CYCLIZATION PROCESS STEP IN THE MAKING OF QUINOLONES AND NAPHTHYRIDINES FIELD OF THE INVENTION The subject invention relates to processes for making quinolones and quinolone derivatives, which are compounds that are active antibacterial and/or are anti-HIV agents. The invention also relates to useful intermediates in making these compounds.

BACKGROUND OF THE INVENTION The chemical and medical literature describes compounds that are said to be antimicrobial, i. e., capable of destroying or suppressing the growth or reproduction of microorganisms, such as bacteria. For example, such antibacterials and other antimicrobials are described in Antibiotics, Chemotherapeutics, and Antibacterial Agents for Disease Control (M. Grayson, editor, 1982), and E. Gale et al., The Molecular Basis of Antibiotic Action 2d edition (1981).

The mechanism of action of these antibacterials vary. However, they are generally believed to function in one or more of the following ways: by inhibiting cell wall synthesis or repair; by altering cell wall permeability; by inhibiting protein synthesis; or by inhibiting synthesis of nucleic acids. For example, beta-lactam antibacterials act through inhibiting the essential penicillin binding proteins (PBPs) in bacteria, which are responsible for cell wall synthesis. As another example, quinolones act, at least in part, by inhibiting synthesis of DNA, thus preventing the cell from replicating.

The pharmacological characteristics of antimicrobials, and their suitability for any given clinical use, vary. For example, the classes of antimicrobials (and members within a class) may vary in 1) their relative efficacy against different types of microorganisms, 2) their susceptibility to development of microbial resistance and 3) their pharmacological characteristics, such as their bioavailability, and biodistribution. Accordingly, selection of an appropriate antibacterial (or other antimicrobial) in a given clinical situation requires analysis of many factors, including the type of organism involved, the desired method of administration, the location of the infection to be treated and other considerations.

Cyclization processes for making intermediate compounds useful in the synthesis of quinolone, naphthyridine, and related compounds are disclosed in a number of references including the following: European Patent Application No. 0 168,733 published January 22, 1986; and U. S. Patent No. 5,703,231 issued December 30,1997. While the methods disclosed in the those publications represent useful advances in quinolone chemistry, Applicants have

discovered that the use of certain leaving groups, not contemplated in those or other prior art references, in combination with the use of a silylating reactant provide several advantages relative to the processes disclosed in the prior art. For example, the present process allows the synthesis of various quinolones and related compounds by an intramolecular cyclization process in which the key leaving group on the starting aromatic ring precursor (depicted as XR9 in Formula (A) below) is electron donating in nature. The aromatic ring precursor may contain other substituents which may be electron donating or electron withdrawing in nature. Certain prior cyclization methods to form quinolones disclose an electron withdrawing group as the leaving group on the starting aromatic ring and also may require the presence of other electron withdrawing groups at the ortho or para positions on that ring. See, e. g., U. S. Patent No.

5,703,231. Further, when other prior art has discussed the use of methoxy and thiomethyl leaving groups, reaction conditions disclosed are harsh insofar as they use sodium hydride and require high temperatures (140-160°C) in polar solvents.

The present process, in contrast, allows the use of a broader group of starting materials in the manufacture of quinolones, possibly leading to a more efficient and cost effective process.

The process also allows the use of less harsh reaction conditions than the methods described in the art generally, which may also provide improved synthetic yields.

Accordingly, the present invention provides an improved means to obtain quinolones and derivatives of quinolones, which themselves may be active or may be intermediates for forming other active molecules.

SUMMARY OF THE INVENTION The subject invention relates to a process for making a compound having a structure according to Formula (I), or an optical isomer, diastereomer or enantiomer thereof, or a pharmaceutically-acceptable salt, hydrate, or biohydrolyzable ester, amide or imide thereof: the process comprising reacting one or more organosilicon reagents with a compound having a structure according to Formula (A):

wherein with regard to Formula (I) and Formula (A): (A) (1) A is N or C-R8, where R8 is selected from hydrogen, alkyl, aryl, halo, a heterocyclic ring, amino, alkylamino, arylamino, alkoxy, nitro, cyano, aryloxy, esters of hydroxy, alkylthio, arylthio, aryloxy, esters of thio, alkylsulfonyl, arylsulfonyl, alkylphosphonyl, arylphosphonyl, alkylacyl, arylacyl, and aryl esters and amides of carboxy; (2) R is selected from hydrogen, alkyl, aryl, a heterocyclic ring, amino, alkylamino, arylamino, halo, nitro, cyano, alkoxy, aryloxy, esters of hydroxy, alkylthio, arylthio, esters of thio, alkylsulfonyl, arylsulfonyl, alkylphosphonyl, arylphosphonyl, alkylacyl, arylacyl, and alkyl and aryl esters and amides of carboxy; (3) R6 is selected from hydrogen, halo, alkyl, aryl, a heterocyclic ring, amino, alkylamino, arylamino, nitro, cyano, alkoxy, aryloxy, esters of hydroxy, alkylthio, arylthio, esters of thio, alkylsulfonyl, arylsulfonyl, alkylphosphonyl, arylphosphonyl, alkylacyl, arylacyl, and alkyl and aryl esters and amides of carboxy; (4) R5 is selected from hydrogen, alkyl, aryl, cyano, a heterocyclic ring, amino, alkylamino, arylamino, alkylacyl, arylacyl, and aryl esters and amides of carboxy; (5) Rl is selected from a carbocyclic ring, a heterocyclic ring, lower alkyl, lower alkene, lower alkyne and-CH (Rl°) (Rm) where Rl° is selected from lower alkyl and phenyl and Rll is-CH2Y (O=) CRl2 where R12 is selected from lower alkyl and phenyl and Y is selected from-NH-,-0-and-S- ; (6) R2 is selected from hydrogen, alkyl, aryl, a heterocyclic ring, alkylthio and arylthio; and (7) R3 is selected from hydrogen, alkoxy, aryloxy, alkyl and aryl; or (B) Rl and R2 can join to form a 5-or 6-membered carbocyclic or heterocyclic. ring, where A, R3, R5, R, R7 and R8, if present, are as described in (A); or (C) R6 and R7 can join to form a 5-or 6-membered carbocyclic or heterocyclic ring, where A, Rl, R2, R3, R'and R', if present, are as described in (A); and wherein with regard to Formula (A): (D) X is selected from-O-and-S-and R9 is selected from Cl-Clo alkyl, aryl and heteroaryl.

The compounds of Formula (I) may themselves be effective antimicrobial or anti-HIV agents, or they may be further reacted using well known chemistry to provide a molecule having antimicrobial or anti-HIV activity. As such, the compounds of Formula (I) may be useful intermediates in the formation of other active quinolones and quinolone derivatives.

The invention also relates to novel intermediates, having a structure of Formula (A), that are useful in the present process.

DETAILED DESCRIPTION OF THE INVENTION I. Terms and Definitions: The following is a list of definitions for terms used herein: "Acyl"or"carbonyl"is a radical formed by removal of the hydroxy from a carboxylic acid (i. e., R-C (=O)-)."Alkylacyl"is-C (=O)-alkyl and"Arylacyl is-C (=O)-aryl. Preferred acyl groups include (for example) acetyl, formyl, and propionyl.

"Alkyl"is a saturated hydrocarbon chain having 1 to 15 carbon atoms, preferably 1 to 10, more preferably 1 to 4 carbon atoms."Alkene"is a hydrocarbon chain having at least one (preferably only one) carbon-carbon double bond and having 2 to 15 carbon atoms, preferably 2 to 10, more preferably 2 to 4 carbon atoms."Alkyne"is a hydrocarbon chain having at least one (preferably only one) carbon-carbon triple bond and having 2 to 15 carbon atoms, preferably 2 to 10, more preferably 2 to 4 carbon atoms. Alkyl, alkene and alkyne chains (referred to collectively as"hydrocarbon chains") may be straight or branched and may be unsubstituted or substituted. Preferred branched alkyl, alkene and alkyne chains have one or two branches, preferably one branch. Preferred chains are alkyl. Alkyl, alkene and alkyne hydrocarbon chains each may be unsubstituted or substituted with from 1 to 4 substituents; when substituted, preferred chains are mono-, di-, or tri-substituted. Alkyl, alkene and alkyne hydrocarbon chains each may be substituted with halo, hydroxy, aryloxy (e. g., phenoxy), heteroaryloxy, acyloxy (e. g., acetoxy), carboxy, aryl (e. g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, amido, acylamino, keto, thioketo, cyano, or any combination thereof. Preferred hydrocarbon groups include methyl, ethyl, propyl, isopropyl, butyl, vinyl, allyl, butenyl, and exomethylenyl.

"Alkoxy"is an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl (i. e.,-O-alkyl or-O-alkenyl) that is unsubstituted or substituted as described above. In the case of substituted alkoxy, preferred substituents include

1-5 fluorine atoms. Preferred alkoxy groups include (for example) methoxy, di-fluoro methoxy, ethoxy, penta-fluoro ethoxy, propoxy and allyloxy.

Also, as referred to herein, a"lower"alkoxy, alkyl, alkene or alkyne moiety (e. g., "lower alkyl") is a chain comprised of 1 to 6, preferably from 1 to 4, carbon atoms in the case of alkyl and alkoxy, and 2 to 6, preferably 2 to 4, carbon atoms in the case of alkene and alkyne.

"Alkylphosphonyl"is-PO3-alkyl (e. g.-PO3-CH3).

"Alkylsulfonyl"is-SO2-alkyl (e. g.,-SO2-CH3).

"Alkylthio"is-S-alkyl (e. g.-S-CH3).

"Amino"refers to-NH2."Alkylamino"is an amino substituted with at least one alkyl moiety (e. g.,-NH (CH3)."Arylamino"is an amino substituted with at least one aryl moiety (e. g., -(C6H5).

"Aryl"is an aromatic hydrocarbon ring. Aryl rings are monocyclic or fused bicyclic ring systems. Monocyclic aryl rings contain 6 carbon atoms in the ring. Monocyclic aryl rings are also referred to as phenyl rings. Bicyclic aryl rings contain from 8 to 17 carbon atoms, preferably 9 to 12 carbon atoms, in the ring. Bicyclic aryl rings include ring systems wherein one ring is aryl and the other ring is aryl, cycloalkyl, or heterocycloakyl. Preferred bicyclic aryl rings comprise 5-, 6-or 7-membered rings fused to 5-, 6-, or 7-membered rings. Aryl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Aryl may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, aryloxy, alkoxy, heteroalkyloxy, carbamyl, haloalkyl, methylenedioxy, heteroaryloxy, or any combination thereof. Preferred aryl rings include naphthyl, tolyl, xylyl, and phenyl. The most preferred aryl ring radical is phenyl.

"Aryloxy"is an oxygen radical having an aryl substituent (i. e.,-O-aryl). Preferred aryloxy groups include (for example) phenoxy, napthyloxy, methoxyphenoxy, and methylenedioxyphenoxy.

"Arylphosphonyl"is-PO3-aryl (e. g.,-P03-C6HS).

"Arylsulfonyl"is-S02-aryl (e. g.,-SO2-C6Hs).

"Arylthio"is-S-aryl (e. g.,-S-C6Hs).

"Biohydrolyzable amides"are aminoacyl, acylamino, or other amides of the compounds of the invention, where the amide does not essentially interfere, preferably does not interfere, with the activity of the compound, or where the amide is readily converted in vivo by a host to yield an active compound.

"Biohydrolyzable imides"are imides of compounds of the invention, where the imide does not essentially interfere, preferably does not interfere, with the activity of the compound, or where the imide is readily converted in vivo by a host to yield an active compound. Preferred imides are hydroxyimides.

"Biohydrolyzable esters"are esters of compounds of the invention, where the ester does not essentially interfere, preferably does not interfere, with the antimicrobial activity of the compound, or where the ester is readily converted in a host to yield an active compound. Many such esters are known in the art, as described in U. S. Patent No. 4,783,443, issued to Johnston and Mobashery on November 8,1988 (incorporated by reference herein). Such esters include lower alkyl esters, lower acyloxy-alkyl esters (such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such as methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters and alkylacylaminoalkyl esters (such as acetamidomethyl esters).

"Carbocyclic ring"encompasses both cycloalkyl and aryl moieties, as those terms are defined herein.

"Carbonyl"is-C(=O)-.

"Cycloalkyl"is a saturated or unsaturated hydrocarbon ring. Cycloalkyl rings are not aromatic. Cycloalkyl rings are monocyclic, or are fused, spiro, or bridged bicyclic ring systems.

Monocyclic cycloalkyl rings contain from about 3 to about 9 carbon atoms, preferably from 3 to 7 carbon atoms, in the ring. Bicyclic cycloalkyl rings contain from 7 to 17 carbon atoms, preferably from 7 to 12 carbon atoms, in the ring. Preferred bicyclic cycloalkyl rings comprise 4-, 5-, 6-or 7-membered rings fused to 5-, 6-, or 7-membered rings. Cycloalkyl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Cycloalkyl may be substituted with halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, or any combination thereof. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl, and cyclohexyl.

"Halo"or"halogen"is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo; more preferred typically are chloro and fluoro, especially fluoro.

"Haloalkyl"is a straight, branched, or cyclic hydrocarbon substituted with one or more halo substituents. Preferred are Cl-Cl2 haloalkyls; more preferred are Cl-C6 haloalkyls; still

more preferred still are Cl-C3 haloalkyls. Preferred halo substituents are fluoro and chloro. The most preferred haloalkyl is trifluoromethyl.

"Heteroatom"is a nitrogen, sulfur, or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms.

"Heteroalkyl"is a saturated or unsaturated chain containing carbon and at least one heteroatom, wherein no two heteroatoms are adjacent. Heteroalkyl chains contain from 2 to 15 member atoms (carbon and heteroatoms) in the chain, preferably 2 to 10, more preferably 2 to 5.

For example, alkoxy (i. e.,-O-alkyl or-O-heteroalkyl) radicals are included in heteroalkyl.

Heteroalkyl chains may be straight or branched. Preferred branched heteroalkyl have one or two branches, preferably one branch. Preferred heteroalkyl are saturated. Unsaturated heteroalkyl have one or more carbon-carbon double bonds and/or one or more carbon-carbon triple bonds.

Preferred unsaturated heteroalkyls have one or two double bonds or one triple bond, more preferably one double bond. Heteroalkyl chains may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted heteroalkyl are mono-, di-, or tri-substituted. Heteroalkyl may be substituted with lower alkyl, haloalkyl, halo, hydroxy, aryloxy, heteroaryloxy, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, acylamino, amido, keto, thioketo, cyano, or any combination thereof.

"Heteroaryl"is an aromatic ring containing carbon atoms and from 1 to about 6 heteroatoms in the ring. Heteroaryl rings are monocyclic or fused bicyclic ring systems.

Monocyclic heteroaryl rings contain from about 5 to about 9 member atoms (carbon and heteroatoms), preferably 5 or 6 member atoms, in the ring. Bicyclic heteroaryl rings contain from 8 to 17 member atoms, preferably 8 to 12 member atoms, in the ring. Bicyclic heteroaryl rings include ring systems wherein one ring is heteroaryl and the other ring is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl. Preferred bicyclic heteroaryl ring systems comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings. Heteroaryl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Heteroaryl may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy, heteroaryloxy, or any combination thereof. Preferred heteroaryl rings include, but are not limited to, the following:

Furan Thiophene Pyrrole Pyrazole Imidazole Oxazole Isoxazole Isothiazole Thiazole 1,2,5-Thiadiazole 1,2,3-Triazole 1,3,4-Thiadiazole Furazan 1,2,3-Thiadiazole 1,2,4-Thiadiazole Benzotriazole 1,2,4-Triazole Tetrazole 1,2,4-Oxadiazole 1,3,4-Oxadiazole 1,2,3,4-Oxatriazole 1,2,3,4-Thiatriazole 1,2,3,5-Thiatriazole 1,2,3,5-Oxatriazole 1,2,3-Triazine 1,2,4-Triazine 1,2,4,5-Tetrazine Dibenzofuran Pyridine Pyridazine Pyrimidine Pyrazine 1,3,5-Triazine Indolizine Indole Isoindol Benzofuran Benzothiophene 1H-Indazole Purine Quinoline Benzimidazole Benzthiazole Benzoxazole Pteridine Carbazole Isoquinoline Cinnoline Phthalazine Quinazoline Quinoxaline 1,8-Napthypyridine

Acridine Phenazine "Heteroaryloxy"is an oxygen radical having a heteroaryl substituent (i. e.,-O-heteroaryl).

Preferred heteroaryloxy groups include (for example) pyridyloxy, furanyloxy, (thiophene) oxy, (oxazole) oxy, (thiazole) oxy, (isoxazole) oxy, pyrmidinyloxy, pyrazinyloxy, and benzothiazolyloxy.

"Heterocycloalkyl"is a saturated or unsaturated ring containing carbon atoms and from 1 to about 4 (preferably 1 to 3) heteroatoms in the ring. Heterocycloalkyl rings are not aromatic.

Heterocycloalkyl rings are monocyclic or bicyclic ring systems. Monocyclic heterocycloalkyl rings contain from about 3 to about 9 member atoms (carbon and heteroatoms), preferably from 5 to 7 member atoms, in the ring. Bicyclic heterocycloalkyl rings contain from 7 to 17 member atoms, preferably 7 to 12 member atoms, in the ring. Bicyclic heterocycloalkyl rings contain from about 7 to about 17 ring atoms, preferably from 7 to 12 ring atoms. Bicyclic heterocycloalkyl rings may be fused, spiro, or bridged ring systems. Preferred bicyclic heterocycloalkyl rings comprise 5-, 6-or 7-membered rings fused to 5-, 6-, or 7-membered rings. Heterocycloalkyl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Heterocycloalkyl may be substituted with halo, cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy or any combination thereof. Preferred substituents on heterocycloalkyl include halo and haloalkyl.

Preferred heterocycloalkyl rings include, but are not limited to, the following: Oxirane Aziridine Oxetane Azetidine Tetrahydrofuran Pyrrolidine 3H-Indole 1,3-Dioxolane 1,2-Dithiolane 1,3-Dithiolane 4,5-Dihydroisoxazole 2,3-Dihydroisoxazole

4,5-Dihydropyrazole Imidazolidine Indoline 2H-Pyrrole Phenoxazine 4H-Quinolizine Pyrazolidine 2H-Pyran 3,4-Dihydro-2H-pyran Tetrahydropyran 2H-Chromene Chromone Chroman Piperidine Morpholine 4H-1, 3-Oxazine 6H-1,3-Oxazine 5,6-dihydro-4H-1,3-oxazine 4H-3,1-benzoxazine Phenothiazine 1,3-Dioxane Cepham Piperazin Hexahydroazepine 1,3-Dithiane 1,4-Dioxane jenem Coumarin Thiomorpholine Uracil Thymine Cytosine Thiolane 2,3-Dihydro-1 H-Isoindole Phthalan 1,4-Oxathiane 1,4-Dithiane hexahydro-Pyridazine 1,2-Benzisothiazoline Benzylsultam

"Heterocyclic ring"encompasses both heterocycloalkyl and heteroaryl moieties, as those terms are defined herein.

"Host"is a substrate capable of sustaining a microbe, preferably it is a living organism, more preferably an animal, more preferably a mammal, more preferably still a human.

The terms"optical isomer","stereoisomer", and"diastereomer"have the standard art recognized meanings (see, e. g., Hawley's Condensed Chemical Dictionary, llth Ed.). The illustration of specific protected forms and other derivatives of the compounds of the instant invention is not intended to be limiting. The application of other useful protecting groups, salt forms, etc. is within the ability of the skilled artisan.

The compounds of the invention may have one or more chiral centers. As a result, one may selectively prepare one optical isomer, including diastereomer and enantiomer, over another, for example by use of chiral starting materials, catalysts or solvents, one may prepare both stereoisomers or both optical isomers, including diastereomers and enantiomers at once (a racemic mixture). Since the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, or stereoisomers, they may be separated using known methods, such as chiral resolution, chiral chromatography and the like.

In addition, it is recognized that one optical isomer, including diastereomer and enantiomer, or stereoisomer may have favorable properties over the other. Thus when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.

An"organosilicon reagent"is any silicon-containing reagent that is commonly utilized in silylation reactions, that is, reactions which substitute a hydrogen atom bound to a heteroatom (e. g.,-OH, =NH,-SH, etc.) with a silyl group, usually a trialkylsilyl group, including reactions of a tautomer of a heteroatom system to form a silyl derivative (e. g., silyl emol ethers), thus forming a silicon-heteroatom bond. Many such compounds are known in the art, as described in the following articles: E. Plueddemann,"Silylating Agents", in: Kirk-Othmer, 3d ed., Vol. 20, "Encyclopedia of Chemical Technology" (1982); I. Fleming,"Organic Silicon Chemistry", in: Vol. 3,"Comprehensive Organic Chemistry" (D. Jones, editor, 1979); B. Cooper,"Silylation in Organic Synthesis", Proc. Biochem. 9 (1980); B. Cooper,"Silylation as a Protective Method in Organic Synthesis", Chem. Ind. 794 (1978); J. Rasmussen,"O-Silylated Enolates-Versatile Intermediates for Organic Synthesis"91 Synthesis (1977). Representative organosilicon reagents

useful in the present process include, but are not limited to, chlorotrimethylsilane, N, O- bis (trimethylsilyl) acetamid, N, O-bis (trimethylsilyl) trifluoroacetamide, 1,3- bis (trimethylsilyl) urea, 1,1,1,3,3,3-hexamethyldisilazane, N-methyl-N- trimethylsilyltrifluoroacetamide, 1-trimethylsilylimidazole, trimethylsilyl trifluoromethanesulfonate, tert-butyldimethylchlorosilane, 1- (tert-butyldimethylsilyl) imidazole, ethyl (trimethylsilyl) acetate, N-tert-butyldimethyl-N-methyltrifluoroacetamide, tert- butyldimethylsilyl trifluoromethanesulfonate, tert-butyldiphenylchlorosilane, tert-butyl- methoxyphenylbromosilane, dimethylphenylchlorosilane, triethylchlorosilane, triethylsilyl trifluoromethane-sulfonate, and triphenylchlorosilane. Of the various organosilicon reagents useful herein, N, O-bis (trimethylsilyl) acetamide, N, O-bis (trimethylsilyl) trifluoroacetamide, N- methyl-N-trimethylsilyltrifluoroacetamide and tert-butyldiphenylchlorosilane are particularly preferred. More than one organosilicon reagent may be used in the present process.

A"pharmaceutically-acceptable salt"is a cationic salt formed at any acidic (e. g., carboxyl) group, or an anionic salt formed at any basic (e. g., amino, alkylamino, dialkylamino, morphylino, and the like) group on the compound of the invention. Since many of the compounds of the invention are zwitterionic, either salt is possible and acceptable. Many such salts are known in the art. Preferred cationic salts include the alkali metal salts (such as sodium and potassium), alkaline earth metal salts (such as magnesium and calcium) and organic salts, such as ammonio. Preferred anionic salts include halides, sulfonates, carboxylates, phosphates, and the like. Clearly contemplated in such salts are addition salts that may provide an optical center, where once there was none. For example, a chiral tartrate salt may be prepared from the compounds of the invention, and this definition includes such chiral salts. Salts contemplated are nontoxic in the amounts administered to the patient-animal, mammal or human.

The compounds made by the present process may be sufficiently basic to form acid- addition salts. The compounds are useful both in the free base form and the form of acid-addition salts, and both forms are within the purview of the invention. The acid-addition salts are in some cases a more convenient form for use. In practice, the use of the salt form inherently amounts to the use of the base form of the active. Acids used to prepare acid-addition salts include preferably those which produce, when combined with the free base, medicinally acceptable salts.

These salts have anions that are relatively innocuous to the animal organism, such as a mammal, in medicinal doses of the salts so that the beneficial property inherent in the free base are not vitiated by any side effects ascribable to the acid's anions.

Examples of appropriate acid-addition salts include, but are not limited to hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogensulfate, acetate, trifluoroacetate, nitrate, citrate, fumarate, formate, stearate, succinate, maleate, malonate, adipate, glutarate, lactate, propionate, butyrate, tartrate, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, dodecyl sulfate, cyclohexanesulfamate, and the like. However, other appropriate medicinally acceptable salts within the scope of the invention are those derived from other mineral acids and organic acids. The acid-addition salts of the basic compounds are prepared by several methods. For example, the free base can be dissolved in an aqueous alcohol solution containing the appropriate acid and the salt is isolated by evaporation of the solution. Alternatively, they may be prepared by reacting the free base with an acid in an organic solvent so that the salt separates directly.

Where separation of the salt is difficult, it can be precipitated with a second organic solvent, or can be obtained by concentration of the solution.

Although medicinally acceptable salts of the basic compounds are preferred, all acid- addition salts are within the scope of the present invention. All acid-addition salts are useful as sources of the free base form, even if the particular salt per se is desired only as an intermediate product. For example, when the salt is formed only for purposes of purification or identification, or when it is used as an intermediate in preparing a medicinally acceptable salt by ion exchange procedures, these salts are clearly contemplated to be a part of this invention.

Such salts are well understood by the skilled artisan, and the skilled artisan is able to prepare any number of salts given the knowledge in the art. Furthermore, it is recognized that the skilled artisan may prefer one salt over another for reasons of solubility, stability, formulation ease and the like. Determination and optimization of such salts is within the purview of the skilled artisan's practice.

As used herein, a"quinolone derivative"includes prodrugs of a quinolone, or an active drug made from a quinolone. Preferably, such derivatives include lactams (e. g., cephems, carbacephems, penems, monolactams, etc.) covalently linked to the quinolone optionally via a spacer. Such derivatives and methods to make and use them are apparent to the skilled artisan, given the teachings of this specification.

"Spirocycle"is an alkyl or heteroalkyl diradical substituent of alkyl or heteroalkyl wherein said diradical substituent is attached geminally and wherein said diradical substituent forms a ring, said ring containing 4 to 8 member atoms (carbon or heteroatom), preferably 5 or 6 member atoms.

A"solvate"is a complex formed by the combination of a solute (e. g., a quinolone) and a solvent (e. g., water). See J. Honig et al., The Van Nostrand Chemist's Dictionary, p.

650 (1953). Pharmaceutically-acceptable solvents used according to this invention include those that do not interfere with the biological activity of the quinolone (e. g., water, ethanol, acetic acid, N, N-dimethylformamide and others known or readily determined by the skilled artisan).

While alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups may be substituted with hydroxy, amino, and amido groups as stated above, the following are not envisioned in the invention: 1. Enols (OH attached to a carbon bearing a double bond).

2. Amino groups attached to a carbon bearing a double bond (except for vinylogous amides).

3. More than one hydroxy, amino, or amido attached to a single carbon (except where two nitrogen atoms are attached to a single carbon atom and all three atoms are member atoms within a heterocycloalkyl ring).

4. Hydroxy, amino, or amido attached to a carbon that also has a heteroatom attached to it.

5. Hydroxy, amino, or amido attached to a carbon that also has a halogen attached to it.

The illustration of the use of specific protected forms and other derivatives of the Formula 1 compounds in the present process are not intended to be limiting. The application of other useful protecting groups, salt forms, etc. is within the ability of the skilled artisan.

II. Preferred Compounds Made By the Subject Process: The subject invention relates to a process comprising the following process step: RS O O RS O O 6 organosilicon zea N I R H k Formula (A) Formula (I) where Rl, R2, R3, R5, R6, R7, A, X and R9 are as defined in the Summary of the Invention section above.

With reference to Formula (I) and Formula (A), the description above indicates that in one embodiment (defined in sub-part (A)), the nucleus of the final compounds of Formula (I) will include two fused rings as depicted. Alternatively, the nucleus of the Formula (I) compounds will, upon cyclization via the present process, include three fused rings, as defined in sub-parts (B) and (C). These alternative embodiments are depicted as Formula (B) and Formula (C), respectively, below.

In the above structures, Rs is selected from hydrogen, alkyl, aryl, cyano, a heterocyclic ring, amino, alkylamino, arylamino, alkylacyl, arylacyl, and aryl esters and amides of carboxy. Preferred Rs is selected from hydrogen, Ci to about C4 alkyl, phenyl, amino and C1 to about C4 mono-or dialkylamino. More preferred Rs is selected form hydrogen, amino, methyl, ethyl, methylamino and dimethylamino. Alkyl and aryl portions of the Rs moieties are preferably unsubstituted or substituted with fluoro.

In the above structures, R6 is selected from hydrogen, halo, alkyl, aryl, a heterocyclic ring, amino, alkylamino, arylamino, nitro, cyano, alkoxy, aryloxy, esters of hydroxy, alkylthio, arylthio, esters of thio, alkylsulfonyl, arylsulfonyl, alkylphosphonyl, arylphosphonyl, alkylacyl, arylacyl, and alkyl and aryl esters and amides of carboxy. Preferred R is selected from hydrogen, halo, nitro, C1 to about C4 alkylamino, C1 to about C4 alkoxy, and C1 to about C4 esters of hydroxy. More preferred R is selected from hydrogen, fluoro, chloro, methyl, methylamino, dimethylamino, nitro, methoxy and acetoxy. Alkyl and aryl portions of the R6 moieties are preferably unsubstituted or substituted with fluoro.

In the above structures, R7 is selected from hydrogen, alkyl, aryl, a heterocyclic ring, amino, alkylamino, arylamino, halo, nitro, cyano, alkoxy, aryloxy, esters of hydroxy, alkylthio, arylthio, esters of thio, alkylsulfonyl, arylsulfonyl, alkylphosphonyl, arylphosphonyl, alkylacyl, arylacyl, and alkyl and aryl esters and amides of carboxy. Preferred R7 is selected from hydrogen, halo, nitro, Cl to about C4 alkyl, unsubstituted amino, Cl to about C4 mono-or di-alkylamino, phenyl, naphthyl, a heterocyclic ring having one ring with 5 or 6 ring atoms or two fused rings with 8-10 ring atoms, Cl to about C4 alkylthio, phenylthio, phenoxy and Ci to about C4 esters of hydroxy. More preferred R7 is selected from hydrogen, fluoro, chloro, bromo, nitro, unsubstituted amino, methylamino, dimethylamino and trifluoroacetoxy. Alkyl and aryl portions of the R7 moieties are preferably unsubstituted or substituted with one or more fluoro atoms.

In the above structures, A is N or C-R3, preferably C-R8. Rg is selected from hydrogen, alkyl, aryl, halo, a heterocyclic ring, amino, alkylamino, arylamino, alkoxy, nitro, cyano, aryloxy,

esters of hydroxy, alkylthio, arylthio, esters of thio, alkylsulfonyl, arylsulfonyl, alkylphosphonyl, arylphosphonyl, alkylacyl, arylacyl, and aryl esters and amides of carboxy. Preferred R8 is selected form hydrogen, halo, about C1-C4 alkyl, phenyl, about Cl-C4 alkoxy, about C1-C4 alkylthio, and phenoxy. More preferred R8 is selected from hydrogen, fluoro, chloro, methoxy, di-and trifluoromethoxy, methylthio, di-and trifluoromethylthio, methyl, ethyl, cyclopropyl and phenyl.

In the above structures, Rl is selected from a carbocyclic ring, a heterocyclic ring, lower alkyl, lower alkene, lower alkyne, and-CH (Rl°) (R") where Rl° is selected from lower alkyl and phenyl and R"is-CH2Y (O=) CR 12 where R12 is selected from lower alkyl and phenyl and Y is selected from-NH-,-O-and-S-. Preferred Rl is selected from C1-C4 alkyl, C3-C6 cycloalkyl and aryl. More preferred Rl is selected from cyclopropyl, ethyl, 2,4-difluorophenyl, 2-methyl-1- acetoxypropane, 2-methyl-1-thioacetoxypropane. Akyl, cycloalkyl and aryl portions of the moieties are preferably unsubstituted or substituted with fluoro.

In the above structures, R2 is selected from hydrogen, alkyl, aryl, a heterocyclic ring, alkylthio and arylthio. Preferred R2 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkylthio and phenyl. More preferred R2 is hydrogen and methylthio.

In the above structures, R3 is selected from hydrogen, alkoxy, aryloxy, alkyl and aryl.

Preferred R3 is selected from hydrogen, about C1-C4 alkoxy and phenoxy. Most preferred are hydrogen, methoxy and ethoxy.

In Formula (A), X is selected from-O-and-S-and R9 is selected from Cl-Clo alkyl, aryl and heteroaryl. Preferred XR9 moieties are selected from alkoxy and alkylthio having from about 1 to about 10 carbon atoms, phenoxy and phenylthio. More preferred XR9 moieties are selected from methoxy, ethoxy, methylthio, ethylthio, phenoxy and phenylthio, all unsubstituted.

With respect to compounds defined in sub-part (A) of Formula (I), where the compounds include only two fused rings as the compound's nucleus, preferred compounds made according to the present process are those listed in Table I.

Table I A Ri R2 R3 Rs R6 R7 I5OMeS N H OMe H F F . COMe l H OMe H F | CMe OMe F I t CCl I H OMe H F F I A CF H OMe H F F l A I CH H OMe H F F I A COCF3 H OMe H F F I A I | COCHF2 l H OMe H F F I A OMe F LLF | COMe OMe F z | CMe OMe F l bF CCl I H OMe H F F l bF CF H OMe H F F l bF I CH H OMe H F F F I COCF3 H OMe H F F F | COCHF2 OMe F F N Et H OMe H F F | COMe Et H OMe H T F F CMe Et H OMe H F F CC1 Et H OMe H F F I CF Et H OMe H F F CH Et H OMe H F F COCF3 Et H OMe H F F COCHF2 Et H OMe H F F N t-But H OMe H F F | CC1 t-But H OMe H F F CF t-But H OMe H F F CH t-But H OMe H F F N F H OMe H F F I COMe F H OMe H F F F F CMe f F H OMe H F F RIZ F CC1 F H OMe H F F F F CF F H OMe H F F RIZ F CH F H OMe H F F F F COCF3 f F H OMe H F F RIZ F COCHF2 F H OMe H F F F I N I SMe OMe H F F COMe l SMe OMe H F F 0 CMe l SMe OMe H F F 0 CCI l SMe OMe H F F CF l SMe OMe H F F A I CH l SMe OMe H F F A I COCF3 l SMe OMe H F F COCHF2 l SMe OMe H F F A N Et SMe OEt H F F COMe Et SMe OEt H F F CMe Et SMe OEt H F F CC1 Et SMe OEt H F F CF Et SMe OEt H F F CH Et SMe OEt H F F COCF3 Et SMe OEt H F F COCHF2 Et SMe OEt H F F N t-But SMe OEt H F F CMe t-But SMe OEt H F F CC1 t-But SMe OEt H F F I CF t-But SMe OEt H F F CH t-But SMe OEt H F F COCF3 t-But SMe OEt H F F COCHF2 t-But SMe OEt H F F N F SMe OEt H F F F ? F COMe F SMe OEt H F F F F CMe F SMe OEt H F F F F cul F SMe OEt H F F RIZ F CF F SMe OEt H F F F CH F SMe OEt H F F I F COCF3 F SMe OEt H F F P COCHE2 ¢ SMe OEt H F F l F l p N I H OMe NH2 F F COMe l H OMe NH2 F F CMe H OMe NH2 F F 0 CC1 l H OMe NH2 F F 0 CF H OMe NH2 F F l CH H OMe NH2 F F A COCF3 l H OMe NH2 F F COCHF2 l H OMe NH2 F F N H OMe NH2 F F N I H OMe NH2 F F LF COMe 1/F H OMe NH2 F F F CMe H ome NH2 F F F CC1 i H OMe NH2 F F bF CFtHOMeNH2FF LLF CH H OMe NH2 F F F COCF3 tF H OMe NH2 F F LF COCHF2 OMe NH2 F bF N Et H OMe NH2 F F COMe Et H OMe NH2 F CMe Et H OMe NH2 F F CC1 Et H OMe NH2 F F CF Et H OMe NH2 F F CH Et H OMe NH2 F F COCF3 Et H OMe NH2 F F COCHF2 Et H OMe NH2 F F CMe t-But H OMe NH2 F F CC1 t-But OMe NH2 F CF t-But H OMe NH2 F F CH t-But H OMe NH2 F F N F H OMe NH2 F F V F COMe F H OMe NH2 F F F F CMe F H OMe NH2 F F F F Cul F H OMe NH2 F F I F CF F H OMe NH2 F F I F CH F H OMe NH2 F F F F COCF3 F H OMe NH2 F F RIZ COCHF2 F H OMe NH2 F F Y F N 1 H OMe Me F F l COMe H OMe Me F F CMe 1 H OMe Me F F CCI 1 H OMe Me F F 0 CF H OMe Me F F 0 CH H OMe Me F F a COCF3 H OMe Me F F 0 COCHF2 1 H OMe Me F F N H OMe Me F F COMe LF H OMe Me F F F CMe 1 H OMe Me F F F CC1 tF H OMe Me F F LLF CF} H ÖMe Me F F F | CH OMe Me F F l bF | COCF3 I H OMe Me F F l F I COCHF2 I H OMe Me F F L F N Et H OMe Me F F I COMe Et H OMe Me F F I CMe Et H OMe Me F F I l CC1 Et H OMe Me F F CF Et H OMe Me F F CH Et H OMe Me F F COCF3 Et H OMe Me F F COCHF2 Et H OMe Me F F N t-But H OMe Me F F I CMe t-But H OMe Me F F I CC1t-ButHOMeMeFF CF t-But H OMe Me F F CH t-But H OMe Me F F N H OMe Me F F l f F l COMe F H OMe Me F F l 9 l F I I CMe F H OMe Me F F l ? I l F CCl F H OMe Me F F l F F CF H OMe Me F F F F CH F H OMe Me F F l tF F COCF3 F H OMe Me F F I F COCHF2 F H OMe Me F F F F SMe OEt H H F COMe I SMe OEt H H F CMe I SMe OEt H H F t l SMe OEt H H F A CFSMeOEtHHF CH l SMe OEt H H F COCF3 SMe OEt H H F COCHF2 l SMe OEt H H F N SMe OEt H H F Lr COMe 1 SMe OEt H H F F CMe l SMe OEt H H F I I CCliSMeOEtHHF LLF SMe OEt H H F CF LF CH 1 SMe OEt H H F LLF COCF3 1/F SMe OEt H H F F 24 COCHF2 SMe OEt H H F L F N Et SMe OEt H H F COMe Et SMe OEt H H F CMe Et SMe OEt H F CC1 Et SMe OEt H H F CF Et SMe OEt H H F CH Et SMe OEt H H F COCF3 Et SMe OEt H H F COCHF2 Et SMe OEt H H F n5S N t-But SMe OEt H H F CMe t-But SMe OEt H H F CC1 t-But SMe OEt H H F CF t-But SMe OEt H H F CH t-But SMe OEt H H F N SMe OEt H H F . s F COMe F SMe OEt H H F I F CMe F SMe OEt H H F I F CC1 f SMe OEt H H F I F CF F SMe OEt H H F F F CH F SMe OEt H H F RIZ F COCF3 F SMe OEt H H F F F COCHF2 F SMe OEt H H F RIZ F H OMe NH2 H F COMe) HOMeNH2HF CMe H OMe NH2 H F A i CCl I H OMe NH2 H F H OMe NH2 H F CH H OMe NH2 H F COCF3 H OMe NH2 H F COCHF2 H OMe NH2 H F 0 H OMe NH2 H F F COMe 1 H OMe NH2 H F LLF CMe H OMe NH2 H F LLF CCI tF H OMe N 2 H F F CF H OMe NH2 H F F CH 1 H OMe NH2 H F LLF COCF3 H OMe NH2 H F L F COCHF2 1XF H OMe NH2 H F z' N Et H OMe NH2 H F COMe Et H OMe NH2 H F CMe Et H OMe NH2 H F CCI Et H OMe NH2 H F CF. Et H OMe NH2 H F CH Et H OMe NH2 H F COCF3 Et H OMe NH2 H F COCHF2 Et H OMe NH2 H F CMe t-But H OMe NH2 H F CC1 t-But H OMe NH2 H F CF t-But H OMe NH2 H F CH t-But H OMe NH2 H F N F H OMe NH2 H F RIZ F COMe ß} H OMe NH2 H F F F CMe F H OMe NH2 H F F F CC1 F H OMe NH2 H F F F CF F H OMe NH2 H F I CH F H OMe NH2 H F I COCF3 F H OMe NH2 H F F F COCHF2 F H OMe NH2 H F F _t F H OMe Me H F N H OMe Me H F CMe I H OMe Me H F 0 < 1 H OMe Me H F CF 1 H OMe Me H F A CH H OMe Me H F COCF3 H OMe Me H F COCHF2 H ome Me H F H OMe Me H F A COMe H OMe Me H F . CMe _ H OMe Me H F cci H ome Me H F F LLF CF tF H OMe Me H F F CH 1 H OMe Me H Liz COCF3 H OMe Me H F F COCHF2 H OMe Me H F LLF Et H OMe Me H COMe Et H OMe Me H F CMe Et H OMe Me H CC1 Et H OMe Me H F I CF Et H OMe Me H F CH Et H OMe Me H F COCF3 Et H OMe Me H F COCHF2 Et H OMe Me H F l N H OMe Me H F F F COMe F H OMe Me H F RIZ F CMe F H OMe Me H F I F cul F H OMe Me H F RIZ F CF CF H OMe Me H F RIZ F CH F H OMe Me H F I F COCF3 H OMe Me H F I F COCHFZ CCF H OMe Me H F I N H ome H ci F 0 | COMe 1 H OMe H C1 F 0 | CMe H OMe H C1 F A CCl I H OMe H ci F CF H OMe H C1 F A_ CH OMe H C1 F A COCF3 l H OMe H C1 F 0 COCHF2 l H OMe H C1 F A N 1XF H OMe H C1 F F COMe tF H OMe H C1 F F CMe LF H OMe H C1 F LF CC1 1/F H OMe H Cl F F CF 1/F H OMe H C1 F F CH 1/H OMe H C1 F AU COCF3 1 H OMe H Cl F F COCHF2 1XF H OMe H Cl F LI : N Et H OMe H ci F COMe Et H OMe H Cl F CMe Et H OMe H Cl F CCI Et H OMe H C1 F CF Et H OMe H Cl F CH Et H OMe H Cl F COCF3 Et H OMe H Cl F COCHF2 Et H OMe H Cl F N t-But H OMe H C1 F COMe t-But H OMe H Cl F CMe t-But H OMe H Cl F 30 CC1 t-But H OMe H Cl F CF t-But H OMe H Cl F CH t-But H OMe H Cl F COCF3 t-But H OMe H Cl F COCHF2 t-But H OMe H Cl F N F H OMe H Cl F I COMe F H OMe H Cl F I F CMe p H OMe H Cl F F F Ceci t'H OMe H C1 F RIZ F CF F H OMe H Cl F F F CH F H OMe H Cl F I F COCF3 F H OMe H Cl F I F COCHF2 F H OMe H Cl F I P N. I SMe OMe H Cl F COMe l SMe OMe H C1 F CMe l SMe OMe H Cl F 0 | CC1 1 SMe OMe H Cl F 0 CF 1 SMe OMe H Cl F CH 1 SMe OMe H C1 F COCF3 1 SMe OMe H C1 F 0 COCHF2 l SMe OMe H Cl F N Et SMe OMe H C1 F COMe Et SMe OMe H Cl F CMe Et SMe OMe H Cl F CC1EtSMeOMeHClF CF Et SMe OMe H Cl F CH Et SMe OMe H Cl F L COCF3 Et SMe OMe H C1 F COCHF2 Et SMe OMe H Cl F N 1 SMe OEt H Cl F LU COMe, SMe OEt H Cl F LLF CCI} SMe OEt H Cl F F Cri se OEt H Cul F DZ CF SMe OEt H Cl F F CH I SMe OEt H Cl F LOF COCF3 tF SMe OEt H Cl F F COCHF2 1XF SMe OEt H Cl F F CMe t-But SMe OEt H C1 F CC1 t-But SMe OEt H C1 F CF t-But SMe OEt H C1 F CH t-But SMe OEt H Cl F X e SMe OEt H C1 F I F COMe F SMe OEt H Cl F I F CMe F SMe OEt H Cl F RIZ F X f F SMe OEt H C1 F CF F SMe OEt H Cl F RIZ F CH F SMe OEt H Cl F RIZ F COCF3 F SMe OEt H Cl F I COCHF2 ¢ (F SMe OEt H C1 F N l H OMe NH2 C1 F F N I H OMe NH2 Cl F 0 COMe l H OMe NH2 Cl F CMe l H OMe NH2 Cl F CC1 l H OMe NH2 Cl F CF l H OMe NH2 C1 F CH l H OMe NH2 Cl F COCF3 COCF3 H OMe NH2 ci F | COCHF2 OMe NH2 C1 F I A OMe NH2 C1 F F COMe l H OMe NH2 C1 F l F CMe 1/F H OMe NH2 C1 F CC1 H OMe NH2 C1 F F I CF l H OMe NH2 Cl F l l bF CH 1XF H OMe NH2 Cl F l L F COCF3 tF H OMe NH2 Cl F COCHF2 l H OMe NH2 C1 L F N Et H OMe NH2 C1 F COMe Et H OMe NH2 Cl F CMe Et H OMe NH2 Cl F CC1EtHOMeNH2ClF CF Et H OMe NH2 Cl F CH Et H OMe NH2 C1 F COCF3 Et H OMe NH2 Cl F COCHF2 Et H OMe NH2 Cl F N t-But H OMe NH2 C1 F CMe t-But H OMe NH2 Cl F CC1 t-But H OMe NH2 C1 F CF t-But H OMe NH2 Cl F CH t-But H OMe NH2 Cl F N F H OMe NH2 Cl F . P P COMe F H OMe NH2 Cl F F F CMe F H OMe NH2 Cl F F F 0} H OMe NH2 C1 F RIZ F CF F H OMe NH2 C1 F I CH F H OMe NH2 Cl F I F COCF3 F H OMe NH2 Cl F F F MCOCHF2 F H OMe NH2 Cl F F F N 1 H OMe Me C1 F I COMe 1 H OMe Me C1 F 2 CMe 1 H OMe Me C1 F CF ! HOMeMeClI ? CF I H OMe Me Cl F | CH 1 H OMe Me C1 F I COCF3 1 H OMe Me C1 F A COCHF2 1 H OMe Me C1 F N H OMe Me ci F F COMe l H OMe Me C1 F F CMe l H OMe Me C1 F LLF CC1 ! HOMeMeClF F CF 1/F H OMe Me C1 F I CH LF H OMe Me C1 F L F COCF3 l H OMe Me C1 F LF |COCHF2 OMe Me C1 F bS N Et H OMe Me ci F COMe Et H OMe Me Cl F CMe Et H OMe Me Cl F CC1EtHOMeMeClF CF Et H OMe Me Cl F I CH Et H OMe Me Cl F COCF3 Et H OMe Me Cl F I COCHF2 Et H OMe Me Cl F I N t-But H OMe Me Cl F CMe t-But H OMe Me ci F | CC1 t-But H OMe Me C1 F I CF t-But H OMe Me C1 F CH t-But H OMe Me Cl F N F H OMe Me ci F I F COMe F H OMe Me Cl F 9 F | CMe 1 F OMe Me Cl F F l 11 CCl F H OMe Me Cl F F F CF F H OMe Me Cl F RIZ F CH F H OMe Me Cl F F F COCF3 F H OMe Me Cl F I F 2 COCHF2 CF H OMe Me C1 F F F N H OMe H F Br COMe I H OMe H F Br I 11 CMe H OMe H F Br CC1iHOMeHFB CF H ome H F Br l 11 CH H ome H F Br | COCF3 1 H OMe H F Br I.. COCHF2 I H OMe H F Br N l H OMe H F Br LF COMe OMe Br F CMe I H OMe H F Br F CC1 l H OMe H F Br bF CF OMe Br F CH H OMe H F Br F COCF3 H OMe H F Br F COCHF2 OMe Br F N Et H OMe H F Br COMe Et H OMe H F Br CMe Et H OMe H F Br CC1 Et H OMe H F Br CF Et H OMe H F Br CH Et H OMe H F Br COCF3 Et H OMe H F Br COCHF2 Et H OMe H F Br N t-But H OMe H F Br CMe t-But H OMe H F Br CC1 t-But H OMe H F Br CF t-But H OMe H F Br CH t-But H OMe H F Br N 11 H OMe H F Br Y COMe F H OMe H F Br F F CMe F H OMe H F Br F F Cul F H OMe H F Br F F CF F H OMe H F Br F F CH F H OMe H F Br RIZ F COCF3 F H OMe H F Br F F COCHF2 F H OMe H F Br F F N F SMe OMe H F Br F F N I SMe OEt H F Br 0 COMe ! SMeOEtHFB CMe SMe OEt H F Br 0 CC1 l SMe OEt H F Br CF SMe OEt H F Br i CH l SMe OEt H F Br COCF3 l SMe OEt H F Br COCHF2 l SMe OEt H F Br N I SMe OEt H F Br A COMe SMe OEt Br bF l CMe 1/F | SMe OEt H F Br LOF CC1 SMe OEt H F Br { F CF 1XF SMe OEt H F Br F CH SMe OEt H F Br F COCF3tSMeOEtHFBr L F COCHF2 I SMe OEt H F Br L F N Et SMe OEt H F Br COMe Et SMe OEt H F Br CMe Et SMe OEt H F Br CC1 Et SMe OEt Br I | CF Et SMe OEt H F Br 11 | CH Et SMe OEt H F Br l 11 COCF3 Et SMe OEt H F Br I COCHF2 Et SMe OEt. H Br N t-But SMe OEt H F Br CMe t-But SMe OEt H F Br CC1 t-But SMe OEt Br CF t-But SMe OEt H F Br CH t-But SMe OEt H F Br N El SMe OEt H F Br F F COMe F SMe OEt H F Br F F CMe ! SMeOEtHFBr F F CC1 SMe OEt Br F F CF F SMe OEt H F Br F F CH F SMe OEt H F Br I COCF3 F SMe OEt H F Br F COCHF2 SMe OEt H F Br F F N I H OMe NH2 F Br 0 COMe H OMe NH2 F Br CMe I H OMe NH2 F Br _ cci H OMe NH2 F Br 0 CF H OMe NH2 F Br CH H OMe NH2 F Br COCF3 I H OMe NH2 F Br COCHF2 I H OMe NH2 F Br N H OMe NH2 F Br LOF COMe 1/F H OMe NH2 F Br '' CMe tF H OMe NH2 F Br F cci H ome NH2 F Br LLF CF ! IIOMeNH2FBr I CHtHOMeNH2FBr F COCF3 H OMe NH2 F Br LLF |COCHF2 1/F H OMe NH2 F Br L F N Et H OMe NH2 F Br COMe Et H OMe NH2 Br CMe Et H OMe NH2 F Br CC1 Et H OMe NH2 F Br CF Et H OMe NH2 F Br CH Et H OMe NH2 F Br COCF3 Et H OMe NH2 F Br COCHF2 Et H OMe NH2 F Br N t-But H OMe NH2 F Br COMe t-But, H OMe NH2 F Br CMe t-But H OMe NH2 F Br CC1 t-But H OMe NH2 Br CF t-But H OMe NH2 F Br CH t-But H OMe NH2 F Br COCF3 t-But H OMe NH2 F Br COCHF2 t-But H OMe NH2 F Br N F H OMe NH2 F Br RIZ F COMe F H OMe NH2 F Br RIZ F CMe F H OMe NH2 F Br w P CC1 F H OMe NH2 F Br I F CF F H OMe NH2 F Br I F CH F H OMe NH2 F Br I F COCF3 F H OMe NH2 F Br I F COCHF2 F H OMe NH2 F Br . F N I H OMe Me F Br COMe 1 H OMe Me F Br CMe 1 H OMe Me F Br CCI H OMe Me F Br CF l H OMe Me F Br 0 CH H OMe Me F Br A COCF3 l H OMe Me F Br COCHE 1 H OMe Me F Br N H OMe Me F Br LLF COMe 1XF H OMe Me F Br L F CMe I H OMe Me F Br LvF CCl I H OMe Me F Br L F I CF H OMe Me F Br l bF | CH l H OMe Me Br LE ; | COCF3 l H OMe Me F Br L F I |COCHF2 l H OMe Me F Br L F Et H OMe Me Br I COMe Et H OMe Me F Br I CMe Et H OMe Me F Br CC1EtHOMeMeFBr CF Et H OMe Me F Br I CH Et H OMe Me F Br l COCF3 Et H OMe Me F Br l COCHF2 Et H OMe Me F Br l N t-But H OMe Me F Br CMe t-But H OMe Me F Br CC1t-ButHOMeMeFBr CF t-But H OMe Me F Br CH t-But H OMe Me F Br N H OMe Me F Br F F 0 COMe Ff H OMe Me F Br p F CMe ¢$ H OMe Me F Br I F CCl F H OMe Me F Br If F CF F H OMe Me F Br I F CH F H OMe Me F Br F F S H OMe Me F wl L F F COCHF2 d H OMe Me F X N SMe OEt H H Br F N SMe OEt H H Br COMetSMeOEtHHB CMe I SMe OEt H H Br CCljSMeOEtHHB I CF 1 SMe OEt H H Br 0 CH 1 SMe OEt H H Br COCF3 1 SMe OEt H H Br COCHF2 1 SMe OEt H H Br N SMe OEt H H Br LF COMe I SMe OEt H H Br LLF CMe SMe OEt H H Br F CCl I SMe OEt H H Br F CF SMe OEt H H F CH SMe OEt H H Br LLF COCF3 1XF SMe OEt H H Br F COCHF2 SMe OEt Br L F I N Et SMe OEt H H Br COMe Et SMe OEt H H Br | CMe Et SMe OEt H H Br 11 CC1EtSMeOEtHHBr CF Et SMe OEt H H Br CH Et SMe OEt H H Br COCF3 Et SMe OEt H H Br COCHF2 Et SMe OEt H H Br || t-But515IS' N t-But SMe OEt H H Br CMe t-But SMe OEt H H Br CC1 t-But SMe OEt H H Br CF t-But SMe OEt H H Br . II CH t-But SMe OEt H H Br N F SMe OEt H H Br 11 COMe F SMe OEt H H Br F CMe F SMe OEt H H Br F F CCl F SMe OEt H H Br RIZ F CF ¢ SMe OEt H H Br IN F CH SMe OEt H H Br I F COCF3 F SMe OEt H H Br ... I F COCHF2 F SMe OEt H H Br N l H OMe NH2 H Br COMe l H OMe NH2 H Br CMe l H OMe NH2 H Br s CC1 l H OMe NH2 H Br CF l H OMe NH2 H Br CH l H OMe NH2 H Br COCF3 l H OMe NH2 H Br COCHF2 l H OMe NH2 H Br N 1/F H OMe NH2 H Br F COMe I H OMe NH2 H Br F CMe _ H OMe NH2 H Br CC1 1z} H OMe NH2 H Br F CF LF H OMe NH2 H Br F CH 1 H OMe NH2 H Br LLF COCF3 1SF H OMe NH2 H Br L COCHF2 OMe NH2 H Br F N Et H OMe NH2 H Br COMe Et OMe NH2 Br CMe Et H OMe NH2 H Br CC1 Et H OMe | NH2 H Br CF Et H OMe NH2 H Br CH Et H OMe NH2 H Br COCF3 Et H OMe NH2 H Br COCHF2 Et H OMe NH2 H Br N t-But H OMe NH2 Br COMe t-But H OMe NH2 H Br CMe t-But H OMe NH2 H Br CCl t-But H OMe NH2 H Br CF t-But H OMe NH2 H Br CH t-But H OMe NH2 H Br COCF3 t-But H OMe NH2 H Br COCHF2 t-But H OMe NH2 H Br N F H OMe NH2 H Br F F COMe F H OMe NH2 H Br F F CMe F H OMe NH2 H Br f CCl F H OMe NH2 H Br F F CF ¢F H OMe NH2 H Br F F CH F H OMe NH2 H Br p F COCF3 F H OMe NH2 H Br RIZ F COCHF2 F H OMe NH2 H Br RIZ I N l H OMe Me H Br COMe 1 H OMe Me H Br CMe 1 H OMe Me H Br 0 cci H ome Me H Br 0 CF l F H OMe Me H Br CH H OMe Me H Br COCF3 1 H OMe Me H Br COCHF2 l H OMe Me H Br N H OMe Me H Br F COMe 1Z H OMe Me H Br LLF CMe 1/H OMe Me H Br F CC1 1XF H OMe Me H Br F CF 1/F H OMe Me H Br LOF CH tF H OMe Me H Br F COCF3 1/F H OMe Me H Br COCHF2 OMe Me H Br F N Et H OMe Me Br COMe Et H OMe Me H Br CMe Et H OMe Me H Br CC1 Et H OMe Me H Br I CF Et H OMe Me H Br CH Et H OMe Me H Br COCF3 Et H OMe Me H Br COCHF2 Et H OMe Me H Br N t-But H OMe Me H Br CMe t-But H OMe Me H Br CC1 t-But H OMe Me Br CF t-But H OMe Me H Br CH t-But H OMe Me H Br N F H ome Me H Br RIZ F COMe F H OMe Me H Br I CMe F H OMe Me H Br F F cci H ome Me H Br F F CF F H OMe Me H Br I CH H ome Me H Br If F COCF3 OMe Me H Br F F COCHF2 H ome Me H Br F F N 1 H OMe H C1 Br I CO Me 1 H OMe H Cl Br CMe 1 H OMe H Cl Br CC1 1 H OMe H C1 Br I CF 1 H OMe H C1 Br CH 1 H OMe H C1 Br COCF3 l H OMe H C1 Br A COCHF2 l H OMe H Cl Br N H ome H ci Br F CO Me LF H O Me H Cl Br F CMe 1/} H OMe H C1 Br F CCI tF H OMe H C1 Br F CF tF H OMe H C1 Br F CH 1 H O Me H C1 Br F COCF3 _ H OMe H Cl Br F COCHF2 1XF H OMe H C1 Br F N Et H OMe H ci Br COMe Et H OMe H Cl Br CMe Et H OMe H Cl Br CC1 Et H OMe H C1 Br l I CF Et H OMe H Cl Br CH Et H OMe H Cl Br COCF3 Et H OMe H Cl Br COCHF2 Et H OMe H Cl Br N t-But H OMe H C1 Br 11 CMe t-But H OMe H Cl Br CC1 t-But H OMe C1. Br 11 CF t-But H OMe H Cl Br CH t-But H OMe H Cl Br N F H OMe H Cl Br F F COMe H OMe C1 Br gF F CMe ¢ ZF H OMe H Cl Br F F CCl F H OMe H Cl Br I CF F H OMe H Cl Br ? F CH F H OMe H Cl Br F F COCF3 F H OMe H Cl Br I COCHF2 F H OMe H Cl Br I F N I SMe OMe H Cl Br COMe I SMe OMe H Cl Br 0 CMe 1 SMe OMe H C1 Br CC1 1 SMe OMe H C1 Br 0 CF I SMe OMe H Cl Br CH I SMe OMe H Cl Br COCF3 1 SMe OMe H C1 Br COCHF2 1 SMe OMe H C1 Br N SMe OMe H ci Br F COMe LF SMe OMe H C1 Br F CMe 1 SMe OMe H Cul Br LLF CC1 ! SMeOMeHClB F CF 1 SMe OMe H Cl Br 11 CH I SMe OMe H C1 Br | F COCF3 I SMe OMe H Cl Br LF COCHF2 I SMe OMe H Cl Br F CF SMe OEt H Cl Br F CH I F I SMe I OEt I H I Cl I Br COCF3 SMe OEt H Cl Br F X COCHF2 SMe OEt Cl Br . bF N Et SMe OEt H Cl Br COMe Et SMe OEt Cl Br CMe Et SMe OEt Cl Br CCl Et SMe OEt H Cl Br CF Et SMe OEt H Cl Br CH Et SMe OEt H Cl Br COCF3 Et SMe OEt H Cl Br COCHF2 Et SMe OEt H Cl Br N t-But SMe OEt H C1 Br CMe t-But SMe OEt H Cl Br CCl t-But SMe OEt H Cl Br CMeEtHOMeHFN02 CC1 Et H OMe H F NO2 CF Et H OMe H F N02 CH Et H OMe H F N02 COCF3 Et H OMe H F N02 COCHF2 Et H OMe H F N02 N t-But H OMe H F N02 CMet-ButHOMeHFN02 CC1 t-But H OMe H F NO2 CF t-But H OMe H F N02 CH t-But H OMe H F N02 N F H OMe H F NO2 F F COMe F H OMe H F N02 F F CMe F H OMe H F N02 F F Cul F H OMe H F N02 F F CF F H OMe H F N02 I. F CH F H OMe H F N02 F F COCF3 F H OMe H F N02 F F X C H OMe H F NO2 F F N I SMe OEt H F N02 COMe I SMe OEt H F N02 CMe I SMe OEt H F N02 0 CCl I SMe OEt H F N02 A CF I SMe OEt H F N02 CH I SMe OEt H F N02 COCF3 I SMe OEt H F N02 a COCHF2 I SMe OEt H F N02 SMe OEt H F N02 N I SMe OEt H F N02 LLF COMe SMe OEt H F N02 l bF CMe l SMe OEt H F N02 l bF CCl I SMe OEt H F N02 | CC1 l SMe OEt H F N02 F CF SMe OEt H F N02 I b I CH SMe OEt H F N02 F | COCF3 SMe OEt N02 l bF | COCHF2 l SMe OEt H F N02 l F N Et SMe OEt H F N02 COMeEtSMeOEtHFN02 CMe Et SMe OEt H F N02 | CC1 Et SMe OEt N02 I CF Et SMe OEt H F N02 I CH Et SMe OEt H F N02 COCF3 Et SMe OEt H F N02 COCHF2 Et SMe OEt H F N02 t-But55E N t-But SMe OEt H F N02 CMe t-But SMe OEt H F N02 | CC1 t-But SMe OEt H F N02 | CF t-But SMe OEt H F N02 l CH t-But SMe OEt H F N02 N F SMe OEt H F N02 9 I F l I COMe AF SMe OEt H F N02 S F I I' CMe F SMe OEt H F N02 I CUL F SMe OEt H F N02 RIZ F CF SMe OEt H F N02 p F CH F SMe OEt H F N02 I F COCF3 P SMe OEt H F N02 I F COCHF2 F SMe. OEt H F N02 N H OMe NH2 F N02 F N I H OMe NHZ F N02 0 COMe l H OMe NH2 F NO2 CMe l H OMe NH2 F NO2 CC1 l H OMe NH2 F NO2 0 CF H OMe NH2 F N02 0 CH H OMe NH2 F N02 COCF3 H OMe NH2 F N02 COCHF2 l H OMe NH2 F NO2 0 N l H OMe NH2 F N02 A COMe 1/F H OMe NH2 F NO2 F CMe l H OMe NH2 F N02 F CCl I H OMe NH2 F N02 CF H OMe NH2 F N02 F r CH LF H OMe NH2 F N02 F COCF3 H OMe NH2 F N02 I COCHF2 l H OMe NH2 F N02 F N Et H OMe NH2 F N02 COMe Et H OMe NH2 F N02 CMe Et H OMe NH2 F N02 | CCI Et H OMe NH2 F N02 | CF Et H OMe NH2 F N02 I CH Et H OMe NH2 F N02 COCF3 Et H OMe NH2 F N02 COCHF2EtHOMeNH2FN02 N t-But H OMe NH2 F N02 I CMe t-But H OMe NH2 F N02 CCl t-But H OMe NH2 F N02 CF t-But H OMe NH2 F N02 CH t-But H OMe NH2 F N02 N F H OMe NH2 F N02 F t. F rCOMe H OMe NH2 F N02 F F CMe F H OMe NH2 F N02 F I CUL F H OMe NH2 F N02 F F 02 H OMe NH2 F N02 I CH OMe NH2 F N02 CH I COCF3 AF H OMe NH2 F N02 l F l COCHF2 AF H OMe NH2 F N02 F H OMe Me F N02 COMe 1 H OMe Me F N02 CMe 1 H OMe Me F N02 CC1 1 H OMe Me F N02 CF 1 H OMe Me F N02 1 H OMe Me F N02 cl COCF3 1 H OMe Me F N02 COCHE2 1 H OMe Me F N02 11 H OMe Me F N02 F COMe H OMe LLF H OMe Me F N02 CYME Me F N02 / F F N02 CH H OMe Me F N02 L F COCF3 HOMeMeFN02 LF COCHF2 OMe Me N02 LF N Et H OMe Me F N02 COMe Et H OMe Me F N02 CMe Et H OMe Me F N02 CC1 Et H OMe Me N02 CF Et H OMe Me F N02 CH Et H OMe Me F N02 COCF3 Et H OMe Me F N02 COCHF2 Et H OMe Me F N02 N t-But H OMe Me F N02 CMe t-But H OMe Me F N02 CC1 t-But OMe Me N02 CF t-But H OMe Me N02 CH t-But H OMe Me F N02 N F H OMe Me F N02 I F COMe (F H OMe Me F N02 RIZ F CMe F H OMe Me F N02 p F Cl1 F H OMe Me F N02 RIZ F CF F H OMe Me F N02 p F CH F H OMe Me F N02 F l COCF3 F H OMe Me F N02 IN COCHF2 F H OMe Me F N02 F F N I SMe OEt H H N02 COMe I SMe OEt H H N02 I 11 CMe SMe OEt H H N02 CCl 1 SMe OEt H H N02 CFjSMeOEt11HN02 CH ! SMeOEtHHN02 COCF3 I SMe OEt H H N02 I 11 z 1 SMe OEt H H N02 N SMe OEt H H N02 N SMe OEt H H N02 F COMe I SMe OEt H H N02 DZ CMe l SMe OEt H H N02 LLF CC1iSMeOEtHHN02 F CF LF SMe OEt H H N02 F CH I SMe OEt H H N02 F COCF3 ! SMeOEtHHN02 j COCHF2 SMe OEt NO2 F N Et SMe OEt H H N02 COMeEtSMeOEtHHN02 CMe Et SMe OEt H H N02 CClEtSMeOEtHHN02 CF Et SMe OEt H H N02 CHEtSMeOEtHHN02 l I COCF3 Et SMe OEt H H N02 l I } COCHF2 Et SMe OEt H H NO2 N t-But SMe OEt H H N02 CMe t-But SMe OEt H H N02 CClt-ButSMeOEtHHN02 CFt-ButSMeOEtHHN02 CH t-But SMe OEt H H N02 N F SMe OEt H H N02 F F COMe F SMe OEt H H N02 I r CMe F SMe OEt H H N02 F F CCl ¢ SMe OEt H H N02 F F CF ¢t SMe OEt H H N02 RIZ F CH F SMe OEt H H NOZ RIZ F COCF3 SMe OEt H H N02 I F COCHF2 F SMe OEt H H N02 F F N H OMe NH2 H N02 COMe 1 H OMe NH2 H N02 CMe H OMe NH2 H N02 CC1 1 H OMe NH2 H N02 CF 1 H OMe NH2 H N02 CH H OMe NH2 H N02 COCF3 H OMe NH2 H N02 0 COCHF 1 H OMe NH2 H NO2 N lor H OMe NH2 H NO2 F COMe tF | H OMe NH2 H N02 F CMe H OMe NH2 H N02 if CC1 1/F H OMe NH2 H N02 F CL H OMe NH2 H N02 F CH tF H OMe NH2 H N02 F COCF3 LF H OMe NH2 H N02 Z COCBF2 H ome NH2 H N02 F N Et H OMe NH2 H N02 COMe Et H OMe NH2 H N02 CMe Et H OMe NH2 H N02 | CC1 Et H OMe NH2 H N02 CF Et H OMe NH2 H N02 CH Et H OMe NH2 H N02 COCF3 Et H OMe NH2 H N02 COCHF2 Et H OMe NH2 H N02 t-But H OMe NH2 H N02 CMe t-But H OMe NH2 H N02 CCl t-But H OMe NH2 H N02 CF t-But H OMe NH2 H N02 CH t-But H OMe NH2 H N02 N F H OMe NH2 H N02 RIZ F COMe-H OMe NH2 H N02 p cme F H ome NH2 H N02 CMe F H OMe NH2 H N02 I F CC1 g H OMe NH2 H N02 F F CF F H OMe NH2 H N02 p F CH F H OMe NH2 H N02 Iw F COCF3 F H OMe NH2 H N02 F COCHF2 OMe NH2 N02 F F N 1 H OMe Me H N02 come H OMe Me H N02 CMe 1 H OMe Me H N02 CCI 1 H OMe Me H N02 CF H OMe Me H N02 0 CH I H OMe Me H N02 0 COCF3 1 H OMe Me H N02 COCHF2 H OMe Me H N02 N H OMe Me H N02 DZ COMe I H OMe Me H N02 F CMe ! HOMeMeHN02 LF CC1 tF H OMe Me H N02 F CF LF H OMe Me H N02 LF CH H OMe Me H N02 F COCF3tHOMeMeHN02 LLF COCHF2 t} H OMe Me H N02 F N Et H ome Me H N02 COMe Et H OMe Me H N02 CMe Et H OMe Me H N02 | CC1 Et H OMe Me H N02 CF Et H OMe Me H N02 CH Et H OMe Me H N02 COCF3 Et H OMe Me H N02 COCHF2 Et H OMe Me H N02 N t-But H OMe Me H N02 CMe t-But H OMe Me H N02 | CC1 t-But H OMe Me H N02 CF t-But H OMe Me H N02 I CH t-But H OMe Me H N02 N F H OMe Me H N02 F I COMe F H OMe Me H N02 F I CMe F H OMe Me H N02 F I Cl1 F H OMe Me H N02 F I CF F H OMe Me H N02 F F CH F H OMe Me H N02 F I COCF3 F H OMe Me H N02 F F COCHF2 F H OMe Me H N02 L ? F N I H OMe H ci N02 COMe I H OMe H Cl N02 I CMe 1 H OMe H C1 N02 CC1 H OMe H C1 N02 CF l H oMe H Cl NO2 CH l H OMe H C1 NO2 COCF3 I H OMe H Cl N02 0 COCHF2 HOMeHClN02 N H OMe H ci N02 N H OMe H Cl N02 F COMe H OMe H Cl N02 F CMe 1 H OMe H Cl N02 F CCl I H OMe H Cl N02 L F CL H ome H Cul N02 F CHiHOMe11ClN02 F COCF3 LF H OMe H C1 N02 F COCHF2 _ H OMe H C1 NO2 L F Et OMe H C1 N02 COMe Et H OMe H Cl N02 CMe Et H OMe H Cl N02 CC1 Et H OMe H C1 N02 CF Et H OMe H Cl N02 CHEtHOMeHClN02 CH Et H OMe H C1 N02 COCF3 Et H OMe H ci N02 COCHF2 Et H OMe H Cl N02 N t-But OMe C1 N02 COMe t-But H OMe H Cl N02 CMe t-But H OMe H Cl N02 CC1 t-But H OMe H C1 N02 CF t-But H OMe H Cl N02 CH t-But H OMe H Cl N02 COCF3 t-But H OMe H Cl N02 COCHF2 t-But H OMe H Cl N02 N ¢$F H OMe H C1 N02 F F COMe F H OMe H C1 N02 RIZ F CMe F H OMe H Cl N02 F I Cul F H OMe H Cl N02 I CF AF H OMe H C1 N02 Y F CH F H OMe H Cl N02 F F COCF3 ¢F H OMe H C1 N02 I COCHF2 F H OMe H Cl N02 F F N l SMe OEt H ci NO2 l COMe I SMe OEt H Cl N02 CMe 1 SMe OEt H C1 N02 CC1 SMe OEt C1 N02 CF I SMe OEt H Cl N02 CF l SMe OEt H C1 NO2 0 COCF3 I SMe OEt H Cl N02 0 COCHF2 l SMe OEt H Ct NO2 N'SMe OEt H Cl N02 F COMe LF SMe OEt H C1 N02 F CMe 1 SMe OEt H Cl N02 LF CC1SMeOEtHClN02 AU CF 1XF SMe OEt H C1 N02 F CH I SMe OEt H Cl N02 F COCF3 l SMe OEt H Cl N02 F COCHF2 1XF SMe OEt H C1 NO2 F N Et sme OEt H Cul N02 COMe Et SMe OEt H Cl N02 CMe Et SMe OEt H Cl N02 CC1EtSMeOEtHClN02 CF Et SMe OEt H Cl N02 CH Et SMe OEt H C1 N02 COCF3 Et SMe OEt H Cl N02 COCHF2 Et SMe OEt H Cl N02 t-But SMe OEt C1 N02 CMe t-But SMe OEt H Cl N02 CC1 t-But SMe OEt H C1 N02 CF t-But SMe OEt H Cl N02 CH t-But SMe OEt H Cl N02 N F SMe OEt H Cl N02 I COMe p SMe OEt H Cl N02 I F CMe F SMe OEt H Cl N02 F F Cul F SMe OEt H Cl N02 F F CF F SMe OEt H Cl N02 I F CH F SMe OEt H Cl N02 RIZ F COCF3 F SMe OEt H Cl N02 I COCHF2 F SMe OEt H Cl N02 F F N 1 H OMe NH2 Cl N02 COMe I H OMe NH2 Cl N02 CMe t H OMe NH2 ci N02 t CCl I H OMe NH2 Cl N02 CF H ome NH2 ci N02 CH 1 H OMe NH2 C1 N02 COCF3 H OMe NH2 C1 N02 A COCHF2 I H OMe NH2 Cl N02 N 1 H OMe NH2 Cl N02 LF COMe 1/H OMe N 2 Cl NO2 AU CMe tF H OMe NH2 C1 N02 L1F CC1iHOMeNH2ClN02 LLF CF ! H OMe NH2 Cl N02 F CH I H OMe NH2 Cl N02 LLF COCF3 l H OMe NH2 Cl N02 LF COCBIF2 H OMe NH2 ci N02 F N Et H OMe NH2 Cul N02 COMe Et H OMe NH2 Cl N02 CMe Et H OMe NH2 Cl N02 CC1EtHOMeNH2ClN02 CF Et H OMe NH2 Cl N02 CH Et H OMe NH2 Cl N02 COCF3 Et H OMe NH2 Cl N02 COCHF2 Et H OMe NH2 Cl N02 N t-But H OMe NH2 C1 N02 CMe t-But H OMe NH2 Cl N02 CCl t-But H OMe NH2 Cl N02 CF t-But H OMe NH2 Cl N02 CH t-But H OMe NH2 Cl N02 H OMe NH2 Cl N02 RIZ COMe F F H OMe NH2 Cl N02 IN H OMe NH2 Cl N02 CMe I CC1 f F H OMe NH2 C1 NO2 F H OMe NH2 Cl N02 CE l H OMe NH2 Cl NO2 CL I COCF3 F H Cl RIZ COCHF2 F F H OMe NH2 Cl N02 IN H OMe Me Cl N02 COMe l H OMe Me C1 NO2 0 CMe l H OMe Me Cl N02 H OMe Me Cl NO2 CF H OMe Me ci N02 L CH H OMe Me C1 N02 A_ _ COCF3 OMe Me C1 N02 , A COCHF2 HOMeMeClN02 N Lr H OMe Me C1 N02 F COMe 1/F H OMe Me C1 N02 F CMe HOMeMeClN02 CC1 OMe Me C1 N02 LF CF 1/F H OMe Me C1 N02 F CH I H OMe Me Cl N02 F COCF3 l H OMe Me Cl N02 LF COCHF2 l H OMe Me Cl N02 F N Et H OMe Me ci N02 COMe Et H OMe Me Cl N02 CMe Et H OMe Me Cl N02 CC1EtHOMeMeClN02 CF Et H OMe Me Cl N02 CH Et H OMe Me Cl N02 COCF3 Et H OMe Me Cl N02 COCHF2 Et H OMe Me C1 N02 nS51E N t-But H OMe Me Cl N02 CMe t-But H OMe | Me C1 N02 CC1 t-But H OMe Me C1 N02 CF t-But H OMe Me Cl N02 | CH | t-But | H | OMe | Me | C1} N02 CH t-But H OMe Me Cl N02 COCF3 t-But H OMe Me Cl N02 I COCHF2 t-But H OMe Me Cl N02 N F H OMe Me C1 I F COMe F H OMe Me Cl N02 I F CMe F H OMe Me Cl N02 I X f H OMe Me C1 X RIZ F CF F H OMe Me Cl N02 F F CH F H OMe Me Cl N02 I F COCF3 F H OMe Me Cl N02 RIZ F COCHF2 ! H OMe Me Cl X If F N I SMe OEt H Me N02 COMe I SMe OEt H Me N02 0 CMe SMe OEt H Me N02 11 CCI l SMe OEt H Me NO2 CF SMe OEt H Me N02 A CH SMe OEt H Me N02 COCF3 SMe OEt Me N02 A COCHF2 SMe OEt H Me N02 A N tF SMe OEt H Me N02 F COMe SMe OEt Me N02 F CMe SMe OEt H Me N02 LLF CC1 tF SMe OEt H Me N02 LLF CF LF SMe OEt H Me N02 F CH I'SMe OEt H Me N02 IF COCF3 SMe OEt H Me N02 F COCHF2 l SMe OEt H Me N02 F N Et SMe OEt H Me N02 COMe Et SMe OEt H Me N02 CMe Et SMe OEt H Me N02 CC1 Et SMe OEt H Me N02 CF Et SMe OEt H Me N02 CH Et SMe OEt H Me N02 COCF3 Et SMe OEt H Me N02 COCHF2 Et SMe OEt H Me N02 t-But51 N t-But SMe OEt H Me N02 CMe t-But SMe OEt H Me N02 CC1 t-But SMe OEt H Me N02 CF t-But SMe OEt H Me N02 | CH t-But SMe OEt H Me N02 SMe OEt H Me N02 V F COMe F SMe OEt H Me N02 ''tJ F CMe F SMe OEt H Me N02 ? F Ceci SMe OEt H Me N02 CF F SMe OEt H Me N02 F F CH F SMe OEt H Me N02 RIZ COCF3 CF SMe OEt H Me N02 Iw COCHF2 F SMe OEt H Me N02 If N I H OMe NH2 Me N02 come H OMe NH2 Me N02 0 CMe 1 H OMe NH2 Me N02 0 CCI 1 H OMe NH2 Me N02 CF 1 H OMe NH2 Me N02 CH 1 H OMe NH2 Me N02 0 COCF3 COCF3 OMe NH2 Me N02 I t |COCHF2 1 H OMe NH2 Me N02 I S N OMe NH2 Me N02 bF r COMe OMe NH2 Me N02 F | CMe OMe NH2 Me N02 l bF I | CC1 i H OMe NH2 Me N02 F I CF l H OMe NH2 Me N02 l bF CH I H OMe NH2 Me N02 l bF COCF3 I H OMe NH2 Me N02 IF |COCHF2 OMe NH2 Me N02 F Et OMe NH2 Me N02 I COMe Et H OMe NH2 Me N02 r Et OMe NH2 Me N02 CC1EtHOMeNH2MeN02 CF Et H OMe NH2 Me N02 CH Et H OMe NH2 Me N02 | COCF3 Et H OMe NH2 Me N02 COCHF2 Et OMe NH2 Me N02 N t-But H OMe NH2 Me N02 I CMe t-But H OMe NH2 Me N02 CC1t-ButHOMeNH2MeN02 CF t-But H OMe NH2 Me N02 CH t-But H OMe NH2 Me N02 N F H OMe NH2 Me N02 I 9 F COMe F H OMe NH2 Me NO2 F F CMe F H OMe NH2 Me N02 F F CCl F H OMe NH2 Me N02 F CF F H OMe NH2 Me N02 I F CH F H OMe NH2 Me N02 F F COCF3 F H OMe NH2 Me N02 RIZ F COCHF2 F H OMe NH2 Me N02 F F N l H OMe Me Me N02 COMe l H OMe Me Me NO2 CMe 1 H OMe Me Me NO2 CC1 l H OMe Me Me NO2 CF l H OMe Me Me NO2 A CH H OMe Me Me N02 COCF3 H ome Me Me N02 0 COCHF2 \ H OMe Me Me NO2 OMe Me Me N02 F I COMe I H OMe Me Me N02 F CMe H OMe Me Me N02 F CC1 l H OMe Me Me N02 bF I CF H OMe Me Me N02 F CH H OMe Me Me N02 bF COCF3 OMe Me Me N02 LLF COCHF2 OMe Me Me N02 Dz N Et H OMe Me Me N02 COMe Et H OMe Me Me N02 CMe Et H OMe Me Me N02 CC1 Et H OMe Me Me N02 CF Et H OMe Me Me N02 CH Et H OMe Me Me N02 COCF3 Et H OMe Me Me N02 COCHF2 Et H OMe Me Me N02 t-But551 N t-But H OMe Me Me N02 CMe t-But H OMe Me Me N02 CC1 t-But H OMe Me Me N02 CF t-But H OMe Me Me N02 CH t-But H OMe Me Me N02 N} H OMe Me Me N02 F F COMe F H OMe Me Me N02 9 F CMe F H OMe Me Me N02 F F CCl F H OMe Me Me N02 .. F CF H OMe Me Me NO2 I CH F H OMe Me Me N02 RIZ F COCF3 F H OMe Me Me N02 RIZ F COCHF2 F H OMe Me Me N02 RIZ F COMe I H OEt H H- r0 N" COMe 1 H OEt H F, NX rU N come H OMe H H rU N Come H ome H F CF Aco/- (H OEt H F F N" //55 Au0 CF A sC H OEt H Cl F Au0 CF AcO (H OEt NH2 H F Au0 CF AcO (H OEt Me F F Au0 CF//HOEtHFF Aces CF AcS< H OEt NH2 F F Aces CF/HOEtMeClF AcS \ E//55S Aces With regard to Formula (B) compounds, R O O 6 1 1 R R7 A Ng Formula (B)

Rl and R2 of Formula (I) join to form ring L, which is a mono-or bicyclic heterocycle comprising N'.

Preferred compounds of Formula (B) made according to the present process are described in Table B.

Table B t Al | R3 | Rs | R6 | R7 | L A'R3 RS R R'L CH OEt H F Cl -N\6 CH OEt H Cl F "--S -N \6- '0 11-S CHOEtNHFF _N S CFOEtNHzFF 'l-S ---Nb CH OEt H F F - N N -N'I-N-H - N Y CH OEt H Cl F-N, H zu CF OEt H F F CH OEt NH2 F F i ? - N N CF OEt NH2 F F _NH _N N \ CH OEt H F F CH OEt H C1 F N01 - C CF OEt H F F - b CH OEt NH2 F F N01 - 0 CF OEt a F F tg CH OEt H F F -nib N E H C r N I I I I CF OEt H F F - 0 CH OEt NH2 F F $ ß - 0 r OEt NH2 F 1 t - 0 CH OEt H F F - CH OEt H Cl F - N CF OEt H F F - N CH OEt NH2 F F - N CF OEt NHz F F - 0 With regard to Formula (C) Rs o O a A N RZ AR3 Formula (C)

R6 and R7 of Formula (I) join to form ring Q, which is a 5-or 6-membered carbocyclic or heterocyclic ring.

Preferred compounds of Formula (C) made according to the present process are described in Table C. A | R1 | R2 | R3 | R5 | Q A Et R3 OEt 5 Q COMe Et H OEt H N CMe F H OEt Me m fj rY c N F H CCl I H OEt Me Ff Fui LF CH t-But H OEt 11, o NI I COCF3 Et H OEt H I COCHF2 I H OEt H A) nu i

Ill. Process Conditions: The above subject invention process step utilizes a silylating agent that is an organosilicon reagent, which is defined above.

In the key process step, the molar ratio of the organosilicon reagent to reactant (i. e., compound of Formula (A)) is preferably from about 0.5: 1 to about 12: 1, more preferably from about 1: 1 to about 4: 1. It will be recognized that these process conditions are merely preferred ranges and is it possible to use both lower and higher molar ratios and still benefit from the inventive process.

The subject invention process step is preferably carried out in an aprotic solvent or combination of solvents. Preferred solvents in which the process step is carried out include, but are not limited to, acetonitrile, N-methylpyrrolidinone (NMP), dimethylformide, N, N- dimethylacetamide, toluene, xylene, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme; more preferred solvents include acetonitrile, toluene and NMP. Mixtures of one or more solvents may be utilized.

The temperature at which the subject process step is carried out is preferably from about- 50°C to about 250°C, more preferably from about-10 °C to about 160°C, more preferably still from about 20°C to about 140°C. The pressure at which the subject reaction step is carried is preferably from about 0.5 atm to about 50 atm, more preferably from about 0.8 atm to about 10 atm, more preferably still from about 1 atm to about 2 atm. Also preferred is that the process step be carried out at about ambient temperature and pressure, or at about reflux temperature and ambient pressure.

Again, these process conditions are merely representative and should not be interpreted as in anyway limiting the processes claimed below.

IV. Specific Synthetic Examples The following are exemplary, but are not meant to be limiting, regarding variations of the subject invention process step.

Example 1 Preparation of Ethyl-1-cyclopropyl-1, 4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylate: 0 o 0 OH Step a ci Step bcooEt OCH3 OCH3 OCH3 CHs QCHs OCHs 1 2 | Step c 0 0 9 o cooEt Step d cooEt E OCH3 NH OCH OCH3 5 4 Step a: To a solution of 2,3-dimethoxybenzoic acid (20 g) 1 in dichloromethane (100 ml) is added oxalyl chloride (34.83 g) followed by 2 drops of anhydrous DMF. The mixture is stirred at room temperature for 1 hr, then heated to reflux for 4h. The solvent is removed by evaporation to give 2,3-dimethoxy benzoyl chloride 2.

Step b: Product 2 is dissolved in anhydrous acetonitrile (20 mL) and is introduced to a stirred solution of triethyl amine (38.3 mL) and ethyl dimethylaminoacrylate (17.29 g) in acetonitrile (130 mL). The mixture is stirred at room temperature for 5 minutes, and then heated to reflux until the reaction goes to completion.

Step c: To the reaction mixture product of Step b, cyclopropylamine (19.01 mL) is added at ambient temperature and stirred until the reaction is complete. The solvent is evaporated, and

the residue is diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to furnish product 4.

Step d: Product 4 is dissolved in anhydrous acetonitrile (150 mL). N, O- bis (trimethylsilyl) acetamid (115 g) is added. The solution is stirred at room temperature for 0.5 h and heated to reflux. Heating is continued until the reaction is complete. The reaction mixture is concentrated to an oily residue, poured into water, extracted with ethyl acetate, and the solvent removed to furnish product 5.

Example 2 Ethyl-l-cyclopropyl-1, 4-dihydro-7,8-dimethoxy-4-oxoquinoline-3-carboxylate 10 is prepared by a process similar to that of Example 1 from commercially available 2,3,4-trimethoxy benzoic acid 6. 0 0 0 0 1 OEt Step d I OEt MeO OMe NH MeO N OMe ß OMe% g j i. Stepc jo O O O OEt Step b Step a 0 '-C'-o Me0 OMe N Me0 OMe Me0 OMe OMe OMe Orme a z g

Example 3 Ethyl-l-cyclopropyl-1, 4-dihydro-8-methoxy-7-nitro-4-oxoquinoline-3-carboxylate 16 is prepared by a process similar to that of Example 1 from 4-nitro-3,4-dimethoxy benzoic acid 12.

The 4-nitro-3,4-dimethoxy benzoic acid is prepared from 11 according to literature procedures. <BR> <BR> <P>(See, e. g., J. Org. Chem. 42, (6) 1068-1070 (1977) and J. Heterocvclic Chemistry 33, 1171 (1996).) 0 0 0 0 0 0 OEt Step c OEt Step d OEt 02N Y OM N O2N4f O NH 02NtN OMe I OMe A OMeA 14 Step a 0 0 O CI Step a 'H OMe 02N XOMe < OAc 13 12 11 OMe OMe OMe 13 12 11

Example 4 Ethyl-l-ethyl-1, 4-dihydro-8-methoxy-8-bromoquinolone carboxylate 21 is prepared by a process similar to that of Example 1 from 4-bromo-3,4-dimethoxy benzoic acid 17. The 4-bromo- 2,3-dimethoxy benzoic acid is prepared according to a literature method. (See e. g., J. Org. Chem.

42 (6), 1068-70 (1977).) 0 0 0 0 Step d l ; OEt, \ I I OEt Br OMe NH Br N OMe 9 OMe 9 Step c O O O OEt Step b Step a ci oH Br OM N Br OMe Br OMe OMe I ome OMe

19 18 17 Example 5: Ethyl-l-cyclopropyl-1, 4-dihydro-8-methoxy-7-fluoroquinolone carboxylate 27 is prepared by a process similar to that of Example 1 from 4-fluoro-3-methoxy-2-methylthio benzoic acid 23 or 4-fluoro-2,3-dimethoxybenzoic acid 62. The starting benzoic acids are prepared from 4-fluoro-3- methoxy benzoic acid 22 by a procedure similar to that disclosed in the literature. (See, e. g., US Patent No. 5,334,753, which is incorporated herein by reference.)

00 00 OEt Step c OEt Step d OEt F SMe N-F SMe NH F N OMe OMe OMe A OMeA 25 t 26 27 Step b 0 0 0 CI S I OH I OH F \ SMe F, \ SMe F OMe OMe OMe 22 24 23 22 0 O O O Step C OEt Step d OEt -' J F OMe N-F OMe NH F N OMe I OMe ß OMe& 64 A S5 66 Step b 0 0 0 -C Step a 0 OH E E OMe OMe OMe 22 OMe OMe OMe Example 6 Ethyl-1, 4-dihydro-1- (4-fluorophenyl)-8-fluoro-7-piperidinyl-1, 4-dihydro-4-oxo-3-quiniline carboxylic acid 32 is prepared by a process similar to that of Example 1 from 3-fluoro-2-methoxy- 4-piperidinyl benzoic acid 28. The starting material 28 is prepared from 2,3,4-trifluorobenzoic acid by sequential displacement of ortho and para fluorine groups with methoxy and piperidinyl groups by a procedure similar to that reported in literature. (See e. g., Tetrahedron Letters 37 (36) 6439- 6442 (1996).)

00 00 oxo OEt Step c OEt Step d OEt N OMe N'N OMe NH N Nu 30 Step b 32 HCI Step F F CI tep a i I oH GN OMe N \ OMe 29 28 28 Example 7 Ethyl-1-cyclopropyl-7-isoindoline-5-yl)-8-methoxy-1, 4-dihydro-4-oxoquinoline-3- carboxylate 30 is prepared by a process similar to Step d of Example 1 from the corresponding acrylate derivative 29. This acrylate derivative 29 is prepared by methods depicted in the literature.

(See e. g., PCT Application No WO 97/29102.) 0 0 0 0 out OMepNH-'- . TYONH-------N'"T"TV - N /oMe OMe, 29 Example 8 Ethyl 2-chloro-3-nitro-5,12-dihydro-5-oxobenzothiazolo [3,2-a] quinoline-6-carboxy-late 33 is prepared by a process similar to Step d of Example 1 from its cyclization precursor 32. 32 is prepared by reacting 2-chlorobenzothiazole 34 with ethyl-2-methoxy-4-chloro-5-nitrobenzoyl acetate 31 in the presence of sodium hydride. s 0 0 0 0 O O CI \ O O O O O2N OEt N 34/2N OEt zN OEt I I/HN g I N I S Cl OMe Me) = () b 9 c 9 31 32 33 31 32 33 Examples 9-11 Cyclization precursors 37,40 and 43 are prepared by condensing ethyl 2-methoxy-4- chloro-5-fluoro benzoylacetate 35 with appropriate imino ethers 36,39 and 42, respectively. The cyclization is carried out as described in Example 1 Step d to produce 38, 41 and 44, respectively.

o o o o OEt Fn) 9OEt Step d Fo<OEt CI Ne CI N zut S S 00 00 Nb/CIO N O O O O I OEt OEt Step d-) D- ITOET OMe CI I OMe 39 CI H-N CI N 35 40 Nu O O O O 0 0 0 0 42 CI MN CI N 44 43 Example 12 Ethyl 1, 4-dihydro-4-oxo-6-nitro-7-chloro-lH-benz [d] imidazolo [2,3-a] quinoline-3- carboxylate 50 is prepared form cyclization precursor 49 as described in Step d of Example 1.

The cyclization precursor 49 is prepared form 2-methoxy-4-chloro-5-nitrobenzoic acid 45 as shown below using similar procedures reported in literature. (See e. g., J. Med. Chem. 36 (11) 1580-1596 (1993).) . 0 0 0 0 02N OEt Step d 02 1 OEt HNNH CI N NH 49 U 50 C Ci orme _ I H 4S 48 O O p OEt 2N y OEt 2N I OH . se Cl OMe SMe Cl OMe Cl OMe 47 46 45 Example 13 (-)-9,10-Difluoro-2,3-dihydro-3 (S)-methyl-7-oxo-7H-pyrido [1, 2,3-de]-1,4-benzox-aine-6- carboxylic acid 56 is prepared from (+)-Ethyl 2- (2-methoxy-3, 4,5-trifluorobenzoyl)-3- [ (1- acetoxyprop-2 (S)-yl) amino] acrylate 54 by first doing Step d as in Example 1, followed by refluxing the resulting reaction mixture with a 10% aq. KOH solution. 0 0 0 0 0 0 F FOMe N FN F-N F OMe N F NJ F NJ X V ° 1 < 5 onc act 55 O O U ? o rr"OEt F-k p A OEt F) C F) ql F OMe F OMe F F AcO 53 52 51 The cyclization precursor 54 is prepared from 2-methoxy-3,4,5-trifluorobenzoyl chloride 51 as shown by using literature procedures. (See E. g., in Heterocycles 45 (1), 137-145 (1997).) Example 14 Ethyl ester of oxolinic acid 61 is prepared by a process similar to that of Example 1 from 2-methoxy-4,5- (methylenedioxy) benzoic acid 57 as shown below. In Step c, ethylamine is used instead of cyclopropylamine. 0 0 0 OH S C Step O COOEt OCH3 O OCH3 0 OCH3 57 58 OCH3 gg OCH3 Step c v co"'<" YVr"" O N 0 I H OCH3JN OCH3) OCH3) 61 60 Example 15:

Ethyl-l-cyclopropyl-1, 4-dihydro-8-methoxy-7-fluoroquinolone carboxylate 66 is prepared by a process similar to that of Example 1 from 4-fluoro-3-methoxy-2-phenylthio benzoic acid 62. The benzoic acid 62 is prepared from 4-fluoro-3-methoxy benzoic acid 22 by a procedure similar to that disclosed in literature. (See, e. g., US Patent No. 5,334,753, which is incorporated herein by reference.) 00 00 00 OEt Step c OEt Step d OEt - ; F SPh N-F SP NH F N OMe I OMe A OMeA S 4 Step b o o oye step b F SPh F SPh F OMe OMe OMe 63 62 22