MX2008001344A - 8-methoxy-9h-isothiazolo[5,4-b]quinoline-3,4-diones and related compounds as anti-infective agents - Google Patents

Abstract

The invention provides compound and salts of Formula (I) and (II), disclosed herein, which includes compounds of Formula (A) and Formula (B) such compounds possess useful antimicrobial activity. The variables R2, R3, R5, R6, R7, and R9shown in Formula A and B are defined herein. Certain compounds of Formula (I) and Formula (II) disclosed herein are potent and/ or selective inhibitors of bacterial DNA synthesis and bacterial replication. The invention also provides antimicrobial compositions, including pharmaceutical compositions, containing one or more compounds of Formula (I) or Formula (II) and one or more carriers, excipients, or diluents. Such compositions may contain a compound of Formula (I) or Formula (II) as the only active agent or may contain a combination of a compound of Formula I or Formula II and one or more other active agents. The invention also provides methods for treating microbial infections in animals.

Description

8-METOXY-9H-ISOTIAZOL? R5.4-BlQUINOLIN-3.4-DIONAS AND RELATED COMPOUNDS AS ANTI-INFECTIOUS AGENTS Field of the Invention The present invention provides 8-methoxy-9H-isothiazolo [5,4-b] quinoline-3,4-diones and related compounds, wherein the substituent at the 7-position is generally a heterocycloalkyl or heterocycloalkenyl substituent N -linked, which possesses 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, that contain one or more carriers, diluents, or excipients. The invention provides pharmaceutical compositions containing an 8-methoxy-9H-isothiazolo [5,4-b] quinoline-3,4-dione or a related compound as the sole active agent or containing an 8-methoxy-9H-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 infections microbial in animals by administering an effective amount of a 7-substituted-9H-isothiazolo [5,4-b] quinoline-3,4-dione or related compound, to an animal suffering from or susceptible to microbial infection. The invention also provides methods for inhibiting microbial growth and survival by applying an effective amount of a 7-substituted-9H-isothiazolo [5,4-b] quinoline-3,4-diones or related compound. Background of the Invention 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 the action of antimicrobial compounds varies. However, they are generally believed to work in one or more of the following ways: by inhibiting cell wall synthesis or repair; by altering the permeability of the cell wall; by inhibiting protein synthesis; or by inhibiting the synthesis of nucleic acids. For example, beta-lactam antibacterials inhibit essential penicillin-binding proteins (PBPs) in bacteria, which are responsible for cell wall synthesis. The action of quinolones, at least in part, by inhibiting DNA synthesis, thus preventing the cell from replicating. Many trials to produce improved antimicrobials they produce equivocal results. In fact, few antimicrobials are produced that are truly clinically acceptable in terms of their spectrum of antimicrobial activity, prevention of microbial resistance, and pharmacology. There is a continuing need for broad-spectrum antimicrobials, and a particular need for effective antimicrobials against resistant microbes. Pathogenic bacteria are known to acquire resistance via various different mechanisms including inactivation of antibiotics by bacterial enzymes (for example, beta-lactamases that hydrolyze penicillin and cephalosporins); elimination of antibiotics using discharge pumps; modification of the target of the antibiotic via mutation and genetic recombination (for example, resistance to penicillin in Neiserria gonorrhea); and acquisition of an easily transferable gene from an external source to create a resistant target (eg, resistance to methicillin in Staphylococcus aureus). There are certain Gram-positive pathogens, such as Enterococcus faecium resistant vancomycin, which are resistant to virtually all commercially available antibiotics. Resistant organisms of particular note include methicillin-resistant Staphylococcus aureus and vancomycin-resistant Streptococcus pneumoniae resistant to penicillin, vancomycin-resistant enterococci, E. coli resistant to fluoroquinolone, aerobic gram-negative rods resistant to cephalosporin and Pseudomonas aeruginosa resistant to imipenem. These organisms are significant causes of nosocomial infections and are clearly associated with increased morbidity and mortality. The increased numbers of elderly and immunocompromised patients are particularly at risk of infection with these pathogens. Therefore, there is a great medical need for the development of new antimicrobial agents. In recent years, methicillin-resistant Staphylococcus aureus infections (MRSA) have become more common, particularly in institutional or hospital settings. Up to 60% of staphylococcus infections are attributable to methicillin-resistant strains, in some parts of the United States. Some strains of MRSA are now resistant to both Vencomycin and Gentamicin, drugs once considered the last defense against staphylococcal infections. Thus, there is a particularly urgent need for effective drugs against MRSA strains. The usefulness of isothiazoloquinolines as pharmaceutical agents have been discussed in the literature. For example, Pinol, et al. Discusses the use of isothiazoloquinolines as medical bactericides in U.S. Patent 5,087,621, including The Proctor & The Gamble Company discussed antimicrobial quinolones that include the following compound: in the published application no. US 2003008894. The use of isothiazoloquinoline compounds as inhibitors of TNF production have also been discussed, for example by Sankyo Co., Ltd. in JP1010149, which includes the following compound Bayer Aktingesellschaft has discussed bicyclo [3.3.0] oct-7-yl containing compounds useful for treating H. pylori infections in WO 98/26768, including isothiazoloquinoline, which have the general structure shown below in which Y can be sulfur attached to the carboxamide group to form a member ring Otsuka Pharmaceutical Co., Ltd., has discussed the use of isothiazoloquinolines as antibacterial agents in JP 01193275, including the following carbamate-containing compound Abbott Laboratories has discussed the use of isothiazoloquinolines as anti-neoplastic agents in U.S. Patent No. 5,071,848 and has discussed the use of tricyclic quinolones as antibacterial agents in US 4,767,762. The Abbott compounds have hydrogen, halogen, or lower alkyl as substituents at positions 6 and 8 of the isothiazoloquinoline core. The present invention meets the need for effective drugs against bacterial strains of MRSA, and provides related advantages that are described herein.

Brief Description of the Invention The invention provides compounds of Formula I and Formula II (shown below) and includes 8-methoxy-9H-isothiazolo [5,4-b] quinoline-3,4-diones and related compounds of Formula I and II, which possess antimicrobial activity. The invention provides compounds of Formula I and Formula II, which possess potent and / or selective antibacterial, antiprotozoal or antifungal activity. The invention also provides compositions containing one or more compounds of Formula I or Formula II, or a salt, solvate, or prodrug, such as an acylated prodrug of a compound, and one or more potions, excipients, or diluents. The invention further comprises methods for 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 an animal that suffers from or is susceptible to a microbial infection. These microbial infections include bacterial infections, for example E. coli infections, Staphylococcus infections, including Methicillin-Resistant Staphylococcus Aureus infections, Salmonella infections and protozoal infections, for example Chlamydia infections. The invention particularly includes methods for preventing or treating microbial infections in mammals, including humans, but also encompasses methods for preventing or treating microbial infections in other animals, including fish, birds, reptiles, and amphibians. Methods for treatment include administering a compound of Formula I or Formula II as the single active agent or administering a compound of Formula I or Formula II in combination with one or more other therapeutic agents, such as an antibacterial, antifungal, antiviral, an interferon or other immune system modulator, a discharge pump inhibitor, a beta-lactamase inhibitor, an anti-inflammatory, or another compound of Formula I or Formula II. The invention also provides methods for inhibiting microbial growth and survival by applying an effective amount of an 8-methoxy-9H-isothiazolo [5,4-b] quinoline-3,4-dione or related compound. The invention includes, for example, methods for inhibiting microbial growth and survival in medical instruments or on surfaces used for food preparation by applying a composition containing a compound of Formula I or Formula II. Thus, the invention includes compounds and pharmaceutically acceptable salts of Formula I and Formula II, shown in the section of the Detailed Description, and includes certain preferred compounds of Formula A and B Within Formula I and Formula II the variables (for example, AL A8, R2, R3, and R5 to R9) carry the definitions, which follow. AT is S, O, SO, or SO2. R2 is hydrogen. Or, R2 is C? -C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C7 cycloalkyl) C0-C4 carbohydryl, (C-C7 cycloalkenyl) C0-C carbohydryl, (aryl) C0-C4 carbohydryl) or (C2-C6 heterocycloalkyl) C0-C4 carbohydryl, each of which is substituted with 0 to 5 independently chosen substituents of halogen, hydroxy, amino, cyano, nitro, C? -C, C? -C4 alkoxy, C? -C2 haloalkyl, C1-C2 haloalkoxy, C? -C4 mono- and dialkylamino, C2-C4 alkanoyl, C? -C alkylthio, = NOR10 , = NR10, -O (C = O) R? O, - (C = O) N R10R? 1, -O (C = O) NR? 0R? 1, - (C = O) OR? O. - (C = O) NR? OOR11, -NR10 (C = O) R1, -NR? 0 (C = O) ORn, -NR10 (C = O) NR11R12) -NR? O (C = S) NR11Ri2, -NR10NR11 R12, -SO3R? Or, - (S = O) OR? O, -SO2R13, -SO2NR10Rn, and -NR10SO2R? 3; wherein R 10, R 11, and R 2 are independently halogen, C 1 -C alkyl, or aryl, and R 3 is C 1 -C alkyl or aryl. R 3 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, mono- or di-alkylcarbamate or C 1 -C 6 alkyl sulfonate; each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, C? -C alkoxy, mono- and di-alkylamino of C? -C4, haloalkyl of C? -C2, and haloalkoxy of C? -C2. R 5 is hydrogen, halogen, hydroxy, amino, cyano, nitro, or -NHNH 2, or R 5 is C 1 -C alkyl, C 1 -C alkoxy, mono- or di- (C 1 -C 4) alkyl amino, mono- , di- or tri-alkylhydrazinyl of C ^ -C4, C2-C4 alkanoyl, C? -C4 alkyl ester, Ci-C2 haloalkyl, or C? -C2 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, C 1 -C 2 haloalkoxy, and mono- and di-alkylamino R 6 is hydrogen, halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 C-t alkoxy, mono- or di- (C 1 -C 4 alkyl) amino, -SO 3 R 2 or, -SO 2 R 10, or -SO 2 NR 10 R n. R7 is a nitrogen-linked heterocycloalkyl group, having 4 to 8 ring members, including 0, 1 or 2 additional ring heteroatoms independently chosen from N, O, and S. O, R7 is an alkylamino of C? C attached to the nitrogen substituted with a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently chosen from N, O, and S, or substituted with a heterocycloalkyl group, having 4 to 8 members in the ring, including 1 or 2 heteroatoms in the ring independently chosen from N, O, and S. O, R7 is a heterocycloalkyl or heterocycloalkenyl group attached to nitrogen, each of which has 4 to 8 members in the ring, including 0, 1, or 2 heteroatoms in the ring additional independently chosen N, O, and S, forming part of a bicyclic system with a cycloalkyl or heterocycloalkyl ring of 3 to 8 members in fused or spiro orientation. Or, R7 is a 6-membered heterocycloalkyl group attached to nitrogen, 0, 1 or 2 heteroatoms in the additional ring independently chosen from N, O, and S, and bridged with a methylene or ethylene bridge. Each of R is substituted with 0 or 1 or more independently chosen substituents of (a) and 0 or 1 substituents chosen from (b); wherein (a) is chosen from halogen, hydroxy, amino, nitro, C? -C alkyl, C1-C alkoxy, haloalkyl of C? -C2, and haloalkoxy of C C2, and (b) is oxo, amino , cyano, C 1 -C 4 -hydroxy-alkyl, C 1 -C-aminoalkyl, C 1 -C 6 -alkylthio, C 2 -C 6 -alkanoyl, C 1 -C-mono- or di-alkyl-amino-C 0 -alkyl -C4, (C -C7 cycloalkyl) C0-C4 alkyl, (C3-C7 cycloalkylamino) C0-C4 alkyl, (C3-C7 cycloalkyl) (C? -C4 alkyl) amino-C0-alkyl C4, (heterocycloalkyl) C0-C4 alkyl, or (aryl) C0-C4 alkyl, wherein each of (b) other than oxo and cyano are substituted with 0 to 2 substituents independently chosen from halogen, hydroxy, amino, cyano , nitro, oxo, -COOH, -CONH2, C? -C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, mono- and di- (C? -C) alkyl amino, C? haloalkyl- C2, and haloalkoxy of C -? - C2. R9 is C?-C8 alkyl, (C3-C cycloalkyl) C de-C4 alkyl, or phenyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -CONH2) C? -C alkyl, C2-C alkenyl, C2-C alkynyl, C? -C alkoxy, (C3-C7 cycloalkyl) C0-C alkyl, (C3- cycloalkyl) C7) C0-C4 alkoxy, mono- and di- (C1-C4 alkyl) amino, C? -C2 haloalkyl, C? -C2 haloalkoxy, and C2-C4 alkanoyl. Detailed Description of the Invention CHEMICAL DESCRIPTION AND TERMINOLOGY Before presenting the invention in detail, it may be useful to provide definitions of certain terms that are used herein. Compounds of the present invention are generally described using the standard nomenclature. 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, for example asymmetric carbon atoms, so that the compounds may 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 optical isomers and mixtures thereof are encompassed. In addition, compounds with carbon-carbon double bonds can occur in Z and E forms, with all isomeric forms of the compounds that are included in the present invention. In these situations, simple enantiomers, that is, optically active forms can be obtained by asymmetric synthesis, synthesis of optically pure precursors, or by resolution of the racemates. The resolution of the racemates can also be carried out, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral HPLC column. When a compound exists in various tautomeric forms, the invention is not limited to any of the specific tautomers, but rather includes all tautomeric forms. The present invention is intended to include all isotopes of atoms that occur in the present compounds. Isotopes include those atoms that have the same atomic number but different mass numbers. By way of general example, and without limitation, the isotopes of hydrogen include tritium and deuterium and the carbon isotopes include 11C, 13C, and 14C. Certain compounds are described herein using a general formula including variables, for example A R2, R3-R5, Re, R7 > A8, and R9. Unless otherwise specified, each variable within a formula is defined independently of other variables. In this way, if a group is to be substituted, for example, with 0-2 R *, then the group can be substituted with up to two groups R * and R * in each case is selected independently of 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 replaced 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, for example, a pyridyl substituted with oxo is a pyridone. The term "substituted", as used herein, means that any one or more hydrogens in the designated atom or group is replaced with a selection of the indicated group, with the proviso that the normal valence of the designated atom is not exceeded. . When a substituent is oxo (ie, = O), then 2 hydrogens are replaced in the atom. 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 means that it implies a compound that is sufficiently robust or strong for survival isolation of a reaction mixture, and subsequent formulation into an effective therapeutic agent. Unless otherwise specified the substituents are named in 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. The exception to naming substituents in the ring is when the substituted is listed with a stripe ("-") or double bond ("=") that is not between two letters or symbols. In that case the line or double bond symbol is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. As used herein, "alkyl" is intended to include both straight or branched chain saturated, aliphatic hydrocarbon groups, having the specified number of carbon atoms. Thus, the term Ci-C6 alkyl as used herein includes alkyl groups of 1 to about 6 carbon atoms. When C0-Cn alkyl is used herein in conjunction with another group, for example, (aryl) Co-C alkyl, the indicated group, in this case aryl, is either directly linked by a single covalent bond (C0). ), or linked by an alkyl chain having the specified number of carbon atoms, in this case of 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. "Alkenyl" as used herein, denotes 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. "Alkynyl" as used herein, denotes a hydrocarbon chain of either a straight or branched configuration having one or more triple carbon-carbon bonds that can occur at any stable point along the chain, such as ethynyl and propinyl. "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. A "(alkoxy) alkyl group" is an alkoxy group as defined herein linked through its oxygen atom to an alkyl bridge where the point of attachment to the substituted group is in the alkyl group. "Alkanoyl" denotes an alkyl group as defined previously, joined through a keto bridge (- (CO) -). Alkanoyl groups have the indicated number of carbon atoms, with the carbon of the keto group that is included in the numbered carbon atoms. For example, an alkanoyl group of C2 is an acetyl group having the formula CH3 (C = O) -. As used herein, the terms "mono- or dialkylamino" and "mono- and di-alkylamino" indicate secondary or tertiary alkylamino 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 in the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propylamino. A mono- or di (C 1 -C 6) alkyl (C 0 -C 4 alkyl) amino group is an alkylamino substituent in which a first alkyl group of C 3 -C 6 alkyl and a second alkyl group of C0-C alkyl, wherein Co indicates the absence of a secondary alkyl group, ie a mono-alkylamino of The term "mono- or di-alkylcarbamate" denotes 1 or 2 independently chosen alkyl groups, as defined above, linked through a carbamate bond (-O (C = O) NRR) where R represents the alkyl groups. Mono-alkylcarbamate groups have the formula (-O (C = O) NHR). The term "alkyl ester" denotes an alkyl group as defined above linked through an ester linkage. He The ester linkage can be in any orientation, for example, a group of the formula -O (C = O) alkyl or a group of the formula - (C = O) Oalkyl. The term "mono-, di- or tri-alkylhydrazinyl" denotes from 1 to 3 independently-selected alkyl groups as defined above linked through a single bonded nitrogen-nitrogen bond. At least one of the alkyl groups is attached to the terminal nitrogen (nitrogen does not bind to the core structure). When the term mono- or di-alkylhydrazinyl is used only in the terminal nitrogen it is substituted alkyl. Examples of alkyihydroxy groups include 2-butyl-1-hydrazinyl, 2-butyl-2-methyl-1-hydrazinyl, and 1,2-dimethyl-2-propyl-1-hydrazinyl. The term "alkylsulfonate" denotes an alkyl group as defined above linked through a sulfonate linkage (for example a group of -S (= O) 2 O-alkyl). The term "alkylthio" denotes an alkyl group as defined above linked through a sulfur bond, ie, a group of the formula alkyl-S-. Examples include ethylthio and pentylthio. As used herein, the term "aminoalkyl" denotes an alkyl group as defined above substituted with at least one amino substituent. Similarly, the term "hydroxyalkyl" denotes an alkyl group as defined above, substituted with at least one substituent hydroxyl In certain cases the alkyl group of the aminoalkyl or hydroxyalkyl group can be further substituted. As used herein, the term "aryl" denotes aromatic groups that contain 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 can be further substituted with carbon atoms or without carbon or groups. Such substitution may include fusion to a saturated 5- to 7-membered cyclic group optionally containing 1 or 2 independently selected heteroatoms of N, O, and S, to form, for example, a 3,4-methylenedioxy-phenyl group. Aryl groups include, for example, phenyl, naphthyl, including 1-naphthyl and 2-naphthyl, and bi-phenyl. In the term "(aryl) alkyl", aryl and alkyl are as defined above, and the point of attachment is in the alkyl group. This term encompasses, but is not limited to, benzyl, phenylethyl, and piperonyl. Also, in the term (aryl) carbohydryl, aryl and carbohydryl are as defined above and the point of attachment is in the carbohydryl group, for example a phenylpropen-1-yl group. Similarly, in the term (aryl) alkoxy, aryl and alkoxy are as defined above and the point of attachment is through the oxygen atom of the alkoxy group; if the alkoxy is C0 alkoxy the aryl It is linked through an oxygen bridge. "Carbohydryl" as used herein, include both straight and branched chain hydrocarbon groups, which are saturated or unsaturated, having the specified number of carbon atoms. When C0-Cn carbohydril is used herein in conjunction with another group, for example, C0-C4 (cycloalkyl) carbohydride, the indicated group, in this case cycloalkyl, is either directly attached by a single covalent bond (C0). ), or linked by a carbohydride chain, such as an alkyl chain, having the specified number of carbon atoms, in this case from 1 to about 4 carbon atoms. Examples of carbohydryl groups include d-Cβ alkyl, such as methyl, or 5-butyl, C2-C6 alkynyl such as hydroxyl, and C2-C6 alkenyl, such as 1-propenyl. "Cycloalkyl" as used herein, denotes a saturated hydrocarbon ring group, having only carbon ring atoms and having the specified number of carbon atoms, typically from 3 to about 8 carbon atoms in the ring , 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. "Cycloalkenyl" as used herein, indicates a unsaturated, but not aromatic, hydrocarbon ring having a carbon-carbon double bond. Cycloalkenyl groups contain from 4 to about 8 carbon atoms, typically from 4 to about 7 carbon atoms. Examples include cyclohexenyl and cyclobutenyl. 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 in the alkyl, carbohydryl, or alkoxy group respectively. These terms include examples such as cyclopropylmethyl, cyclohexylmethyl, cyclohexylpropenyl, and cyclopentylethoxy. In the terms "(cycloalkenyl) alkyl" and "(cycloalkenyl) carbohydryl" the terms cycloalkenyl, alkyl and carbohydryl are as defined above, and the point of attachment is in the alkyl or carbohydryl group respectively. These terms include examples such as cyclobutenylmethyl, cyclohexenylmethyl, and cyclohexylpropenyl. "Haloalkyl" denotes both saturated, straight-chain or branched aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, generally up to the maximum allowable halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

"Haloalkoxy" denotes a haloalkyl group as defined above linked through an oxygen bridge. "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo or iodo. As used herein, "heteroaryl" denotes a 7 to 10 membered bicyclic or 5 to 7 membered monocyclic heterocyclic ring containing at least 1 aromatic ring containing 1 to 4, or preferably 1 to 3, heteroatoms chosen from N, O, and S, with remaining ring atoms that are carbon. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. 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 be optionally quaternized. When indicated, such heteroaryl groups can be further substituted with carbon atoms or without carbon or groups. Such substitution may include fusion to a 5- to 7-membered saturated cyclic group optionally containing 1 or 2 independently selected heteroatoms of N, O, and S, to form, for example, a [1, 3] dioxolo [4,5] group. -cjpyridyl. Examples of heteroaryl groups include, but are not limited to, pyridyl, indolyl, pyrimidinyl, pyridyzinyl, 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. In the "terms" (heteroaryl) alkyl "and" (heteroaryl) carbohydryl ", heteroaryl, alkyl and carbohydryl are as defined above, and the point of attachment is in the alkyl or carbohydryl group respectively, These terms include such examples as pyrid i nyl methyl, thiophenylmethyl, and (pyrrolyl) -l-ethyl The term "heterocycloalkyl" denotes a saturated cyclic group of 1 to about 3 heteroatoms selected from N, O, and S, with remaining ring atoms that are carbon. heterocycloalkyl groups have from 3 to about 8 ring atoms, and more typically have from 5 to 7 ring atoms Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl groups A nitrogen in a heterocycloalkyl group can optionally be The term "heterocyclic group" means a saturated, partially unsaturated, or aromatic 5-6 member ring containing from 1 to about 4 heteroatoms chosen from N, O and S, with remaining ring atoms that are carbon or a saturated, partially unsaturated, or aromatic, 7-10 membered heterocyclic ring system containing at least 1 heteroatom in the two-ring system rings chosen from N, O, and S and containing up to about 4 independently selected heteroatoms of N, O, and S in each ring of the two-ring system. Unless indicated otherwise, the heterocyclic ring may be attached to its pendant group on any heteroatom or carbon atoms resulting in a stable structure. When indicated the heterocyclic rings described herein may be substituted on a carbon atom or on a nitrogen atom if the resulting compound is stable. A nitrogen atom in the heterocycle can optionally be quaternized. It is preferred that the total number of heteroatoms in a heterocyclic group 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, pyridyzinyl, 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. Additional examples of heterocyclic groups include, but are not limited to, phthalazinyl, oxazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzoisoxolilo, 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, benzotetrahidrotienilo, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, 5-pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihidrobenzisoxazinilo, benzisoxazinilo, benzoxazinyl, dihidrobenzisotiazinilo, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromanyl, tetrahydroquinolinyl, dihydroquinolinyl, dihidroquinolinonilo, dihidroisoquinolinonilo, dihydrocoumarinyl, dihydroisocumarinyl, isoindolinonyl, benzodioxanil, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinoli nyl 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. As used herein, "Active agents" are compounds that have pharmaceutical utility, for example, they can be used to treat a patient suffering from a disease or condition, or can be used prophylactically to prevent the onset of a disease or condition in a patient, or that can be used to improve the pharmaceutical activity of other compounds. "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. The pharmaceutical compositions meet U.S. standards. FDA's GMP (good manufacturing practice) for human and non-human drugs. "Salts" of the compounds of the present invention include base addition salts and inorganic and organic acids. The salts of the present compounds can be synthesized from an original compound containing a basic or acid portion by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of those 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 base forms. free of those 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 such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable. Salts of the present compounds further include solvates of the compounds and salts of the compound. "Pharmaceutically acceptable salts" include derivatives of the disclosed compounds wherein the parent compound is modified by the preparation of non-toxic acid or base salts thereof, and further refers to pharmaceutically acceptable solvates of such compounds and such salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkaline or organic salts of acidic residues such as carboxylic acids; and similar. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the original compound formed, for example, of 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 prepared salts of organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroximic, phenylacetic, glutamic, benzoic, salicylic, mesylic, silyl, besylic, sulphanilic , 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, HOOC- (CH2) n -COOH where n is 0-4, and the like. Additional suitable salt lists can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., P. 1418 (1985). The term "prodrugs" includes any compounds that become compounds of Formula I when administered to a mammalian subject, for example, with metabolic processing of the prodrug. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate and similar derivatives of functional groups (such as alcohol or amine groups) in the compounds of Formula I and Formula II. The term "therapeutically effective amount" of a compound of this invention means an effective amount, when administered to a human or non-human patient, to provide a therapeutic benefit such as an improvement in symptoms, for example, an effective amount 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 show symptoms of being infected. In this way a therapeutically effective amount of a compound is also an amount sufficient to prevent a significant or significant increase reduces the detectable level of microorganisms or antibodies against microorganisms in the patient's blood, serum, other body fluids, or tissues. The invention also includes using compounds of Formula I and Formula II in prophylactic therapies. In the context of prophylactic or preventive treatment a "therapeutically effective amount" is an amount sufficient to significantly reduce the risk of the animal treated to contract an infection of microorganisms. A significant reduction is any detectable negative change that is statically significant, for example static significance can be measured in a standard parametric test of static meaning such as the Student's T test, where p < 0.05. ANTIMICROBIAL COMPOUNDS For the purposes of this document, the following numbering system will apply to the 9H-isothiazolo [5,4-b] quinoline-3,4-dione core structure (when Ai = sulfur) or 9H-isoxazolo structure [ 5,4-b] quinoline-3,4-dione of the nucleus (when Ai = oxygen). The numbers 1 to 9 refer specifically to the positions within the tricyclic ring system while the letters A, B and C refer to the specific rings of six (rings A and B) or five (ring C) members as shown then.

In addition to the compounds of Formula A and Formula B, described above, the invention also includes compounds of Formula I and Formula II and pharmaceutically acceptable salts thereof, in which the 8-position of the tricyclic structure is not required to be an atom. of aromatic carbon substituted with a methoxy, but it is A8.

Formula I Formula II Within Formula I and Formula II, A8 is a nitrogen atom or CR8 and R8 is hydrogen, halogen, hydroxy, amino, cyano, nitro, or -NHNH2, or R8 is C?-C4 alkyl, C alco-alkoxy, C, mono- or di- (C? -C) alkyl amino, mono-, di-, or tri-alkylhydrazin of C? -C, C2-C4 alkanoyl, Ci-C4 alkyl ester, haloalkyl of C- ? -C2, C1-C2 haloalkyl, or C-? - C2 haloalkoxy, each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, amino, halogen, oxo, C? -C alkoxy, haloalkyl of C? -C2, C1-C2 haloalkoxy, and mono- and di-alkylamino of C? -C4. In this way the Compounds of Formula A and B are preferred compounds of Formula I and Formula II in which A8 is CR8 and R8 is methoxy. On each occasion the "Formula I and / or Formula II" include compounds of Formula A and Formula B. Variables A ^ A8, and R] to R9 carry the definitions that follow.

R2 is hydrogen, or R2 is d-Cs alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C7 cycloalkyl) C0-C carbohydryl, (C4-C7 cycloalkenyl) carbohydryl of C0-C , (aryl) carbohydryl of C0-C4, or (C2-C6 heterocyclealkyl) carbohydryl of Co-C4, each of which is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, alkyl of C 1 -C 4, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 4 mono- and dialkylamino, C 2 -C 4 alkanoyl, C 1 -C alkylthio, = NOR 10, = NR? O, -O (C = O) R10, - (C = O) NR10R? 1, -O (C = O) N R10Rn, - (C = O) OR? 0, - (C = 0) NR? OORn, -NR10 (C = O) Rn, -NR10 (C = O) ORn, -NR10 (C = O) NR11R12, -NR10 (C = S) NR1? R12, -NR? Or NRnR? 2, -SO3R10, - (S = O) OR10, -SO2R13, -SO2NR10Rn, and -NR10SO2R13; where R10, R11. and R 12 are independently halogen, C 1 -C 4 alkyl, or aryl, and R 3 is C 1 -C 4 alkyl or aryl. R 3 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, C 1 -C 6 mono- or di-alkylcarbamate, or C 1 -C 6 alkylsulfonate; each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, C1-C alkoxy, C1- C mono- and di-alkylamino, C? -C2 haloalkyl, and C? -C2 haloalkoxy. R 5 is hydrogen, halogen, hydroxy, amino, cyano, nitro, or -NHNH 2 1 or R 5 is C 1 -C 4 alkyl, dC- * alkoxy, mono- or di- (C 1 -C 4 alkyl) amino, mono-, di- - or Ci-C4 tri-alkylhydrazinyl, C2-C4 alkanoyl, C? -C alkyl ester, d-C2 haloalkyl, or C -? - C2 haloalkoxy; each of which is substituted with 0 to 3 independently selected substituents of hydroxy, amino, halogen, oxo, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, and mono- and di-alkylamino of C1-C4. R6 is hydrogen, halogen, hydroxy, amino, cyano, C? -C4 alkyl, C? -C alkoxy, mono- or di- (C1-C4 alkyl) amino, -SO3R10, -SO2R? 0, or - SO2NR10Rn. R7 is a heterocycloalkyl or heterocycloalkenyl group attached to nitrogen, each of which has 4 to 8 members in the ring, including 0, 1 or 2 additional ring heteroatoms independently chosen from N, O, and S, each of which which the heterocycloalkyl or heterocycloalkenyl group is substituted with at least one group (ii) and is substituted with 0 or 1 or more of (i) and (iii). Or, R7 is a C? -C4 alkylamino bonded to the nitrogen substituted with a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently chosen from N, O, and S, or substituted with a heterocycloalkyl group or a group heterocycloalkenyl, each of which has 4 to 8 members in the ring, including 1 or 2 heteroatoms in the ring independently chosen from N, O, and S, each of which the heteroaryl, heterocycloalkyl or heterocycloalkenyl group is substituted with 0 or 1 or more independently chosen substituents of (i), (ii) and (iii). Or, R7 is a heterocycloalkyl or heterocycloalkenyl group attached to nitrogen, each of which has 4 to 8 members in the ring, including 0, 1, or 2 additional ring heteroatoms independently chosen from N, O, and S, whose heterocycloalkyl or heterocycloalkenyl groups form part of a bicyclic system with a carbocyclic or heterocyclic ring of 3 to 8 members in fused or spiro orientation, and is substituted with 0 or 1 or more independently chosen substituents of (i), (ii), and ( iii), wherein R7 is not 5H-furo [2,3-c] pyrrol-5-yl]. Or, R is a heterocycloalkyl group attached to the nitrogen having 5 to 8 ring members, including 0, 1 or 2 additional ring heteroatoms independently chosen from N, O, and S, and bridged with a methylene or ethylene bridge , with the proviso that when R7 is a piperazine bridged with 2,5-methylene it is substituted with at least one group (ii) or (iii). Where: (i) is chosen from halogen, hydroxy, amino, nitro, alkyl d-C2, hydroxy-C1-C2 alkyl, amino-C-C2-alkyl, mono- and di-alkylamino of d-C2, and -CH2CH2F, (ii) is selected from oxo, cyano, C3-alkyl C6, C2-C6 alkenyl, C2-C6 alkynyl, (C6-alkoxy) C0-C alkyl, mono- and di- (C3-C6 alkoxy) (C0-C alkyl) amino, di- (C 1 -C 4 alkyl) amino C 1 -C 4 alkyl, mono- and di-alkylamino (branched C 2 -C 4 alkyl), (C 3 -C 7 cycloalkylamino) C 1 -C 4 alkyl, haloalkyl d -C2 other than -CH2CH2F, C1-C2 haloalkoxy, (C3-C7 cycloalkyl) C0-C4 carbohydryl, (C3-C7 cycloalkyl) C0-C-C- carbohydryl, (C4-C7 cycloalkenyl) carbohydryl of C0-C4, (aryl) carbohydryl of C0-C6, (aryl) alkoxy of C? -C, (heterocycloalkyl of C2-C6) carbohydryl of C0-C4, (heteroaryl) carbohydryl of C0-C4 other than pyrimidin-2 unsubstituted alkyl, d-C6 alkylthio, = NR 0, (C0-C4 alkyl) (C = O) R10, - (C0-C4 alkyl) O (C = O) R10, - (C0 alkyl) -C4) (C = O) NR10Rn, - (C0-C4 alkyl) O (C = O) NH2, - (C0-C4 alkyl) O (C = O) NR10 (alk) uilo of dC), - (C0-C4 alkyl) (C = O) OR10, - (C0-C4 alkyl) NR10 (C = O) R11 other than -N (CH2CH3) (C = O) CF3, - (C0-C4 alkyl) NR? 0 (C = O) ORn other than -NH (C = O) O-alkyl of d-C6), - (C0-C4 alkyl) NR? 0 (C = O) NR11R12, - (C0-C4 alkyl) NR10 (C = O) (C1-C4 alkyl) NR (C = O) O-R12, - (C0-C4 alkyl) NR10 (C = S) NR1, R12 , - (C0-C) alkyl NR? or NRnR12, - (C0-C4 alkyl) N = NR? 3, - (C0-C4 alkyl) SO3R? or, - (C0-C4 alkyl) (S = O) OR10, - (C0-C alkyl) SO2R13, - (C0-C alkyl) SO2NR10Rn, and - (C0-C4 alkyl) NR? 0SO2R13; and (iii) is chosen from -ORD, - (C = O) RD, -SO2RD, -SO3RD, -NR10SO2RD, where RD is C? -C alkyl, (C3-C-cycloalkyl) C0-C2 alkyl, (C2-C6 heterocycloalkyl) C0-C2 alkyl, (aryl) C0-C2 alkyl, or (heteroaryl) C0-C2 alkyl; wherein each of (ii) other than oxo and cyano and each of (iii) is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH, -CONH2, C1 alkyl -C4, C2-C alkenyl, C2-C4 alkynyl, C? -C4 alkoxy, C? -C4 alkoxy, (C3-C7 cycloalkyl) C0-C4 carbohydryl, (C3-C7 cycloalkyl) alkoxy of C0-C, (C3-C7 cycloalkyl) C0-C2 alkylamino, (heterocycloalkyl) C 0 -C 2 alkylamino, mono- and di- (C 1 -C 4 alkyl) amino, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 2 -C alkanoyl, and phenyl. Aß is N or CR8. R8 is hydrogen, halogen, hydroxy, amino, cyano, nitro, or -NHNH2. O, R8 is C? -C alkyl, C? -C alkoxy, mono- or di- (C? -C) alkyl amino, mono-, di-, or tri-alkylhydrazinyl Ci-C4, alkanoyl C2-C4, C? -C4 alkyl ester, Ci-C2 haloalkyl, or C2-C4 haloalkoxy; each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, amino, halogen, oxo, C1-C4 alkoxy, haloalkyl of C? -C2, haloalkoxy of C? -C2, and mono- and di-alkylamino of C? -C4.

R9 is C?-C8 alkyl, (C3-C7 cycloalkyl) C0-C) alkyl or phenyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -CONH2, C? -C4 alkyl, C2-C alkenyl, C2-C4 alkynyl, C1-C alkoxy, (C3-C7 cycloalkyl) C0-C alkyl, (C3-C7 cycloalkyl) ) C0-C4 alkoxy, mono- and di- (C? -C4 alkyl) amino, C? -C2 haloalkyl, C? -C2 haloalkoxy, and C2-C alkanoyl.

The invention further provides compounds and salts of Formula I and Formula II in which the variables (eg, Ai, R2, R3, R4, etc.) carry definitions different from those set forth above. The embodiments in which one or more of the following conditions is convenient are included in the invention: The variable A1 (1) Ai is S; for example compounds and salts of Formula III and Formula IV are included herein.

Formula IV Formula (2) A is SO; for example compounds and salts of Formula V and VI are included herein: Formula V Formula VI (3) A is SO2; for example compounds and salts of Formula VII and VIII are included in this.

Formula VI Formula VIII (4) Ai is O; for example, compounds and salts of Formula IX and X are included herein.

Formula IX The variable R2 (compounds and salts of Formula I): (1) R2 is hydrogen, or R2 is d-Cß alkyl or (C3-C cycloalkyl) C0-C4 alkyl, each of which is substituted with at least one substituent chosen from hydroxy, amino, -COOH, - (C = O) NR10ORn and -CONH2; and it is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -CONH2, C? -C alkyl, C1-C alkoxy, C? -C2 haloalkyl, haloalkoxy C? ? -C2, and C1- C4 mono- and di-alkylamino, and C2-C4 alkanoyl. (2) R2 is hydrogen. The variable R3 (compounds and salts of Formula II): (1) R3 is hydrogen, d-C6 alkyl or C2-C6 alkanoyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C? -C2 alkoxy, mono- and dialkylamino of C? -C2, haloalkyl of C1-C2, and haloalkoxy of C? -C2. (2) R3 is hydrogen, d-C6 alkyl, or C2-c alca alkanoyl. (3) R3 is hydrogen. (4) R3 is C1-C2 alkyl. The variable R5 (1) R5 is hydrogen, hydroxy, amino, C? -C2 alkyl, C? -C2 alkoxy, mono- or di- (C? -C4 alkyl) amino, or mono- or di-alkylhydrazinyl of C? -C. (2) R5 is hydrogen, amino, mono- or di-alkylamino of Ci-C2, or mono- or di-alkylhydrazinyl of C? -C2. (3) R5 is hydrogen. The variable R6 (1) R6 is hydrogen, halogen, or amino. (2) R6 is fluoro or hydrogen. (3) R6 is fluoro. (4) R6 is fluoro, and A8 is CR8 where R8 is methoxy. The variable R? (1) R7 is a heterocycloalkyl group or heterocycloalkenyl attached to nitrogen, each of which has 4 to 8 members in the ring, including 0, 1 or 2 additional ring heteroatoms independently chosen from N, O and S, each of which of the heterocycloalkyl or heterocycloalkenyl group is substituted with at least one group (ii) and is substituted with 0 or 1 or more of (i) or (iii); or R7 is a C1-C4 alkylamino bonded to nitrogen, substituted with a 5- or 6-membered heteroaryl group having 1 or 2 independently selected heteroatoms of N, O, and S, or substituted with a heterocycloalkyl group, heterocycloalkenyl group, each one of which has 4 to 8 members in the ring, including 1 or 2 heteroatoms in the ring independently chosen from N, O and S, each of which the heteroaryl, heterocycloalkyl or heterocycloalkenyl group is substituted with 0 or 1 or more independently chosen substituents of (i), (ii), and (iii); or R is a heterocycloalkyl or heterocycloalkenyl group attached to nitrogen, each of which has 4 to 8 members in the ring, including 0, 1 or 2 additional ring heteroatoms independently chosen from N, O and S, forming part of a bicyclic system with a carbocyclic or heterocyclic ring of 3 to 8 members in fused or spiro orientation, and is substituted with 0 or 1 or more independently chosen substituents of (i), (ii), and (iii); or R7 is a heterocycloalkyl group attached to nitrogen, having 5 to 8 ring members, including 0, 1 or 2 additional ring heteroatoms independently chosen from N, O and S, and bridged with a methylene or ethylene bridge, with the proviso that when R7 is a piperazine bridged with 2,5-methylene it is substituted with at least one group (ii). Within this definition of R7 (i) is chosen from halogen, hydroxy, amino, nitro, C? -C2 alkyl, mono- and di-alkylamino of C? -C2, and -CH2CH2F; (ii) is chosen from cyano, oxo, C3-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C? -C alkoxy) C0-C alkyl, mono- and di- C3-C6) (C0-C4 alkyl) amino, di- (C? -C) alkyl amino-C? -C4 alkyl, mono- or di-alkylamino (branched C2-C4 alkyl), (cycloalkylamino) C -C7) Ci-C4 alkyl, C1-C2 haloalkyl other than -CH2CH2F, d-C2 haloalkoxy, (C3-C7 cycloalkyl) C0-C2 alkyl, (C3-C7 cycloalkyl) Co-alkoxy C2, (C2-C6 heterocycloalkyl) C0-C2 alkyl, C? -C6 alkylthio, = NR10, - (C0-C4 alkyl) (C = O) R? 0; and (iii) is chosen from -ORD, - (C = O) RD, -SO2RD, -SO3RD, -NR10SO2RD, where RD is C? -C alkyl, (C3-C7 cycloalkyl) C0-C2 alkyl, (C2-C6 heterocycloalkyl) C0-C2 alkyl, (aryl) C0-C2 alkyl, or (heteroaryl) C0-C2 alkyl; wherein each of (ii) and (iii) is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH, -CONH2, d-C4 alkyl, C2-C4 alkenyl, C2-C alkynyl, C? -C4 alkoxy, (C3-C cycloalkyl) C0-C2, (C3-C7 cycloalkyl) C0-C2 alkylamino, (C3-C7 cycloalkyl) C0-C4 alkoxy, mono- and di- (d-C4 alkyl) amino, haloalkyl of C? -C2 , C? -C2 haloalkoxy, C2-C alkanoyl, and phenyl. (2) R7 is a heterocycloalkyl or heterocycloalkenyl group attached to nitrogen, each of which has 4 to 8 members in the ring, including 0, 1 or 2 additional ring heteroatoms independently chosen from N, O, and S, each one of which is substituted with at least one group (ii) and is substituted with 0 or 1 or more of (i) and (iii). Within this definition of R7 (i) is chosen from halogen, hydroxy, amino, nitro, alkyl, C1-C2, mono- and di-alkylamino of C? -C2, and -CH2CH2F; (ii) is selected from oxo and cyano, C3-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C1-C alkoxy) C0-C alkyl, mono- and di- (C3 alkyl) -C6) (C0-C4 alkyl) amino, di- (d-C4 alkyl) amino-alkylene of d-C4, mono- or di-alkylamino (branched C2-C alkyl), (C3 cycloalkylamino) -C7) alkyl of dC, haloalkyl of d-C2 other than -CH2CH2F, haloalkoxy of C? -C2, (C3-C7 cycloalkyl) C0-C2 alkyl, (C3-C7 cycloalkyl) C0-C2 alkoxy, (C2-C6 heterocycloalkyl) C0-C2 alkyl, d-C6 alkylthio, = NR10, - (C0-C) alkyl (C = O) R? 0; Y (iii) is selected from -ORD, - (C = O) RD, -SO2RD, -SO3RD, -NR10SO2RD, where RD is C1-C alkyl, (C3-C-cycloalkyl) C0-C2 alkyl, (heterocycloalkyl) of C2-C6) C0-C2 alkyl, (aryl) C0-C2 alkyl, and (heteroaryl) C0-C2 alkyl. Where each of (ii) other than oxo and cyano and each of (iii) is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH, -CONH2, C-alkyl, -C4, C2-C alkenyl, C2-C4 alkynyl, dd alkoxy, (C3-C7 cycloalkyl) C0-C2 alkyl, (C3-C7 cycloalkyl) C0-C2 alkylamino, (C3 cycloalkyl) -C) Co-C4 alkoxy, mono- and di- (C 1 -C) alkylamino, C 1-C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 2 -C 4 alkanoyl, and phenyl. (3) R7 is a 4, 5 or 6 membered nitrogen-bonded heterocycloalkyl having 0 or 1 additional nitrogen atoms, the 4, 5 or 6 membered heterocycloalkyl attached to nitrogen being substituted with 0 to 2 independently selected substituents of (i) and a substituent (ii). Within this embodiment (i) is chosen from halogen, hydroxy, amino, C? -C2 alkyl, hydroxyC? -C2 alkyl, amino-C1-C2 alkyl, and cyano, and (ii) is chosen from oxo, cyano, C3-C4 alkyl, C2-C6 alkenyl, (C? -C4 alkoxy) C0-C4 alkyl, mono- and di- (to C3-C6) (C0-alkyl) C4) amino, di- (C? -C4 alkyl) amino-C? -C4 alkyl, mono- or di-alkylamino (C2-C alkyl) branched), (C3-C7 cycloalkylamino) C1-C4 alkyl, d-C2 haloalkyl other than -CH2CH2F, C1-C2 haloalkoxy, (C3-C-cycloalkyl) C0-C2 alkyl, (C2- heterocycloalkyl) C6) C0-C2 alkyl, = NR10, and - (C0-C4 alkyl) (C = O) R10. Where each of (ii) other than oxo and cyano is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, oxo, C? -C alkyl, C2-C alkenyl, (C3- cycloalkyl) C7) C0-C2 alkyl, (C3-C7 cycloalkyl) C0-C2 alkylamino, mono- and di (C1-C) amino, haloalkyl of C? -C2, and haloalkoxy of C? -C2. (4) R7 is a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or azepanyl group substituted with at least one group (ii) and substituted with 0 or one or more of (i) and (iii). Here (i) and (iii) carry any of the definitions stated above. (5) R is a pyrrolidinyl or piperazinyl group substituted with a group (ii) and 0, 1 or 2 substituents independently chosen from halogen, hydroxy, trifluoromethyl, or trifluoromethoxy, wherein (ii) is oxo, cyano, C2- alkanoyl C4 or (ii) C3-C7 cycloalkyl substituted with 0 or 1 d-C2 or amino alkyl substituents, or (ii) is C3-C6 alkyl, di- (C1-C alkyloxy) amino-alkyl d-C4, mono- or di-alkylamino (branched C2-C4 alkyl), or (C3-C7 cycloalkylamino) C? -C4 alkyl, each of which is substituted with 0, 1 or 2 independently chosen substituents of amino, hydroxy, (cycloalkyl C3-C7) C0-C2 alkyl, (C3-C7 cycloalkyl) C0-C2 alkylamino, and (heterocycloalkyl) C0-C2 alkylamino. (6) R7 is a pyrrolidinyl or piperazinyl group substituted with a group (ii) and optionally substituted with 1 methyl substituent or halogen wherein (ii) is cycloalkyl of d-C7 which is unsubstituted or substituted by an amino substituent, or ( ii) is C3-C6 alkyl substituted with 1 amino substituent, hydroxy, C3-C7 cycloalkyl or (C3-C7 cycloalkyl) C0-C2 alkylamino, or (ii) is di- (C? -C4 alkyl) amino-C 1 -C 4 alkyl, mono- or di-alkylamino (branched C 2 -C 4 alkyl) or (C 3 -C 7 cycloalkylamino) C 1 -C 4 alkyl, each of which is substituted with 0 or 1 cycloalkyl of C3-C7. (7) R7 is a group of formula (a) - (e) N X z? ß (e). wherein R15 is (ii); and R16 is 0 or 1 or more independently chosen substituents of chloro, fluoro, methyl, methoxy, aminomethyl, aminoethyl, trifluoromethyl, and trifluoromethoxy. (8) R7 is a group of formula (a) - (e) wherein R15 is oxo or cyano; or R15 is C3-C7 cycloalkyl substituted with 0 or 1 C 1 -C 2 alkyl substituent or amino, or R 15 is C 3 -C 6 alkyl, di- (C 1 -C 4 alkyl) amino-C 1 -C alkyl, mono- or di-alkylamino (C 1 -C alkyl) branched), or (C3-C7 cycloalkylamino) C? -C alkyl, each of which is substituted with 0, 1 or 2 independently selected amino, hydroxy, and (C3-C7 cycloalkyl) C0 alkyl substituents -C2; or R15 is mono- or di- (C3-C6 alkyl) (C0-C4 alkyl) amino, or R15 is = NR10 or - (C0-C4 alkyl) (C = O) R? 0, or - ( alkyl of Co-C) NCH 3 (C = O) OR n, wherein each R 10 and R n are hydrogen or C 1 -C 4 alkyl. (9) R7 is a group of formula (a) - (e) wherein R15 is C3-C7 cycloalkyl, which is unsubstituted or substituted by one amino substituent, or R15 is C3-C6 alkyl, di- (alk) C 1 -C-C) amino-C 1 -C 4 alkyl, mono- or di-alkylamino (branched C 2 -C 4 alkyl) or (C 3 -C) cycloalkylamino) C 1 -C alkyl, each of which is substituted with 0, 1 or 2 substituents independently chosen from amino, hydroxy, and (C3-C7 cycloalkyl) C0-C2 alkyl. R16 is 0 or 1 substituent selected from chlorine, fluoro, and methyl. (10) R7 is a group of formula (a) - (e) wherein R15 is cyclopropyl substituted with amino, or R15 is C3-C6 alkyl substituted with amino or C3-C5 cycloalkylamino, or R15 is mono- - (at least one of C? -C4) amino-C? -C4 alkyl.

Laughter is O or 1 chosen substituent of chlorine, fluoro, and methyl. (11) R7 is a group of the formula (12) R7 is a C? -C alkylamino linked to nitrogen substituted with a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently chosen from N, O and S, or substituted with a heterocycloalkyl group, a heterocycloalkenyl group , each of which has 4 to 8 members in the ring, and 1 or 2 heteroatoms in the ring independently chosen from N, O and S, each of which of the heteroaryl, heterocycloalkyl or heterocycloalkenyl group is substituted with 0 or 1 or more independently chosen substituents of (i), (ii), and (iii). Here (i), (ii) and (iii) carry any of the definitions stated above. (13) R is a C? -C alkylamino linked to N substituted with a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently chosen from N, O and S, or substituted with a 5- or 6-membered heterocycloalkyl having 1 or 2 heteroatoms in the ring independently chosen from N, O and S, each of which heteroaryl or heterocycloalkyl is substituted with 0, 1 or 2 substituents independently chosen from halogen, hydroxy, amino, oxo, cyano, alkyl of C1-C2, C? -C2 alkoxy, C1-C2 haloalkyl, and C? -C2 haloalkoxy. (14) R7 is C1-C alkylamino substituted with a pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thienyl, pyrrolidinyl, furanyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl group, or pyrrolidinyl, each of which is substituted with 0, 1 or 2 substituents independently chosen from halogen, hydroxy, amino, oxo, cyano, C? -C2 alkyl, d-C2 alkoxy, C? -C2 haloalkyl, and haloalkoxy of C? -C2. (15) R7 is d-C2 alkylamino substituted with pyridyl, pyrazinyl, piperidinyl, or morpholinyl, each of which is substituted with 0, 1, or 2 substituents independently chosen from halogen, methyl and methoxy. (16) R7 is a heterocycloalkyl or heterocycloalkenyl group attached to nitrogen, each of which has from 4 to 8 members in the ring, including 0, 1 or 2 additional ring heteroatoms independently chosen from N, O and S, forming part of a bicyclic system with a carbocyclic or heterocyclic ring of 3 to 7 member in fused or spiro orientation, and is substituted with 0 or 1 or more independently chosen substituents of (i), (ii) and (iii). Here (i), (ii) and (iii) carry any of the definitions stated above. (17) R is a group of the formula wherein R 7 is hydrogen, chloro, fluoro, amino, methyl, ethyl, methoxy, C 1 -C 6 alkyl substituted with amino or hydroxy, mono- and d i- (a I i or C 0 -C 4) amino; = NR? 0, or - (Co-alkyl) C4) (C = O) R10, wherein each R10 is hydrogen or C? -C alkyl. (18) R7 is a 5- or 6-membered nitrogen-linked heterocycloalkyl having 0 or 1 additional nitrogen atoms, the 5 or 6 membered nitrogen-linked heterocycloalkyl thereof being part of a bicyclic ring system having a cycloalkyl of - d fused or a fused 4 to 6 membered heterocycloalkyl containing 1 nitrogen atoms, whose bicyclic ring system is substituted with 0 to 3 independently chosen substituents of (i) and (ii). Within this embodiment, (i) is chosen from halogen, hydroxy, and amino, and (ii) is selected from C 1 -C 4 alkyl, C 2 -C 6 alkenyl, (C 1 -C 4 alkoxy) C 0 -C 4 alkyl , mono- and di- (Ccylamino alkyl, C? -C2 haloalkyl, C1-C2 haloalkoxy, (C3-C7 cycloalkyl) dd alkyl, (C2-C6 heterocycloalkyl) C0-C2 alkyl, = NR10 , and - (C0-C4 alkyl) (C = O) R? 0. Each of (ii) is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, oxo, C1-alkyl C4, C2-C4 alkenyl, Ci-C alkoxy, C3-C7 cycloalkyl, Co-C2 alkyl, mono- and d- (C? -C4 alkyl) amino, C-C2 haloalkyl, and haloalkoxy In certain of these embodiments, the 5 or 6 membered nitrogen-linked heterocycloalkyl which is part of a bicyclic ring system is a pyrrolidinyl or piperidinyl and is fused with a C3-C6 cycloalkyl, pyrrolidinyl, or piperidinyl; wherein the bicyclic ring is substituted with 0, 1 or 2 substituents independently chosen from halogen, methyl or methoxy. In certain of these embodiments, the bicyclic ring system is a 3-aza-bicyclo [3.1.0] hexanyl or octahydro-1H-pyrrolo [3,4-b] pyridinyl ring system. (19) R7 is a heterocycloalkyl group attached to nitrogen, having 5 to 8 ring members, including 0, 1 or 2 additional ring heteroatoms independently chosen from N, O and S, and bridged with a methylene bridge or ethylene, with the proviso that when R7 is a 2,5-methylene bridge piperazine, it is substituted with at least one group (ii) or (iii) (other R7 groups of this embodiment are optionally substituted with one or more of ( i), (ii) and (iii)). Where (i), (ii) and (iii) bear any of the definitions stated above. (20) R7 is a bridged pyridinyl or bridged piperazinyl, each of which is substituted with 0 to 3 independently chosen substituents of (i) and (ii). Within this embodiment (i) is chosen from halogen, hydroxy, and amino; and (ii) is selected from oxo, cyano, C? -C alkyl, C2-C6 alkenyl, (C? -C4 alkoxy) C0-d alkyl, mono- and di- (C? -C4 alkyl) ) amino, C1-C2 haloalkyl, d-C2 haloalkoxy, (C3-C7 cycloalkyl) C0-d alkyl, (C2-C6 heterocycloalkyl) C0-d alkyl, = NR10, and - (C0 alkyl) -C4) (C = O) R10.

Each of (ii) other than oxo and cyano is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, oxo, C1-C alkyl, C2-C alkenyl, C-C4 alkoxy, (C3-C7 cycloalkyl) C0-C2 cycloalkyl, mono- and di- (C-? C4 alkyl) amino, C? -C2 haloalkyl, and d-C2 haloalkoxy. (21) R7 is a bridged piperidinyl or bridged piperazinyl, each of which is substituted with 0 to 2 substituents independently chosen from halogen, hydroxy, amino, cyano, d-C2 alkyl, and d-C2 alkoxy. (22) R8 is methoxy; and R7 is a nitrogen-bonded heterocycloalkyl group, having 4 to 8 ring members, including 0, 1 or 2 additional ring heteroatoms independently chosen from N, O and S whose heterocycloalkyl, which R7 is substituted with 0 or 1 or more independently chosen substituents of (a) and 0 or 1 substituents chosen from (b), wherein (a) is chosen from halogen, hydroxy, amino, nitro, C -? - C alkyl, C1-C alkoxy , haloalkyl of C? -C2, haloalkoxy of Ci-C2, (b) is oxo, amino, cyano, hydroxy-alkyl of C? -C, aminoalkyl of C? -C4, alkylthio of d-C6, alkanoyl of C2- C6, (mono- or di-C1-C4 alkyl) amino-C0-d alkyl, (C3-C7 cycloalkylamino) C0-C4 alkyl, (C3-C7 cycloalkyl) (Ci-C4 alkyl) amino -C0-d alkyl, (heterocycloalkyl) C0-C4 alkyl, or (aryl) C0-C4 alkyl. Each of (b) other than oxo and cyano is substituted with 0 to 2 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH, -CONH2, d-C4 alkyl, C2-C4 alkenyl , C2-C4 alkynyl, C1-C4 alkoxy, mono- and di- (dC alkyl) amino, C1-C2 haloalkyl, and C? -C2 haloalkoxy. (23) R8 is methoxy; and R7 is a 4, 5 or 6 membered nitrogen-linked heterocycloalkyl having 0 or 1 additional N, S or O atoms, whose 4, 5 or 6 membered nitrogen-linked heterocycloalkyl is substituted with 0 to 2 substituents independently chosen from (a) and 0 or 1 substituent (b), where (a) and (b) bear the definitions stated above. (24) R8 is methoxy; and R7 is a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or azepanyl group substituted with 0 to 2 independently chosen substituents of 1 or more of (a) and 0 or 1 substituents (b), where (a) and (b) bear the definitions stated above. (25) R8 is methoxy; and R is a piperazinyl or thiomorpholinyl group, each of which is substituted with 0 to 2 substituents independently chosen from 1 or more of (a) and 0 or 1 substituents (b); where (a) is chosen from halogen, hydroxy, amino, C? -C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, and d-C2 haloalkoxy, and (b) is oxo, amino, cyano, hydroxy -alkyl of C? -C4, aminoalkyl of C? -C, alkanoyl of C2-C, (mono- and di-alkyl of Ci-C) amino-alkyl of C0-d, (cycloalkyl of C3-C) alkyl of C0-C4 substituted with amino, (C3-C7 cycloalkylamino) C0-C alkyl, or (C3-C7 cycloalkyl) (d-C4 alkyl) amino-alkyl of Co-C. (26) R8 is methoxy and R7 is a pyrrolidinyl group, which is substituted with 0 to 2 independently chosen substituents of 1 or more of (a) and 0 or 1 substituents (b), wherein (a) and (b) can carry any of the definitions previously stated for these variables (27) R8 is methoxy, and R7 is a pyrrolidinyl group substituted with a group (b) and optionally substituted with 1 methyl substituent or halogen wherein (b) is oxo, amino, cyano, hydroxy-alkyl of dC-amino-C-C4 alkyl, C2-C4 alkanoyl, (mono- and di-alkyl of d- C4) amino-alkyl of Co-C4, (C3-C7 cycloalkyl) C0-C2 alkyl substituted with amino, (C3-C7 cycloalkylamino) Co-C alkyl, or (C3-C7 cycloalkyl) dC) amino-C0-C4 alkyl. (28) R8 is methoxy, and R7 is Where R15 is (b); and R16 is 0 or 1 or more substituents selected from amino, hydroxy, chloro, fluoro, methyl, methoxy, trifluoromethyl, and trifluoromethoxy; (b) can carry any of the definitions established above for those variables. (29) Certain compounds that meet the requirements of (28) above, R15 is oxo, amino, cyano, hydroxy-alkyl of dC, amino-C1-C alkyl, C2-C alkanoyl, (mono- and dialkylamino dC) ) C0-d alkyl, (C3-C7 cycloalkyl) C0-C2 alkyl substituted with amino, (C3-C7 cycloalkylamino) C0-C alkyl, or (C3-C7 cycloalkyl) (Ci-C4 alkyl) ) amino-C0-C alkyl. In certain of these compounds, R 5 is oxo, cyano, hydroxyalkyl of d-d. amino-d-C4 alkyl, acetyl, (C1- C2 mono- and di-alkylamino) d-C4 alkyl, cyclopropyl substituted with amino, or (C3-C7 cycloalkylamino) C0-C4 alkyl; and R-? 6 is 0 or 1 substituent selected from hydroxy, amino, chloro, and methyl. (30) R7 is a group of the formula (31) R8 is methoxy; and R7 is a dC alkylamino bonded to nitrogen substituted with a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently chosen from N, O and S, or substituted with a heterocycloalkyl group, having 4 to 8 members in the ring, including 1 or 2 heteroatoms in the ring independently chosen from N, O and S; Each of R7 is substituted with 0 or 1 or more independently chosen substituents of (a) and 0 or 1 substituents chosen from (b), wherein (a) and (b) can carry any of the definitions previously established for those variables. (32) R8 is methoxy; and R is a C? -C alkylamino linked to nitrogen substituted with a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently chosen from N, O and S, or substituted with a heterocycloalkyl group, having 4 to 8 members in the ring, including 1 or 2 heteroatoms in the ring independently chosen from N, O and S; each of which the heteroaryl or heterocycloalkyl is substituted with 0, 1 or 2 substituents independently chosen from halogen, hydroxy, amino, oxo, cyano, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl , and C? -C2 haloalkoxy. (33) R8 is methoxy, and R7 is d-C4 alkylamino substituted with a pyridyl, pyrimidinyl, piperazinyl, piperidinyl, or morpholinyl group, each of which is substituted with 0, 1 or 2 substituents independently chosen from halogen, hydroxy , amino, oxo, cyano, C? -C2 alkyl, C? -C2 alkoxy, d-C2 haloalkyl, and d-C2 haloalkoxy. (34) R8 is methoxy; and R7 is a heterocycloalkyl or heterocycloalkenyl group attached to nitrogen, each of which has 4 to 8 members in the ring, including 0, 1 or 2 additional ring heteroatom independently chosen from N, O and S, forming part of a bicyclic system with a cycloalkyl ring or 3- to 8-membered heterocycloalkyl in fused or spiro orientation. Each of R7 is substituted with 0 or 1 or more independently chosen substituents of (a) and 0 or 1 substituents chosen from (b) wherein (a) and (b) bear any of the definitions set forth above for those variables. (35) R8 is methoxy, and R7 is a piperidinyl, piperazinyl or pyrrolidinyl group, which is part of a bicyclic system having a cycloalkyl group of C3-C4l, dioxolanyl or azetidinyl attached to spiro, whose bicyclic system is substituted with 0, 1 or 2 substituents independently chosen from halogen, hydroxy, amino, oxo, cyano, C? -C2 alkyl, C? -C2 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy. (36) R8 is methoxy, and R7 is a 5- or 6-membered nitrogen-linked heterocycloalkyl, having 0 or 1 additional nitrogen atoms, whose 5 or 6 membered nitrogen-linked heterocycloalkyl is part of a bicyclic ring system which has a fused C3-C6 cycloalkyl or a fused 4 to 6 membered heterocycloalkyl containing 1 nitrogen atom, whose bicyclic ring system is substituted with 0, 1 or 2 substituents independently chosen from halogen, hydroxy, amino, oxo, cyano , d-C2 alkyl, dd alkoxy, d-C2 haloalkyl, and d-C2 haloalkoxy. (37) R7 is an octahydropyrrolo ring system [3,4- b] pi rid i n-ß-il or which is substituted with 0, 1 or 2 substituents independently chosen from halogen, methyl, or methoxy. (38) R8 is methoxy, and R is a 6-membered heterocycloalkyl group bonded to nitrogen, 0, 1 or 2 additional ring heteroatoms independently chosen from N, O and S, and bridged with a methylene or ethylene bridge. Each of R7 is substituted with 0 or 1 or more independently chosen substituents of (a) and 0 or 1 substituents chosen from (b), wherein (a) and (b) can carry any of the definitions set forth above for those variables . The variable A8 (1) A8 is nitrogen. (2) A8 is CR8. (3) A8 is CR8, and Re is hydrogen, halogen, Ci-C2 alkyl, C? -C2 alkoxy, C1-C2 haloalkyl, or d-C2 haloalkoxy. (4) A8 is CR8, and R8 is hydrogen, halogen, Ci-C2 alkyl, C1-C2 alkoxy, trifluoromethyl, or trifluoromethoxy. (5) A8 is CR8, and R8 is hydrogen, halogen, or C? -C2 alkoxy. (6) A8 is CR8 and R8 is hydrogen or methoxy. (7) A8 is CR8 is methoxy. (8) R6 is fluoro and R8 is methoxy. Variable R9 (1) R9 is d-C8 alkyl, d-C4 alkoxy, mono- or di- (C? -d) amino alkyl, C2-C4 alkanoyl, haloalkyl of Ci- C2, C1-C2 haloalkoxy, (C3-C cycloalkyl) C0-d alkyl, or phenyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, C1-C2 alkyl , C? -C2 alkoxy, C? -C2 mono- and di-alkylamino, C? -C2 haloalkyl, and Ci-d haloalkoxy. (2) Rg is C? -C alkyl, cyclopropyl, or phenyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, C -C2 alkyl, C1-C2 alkoxy, mono- and di-alkylamino of d-C2, haloalkyl of C-C2, and haloalkoxy of C? -C2. (3) Rg is C? -C alkyl or cyclopropyl, or (4) Rg is phenyl substituted with 2 substituents chosen from halogen, hydroxy, amino, C1-C2 alkyl, C? -C2 alkoxy, mono- and di- -alkylamino of d-C2, haloalkyl of C? -C2, and haloalc xi of C1-C2. (4) R9 is ethyl, t-butyl, cyclopropyl, or 2,4-difluorophenyl. (5) Rg is cyclopropyl. Any of the above conditions may be combined, so long as stable compounds of Formula I (or a tautomer or sub-formula thereof) result. For example, the invention includes compounds of Formula III (a sub-formula of Formula I), wherein condition (3) for variable R is found, condition (8) for variable R7 is found, condition (7) for the variable A8 is found, and condition (4) for variable R9 is found, that is, the invention includes compounds of Formula III Formula III and pharmaceutically acceptable salts thereof in which the variable R5 to Rg carry the definitions that follow. R5 is hydrogen (3). R6 is fluoro or hydrogen (2). R7 is a group of formula (a) - (e) Where: R15 is oxo or cyano; or R15 is C3-C7 cycloalkyl substituted with 0 or 1 d-C2 or amino alkyl substituents, or R15 is C3-C6 alkyl or mono- or di- (Ci-C alkyl) amino-C-alkyl ? -C4, each of which is substituted with 0, 1 or 2 independently chosen substituents of amino, hydroxy, (C3-C7 cycloalkyl) C0-C2 alkyl, (C3-C7 cycloalkyl) C0-C2 alkylamino, and (heterocycloalkyl) C 1 -C 2 alkylamino; or R15 is mono- or di- (C3-C6 alkyl) (C0-C) alkyl amino, or R15 is = NR10 or - (C0-C4 alkyl) (C = O) R10, or - ( C0-C) NCH3 (C = O) OR11, where each Rio and Rn are hydrogen or C1-C4 alkyl. R is 0 or 1 or more independently chosen substituents of chloro, fluoro, methyl, methoxy, aminomethyl, aminoethyl, trifluoromethyl, and trifluoromethoxy (8). A8 is CR8 and Rs is methoxy (7); and Rg is ethyl, t-butyl, cyclopropyl, or 2,4-difluorophenyl (4). Certain compounds of Formula I and Formula II possess potent antibacterial, antifungal and / or antiprotozoal activity. Particular compounds of the invention present Minimum Inhibitory Concentrations (Ml) of 64 μg / ml or less against Staphyloccocus aureus and / or Eschericia coli in a standard assay to determine the MICs of a compound against these bacteria, such as the assay provided in Example 9 below. Preferred compounds of Formula I and II have MIC values of 10 μg / ml or less against Staphyloccocus aureus and / or Eschericia coll. The most preferred compound of Formula I and II has Ml values of 4 μg / ml or less, or even more preferably 1 μg / ml or less, against Staphyloccocus aureus and / or Eschericia coli.

Certain compounds of Formula I and Formula II are selective antimicrobial agents; which have 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 the compounds of Formula I and Formula II can be assessed by determining the CC50 (the concentration in which 50% of the cells are killed) for cultured cells of a higher animal, such as fish, reptiles, amphibians, birds or mammals. . Certain compounds of the invention exhibit a CC50 of more than 100 micromolar for mammalian cells. Certain compounds of the invention have a CC50 of more than 100 micromolar for cultured human hepatocytes, and also have MIC values of 64 μg / ml or less, preferably 10 μg / ml or less, or more preferably 4 μg / ml or less , or still more preferably 1 μg / ml or less against Staphyloccocus aureus and / or Eschericia coli. Without wishing to be found in any particular theory it is believed that the antimicrobial properties of the 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 enzyme. analogous, topoisomerase II, present in higher organisms. Certain preferred compounds of the invention are 100 times or more selective for bacterial DNA gyrases than for topoisomerase II of mammals, particularly humans. COMPOUNDS WITH INCREASED THERAPEUTIC INTERVAL It has been unexpectedly discovered that replacement of the compounds of Formula I and Formula II with a methoxy substituent at the R8 position increases the anti-microbial activity of the compound against Methicillin-resistant Staphylococcus Aureus bacteria while at At the same time, the cellular toxicity of the compound decreases. The simultaneous increase in the activity of the compound and decrease in the toxicity of the compound provides a greater therapeutic range for compounds of Formula I and Formula II in which R8 is methoxy; that is, the dose range of such compounds that would produce beneficial effects without harmful side effects is increased. The antimicrobial activity is determined using a standard assay to determine the MIC of a compound against a methicillin resistant strain of Staphylococcus Aureus bacteria, such as the assay provided in Example 9 below. The therapeutic range is determined using a standard cytotoxicity assay such as the Alamar blue assay provided in Example 10. Table I provides a comparison of antimicrobial activity and cellular toxicity of a variety of compounds described herein without and with a substituent methoxy in the -s or TABLE co Ul O Ul Ul l Compound A is described by Abbott in U.S. Patent No. 5,071,848, which is incorporated herein by reference for its teachings with respect to Compound A. The MRSA strain used in this study was ATCC 700699, of ATTC, Manassas VA.

Hep2 cells are from ATCC catalog number CCL-23, Manassas VA.

ANTIMICROBIAL AND PHARMACEUTICAL PREPARATIONS The invention provides anti-microbial compositions, including antibacterial compositions, which comprise a compound or salt thereof of Formula I or Formula II, together with a carrier, diluent or excipient. In certain embodiments, the invention provides pharmaceutical compositions comprising a compound or salt of the salt thereof of Formula I or Formula II, together with a pharmaceutically acceptable carrier, diluent or excipient. The pharmaceutical composition can be formulated as any pharmaceutically useful form, for example, as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution. Compounds and salts of Formula I and Formula II may be administered as the pure 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 carriers, excipients, adjuvants, diluents or other ingredient. Compounds of the general formula I and Formula II can be administered orally, topically, parenterally, by inhalation or spray, sublingual, transdermal, administration via buccal, rectal, as an ophthalmic solution, or by other means, in dosage unit formulations containing pharmaceutically acceptable non-toxic carriers, excipients, adjuvants and vehicles. 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 diluents or encapsulating substances, which are suitable for administration to an animal. The carriers should be of sufficiently high purity and sufficiently low toxicity to produce them suitable for administration to the animal being treated. The carrier may be inert or may possess proprietary pharmaceutical benefits. The amount of the carrier employed in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. 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; jelly; talcum powder; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, oil olive, and corn oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as TWEENS; wetting agents, such as sodium lauryl sulfate; coloring agents; flavoring agents; rattlers, stabilizers; antioxidants; conservatives; pyrogen-free water; isotonic saline solution; and phosphate buffer solutions. 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, saline solution isotonic, and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Optional active agents can be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention. 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 cases in which the compounds exhibit insufficient solubility, methods can be used to solubilize compounds. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethyl sulfoxide (DMSO), using surfactants or surfactants, such as Tween, or aqueous sodium bicarbonate solution. Derivatives of the compounds, such as salts of the compounds or prodrugs of the compounds can also be used in formulating effective pharmaceutical compositions. With mixing or addition of the compounds of Formula I and / or Formula II, the resulting mixture may be a solution, suspension, emulsion or the like. The shape of the resulting mixture depends on a number of factors, including the intended mode of administration and the solubility of the compound in the carrier or vehicle chosen. The effective enough concentration to improve the symptoms of the disease, disorder or condition treated and can be determined empirically. Pharmaceutical compositions containing general compounds of 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 capsules or soft, or syrups or elixirs. Compositions intended for oral use can be prepared according to any methods known in 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 preservatives, to provide pharmaceutically refined and admissible preparations. Oral formulations contain between 0.1 and 99% of a compound of the invention and usually at least about 5% (% by 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 the invention. Liquid Formulations Compounds of the invention can be incorporated in liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, for example. In addition, formulations containing these compounds can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents (eg, sorbitol syrup, methylcellulose, glucose / sugar, syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and hydrogenated edible fats), emulsifying agents ( for example, lecithin, sorbitan monooleate, or acacia), non-aqueous vehicles, which may include edible oils (e.g., almond oil, fractionated coconut oil, silyl esters, propylene glycol and ethyl alcohol), and preservatives (e.g. methyl or propyl p-hydroxybenzoate and sorbic acid). Orally administered compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, dyes, syrups, and the like. Suitable pharmaceutically acceptable carriers for the 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. Typical carrier components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent. Suspensions For a suspension, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate; Typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate.

Aqueous suspensions contain the active materials 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 acacia gum; dispersing and wetting agents; they 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 a polyoxyethylene sorbitol substitute or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example substitute of polyethylene sorbitan. The aqueous suspensions may also contain one or more preservatives, for example n-propyl or ethyl p-hydroxybenzoate. Oily suspensions can 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. 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 acceptable oral preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid. Emulsions Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents can be gums that occur naturally, for example acacia gum or tragacanth gum, phosphatides that occur naturally, for example, soybean, lecithin, and partial esters or esters derived from degrees and hexitol acids, anhydrides , for example sorbitan monoleate, and condensation products of the partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. Dispersible powders Dispersible powders and granules suitable for the 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 Conservatives Suitable dispersants or wetting agents and suspending agents are exemplified by those already mentioned above. Tablets and Capsules Tablets typically comprise conventional pharmaceutically compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. Slides such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. Coloring agents, such as FD &C dyes, can be added for appearance. Sweetening and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules (including time-release and sustained-release formulations) typically comprise one or more solid diluents described above. The selection of carrier components often depends on secondary considerations such as flavor, cost, and shelf stability. Such compositions can also be coated by conventional methods, typically with pH or coatings time dependent, such that the subject compound is released into 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, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, Eudragit coatings, waxes and shellac. Formulations for oral use can 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 mix with water or a medium of oil, for example peanut oil, liquid paraffin or olive oil. Injectable and Parenteral Formulations Pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known technique using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Between the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, fixed, sterile oils are conventionally employed as a solvent or suspension medium. For this purpose any soft fixed oil can be employed including synthetic mono- or diglycerides. In addition, acid grades such as oleic acid are useful in the preparation of injectables. Compounds of Formula I and Formula II can be administered parenterally in a sterile medium. Parenteral administration includes subcutaneous, intravenous, intramuscular injections, intrathecal injection or infusion techniques. The drug, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and deadening 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. Compound suppositories of Formula I and Formula II can 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 which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum until the drug is released. Such materials are cocoa butter and polyethylene glycols. Topical Formulations Compounds of the invention may be 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 application intracisternal or intraspinal. 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. Such solutions can be formulated as isotonic solutions at 0.01% -10%, pH of about 5-7, with appropriate salts. Compounds of the invention can also be formulated for transdermal administration as a transdermal patch. Topical compositions containing the active compound can be mixed with a variety of carrier materials well known in the art, for example, water, alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, propionate. of myristyl PPG-2, and the like.

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 may be used simply or as mixtures of one or more materials, are as follows: Emollients, such as stearyl alcohol, glyceryl monorricinoleate, glyceryl monostearate, propan-1,2-diol, butan-1, 3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol , isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanuts, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate o, decyl oleate, and myristyl myristate; propellants, such as propane, butane, isobutane, dimethyl ether, carbon dioxide, and nitrous oxide; solvents, such as ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethyl formamide, tetrahydrofuran; humectants, such as glycerin, sorbitol, sodium 2-pyrrolidin-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin; and powders, such as chalk, talc, fuller's earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, trialkylammonium smectites, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrous aluminum silicate , fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate. The compounds of the invention can also be administered topically 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 Other compositions useful to achieve systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more soluble fillers such as sucrose, sorbitol and mannitol, and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose. Slides, lubricants, sweeteners, dyes, antioxidants and flavoring agents described above. Compositions for inhalation can typically be provided in the form of a solution, suspension or emulsion which can be administered as a dry powder or in the form of an aerosol using a conventional propellant (for example, dichlorodifluoromethane or trichlorofluoromethane). Additional components The compositions of the present invention may also optionally comprise an activity enhancer. The activity enhancer may be chosen from a wide variety of molecules that function in different ways to increase antimicrobial effects of compounds of the present invention. Particular classes of activity enhancers include skin penetration enhancers and absorption enhancers. Pharmaceutical compositions of the invention may also contain additional active agents and may be chosen from a wide variety of molecules, which may function in different ways to enhance the antimicrobial or therapeutic effects of a compound of the present invention. These optional different 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 modalities contain 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. Packaging Formulations The invention includes packaged pharmaceutical formulations. Such packaged formulations include a pharmaceutical composition containing one or more compounds or salts of Formula I or Formula II in a container and instructions for using the composition to treat an animal (typically a human patient) suffering from an infection of microorganisms) or prevent an infection of microorganisms in an animal. The instructions may be instructions for using the compositions to treat a bacterial, mycoplasmal or protozoal infection. For example, the instructions may be instructions for using the composition to treat a urinary tract infection or genital tract, such as pyelonephritis, gonococcal cervical infections, cystitis, chlamydial urethral infections, cervical chlamydial infections, gonococcal urethral infections, and prostatitis, a respiratory infection, 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, syndrome of scalded skin, and cellulites, and other infections such as bone infections, joint infections, infectious diarrhea, typhoid fever, intra-abdominal infections, gynecological infections, including toxic shock syndrome, pelvic infections, and post-surgery infections. The instructions may be instructions for using the composition to treat a patient suffering from a bacterial infection, such as S. aureus infection. In all of the above the compounds of the invention can be administered alone or as mixtures, and the compositions can further include drugs or excipients as appropriate to the indication. METHODS OF TREATMENT The invention includes methods for preventing and treating infections of microorganisms, particularly bacterial and protozoal infections, by administering an effective amount of one or more compounds of Formula I or Formula II to an animal at risk of infection of microorganisms or suffering of an infection of microorganisms. The animal may be a fish, amphibian, reptile or bird, but it is preferably a mammal. Methods for treating and preventing infections of microorganisms in livestock animals, companion animals, and human patients are particularly preferred. The compounds described herein are useful for preventing and treating bacterial infections in animals. further The compounds of the invention can be used to treat a variety of conditions not attributed to bacterial infections. These include diseases and disorders caused by fungal infections, microplasmatic infections, protozoan infections, or other conditions involving infectious organisms. In some circumstances an effective amount of a compound of Formula I or Formula II may be an amount sufficient to reduce the symptoms of microorganism infection. Alternatively an effective amount of a Compound of Formula I may be an amount sufficient to significantly reduce the amount of microorganisms or antibodies against the detectable in patient tissues or body fluids. Methods of treatment also include inhibiting the replication of microorganisms in vivo, in an animal at risk of an infection of microorganisms or suffering from 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 concentration can be ascertained experimentally, for example by testing the blood concentration of the compound, or theoretically, calculating bioavailability. The amount of a compound sufficient to inhibit bacterial survival in vitro can be determined with a conventional assay for bacterial survival such as the Minimum Inhibitory Concentration Assay (MIC) described in Example 9, which follows. The invention also includes using compounds of Formula I and Formula II in prophylactic therapies. In the context of prophylactic or preventive treatment an effective amount of a compound of the invention is an amount sufficient to significantly decrease the risk of the animal treated to contract an infection of microorganisms. Compounds of the invention are particularly useful for treating and preventing infectious disorders. These include, for example: eye infections such as conjunctivitis; urinary tract and genital infections, such as complicated urinary tract infections, acute urinary and genital tract infections, such as pyelonephritis, cervical gonococcal infections, cystitis, chlamydial urethral infections, cervical chlamydial infections, gonococcal urethral 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 cellulitis, and other infections such as bone infections, joint infections, infectious diarrhea, typhoid fever, intra-abdominal infections, gynecological infections, including toxic shock syndrome, pelvic infections, and post-surgery infections. The disclosed compounds are useful for treating infections caused by the following microorganisms: Aerobic Gram-positive Microorganisms: Including but not limited to Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus (including S. aureus methicillan), Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus haemolyticus, and Staphylococcus hominis. Aerobic Gram-negative Microorganisms: Including but not limited to Campylobacter jejuni, Citrobacter diversus, Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoene, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa, Stenotrophomonas maltophila, Salmonella typhi, Serratia marcescens, Shigella boydii, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Acinetobacter lwoffi, Aeromonas hydrophila, Edwardsiella tarda, Enterobacter aerogenes, Klebsiella oxytoca, Legionella pneumophila, Pasteurella multocida, Salmonella ßnteritidis, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, Yersinia enterocolitica and H. Pylorii. Non-bacterial microorganisms: Mycoplasma, Legionella and Chlamydia. Dosage levels of the order of about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the conditions indicated above (approximately 0.5 mg to approximately 7 g per patient per day). The amount of active ingredient that can be combined with the carrier materials to produce a simple dosage form will vary depending on the host treated and the particular mode of administration. Unit dosage forms will generally contain between about 1 mg to about 500 mg of an active ingredient. The dosage frequency may also vary depending on the compound used and the particular disease treated. However, for the treatment of more infectious disorders, a dosage regimen of 4 times a day or less is preferred and a dosage regimen of 1 or 2 times a day is particularly preferred. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, combination of the drug and the severity of the particular disease of the therapy which is submitted. COMBINATION ADMINISTRATION The compounds of the invention may also be useful in combination with other pharmaceutically active agents such as antibacterial agents, antiviral agents, antifungal agents, anti-inflammatory agents, interferon, pump pump inhibitors, and beta-lactamase inhibitors. Antibiotic agents include any molecule that tends to prevent, inhibit or destroy life and as such, includes antibacterial agents, anti-fungicides, antiviral agents, and antiparasitic agents. Pharmaceutical compositions of the invention include simple dosage forms containing a compound of Formula I and / or Formula II and one or more other active agents, 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. The following active agents, which are useful in combinations of the invention, can be isolated from an organism produced by the agent or synthesized by methods known to those of ordinary skill in the medicinal chemistry art or acquired from a commercial source. Antibacterial antibiotic agents include, but are not limited to, penicillins, cephalosporins, carbacephems, cefamycins, carbapenems, monobactams, aminoglycosides, glycopeptides, quinolones, tetracyclines, macrolides, and fluoroquinolones (see Table below). Examples of antibiotic agents include, but are not limited to, Penicillin G (CAS Registration No.: 61-33-6); Methicillin (CAS Registration No.: 61-32-5); Nafcillin (CAS Registration No.: 147-52-4); Oxacillin (CAS Registration No.: 66-79-5); Cloxacillin (CAS Registration No. 61-72-3); Dicloxacillin (CAS Registration No. 3116-76-5); Ampicillin (CAS Registration No.: 69-53-4); Amoxicillin (CAS Registration No. 26787-78-0); Ticarcillin (CAS Registration No. 34787-01-4); Carbenicillin (CAS Registration No. 4697-36-3); Mezlocillin (CAS Registration No.: 51481-65-3); Azlocillin (CAS Registration No.: 37091-66-0); Piperacillin (CAS Registration No .: 61477-96-1); Imipenem (CAS Registration No.: 74431-23-5); Aztreonam (CAS Registration No.: 78110-38-0); Cefalotin (CAS Registration No.: 153-61-7); Cefazolin (CAS Registration No.: 25953-19-9); Cefaclor (CAS Registration No. 70356-03-5); Cefamandol sodium format (CAS Registration No.: 42540-40-9); Cefoxitin (CAS Registration No .: 35607-66-0); Cefuroxime (CAS Registration No.: 55268-75-2); Cefonicid (CAS Registration No.: 61270-58-4); Cefmetazole (CAS Registration No. 56796-20-4); Cefotetan (CAS Registration No .: 69712-56-7); Cefprozil (CAS Registration No.: 92665-29-7); Loracarbef (CAS Registration No.: 121961-22-6); Cefetamet (CAS Registration No.: 65052-63-3); Cefoperazone (CAS Registration No.: 62893-19-0); Cefotaxime (CAS Registration No.: 63527-52-6); Ceftizoxime (CAS Registration No.: 68401-81-0); Ceftriazone (CAS Registration No.: 73384-59-5); Ceftazidime (CAS Registration No.: 72558-82-8); Cefepima (CAS Registration No.: 88040-23-7); Cefixime (CAS Registration No.: 79350-37-1); Cefpodoxime (CAS Registration No.: 80210-62-4); Cefsulodin (CAS Registration No.: 62587-73-9); Fleroxacin (CAS Registration No.: 79660-72-3); Nalidixic acid (CAS Registration No .: 389-08-2); Norfloxacin (CAS Registration No. 70458-96-7); Ciprofloxacin (CAS Registration No.: 85721-33-1); Ofloxacin (CAS Registration No.: 82419-36-1); Enoxacin (CAS Registration No.: 74011-58-8); Lomefloxacin (CAS Registration No.: 98079-51-7); Cinoxacin, (CAS Registration No.: 28657-80-9); Doxycycline (CAS Registration No. 564-25-0); Minocycline (CAS Registration No.: 10118-90-8); Tetracycline (CAS Registration No.: 60-54-8); Amicacina (CAS Registration No.: 37517-28-5); Gentamicin (CAS Registration No. 1403-66-3); Kanamycin (CAS Registration No.: 8063-07-8); Netilmicin (CAS Registration No. 56391-56-1); Tobramycin (CAS Registration No .: 32986-56-4); Streptomycin (CAS Registration No.: 57-92-1); Azithromycin (CAS Registration No .: 83905- 01-5); Clarithromycin (CAS Registration No.: 81103-11-9); Erythromycin (CAS Registration No. 114-07-8); Erythromycin estolate (CAS Registration No.: 3521-62-8); Ethyl-erythromycin Succinate (CAS Registration No .: 41342-53-4); Erythromycin Glucoheptonate (CAS Registration No.: 23067-13-2); Erythromycin Lactobionate (CAS Registration No.: 3847-29-8); Erythromycin stearate (CAS Registration No. 643-22-1); Vancomycin (CAS Registration No. 1404-90-6); Teicoplanin (CAS Registration No.: 61036-64-4); Chloramphenicol (CAS Registration No. 56-75-7); Clindamycin (CAS Registration No.: 18323-44-9); Trimethoprim (CAS Registration No. 738-70-5); Sulfamethoxazole (CAS Registration No.: 723-46-6); Nitrofurantoin (CAS Registration No. 67-20-9); Rifampin (CAS Registration No.: 13292-46-1); Mupirocin (CAS Registration No.: 12650-69-0); Metronidazole (CAS Registration No.: 443-48-1); Cephalexin (CAS Registration No.: 15686-71-2); Roxithromycin (CAS Registration No.: 80214-83-1); Co-amoxiclavuanato; combinations of Piperacillin and Tazobactam; and its various salts, acids, bases and other derivatives. Antifungal agents include but are not limited to Amphotericin B, Candicidin, Dermostatin, Philippine, Fungicromine, Hachymycin, Hamicin, Lucensomycin, Meparticin, Natamycin, Nystatin, Pecillin, Perimycin, Azaserin, Griseofulvin, Oligomycins, Neomycin, Pyrrolnitrine, Sicanin, Tubercidin, Viridine, Butenafin, Naftifin, Terbinafine, Bifonazole, Butoconazole, Clordantoin, Clormidazole, Cloconazole, Clotrimazole, Econazole, Enilconazole, Fenticonazole, Flutrimazole, Isoconazole, Ketoconazole, Lanoconazole, Miconazole, Omoconazole, Oxiconazole, Sertaconazole, Sulconazole, Tioconazole, Tolciclate, Tolindate, Tolnaftate, Fluconawle, Itraconazole, Saperconazole, Terconazole, Acrisorcin, Amorolfine, Bifenamine, Bromosalicycloanilide, Buclosamide, Calcium Propionate, Clorphenesin, Cyclopirox, Cloxyquin, Coparafinate, Exalamide, Flucytosine, Haletazole, Hexetidine, Loflucarban, Nifuratel, Potassium Iodide, Propionic Acid, Pyrithione, Sal ici lan Iliad, Sodium Propionate, Sulbentin, Tenonitrozole, Triacetin, Ujotion, Undecylenic Acid and Zinc Propionate. Antiviral agents include, but are not limited to, Acyclovir, Cidofovir, Citarabine, Dideoxiadenosine, Didanosine, Edoxudin, Famciclovir, Floxuridine, Ganciclovir, Idoxuridine, Inosine, Pranobex, Lamivudine, MADU, Penciclovir, Sorivudine, Stavudine, Trifluridine, Valaciclovir, Vidarabine, Zalcitabine, Zidovudine, Acemannan, Acetyl Leucine, Amantadine, Amidinomycin, Delaviridin, Foscarnet, Indinavir, Interferon-a, Interferon-ß, Interferon- ?, Ketoxal, Lysozyme, Metisazone, Moroxidine, Nevirapine, Podofilotoxin, Ribavirin, Rimantadine, Ritonavir-2, Saquinavir, Stailimycin, Estatolone, Tromantadine, and Xenazoic Acid. Anti-inflammatory agents include, but are not limited to, Enfenamic Acid, Etofenamate, Flufenamic Acid, Isonixina, Meclofenámico Acid, Mefenámico Acid, Niflúmico Acid, Talniflumato, Terofenamato, Tolfenámico Acid, Aceclofenac, Acemetacina, Alclofenac, Amfenac, Amotolmetina Guacil, Bromfenac, Bufexamac, Cinmetacina, Clopirac, Diclofenac, Etodolac, Felbinac, Fenclozic acid, Fentiazac, Glucametacina, Ibufenac, Indomethacin, Isofezolac, Isoxepac, Lonazolac, Methiazine, Mofezolac, Oxametacin, Pirazolac, Proglumetacin, Sulindac, Tiaramide, Tolmethine, Tropeline, Zomepirac, Bumadizon, Butibufen, Fenbufen, Xenbucine, Clidanac, Ketorolac, Tinoridine, Alminoprofen, Benoxaprofen, Bermoprofen , Bucilloxic Acid, Carprofen, Fenoprofen, Flunoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin, Picetoprofen, Pirprofen, Pranoprofen, Protizinic Acid, Suprofen, Tiaprofenic Acid, Ximoprofen, Zaltoprofen, Difenamizol, Epirizol, Apazona, Benzpiperilón, Feprazona, Mofebutazona, Morazona, Oxifenbutazona, Phenylbutazone, Pipebuzon a, Propylphenazone, Ramifenazone, Suxibuzone, Tiazolinobutazone, Acetaminosalol, Aspirin, Benorilate, Bromosaligenin, Calcium Acetylsalicylate, Diflunisal, Etersalate, Fendosal, Gentisic Acid, Glycol Salicylate, Imidazole Salicylate, Lysine Acetylsalicylate, Mesalamine, Morpholine Salicylate, Salicylate of I-Naftyl, Olsalazine, Parsalmide, Phenyl Acetylsalicylate, Phenyl Salicylate, Salacetamide, O-Acetic Acid of Salicylamide, Acid Salicylsulfuric acid, Salsalate, Sulfasalazine, Ampiroxicam, Droxicam, Isoxicam, Lornoxicam, Piroxicam, Tenoxicam, Epsilon-Acetamidocaproic acid, S-Adenosylmethionine, 3-Amino-4-hydroxybutyric acid, Amixetrin, Bendazac, Benzyldamine, Alpha-Bisabolol, Bucoloma, Difenpyramide, Ditazole, Emorfazone, Fepradinol, Guaiazulene, Nabumetone, Nimesulide, Oxaceprol, Paramuna, Perisoxal, Procuazone, Superoxide Dismutase, Tenidap, Zileuton, 21-Acetoxypregnenolone, Alclomethasone, Algestone, Amcinonide, Beclomethasone, Betamethasone, Budesonide, Cloroprednisone, Clobetasol, Clobetasone, Clocortolone , Cloprednol, Corticosterone, Cortisone, Cortivazole, Deflazacort, Desonide, Desoximetasone, Desametasone, Difloroasone, Diflucortolone, Difluprednate, Enoxolone, Fluazacort, Flucloronide, Flumetasone, Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortin-Butyl, Fluocortolone, Fluorometolone, Fluperolone Acetate, Fluprednidene Acetate, Fluprednisolone, Flurandrenolide, Fluticasone Propionate, Formocortal, Halcinonide, Halobetasol Propionate, Halometasone, Acetate Haloprdone, Hydrocortamate, Hydrocortisone, Loteprednol-Etabonal, Mazipredone, Medrisone, Meprednisone, Methylprednisolone, Mometasone Furoate, Parametasone, Prednicarbate, Prednisolone, Prednisolone 25-Diethylamino Acetate, Prednisolone-Sodium Phosphate, Prednisone, Prednant, Prednilidene, Rimexolone, Tixocortol, Triamcinolone, Acetonide of Triamcinolone, Triamcinolone Benetonide, and Triamcinolone Hexacetonide. Compounds of the invention may be combined with one or more beta-lactamase inhibitors 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. Compounds of the invention can also be combined with one or more discharge pump inhibitors, such as quinazolinone discharge pump inhibitors, d-ornithine-d-homophenylalanine-3-aminoquinoline, Phe-Arg-b-naphthalamide, propafenone. , a phenothiazine or thioxanthene discharge pump inhibitor, 1-aza-9-oxafluorenos, N- [4- [2- (3,4-dihydro-6,7-dimethoxy-2 (1H) -isoquinolinyl ) ethyl] phenyl] -9,10-dihydro-5-methoxy-9-oxo-4-Acridinecarboxamide, reserpine, MMbemycin, Cinconine, Verapamil, L-phenylalanyl-N-2-naphthalenyl-L-Argininamide (and analogs), 5'-methoxyhydrocarpin-D, methylxanthines, FK506, a cyclosporin pump inhibitor, Nocardamine and other siderophors, Amiodarone, Cyclosporin A, Ro11-2933 (DMDP), Quinidine, and the optical isomers of Propranolol, Quinine (SQ1) and Quinidine, Quinine-10,11-Epoxide, Quercetin, Amitriptyline, Taxuspin C derivatives, Emodin, MC-002434; Agosterol A; Feoforbide; pyridoquinolines such as 2,2 '- [(2,8,10-trimethyloprid [3,2-g] quinoline-4,6-diyl) bis (oxy)] bs [ N, N- dimethyl-ethanamine, Gitonavir, and Gemfibrozil. SYNTHESIS OF COMPOUNDS The compounds of the invention are prepared according to methods well known to those skilled in the art of organic chemistry synthesis. The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available. It is recognized that the artisan skilled in the art of organic chemistry can easily carry out standard manipulations of organic compounds without additional guidance. The skilled artisan will readily appreciate that certain reactions are best carried out when other functionalities are masked or protected in the compound, thereby increasing the performance of the reaction and / or avoiding any undesirable side reactions. Frequently, the skilled artisan uses protective groups to perform such increased performances or to avoid undesired reactions. These reactions are found in the literature and are also within the reach of the skilled artisan. The compounds of the invention may have one or more chiral centers. As a result, one can selectively prepare an optical isomer, including diastereomers and enantiomers, over others, for example by materials of starting chirals, catalysts or solvents, or can prepare both stereoisomers or both optical isomers, including diastereomers and enantiomers at once (a racemic mixture). Since the compounds of the invention can exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, or stereoisomers can be separated using known methods, such as through the use of, for example, chiral salts and chiral chromatography. Furthermore, it is recognized that an 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. The invention also includes all the energetically accessible conformational and trosional isomers of the disclosed compounds. 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 The following abbreviations are used in the reaction schemes and synthetic examples, which follow. This list is not meant to be a list of all abbreviations even used in the application as additional standard abbreviations, which are easily understood by those skilled in the art of organic synthesis, can also be used in synthetic schemes and examples. (Boc) 2O - Di-t-butyl dicarbonate Cbz-CI - Benzyloxycarbonyl chloride m-CPBA - M-chloroperoxybenzoic acid DMF - N, N - Dimethylformamide DMSO - Dimethyl sulfoxide Et3N - Triethylamine Et2O - Diethyl ether EtOH - Ethanol EtOAc - Acetate ethyl LDA PPh3 - Triphenyl Phosphate PTLC - Preparative thin layer chromatography t-BuOK - Tert-butyl oxide TSCI - Tosyl chloride TFA - Trifluoroacetic acid THF - Tetrahydrofuran GENERAL METHODS All non-aqueous reactions are carried out under an atmosphere of dry argon gas (99.99%) using oven-dried or flame-dried glassware. The microwave-assisted syntheses are conducted in a commercial microwave reactor (Discover System, CEM Corporation). The progress of the reactions is monitored using thin layer chromatography (TLC) on glass plates covered with Merck silica gel 60 (F254). The flash column chromatography is performed on Merck silica gel 60 (230-400 mesh). NMR spectra were recorded at room temperature using a Bruker Avance 300 spectrometer (1H at 300.1 MHz, 13C at 75.5 MHz, and 19F at 282.4 MHz). The chemical changes for 1H and 13C are reported in parts per million (d) relative to external tetramethylsilane and are referenced to residual proton signals in the deuterated solvent. Chemical changes for 19F are reported in parts per million (d) relative to external fluorotrichloromethane. The assignment of the NMR data is based on two dimensional correlation experiments (1H-1H COZY, 1H-13C HMQC, 1H-13C HMBC, and 1H-1H NOESY) and the usual principles of NMR spectroscopy (the magnitudes of constants coupling and chemical changes). Analytical HPLC is performed using a YMC Pack Pro C18 50 x 4.6 mm 5 μm column with a Socratic elution of 0.24 min., At 90:10 H2O: CH3CN containing a 0.1% TFA followed by a 4 minute linear gradient elution from 90:10 to 10:90 at a flow rate of 2.5 mL / min., With a UV detection at 254 nm. Unless otherwise noted, preparative HPLC was performed using a UMC Pack Pro C18 column of 150 x 20.0 mm 5 μm with a Socratic elution of 0.24 min., At 97: 3 H2O: CH3CN containing 0.1% of TFA followed by a linear gradient elution of 10 min., 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 were recorded on a Thermo Finningan Surveyor MSQ instrument (operation in APCI mode) equipped with Gilson liquid chromatography. Unless otherwise noted, the nearly molecular ions, [M + H] +, observed in the low resolution mass spectra are the base peaks. Elemental analyzes are performed at Atlantic Microlab, Inc. (Norcross, GA). EXAMPLE 1. PREPARATION OF 8-METOXY-SUBSTITUTE DO-9H-ISOTIAZOLO [5,4-B] QUINOLIN-3,4-DIONES 8-methoxy-substituted-9H-isothiazolo [5,4-b] quinolin-3 was prepared , 4-diones from the intermediates of the corresponding nucleus (1-4) according to the synthetic scheme described below.

EXAMPLE 2. SYNTHESIS OF COMPOUNDS OF FORMULAS 1 AND 2. 7-Chloro-9-cyclopropyl-6-fluoro-9H-1-thia-2,8,9-triazacyclopenta [b] naphthalene-3,4-dione (1) was prepared from 2,6-dichloro-5 ethyl fluoride-ethylacetate using the procedure of Chu and Claiborne (Chu, D. T. W .; Claiborne, A. K. J. Heterocycl.

Chem. 1990, 27, 1191-1195). 9-Cyclopropyl-6,7-difluoro-9H-isothiazolo [5,4-b] quinoline-3,4-dione was prepared from acid 2,4,5-trifluorobenzoic using the Chu procedure (Chu, D.W.J.J. Heterocycl.Chem. 1990, 27, 839-843). EXAMPLE 3. SYNTHESIS OF 9-CICLOPROPI L-6.7-DI FLUORO-8-METOXY-9H-ISOTIAZOLO [5,4-B] QUINOLIN-3,4-DIO A (Compound 3). 9-Cyclopropyl-6,7-difluoro-8-methoxy-9H-isothiazolo [5,4-b] quinoline-3,4-dione (3) was prepared according to the synthetic scheme below.

Step 1. Synthesis of 2,4,5-trifluoro-3-methoxybenzoyl chloride (A) A mixture of 2,4,5-trifluoro-3-methoxybenzoic acid (154 mg, 0.75 mmol) and thionyl chloride (8 mL ) was refluxed for 4 hours. Excess thionyl chloride was removed in vacuo, and the remaining residue is used directly in the next synthetic step. Step 2. Synthesis of (Z) -ethyl-3-hydroxy-3- (2,4,5-trifluoro-3-methoxyphenyl) acrylate (B). Compound B was prepared using the general method of Wierenga and Skulnick (Wierenga, W .; Skulnick, H. I. J. Org. Chem. (1979) 44: 310-311). N-Butyl-lithium (1.6 M in hexanes) to a cooled solution (-78 ° C) of tetrahydrofuran (10 mL) containing ethyl hydrogen malonate (180 μL, 1.50 mmol) and 2,2'-bipyridyl (-1 mg as indicator). The temperature of the reaction mixture was allowed to rise to approx. -5 ° C during the addition of n-butyl-lithium. Sufficient n-butyl-lithium (2.8 mL, 4.48 mmol) was added until a pink color persisted at -5 ° C for 5-10 minutes. A solution of 2,4,5-trifluoro-3-methoxybenzoyl chloride (0.75 mmol, vide supra) in tetrahydrofuran (~ 3 mL) was added in one portion to the reaction mixture which has been re-cooled to -78 ° C. The resulting mixture was allowed to warm to room temperature, diluted with ethyl acetate (50 mL), and warmed with a 1M aqueous solution of hydrochloric acid. The organic layer was washed with a 5% aqueous solution of sodium bicarbonate (2 x 30 mL), followed by brine (2 x 50 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the product raw. This material was purified by flash column chromatography (eluting with 20% ethyl acetate in hexanes v / v) to give pure B as a white solid. 1 H NMR (300 MHz, CDCl 3): enol, predominant tautomer, > 90%) d 1.32 (t, JH-H = 7.0 Hz, 3H, CO2CH2CH3), 4.02 (apparent t, JH-F = 1.0 Hz, 3H, OCH3), 4.25 (q, JH-H = 7.0 Hz, 2H, CO2CH2CH3), 5.79 (s, 1H, CH3C (OH) = CH-CO2CH2CH3), 7.39 (ddd, JH-F = 11.0 Hz, 6.5 Hz, 1H, aromatic), 12.68 (s, 1H, OH). 19F. { 1 HOUR} NMR (282 MHz, CDCl 3): d-146.8 (dd, JF-F = 21.5 Hz, 10.5 Hz, 1F), -140.2 (dd, JF-F = 21.5 Hz, 13.5 Hz, 1F), -131.3 (dd, JF.F = 13.5 Hz, 10.5 Hz, 1F). Step 3. Synthesis of 2 - ((Z) -N-cyclopropyl (methylthio) carbon orimidoyl) -3-h idroxy-3- (2,4,5-trifluoro-3-methoxyphenyl) acrylate ( E) -ethyl (C) Sodium hydride (60% in mineral oil, 31 mg, 0.78 mmol) was added in portions to a cooled solution (0 ° C) containing B (200 mg, 0.73 mmol), cyclopropyl isothiocyanate. (120 μL, 1.2 mmol) and dimethylformamide (2 mL). The resulting mixture was allowed to warm to room temperature with stirring overnight (18 hours). Methyl iodide (80 μL, 1.2 mmol) was added to the resulting solution and stirred for an additional 4 hours (until the CCF indicated full consumption of B). The reaction mixture was diluted with ethyl acetate (100 mL) and warmed by the addition of a saturated aqueous solution of ammonium chloride (30 mL). The organic layer was washed with brine (4 x 30 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product. This material was purified by flash column chromatography (eluting with 40% ethyl acetate in hexanes v / v) to give C as a yellow oil. 1 H NMR (300 MHz, CDCl 3): d 0.86 (m, 2H, cyclopropyl CH 2), 0.97 (m, 5H), 2.52 (s, 3H, SCH 3), 3.00 (m, 1H, cyclopropyl CH), 3.96 (q, JH-H = 7.0 Hz, 2H, CO2CH2CH3), 4.02 (apparent t, JH-F = 1.0 Hz, 3H, OCH3), 6.96 (m, 1H, aromatic), 11.71 (s, 1H). 19F. { 1 HOUR} NMR (282 MHz, CDCl 3): d -149.9 (br, 1F), -141.4 (br, 1F), -135.7 (br, 1F). Step 4. Synthesis of ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-2- (methylthio) -4-oxo-1,4-dihydroquinoline-3-carboxylate (D) Sodium hydride was added in portions (60% in mineral oil, 82 mg, 2.1 mmol) was added to a solution of C (760 mg, 1.95 mmol) in dimethylformamide (15 mL) at room temperature. The reaction mixture was heated to 80CC for 3 days (until TLC indicated full consumption of B), cooled to room temperature, and warmed by the addition of a saturated aqueous solution of ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (4 x 30 mL), dried over sodium sulfate, and evaporated under reduced pressure to give crude D. This material was purified by flash column chromatography (eluting with 30% ethyl acetate in hexanes v / v) to give D as a pale yellow oil. 1 H NMR (300 MHz, CDCl 3): d 0.73 (m, 2H, cyclopropyl CH 2), 1.19 (m, 2H, cyclopropyl CH 2), 1.38 (t, JH-H = 7.0 Hz, 3H, CO2CH 2 CH 3), 2.66 (s, 3H, SCH3), 3.74 (m, 1H, cyclopropyl CH), 4.08 (d, JH-F = 2.5 Hz, 3H, OCH3), 4.40 (q, JH-H = 7.0 Hz, 2H, CO2CH2CH3), 7.76 (dd , JH-F = 10.5 Hz, 8.5 Hz, 1H, aromatic). 19F. { 1H) NMR (282 MHz, CDCl 3): d -146.8 (d, JF-F = 21.0 Hz, 1F), -137.7 (d, JF-F = 21.0 Hz, 1F). LCMS m / z calculated for C? 7H? 7F2NO4S 369 ([M +]): found 370 ([M + H] +).

Step 5. Synthesis of ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-2- (methylsulfinyl) -4-oxo-1,4-dihydroquinoline-3-carboxylate (E) M-chloroperoxybenzoic acid ( < 77%, 34 mg, 0.15 mmol) in one portion to a solution of D (50 mg, 0.14 mmol) in methylene chloride (3 mL) at room temperature. The reaction mixture was stirred for 1 hour, diluted with ethyl acetate (20 mL), and washed with a 5% aqueous solution of sodium bicarbonate (2 x 10 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the crude product. This material was purified by preparative thin layer chromatography (eluting with 10% hexanes in ethyl acetate v / v) to give pure E as a white solid. 1 H NMR (300 MHz, CDCl 3): d 0.62 (m, 1H, cyclopropyl CH 2), 1.00 (m, 1H, cyclopropyl CH 2), 1.13 (m, 1H, cyclopropyl CH 2), 1.29 (m, 1H, cyclopropyl CH 2), 1.36 (t, JH-H = 7.5 Hz, 3H, CO2CH2CH3), 3.22 (s, 3H, S (O) CH3), 3.85 (m, 1H, cyclopropyl CH), 4.09 (d, JH-F = 2.5 Hz, 3H, OCH3), 4.37 (q, JH-H = 7.5 Hz, 2H, CO2CH2CH3), 7.75 (dd, JH-F = 10.0, 8.0 Hz, 1H, aromatic). 19F. { 1 HOUR} NMR (282 MHz, CDCl 3): d -145.2 (d, JF-F = 21.0 Hz, 1F), -136.2 (d, JF-F = 21.0 Hz, 1F). LCMS m / z calculated for C17H17NO5S 385 ([M +]); found 386 ([M + H] +). Step 6. Synthesis of ethyl 1-cyclopropyl-6,7-difluoro-2-mercapto-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (F). Sodium hydrogen sulfide was added in one portion anhydrous (Alfa Aesar, 20 mg, 0.36 mmol) to a solution of DMF (6 mL) containing E (93 mg, 0.24 mmol) at room temperature. The resulting solution was heated at 40 ° C for 2-3 hours (until the CCF indicated full consumption of E) and allowed to cool to room temperature. The reaction mixture was quenched by the addition of a 5% aqueous solution of hydrochloric acid (20 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic extracts were washed with brine (4 x 25 mL), dried over sodium sulfate, and evaporated to dryness under reduced pressure to give crude F in a quantitative yield. This material is used directly in the next synthetic stage to prevent its oxidative degradation. LCMS m / z calculated for C 16 H 15 F 2 NO 4 S 355 ([M +]); found 356 ([M + H] +). Step 7. Synthesis of 9-cyclopropyl-6,7-difluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione (3). A solution of sodium bicarbonate (820 mg, 9.8 mmol) in water (14 mL) was added to a solution of F (348 mg, 0.98 mmol) in tetrahydrofuran (10 mL) at room temperature. Hydroxylamine-O-sulfonic acid (465 mg, 4.1 mmol) was added in one portion to this mixture. The reaction mixture was stirred at room temperature for ~ 3 hours and quenched by the addition of an aqueous solution of 5% hydrochloric acid (100 mL). The precipitate that formed was collected by filtration, washed with water (3 x 5 mL), and dried in vacuo to give 3 as a white solid. This product is of sufficient purity (> 95% by 1 H NMR spectroscopy) to be used directly in the final amine coupling step. H-NMR (300 MHz, DMSO-de): d 1.12 (m, 4H, cyclopropyl CH2), 3.85 (m, 1H, cyclopropyl CH), 4.01 (d, JH-F = 1.5 Hz, 3H, OCH3), 7.85 ( dd, JH- F = 11.0 Hz, 9.0 Hz, 1H, aromatic). 19F. { 1 HOUR} NMR (282 MHz, DMSO-d6): d -146.4 (d, JF-F = 23.0 Hz, 1F), -140.2 (d, JF-F = 23.0 Hz, 1F). LCMS m / z calculated for C? 4H10F2N2O3S 324 ([M +]); found 325 ([M + H] +). EXAMPLE 4. SYNTHESIS OF 9-CICLOPROPI L-7-FLUORO-8-METOXY-9H-ISOTIAZOLO [5,4-B] QUINOLINE-3,4-DIO A (4) 9-cyclopropyl-7-fluoro-8- was prepared methoxy-9H-isothiazolo [5,4-b] quinoline-3,4-dione (4) according to the following synthetic scheme.

M Stage 1. Synthesis of 2,4-difluoro-3-methoxybenzoic acid (G). Lithium diisopropylamide (LDA) was formed by the dropwise addition of n-butyllithium (1.6 M in hexanes, 39 mL, 62 mmol) to a stirred solution of diisopropylamine (9.1 mL, 65 mmol) in tetrahydrofuran (120 mL). at -78 ° C. The resulting solution was stirred at -78 ° C for 5 minutes, -20 ° C for 15 minutes, and then cooled again to -78 ° C. This solution of LDA was added dropwise to a cooled solution (-78 ° C) of 1,3-difluoro- 2-methoxybenzene (7.15 g, 50 mmol) in tetrahydrofuran (150 mL) over a period of 30 minutes. The reaction mixture was allowed to warm to -20 ° C, was cooled to -78 ° C, and was bubbled with carbon dioxide gas for -30 minutes. The resulting mixture was acidified to pH ~ 2 by the addition of a 2 M aqueous solution of hydrochloric acid, and the product was extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, and evaporated under reduced pressure. The remaining residue was suspended in water (80 mL). The residue was dissolved once the solution was adjusted to pH ~ 9 via the addition of a 2 M aqueous solution of sodium hydroxide. This solution was washed with diethyl ether (2 x 30 mL) and acidified slowly to pH ~ 2 by the addition of a 2 M aqueous solution of hydrochloric acid. The product was extracted with ethyl acetate (2 x 200 mL), and the combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give G as a pale yellow solid. . This product is used directly in the next synthetic stage. 1 H NMR (300 MHz, DMSO-d 6) d 3.93 (s, 3 H, OCH 3), 7.24 (ddd, JH-F = 10.5 Hz, JH-H = 9.0 Hz, JH-F = 2.0 Hz, 1H, H-5 aromatic), 7.62 (ddd, JH-H = 9.0 Hz, JH-F = 8.0 Hz, JH-F 6.0 Hz, 1H, aromatic H-6). Step 2. Synthesis of 2,4-difluoro-3-methoxybenzoyl chloride (H).

A mixture of 2,4-difluoro-3-methoxybenzoic acid (2.1 g, 11. 1 mmol), thionyl chloride (5 mL), and ethyl acetate (30 mL) were refluxed for 4 hours. All volatile materials were removed in vacuo, and the remaining residue is used directly in the next synthetic step. Step 3. Synthesis of (Z) -ethyl-3-hydroxy-3- (2,4-difluoro-3-methoxyphenyl) acrylate (I). Compound I was prepared using the general method of Wierenga and Skulnick (Wierenga, W .; Skulnick, H. I. J. Org. Chem. 1979, 44, 310-311). N-Butyllithium (1.6 M in hexanes) was added to a cooled solution (-78 ° C) of tetrahydrofuran (50 mL) containing ethyl hydrogen malonate (2.6 mL, 22 mmol) and 2,2'-bipyridyl (~ 1 mg as indicator). The temperature of the reaction mixture was allowed to rise to approx. -5 ° C during the addition of n-butyl-lithium. Sufficient n-butyl lithium (30 mL, 48 mmol) was added until a pink color persisted at -5 ° C for 5-10 minutes. A solution of 2,4-difluoro-3-methoxybenzoyl chloride (H) (11.1 mmol, vide supra) in tetrahydrofuran (10 mL) was added in one portion to the reaction mixture which has been re-cooled to -78 ° C. The resulting mixture was allowed to warm to room temperature, diluted with ethyl acetate (100 mL), and warmed with a 1 M aqueous solution of hydrochloric acid. The organic layer was washed with a 5% aqueous solution of sodium bicarbonate (2 x 80 mL), followed by brine (2 x 80 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product. This material was purified by flash column chromatography (eluting with 20% ethyl acetate in hexanes v / v) to give pure I as a white solid. 1 H NMR (300 MHz, CDCl 3): (keto, predominant tautomer, -80%) d 1.20 (t, JH-H = 7.0 Hz, 3H, CO2CH2CH3), 3.88 (d, JH-F = 4.0 Hz, 2H, CH2CO2CH2CH3 ), 3.98 (apparent t, JH-F = 1.0 Hz, 3H, OCH3), 4.15 (q, JH-H = 7.0 Hz, 2H, CO2CH2CH3), 6.92 (ddd, JH-F = 11.0 Hz, JH-H = 9.0 Hz, JH-F = 2.0 Hz, 1H, aromatic H-5), 7.57 (ddd, JH- = 9.0 Hz, JH-F = 7.5 Hz, JH-F = 6.0 Hz, 1H, aromatic H-6). LCMS m / z calculated for C? 2 H12F2O4258 ([M +]); Found 259 ([M + H] +). Step 4. Synthesis of 2 - ((Z) -N-cyclopropyl (methylthio) carboni midoyl) -3-hydroxy-3- (2,4-dif-uoro-3-methoxyphenyl) acrylate of (E) -ethyl (J ). - Sodium hydride (60% in mineral oil, 212 mg, 5.31 mmol) was added in portions to a cooled solution (0 ° C) containing I (1.28 g, 4.96 mmol), cyclopropyl isothiocyanate (781 μL, 8.43 mmol ), and dimethylformamide (13 mL). The resulting mixture was allowed to warm to room temperature with stirring overnight (18 hours). Methyl iodide (525 μL, 8.43 mmol) was added to the resulting solution and stirred for an additional 4 hours (until TLC indicated full consumption of I). The reaction mixture was diluted with ethyl acetate (250 mL) and warmed by addition of a saturated aqueous solution of ammonium chloride (75 mL). The Organic layer was washed with brine (4 x 100 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product. This material was purified by flash column chromatography (eluting with 40% ethyl acetate in hexanes v / v) to give J as a yellow oil. 1 H NMR (300 MHz, CDCl 3): d 0.80-1.01 (m, 7H), 2.52 (s, 3H, SCH 3), 3.02 (m, 1H, cyclopropyl CH), 3.91 (q, JH-H = 7.5 Hz, 2H , CO2CH2CH3), 3.97 (s, 3H, OCH3), 6.88 (ddd, JH-F = 10.0 HZ, JH-H = 9.0 Hz, JH-F = 1.5 Hz, 1H, aromatic H-5), 7.07 (ddd, JH-H = 9.0 Hz, JH-F = 7.0 Hz, JH-F = 6.0 Hz, 1H, aromatic H-6), 11.78 (s, 1H, OH). 19F. { 1 HOUR} NMR (282 MHz, CDCl 3): d -130.8 (d, JF-F = 10.5 Hz, 1F), -126.8 (d, JF-F = 10.5 Hz, 1F), LCMS m / z calculated for C17H19F2NO4S 371 ([M +]): found 372 ([M + H] +). Step 5. Synthesis of 1-cyclopropyl-7-fluoro-8-methoxy-2- (methylthio) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (K). Hydrup sodium (60% in mineral oil, 142 mg, 3.54 mmol) was added portionwise to a solution of J (1.25 g, 3.37 mmol) in dimethylformamide (18 mL) at room temperature. The reaction mixture was heated at 75 ° C for 18 hours (until the TLC indicated full consumption of J), cooled to room temperature, and warmed by the addition of a saturated aqueous solution of ammonium chloride (20 mL ). The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine (4 x 50 mL), dried over sodium sulfate, and evaporated under reduced pressure to give crude K as a pale yellow oil. This product is of sufficient purity (> 95% by NMR spectroscopy) to be used directly in the next synthetic step. 1 H NMR (300 MHz, CDCl 3): d 0.72 (m, 2H, cyclopropyl CH 2), 1.17 (m, 2H, cyclopropyl CH 2), 1.38 (t, JH-H = 7.0 Hz, 3H, CO2CH 2 CH 3), 2.62 (s, 3H, SCH3), 3.75 (m, 1H, cyclopropyl CH), 4.00 (d, JH-F = 2.0 Hz, 3H, OCH3), 4.39 (q, JH-H = 7.0 Hz, 2H, CO2CH2CH3), 7.12 (dd , JH-F = 11 0 Hz, JH-H = 9.0 Hz, 1H, aromatic H-6), 7.95 (dd, JH-H = 9.0 Hz, JH-F = 6.0 Hz, 1H, aromatic H-5). 19F. { 1 HOUR} NMR (282 MHz, CDCl 3): d -123.7 (s, 1F). LCMS m / z calculated for C17H? 8FNO4S 351 ([M +]): found 352 ([M + H] +). Step 6. Synthesis of 1-cyclopropyl-7-fluoro-8-methoxy-2- (methylsulfonyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (L). A portion of m-chloroperoxybenzoic acid (5.77%, 527 mg, 2.35 mmol) was added to a cooled solution (-5 ° C) of K (0.75 g, 2.14 mmol) in methylene chloride (20 mL). The reaction mixture was stirred at 0 ° C for 2.5 hours, diluted with ethyl acetate (100 mL), and washed with a 5% aqueous solution of sodium bicarbonate (2 x 30 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the crude product. This material was purified by flash column chromatography (eluting with 5% chloroform in ethyl acetate v / v) to give pure L as a solid yellow. 1 H NMR (300 MHz, CDCl 3): d 0.60 (m, 1H, cyclopropyl CH 2), 0.99 (m, 1H, cyclopropyl CH 2), 1.11 (m, 1H, cyclopropyl CH 2), 1.26 (m, 1H, cyclopropyl CH 2), 1.35 (t, JH-H = 7.5 Hz, 3H, CO2CH2CH3), 3.19 (s, 3? S (O) CH3), 3.81 (m, 1H, cyclopropyl CH), 4.00 (d, JH-F = 2.0 Hz , 3H, OCH3), 4.37 (m, 2H, CO2CH2CH3), 7.15 (dd, JH-F = 10.5 Hz, JH-H = 9.0 Hz, 1H, aromatic H-6), 7.93 (dd, JH-H = 9.0 Hz, JH-F = 6.0 Hz, 1H, aromatic H-5). 19F. { 1 HOUR} NMR (282 MHz, CDCl 3): d -122.1 (s). LCMS m / z calculated for C17H18FNO5S 367 ([M +]): found 368 ([M + H] +). Step 7. Synthesis of ethyl 1-cyclopropyl-7-fluoro-2-mercapto-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (M). Anhydrous sodium hydrogen sulfide (Alfa Aesar, 137 mg, 2.45 mmol) was added in one portion to a solution of dimethylformamide (10 mL) containing L (600 mg, 1.63 mmol) at -5 ° C. The reaction mixture was stirred for 15 minutes (until TLC indicated full consumption of L) and allowed to warm to room temperature. The reaction mixture was quenched by the addition of a 5% aqueous solution of hydrochloric acid (75 mL) and exted with ethyl acetate (2 x 100 mL). The combined organic exts were washed with brine (4 x 75 mL), dried over sodium sulfate, and evaporated to dryness under reduced pressure to give crude M (> -90% purity by LC-MS). This material is used directly in the next synthetic stage to prevent its degradation oxidative LCMS m / z calculated for C16H16FNO S 337 ([M +]); found 338 ([M + H] +). Synthesis of 9-cycle ropil-7-fluoro-8-methoxyisothiazolo [5,4-b] quinolin-3,4 (2H, 9H) -dione (4). A solution of sodium bicarbonate (1.3 g, 15.47 mmol) in water (22 mL) was added to a solution of M (540 mg, 1.60 mmol) in teydrofuran (16 mL) at room temperature. Hydroxylamine-O-sulfonic acid (761 mg, 6.73 mmol) was added in one portion to this mixture. The reaction mixture was stirred at room temperature for -3 hours and warmed by the addition of an aqueous solution of 5% hydrochloric acid (150 mL). The precipitate that formed was collected by filion, washed with water (3 x 10 mL), and dried in vacuo to give 4 as a white solid. This product is of sufficient purity (> 95% by 1 H NMR spectroscopy) to be used directly in the final amine coupling step. 1 H NMR (300 MHz, DMSO-d 6): d 1.11 (m, 2H, cyclopropyl CH 2), 1.26 (m, 2H, cyclopropyl CH 2), 3.92 (m, 1H, cyclopropyl CH), 4.00 (d, JH-F = 1.5 Hz, 3H, OCH3), 7.43 (dd, JH-F = 10.5 Hz, JH-H = 9.0 Hz, 1H, aromatic H-6), 8.06 (dd, JH-H = 9.0 Hz, JH-F = 6.0 Hz, 1H, aromatic H-5). 19F. { 1 HOUR} NMR (282 MHz, CDCl 3): d -119.1 (s). LCMS m / z calculated for C 14 HnFN 2 O 3 S 306 ([M +]); found 307 ([M + H] +). EXAMPLE 5. SYNTHESIS OF 1 -METÍ L-1 -Pl RROLI DIN-3-ILETILAMINE (5) 1-Methyl-1-pyrrolidin-3-yl-ethylamine was prepared according to the following synthetic scheme.

OR Step 1. Synthesis of methansulfonate (S) -1-benzylpyrrolidin-3-yl (N). Methanesulfonyl chloride (15 mL, 0.19 mol) was added to a cooled (0 ° C) solution of toluene (300 mL) containing (S) -1-benzylpyrrolidin-3-ol (24.5 g, 0.14 mol) and triethylamine ( 80 mL, 0.57 mol). The resulting mixture was stirred at 0 ° C for 15 minutes, and allowed to warm to room temperature with stirring for 2 hours. The mixture was warmed with a 5% aqueous solution of sodium bicarbonate (250 mL). The organic layer was washed with a 5% aqueous solution of sodium bicarbonate (2 x 250 mL), washed with water (1 x 250 mL), dried over magnesium sulfate, and concened under reduced pressure to give N. (35.1 g, 99%) as an orange oil. 1 H NMR (300 MHz, CDCl 3): d 2.07 (m, 1 H), 2.30 (m, 1 H), 2.49 (m, 1 H), 2.75-2.90 (m, 3 H), 2.98 (s, 3 H), 3.61 (d , J = 13.0 Hz, 1H), 3.68 (d, J = 13.0 Hz, 1H), 5.18 (m, 1H), 7.15-7.30 (m, 5H). LCMS m / z calculated for C12H17NO3S 255 ([M +]); found 256 ([M + H] p 100%), 160 (40%). Stages 2 and 3. Synthesis of (R) -1-benzylpyrrolidine-3-carbonitrile (O) and 2 - ((R) -1-benzylpyrrolidin-3-yl) propan-2-amine (P). The synthesis of O and P are previously described by Fedij er al. (Fedij, V, Lenoir, E.A., III, Suto, M.J., Zeller, J.R., Wemple, J. Tetrahedron: Asymmetry 1994, 5, 1131-1134). Step 4. Synthesis of 1 - ((R) -Methyl-1-pyrrolidin-3-yl) -ethylamine (5).

A mixture containing P (7.4 g), 20% palladium hydroxide on carbon (7.5 g), and ethanol (75 ml) was stirred under an atmosphere of hydrogen gas (50 psi) at 45 ° C for 24 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 5 (4.1 g, 95%) as a yellow oil. This material was stored under an argon gas atmosphere. 1 H NMR (300 MHz, CDCl 3): d 1.09 (s, 6H), 1.51 (m, 1H), 1.64 (br s, 3H), 1.81 (m, 1H), 2.06 (apparent pente, J = 8.5 Hz, 1H ), 2.69 (dd, J = 11.0 Hz, J = 8.5 Hz, 1H), 2.94 (m, 2H), 3.00 (dd, J = 11.0 Hz, J = 8.5 Hz, 1H). LCMS m / z calculated for C7H16N2 128 ([M +]); Found 129 ([M + H] +, 60%), 112 (100%). EXAMPLE 6. GENERAL METHOD FOR THE FINAL AMINA COUPLING STAGE: SYNTHESIS OF CHLORHYDRATE OF 7 - ((R) -3- (2-AMI NOPROPAN-2-IL) PIRROLIDIN-1-IL) -9-CICLOPROPYL-6-FLUORO-8-METHOXYISOTIAZOLO [5,4-B] QUINOLIN-3, 4 (2H, 9H) -DIONA 7 - ((R) -3- (2-Aminopropan-2-yl) pyrrolidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo hydrochloride [5] was prepared. ,4- b] quinolin-3,4 (2H, 9H) -dione according to the following synthetic scheme.

Synthesis of 7 - ((R) -3- (2-aminopropan-2-yl) pyrrolidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinolin-3 hydrochloride , 4 (2H, 9H) -dione (6). Under an argon atmosphere, a reaction vessel was charged with 5 (206.0 mg, 1.6 mmol), 3 (328.6 mg, 1.0 mmol), dimethyl sulfoxide (4.5 mL), and N, N-diisopropylethylamine (750 μL, 4.3 mmol). The resulting mixture was irradiated with microwaves (CEM Disover) at 125 ° C for 1 hour (conventional heating can also be used - 115 ° C in an oil bath for 14 hours), allowed to cool, and evaporated to dryness under reduced pressure (~ 70 ° C / 2-3 mm Hg). The oily residue was triturated with ethyl acetate (15 mL) and the resulting powder was collected by centrifugation. This solid was purified using preparative HPLC to give the desired product. Preparative HPLC was performed using a YMC Pack Pro C18 150 x 30 mm 5 μm column coupled with a 50 x 20 mm 5 μm YMC Pack Pro column with a Socratic elution from 0.37 minutes to 95: 5 H2O: CH3CN which It contains 0.1% TFA followed by a linear gradient elution of 15.94 minutes of 95: 5 to 25:75, followed by a linear gradient of 0.69 minutes from 25:75 to 5:95 at a flow rate of 30.0 mL / min., With UV detection at 254. The raw material was loaded as a solution containing acetic acid (-2 mL), methanol (~ 1 mL), and water (-1 mL). The purified product was isolated as the TFA salt and converted to the corresponding hydrochloride salt by the addition of a solution of hydrogen chloride (-1.25 M in methanol) followed by evaporation; this process was repeated twice to give a yellow solid. The purity of HPLC: > 99%; tR = 10.08 min. 1 H-NMR (300 MHz, TFA-d): d 1.28 (m, 2 H), 1.53 (m, 2 H), 1.66 (s, 6 H), 2.43 (m, 1 H), 2.57 (m, 1 H), 3.35 (m , 1H), 3.97 (s, 3H), 4.01-4.38 (m, 5H), 8.17 (d, J = 12.0 Hz, 1H, aromatic). 19F. { 1 HOUR} (282 MHz, TFA-d): d - 118.0 (s). 13C. { 1 HOUR} (75 MHz, TFA-d): d 13.5, 13.9, 25.0, 25.1, 29.1, 39.7, 49.6, 59.4 (br, W1 / 2 * 14 Hz), 59.8 (br, W1 / 2 «14 Hz), 60.0, 66.8, 106.0, 112.1 (d JC-F = 23.0 Hz), 137.5 (br m, W1 / 2 «24 Hz), 138.4, 144.8 (br, W1 / 2» 10 Hz), 155.3 (d Jc-F = 255.0 Hz), 169.8-, 170.1, 171.5 (br, W? «9 Hz). LCMS m / z calculated for C 21 H 25 FN 4 O 3 S 432 ([M +]); found 433 ([M + H] +). Analysis Calculated for C 21 H 25 FN 4 O 3 S-l 5 H C M 5 H 2 O: C, 49.05; H, 5.78; N, 10.90; Cl, 10.34. Found: C, 49.30; H, 5.60; N, 10.83; Cl, 10.00. EXAMPLE 7. SYNTHESIS OF 7 - ((R) -3- (2-AMINOPROPAN-2-IL) PYRROLIDIN-1-IL) -9-CICLOPROPIL-8-METHODOXYISOTIAZOLO [5,4-B] QUINOLIN-3 SYNTHESIS OF CHLORHYDRATE 4 (2H, 9H) -DIONA 7 - ((R) -3- (2-aminopropan-2-hydrochloride was prepared il) pyrrolidin-1-yl) -9-cyclopropyl-8-methoxyisothiazolo [5,4-b] quinolin-3,4 (2H, 9H) -dione (7) via the process described above in Example 6 for 6 using 4 as starting material. Purity by HPLC: > 99% 1 H-NMR (300 MHz, DMSO-de): d 0.92 (m, 2 H), 1.34 (m, 2 H), 1.33 (s, 6 H), 1.84 (m, 1 H), 2.05 (m, 1 H), 2.55 (m , 1H), 3.44 (m, 2H), 3.49 (s, 3H), 3.55 (m, 2H), 3.78 (m, 1H), 6.86 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H). LCMS m / z calculated for C 21 H 26 N 4 O 3 S 414 ([M +]); found 415 ([M + H] +).

Synthesis of 7 - ((R) -3- (2-aminopropan-2-yl) pyrrolidin-1-yl) -9-cyclopropyl-6-fluoro isothiazolo [5,4-b] quinol i n-3 hydrochloride, 4 (2H, 9H) -dione (8). 7 - ((R) -3- (2-aminopropan-2-yl) pyrrolidin-1-yl) -9-cyclopropyl-6-fluoroisothiazolo hydrochloride [5,4-b] was prepared. ] quinolin-3,4 (2H, 9H) -dione via the procedure described above in Example 6 for 6 using 2 as the starting material. Purity by HPLC: > 98%. 1 H NMR (300 MHz, DMSO-d 6) / acetic acid-d 4 (-10: 1 v / v)): d 1.15 (m, 2H), 1.30 (s, 6H), 1.33 (m, 2H), 1.84 ( m, 1H), 2.04 (m, 1H), 2.54 (m, 1H), 3.32-3.71 (m, 5H), 6.89 (d, JH- = 7.5 Hz, 1H), 7.60 (d, JH-f = 14.0 Hz, 1H). 19F. { 1 HOUR} (282 MHz, DMSO-d6) / aetic acid-d4 (-10: 1 v / v)): d - 131. 8 (s). LCMS m / z calculated for C20H23FN4O2S 401 ([M +]); found 403 ([M + H] +).

Synthesis of 7 - ((R) -3- (2-aminopropan-2-yl) pyrrolidin-1-yl) -9-cyclopropyl-6-fluoroisothiazolo [5,4-b] [1,8] naphthyridine- hydrochloride 3.4 (2H, 9H) -dione (9). 7 - ((R) -3- (2-aminopropan-2-yl) pyr rolidin-1-yl) -9-cyclopropyl-6-fluoro isothiazolo hydrochloride [5, 4-b] [1, 8] Naphthyridine-3,4 (2H, 9H) -dione via the procedure described above in Example 6 for 6 using 1 as starting material. Purity by HPLC: > 98%. 1 H NMR (300 MHz, DMSO-d 6) / acetic acid-d 4 (-10: 1 v / v)): d 1.11 (m, 2 H), 1.20 (m, 2 H), 1.28 (m, 6 H), 1.82 ( m, 1H), 2.02 (m, 1H), 2.48 (m, 1H), 3.27 (m, 1H), 3.51 (m, 1H), 3.64 (m, 1H), 3.93 (m, 2H), 7.82 (d , JH-F = 13.0 Hz, 1H). 19F. { 1 HOUR} (282 MHz, DMSO-d6) / acetic acid-d4 (-10: 1 v / v)): d-139.8 (s). LCMS m / z calculated for C19H22FN5O2S 403 ([M +]); found 404 ([M + H] +).

Synthesis of 1 - ((R) -pyrrolidin-3-yl) cyclopropanamine (10). 1 - ((R) -pyrrolidin-3-yl) -cyclopropanamine (10) was prepared using the method of Inagaki et al. (Inagaki, H., Miyauchi, S., Miyauchi, RN, Kawato, H. C, Ohki, H., Matsuhashi, N., Kawakami, K., Takahashi, H., Takemura, MJ Med. Chem. 2003, 46, 1005-1015).

Synthesis of 7 - ((R) -3- (1-aminociclopropyl) pyrrolidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H) hydrochloride , 9H) -dione (11). 7 - ((R) -3- (1-Aminocyclopropyl) pyrrolidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H hydrochloride was prepared , 9H) -dione (11) via the procedure described above in Example 6 for 6 using 10 as starting material. Purity by HPLC: > 98%. 1 H NMR (300 MHz, CD3OD): d 1.02 (m, 6H), 1.26 (m, 2H), 1.74 (m, 1H), 2.16 (m, 1H), 2.70 (m, 1H), 3.60 (s, 3H ), 3.62 (m, 2H), 3.74 (m, 1H), 3.87 (m, 2H), 7.69 (d, JH-F = 14.0 Hz, 1H). 19F. { 1 HOUR} NMR (282 MHz, CD3OD): d-126.2. LCMS m / z calculated for C 21 H 23 FN 4 O 3 S 430 ([M +]); found 431 ([M + H] +).

Synthesis of 7 - ((R) -3- (1-aminociclopropyl) pyrrolidin-1-yl) -9-cyclopropyl-8-methoxyisothiazolo [5, 4-b] quinolin-3,4 (2H, 9H) hydrochloride - diona (12) 7 - ((R) -3- (1-Aminocyclopropyl) pyrrolidin-1-yl) -9-cyclopropyl-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) hydrochloride was prepared dione (12) via the procedure described above in Example 6 for 6 using 4 and 10 as starting materials. Purity by HPLC: > 98%. 1 H NMR (300 MHz, CD 3 OD): d 0.93 (m, 6 H), 1.18 (m, 2 H), 1.69 (m, 1 H), 2.10 (m, 1 H), 2.65 (m, 1 H), 3.32 (m, 1 H) ), 3.47 (s, 3H), 3.60 (m, 3H), 3.80 (m, 1H), 6.91 (d, JH-H = 9.0 Hz, 1H), 7.91 (d, JH-H = 9.0 Hz, 1H) . LCMS m / z calculated for C 21 H 24 N 4 O 3 S 412 ([M +]); found 413 ([M + H] +).

Synthesis of 9-cyclopropyl-6-fluoro-7- (octahydropyrrolo [3,4-b] iridin-6-yl) -8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) hydrochloride -diona (13). 9-Cyclopropyl-6-fluoro-7- (octahydropyrrolo [3,4-b] pyridin-6-yl) -8-methoxy-isothiazolo [5,4-b] quinoline-3,4 (2H, 9H) hydrochloride was prepared -dione (13) via the procedure described above in Example 6 for 6 using (rac) -cis-octahydropyrrolo [3,4-b] pyridine commercially available as Starting material. Purity by HPLC: > 98%. 1 H NMR (300 MHz, DMSO-de): d 1.13 (m, 2H, cyclopropyl CH2), 1.16 (m, 2H, cyclopropyl CH2), 1.78 (m, 4H), 2.54 (m, 1H), 2.89 (m, 1H), 3.17 (m, 1H), 3.56 (s, 3H, OCH3), 3.61-4.19 (m, 6H), 7.56 (d, JH-F = 13.5 Hz, 1H, aromatic). 19F. { 1 HOUR} NMR (282 MHz, DMSO-d6): d -125.3 (s). LCMS m / z calculated for C 21 H 23 FN 4 O 3 S 430 ([M +]); found 431 ([M + H] +).

Synthesis of 9-cyclopropyl-6-fluoro-7- (octahydro pyrro] [3,4-b] pyrid di n-6-yl) isothiazolo [5,4-b] quinoline-3,4 (2H, 9H ) -diona (14). 9-Cyclopropyl-6-fluoro-7- (octahydropyrrolo [3,4-b] pyridin-6-yl) -isothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione hydrochloride was prepared (14) via the procedure described above in Example 6 for 6 using 2 and (rac) -cis-octahydropyrrolo [3,4-b] pyridine commercially available as starting materials. Purity by HPLC: > 98%. 1 H NMR (300 MHz, CD3OD): d 1.22 (m, 4H, cyclopropyl CH2), 1.81 (m, 4H), 2.89 (m, 3H), 3.20 (m, 1H), 3.63 (m, 2H), 3.89 ( m, 3H), 6.75 (br, 1H, aromatic H-8), 7.44 (d, JH-F = 14.0 Hz, 1H, aromatic H-6). 19F. { 1 HOUR} NMR (282 MHz, CD3OD): d-132.2 (s). LCMS m / z calculated for C20H21FN4O2S 400 ([M +]); found 401 ([M + H] +).

Synthesis of 9-cyclopropyl-6-fluoro-7- (octahydropyrrolo [3,4-b] pyridin-6-yl) isothiazolo [5,4-b] [1,8] naphthyridine-3,4 (2H, hydrochloride 9H) -dione (15). 9-Cyclopropyl-6-fluoro-7- (octahydropyrrolo [3,4-b] pyridin-6-yl) -isothiazolo [5,4-b] [1, 8] naphthyridine-3,4 (2H hydrochloride was prepared , 9H) -dione (15) via the procedure described above in Example 6 for 6 using 1 and (rac) -cis-octahydropyrrolo [3,4-b] pyridine commercially available as starting materials. Purity by HPLC: > _98%. 1 H NMR (300 MHz, DMSO-d 6): (data selected) d 7.58 (br, aromatic). 19F. { 1 HOUR} NMR (282 MHz, DMSO-d6): d-140.5 (br). LCMS m / z calculated for d9H20FN5O2S 401 ([M +]); found 402 ([M + H] +).

Synthesis of 9-cyclopropyl-6-fluoro-7 - ((4aS, 7aS) -octahydropyrrolo [3,4-b] pyridin-6-yl) -8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione (16). 9-Cyclopropyl-6-fluoro-7 - ((4aS, 7aS) -octahydropyrrolo [3,4-b] pyridin-6-yl) -8-methoxyisothiazolo [5,4-b] quinolin-3 hydrochloride was prepared, 4 (2H, 9H) -dione (16) via the procedure described above in Example 6 for 6 using 3 and (4aS, 7aS) -octahydro-1 H -pyrrolo [3,4-b] pyridine as starting materials. MW 430,496.

EXAMPLE 8. Additional 9H-Isocyanol [5,4-B] QUINOLIN-3,4-DIONAI AND RELATED COMPOUNDS Additional compounds of Formula I and II prepared by the methods exemplified in Examples 1 to 7 in TABLE II are described.

Ul O Ul l TABLE II OO CD Ul O l Ul Ul O Ul Ul ? o? o Ul or Ul Ul ? to ro ro Ul or Ul Ul Ul n Ul co -vi ro ro Ul o n n ro ro Ul or Ul n CO CD d - 4- * O 124.76 ro or ro ro n o in Ul ro ro Ui or Ul u? ro 10 n o in Ul ro 10 Ul or in Ul 00 Ro Ro n Ul Ul in or ro Ul or n u? Ul Ul ro ro ro in or in ? o ro on or in Ul faith. ro ro Ul s in Ul CJ1 in ro ro Ul or Ul Ul EXAMPLE 9. ANTI MICROBIAL ACTIVITY OF COMPOUNDS The antimicrobial activity of the compounds of the invention can be evaluated by a variety of methods, including the following minimum visual inhibitory concentration (MIC) test. This assay determines the minimum concentration of compound required to inhibit the growth of a bacterial strain. TEST OF CONCENTRATION INHIBITORA MIMIMA (MIC) All the cellular antibacterial activity is determined by microdilution of the broth using conditions recommended by the NCCLS (see the National Committee for Clinical Laboratory Standards 2001. Standards of performance for susceptible antimicrobial tests: 11th informational supplement. Vol. 21, do not. 1, M100-S11. National Committee for Clinical Laboratory Standards, Wayne, PA). The test compounds are dissolved in DMSO and diluted 1:50 in Mueller-Hinton broth (Becton-Dickinson) to produce a stock solution of 256 μg / ml. In a 96-well microtiter plate, the solution of the compound is twice serially diluted in Mueller-Hinton broth. After the compounds were diluted, an aliquot of 50 μl of the test organism (~ 1 x 106 cfu / mL) was added to each well of the microtiter plate. The final test concentrations vary from 0.125-128 μg / mL. The inoculated plates were incubated in ambient air at 37 ° C for 18 to 24 hours. Organisms are selected from the test included in the laboratory strains S. aureus ATCC 29213 and E. coli ATCC 25922 (strains acquired from American Type Culture Collection, Manassas, VA), S. aureus FQR700699, and Paeruginosa 27853. The minimum inhibitory concentration (MIC) was determined as the lowest concentration of the compound that inhibits the visible growth of the test organism Compounds 17-46, 49, 52-113 were tested in this assay for anti-activity. microbial against S. aureus Certain of these compounds have an MIC value of 0.1 microgram / ml or lower against S. aureus, and certain of these compounds also have a MIC value of 0.01 microgram / ml against S. aureus when tested in this Testing Compounds 17, 20, 22, 38-46, 49, and 52-113 were tested in this assay for anti-microbial activity against Methicillin-Resistant S. aureus Compounds 42, 52-57, 59, 63, 66-67, 70-71, 73-77, 87-89, 92-95, 100, 102-103, 107-108, and 111-112 present MIC values of 1 microgram / ml or less against S. aureus Resistant to Methicillin Compounds 17-22, 26-46, 49, 52-58, 63, 67-68, 70-90, 93-95 and 100-106 were also tested in this trial for active anti-microbial ad against £. coli Compounds 17-22, 26-42, 44-46, 49, 52-58, 63, 67-68, 70-90, 93-95, 100-103, and 105-106 presented MIC values of 1 microgram / ml or lower against E. coli. EXAMPLE 10. COLORATION OF CELLULAR VIABILITY WITH BLUE ALAMAR To determine if the microcidal effect observed against S. aureus and E. coli is specific to bacterial cells, the compounds designed for cell viability effects in various types of human cells. Optimum cell density is first determined by coating cells in standard sterile 96-well plate tissue culture plates in 100 μl, 10% FBS media at six cell densities of 500 cells / well at 15,000 cells / well. A cell-free well containing only media is used as a control. The cells were incubated at 37 ° C in a 5% CO2 incubator for 24 hours. Then, 10% culture volume (10 ul) of Alamar Blue (Biosource, DAL1100, 100 mL) was added. The cells were incubated at 37 ° C in a 5% CO2 incubator and read on a Victor V plate reader, excitation at 544 nm, emission at 590 nm, at 3, 4 and 24 hours after the addition of Blue Alamar The cell number against the change in fluorescence was plotted to determine signal linearity versus cell number. The optimum density varies between 500-15,000 cells / well depending on the specific cell type. The optimum density is selected based on the highest number of cells that is still in the linear response range. Determination of Compound Cytotoxicity The cells were coated in optimal cell density in a standard 96-well sterile tissue culture plate and incubated at 37 ° C O / N in a 5% CO2 incubator. 12 to 48 hours post-coating media were removed. The cells were washed 1 or 2 times with 1X PBS and replaced with fresh media containing the test compound in 1% DMSO. From 24 to 72 hours after the addition of the compound, the media was removed, and the cells were washed 1 to 2 times with 1X PBS. Then, fresh media containing 1/10 volume of Alamar Blue was added. The plates were incubated for 4 hours at 37 ° C in a 5% CO2 incubator and read on a Victor V plate reader, excitation at 544 nm, emission at 590 nm. Compounds were diluted at 20 micromolar in 1% DMSO and media and projected in duplicate to obtain simple concentration cytotoxicity data. Eight concentration points from 0.78 micromolar to 100 micromolar, duplicate assays, were used to determine CC50 cytotoxicity values. Cells were used with 1% DMSO and media as a negative control, compounds having a known CC50 against a particular cell type were used as positive controls. The change in fluorescence against the concentration of the test compound was plotted to determine the cytotoxicity of the compound. Conditions of sample media, optimal coating densities, and positive control compounds for two projected cell types are presented in Table III. Certain compounds described in Examples 1 to 8 present CC50 values greater than 10 uM against each of the cell lines listed below. Other cell types that can be used include but are not limited to Balb / 3TC, CEM-SS, HeLa, Hep2, HepG2, HT-29, MRC-5, SK-N-SH, U-87 MG, 293T, and Huh -7. More preferred compounds with a CC50 value greater than 50 uM. They are highly preferred compounds with a CC50 value greater than 100 uM. TABLE III

Claims (30)

1. CLAIMS A compound of Formula A
2. Formula A or a tautomer of Formula B
3. Formula B or a pharmaceutically acceptable salt of Formula A or
4. Formula B, characterized in that R3 is hydrogen, d-C6 alkyl, or C2-C6 alkanoyl; R5 is hydrogen, hydroxy, amino, C1-C2 alkyl, Ci- C2 alkoxy, mono- or di- (C? -C) alkyl amino, or mono- or dialkylhydrazinyl of C? -C4; R6 is hydrogen, halogen, or amino; R7 is a nitrogen-linked heterocycloalkyl group, having 4 to 8 ring members, including 0, 1 or 2 additional ring heteroatoms independently chosen from N, O and S, or R7 is a C? -C alkylamino linked to nitrogen substituted with a 5 or 6 membered heteroaryl group having 1 or 2 independently selected heteroatoms of N, O and S, or substituted with a heterocycloalkyl group, having 4 to 8 members in the ring, including 1 or 2 heteroatoms in the ring independently chosen from N, O, and S; R7 is a heterocycloalkyl or heterocycloalkenyl group attached to nitrogen, each of which has 4 to 8 members in the ring, including 0, 1 or 2 additional ring heteroatoms independently chosen from N, O and S, forming part of a system bicyclic with a 3 to 8 membered cycloalkyl or heterocycloalkyl ring in fused or spiro orientation, R7 is a 6 membered heterocycloalkyl group attached to nitrogen, 0, 1 or 2 additional ring heteroatoms independently chosen from N, O and S, and bridged with a methylene or ethylene bridge; each of R7 is substituted with 0 or 1 or more independently chosen substituents of (a) and 0 or 1 substituents chosen from (b); wherein (a) is chosen from halogen, hydroxy, amino, nitro, C 1 -C 4 alkyl, C 1 -C alkoxy, d-C 2 haloalkyl, and C 2 -C 2 haloalkoxy, (b) is oxo, amino, cyano, hydroxy-C1-C4 alkyl, amino-C1-C4 alkyl, C12-C6 alkylthio, C2-C6 alkanoyl, (mono- or di-C1-C alkyl) amino-C0-C4 alkyl , (C3-C7 cycloalkyl) C0-C alkyl, (C3-C7 cycloalkylamino) C0-C alkyl, (C3-C7 cycloalkyl) (C? -C4 alkyl) amino-C0-C alkyl, (heterocycloalkyl) C0-C alkyl, or (aryl) C0-C alkyl, wherein each of (b) other than oxo and cyano are substituted with 0 to 2 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH, -CONH2, alkyl of C1-C4, C2-C4 alkenyl, C2-C4 alkynyl, mono- and di- (C? -C) alkylamino, dC? haloalkyl, and Ct-C2 haloalkoxy; R9 is C? -C alkyl, cyclopropyl, or phenyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, C -? - C2 alkyl, C1-C2 alkoxy, mono - and di-alkylamino of C? -C2, haloalkyl of C1-C2, and haloalkoxy of d-C2. 2. A compound or salt according to claim 1, characterized in that it is of Formula A. 3. A compound or salt according to claim 1, characterized in that R5 is hydrogen, amino, mono- or di-alkylamino of C ? -C2, or C1- C2 mono- or di-alkylhydrazinyl. 4. A compound or salt according to claim 3, characterized in that R5 is hydrogen.
5. 5. A compound according to claim 4, characterized in that R6 is fluoro or hydrogen.
6. 6. A compound or salt according to claim 5, characterized in that R6 is fluoro.
7. 7. A compound or salt in accordance with claim 5, characterized in that R7 is a heterocycloalkyl group attached to nitrogen, having from 4 to 8 members in the ring, including 0, 1 or 2 additional heteroatoms in the ring independently chosen from N, O and S, of which heterocycloalkyl, wherein R7 is substituted with 0 or 1 or more independently chosen substituents of (a) and 0 or 1 substituents chosen from (b); wherein (a) is chosen from halogen, hydroxy, amino, nitro, C1-C alkyl, C1-C4 alkoxy, C1-C2 haloalkyl, and Ci- C2 haloalkoxy, (b) is oxo, amino, cyano , hydroxy-C 1 -C 4 alkyl, amino C 1 -C alkyl, C 1 -C 6 alkylthio, C 2 -C 6 affinyl, (C 1 -C 4 mono- or di-alkyl) C 1 -C 4 amino-alkyl -C, (C3-C7 cycloalkyl) C0-C4 alkyl, (C3-C cycloalkylamino) C0-C alkyl, (C3-C7 cycloalkyl) (C? -C4 alkyl) amino- C0- alkyl C, (heterocycloalkyl) Co-C alkyl, or (aryl) C0-C4 alkyl, wherein each of (b) other than oxo and cyano is substituted with 0 to 2 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH, - CONH2, alkyl of C1-C4, C2-C4 alkenyl, C2-C4 alkynyl, mono- and d- (C6-4 alkyl) amino, C1-C2 haloalkyl, and d-C2 haloalkoxy.
8. 8. A compound or salt in accordance with claim 7, characterized in that R7 is a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or azepanyl group substituted with 0 to 2 independently chosen substituents of one or more of (a) and 0 or 1 substituents (b).
9. 9. A compound or salt according to claim 8, characterized in that R7 is a pyrrolidinyl group, which is substituted with 0 to 2 independently chosen substituents of one or more of (a) and 0 or 1 substituents (b).
10. 10. A compound or salt according to claim 9, characterized in that R7 is a pyrrolidinyl group substituted with a group (b) and optionally substituted with 1 methyl or halogen substituent wherein (b) is oxo, amino, cyano, hydroxyalkyl of C? -C4, amino-C? -C4 alkyl, C2-C4 alkanoyl, (C? -C4 mono- or di-alkyl) C0-C amino, (C3-C7 cycloalkyl) alkyl of C0-C2 substituted with amino, (C3-C7 cycloalkylamino) C0-C4 alkyl, or (C3-C7 cycloalkyl) (d-C4 alkyl) aminoCo-C4 alkyl.
11. 11. A compound or salt according to claim 6, characterized in that R is a group of the formula ^ * N X r iß where R is 0 or 1 or more substituents selected from amino, hydroxy, chloro, fluoro, methyl, methoxy, trifluoromethyl, and trifluoromethoxy.
12. 12. A compound or salt according to claim 11, characterized in that R15 is oxo, amino, cyano, hydroxyC1-C4 alkyl, amino-d-C4 alkyl, C2-C4 alkanoyl, (mono- or di-alkylamino of d-C4) C0-C4 alkyl, (C3-C7 cycloalkyl) alkyl of C0-C2 substituted with amino, (C3-C7 cycloalkylamino) C0-C alkyl, or (C3-C cycloalkyl) (C? -C alkyl) amino-C0-C4 alkyl.
13. 13. A compound or salt according to claim 11, characterized in that R15 is oxo, cyano, hydroxy-C1-C alkyl, amino-alkyl of d-C4, acetyl, (mono- or di-alkylamino of C? -C2) alkyl of C? -C, cyclopropyl substituted with amino, or (C3-C7 cycloalkylamino) C0-C4 alkyl; and Rie is 0 or 1 selected substituent of hydroxy, amino, chloro and methyl.
14. 14. A compound or salt according to claim 6, characterized in that R7 is
15. 15. A compound or salt according to claim 5, characterized in that R7 is a C? -C4 alkylamino bonded to the nitrogen substituted with a 5- or 6-membered heteroaryl group having 1 or 2 independently selected heteroatoms of N, O, and S , or substituted with a heterocycloalkyl group, having 4 to 8 members in the ring, including 1 or 2 heteroatoms in the independently chosen ring of N, O, and S; each of which R7 is substituted with 0 or 1 or more independently chosen substituents of (a) and 0 or 1 substituents chosen from (b).
16. 16. A compound or salt according to claim 15, characterized in that R7 is a C? -C alkylene substituted with a priridyl, pyrimidinyl, piperazinyl, piperidinyl or morpholinyl group, each of which is substituted with 0, 1 or 2 substituents independently chosen from halogen, hydroxy, amino, oxo, cyano, C? -C2 alkyl, C1-C2 alkoxy, C? -C2 haloalkyl and d-C2 haloalkoxy.
17. 17. A compound or salt according to claim 15, characterized in that R7 is a C? -C2 alkylamino substituted with a pyridyl, piperazinyl, piperidinyl, or morpholinyl group, each of which is substituted with 0, 1 or 2 substituents independently chosen from halogen, methyl and methoxy.
18. 18. A compound or salt according to claim 5, characterized in that R7 is a heterocycloalkyl or heterocycloalkenyl group attached to nitrogen, each of which has 4 to 8 members in the ring, including 0, 1 or 2 heteroatoms in the ring additional independently chosen N, O and S, forming part of a bicyclic system with a cycloalkyl or heterocycloalkyl ring of 3 to 8 members in fused or spiro orientation, each of R7 is substituted with 0 or 1 or more independently chosen substituents of (a) and 0 or 1 substituents chosen from (b)
19. 19. A compound or salt according to claim 18, characterized in that R7 is a piperidinyl, piperazinyl or pyrrolidinyl group, which is part of a bicyclic system having a cycloalkyl group of C3-C4, dioxolanyl or azetidinyl attached to spiro, which The bicyclic system is substituted with 0, 1 or 2 substituents independently chosen from halogen, hydroxy, amino, oxo, cyano, d-C2 alkyl, d-C2 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy.
20. 20. A compound or salt according to claim 18, characterized in that R is a 5- or 6-membered nitrogen-linked heterocycloalkyl, having 0 or 1 additional nitrogen atoms, of which 5 or 6 membered heterocycloalkyl attached to nitrogen is part of a bicyclic ring system having a fused C3-C ciclo cycloalkyl or a fused 4 to 6-membered heterocycloalkyl containing 1 nitrogen atom, whose bicyclic ring system is substituted with 0, 1 or 2 substituents independently chosen from halogen, hydroxy, amino, oxo, cyano, C1-C2 alkyl, C? -C2 alkoxy, C? -C2 haloalkyl, and C? -C2 haloalkoxy.
21. 21. A compound or salt according to claim 20, characterized in that the 5 or 6 membered nitrogen-linked heterocycloalkyl which is part of a bicyclic ring system is a pyrrolidinyl or piperidinyl and is fused with a C3-C6 cycloalkyl. , pyrrolidinyl, or piperidinyl; wherein the bicyclic ring is substituted with 0, 1 or 2 substituents independently chosen from halogen, methyl or methoxy.
22. 22. A compound or salt according to claim 5, characterized in that R9 is C1-C4 alkyl or cyclopropyl, or Rg is phenyl substituted with 2 substituents chosen from halogen, hydroxy, amino, C? -C2 alkyl, alkoxy d- C2, mono- and di-alkylamino of C? -C2, haloalkyl of C? -C2, and haloalkoxy of d-C2.
23. 23. A compound or salt according to claim 22, characterized in that R9 is cyclopropyl.
24. 24. A compound or salt according to claim 1, characterized in that the compound is 9-cyclopropyl-6-fluoro-8-methoxy-7- (piperazin-1-yl) isothiazolo [5,4- b] quinolin-3. , 4 (2H, 9H) -dione; 9-cyclopropyl-7- (dimethylamino) -6-fluoro-8-methoxyisothiazolo [5,4- b] quinoline-3,4 (2H, 9H) -dione; 9-cyclopropyl-8-methoxy-7- (4-methylpiperazin-1-yl) isothiazolo [5,4- b] quinoline-3,4 (2 H, 9 H) -dione; 9-cyclopropyl-6-fluoro-8-methoxy-7- (octahydropyrrolo [3,4-b] pyridin-6-yl) isothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; 9-cyclopropyl-7- (3- (dimethylamino) pyrrolidin-1-yl) -6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; (R) -7- (3- (2-aminopropan-2-yl) pyrrolidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H , 9H) -dione; (R) -7- (3- (2-aminopropan-2-yl) pyrrolidin-1-yl) -9-cyclopropyl-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2 H, 9 H) - diona; (R) -7- (3- (1-aminocyclopropyl) pyrrolidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) - diona; (R) -7- (3- (1-aminocyclopropyl) pyrrolidi-1-yl) -9-cyclopropyl-8-methoxy-isothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; 7- (3- (2-aminopropan-2-yl) pyrrolidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) - diona; (S) -7- (3- (2-aminopropan-2-yl) pyrrolidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H , 9H) -dione; (R) -7- (3- (2-aminopropan-2-yl) pyrrolidin-1-yl) -9-ethyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H , 9H) -dione; (S) -7- (3- (2-aminopropan-2-yl) pyrrolidin-1-yl) -9-cyclopropyl-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) - diona; 9-ethyl-6-fluoro-8-methoxy-7- (piperazin-1-yl) isothiazolo [5,4- b] quinolin-3,4 (2H, 9H) -dione; (S) -7- (3- (aminomethyl) pyrrolidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; (S) -7- (3- (aminomethyl) pyrrolidin-1-yl) -9-cyclopropyl-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2 H, 9 H) -dione; 7- (3- (aminomethyl) pyrrolidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; (R) -7- (3- (aminomethyl) pyrrolidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; 9-cyclop ropil-6-f luoro-8-methoxy-7 - ((4aS, 7aS) - octahydropyrrolo [3,4-b] pyridin-6-yl) isothiazolo [5,4-b] quinolin- 3,4 (2H, 9H) -dione; 7- (3- (2-aminopropan-2-yl) -2,2,5,5-tetradeuterated-pyrrolidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinolin-3,4 (2H, 9H) -dione; 9-cyclopropyl-8-methoxy-7- (piperazin-1-yl) isothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; (R) -7- (3- (1-aminoethyl) pyrrolidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) - diona; (R) -9-Cyclopropyl-6-fluoro-8-methoxy-7- (3- (1- (methylamino) ethyl) pyrrolidin-1-yl) isothiazolo [5,4-b] quinoline-3,4 (2H , 9H) -dione; (R) -9-Cyclopropyl-6-fluoro-8-methoxy-7- (3- (2- (methylamino) propan-2-yl) pyrrolidin-1-yl) isothiazolo [5,4-b] quinoline-3 4 (2H, 9H) -dione; (R) -9-Cyclopropyl-7- (3- (1- (ethylamino) ethyl) pyrrolidin-1-yl) -6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; 9-cyclopropyl-8-methoxy-7 - ((4aR, 7aR) -Qctahydropyrrolo [3,4- b] pyridin-6-yl) isothiazolo [5,4-b] quinoline-3,4 (2H, 9H) - diona; (R) -9-Cyclopropyl-8-methoxy-7- (3- (2- (methylamino) propan-2-yl) pyrrolidin-1-yl) isothiazolo [5,4-b] quinoline-3,4 (2H , 9H) -dione; (R) -9-Cyclopropyl-7- (3- (1- (dimethylamino) ethyl) pyrrolidin-1-yl) -6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; (R) -9-Cyclopropyl-7- (3- (2- (dimethylamino) propan-2-yl) pyrrolidin-1-yl) -6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3, 4 (2H, 9H) -dione; (S) -9-Cyclopropyl-7- (3 - ((dimethylamino) methyl) pyrrolidin-1-yl) -6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -diona; (S) -9-Cyclopropyl-6-fluoro-8-methoxy-7- (3- ((methylamino) methyl) pyrrolidin-1-yl) isothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; (S) -9-Cyclopropyl-7- (3 - ((cyclopropylamino) methyl) pyrrolidin-1-yl) -6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -diona; (R) -9-Cyclopropyl-7- (3- (2- (ethylamino) propan-2-yl) pyrrolidin-1-yl) -6-fluoro-8-methoxyisothiazolo [5,4-b] guinolin-3, 4 (2H, 9H) -dione; (R) -7- (3- (aminomethyl) pyrrolidin-1-yl) -9-cyclopropyl-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; 9-cyclopropyl-6-fluoro-8-methoxy-7 - ((R) -3 - ((S) -1- (methylamino) propyl) pyrrolidin-1-yl) isothiazolo [5,4-b] quinoline- 3 , 4 (2H, 9H) -dione; 9-cyclopropyl-6-fluoro-8-methoxy-7 - ((R) -3 - ((R) -1- (methylamino) propyl) pyrrolidin-1-yl) isothiazolo [5,4-b] quinoline- 3 , 4 (2H, 9H) -dione; (R) -9-Cyclopropyl-7- (3- (1- (cyclopropylamino) ethyl) pyrrolidin-1-yl) -6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; (S) -9-Cyclopropyl-7- (3- (1- (cyclopropylamino) ethyl) pyrrolidin-1-yl) -6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; 7- (3- (aminomethyl) -4-methylpyrrolidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; (R) -7- (3-aminopyrrolidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; (R) -7- (3-aminopyrrolidin-1-yl) -9-cyclopropyl-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2 H, 9 H) -dione; (R) -9-Cyclopropyl-6-fluoro-8-methoxy-7- (3- (methylamino) pyrrolidin-1-yl) isothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; (R) -9-Cyclopropyl-8-methoxy-7- (3- (methylamino) pyrrolidin-1-yl) isothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; 1- (9-cyclopropyl-6-fluoro-8-methoxy-3,4-dioxo-2, 3,4,9-tetrahydroisothiazolo [5,4-b] quinolin-7-yl) -4-methylpyrrolidin-3- carbonitrile; (S) -9-Cyclopropyl-7- (3 - ((cyclopropylamino) methyl) pyrrolidin-1-yl) -8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2 H, 9 H) -dione; (R) -7- (3- (1-aminomethyl) pyrrolidin-1-yl) -9-cyclopropyl-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; (R) -9-Cyclopropyl-8-methoxy-7- (3- (1- (methylamino) ethyl) pyrrolidin-1- il) isothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; 7- (3- (aminomethyl) azetidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; 7- (3-aminoazetidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxy-isothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; 9-cyclopropyl-7- (3- (ethylamino) azetidin-1-yl) -6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; 9-cyclopropyl-6-fluoro-8-methoxy-7 - ((R) -3 - ((R) -1- (methylamino) ethyl) pyrrolidin-1-yl) isothiazolo [5,4-b] quinoline- 3 , 4 (2H, 9H) -dione; 9-cyclopropyl-6-fluoro-8-methoxy-7 - ((R) -3 - ((S) -1- (methylamino) ethyl) pyrrolidin-1-yl) isothiazolo [5,4-b] quinoline- 3 , 4 (2H, 9H) -dione; 7- (3-amino-3- (hydroxymethyl) pyrrolidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; 7 - ((R) -3 - ((R) -1-aminoethyl) pyrrolidin-1-yl) -9-cyclopropyl-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) - diona; 7 - ((R) -3 - ((S) -1-aminoethyl) pyrrolidin-1-yl) -9-cyclopropyl-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) - diona; (R) -9-Cyclopropyl-6-fluoro-7- (3- (1- (isopropylamino) ethyl) pyrrolidin-1-yl) -8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H, 9H) -dione; or (R) -7- (3- (1- (Cyclopentylamino) ethyl) pyrrolidin-1-yl) -9-cyclopropyl-6-fluoro-8-methoxyisothiazolo [5,4-b] quinoline-3,4 (2H , 9H) -dione.
25. 25. A pharmaceutical composition characterized in that it comprises a compound or salt in accordance with claim 1, together with a pharmaceutically acceptable carrier, diluent or excipient.
26. 26. A pharmaceutical composition according to claim 25, characterized in that 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 a ophthalmic solution.
27. 27. A package characterized in that it comprises the pharmaceutical composition according to claim 25 in a container and further comprises instructions for using the composition to treat a patient suffering from an infection of microorganisms.
28. 28. A package according to claim 27, characterized in that the instructions are instructions for using the composition to treat a patient suffering from a bacterial infection.
29. 29. A method for treating or preventing a bacterial or protozoal infection, characterized in that it comprises administering to a patient in need thereof a therapeutically effective amount of a compound or salt according to claim 1.
30. 30. The method according to claim 29, characterized in that the infection is an S. Aureus infection and the patient is a human patient.