: 1/1) to afford 6 as a clear oil. Starting material 5 is also recovered (700 mg, 50 %). LCMS (API) m/z calcd for C 14
    H
    1 8
    N
    2 0 4 278 ([M+]); found 279 ([M+H]+). 1 H NMR (300 MHz, CDC1 3 ): 32.55 (bs, 1H), 3.14 (min, 1H), 3.40 (min, 1H), 3.76 (d, J=6.8 Hz, 2H), 3.85 (s, 3H), 3.90-3.95 (min, 1H), 4.20 (min, 2H), 5.17 (s, 2H), 7.31-7.41 (in, 5H). Step 7. 3-Methoxyimino-4-(toluene-4-sulfonyloxymnethyl)-pyrrolidine-l-carboxylic acid benzyl ester (7). [0209] A mixture of 6 (600 mg, 2.2 mmnol), Et 3 N (2 ml, 14.3 mmol), TsC1 (492 mg, 2.6 mmol) in CH 2 C1 2 (20 ml) is stirred for 2 days at room temperature. The solvents are then removed in vacuo. The residue is purified by flash chromatography (EtOAc/CHC1 3 : 1/15) to afford 7 as a pale yellow oil. Starting material 6 is also recovered. LCMS (API) m/z calcd for C 21
    H
    24
    N
    2 0 6 S 432 ([M ]); found 433 ([M+H] ). 1 H NMR (300 MHz, CDC1 3 ): 32.45 (s, 3H), 3.22 (min, 1H), 3.42 (min, 1H), 3.78-3.89 (min, 1H), 3.82 (s, 3H), 3.97-4.33 (min, 4H), 5.13 (s, 2H), 7.28-7.40 (min, 7H), 7.78 (d, J=8.2 Hz, 2H). Step 8. 3-Azidomethliyl-4-methoxyimino-pyrrolidine-1-carboxylic acid benzyl ester (8). [0210] A mixture of 7 (340 mg, 0.79 mmol) and NaN 3 (102 mg, 1.57 mmol) in DMF (5 ml) is stirred for 2 hr at 80 oC. The solvents are then removed in vacuo. The residue is extracted with EtOAc/H 2 0 (2 x 30 mL) and the organic layer is washed with water (5 mL) and brine (5 mL), dried (Na 2
    SO
    4 ), and the EtOAc removed in vacuo. The residue is used in the next reaction without any purification. LCMS (API) m/z calcd for C 14
    H
    17
    N
    5 0 3 303 ([M+]); found 276 ([M-N 2 +H] ). 1H NMR (300 MHz, CDC1 3 ): 33.12 (min, 1H), 3.47 (min, 2H), 3.57-3.71 (min, 1H), 3.89 (s, 3H), 3.89-3.90 (min, 1H), 4.17 (min, 2H), 5.15 (s, 2H), 7.30-7.39 (inm, 5H).
    WO 2006/118605 PCT/US2005/040725 50 Step 9. 3-Aminomnethyl-4-mnethoxyimino-pyrrolidine-1l-carboxylic acid benzyl ester (9). [0211] A mixture of 8 (50 mg, 0.16 mmol) and PPh 3 (250 mg, 0.95 mmol) in aqueous THF. (THF/H 2 0: 8.5 ml/1.5 ml) is refluxed for 3 hr. The solvents are then removed in vacuo. The residue is purified by flash chromatography (EtOAc, CHCl 3 /MeOH: 10/1) to afford 9 (37 mg, 81 %) as a clear oil to solid. LCMS (API) m/z calcd for C 14
    H
    19
    N
    3 0 3 277 ([M+]); found 278 ([M+H] ). H NMR (300 MHz, CDC1 3 ): 62.88-3.16 (mn, 2H), 3.38 (mn, 1H), 3.68 (inm, 2H), 3.88 (s, 3H), 4.17 (min, 2H), 4.17 (min, 2H), 5.14 (s, 2H), 7.27-7.40 (mn, 5H). Step 10. 3-(tert-Butoxycarbonylamnino-methyl)-4-minethoxyimnino-pyrrolidine-1-carboxylic acid benzyl ester (10). [0212] A mixture of 9 (35 mg, 0.13 mmol), K 2
    CO
    3 (35 mg, 0.25 mmol), Boc 2 0 (29 mg, 16.6 nmmol) in CH 2 C1 2
    /H
    2 0 (5 ml/5 ml) is stirred for 15 hr at room temperature. The organic layer is separated, dried (Na 2
    SO
    4 ), and the solvent removed in vacuo. The residue is purified by flash chromatography (EtOAc/hexanes: 1/3, 1/2) to afford 10 as a clear oil. LCMS (API) m/z calcd for C 19
    H
    27
    N
    3 0 5 377 ([M+]); found 378 ([M+H]+). 1 H NMR (300 MHz, CDC1 3 ): 51.43 (s, 9H), 3.02 (min, 1H), 3.33 (mn, 3H), 3.84 (mn, 1H), 3.88 (s, 3H), 4.16 (min, 2H), 4.98 (bs, 1H), 5.14 (s, 2H), 7.27-7.41 (mn, 5H). Step 11. (4-Methoxyimnino-pyrrolidin-3-ylmethyl)-carbamnic acid tert-butyl ester (11). [0213] A mixture of 10 (240 mg, 0.64 mmol) and Pd/C (20 mg) in EtOH is stirred under H2 (1 atm) for 4 hr. at room temperature. The mixture is filtered and the residue (156 mg) is used for next reaction without any purification. LCMS (API) m/z calcd for
    C
    11
    H
    21
    N
    3 0 3 243 ([M+]); found 244 ([M+H]+). 1H NMR (300 MHz, CDC1 3 ): 61.45 (s, 9H), 3.09 (min, 2H), 3.25-3.61 (min, 3H), 3.89 (s, 3H), 3.94 (mn, 1H), 5.22 (bs, 1H), 6.45 (bs, 2H). Step 12. 7-(3-Aminomethyl-4-methoxyimino-pyrrolidin-1-yl)-9-cyclopropyl-6-fluoro-9H isothiazolo[5, 4-b] quinoline-3, 4-dione (13). A solution of 12 (300 mg, 0.58 mmol) in HCl/MeOH (-1.25 M, 4.6 mL.) is stirred for 24 hr at room temperature. Et 2 0 (50 ml) is added to the reaction mixture and the precipitate is collected and washed with Et 2 0 (3 x 30 mL). The solid is dried in vacuo to give 13. LCMS (API) m/z calcd for C19H 2 1 C1FN 5 0 3 S 417 ([M+]), found 418 (M+1). 1H NMR (300 MHz, DMSO-d 6 ) 5 1.23 (min, 2H), 1.39 (min, 2H), 3.21 (min, 2H), 3.49 (mn, 3H), 3.87 (s, 3H), 4.01 (min, 1H), 4.38 (s, 2H), 7.09 (d, 1H, J=6.6 Hz), 7.73 (d, 1H, J=14.4 Hz). 19F NMR (350 MHz, WO 2006/118605 PCT/US2005/040725 51 DMSO-d 6 ) 5 130 (s, 1F). Anal. Calcd for C 1 9
    H
    21 C1FN 5 sO 3 S-1.5H 2 0: C, 47.45; H, 5.03; N, 14.56. Found: C, 47.04; H, 4.52; N, 14.35. Alternate preparation of 7-[(4Z)-3-Ainomethyl-4-methoxyimino-pyrrolidin-1-yl]]-9 cyclopropyl-6-fluoro-9H-isothiazolo[5, 4-b] quinoline-3, 4-dione (13). 0 0 0 0 NH 1) B(OH) 3 , Ac 2 0 -0 N NH E N ON NH N N S 1
    H
    2 N__ 2 HCI H313 [0214] A mixture of boric acid (43 mg, 0.70 mmole), acetic anhydride (0.22 ml, 2.33 mmole) and acetic acid (0.13 ml) in toluene (0.43 ml) is refluxed for 3 hours. Intermediate 1 (172 mg, 0.58 mmole) is then added to the reaction mixture and refluxed another 4 hours. The volatiles are then removed in vacuo. 4-Aminomethyl-pyrrolidin-3-one O-methyl-oxime dihydrochloride (Tyger Scientific Inc., 380 rmg, 1.76 mmole), triethyl amine (1 ml), and acetonitrile (10 ml) are then added to the residue, and the reaction mixture is refluxed for 4 hours. The volatiles are then removed in vacuo. The residue is washed with diethyl ether (1 x mL), a mixture of chloroform and methanol (1 x mL), and water (1 x mL). The residue is then purified by reverse phase HPLC (conditions) to afford 13. EXAMPLE 2. ADDITIONAL COMPOUNDS [0215] The following compounds of TABLE I are made by the methods given in Example 1. Those having skill in the art will recognize that the starting materials and reaction conditions may be varied and additional steps employed to produce the compounds shown in TABLE I. [0216] Unless designated, the stereochemistry of the R7 group oxime double bond can be either Z or E, and the stereochemistry of other chiral carbons within the group can be racemic, R, or S.
    WO 2006/118605 PCT/US2005/040725 52 z C C,,, SU 0, I T I I' l 0 E ~ 0 Nw~ o U 0 ZIU 0 z ) 0zU o - 0 o- o - 0l z z C I, C _ _C_0 WO 2006/118605 PCT/US2005/040725 53 z
    L
    z 'I-D C,, ,c 4 ON 0 0 ON C ~0 _ 0 o 4 of a,)0 Z ) 0 Z,~~** Cl) 0 '-z- I)0 Zl I I 2: 2: 2:2 2: I Zl 0 C Z, 0 'e'0 z oL 0 0 o o C.,q WO 2006/118605 PCT/US2005/040725 54 z LL 0~0 0 0 I i0iz OI 2. -0 u~ 40 C* ~ X " 0 - 0 0 - 0 0 -4-ar LL. oz zz z 0 z 0 -Z z 0 I O04 cliC' 0o C4C WO 2006/118605 PCT/US2005/040725 55 z 4 o 00~ CL 0 4, 0 I . ) 0 - * 0 0 *~z:I- I ~ m I 0 ~j " 0 -0 zn .- ~ 'T o _II 0 0l/ ,U I/ 0 Z- 0 Z- Z- o C.C z z z z z z z 0' 4 0 0 4 0' 1 0' I I II WO 2006/118605 PCT/US2005/040725 56 z
    U
    z U I ~ 0 -- I II E I N' It P "yV I I' c 0*'- I 00 0 ~0 0 Z< 0' z 0 z 00' 0 a:3 C- U I I U- Z WO 2006/118605 PCT/US2005/040725 57 z z' -, - C,-) Co c- T 0 0 Z, 0~ Zl) 0 ZU ,U 0 0 -II z 0~ -- z z z LL. I O0 (~0T~ WO 2006/118605 PCT/US2005/040725 58 z Co C,,0 p p IM I 0 00 00 0 E 0 0 0 ZI) 0Z 0 Z) 0o- 0 Z<0 0 z z u-0 z z I It WO 2006/118605 PCT/US2005/040725 59 CI z IL Z cn C,)f 'IIt (U Ci,, w o z o 4t *~ In ,.d 4U 71 Ql r 0 . o oL ZN WO 2006/118605 PCT/US2005/040725 60 EXAMPLE 3. ANTIMICROBIAL ACTIVITY OF COMPOUNDS [0217] 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. MINIMUM INHIBITORY CONCENTRATION (MIC) ASSAY [0218] 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, M100-S11. 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 tg/ml stock solution. In 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 pl 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 pg/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). The minimum inhibitory concentration (MIC) is determined as the lowest concentration of compound that inhibited visible growth of the test organism.
    WO 2006/118605 PCT/US2005/040725 61 [0219] Table II below shows the minimum inhibitory concentration required to kill S. aureus and E. coli cells for several compounds of Formula I. TABLE II COMPOUND MIC S. aureus MIC E. coli (ug/ml) (ug/ml) 13 <0.05 <0.05 27 <0.05 <0.05 32 <0.05 <0.05 39 <0.05 0.125 41 <0.05 <0.10 42 <0.10 <0.125
    权利要求:
    Claims (53)
    [1] 1. A compound of Formula I or Formula II R7 R R .N-R2 RR N R 3 R 5 0 0 R 5 o N- n A N N R INA N A N~ ZN A 8 N A 1 (RBN P m R 9 (RBN R 9 RA RA Formula I Formula II or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein A 1 is S, O, SO, or SO 2 ; R 2 is hydrogen, or R 2 is C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 7 cycloalkyl)Co-C 4 carbohydryl, (C 4 C 7 cycloalkenyl)Co-C 4 carbohydryl, (aryl)Co-C 4 carbohydryl, or (C 2 -C 6 heterocycloalkyl)Co C 4 carbohydryl, each of which is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, C 1 -C 4 alkyl, Cl-C 4 alkoxy, Ci-C 2 haloalkyl, Cl-C 2 haloalkoxy, mono- and di-C 1 -C 4 alkylamino, C 2 -C 4 alkanoyl, C 1 -C 4 alkylthio, -O(C=O)Ri 0 , -(C=O)NRo 10 Rl, -O(C=O)NRo 0 RI, -(C=O)OR10, -(C=O)NR 1 oOR 11 , -NRio(C=O)Rll, -NRio(C=O)ORt, -NRlo(C=O)NRlR 1 2 , -NR 1 o(C=S)NRIR 1 2 , -NRIoNR 11 R 1 2 , -SO 3 Rio, -(S=O)ORlo, -SO 2 R 13 , -SO 2 NRioR 11 , =N-ORlo and -NR 10 SO 2 R 13 ; where each Ro 1 0 , Ru,I and R 1 2 is independently hydrogen, Ci-C 4 alkyl, or aryl, and each R 1 3 is independently Ci-C 4 alkyl or aryl; R 3 is hydrogen, C 1 -C 6 alkyl, Ct-C 6 alkanoyl, mono- or di-Cl-C 6 alkylcarbamate, Ci C 6 alkylphosphate, or C 1 -C 6 allkylsulfonate; each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, Ct C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; Rs is hydrogen, halogen, hydroxy, amino, cyano, nitro, -NHNH 2 , C 1 -C 2 haloalkyl, or C 1 C 2 haloalkoxy; or WO 2006/118605 PCT/US2005/040725 63 R 5 is Ci-C 4 alkyl, C 1 -C 4 alkoxy, mono- or di-C 1 -C 4 alkylamino, mono-, di-, or tri-Cl-C 4 alky1hydrazinyl, C 2 -C 4 alkanoyl, or C 1 -C 4 alkylester; each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, amino, halogen, oxo, C 1 -C 4 alkoxy, Cl-C 2 haloalkyl, C 1 -C 2 haloalkoxy, and mono- and di-C 1 -C 4 alkylamino; R 6 is hydrogen, halogen, hydroxy, amino, cyano, Ci-C 4 alkyl, Cl-C 4 alkoxy, mono- or di-C 1 C 4 alkylamino, -SO 3 R 10 , -SO 2 R 1 0 , -SO 2 NRo 0 R 1 1 ; nis 1,2,or3; m is 1,2,or3; p is 0 or l; each RA is independently (i), (ii), or (iii); where (i) is hydrogen, hydroxy, amino, or cyano, (ii) is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyCo-C 4 alkyl, mono- or di-Cl C 4 alkylamino, C 1 -C 2 haloalkoxy, (C 3 -C 7 cycloalkyl)Co-C 4 carbohydryl, (C 4 C 7 cycloalkenyl)Co-C 4 carbohydryl, (aryl)Co-C 6 carbohydryl, (aryl)C 1 -C 4 alkoxy, (C 2 C 6 heterocycloalkyl)Co-C 4 carbohydiyl, (heteroaryl)Co-C 6 carbohydryl, C 1 -C 6 alkylthio, -(Co-C 4 alkyl)O(C=O)Ro, -(Co-C 4 alkyl)(C=O)NRioRI1, -(Co-C 4 alkyl)O(C=O)NRioR1I1, -(Co-C 4 alkyl) (C=O)ORio, -(Co-C 4 alkyl)NRo(C=O)Ri, -(Co-C 4 alkyl)NRio(C=O)OR11, -(Co-C 4 alkyl)NRo(C=O)NRI 1 R 1 2 , -(C0-C 4 alkyl)NR 1 o(C=S)NR1I 1 R 1 2 , -(Co C 4 alkyl)NRIoNR11R 1 2 , -(Co-C 4 alkyl)N=NR1 3 , -(C0-C 4 alkyl)SO 3 Rio, -(Co C 4 alkyl)(S=O)OR10, -(Co-C 4 alkyl)SO 2 R 1 3 , -(C0-C 4 alkyl)SO 2 NRioR1I, -(Co C 4 alkyl)NRtoSO 2 RI 3 ; =N-OH, or =N-O(Co-C 4 alkyl); (iii) is -ORD, -(C=O)RD, -SO2RD, -SO3RD, or -NRIOSO 2 RD, where RD is C 1 -C 4 alkyl, (C 3 C 7 cycloalkyl)Co-C 2 alkyl, (C 2 -C 6 heterocycloalkyl)Co-C 2 alkyl, (aryl)Co-C 2 alkyl, or (heteroaryl)Co-C 2 alkyl; where each of (ii) and (iii) is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -(C=O)OCH 3 , -CONH 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, CI 1 -C 4 alkoxy, (C 3 C 7 cycloalkyl)Co-C 4 carbohydryl, (C 3 -C 7 cycloalkyl)Co-C 4 alkoxy, mono- and di-Cl C 4 alkylamino, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, and C 2 -C 4 alkanoyl; or any two RA bound to the same carbon atom may be joined to form a C 3 -C 7 cycloalkyl, or a 3- to
    [2] 7- membered heterocycloalkyl group; having 1 or 2 heteroatoms independently chosen WO 2006/118605 PCT/US2005/040725 64 from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from CI-C 2 alkyl, and Ci-C 2 alkoxy; or any two RA bound to different carbon atoms may be joined to form a C 3 -C 7 cycloalkyl or a 3- to 7 membered heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from C 1 -C 2 alkyl, and C 1 I-C 2 alkoxy; RB is hydrogen or C1-C 4 alkyl; R 7 is hydrogen, or R 7 is C 1 I-Csalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkanoy, (C 3 -C 7 cycloalkyl)Co C 4 carbohydryl, (C 4 -C 7 cycloalkenyl)Co-C 4 carbohydryl, (aryl)Co-C 4 carbohydryl, (aryl)(C=O)-, mono- or di-(C 1 -C 6 alkyl)carboxamide, C 1 -C 6 alkylester, or (C 2 C6heterocycloalkyl)Co-C 4 carbohydryl, each of which is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, C 1 C 4 alkyl, C1-C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, mono- and di-C 1 -C 4 alkylamino, C 2 -C 4 alkanoyl, C 1 -C 4 alkylthio, -O(C=O)Ro 0 , -(C=O0)NRoR 11 , -O(C=0)NR 1 0 R 1 , -(C=O)ORo 10 , -(C=0)NR 1 0 oR 1 , -NR 1 o(C=0)R 11 , -NR 1 o(C=0)OR 11 , -NR 1 o(C=O)NR 1 1 R 1 2 , -NR 1 o(C=S)NR 1 1 R 12 , -NRIoNR 11 R 1 2 , -SO 3 Ro 10 , -(S=O)ORio, -SO 2 R 1 3 , -SO 2 NRo 10 R 11 I, or -NRioSO 2 R 1 3 ; As is nitrogen or CRs; where R 8 is hydrogen, halogen, hydroxy, amino, cyano, nitro, or -NHNH 2 , or Rs is Ci-C 4 alkyl, C1-C 4 alkoxy, mono- or di-C 1 -C 4 alkylamino, mono-, di-, or tri-C 1 -C 4 alkylhydrazinyl, C 2 -C 4 alkanoyl, Ci-C 4 alkylester, C 1 -C 2 haloalkyl, or C1-C 2 haloalkoxy, each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, amino, halogen, oxo, Ci-C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, and mono- and di Ci-C 4 alkylamino; and R 9 is CI-C8alkyl, (C3-C 7 cycloalkyl)Co-C 4 alkyl, or phenyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -CONH 2 , C1-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 I-C 4 alkoxy, (C 3 -C 7 cycloalkyl)Co C 4 alkyl, (C 3 -C 7 cycloalkyl)Co-C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, and C 2 -C 4 alkanoyl. WO 2006/118605 PCT/US2005/040725 65 2. A compound or salt of Claim 1 of the formula R 5 0 0 RA RA R 6 N-R 2 N n N A 8 N A 1 (R B N R9 RA RA 3. A compound or salt of Claim 1 of formula R 5 0 01 R 3 RA OA R6 R 7 0 R 6 / SN 8 N A 1 " 1 (RBN R 9 RA RA 4. A compound or salt of any one of Claims 1 to 3, wherein A 1 is S. 5. A compound or salt of any one of Claims 1 to 3, wherein A 1 is SO. 6. A compound or salt of any one of Claims 1 to 3, wherein A 1 is SO 2 . 7. A compound or salt of any one of Claims 1 to 3, wherein A 1 is O.
    [3] 8. A compound or salt of any one of Claims 3 to 7, wherein R 2 is hydrogen, or R 2 is C1-C 6 alkyl or (C 3 -C 7 cycloalkyl)Co-C 4 alkyl, each of which is substituted with at least one substituent chosen from hydroxy, amino, -COOH, -(C=O)NR 10 oR 1 1 , and -CONH 2 ; and is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -CONH 2 , C1-C 4 alkyl, CI-C 4 alkoxy, Ci-C 2 haloalkyl, C 1 C 2 haloalkoxy, and mono- and di-C 1 -C 4 alkylamino, and C 2 -C 4 alkanoyl. WO 2006/118605 PCT/US2005/040725 66
    [4] 9. A compound or salt of Claim 8 wherein R 2 is hydrogen.
    [5] 10. A compound or salt of any one of Claims 1 or 3 to 7 wherein R 3 is C1-C 4 alkyl or C 2 -C 4 alkanoyl.
    [6] 11. A compound or salt of any one of Claims 1 to 10 wherein R 5 is hydrogen, amino, Ci-C 2 alkyl, C 1 -C 2 alkoxy, mono- or di-Ci-C 4 alkylamino, or mono- or di C 1 -C 4 alkylhydrazinyl.
    [7] 12. A compound or salt of Claim 11 wherein R 5 is hydrogen, amino, mono- or di-Ci-C 2 alkylamino, or mono- or di-C 1 -C 2 alky1hydrazinyl.
    [8] 13. A compound or salt of Claim 11 wherein R 5 is hydrogen.
    [9] 14. A compound or salt of any one of Claims 1 to 12 wherein: R 6 is hydrogen, halogen, or amino.
    [10] 15. A compound or salt of Claim 14 wherein R 6 is fluoro.
    [11] 16. A compound or salt of any one of Claims 1 to 15 wherein A 8 is nitrogen.
    [12] 17. A compound or salt of any one of Claims 1 to 15 wherein A 8 is CRs.
    [13] 18. A compound or salt of Claim 17 wherein R 8 is hydrogen, halogen, CI-C 2 alkyl, C 1 C 2 alkoxy, Ci-C 2 haloalkyl, or Ci-C 2 haloalkoxy.
    [14] 19. A compound or salt of Claim 18 wherein R 8 is hydrogen or methoxy. WO 2006/118605 PCT/US2005/040725 67
    [15] 20. A compound or salt of any one of Claims 1 to 19 wherein R 9 is CI-C 4 alkyl, cyclopropyl, or phenyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, C1-C 2 alkyl, Ci-C 2 alkoxy, mono- and di-Ci-C 2 alkylamino, C1-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
    [16] 21. A compound or salt of Claim 20 wherein R 9 is C1-C 4 alkyl or cyclopropyl, or R 9 is phenyl substituted with 2 substituents chosen from halogen, hydroxy, amino, C 1 C 2 alkyl, C 1 -C 2 alkoxy, mono- and di-Ci-C 2 alkylamino, Cl-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
    [17] 22. A compound or salt of Claim 20 wherein R 9 is ethyl, t-butyl, cyclopropyl, or 2,4-difluorophenyl.
    [18] 23. A compound or salt of Claim 20, wherein R 9 is cyclopropyl.
    [19] 24. A compound or salt of any one of Claim 1 to 23 wherein R 7 is hydrogen or R 7 is Ci-Csalkyl, C 2 -C 6 alkanoyl, (C 3 -C 7 cycloalkyl)Co-C 4 carbohydryl, (aryl)Co-C 4 carbohydryl, (aryl)(C=O)-, mono- or di-(Ci-C 6 alkyl)carboxamide, Ci-C 6 alkylester,or (C 2 C 6 heterocycloalkyl)Co-C 4 carbohydryl, each of which is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, C 1 C 4 alkyl, Cl-C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, mono- and di-C 1 -C 4 alkylamino, C 2 -C 4 alkanoyl, Ci-C 4 alkylthio, -O(C=O)Ro 10 , -(C=O)NRoRi, -O(C=O)NR 0 Rll, -(C=O)ORio, -(C=O)NRoOR 11 , -NRio(C=O)Rll, -NRio(C=O)OR 1 , -NRio(C=O)NR 1 1 R 1 2 , -NR 1 o(C=S)NRjiRI 2 , -NRo 1 0 NR 1 1 R 1 2 , -SO 3 Ro 10 , -(S=O)ORio, -SO 2 R 1 3 , -SO 2 NRo 10 R 11 , or -NRioSO 2 R13. WO 2006/118605 PCT/US2005/040725 68
    [20] 25. A compound or salt of Claim 24 wherein R 7 is hydrogen, or R 7 is C 1 -Csalkyl, (C 3 -C 7 cycloalkyl)Co-C 4 carbohydryl, (aryl)Co-C 4 carbohydryl, or (C 2 C 6 heterocycloalkyl)Co-C 4 carbohydryl, each of which is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, cyano, CI-C 4 alkyl, Ci C 4 alkoxy, Ci-C 2 haloalkyl, C 1 I-C 2 haloalkoxy, mono- and di-Ci-C 4 alkylamino, C 2 C 4 alkanoyl, -(C=O)NRoRIl, -NR 1 o(C=O)Rll.
    [21] 26. A compound or salt of Claim 25 wherein R 7 is hydrogen, or R 7 is C 1 -C 8 alkyl, or (aryl)Co-C 4 alkyl, each of which is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, cyano, C1-C 4 alkyl, Ci-C 4 alkoxy, C 1 -C 2 haloalkyl, Cl-C 2 haloalkoxy, mono- and di-C 1 -C 4 alkylamino, C 2 -C 4 alkanoyl, (C=O)NRioRll, -NR 1 o(C=O)R 1 .
    [22] 27. A compound or salt of Claim 25 wherein R 7 is hydrogen, C 1 -C 2 alkyl, or benzyl.
    [23] 28. A compound or salt of any one of Claims 1 to 27 wherein n is 1; m is 2, p is 1 and RB is hydrogen.
    [24] 29. A compound or salt of any one of Claims 1 to 27 wherein n is 1, mis 1, p is 1 and RB is hydrogen.
    [25] 30. A compound or salt of any one of Claims 1 to 27 wherein p is 0.
    [26] 31. A compound or salt of Claim 30 wherein n is 1 and m is 2.
    [27] 32. A compound or salt of Claim 30 wherein n is 2 and m is 2. WO 2006/118605 PCT/US2005/040725 69
    [28] 33. A compound or salt of any one of Claims 1 to 32 wherein each RA is independently (i), (ii), or (iii); where (i) is hydrogen, hydroxy, amino, or cyano, (ii) is Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 1 -C 6 alkoxy)Co-C 4 alkyl, mono- or di-C 1 C 4 alkylamino, C 1 -C 2 haloalkoxy, (C 3 -C 7 cycloallkyl)Co-C 4 carbohydryl, (C 4 C 7 cycloalkenyl)Co-C 4 carbohydryl, (aryl)Co-C 6 carbohydryl, (aryl)Ci-C 4 alkoxy, (C 2 C 6 heterocycloalkyl)Co-C 4 carbohydryl, (heteroaryl)Co-C 6 carbohydryl, C 1 -C 6 alkylthio, -(Co-C 4 alkyl)(C=O)NRioRi1, -(Co-C 4 alkyl)NRio(C=O)RI, =N-OH, or =N-O(Co-C 4 alkyl); (iii) is -ORD or -(C=O)RD, where RD is C1-C 4 alkyl, (C 3 -C 7 cycloalkyl)Co-C 2 alkyl, (C 2 C 6 heterocycloalkyl)Co-C 2 alkyl, (aryl)Co-C 2 allkyl, or (heteroalyl)Co-C 2 alkyl; where each of (ii) and (iii) is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -(C=O)OCH 3 , -CONH 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, Ci-C 4 alkoxy, (C 3 C 7 cycloalkyl)Co-C 4 carbohydryl, (C 3 -C 7 cycloalkyl)Co-C 4 alkoxy, mono- and di-Cl C 4 alkylamino, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, and C 2 -C 4 alkanoyl; or any two RA bound to the same carbon atom may be joined to form a C 3 -C 7 cycloalkyl or a 3- to 7 membered heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from C 1 -C 2 alkyl, and C 1 -C 2 alkoxy; or any two RAbound to different carbon atoms may be joined to form a C 3 -C 7 cycloalkyl or a 3- to 7-membered heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from Ci-C 2 alkyl and C 1 -C 2 alkoxy; WO 2006/118605 PCT/US2005/040725 70
    [29] 34. A compound or salt of Claim 33 wherein each RA is independently (i) or (ii); where (i) is hydrogen or amino, (ii) is Ci-C 6 alkyl, (C 1 -C 6 alkoxy)Co-C 4 alkyl, mono- or di-C 1 -C 4 alkylamino, (C 3 C 7 cycloalkyl)Co-C 4 carbohydryl, (aryl)Co-C 6 carbohydryl, (C 2 -C 6 heterocycloalkyl)Co C 4 carbohydryl, (heteroaryl)Co-C 6 carbohydryl, -(Co-C 4 alkyl)(C=0)NRioRi, -(Co C 4 alkyl)NRio(C=O)Rit, =N-OH, or =N-O(Co-C 4 alkyl); where each of (ii) is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -(C=O)OCH 3 , -CONH 2 , C1-C 4 alkyl, C 2 C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, (C 3 -C 7 cycloalkyl)Co-C 4 carbohydryl, (C 3 C 7 cycloalkyl)Co-C4alkoxy, mono- and di-C 1 -C 4 alkylamino, Ci-C 2 haloalkyl, C 1 C 2 haloalkoxy, and C 2 -C 4 alkanoyl; or any two RA bound to the same carbon atom may be joined to form a C 3 -C 7 cycloalkyl or a 3- to 7 membered heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from C 1 -C 2 alkyl, and C 1 -C 2 alkoxy; or any two RAbound to different carbon atoms may be joined to form a C 3 -C 7 cycloalkyl or heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from C 1 C 2 alkyl, and Ci-C 2 alkoxy; WO 2006/118605 PCT/US2005/040725 71
    [30] 35. A compound or salt of Claim 33 wherein each RA is independently (i) or (ii); where (i) is hydrogen or amino; (ii) is Ci-C 6 alkyl, mono- or di-Ci-C 4 alkylamino, (C 3 -C 7 cycloalkyl)Co-C 4 alkyl, (C 2 C 6 heterocycloalkyl)Co-C 4 alkyl, -(Co-C 4 alkyl)(C=O)NR 1 oR 11 , -(Co C 4 alkyl)NRio(C=O)Rl 1 , =N-OH, or =N-O(Co-C 4 alkyl); where each of (ii) is substituted with 0 to 3 substituents independently chosen from hydroxy, amino, cyano, and -CONH 2 . any two RA bound to the same carbon atom may be joined to form a C 3 -C 7 cycloalkyl or heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from Ci C 2 alkyl and Ci-C 2 alkoxy.
    [31] 36. A compound or salt of Claim 33 wherein each RA is independently (i) or (ii); where (i) is hydrogen or amino, (ii) is Ci-C 6 alkyl, (C 3 -C 7 cycloalkyl)Co-C 2 alkyl, or mono- or di-Ci-C 4 alkylamino, where each of (ii) is substituted with 0 to 3 amino, any two RA bound to the same carbon atom may be joined to form a C 3 -C 7 cycloalkyl or a 3- to 7 membered heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from C 1 -C 2 alkyl and Ci-C 2 alkoxy; or any two RAbound to different carbon atoms may be joined to form a C 3 -C 7 cycloalkyl or a membered heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from C 1 -C 2 alkyl and C 1 -C 2 alkoxy.
    [32] 37. A compound or salt of Claim 33 wherein each RA is independently hydrogen, C 1 -C 4 alkyl, or Ci-C 4 alkyl substituted with one amino substituent. WO 2006/118605 PCT/US2005/040725 72
    [33] 38. A compound or salt of Claim 37 wherein: one or two RAis C 1 -C 4 alkyl substituted with one amino substituent and the remaining RA are hydrogen.
    [34] 39. A compound or salt of Claim 33 wherein two RA bound to the same carbon atom are joined to form a C 3 -C 7 cycloalkyl or a 3- to 7 membered heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from Ci C 2 alkyl and C 1 -C 2 alkoxy; and the remaining RA are independently chosen from hydrogen, C 1 -C 2 alkyl and C 1 -C 2 alkoxy.
    [35] 40. A compound of salt of Claim 39 wherein: two RA bound to the same carbon atom are joined to form a C 3 -C 4 cycloalkyl or a 3- to 4 membered heterocycloalkyl group having 1 N atom; each of which is substituted with 0 to 2 substituents independently chosen from C1-C 2 alkyl and C 1 -C 2 alkoxy; and the remaining RA are independently chosen from hydrogen, C 1 -C 2 alkyl and C 1 -C 2 alkoxy. WO 2006/118605 PCT/US2005/040725 73
    [36] 41. A compound or salt of Claim 2 wherein: R 2 is hydrogen or C 1 -C 6 alkyl substituted with one substituent chosen from hydroxy, amino, -COOH, -(C=O)NR 10 ioOR 1 , and -CONH 2 ; R 5 is hydrogen; R 6 is halogen or amino; R 7 is hydrogen, Ci-C 2 alkyl, or benzyl; A 8 is nitrogen or CRs, and when A 8 is CRs, R 8 is hydrogen or methoxy R 9 is ethyl, t-butyl, cyclopropyl, or 2,4-difluorophenyl; and Each RA is independently hydrogen or C 1 -C 4 alkyl optionally substituted with one amino substituent; or any two RA bound to the same carbon atom may be joined to form a C 3 -C 7 cycloalkyl or a 3- to 7 membered heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from C 1 -C 2 alkyl, and Ci-C 2 alkoxy; or any two RAbound to different carbon atoms may be joined to form a C 3 -C 7 cycloalkyl or heterocycloalkyl group having 1 or 2 heteroatoms independently chosen from N, O, and S; each of which is substituted with 0 to 2 substituents independently chosen from C 1 C 2 alkyl, and C 1 -C 2 alkoxy. WO 2006/118605 PCT/US2005/040725 74
    [37] 42. A compound or salt of Claim 1 wherein the compound is 7-[(4Z)-3-Aminomethyl-4-methoxyimino-pyrrolidin-1-yl)]-9-cyclopropyl-6-fluoro-9H isothiazolo[5,4-b]quinoline-3,4-dione; 7-[(3R,4Z)-3-Aminomethyl-4-methoxyimino-pyrrolidin- 1-yl)]-9-cyclopropyl-6-fluoro-9H isothiazolo[5,4-b]quinoline-3,4-dione; 7-[(3S,4Z)-3-Aminomethyl-4-methoxyimino-pyrrolidin-1-yl)]-9-cyclopropyl-6-fluoro-9H isothiazolo[5,4-b]quinoline-3,4-dione; 7-[(4E)-3-Aminomethyl-4-methoxyimino-pyrrolidin-1-yl)]-9-cyclopropyl-6-fluoro-9H isothiazolo[5,4-b]quinoline-3,4-dione; 7-[(3R,4E)-3-Aminomethyl-4-methoxyimino-pyrrolidin-1-yl)]-9-cyclopropyl-6-fluoro-9H isothiazolo[5,4-b]quinoline-3,4-dione; 7-[(3S,4E)-3-Aminomethyl-4-methoxyimino-pyrrolidin-1-yl)]-9-cyclopropyl-6-fluoro-9H isothiazolo[5,4-b]quinoline-3,4-dione; 9-Cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-9H-isothiazolo[5,4 b]quinoline-3,4-dione; 9-Cyclopropyl-6-fluoro-7-(7-methoxyimino- 1,5-diaza-spiro[2.4]hept-5-yl)-9H-isothiazolo[5,4 b]quinoline-3,4-dione; 7-[3-(1-Amino-cyclopropyl)-4-methoxyimino-pyrrolidin- 1-yl]-9-cyclopropyl-6-fluoro-9H isothiazolo[5,4-b]quinoline-3,4-dione; 9-Cyclopropyl-6-fluoro-7-(7-methoxyimino-5-aza-spiro[2.4]hept-5-yl)-9H-isothiazolo [5,4 b]quinoline-3,4-dione; 7-(3-Aminomethyl-4-hydroxyimino-pyrrolidin- 1 -yl)-9-cyclopropyl-6-fluoro-9H-isothiazolo[5,4 b]quinoline-3,4-dione; 7-[3-(2-Amino-ethyl)-4-methoxyimino-pyrrolidin-1-yl]-9-cyclopropyl-6-fluoro-9H isothiazolo[5,4-b]quinoline-3,4-dione; 7-(3-Aminomethyl-4-benzyloxyimino-pyrrolidin- 1 -yl)-9-cyclopropyl-6-fluoro-9H isothiazolo[5,4-b]quinoline-3,4-dione; 7-(3-Amino-4-methoxyimino-pyrrolidin- 1 -yl)-9-cyclopropyl-6-fluoro-9H-isothiazolo[5,4 b]quinoline-3,4-dione; WO 2006/118605 PCT/US2005/040725 75 7-(3-Aminomethyl-4-methoxyimino-3-methy1-pyrrolidin-1-yl)-9-cyclopropyl-6-fluoro-9H isothiazolo[5,4-b]quinoline-3,4-dione; 7-[3-(1 -Amino-ethyl)-4-methoxyimino-pyrrolidin-1-yl]-9-cyclopropyl-6-fluoro-9H isothiazolo[5,4-b]quinoline-3,4-dione; 7-(3,3-Bis-aminomethyl-4-methoxyimino-pyrrolidin- 1-yl)-9-cyclopropyl-6-fluoro-9H isothiazolo[5,4-b]quinoline-3,4-dione; 7-[3-(1-Amino- 1-methyl-ethyl)-4-methoxyimino-pyrrolidin- 1-yl]-9-cyclopropyl-6-fluoro-9H isothiazolo[5,4-b]quinoline-3,4-dione; 9-Cyclopropy1-6-fluoro-7-(3-methoxyimino-piperazin-1-yl)-9H-isothiazolo[5,4-b]quinoline-3,4 dione; 9-Cyclopropyl-6-fluoro-7-(4-methoxyimino-piperidin- 1-yl)-9H-isothiazolo[5,4-b]quinoline-3,4 dione; 7-(3-Aminomethyl-4-methoxyimino-pipetidin- 1 -yl)-9-cyclopropyl-6-fluoro-9H-isothiazolo[5,4 b]quinoline-3,4-dione; 7-(3-Aminomethyl-4-methoxyimino-pyrrolidin- -yl)-9-cyclopropyl-6-fluoro- 1, -dioxo- 1,2 dihydro-9H-116-isothiazolo[5,4-b]quinoline-3,4-dione; 4-[7-(3-Aminomethyl-4-methoxyimino-pyrrolidin- 1 -yl)-9-cyclopropyl-6-fluoro-3,4-dioxo-4,9 dihydro-3H-isothiazolo[5,4-b]quinolin-2-yl]-butyric acid; Acetic acid 7-(3-aminomethyl-4-methoxyimino-pyrrolidin-1-yl)-9-cyclopropyl-6-fluoro-4-oxo 4,9-dihydro-isothiazolo[5,4-b]quinolin-3-yl ester; 7-(3-Aminomethyl-4-methoxyimino-pyrrolidin- 1-yl)-9-cyclopropyl-6-fluoro-5-(N'-methyl hydrazino)-9H-isothiazolo[5,4-b]quinoline-3,4-dione; 6-Amino-7-(3-aminomethyl-4-methoxyimino-pyrrolidin- 1 -yl)-9-cyclopropyl-9H-isothiazolo[5,4 b]quinoline-3,4-dione; 7-(3-Aminomethyl-4-methoxyimino-pyrrolidin- 1-yl)-9-cyclopropyl-6-fluoro-8-methoxy-9H isothiazolo[5,4-b]quinoline-3,4-dione; 7-(3-Aminomethyl-4-methoxyimino-pyrrolidin-1-yl)-9-cyclopropyl-8-methoxy-9H isothiazolo[5,4-b]quinoline-3,4-dione; and [1-(9-Cyclopropyl-6-fluoro-3,4-dioxo-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinolin-7-yl)- 4 methoxyimino-pyrrolidin-3-ylmethyl]-carbamic acid tert-butyl ester. WO 2006/118605 PCT/US2005/040725 76
    [38] 43. An anti-bacterial composition comprising a compound or salt of any one of Claims 1 to 42, together with a carrier, diluent, or excipient.
    [39] 44. A pharmaceutical composition comprising a compound or salt of any one of Claims 1 to 42, together with a pharmaceutically acceptable carrier, diluent, or excipient.
    [40] 45. A pharmaceutical composition of Claim 43, 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.
    [41] 46. A composition comprising a compound or salt of any one of Claims 1 to 40 in combination with another one or more antibacterial agent, antiprotozoal agent, antifungal agent, antiviral agent, interferon, efflux-pump inhibitor, or beta-lactamase inhibitor.
    [42] 47. A package comprising the pharmaceutical composition of Claim 44 in a container and further comprising instructions for using the composition to treat a patient suffering from a microorganism infection.
    [43] 48. A package of Claim 47 wherein the instructions are instruction for using the composition to treat a patient suffering from a bacterial infection.
    [44] 49. A method for treating or preventing a bacterial or protozoal infection comprising administering to an animal in need thereof a therapeutically effective amount of a compound or salt of any one of Claims 1 to 42. WO 2006/118605 PCT/US2005/040725 77
    [45] 50. The method of Claim 48 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.
    [46] 51. The method of Claim 49 wherein the animal is a fish, amphibian, reptile, bird, or mammal.
    [47] 52. The method of Claim 50 wherein the animal is a mammal.
    [48] 53. The method of Claim 52 wherein the mammal is a human.
    [49] 54. A compound or salt of any one of Claim 1 to 42 that exhibits an MIC of 10 Ag/ ml or less against S. aureus or E. coli.
    [50] 55. A compound or salt of any one of Claims 1 to 42 that exhibits an MIC of 1 yg/ ml or less against S. aureus and E. coli.
    [51] 56. The use of a compound of Claim 1 for the manufacture of a medicament for the treatment of a bacterial or protozoal infrection.
    [52] 57. The use of Claim 56 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. WO 2006/118605 PCT/US2005/040725 78
    [53] 58. The use of Claim 56 wherein the bacterial infection is an S. aureus or E. coli infection.
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    同族专利:
    公开号 | 公开日
    WO2006118605A3|2006-12-21|
    DE602005017178D1|2009-11-26|
    AT445623T|2009-10-15|
    WO2006118605A2|2006-11-09|
    EP1809639A2|2007-07-25|
    CN101120004A|2008-02-06|
    IL183153D0|2007-09-20|
    MX2007005731A|2007-07-19|
    EP1809639B1|2009-10-14|
    US20060100215A1|2006-05-11|
    CA2587485A1|2006-11-09|
    KR20070085791A|2007-08-27|
    JP2008519842A|2008-06-12|
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    法律状态:
    2009-11-19| MK1| Application lapsed section 142(2)(a) - no request for examination in relevant period|
    优先权:
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    US62696104P| true| 2004-11-11|2004-11-11||
    US60/626,961||2004-11-11||
    PCT/US2005/040725|WO2006118605A2|2004-11-11|2005-11-10|8a, 9-dihydro-4a-h-isothiazolo[5,4-b] quinoline-3, 4-diones and related compounds as anti-infective agents|
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